WO2012103105A1

WO2012103105A1 - Processes for preparing raltegravir and intermediates in the processes

Info

Publication number: WO2012103105A1
Application number: PCT/US2012/022385
Authority: WO
Inventors: Lilach Hedvati; Rotem Erez; Meital Cohen; Vinod Kumar Kansal; Harish Ranjan; Debashish Das; Sanjay Jaiswal; Elluru SUBBIREDDY
Original assignee: Teva Pharmaceutical Industries Ltd; Assia Chemical Industries Ltd; Teva Pharmaceuticals USA Inc
Current assignee: Teva Pharmaceutical Industries Ltd; Assia Chemical Industries Ltd; Teva Pharmaceuticals USA Inc
Priority date: 2011-01-24
Filing date: 2012-01-24
Publication date: 2012-08-02
Anticipated expiration: 2013-07-24

Abstract

The present invention provides a process for preparing benzyl-2-(4-(4- fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2- ylcarbamate (RLT-8), a process for preparing Raltegravir via RLT-8, a process for preparing methyl 2-(2-(benzyloxycarbonylamino)propan-2-yl)-5 -hydroxy-1-methyl-6- oxo-1,6-dihydropyrimidine-4-carboxylate (RLT-7'), a process for preparing Raltegravir via RLT-7', and a process for preparing crystalline form V of Raltegravir potassium.

Description

PROCESSES FOR PREPARING RALTEGRAVIR AND INTERMEDIATES IN

THE PROCESSES

Cross Reference to Related Applications

This patent application claims the priority of U.S. provisional applications, Serial Nos. 61/435,538 filed January 24, 201 1 , 61 /467, 194 filed March 24, 201 1 , 61/496,389 filed June 13, 201 1 and 61 /545,876 filed October 1 1 , 201 1 , the disclosures of which are herein incorporated by reference.

Field of the Invention

The present invention encompasses processes for preparing Raltegravir, its crystalline forms V and II, and intermediates in said processes of preparing Raltegravir.

Background of the Invention

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;

is an antiretroviral drug used to treat HIV infection. 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 ISENTRESS™ by Merck & Co.

The processes for preparing Raltegravir that are known in the art either require a protection step for the 5-hydroxy group prior to the methylation step, or lead to an impurity resulting from the methylation of the 5-hydroxy group.

U.S. Patent No. 7, 169,780 discloses Raltegravir and preparation thereof, as described in the following reaction scheme:

Scheme 1

J. Med. Chem. 2008, 51 , 5843-5855 discloses another process for preparing Raltegravir as described in the following reaction scheme:

RLT K-salt

Scheme 2 U.S. Publication No. US 2006/0122205 describes an alternative process for preparing Raltegravir, in which the alkylation step does not include a step for protecting the 5-hydroxy group. The process is described in the following reaction scheme:

Scheme 3

Provided herein is an industrially applicable process 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.

US Publication No. US 2006/0122205, WO 2010/1401 56 and WO 201 1 /

024192 describe the potassium salt of Raltegravir, including amorphous and crystalline forms I, II, III and H I , as well as amorphous and crystalline forms of Raltegravir free- hydroxy. PCT publication No. WO 201 1/123754 describes certain Raltegravir salts and polymorphs, including form V of Raltegravir potassium.

The present invention also relates to new processes for preparing forms I I and V of

Raltegravir potassium salt.

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. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

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

In one embodiment, 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.

In another embodiment, 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.

In yet another embodiment, 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. In one embodiment, the present invention provides a process for preparing crystalline form V of Raltegravir.

Brief Description of the Drawings

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 . Detailed Description of the Invention

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

(compound RLT-9), and 2-(2-aminopropan-2-yl)-4-(4-fluorobenzylcarbamoyl)-l -methyl- 6-oxo- l ,6-dihydropyrimidin-5-yl pivalate (compound RLT-9-OP).

As used herein, the terms "room temperature" or "RT" refer to a temperature of about 15°C to about 35°C. For example, "RT" can refer to a temperature of about 25°C.

As used herein, the term "overnight" refers to a time interval from about 12 hours to about 20 hours.

As used herein, the terms "vol." or "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.

As used herein, the term "H-donor" refers to a chemical compound that has a hydrogen atom available for hydrogen bonding.

As used herein, the terms "compound RLT-7'," or "RLT-7' " refer to methyl 2-(2-

(benzyloxycarbonylamino)propan-2-yl)-5-hydroxy-l -methy 1-6-oxo- 1,6-dihydro- pyrimidine-4-carboxylate, an intermediate. in the synthesis of Raltegravir. As used herein, the terms "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.

As used herein, the terms "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.

As used herein, the terms "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.

As used herein, the terms "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.

As used herein, the terms "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.

