WO2018046681A1 - Forms of 5-{[(1s,2s)-1-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1h-quinolin-2-one - Google Patents

Abstract

This present invention relates to forms of 5-{[(1S,2S)-1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one comprising its Modification I, Modification II, the Monohydrate and the amorphous form as well as processes for making those forms.

Description

Forms of 5-{raS,2S)-l- -Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hvdroxy-2- fmethoxymethyl)propyllamino}-7-fluoro-lH- uinolin-2-one

Specification

The present invention relates to specific forms of the chemical compound 5-{[(lS,2S)-l-(2- Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxy-methyl)propyl]- amino}-7-fluoro-lH-quinolin-2-one of the formula (I):

(I)

Moreover, the present invention relates to a process for preparing the respective forms of the compound of the formula (I) and the use of these forms of the compound of the formula (I) in pharmaceutical app lications .

WO 2009/065503 A discloses non-steroidal selective glucocorticoid receptor agonists (SEGRAs) in form of e.g. the compound of formula (I), their synthesis and their potential use as agents for the prophylaxis and/or treatment of inflammatory disorders, especially inflammatory dermato logical diseases. The present invention relates to new forms of 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4- methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-lH- quinolin-2-one of the formula (I) (in the following as referred to compound of the formula (I).

Surprisingly it has been found that the compound of formula (I) crystallizes in two modifications with different X-ray powder diffraction patterns (in the following as referred to Modification I and Modification II) and in one monohydrate form (in the following as referred to Monohydrate). These new forms (Modification I, Modification II and Monohydrate) are covered by the present invention. The amorphous form of the compound of the formula (I) is known from WO 2009/065503 A, example 5. Example 5 is disclosed as racemate and it can be purified by chiral HPLC Chiralpak IC 5 μιη with Hexane/Ethanol (4 : 1) as eluent. The diastereomers can be separated by column chromatography or by cristallisation. In the context of the present invention, modifications and polymorphs have the same meaning.

All together - modifications or polymorphs, hydrates and amorphous forms - are different forms of the compound of formula (I) according to the present invention.

In the present invention, the Modification I, the Modification II and the Monohydrate of the compound of the formula (I) as well as pharmaceutical formulations comprising at least one of these forms of the compound of the formula (I) and their use in pharmaceutical applications are described and claimed.

In the following, the different forms of the compound of the formula (I) - Modification I, Modification II and Monohydrate - are described.

Modification I, Modification II and Monohydrate These different forms of the compound of formula (I) can be distinguished by X-ray powder diffraction or Raman-Spectroscopy:

Figure 1 : X-Ray powder diffractogram of the Modification I Figure 2: Raman-Spectrum of Modification I Figure 3: X-Ray powder diffractogram of the Modification II Figure 4: Raman-Spectrum of the Modification II

Figure 5: X-Ray powder diffractogram of the Monohydrate Figure 6: Raman-Spectrum of the Monohydrate Figure 7: Raman-Spectrum of the amorphous form

The absolute configuration of the Monohydrate form has been determined to be (1S,2S). Figure 8: absolute 3D structure of Monohydrate form Figure 9: Ortep-Plot (50 %) with labeling scheme, Monohydrate form

Figure 10: independent molecules of Monohydrate form of asymmetric unit

Figure 11 : configuration of C7A of Monohydrate form (C7A corresponds to benzylic carbon bearing the amino substituent)

Figure 12: configuration of C8A of Monohydrate form (C8A corresponds to carbon bearing the hydroxy substituent)

Figure 13: configuration of C7B of Monohydrate form (C7B corresponds to benzylic carbon bearing the amino substituent) Figure 14: configuration of C8B of Monohydrate form (C8B corresponds to carbon bearing the hydroxy substituent)

Figure 15: configuration of C7C of Monohydrate form (C7C corresponds to benzylic carbon bearing the amino substituent)

Figure 16: configuration of C8C of Monohydrate form (C8C corresponds to carbon bearing the hydroxy substituent)

Modification I:

The compound of formula (I) in the Modification I can be characterized unambiguously by a X- Ray powder diffractogram, comprising peak maxima of the 2 Theta angle of 5.0, 12.2, 13.1, 17.2, 17.9, 19.3, 21.7, and 26.0 (Figure 1).

The compound of formula (I) in the Modification I can be characterized unambiguously by a Raman spectrum, comprising band maxima at a wave number of 3107, 3081, 1400, 1557, 1030, 296, 265, and 116, preferably by band maxima at a waver number of 3107, 3081, and 1400 cm^"1 (Figure 2). The compound of the formula (I) comprises an amount of solvent in general less than 2.5 wt.-%, more general less than 1.75 wt.-%, much more general less than 1.2 wt.-%, based on the weight of the compound of the formula (I). The compound of the formula (I) in form of Modification I thus prepared by the procedure mentioned below, comprising steps (1) to (7) comprises an amount of solvent in general less than 2.5 wt.-%, more general less than 1.75 wt.-%, much more general less than 1.2 wt.-%, based on the weight of the compound of the formula (I), especially up to 0,5 wt% EtOAc and cyclohexane not detected, especially up to 0,4 wt% EtOAc and cyclohexane not detected, especially preferably up to 0.1% EtOAc and no cyclohexane detectable, especially up to detection limit.

Modification II:

The compound of formula (I) in the Modification II can be characterized unambiguously by a X- Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 9.7, 10.4, 14.1, 16.9, 19.1, 20.0, 21.5, and 23.6 (Figure 3).

The compound of formula (I) in the Modification II can be characterized unambiguously by a Raman spectrum comprising band maxima at a wave number of 3099, 3072, 3036, 2954, 1624, 1394, 1022, 808, 190, 137, and 121 cm^"1, preferably by band maxima at a wave number of 3099, 2954, and 1394 cm^"1 (Figure 4). Monohydrate:

The Monohydrate of the compound of formula (I) can be characterized unambiguously by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 11.8, 13.4, 15.6, 15.8, 17.1, 19.9, 20.7, and 24.4 (Figure 5).

The Monohydrate of the compound of formula (I) can be characterized unambiguously by a Raman spectrum comprising band maxima at a wave number of 3096, 2972, 1472, 1402, 1336, 1310, 1024, 840, 800, 679, and 134 cm^"1, preferably by band maxima at a wave number of 3096, 2972, and 1402 cm^"1 (Figure 6).

Anhydrous form:

Only for reference information, the amorphous form of the compound of formula (I) can be characterized unambiguously by a Raman spectrum comprising band maxima at a wave number of 3090, 2948, 1469, 1397, 1027, 855, and 128 cm-1, preferably by band maxima at a wave number of 3090, 2948, and 1397 cm ¹ (Figure 7).

Aspects of some embodiments of the present invention which may be beneficial in the present pharmaceutical field may include for the claimed forms of the compound of the formula (I) stability (e.g. pressure stability, chemical stability, storage stability), compatibility over other ingredients, purity, solubility (thermo dynamically, kinetically), crystallization properties, properties regarding isolation during the chemical synthesis and bioavailability of the different forms of the compound of formula (I). Embodiments of the present invention are not only each single form of the compound of the formula (I), which are Modification I, Modification II and the Monohydrate of the compound of the formula (I), but also mixtures comprising one, two or three of the afore-mentioned forms.

Mixtures of Modification I, Modification II and Monohydrate

In a further aspect, the present invention relates to specific mixtures of the forms of the compound of the formula (I) (i.e., specific mixtures of Modification I, Modification II and Monohydrate).

A first mixture according to the present invention comprises preferably only one of the forms selected from the group consisting of Modification I, Modification II and the Monohydrate of the compound of the formula (I) and no significant fractions of another form, e.g. the amorphous form of the compound of the formula (I), for example of another modification or hydrate of the compound of the formula (I).

More preferably, the mixture according to the present invention comprises more than 85 percent by weight, more preferably more than 90 percent by weight, most preferably more than 95 percent by weight, and up to 100 percent by weight, of the compound of the formula (I) in one of the aforementioned forms (Modification I, Modification II or Monohydrate) related to the total amount of all forms of the compound of the formula (I) present in the composition, and no significant fractions of another form of the compound of the formula (I), for example of another modification or hydrate of the compound of the formula (I).

Further preference is given to a mixture, comprising the compound of the formula (I) in the Modification I and no significant fractions of the Modification II or the Monohydrate form of the compound of the formula (I) and the amorphous form of the compound of the formula (I). The mixture preferably contains more than 85 percent by weight, more preferably more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent by weight of the compound of the formula (I) in the Modification I, each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture. Further preference is given to a mixture, comprising the compound of the formula (I) in the Modification II and no significant fractions of the Modification I, the Monohydrate form of the compound of the formula (I) and the amorphous form of the compound of the formula (I). The mixture preferably contains more than 85 percent by weight, more preferably more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent by weight of the compound of the formula (I) in the Modification II, each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture.

Further preference is given to a mixture, comprising the Monohydrate of the compound of the formula (I) and no significant fractions of the Modification I, the Modification II, and the amorphous form of the compound of the formula (I). The mixture preferably contains more than 85 percent by weight, more preferably more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent by weight of the Monohydrate of the compound of the formula (I), each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture.

In the afore-mentioned paragraphs, mixtures might mean pharmaceutical compositions, i.e. compositions comprising the respective form(s) of the compound of the formula (I) (Modification I, Modification II, or Monohydrate) in combination with components of usual pharmaceutical formulations (carriers, additives etc.).

In the above-mentioned mixtures or pharmaceutical compositions one form of the compound of the formula (I) is used alone (i.e., no other form of the compound of the formula (I) is present in a significant amount).

However, in a further aspect of the present invention, mixtures are covered by the present invention which comprises two of the forms of the compound of the formula (I) (Modification I, Modification II or Monohydrate). This mixture of two forms of the compound of the formula (I) can be used, for example, in pharmaceutical applications.

As first mixtures of two forms of the compound of the formula (I), a mixture of the compound of formula (I) in the Modification I and the compound of formula (I) in the Modification II and a combination of the compound of formula (I) in the Modification I and the compound of formula (I) in the Monohydrate form, are preferred. According to this, preference is given to a mixture, comprising

(a) 90 to 99.9 percent by weight of Modification I of the compound of the formula (I); and

(b) 0.1 to 10 percent of Modification II of the compound of the formula (I) and no significant fractions of another form of the compound of the formula (I), each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture.

Further preference is given to a mixture, comprising

(a) 92.5 to 97.5 percent by weight of Modification I of the compound of the formula (I); and (b) 2.5 to 7.5 percent by weight of Modification II of the compound of the formula (I) and no significant fractions of another form of the compound of the formula (I), each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture. Further preference is given to a mixture, comprising

(a) 94 to 96 % by weight of Modification I of the compound of the formula (I); and

(b) 4 to 6 percent by weight of Modification II of the compound of the formula (I) and no significant fractions of another form of the compound of the formula (I), each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture.

Further preference is given to a mixture, comprising

(a) 90 to 99.9 percent by weight of Modification I of the compound of the formula (I); and

(b) 0.1 to 10 percent by weight of Monohydrate of the compound of the formula (I) and no significant fractions of another form of the compound of the formula (I), each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture.

Further preference is given to a mixture, comprising

(a) 92.5 to 97.5 percent by weight of Modification I of the compound of the formula (I); and

(b) 2.5 to 7.5 percent by weight of Monohydrate of the compound of the formula (I) and no significant fractions of another form of the compound of the formula (I), each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture.

