阅读说明：本技术 2-([1,2,3]***-2-基)-苯甲酸衍生物的制备 (Preparation of 2- ([1,2,3] triazol-2-yl) -benzoic acid derivatives ) 是由 帕特里克·德尔韦希特 冈泽尔·施密特 于 2018-05-02 设计创作，主要内容包括：本发明涉及一种用于制备尤其式(I)的2-(2H-[1,2,3]三唑-2-基)-苯甲酸衍生物的方法,涉及式(I<Sub>K</Sub>)的该2-(2H-[1,2,3]三唑-2-基)-苯甲酸衍生物的钾盐的某些结晶形式,涉及式(I)的该2-(2H-[1,2,3]三唑-2-基)-苯甲酸衍生物的某些结晶形式,且涉及其在制备诸如(S)-(2-(5-氯-4-甲基-1H-苯并[d]咪唑-2-基)-2-甲基吡咯烷-1-基)-(5-甲氧基-2-(2H-1,2,3-三唑-2-基)苯基)甲酮的药剂中的用途。<Image he="488" wi="355" file="DDA0002255090400000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a process for the preparation of 2- (2H- [1,2, 3), in particular of formula (I)]Process for triazol-2-yl) -benzoic acid derivatives, involving K ) The 2- (2H- [1,2, 3)]Certain crystalline forms of the potassium salt of a triazol-2-yl) -benzoic acid derivative, to said 2- (2H- [1,2, 3) of formula (I)]Certain crystalline forms of triazol-2-yl) -benzoic acid derivatives, and their use in the preparation of pharmaceutical compositions such as (S) - (2- (5-chloro-4-methyl-1H-benzo [ d ]]Use of imidazol-2-yl) -2-methylpyrrolidin-1-yl) - (5-methoxy-2- (2H-1,2, 3-triazol-2-yl) phenyl) methanone in medicine.)

1. Is used for synthesizing formula (I)_K) 2- (2H- [1,2, 3)]Process for the crystallization of potassium salt of triazol-2-yl) -benzoic acid derivative:

wherein

R¹Represents methoxy and R²Represents hydrogen; or

R¹Represents hydrogen and R²Represents a methyl group;

the process comprises the following coupling:

a compound of formula (II):

and [1,2,3]]Triazole:

wherein the process is carried out in the presence of:

copper (I) iodide (CuI);

an inorganic potash; and

a solvent or solvent mixture of

A water-miscible ether solvent; or

A polar aprotic solvent;

or any mixture thereof;

wherein the solvent or solvent mixture is present in an amount of about 5 to 100 volumes relative to the compound of formula (II);

wherein the coupling of the compound of formula (II) with [1,2,3] triazole is performed at a temperature greater than about 60 ℃;

wherein the formula (I)_K) The crystalline compound is separated from the reaction mixture by solid-liquid separation.

2. The process of claim 1, wherein the process is carried out in the presence of copper (I) iodide; wherein copper (I) iodide is present in an amount of about 0.01 to 0.5 equivalents relative to the compound of formula (II).

3. The process of claim 1 or 2, wherein the inorganic potash is K₂CO₃(ii) a Wherein K₂CO₃Is present in an amount of about 1 to 10 equivalents relative to the compound of formula (II).

4. The process of any one of claims 1 to 3, wherein 1H-1,2, 3-triazole is present in an amount of about 1 to 10 equivalents relative to the compound of formula (II).

5. The process of any one of claims 1 to 4, wherein the process is carried out in the presence of:

a solvent which is a water-miscible ether solvent; wherein the water-miscible ether solvent is present in an amount of about 5 to 100 volumes relative to the compound of formula (II); and

water in an amount of about 0.05 to 2 volumes relative to the compound of formula (II);

wherein the ratio of water-miscible ether solvent to water is greater than about 10:1 (v/v).

6. The process as claimed in any of claims 1 to 5, wherein the formula (I) is separated from the reaction mixture by solid-liquid separation_K) Cooling the reaction mixture to a temperature of less than about 50 ℃ prior to crystallizing the compound of (a); and wherein the cooling of the reaction mixture is effected in about 2 hours or less than 2 hours.

