WO2022143715A1 - 氧杂螺环取代的吡咯并吡唑衍生物及其中间体和制备方法 - Google Patents

氧杂螺环取代的吡咯并吡唑衍生物及其中间体和制备方法 Download PDF

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WO2022143715A1
WO2022143715A1 PCT/CN2021/142283 CN2021142283W WO2022143715A1 WO 2022143715 A1 WO2022143715 A1 WO 2022143715A1 CN 2021142283 W CN2021142283 W CN 2021142283W WO 2022143715 A1 WO2022143715 A1 WO 2022143715A1
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alkyl
formula
compound represented
stereoisomer
compound
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PCT/CN2021/142283
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English (en)
French (fr)
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曾振亚
阚超
高清富
冯一骁
吴波
张兴松
马有红
孙科军
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to JP2023540120A priority Critical patent/JP2024501554A/ja
Priority to EP21914449.0A priority patent/EP4265604A1/en
Priority to US18/259,743 priority patent/US20240109895A1/en
Priority to CN202180071002.8A priority patent/CN116368138A/zh
Publication of WO2022143715A1 publication Critical patent/WO2022143715A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of organic chemical synthesis, in particular to oxaspiro-substituted pyrrolopyrazole derivatives, intermediates and preparation methods thereof.
  • Opioid receptors are an important class of G protein-coupled receptors (GPCRs), which are targets for the binding of endogenous opioid peptides and opioids. Endogenous opioid peptides are naturally produced in mammals. Opioid active substances, currently known endogenous opioid peptides are roughly divided into enkephalins, endorphins, dynorphins and neoorphins. There are corresponding opioid receptors in the central nervous system, namely ⁇ (MOR), ⁇ (DOR), ⁇ (KOR) receptors and so on. Studies have found that the strength of the analgesic effect of endogenous opioid peptides mainly depends on the expression of opioid receptors, and opioid receptors are the targets of opioid drugs and endogenous opioid peptides for analgesia.
  • GPCRs G protein-coupled receptors
  • MOR agonists have different structures and disclosed the preparation methods of these compounds, including WO2017106547, WO2017063509, WO2012129495, WO2017106306 and so on.
  • the development of efficient, low-cost, easy-to-scale, and reproducible synthetic processes for new MOR agonists with better activity and selectivity is of great significance to the pharmaceutical field and industrial production.
  • the purpose of the present invention is to further develop an intermediate suitable for industrial production and a process preparation method thereof on the basis of the developed novel MOR agonist.
  • the preparation method has the characteristics of high efficiency, low cost, easy amplification, and good repeatability.
  • a first aspect of the present invention provides a compound represented by formula C, or a stereoisomer thereof:
  • R is C 1-8 alkyl (preferably C 1-4 alkyl), -C 1-4 alkyl-C 6-10 aryl (preferably -CH 2 -aryl, more preferably benzyl), C 6-10 aryl (preferably phenyl);
  • a ring is a C 6-10 aromatic ring (preferably a benzene ring) or a 5- to 6-membered monocyclic heteroaryl ring (preferably a pyridine ring);
  • R 0 is that the hydrogen on the A ring is substituted by n R 0 , and n is 0, 1, 2, 3 or 4; each R 0 is the same or different, and each is independently hydrogen, cyano, acetyl , hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, halogenated C 1-8 alkyl (preferably halogenated C 1-4 alkyl), halogen (preferably F or Cl), nitro, C 6-10 Aryl (preferably phenyl), 5- to 6-membered monocyclic heteroaryl, C 1-8 alkyl (preferably C 1-4 alkyl), C 1-8 alkoxy (preferably C 1-4 alkane) oxy), C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, NR 11 R 12 , -CONR 11 R 12 , -C(O ) OC 1-8 alkyl (preferably -C(O)OC 1-4
  • R 11 and R 12 are each independently hydrogen, C 1-8 alkyl (preferably C 1-4 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-4 alkyl), C 3-6 cycloalkyl or 4- to 6-membered saturated mono-heterocycle; or R 11 , R 12 and the connected nitrogen atom together form a 4- to 6-membered saturated mono-heterocycle; wherein the 4- to 6-membered saturated mono-heterocycle is Unsubstituted or substituted with 1, 2 or 3 C 1-4 alkyl.
  • R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, phenyl or benzyl, preferably methyl.
  • A is a benzene ring, a pyridine ring, a pyrimidine ring, or a triazine ring.
  • n is zero.
  • the compound of formula C is a compound of formula C:
  • R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl or benzyl (preferably methyl).
  • the compound shown in formula C is a compound of formula C3:
  • R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl or benzyl (preferably methyl).
  • the second aspect of the present invention provides the preparation method of the compound represented by formula C or its stereoisomer described in the first aspect, comprising the following steps:
  • step S200 the compound represented by formula E or its stereoisomer is reacted in one or more steps to prepare the compound represented by formula C or its stereoisomer; further, in step S200, the compound represented by formula E or its stereoisomer The isomer is subjected to alcoholysis reaction to prepare the compound represented by formula C or its stereoisomer.
  • step S200 a compound represented by formula E or a stereoisomer thereof is subjected to a one-step reaction to prepare a compound represented by formula C or a stereoisomer thereof.
  • step S200 includes the following steps:
  • the alcohol ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, phenol or benzyl alcohol; further, the alcohol is methanol or ethanol .
  • the acid is an inorganic acid or an organic acid; further, the acid is hydrochloric acid or p-toluenesulfonic acid.
  • step S211 the step of separation and purification includes the following steps:
  • the reaction solution is added to an organic solvent for extraction, and spin-dried to obtain the compound represented by formula C or its stereoisomer.
  • the organic solvent is methyl tert-butyl ether.
  • step S200 the compound represented by formula E or its stereoisomer is subjected to a two-step reaction to prepare the compound represented by formula C or its stereoisomer:
  • step S200 includes the following steps:
  • step S221 includes the following steps:
  • the compound represented by formula E or its stereoisomer, water and acid are mixed, and the reaction is carried out at a temperature of 30°C-60°C (preferably 45°C-50°C). After the reaction is completed, separation and purification are carried out to obtain formula The compound shown in D or its stereoisomer.
  • the acid in step S221, is an inorganic acid; further, the acid is sulfuric acid.
  • the concentration of the acid is 30 g/mL-60 g/mL.
  • step S221 the compound represented by formula E or its stereoisomer is mixed with water, cooled to 10°C-15°C, and then sulfuric acid is slowly added dropwise. After the dropwise addition, the temperature is 30°C.
  • Carry out the reaction (preferably 40min-80min) under the condition of -60°C (preferably 45°C-50°C), after the reaction is completed, cool down to 5°C-10°C, add an organic solvent (preferably toluene) and an alkaline solution (preferably a mass The percentage content is 10%-30% sodium hydroxide or potassium hydroxide solution), stirring for a predetermined time (preferably 40min-80min). Standing, extracting, washing and drying to obtain the compound represented by formula D or its stereoisomer.
  • step S222 includes the following steps:
  • the compound represented by formula D or its stereoisomer and alcohol are reacted under the catalyzed condition of acid (such as thionyl chloride), and after the reaction is complete, post-treatment and drying are performed to obtain the compound represented by formula C or its stereoisomers.
  • acid such as thionyl chloride
  • the stereoisomer of the compound represented by the formula C is the compound represented by the formula C1
  • the stereoisomer of the compound represented by the formula E is the compound represented by the formula E1
  • the reaction scheme is as follows:
  • the compound represented by the formula E1 is reacted in one or more steps to prepare the compound represented by the formula C1.
  • the compound represented by formula C is the compound represented by formula C2
  • the compound represented by formula E is the compound represented by formula E2
  • the reaction scheme is as follows:
  • the compound represented by formula E2 or its stereoisomer is reacted in one or two steps or more to prepare a stereoisomer of the compound represented by formula C2.
  • the stereoisomer of the compound represented by the formula C is the compound represented by the formula C3
  • the stereoisomer of the compound represented by the formula E is the compound represented by the formula E3
  • the reaction scheme is as follows:
  • the compound represented by the formula E3 is reacted in one or more steps to prepare the compound represented by the formula C3.
  • the compound represented by the formula E or its stereoisomer is used as the reaction raw material, and the compound represented by the formula C or its stereoisomer is generated through the selection of a reasonable reaction route. It is simple, and a product with higher purity can be obtained only by simple purification treatment, and the target purity can be obtained without column separation, which can greatly reduce the production difficulty and production cost, and is more conducive to industrial production.
  • a third aspect of the present invention provides a compound of formula B or a stereoisomer thereof:
  • a ring and (R 0 ) n are as described in the first aspect.
  • the compound represented by the formula B is the compound of formula B2:
  • the compound represented by the formula B is the compound of formula B3:
  • the fourth aspect of the present invention provides the preparation method of the compound represented by the formula B or its stereoisomer described in the third aspect, comprising the following steps:
  • a reduction reaction is performed in step S400. Further, in step S400, a red aluminum toluene solution is used for reduction reaction.
  • step S400 includes the following steps:
  • step S410 after preparing the compound represented by formula B, it also includes the step of performing chiral resolution to obtain the compound represented by formula B1;
  • the method of chiral resolution is instrumental resolution or chemical resolution.
  • the resolving reagent for chiral resolution is D-tartaric acid, D-dibenzoyltartaric acid, D-malic acid, D-mandelic acid, D-camphorsulfonic acid or R-binaphthol phosphate;
  • the preferred resolving reagent is R-binaphthol phosphate.
  • the method for chemical splitting comprises the following steps: mixing the compound shown in formula B, the splitting reagent and the first solvent for reaction, after the reaction is completed, removing the first solvent, and using the second solvent for beating, Filter, dry to obtain solid; Dissolve the solid in the first solvent, process under reflux conditions for a predetermined time (preferably 40min-80min, more preferably 50min-70min), cool, there is solid precipitation, filter, dry, the formula The compound shown in B1.
  • the first solvent is tetrahydrofuran; further, the second solvent is ethyl acetate.
  • the molar ratio of the compound represented by formula B and the resolution reagent is 1:0.9-1:1.1.
  • step S410 the compound represented by formula C1 is used to react to obtain the compound represented by formula B1
  • step S400 before step S400, a step of preparing the compound represented by formula C or a stereoisomer thereof using the preparation method of the second aspect is further included.
  • the fifth aspect of the present invention provides the preparation method of the compound represented by formula B or its stereoisomer described in another third aspect, comprising the following steps:
  • a reduction reaction is performed in step S500. Further, in step S500, a red aluminum toluene solution is used for reduction reaction.
  • the stereoisomer of the compound represented by formula D is represented by formula D2
  • the stereoisomer of compound represented by formula B is represented by formula B3
  • the reaction scheme is as follows:
  • step S500 includes the following steps:
  • step S510 after preparing the compound represented by formula B, it also includes the step of performing chiral resolution to obtain the compound represented by formula B1;
  • the method of chiral resolution is instrumental resolution or chemical resolution.
  • the resolving reagent for chiral resolution is D-tartaric acid, D-dibenzoyltartaric acid, D-malic acid, D-mandelic acid, D-camphorsulfonic acid or R-binaphthol phosphate;
  • the preferred resolving reagent is R-binaphthol phosphate.
  • the method for chemical splitting comprises the following steps: mixing the compound shown in formula B, the splitting reagent and the first solvent for reaction, after the reaction is completed, removing the first solvent, and using the second solvent for beating, Filter, dry to obtain solid; Dissolve the solid in the first solvent, process under reflux conditions for a predetermined time (preferably 40min-80min, more preferably 50min-70min), cool, there is solid precipitation, filter, dry, the formula The compound shown in B1.
  • the first solvent is tetrahydrofuran; further, the second solvent is ethyl acetate.
  • the molar ratio of the compound represented by formula B and the resolution reagent is 1:0.9-1:1.1.
  • the step of preparing the compound represented by formula D or its stereoisomer is also included before step S500.
  • the step of preparing the compound represented by formula D or its stereoisomer includes the following steps:
  • the acid in step S520, is an inorganic acid; further, the acid is sulfuric acid; further, the concentration of the acid is 30g/mL-60g/mL.
  • step S520 the compound represented by formula E or its stereoisomer is mixed with water, cooled to 10°C-15°C, and then sulfuric acid is slowly added dropwise. After the dropwise addition, the temperature is 30°C.
  • Carry out the reaction (preferably 40min-80min) under the condition of -60°C (preferably 45°C-50°C), after the reaction is completed, cool down to 5°C-10°C, add an organic solvent (preferably toluene) and an alkaline solution (preferably a mass The percentage content is 10%-30% sodium hydroxide or potassium hydroxide solution), stirring for a predetermined time (preferably 40min-80min). Standing, extracting, washing and drying to obtain the compound represented by formula D or its stereoisomer.
  • the stereoisomer of the compound represented by formula E is represented by formula E3
  • the stereoisomer of compound represented by formula D is represented by formula D2
  • the reaction scheme is as follows:
  • the sixth aspect of the present invention provides a structural compound represented by formula X or formula Y:
  • R a and R b are each independently hydrogen, halogen (preferably F or Cl), C 1-6 alkyl (preferably C 1-3 alkyl), halogenated C 1-6 alkyl (preferably halo C 1-3 alkyl), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy); or R a , R b and the attached carbon atoms together form a 4- to 6-membered saturated monolayer Heterocycle or 3 to 6 membered saturated monocycle; wherein the 4 to 6 membered saturated monoheterocycle and 3 to 6 membered saturated monocycle are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of : cyano, hydroxyl, methylol, cyanomethyl, halogen, C 1-3 alkoxy, C 1-3 alkyl, -COC 1-3 alkyl, -CONR a1 R b1 , NR a1 R b1 , -NHCOC 1-3
  • R c is hydrogen, halogen (preferably F or Cl), C 1-6 alkyl (preferably C 1-3 alkyl), C 2-6 alkenyl (preferably C 2-4 alkenyl), C 2 -6 alkynyl (preferably C 2-4 alkynyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably halogenated C 1- 3 alkyl), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy), -COC 1-6 alkyl (preferably -COC 1-3 alkyl), -CONR a1 R b1 , NR a1 R b1 , -NHCOC 1-6 alkyl (preferably -NHCOC 1-3 alkyl), -NHCONR a1 R b1 , -NHSO 2 C 1-3 alkyl, -NHSO 2 N R a1 R b1 , -NHSO 2 C 3-6 cycloalkyl,
  • R a1 and R b1 are each independently hydrogen, C 1-6 alkyl (preferably C 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), C 3-6 cycloalkyl or 4- to 6-membered saturated mono-heterocycle; or R a1 , R b1 and the connected nitrogen atom together form a 4- to 6-membered saturated mono-heterocycle; wherein the 4- to 6-membered saturated mono-heterocycle is Unsubstituted or substituted with 1, 2 or 3 C 1-3 alkyl.
