WO2025027567A1

WO2025027567A1 - Process for preparing mavacamten and process intermediate

Info

Publication number: WO2025027567A1
Application number: PCT/IB2024/057464
Authority: WO
Inventors: Benedetta RICCI; Marco Rognoni; Matteo VALLI
Original assignee: Olon SpA
Current assignee: Olon SpA
Priority date: 2023-08-03
Filing date: 2024-08-01
Publication date: 2025-02-06
Anticipated expiration: 2026-02-03
Also published as: IT202300016653A1

Abstract

A process for preparing the Pharmaceutical Active Ingredient (API) Mavacamten or a salt thereof, which advantageously allows an industrial implementation and a control of the impurity profile on the final product The process includes as key intermediate a compound of Formula IV: Formula IV wherein: M is a metal selected from lithium, sodium, potassium; n is an integer selected from 1 and 2. The process allows to obtain a final product characterized by a high purity (generally equal or higher than 99.0%, preferably equal or higher than 99.5%, more preferably equal or higher than 99.9%) and an impurity profile in compliance with the specifications required for Mavacamten.

Description

PROCESS FOR PREPARING MAVACAMTEN AND PROCESS INTERMEDIATE

Field of the invention .

The present invention relates to a process for preparing the Pharmaceutical Active Ingredient (API ) Mavacamten or a salt thereof . Said process advantageously allows an industrial implementation and a control of the impurity profile on the final product . The present invention also relates to an intermediate of said process . Background of the invention .

Mavacamten, 6 - { [ ( IS ) - 1 -phenyl ethyl amino ) -3- (propan-2 -yl ) - 1 , 2 , 3 , 4- tetrahydropyrimidine-2 , 4-dione , has the following chemical structure :

Formula I

Mavacamten is developed for the treatment of obstructive hypertrophic cardiomyopathy ( oHCM) .

A process for its preparation is described in international patent application WO2014205223A1 by Myocardia, and also in US2 0210346379A1 , a divisional application directed to the process . In particular, the following synthesis route is reported at page 26, example 1 ) , in which the key intermediates are isolated by chromatographic technique ( silica gel ) :

Dimethyl

purified by silica (S)-I-Phenyl gel column ethylamine chromatography

Scheme 1

A process that is said to be applicable on an industrial scale is described in international patent application WO2021092598A1 by Myocardia .

Actually, such processes show many drawbacks , with a low yield which continues to be far from a standard suitable for a fully industriali zable process .

Therefore , there is a strong need for a process for preparing Mavacamten which is suitable for a scale up and industriali zation, as well as a process which allows to control impurities profile thus obtaining a product characteri zed by high purity .

Summary of the invention .

The Applicant has now found a process for the preparation of the active principle Mavacamten which overcomes said problems and which represents a process which can be implemented on an industrial scale . Therefore , in accordance with a first aspect , the present invention relates to a process as defined in the appended claims .

In accordance with another aspect , the present invention relates to an intermediate defined in the appended claims .

Higher yields are obtained in comparison to processes described by

Myocardia in WO2014205223A1 and in WO2021092598A1 , and at the same time it is obtained a complete control of the impurity profile on the final product.

The process according to the invention allows to obtain a final product characterized by a high purity (generally equal to or higher than 99.0%, preferably equal to or higher than 99.5%, more preferably equal to or higher than 99.9%) and an impurity profile in compliance with the specifications required for Mavacamten.

Furthermore, the process according to the invention advantageously allows to obtain high yields with respect to those obtainable from the processes of the prior art.

Moreover, in comparison with the process disclosed in WO2014205223A1 and WO2021092598A1, the process of the invention is easier and more performing .

Particularly, referring to the synthesis of compound VI, lowering the POCI3 equivalents to 0.9 eq. and avoiding the addition of any base to the reaction mixture is a remarkable improvement. At the end of the reaction, the POCI3 byproducts may be quenched with water, also allowing the product to precipitate. Performing the reaction with POCI3 on a purified 1-isopropyl barbituric acid (compound V) allows to reach a higher yield of 6-chloro-3-isopropylpyrimidine- 2,4 ( 1H, 3H) -dione (compound VI) in comparison to data of yield reported for reaction performed on a crude 1-isopropyl barbituric acid (compound V) .

