EP4298100A1

EP4298100A1 - Process for obtaining avapritinib and its intermediates

Info

Publication number: EP4298100A1
Application number: EP22759019.7A
Authority: EP
Inventors: Márta PORCS-MAKKAY; Ferenc Bertha; Enik MOLNÁR; Gábor NÉMETH; Simon HORVÁTH; Ildikó SZEBELÉDI; Beatrix BALI; Mónika TELLÉR; Katalin KÁTAINÉ FADGYAS
Original assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Current assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Priority date: 2021-02-26
Filing date: 2022-02-28
Publication date: 2024-01-03
Also published as: HUP2100077A1; HU231413B1; WO2022180416A1

Abstract

The present invention relates to process for obtaining Avapritinib of the formula (I) and its intermediates. Avapritinib, is used for treatment of gastrointestinal stromal tumors (GIST) and for tumors of stomach and intestines.

Description

Process for obtaining Avapritinib and its intermediates

Field of the disclosure

The present invention relates to process for obtaining avapritinib(l) and its intermediates. Avapritinib (I), (1 S)-1-(4-f!uorophenyl)-1-[2-[4-[6-(1-methy!pyrazol-4- yl)pyrrolo[2,1 -f][1 ,2,4]triazin-4-yl]piperazin-1 -yl]-pyrimidin-5-yl]ethanamine, is used for treatment of gastrointestinal stromal tumors (GIST) and for tumors of stomach and intestines.

Background of the disclosure WO 2015057873 international patent application discloses process for preparing a mixture of avapritinib and its enantiomer. The S-enantiomer (Formula I) is separated from the racemate by chiral chromatography, which process is not applicable on industrial scale.

WO201 5058129 and W02020210293 disclose the synthesis of the compounds of the Formula (VI) and (V) which compounds contain the structural elements of avapritinib. An alternative synthesis of avapritinib(l) is disclosed in the patent application No. CN1 10938077. The process according to the application does not require the separation on a chiral column, in contrast to that disclosed in the basic patent (WO 2015057873). In the process according to CN110938077, the compound of the Formula (VI) is resolved with L-dibenzoyltartaric acid (L-DBTA), and then the salt thus obtained [(ll)^*L-DBTA] is reacted with the compound of the Formula (X) also disclosed in the basic patent (WO 2015057873). By this step, the L-dibenzoyl tartrate salt of avapritinib [(l)^*L-DBTA] is formed, from which avapritinib (I) is released. Flowever, in our experiments the procedure according to CN110938077 could not be reproduced, the reaction of racemic 1-(4-fluorophenyl)-1-[2-(piperazin-1-yl pyrimidin-5-yl]ethan-1- amine (VI) with L-DBTA did not yield the crystalline form of [(ll)^*L-DBTA] under any of the reaction conditions described in the application. For example, reproducing a preferred embodiment of CN110938077, the Compound of the Formula (VI) was added to ethanol/water/acetic acid mixed solution (preparation method: mixing ethanol, water, Acetic acid was mixed according to the volume ratio of 7:3:1), heated to 70 ° C, and then kept at 70 ° C and added dropwise 1.2 eq. L-DBTA and ethanol/water/acetic acid (volume ratio 7:3: 1 ), the resulting solution was stirred at 70°C for 16 hours, then cooled to room temperature. However, no solids could be collected after cooling to room temperature. There was no crystallization even after stirring at lower temperature 0-5 °C or storing in freezer. We got the same result with the other reaction conditions disclosed in CN110938077. The patent application No. CN110950872 discloses another possible synthesis of avapritinib (I). The starting material for the process is S-1-(4-fluorophenyl)-1-[2- (piperazin-1-yl)pyrimidin-5-yl]ethan-1 -amine (the compound of the Formula (II), which is the S enantiomer of the compound of the Formula (VI)). In the first step of the synthesis, the primary amino group of the starting material is protected with a tert- butyloxycarbonyl group (hereinafter Boc). The product thus obtained is reacted with the compound of the Formula (X) and finally, after removal of the Boc protecting group, avapritinib (I) is obtained as the final product. However, in our experience - which is described below - in the reaction of the compound of the Formula (II) with di-t-butyl dicarbonate, in reality the Boc group reacts with the secondary amino group of the piperazine group.

