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WO2024134671A1 - Préparation de 3-ethylbicyclo[3.2.0]hept-3-en-6-one - Google Patents

Préparation de 3-ethylbicyclo[3.2.0]hept-3-en-6-one Download PDF

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Publication number
WO2024134671A1
WO2024134671A1 PCT/IN2023/051150 IN2023051150W WO2024134671A1 WO 2024134671 A1 WO2024134671 A1 WO 2024134671A1 IN 2023051150 W IN2023051150 W IN 2023051150W WO 2024134671 A1 WO2024134671 A1 WO 2024134671A1
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Prior art keywords
formula
compound
solvent
acid
mixture
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PCT/IN2023/051150
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English (en)
Inventor
Swapnil Sonawane
Nilima SONAWANE
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Bhisaj Pharmaceuticals Pvt Ltd
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Bhisaj Pharmaceuticals Pvt Ltd
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Publication of WO2024134671A1 publication Critical patent/WO2024134671A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/86—Use of additives, e.g. for stabilisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/48—Preparation of compounds having groups
    • C07C41/50—Preparation of compounds having groups by reactions producing groups
    • 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
    • C07C2602/20—All rings being cycloaliphatic the ring system containing seven carbon atoms

Definitions

  • the present invention relates to a process for preparation of 3 -ethylbicyclo [3.2.0] hept-3-en-6-one (7).
  • the compound of formula (1) is a medication developed by Daiichi Sankyo, a gabapentinoid. Gabapentin and pregabalin are belongs to members of this class. It binds to the a25 subunit of voltage-gated calcium channel (1 and 2), but compound of formula 1 has significantly higher potency than pregabalin. It has shown promising results in Phase II clinical trials for the treatment of diabetic peripheral neuropathic pain.
  • the present invention relates to provide a method of preparation of 3 -ethylbicyclo [3.2.0] hept-3-en-6-one of formula (7).
  • the present invention provides an improved process for preparation of racemic mixture of compound of formula (7) and compound of formula (8), comprising; a) reacting butanal of formula (2) with allyl alcohol of formula (3) in a solvent and in presence of a catalyst to provide l,l-bis(allyloxy)butane of formula (4); b) heating the l,l-bis(allyloxy)butane of formula (4) in presence of an acid anhydride and an acid in a solvent to provide 2-ethylpent-4-enal of formula (5); c) heating 2-ethylpent-4-enal of formula (5) with malonic acid in a presence of base or a mixture of bases in a solvent to provide (2E)-4-Methylhepta- 2,6-dienoic acid of formula (6);
  • the solvent used in step (a), step (b) , step (c) and step (d) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2 -methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4- bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl
  • the catalyst used in step (a) is magnesium sulfate.
  • the step (b) is performed in by heating to approximately 100° C to 130° C.
  • the acid anhydride used in step (b) and step (d) is selected from acetic anhydride, propionic anhydride, butanoic anhydride, succinic anhydride, more preferably acetic anhydride.
  • the acid used in step (b) as a catalyst is preferably a carboxylic acid, more preferably maleic acid.
  • the addition of an acid in a catalytic amount can promote the reaction.
  • the base used in step (c) and step (d) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal and alkali earth metal salts of acetic acid selected from sodium acetate, potassium acetate, magnesium acetate, calcium acetate; alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, or organic amines selected from diethylamine, triethylamine, di-n-propyl amine, diisopropyl amine, tertbutylamine, morpholine, piperidine, diisopropylethylamine, pyridine, 4-dimethyl aminopyridine, l,8-d
  • the step (c) is performed in by heating at 70° C to 80° C.
  • the step (d) reaction proceeds by heating.
  • the reaction temperature is preferably 100° C to 120° C.
  • the present invention provides a process for preparation of 3 -ethylbicyclo [3.2.0] hept-3-en-6-one of formula (7), comprising; a) reacting the racemic mixture of the compound of formula (7) and the compound of formula (8) with an aromatic aldehyde in presence of a base and optionally in presence of a chiral auxiliary compound of formula (9) to provide reaction mixture having compound of formula (7); and
  • Optional Chiral auxiliary(9) b) stir reaction mixture having compound of formula (7) at 70-80°C then treating this mixture with di-polar solvent to provide compound of formula (7) having chiral purity more than 99%.
  • the aromatic aldehyde used in step (a) is selected from 4-formyl benzoic acid, 1,2-benzenedicarboxaldehyde, 1,3-benzenedicarboxaldehyde, 1,4- benzenedicarbox-aldehyde or 2-hydroxybenzene- 1 ,3 ,5 -tricarbaldehyde .
  • the base used in step (a) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal and alkali earth metal salts of acetic acid selected from sodium acetate, potassium acetate, magnesium acetate, calcium acetate; alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, or organic amines selected from diethylamine, triethylamine, di-n-propyl amine, di-isopropyl amine, tertbutylamine, morpholine, piperidine, N,N-diisopropylethylamine, pyridine, 4- dimethyl aminopyridine, l,8-d
  • the dipolar solvent used in step (b) is selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), N-ethyl -2- pyrrolidone (NEP), Dimethylacetamide (DMAc or DMA), acetonitrile (CHsCN), acetone or tetrahydrofuran (THF).
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • NMP N-methyl-2-pyrrolidinone
  • NEP N-ethyl -2- pyrrolidone
  • DMAc or DMA Dimethylacetamide
  • CHsCN acetonitrile
  • THF acetone or tetrahydrofuran
  • the chiral auxiliary used in step (a) is a compound of formula (9) is structurally shown as: Free base or acid addition salt selected from hydrochloride, sulfate, acetate, formate etc. wherein
  • X OH, F, Cl, Br, I or any group selected from alkyl, aryl, aromatic, substituted aromatic, diphenyl alkyl or substituted diphenyl alkyl;
  • Y any salt such as HC1, HBr, HI.
  • the chiral auxiliary used in step (a) is (R)-2-(diphenylmethyl)pyrrolidine hydrochloride or (S)-3 -hydroxypyrrolidine HC1 of formula (9).
  • the aqueous layer was subjected to extraction with toluene (153 mL), and the extract was combined with the organic layer, followed by two extractions of the compound of interest into aqueous layers using a 2 M aqueous NaOH solution (360 mfx 1 and 90 mfx 1).
  • the aqueous layers were combined and then adjusted to be acidic by the addition of concentrated hydrochloric acid (80 mL), followed by two extractions with toluene (each with 204 mL).
  • the organic layers were combined and then washed with water (102 mL).
  • the organic layer was concentrated under reduced pressure to provide the title compound (72 g, oil substance).
  • (2E)-4-Ethylhepta-2,6-dienoic acid (6) (145 g) obtained by the method described above was dissolved in N,N-dimethylacetamide (367.6 mL) under a nitrogen atmosphere. To the solution, acetic anhydride (167 g) and triethylamine (114 mL) were added. The reaction mixture was warmed and stirred at 115 to 117° C. for 5 - 6 hours. The reaction mixture was cooled to room temperature, and n-hexane (510 mL) and water (714 mL) were added thereto to separate an organic layer.
  • the aqueous layer was subjected to two extractions with hexane (each with 255 mL), and all the organic layers were combined and then washed with a 5% aqueous sodium bicarbonate solution (102 mL) and water (102 mL) in this order.
  • the obtained organic layer was concentrated under reduced pressure, and the residue was distilled to provide the title compound (100 g, oil substance).
  • (2E)-4-Ethylhepta-2,6-dienoic acid (6) (14.5 g) obtained by the method described above was dissolved in N,N-dimethylacetamide (36.76 mL) under a nitrogen atmosphere.
  • acetic anhydride (16.7 g) and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) (12.36 g) were added.
  • DBU 1,8- Diazabicyclo[5.4.0]undec-7-ene
  • the aqueous layer was subjected to two extractions with hexane (each with 25.5 mL), and all the organic layers were combined and then washed with a 5% aqueous sodium bicarbonate solution (10.2 mL) and water (10.2 mL) in this order.
  • the obtained organic layer was concentrated under reduced pressure, and the residue was distilled to provide the title compound (10g, oil substance)
  • (2E)-4-Ethylhepta-2,6-dienoic acid (6) (14.5 g) obtained by the method described above was dissolved in acetic anhydride (100 mL) under a nitrogen atmosphere. To the solution, potassium acetate (23.07 g) was added and stirred at room temperature. The reaction mixture was warmed and stirred at 110 to 120° C. The reaction mixture was cooled to room temperature and poured over ice water & extracted with n- hexane. The hexane layer was washed with IN aqueous NaOH, and saturated sodium chloride solution. The hexane layer was distilled under reduced pressure to provide the title compound (8g, oil substance).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé industriellement réalisable, robuste et économiquement viable de préparation de 3-éthylbicyclo[3.2.0]hept-3-en-6-one (7). Le procédé permet d'obtenir un composé (7) présentant une pureté chirale supérieure à 99 %.
PCT/IN2023/051150 2022-12-21 2023-12-09 Préparation de 3-ethylbicyclo[3.2.0]hept-3-en-6-one Ceased WO2024134671A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202221074331 2022-12-21
IN202221074331 2022-12-21