Referring to the synthesis of crude Mavacamten, US20210346379A1 describes the use of dioxane at high temperature as solvent, while WO2021092598A1 describes two methods: the first one in 1-propanol with a stochiometric amount of compound of formula II, crystallizing the product by dripping water; the second one without solvent, i.e. a neat reaction with compound of Formula II as solvent. This latest version is not suitable for the scale-up of the process.

Surprisingly the Applicant has found that water can be efficiently employed as solvent in the same reaction (synthesis of crude Mavacamten, step c) according to the process of the present invention) , with safety and environmental benefits.

Moreover, in the synthesis of 1-isopropyl barbituric acid (compound V, steps a)+a' ) ) , the reaction is preferably performed in n-BuOH, allowing to shorten the reaction time by heating the mixture at a higher temperature while distilling away MeOH. The reaction time is shortened from overnight to few hours. The preferred use of n-BuOH allows to more readily isolate 1-isopropyl barbituric acid salt (compound TV) when the reaction is complete. This allows a first purification of the intermediate with high yield.

In step a) , 1-isopropyl barbituric salt (compound IV) is then acidified to obtain 1-isopropyl barbituric acid (compound V) . The isolation of the product is achieved by crystallization instead of chromatographic column, to avoid excessive use of solvent.

For the synthesis of 6-chloro-3-isopropylpyrimidine-2 , 4 (1H,3H)- dione (step b, compound VI) , the reaction may be carried out in acetonitrile. POCI3 may be used as a stoichiometric reagent instead of solvent, making the procedure safer.

The crude may be used as such in the following step, since any further purification does not improve the quality of the final product .

The final reaction (step c) may be carried out with water as the solvent: 6-chloro-3-isopropylpyrimidine-2 , 4 ( 1H, 3H) -dione (compound VI) and ( S ) -benzylmethylamine may be both suspended in water and heated up to 95°C for 2 days. The crude may be directly isolated by filtration .

Once again, the product may be purified by crystallization in 1- BuOH, avoiding the use of a chromatographic column, as reported in the prior art processes.

Moreover, through the present process a better yield in each step can be obtained. The process of the invention also allows to reduce the variety of solvents used in the whole process and to lower the molar equivalent of each reagent. The process according to the invention is scalable and optimized on an industrial level. The overall yield is by far higher than the known process.

Further aspects, features and advantages of the invention will become apparent from the following detailed description.

Brief description of the drawings.

Figure 1 shows an NMR spectrum relating to the compound of formula VII;

Figure 2 shows an IR spectrum relating to the compound of formula VII .

Detailed description of the invention.

In the following description and claims, definitions of numerical ranges comprise the single values within the range itself and the corresponding endpoints, unless otherwise specified.

In the following description and claims, the term "comprising" also includes the terms "consisting of" or "consisting essentially of".

The present invention relates to a preparation of the active principle Mavacamten (compound of formula I) or a salt thereof.

The process of the present invention comprises the following steps: a) reacting isopropyl urea of Formula II:

Formula II and a dialkyl malonate of Formula III:

Formula III wherein Ri and R2 are independently selected from straight or branched Ci- Cg alkyl group; with a base in a solvent to obtain a compound of Formula IV:

Formula IV wherein: M is a metal selected from lithium, sodium, potassium; n is an integer selected from 1 and 2; the solvent is selected from: alcohols, toluene, dimethylformamide (DMF) , and mixtures thereof; and isolating the compound of Formula IV by precipitation; a' ) reacting the isolated compound of Formula IV with an acid in a solvent to obtain the compound of Formula V:

Formula V wherein the solvent is selected from: water, alcohols, ketones, and mixtures thereof; and isolating the compound of Formula V at a pH from 2 to 6; b) reacting the isolated compound of Formula V with a halogenating agent in a solvent to obtain the compound of Formula VI:

Formula VI wherein X is a halogen selected from chlorine, bromine and iodine, and the solvent is selected from: nitriles, ethers, dichlorometane (CH2CI2) , tetrahydrofurane (THF) , chlorobenzene; c) reacting the compound of Formula VI with ( S ) -phenyl-ethylamine in a solvent to obtain Mavacamten of Formula I, wherein the solvent is selected from: water, alcohols, ethers, and mixtures thereof.

