WO2019150181A1 - Procédé amélioré pour la préparation de 7-cyclopentyl-n, n-diméthyl-2-(5-(pipérazine-1-yl) pyridine-2-ylaminuteso)-7h-pyrrolo[2,3-d] pyrimidine-6-carboxamide succinate (succinate de ribociclib) et de formes cristallines de ce dernier - Google Patents

Procédé amélioré pour la préparation de 7-cyclopentyl-n, n-diméthyl-2-(5-(pipérazine-1-yl) pyridine-2-ylaminuteso)-7h-pyrrolo[2,3-d] pyrimidine-6-carboxamide succinate (succinate de ribociclib) et de formes cristallines de ce dernier Download PDF

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Publication number
WO2019150181A1
WO2019150181A1 PCT/IB2018/054365 IB2018054365W WO2019150181A1 WO 2019150181 A1 WO2019150181 A1 WO 2019150181A1 IB 2018054365 W IB2018054365 W IB 2018054365W WO 2019150181 A1 WO2019150181 A1 WO 2019150181A1
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WIPO (PCT)
Prior art keywords
ribociclib
succinate
ribociclib succinate
crystalline form
acid
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PCT/IB2018/054365
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English (en)
Inventor
Manik Reddy Pullagurla
Bhaskar Reddy Pitta
Jagadeesh Babu Rangisetty
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Biophore India Pharmaceuticals Pvt Ltd
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Publication of WO2019150181A1 publication Critical patent/WO2019150181A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • Ribociclib succinate (1) is a selective cyclin-dependent kinase inhibitor that help to slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). It is used for the treatment of certain kinds of breast cancer and is being studied for the treatment for other drug-resistant cancers. Chemically, it is 7-cyclopentyl-N, N-dimethyl-2-(5-(piperazin-l-yl) pyridin-2- ylaminuteso)-7H-pyrrolo[2,3-D] pyrimidine-6-carboxamide succinate (1).
  • US2012115878 discloses the synthesis of intermediates 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide and 4-(6-nitro-pyridin-3- yl)-piperazine-l -carboxylic acid tert-butyl ester used for the preparation of Ribociclib free base (1).
  • US2017342075 discloses form A of hemi-succinate, adipate, maleate and glycolate salts of Ribociclib. It further discloses the mono-succinate crystalline form-I of Ribociclib along with the XRD and DSC data.
  • one objective of the invention is to provide an improved process for the preparation of Ribociclib succinate (1) with purity greater than 99.5% by HPLC.
  • Another objective of the invention is to provide novel crystalline forms of Ribociclib succinate (1)
  • Another objective of the invention is to provide a process for the preparation of novel crystalline forms of Ribociclib succinate (1)
  • the present invention relates to an improved process for the preparation of Ribociclib succinate (1), which comprises of the following steps:
  • the present invention provides novel crystalline forms of Ribociclib succinate (1).
  • the invention provides a process for preparation of crystalline forms of Ribociclib succinate (1) comprising the steps of:
  • Ribociclib succinate (I) produced by the process is any of polymorphic forms form I, form II, form II and form IV, each crystalline form is characterized by XRPD peaks patterns as depicted in figure- 1, figure-2, figure-3 and figure-4 respectively.
  • the solvent or solvents mixture can be selected from the protic solvents selected from the group comprising water, methanol, ethanol, propanol, isopropyl alcohol, butanol, benzyl alcohol or the like, preferably methanol, benzyl alcohol and water were used in the present invention.
  • the aprotic solvents used for the preparation of crystalline forms of Ribociclib succinate (1) was selected from the group comprising acetone, acetonitrile, nitromethane, l,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, 3-butyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like, preferably acetonitrile, nitromethane, butyl acetate and dichloromethane were used in the present invention.
  • the crystalline forms of Ribociclib succinate obtained in the present invention is having purity greater than 99.5% by High-performance liquid chromatography, (HPLC).
  • Figure 1 X-Ray powder diffraction (XPRD) pattern of crystalline form I of Ribociclib succinate (1) as prepared in example-4a
  • the present invention provides an improved process for the preparation of Ribociclib succinate (1) with purity greater than or equal to 99.5% by HPLC.
  • Ribociclib succinate (1) prepared in the present invention is as represented in Scheme- 1 below:
  • Step a) proceeds with the coupling of 2-chloro-7-cyclopentyl-N, N-dimethyl-7H- pyrrolo[2,3-d] pyrimidine-6-carboxamide (5) with tert-butyl 4-(6- aminutesopyridin-3-yl) piperazine- l-carboxylate (4).
