WO2019062804A1 - 一种氧杂螺环类衍生物的制备方法及其中间体 - Google Patents

一种氧杂螺环类衍生物的制备方法及其中间体 Download PDF

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Publication number
WO2019062804A1
WO2019062804A1 PCT/CN2018/107901 CN2018107901W WO2019062804A1 WO 2019062804 A1 WO2019062804 A1 WO 2019062804A1 CN 2018107901 W CN2018107901 W CN 2018107901W WO 2019062804 A1 WO2019062804 A1 WO 2019062804A1
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Prior art keywords
group
compound
formula
aryl
heteroaryl
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PCT/CN2018/107901
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English (en)
French (fr)
Inventor
李文海
齐维兴
邱振均
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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Priority to CN201880035013.9A priority Critical patent/CN110678453B/zh
Priority to MX2020003784A priority patent/MX395589B/es
Priority to RU2020113709A priority patent/RU2777983C2/ru
Priority to CA3076395A priority patent/CA3076395A1/en
Priority to JP2020517594A priority patent/JP2020535177A/ja
Priority to BR112020005858-0A priority patent/BR112020005858A2/pt
Priority to AU2018341782A priority patent/AU2018341782A1/en
Priority to KR1020207012222A priority patent/KR20200060750A/ko
Application filed by Jiangsu Hengrui Medicine Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Priority to US16/651,922 priority patent/US11111236B2/en
Priority to EP18862192.4A priority patent/EP3689859A4/en
Publication of WO2019062804A1 publication Critical patent/WO2019062804A1/zh
Anticipated expiration legal-status Critical
Priority to ZA2020/02138A priority patent/ZA202002138B/en
Ceased legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to a preparation method of an oxaspirocyclic derivative and an intermediate thereof.
  • Postoperative pain is the most common acute pain.
  • Commonly used drugs are opioids, such as fentanyl, morphine, meperidine, oxycodone, etc.
  • the pharmacological activity of analgesia is activated by activation in the central nervous system as well as the gastrointestinal tract.
  • the G ⁇ i protein receptor ( ⁇ opioid receptor, MOR) on the cell membrane inhibits the hyperpolarization of nerve fibers to achieve.
  • Opioid receptors are an important class of G protein-coupled receptors (GPCRs), which are targets for the binding of endogenous opioid peptides and opioids.
  • GPCRs G protein-coupled receptors
  • the opioid receptors activate the nervous system and the endocrine system. It has a regulating effect, and opioids are the strongest and commonly used central analgesics.
  • Endogenous opioid peptides are naturally occurring opioid active substances in mammals.
  • endogenous opioid peptides are broadly classified into enkephalins, endorphins, dynorphins and neomorphins (Pharmacol Rev 2007; 59:88-123).
  • opioid receptors in the central nervous system namely ⁇ (MOR), ⁇ (DOR), ⁇ (KOR) receptors and the like.
  • MOR is a target for endogenous enkephalins and opioid analgesics such as morphine.
  • the method has the problems of small batch size, post-treatment method using chiral column separation and purification, thin layer chromatography purification, low yield, etc., wherein the reaction yield of preparing compound 19 is only 35%; the reduction used in the preparation of compound 5a
  • the agent DIBAL is a dangerous flammable reagent, and large impurities are generated during the reaction, which is not conducive to industrial expansion, and it is necessary to improve the preparation method.
  • the present invention provides a method for producing a compound represented by D1 or a salt thereof,
  • the method comprises the steps of chiral resolution of a compound represented by formula D or a salt thereof, which is preferably a chromatographic resolution method (such as chiral HPLC) or chemical resolution (such as using a hand). Separation of sexual resolving agents),
  • R is selected from aryl or heteroaryl, which is optionally selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, oxo, alkenyl, haloalkoxy Base, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR 3 , C(O)R 3 , C(O)OR 3 , S(O) m R 3 or NR 4 R 5 Substituted by one or more substituents;
  • R 3 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group , heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, halo, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or Substituting one or more substituents in the heteroaryl;
  • R 4 and R 5 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a carboxylate group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group.
  • the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkane Substituted by one or more substituents in the group, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • n 0, 1, or 2.
  • the resolving agent used in the chiral resolution method is an alkaline chiral resolving agent, which may be S-phenylethylamine, quinidine, cinchonidine or arginine.
  • the resolving agent used in the chiral resolution method is S-phenylethylamine.
  • the method for producing the compound represented by D1 or a salt thereof further comprises the step of preparing a compound of the formula D, wherein the reaction condition is preferably from alkaline hydrolysis,
  • R is as defined in the compound of formula D.
  • the base used in the hydrolysis reaction is selected from the group consisting of sodium hydroxide, potassium hydroxide or lithium hydroxide, and the like.
  • the compound of Formula D1 is:
  • the preparation method comprises the following steps:
  • a method of preparing a compound of D1 or a salt thereof comprising:
  • R is as defined in the compound of formula D.
  • a method of preparing a compound of the formula D2 or a salt thereof comprising:
  • the present invention also provides a compound of the formula D1 or a salt thereof,
  • the compound of Formula D1 is:
  • the compound salt of formula D1 is:
  • M is selected from the group consisting of S-phenylethylamine, quinidine, cinchonidine or arginine.
  • the salt of the compound of formula D1 is
  • the invention also provides a process for the preparation of a compound of formula D1-1, comprising the steps of reacting a compound of formula D with a chiral resolving agent M to give a compound of formula D1-1, said chiral resolution
  • the agent is preferably an alkaline chiral resolving agent, more preferably S-phenylethylamine, quinidine, cinchonidine or arginine.
  • the method for preparing the compound represented by the formula D1-1 further comprises:
  • R is as defined in formula D1.