7. The method of any one of claims 1 to 6, wherein formula (I)_K) The isolated crystalline compound of (a):

wherein

R¹Represents methoxy and R²Represents hydrogen; or

R¹Represents hydrogen and R²Represents a methyl group;

further transformed into the respective crystalline 2- (2H- [1,2,3] triazol-2-yl) -benzoic acid derivatives of formula (I):

the process comprises a crystallization step from an acidic aqueous medium.

8. The method of claim 7, wherein the crystallization step from an acidic aqueous medium is performed at a temperature of about 30 ℃ to 60 ℃; and wherein the crystalline compound of formula (I) is isolated by solid-liquid separation; wherein the solid-liquid separation is performed at a temperature of about 10 ℃ to 50 ℃.

9. The method of claim 8, wherein, in the crystallizing step from an acidic aqueous medium, the pH of the acidic aqueous solution is less than about 4.

10. Formula (I)_K) Crystalline forms of the compound:

wherein R is¹Represents methoxy and R²Represents hydrogen; wherein:

a) in the X-ray powder diffraction pattern, there are peaks at the following angles of refraction 2 θ: 6.7 °,7.4 °, 15.4 °, 23.3 °, 27.0 °; or

b) In the X-ray powder diffraction pattern, there are peaks at the following angles of refraction 2 θ: 10.8 °, 15.1 °, 25.0 °, 25.9 °, 27.1 °

Or wherein R is¹Represents hydrogen and R²Represents a methyl group;

wherein in the X-ray powder diffraction pattern there are peaks at the following refraction angles 2 θ: 5.4 °, 10.7 °, 16.1 °, 21.6 °, 27.0 °;

wherein the X-ray powder diffraction pattern is obtained by using combined Cu ka 1 and ka 2 radiation (no ka 2 exfoliation); and the accuracy of the 2theta value is within +/-0.2 deg. of 2 theta.

11. A crystalline form of a compound of formula (I):

wherein R is¹Represents methoxy and R²Represents hydrogen;

a) wherein in the X-ray powder diffraction pattern there are peaks at the following refraction angles 2 θ: 5.7 °, 11.5 °, 17.2 °, 21.3 °, 25.0 °; or

b) Wherein in the X-ray powder diffraction pattern there are peaks at the following refraction angles 2 θ: 11.4 °, 12.3 °, 15.5 °, 21.3 °, 23.6 °;

or wherein R is¹Represents hydrogen and R²Represents a methyl group;

wherein in the X-ray powder diffraction pattern there are peaks at the following refraction angles 2 θ: 6.2 °, 12.5 °, 15.1 °, 18.8 °, 25.2 °;

wherein the X-ray powder diffraction pattern is obtained by using combined Cu ka 1 and ka 2 radiation (no ka 2 exfoliation); and the accuracy of the 2theta value is within +/-0.2 deg. of 2 theta.

12. A crystalline form of the compound of formula (I) according to claim 11; wherein R is¹Represents methoxy and R²Represents hydrogen; wherein in the X-ray powder diffraction pattern, there are peaks at the following refraction angles 2 θ: 5.7 °, 11.5 °, 16.0 °, 17.2 °, 18.9 °, 19.7 °, 21.3 °, 23.7 °, 25.0 °, 27.9 °; wherein the X-ray powder diffraction pattern is obtained by using combined CuK α 1 and K α 2 radiation (no K α 2 exfoliation); and the accuracy of the 2theta value is within +/-0.2 deg. of 2 theta.

13. A crystalline form of the compound of formula (I) according to claim 12; it has a melting point of about 80 ℃ as determined by differential scanning calorimetry.

14. A crystalline form of the compound of formula (I) according to claim 11; wherein R is¹Represents hydrogen and R²Represents a methyl group; wherein in the X-ray powder diffraction pattern there are peaks at the following refraction angles 2 θ: 6.2 °, 11.3 °, 12.5 °, 13.3 °, 15.1 °, 17.0 °, 17.8 °, 18.8 °, 22.6 °, 25.2 °; wherein the X-ray powder diffraction pattern is obtained by using combined Cu ka 1 and ka 2 radiation (no ka 2 exfoliation); and the accuracy of the 2theta value is within +/-0.2 deg. of 2 theta.

