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WO2016191835A1 - Procédé de préparation d'ingénol-5,20-acétonide, procédé de préparation de 3-éthynyl-3-hydroxy-4.7.7-triméthylbicyclo[4.1.0]heptane-2-carbaldéhyde, procédé de préparation du composé 2,2-diméthyl-4-éthynyl-5-triphénylphosphoranylidène-1,3-dioxane, et composé intermédiaire - Google Patents

Procédé de préparation d'ingénol-5,20-acétonide, procédé de préparation de 3-éthynyl-3-hydroxy-4.7.7-triméthylbicyclo[4.1.0]heptane-2-carbaldéhyde, procédé de préparation du composé 2,2-diméthyl-4-éthynyl-5-triphénylphosphoranylidène-1,3-dioxane, et composé intermédiaire Download PDF

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Publication number
WO2016191835A1
WO2016191835A1 PCT/BR2015/050068 BR2015050068W WO2016191835A1 WO 2016191835 A1 WO2016191835 A1 WO 2016191835A1 BR 2015050068 W BR2015050068 W BR 2015050068W WO 2016191835 A1 WO2016191835 A1 WO 2016191835A1
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WIPO (PCT)
Prior art keywords
compound
called
reaction
heptane
give
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Ceased
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PCT/BR2015/050068
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English (en)
Portuguese (pt)
Inventor
Luiz Francisco Pianowski
Lech W. Dudycz
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Amazonia Fitomedicamentos Ltda
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Amazonia Fitomedicamentos Ltda
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Priority to PCT/BR2015/050068 priority Critical patent/WO2016191835A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/20—Polycyclic condensed hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/20—Polycyclic condensed hydrocarbons
    • C07C15/38—Polycyclic condensed hydrocarbons containing four rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G8/00—Condensation polymers of aldehydes or ketones with phenols only
    • C08G8/28—Chemically modified polycondensates
    • C08G8/30—Chemically modified polycondensates by unsaturated compounds, e.g. terpenes

