WO2014075978A1

WO2014075978A1 - Process for the production of abiraterone-3-acetate involving an enol trliflation reaction in the presence of an alkoxy-pyridine compound

Info

Publication number: WO2014075978A1
Application number: PCT/EP2013/073210
Authority: WO
Inventors: Pascal Renart VERKERK; Reinerus Gerardus Gieling
Original assignee: Synthon B.V.
Priority date: 2012-11-16
Filing date: 2013-11-07
Publication date: 2014-05-22

Abstract

The present invention relates to a process for making abiraterone-3-acetate of formula (1) starting from dehydroepiandrosterone-3-acetate of formula (2) by converting it into the triflate of formula (5) in an inert solvent in the presence of an alkoxy group-substituted pyridine.

Description

PROCESS FOR THE PRODUCTION OF ABIRATERONE-3-ACETATE INVOLVING AN

ENOL

TRLIFLATION REACTION IN THE PRESENCE OF AN ALKOXY-PYRIDINE COMPOUND

Abiraterone- 3 -acetate (3P-acetoxy-17-(3-pyridyl)androsta-5,16-diene) of formula (1)

is a pharmaceutically active compound used for treatment of castration-resistant prostate cancer. It is sold under trade name Zytiga by Johnson and Johnson.

The compound was discovered in 1990 at the Institute of Cancer Research UK and is disclosed in WO 93/20097.

The basic process for making abiraterone-3-acetate disclosed in WO 93/20097 comprises

= replacing the enol-form of 17-oxo group in dehydroepiandrosterone-3-acetate of formula

(2)

by a leaving group L, which is capable of being replaced by a 3-pyridyl group in a palladium(O) complex-catalysed cross-coupling reaction with a 3-pyridinyl (dialkyl/dialkoxy) - boron compound (a so-called Suzuki coupling reaction), and

= carrying out said Suzuki coupling reaction. The palladium complex in the Suzuki coupling reaction is preferably a palladium(O) complex such as tetrakis(triphenylphosphine)palladium(0) or a complex reducible in situ to such palladium(0)phosphine species.

The leaving groups L actually used in prior art documents were the iodo group and the trifluoromethanesulfonate (triflate) group.

The first known route employing the iodo-leaving group has been described in WO 95/09178 and is shown in the Scheme below. In an important aspect, the 3-acetate group can be introduced only after introducing the 17-(3-pyridyl)-group, thus the actual starting material is not the compound of formula (2) but dehydroepiandrosterone (DHEA) of formula (3). The compound of formula (3) is converted to the corresponding iodo-compound of formula (4) in two steps; subsequently, after performing the Suzuki coupling reaction on compound (4), de- acetylated abiraterone of formula (1A) is obtained. In the final step, said abiraterone (1A) is acetylated to the desired abiraterone- 3 -acetate.

The second known route employing the triflate leaving group L is two steps shorter and thus more advantageous. The triflate intermediate compound of formula (5)

was prepared in WO 93/20097 by contacting DHEA-3-acetate of formula (2) with trifluoromethanesulfonic (triflic) anhydride in dichloromethane in the presence of a molar amount of 2,6 di-t-butyl-4-methylpyridine (having pKa of 4.41). The reaction gave, after chromatographic separation, the desired triflate of formula (5) in 58% yield, but also de- acetylated product of elimination of formula (6) in 10% yield.

In the second step, diethyl(3-pyridyl)borane was added to compound (5) in THF containing a catalytic amount of bis(triphenylphosphine)palladium(II)chloride and sodium carbonate as a nucleophilic activator. After extraction and chromatography, the desired compound of formula (1) was obtained as a free base in 84% yield (recrystallized from hexane).

As disclosed in WO 2006/021776, the elimination by-products of formula (6) and (IB) cannot be removed by recrystallization in either reaction step.

Therefore, column chromatography was required after both steps of the original process.

WO 2006/021776 and WO 2006/021777 suggest an improvement in the original process. In said improvement, the inflating step is advantageously conducted in the presence of a base comprising a tertiary or heterocyclic amine having a pKa value of the conjugate acid at 25 °C within the range of 5.21 (e.g. pyridine) to 12 (e.g. diazabicycloundecene). By using such base, the amount of the elimination by-product of formula (6) is minimized to an acceptable level. Furthermore, it was found that if the base used had a relatively low pKa, it gave bad results also because of competing deacetylation reaction. E.g. Ν,Ν-diethylaniline having a pKa of 5.20 (and, to a certain extent, also pyridine having a pKa of 5.21) gave the deacetylated product of formula (2A)

as the major product.