  • Intermediate (5) was added to the reaction mass containing intermediate (4) dissolved in an aprotic solvent and a suitable base at a temperature range of 10-30 °C. Reaction completion time ranges from 10-14 hrs. On completion of reaction, reaction mass was cooled to 10-15 °C and suitable protic solvent was added. The aqueous layer was extracted with a suitable aprotic solvent.
  • the suitable base used in step a) was selected from a group comprising lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS) and sodium bis(trimethylsilyl)amide (NaHDMS) or the like; preferably lithium bis (trimethylsilyl)amide (LiHMDS) was used in the present invention.
  • Step b) proceeds with the deprotection of amine protecting group of tert-butyl 4-(6- (7-cyclopentyl-6-(dimethyl carbamoyl)-7H-pyrrolo[2,3-d] pyrimidin-2- ylaminuteso) pyridin-3-yl) piperazine- l-carboxylate (3).
  • Intermediate (3) was treated with a suitable deprotecting agent in a protic solvent.
  • the deprotecting agent is an acid, more preferably an organic acid.
  • the reaction temperature ranges from 25 to 65 °C, preferably 60 to 65°C.
  • the reaction mass was cooled to 10-15 °C and pH was adjusted to an optimum range in between 10 to 11 using a suitable base.
  • the solid so formed was then filtered and optionally treated with a protic solvent to obtain Ribociclib free base (2).
  • the acid used for deprotection in step b) was selected from a group comprising of organic or inorganic acids.
  • the organic acid may be selected form the group consisting of carboxylic acid or sulphonic acid such as trifluoro acetic acid, trifluoromethanesulphonic acid, methane sulphonic acid, formic acid, tartaric acid, p-touenesulphonic acid or the like.
  • the inorganic acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid or the like. More preferably p-touenesulphonic acid was used in the present invention.
  • the base used in step b) was selected from a group comprising sodium hydroxide, potassium hydroxide, sodium carbonate potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate cesium bicarbonate, sodium methoxide, sodium ethoxide; potassium methoxide, potassium ethoxide or the like.
  • sodium hydroxide was used in the present invention.
  • Step c) involves the conversion of Ribociclib free base (2) to succinate salt of Ribociclib (1).
  • Ribociclib free base (2) was added to a suitable protic solvent and heated to 60 to70 °C.
  • Succinic acid was added to the reaction mass.
  • the temperature of the reaction may range from 15-85 °C.
  • the reaction completion time range from lhr to 3 hr., preferably lhr to 2 hr.
  • the final compound was isolated from a protic solvent to obtain pure Ribociclib succinate (1).
  • the suitable protic solvent used in step a), step b) and step c) were selected from a group comprising of methanol, ethanol, isopropyl alcohol (IP A), n-propanol, n- butanol, water or the like, preferably methanol, water and isopropyl alcohol were used in the present invention.
  • the suitable aprotic solvents used in step a) were selected from a group comprising of acetone, acetonitrile, l,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like; preferably tetrahydrofuran, toulene and ethyl acetate were used in the present invention.
  • Ribociclib succinate (1) obtained by the above process was having purity greater than equal to 99.5% by HPLC.
  • the invention provides a process for preparation of crystalline forms of Ribociclib succinate (1) comprising the steps of:
  • the protic solvents used for the preparation of crystalline forms of Ribociclib succinate (1) was selected from a group comprising of water, methanol, ethanol, propanol, isopropyl alcohol, butanol, benzyl alcohol or the like, preferably methanol, benzyl alcohol and water were used in the present invention.
  • the aprotic solvents used for the preparation of crystalline forms of Ribociclib succinate (1) was selected from a group comprising of acetone, acetonitrile, nitromethane, l.4-dioxane.
  • the crystalline forms of Ribociclib succinate (1) obtained in the present invention was having purity greater than equal to 99.5% by HPLC.
  • the crystalline forms I, II, III and IV of Ribociclib succinate (1) may produce an X-ray diffraction (XRD) pattern as illustrated in figure 1, figure 2, figure 3 and figure 4 and whose 2 theta values are tabulated in table 1, table 2, table 3 and table 4 below.
  • XRD X-ray diffraction