  • R is M is S-phenethylamine
  • the preparation method is as follows:
  • the present invention also provides a process for the preparation of a compound of the formula B or a stereoisomer thereof, which comprises: the compound of the formula D or a stereoisomer thereof is prepared by a one-step or one-step reaction to obtain a compound of the formula B or The steps of its stereoisomers,
  • R is as defined in the compound represented by formula D1, preferably from
  • the compound of Formula B is:
  • the preparation method comprises the following:
  • a compound containing an aldehyde group is usually produced by a one-step reaction, a two-step reaction or a two-step reaction.
  • the preferred two-step reaction of the present invention is preferred.
  • a compound containing an aldehyde group is prepared.
  • a method of preparing a compound of Formula B or a stereoisomer thereof comprises:
  • R is as defined in the compound represented by formula D1, preferably from
  • the compound of formula B or a stereoisomer thereof is
  • the preparation method comprises the following:
  • the compound of Formula B or a stereoisomer thereof is
  • the preparation method comprises the following:
  • a method of preparing a compound of Formula B or a stereoisomer thereof comprises:
  • R is as defined in the compound represented by formula D1.
  • the method of preparing a compound of Formula B or a stereoisomer thereof further comprises the method steps described above for the preparation of a compound of Formula D1 or a salt thereof.
  • the compound of Formula B or a stereoisomer thereof is
  • the preparation method comprises the following:
  • R is as defined in the compound represented by formula D1.
  • the compound of Formula B or a stereoisomer thereof is
  • the preparation method comprises the following:
  • the invention also provides a compound of formula C,
  • R is as defined in the compound represented by formula D1, preferably from
  • the compound of Formula C is:
  • R is as defined in the compound represented by formula D1, preferably from
  • the compound of Formula C is:
  • the invention also provides a process for the preparation of a compound of formula C, which comprises:
  • R is as defined in the compound represented by formula D1.
  • the compound of Formula C is:
  • the preparation method comprises the following:
  • the method of preparing a compound of Formula C1 further comprises the steps of the foregoing method of preparing a compound of Formula D1.
  • a method of preparing a compound of Formula C1 includes:
  • R is as defined in the compound represented by formula D1.
  • the compound of Formula C is:
  • the preparation method comprises the following:
  • the method of preparing a compound of Formula C2 further comprises the steps of the foregoing method of preparing a compound of Formula D-1.
  • a method of preparing a compound of Formula C2 includes:
  • the present invention also provides a process for the preparation of a compound of the formula I or a salt thereof, which comprises reacting a compound of the formula D or a stereoisomer thereof to give a compound of the formula B or a stereoisomer thereof, the formula B A step of reacting a compound or a stereoisomer thereof with a compound of formula A or a stereoisomer thereof to give a compound of formula I,
  • R1 is selected from a hydrogen atom or an alkyl group
  • R2 is selected from an optionally substituted aryl or heteroaryl group selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a cyano group, Oxo, alkenyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR3, -C(O)R3, -C(O)OR3, -S( O) mR3 or -NR4R5, wherein the alkyl, alkoxy, alkenyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally selected from the group consisting of a halogen atom, an alkyl group, an alkyl halide Substituted by one or more substituents in the group, hal
  • the method for the preparation of a compound of Formula I or a salt thereof further comprises:
  • R is as defined in the compound represented by formula D1.
  • the method for preparing the compound of the formula I or a salt thereof further comprises:
  • the method of preparing a compound of Formula I or a salt thereof further comprises the method steps described above for the preparation of a compound of Formula D1 or a salt thereof.
  • the method of preparing a compound of Formula I or a salt thereof further comprises the aforementioned method steps of preparing a compound of Formula B or a stereoisomer thereof.
  • the compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the preparation method comprises the following:
  • a method of preparing a compound of Formula II includes:
  • the compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the preparation method comprises the following:
  • a method for preparing a compound of Formula III includes:
  • the method for preparing a compound of formula III comprises:
  • the compound of the formula (E) is reacted with a base in an organic solvent to be hydrolyzed to a compound of the formula D-1;
  • the basic condition is preferably sodium hydroxide, potassium hydroxide or aqueous ammonia.
  • the compound of the formula D-1 is reacted with a chiral resolving reagent in an alcohol solvent to form a compound of the formula D2-1;
  • the chiral resolving agent is preferably an alkaline chiral resolving agent, more preferably S-phenylethyl An amine, quinidine, cinchonidine or arginine;
  • the alcohol solvent is preferably methanol, ethanol or isopropanol.
  • the compound of the formula D2-1 is freed under basic conditions to give a compound of the formula D2; the basic condition is preferably sodium hydroxide, potassium hydroxide or aqueous ammonia.
  • the compound of the formula C2 is reacted with a reducing agent to give a compound of the formula B2; the reducing agent is preferably red aluminum.
  • the compound of formula B2 is reacted with a compound of formula A1 to give a compound of formula III.
  • the compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the preparation method comprises the following:
  • methods for preparing a compound of Formula IV include:
  • the present invention also provides the use of the compound of the formula D1, the compound of the formula C or a salt thereof for the preparation of the compound of the formula I,
  • the compound of Formula I is:
  • the compound of Formula I is:
  • the present invention also provides a process for the preparation of a pharmaceutically acceptable salt of a compound of Formula I, Formula II, Formula III, Formula IV, including the steps of the foregoing schemes, and by Formula I, Formula II, Formula III, Formula a step of reacting a compound of IV with an acid to prepare a pharmaceutically acceptable salt thereof, the acid being selected from the group consisting of an organic acid or a mineral acid, preferably an organic acid; the organic acid being selected from the group consisting of acetic acid, maleic acid, and fumaric acid.
  • Tartaric acid citric acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, preferably fumaric acid; the inorganic acid being selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
  • halogen or halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
  • alkyl group in the present invention means a linear or branched alkyl group having 1 to 20 carbon atoms, and includes, for example, "C 1-6 alkyl group", “C 1-4 alkyl group”, etc., specific examples Including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, Neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2- Ethyl butyl,
  • alkenyl group as used in the present invention means a straight or branched chain group having at least one double bond and having 2 to 20 carbon atoms, and includes, for example, "C 2-6 alkenyl group, C 2-4 alkenyl group”. Wait. Examples thereof include, but are not limited to, ethenyl, propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, and the like.