Definitions

  • the present invention relates to the method of preparing ingenol-5,20-acetonide as well as ingenol-5,20-acetonide obtained by such a process.
  • the invention also relates to novel intermediate compounds of the ingenol-5,20-acetonide preparation.
  • ingenol-5,20-acetonide An example prior art synthesis of ingenol-5,20-acetonide is shown in patent application WO2012010172, wherein the ingenol compound (CAS # 30220-46-3) is reacted with acetone in the presence of p-toluenesulfonic acid. catalyst followed by neutralization with sodium hydrogen carbonate.
  • acetonide is an intermediate in obtaining ingenol-3-angelate, having ingenol as the starting material. This process is unsuitable for scale-up, especially as it cannot prevent a large loss of the precious ingenol raw material in the reaction of obtaining ingenol-5,20-acetonide from ingenol.
  • the present invention aims at a state of the art process optimized for obtaining ingenol-5,20-acetonide, particularly suitable for industrial scale production.
  • Cryogenic conditions in the following context, unless otherwise stated, refer to typical temperatures between -40 ° C and -80 ° C, and use of suitable equipment for this purpose.
  • the present invention aims at obtaining ingenol-5,20-acetonide from the reaction between 3-ethynyl-3-hydroxy-4,7,7-trimethylbicyclo [4.1.0] heptane-2-carbaldehyde (hereinafter as compound 9) and 2,2-dimethyl-4-ethynyl-5-triphenylphosphoranylidene-1,3-dioxane (hereinafter referred to as compound 19), illustrated below:
  • the synthesis of the ingenol-5,20-acetonide compound from compounds 9 and 19 involves a sequence of Wittig reactions, Pauson-Khand cyclization, alkene oxidation, Grignard reaction and a rearrangement of Pinacol.
  • Step 1 is a Wittig reaction, also called Wittig olefination, in which compound 9, an aldehyde, reacts with compound 19, a phosphorus ylide called Wittig reagent in organic solution at a high temperature of the order 100 ° C in the presence of strong bases, for example potassium tert-butoxide.
  • An alkene - intermediate 1 - and triphenylphosphine oxide to be removed are obtained. Ilet instability results in high prevalence of alkene - ie intermediate 1 - of Z configuration.
  • This ring formation step is a addition [2 + 2 + 1] between intermediate 1, an alkene, and carbon monoxide, in the presence of a suitable catalyst, for example a transition metal complex such as dicobalt octacarbonyl Co 2 (CO) 8 , under atmospheric pressure of CO.
  • a suitable catalyst for example a transition metal complex such as dicobalt octacarbonyl Co 2 (CO) 8 , under atmospheric pressure of CO.
  • This step refers to a dihydroxylation of intermediate 2, which can be done in alternate ways:
  • Os0 4 osmium tethoxide
  • periodate particularly metaperiodate, or potassium peroxymonosulfate (eg Oxone ® marketed by Dupont de Nemours), in the presence of ruthenium or cerium catalyst under neutral conditions.
  • periodate particularly metaperiodate, or potassium peroxymonosulfate (eg Oxone ® marketed by Dupont de Nemours)
  • ruthenium or cerium catalyst under neutral conditions.
  • Intermediate 3 is identified as (1R, 5R, 6R, 7R, 14S, 15R, 17R, 19R) -1,5,6-trihydroxy-1 H, and g-pentamethyl-S 2 O-dioxapentacyclothiazol. O, 1 .0 2 ⁇ , 2.12 ⁇ nonadeca-dien-4-one.
  • Intermediate 4 is identified as (1S, 2R, 9S, 10R, 12R, 14R, 15R, 19R) -15-hydroxy-4,4, H, 11,14-pentamethyl-3,5,20,22-tetraoxahexacyclo [ 14.6.0.0 1, 1 .0 2 .0, 1 1 .0 12] docosahexaenoic 18,21-diene-7,16-dione.
  • Step 4 relates to methylation of the cyclopentenone ring with a Grignard reagent, methyl magnesium bromide under cryogenic conditions. This reaction turns ketone on carbon 2 into tertiary alcohol, yielding intermediate 5 of tiglian structure.
  • Step 5 is a pinacol rearrangement, in which tertiary alcohol loses the hydroxyl group, generating a carbo-cation at position 2.
  • the arrows in the image of intermediate 5 above indicate the parts involved in the transformation.
  • the reaction is catalyzed, for example, with boron trifluoride etherate, organoaluminum compounds or any other suitable one.
  • Step 3 Removal of the useful diol protection introduced in step 3 by any suitable means, for example by using a base, TBAF (tetrabutylammonium fluoride) or pyridinium hydrofluoride.
  • TBAF tetrabutylammonium fluoride
  • pyridinium hydrofluoride tetrabutylammonium fluoride
  • the present invention further relates to the synthesis of compound 9 used in the synthesis of ingenol-5,20-acetonide described above.
  • the reaction of this step is itself known, for example described in Polish J. Chem. 74, 777, 2000, using free radical catalyst such as N-chloro-succinamide (NCS) in the presence of base under argon atmosphere.
  • NCS N-chloro-succinamide
  • the catalyst base may be 1,4-diazabicyclo [2.2.2] octane (as the DABCO ® commercial product of Air Products), DMAP (4-dimethylaminopyridine), or silica gel.
  • compound 2 is ozonolysis in a suitable solvent, particularly aqueous acetone, under cooling.
  • This step is a reductive catalytic dechlorination.
