WO2016191835A1 - Method for preparing ingenol-5,20-acetonide, method for preparing 3-ethynyl-3-hydroxy-4,7,7-trimethylbicyclo[4.1.0]heptane-2-carbaldehyde, method for preparing the compound 2,2-dimethyl-4-ethynyl-5-triphenylphosphorus anylidene-1,3-dioxane and intermediate compound - Google Patents

Abstract

The present invention relates to a method for preparing ingenol-5,20-acetonide, and to the ingenol-5,20-acetonide obtained by this method. The invention is also directed to new intermediate compounds for the preparation of ingenol-5,20-acetonide.

Description

 INGENOL-5,20-ACETONIDE PREPARATION METHOD, 3-ETHINYL-3-HYDROXI-4.7.7-TRIMETHYLBICICLE PREPARATION METHOD [4.1.0] HEPTAN-2-CARBALDEIDE, COMPOSITE PREPARATION METHOD 2,2-DIMETHYL -4-ETINYL-5 - TRYPHENYLPHOSPHORANYLIDEN-1,3-DIOXANE AND INTERMEDIATE COMPOUND

 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.

 Background of the Invention

 lngenol-5,20-acetonide, illustrated below, identified by CAS number 77573-

43-4, is a compound known as an intermediate in the synthesis of ingenol 3-ester derivatives, among other applications longer than ingenol.

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. In the context of that document, 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.

Description of the Invention

 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:

Compound 9 Compound 19

In a first aspect of the invention, 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.

 The following description illustrates a first aspect of the invention, namely the steps of obtaining ingenol-5,20-acetonide from the above mentioned compounds 9 and 19.

 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.

Step 1 9 + 9

Intermediate 1

 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.

 Intermediate 1 is identified as (1R, 2R, 3R, 4R, 6R) -3-ethinyl-2- {1 - [(4S, 5Z) -

4-ethinyl-2,2-dimethyl-1,3-dioxan-5-ylidene] ethyl} -4.7.7-trimethylbicyclo [4.1.0] heptan-3-ol.

Intermediate 1 Intermediate 2

This ring formation step, a Pauson-Khand reaction, 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.

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 .0V] nonadeca-2,5,12- trien-4-one.

Step 3

Intermediate 2 Intermediate 3

 This step refers to a dihydroxylation of intermediate 2, which can be done in alternate ways:

via an osmylation reaction, catalyzed with osmium tethoxide (Os0 ₄ ), for example in solution or supported on a polymer;

- 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.

Subsequent protection of useful diols, shown below, is performed using bisimidazolyl carbonate or silylating reagents.

Intermediate 3 Intermediate 4

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 Ί,} 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

Intermediate 4 Intermediate 5

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.

 Intermediate 5 is identified as (1S, 2R, 9S, 10R, 12R, 14R, 15R, 18R, 19S) -15,18-dihydroxy-4,4,11,11,11,18-hexamethyl-3,5, 20,22-tetraoxahexacyclo

[14.6.0.0 ^{1, 1} .0 ² .0, ^{1 1} .0 ^12] docosahexaenoic 7,16-dien-21-one. Step 5

Intermediate 5 Intermediate 6

 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.

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 6

 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.

Intermediate 6 ingenol-5,20-acetonide In a further aspect, the invention relates to intermediate compounds numbered from 1 to 6 within the sequence of ingenol-5,20-acetonide obtaining steps described above.

Obtaining Compound 9

 The present invention further relates to the synthesis of compound 9 used in the synthesis of ingenol-5,20-acetonide described above.

Compound 1 Compound 2

 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.

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.

Step 2A

Compound 2 Compound 3

 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.

Possible residual peroxides are reacted with dimethyl sulfide prior to acetone removal.

Step 3 A

Compound 3 Compound 4

 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 4

Compound 4 Compound 5

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 5 A

Compound 5 Compound 6 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).

Step 6A

Compound 6 Compound 7

 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.

Step 7A

Compound 7 Compound 8

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 a temperature of -78 ° C. Step 8A

Compound 8 Compound 9

 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.

 Alternatively, steps 3A, 4A, 5A and 6A described above may be replaced by steps 3AA, 4AA and 5AA described below.

Step 3AA

Compound 3 Compound 10

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.

Step 4AA

Compound 10 Compound 11

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.

Step 5AA

Composto 11 Composto 7

Compound 11 Compound 7

 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).

Obtaining Compound 19

 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).

 Note: Boc = tert-butoxy carbonyl

Step 1B

Compound 12 Compound 13

Reaction of L-serine methyl ester, named compound 12, with anhydride of tert-butoxycarbonyl 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 compound 13: 3-Boc-2,2-dimethyl-1,3-oxazolidine-4-carboxylate

Step 2B

Compound 13 Compound 14

Compound 13 is reacted with DIBAL (diisobutylaluminum hydride) resulting in 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.

Step 3B

Compound 14 Compound 15

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-dihydroxy- pent-4-yn-1,2-acetal

Step 4B

Compound 15 Compound 16

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.

Step 5B

Composto 16 Composto 17

Compound 16 Compound 17

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. Step 6B

Composto 17 Composto 18

Compound 17 Compound 18

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.

Step 7B

Compound 18 Compound 19

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, butyllithium or phenyl lithium.

