DESC:FIELD OF THE INVENTION

The present invention relates to a recycling process for preparation of (R,S,S) isomer of Tenofovir alafenamide from (R,R,S) isomer of Tenofovir alafenamide.

BACKGROUND OF THE INVENTION

Tenofovir alafenamide is chemically known as 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxylcarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl] adenine and represented by following structure:

US 7390791 disclose prodrugs of methoxy phosphate nucleotide analogs including Tenofovir alafenamide. However process step includes formation of both desired (R,S,S)-Tenofovir alafenamide (GS-7340) and undesired (R,R,S)-Tenofovir alafenamide (GS-7339) isomers. Finally desired isomer (R,S,S) was purified by simultaneous moving bed chromatography (SMB) over chiral AS column by eluting with 30% methanol in acetonitrile provided 98.7% diastereomeric purity. The resulting desired diastereomer was further converted to corresponding fumarate salt.

US 8664386 discloses a process for selective crystallization of Tenofovir alafenamide by subjecting racemic mixture of Tenofovir alafenamide to crystallization induced dynamic resolution in the presence of 1,8-Diazabicycloundec-7-ene, phenol and seed crystals of specific (R,S,S)-isomer to provide epimerization of phosphorous center.

WO 2014195724 discloses separation of diastereomers by salt formation method using different chiral organic acid.

WO 2015079455 (F: IN 2013CH05455) discloses recycling process of diastereomers of Tenofovir alafenamide.

WO 2015107451 discloses process for resolution of diastereomers of Tenofovir alafenamide using acids and resolution of mono phenyl Tenofovir using chiral amines.

Generally, synthesis of Tenofovir alafenamide results into equal formation of both undesired (R,R,S) and desired (R,S,S) isomers.

However the undesired isomer (R,R,S) produced is discarded at the stage of Tenofovir alafenamide preparation or in the final stage of separation of diastereomers by any conventional techniques such as crystallization, RP-HPLC, simulated moving bed technique or batch elution chromatography. Instead of discarding the undesired diastereomer which contributes to the production loss, it is beneficial to convert this undesired isomer into desired isomer which can be helpful in increasing overall product yield and decreasing the manufacturing cost.

Although processes have been described in the art for preparation of Tenofovir alafenamide and salts thereof and techniques to separate or recycle the resulting diastereomers, there still remains an on-going need for identifying new or alternate processes for converting undesired diastereomer to the desired diastereomer which is addressed by present invention and described thereafter.

OBJECT OF THE INVENTION

In one aspect, the object of present invention is to provide a recycling process of converting undesired (R,R,S) isomer to the desired (R,S,S) isomer of Tenofovir alafenamide.

In another aspect, the object of present invention is to develop a process of recycling undesired (R,R,S) isomer to desired (R,S,S) isomer through formation of either mono phenyl Tenofovir of formula (I) or Tenofovir (PMPA).

In another aspect, mono phenyl Tenofovir of formula (I) or Tenofovir (PMPA) can be converted into Tenofovir alafenamide through the processes known in prior art.

In further aspect, the present invention recycling process increases overall yield of desired diastereomer (R,S,S) thereby making overall process not only economically but also feasible at industrial scale.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides a new synthetic approach for recycling undesired (R,R,S) isomer of Tenofovir alafenamide produced during the manufacturing or purification of desired (R,S,S) isomer of Tenofovir alafenamide (GS-7340).

In another embodiment, the present invention recycling process comprises of conversion of undesired (R,R,S) isomer into either mono phenyl Tenofovir (I) or Tenofovir (PMPA) using suitable reagents and suitable solvents. Further these intermediates are converted into racemic Tenofovir alafenamide using processes known in prior art. Tenofovir alafenamide obtained is separated into desired (R,S,S) and undesired (R,R,S) diastereomers using known purification/separation techniques. Hence the recycling process continues with the undesired (R,R,S) isomer which helps to increase the overall yield and diastereomeric purity of desired (R,S,S)-Tenofovir alafenamide.

