Synthesis route for preparing 8-(1,3-dimethyl-1h-pyrazol-4-YL)-1-(SA)-(3-fluoro-5-methoxy-pyridin-4-YL)-7-methoxy-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

Abstract

The present invention relates to a novel and improved process for preparing M4076.

Description

SYNTHESIS ROUTE FOR PREPARING 8-(1 ,3-DIMETHYL-1 H-PYRAZOL-4-YL)-1-(SA)-(3-FLUORO-5-METHOXY-PYRIDIN-4- YL)-7-METHOXY-3-METHYL-1 ,3-DIHYDRO-IMIDAZO[4,5-C]QUINOLIN-2-ONE >FIELD OF THE INVENTION

[0001] The present invention provides a novel process for preparing 8-(1 ,3-dimethyl- 1 H-pyrazol-4-yl)-1-(Sa)-(3-fluoro-5-methoxy-pyridin-4-yl)-7-methoxy-3-methyl-1 ,3- dihydro-imidazo[4,5-c]quinolin-2-one - also known as “Lartesertib” or “M4076” - or a pharmaceutically acceptable salt thereof.

[0002] The chemical formula of this compound (in the following referred to as M4076) is as follows:M4076BACKGROUND OF THE INVENTION

[0003] The ATM kinase inhibitor M4076 is an orally bioavailable ATP-competitive inhibitor of ataxia telangiectasia mutated kinase (ATM), with potential chemo- / radio- sensitizing and antineoplastic activities. Upon oral administration, M4076 targets and binds to ATM, thereby inhibiting the kinase activity of ATM and ATM-mediated signaling. This prevents DNA damage checkpoint activation, disrupts DNA damage repair, induces tumor cell apoptosis, and leads to cell death of ATM -overexpressing tumor cells. In addition, by preventing DNA damage repair, M4076 sensitizes tumor cells to chemo- and radiotherapyand increases their anti-tumor activity. ATM, a serine / threonine protein kinase upregulated in a variety of cancer cell types, is activated in response to DNA damage and plays a key role in DNA-strand repair.

[0004] M4076 is the Sa-atropisomer (also referred to as the / W-atropisomer) of 8-(1 ,3- Dimethyl-1 H-pyrazol-4-yl)-1 -(3-fluoro-5-methoxy-pyridin-4-yl)-7-methoxy-3-methyl-1 ,3- dihydro-imidazo[4,5-c]quinolin-2-one and has the following chemical formula:M4076

[0005] The other atropisomer of 8-(1 ,3-Dimethyl-1 H-pyrazol-4-yl)-1-(3-fluoro-5- methoxy-pyridin-4-yl)-7-methoxy-3-methyl-1 ,3-dihydro-imidazo[4,5-c]quinolin-2-one is the Ra-atropisomer (also referred to as the P-atropisomer). This compound has the following structure and is also referred to herein as Compound Z:

[0006] The term "atropisomer" as used herein refers to a stereoisomer which arises due to a restricted rotation around a single bond that creates a chiral axis, whereby the rotation barrier around said single bond has to be sufficiently high to permit the isolation of a single atropisomer. Said rotation barrier can result, for example, from steric interactions with other residues of the same molecule thereby restricting said rotation around saidsingle bond. Both steric and electronic factors come into play and may reinforce or counteract one another.

[0007] The utilization of chiral compounds that contain asymmetric carbon atoms is well established in drug discovery, in principle. In particular, it is known in the art that racemic mixtures of two chiral compounds usually consist of one more active and one less active enantiomer as compared to the racemic mixture. Thus, the utilization of only one of the two enantiomers can be advantageous to improve the overall potency of the compound.

[0008] However, the utilization of atropisomers is generally seen as undesirable. In particular atropisomers are commonly regarded as a liability in drug discovery, since the stability of these isomers depends on energy differences resulting from steric strain or other factors that create a barrier to the rotation around said single bond. In contrast to chiral compounds resulting from asymmetric carbon atoms, atropisomerism cannot be readily predicted. In particular, it is generally not possible to readily predict the stability of an atropisomer. In particular, the height of said energy barrier determines the time of the interconversion of two corresponding atropisomers. The interconversion of a biologically active atropisomer into the corresponding other atropisomer can, thus, reduce its biological activity and introduce off-target or other unwanted effects. Therefore, only stable atropisomers that possess a sufficiently high energy barrier may be suitable in drug discovery.

[0009] However, both atropisomers of 8-(1 ,3-Dimethyl-1 H-pyrazol-4-yl)-1-(3-fluoro-5- methoxy-pyridin-4-yl)-7-methoxy-3-methyl-1 ,3-dihydroimidazo[4,5-c]quinolin-2-one surprisingly have sufficient stability and can be used separately for drug development. Further, it has been found earlier that the Sa-atropisomer (i.e. M4076) exhibits especially good properties superior to those of the Ra-atropisomer (i.e. Compound Z), e.g. in terms of its efficacy and selectivity, which make the Sa-atropisomer a very suitable candidate for development of a medicament for the treatment of cancer (see for example WO 2020 / 193660).

[0010] The last four steps of the existing manufacturing process for M4076 are as follows: STEP 1) methylation of Compound 1 (present as a racemic mixture) to obtain Compound 2 as a racemic mixture; STEP 2) Suzuki coupling with Compound 3 to form a racemic mixture of 8-(1 ,3-Dimethyl-1 H-pyrazol-4-yl)-1-(3-fluoro-5-methoxy-pyridin-4-yl)-7- methoxy-3-methyl-1 ,3-dihydroimidazo[4,5-c]quinolin-2-one; STEP 3) isolation of M4076from the racemic mixture; STEP 4) final crystallization to obtain M4076 in the desired solid form and purity:STEP 1 STEP 2Scheme 1

[0011] This process, however, has a rather low overall yield (8-18%), is quite costly, and has high production timelines.

[0012] Thus, it is desired to provide for an improved manufacturing process for M4076. In particular, it is desired to reduce the high manufacturing costs, to increase the overall process yields, and to decrease the production timelines.SUMMARY OF THE PRESENT INVENTION

[0013] It is an object of the present invention to overcome all or some of the above- mentioned drawbacks. In particular, it is an object of the present invention to provide for an improved process for preparing M4076, or a pharmaceutically acceptable salt thereof. In particular, the process should be robust, cost-efficient, and timesaving.

[0014] These objects have been solved by the claimed processes, which have been developed upon surprisingly finding out that Compounds 1 and 2, which are used in theexisting manufacturing process of M4076 (see scheme 1 above), show atropoisomeric behavior.

[0015] In contrast to the existing manufacturing process for M4076 (which performs a coupling reaction on a racemic mixture of Compound 2, followed by chiral resolution of the two resulting atropisomers), the process of the present invention provides Compound 2 in an atropisomerically enriched form (enriched in the Sa-atropisomer relative to the Ra- atropisomer), followed by a coupling reaction to directly generate M4076. In this way, the generation of the undesired Ra-atropisomer (i.e. Compound Z) is avoided and undesired atropisomers can be recycled at an early stage of the proceedings.

