WO2016191836A1 - Method for preparing ingenol-3-dodecanoate, method for preparing 3-ethynyl-3-hydroxy-4,7,7-trimethylbicyclo[4.1.0]heptane-2-carbaldehyde, and method for preparing 2,2-dimethyl-4-ethynyl-5-triphenylphosphorus anylidene-1,3-dioxane - Google Patents

Method for preparing ingenol-3-dodecanoate, method for preparing 3-ethynyl-3-hydroxy-4,7,7-trimethylbicyclo[4.1.0]heptane-2-carbaldehyde, and method for preparing 2,2-dimethyl-4-ethynyl-5-triphenylphosphorus anylidene-1,3-dioxane Download PDF

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WO2016191836A1
WO2016191836A1 PCT/BR2015/050069 BR2015050069W WO2016191836A1 WO 2016191836 A1 WO2016191836 A1 WO 2016191836A1 BR 2015050069 W BR2015050069 W BR 2015050069W WO 2016191836 A1 WO2016191836 A1 WO 2016191836A1
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compound
called
ingenol
reaction
give
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PCT/BR2015/050069
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French (fr)
Portuguese (pt)
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Luiz Francisco Pianowski
Lech W. Dudycz
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Amazônia Fitomedicamentos Ltda.
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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
    • C07C15/38—Polycyclic condensed hydrocarbons containing four rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • 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-3-dodecanoate as well as ingenol-3-dodecanoate obtained by such a process.
  • ingenol-3-dodecanoate an ingenol ester. It is a compound that has various uses in the pharmaceutical field, for example as disclosed in PCT / BR2013 / 000455. In the following text, it will also be referred to as ingenol C.
  • ingenol ester synthesis similar to the invention, of the ingenol-3-angelate compound is disclosed in patent application WO2012010172, wherein the starting compound is ingenol, reacted with acetone in the presence of p-acid. -toluenesulfonic catalyst, generating ingenol-5,20-acetonide.
  • This acetonide is then reacted with angelic anhydride, generating ingenol-5,20-acetonide-3-angelate which, dissolved in THF and aqueous HCl solution, results in ingenol-3-angelate.
  • This process is unsuitable for industrial production, mainly because 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 optimized process for obtaining ingenol-3-dodecanoate, particularly suitable for semi-industrial and industrial scale production.
  • Cryogenic conditions in the context of the following, unless otherwise noted, refer to typical temperatures between -40 ° C and -80 ° C, and use of suitable equipment and resources for this purpose.
  • the present invention aims to obtain ingenol-3-dodecanoate from the reaction between 3-ethynyl-3-hydroxy-4,7,7-trimethylbicyclo [4.1.0] heptane-2-carbaldehyde (hereinafter as compound 9) and 2 2,2-Dimethyl-4-ethynyl-5-triphenylphosphoranylidene-1,3-dioxane (hereinafter referred to as compound 19), illustrated below:
  • 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 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 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 CO atmosphere pressure.
  • a suitable catalyst for example a transition metal complex such as dicobalt octacarbonyl Co 2 (CO) 8 under CO atmosphere pressure.
  • Intermediate 2 is identified as (1R, 7S, 14S, 15R, 17R, 19R) -1-hydroxy-9,9,16,16,19-pentamethyl-8,10-dioxapentacyclo [12.5.0.0 2 , .0, 12 .0 1, 1] nonadeca-2,5,12- trien-4-one.
  • 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 e-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-4,4,11,11,14-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 from intermediate 4 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, wherein the tertiary alcohol of intermediate 5 loses the hydroxyl group, generating a carbohydration at position 2 of intermediate 6.
  • the arrows in the image of intermediate 5 above indicate the parties involved in the transformation. .
  • the reaction is catalyzed, for example, with boron trifluoride etherate, organoaluminum compounds or any other suitable one.
  • Intermediate 6 is identified as (1S, 4S, 8S, 9R, 16S, 17R, 19R, 21R) -3,11,11,18,18,21-hexamethyl-5,7,10,12-tetraoxahexacyclo [14.5. 1.0 1 .0, .0, 1 .0V] docosahexaenoic 2,14-diene-6,22-dione.
  • 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
  • inorganic base such as cesium carbonate, potassium carbonate or calcium carbonate or carboxylic acids
  • condensing agents for example carbodiimides, particularly water-soluble carbodiimides, such as (1-ethyl)
  • carbodiimides particularly water-soluble carbodiimides, such as (1-ethyl
  • the present invention further relates to the synthesis of compound 9, used as a starting material in the synthesis of ingenol-5,20-acetonide, described above. Such synthesis comprises the steps described below.
  • 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.
  • the resulting hydrogen chloride may be collected in situ by carbonate salts.
  • This step refers to the hydroxymethylation of compound 5 to give 2-hydroxymethyl-7,7-dimethylbicyclo [4.1.0] heptane-3-one (compound 6).
  • 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.
  • TMS 4-methyl-5-trimethylsilyl 7,7-dimethylbicyclo [4.1.0] -2-heptene-3-ol, a TMS enol, is prepared in a suitable solvent, such as THF, in reaction of compound 10.
  • 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 itself is known, for example as revealed 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 as a starting material 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 DI BAL (diisobutylaluminum hydride) yielding compound 14: 3-Boc-2,2-dimethyl-1,3-oxazolidine-4-formyl.
  • 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.
  • DI BAL diisobutylaluminum hydride
  • 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
  • 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

The present invention relates to a method for preparing ingenol-3-dodecanoate, and to the ingenol-3-dodecanoate obtained by this method.

Description

MÉTODO DE PREPARAÇÃO DE INGENOL-3-DODECANOATO, MÉTODO DE PREPARAÇÃO DE 3-ETINIL-3-HIDROXI-4.7.7-TRIMETILBICICLO[4.1.0]HEPTANO-2- CARBALDEÍDO E MÉTODO DE PREPARAÇÃO DE 2,2-DIMETIL-4-ETINIL-5- TRIFENILFOSFORANILIDENO-l,3-DIOXANO  INGENOL-3-DODECANOATE PREPARATION METHOD, 3-ETHINYL-3-HYDROXY-4.7.7-TRIMETHYLBICYCLE [4.1.0] HEPTAN-2- CARBALDEIDE AND PREPARATION METHOD OF PREPARATION ETINYL-5- TRIPHYLPHOSPHORANYLIDEN-1,3-DIOXAN
A presente invenção refere-se a método de preparação de ingenol-3- dodecanoato, assim como ingenol-3-dodecanoato obtida por tal processo.  The present invention relates to the method of preparing ingenol-3-dodecanoate as well as ingenol-3-dodecanoate obtained by such a process.
