WO2017118928A1

WO2017118928A1 - Process for the separation of diastereomers of tenofovir alafenamide

Info

Publication number: WO2017118928A1
Application number: PCT/IB2017/050032
Authority: WO
Inventors: Dinesh Dnyaneswar DIXIT; Manoj Kunjabihari AGARWAL; Narotham Venkata Maddireddy; Himanshu Madhav Godbole; Girij Pal Singh
Original assignee: Lupin Limited
Priority date: 2016-01-06
Filing date: 2017-01-05
Publication date: 2017-07-13
Also published as: WO2017118928A9

Abstract

The invention describes a process and diastereomeric salts useful for the optical resolution of 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl] methoxy] propyl] adenine and intermediates thereof. The process comprises placing into solution a chiral resolving agent, either L/D-Proline or L/D-Phenylalanine, precipitating the resulting diastereomeric salt between the chiral resolving agent and the target enantiomer and separating the enantiomer.

Description

PROCESS FOR THE SEPARATION OF DIASTEREOMERS OF TENOFOVIR ALAFENAMIDE

Technical field of invention: The present invention is relates to an effective process for the separation of diastereomers of Tenofovir alafenamide or its intermediate. The process comprises the steps of resolving a Tenofovir alafenamide or its intermediate raceme by taking Proline or Phenylalanine compound as a resolving agent to obtain a diastereomeric salt; separation of isomers and desaltification of salt to obtain diastereomerically pure Tenofovir alafenamide or its intermediate. The preparation process of diastereomerically pure Tenofovir alafenamide or its intermediate is simple and feasible to operate and cheap in required reagent; the resolving agent is easily available and non-toxic and easy to recycle; the preparation process is applicable to industrial production. Background of the invention:

Tenofovir alafenamide is chemically known as 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl]adenine, an isopropylalaninyl monoamidate phenyl monoester prodrug of tenofovir. Tenofovir alafenamide has the structure shown in Formula-I:

Formula- 1

PCT Publication No. WO2002008241, which is hereby incorporated by reference, discloses prodrugs of phosphonate nucleotide analogues, including tenofovir alafenamide, as well as methods for diasteriomeric separation by the use of chromatography. The chromatography techniques described are batch elution chromatography, simulated bed chromatography. PCT Publication No. WO2013052094, describes crystallization techniques for the diastereomeric separation of 9-[(R)-2-[[(R,S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]- phenoxyphosphinyl] methoxy] propyl] adenine to give 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl] amino] phenoxyphosphinyl] methoxy]propyl] adenine. Other PCT Publications WO2014195724 and WO2015107451 describes diastereomeric separation of 9- [(R)-2- [[(R,S)- [ [(S)- 1 -(isopropoxycarbonyl)ethyl] amino] - phenoxyphosphinyl] methoxy] propyl] adenine by the resolution techniques.

It is known in the art that use of chromatographic techniques for the separation of diastereomers at the industrial scale requires a remarkable starting investment. Building the set-up for chromatography is an expensive process. Also, large volumes of solvent(s) are required for separation which not only increase the overall cost of the process, but also is environment unfriendly. Further, the separation of diastereomers by chromatography is a tedious and time- consuming process. The method of optical resolution incorporating the formation of a diastereomeric complex with a chiral resolving agent and a single enantiomer of the racemic compound and subsequent crystallization of the complex has been traditionally a very significant technique of optical resolution. Also known as fractional crystallization, it is very tedious in that the choice of suitable solvents and chiral resolving agents is largely a matter of trial and error. The technique is further limited in that it is only applicable to solids. As a result, a search for other methods of efficient optical resolution is ongoing.

Numerous chiral resolving agents have been available and are known. However, as mentioned previously, useful chiral resolving agents for crystallization on an industrial scale have particular requirements. For example, they should be relatively inexpensive and of a high state of optical purity. They should react easily with the desired target enantiomer and form a diastereomeric complex with physical properties sufficiently different from other associative complexes in the solution so as to precipitate relatively exclusively, and in a state free from the other associative complexes. Precipitation in such degree of relative exclusivity is necessary in order to achieve a high degree of optical purity of the enantiomeric target compound. Additionally, good resolving agents should be recyclable, that is, recoverable from the solution in significant quantitative yield.

