WO2017001996A1 - Procédé de préparation de la forme 3 de raltégravir potassique - Google Patents

Procédé de préparation de la forme 3 de raltégravir potassique Download PDF

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Publication number
WO2017001996A1
WO2017001996A1 PCT/IB2016/053819 IB2016053819W WO2017001996A1 WO 2017001996 A1 WO2017001996 A1 WO 2017001996A1 IB 2016053819 W IB2016053819 W IB 2016053819W WO 2017001996 A1 WO2017001996 A1 WO 2017001996A1
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Prior art keywords
potassium
raltegravir
temperature
solution
preparation
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English (en)
Inventor
Shashank Gopalrao POTDAR
Ram Thaimattam
Sathyanarayana SWARGAM
Venkata Sunil Kumar Indukuri
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Laurus Labs Pvt Ltd
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Laurus Labs Pvt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention generally relates to a process for the preparation of Raltegravir potassium Form 3 and its pharmaceutical composition thereof.
  • Raltegravir also referred to as N-(2-(4-(4- fluorobenzylcarbamoyl)-5-hydroxy- 1 - methyl-6-oxo- 1 ,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-l,3,4-oxadiazole-2- carboxamide, is an antiretroviral drug used to treat HIV infection and has the following formula I;
  • Raltegravir is an antiretroviral drug which is marketed as potassium salt under the trade name ISENTRESSTM by Merck & Co to treat human immunodeficiency virus (HIV) infection. It is a first line HIV-integrase strand transfer inhibitor drug that targets Integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes.
  • N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase including raltegravir or a pharmaceutically acceptable salt thereof and its preparation are described in US Patent No. 7, 169,780 and U.S. Patent No. 7,754,731 is specifically directed to a potassium salt, particularly a crystalline potassium salt of Raltegravir.
  • Raltegravir exhibits poor aqueous solubility where as the potassium salt of Raltegravir is significantly more soluble in water and exhibit improved pharmacokinetics in animal models over Raltegravir free base.
  • Raltegravir potassium can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties and pharmacokinetics. The following documents in the art are directed towards polymorphs of Raltegravir potassium, which are incorporated here by way reference.
  • U.S. Patent No. 7,754,731 (the "731 patent) disclosed polymorphic forms of raltegravir potassium namely anhydrous crystalline Form 1, Form 3; hydrated crystalline Form 2 and amorphous form including their preparation process.
  • Raltegravir potassium form 3 is prepared by reacting raltegravir with aqueous potassium hydroxide in acetonitrile solvent, frozen drying the resulting solution at - 78°C followed by freeze drying to obtain amorphous raltegravir potassium, a portion of which is then crystallized from hot ethanol to yield raltegravir potassium form 3.
  • IP.Com journal disclosure No. IPCOM000243081D disclosed a process for the preparation of raltegravir potassium form 3 by suspending or dissolving raltegravir in a solvent or mixture of solvents such as ethanol, water, methanol and the like, adding a potassium base and isolating form 3.
  • IN Publication No. 5282/CHE/2013 (“the '5282 application”) disclosed the preparation of Raltegravir potassium Form-3 by providing a solution or suspension of Raltegravir in ethanol, adding aq KOH, optionally seeding and isolating Form 3.
  • IN Publication No. 3346/DEL/2012 (“the '346 application”) disclosed the preparation of Raltegravir potassium Form-3 by using an alcoholic solvent.
  • PCT Publication No. 2011/123754 disclosed crystalline Forms such as Form IV, Form V, Form VI, Form VII, Form VIII, Form IXa, Form IXb, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, and Form XVI of raltegravir potassium and preparation thereof.
  • PCT Publication No. WO2012/103105 disclosed the preparation of raltegravir potassium Form V.
  • PCT Publication No. 2013/037731 disclosed crystalline raltegravir potassium hydrate form IV and its preparation
  • IP.Com journal disclosure Number IPCOM000194495D discloses an amorphous form of Raltegravir potassium.
  • IP.Com journal disclosure Number IPCOM000224583D discloses the preparation of Form I of Raltegravir potassium.
  • IP.Comjournal disclosure Number IPCOM000223913D discloses a crystalline form of Raltegravir potassium characterized by X-ray powder diffraction pattern having peaks at 7.6, 11.4, 15.1, 16.7, 18.2, 19.1, 22.9, 24.3, 27.2 and 27.8°2 ⁇ .
  • IP.Comjournal disclosure Number IPCOM000209501D discloses a crystalline form of Raltegravir potassium characterized by X-ray powder diffraction pattern having peaks at 8.0, 11.9, 14.9, 18.2, 19.8, 24.9, 26.6, 27.7 and 28.9°2 ⁇ and a process for preparing crystalline form of Raltegravir potassium by exposing amorphous Raltegravir potassium to water.
