DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Mavacamten.
BACKGROUND OF THE INVENTION
Mavacamten, 6-{[(1S)-1-phenylethyl]amino}-3-(propan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione also known as Camzoys®, has following chemical structure:

Camzoys® is developed by Myokardia and first approved by USFDA as a cardiac myosin inhibitor indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.
Mavacamten and its preparation is disclosed in multiple patent references for instance US9181200, WO2021/092598A1, WO2022/162701A1, WO2021/154904A1, WO2022/189599A1, WO2023199258 A1, IN202241056933 and IN202241029652.
The process described in US ‘200 is schematically represented below:

In US’ 200, Mavacamten is isolated from the solvent ethyl acetate by addition of anti-solvent i.e. hexane, as a white solid; though there is no information about the polymorphic form obtained. Similar process of isolating Mavacamten using solvent/anti-solvent technique is also described in WO2022/162701A1. As per WO’701, Mavacamten obtained by such a technique as well as the one obtained by repeating the process of US’200 (i.e. the product patent), is in the form of a crystalline solid labelled as Form A. Apart from this WO’598 describes isolation of Crystalline solid Form A from multiple solvent systems.
Besides the above mentioned Form A, there are multiple polymorphic forms of Mavacamten also reported in literature. WO’701 describes crystalline Forms A, B, C, D and E as well as amorphous form whereas WO’904 discloses crystalline Forms 1, 2, 4, 5 and 6 as well as amorphous form of Mavacamten.
From the comparison of above-mentioned disclosures, it is clear that Form A of WO’598 and WO’701 as well as the Form 1 of WO’904, which have been described as the most stable form(s), are identical, thus implying that the stable Mavacamten having pharmaceutically acceptable purity, remains the same since its first derivation from the product patent i.e. US’200. Similar conclusion has been provided in USFDA Product Quality Review of Camzoys®, wherein its recorded that Mavacamten exhibits polymorphism but only one stable form is observed.
As far as the synthetic process for preparation of Mavacamten described in prior art is concerned, it has been observed that there are multiple drawbacks/challenges involved for e.g. variable amount of starting material remains unreacted and impurity levels are high, which requires multiple purifications at API stage, thereby makes it industrially non-viable with reference to high costs and low yield. Thus, there remains a need to provide a commercially viable and advantageous processes for preparation of pure Mavacamten to cater all drawbacks of earlier known processes.
SUMMARY OF THE INVENTION
The process of the present invention overcomes the drawbacks of prior art by providing a process wherein the Mavacamten API is obtained directly in pure form, thus obviating the need for multiple purifications. The process of the present invention is industrially viable, economical and provides high yield.
In one aspect of the present application, Mavacamten obtained by the improved process of current invention is consistently obtained as crystalline Form A.
In another aspect of the present application, the obtained crystalline Form A of Mavacamten is substantially free of impurities for e.g. Impurity-M and/or Impurity-N, wherein impurity of Formula-N as a compound itself is hitherto unknown.
In a further aspect, the present application provides Mavacamten with purity of at least 99.9% even at industrial scale without requirement of any additional purifications.
BRIEF DESCRIPTION OF DRAWINGS/FIGURES
Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Mavacamten as per Reference Example 1.
Figure 2 shows a characteristic X-ray powder diffraction pattern (XRPD) of Mavacamten as per Example 1.
DETAILED DESCRITPION OF THE INVENTION
The present invention provides a process for preparation of Mavacamten.
An embodiment of the present invention provides a process of preparing pure Mavacamten (I) by following process:

comprising the steps of:
a) reacting 6-chloro-3-(propan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione (II) with (S)-(-)-1-phenylethylamine (III) in presence of a first solvent;
b) heating the reaction mixture and stirring;
c) cooling the reaction mixture to an room temperature to obtain a solid material;
d) dissolving/slurrying the solid obtained in a polar second solvent, optionally by heating;
e) allowing the reaction mixture to stir at room temperature; and
f) isolating pure Mavacamten; wherein, optionally a third solvent is added to the reaction system prior to, during or after the completion of step c) and/or e).
In a further embodiment, the first solvent is selected from the group comprising of alcohols such as n-propanol, isopropyl alcohol, ethers such as dioxane, tetrahydrofuran, water, ketones such as acetone, methyl isobutyl ketone, esters such as Ethyl acetate, DMSO or mixtures thereof. The reaction may be carried out at a temperature of about 20 °C to about 120 °C, preferably about 30 °C to about 110 °C, and more preferably about 40 °C to about 100 °C.
In another embodiment, the compounds of Formula (II) and/or (III) can be used either as free base or in their salt forms. Compound of Formula (II) can be obtained from any process known in prior art or the general modifications of the same as generically known to a medicinal chemist. Compound of Formula (III) can be added to the reaction mixture either as a single lot or in batch-wise manner.
The reaction of Compound of Formula (II) and (III) can optionally be carried out in presence of a base, preferably an organic base such as diisopropyl ethyl amine (DIPEA), diisopropyl amine (DIPA), triethylamine, pyridine more preferably pyridine and/or DIPEA.
In another embodiment, the second and third solvent are same or different and is independently selected from the group comprising dichloromethane (DCM), methanol, ethanol, NMP, water, DMSO, methyl ethyl ketone (MEK), ethyl acetate (EtOAc), acetone, isopropylacetate (IPAc), DMF, acetonitrile (ACN) or mixture thereof. The second and third solvent(s) are either used for washing the solid already obtained by filtration or as an anti-solvent, to precipitate out the pure material.
In a further embodiment, as per requirement the product obtained in any of the above mentioned steps may also be optionally washed/treated with suitable solvents for e.g. ethyl acetate (EtOAc), water, methanol, ethanol, dichloromethane, DMSO, methyl tert-butyl ether (MTBE) etc. All the solvents used in this process may be added as a single batch or in a lot-wise manner.
In a further embodiment, Mavacamten is isolated as a crystalline from the suspension and/or solution by filtration or by decantation or by any suitable method known in prior art. The crystalline form of Mavacamten may be dried under ambient conditions or under vacuum.
In another embodiment of the present invention, solid Mavacamten obtained is characterized by PXRD pattern as shown in Figure 2. Mavacamten API of the present invention is further characterized by characteristic PXRD °2? peaks at about 11.6, 15.7, 17.3, 18.7, 19.9, 22.3, 25.6, 29.1 and 31.5 ± 0.2°. This resembles the Form A of Mavacamten as has been disclosed in prior art, and is stable under thermal, humid and stressed conditions.
In a further embodiment, the Mavacamten API as per present invention is obtained directly in pure form without the need for multiple purifications or cumbersome techniques like chromatography. The process of the present invention, provides of crystalline Mavacamten Form A with purity of about 99.5 %, preferably 99.7 %, more preferably 99.9 % as measured by HPLC. The Mavacamten API as per present invention is a crystalline Mavacamten Form A, having less than 0.5% w/w, preferably less than 0.3% w/w, more preferably less than 0.1% w/w of Impurity-M, which has been well characterized by FT-IR, 1H-NMR and 13C-NMR.

In another embodiment, the Mavacamten API as per present invention is a crystalline Mavacamten Form A, having less than 0.5% w/w, preferably less than 0.3% w/w, more preferably less than 0.1% w/w of impurity of Formula-N, which has been well characterized by FT-IR, 1H-NMR and 13C-NMR.

