WO2020216034A1 - 艾日布林的中间体及其合成方法和用途 - Google Patents

艾日布林的中间体及其合成方法和用途 Download PDF

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WO2020216034A1
WO2020216034A1 PCT/CN2020/082933 CN2020082933W WO2020216034A1 WO 2020216034 A1 WO2020216034 A1 WO 2020216034A1 CN 2020082933 W CN2020082933 W CN 2020082933W WO 2020216034 A1 WO2020216034 A1 WO 2020216034A1
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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 EP20796052.7A priority patent/EP3925948B1/en
Priority to US17/594,693 priority patent/US11976081B2/en
Publication of WO2020216034A1 publication Critical patent/WO2020216034A1/zh

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    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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    • C07D301/00—Preparation of oxiranes
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    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
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    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
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    • 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
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    • 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
    • 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
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    • 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 belongs to the field of drug synthesis, and specifically relates to an intermediate of Eribulin and its synthesis method and application.
  • Halicondrin B (Halichondrin B) is a complex structure natural product that exists in the sponge, with strong anti-tumor effects and broad medicinal prospects.
  • halichondrin B due to the limited supply of halichondrin B from natural sources, its research and development progress has also been restricted.
  • Eribulin is a macrocyclic ketone analogue obtained by structural optimization of halichondrin B. Eribulin mesylate injection has been approved by the US FDA for the treatment of metastatic breast cancer.
  • Eribulin has a complex structure and contains 19 chiral carbon atoms in its molecule.
  • the currently used total synthesis route is as long as 62 steps, and the three-dimensional control in the total synthesis process is a technical problem, and even some insiders call it It is the "Mount Everest" in the field of chemical drug synthesis.
  • PG 1 and PG 2 are the same or different, and are independently selected from hydroxyl protecting groups.
  • the absolute configuration of its chiral center is (2R, 3S).
  • the hydroxy protecting group may be selected from the following substituted or unsubstituted groups: alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, acyl, sulfonyl, An alkyloxycarbonyl group, an arylalkyloxycarbonyl group, a group obtained by removing an OH group from an inorganic acid, a phosphinyl group, and a silyl group.
  • PG 1 and PG 2 are the same or different and are independently selected from substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and silyl groups; As an example, it can be selected from methoxybenzyl (PMB), benzyl (Bn), triphenylmethyl (Tr), trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS) , Tert-butyldimethylsilyl (TBS).
  • PMB methoxybenzyl
  • Bn benzyl
  • Tr triphenylmethyl
  • TMS trimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • TBS Tert-butyldimethylsilyl
  • the present invention also provides a method for preparing the compound of formula (IX), which includes the following steps: taking D-2-deoxyribose (I) as a raw material, undergoing multi-step reactions such as oxidation, hydroxyl protection, reduction ring opening, and removal of hydroxyl protection to obtain The compound of formula (IX).
  • the compound of formula (IX) can be prepared from D-2-deoxyribose (I) as a raw material through the following route:
  • PG 1 and PG 2 have the above-mentioned definitions; PG 3 is independently selected from the above-mentioned hydroxyl protecting groups; each X is the same or different and is independently selected from halogen.
  • the compound of formula (II) is obtained by liquid bromine oxidation reaction of compound of formula (I); compound of formula (III) is obtained by substitution reaction of compound of formula (II) with TrX under the action of DMAP and pyridine; formula (IV) The compound is obtained by reacting the compound of formula (III) with PG 3 X under the action of DMAP and imidazole; the compound of formula (V) is obtained by removing Tr from the compound of formula (IV) under the action of BX 3 at low temperature; the compound of formula (VI) is obtained by (V) Compound and The reaction is obtained; the compound of formula (VII) is obtained by reduction and ring opening of the compound of formula (VI) under the action of borane dimethyl sulfide; the compound of formula (VIII
  • the base may be selected from organic bases or inorganic bases, for example, one, two or more of the following: sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, carbonic acid Potassium hydrogen, sodium hydroxide, potassium hydroxide, lithium hydroxide, alkyl lithium, sodium methoxide, sodium ethoxide, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, diisopropylamine, triethyl Amine;
  • X can be selected from fluorine, chlorine, bromine, iodine, such as chlorine or bromine.
  • the optical purity of the compound of formula (IX) can reach more than 99.9%.
  • the present invention also provides a method for preparing the compound of the following formula (X) using the compound of formula (IX) as a raw material, which comprises the following steps:
  • PG 1 , PG 2 and each X independently have the above-mentioned definition; R 1 , R 2 , R 3 are the same or different, and are independently selected from H, alkyl or aryl; R 6 is selected from alkyl.
  • the reaction can be carried out in the presence of a catalyst, preferably an acidic catalyst.
  • the acid catalyst may be selected from acid catalysts suitable for transesterification, for example, one, two or more selected from pyridine p-toluenesulfonate (PPTs) or protic acids (such as sulfuric acid, phosphoric acid, hydrogen chloride);
  • PPTs pyridine p-toluenesulfonate
  • protic acids such as sulfuric acid, phosphoric acid, hydrogen chloride
  • orthoester compounds such as any of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate, trimethyl orthobenzoate, and triethyl orthobenzoate.
  • the reaction temperature can be 10°C to 40°C, for example, 20°C to 30°C; the reaction time can be 0.5 to 2 hours, such as 1 hour;
  • the compound of formula (IX) and The molar ratio can be 1:(1 ⁇ 5), such as 1:(1 ⁇ 3), such as 1:(1.2 ⁇ 1.8), such as 1:1.5; when the catalyst exists, the molar ratio of the compound of formula (IX) to the catalyst The ratio can be 1:(0.01 ⁇ 0.2), such as 1:(0.01 ⁇ 0.1), such as 1:0.05;
  • the molar ratio of the halogenated silane R 3 3 SiX can be 1:(1-5), such as 1:(1-3), such as 1:(1.2-1.8), such as 1:1.5;
  • the reaction may be carried out in the presence of a base;
  • the reaction temperature may be 10°C-40°C, for example 20°C-30°C;
  • the reaction time may be 5-15h, such as 8-12h;
  • the molar ratio of the compound of formula (IXb-1) and/or the compound of formula (IXb-2) to the base can be 1:(1-10), such as 1:(1-5), such as 1:(1.5-2.5), Such as 1:2.
  • step (3) can be carried out in a solvent, such as an alcohol solvent (such as methanol, ethanol, isopropanol, ethylene glycol), water or a mixture thereof; for example, formula (IX )
  • a solvent such as an alcohol solvent (such as methanol, ethanol, isopropanol, ethylene glycol), water or a mixture thereof; for example, formula (IX )
  • the weight-to-volume ratio of the compound to the solvent may be 1 g: (1-20) mL, for example, 1 g: 10 mL.
  • the above preparation method can ensure that the absolute configuration of the two chiral centers remains unchanged during the conversion process of the compound of formula (IX) to the compound of formula (X), thereby ensuring the optical purity of the compound of formula (X) and that of the compound of formula (IX).
  • the correlation between the optical purity of the compound, that is, the compound of formula (X) prepared from the compound of formula (IX) with high purity also has corresponding high purity.
  • the present invention also provides compounds of the following formula (XI):
  • R 7 is hydrogen or a terminal alkyne protecting group.
  • the protecting group can be selected from silyl groups, such as trialkylsilyl groups (such as trimethylsilyl, triethylsilyl, triisopropylsilyl), tert-butyldiphenylsilyl, tert-butyldimethylsilyl Silyl, tribenzylsilyl, and triphenylsilyl.
  • the preparation method of the compound of formula (XI) includes reacting the compound of formula (X) with R 7 -C ⁇ CH in the presence of a strong base, such as alkyl lithium or alkyl Grignard reagent, to obtain the compound of formula (XI) .
  • a strong base such as alkyl lithium or alkyl Grignard reagent
  • PG 1 , PG 2 , and R 7 have the above-mentioned definitions.
  • the reaction may be carried out in the presence of a catalyst.
  • the catalyst may be selected from Lewis acids, such as boron trifluoride or its complexes, such as boron trifluoride or boron trifluoride methanol complex, boron trifluoride ether complex, boron trifluoride One, two or more of acetonitrile complex, boron trifluoride tetrahydrofuran complex, and boron trifluoride ethylamine complex;
  • the molar ratio of the compound of formula (X) to R 7 -C ⁇ CH may be 1:(1-10), such as 1:(1-5), such as 1:(1.5-3 ), such as 1:2;
  • the molar ratio of the compound of formula (X) to the alkyl lithium can be 1:(1-10), for example, 1:(1-5), such as 1:(1.5-3), such as 1:2;
  • the molar ratio of the compound of formula (X) to the catalyst can be 1:(1-10), such as 1:(1-5), such as 1:(1.5-3), such as 1:2;
  • the strong base may be alkyl lithium, such as methyl lithium, ethyl lithium, propyl lithium, isopropyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, pentyl One, two or more of lithium and hexyllithium; or alkyl Grignard reagents, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl One, two or more of Grignard reagents such as hexyl, hexyl, and phenyl, wherein the halogen contained in the Grignard reagent can be chlorine, bromine or iodine.
  • alkyl lithium such as methyl lithium, ethyl lithium, propyl lithium, isopropyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, pen
  • the reaction may be performed in the presence of an organic solvent.
  • the organic solvent may be an inert organic solvent, which may be selected from organic solvents that are inert under reaction conditions, especially those that do not chemically react with raw materials and products, including, for example, one, two or more selected from the following Mixtures: hydrocarbon solvents such as benzene, toluene, xylene, hexane and cyclohexane; halogenated hydrocarbon solvents such as methylene chloride, chloroform, 1,2-dichloroethane and chlorobenzene; Or other solvents, such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), acetonitrile or pyridine; ether solvents, such as ether, tetrahydrofuran, etc.
  • the reaction temperature may be -80°C to 0°C, such as
  • the product further comprises a compound of formula (XIa):
  • the content of other isomers of the compound of formula (XI) is ⁇ 0.1%.
  • the method for preparing the compound of formula (XI) further includes a step of separating XI and XIa compounds by chromatography (such as column chromatography).
  • the packing medium of the column chromatography may be silica gel; the eluent of the column chromatography may be a mixture of petroleum ether and ethyl acetate, and the volume ratio of the mixture may be (5-20) :1, such as 10:1.
  • the content of the compound of formula (XIa) in the product of the preparation method of the compound of formula (XI) is ⁇ 0.1%.
  • the present invention also provides compounds represented by the following formulas (XI), (XII), (XIII), (XIV), (XV) or (XVI):
  • PG 1 , PG 2 , and R 7 have the above-mentioned definitions; PG 4 and PG 5 are the same or different, and are independently selected from the above-mentioned hydroxyl protecting groups;
  • the condition is that any one of PG 4 and PG 5 is not the same as PG 1 or PG 2 , and PG 1 and PG 2 do not react under the conditions of removing PG 4 and PG 5 .
  • PG 4 and PG 5 are the same or different, and are independently selected from silyl groups; for example, PG 4 and PG 5 are the same or different, and are independently selected from trialkylsilyl groups (such as trimethylsilyl).
  • hydroxy protecting groups other than silyl groups such as alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, tetrahydropyranyl, acyl ,
  • the present invention also provides a preparation method of the compound of the following formula (XVI), which includes the following steps: the compound of formula (XIII) and the compound of formula (XIV) are reacted by epoxy ring opening to obtain the compound of formula (XV), and then the compound of formula (XV) The compound shown in) is reacted under the conditions of removing PG 4 and PG 5 to obtain a compound of formula (XVI):
  • PG 1 , PG 2 , PG 4 , and PG 5 have the above-mentioned definitions.
  • reaction of the compound of formula (XIII) and the compound of formula (XIV) is carried out in the presence of n-butyl lithium and BF 3 Et 2 O.
  • the conditions for removing PG 4 and PG 5 may be selected from conditions known in the art to remove such hydroxyl protecting groups, for example, the removal of silyl groups may be performed under acidic conditions.
  • the organic solvent system containing HCl the system of acetic acid and tetrahydrofuran, the system of trifluoroacetic acid, hydrogen fluoride and pyridine, the system of potassium fluoride and acetonitrile, etc.
  • ammonium fluoride compounds such as tetramethylammonium fluoride, In the presence of tetraethylammonium fluoride, tetrabutylammonium fluoride).
  • the crude compound of formula (XVI) when the enantiomeric purity of the compound of formula (XIV) used is less than 99.9%, the crude compound of formula (XVI) can be purified by recrystallization to make the compound contained therein The content of the compound of the following formula (XVIa) ⁇ 0.1%.
  • the recrystallization operation includes: dissolving the crude compound of formula (XVI) containing the compound of formula (XVIa) in a good solvent, adding the poor solvent after heating to dissolve, and cooling to obtain the purified formula ( XVI) Compound.