  • haloalkyl refers to a group derived by substituting one or more "halogen atoms” for one or more hydrogen atoms on an "alkyl group” as described above. Defined.
  • hydroxyalkyl or hydroxyalkyl refers to a radical derived from one or more "hydroxy” groups substituted by one or more hydrogen atoms on an "alkyl” group as previously described. definition.
  • alkylsulfonylamino or alkylsulfonyl means alkyl-O-, haloalkyl-O-, alkyl-C(O)-, alkyl-OC(O)-, C(O)-alkane -O-, alkyl-C(O)-NH-, alkyl-NH-C(O)-, alkyl-NH-, (alkyl) 2 -N-, alkyl-S(O) 2 a group to which -NH- or alkyl-S(O) 2 - is attached, wherein "alkyl, haloalkyl” is as defined above.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which includes from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably cycloalkyl.
  • the ring contains from 3 to 10 carbon atoms, and most preferably the cycloalkyl ring contains from 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • the "aryl group” as used in the present invention means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (that is, a ring sharing a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10
  • the aryl group is more preferably a phenyl group, a naphthyl group, a dihydronaphthyl group, a tetrahydronaphthyl group, an anthracenyl group or a fluorenyl group, and most preferably a phenyl group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein at least one of the ring atoms is a hetero atom such as a nitrogen atom or oxygen.
  • An atom or a sulfur atom, and the remaining ring atoms are carbon; optionally, a ring atom (for example, a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxidized.
  • it comprises 3 to 12 ring atoms or 5 to 12 ring atoms, wherein 1 to 4 are hetero atoms, more preferably the heterocyclic ring contains 3 to 8 ring atoms, and more preferably the heterocyclic ring contains 5 to 6 Ring atom.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, dihydrofuranyl, tetrahydrofuranyl Wait.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • heteroaryl refers to a 5 to 14 membered aryl group having from 1 to 4 heteroatoms as ring atoms and the remainder of the ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur or nitrogen.
  • the "alcohol solvent” as used in the present invention means a group derived from one or more "hydroxyl groups” substituted with one or more hydrogen atoms on the "C 1-6 alkyl group", said "hydroxyl group” and "C” 1-6 alkyl” is as defined above, and specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol.
  • the “stereoisomers” described in the present invention are classified into conformational and conformational isomers, and the configurational isomerization is further classified into cis-trans isomerization and optical isomerization (or enantiomeric).
  • Conformational isomerism refers to a stereoisomerism in which organic molecules of a certain configuration cause different arrangement of atoms or groups of molecules in space due to the rotation or distortion of carbon and carbon single bonds. Common alkanes and rings are common. The structure of an alkane compound, such as the chair conformation and the ship conformation that appear in the cyclohexane structure.
  • optical isomer means that when the compound of the invention contains one or more asymmetric centers, it can be used as a racemate and a racemic mixture, a single enantiomer, or a non- Enantiomeric mixtures and single diastereomers.
  • the compounds of the invention have asymmetric centers, each of which will independently produce two optical isomers, the scope of the invention including all possible optical isomers and mixtures of diastereomers and pure or partially Pure compound. If the compound of the present invention contains an olefinic double bond, the present invention includes a cis isomer and a trans isomer unless otherwise specified.
  • the compounds of the present invention may exist in tautomeric forms which have different hydrogen attachment points by displacement of one or more double bonds.
  • a ketone and its enol form are keto-enol tautomers.
  • Each tautomer and mixtures thereof are included in the present invention.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR shift is given in units of 10-6 (ppm).
  • the NMR measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was determined to be a deuterated reagent, and the internal standard was tetramethylsilane (TMS).
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • HPLC measurements were performed using an Agilent 1200 DAD high pressure liquid chromatograph and a Waters 2695-2996 high pressure liquid chromatograph with octadecylsilane bonded silica as the column packing.
  • the compound (25 g) represented by the formula (E1), potassium hydroxide (22.4 g) and ethylene glycol (150 mL) were mixed, and stirred at 150 ° C for 16 hours to terminate the reaction.
  • the reaction solution was cooled to room temperature, diluted with water (150 mL), extracted with dichloromethane (150 mL ⁇ 2), the aqueous phase was adjusted to pH 6 to 7 with 3M hydrochloric acid, and extracted with dichloromethane (200 mL ⁇ 4) The mixture was washed with EtOAc EtOAc (EtOAc m.
  • the compound of the formula (D-1) (28 g) was dissolved in absolute ethanol (100 mL), and the temperature was raised to 50 ° C.
  • the resolving reagent S-phenylethylamine (6.2 g) was dissolved in anhydrous ethanol (100 mL).
  • the S-phenylethylamine solution was dropped into the above solution at 50 ° C, and the mixture was heated to reflux and stirred for 2 hours.
  • the compound of formula (C2) (334.4 g) was dissolved in toluene (2.2 kg) in a reaction flask, cooled to -45 ° C to -35 ° C, argon gas was protected, and the dropping temperature was controlled from -45 to -35 ° C.
  • Red aluminum (348.76g) was added dropwise, and the reaction was stirred at -45 to -35 ° C for 3 to 4 hours.
  • 10% aqueous citric acid solution (1 kg) was added dropwise to the reaction solution at -45 to -35 ° C, and then added.
  • Concentrated hydrochloric acid solution was adjusted to pH 2-3, ethyl acetate (1.8 kg) was added, stirred, and allowed to stand for separation.
  • the aqueous phase was adjusted to pH 11-13 with 5N sodium hydroxide solution and extracted with dichloromethane (3.3 kg ⁇ 2), the methylene chloride layer was combined, washed with a saturated sodium chloride solution (2.7 kg), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Light red oil, directly into the next reaction.