As used herein 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.

As used herein, 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.

As used herein, 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.

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. Typically, 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.

Alternatively, 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. Alternatively, 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. Typically, 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. Alternatively, 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. In conventional processes for preparing Raltegravir, the deprotection step for obtaining the compound RLT-9, requires the presence of H₂ gas. For at least that reason, this route is less preferred for industrial use. In addition hydrogenation leads to the formation of the impurity RLT-9-Des-Fluoro of the following formula:

RLT-9- Des-F

The RLT-9-Des-Fluoro impurity may serve as precursor to the formation of RLT-des-Fluoro impurity of the following formula:

RLT-des-Fluoro

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 H₂, 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. Typically, 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 HC0₂K or HC0₂Na.

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"),

H₂SC , acetic acid, or a mixture thereof.

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. 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. Typically, 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

The obtained crystalline forms of Raltegravir potassium can be used to prepare Raltegravir salts, solid state forms thereof and pharmaceutical composition thereof.

Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The disclosures of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. Examples

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. Some of the processes for preparing the compounds RLT-7', RLT-8, RLT-9 and Raltegravir according to the present invention are exemplified below.

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.

The HPLC purity observed for product RLT-7' (before isolation) was 73%.

Example 2: Preparation of RLT-8

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.

The purity observed for the product RLT-8 (before isolation) was 76%.

Example 3: Preparation of RLT-8

A flask ( 100 mL) was charged with aqueous lithium hydroxide 57% (0.648 g,

100%), anisole (20 mL) and RLT-8-des-methyl (2 g). The mixture was stirred at 38 °C for 60 min. and then cooled to RT. DMS (1.04 mL) was added dropwise at RT and the reaction mixture was heated to 40°C, stirred for overnight and monitored by HPLC. Full conversion was obtained (Purity 85%).

Example 4: Preparation of RLT-8

To a flask (1000 ml) was added lithium hydroxide-H₂0 57% (23.13 g), anisole (250 ml), RLT-8-des-methyl (50.0 g) and dimethyl sulfate (69.38 g). The mixture was stirred at 28°C for 1 5 hours and the reaction mixture was monitored by HPLC after 15 hours. Less than 1.5% of RLT-8-des-methyl was observed. Water ( 150 ml) and anisole (250 ml) were added to the reaction mixture and the pH of the resulting mixture was adjusted to 1.0-2.0 with 2N HCl. The obtained reaction mixture was stirred and the phases were separated. 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 RLT-8 (25.0 g) was dissolved in 300 ml methanol at reflux temperature. To this solution was added demineralized water (50 ml) at 65°C over a period of 45 minutes. The resulting mixture was stirred for one hour at 65°C followed by addition of additional demineralized water (50 mL) at 65°C. The resulting mixture was stirred at same temperature for 1.0 hours and then stirred overnight at ambient temperature. The obtained solid was collected by filtration; washed with a mixture of methanol water (1 : 1 , 50.0 ml), and dried under vacuum at 50° (22.50 g, purity: 99.0%) Example 5: Preparation of RLT-8

To a flask (1000 ml) was added aqueous lithium hydroxide 57% (13.88 g), anisole (250 ml), RLT-8-des-methyl (50.0 g) and dimethyl sulfate (69.38 g). The mixture was stirred at 27 °C for 15hours and then monitored by HPLC. The HPLC analysis indicated that less than 1.5% of RLT-8-des-methyl was present. Water (150 ml) and anisole (250 ml) were added to the reaction mixture and the pH was adjusted to 1 .0-2.0 with 2N HC1. The resulting reaction mixture was stirred and the phases were separated. 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. 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%

Example 7: Preparation of RLT-8

To a flask ( 1000 ml) was added aqueous lithium hydroxide 43% (16.19 g), anisole (250 ml), RLT-8-des-methyl (50.0 g) and dimethyl sulfate (34.69 g) to obtain a mixture. The mixture was stirred at 60°C for 3 hours and then monitored by HPLC, which showed less than 1.5% of RLT-8-des-methyl. Water (150 ml) and anisole (250 ml) were 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. 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%)

Example 8: Preparation of RLT-9

To a 3L, three-necked flask equipped with a mechanical stirrer and thermometer, was added the compound RLT-8 (200g), methanol (2000 ml), formic acid (24.2 ml), Pd/C 10% (50% water wet, 5.5g) and potassium formate (5.5g) (dissolved in 300 ml of water). The resulting mixture was heated to 50°C and stirred for 2.5 hours. Water (300 ml) and sulfuric acid (26 ml) were added and the palladium was filtered off. The filter cake was washed with methanol 80% solution (250 ml).

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%).