  • the good solvent may be methanol, isopropanol, ethanol, acetonitrile, ethyl acetate, tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, chloroform, acetone, dioxane
  • the poor solvent can be any one of petroleum ether, n-octane, cyclohexane, n-hexane, heptane, benzene, and toluene; the crude compound of formula (XVI) and a good solvent,
  • the weight-to-volume ratio of the poor solvent can be 1g: (1-5) mL: (1-5) mL, for example, 1 g: (1-2) mL: (1-2) mL; as required, the recrystallization operation can be Repeat multiple times, for example 1 to 3 times.
  • the compound represented by formula (XIII) can be prepared by one or more of the following steps:
  • PG 1 , PG 2 , PG 5 , and R 7 have the definitions described above, and L is a leaving group, such as OTS, OMS, OTf, Cl, Br, I and the like.
  • the present invention also provides a compound represented by the following formula (XIX) and a preparation method thereof:
  • PG 1 and PG 2 have the above definitions; PG 6 is independently selected from substituted or unsubstituted aromatic acyl groups, such as substituted or unsubstituted benzoyl and naphthoyl. PG 7 is an ortho-dihydroxy protecting group. Preferably, the ortho-dihydroxy protecting group and its combined oxygen form: cyclic acetals and ketals; cyclic silylene derivatives; cyclic carbonates and cyclic borates.
  • Acetal refers to -CHR-; ketal refers to -CR 2 -; cyclic carbonate refers to -OC(O)O-; cyclic borate refers to OBRO-; where R is H, alkyl, alkenyl, aromatic Group, or aralkyl group.
  • the ortho-dihydroxy protecting group may be selected from the following substituted or unsubstituted groups: alkylene, cycloalkylene, silylene, acyl.
  • alkylene cycloalkylene
  • silylene acyl
  • it can be substituted or unsubstituted methylene, ethylene, isopropylidene, cyclohexylene, cyclopentylene, phenylmethylene, diphenylmethylene, p-methoxyphenylene Methyl, 2,4,6-trimethylphenylmethylene, di-tert-butylsilylene, 1,1,3,3-tetraisopropylsiloxane, carbonyl, etc.
  • the compound represented by formula (XIX) can be prepared by the following steps:
  • PG 1 , PG 2 , and PG 6 have the above definitions
  • PG 7 is selected from substituted or unsubstituted alkylene groups, such as dialkyl substituted methylene groups, such as diethyl substituted methylene groups.
  • the present invention also provides compounds of formula (XX):
  • PG 1 , PG 2 , PG 6 , and PG 7 have the above-mentioned definitions.
  • the present invention also provides a method for preparing the compound of formula (XX), which comprises subjecting the compound of formula (XIX) to a dihydroxylation oxidation reaction under the action of an oxidizing agent to obtain the compound of formula (XX):
  • PG 1 , PG 2 , PG 6 , and PG 7 have the above-mentioned definitions.
  • the oxidant may be selected from one of potassium permanganate, sodium periodate, hydrogen peroxide, potassium ferricyanide, N-methyl-N-morpholine oxide (NMO) or Many kinds.
  • a co-oxidant can be added to the reaction as required, and the co-oxidant can be any one of osmium tetroxide and potassium osmate.
  • the reaction may be carried out under the catalysis of a base, and the base may be 1,4-diazabicyclo[2.2.2]octane (DABCO), triethylamine, N, One or more of N-diisopropylethylamine.
  • DABCO 1,4-diazabicyclo[2.2.2]octane
  • the molar ratio of the compound of formula (XIX) to the oxidant is 1:(1-5), preferably 1:(1-3); the compound of formula (XIX) and the co-oxidant
  • the molar ratio of the compound is 1:(0.005-0.15), preferably 1:(0.005-0.1); the molar ratio of the compound of formula (XIX) to the base is 1:(0.4-2), preferably 1:( 0.5 ⁇ 1.5).
  • the reaction may be carried out in a mixed solvent, and the mixed solvent may be a mixture of an organic solvent and water, for example, one selected from the following systems: tert-butanol/water, acetone/water, Acetonitrile/water; in the mixed solvent, the volume ratio of organic solvent to water can be (1:5) ⁇ (5:1), for example (2 ⁇ 2.5): (2.5 ⁇ 2); according to an embodiment of the present invention
  • the ratio of the weight of the compound of formula (XIX) to the total volume of the mixed solvent may be 1 g: (2-50 mL), for example, 1 g: 4 mL, 1 g: 22.2 mL; according to an embodiment of the present invention, the reaction temperature is ⁇ 10°C to 50°C, for example, 35°C to 45°C; the reaction time can be 10 to 60 hours, for example, 24 hours.
  • the stereoselectivity of the reaction is greatly improved by optimizing the reaction time, reaction temperature and reaction solvent.
  • the content of the compound of formula (XX) as the target product may be higher than 95%, and the content of the compound of formula (XXa) as the by-product is lower than 5%.
  • the existing technology when PG 6 is an acetyl group, the content of the compound of formula (XX) in the target product is less than 85%.
  • the technology used in the present invention significantly reduces the proportion of by-products in the product, and significantly reduces the separation difficulty of the compound of formula (XX) and its subsequent derivative products, such as the compound represented by formula (XXIIIa).
  • the present invention also provides a preparation method of the compound of the following formula (XXIII), including one or two of the preparation methods of the above-mentioned formula (IX), formula (X), formula (XI), formula (XVI), and formula (XX) compound One or more:
  • PG 1 , PG 2 , and PG 7 have the definitions described above.
  • the preparation method of the compound of formula (XXIII) further includes the product obtained by column chromatography.
  • the content of the compound (XXIIIa) represented by the following formula in the product obtained after column chromatography separation is ⁇ 0.1%.
  • PG 1 , PG 2 , and PG 7 have the definitions described above.
  • the present invention also provides a preparation method of the compound of the following formula 23, which includes at least one of the following steps:
  • the compound of formula 2 is obtained by the liquid bromine oxidation reaction of the compound of formula 1; the compound of formula 3 is obtained by the substitution reaction of the compound of formula 2 and TrX under the action of DMAP and pyridine; the compound of formula 4 is obtained by the compound of formula 3 and TBDPSX in DMAP, Under the action of imidazole, the compound of formula 5 is obtained by removing Tr from the compound of formula 4 under the action of BX 3 at low temperature; the compound of formula 6 is obtained from the compound of formula 5 and The reaction is obtained; the compound of formula 7 is obtained by ring opening of the compound of formula 6 under the action of borane dimethyl sulfide; the compound of formula 8 is obtained from the compound of formula 7 and BnX, The compound of formula 9 is obtained by removing TBDPS from the compound of formula 8 under the action of TBAF; the compound of formula 13 and the compound of formula 14 are reacted in the presence of n-butyl lithium and BF 3 Et 2 O ; Formula 16 compound and pentan
  • the present invention also provides a method for preparing Eribulin, its analogues or their C27-C35 part, which comprises using any of the above-mentioned compounds of formula (I) to (XXIII), and/or using one or Various preparation methods.
  • the present invention also provides the use of any one of the above formulas (I) to (XIII) in the preparation of eribulin, its analogs or their C27-C35 parts.
  • the numerical ranges described in this specification and claims are equivalent to at least recording each specific integer value therein.
  • the numerical range "1-40” should be understood as recording at least each integer value in the numerical range “1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.
  • each integer value in the value range “11-40” is 11, 12, 13, 14, 15, ..., 35, 36, 37, 38, 39, 40.
  • a certain numerical range is defined as a "number” it should be understood to record the two end points of the range, each integer in the range, and each decimal in the range.
  • "a number from 0 to 10" should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also recording at least each of the integers.
  • alkyl should be understood to preferably mean a straight or branched chain saturated monovalent hydrocarbon group having 1 to 40 carbon atoms, preferably a C 1-10 alkyl group.
  • C 1-10 alkyl is understood to preferably mean a straight or branched 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-dimethylbutyl, 1,2-dimethylbutyl, etc.
  • 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 Or isopropyl.
  • C 1-3 alkyl such as methyl, ethyl, n-propyl Or isopropyl.
  • alkenyl should be understood to preferably mean a straight or branched monovalent hydrocarbon group which contains one or more double bonds and has 2 to 40 carbon atoms, preferably "C 2-6 alkenyl".
  • C 2-6 alkenyl should be understood to preferably mean a straight or branched monovalent hydrocarbon group which contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms, especially 2 or 3 carbon atoms ("C 2-3 alkenyl”), it should be understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -Pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-ene Group, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-eny
  • cycloalkyl should be understood to preferably mean a saturated or unsaturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane, which has 3 to 40 carbon atoms, preferably "C 3-10 cycloalkyl".
  • C 3-10 cycloalkyl should be understood as meaning a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic Hydrocarbyl such as decalin ring.
  • heterocyclic group should be understood to preferably mean a saturated or unsaturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane, which contains an assembly of 1-5 heteroatoms independently selected from N, O and S
  • a non-aromatic cyclic group having 3-20 ring atoms (for example, 3, 4, 5, 6, 7, 8, 9, 10, etc.) is preferably a "3-10 membered heterocyclic group".
  • the term "3-10 membered heterocyclic group” means a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane, which contains 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclic group may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present).
  • the heterocyclic group may include but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl Or trithiaalkyl; or 7-membered ring, such as diazeppanyl.
  • the heterocyclic group may be benzo-fused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5, 5-membered ring, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5, 6-membered bicyclic ring, such as hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing nitrogen atoms may be partially unsaturated, that is, it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadi Azinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
  • the heterocyclic group is non-aromatic.
  • aryl should be understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-14 aryl".
  • C 6-14 aryl should be understood to preferably mean a monocyclic, bicyclic, or partially aromatic monocyclic or partially aromatic monocyclic ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms.
  • Tricyclic hydrocarbon ring (“C 6-14 aryl”), especially a ring with 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or one with 9 carbon atoms
  • a ring (“C 9 aryl”), such as indanyl or indenyl, or a ring with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • the C 6-20 aryl group When the C 6-20 aryl group is substituted, it may be mono-substituted or multi-substituted.
  • there is no restriction on the substitution site for example, ortho, para, or meta substitution can be adopted.
  • heteroaryl should be understood to preferably include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5-20 ring atoms and containing 1-5 independently selected from N, O and S Heteroatoms, such as "5-14 membered heteroaryl".
  • the term “5-14 membered heteroaryl” should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and it contains 1-5, preferably 1-3 heteroatoms each independently selected from N, O and S and, in addition, in each case The bottom can be benzo-fused.
  • the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thio Diazolyl, thio-4H-pyrazolyl, etc.
  • the carbon atom on the 5-20 membered heteroaryl ring may be connected to the other group, or it may be a 5-20 membered heterocyclic group.
  • the heteroatoms on the aryl ring are connected to other groups.
  • the 5-20 membered heteroaryl group When the 5-20 membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Moreover, there is no restriction on the substitution position, for example, the hydrogen connected to the carbon atom on the heteroaryl ring is substituted, or the hydrogen connected to the heteroatom on the heteroaryl ring is substituted.
  • heterocyclic group, heteroaryl group or heteroarylene group includes all possible isomeric forms thereof, such as positional isomers thereof. Therefore, for some illustrative non-limiting examples, it can be included in its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12 -Position etc.
  • pyridin-2-yl pyridin-2-yl, pyridin-3-yl, Pyridin-3-yl, pyridin-4-yl and pyridin-4-yl
  • thienyl or thiophene include thiophen-2-yl, thiophen-2-yl, thiophen-3-yl and thiophene-3 -Base
  • pyrazol-1-yl pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.
  • alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be substituted by the following groups: halogen, hydroxy, amino (substituted or unsubstituted amino, such as -N(C 1-6 Alkyl) 2 , -NHC 1-6 alkyl), nitro, cyano, carboxy, azido, alkyl, alkoxy, cycloalkyl, acyl, aryl, heteroaryl.
  • halogen means fluorine, chlorine, bromine and iodine.
  • C 1-6 alkyl is also applicable to C 1-6 alkyloxy, -N(C 1-6 alkyl ) 2 , -NHC 1-6 alkyl or -S(O) 2 -C 1-6 alkyl, etc.
  • hydroxyl protecting group in the present invention refers to a group that protects the hydroxyl group introduced during the synthesis process. The purpose is to avoid undesired chemical reactions of the hydroxyl group under reactive conditions, and the hydroxyl protecting group will be used in subsequent synthesis. Removed in the step to restore the hydroxyl group.
