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WO2012103105A1 - Procédés de préparation du raltégravir et de ses intermédiaires dans lesdits procédés - Google Patents

Procédés de préparation du raltégravir et de ses intermédiaires dans lesdits procédés Download PDF

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Publication number
WO2012103105A1
WO2012103105A1 PCT/US2012/022385 US2012022385W WO2012103105A1 WO 2012103105 A1 WO2012103105 A1 WO 2012103105A1 US 2012022385 W US2012022385 W US 2012022385W WO 2012103105 A1 WO2012103105 A1 WO 2012103105A1
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Prior art keywords
rlt
raltegravir
methyl
preparing
stirred
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PCT/US2012/022385
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English (en)
Inventor
Lilach Hedvati
Rotem Erez
Meital Cohen
Vinod Kumar Kansal
Harish Ranjan
Debashish Das
Sanjay Jaiswal
Elluru SUBBIREDDY
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Assia Chemical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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Application filed by Assia Chemical Industries Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Assia Chemical Industries Ltd.
Publication of WO2012103105A1 publication Critical patent/WO2012103105A1/fr

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    • 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
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid

Definitions

  • the present invention encompasses processes for preparing Raltegravir, its crystalline forms V and II, and intermediates in said processes of preparing Raltegravir.
  • Raltegravir also referred to as Raltegravir free-hydroxy, N-(2-(4-(4-fluorobenzyl- carbamoyl)-5-hydroxy-l-methyl-6-oxo-l ,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl- l ,3,4-oxadiazole-2-carboxamide, having the following structure;
  • Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV.
  • Raltegravir potassium salt is marketed under the trade name ISENTRESSTM by Merck & Co.
  • RLT-7', RLT-8, RLT-9 and RLT-9-OP are industrially applicable processes for preparing RLT-7', RLT-8, RLT-9 and RLT-9-OP, intermediates in the synthesis of Raltegravir, as well as processes for preparing Raltegravir and crystalline forms thereof.
  • the present invention also relates to new processes for preparing forms I I and V of
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - “DSC”), X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.
  • TGA thermogravimetric analysis -
  • DSC differential scanning calorimetry -
  • Discovering new salts and new polymorphic forms and solvates of a pharma- ceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharma- ceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid state forms of Raltegravir potassium and processes for their preparation. Summary of the Invention
  • the present invention provides a process for preparing the compound RLT-8 (benzyl 2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-l-methyl-6-oxo- l ,6-dihydropyrimidin-2-yl)propan-2-ylcarbamate).
  • This process comprises: combining the compound RLT-8-des-methyl (benzyl-2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-6- oxo-l ,6-dihydropyrimidin-2-yl)propan-2-ylcarbamate) with anisole and lithium hydroxide or lithium hydride to obtain a reaction mixture; and adding dimethyl sulfate to that reaction mixture.
  • the present invention provides a process for preparing the compound RLT-7' (methyl 2-(2-(benzyloxycarbonylamino)propan-2-yl)-5-hydroxy- l - methy 1-6-oxo-l ,6-dihydropyrimidine-4-carboxylate).
  • This process comprises: combining the compound RLT-5 (methyl 2-(2-(benzyloxycarbonylamino)propan-2-yl)-5,6- dihydroxypyrimidine-4-carboxylate) with anisole and lithium hydride to obtain a reaction mixture; and adding dimethyl sulfate to that reaction mixture.
  • the present invention provides a process for preparing Raltegravir comprising: preparing any of the above described intermediates of Raltegravir: RLT-7' and RLT-8 according to the processes of the present invention and converting it to Raltegravir or a salt thereof.
  • the present invention provides a process for preparing crystalline form V of Raltegravir.
  • Figure 1 shows an X-ray powder diffractogram of Raltegravir potassium Form V.
  • Figure 2 shows an X-ray powder diffraction of Raltegravir potassium Form II.
  • Figure 3 shows a DSC curve of Raltegravir potassium Form II.
  • Figure 4 shows an X-ray powder diffraction of Raltegravir free-hydroxy Form A l .