Apart from the undesired impurities of formula (6) and (2A), also some unreacted starting material (2) remains in the reaction mixture, both after the triflation reaction and after the Suzuki coupling reaction (in a ratio of approx. 1:3 with respect to the desired reaction product). This starting material may be removed from the reaction mixture by converting the product (1) into an acid addition salt, separating the salt in the solid state, recrystallizing the salt, and converting the salt into product (1). The mesylate salt of (1) was found as the most advantageous by WO'776. Such salt may be obtained from a solution of free base of (1) in a suitable solvent, e.g. in an ester or an ether solvent, preferably in methyl-t-butyl ether, by treatment with methanesulfonic acid. While several processes of making abiraterone-3-acetate are known in prior art documents, an improvement in the matter is still desirable.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to an improved process for making abiraterone-3-acetate of formula (1) starting from dehydroepiandrosterone-3-acetate of formula (2).

In one aspect, the invention provides a process comprising converting dehydroepi- androsterone-3-acetate of formula (2)

into the triflate of formula (5)

in an inert solvent in the presence of an alkoxy group-substituted pyridine.

In another aspect, the triflate of formula (5) is converted into abiraterone-3-acetate of formula (1) under the conditions of a Suzuki coupling reaction, preferably by reaction with dialkyl(3-pyridyl)borane in an inert solvent in the presence of a catalytic amount of

bis(triphenylphosphine)palladium(II)chloride.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a process for making abiraterone-3-acetate of formula (1) starting from dehydroepiandrosterone-3-acetate of formula (2). In particular, it relates to an improved process for making a key intermediate in said process, the compound 3P-acetoxy- androsta-5,16-dien-17-yl trifluoromethanesulfonate of formula (5).

It has been taught in prior art documents that the process for making the compound of formula (5) by reaction of dehydroepiandrosterone- 3 -acetate of formula (2) with a triflating agent, such as trifluoromethanesulfonic anhydride in the presence of the relatively strong base 2,6-di-t-butyl-4-methylpyridine is associated with the formation of a considerable amount of the by-product of formula (6), caused by an elimination reaction of the 3-acetoxy group. In a later improvement, the formation of the elimination by-product was suppressed by using relatively weak bases for said purpose, having a pKa value of the conjugate acid higher than 5.21.

However, the reaction mixture contained a relatively high amount of unreacted starting material as well. As this starting material can be removed from the desired product in a later purification step, said improvement could still be considered to be advantageous over the original process. However, incomplete conversion of the relatively expensive starting material, associated with accordingly lower total yield, still represents an economical disadvantage.

The present inventors surprisingly have found that certain organic bases, which should be considered as not-advantageous for making compound (5) because of their relatively high basicity (having a pKa value lower than 5.20), can nevertheless be used in said process.

Furthermore, the reaction of compound (2) with trifluoromethanesulfonic anhydride in the presence of these bases often exhibits an even higher conversion than obtained with bases of the prior art, without considerable formation of the elimination by-product. In general, the present invention relates to the use of an alkoxy group-substituted pyridine for making abiraterone-3- acetate of formula (1) and, in particular, for making the triflate of formula (5).

The "pKa of the conjugate acid" as used throughout this specification is the negative logarithm of the acid dissociation constant Ka and generally refers to the ability of an ionizable group to donate protons in aqueous media. In the context of the present invention the alkoxy group-substituted pyridine has a pKa value of the conjugate acid at 25°C of less than 5.20, preferably less than 4.40.

In one embodiment of the present invention, the alkoxy group is a C1-C4 alkoxy group, in a preferred embodiment the alkoxy group-substituted pyridine is 3-methoxypyridine or 2- methoxypyridine.

As disclosed in the prior art and as reworked by the present inventors, the known nitrogen bases having a pKa value of 5.21 and higher have the disadvantage that they are not effective enough for giving full conversion of the compound of formula (2) into the compound of formula (5). Up to one third of the starting material remains unreacted. When repeating the known triflation reaction using triethylamine (pK_a of 10.8), which was considered as the most preferred base in the prior art, it was found that the reaction product comprised 17% of unreacted starting material and 75% of the desired triflate. In contrast, using 2-methoxypyridine as an example of a base in accordance with the present invention, the reaction product comprised only 3.2% of starting material and 85.8% of the desired triflate. No elimination product was found in the latter reaction mixture.