ANTECEDENTES DA INVENÇÃO BACKGROUND OF THE INVENTION
O composto objeto de proteção, ilustrado abaixo, é o ingenol-3-dodecanoato, um éster de ingenol. É um composto que tem vários usos na área medicamentosa, por exemplo conforme revelado em PCT/BR2013/000455. No texto que segue, será também referenciado como ingenol C.  The protective object illustrated below is ingenol-3-dodecanoate, an ingenol ester. It is a compound that has various uses in the pharmaceutical field, for example as disclosed in PCT / BR2013 / 000455. In the following text, it will also be referred to as ingenol C.
genol-3-dodecanoato Ingenol C
Figure imgf000002_0001
genol-3-dodecanoate Ingenol C
Figure imgf000002_0001
Um exemplo próximo de síntese de éster de ingenol, semelhante ao da invenção, qual seja do composto ingenol-3-angelato, é revelado no pedido de patente WO2012010172, em que o composto de partida é ingenol, reagido com acetona em presença de ácido p-toluenosulfônico catalisador, gerando ingenol-5,20-acetonida. Esta acetonida é então reagida com anidrido angélico, gerando ingenol-5,20- acetonida-3-angelato que, dissolvido em THF e solução aquosa de HCI, resulta em ingenol-3-angelato. Esse processo é inadequado para produções industriais, principalmente por não conseguir evitar uma grande perda da preciosa matéria prima ingenol na reação de obtenção de ingenol-5,20-acetonida a partir de ingenol. A close example of ingenol ester synthesis, similar to the invention, of the ingenol-3-angelate compound is disclosed in patent application WO2012010172, wherein the starting compound is ingenol, reacted with acetone in the presence of p-acid. -toluenesulfonic catalyst, generating ingenol-5,20-acetonide. This acetonide is then reacted with angelic anhydride, generating ingenol-5,20-acetonide-3-angelate which, dissolved in THF and aqueous HCl solution, results in ingenol-3-angelate. This process is unsuitable for industrial production, mainly because it cannot prevent a large loss of the precious ingenol raw material in the reaction of obtaining ingenol-5,20-acetonide from ingenol.
A presente invenção visa um processo otimizado em relação ao estado da técnica, voltado à obtenção de ingenol-3-dodecanoato, particularmente adequado à produção em escala semi-industrial e industrial. The present invention aims at a state of the art optimized process for obtaining ingenol-3-dodecanoate, particularly suitable for semi-industrial and industrial scale production.
Descrição da invenção Description of the invention
Condições criogênicas, no contexto do que segue, exceto menção em contrário, refere-se a temperaturas típicas entre -40°C e -80°C, e utilização de equipamentos e recursos adequados para esse fim.  Cryogenic conditions, in the context of the following, unless otherwise noted, refer to typical temperatures between -40 ° C and -80 ° C, and use of suitable equipment and resources for this purpose.
A presente invenção visa a obtenção de ingenol-3-dodecanoato a partir da reação entre 3-etinil-3-hidroxi-4.7.7-trimetilbiciclo[4.1.0]heptano-2-carbaldeído (a seguir referido como composto 9) e 2,2-dimetil-4-etinil-5-trifenilfosforanilideno-l,3- dioxano (a seguir referido como composto 19), ilustrados abaixo:  The present invention aims to obtain ingenol-3-dodecanoate from the reaction between 3-ethynyl-3-hydroxy-4,7,7-trimethylbicyclo [4.1.0] heptane-2-carbaldehyde (hereinafter as compound 9) and 2 2,2-Dimethyl-4-ethynyl-5-triphenylphosphoranylidene-1,3-dioxane (hereinafter referred to as compound 19), illustrated below:
Figure imgf000003_0001
Figure imgf000003_0001
A descrição a seguir ilustra o aspecto central da invenção, qual seja, as etapas de obtenção de ingenol-3-dodecanoato a partir dos compostos 9 e 19 mencionados acima. The following description illustrates the central aspect of the invention, namely the steps of obtaining ingenol-3-dodecanoate from compounds 9 and 19 mentioned above.
Mais adiante serão descritos outros aspectos da invenção, quais sejam, as sínteses de tais compostos 9 e 19 a partir de matérias primas adequadas quanto à disponibilidade comercial abundante e baixo custo, respectivamente (+) 3-careno e metil serina.  Further aspects of the invention will be described below, such as syntheses of such compounds 9 and 19 from suitable starting materials for abundant commercial availability and low cost, respectively (+) 3-carene and methyl serine.
Assim, o processo da invenção compreende as etapas descritas a seguir.  Thus, the process of the invention comprises the steps described below.
Etapa 1 COMPOSTO 9 + COMPOSTO 19 Step 1 9 + 9
Figure imgf000004_0001
Figure imgf000004_0001
Intermediário 1 Intermediate 1
A etapa 1 é uma reação de Wittig, também chamada de olefinação de Wittig, em que o composto 9, um aldeído, reage com o composto 19, um ileto de fósforo, chamado reagente de Wittig, em solução orgânica, em temperatura alta da ordem de 100°C, em presença de terc-butóxido de potássio. Obtém-se um alceno (o intermediário 1) e óxido de trifenilfosfina, a ser eliminada. A instabilidade do ileto resulta em grande prevalência de alceno - ou seja, o intermediário 1 - de configuração Z.  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 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.
O intermediário 1 é identificado como (lR,2R,3R,4R,6R)-3-ethinil-2-{l-[(4S,5Z)- Intermediate 1 is identified as (1R, 2R, 3R, 4R, 6R) -3-ethinyl-2- {1 - [(4S, 5Z) -
4-ethinil-2,2-dimetil-l,3-dioxan-5-ilideno] etil}-4.7.7-trimetilbiciclo[4.1.0]heptan-3-ol. 4-ethinyl-2,2-dimethyl-1,3-dioxan-5-ylidene] ethyl} -4.7.7-trimethylbicyclo [4.1.0] heptan-3-ol.
Figure imgf000004_0002
Figure imgf000004_0002
Intermediário 1 Intermediário 2 Intermediate 1 Intermediate 2
Esta etapa de formação de anel, uma reação de Pauson-Khand, é uma ciclo- adição [2+2+1] entre o intermediário 1 e monóxido de carbono, em presença de catalisador adequado, por exemplo um complexo de metal de transição como dicobalto octacarbonila Co2(CO)8, sob pressão de atmosfera de CO. This ring formation step, a Pauson-Khand reaction, is a addition [2 + 2 + 1] between intermediate 1 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 CO atmosphere pressure.
O intermediário 2 é identificado como (lR,7S,14S,15R,17R,19R)-l-hidroxi- 9,9,16,16,19-pentametil-8,10-dioxapentaciclo[12.5.0.02,.0,12.01,1] nonadeca-2,5,12- trien-4-ona. Intermediate 2 is identified as (1R, 7S, 14S, 15R, 17R, 19R) -1-hydroxy-9,9,16,16,19-pentamethyl-8,10-dioxapentacyclo [12.5.0.0 2 , .0, 12 .0 1, 1] nonadeca-2,5,12- trien-4-one.
Etapa 3 Step 3
Figure imgf000005_0001
Figure imgf000005_0001
Intermediário 2 Intermediário 3 Intermediate 2 Intermediate 3
Esta etapa refere-se a uma diidroxilação do intermediário 2, que pode ser feita de maneiras alternativas:  This step refers to a dihydroxylation of intermediate 2, which can be done in alternate ways:
- via uma reação de osmilação, catalisada com tetróxido de ósmio (Os04), por exemplo em solução ou suportado em um polímero; via an osmylation reaction, catalyzed with osmium tethoxide (Os0 4 ), for example in solution or supported on a polymer;
- via reação com periodato, particularmente metaperiodato, ou peroximonosulfato de potássio (por exemplo Oxone® comercializado por Dupont de Nemours), em presença de catalisador de rutênio ou cério sob condições neutras. - via reaction with periodate, particularly metaperiodate, or potassium peroxymonosulfate (eg Oxone ® marketed by Dupont de Nemours), in the presence of ruthenium or cerium catalyst under neutral conditions.