The present invention thus provides a simple, effective and industrial feasible process for the separation of diastereomers of 9-[(R)-2-[[(R,S)-[[(S)-l- (isopropoxycarbonyl)ethyl] amino] -phenoxyphosphinyl] methoxy] propyl] adenine or its intermediate. Summary of the invention:

In one aspect, the present invention relates to a process for the separation of diastereomers of 9-[(R)-2-[[(R,S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]- phenoxyphosphinyl] methoxy] propyl] adenine.

In another aspect, the present invention relates to a process for the separation of diastereomers of 9-[(R)-2-[[(R,S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]- phenoxyphosphinyl] methoxy] propyl] adenine by using a Proline compound as a resolving agent.

In another aspect, the present invention relates to a process for the separation of diastereomers of 9-[(R)-2-[[(R,S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]- phenoxyphosphinyl] methoxy] propyl] adenine by using a Phenylalanine compound as a resolving agent.

In another aspect, the present invention relates to a process for the separation of diastereomers of intermediate compound of formula II by using Proline or Phenylalanine compounds as resolving agents.

II

III Description of the invention:

As used herein, the notation ^OR indicates a bond which protrudes back from the plane of the paper; the notation " ^OR " indicates a bond which protrudes forward from the plane of the paper; and the notation ^™" ^{OR ^} indicates a bond for which the stereochemistry is not designated (a racemic).

As used herein, "chiral resolving agent" or "optically active resolving agent" refers to either the dextro or levo rotatory optical isomer of the following compounds: Proline and Phenylalanine i.e., D or L- isomer. As used herein the term "salt" or "diastereomeric salt" has the general meaning imputed to the term by the art. For example, it can refer to the associative complex which results when the anionic element of an acidic chiral resolving agent associates with the cationic portion of the desired enantiomer of a basic racemic target compound (enantiomer) which results from one or more points of interaction due to one or more weak attractive forces.

According to one aspect, the present invention provides a preparation of 9-[(R)-2-[[(S)- [ [(S)- 1 - (isopropoxycarbonyl)ethyl] amino] phenoxyphosphinyl] methoxy]propyl] adenine comprising the steps of:

a) preparing a solution of 9-[(R)-2-[[(R,S)-[[(S)-l- (isopropoxycarbonyl)ethyl] amino] -phenoxyphosphinyl] methoxy] propyl] adenine and an optically active resolving agent, L-Proline or L-Phenylalanine, in a suitable organic solvent;

b) heating the solution of step (a) to an elevated temperature to form a solution of a diastereomeric salt of the optically active resolving agent and 9-[(R)-2-[[(R,S)- [ [(S)- 1 -(isopropoxycarbonyl)ethyl] amino] -phenoxyphosphinyl] methoxy] propyl] adenine;

c) cooling the solution from step (b) for a period of time to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) desaltifying the diastereomeric salt to isolate 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl]adenine.

The process is equally applicable when substituting D-Proline or D-Phenylalanine as resolving agents, resulting in a process including the steps of:

a) preparing a solution of 9-[(R)-2-[[(R,S)-[[(S)-l-

(isopropoxycarbonyl)ethyl] amino] -phenoxyphosphinyl] methoxy] propyl] adenine and an optically active resolving agent, D-Proline or D-Phenylalanine, in a suitable organic solvent;

b) heating the solution of step (a) to an elevated temperature to form a solution of a diastereomeric salt of the optically active resolving agent and the 9-[(R)-2- [[(R,S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl] methoxy] propyl] adenine;

d) collecting the diastereomeric salt; and

e) desaltifying the diastereomeric salt to isolate 9-[(R)-2-[[(R)-[[(S)-l-

(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl]adenine.

