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Title:
A METHOD OF PRODUCING HIGHLY PURE RILPIVIRINE AND ITS SALTS
Document Type and Number:
WIPO Patent Application WO/2016/116074
Kind Code:
A1
Abstract:
A method of preparing Rilpivirine of formula I, or a suitable salt thereof, comprising a reaction of a hydrogen halide of the aniline derivative of formula II with chloropyrimidine of formula III in methyl isobutyl ketone and in the presence of a polar additive.

Inventors:
HAJICEK, Josef (Do Nehvizdek 588, Nehvizdy, 250 81, CZ)
SLAVIKOVA, Marketa (Letecka 482, Libcice nad Vitavou, 252 66, CZ)
ZEBULA, Josef (Dobroutov 27, Polna, 588 13, CZ)
Application Number:
CZ2016/000004
Publication Date:
July 28, 2016
Filing Date:
January 13, 2016
Export Citation:
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Assignee:
ZENTIVA, K.S. (U Kabelovny 130, Praha 10, 102 37, CZ)
International Classes:
C07D239/48
Domestic Patent References:
WO2013038425A12013-03-21
WO2012143937A22012-10-26
WO2004016581A12004-02-26
WO2003016306A12003-02-27
WO2004016581A12004-02-26
WO2012147091A22012-11-01
WO2013179105A12013-12-05
Attorney, Agent or Firm:
JIROTKOVA, Ivana et al. (ROTT, RUZICKA & GUTTMANNVinohradska 37, Praha 2, 120 00, CZ)
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Claims:
1. a I, or a suitable salt thereof, comprising a reaction of a hydrogen halide of the aniline

with chloropyrimidine of formula III in methyl isobutyl ketone and in the presence of a polar additive.

2. The method of preparing Rilpivirine according to claim 1 , characterized in that the hydrogen ha!ide of the aniline derivative II is the hydrochloride or hydrobromide.

3. The method of preparing Rilpivirine according to claim 1 , characterized in that the polar additive is water in an amount of 5 to 100 mol%, or a higher-boiling alcohol selected from (C4 to Cs) in an amount of 5 to 100 mol%.

4. The method of preparing Rilpivirine according to claim 3, characterized in that the additive is n-pentanol.

5. The method of preparing Rilpivirine according to claim 1 , characterized by further comprising the step of purification of the obtained rilpivirine hydrochloride by recrystaliization from an aqueous alcohol, preferably 50% vol./vol. H20-active pharmaceutical ingredient-IPA.

Description:
A method of producing highly pure Rilpivirine and its salts

Technical Field The invention relates to a new process for the production and purification of Rilpivirine, of chemical name (E)-4-({4-((4-(2-cyanovinyl)-2,6-dimethylphenyl)- nitrile, in the form of both the free base and a salt. Background Art

The first synthesis of Rilpivirine is described in the patent WO03016306 by means of a reaction of the aniline derivative 1 with chloropyrimidine 2 at a high temperature. Rilpivirine was isolated in a low yield and this reaction without a solvent is not technologically suitable due to its strongly exothermic course (DSC). During the reaction, epimerization of the double bond takes place and a side product (Z-isomer 4) is one of the main impurities.

In the following patent application WO2004016581 the reaction is conducted in a suspension in a solvent, in particular acetonitrile and W-methylpyrrolidone (NMP) are mentioned as solvents. Scheme 2

Another patent application, WO2012147091, describes carrying out this reaction in 1 ,4-dioxane in the presence of para-toluenesulfonic acid (Scheme 2). Carrying out this reaction in the presence of a phase transfer catalyst (e.g. Bu 4 N*AcO ~ ) in a solvent is described in the application WO2013179 05.