In another embodiment, the present invention provides a recycling process as disclosed in scheme-I; comprising of following steps:
(i) reacting (R,R,S) isomer with suitable reagent(s) in water to obtain compound of formula (I) wherein R is phenyl or hydrogen;
(ii) converting compound of formula (I) to racemic Tenofovir alafenamide; and
(iii) resolving racemic Tenofovir alafenamide to yield (R,S,S) isomer of Tenofovir alafenamide.

In further embodiment, the present invention provides a recycling process as disclosed in scheme-I; comprising of following steps:
(i) reacting (R,R,S) isomer with suitable reagent(s) in water to obtain compound of formula (I) wherein R is hydrogen;
(ii) reacting compound of formula (I) with phenol to obtain mono phenyl Tenofovir;
(iii) reacting mono phenyl Tenofovir or its activated derivative with (L)-alanine isopropyl ester or its hydrochloride salt to obtain racemic Tenofovir alafenamide.
(iv) resolving racemic Tenofovir alafenamide to yield (R,S,S) isomer of Tenofovir alafenamide.

In another embodiment, resolving racemic Tenofovir alafenamide to precipitate (R,S,S) isomer of Tenofovir alafenamide is carried out by crystallization in acetonitrile.

Suitable reagent(s) in step (i) include but not limited to organic acids or inorganic acids such as fumaric acid, hydrochloric acid or mixtures thereof.
Suitable reagent(s) in step (i) include but not limited to organic base or inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide or mixtures thereof.

In another embodiment, Tenofovir (PMPA) or mono phenyl Tenofovir (I) obtained can be converted into Tenofovir alafenamide using reagent(s) and solvent(s) known in prior art.

In further embodiment, Tenofovir alafenamide is resolved to give desired (R,S,S) and undesired (R,R,S) isomers using known techniques in prior art such as crystallization, recrystallization, with or without seeding, HPLC, simultaneous moving bed chromatography, batch elution chromatography or reverse phase column chromatography.

In yet another embodiment, recycling process using (R,R,S) isomer may contain (R,S,S) isomer not more than about 5% of total weight.

In another embodiment, (R,R,S) isomer may contain (R,S,S) isomer in the range of 5% to 0.01% of total weight.

In another embodiment, the present invention also provides preparation of Tenofovir alafenamide salts preferably selected from fumarate or hemifumarate salt of Tenofovir alafenamide from Tenofovir alafenamide.

The following examples are provided to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it is not intended in any way to limit the scope of the present invention

EXAMPLES

Example-1:
To acetonitrile (20 ml) racemic tenofovir alafenamide (14.9 g) was added and stirred to obtain clear solution. The solvent from reaction mixture was partially distilled out and further seeded with a crystal of (R,S,S) tenofovir alafenamide. The mixture was stirred overnight, filtered and dried to obtain (R,S,S) tenofovir alafenamide. The filtrate obtained was distilled out to obtain (R,R,S) tenofovir alafenamide which is used for recycling process.

Example-2:
To water (200 ml) (R,R,S) tenofovir alafenamide (10 g) and fumaric acid (4.84 g) were added and the mixture was heated and stirred at 60-70oC for 24 hrs. The water was distilled out till the residual quantity of 30 ml. The reaction mass was cooled to 25-30oC and 25% NaOH solution was added to bring the pH to 9-11. The aqueous layer was washed twice with ethyl acetate (25 ml). Aqueous layer was acidified with HCl till pH 1-3 and stirred at 25-30oC for 8 hrs. The reaction mass was cooled to 5-10oC. The solid formed was filtered and dried to give phenyl hydrogen ({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy} methyl) phosphonate (6.5 g) (mono phenyl Tenofovir). (compound of Formula (I) where R is phenyl)
The above solid (5 g) was reacted with thionyl chloride (3.6 g) in acetonitrile (25 ml) at 70-75oC. A solution of L-alanine isopropyl ester HCl (3.9 g) in MDC (20 ml) was added to the reaction mixture at -18 to -30oC. To this was added TEA (4.2 g) at -12 to -18oC. The reaction mass was warmed to 25 to 30oC and quenched in aqueous 10% NaH2PO4 solution. MDC layer was separated and distilled to give tenofovir alafenamide base (racemic compound) (5 g). Chiral Purity by HPLC (% area): 56.75: 43.25 (R,S,S : R,R,S).