  • exemplary hydroxyl protecting groups include but are not limited to the following groups:
  • Substituted or unsubstituted alkyl groups for example: methyl, tert-butyl and other C 1 -C 6 alkyl groups; methoxymethyl, methylthiomethyl, benzyloxymethyl, tert-butoxymethyl , 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl and 2-(trimethylsilyl)ethoxy Methyl; 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-isopropoxyethyl, 2,2,2-trichloroethyl and 2-methoxyethyl Ethyl; 1-hydroxyalkyl, such as 1-hydroxyethyl, 1-hydroxyhexyl, 1-hydroxydecyl, 1-hydroxyhexadecyl and 1-hydroxy-1-phenylmethyl; substituted or unsubstituted Arylalkyl groups, such as benzyl, methoxybenzyl, 2,6
  • Substituted or unsubstituted alkenyl such as allyl
  • cycloalkyl such as cyclohexyl
  • Substituted or unsubstituted aryl groups such as phenyl, 2,4-dinitrophenyl;
  • Substituted or unsubstituted acyl such as formyl, substituted or unsubstituted alkylcarbonyl, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl, neopentylcarbonyl , Hexyl carbonyl, heptyl carbonyl, octyl carbonyl, decyl carbonyl, nonyl carbonyl, dodecyl carbonyl, tetradecyl carbonyl, hexadecyl carbonyl, octadecyl carbonyl and other substituted or unsubstituted Alkylcarbonyl; acetoacetyl; substituted or unsubstituted cycloalkylcarbonyl, such as cyclopentylcarbonyl, cyclohexylcarbonyl; substituted or
  • Substituted or unsubstituted sulfonyl groups such as methylsulfonyl, ethylsulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl and naphthalenesulfonyl;
  • a substituted or unsubstituted alkyloxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and other C 1 -C 6 alkoxycarbonyl groups;
  • Substituted or unsubstituted arylalkyloxycarbonyl such as benzyloxycarbonyl and p-methoxybenzyloxycarbonyl;
  • Groups derived from inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, and boric acid) by removing OH groups;
  • Phosphine group for example, dialkyl phosphine group (for example, dimethyl phosphine group), diaryl group of phosphinyl group (for example, diphenyl phosphine group);
  • Silyl group wherein the definition of alkyl group is the same as before.
  • trialkylsilyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl
  • tert-butyldiphenylsilyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl
  • tert-butyldiphenylsilyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl
  • tert-butyldiphenylsilyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl
  • tert-butyldiphenylsilyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl
  • tert-butyldiphenylsilyl such as trimethylsilyl, triethylsilyl,
  • the oxygen atom bound to the "hydroxyl protecting group" of the present invention can form the following specific examples: formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, Triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxoanoate, 4,4-(ethylenedithio)pentanoate, Pivalate (trimethylacetyl), crotonate, 4-methoxycrotonate, benzoate, p-benzyl benzoate, 2,4,6-trimethylbenzoic acid Ester; or carbonate of the following groups: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2 -(Benzenesulfonyl) ethyl, vinyl, propenyl, p-nitrophenyl; the following silyl ethers: tri
  • the “o-dihydroxy protecting group” in the present invention means a group that protects the ortho-dihydroxy group introduced during the synthesis process, and the purpose is to prevent the ortho-dihydroxy group from undesired chemical reactions under reactive conditions, and the ortho-dihydroxy group
  • the hydroxyl protecting group will be removed in a subsequent synthesis step to restore the o-dihydroxy group.
  • the dihydroxy protecting group and its combined oxygen form cyclic acetals and ketals; cyclosilylene derivatives; cyclic carbonates and cyclic borates.
  • Acetal refers to -CHR-; ketal refers to -CR 2 -; cyclic carbonate refers to -OC(O)O-; cyclic borate refers to OBRO-; where R is H, alkyl, alkenyl, aromatic Groups, or aralkyl groups; exemplary ortho-dihydroxy protecting groups include, but are not limited to, substituted or unsubstituted groups such as alkylene (such as methylene, ethylene, isopropylene, phenylmethylene Group, diphenylmethylene, p-methoxyphenylmethylene, 2,4,6-trimethylphenylmethylene); cycloalkylene (such as cyclohexylene, cyclopentylene) , Di(C1-6 alkyl)silylene (such as di-tert-butylsilylene, 1,1,3,3-tetraisopropylsiloxane), methyl borate, ethyl boronic acid Esters
  • the solvent in the present invention is preferably an anhydrous solvent.
  • the beneficial effects of the present invention provides intermediates that can be used to synthesize Eribulin or its analogs, especially its C27-C35 structural fragments, and its preparation method and use.
  • the design of the synthetic route of the present invention changes the raw materials and route steps of the existing methods in the prior art. Because the starting materials are cheap and easy to obtain, the optical purity is controllable, and the step method for constructing the chiral center has higher diastereoselectivity.
  • FIG. 1 shows the HPLC spectrum of compound 16.
  • FIG. 1 shows the HPLC spectrum of compound 23.
  • Dissolve deoxyribose 1 100g in water (400mL), lower the temperature to about 5°C, slowly add liquid bromine (200g) over 3h, and increase the temperature to 30°C for 24h (disappearance of raw materials detected by dot plate).
  • Post-treatment 1) Add ethyl acetate (100mL ⁇ 2) to extract, the organic phase is in the lower layer, add ethyl acetate (50mL) for the third time, and the organic phase is in the upper layer; 2) Combine the organic phases with water (50mL ⁇ 2) Extract the product contained therein; 3) Combine the aqueous phases, neutralize bromine with saturated sodium thiosulfate (a small amount), then cool to 0°C, adjust the pH of the solution to about 3 (solid NaOH dosage is about 61g), Diatomite filtration; 4) When the filtrate is concentrated to a viscous liquid with a small amount of solids, add isopropanol (200mL), stir and heat to 80°C, filter while hot, wash the solids with isopropanol (100mL), and concentrate the filtrate to leave a residue Add isopropanol (100mL) to dissolve, filter, wash the solid with isopropanol (40mL), concentrate the filtrate
  • the crude compound 2 (44 g) was dissolved in pyridine (200 mL), trityl chloride (88 g), 4-dimethylaminopyridine, or DMAP (4.5 g) were added, and the mixture was heated to 50° C. to react overnight.
  • Post-treatment add water (300mL ⁇ 2), separate the liquids, extract with dichloromethane (100mL) each time, combine the organic phases, dry, concentrate, add methanol (150mL ⁇ 2) and concentrate twice, and finally add methanol (300mL) , N-hexane (100 mL), concentrated under reduced pressure to about 200-300 mL, stirred and cooled to about 10° C. The solution precipitated a white solid, filtered, and washed the solid with a small amount of cold methanol. The solid was taken out, and the remaining solvent was evaporated under reduced pressure to obtain about 136 g of compound 4.
  • the crude compound 6 obtained in the previous step was dissolved in tetrahydrofuran (700 mL), cooled to an ice bath, protected by argon, and borane dimethyl sulfide (10M, 70 mL) was slowly added dropwise, and the temperature was raised to room temperature for ten minutes. Then it was heated to 55°C-60°C and reacted overnight.
  • Post-treatment Cool down in an ice bath, slowly add methanol to quench the reaction (until no bubbles are generated), concentrate under reduced pressure, dissolve the residue in ethyl acetate, wash with saturated sodium bicarbonate, extract with ethyl acetate, and dry , Concentrated, the residue was evaporated to dryness with methanol, repeated twice, column chromatography obtained about 156 g of compound 7 with a total yield of 68%.
  • Dissolve compound 7 (103.4g) in acetonitrile (1L), add SM2 (4.7g), potassium carbonate (37.5g), potassium iodide (38.2g) and benzyl bromide (37.3mL), heat to 70°C ⁇ 80°C for reaction 3-5 hours (point board to detect the disappearance of raw materials or only a few remaining and no longer change).
  • Post-treatment add water, extract with ethyl acetate 2-3 times, dry, concentrate, and proceed directly to the next reaction.
  • the crude compound 8 was dissolved in tetrahydrofuran (314 mL), tetrabutylammonium fluoride (TBAF, 314 mL) was added, and the reaction was carried out at 25° C. overnight.
  • the reaction was quenched by adding saturated ammonium chloride (200 mL) aqueous solution, the layers were separated, the aqueous phase was extracted with dichloromethane (200 mL ⁇ 2), and the organic phases were combined, washed with 1N hydrochloric acid to remove 2,6-lutidine, and then saturated Wash with sodium chloride (200 mL ⁇ 2), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 25.7 g of crude product (compound 12).
  • the above crude compound 12 was dissolved in 200 mL of anhydrous methanol, potassium carbonate powder (13.5 g) was added, and the reaction was carried out at room temperature overnight. TLC detected that the reaction was complete.
  • reaction solution was extracted with ethyl acetate (10mL ⁇ 3), the organic phases were combined, washed with water (10mL ⁇ 2), and saturated Wash with sodium chloride (10 mL ⁇ 2), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 110 mg of crude product, which is separated by silica gel column chromatography to obtain compound 20 67 mg, with a yield of 70%.
  • Extract with methyl chloride 300 mL ⁇ 2), combine the organic phases, wash with saturated sodium chloride (300 mL ⁇ 2), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 33 g of crude product, which is separated by silica gel column chromatography to obtain compound 22 about 27 g , The total yield of the two steps is 90%.
  • TLC detects the reaction Complete, add dropwise saturated ammonium chloride (100mL) to quench the reaction, extract with ethyl acetate (100mL ⁇ 3), combine the organic phases, wash with saturated sodium chloride (200mL ⁇ 2), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate Obtain 8 g of the colorless oily crude product, which was separated by silica gel column chromatography to obtain 5.8 g of compound 23 with a yield of 86%; meanwhile, 0.2 g of compound 23' was obtained. The purity of compound 23 is >99.9%.
  • the HPLC spectrum is shown in Figure 2.