The present invention provides an improved process for making abiraterone-3-acetate of formula (1) comprising a triflating step by which dehydroepiandrosterone- 3 -acetate of formula (2) is converted into the triflate of formula (5), characterized in that the triflating step is conducted in an inert solvent in the presence of an alkoxy group-substituted pyridine, in particular a C1-C4 alkoxy group-substituted pyridine. More in particular, such substituted pyridine is 2-methoxypyridine having a pKa value of 3.28. In another embodiment, such substituted pyridine is 3-methoxypiridine having pKa value of 4.88.

The starting material dehydroepiandrosterone- 3 -acetate of formula (2) is commercially available or can be produced by processes known in the art. It should be understood that the structure of formula (2) shown in this specification represents only one of possible tautomeric forms; the compound dehydroepiandrosterone-3-acetate may also exist as an enol. It is to be understood that the invention is not limited merely to the one tautomeric form shown.

The inert solvent to be used in accordance with the present invention comprises, without limitation, an aliphatic acid ester, preferably having from 2 to 10 carbon atoms or a chlorinated aliphatic or aromatic hydrocarbon, preferably having from 1 to 8 carbon atoms. Suitable solvents include ethyl acetate, isopropyl acetate, dichloro methane, 1,2-dichloroethane, and mixtures thereof.

The preferred triflating agent is trifluoromethanesulfonic (triflic) anhydride, which is commercially available. Preferably, it is used in a slight molar excess (5-20 molar %) with respect to the compound of formula (2). The pyridine base to be used in accordance with the present invention, notably 2- methoxypyridine or 3-methoxypyridine, is preferably used in a molar equivalent amount or in a slight molar excess (up to 10 %) with respect to the compound of formula (2). Preferably, the base is added with some delay, typically of 5-15 minutes, after mixing the compound of formula (2) with the inflating agent.

The reaction typically proceeds at ambient temperature or at a temperature close to ambient (between 5 and 30°C). Advantageously, the course of the reaction is monitored by a suitable analytical technique, for instance by HPLC.

After termination of the reaction, the reaction mixture is advantageously elaborated with the aim to remove undesired products, particularly the base used. Typically, the mixture is extracted with water, which may be optionally acidified, and residual water is removed by drying.

The so-obtained solution of crude triflate (5) is used in the next step as such or, if desired or advantageous, the triflate product is isolated therefrom, e.g. by evaporation of volatiles. It is advantageous that the triflate (5) or a solution comprising it, is used in the next step without delay. Otherwise, it may be stored for a certain time in the dark and at a temperature well below 0°C.

In a further step, the triflate of formula (5) prepared by the above process, is converted into crude abiraterone-3-acetate under the conditions of a Suzuki coupling reaction. The conditions of the Suzuki coupling reaction are well-known in the art and were disclosed in prior art documents cited above. Typically, diethyl(3-pyridyl)borane is added to the triflate compound (5) in a suitable inert solvent, e.g. in tetrahydrofuran, containing a catalytic amount of

bis(triphenylphosphine)palladium(II) dichloride and sodium carbonate as a nucleophilic activator. The reaction proceeds by stirring the mixture at an elevated temperature (typically 60- 90°C) and typically is controlled by a suitable analytical technique, for instance by HPLC. After termination of the reaction, the reaction mixture is elaborated with the aim to isolate the crude abiraterone- 3 -acetate. Typically, the mixture is partitioned between ethyl acetate and water, the organic layer is separated and the solvent is evaporated.

The obtained crude abiraterone-3-acetate still comprises some unreacted starting material (typically less than 10%) and traces of other impurities. It may be purified by converting it into an acid addition salt. The prior art suggests using methanesulfonic acid as the best acid for said purposes. This acid forms the mesylate salt of abiraterone-3-acetate in a good yield and purity. The acid addition salt is subsequently converted into abiraterone-3-acetate (1) as known in the art.

The invention is further illustrated by the following examples.