Example 9: Preparation of Raltegravir

To a 0.5 liter reactor was added acetonitrile ( 15 vol), N-methylpyrrolidinone ( 1 vol) and N-methylmorpholine (0.5 g). The resulting solution was cooled to about 0°C and then methyl oxadiazole- potassium (8g) was added. Pivaloyl chloride (7.22 ml) was then added dropwise (over 10 min). The resulting mixture was stirred for about 6 h.

N-Methylmorpholine (5.9 g) and RLT-9 were then added. The resulting mixture was then heated to 20°C and stirred for 16h. The solvent was then evaporated to provide a residue. Water (75 ml) and isopropyl alcohol (25 ml) were added to the residue. The resulting solution was stirred overnight at RT. A precipitate formed and was filtered and washed with water (10 ml) and IPA (20 ml). The product was dried under vacuum at 60°C overnight to give 8.76g Raltegravir (85.7% assay, 77% yield). The obtained crude product was purified by slurry in MeOH/Water mixture. Example 10: Preparation of Raltegravir potassium form V

A vial (20 ml) was charged with Raltegravir free hydroxy (500 mg) and cyclo- hexane (2.5 ml) at room temperature. A solution of 30% aqueous KOH (0.162 ml) was added. Additional cyclohexane (5 ml) was added. The resulting mixture was stirred for 25 hours at room temperature. A gel solid precipitated and was separated by filtering under reduced pressure to produce wet Raltegravir potassium crystalline Form V. The product was dried overnight in a vacuum oven at 40°C to provide Raltegravir potassium crystalline Form V.

Example 1 1 : Preparation of Raltegravir potassium Form V

A 1 liter reactor equipped with a mechanical stirrer and a reflux condenser was charged with Raltegravir free hydroxy (15 g) and THF (225 ml). The resulting mixture was heated to dissolution (30°C). The solution was filtered. A solution of KOH (2.26 g, 1.05 equiv.) in EtOH:H₂0 (8:2 v/v respectively) was added followed by addition of toluene (225 ml).

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.

Example 12: Preparation of Raltegravir potassium Form V

A 50 mL round bottom flask was charged with Raltegravir free hydroxy (2 g) and EtOAc (10 vol.) to form a slurry. The slurry was stirred at room temperature. KOH solution (1 g in 1 ml H?0), was added, immediately followed by addition of H₂O (1 mL). Seeding with Raltegravir potassium form V was done and the mixture was stirred at RT for 3 h. The product precipitated and was filtered under reduced pressure and dried in vacuum oven at 45°C overnight to yield Raltegravir potassium form V. Example 13: Preparation of Raltegravir potassium Form V

A 100 mL round bottom flask was charged with Raltegravir free hydroxy (2 g) and iso-BuOAc (25 vol.). The resulting slurry was stirred at RT. KOH solution (0.3 g in 0.3 mL H₂0, was added, and then H₂0 (0.3 mL) was added immediately. Seeding with Raltegravir potassium form V was done and the mixture was stirred at RT for 2.5 h. The product precipitated and was filtered under reduced pressure and dried in vacuum oven at 45 °C overnight to yield Raltegravir potassium form V.

Example 14: Preparation of Raltegravir potassium Form II

To a 1 L glass reactor equipped with mechanical stirrer, Raltegravir free hydroxy

(20 g) and isopropyl-alcohol (500 mL) were charged. The resulting white slurry was heated to 60°C and stirred for 30 minutes. A solution of KOH (89.6%, 0.95 equiv.) in IPA/water (1 .6 vol/0.4 vol.) was added dropwise and the reaction mixture was stirred at 60°C for 2.5 hours. Then, the reaction mixture was cooled to room temperature, filtered, and the collected solid was washed with IPA (2 vol.), and dried overnight in a vacuum oven at 40°C. The resulting product was analyzed by XRPD and found to give a pattern corresponding to Raltegravir potassium crystalline Form II (16.88 g, 84% yield).

Example 15: Preparation of 2-(2-aminopropan-2-yl)-4-(4-fluorobenzylcarbamoyl)- l - methyl-6-oxo-l ,6-dihydropyrimidin-5-yl pivalate ( RLT-9-OP)

To 1 L reactor was added water (150 mL), K2CO₃ (59 g), 4-dimethylaminopyridine ("DMAP") (1 g), ethyl acetate (450 mL), and RLT-8 (100 g, 1 eq.). The mixture was stirred and pivaloyl chloride (30 mL) was added. The reaction mixture was then stirred at RT overnight. The two phases were then separated, and ethyl acetate ( 100 mL) was added to the organic phase to form a mixture. Formic acid (20 mL), Pd/C 5% (2.5 g), KHCO2 (3.6 g) and ethyl acetate (100 mL) were added to the mixture and the resulting reaction mixture was stirred for 3 hours at 25° C. Water (500 mL) and formic acid (16 mL) were then added and the resulting mixture was heated to 50° C and then filtered. The ethyl acetate layer was washed with water (100 mL). To the combined aqueous phases, ethanol (300 mL) and a solution of K2CO₃ (56 g) in water (100 mL) were added, thus forming a slurry. The slurry was stirred at RT for 2 h and the solid was collected by filtration, washed with water (200 mL) and dried under vacuum at 50°C overnight. RLT-9-OP was obtained (-90% yield). Example 16: Preparation of Raltegravir