W0202021 0669 discloses a process for the manufacture of avapritinib which does not require a column chromatography process. In the process, the diastereomeric mixture of the compound of the Formula (V) already known is prepared in a reaction medium from which mainly the S, S-diastereomer of the compound of the Formula (V) is precipitated, and the diastereomeric purity of the latter is increased by recrystallization from heptane-methanol. The intermediate thus obtained is reacted with hydrochloric acid to simultaneously remove the two protecting groups to give the intermediate salt (ll^*3,5HCI). This is reacted with the compound of the Formula (X) to get the final avapritinib (I) product.

Summary of the invention

The present invention provides a novel process for the preparation of avapritinib (I) via the novel key intermediate the compound of the Formula (IV). Another aspect of the invention is the compound of the Formula (IV). The key intermediate, the compound of Formula (IV) is prepared by selectively introducing a Boc protecting group from the compound of Formula (VI) known in the literature or by removing the t-butylsulfinyl group from the compound of the Formula (V) also known in the literature (Scheme 1.).

Another object of the present invention is to provide a process for the preparation of avapritinib (I) via the novel intermediate the compound of the Formula (III).

A further object of the present invention is the compound of Formula (III), which is a diastereomeric salt of the S enantiomer of the compound of Formula (IV) with the compound of Formula (IX) wherein the meaning of R in Formula (IX) is FI or o-, m- or p- methyl group, and a process for obtaining the compound of the Formula (III), wherein the compound of Formula (IV) is resolved with a D-diaroyltartaric acid derivative [compound of the Formula (IX) in which the meaning of R is FI or methyl in the o-, m- or p-position]. Another object of the present invention is a process for obtaining avapritinib (I) by converting the compound of the Formula (III) to avapritinib (I) in a one-pot process after removal of the resolving acid (Formula (IX)) and the Boc protecting group by reaction with the compound of Formula (X). Another object of the present invention is a process for obtaining avapritinib (I) by 85 releasing the compound of Formula S-(IV) from the compound of Formula (III) and then converting it to avapritinib (I) by reaction with the compound of Formula (X) after removing the protecting group Boc in a one-pot process.

Another object of the present invention is a process for obtaining avapritinib (I) by 90 removing the resolving acid (Formula (IX)) and the Boc protecting group from the compound of the Formula (III) in a one-pot process, and then reacting the arising trihydrochloride monohydrate of the compound of Formula (II) (ll^*3HCI^*H20) with the compound of Formula (X). Concentrated hydrochloric acid is used to remove the Formula (IX) and Boc, thereby a new, unknown form of the compound of Formula (II), 95 trihydrochloride monohydrate of Formula II (I l^*3HCI^*H20) is obtained.

Detailed description of the invention

The present invention provides a novel process for the preparation of avapritinib (I) via loo the novel key intermediate of the compound of the Formula (IV).

The present invention further provides the compound of Formula (IV) and a process for obtaining the compound of the Formula (IV) as shown in Scheme 1. The compound of the Formula (IV) can be prepared by two methods, from the starting material of compound (V) or (VI).

Scheme 1.

The starting materials of the compound of the Formula (V) and (VI) and their preparation are known from the prior art (WO 2015058129 and WO 2020210669). no Reaction of the compound of the Formula (VII) with (S)-t-butylsulfinamide leads to the compound of the Formula (VIII), and the Grignard reaction of the product with methylmagnesium iodide gives a diastereomeric mixture of the compound of the Formula (V). Then, after removal of the t-butylsulfinyl group, the resulting compounds of the Formula (IV) and (VI) are enantiomeric mixtures (Scheme 1.).