  • the crystalline form I of Ribociclib succinate (1) may produce an X-Ray diffraction (XRD) pattern comprising one or more of the following characteristic reflections: 4.51 ,10.57, 13.00, 13.82, 16.13, 16.44, 18.18, 19.95, 21.41, 21.93, 23.42, 25.18 and 26.23 ⁇ 20 or that produces an X-ray powder diffraction pattern further comprising one or more of the following additional reflections at 8.40, 8.84, 9.23, 11.91, 24.39, 25.18, 27.88, 28.65, 29.83, 30.52 and 34.06 ⁇ 20 or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table- 1
  • XRD X-Ray diffraction
  • the crystalline form II of Ribociclib succinate (1) may produce an X-Ray diffraction (XRD) pattern comprising one or more of the following characteristic reflections at 6.45, 7.60, 11.19, 12.62, 13.92, 14.68, 15.13, 16.54, 17.52, 18.46, 18.95, 19.30, 19.78, 20.58, 21.24, 21.79, 22.19, 23.72, 25.16, 25.34, 25.58, 26.26, 26.62, 28.05, 28.59, 30.05 aid 30.6l ⁇ 20 or that produces an X-ray powder diffraction pattern further comprising one or more of the following additional reflections at 10.09, 24.83, 29.37, 31.18, 32.04, 34.21 and 35.06 ⁇ 20 or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table-2
  • the crystalline form III of Ribociclib succinate (1) may produce an X-Ray diffraction (XRD) pattern comprising one or more of the following characteristic reflections at 4.41, 6.91, 11.16, 12.37, 12.76, 14.86, 15.79, 17.55, 18.13, 19.22, 19.68, 21.16, 21.43, 21.81, 22.51 and 23.79 ⁇ 20 or that produces an X-ray powder diffraction pattern further comprising one or more of the following additional reflections at 4.73, 6.15, 8.85, 9.26, 9.63, 10.11, 10.59, 13.49, 24.65, 25.86, 29.41, 30.18, 30.76, 31.60 and 36.02 ⁇ 20 or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table-3
  • the crystalline form IV of Ribociclib succinate (1) may produce an X-Ray diffraction (XRD) pattern comprising one or more of the following characteristic reflections at 5.22,9.18, 9.60, 10.20, 10.44, 13.81, 16.88, 17.30, 17.83, 18.08, 20.32, 20.79, 21.41, 22.70, 23.05, 23.79 and 25.15 ⁇ 20 or that produces an X-ray powder diffraction pattern further comprising one or more of the following additional reflections at 4 .83, 8.25, 11.85, 12.48, 12.96, 14.31, 15.44, 15.75, 16.620, 18.37, 19.33, 24.97, 26.02, 26.88, 27.39, 28.10, 28.40, 29.86, 32.30, 33.48, 37.48 and 39.67 ⁇ 20 or that produces an X-ray powder diffraction pattern comprising the 2 theta values tabulated in Table-4
  • Ribociclib succinate (1) is obtained by heating Ribociclib succinate in methanol and isolating by cooling to 25-30°C -The crystalline form II of Ribociclib succinate (1) is obtained by stirring in benzyl alcohol at 25-30°C for lOhrs to l2hrs
  • Ribociclib succinate (1) is obtained by 3-butyl acetate at 25-30°C for lOhrs to l2hrs - the crystalline form IV of Ribociclib succinate (1) is obtained by heating Ribociclib succinate in methanol and isolating by distilling off the solvent under vacuum
  • Ribociclib free base (2) was dissolved in 2500mL of methanol, stirred for 10 minutes and heated to 60-65 °C. 28.5g of succinic acid was added to the reaction mass and the reaction mass heated to 75-80 °C for 2hrs. The reaction mixture was cooled to 15-20 °C, stirred for 2hrs and filtered. The solid so obtained was then washed with 100 mL of cold methanol (0-5°C) and dried below 65 °C to obtain Ribociclib succinate (1)
  • Ribociclib succinate (1) 5.0g was suspended in l25mL of methanol at 25-30 °C, heated to 60-65 °C and stirred for 10-15 mins. 2.0mL of water was added to the reaction mixture and stirred to form a clear solution. The clear solution was then cooled to 25-30 °C and stirred for 30 mins to form a solid mass. The solid so formed was filtered, washed with lOmL of methanol and dried under vacuum for 15 mins to obtain crystalline of Ribociclib succinate (1)
  • Ribociclib succinate (1) was charged with 20mL of benzyl alcohol at 25-30 °C and stirred for l0-l5mins to form a clear solution. The reaction mixture was maintained for l2hrs at 25-30 °C. The slurry so formed was then filtered and the residue was washed with 2mL of benzyl alcohol. The wet cake so obtained was dried under vacuum for 10-15 mins to obtain crystalline Ribociclib succinate (1) Yield: 73%
  • Ribociclib succinate (1) was charged 25mL of 3-butyl acetate and stirred for 10 mins at 25-30 °C. The reaction mixture was maintained for l2hrs at 25-30 °C. The slurry so formed was then filtered and the residue so obtained was dried under vacuum for 15 mins to obtain crystalline form of Ribociclib succinate (1) Yield: 78%
  • Ribociclib succinate (1) 3.0g was charged in 300mL of methanol and stirred for 30 mins at 25-30 °C. The reaction mixture was then heated to 60-65 °C for 30mins to form a clear solution. The clear solution was then distilled off under vacuum to obtain crystalline form of Ribociclib succinate (1)

