WO2012170647A1

WO2012170647A1 - Process for the preparation of etravirine and intermediates in the synthesis thereof

Info

Publication number: WO2012170647A1
Application number: PCT/US2012/041277
Authority: WO
Inventors: Maja ŠEPELJ MAJER; Irena Krizmanic; Dragan ŠEPAC
Original assignee: Assia Chemical Industriew Ltd.; Teva Pharmaceuticals Usa, Inc.
Priority date: 2011-06-09
Filing date: 2012-06-07
Publication date: 2012-12-13

Abstract

The present patent application provides intermediates, e.g., 4-(6-(acetylamino)-2- chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile, for preparing Etravirine or the salts of Etravirine, and processes for preparing Etravirine or its salts as disclosed in the specification herein. The application also provides processes for preparing 4-(6-(acetylamino)-2- chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile.

Description

PROCESS FOR THE PREPARATION OF ETRAVIRINE AND INTERMEDIATES IN THE SYNTHESIS THEREOF

Cross Reference to Related Patent Applications

This patent application claims the benefits of U.S. Provisional Patent Application No. 61/495,178 filed June 9, 201 1 , No. 61/532,415 filed September 8, 201 1 and No. 61/562,188 filed November 21, 201 1 , the disclosures of which are herein incorporated by reference.

Field of the Invention

The present invention relates to novel processes for preparing Etravirine and synthetic intermediates in these processes.

Background of the Invention

Etravirine ("ETV"), 4-(6-amino-5-bromo-2-(4-cyanophenylamino)pyrimidin-4-yloxy)- 3,5-dimethylbenzonitrile of the following chemical structure:

is a drug used for the treatment of HIV.

Etravirine was formerly known as TMC-125, and has the brand name INTELENCE^®.

Etravirine, certain analogs of Etravirine, and their synthesis are described in US patent No. 7,037,917. In this patent, Etravirine is prepared by reacting a tetra halogenated pyrimidine derivative and an aminobenzene derivative, and optionally brominating the obtained product of that reaction, to obtain Etravirine. This process includes two steps that require chromatographic purification of intermediates, and the final product is obtained in very poor overall yield. EP 945443 discloses a general process for preparing anilinopyrimidine derivatives, and salts thereof, e.g., by aminolysis reactions of pyrimidine compounds containing leaving groups.

Bioorg.Med. Chem.Lett. 1 1 (2001) 2235-2239 describes a process for preparing Etravirine, according to the following scheme:

fa) Keihyl malonats, NaOB in EtOH, 76%; (b) POCI_a 86%; (c) Br_z NaHCO^ H_jO, MeOH, 78%: (d) sodium 4-c ano--⁶-dimet y!phenolale, N R 1,4-dioxane, 45%; (e) NH i-PrOH, 41%.

where Etravirine is obtained in a very poor overall yield of less than 10%.

WO 01/85700 describes a preparation of Etravirine analogues, which do not include an NH₂ group. The Etravirine analogues in this process were purified by column chromatography, and were obtained in very poor overall yield of about 2-5%.

WO 2006/094930, WO 2008/071587 and WO 2000/027825 describe different processes for preparing different Etravirine intermediates and derivatives, all of which require at least one chromatographic purification step.

WO 2008/068299 discloses that Etravirine has very poor solubility in water, and describes a hydrobromide salt of Etravirine, which is prepared by dissolving Etravirine in dichioromethane and reacting this solution with hydrobromic acid.

WO201 1/017079 and WO2010/150279 disclose additional processes for preparation of Etravirine and Etravirine intermediates.

The disclosures of the patents, patent applications, and publications cited in this application are hereby incorporated herein by reference in their entirety.

The present invention provides a novel process for preparing Etravirine.

Summary of the Invention

In one embodiment, the present invention encompasses the compound 4-(6-(acetyl- amino)-2-chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile ("CAPE-Ac"), and salts thereof (structure shown below), which may alternatively be named as N-(2-chloro-6-(4-cyano-2,6- dimethylphenoxy)pyrimidin-4-yl)acetamide:

CAPE-Ac

In another embodiment the present invention encompasses the use of CAPE-Ac and salts thereof to prepare Etravirine and Etravirine intermediates, and salts thereof.

In yet another embodiment the present invention encompasses a process for preparing Etravirine and salts thereof comprising preparing CAPE-Ac by the process of the present invention, and converting it to Etravirine and salts thereof.

In yet another embodiment the present invention encompasses a process for preparing CAPE-Ac comprising acetylating 2,6-dichloropyrimidin-4-amine ("DCAP") of the following structure:

DCAP

In one embodiment the present invention encompasses a process for preparing Etravirine comprising:

a) Acetylating 2,6-dichloropyrimidin-4-amine ("DCAP") of the following structure:

DCAP

to obtain acetyl-N-(2,6-dichloropyrimidin-4-yl)amine ("DCAP-Ac"), which may alternatively be named as N-(2,6-dichloropyrimidin-4-yl)acetamide, of the following structure:

DCAP-Ac b) Reacting DCAP-Ac and 4-hydroxy-3,5-dimethylbenzonitrile ("DMHB") of the following structure:

to obtain 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile ("CAPE-Ac") of the following structure:

CAPE-Ac c) Reacting CAPE-Ac and 4-aminobenzonitrile ("ABN") of the following structure:

ABN

to obtain 4-(6-(acetylamino)-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5- dimethylbenzonitrile ("DEBETV-Ac"), which may alternatively be named as N-(6-(4- cyano-2,6-dimethylphenoxy)-2-(4-cyanophenylamino)pyrimidin-4-yl)acetamide, of the following structure:

DEBETV-Ac d) De-protecting the DEBETV-Ac to obtain 4-(6-amino-2-(4 cyanophenylamino)- pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (DEBETV) of the following structure:

DEBETV e) Brominating the DEBETV to obtain Etravirine; and

f) Optionally converting the Etravirine to an Etravirine salt

In one embodiment, the present invention encompasses a compound of the following formula 1 , and salts thereof:

Formula 1 .

wherein X is a halogen, e.g., -Cl, -Br,-I or -F (preferably Cl); or a tosyl group.

