WO2015107451A2 - Purification of tenofovir alafenamide and its intermediates - Google Patents

Purification of tenofovir alafenamide and its intermediates Download PDF

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Publication number
WO2015107451A2
WO2015107451A2 PCT/IB2015/050239 IB2015050239W WO2015107451A2 WO 2015107451 A2 WO2015107451 A2 WO 2015107451A2 IB 2015050239 W IB2015050239 W IB 2015050239W WO 2015107451 A2 WO2015107451 A2 WO 2015107451A2
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WO
WIPO (PCT)
Prior art keywords
acid
formula
tenofovir alafenamide
process according
salt
Prior art date
Application number
PCT/IB2015/050239
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English (en)
French (fr)
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WO2015107451A3 (en
Inventor
Siva Ram Prasad Vellanki
Raja Babu Balusu
Subba Rayudu PUTTA
Mastan Rao RAAVI
Sivalakshmi Devi ARIKATLA
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Mylan Laboratories Ltd.
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Publication date
Application filed by Mylan Laboratories Ltd. filed Critical Mylan Laboratories Ltd.
Priority to EP15705378.6A priority Critical patent/EP3077404B1/en
Priority to ES15705378T priority patent/ES2842123T3/es
Publication of WO2015107451A2 publication Critical patent/WO2015107451A2/en
Publication of WO2015107451A3 publication Critical patent/WO2015107451A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • the present disclosure relates to an improved process for the preparation of tenofovir alafenamide and its intermediates.
  • Tenofovir alafenamide is chemically known as 9- ⁇ (R)-2-[((S)- ⁇ [(S)-l- (isopropoxycarbonyl) ethyl]amino ⁇ phenoxyphosphinyl)methoxy]propyl ⁇ adenine.
  • Tenofovir alafenamide has the structure shown in Formula-I and is a prodrug of tenofovir, a phosphonate nucleotide analogue.
  • WO2013052094 which is hereby incorporated by reference, also discloses crystallization techniques for the diastereomeric separation of 9- ⁇ (R)-2-[((R,S)- ⁇ [(S)-l-(isopropoxycarbonyl)ethyl]amino ⁇ phenoxyphosphinyl) methoxy] propyl ⁇ adenine to give tenofovir alafenamide.
  • One aspect of the present disclosure provides a process for the purification of Formula- IV, which may exist as a mixture of enantiomers, to give tenofovir alafenamide, 9- ⁇ (R)- 2-[((R,S)- ⁇ [(S)-l-(isopropoxycarbonyl)ethyl]amino ⁇ phenoxyphosphinyl) methoxy] propyl ⁇ adenine.
  • Formula-IV One embodiment of the present invention provides a process for the resolution of the enantiomers of Formula-IV using acids.
  • Another aspect of the present invention provides a process for the resolution of the enantiomers represented by Formula-Ill using chiral amines to give monophenyl tenofovir.
  • Figure 1 is an X-ray powder diffraction pattern of tenofovir alafenamide orate salt.
  • One aspect of the present disclosure is to provide a process for the enantiomeric purification Formula-IV using acids.
  • Formula-IV may be reacted with a suitable acid in the presence of a suitable solvent to produce a corresponding acid salt of Formula-IV.
  • Desaltification of the obtained acid salt of Formula-IV with a base gives tenofovir alafenamide of Formula-I.
  • the acid may be chiral or achiral.
  • a suitable chiral acid may be, for example, (S)-(+)-mandelic acid, (R)-(-)-mandelic Acid, (l S)-(+)- 10-camphor sulfonic acid, (lR)-(-)-10-camphor sulfonic acid, (D)-(-)-tartaric acid, (L)- (+)-tartaric acid, (-)-Di-p-toluoyl-L-tartaric acid, (+)-Di-p-toluoyl-D-tartaric acid, (L)-(- )-malic acid, (D)-(+)-malic acid, (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (1R, 3S)-(+)-camphoric acid, (IS, 3R)-(-camphoric acid, (IS, 3
  • achiral acids include orotic acid, fumaric acid, oxalic acid, maleic acid, benzoic acid, p-toluenesulphonic acid, succinic acid, orthophosphoric acid, and malonic acid.