  • Journal of Medicinal Chemistry (2008), 51(18), 5843-5855 describes the preparation of potassium salt of Raltegravir by freeze-drying a solution of Raltegravir in acetonitrile and aqueous KOH, followed by crystallization of the freeze-dried material from ethanol.
  • the Raltegravir potassium salt reported in this publication is characterized by M.P 282°C.
  • the present invention fulfills the need in the art and provides a simple, commercially viable and scalable process for the preparation of Raltegravir potassium Form 3 that circumvent disadvantages associate with prior-art.
  • the present invention provides a process for preparation of Raltegravir potassium Form 3, which process reduces the number of solvent usage, avoids cryogenic temperatures and specialized equipment, thereby the process is advantageous for scale-up production, especially in terms of operating efficiency and makes the process commercially viable.
  • the invention further provides use of tertiary alcoholic potassium base as potassium source, which process provides Raltegravir potassium Form 3 consistently.
  • the main object of the present invention is to provide convenient, commercially viable, and economical process for the preparation of raltegravir potassium form 3.
  • the present invention provides a process for the preparation of raltegravir potassium form 3, comprising:
  • the present invention provides a process for the preparation of raltegravir potassium form 3, comprising:
  • organic solvent is selected from ethyl acetate, dichloromethane, N,N- dimethyl acetamide, ethanol, 2-butanol and tert-butanol or mixtures thereof; wherein the potassium source is selected from potassium tertiary butoxide or potassium hydroxide.
  • the present invention provides a process for the preparation of raltegravir potassium form 3, comprising:
  • step b) treating the step a) reaction mixture with potassium tertiary butoxide in tertiary butanol,
  • the present invention provides a process for the preparation of raltegravir potassium Form 3, comprising:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising raltegravir potassium form 3 prepared by the process of the present invention and at least one pharmaceutically acceptable excipient.
  • Figure 1 is the characteristic powder XRD pattern of raltegravir potassium form 3.
  • Figure 2 is the characteristic DSC thermogram of raltegravir potassium form 3.
  • the main object of the present invention is to provide convenient, commercially viable, and economical process for the preparation of Raltegravir potassium form 3 and pharmaceutical compositions comprising the same.
  • the present invention provides a process for the preparation of raltegravir potassium form 3, comprising:
  • organic solvent selected from esters, halogenated hydrocarbons, alcohols, amides, cyclic ethers and ketonic solvents or mixtures thereof
  • the starting material raltegravir free base used in the present invention can be obtained by any of the methods known in the art, for example according to U.S. Patent No. 7,169,780 and U.S. Patent No. 7,754,731 or it may be obtained as a solution directly from a reaction mixture in which raltegravir is formed and used as such without isolation.
  • the step of providing a solution or suspension of raltegravir in an organic solvent may include stirring any form of raltegravir in an organic solvent in suspension state or by stirring any form of raltegravir in an organic solvent until clear solution is obtained.
  • raltegravir may be obtained as a suspension or solution directly from a reaction mixture in which raltegravir is formed and used as such without isolation.
  • organic solvents used herein for step (a) includes but are not limited to esters such as ethyl acetate, n-butyl acetate, n-propyl acetate, t-butyl acetate, isopropyl acetate and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; amides such as ⁇ , ⁇ -dimethyl acetamide, N,N-diethylacetamide and the like; alcohols such as methanol, ethanol, n-butanol, 2- butanol, tert-butanol, and the like; cyclic ethers such as tetrahydrofuran, 1 ,4-dioxane, 2-methyl tetrahydrofuran and the like; ketones such as acetone, methyl ethyl ketone or mixtures thereof.
  • esters such as ethyl acetate, n
  • the organic solvent is selected from the group consisting of ethyl acetate, dichloromethane, ⁇ , ⁇ -dimethyl acetamide, ethanol, tert-butanol, 2- butanol or mixtures thereof.
  • the step a) is carried out at a temperature of about 20°C to reflux temperature, preferably at about 25°C to about 45°C.
  • a suitable potassium source at a temperature of from about 10°C to about 50°C for a period of about 5 minutes to about 120 minutes.
  • the suitable potassium source is selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, or potassium alkoxide i.e a potassium salt of an alkyl alcohol selected from potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide and potassium tertiary butoxide; preferably the suitable potassium source is selected from potassium tertiary butoxide or potassium hydroxide.
  • potassium alkoxide such as potassium tertiary butoxide, was found to be particularly useful.