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Abstract

本发明涉及一种氧杂螺环类衍生物的制备方法及其中间体，该方法缩短了反应步骤、提高了反应产率、简单易操控、利于工业扩大生产。

Description

一种氧杂螺环类衍生物的制备方法及其中间体
本申请要求申请日为2017年9月28日的中国专利申请CN201710896555.2的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种氧杂螺环类衍生物的制备方法及其中间体。
背景技术
术后疼痛是最常见的急性疼痛，常用药物是阿片类药，如芬太尼、吗啡、哌替啶、羟考酮等，其镇痛的药理活性是通过激活表达于中枢神经系统以及肠胃道的细胞膜上的Gαi蛋白受体(μ阿片受体，MOR)，抑制神经纤维超极化来实现。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，阿片受体激活后对神经系统免疫及内分泌系统具有调节作用，阿片类药物是目前最强且常用的中枢镇痛药。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(Pharmacol Rev2007；59:88-123)。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。MOR是内源性脑啡肽和吗啡等阿片类镇痛药物的作用靶点。
阿片类药物长期使用会产生耐受以及呼吸抑制、便秘等副作用，而这些副作用被证明与β-arrestin的功能密切相关。为了减小阿片类药物的副作用，可基于MOR的负性β-arrestin偏爱性配体设计药物，使β-arrestin介导的副作用降低，增强治疗效果，对于本发明的氧杂螺环类衍生物在作为MOR选择性药物的研究中，TrevenaInc公司研究发现芳基苄位取代时活性较差(J.Med.Chem.2013,56,8019-8031)；专利申请WO2017063509A1(公开日2017-04-20)公开了单一构型的MOR化合物(式(III)所示)，化学名为(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺的化合物，其制备方法如下，
Figure PCTCN2018107901-appb-000001
Figure PCTCN2018107901-appb-000002
该方法存在批量小、后处理方法使用手性色谱柱分离提纯、薄层色谱法纯化、产率低等问题，其中制备化合物19的反应产率仅为35％；在制备5a化合物中所用的还原剂DIBAL是一种危险易燃试剂，并且，反应过程中产生较大的杂质，不利于工业扩大生产，有必要改进其制备方法。
发明内容
本发明提供一种用于制备D1所示化合物或其盐的方法，
Figure PCTCN2018107901-appb-000003
其包括：式D所示化合物或其盐经手性拆分的步骤，所述手性拆分方法优选自色谱拆分法(如手性高效液相法HPLC)或化学拆分法(如使用手性拆分剂拆分)，
Figure PCTCN2018107901-appb-000004
其中，R选自芳基或杂芳基，所述芳基或杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、氧代基、烯基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、OR 3、C(O)R 3、C(O)OR 3、S(O) mR 3或NR 4R 5中的一个或多个取代基所取代；
R 3选自氢原子、烷基、氘代烷基、氨基、烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基中的一个或多个取代基所取代；
R 4和R 5各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基中的一个或多个取代基所取代；
m为0、1或2。
在一些实施方案中，手性拆分法中所用拆分剂为碱性手性拆分剂，可以为S-苯乙胺、奎尼丁、辛可尼丁或精氨酸。
在一些实施方案中，手性拆分法中所用拆分剂为S-苯乙胺。
进一步地，制备D1所示化合物或其盐的方法还包括式E所示化合物制备得式D所示化合物的步骤，所述反应条件优选自碱性水解，
Figure PCTCN2018107901-appb-000005
其中，R如式D所示化合物中所定义。
在一些实施方案中，水解反应所用碱选自氢氧化钠、氢氧化钾或氢氧化锂等。
在一些实施方案中，所述式D1所示化合物为：
Figure PCTCN2018107901-appb-000006
其制备方法，包括：
Figure PCTCN2018107901-appb-000007
在一些实施方案中，制备D1所示化合物或其盐的方法，包括：
Figure PCTCN2018107901-appb-000008
其中，R如式D所示化合物中所定义。
在优选实施方案中，制备D2所示化合物或其盐的方法，包括：
Figure PCTCN2018107901-appb-000009
本发明还提供了式D1所示化合物或其盐，
Figure PCTCN2018107901-appb-000010
其中，R如前述所述。
在一些实施方案中，所述式D1所示化合物为：
Figure PCTCN2018107901-appb-000011
在一些实施方案中，所述式D1所示化合物盐为：
Figure PCTCN2018107901-appb-000012
其中，所述M选自S-苯乙胺、奎尼丁、辛可尼丁或精氨酸。
在优选实施方案中，所述式D1所示化合物盐为
Figure PCTCN2018107901-appb-000013
本发明还提供用于制备式D1-1所示化合物的方法，包括：包括式D所示化合物与手性拆分剂M反应得到式D1-1所示化合物的步骤，所述手性拆分剂优选碱性手性拆分剂，更优选S-苯乙胺、奎尼丁、辛可尼丁或精氨酸，
Figure PCTCN2018107901-appb-000014
其中，R如式D1中所定义。
进一步地，制备式D1-1所示化合物的方法还包括：
Figure PCTCN2018107901-appb-000015
其中，其中，R如式D1中所定义。
在一些实施方案中，R为
Figure PCTCN2018107901-appb-000016
M为S-苯乙胺，其制备方法为：
Figure PCTCN2018107901-appb-000017
进一步地，还包括：
Figure PCTCN2018107901-appb-000018
本发明还提供了用于制备式B所示化合物或其立体异构体的方法，其包括：式D所示化合物或其立体异构体通过一步或一步以上反应制备得式B所示化合物或其立体异构体的步骤，
Figure PCTCN2018107901-appb-000019
其中，R如式D1所示化合物中所定义，优选自
Figure PCTCN2018107901-appb-000020
在一些实施方案中，式B所示化合物为：
Figure PCTCN2018107901-appb-000021
其制备方法包括：
Figure PCTCN2018107901-appb-000022
本领域中，由含有羧基的化合物经还原得到含有醛基的化合物有诸多熟知的方法，通常经由一步反应、两步反应或两步以上的反应制备含有醛基的化合物，本发明优选两步反应制备得到含有醛基的化合物。
在一些实施方案中，制备式B所示化合物或其立体异构体的方法包括：
Figure PCTCN2018107901-appb-000023
其中，R如式D1所示化合物中所定义，优选自
Figure PCTCN2018107901-appb-000024
优选地，在一些实施方案中，式B所示化合物或其立体异构体为
Figure PCTCN2018107901-appb-000025
其制备方法包括：
Figure PCTCN2018107901-appb-000026
其中，R优选自
Figure PCTCN2018107901-appb-000027