  • the present invention encompasses processes for preparing Raltegravir, and the following intermediates of Raltegravir: benzyl 2-(4-(4-fluorobenzylcarbamoyl)-5- hydroxy- 1 -methy 1-6-oxo- 1 ,6-dihydropyrimidin-2-yl)propan-2-ylcarbamate (compound RLT-8), methyl 2-(2-(benzyloxycarbonylamino)propan-2-yl)-5-hydroxy-l -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxylate (compound RLT-7'), 2-(2-aminopropan-2-yl)-N-(4- fluorobenzyl)-5-hydroxy- l-methyl-6-oxo-l ,6-dihydropyrimidine-4-carboxamide
  • room temperature or "RT” refer to a temperature of about 15°C to about 35°C.
  • RT can refer to a temperature of about 25°C.
  • the term “overnight” refers to a time interval from about 12 hours to about 20 hours.
  • volume can be used to refer to the proportion of the volume of one substance in a mixture with the mass of a second substance in the mixture, wherein the units are typically ml per gram. For example, when 2 g of substance A is said to be dissolved in 10 volumes of solvent B, this would be understood to mean that 20 mL of solvent B was used.
  • H-donor refers to a chemical compound that has a hydrogen atom available for hydrogen bonding.
  • compound RLT-9 or “RLT-9” refer to 2-(2-amino- propan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy- l -methyl-6-oxo-l ,6-dihydropyrimidine-4- carboxamide, an intermediate in the synthesis of Raltegravir.
  • compound RLT-5" or RLT-5" refer to methyl 2-(2- (benzyloxycarbonylamino)propan-2-yl)-5,6-dihydroxypyrimidine-4-carboxylate, an intermediate in the synthesis of Raltegravir.
  • compound RLT-8 or “RLT-8” refer to benzyl-2-(4-(4- fluorobenzylcarbamoyl)-5-hydroxy-l -methyl-6-oxo-l,6-dihydropyrimidin-2-yl)propan-2- ylcarbamate, a synthetic intermediate in the synthesis of Raltegravir.
  • compound RLT-8-des-methyl or “RLT-8-des-methyl” refer to benzyl-2-(4-(4-fluorobenzy lcarbamoyl)-5-hydroxy-6-oxo- 1 ,6-dihydropyrimidin-2- yl)propan-2-ylcarbamate, a synthetic intermediate in the synthesis of Raltegravir.
  • compound RLT-9-OP or “RLT-9-OP” refer to 2-(2- aminopropan-2-yl)-4-(4-fluorobenzylcarbamoyl)- l -methy 1-6-oxo- l ,6-dihydropyrimidin-5- yl pivalate.
  • Raltegravir potassium Form V refers to a crystalline form which is characterized by data selected from: an X-ray powder diffraction pattern having peaks at 8.0, 1 1 .9, 18.2 and 26.6 degrees two theta ⁇ 0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in Figure 1 ; and a combination thereof.
  • Crystalline Form V of Raltegravir potassium may be further characterized by the X-ray powder diffraction pattern having additional peaks at 14.9, 19.8, 24.9, 27.7 and 28.9 degrees two theta ⁇ 0.2 degrees two theta.
  • Raltegravir potassium Form II refers to a crystalline form which may be characterized by analytical data for example, an X-ray powder diffraction pattern having peaks at 7.9, 13.8, 15.7, 24.5 and 31.5 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in Figure 2; a DSC curve substantially as depicted in Figure 3; and a DSC curve having a broad endotherm peak at about 146 °C, a broad endotherm peak at about 238 °C, and a sharp endotherm at about 276 °C.
  • Raltegravir free-hydroxy Form A l refers to a crystalline form which is characterized by data selected from: an X-ray powder diffraction pattern having peaks at 6.4, 8.3, 10.9, 12.8 and 15.6 degrees two theta ⁇ 0.2 degrees two theta; an X-ray powder diffraction pattern as depicted in Figure 4; and a combination thereof.
  • Crystalline Form A l of Raltegravir free hydroxy may be further characterized by the X-ray powder diffraction pattern having additional peaks at 1 1.9, 13.8, 16.3, 21.7 and 23.8 degrees two theta ⁇ 0.2 degrees two theta.
