WO2020029762A1 - PREPARATION METHOD FOR FUSED TRICYCLIC γ-AMINO ACID DERIVATIVE AND INTERMEDIATE THEREOF - Google Patents

PREPARATION METHOD FOR FUSED TRICYCLIC γ-AMINO ACID DERIVATIVE AND INTERMEDIATE THEREOF Download PDF

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WO2020029762A1
WO2020029762A1 PCT/CN2019/096522 CN2019096522W WO2020029762A1 WO 2020029762 A1 WO2020029762 A1 WO 2020029762A1 CN 2019096522 W CN2019096522 W CN 2019096522W WO 2020029762 A1 WO2020029762 A1 WO 2020029762A1
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compound
formula
acid
reaction
iii
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PCT/CN2019/096522
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Chinese (zh)
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范江
陈清平
汪成涛
冯建川
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四川海思科制药有限公司
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Publication of WO2020029762A1 publication Critical patent/WO2020029762A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings
    • C07C211/19—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/12—Formation of amino and carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/08—Acetic acid
    • C07C53/10—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/132—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing rings
    • C07C53/136—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing rings containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C61/12—Saturated polycyclic compounds
    • C07C61/125—Saturated polycyclic compounds having a carboxyl group bound to a condensed ring system
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medicine, specifically, the present invention relates to a method for preparing a fused tricyclic ⁇ -amino acid derivative and an intermediate thereof.
  • the voltage-gated calcium channel is composed of ⁇ 1 subunit and auxiliary protein ⁇ 2 ⁇ , ⁇ , ⁇ subunits.
  • ⁇ 2 ⁇ protein can regulate the density of calcium channels and voltage-dependent kinetics of calcium channels (Felix et al. (199) J. Neuroscience 17: 6884-6891; Klugbauer et al. (1999) J. Neuroscience 19: 684-691; Hobom et et. al (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al (2002) Mol. Pharmacol. 62: 485-496).
  • An object of the present invention is to provide a method for preparing a fused tricyclic ⁇ -amino acid derivative.
  • Another object of the present invention is to provide an intermediate for preparing a fused tricyclic ⁇ -amino acid derivative.
  • the present invention provides a method for preparing a compound represented by formula (I), wherein the method includes preparing the compound by reacting with a compound of formula (III) as a raw material,
  • A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
  • R 2 is selected from a carboxy protecting group or a C 1-6 alkyl group
  • R 11 is selected from C 1-6 alkyl.
  • A is selected from benzenesulfonic acid.
  • R 2 is selected from methyl, ethyl, propyl, n-butyl or tert-butyl.
  • R 2 is selected from tert-butyl.
  • R 11 is selected from methyl, ethyl, propyl or butyl.
  • R 11 is selected from methyl.
  • the compound of the formula (I) is prepared by reacting the compound of the formula (III) as a raw material, which can be firstly hydrolyzed to obtain a free base, and then the acid A is added to remove the carboxy protecting group and form a salt. It is also possible to remove the carboxyl protecting group first, then hydrolyze to obtain a free base, and then form a salt with acid A.
  • the present invention provides a method for preparing a compound represented by formula (I), wherein the method includes preparing the compound by reacting with a compound of formula (II) as a raw material;
  • R 2 is as defined above.
  • A is as defined above.
  • the invention provides a method for preparing a compound of formula (II), which is prepared by using a compound of formula (III) as a raw material.
  • R 1 and R 2 are the same as above.
  • the method includes preparing a compound of formula (II) by using a compound of formula (III) as a raw material, and then preparing a compound of formula (I) by using a compound of formula (II) as a raw material,
  • the method comprises preparing a compound of formula (II) by using a compound of formula (III) as a raw material, and then reacting the compound of formula (II) as a raw material in the presence of acid A to obtain a formula ( I) Compounds.
  • the present invention also provides a method for preparing a compound represented by formula (I), wherein the method comprises reacting a compound represented by formula (II) as a raw material to prepare a compound represented by formula (I).
  • A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
  • R 2 is selected from a carboxy protecting group or a C 1-6 alkyl group.
  • R 2 is selected from tert-butyl.
  • a compound of formula (II) is reacted with acid A to prepare a compound of formula (I).
  • the molar ratio of the acid A to the compound of formula (II) is 1.1: 1 to 5: 1.
  • the molar ratio of the acid A to the compound of formula (II) is 1.1: 1, 1.2: 1, 1.3: 1, 1.5: 1, 2: 1, 3: 1, 4: 1, or 5: 1.
  • reaction of the compound of formula (II) and the acid A can be reacted at room temperature to reflux;
  • the reaction temperature is 70-90 ° C
  • the reaction temperature is 80-85 ° C.
  • the solvent in which the compound of formula (II) reacts with acid A is selected from any solvent compatible with the compound of formula (II), such as acetonitrile, dichloromethane, ethanol, methanol, isopropyl acetate, water , Toluene, dioxane and their combined solvents.
  • the solvent is selected from water, acetonitrile, isopropyl acetate, acetonitrile / water.
  • the compound of formula (II) is reacted with acid A in a solvent compatible with the compound of formula (II) to obtain a compound of formula (I),
  • the solvent is selected from the group consisting of acetonitrile, dichloromethane, ethanol, Methanol, isopropyl acetate, water, toluene, dioxane or a combination thereof; more preferably, the molar ratio of acid A to the compound of formula (II) is 1.1: 1 to 5: 1, and the reaction is performed at 70-90 ° C.
  • the molar ratio of the acid A to the compound of formula (II) is 1.1: 1, and the reaction is performed at 80-85 ° C; even more preferably, the solvent is selected from acetonitrile, dichloromethane or isopropyl acetate .
  • the method further comprises the step of preparing a compound represented by formula (II) by using a compound of formula (III) as a raw material
  • R 2 is selected from a carboxy protecting group or a C 1-6 alkyl group
  • R 11 is selected from C 1-6 alkyl.
  • R 2 is selected from tert-butyl.
  • R 11 is selected from methyl.
  • the invention also provides a method for preparing a compound of formula (III), wherein the method comprises the step of obtaining a compound of formula (III) by using a compound of formula (IV) as a raw material through a reaction,
  • R 2 is as defined above.
  • R 1 has the same definition as above.
  • a method for preparing a compound of formula (III), wherein the preparation of a compound of (III) includes preparing a compound of formula (III) using a compound of formula (IV) and a chiral acid as raw materials.
  • the chiral acid according to the present invention is selected from the group consisting of a compound of formula (XI), R- ⁇ -methylphenylacetic acid, (-)-diacetyl-L-tartaric acid, L-aspartic acid, or d-quinic acid,
  • R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl.
  • R 2 is selected from a carboxy protecting group or a C 1-6 alkyl group
  • R 11 is selected from C 1-6 alkyl.
  • R 2 is selected from tert-butyl.
  • R 11 is selected from methyl.
  • the chiral acid is (S)-(+)-O-acetyl-L-mandelic acid or L-mandelic acid.
  • the method comprises using a compound of formula (IV) as a raw material to obtain a compound of formula (III) through a reaction, and then recrystallizing the compound of formula (III).
  • the invention also provides a method for purifying the compound represented by formula (III), and the compound of formula (III) is recrystallized in a recrystallization solvent:
  • R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
  • R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl.
  • a method for purifying a compound represented by formula (III), wherein the organic solvent is isopropanol isopropanol.
  • a method for purifying a compound represented by formula (III), wherein the recrystallization solvent is isopropyl alcohol and water is isopropyl alcohol and water.
  • a method for purifying a compound represented by formula (III), wherein the preparation of a compound of formula (III) includes first preparing a compound of formula (III) using a compound of formula (IV) and a chiral acid as raw materials. Then, the compound of formula (III) is recrystallized to obtain a purified compound.
  • the chiral acid is selected from the group consisting of a compound of formula (XI), R- ⁇ -methylphenylacetic acid, (-)-diacetyl-L-tartaric acid, L-aspartic acid, or right Quinic acid,
  • R 11 is selected from C 1-6 alkyl
  • R 11 is selected from methyl, ethyl, propyl, or butyl;
  • R 11 is selected from methyl.
  • R 11 is selected from methyl.
  • the chiral acid is (S)-(+)-O-acetyl-L-mandelic acid or L-mandelic acid.
  • the molar ratio of the compound of formula (XI) to the compound of formula (IV) is 0.5: 1 to 1: 1.
  • the molar ratio of the compound of formula (XI) to the compound of formula (IV) is 0.5: 1 to 0.8: 1.
  • the compound of formula (XI) and the compound of formula (IV) are reacted at 80-90 ° C.
  • the method comprises using a compound of formula (IV) as a raw material to obtain a crude compound of formula (III) through a reaction, and then using a recrystallization solvent such as an organic solvent and / or water to The crude product was recrystallized.
  • a recrystallization solvent such as an organic solvent and / or water
  • the organic solvent is selected from a mixture of one or more of isopropyl alcohol, acetonitrile, ethanol, and water; preferably, a mixture of isopropyl alcohol and water, or a mixture of ethanol and water.
  • the volume ratio of isopropanol and water is (10-30): 1.
  • the volume ratio of isopropanol and water is (10-20): 1.
  • volume ratio of ethanol to water is (10-30): 1.
  • the volume ratio of ethanol to water is (10-20): 1.
  • the mass-volume ratio of the compound of formula (III) to the recrystallization solvent is from 1:10 to 1:30; in some embodiments, the mass-to-volume ratio is from 1:10 to 1:20.
  • the recrystallization solvent is isopropyl alcohol and water
  • the volume ratio of isopropyl alcohol and water is 10: 1 to 30: 1.
  • the recrystallization step includes dissolving the crude product of formula (III) in a recrystallization solvent, and stirring for 0.5 to 1 hour before crystallization.
  • the recrystallization is repeated 1-2 times.
  • the repetition is repeated on the basis of the first time. For example, if it is repeated once, it is recrystallized twice; if it is repeated twice, it is equivalent to recrystallize three times.
  • the method further comprises the step of preparing a compound of formula (IV) by using a compound of formula (V) as a raw material
  • R 2 is as defined above.
  • the preparation of the compound of formula (IV) includes: using the compound of formula (V) as a raw material in the presence of a catalyst and a reducing agent to prepare a compound of formula (IV) at 0-40 ° C.
  • the catalyst / reducing agent that undergoes a reduction reaction of compound (V) to form compound (IV) may be selected from Raney nickel / hydrazine hydrate, nickel chloride hexahydrate / sodium borohydride, iron powder / chlorination Ammonium, 10% palladium carbon / triethyl silicon, Raney nickel / hydrogen, 10% palladium carbon / hydrogen or zinc powder / acetic acid.
  • the catalyst / reducing agent is selected from nickel chloride hexahydrate / sodium borohydride or 10% palladium carbon / hydrogen.
  • the reduction conditions are: 0-40 ° C, in an alcohol solvent, nickel chloride hexahydrate as a catalyst, and sodium borohydride as a reducing agent; or, 0-40 ° C, in an alcohol solvent, palladium carbon as Catalyst, hydrogen as reducing agent.
  • the alcohol solvent is methanol or ethanol.
  • the temperature of the reduction reaction is from 20 ° C to 30 ° C.
  • the molar ratio of the compound of formula (V) to the catalyst is from 1: 1 to 10: 1, in some embodiments, the molar ratio is from 2: 1 to 5: 1, and in some embodiments, The molar ratio is 2: 1, 3: 1, 4: 1, 5: 1.
  • the molar ratio of the compound of formula (V) to the reducing agent is from 1: 2 to 1:10. In some embodiments, the molar ratio is from 1: 2.5 to 1: 5. In some embodiments The molar ratio is 1: 2.5, 1: 3, 1: 4, 1: 5.
  • the molar ratio of the compound of formula (V): catalyst: reducing agent is 1: 0.2: 2.5-1: 0.5: 5. In some embodiments, the molar ratio is 1: 0.2: 2.5, 1: 0.2: 5, 1: 0.2: 4, 1: 0.5: 5, and in some embodiments, the molar ratio is 1: 0.2: 4.
  • the method further comprises the preparation of a compound of formula (V): comprising preparing a compound of formula (V) using a compound of formula (VI) as a raw material,
  • R 2 is as defined above.
  • compound (VI) in the presence of a base, compound (VI) undergoes an addition reaction with nitromethane to form compound (V);
  • a solvent may be present, said solvent being selected from dimethyl sulfoxide , N, N-dimethylformamide, N-methylpyrrolidone or tetrahydrofuran.
  • the preparation of the compound of formula (V) comprises: reacting the compound of formula (VI) and nitromethane in the presence of a base in the absence of other solvents to prepare the compound of formula (V).
  • the base is selected from the group consisting of cesium carbonate, potassium tert-butoxide, or 1,8-diazabicycloundec-7-ene.
  • the temperature of the addition reaction is 60 ° C. to reflux.
  • the temperature of the addition reaction is 80 ° C to 100 ° C.
  • the temperature of the addition reaction is from 85 ° C to 90 ° C.
  • the temperature of the addition reaction is 80 ° C to 85 ° C.
  • compound (VI) in the presence of a base, compound (VI) undergoes an addition reaction with nitromethane to form compound (V);
  • a solvent may be present, said solvent being selected from dimethyl sulfoxide Or N, N-dimethylformamide.
  • the compound (V) is reacted with nitromethane in a molar ratio of 1: 2.5 to 1:10, 1: 3 to 1: 9, 1: 3 to 1: 8,1: 3 ⁇ 1: 7, 1: 3 ⁇ 1: 6, 1: 3 ⁇ 1: 5 or 1: 3 ⁇ 1: 4.
  • the molar ratio of the compound (V) to nitromethane is 1: 2.5, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1 : 9 or 1:10.
  • the method further comprises the preparation of a compound of formula (VI): comprising preparing a compound of formula (VI) by using a compound of formula (VII) as a raw material,
  • the preparation of the compound of formula (VI) comprises: in the presence of a base, the compound of formula (VII) and t-butyl dimethoxyphosphonoacetate, diethoxyphosphoryl acetate Any one of t-butyl ester, t-butyl bromoacetate, t-butyl chloroacetate, or t-butyl acetoacetate reacts to form a compound of formula (VI).
  • the base used for preparing the compound (VI) is selected from potassium tert-butoxide, 1,8-diazabicycloundec-7-ene, lithium diisopropylamino, Potassium carbonate or lithium hydride.
  • the base used for preparing the compound (VI) is selected from potassium tert-butoxide or 1,8-diazabicycloundec-7-ene.
  • the reaction temperature of the compound of formula (VII) with dimethoxyphosphono t-butyl acetate is 10 ° C to 40 ° C.
  • the reaction temperature of the compound of formula (VII) with dimethoxyphosphono t-butyl acetate is 10 ° C-30 ° C.
  • the reaction temperature of the compound of formula (VII) with dimethoxyphosphonoacetic acid tert-butyl ester is 10 ° C-15 ° C.
  • the reaction temperature of the compound of the formula (VII) with dimethoxyphosphono t-butyl acetate is 20 ° C-40 ° C.
  • the reaction temperature of the compound of formula (VII) with dimethoxyphosphono t-butyl acetate is 30 ° C-40 ° C.
  • the tert-butyl dimethoxyphosphonoacetate can be replaced with tert-butyl diethoxyphosphoryl acetate, tert-butyl bromoacetate, tert-butyl chloroacetate, or tert-butyl acetoacetate. ester.
  • the molar ratio of compound (VII) to dimethoxyphosphono t-butyl acetate is 1: 1 to 1:10.
  • the molar ratio of the compound (VII) to the dimethoxyphosphono t-butyl acetate is 1: 1.1 to 1: 5.
  • the molar ratio of compound (VII) to dimethoxyphosphono t-butyl acetate is 1: 1.1 to 1: 2.
  • the compound (VII) is reacted with tert-butyl dimethoxyphosphonoacetate in a solvent.
  • the solvent is selected from tetrahydrofuran.
  • the present invention also provides a method for preparing a compound represented by formula (VII), wherein the method includes preparing a compound of formula (VII) using a compound of formula (VIII) as a raw material,
  • R 3 and R 4 are each independently selected from C 1-6 alkyl groups
  • R 3 and R 4 and the carbon atom to which they are attached together form a ring.
  • R 3 and R 4 are each independently selected from methyl, ethyl or isopropyl.
  • R 3 and R 4 form a piperidine ring or a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
  • R 3 and R 4 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
  • the method comprises reacting a compound of formula (VIII) and an acid anhydride in the presence of a pyridine base to prepare a compound of formula (VII).
  • the anhydride described in the present invention is selected from trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride.
  • the pyridine base in the present invention refers to a base containing a pyridine structure, such as 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, or pyridine.
  • the method comprises reacting a compound of formula (VIII) and a base of trifluoromethanesulfonic anhydride and pyridines to prepare a compound of formula (VII).
  • the method further includes a step of subjecting the reaction solution to alkali treatment with a base.
  • the reaction solution is subjected to alkali treatment with a base to adjust the pH value to be basic; in some implementations, In the protocol, adjust the pH to 10-11.
  • the base may be selected from inorganic bases.
  • the inorganic base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, cesium fluoride, or cesium carbonate; pH to basicity may be selected from a pH of 8- 14, 8-11, 9-11, or 10-11.
  • the reaction solution is subjected to alkali treatment with a base, and the reaction is continued until the intermediate reaction is completed, further including A step of acidifying the reaction solution with an acid.
  • the acidification treatment refers to adjusting the pH of the reaction solution to be acidic with an acid.
  • the acidification treatment refers to adjusting the reaction solution to be acidic with an inorganic acid.
  • the acidification treatment refers to adjusting the pH of the reaction solution to 1-4.
  • the inorganic acid is sulfuric acid, hydrochloric acid, phosphoric acid, or nitric acid.
  • the reaction solution is subjected to alkali treatment with a base, and the reaction is continued until the intermediate reaction is completed, further including Acidify the reaction solution with acid and adjust the pH to 1-2;
  • the acid is an inorganic acid; in some embodiments, a mixture of one or more of sulfuric acid, hydrochloric acid, phosphoric acid, and nitric acid.
  • the compound of formula (VIII) is reacted with a base of pyridine and trifluoromethanesulfonic anhydride at room temperature to reflux. In certain embodiments, the reaction is performed under reflux.
  • a method for preparing a compound represented by formula (VII) includes the following steps:
  • the compound of formula (VIII) is in an acid anhydride (preferably trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride) and a pyridine base (preferably 2,4,6-trimethylpyridine, 2,6-dimethylpyridine or pyridine ) In the presence of a reaction;
  • an acid anhydride preferably trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride
  • a pyridine base preferably 2,4,6-trimethylpyridine, 2,6-dimethylpyridine or pyridine
  • the base preferably an inorganic base, more preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, or cesium carbonate
  • the base is used to adjust the pH of the reaction solution obtained in step (1) to alkaline, and it is preferably adjusted pH is 8-11;
  • step (3) Acidifying the mixture obtained in step (2) with an inorganic acid (preferably sulfuric acid, hydrochloric acid, phosphoric acid, or nitric acid) to obtain a compound of formula (VII).
  • an inorganic acid preferably sulfuric acid, hydrochloric acid, phosphoric acid, or nitric acid
  • the method for preparing the compound represented by formula (VII) includes the following steps:
  • the inorganic base adjusts the pH of the reaction solution to alkaline and hydrolyzes to obtain a mixture of formula (VII) and formula (VII-1); wherein the inorganic base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, carbonic acid Sodium hydrogen, cesium fluoride or cesium carbonate;
  • the acid is an inorganic acid, which is a mixture of one or more selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid and nitric acid.
  • a method for preparing a compound represented by formula (VII) includes the following steps:
  • pyridine base refers to a structure containing pyridine Base, such as 2,4,6-trimethylpyridine, 2,6-dimethylpyridine or pyridine;
  • the inorganic base adjusts the pH of the reaction solution to alkaline and hydrolyzes to obtain a mixture of formula (VII) and formula (VII-1); wherein the inorganic base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, carbonic acid Sodium hydrogen, cesium fluoride, or cesium carbonate; pH to basic can be selected from pH values of 8-14, 8-11, 9-11, or 10-11;
  • a compound of formula (VII-1) in a mixture of formula (VII) and formula (VII-1) undergoes a rearrangement reaction to convert to a compound of formula (VII), wherein the solvent of the reaction may be any acid stable
  • the solvent is selected in some embodiments from acetone or acetonitrile.
  • the acidic condition may be selected from a pH value of 1-4, 1-3 or 1-2, and in some embodiments a pH value of 1-2.
  • the acidic conditions may be adjusted using common inorganic acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • the molar ratio of the compound of formula (VIII): pyridine base: trifluoromethanesulfonic anhydride is 1: (1.1-2.0): (1.1-2.0), 1: (1.1-1.5): ( 1.1-1.5) or 1: 1.5: 1.5.
  • the compound of formula (VIII) is reacted with a base of pyridine and trifluoromethanesulfonic anhydride at room temperature to reflux. In certain embodiments, the reaction is performed under reflux.
  • the method for preparing a compound represented by formula (VIII) further comprises reacting a compound of formula (IX) as a raw material with a secondary amine NH (R 3 ) (R 4 ) to prepare a compound of formula (VIII) step,
  • R 3 and R 4 are as defined above.
  • R 3 and R 4 of the secondary amine are defined as previously described in the present invention.
  • R 3 and R 4 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
  • the condensing agent is selected from the group consisting of oxalyl chloride, dichlorosulfoxide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1- Hydroxybenzotriazole or N, N'-carbonyldiimidazole.
  • the molar ratio of the compound of formula (IX) to the secondary amine is not greater than 1, in some embodiments, the molar ratio is 1: 1 to 5, and in some embodiments, the molar ratio is 1: 1 to 2, in some embodiments, the molar ratio is 1: 1.1.
  • the reaction temperature of the compound of formula (IX) with the secondary amine NH (R 3 ) (R 4 ) to produce the compound of formula (VIII) is room temperature. In some embodiments, the reaction temperature is 20- 30 ° C.
  • the method further comprises the step of preparing a compound of formula (IX) by using a compound of formula (X) as a raw material
  • the compound of formula (IX) is prepared by using a compound of formula (X) and a cyclic (iso) isopropyl malonate as raw materials.
  • a compound of formula (X) is reacted with a cyclic (iso) isopropyl malonate to form a compound of formula (IX) under the catalysis of triethylamine formate.
  • the method comprises the reaction of a compound of formula (X) with a cyclic (iso) malonate of malonate under the catalysis of triethylamine formate and reduction and decarboxylation to form formula (IX) Compound.
  • the triethylamine formate can be prepared from formic acid and triethylamine.
  • the molar ratio of the compound of formula (X) to the cyclic (sub) isopropyl malonate is not greater than 1, in some embodiments, the molar ratio is 1: 1 to 5, in some embodiments In the scheme, the molar ratio is 1: 1 to 2, and in some embodiments, the molar ratio is 1: 1.
  • the reaction temperature of the compound of formula (X) and the cyclic (iso) isopropylmalonate is 100-180 ° C. In some embodiments, the reaction temperature is 140-160 ° C. In some embodiments, the reaction temperature is from 140 to 150 ° C.
  • the reduction decarboxylation reaction is performed under acidic conditions, where the acidic conditions are pH 1-5, In some embodiments it is 1-4, in some embodiments it is 1-3, and in some embodiments it is 1-2.
  • the acid conditions are provided by common inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid.
  • the present invention also provides a method for preparing a compound represented by formula (VII), wherein the method includes the following steps:
  • R 3 and R 4 are each independently selected from C 1-6 alkyl groups
  • R 3 and R 4 and the carbon atom to which they are attached together form a ring.
  • R 3 and R 4 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
  • the method includes the following steps:
  • the method includes the following steps:
  • step (2) is a condensation reaction in the presence of a condensing agent.
  • the condensing agent in step (2) is selected from oxalyl chloride, dichlorosulfoxide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Salt, 1-hydroxybenzotriazole or N, N'-carbonyldiimidazole.
  • R 3 and R 4 of the secondary amine are defined as previously described in the present invention.
  • R 3 and R 4 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
  • a method of preparing a compound of formula (VII) comprises the following steps:
  • the present invention also provides a method for purifying the compound represented by formula (VII):
  • the method comprises adding a compound of the formula (VII) and sodium bisulfite to form a salt at normal temperature, extracting impurities with an organic solvent, and then adding the acid or base at normal temperature to obtain an after-treatment.
  • the method comprises adding a compound of formula (VII) to sodium bisulfite to form a salt, extracting impurities with an organic solvent, and then adding an acid or a base at room temperature to complete the reaction to obtain a high-purity formula.
  • VII Compound:
  • the above-mentioned post-treatment includes one or more operations of extraction, filtration, concentration, drying, and the like.
  • the organic solvent may be selected from ethyl acetate, dichloromethane, or methyl tert-butyl ether.
  • the acid is selected from inorganic acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • the acid is selected from hydrochloric acid or sulfuric acid.
  • the base is selected from inorganic bases, such as sodium hydroxide.
  • the present invention also provides a method for preparing a compound represented by formula (I), wherein the method includes the following steps:
  • a compound of formula (III) is reacted to obtain a compound of formula (II), and then a compound of formula (II) is reacted with acid A to form a compound of formula (I).
  • a compound of formula (IV) is first reacted to obtain a compound of formula (XII), and then a compound of formula (XII) is reacted to form a compound of formula (I),
  • the present invention also provides a method for preparing a compound represented by formula (I), wherein the method includes the following steps:
  • A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
  • R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
  • R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl.
  • the method includes the following steps:
  • a compound of formula (III) is reacted to obtain a compound of formula (II), and then a compound of formula (II) is reacted with acid A to form a compound of formula (I).
  • the compound of formula (V) undergoes a reduction reaction, is hydrolyzed, and then reacts with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (XII). Hydrolyzed and reacted with acid A to form a compound of formula (I);
  • the compound of formula (XII) is first reacted, and then the compound of formula (XII) is reacted to generate the compound of formula (I);
  • A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
  • R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
  • R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl.
  • R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
  • R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl;
  • A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid.
  • the method includes the following steps:
  • the method includes the following steps:
  • the base of step (1) is selected from potassium tert-butoxide or 1,8-diazabicycloundec-7-ene.
  • the base of step (2) is selected from cesium carbonate, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene.
  • step (3) wherein the chiral acid of step (3) is selected from the compound of formula (XI);
  • R 1 has the same definition as above.
  • step (3) wherein the chiral acid of step (3) is selected from (S)-(+)-O-acetyl-L-mandelic acid or L-mandelic acid.
  • the invention also provides a method for preparing a compound represented by formula (I), comprising the following steps:
  • a compound of formula (III) is obtained by a reaction to obtain a compound of formula (II), and then reacted with acid A to form a compound of formula (I);
  • A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
  • R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
  • R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl;
  • R 3 and R 4 are each independently selected from C 1-6 alkyl groups
  • R 3 and R 4 and the carbon atom to which they are attached together form a ring (preferably, R 3 and R 4 form a pyridine ring or a tetrahydropyrrole ring with the nitrogen atom to which they are attached).
  • the invention also provides a method for preparing a compound represented by formula (I), comprising the following steps:
  • a compound of formula (III) is reacted to obtain a compound of formula (II), and then a compound of formula (II) is reacted with acid A to form a compound of formula (I).
  • the compound of formula (IV) is first reacted to obtain a compound of formula (XII), and then the compound of formula (XII) is reacted to form a compound of formula (I);
  • R 1 , R 2 , R 3 , R 4 and other related definitions are the same as above.
  • the invention also provides a method for preparing a compound represented by formula (I), comprising the following steps:
  • R 1 , R 2 , R 3 , R 4 and other related definitions are the same as above.
  • the invention also provides a method for preparing a compound represented by formula (I), comprising the following steps:
  • the present invention also provides a compound represented by formula (III),
  • A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
  • R 11 is selected from C 1-6 alkyl;
  • R 2 is selected from a carboxy protecting agent or a C 1-6 alkyl group
  • R 3 and R 4 are each independently selected from C 1-6 alkyl groups
  • R 3 and R 4 and the carbon atom to which they are attached together form a ring (preferably, R 3 and R 4 form a pyridine ring or a tetrahydropyrrole ring with the nitrogen atom to which they are attached).
  • the compound represented by the formula (III) can be used as an intermediate for preparing the compound represented by the formula (I).
  • R 11 is selected from methyl, ethyl, propyl or tert-butyl.
  • R 2 is selected from methyl, ethyl, propyl, or tert-butyl.
  • the present invention also provides a compound represented by formula (II),
  • R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl.
  • the invention also provides a method for preparing a compound represented by formula (II), which method comprises using a compound of formula (IV) as a raw material, reacting with a chiral acid to prepare a compound of formula (III), and hydrolyzing to obtain a compound of formula (II)
  • the chiral acid is L-mandelic acid.
  • the invention also provides the application of the compound represented by formula (XI) in the preparation of a reference substance for the compound of formula (II).
  • the present invention also provides a compound represented by formula (VIII) and a preparation method thereof,
  • R 3 and R 4 are each independently selected from C 1-6 alkyl or R 3 and R 4 form a ring;
  • R 3 and R 4 are not both methyl.
  • R 3 and R 4 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
  • the invention also provides the following compounds and their preparation methods:
  • R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
  • R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl.
  • the invention also provides compounds of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VIII) or formula (XII) and isomers or pharmaceutically acceptable Salt
  • R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
  • R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl;
  • R 3 and R 4 are each independently selected from C 1-6 alkyl or R 3 and R 4 to form a ring (preferably R 3 and R 4 form a pyridine ring or a tetrahydropyrrole ring with the nitrogen atom to which they are attached);
  • R 3 and R 4 are not both methyl.
  • the present invention also provides a method for purifying a compound represented by formula (I), wherein the compound of formula (I) is heated to dissolve in an organic solvent (preferably N-methylpyrrolidone or dimethyl sulfoxide), and isopropyl acetate is added Esters and / or water, stirred for crystallization, filtered, and dried under reduced pressure to obtain:
  • an organic solvent preferably N-methylpyrrolidone or dimethyl sulfoxide
  • A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid.