在一些实施方案中，式B所示化合物或其立体异构体为
Figure PCTCN2018107901-appb-000028
其制备方法包括：
Figure PCTCN2018107901-appb-000029
进一步地，在一些实施方案中，制备式B所示化合物或其立体异构体的方法包括：
Figure PCTCN2018107901-appb-000030
其中，R如式D1所示化合物中所定义。
在一些实施方案中，制备式B所示化合物或其立体异构体的方法还包括前述制备式D1所示化合物或其盐的方法步骤。
在另一些实施方案中，式B所示化合物或其立体异构体为
Figure PCTCN2018107901-appb-000031
其制备方法包括：
Figure PCTCN2018107901-appb-000032
其中，R如式D1所示化合物中所定义。
在另一些实施方案中，式B所示化合物或其立体异构体为
Figure PCTCN2018107901-appb-000033
其制备方法包括：
Figure PCTCN2018107901-appb-000034
本发明还提供式C所示化合物，
Figure PCTCN2018107901-appb-000035
其中，R如式D1所示化合物中所定义，优选自
Figure PCTCN2018107901-appb-000036
在一些实施方案中，式C所示化合物为：
Figure PCTCN2018107901-appb-000037
其中，R如式D1所示化合物中所定义，优选自
Figure PCTCN2018107901-appb-000038
在一些实施方案中，式C所示化合物为：
Figure PCTCN2018107901-appb-000039
本发明还提供用于制备式C所示化合物的方法，其包括：
Figure PCTCN2018107901-appb-000040
其中，R如式D1所示化合物中所定义。
在一些实施方案中，式C所示化合物为：
Figure PCTCN2018107901-appb-000041
其制备方法包括：
Figure PCTCN2018107901-appb-000042
在一些实施方案中，制备式C1所示化合物的方法还包括前述制备式D1所示化合物方法的步骤。
在一些实施方案中，制备式C1所示化合物的方法包括：
Figure PCTCN2018107901-appb-000043
其中，R如式D1所示化合物中所定义。
在一些实施方案中，式C所示化合物为：
Figure PCTCN2018107901-appb-000044
其制备方法包括：
Figure PCTCN2018107901-appb-000045
在一些实施方案中，制备式C2所示化合物的方法还包括前述制备式D-1所示化合物方法的步骤。
在一些实施方案中，制备式C2所示化合物的方法包括：
Figure PCTCN2018107901-appb-000046
本发明还提供了用于制备式I所示化合物或其盐的方法，其包括式D所示化合物或其立体异构体反应后得到式B所示化合物或其立体异构体，式B所示化合物或其立体异构体与式A所示化合物或其立体异构体反应得到式I所示化合物的步骤，
Figure PCTCN2018107901-appb-000047
其中，R1选自氢原子或烷基；R2选自任选取代的芳基或杂芳基，所述取代基选自氢原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、氧代基、烯基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR3、-C(O)R3、-C(O)OR3、-S(O)mR3或-NR4R5，其中所述的烷基、烷氧基、烯基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基中的一个或多个取代基所取代；n选自0、1、2或3；R、R3、R4、R5、m如式D1所示化合物所定义。
在一些实施方案中，用于制备式I所示化合物或其盐的方法还包括：
Figure PCTCN2018107901-appb-000048
其中，R如式D1所示化合物中所定义。
进一步地，用于制备式I所示化合物或其盐的方法还包括：
Figure PCTCN2018107901-appb-000049
在一些实施方案中，制备式I所示化合物或其盐的方法还包括前述制备式D1所示化合物或其盐的方法步骤。
在一些实施方案中，制备式I所示化合物或其盐的方法还包括前述制备式B所示化合物或其立体异构体的方法步骤。
在一些实施方案中，所述式I所示化合物为
Figure PCTCN2018107901-appb-000050
其制备方法包括：
Figure PCTCN2018107901-appb-000051
进一步地，制备式II所示化合物的方法包括：
Figure PCTCN2018107901-appb-000052
在一些实施方案中，所述式I所示化合物为
Figure PCTCN2018107901-appb-000053
其制备方法包括：
Figure PCTCN2018107901-appb-000054
在一些实施方案中，用于制备式III所示化合物的方法包括：
Figure PCTCN2018107901-appb-000055
优选地，用于制备式III所示化合物的方法，包括：
第一步、中间体D-1的合成
式(E)所示化合物在有机溶剂中与碱反应、水解成式D-1所示化合物；所述碱性条件优选氢氧化钠、氢氧化钾或氨水。
第二步、中间体D2-1的合成
式D-1所示化合物在醇类溶剂中与手性拆分试剂反应生成式D2-1所示化合物；所述手性拆分试剂优选碱性手性拆分剂，更优选S-苯乙胺、奎尼丁、辛可尼丁或精氨酸；所述醇类溶剂优选甲醇、乙醇或异丙醇。
第三步、中间体D2的合成
在碱性条件下将式D2-1所示化合物游离，得到式D2所示化合物；所述碱性条件优选氢氧化钠、氢氧化钾或氨水。
第四步、中间体C2的合成
式D2所示化合物与N,O-二甲羟胺盐酸盐、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、4-二甲氨基吡啶在碱性条件下反应得式C2所示化合物；所述碱性条件优选N,N-二异丙基乙胺、三乙胺或二异丙胺。
第五步、中间体B2的合成
式C2所示化合物与还原剂反应得式B2所示化合物；所述还原剂优选红铝。
第六步、式(III)所示化合物的合成
式B2所示化合物与式A1所示化合物反应得到式III所示化合物。
在一些实施方案中，所述式I所示化合物为
Figure PCTCN2018107901-appb-000056
其制备方法包括：
Figure PCTCN2018107901-appb-000057
在一些实施方案中，用于制备式IV所示化合物的方法包括：
Figure PCTCN2018107901-appb-000058
本发明还提供了式D1所示化合物、式C所示化合物或其盐在制备式I所示化合物中的用途，
Figure PCTCN2018107901-appb-000059
在一些实施方案中，式I所示化合物为：
Figure PCTCN2018107901-appb-000060
在一些实施方案中，式I所示化合物为：
Figure PCTCN2018107901-appb-000061
本发明还提供一种制备式I、式II、式III、式IV所示化合物的药学上可接受的盐的方法，包括前述方案中的步骤，以及通过式I、式II、式III、式IV所示化合物与酸反应制备得到其药学上可接受的盐的步骤，所述酸选自有机酸或无机酸，优选有机酸；所述有机酸选自乙酸、马来酸、富马酸、酒石酸、柠檬酸、甲磺酸、苯磺酸或对甲苯磺酸，优选富马酸；所述无机酸选自盐酸、氢溴酸、硫酸或磷酸。
术语：本发明所述“卤素或卤素原子”是指氟原子、氯原子、溴原子、碘原子等。
本发明所述“烷基”是指直链或支链的含有1-20个碳原子的烷基，包括例如“C 1-6烷基”、“C 1-4烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本发明所述“烯基”是指含有至少一个双键且碳原子数为2-20的直链或支链的基团，包括例如“C 2-6烯基、C 2-4烯基”等。其实例包括但不限于：乙烯基、丙烯基、2-丁烯基、2-戊烯基、3-戊烯基、2-己烯基、3-己烯基等。