In the process of Method A of the present invention (Scheme 1.), the compound of Formula (IV) is prepared by reacting a solution of the compound of the Formula (V) in an organic solvent with 1 to 6 equivalents, preferably 1 .5 to 2 equivalents of a strong acid, in which reaction the t-butylsulfinyl group can be selectively removed. For the reaction, the compound of the Formula (V) is dissolved in an organic solvent, preferably THF, and then excess strong acid is added dropwise, preferably 1.5-2 equivalents of concentrated hydrochloric acid. After stirring at room temperature, the reaction mixture is adjusted to an alkaline pH, the precipitated crystals are washed with water and, optionally, recrystallized from a C1 -C4 aliphatic alcohol, preferably ethanol, to obtain the compound of the Formula (IV).

According to Method B of the present invention (Scheme 1.), an organic solvent solution of the compound of the Formula (VI) is reacted with di-tert-butyl dicarbonate (B0C2O) to obtain the compound of the Formula (IV) in good yield.

Contrary to the disclosure of CN1 10950872, it has surprisingly been found that the tert- butyloxycarbonylation of the compound of the Formula (VI) on the secondary amino group takes place with good selectivity.

During the reaction, the compound of the Formula (VI) is dissolved in an organic solvent, preferably THF, and then a base, for example NaFIC03 is added. The reaction mixture is cooled to 0-5 ⁰ C and then a solution of di-tert-butyl dicarbonate in an organic solvent, preferably THF, is added dropwise. It is stirred for one hour at room temperature, then after addition of water it is stirred for additional half hour at 0-5 ⁰ C. After the precipitated crystals are filtered off and washed with water, the compound of the Formula (IV) is obtained. An object of the present invention is to provide a process for the preparation of avapritinib (I) via the new intermediate, the compound of the Formula (III).

An object of the present invention is the compound of the Formula (III) which is a diastereomeric salt of the compound of the Formula S-(IV) with compound (IX), wherein R means FI or methyl in the 0-, m- or p- position. Another object of the present invention is a process for obtaining the compound of the Formula (III), wherein the compound of the Formula (IV) is resolved with a D-diaroyltartaric acid derivative [compound of the Formula (IX) wherein R in the Formula (IX) means FI or methyl group in the 0-, m- or p-position] (Scheme 2.).

Scheme 2. It has been found that by reacting the compound of the Formula (IV) with the compound of the Formula (IX), the S enantiomer of the compound of Formula (IV) [S-(IV)] forms a salt with the compound of the Formula (IX) to precipitate from the solution the compound of the Formula (III) as a filterable crystal. The salt of the enantiomer R of the compound of the Formula (IV) with the Formula (IX) remains in solution. In the compound of the Formula (IX) R means FI or methyl group in the 0-, m- or p- position. The compound of the Formula (IX) is preferably D-di-benzoyltartaric acid [(2S,3S)-2,3-bis(benzoyloxy)butanedioic acid (IXa)], or, more preferably D-di- toluyltartaric acid [(2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedicarboxylic acid (IXb)]. The resulting compound of the Formula (III) is preferably (2S,3S)-2,3-bis (benzoyloxy) butanedioic acid tert-butyl 4-{5-[(1S)-1 -amino-1 -(4-fluorophenyl)ethyl]pyrimidine-2- yl}piperazine-1-carboxylate salt (1 :1) (Ilia), or, more preferably (2S,3S)-2,3-bis(4- methylbenzoyloxy) butanedioic acid tert-butyl4-{5-[(1S))-1 -amino-1 -(4- fluorophenyl)ethyl]pyrimidin-2-yl}piperazine-1-carboxylate salt (1 : 1) (lllb).

During the reaction, the compound of the Formula (IV) is suspended in a C1- C4 aliphatic alcohol, preferably ethanol, and heated to reflux, and a solution of the compound of Formula (IX) in a C1- C4 aliphatic alcohol, preferably ethanol, is added and stirred at room temperature for 24 hours. The precipitated crystals of the compound of the Formula (III) are filtered off, washed with a C1-C4 aliphatic alcohol, preferably ethanol, and then recrystallized from ethanol / C1-C4 aliphatic alcohol. The preparation of the compound of the Formula (III) is of key importance, since by the reaction of Scheme 2., the S enantiomer of the compound of the Formula (IV) (S-(IV)) can be separated selectively and on an industrial scale via the compound of the Formula (III), so that avapritinib (I) can be produced without the use of a chromatographic purification step. As a result of the reaction shown in Scheme 2., the S:R ratio of the resulting compound of the Formula (III) is at least 98:2.