  • suitable solvents include ethyl acetate, acetone, acetonitrile, methanol, ethanol, n-propanol, 2-propanol, isopropyl acetate, methyl t-butyl ether, toluene, diisopropyl ether, hexane, THF, and mixtures thereof.
  • Formula-IV may exist as a mixture of two enantiomers, which are shown below as Formula-IVa and Formula-IVb.
  • the compound represented by Formula-IVa is identical to the tenofovir alafenamide of Formula I.
  • the percentage of Formula-IVa in the starting enantiomeric mixture of Formula IV may range from about 0% to about 99% prior to purification. In some embodiment of the invention, the percentage of Formula-IVa in the starting enantiomeric mixture ranges from above 0% to about 20%. In other embodiments, the percentage of Formula-IVa in the starting enantiomeric mixture ranges from about 20% to about 99%. In yet other embodiments, the percentage of Formula-IVa in the starting enantiomeric mixture ranges from about 50% to about 99%. In some embodiments, Formula-I, which may be purified from Formula-IV, contains less than 1% of enantiomeric impurities. In some particular embodiments, the purified Formula-I is substantially free of any detectable enantiomeric impurities.
  • Tenofovir alafenamide salts of the present invention may be characterized by their X-ray powder diffraction patterns. X-ray diffraction patterns were measured on a BRUKER D- 8 Discover powder diffractometer equipped with a goniometer of ⁇ /2 ⁇ configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
  • One aspect of the present invention provides the orate salt of tenofovir alafenamide.
  • the tenofovir alafenamide orate salt may be characterized by a powder X-ray diffraction pattern having significant peaks at 2 ⁇ values of 3.7, 9.3, 12.3, 15.6, 18.9, 22.8 and 28.8 ⁇ 0.2°
  • the tenofovir alafenamide orate salt may be further characterized by a powder X-ray diffraction pattern as depicted in Figure 1.
  • Another aspect of the present disclosure is to provide methods for the crystallization of Formula-IV using a suitable solvents to give substantially pure tenofovir alafenamide of Formula-I.
  • suitable solvents may be, for example, ethyl acetate, acetone, dimethyl formamide, toluene, isopropyl ether, methyl tertiary butyl ether, water, alcoholic solvents, or mixtures thereof.
  • suitable alcoholic solvents include methanol, ethanol, isopropanol, and mixtures thereof.
  • the present disclosure further provides a process for the resolution of monophenyl tenofovir from a mixture of enantiomers depicted by Formula-Ill using chiral amines.
  • the chiral amine may be, for example, (R)- (+)-l -phenylethylamine, (S)-(-) -1 -phenylethylamine, (R)-(+)-l-(l-naphthyl)ethyl amine, or (S)-(-)-l-(l-naphthyl)ethyl amine.
  • Formula-Ill may be dissolved in suitable solvent such as acetonitrile, acetone, ethyl acetate, chloroform, N-methyl pyrrolidone and dimethyl formamide.
  • suitable solvent such as acetonitrile, acetone, ethyl acetate, chloroform, N-methyl pyrrolidone and dimethyl formamide.
  • a chiral amine may then be added and the mixture stirred.
  • suitable chiral amines include R-(+)-l -phenylethylamine and (S)-(-)-l- phenylethylamine.
  • the reaction mass may then be cooled and filtered.
  • the obtained material may then be dried to get the R-(+)-l -phenylethylamine salt or (S)-(-)-l- phenylethylamine salt of Formula-Ill.
  • the obtained salt may then be treated with an acid to get a substantially pure compound of Formula-Ill
  • monophenyl tenofovir may then be further converted into tenofovir alafenamide or pharmaceutically acceptable salts thereof.
  • Example 1 Process for the preparation of L-alanine isopropyl ester hydrochloride.
