WO2021208331A1 - Procédé de préparation de 3-carbonyl-bicyclo[2,2,2]octane-2-carboxylate - Google Patents

Procédé de préparation de 3-carbonyl-bicyclo[2,2,2]octane-2-carboxylate Download PDF

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Publication number
WO2021208331A1
WO2021208331A1 PCT/CN2020/113043 CN2020113043W WO2021208331A1 WO 2021208331 A1 WO2021208331 A1 WO 2021208331A1 CN 2020113043 W CN2020113043 W CN 2020113043W WO 2021208331 A1 WO2021208331 A1 WO 2021208331A1
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WIPO (PCT)
Prior art keywords
octane
carbonyl
bicyclo
carboxylate
preparing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2020/113043
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English (en)
Chinese (zh)
Inventor
黄志宁
叶伟平
周章涛
费安杰
陈润林
崔锦栋
蓝天琪
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong Raffles Pharmatech Co Ltd
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Guangdong Raffles Pharmatech Co Ltd
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Publication of WO2021208331A1 publication Critical patent/WO2021208331A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/303—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by hydrogenation of unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/18—All rings being cycloaliphatic the ring system containing six carbon atoms

Definitions

  • the invention belongs to the field of organic chemical synthesis of pharmaceutical intermediates, and relates to a pharmaceutical intermediate, in particular to a method for preparing 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate.
  • 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate is a class of small molecules that are difficult to synthesize.
  • 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylic acid The synthesis report of this structural fragment of ester mainly has the following route.
  • This route uses cyclohexadiene as the starting material, and undergoes Diels-Alder reaction with methyl 3-bromopropiolate. Under the action of sodium methoxide, it is substituted and added with methanol. Formation reaction, followed by acidic hydrolysis, and finally catalytic hydrogenation under palladium catalyst conditions to obtain 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylic acid methyl ester.
  • the main disadvantages of this route include the poor stability of the starting material cyclohexadiene, which is not conducive to mass transportation and long-term storage; methyl 3-bromopropiolate is expensive and the production cost is high; the total yield is less than 45% .
  • the method for preparing 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate of the present invention uses 2-(4-alkoxycarbonylcyclohexylidene) acetate as the starting material and successively carries out catalytic hydrogenation And condensation to obtain the 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate, the reaction process is:
  • X and Y are independently selected from an alkyl group or an aryl group.
  • X and Y are independently selected from methyl, ethyl, propyl, isopropyl, butyl, or phenyl.
  • the step of preparing 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate is:
  • the metal catalyst is selected from platinum on carbon, palladium on carbon, platinum dioxide or metal ruthenium catalysts.
  • the strong base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-amyloxide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, bis(trimethylsilyl) ) Sodium amide or potassium bis(trimethylsilyl)amide.
  • the polar solvent is selected from methanol, ethanol, isopropanol, tert-amyl alcohol or tetrahydrofuran.
  • the method for preparing 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate of the present invention has the following beneficial effects:
  • the synthesis route is short, the reaction conditions are mild, and the total yield is greater than 80%.
  • the method for preparing 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate of the present invention uses raw materials that are easily available, has low production cost, and does not require high equipment, and is suitable for large-scale industrial production.
  • X and Y are independently selected from an alkyl group or an aryl group.
  • organic substituent group refers to a group that replaces a hydrogen atom in an organic compound in organic chemistry.
  • catalytic hydrogenation refers to a reaction in which hydrogen molecules are added to unsaturated groups of organic compounds under the action of a catalyst.
  • 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate can be used as a key intermediate (2S,3S)-3-amino-bicyclo, which is a type of influenza virus RNA polymerase inhibitor pimodivir [2.2.2] Preparation of octane-2-carboxylate,
  • the catalytic hydrogenation is the catalytic hydrogenation of the carbon-carbon double bond in 2-(4-alkoxycarbonylcyclohexylidene) acetate under the condition of a metal catalyst to form 2-(4-alkoxycarbonylcyclohexyl) Acetate;
  • Condensation is the Claisen ester condensation (Claisencondensation), also known as Dieckmann reaction (Dieckmann reaction), in strong base conditions and polar solvents.
  • 2-(4-Alkoxycarbonylcyclohexyl) acetate contains ⁇ -active hydrogen.
  • the method for preparing 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate of the present invention has a short synthetic route, mild reaction conditions, and a total yield of more than 80%; and the preparation of 3-carbonyl-bicyclo[2.2 .2]
  • the raw materials used in the method of octane-2-formate are easily available, the production cost is low, and the equipment requirements are not high, and it is suitable for large-scale industrial production.
  • the X and Y are independently selected from methyl, ethyl, propyl, isopropyl, butyl or phenyl.
  • X is preferably methyl or ethyl
  • Y is preferably methyl or ethyl
  • selected from means to select one of the following substances; “independently selected from” the two do not affect each other, and one of the following substances can be independently selected, and the two may be different or the same.
  • the metal catalyst is selected from platinum carbon, palladium carbon, platinum dioxide or metal ruthenium catalysts.
  • the strong base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-amyloxide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or bis(trimethylsilyl) Silicon-based) potassium amide.
  • the strong base is preferably sodium tert-amyloxide.
  • the base used in the condensation reaction is the necessary external condition for the generation of carbanion. According to the strength of the carbanion conjugate acid, a suitable base should be selected.
  • Acid ester select sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-amyloxide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or bis(trimethylsilyl)
  • Potassium amide is used as an alkaline agent, that is, the strong base used in the formation of strong base conditions, it will be easier to form carbanion, and then proceed to the next step of the reaction.
  • the polar solvent is selected from methanol, ethanol, isopropanol, tert-amyl alcohol or tetrahydrofuran.
  • the dicarboxylic acid ester compound 2-(4-alkoxycarbonylcyclohexyl) acetate can undergo intramolecular ester condensation reaction, but also requires the conditions of a polar solvent.
  • the acidity of the solvent is much stronger than the original compound, so it cannot be produced.
  • heating and reflux temperature mentioned in the present invention is the boiling point of the polar solvent used in the preparation process.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de préparation de 3-carbonyl-bicyclo[2,2,2]octane-2-carboxylate. La présente invention met en œuvre de manière séquentielle une hydrogénation catalytique et une condensation pour obtenir du 3-carbonyl-bicyclo[2,2,2]octane-2-carboxylate à l'aide de 2-(4-alcoxycarbonylcyclohexylidène)acétate en tant que matériau de départ, X et Y étant indépendamment choisis parmi alkyle et aryle. Le procédé a un processus de synthèse court, se déroule dans des conditions de réaction modérées, a un rendement total supérieur à 80 %, utilise des matières premières qui sont faciles à acquérir, a un faible coût de production, a de faibles besoins en équipement et est approprié pour une production industrielle à grande échelle.
PCT/CN2020/113043 2020-04-16 2020-09-02 Procédé de préparation de 3-carbonyl-bicyclo[2,2,2]octane-2-carboxylate Ceased WO2021208331A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010300391.4 2020-04-16
CN202010300391.4A CN111689854A (zh) 2020-04-16 2020-04-16 制备3-羰基-二环[2.2.2]辛烷-2-甲酸酯的方法