Disclosure of Invention The r preparing Rilpivirine of formula I,

or a suitable salt thereof, comprising a reaction of a hydrogen halide of the aniline deri

with chloropyrimidine of formula 111

in methyl isobutyl ketone and in the presence of a polar additive, which is water in an amount of 5 to 100 mol% or a higher-boiling alcohol selected from (C4-C8), preferably n-pentanol, in an amount of 5 to 100 mol%. The hydrogen halide of the aniline derivative II is the hydrochloride or hydrobromide. Purification of the obtained rilpivirine hydrochloride is done by recrystallization from an aqueous alcohol, preferably 50% vo!Jvol. H 2 0-active pharmaceutical ingredient-IPA. in the above mentioned reaction of the aniline derivative 1.HCI with chloropyrimidine 2 a number of various solvents have been tested (decane, anisoie, toluene, xylene, dimethyl formamide, dimethyl sulfoxide, MIBK). It has been found out that 2-methyl-3- pentanone (methyl isobutyl ketone - MIBK) can be successfully used in the condensation reaction in accordance with Scheme 2 in the presence of a catalytic amount of water (5-15 mol%). Also, addition of higher-boiling alcohols, e.g. n- pentano!, to MIBK has a positive influence on the yield and purity of the product from the reaction in MIBK.

It has also been found out that the hydrochloride of the product can be advantageously prepared in aqueous isopropanol to obtain the crystalline product in a high purity.

Detailed description of the invention MIBK is a solvent with a high boiling point (117 to 118 °C) and low solubility in water; therefore, it is frequently used in the chemical industry. Compared to acetonitrile, which is used in WO2004016581 , the reaction in the higher-boiling MIBK runs faster. Water added to the reaction in MIBK successfully suppresses formation of the side products of the reaction of MIBK and the aniline derivative 1 and at the same time the hydrolysis of the starting derivative 2 is slow. The reaction in wet MIBK then runs faster due to the higher boiling point than in acetonitrile and also processing of the reaction by addition of an aqueous solution of potash and separation of the aqueous phase and subsequent concentration of the solution of the free base of Rilpivirine by distillation leads, after cooling, to crystallization of the product in a good purity and yield. Also, the solution of crude Rilpivirine in MIBK prepared this way can be advantageously used for the preparation of salts thereof by addition of an alcoholic or aqueous solution of a suitable acid (e.g. hydrochloric, methanesulfonic, adipic, saccharine etc.). The thus prepared free base can be purified by suspending in a mixed solvent (isopropanol, acetonitrile). Then, the fast stage is conversion of the base to the hydrochloride, which can be preferably carried out in aqueous isopropanol by addition of concentrated aqueous hydrochloric acid. In the boiling state a solution is obtained, from which Rilpivirine hydrochloride crystallizes after cooling at a high purity. Rilpivirine hydrochloride can also be advantageously purified by crystallization from 50% aqueous isopropanol. The room temperature (rt) is defined as a temperature between 15°C and 30°C; preferably it is a temperature between 20 and 25°C.

The following working examples illustrate, but do not restrict in any way, the general character of the production method in accordance with the invention.

Examples

Example 1: Procedure in accordance with WO03016306

The aniline derivative 1 {hydrochloride 710 mg, 3.38 mmol) is dosed into a flask {50 ml), DCM (dichloromethane) (10 ml) and a 10% aqueous solution of potassium carbonate (5 ml) are added. The suspension slowly passes into a solution while being stirred at rt. The organic phase is separated, dried and evaporated until dry at a reduced pressure. The base of the aniline derivative 1 (582 mg, 99.32%) is obtained. Chioropyrimidine 2 (401 mg, 1.7 mmol) is added to it and the mixture is melted in a bath at a temperature of 160-165°C for 1 hour. After cooling, a 10% aqueous solution of K2CO3 (5 ml), as well as a solvent mixture of DCM and methanol (2:1 , 10 ml) are added to the mixture. The organic layer is separated, evaporated and the obtained evaporation product (0.9 g) is purified by column chromatography, eluent DCM/ethyl- acetate 80:20. The product is obtained in the 51.8% yield (330 mg), HPLC 84.18%, Z- isomer 14.8%.