A subsequente proteção dos dióis eis, mostrada abaixo, é efetuada utilizando bis-imidazolil carbonato ou reagentes sililantes. Subsequent protection of useful diols, shown below, is performed using bisimidazolyl carbonate or silylating reagents.
Figure imgf000006_0001
Figure imgf000006_0001
Intermediário 3 Intermediário 4 Intermediate 3 Intermediate 4
O intermediário 3 é identificado como (1R,5R,6R,7R,14S,15R,17R,19R)-1,5,6- triidroxi-^^ie e^g-pentametil-S^O-dioxapentaciclotlZ.S.O.O^.O,1 2.0Ί , ^nonadeca- 2,12-dien-4-ona. Intermediate 3 is identified as (1R, 5R, 6R, 7R, 14S, 15R, 17R, 19R) -1,5,6-trihydroxy-1 H and e-g-pentamethyl-S 2 O-dioxapentacyclothiazol. O, 1 .0 2 Ί, 2.12 ^ nonadeca-dien-4-one.
O intermediário 4 é identificado como (1S,2R,9S,10R,12R,14R,15R,19R)-15- hidroxi-4,4,ll,ll,14-pentametil-3,5,20,22-tetraoxahexaciclo[14.6.0.01,1.02,.0,1.01,12] docosa-7,16-dieno-18,21-diona. Intermediate 4 is identified as (1S, 2R, 9S, 10R, 12R, 14R, 15R, 19R) -15-hydroxy-4,4,11,11,14-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.
Etapa 4  Step 4
Figure imgf000006_0002
Figure imgf000006_0002
Intermediário 4 Intermediário 5  Intermediate 4 Intermediate 5
A etapa 4 refere-se à metilação do anel ciclopentenona do intermediário 4 com um reagente de Grignard, brometo de metil magnésio, sob condições criogênicas. Esta reação transforma a cetona no carbono 2 em álcool terciário, originando o intermediário 5 de estrutura de tigliano.  Step 4 relates to methylation of the cyclopentenone ring from intermediate 4 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.
O intermediário 5 é identificado como (1S,2R,9S,10R,12R,14R,15R,18R,19S)- Intermediate 5 is identified as (1S, 2R, 9S, 10R, 12R, 14R, 15R, 18R, 19S) -
15,18-diidroxi-4,4,ll,ll,14,18-hexametil-3,5,20,22-tetraoxahexaciclo 15,18-dihydroxy-4,4,11,11,11,18-hexamethyl-3,5,20,22-tetraoxahexacyclo
[14.6.0.01,1.02,.0,1.01,12] docosa-7,16-dien-21-ona. Etapa 5 [14.6.0.0 1, 1 .0 2 .0, 1 1 .0 12] docosahexaenoic 7,16-dien-21-one. Step 5
Figure imgf000007_0001
Figure imgf000007_0001
Intermediário 5 Intermediário 6 Intermediate 5 Intermediate 6
A etapa 5 é um rearranjo de pinacol, em que o álcool terciário do intermediário 5 perde o grupo hidroxila, gerando uma carbo-cátion na posição 2, de um intermediário 6. As setas na imagem do intermediário 5 acima indicam as partes envolvidas na transformação. A reação é catalisada, por exemplo, com eterato de trifluoreto de boro, compostos de organoalumínio ou qualquer outro adequado.  Step 5 is a pinacol rearrangement, wherein the tertiary alcohol of intermediate 5 loses the hydroxyl group, generating a carbohydration at position 2 of intermediate 6. The arrows in the image of intermediate 5 above indicate the parties involved in the transformation. . The reaction is catalyzed, for example, with boron trifluoride etherate, organoaluminum compounds or any other suitable one.
O intermediário 6 é identificado como (1S,4S,8S,9R,16S,17R,19R,21R)- 3,ll,ll,18,18,21-hexametil-5,7,10,12-tetraoxahexaciclo[14.5.1.01,.0,.0,1.0V]docosa- 2,14-dieno-6,22-diona. Intermediate 6 is identified as (1S, 4S, 8S, 9R, 16S, 17R, 19R, 21R) -3,11,11,18,18,21-hexamethyl-5,7,10,12-tetraoxahexacyclo [14.5. 1.0 1 .0, .0, 1 .0V] docosahexaenoic 2,14-diene-6,22-dione.
Etapa 6 Step 6
Trata-se da remoção da proteção aos dióis eis, introduzida na etapa 3, por qualquer meio adequado, por exemplo empregando-se uma base, TBAF (fluoreto de tetrabutilamônio) ou hidrofluoreto de piridínio.  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.
Figure imgf000007_0002
Intermediário 6 ingenol-5,20-acetonida
Figure imgf000007_0002
Intermediate 6 ingenol-5,20-acetonide
Etapa 7 Step 7
Esterificação da ingenol-5,20-acetonida com ácido dodecanóico ou seu anidrido, em solvente adequado, por exemplo acetonitrila, tolueno ou diclorometano. Resulta o composto 20-isopropilideno-ingenol-3-dodecanoato:  Esterification of ingenol-5,20-acetonide with dodecanoic acid or its anhydride in a suitable solvent, for example acetonitrile, toluene or dichloromethane. The compound 20-isopropylidene-ingenol-3-dodecanoate results:
Figure imgf000008_0001
Figure imgf000008_0001
É vantajosa, nessa etapa, a presença de base inorgânica como carbonato de césio, carbonato de potássio ou carbonato de cálcio ou de ácidos carboxílicos em presença de agentes de condensação, por exemplo carbodiimidas, particularmente carbodiimidas solúveis em água, tal como (l-etil-3-(3-dimetil aminopropil) carbodiimida). The presence of inorganic base such as cesium carbonate, potassium carbonate or calcium carbonate or carboxylic acids in the presence of condensing agents, for example carbodiimides, particularly water-soluble carbodiimides, such as (1-ethyl), is advantageous at this stage. -3- (3-dimethyl aminopropyl) carbodiimide).
Etapa 8  Step 8
Remoção seletiva dos grupos protetores das posições 5 e 20 do núcleo ingenol, em solução ácida, por exemplo com HCI, diluída em solventes orgânicos, como metanol, na presença de pequenas quantidades de água. Resulta o ingenol C.  Selective removal of the protecting groups of positions 5 and 20 from the ingenol nucleus in acid solution, for example with HCl, diluted in organic solvents such as methanol in the presence of small amounts of water. Ingenol C results.
Obtenção do Composto 9 Obtaining Compound 9
A presente invenção refere-se adicionalmente à síntese do composto 9, utilizado como material de partida na síntese de ingenol-5,20-acetonida, já descrita mais atrás. Tal síntese compreende as etapas descritas a seguir.  The present invention further relates to the synthesis of compound 9, used as a starting material in the synthesis of ingenol-5,20-acetonide, described above. Such synthesis comprises the steps described below.
Etapa IA
Figure imgf000008_0002
Composto 1 Composto 2IA stage
Figure imgf000008_0002
Compound 1 Compound 2
Trata-se de uma etapa de cloração do (+)-3- careno (composto 1), obtendo-se trans-4-cloro-3-careno (composto 2). A reação desta etapa é em si conhecida, por exemplo descrita em Polish J. Chem. 74, 777, 2000, utilizando catalisador de radicais livres, como N-cloro-succinamida (NCS) em presença de base, sob atmosfera de argônio. This is a chlorination step for (+) -3-carene (compound 1) to give trans-4-chloro-3-carene (compound 2). 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.