Particularly, the present invention encompasses 5-bromo-2,6-dichloropyrimidin-4- amine ("BDCAP") of the following structure, and salts thereof:

BDCAP

In another embodiment the present invention encompasses the use of BDCAP and salts thereof to prepare Etravirine and Etravirine intermediates, and salts thereof.

In yet another embodiment the present invention encompasses a process for preparing Etravirine and salts thereof comprising preparing BDCAP by the process of the present invention, and converting it to Etravirine and salts thereof.

In yet another embodiment, the present invention encompasses a process for preparing a compound of Formula 1 and salts thereof comprising brominating a compound of Formula 2:

Formula 2 wherein X is a halogen, e.g., -CI, -Br, -I or -F; or a tosyl group, to obtain a compound of Formula 1 .

In a further embodiment, the present invention encompasses a process for preparing Etravirine and salts thereof comprising:

A) Brominating a compound of Formula 2:

Formula 2 wherein X is a halogen, e.g., -CI, -Br, -I or -F; or a tosyl group, to obtain a compound of

Formula 1 ;

B) Reacting the compound of Formula 1 and 4-hydroxy-3,5-dimethylbenzonitrile ("DMHB") of the following structure:

to obtain a compound of Formula 3, of the following structure:

Formula 3 wherein X is as defined above;

C) Reacting the compound of Formula 3 and 4-aminobenzonitrile ("ABN") of the following structure:

ABN to obtain Etravirine; and

D) Optionally converting the Etravirine to an Etravirine salt.

Brief Description of the Figures

Figure 1 provides aΉ NMR spectrum of 4-(6-amino-5-bromo-2-chloropyrimidin-4- yloxy)-3,5-dimethylbenzonitrile ("BCAPE")

Figure 2 provides a ^{l 3}C NMR spectrum of 4-(6-amino-5-bromo-2-chloropyrimidin-4- yloxy)-3,5-dimethylbenzonitrile ("BCAPE")

Figure 3 provides a ^{l 5}N NMR spectrum of 4-(6-amino-5-bromo-2-chloropyrimidin-4- yloxy)-3,5-dimethylbenzonitrile ("BCAPE")

8 1

Figure 4 provides a Br NMR spectrum of 4-(6-amino-5-bromo-2-chloropyrimidin-4- yloxy)-3,5-dimethylbenzonitrile ("BCAPE") Detailed Description of the Invention

The present invention provides novel processes for preparing Etravirine, as well as novel intermediates in these processes.

As used herein, the term "room temperature" refers to a temperature from about 20°C to about 30 °C. Usually, room temperature ranges from about 20°C to about 25°C.

As used herein, the term "overnight" refers to a period of between about 15 hours and about 20 hours, typically between about 16 hours to about 20 hours.

As used herein, unless indicated otherwise, the term "isolated" in reference to Etravirine and Etravirine intermediates, such as BDCAP, corresponds to Etravirine, or an Etravirine intermediate, that is physically separated from the reaction mixture in which it is formed.

The term "tosyl," as used herein and unless indicated otherwise, refers to a 4- methylbenzenesulfonate substituent on an aromatic ring, i.e., having the structure -0-S0₂- C6H4CH3. Examples include 6-amino-5-bromopyrimidine-2,4-diyl bis(4-methylbenzene- sulfonate), shown in the structure below:

The present invention provides a novel process for preparing Etravirine or a salt thereof via a novel intermediate: 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5- dimethylbenzonitrile ("CAPE-Ac"). This process provides Etravirine in high purity, and in good overall yield, preferably of about 30%. The bromination reaction, which is performed in the last step, can be carried out under mild conditions. The crude product is obtained in a high purity, which purity can be further increased using simple methods, such as crystallization.

This process can be illustrated by Scheme 1 , below.

ETV DEBETV DEBETV-Ac

In one embodiment, the present invention encompasses the compound, 4-(6-(acetyl- amino)-2-chloropyrimidin-4-yloxy)-3, 5-dimethylbenzonitrile ("CAPE-Ac"), and salts thereof of the following structure:

CAPE - Ac

The intermediate CAPE-Ac can be isolated, and, according to some embodiments, this intermediate is crystalline.

The intermediate CAPE-Ac can be prepared by a process comprising acetylating 2,6- dichloropyrimidin-4-amine ("DCAP") of the following structure:

DCAP

Suitable acetylating agents for step a) include, for example, acetyl chloride or acetic anhydride. The acetylation can optionally be done in the presence of a suitable base. Suitable bases include, for example, a carbonate base such as sodium or potassium carbonate or sodium or potassium bicarbonate. The acetylation can optionally be done in the presence of a suitable solvent. Suitable solvents include organic solvents that are inert to the acetylation reagent. Alternatively, the acetylation reaction can be performed neat, for example by mixing the DECAP with neat acetic anhydride. The acetylation can be carried out at a suitable temperature, for example from about room temperature up to about the reflux temperature of the solvent, if a solvent is used, or of acetic anhydride, if the reaction is carried out in acetic anhydride with no additional solvent.

The above described CAPE-Ac can be used to prepare Etravirine and salts thereof. The present invention provides a process for preparing Etravirine and salts thereof comprising preparing CAPE-Ac by the process of the present invention, and converting it to Etravirine or a salt thereof. The conversion can be done, for example, by a) reacting CAPE-Ac and ABN to obtain DEBETV-Ac; b) de-protecting DEBETV-Ac to obtain DEBETV; and c) brominating DEBETV to obtain Etravirine. The process can further include converting the Etravirine produced in step c) to an Etravirine salt, for example by reacting the Etravirine product with a suitable acid.