Example 2: Reaction in acetonitriie in accordance with the process application WO2004016581

The aniline derivative 1 (hydrochloride 940 mg, 4.5 mmol) and chioropyrimidine 2 (1092 mg, 4.76 mmol, 1.05 equiv.) is dosed into a flask (50 ml), acetonitriie (18 ml) is added and the thick suspension is heated up in an inert atmosphere at the bath temperature of 84°C for 69 hours. After cooling, the crystals are aspirated, washed with acetonitriie (3+1 ml) and dried in a vacuum drier at 50°C overnight. Off-white crystals are obtained (1.467 g, 81%). This rilpivirine hydrochloride (1.423 g) is stirred with a 10% aqueous solution of K2CO3 (11 ml) for 1.5 h. The yellow crystals are aspirated, washed with water (2x5 ml) and dried in a vacuum drier at 50°C overnight. Yellow crystals are obtained (1.359 g). These crystals (1.310 g) are stirred up in IPA (2-propanol) (60 ml), the mixture is refluxed for 2 hours and then stirred at rt overnight. The crystals are aspirated, washed with IPA (2x5 ml) and dried in a vacuum drier at 50°C overnight. Light yellow crystals of the base are obtained (1.359 g). Total yield 77.82%, HPLC 95.19%, Z-isomer 0.43%. Example 3: Reaction in acetonitrile under pressure

Acetonitrile (2.5 ml) is added to chloropyrimidine 2 (129 mg, 1.06 equiv.) and the aniline derivative 1 (110 mg, 1 equiv.), the tube is closed and heated up at the bath temperature of 130°C for 4 hours. After cooling, the crystals are aspirated, washed with acetonitrile and then dried in a vacuum drier at 50°C overnight. 136 mg is obtained; yield 70.5%, HPLC 98.48%, Z-isomer 0.59%.

Example 4: Reaction in W-methylpyrrolidone

N P (80 ml; 0.09% of water, dried 4A MS - molecular sieves) is added to a mixture of 8.35 g (40 mmol) of 1.HCI and 10.84 g (47 mmol) of 2 and the mixture is heated up to 95°C NMP (80 ml; 0.09 % of water, dried 4A MS - molecular sieves) is added for 17 h. A solution of sodium carbonate (50 g of Na2C03, topped up with water to 500 ml) is gradually added to the mixture cooled down to 30°C until pH 7.5-8 is obtained (58 ml in total). Then, water (200 ml) is gradually added and the suspension is stirred at the room temperature (rt) for 3 h. The solid substance is aspirated on glass frit, washed with aqueous DMF (1:2 vol./vol.; 30 ml) and dried. 15.13 g (103.2%) of the crude product is obtained; UPLC 72.5%, Z-isomer 8.7%, hydroxy derivative 3.3%.

The solid substance is suspended in a mixture of methyl ethyl ketone (MEK; 14 ml), isopropyl alcohol (IPA; 42 ml) and acetonitrile (MeCN; 42 mi) and heated up to boiling under stirring for 1 h. Then, the mixture is left to cool down to the room temperature under stirring and after that it is cooled down to 10°C for 2 h. The crystals are aspirated on glass frit, washed with 25 ml of a MEK/IPA/MeCN mixture (1/3/3) and dried in vacuo at 50°C. 10.47 g (71.4%) of crude rilpivirine is obtained; UPLC 82.3%, Z-isomer 0.7%, hydroxy derivative 16.6%.

Concentrated hydrochloric acid (7.5 ml; excess) and subsequently water (100 ml) is added to a suspension of rilpivirine (10.42 g) in IPA (100 ml) and the mixture is heated up to moderate reflux while an IPA/water mixture (1 :1) (140 ml) is gradually added in several parts. After 1 h of heating to boiling, Norit - activated carbon (1.1 g) is carefully added to the obtained solution, the solution is further heated up to boiling for 1 h and filtered through a kiese!guhr layer on pre-heated frit. The obtained solution is left to cool down to rt under stirring and after 2 more hours at rt it is cooled down to 10°C for 1 h. The crystals are aspirated, washed with 30 ml of a 1 :1 mixture of IPA/water and dried in vacuo at 50°C. 8.55 g (58.3%) of rilpivirine hydrochloride is obtained, UPLC 91.2%, Z-isomer 0.2%, hydroxy derivative 8.0%. Rilpivirine hydrochloride (8.5 g) is suspended in water (40 ml), 40 ml of acetic acid is added and the magnetically stirred mixture is heated up in a bath having the temperature of 105°C. Then, aqueous acetic acid (1:1 vol./vol.) is gradually added until clarification (58 ml). The obtained solution is left to slowly cool down, it is inoculated with form A and, after cooling down to the room temperature, it is further stirred for 2 h. The separated crystals are aspirated, washed with water (30 ml) and dried in vacuo at 50°C. 6.34 g (74.6%; 43.3 % from 1.HCI) of rilpivirine hydrochloride is obtained; UPLC 90.1%, Z-isomer 0.05%, hydroxy derivative 9.7%.

