WO2020029762A1 - PROCÉDÉ DE PRÉPARATION D'UN DÉRIVÉ D'ACIDE γ-AMINÉ TRICYCLIQUE FUSIONNÉ ET D'INTERMÉDIAIRE DE CELUI-CI - Google Patents

PROCÉDÉ DE PRÉPARATION D'UN DÉRIVÉ D'ACIDE γ-AMINÉ TRICYCLIQUE FUSIONNÉ ET D'INTERMÉDIAIRE DE CELUI-CI 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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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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Priority to CN201980045725.3A priority Critical patent/CN112384493B/zh
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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.

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Abstract

L'invention concerne un procédé de préparation d'un dérivé d'acide γ-aminé tricyclique fusionné et d'un intermédiaire de celui-ci, et un procédé de préparation d'un intermédiaire du dérivé d'acide γ-aminé tricyclique fusionné. Le dérivé d'acide γ-aminé tricyclique fusionné a une structure telle que représentée par la formule (I). Le procédé de préparation utilise des matières premières facilement disponibles et comporte des étapes simples ; l'ensemble du procédé de synthèse utilise une purification par cristallisation, tandis que la chromatographie sur colonne de gel de silice ou d'autres procédés de chromatographie préparatoire ne sont pas utilisés, le procédé étant approprié pour une production industrielle à grande échelle.
PCT/CN2019/096522 2018-08-09 2019-07-18 PROCÉDÉ DE PRÉPARATION D'UN DÉRIVÉ D'ACIDE γ-AMINÉ TRICYCLIQUE FUSIONNÉ ET D'INTERMÉDIAIRE DE CELUI-CI WO2020029762A1 (fr)

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