Avapritinib (I) may be prepared from the compound of Formula (III) in three alternative ways according to the present invention.

1. According to the first method, the compound of the Formula (III) is reacted with the compound of the Formula (X) after removal of the resolving acid of Formula (IX) and the Boc protecting group in a one-pot process. In this process, the compound of the Formula (III) is dissolved in an organic solvent, preferably TFIF at room temperature, and then a strong acid is added dropwise, preferably concentrated hydrochloric acid. After stirring the reaction mixture for 1 -24 hours, water is added and then the solution is made alkaline. The phases are separated, a base, preferably N, N-diisopropylethylamine (DIPEA) is added dropwise to the organic phase, and then compound of the Formula (X) is added. The reaction mixture is stirred overnight at room temperature and an acid scavenger, preferably saturated NaHCC>3 solution is added. The phases are separated, the aqueous phase is extracted with a water-immiscible organic solvent, preferably ethyl acetate, and the combined organic phases are dried and concentrated. The residue is stirred with ethyl acetate for 1 hour and the precipitated avapritinib (I) is filtered off. The crude final product may be purified by recrystallization. Alternatively, avapritinib (I) may be prepared by setting free the Formula S-(IV) from the compound of the Formula (III) and then converting it to avapritinib (I) by reaction with the compound of Formula (X) after removal of the Boc protecting group in a one-pot process. In this process, the compound of Formula (III) is stirred in a mixture of a water-immiscible organic solvent and water, preferably dichloromethane and water, until dissolved at room temperature and then the mixture is made alkaline. The aqueous phase is extracted with a water- immiscible organic solvent, preferably dichloromethane, and the combined organic phases are washed, dried and then concentrated in vacuum. The residue is dissolved in an organic solvent, preferably TFIF or ethyl acetate, more preferably TFIF, at room temperature, and then a strong acid is added dropwise, preferably concentrated hydrochloric acid. The reaction mixture is stirred for 1 - 24 hours, then water is added, and the mixture is made alkaline. The phases are separated, a base, preferably DIPEA, is added dropwise to the organic phase, then the compound of the Formula (X) is added. The reaction mixture is stirred overnight at room temperature and an acid scavenger, preferably saturated NaFIC03 solution is added. The phases are separated, the aqueous phase is extracted with a water-immiscible organic solvent, preferably ethyl acetate, and the combined organic phases are dried and concentrated. The residue is stirred with ethyl acetate for 1 hour and the precipitated avapritinib (I) is filtered off. The crude final product may be purified by recrystallization. A third method of preparing avapritinib (I) from the compound of the Formula (III) is to remove the resolving acid of Formula (IX) and the Boc protecting group in a one-pot process; isolating the arising compound: trihydrochloride monohydrate of the compound of the Formula (II) (ll^*3HCI^*H20) which is a new salt of the compound of the Formula (II), and then converting the said compound to avapritinib (I) by reaction with the compound of the Formula (X). In this process, as shown in Scheme 3., the compound of the Formula (III) is reacted with a mixture of concentrated hydrochloric acid and an organic solvent to obtain the compound of the Formula (N^*3FICrFl20). During the reaction, the compound of the Formula (III) is dissolved in an organic solvent, preferably TFIF at room temperature, and then a strong acid, preferable concentrated hydrochloric acid is added dropwise. After stirring the reaction mixture for 1 -24 hours, the precipitated crystals are filtered and after washing with water, the compound of the Formula (M^*3FICI^*Fl20) can be collected. Then, by reacting the compound of the Formula (I l^*3HCI^*H20) and the compound of the Formula (X), avapritinib (I) is obtained as the final product in the reaction shown in Scheme 4. During the reaction, the previously collected salt of the compound of the Formula (II) is suspended in a C1-C4 aliphatic alcohol, preferably ethanol, and then a base, preferably a tertiary amine, more preferably DIPEA, is added dropwise. The compound of the Formula (X) is added while stirring, and after stirring for 2.5 hours, water is added. After stirring for an additional 1 hour, the precipitated crystalline avapritinib (I) is filtered and washed with water. The crude final product can be purified by recrystallization.