Example 5: Comparison of the reaction in dry (A) and wet (B) MIBK

The same doses of all the solid components are placed into two flasks (A and B) - aniline derivative 1 (hydrochloride, 1.21 g, 5.80 mmol, (SM1)) and chioropyrimidine 2 (1.34 g, 5.80 mmol, 1.0 equiv., SM2), then methyl isobutyl ketone (MIBK, 20 ml) is added), additionally, water is added to flask B (5 μΙ, 0.29 mmol, 5 mol%); both the suspensions are heated up in a nitrogen atmosphere in an oil bath (120-125°C) for 20 hours.

Non-calibrated HPLC analyses (C8 column, CH 3 CN :H 2 0 60 :40 (+0,1% v/v Et 3 N), Iml/min, 215 nm) proved significant suppression of formation of the MIBK impurity (imine produced by condensation of SM1 and MIBK) in experiment B, wherein the water present hydrolyses this impurity.

After another 4 hours of reflux, both the mixtures are cooled down to 70°C and processed in the same way as described beiow. A 10% wt. aqueous solution of K 2 C0 3 (20 ml) and MIBK (10 ml) is added to the suspension and the mixture is intensively stirred for 1 h. After separation of the aqueous phase, water is added to the organic phase, the mixture is heated up to 70°C and intensively stirred for 30 min. After separation of the aqueous fraction, 35% aqueous HCI (0.56 ml, 6.38 mmol, 1.1 equiv.) is added to the organic layer and the organic fraction is then concentrated by distillation at the atmospheric pressure (20 ml of the MIBK - H 2 0 mixture is removed by distillation). After cooling down to ca. 100°C, isopropanol (25 ml) is added and distillation is restored (another 20 ml are removed by distillation). The mixture is further cooled down to the room temperature and further to -17°C.

The separated hydrochloride crystals are filtered off, washed with isopropanol (3 x 1 ml) and dried by air suction on frit. The analytic results clearly show a positive influence of addition of water to the reaction of batch B, which is manifested in a much better purity and yield of the desired product.

Example 6: Addition of n-pentanol

The same doses are used for the reaction as in example 5B, but instead of water /?- pentanol (31.5 μΙ, 5 mol%) is added. Formation of MIBK impurities is also lower; the product is isolated as the hemiadipate. Z- Sum of IUIIBK

Batch Yield HPLC isomer impurities

A 33% 98.76% 0.19% 0.20%

Example 7 Reaction of aniline hydrobromide

The following ingredients are charged in a flask under an inert nitrogen atmosphere: free base of the aniline derivative 1 (1.0 g, 5.81 mmol) and chloropyrimidine 2 (1.34 g, 5.81 mmol, 1.0 equiv.), the solvent MIBK (20 ml), 33% HBr in AcOH (365 μΐ_, 1.0 equiv.) and water (105 μΙ, 1.0 equiv.) are added. The suspension is stirred and heated up in a nitrogen atmosphere for 48 h. The reaction mixture is cooled down to 40°C and then 5% wt. aqueous solution of K 2 C0 3 (20 ml) and MIBK (20 ml) is added and the mixture is intensively stirred for 10 min. After separation of the aqueous phase, water is added to the organic phase and the mixture is intensively stirred at 50°C for 10 min. After separation of the aqueous fraction, 35% aqueous HCI (0.468 ml, 5.30 mmol, 1.05 equiv.) is added to the organic layer and the separated organic fraction is then concentrated by distillation at the atmospheric pressure (26 ml of the MIBK - H2O mixture is removed by distillation). The mixture is then cooled down to the room temperature (rt) and further to 5°C and the separated hydrochloride is aspirated and washed with MIBK (10 ml). Drying at 50°C/180 hPa (24 h) provides the product (1.25 g, 53%; HPLC: 87.66%, Z-isomer 3.53%).