In step a) , preferably the reaction temperature is from 90°C to 95°C. The process according to the present invention is reported in the following Scheme 2.

Scheme 2

As for step a) , the solvent is preferably selected from alcohols, preferably is selected from: methanol, ethanol, butanol (BuOH) (more preferably n-butanol (n-BuOH) ) , pentanol, and mixtures thereof. Particularly preferred are butanol and pentanol, even more preferred is n-butanol. They are preferred because the solubility of the intermediate of Formula IV is lower in such solvents with respect to methanol and ethanol, and thus the isolation of said intermediate by precipitation is much easier. Moreover, butanol and pentanol have higher boiling points with respect to methanol and ethanol, thus allowing to carry out the reaction at higher temperatures, so as to complete it in a shorter time (about 2-4 hours) .

Furthermore, according to a preferred embodiment, in step a) : when M=Na, the base is selected from NaOR, wherein R is C1-C4 alkyl group, preferably NaOMe and NaOEt, more preferably the base is NaOMe; when M=Li, the base is selected from LiOR, wherein R is C1-C4 alkyl group, preferably LiOMe and LiOEt, more preferably the base is LiOMe; when M=K, the base is selected from KOR, wherein R is C1-C4 alkyl group, preferably KOMe and KOEt, more preferably the base is KOMe .

According to a preferred embodiment of the process of the present invention, in step a' ) the acid is selected from inorganic or organic acid; when the acid is an inorganic acid, it is preferably HX, where X is a halogen, more preferably the acid is HC1.

As for step b) , according to a preferred embodiment, when X=C1, the halogenating agent is selected from POCI3, POCI5, SOCI2 and N- chlorosuccinimide (NCS) .

According to a preferred embodiment, the process of the invention further comprises the step of crystallizing crude Mavacamten. Preferably, the crystalizzation is carried out according to the following process:

A) suspending and then dissolving Mavacamten in a solvent, wherein the solvent is an alcohol;

B) heating the so obtained solution to reflux;

C) decreasing gradually temperature to 0-5 °C to obtain a precipitate of Mavacamten;

D) isolating Mavacamten.

Preferably, in step A of the crystallization process, the solvent is n-butanol.

According to a preferred embodiment, the process of the invention is as reported in the following scheme 3:

Dimethyl

Formula II

Formula V malonate

(S)-1 -Phenyl

Formula V Formula VI' ethylamine Mavacamten Formula I

Scheme 3 The following preferred embodiment refers to the process as reported in scheme 3.

The preferred embodiment comprises the following steps: a) reacting the isopropyl urea of Formula IT:

Formula IT and a dialkyl malonate of Formula ITT:

Formula ITT wherein Ri and R2 are methyl groups; with a base in a solvent to obtain a compound of Formula VII:

Formula VII wherein: n is an integer selected from 1 and 2; the base is NaOR, wherein R is C1-C4 alkyl group, preferably NaOMe or NaOEt, more preferably the base is NaOMe; the solvent is selected from: alcohols, toluene, dimethylformamide (DMF) , and mixtures thereof; and isolating the compound of Formula VII by precipitation; a' ) reacting the isolated compound of Formula VII with an acid in a solvent to obtain the compound of Formula V:

According to a preferred embodiment, in step a) dimethylmalonate of Formula III is employed according to a stochiometric molar ratio of 1.3 - 1.5 eq .

According to a further preferred embodiment, in step a' ) the solvent is selected preferably from water, alcohols, and mixtures thereof, more preferably the solvent is water. Advantageously, the reaction of step a) is performed in an alcohol as solvent, preferably in n-BuOH. A shorter reaction time is achieved by heating the mixture at a higher temperature while distilling away MeOH (which is present in the reactant sodium methylate in methanol) . Particularly, the reaction time is thus reduced from overnight to few hours. Preferably, the use of n-BuOH allows to isolate the intermediate 1-isopropyl barbituric acid sodium salt (compound VII) when the reaction is complete. This allows a first purification of the intermediate with a high yield.