[0016] It is to be understood that the present invention also relates to deuterated derivatives of M4076. That means that one or more hydrogen atoms of M4076 can be substituted by deuterium atoms. The skilled person understands that if this is the case, i.e. if one or more hydrogen atoms on M4076 are substituted by deuterium atoms, the same hydrogen atoms are also substituted in the precursor molecules, for example Compounds 1 and 2 or the boronic acid used in a Suzuki coupling reaction.FIGURE DESCRIPTION

[0017] Fig. 1 shows a chromatogram regarding the separation of a racemic mixture of Compound 2 into the two atropisomers of Formulae 2.1 and 2.2. The peak at 8.105 minutes corresponds to the atropisomer of Formula 2.2; the peak at 13.678 minutes corresponds to the atropisomer of Formula 2.1.

[0018] Fig. 2 shows an illustration of the process of the present invention (including selected preferred embodiments and some sub-steps; other preferred embodiments - e.g. an optional final crystallization step - have been omitted for the sake of clarity).

[0019] Fig. 3 shows the reactions performed by the inventors and referred to in the Examples section.

[0020] In the present disclosure, the following structural representationshall be understood as equally illustrating. The same consideration applies for corresponding structures and structural pairs as used herein.DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention is based on the surprising finding that Compounds 1 andwhich are used in the existing manufacturing process of M4076 (see scheme 1 above), shows atropoisomeric behavior and can be separated into two stable atropisomers, herein described by Formulae 1.1 and 1.2 and Formulae 2.1 and 2.2, respectivelyFormula 2.1 Formula 2.2

[0022] Further, the inventor of the present invention has found that unlike the Ra- atropisomer of M4076 (i.e. Compound Z), the Ra-atropisomers of Compounds 1 and 2 (i.e. the compounds of Formula 1.2 and 2.2) can be racemized at moderate temperatures.

[0023] The above surprising finding allowed the inventors of the present invention to develop a manufacturing process that selectively generates M4076, or a pharmaceutically acceptable salt thereof, without generating its undesired Ra-atropisomer (i.e. CompoundZ) as a by-product. The inventive process has been shown to be robust, highly costefficient, and timesaving.

[0024] The present invention relates to a process for preparing M4076or a pharmaceutically acceptable salt thereof, which is characterized in that it comprises the following steps:(1) providing a Compound 2Compound 2, which is atropisomerically enriched in the Sa-atropisomer of Formula 2.1Formula 2.1 and(2) converting Compound 2 that is atropisomerically enriched in the Sa-atropisomer of Formula 2.1 into M4076.

[0025] “Atropisomerically enriched in the Sa-atropisomer of Formula 2.1” means that the Compound 2 comprises an excess of the Sa-atropisomer relative to the Ra- atropisomer”.

[0026] Also, the present invention relates to a process for preparing M4076or a pharmaceutically acceptable salt thereof, which is characterized in that no or substantially no Compound Z is producedCompound Z.

[0027] As noted above, the inventor has surprisingly found that Compounds 1 and 2 show atropoisomeric behavior and can be separated into two stable atropisomers, herein described by Formulae 1.1 and 1.2 and Formula 2.1 and 2.2, respectively. Specifically, by using HPLC chiral chromatography, two well-distinguished peaks, one corresponding to the compound of Formula 2.1 (at 13.678 minutes) and the other one corresponding to thecompound of Formula 2.2 (at 8.105 minutes), were detected (See Figure 1). Compound 1 could also be separated into two stable atropisomers, herein referred to by Formulae 1.1 and 1.2.

[0028] It has further been found that a usual racemic mixture of Compound 2, as used in the existing manufacturing process of M4076, contains a slight excess of the undesired Ra-atropisomer of Formula 2.2 relative to the desired Sa-atropisomer of Formula 2.1 (Ra- atropisomer : Sa-atropisomer = about 51 : 49).

[0029] As noted above, the inventive process uses an atropisomerically enriched Compound 2, comprising an excess of the Sa-atropisomer of Formula 2.1 relative to the Ra-atropisomer of Formula 2.2. The excess of the Sa-atropisomer of Formula 2.1 relative to the Ra-atropisomer of Formula 2.2 can be expressed in terms of the “enantiomeric excess”, herein denoted as “ee”, which is calculated according to the following formula: ee = [(I m2.i - m2 21) I (m2.i + m2 2)] * 100%. m2.i is the weight of the compound of Formula 2.1 . and m2 2is the weight of the compound of Formula 2.2.

[0030] Preferably, the enantiomeric excess (ee) of the Sa-atropisomer of Formula 2.1 is at least 20%, preferably at least 30%, more preferably at least 40%, even more preferably at least 40%, even more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98%, even more preferably at least 99%.

[0031] Also, it is preferred that Compound 2 provided in step (1) of the inventive process comprises no or substantially no Ra-atropisomer of Formula 2.2. In this respect, “substantially no” refers to an amount of less than 5 wt.%, preferably less than 1 wt.%, more preferably less than 0.5 wt.%.

[0032] It is particularly preferred that Compound 2 provided in step (1 ) of the inventive process is an atropisomerically pure compound of Formula 2.1 , wherein “atropisomerically pure” refers to a weight ratio of the Sa-atropisomer of Formula 2.1 to the Ra-atropisomer of Formula 2.2 of greater than 98 : 2, preferably greater than 99 : 1 , more preferably greater than 99.2 : 0.8, more preferably greater than 99.5 : 0.5.

[0033] It has further been found that Compounds 2 can be racemized by thermal treatment, i.e. by applying thermal energy that exceeds the rotation barrier. Thus, in order to provide for a highly pure end product (M4076), the inventive process is preferably conducted in a way that a racemization of the atropisomerically enriched Compound 2during process step (2) is avoided. Hence, step (2) of the process is preferably performed at a temperature below the racemization temperature of Compound 2.1 and of M4076.

[0034] In the existing manufacturing process of M4076, Compound 2 reacts with a boronic ester (Compound of Formula 3) at a temperature of about 90 °C for a duration of about 35 hours to form a racemic mixture of 8-(1 ,3-Dimethyl-1 H-pyrazol-4-yl)-1-(3-fluoro- 5-methoxy-pyridin-4-yl)-7-methoxy-3-methyl-1 ,3-dihydroimidazo[4,5-c]quinolin-2-one.The inventor of the present invention, however, has found out that Compound 2 is a racemic mixture and that the Compound of Formula 2.1 , once isolated from the Compound of Formula 2.2, does not undergo racemization at the right conditions. In particular, it has been found that the Compounds of Formulae 2.1 and 2.2 react with the Compound of Formula 3 to form, respectively, M4076 and its undesired atropoisomer

[0035] These findings can be used in two ways:(1): by reacting the atropisomerically pure form of the Sa-atropoisomer of Formula 2.1 , M4076 can be obtained in excellent atropoisomeric and chemical purity(2): by racemizing the (undesired) Ra-atropisomer of Formula 2.2, the same can be recycled in the process and can be used to prepare M4076. This renders the process highly efficient and cost-effective.