  • the present invention provides processes for preparing the compound RLT-8 or the compound RLT-7' by selective methylation on the nitrogen, without adding a protection step for the 5-hydroxy group prior to the methylation step. Furthermore, the process of the present invention uses safer solvents than those used in other described syntheses of these compounds.
  • the process for preparing the compound RLT-8 comprises: combining the compound RLT-8-des-methyl with anisole and lithium hydroxide or lithium hydride to obtain a reaction mixture; and adding dimethyl sulfate ("DMS”) to that reaction mixture.
  • DMS dimethyl sulfate
  • the reaction mixture may be stirred at a suitable temperature, for example from about 25°C to about 45°C, or in some embodiments, of about 25°C to about 35°C.
  • the stirring may be done for a suitable time period, for example, from about 45 minutes to about 60 minutes, or for a time period of about 60 minutes.
  • the DMS may be added drop-wise at a temperature of about RT.
  • the addition of DMS may be followed by heating to a temperature ranging for example from about 40 °C to about 80 °C, or, according to some embodiments, to about 40°C.
  • the heating, typically while stirring may be done for a time period ranging, for example, from about 10 hours to about 72 hours.
  • the above process can optionally further comprise recovery and/or purification of the obtained RLT-8.
  • the recovery can comprise, for example, filtering the reaction mixture to separate the RLT-8; and drying the collected RLT-8.
  • RLT-8 can be extracted from the reaction mixture.
  • the extraction can comprise adding water to the reaction mixture; adjusting the pH of the resulting mixture; extracting the pH adjusted mixture; exchanging the solvent in the resulting extract to form a solvent-exchanged extract; and filtering and drying the solvent- exchanged extract .
  • the purification may be done for example, by using methanol/water.
  • the RLT-8 (isolated or extracted) can be used to prepare Raltegravir or a salt thereof.
  • the RLT-8 may be directly used to prepare Raltegravir or a salt thereof in a one-pot manner, i.e., using the reaction mixture comprising it in the next step.
  • the conversion of RLT-8 to Raltegravir or a salt thereof can be done, for example, according to the process described in US 2006/0122205.
  • the present invention also provides a process for preparing the compound RLT-7' comprising: combining the compound RLT-5 with anisole and lithium hydride to obtain a reaction mixture; and adding DMS to that reaction mixture.
  • the reaction mixture may be stirred at a suitable temperature, for example from about 35 to about 45°C, or in some embodiments, of about 38 °C.
  • the stirring may be done for a time period ranging from about 45 minutes to about 60 minutes, or for a time period of about 45 minutes.
  • the DMS may be added drop-wise at a temperature of about RT.
  • the addition of DMS may be followed by heating to a temperature ranging for example from about 40 °C to about 80 °C, or according to some embodiments, to about 60°C.
  • the heating, typically while stirring may be done for a time period ranging for example from about 10 hours to about 72 hours.
  • the above process can optionally further comprise a recovery of the obtained RLT-7'.
  • the recovery can comprise, for example, concentrating the reaction mixture, for example, to a volume from about 1 0% to about 50% of the original volume; filtering the concentrated reaction mixture to separate the RLT-7'; and drying the collected product.
  • the recovered RLT-7' can be used to prepare Raltegravir or a salt thereof.
  • the RLT-7' may be directly used to prepare Raltegravir or a salt thereof in a one-pot manner, i.e., using the reaction mixture comprising it in the next step.
  • the conversion of RLT-7' to Raltegravir or a salt thereof can be done, for example, according to the process described in US 2006/0122205.
  • the present invention further provides a process for preparing RLT-9.
  • the deprotection step for obtaining the compound RLT-9 requires the presence of H 2 gas. For at least that reason, this route is less preferred for industrial use.
  • hydrogenation leads to the formation of the impurity RLT-9-Des-Fluoro of the following formula:
  • the RLT-9-Des-Fluoro impurity may serve as precursor to the formation of RLT-des-Fluoro impurity of the following formula:
  • the present invention further comprises a process for preparing the compound RLT-9, wherein an H-donor is used in the deprotection step instead of H 2 , thus resulting in a process that is both industrially applicable, and which does not produce the RLT-9-Des- F impurity.