  • Compound 4 (7,7-dimethylbicyclo [4.1.0] heptane-3-one) is obtained by catalytic hydrogenolysis of compound 3 using a suitable catalyst, for example palladium, under pressure.
  • a suitable catalyst for example palladium, under pressure.
  • the resulting hydrogen chloride may be collected in situ by carbonate salts.
  • Compound 5 This step refers to the hydroxymethylation of compound 5 to give compound 6 (2-hydroxymethyl-7,7-dimethylbicyclo [4.1.0] heptane-3-one).
  • the reaction is also known, for example as disclosed in the aforementioned article by A. Sekine et al. (Tetrahedron Letters 41 (2000) 509), performed with formaldehyde in the presence of Yb (OTf) 3 (ytterbium trifluoromethanesulfonate III).
  • Compound 7 (2-hydroxymethyl-4,7,7-trimethylbicyclo [4.1.0] heptane-3-one) is obtained by methylation of compound 6, initiated by the transient protective reaction of compound 6 with trimethylsilyl chloride (TMS), TMS enol formation, lithium enol lithium, and subsequent reaction in a vessel with methyl iodate under cryogenic conditions at a temperature of -78 ° C.
  • TMS trimethylsilyl chloride
  • Compound 9 is obtained by reacting compound 8 with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one, the Dess-Martin periodinane reagent.
  • steps 3A, 4A, 5A and 6A described above may be replaced by steps 3AA, 4AA and 5AA described below.
  • Compound 3 is transformed into Grignard reagent using magnesium followed by reaction with methyl iodide, with or without catalyst, for example NiBr 2 or CuCl 2 to give compound 10, which is 4-methyl-7, 7-dimethylbicyclo [4.1.0] heptane-3-one.
  • Compound 11 which is 4-methyl-5-trimethylsilyl 7,7-dimethylbicyclo [4.1.0] -2-hepten-3-ol, a TMS enol, is prepared in a suitable solvent, such as THF, in reaction. of compound 10 with TMS and lithium bis (trimethylsilyl) amide chloride (LiHDMS) under cryogenic conditions at a temperature of -78 ° C.
  • a suitable solvent such as THF
  • This step refers to the hydroxymethylation of compound 11 to yield compound 7 (2-hydroxymethyl-7,7-dimethylbicyclo [4.1.0] heptane-3-one).
  • the reaction is also known, for example as disclosed in the aforementioned article by A. Sekine et al. (Tetrahedron Letters 41 (2000) 509), performed with formaldehyde in the presence of Yb (OTf) 3 (ytterbium trifluoromethanesulfonate III).
  • the present invention further relates to the synthesis of compound 19, used in the synthesis of ingenol-5,20-acetonide, described above.
  • Compound 19 is obtained from L-serine methyl ester (N-methyl-L-serine).
  • compound 13 is reacted with DIBAL (diisobutylaluminum hydride) resulting in compound 14: 3-Boc-2,2-dimethyl-1,3-oxazolidine-4-formyl.
  • DIBAL diisobutylaluminum hydride
  • compound 13 is subjected to reduction, for example with lithium aluminum hydride or lithium borohydride, followed by oxidation, for example Swern oxidation, or via the use of a suitable bleach such as sodium or calcium hypochlorite, in the presence of catalyst TEMPO (2,2,6,6-tetramethylpiperidinyloxy, CAS No 2564-83-2), resulting compound 14.
  • TEMPO 2,2,6,6-tetramethylpiperidinyloxy, CAS No 2564-83-2
  • This step is aimed at deprotecting compound 15 to generate compound 16, which is (2S, 3S) -2-amino-1,3-dihydroxy-pent-4-yo, occurs in the presence of aqueous TFA (trifluoroacetic acid) or inorganic acids such as HCl or HBr.
  • TFA trifluoroacetic acid
  • HCl HCl
  • HBr HBr
  • Aqueous solution of compound 16 is diazotized in the presence of HBr and KBr to obtain compound 17: (2S, 3S) -2-bromo-1,3-dihydroxy-pent-4-yn.
  • the amino group is initially converted to the diazo moiety, which in turn is readily displaced by bromine anions.
  • Compound 17 is recovered by extraction in organic solvents.
  • Compound 17 is dissolved in a suitable solvent, for example mixture of acetone and 2,2-dimethoxypropane and treated with catalytic amount of sulfonic acid or BF 3 etherate, resulting in compound 18: (2S, 3S) -2-bromo-1,3 -dihydroxy-pent-4-yne acetonide.
  • a suitable solvent for example mixture of acetone and 2,2-dimethoxypropane and treated with catalytic amount of sulfonic acid or BF 3 etherate, resulting in compound 18: (2S, 3S) -2-bromo-1,3 -dihydroxy-pent-4-yne acetonide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation d'ingénol-5,20-acétonide, ainsi que l'ingénol-5,20-acétonide obtenu au moyen de ce procédé. L'invention concerne également de nouveaux composés intermédiaires pour la préparation d'ingénol-5,20-acétonide.
PCT/BR2015/050068 2015-06-03 2015-06-03 Procédé de préparation d'ingénol-5,20-acétonide, procédé de préparation de 3-éthynyl-3-hydroxy-4.7.7-triméthylbicyclo[4.1.0]heptane-2-carbaldéhyde, procédé de préparation du composé 2,2-diméthyl-4-éthynyl-5-triphénylphosphoranylidène-1,3-dioxane, et composé intermédiaire Ceased WO2016191835A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/BR2015/050068 WO2016191835A1 (fr) 2015-06-03 2015-06-03 Procédé de préparation d'ingénol-5,20-acétonide, procédé de préparation de 3-éthynyl-3-hydroxy-4.7.7-triméthylbicyclo[4.1.0]heptane-2-carbaldéhyde, procédé de préparation du composé 2,2-diméthyl-4-éthynyl-5-triphénylphosphoranylidène-1,3-dioxane, et composé intermédiaire