When L-Proline or L-Phenylalanine is used in the first step (step a) of a process of the present invention, a diastereomeric salt of 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl] adenine with L- Proline or L- Phenylalanine is obtained in a solid form, while the filtrate contains the other diastereomer (RRS) salt. When D- Proline or D-Phenylalanine is used in the first step (step a) of a process of the present invention, a diastereomeric salt of 9-[(R)-2-[[(R)-[[(S)-l- (isopropoxycarbonyl)ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine with D- Proline or D-Phenylalanine is obtained in a solid form, while the filtrate contains the other diastereomer (RSS) salt.

The starting material used in the first step (step a), 9-[(R)-2-[[(R,S)-[[(S)-l- (isopropoxycarbonyl)ethyl] amino] -phenoxyphosphinyl] methoxy] propyl] adenine can be taken from previous reaction step as an in-situ or as an isolated form. The "suitable organic solvent" refers to any polar organic solvent in which the interactive complex formed between the chiral resolving agent and the compound. Exemplary the organic solvent selected from but not limited to methanol, ethanol, ethyl acetate, acetone, 2-butanone, acetonitrile, dioxane or mixtures thereof. The "elevated temperature" facilitating formation of the interactive complex may be any temperature at which the complex is soluble, but is typically in the range of about 50° C. to about 100° C. When the organic solvent is ethyl acetate the range is about 65° C. to about 70° C.

The temperature to which the solution is cooled can be any temperature lower than the temperature at which the interactive complex begins to precipitate, but is typically between -20° C. and 45° C. Preferably, it is -10° C. to 35° C. and most preferably it is 5° C. to 30° C.

The period of time for which the solution is cooled is a time period sufficient for the diastereomeric salt in the solution to precipitate. It can vary depending upon temperature and degree of agitation during the crystallization period.

The isolation of the compound i.e., 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl] adenine or 9- [(R)-2-[[(R)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]

methoxy] propyl] adenine by using conventional methods known in the art. Exemplary isolation methods include such as filtration, vacuum distillation, crystallization and the like. Preferably, the filtrate is further treated in order to recover the diastereomer which was not previously removed by precipitation. Preferably, the further treatment involves the conversion of the salt in the filtrate to its base using ammonia, or other similar bases, in water, followed by extraction and isolation of the base. In another aspect of the present invention, optionally the separated 9-[(R)-2-[[(R)-[[(S)-l - (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine or 9- [(R)-2-[[(S)- [[(S)-l

(isopropoxycarbonyl)ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine may be converted to the corresponding salt by reacting with a suitable acid, such as fumaric acid, lactic acid, malic acid, succinic acid, malonic acid, oxalic acid and the like. Preferably, the acid used is fumaric acid. In another aspect of the present invention, there is provided a pharmaceutical composition comprising 9- [(R)-2- [ [(R)- [[(S)- 1 -(isopropoxycarbonyl)ethyl] amino]phenoxy- phosphinyljmethoxy] propyl] adenine or a pharmaceutically acceptable salt thereof OR 9- [(R)-2- [[(S)- [ [(S)- 1 - (isopropoxycarbonyl)ethyl] amino]phenoxyphosphinyl] methoxy] propyl] adenine or a pharmaceutically acceptable salt thereof, prepared according to the process of the present invention, and one or more pharmaceutically acceptable excipients.

In yet another aspect, the present invention provides for the preparation of an intermediate compound of formula III comprising the steps of:

a) preparing a solution of a compound of formula II with an optically active resolving agent, L-Proline or L-Phenylalanine, in a suitable organic solvent;

b) heating the solution from step a) to an elevated temperature to form a solution of a diastereomeric salt of the optically active resolving agent and the compound of formula II;

c) cooling the solution from step b) for a period of time to precipitate the diastereomeric salt;

d) collecting the diastereomeric salt; and

e) desaltifying the diastereomeric salt to isolate the compound of formula III.