  • the crude compound of formula (I) is heated to 80 ⁇ 5 ° C. in N-methylpyrrolidone. After the solid is completely dissolved, it is added with activated carbon and stirred, filtered while hot, and the filtrate is added with acetic acid. The propyl ester was crystallized by stirring and filtered.
  • the crude compound of formula (I) and dimethyl sulfoxide are heated to 50 ⁇ 5 ° C. After the solid is completely dissolved, purified water is added and the crystals are stirred and crystallized. Filter, that's it.
  • the preparation method involved in the present invention enumerates the reaction steps that the method goes through, and some of which are literally two or more reaction steps in the present invention, but in practice, the reaction can be performed in one reaction. It is completed in the operation (that is, the intermediate product does not need to be discharged after feeding, and the next reaction is continued in the reaction solution, such as the so-called "one-pot cooking” method), which makes people mistakenly think that it is a one-step reaction, or it is literally in the present invention It is a one-step reaction, but it can be split into two or more reaction steps in practice to make people think that it is a multi-step reaction, which are all within the protection scope of the present invention.
  • a compound of formula (III) is prepared into a compound of formula (II), and then a compound of formula (II) is used to prepare a compound of formula (I) in one step reaction operation. It should be understood that both steps of the reaction It is described in the invention examples.
  • a compound of formula (V) is used to prepare a compound of formula (IV), and then a compound of formula (IV) is used to prepare a compound of formula (III) in one step reaction operation. It should be understood that both steps of the reaction It is described in the examples of the present invention.
  • (+/-) in the chemical structural formula of the present invention represents a mixture of enantiomers whose structures are shown to be completely opposite to the chirality of the structures shown.
  • reaction process of the present invention is generally monitored by TLC, MS, LCMS or / and nuclear magnetic resonance methods.
  • the present invention provides a method for preparing a fused tricyclic ⁇ -amino acid derivative and an intermediate thereof.
  • the preparation method of the invention has the following advantages:
  • the compound of formula (VII) of the present invention has very low polarity, is easily soluble in most solvents, has a low melting point, and is difficult to recrystallize and purify. And because it is a solid at normal temperature, it is easy to sublimate and block the distillation device when heated, and it does not tolerate high temperatures, and conventional distillation or vacuum distillation cannot be purified.
  • the purity of the crude product is only 50%, and after purification according to the present invention, the purity can be above 98%.
  • the preparation method of the invention shortens the synthesis steps, simplifies the synthesis operation, and the raw materials are cheap and easily available, which greatly reduces the production of finished products. Secondly, the entire synthesis process is purified by crystallization, and no silica gel column chromatography or other preparative chromatography methods are used. Suitable for large-scale industrial production.
  • FIG. 1 is an X-ray single crystal diffraction pattern of Compound 1.
  • FIG. 2 is a single-molecule mid-ball club model of Compound 1.
  • FIG. 3 is an absolute configuration of Compound 1.
  • 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).
  • NMR measurements were performed using (BrukerAvance III 400 and BrukerAvance 300) nuclear magnetic analyzers.
  • the measurement solvents were deuterated dimethylsulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD).
  • DMSO-d 6 deuterated dimethylsulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • CD 3 CN deuterated acetonitrile
  • TMS internal standard tetramethylsilane
  • MS was measured using Agilent 6120B (ESI) and Agilent 6120B (APCI).
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the thin-layer chromatography (TLC) silica gel plate uses a size of 0.15mm to 0.20mm, and the thin-layer chromatography purification product uses a size of 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from Titan Technology, Anagi Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Braunwell Technology And other companies.
  • the ratio shown in the silica gel column chromatography of the present invention is a volume ratio.
  • Step 3 Tricyclo [4.2.1.0 3,8 ] nonan-2-one (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemate) (1D)
  • Method 1 Dissolve anhydrous sodium bisulfite (5.735kg, 55.147mol) in 66L of purified water and add it to a 100L reaction kettle. Add 1D crude (3.00kg, 22.059mol) ethanol (3.0L) under room temperature stirring. The solution was stirred at room temperature overnight, and extracted with ethyl acetate (20L ⁇ 2). The aqueous phase was added to the reaction kettle and stirred and cooled to 10 ° C.
  • Method 2 Sodium bisulfite (1529g, 14.706mol) was dissolved in 22L of water, and a 1D crude product (1000g, 7.353mol) in anhydrous ethanol (1000mL) was added dropwise under stirring, and stirred at room temperature overnight (24 hours) .
  • the reaction solution was extracted with dichloromethane (5L ⁇ 2) to remove impurities, and a sulfuric acid solution (prepared by 6.4L concentrated sulfuric acid and 6 kg of crushed ice) was added dropwise to the aqueous phase, and the mixture was stirred at room temperature for 5 hours.
  • Step 4 tert-Butyl 2- (tricyclo [4.2.1.0 3,8 ] nonyl-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemic Body) (1E)
  • Step 5 tert-Butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate) (1F)
  • Step 6 tert-Butyl 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (S) -2-acetoxy-2 phenylacetic acid (1H)
  • the filtrate was extracted with dichloromethane (3.0 L ⁇ 2) and the combined organic phases were washed with saturated brine (4 L ⁇ 1) and dried over anhydrous sodium sulfate. After filtration, the filtrate was added with (S)-(+)-O-acetyl-L-mandelic acid (384 g, 1.97 mol, 0.8 eq) and stirred for 20 minutes after the addition.
  • the organic phase was concentrated by distillation until no solvent was distilled off, and then stirred and slurried with isopropyl alcohol (5.9 L) for 2 hours, and the temperature was lowered to 5 ° C and stirred for 1 hour.
  • Second crystallization The first crystal of 1H (177 g, 0.39 mol), isopropanol (2.53 L), and water (0.126 L) were sequentially added to the reaction kettle. The temperature was raised to 82 ° C to completely dissolve the solid, and the temperature was maintained for 0.5 hours. The temperature was lowered to 20 ° C. and crystallized for about 4.5 hours. When the internal temperature reached 30 ° C., it was filtered, and the filter cake was washed with isopropyl alcohol (0.10 L ⁇ 1). The solids were combined and air-dried at 60-65 ° C for 4 hours to dry to constant weight. 1H pure product (128 g, yield: 72%) was obtained as a white solid, and the ee value was determined to be 99.73% after derivatization with the solid.
  • the organic phase was decolorized by adding activated carbon (5.0 g), and dried over anhydrous sodium sulfate. It was filtered and the filtrate was concentrated. The residue in the concentration kettle was dissolved with acetonitrile (280 mL).
  • the benzenesulfonic acid monohydrate (77.0 g, 0.437 mol) was prepared as a solution with purified water (280 mL) and added dropwise to the above acetonitrile solution. The temperature was raised to 80-85 ° C, and the reaction was incubated for 4-6 hours. The reaction solution is cooled to 10-20 ° C and crystallized for about 4-6 hours.
  • Compound 1 (100 mg) was placed in a glass vial, 0.2 ml of water and 0.2 ml of dimethyl sulfoxide were added, the temperature was raised to 80 degrees Celsius, and the solution was naturally cooled to room temperature for 5 minutes to obtain rod-shaped crystals.
  • Second step tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate) (1F)
  • Second step tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate) (1F)
  • a 1D (1.36 kg, 10.0 mol, 1.0 eq) solution of tetrahydrofuran (3.60 L) was added dropwise to the reaction solution, and the addition was completed within 0.5 hours. After the addition, it was allowed to rise to room temperature for 2 hours. After the central control detects that the reaction of the raw materials is complete, a 5% ammonium chloride solution (6.0 L) is sequentially added to the reaction kettle to quench the reaction. After stirring for 20 minutes, the layers were allowed to stand still, and the aqueous phase was extracted with dichloromethane (5.0 L ⁇ 1). The organic phases were combined, washed with 5% saline (5.0 L ⁇ 1), and dried over anhydrous sodium sulfate. Filtration and concentration gave 1E (2.40 kg) as a yellow liquid.
  • Second step tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate) (1F)
  • the organic phase was decolorized by adding activated carbon (0.5 g), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and acetonitrile (26.0 mL) and benzenesulfonic acid monohydrate (3.50 g, 20.0 mmol) were added. The temperature was raised to 80 ° C. Incubate the reaction for 4-6 hours. The ice water was cooled to 25 ° C and crystallized for about 2 hours. When the internal temperature reached 25 ° C., it was filtered, and the filter cake was washed with acetonitrile (3.0 mL ⁇ 2). After drying, Compound 1 (3.4 g, yield: 92.6%) was obtained as a white solid.
  • the organic phase was added with activated carbon (5.0 g) and stirred for decolorization. Filter through celite, add acetonitrile (328.0 mL) after concentrating the filtrate, purified water (328.0 mL) and benzenesulfonic acid monohydrate (114 g, 0.66 mol). The temperature was raised to 80 ° C. The reaction was held for 12 hours, and the control materials were less than 0.2% to complete the reaction. The ice water was cooled to 10 ⁇ 5 ° C, and crystallized after stirring for about 6 hours.
  • Compound 1 can be further purified by the following methods:
  • Method 1 Compound 1 (430.0 g, 1.17 mol) and N-methylpyrrolidone (2.15 L) were added to a 5 L reaction flask. After the addition is completed, heat to 80 ⁇ 5 ° C and hold for 0.5 hours. After the solid was completely dissolved, activated carbon (10 g) was added and stirring was continued for 10 minutes. Filtered while hot, the filter cake was washed with N-methylpyrrolidone (400 mL ⁇ 1), and dried. Isopropyl acetate (7.5 L) was added dropwise to the filtrate, and after the addition was completed, crystallization was continued for 2 hours with stirring.
  • Method 2 Compound 1 (410 g, 1.12 mol) and dimethyl sulfoxide (1230 mL) were added to a 5 L reaction flask. After the addition, heat to 50 ⁇ 5 ° C and hold for 0.5 hours. After the solid was completely dissolved, purified water (2460 mL) was added dropwise. After the addition was completed, the temperature of the water bath was lowered to 15 ° C., and the crystallization was continued for 2 hours. After filtration, the filter cake was washed with purified water (400.0 mL ⁇ 1), dichloromethane (400.0 mL ⁇ 2), dried, and dried under reduced pressure to obtain a white solid compound 1 (352 g, yield: 85.8%).
  • purified water 400.0 mL ⁇ 1
  • dichloromethane 400.0 mL ⁇ 2
  • Second crystallization The first crystal (1.0 g), ethanol (16.0 mL), and water (1.3 mL) were sequentially added to a 100 mL reaction flask. The temperature was raised to 82 ° C. to completely dissolve the solid, and the temperature was lowered to 20 ° C. for crystallization for about 4.5 hours after holding for 0.5 hours. When the internal temperature reached 30 ° C, it was filtered, and the filter cake was washed with ethanol (1.0 mL x 2). The solids were combined, dried for 1 hour, and dried to constant weight to obtain compound 2 (0.63 g, yield 63%). The ee value was 72% after derivatization.
  • 3-Cyclohexene-1-propionic acid (4.11 kg, 26.68 mol, 1 eq) was dissolved in dichloromethane (20.0 L), and then added to a 50 L reaction kettle, and the addition was completed. The temperature was lowered to 20 ° C, and triethylamine (4.04 Kg, 40.03 mol, 1.5 eq) was added. Then add 1-hydroxybenzotriazole (4.32kg, 32.02mol, 1.2eq), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.11kg, 32.02mol) , 1.2eq), and stirred for 30 minutes after the addition.

Abstract

A preparation method for a fused tricyclic γ-amino acid derivative and an intermediate thereof, and a method for preparing an intermediate of the fused tricyclic γ-amino acid derivative. The fused tricyclic γ-amino acid derivative has a structure as represented by formula (I). The preparation method uses readily available raw materials and comprises simple steps; the entire synthesis process uses crystallization purification, while silica gel column chromatography or other preparatory chromatography methods are not used, being suitable for large-scale industrial production.

Description

稠合三环γ-氨基酸衍生物的制备方法及中间体Preparation method and intermediate of fused tricyclic γ-amino acid derivative 技术领域Technical field
本发明涉及医药领域，具体的说，本发明涉及一种稠合三环γ-氨基酸衍生物的制备方法及中间体。The present invention relates to the field of medicine, specifically, the present invention relates to a method for preparing a fused tricyclic γ-amino acid derivative and an intermediate thereof.
背景技术Background technique
电压门控钙通道由α1亚单位和辅助蛋白α2δ、β、γ亚基共同构成。α2δ蛋白可以调节钙通道的密度及钙通道电压依赖性动力学(Felix et al(199 7)J.Neuroscience 17:6884-6891；Klugbauer et al(1999)J.Neuroscience 19:684-691；Hobom et al(2000)Eur.J.Neuroscience 12:1217-1226；and Qin et al(2002)Mol.Pharmacol.62:485-496)。已经证实，对电压依赖性钙通道亚基α2δ表现出高亲合力结合的化合物可有效治疗疼痛，例如普瑞巴林和加巴喷丁。在哺乳动物中，α2δ蛋白有4个亚型，每个亚型均由不同的基因编码。α2δ亚型1和亚型2与普瑞巴林表现出高亲和力，而α2δ亚型3和亚型4无显著的药物结合力。The voltage-gated calcium channel is composed of α1 subunit and auxiliary protein α2δ, β, γ subunits. α2δ protein can regulate the density of calcium channels and voltage-dependent kinetics of calcium channels (Felix et al. (199) J. Neuroscience 17: 6884-6891; Klugbauer et al. (1999) J. Neuroscience 19: 684-691; Hobom et et. al (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al (2002) Mol. Pharmacol. 62: 485-496). Compounds that exhibit high affinity binding to the voltage-dependent calcium channel subunit α2δ have been shown to be effective in treating pain, such as pregabalin and gabapentin. In mammals, there are four subtypes of the α2δ protein, each of which is encoded by a different gene. α2δ subtype 1 and subtype 2 showed high affinity with pregabalin, while α2δ subtype 3 and subtype 4 had no significant drug-binding ability.
然而，对于加巴喷丁，其较大程度改善糖尿病周围神经病变患者病痛的比例约为60％(Acta Neurol.Scand.101:359-371,2000)，对于普瑞巴林，虽然其耐受性优于加巴喷丁，但其安全性更低，且有滥用或者使患者产生依赖的可能(Am J Health Syst Pharm.2007；64(14):1475-1482)。However, for gabapentin, the proportion of patients with diabetic peripheral neuropathy that greatly improves pain is about 60% (Acta Neurol. Scand. 101: 359-371, 2000). For pregabalin, although its tolerance is better than gabapentin However, its safety is lower, and it may be abused or may cause patients to become dependent (Am J Health Syst Pharm. 2007; 64 (14): 1475-1482).
开发新的对电压依赖性钙通道亚基α2δ表现出高亲合力结合的化合物仍然有很大的需求。There is still a great need to develop new compounds that exhibit high affinity binding to the voltage-dependent calcium channel subunit α2δ.
发明内容Summary of the invention
本发明的一个目的在于提供一种稠合三环γ-氨基酸衍生物的制备方法。An object of the present invention is to provide a method for preparing a fused tricyclic γ-amino acid derivative.
本发明的另一目的在于提供用于制备稠合三环γ-氨基酸衍生物的中间体。Another object of the present invention is to provide an intermediate for preparing a fused tricyclic γ-amino acid derivative.
为达上述目的，一方面，本发明提供了一种式(I)所示化合物的制备方法，其中，所述方法包括以式(III)化合物为原料进行反应制备得到，In order to achieve the above object, in one aspect, the present invention provides a method for preparing a compound represented by formula (I), wherein the method includes preparing the compound by reacting with a compound of formula (III) as a raw material,
Figure PCTCN2019096522-appb-000001
Figure PCTCN2019096522-appb-000001
A选自苯磺酸、对甲苯磺酸或甲磺酸；A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
R 2选自羧基保护基或C 1-6的烷基； R 2 is selected from a carboxy protecting group or a C 1-6 alkyl group;
R 11选自C 1-6的烷基。 R 11 is selected from C 1-6 alkyl.
根据本发明一些具体实施方案，其中，A选自苯磺酸。According to some embodiments of the present invention, wherein A is selected from benzenesulfonic acid.
根据本发明一些具体实施方案，其中，R 2选自甲基、乙基、丙基、正丁基或叔丁基。 According to some embodiments of the present invention, R 2 is selected from methyl, ethyl, propyl, n-butyl or tert-butyl.
根据本发明一些具体实施方案，其中，R 2选自叔丁基。 According to some embodiments of the invention, R 2 is selected from tert-butyl.
根据本发明一些具体实施方案，其中，R 11选自甲基、乙基、丙基或丁基。 According to some embodiments of the present invention, R 11 is selected from methyl, ethyl, propyl or butyl.
根据本发明一些具体实施方案，其中，R 11选自甲基。 According to some embodiments of the invention, R 11 is selected from methyl.
其中可以理解的是，以式(III)化合物为原料进行反应制备得到式(I)化合物，可以先水解得到游离碱，然后加入酸A脱去羧基保护基和成盐。也可以是先将羧基保护基脱除，然后水解得到游离碱，再与酸A成盐。It can be understood that the compound of the formula (I) is prepared by reacting the compound of the formula (III) as a raw material, which can be firstly hydrolyzed to obtain a free base, and then the acid A is added to remove the carboxy protecting group and form a salt. It is also possible to remove the carboxyl protecting group first, then hydrolyze to obtain a free base, and then form a salt with acid A.
本发明提供了一种式(I)所示化合物的制备方法，其中，所述方法包括以式(II)化合物为原料进行反应制备得到；The present invention provides a method for preparing a compound represented by formula (I), wherein the method includes preparing the compound by reacting with a compound of formula (II) as a raw material;
Figure PCTCN2019096522-appb-000002
Figure PCTCN2019096522-appb-000002
R 2定义同前。 R 2 is as defined above.
其中，式(I)所示化合物如下：The compounds represented by formula (I) are as follows:
Figure PCTCN2019096522-appb-000003
A定义同前。
Figure PCTCN2019096522-appb-000003
A is as defined above.
本发明提供了一种式(II)化合物的制备方法，以式(III)化合物为原料制备得到The invention provides a method for preparing a compound of formula (II), which is prepared by using a compound of formula (III) as a raw material.
Figure PCTCN2019096522-appb-000004
Figure PCTCN2019096522-appb-000004
R 1、R 2的定义同前。 The definitions of R 1 and R 2 are the same as above.
根据本发明一些具体实施方案，所述方法包括以式(III)化合物为原料先制备得到式(II)化合物，再以式(II)化合物为原料制备得到式(I)化合物，According to some specific embodiments of the present invention, the method includes preparing a compound of formula (II) by using a compound of formula (III) as a raw material, and then preparing a compound of formula (I) by using a compound of formula (II) as a raw material,
Figure PCTCN2019096522-appb-000005
Figure PCTCN2019096522-appb-000005
A、R 1、R 2定义同上。 The definitions of A, R 1 and R 2 are the same as above.
根据本发明一些具体实施方案，其中，所述方法包括以式(III)化合物为原料先制备得到式(II)化合物，再以式(II)化合物为原料在酸A的存在下反应得到式(I)化合物。According to some specific embodiments of the present invention, the method comprises preparing a compound of formula (II) by using a compound of formula (III) as a raw material, and then reacting the compound of formula (II) as a raw material in the presence of acid A to obtain a formula ( I) Compounds.
本发明还提供了一种式(I)所示化合物的制备方法，其中，所述方法包括以式(II)化合物为原料进行反应制备式(I)所示化合物。The present invention also provides a method for preparing a compound represented by formula (I), wherein the method comprises reacting a compound represented by formula (II) as a raw material to prepare a compound represented by formula (I).
A选自苯磺酸、对甲苯磺酸或甲磺酸；A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
R 2选自羧基保护基或C 1-6的烷基。 R 2 is selected from a carboxy protecting group or a C 1-6 alkyl group.
根据本发明一些具体实施方案，其中，R 2选自叔丁基。 According to some embodiments of the invention, R 2 is selected from tert-butyl.
根据本发明一些具体实施方案，其中式(II)化合物与酸A反应制备得到式(I)所示化合物。According to some embodiments of the present invention, a compound of formula (II) is reacted with acid A to prepare a compound of formula (I).
根据本发明一些具体实施方案，其中，酸A与式(II)化合物的摩尔比为1.1:1～5:1。According to some specific embodiments of the present invention, the molar ratio of the acid A to the compound of formula (II) is 1.1: 1 to 5: 1.
根据本发明一些具体实施方案，酸A与式(II)化合物的摩尔比为1.1:1、1.2:1、1.3:1、1.5:1、2:1、3:1、4:1或者5:1。According to some specific embodiments of the present invention, the molar ratio of the acid A to the compound of formula (II) is 1.1: 1, 1.2: 1, 1.3: 1, 1.5: 1, 2: 1, 3: 1, 4: 1, or 5: 1.
根据本发明一些具体实施方案，其中，式(II)化合物和酸A的反应在室温至回流均可以反应；According to some embodiments of the present invention, wherein the reaction of the compound of formula (II) and the acid A can be reacted at room temperature to reflux;
在一些具体实施方案中，反应温度为70～90℃；In some specific embodiments, the reaction temperature is 70-90 ° C;
在一些具体实施例中，反应温度为80～85℃。In some embodiments, the reaction temperature is 80-85 ° C.
在一些具体实施方案中，式(II)化合物与酸A反应的溶剂选自能与式(II)化合物相溶的任意溶剂，比如乙腈、二氯甲烷、乙醇、甲醇、乙酸异丙酯、水、甲苯、二氧六环及其组合溶剂。In some embodiments, the solvent in which the compound of formula (II) reacts with acid A is selected from any solvent compatible with the compound of formula (II), such as acetonitrile, dichloromethane, ethanol, methanol, isopropyl acetate, water , Toluene, dioxane and their combined solvents.
在一些实施方案中，溶剂选自水、乙腈、乙酸异丙酯、乙腈/水。In some embodiments, the solvent is selected from water, acetonitrile, isopropyl acetate, acetonitrile / water.
在一些实施方案中，溶剂选自乙腈/水(v/v＝1:1)。In some embodiments, the solvent is selected from acetonitrile / water (v / v = 1: 1).
在一些实施方案中，式(II)化合物与酸A在能与式(II)化合物相溶的溶剂中反应得到式(I)所示化合物，所述溶剂选自乙腈、二氯甲烷、乙醇、甲醇、乙酸异丙酯、水、甲苯、二氧六环或其组合；进一步优选的，酸A与式(II)化合物的摩尔比为1.1:1～5:1，在70-90℃下反应；更进一步优选的，酸A与式(II)化合物的摩尔比为1.1:1，在80-85℃下反应；更进一步优选的，所述溶剂选自乙腈、二氯甲烷或乙酸异丙酯。In some embodiments, the compound of formula (II) is reacted with acid A in a solvent compatible with the compound of formula (II) to obtain a compound of formula (I), the solvent is selected from the group consisting of acetonitrile, dichloromethane, ethanol, Methanol, isopropyl acetate, water, toluene, dioxane or a combination thereof; more preferably, the molar ratio of acid A to the compound of formula (II) is 1.1: 1 to 5: 1, and the reaction is performed at 70-90 ° C. Still more preferably, the molar ratio of the acid A to the compound of formula (II) is 1.1: 1, and the reaction is performed at 80-85 ° C; even more preferably, the solvent is selected from acetonitrile, dichloromethane or isopropyl acetate .
根据本发明一些具体实施方案，其中，所述方法还包括以式(III)化合物为原料制备 式(II)所示化合物的步骤，According to some specific embodiments of the present invention, wherein the method further comprises the step of preparing a compound represented by formula (II) by using a compound of formula (III) as a raw material,
Figure PCTCN2019096522-appb-000006
Figure PCTCN2019096522-appb-000006
R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
R 2选自羧基保护基或C 1-6的烷基； R 2 is selected from a carboxy protecting group or a C 1-6 alkyl group;
R 11选自C 1-6的烷基。 R 11 is selected from C 1-6 alkyl.
根据本发明一些具体实施方案，其中，R 2选自叔丁基。 According to some embodiments of the invention, R 2 is selected from tert-butyl.
根据本发明一些具体实施方案，其中，R 11选自甲基。 According to some embodiments of the invention, R 11 is selected from methyl.
本发明还提供了一种式(III)化合物的制备方法，其中，所述方法包括以式(IV)化合物为原料经过反应得到式(III)化合物的步骤，The invention also provides a method for preparing a compound of formula (III), wherein the method comprises the step of obtaining a compound of formula (III) by using a compound of formula (IV) as a raw material through a reaction,
Figure PCTCN2019096522-appb-000007
Figure PCTCN2019096522-appb-000007
R 2定义同上。 R 2 is as defined above.
其中，式(III)化合物如下：The compound of formula (III) is as follows:
Figure PCTCN2019096522-appb-000008
R 1定义同上。
Figure PCTCN2019096522-appb-000008
R 1 has the same definition as above.
根据本发明一些具体实施方案，一种式(III)化合物的制备方法，其中，(III)化合物的制备包括以式(IV)化合物和手性酸为原料制备式(III)化合物。According to some specific embodiments of the present invention, a method for preparing a compound of formula (III), wherein the preparation of a compound of (III) includes preparing a compound of formula (III) using a compound of formula (IV) and a chiral acid as raw materials.
本发明所述手性酸选自式(XI)化合物、R-α-甲基苯乙酸、(-)-二乙酰基-L-酒石酸、L-天冬氨酸或者右旋奎宁酸，The chiral acid according to the present invention is selected from the group consisting of a compound of formula (XI), R-α-methylphenylacetic acid, (-)-diacetyl-L-tartaric acid, L-aspartic acid, or d-quinic acid,
Figure PCTCN2019096522-appb-000009
Figure PCTCN2019096522-appb-000009
R 1选自H、羟基保护基或-C(＝O)R 11；R 11选自C 1-6的烷基；优选R 11选自甲基。 R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ; R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl.
根据本发明的一些具体实施方案，一种式(III)化合物的制备方法，其中：According to some specific embodiments of the present invention, a method for preparing a compound of formula (III), wherein:
Figure PCTCN2019096522-appb-000010
Figure PCTCN2019096522-appb-000010
R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
R 2选自羧基保护基或C 1-6的烷基； R 2 is selected from a carboxy protecting group or a C 1-6 alkyl group;
R 11选自C 1-6的烷基。 R 11 is selected from C 1-6 alkyl.
根据本发明一些具体实施方案，其中，R 2选自叔丁基。 According to some embodiments of the invention, R 2 is selected from tert-butyl.
根据本发明一些具体实施方案，其中，R 11选自甲基。 According to some embodiments of the invention, R 11 is selected from methyl.
根据本发明一些具体实施方案，手性酸为(S)-(+)-O-乙酰基-L-扁桃酸或L-扁桃酸。According to some specific embodiments of the present invention, the chiral acid is (S)-(+)-O-acetyl-L-mandelic acid or L-mandelic acid.
根据本发明一些具体实施方案，一种式(III)化合物的制备方法，其中，所述手性酸和式(IV)化合物的摩尔比为0.5:1-1:1。According to some specific embodiments of the present invention, a method for preparing a compound of formula (III), wherein the molar ratio of the chiral acid to the compound of formula (IV) is 0.5: 1-1: 1.
根据本发明一些具体实施方案，一种式(III)化合物的制备方法，其中，手性酸和式(IV)化合物在室温到回流条件下反应。According to some specific embodiments of the present invention, a method for preparing a compound of formula (III), wherein the chiral acid and the compound of formula (IV) are reacted under the conditions of room temperature to reflux.
根据本发明一些具体实施方案，一种式(III)化合物的制备方法，其中，所述手性酸选自式(XI)化合物、R-α-甲基苯乙酸、(-)-二乙酰基-L-酒石酸、L-天冬氨酸或者右旋奎宁酸；进一步优选的，所述手性酸和式(IV)化合物的摩尔比为0.5:1-1:1，在室温到回流条件下反应。According to some specific embodiments of the present invention, a method for preparing a compound of formula (III), wherein the chiral acid is selected from a compound of formula (XI), R-α-methylphenylacetic acid, (-)-diacetyl -L-tartaric acid, L-aspartic acid or dextroquinic acid; further preferably, the molar ratio of the chiral acid to the compound of formula (IV) is 0.5: 1-1: 1, at room temperature to reflux conditions Down reaction.
根据本发明一些具体实施方案，其中，所述方法包括以式(IV)化合物为原料经过反应得到式(III)化合物，然后再对所述式(III)化合物进行重结晶。According to some specific embodiments of the present invention, the method comprises using a compound of formula (IV) as a raw material to obtain a compound of formula (III) through a reaction, and then recrystallizing the compound of formula (III).
本发明还提供了一种式(Ⅲ)所示化合物的精制方法，将式(III)化合物在重结晶溶剂中重结晶：The invention also provides a method for purifying the compound represented by formula (III), and the compound of formula (III) is recrystallized in a recrystallization solvent:
Figure PCTCN2019096522-appb-000011
Figure PCTCN2019096522-appb-000011
R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
R 2选自羧基保护基或C 1-6的烷基；优选R 2选自叔丁基； R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
R 11选自C 1-6的烷基；优选R 11选自甲基。 R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl.
根据本发明一些具体实施方案，一种式(Ⅲ)所示化合物的精制方法，其中，将式(Ⅲ)化合物在重结晶溶剂中进行重结晶，所述重结晶溶剂为有机溶剂和/或水，优选重结晶1-2 次。According to some specific embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the compound of formula (III) is recrystallized in a recrystallization solvent, and the recrystallization solvent is an organic solvent and / or water It is preferred to recrystallize 1-2 times.