  • L-alanine (100 g) and isopropyl alcohol (600 g) were combined in a round bottom flask and stirred for 10 to 15 minutes. Trimethylsilyl chloride (243.8 g) was then added and stirring continued for 15 minutes. The reaction mass temperature was raised to 74 ⁇ 3 °C and maintained for 4-6 hours. The reaction progress was monitored by HPLC. After completion, isopropyl alcohol was distilled out under vacuum and then cooled to 42 ⁇ 3 °C. Methyl tert-butyl ether (500 ml) was then added and stirred for 30 minutes. The reaction mass was cooled to room temperature, then crystallized. The product was filtered under nitrogen atmosphere, washed with methyl tert-butyl ether (200 ml) and dried under vacuum to get L-alanine isopropyl ester hydrochloride.
  • Example 2 Process for the preparation of monophenyl PMPA hydrate
  • Methylene dichloride (200 ml) was then added and stirred for 30 minutes before cooling to 8 ⁇ 2 °C. Water was added (400 ml) and stirred for 10 min. The temperature was slowly raised to 25 ⁇ 3 0 C, stirred for 30 minutes, then the mixture was allowed to settle. The bottom organic layer was then separated. Methylene dichloride (200 ml) was added to the aqueous layer, stirred for 30 minutes, and the mixture was allowed to settle again before separating the bottom organic layer. This process was repeated once again, adding methylene dichloride (200 ml), allowing the reaction to settle, and then separating the organic layer. The pH of the aqueous layer was then adjusted to 2.25 ⁇ 0.25 with chemically pure HCl. The product was filtered, washed with chilled water followed by acetone and dried to yield monophenyl PMPA hydrate.
  • Example 5 Process for the preparation of tenofovir alafenamide
  • reaction mass was maintained at 70 ⁇ 3 °C for 26 hours and monitored for reaction completion by HPLC. Toluene and acetonitrile were distilled out under vacuum, keeping the temperature below 70 °C, and the reaction mixture was then cooled to room temperature. Methylene dichloride (1000 ml) and trimethylsilyl chloride (9.12 g) were then added. In a second flask, methylene dichloride (1000 ml) and L-alanine isopropyl ester hydrochloride (131.8 g) were mixed at room temperature. Trimethylsilyl chloride (9.12 g) was then added and the reaction conditions maintained for 60 minutes before cooling to 3 ⁇ 2 °C.
  • Triethylamine (106.2 g) was then added and reaction conditions maintained for 60 minutes before again cooling to -25 ⁇ 3 0 C.
  • the mixture in the first reaction flask was then added to the mixture in the second reaction flask slowly at -25 ⁇ 3 °C for 180 minutes, then stirring for 120 minutes before raising the mixture to room temperature.
  • Water was then added and the aqueous and organic layers were separated.
  • the organic layer was washed with a sodium dihydrogen orthophosphate solution (10%) and layers were again separated.
  • the organic layer was then washed with potassium bicarbonate solution (10%) and layers were separated.
  • the organic layer was then washed with sodium chloride solution (10%) and separated again.
  • the organic layer was then dried with sodium sulphate for up to 60 minutes.
  • Example 21 Process for the preparation of Tenofovir alafenamide orate salt
  • Formula-IV (2.5 g) was dissolved in a mixture of acetone (14 ml) and water (12.5 ml). Orotic acid/orotic acid monohydrate/orotic acid dihydrate (0.82 g) in a dimethyl sulfoxide (8 ml) solution was then added to this solution. The reaction mixture was stirred for 10- 15 minutes and water (12.5 ml) was added. The reaction mass was stirred for 90 minutes. The product was filtered from the reaction mass, washed with acetone (12.5 ml), and dried under vacuum to get tenofovir alafenamide orate salt.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/IB2015/050239 2014-01-14 2015-01-13 Purification of tenofovir alafenamide and its intermediates WO2015107451A2 (en)