15. A crystalline form of the compound of formula (I) according to claim 14; it has a melting point of about 125 ℃ as determined by differential scanning calorimetry.

Technical Field

The invention relates to a process for the preparation of 2- (2H- [1,2, 3), in particular of formula (I)]Process for triazol-2-yl) -benzoic acid derivatives, involving_K) The 2- (2H- [1,2, 3)]Certain crystalline forms of the potassium salt of a triazol-2-yl) -benzoic acid derivative, to said 2- (2H- [1,2, 3) of formula (I)]Certain crystalline forms of triazol-2-yl) -benzoic acid derivatives, and to their use in the preparation of medicaments, in particular certain orexin receptor antagonists, such as (S) - (2- (5-chloro-4-methyl-1H-benzo [ d ]]Imidazol-2-yl) -2-methylpyrrolidin-1-yl) - (5-methoxy-2- (2H-1,2, 3-triazol-2-yl) phenyl) methanone.

Background

Orexin receptor antagonists comprising a 2- (2H- [1,2,3] triazol-2-yl) -benzoic acid moiety are known, for example, from WO2008/020405, WO2008/038251, WO2008/081399, WO2008/139416, WO2008/150364, WO2011/050200, WO2012/148553, WO2013/068935, WO2013/169610, WO2013/182972, WO2014/057435, WO2104/141065, WO2015/083071, WO2015/083070, WO2015/083094, WO2016/020403, j.med chem.2010,53,5320-5332, Current Topics in Medicinal Chemistry,2011,11,696-725.

Preparation of 2- (2H- [1,2, 3)]Typical conditions for triazol-2-yl) -benzoic acid derivatives include contacting the corresponding 2-iodo-benzoic acid derivative in Cs₂CO₃And copper (I) iodide (CuI) in a high boiling point solvent (DMF) at elevated temperature/under microwave conditions with 1H- [1,2,3]Triazole undergoes a coupling reaction. The purification steps generally use the following sequence: i) extracting a mixture of regioisomers from the acidified reaction mixture; and ii) removal of the undesired regioisomer (regioisomer) by slurrying in EtOAc or by crystallization from EtOAc and/or by flash chromatography/preparative HPLC, therefore, conditions are generally not suitable for large scale industrial production.

For example, WO2015/083071, WO2015/083070 and WO2015/083094 disclose that 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid:

obtained without flash chromatography or preparative HPLC but containing 6% triazole N1-regioisomer as an impurity.

WO2011/050200 discloses a process for the synthesis of the regioisomeric compound 4-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid (intermediate 49):

starting from the corresponding 2-bromo-benzoic acid derivative: use of Cs in dioxane at 100 ℃₂CO₃2-bromo-4-methoxy-benzoic acid,/CuI/(1R, 2R) -N1, N2-dimethylcyclohexane-1, 2-diamine. Purification was similar to the general conditions described previously. WO2011/050200 also discloses the regioisomeric compound 5-methoxy-2- (2H- [1,2, 3)]Triazol-2-yl) -benzoic acid (intermediate 61) and compound 5-methyl-2- (2H- [1,2, 3)]Triazol-2-yl) -benzoic acid (intermediate 59), prepared from the corresponding iodo-benzoic acid using the general conditions described above.

WO2013/068935 discloses the synthesis of several 2- (2H- [1,2,3] triazol-2-yl) -benzoic acid derivatives including the compound 4-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid (intermediate E-4):

starting from the corresponding iodo-benzoic acid derivative.

With respect to the pharmaceutical chemical process steps disclosed in some of the above references, certain processes suitable for large scale industrial production have been disclosed. For example, WO2013/169610 and C.A. Baxter et al (Organic Process Research & Development 2011,15, 367-. The 2- ([1,2,3] triazol-2-yl) -benzoic acid derivative 5 was prepared starting from the corresponding iodine 19.

Under the best conditions, the method can be used,use of CuI/K in THF/DMF at 65 ℃₂CO₃Forming regioisomer 5/20 in a ratio of 81: 19. It is stated in Baxter et al that "attempting to expel regioisomer 20 by crystallization under conditions is unsuccessful because the solubility of this compound is low compared to that of 5. On this basis, purification via salt formation was explored. Cesium and potassium salts have not been significantly upgraded; however, with adjustment of the solvent volume, the formation of the sodium salt in THF leads to the undesired isomer being expelled at the expense of about 15% of the desired isomer ".