In another embodiment the present invention encompasses a process for preparing Etravirine comprising:

DCAP to obtain acetyl-N-(2,6-dichloropyrimidin-4-yl)amine ("DCAP-Ac") of the following structure:

DCAP-Ac b) Reacting the DCAP-Ac and 4-hydroxy-3,5-dimethylbenzonitrile ("DMHB") of the following structure:

DMHB to obtain 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile ("CAPE-Ac") of the following structure:

CAPE - Ac c) Reacting the CAPE-Ac and 4-aminobenzonitrile ("ABN") of the following

structure:

ABN

to obtain 4-(6-(acetylamino)-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5- dimethylbenzonitrile ("DEBETV-Ac") of the following structure:

DEBETV e) Brominating the DEBETV to obtain Etravirine; and

f) Optionally converting the Etravirine to an Etravirine salt.

Suitable acetylating agents for step a) include, for example, acetyl chloride or acetic anhydride. The acetylation can optionally be done in the presence of a suitable base, and optionally in the presence of a suitable solvent, as described above.

The reaction in step b) can typically be done in the presence of a suitable base.

Suitable bases include: metal hydrides such as, for example, sodium hydride; non- nucleophilic bases, such as, for example, lithium diisopropylamide ("LDA"); alkoxide bases, such as, for example sodium methoxide or potassium methoxide; and carbonate bases, such as, for example, potassium carbonate or sodium carbonate. This step can also be done in the presence of a suitable solvent. Suitable solvents include amide solvents, such as N- methyl- pyrrolidone ("NMP"), DMF, dimethylacetamide ("DMA"), 2-pyrrolidone, l ,3-dimethyl-2- imidazolidinone ("DMI") and imidazolidinone; sulfoxide and sulfone solvents, such as dimethylsulfoxide ("DMSO"), and methylsulfonylmethane ("MSM"). Typically, the reaction is done at a temperature from about 0°C to about 130°C, or from about 30°C to 130°C, or from about 60°C to about 120°C, or from about 80°C to about 120°C, or from about 100°C to about 120^oC.jDne suitable reaction temperature is about 100°C. The reaction is continued for a period of time sufficient to complete the reaction, for instance from about 1 hour to about 20 hours, or from about 1 hour to about 10 hours, or from about 1 hour to about 5 hours. In some instances, the reaction is complete in about 1 hour.

Step c) can be done in the presence of a suitable solvent. Suitable solvents include polar aprotic solvents, such as acetonitrile; DMF (or other amide solvents); DMSO or DMA, ether solvents, such as dioxane; ester solvents, such as ethyl acetate; or ketone solvents, such as acetone. Typically the reaction in step c) can be carried out in the presence of zinc chloride. The process in step c) can be performed at a suitable temperature, for example, from about from about 0°C to about 130°C, or from about 30°C to about 130°C, or from about 60°C to about 120°C, or from about 80°C to about 120°C or from about 100°C to about 120°C. One suitable temperature is about 100°C. The reaction is continued for a period of time sufficient to complete the reaction, for instance from about 1 hour to about 20 hours, from about 1 hour to about 10 hours, or from about 1 hour to about 5 hours. In some instances, the reaction is complete in about 1 hour.

The deprotection reaction in step d) is typically done in the presence of a suitable base. Suitable bases include inorganic bases, such as metal hydroxides, e.g., sodium hydroxide or potassium hydroxide, alkoxide bases, such as sodium methoxide or potassium methoxide, and hydrazine bases. Alternatively, the deprotection can be accomplished with a reducing agent, such as sodium borohydride, or by enzymatic hydrolysis. The de-protection is typically done in the presence of a suitable solvent, for example, an alcoholic solvent, such as a Ci-C₆ alcohol, or a C1 -C4 alcohol, such as, for example ethanol, methanol, propanol, isopropanol or butanol.

The process in step d) can be performed at a temperature from about 10°C to about 30°C, or from about 15°C to about 30°C, or from about 20°C to about 30°C. The reaction can be continued for a period of time sufficient to complete the reaction, for example, from about 1 hour to about 20 hours, or from about 1 hour to about 10 hours, or from about 1 hour to about 5 hours. In some instances, the reaction is complete in about 1 hour.

The obtained DEBETV of step d) is brominated to obtain Etravirine. The bromination can be done in the presence of a suitable solvent. Suitable solvents include alcohol solvents, e.g., C]-C₄ alcohol solvents, such as methanol, ethanol, 1 -propanol or 1 -butanol; organic acids, such as acetic acid; amide solvents, such as DMF; ether solvents, such as THF; nitrile solvents, such as acetonitrile, and mixtures thereof. The bromination can be performed at a temperature from about 0°C to about 30°C, from about 10°C to about 30°C, or from about 15°C to about 30°C; preferably from about 5°C to about 15°C. The reaction can be continued for a period of time sufficient to complete the reaction, for instance from about 1 hour to about 4 hours, from about 2 hour to about 4 hours, or from about 1 hour to about 3 hours. In some instances, the reaction is complete in about 1 to 2 hours.

The obtained Etravirine can be purified, by any suitable method known in the art, for example, by column chromatography or by crystallization. Alternatively, Etravirine can be purified by converting it to an Etravirine salt, which can then be recrystallized. Such a conversion is typically done by reacting the Etravirine with a suitable acid.

The present invention also provides an alternative process for preparation of

Etravirine, via the compound of Formula 1 or salts of said compound, particularly 5-bromo- 2,6-dichloropyrimidin-4-amine ("BDCAP").

This process provides Etravirine in high purity, and in overall yield of more than 36%, via a process that comprises only three synthetic steps.

This process can be illustrated by the following Scheme 2:

wherein X is a halogen, e.g., -CI, -Br, -I or -F; or a tosyl group. In one embodiment, the present invention encompasses a compound of Formula 1 and salts thereof:

Form ula 1

wherein X is a halogen, e.g., -CI, -Br, -I or -F; or a tosyl group.

Particularly, the present invention encompasses 5-bromo-2,6-dichloropyrimidin-4- amine ("BDCAP") of the following structure and salts thereof:

BDCAP

The compound of Formula 1, particularly the intermediate BDCAP, can be isolated, and preferably, it is crystalline.