A base do catalisador pode ser l,4-diazabiciclo[2.2.2]octano (como o produto comercial DABCO®, da empresa Air Products), DMAP (4-dimetilaminopiridina), ou sílica gel. 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.
Etapa 2A
Figure imgf000009_0001
Step 2A
Figure imgf000009_0001
Composto 2 Composto 3 Compound 2 Compound 3
Nesta etapa, para obtenção do composto 3, 4-cloro-7,7- dimetilbiciclo[4.1.0]heptano-3-ona), faz-se a ozonólise do composto 2, em solvente adequado, particularmente acetona aquosa, sob resfriamento.  In this step, to obtain compound 3,4-chloro-7,7-dimethylbicyclo [4.1.0] heptane-3-one), compound 2 is ozonolysis in a suitable solvent, particularly aqueous acetone, under cooling.
Eventuais peróxidos residuais são reagidos com dimetilsulfeto antes da remoção da acetona.  Possible residual peroxides are reacted with dimethyl sulfide prior to acetone removal.
Etapa 3A  Step 3A
Figure imgf000009_0002
Figure imgf000009_0002
Composto 3 Composto 4 Compound 3 Compound 4
Esta etapa é uma descloração catalítica redutiva. O composto 4 (7,7- dimetilbiciclo[4.1.0]heptano-3-ona) é obtido por hidrogenólise catalítica do composto 3, empregando-se catalisador adequado, por exemplo de paládio, sob pressão. O cloreto de hidrogénio resultante pode ser recolhido in situ por sais de carbonato. Etapa 4A 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. The resulting hydrogen chloride may be collected in situ by carbonate salts. Step 4A
Figure imgf000010_0001
Figure imgf000010_0001
Composto 4 Composto 5 Compound 4 Compound 5
A reação de obtenção do composto 5 (trimetilsilil 7,7-dimetilbiciclo[4.1.0]2- hepteno-3-ol) a partir do composto 4 é, em sua generalidade, conhecida do estado da técnica, por exemplo o artigo de A. Sekine et al. (Tetrahedron Letters 41 (2000) 509), utilizando cloreto de TMS (trimetilsilila) e lítio bis(trimetilsilil)amida (LiHMDS ) em tetraidrofurano (THF) em condições criogênicas, em temperatura da ordem de -78° C. Etapa 5A  The reaction of obtaining compound 5 (trimethylsilyl 7,7-dimethylbicyclo [4.1.0] 2-hepten-3-ol) from compound 4 is generally known in the art, for example the article in A Sekine et al. (Tetrahedron Letters 41 (2000) 509) using TMS (trimethylsilyl) and lithium bis (trimethylsilyl) amide (LiHMDS) chloride in tetrahydrofuran (THF) under cryogenic conditions at a temperature of -78 ° C. Step 5A
Figure imgf000010_0002
Figure imgf000010_0002
Composto 5 Composto 6 Compound 5 Compound 6
Esta etapa refere-se à hidroximetilação do composto 5 para gerar 2- hidroximetil-7,7-dimetilbiciclo[4.1.0]heptano-3-ona (composto 6). A reação é também conhecida, por exemplo como revelado no artigo já mencionado de A. Sekine et al. (Tetrahedron Letters 41 (2000) 509), realizada com formaldeído em presença de Yb(OTf)3 (trifluorometanosulfonato de itérbio III).  This step refers to the hydroxymethylation of compound 5 to give 2-hydroxymethyl-7,7-dimethylbicyclo [4.1.0] heptane-3-one (compound 6). 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).
Etapa 6 A Step 6 A
Figure imgf000011_0001
Figure imgf000011_0001
Composto 6 Composto 7 Compound 6 Compound 7
O composto 7 (2-hidroximetil-4.7.7-trimetilbiciclo[4.1.0]heptano-3-ona) é obtido por metilação do composto 6, iniciada com a reação de proteção transitória do composto 6 com cloreto de trimetilsilila (TMS), formação de TMS enol, litiação do enol com metil lítio, e subsequente reação em um vaso com metil iodato em condições criogênicas, em temperatura da ordem de -78°C.  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.
Etapa 7 A Step 7 A
Figure imgf000011_0002
Figure imgf000011_0002
Composto 7 Composto 8 Compound 7 Compound 8
O composto 8 (3-etinil-2-hiydroximetil-4.7.7-trimetilbiciclo [4.1.0] heptano-3-ol) é obtido reagindo-se o composto 7 com excesso de brometo de etinilmagnésio em solvente como THF em condições criogênicas, em temperatura da ordem de -78 C. Etapa 8 A  Compound 8 (3-ethynyl-2-hydroxymethyl-4,7,7-trimethylbicyclo [4.1.0] heptane-3-ol) is obtained by reacting compound 7 with excess ethinylmagnesium bromide in solvent as THF under cryogenic conditions, at -78 ° C. Step 8 A
Figure imgf000011_0003
Figure imgf000011_0003
Composto 8 Composto 9 Compound 8 Compound 9
A obtenção do composto 9 ocorre pela reação do composto 8 com 1,1,1- triacetoxi-l,l-diidro-l,2-benziodoxol-3(lH)-ona, o reagente de Dess-Martin periodinano. 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.
Síntese Alternativa do Composto 9  Alternative Synthesis of Compound 9
De forma alternativa, as etapas 3A, 4A, 5A e 6A acima descritas podem ser substituídas pelas etapas 3AA, 4AA e 5AA, descritas a seguir.  Alternatively, steps 3A, 4A, 5A and 6A described above may be replaced by steps 3AA, 4AA and 5AA described below.
Etapa 3AA Step 3AA
Figure imgf000012_0001
Figure imgf000012_0001
Composto 3 Composto 10Compound 3 Compound 10
O composto 3 é transformado em reagente de Grignard utilizando-se magnésio, seguindo-se reação com iodeto de metila, com ou sem catalisador, por exemplo NiBr2 ou CuCI2, dando origem ao composto 10, que é 4-metil-7,7- dimetilbiciclo[4.1.0]heptano-3-ona. 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.
Etapa 4AA Step 4AA
Figure imgf000012_0002
Composto 10 Composto 11
Figure imgf000012_0002
Compound 10 Compound 11
O composto 11, qual seja 4-metil-5-trimetilsilil 7,7-dimetilbiciclo[4.1.0]-2- hepteno-3-ol, um TMS enol, é preparado em solvente adequado, como THF, em reação do composto 10 com cloreto de TMS e lítio bis(trimetilsilil)amida (LiHDMS) em condições criogênicas, em temperatura da ordem de -78°C. Compound 11, which is 4-methyl-5-trimethylsilyl 7,7-dimethylbicyclo [4.1.0] -2-heptene-3-ol, a TMS enol, is prepared in a suitable solvent, such as THF, in reaction of compound 10. TMS with lithium bis (trimethylsilyl) amide chloride (LiHDMS) under cryogenic conditions at a temperature of -78 ° C.