Further preference is given to a mixture, comprising (a) 94 to 96 % by weight of Modification I of the compound of the formula (I); and

(b) 4 to 6 percent by weight of Monohydrate of the compound of the formula (I) and no significant fractions of another form of the compound of the formula (I), each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture.

In the afore-mentioned paragraphs, mixtures might mean pharmaceutical compositions, i.e. compositions comprising two respective forms of the compound of the formula (I) (Modification I, Modification II, or Monohydrate) in combination with components of usual pharmaceutical formulations (carriers, additives etc.). In the above-mentioned mixtures or pharmaceutical compositions two forms of the compound of the formula (I) are used alone (i.e., no third or further form of the compound of the formula (I) is present in a significant amount).

In a further aspect of the present invention, mixtures of three forms of the compound of the formula (I) are provided. Accordingly, further preference is given to a mixture, comprising

(a) 90 to 99.9 percent by weight of Modification I of the compound of the formula (I), and

(b) 0.1 to 10 percent of a mixture, comprising Modification II of the compound of the formula (I) and Monohydrate of the compound of the formula (I), each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture. Further preference is given to a mixture, comprising

(a) 92.5 to 97.5 percent by weight of Modification I of the compound of the formula (I), and

(b) 2.5 to 7.5 percent of a mixture, comprising Modification II of the compound of the formula (I) and Monohydrate of the compound of the formula (I), each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture.

Further preference is given to a mixture, comprising

(a) 94 to 96 percent by weight of Modification I of the compound of the formula (I), and

(b) 4 to 6 percent of a mixture, comprising Modification II of the compound of the formula (I) and Monohydrate of the compound of the formula (I), each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture.

The term 'significant fraction' in all embodiments mentioned above shall have the meaning of no more than 10 percent by weight of the mentioned Modifications I or II or Monohydrate of compound of formula (I), preferably no more than 5 percent by weight of the mentioned Modifications I or II or Monohydrate of compound of formula (I), more preferably no more than 2,5 percent by weight of the mentioned Modifications I or II or Monohydrate of compound of formula (I), more preferably no more than 1 percent by weight of the mentioned Modifications I or II or Monohydrate of compound of formula (I), more preferably no more than 0.5 percent by weight of the mentioned Modifications I or II or Monohydrate of compound of formula (I). Process for making the specific forms of compound of formula (I), e.g. Modification I, Modification II and Monohydrate

The specific forms of compound of the formula (I) were obtained by selective crystallization of the compound of formula (I) which in itself can be obtained by the synthetic procedures described in WO 2009/065503 A, e,g, examples 3 and 5, process a).

Accordingly, the claimed invention is also directed to a process for the preparation of the specific forms of the compound of the formula (I), characterized by the following process steps: by either suspending the compound of the formula (I) in acetonitrile, stirring at room temperature and drying the residue in order to obtain Modification (I); or by suspending the compound of the formula (I) in ethanol / water, stirring at room temperature and drying the residue in order to obtain Modification (II); or by suspending the compound of the formula (I) in methanol/water, stirring at room temperature and drying the residue to obtain the Monohydrate.

Typically the compound of formula (I) might be provided in form of the amorphous form. Further a mixture of modifications might be used as starting material, e.g. a mixture of Monohydrate and Modification I might be used as starting material to obtain pure Modification I, e.g. a mixture of Monohydrate and Modification II might be used as starting material to obtain pure Modification II, e.g. Modification I or a mixture of Monohydrate and Modification II might be used as starting material to obtain pure Monohydrate. Relationship between the Modification I, Modification II and Monohydrate

The compound of the formula (I) needs to be provided preferably in a stable form which is the Modification I. This Modification I needs to be prepared preferably with a low level of solvent enclosures for the pharmaceutical application thereof .

One basic problem in this regard is that the Modification I which is the stable modification of the compound of the formula (I) tends to high level solvent enclosures of up to 20 wt.-%.

In order to prepare the Modification I of the compound of the formula (I) with a reduced level of solvent enclosures, drying of the Monohydrate is not an alternative since upon over-drying, which already takes place under mild conditions at room temperature and under a slight vacuum, the Monohydrate transforms into the less stable Modification II. Thus, there is need for an efficient way to prepare the Modification I with low solvent enclosures.

To solve this further problem, The present invention describes a process to obtain the stable modification I with minimal residual solvent levels by a synthetic route via conversion to the Monohydrate of the compound of the formula (I).

The compound of the formula (I) as obtained via the route described in the experimental section of the present invention can be crystallized from a mixture of ethyl acetate (EtOAc) and cyclohexane to give crystals of the Modification I. This crystallization is efficient to isolate the compound in order to reach the required purity profile, however the crystals obtained contain in general up to 15 wt.-% EtOAc and up to 3 wt.-% cyclohexane enclosures.

Prolonged drying of this Modification I at 40°C under a slight vacuum does not remove the solvent enclosures, upon drying the crystals at 80°C, EtOAc levels can be reduced to minimal residual levels, however the cyclohexane value remains in the Modification I of the compound of the formula (I).

Therefore there was a need to provide a novel, effective process to obtain modification I of the compound of the formula (I) in pure form.

Process for making Modification I of compound of formula (I)

However, from these sufficiently dried crystals the Monohydrate form of the compound of the formula (I) can be formed by suspending them in a mixture of methanol (MeOH) and water at ambient temperature in quantitative yield. The respective Monohydrate crystals are free of residual solvents and, thus, it provides a process to remove the cyclohexane.

The Monohydrate form obtained can be transformed into the desired Modification I form by suspending the Monohydrate form crystals in MeOH/water and adding EtOAc. Modification I crystals with a reduced amount of solvent enclosures can be obtained by filtering the compound of the formula (I) out of the suspension and drying at elevated temperatures.

Accordingly, the claimed invention is also directed to a process for the preparation of the compound of the formula (I) in the Modification I with a reduced amount of solvent enclosures, characterized by the following process steps: (1) providing the compound of the formula (I)

(2) crystallization of the compound of the formula (I) from EtOAc/cyclohexane to obtain the compound of the formula (I) in the Modification I with solvent enclosures;

(3) drying the compound of the formula (I) in the Modification I at 60 to 100°C; optionally steps (2) and (3) are repeated up to several times, if undesired diastereomer has to be removed and optionally seeding with pure Modification I form of compound of the formula

(I)

(4) suspending the compound of the formula (I) in the Modification I in MeOH/H₂0, preferably seeding with pure Monohydrate form of compound of the formula (I) and thereby forming the compound of the formula (I) as Monohydrate form in a suspension of

MeOH/H₂0;

(5) isolating the compound of the formula (I) as Monohydrate by filtration to obtain crystals of the compound of the formula (I) as Monohydrate;

(6) re-transformation of the compound of the formula (I) in the Monohydrate form into Modification I by adding EtOAc to a suspension of the Monohydrate form in MeOH/H₂0;

(7) filtering the compound of the formula (I) out of the suspension and drying to obtain the compound in Modification I with a reduced amount of solvent enclosures.

Typically the compound of formula (I) in step (1) might be provided in form of the amorphous form. Typically the modification I, obtained through step (2) contains e.g. up to 15 wt.-% EtOAc and up to 3 wt.-% Cyclohexane.

Typically the the Modification I, obtained through step (3) (after drying) contains less than 5 wt.-% EtOAc and up to 3 wt.-% Cyclohexane, preferably less than 1 wt.-% EtOAc, preferably up to 0,85 wt% cyclohexane, most preferably EtOAc not detected) Typically the the Monohydrate, obtained through steps (4) and (5) contains less than 5 wt.-% EtOAc and up to 3 wt.-% Cyclohexane

The compound of the formula (I) in form of Modification I thus prepared by the above mentioned procedure, comprising steps (1) to (7) comprises an amount of solvent in general less than 2.5 wt- %, more general less than 1.75 wt.-%, much more general less than 1.2 wt.-%, based on the weight of the compound of the formula (I), especially up to 0,5 wt% EtOAc and cyclohexane not detected, especially up to 0,4 wt% EtOAc and cyclohexane not detected, especially preferably up to 0.1% EtOAc and no cyclohexane detectable, especially up to detection limit . In the following, the process steps are described in detail: Process step (1):

The compound of the formula (I) is prepared according to experimental section of the present invention by using basically the technology described in WO 2009/065503 A, see process a), examples 3 and 5 and as described in the experimental part, example 1 of the present specification.

Process step (2):

In process step (2) the compound of the formula (I) obtained by process step (1) is crystallized from a mixture of EtOAc/cyclohexane (1 : 2 to 1 : 3 ratio of volume), ca. 3 to 5 , preferably close to 4 , especially preferred 3,8 fold weight of EtOAc in relation to weight of compound of the formula (I) resulting in the Modification I of the compound of the formula (I). However, the Modification I thus prepared suffers from the disadvantage that the crystals of Modification I contain in general up to 15 wt.-% EtOAc and up to 3 wt.-% cyclohexane enclosures. The presence of remaining solvent in the crystalline modification of the compound of the formula (I) in such a range is of a disadvantage especially for pharmaceutical uses.

Process step (3):

To reduce the amount of solvent in the compound of the formula (I), the compound of the formula (I) in the Modification I is dried at a temperature of 60 to 100°C, preferably at a temperature of 70 to 90°C, more preferably of 75 to 85°C. It is observed that in a closed vessel system the Monohydrate in the next process step (4) does not form if the residual EtOAc level in the Modification I is too high, and therefore the step of drying (process step (3)) is preferred. Preferably, the residual amount of EtOAc after this drying step (3) is less than 5 wt.-%, more preferably the amount is less than 1 wt.-%., to ensure transformation.

The EtOAc as well as the Cylohexane levels are monitored by routine analytical methods, e.g GC headspace.

Process step (4):

In the process step (4), the compound of the formula (I) in Modification I is suspended in MeOH/H₂0, preferably in a 1/1 mixture ratio of volume), ca. 4 to 10, especially preferred ca 6.6 fold weight of MeOH/H₂0 mixture in relation to weight of compound of the formula (I) and thereby forming the compound of the formula (I) as Monohydrate in the suspension of MeOH/H₂0. Preferable, the batch is also seeded with crystals of the Monohydrate form to ensure faster transformation. The transformation occurs preferably in quantitative yield.

Process step (5):

In process step (5) the resulting crystals of the Monohydrate are filtered out of the suspension of step (4); the resulting crystals are substantially free of residual solvents, preferably less than 0.5 wt.-% and, thus, process steps (4) and (5) provides an efficient procedure to remove cyclohexane present in the compound of the formula (I) used as starting material in process step (1).

Process step (6):

The compound of the formula (I) as Monohydrate is suspended in MeOH/H₂0 and can be re- transformed into compounds of the formula (I) in the Modification I by adding a small amount of EtOAc to the suspension in MeOH/H₂0, preferably 1 :1 ratio of volume), ca. 4 to 10 , especially preferred ca 6.6 fold weight of MeOH/H₂0 mixture in relation to weight of compound of the formula (I), . For this re-transformation, amounts of EtOAc preferably in a range of from 20 to 60 wt.-%, more preferably of from 30 to 50 wt.-%, further more preferably of from 35 to 45 wt.-%, each relates to the amounts of crystals in the Monohydrate form, are necessary. The re- transformation proceeds reliably in a time period of less than 24 hours, more preferably less than 18 hours, further more preferably less than 12 hours.