本发明所述的“卤代烷基”指一个或多个“卤素原子”取代“烷基”上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“烷基”如前文所定义。
本发明所述的“羟基烷基或羟烷基”指一个或多个“羟基”取代“烷基”上的一个或多个氢原子所衍生的基团，所述“烷基”如前文所定义。
本发明所述的“烷氧基、卤代烷氧基、烷基羰基、烷氧羰基、烷氧羰基、羰基烷氧基、烷基羰基氨基、烷基氨基羰基、烷基氨基、二烷基氨基、烷基磺酰氨基或烷基磺酰基”是指以烷基-O-、卤代烷基-O-、烷基-C(O)-、烷基-O-C(O)-、C(O)-烷基-O-、烷基-C(O)-NH-、烷基-NH-C(O)-、烷基-NH-、(烷基) 2-N-、烷基-S(O) 2-NH-或烷基-S(O) 2-方式连接的基团，其中“烷基、卤代烷基”如前文所定义。
本发明所述的“氧代基”指＝O。
本发明所述“环烷基”是指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至10个碳原子，最优选环烷基环包含3至6个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。多环环烷基包括螺环、稠环和桥环的环烷基。
本发明所述的“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元的芳基，更优选苯基、萘基、二氢萘基、四氢萘基、茚基或芴基，最优选苯基。
本发明所述的“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子，其余环原子为碳；任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧化。优选包括3至12个环原子或5至12个环原子，其中1-4个是杂原子，更优选杂环基环包含3至8个环原子，更优选杂环基环包含5至6个环原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、二氢呋喃基、四氢呋喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。
本发明所述的“杂芳基”指具有1至4个杂原子作为环原子，其余的环原子为碳的5至14元芳基，其中杂原子包括氧、硫或氮。优选为5至10元的杂芳基，更优选为5元至6元的杂芳基，具体实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、、二氢吲哚基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等；所述杂芳基还可以稠合于芳基、杂环基或环烷基环上。
本发明所述的“碳原子、氮原子或硫原子被氧代/氧化”是指形成C＝O、N＝O、S＝O或SO 2的结构。
本发明所述的“醇类溶剂”是指一个或多个“羟基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“羟基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。
本发明所述的“立体异构”分为构象异构和构型异构，而构型异构还分为顺反异构和旋光异构(或对映异构)。构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象，常见的有烷烃和环烷烃类化合物的结构，如环己烷结构中出现的椅式构象和船式构象。“旋光异构体(或对映异构体)”，指当本发明化合物含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心，这类不对称中心各自会独立地产生两个光学异构体，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。本发明所述的化合物若含有烯烃双键，除非特别说明，本发明包括顺式异构体和反式异构体。本发明所述的化合物可以以互变异构体形式存在，其通过一个或多个双键位移而具有不同的氢的连接点。例如，酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明中。对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物，均包括在本发明范围中。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代试剂，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号：Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪和Waters 2695-2996高压液相色谱仪，以十八烷基硅烷键合硅胶为色谱柱填料。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。
2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙腈(式(E1)化合物)的制备可参照专利申请WO2012129495A1(公开日2012-09-27)中的方法，
Figure PCTCN2018107901-appb-000062
实施例1、(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺的制备
Figure PCTCN2018107901-appb-000063
第一步、中间体(D-1)的合成
将式(E1)所示化合物(25g)、氢氧化钾(22.4g)和乙二醇(150mL)混合，在150℃下搅拌16小时，停止反应。反应液冷却至室温，加入水(150mL)稀释，用二氯甲烷萃取(150mL×2)，水相用3M的盐酸调节pH为6～7，用二氯甲烷萃取(200mL×4)，合并有机相，用饱和氯化钠溶液洗涤(200mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物(26.1g，淡黄色油状物)，产率97.4％，HPLC纯度92％。
第二步、中间体(D2-1)的合成
将式(D-1)所示化合物(28g)溶于无水乙醇(100mL)中，升温至50℃，将拆分试剂S-苯乙胺(6.2g)溶于无水乙醇(100mL)中，50℃下将S-苯乙胺溶液滴入上述溶液中，升温至回 流，搅拌2小时。自然降温至10℃，固体析出，过滤，洗涤，得到产物(13g，固体)，ee值：96.7％；
重结晶：将13g固体加入无水乙醇(80mL)中，升温至回流，搅拌6小时，自然冷却至10℃，固体析出，过滤，洗涤，干燥，得到产物(10.6g)，ee值：99.0％。
第三步、中间体(D2)的合成
将KOH(2.18g)溶于水(120mL)中，将式(D2-1)所示化合物溶于该溶液中，二氯甲烷萃取(100mL×3)，用1N HCl溶液调节水相pH值至6～7，二氯甲烷萃取(150mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物(7g)，产率50％。ee值：99.4％
MS m/z(ESI):276.71[M+H] +，298.68[M+Na] +
1H NMR(400MHz,CDCl3)δ8.50-8.51(m,1H),7.73-7.77(m,1H),7.51-7.53(d,1H),7.21-7.24(m,1H),3.73-3.84(m,2H),2.78-2.81(d,1H),2.58-2.63(m,1H),2.53-2.56(d,1H),2.39-2.43(m,1H),1.98-2.02(d,1H),1.87-1.94(m,1H),1.76-1.80(m,1H),1.61-1.65(m,1H),1.39-1.58(m,4H),1.14-1.19(m,1H),(m,1H),(m,1H).