Etapa 5AA Step 5AA
Figure imgf000013_0001
Figure imgf000013_0001
Composto 11 Composto 7 Compound 11 Compound 7
Esta etapa refere-se à hidroximetilação do composto 11 para gerar o composto 7 (2-hidroximetil-7,7-dimetilbiciclo[4.1.0]heptano-3-ona). A reação em si é conhecida, por exemplo como revelado no artigo já mencionado de A. Sekine et al. (Tetrahedron Letters 41 (2000) 509), realizada com formaldeído em presença de Yb(OTf)3 (trifluorometanosulfonato de itérbio III).  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 itself is known, for example as revealed 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).
Obtenção do Composto 19 Obtaining Compound 19
A presente invenção refere-se adicionalmente à síntese do composto 19, utilizado como material de partida na síntese de ingenol-5,20-acetonida, já descrita mais atrás.  The present invention further relates to the synthesis of compound 19, used as a starting material in the synthesis of ingenol-5,20-acetonide, described above.
A obtenção do composto 19 se dá a partir do éster metílico de L-serina (N- metil-L-serina).  Compound 19 is obtained from L-serine methyl ester (N-methyl-L-serine).
Obs: BoC = terc-butoxi carbonila  Note: BoC = tert-butoxy carbonyl
Etapa 1B Step 1B
Figure imgf000013_0002
Figure imgf000013_0002
Composto 12 Composto 13Compound 12 Compound 13
Reação do éster metílico de L-serina, denominado composto 12, com anidrido de terc-butoxi carbonila em presença de trietilamina, resultando éster metílico de Boc- L-serina, o qual, em solvente adequado, como acetona, é reagido com 2,2- dimetoxipropano em presença de quantidade catalítica de trifluoreto de boro eterato, resultando o composto 13: 3-Boc-2,2-dimetil-l,3-oxazolidina-4-carboxilato Reaction of L-serine methyl ester, named compound 12, with tert-butoxycarbonyl anhydride in the presence of triethylamine, resulting in Boc-L-serine methyl ester which, in suitable solvent, such as acetone, is reacted with 2, 2- dimethoxypropane in the presence of catalytic amount of boron trifluoride etherate resulting 13: 3-Boc-2,2-dimethyl-1,3-oxazolidine-4-carboxylate
Etapa 2B Step 2B
Figure imgf000014_0001
Composto 13 Composto 14
Figure imgf000014_0001
Compound 13 Compound 14
O composto 13 é reagido com DI BAL (hidreto de diisobutilalumínio) resultando o composto 14: 3-Boc-2,2-dimetil-l,3-oxazolidina-4-formila. Alternativamente, submete-se o composto 13 a uma redução, por exemplo com hidreto de lítio alumínio ou boroidreto de lítio, seguida de oxidação, por exemplo uma oxidação de Swern, ou via uso de um alvejante adequado, como hipoclorito de sódio ou cálcio, em presença de catalisador TEMPO (2,2,6,6-tetrametilpiperidiniloxi, número CAS 2564-83-2 ), resultando o composto 14. Compound 13 is reacted with DI BAL (diisobutylaluminum hydride) yielding compound 14: 3-Boc-2,2-dimethyl-1,3-oxazolidine-4-formyl. Alternatively, 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.
Etapa 3B Step 3B
Figure imgf000014_0002
Composto 14 Composto 15
Figure imgf000014_0002
Compound 14 Compound 15
Reação do composto 14 com brometo de magnésio acetileno ou lítio acetilida em meio solvente adequado, por exemplo THF ou etil éter, preferivelmente conduzida sob condições criogênicas. Resulta um composto 15 : Boc-(2S,3S)-2-Amino-l,3-diidroxi- pent-4-ina 1,2-acetal. Etapa 4B Reaction of compound 14 with magnesium acetylene bromide or lithium acetylide in a suitable solvent medium, for example THF or ethyl ether, preferably conducted under cryogenic conditions. A compound 15 is obtained: Boc- (2S, 3S) -2-Amino-1,3-dihydroxypent-4-one 1,2-acetal. Step 4B
Figure imgf000015_0001
Figure imgf000015_0001
Composto 15 Composto 16Compound 15 Compound 16
Esta etapa visa a desproteção do composto 15, para gerar o composto 16, qual seja (2S,3S)-2-amino-l,3-dihidroxi-pent-4-ino, ocorre em presença de TFA (ácido trifluoroacético) aquoso ou ácidos inorgânicos como HCI ou HBr. O material em solução aquosa é utilizado diretamente na próxima etapa. 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. The aqueous solution material is used directly in the next step.
Etapa 5B Step 5B
Figure imgf000015_0002
Figure imgf000015_0002
Composto 16 Composto 17 Compound 16 Compound 17
Para obter o composto 17, (2S,3S)-2-Bromo-l,3-diidróxi-pent-4-ino, a solução aquosa do composto 16 é diazotizada em presença de HBr e KBr. O grupo amino é convertido inicialmente à fração diazo, que por sua vez é prontamente deslocada por ânions bromo. O produto é recuperado por extração em solventes orgânicos. To obtain compound 17, (2S, 3S) -2-Bromo-1,3-dihydroxy-pent-4-yn, the aqueous solution of compound 16 is diazotized in the presence of HBr and KBr. The amino group is initially converted to the diazo moiety, which in turn is readily displaced by bromine anions. The product is recovered by extraction in organic solvents.
Etapa 6B Step 6B
Figure imgf000015_0003
Composto 17 Composto 18
Figure imgf000015_0003
Compound 17 Compound 18
O composto 17 é dissolvido em solvente adequado, por exemplo mistura de acetona e 2,2-dimetóxipropano e tratado com quantidade catalítica de ácido sulfônico ou BF3 eterato, resultando um composto 18: (2S,3S)-2-bromo-l,3-diidróxi-pent-4-ino acetonida. 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.
Etapa 7B Step 7B
Figure imgf000016_0001
Figure imgf000016_0001
Composto 18 Composto 19Compound 18 Compound 19
Nesta etapa, para chegar ao composto 19 na sua forma ileto, após proteção do acetileno com TMS, o composto 18 é reagido com trifenilfosfina para formar o sal trifenilfosfônio. Para formar o reagente de Wittig, o sal fosfônio é suspenso em solvente adequado, como dietil éter ou THF e tratado com base forte, por exemplo terc-butóxido de potássio, butil-lítio ou fenil-lítio. In this step, to reach compound 19 in its ylide form, after protection of acetylene with TMS, compound 18 is reacted with triphenylphosphine to form the triphenylphosphonium salt. To form Wittig's reagent, the phosphonium salt is suspended in a suitable solvent such as diethyl ether or THF and treated with a strong base, for example potassium tert-butoxide, butyl lithium or phenyl lithium.
O homem da técnica, a partir dos ensinamentos aqui contidos, saberá propor realizações de maneira não expressamente descritas, mas com função e resultado da mesma natureza em cada etapa, estando assim tais realizações englobadas pelas reivindicações anexas  The person skilled in the art, from the teachings herein, will be able to propose embodiments not expressly described, but of similar function and outcome at each stage, and such embodiments are encompassed by the appended claims.

Claims

REIVINDICAÇÕES
1. Método de preparação de ingenol-3-dodecanoato caracterizado pelo fato de compreender as seguintes etapas:  1. Method of preparation of ingenol-3-dodecanoate comprising the following steps:
- etapa 1: reagir um composto de estrutura uímica abaixo  - step 1: react a compound of chemical structure below
Figure imgf000017_0001
denominado composto 9, com um composto de estrutura química abaixo
Figure imgf000017_0001
compound 9, with a chemical structure compound below
Figure imgf000017_0002
denominado composto 19, em solução orgânica, em temperatura alta da ordem de 100°C, em presença de terc-butóxido de potássio, obtendo-se um composto conforme estrutura química abaixo
Figure imgf000017_0002
compound 19, in an organic solution, at a high temperature of the order of 100 ° C, in the presence of potassium tert-butoxide, obtaining a compound according to the chemical structure below.