Process step (7):

The compound of the formula (I) in the Modification I is provided by filtering the suspension of process step (6). The resulting modification I crystals contain EtOAc enclosures, which can be removed by drying the batch preferably at a temperature of 60 to 100°C, more preferably at a temperature of 70 to 90°C, further more preferably at a temperature of 75 to 85°C, and preferably under vacuum.

The compound of the formula (I) in Modification I thus prepared comprises an amount of solvent in general less than 2.5 wt.-%, more general less than 1.75 wt.-%, much more general less than 1.2 wt.-%, preferably less than 0.5 wt.-%, preferably no cyclohexane is detectable and EtOAc is contained not more than than 0.4 wt.-% based on the weight of the compound of the formula (I) especially preferably up to 0.1% EtOAc and no cyclohexane detectable, especially up to detection limit.

In summary, the present invention describes a process to obtain the stable modification I without solvent enclosures. As part of this process the compound of the formula (I) as the Monohydrate is formed to remove cyclohexane residues trapped in the crystals. The Monohydrate can be transformed back to Modification I from a suspension in MeOH/H₂0 if a small amount of EtOAc is added. Upon drying the stable modification I without solvent enclosures is obtained.

Pharmaceutical uses:

A compound of the formula (I) might be used in the treatment and/or prophylaxis of the following dermato logical diseases:

Atopic dermatitis (primarily in children)

All forms of eczema, such as, e.g., atopic eczema (primarily in children)

Rashes of any origin or dermatoses

Psoriasis and parapsoriasis groups

Pityriasis rubra pilaris

Erythematous diseases, triggered by different noxae, e.g., radiation, chemicals, burns, etc.

Bullous dermatoses, such as, e.g., autoimmune pemphigus vulgaris, bullous pemphigoid

Diseases of the lichenoid group,

Pruritis (e.g., of allergic origin)

Seborrheal eczema

Rosacea group

Erythema exudativum multiforme

Balanitis

- Vulvitis

Manifestation of vascular diseases

Hair loss such as alopecia areata

Cutaneous lymphoma Another aspect of the invention are forms of compounds of formula (I), Modification I,

Modification II and Monohydrate for use in therapy, especially in dermato logical diseases, especially in inflammatory skin diseases such as psoriasis, atopic dermatitis and allergic contact dermatitis in adults, adolescents, children and infants.

For the therapeutic actions in the above-mentioned pathologic conditions, the suitable dose varies and depends on, for example, the active strength of the compound of general formula I, the host, the type of administration, and the type and severity of the conditions that are to be treated, as well as the use as a prophylactic agent or therapeutic agent.

In addition, the invention provides:

(i) The use of one of the compounds of formula I according to the invention or

mixture thereof for the production of a medication for treating a dermato logical disease;

(ii) A process for treating a dermato logical diseases, said process comprises an

administration of an amount of the compound according to the invention, wherein the amount suppresses the disease and wherein the amount of compound is given to a patient who requires such a medication;

(iii) A pharmaceutical composition for treating a dermato logical diseases, said

treatment comprises one of the compounds according to the invention or mixture thereof and at least one pharmaceutical adjuvant and/or vehicle.

In general, satisfactory results can be expected in animals when the daily doses comprise a range of 1 μg to 100,000 μg of the compound according to the invention per kg of body weight. In the case of larger mammals, for example the human, a recommended daily dose lies in the range of 1 μg to 100,000 μg per kg of body weight. Preferred is a dose of 10 to 30,000 μg per kg of body weight, and more preferred is a dose of 10 to 10,000 μg per kg of body weight. For example, this dose is suitably administered several times daily. For treating acute shock (e.g., anaphylactic shock), individual doses can be given that are significantly above the above-mentioned doses.

Pharmaceutical compositions: This invention also relates to pharmaceutical compositions containing one of the forms of the compound of the formula (I) or a mixture thereof. Respective mixtures with regard to the amounts of the Modification I, Modification II, and Monohydrate are already described above.

These compositions may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of one of the forms of the compound of the formula (I) or a mixture thereof. A pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated. The forms of the compound of the formula (I) of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.

For oral administration, the form of the compound of the formula (I) of the present invention can be formulated into solid or liquid preparations such as solid dispersion, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch. In another embodiment, the form of the compound of the formula (I) of the present invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.

For topical application, formulations in gels, ointments, fatty ointments, creams, pastes, powders, milk and tinctures are possible. The dosage of the compounds of general formula I should be 0.01%-20% in these preparations to achieve a sufficient pharmacological action. The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.

In the following, a preferred formulation being a waterless multi-phase gel system is described (as described in WO / 2007/014563 A for ascrolimus).

The multi-phase gel system comprises an exterior lipid matrix and an interior phase coagulated by means of polymer, which is obtained by a) melting the lipid phase to form a liquid lipid phase, b) mixing and homogenizing swellable polymer or polymer mixture to form a dispersing polymer phase, c) dissolving the compound of the formula (I) in the Modification I, Modification II and/or Monohydrate in the polymer phase, d) combining the polymer phase with the liquid lipid phase and homogenizing the phases and, e) stirring the phase mixture to form a solid gel-like mixture structure of the overall system. It is surprising that the multi-phase gel system described above, which is preferably provided for application and infiltrate of hardly soluble at high concentration and/or hydrolysis-sensitive active ingredient in combination with the substance class of the compounds of the formula (I) in the Modification I, Modification II and/or Monohydrate, has unexpected advantageous properties. So the developed multi-phase gel system with the compound of the formula (I) in the Modification I, Modification II and/or Monohydrate is characterized by an excellent storage- stability over a period of at least 24 months. The physical stability surprisingly outperforms the conventionally ointments and those parallel-developed corresponding cream formulations containing the same active ingredient. In addition, the developed system is characterized by an excellent skin-compatibility. This is especially surprising, because the formulation does not contain insubstantial proportions of solvents such as propylene glycol and propylene carbonate. In studies on homo sapiens, the compatibility was identically good or even better than those of parallel-developed cream formulations containing a significantly small proportion of solvents. In addition, the formulation expectedly exhibits a highly dermal availability in in vitro model in comparison to conventional systems.

In terms of the present invention, a multi-phase gel system is referred to as a system is formed of two or more phases.

A preferred system has a lipid phase which contains skin-compatible lipids. It is particularly preferred that the lipids are selected from petrolatum, paraffin, beeswax, silicone oils and mixtures thereof.

A system is further preferred which contains polymers such as cellulose derivatives, acrylate polymers and their derivatives or mixture. Particularly preferred is also that the cellulose derivative is hydroxypropyl cellulose.

In particular, it is also preferred that the acrylate polymer is cross-linked acrylate.

A system is further preferred that swellable polymers or polymer mixtures are swelled by means of OH-group-containing swelling agents. It is preferred that the swelling agent is multivalent aliphatic alcohols (polyols) having a chain length of up to 3 carbon atoms or mixtures thereof.

In addition, according to the present invention, it is preferred that the polyol is propylene glycol.

It is also preferred that the swelling agent further comprises carbonic acid diester or mixtures of carbonic acid diesters.

Here is particularly preferred that the carbonic acid diester is propylene carbonate.

The system is exceptionally preferred that the polymer phase contains the active ingredients.

Specific embodiments

1. A compound of the formula (I) in the form of Modification I, Modification II, or Monohydrate form or a mixture thereof:

(I)

2. The compound of claim 1, characterized by a X-Ray powder diffractogram, comprising peak maxima of the 2 Theta angle of 5.0, 12.2, 13.1, 17.2, 17.9, 19.3, 21.7, and 26.0 (Modification I). The compound of claim 1, characterized by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 9.7, 10.4, 14.1, 16.9, 19.1, 20.0, 21.5, and 23.6 (Modification II). The compound of claim 1 by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 11.8, 13.4, 15.6, 15.8, 17.1, 19.9, 20.7, and 24.4 (Monohydrate) A mixture, comprising only one of the forms of the compound of formula (I) according to claims 2 to 4 (Modification I, Modification II and Monohydrate) and no significant fraction(s) of another form of the compound of the formula (I). The mixture according to claim 5, characterized in that the mixture comprises more than 85 percent by weight, more preferably more than 90 percent by weight, most preferably more than 95 percent by weight, and up to 100 percent by weight, of the compound of the formula (I) in one of the forms according to claims 2 to 4, related to the total amount of all forms of the compound of the formula (I) present in the composition. The mixture according to claim 5 or 6, characterized in that the mixture comprises the compound of the formula (I) in the Modification I according to claim 2 and no significant fractions of the Modification II or the Monohydrate form of the compound of the formula (I) and the amorphous form of the compound of the formula (I). The mixture according to claim 7, characterized in that the mixture comprises more than 85 percent by weight, more preferably more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent by weight of the compound of the formula (I) in the Modification I according to claim 2, each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture. The mixture according to claim 5 or 6, characterized in that the mixture comprises the compound of the formula (I) in the Monohydrate form according to claim 4 and no significant fractions of the Modification I, the Modification II, and the amorphous form of the compound of the formula (I). The mixture according to claim 9, characterized in that the mixture comprises more than 85 percent by weight, more preferably more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent by weight of the Mono hydrate of the compound of the formula (I) according to claim 4, each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture. A method for the preparation of the compound of the formula (I) in the Modification I according to claim 2, Modification II according to claim 3 or in the Monohydrate form according to claim 4 by either suspending the compound of the formula (I) in acetonitrile, stirring at room temperature and drying the residue in order to obtain Modification (I); or by suspending the compound of the formula (I) in ethanol/ water, stirring at room temperature and drying the residue in order to obtain Modification (II); or by suspending the compound of the formula (I) in methanol/water, stirring at room temperature and drying the residue to obtain the Monohydrate. A pharmaceutical composition, comprising the compound of the formula (I) according to any one of claims 1 to 11 for the treatment and/or prophylaxis of inflammatory dermato logical diseases. A method for preparing the compound of the formula (I) in the Modification I according to claim 2, characterized by the following process steps:

(1) providing the compound of the formula (I);

(2) crystallization of the compound of the formula (I) from EtOAc/cyclohexane to give the compound of the formula (I) in the Modification I with solvent enclosures;

(3) drying the compound of the formula (I) in the Modification I at 60 to 100°C;

(4) suspending the compound of the formula (I) in the Modification I in MeOH/H₂0 and thereby forming the compound of the formula (I) as Monohydrate form in a suspension of MeOH/H₂0;

(5) isolating the compound of the formula (I) as Monohydrate by filtration to result crystals of the compound of the formula (I) as Monohydrate; (6) re-transformation of the compound of the formula (I) in the Monohydrate form into Modification I by adding EtOAc to a suspension of the Monohydrate form in MeOH/H₂0;

(?) filtering the compound of the formula (I) out of the suspension and drying to obtain the compound in Modification I with a reduced amount of solvent enclosures.