  • R a , R b are each independently hydrogen, fluorine or methyl; or R a , R b and the attached carbon atoms together form a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring; R c is hydrogen, fluorine, methyl, ethyl, methoxy or trifluoromethyl.
  • R a and R b are each independently hydrogen, fluorine or methyl; R c is hydrogen, fluorine, methyl, ethyl, methoxy or trifluoromethyl.
  • R a is methyl
  • R b is H
  • R c is methyl
  • the compound represented by the formula X is the compound represented by the formula X-1
  • the compound represented by the formula Y is the compound represented by the formula Y-1:
  • the compound represented by the formula X is the compound represented by the formula X1:
  • the seventh aspect of the present invention provides the preparation method of the compound represented by the formula X or its stereoisomer described in the sixth aspect, comprising the following steps:
  • step S710 includes the following steps: mixing the compound represented by formula Z, hydroxylamine hydrochloride, a base (preferably pyridine) and an alcohol solvent (preferably anhydrous methanol) at a temperature of 50°C-70°C (preferably The reaction is carried out under the condition of 65°C) to obtain the compound represented by formula Y.
  • a base preferably pyridine
  • an alcohol solvent preferably anhydrous methanol
  • the molar ratio of the compound represented by formula Z and hydroxylamine hydrochloride is 1:1.1-1:1.5; further, the molar ratio of the compound represented by formula Z and base is 1:1.1-1:1.5; further , the molar ratio of the compound represented by formula Z and the base is 1:1.2.
  • step S720 a reduction method is used to obtain the compound represented by formula X or a stereoisomer thereof; further, step S720 includes the following steps: the compound represented by formula Y or its stereoisomer and The solvent (preferably anhydrous methanol) is mixed, Pd/C is added, and the reaction is carried out at a pressure of 15 atm to 20 atm in a hydrogen atmosphere (preferably 50°C-75°C), and after the reaction is complete (preferably 1h-3h), prepared The compound represented by formula X or its stereoisomer.
  • the solvent preferably anhydrous methanol
  • step S720 the stereoisomer of the compound represented by the formula X is the compound represented by the formula X1, and the preparation of the compound represented by the formula X1 includes the following steps:
  • the method of chiral resolution is instrumental resolution or chemical resolution.
  • the method of chemical resolution is adopted for resolution, and further, the resolution reagent is L-tartaric acid, L-dibenzoyltartaric acid, L-malic acid, L-mandelic acid, L-camphorsulfonic acid or S-binaphthol phosphate, preferably L-tartaric acid.
  • the method for above-mentioned chemical resolution comprises the following steps: mixing the compound represented by formula X and a solvent (preferably ethanol) to obtain a first solution, and separating a reagent (preferably L-tartaric acid) and a solvent (preferably ethanol) ) mixing to obtain the second solution; the second solution is slowly added to the first solution, a large amount of solid is precipitated, filtered, washed and dried to obtain the salt crude product of the compound shown in formula X1; further, the compound shown in the obtained formula X1 The crude salt is subjected to a refining step.
  • a solvent preferably ethanol
  • the salt crude product of the compound represented by formula X1 also comprises the following steps:
  • step S721 two recrystallization treatments are performed, the first recrystallization treatment is performed on the salt crude product of the compound represented by the formula X1, and the collected crystals are subjected to a second recrystallization treatment;
  • the first recrystallization treatment step is: adding the salt crude product of the compound shown in formula X1 into an alcohol-water solvent (preferably a mixed solvent composed of methanol and water in a volume ratio of 1:0.8-1:1.2), and warming up to The internal temperature is 65-70°C until the system is clear; slowly add an alcohol solvent (preferably methanol) dropwise to the system, control the internal temperature to not be lower than 55°C, lower the internal temperature to 46-47°C and continue stirring for 30-90min, gradually reduce to At room temperature, stirring, a solid is precipitated, and the solid is collected to obtain a primary product;
  • an alcohol-water solvent preferably a mixed solvent composed of methanol and water in a volume ratio of 1:0.8-1:1.2
  • the second recrystallization treatment step is: dissolving the primary fine product obtained by the first recrystallization treatment in water, then adding an alcohol solvent (preferably anhydrous methanol), heating up to reflux for dissolution; the internal temperature is reduced to about 40 °C-55 °C (preferably 50 °C) stirring for 30-90min, gradually lowering to room temperature, stirring, there is solid precipitation, the solid is collected, washed (preferably using isopropanol), to obtain the refined salt of the compound represented by formula X1.
  • an alcohol solvent preferably anhydrous methanol
  • the step of the first recrystallization treatment 2-5 mL of alcoholic solvent is added to each 1 g of the crude salt of the compound represented by formula X1, and 8-12 mL of alcoholic solvent is added after the temperature is raised to an internal temperature of 65-70 °C.
  • the second recrystallization treatment step 1-3 mL of water and 7-1 mL of alcohol solvent are added per 1 g of primary fine product.
  • step S722 4-6 mL of water is added per 1 g of the refined salt of the compound represented by formula X1.
  • step S723 0.2-0.5 mL of water and 0.2-0.5 mL of methanol are added per 100 mg of the refined salt of the compound represented by formula X1.
  • the eighth aspect of the present invention provides the preparation method of the compound shown in formula I, comprises the following steps:
  • a ring and (R 0 ) n are as described in the first aspect; R a , R b and R c are as described in the sixth aspect.
  • step S810 the preparation method of the compound represented by formula B is as described in the fourth aspect and the fifth aspect.
  • step S810 2-iodoyl benzoic acid (IBX) is used to oxidize the alcohol hydroxyl group to aldehyde; further, in step S810, the molar ratio of the compound shown in formula B and IBX is 1:2-1: 3.
  • IBX 2-iodoyl benzoic acid
  • the compound represented by the formula B is the compound represented by the formula B3, and the compound represented by the formula B3 is oxidized to obtain the compound represented by the formula A1:
  • the compound shown in formula B3 is prepared by the following method:
  • the compound shown in formula B3 is prepared by the following method:
  • the compound shown in formula B3 is prepared by the following method:
  • the compound shown in formula B3 is prepared by the following method:
  • step S820 the preparation method of the compound represented by formula X or its stereoisomer is as described in the seventh aspect.
  • step S820 the molar ratio of the compound represented by formula A and the compound represented by formula X is 1:0.8-1:1.2.
  • step S820 includes the following steps: mixing the compound represented by formula A or its stereoisomer, the compound represented by formula X or its stereoisomer, sodium cyanoborohydride and a solvent, reacting, and separating After purification, the compound represented by formula I or its stereoisomer is obtained.
  • the compound represented by the formula A is the compound represented by the formula A1
  • the compound represented by the formula X is the compound represented by the formula X1-1
  • step S820 the compound represented by the formula A1 and the compound represented by the formula X1-1 are used to carry out reaction to obtain the compound represented by formula I-1:
  • the compound of formula X1-1 is selected from the free base of formula X1-1 or its L-tartrate, L-dibenzoyltartrate, L-malate, L-mandelate, L- Camphorsulfonate or S-binaphthol phosphate, preferably L-tartrate.
  • the present invention can obtain a new type of MOR agonist compound represented by formula I with higher ee value in higher yield by optimizing the reaction route, and the reaction conditions of each step of the above method are relatively mild, the post-processing is simple and convenient, and it is easy to enlarge production, with high industrial application value.
  • FIG. 1 is a single crystal structure diagram of the L-tartrate salt of compound X1-1.
  • alkyl refers to straight and branched chain saturated aliphatic hydrocarbon groups
  • C 1-8 alkyl is an alkyl group containing 1 to 8 carbon atoms, preferably C 1-4 alkyl, more preferably C1-3 alkyl, similarly defined; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-di
  • alkenyl means a straight or branched carbon chain containing at least one carbon-carbon double bond, C 1-4 alkenyl is an alkenyl group containing 1 to 4 carbon atoms; alkenyl
  • Non-limiting examples of include: vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl.
  • alkynyl means a straight or branched carbon chain containing at least one carbon-carbon triple bond
  • C 1-4 alkynyl is an alkynyl group containing 1 to 4 carbon atoms
  • alkynyl Examples include ethynyl, propargyl.
  • C 6-10 aryl and C 6-10 aromatic ring are used interchangeably, and both refer to an all-carbon monocyclic or fused polycyclic ring (that is, sharing an adjacent pi-electron system)
  • a carbon atom pair ring) group refers to an aryl group containing 6 to 10 carbon atoms; preferably phenyl and naphthyl, more preferably phenyl.
  • 5- to 6-membered monocyclic heteroaryl ring and “5- to 6-membered monocyclic heteroaryl” are used interchangeably and both refer to a single heteroaryl ring containing 5 to 6 ring atoms
  • Examples include (but are not limited to): thiophene ring, N-alkylcyclopyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring
  • haloC 1-8 alkyl refers to an alkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) halogens, wherein alkyl is as defined above. Selected as halogenated C 1-4 alkyl.
  • halogenated C 1-8 alkyl examples include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl and the like.
  • C 1-8 alkoxy refers to -O-(C 1-8 alkyl), wherein alkyl is as defined above.
  • a C 1-4 alkoxy group is preferable, and a C 1-3 alkoxy group is more preferable.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.
  • cycloalkyl and “cycloalkyl ring” are used interchangeably, both refer to saturated or partially unsaturated monocyclic cyclic hydrocarbon groups, and "C 3-6 cycloalkyl” refers to a group containing 3 to 6 A cyclic hydrocarbon group of carbon atoms.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like, preferably cyclopropyl, cyclopentyl , cyclohexenyl.
  • C 3-6 cycloalkoxy refers to -O-(C 3-6 cycloalkyl), wherein cycloalkyl is as defined above.
  • Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • 3- to 6-membered saturated monocyclic ring refers to a saturated all-carbon monocyclic ring containing 3 to 6 ring atoms.
  • 3- to 6-membered saturated monocycles include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 4- to 6-membered saturated monoheterocycle means that 1, 2, or 3 carbon atoms in the 4- to 6-membered monocycle are selected from nitrogen, oxygen, or S(O) t (where t is an integer 0 to 2), but excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms are carbon; preferably 5 to 6 members.
  • Examples of 4 to 6 membered saturated monoheterocycles include, but are not limited to, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxygen pentane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, etc.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • stereoisomers in the present invention means that the compounds of the present invention may contain one or more chiral centers and exist in different optically active forms. When the compounds of the present invention contain one chiral center, each of such chiral centers independently produces two optical isomers. When the compounds described herein contain more than one chiral center, diastereomers may exist.
  • the scope of the present invention includes all possible optical isomers and diastereoisomeric mixtures and pure or partially pure compounds.
  • the compound represented by formula E can use commercially available raw materials (for example: CAS NO. 1401031-37-5; CAS NO. 1401031-38-6 ).
  • the timing of introduction of the chiral center is not particularly limited.
  • the chiral separation can be carried out after the corresponding compound is prepared, or the raw material with chirality can be directly used for preparation, which should be understood as being within the protection scope of the present invention. .
  • THF is tetrahydrofuran
  • EA is ethyl acetate
  • PE is petroleum ether
  • DMF is dimethylformamide
  • DMSO is dimethylsulfoxide
  • r.t. room temperature
  • DCM is dichloromethane
  • DBU is 1,8 - Diazabicycloundec-7-ene
  • TEMPO is 2,2,6,6-tetramethylpiperidine oxide
  • Oxone is potassium peroxymonosulfonate
  • IBX is 2-iodoylbenzoic acid
  • MeOH is methanol
  • EtOH is ethanol
  • IPA is isopropanol
  • ACN is acetonitrile.
  • room temperature refers to about 20-25°C.
  • Step 1 Add triethylphosphonoacetate (476mL, 2.4mol), DBU (365g, 2.4mol), lithium chloride (127g, 3mol) and acetonitrile (1.2L) to a 3L one-neck flask, argon protection Stir at room temperature for 20 minutes. After cooling to 0°C (internal temperature), isobutyraldehyde (144 g, 2 mol) was slowly added dropwise. Stir at room temperature for 12 hours. Filtered and the filter cake was washed with EA (100 mL x 2). Water (1L) was added, extracted with EA (1.5L*2), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to obtain compound v1 (175g).
  • Step 2 Add DMF (1L) to the 3L single-neck flask containing compound v1 (300g, 2.1mol), under stirring, add potassium carbonate (579g, 4.2mol), pyrazole (287g, 4.2mol), 65°C, Stir for 18 hours and spin dry directly. The remaining solid was slurried with acetonitrile (150 ml) and filtered to give a white solid. Filtered and the filter cake was washed with EA (500 mL x 2). Wash with saturated brine (300 mL x 3), dry over anhydrous sodium sulfate, spin dry, and purify by column chromatography (PE containing 5% EA as mobile phase) to obtain compound v2 (258 g). MS m/z (ESI): 211.1 [M+1] + .