Specific purification steps used the following sequence: i) extracting a mixture of regioisomers from the acidified reaction mixture; ii) sodium tert-butoxide in THF to form the sodium salt, crystallized and filtered; iii) salt decomposition and crystallization; and iv) recrystallization to give (Baxter et al) 5 having 60% of the melting point 174-176 ℃ (167.5 ℃ in WO 2013/169610).

Disclosure of Invention

The present invention provides a process for the preparation of specific 2- (2H- [1,2,3] s of formula (I) from respective bromo-benzoic acid precursors]Novel processes for triazol-2-yl) -benzoic acid derivatives, the bromo-benzoic acid precursors are generally less costly and therefore more readily available than the corresponding iodo derivatives. The process uses direct solid-liquid separation, for example by precipitation of formula (I) from the reaction mixture_K) Respectively 2- (2H- [1,2, 3)]Triazol-2-yl) -benzoic acid potassium salt, thus resulting in crystalline and regioisomerically enriched 2- (2H- [1,2, 3)]The process for the potassium triazol-2-yl) -benzoate salt is shortened. The crystalline potassium salts are novel and yield 2- (2H- [1,2, 3) of formula (I) after salt decomposition]Novel crystalline forms of triazol-2-yl) -benzoic acid derivatives which are regioisomerically substantially pure and which may serve as valuable intermediates in the synthesis of certain orexin receptor antagonists. Thus, the process of the invention reduces the amount of crystalline and regioisomerically substantially pure crystalline 2- (2H- [1,2, 3) of formula (I) obtained]Triazol-2-yl) -benzoic acid derivatives require a number of steps and can be suitable for the efficient large-scale synthesis of pharmaceutically active compounds.

Brief description of the drawings

FIG. 1 shows the X-ray powder diffraction pattern of crystalline potassium 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoate salt (compound of example 1.1). The X-ray diffraction diagram shows peaks with relative intensities (relative peak intensities given in parentheses) at the indicated angle of refraction 2 θ in the following percentages compared to the strongest peak in the diagram (the peaks selected from the range 3-40 ° 2 θ are reported): 6.7 ° (100%), 7.4 ° (24%), 8.7 ° (10%), 15.4 ° (43%), 16.4 ° (16%), 20.2 ° (10%), 21.7 ° (10%), 23.3 ° (18%), 24.4 ° (9%), 27.0 ° (87%), 28.1 ° (15%), 31.4 ° (85%).

Figure 2 shows the X-ray powder diffraction pattern of crystalline 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as obtained from example 1.2. The X-ray diffraction pattern measured using method 2 shows peaks with relative intensities (relative peak intensities given in parentheses) at the indicated angle of refraction 2 θ in the following percentages compared to the strongest peak in the pattern (reported for peaks selected from the range 3-40 ° 2 θ): 5.7 ° (66%), 11.5 ° (66%), 16.0 ° (24%), 16.1 ° (20%), 16.3 ° (19%), 17.2 ° (100%), 18.9 ° (29%), 19.7 ° (25%), 21.3 ° (37%), 23.7 ° (19%), 25.0 ° (75%), 27.0 ° (12%), 27.9 ° (14%).

FIG. 3 shows crystalline 5-methoxy-2- (2H- [1,2, 3)]X-ray powder diffraction pattern of triazol-2-yl) -benzoic acid potassium salt (compound of example 1.3). The X-ray diffraction diagram shows peaks with relative intensities (relative peak intensities given in parentheses) at the indicated angle of refraction 2 θ in the following percentages compared to the strongest peak in the diagram (the peaks selected from the range 3-40 ° 2 θ are reported): 6.7 ° (15%), 8.4 ° (19%), 10.8 ° (100%), 12.3 ° (15%), 15.1 ° (33%), 16.4 ° (11%), 17.5 ° (12%), 20.6 ° (10%), 21.8 ° (24%), 24.7 ° (14%), 25.0 ° (25%), 25.9 ° (35%), 27.1 ° (63%), 27.9 ° (12%), 28.8 ° (29%). Fig. 3 additionally shows KHCO attributable to 12.1 ° (6%), 24.1 ° (5%), 30.1 ° (36%), 31.3 ° (52%), 31.8 ° (11%), 34.1 ° (23%)₃Peak of impurity.