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/BR2015/050068 WO2016191835A1 (fr) 2015-06-03 2015-06-03 Procédé de préparation d'ingénol-5,20-acétonide, procédé de préparation de 3-éthynyl-3-hydroxy-4.7.7-triméthylbicyclo[4.1.0]heptane-2-carbaldéhyde, procédé de préparation du composé 2,2-diméthyl-4-éthynyl-5-triphénylphosphoranylidène-1,3-dioxane, et composé intermédiaire

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PCT/BR2015/050068 Ceased WO2016191835A1 (fr) 2015-06-03 2015-06-03 Procédé de préparation d'ingénol-5,20-acétonide, procédé de préparation de 3-éthynyl-3-hydroxy-4.7.7-triméthylbicyclo[4.1.0]heptane-2-carbaldéhyde, procédé de préparation du composé 2,2-diméthyl-4-éthynyl-5-triphénylphosphoranylidène-1,3-dioxane, et composé intermédiaire

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012010172A1 (fr) * 2010-07-20 2012-01-26 Leo Pharma A/S Procédé de production d'ingénol-3-angélate
WO2012085189A1 (fr) * 2010-12-22 2012-06-28 Leo Pharma A/S Ingénol-3-acylates i
WO2012083953A1 (fr) * 2010-12-22 2012-06-28 Leo Pharma A/S Ingénol-3-acylates iii et ingénol-3-carbamates
WO2014001215A2 (fr) * 2012-06-26 2014-01-03 Leo Laboratories Limited 3-o-hétéroaryl-ingénol

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012010172A1 (fr) * 2010-07-20 2012-01-26 Leo Pharma A/S Procédé de production d'ingénol-3-angélate
WO2012085189A1 (fr) * 2010-12-22 2012-06-28 Leo Pharma A/S Ingénol-3-acylates i
WO2012083953A1 (fr) * 2010-12-22 2012-06-28 Leo Pharma A/S Ingénol-3-acylates iii et ingénol-3-carbamates
WO2014001215A2 (fr) * 2012-06-26 2014-01-03 Leo Laboratories Limited 3-o-hétéroaryl-ingénol

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