  • Step 3 Water (200 mL) was added to potassium hydroxide (133 g, 3.32 mol) to dissolve, and pre-cooled to 5°C.
  • Compound v2 (465 g, 2.21 mol), methanol (0.5 L), and THF (0.5 L) were added to a 3 L flask, and a pre-cooled aqueous potassium hydroxide solution was added, followed by stirring for 2 hours.
  • the pH was adjusted to about 3 with concentrated hydrochloric acid, extracted with DCM (800 ml x 2), all organic phases were combined, washed with saturated brine, dried, and concentrated to obtain compound v3 (410.5 g).
  • Step 4 Under nitrogen protection, compound v3 (10.2 g, 0.055 mol) and THF (200 mL) were added to a three-necked flask (500 mL), and the temperature was lowered to -75°C. A 2.5M solution of n-butyllithium in THF (55 mL, 0.137 mol) was slowly added dropwise, the dropwise addition was completed, the temperature was slowly raised to -10°C, and stirring was continued for 3 hours. Quenched with saturated ammonium chloride, added water (100 mL), extracted with EA (400 ml x 2), combined the organic phases, washed with saturated brine, dried, and concentrated to obtain a brown liquid. Column chromatography purification (PE containing 30% EA as mobile phase) gave compound X1-1a (4g), MS m/z (ESI): 165.1 [M+1] + .
  • Step 1 Add compound X1-1a (16.0g, 97.4mmol, 1.0equiv) into a 250mL there-necked flask, add anhydrous methanol (128mL, 8.0v/w), hydroxylamine hydrochloride (6.85g, 98.6mmol, 1.2equiv), Pyridine (7.80 g, 98.6 mmol, 1.2 equiv). The temperature was raised to 65°C, and the reaction was carried out for 1 hour. The reaction solution was spin-dried, 160 mL of water was added and stirred, extracted with dichloromethane (80 mL*2), and the organic phases were combined.
  • Step 2 Compound X1-1b (4.0 g, 22.3 mmol, 1.0 equiv) was dissolved in 80 mL of anhydrous methanol, and Pd/C (0.4 g) was added; hydrogen was replaced three times, and the external temperature of the autoclave was maintained at 65 °C. Keep the pressure in the kettle at 15-20 atm, stop absorbing hydrogen for 1.5 h, continue the reaction for 0.5 h, filter, and spin dry to obtain compound X1-1c. MS m/z (ESI): 166.1 [M+1] + .
  • Step 3 Compound X1-1c (10.1 g, 61.1 mmol, 1.0 equiv) was dissolved in absolute ethanol (20 mL) and stirred at room temperature to obtain an ethanol solution of compound X1-1c.
  • L-tartaric acid (11.0 g, 73.4 mmol, 1.2 equiv) was dissolved in absolute ethanol (175 mL), and then slowly added dropwise to the ethanol solution of X1-1c, and a large amount of solid was precipitated. After filtration, the filter cake was washed with a small amount of ethanol and dried to obtain 21.0 g of solid.
  • Step 4 Dissolve the L-tartrate of X1-1 (39 g) in water (200 mL), adjust the pH to about 11 with saturated aqueous sodium carbonate solution, extract six times with dichloromethane 40 mL, and dry the organic acid with anhydrous sodium sulfate. phase, and the solvent was evaporated under reduced pressure to obtain compound X1-1 (18.0 g).
  • Step 1 Add E2 (20g, CAS NO.1401031-37-5) and 80mL of water into a 250mL three-necked bottle, cool down to 10-15°C, stir, drop into sulfuric acid solution (configured by adding 11.5g concentrated sulfuric acid to 20mL water) After dropping, the temperature was raised to 45-50°C, and the temperature was kept stirring for 1 hour. Cool to 5-10°C, add 100mL of toluene, dropwise add 30g of 20% sodium hydroxide solution, and stir at room temperature for 1 hour after dropping. The organic phase was separated and the aqueous phase was extracted twice with 2 ⁇ 100 mL of toluene. The organic phases were combined, washed once with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and put into the next step with toluene solution.
  • Step 2 Take the above toluene solution (containing about 5.1 g D1), protect with nitrogen, cool down to 0-10° C., and add 16.9 g of 70% red aluminum toluene solution dropwise at the temperature. After dropping, the temperature was raised to 40-45°C, and the temperature was kept stirring for 1 hour. The temperature was lowered to 0-10° C., 25 mL of water was added dropwise to quench the reaction, 10 mL of 20% sodium hydroxide solution was added, and the mixture was heated to room temperature and stirred for 1 hour.
  • the filter cake was rinsed with 100 mL of methyl tert-butyl ether, the mother liquor was left to stand for layers, the organic phase was separated, and the aqueous phase was extracted again with 50 mL of methyl tert-butyl ether.
  • the organic phases were combined, washed once with 25 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filter cake was rinsed with a small amount of methyl tert-butyl ether, and the filtrate was concentrated under reduced pressure to obtain B2 (4.66 g of yellow oily product, yield 91.4%) , purity 92.6%).
  • Step 1 Dissolve compound D1 (2.0 g, 7.26 mmol, 1.0 equiv) with methanol (10.0 mL, 5.0 v/w) and add it to a 50 mL three-necked flask; N2 protection, cool down to 5-10 °C; add dropwise to the three-necked flask SOCl 2 (1.08g, 9.08mmol, 1.25equiv), dripped in about 10min, control the internal temperature to 10 ⁇ 15°C; heat up to 50 ⁇ 55°C and react for 3h; spin the reaction solution to dryness, add 15ml of methyl tertiary ether; add to the system 25% sodium carbonate aqueous solution to the pH of the water phase to about 9, and control the internal temperature to 10 ⁇ 15 ° C; liquid separation, the water phase was extracted twice with 10 mL*2 methyl tertiary ether; the combined organic phases were spin-dried to obtain C2-1 (2.0 g , purity 98.0%, yield
  • Step 2 Add C2-1 (1.86g) and 15mL toluene into a 100mL three-necked flask, replace it with nitrogen three times, cool it to an internal temperature of 0-10°C, add red aluminum solution (6.5g) dropwise, and control the internal temperature to ⁇ 10°C, After the dropwise addition was completed in about 30 minutes, the temperature was raised to 40-45°C and the reaction was stirred for 1 hour. The reaction solution was cooled to 0-10 °C, water (9.3 mL) was added dropwise to quench the reaction, and then 20% NaOH solution (3.7 mL) was added dropwise. After filtration, the filter cake was rinsed with methyl tert-butyl ether (37 mL).
  • the solid was refluxed in 50 mL of tetrahydrofuran for 1.5 h, cooled to room temperature for 1.5 h, filtered and dried to obtain a light yellow solid (1.83 g, ee%: 84.58%). 18 mL of tetrahydrofuran was added to the obtained solid and refluxed for 1 h, cooled to room temperature for 1 h, filtered, and the filter cake was dried to obtain a pale yellow solid (1.03 g, ee%: 91.64%).
  • Step 1 Under nitrogen protection, add compound E3 (CAS NO.1401031-38-6) (1.03g), hydrochloric acid methanol solution (4mol/L, 7mL) and anhydrous methanol (10mL) into a 50mL single-neck flask, and stir at room temperature for 7h , additionally add hydrochloric acid methanol solution (4mol/L, 3mL), and stir at room temperature for 2h.
  • Step 2 Take C3-1 (0.58g) and toluene (12mL) into the three-necked flask, cool down to 0-5°C; slowly add 3.0eq red aluminum toluene solution dropwise, and control the temperature to 0-5°C; keep stirring after the dropwise addition 0.5h; warmed to room temperature (27°C) and kept stirring for 1h; post-processing to obtain B3 (0.33g, yield: 63.2%, purity: 99.33%). MS m/z (ESI): 262.2 [M+1] + .
  • Step 1 Compound E3 (0.78 g, 3.0 mmol, 1.0 equiv) and TsOH ⁇ H 2 O (628 mg, 3.3 mmol, 1.1 equiv) were added to the flask, and absolute ethanol (7.8 mL, 10.0 v/w) and water were added (54mg, 3.0mmol, 1.0equiv), refluxed for 8h.
  • the reaction solution was evaporated to dryness under reduced pressure, 10 mL of water was added, and the aqueous phase was adjusted to pH ⁇ 9 with saturated sodium carbonate.
  • Step 2 Prepare by referring to the method of Step 2 of Example 4 to obtain compound B3.
  • Step 1 Compound E3 (100 g) and water (400 mL) were added to the reaction flask, and the temperature was lowered to 5-15°C. Dissolve 57.4 g of concentrated sulfuric acid in 100 mL of water and add it dropwise to the reaction flask. After dropping, the temperature is raised to 45-50 °C, and the temperature is kept stirring for 1.5 h. The system was cooled to an internal temperature of 0-10° C., 500 mL of toluene was added, and 20% NaOH solution (150 g) was added dropwise.
  • Step 2 Add the toluene solution (836 g in total) containing compound D2 (107.4 g) into the reaction flask, cool the internal temperature to 0-10 ° C, and replace with nitrogen three times; slowly add red aluminum solution (394.3 g) dropwise, control the internal temperature Temperature 0-10 °C. After the dropwise addition was completed, the internal temperature was raised to 43° C. and kept stirring for 1 h. The reaction solution was cooled to 0-10° C., 500 mL of water was added dropwise to quench the reaction, and then 1500 mL of 20% NaOH solution was added dropwise. The reaction solution was stirred and extracted with methyl tert-butyl ether 1000 mL ⁇ 2, and the two organic phases were combined. Dry and filter over anhydrous Na 2 SO 4 , and the filtrate was concentrated under reduced pressure to obtain compound B3 (91.5 g, yield 89.8%).
  • 1 ⁇ Stimulation buffer solution Take 1ml of 5 ⁇ Stimulation buffer storage solution and add it to 4ml of distilled water, and mix well.
  • 50uM NK477 1ml Take 1 ⁇ l 50mM NKH477 storage solution and add it to 999 ⁇ l 1 ⁇ Stimulation buffer solution, shake and mix well.
  • cAMP-Cryptate (donor, lyophilized) reaction solution add 1ml of 5 ⁇ cAMP-Cryptate stock solution to 4ml of 1 ⁇ Lysis & Detection Buffer, and mix gently.
  • Anti-cAMP-d2 (acceptor, lyophilized) reaction solution Take 1ml of 5 ⁇ Anti-cAMP-d2 stock solution and add it to 4ml of 1 ⁇ Lysis & Detection Buffer, and mix gently.
  • the data was exported from the corresponding software in the computer connected to the multi-function plate reader, and the data was analyzed with GraphPad Prism software.
  • the best fitting curve is log(agonist) vs.response.