The compound of Formula 1 , particularly the intermediate BDCAP, and salts thereof can be prepared by a process comprisi rominating a compound of Formula 2:

Formula 2 wherein X is a halogen, e.g., -CI, -Br, -I or -F; or a tosyl group, to obtain a compound of Formula 1.

The above described compound of Formula 1 and salts thereof, particularly BDCAP, can be used to prepare Etravirine, salts thereof and solid state forms thereof. The present invention provides a process for preparing Etravirine, salts thereof and solid state forms thereof comprising preparing compound of Formula 1, e.g., BDCAP, by the process of the present invention, and converting it to Etravirine or a salt thereof. The conversion can be done, for example, by a) reacting the compound of Formula 1 (e.g., BDCAP) and DMHB to obtain BCAPE; b) reacting the BCAPE and ABN to obtain Etravirine; and c) optionally converting the Etravirine to an Etravirine salt, for example by reacting Etravirine with a suitable acid.

In a further embodiment the present invention encompasses a process for preparing Etravirine comprising:

A) Brominating a compound of the following Formula 2 or a salt thereof:

Formula 2

wherein X is a halogen, e.g., -CI, -Br, -I or -F; or a tosyl group to obtain a compound of formula 1 , particularly BDCAP;

B) Reacting the compound of Formula 1 and 4-hydroxy-3,5-dimethylbenzonitrile

("DMHB") of the following structure:

DMHB to obtain a compound of Formula 3, or a salt thereof:

Formula 3 wherein X is defined as above, e.g., BCAPE of the following structure:

BCAPE

C) Reacting the compound of Formula 3, particularly BCAPE, and 4- benzonitrile ("ABN") of the following structure:

ABN

to obtain Etravirine; and

D) Optionally converting the Etravirine to an Etravirine salt.

Step A) can be done in the presence of a suitable solvent. Suitable solvents for step A) include alcohol solvents, e.g., C1 -C4 alcohol solvents, for example, methanol, ethanol, 1- propanol or 1-butanol; organic acid solvents, such as acetic acid; amide solvents, such as dimethylformamide ("DMF"); ether solvents, such as tetrahydrofuran ("THF"); nitrile solvents, such as acetonitrile, and mixtures thereof.

Step B) can be done in the presence of a suitable base. Suitable bases for step B) include metal hydrides; such as sodium hydride; non-nucleophilic bases, such as lithium diisopropylamide ("LDA"); alkoxide bases, e.g., sodium methoxide or potassium methoxide; and carbonate bases, e.g., potassium carbonate or sodium carbonate. This step can also be done in the presence of a suitable solvent. Suitable solvents for this step include, for example, amide solvents, such as N-methylpyrrolidone ("NMP"), DMF, dimethylacetamide ("DMA"), 2-pyrrolidone, l ,3-dimethyl-2-imidazolidinone ("DMI") or imidazolidinone; and sulfoxide solvents, for example dimethyl sulfoxide ("DMSO") or methylsulfonylmethane ("MSM") . Typically, the process in step B) is done at a temperature from about 10°C to about 100°C, preferably at about 60°C to 65°C, for period of time sufficient to complete the reaction, for example, from about 1 hour to about 24 hours.

Step C) can be done in the presence of a solvent and a base, as described above.

Typically, step C) is carried out at a temperature from about 10°C to about 100°C, preferably about 90 to about 100°C, for time period sufficient to complete the reaction, such as from about 1 hour to about 48 hours, preferably from about 40 to about 48 hours.

The obtained Etravirine product can be purified by any suitable method known in the art, for example, by column chromatography or by crystallization. Alternatively, the

Etravirine product can be purified by converting it to an Etravirine salt, which can then be recrystallized. Such a conversion is typically done by reacting the Etravirine product with a suitable acid.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Nuclear Magnetic Resonance ("NMR" method(Ή-NMR, ¹³C-NMR. ¹⁵N-NMR and ⁸¹Br- NMR)

The sample was dissolved in DMSO-d₆. A small amount of TMS was added as a reference. NMR spectra were acquired on a Varian Unity Inova 300 MHz spectrometer equipped with ID and ATB probes at the Slovenian NMR Centre at the National Institute of Chemistry in Ljubljana. Sample temperature was set at 298 K. Ή and ^{l 3}C NMR chemical shifts were referenced with respect to TMS (δ 0.0 ppm). ¹⁵N chemical shifts were referenced externally to ammonia at 5 0.0 ppm. Br chemical shifts were referenced externally to NaBr at δβ_Γ 0.0 ppm. NaBr salt was dissolved in H₂0/D₂0 9: 1 mixture.

Examples

Example 1 : Preparation of 5-bromo-2.6-dichloropyrimidin-4-amine (BDCAP)

A suspension of 2,6-dichloropyrimidin-4-amine (0.5 g; 3.05 mmol) in methanol (25 ml) was cooled to 0-5 °C. Bromine (313.4 μΐ; 6.1 mmol; 2 eq) was added dropwise to the suspension over 20 minutes. The resulting reaction mixture was stirred at 0-5 °C for 2 h, and then neutralized by adding 10 % aqueous NaOH (2 ml). Water (5 ml) was added to the resulting mixture at 0-5 °C, and the mixture was then concentrated by evaporation of the MeOH at room temperature. To the resulting thick suspension, water (5 ml) was added, and this mixture was stirred for 45 min at 0-5 °C. A solid was separated from the suspension by filtration and washed with a MeOH / water mixture (1 : 1 ; 4 ml), and dried (4h/ 40 °CI 10 mbar).

Yield: 614 mg (83 %) of 5-bromo-2,6-dichloropyrimidin-4-amine (98.3 Area %).

