WO2016116074A1 - A method of producing highly pure rilpivirine and its salts - Google Patents

A method of producing highly pure rilpivirine and its salts Download PDF

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Publication number
WO2016116074A1
WO2016116074A1 PCT/CZ2016/000004 CZ2016000004W WO2016116074A1 WO 2016116074 A1 WO2016116074 A1 WO 2016116074A1 CZ 2016000004 W CZ2016000004 W CZ 2016000004W WO 2016116074 A1 WO2016116074 A1 WO 2016116074A1
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WO
WIPO (PCT)
Prior art keywords
rilpivirine
added
reaction
mixture
water
Prior art date
Application number
PCT/CZ2016/000004
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English (en)
French (fr)
Inventor
Josef Hajicek
Marketa Slavikova
Josef ZEBULA
Original Assignee
Zentiva, K.S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2016116074A1 publication Critical patent/WO2016116074A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Definitions

  • 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.
  • Rilpivirine 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.
  • DSC strongly exothermic course
  • 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.
  • hydrochloride of the product can be advantageously prepared in aqueous isopropanol to obtain the crystalline product in a high purity.
  • 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.
  • 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.).
  • 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 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.
  • 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%).
  • 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%.
  • N P 80 ml; 0.09% of water, dried 4A MS - molecular sieves
  • a solution of sodium carbonate 50 g of Na2C03, topped up with water to 500 ml
  • pH 7.5-8 pH 7.5-8 is obtained (58 ml in total).
  • water 200 ml is gradually added and the suspension is stirred at the room temperature (rt) for 3 h.
  • 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%.
  • 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.
  • 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.
  • water is added to the organic phase, the mixture is heated up to 70°C and intensively stirred for 30 min.
  • aqueous HCI 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.
  • aqueous phase 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).
  • 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%).
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/CZ2016/000004 2015-01-21 2016-01-13 A method of producing highly pure rilpivirine and its salts WO2016116074A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2015-32A CZ201532A3 (cs) 2015-01-21 2015-01-21 Způsob výroby vysoce čistého Rilpivirinu a jeho solí
CZ2015-32 2015-01-21

Publications (1)

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WO2016116074A1 true WO2016116074A1 (en) 2016-07-28

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CZ (1) CZ201532A3 (cs)
WO (1) WO2016116074A1 (cs)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109293581A (zh) * 2018-09-21 2019-02-01 宜昌人福药业有限责任公司 一种制备盐酸利匹韦林异构体z和杂质x的方法及杂质x作为杀虫剂在农业中的应用
WO2020084142A1 (en) 2018-10-25 2020-04-30 Minakem Process for the preparation of rilpivirine

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003016306A1 (en) 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. Hiv inhibiting pyrimidines derivatives
WO2004016581A1 (en) 2002-08-09 2004-02-26 Janssen Pharmaceutica N.V. Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile
WO2012143937A2 (en) * 2011-04-15 2012-10-26 Emcure Pharmaceuticals Limited An improved rilpivirine process
WO2012147091A2 (en) 2011-04-25 2012-11-01 Hetero Research Foundation Process for rilpivirine
WO2013038425A1 (en) * 2011-09-16 2013-03-21 Hetero Research Foundation Rilpivirine hydrochloride
WO2013179105A1 (en) 2012-06-01 2013-12-05 Laurus Labs Private Limited Improved process for preparation of rilpivirine and pharmaceutically acceptable salts thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003016306A1 (en) 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. Hiv inhibiting pyrimidines derivatives
WO2004016581A1 (en) 2002-08-09 2004-02-26 Janssen Pharmaceutica N.V. Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile
WO2012143937A2 (en) * 2011-04-15 2012-10-26 Emcure Pharmaceuticals Limited An improved rilpivirine process
WO2012147091A2 (en) 2011-04-25 2012-11-01 Hetero Research Foundation Process for rilpivirine
WO2013038425A1 (en) * 2011-09-16 2013-03-21 Hetero Research Foundation Rilpivirine hydrochloride
WO2013179105A1 (en) 2012-06-01 2013-12-05 Laurus Labs Private Limited Improved process for preparation of rilpivirine and pharmaceutically acceptable salts thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109293581A (zh) * 2018-09-21 2019-02-01 宜昌人福药业有限责任公司 一种制备盐酸利匹韦林异构体z和杂质x的方法及杂质x作为杀虫剂在农业中的应用
CN109293581B (zh) * 2018-09-21 2020-03-27 宜昌人福药业有限责任公司 一种制备盐酸利匹韦林异构体z和杂质x的方法及杂质x作为杀虫剂在农业中的应用
WO2020084142A1 (en) 2018-10-25 2020-04-30 Minakem Process for the preparation of rilpivirine

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