[0036] Accordingly, process step (2) is preferably performed at a temperature below the racemization temperature and / or for rather short timeframes. Preferably, process step (2) is performed at a temperature of 75°C or less, preferably at a temperature of 73°C or less, more preferably at a temperature of 70°C or less, more preferably at a temperature of 65°C to 70°C, more preferably at a temperature of 68°C to 70°C. At a temperature of 65 °C to 70 °C and 68 °C to 70 °C a particularly good balance of reaction temperature and reaction time is achieved.

[0037] Further, it is preferred that step (2) is performed for rather short timeframes. Preferably, step (2) is performed for a duration of less than 30 hours, preferably less than 20 hours, more preferably less than 10 hours, more preferably less than 5 hours, more preferably less than 3 hours.

[0038] It has been found that it is possible to perform step (2) in high yields at such low temperatures and short reaction times.

[0039] Preferably, process step (2) is a Suzuki coupling reaction, wherein Compound 3 is usedCompound 3.

[0040] Further, it has been found that acetonitrile is a particularly good solvent, PdCl2(PPh)3)2 is a particularly good catalyst, and KOH is a particularly good base for performing process step (2) at lower temperatures and reduced reaction times. Thus, it is preferred that step (2) is performed in the presence of a PdCl2(PPh)3)2 catalyst. Further, it is preferred that KOH is used as a base in step (2). Further, it is preferred that acetonitrile is used as a solvent in step (2). These conditions have been shown to be particularly suitable for performing step (2) in high yields at lower temperatures and reduced reaction times without generating the Ra-atropisomer. In contrast, the existing manufacturing process uses a dioxane / H2O mixture as a solvent, K2CO3as a base, and Pd(PPh3)4as a catalyst and uses rather high temperatures (about 90 °C) and long reaction times (more than 30 hours).

[0041] The inventor of the present invention has further found that there are two particularly advantageous ways for providing Compound 2 in an atropisomerically enriched form (enriched in the Sa-atropisomer relative to the Ra-atropisomer):

[0042] First, one can provide a racemic mixture of Compound 2 and perform a chiral resolution step for separating said racemic mixture of Compound 2 into (a) a Compound 2 that is atropisomerically enriched in the Sa-atropisomer of Formula 2.1 , and (b) a Compound 2 that is atropisomerically enriched in the Ra-atropisomer of Formula 2.2. Fraction (a) can then be used for synthesizing M4076 in atropisomerically enriched form; fraction (b) can be racemized at moderate temperature and recycled to the process.

[0043] Second, one can provide a racemic mixture of Compound 1 and perform a chiral resolution step on said racemic mixture of Compound 1 , thereby obtaining (a) a Compound 1 that is atropisomerically enriched in the Sa-atropisomer of Formula 1.1 , and (b) a Compound 1 that is atropisomerically enriched in the Ra-atropisomer of Formula 1 .2, followed by a conversion of the thus obtained Compound 1 that is atropisomerically enriched in the Sa-atropisomer of Formula 1.1 into a Compound 2 that is atropisomerically enriched in the Sa-atropisomer of Formula 2.1. Since the methylation reaction conducted for this conversion is usually performed at room temperature, a racemization during themethylation reaction is avoided. The Compound 1 that is atropisomerically enriched in the Ra-atropisomer of Formula 1.2 can then be racemized at moderate temperature (see above) and recycled into the process.

[0044] Accordingly, it is preferred that the inventive process comprises(i) a step (A) performed prior to step (1) or (ii) steps (a) and (P) performed prior to step (1).Step A

[0045] Step (A) is a chiral resolution step of separating a racemic mixture of Compound 2 into (a) a Compound 2 that is atropisomerically enriched in the Sa- atropisomer of Formula 2.1 , thereby obtaining the Compound 2 provided in step (1), and (b) a Compound 2 that is atropisomerically enriched in the Ra-atropisomer of Formula 2.2.

[0046] Preferably, the enantiomeric excess (ee) of the Sa-atropisomer of Formula 2.1 is at least 20%, preferably at least 30%, more preferably at least 40%, even more preferably at least 40%, even more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98%, even more preferably at least 99%.

[0047] Also preferably, the Compound 2 that is atropisomerically enriched in the Sa- atropisomer of Formula 2.1 , as obtained in step (A), comprises no or substantially no Ra- atropisomer of Formula 2.2. The term “substantially no” refers to an amount of less than 5 wt.%, preferably less than 1 wt.%, more preferably less than 0.5 wt.%, based on the total weight of the compounds of Formula 2.1 and 2.2.

[0048] Step (A) preferably comprises the following sub-steps:(A1) converting the compounds of Formula 2.1 and 2.2 in the racemic mixture of Compound 2 into the diastomeric salts A and B, wherein salt A is the salt of the compound of Formula 2.1 and salt B is the salt of the compound of formula 2.2, (A2) separating salts A and B, and(A3) converting salt A back to the compound of Formula 2.1 , thereby obtaining the Compound 2 that is atropisomerically enriched in the Sa-atropisomer of Formula 2.1 .

[0049] Step (A1) is preferably performed by reacting the compounds of Formula 2.1 and 2.2 in the racemic mixture with (S,S)-di-p-anisoyltartaric acid.

[0050] Step (A2) is preferably performed by filtration.

[0051] Step (A3) is preferably performed by reacting salt A with a base, preferably K2CO3.

[0052] As noted above, the compound of Formula 2.2 can be racemized by applying heat. Thus, it is preferred that the Compound 2 that is atropisomerically enriched in the Ra-atropisomer of Formula 2.2, as obtained in step (A), is racemized and recycled to the process.

[0053] For this purpose, the Compound 2 that is atropisomerically enriched in the Ra- atropisomer of Formula 2.2 as obtained in step (A) is converted into a racemic mixture of Compound 2, and the thus obtained racemic mixture of Compound 2 is then subjected to step (A). And so on, and so forth.

[0054] This conversion is preferably performed by converting salt B as obtained in step (A2) back to the compound of Formula 2.2, followed by a racemization of the thus obtained compound of Formula 2.2, thereby producing a racemic mixture of Compound 2. Preferably, said conversion of salt B back to the compound of Formula 2.2 is performed by reacting salt B with a base, preferably K2CO3. The racemization of the compound of Formula 2.2 is preferably performed by heating the compound of Formula 2.2 above its racemization temperature, preferably to a temperature of 120°C to 140°C.

[0055] In a preferred embodiment, step (A) further comprises a recrystallization step (A2.1) performed after step (A2) and before step (A3). The recrystallization step (A2.1) comprises a recrystallization of salt A obtained in step (A2), thereby obtaining a recrystallized salt A. It is to be understood that if the recrystallization step (A2.1) is performed, the recrystallized salt A is converted back to the compound of Formula 2.1 in step (A3).

[0056] Step (a) is a chiral resolution step of separating a racemic mixture of Compound 1 into (a) a Compound 1 that is atropisomerically enriched in the Sa-atropisomer of Formula 1.1 , and (b) a Compound 1 that is atropisomerically enriched in the Ra- atropisomer of Formula 1.2.