EXAMPLES

Comparative Example A

In accordance with the prior art, a mixture of dehydroepiandrosterone- 3 -acetate (1.04 g, 3.15 mmol) and triflic anhydride (0.585 ml, 3.46 mmol) in dry dichloromethane (10 ml) was stirred under a nitrogen atmosphere. After 5 min, a solution of triethylamine (0.437 ml, 3.15 mmol) in dry dichloromethane (10 ml) was added over a period of 15 minutes. The reaction mixture was stirred at room temperature. The reaction was monitored with HPLC.

The reaction mixture (which was almost black), was quenched by addition of water (15 ml) and the layers were separated. The aqueous layer was extracted with dichloromethane (2x 20 ml) and the combined organic layers were washed with IN HCl (20 ml). The organic layer was dried (sodium sulfate) and activated charcoal was added. The mixture was filtered over Celite and concentrated under reduced pressure to afford 1.24 g of the product (5) as a brown oil in a yield of 85%. HPLC: -17% starting material and 75% inflate.

Example 1

A mixture of dehydroepiandrosterone-3-acetate (15.56 g, 47.1 mmol) and triflic anhydride (9 ml, 53.3 mmol) in dichloromethane (120 ml) was stirred for 5 minutes at room temperature, giving a purple solution. To the mixture was added a solution of 2-methoxypyridine (5 ml, 47.6 mmol) in dichloromethane (120 ml) over a period of 30 minutes. The reaction temperature increased to 30°C and the color of the mixture turned from purple to dark purple. Stirring was continued at room temperature for 2 hr.

The reaction mixture was quenched with water (160 ml) and stirred for 10 minutes. The layers were separated and the organic layer was washed with 1 molar aqueous hydrochloric acid (2x 100 ml) and brine (100 ml). The brown organic layer was treated with sodium sulfate and activated charcoal and then was filtered over Celite. The resulting red/brown solution was concentrated to give compound (5) (20.18 g, 43.6 mmol, 93 % yield) as a red-brown oily residue. HPLC: -3.2% starting material and 85.8% triflate. The crude product was used in the next step.

Example 2

In a 500 ml three-necked flask compound (5) (20.18 g, 43.6 mmol) was dissolved with stirring in tetrahydrofuran (200 ml) to give a purple solution. To the resulting solution was added 3-(diethylboryl)pyridine (8.27 g, 56.2 mmol), mono(bis(triphenylphosphonio)palladium(IV)) dichloride (0.58 g, 0.826 mmol) and sodium carbonate (18.50 g, 175 mmol) as an aqueous solution (40 ml). The resulting red/brown solution was heated on an oil bath to 66°C for 90 min. TLC after 3.5hr showed complete conversion of the triflate. The mixture was then allowed to cool to room temperature, was diluted with water (200 ml) and ethyl acetate (150 ml) and stirred for 5 minutes. The organic phase was separated and the aqueous phase was extracted once with ethyl acetate (150 ml). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to a volume of 50 ml. The solution was diluted with methanol (150 ml) and concentrated again to a volume of 100 ml. The resulting light brown suspension was stirred over the weekend and then was filtered off. The filtrate was concentrated to a brown oily residue to give 15.68 g of crude abiraterone- 3 -acetate (1), which was purified as known in the art via crystallization of an acid addition salt thereof, and conversion of the salt to give abiraterone-3- acetate as a beige solid with a purity of 98.52%.

Claims

1. A process comprising converting dehydroepiandrosterone-3-acetate of formula (2)

into the triflate of formula (5)

in an inert solvent in the presence of an alkoxy group-substituted pyridine.

The process according to claim 1, wherein the alkoxy group is a C1-C4 alkoxy group.

The process according to claim 1 or 2, wherein the substituted pyridine is 2-methoxypyridine.

The process according to claim 1 or 2, wherein the substituted pyridine is 3-methoxypyridine.

The process according to any one of claims 1-4, wherein the inert solvent comprises an aliphatic acid ester, preferably having from 2 to 10 carbon atoms or a chlorinated aliphatic or aromatic hydrocarbon, preferably having from 1 to 8 carbon atoms.

The process according to any one of claims 1-5, wherein the triflating agent used is trifluoromethanesulfonic anhydride.

The process according to any one of claims 1-6, wherein the triflate of formula (5) is converted into abiraterone-3-acetate of formula (1) under the conditions of a Suzuki coupling reaction, preferably by reaction with dialkyl(3-pyridyl)borane in an inert solvent in the presence of a catalytic amount of bis(triphenylphosphine)-palladium(II)chloride.