Publications (1)

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WO2021208331A1 true WO2021208331A1 (fr) 2021-10-21

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PCT/CN2020/113043 Ceased WO2021208331A1 (fr) 2020-04-16 2020-09-02 Procédé de préparation de 3-carbonyl-bicyclo[2,2,2]octane-2-carboxylate

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CN (1) CN111689854A (fr)
WO (1) WO2021208331A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3651142A (en) * 1969-02-06 1972-03-21 Colgate Palmolive Co 3-amino-2-(3 4-dihalophenyl) bicyclo(2.2.2)octan-2-ol
US6159984A (en) * 1997-06-17 2000-12-12 Schering Corporation Farnesyl protein transferase inhibitors
WO2001032634A1 (fr) * 1999-10-29 2001-05-10 Merck & Co., Inc. Antagonistes nmda/nr2b a base de 2-cyclohexyle benzimidazole
WO2011002887A1 (fr) * 2009-07-02 2011-01-06 Schering Corporation COMPOSÉS TRICYCLIQUES FUSIONNÉS COMME NOUVEAUX INHIBITEURS DE mTOR

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3152206A1 (fr) * 2014-06-06 2017-04-12 Biogen MA Inc. Agents de modulation d'atx

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3651142A (en) * 1969-02-06 1972-03-21 Colgate Palmolive Co 3-amino-2-(3 4-dihalophenyl) bicyclo(2.2.2)octan-2-ol
US6159984A (en) * 1997-06-17 2000-12-12 Schering Corporation Farnesyl protein transferase inhibitors
WO2001032634A1 (fr) * 1999-10-29 2001-05-10 Merck & Co., Inc. Antagonistes nmda/nr2b a base de 2-cyclohexyle benzimidazole
WO2011002887A1 (fr) * 2009-07-02 2011-01-06 Schering Corporation COMPOSÉS TRICYCLIQUES FUSIONNÉS COMME NOUVEAUX INHIBITEURS DE mTOR

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FARMER ERNEST HAROLD, ROSS JOHN: "The Formation and Stability of Associated dlicyclic Systems. Part I I . The Fornuttion and Disruption of Dicyclic Dih ydroresorcinols", JOURNAL OF THE CHEMICAL SOCIETY, TRANSACTIONS, vol. 127, 31 December 1925 (1925-12-31), XP055858565 *
FINNEGAN R. A., BACHMAN P. L.: "Synthesis of (ÍZ-12-Oxo-6,9-ethano-c2s-A1'2-octalin 4145 Studies on Terpenes. III.1 The Synthesis of d7-12-Oxo-6,9-ethano- cis-12-octalin, a Potentially Useful Intermediate for the Total Synthesis of the Diterpene Alkaloid, Atisine2", JOURNAL OF ORGANIC CHEMISTRY, vol. 30, no. 12, 31 December 1965 (1965-12-31), pages 4145 - 4150, XP055858566 *

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