14. A method for preparing the compound of the formula (I) in the Modification I according to claim 13, characterized in that in step (2) a mixture of EtOAc/cyclohexane (1 : 2 to 1 : 3 ratio of volume), ca. 3 to 5 , preferably close to 4 , especially preferred 3,8 fold weight of EtOAc in relation to weight of compound of the formula (I) is utilized. 15. A method for preparing the compound of the formula (I) in the Modification I according to claim 13 or 14, characterized in that in step (4) the compound of the formula (I) in Modification I is suspended in MeOH/H₂0, preferably in a 1/1 mixture ratio of volume), ca. 4 to 10, especially preferred ca 6.6 fold weight of MeOH/H₂0 mixture in relation to weight of compound of the formula (I). 16. A method for preparing the compound of the formula (I) in the Modification I according to claim 13, 14 or 15, characterized in that in step (6) compound of the formula (I) as Monohydrate is suspended in MeOH/H₂0 , preferably 1 : 1 ratio of volume), ca. 4 to 10 , especially preferred ca 6.6 fold weight of MeOH/H₂0 mixture in relation to weight of compound of the formula (I),

17. A method for preparing the compound of the formula (I) in the Modification I according to claim 13, 14, 15 or 16, characterized in that in step (6) amounts of EtOAc preferably in a range of from 20 to 60 wt.-%, more preferably of from 30 to 50 wt.-%, further more preferably of from 35 to 45 wt.-%, each relates to the amounts of crystals in the Monohydrate form are used.

18. The compound according to claim 2 with solvent enclosures of less than less than 2.5 wt- %, more general less than 1.75 wt.-%, much more general less than 1.2 wt.-%, based on the weight of the compound of the formula (I).

19. The compound according to claim 18, obtainable by a process according to one of claims

13 to 17.

20. A pharmaceutical composition, comprising the compound of the formula (I) according to any one of claims 1 to l lor 18 or 19 for the treatment and/or prophylaxis of inflammatory dermato logical diseases.

21. A pharmaceutical composition according to claim 20 wherein the disease is selected from the group consisting of psoriasis, atopic dermatitis and allergic contact dermatitis in adults, adolescents, children and infants. 22. A pharmaceutical composition according to claim 20 or 21 wherein the composition is a waterfree multi phase-gel-system characterized in, that it contains a form of 5-{[(lS,2S)-l-(2-Chlor)-3-fiuor-4-methoxyphenyl)-3,3,3-trifiuor-2- hydroxy-2-(methoxymethyl)propyl]amino}-7-fluor-lH-chinolin-2-on of formula I selected from the group consisting of Modification I, Modification II, Monohydrate or amorphous form

, further characterized in, that it contains 70 bis 90 wt.-% lipid phase, further characterized in, that the lipid phase comprises

62.9 to 68.5 wt.-% petrolatum, especially white vaseline;

5 to 13 wt.-% paraffine oil; - 1 to 4 wt.-% bees wax;

5 to 13 wt.-% hard paraffin; and

1 to 4 wt.-% cyclomethicon,

, wherein all wt.-% are in reference to the multi-Phase-gel-system, further charcterized in that the inner gelled Phase comprises 10 to 30 wt.-%, of multi phase-gel-system, further charcterized in that the inner gelled Phase comprises a combination of cross- linked acrylate polymer and hydro xypropylcellulose, further charcterized in that the inner gelled Phase contains

0.1 to 0.3 wt.-%, of cross-linked acrylate polymers, especially Carbomer Copolymer (Pemulen TR-l/TR-2); 0.019 to 0.056 wt.-%, hydro xypropylcellulose;

2.3 to 6.9 wt.-%, propylene carbonate; and

4.61 to 6.93 wt.-%, propylene glycol, wherein all wt.-% are in reference to the multi-Phase- gel-system.

It is also preferred that the lipid phase and the polymer phase contain different active ingredients.

A preferred system further comprises one or more additives which are useful for a topically applicable composition.

Another object of the present invention is the application of the above-mentioned system for preparing a pharmaceutical composition for utilization on skin, the mucous membranes and/or on wound surfaces.

Preferred is the application for manufacturing a human or veterinary medical product, also use for humans and for animals.

Moreover, a process for preparation of a waterless multi-phase gel system consisting of exterior lipid matrix and an interior phase coagulated by means of polymer, wherein the following steps are carried out is also provided: a) melting the lipid phase to form a liquid lipid phase, b) mixing and homogenizing swellable polymers or polymer mixtures to form a dispersing polymer phase, c) dissolving the compound of the formula (I) in the Modification I, Modification II and/or Monohydrate in the polymer phase, d) combining the polymer phase with the liquid lipid phase and homogenizing the phases e) stirring the phase mixture until forming the system of a solid gel-like mixed structure.

In terms of waterless, up to 1% water may be present in the composition. Waterless solvents according to the invention may contain up to 5% water. For example, ethanol used in the present invention may contain up to 4.5% water (azeotrope).

The polymers, which are swellable through OH group, may be selected from acrylate polymers or the mixtures thereof. Several exemplary products from firm Noveon Inc. are referred to as:

Carbopol 934 NF, Carbopol 934P NF, Carbopol 940 NF, Carbopol 97 IP NF, Carbo-pin 71G NF, Carbopol 974P NF, Carbopol 980 NF, Carbopol 981 NF, Carbopol 1342 NF, Carbopol 5984 EP, Pemulen TR-1 NF, Pemulen TR -2 NF, Noveon AA-1 USP, Noveon CA-1 USP and Noveon CA-2 USP.

In the context of the present invention, the term of short chain alcohols refer to mono- to tri valent aliphatic alcohols having up to five carbon atoms. All process steps for producing the compositions according to the present invention can be carried out by means of techniques, which are familiar to the average person skilled in the art. The mixing and homogenizing the components in step b) for producing the dispersing polymer phase can be performed by conventional mixing systems and homogenizers.

The adjustment of the viscosity of the prepared polymer phase can be done for example by heating.

In addition to the already-specified ingredients, composition according to the present invention may comprise further one or more useful additives for application as a topically applicable composition. These additives may be selected, for example, from dyes, odorous substances, preservatives and absorption-supporting agents. Dosage of the pharmaceutical compositions of the present invention:

Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of disorders, by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredient to be administered will generally range from about 0.0001 mg/kg to about 20 mg/kg, and preferably from about 0.001 mg/kg to about 2 mg/kg body weight per day. A unit dosage may contain from about 0.05 mg to about 150 mg of active ingredient, and can be administered one or more times per day. Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

The weight data in the tests and examples which follow are, unless stated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid/liquid solutions are based on each case on the volume. Examples

Methods

X-Ray diffraction patterns were recorded at room temperature using XRD-diffractometers XTert PRO (PANalytical) and STOE STADI-P (radiation Cu K alpha 1, wavelength 1.5406 A). There was no sample preparation. Raman spectra were recorded at room temperature using FT-Raman-spectrometers (model RFS 100 and MultiRam) from Bruker. Resolution was 2 cm^"1. Measurements were perfomed in glass vials or aluminium discs. There was no sample preparation.

IR-ATR-spectra were recorded at room temperature using a FT-IR-spectrometer one with universal diamond ATR device from Perkin-Elmer. Resolution was 4 cm^"1. There was no sample preparation.

Example 1

The compound of the formula (I) in its amorphous form can be obtained starting with 2-chloro-3- fluoro-4-methoxybenzaldehyde (according to example 3 of WO 2009/065503 A), 5-amino-7- fluoro-lH-quinolin-2-one (according to example 3 of WO 2009/065503 A) and the chiral (S)- TFM-epoxide (CAS Nr 130025-34-2) in an identical cascade of reactions as outlined in process a) and examples 3 and 5 described in WO 2009/065503 A, diastereomers can be separated by column chromatography (methanol in dichloromethane 0 to 5%), enantiomers can be separated by chiral chromatography:

HPLC analytical conditions a): column size: 150 x 4.6 mm stationary phase: Chiralpak IC 5 μιη mobile phase: hexane/ethanol 4 : 1 flow rate: 1 mL/min temperature: 25°C detector: uv detection wavelength: 254 nm retention time: 3.76 min

HPLC gPreparative conditions (for the separation of the racemate): column size: 250 x 20 mm stationary phase: Chiralpak IC 5 μιη mobile phase: hexane/ethanol 4 : 1 flow rate: 20 mL/min temperature: room temperature detector: UV detection wavelength: 254 nm retention time: 6.3 min collecting time: 5.9 - 7.0 min purity: 99.6 HPLC analytical conditions b):

Enantiomeric purity ^■performance liquid chromatography

(HPLC)

Chiral phase method

Detection: UV range

Apparatus 1. High performance liquid chromatograph with thermostatically controlled column oven, UV- detector and data evaluation system

2. Stainless steel column

Length: 25 cm

Internal diameter: 4.6 mm

Filling: Chiralpak IC, 5 μιη

Reagents 1. n-Hexane, gradient grade for HPLC

2. 2-Propanol, gradient grade for HPLC

Test solution Dissolve the sample in 2-Propanol in a concentration of 0.5 mg/mL. Eluent A.

Eluent ^Β· n-Hexane

2-Propanol

Flow rate l .O mL/min

Temperature of the column oven

Detection Measuring wavelength:

Detection Bandwidth: 232 nm

6 nm

Injection volume 15

Equilibration time 1 min (at starting conditions)

Eluent composition Mix A and B in volume ratio of 80:20. retention time: Approx.. 12.1 min

Runtime of the chromatogram 31 min

Procedure

The different forms of compound of the formula (I) have been isolated as outlined in the following.

Example 2

Preparation of purified 5-{(lS,2S)-[l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro- 2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one (I) in its Modification I

3075 mg (mixture of Mono hydrate and Mod. I) was suspended 15 mL in acetonitrile and stirred at room temperature (25 °C) for one week. The residue was dried at RT and ambient humidity

Example 3 Preparation of 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one of formula (I) in its Modification II 5000 mg (mixture of Monohydrate and Mod. II) was suspended in 12.5 mL ethanol/water 1 : 1 and stirred at room temperature for two days. The residue was dried at room temperature and ambient humidity followed by drying in a vacuum-drying oven for 24 hours at 50°C.

Example 4 Preparation of methyl 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one of formula (I) as Monohydrate

3500 mg of (Mod. I including solvent) was nearly dissolved in 15 mL methanol and precipitated with 15 mL water. This suspension was stirred at room temperature for one week. The residue was dried at room temperature and ambient humidity.

200 mg of (mixture of Monohydrate and Mod. II) was suspended in 0.5 mL ethanol/water or in 0.5 mL methanol/water. This suspension was stirred at room temperature for one week. The residue was dried at room temperature and ambient humidity. Absolute configuration (lS,2S)-was determined and confirmed by Single Crystal X-ray Structure Analysis.

Example 5

Preparation of 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one of formula (I) in its amorphous form.

3300 mg of (Monohydrate) was dissolved in 35 mL methanol under reflux, filtered and precipitated with water. After filtration the residue was filled into a 10 mL ceramic cartridge. One 12 mm ceramic ball was added and the substance was milled in a RETSCH vibration tube mill MM200 for 20 minutes at a frequency of 30 s ¹.]