Figure imgf000017_0003
denominado intermediário 1;
Figure imgf000017_0003
called intermediate 1;
- etapa 2: reagir o intermediário 1 com monóxido de carbono em presença de catalisador da reação de Pauson-Khand, obtendo-se um composto conforme estrutura abaixo  - step 2: reacting intermediate 1 with carbon monoxide in the presence of Pauson-Khand reaction catalyst to obtain a compound according to the structure below.
Figure imgf000018_0001
denominado intermediário 2;
Figure imgf000018_0001
called intermediate 2;
- etapa 3: efetuar um diidroxilação do intermediário 2, seja via reação de osmilação catalisada com tetróxido de ósmio (Os04) em solução ou suportado em um polímero, seja via reação com periodato, ou peroximonosulfato de potássio, em presença de catalisador de rutênio ou cério, obtendo-se um composto conforme estrutura química abaixo - step 3: perform a dihydroxylation of intermediate 2, either via osmillation catalyzed reaction with osmium tethoxide (Os0 4 ) in solution or supported on a polymer, either via reaction with periodate or potassium peroxymonosulfate in the presence of ruthenium catalyst or cerium, obtaining a compound according to the chemical structure below
Figure imgf000018_0002
denominado intermediário 3, que é então reagido com bis-imidazolil carbonado ou reagentes sililantes, obtendo-se um composto conforme estrutura química abaixo
Figure imgf000018_0002
intermediate 3, which is then reacted with carbon bis-imidazolyl or silylating reagents to give a compound according to the chemical structure below.
Figure imgf000019_0001
denominado intermediário 4;
Figure imgf000019_0001
called intermediate 4;
- etapa 4: reagir o intermediário 4 com reagente de Grignard, particularmente brometo de metil magnésio, sob condições criogênicas, obtendo-se um composto conforme estrutura química abaixo  - step 4: reacting intermediate 4 with Grignard reagent, particularly methyl magnesium bromide, under cryogenic conditions, yielding a compound according to the chemical structure below.
Figure imgf000019_0002
denominado intermediário 5;
Figure imgf000019_0002
called intermediate 5;
- etapa 5: conduzir um rearranjo de pinacol do composto 5, em presença de catalisador adequado, particularmente eterato de trifluoreto de boro ou compostos de organoalumínio, dando origem a um composto conforme estrutura química abaixo Step 5: Conduct a pinacol rearrangement of compound 5 in the presence of a suitable catalyst, particularly boron trifluoride etherate or organoaluminium compounds, to give a compound according to the chemical structure below.
Figure imgf000020_0001
denominado intermediário 6;
Figure imgf000020_0001
called intermediate 6;
- etapa 6: remover a proteção aos dióis eis introduzido na etapa 3, reagindo-se o intermediário 6 com meio adequado, particularmente uma base, TBAF ou hidrofluoreto de piridínio, dando origem ao composto ingenol-5,20-acetonida  - step 6: remove the diols protection introduced in step 3 by reacting intermediate 6 with a suitable medium, particularly a base, TBAF or pyridinium hydrofluoride to give the compound ingenol-5,20-acetonide.
Figure imgf000020_0002
ingenol-5,20-acetonida
Figure imgf000020_0002
ingenol-5,20-acetonide
- etapa 7 - esterificação da ingenol-5,20-acetonida com ácido dodecanoico ou anidrido dodecanoico, em solvente adequado, particularmente acetonitrila, tolueno ou diclorometano, resultando o composto 20-isopropilideno-ingenol-3-dodecanoato step 7 - esterification of ingenol-5,20-acetonide with dodecanoic acid or dodecanoic anhydride in a suitable solvent, particularly acetonitrile, toluene or dichloromethane, resulting in 20-isopropylidene-ingenol-3-dodecanoate compound
Figure imgf000021_0001
Figure imgf000021_0001
- etapa 8 - remoção seletiva dos grupos protetores das posições 5 e 20 do composto 20-isopropilideno-ingenol-3-dodecanoato, em solução ácida, particularmente com HCI, diluída em solventes orgânicos, particularmente metanol, na presença de pequena quantidade de água, resultando o ingenol-3-dodecanoato. - step 8 - selective removal of the protecting groups of positions 5 and 20 of compound 20-isopropylidene-ingenol-3-dodecanoate in acidic solution, particularly with HCl, diluted in organic solvents, particularly methanol, in the presence of small amount of water, resulting ingenol-3-dodecanoate.
2. Método de preparação de ingenol-3-dodecanoato de acordo com a reivindicação 1, caracterizado pelo fato de utilizar, na dita etapa 7, base inorgânica, particularmente carbonato de césio, carbonato de potássio ou carbonato de cálcio ou de ácidos carboxílicos, em presença de agente de condensação, particularmente carbodiimida, mais particularmente carbodiimida solúvel em água, opcionalmente (l-etil-3-(3-dimetil aminopropil) carbodiimida).  Method for preparing ingenol-3-dodecanoate according to claim 1, characterized in that, in said step 7, it uses inorganic base, particularly cesium carbonate, potassium carbonate or calcium carbonate, or carboxylic acids in presence of condensing agent, particularly carbodiimide, more particularly water soluble carbodiimide, optionally (1-ethyl-3- (3-dimethyl aminopropyl) carbodiimide).
3. Método de preparação de 3-etinil-3-hidroxi-4.7.7- trimetilbiciclo[4.1.0]heptano-2-carbaldeído caracterizado pelo fato de compreender as seguintes etapas :  3. Method of preparation of 3-ethynyl-3-hydroxy-4,7,7-trimethylbicyclo [4.1.0] heptane-2-carbaldehyde comprising the following steps:
- etapa IA - cloração de um composto 1: (+)-3- careno, denominado composto 1  - step IA - chlorination of compound 1: (+) - 3-carene called compound 1
Figure imgf000021_0002
Figure imgf000021_0002
composto 1 utilizando catalisador de radicais livres, particularmente N-cloro-succinamida (NCS) em presença de base, sob atmosfera de argônio, tendo como base do catalisador 1,4- diazabiciclo[2.2.2]octano, DMAP ou sílica gel, obtendo-se trans-4-cloro-3-careno, denominado composto 2
Figure imgf000022_0001
compound 1 using free radical catalyst, particularly N-chloro-succinamide (NCS) in the presence of base, under argon atmosphere, based on the catalyst 1,4-diazabicyclo [2.2.2] octane, DMAP or silica gel. trans-4-chloro-3-carene called compound 2
Figure imgf000022_0001
composto 2 compound 2
- etapa 2A - ozonólise do composto 2 em solvente adequado, particularmente acetona aquosa, sob resfriamento, obtendo-se 4-cloro-7,7-dimetilbiciclo [4.1.0]heptano-3-ona), denominado composto 3
Figure imgf000022_0002
composto 3 - step 2A - ozonolysis of compound 2 in a suitable solvent, particularly aqueous acetone, under cooling to give 4-chloro-7,7-dimethylbicyclo [4.1.0] heptane-3-one) called compound 3
Figure imgf000022_0002
compound 3
- etapa 3A - hidrogenólise catalítica do composto 3, empregando-se catalisador adequado, particularmente paládio, sob pressão, obtendo-se 7,7- dimetilbiciclo[4.1.0]heptano-3-ona, denominado composto 4
Figure imgf000022_0003
composto 4 - Step 3A - Catalytic hydrogenolysis of compound 3, using suitable catalyst, particularly palladium, under pressure to give 7,7-dimethylbicyclo [4.1.0] heptane-3-one, called compound 4.