In the reaction step a' ) , 1-isopropyl barbituric sodium salt (compound VII) is then acidified to obtain 1-isopropyl barbituric acid (compound V) . The isolation of the product is achieved by crystallization.

In step a' ) the acid is preferably HX, where X is a halogen, more preferably the acid is HC1.

In step b) the solvent is preferably acetonitrile (CH₃CN) .

According to a preferred embodiment, when X=C1, the halogenating agent is selected from POCI3, POCI5, SOCI2 and N-chlorosuccinimide (NCS) , preferably the halogenating agent is POCI3 wherein POCI3 is employed with a stochiometric molar ratio of 0.9 to 2.2 equivalent to compound of formula V, preferably of 0.9 - 1.15 eq.

According to a preferred aspect, when X=C1, the halogenating agent is POCI3 and the compound of Formula VI is:

Formula VI ' .

Advantageously, POCI3 is used as a stochiometric reagent instead of solvent, thus making the procedure safer.

Furthermore, additional advantages can be found in the fact that POCI3 equivalents are reduced (to 0.9 eq.) and the addition of any base to the reaction mixture is avoided. Moreover, at the end of the reaction, the POC13 byproducts may be quenched with water, also allowing the product to precipitate . Performing the reaction with POCI3 on a puri fied 1-isopropyl barbituric acid allows to reach higher yield of 6-chloro-3-i sopropylpyrimidine-2 , 4 ( 1H, 3H) -dione with respect to the data of yield reported for reaction performed on a crude 1-isopropyl barbituric acid .

According to another aspect, the present invention relates to a compound of Formula IV :

Formula IV wherein : M is a metal selected from lithium, sodium, potassium; n is an integer selected from 1 and 2 .

Preferably, the above compound has Formula VI I :

Formula VI I .

Preferably, the compound of Formula VI I is a compound of Formula

Vi la

Formula Vi la ; or a compound of Formula VI lb :

Formula VI lb ; or a mixture thereof.

The present invention also relates to the use of a compound of Formula IV, preferably of Formula VII, as intermediate for preparing Mavacamten .

List of abbreviations:

1. MeOH: Methanol

2. EtOH: Ethanol

3. t-BuOH: tert-Butyl alcohol

4. THE: Tetrahydrofuran

5. NaOMe : Sodium methylate

6. HC1 : Hydrochloric acid

7. ACN : Acetonitrile

8. POCI3: Phosphorus oxychloride

9. CH2CI2: Dichlorometane ;

10. NCS : N-Chlorosuccinimide ;

RT : Room Temperature.

In order to further illustrate, but not-limiting, the present invention, the following examples are reported below.

Example 1 : Synthesis of the compound of Formula VII (1-isopropyl barbituric acid sodium salt) .

100 g of isopropyl urea and 167.9 g of dimethylmalonate were dissolved in 1000 ml of n-butanol. The solution was added dropwise in a reactor containing 624.7 g of NaOMe solution in methanol (25% w/w) in about 10 minutes, then the mixture was heated to 92°-94°C and 650 ml of solvent were distilled. The reaction mixture was stirred for 3 hours at 92-94°C. The precipitation of the product was observed during the reaction time. After 3 hours, the mixture was cooled to 15°-20°C and the product was filtered. The cake was washed with 200 ml of n-butanol and 300 ml of acetone. The wet product was dried under vacuum at 50°C for 12 hours. 200 gr of 1-isopropyl barbituric acid sodium salt of Formula VII were obtained.

Yield obtained: 95.4% Example 2: Synthesis of the compound of Formula V (1-isopropyl barbituric acid) .

200 gr of 1-isopropyl barbituric sodium salt were dissolved in 675 ml of water. In case of a turbid solution, a filtration step was added. Under stirring, HC1 37% was added dropwise in about 45 minutes, maintaining the temperature between 15°-20°C, until the pH=3 (about 150 ml of HC1 37% were nedeed) . The mixture was then cooled to 0°-5°C and the product was isolated by filtration and the cake was washed with 400 ml of water. The solid obtained was suspended in 400 ml of n-butanol. The mixture was heated to reflux and the water was distilled until the internal temperature reaches 110°C, the solution was then cooled to 0°-5°C in 3 hours and the reaction mixture was stirred for 2 hours. The solid was isolated by filtration and the cake was washed with 100 ml of n-butanol. The wet product was dried under vacuum at 50°C for 12 hours, to obtain 130 g of crystallized 1-isopropyl barbituric acid.