M+ 244.2/ 246.2

Example 2a: Preparation of 4-(6-amino-5-bromo-2-chloropyrimidin-4-yloxy)-3.5-dimethyl- benzonitrile (ESCAPE

A solution of 5-bromo-2,6-dichloropyrimidin-4-amine (BDCAP; 0.5 g; 2.06 mmol) in dime thy lacetamide (DMA) (5 ml) was cooled to 0-5 °C under nitrogen. Sodium hydride (60 % suspension in mineral oil; 90.6 mg; 2.26 mmol; 1.1 eq) was added to the solution. The resulting suspension was stirred 20 minutes at 0-5 °C. Then, a solution of 4-hydroxy-3,5- dimethylbenzonitrile (DMHB; 333.2 mg; 2.26 mmol) in DMA (3.6 ml) was added dropwise. The resulting mixture was stirred at 0-5 °C for 3.5 h, and then at room temperature (25-30 °C) for 18 h, and then at 62 °C for an additional 23 h, and then at 85 °C for l h with addition of an additional 0.275 eq of NaH. The reaction mixture was then cooled to 0-5 °C and water (5 ml) was added, and this mixture was stirred for 2h. A solid precipitated and was separated by filtration. The filtered solid was washed with water (1 ml) and then dried under vacuum 5h/ 40 °C/ 10 mbar, 516 mg (71 %). The product was triturated in methyl isobutyl ketone: 460 mg of crude material was suspended in the solvent (5 ml) and stirred for 20 h at room temperature.

Yield: After trituration 330 mg (72 %) was obtained of a mixture of 4-(6-amino-5-bromo-2- chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile, 4-(4-amino-5-bromo-6-chloropyrimidin- 2-yloxy)-3,5-dimethylbenzonitrile and 4,4'-(6-amino-5-bromopyrimidine-2,4-diyl)bis(oxy)- bis(3,5-dimethylbenzonitrile) in a ratio of 87.7 : 2.75 : 6.14.

Ή NMR (300 MHz, DMSO-d6, 298 K, TMS), 6/ ppm

1³C NMR (300 MHz, DMSO-d6, 298 K, TMS), 5/ ppm

,⁵N NMR (300 MHz, DMSO-d6, 298 K, ammonia), 5/ ppm

Table 1 . Ή. ^{I 3}C and ^{l 5}N NMR chemical shifts (in ppm).

Ή ¹³C . ¹⁵N

81.99 -

*a -

7.5 (b), 8.2 (b) - 101.3

- 153.00 -

- 132.31 -

2.10 (s) 15.53 -

7.69 (s) 132.50

- 108.67

- 1 18.36 247.8

* NMR chemical shifts could not be unequivocally assigned:

[a] C2, C4 and C6 exhibited δ 156.62, 163.50 and 163.60 ppm;

[b] Nl or N3 exhibited one signal at δ 229.2 ppm, while one signal could not be observed.

Example 2b: Preparation of 4-(6-amino-5-bromo-2-chloropyrimidin-4-yloxy)-3.5-dimethyl- benzonitrile (BCAPE)

A solution of 5-bromo-2,6-dichloropyrimidin-4-amine (BDCAP; 2.8 g; 1 1.54 mmol) in DMA (28 ml) was cooled to 0-5 °C under nitrogen. Sodium hydride (60 % suspension in mineral oil; 646.8 mg; 16.14 mmol; 1.1 eq) was added to the solution. The resulting suspension was stirred 20 minutes at 0-5 °C. Then, a solution of 4-hydroxy-3,5-dimethyl- benzonitrile (DMHB; 1.866 g; 12.66 mmol) in DMA (20 ml) was added dropwise. The resulting mixture was stirred at 10 °C for 15 minutes, then at room temperature (25-30 °C) for 15 minutes, then at 60 °C for an additional 18 h, and then at 80 °C for lh. The reaction mixture was then cooled to room temperature and water was added (28 ml), and this mixture was stirred for 2h at 0-5 °C. A solid was separated by filtration. The filtered solid was washed with water and then dried under vacuum 4h/ 40 °C/ 10 mbar, 3.8 g (93.1 %), with HPLC purity of 73.3 area% (a mixture of 4-(6-amino-5-bromo-2-chloropyrimidin-4-yloxy)-3,5- dimethylbenzonitrile, 4-(4-amino-5-bromo-6-chloropyrimidin-2-yloxy)-3,5-dimethylbenzo- nitrile and 4,4'-(6-amino-5-bromopyrimidine-2,4-diyl)bis(oxy)bis(3,5-dimethylbenzonitrile) in a ratio of 73.3 : 9.3 : 14.6).

The product was recrystallized from acetone: 3.0 g of crude material was dissolved in acetone (300 ml) at reflux and stirred for 15 minutes at reflux and then cooled to room temperature. Water was added dropwise (150 ml) and the resulting suspension was stirred at room temperature for 2 h. A solid precipitated and was filtered off and dried 5h / 40 °C / 10 mbar.

Yield: After recrystallization 2.1 1 g (70.3 %) of desired product, 4-(6-amino-5-bromo-2- chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile was obtained, purified from isomers, 4-(4- amino-5-bromo-6-chloropyrimidin-2-yloxy)-3,5-dimethylbenzonitrile and 4,4'-(6-amino-5- bromopyrimidine-2,4-diyl)bis(oxy)bis(3,5-dimethylbenzonitrile). Total yield for the reaction and purification was 65.5%. Purity (HPLC/ MS): 93.3 Area %.

Example 3a: Preparation of 4-(6-amino-5-bromo-2-(4-cyanophenylamino pyrimidin-4- yloxy)-3.5-dimethylbenzonitrile (Etravirine)

Potassium bromide (0.0673 g; 0.566 mmol; 1 eq) was added to a solution of the mixture of products obtained in the Example 2b (0.2 g; 0.566 mmol) in DMA (4 ml). The resulting suspension was cooled to 0-5 °C and sodium hydride (60 % suspension in mineral oil; 0.034 g; 1.41 mmol; 1.5 eq) was added under nitrogen. The resulting light yellow suspension was stirred 10 minutes at 0-5 °C, and then 4-aminobenzonitrile (0.0668 g; 0.566 mmol; 1 eq, dissolved in 1.5 mL of DMA) was added dropwise over 10 minutes. The reaction mixture was stirred at 0-5 °C for lh, then at room temperature for 2 h, and then at 100 °C for 44 h. The resulting mixture was then cooled to room temperature and water (3ml) was added dropwise. A solid precipitated. After a few minutes, a solution was obtained. The solution was stirred 1 h at room temperature before additional water (3 ml) was added and crystals began to form. The solution was left for 20 h at 2 °C, then filtered to provide 107 mg (43.5 %) of the crude product.