  • Table 2 The results are shown in Table 2:

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Abstract

一种氧杂螺环取代的吡咯并吡唑衍生物及其中间体和制备方法。

Description

氧杂螺环取代的吡咯并吡唑衍生物及其中间体和制备方法 技术领域
本发明涉及有机化学合成领域，具体地涉及氧杂螺环取代的吡咯并吡唑衍生物及其中间体和其制备方法。
背景技术
阿片受体是一类重要的G蛋白偶联受体(G protein coupled receptor,GPCR)，是内源性阿片肽及阿片类药物结合的靶点，内源性阿片肽是哺乳动物体内天然生成的阿片样活性物质，目前已知的内源性阿片肽大致分为脑啡肽、内啡肽、强啡肽和新啡肽几类。中枢神经系统中存在其相应的阿片受体，即μ(MOR)、δ(DOR)、κ(KOR)受体等。研究发现，内源性阿片肽镇痛作用的强弱，主要取决于阿片受体表达的多少，阿片受体是阿片类药物以及内源性阿片肽镇痛作用的靶点。
目前已有多篇文献报道了不同结构的MOR激动剂并公开了这些化合物的制备方法，包括WO2017106547、WO2017063509、WO2012129495、WO2017106306等。开发针对新的具有更好活性及选择性的MOR激动剂的高效、低成本、易放大、可重复性好的合成工艺对制药领域及工业化生产都有着很重要的意义。
发明内容
本发明的目的是在已开发的新型MOR激动剂基础上进一步开发适宜工业化生产的中间体及其工艺制备方法，该制备方法具有高效、低成本、易放大、可重复性好等特点。
本发明第一方面提供了式C所示的化合物，或其立体异构体：
Figure PCTCN2021142283-appb-000001
其中，
R为C 1-8烷基(优选为C 1-4烷基)，-C 1-4烷基-C 6-10芳基(优选为-CH 2-芳基，更优选为苄基)，C 6-10芳基(优选为苯基)；
A环为C 6-10芳环(优选苯环)或5至6元单环杂芳基环(优选吡啶环)；
(R 0) n为A环上的氢被n个R 0取代，n为0、1、2、3或4；每个R 0相同或不同，并且各自独立地为氢、氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代C 1-4烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、5至6元单环杂芳基、C 1-8烷基(优选为C 1-4烷基)、C 1-8烷氧基(优选为C 1-4烷氧基)、C 3-6环烷基、C 3-6环烷氧基、C 2-4烯基、C 2-4炔基、NR 11R 12、-CONR 11R 12、-C(O)OC 1-8烷基(优选为-C(O)OC 1-4烷基)、-OC(O)C 1-8烷基(优选为-OC(O)C 1-4烷基)、-SO 2C 1-8烷基(优选为-SO 2C 1-4烷基)、-SO 2C 6-10芳基(优选为 -SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)、4至6元饱和单杂环或3至6元饱和单环，其中所述C 6-10芳基、5至6元单环杂芳基、4至6元饱和单杂环和3至6元饱和单环为未取代的或被1、2或3个选自乙酰基、羟基、氰基、卤素、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、NR 11R 12的取代基取代；
R 11、R 12各自独立地为氢、C 1-8烷基(优选为C 1-4烷基)、卤代C 1-8烷基(优选为卤代C 1-4烷基)、C 3-6环烷基或4至6元饱和单杂环；或者R 11、R 12与相连的氮原子共同形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-4烷基取代。
在一些实施例中，R为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基、苯基或苄基，优选为甲基。
在一些实施例中，A为苯环、吡啶环、嘧啶环或三嗪环。
在一些实施例中，n为0。
在一些实施例中，式C所示的化合物为式C2化合物：
Figure PCTCN2021142283-appb-000002
其中，R为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基(优选为甲基)。
在一些实施例中，式C所示的化合物为式C3化合物：
Figure PCTCN2021142283-appb-000003
其中，R为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基(优选为甲基)。
本发明第二方面提供了第一方面所述的式C所示化合物或其立体异构体的制备方法，包括以下步骤：
Figure PCTCN2021142283-appb-000004
S200：将式E所示化合物或其立体异构体进行一步或两步以上反应，制备式C所示化合物或其立体异构体；进一步地，步骤S200中，式E所示化合物或其立体异构体进行醇解反应制备式C所示化合物或其立体异构体。
在一些实施例中，步骤S200中，将式E所示化合物或其立体异构体进行一步反应，制备得式C所示化合物或其立体异构体。具体地，步骤S200包括以下步骤：
S211：式E所示化合物或其立体异构体在酸的催化下，与醇ROH进行反应，待反应完 成后，进行分离提纯，制得式C所示化合物或其立体异构体。
在一些实施例中，步骤S211中，醇ROH为甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、苯酚或苄醇；进一步地，醇为甲醇或乙醇。
在一些实施例中，步骤S211中，酸为无机酸或有机酸；进一步地，酸为盐酸或对甲苯磺酸。
在一些实施例中，步骤S211中，分离提纯的步骤包括以下步骤：
向反应完成的反应液中加入水得到混合物，将混合物加入有机溶剂进行萃取，旋干，制得式C所示化合物或其立体异构体。进一步地，有机溶剂为甲基叔丁基醚。
在一些实施例中，步骤S200中，将式E所示化合物或其立体异构体进行两步反应，制备得式C所示化合物或其立体异构体：
Figure PCTCN2021142283-appb-000005
具体地：步骤S200包括以下步骤：
S221：将式E所示化合物或其立体异构体进行反应，制得式D所示化合物或其立体异构体；以及
S222：将式D所示化合物或其立体异构体与ROH进行反应，制得式C所示化合物或其立体异构体。
在一些实施例中，步骤S221包括以下步骤：
将式E所示化合物或其立体异构体、水和酸混合，在温度为30℃-60℃(优选45℃-50℃)的条件下进行反应，反应完成后，分离纯化，制得式D所示化合物或其立体异构体。
在一些实施例中，步骤S221中，酸为无机酸；进一步地，酸为硫酸。
在一些实施例中，步骤S221中，酸的浓度为30g/mL-60g/mL。
在一些实施例中，步骤S221中，将式E所示化合物或其立体异构体和水混合，降温至10℃-15℃，再缓慢滴加硫酸，滴加完毕后，在温度为30℃-60℃(优选45℃-50℃)的条件下进行反应(优选40min-80min)，反应完毕后，降温至5℃-10℃，加入有机溶剂(优选为甲苯)和碱溶液(优选为质量百分含量为10％-30％的氢氧化钠或氢氧化钾溶液)，搅拌预定时间(优选40min-80min)。静置、萃取，洗涤，干燥，制得式D所示化合物或其立体异构体。
在一些实施例中，步骤S222包括以下步骤：
式D所示化合物或其立体异构体和醇(例如甲醇、乙醇)在酸(例如二氯亚砜)催化条件下进行反应，反应完全后，后处理，干燥，制得式C所示化合物或其立体异构体。
在一些实施例中，式C所示化合物的立体异构体为式C1所示化合物，式E所示化合物的立体异构体为式E1所示化合物，反应路线如下：
Figure PCTCN2021142283-appb-000006
将式E1所示化合物进行一步或两步以上反应，制备得式C1所示化合物。
在一些实施例中，式C所示化合物为式C2所示化合物，式E所示化合物为式E2所示化合物，反应路线如下：
Figure PCTCN2021142283-appb-000007
将式E2所示化合物或其立体异构体进行一步或两步以上反应，制备得式C2所示化合物立体异构体。
在一些实施例中，式C所示化合物的立体异构体为式C3所示化合物，式E所示化合物的立体异构体为式E3所示化合物，反应路线如下：
Figure PCTCN2021142283-appb-000008
将式E3所示化合物进行一步或两步以上反应，制备得式C3所示化合物。
本发明第二方面的制备方法通过采用式E所示化合物或其立体异构体作为反应原料，通过合理反应路线的选择，生成式C所示化合物或其立体异构体，操作简便，后处理简单，仅需进行简单的纯化处理即可获得纯度较高的产物，无需进行柱分离等即可获得目标纯度，能够大幅度降低生产难度，降低生产成本，更利于工业生产。
本发明第三方面提供了一种式B所示的化合物或其立体异构体：
Figure PCTCN2021142283-appb-000009
其中，A环和(R 0) n如第一方面所述。
在一些实施例中，所述式B所示的化合物为式B2化合物：
Figure PCTCN2021142283-appb-000010
在一些实施例中，所述式B所示的化合物为式B3化合物：
Figure PCTCN2021142283-appb-000011
本发明第四方面提供了第三方面所述的式B所示化合物或其立体异构体的制备方法，包括以下步骤：
Figure PCTCN2021142283-appb-000012
S400：将式C所示化合物或其立体异构体进行反应，制备得式B所示化合物或其立体异构体；
在一些实施例中，步骤S400中进行还原反应。进一步地，步骤S400中采用红铝甲苯溶液进行还原反应。
在一些实施例中，步骤S400包括以下步骤：
S410：将式C所示化合物或其立体异构体和甲苯混合，降温至0℃-10℃，缓慢加入红铝甲苯溶液后反应，后处理制得式B所示化合物或其立体异构体。
在一些实施例中，步骤S410中，制得式B所示化合物后，还包括进行手性拆分获得式B1所示化合物的步骤；
Figure PCTCN2021142283-appb-000013
在一些实施例中，手性拆分的方法为仪器拆分或化学拆分。
在一些实施例，手性拆分的拆分试剂为D-酒石酸、D-二苯甲酰酒石酸、D-苹果酸、D-扁桃酸、D-樟脑磺酸或R-联萘酚磷酸酯；优选拆分试剂为R-联萘酚磷酸酯。
在一些实施例中，化学拆分的方法包括以下步骤：将式B所示的化合物、拆分试剂和第一溶剂混合进行反应，反应完成后，除去第一溶剂，采用第二溶剂进行打浆，过滤，烘干得固体；将固体溶解于第一溶剂中，在回流的条件下处理预定时间(优选40min-80min，更优选50min-70min)，冷却，有固体析出，过滤、干燥，制得式B1所示化合物。进一步地，第一溶剂为四氢呋喃；进一步地，第二溶剂为乙酸乙酯。进一步地，式B所示化合物和拆分试剂的摩尔比为1:0.9-1:1.1。
通过采用消旋体式E所示化合物为起始原料，然后经过简单反应，获得式C所示化合物后，再进行还原反应，制得式B所示化合物，然后再进行手性拆分，能够降低手性拆分的难度，进而提高生产效率，降低生产成本。
在一些实施例中，步骤S410中，采用式C1所示化合物进行反应，制得式B1所示化合 物
Figure PCTCN2021142283-appb-000014
在一些实施例中，步骤S400之前还包括采用第二方面的制备方法，制备式C所示化合物或其立体异构体的步骤。
本发明第五方面提供了另一种第三方面所述的式B所示化合物或其立体异构体的制备方法，包括以下步骤：
Figure PCTCN2021142283-appb-000015
S500：将式D所示化合物或其立体异构体进行反应，制备得式B所示化合物或其立体异构体。
在一些实施例中，步骤S500中进行还原反应。进一步地，步骤S500中采用红铝甲苯溶液进行还原反应。
在一些实施例中，式D所示化合物的立体异构体如式D2所示，式B所示化合物的立体异构体如式B3所示，反应路线如下：
Figure PCTCN2021142283-appb-000016
更进一步地，步骤S500包括以下步骤：
S510：将式D所示化合物或其立体异构体和甲苯混合，降温至0℃-10℃，加入红铝甲苯溶液，升温至20℃-45℃反应，反应完成后，淬灭反应，后处理制得式B所示化合物或其立体异构体。
在一些实施例中，步骤S510中，制得式B所示化合物后，还包括进行手性拆分获得式B1所示化合物的步骤；
Figure PCTCN2021142283-appb-000017
在一些实施例中，手性拆分的方法为仪器拆分或化学拆分。
在一些实施例，手性拆分的拆分试剂为D-酒石酸、D-二苯甲酰酒石酸、D-苹果酸、D-扁桃酸、D-樟脑磺酸或R-联萘酚磷酸酯；优选拆分试剂为R-联萘酚磷酸酯。
在一些实施例中，化学拆分的方法包括以下步骤：将式B所示的化合物、拆分试剂和第 一溶剂混合进行反应，反应完成后，除去第一溶剂，采用第二溶剂进行打浆，过滤，烘干得固体；将固体溶解于第一溶剂中，在回流的条件下处理预定时间(优选40min-80min，更优选50min-70min)，冷却，有固体析出，过滤、干燥，制得式B1所示化合物。进一步地，第一溶剂为四氢呋喃；更进一步地，第二溶剂为乙酸乙酯。进一步地，式B所示化合物和拆分试剂的摩尔比为1:0.9-1:1.1。
通过采用消旋体式D所示化合物为原料，然后经过还原反应，制得式B所示化合物，然后再进行手性拆分，能够降低手性拆分的难度，进而提高生产效率，降低生产成本。在一些实施例中，步骤S500之前还包括制备式D所示化合物或其立体异构体的步骤，具体地制备式D所示化合物或其立体异构体的步骤包括以下步骤：
Figure PCTCN2021142283-appb-000018
S520：将式E所示化合物或其立体异构体、水和酸混合，在温度为30℃-60℃(优选45℃-50℃)的条件下进行反应，反应完成后，分离纯化，制得式D所示化合物或其立体异构体；
在一些实施例中，步骤S520中，酸为无机酸；更进一步地，酸为硫酸；更进一步地，酸的浓度为30g/mL-60g/mL。
在一些实施例中，步骤S520中，将式E所示化合物或其立体异构体和水混合，降温至10℃-15℃，再缓慢滴加硫酸，滴加完毕后，在温度为30℃-60℃(优选45℃-50℃)的条件下进行反应(优选40min-80min)，反应完毕后，降温至5℃-10℃，加入有机溶剂(优选为甲苯)和碱溶液(优选为质量百分含量为10％-30％的氢氧化钠或氢氧化钾溶液)，搅拌预定时间(优选40min-80min)。静置、萃取，洗涤，干燥，制得式D所示化合物或其立体异构体。
在一些实施例中，式E所示化合物的立体异构体如式E3所示，式D所示化合物的立体异构体如式D2所示，反应路线如下：
Figure PCTCN2021142283-appb-000019
本发明第六方面提供了式X或式Y所示结构化合物：
Figure PCTCN2021142283-appb-000020
R a、R b各自独立地为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)；或者R a、R b与相 连的碳原子共同形成4至6元饱和单杂环或3至6元饱和单环；其中所述4至6元饱和单杂环和3至6元饱和单环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1、-NHSO 2C 3-6环烷基；
R c为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、C 2-6烯基(优选为C 2-4烯基)、C 2-6炔基(优选为C 2-4炔基)、C 1-6烷氧基(优选为C 1-3烷氧基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)、-COC 1-6烷基(优选为-COC 1-3烷基)、-CONR a1R b1、NR a1R b1、-NHCOC 1-6烷基(优选为-NHCOC 1-3烷基)、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2N R a1R b1、-NHSO 2C 3-6环烷基、-SO 2C 1-3烷基、-SO 2NR a1R b1、4至6元饱和单杂环、C 6-10芳基或5或6元单环杂芳基；其中所述4至6元饱和单杂环、C 6-10芳基和5或6元单环杂芳基为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1、-NHSO 2C 3-6环烷基；