Figure imgf000022_0003
compound 4
- etapa 4A - reação do composto 4 com cloreto de TMS (trimetilsilila) e lítio bis(trimetilsilil)amida (LiHMDS ) em tetraidrofurano (THF) em condições criogênicas, obtendo-se um composto 5: trimetilsilil 7,7-dimetilbiciclo[4.1.0]2-hepteno-3-ol - Step 4A - Reaction of compound 4 with TMS (trimethylsilyl) and lithium bis (trimethylsilyl) amide (LiHMDS) chloride in tetrahydrofuran (THF) to cryogenic conditions affords compound 5: trimethylsilyl 7,7-dimethylbicyclo [4.1. 0] 2-heptene-3-ol
Figure imgf000023_0001
composto 5
Figure imgf000023_0001
compound 5
- etapa 5A - hidroximetilação do composto 5, em formaldeído, em presença de Yb(OTf)3 (trifluorometanosulfonato de itérbio III), obtendo-se 2-hidroximetil-7,7- dimetilbiciclo[4.1.0]heptano-3-ona, denominado composto 6 - step 5A - hydroxymethylation of compound 5 in formaldehyde in the presence of Yb (OTf) 3 (ytterbium trifluoromethanesulfonate III) to give 2-hydroxymethyl-7,7-dimethylbicyclo [4.1.0] heptane-3-one, called compound 6
Figure imgf000023_0002
composto 6
Figure imgf000023_0002
compound 6
- etapa 6A - metilação do composto 6, iniciada com a reação de proteção transitória do composto 6 com cloreto de trimetilsilila (TMS), formando-se um TMS enol, que é submetido a litiação com metil lítio, e subsequente reação em um vaso com metil iodato em condições criogênicas, obtendo-se 2-hidroximetil-4.7.7- trimetilbiciclo[4.1.0]heptano-3-ona, denominado composto 7 - step 6A - methylation of compound 6, initiated by the transient protective reaction of compound 6 with trimethylsilyl chloride (TMS), forming an enol TMS, which is subjected to lithium with lithium, and subsequent reaction in a pot with methyl iodate under cryogenic conditions to give 2-hydroxymethyl-4,7,7-trimethylbicyclo [4.1.0] heptane-3-one, called compound 7
Figure imgf000023_0003
composto 7
Figure imgf000023_0003
compound 7
- etapa 7A - reação do composto 7 com excesso de brometo de etinilmagnésio em solvente adequado, particularmente THF, em condições criogênicas, obtendo-se 3- etinil-2-hiyd roximetil-4.7.7-trimetilbiciclo [4.1.0] heptano-3-ol, denominado composto 8 - Step 7A - Reaction of compound 7 with excess ethinylmagnesium bromide in a suitable solvent, particularly THF under cryogenic conditions, yielding 3-ethinyl-2-hiyd roximethyl-4,7.7-trimethylbicyclo [4.1.0] heptane-3 -ol, called compound 8th
Figure imgf000024_0001
composto 8
Figure imgf000024_0001
compound 8
- etapa 8A - reação do composto 8 com l,l,l-triacetoxi-l,l-diidro-l,2-benziodoxol- 3(lH)-ona, reagente de Dess-Martin periodinano, obtendo-se etinil-3-hidroxi-4.7.7- trimetilbiciclo[4.1.0]heptano-2-carbaldeído, denominado composto 9  - Step 8A - Reaction of compound 8 with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one, Dess-Martin periodinane reagent to give ethinyl-3- hydroxy-4.7.7-trimethylbicyclo [4.1.0] heptane-2-carbaldehyde, called compound 9
Figure imgf000024_0002
Figure imgf000024_0002
Composto 9 9
4. Método de preparação de 3-etinil-3-hidroxi-4.7.7- trimetilbiciclo[4.1.0]heptano-2-carbaldeído, de acordo com a reivindicação 3 , caracterizado pelo fato de que as ditas etapas 3A, 4A, 5A e 6A são substituídas pelas etapas 3 A A, 4AA e 5 A A, que são:  Method of preparing 3-ethynyl-3-hydroxy-4,7,7-trimethylbicyclo [4.1.0] heptane-2-carbaldehyde according to claim 3, characterized in that said steps 3A, 4A, 5A and 6A are replaced by steps 3 AA, 4AA, and 5 AA, which are:
- etapa 3AA - reage-se o composto 3 com magnésio, gerando-se um reagente de Grignard, seguindo-se reação com iodeto de metila, com ou sem catalisador, particularmente NiBr2 ou CuCI2, obtendo-se 4-metil-7,7-dimetilbiciclo[4.1.0]heptano-3- ona, denominado composto 10 - Step 3AA - Compound 3 is reacted with magnesium, generating a Grignard reagent, followed by reaction with methyl iodide, with or without catalyst, particularly NiBr 2 or CuCl 2 , yielding 4-methyl-7. 7-dimethylbicyclo [4.1.0] heptane-3-one, called compound 10
Figure imgf000024_0003
composto 10
Figure imgf000024_0003
compound 10
- etapa 4AA - o composto 10 é reagido em solvente adequado, particularmente THF, com cloreto de TMS e lítio bis(trimetilsilil)amida (LiHDMS), em condições criogênicas, obtendo-se 4-metil-5-trimetilsilil 7,7-dimetilbiciclo[4.1.0]-2-hepteno-3-ol, denominado composto 11  - Step 4AA - Compound 10 is reacted in a suitable solvent, particularly THF, with TMS and lithium bis (trimethylsilyl) amide chloride (LiHDMS) under cryogenic conditions to give 4-methyl-5-trimethylsilyl 7,7-dimethylbicyclo. [4.1.0] -2-heptene-3-ol, called compound 11
Figure imgf000025_0001
composto 11
Figure imgf000025_0001
compound 11
- etapa 5AA - reação de hidroximetilação do composto 11 com formaldeído em presença de Yb(OTf)3, resultando o composto 7  - step 5AA - hydroxymethylation reaction of compound 11 with formaldehyde in the presence of Yb (OTf) 3, resulting compound 7
Figure imgf000025_0002
composto 7
Figure imgf000025_0002
compound 7
5. Método de preparação de 2,2-dimetil-4-etinil-5-trifenilfosforanilideno-l,3- dioxano, caracterizado por compreender as seguintes etapas:  Method for the preparation of 2,2-dimethyl-4-ethynyl-5-triphenylphosphoranylidene-1,3-dioxane, comprising the following steps:
- etapa 1B - reação do éster metílico de L-serina (composto 12) com anidrido de terc- butoxi carbonila em presença de trietilamina, resultando éster metílico de Boc-L- serina, o qual, em solvente adequado, particularmente acetona, é reagido com 2,2- dimetoxipropano em presença de quantidade catalítica de trifluoreto de boro eterato resultando em 3-Boc-2,2-dimetil-l,3-oxazolidina-4-carboxilato, denominado composto 13
Figure imgf000026_0001
- Step 1B - Reaction of L-serine methyl ester (compound 12) with tert-butoxycarbonyl anhydride in the presence of triethylamine, resulting in Boc-L-serine methyl ester which, in a suitable solvent, particularly acetone, is reacted. with 2,2-dimethoxypropane in the presence of catalytic amount of boron trifluoride etherate resulting in 3-Boc-2,2-dimethyl-1,3-oxazolidine-4-carboxylate called compound 13
Figure imgf000026_0001
Composto 13 13
- etapa 2B - reação do composto 13 com DIBAL (hidreto de diisobutilalumínio) resultando 3-Boc-2,2-dimetil-l,3-oxazolidina-4-formila, denominado compostol4, ou submete-se o composto 13 a uma redução, particularmente com hidreto de lítio alumínio ou boroidreto de lítio, seguida de oxidação, particularmente uma oxidação de Swern, ou via uso de um alvejante adequado, particularmente hipoclorito de sódio ou cálcio, em presença de catalisador TEMPO, resultando o composto 14  - step 2B - reacting compound 13 with DIBAL (diisobutyl aluminum hydride) resulting in 3-Boc-2,2-dimethyl-1,3-oxazolidine-4-formyl, called compostol4, or subjecting compound 13 to a reduction, particularly with lithium aluminum hydride or lithium borohydride, followed by oxidation, particularly a Swern oxidation, or via the use of a suitable bleach, particularly sodium or calcium hypochlorite, in the presence of TEMPO catalyst, resulting compound 14.