Purification of Etravirine:

The crude product (100 mg) was purified by column chromatography (silica gel, 18 g) eluting with methylene chloride: methanol (20 : 1). The pure product, 51 mg was obtained. HPLC purity: 63.5 Area %.

Example 3b: Preparation of 4-(6-amino-5-bromo-2-(4-cvanophenylamino) pyrimidin-4- yloxy)-3.5-dimethylbenzonitrile (Etravirine)

To a suspension of 4-(6-amino-5-bromo-2-chloropyrimidin-4-yloxy)-3,5-dimethyl- benzonitrile (BCAPE; 400 mg; 1.13 mmol; 1 eq) in dioxane (5 ml), at room temperature, 4- aminobenzonitrile (ABN, 280.6 mg; 2.375 mmol; 2.1 eq) and ZnCl₂ (188.1 1 mg, 1.38 mmol, 1.22 eq) were added under argon. The resulting suspension was heated to 100 °C, and stirred for 26 h at 100 °C. Then, more ZnCl₂ (94.05 mg, 0.69 mmol, 0.61 eq) was added to the solution, and stirring was continued for 18 h at 100 °C. The resulting mixture was cooled to room temperature and diluted with ethyl acetate (10 ml) and brine (5 ml). After separation of the layers, the organic layer was washed with brine (5 ml), and the collected water layers were washed with ethyl acetate (5 ml). The collected organic extracts were dried over Na₂S0₄, and filtered, and the filtrate was evaporated to dryness. The resulting dry residue was dissolved in N-methylpyrrolidone (NMP, 5 ml), and water (6 ml) was added dropwise. The resulting mixture was stirred 1 h/ 0-5 °C. A solid precipitated and was separated from the suspension by filtration and dried (5 hi 40 °C/ 10 mbar).

Yield: 379 mg (77 %) of 4-(6-amino-5-bromo-2-(4-cyanophenylamino)pyrimidin-4-yloxy)- 3,5-dimethylbenzonitrile (Etravirine)._ Purity (HPLC/ MS): 74 Area %. M+ 435.7

Example 3c: Purification of 4-(6-amino-5-bromo-2-(4-cvanophenylamino)-pyrimidin-4- yloxy)-3,5-dimethylbenzonitrile (Etravirine)

Crude etravirine (obtained in 3b, 379 mg, 74 Area %, 0.645 mmol) was suspended in acetone (6.8 ml), and a solution of p-toluenesulfonic acid monohydrate (135.06 mg; 0.71 mmol, 1.1 eq) in acetone (1.55 ml) was added dropwise. The resulting mixture was stirred at r.t. for 1 h. The suspension was then filtered, and the collected solid was washed with 1.3 ml of water.

The thus obtained wet etravirine tosylate was suspended in acetone (8.2 ml) and 10% NaOH (0.284 ml) was added dropwise. The resulting mixture was stirred 30 min at room temperature and water (4.3 ml) was added. The suspension was immediately dissolved and quickly precipitated afterwards. The thus obtained suspension was cooled to 0-5 °C, stirred for 1 h and then filtered. The collected solid was washed with cold water (2x0.7 ml) and dried (4 h/ 50 °C/ 10 mbar).

Yield: 330 mg (87 %) of 4-(6-amino-5-bromo-2-(4-cyanophenylamino) pyrimidin-4-yloxy)- 3,5-dimethylbenzonitrile. Purity (HPLC/ MS): 96.9 Area %. M+ 435.7

Example 4a: Preparation of aceryl-N-(2.6-dichloropyrimidin-4-yl hydroxylamine (DCAP-Ac)

2,6-Dichloropyrimidin-4-amine (DCAP, 3 g, 18.29 mmol) was suspended in acetic anhydride (60 mL, 635.91 mmol, 35 molEq), and the suspension was heated to reflux. The obtained solution was stirred at reflux for 6.5 hours, and then at room temperature overnight, and finally at reflux for an additional 4.5 hours. The mixture was then cooled to room temperature, concentrated in vacuo to reduce the volume by half, and was kept in the refrigerator for 1 hour. The precipitate was collected by filtration and washed with cold acetic anhydride and then with diisopropyl ether. The collected crystals were dried on air and in a vacuum desiccator.

Yield: 2.1 g (51.7%) of acetyl-N-(2,6-dichloropyrimidin-4-yl)hydroxylamine (DCAP-Ac). Purity (HPLC): 100 area %.

Example 4b: Preparation of acetyl-N-(2.6-dichloropyrimidin-4-yl)hvdroxylamine (DCAP-Ac)

2,6-Dichloropyrimidin-4-amine (DCAP, 20 g, 121.95 mmol) was suspended in acetic anhydride (400 mL, 4.27 mol, 35 molEq), and the suspension was heated to reflux. The obtained solution was stirred at reflux for 3.5 hours. The resulting reaction mixture was then cooled, concentrated to dryness in vacuo and the remaining acetic anhydride was removed by evaporation with toluene portions. The residue was dissolved in ethyl acetate (333 mL) and water (333 mL) and pH was adjusted to 7 by addition of 10% NaHC0₃. The organic layer was washed with saturated NaCl solution, and then evaporated to dryness. The residue was dissolved in acetic anhydride (cca 200 mL) and stirred at 0-5 °C for 2 h. The precipitate that formed was filtered off and dried 5h / 40 °C / 10 mbar.

Yield: 18.34 (68%) of acetyl-N-(2,6-dichloropyrimidin-4-yl)hydroxylamine (DCAP-Ac). Purity (HPLC): 100 area %.