根据本发明一些具体实施方案，一种式(Ⅲ)所示化合物的精制方法，其中，式(III)化合物与重结晶溶剂的质量体积比为1:10-1:30。According to some specific embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the mass-volume ratio of the compound of formula (III) to the recrystallization solvent is from 1:10 to 1:30.
根据本发明一些具体实施方案，一种式(Ⅲ)所示化合物的精制方法，其中，所述有机溶剂选自异丙醇、乙腈或乙醇中的一种或多种的混合；According to some specific embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the organic solvent is selected from a mixture of one or more of isopropyl alcohol, acetonitrile, or ethanol;
根据本发明一些具体实施方案，一种式(Ⅲ)所示化合物的精制方法，其中，所述有机溶剂为异丙醇。According to some specific embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the organic solvent is isopropanol.
根据本发明一些具体实施方案，一种式(Ⅲ)所示化合物的精制方法，其中，重结晶溶剂为异丙醇和水。According to some specific embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the recrystallization solvent is isopropyl alcohol and water.
根据本发明一些具体实施方案，一种式(Ⅲ)所示化合物的精制方法，其中，异丙醇和水的体积比为(10-20):1。According to some specific embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the volume ratio of isopropanol and water is (10-20): 1.
根据本发明一些具体实施方案，一种式(Ⅲ)所示化合物的精制方法，其中，异丙醇和水的体积比为10:1-30:1。According to some specific embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the volume ratio of isopropanol and water is 10: 1-30: 1.
根据本发明一些具体实施方案，一种式(Ⅲ)所示化合物的精制方法，其中，重结晶重复1-2次。According to some embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein recrystallization is repeated 1-2 times.
根据本发明一些具体实施方案，一种式(Ⅲ)所示化合物的精制方法，其中，式(III)化合物的制备包括首先以式(IV)化合物和手性酸为原料制备式(III)化合物，然后再将式(III)化合物重结晶得到精制化合物。According to some embodiments of the present invention, a method for purifying a compound represented by formula (III), wherein the preparation of a compound of formula (III) includes first preparing a compound of formula (III) using a compound of formula (IV) and a chiral acid as raw materials. Then, the compound of formula (III) is recrystallized to obtain a purified compound.
根据本发明一些具体实施方案，其中，手性酸选自式(XI)化合物、R-α-甲基苯乙酸、(-)-二乙酰基-L-酒石酸、L-天冬氨酸或者右旋奎宁酸，According to some specific embodiments of the present invention, the chiral acid is selected from the group consisting of a compound of formula (XI), R-α-methylphenylacetic acid, (-)-diacetyl-L-tartaric acid, L-aspartic acid, or right Quinic acid,
Figure PCTCN2019096522-appb-000012
Figure PCTCN2019096522-appb-000012
其中，R 1选自H、羟基保护基或-C(＝O)R 11； Wherein R 1 is selected from H, a hydroxy protecting group, or -C (= O) R 11 ;
R 11选自C 1-6的烷基； R 11 is selected from C 1-6 alkyl;
在一些具体实施方案中，R 11选自甲基、乙基、丙基或丁基； In some specific embodiments, R 11 is selected from methyl, ethyl, propyl, or butyl;
在一些具体实施方案中，R 11选自甲基。 In some embodiments, R 11 is selected from methyl.
根据本发明一些具体实施方案，其中，手性酸选自式(XI)化合物，According to some embodiments of the present invention, wherein the chiral acid is selected from a compound of formula (XI),
Figure PCTCN2019096522-appb-000013
Figure PCTCN2019096522-appb-000013
其中，R 1选自H或-C(＝O)R 11； Wherein R 1 is selected from H or -C (= O) R 11 ;
R 11选自甲基。 R 11 is selected from methyl.
根据本发明一些具体实施方案，手性酸为(S)-(+)-O-乙酰基-L-扁桃酸或L-扁桃酸。According to some specific embodiments of the present invention, the chiral acid is (S)-(+)-O-acetyl-L-mandelic acid or L-mandelic acid.
根据本发明一些具体实施方案，其中，式(XI)化合物和式(IV)化合物的摩尔比为0.5:1～1:1。According to some specific embodiments of the present invention, the molar ratio of the compound of formula (XI) to the compound of formula (IV) is 0.5: 1 to 1: 1.
在一些具体实施方案中，式(XI)化合物和式(IV)化合物的摩尔比为0.5:1～0.8:1。In some embodiments, the molar ratio of the compound of formula (XI) to the compound of formula (IV) is 0.5: 1 to 0.8: 1.
根据本发明一些具体实施方案，其中，式(IV)化合物和式(XI)化合物在室温至回流条件下进行反应；According to some embodiments of the present invention, wherein the compound of the formula (IV) and the compound of the formula (XI) are reacted under the conditions of room temperature to reflux;
根据本发明一些具体实施方案，式(XI)化合物和式(IV)化合物在80～90℃下反应。According to some embodiments of the invention, the compound of formula (XI) and the compound of formula (IV) are reacted at 80-90 ° C.
根据本发明一些具体实施方案，其中，所述方法包括以式(IV)化合物为原料经过反应得到式(III)化合物的粗品，然后再利用重结晶溶剂，如有机溶剂和/或水对所述粗品进行重结晶。According to some specific embodiments of the present invention, the method comprises using a compound of formula (IV) as a raw material to obtain a crude compound of formula (III) through a reaction, and then using a recrystallization solvent such as an organic solvent and / or water to The crude product was recrystallized.
根据本发明一些具体实施方案，其中，所述有机溶剂选自异丙醇、乙腈、乙醇和水中的一种或多种的混合；优选为异丙醇和水的混合，或者乙醇和水的混合。According to some specific embodiments of the present invention, the organic solvent is selected from a mixture of one or more of isopropyl alcohol, acetonitrile, ethanol, and water; preferably, a mixture of isopropyl alcohol and water, or a mixture of ethanol and water.
根据本发明一些具体实施方案，其中，异丙醇和水的体积比为(10-30)：1。According to some specific embodiments of the present invention, the volume ratio of isopropanol and water is (10-30): 1.
根据本发明一些具体实施方案，其中，异丙醇和水的体积比为(10-20)：1。According to some specific embodiments of the present invention, the volume ratio of isopropanol and water is (10-20): 1.
根据本发明一些具体实施方案，其中，乙醇和水的体积比为(10-30)：1。According to some specific embodiments of the present invention, wherein the volume ratio of ethanol to water is (10-30): 1.
在一些实施方式中，乙醇和水的体积比为(10-20)：1。In some embodiments, the volume ratio of ethanol to water is (10-20): 1.
根据本发明一些具体实施方案，其中，式(III)化合物与重结晶溶剂的质量体积比为1:10-1:30；在一些实施方案中，质量体积比为1:10-1:20。According to some specific embodiments of the present invention, wherein the mass-volume ratio of the compound of formula (III) to the recrystallization solvent is from 1:10 to 1:30; in some embodiments, the mass-to-volume ratio is from 1:10 to 1:20.
根据本发明一些具体实施方案，其中，重结晶溶剂为异丙醇和水，异丙醇和水的体积比为10:1～30:1。According to some specific embodiments of the present invention, wherein the recrystallization solvent is isopropyl alcohol and water, and the volume ratio of isopropyl alcohol and water is 10: 1 to 30: 1.
根据本发明一些具体实施方案，其中，所述重结晶的步骤包括式(III)粗品溶解于重结晶溶剂中，搅拌反应0.5～1小时后，析晶。According to some specific embodiments of the present invention, the recrystallization step includes dissolving the crude product of formula (III) in a recrystallization solvent, and stirring for 0.5 to 1 hour before crystallization.
根据本发明一些具体实施方案，其中，重结晶重复1-2次。According to some embodiments of the present invention, the recrystallization is repeated 1-2 times.
其中可以理解的是，所述的重复，是在首次的基础上进行重复，譬如，重复1次，则是重结晶2次；重复2次，则相当于重结晶3次。It can be understood that the repetition is repeated on the basis of the first time. For example, if it is repeated once, it is recrystallized twice; if it is repeated twice, it is equivalent to recrystallize three times.
根据本发明一些具体实施方案，其中，所述方法还包括以式(V)化合物为原料制备式(IV)化合物的步骤，According to some specific embodiments of the present invention, wherein the method further comprises the step of preparing a compound of formula (IV) by using a compound of formula (V) as a raw material,
Figure PCTCN2019096522-appb-000014
Figure PCTCN2019096522-appb-000014
R 2定义同上。 R 2 is as defined above.
根据本发明一些具体实施方案，其中，式(IV)化合物的制备包括：以式(V)化合物为原料在催化剂和还原剂的存在下，在0-40℃下制备式(IV)化合物。According to some specific embodiments of the present invention, the preparation of the compound of formula (IV) includes: using the compound of formula (V) as a raw material in the presence of a catalyst and a reducing agent to prepare a compound of formula (IV) at 0-40 ° C.
在某些实施方案中，化合物(V)发生还原反应生成化合物(IV)的催化剂/还原剂可以选自雷尼镍/水合肼、氯化镍六水合物/硼氢化钠、铁粉/氯化铵、10％钯碳/三乙基硅、雷尼镍/氢气、10％钯碳/氢气或者锌粉/乙酸。In certain embodiments, the catalyst / reducing agent that undergoes a reduction reaction of compound (V) to form compound (IV) may be selected from Raney nickel / hydrazine hydrate, nickel chloride hexahydrate / sodium borohydride, iron powder / chlorination Ammonium, 10% palladium carbon / triethyl silicon, Raney nickel / hydrogen, 10% palladium carbon / hydrogen or zinc powder / acetic acid.
在某些实施方案中，催化剂/还原剂选自氯化镍六水合物/硼氢化钠或者10％钯碳/氢气。In certain embodiments, the catalyst / reducing agent is selected from nickel chloride hexahydrate / sodium borohydride or 10% palladium carbon / hydrogen.
在某些实施方案中，还原条件是：0-40℃，醇溶剂中，氯化镍六水合物作催化剂，硼氢化钠作还原剂；或者，0-40℃，醇溶剂中，钯碳作催化剂，氢气作还原剂。在某些实施方案中，醇溶剂为甲醇或者乙醇。In certain embodiments, the reduction conditions are: 0-40 ° C, in an alcohol solvent, nickel chloride hexahydrate as a catalyst, and sodium borohydride as a reducing agent; or, 0-40 ° C, in an alcohol solvent, palladium carbon as Catalyst, hydrogen as reducing agent. In certain embodiments, the alcohol solvent is methanol or ethanol.
在某些实施方案中，还原反应的温度为20℃～30℃。In some embodiments, the temperature of the reduction reaction is from 20 ° C to 30 ° C.
在某些实施方案中，式(V)化合物与催化剂摩尔比为1:1～10:1，在某些实施方案中，摩尔比为2:1～5:1，在某些实施方案中，摩尔比为2:1、3:1、4:1、5:1。In certain embodiments, the molar ratio of the compound of formula (V) to the catalyst is from 1: 1 to 10: 1, in some embodiments, the molar ratio is from 2: 1 to 5: 1, and in some embodiments, The molar ratio is 2: 1, 3: 1, 4: 1, 5: 1.
在某些实施方案中，式(V)化合物与还原剂摩尔比为1:2～1:10，在某些实施方案中，摩尔比为1:2.5～1:5，在某些实施方案中，摩尔比为1:2.5、1:3、1:4、1:5。In some embodiments, the molar ratio of the compound of formula (V) to the reducing agent is from 1: 2 to 1:10. In some embodiments, the molar ratio is from 1: 2.5 to 1: 5. In some embodiments The molar ratio is 1: 2.5, 1: 3, 1: 4, 1: 5.
在某些实施方案中，式(V)化合物：催化剂:还原剂的摩尔比为1:0.2:2.5-1:0.5:5。在某些实施方案中，摩尔比为1:0.2:2.5、1:0.2:5、1:0.2:4、1:0.5:5，在某些实施方案中，摩尔比为1:0.2:4。In certain embodiments, the molar ratio of the compound of formula (V): catalyst: reducing agent is 1: 0.2: 2.5-1: 0.5: 5. In some embodiments, the molar ratio is 1: 0.2: 2.5, 1: 0.2: 5, 1: 0.2: 4, 1: 0.5: 5, and in some embodiments, the molar ratio is 1: 0.2: 4.
根据本发明一些具体实施方案，其中，所述方法还包括式(V)化合物的制备：包括以式(VI)化合物为原料制备式(V)化合物，According to some specific embodiments of the present invention, wherein the method further comprises the preparation of a compound of formula (V): comprising preparing a compound of formula (V) using a compound of formula (VI) as a raw material,
Figure PCTCN2019096522-appb-000015
Figure PCTCN2019096522-appb-000015
R 2定义同上。 R 2 is as defined above.
根据本发明一些具体实施方案，其中，在碱存在下，化合物(VI)与硝基甲烷发生加成反 应生成化合物(V)；作为选择，可以有溶剂存在，所述溶剂选自二甲亚砜、N，N-二甲基甲酰胺、N-甲基吡咯烷酮或四氢呋喃。According to some specific embodiments of the present invention, in the presence of a base, compound (VI) undergoes an addition reaction with nitromethane to form compound (V); alternatively, a solvent may be present, said solvent being selected from dimethyl sulfoxide , N, N-dimethylformamide, N-methylpyrrolidone or tetrahydrofuran.
根据本发明一些具体实施方案，其中，式(V)化合物的制备包括：式(VI)化合物和硝基甲烷在碱存在下，无其他溶剂环境中反应制备式(V)化合物。According to some specific embodiments of the present invention, the preparation of the compound of formula (V) comprises: reacting the compound of formula (VI) and nitromethane in the presence of a base in the absence of other solvents to prepare the compound of formula (V).
根据本发明一些具体实施方案，其中，碱选自碳酸铯、叔丁醇钾或者1,8-二氮杂二环十一碳-7-烯。According to some embodiments of the present invention, the base is selected from the group consisting of cesium carbonate, potassium tert-butoxide, or 1,8-diazabicycloundec-7-ene.
根据本发明一些具体实施方案，其中，加成反应的温度为60℃～回流。According to some specific embodiments of the present invention, the temperature of the addition reaction is 60 ° C. to reflux.
根据本发明一些具体实施方案，其中，加成反应的温度为80℃～100℃。According to some specific embodiments of the present invention, the temperature of the addition reaction is 80 ° C to 100 ° C.
根据本发明一些具体实施方案，其中，加成反应的温度为85℃～90℃。According to some specific embodiments of the present invention, the temperature of the addition reaction is from 85 ° C to 90 ° C.
根据本发明一些具体实施方案，其中，加成反应的温度为80℃～85℃。According to some specific embodiments of the present invention, the temperature of the addition reaction is 80 ° C to 85 ° C.
根据本发明一些具体实施方案，其中，在碱存在下，化合物(VI)与硝基甲烷发生加成反应生成化合物(V)；作为选择，可以有溶剂存在，所述溶剂选自二甲亚砜或N，N-二甲基甲酰胺。According to some specific embodiments of the present invention, in the presence of a base, compound (VI) undergoes an addition reaction with nitromethane to form compound (V); alternatively, a solvent may be present, said solvent being selected from dimethyl sulfoxide Or N, N-dimethylformamide.
根据本发明一些具体实施方案，其中，化合物(V)与硝基甲烷反应的投料摩尔比为1:2.5～1:10,1:3～1:9,1:3～1:8,1:3～1:7,1:3～1:6,1:3～1:5或1:3～1:4。According to some specific embodiments of the present invention, the compound (V) is reacted with nitromethane in a molar ratio of 1: 2.5 to 1:10, 1: 3 to 1: 9, 1: 3 to 1: 8,1: 3 ～ 1: 7, 1: 3 ～ 1: 6, 1: 3 ～ 1: 5 or 1: 3 ～ 1: 4.
在某些实施方案中，化合物(V)与硝基甲烷反应的投料摩尔比为1:2.5、1:3、1:4、1:5、1:6、1:7、1:8、1:9或1:10。In certain embodiments, the molar ratio of the compound (V) to nitromethane is 1: 2.5, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1 : 9 or 1:10.
根据本发明一些具体实施方案，其中，所述方法还包括式(VI)化合物的制备：包括以式(VII)化合物为原料制备式(VI)化合物，According to some specific embodiments of the present invention, wherein the method further comprises the preparation of a compound of formula (VI): comprising preparing a compound of formula (VI) by using a compound of formula (VII) as a raw material,
Figure PCTCN2019096522-appb-000016
Figure PCTCN2019096522-appb-000016
根据本发明一些具体实施方案，其中，式(VI)化合物的制备包括：在碱存在下，式(VII)化合物与选自二甲氧基膦酰基乙酸叔丁酯、二乙氧基磷酰基乙酸叔丁酯、溴乙酸叔丁酯、氯乙酸叔丁酯或者乙酰乙酸叔丁酯中任意一种化合物发生反应生成式(VI)化合物。According to some specific embodiments of the present invention, wherein the preparation of the compound of formula (VI) comprises: in the presence of a base, the compound of formula (VII) and t-butyl dimethoxyphosphonoacetate, diethoxyphosphoryl acetate Any one of t-butyl ester, t-butyl bromoacetate, t-butyl chloroacetate, or t-butyl acetoacetate reacts to form a compound of formula (VI).
根据本发明一些具体实施方案，其中，制备(VI)化合物所用的碱选自叔丁醇钾、1,8-二氮杂二环十一碳-7-烯、二异丙基胺基锂、碳酸钾或者氢化锂。According to some embodiments of the present invention, wherein the base used for preparing the compound (VI) is selected from potassium tert-butoxide, 1,8-diazabicycloundec-7-ene, lithium diisopropylamino, Potassium carbonate or lithium hydride.
根据本发明一些具体实施方案，其中，制备(VI)化合物所用的碱选自叔丁醇钾或1,8-二氮杂二环十一碳-7-烯。According to some specific embodiments of the present invention, the base used for preparing the compound (VI) is selected from potassium tert-butoxide or 1,8-diazabicycloundec-7-ene.
根据本发明一些具体实施方案，其中，式(VII)化合物与二甲氧基膦酰基乙酸叔丁酯 反应的温度为10℃～40℃。According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (VII) with dimethoxyphosphono t-butyl acetate is 10 ° C to 40 ° C.
根据本发明一些具体实施方案，其中，式(VII)化合物与二甲氧基膦酰基乙酸叔丁酯反应的温度为10℃～30℃。According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (VII) with dimethoxyphosphono t-butyl acetate is 10 ° C-30 ° C.
根据本发明一些具体实施方案，其中，式(VII)化合物与二甲氧基膦酰基乙酸叔丁酯反应的温度为10℃～15℃。According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (VII) with dimethoxyphosphonoacetic acid tert-butyl ester is 10 ° C-15 ° C.
根据本发明一些具体实施方案，其中，式(VII)化合物与二甲氧基膦酰基乙酸叔丁酯反应的温度为20℃～40℃。According to some specific embodiments of the present invention, the reaction temperature of the compound of the formula (VII) with dimethoxyphosphono t-butyl acetate is 20 ° C-40 ° C.
根据本发明一些具体实施方案，其中，式(VII)化合物与二甲氧基膦酰基乙酸叔丁酯反应的温度为30℃～40℃。According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (VII) with dimethoxyphosphono t-butyl acetate is 30 ° C-40 ° C.
根据本发明一些具体实施方案，其中，二甲氧基膦酰基乙酸叔丁酯可以替换为二乙氧基磷酰基乙酸叔丁酯、溴乙酸叔丁酯、氯乙酸叔丁酯或者乙酰乙酸叔丁酯。According to some embodiments of the present invention, the tert-butyl dimethoxyphosphonoacetate can be replaced with tert-butyl diethoxyphosphoryl acetate, tert-butyl bromoacetate, tert-butyl chloroacetate, or tert-butyl acetoacetate. ester.
根据本发明一些具体实施方案，其中，化合物(VII)与二甲氧基膦酰基乙酸叔丁酯的摩尔比为1:1～1:10。According to some specific embodiments of the present invention, the molar ratio of compound (VII) to dimethoxyphosphono t-butyl acetate is 1: 1 to 1:10.
根据本发明一些具体实施方案，其中，化合物(VII)与二甲氧基膦酰基乙酸叔丁酯的摩尔比为1:1.1～1:5。According to some specific embodiments of the present invention, the molar ratio of the compound (VII) to the dimethoxyphosphono t-butyl acetate is 1: 1.1 to 1: 5.
根据本发明一些具体实施方案，其中，化合物(VII)与二甲氧基膦酰基乙酸叔丁酯的摩尔比为1:1.1～1:2。According to some specific embodiments of the present invention, the molar ratio of compound (VII) to dimethoxyphosphono t-butyl acetate is 1: 1.1 to 1: 2.
根据本发明一些具体实施方案，其中，化合物(VII)与二甲氧基膦酰基乙酸叔丁酯的摩尔比为1:1.1～1:1.5。According to some specific embodiments of the present invention, wherein the molar ratio of compound (VII) to dimethoxyphosphono t-butyl acetate is 1: 1.1 to 1: 1.5.
根据本发明一些具体实施方案，其中，化合物(VII)与二甲氧基膦酰基乙酸叔丁酯在溶剂中进行反应。在某些实施方案中，溶剂选自四氢呋喃。According to some specific embodiments of the present invention, the compound (VII) is reacted with tert-butyl dimethoxyphosphonoacetate in a solvent. In certain embodiments, the solvent is selected from tetrahydrofuran.
本发明还提供了一种式(VII)所示化合物的制备方法，其中，所述方法包括以式(VIII)化合物为原料制备式(VII)化合物，The present invention also provides a method for preparing a compound represented by formula (VII), wherein the method includes preparing a compound of formula (VII) using a compound of formula (VIII) as a raw material,
Figure PCTCN2019096522-appb-000017
Figure PCTCN2019096522-appb-000017
R 3和R 4各自分别独立的选自C 1-6的烷基； R 3 and R 4 are each independently selected from C 1-6 alkyl groups;
可选的，R 3和R 4和与其连接的碳原子共同形成环。 Optionally, R 3 and R 4 and the carbon atom to which they are attached together form a ring.
根据本发明一些具体实施方案，其中，R 3和R 4各自分别独立选自甲基、乙基或者异丙基。 According to some embodiments of the present invention, R 3 and R 4 are each independently selected from methyl, ethyl or isopropyl.
根据本发明一些具体实施方案，其中，R 3和R 4与所连接的氮原子形成哌啶环或者四氢吡咯环。 According to some embodiments of the present invention, wherein R 3 and R 4 form a piperidine ring or a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
根据本发明一些具体实施方案，其中，R 3和R 4与所连接的氮原子形成四氢吡咯环。 According to some embodiments of the invention, wherein R 3 and R 4 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
根据本发明一些具体实施方案，其中，所述方法包括以式(VIII)化合物和酸酐在吡啶类的碱存在下反应制备式(VII)化合物。According to some specific embodiments of the present invention, wherein the method comprises reacting a compound of formula (VIII) and an acid anhydride in the presence of a pyridine base to prepare a compound of formula (VII).
本发明所述酸酐选自三氟甲烷磺酸酐或对甲苯磺酸酐。The anhydride described in the present invention is selected from trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride.
本发明所述吡啶类的碱是指包含吡啶结构的碱，比如2,4,6-三甲基吡啶、2,6-二甲基吡啶或者吡啶。The pyridine base in the present invention refers to a base containing a pyridine structure, such as 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, or pyridine.
根据本发明一些具体实施方案，其中，所述方法包括以式(VIII)化合物和三氟甲烷磺酸酐和吡啶类的碱存在下反应制备式(VII)化合物。According to some specific embodiments of the present invention, wherein the method comprises reacting a compound of formula (VIII) and a base of trifluoromethanesulfonic anhydride and pyridines to prepare a compound of formula (VII).
根据本发明一些具体实施方案，其中，式(VIII)化合物和吡啶类的碱、三氟甲烷磺酸酐反应结束后，还包括用碱对反应液进行碱处理的步骤。According to some specific embodiments of the present invention, after the reaction of the compound of formula (VIII) with a base of pyridine and trifluoromethanesulfonic anhydride, the method further includes a step of subjecting the reaction solution to alkali treatment with a base.
根据本发明一些具体实施方案，其中，式(VIII)化合物和吡啶类的碱、三氟甲烷磺酸酐反应结束后，用碱对反应液进行碱处理，调节pH值为碱性；在某些实施方案中，调至pH值为10-11。According to some specific embodiments of the present invention, after the reaction of the compound of formula (VIII) with a pyridine base and trifluoromethanesulfonic anhydride is completed, the reaction solution is subjected to alkali treatment with a base to adjust the pH value to be basic; in some implementations, In the protocol, adjust the pH to 10-11.
在某些实施方案中，碱可以选自无机碱。In certain embodiments, the base may be selected from inorganic bases.
在某些实施方案中，无机碱可以选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸氢钠、氟化铯或者碳酸铯；pH至碱性可以选自pH值为8-14、8-11、9-11或者10-11。In certain embodiments, the inorganic base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, cesium fluoride, or cesium carbonate; pH to basicity may be selected from a pH of 8- 14, 8-11, 9-11, or 10-11.
根据本发明一些具体实施方案，其中，式(VIII)化合物和吡啶类的碱、三氟甲烷磺酸酐反应结束后，用碱对反应液进行碱处理后，继续反应至中间体反应完毕，还包括用酸对反应液进行酸化处理的步骤。According to some specific embodiments of the present invention, after the reaction of the compound of formula (VIII) with a pyridine base and trifluoromethanesulfonic anhydride is completed, the reaction solution is subjected to alkali treatment with a base, and the reaction is continued until the intermediate reaction is completed, further including A step of acidifying the reaction solution with an acid.
本发明所述酸化处理指用酸调节反应液pH为酸性。In the present invention, the acidification treatment refers to adjusting the pH of the reaction solution to be acidic with an acid.
根据本发明一些具体实施方案，所述酸化处理指用无机酸调节反应液为酸性。According to some specific embodiments of the present invention, the acidification treatment refers to adjusting the reaction solution to be acidic with an inorganic acid.
根据本发明一些具体实施方案，所述酸化处理指调节反应液pH为1-4。According to some specific embodiments of the present invention, the acidification treatment refers to adjusting the pH of the reaction solution to 1-4.
根据本发明一些具体实施方案，所述无机酸为硫酸、盐酸、磷酸或硝酸。According to some embodiments of the present invention, the inorganic acid is sulfuric acid, hydrochloric acid, phosphoric acid, or nitric acid.
根据本发明一些具体实施方案，其中，式(VIII)化合物和吡啶类的碱、三氟甲烷磺酸酐反应结束后，用碱对反应液进行碱处理后，继续反应至中间体反应完毕，还包括用酸对反应液进行酸化，pH调节为1-2；According to some specific embodiments of the present invention, after the reaction of the compound of formula (VIII) with a pyridine base and trifluoromethanesulfonic anhydride is completed, the reaction solution is subjected to alkali treatment with a base, and the reaction is continued until the intermediate reaction is completed, further including Acidify the reaction solution with acid and adjust the pH to 1-2;
根据本发明一些具体实施方案，其中，所述的酸为无机酸；在某些实施方案中为硫酸、盐酸、磷酸和硝酸中的一种或多种的混合。According to some specific embodiments of the present invention, wherein the acid is an inorganic acid; in some embodiments, a mixture of one or more of sulfuric acid, hydrochloric acid, phosphoric acid, and nitric acid.
根据本发明一些具体实施方案，其中，式(VIII)化合物和吡啶类的碱、三氟甲烷磺酸酐是在室温至回流下进行反应。在某些实施方案中，在回流下进行反应。According to some embodiments of the present invention, the compound of formula (VIII) is reacted with a base of pyridine and trifluoromethanesulfonic anhydride at room temperature to reflux. In certain embodiments, the reaction is performed under reflux.
在某些实施方案中，式(VII)所示的化合物的制备方法包括以下步骤：In some embodiments, a method for preparing a compound represented by formula (VII) includes the following steps:
(1)式(VIII)化合物在酸酐(优选三氟甲烷磺酸酐或对甲苯磺酸酐)和吡啶类碱(优选2,4,6-三甲基吡啶、2,6-二甲基吡啶或吡啶)存在下发生反应；(1) The compound of formula (VIII) is in an acid anhydride (preferably trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride) and a pyridine base (preferably 2,4,6-trimethylpyridine, 2,6-dimethylpyridine or pyridine ) In the presence of a reaction;
(2)用碱(优选无机碱，进一步优选氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸氢钠或碳酸铯)调节步骤(1)得到的反应液pH至碱性，优选调节pH为8-11；(2) The base (preferably an inorganic base, more preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, or cesium carbonate) is used to adjust the pH of the reaction solution obtained in step (1) to alkaline, and it is preferably adjusted pH is 8-11;
(3)用无机酸(优选硫酸、盐酸、磷酸或硝酸)将步骤(2)得到的混合物进行酸化处理得式(VII)化合物。(3) Acidifying the mixture obtained in step (2) with an inorganic acid (preferably sulfuric acid, hydrochloric acid, phosphoric acid, or nitric acid) to obtain a compound of formula (VII).
根据本发明一些具体实施方案，其中，式(VII)所示化合物的制备方法包括如下步骤：According to some specific embodiments of the present invention, the method for preparing the compound represented by formula (VII) includes the following steps:
Figure PCTCN2019096522-appb-000018
Figure PCTCN2019096522-appb-000018
(1)式(VIII)化合物在三氟甲烷磺酸酐和吡啶类碱存在下发生加成反应；(1) the compound of formula (VIII) undergoes an addition reaction in the presence of trifluoromethanesulfonic anhydride and a pyridine base;
(2)无机碱调节反应液pH至碱性，水解得到式(VII)和式(VII-1)混合物；其中无机碱可以选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸氢钠、氟化铯或者碳酸铯；(2) The inorganic base adjusts the pH of the reaction solution to alkaline and hydrolyzes to obtain a mixture of formula (VII) and formula (VII-1); wherein the inorganic base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, carbonic acid Sodium hydrogen, cesium fluoride or cesium carbonate;
(3)在酸性条件下，对反应液进行酸化处理，调节pH为1-4，将步骤(2)得到的混合物中的式(VII-1)化合物发生重排反应得式(VII)化合物；其中，所述的酸为无机酸，选自硫酸、盐酸、磷酸和硝酸中的一种或多种的混合。(3) under acidic conditions, acidify the reaction solution, adjust the pH to 1-4, and rearrange the compound of formula (VII-1) in the mixture obtained in step (2) to obtain a compound of formula (VII); Wherein, the acid is an inorganic acid, which is a mixture of one or more selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid and nitric acid.