FIG. 4 shows the X-ray powder diffraction pattern of crystalline 4-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid potassium salt (compound of example 2.1). The X-ray diffraction diagram shows peaks with relative intensities (relative peak intensities given in parentheses) at the indicated angle of refraction 2 θ in the following percentages compared to the strongest peak in the diagram (the peaks selected from the range 3-40 ° 2 θ are reported): 5.4 ° (100%), 8.8 ° (1%), 10.7 ° (56%), 12.0 ° (1%), 16.1 ° (60%), 21.6 ° (5%), 23.3 ° (4%), 24.2 ° (3%), 27.0 ° (21%), 32.6 ° (8%).

Figure 5 shows the X-ray powder diffraction pattern of crystalline 4-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as obtained from example 2.2. The X-ray diffraction pattern measured using method 2 shows peaks with relative intensities (relative peak intensities given in parentheses) at the indicated angle of refraction 2 θ in the following percentages compared to the strongest peak in the pattern (reported for peaks selected from the range 3-40 ° 2 θ): 6.2 ° (11%), 11.3 ° (2%), 12.5 ° (100%), 13.3 ° (2%), 15.1 ° (7%), 17.0 ° (4%), 17.8 ° (3%), 18.8 ° (15%), 22.6 ° (4%), 25.2 ° (8%).

Figure 6 shows the X-ray powder diffraction pattern of crystalline 5-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid sodium salt (compound of reference example 3.1). The X-ray diffraction pattern measured using method 2 shows peaks with relative intensities (relative peak intensities given in parentheses) at the indicated angle of refraction 2 θ in the following percentages compared to the strongest peak in the pattern (reported for peaks selected from the range 3-40 ° 2 θ): 6.5 ° (100%), 7.7 ° (91%), 11.9 ° (18%), 12.9 ° (5%), 13.9 ° (3%), 15.3 ° (47%), 17.5 ° (20%), 18.6 ° (6%), 19.0 ° (13%), 19.2 ° (9%), 20.1 ° (28%), 21.7 ° (7%), 23.2 ° (24%), 23.6 ° (38%), 24.5 ° (5%), 25.6 ° (17%).

FIG. 7 shows the X-ray powder diffraction pattern of crystalline 5-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid (compound of reference example 3.2). The X-ray diffraction pattern measured using method 2 shows peaks with relative intensities (relative peak intensities given in parentheses) at the indicated angle of refraction 2 θ in the following percentages compared to the strongest peak in the pattern (reported for peaks selected from the range 3-40 ° 2 θ): 10.4 ° (3%), 11.8 ° (10%), 13.0 ° (100%), 13.9 ° (44%), 15.8 ° (8%), 16.6 ° (74%), 17.5 ° (5%), 18.1 ° (13%), 21.1 ° (41%), 21.3 ° (10%), 21.6 ° (12%), 21.9 ° (58%), 23.3 ° (62%), 23.8 ° (37%), 24.1 ° (16%), 24.6 ° (1%), 25.6 ° (6%), 26.6 ° (71%), 28.0 ° (32%), 29.4 ° (3%), 30.0 ° (2%), 30.5 ° (11%).

Figure 8 shows the X-ray powder diffraction pattern of crystalline 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as obtained from reference example 1. The X-ray diffraction pattern measured using method 2 shows peaks with relative intensities (relative peak intensities given in parentheses) at the indicated angle of refraction 2 θ in the following percentages compared to the strongest peak in the pattern (reported for peaks selected from the range 3-40 ° 2 θ): 11.4 ° (28%), 12.3 ° (44%), 14.6 ° (21%), 14.7 ° (10%), 15.5 ° (15%), 18.7 ° (11%), 20.8 ° (14%), 21.3 ° (76%), 23.1 ° (10%), 23.6 ° (100%), 24.8 ° (16%), 25.6 ° (16%), 29.9 ° (11%).

