DESC:FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of Letermovir and its intermediates.

BACKGROUND OF THE INVENTION:
Letermovir is marketed by Merck, sold under the brand name of PREVYMIS, is an antiviral drug for the treatment of cytomegalovirus (CMV) infections. Letermovir exhibits stereoisomerism due to the presence of one chiral center. Letermovir, chemically known as (4S)-2-{8-Fluoro-2-[4-(3-methoxyphenyl) piperazin-1-yl]-3-[2-methoxy-5(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetic acid, is represented by the following structural formula I:

Formula I
Letermovir and process for its preparation was first time disclosed in US8513255B2. The disclosed process comprises preparation of racemic Letermovir followed by separating the required S-isomer using chiral column chromatography. The disclosed process is depicted below in scheme 1:


Scheme 1

US8372972B2 discloses another process for the preparation of Letermovir, wherein racemic Letermovir methyl ester compound was subjected to resolution with (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid/ Di-p-toluoyl-D-tartaric acid to get (S)-Letermovir methyl ester, which on hydrolysis to produce Letermovir. The respective disclosed process is depicted below in scheme 2.

Scheme 2
The reported process requires chiral column purification, which is expensive, technically time-consuming and labor-consuming, and the solvent consumption is high, resulting in high cost, and is not suitable for industrial production.

Still there is a need in the art for alternate process for the preparation of Letermovir, which devoid of the prior art problems.

OBJECTIVE OF THE INVENTION:
The main objective of the present invention is to provide an improved process for the preparation of Letermovir and its intermediates.

SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a process for the preparation of Letermovir of Formula I,

Formula I
which comprises,
a) reacting a racemic Letermovir of Formula II,

Formula II
with a suitable chiral amine to provide a corresponding chiral amine salt compound of formula IIa; and

Formula IIa
b) treating the chiral amine salt compound of formula IIa with an acid to provide Letermovir of formula I.

In another aspect, the present invention provides a chiral amine salt compound of Formula IIa,

Formula IIa.

In another aspect, the present invention provides the use of compound of Formula IIa in the preparation of Letermovir of formula I.
In another aspect, the present invention provides a process for the preparation of a compound of Formula III,

Formula III
which comprises,
reacting 2-fluoroaniline of Formula IV,

Formula IV
with 2-methoxy-5-(trifluoromethyl)aniline of Formula V,

Formula V
in the presence of a suitable coupling agent to provide a compound of Formula III.

In another aspect, the present invention provides pharmaceutical composition comprising Letermovir or its pharmaceutically acceptable salts prepared according to the present invention and having one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION:
The term “suitable solvent” used in the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethylketone and the like; and water.
The term “suitable base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tertbutoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia and organic bases such as triethylamine, methylamine, ethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl aminopyridine (DMAP), morpholine and/or mixture thereof.

The term “chiral amine” used herein the present invention until unless specified is selected from (S)-(-)-1-phenylethylamine, (R)-(+)-1-phenylethylamine, (S)-Phenyl glycenol, R-(1-naphthyl)-ethylamine, R-benzylethylamine, a-(2-naphthyl)-ethyl amine, R-alpha-phenylneopentylamine, R-alpha-phenylisobutylamine, L-Alanine ethyl ester, n-phenylglycine ethyl ester, (S)-(+)-2-aminobutane, L-phenyl alanine ethyl ester, O-methyl-L-tyrosine, ethyl L-leucinate, L-methionine ethyl ester, L-isoleucine ethyl ester, (S)-1-phenyl-2-(p-tolyl) ethylamine.

In one aspect, the present invention provides a process for the preparation of Letermovir of Formula I,

Formula I
which comprises,
a) reacting a racemic Letermovir of Formula II,

Formula II
with a suitable chiral amine to provide a corresponding chiral amine salt compound of formula IIa; and

Formula IIa
b) treating the chiral amine salt compound of formula IIa with an acid to provide Letermovir of formula I.

The racemic Letermovir of compound of formula II is well known in the art and can be prepared by the known methods; for example, may be prepared as per the process disclosed in US8513255B2.

The step a) of the forgoing process involves the reaction of a racemic Letermovir of formula II with a suitable chiral amine in the presence or absence of a base, in a suitable solvent under appropriate reaction conditions to provide a corresponding chiral amine salt compound of formula IIa. The step a) reaction is carried out at a suitable temperature from about 25°C to about reflux temperature of the solvent used, and maintain for a sufficient period of time till completion of the reaction; preferably the step a) reaction is carried out at about 50°C to about 70°C for about 4-6 hrs. The chiral amine, base and solvent used herein are selected from the list as mentioned above; preferably the chiral amine is (S)-(-)-1-phenylethylamine and the solvent is alcoholic solvent, more preferably ethanol.