在某些实施方案中，式(VII)所示的化合物的制备方法包括以下步骤：In some embodiments, a method for preparing a compound represented by formula (VII) includes the following steps:
(1)二氯甲烷或者1,2-二氯乙烷作溶剂，吡啶类的碱和三氟甲烷磺酸酐存在下，式(VIII)发生加成反应；其中吡啶类的碱是指包含吡啶结构的碱，比如2,4,6-三甲基吡啶、2,6-二甲基吡啶或者吡啶；(1) Dichloromethane or 1,2-dichloroethane as a solvent, in the presence of a pyridine base and trifluoromethanesulfonic anhydride, an addition reaction of formula (VIII) occurs; wherein a pyridine base refers to a structure containing pyridine Base, such as 2,4,6-trimethylpyridine, 2,6-dimethylpyridine or pyridine;
(2)无机碱调节反应液pH至碱性，水解得到式(VII)和式(VII-1)混合物；其中无机碱可以选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸氢钠、氟化铯或者碳酸铯；pH至碱性可以选自pH值为8-14、8-11、9-11或者10-11；(2) The inorganic base adjusts the pH of the reaction solution to alkaline and hydrolyzes to obtain a mixture of formula (VII) and formula (VII-1); wherein the inorganic base can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, carbonic acid Sodium hydrogen, cesium fluoride, or cesium carbonate; pH to basic can be selected from pH values of 8-14, 8-11, 9-11, or 10-11;
(3)在酸性条件下，式(VII)和式(VII-1)混合物中式(VII-1)化合物发生重排反应转换为式(VII)化合物，其中反应的溶剂可以是对酸稳定的任何溶剂，在某些实施方案中选自丙酮或者乙腈。其中酸性条件可以选自pH值为1-4、1-3或者1-2，在某些实施方案中选自pH值1-2。所述的酸性条件可以是采用常用无机酸调节的，比如盐酸、硫酸或者磷酸。(3) Under acidic conditions, a compound of formula (VII-1) in a mixture of formula (VII) and formula (VII-1) undergoes a rearrangement reaction to convert to a compound of formula (VII), wherein the solvent of the reaction may be any acid stable The solvent is selected in some embodiments from acetone or acetonitrile. Wherein the acidic condition may be selected from a pH value of 1-4, 1-3 or 1-2, and in some embodiments a pH value of 1-2. The acidic conditions may be adjusted using common inorganic acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
在某些实施方案中，式(VIII)化合物:吡啶类的碱:三氟甲烷磺酸酐的摩尔比为1:(1.1-2.0):(1.1-2.0)，1:(1.1-1.5):(1.1-1.5)或者1:1.5:1.5。In certain embodiments, the molar ratio of the compound of formula (VIII): pyridine base: trifluoromethanesulfonic anhydride is 1: (1.1-2.0): (1.1-2.0), 1: (1.1-1.5): ( 1.1-1.5) or 1: 1.5: 1.5.
在某些具体实施方案，其中，式(VIII)化合物和吡啶类的碱、三氟甲烷磺酸酐是在室温至回流下进行反应。在某些实施方案中，在回流下进行反应。In certain embodiments, the compound of formula (VIII) is reacted with a base of pyridine and trifluoromethanesulfonic anhydride at room temperature to reflux. In certain embodiments, the reaction is performed under reflux.
根据本发明一些具体实施方案，式(VIII)所示的化合物的制备方法还包括以式(IX)化合物为原料与二级胺NH(R 3)(R 4)反应制备式(VIII)化合物的步骤， According to some specific embodiments of the present invention, the method for preparing a compound represented by formula (VIII) further comprises reacting a compound of formula (IX) as a raw material with a secondary amine NH (R 3 ) (R 4 ) to prepare a compound of formula (VIII) step,
Figure PCTCN2019096522-appb-000019
Figure PCTCN2019096522-appb-000019
R 3、R 4定义同上。 R 3 and R 4 are as defined above.
根据本发明一些具体实施方案，其中，式(IX)化合物与二级胺NH(R 3)(R 4)是在缩合剂存在下反应制备式(VIII)化合物。 According to some embodiments of the present invention, wherein the compound of formula (IX) is reacted with a secondary amine NH (R 3 ) (R 4 ) in the presence of a condensing agent to prepare a compound of formula (VIII).
其中二级胺的R 3和R 4定义如本发明前面所述。在一些具体实施方案中，R 3和R 4与所连接的氮原子形成四氢吡咯环。 Wherein R 3 and R 4 of the secondary amine are defined as previously described in the present invention. In some embodiments, R 3 and R 4 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
根据本发明一些具体实施方案，其中，所述缩合剂选自草酰氯、二氯亚砜、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑或者N,N'-羰基二咪唑。According to some specific embodiments of the present invention, the condensing agent is selected from the group consisting of oxalyl chloride, dichlorosulfoxide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1- Hydroxybenzotriazole or N, N'-carbonyldiimidazole.
在某些实施方案中，式(IX)化合物与二级胺摩尔比不大于1，在某些实施方案中，摩尔比为1:1～5，在某些实施方案中，摩尔比为1:1～2，在某些实施方案中，摩尔比为1:1.1。In some embodiments, the molar ratio of the compound of formula (IX) to the secondary amine is not greater than 1, in some embodiments, the molar ratio is 1: 1 to 5, and in some embodiments, the molar ratio is 1: 1 to 2, in some embodiments, the molar ratio is 1: 1.1.
在某些实施方案中，式(IX)化合物与二级胺NH(R 3)(R 4)反应制备式(VIII)化合物的反应温度为室温，在某些实施方案中，反应温度为20～30℃。 In some embodiments, the reaction temperature of the compound of formula (IX) with the secondary amine NH (R 3 ) (R 4 ) to produce the compound of formula (VIII) is room temperature. In some embodiments, the reaction temperature is 20- 30 ° C.
根据本发明一些具体实施方案，其中，所述方法还包括以式(X)化合物为原料制备式(IX)化合物的步骤，According to some specific embodiments of the present invention, wherein the method further comprises the step of preparing a compound of formula (IX) by using a compound of formula (X) as a raw material,
Figure PCTCN2019096522-appb-000020
Figure PCTCN2019096522-appb-000020
根据本发明一些具体实施方案，其中，是以式(X)化合物和丙二酸环(亚)异丙酯为原料制备式(IX)化合物。According to some embodiments of the present invention, the compound of formula (IX) is prepared by using a compound of formula (X) and a cyclic (iso) isopropyl malonate as raw materials.
根据本发明一些具体实施方案，其中，是在三乙胺甲酸盐催化下，式(X)化合物与丙二酸环(亚)异丙酯反应生成式(IX)化合物。According to some specific embodiments of the present invention, a compound of formula (X) is reacted with a cyclic (iso) isopropyl malonate to form a compound of formula (IX) under the catalysis of triethylamine formate.
根据本发明一些具体实施方案，其中，所述方法包括三乙胺甲酸盐催化下，式(X)化合物与丙二酸环(亚)异丙酯反应，并被还原脱羧生成式(IX)化合物。According to some specific embodiments of the present invention, wherein the method comprises the reaction of a compound of formula (X) with a cyclic (iso) malonate of malonate under the catalysis of triethylamine formate and reduction and decarboxylation to form formula (IX) Compound.
根据本发明一些具体实施方案，其中，所述三乙胺甲酸盐可以由甲酸和三乙胺制备得 到。According to some embodiments of the present invention, the triethylamine formate can be prepared from formic acid and triethylamine.
根据本发明一些具体实施方案，其中，式(X)化合物和丙二酸环(亚)异丙酯是以无水甲酸为反应介质进行反应。According to some embodiments of the present invention, wherein the compound of formula (X) and the cyclic (iso) isopropyl malonate are reacted with anhydrous formic acid as a reaction medium.
在某些实施方案中，式(X)化合物与丙二酸环(亚)异丙酯摩尔比为不大于1，在某些实施方案中，摩尔比为1:1～5，在某些实施方案中，摩尔比为1:1～2，在某些实施方案中，摩尔比为1:1。In certain embodiments, the molar ratio of the compound of formula (X) to the cyclic (sub) isopropyl malonate is not greater than 1, in some embodiments, the molar ratio is 1: 1 to 5, in some embodiments In the scheme, the molar ratio is 1: 1 to 2, and in some embodiments, the molar ratio is 1: 1.
根据本发明一些具体实施方案，式(X)化合物和丙二酸环(亚)异丙酯的反应温度为100～180℃，在某些实施方案中，反应温度为140～160℃，在某些实施方案中，反应温度为140～150℃。According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (X) and the cyclic (iso) isopropylmalonate is 100-180 ° C. In some embodiments, the reaction temperature is 140-160 ° C. In some embodiments, the reaction temperature is from 140 to 150 ° C.
根据本发明一些具体实施方案，式(X)化合物和丙二酸环(亚)异丙酯的反应后，还原脱羧反应是在酸性条件下进行的，其中酸性条件为pH值为1-5，在某些实施方案中为1-4，在某些实施方案中为1-3，在某些实施方案中为1-2。其中酸条件通过常用无机酸提供，例如盐酸、硫酸或者磷酸。According to some specific embodiments of the present invention, after the reaction of the compound of formula (X) and cyclic (iso) malonyl malonate, the reduction decarboxylation reaction is performed under acidic conditions, where the acidic conditions are pH 1-5, In some embodiments it is 1-4, in some embodiments it is 1-3, and in some embodiments it is 1-2. The acid conditions are provided by common inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid.
本发明还提供了一种式(VII)所示的化合物的制备方法，其中，所述的方法包括以下步骤：The present invention also provides a method for preparing a compound represented by formula (VII), wherein the method includes the following steps:
Figure PCTCN2019096522-appb-000021
Figure PCTCN2019096522-appb-000021
(1)式(X)化合物与丙二酸环(亚)异丙酯反应生成式(IX)化合物；(1) reacting a compound of formula (X) with a cyclic (iso) isopropyl malonate to form a compound of formula (IX);
(2)式(IX)化合物与二级胺NH(R 3)(R 4)反应生成式(VIII)化合物； (2) reacting a compound of formula (IX) with a secondary amine NH (R 3 ) (R 4 ) to form a compound of formula (VIII);
(3)式(VIII)化合物反应生成式(VII)化合物；(3) reacting a compound of formula (VIII) to produce a compound of formula (VII);
R 3和R 4各自分别独立的选自C 1-6的烷基； R 3 and R 4 are each independently selected from C 1-6 alkyl groups;
可选的，R 3和R 4和与其连接的碳原子共同形成环。 Optionally, R 3 and R 4 and the carbon atom to which they are attached together form a ring.
根据本发明一些具体实施方案，其中，R 3和R 4与所连接的氮原子形成四氢吡咯环。 According to some embodiments of the invention, wherein R 3 and R 4 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
根据本发明一些具体实施方案，其中，所述方法包含如下步骤：According to some specific embodiments of the present invention, the method includes the following steps:
(1)三乙胺甲酸盐催化下，式(X)化合物与丙二酸环(亚)异丙酯反应，生成式(IX)化合物；(1) under the catalysis of triethylamine formate, a compound of formula (X) reacts with a cyclic (sub) isopropyl malonate to form a compound of formula (IX);
(2)式(IX)化合物与二级胺NH(R 3)(R 4)反应生成式(VIII)化合物； (2) reacting a compound of formula (IX) with a secondary amine NH (R 3 ) (R 4 ) to form a compound of formula (VIII);
(3)二氯甲烷或者1,2-二氯乙烷作溶剂，吡啶类的碱存在下，式(VIII)与三氟甲烷磺酸酐反应后，无机碱调节反应液pH至碱性，再在酸性条件下制备得式(VII)化合物。(3) Dichloromethane or 1,2-dichloroethane as a solvent, in the presence of a pyridine base, after the reaction of formula (VIII) with trifluoromethanesulfonic anhydride, the inorganic base adjusts the pH of the reaction solution to alkaline, and then A compound of formula (VII) is prepared under acidic conditions.
根据本发明一些具体实施方案，其中，所述方法包含如下步骤：According to some specific embodiments of the present invention, the method includes the following steps:
(1)三乙胺甲酸盐催化下，式(X)化合物与丙二酸环(亚)异丙酯反应，并被还原脱羧生成式(IX)化合物；(1) under the catalysis of triethylamine formate, a compound of formula (X) reacts with a cyclic (iso) isopropyl malonate and is reduced and decarboxylated to form a compound of formula (IX);
(2)式(IX)化合物与二级胺NH(R 3)(R 4)发生缩合反应生成式(VIII)化合物； (2) a compound of formula (IX) and a secondary amine NH (R 3 ) (R 4 ) undergo a condensation reaction to form a compound of formula (VIII);
(3)二氯甲烷或者1,2-二氯乙烷作溶剂，吡啶类的碱存在下，式(VIII)与三氟甲烷磺酸酐反应后，无机碱调节反应液pH至碱性，再在酸性条件下制备得式(VII)化合物。(3) Dichloromethane or 1,2-dichloroethane as a solvent, in the presence of a pyridine base, after the reaction of formula (VIII) with trifluoromethanesulfonic anhydride, the inorganic base adjusts the pH of the reaction solution to alkaline, and then A compound of formula (VII) is prepared under acidic conditions.
根据本发明一些具体实施方案，其中，步骤(2)是在缩合剂存在下发生缩合反应。According to some specific embodiments of the present invention, wherein step (2) is a condensation reaction in the presence of a condensing agent.
根据本发明一些具体实施方案，其中，步骤(2)所述缩合剂选自草酰氯、二氯亚砜、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑或者N,N'-羰基二咪唑。According to some specific embodiments of the present invention, wherein the condensing agent in step (2) is selected from oxalyl chloride, dichlorosulfoxide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Salt, 1-hydroxybenzotriazole or N, N'-carbonyldiimidazole.
其中二级胺的R 3和R 4定义如本发明前面所述。 Wherein R 3 and R 4 of the secondary amine are defined as previously described in the present invention.
在一些具体实施方案中，R 3和R 4与所连接的氮原子形成四氢吡咯环。 In some embodiments, R 3 and R 4 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
在一些实施方案中，制备式(VII)化合物的方法包含如下步骤：In some embodiments, a method of preparing a compound of formula (VII) comprises the following steps:
(1)、三乙胺甲酸盐催化下，式(X)化合物与丙二酸环(亚)异丙酯反应，并被还原脱羧生成式(IX)化合物；(1) Under the catalysis of triethylamine formate, a compound of formula (X) reacts with a cyclic (iso) isopropyl malonate and is decarboxylated by reduction to form a compound of formula (IX);
(2)、式(IX)化合物与四氢吡咯发生缩合反应生成式(VIII)化合物；(2) a condensation reaction between a compound of formula (IX) and tetrahydropyrrole to generate a compound of formula (VIII);
(3)、二氯甲烷或者1,2-二氯乙烷作溶剂，2,4,6-三甲基吡啶和三氟甲烷磺酸酐存在下，式(VIII)发生加成反应，然后用无机碱调节反应液的pH至碱性发生水解反应，再在酸性条件下发生重排反应得式(VII)化合物。(3), methylene chloride or 1,2-dichloroethane as a solvent, in the presence of 2,4,6-trimethylpyridine and trifluoromethanesulfonic anhydride, an addition reaction of formula (VIII) occurs, and then an inorganic Alkali adjusts the pH of the reaction solution to alkaline to cause a hydrolysis reaction, and a rearrangement reaction under acidic conditions to obtain a compound of formula (VII).
本发明还提供了一种纯化式(VII)所示的化合物的方法：The present invention also provides a method for purifying the compound represented by formula (VII):
Figure PCTCN2019096522-appb-000022
Figure PCTCN2019096522-appb-000022
所述方法包括将式(VII)化合物与亚硫酸氢钠常温下加成成盐，用有机溶剂萃取杂质，然后常温下加酸或者碱反应结束后经后处理即得。The method comprises adding a compound of the formula (VII) and sodium bisulfite to form a salt at normal temperature, extracting impurities with an organic solvent, and then adding the acid or base at normal temperature to obtain an after-treatment.
在一些实施方案中，所述方法包括将式(VII)化合物与亚硫酸氢钠加成成盐，用有机溶剂萃取杂质，然后常温下加酸或者碱反应结束后经后处理得到高纯度的式(VII)化合物:In some embodiments, the method comprises adding a compound of formula (VII) to sodium bisulfite to form a salt, extracting impurities with an organic solvent, and then adding an acid or a base at room temperature to complete the reaction to obtain a high-purity formula. (VII) Compound:
Figure PCTCN2019096522-appb-000023
Figure PCTCN2019096522-appb-000023
根据本发明的一些具体实施方案，上述后处理包括萃取、过滤、浓缩、干燥等中的一个或多个操作。According to some specific embodiments of the present invention, the above-mentioned post-treatment includes one or more operations of extraction, filtration, concentration, drying, and the like.
根据本发明一些具体实施方案，其中，上述有机溶剂可以选自乙酸乙酯、二氯甲烷或者甲基叔丁基醚。According to some specific embodiments of the present invention, the organic solvent may be selected from ethyl acetate, dichloromethane, or methyl tert-butyl ether.
根据本发明一些具体实施方案，其中，上述酸选自无机酸，比如盐酸、硫酸或者磷酸。According to some specific embodiments of the present invention, the acid is selected from inorganic acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
根据本发明一些具体实施方案，其中，上述酸选自盐酸或硫酸。According to some embodiments of the present invention, the acid is selected from hydrochloric acid or sulfuric acid.
根据本发明一些具体实施方案，其中，上述碱选自无机碱，比如氢氧化钠。According to some embodiments of the present invention, the base is selected from inorganic bases, such as sodium hydroxide.
根据本发明一些具体实施方案，其中，式(VI)化合物与亚硫酸氢钠加成成盐在室温条件下进行。According to some embodiments of the present invention, wherein the addition of the compound of formula (VI) with sodium bisulfite is performed at room temperature.
本发明还提供了一种式(I)所示的化合物的制备方法，其中，所述的方法包括以下步骤：The present invention also provides a method for preparing a compound represented by formula (I), wherein the method includes the following steps:
(1)化合物(VII)发生Horner–Wadsworth–Emmons反应或者Wittig反应生成式(VI)化合物；(1) Compound (VII) undergoes a Horner-Wadsworth-Emmons reaction or Wittig reaction to generate a compound of formula (VI);
(2)式(VI)化合物与硝基甲烷发生反应生成式(V)化合物；(2) a compound of formula (VI) reacts with nitromethane to form a compound of formula (V);
(3)式(V)化合物发生还原反应后，与手性酸反应得到式(III)化合物；(3) after the compound of formula (V) undergoes a reduction reaction, it is reacted with a chiral acid to obtain a compound of formula (III);
(4)式(III)化合物反应生成式(I)化合物。(4) A compound of formula (III) is reacted to form a compound of formula (I).
根据本发明一些具体实施方案，式(III)化合物反应先得到式(II)化合物，再由式(II)化合物与酸A反应生成式(I)化合物。According to some embodiments of the present invention, a compound of formula (III) is reacted to obtain a compound of formula (II), and then a compound of formula (II) is reacted with acid A to form a compound of formula (I).
根据本发明的一些具体实施方案，式(IV)化合物先反应得到式(XII)化合物，再由式(XII)化合物反应生成式(I)化合物，According to some specific embodiments of the present invention, a compound of formula (IV) is first reacted to obtain a compound of formula (XII), and then a compound of formula (XII) is reacted to form a compound of formula (I),
Figure PCTCN2019096522-appb-000024
Figure PCTCN2019096522-appb-000024
R 1选自H、羟基保护基或-C(＝O)R 11。 R 1 is selected from H, a hydroxy protecting group, or -C (= O) R 11 .
本发明还提供了一种式(I)所示的化合物的制备方法，其中，所述的方法包括以下步骤：The present invention also provides a method for preparing a compound represented by formula (I), wherein the method includes the following steps:
(1)以化合物(VII)为原料制备得到式(VI)化合物；(1) using compound (VII) as a raw material to obtain a compound of formula (VI);
(2)式(VI)化合物与硝基甲烷发生反应生成式(V)化合物；(2) a compound of formula (VI) reacts with nitromethane to form a compound of formula (V);
(3)式(V)化合物发生还原反应得到(Ⅳ)，再与手性酸(优选为式(XI)化合物)反应得到式(III)化合物；(3) a compound of formula (V) undergoes a reduction reaction to obtain (IV), and then reacts with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (III);
(4)式(III)化合物通过反应得到式(II)化合物，再与酸A反应得到式(I)化合物；(4) A compound of formula (III) is reacted to obtain a compound of formula (II), and then reacted with acid A to obtain a compound of formula (I);
Figure PCTCN2019096522-appb-000025
Figure PCTCN2019096522-appb-000025
A选自苯磺酸、对甲苯磺酸或甲磺酸；A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
R 2选自羧基保护基或C 1-6的烷基；优选R 2选自叔丁基； R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
R 11选自C 1-6的烷基；优选R 11选自甲基。 R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl.
根据本发明的一些具体实施方案，所述的方法包括以下步骤：According to some specific embodiments of the present invention, the method includes the following steps:
(1)化合物(VII)发生Horner–Wadsworth–Emmons反应或者Wittig反应生成式(VI)化合物；(1) Compound (VII) undergoes a Horner-Wadsworth-Emmons reaction or Wittig reaction to generate a compound of formula (VI);
(2)式(VI)化合物与硝基甲烷发生反应生成式(V)化合物；(2) a compound of formula (VI) reacts with nitromethane to form a compound of formula (V);
(3)式(V)化合物发生还原反应后，与手性酸反应得到式(III)化合物；(3) after the compound of formula (V) undergoes a reduction reaction, it is reacted with a chiral acid to obtain a compound of formula (III);
(4)式(III)化合物反应生成式(I)化合物；(4) reacting a compound of formula (III) to produce a compound of formula (I);
根据本发明的一些具体实施方案，式(III)化合物反应先得到式(II)化合物，再由式(II)化合物与酸A反应生成式(I)化合物。According to some specific embodiments of the present invention, a compound of formula (III) is reacted to obtain a compound of formula (II), and then a compound of formula (II) is reacted with acid A to form a compound of formula (I).
根据本发明的一些具体实施方案，式(V)化合物发生还原反应后，经水解后，再与手性酸(优选式(XI)化合物)反应得到式(XII)化合物，式(XII)化合物经水解，再与酸A反应生成式(I)化合物；According to some specific embodiments of the present invention, the compound of formula (V) undergoes a reduction reaction, is hydrolyzed, and then reacts with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (XII). Hydrolyzed and reacted with acid A to form a compound of formula (I);
根据本发明的一些具体实施方案，式(V)化合物发生还原反应后，先反应得到式(XII)化合物，再由式(XII)化合物反应生成式(I)化合物；According to some specific embodiments of the present invention, after the compound of formula (V) undergoes a reduction reaction, the compound of formula (XII) is first reacted, and then the compound of formula (XII) is reacted to generate the compound of formula (I);
Figure PCTCN2019096522-appb-000026
Figure PCTCN2019096522-appb-000026
A选自苯磺酸、对甲苯磺酸或甲磺酸；A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
R 2选自羧基保护基或C 1-6的烷基；优选R 2选自叔丁基； R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
R 11选自C 1-6的烷基；优选R 11选自甲基。 R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl.
根据本发明的一些具体实施方案，According to some specific embodiments of the present invention,
Figure PCTCN2019096522-appb-000027
Figure PCTCN2019096522-appb-000027
R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
R 2选自羧基保护基或C 1-6的烷基；优选R 2选自叔丁基； R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
R 11选自C 1-6的烷基；优选R 11选自甲基； R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl;
A选自苯磺酸、对甲苯磺酸或甲磺酸。A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid.
根据本发明一些具体实施方案，其中，所述的方法包括以下步骤：According to some specific embodiments of the present invention, the method includes the following steps:
(1)碱存在下，化合物(VII)与二甲氧基膦酰基乙酸叔丁酯在10℃～40℃反应生成化合物(VI)；(1) Compound (VII) reacts with tert-butyl dimethoxyphosphonoacetate in the presence of a base at 10 ° C to 40 ° C to form compound (VI);
(2)碱存在下，化合物(VI)与硝基甲烷在80℃～100℃发生反应生成化合物(V)；(2) In the presence of a base, the compound (VI) reacts with nitromethane at 80 ° C to 100 ° C to form the compound (V);
(3)甲醇溶剂中，氯化镍六水合物作催化剂，硼氢化钠作还原剂，化合物(V)发生还原反应后，与手性酸在0-40℃下反应得到式(III)化合物；(3) In a methanol solvent, nickel chloride hexahydrate is used as a catalyst, and sodium borohydride is used as a reducing agent. After the reduction reaction of the compound (V), it is reacted with a chiral acid at 0-40 ° C to obtain a compound of formula (III);
(4)式(III)化合物水解得到式(II)化合物；(4) hydrolysis of a compound of formula (III) to obtain a compound of formula (II);
(5)式(II)化合物与A反应得到式(I)化合物。(5) A compound of formula (II) is reacted with A to obtain a compound of formula (I).
根据本发明一些具体实施方案，其中，所述的方法包括以下步骤：According to some specific embodiments of the present invention, the method includes the following steps:
(1)10℃～40℃和碱存在下，化合物(VII)与二甲氧基膦酰基乙酸叔丁酯反应生成化合物(VI)；(1) Compound (VII) is reacted with tert-butyl dimethoxyphosphonoacetate in the presence of a base at 10 ° C to 40 ° C to form compound (VI);
(2)80℃～100℃，碱存在下，化合物(VI)与硝基甲烷发生反应生成化合物(V)；(2) Compound (VI) reacts with nitromethane to form compound (V) in the presence of a base at 80 ° C to 100 ° C;
(3)0-40℃，甲醇溶剂中，氯化镍六水合物作催化剂，硼氢化钠作还原剂，化合物(V)发生还原反应后，与手性酸反应得到式(III)化合物；(3) In a methanol solvent at 0-40 ° C, nickel chloride hexahydrate is used as a catalyst, and sodium borohydride is used as a reducing agent. After the reduction reaction of the compound (V), it is reacted with a chiral acid to obtain a compound of the formula (III);
(4)式(III)化合物水解得到式(II)化合物；(4) hydrolysis of a compound of formula (III) to obtain a compound of formula (II);
(5)式(II)化合物与苯磺酸反应得到式(I)化合物。(5) A compound of formula (II) is reacted with benzenesulfonic acid to obtain a compound of formula (I).
根据本发明一些具体实施方案，其中，步骤(1)的碱选自叔丁醇钾或1,8-二氮杂二环十一碳-7-烯。According to some embodiments of the present invention, wherein the base of step (1) is selected from potassium tert-butoxide or 1,8-diazabicycloundec-7-ene.
根据本发明一些具体实施方案，其中，步骤(2)的碱选自碳酸铯、叔丁醇钾或1,8-二氮杂二环十一碳-7-烯。According to some specific embodiments of the present invention, the base of step (2) is selected from cesium carbonate, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene.
根据本发明一些具体实施方案，其中，步骤(3)的手性酸选自式(XI)化合物；According to some specific embodiments of the present invention, wherein the chiral acid of step (3) is selected from the compound of formula (XI);
Figure PCTCN2019096522-appb-000028
Figure PCTCN2019096522-appb-000028
R 1定义同上。 R 1 has the same definition as above.
根据本发明一些具体实施方案，其中，步骤(3)的手性酸选自(S)-(+)-O-乙酰基-L-扁桃酸或L-扁桃酸。According to some specific embodiments of the present invention, wherein the chiral acid of step (3) is selected from (S)-(+)-O-acetyl-L-mandelic acid or L-mandelic acid.
本发明还提供了一种式(I)所示的化合物的制备方法，包括如下步骤：The invention also provides a method for preparing a compound represented by formula (I), comprising the following steps:
Figure PCTCN2019096522-appb-000029
Figure PCTCN2019096522-appb-000029
(1)式(X)化合物与丙二酸环(亚)异丙酯反应生成式(IX)化合物；(1) reacting a compound of formula (X) with a cyclic (iso) isopropyl malonate to form a compound of formula (IX);
(2)式(IX)化合物与二级胺NH(R 3)(R 4)发生反应生成式(VIII)化合物； (2) a compound of formula (IX) reacts with a secondary amine NH (R 3 ) (R 4 ) to form a compound of formula (VIII);
(3)式(VIII)化合物发生反应生成式(VII)化合物；(3) a compound of formula (VIII) reacts to form a compound of formula (VII);
(4)以化合物(VII)为原料制备得到式(VI)化合物；(4) using compound (VII) as a raw material to prepare a compound of formula (VI);
(5)式(VI)化合物与硝基甲烷发生反应生成式(V)化合物；(5) a compound of formula (VI) reacts with nitromethane to form a compound of formula (V);
(6)式(V)化合物发生还原反应后，与手性酸(优选为式(XI)化合物)反应得到式(III)化合物；(6) a reduction reaction of the compound of formula (V), followed by reaction with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (III);
(7)式(III)化合物通过反应得到式(II)化合物，再与酸A反应生成式(I)化合物；(7) A compound of formula (III) is obtained by a reaction to obtain a compound of formula (II), and then reacted with acid A to form a compound of formula (I);
或者式(V)化合物发生还原反应后，经水解后，再与手性酸(优选式(XI)化合物)反 应得到式(XII)化合物，式(XII)化合物经水解，再与酸A反应生成式(I)化合物；Or after the reduction reaction of the compound of formula (V), after hydrolysis, it is then reacted with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (XII). A compound of formula (I);
Figure PCTCN2019096522-appb-000030
Figure PCTCN2019096522-appb-000030
A选自苯磺酸、对甲苯磺酸或甲磺酸；A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
R 2选自羧基保护基或C 1-6的烷基；优选R 2选自叔丁基； R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
R 11选自C 1-6的烷基；优选R 11选自甲基； R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl;
R 3和R 4各自分别独立的选自C 1-6的烷基； R 3 and R 4 are each independently selected from C 1-6 alkyl groups;
可选的，R 3和R 4和与其连接的碳原子共同形成环(优选R 3和R 4与所连接的氮原子形成吡啶环或四氢吡咯环)。 Optionally, R 3 and R 4 and the carbon atom to which they are attached together form a ring (preferably, R 3 and R 4 form a pyridine ring or a tetrahydropyrrole ring with the nitrogen atom to which they are attached).