第四步、中间体(C2)的合成
在反应瓶中加入二氯甲烷(8.5kg)，搅拌下加入原料(R)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙酸(350g)、N,O-二甲羟胺盐酸盐(148.8g)、EDCI(292.3g)、DMAP(15.5g)，搅拌15～25min后加入DIPEA(492.4g)，氩气保护，室温搅拌反应16～18h，反应液加入饱和氯化铵水溶液(2.8kg)，搅拌5～10min后分液；有机相用饱和氯化铵水溶液(2.8kg×2)洗涤，饱和食盐水(2.7kg)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干，再加入二氯甲烷(2.5kg)继续减压浓缩至干得油状物(372.03g)，产率92.0％。
MS m/z(ESI):319.1[M+H]+，341.3[M+Na]+
1H NMR(400MHz,CDCl3)δ8.50-8.51(m,1H),7.66-7.71(m,1H),7.43-7.45(d,1H),7.15-7.18(m,1H),3.63-3.66(m,2H),3.47(s,3H),2.86-2.88(d,3H),2.62-2.65(d,1H),2.50-2.57(m,1H),2.36-2.39(d,1H),1.96-2.00(d,1H),1.80-1.86(m,1H),1.68-1.72(m,1H),1.48-1.55(m,1H),1.31-1.46(m,4H),1.03-1.07(m,1H),0.63-0.71(m,1H).
第五步、中间体(B2)的合成
在反应瓶中将式(C2)所示化合物(334.4g)溶于甲苯(2.2kg)中，冷却至-45℃～-35℃，氩气保护，控制滴加温度-45～-35℃，滴加红铝(348.76g)，加毕于-45～-35℃搅拌反应3～4h， 然后在-45～-35℃向反应液中滴加10％的柠檬酸水溶液(1kg)，再加入浓盐酸溶液调节pH至2～3，加入乙酸乙酯(1.8kg)，搅拌，静置分层，水相用5N氢氧化钠溶液调pH至11～13，用二氯甲烷萃取(3.3kg×2)，合并二氯甲烷层，用饱和氯化钠溶液(2.7kg)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，再加入二氯甲烷(3.3kg)继续减压浓缩，得淡红色油状物，，直接投入下一步反应。
第六步、式(III)所示化合物的合成
将上述油状物加入到反应瓶中，再将二氯甲烷(8.5kg)、式(A1)所示化合物(134.56g)加入反应瓶中，搅拌反应2～3h，反应液中加入三乙酰氧基硼氢化钠(373.86g)，室温搅拌反应16～18h，加入饱和碳酸钠溶液(2.66kg)，再用5N氢氧化钠水溶液调pH至11～13，分层，有机相用饱和氯化铵水溶液(2.83kg)洗涤，饱和氯化钠水溶液(2.74kg)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩干，加入乙腈(120g)，室温搅拌16～18h析晶，过滤，干燥得到产物(206.87g)，产率68.0％。
MS m/z(ESI):435.3[M+H] +
1H NMR(400MHz,CDCl 3)δ9.74(d,1H),9.58(d,1H),8.94(d,1H),8.37(d,1H),7.94(d,1H),7.67(d,1H),7.52(d,1H),7.47(t,1H),4.46-4.49(m,1H),4.30-4.33(m,1H),3.84-3.87(m,1H),3.66-3.70(m,2H),3.53-3.56(m,2H),2.82-2.85(d,2H),2.67(s,2H),2.39-2.41(m,4H),2.30-2.33(m,4H),1.85(s,2H),1.48-1.52(m,6H),1.27(m,3H).