[0057] Preferably, the enantiomeric excess (ee) of the Sa-atropisomer of Formula 1 .1 is at least 20%, preferably at least 30%, more preferably at least 40%, even more preferably at least 40%, even more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least98%, even more preferably at least 99%, wherein the enantiomeric excess (ee) is calculated according to the following formula: ee = [(I mu - mi.21) I (mu + mi.2)] * 100%, wherein mu is the weight of the compound of Formula 1.1. and mi.2is the weight of the compound of Formula 1.2.

[0058] Also preferably, the Compound 1 that is atropisomerically enriched in the Sa- atropisomer of Formula 1.1 , as obtained in step (a), comprises no or substantially no Ra- atropisomer of Formula 1 .2. The term “substantially no” refers to an amount of less than 5 wt.%, preferably less than 1 wt.%, more preferably less than 0.5 wt.%, based on the total weight of the compounds of Formula 2.1 and 2.2.

[0059] Step (a) preferably comprises the following sub-steps:(a1) converting the compounds of Formula 1.1 and 1.2 in the racemic mixture of Compound 1 into the diastomeric salts C and D, wherein salt C is the salt of the compound of Formula 1.1 and salt D is the salt of the compound of Formula 1 .2, (a2) separating salts C and D, and(a3) converting salt C back to the compound of Formula 1.1 , thereby obtaining the Compound 1 that is atropisomerically enriched in the Sa-atropisomer of Formula 1.1.

[0060] Step (p) is a step of converting the Compound 1 that is atropisomerically enriched in the Sa-atropisomer of Formula 1.1 into the Compound 2 that is atropisomerically enriched in the Sa-atropisomer of Formula 2.1 provided in step (1).

[0061] Step (a1) is preferably performed by reacting the compounds of Formula 1.1 and 1 .2 in the racemic mixture of Compound 1 with (S,S)-di-p-anisoyltartaric acid.

[0062] Step (a2) is preferably performed by filtration.

[0063] Step (a3) is preferably performed by reacting salt C with a base, preferably K2CO3.

[0064] As noted above, also the compound of Formula 1.2 can be racemized by applying heat. Thus, it is preferred that the Compound 1 that is atropisomerically enriched in the Ra-atropisomer of Formula 1 .2, as obtained in step (a), is recycled to the process.

[0065] For this purpose, the Compound 1 that is atropisomerically enriched in the Ra- atropisomer of Formula 1.2 as obtained in step (a), is converted into a racemic mixture of Compound 1 , and the thus obtained racemic mixture of Compound 1 is then subjected to step (a). And so on, and so forth.

[0066] This conversion is preferably performed by converting salt D as obtained in step (a 2) back to the compound of Formula 1.2, followed by a racemization of the thus obtained compound of Formula 1.2, thereby producing a racemic mixture of Compound 1 . Preferably, said conversion of salt D back to the compound of Formula 1.2 is performed by reacting salt D with a base, preferably K2CO3. The racemization of the compound of Formula 1.2 is preferably performed by heating the compound of Formula 1.2 above its racemization temperature, preferably to a temperature of 120°C to 140°C.

[0067] In a preferred embodiment, step (a) further comprises a recrystallization step (a2.1) performed after step (a2) and before step (a3). The recrystallization step (a2.1) comprises a recrystallization of salt C obtained in step (a2), thereby obtaining a recrystallized salt C. It is to be understood that if the recrystallization step (a2.1) is performed, the recrystallized salt C is converted back to the compound of Formula 1.1 in step (a3).

[0068] Step (p) is preferably performed by a reaction with methyl iodide. Preferably, step (p) is performed at a temperature below the racemization temperature, preferably room temperature.

[0069] Preferably, the inventive process further comprises a step (3), wherein step (3) is a final crystallization step.

[0070] The inventive chiral resolution and recycling procedure has been successfully demonstrated on kilo-scale (see Examples section below).

[0071] An illustration of the process of the present invention (including selected preferred embodiments and some sub-steps; other preferred embodiments - e.g. an optional final crystallization step - have been omitted for the sake of clarity) is shown in Figure 2.

[0072] In line with the above findings, the present invention also relates to a process for preparing M4076, or a pharmaceutically acceptable salt thereof, the process being characterized in that no or substantially no Compound Z is produced in the process. Again, the term “substantially no” refers to an amount of less than 5 wt.%, preferably less than 1 wt.%, more preferably less than 0.5 wt.%, based on the total weight of Compounds M4076 and Z. This process preferably comprises steps (1) and (2) of the above-described process.