  • the process for preparing the compound RLT-9 comprises: combining the compound RLT-8 with a solvent, such as a C1-C4 alcohol, toluene, tetrahydrofuran (THF), acetonitrile (ACN), or a mixture thereof; Pd/C; and an H-donor; and optionally adding water and an acid to obtain a reaction mixture.
  • a solvent such as a C1-C4 alcohol, toluene, tetrahydrofuran (THF), acetonitrile (ACN), or a mixture thereof
  • Pd/C acetonitrile
  • H-donor optionally adding water and an acid to obtain a reaction mixture.
  • the amount of Pd is from about 0.5% to about 5% w/w or from about 2.5% to about 3% w/w, based on the weight of the starting RLT-8.
  • the Pd reagent may be, for example, Pd/C 5% or Pd/C 10%.
  • Suitable H- donors include, for example, formic acid and ammonium formate in the presence of catalytic alkaline formate such as HC0 2 K or HC0 2 Na.
  • the reaction mixture may be heated, for example, to a temperature from about 30°C to about the reflux temperature of the mixture, or from about 45°C to about 55°C.
  • the heating typically while stirring, may be done for a time period ranging from about 1 hour to about 24 hours, or from about 2 hours to about 6 hours.
  • the heating is optionally followed by addition of water and an acid such as methanesulphonic acid ("MSA"),
  • the process may further comprise filtering off the Pd catalyst, washing the filtered material with an appropriate solvent, such as a C1-C4 alcohol, toluene, THF, ACN, or mixture thereof; adjusting the pH of the filtrate to a pH of about 5 to about 10, or according to some embodiments to a pH of about 8 to about 9, or according to some embodiments, to a pH of about 8.5; and maintaining the pH adjusted filtrate, for example, at about room temperature for a time period of about 2 hours to about 24 hours, or according to some embodiments for a time period of about 19 hours; and then at a temperature of about 5°C for a time period of about 1 hour to about 24 hours, or according to some embodiments, for about 2 hours to precipitate the product compound RLT-9.
  • an appropriate solvent such as a C1-C4 alcohol, toluene, THF, ACN, or mixture thereof
  • adjusting the pH of the filtrate to a pH of about 5 to about 10
  • a pH of about 8 to about 9 or
  • the process may further comprise separating the product, e.g., by filtering; washing the separated product with an appropriate solvent such as water; and drying the washed product to obtain the compound RLT-9.
  • the drying may be done, for example, at a temperature of about 45-65°C for about overnight.
  • the RLT-9 obtained as a product of the above process may be used to prepare Raltegravir, for example, according to the process described in US 2006/0122205 or according to the process of the present invention.
  • the obtained Raltegravir is pure with respect to the RLT-des-Fluoro impurity.
  • the present invention further provides a process for preparing crystalline form V of Raltegravir potassium.
  • the process comprises combining Raltegravir free-hydroxy with a potassium source such as OH to form the potassium salt, and crystallizing that potassium salt from a suitable solvent such as: cyclohexane, THF, EtOAc, iso-BuOAc or mixtures thereof.
  • a potassium source such as OH
  • crystallizing that potassium salt from a suitable solvent such as: cyclohexane, THF, EtOAc, iso-BuOAc or mixtures thereof.
  • the Raltegravir free hydroxy starting material is Raltegravir free hydroxy Form A l .
  • the addition of the potassium source may be followed by seeding with Raltegravir potassium Form V.
  • the obtained Raltegravir potassium may further be isolated. The isolation may be done by filtering, and optionally washing and drying the collected product.
  • the present invention further provides a process for preparing crystalline form II of Raltegravir potassium.
  • the process comprises combining Raltegravir free-hydroxy with a potassium source such as KOH to form the potassium salt, and crystallizing that potassium salt from a suitable solvent, such as iso-propyl alcohol (IPA)/water
  • a potassium source such as KOH
  • IPA iso-propyl alcohol
  • the obtained crystalline forms of Raltegravir potassium can be used to prepare Raltegravir salts, solid state forms thereof and pharmaceutical composition thereof.