本发明还提供了一种式(I)所示的化合物的制备方法，包括如下步骤：The invention also provides a method for preparing a compound represented by formula (I), comprising the following steps:
(1)式(X)化合物与丙二酸环(亚)异丙酯反应生成式(IX)化合物；(1) reacting a compound of formula (X) with a cyclic (iso) isopropyl malonate to form a compound of formula (IX);
(2)式(IX)化合物与二级胺NH(R 3)(R 4)发生缩合反应生成式(VIII)化合物； (2) a compound of formula (IX) and a secondary amine NH (R 3 ) (R 4 ) undergo a condensation reaction to form a compound of formula (VIII);
(3)式(VIII)化合物发生关环反应生成式(VII)化合物；(3) a compound of formula (VIII) undergoes a ring-closure reaction to produce a compound of formula (VII);
(4)化合物(VII)发生Horner–Wadsworth–Emmons反应或者Wittig反应生成式(VI)化合物；(4) Compound (VII) undergoes a Horner-Wadsworth-Emmons reaction or Wittig reaction to generate a compound of formula (VI);
(5)式(VI)化合物与硝基甲烷发生反应生成式(V)化合物；(5) a compound of formula (VI) reacts with nitromethane to form a compound of formula (V);
(6)式(V)化合物发生还原反应后，与手性酸反应得到式(III)化合物；(6) a compound of formula (V) is reduced to react with a chiral acid to obtain a compound of formula (III);
(7)式(III)化合物反应生成式(I)化合物。(7) A compound of formula (III) is reacted to form a compound of formula (I).
根据本发明一些具体实施方案，式(III)化合物反应先得到式(II)化合物，再由式(II)化合物与酸A反应生成式(I)化合物。According to some embodiments of the present invention, a compound of formula (III) is reacted to obtain a compound of formula (II), and then a compound of formula (II) is reacted with acid A to form a compound of formula (I).
根据本发明的一些具体实施方案，式(IV)化合物先反应得到式(XII)化合物，再由式(XII)化合物反应生成式(I)化合物；According to some specific embodiments of the present invention, the compound of formula (IV) is first reacted to obtain a compound of formula (XII), and then the compound of formula (XII) is reacted to form a compound of formula (I);
Figure PCTCN2019096522-appb-000031
Figure PCTCN2019096522-appb-000031
A、R 1、R 2、R 3、R 4等相关定义同上。 A, R 1 , R 2 , R 3 , R 4 and other related definitions are the same as above.
本发明还提供了一种式(I)所示的化合物的制备方法，包括如下步骤：The invention also provides a method for preparing a compound represented by formula (I), comprising the following steps:
(1)式(X)化合物与丙二酸环(亚)异丙酯反应生成式(IX)化合物；(1) reacting a compound of formula (X) with a cyclic (iso) isopropyl malonate to form a compound of formula (IX);
(2)式(IX)化合物与二级胺NH(R 3)(R 4)发生缩合反应生成式(VIII)化合物； (2) a compound of formula (IX) and a secondary amine NH (R 3 ) (R 4 ) undergo a condensation reaction to form a compound of formula (VIII);
(3)式(VIII)化合物发生关环反应生成式(VII)化合物；(3) a compound of formula (VIII) undergoes a ring-closure reaction to produce a compound of formula (VII);
(4)化合物(VII)发生Horner–Wadsworth–Emmons反应或者Wittig反应生成式(VI)化合物；(4) Compound (VII) undergoes a Horner-Wadsworth-Emmons reaction or Wittig reaction to generate a compound of formula (VI);
(5)式(VI)化合物与硝基甲烷发生反应生成式(V)化合物；(5) a compound of formula (VI) reacts with nitromethane to form a compound of formula (V);
(6)式(V)化合物发生还原反应后，与手性酸反应得到式(III)化合物；(6) a compound of formula (V) is reduced to react with a chiral acid to obtain a compound of formula (III);
(7)式(III)化合物水解得到式(II)化合物；(7) a compound of formula (III) is hydrolyzed to obtain a compound of formula (II);
(8)式(II)化合物与酸A反应生成式(I)化合物。(8) A compound of formula (II) is reacted with acid A to form a compound of formula (I).
Figure PCTCN2019096522-appb-000032
Figure PCTCN2019096522-appb-000032
A、R 1、R 2、R 3、R 4等相关定义同上。 A, R 1 , R 2 , R 3 , R 4 and other related definitions are the same as above.
本发明还提供了一种式(I)所示的化合物的制备方法，包括如下步骤：The invention also provides a method for preparing a compound represented by formula (I), comprising the following steps:
(1)式(X)化合物与丙二酸环(亚)异丙酯反应生成式(IX)化合物；(1) reacting a compound of formula (X) with a cyclic (iso) isopropyl malonate to form a compound of formula (IX);
(2)式(IX)化合物与二级胺NH(R 3)(R 4)发生缩合反应生成式(VIII)化合物； (2) a compound of formula (IX) and a secondary amine NH (R 3 ) (R 4 ) undergo a condensation reaction to form a compound of formula (VIII);
(3)式(VIII)化合物发生关环反应生成式(VII)化合物；(3) a compound of formula (VIII) undergoes a ring-closure reaction to produce a compound of formula (VII);
(4)化合物(VII)发生HWE反应或者Wittig反应生成式(VI)化合物；(4) Compound (VII) undergoes HWE reaction or Wittig reaction to generate compound of formula (VI);
(5)式(VI)化合物与硝基甲烷发生反应生成式(V)化合物；(5) a compound of formula (VI) reacts with nitromethane to form a compound of formula (V);
(6)式(V)化合物发生还原反应后，水解得到化合物2B；(6) After the compound of formula (V) undergoes a reduction reaction, it is hydrolyzed to obtain compound 2B;
(7)化合物2B与手性酸反应得到式(XII)化合物；(7) Compound 2B is reacted with a chiral acid to obtain a compound of formula (XII);
(8)式(XII)化合物反应生成式(I)化合物。(8) A compound of formula (XII) is reacted to form a compound of formula (I).
Figure PCTCN2019096522-appb-000033
Figure PCTCN2019096522-appb-000033
另一方面，本发明还提供了式(III)所示的化合物，In another aspect, the present invention also provides a compound represented by formula (III),
Figure PCTCN2019096522-appb-000034
Figure PCTCN2019096522-appb-000034
A选自苯磺酸、对甲苯磺酸或甲磺酸；A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
R 1选自H、羟基保护基或-C(＝O)R 11；R 11选自C 1-6的烷基； R 1 is selected from H, hydroxy protecting group or -C (= O) R 11 ; R 11 is selected from C 1-6 alkyl;
R 2选自羧基保护剂或C 1-6的烷基； R 2 is selected from a carboxy protecting agent or a C 1-6 alkyl group;
R 3和R 4各自分别独立的选自C 1-6的烷基； R 3 and R 4 are each independently selected from C 1-6 alkyl groups;
可选的，R 3和R 4和与其连接的碳原子共同形成环(优选R 3和R 4与所连接的氮原子形成吡啶环或四氢吡咯环)。 Optionally, R 3 and R 4 and the carbon atom to which they are attached together form a ring (preferably, R 3 and R 4 form a pyridine ring or a tetrahydropyrrole ring with the nitrogen atom to which they are attached).
式(III)所示的化合物可以用作制备式(I)所示的化合物的中间体。The compound represented by the formula (III) can be used as an intermediate for preparing the compound represented by the formula (I).
根据本发明一些具体实施方案，其中，R 11选自甲基、乙基、丙基或叔丁基。 According to some embodiments of the present invention, R 11 is selected from methyl, ethyl, propyl or tert-butyl.
根据本发明一些具体实施方案，其中，R 2选自甲基、乙基、丙基、或叔丁基。 According to some embodiments of the present invention, R 2 is selected from methyl, ethyl, propyl, or tert-butyl.
本发明还提供了式(Ⅱ)所示的化合物，The present invention also provides a compound represented by formula (II),
Figure PCTCN2019096522-appb-000035
Figure PCTCN2019096522-appb-000035
R 2选自羧基保护基或C 1-6的烷基；优选R 2选自叔丁基。 R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl.
本发明还提供了式(Ⅱ)所示的化合物的制备方法，所述方法包括以式(IV)化合物为原料，与手性酸反应制备式(Ⅲ)化合物后水解得到式(Ⅱ)化合物，The invention also provides a method for preparing a compound represented by formula (II), which method comprises using a compound of formula (IV) as a raw material, reacting with a chiral acid to prepare a compound of formula (III), and hydrolyzing to obtain a compound of formula (II)
Figure PCTCN2019096522-appb-000036
Figure PCTCN2019096522-appb-000036
根据本发明一些具体实施方案，其中，手性酸为式(XI)所示的化合物，According to some embodiments of the present invention, wherein the chiral acid is a compound represented by formula (XI),
Figure PCTCN2019096522-appb-000037
Figure PCTCN2019096522-appb-000037
根据本发明一些具体实施方案，其中，手性酸为L-扁桃酸。According to some embodiments of the present invention, the chiral acid is L-mandelic acid.
本发明还提供了式(XI)所示的化合物在制备式(II)化合物的对照品中的应用。The invention also provides the application of the compound represented by formula (XI) in the preparation of a reference substance for the compound of formula (II).
本发明还提供了式(VIII)所示的化合物及其制备方法，The present invention also provides a compound represented by formula (VIII) and a preparation method thereof,
Figure PCTCN2019096522-appb-000038
Figure PCTCN2019096522-appb-000038
其中among them
R 3和R 4各自独立的选自C 1-6烷基或者R 3和R 4成环； R 3 and R 4 are each independently selected from C 1-6 alkyl or R 3 and R 4 form a ring;
条件是R 3和R 4不同时为甲基。 Provided that R 3 and R 4 are not both methyl.
根据本发明一些具体实施方案，其中，R 3和R 4与所连接的氮原子形成四氢吡咯环。 According to some embodiments of the invention, wherein R 3 and R 4 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached.
本发明还提供了下述化合物及其制备方法：The invention also provides the following compounds and their preparation methods:
Figure PCTCN2019096522-appb-000039
Figure PCTCN2019096522-appb-000039
Figure PCTCN2019096522-appb-000040
Figure PCTCN2019096522-appb-000040
R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
R 2选自羧基保护基或C 1-6的烷基；优选R 2选自叔丁基； R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
R 11选自C 1-6的烷基；优选R 11选自甲基。 R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl.
本发明还提供了式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VIII)或式(XII)化合物及其异构体或药学上可接受的盐，The invention also provides compounds of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VIII) or formula (XII) and isomers or pharmaceutically acceptable Salt
Figure PCTCN2019096522-appb-000041
Figure PCTCN2019096522-appb-000041
R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
R 2选自羧基保护基或C 1-6的烷基；优选R 2选自叔丁基； R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
R 11选自C 1-6的烷基；优选R 11选自甲基； R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl;
R 3和R 4各自独立的选自C 1-6烷基或者R 3和R 4成环(优选R 3和R 4与所连接的氮原子形成吡啶环或四氢吡咯环)； R 3 and R 4 are each independently selected from C 1-6 alkyl or R 3 and R 4 to form a ring (preferably R 3 and R 4 form a pyridine ring or a tetrahydropyrrole ring with the nitrogen atom to which they are attached);
条件是R 3和R 4不同时为甲基。 Provided that R 3 and R 4 are not both methyl.
本发明还提供了式(Ⅰ)所示的化合物的精制方法，其中，将式(I)化合物在有机溶剂(优选N-甲基吡咯烷酮或二甲亚砜)中加热至溶解，加入乙酸异丙酯和/或水，搅拌析晶，过滤，减压干燥，即得：The present invention also provides a method for purifying a compound represented by formula (I), wherein the compound of formula (I) is heated to dissolve in an organic solvent (preferably N-methylpyrrolidone or dimethyl sulfoxide), and isopropyl acetate is added Esters and / or water, stirred for crystallization, filtered, and dried under reduced pressure to obtain:
Figure PCTCN2019096522-appb-000042
Figure PCTCN2019096522-appb-000042
A选自苯磺酸、对甲苯磺酸或甲磺酸。A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid.
根据本发明的一些具体实施方案，其中，将式(I)化合物粗品在N-甲基吡咯烷酮中加热至80±5℃，待固体完全溶解后，加入活性炭搅拌，趁热过滤，滤液加入乙酸异丙酯，搅拌析晶，过滤，即得。According to some specific embodiments of the present invention, the crude compound of formula (I) is heated to 80 ± 5 ° C. in N-methylpyrrolidone. After the solid is completely dissolved, it is added with activated carbon and stirred, filtered while hot, and the filtrate is added with acetic acid. The propyl ester was crystallized by stirring and filtered.
根据本发明的一些具体实施方案，其中，将式(I)化合物粗品和二甲亚砜加热至50±5℃，待固体完全溶解后，加入纯化水，搅拌析晶。过滤，即得。According to some specific embodiments of the present invention, the crude compound of formula (I) and dimethyl sulfoxide are heated to 50 ± 5 ° C. After the solid is completely dissolved, purified water is added and the crystals are stirred and crystallized. Filter, that's it.
其中可以理解的是，本发明所涉及的制备方法是列举了该方法所经过的反应步骤，而有些在本发明字面上是两步或者两步以上的反应步骤，但在实际中可以在一次反应操作中完成(即投料后无需出料得到中间产物，而继续在反应液中进行下一步反应，如所谓“一锅煮”的方式)而让人误以为是一步反应的，或者是在本发明字面上是一步反应，但可以在实际中将其拆成两步或两步以上反应步骤而让人误以为是多步反应的，均在本发明保护范围之内。It can be understood that the preparation method involved in the present invention enumerates the reaction steps that the method goes through, and some of which are literally two or more reaction steps in the present invention, but in practice, the reaction can be performed in one reaction. It is completed in the operation (that is, the intermediate product does not need to be discharged after feeding, and the next reaction is continued in the reaction solution, such as the so-called "one-pot cooking" method), which makes people mistakenly think that it is a one-step reaction, or it is literally in the present invention It is a one-step reaction, but it can be split into two or more reaction steps in practice to make people think that it is a multi-step reaction, which are all within the protection scope of the present invention.
譬如在本发明实施例中，将式(III)化合物制备式(II)化合物，再以式(II)化合物制备式(I)化合物合并在一步反应操作中，应当理解这两步反应均在本发明实施例中得到了记载。For example, in the embodiment of the present invention, a compound of formula (III) is prepared into a compound of formula (II), and then a compound of formula (II) is used to prepare a compound of formula (I) in one step reaction operation. It should be understood that both steps of the reaction It is described in the invention examples.
同样，在本发明实施例中，将式(Ⅴ)化合物制备式(Ⅳ)化合物，再以式(Ⅳ)化合物制备式(Ⅲ)化合物合并在一步反应操作中，应当理解这两步反应均在本发明实施例中得到了记载。Similarly, in the examples of the present invention, a compound of formula (V) is used to prepare a compound of formula (IV), and then a compound of formula (IV) is used to prepare a compound of formula (III) in one step reaction operation. It should be understood that both steps of the reaction It is described in the examples of the present invention.
本发明化学结构式中(+/-)表示所示结构与所示结构手性完全相反的对映异构体的混合物。(+/-) in the chemical structural formula of the present invention represents a mixture of enantiomers whose structures are shown to be completely opposite to the chirality of the structures shown.
本发明反应过程的监测一般采用TLC、MS、LCMS或者/和核磁共振的方法。The reaction process of the present invention is generally monitored by TLC, MS, LCMS or / and nuclear magnetic resonance methods.
综上所述，本发明提供了一种稠合三环γ-氨基酸衍生物的制备方法及中间体。本发明的制备方法具有如下优点：In summary, the present invention provides a method for preparing a fused tricyclic γ-amino acid derivative and an intermediate thereof. The preparation method of the invention has the following advantages:
本发明式(VII)化合物极性很小，极易溶解于大多数溶剂，且熔点不高，难于重结晶纯化。并且因为常温下为固体，受热容易升华堵塞蒸馏装置，且不耐受高温，常规蒸馏或者减压蒸馏不能纯化。粗品纯度只有50％，经过本发明精制后，纯度可以在98％以上。The compound of formula (VII) of the present invention has very low polarity, is easily soluble in most solvents, has a low melting point, and is difficult to recrystallize and purify. And because it is a solid at normal temperature, it is easy to sublimate and block the distillation device when heated, and it does not tolerate high temperatures, and conventional distillation or vacuum distillation cannot be purified. The purity of the crude product is only 50%, and after purification according to the present invention, the purity can be above 98%.
本发明的制备方法缩短了合成步骤，简化了合成操作，且原料便宜易得，大大缩减了生产成品；其次，整个合成工艺都用结晶纯化，没有用到硅胶柱层析或其他制备色谱方法，适宜大规模工业化生产。The preparation method of the invention shortens the synthesis steps, simplifies the synthesis operation, and the raw materials are cheap and easily available, which greatly reduces the production of finished products. Secondly, the entire synthesis process is purified by crystallization, and no silica gel column chromatography or other preparative chromatography methods are used. Suitable for large-scale industrial production.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1是化合物1的X射线单晶衍射图。FIG. 1 is an X-ray single crystal diffraction pattern of Compound 1. FIG.
图2是化合物1的单晶中分子球棍模型。FIG. 2 is a single-molecule mid-ball club model of Compound 1. FIG.
图3是化合物1的绝对构型。FIG. 3 is an absolute configuration of Compound 1. FIG.
具体实施方式detailed description
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The technical solutions of the present invention are described in detail below with reference to the drawings and embodiments, but the protection scope of the present invention includes but is not limited to this.
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(δ)以10 -6(ppm)的单位给出。NMR的测定是用(BrukerAvance III 400和BrukerAvance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，氘代乙腈(CD 3CN)，内标为四甲基硅烷(TMS)。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). NMR measurements were performed using (BrukerAvance III 400 and BrukerAvance 300) nuclear magnetic analyzers. The measurement solvents were deuterated dimethylsulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). Deuterated acetonitrile (CD 3 CN) with internal standard tetramethylsilane (TMS).
MS的测定用Agilent 6120B(ESI)和Agilent 6120B(APCI)。MS was measured using Agilent 6120B (ESI) and Agilent 6120B (APCI).
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。For HPLC measurement, an Agilent 1260DAD high pressure liquid chromatography (Zorbax SB-C18 100 × 4.6 mm) was used.
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The thin-layer chromatography (TLC) silica gel plate uses a size of 0.15mm to 0.20mm, and the thin-layer chromatography purification product uses a size of 0.4mm. ~ 0.5mm.
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。The known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from Titan Technology, Anagi Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Braunwell Technology And other companies.
本发明硅胶柱层析所示比例为体积比。The ratio shown in the silica gel column chromatography of the present invention is a volume ratio.
实施例1Example 1
2-((1S,2S,3R,6S,8S)-2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸苯磺酸盐(1:1)(化合物1) 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetic acid benzene sulfonate (1: 1) (Compound 1)
2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetic acid compound with benzenesulfonic acid(1:1) 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetic acid compound with benzenesulfonic acid (1: 1)
Figure PCTCN2019096522-appb-000043
Figure PCTCN2019096522-appb-000043
Figure PCTCN2019096522-appb-000044
Figure PCTCN2019096522-appb-000044
第一步：3-(环己基-3-烯-1-基)丙酸(1B)First step: 3- (cyclohexyl-3-en-1-yl) propionic acid (1B)
3-(cyclohex-3-en-1-yl)propanoic acid3- (cyclohex-3-en-1-yl) propanoic
Figure PCTCN2019096522-appb-000045
Figure PCTCN2019096522-appb-000045
将无水甲酸(18.82kg,409.09mol)抽入100升的反应釜中，抽毕。降温至10℃。将三乙胺(16.53kg,163.64mol)滴加到反应液中，加毕,搅拌20分钟，当内温为10℃时，将丙二酸环(亚)异丙酯(7.86kg,54.55mol)加入反应釜，再将3-环己烯-1-甲醛(6.00kg,54.55mol)于内温40℃下滴加到反应液中，加毕,程序升温到140-150℃反应至无气体再放出。用6N盐酸(24.0L)调节反应液pH 1-2之间。水相用二氯甲烷(12L×2)萃取产品，合并有机相，并用饱和食盐水(10L×2)洗涤。有机相用无水硫酸钠(2.0kg)干燥1小时，过滤，滤液浓缩蒸干得黄色油状物1B(8.80kg)。Anhydrous formic acid (18.82 kg, 409.09 mol) was pumped into a 100 liter reaction kettle and pumped. Cool down to 10 ° C. Triethylamine (16.53 kg, 163.64 mol) was added dropwise to the reaction solution. After the addition was completed, the mixture was stirred for 20 minutes. When the internal temperature was 10 ° C, cyclic (sub) isopropyl malonate (7.86 kg, 54.55 mol) was added. ) Add to the reaction kettle, and then add 3-cyclohexene-1-formaldehyde (6.00kg, 54.55mol) to the reaction solution dropwise at an internal temperature of 40 ° C. After the addition is completed, the temperature is raised to 140-150 ° C to react without gas. Release it again. The pH of the reaction solution was adjusted between 1-2 with 6N hydrochloric acid (24.0L). The aqueous phase was extracted with dichloromethane (12 L x 2), and the organic phases were combined and washed with saturated brine (10 L x 2). The organic phase was dried over anhydrous sodium sulfate (2.0 kg) for 1 hour, filtered, and the filtrate was concentrated to dryness to give 1B (8.80 kg) as a yellow oil.
1H NMR(400MHz,CDCl 3)δ10.23(s,1H),5.73–5.55(m,2H),2.46–2.30(m,2H),2.09–1.96(m,2H),1.81–1.53(m,6H),1.35–1.17(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 10.23 (s, 1H), 5.73–5.55 (m, 2H), 2.46–2.30 (m, 2H), 2.09–1.96 (m, 2H), 1.81–1.53 (m , 6H), 1.35–1.17 (m, 1H).
LCMS m/z＝153.1[M-1]。LCMS m / z = 153.1 [M-1].
第二步：3-(环己基-3-烯-1-基)-1-(吡咯烷基-1-基)丙基-1-酮(1C)Second step: 3- (cyclohexyl-3-en-1-yl) -1- (pyrrolidin-1-yl) propyl-1-one (1C)
3-(cyclohex-3-en-1-yl)-1-(pyrrolidin-1-yl)propan-1-one3- (cyclohex-3-en-1-yl) -1- (pyrrolidin-1-yl) propan-1-one
Figure PCTCN2019096522-appb-000046
Figure PCTCN2019096522-appb-000046
将1B(11.20kg,72.727mol)用二氯甲烷(60.0L)溶解后，抽入100L反应釜中。加入DMF(3.0mL)并将草酰氯(9.046kg,71.272mol)滴加到反应液中。加毕，室温搅拌2.0小时。将四氢吡咯(5.689kg,79.999mol)和三乙胺(8.814kg,87.272mol)先后滴加入反应釜中。控制内温低于10℃，加毕，于室温下搅拌过夜。将反应液冷却至10℃。滴加3N盐酸(20.0L)调节反应液pH1-2之间。静置，分液，水相用二氯甲烷(10.0L×1)萃取。合并有机相，依次用5％氢氧化钠溶液(10.0L×1)，饱和氯化铵溶液(20.0L×1)洗涤。有机相用无水硫酸钠(2.0kg)干燥30分钟后，过滤，滤液浓缩得到棕色液体1C(15.00kg,收率99.6％)。After 1B (11.20 kg, 72.727 mol) was dissolved in dichloromethane (60.0 L), it was drawn into a 100 L reaction kettle. DMF (3.0 mL) was added and oxalyl chloride (9.046 kg, 71.272 mol) was added dropwise to the reaction solution. After the addition, the mixture was stirred at room temperature for 2.0 hours. Tetrahydropyrrole (5.689 kg, 79.999 mol) and triethylamine (8.814 kg, 87.272 mol) were added dropwise to the reactor. Keep the internal temperature below 10 ° C. After the addition, stir at room temperature overnight. The reaction solution was cooled to 10 ° C. 3N hydrochloric acid (20.0L) was added dropwise to adjust the reaction solution between pH 1-2. It was allowed to stand, separated, and the aqueous phase was extracted with dichloromethane (10.0 L × 1). The organic phases were combined and washed with a 5% sodium hydroxide solution (10.0 L × 1) and a saturated ammonium chloride solution (20.0 L × 1) in this order. The organic phase was dried over anhydrous sodium sulfate (2.0 kg) for 30 minutes, filtered, and the filtrate was concentrated to obtain brown liquid 1C (15.00 kg, yield 99.6%).
1H NMR(400MHz,CDCl 3)δ5.73–5.56(m,2H),3.43(dd,4H),2.37–2.22(m,2H),2.16–2.01(m,4H),1.90(dt,4H),1.81–1.51(m,6H),1.30–1.15(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.73–5.56 (m, 2H), 3.43 (dd, 4H), 2.37–2.22 (m, 2H), 2.16–2.01 (m, 4H), 1.90 (dt, 4H ), 1.81–1.51 (m, 6H), 1.30–1.15 (m, 2H).
LCMS m/z＝208.1[M+1]。LCMS m / z = 208.1 [M + 1].
第三步：三环[4.2.1.0 3,8]壬烷基-2-酮(1R,3S,6R,8R和1S,3R,6S,8S消旋体)(1D) Step 3: Tricyclo [4.2.1.0 3,8 ] nonan-2-one (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemate) (1D)
tricyclo[4.2.1.0 3,8]nonan-2-one(1R,3S,6R,8R and 1S,3R,6S,8S racemate) tricyclo [4.2.1.0 3,8 ] nonan-2-one (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000047
Figure PCTCN2019096522-appb-000047
将1C(5.64kg，27.22mol)用二氯甲烷(40.0L)溶解后，抽入100L的反应釜中。降温至-10℃，加入2，4，6-三甲基吡啶(4.94kg，40.83mol)。将三氟甲烷磺酸酐(11.50kg，40.83mol)的二氯甲烷溶液(16.0L)滴加到反应液中，加毕。加热回流12小时。中控检测反应完全后，将氢氧化钠(3.10kg，77.5mol)的水溶液(23.0L)滴加到反应液中，调节反应液pH10-11之间。继续回流5-6小时。静置分液，水相用二氯甲烷(5.0L×1)萃取，合并有机相。将有机相抽入反应釜中，降温到10℃。滴加2.0N盐酸溶液(20.0L)调节反应液pH 1-2之间。静置分液，有机相用饱和食盐水(20L×1)洗涤，浓缩，残留物用丙酮(20.0L)溶解后，抽入100L反应釜中搅拌，滴加浓硫酸(4.0L)和水(20.0L)的配制溶液，加毕回流2小时。降温到15℃，向反应液中加入饱和食盐水(20.0L)，并用正己烷(15.0L×2)萃取。合并有机相，用饱和食盐水(20.0L×1)洗涤，有机相用无水硫酸钠干燥过夜。过滤，滤液减压浓缩后得黄色固体粗品1D(3.00kg,收率81％)，纯度为50％。After 1C (5.64 kg, 27.22 mol) was dissolved in dichloromethane (40.0 L), it was drawn into a 100 L reaction kettle. The temperature was lowered to -10 ° C, and 2,4,6-trimethylpyridine (4.94 kg, 40.83 mol) was added. A dichloromethane solution (16.0 L) of trifluoromethanesulfonic anhydride (11.50 kg, 40.83 mol) was added dropwise to the reaction solution, and the addition was completed. Heat to reflux for 12 hours. After the completion of the central detection reaction, an aqueous solution (23.0 L) of sodium hydroxide (3.10 kg, 77.5 mol) was added dropwise to the reaction solution, and the pH of the reaction solution was adjusted between 10-11. Continue refluxing for 5-6 hours. The liquid phase was allowed to stand for separation, the aqueous phase was extracted with dichloromethane (5.0 L × 1), and the organic phases were combined. The organic phase was drawn into a reaction kettle and the temperature was lowered to 10 ° C. A 2.0N hydrochloric acid solution (20.0L) was added dropwise to adjust the pH of the reaction solution between 1-2. The liquid phase was allowed to stand for separation, and the organic phase was washed with saturated brine (20 L × 1), concentrated, and the residue was dissolved in acetone (20.0 L). The mixture was drawn into a 100 L reaction kettle and stirred. 20.0L) of the prepared solution, and refluxed for 2 hours. The temperature was lowered to 15 ° C., and saturated brine (20.0 L) was added to the reaction solution, and the mixture was extracted with n-hexane (15.0 L × 2). The organic phases were combined, washed with saturated brine (20.0 L × 1), and the organic phase was dried over anhydrous sodium sulfate overnight. After filtration, the filtrate was concentrated under reduced pressure to obtain crude yellow solid 1D (3.00 kg, yield 81%) with a purity of 50%.