Scheme 3.

Scheme 4.

Examples

Example 1 : Preparation of tert-Butyl 4-15-H -amino-1 -(4-fluorophenyl)ethyllpyrimidin-2- yl)piperazine-1 -carboxylate (IV) with Method A:

3.8 g (7.52 mmol) of tert-butyl 4-{5-[1-(4-fluorophenyl)-1 _{[(§) -2-methylpropane-2- sulfinyl] aminojethyl] pyrimidine-2-yl} piperazine-1 -carboxylate (V) is dissolved in 38 ml of THF and 37% aqueous hydrochloric acid is added dropwise (0.93 ml, 11.27 mmol). After stirring for 1 hour at room temperature, the reaction mixture is adjusted to pH 8- 9 with saturated NaHCC>3 solution (ca. 75 ml). The precipitated crystals are filtrated, washed with water and then with diisopropyl ether, and the resulting crude product (2.77 g) is stirred with water (27.7 ml) for 30 minutes, filtered and washed with water to give 2.17 g (72.2%) of crystals.

Optionally, the crude product is recrystallized from ethanol.

M.p .: 169.6-170.9 ° C.

¹HNMR (DMSO- e, 400 MHz) J8.36 (2H, s); 7.45 (2H, dd, J= 9.0; 5.5 Hz); 7,09 (2H, t, J= 9.0 Hz); 3.67 (4H, m); 3.36 (4H, m); 2.41 (2H, s); 2.41 (3H, s); 1.41 (9H, s).

Example 2: Preparation of tert-Butyl 4-15-H -amino-1 -(4-fluorophenyl)ethyllpyrimidin-2- yl)piperazine-1 -carboxylate (IV) with Method B: 5.0 g (16.59 mmol) of 1 - (4-fluorophenyl)-1 -[2- (piperazin-1 -yl) pyrimidin-5-yl] ethan-1 - amine (VI) is dissolved in 32.5 ml of THF with stirring, then 1.53 g (18.25 mmol) of NaHC03 dissolved in 16 ml of water is added. The reaction mixture is cooled to 0-5 ° C and a solution of di-tert-butyl-dicarbonate (3.62 g, 16.59 mmol) in THF (12 ml) is added dropwise. After stirring for 1 hour at room temperature, 50 ml of water is added and the mixture is stirred for further 30 minutes at 0-5 ° C. The precipitated crystals are filtrated and washed with water to obtain 5.76 g (86.5%) of white crystals.

{5-[(1 S)-1 -amino-1 - (4-fluorophenyl)ethyllpyrimidin-2-yl)piperazin-1 -carboxylate salt

(1 :1 ) (Ilia):

0.5 g (1.25 mmol) of the compound of Formula (IV) is suspended in ethanol (5.6 ml), heated to reflux, and then 0.45 g (1.25 mmol) of D-dibenzoyltartaric acid (IXa) dissolved in 4.6 ml ethanol is added. The reaction mixture is stirred at room temperature for 24 hours, and the precipitated crystals are filtered off and washed with ethanol to obtain 0.08 g (8.5%) of a salt having an S/R ratio of 98.22: 1 .78.