  • the impurity 23' content shown in the following formula is 0.09%:

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Abstract

提供可用于合成软海绵素B、艾日布林或其类似物，特别是其C27-C35结构片段的中间体、其制备方法和用途。合成路线的起始原料廉价易得，其光学纯度可以得到保障，从而保证了软海绵素、艾日布林或其类似物中C27-C35结构片段的光学纯度；构建C27-C35结构片段手性中心的步骤方法，具有较高的非对映选择性和产率，尤其是式(X)、式(XI)、式(XVI)和式(XV)所示化合物的制备方法；部分反应的副产物仅需重结晶即可除去，便于纯化，大大降低了成本。

Description

艾日布林的中间体及其合成方法和用途
本申请要求2019年4月26日向中国国家知识产权局提交的专利申请号为2019103461407，发明名称为“艾日布林的中间体及其合成方法和用途”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
本发明属于药物合成领域，具体涉及艾日布林的中间体及其合成方法和用途。
背景技术
软海绵素B(Halichondrin B)是一种存在于海绵体内的复杂结构天然产物，具有强烈的抗肿瘤作用和广阔的药用前景。然而由于天然来源的软海绵素B供应量有限，其研发进展也受到了限制。
艾日布林(Eribulin)是由软海绵素B经结构优化得到的一种大环酮类似物。甲磺酸艾日布林注射剂已获美国FDA批准用于治疗转移性乳腺癌。
Figure PCTCN2020082933-appb-000001
艾日布林结构复杂，其分子中含有19个手性碳原子，目前使用的全合成路线长达62步，且其全合成过程中的立体控制是一项技术难题，甚至有业内人士称其为化学药物合成界的“珠穆朗玛峰”。
现有的艾日布林、或其类似物的合成方法存在诸多缺陷。例如，合成路线过于冗长，起始原料光学纯度难以控制，而且中间体纯化复杂，成本高。此外，上述合成方法中使用的某些反应还存在立体选择性不佳的缺点，加之产品分子中手性碳原子众多，合成过程中极易形成性质相近、难以除去的异构体，不利于保证产品的纯度。
因此，亟需开发一条既可改善合成效率，又可提高立体选择性，同时纯化操作更为简便的艾日布林、或其类似物的中间体的合成方法。
发明内容
为了改善上述问题，本发明提供下式(Ⅸ)化合物：
Figure PCTCN2020082933-appb-000002
其中，PG 1、PG 2相同或不同，彼此独立地选自羟基保护基。其手性中心绝对构型为(2R,3S)。
根据本发明的实施方案，所述羟基保护基可以选自取代或未取代的下列基团：烷基、烯基、环烷基、芳基、杂芳基、杂环基、酰基、磺酰基、烷基氧基羰基、芳基烷基氧基羰基、由无机酸通过除去OH基团得到的基团、硫膦基、硅烷基。
根据本发明的实施方案，PG 1、PG 2相同或不同，彼此独立地选自取代或未取代的烷基、烯基、环烷基、芳基、杂芳基、杂环基、硅烷基；作为实例，可以选自甲氧基苄基(PMB)、苄基(Bn)、三苯基甲基(Tr)、三甲基硅基(TMS)、叔丁基二苯基硅基(TBDPS)、叔丁基二甲基硅基(TBS)。
本发明还提供式(Ⅸ)化合物的制备方法，包括如下步骤：以D-2-脱氧核糖(I)为原料，经氧化、羟基保护、还原开环、脱除羟基保护等多步反应，得到式(Ⅸ)化合物。
根据本发明的实施方案，式(Ⅸ)化合物可以D-2-脱氧核糖(I)为原料通过下列路线制备：
Figure PCTCN2020082933-appb-000003
其中，PG 1、PG 2具有上文所述的定义；PG 3独立地选自上文所述的羟基保护基；每一个X相同或不同，独立地选自卤素。优选地，式(II)化合物由式(I)化合物经液溴氧化反应得到；式(III)化合物由式(II)化合物与TrX在DMAP、吡啶的作用下发生取代反应得到；式(IV)化合物由式(III)化合物与PG 3X在DMAP、咪唑的作用下反应得到；式(V)化合物由式(IV)化合物在BX 3作用下低温脱除Tr得到；式(VI)化合物由式(V)化合物与
Figure PCTCN2020082933-appb-000004
反应得到；式(VII)化合物由式(VI)化合物在硼烷二甲硫醚作用下还原开环得到；式(VIII)化合物由式(VII)化合物与PG 2X，以
Figure PCTCN2020082933-appb-000005
为催化剂，在碱和碘化钾的作用下反应得到；式(Ⅸ)化合物由式(VIII)化合物在TBAF作用下脱除PG 3得到；其中，PG 1、PG 2、PG 3、X具有上文所述的定义。
据本发明的实施方案，所述的碱可以选自有机碱或无机碱，例如选自下列中的一种、两种或更多种：碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、烷基锂、甲醇钠、乙醇钠、甲胺、乙胺、丙胺、异丙胺、二甲胺、二乙胺、二异丙胺、三乙胺；X可以选自氟、氯、溴、碘，例如氯或溴。鉴于市售D-2-脱氧核糖(I)价格低廉，且光学纯度可达100％，根据本发明的实施方案，式(Ⅸ)化合物的光学纯度可达99.9％以上。
本发明还提供以式(Ⅸ)化合物为原料的下式(X)化合物的制备方法，包括如下步骤：
(1)式(Ⅸ)化合物与
Figure PCTCN2020082933-appb-000006
反应，得到式(Ⅸa)化合物；
(2)式(Ⅸa)化合物与酰卤
Figure PCTCN2020082933-appb-000007
或卤代硅烷R 3 3SiX反应，得到式(Ⅸb-1)化合物和/或式(Ⅸb-2)化合物；
(3)式(Ⅸb-1)化合物和/或式(Ⅸb-2)化合物在碱性条件下醇解并进一步发生分子内S N2关环反应，得到式(X)化合物；
Figure PCTCN2020082933-appb-000008
其中，PG 1、PG 2和每一个X独立地具有上文所述的定义；R 1、R 2、R 3相同或不同，彼此独立地选自H、烷基或芳基；R 6选自烷基。
根据本发明的实施方案，其中：
步骤(1)中，反应可在催化剂，优选酸性催化剂的存在下进行。所述酸性催化剂可以选自适用于酯交换的酸性催化剂，例如选自吡啶对甲苯磺酸盐(PPTs)或质子酸(如硫酸、磷酸、氯化氢)中的一种、两种或更多种；
Figure PCTCN2020082933-appb-000009
可选自原酸酯类化合物，例如原甲酸三甲酯、原甲酸三乙酯、原乙酸三甲酯、原乙酸三乙酯、原苯甲酸三甲酯、原苯甲酸三乙酯中的任一种；
反应温度可以为10℃～40℃，例如可以为20℃～30℃；反应时间可以为0.5～2h，例如1h；
式(IX)化合物与
Figure PCTCN2020082933-appb-000010
的摩尔比可以为1:(1～5)，例如1:(1～3)，例如1:(1.2～1.8)，如1:1.5；当催化剂存在时，式(IX)化合物与催化剂的摩尔比可以为1:(0.01～0.2)，例如1:(0.01～0.1)，如1:0.05；
步骤(2)中，反应温度可以为10℃～40℃，例如20℃～30℃；反应时间可以为0.1～2h，例如0.5h；
式(IXa)化合物与酰卤
Figure PCTCN2020082933-appb-000011
或卤代硅烷R 3 3SiX的摩尔比可以为1:(1～5)，例如1:(1～3)，例如1:(1.2～1.8)，如1:1.5；
步骤(3)中，反应可在碱的存在下进行；反应温度可以为10℃～40℃，例如20℃～30℃；反应时间可以为5～15h，例如8～12h；
式(Ⅸb-1)化合物和/或式(Ⅸb-2)化合物与碱的摩尔比可以为1:(1～10)，例如1:(1～5)，例如1:(1.5～2.5)，如1:2。
根据本发明的实施方案，步骤(3)可以在溶剂中进行，所述溶剂例如为醇类溶剂(如甲醇、乙醇、异丙醇、乙二醇)、水或其混合物；例如，式(IX)化合物与所述溶剂的重量体积比可以为1g:(1～20)mL，例如可以为1g:10mL。
上述制备方法可以保证式(Ⅸ)化合物至式(X)化合物的转化过程中，两个手性中心的绝对构型均保持不变，从而保证了式(X)化合物的光学纯度与式(Ⅸ)化合物的光学纯度之间的相关性，即以高纯度式(Ⅸ)化合物为原料制得的式(X)化合物也具有相应的高纯度。
本发明还提供下式(XI)化合物：
Figure PCTCN2020082933-appb-000012
其中，PG 1、PG 2具有上文所述的定义；R 7为氢或端炔保护基。保护基可选自硅烷基，例如三烷基硅基(如三甲基硅基、三乙基硅基、三异丙基硅基)、叔丁基二苯基硅基、叔丁基二甲基硅基、三苄基硅基和三苯基硅基。
式(XI)化合物的制备方法，包括式(X)化合物与R 7-C≡CH在强碱，如烷基锂或烷基格氏试剂，的存在下反应，得到式(XI)所示化合物。
Figure PCTCN2020082933-appb-000013
其中，PG 1、PG 2、R 7具有上文所述的定义。
根据本发明的实施方案，所述反应可以在催化剂的存在下进行。例如，所述催化剂可以选自路易斯酸，例如三氟化硼或其络合物，例如三氟化硼或三氟化硼甲醇络合物、三氟化硼乙醚络合物、三氟化硼乙腈络合物、三氟化硼四氢呋喃络合物、三氟化硼乙胺络合物中的一种、两种或更多种；
根据本发明的实施方案，所述式(X)化合物与R 7-C≡CH的摩尔比可以为1:(1～10)，例如1:(1～5)，如1:(1.5～3)，如1:2；所述式(X)化合物与烷基锂的摩尔比可以为1:(1～10)，例如1:(1～5)，如1:(1.5～3)，如1:2；所述式(X)化合物与催化剂的摩尔比可以为1:(1～10)，例如1:(1～5)，如1:(1.5～3)，如1:2；
根据本实施方案，所述强碱可以为烷基锂，例如甲基锂、乙基锂、丙基锂、异丙基锂、正丁基锂、仲丁基锂、叔丁基锂、戊基锂、己基锂中的一种、两种或更多种；或烷基格氏试剂，如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、己基、苯基等格氏试剂中的一种、两种或更多种，其中格氏试剂所含卤素可以是氯、溴或者碘。
根据本发明的实施方案，所述反应可以在有机溶剂的存在下进行。所述有机溶剂可以是惰性有机溶剂，其可选自在反应条件下呈惰性，特别是不与原料和产品发生化学反应的有机溶剂，包括例如选自下列的一种、两种或多种的混合物：碳氢化合物类溶剂，例如苯、甲苯、二甲苯、己烷和环己烷；卤代烃类溶剂，例如二氯甲烷、三氯甲烷、1,2-二氯乙烷和氯苯；或者其它溶剂，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；醚类溶剂，例如乙醚、四氢呋喃等。根据本发明的实施方案，反应温度可以为-80℃～0℃，例如-60℃～-30℃；反应时间可以为0.5～5h，例如1～3h。
根据本发明的实施方案，在上述式(XI)化合物的制备方法中，产品还包含下式(XIa)化合物：
Figure PCTCN2020082933-appb-000014
根据本发明的实施方案，在上述式(XI)化合物的制备方法的产品中，除式(XIa)化合物外，式(XI)化合物的其他异构体的含量≤0.1％。
根据本发明的一个实施方案，上述式(XI)化合物的制备方法中，还包括色谱方式(如柱色谱)分离XI和XIa化合物的步骤。
根据示例性的实施方案，所述柱色谱的填充介质可以为硅胶；所述柱色谱的洗脱剂可以为石油醚和乙酸乙酯的混合物，所述混合物的体积比可以为(5～20):1，如10:1。优选地，经色谱分离后，上述式(XI)化合物的制备方法的产品中式(XIa)化合物的含量≤0.1％。
本发明还提供下式(XI)、(XII)、(XIII)、(XIV)、(XV)或(XVI)所示的化合物：
Figure PCTCN2020082933-appb-000015
其中，PG 1、PG 2、R 7具有上文所述定义；PG 4、PG 5相同或不同，彼此独立地选自上文所述的羟基保护基；
条件是PG 4和PG 5中的任一个与PG 1或PG 2均不相同，且PG 1和PG 2在脱除PG 4和PG 5的条件下不发生反应。
根据本发明的实施方案，PG 4、PG 5相同或不同，彼此独立地选自硅烷基；例如，PG 4、PG 5相同或不同，彼此独立地选自三烷基硅基(如三甲基硅基、三乙基硅基、三异丙基硅基)、叔丁基二苯基硅基、叔丁基二甲基硅基、三苄基硅基和三苯基硅基，而PG 1和PG 2相同或不同，彼此独立地选自除硅烷基以外的羟基保护基，例如烷基、烯基、环烷基、芳基、杂芳基、杂环基、四氢吡喃基、酰基、磺酰基、烷基氧基羰基、芳基烷基氧基羰基、由无机酸通过除去OH基团得到的基团、硫膦基。
本发明还提供下式(XVI)化合物的制备方法，包括如下步骤：将式(XIII)化合物与式(XIV)化合物发生环氧开环反应得到式(XV)所示化合物，再将式(XV)所示化合物在脱除PG 4和PG 5的条件下反应，得到式(XVI)化合物：
Figure PCTCN2020082933-appb-000016
其中，PG 1、PG 2、PG 4、PG 5具有上文所述定义。
优选地，所述式(XIII)化合物与式(XIV)化合物的反应在正丁基锂与BF 3Et 2O的存在下进行。
根据本发明示例性的实施方案，所述脱除PG 4和PG 5的条件可以选自本领域已知的脱除该类羟基保护基的条件下进行，例如硅烷基的脱除可以在酸性条件下(如含HCl的有机溶剂体系、醋酸和四氢呋喃的体系，三氟乙酸，氟化氢和吡啶的体系，氟化钾和乙腈的体系等)或氟化铵类化合物(如四甲基氟化铵，四乙基氟化铵，四丁基氟化铵)的存在下进行。