1D进一步纯化步骤：1D further purification steps:
方法1:将无水亚硫酸氢钠(5.735kg，55.147mol)溶于66L纯化水中并加入到100L的反应釜中，室温搅拌下加入1D粗品(3.00kg,22.059mol)的乙醇(3.0L)溶液，加毕于室温下搅拌过夜，用乙酸乙酯(20L×2)萃取，水相加入反应釜中搅拌并降温到10℃下，滴加入氢氧化钠(2.250kg,56.250mol)的水(10L)溶液，调pH至10-12,加毕于室温下搅拌2小时，用正己烷(20L×2)萃取，合并有机相并用纯化水(20L×1)洗涤，有机相用无水硫酸钠(2kg)干燥1小时，过滤，将滤液蒸干得1D，无色晶状固体(2.7kg,收率90％)测定纯度为98.3％。Method 1: Dissolve anhydrous sodium bisulfite (5.735kg, 55.147mol) in 66L of purified water and add it to a 100L reaction kettle. Add 1D crude (3.00kg, 22.059mol) ethanol (3.0L) under room temperature stirring. The solution was stirred at room temperature overnight, and extracted with ethyl acetate (20L × 2). The aqueous phase was added to the reaction kettle and stirred and cooled to 10 ° C. Sodium hydroxide (2.250kg, 56.250mol) of water was added dropwise ( 10L) solution, adjust the pH to 10-12, stir at room temperature for 2 hours, extract with n-hexane (20L × 2), combine the organic phases and wash with purified water (20L × 1), and dry the organic phase with anhydrous sodium sulfate (2kg) was dried for 1 hour, filtered, and the filtrate was evaporated to dryness to give 1D. The colorless crystalline solid (2.7kg, yield 90%) was 98.3% in purity.
方法2:将亚硫酸氢钠(1529g,14.706mol)溶于22L水中，搅拌下滴加入1D粗品(1000g,7.353mol)的无水乙醇(1000mL)溶液，加毕于室温搅拌过夜(24小时)。反应液用二氯甲烷(5L×2)萃取除杂，向水相滴加入硫酸溶液(6.4L浓硫酸和6公斤碎冰配制而成)，室温下搅拌5小时，反应液用正己烷(萃取3-4次，每次4L)萃取，合并有机相 并用饱和氯化钠水溶液(5L×2)洗涤，有机相用1kg无水硫酸钠干燥2小时，过滤，滤液蒸干得1D，白色固体(900g，收率：90％)，测定纯度为98.1％。Method 2: Sodium bisulfite (1529g, 14.706mol) was dissolved in 22L of water, and a 1D crude product (1000g, 7.353mol) in anhydrous ethanol (1000mL) was added dropwise under stirring, and stirred at room temperature overnight (24 hours) . The reaction solution was extracted with dichloromethane (5L × 2) to remove impurities, and a sulfuric acid solution (prepared by 6.4L concentrated sulfuric acid and 6 kg of crushed ice) was added dropwise to the aqueous phase, and the mixture was stirred at room temperature for 5 hours. 3-4 times, 4L each time, the organic phases were combined and washed with saturated sodium chloride aqueous solution (5L × 2), the organic phase was dried over 1kg of anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was evaporated to dryness to give 1D, a white solid ( 900 g, yield: 90%), and the measured purity was 98.1%.
1H NMR(400MHz,CDCl 3)δ3.39(m,1H),3.19(m,1H),2.77(m,1H),2.38(m,1H),2.05(m,1H),1.93(d,1H),1.77(m,1H),1.45(m,4H),1.20(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 3.39 (m, 1H), 3.19 (m, 1H), 2.77 (m, 1H), 2.38 (m, 1H), 2.05 (m, 1H), 1.93 (d, 1H), 1.77 (m, 1H), 1.45 (m, 4H), 1.20 (m, 1H).
LCMS m/z＝137.1[M+1]。LCMS m / z = 137.1 [M + 1].
第四步：叔丁基2-(三环[4.2.1.0 3,8]壬烷基-2-叶立德烯)乙酸酯(1R,3S,6R,8R和1S,3R,6S,8S消旋体)(1E) Step 4: tert-Butyl 2- (tricyclo [4.2.1.0 3,8 ] nonyl-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemic Body) (1E)
tert-butyl 2-tricyclo[4.2.1.0 3,8]nonan-2-ylidene)acetate(1R,3S,6R,8R and 1S,3R,6S,8S racemate) tert-butyl 2-tricyclo [4.2.1.0 3,8 ] nonan-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000048
Figure PCTCN2019096522-appb-000048
将叔丁醇钾(742.0g,6.62mol)和四氢呋喃(6.20L)加入20L反应釜中。降温到5℃，滴加二甲氧基膦酰基乙酸叔丁酯(1480g,6.62mol,1.1eq)到反应液中，控制反应温度10℃-15℃，继续搅拌1小时。再将1D(820.0g,6.02mol,1.0eq)的四氢呋喃(2.0L)溶液滴加到反应液中，1小时内滴加完，加毕自然升到室温反应2小时。向反应釜依次加入饱和氯化铵(2.0L)溶液，纯化水(2.0L)。搅拌20分钟后静置分层，水相用甲基叔丁基醚(1.5L×2)萃取。合并有机相，用饱和食盐水(2L×2)洗涤，无水硫酸钠干燥。过滤，浓缩，得到1E，黄色液体(1.50kg)。Potassium tert-butoxide (742.0 g, 6.62 mol) and tetrahydrofuran (6.20 L) were added to a 20 L reaction kettle. The temperature was lowered to 5 ° C, and tert-butyl dimethoxyphosphonoacetate (1480 g, 6.62 mol, 1.1 eq) was added dropwise to the reaction solution. The reaction temperature was controlled to 10 ° C to 15 ° C, and stirring was continued for 1 hour. Then a 1D (820.0 g, 6.02 mol, 1.0 eq) solution of tetrahydrofuran (2.0 L) was added dropwise to the reaction solution, and the dropwise addition was completed within 1 hour. After the addition, the mixture was allowed to rise to room temperature and react for 2 hours. A saturated ammonium chloride (2.0 L) solution was sequentially added to the reaction kettle, and purified water (2.0 L) was added. After stirring for 20 minutes, the layers were allowed to stand still, and the aqueous phase was extracted with methyl tert-butyl ether (1.5 L × 2). The organic phases were combined, washed with saturated brine (2 L × 2), and dried over anhydrous sodium sulfate. Filtration and concentration gave 1E as a yellow liquid (1.50 kg).
LCMS m/z＝235.3[M+1]。LCMS m / z = 235.3 [M + 1].
第五步：叔丁基2-(2-(硝基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸酯(1R,2R,3S,6R,8R和1S,2S,3R,6S,8S消旋体)(1F) Step 5: tert-Butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate) (1F)
tert-butyl 2-(2-(nitromethyl)tricyclo[4.2.1.03,8]nonan-2-yl)acetate(1R,2R,3S,6R,8R and 1S,2S,3R,6S,8S racemate)tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.03,8] nonan-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000049
Figure PCTCN2019096522-appb-000049
向20L反应釜中依次加入1E(1.40kg,5.97mol,1.0eq)，硝基甲烷(1.82kg,29.85mol,5.0eq)和二甲基亚砜(9.8L)。搅拌，将碳酸铯(2.34kg,7.16mol,1.2eq)加到反应液中。加毕，加热到80℃-85℃，继续保温反应5小时后冷却到室温，向反应釜加入纯化水(20.0L)，水相用甲基叔丁基醚(8.0L×3)萃取。合并有机相，用饱和食盐水(8.0L×2)洗涤，无水硫酸钠干燥。 过滤，浓缩，得到棕色液体1F(1.62kg，产率：92％)。1E (1.40 kg, 5.97 mol, 1.0 eq), nitromethane (1.82 kg, 29.85 mol, 5.0 eq), and dimethyl sulfoxide (9.8 L) were sequentially added to a 20-L reaction kettle. With stirring, cesium carbonate (2.34 kg, 7.16 mol, 1.2 eq) was added to the reaction solution. After the addition was completed, the mixture was heated to 80 ° C-85 ° C, and the reaction was kept at room temperature for 5 hours, and then cooled to room temperature. Purified water (20.0L) was added to the reaction kettle, and the aqueous phase was extracted with methyl tert-butyl ether (8.0L × 3). The organic phases were combined, washed with saturated brine (8.0 L × 2), and dried over anhydrous sodium sulfate. Filtration and concentration gave brown liquid 1F (1.62 kg, yield: 92%).
LCMS m/z＝318.1[M+23]。LCMS m / z = 318.1 [M + 23].
第六步：叔丁基2-((1S,2S,3R,6S,8S)-2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸酯(S)-2-乙酰氧基-2苯乙酸(1H) Step 6: tert-Butyl 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (S) -2-acetoxy-2 phenylacetic acid (1H)
tert-butyl2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.03,8]nonan-2-yl)acetate(S)-2-acetoxy-2-phenylacetatetert-butyl2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.03,8] nonan-2-yl) acetate (S) -2-acetoxy-2-phenylacetate
Figure PCTCN2019096522-appb-000050
Figure PCTCN2019096522-appb-000050
向50L反应釜加入1F(730.0g,2.47mol)和甲醇(7.3L)。搅拌，将氯化镍六水合物(118g,0.49mol,0.2eq)加到反应中，反应液降温到5℃，分批加入硼氢化钠(374g,9.88mol,4.0eq)，保持反应体系温度20℃-30℃，约3小时加完。加毕继续搅拌反应2小时。向反应釜加入冰水(16.4L)，水相用硅藻土过滤。滤液用二氯甲烷(3.0L×2)萃取合并有机相，用饱和食盐水(4L×1)洗涤，无水硫酸钠干燥。过滤，滤液加入(S)-(+)-O-乙酰基-L-扁桃酸(384g,1.97mol,0.8eq)，加毕搅拌20分钟。将有机相蒸馏浓缩直到无溶剂蒸出后，用异丙醇(5.9L)搅拌打浆2小时，降温到5℃搅拌1小时。过滤，滤饼用异丙醇洗涤(0.4L×1)，烘干得到白色固体产品1H粗品(422g，产率：34.96％)。取固体经衍生后测定ee值为48.35％。To a 50 L reactor, 1F (730.0 g, 2.47 mol) and methanol (7.3 L) were added. With stirring, nickel chloride hexahydrate (118g, 0.49mol, 0.2eq) was added to the reaction, the reaction solution was cooled to 5 ° C, and sodium borohydride (374g, 9.88mol, 4.0eq) was added in portions to maintain the temperature of the reaction system. Add 20 ° C to 30 ° C in about 3 hours. After the addition, the reaction was stirred for 2 hours. Ice water (16.4 L) was added to the reaction kettle, and the aqueous phase was filtered through celite. The filtrate was extracted with dichloromethane (3.0 L × 2) and the combined organic phases were washed with saturated brine (4 L × 1) and dried over anhydrous sodium sulfate. After filtration, the filtrate was added with (S)-(+)-O-acetyl-L-mandelic acid (384 g, 1.97 mol, 0.8 eq) and stirred for 20 minutes after the addition. The organic phase was concentrated by distillation until no solvent was distilled off, and then stirred and slurried with isopropyl alcohol (5.9 L) for 2 hours, and the temperature was lowered to 5 ° C and stirred for 1 hour. It was filtered, and the filter cake was washed with isopropyl alcohol (0.4 L × 1) and dried to obtain a crude 1H product (422 g, yield: 34.96%) as a white solid. After taking the solid and derivatizing it, the ee value was 48.35%.
第一次结晶：将粗产品1H(420.0g,0.92mol)，异丙醇(4.20L)和水(0.21L)依次加入反应釜中。程序升温至82℃，使固体完全溶解，保温0.5小时。降温至20℃析晶，约6小时。内温至20℃时，过滤，滤饼用异丙醇(0.40L×1)洗涤。合并固体，60-65℃鼓风干燥4小时烘干至恒重。得1H第一次结晶物(260g，产率：62％)，取固体衍生后测定ee值为81.25％。First crystallization: The crude product 1H (420.0 g, 0.92 mol), isopropanol (4.20 L), and water (0.21 L) were sequentially added to the reaction kettle. The temperature was raised to 82 ° C to completely dissolve the solid, and the temperature was maintained for 0.5 hours. The temperature was lowered to 20 ° C. and crystallized for about 6 hours. When the internal temperature reached 20 ° C., it was filtered, and the filter cake was washed with isopropyl alcohol (0.40 L × 1). The solids were combined and air-dried at 60-65 ° C for 4 hours to dry to constant weight. The first crystal of 1H (260 g, yield: 62%) was obtained, and the ee value was 81.5% after derivatization with solids.
第二次结晶：将1H第一次结晶物(177g,0.39mol)，异丙醇(2.53L)和水(0.126L)依次加入反应釜中。程序升温至82℃，使固体完全溶解，保温0.5小时。降温至20℃析晶，约4.5小时。内温至30℃时，过滤，滤饼用异丙醇(0.10L×1)洗涤。合并固体，60-65℃鼓风干燥4小时烘干至恒重。得白色固体1H纯品(128g，产率：72％)，取固体衍生后测定ee值为99.73％。Second crystallization: The first crystal of 1H (177 g, 0.39 mol), isopropanol (2.53 L), and water (0.126 L) were sequentially added to the reaction kettle. The temperature was raised to 82 ° C to completely dissolve the solid, and the temperature was maintained for 0.5 hours. The temperature was lowered to 20 ° C. and crystallized for about 4.5 hours. When the internal temperature reached 30 ° C., it was filtered, and the filter cake was washed with isopropyl alcohol (0.10 L × 1). The solids were combined and air-dried at 60-65 ° C for 4 hours to dry to constant weight. 1H pure product (128 g, yield: 72%) was obtained as a white solid, and the ee value was determined to be 99.73% after derivatization with the solid.
LCMS m/z＝266.3[M+1]。LCMS m / z = 266.3 [M + 1].
第七步：2-((1S,2S,3R,6S,8S)-2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸苯磺酸化合物(1:1)(化合物1) Seventh step: 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetic acid benzenesulfonic acid compound ( 1: 1) (Compound 1)
2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetic acid compound with benzenesulfonic acid(1:1) 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetic acid compound with benzenesulfonic acid (1: 1)
Figure PCTCN2019096522-appb-000051
Figure PCTCN2019096522-appb-000051
将1H纯品(100.0g，0.218mol)和纯化水(0.8L)依次加入反应釜中，降温到0-10℃。内温至0-10℃，滴加1mol/L NaOH(218mL)水溶液到反应釜中，调节反应液pH 9-10。静置分层，水相用二氯甲烷(0.30L×2)萃取。合并有机相，依次用1mol/L NaOH(0.10L×1)溶液和饱和食盐水(0.15L×1)洗涤。有机相中加入活性炭(5.0g)脱色，无水硫酸钠干燥。过滤，滤液浓缩，浓缩釜中剩余物用乙腈(280mL)溶解。将苯磺酸一水合物(77.0g，0.437mol)用纯化水(280mL)配制成溶液滴加至上述乙腈溶液中，加毕。程序升温至80-85℃，保温反应4-6小时。将反应液降温至10-20℃析晶，约4-6小时。内温至10-20℃时，过滤，滤饼依次用水(30mL×1)，乙腈(50mL×1)洗涤。干燥后得到化合物1，白色固体(72g，产率：90％)。1H pure product (100.0 g, 0.218 mol) and purified water (0.8 L) were sequentially added to the reaction kettle, and the temperature was lowered to 0-10 ° C. The internal temperature was from 0 to 10 ° C, and a 1 mol / L NaOH (218 mL) aqueous solution was added dropwise to the reaction kettle to adjust the reaction solution pH to 9-10. The layers were allowed to stand and the aqueous phase was extracted with dichloromethane (0.30 L x 2). The organic phases were combined, and washed successively with a 1 mol / L NaOH (0.10 L × 1) solution and a saturated saline solution (0.15 L × 1). The organic phase was decolorized by adding activated carbon (5.0 g), and dried over anhydrous sodium sulfate. It was filtered and the filtrate was concentrated. The residue in the concentration kettle was dissolved with acetonitrile (280 mL). The benzenesulfonic acid monohydrate (77.0 g, 0.437 mol) was prepared as a solution with purified water (280 mL) and added dropwise to the above acetonitrile solution. The temperature was raised to 80-85 ° C, and the reaction was incubated for 4-6 hours. The reaction solution is cooled to 10-20 ° C and crystallized for about 4-6 hours. When the internal temperature reached 10-20 ° C, it was filtered, and the filter cake was washed with water (30 mL × 1) and acetonitrile (50 mL × 1) in this order. After drying, Compound 1 was obtained as a white solid (72 g, yield: 90%).
1H NMR(400MHz,MeOD)δ7.83(m,2H),7.42(m,3H),3.31(dt,4H),2.86(m,1H),2.55(d,2H),2.48(ddd,1H),2.32(dd,1H),2.15(m,1H),2.04(m,1H),1.77(m,1H),1.62(m,4H),1.45(m,1H),1.28(dt,1H)。 1 H NMR (400MHz, MeOD) δ 7.83 (m, 2H), 7.42 (m, 3H), 3.31 (dt, 4H), 2.86 (m, 1H), 2.55 (d, 2H), 2.48 (ddd, 1H ), 2.32 (dd, 1H), 2.15 (m, 1H), 2.04 (m, 1H), 1.77 (m, 1H), 1.62 (m, 4H), 1.45 (m, 1H), 1.28 (dt, 1H) .
LCMS m/z＝210.1[M+1]。LCMS m / z = 210.1 [M + 1].
将化合物1(100mg)放置于玻璃小瓶中，加入0.2ml水和0.2ml二甲亚砜升温至80摄氏度溶清，保持5分钟后自然降温至室温，得到棒状晶体。Compound 1 (100 mg) was placed in a glass vial, 0.2 ml of water and 0.2 ml of dimethyl sulfoxide were added, the temperature was raised to 80 degrees Celsius, and the solution was naturally cooled to room temperature for 5 minutes to obtain rod-shaped crystals.
热台偏振光显微镜(PLM)和单晶衍射仪检测(见表1)，Detection by hot stage polarized light microscope (PLM) and single crystal diffractometer (see Table 1),
表1 检测方法Table 1 Detection methods
Figure PCTCN2019096522-appb-000052
Figure PCTCN2019096522-appb-000052
结果见表2、表3、图1-图3：The results are shown in Table 2, Table 3, and Figures 1-3:
表2 单晶结构数据Table 2 Single crystal structure data
Figure PCTCN2019096522-appb-000053
Figure PCTCN2019096522-appb-000053
表3 单晶手性解析结果Table 3 Chiral analysis results of single crystal
Figure PCTCN2019096522-appb-000054
Figure PCTCN2019096522-appb-000054
用上述同样的方法，浓缩釜中剩余物用乙腈溶解后，分别将对甲苯磺酸或甲磺酸配制成溶液，滴加到乙腈溶液中，反应完成后经后处理，分别得到下述产物：In the same way as above, after the residue in the concentration kettle was dissolved with acetonitrile, p-toluenesulfonic acid or methanesulfonic acid was respectively prepared into a solution and added dropwise to the acetonitrile solution. After the reaction was completed, the following products were obtained:
Figure PCTCN2019096522-appb-000055
Figure PCTCN2019096522-appb-000055
实施例2Example 2
叔丁基2-(2-(硝基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸酯(1R,2R,3S,6R,8R和1S,2S,3R,6S,8S消旋体)(1F) Tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, (3R, 6S, 8S racemate) (1F)
tert-butyl 2-(2-(nitromethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetate(1R,2R,3S,6R,8R and 1S,2S,3R,6S,8S racemate) tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000056
Figure PCTCN2019096522-appb-000056
第一步：叔丁基2-(三环[4.2.1.0 3,8]壬烷基-2-叶立德烯)乙酸酯(1R,3S,6R,8R和1S,3R,6S,8S消旋体)(1E) First step: tert-butyl 2- (tricyclo [4.2.1.0 3,8 ] nonyl-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemic Body) (1E)
tert-butyl 2-(tricyclo[4.2.1.0 3,8]nonan-2-ylidene)acetate(1R,3S,6R,8R and 1S,3R,6S,8S racemate) tert-butyl 2- (tricyclo [4.2.1.0 3,8 ] nonan-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000057
Figure PCTCN2019096522-appb-000057
室温下，将1,8-二氮杂二环十一碳-7-烯(288g,1.90mol)和二甲氧基膦酰基乙酸叔丁酯(197g,0.88mol)到反应瓶中，加毕继续搅拌20分钟。再将1D(100g,0.73mol)加到反应夜中，加毕。升温到40℃反应6小时。得到黄色液体，直接进行下一步反应1E(172g)。At room temperature, add 1,8-diazabicycloundec-7-ene (288g, 1.90mol) and dimethoxyphosphono t-butyl acetate (197g, 0.88mol) to the reaction flask. Continue stirring for 20 minutes. 1D (100 g, 0.73 mol) was added to the reaction overnight, and the addition was completed. The temperature was raised to 40 ° C for 6 hours. A yellow liquid was obtained and proceeded directly to the next reaction 1E (172 g).
LCMS m/z＝257.1[M+23]。LCMS m / z = 257.1 [M + 23].
第二步：叔丁基2-(2-(硝基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸酯(1R,2R,3S,6R,8R和1S,2S,3R,6S,8S消旋体)(1F) Second step: tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate) (1F)
tert-butyl 2-(2-(nitromethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetate(1R,2R,3S,6R,8R and 1S,2S,3R,6S,8S racemate) tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000058
Figure PCTCN2019096522-appb-000058
向2L反应釜依次加入1E反应液(172g,0.73mol)，硝基甲烷(224g,3.67mol)，1,8-二氮杂二环十一碳-7-烯(134g，0.88mol)和二甲基亚砜(500mL)。加热到80℃-85℃，继续保温反应5小时。冷却到室温，向反应釜加入纯化水(2.0L)，水相用甲基叔丁基醚(800mL×3)萃取。合并有机相，用饱和食盐水(800mL×2)洗涤，无水硫酸钠干燥。过滤，浓缩，得到棕色液体1F(193g，产率：90％)。To a 2L reactor, 1E reaction solution (172g, 0.73mol), nitromethane (224g, 3.67mol), 1,8-diazabicycloundec-7-ene (134g, 0.88mol), and Methyl sulfoxide (500 mL). It was heated to 80 ° C-85 ° C, and kept warm for 5 hours. After cooling to room temperature, purified water (2.0 L) was added to the reaction kettle, and the aqueous phase was extracted with methyl tert-butyl ether (800 mL × 3). The organic phases were combined, washed with saturated brine (800 mL × 2), and dried over anhydrous sodium sulfate. Filtration and concentration gave 1F as a brown liquid (193 g, yield: 90%).
LCMS m/z＝318.1[M+23]。LCMS m / z = 318.1 [M + 23].
实施例3Example 3
叔丁基2-(2-(硝基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸酯(1R,2R,3S,6R,8R和 1S,2S,3R,6S,8S消旋体)(1F) Tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, (3R, 6S, 8S racemate) (1F)
tert-butyl 2-(2-(nitromethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetate(1R,2R,3S,6R,8R and 1S,2S,3R,6S,8S racemate) tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000059
Figure PCTCN2019096522-appb-000059
第一步：叔丁基2-(三环[4.2.1.0 3,8]壬烷基-2-叶立德烯)乙酸酯(1R,3S,6R,8R和1S,3R,6S,8S消旋体)(1E) First step: tert-butyl 2- (tricyclo [4.2.1.0 3,8 ] nonyl-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemic Body) (1E)
tert-butyl 2-(tricyclo[4.2.1.0 3,8]nonan-2-ylidene)acetate(1R,3S,6R,8R and 1S,3R,6S,8S racemate) tert-butyl 2- (tricyclo [4.2.1.0 3,8 ] nonan-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000060
Figure PCTCN2019096522-appb-000060
将叔丁醇钾(9.06g,80.76mmol)和四氢呋喃(150mL)加入1L反应釜中。降温到5℃，滴加二甲氧基膦酰基乙酸叔丁酯(18.11g，80.76mmol,1.1eq)到反应液中，控制反应温度10℃-15℃，约20分钟滴加完毕。继续搅拌0.5小时，控温10℃-15℃。再将1D(10.0g,73.42mmol,1.0eq)的四氢呋喃(50.0mL)溶液滴加到反应液，0.5小时内滴加完，加毕自然升到室温反应2小时。向反应釜依次加入饱和氯化铵(100.0mL)，纯化水(100.0mL)淬灭反应。搅拌20分钟后静置分层，水相用甲基叔丁基醚(50.0mL×1)萃取。合并有机相，用饱和食盐水(100.0mL×1)洗涤，无水硫酸钠干燥。过滤，浓缩，得到黄色液体1E(17.5g)。Potassium tert-butoxide (9.06 g, 80.76 mmol) and tetrahydrofuran (150 mL) were added to a 1 L reaction kettle. The temperature was lowered to 5 ° C, and tert-butyl dimethoxyphosphonoacetate (18.11 g, 80.76 mmol, 1.1 eq) was added dropwise to the reaction solution. The reaction temperature was controlled at 10 ° C to 15 ° C, and the addition was completed in about 20 minutes. Continue stirring for 0.5 hours and control the temperature between 10 ° C and 15 ° C. Then a 1D (10.0 g, 73.42 mmol, 1.0 eq) solution of tetrahydrofuran (50.0 mL) was added dropwise to the reaction solution, and the addition was completed within 0.5 hours. After the addition, the solution was allowed to rise to room temperature and react for 2 hours. Saturated ammonium chloride (100.0 mL) was sequentially added to the reaction kettle, and the reaction was quenched by purified water (100.0 mL). After stirring for 20 minutes, the layers were allowed to stand still, and the aqueous phase was extracted with methyl tert-butyl ether (50.0 mL × 1). The organic phases were combined, washed with saturated brine (100.0 mL × 1), and dried over anhydrous sodium sulfate. Filtration and concentration gave 1E (17.5 g) as a yellow liquid.
LCMS m/z＝257.1[M+23]。LCMS m / z = 257.1 [M + 23].
第二步：叔丁基2-(2-(硝基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸酯(1R,2R,3S,6R,8R和1S,2S,3R,6S,8S消旋体)(1F) Second step: tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate) (1F)
tert-butyl 2-(2-(nitromethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetate(1R,2R,3S,6R,8R and 1S,2S,3R,6S,8S racemate) tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000061
Figure PCTCN2019096522-appb-000061
向250mL反应瓶依次加入1E(16.5g,70.41mmol,1.0eq)，硝基甲烷(24.49g,0.35mol,5.0eq)和二甲基亚砜(116mL)。再将叔丁醇钾(15.8g,0.14mol,2.0eq)加到反应液中。加毕， 加热到80℃-85℃，继续保温反应8小时。冷却到室温，向反应釜加入纯化水(450mL)，水相用甲基叔丁基醚(150mL×3)萃取。合并有机相，用饱和食盐水(150mL×2)洗涤，无水硫酸钠干燥。过滤，浓缩，得到棕色液体1F(20.8g)。To a 250 mL reaction flask were added 1E (16.5 g, 70.41 mmol, 1.0 eq), nitromethane (24.49 g, 0.35 mol, 5.0 eq) and dimethyl sulfoxide (116 mL) in this order. Potassium tert-butoxide (15.8 g, 0.14 mol, 2.0 eq) was added to the reaction solution. After the addition was completed, the mixture was heated to 80 ° C-85 ° C, and the reaction was kept for 8 hours. After cooling to room temperature, purified water (450 mL) was added to the reaction kettle, and the aqueous phase was extracted with methyl tert-butyl ether (150 mL × 3). The organic phases were combined, washed with saturated brine (150 mL × 2), and dried over anhydrous sodium sulfate. Filtration and concentration gave 1F (20.8 g) as a brown liquid.
LCMS m/z＝318.1[M+23]。LCMS m / z = 318.1 [M + 23].
实施例4Example 4
叔丁基2-(2-(硝基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸酯(1R,2R,3S,6R,8R和1S,2S,3R,6S,8S消旋体)(1F) Tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, (3R, 6S, 8S racemate) (1F)
tert-butyl 2-(2-(nitromethyl)tricyclo[4.2.1.03,8]nonan-2-yl)acetate(1R,2R,3S,6R,8R and 1S,2S,3R,6S,8S racemate)tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.03,8] nonan-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000062
Figure PCTCN2019096522-appb-000062
第一步：叔丁基2-(三环[4.2.1.0 3,8]壬烷基-2-叶立德烯)乙酸酯(1R,3S,6R,8R和1S,3R,6S,8S消旋体)(1E) First step: tert-butyl 2- (tricyclo [4.2.1.0 3,8 ] nonyl-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemic Body) (1E)
tert-butyl 2-(tricyclo[4.2.1.0 3,8]nonan-2-ylidene)acetate(1R,3S,6R,8R and 1S,3R,6S,8S racemate) tert-butyl 2- (tricyclo [4.2.1.0 3,8 ] nonan-2-ylidene) acetate (1R, 3S, 6R, 8R and 1S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000063
Figure PCTCN2019096522-appb-000063
将叔丁醇钾(1.23kg,11.0mol)和四氢呋喃(10.0L)加入50L反应釜中。降温到5℃，滴加二甲氧基膦酰基乙酸叔丁酯(2.50kg,11.0mol,1.1eq)到反应液中，控制反应温度10℃-15℃，约40分钟滴加完毕。继续搅拌0.5小时，控温10℃-15℃。再将1D(1.36kg,10.0mol,1.0eq)的四氢呋喃(3.60L)溶液滴加到反应液，0.5小时内滴加完。加毕自然升到室温反应2小时。中控检测原料反应完全后，向反应釜依次加入5％氯化铵溶液(6.0L)淬灭反应。搅拌20分钟后静置分层，水相用二氯甲烷(5.0L×1)萃取。合并有机相，用5％食盐水(5.0L×1)洗涤，无水硫酸钠干燥。过滤，浓缩，得到黄色液体1E(2.40kg)。Potassium tert-butoxide (1.23 kg, 11.0 mol) and tetrahydrofuran (10.0 L) were added to a 50 L reaction kettle. The temperature was lowered to 5 ° C, and tert-butyl dimethoxyphosphonoacetate (2.50kg, 11.0mol, 1.1eq) was added dropwise to the reaction solution, and the reaction temperature was controlled at 10 ° C to 15 ° C. The addition was completed in about 40 minutes. Continue stirring for 0.5 hours and control the temperature between 10 ° C and 15 ° C. A 1D (1.36 kg, 10.0 mol, 1.0 eq) solution of tetrahydrofuran (3.60 L) was added dropwise to the reaction solution, and the addition was completed within 0.5 hours. After the addition, it was allowed to rise to room temperature for 2 hours. After the central control detects that the reaction of the raw materials is complete, a 5% ammonium chloride solution (6.0 L) is sequentially added to the reaction kettle to quench the reaction. After stirring for 20 minutes, the layers were allowed to stand still, and the aqueous phase was extracted with dichloromethane (5.0 L × 1). The organic phases were combined, washed with 5% saline (5.0 L × 1), and dried over anhydrous sodium sulfate. Filtration and concentration gave 1E (2.40 kg) as a yellow liquid.