[0073] The present invention is now further described by means of the following items:Item 1 . Process for preparing the Compound M4076or a pharmaceutically acceptable salt thereof, characterized in that the process comprises the following steps: (1) providing a Compound 2Compound 2, wherein the Compound 2 is atropisomerically enriched in the Sa-atropisomer of Formula 2.1Formula 2.1and(2) converting said Compound 2 that is atropisomerically enriched in the Sa- atropisomer of Formula 2.1 into M4076.Item 2. Process according to Item 1 , wherein the enantiomeric excess (ee) of the Sa- atropisomer of Formula 2.1 is at least 20%, preferably at least 30%, more preferably at least 40%, even more preferably at least 40%, even more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98%, even more preferably at least 99%, wherein the enantiomeric excess ee is calculated according to the following formula: ee = [(I m2.i - m2 21) I (m2.i + m2 2)] * 100%, wherein mu is the weight of the compound of Formula 2.1. and m2 2is the weight of the compound of Formula 2.2.Item 3. Process according to any one of the preceding Items, wherein the Compound 2 provided in step (1) comprises no or substantially no Ra-atropisomer of Formula 2.2.Item 4. Process according to Item 3, wherein “substantially no” refers to an amount of less than 5 wt.%, preferably less than 1 wt.%, more preferably less than 0.5 wt.%, based on the total weight of the compounds of Formula 2.1 and 2.2.Item 5. Process according to any one of the preceding Items, wherein step (2) is performed at a temperature below the racemization temperature of the compound of Formula 2.1 and of M4076, preferably at a temperature of 75°C or less, preferably at a temperature of 73°C or less, more preferably at a temperature of 70°C or less, more preferably at a temperature of 65°C to 70°C, more preferably at a temperature of 68°C to 70°C.Item 6. Process according to any one of the preceding Items, wherein step (2) is performed for a duration of less than 30 hours, preferably less than 20 hours, more preferably less than 10 hours, more preferably less than 5 hours, more preferably less than 3 hours.Item 7. Process according to any one of the preceding Items, wherein step (2) is performed at a temperature of 68°C to 70°C and a duration of less than 3 hours.Item 8. Process according to any one of the preceding Items, wherein step (2) is a suzuki coupling reaction, wherein preferably Compound 3 is used in the Suzuki coupling reactionCompound 3.Item 9. Process according to any one of the preceding Items, wherein step (2) is performed in the presence of a PdCl2(PPh)3)2 catalyst.Item 10. Process according to any one of the preceding Items, wherein KOH is used as a base in step (2).Item 11. Process according to any one of the preceding Items, wherein acetonitrile is used as a solvent in step (2).Item 12. Process according to any one of the preceding Items, wherein step (2) is performed in acetonitrile solution and in the presence of KOH and PdCl2(PPh)3)2.Item 13. Process according to any one of the preceding Items, wherein the process comprises:(i) a step (A) performed prior to step (1), wherein step (A) is a chiral resolution step of separating a racemic mixture of Compound 2 into (a) a Compound 2 that is atropisomerically enriched in the Sa-atropisomer of Formula 2.1 , thereby obtaining the Compound 2 provided in step (1), and (b) a Compound 2 that is atropisomerically enriched in the Ra-atropisomer of Formula 2.2Formula 2.2,(ii) steps (a) and (p) performed prior to step (1), wherein step (a) is a chiral resolution step of separating a racemic mixture of Compound 1into (a) a Compound 1 that is atropisomerically enriched in the Sa- atropisomer of Formula 1.1Formula 1.1 , and (b) a Compound 1 that is atropisomerically enriched in the Ra- atropisomer of Formula 1 .2Formula 1.2, and step (p) is a step of converting the Compound 1 that is atropisomerically enriched in the Sa-atropisomer of Formula 1.1 into the Compound 2 that is atropisomerically enriched in the Sa-atropisomer of Formula 2.1 provided in step (1).Item 14. Process according to Item 13, wherein step (A) comprises the steps of:(A1) converting the compounds of Formula 2.1 and 2.2 in the racemic mixture of Compound 2 into the diastomeric salts A and B, wherein salt A is the salt of the compound of Formula 2.1 and salt B is the salt of the compound of formula 2.2,(A2) separating salts A and B, and(A3) converting salt A back to the compound of Formula 2.1 , thereby obtaining the Compound 2 that is atropisomerically enriched in the Sa-atropisomer of Formula 2.1.Item 15. Process according to Item 14, wherein step (A1) is performed by reacting the compounds of Formula 2.1 and 2.2 in the racemic mixture of Compound 2 with (S,S)- di-p-anisoyltartaric acid.Item 16. Process according to Item 14 or 15, wherein step (A2) is performed by filtration.Item 17. Process according to any one of Items 14 to 16, wherein step (A3) is performed by reacting salt A with a base, preferably K2CO3.Item 18. Process according to any one of Items 13 to 17, further comprising a step of recycling Compound 2 that is atropisomerically enriched in the Ra-atropisomer of Formula 2.2 to the process.Item 19. Process according to Item 18, wherein said step of recycling comprises the conversion of Compound 2 that is atropisomerically enriched in the Ra- atropisomer of Formula 2.2 into a racemic mixture of Compound 2, and subjecting the thus-obtained racemic mixture of Compound 2 to step (A).Item 20. Process according to Item 19, wherein said conversion is performed by converting salt B as obtained in step (A2) to the compound of Formula 2.2, followed by a racemization of the thus obtained compound of Formula 2.2, thereby producing a racemic mixture of Compound 2.Item 21. Process according to Item 20, wherein said conversion of salt B to the compound of Formula 2.2 is performed by reacting salt B with a base, preferably K2CO3.Item 22. Process according to Item 20 or 21 , wherein said racemization of the compound of Formula 2.2 is performed by heating the compound of Formula 2.2 above its racemization temperature, preferably to a temperature of 120°C to 140°C.Item 23. Process according to Item 13, wherein step (a) comprises the steps of:(a1) converting the compounds of Formula 1.1 and 1.2 in the racemic mixture of Compound 1 into the diastomeric salts C and D, wherein salt C is the salt of the compound of Formula 1.1 and salt D is the salt of the compound of Formula 1.2,(a2) separating salts C and D, and(a3) converting salt C back to the compound of Formula 1.1 , thereby obtaining the Compound 1 that is atropisomerically enriched in the Sa-atropisomer of Formula 1.1.Item 24. Process according to Item 23, wherein step (a1) is performed by reacting the compounds of Formula 1.1 and 1.2 in the racemic mixture of Compound 1 with (S,S)-di-p-anisoyltartaric acid.Item 25. Process according to Item 23 or 24, wherein step (a2) is performed by filtration.Item 26. Process according to any one of Items 23 to 25, wherein step (a3) is performed by reacting salt C with a base, preferably K2CO3.Item 27. Process according to any one of Items 13 and 23 to 26, further comprising a step of recycling Compound 1 that is atropisomerically enriched in the Ra-atropisomer of Formula 1 .2 to the process.Item 28. Process according to Item 27, wherein said step of recycling comprises the conversion of Compound 1 that is atropisomerically enriched in the Ra- atropisomer of Formula 1 .2 into a racemic mixture of Compound 1 , and subjecting the thus-obtained racemic mixture of Compound 1 to step (a).Item 29. Process according to Item 28, wherein said conversion is performed by converting salt D as obtained in step (a2) to the compound of Formula 1.2, followed by a racemization of the thus obtained compound of Formula 1.2, thereby producing a racemic mixture of Compound 1 .Item 30. Process according to Item 29, wherein said conversion of salt D to the compound of Formula 1.2 is performed by reacting salt D with a base, preferably K2CO3.Item 31. Process according to Item 29 or 30, wherein said racemization of the compound of Formula 1.2 is performed by heating the compound of Formula 1.2 above its racemization temperature, preferably to a temperature of 120°C to 140°C.Item 32. Process according to any one of Items 13 and 22-31 , wherein step (p) is performed by a reaction with methyl iodide.Item 33. Process according to any one of Items 13 and 22-30, wherein step (p) is performed at a temperature below the racemization temperature, preferably room temperature.Item 34. Process according to any one of Items 1 to 33, wherein one or more hydrogens are substituted by deuterium.Item 35. Process for preparing the compound M4076M4076 or a pharmaceutically acceptable salt thereof, wherein the process is characterized in that no or substantially no Compound Z is producedCompound Z.Item 36. Process according to Item 35, wherein “substantially no” refers to an amount of less than 5 wt.%, preferably less than 1 wt.%, more preferably less than 0.5 wt.%, based on the total weight of Compounds M4076 and Z.Item 37. Process according to Item 35 or 36, wherein one or more hydrogens are substituted by deuterium.EXAMPLESPerforming the inventive process

[0074] The inventor has performed and analyzed the reaction process shown in Figure3 in detail. Further details regarding the conditions used for performing each step are described in detail in the experimental section below.ResultsChiral resolution and re-crystallization of Compound 2Table 1*D-(+)-DATA: (S,S)-Di-p-anisoyltartaric acidFree-basing of salt ATable 2Recycling of salt B - Mother liquor concentration and free-basingTable 3- RacemizationTable 4Suzuki couplingTable 5Final crystallizationTable 6Conclusion It was found that the inventive process results in the following advantages over the existing manufacturing process for M4076:- The yield of the desired atropisomer of Formula 2.1 could be increased to more than 69% by recycling the undesired atropisomer of Formula 2.2.- The overall yield over 3 final steps was increased from 8-17.8% to 33% (up to 60% with distomer recycling).- The overall manufacturing process timelines were significantly reduced- A significant cost saving of about 62% was achieved.Table 7ExperimentalSynthesis of Compounds 1 and 2