In an embodiment, the intermediate compound of formula IIa obtained above can be isolated from the reaction mass by the methods known and purified by recrystallizing or slurring in a suitable solvent or mixture of solvents or proceed in-situ to next step without isolation, preferably the intermediate compound of formula IIa is isolated as a solid from the reaction mass.

The step b) of the forgoing process involves, reacting the chiral amine salt compound of formula IIa with an acid selected from HCl, HBr, H2SO4, acetic acid, trifluoroacetic acid, nitric acid and the like; preferably aqueous HCl; in the presence or absence of a solvent under appropriate reaction conditions to provide Letermovir of formula I. The step b) reaction is carried out at a suitable temperature from about 0°C to about reflux temperature of the solvent used, and maintain for a sufficient period of time till completion of the reaction; preferably carried out at about 0°C to about 30°C for 1-2 hrs. The solvent used herein is selected from the list as mentioned above, preferably water and/or ester solvent, more preferably a mixture of water and ethyl acetate.

The obtained Letermovir of formula I isolated from the reaction mass by the methods known in the art and optionally purified using a suitable solvent or a mixture of solvents. The obtained Letermovir further may be dried in a tray dryer, vacuum oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like or any other suitable dryer at a suitable temperature for a sufficient period of time with or without vacuum.

In another aspect, the present invention provides a chiral amine salt compound represented by the following structural Formula IIa as shown below:

Formula IIa

The chiral amine in the formula IIa is selected from but not limited to (S)-(-)-1-phenylethylamine, (R)-(+)-1-phenylethylamine, (S)-Phenyl glycenol, R-(1-naphthyl)-ethylamine, R-benzylethylamine, a-(2-naphthyl)-ethylamine, R-alpha-phenyl neopentylamine, R-alpha-phenylisobutylamine, L-Alanine ethyl ester, n-phenyl glycine ethyl ester, (S)-(+)-2-aminobutane, L-phenyl alanine ethyl ester, O-methyl-L-tyrosine, ethyl L-leucinate, L-methionine ethyl ester, L-isoleucine ethyl ester, (S)-1-phenyl-2-(p-tolyl) ethylamine. In an embodiment, the chiral amine in the formula IIa is (S)-(-)-1-phenylethylamine.

In another aspect, the present invention provides a process for the preparation of chiral amine salt compound of formula IIa,

Formula IIa
which comprises,
reacting a racemic Letermovir of Formula II,

Formula II
with a suitable chiral amine in a suitable solvent to provide a corresponding chiral amine salt compound of formula IIa.

The aforementioned process is carried out as per the step a) process described above in the first aspect of the present invention.
In another aspect, the present invention provides the use of compound of Formula IIa in the preparation of Letermovir of formula I.

In another aspect, the present invention provides a process for the preparation of a compound of Formula III,

Formula III
which comprises,
reacting 2-fluoroaniline of Formula IV,

Formula IV
with 2-methoxy-5-(trifluoromethyl)aniline of Formula V,

Formula V
in the presence of a suitable coupling agent to provide a compound of Formula III.

The forgoing process involves the reaction of 2-fluoroaniline of formula IV with 2-methoxy-5-(trifluoromethyl)aniline of formula V, in the presence of a coupling agent and with or without adding a base in a suitable solvent under appropriate reaction conditions to provide a compound of formula III. The coupling agent used is selected from ethyl chloroformate, isobutyl chloroformate, Carbonyl diimidazole (CDI) and/or mixture thereof. The base and a solvent are selected from the list as mentioned above. The step a) reaction is carried out at a suitable temperature from about 25°C to about reflux temperature of the solvent used, and maintain for a sufficient period of time till completion of the reaction.

The compound of formula III may further converted into Letermovir of formula I by known methods, for example as per the method described in US8084604B2.
In another aspect, the present invention provides pharmaceutical composition comprising Letermovir or its pharmaceutically acceptable salts prepared according the present invention and having one or more pharmaceutically acceptable excipients.
Example-1:
Preparation of Letermovir of formula I:
To a clean and dry RBF, racemic Letermovir (24 g), (S)-(-)-1-phenylethylamine (17.5 g) and ethanol (144 ml) were added at 25-35°C, heated to 60-65°C and maintained for 4 hrs at the same temperature. After the reaction completion, the reaction mass was cooled to 30-35°C. The solid obtained was filtered, washed with ethanol and dried under vacuum at 60-65°C. Water and ethyl acetate were added to the above dried solid taken in another RBF and cooled to 0-5°C. The pH of the reaction mass was adjusted to 2-3 with aqueous hydrochloric acid and stirred for 15 mins at room temperature. The organic and aqueous layers were separated; and the aqueous layer was extracted with ethyl acetate. The combined organic layers was washed with water, dried over sodium sulfate and then distilled off the solvent under vacuum at below 45°C to get the title compound.
Yield: 8.2 g.