LCMS m/z＝257.1[M+23]。LCMS m / z = 257.1 [M + 23].
第二步：叔丁基2-(2-(硝基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸酯(1R,2R,3S,6R,8R和1S,2S,3R,6S,8S消旋体)(1F) Second step: tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate) (1F)
tert-butyl 2-(2-(nitromethyl)tricyclo[4.2.1.03,8]nonan-2-yl)acetate(1R,2R,3S,6R,8R and  1S,2S,3R,6S,8S racemate)tert-butyl 2- (2- (nitromethyl) tricyclo [4.2.1.03,8] nonan-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000064
Figure PCTCN2019096522-appb-000064
向50L反应釜依次加入1E(2.34kg,10.0mol,1.0eq)，硝基甲烷(1.53kg,25.0mol,2.5eq)和二甲基亚砜(2.34L)。开启搅拌，再将叔丁醇钾(15.8g,0.14mol,2.0eq)加到反应液中。加毕，加热到85℃-90℃，继续保温反应10小时。中控，原料小于2％时，冷却到25℃，向反应釜加入纯化水(8.50L)，水相用二氯甲烷(3.50L×3)萃取。合并有机相，依次用0.5mol/L盐酸溶液(2.0L×1)，0.5mol/L氢氧化钠溶液(2.0L×1)和5％氯化钠溶液(2.0L×1)洗涤。过滤，将滤液控温在35±5℃以下减压浓缩至无大量馏分流出。升温至55±5℃继续减压蒸除硝基甲烷，取样中控，控制硝基甲烷含量小于5％。得到棕色液体1F(2.95kg)。1E (2.34 kg, 10.0 mol, 1.0 eq), nitromethane (1.53 kg, 25.0 mol, 2.5 eq), and dimethyl sulfoxide (2.34 L) were sequentially added to a 50-L reactor. Turn on stirring and add potassium tert-butoxide (15.8 g, 0.14 mol, 2.0 eq) to the reaction solution. After the addition was completed, the mixture was heated to 85 ° C-90 ° C, and the reaction was kept for 10 hours. In the control, when the raw material is less than 2%, cool to 25 ° C, add purified water (8.50L) to the reaction kettle, and extract the aqueous phase with dichloromethane (3.50L × 3). The organic phases were combined and washed with a 0.5 mol / L hydrochloric acid solution (2.0 L × 1), a 0.5 mol / L sodium hydroxide solution (2.0 L × 1), and a 5% sodium chloride solution (2.0 L × 1) in this order. Filter and concentrate the filtrate at 35 ± 5 ° C under reduced pressure until no large fractions flow out. The temperature was raised to 55 ± 5 ℃, and the nitromethane was distilled off under reduced pressure. The sampling was controlled to control the nitromethane content to be less than 5%. This gave 1F (2.95 kg) as a brown liquid.
LCMS m/z＝318.1[M+23]。LCMS m / z = 318.1 [M + 23].
实施例5Example 5
叔丁基2-(2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸酯(1R,2R,3S,6R,8R与1S,2S,3R,6S,8S的消旋体)(2A) Tert-Butyl 2- (2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R (6S, 8S racemate) (2A)
tert-butyl2-((1R,2R,3S,6R,8R)-2-(aminomethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetate(1R,2R,3S,6R,8R and 1S,2S,3R,6S,8S racemate) tert-butyl2-((1R, 2R, 3S, 6R, 8R) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S , 2S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000065
Figure PCTCN2019096522-appb-000065
向反应瓶中依次加入1F(90g,0.31mol)，甲醇(900mL)，钯碳10％(9.0g)，氢气换气三次，室温下氢化反应16小时。将反应液过滤，滤液减压浓缩，得到黄色液体2A(73.5g,产率：91％)。1F (90 g, 0.31 mol), methanol (900 mL), palladium carbon 10% (9.0 g) were sequentially added to the reaction flask, and hydrogen was exchanged for three times, and the reaction was hydrogenated at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 2A (73.5 g, yield: 91%) as a yellow liquid.
Ms m/z(ESI):266.1(M+1)。Ms m / z (ESI): 266.1 (M + 1).
实施例6Example 6
叔丁基2-(2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸酯(1R,2R,3S,6R,8R与1S,2S,3R,6S,8S的消旋体)(2A) Tert-Butyl 2- (2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R (6S, 8S racemate) (2A)
tert-butyl2-((1R,2R,3S,6R,8R)-2-(aminomethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetate(1R,2R,3S,6R,8R and 1S,2S,3R,6S,8S racemate) tert-butyl2-((1R, 2R, 3S, 6R, 8R) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetate (1R, 2R, 3S, 6R, 8R and 1S , 2S, 3R, 6S, 8S racemate)
Figure PCTCN2019096522-appb-000066
Figure PCTCN2019096522-appb-000066
向反应瓶中加入1F(70g,0.24mol)，乙醇(360mL)和水(120mL)，依次加入铁粉(67.2g，1.2mol)和氯化铵(38.5g，0.72mol)，加毕于90℃反应4小时。将反应液过滤，滤液减压浓缩后加入纯化水(450mL)，水相用二氯甲烷(150mL×3)萃取。合并有机相，用饱和食盐水(150mL×2)洗涤，无水硫酸钠干燥。过滤，浓缩得到黄色液体2A(55g,产率：88％)。Add 1F (70g, 0.24mol), ethanol (360mL), and water (120mL) to the reaction flask, add iron powder (67.2g, 1.2mol), and ammonium chloride (38.5g, 0.72mol) in this order. The reaction was carried out at 4 ° C for 4 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, purified water (450 mL) was added, and the aqueous phase was extracted with dichloromethane (150 mL × 3). The organic phases were combined, washed with saturated brine (150 mL × 2), and dried over anhydrous sodium sulfate. Filtration and concentration gave 2A (55 g, yield: 88%) as a yellow liquid.
Ms m/z(ESI):266.1(M+1)。Ms m / z (ESI): 266.1 (M + 1).
实施例7Example 7
叔丁基2-((1S,2S,3R,6S,8S)-2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸酯(S)-2-乙酰氧基-2苯乙酸(1H)重结晶 Tert-butyl 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetate (S)- 2-acetoxy-2phenylacetic acid (1H) recrystallized
tert-butyl2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.03,8]nonan-2-yl)acetate(S)-2-acetoxy-2-phenylacetatetert-butyl2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.03,8] nonan-2-yl) acetate (S) -2-acetoxy-2-phenylacetate
Figure PCTCN2019096522-appb-000067
Figure PCTCN2019096522-appb-000067
方法一：method one:
将粗产品1H(80.0g,0.17mol)，异丙醇(750mL)和水(50mL，v:v＝15:1)依次加入反应瓶中。升温使固体完全溶解，保温0.5小时。降温至20℃析晶，过滤，滤饼用异丙醇(0.40L×1)洗涤，60-65℃干燥4小时。得1H第一次重结晶产品60g，产率：75％)，取固体衍生后测定ee值为97.22％。The crude product 1H (80.0 g, 0.17 mol), isopropanol (750 mL), and water (50 mL, v: v = 15: 1) were sequentially added to the reaction flask. The temperature was raised to completely dissolve the solid, and the temperature was maintained for 0.5 hours. The temperature was lowered to 20 ° C for crystallization, and the filter cake was washed with isopropyl alcohol (0.40L × 1), and dried at 60-65 ° C for 4 hours. 60 g of the first recrystallized product of 1H was obtained, yield: 75%), and the ee value was determined to be 97.22% after solid derivatization.
第二次重结晶：将1H第一次重结晶产品(137g,0.30mol)，异丙醇(1284mL)和水(85.6mL，v:v＝15:1)依次加入反应釜中。升温使固体完全溶解，保温0.5小时。降温至20℃析晶，过滤，滤饼用异丙醇(0.10L×1)洗涤，60-65℃干燥。得白色固体1H第二次重结晶产品(112g，产率：82％)，取固体衍生后测定ee值为99.72％。Second recrystallization: The product (137g, 0.30mol), isopropanol (1284mL), and water (85.6mL, v: v = 15: 1) from the first recrystallization of 1H were sequentially added to the reaction kettle. The temperature was raised to completely dissolve the solid, and the temperature was maintained for 0.5 hours. The temperature was lowered to 20 ° C for crystallization, and the filter cake was washed with isopropanol (0.10L × 1) and dried at 60-65 ° C. A white solid 1H second recrystallization product (112 g, yield: 82%) was obtained, and the ee value was determined to be 99.72% after derivatization of the solid.
LCMS m/z＝266.3[M+1]。LCMS m / z = 266.3 [M + 1].
方法二：Method Two:
第二次重结晶：将1H第一次重结晶产品(10.0g,21.76mmol，ee％＝77％)，异丙醇和水(290mL/10mL，v:v＝29:1)依次加入反应瓶中。升温使固体完全溶解，保温0.5小时。降温至30℃析晶，过滤，滤饼用异丙醇(10.0m L×1)洗涤。合并固体，60-65℃干燥。得白 色固体1H第二次重结晶产品(6.1g，产率：61％)，取固体衍生后测定ee值为97.3％。Second recrystallization: Add 1H first recrystallized product (10.0g, 21.76mmol, ee% = 77%), isopropanol and water (290mL / 10mL, v: v = 29: 1) to the reaction bottle in order . The temperature was raised to completely dissolve the solid, and the temperature was maintained for 0.5 hours. The temperature was lowered to 30 ° C to crystallize, and the filter cake was washed with isopropanol (10.0 mL × 1). The solids were combined and dried at 60-65 ° C. A white recrystallized product of 1H (6.1 g, yield: 61%) was obtained as a white solid. The ee value was 97.3% after derivatization of the solid.
LCMS m/z＝266.3[M+1]。LCMS m / z = 266.3 [M + 1].
实施例8Example 8
2-((1S,2S,3R,6S,8S)-2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸苯磺酸盐(1:1)(化合物1) 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetic acid benzene sulfonate (1: 1) (Compound 1)
2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetic acid compound with benzenesulfonic acid(1:1) 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetic acid compound with benzenesulfonic acid (1: 1)
Figure PCTCN2019096522-appb-000068
Figure PCTCN2019096522-appb-000068
将1H(10.0g，21.77mol)和纯化水(100.0mL)依次加入反应瓶中。降温到0-10℃。内温至0-10℃时，滴加25％氨水溶液(4.0mL)到反应液中，调节反应液pH至9-10。静置分层，水相用乙酸异丙酯(50.0mL×2)萃取。合并有机相，用饱和食盐水(50.0mL×1)洗涤。有机相中加入活性炭(0.5g)脱色，无水硫酸钠干燥。过滤，滤液加入苯磺酸一水合物(8.06g，43.54mmol)，加毕。加热升温至80-85℃。保温反应4-6小时，中控检测原料反应完全。冰水降温至20-25℃析晶，约2小时。内温至20-25℃时，过滤，滤饼用乙酸异丙酯(10mL×1)洗涤。干燥后得到白色固体化合物1(7.8g，产率：97.6％)。1H (10.0 g, 21.77 mol) and purified water (100.0 mL) were sequentially added to the reaction flask. Cool down to 0-10 ° C. When the internal temperature reached 0-10 ° C, a 25% aqueous ammonia solution (4.0 mL) was added dropwise to the reaction solution, and the pH of the reaction solution was adjusted to 9-10. The layers were allowed to stand and the aqueous phase was extracted with isopropyl acetate (50.0 mL × 2). The organic phases were combined and washed with saturated brine (50.0 mL × 1). The organic phase was decolorized by adding activated carbon (0.5 g), and dried over anhydrous sodium sulfate. After filtration, benzenesulfonic acid monohydrate (8.06 g, 43.54 mmol) was added to the filtrate, and the addition was completed. Heat up to 80-85 ° C. Incubate the reaction for 4-6 hours. The ice water is cooled to 20-25 ° C for crystallization, about 2 hours. When the internal temperature reached 20-25 ° C, it was filtered, and the filter cake was washed with isopropyl acetate (10 mL x 1). After drying, Compound 1 (7.8 g, yield: 97.6%) was obtained as a white solid.
实施例9Example 9
2-((1S,2S,3R,6S,8S)-2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸苯磺酸化合物(1:1)(化合物1) 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetic acid benzenesulfonic acid compound (1: 1) (Compound 1)
2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetic acid compound with benzenesulfonic acid(1:1) 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetic acid compound with benzenesulfonic acid (1: 1)
Figure PCTCN2019096522-appb-000069
Figure PCTCN2019096522-appb-000069
将1H(4.59g，10.0mmol)和纯化水(40.0mL)依次加入反应瓶中。降温到0-10℃。内温至0-10℃时，滴加1.0mol/L氢氧化钠溶液(11.0mL)到反应液中，调节反应液pH至9-10。静置分层，水相用二氯甲烷(25.0mL×2)萃取。合并有机相，依次用0.5mol/L氢氧化钠溶液(20.0mL×1)和饱和食盐水(25.0mL×1)洗涤。有机相中加入活性炭(0.5g)脱色，无水硫酸钠干燥。过滤，滤液浓缩后加入乙腈(26.0mL)和苯磺酸一水合物(3.50g，20.0mmol)，加毕。加热升温至80℃。保温反应4-6小时，中控检测原料反应完全。冰水降温至25℃析 晶，约2小时。内温至25℃时，过滤，滤饼用乙腈(3.0mL×2)洗涤。干燥后得到白色固体化合物1(3.4g，产率：92.6％)。1H (4.59 g, 10.0 mmol) and purified water (40.0 mL) were sequentially added to the reaction flask. Cool down to 0-10 ° C. When the internal temperature reaches 0-10 ° C, a 1.0 mol / L sodium hydroxide solution (11.0 mL) is added dropwise to the reaction solution, and the pH of the reaction solution is adjusted to 9-10. The layers were allowed to stand and the aqueous phase was extracted with dichloromethane (25.0 mL x 2). The organic phases were combined and washed with a 0.5 mol / L sodium hydroxide solution (20.0 mL × 1) and a saturated saline solution (25.0 mL × 1) in this order. The organic phase was decolorized by adding activated carbon (0.5 g), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and acetonitrile (26.0 mL) and benzenesulfonic acid monohydrate (3.50 g, 20.0 mmol) were added. The temperature was raised to 80 ° C. Incubate the reaction for 4-6 hours. The ice water was cooled to 25 ° C and crystallized for about 2 hours. When the internal temperature reached 25 ° C., it was filtered, and the filter cake was washed with acetonitrile (3.0 mL × 2). After drying, Compound 1 (3.4 g, yield: 92.6%) was obtained as a white solid.
实施例10Example 10
2-((1S,2S,3R,6S,8S)-2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸苯磺酸盐(1:1)(化合物1) 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetic acid benzene sulfonate (1: 1) (Compound 1)
2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetic acid compound with benzenesulfonic acid(1:1) 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetic acid compound with benzenesulfonic acid (1: 1)
Figure PCTCN2019096522-appb-000070
Figure PCTCN2019096522-appb-000070
将1H(150g，0.33mol)和纯化水(1500mL)依次加入反应瓶中。降温到0-10℃，滴加1.0mol/L氢氧化钠溶液(360mL)到反应液中，调节反应液pH至9-10并搅拌1小时。静置分层，水相用二氯甲烷(800mL×2)萃取。合并有机相，依次用1.0mol/L氢氧化钠溶液(300.0mL×1)和10％食盐水(300.0mL×1)洗涤。有机相中加入活性炭(5.0g)搅拌脱色。硅藻土过滤，滤液浓缩后加入乙腈(328.0mL)，纯化水(328.0mL)和苯磺酸一水合物(114g，0.66mol)，加毕。加热升温至80℃。保温反应12小时，中控检测原料小于0.2％反应完全。冰水降温至10±5℃，搅拌约6小时析晶。内温至10℃时，过滤，滤饼依次用乙腈和水(V:V＝1：1，150mL×1)，二氯甲烷(150mL×1)洗涤，抽干。固体减压干燥得到白色固体化合物1(104g，产率：86.9％)。1H (150 g, 0.33 mol) and purified water (1500 mL) were sequentially added to the reaction flask. The temperature was lowered to 0-10 ° C, and a 1.0 mol / L sodium hydroxide solution (360 mL) was added dropwise to the reaction solution. The pH of the reaction solution was adjusted to 9-10 and stirred for 1 hour. The layers were allowed to stand and the aqueous phase was extracted with dichloromethane (800 mL x 2). The organic phases were combined and washed with a 1.0 mol / L sodium hydroxide solution (300.0 mL × 1) and a 10% saline solution (300.0 mL × 1) in this order. The organic phase was added with activated carbon (5.0 g) and stirred for decolorization. Filter through celite, add acetonitrile (328.0 mL) after concentrating the filtrate, purified water (328.0 mL) and benzenesulfonic acid monohydrate (114 g, 0.66 mol). The temperature was raised to 80 ° C. The reaction was held for 12 hours, and the control materials were less than 0.2% to complete the reaction. The ice water was cooled to 10 ± 5 ° C, and crystallized after stirring for about 6 hours. When the internal temperature reached 10 ° C, it was filtered, and the filter cake was washed with acetonitrile and water (V: V = 1: 1, 150 mL x 1), dichloromethane (150 mL x 1), and dried. The solid was dried under reduced pressure to obtain Compound 1 (104 g, yield: 86.9%) as a white solid.
化合物1可以进一步通过以下方法精制： Compound 1 can be further purified by the following methods:
方法1：化合物1(430.0g，1.17mol)和N-甲基吡咯烷酮(2.15L)加入5L反应瓶。加毕，加热至80±5℃并保温0.5小时。待固体完全溶解后，加入活性炭(10g)继续搅拌10分钟。趁热过滤，滤饼用N-甲基吡咯烷酮(400mL×1)洗涤，抽干。滤液滴加乙酸异丙酯(7.5L)，加毕，继续搅拌析晶2小时。过滤，滤饼用乙酸异丙酯(500.0mL)洗涤，抽干，减压干燥8小时，得到白色固体化合物1(420.0g，产率：97.7％)。Method 1: Compound 1 (430.0 g, 1.17 mol) and N-methylpyrrolidone (2.15 L) were added to a 5 L reaction flask. After the addition is completed, heat to 80 ± 5 ° C and hold for 0.5 hours. After the solid was completely dissolved, activated carbon (10 g) was added and stirring was continued for 10 minutes. Filtered while hot, the filter cake was washed with N-methylpyrrolidone (400 mL × 1), and dried. Isopropyl acetate (7.5 L) was added dropwise to the filtrate, and after the addition was completed, crystallization was continued for 2 hours with stirring. After filtration, the filter cake was washed with isopropyl acetate (500.0 mL), suction-dried, and dried under reduced pressure for 8 hours to obtain Compound 1 (420.0 g, yield: 97.7%) as a white solid.
方法2：化合物1(410g，1.12mol)和二甲亚砜(1230mL)加入5L反应瓶。加毕，加热至50±5℃并保温0.5小时。待固体完全溶解后，加入滴加纯化水(2460mL)，加毕，水浴降温至15℃继续搅拌析晶2小时。过滤，滤饼依次用纯化水(400.0mL×1)，二氯甲烷(400.0mL×2)洗涤，抽干，减压干燥得到白色固体化合物1(352g，产率：85.8％)。Method 2: Compound 1 (410 g, 1.12 mol) and dimethyl sulfoxide (1230 mL) were added to a 5 L reaction flask. After the addition, heat to 50 ± 5 ° C and hold for 0.5 hours. After the solid was completely dissolved, purified water (2460 mL) was added dropwise. After the addition was completed, the temperature of the water bath was lowered to 15 ° C., and the crystallization was continued for 2 hours. After filtration, the filter cake was washed with purified water (400.0 mL × 1), dichloromethane (400.0 mL × 2), dried, and dried under reduced pressure to obtain a white solid compound 1 (352 g, yield: 85.8%).
实施例11Example 11
(S)-2-羟基-2-苯乙酸2-((1S,2S,3R,6S,8S)-2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸 (1:1)(化合物2) (S) -2-Hydroxy-2-phenylacetic acid 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2- Propyl) acetic acid (1: 1) (compound 2)
(S)-2-hydroxy-2-phenylacetic acid compound with2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetic acid(1:1) (S) -2-hydroxy-2-phenylacetic acid compound with 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetic acid (1: 1)
Figure PCTCN2019096522-appb-000071
Figure PCTCN2019096522-appb-000071
第一步：2-(2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸(1R,2R,3S,6R,8R与1S,2S,3R,6S,8S的消旋体)(2B) First step: 2- (2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2-yl) acetic acid (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racemate) (2B)
2-(2-(aminomethyl)tricyclo[4.2.1.03,8]nonan-2-yl)acetic acid(1R,2R,3S,6R,8R and 1S,2S,3R,6S,8S racemate)2- (2- (aminomethyl) tricyclo [4.2.1.03,8] nonan-2-yl) acetic acid (1R, 2R, 3S, 6R, 8R and 1S, 2S, 3R, 6S, 8S racerace)
Figure PCTCN2019096522-appb-000072
Figure PCTCN2019096522-appb-000072
向反应瓶中依次加入2A(44.45g,0.17mol)和二氯甲烷(150.0mL)。搅拌并降温到0℃-5℃，将三氟乙酸(60.0mL)滴加到反应液中。加毕于0℃-10℃反应6小时，TLC监控原料完全转化，将反应液浓缩除去溶剂。剩余物加入二氯甲烷(150.0mL)，降温到0℃-5℃。用三乙胺(60.0mL)调节pH至7-8，析出白色固体并搅拌1小时。过滤，滤饼用二氯甲烷(50.0mL)洗涤，合并固体干燥得到白色固体2B(22.0g，产率：68.4％)。To the reaction flask were added 2A (44.45 g, 0.17 mol) and dichloromethane (150.0 mL) in this order. The mixture was stirred and cooled to 0 ° C to 5 ° C, and trifluoroacetic acid (60.0 mL) was added dropwise to the reaction solution. After 6 hours of addition at 0 ° C-10 ° C, the starting material was monitored for complete conversion by TLC, and the reaction solution was concentrated to remove the solvent. Dichloromethane (150.0 mL) was added to the residue, and the temperature was lowered to 0 ° C to 5 ° C. The pH was adjusted to 7-8 with triethylamine (60.0 mL), a white solid was precipitated and stirred for 1 hour. Filtration, the filter cake was washed with dichloromethane (50.0 mL), and the combined solids were dried to give 2B (22.0 g, yield: 68.4%) as a white solid.
LCMS m/z＝210.1[M+1]。LCMS m / z = 210.1 [M + 1].
第二步：(S)-2-羟基-2-苯乙酸2-((1S,2S,3R,6S,8S)-2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸(1:1)(化合物2) Second step: (S) -2-hydroxy-2-phenylacetic acid 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonane 2-yl) acetic acid (1: 1) (compound 2)
(S)-2-hydroxy-2-phenylacetic acid compound with2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetic acid(1:1) (S) -2-hydroxy-2-phenylacetic acid compound with 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetic acid (1: 1)
Figure PCTCN2019096522-appb-000073
Figure PCTCN2019096522-appb-000073
向100mL反应瓶中依次加入2B(6.32g,30.0mmol)，L-扁桃酸(8.86g,45.0mmol)，异丙 醇(62.0mL)和水(12.4mL)。加毕，加热升温至82℃，使固体完全溶解，保温0.5小时后自然降温至20℃析晶，约6小时。内温至20℃时，过滤，滤饼用异丙醇(5.0mL×2)洗涤。固体干燥1小时，得到白色固体(3.2g，产率：24.2％)。To a 100 mL reaction flask were added 2B (6.32 g, 30.0 mmol), L-mandelic acid (8.86 g, 45.0 mmol), isopropanol (62.0 mL), and water (12.4 mL) in this order. After the addition is completed, the temperature is raised to 82 ° C to completely dissolve the solid, and the temperature is naturally lowered to 20 ° C after crystallization for 0.5 hours for about 6 hours. When the internal temperature reached 20 ° C, it was filtered, and the filter cake was washed with isopropyl alcohol (5.0 mL x 2). The solid was dried for 1 hour to obtain a white solid (3.2 g, yield: 24.2%).
第一次结晶：将白色固体盐(3.2g)，异丙醇(32mL)和水(5.2mL)依次加入100mL反应瓶中。加热，程序升温至82℃，使固体完全溶解，保温0.5小时后降温至20℃析晶，约6小时。内温至20℃时，过滤，滤饼用异丙醇(5.0mL×2)洗涤。合并固体，干燥1小时，得到第一次结晶物(2.0g，产率：62.5％)，衍生后测定ee值为53％。First crystallization: White solid salt (3.2 g), isopropanol (32 mL), and water (5.2 mL) were sequentially added to a 100 mL reaction flask. Heating, the program was raised to 82 ° C to completely dissolve the solid, and the temperature was lowered to 20 ° C for crystallization after holding for 0.5 hours, about 6 hours. When the internal temperature reached 20 ° C, it was filtered, and the filter cake was washed with isopropyl alcohol (5.0 mL x 2). The solids were combined and dried for 1 hour to obtain a first crystal (2.0 g, yield: 62.5%). The ee value was 53% after derivatization.
第二次结晶：将第一次结晶物(1.0g)，乙醇(16.0mL)和水(1.3mL)依次加入100mL反应瓶中。加热升温至82℃，使固体完全溶解，保温0.5小时后降温至20℃析晶，约4.5小时。内温至30℃时，过滤，滤饼用乙醇(1.0mL×2)洗涤。合并固体，干燥1小时，烘干至恒重，得到化合物2(0.63g,收率63％)，衍生后测定ee值为72％。Second crystallization: The first crystal (1.0 g), ethanol (16.0 mL), and water (1.3 mL) were sequentially added to a 100 mL reaction flask. The temperature was raised to 82 ° C. to completely dissolve the solid, and the temperature was lowered to 20 ° C. for crystallization for about 4.5 hours after holding for 0.5 hours. When the internal temperature reached 30 ° C, it was filtered, and the filter cake was washed with ethanol (1.0 mL x 2). The solids were combined, dried for 1 hour, and dried to constant weight to obtain compound 2 (0.63 g, yield 63%). The ee value was 72% after derivatization.
Figure PCTCN2019096522-appb-000074
Figure PCTCN2019096522-appb-000074
将化合物2用实施例1类似方法，制备得到化合物1。Compound 2 was prepared in a similar manner as in Example 1 to obtain Compound 1.
实施例12Example 12
3-(环己基-3-烯-1-基)-1-(吡咯烷基-1-基)丙基-1-酮(1C)3- (cyclohexyl-3-en-1-yl) -1- (pyrrolidin-1-yl) propyl-1-one (1C)
3-(cyclohex-3-en-1-yl)-1-(pyrrolidin-1-yl)propan-1-one3- (cyclohex-3-en-1-yl) -1- (pyrrolidin-1-yl) propan-1-one
Figure PCTCN2019096522-appb-000075
Figure PCTCN2019096522-appb-000075
将3-环己烯-1-丙酸(4.11kg，26.68mol，1eq)用二氯甲烷(20.0L)溶解后加入50L反应釜中，加毕。降温至20℃，加入三乙胺(4.04Kg，40.03mol,1.5eq)。再依次加入1-羟基苯并三唑(4.32kg，32.02mol，1.2eq),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(6.11kg，32.02mol，1.2eq)，加毕搅拌30分钟。降温到0℃时滴加四氢吡咯(2.46kg，34.69mol，1.3eq)，加毕，于室温搅拌过夜。反应液用纯化水(15.0L×2)，2.0mol/L盐酸(15.0L×3)洗涤。有机相用无水硫酸钠(2.0kg)干燥，过滤，滤液浓缩蒸干得棕色油状物1C(6.60kg)。3-Cyclohexene-1-propionic acid (4.11 kg, 26.68 mol, 1 eq) was dissolved in dichloromethane (20.0 L), and then added to a 50 L reaction kettle, and the addition was completed. The temperature was lowered to 20 ° C, and triethylamine (4.04 Kg, 40.03 mol, 1.5 eq) was added. Then add 1-hydroxybenzotriazole (4.32kg, 32.02mol, 1.2eq), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.11kg, 32.02mol) , 1.2eq), and stirred for 30 minutes after the addition. When the temperature was lowered to 0 ° C, tetrahydropyrrole (2.46 kg, 34.69 mol, 1.3 eq) was added dropwise. After the addition was completed, the mixture was stirred at room temperature overnight. The reaction solution was washed with purified water (15.0 L × 2) and 2.0 mol / L hydrochloric acid (15.0 L × 3). The organic phase was dried over anhydrous sodium sulfate (2.0 kg), filtered, and the filtrate was concentrated to dryness to give 1C (6.60 kg) as a brown oil.