R a1、R b1各自独立地为氢、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、C 3-6环烷基或4至6元饱和单杂环；或者R a1、R b1与相连的氮原子共同形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-3烷基取代。
在一实施例中，R a、R b各自独立地为氢、氟或甲基；或者R a、R b与相连的碳原子共同形成环丙基环、环丁基环或环戊基环；R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在一实施例中，R a、R b各自独立地为氢、氟或甲基；R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在一实施例中，R a为甲基，R b为H，R c为甲基。
在一实施例中，式X所示化合物为式X-1所示化合物，式Y所示化合物为式Y-1所示化合物：
Figure PCTCN2021142283-appb-000021
在一实施例中，式X所示化合物为式X1所示化合物：
Figure PCTCN2021142283-appb-000022
本发明第七方面提供了第六方面所述的式X所示化合物或其立体异构体的制备方法，包括以下步骤：
Figure PCTCN2021142283-appb-000023
S710：将式Z所示化合物或其立体异构体进行反应，制得式Y所示化合物或其立体异构体；
S720：将式Y所示化合物或其立体异构体进行反应，制备得式X所示化合物或其立体异构体。
在一些实施例中，步骤S710包括以下步骤：将式Z所示化合物、盐酸羟胺、碱(优选为吡啶)和醇溶剂(优选为无水甲醇)混合，在温度为50℃-70℃(优选为65℃)的条件下进行反应，制得式Y所示化合物。
在一些实施例中，式Z所示化合物和盐酸羟胺的摩尔比为1:1.1-1:1.5；进一步地，式Z所示化合物和碱的摩尔比为1:1.1-1:1.5；进一步地，式Z所示化合物和碱的摩尔比为1:1.2。
在一些实施例中，步骤S720中采用还原的方法制得式X所示化合物或其立体异构体；更进一步地，步骤S720包括以下步骤：将式Y所示化合物或其立体异构体和溶剂(优选无水甲醇)混合，加入Pd/C，在氢气的氛围下，于15atm～20atm的压力下进行反应(优选50℃-75℃)，反应完全后(优选1h-3h)，制得式X所示化合物或其立体异构体。
在一些实施例中，步骤S720中，式X所示化合物的立体异构体为式X1所示化合物，制备式X1所示化合物包括以下步骤：
将式X所示化合物进行手性拆分，制得式X1所示化合物
Figure PCTCN2021142283-appb-000024
在一些实施例中，手性拆分的方法为仪器拆分或化学拆分。
在一些实施例中，采用化学拆分的方法进行拆分，进一步地，拆分试剂为L-酒石酸、L-二苯甲酰酒石酸、L-苹果酸、L-扁桃酸、L-樟脑磺酸或S-联萘酚磷酸酯，优选为L-酒石酸。
在一些实施例中，上述化学拆分的方法包括以下步骤：将式X所示化合物和溶剂(优选乙醇)混合，得到第一溶液，将拆分试剂(优选L-酒石酸)和溶剂(优选乙醇)混合，得到第二溶液；将第二溶液缓慢加入第一溶液中，有大量固体析出，过滤，洗涤干燥，得到式X1所示化合物的盐粗品；进一步地，所得到的式X1所示化合物的盐粗品进行精制的步骤。
在一些实施例中，式X1所示化合物的盐粗品后还包括以下步骤：
S721：将式X1所示化合物的盐粗品反复进行重结晶处理，得到式X1所示化合物的精制盐；
S722：式X1所示化合物的精制盐溶于水，并调pH至10.5-11.5，萃取，制得式X1所示 化合物的立体异构体；以及
S723：将式X1所示化合物的精制盐溶于水中，过滤除去不溶物，收集滤液，向滤液中加入甲醇，静置过夜，至有晶体析出，得到式X1所示化合物的盐的单晶。
在一些实施例中，步骤S721中，进行两次重结晶处理，将式X1所示化合物的盐粗品进行第一次重结晶处理，收集到的晶体再进行第二次重结晶处理；
其中，第一次重结晶处理步骤为：将式X1所示化合物的盐粗品加入醇水溶剂(优选为甲醇和水以体积比为1：0.8-1：1.2组成的混合溶剂)中，升温至内温65～70℃，至体系澄清；体系中缓慢滴加醇溶剂(优选为甲醇)，控制内温不低于55℃，降低内温至46～47℃继续搅拌30-90min，逐渐降至室温，搅拌，有固体析出，收集固体，得到初级精品；
第二次重结晶处理步骤为：将第一次重结晶处理得到的初级精品溶于水中，再加入醇溶剂(优选为无水甲醇)，升温至回流溶解；内温降低至约40℃-55℃(优选50℃)搅拌30-90min，逐渐降至室温，搅拌，有固体析出，收集固体，洗涤(优选采用异丙醇)，得到式X1所示化合物的精制盐。
在一些实施例中，第一次重结晶处理的步骤中，每1g式X1所示化合物的盐粗品加入2-5mL醇水溶剂，升温至内温65～70℃后加入8-12mL醇溶剂。
在一些实施例中，第二次重结晶处理步骤中，每1g初级精品加入1-3mL水，7-1mL醇溶剂。
在一些实施例中，步骤S722中，每1g式X1所示化合物的精制盐加入4-6mL水。
在一些实施例中，步骤S723中，每100mg式X1所示化合物的精制盐加入0.2-0.5mL水，加入0.2-0.5mL甲醇。
本发明第八方面提供了式I所示化合物的制备方法，包括以下步骤：
S810：将式B所示化合物或其立体异构体进行反应，制得式A所示化合物或其立体异构体：
Figure PCTCN2021142283-appb-000025
S820：将式A所示化合物或其立体异构体和式X所示化合物或其立体异构体反应得式I所示化合物或其立体异构体：
Figure PCTCN2021142283-appb-000026
其中，A环和(R 0) n如第一方面所述；R a、R b和R c如第六方面所述。
在一些实施例中，步骤S810中，式B所示化合物的制备方法如第四方面和第五方面所述。
在一些实施例中，S810中，采用2-碘酰基苯甲酸(IBX)将醇羟基氧化为醛；进一步地，步骤S810中，式B所示化合物和IBX的摩尔比为1:2-1:3。
在一些实施例中，式B所示化合物为式B3所示化合物，将式B3所示化合物进行氧化制得式A1所示化合物：
Figure PCTCN2021142283-appb-000027
在一些实施例中，采用以下方法制备式B3所示化合物：
Figure PCTCN2021142283-appb-000028
(1)将式E2所示化合物进行反应，制得式D1所示化合物；
(2)将式D1所示化合物进行反应，制得式B2所示化合物；以及
(3)将式B2所示化合物进行手性拆分，制得式B3所示化合物。
在一些实施例中，采用以下方法制备式B3所示化合物：
Figure PCTCN2021142283-appb-000029
(1)将式E2所示化合物进行反应，制得式D1所示化合物；
(2)将式D1所示化合物进行反应，制得式C2所示化合物；
(3)将式C2所示化合物进行反应，制得式B2所示化合物；式C2所示化合物中R基团如第一方面所述；以及
(4)将式B2所示化合物进行手性拆分，制得式B3所示化合物。
在一些实施例中，采用以下方法制备式B3所示化合物：
Figure PCTCN2021142283-appb-000030
(1)将式E3所示化合物进行反应，制得式C3所示化合物；以及
(2)将式C3所示化合物进行反应，制得式B3所示化合物。
在一些实施例中，采用以下方法制备式B3所示化合物：
Figure PCTCN2021142283-appb-000031
(1)将式E3所示化合物进行反应，制得式D2所示化合物；以及
(2)将式D2所示化合物进行反应，制得式B3所示化合物。
在一些实施例中，步骤S820中，式X所示化合物或其立体异构体的制备方法如第七方面所述。
在一些实施例中，步骤S820中，式A所示化合物和式X所示化合物的摩尔比为1:0.8-1:1.2。
在一些实施例中，步骤S820包括以下步骤：将式A所示化合物或其立体异构体、式X所示化合物或其立体异构体、氰基硼氢化钠和溶剂混合，进行反应，分离提纯后制得式I所示化合物或其立体异构体。
在一些实施例中，式A所示化合物为式A1所示化合物，式X所示化合物为式X1-1所示化合物，步骤S820中采用式A1所示化合物和式X1-1所示化合物进行反应，制得式I-1所示化合物：
Figure PCTCN2021142283-appb-000032
在一些实施例中，式X1-1化合物选自式X1-1的游离碱或其L-酒石酸盐、L-二苯甲酰酒石酸盐、L-苹果酸盐、L-扁桃酸盐、L-樟脑磺酸盐或S-联萘酚磷酸酯盐，优选为L-酒石酸盐。
本发明通过反应路线的优化，能够以较高收率地获得具有较高ee值的新型MOR激动剂式I所示化合物，且上述方法的各步骤反应条件较为温和，后处理简单方便，易于放大生产，具有较高的工业应用价值。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为化合物X1-1的L-酒石酸盐的单晶结构图。
具体实施方式
术语定义
如本文所用，“烷基”指直链和支链的饱和的脂族烃基，C 1-8烷基为包含1至8个碳原子的烷基，优选为C 1-4烷基，更优选为C 1-3烷基，定义类似；烷基的非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基 丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基，及其各种支链异构体等更优选。
如本文所用，“烯基”表示一种直链或支链的碳链，其包含至少一个碳-碳双键，C 1-4烯基为包含1至4个碳原子的烯基；烯基的非限制性的例子包括：乙烯基、烯丙基、异丙烯基、戊烯基、己烯基、庚烯基、1-丙烯基、2-丁烯基。
如本文所用，“炔基”表示一种直链或支链的碳链，其包含至少一个碳-碳三键，C 1-4炔基为包含1至4个碳原子的炔基；炔基的实例包括乙炔基、炔丙基。
如本文所用，“C 6-10芳基”和“C 6-10芳环”可互换使用，均指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，指含有6至10个碳原子的芳基；优选苯基和萘基，更优选苯基。
如本文所用，“5至6元单环杂芳基环”和“5至6元单环杂芳基”可互换使用，均是指含5至6个环原子的单杂芳基环，例如包括(但不限于)：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等；优选吡啶环。
如本文所用，“卤代C 1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。选为卤代C 1-4烷基。卤代C 1-8烷基的例子包括(但不限于)一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。
如本文所用，“C 1-8烷氧基”指-O-(C 1-8烷基)，其中烷基的定义如上所述。优选C 1-4烷氧基，更优选C 1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。
如本文所用，“环烷基”和“环烷基环”可互换使用，均指饱和或部分不饱和单环环状烃基，“C 3-6环烷基”是指包含3至6个碳原子的环烃基。环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等，优选环丙基、环戊基、环己烯基。
如本文所用，“C 3-6环烷氧基”指-O-(C 3-6环烷基)，其中环烷基的定义如上所述。非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。
如本文所用，“3至6元饱和单环”是指含3至6个环原子的饱和全碳单环。3至6元饱和单环的实例包括(但不限于)：环丙基环、环丁基环、环戊基环、环己基环等。
如本文所用，“4至6元饱和单杂环”是指4至6元单环中的1、2或3个碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其 余环原子为碳；优选5至6元。4至6元饱和单杂环的实例包括(但不限于)氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃等。
如本文所用，“卤素”指氟、氯、溴或碘。
本发明所述的“立体异构体”是指本发明化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当本发明所述化合物含有一个手性中心时，这类手性中心各自会独立地产生两个光学异构体。当本发明所述化合物含有多于一个手性中心时，可以存在非对映异构体。本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。
本发明中，式E所示化合物可以采用市售的原料(例如：CAS NO.1401031-37-5；CAS NO. 1401031-38-6)。
本发明中，手性中心的引入时机无特别限定，可以在制得相应化合物后进行手性拆分，也可以直接采用具有手性的原料进行制备，应理解为均在本发明的保护范围内。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
如本文所用，THF为四氢呋喃，EA为乙酸乙酯，PE为石油醚，DMF为二甲基甲酰胺，DMSO为二甲基亚砜，r.t.为室温，DCM为二氯甲烷，DBU为1,8-二氮杂二环十一碳-7-烯，TEMPO为2,2,6,6-四甲基哌啶氧化物，Oxone为过氧单磺酸钾，IBX为2-碘酰基苯甲酸，MeOH为甲醇，EtOH为乙醇，IPA为异丙醇，ACN为乙腈。
如本文所用，室温是指约为20-25℃。
实施例1：中间体X1-1a的制备
Figure PCTCN2021142283-appb-000033
步骤1：向3L单口瓶中加入三乙基膦酰乙酸酯(476mL,2.4mol)，DBU(365g，2.4mol)，氯化锂(127g，3mol)和乙腈(1.2L)，氩气保护下室温搅拌20分钟。冷却到0℃(内温)，缓慢滴加异丁醛(144g，2mol)。室温搅拌12小时。过滤，滤饼用EA洗涤(100mL x2)。加入水(1L),用EA萃取(1.5L*2)，饱和氯化钠洗涤，无水硫酸钠干燥，旋干得化合物v1(175g)。
步骤2：向装有化合物v1(300g,2.1mol)的3L单口瓶中加入DMF(1L)，搅拌下，加入碳酸钾(579g,4.2mol)，吡唑(287g,4.2mol)，65℃，搅拌18小时，直接旋干。剩余固体用乙腈(150ml)打浆，过滤得白色固体。过滤，滤饼用EA洗涤(500mL x2)。饱和食盐水 洗(300mL x3)，无水硫酸钠干燥，旋干，柱层析纯化(含5％EA的PE为流动相)得到化合物v2(258g)。MS m/z(ESI):211.1[M+1] +。
步骤3：将水(200mL)加入到氢氧化钾(133g，3.32mol)中溶解，预冷却到5℃。在3L烧瓶中加入化合物v2(465g，2.21mol)、甲醇(0.5L)、THF(0.5L)，再加入预冷的氢氧化钾水溶液，搅拌2小时。用浓盐酸调PH到3左右，用DCM萃取(800ml x2)，合并所有的有机相，饱和食盐水洗涤，干燥，浓缩得到化合物v3(410.5g)。MS m/z(ESI):183.1[M+1] +。
步骤4：在氮气保护下，向三口瓶(500mL)中加入化合物v3(10.2g，0.055mol)和THF(200mL)，降温到-75℃。缓慢滴加2.5M的正丁基锂的THF溶液(55mL,0.137mol)，滴加完毕，缓慢升至-10℃，继续搅拌3小时。饱和氯化铵淬灭，加入水(100mL)，用EA(400ml x2)萃取，合并有机相，饱和食盐水洗涤，干燥，浓缩得棕色液体。柱层析纯化(PE含30％EA为流动相)得到化合物X1-1a(4g)，MS m/z(ESI):165.1[M+1] +。
实施例2：胺X1-1的制备
Figure PCTCN2021142283-appb-000034