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Application Number Priority Date Filing Date Title
EP15705378.6A EP3077404B1 (en) 2014-01-14 2015-01-13 Purification of tenofovir alafenamide and its intermediates
ES15705378T ES2842123T3 (es) 2014-01-14 2015-01-13 Purificación de tenofovir alafenamida y sus intermedios

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IN118/MUM/2014 2014-01-14
IN118MU2014 IN2014MU00118A (enEXAMPLES) 2014-01-14 2015-01-13

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Cited By (23)

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WO2016192692A1 (en) * 2015-06-05 2016-12-08 Zentiva K.S. Solid forms of tenofovir alafenamide
WO2016205141A1 (en) * 2015-06-17 2016-12-22 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
CN106478725A (zh) * 2016-10-14 2017-03-08 上海礼泰医药科技有限公司 高纯度膦丙替诺福韦中间体的制备方法及其应用
CN106699812A (zh) * 2015-11-12 2017-05-24 江苏豪森药业集团有限公司 替诺福韦前药的制备和纯化方法
WO2017118928A1 (en) 2016-01-06 2017-07-13 Lupin Limited Process for the separation of diastereomers of tenofovir alafenamide
CN106946935A (zh) * 2017-04-28 2017-07-14 福建广生堂药业股份有限公司 一种非对映异构体核苷衍生物的制备方法
WO2017134089A1 (en) 2016-02-02 2017-08-10 Sandoz Ag Crystalline forms of tenofovir alafenamide monofumarate
CN107179355A (zh) * 2016-03-11 2017-09-19 广东东阳光药业有限公司 一种分离检测替诺福韦艾拉酚胺及其有关物质的方法
WO2017157352A1 (en) * 2016-03-17 2017-09-21 Zentiva, K.S. A preparation method of diastereomerically pure tenofovir alafenamide or its salts
CN107226826A (zh) * 2016-03-25 2017-10-03 江苏奥赛康药业股份有限公司 替诺福韦艾拉酚胺富马酸盐化合物及其药物组合物
CN108117570A (zh) * 2016-11-28 2018-06-05 正大天晴药业集团股份有限公司 一种替诺福韦艾拉酚胺半富马酸盐的结晶及其制备方法
CN108341841A (zh) * 2017-01-22 2018-07-31 成都倍特药业有限公司 一种替诺福韦艾拉酚胺与门冬氨酸的盐
WO2018144390A1 (en) * 2017-01-31 2018-08-09 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
CN108467410A (zh) * 2018-04-09 2018-08-31 重庆三圣实业股份有限公司 一种taf中间体的制备方法及产品和应用
CN108484672A (zh) * 2018-05-23 2018-09-04 中国药科大学制药有限公司 磷丙替诺福韦的手性拆分方法
CN109942633A (zh) * 2017-12-20 2019-06-28 上海博志研新药物技术有限公司 替诺福韦艾拉酚胺中间体的制备方法
CN109942632A (zh) * 2017-12-20 2019-06-28 上海博志研新药物技术有限公司 替诺福韦艾拉酚胺中间体的制备方法
CN110105392A (zh) * 2019-06-04 2019-08-09 石家庄凯赛医药科技有限公司 一种替诺福韦艾拉酚胺的高效合成工艺
CN110283208A (zh) * 2018-06-22 2019-09-27 南京济群医药科技股份有限公司 一种替诺福韦艾拉酚胺的手性拆分方法
WO2021165995A1 (en) 2020-02-20 2021-08-26 Cipla Limited Novel salts and/or co-crystals of tenofovir alafenamide
CN114907409A (zh) * 2022-06-21 2022-08-16 辰欣药业股份有限公司 一种丙酚替诺福韦的制备方法
US11667656B2 (en) 2021-01-27 2023-06-06 Apotex Inc. Crystalline forms of Tenofovir alafenamide
WO2024147616A3 (en) * 2023-01-04 2025-09-12 Chong Kun Dang Pharmaceutical Corp. Pharmaceutical composition with improved stability comprising tenofovir alafenamide or pharmaceutically acceptable salt thereof

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WO2016192692A1 (en) * 2015-06-05 2016-12-08 Zentiva K.S. Solid forms of tenofovir alafenamide
AU2016277859B2 (en) * 2015-06-17 2019-08-01 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
EP4092037A1 (en) * 2015-06-17 2022-11-23 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
WO2016205141A1 (en) * 2015-06-17 2016-12-22 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
US9777028B2 (en) 2015-06-17 2017-10-03 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
US10155781B2 (en) 2015-06-17 2018-12-18 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
CN106699812A (zh) * 2015-11-12 2017-05-24 江苏豪森药业集团有限公司 替诺福韦前药的制备和纯化方法
WO2017118928A1 (en) 2016-01-06 2017-07-13 Lupin Limited Process for the separation of diastereomers of tenofovir alafenamide
WO2017134089A1 (en) 2016-02-02 2017-08-10 Sandoz Ag Crystalline forms of tenofovir alafenamide monofumarate
CN107179355A (zh) * 2016-03-11 2017-09-19 广东东阳光药业有限公司 一种分离检测替诺福韦艾拉酚胺及其有关物质的方法
WO2017157352A1 (en) * 2016-03-17 2017-09-21 Zentiva, K.S. A preparation method of diastereomerically pure tenofovir alafenamide or its salts
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CN110234655A (zh) * 2017-01-31 2019-09-13 吉利德科学公司 替诺福韦艾拉酚胺的结晶形式
US11440928B2 (en) 2017-01-31 2022-09-13 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
US12202849B2 (en) 2017-01-31 2025-01-21 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
AU2022283687B2 (en) * 2017-01-31 2024-09-05 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
TWI820984B (zh) * 2017-01-31 2023-11-01 美商基利科學股份有限公司 替諾福韋埃拉酚胺(tenofovir alafenamide)之晶型
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US10287307B2 (en) 2017-01-31 2019-05-14 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
WO2018144390A1 (en) * 2017-01-31 2018-08-09 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
JP2020505411A (ja) * 2017-01-31 2020-02-20 ギリアード サイエンシーズ， インコーポレイテッド テノホビルアラフェナミドの結晶形態
AU2021200857B2 (en) * 2017-01-31 2022-09-08 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
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CN108467410B (zh) * 2018-04-09 2021-04-09 重庆三圣实业股份有限公司 一种taf中间体的制备方法及产品和应用
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CN110283208B (zh) * 2018-06-22 2022-07-08 南京济群医药科技股份有限公司 一种替诺福韦艾拉酚胺的手性拆分方法
CN110105392A (zh) * 2019-06-04 2019-08-09 石家庄凯赛医药科技有限公司 一种替诺福韦艾拉酚胺的高效合成工艺
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