Example-2:
Preparation of racemic Letermovir of formula II:
To a clean and dry RBF, racemic Letermovir methyl ester (15 g), sodium bicarbonate solution (12 g in 150 ml of water) and ethyl acetate (100 ml) were added at 25-35°C and stirred for 30 mins at the same temperature. The organic and aqueous layers were separated; the separated organic layer was dried over sodium sulfate and then distilled off the solvent under vacuum at below 35°C. Tetrahydrofuran (75 ml) was added to the obtained crude at 25-35°C and cooled to 10-15?. Sodium hydroxide solution (4.2 g in 75 ml of water) was added at 25-35? to above mass and stirred at 25-35°C. After the reaction completion, the reaction mass pH was adjusted to 7-7.5 with hydrochloric acid solution. Ethyl acetate (150 ml) was added to the reaction mass at 25-35°C and stirred for 15 min. The organic and aqueous layers were separated; the organic layer was dried over sodium sulfate and then distilled off the solvent under vacuum followed by co-distilled with n-heptane at below 35°C. Methyl tert-butyl ether (105 ml) was added to the above crude at 25-35°C and maintained for 30 min. The reaction mass was cooled to -5 to -10°C, n-Heptane was added to it at 25-35°C, and maintained for 2 hrs. The solid obtained was filtered, washed with n-heptane and dried under vacuum to get the title compound.
Yield: 7.5 g.
,CLAIMS:1. A process for the preparation of Letermovir of Formula I,

Formula I
which comprises,
a) reacting a racemic Letermovir of Formula II,

Formula II
with a suitable chiral amine to provide a corresponding chiral amine salt compound of formula IIa; and

Formula IIa
b) treating the chiral amine salt compound of formula IIa with an acid to provide Letermovir of formula I.
2. The process as claimed in claim 1, wherein in step a), the suitable chiral amine is selected from (S)-(-)-1-phenylethylamine, (R)-(+)-1-phenylethylamine, (S)-Phenylglycenol, R-(1-naphthyl)-ethylamine, R-benzylethylamine, a-(2-naphthyl)-ethylamine, R-alpha-phenylneopentylamine, R-alpha-phenylisobuty lamine, L-Alanine ethyl ester, n-phenylglycine ethyl ester, (S)-(+)-2-amino butane, L-phenylalanine ethyl ester, O-methyl-L-tyrosine, ethyl L-leucinate, L-methionine ethyl ester, L-isoleucine ethyl ester and/or (S)-1-phenyl-2-(p-tolyl)ethylamine.

3. The process as claimed in claim 1, wherein in step b), the acid is selected from HCl, HBr, H2SO4, acetic acid, trifluoroacetic acid and/or nitric acid.

4. The process as claimed in claim 1, wherein the step a) and the step b) reactions are carried out in a suitable solvent selected from water, alcohols, ketones, nitriles, chloro solvents, ethers, esters and/or mixtures thereof.

5. The process as claimed in claim 1, wherein the suitable chiral amine in step a) is (S)-(-)-1-phenylethylamine and the acid in step b) is HCl.

6. The process as claimed in claim 4, wherein the solvent used in step a) is ethanol and the solvent used in step b) is a mixture of water and ethyl acetate.

7. A chiral amine salt compound represented by the following structural Formula IIa

Formula IIa.
8. A process for the preparation of chiral amine salt compound of formula IIa as claimed in claim 7, which comprises reacting a racemic Letermovir of Formula II with a suitable chiral amine in a suitable solvent to provide a corresponding chiral amine salt compound of formula IIa.

9. The process as claimed in claim 8 or the compound as claimed in claim 7, wherein the suitable chiral amine is selected from (S)-(-)-1-phenylethylamine, (R)-(+)-1-phenylethylamine, (S)-Phenylglycenol, R-(1-naphthyl)-ethylamine, R-benzyl ethylamine, a-(2-naphthyl)-ethylamine, R-alpha-phenylneopentylamine, R-alpha-phenylisobuty lamine, L-Alanine ethyl ester, n-phenylglycine ethyl ester, (S)-(+)-2-amino butane, L-phenylalanine ethyl ester, O-methyl-L-tyrosine, ethyl L-leucinate, L-methionine ethyl ester, L-isoleucine ethyl ester and/or (S)-1-phenyl-2-(p-tolyl)ethylamine.

10. The process as claimed in claim 8 or claim 9, wherein the suitable chiral amine is (S)-(-)-1-phenylethylamine.