Example 5: Preparation of 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy -3,5-dimethyl- benzonitrile (CAPE-Ac)

Acetyl-N-(2,6-dichloropyrimidin-4-yl)hydroxylamine (DCAP-Ac, 1 g, 4.50 mmol) was suspended in DMA (10 mL), and 4-hydroxy-3,5-dimethylbenzonitrile (DMHB, 0.71 g, 4.82 mmol, 1.07 molEq), K₂C0₃ (1 g, 16.66 mmol, 3.70 molEq) and Nal (0.1 1 g, 0.73 mmol, 0.16 molEq) were added. The resulting reaction mixture was heated to 100 °C and stirred for 1 hour, then cooled to room temperature and diluted with ethyl acetate (60 mL) and salt water (60 mL). The layers were separated, and the organic layer was washed with saturated NaCl solution, dried over Na₂S0₄, filtered and the filtrate concentrated in vacuo to reduce the volume to half to induce precipitation. The precipitate was filtered and the collected crystals were washed with cold ethyl acetate.

Yield: 0.86 g (57.4%) of 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethyl- benzonitrile (CAPE-Ac). Purity (HPLC): 97.7 area % (1.3 area % of C-2 isomer). Example 6a: Preparation of 4-(6-(acetylamino)-2-(4-cvanophenylamino)pyrimidin-4-yloxy)- 3.5-dimethylbenzonitrile (DEBETV-Ac^{^})

4-(6-(Acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (CAPE-Ac, 30 mg, 0.09 mmol) was suspended in dioxane (0.4 mL), and 4-aminobenzonitrile (ABN, 22.3 mg, 0.19 mmol, 2.10 molEq) and ZnCl₂ (15 mg, 0.1 1 mmol, 1.22 molEq) were added to produce a thick white suspension. The reaction mixture was heated to 100 °C. After 15 minutes of stirring at 100 °C, the thick white suspension was dissolved. The solution was stirred at 100 °C overnight, then cooled to room temperature and diluted with ethyl acetate and salt water. The layers were separated, and the organic layer was washed with saturated NaCl solution. The collected water layers were washed with ethyl acetate, and the collected organic extracts were dried over Na₂S0₄, filtered and the filtrate was evaporated to dryness. The resulting residue (43 mg) was triturated with ethyl acetate and filtered. The resulting solid was washed with cold ethyl acetate / diisopropyl ether and dried.

Yield: 16 mg (42.8%) of 4-(6-(acetylamino)-2-(4-cyanophenylamino)pyrimidin_r4-yloxy)-3,5- dimethylbenzonitrile (DEBETV-Ac). Purity (HPLC): 93.2 area %

Example 6b: Preparation of 4-(6-(acetylamino)-2-(4-cvanophenylamino pyrimidin-4-yloxy - 3.5-dimethylbenzonitrile (DEBETV-Ac)

4-(6-(Acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (CAPE-Ac, 437 mg, 1.31 mmol) was suspended in dioxane (1 1 mL), and 4-aminobenzonitrile (ABN, 324.7 mg, 2.75 mmol, 2.10 molEq) and ZnCl₂ (218.5 mg, 1.603 mmol, 1.22 molEq) were added. The reaction mixture was heated to 90-100 °C and stirred for 43 h. The reaction mixture was then cooled to room temperature and evaporated to dryness in vacuo. The resulting residue was dissolved in ethyl acetate (120 mL) and water (120 mL). The layers were separated, and the organic layer was washed with saturated NaCl solution (40 mL), dried over MgS0₄, and filtered. The filtrate was evaporated to dryness. The resulting residue was dissolved in DMA (3 mL), and water (2.5 mL) was added dropwise. The resulting suspension was stirred at 0-5 °C for 1 h, and filtered. The collected solid was washed with water and dried 5h / 40 °C / 10 mbar.

Yield: 476 mg (87.5%) of 4-(6-(acetylamino)-2-(4-cyanophenylamino)pyrimidin-4-yloxy)- 3,5-dimethylbenzonitrile (DEBETV-Ac). Purity (HPLC): 93.3 area % Example 7a: Preparation of 4-(6-amino-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3.5- dimethylbenzonitrile (DEBETV)

4-(6-(Acetylamino)-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzo- nitrile (DEBETV-Ac, 15 mg, 0.036 mmol) was suspended in ethanol (0.3 mL) and a solution of KOH (8.4 mg, 0.15 mmol, 4.17 molEq) in water (0.02 mL) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with saturated NaCl (3 mL), and extracted with ethyl acetate. The organic layer was dried over Na₂S0₄, filtered and the filtrate was evaporated to dryness. ^'

Yield: 15 mg (crude product) of 4-(6-amino-2-(4-cyanophenylamino)pyrimidin-4-yl- oxy)-3,5-dimethylbenzonitrile (DEBETV) as solid/resin which is used in the next step as is. Purity (HPLC): 90.9 area %.

Example 7b: Preparation of 4-(6-amino-2-(4-cvanophenylamino)pyrimidin-4-yloxy)-3,5- dimethylbenzonitrile (DEBETV)

4-(6-(Acetylamino)-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzo- nitrile (DEBETV-Ac, 400 mg, 0.965 mmol) was suspended in ethanol (8 mL) and a solution of KOH (225.8 mg, 4.02 mmol) in water (0.533 mL) was added. The resulting reaction mixture was stirred at room temperature overnight. Additional KOH (45 mg, 0.80 mmol) in water (0.1 10 mL) was added, and the reaction mixture was stirred at room temperature for an additional 2h. The reaction mixture was then diluted with saturated aqueous NaCl (80 mL), and extracted with ethyl acetate (80 mL). The organic layer was dried over MgS0₄, and filtered, and the filtrate was evaporated to dryness.

Yield: 314 mg (91.3% of crude product) of 4-(6-amino-2-(4-cyanophenylamino)pyrimidin-4- yloxy)-3,5-dimethylbenzonitrile (DEBETV) as solid/resin which is used in the next step as is. Purity (HPLC): 90.8 area %.