1H NMR(400MHz,CDCl 3)δ5.73–5.56(m,2H),3.43(dd,4H),2.37–2.22(m,2H),2.16–2.01(m,4H),1.90(dt,4H),1.81–1.51(m,6H),1.30–1.15(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.73–5.56 (m, 2H), 3.43 (dd, 4H), 2.37–2.22 (m, 2H), 2.16–2.01 (m, 4H), 1.90 (dt, 4H ), 1.81–1.51 (m, 6H), 1.30–1.15 (m, 2H).
LCMS m/z＝208.1[M+1]。LCMS m / z = 208.1 [M + 1].
实施例13Example 13
(R)-2-羟基-2-苯乙酸2-((1S,2S,3R,6S,8S)-2-(氨基甲基)三环[4.2.1.0 3,8]壬烷基-2-基)乙酸(1:1)(化合物2) (R) -2-Hydroxy-2-phenylacetic acid 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonyl-2- Propyl) acetic acid (1: 1) (compound 2)
(S)-2-hydroxy-2-phenylacetic acid compound with2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 3,8]nonan-2-yl)acetic acid(1:1) (S) -2-hydroxy-2-phenylacetic acid compound with 2-((1S, 2S, 3R, 6S, 8S) -2- (aminomethyl) tricyclo [4.2.1.0 3,8 ] nonan-2-yl) acetic acid (1: 1)
Figure PCTCN2019096522-appb-000076
Figure PCTCN2019096522-appb-000076
将2A(1.0g,3.77mmol)用乙腈(25.0mL)溶解后。将D-扁桃酸(286.0mg，1.89mmol，0.5eq)溶解乙腈(5mL)滴加到反应中，加毕室温搅拌4小时。过滤，滤饼用乙腈(2.0mL×1)洗涤，烘干得到白色固体化合物3粗品(0.48g，产率：37％)。取固体衍生后测定ee值为41.9％。After 2A (1.0 g, 3.77 mmol) was dissolved with acetonitrile (25.0 mL). D-mandelic acid (286.0 mg, 1.89 mmol, 0.5 eq) in acetonitrile (5 mL) was added dropwise to the reaction, and the mixture was stirred at room temperature for 4 hours. It was filtered, and the filter cake was washed with acetonitrile (2.0 mL × 1) and dried to obtain a crude white compound 3 (0.48 g, yield: 37%). After taking the solid derivatization, the ee value was determined to be 41.9%.
重结晶：将化合物3粗品(0.48g,1.15mmol)和乙腈(15.0mL)加入反应瓶中。加毕室温搅拌3小时。过滤，滤饼用乙腈(2.0mL×1)洗涤，烘干得到白色固体化合物3(0.22g，产率：45％)。取样衍生测定ee值为73.00％。Recrystallization: Add crude compound 3 (0.48 g, 1.15 mmol) and acetonitrile (15.0 mL) to the reaction flask. Stir at room temperature for 3 hours. It was filtered, and the filter cake was washed with acetonitrile (2.0 mL × 1) and dried to obtain compound 3 (0.22 g, yield: 45%) as a white solid. The sample derived ee value was 73.00%.

Claims (23)

  1. 一种式(I)所示化合物的制备方法，其中，所述方法包括以式(III)化合物为原料进行反应制备得到，A method for preparing a compound represented by the formula (I), wherein the method includes preparing the compound by using a compound of the formula (III) as a raw material for reaction,
    Figure PCTCN2019096522-appb-100001
    Figure PCTCN2019096522-appb-100001
    A选自苯磺酸、对甲苯磺酸或甲磺酸；A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid;
    R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
    R 2选自羧基保护基或C 1-6的烷基；优选R 2选自叔丁基； R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
    R 11选自C 1-6的烷基；优选R 11选自甲基。 R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl.
  2. 一种式(I)所示化合物的制备方法，其中，所述方法包括以式(II)化合物为原料进行反应制备得到；A method for preparing a compound represented by the formula (I), wherein the method includes preparing the compound by using a compound of the formula (II) as a raw material for reaction;
    Figure PCTCN2019096522-appb-100002
    Figure PCTCN2019096522-appb-100002
    A、R 2定义与权利要求1相同。 The definitions of A and R 2 are the same as those of claim 1.
  3. 一种式(II)化合物的制备方法，以式(III)化合物为原料制备得到Method for preparing compound of formula (II), prepared by using compound of formula (III) as raw material
    Figure PCTCN2019096522-appb-100003
    Figure PCTCN2019096522-appb-100003
    R 1、R 2的定义与权利要求1相同。 The definitions of R 1 and R 2 are the same as those in claim 1.
  4. 根据权利要求1、2或3所述的制备方法，其中，所述方法包括以式(III)化合物为原料先制备得到式(II)化合物，再以式(II)化合物为原料制备得到式(I)化合物。The preparation method according to claim 1, 2 or 3, wherein the method comprises preparing a compound of formula (II) by using a compound of formula (III) as a raw material, and then preparing a compound of formula (II) by using a compound of formula (II) as a raw material. I) Compounds.
  5. 根据权利要求2或4所述的制备方法，其中The production method according to claim 2 or 4, wherein
    式(II)化合物与酸A在能与式(II)化合物相溶的溶剂中反应得到式(I)所示化合物，所述溶剂选自乙腈、二氯甲烷、乙醇、甲醇、乙酸异丙酯、水、甲苯、二氧六环或其组合；进一步优选的，酸A与式(II)化合物的摩尔比为1.1:1～5:1，在70-90℃下反应；更进一步优选的，酸A与式(II)化合物的摩尔比为1.1:1，在80-85℃下反应；更进一步优选的，所述溶剂选自乙腈、二氯甲烷或乙酸异丙酯。The compound of formula (II) is reacted with acid A in a solvent compatible with the compound of formula (II) to obtain a compound of formula (I), the solvent is selected from the group consisting of acetonitrile, dichloromethane, ethanol, methanol, isopropyl acetate , Water, toluene, dioxane or a combination thereof; further preferably, the molar ratio of the acid A to the compound of the formula (II) is 1.1: 1 to 5: 1, and the reaction is performed at 70-90 ° C; The molar ratio of the acid A to the compound of formula (II) is 1.1: 1, and the reaction is performed at 80-85 ° C; more preferably, the solvent is selected from acetonitrile, dichloromethane or isopropyl acetate.
  6. 一种式(III)化合物的制备方法，其中，所述方法包括以式(IV)化合物为原料经过反应得到式(III)化合物的步骤，A method for preparing a compound of formula (III), wherein the method includes a step of obtaining a compound of formula (III) by using a compound of formula (IV) as a raw material through a reaction,
    Figure PCTCN2019096522-appb-100004
    Figure PCTCN2019096522-appb-100004
    R 1、R 2定义与权利要求1相同。 The definitions of R 1 and R 2 are the same as those of claim 1.
  7. 根据权利要求6所述的制备方法，其中，(III)化合物的制备包括以式(IV)化合物和手性酸为原料制备式(III)化合物；The method according to claim 6, wherein the preparation of the compound (III) comprises preparing the compound of the formula (III) by using the compound of the formula (IV) and a chiral acid as raw materials;
    优选的，所述手性酸选自式(XI)化合物、R-α-甲基苯乙酸、(-)-二乙酰基-L-酒石酸、L-天冬氨酸或者右旋奎宁酸；进一步优选的，所述手性酸和式(IV)化合物的摩尔比为0.5:1-1:1，在室温到回流条件下反应；Preferably, the chiral acid is selected from the group consisting of a compound of formula (XI), R-α-methylphenylacetic acid, (-)-diacetyl-L-tartaric acid, L-aspartic acid, or d-quinic acid; Further preferably, the molar ratio of the chiral acid and the compound of formula (IV) is 0.5: 1-1: 1, and the reaction is performed under the conditions of room temperature to reflux;
    Figure PCTCN2019096522-appb-100005
    Figure PCTCN2019096522-appb-100005
    R 1定义与权利要求1相同。 R 1 is the same as defined in claim 1.
  8. 一种式(III)化合物的精制方法，将式(III)化合物在重结晶溶剂中重结晶；A method for purifying a compound of formula (III), wherein the compound of formula (III) is recrystallized in a recrystallization solvent;
    Figure PCTCN2019096522-appb-100006
    Figure PCTCN2019096522-appb-100006
    R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
    R 2选自羧基保护基或C 1-6的烷基；优选R 2选自叔丁基； R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
    R 11选自C 1-6的烷基；优选R 11选自甲基； R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl;
    优选的，式(III)化合物与重结晶溶剂的质量体积比为1:10-1:30；进一步优选的，重结晶重复1-2次；其中Preferably, the mass-volume ratio of the compound of formula (III) to the recrystallization solvent is from 1:10 to 1:30; further preferably, the recrystallization is repeated 1-2 times;
    所述重结晶溶剂为有机溶剂和/或水；优选的，所述有机溶剂选自异丙醇、乙腈或乙醇中的一种或多种的混合；进一步优选所述有机溶剂为异丙醇；The recrystallization solvent is an organic solvent and / or water; preferably, the organic solvent is selected from a mixture of one or more of isopropyl alcohol, acetonitrile, or ethanol; further preferably, the organic solvent is isopropyl alcohol;
    优选的，所述重结晶溶剂为异丙醇和水；进一步优选的，异丙醇和水的体积比为10:1-30:1。Preferably, the recrystallization solvent is isopropanol and water; further preferably, the volume ratio of isopropanol and water is 10: 1-30: 1.
  9. 根据权利要求6～7任意一项所述的制备方法，其中，所述方法还包括以式(V)化 合物为原料制备式(IV)化合物的步骤；优选在催化剂/还原剂存在下，在0-40℃下制备式(IV)化合物；进一步优选的，所述催化剂/还原剂选自雷尼镍/水合肼、氯化镍六水合物/硼氢化钠、铁粉/氯化铵、10％钯碳/三乙基硅、雷尼镍/氢气、10％钯碳/氢气或者锌粉/乙酸；更进一步优选的，所述催化剂/还原剂选自氯化镍六水合物/硼氢化钠或10％钯碳/氢气，The preparation method according to any one of claims 6 to 7, wherein the method further comprises a step of preparing a compound of formula (IV) using a compound of formula (V) as a raw material; preferably in the presence of a catalyst / reducing agent, at 0 A compound of formula (IV) is prepared at -40 ° C; further preferably, the catalyst / reducing agent is selected from Raney nickel / hydrazine hydrate, nickel chloride hexahydrate / sodium borohydride, iron powder / ammonium chloride, 10% Palladium carbon / triethyl silicon, Raney nickel / hydrogen, 10% palladium carbon / hydrogen or zinc powder / acetic acid; more preferably, the catalyst / reducing agent is selected from nickel chloride hexahydrate / sodium borohydride or 10% palladium carbon / hydrogen,
    Figure PCTCN2019096522-appb-100007
    Figure PCTCN2019096522-appb-100007
    R 2定义与权利要求1相同。 R 2 is the same as defined in claim 1.
  10. 根据权利要求9所述的制备方法，其中，所述方法还包括式(V)化合物的制备：包括以式(VI)化合物为原料制备式(V)化合物，优选在碱(优选碱选自碳酸铯、叔丁醇钾或者1,8-二氮杂二环十一碳-7-烯)存在下，化合物(VI)与硝基甲烷发生反应(优选反应的温度为60℃～回流，更优选为80℃～100℃)生成化合物(V)；作为选择，可以有溶剂存在，所述溶剂选自二甲亚砜、N，N-二甲基甲酰胺、N-甲基吡咯烷酮或四氢呋喃，优选二甲亚砜或N，N-二甲基甲酰胺，The preparation method according to claim 9, wherein the method further comprises the preparation of a compound of formula (V): comprising using the compound of formula (VI) as a raw material to prepare a compound of formula (V), preferably in a base (preferably a base selected from carbonic acid) Compound (VI) reacts with nitromethane in the presence of cesium, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene (preferably at a reaction temperature of 60 ° C to reflux, more preferably (From 80 ° C to 100 ° C) to generate compound (V); alternatively, a solvent may be present, said solvent being selected from dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone or tetrahydrofuran, preferably Dimethyl sulfoxide or N, N-dimethylformamide,
    Figure PCTCN2019096522-appb-100008
    Figure PCTCN2019096522-appb-100008
    R 2定义与权利要求1相同。 R 2 is the same as defined in claim 1.
  11. 根据权利要求10所述的制备方法，其中，所述方法还包括式(VI)化合物的制备：包括以式(VII)化合物为原料制备式(VI)化合物，优选在碱(优选碱选自叔丁醇钾、1,8-二氮杂二环十一碳-7-烯、二异丙基胺基锂、碳酸钾或者氢化锂)存在下，式(VII)化合物与选自二甲氧基膦酰基乙酸叔丁酯、二乙氧基磷酰基乙酸叔丁酯、溴乙酸叔丁酯、氯乙酸叔丁酯或者乙酰乙酸叔丁酯中任意一种化合物发生反应生成式(VI)化合物：(优选反应温度为10℃～40℃，更优选为20℃～40℃)，The preparation method according to claim 10, wherein the method further comprises the preparation of a compound of formula (VI): comprising using the compound of formula (VII) as a raw material to prepare a compound of formula (VI), preferably in a base (preferably a base selected from tertiary In the presence of potassium butoxide, 1,8-diazabicycloundec-7-ene, lithium diisopropylamino, potassium carbonate or lithium hydride), the compound of formula (VII) is selected from the group consisting of dimethoxy Any one of the compounds of t-butyl phosphonoacetate, t-butyl diethoxyphosphoryl acetate, t-butyl bromoacetate, t-butyl chloroacetate or t-butyl acetoacetate reacts to produce a compound of formula (VI): ( (The reaction temperature is preferably 10 ° C to 40 ° C, and more preferably 20 ° C to 40 ° C.),
    Figure PCTCN2019096522-appb-100009
    Figure PCTCN2019096522-appb-100009
  12. 一种式(VII)所示化合物的制备方法，其中，所述方法包括以式(VIII)化合物为原料制备式(VII)化合物，A method for preparing a compound represented by formula (VII), wherein the method comprises preparing a compound of formula (VII) using a compound of formula (VIII) as a raw material,
    Figure PCTCN2019096522-appb-100010
    Figure PCTCN2019096522-appb-100010
    R 3和R 4各自分别独立的选自C 1-6的烷基； R 3 and R 4 are each independently selected from C 1-6 alkyl groups;
    可选的，R 3和R 4和与其连接的碳原子共同形成环(优选R 3和R 4与所连接的氮原子形成吡啶环或四氢吡咯环)。 Optionally, R 3 and R 4 and the carbon atom to which they are attached together form a ring (preferably, R 3 and R 4 form a pyridine ring or a tetrahydropyrrole ring with the nitrogen atom to which they are attached).
  13. 根据权利要求12所述的制备方法，其中，所述方法包括如下步骤：The method according to claim 12, wherein the method comprises the following steps:
    (1)式(VIII)化合物在酸酐(优选三氟甲烷磺酸酐或对甲苯磺酸酐)和吡啶类碱(优选2,4,6-三甲基吡啶、2,6-二甲基吡啶或吡啶)存在下发生反应；(1) The compound of formula (VIII) is in an acid anhydride (preferably trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride) and a pyridine base (preferably 2,4,6-trimethylpyridine, 2,6-dimethylpyridine or pyridine ) In the presence of a reaction;
    (2)用碱(优选无机碱，进一步优选氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸氢钠或碳酸铯)调节步骤(1)得到的反应液pH至碱性，优选调节pH为8-11；(2) The base (preferably an inorganic base, more preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, or cesium carbonate) is used to adjust the pH of the reaction solution obtained in step (1) to alkaline, and it is preferably adjusted pH is 8-11;
    (3)用无机酸(优选硫酸、盐酸、磷酸或硝酸)将步骤(2)得到的混合物进行酸化处理得式(VII)化合物。(3) Acidifying the mixture obtained in step (2) with an inorganic acid (preferably sulfuric acid, hydrochloric acid, phosphoric acid, or nitric acid) to obtain a compound of formula (VII).
  14. 根据权利要求12或13所述的制备方法，其中，所述方法还包括以式(IX)化合物为原料与二级胺NH(R 3)(R 4)反应制备式(VIII)化合物的步骤；优选式(IX)化合物与二级胺NH(R 3)(R 4)是在缩合剂(优选所述缩合剂选自草酰氯、二氯亚砜、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑或者N,N'-羰基二咪唑)存在下反应制备式(VIII)化合物， The method according to claim 12 or 13, further comprising the step of preparing a compound of formula (VIII) by reacting a compound of formula (IX) as a raw material with a secondary amine NH (R 3 ) (R 4 ); Preferably, the compound of formula (IX) and the secondary amine NH (R 3 ) (R 4 ) are in a condensing agent (preferably the condensing agent is selected from oxalyl chloride, dichlorosulfoxide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole or N, N'-carbonyldiimidazole) to prepare a compound of formula (VIII),
    Figure PCTCN2019096522-appb-100011
    Figure PCTCN2019096522-appb-100011
  15. 根据权利要求14所述的制备方法，其中，所述方法还包括以式(X)化合物为原料(优选以式(X)化合物和丙二酸环(亚)异丙酯为原料)制备式(IX)化合物的步骤(优选是在三乙胺甲酸盐催化下，式(X)化合物与丙二酸环(亚)异丙酯反应生成式(IX)化合物)，The preparation method according to claim 14, wherein the method further comprises preparing a compound of formula (X) as a raw material (preferably using a compound of formula (X) and a cyclic (methylene) isopropyl malonate as raw material). IX) a step of a compound (preferably, the reaction of a compound of formula (X) with a cyclic (sub) isopropyl malonate under the catalysis of triethylamine formate to form a compound of formula (IX)),
    Figure PCTCN2019096522-appb-100012
    Figure PCTCN2019096522-appb-100012
    Figure PCTCN2019096522-appb-100013
    Figure PCTCN2019096522-appb-100013
  16. 一种式(VII)所示的化合物的制备方法，其中，所述的方法包括以下步骤：A method for preparing a compound represented by formula (VII), wherein the method includes the following steps:
    Figure PCTCN2019096522-appb-100014
    Figure PCTCN2019096522-appb-100014
    (1)式(X)化合物与丙二酸环(亚)异丙酯反应生成式(IX)化合物；(1) reacting a compound of formula (X) with a cyclic (iso) isopropyl malonate to form a compound of formula (IX);
    (2)式(IX)化合物与二级胺NH(R 3)(R 4)反应生成式(VIII)化合物； (2) reacting a compound of formula (IX) with a secondary amine NH (R 3 ) (R 4 ) to form a compound of formula (VIII);
    (3)式(VIII)化合物反应生成式(VII)化合物；(3) reacting a compound of formula (VIII) to produce a compound of formula (VII);
    R 3和R 4各自分别独立的选自C 1-6的烷基； R 3 and R 4 are each independently selected from C 1-6 alkyl groups;
    可选的，R 3和R 4和与其连接的碳原子共同形成环(优选R 3和R 4与所连接的氮原子形成四氢吡咯环)。 Optionally, R 3 and R 4 and the carbon atom to which they are attached together form a ring (preferably, R 3 and R 4 form a tetrahydropyrrole ring with the nitrogen atom to which they are attached).
  17. 根据权利要求16所述的方法，其中，所述方法包含如下步骤：The method according to claim 16, wherein the method comprises the following steps:
    (1)三乙胺甲酸盐催化下，式(X)化合物与丙二酸环(亚)异丙酯反应，生成式(IX)化合物；(1) under the catalysis of triethylamine formate, a compound of formula (X) reacts with a cyclic (sub) isopropyl malonate to form a compound of formula (IX);
    (2)式(IX)化合物与二级胺NH(R 3)(R 4)反应生成式(VIII)化合物； (2) reacting a compound of formula (IX) with a secondary amine NH (R 3 ) (R 4 ) to form a compound of formula (VIII);
    (3)二氯甲烷或者1,2-二氯乙烷作溶剂，吡啶类的碱存在下，式(VIII)与三氟甲烷磺酸酐反应后，无机碱调节反应液pH至碱性，再在酸性条件下制备得式(VII)化合物。(3) Dichloromethane or 1,2-dichloroethane as a solvent, in the presence of a pyridine base, after the reaction of formula (VIII) with trifluoromethanesulfonic anhydride, the inorganic base adjusts the pH of the reaction solution to alkaline, and then A compound of formula (VII) is prepared under acidic conditions.
  18. 一种式(VII)所示的化合物的精制方法：A method for purifying a compound represented by formula (VII):
    Figure PCTCN2019096522-appb-100015
    Figure PCTCN2019096522-appb-100015
    所述方法包括将式(VII)化合物与亚硫酸氢钠常温下加成成盐，用有机溶剂(优选所述有机溶剂选自乙酸乙酯、二氯甲烷或者甲基叔丁基醚)萃取杂质，然后常温下加酸(优选盐酸或硫酸)或者碱(优选氢氧化钠)反应结束后经后处理即得。The method comprises adding a compound of formula (VII) and sodium bisulfite to form a salt at normal temperature, and extracting impurities with an organic solvent (preferably, the organic solvent is selected from ethyl acetate, dichloromethane or methyl tert-butyl ether). Then, at room temperature, an acid (preferably hydrochloric acid or sulfuric acid) or a base (preferably sodium hydroxide) is added, and the reaction is obtained by post-treatment.
  19. 一种式(I)所示的化合物的制备方法，其中，所述的方法包括以下步骤：A method for preparing a compound represented by formula (I), wherein the method includes the following steps:
    (1)以化合物(VII)为原料制备得到式(VI)化合物；(1) using compound (VII) as a raw material to obtain a compound of formula (VI);
    (2)式(VI)化合物与硝基甲烷发生反应生成式(V)化合物；(2) a compound of formula (VI) reacts with nitromethane to form a compound of formula (V);
    (3)式(V)化合物发生还原反应得到(Ⅳ)，再与手性酸(优选为式(XI)化合物) 反应得到式(III)化合物；(3) A compound of formula (V) undergoes a reduction reaction to obtain (IV), and then reacts with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (III);
    (4)式(III)化合物通过反应得到式(II)化合物，再与酸A反应得到式(I)化合物；(4) A compound of formula (III) is reacted to obtain a compound of formula (II), and then reacted with acid A to obtain a compound of formula (I);
    Figure PCTCN2019096522-appb-100016
    Figure PCTCN2019096522-appb-100016
    优选的，式(III)化合物先反应得到式(II)化合物，再由式(II)化合物与酸A反应生成式(I)化合物；Preferably, the compound of formula (III) is first reacted to obtain a compound of formula (II), and then the compound of formula (II) is reacted with acid A to form a compound of formula (I);
    或者式(V)化合物发生还原反应后，经水解后，再与手性酸(优选式(XI)化合物)反应得到式(XII)化合物，式(XII)化合物经水解，再与酸A反应生成式(I)化合物；Or after the reduction reaction of the compound of formula (V), after hydrolysis, it is then reacted with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (XII). The compound of formula (XII) is hydrolyzed and then reacted with acid A to form A compound of formula (I);
    Figure PCTCN2019096522-appb-100017
    Figure PCTCN2019096522-appb-100017
    A、R 1、R 2定义与权利要求1相同。 The definitions of A, R 1 and R 2 are the same as those in claim 1.
  20. 根据权利要求19所述的制备方法，其中，所述的方法包括以下步骤：The method according to claim 19, wherein the method comprises the following steps:
    (1)碱(优选所述碱选自叔丁醇钾或1,8-二氮杂二环十一碳-7-烯)存在下，化合物(VII)与二甲氧基膦酰基乙酸叔丁酯在10℃～40℃反应生成化合物(VI)；(1) In the presence of a base (preferably the base is selected from potassium tert-butoxide or 1,8-diazabicycloundec-7-ene), compound (VII) and dimethoxyphosphonoacetic acid tert-butyl The ester reacts at 10 ° C to 40 ° C to form compound (VI);
    (2)碱(优选所述碱选自碳酸铯、叔丁醇钾或1,8-二氮杂二环十一碳-7-烯)存在下，化合物(VI)与硝基甲烷在80℃～100℃发生反应生成化合物(V)；(2) In the presence of a base (preferably the base is selected from cesium carbonate, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene), compound (VI) and nitromethane at 80 ° C Reaction occurs at ~ 100 ° C to produce compound (V);
    (3)甲醇溶剂中，氯化镍六水合物作催化剂，硼氢化钠作还原剂，化合物(V)发生还原反应后，与手性酸(优选所述手性酸选自式(XI)化合物，进一步优选(S)-(+)-O-乙酰基-L-扁桃酸或L-扁桃酸)在0-40℃下反应得到式(III)化合物；(3) In a methanol solvent, nickel chloride hexahydrate is used as a catalyst, and sodium borohydride is used as a reducing agent. After the reduction reaction of the compound (V), it is reacted with a chiral acid (preferably, the chiral acid is selected from the compound of formula (XI) It is further preferred that (S)-(+)-O-acetyl-L-mandelic acid or L-mandelic acid) is reacted at 0-40 ° C to obtain a compound of formula (III);
    (4)式(III)化合物水解得到式(II)化合物；(4) hydrolysis of a compound of formula (III) to obtain a compound of formula (II);
    (5)式(II)化合物与A反应得到式(I)化合物。(5) A compound of formula (II) is reacted with A to obtain a compound of formula (I).
  21. 一种式(I)所示的化合物的制备方法，其中，所述方法包括如下步骤：A method for preparing a compound represented by formula (I), wherein the method includes the following steps:
    (1)式(X)化合物与丙二酸环(亚)异丙酯反应生成式(IX)化合物；(1) reacting a compound of formula (X) with a cyclic (iso) isopropyl malonate to form a compound of formula (IX);
    (2)式(IX)化合物与二级胺NH(R 3)(R 4)发生反应生成式(VIII)化合物； (2) a compound of formula (IX) reacts with a secondary amine NH (R 3 ) (R 4 ) to form a compound of formula (VIII);
    (3)式(VIII)化合物发生反应生成式(VII)化合物；(3) a compound of formula (VIII) reacts to form a compound of formula (VII);
    (4)以化合物(VII)为原料制备得到式(VI)化合物；(4) using compound (VII) as a raw material to prepare a compound of formula (VI);
    (5)式(VI)化合物与硝基甲烷发生反应生成式(V)化合物；(5) a compound of formula (VI) reacts with nitromethane to form a compound of formula (V);
    (6)式(V)化合物发生还原反应后，与手性酸(优选为式(XI)化合物)反应得到式(III)化合物；(6) a reduction reaction of the compound of formula (V), followed by reaction with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (III);
    (7)式(III)化合物通过反应得到式(II)化合物，再与酸A反应生成式(I)化合物；(7) A compound of formula (III) is obtained by a reaction to obtain a compound of formula (II), and then reacted with acid A to form a compound of formula (I);
    Figure PCTCN2019096522-appb-100018
    Figure PCTCN2019096522-appb-100018
    或者式(V)化合物发生还原反应后，经水解后，再与手性酸(优选式(XI)化合物)反应得到式(XII)化合物，式(XII)化合物经水解，再与酸A反应生成式(I)化合物；Or after the reduction reaction of the compound of formula (V), after hydrolysis, it is then reacted with a chiral acid (preferably a compound of formula (XI)) to obtain a compound of formula (XII). The compound of formula (XII) is hydrolyzed and then reacted with acid A to form A compound of formula (I);
    Figure PCTCN2019096522-appb-100019
    Figure PCTCN2019096522-appb-100019
    A、R 1、R 2定义与权利要求1相同； A, R 1 and R 2 are the same as defined in claim 1;
    R 3、R 4定义与权利要求12相同。 R 3 and R 4 are the same as defined in claim 12.
  22. 一种式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VIII)或式(XII)化合物及其异构体或药学上可接受的盐，A compound of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VIII) or formula (XII) and isomers or pharmaceutically acceptable salts thereof,
    Figure PCTCN2019096522-appb-100020
    Figure PCTCN2019096522-appb-100020
    Figure PCTCN2019096522-appb-100021
    Figure PCTCN2019096522-appb-100021
    R 1选自H、羟基保护基或-C(＝O)R 11； R 1 is selected from H, a hydroxy protecting group or -C (= O) R 11 ;
    R 2选自羧基保护基或C 1-6的烷基；优选R 2选自叔丁基； R 2 is selected from a carboxy protecting group or C 1-6 alkyl; preferably R 2 is selected from tert-butyl;
    R 11选自C 1-6的烷基；优选R 11选自甲基； R 11 is selected from C 1-6 alkyl; preferably R 11 is selected from methyl;
    R 3和R 4各自独立的选自C 1-6烷基或者R 3和R 4成环(优选R 3和R 4与所连接的氮原子形成吡啶环或四氢吡咯环)； R 3 and R 4 are each independently selected from C 1-6 alkyl or R 3 and R 4 to form a ring (preferably R 3 and R 4 form a pyridine ring or a tetrahydropyrrole ring with the nitrogen atom to which they are attached);
    条件是R 3和R 4不同时为甲基。 Provided that R 3 and R 4 are not both methyl.
  23. 一种式(I)所示的化合物的精制方法，其中，将式(I)化合物在有机溶剂(优选N-甲基吡咯烷酮或二甲亚砜)中加热至溶解，加入乙酸异丙酯和/或水，搅拌析晶，过滤，减压干燥，即得：A method for purifying a compound represented by formula (I), wherein the compound of formula (I) is heated to dissolve in an organic solvent (preferably N-methylpyrrolidone or dimethyl sulfoxide), and isopropyl acetate and / Or water, stirring and crystallization, filtering, drying under reduced pressure, that is:
    Figure PCTCN2019096522-appb-100022
    Figure PCTCN2019096522-appb-100022
    A选自苯磺酸、对甲苯磺酸或甲磺酸。A is selected from benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid.
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WO2018050046A1 (en) * 2016-09-14 2018-03-22 四川海思科制药有限公司 Fused tricyclic γ-amino acid derivative, preparation method therefor, and medical use thereof

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