步骤1：将化合物X1-1a(16.0g,97.4mmol,1.0equiv)加入250mL三口瓶中，加入无水甲醇(128mL,8.0v/w)，盐酸羟胺(6.85g,98.6mmol,1.2equiv)，吡啶(7.80g,98.6mmol,1.2equiv)。升温至65℃，反应1小时。反应液旋干，加160mL水搅拌，用二氯甲烷(80mL*2)萃取，合并有机相。有机相用50mL饱和食盐水洗涤一次，用无水硫酸钠干燥，过滤，浓缩得化合物X1-1b(16.5g 1HNMR：顺反异构比例1:0.4)。
步骤2：将化合物X1-1b(4.0g,22.3mmol,1.0equiv)溶于80mL无水甲醇，加入Pd/C(0.4g)；氢气置换三次，维持高压釜外温65℃。保持釜内压力15～20atm，反应1.5h停止吸氢，继续反应0.5h，过滤，旋干得化合物X1-1c。MS m/z(ESI):166.1[M+1] +。
步骤3：将化合物X1-1c(10.1g,61.1mmol,1.0equiv)溶于无水乙醇(20mL)中，室温搅拌得到化合物X1-1c的乙醇溶液。将L-酒石酸(11.0g,73.4mmol,1.2equiv)溶于无水乙醇(175mL)中，再缓慢滴入到X1-1c的乙醇溶液中，析出大量固体。过滤，滤饼用少量乙醇洗涤，干燥得21.0g固体。取其中20g固体加入500mL三口瓶中，加入20mL水和20mL无水甲醇，升温至内温65～70℃，至体系澄清；体系中缓慢滴加200mL无水甲醇，控制内温不低于55℃；降低内温至46～47℃继续搅拌1h，约2h降至室温搅拌过夜；过滤，滤饼用20mL异丙醇洗涤；滤饼干燥至恒重得10.3g白色固体。往10.3g白色固体中加入15mL水，再加入80mL无水甲醇，升温至回流溶解；内温降低至约50℃搅拌1h，约2h降至室温搅拌过夜；过滤，滤饼用10mL异丙醇洗涤；滤饼干燥至恒重得到化合物X1-1的L-酒石酸盐(5.02g)。
化合物X1-1的L-酒石酸盐单晶的制备：将化合物X1-1的L-酒石酸盐(300mg)溶于水(1mL)中，过滤除去不溶物。滴加1mL无水甲醇，放置过夜，溶液中析出少量无色透明晶 体。通过布鲁克公司D8Venture X单晶衍射仪对本实施例所得无色透明晶体进行单晶X-ray分析，所得产物的晶体结构图如图1所示。因此化合物X1-1可由化合物X1-1的L-酒石酸盐的单晶结构推断其绝对构型为(4S，6S)构型。
仪器参数：
Figure PCTCN2021142283-appb-000035
步骤4：将X1-1的L-酒石酸盐(39g)溶于水(200mL)中，用饱和碳酸钠水溶液调节pH至11左右，用二氯甲烷40mL萃取六次，用无水硫酸钠干燥有机相，减压蒸除溶剂，得化合物X1-1(18.0g)。
实施例3-1：消旋醇的制备
Figure PCTCN2021142283-appb-000036
步骤1：在250mL三口瓶中加入E2(20g，CAS NO.1401031-37-5)和80mL水，降温至10-15℃，搅拌，滴入硫酸溶液(由11.5g浓硫酸加入到20mL水中配置而成)，滴完后升温至45-50℃，保温搅拌1小时。降温至5-10℃，加入100mL甲苯，滴加30g 20％氢氧化钠溶液，滴完后室温搅拌1小时。静置分层，分出有机相，水相用2x 100mL甲苯萃取2次，合并有机相，用100mL饱和食盐水洗涤一次，无水硫酸钠干燥后过滤，以甲苯溶液投入下一步。
步骤2：取上述甲苯溶液(约含5.1g D1)，氮气保护，降温至0-10℃，保温滴加16.9g 70％红铝甲苯溶液。滴完后升温至40-45℃，保温搅拌1小时。降温至0-10℃，滴加25mL水淬灭反应，再加入10mL 20％氢氧化钠溶液，升至室温搅拌1小时。过滤，用100mL甲基叔丁基醚淋洗滤饼，母液静置分层，分出有机相，水相再用50mL甲基叔丁基醚萃取一遍。合并有机相，用25mL饱和食盐水洗涤一遍，无水硫酸钠干燥，过滤，滤饼用少量甲基叔丁基醚淋洗，滤液减压浓缩得B2(4.66g黄色油状产品，收率91.4％，纯度92.6％)。 1H NMR(400MHz,CDCl 3):δ8.55-8.53(m,1H),7.64(td, 3J＝7.6Hz, 4J＝2.0Hz,1H),7.32(d, 3J＝8.0Hz,1H),7.12(ddd, 3J＝7.6Hz, 3J＝4.8Hz, 4J＝1.2Hz,1H),3.74-3.71(m,2H),3.53-3.47(m,1H),3.27-3.21(m,1H),2.43-2.40(m,2H),2.27(br,1H),2.01-1.91(m,2H),1.82-1.72(m,3H),1.67-1.58(m,1H),1.55-1.44(m,3H),1.43-1.33(m,1H),1.12-1.06(m,1H),0.74-0.66(m,1H).MS m/z(ESI):262.1[M+1] +.
实施例3-2：消旋醇的制备
Figure PCTCN2021142283-appb-000037
步骤1：用甲醇(10.0mL,5.0v/w)溶解化合物D1(2.0g,7.26mmol,1.0equiv)加入50mL三口瓶中；N 2保护，降温至5～10℃；向三口瓶中滴加SOCl 2(1.08g,9.08mmol,1.25equiv)，约10min滴完，控制内温10～15℃；升温至50～55℃反应3h；将反应液旋干，加入甲叔醚15ml；体系中加入25％碳酸钠水溶液至水相pH至9左右，控制内温10～15℃；分液，水相用10mL*2甲叔醚萃取2次；合并有机相旋干，得C2-1(2.0g，纯度98.0％，收率94.7％)。 1H NMR(400MHz,CDCl 3):δ8.57-8.56(m,1H),7.63(td, 3J＝7.6Hz, 4J＝1.6Hz,1H),7.32(d, 3J＝8.0Hz,1H),7.11(ddd, 3J＝7.6Hz, 3J＝4.8Hz, 4J＝0.8Hz,1H),3.79-3.77(m,2H),3.42(s,3H),2.83(d, 2J＝14.0Hz,1H),2.57-2.43(m,3H),2.00-1.88(m,2H),1.82-1.78(m,1H),1.71-1.61(m,1H),1.57-1.47(m,3H),1.44-1.35(m,1H),1.22-1.16(m,1H),0.82-0.74(m,1H).MS m/z(ESI):290.1[M+1] +.
步骤2：在100mL三口瓶中加入C2-1(1.86g)，15mL甲苯，氮气置换三次，冷却至内温0-10℃，滴加红铝溶液(6.5g)，控制内温<10℃，约30分钟滴加完毕，升温至40-45℃搅拌反应1h。将反应液降温至0-10℃，滴加水(9.3mL)萃灭反应，再滴加20％NaOH溶液(3.7mL)，滴完，升至室温20-25℃搅拌1h。过滤，滤饼用甲基叔丁醚(37mL)淋洗。分液，水相用甲基叔丁醚(19mL)萃取，分液，合并有机相，用饱和NaCl(9.3mL)洗涤，搅拌15分钟，分液，有机相用3.7g无水Na 2SO 4干燥，减压浓缩至无溶剂蒸出，得到B2(1.66g，纯度：98.49％，收率：98.8％)。
实施例3-3：醇的拆分
Figure PCTCN2021142283-appb-000038
将化合物B2(2.50g,9.56mmol,1.0equiv)和R-联萘酚磷酸酯(3.33g,9.56mmol,1.0equiv)加入25mL四氢呋喃后，室温搅拌1h，减压蒸除溶剂，加入20mL乙酸乙酯打浆，过滤，烘干得固体(5.0g)，将固体在50mL四氢呋喃中回流打浆1.5h，冷却至室温打浆1.5h，过滤烘干得淡黄色固体(1.83g，ee％:84.58％)。将所得固体中加入18mL四氢呋喃继续回流1h，冷却至室温打浆1h，过滤，滤饼烘干得淡黄色固体(1.03g，ee％:91.64％)。将1.03g滤饼加入10mL四氢呋喃继续回流1h，冷却至室温打浆1h，过滤，滤饼烘干得淡黄色固体(0.53g，ee％:97.34％)。将滤饼溶于10mL水中，利用饱和碳酸钠溶液调节pH9～10，二氯甲烷萃取(10mL*3)，无水硫酸钠干燥，过滤，旋干，得无色油状物(0.23g，收率9.1％)。 1H NMR(400MHz, CDCl 3):δ8.55-8.54(m,1H),7.65(td, 3J＝7.6Hz, 4J＝2.0Hz,1H),7.32(d, 3J＝8.0Hz,1H),7.12(ddd, 3J＝7.6Hz, 3J＝4.8Hz, 4J＝1.2Hz,1H),3.75-3.72(m,2H),3.54-3.48(m,1H),3.28-3.22(m,1H),2.44-2.40(m,2H),2.03-1.91(m,2H),1.82-1.72(m,3H),1.67-1.59(m,1H),1.55-1.44(m,3H),1.42-1.34(m,1H),1.12-1.06(m,1H),0.74-0.66(m,1H).MS m/z(ESI):262.2[M+1] +.将所得到无色油状物和实施例4中合成的化合物B3通过HPLC进行分析比对，二者保留时间一致。结合质谱数据可以确定，本实施例所得无色油状物为化合物B3。
实施例4：手性醇的制备
Figure PCTCN2021142283-appb-000039
步骤1：氮气保护下，将化合物E3(CAS NO.1401031-38-6)(1.03g)，盐酸甲醇溶液(4mol/L，7mL)和无水甲醇(10mL)加入50mL单口瓶，室温搅拌7h，补加盐酸甲醇溶液(4mol/L，3mL)，室温再搅拌2h。向上述反应中加入10mL水，室温搅拌1.0h，反应液减压浓缩干，加入20mL甲基叔丁基醚和10mL水，再加入饱和碳酸钠溶液调节PH＝8，控温10-30℃；分液，水相再用2*20mL甲基叔丁基醚萃取两次；分液，合并有机相，用20mL饱和氯化钠溶液洗涤，有机相加入5g无水硫酸钠干燥；抽滤，用10mL甲基叔丁基醚洗涤滤饼，滤液浓缩干，得到C3-1(1.08g，收率：93.1％，纯度：99.6％)。 1H NMR(400MHz,CDCl 3):δ8.57-8.56(m,1H),7.63(td, 3J＝7.6Hz, 4J＝1.6Hz,1H),7.32(d, 3J＝8.0Hz,1H),7.13-7.10(m,1H),3.79-3.77(m,2H),3.42(s,3H),2.83(d, 2J＝14.4Hz,1H),2.57-2.43(m,3H),2.00-1.86(m,2H),1.82-1.75(m,1H),1.69-1.61(m,1H),1.57-1.47(m,3H),1.46-1.34(m,1H),1.22-1.16(m,1H),0.82-0.74(m,1H).MS m/z(ESI):290.1[M+1] +。
步骤2：取C3-1(0.58g)和甲苯(12mL)加入三口瓶，降温至0-5℃；缓慢滴加3.0eq红铝甲苯溶液，控温0-5℃；滴加结束后保温搅拌0.5h；升温至室温(27℃)保温搅拌1h；后处理得到B3(0.33g，收率：63.2％，纯度：99.33％)。MS m/z(ESI):262.2[M+1] +。
实施例5：手性醇的制备
Figure PCTCN2021142283-appb-000040
步骤1：将化合物E3(0.78g,3.0mmol,1.0equiv)和TsOH·H 2O(628mg,3.3mmol,1.1equiv)加入烧瓶中，加入无水乙醇(7.8mL,10.0v/w)和水(54mg,3.0mmol,1.0equiv)，回流反应8h。反应液减压蒸干，加入水10mL，再用饱和碳酸钠调节水相至pH～9。用甲基叔丁 基醚萃取水相(10mL×2)，有机相旋干合并，得C3-2(0.84g，收率91.3％，纯度91.2％)。1H NMR(400MHz,CDCl3):δ8.58-8.57(m,1H),7.63(td,3J＝7.6Hz,4J＝2.0Hz,1H),7.32(d,3J＝8.0Hz,1H),7.14-7.10(m,1H),3.87(q,3J＝7.2Hz,2H),3.81-3.78(m,2H),2.83(d,2J＝14.0Hz,1H),2.57-2.50(m,2H),2.46(d,2J＝14.0Hz,1H),2.01-1.90(m,2H),1.84-1.79(m,1H),1.72-1.60(m,1H),1.59-1.48(m,3H),1.46-1.34(m,1H),1.22-1.18(m,1H),1.01(t,3J＝7.2Hz,3H)0.83-0.75(m,1H).MS m/z(ESI):304.2[M+1] +。
步骤2：参考实施例4步骤2的方法制备，得到化合物B3。
实施例5-1：手性醇的制备
Figure PCTCN2021142283-appb-000041
步骤1：将化合物E3(100g)和水(400mL)加入反应瓶中，降温至5-15℃。将57.4g浓硫酸溶于100mL水中再滴加到反应瓶中，滴完，升温至45～50℃，保温搅拌1.5h。体系降温至内温在0-10℃，加入500mL甲苯，并滴加20％NaOH溶液(150g)。静置，分液，水相用甲苯(500mL*2)萃取两次，每次搅拌萃取0.5h，静置，分液，合并三次有机相。用饱和NaCl(500mL)洗涤合并后的有机相，有机相用无水Na 2SO 4干燥，旋干，得到化合物D2(108g)。
步骤2：将含化合物D2(107.4g)的甲苯溶液(共836g)加入到反应瓶中，冷却内温至0-10℃，氮气置换三次；缓慢滴加红铝溶液(394.3g)，控制内温0-10℃。滴加结束后，升至内温43℃保温搅拌反应1h。将反应液降温至0-10℃，滴加水500mL淬灭反应，再滴加20％NaOH溶液1500mL。反应液用甲基叔丁基醚1000mL×2搅拌萃取，合并两次有机相。无水Na 2SO 4干燥过滤，滤液减压浓缩，得到化合物B3(91.5g，收率89.8％)。
实施例6：醛的制备
Figure PCTCN2021142283-appb-000042
将化合物B3(1.19g，4.55mmol,1.0equiv)加入25mL单口瓶，再加入DMSO(6.0mL,5.0v/w)，溶解澄清；加入IBX(3.10g,11.4mmol,2.5equiv)，室温搅拌90min，经TLC确认，有少量原料剩余；补加IBX(0.65g,2.27mmol,0.5equiv)，同时补加DMSO(3.6mL,3.0v/w)，搅拌1h，TLC基本无原料；将反应液倒入40mL水中，析出大量固体过滤，滤饼用5mL×2水洗涤；水相用10％Na 2CO 3水溶液调节至pH 8～9，水相用DCM萃取(15mL×3)；DCM相用饱和食盐水洗涤(6mL×2)，DCM相旋干后，有少量固体颗粒存在于油状物中；加入5mL乙酸乙酯于油状物中，取清液旋干；得到化合物A1(0.76g，收率64.4％，纯度>98.0％)，MS m/z(ESI):260.2[M+1] +。
实施例7：
Figure PCTCN2021142283-appb-000043
将化合物A1(50mg，0.3mmol)溶解于(5mL)甲醇中，加入化合物X1-1(78.3mg，0.3mmol)和氰基硼氢化钠(94mg，1.5mmol),20℃搅拌反应3小时。向反应液中加入20mL水，用DCM(30mL×2)萃取，无水硫酸钠干燥，减压浓缩，浓缩物用制备色谱法纯化(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)，得到单一构型化合物I-1(10.12mg)。MS m/z(ESI):409.2[M+1] +； 1H NMR(400MHz,CD 3OD)δ8.51(ddd,J＝4.9,1.8,0.8Hz,1H),7.79–7.71(m,1H),7.50(d,J＝8.1Hz,1H),7.41(d,J＝1.9Hz,1H),7.22(ddd,J＝7.5,4.9,1.0Hz,1H),5.87(dd,J＝1.9,0.6Hz,1H),4.07(ddd,J＝21.0,11.7,6.2Hz,2H),3.81–3.69(m,2H),2.73–2.58(m,2H),2.52(dd,J＝14.0,2.3Hz,1H),2.48–2.35(m,2H),2.12–1.97(m,2H),1.95–1.82(m,2H),1.78–1.65(m,3H),1.64–1.36(m,5H),1.14–1.04(m,1H),0.99(d,J＝7.0Hz,3H),0.79–0.65(m,4H).