  • the potassium source can be used as a solid or in dissolved form in a solvent; preferably potassium tertiary butoxide or potassium hydroxide is dissolved in a solvent such as alcohols selected from methanol, ethanol, isopropanol, tertiary butanol, 1- pentanol and the like; cyclic ethers such as tetrahydrofuran.
  • a solvent such as alcohols selected from methanol, ethanol, isopropanol, tertiary butanol, 1- pentanol and the like; cyclic ethers such as tetrahydrofuran.
  • the potassium source can be dissolved in ethanol, 1 -pentanol, tertiary butanol or mixtures thereof.
  • the suitable potassium source can be added either as a solution in one or more solvents or it may be added as a solid to the solution of raltegravir in one or more solvents or the solution of raltegravir in one or more solvents may be added to a solution of potassium source.
  • the way of addition of the potassium source is not particularly critical.
  • the step b) reaction may typically be carried out at a temperature of about 10° C to 50°C and the potassium salt emission occurred during the addition of potassium source.
  • step b) reaction is preferably carried out at a temperature of about 25 °C to about 35 °C and stirred for appropriate period of time for precipitation of the product, preferably over a period from about 10 mins to about 6 hours such that the resulting raltegravir potassium form 3 can be isolated by conventional techniques.
  • the raltegravir potassium isolated using the process of the present invention is substantially in polymorph form 3.
  • the resultant raltegravir potassium form 3 can be isolated by any conventional technique known in the art, for example, filtration and the resultant raltegravir potassium may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 150°C for a time period ranging from about 1 hour to about 20 hours.
  • the present invention provides a process for the preparation of raltegravir potassium form 3, comprising:
  • the step a) is carried out at a temperature of about 20°C to reflux temperature, preferably at about 25 °C to about 45 °C. Then, the reaction mixture is treated with potassium tertiary butoxide in tertiary butanol at a temperature of from about 10°C to about 50°C for a period of about 5 minutes to about 120 minutes.
  • the potassium tertiary butoxide solution can be added to the solution or suspension of raltegravir in ethyl acetate or the solution or suspension of raltegravir in ethyl acetate may be added to a potassium tertiary butoxide solution.
  • the way of addition of the potassium source is not particularly critical; preferably the potassium source is added to the suspension of raltegravir in ethyl acetate.
  • potassium tertiary butoxide solution typically carried out at a temperature of about 25° C to 35°C and the potassium salt emission occurred during the addition of potassium source.
  • the reaction is stirred for a period of about 10 mins to about 6 hours at a temperature of about 25 °C to about 35°C and the reaction mass may optionally be cooled to less than 20°C and the resulting raltegravir potassium form 3 can be isolated by filtration.
  • the resultant raltegravir potassium may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 150°C for a time period ranging from about 1 hour to about 20 hours.
  • the present invention provides a process for the preparation of raltegravir potassium Form 3, comprising:
  • step b) treating the step a) reaction mixture with potassium tertiary butoxide in tetrahydrofuran,
  • the step a) is carried out at a temperature of about 20°C to reflux temperature.
  • the step b) reaction may typically be carried out at a temperature of about 20° C to 65 °C and the potassium salt emission occurred during the addition of potassium tert- butoxide solution.
  • the reaction is stirred for a period of about 10 mins to about 6 hours at a temperature of about 25 °C to about 45 °C and the reaction mass may optionally be cooled to less than 20°C and the resulting raltegravir potassium form 3 can be isolated by filtration.
  • the resultant raltegravir potassium may optionally be further dried.
  • Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.
  • the drying can be carried out at a temperature ranging from about 30°C to about 150°C for a time period ranging from about 1 hour to about 20 hours.
  • the reported process for the preparation of raltegravir potassium form 3 involves a two-step process of preparing amorphous form of raltegravir potassium in the first step and then converting it to form 3 in the second step. Further, the reported process involves the techniques such as frozen drying and freeze drying which are not commercially viable and requires specialized equipment and cryogenic temperatures. In contrast, the process of the present invention involves a simple and economical process and does not require any specialized equipment and cryogenic temperatures and is conveniently carried out at room temperature in one step. According to the present inventive process raltegravir potassium Form 3 can be prepared consistently.
  • the raltegravir potassium form 3 can be characterized by one or more of the techniques such as PXRD and DSC techniques.
  • the DSC data reported herein were analyzed in hermitically sealed pinhole aluminium pan, with a blank hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute to 350°C with an Indium standard.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the raltegravir potassium form 3 prepared according to the process of the present invention and at least one or more pharmaceutically acceptable excipients.
  • Raltegravir 500 mg was suspended in a mixture of tert-butanol (4 ml), ethanol (8 ml) containing potassium tertiary butoxide solution (1M, 1.2 ml) in tert-butanol at 25- 35°C.