Mp: 154.2-163.8 °C (crude)

¹HNMR (DMSO-de, 400 MHz) 8.31 (2H, s); 7,95 (4H, d, J= 7.5 Hz); 7.65 (2H, t, J=7.4 Hz); 7.51 (4H, t, J= 7.6 Hz); 7.41 (2H, dd, J=8.5; 5.3 Hz); 7.18 (2H, t, J=8.5 Hz); 5.68 (2H, s); 3.70 (4H, m); 3.38 (4H, m); 1 .90 (3H, s); 1 .42 (9H, s). carboxylate salt (1 :1 ) (lllb):

3.21 g (8.0 mmol) of the compound of Formula (IV) is suspended in 32.2 ml ethanol, heated to reflux, and then D-di-toluic tartaric acid (IXb) (3.09 g, 8.0 mmol) dissolved in ethanol (30 ml) is added. The reaction mixture is stirred at room temperature for 24 hours, and the precipitated crystals are filtered off and washed with ethanol to obtain 1.95 g (31 %) of a salt having an S/R ratio of 96.96: 2.57. The crude salt is recrystallized from ethanol to obtain an S/R ratio of 99.74: 0.26.

Mp: 157.4-162.0 °C

¹HNMR (DMSO-de, 400 MHz) d 8.32 (2H, s); 7.80 (4H, d, J=8.1 Hz); 7.41 (2H, dd, J=8.9; 5.3 Hz); 7.31 (4H, d, J=8.0 Hz); 7.20 (2H, t, J=8.9 Hz); 5.63 (2H, s); 3.70 (4H, m); 3.36 (4H, m); 2.36 (6H, s); 1.90 (3H, s); 1.41 (9H, s)

Example 5: Preparation of tert-Butyl 4-{5-[(1S)-1 -amino-1 -(4- fluorophenyl)ethyllpyrimidin-2-yl)piperazine-1 -carboxylate (S- (IV)):

2.00 g (2.54 mmol) of (2S,3S)-2,3-Bis(4-methylbenzoyloxy)butanedioic acid tert-butyl 4-{5- [(1 S)-1 -amino-1 -(4-fluorophenyl))ethyl]pyrimidin-2-yl}piperazine-1 -carboxylate salt (lll/b) is stirred in a mixture of dichloromethane (15 ml) and water (15 ml) until dissolved at room temperature and then the mixture is made alkaline with 40% aqueous NaOH solution. The phases are separated, the aqueous phase is extracted with dichloromethane (10 ml), and the combined organic layers are washed with saturated NaCI solution, dried over magnesium sulfate, and concentrated in vacuum. The residue is crystallized from hexane (15 ml), filtered and washed with hexane (2 ml). 0.97 g (95.2%) of S-(IV) is obtained. Mp: 171.3-172.9 °C

¹HNMR (DMSO-de, 400 MHz) J8.36 (2H, s); 7.44 (2H, dd, J=8.9; 5.3 Hz); 7.09 (2H, t, J=8.9 Hz); 3.66 (4H, m); 3.36 (4H, m); 1.71 (3H, s); 1.41 (9H, s).

Example 6: Preparation of (1S)-1-(4-fluorophenvD-1-[2-(piperazin-1-vDpyrimidin-5- yllethan-1 -amine trihvdrochloride monohvdrate

788 mg (1 mmol) of (2S,3S)-2,3-bis(methylbenzoyloxy)butanedioic acid tert-butyl 4-{5- [(1 S)-1 -amino-1 -(4-fluorophenyl)ethyl]pyrimidin-2-yl}piperazine-1 -carboxylate salt (Ilia) is dissolved in THF (5 ml) with stirring at room temperature and then 0.5 ml of cc. hydrochloric acid is added dropwise. The reaction mixture is stirred for 20 hours, and the precipitated crystals are filtered off and washed with water to obtain 410 mg (95.6%) of (ll^*3HCI^*H 0). ¹HNMR (DMSO-afe, 400 MHz) J9.53 (3H, bs); 9.45 (2H, bs); 8.46 (2H, s); 7.52 (4H, dd, J= 9.0; 5.1 Hz); 7.28 (2H, t, J=8.9 Hz); 3.97 (4H, m); 3.14 (4H, m); 2.02 (3H, s). Example 7: Preparation of Avapritinib (0 with the 1. method:

788 mg (1 mmol) of (2S,3S)-2,3-bis(4-methylbenzoyloxy)butanedioic acid tert-butyl 4- {5 - [(1 S)-1 -amino-1 -(4-fluorophenyl)ethyl]pyrimidine-2-yl}piperazine-1 -carboxylate (lll/b) is dissolved in THF (5 ml) with stirring at room temperature, then 0.5 ml of cc. hydrochloric acid is added dropwise. The reaction mixture is stirred for 20 hours, then water (5 ml) is added and then the mixture is made alkaline with 40% aqueous NaOH solution with stirring. The layers are separated and DIPEA (0.20 ml_, 156 mg, 1.2 mmol) is added dropwise to the organic phase, then 234 mg (1.0 mmol) of 4-{4- chloropyrrolo[2,1-f] [1 ,2,4]triazin-6-yl} -1 -methyl-1 H-pyrazole (X) is added and the mixture is stirred overnight at room temperature, then 4.5 ml of saturated NaHCC>3 solution is added, the phases are separated and the aqueous phase is extracted with 3 ml of ethyl acetate, the combined organic phases are dried over MgSC and concentrated by evaporation in a vacuum. The residue is stirred with ethyl acetate (4 ml) for 1 hour, and the crystals are filtered off to obtain the crude product (303 mg, 60.8%), which is recrystallized from acetonitrile. Example 8: Preparation of Avapritinib (I) with the 2. method:

970 mg (2.5 mmol) of the tert-butyl 4-{5 -[(1 S)-1 -amino-1 -(4-fluorophenyl)ethyl] pyrimidin-2-yl}piperazin-1- carboxilate(S- (IV)) prepared in Example 5 is dissolved in in THF (12.5 ml) and then 1.25 ml(15 mmol) of cc. hydrochloric acid is added dropwise. The reaction mixture is stirred for 20 hours, then water (15 ml) is added and then the mixture is made alkaline with 40% aqueous NaOH solution with stirring. The phases are separated and DIPEA (0.51 ml, 387 mg, 3.0 mmol) is added dropwise to the organic phase, then 585 mg (2.5 mmol) of 4-{4-chloropyrrolo[2,1 -f] [1 ,2,4]triazin-6-yl}- 1 -methyl-1 H-pyrazole (X) is added and the mixture is stirred overnight at room temperature. After that saturated NaHC03 (10 ml) is added, the phases are separated, the aqueous phase is extracted with ethyl acetate (9 ml), and the combined organic phases are dried over MgS04 and concentrated in vacuum. The residue is stirred with ethyl acetate (10 ml) for 1 hour, and the crystals are filtered off to obtain 1 .0 g (80.4%) of crude product, which is recrystallized from acetonitrile.

Example 9: Preparation of Avapritinib (I) with the 3. method: 1.05 g (2.45 mmol) of (1S)-1 -(4-fluorophenyl)-1 -[2- (piperazin-1 -yl)pyrimidin-5- yl]ethan-1 -amine trihydrochloride-hydrate (ll^*3HCI^*H20) is suspended in 9.1 ml of ethanol with vigorous stirring at room temperature, then 1.7 ml (1.29 g; 10.0 mmol) of DIPEA is added dropwise, stirred until complete dissolution, and 0.57 g (2.45 mmol) of 4-{4-chloropyrrolo [2,1 -f] [1 ,2, 4]triazin-6-yl}-1 -methyl-1 H-pyrazole (X) is added with stirring. The Compound (X) gradually dissolves and meantime the product begins to precipitate. The reaction mixture is stirred at room temperature for 2.5 hours, then water (13 ml) is added, and the mixture is stirred for an additional 1 hour. The crystals are filtered off and washed with water to obtain 1 .13 g (92.6%) of crude product which is recrystallized from acetonitrile. ¹HNMR (DMSO-de, 400 MHz) S8.40 (2H, s); 8.03 (1 H, s); 7.98 (1 H, d, J=1 .6 Hz); 7.87 (1 H, s); 7.81 (1 H, s); 7.46 (4H, dd, J= 9.0; 5.5 Hz); 7.23 (1 H, d, J= 1 .6 Hz); 7.12 (2H, t, J=8.9 Hz); 4.09 (4H, m); 3.90 (4H, m); 3.85 (3H, s); 1 .75 (3H, s).