The product (0.5 g) is dissolved in 50% aqueous isopropanol (10 ml) under boiling conditions, activated carbon (0.13 g) is added and the mixture is refluxed for 1 h. After filtration in a hot state and cooling to rt and further to 5°C the separated product is aspirated and washed with 50% aqueous isopropanol (2 x 1 ml).

The product is dried by air suction on frit; 0.355 g (71%) of the product is obtained, HPLC 95.66%.

Example 8:

The following ingredients are charged in a one-litre duplicated reactor: hydrochloride of the aniline derivative 1 (40.63 g, 176 mmol, 1.1 equiv.) and chloropyrimidine 2 (33.45 g, 160 mmol), and the solvent MIBK (400 ml) and 1 ml of water are added. The suspension is stirred and heated up in a nitrogen atmosphere for 28 h. The bath temperature was 126°C and the reaction mixture temperature was 110°C. After 5.5 h, 1 ml of water is added and overnight, the temperature of the bath is reduced to 116°C for safety reasons. After 23.5 h, another 1 ml of water is added to the reaction mixture. The reaction is monitored by HPLC. After 28 h the temperature of the bath is reduced to 75°C and MIBK (400 ml) is added, followed by a 10% wt. aqueous solution of potassium carbonate (200 ml). The temperature of the reaction mixture has dropped to 72°C and at this temperature the mixture is stirred for 20 min. A two-phase solution is formed, pH is checked (alkaline 9-10), the bottom clear aqueous layer is drained and the brown organic layer is mixed with water (50 ml) for 5 min and separated again after division of the phases. Washing with water (50 ml) is repeated once again.

Distillation of the solvent at a reduced pressure begins at the reaction mixture temperature of 60°C and the reduced pressure of 350 hPa. First the azeotrope with water is removed by distillation and then the solvent volume continues to be reduced. During the distillation the product is separated. The reaction mixture temperature is slowly increased up to 65°C and the vacuum is reduced to 200 hPa. The total volume of 570 ml of solvents (ca. 70%) is removed by distillation. The suspension is cooled down to 20°C and stirred at this temperature overnight. The separated light yellow crystals are aspirated. HPLC 92.32%, Z-isomer 3.88%).

These crystals (34.6 g, <59% slightly wet, still containing a solvent) are returned to the pot and a mixture of solvents is added (230 ml, MIBK:IPA:MeCN 1 :3:3) and heated up to reflux (reaction mixture temperature 76°C). At this temperature, the suspension is stirred for 5 min and then the reaction mixture is cooled down to 15°C. After 30 min of stirring, light yellow crystals are aspirated. Yield 26.35 g (44.86%) (HPLC 98.31%, Z-isomer 1.01%). This base is purified by conversion to hydrochloride, see Example 7.

Example 9: Hydrochloride formation

Rilpivirine base (26.25 g, 71.6 mmol) and isopropanol (260 ml) are charged into a one-litre duplicated reactor (1 L), then concentrated aqueous HCI (20 ml, 233 mmol, 3.2 equiv.) is added dropwise during 5 min. The reaction mixture temperature rises from 20°C to 26°C. After 10 min of stirring the same volume of water (260 ml) is added and the bath temperature is increased to 90°C while the reaction moderately refluxes at ca. 80°C. Gradually, a water/IPA mixture (1:1 vol.) is added until a yellow solution is obtained. 450 ml of the mixture altogether is added during 1.5 hours. Then, the reaction mixture is slightly cooled down (to approx. 60°C) to prevent foaming, activated carbon (2.8 g) is added and the mixture is heated up to reflux again. After 1 hour the mixture is filtered through kieselguhr in a hot state and the filtrate (suspension, on cooling the product gets separated immediately) is stirred at rt overnight. Then, the suspension is cooled down to 10°C, stirred for 1 h, the white crystals are aspirated and dried in a vacuum drier at 50°C overnight.

22.26 g of bright white crystals is obtained (77.13%, HPLC 99.93%, Z-isomer 0.04%, MIBK impurity 0.03%). The total yield of the reaction corresponds to 34.6%, according to US 110008343 it is form C, sulphate ash 0.08%, water content 0.14%. Residual solvents: acetonitrile < 50 ppm; IPA 1100 ppm; MIBK<50 ppm, sum 0.11%. Titration 100%.