To avoid any doubt, the peaks listed above describe the experimental results of X-ray powder diffraction shown in the above figures. It is to be understood that, in contrast to the above peak list, only characteristic peaks need to be selected to fully and unambiguously characterize the respective compound/compound salt in the respective crystalline forms of the present invention.

In the X-ray diffraction diagram, the angle of refraction 2 θ (2theta) is plotted on the horizontal axis and the count is plotted on the vertical axis.

Detailed Description

1) A first aspect of the present invention relates to a process for the synthesis of a crystalline potassium salt of a 2- (2H- [1,2,3] triazol-2-yl) -benzoic acid derivative,

formula (I)_K) The crystalline compound of (a):

wherein

·R¹Represents methoxy and R²Represents hydrogen; or

·R¹Represents hydrogen and R²Represents a methyl group;

the process comprises the following coupling:

a compound of formula (II):

and [1,2,3]]Triazole:

wherein the process is carried out in the presence of:

copper (I) iodide (CuI);

inorganic Potassium alkali (in particular K)₂CO₃) (ii) a And

a solvent or solvent mixture of

Water-miscible ether solvents (in particular THF, 2-methyl-THF, dioxane, 1, 2-dimethoxyethane); or

Polar aprotic solvents (especially DMF, dimethylacetamide, NMP); or any mixture thereof;

wherein the solvent or solvent mixture is present in an amount of about 5 to 100 volumes (especially about 10 to 50 volumes, especially about 20 to 40 volumes) relative to the compound of formula (II);

wherein the coupling of the compound of formula (II) and [1,2,3] triazole is carried out at a temperature of greater than about 60 ℃ (especially about 60 ℃ to 120 ℃, particularly about 80 ℃ to 120 ℃, particularly about 90 ℃ to 110 ℃);

wherein the formula (I)_K) The crystalline compound is separated from the reaction mixture by solid-liquid separation.

It is well known that [1,2,3] triazole can exist in its tautomeric forms 1H- [1,2,3] triazole and 2H- [1,2,3] triazole, and both tautomeric forms are covered by the name [1,2,3] triazole.

The solvent or solvent mixture which can be used in the process according to embodiment 1) can be defined in particular as consisting essentially of:

water-miscible ether solvents, in particular water-miscible ether solvents having a boiling point of at least 60 ℃, such as (in particular) 1, 4-dioxane; or 1, 2-dimethoxyethane, Tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-Me-THF) or 4-methyltetrahydropyran (4-Me-THP); or

Polar aprotic solvents, in particular polar aprotic amides containing solvents such as, in particular, Dimethylformamide (DMF); or dimethylacetamide, N-methylpyrrolidin-2-one (NMP) or Dimethylsulfoxide (DMSO); or

A mixture of more than one water-miscible ether solvent;

or a mixture of one or more water-miscible ether solvents and one or more polar aprotic solvents;

wherein the solvent or solvent mixture is present in an amount of about 5 to 100 volumes (especially about 10 to 50 volumes, especially about 20 to 40 volumes) relative to the compound of formula (II).

A preferred example of such a solvent or solvent mixture is the water-miscible ether solvent 1, 4-dioxane (dioxane).

The term "ethereal solvent" means a solvent consisting of a saturated linear or branched acyclic hydrocarbon radical or a saturated cyclic hydrocarbon radical optionally mono-substituted with a linear or branched acyclic hydrocarbon radical, wherein the acyclic hydrocarbon radical or the cyclic hydrocarbon radical contains at least one divalent bonded oxygen atom. The term "water-miscible ether solvent" includes partially water-miscible ether solvents. A partially water-miscible ether solvent may be defined as an ether solvent that is miscible with at least 1% wt/wt of water dissolved in the respective ether solvent (it being understood that if such a solvent is partially miscible, it is not fully miscible with water in any ratio). Preferred water-miscible ether solvents have a boiling point of at least 60 ℃. Examples of such ether solvents are the water-miscible ether solvents 1, 4-dioxane and 1, 2-dimethoxyethane and the partially miscible ether solvents Tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-Me-THF) and 4-methyltetrahydropyran (4-Me-THP).