Example-3:
To water (250 ml) (R,R,S) tenofovir alafenamide (50 g) and sodium hydroxide (10.0 g) was added at 30-40oC and stirred for 24 hrs. The reaction mass was cooled to 5-10oC and aqueous HCl (26 ml) was added to the reaction mass. This mixture was further heated to 50-60oC and maintained for 12 hrs. The reaction mass was cooled to 25-30oC and ethyl acetate (250 ml) was added to reaction mass. The mixture was stirred for one hour and solid ({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl) phosphonic acid (PMPA) was filtered and dried. Yield 25 gm.
The obtained solid (10 g) was reacted with Phenol (6.5 g) in NMP (25 ml) in the presence of DCC (15.8) and TEA (4.4 g) at 105-110oC. After stirring the reaction for 3 hrs the reaction mass was dumped in chilled water (200 ml). The solid dicyclohexyl urea (DCC) was filtered and discarded. The aqueous layer was acidified with aqueous HCl to pH 2-4 and was stirred for 8 hrs. The solid formed phenyl hydrogen ({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl) phosphonate (mono phenyl Tenofovir) was filtered and dried. Yield: 6 gm.
The obtained solid (5 g) was reacted with Thionyl chloride (3.6 g) in acetonitrile (25 ml) at 70-75oC. After disappearance of the starting material by HPLC the volatiles were removed via distillation. A solution of L-alanine isopropyl ester HCl (3.9 g) in MDC (20 ml) was added to the reaction mixture at -18 to -30oC. To this was added TEA (4.2 g) at -12 to -18oC. The reaction mass was warmed to 25 to 30oC and quenched in aqueous 10% NaH2PO4 solution. MDC layer was separated and distilled to give tenofovir alafenamide base (racemic) (5.1 g)
Chiral Purity by HPLC (% area): 56.17: 43.83 (R,S,S : R,R,S).

Dated this 28th day of June 2018

,CLAIMS:WE CLAIM:
1. A recycling process for preparing (R,S,S) isomer of Tenofovir alafenamide comprising of:
(i) reacting (R,R,S) isomer of Tenofovir alafenamide with suitable reagent(s) in water to obtain compound of formula (I)

wherein R is hydrogen or phenyl;
(ii) converting compound of formula (I) to racemic Tenofovir Alafenamide; and
(iii) resolving racemic Tenofovir alafenamide to yield (R,S,S) isomer of Tenofovir alafenamide..
2. The process as claimed in claim 1, wherein suitable reagent(s) used in step (i) is acid selected from fumaric acid or hydrochloric acid or mixtures thereof to obtain compound of formula (I) wherein R is phenyl.
3. The process as claimed in claim 1, wherein suitable reagent(s) used in step (i) is base selected from sodium hydroxide, potassium hydroxide or lithium hydroxide or mixtures thereof to obtain compound of formula (I) wherein R is hydrogen.
4. The process as claimed 1, further comprises the following steps when R represents hydrogen in compound of formula (I) in step (ii):
(i) reacting compound of formula (I) with phenol to obtain mono phenyl Tenofovir;

(ii) reacting mono phenyl Tenofovir or its activated derivative with (L)-alanine isopropyl ester or its hydrochloride salt to obtain racemic Tenofovir alafenamide.

5. The process at claimed in step (iii) of claim 1 which comprises resolving racemic Tenofovir alafenamide to precipitate (R,S,S) isomer of Tenofovir alafenamide by crystallization in acetonitrile.