根据本发明优选的实施方案，当所使用的式(XIV)化合物的对映体纯度低于99.9％时，可在得到式(XVI)化合物粗品后，通过重结晶对其进行纯化，使其中所含下式(XVIa)化合物的含量≤0.1％。
Figure PCTCN2020082933-appb-000017
根据本发明的实施方案，所述重结晶的操作包括：将含有式(XVIa)化合物的式(XVI)化合物粗品溶于良溶剂中，加热溶解后加入不良溶剂，冷却，得到纯化后的式(XVI)化合物。
根据本发明示例性的实施方案，所述良溶剂可以为甲醇、异丙醇、乙醇、乙腈、乙酸乙酯、四氢呋喃、甲基叔丁基醚、异丙醚、氯仿、丙酮、二氧六环中的任一种；所述不良溶剂可以为石油醚、正辛烷、环己烷、正己烷、庚烷、苯、甲苯中的任一种；所述式(XVI)化合物粗品与良溶剂、不良溶剂的重量体积比可以为1g:(1～5)mL:(1～5)mL，例如1g:(1～2)mL:(1～2)mL；根据需要，所述重结晶操作可重复多次，例如重复1～3次。
根据本发明示例性的实施方案，式(XIII)所示化合物可通过下列步骤中的一个或多个制备：
Figure PCTCN2020082933-appb-000018
其中，PG 1、PG 2、PG 5、R 7具有上文所述定义，L为离去基团，例如OTS，OMS，OTf，Cl，Br，I等。
本发明还提供下式(XIX)所示化合物及其制备方法：
Figure PCTCN2020082933-appb-000019
其中，PG 1、PG 2具有上文所述定义；PG 6独立地选自取代或未取代的芳香酰基，如取代或未取代的苯甲酰基、萘甲酰基。PG 7为邻二羟基保护基。优选的，所述邻二羟基保护基与其结合的氧形成：环缩醛和缩酮；环亚甲硅基衍生物；环碳酸酯和环硼酸酯。缩醛指-CHR-；缩酮是指-CR 2-；环碳酸酯是指-OC(O)O-；环硼酸酯是指OBRO-；其中R为H，烷基、烯基、芳基、或芳烷基。
根据本发明的实施方案，所述邻二羟基保护基可以选自取代或未取代的下列基团：亚烷基、亚环烷基、亚硅烷基、酰基。例如可以为取代或未取代的亚甲基、亚乙基、亚异丙基、亚环己基、亚环戊基、苯基亚甲基、二苯基亚甲基、对甲氧基苯基亚甲基、2,4,6-三甲基苯基亚甲基、二叔丁基亚硅烷基、1,1,3,3-四异丙基硅氧烷基，碳酰基等。
根据本发明的一个实施方案，式(XIX)所示化合物可通过下列步骤制备：
Figure PCTCN2020082933-appb-000020
其中，PG 1、PG 2、PG 6具有上文所述定义，
PG 7选自取代或未取代的亚烷基，例如二烷基取代的亚甲基，如二乙基取代的亚甲基。
优选地，式(XVI)化合物与
Figure PCTCN2020082933-appb-000021
在三氟甲磺酸钪的作用下反应得到式(XVII)化合物；式(XVIII)化合物由式(XVII)化合物在Lindlar催化剂作用下加氢还原得到；式(XIX)化合物由式(XVIII)化合物与PG 6X在DMAP、吡啶的作用下反应得到；其中，PG 6、PG 7、X具有上文所述定义。
本发明还提供式(XX)化合物：
Figure PCTCN2020082933-appb-000022
其中，PG 1、PG 2、PG 6、PG 7具有上文所述定义。
本发明还提供式(XX)化合物的制备方法，包括将式(XIX)化合物在氧化剂的作用下进行双羟化氧化反应，得到式(XX)化合物：
Figure PCTCN2020082933-appb-000023
其中，PG 1、PG 2、PG 6、PG 7具有上文所述定义。
根据本发明的实施方案，所述氧化剂可以选自高锰酸钾、高碘酸钠、过氧化氢、铁氰化钾、N-甲基-N-氧化吗啉(NMO)中的一种或多种。根据本发明的实施方案，所述反应中可根据需要加入共氧化剂，所述共氧化剂可以为四氧化锇、锇酸钾中的任一种。根据本发明的实施方案，所述反应可在碱的催化作用下进行，所述碱可以为1,4-二氮杂二环[2.2.2]辛烷(DABCO)、三乙胺、N,N-二异丙基乙胺中的一种或多种。根据本发明的实施方案，所述式(XIX)化合物与氧化剂的摩尔比为1:(1～5)，优选为1:(1～3)；所述式(XIX)化合物与所述共氧化剂的摩尔比为1:(0.005～0.15)，优选为1:(0.005～0.1)；所述式(XIX)化合物与所述碱的摩尔比为1:(0.4～2)，优选为1:(0.5～1.5)。根据本发明的实施方案，所述反应可以在混合溶剂下进行，所述混合溶剂可以为有机溶剂与水的混合物，例如选自下列体系中的一种：叔丁醇/水、丙酮/水、乙腈/水；所述混合溶剂中，有机溶剂与水的体积比可以为(1:5)～(5:1)，例如(2～2.5):(2.5～2)；根据本发明的实施方案，所述式(XIX)化合物的重量与混合溶剂总体积的比可以为1g:(2～50mL)，例如1g:4mL，1g:22.2mL；根据本发明的实施方案，所述反应温度为-10℃～50℃，例如可以为35℃～45℃；反应时间可以为10～60h，例如可以为24h。
根据本发明优选的实施方案，鉴于采用了与现有技术不同的PG 6,通过对反应时间、反应温度以及反应溶剂的优化，大幅提高了反应的立体选择性。所述反应得到的产物中，目标产物式(XX)化合物的含量可高于95％，副产物式(XXa)化合物的含量低于5％。相应的利用现有技术(PG 6为乙酰基时)，目标产物式(XX)化合物含量低于85％。本发明使用的技术明显降低了产物中副产物的比例，显著降低了式(XX)化合物及其后续衍生产物，如式(XXIIIa)所示化合物的分离难度。
本发明还提供下式(XXIII)化合物的制备方法，包括上述式(IX)、式(X)、式(XI)、式(XVI)、式(XX)化合物的制备方法中的一种、两种或更多种：
Figure PCTCN2020082933-appb-000024
其中，PG 1、PG 2、PG 7具有上文所述的定义。
优选地，所述式(XXIII)化合物的制备方法还包括柱层析分离得到的产品。优选地，所述式(XXIII)化合物的制备方法中，柱层析分离后得到的产品中，下式所示化合物(XXIIIa)的含量≤0.1％。
Figure PCTCN2020082933-appb-000025
其中，PG 1、PG 2、PG 7具有上文所述的定义。
作为实例，本发明还提供下式23化合物的制备方法，包括下列步骤中的至少一种：
Figure PCTCN2020082933-appb-000026
优选地，式2化合物由式1化合物经液溴氧化反应得到；式3化合物由式2化合物与TrX在DMAP、吡啶的作用下发生取代反应得到；式4化合物由式3化合物与TBDPSX在DMAP、咪唑的作用下反应得到；式5化合物由式4化合物在BX 3作用下低温脱除Tr得到；式6化合物由式5化合物与
Figure PCTCN2020082933-appb-000027
反应得到；式7化合物由式6化合物在硼烷二甲硫醚作用下开环得到；式8化合物由式7化合物与BnX、
Figure PCTCN2020082933-appb-000028
在碱和碘化钾的作用下反应得到；式9化合物由式8化合物在TBAF作用下脱除TBDPS得到；式13化合物与式14化合物的反应在正丁基锂与BF 3Et 2O的存在下进行；式16化合物与戊酮、
Figure PCTCN2020082933-appb-000029
在三氟甲磺酸钪的作用下反应得到式17化合物；式18化合物由式17化合物在Lindlar催化剂作用下加氢还原得到；式19化合物由式18化合物与BzX在DMAP、吡啶的作用下反应得到；式21化 合物由式20化合物与MsX在DMAP、碱的作用下反应得到；式22化合物由式21化合物在碱的作用下发生关环反应得到；式23化合物由式22化合物在烷基格氏试剂作用下脱除Ms保护基得到；其中，每一个X相同或不同，彼此独立地选自卤素。
本发明还提供一种制备艾日布林、其类似物或它们的C27-C35部分的方法，包括使用上述式(I)至(XXIII)中的任一化合物，和/或使用上述一种或多种制备方法。
本发明还提供上述式(I)至(XIII)中的任一种化合物在制备艾日布林、其类似物或它们的C27-C35部分中的用途。
术语和定义
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
除非另有说明，本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如，数值范围“1-40”应被理解为至少记载了数值范围“1-10”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10，以及数值范围“11-40”中的每一个整数数值即11、12、13、14、15、......、35、36、37、38、39、40。如果可能，当某些数值范围被定义为“数”时，应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如，“0～10的数”应当理解为不仅记载了0、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独立地与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8或0.9的加和。应当理解，本文在描述一个、两个或更多个时，“更多个”应当是指≥3的整数，例如3、4、5、6、7、8、9或10。
术语“烷基”应理解为优选表示具有1～40个碳原子的直连或支链饱和一价烃基，优选为C 1-10烷基。“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“烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2～40个碳原子，优选“C 2-6烯基”。“C 2-6烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5或6个碳原子，特别是2或3个碳原子(“C 2-3烯基”)，应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁 -2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“环烷基”应理解为优选表示饱和或不饱和的的一价单环、双环烃环或桥环烷烃，其具有3～40个碳原子，优选“C 3-10环烷基”。术语“C 3-10环烷基”应理解为表示饱和的一价单环、双环烃环或桥环烷烃，其具有3、4、5、6、7、8、9或10个碳原子。所述C 3-10环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。
术语“杂环基”应理解为优选表示饱和或不饱和的的一价单环、双环烃环或桥环烷烃，其包含1-5个独立选自N、O和S的杂原子的总成环原子数为3-20(如原子数为3、4、5、6、7、8、9、10等)的非芳族环状基团，优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环、双环烃环或桥环烷烃，其包含1-5个，优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢恶唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。根据本发明，所述杂环基是无芳香性的。
术语“芳基”应理解为优选表示具有6～20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，优选“C 6-14芳基”。术语“C 6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C 6-14芳基”)，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C 13芳基”)，例如芴基，或者是具有14个碳原子的环(“C 14芳基”)，例如蒽基。当所述C 6-20芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。
术语“杂芳基”应理解为优选包括这样的一价单环、双环或三环芳族环系：其具有5～20个环原子且包含1-5个独立选自N、O和S的杂原子，例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3各独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、恶唑基、噻唑基、咪唑基、吡唑基、异恶唑基、异噻唑基、恶二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并恶唑基、苯并异恶唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩恶嗪基等。当所述5-20元杂芳基与其它基团相连构成本发明的化合物时，可以为5-20元杂芳基环上的碳原子与其它 基团相连，也可以为5-20元杂芳基环上的杂原子与其它基团相连。当所述5-20元杂芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为杂芳基环上与碳原子相连的氢被取代，或者杂芳基环上与杂原子相连的氢被取代。