Publications (1)

Publication Number Publication Date
WO2024134671A1 true WO2024134671A1 (fr) 2024-06-27

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PCT/IN2023/051150 Ceased WO2024134671A1 (fr) 2022-12-21 2023-12-09 Préparation de 3-ethylbicyclo[3.2.0]hept-3-en-6-one

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WO (1) WO2024134671A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140296569A1 (en) * 2011-12-15 2014-10-02 Daiichi Sankyo Company, Limited Optical Resolution Method for Bicyclic Compound Using Asymmetric Catalyst
US9162971B2 (en) * 2011-06-08 2015-10-20 Daiichi Sankyo Company, Limited Methods for producing bicyclic compounds via claisen rearrangements
US10150723B2 (en) * 2015-05-27 2018-12-11 Novassay S.A. Separation of enantiomers of 3-ethylbicyclo[3.2.0]hept-3-en-6-one

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9162971B2 (en) * 2011-06-08 2015-10-20 Daiichi Sankyo Company, Limited Methods for producing bicyclic compounds via claisen rearrangements
US20140296569A1 (en) * 2011-12-15 2014-10-02 Daiichi Sankyo Company, Limited Optical Resolution Method for Bicyclic Compound Using Asymmetric Catalyst
US10150723B2 (en) * 2015-05-27 2018-12-11 Novassay S.A. Separation of enantiomers of 3-ethylbicyclo[3.2.0]hept-3-en-6-one

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