  • the compound RLT-5 and the starting Raltegravir free hydroxy may be prepared according to US 2006/0122205, incorporated herein by reference.
  • the compound RLT-8- des-methyl may be prepared according to WO 2009/088729, example 1 , step 1 , incorporated herein by reference.
  • Example 1 Preparation of RLT-7' RLT-5 (2 g) was added to a mixture of LiH (2.8 eq., 124 mg) and anisole (40 mL). The mixture was heated to 38°C and was stirred for 45 min. DMS (1.5 eq. 0.78 mL) was added dropwise at room temperature and the resulting reaction mixture was heated to 60°C. The reaction was stirred at this temperature for 3 days and was monitored by HPLC.
  • PvLT-8-des-methyl (2 g) was added to a mixture of LiH (98 mg) and anisole (20 mL). The resulting mixture was heated to 38°C and was stirred for 45 min. Dimethyl sulfate (DMS) (0.66 mL) was added dropwise at room temperature and the reaction mixture was heated to 60°C. The reaction was stirred for 3 days at this temperature and was monitored by HPLC.
  • DMS dimethyl sulfate
  • the anisole phase was washed twice with a saturated sodium chloride solution (28% w/v) (250.0 ml each), and then concentrated under reduced pressure on rotary evaporator to obtain a thick residue.
  • Toluene 250 ml was added to the thick residue and stirred at 65 °C. A solid precipitate was obtained. This mixture was stirred overnight at ambient temperature, after which the solid was collected by filtration, washed with toluene (50 ml) and dried under vacuum to provide RLT-8 crude (26.5 g, purity 95.0%)
  • the crude RLT-8 was further purified using methanol/water as follows.
  • the anisole phase was washed twice with a saturated sodium chloride solution (28% w/v) (250.0 ml each), and then concentrated under reduced pressure on a rotary evaporator to obtain a thick residue.
  • Toluene 250 ml was added to the thick residue and stirred at 65°C thus producing a solid precipitate. This mixture was stirred overnight at ambient temperature. Then the solid was separated by filtration, washed with toluene (50 ml) and dried under vacuum to provide RLT-8 crude (26.5 g, purity 95.0%)
  • the crude RLT-8 was further purified using methanol/water as follows.
  • the RLT-8 (25.0 g) was dissolved in 300 ml methanol at reflux and demineralized water (50 ml) was added at 65°C over a period of 40-45 minutes. The mixture was then stirred for one hour at 65°C followed by addition of additional water (50 ml) at 65°C temperature. The resulting mixture was stirred at the same temperature for an hour and then stirred overnight at ambient temperature (27°C). A solid was obtained, which was separated by filtering, washed with a mixture of methanol water (1 : 1 , 50.0 ml), and dried under vacuum at 50°C (22.50 g, Purity 99.0%)
  • Example 6 Preparation of RLT-8 To a flask (1000 ml) was added aqueous lithium hydroxide (57%, 23.13 g), anisole (500 ml), RLT-8-des-methyl (50.0 g) and dimethyl sulfate (69.38 g) to obtain a mixture. The mixture was stirred at 28 °C for 30 hours and then monitored by HPLC, which indicated that less than 1.5% of RLT-8-des-methyl was present. Water (150 ml) was added to the reaction mixture and the pH was adjusted to 1.0-2.0 with 2N HC1. The resulting mixture was stirred and the phases were separated.
  • aqueous lithium hydroxide 57%, 23.13 g
  • anisole 500 ml
  • RLT-8-des-methyl 50.0 g
  • dimethyl sulfate 69.38 g
  • the anisole phase was washed twice with a saturated sodium chloride solution (28% w/v) (250.0 ml each), and concentrated under reduced pressure on a rotary evaporator to obtain a thick residue.