除非另有说明，杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，可以包括在其1-、2-、3-、4-、5-、6-、7-、8-、9-、10-、11-、12-位等(如果存在)中的一个、两个或更多个位置上取代或与其他基团键合的形式，包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基；吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基。
上述的烷基、烯基、环烷基、杂环基、芳基、杂芳基可被以下基团取代：卤素、羟基、氨基(取代或未取代的氨基，例如-N(C 1-6烷基) 2、-NHC 1-6烷基)、硝基、氰基、羧基、叠氮基、烷基、烷氧基、环烷基、酰基、芳基、杂芳基。
术语“卤素”表示氟、氯、溴和碘。
除非另有说明，本文中术语的定义同样适用于包含该术语的基团，例如C 1-6烷基的定义也适用于C 1-6烷基氧基、-N(C 1-6烷基) 2、-NHC 1-6烷基或-S(O) 2-C 1-6烷基等。
本发明所述的“羟基保护基”意指在合成过程中引入的保护羟基的基团，目的是避免羟基在反应性条件下发生不期望的化学反应，并且该羟基保护基将在随后的合成步骤中除去，以使羟基恢复。示例性的羟基保护基包括但不限于下列基团：
取代或未取代的烷基，例如：甲基、叔丁基和其它C 1-C 6烷基；甲氧基甲基、甲硫基甲基、苄氧基甲基、叔丁氧基甲基、2-甲氧基乙氧基甲基、2,2,2-三氯乙氧基甲基、双(2-氯乙氧基)甲基和2-(三甲基甲硅烷基)乙氧基甲基；1-乙氧基乙基、1-甲基-1-甲氧基乙基、1-异丙氧基乙基、2,2,2-三氯乙基和2-甲氧基乙基；1-羟基烷基，如1-羟基乙基、1-羟基己基、1-羟基癸基、1-羟基十六烷基和1-羟基-1-苯基甲基；取代或未取代的芳基烷基，例如苄基、甲氧基苄基、2,6-二氯苄基、3-溴苄基、2-硝基苄基和三苯基甲基；取代或未取代的杂芳基烷基；取代或未取代的杂环基烷基；
取代或未取代的烯基，例如烯丙基；
取代或未取代的环烷基，例如环己基；
取代或未取代的芳基，例如苯基、2,4-二硝基苯基；
取代或未取代的杂芳基；
取代或未取代的杂环基；
取代或未取代的四氢吡喃基、取代或未取代的四氢呋喃基，和其它能够与羟基形成缩醛基或半缩醛基的基团；
取代或未取代的酰基，例如甲酰基、取代或未取代的烷基羰基，如甲基羰基、乙基羰基、丙基羰基、丁基羰基、异丁基羰基、戊基羰基、新戊基羰基、己基羰基、庚基羰基、辛基羰基、癸基羰基、壬基羰基、十二烷基羰基、十四烷基羰基、十六烷基羰基、十八烷基羰基和其它取代或未取代的烷基羰基；乙酰乙酰基；取代或未取代的环烷基羰基，如环戊基羰基、环己基羰基；取代或未取代的芳基酰基，如苯甲酰基、萘甲酰基；取代或未取代的氨基甲酰基，如氨基甲酰基、甲基氨基甲酰基和苯基氨基甲酰基；
取代或未取代的磺酰基，例如甲磺酰基、乙磺酰基、三氟甲磺酰基、苯磺酰基、对甲苯磺酰基和萘磺酰基；
取代或未取代的烷基氧基羰基，例如甲氧基羰基、乙氧基羰基、叔丁氧基羰基和其它C 1-C 6烷氧基羰基；
取代或未取代的芳基烷基氧基羰基，例如苄基氧基羰基和对甲氧基苄基氧基羰基；
由无机酸(例如硫酸、硝酸、磷酸和硼酸)通过除去OH基团得到的基团；
硫膦基，例如二烷基硫膦基(例如二甲基硫膦基)、二芳基硫膦基(例如二苯基硫膦基)；
硅烷基，其中烷基的定义同前。例如三烷基硅基(如三甲基硅基、三乙基硅基、三异丙基硅基)、叔丁基二苯基硅基、叔丁基二甲基硅基、三苄基硅基和三苯基硅基。
本发明的“羟基保护基”与之结合的氧原子可形成如下的具体实例：甲酸酯、苯甲酰甲酸酯、氯乙酸酯、三氟乙酸酯、甲氧基乙酸酯、三苯基甲氧基乙酸酯、对氯苯氧乙酸酯、3-苯基丙酸酯、4-氧代无酸酯、4,4-(亚乙基二硫代)戊酸酯、新戊酸酯(三甲基乙酰基)、巴豆酸酯、4-甲氧基巴豆酸酯、苯甲酸酯、对苄基苯甲酸酯、2,4,6-三甲基苯甲酸酯；或者是下述基团的碳酸酯：甲基、9-芴基甲基、乙基、2,2,2-三氯乙基、2-(三甲基甲硅烷基)乙基、2-(苯磺酰)乙基、乙烯基、丙烯基、对硝基苯基；下述的甲硅烷基醚：三甲基甲硅烷基醚、三乙基甲硅烷基醚、叔丁基二甲基甲硅烷基醚、叔丁基二苯基甲硅烷基醚、三异丙基甲硅烷基醚；家属的烷基醚：甲基醚、苄基醚、对甲氧基苄基醚、3,4-二甲氧基苄基醚、三苯甲基醚、叔丁基醚、烯丙基醚、烯丙氧羰基醚；下述的烷氧基烷基醚：甲氧基甲基醚、甲硫基甲基醚、(2-甲氧基乙氧基)甲基醚、苄氧基甲基醚、β-(三甲基甲硅烷基)乙氧基甲基醚、四氢吡喃基醚；如下的芳基烷基醚：苄基醚、2,6-二氯苄基醚、对氰基苄基醚、2-和4-吡啶甲基醚。
本发明所述的“邻二羟基保护基”意指在合成过程中引入的保护邻二羟基的基团，目的是避免邻二羟基在反应性条件下发生不期望的化学反应，并且该邻二羟基保护基将在随后的合成步骤中除去，以使邻二羟基恢复。所述二羟基保护基与其结合的氧形成环缩醛和缩酮；环亚甲硅基衍生物；环碳酸酯和环硼酸酯。缩醛指-CHR-；缩酮是指-CR 2-；环碳酸酯是指-OC(O)O-；环硼酸酯是指OBRO-；其中R为H，烷基、烯基、芳基、或芳烷基；示例性的邻二羟基保护基包括但不限于取代或未取代的下列基团例如亚烷基(如亚甲基、亚乙基、亚异丙基、苯基亚甲基、二苯基亚甲基、对甲氧基苯基亚甲基、2,4,6-三甲基苯基亚甲基)；亚环烷基(如亚环己基、亚环戊基)、二(C1-6烷基)亚硅烷基(如二叔丁基亚硅烷基、1,1,3,3-四异丙基硅氧烷基)、甲基硼酸酯、乙基硼酸酯、苯基硼酸酯、2,6-二乙酰氨基苯基硼酸酯。
除非另有说明，本发明中的溶剂优选为无水溶剂。
本发明的有益效果：本发明提供了可用于合成艾日布林或其类似物，特别是其C27-C35结构片段的中间体、其制备方法和用途。本发明合成路线的设计，改变了现有技术已有方法的原料和路线步骤，因其起始原料廉价易得，光学纯度可控，构建手性中心的步骤方法具有较高的非对映选择性和产率(尤其是式(X)、式(XI)、式(XVI)和式(XV)所示化合物的合成步骤)，从而保证了艾日布林或其类似物中C27-C35结构片段终产物的光学纯度，其杂质种类少，所有立体异构体杂质含量可控制在千分之一以下，满足原料药相关杂质控制指导原则的界限，减少了后续杂质研究和纯化的步骤；多步反应不需要柱层析纯化即可投入下一步，从而降低了纯化成本；部分反应只需简单后处理后，进行重结晶即可除去副产物以及部分异构体，使其纯度高于99.9％，不仅简化了纯化步骤，而且对终产物的光学纯度也有了保证，大大降低了杂质合成以及分离纯化的成本。
附图说明
图1为化合物16的HPLC谱图。
图2为化合物23的HPLC谱图。
具体实施方式
下文将结合具体实施例对本发明的制备方法做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法；下述实施例中所用的试剂、材料等，如无特殊说明，均可从商业途径得到。
实施例1 化合物9的合成
1.1化合物4的合成
Figure PCTCN2020082933-appb-000030
将脱氧核糖1(100g)溶于水(400mL)中，降温至5℃左右，经3h慢慢滴加液溴(200g)，滴毕升至30℃反应24h(点板检测原料消失)。后处理：1)加乙酸乙酯(100mL×2)提取，有机相在下层，第三次加乙酸乙酯(50mL)提取，有机相在上层；2)合并有机相，用水(50mL×2)提取其中所含产物；3)合并水相，用饱和硫代硫酸钠中和溴素(用量很少)，然后又降温至0℃，调节溶液的pH至3左右(固体NaOH用量约61g)，硅藻土过滤；4)滤液浓缩至含少量固体的粘稠液体时加异丙醇(200mL)，搅拌加热至80℃，趁热过滤，固体用异丙醇(100mL)洗，滤液浓缩，残留物加异丙醇(100mL)溶解，过滤，固体用异丙醇(40mL)洗，滤液浓缩，残留物加入丙酮(100mL)溶解，过滤，固体用丙酮(100mL×2)加热至80℃提取，合并滤液，蒸干得化合物2粗品为油状物(含少量固体)约95g。
将化合物2粗品(44g)溶于吡啶(200mL)中，加入三苯甲基氯(88g)，4-二甲氨基吡啶即DMAP(4.5g)，加热至50℃反应过夜。后处理：减压蒸除吡啶，加入二氯甲烷即DCM(500mL)，加入1N盐酸(300+200mL)分液，饱和碳酸氢钠(200mL)洗，每次水相用DCM(100mL)提取，合并有机相，干燥，过滤，浓缩直接下一步。
将化合物3的粗品溶于DCM(400mL)中，然后加入咪唑(29g)，DMAP(4.5g)，降温至0℃，慢慢滴加叔丁基二苯基氯硅烷(TBDPSCl，77mL)，滴毕升至室温反应2-6h。后处理：加水(300mL×2)，分液，每次用二氯甲烷(100mL)提取，合并有机相，干燥，浓缩，加甲醇(150mL×2)浓缩带两遍，最后加甲醇(300mL)，正己烷(100mL)，减压浓缩至200-300mL左右，搅拌降温至10℃左右溶液析出白色固体，过滤，固体用少量冷甲醇洗涤。取出固体，减压蒸除残留的溶剂可得产物化合物4约136g。 1H NMR(500MHz,CDCl 3)δ7.58–7.25(m,25H),4.41(d,J＝3.5Hz,1H),4.37(d,J＝6.4Hz,1H),3.32(dd,J＝10.6,3.2Hz,1H),2.88(dd,J＝17.8,6.6Hz,1H),2.70(dd,J＝10.7,3.0Hz,1H),2.55(dd,J＝17.8,1.8Hz,1H),1.07(s,9H).
1.2化合物7的合成
Figure PCTCN2020082933-appb-000031
将化合物4(286g)溶于二氯甲烷中，降温至-20℃，经1h慢慢滴加三氯化硼(1M的二氯甲烷溶液233mL)，滴毕继续反应0.5h。后处理：加无水甲醇(700mL)，搅拌十分钟，然后加入碳酸氢钠溶液调节pH至碱性，分液，水相用二氯甲烷(500mL×2)提取，干燥，过滤，浓缩。残留物溶于无水甲醇(350mL)中，搅拌十分钟，过滤，固体用少量甲醇洗(此步可除掉80％以上的TrOMe)，滤液浓缩，残留物用甲苯带两遍以除去残留的甲醇，最终的产物约190g。
将上一步粗品5溶于二氯甲烷(1500mL)中，加入樟脑磺酸(外消旋体，16g)，降温至水浴，然后慢慢滴加PMB的三氯亚胺酯(158g)，滴毕升至室温反应过夜。后处理：加饱和碳酸氢钠溶液，分液，水相二氯甲烷提取，有机相过滤除掉樟脑磺酸盐固体，用饱和氯化钠洗，干燥，过滤，浓缩，得化合物6粗品约313g。
将上一步得到的化合物6粗品溶于四氢呋喃(700mL)中，降温至冰浴，氩气保护，慢慢滴加硼烷二甲硫醚(10M，70mL)，滴毕升至室温反应十分钟，然后加热至55℃～60℃反应过夜。后处理：至冰浴中降温，慢慢滴加甲醇淬灭反应(至不产生气泡为止)，减压浓缩，残留物溶于乙酸乙酯中，饱和碳酸氢钠洗，乙酸乙酯提取，干燥，浓缩，残留物加甲醇蒸干，重复两次，柱层析得化合物7约156g，总收率68％。 1H NMR(500MHz,CDCl 3)δ7.72(t,J＝6.7Hz,4H),7.57–7.48(m,2H),7.43(t,J＝7.5Hz,4H),7.22(d,J＝8.2Hz,2H),6.91(d,J＝8.2Hz,2H),4.50–4.34(m,2H),3.96(dt,J＝7.8,4.5Hz,2H),3.87(s,3H),3.79(td,J＝7.1,3.5Hz,1H),3.55(td,J＝8.5,7.3,4.1Hz,2H),3.43(dd,J＝9.7,6.7Hz,1H),1.83(ddt,J＝11.3,7.8,3.9Hz,1H),1.76(q,J＝12.7,1H),1.10(s,9H)。
1.3化合物9的合成
Figure PCTCN2020082933-appb-000032
将化合物7(103.4g)溶于乙腈(1L)中，加入SM2(4.7g)，碳酸钾(37.5g)，碘化钾(38.2g)和溴苄(37.3mL)，加热至70℃～80℃反应3-5小时(点板检测原料消失或仅剩余很少且不再变化)。后处理：加水，乙酸乙酯提取2-3遍，干燥，浓缩，直接进行下一步反应。
将化合物8的粗品溶于四氢呋喃(314mL)中，加入四丁基氟化铵(TBAF，314mL)，25℃反应过夜。后处理：减压浓缩，残留物溶于水和乙酸乙酯中，分液，乙酸乙酯提取，干燥，浓缩，柱层析(石油醚：乙酸乙酯＝2:1-1:1)。最后得化合物9约62g，两步总收率约为86％。 1H NMR(400MHz,CDCl 3)δ7.44–7.21(m,7H),6.85(s,2H),4.50(s,2H),4.47(s,2H),3.82(m,1H),3.79(s,3H),3.76–3.64(m,3H),3.65–3.54(m,2H),1.89(m,1H),1.85–1.72(m,1H).
实施例2 化合物10的合成
Figure PCTCN2020082933-appb-000033
将化合物9(149.5g)溶于DCM(818mL)中，加入PPTs(5.4g)，滴加原乙酸三甲酯(82.4mL)，滴毕室温反应1h，蒸干溶剂得产物差向异构体混合物9a。以上所得化合物9a重新溶于DCM(818mL)中，滴加乙酰溴(47.9mL)，滴毕室温反应0.5h，蒸干溶剂得化合物9b-1与9b-2的混合物。上述化合物9b-1与9b-2混合物溶于无水甲醇(1500mL)中，加入碳酸钾(119g)，室温反应8h。后处理：加饱和氯化铵溶液，DCM提取，干燥，过滤，浓缩，硅胶柱层析得化合物10精制品123g，收率87％。 1H NMR(400MHz,CDCl 3)δ7.38–7.25(m,7H),6.87(d,J＝13.2Hz,2H),4.60–4.38(m,4H),3.79(s,3H),3.73–3.65(m,1H),3.62(d,J＝11.5Hz,2H),3.56–3.44(m,1H),3.25–3.17(m,1H),3.13(s,1H),2.00–1.66(m,2H).