实施例8：
Figure PCTCN2021142283-appb-000044
向反应釜中加入化合物A1(950g)、化合物X1-1的L-酒石酸盐(1.16kg)、无水乙醇(7.51kg)、三乙胺(0.74kg)，将体系降温到10～15℃，分批加入三乙酰氧基硼氢化钠(1.32kg)，继续搅拌反应2小时。向反应釜中加入纯化水(38.0kg)，搅拌0.5小时，再向反应釜中缓慢滴加适量盐酸水溶液调节pH至约4.5。向反应釜中加入7.04kg甲叔醚，搅拌15分钟，静置分层，收集水相。水相中加入适量碳酸钠水溶液调节水相pH至6.5。再向水相中加入7.04kg×2甲叔醚萃取分液，收集有机相。合并有机相，用5.70kg纯化水洗涤，分液。滤液减压浓缩至恒重，得到化合物I-1(823g，收率55％)。
测试例1 HTRF-cAMP细胞实验
实验方法和步骤
一、细胞复苏
1、将复苏液从4℃冰箱中取出放37℃水浴锅中预热15分钟。
2、从液氮罐中取出P6代细胞，将冰冻的细胞冻存管迅速放在37℃水浴锅中轻轻晃动30秒到1分钟，直到看见小冰晶或细胞即将完全融化。
3、用70％的酒精进行彻底的消毒擦干。
4、离心去除冻存液，用预先预热的新鲜复苏液重悬细胞。
a、吸取3ml预先预热的细胞复苏液到15ml离心管。
b、1300rpm离心3分钟。
c、去除上清冻存液，用4ml预热的复苏液重悬细胞。
5、将细胞混悬液转移到T25细胞培养瓶中培养24小时，37℃，5％CO2。
6、培养24小时后，将细胞培养瓶中的复苏液换成预热好的细胞培养基。
二、细胞传代
1、当细胞在T25培养瓶中的生长密度>70％时,用细胞消化液对细胞进行消化传代培养。
a、吸出培养瓶中的培养基，加入4ml预先预热的PBS，轻轻晃动润洗细胞，吸弃PBS。
b、吸取1ml细胞消化液加入到T25培养瓶中。
c、反复摇晃培养瓶使消化液彻底覆盖培养瓶，放在37℃,5％CO2培养箱中5分钟。
d、取出细胞培养瓶，在显微镜下观察细胞，看细胞是否被分离。
e、加入3ml预热好的细胞培养基，终止消化。
f、用细胞培养基反复轻轻冲洗培养瓶，收集细胞悬液到15ml离心管。
g、1300rpm离心3分钟，去除上清。
h、用3ml细胞培养基重悬。
2、按1：3的比例进行细胞传代(每瓶加入1ml的细胞重悬液+3ml的细胞培养基，传至T25瓶)。
三、细胞种板
1、重复步骤2.2.1(a-h)，直到细胞传到P8代。细胞计数，然后用2×/1mM IBMX stimulation buffer液重悬细胞，使细胞密度为1.2*10^6/ml.
2、使用多通道移液器，将1.2*10^6/ml的细胞溶液，以每孔10μl的体积(即每孔12000个细胞)种在384孔板内。
四、c-AMP试验
1、配置相关试剂，按药物稀释配置表，配置化合物。
a、1×Stimulation buffer液：取1ml的5×Stimulation buffer存储液加到4ml的蒸馏水中，混匀。
b、2×/1mM IBMX stimulation buffer液5ml：取10ul 500mM IBMX存储液加到4990μl细胞培养基中，轻轻吹打混匀。
c、吗啡的梯度稀释配置表：
Figure PCTCN2021142283-appb-000045
d、化合物稀释之前，先将化合物用DMSO溶解，使其存储浓度为10mM.
化合物I-1稀释配置表：
Figure PCTCN2021142283-appb-000046
e、50uM NK477 1ml：取1μl 50mM NKH477存储液加到999μl 1×Stimulation buffer液中，震荡混匀。
f、检测试剂
A.cAMP-Cryptate(donor,lyophilized)反应液：取1ml 5×cAMP-Cryptate存储液加到4ml 1×Lysis & Detection Buffer液中，轻轻混匀。
B.Anti-cAMP-d2(acceptor,lyophilized)反应液：取1ml 5×Anti-cAMP-d2存储液加到4ml 1×Lysis & Detection Buffer液中，轻轻混匀。
2、cAMP试验步骤
a、以12000个细胞/每孔将细胞接种在10μl含2xIBMX stimulation缓冲液中。
b、在每孔细胞中加入8μl的化合物样品稀释液。
c、每孔中加入配置好的2μl 10xNKH477液。
d、37℃孵育45mins。
e、加入10μl cAMP-d2和10μl抗cAMP Cryptate反应液。
f、室温避光孵育60mins。
g、HTRF读板。
3、RFU检测读板
孵育60分钟后，所有的样品将通过均相时间分辨荧光的方法检测读板。
数据分析
将数据从多功能读板仪连接的电脑中对应软件导出，包括665nm和620nm两个信号值。比率的计算公式为：比率＝665nm信号值/620nm信号值×10000。用GraphPad Prism软件对数据进行分析。最佳拟合曲线选用log(agonist)vs.response.利用计算机辅助剂量-反应曲线的非线性回归分析方式确定化合物的EC50值；PEC50＝-logEC50(EC50值的单位是摩尔)；％吗啡的最大效应值＝(化合物样品比率-空白孔比率)/TOP×100(注：TOP值是吗啡样品比率-空白孔比率后通过软件Graphpad Prism分析拟合的曲线Top值)。结果如表1所示：
表1 化合物对cAMP的活性
Figure PCTCN2021142283-appb-000047
测试例2 β-Arrestin细胞实验
实验方法和步骤
一、细胞复苏
1、将复苏液从4℃冰箱中取出放37℃水浴锅中预热15分钟。
2、从液氮罐中取出P6代细胞，将冰冻的细胞培养管迅速放在37℃水浴锅中轻轻晃动30秒到1分钟，直到看见小冰晶或细胞即将完全融化。
3、用70％的酒精进行彻底的消毒擦干。
4、离心去除冻存液，用预先预热的新鲜复苏液重悬细胞。
a、吸取3ml预先预热的细胞复苏液到15ml离心管。
b、1300rpm离心3分钟。
c、去除上清，用4ml预热的复苏液重悬细胞。
5、将细胞混悬液转移到T25细胞培养瓶中培养24小时，37℃，5％CO 2。
6、培养24小时后，将细胞培养瓶中的复苏液换成预热好的细胞培养基。
二、细胞传代
1、当细胞在T25培养瓶中的生长密度>70％时,用细胞消化液对细胞进行消化传代培养。
a.吸出培养瓶中的培养基，加入4ml预先预热的PBS，轻轻晃动润洗细胞，吸弃PBS。
b.吸取1ml细胞消化液加入到T25培养瓶中。
c.反复摇晃培养瓶使消化液彻底覆盖培养瓶，放在37℃,5％CO 2培养箱中5分钟。
d.取出细胞培养瓶，在显微镜下观察细胞，看细胞是否被分离。
e.加入3ml预热好的细胞培养基，终止消化。
f.用细胞培养基反复轻轻冲洗培养瓶，最后将细胞悬液转移到15ml离心管。
g.1300rpm离心3分钟，去除上清。
h.用3ml细胞培养基重悬。
2、按1：3的比例进行细胞传代(每瓶加入1ml的细胞重悬液+3ml的细胞培养基，传至T25瓶)。
3、重复步骤2.2.1(a-h)，直到细胞传到P8代。
三、细胞种板
1、用移液器取20μl的细胞悬液用细胞计数仪测量细胞数。
2、1300rpm离心3分钟，沉淀细胞。
3、去除上清，加入相应细胞铺板液使细胞浓度为2×10^5/ml。
4、使用多通道移液器，根据实验设计，将2×10^5/ml的细胞溶液，以每孔20μl的体积(即每孔4000个细胞)接种在384孔板内。
5、将接种好细胞的384孔板放到37℃,5％CO 2培养箱中培养24h。
四、β-arrestin试验
1、按照下列稀释表配置化合物。
a.吗啡的梯度稀释配置表：
Figure PCTCN2021142283-appb-000048
b.化合物稀释之前，先将化合物用DMSO溶解，使其存储浓度为10mM.