The spectroscopic data of the three forms of the compound of the formula (I) obtained are as follows: Tab. 1 : Raman bands of the different crystalline forms as well as the amorphous form

Raman Band Maxima [cm ¹]

Mod. I Mod. II Monohydrat Amorphous

3107 3099 3096 3090

3081 3072 3020 3016

3056 3036 3000 2948

2997 2954 2972 2844

2933 2901 2932 1617

2846 2847 2843 1566

2821 1659 2820 1531

1632 1640 1669 1469

1616 1624 1631 1397

1581 1566 1615 1319

1562 1530 1574 1290

1535 1505 1563 1252

1470 1465 1533 1212

1445 1442 1472 1164

1400 1394 1402 1073

1339 1339 1336 1027

1318 1317 1310 968

1257 1283 1283 855

1211 1253 1253 804

1183 1209 1209 759

1169 1189 1180 724

1146 1177 1166 671

1030 1157 1147 663

971 1126 1074 618

886 1080 1055 572

857 1065 1024 507

844 1022 972 432 Raman Band Maxima [cm ¹]

Mod. I Mod. II Monohydrat Amorphous

805 979 900 293

794 961 840 128

763 857 800

747 842 761

676 808 736

665 795 710

617 764 679

578 733 662

512 665 620

466 629 581

435 617 562

418 591 526

355 573 507

296 531 484

265 509 448

116 477 435

433 421

366 407

343 366

304 292

284 282

273 261

254 225

217 134

190 86

137

121

86 Tab. 2: 10 Major Peaks of IR bands of the different crystalline forms as well as the amorphous form

Raman Major Bands Maxima [cm ¹]

Mod. I Mod. II Monohydrate Amorphous

3107 3099 3096 3090

3081 3072 2972 2948

1400 3036 1472 1469

1257 2954 1402 1397

1030 1624 1336 1027

296 1394 1310 855

265 1022 1024 128

116 808 840

190 800

137 679

121 134

Tab. 3: X-Ray powder diffractogram of the different crystalline forms

Reflexes [ Position °2Theta Peak Maxima]

Mod. I Mod. II Monohydrate

5,0 5,2

5,0 9,7 9,6

7,0 10,1 9,9

8,6 10,4 10,4

11,1 11,8 11,8

12,2 13,1 12,6

13,1 13,4 13,4

14,1 14,1 15,6

14,9 14,9 15,8

15,7 15,5 16,1

16,5 16,4 16,5

17,2 16,9 17,1

17,9 17,6 17,7

19,3 18,6 18,8

19,9 19,1 19,9

20,5 19,5 20,7

21,1 20,0 20,9

21,7 20,8 22,1

22,3 21,4 22,6

22,9 21,5 22,9

23,4 23,3 23,5

24,0 23,6 24,4

24,5 24,3 24,8

25,0 24,7 25,4

25,5 25,2 26,1

26,0 26,1 26,6

26,5 26,7 26,8

27,9 27,2 27,6 Reflexes [ Position °2Theta Peak Maxima]

Mod. I Mod. II Monohydrate

28,3 28,4 28,2

28,8 28,7 28,8

29,2 29,1 29,1

30,1 30,2 29,8

30,5 30,7 29,9

31,3 31,5 31,3

32,2 32,4 31,7

32,6 33,0 32,0

33,0 33,7 32,5

33,7 34,2 33,4

34,5 35,6 33,9

34,9 36,2 34,6

35,3 37,8 35,3

36,4 35,7

36,7 36,1

37,1 37,1

37,4

Tab. 4: 10 Major Reflexes of X-Ray powder diffractogram of the different crystalline forms

Mod. I Mod. II Monohydrate

5.0 9.7 11.8

12.2 10.4 13.4

13.1 14.1 15.6

17.2 16.9 15.8

17.9 19.1 17.1

19.3 20.0 19.9

21.7 21.5 20.7

Chirality

H. D. Flack, Acta Cryst, 1983, A39, 876-881

H. D. Flack, G. Bernardinelli, J. Appl. Cryst., 2000, 33, 1143-1148

S. Parsons, H. D. Flack, T. Wagner, Acta Cryst, 2013, B69, 249-259.

After validation by determination of the absolute configuration using CuK_a-radiation from 50 CXHYNZON known compounds, the following conditions are set:

A) Before crystallization and single crystal X-ray structure analysis it must be guaranteed by the customer / chemist that the compound is pure chiral and racemization is excluded.

B) The selected single crystal for structure determination has to be representative for the crystals of the analyzed compound and correspond to a fraction > 5 % of the crystallized sample (in order to avoid impurities). If this is not possible, the statement regarding the absolute configuration is only valid for the examinated crystal. C) The Flack Parameter has to be close to zero and the standard deviation smaller than 0.33. Usually only standard deviations less than 0.15 are accepted. Expected values for the Flack parameter are 0 for correct and +1 for inverted structure.

D) It is recommended, but not necessary to determine the absolute configuration of the same compound using two different crystals or an additional single crystal of the inverted compound.

Experimental The Crystal structure determination was carried out using a diffractometer (Oxford Diffraction, Xcalibur series) equipped with a CCD area detector (model Ruby), a sealed tube with CuKa radiation, osmic mirrors as monochromator and a Cryojet low temperature device (T =110 K). Fullsphere data collection omega and phi scans. Programs used: Data collection and reduction CrysAlis Version (Oxford Diffraction 2013). Crystal structure solution was achieved using direct methods as implemented in SHELXTL Version 6.14 (Bruker AXS, 2003) and visualized using XP program. Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F² using all measured intensities was carried out using the program SHELXTL Version 6.14 (Bruker AXS, 2003). All non hydrogen atoms were refined including anisotropic displacement parameters.

Table 1. Crystal data and structure refinement for Monohydrate Form of compound I.

Identification code Monohydrate form

Empirical formula C21 H20 C1 F5 N2 05

Formula weight 510.84

Temperature 110 K

Wavelength 1.54178 A

Crystal system Monoclinic

Space group P 21

Unit cell dimensions a = 21.2557(3) A ^ 90°.

b = 7.10279(10) A □= 99.8816(13)°.

c = 22.6181(3) A Π= 90°.

Volume 3364.11(8) A³

Z 6 Density (calculated) 1.513 Mg/m³

Absorption coefficient 2.229 mm-¹

F(000) 1572

Crystal size 0.10 x 0.06 x 0.04 mm³

Theta range for data collection 3.134 to 65.647°.

Index ranges -25 < h < 23, -8 < k < 8, -26 < 1 < 14 Reflections collected 21744

Independent reflections 10698 [R(int) = 0.0454]

Completeness to theta = 67.679° 93.9 %

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.91 and 0.85

Refinement method Full-matrix least-squares on F^

Data / restraints / parameters 10698 / 1 / 952

Goodness-of-fit on 1.058

Final R indices [I>2sigma(I)] Rl = 0.0384, wR2 = 0.0903

R indices (all data) Rl = 0.0502, wR2 = 0.0983

Absolute structure parameter 0.007(8)

Extinction coefficient n/a

Largest diff. peak and hole 0.311 and -0.308 e.A^"3

Table 2. Bond lengths [A] and angles [°] for Monohydrate form of compound I

C1(1A)-C(1A) 1.726(5) F(3B)-C(11B) 1.336(6)

F(1A)-C(2A) 1.346(6) F(4B)-C(11B) 1.346(6)

F(2A)-C(11A) 1.347(6) F(5B)-C(14B) 1.371(5)

F(3A)-C(11A) 1.347(6) 0(1B)-C(3B) 1.370(6)

F(4A)-C(11A) 1.334(6) 0(1B)-C(21B) 1.445(7)

F(5A)-C(14A) 1.367(5) O(2B)-C(10B) 1.417(6)

0(1A)-C(3A) 1.368(6) 0(2B)-C(9B) 1.424(6)

0(1A)-C(21A) 1.430(7) 0(3B)-C(8B) 1.417(6)

O(2A)-C(10A) 1.419(6) 0(4B)-C(17B) 1.259(5)

0(2A)-C(9A) 1.422(6) N(1B)-C(12B) 1.374(6)

0(3A)-C(8A) 1.408(6) N(1B)-C(7B) 1.448(6)

0(4A)-C(17A) 1.254(5) N(2B)-C(17B) 1.358(6) N(1A)-C(12A) 1.371(6) N(2B)-C(16B) 1.387(6)

N(1A)-C(7A) 1.445(6) C(1B)-C(2B) 1.382(8)

N(2A)-C(17A) 1.358(6) C(1B)-C(6B) 1.403(7)

N(2A)-C(16A) 1.377(6) C(2B)-C(3B) 1.387(8)

C(1A)-C(2A) 1.385(7) C(3B)-C(4B) 1.381(7)

C(1A)-C(6A) 1.396(7) C(4B)-C(5B) 1.380(7)

C(2A)-C(3A) 1.379(7) C(5B)-C(6B) 1.386(7)

C(3A)-C(4A) 1.374(7) C(6B)-C(7B) 1.535(7)

C(4A)-C(5A) 1.385(7) C(7B)-C(8B) 1.548(6)

C(5A)-C(6A) 1.394(7) C(8B)-C(9B) 1.522(6)

C(6A)-C(7A) 1.523(7) C(8B)-C(11B) 1.548(7)

C(7A)-C(8A) 1.547(7) C(12B)-C(13B) 1.391(7)

C(8A)-C(9A) 1.526(6) C(12B)-C(20B) 1.427(6)

C(8A)-C(11A) 1.547(7) C(13B)-C(14B) 1.382(7)

C(12A)-C(13A) 1.387(7) C(14B)-C(15B) 1.360(7)

C(12A)-C(20A) 1.431(6) C(15B)-C(16B) 1.400(7)

C(13A)-C(14A) 1.390(7) C(16B)-C(20B) 1.405(6)

C(14A)-C(15A) 1.356(7) C(17B)-C(18B) 1.429(7)

C(15A)-C(16A) 1.405(7) C(18B)-C(19B) 1.343(7)

C(16A)-C(20A) 1.413(7) C(19B)-C(20B) 1.443(7)

C(17A)-C(18A) 1.432(7) C1(1C)-C(1C) 1.738(5)

C(18A)-C(19A) 1.346(7) F(1C)-C(2C) 1.350(6)

C(19A)-C(20A) 1.427(7) F(2C)-C(11C) 1.343(6)

C1(1B)-C(1B) 1.730(5) F(3C)-C(11C) 1.347(6)

F(1B)-C(2B) 1.349(6) F(4C)-C(11C) 1.354(6)

F(2B)-C(11B) 1.348(5) F(5C)-C(14C) 1.363(5)

0(1C)-C(3C) 1.365(6) C(5C)-C(6C) 1.398(7)

0(1C)-C(21C) 1.427(6) C(6C)-C(7C) 1.528(7)

O(2C)-C(10C) 1.410(7) C(7C)-C(8C) 1.548(7)

0(2C)-C(9C) 1.411(6) C(8C)-C(9C) 1.519(7)

0(3C)-C(8C) 1.408(6) C(8C)-C(11C) 1.533(8)

0(4C)-C(17C) 1.256(6) C(12C)-C(13C) 1.393(7)

N(1C)-C(12C) 1.378(6) C(12C)-C(20C) 1.429(6)

N(1C)-C(7C) 1.447(6) C(13C)-C(14C) 1.382(7)

N(2C)-C(17C) 1.355(6) C(14C)-C(15C) 1.371(7)

N(2C)-C(16C) 1.379(6) C(15C)-C(16C) 1.404(7) C(1C)-C(2C) 1.378(8; C(16C)-C(20C) 1.408(7) C(1C)-C(6C) 1.392(7 C(17C)-C(18C) 1.442(7) C(2C)-C(3C) 1.383(7; C(18C)-C(19C) 1.355(7) C(3C)-C(4C) 1.390(7 C(19C)-C(20C) 1.425(7) C(4C)-C(5C) 1.384(7

C(3A)-0(1A)-C(21A) 116 7(4) C(9A)-C(8A)-C(7A) 112 8(4)