[0075] Compounds 1 and 2 (as a racemic mixture) can be prepared in accordance with the procedure described in WO 2016 / 155884 and WO 2020 / 193660, the same is illustrated by the following reaction scheme:

[0076] a. Synthesis of 6-bromo-N-(3-fluoro-5-methoxy-4-oyridyl)-7-methoxy-3-nitro- quinolin-4-amineUnder a dry nitrogen atmosphere, a solution of 3-fluoro-5-methoxypyridin-4-amine (447 mg, 3.02 mmol) dissolved in N,N-dimethylformamide (5 ml_) is provided. Then, sodium hydride (504 mg, 12.6 mmol, 60%) is added to the solution and stirring continued for 5 minutes at room temperature. 6-Bromo-4-chloro-7-methoxy-3-nitro-quinoline (800 mg, 2.52 mmol) is then added to the reaction mixture, followed by 15 minutes of stirring at room temperature, then by quenching of the reaction through addition of ice water (100 ml_). The precipitate is filtered off, washed with ice water and dried to give 1.00 g (94 %) 6-bromo- N-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-nitro-quinolin-4-amine as a yellow solid.

[0077] b. Synthesis of 6-bromo-N4-(3-fluoro-5-methoxy-4-oyridyl)-7-methoxy- quinoline-3,4-diamine6-Bromo-N-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-nitro-quinolin-4-amine (990 mg, 2.20 mmol) dissolved in methanol (100 ml_) is provided under a protective nitrogenatmosphere. Then, Raney-Ni (100 mg, 1.17 mmol) is added to the solution, and the reaction mixture is stirred for 30 minutes under a hydrogen atmosphere at normal pressure. After introducing nitrogen, the suspension is filtered and the filtrate dried under vacuum. The filtrate is evaporated to dryness under vacuum. The residue is crystallized from a mixture of ethyl acetate / petroleum ether, yielding 0.86 g (99 %) 6-bromo-N4-(3- fluoro-5-methoxy-4-pyridyl)-7-methoxy-quinoline-3,4-diamine as a yellow solid.

[0078] c. Synthesis of 8-bromo-1-(3-fluoro-5-methoxy-4-oyridyl)-7-methoxy- 1 H,2H,3H-imidazo[4,5-c]quinolin-2-one (racemic mixture of Compound 1)A solution of 6-bromo-N4-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxyquinoline-3,4-diamine (0.85 g, 2.20 mmol) dissolved in tetrahydrofuran (20 ml_) is provided. Then, 1,1'- carbonyldiimidazole (1.84 g, 11.3 mmol) and Hunig's-base (1.46 g, 11.3 mmol) were added. The reaction mixture is heated to 40°C and stirred for 16 hours. The reaction is then quenched by the addition of ice water (200 m L) . The precipitate is filtered off, washed with ice water and dried to give 0.87 g (94 %) 8-bromo-1-(3-fluoro-5methoxy-4-pyridyl)-7- methoxy-1 H,2H,3H-imidazo[4,5-c]quinolin-2-one as a light yellow solid.

[0079] d. Synthesis of 8-bromo-1-(3-fluoro-5-methoxy-4-oyridyl)-7-methoxy-3-methyl- 1 H,2H,3H-imidazo[4,5-c]quinolin-2-one (racemic mixture of Compound 2)In a dry protective nitrogen gas atmosphere, 8-bromo-1-(3-fluoro-5methoxy-4-pyridyl)-7- methoxy-1 H,2H,3H-imidazo[4,5-c]quinolin-2-one (0.86 g, 1.94 mmol) dissolved in N,N- dimethylformamide (5 ml_) is provided. Then, sodium hydride (388 mg, 9.71 mmol, 60%) and methyl iodide (2.76 g, 19.4 mmol) were added. The reaction mixture is stirred for 10 minutes at room temperature. Then the reaction is quenched by the addition of ice water (100 mL). The resulting precipitate is filtrated and dried under vacuum to give 0.70 g (80%) 8-bromo-1-(3-fluoro-5-methoxy-4-pyridyl)-7-methoxy-3-methyl-1 H,2H,3H-imidazo[4,5- c]quinolin-2-one as a light yellow solid.HPLC Chiral Chromatoaraphv of Compound 2 and crystal structure of compound ofFormula 2.1 and 2.2

[0080] The following equipment was used:- HPLC Alliance 2695 (Waters)- 2487 Dual Wavelength detector (Waters)Empower Software 2 (Waters)

[0081] The following operating conditions were used:- Chromatographic column: Cellulose SC 5 pm 150 x 4.6 mm (YMC) or equivalent- Wavelength: 260 nm- Injection volume: 10 pL- Column temperature: 25 ± 5 ° C- Self-sampling temperature: 25 ± 5 ° C- Chromatographic run time: from 13 to 20 minutes- Mobile phase flow: 1 .0 mL / min- Mobile Phase Composition: H2O / ACN 50 / 50 Isocratic

[0082] The chromatogram is shown in Figure 1 .

[0083] The two peaks were then separated via preparative HPLC chiral chromatography.

[0084] The following equipment was used:- HPLC: Waters 2525, Binary Gradient Module- Detector: Waters 2487, Dual wavelength Absorbance Detector- Software: MassLinx

[0085] The following operating conditions were used:- Chromatographic column: Cellulose SC 5 pm 150 x 10mm (Chiral Art)- Wavelength: 260 nm- Injection volume: 2 mL- Column temperature: 25 ± 5 ° C.- Chromatographic run time: 30 minutes- Mobile phase flow: 5.0 mL / min- Mobile Phase Composition: H2O / ACN 30 / 70 Isocratic

[0086] The HPLC fractions collected for Peak 1 (Compound 2.2) and Peak 2 (Compound 2.1) were concentrated under vacuum conditions to obtain a yellow solid and a white solid respectively with HPLC purities suitable to apply the single crystal X-Ray Diffraction and to assign the atropoisomeric structure to each isolated peak.

[0087] The X-ray measurement was performed at 130.0(5) K on a Bruker D8 venture Photonll diffractometer equipped with an INCOATEC I p S micro-focus source (CuKa, A =1.54178 A) and a mirror monochromator. A total of 8578 frames were collected with Bruker APEX3 program. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm.

[0088] Both measured samples of Peak 1-distomer and Peak 2-eutomer were very good, not twinned single crystals. It was found that the sample Peak 1 is a Ra (P) atropisomer whereas the sample Peak 2 corresponds to a Sa (M) atropisomer. The crystal data and final refinement parameters are listed in the table below:Table 8Thermal stability

[0089] As described above, in the existing manufacturing process of M4076, Compound 2 (as a racemic mixture) reacts with a boronic ester at high temperature in a dioxane / water mixture to form the racemic mixture of the drug substance:

[0090] In order to check the thermal stability of the compounds of Formula 2.1 and 2.2 and to exclude that they undergo racemization, thus returning to a racemic mixture of Compound 2, two separate Suzuki coupling reactions using the conditions of the existing manufacturing process (Pd(PPh3)4, K2CO3, dioxane / water, 90 °C, about 35 hours) were carried out starting from Compounds 2.1 and 2.2, respectively.