Formula-N

It is to be noted that compound of Formula-N which is a potential impurity of Mavacamten.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES
REFERENCE EXAMPLE 1
Process for preparation of Mavacamten as per the process of US’200:
To a solution 1g of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione in 20mL 1,4-dioxane 1.4g (S)-a-methylbenzylamine was added. The reaction mixture was stirred at 80° C for 24 h and then cooled to room temperature (RT). Thereafter, the mixture was concentrated under reduced pressure to obtain a residue. To the residue was added 70mL EtOAc and washing was given with aqueous 1N HCl (2×50 mL) and brine (40 mL). The organic layer was dried with anhydrous Na2SO4 and concentrated under reduced pressure to half the original volume. Thereafter, 20mL hexane was added to reaction mixture which was then stirred, filtered, washed with 20mL hexane and dried to finally obtain a white solid. PXRD pattern of this white solid is shown in Figure l.
Process for preparation of Mavacamten as per present invention:
EXAMPLE 1
A round bottom flask was charged with 100g 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (II), 300mL 1- propanol, and 120g (S)-(-)-1-phenylethylamine (III). The reaction mixture was heated upto 80 °C. The solution was then cooled, and water was added, which was stirred for some time followed by filtration. The solid obtained was washed with water and ethyl acetate and then dried. The dried solid was then dissolved in DMSO and heated with stirring to obtain a clear solution, which on cooling to RT provided Mavacamten with purity of >99.90% (by HPLC). Yield: 85% (w/w)
PXRD pattern of the crystalline material as obtained in this example is shown in Figure 2.
EXAMPLE 2
A round bottom flask was charged with 6-chloro-3-isopropylpyrimidine-2,4-(1H,3H)dione (II) (120g), 1-propanol (360mL), and (S)-(-)-1-phenylethylamine (III) (260g). The reaction mixture was heated to 100°C. Water was added slowly to the reaction mixture and cooled to room temperature. The solid obtained was treated with DCM/MeOH (1600 ml) and stirred followed by filtration to get the crude Mavacamten. To the crude Mavacamten obtained, DMSO was added and the reaction mixture was heated to 100°C with stirring, followed by addition of water, wherein a solid mass was obtained. The solid mass was washed with ethyl acetate and then dried to provide Mavacamten with purity of >99.92% (by HPLC). Yield: 87% (w/w). Imp-M (Not detected). Imp-N [0.02% (w/w)]
PXRD pattern of the crystalline material as obtained in this example is similar to the one shown in Figure 2.
,CLAIMS:1. An improved process for preparation of pure Mavacamten (I),

comprising the steps of:
a) reacting 6-chloro-3-(propan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione (II) or salt thereof

with (S)-(-)-1-phenylethylamine (III) or salt thereof in presence of a first solvent to obtain a reaction mixture;

b) heating and stirring the reaction mixture at a temperature above 50 °C;
c) cooling the reaction mixture to room temperature to obtain a solid material;
d) dissolving/slurrying the solid obtained in a polar second solvent, optionally by heating to obtain a reaction mass;
e) allowing the reaction mass to stir at room temperature; and
f) isolating pure Mavacamten (I);
wherein, optionally a third solvent is added prior to or during or after the completion of step c) and/or e).

2. The process as claimed in claim 1, wherein the reaction in step a) is carried out in presence of a base, preferably an organic base selected from the group comprising diisopropyl ethyl amine (DIPEA), diisopropyl amine (DIPA), trimethylamine and pyridine.

3. The process as claimed in claim 1, wherein the compound III is added batch-wise or in a single lot, into the reaction system.

4. The process as claimed in claim 1, wherein the first solvent is selected from the group comprising alcohols, n-propanol, isopropyl alcohol, ethers, dioxane, tetrahydrofuran, water, ketones, acetone, methyl isobutyl ketone, esters ethyl acetate, DMSO or mixtures thereof.

5. The process as claimed in claim 1, wherein the second and third solvent is same or different and is independently selected from the group comprising dichloromethane (DCM), methanol, ethanol, NMP, water, dimethyl sulfoxide (DMSO), methyl ethyl ketone (MEK), ethyl acetate (EtOAc), acetone, isopropylacetate (IPAc), dimethylformaide (DMF), acetonitrile (ACN) or mixture thereof.

6. The process as claimed in claim 1, wherein the pure Mavacamten (I) is obtained in the form of crystalline Form A.

7. The process as claimed in claim 6, wherein the crystalline Form A obtained has less than 0.5% w/w, preferably less than 0.3% w/w, more preferably less than 0.1% w/w of Impurity-M.

8. The process as claimed in claim 6, wherein the crystalline Form A obtained has less than 0.5% w/w, preferably less than 0.3% w/w, more preferably less than 0.1% w/w of Formula-N as impurity.

Formula-N

9. A compound of Formula-N:

Formula-N

10. Mavacamten substantially free of the impurity M and/or N, prepared by the process as claimed in claims 1-8, wherein the Mavacamten is having chemical purity of about 99.9 % as measured by HPLC; and the impurities M and/or N, each one, in an amount of less than 0.1% as measured by HPLC.