Yield obtained: 81.2%

Example 3: Synthesis of the compound of Formula VI' ( 6-chloro-3- isopropylpyrimidine-2 , 4 ( 1H, 3H) -di one )

In a reactor 1-isopropyl barbituric acid (130 g) , ACN (390 ml) and POCI3 (105.4 g) were charged. The mixture was heated up to 70°C and left stirring for 6h. The mixture was cooled down to 20°C and quenched with 720 ml of water added dropwise (internal temperature was maintained not exceeding 40°C) . The mixture was then left stirring at RT for 5 h to allow the full quench. It was then cooled down to 0-5°C and filtered after Ih. The crude was washed with 150 ml of water. The crude was dried under vacuum at 50°C for 12h and used as such in the next step. Grams obtained= 125g Yield obtained: 87%

Example 4 : Synthesis of the compound of Formula 1 (Mavacamten) .

In a 1000 ml reactor, 125 g of 6-chloro-3-isopropylpyrimidine-2 , 4

( IH, 3H) -dione were suspended in 750 ml of water. 200.7 g of (S)- phenyl-ethylamine were added to the suspension. The mixture was then heated up to 94-96°C for 40-45 hours. The mixture was cooled down to 15°C. After Ih at 15°C, the suspension was filtered and the solid was washed with 280 ml of water.

The crude product was then suspended in 1.4 vol (calculated on 6- chloro-3-isopropylpyrimidine-2 , 4 ( IH, 3H) -dione ) of acetone, and left stirring for 30 min at RT, then cooled down to 5°C and filtered after 30 min. The solid was filtered and washed with 65 ml of acetone. The product was dried under vacuum at 50°C for 12h, to obtain 165 g of crude product .

Yield obtained: 91%

Example 5: Crystalizzation step

In a 1000 ml bottom flask, 165 g of crude Mavacamten were suspended in 660 ml of n-butanol (4 vol) . The mixture was heated up to reflux until complete dissolution. The mixture was then cooled down spontaneously to RT and left stirring for Ih. The mixture was then cooled to 0-5°C and filtered after Ih. The solid was washed with 100 ml of n-butanol. The solid was dried under vacuum @50°C for 12h to obtain 159 g of white solid.

Yield obtained: 96%.

The so obtained solid was analyzed by chromatography to determine purity degree, which resulted to be > 99.9%.

Overall yield obtained for the whole process: 59%.

Overall yield for the whole process according to WO2014205223 : 14% Example 6: Comparative experiment, synthesis of the compound of Formula V.

As a comparative experiment, the procedure disclosed in WO2014205223 for the synthesis of the compound of Formula V has been tested. In order to better compare the yield and purity of the product obtained with the WO2014205223 procedure and that of the present invention (Examples 1-2 above) , the purification step disclosed in the prior art, i.e. column chromatography, has been replaced by a crystallization. To a stirred solution of 20 gr of 1-isopropylurea in 350 ml of methanol, 27,4 gr of dimethylmalonate and 26,4 gr of NaOMe were added. The mixture was heated to 65°C and left stirring overnight. A process control showed a residual 28% of 1-isopropylurea. The mixture was then cooled to 0°C. Under stirring, HC1 37% aq. was added dropwise until the pH=3. The mixture was concentrated under vacuum to residue. The residue was taken up in 70 ml of water at 50°C, then 14 ml of isopropanol were added. The mixture was heated up to 72- 75°C to dissolution. The mixture was then cooled down to 45°C and left stirring for 1 hour. The mixture was then cooled down to RT and left stirring overnight. The solid was isolated by filtration and the cake was washed with 20 ml of water two times. The wet product was dried under vacuum at 40°C for 12 hours, to obtain 18,7 gr of 1-isopropyl barbituric acid.

Yield obtained. 55.9%

Therefore, following the procedure of the prior art (example 6) the overall yield from compound of Formula IT to compound of Formula V was 55.9%, way lower than that obtained with the procedure of the present invention corresponding to examples 1-2, i.e. 77.4%.