 The person skilled in the art, from the teachings herein, will know how to propose embodiments in ways not expressly provided herein, but with function and result, at each stage, of the same nature, and thus such embodiments are encompassed by the appended claims.

Claims

 1. Method of preparation of ingenol-5,20-acetonide characterized in that it comprises the following steps:  - Step 1: React the chemical compost below

compound 9, with the compound having the chemical structure below

compound 19, in a high temperature organic solution of the order of 100 ° C, in the presence of a strong base, particularly potassium tert-butoxide, yielding a compound having the chemical structure below.

referred to as intermediate 1. - step 2: reacting intermediate 1 with carbon monoxide in the presence of Pauson-Khand reaction catalyst to obtain a compound with the structure chemistry below

referred to as intermediate 2. - 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, to obtain a compound with the chemical structure below.

intermediate 3, which is then reacted with bisimidazolyl carbonate silylating reagents to give a compound having the chemical structure below.

called intermediate 4; - step 4: reacting intermediate 4 with Grignard reagent, particularly methyl magnesium bromide, under cryogenic conditions to give a compound having the chemical structure below.

called intermediate 5;  - step 5: conduct a pinacol rearrangement of compound 5, in the presence of a suitable catalyst, particularly boron etherate fluoride or organoaluminium compound, to give a compound having the chemical structure below.

called intermediate 6;  - 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, dand genol-5,20-acetonide.

ingenol-5,20-acetonide 2. Method of preparation of 3-ethynyl-3-hydroxy-4,7,7-trimethylbicyclo [4.1.0] heptane-2-carbaldehyde comprising the steps of: - stage IA - chlorination of (+) - 3-carene called compound 1

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

compound 2 - 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

 compound 3 - step 3A - catalytic hydrogenolysis of compound 3 using a suitable catalyst, particularly palladium, under pressure to give 7,7-dimethylbicyclo [4.1.0] heptane-3-o

compound 4 - Step 4A - Reaction of compound 4 with TMS (trimethylsilyl) and lithium bis (trimethylsilyl) amide (LiHMDS) chloride in tetrahydrofuran (THF) under cryogenic conditions to give compound 5: tr [4.1.0] 2-heptene -3-ol

compound 5  - 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

compound 6  - 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

compound 7 - Step 7A - Reaction of compound 7 with excess ethinylmagnesium bromide in a suitable solvent, particularly THF, under cryogenic conditions to give 3-ethynyl-2-hydroxymethyl-4,7.7-trimethylbicyclo [4.1.0] heptane-3 ol, called compound 8

compound 8  - 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-compound 9

9  Method of preparing 3-ethynyl-3-hydroxy-4,7,7-trimethylbicyclo [4.1.0] heptane-2-carbaldehyde according to claim 2, characterized in that said steps 3A, 4A, 5A and 6A are replaced by steps 3AA, 4AA and 5AA, according to which: - 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

compound 10 - step 4AA - compound 10 is reacted in a suitable solvent, particularly THF, with TMS and lithium bis (trimethylsilyl) amide chloride (LiHDMS) under cryogenic conditions, 4-methyl-5-trimethylsilyl 7,7-dimethylbicyclo [4.1.0] -2-heptene-3-ol, called compound 11

compound 11  - step 5AA - hydroxymethylation reaction of compound 11 with formaldehyde in the presence of Yb (OTf) 3, resulting compound 7

compound 7  Method of preparing 2,2-dimethyl-4-ethynyl-5-triphenylphosphoranylidene-1,3-dioxane, comprising the steps of: - 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

13 - step 2B - reacting compound 13 with DIBAL (diisobutyl aluminum hydride) resulting in 3-Boc-2,2-dimethyl-1,3-oxazolidine-4-formyl, called compound 14, or subject 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 catalyst or compound 14.

compound 14  - 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

compound 15  - step 4B - subjecting compound 15 to a suitable acidic medium, particularly aqueous TFA (trifluoroacetic acid) or inorganic acids such as HCl or HBr, yielding (2S, 3S) -2-amino-1,3-dihydroxy-pentaphosphate. 4-ino, called compound 16

compound 16 - step 5B - diazotization of compound 16 in the presence of HBr and KBr, obtaining (2S, 3S) -2-Bromo-1,3-dihydroxy-pent-4-yne called compound 17

 OH compound 17 - 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

compound 18  - step 7B - reacting compound 18 with triphenylphosphine, followed by suspension of the phosphonium salt formed in a suitable solvent, particularly diethyl ether or THF, and treatment with strong base, particularly potassium tert-butoxide, butyllithium or phenyl lithium, resulting 2,2-dimethyl-4-ethynyl-5-triphenylphosphoranylidene-1,3-dioxane, named compound 19

compound 19  5. Intermediate compound, characterized in that it has the following structure ca, called intermediate 1

Intermediate 1  6. Intermediate compound, characterized in that it has the following chemical structure

referred to as intermediate 2. 7. Intermediate compound, characterized in that it has the following chemical structure

called intermediate 3.  8. Intermediate compound, characterized in that it has the following chemical structure

called intermediate 4.  9. Intermediate compound, characterized in that it has the following chemical structure

called intermediate 5. 10. Intermediate compound, characterized in that it has the following chemical structure

called intermediate 6.