  • Toluene 250 ml was added to the thick residue and stirred at 65 °C to produce a solid precipitate. This mixture was then stirred overnight at ambient temperature and the solid was then separated by filtering, washed with toluene (50 ml) and dried under vacuum to obtain RLT-8 crude (26.5 g, purity 95.0%).
  • the crude RLT-8 was further purified as follows.
  • the RLT-8 (25.0 g) was dissolved in 300 ml methanol at reflux demineralized water (50 ml) was added at 65°C over a period of 45 minutes. The reaction mixture was stirred for one hour at 65°C and then additional DM water (50 ml) was added at 65°C. The reaction mixture was then stirred at same temperature for 1 hour followed by stirring overnight at ambient temperature to obtain a solid precipitate. The solid was collected by filtering, washed with a mixture of methanol water (1 : 1 ) 50.0 ml, and dried under vacuum at 45- 50°C (22.50 g, Purity: 99.0%
  • the anisole phase was washed twice with a saturated sodium chloride solution (28% w/v) (250.0 ml each), and concentrated under reduced pressure on a rotary evaporator to obtain a thick residue.
  • Toluene 250 ml was added to the thick residue and stirred at 65°C to produce a solid precipitate. This mixture was stirred overnight at ambient temperature, and the solid was separated by filtering, washed with toluene (50 ml) and dried under vacuum to provide RLT-8 crude (26.5 g, purity 95.0%)
  • the crude RLT-8 was further purified as follows.
  • the RLT-8 (25.0 g) was dissolved in 300 ml methanol at reflux and demineralized water (50 ml) was then added at 65°C over a period of 45 minutes to obtain a reaction mixture. The mixture was stirred for one hour at 65°C and then additional demineralized water (50 ml) was added at 65°C. The resulting mixture was stirred at the same temperature for an hour and then stirred overnight at ambient temperature to produce a solid precipitate. The solid was separated by filtering, washed with a mixture of methanol water (1 : 1 ) 50.0 ml, and dried under vacuum at 50°C (22.50 g, Purity 99.0%)
  • the combined filtrate was then added to a 5 L flask and the pH was adjusted to 8.5 with aqueous sodium hydroxide (940 ml, IN). The resulting mixture was stirred at room temperature for 19 hours and then was cooled to 5°C. After 2 hours of stirring at 5°C, a solid precipitate formed and was separated by filtering. The filter cake was washed with water (200 ml). The solid was then dried overnight at 45°C to provide the compound RLT-9 as a white solid. (143.4g, 98% yield, purity 98.75%).
  • the resulting mixture was cooled to 15°C and seeded with Raltegravir potassium form V (0.15% w/w). The resulting mixture was cooled to -10°C over 3 hours. The product precipitated and was filtered under reduced pressure at RT, and the collected solid was then washed with toluene (45 ml). The product was dried in a vacuum oven at 40°C overnight. Raltegravir potassium form V was obtained.

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Abstract

La présente invention concerne un procédé de préparation de benzyl-2-(4-(4- fluorobenzylcarbamoyl)-5-hydroxy-1-méthyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2- ylcarbamate (RLT-8), un procédé de préparation du Raltégravir via RLT-8, un procédé de préparation de méthyl 2-(2-(benzyloxycarbonylamino)propan-2-yl)-5 -hydroxy-1-methyl-6- oxo-1,6-dihydropyrimidine-4-carboxylate (RLT-7'), un procédé de préparation du Raltégravir via RLT-7', et un procédé de préparation de la forme cristalline V du potassium de Raltégravir.
PCT/US2012/022385 2011-01-24 2012-01-24 Procédés de préparation du raltégravir et de ses intermédiaires dans lesdits procédés WO2012103105A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015114608A1 (fr) * 2014-02-03 2015-08-06 Mylan Laboratories Ltd Procédés pour la préparation d'intermédiaires de raltégravir
WO2016075605A1 (fr) * 2014-11-10 2016-05-19 Aurobindo Pharma Ltd Procédé perfectionné pour la préparation de raltégravir
US10391178B2 (en) 2014-03-21 2019-08-27 Mylan Laboratories Limited Premix of crystalline raltegravir potassium salt and a process for the preparation thereof

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