Example 8: Preparation of 4-(6-amino-5-bromo-2-(4-cvanophenylamino)pyrimidin-4-yloxy - 3.5-dimethylbenzonitrile (Etravirine)

4-(6-Amino-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (DEBETV, 15 mg, 0.042 mmol) was dissolved in Ν,Ν-dimethylformamide (DMF, 0.3 mL) and cooled to -10/-5 °C. A solution of bromine ( 13.5 mg, 0.084 mmol, 2 molEq) in DMF (0.1 mL) was added dropwise and the mixture was stirred at -5/0 °C for 1 hour. The reaction mixture was then diluted with ethyl acetate (3 mL) and saturated aqueous NaCl/NaHC0₃, and extracted. The water layer was washed with ethyl acetate, and the collected organic extracts were washed with saturated aqueous NaCl, dried over Na₂S0₄, filtered, and the filtrate was evaporated to dryness.

Yield: 16.2 mg (88.6%) of 4-(6-amino-5-bromo-2-(4-cyanophenylamino)pyrimidin-4-yloxy)- 3,5-dimethylbenzonitrile (ETV). Purity (HPLC): 92.4 area %.

Claims

What is claimed is:

1 A use of a compound of Formula 1 :

Formula 1

wherein X is halogen or a tosyl group, or salts of said compound in preparation of Etravirine, salts thereof and solid state forms thereof.

2. A process for preparing Etravirine, a salt thereof and a solid state form thereof; said process comprising:

a) preparing a compound of Formula 1 :

Formula 1

wherein X is halogen or a tosyl group, or a salt of said compound, and

b) converting said compound of Formula 1, or a salt of said compound of Formula 1, to Etravirine, a salt thereof or a solid state form thereof.

3. The process of claim 2, wherein the converting step comprises:

a) reacting the compound of Formula 1, or a salt of said compound of Formula 1, and 4-hydroxy-3,5-dimethylbenzonitrile to obtain a com ound of Formula 3:

Formula 3 wherein X is halogen or a tosyl group, or a salt of said compound of Formula 3; b) reacting the compound of Formula 3, or a salt of said compound of Formula 3, and 4-aminobenzonitrile to obtain Etravirine or a salt of Etravirine; and

c) optionally converting the Etravirine to an Etravirine salt.

A process for preparing Etravirine comprising:

a) brominating a compound of Formula 2:

Formula 2 wherein X is halogen or a tosyl group, or a salt of said compound of Formula 2, to obtain a compound of Formula 1 :

Formula 1

b) reacting the compound of Formula 1, or a salt of said compound of Formula 1, and 4-hydroxy-3,5-dimethylbenzonitrile ("DMHB") to obtain a compound of Formula 3:

Formula 3 wherein X is halogen or a tosyl group, or a salt of said compound of Formula 3; c) reacting the compound of Formula 3, or a salt of said compound of Formula 3, and 4-aminobenzonitrile ("ABN") to obtain Etravirine or a salt of Etravirine; and d) optionally converting the Etravirine to an Etravirine salt.

5. The process of claim 4, wherein X is -CI.

6. The process of any one of claims 2 to 5, further comprising purifying the obtained Etravirine or Etravirine salt.

7. The compound, 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethyl- benzonitrile ("CAPE- Ac"),:

CAPE - Ac

and salts thereof.

8. The compound 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethyl- benzonitrile according to claim 7, wherein it is isolated.

9. The compound 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethyl- benzonitrile according to claim 7 or 8, wherein it is in crystalline form.

10. The compound 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethyl- benzonitrile according to any one of claims 7 to 9, for use in preparation of Etravirine, salts thereof and solid state forms thereof.

11. A process for preparing the compound 4-(6-(acetylamino)-2-chloropyrimidin-4- yloxy)-3,5-dimethylbenzonitrile according to any one of claims 7 to 9 comprising acetylating 2,6-dichloropyrimidin-4-amine ("DCAP") of the following structure:

DCAP to obtain the compound 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethyl- benzonitrile.

12. A process for preparing Etravirine, a salt thereof and a solid state form thereof, said process comprising:

a) preparing 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3 ,5 -dimethylbenzonitrile according to the process of claim 11 ; and

b) converting it to Etravirine, a salt thereof or a solid state form thereof.

13. The process of claim 12, wherein the converting in step b) comprises:

i) reacting 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile and 4-aminobenzonitrile to obtain 4-(6-(acetylamino)-2-(4-cyano- phenylamino)pyrimidin-4-yloxy)-3 ,5 -dimethylbenzonitrile (DEBETV-Ac);

ii) deprotecting the DEBETV-Ac to obtain 4-(6-amino-2-(4 cyanophenylamino)- pyrimidin-4-yloxy)-3, 5 -dimethylbenzonitrile (DEBETV);

iii) brominating the DEBETV to obtain Etravirine; and

iv) optionally converting the Etravirine to an Etravirine salt or a solid state form of Etravirine.

14. A process for preparing Etravirine or a salt thereof comprising:

a) acetylating 2,6-dichloropyrimidin-4-amine ("DCAP") to obtain acetyl-N-(2,6- dichloropyrimidin-4-yl)hydroxylamine ("DCAP -Ac");

b) reacting the DCAP-Ac and 4-hydroxy-3, 5 -dimethylbenzonitrile ("DMHB") to obtain 4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile ("CAPE-Ac");

c) reacting the CAPE-Ac and 4-aminobenzonitrile ("ABN") to obtain 4-(6- (acetoxyamino)-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile ("DEBETV-Ac");

d) deprotecting the DEBETV-Ac to obtain 4-(6-amino-2-(4 cyanophenylamino)- pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (DEBETV);

e) brominating the DEBETV to obtain Etravirine; and

f) optionally converting the Etravirine to an Etravirine salt.

15. The process of claim 14, further comprising purifying the obtained Etravirine or

Etravirine salt.