[0091] First, it was found that the compound of Formula 2.1 reacts with the boronic ester to give directly the M4076 drug substance, while the compound of Formula 2.2 gave its distomer.

[0092] Furthermore, the thermal stability of the M4076 drug substance and its distomer in the dioxane / water mixture at 90-95°C was checked. After more than 24 hours, no racemization was observed. However, a slight decrease of the chiral purity of the isolated M4076 drug substance was observed after the 35 hours.

[0093] Therefore, a temperature screening to monitor the chiral stability of the compound of Formula 2.1 and M4076 during the Suzuki coupling was carried out and the results are summarized in the table below:Table 9

[0094] It can be seen that at the conditions used in the existing manufacturing process, the compound of Formula 2.1 and M4076 tend to racemize. However, the compound of Formula 2.1 and M4076 were relatively stable at 70°C and 75°C, respectively.

[0095] Therefore, the reaction conditions of the Suzuki coupling were optimized accordingly.

[0096] Three main reaction components were screened in order to reduce the reaction temperature and the reaction duration for increasing chiral stability: the catalyst, the base and the solvent, as summarized in the table below:Table 10

[0097] It was surprisingly found that by modifying the catalyst, the base and the solvent used in the Suzuki coupling, it was possible to carry out the reaction at 68-70°C versus 90°C and to reach the completeness of the reaction in 2 hours versus > 35 hours. This is a significant improvement, both in terms of chiral stability and energy and time consumption during the process.Suzuki coupling

[0098] The Suzuki coupling reaction for converting the compound of Formula 2.1 into M4076 was performed as follows:1. Charge CH3CN, the compound of Formula 2.1 , the boronic ester to the reactor at 15-25 °C under a nitrogen flow.2. Bubble a nitrogen flow through the reaction mixture for 30 minutes.3. Charge catalytic amounts of PdCl2(PPh3)2 to the reaction mixture.4. Bubble a nitrogen flow through the reaction mixture for additional 30 minutes.5. Heat the reaction mixture up to 68-70 °C.6. Charge drop-wise an aqueous KOH solution previously bubbled with a nitrogen flow for 1 hour (to the pre-warmed reaction mixture.7. Stir the reaction mixture for two (2) hours at 68-70 °C then cool down to 15-25 °C.8. Charge an aqueous HCI solution dropwise until pH=6-7 at 15-25 °C.9. Concentrate the reaction mixture under vacuum conditions at 45-55 °C 10. Cool down to 15-25 °C.11. Charge an aqueous HCI solution (at 15-25 °C and stir for 0.5h at 15-25 °C.12. Charge EtOAc and stir for 0.5 hour (30 minutes).13. Filter off the solid and wash with an aqueous HCI solution , then settle down the bi-layer system for at least 30 minutes to allow separation.14. Separate the aqueous layer and charge EtOAc.15. Stir for 30 minutes and then settle down the bi-layer system for at least 30 minutes in order to allow separation.16. Separate the aqueous layers and collect together the aqueous layers.17. Adjusted the pH to 8-9 with an aqueous solution of K2CO3.18. Stir the mixture for 0.5 hour at 15-25 °C and charge DCM.19. Stir for 30 minutes and then settle down the bi-layer system for at least 30 minutes in order to allow separation.20. Separate the organic phase and charge an aqueous solution of NaHSOs21. Stir for 16 h and then settle down the bi-layer system for at least 30 minutes in order to allow separation.22. Separate the organic phase and wash with water.23. Separate the organic phase and filter off.24. Concentrate the DCM solution to 3 V.25. Charge MeOH and concentrate via distillation.26. Charge MeOH and concentrate via distillation.27. Stir for 2 hours at 15-25 °C.28. Filter off and wash the cake with MeOH.29. Dry the isolated solid under vacuum conditions at 65-70 °C (HPLC purity: 99.5%, chiral purity: 99.8%, yield: 90.5%).Equivalent reactions were done with a starting material obtained from a 1strecycle of the mother liquor. The results are summarized in Table 5 above.Chiral resolution of a racemic mixture of Compound 2

[0099] The chiral resolution of the racemic mixture of Compound 2 has been conducted as follows (chiral resolution of a racemic mixture of Compound 1 can be performed accordingly):1. Charge the solvents mixture (CH3CN / H2O) racemic mixture of Compound 2 (1 .0 eq.), and (S,S)-Di-p-anisoyltartaric acid (D-(+) DATA) 1.1 eq.) into a reactor.2. Heat up to 68 °C and stir for 30 minutes to give a clear solution.3. Cool down to 45 °C.4. Charge the seed crystals, and then stir for 2 hours at 45 °C.5. Cool down to 4 °C and stir for 1 hour.6. Cool down to 30 °C and stir for 1 hour.7. Cool down to 15 °C and stir for 15 hours (overnight, at least 3 hours) at 15 °C.8. Filter off and wash the cake with the solvents mixture (CH3CN / H2O) at 10-15 °C.9. Dry the wet cake at 50-60 °C under vacuum conditions for at least four (4) hours.Equivalent reactions were done with a starting material obtained from a 1stand a 2ndrecycle of the mother liquor. The results are summarized in Table 1 above.Re-crystallization

[0100] The re-crystallization of Salt A (obtained in the reaction described in the previous section) has been conducted as follows:10. Charge the solvents mixture (CH3CN / H2O) and Salt A into a reactor. 11. Heat up to 68-70 °C and stir for 30 minutes to give a clear solution.12. Cool down to 60 °C and charge the seed crystals and then stir for 1 hour.13. Cool down to 50 °C and stir for 1 hour.14. Cool down to 30 °C and stir for 1 hour.15. Cool down to 10 °C and stir for at least 3 hours. 16. Filter off and wash the cake with the solvents mixture (CH3CN / H2O) at 10 °C. Dry the wet cake at 50-60 °C under vacuum conditions for at least 6 hoursRe-crystallization of Salts B, C, and D can be performed accordingly.Equivalent reactions were done with a starting material obtained from a 1stand a 2ndrecycle of the mother liquor. The results are summarized in Table 1 above.Free-basing of salt A

[0101] The conversion of salt A back to the compound of Formula 2.1 was conducted as follows:1 . Charge water and the salt A into a reactor at 15-25 °C. 2. Charge an aqueous K2CO3 solution dropwise at 15-25 °C.3. Stir overnight (~16 h) at 15-25 °C.4. Filter off and wash the cake with water for two times.Dry the wet cake at 50-60 °C under vacuum conditions for at least 6 hoursEquivalent reactions were done with a starting material obtained from a 1stand a 2ndrecycle of the mother liquor. The results are summarized in Table 2 above.of salt B