Abstract

La présente invention concerne un procédé amélioré pour la préparation de succinate de ribociclib (1) et de nouvelles formes cristallines de ce dernier. Plus particulièrement, l'invention concerne le procédé de préparation de nouvelles formes cristallines de succinate de ribociclib (1).
PCT/IB2018/054365 2018-02-05 2018-06-14 Procédé amélioré pour la préparation de 7-cyclopentyl-n, n-diméthyl-2-(5-(pipérazine-1-yl) pyridine-2-ylaminuteso)-7h-pyrrolo[2,3-d] pyrimidine-6-carboxamide succinate (succinate de ribociclib) et de formes cristallines de ce dernier WO2019150181A1 (fr)

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IN201841004284 2018-02-05

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10611772B2 (en) 2018-07-02 2020-04-07 Apotex Inc. Crystalline form of Ribociclib succinate
WO2022207788A2 (fr) 2021-04-01 2022-10-06 Krka, D.D., Novo Mesto Procédé de préparation de ribociclib et de sels pharmaceutiquement acceptables de celui-ci
EP3672968B1 (fr) * 2017-08-25 2023-11-01 Assia Chemical Industries Ltd Forme à l'état solide du succinate de ribociclib

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012064805A1 (fr) * 2010-11-10 2012-05-18 Novartis Ag Sels du dimethylamide de l'acide 7-cyclopentyl-2-(5-piperazin-1-ylpyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylique et leurs procedes de fabrication

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012064805A1 (fr) * 2010-11-10 2012-05-18 Novartis Ag Sels du dimethylamide de l'acide 7-cyclopentyl-2-(5-piperazin-1-ylpyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylique et leurs procedes de fabrication

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LOUIE J ET AL.: "Palladium-catalyzed synthesis of arylamines from aryl halides. Mechanistic studies lead to coupling in the absence of tin reagents", TETRAHEDRON LETTERS, vol. 36, no. 21, 22 May 1995 (1995-05-22), pages 3609 - 3612, XP004028031, doi:10.1016/0040-4039(95)00605-C *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3672968B1 (fr) * 2017-08-25 2023-11-01 Assia Chemical Industries Ltd Forme à l'état solide du succinate de ribociclib
US10611772B2 (en) 2018-07-02 2020-04-07 Apotex Inc. Crystalline form of Ribociclib succinate
WO2022207788A2 (fr) 2021-04-01 2022-10-06 Krka, D.D., Novo Mesto Procédé de préparation de ribociclib et de sels pharmaceutiquement acceptables de celui-ci
WO2022207788A3 (fr) * 2021-04-01 2023-04-06 Krka, D.D., Novo Mesto Procédé de préparation de ribociclib et de sels pharmaceutiquement acceptables de celui-ci

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