C(10A)-O(2A)-C(9A) 110 6(4) 0(3A)-C(8A)-C(11A) 108 9(4)

C(12A)-N(1A)-C(7A) 124 0(4) C(9A)-C(8A)-C(11A) 109 2(4)

C(17A)-N(2A)- 125 5(4) C(7A)-C(8A)-C(11A) 109 7(4)

C(2A)-C(1A)-C(6A) 120 3(5) 0(2A)-C(9A)-C(8A) 109 0(4)

C(2A)-C(1A)-C1(1A) 116 4(4) F(4A)-C(11A)-F(3A) 106 6(4)

C(6A)-C(1A)-C1(1A) 123 2(4) F(4A)-C(11A)-F(2A) 105 9(4)

F(1A)-C(2A)-C(3A) 118 7(5) F(3A)-C(11A)-F(2A) 105 9(4)

F(1A)-C(2A)-C(1A) 119 0(4) F(4A)-C(11A)-C(8A) 113 0(4)

C(3A)-C(2A)-C(1A) 122 2(5) F(3A)-C(11A)-C(8A) 113 0(4)

0(1A)-C(3A)-C(4A) 126 6(5) F(2A)-C(11A)-C(8A) 111 8(4)

0(1A)-C(3A)-C(2A) 115 2(4) N(1A)-C(12A)-C(13A) 122 3(4)

C(4A)-C(3A)-C(2A) 118 1(5) N(1A)-C(12A)-C(20A) 118 5(4)

C(3A)-C(4A)-C(5A) 120 2(5) C(13A)-C(12A)- 119 2(4)

C(4A)-C(5A)-C(6A) 122 5(5) C(12A)-C(13A)- 118 3(4)

C(1A)-C(6A)-C(5A) 116 7(5) C(15A)-C(14A)-F(5A) 117 8(4)

C(1A)-C(6A)-C(7A) 122 8(4) C(15A)-C(14A)- 125 7(4)

C(5A)-C(6A)-C(7A) 120 4(4) F(5A)-C(14A)-C(13A) 116 5(4)

N(1A)-C(7A)-C(6A) 113 1(4) C(14A)-C(15A)- 116 3(4)

N(1A)-C(7A)-C(8A) 106 1(4) N(2A)-C(16A)-C(15A) 120 4(4)

C(6A)-C(7A)-C(8A) 113 5(4) N(2A)-C(16A)-C(20A) 118 1(4)

0(3A)-C(8A)-C(9A) 109 2(4) C(15A)-C(16A)- 121 5(4)

0(3A)-C(8A)-C(7A) 106 9(4) 0(4A)-C(17A)-N(2A) 119 6(4)

0(4A)-C(17A)-C(18A) 124 3(4) F(4B)-C(11B)-C(8B) 112 3(4)

N(2A)-C(17A)-C(18A) 116 1(4) F(2B)-C(11B)-C(8B) 111 5(4)

C(19A)-C(18A)- 120 8(4) N(1B)-C(12B)-C(13B) 122 0(4)

C(18A)-C(19A)- 122 0(4) N(1B)-C(12B)-C(20B) 118 7(4)

C(16A)-C(20A)- 117 4(4) C(13B)-C(12B)- 119 2(4)

C(16A)-C(20A)- 119 0(4) C(14B)-C(13B)- 117 9(4) C(19A)-C(20A)- 123 6(4) C(15B)-C(14B)-F(5B) 117 4(4)

C(3B)-0(1B)-C(21B) 116 4(4) C(15B)-C(14B)- 126 0(4)

C(10B)-O(2B)-C(9B) 111 2(4) F(5B)-C(14B)-C(13B) 116 6(4)

C(12B)-N(1B)-C(7B) 124 0(4) C(14B)-C(15B)- 115 9(4)

C(17B)-N(2B)-C(16B) 125 2(4) N(2B)-C(16B)-C(15B) 119 8(4)

C(2B)-C(1B)-C(6B) 120 7(5) N(2B)-C(16B)-C(20B) 118 4(4)

C(2B)-C(1B)-C1(1B) 116 9(4) C(15B)-C(16B)- 121 9(4)

C(6B)-C(1B)-C1(1B) 122 4(4) 0(4B)-C(17B)-N(2B) 118 9(4)

F(1B)-C(2B)-C(1B) 119 8(5) 0(4B)-C(17B)-C(18B) 124 8(4)

F(1B)-C(2B)-C(3B) 118 3(5) N(2B)-C(17B)-C(18B) 116 3(4)

C(1B)-C(2B)-C(3B) 121 8(5) C(19B)-C(18B)- 121 0(5)

0(1B)-C(3B)-C(4B) 125 7(5) C(18B)-C(19B)- 122 0(4)

0(1B)-C(3B)-C(2B) 116 1(5) C(16B)-C(20B)- 118 9(4)

C(4B)-C(3B)-C(2B) 118 2(5) C(16B)-C(20B)- 117 0(4)

C(5B)-C(4B)-C(3B) 119 7(5) C(12B)-C(20B)- 124 1(4)

C(4B)-C(5B)-C(6B) 123 4(5) C(3C)-0(1C)-C(21C) 117 0(4)

C(5B)-C(6B)-C(1B) 116 2(5) C(10C)-O(2C)-C(9C) 113 4(4)

C(5B)-C(6B)-C(7B) 120 9(4) C(12C)-N(1C)-C(7C) 122 4(4)

C(1B)-C(6B)-C(7B) 122 8(4) C(17C)-N(2C)-C(16C) 125 8(4)

N(1B)-C(7B)-C(6B) 111 9(4) C(2C)-C(1C)-C(6C) 121 2(5)

N(1B)-C(7B)-C(8B) 106 5(4) C(2C)-C(1C)-C1(1C) 116 4(4)

C(6B)-C(7B)-C(8B) 113 5(4) C(6C)-C(1C)-C1(1C) 122 3(4)

0(3B)-C(8B)-C(9B) 109 4(4) F(1C)-C(2C)-C(3C) 117 9(5)

0(3B)-C(8B)-C(7B) 106 5(4) F(1C)-C(2C)-C(1C) 120 0(5)

C(9B)-C(8B)-C(7B) 113 4(4) C(3C)-C(2C)-C(1C) 122 1(5)

0(3B)-C(8B)-C(11B) 109 0(4) 0(1C)-C(3C)-C(2C) 116 2(5)

C(9B)-C(8B)-C(11B) 109 2(4) 0(1C)-C(3C)-C(4C) 125 7(5)

C(7B)-C(8B)-C(11B) 109 2(4) C(2C)-C(3C)-C(4C) 118 1(5)

0(2B)-C(9B)-C(8B) 110 2(4) C(5C)-C(4C)-C(3C) 119 3(5)

F(3B)-C(11B)-F(4B) 107 0(4) C(4C)-C(5C)-C(6C) 123 4(5)

F(3B)-C(11B)-F(2B) 106 8(4) C(1C)-C(6C)-C(5C) 116 0(5)

F(4B)-C(11B)-F(2B) 105 3(4) C(1C)-C(6C)-C(7C) 123 3(4)

F(3B)-C(11B)-C(8B) 113 4(4) C(5C)-C(6C)-C(7C) 120 5(4)

N(1C)-C(7C)-C(6C) 111 7(4) C(13C)-C(12C)- 119 5(4) N(1C)-C(7C)-C(8C) 108 1(4) C(14C)-C(13C)- 118 5(4)

C(6C)-C(7C)-C(8C) 112 9(4) F(5C)-C(14C)-C(15C) 118 1(4)

0(3C)-C(8C)-C(9C) 110 1(4) F(5C)-C(14C)-C(13C) 116 6(4)

0(3C)-C(8C)-C(11C) 109 4(4) C(15C)-C(14C)- 125 3(4)

C(9C)-C(8C)-C(11C) 109 2(4) C(14C)-C(15C)- 115 8(4)

0(3C)-C(8C)-C(7C) 107 0(4) N(2C)-C(16C)-C(15C) 119 4(4)

C(9C)-C(8C)-C(7C) 112 0(4) N(2C)-C(16C)-C(20C) 118 2(4)

C(11C)-C(8C)-C(7C) 109 2(4) C(15C)-C(16C)- 122 5(4)

0(2C)-C(9C)-C(8C) 109 2(4) 0(4C)-C(17C)-N(2C) 120 1(4)

F(2C)-C(11C)-F(3C) 106 5(4) 0(4C)-C(17C)-C(18C) 124 0(4)

F(2C)-C(11C)-F(4C) 105 2(4) N(2C)-C(17C)-C(18C) 115 9(4)

F(3C)-C(11C)-F(4C) 106 0(4) C(19C)-C(18C)- 120 4(4)

F(2C)-C(11C)-C(8C) 112 3(4) C(18C)-C(19C)- 121 9(4)

F(3C)-C(11C)-C(8C) 113 5(4) C(16C)-C(20C)- 117 5(4)

F(4C)-C(11C)-C(8C) 112 7(4) C(16C)-C(20C)- 118 3(4)

N(1C)-C(12C)-C(13C) 121 7(4) C(19C)-C(20C)- 124 2(4)

N(1C)-C(12C)-C(20C) 118 8(4)

Table 3. Torsion angles [°] for Monohydrate form of compound I

C(6 A)-C( 1 A)-C(2 A)-F( 1 A) -178.6(4)

Cl( 1 A)-C( 1 A)-C(2 A)-F( 1 A) -0.4(6)

C(6A)-C(1A)-C(2A)-C(3A) -2.2(8)

Cl( 1 A)-C( 1 A)-C(2 A)-C(3 A) 176.0(4)

C(21A)-0(1A)-C(3A)-C(4A) 6.1(8)

C(21A)-0(1A)-C(3A)-C(2A) -175.1(5)

F( 1 A)-C(2 A)-C(3 A)-0( 1 A) -0.2(7)

C(1A)-C(2A)-C(3A)-0(1A) -176.6(5)

F( 1 A)-C(2 A)-C(3 A)-C(4 A) 178.7(5)

C(1A)-C(2A)-C(3A)-C(4A) 2.3(8)

0(1A)-C(3A)-C(4A)-C(5A) 177.2(5)

C(2A)-C(3A)-C(4A)-C(5A) -1.6(8)

C(3A)-C(4A)-C(5A)-C(6A) 0.7(8)

C(2A)-C(1A)-C(6A)-C(5A) 1.3(7)

Cl( 1 A)-C( 1 A)-C(6 A)-C(5 A) -176.8(4)

C(2A)-C(1A)-C(6A)-C(7A) 177.0(4)

C1(1A)-C(1A)-C(6A)-C(7A) - 1.1(7) C(4A)-C(5A)-C(6A)-C(1A) - 0.6(7)

C(4A)-C(5A)-C(6A)-C(7A) - 176.4(5)

C( 12 A)-N( 1 A)-C(7 A)-C(6 A) 76.0(6)

C(12A)-N(1A)-C(7A)-C(8A) - 158.9(4)

C(1A)-C(6A)-C(7A)-N(1A) - 136.6(4)

C(5A)-C(6A)-C(7A)-N(1A) 38.9(6)

C(1A)-C(6A)-C(7A)-C(8A) 102.3(5)

C(5A)-C(6A)-C(7A)-C(8A) -82.1(5)

N(1A)-C(7A)-C(8A)-0(3A) -60.3(5)

C(6A)-C(7A)-C(8A)-0(3A) 64.6(5)