实施例2
Figure PCTCN2018107901-appb-000064
第一步、中间体(D-1)的合成
将式(E1)所示化合物(13.5Kg；1.0eq)、氢氧化钾(2.6Kg；2.0eq)和乙二醇(135L；10vol)混合，升温至在110℃下搅拌24小时，停止反应。减压浓缩除掉乙醇；剩余物中加入二氯甲烷(26L搅拌溶解)；用饱和氯化钠溶液洗涤(5L)洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物(13kg，黄色油状物)，产率90％，HPLC纯度95％。
第二步、中间体(D2-1)的合成
将上步产物(13kg)溶于乙二醇(65L；5vol)中，升温至50℃，将拆分试剂S-苯乙胺(5.7Kg；1.0eq)溶于乙二醇(1L)中，50℃下将S-苯乙胺溶液滴入上述溶液中，升温至回流，搅拌3小时。自然降温至室温，固体析出，过滤，洗涤，得到产物(6600g，固体)，
重结晶：将6600g固体加入乙二醇(3L)中，升温至回流，搅拌6小时，自然冷却至室温，固体析出，过滤，洗涤，干燥，得到产物(4700g)，ee值：99.0％。
第三步、中间体(D2)的合成
将4700g固体，加水溶解，再加氢氧化钾1.2eq搅拌溶清，用30L*3二氯甲烷(DCM)萃取，除去有机相，用盐酸将水相调节pH至6-7，用DCM 30L*5，合并有机相，干燥，浓缩，得到产物3200g，ee值：99.42％，纯度：99％。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (21)

  1. 用于制备式D1所示化合物或其盐的方法，
    Figure PCTCN2018107901-appb-100001
    其包括：式D所示化合物或其盐经手性拆分的步骤，所述手性拆分方法优选自色谱拆分法或化学拆分法，
    Figure PCTCN2018107901-appb-100002
    其中，R选自芳基或杂芳基，所述芳基或杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、氧代基、烯基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、OR 3、C(O)R 3、C(O)OR 3、S(O) mR 3或NR 4R 5中的一个或多个取代基所取代；
    R 3选自氢原子、烷基、氘代烷基、氨基、烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基中的一个或多个取代基所取代；
    R 4和R 5各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基中的一个或多个取代基所取代；
    m为0、1或2。
  2. 如权利要求1所述的方法，其中所述化学拆分法所用拆分剂为碱性手性拆分剂，优选自S-苯乙胺、奎尼丁、辛可尼丁或精氨酸。
  3. 如权利要求1或2所述的方法，其中还包括：式E所示化合物制备得式D所示化合物的步骤，所述反应条件优选自碱性水解，
    Figure PCTCN2018107901-appb-100003
    其中，R如权利要求1所述。
  4. 如权利要求1-3任一项所述方法，其中所述式D1所示化合物为：
    Figure PCTCN2018107901-appb-100004
  5. 如权利要求1-4任一项所述的方法，其为：
    Figure PCTCN2018107901-appb-100005
  6. 式D1所示化合物或其盐，
    Figure PCTCN2018107901-appb-100006
    其中，R如权利要求1所述。
  7. 如权利要求6所述的化合物，其为
    Figure PCTCN2018107901-appb-100007
  8. 如权利要求6所述的化合物，其盐为：
    Figure PCTCN2018107901-appb-100008
    其中，所述M选自S-苯乙胺、奎尼丁、辛可尼丁或精氨酸，优选自S-苯乙胺。
  9. 用于制备式B所示化合物或其立体异构体的方法，
    Figure PCTCN2018107901-appb-100009
    其包括：式D所示化合物或其立体异构体通过一步或一步以上反应制备得式B所示化合物或其立体异构体的步骤，
    Figure PCTCN2018107901-appb-100010
    其中，R如权利要求1所述，优选自
    Figure PCTCN2018107901-appb-100011
  10. 如权利要求9所述的方法，其为：
    Figure PCTCN2018107901-appb-100012
    其中，R如权利要求1所述，优选自
    Figure PCTCN2018107901-appb-100013
  11. 如权利要求9或10所述的方法，其中所述式B所示化合物为：
    Figure PCTCN2018107901-appb-100014
  12. 如权利要9-11任一项所述的方法，其中还包括权利要求1-5任一项所述的方法步骤。
  13. 式C所示化合物，
    Figure PCTCN2018107901-appb-100015
    其中，R如权利要求1所述，优选自
    Figure PCTCN2018107901-appb-100016
  14. 如权利要求13所述的化合物，其为
    Figure PCTCN2018107901-appb-100017
  15. 用于制备式I所示化合物或其盐的方法，其包括式D所示化合物或其立体异构体反应后得到式B所示化合物或其立体异构体，式B所示化合物或其立体异构体与式A所示化合物或其立体异构体反应得到式I所示化合物的步骤，
    Figure PCTCN2018107901-appb-100018
    其中，R 1选自氢原子或烷基；R 2选自任选取代的芳基或杂芳基，所述取代基选自氢 原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、氧代基、烯基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 3、-C(O)R 3、-C(O)OR 3、-S(O)mR 3或-NR 4R 5，其中所述的烷基、烷氧基、烯基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基中的一个或多个取代基所取代；n选自0、1、2或3；R、R 3、R 4、R 5、m如权利要1所述。
  16. 如权利要求15所述的方法，其还包括权利要求1-5任一项所述的方法步骤或权利要求9-12任一项所述的方法步骤。
  17. 如权利要求15或16所述的方法，其中所述式I所示化合物为
    Figure PCTCN2018107901-appb-100019
  18. 如权利要求15或16所述的方法，其中所述式I所示化合物为：
    Figure PCTCN2018107901-appb-100020
  19. 用于制备式III所示化合物的方法，其包括：
    Figure PCTCN2018107901-appb-100021
  20. 用于制备式IV所示化合物的方法，其包括：
    Figure PCTCN2018107901-appb-100022
  21. 权利要求6-8、13或14任一项所述的化合物或其盐在制备式I所示化合物中的用途，
    Figure PCTCN2018107901-appb-100023
    其中，R、R 1、R 2、n如权利要求15所述。
PCT/CN2018/107901 2017-09-28 2018-09-27 一种氧杂螺环类衍生物的制备方法及其中间体 Ceased WO2019062804A1 (zh)

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CN116368138B (zh) * 2020-12-29 2026-03-03 上海海雁医药科技有限公司 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
CN117624138A (zh) * 2022-08-29 2024-03-01 江苏恒瑞医药股份有限公司 一种氧杂螺环类衍生物的可药用盐、晶型及制备方法
WO2024153159A1 (zh) 2023-01-18 2024-07-25 上海森辉医药有限公司 一种四氢-1-萘胺及其衍生物的制备方法
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CN118638109A (zh) * 2024-04-30 2024-09-13 中山大学 一种阿片类药物-奥赛利定的制备方法
CN118994123A (zh) * 2024-10-23 2024-11-22 江苏恒瑞医药股份有限公司 制备9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷衍生物的方法
CN118994123B (zh) * 2024-10-23 2025-02-14 江苏恒瑞医药股份有限公司 制备9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷衍生物的方法

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