实施例3 化合物11的合成
Figure PCTCN2020082933-appb-000034
氩气保护条件下，将三甲基硅基乙炔(15.5g)溶于300mL无水甲苯中，冷至-50℃，缓慢滴加64mL 2.5M n-BuLi的正己烷溶液，滴毕，搅拌反应30min后，滴加化合物10的甲苯溶液(26g化合物10溶于100mL甲苯)，滴毕，缓慢滴加BF 3Et 2O(22.6g)，保持温度不高于-30℃，滴毕反应3h后，TLC检测反应完全。加入300mL饱和氯化铵处理反应，分液，水相用乙酸乙酯萃取两次(200mL×2)，合并有机相，饱和氯化钠洗涤(300mL×2)，无水硫酸钠干燥，滤去干燥剂，浓缩，得到粗品44g，硅胶柱层析分离。柱层析结果如下：化合物11有22g，收率65％，下式11’所示的区域异构体10g。
Figure PCTCN2020082933-appb-000035
化合物11  1H NMR(500MHz,CDCl 3)δ7.38–7.15(m,7H),6.87(d,J＝6.8Hz,2H),4.56–4.45(m,4H),4.00(tt,J＝6.3,3.2Hz,1H),3.80(d,J＝2.3Hz,3H),3.75–3.57(m,4H),2.81(tt,J＝5.0,2.8Hz,1H),2.61(d,J＝6.5Hz,1H),1.95(h,J＝6.5Hz,1H),1.89–1.80(m,1H),0.15(d,J＝2.4Hz,9H).HPLC显示化合物11中11’的含量≤0.1％；化合物11的其他差向异构体含量≤0.1％。
实施例4 化合物16的合成
4.1化合物13的合成
Figure PCTCN2020082933-appb-000036
冰水浴条件下，将化合物11(21g)溶于无水二氯甲烷(160mL)中，加入6.8g 2,6-二甲基吡啶后，滴加TBSOTf(叔丁基二甲硅基三氟甲磺酸酯，15.6g)，滴毕，升至室温反应1h后，TLC检测反应完全。加入饱和氯化铵(200mL)水溶液淬灭反应，分液，水相用二氯甲烷萃取(200mL×2)，合并有机相，用1N盐酸洗掉2,6-二甲基吡啶，再用饱和氯化钠洗(200mL×2)，无水硫酸钠干燥，过滤，滤液浓缩，得到粗品25.7g棕黄色油状物(化合物12)。将上述化合物12粗品溶于200mL无水甲醇中，加入碳酸钾粉末(13.5g)，室温反应过夜，TLC检测反应完全，加入200mL乙酸乙酯稀释反应液，硅藻土助滤滤去固体，固体用乙酸乙酯洗涤至无产物残留，浓缩滤液，得到棕黄色粘稠物，加入200mL乙酸乙酯充分搅拌溶解，硅藻土助滤，滤饼用乙酸乙酯洗至无产物残留，浓缩滤液，得到棕黄色油状物粗品30g，硅胶柱层析分离，得到无色油状物化合物13约20.7g，两步收率90％。化合物13  1H NMR(400MHz,CDCl 3)δ7.30–7.22(m,3H),7.24–7.13(m,4H),6.85–6.72(m,2H),4.77(s,1H),4.50–4.24(m,4H),4.13–3.80(m,1H),3.64–3.39(m,3H),2.84–2.65(m,1H),2.07–1.97(m,1H),1.90(dt,J＝12.7,6.1Hz,1H),1.72(dd,J＝13.8,7.0Hz,1H),0.81(s,9H),-0.01(s,6H).
4.2化合物15的合成
Figure PCTCN2020082933-appb-000037
氩气保护条件下，将化合物13(10.8g)溶于100mL无水甲苯中，降至-78℃，滴加2.5N正丁基锂的正己烷溶液(11mL)，滴毕，反应30min后，将5.64g化合物14(市售商品，光学纯度>99％)溶于50mL甲苯后滴加至反应体系中，滴毕，缓慢滴加BF 3Et 2O(4.0g)，滴毕，保持此温度下继续反应2h后，TLC检测，反应完全。加入饱和氯化铵150mL淬灭反应，分液，水相用乙酸乙酯萃取(150mL×2)，合并有机相，饱和氯化钠洗(150mL×2)，无水硫酸钠干燥，过滤，滤液浓缩，得到油状物粗品17.8g，硅胶柱层析分离，得到化合物15约14.5g，收率96％.化合物15  1H NMR(500MHz,CDCl 3)δ7.42–7.24(m,7H),6.90(d,J＝8.0Hz,2H),4.60–4.40(m,4H),4.07(d,J＝7.3Hz,1H),3.90–3.74(m,5H),3.75–3.59(m,2H),3.53(q,J＝6.1,5.1Hz,3H),2.79(d,J＝6.8Hz,1H),2.45(d,J＝6.0Hz,1H),2.13–1.97(m,1H),1.88–1.71(m,2H),1.42–1.22(m,2H),1.02–0.84(m,18H),0.10(s,6H),0.07(s,6H).
4.3化合物16的合成
Figure PCTCN2020082933-appb-000038
室温条件下，将化合物15(46g)溶于500mL无水甲醇中，加入3N的HCl/MeOH溶液13mL，室温反应过夜，TLC检测反应完全，加入8mL氨水(25-28％)，搅拌淬灭反应，加入无水硫酸钠干燥，除掉水，过滤，残渣用乙酸乙酯洗涤，滤液浓缩得到淡黄色油状物34.2g，用乙酸乙酯/正己烷重结晶，得到白色晶体26g，TLC检测为单一产物。此白色晶体进行二次重结晶，得到化合物16为白色晶体25.2g，收率83.3％，光学纯度>99.9％，HPLC谱图如图1所示。化合物16  1H NMR(500MHz,甲醇-d 4)δ7.35–7.24(m,7H),6.90(dd,J＝8.6,2.9Hz,2H),4.66–4.32(m,4H),3.99(dd,J＝8.1,4.3Hz,1H),3.80(s,3H),3.74–3.34(m,7H),2.74(s,1H),2.56–2.24(m,2H),1.91(td,J＝7.9,6.9,3.1Hz,2H).
实施例5 化合物20的合成
5.1化合物17的合成
Figure PCTCN2020082933-appb-000039
将化合物16(24.2g)于70mL乙腈中，加入25mL戊酮和9.8mL原甲酸三甲酯，最后加入270m g三氟甲磺酸钪，室温反应1h后，TLC检测反应完全，向反应液中加入三乙胺淬灭反应，蒸去溶剂，得到粗品29.4g，柱层析分离，得到化合物17 26.6g，收率95％。 1H NMR(500MHz,CDCl 3)δ7.50–7.08(m,7H),6.87(d,J＝8.2Hz,2H),4.60–4.33(m,4H),4.19(t,J＝6.4Hz,1H),4.08(t,J＝7.1Hz,1H),4.04–3.92(m,1H),3.80(s,3H),3.76–3.43(m,5H),2.87–2.64(m,2H),2.56(dd,J＝16.4,4.7Hz,1H),2.42(dd,J＝16.5,7.6Hz,1H),1.93(dd,J＝14.9,7.9Hz,1H),1.79(dq,J＝9.6,4.7Hz,1H),1.63(dq,J＝22.5,7.9,7.4Hz,4H),0.89(q,J＝7.0Hz,6H)
5.2化合物18的合成
Figure PCTCN2020082933-appb-000040
将23.8g化合物17溶于150mL无水甲醇中，加入Lindlar催化剂2.4g，常压氢化反应，TLC监测反应进程，至原料反应完全，滤去催化剂，浓缩滤液，得到化合物18粗品23.6g，未经进一步纯化，直接投入下一步。 1H NMR(500MHz,CDCl 3)δ7.35-7.23(m,7H),6.86(d,J＝8.2Hz,2H),5.61-5.55(m,2H),4.51(s,2H),4.44(t,J＝12.3Hz,2H),4.10-4.05(m,1H),4.03-3.99(m,2H),3.80(s,3H),3.70-3.61(m,2H),3.57(t,J＝8.0Hz,1H),3.49-3.43(m,2H),3.06(s,1H),2.70(s,1H),2.40(dt,J＝12.6,5.7Hz,1H),2.27(dt,J＝14.1,5.9Hz,1H),1.83-1.74(m,1H),1.62(dt,J＝15.6,7.9Hz,4H),0.89(q,J＝7.7Hz,6H).
5.3化合物19的合成
Figure PCTCN2020082933-appb-000041
冰水浴条件下，将化合物18(8.3g)溶于50mL吡啶中，缓慢加入2.58g BzCl(苯甲酰氯)，最后加入200mgDMAP，升至室温反应，3h后，TLC检测反应完全，用100mL乙酸乙酯稀释反应液，加入100mL水淬灭反应，分液，水相用乙酸乙酯萃取(100mL×2)，合并有机相，先用水洗(200mL×2)，再用1N稀盐酸洗至中性，用饱和碳酸氢钠洗去残留HCl，最后用饱和氯化钠洗，无水硫酸钠干燥，过滤，浓缩滤液，得到粗品17g，柱层析分离，得到化合物19约10.1g，收率99％。 1H NMR(400MHz,CDCl 3)δ8.02–7.95(m,2H),7.58-7.54(m,1H),7.44–7.41(m,2H),7.28-7.26(m,5H),7.20(d,J＝9.4Hz,2H),6.78(d,J＝8.0Hz,2H),5.68–5.56(m,3H),4.43(d,J＝2.9Hz,3H),4.36(d,J＝2.8Hz,2H),4.09–4.02(m,1H),3.97–3.93(m,1H),3.75(s,3H),3.53–3.50(m,2H),3.49–3.42(m,2H),3.33(dd,J＝9.3,6.3Hz,1H),3.03–2.97(m,1H),2.44–2.28(m,2H),2.07–1.99(m,2H),1.96-1.88(m,1H),1.66–1.57(m,4H),0.89(dd,J＝14.7,7.2Hz,6H).
5.4化合物20的合成
Figure PCTCN2020082933-appb-000042
室温条件下，将化合物19(10g)溶于叔丁醇/水(20mL/20mL)的混合溶剂中，加入NMO(5.9g)，最后加入四氧化锇的0.05M甲苯溶液(11mL)，加热至45℃搅拌反应24h后，TLC检测反应基本完全，加入饱和亚硫酸钠(50mL)搅拌淬灭反应，用乙酸乙酯(100mL×3)萃取反应液，合并有机相，水洗(200mL×2)，饱和氯化钠洗(200mL×2)，无水硫酸钠干燥，过滤，滤液浓缩，得到粗品11g，硅胶柱层析分离，得到化合物20约9.8g，收率92％。 1H NMR(400MHz,CDCl 3)δ7.98(dt,J＝8.4,1.6Hz,2H),7.55(tt,J＝7.0,1.3Hz,1H),7.46–7.39(m,2H),7.30–7.14(m,7H),6.82(dq,J＝8.7,2.2,1.6Hz,2H),5.51(ddd,J＝8.9,7.4,3.1Hz,1H),4.51–4.35(m,4H),4.35–4.24(m,1H),4.04(dd,J＝8.0,6.0Hz,1H),3.89–3.64(m,7H),3.62–3.51(m,2H),3.47(td,J＝8.1,5.0Hz,1H),3.30(t,J＝5.5Hz,2H),2.41(tt,J＝5.4,2.3Hz,1H),2.21(dtd,J＝14.5,7.2,3.2Hz,1H),2.13–1.91(m,2H),1.74(ddd,J＝14.2,7.6,4.5Hz,1H),1.57(dq,J＝15.1,7.5Hz,4H),0.84(dt,J＝9.8,7.5Hz,6H).
5.5化合物20的合成
Figure PCTCN2020082933-appb-000043
室温条件下，将化合物19(90mg)溶于叔丁醇/水(1mL/1mL)的混合溶剂中，加入DABCO(17mg)和NMO(53mg)，最后加入四氧化锇的0.05M甲苯溶液(0.15mL)，搅拌反应24h后，TLC检测反应基本完全，加入饱和亚硫酸钠(5mL)搅拌淬灭反应，用乙酸乙酯(10mL×3)萃取反应液，合并有机相，水洗(10mL×2)，饱和氯化钠洗(10mL×2)，无水硫酸钠干燥，过滤，滤液浓缩，得到粗品110mg，硅胶柱层析分离，得到化合物20 67mg，收率70％。
5.6化合物20-Ac的合成
Figure PCTCN2020082933-appb-000044
室温条件下，将化合物19-Ac(55g)溶于叔丁醇/水(425mL/425mL)的混合溶剂中，降至0℃，加入NMO(36g)，最后加入四氧化锇的0.05M甲苯溶液(100mL)，升至室温搅拌反应24h后，TLC检测反应有部分原料剩余，处理，加入饱和亚硫酸钠(500mL)搅拌淬灭反应，用乙酸乙酯(500mL×3)萃取反应液，合并有机相，水洗(500mL×2)，饱和氯化钠洗(500mL×2)，无水硫酸钠干燥，过滤，滤液浓缩，得到粗品65g，硅胶柱层析分离，回收原料化合物19-Ac 14.8g，得到化合物20-Ac约38.2g，收率89.6％,纯度85％(其中异构体以化合物20-Ac’为主)。 1H NMR(400MHz,Chloroform-d)δ7.35-7.27(m,5H),7.21(d,J＝8.2Hz,2H),6.86(d,J＝8.2Hz,2H),5.32–5.20(m,1H),4.48-4.40(m,4H),4.34-4.30(m,1H),4.10-4.05(m,1H),3.80(s,3H),3.73(td,J＝9.9,4.7Hz,2H),3.69–3.58(m,2H),3.55–3.38(m,4H),3.18(s,2H),2.31–2.20(m,1H),2.08-2.00(m,1H),1.98(s,3H),1.90-1.82(m,1H),1.78-1.72(m,1H),1.67-1.60(m,5H),0.90(t,J＝7.4Hz,6H).