N(1A)-C(7A)-C(8A)-C(9A) 179.7(4)

C(6A)-C(7A)-C(8A)-C(9A) -55.5(5)

N(l A)-C(7A)-C(8A)-C(11 A) 57.7(5)

C(6A)-C(7A)-C(8A)-C(11 A) -177.4(4)

C( 10 A)-0(2 A)-C(9 A)-C(8 A) -178.8(5)

0(3A)-C(8A)-C(9A)-0(2A) 173.3(4)

C(7A)-C(8A)-C(9A)-0(2A) -68.0(5)

C(l 1 A)-C(8A)-C(9A)-0(2A) 54.2(5)

0(3A)-C(8A)-C(11 A)-F(4A) 33.8(5)

C(9A)-C(8A)-C(11 A)-F(4A) 153.0(4)

C(7A)-C(8A)-C(11 A)-F(4A) -82.9(5)

0(3A)-C(8A)-C(11 A)-F(3A) 155.1(4)

C(9A)-C(8A)-C(11 A)-F(3A) -85.7(5)

C(7A)-C(8A)-C(11 A)-F(3A) 38.4(5)

0(3A)-C(8A)-C(11 A)-F(2A) -85.6(5)

C(9A)-C(8A)-C(11 A)-F(2A) 33.6(6)

C(7A)-C(8A)-C(11 A)-F(2A) 157.7(4)

C(7 A)-N( 1 A)-C( 12 A)-C( 13 A) -1.3(7)

C(7 A)-N( 1 A)-C( 12 A)-C(20 A) 176.9(4)

N( 1 A)-C( 12 A)-C( 13 A)-C( 14 A) -179.5(5)

C(20 A)-C( 12 A)-C( 13 A)-C( 14 A) 2.3 (7)

C( 12 A)-C( 13 A)-C( 14 A)-C( 15 A) 0.4(8)

C( 12 A)-C( 13 A)-C( 14 A)-F(5 A) 179.1 (4)

F(5 A)-C( 14 A)-C( 15 A)-C( 16 A) 179.8(4) C( 13 A)-C( 14 A)-C( 15 A)-C( 16 A) -1.6(8)

C( 17 A)-N(2 A)-C( 16 A)-C( 15 A) 177.3(5)

C( 17 A)-N(2 A)-C( 16 A)-C(20 A) -1.8(7)

C( 14 A)-C( 15 A)-C( 16 A)-N(2 A) -179.0(5)

C( 14 A)-C( 15 A)-C( 16 A)-C(20 A) 0.0(7)

C( 16 A)-N(2 A)-C( 17 A)-0(4 A) -179.9(4)

C( 16 A)-N(2 A)-C( 17 A)-C( 18 A) -0.5(7)

0(4 A)-C( 17 A)-C( 18 A)-C( 19 A) -179.2(5)

N(2 A)-C( 17 A)-C( 18 A)-C( 19 A) 1.4(7)

C( 17 A)-C( 18 A)-C( 19 A)-C(20 A) 0.0(8)

N(2 A)-C( 16 A)-C(20 A)-C( 19 A) 3.1(7)

C( 15 A)-C( 16 A)-C(20 A)-C( 19 A) -176.0(5)

N(2 A)-C( 16 A)-C(20 A)-C( 12 A) -178.5(4)

C( 15 A)-C( 16 A)-C(20 A)-C( 12 A) 2.5(7)

C( 18 A)-C( 19 A)-C(20 A)-C( 16 A) -2.3(7)

C( 18 A)-C( 19 A)-C(20 A)-C( 12 A) 179.3(5)

N( 1 A)-C( 12 A)-C(20 A)-C( 16 A) 178.0(4)

C( 13 A)-C( 12 A)-C(20 A)-C( 16 A) -3.7(7)

N( 1 A)-C( 12 A)-C(20 A)-C( 19 A) -3.6(7)

C( 13 A)-C( 12 A)-C(20 A)-C( 19 A) 174.7(5)

C(6B)-C(1B)-C(2B)-F(1B) -178.4(4)

Cl( 1 B)-C( 1 B)-C(2B)-F( 1 B) 0.3(6)

C(6B)-C(1B)-C(2B)-C(3B) -2.2(8)

C1(1B)-C(1B)-C(2B)-C(3B) 176.4(4)

C(21B)-0(1B)-C(3B)-C(4B) -5.0(7)

C(21B)-0(1B)-C(3B)-C(2B) 173.5(5)

F(1B)-C(2B)-C(3B)-0(1B) -0.1(7)

C(1B)-C(2B)-C(3B)-0(1B) -176.3(5)

F( 1 B)-C(2B)-C(3B)-C(4B) 178.5(4)

C( 1 B)-C(2B)-C(3B)-C(4B) 2.3(8)

0(1B)-C(3B)-C(4B)-C(5B) 177.9(5)

C(2B)-C(3B)-C(4B)-C(5B) -0.6(7)

C(3B)-C(4B)-C(5B)-C(6B) -1.3(7)

C(4B)-C(5B)-C(6B)-C(1B) 1.4(7) C(4B)-C(5B)-C(6B)-C(7B) -175.3(4)

C(2B)-C(1B)-C(6B)-C(5B) 0.4(7)

C1(1B)-C(1B)-C(6B)-C(5B) -178.2(4)

C(2B)-C( 1 B)-C(6B)-C(7B) 177.0(4)

Cl( 1 B)-C( 1 B)-C(6B)-C(7B) -1.5(6)

C( 12B)-N( 1 B)-C(7B)-C(6B) 80.3(6)

C( 12B)-N( 1 B)-C(7B)-C(8B) -155.1(4)

C(5B)-C(6B)-C(7B)-N( 1 B) 38.0(6)

C( 1 B)-C(6B)-C(7B)-N( 1 B) -138.5(4)

C(5B)-C(6B)-C(7B)-C(8B) -82.6(5)

C(1B)-C(6B)-C(7B)-C(8B) 100.9(5)

N(1B)-C(7B)-C(8B)-0(3B) -63.7(5)

C(6B)-C(7B)-C(8B)-0(3B) 59.8(5)

N(1B)-C(7B)-C(8B)-C(9B) 175.9(4)

C(6B)-C(7B)-C(8B)-C(9B) -60.5(5)

N(1B)-C(7B)-C(8B)-C(1 IB) 53.9(5)

C(6B)-C(7B)-C(8B)-C(1 IB) 177.5(4)

C(10B)-O(2B)-C(9B)-C(8B) -150.1(4)

0(3B)-C(8B)-C(9B)-0(2B) 169.2(4)

C(7B)-C(8B)-C(9B)-0(2B) -72.0(5)

C(l 1B)-C(8B)-C(9B)-0(2B) 50.0(5)

0(3B)-C(8B)-C(11B)-F(3B) 155.1(4)

C(9B)-C(8B)-C(11B)-F(3B) -85.5(5)

C(7B)-C(8B)-C(11B)-F(3B) 39.0(5)

0(3B)-C(8B)-C(11B)-F(4B) 33.6(5)

C(9B)-C(8B)-C(11B)-F(4B) 153.0(4)

C(7B)-C(8B)-C(11B)-F(4B) -82.5(5)

0(3B)-C(8B)-C(11B)-F(2B) -84.4(4)

C(9B)-C(8B)-C(11B)-F(2B) 35.1(5)

C(7B)-C(8B)-C(11B)-F(2B) 159.6(4)

C(7B)-N( 1 B)-C( 12B)-C( 13B) -3.3(7)

C(7B)-N( 1 B)-C( 12B)-C(20B) 176.2(4)

N(1B)-C(12B)-C(13B)-C(14B) -177.8(5) C(20B)-C(12B)-C(13B)-C(14B) 2.7(7) C(12B)-C(13B)-C(14B)-C(15B) 0.3(8)

C( 12B)-C( 13B)-C( 14B)-F(5B) 178.4(4)

F(5B)-C(14B)-C(15B)-C(16B) -179.0(4)

C(13B)-C(14B)-C(15B)-C(16B) -1.0(8)

C( 17B)-N(2B)-C( 16B)-C( 15B) 177.3(5)

C( 17B)-N(2B)-C( 16B)-C(20B) -2.2(7)

C( 14B)-C( 15B)-C( 16B)-N(2B) 179.0(5)

C(14B)-C(15B)-C(16B)-C(20B) -1.5(7)

C( 16B)-N(2B)-C( 17B)-0(4B) 179.4(4)

C( 16B)-N(2B)-C( 17B)-C( 18B) -2.1(7)

0(4B)-C(17B)-C(18B)-C(19B) -177.8(5)

N(2B)-C( 17B)-C( 18B)-C( 19B) 3.8(7)

C(17B)-C(18B)-C(19B)-C(20B) -1.2(8)

N(2B)-C(16B)-C(20B)-C(12B) - 176.0(4)

C(15B)-C(16B)-C(20B)-C(12B) 4.5(7)

N(2B)-C( 16B)-C(20B)-C( 19B) 4.7(7)

C(15B)-C(16B)-C(20B)-C(19B) -174.8(5)

N( 1 B)-C( 12B)-C(20B)-C( 16B) 175.5(4)

C(13B)-C(12B)-C(20B)-C(16B) -5.0(7)

N( 1 B)-C( 12B)-C(20B)-C( 19B) -5.2(7)

C(13B)-C(12B)-C(20B)-C(19B) 174.3(5)

C(18B)-C(19B)-C(20B)-C(16B) -3.1(7)

C(18B)-C(19B)-C(20B)-C(12B) 177.6(5)

C(6C)-C(1C)-C(2C)-F(1C) -177.9(4)

C1(1C)-C(1C)-C(2C)-F(1C) -0.3(6)

C(6C)-C(1C)-C(2C)-C(3C) 0.0(8)

C1(1C)-C(1C)-C(2C)-C(3C) 177.6(4)

C(21 C)-0( 1 C)-C(3C)-C(2C) 167.7(4)

C(21 C)-0( 1 C)-C(3C)-C(4C) -11.5(7)

F(1C)-C(2C)-C(3C)-0(1C) -0.2(6)

C(1C)-C(2C)-C(3C)-0(1C) -178.2(4)

F(1C)-C(2C)-C(3C)-C(4C) 179.0(4)

C(1C)-C(2C)-C(3C)-C(4C) 1.1(7)

0(1C)-C(3C)-C(4C)-C(5C) 177.5(4) C(2C)-C(3C)-C(4C)-C(5C) -1.7(7)

C(3C)-C(4C)-C(5C)-C(6C) 1.3(7)

C(2C)-C(1C)-C(6C)-C(5C) -0.4(7)

Cl(l C)-C(l C)-C(6C)-C(5C) - 177.9(3) C(2C)-C(1C)-C(6C)-C(7C) 173.9(4)

C1(1C)-C(1C)-C(6C)-C(7C) -3.5(6)

C(4C)-C(5C)-C(6C)-C(1C) -0.2(7)

C(4C)-C(5C)-C(6C)-C(7C) - 174.8(4)

C(12C)-N(1C)-C(7C)-C(6C) 71.7(6) C(12C)-N(1C)-C(7C)-C(8C) -163.4(4)

C(1C)-C(6C)-C(7C)-N(1C) -128.0(5)

C(5C)-C(6C)-C(7C)-N(1C) 46.1(6)

C(1C)-C(6C)-C(7C)-C(8C) 109.9(5)