Claims

1. A process for the preparation of avapritinib (I), characterized in that the compound of the Formula (IV) is reacted with the compound of the Formula (IX) wherein R means hydrogen or methyl group in the 0-, m- or p-position, and then a)

- the resulting compound of the Formula (III) is isolated and then reacted with a strong acid, preferably concentrated hydrochloric acid, or b)

- the resulting compound of the Formula (III) is isolated and reacted it with alkali,

- the compound of the Formula S-(IV) thus obtained is isolated and reacted with a strong acid, or c)

- the resulting compound of the Formula (III) is isolated and reacted with concentrated hydrochloric acid,

- the compound thus obtained (ll^*3HC FI2O) is isolated, then the product of step a) b) or c) is reacted with the compound of Formula (X).

2. The compound of the Formula (IV):

3. The compound according to claim 2, wherein the compound of the Formula (IV) is the S- enantiomer of Formula (IV) (S-(IV)):

4. The process according to claim 1 characterized in that the compound (IV) is obtained by removing the tert-butylsulfinyl group from the compound of formula (V), or reacting the compound (VI) is with di-tert-butyl dicarbonate.

5. The process according to claim 4, characterized in that the compound of the Formula (IV) is obtained by reacting a solution of compound of the Formula (V) in an organic solvent with 1 to 6 equivalents, preferably 1.5 to 2 equivalents of a strong acid.

6. The process according to claim 5, characterized in that the compound of the Formula (IV) is obtained by reacting a solution of compound of the Formula (V) in tetrahydrofurane with 1.5 to 2 equivalents of concentrated hydrochloric acid.

7. The process according to claim 4, characterized in that the compound of the Formula (IV) is obtained by reacting a solution of compound of the Formula (VI) in an organic solvent with an organic solution of di-tert-butyl dicarbonate.

8. The process according to claim 7, characterized in that the compound of the Formula (IV) is obtained by reacting a solution of compound of the Formula (VI) in tetrahydrofurane with a solution of di-tert-butyl dicarbonate in tetrahydrofurane, in the presence of acid scavenger.

9. The compound of the Formula (III), where R means hydrogen or methyl group in the o-, m- or p-position:

10. The compound of claim 9, wherein R is Hydrogen (Ilia), or methyl group in p- position (lllb).

11. Process for the preparation of compound (III), characterized in that compound (IV) is reacted with compound (IX) wherein R is H or methyl in the o-, m- or p- position and then the resulting compound (III) is isolated.

12. Process according to claim 1 or 11, characterized in that the solution of the compound of the Formula (IV) in a C1 -C4 aliphatic alcohol, preferably in ethanol is reacted with a solution containing an equimolar or small excess amount of the compound of the Formula (IX) dissolved in a C1 -C4 aliphatic alcohol, preferably in ethanol.

13. Process according to any of claims 1, 11 or 12, characterized is that the compound of the Formula (IV) is reacted with the compound of the Formula (IX/a).

14. Process according to any of claims 1 , 11 or 12, characterized is that compound of the Formula (IV) is reacted with the compound of the Formula (IX/b).

15. The compound of the Formula (ll^*3HCI^*H20) :

(M*3HCI*H₂0)

16. Process for the preparation of the compound of the Formula (ll^*3HCI^*H20), characterized in that

- the compound of the Formula (IV) is reacted with the compound of the Formula (IX) in which R means FI or methyl group in the 0-, m- or p-position;

- the resulting compound of the Formula (III) is isolated, then dissolved in an organic solvent, preferably tetrahydrofuran, and reacted with concentrated hydrochloric acid,

- the resulting compound of the Formula (M^*3FHCI^*FH20) is isolated.