[0102] The recycling of salt B involves (1) mother liquor concentration & free-basing, and (2) racemization. These steps are now described in more detail.Mother liquors concentration & free-basinq1. Concentrate the mother liquor solution under vacuum conditions.2. Charge water to reactor at 15-25 °C.3. Charge an aqueous K2CO3 solution dropwise to reactor at 15-25 °C.4. Stir overnight (~14 h) at 15-25 °C.5. Filter off and washed the cake with water for two times.6. Dry the wet cake at 50-60 °C under vacuum conditions for at least eight (8) hours.Equivalent reactions were done with the mother liquor generated in the 1strecycle as a starting material. The results are summarized in Table 3 above.Racemization to obtain racemic mixture of Compound 27. Charge 1 -pentanol and the compound of Formula 2.2 into a reactor.8. Heat up to 128-135 °C.9. Stir for 10 hours.10. Sample for I PC (In-Process Control).11 . Cool down to 20 °C in 4 hours.12. Stir for 2 hours at 15-25 °C.13. Filter off and washed the cake with MeOH.14. Dry the wet cake at 50-60 °C under vacuum conditions for at least six (6) hours.Equivalent reactions were done with the compound of Formula 2.2 obtained in the 2ndrecycle. The results are summarized in Table 4 above.Final crystallization1. Charge 2-PrOH and M4076 anhydrate form to the reactor.2. Heat the reaction mixture to reflux to obtain a clear solution.3. Cool down to 70 °C. 4. Add seed crystals at 70 °C5. Hold the reaction mixture after seeding at 70 °C for 10 mins.6. Cool down from 70 °C to 5 °C.7. Stir the suspension at 5 °C for 3 hours.8. Filter off and wash the cake with 2-PrOH. 9. Dry the cake under vacuum conditions at 65-70 °C for at least 6 hoursThe results are summarized in Table 6 above.

Claims

Claims1. Process for preparing the Compound M4076M4076 or a pharmaceutically acceptable salt thereof, characterized in that the process comprises the following steps:(1) providing a Compound 2Compound 2, wherein the Compound 2 is atropisomerically enriched in the Sa-atropisomer of Formula 2.1Formula 2.1 and(2) converting said Compound 2 that is atropisomerically enriched in the Sa- atropisomer of Formula 2.1 into M4076.

2. Process according to claim 1 , wherein the enantiomeric excess (ee) of the Sa- atropisomer of Formula 2.1 is at least 20%, preferably at least 30%, more preferably at least 40%, even more preferably at least 40%, even more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98%, even more preferably at least 99%, wherein the enantiomeric excess ee is calculated according to the following formula: ee = [(I m2.i - m2 21) I (m2.i + m2 2)] * 100%, wherein mu is the weight of the compound of Formula 2.

1. and m2 2is the weight of the compound of Formula 2.2.

3. Process according to any one of the preceding claims, wherein step (2) is performed at a temperature below the racemization temperature of the compound of Formula 2.1 and of M4076, preferably at a temperature of 75°C or less, preferably at a temperature of 73°C or less, more preferably at a temperature of 70°C or less, more preferably at a temperature of 65°C to 70°C, more preferably at a temperature of 68°C to 70°C.

4. Process according to any one of the preceding claims, wherein step (2) is performed at a temperature of 68°C to 70°C and a duration of less than 3 hours.

5. Process according to any one of the preceding claims, wherein the process comprises:(i) a step (A) performed prior to step (1), wherein step (A) is a chiral resolution step of separating a racemic mixture of Compound 2 into (a) a Compound 2that is atropisomerically enriched in the Sa-atropisomer of Formula 2.1 , thereby obtaining the Compound 2 provided in step (1), and (b) a Compound2 that is atropisomerically enriched in the Ra-atropisomer of Formula 2.2(ii) steps (a) and (p) performed prior to step (1), wherein step (a) is a chiral resolution step of separating a racemic mixture of Compound 1Compound 1 into (a) a Compound 1 that is atropisomerically enriched in the Sa- atropisomer of Formula 1 .1Formula 1.1 ,and (b) a Compound 1 that is atropisomerically enriched in the Ra- atropisomer of Formula 1 .2Formula 1.2, and step (p) is a step of converting the Compound 1 that is atropisomerically enriched in the Sa-atropisomer of Formula 1.1 into the Compound 2 that is atropisomerically enriched in the Sa-atropisomer of Formula 2.1 provided in step (1).

6. Process according to claim 5, wherein step (A) comprises the steps of:(A1) converting the compounds of Formula 2.1 and 2.2 in the racemic mixture of Compound 2 into the diastomeric salts A and B, wherein salt A is the salt of the compound of Formula 2.1 and salt B is the salt of the compound of formula 2.2,(A2) separating salts A and B, and(A3) converting salt A back to the compound of Formula 2.1 , thereby obtaining the Compound 2 that is atropisomerically enriched in the Sa-atropisomer of Formula 2.1.

7. Process according to any one of claims 5-8, further comprising a step of recycling Compound 2 that is atropisomerically enriched in the Ra-atropisomer of Formula 2.2 to the process.

8. Process according to claim 7, wherein said step of recycling comprises the conversion of Compound 2 that is atropisomerically enriched in the Ra-atropisomer of Formula 2.2 into a racemic mixture of Compound 2, and subjecting the thus- obtained racemic mixture of Compound 2 to step (A).

9. Process according to claim 5, wherein step (a) comprises the steps of:(a1) converting the compounds of Formula 1.1 and 1.2 in the racemic mixture of Compound 1 into the diastomeric salts C and D, wherein salt C is the salt of the compound of Formula 1 .1 and salt D is the salt of the compound of Formula 1 .2,(a2) separating salts C and D, and(a3) converting salt C back to the compound of Formula 1.1 , thereby obtaining the Compound 1 that is atropisomerically enriched in the Sa-atropisomer of Formula 1.1.

10. Process according to claim 9, wherein step (a1) is performed by reacting the compounds of Formula 1.1 and 1 .2 in the racemic mixture of Compound 1 with (S,S)- di-p-anisoyltartaric acid.

11. Process according to any one of claims 5, 9, and 10, further comprising a step of recycling Compound 1 that is atropisomerically enriched in the Ra-atropisomer of Formula 1.2 to the process.

12. Process according to claim 11 , wherein said step of recycling comprises the conversion of Compound 1 that is atropisomerically enriched in the Ra-atropisomer of Formula 1.2 into a racemic mixture of Compound 1 , and subjecting the thus- obtained racemic mixture of Compound 1 to step (a).

13. Process for preparing the compound M4076M4076 or a pharmaceutically acceptable salt thereof, wherein the process is characterized in that no or substantially no Compound Z is producedCompound Z.

14. Process according to claim 13, wherein “substantially no” refers to an amount of less than 5 wt.%, preferably less than 1 wt.%, more preferably less than 0.5 wt.%, based on the total weight of Compounds M4076 and Z.

15. Process according to any one of the preceding claims, wherein one or more hydrogens are substituted by deuterium.

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