C(5C)-C(6C)-C(7C)-C(8C) - 76.0(5) N(1C)-C(7C)-C(8C)-0(3C) -65.7(5)

C(6C)-C(7C)-C(8C)-0(3C) 58.4(5)

N(1C)-C(7C)-C(8C)-C(9C) 173.6(4)

C(6C)-C(7C)-C(8C)-C(9C) -62.3(5)

N(1C)-C(7C)-C(8C)-C(11C) 52.5(5) C(6C)-C(7C)-C(8C)-C(11C) 176.6(4)

C(l 0C)-O(2C)-C(9C)-C(8C) - 173.5(6)

0(3C)-C(8C)-C(9C)-0(2C) 175.3(4)

C(11C)-C(8C)-C(9C)-0(2C) 55.2(5)

C(7C)-C(8C)-C(9C)-0(2C) -65.8(6) 0(3C)-C(8C)-C(11C)-F(2C) -84.2(4)

C(9C)-C(8C)-C(11C)-F(2C) 36.4(5)

C(7C)-C(8C)-C(11 C)-F(2C) 159.1 (4)

0(3C)-C(8C)-C(11C)-F(3C) 154.9(4)

C(9C)-C(8C)-C(11C)-F(3C) -84.5(5) C(7C)-C(8C)-C(11C)-F(3C) 38.2(5)

0(3C)-C(8C)-C(11C)-F(4C) 34.5(5)

C(9C)-C(8C)-C(11C)-F(4C) 155.0(4)

C(7C)-C(8C)-C(11C)-F(4C) - 82.2(5)

C(7C)-N(1C)-C(12C)-C(13C) 7.7(7) C(7C)-N( 1 C)-C( 12C)-C(20C) -172.0(4)

N(1C)-C(12C)-C(13C)-C(14C) -178.0(5)

C(20C)-C(12C)-C(13C)-C(14C) 1.6(7)

C(12C)-C(13C)-C(14C)-F(5C) 180.0(4)

C(12C)-C(13C)-C(14C)-C(15C) 1.8(8)

F(5C)-C(14C)-C(15C)-C(16C) -179.9(4)

C(13C)-C(14C)-C(15C)-C(16C) -1.7(8)

C(17C)-N(2C)-C(16C)-C(15C) 175.8(5)

C( 17C)-N(2C)-C( 16C)-C(20C) -4.3(7)

C(14C)-C(15C)-C(16C)-N(2C) 178.1(4)

C(14C)-C(15C)-C(16C)-C(20C) -1.8(7)

C( 16C)-N(2C)-C( 17C)-0(4C) -179.5(4)

C(16C)-N(2C)-C(17C)-C(18C) -0.5(7)

0(4C)-C(17C)-C(18C)-C(19C) -177.9(5)

N(2C)-C(17C)-C(18C)-C(19C) 3.1(7)

C(17C)-C(18C)-C(19C)-C(20C) -0.9(8)

N(2C)-C(16C)-C(20C)-C(19C) 6.3(7)

C(15C)-C(16C)-C(20C)-C(19C) -173.8(5)

N(2C)-C(16C)-C(20C)-C(12C) -175.0(4)

C(15C)-C(16C)-C(20C)-C(12C) 5.0(7)

C(18C)-C(19C)-C(20C)-C(16C) -3.9(7)

C(18C)-C(19C)-C(20C)-C(12C) 177.4(5)

N(1C)-C(12C)-C(20C)-C(16C) 174.9(4)

C(13C)-C(12C)-C(20C)-C(16C) -4.8(7)

N(1C)-C(12C)-C(20C)-C(19C) -6.4(7)

C(13C)-C(12C)-C(20C)-C(19C) 173.9(5 Example 5

Preparation of purified 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro- 2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one (I) in its Modification I with reduced solvent enclosures A) Crystallisation (several recrystallizations were required to remove diastereomer to desired level); optionally this can be done by column chromatography

A crude form of compound of the formula (I) can be prepared in accordance with the experimental procedures described in examples 3 and 5 of WO 2009/065503 A.

1.7 kg of crude material of compound of the formula (I) (54 wt%, 918 g of pure compound of formula (I)) was dissolved in EtOAc (3.5 kg), and cyclohexane (6.14 kg) was charged over a duration of 2 h. It was stirred for 2 hours at 22 °C and the batch was seeded with 9 g of crystals of the modification I of compound of the formula (I) . It was aged for 40 min and additional cyclohexane (3.1 kg) was charged over the duration of 1 h. The suspension was aged for 67 hours and filtered, and the filter cake was washed with cyclohexane/EtOAc (1.9 L, 3 : 1 cyclohexane/EtOAc). The wet filter cake (0.96 kg) was suspended in EtOAc (2.8 kg), heated to reflux and then cooled to 22°C over a period of 2 hours. Cyclohexane (7.4 kg) was charged over the duration of 1 hour and it was aged overnight. It was filtered and the filter cake was washed with cyclohexane/EtOAc (1.5 L, 3: 1 cyclohexane/EtOAc). The wet filter cake (0.98 kg) was suspended in EtOAc (2.7 kg), heated to reflux and then cooled to 22 °C over a period of 2 hours. Cyclohexane (7.1 kg) was charged over the duration of 1 hour and it was aged overnight. It was filtered and the filter cake was washed with cyclohexane/EtOAc (1.2 L, 3: 1 cyclohexane/EtOAc). The product was dried in the drying over under vacuum at 80 °C for 33 hours. The filter cake (0.67 kg) was suspended in EtOAc (2.6 kg), heated to reflux and then cooled to 22 °C over a period of 2 hours. Cyclohexane (6.8 kg) was charged over the duration of 1 hour and it was aged overnight. It was filtered and the filter cake was washed with (1.2 L, 3: 1 6 cyclohexane/EtOAc). The product was dried in the drying over under vacuum at 80 °C for 70 hours. 652 g of the purified product were obtained. (99.3 area-% HPLC, 0,85 wt% cyclohexane, EtOAc not detected, Residual solvent analysis via (headspace-) gas chromatography, on the basis of USP 467, Agilent 6890 gas chromatograph with split-injection and FID. Perkin Elmer Turbomatrix 40 headspace sampler Sample concentration: 20 mg substance in 2 ml DMF). B) Solvent free Modification I via Monohydrate formation

651 g of the compound according to formula (I) in the Modification I (as obtained in example 5, A)) was charged to the vessel, suspended in MeOH/water 1 : 1 (4.31 kg) and aged at 22 °C for 73 hours. It was seeded with Monohydrate form of compound according to formula (I) (1 g) and aged for further 24 hours. It was filtered and the wet filter cake was suspended in MeOH/water 1 : 1 (3.7 kg) and 0.27 kg EtOAc. It was aged for 70 hours and filtered. The product (modification I of compound of formula (I) was dried in the drying over under vacuum at 80 °C for 45 hours. 610 g of the purified product were obtained (0,4 wt% EtOAc, cyclohexane not detected, Residual solvent analysis via (headspace-) gas chromatography, on the basis of USP 467, Agilent 6890 gas chromatograph with split-injection and FID. Perkin Elmer Turbomatrix 40 headspace sampler Sample concentration: 20 mg substance in 2 ml DMF).

Claims

Claims

A compound of the formula (I) in the form of Modification I, Modification II, or Monohydrate form or a mixture thereof:

(I)

2. The compound of claim 1, characterized by a X-Ray powder diffractogram, comprising peak maxima of the 2 Theta angle of 5.0, 12.2, 13.1, 17.2, 17.9, 19.

3, 21.7, and 26.0 (Modification I).

The compound of claim 1, characterized by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 9.7, 10.

4, 14.1, 16.9, 19.1, 20.0, 21.

5, and 23.6 (Modification II).

The compound of claim 1 by a X-Ray powder diffractogram comprising peak maxima of the 2 Theta angle of 11.8, 13.4, 15.

6, 15.8, 17.1, 19.9, 20.

7, and 24.4 (Monohydrate)

A mixture, comprising only one of the forms of the compound of formula (I) according to claims 2 to 4 (Modification I, Modification II and Monohydrate) and no significant fraction(s) of another form of the compound of the formula (I).

The mixture according to claim 5, characterized in that the mixture comprises more than 85 percent by weight, more preferably more than 90 percent by weight, most preferably more than 95 percent by weight, and up to 100 percent by weight, of the compound of the formula (I) in one of the forms according to claims 2 to 4, related to the total amount of all forms of the compound of the formula (I) present in the composition.

The mixture according to claim 5 or 6, characterized in that the mixture comprises the compound of the formula (I) in the Modification I according to claim 2 and no significant fractions of the Modification II or the Monohydrate form of the compound of the formula (I) and the amorphous form of the compound of the formula (I).

8. The mixture according to claim 7, characterized in that the mixture comprises more than 85 percent by weight, more preferably more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent by weight of the compound of the formula (I) in the Modification I according to claim 2, each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture.

9. The mixture according to claim 5 or 6, characterized in that the mixture comprises the compound of the formula (I) in the Monohydrate form according to claim 4 and no significant fractions of the Modification I, the Modification II, and the amorphous form of the compound of the formula (I).

10. The mixture according to claim 9, characterized in that the mixture comprises more than 85 percent by weight, more preferably more than 90 percent by weight, more preferably more than 95 percent by weight, and up to 100 percent by weight of the Monohydrate of the compound of the formula (I) according to claim 4, each related to the total amount of all forms of the compound of the formula (I) (Modification I, Modification II, Monohydrate, and amorphous form of the compound of the formula (I)) present in the mixture.

11. A method for the preparation of the compound of the formula (I) in the Modification I according to claim 2, Modification II according to claim 3 or in the Monohydrate form according to claim 4 by either suspending the compound of the formula (I) in acetonitrile, stirring at room temperature and drying the residue in order to obtain Modification (I); or by suspending the compound of the formula (I) in ethanol/ water, stirring at room temperature and drying the residue in order to obtain Modification (II); or by suspending the compound of the formula (I) in methanol/water, stirring at room temperature and drying the residue to obtain the Monohydrate.

12. A pharmaceutical composition, comprising the compound of the formula (I) according to any one of claims 1 to 11 for the treatment and/or prophylaxis of inflammatory dermato logical diseases.

13. A method for preparing the compound of the formula (I) in the Modification I according to claim 2, characterized by the following process steps:

(1) providing the compound of the formula (I);

(2) crystallization of the compound of the formula (I) from EtOAc/cyclohexane to give the compound of the formula (I) in the Modification I with solvent enclosures;

(3) drying the compound of the formula (I) in the Modification I at 60 to 100°C;

(4) suspending the compound of the formula (I) in the Modification I in MeOH/H₂0 and thereby forming the compound of the formula (I) as Monohydrate form in a suspension of MeOH/H₂0;

(5) isolating the compound of the formula (I) as Monohydrate by filtration to result crystals of the compound of the formula (I) as Monohydrate;

(6) re-transformation of the compound of the formula (I) in the Monohydrate form into Modification I by adding EtOAc to a suspension of the Monohydrate form in MeOH/H₂0;

(7) filtering the compound of the formula (I) out of the suspension and drying to obtain the compound in Modification I with a reduced amount of solvent enclosures.

14. The compound according to claim 2 with solvent enclosures of less than less than 2.5 wt- %, more general less than 1.75 wt.-%, much more general less than 1.2 wt.-%, based on the weight of the compound of the formula (I).

15. The compound according to claim 14, obtainable by a process according to claim 13.