化合物I-1稀释配置表：
Figure PCTCN2021142283-appb-000049
2、取5μl上述配置好的各化合物样品稀释液加到384孔板中。
3、加完样后，将384孔板放回37℃,5％CO 2培养箱中培养90分钟。
五、RLU检测
1、化合物孵育结束前，按下列比例配置Working Detection溶液(注意避光)。然后每孔加入12.5μl，避光、常温、摇床孵育1h。
Figure PCTCN2021142283-appb-000050
Figure PCTCN2021142283-appb-000051
2、化合物孵育结束，每孔加入12.5μl上述工作液，避光、常温、80rpm摇床孵育1h。
3、孵育结束，运用多功能读板仪进行读板。
数据分析
将数据从多功能读板仪连接的电脑中对应软件导出，用GraphPad Prism软件对数据进行分析。最佳拟合曲线选用log(agonist)vs.response.利用计算机辅助剂量-反应曲线的非线性回归分析方式确定化合物的EC50值；PEC50＝-logEC50(EC50值的单位是摩尔)；％吗啡的最大效应值＝(化合物样品的RLU值-空白孔的RLU值)/TOP×100(注：TOP值是吗啡样品的RLU值-空白孔的RLU值后通过软件Graphpad Prism分析拟合的曲线Top值)。结果如表2所示：
表2 化合物对β-arrestin的测试结果
Figure PCTCN2021142283-appb-000052
从表1和表2可以看出，化合物I-1对cAMP具有较高的抑制活性，以及较高的Emax值，对β-arrestin具有较低的Emax值，偏向性好。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (35)

  1. 式C所示的化合物，或其立体异构体：
    Figure PCTCN2021142283-appb-100001
    其中，
    R为C 1-8烷基(优选为C 1-4烷基)、-C 1-4烷基-C 6-10芳基(优选为-CH 2-芳基，更优选为苄基)、或C 6-10芳基(优选为苯基)；
    A环为C 6-10芳环(优选苯环)或5至6元单环杂芳基环(优选吡啶环)；
    (R 0) n为A环上的氢被n个R 0取代，n为0、1、2、3或4；每个R 0相同或不同，并且各自独立地为氢、氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代C 1-4烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、5至6元单环杂芳基、C 1-8烷基(优选为C 1-4烷基)、C 1-8烷氧基(优选为C 1-4烷氧基)、C 3-6环烷基、C 3-6环烷氧基、C 2-4烯基、C 2-4炔基、NR 11R 12、-CONR 11R 12、-C(O)OC 1-8烷基(优选为-C(O)OC 1-4烷基)、-OC(O)C 1-8烷基(优选为-OC(O)C 1-4烷基)、-SO 2C 1-8烷基(优选为-SO 2C 1-4烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)、4至6元饱和单杂环或3至6元饱和单环，其中所述C 6-10芳基、5至6元单环杂芳基、4至6元饱和单杂环和3至6元饱和单环为未取代的或被1、2或3个选自乙酰基、羟基、氰基、卤素、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、NR 11R 12的取代基取代；
    R 11、R 12各自独立地为氢、C 1-8烷基(优选为C 1-4烷基)、卤代C 1-8烷基(优选为卤代C 1-4烷基)、C 3-6环烷基或4至6元饱和单杂环；或者R 11、R 12与相连的氮原子共同形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-4烷基取代。
  2. 如权利要求1所述的化合物，或其立体异构体，其特征在于，所述式C化合物为式C2所示结构：
    Figure PCTCN2021142283-appb-100002
    其中，R为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基、苯基或苄基(优选为甲基)。
  3. 如权利要求1所述的化合物，或其立体异构体，其特征在于，所述式C化合物为式C3所示结构：
    Figure PCTCN2021142283-appb-100003
    其中，R为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基、苯基或苄基(优选为甲基)。
  4. 权利要求1-3任一项所述的式C所示化合物或其立体异构体的制备方法，包括以下步骤：
    Figure PCTCN2021142283-appb-100004
    将式E所示化合物或其立体异构体进行一步或两步以上反应，制备得式C所示化合物或其立体异构体，其中，R、A环以及(R 0) n如权利要求1所定义。
  5. 如权利要求4所述的制备方法，其特征在于，将式E所示化合物或其立体异构体进行两步反应，制备得式C所示化合物或其立体异构体的步骤包括以下步骤：
    Figure PCTCN2021142283-appb-100005
    将式E所示化合物或其立体异构体进行反应，制得式D所示化合物或其立体异构体；
    将式D所示化合物或其立体异构体与ROH进行反应，制得式C所示化合物或其立体异构体。
  6. 如权利要求4所述的制备方法，其特征在于，式C化合物为式C1所示结构，式E化合物为式E1所示结构：
    Figure PCTCN2021142283-appb-100006
    将式E1所示化合物进行一步或两步以上反应，制备得式C1所示化合物。
  7. 一种式B所示的化合物或其立体异构体：
    Figure PCTCN2021142283-appb-100007
    其中，A环为C 6-10芳环(优选苯环)或5至6元单环杂芳基环(优选吡啶环)；
    (R 0) n为A环上的氢被n个R 0取代，n为0、1、2、3或4；每个R 0相同或不同，并且各自独立地为氢、氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代C 1-4烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、5至6元单环杂芳基、C 1-8烷基(优选为C 1-4烷基)、C 1-8烷氧基(优选为C 1-4烷氧基)、C 3-6环烷基、C 3-6环烷氧基、C 2-4烯基、C 2-4炔基、NR 11R 12、-CONR 11R 12、-C(O)OC 1-8烷基(优选为-C(O)OC 1-4烷基)、-OC(O)C 1-8 烷基(优选为-OC(O)C 1-4烷基)、-SO 2C 1-8烷基(优选为-SO 2C 1-4烷基)、-SO 2C 6-10芳基(优选为-SO 2-苯基)、-COC 6-10芳基(-CO-苯基)、4至6元饱和单杂环或3至6元饱和单环，其中所述C 6-10芳基、5至6元单环杂芳基、4至6元饱和单杂环和3至6元饱和单环为未取代的或被1、2或3个选自乙酰基、羟基、氰基、卤素、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、NR 11R 12的取代基取代；
    R 11、R 12各自独立地为氢、C 1-8烷基(优选为C 1-4烷基)、卤代C 1-8烷基(优选为卤代C 1-4烷基)、C 3-6环烷基或4至6元饱和单杂环；或者R 11、R 12与相连的氮原子共同形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-4烷基取代。
  8. 如权利要求7所述的化合物，或其立体异构体，其特征在于，所述式B化合物为式B2所示结构：
    Figure PCTCN2021142283-appb-100008
  9. 如权利要求7所述的化合物，或其立体异构体，其特征在于，所述式B化合物为式B3所示结构：
    Figure PCTCN2021142283-appb-100009
  10. 权利要求7-9任一项所述的式B所示化合物或其立体异构体的制备方法，包括以下步骤：
    Figure PCTCN2021142283-appb-100010
    将式C所示化合物或其立体异构体进行反应，制备得式B所示化合物或其立体异构体，其中，R为C 1-8烷基(优选为C 1-4烷基)、-C 1-4烷基-C 6-10芳基(优选为-CH 2-芳基，更优选为苄基)、或C 6-10芳基(优选为苯基)；
    其中，A环以及(R 0) n如权利要求7所定义。
  11. 如权利要求10所述的制备方法，其特征在于，式B化合物为式B1所示结构：
    Figure PCTCN2021142283-appb-100011
  12. 如权利要求11所述的制备方法，其特征在于，式B1所示化合物的制备方法还包括步骤：
    Figure PCTCN2021142283-appb-100012
    将式B所示化合物进行手性拆分，得到式B1所示化合物。
  13. 如权利要求12所述的制备方法，其特征在于，所述手性拆分的步骤中，所采用的拆分剂为D-酒石酸、D-二苯甲酰酒石酸、D-苹果酸、D-扁桃酸、D-樟脑磺酸或R-联萘酚磷酸酯，优选为R-联萘酚磷酸酯。
  14. 如权利要求10所述的制备方法，其特征在于，式C化合物为式C1所示结构，式B化合物为式B1所示结构：
    Figure PCTCN2021142283-appb-100013
    将式C1所示化合物进行反应，制备得式B1所示化合物。
  15. 如权利要求10-14任一所述的制备方法，其特征在于，还包括采用权利要求4-6任一项所述的制备方法制备式C所示化合物或其立体异构体的步骤。
  16. 权利要求7-9任一项所述的式B所示化合物或其立体异构体的制备方法，包括以下步骤：
    Figure PCTCN2021142283-appb-100014
    将式D所示化合物或其立体异构体进行反应，制备得式B所示化合物或其立体异构体，其中，A环以及(R 0) n如权利要求7所定义。
  17. 如权利要求16所述的制备方法，其特征在于，式B化合物为式B1所示结构：
    Figure PCTCN2021142283-appb-100015
  18. 如权利要求17所述的制备方法，其特征在于，式B1所示化合物的制备方法还包括步骤：
    Figure PCTCN2021142283-appb-100016
    将式B所示化合物进行手性拆分，得到式B1所示化合物。
  19. 如权利要求18所述的制备方法，其特征在于，所述手性拆分的步骤中，所采用的拆分剂为D-酒石酸、D-二苯甲酰酒石酸、D-苹果酸、D-扁桃酸、D-樟脑磺酸或R-联萘酚磷酸酯，优选为R-联萘酚磷酸酯。
  20. 如权利要求16-19任一项所述的制备方法，其特征在于，采用以下方法制备式D所示化合物或其立体异构体：
    Figure PCTCN2021142283-appb-100017
    将式E所示化合物或其立体异构体进行反应，制得式D所示化合物或其立体异构体。
  21. 式X所示化合物或其立体异构体的制备方法，包括以下步骤：
    Figure PCTCN2021142283-appb-100018
    将式Z所示化合物或其立体异构体进行反应，制得式Y所示化合物或其立体异构体；以及
    将式Y所示化合物或其立体异构体进行反应，制得式X所示化合物或其立体异构体，
    其中，在式Z、式Y和式X中，R a、R b各自独立地为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)；或者R a、R b与相连的碳原子共同形成4至6元饱和单杂环或3至6元饱和单环；其中所述4至6元饱和单杂环和3至6元饱和单环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1、-NHSO 2C 3-6环烷基；
    R c为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、C 2-6烯基(优选为C 2-4烯基)、C 2-6炔基(优选为C 2-4炔基)、C 1-6烷氧基(优选为C 1-3烷氧基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)、-COC 1-6烷基(优选为-COC 1-3烷基)、-CONR a1R b1、NR a1R b1、-NHCOC 1-6烷基(优选为-NHCOC 1-3烷基)、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2N R a1R b1、-NHSO 2C 3-6环烷基、-SO 2C 1-3烷基、-SO 2NR a1R b1、4至6元饱和单杂环、C 6-10芳基或5或6元单环杂芳基；其中所述4至6元饱和单杂环、C 6-10芳基和5或6元单环杂芳基为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1、-NHSO 2C 3-6环烷基；
    R a1、R b1各自独立地为氢、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3 烷基)、C 3-6环烷基或4至6元饱和单杂环；或者R a1、R b1与相连的氮原子共同形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-3烷基取代。
  22. 如权利要求21所述的制备方法，其特征在于，所述式X化合物为式X1所示结构：
    Figure PCTCN2021142283-appb-100019
  23. 如权利要求22所述的制备方法，其特征在于，制备式X1所示化合物还包括以下步骤：
    Figure PCTCN2021142283-appb-100020
    将式X所示化合物进行手性拆分，制得式X1所示化合物。
  24. 如权利要求21-23中任一项所述的制备方法，其特征在于，R a为甲基，R b为H，R c为甲基。
  25. 如权利要求23所述的制备方法，其特征在于，所述手性拆分步骤中，所采用的拆分剂为L-酒石酸、L-二苯甲酰酒石酸、L-苹果酸、L-扁桃酸、L-樟脑磺酸或S-联萘酚磷酸酯，优选为L-酒石酸。
  26. 式I所示化合物或其立体异构体的制备方法，包括以下步骤：
    (i)将式B所示化合物或其立体异构体进行反应，制得式A所示化合物或其立体异构体：
    Figure PCTCN2021142283-appb-100021
    (ii)将式A所示化合物或其立体异构体和式X所示化合物或其立体异构体进行反应，制得式I所示化合物或其立体异构体：
    Figure PCTCN2021142283-appb-100022
    其中，A环为C 6-10芳环(优选苯环)或5至6元单环杂芳基环(优选吡啶环)；
    (R 0) n为A环上的氢被n个R 0取代，n为0、1、2、3或4；每个R 0相同或不同，并且各自独立地为氢、氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代 C 1-4烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、5至6元单环杂芳基、C 1-8烷基(优选为C 1-4烷基)、C 1-8烷氧基(优选为C 1-4烷氧基)、C 3-6环烷基、C 3-6环烷氧基、C 2-4烯基、C 2-4炔基、NR 11R 12、-CONR 11R 12、-C(O)OC 1-8烷基(优选为-C(O)OC 1-4烷基)、-OC(O)C 1-8烷基(优选为-OC(O)C 1-4烷基)、-SO 2C 1-8烷基(优选为-SO 2C 1-4烷基)、-SO 2C 6-10芳基(优选为-SO 2-苯基)、-COC 6-10芳基(-CO-苯基)、4至6元饱和单杂环或3至6元饱和单环，其中所述C 6-10芳基、5至6元单环杂芳基、4至6元饱和单杂环和3至6元饱和单环为未取代的或被1、2或3个选自乙酰基、羟基、氰基、卤素、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、NR 11R 12的取代基取代；
    R 11、R 12各自独立地为氢、C 1-8烷基(优选为C 1-4烷基)、卤代C 1-8烷基(优选为卤代C 1-4烷基)、C 3-6环烷基或4至6元饱和单杂环；或者R 11、R 12与相连的氮原子共同形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-4烷基取代；
    R a、R b各自独立地为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)；或者R a、R b与相连的碳原子共同形成4至6元饱和单杂环或3至6元饱和单环；其中所述4至6元饱和单杂环和3至6元饱和单环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1、-NHSO 2C 3-6环烷基；
    R c为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、C 2-6烯基(优选为C 2-4烯基)、C 2-6炔基(优选为C 2-4炔基)、C 1-6烷氧基(优选为C 1-3烷氧基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)、-COC 1-6烷基(优选为-COC 1-3烷基)、-CONR a1R b1、NR a1R b1、-NHCOC 1-6烷基(优选为-NHCOC 1-3烷基)、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2N R a1R b1、-NHSO 2C 3-6环烷基、-SO 2C 1-3烷基、-SO 2NR a1R b1、4至6元饱和单杂环、C 6-10芳基或5或6元单环杂芳基；其中所述4至6元饱和单杂环、C 6-10芳基和5或6元单环杂芳基为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1、-NHSO 2C 3-6环烷基；
    R a1、R b1各自独立地为氢、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、C 3-6环烷基或4至6元饱和单杂环；或者R a1、R b1与相连的氮原子共同形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-3烷基取代。
  27. 如权利要求26所述的制备方法，其特征在于，采用权利要求10-20中任一项所述的制备方法制备式B所示化合物或其立体异构体。
  28. 如权利要求26所述的制备方法，其特征在于，采用权利要求21-25中任一项所述的制备方法制备式X所示化合物或其立体异构体。
  29. 如权利要求26所述的制备方法，其特征在于，所述式I所示化合物为式I-1所示结构：
    Figure PCTCN2021142283-appb-100023
  30. 根据权利要求29所述的制备方法，其特征在于，采用以下合成路线制备式I-1所示化合物：
    Figure PCTCN2021142283-appb-100024
  31. 根据权利要求30所述的制备方法，其特征在于，所述式X1-1化合物选自式X1-1的游离碱或其L-酒石酸盐、L-二苯甲酰酒石酸盐、L-苹果酸盐、L-扁桃酸盐、L-樟脑磺酸盐或S-联萘酚磷酸酯盐，优选为L-酒石酸盐。
  32. 如权利要求30所述的制备方法，其特征在于，采用以下合成路线制备式B3所示化合物：
    Figure PCTCN2021142283-appb-100025
  33. 如权利要求30所述的制备方法，其特征在于，采用以下合成路线制备式B3所示化合物：
    Figure PCTCN2021142283-appb-100026
    其中，R为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基、苯基或苄基(优选为甲基)。
  34. 如权利要求30所述的制备方法，其特征在于，采用以下合成路线制备式B3所示化合物：
    Figure PCTCN2021142283-appb-100027
    其中，R为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、苯基或苄基(优 选为甲基)。
  35. 如权利要求30所述的制备方法，其特征在于，采用以下合成路线制备式B3所示化合物：
    Figure PCTCN2021142283-appb-100028
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