  • the reaction mass was stirred for 4 hours at 25-35°C, filtered, washed with ethanol (2 ml) and suck dried the solids under nitrogen for 30 mins.
  • the obtained compound was dried at 53 °C under vacuum for 4 hours to obtain 501 mg of raltegravir potassium form 3.
  • Raltegravir (5 gms) was suspended in ethanol (100 ml) and charged potassium tertiary butoxide solution (1M, 12 ml) in tert-butanol at 25-35°C. The reaction mass was stirred for 4 hours at 25-35°C, filtered, washed with ethanol (25 ml) and suck dried the solids under nitrogen for 30 mins. The obtained compound was further dried at 53°C under vacuum for 6 hours to obtain 4.9 gms of raltegravir potassium form 3.
  • EXAMPLE 5 Preparation of raltegravir potassium form 3 : Raltegravir (300 mg) was suspended in 2-butanol (2 ml) and ethanolic potassium hydroxide solution (42 mg potassium hydroxide dissolved in ethanol (0.5 ml)) was added at 25-35°C. Further, ethanol (4 ml) was added to the reaction mass and the resulting suspension was stirred at 25-35°C for 2 hours. The reaction mass was filtered, washed with ethanol (1 ml) and suck dried the solids for 30 mins under nitrogen to obtain 130 mg of raltegravir potassium form 3.
  • the obtained wet material was dried initially at 50-55°C for 1 hour, cooled to 35-40°C and milled under nitrogen at room temperature.
  • the semidried raltegravir potassium further dried for 12 hours under vacuum at 120-125°C to obtain 105 gms of the title compound.
  • the reaction mass was stirred for 30 min at 30°C, filtered the reaction mass, washed with ethyl acetate (100 mL) and suck dried.
  • the obtained wet material was dried initially at 50-55°C for 4 hr under vacuum, cooled to 35-40°C and milled under nitrogen at room temperature followed by further drying for 16 hrs under vacuum at 95-105°C and cooled to 25-30°C to obtain 85 gms of raltegravir potassium form 3.
  • the obtained wet material was dried initially at 50-55°C for 1 hr under vacuum, cooled to 35-40°C and milled under nitrogen at room temperature followed by further drying for 16 hrs under vacuum at 95-105°C and cooled to 25-30°C to obtain 87 gms of raltegravir potassium form 3.
  • the obtained wet material was dried initially at 50-55°C for 1 hour, cooled to 35-40°C and milled under nitrogen at room temperature.
  • the semidried raltegravir potassium further dried for 12 hours under vacuum at 120-125°C to obtain 105 gms of raltegravir potassium form 3.
  • the obtained wet material was dried initially at 50-55°C for 1 hour, cooled to 35-40°C and milled under nitrogen at room temperature followed by further dried for 12 hours under vacuum at 120-125°C to obtain 10 gms of raltegravir potassium form 3.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de la forme 3 de raltégravir potassique.
PCT/IB2016/053819 2015-06-29 2016-06-27 Procédé de préparation de la forme 3 de raltégravir potassique Ceased WO2017001996A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN3282CH2015 2015-06-29
IN3282/CHE/2015 2015-06-29
IN201641012263 2016-04-07
IN201641012263 2016-04-07

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WO2017001996A1 true WO2017001996A1 (fr) 2017-01-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018051239A1 (fr) 2016-09-15 2018-03-22 Lupin Limited Procédé de préparation de la forme 3 du potassium de raltégravir cristalline pure et stable
CN112898288A (zh) * 2019-12-04 2021-06-04 上海迪赛诺生物医药有限公司 一种制备拉替拉韦钾晶型3的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2795157A1 (fr) * 2010-04-01 2011-10-06 Teva Pharmaceutical Industries Ltd. Sels de raltegravir et leurs formes cristallines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2795157A1 (fr) * 2010-04-01 2011-10-06 Teva Pharmaceutical Industries Ltd. Sels de raltegravir et leurs formes cristallines

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018051239A1 (fr) 2016-09-15 2018-03-22 Lupin Limited Procédé de préparation de la forme 3 du potassium de raltégravir cristalline pure et stable
US20190248773A1 (en) * 2016-09-15 2019-08-15 Lupin Limited Process for the preparation of pure and stable crystalline raltegravir potassium form 3
US10752618B2 (en) * 2016-09-15 2020-08-25 Lupin Limited Process for the preparation of pure and stable crystalline Raltegravir potassium form 3
CN112898288A (zh) * 2019-12-04 2021-06-04 上海迪赛诺生物医药有限公司 一种制备拉替拉韦钾晶型3的方法

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