Figure PCTCN2020082933-appb-000045
实施例6 化合物23的合成
6.1化合物22的合成
Figure PCTCN2020082933-appb-000046
冰水浴条件下，将化合物20(32g)溶于无水二氯甲烷(160mL)中，加入三乙胺(36.5mL)和DMAP(640mg)，滴加MsCl(19.5mL)，滴毕升至室温反应1h后，TLC检测反应完全，加入饱和氯化铵(200mL)淬灭反应，分液，水相用二氯甲烷(200mL×2)萃取，合并有机相，水洗(250mL×2)，饱和氯化钠洗(250mL×2)，无水硫酸钠干燥，浓缩，得到棕红色油状物粗品化合物21约39.4g(理论产量39.8g)。未经进一步纯化直接投入下一步。将化合物21粗品(39.4g)溶于无水甲醇(300mL)中，加入无水碳酸钾粉末(19g)，搅拌过夜反应，TLC检测反应完全，减压浓缩蒸去溶剂，加入水300mL，用二氯甲烷萃取(300mL×2)，合并有机相，饱和氯化钠洗(300mL×2)，无水硫酸钠干燥，过滤，滤液浓缩，得到粗品33g，硅胶柱层析分离，得到化合物22约27g，两步总收率90％。化合物22  1H NMR(500MHz,CDCl 3)δ7.38–7.17(m,7H),6.86(d,J＝8.0Hz,2H),5.03(s,1H),4.53–4.36(m,4H),4.24(h,J＝6.5Hz,1H),4.06(t,J＝6.9Hz,1H),3.89(q,J＝5.9,5.5Hz,1H),3.80(s,3H),3.67(q,J＝6.6Hz,1H),3.62–3.51(m,4H),3.37(t,J＝8.6Hz,1H),2.96(s,3H),2.40(q,J＝6.6Hz,1H),2.04(dt,J＝14.0,6.8Hz,1H),1.96 (dq,J＝12.4,6.3,5.5Hz,3H),1.62(p,J＝7.7Hz,4H),0.89(t,J＝7.5Hz,6H).
6.2化合物23的合成
Figure PCTCN2020082933-appb-000047
冰水浴条件下，将化合物22(7.8g)溶于无水四氢呋喃(80mL)中，滴加3M甲基溴化镁的四氢呋喃溶液(13.5mL)，滴毕，升至室温反应过夜，TLC检测反应完全，滴加饱和氯化铵(100mL)淬灭反应，乙酸乙酯萃取(100mL×3)，合并有机相，饱和氯化钠洗(200mL×2)，无水硫酸钠干燥，过滤，滤液浓缩，得到无色油状物粗品8g，硅胶柱层析分离，得到5.8g化合物23，收率86％；同时得到0.2g化合物23’。化合物23的纯度>99.9％，HPLC谱图如图2所示，下式所示的杂质23’含量0.09％：
Figure PCTCN2020082933-appb-000048
1H NMR(500MHz,CDCl 3)δ7.35-7.28(m,5H),7.22(d,J＝8.1Hz,2H),6.85(d,J＝8.0Hz,2H),4.49(s,2H),4.43(s,2H),4.32-4.27(m,1H),4.08–4.04(m,2H),3.86(q,J＝5.9Hz,1H),3.79(s,3H),3.72–3.63(m,2H),3.58(dt,J＝21.2,7.5Hz,2H),3.47(d,J＝6.3Hz,2H),2.13(dd,J＝7.1,3.9Hz,1H),2.10–1.97(m,3H),1.93(dt,J＝19.8,6.3Hz,2H),1.63(dq,J＝14.9,7.4Hz,4H),0.89(q,J＝7.3Hz,6H).
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种式(Ⅸ)所示化合物：
    Figure PCTCN2020082933-appb-100001
    其中，PG 1、PG 2相同或不同，彼此独立地选自羟基保护基；其手性中心绝对构型为(2R,3S)；
    优选地，所述羟基保护基选自取代或未取代的下列基团：烷基、烯基、环烷基、芳基、杂芳基、杂环基、酰基、磺酰基、烷基氧基羰基、芳基烷基氧基羰基、由无机酸通过除去OH基团得到的基团、硫膦基、硅烷基。
  2. 权利要求1所述式(Ⅸ)化合物的制备方法，包括如下步骤：以D-2-脱氧核糖(I)为原料，经氧化、羟基保护、还原开环、脱除羟基保护等多步反应，得到式(Ⅸ)化合物；
    优选地，式(Ⅸ)化合物可以D-2-脱氧核糖(I)为原料通过下列路线制备：
    Figure PCTCN2020082933-appb-100002
    其中，PG 1、PG 2具有权利要求1所述的定义；PG 3独立地选自权利要求1所述的羟基保护基；每一个X相同或不同，独立地选自卤素；所述的碱选自有机碱或无机碱，例如选自下列中的一种、两种或更多种：碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、烷基锂、甲醇钠、乙醇钠、甲胺、乙胺、丙胺、异丙胺、二甲胺、二乙胺、二异丙胺、三乙胺。
  3. 式(X)化合物的制备方法，包括如下步骤：
    (1)权利要求1所述的式(Ⅸ)化合物与
    Figure PCTCN2020082933-appb-100003
    反应，得到式(Ⅸa)化合物；
    (2)式(Ⅸa)化合物与酰卤
    Figure PCTCN2020082933-appb-100004
    或卤代硅烷R 3 3SiX反应，得到式(Ⅸb-1)化合物和/或式(Ⅸb-2)化合物；
    (3)式(Ⅸb-1)化合物和/或式(Ⅸb-2)化合物反应，得到式(X)化合物；
    其中，PG 1、PG 2和每一个X独立地具有权利要求1或2所述的定义；R 1、R 2、R 3相同或不同，彼此独立地选自H、烷基或芳基；R 6选自烷基：
    Figure PCTCN2020082933-appb-100005
  4. 根据权利要求3所述的制备方法，其特征在于：
    步骤(1)中，所述反应可在催化剂，优选酸性催化剂的存在下进行，所述酸性催化剂选自适用于酯交换的酸性催化剂，例如选自吡啶对甲苯磺酸盐(PPTs)或质子酸(如硫酸、磷酸、氯化氢)中的一种、两种或更多种；所述
    Figure PCTCN2020082933-appb-100006
    选自原酸酯类化合物，例如原甲酸三甲酯、原甲酸三乙酯、原乙酸三甲酯、原乙酸三乙酯、原苯甲酸三甲酯、原苯甲酸三乙酯中的任一种；所述式(IX)化合物与所述
    Figure PCTCN2020082933-appb-100007
    的摩尔比为1:(1～5)；当所述催化剂存在时，所述式(IX)化合物与所述催化剂的摩尔比为1:(0.01～0.2)；
    步骤(2)中，所述式(IXa)化合物与所述
    Figure PCTCN2020082933-appb-100008
    或卤代硅烷R 3 3SiX的摩尔比为1:(1～5)；
    步骤(3)中，反应在碱的存在下进行，所述式(Ⅸb-1)化合物和/或式(Ⅸb-2)化合物与所述碱的摩尔比为1:(1～10)；
    步骤(3)在溶剂中进行，所述溶剂例如为醇类溶剂(如甲醇、乙醇、异丙醇、乙二醇)、水或其混合物；例如，所述式(IX)化合物与所述溶剂的重量体积比为1g:(1～20)mL。
  5. 下式(XI)、(XII)、(XIII)、(XIV)、(XV)或(XVI)所示的化合物：
    Figure PCTCN2020082933-appb-100009
    其中，PG 1、PG 2具有权利要求1所述定义；R 7为氢或端炔基保护基，所述保护基选自硅烷基，例如三烷基硅基(如三甲基硅基、三乙基硅基、三异丙基硅基)、叔丁基二苯基硅基、叔丁基二甲基硅基、三苄基硅基和三苯基硅基；PG 4、PG 5相同或不同，彼此独立地选自权利要求1所述的羟基保护基；
    条件是所述PG 4和所述PG 5中的任一个与所述PG 1或所述PG 2均不相同，且所述PG 1和所述PG 2在脱除所述PG 4和所述PG 5的条件下不发生反应；
    优选地，所述PG 4、所述PG 5相同或不同，彼此独立地选自硅烷基；例如，所述PG 4、所述PG 5相同或不同， 彼此独立地选自三烷基硅基(如三甲基硅基、三乙基硅基、三异丙基硅基)、叔丁基二苯基硅基、叔丁基二甲基硅基、三苄基硅基和三苯基硅基，而所述PG 1和所述PG 2相同或不同，彼此独立地选自除硅烷基以外的羟基保护基，例如烷基、烯基、环烷基、芳基、杂芳基、杂环基、四氢吡喃基、酰基、磺酰基、烷基氧基羰基、芳基烷基氧基羰基、由无机酸通过除去OH基团得到的基团、硫膦基。
  6. 下式(XIX)所示化合物：
    Figure PCTCN2020082933-appb-100010
    其中，PG 1、PG 2具有权利要求1所述定义；PG 6独立地选自取代或未取代的芳香酰基，如取代或未取代的苯甲酰基、萘甲酰基；PG 7为邻二羟基保护基；
    所述邻二羟基保护基与其结合的氧形成：环缩醛和缩酮；环亚甲硅基衍生物；环碳酸酯和环硼酸酯；缩醛指-CHR-；缩酮是指-CR 2-；环碳酸酯是指-OC(O)O-；环硼酸酯是指OBRO-；其中R为H，烷基、烯基、芳基、或芳烷基；例如可以为取代或未取代的亚甲基、亚乙基、亚异丙基、亚环己基、亚环戊基、苯基亚甲基、二苯基亚甲基、对甲氧基苯基亚甲基、2,4,6-三甲基苯基亚甲基、二叔丁基亚硅烷基、1,1,3,3-四异丙基硅氧烷基、环碳酸酯、甲基硼酸酯、乙基硼酸酯、苯基硼酸酯、2,6-二乙酰氨基苯基硼酸酯。
  7. 式(XX)化合物的制备方法，包括将权利要求6所述式(XIX)化合物在氧化剂的作用下进行双羟化氧化反应，得到式(XX)化合物：
    Figure PCTCN2020082933-appb-100011
    其中，PG 1、PG 2、PG 6、PG 7具有权利要求6所述定义；所述氧化剂选自高锰酸钾、高碘酸钠、过氧化氢、铁氰化钾、N-甲基-N-氧化吗啉(NMO)中的一种或多种；所述反应中可根据需要加入共氧化剂，所述共氧化剂为四氧化锇、锇酸钾中的任一种；所述反应在碱的催化作用下进行，所述碱为1,4-二氮杂二环[2.2.2]辛烷(DABCO)、三乙胺、N,N-二异丙基乙胺中的一种或多种；所述式(XIX)化合物与氧化剂的摩尔比为1:(1～5)，优选为1:(1～3)；所述式(XIX)化合物与所述共氧化剂的摩尔比为1:(0.005～0.15)，优选为1:(0.005～0.1)；所述式(XIX)化合物与所述碱的摩尔比为1:(0.4～2)，优选为1:(0.5～1.5)；所述反应在混合溶剂下进行，所述混合溶剂为有机溶剂与水的混合物，例如选自下列体系中的一种：叔丁醇/水、丙酮/水、乙腈/水；所述混合溶剂中，有机溶剂与水的体积比为(1:5)～(5:1)，例如(2～2.5):(2.5～2)；
    所述式(XIX)化合物的重量与混合溶剂总体积的比为1g:(2～50mL)，例如1g:4mL，1g:22.2mL；
    所述反应温度为-10℃～50℃，例如可以为35℃～45℃；反应时间为10～60h，例如可以为24h。
  8. 式(XXIII)化合物的制备方法，包括权利要求2、3、4、7所述的式(Ⅸ)、式(X)、式(XX)化合物的制备方法中的一种、两种或更多种：
    Figure PCTCN2020082933-appb-100012
    其中，PG 1、PG 2、PG 7具有权利要求7所述的定义；
    优选地，所述式(XXIII)化合物的制备方法还包括柱层析分离得到的产品；
    优选地，所述式(XXIII)化合物的制备方法中，所述柱层析分离后得到的产品中，下式所示化合物(XXIIIa)的含量≤0.1％，
    Figure PCTCN2020082933-appb-100013
    其中，PG 1、PG 2、PG 7具有权利要求7所述的定义。
  9. 一种制备艾日布林、其类似物或它们的C27-C35部分的方法，包括使用权利要求1、5、6任一项所述式(I)至(XXIII)中的任一化合物，和/或使用权利要求2、3、4、7、8任一项所述的一种或多种制备方法。
  10. 权利要求1、5、6任一项所述式(I)至(XXIII)中的任一种化合物在艾日布林、其类似物或它们的C27-C35部分中的用途。
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