The process is equally applicable when substituting D-Proline or D-Phenylalanine as resolving agents, resulting in a process comprising the steps of:

a) preparing a solution of a compound of formula II with an optically active resolving agent, D-Proline or D-Phenylalanine, in a suitable organic solvent;

b) heating the solution from step a) to an elevated temperature to form a solution of a diastereomeric salt of the optically active resolving agent and the compound of formula

II;

d) collecting the diastereomeric salt; and

e) desaltifying the diastereomeric salt to isolate the compound of formula III. The "suitable organic solvent" refers to any polar organic solvent in which the interactive complex formed between the chiral resolving agent and the compound. Exemplary the organic solvent selected from but not limited to methanol, ethanol, ethyl acetate, acetone, 2-butanone, acetonitrile, dioxane or mixtures thereof.

The invention is further illustrated by following examples, which should not be construed as limiting to the scope of invention. Examples:

Example 1: Separation of diastereomers using L-Proline:

To a mixture of [(R)-2-(Phenylphosphonomethoxy) propyl] adenine (1000 gms) in toluene (6000 ml), thionyl chloride (720 gms) was added and heated to 75 °C for 15hr. The solvents were removed, cooled to 25°C, diluted with dichloromethane (3500 ml) and further cooled to -30°C. A solution of L-alanine isopropyl ester hydrochloride (1.81 kg) in dichloromethane (3000 ml) was added and followed by triethylamine (1.91kg, 0.824 mol) over 60 minutes at -20°C. The reaction mixture was heated to 25-30°C and washed with 20% aq. sodium dihydrogenphosphate solution (5 L) at 25 °C. Stirred the reaction mass and separated the layers. The organic layer was distilled under vacuum. Ethyl acetate (5000 ml) and L-Proline (0.31 kg) was added to the residue, contents heated to 65- 70°C, cooled and filtered to obtain 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy] propyl] adenine L- Proline. The above reaction mixture was slurred into mixture of water (3000 ml) and dichloromethane (5000 ml). Stirred the reaction mass and separated the layers. The organic layer was distilled under vacuum. Acetonitrile (6000 ml) and fumaric acid (0.15kg) was added to the residue, contents heated to 70-75°C, cooled and filtered to obtain (9-[(R)-2-[[(S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy] propyl] adenine fumarate.

Yield = 600 gm Diastereomeric purity = 99.6%

Claims

A process for preparing 9-[(R)-2-[[(S)-[[(S)-l-

(isopropoxycarbonyl)ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine comprising:

b) heating the solution of step (a) to an elevated temperature;

c) cooling the solution from step (b) and isolate the diastereomeric salt;

d) desaltifying the diastereomeric salt to isolate 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]

methoxy]propyl]adenine.

The process of claim 1, wherein the organic solvent selected from methanol, ethanol, ethyl acetate, acetone,

2-butanone, acetonitrile, dioxane or mixtures thereof.

3. The process of claim 1, wherein the step (b) is performed at a temperature in the range from about 50° C. to about 100° C.

4. A process for preparing 9-[(R)-2-[[(R)-[[(S)-l-

a) preparing a solution of 9-[(R)-2-[[(R,S)-[[(S)-l-

b) heating the solution of step (a) to an elevated temperature;

c) cooling the solution from step (b) and isolate the diastereomeric salt; d) desaltifying the diastereomeric salt to isolate 9-[(R)-2-[[(R)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]

methoxy]propyl]adenine.

The process of claim 4, wherein the organic solvent selected from methanol, ethanol, ethyl acetate, acetone, 2-butanone, acetonitrile, dioxane or mixtures thereof.

6. The process of claim 4, wherein the step (b) is performed at a temperature in the range from about 50° C. to about 100° C.

7. A process for preparing a compound of Formula III:

III

comprising:

b) heating the solution of step (a) to an elevated temperature;

c) cooling the solution from step (b) and isolate the diastereomeric salt;

d) desaltifying the diastereomeric salt to isolate the compound of formula III.

The process of claim 7, wherein the organic solvent selected from methanol, ethanol, ethyl acetate, acetone, 2-butanone, acetonitrile, dioxane or mixtures thereof.

The process of claim 7, wherein the step (b) is performed at a temperature in the range from about 50° C. to about 100° C.