A reactor (100 ml), equipped with glass impeller was flushed with N₂ flow and then cooled to - 10°C. The reactor was charged with, N-methylmorpholine (0.21 ml), N- methyl-2-pyrrolidone ("NMP") (3.2 ml), acetonitrile (75 ml), and oxadiazole potassium (5g, 1.6eq). To the stirred reaction mixture pivaloyl chloride (2.6 ml, 1.76 eq) was added dropwise at (- 10°C). The resulting slurry was stirred at -10°C for 15 hour. Then RLT-9-

OP (5g, l eq) was added and the resulting mixture was heated to 20°C, and stirred at 20°C. The solvent was then evaporated to form a residue. A solution of NH₄OH 25% (10ml) and isopropanol (1 5ml) were added to the residue and the resulting mixture was stirred at RT for 1 hour. The solvent was then evaporated. 1PA (30ml) and water (60ml) were added to the residue and this mixture was stirred at RT overnight to form a slurry. The slurry was filtered and the collected solid was washed with water (10 ml) and isopropanol (5ml). The product was then dried under vacuum at 50°C overnight. Raltegravir (7.1 g) was obtained. Example 17: Preparation of RLT-8

To a flask (1000 ml) was added aqueous lithium hydroxide 57% (13.88 g), anisole (150 ml), RLT-8-des-methyl (50.0 g) and dimethyl sulfate (69.38 g) to obtain a mixture. The mixture was stirred at 27 °C for 15 hours and then monitored by HPLC. The HPLC analysis indicated that less than 1 .5% of RLT-8-des-methyl was present. Water (300 ml) was added to the reaction mixture and the pH was adjusted to 1.0-2.0 with 2N HC1

Solution. The resulting reaction mixture was stirred and the phases were separated. The anisole phase was washed twice with a saturated sodium chloride solution (28% w/v) (250.0 ml each), and toluene (350 ml) was added to the anisole layer at 25°C and stirred for 8 hours at 25°C followed by stirring at 10°C for additional 2.0 hours, thus producing a solid precipitate. The solid was then separated by filtration, washed with toluene (50 ml) and dried under vacuum to provide RLT-8 crude. (25.0 g, purity 97.0%)

Claims

Claims What is claimed is:

1. A process for preparing benzyl-2-(4-(4-fluorobenzylcarbamoyl)-5 -hydroxy- 1 - methyl-6-oxo- 1 ,6-dihydropyrimidin-2-yl)propan-2-ylcarbamate (RLT-8), said process comprising: combining benzyl-2-(4-(4-fluorobenzylcarbamoyl)-5- hydroxy-6-oxo- 1 ,6-dihydropyrimidin-2-yl)propan-2-ylcarbamate (RLT-8-des- methyl) with anisole and lithium hydroxide, or anisole and lithium hydride, to obtain a reaction mixture; and adding dimethyl sulfate to the reaction mixture.

2. A process for preparing Raltegravir comprising preparing benzyl-2-(4-(4- fluorobenzylcarbamoyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidin-2-yl)- propan-2-ylcarbamate (RLT-8) according to claim 1, and converting it to

Raltegravir.

3. A process for preparing methyl 2-(2-(benzyloxycarbonylamino)propan-2-yl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxylate (RLT-7'), said process comprising: combining methyl 2-(2-(benzyloxycarbonylamino)propan-2- yl)-5,6-dihydroxypyrimidine-4-carboxylate (RLT-5) with anisole and lithium hydride to obtain a reaction mixture; and adding dimethyl sulfate to the reaction mixture.

4. A process for preparing Raltegravir comprising preparing methyl 2-(2- (benzyloxycarbonylamino)propan-2-yl)-5 -hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydro- pyrimidine-4-carboxylate (RLT-7') according to claim 3, and converting it to Raltegravir.

5. A process for preparing crystalline form V of Raltegravir potassium comprising: combining Raltegravir with a potassium source to form the potassium salt of Raltegravir, and crystallizing the potassium salt from a solvent selected from: cyclohexane, tetrahydrofuran, ethyl acetate, isobutylacetate and mixtures thereof.

6. The process according to claim 5, wherein the potassium source is KOH.