Figure imgf000026_0002
composto 14
Figure imgf000026_0002
compound 14
- etapa 3B - reação do composto 14 com brometo de magnésio acetileno ou lítio acetilida em meio solvente adequado, particularmente THF ou etil éter, obtendo-se Boc-(2S,3S)-2-Amino-l,3-diidroxi-pent-4-ina 1,2-acetal, denominado composto 15  - Step 3B - Reaction of compound 14 with magnesium acetylene bromide or lithium acetylide in a suitable solvent medium, particularly THF or ethyl ether to give Boc- (2S, 3S) -2-Amino-1,3-dihydroxypentyl 4-Aine 1,2-acetal, called compound 15
Figure imgf000026_0003
composto 15
Figure imgf000026_0003
compound 15
- etapa 4B - submeter o composto 15 a um meio ácido adequado, particularmente TFA (ácido trifluoroacético) aquoso ou ácidos inorgânicos como HCI ou HBr, obtendo-se (2S,3S)-2-amino-l,3-dihidroxi-pent-4-ino, denominado composto 16 - step 4B - subjecting compound 15 to a suitable acid medium, particularly TFA (trifluoroacetic acid) aqueous or inorganic acids such as HCl or HBr to give (2S, 3S) -2-amino-1,3-dihydroxy-pent-4-yne, called compound 16
Figure imgf000027_0001
composto 16
Figure imgf000027_0001
compound 16
- etapa 5B - diazotização do composto 16 em presença de HBr e KBr, obtendo-se (2S,3S)-2-Bromo-l,3-diidróxi-pent-4-ino, denominado composto 17  - step 5B - diazotization of compound 16 in the presence of HBr and KBr to give (2S, 3S) -2-Bromo-1,3-dihydroxy-pent-4-yn called compound 17
Figure imgf000027_0002
Figure imgf000027_0002
OH  OH
composto 17 compound 17
- etapa 6B - dissolução do composto 17 em solvente adequado, particularmente mistura de acetona e 2,2-dimetóxipropano e tratamento com quantidade catalítica de ácido sulfônico ou BF3 eterato, obtendo-se (2S,3S)-2-bromo-l,3-diidróxi-pent-4-ino acetonida, denominado composto 18 - step 6B - dissolving compound 17 in a suitable solvent, particularly a mixture of acetone and 2,2-dimethoxypropane and treating with catalytic amount of sulfonic acid or BF 3 etherate to give (2S, 3S) -2-bromo-1, 3-dihydroxy-pent-4-yne acetonide, called compound 18
Figure imgf000027_0003
composto 18
Figure imgf000027_0003
compound 18
- etapa 7B - reagir o composto 18 com trifenilfosfina, seguindo-se suspensão do sal fosfônio formado em solvente adequado, particularmente dietil éter ou THF, e tratamento com base forte, particularmente terc-butóxido de potássio, butil-lítio ou fenil-lítio, resultando 2,2-dimetil-4-etinil-5-trifenilfosforanilideno-l,3-dioxano, denominado composto 19. - step 7B - reacting compound 18 with triphenylphosphine followed by suspension of the salt phosphonate formed in a suitable solvent, particularly diethyl ether or THF, and strong base treatment, particularly potassium tert-butoxide, butyllithium or phenyl lithium, resulting in 2,2-dimethyl-4-ethynyl-5-triphenylphosphoranylidene-1, 3-dioxane, called compound 19.
Figure imgf000028_0001
Figure imgf000028_0001
PCT/BR2015/050069 2015-06-03 2015-06-03 Method for preparing ingenol-3-dodecanoate, method for preparing 3-ethynyl-3-hydroxy-4,7,7-trimethylbicyclo[4.1.0]heptane-2-carbaldehyde, and method for preparing 2,2-dimethyl-4-ethynyl-5-triphenylphosphorus anylidene-1,3-dioxane WO2016191836A1 (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012010172A1 (en) * 2010-07-20 2012-01-26 Leo Pharma A/S A method of producing ingenol-3-angelate
WO2012085189A1 (en) * 2010-12-22 2012-06-28 Leo Pharma A/S Ingenol-3-acylates i
WO2012083953A1 (en) * 2010-12-22 2012-06-28 Leo Pharma A/S Ingenol-3-acylates iii and ingenol-3-carbamates
WO2013110753A1 (en) * 2012-01-25 2013-08-01 Leo Pharma A/S Process for the preparation of ingenol-3-angelate
WO2013126980A1 (en) * 2012-03-02 2013-09-06 Amazônia Fitomedicamentos Ltda. Ingenol derivatives in the reactivation of latent hiv
WO2014012836A1 (en) * 2012-07-16 2014-01-23 Leo Laboratories Limited Process for the preparation of ingenol-3-angelate from 20-deoxy-ingenol
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Publication number Priority date Publication date Assignee Title
WO2012010172A1 (en) * 2010-07-20 2012-01-26 Leo Pharma A/S A method of producing ingenol-3-angelate
WO2012085189A1 (en) * 2010-12-22 2012-06-28 Leo Pharma A/S Ingenol-3-acylates i
WO2012083953A1 (en) * 2010-12-22 2012-06-28 Leo Pharma A/S Ingenol-3-acylates iii and ingenol-3-carbamates
WO2013110753A1 (en) * 2012-01-25 2013-08-01 Leo Pharma A/S Process for the preparation of ingenol-3-angelate
WO2013126980A1 (en) * 2012-03-02 2013-09-06 Amazônia Fitomedicamentos Ltda. Ingenol derivatives in the reactivation of latent hiv
WO2014012836A1 (en) * 2012-07-16 2014-01-23 Leo Laboratories Limited Process for the preparation of ingenol-3-angelate from 20-deoxy-ingenol
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