Claims

1. A process for preparing Mavacamten having formula:

Formula I, or a salt thereof, the process comprising the following steps: a) reacting isopropyl urea of Formula II:

Formula II and a dialkyl malonate of Formula III:

Formula III wherein Ri and R₂ are independently selected from straight or branched

Ci- Cg alkyl group; with a base in a solvent to obtain a compound of Formula IV:

2. The process according to claim 1, wherein in step a) the reaction temperature is from 90°C to 95°C.

3. The process according to any of the preceding claims, wherein in step a) the solvent is selected from: methanol, ethanol, butanol (BuOH) , pentanol, and mixtures thereof.

4. The process according to claim 3, wherein in step a) the solvent is n-butanol.

5. The process according to any of the preceding claims, wherein in step a) : when M=Na, the base is selected from NaOR, wherein R is C1-C4 alkyl group, preferably NaOMe and NaOEt, more preferably the base is NaOMe; when M=Li, the base is selected from LiOR, wherein R is C1-C4 alkyl group, preferably LiOMe and LiOEt, more preferably the base is LiOMe; when M=K, the base is selected from KOR, wherein R is C1-C4 alkyl group, preferably KOMe and KOEt, more preferably the base is KOMe .

6. The process according to any of the preceding claims, wherein in step a' ) the acid is HX, where X is a halogen, more preferably the acid is HC1.

7. The process according to any of the preceding claims, wherein in step b) , when X=C1, the halogenating agent is selected from POCI3, POCI5, SOCI2 and N-chlorosuccinimide (NCS) .

8. The process according to any of the preceding claims, wherein in step b) when X=C1, the halogenating agent is POCI3.

9. The process according to claim 8, wherein in step b) the molar ratio of POCI3 is from of 0.9 to 2.2 equivalent to compound of formula V, preferably the molar ratio of POCI3 is from of 0.9 to 1.15 equivalent to compound of formula V.

10. The process according to any of the preceding claims, further comprising the step of crystallizing crude Mavacamten.

11. The process according to claim 10, wherein the step of crystallizing crude Mavacamten comprises:

A) suspending and then dissolving Mavacamten in a solvent, wherein the solvent is an alcohol, preferably n-butanol;

B) heating the so obtained solution to reflux;

D) isolating Mavacamten.

12. The process according to claim 1, said process comprising: a) reacting the isopropyl urea of Formula IT:

Formula IT and a dialkyl malonate of Formula ITT:

Formula VII wherein : n is an integer selected from 1 and 2; the base is NaOR, wherein R is C1-C4 alkyl group, preferably NaOMe or NaOEt, more preferably the base is NaOMe; the solvent is selected from: alcohols, toluene, dimethylformamide (DMF) , and mixtures thereof; and isolating the compound of Formula VII by precipitation; a' ) reacting the isolated compound of Formula VII with an acid in a solvent to obtain the compound of Formula V:

Formula VI wherein X is a halogen selected from chlorine, bromine and iodine, and the solvent is selected from: nitriles, ethers, dichlorometane

(CH2CI2) , tetrahydrofurane (THF) , chlorobenzene; c) reacting the compound of Formula VI with ( S ) -phenyl-ethylamine in a solvent to obtain Mavacamten of Formula I, wherein the solvent is selected from: water, alcohols, ethers, and mixtures thereof.

13. The process according to claim 12, wherein in step a) dimethylmalonate of Formula III is employed according to a stochiometric molar ratio of 1.3 - 1.5 eq.

14. The process according to claim 11 or 12, wherein in step a' ) the solvent is selected from water, alcohols, and mixtures thereof, preferably the solvent is water.

15. A compound of Formula IV:

Formula IV wherein: M is a metal selected from lithium, sodium, potassium; n is an integer selected from 1 and 2.

16. The compound according to claim 15, having Formula VII:

Formula VI I . pound according to claim 16 having formula Vila:

Formula Vila; VI lb:

Formula VI lb; or a mixture thereof.

18 . Use of a compound according to any of claims from 15 to 17 as intermediate for preparing Mavacamten .