The term "polar aprotic solvent" particularly refers to polar aprotic amides containing solvents such as Dimethylformamide (DMF), dimethylacetamide and N-methylpyrrolidin-2-one (NMP). Examples of "mixtures of one or more water-miscible ether solvents with one or more polar aprotic solvents" are THF and DMF, for example in a ratio v/v of about 4:1 to 10:1, in particular in a ratio v/v of about 5: 1. All solvents can be used at the time of purchase without additional drying procedures.

It may be preferred to carry out the coupling reaction of the process according to embodiment 1) in a reaction mixture which contains a certain amount of water, for example about 0.05 to 2 volumes, in particular about 0.1 to 1 volume, relative to the compound of formula (II), in addition to the respective solvent. Where the corresponding solvent is a water-miscible ether solvent, the ratio of water-miscible ether solvent to water (v/v) is greater than about 10:1(v/v), specifically about 20:1 to 100:1(v/v), specifically about 30:1 to 80:1 (v/v). For the avoidance of any doubt, such additional water present in the reaction mixture is not considered to be a "solvent" or part of a "solvent mixture", as previously defined.

The process as in embodiment 1) is carried out in the presence of an inorganic potash. Examples are in particular K₂CO₃And K₃PO₄And KHCO₃。

The process according to embodiment 1) can be carried out in the presence of a ligand. Examples are 8-hydroxyquinoline, N1, N2-dimethylcyclohexane-1, 2-diamine and N, N-dimethyl-ethylene-diamine. In the case of the use of polar aprotic solvents, in particular polar aprotic amides containing solvents such as, in particular, Dimethylformamide (DMF), or mixtures containing such solvents, the process according to embodiment 1) is preferably carried out in the presence of a ligand as stated before.

This process as in embodiment 1) leads to the formation of the compound of the formula (I) in regioisomerically enriched form, in particular with a regioisomeric ratio of more than 70:30, as measured in the reaction mixture before the separation. Separation of the formula (I) from the reaction mixture by solid-liquid separation as in embodiment 1)_K) The crystalline compound of (a) yields the crystalline potassium salt in a regioisomeric further enriched form, and may yield the crystalline potassium salt in a regioisomeric substantially pure form (particularly in a regioisomeric substantially pure form)A regioisomeric ratio of greater than about 80:20 (specifically greater than about 85:15, specifically greater than about 90: 10).

2) Thus, another embodiment relates to the process according to embodiment 1), wherein the compound of formula (I) obtained from the solid-liquid separation_K) Regio-isomerism ratio of the crystalline compound of (a); that is, [ formula (I)_K) Compound (I)]A compound of formula (I)_R-K)]The ratio of (A) to (B):

greater than about 80:20 (specifically greater than about 85:15, specifically greater than about 90: 10).

3) Another embodiment relates to the process of embodiment 1) or 2), wherein the process is carried out in the presence of copper (I) iodide (CuI); wherein copper iodide is present in an amount of about 0.01 to 0.5 equivalents (especially about 0.01 to 0.1 equivalents; especially about 0.05 equivalents) relative to the compound of formula (II).

4) Another embodiment relates to the method of any one of embodiments 1) to 3), wherein the inorganic potash is K₂CO₃(ii) a Wherein K₂CO₃Is present in an amount of about 1 to 10 equivalents (especially about 1.5 to 5 equivalents; especially about 2 to 2.5 equivalents) relative to the compound of formula (II).

5) Another embodiment relates to the process as in any one of embodiments 1) to 4), wherein the 1H-1,2, 3-triazole is present in an amount of about 1 to 10 equivalents (especially about 1.5 to 5 equivalents; particularly about 2 equivalents) is present.

6) Another embodiment relates to the process of any one of embodiments 1) to 5), wherein the process is carried out in the presence of a ligand selected from the group consisting of 8-hydroxyquinoline, N1, N2-dimethylcyclohexane-1, 2-diamine, and N, N-dimethyl-ethylene-diamine; wherein the ligand is present in an amount of about 0.01 to 0.5 equivalents (especially about 0.05 to 0.2 equivalents; especially about 0.1 equivalent) relative to the compound of formula (II).

7) Another embodiment relates to the process of any one of embodiments 1) to 5), wherein the process is carried out in the absence of a ligand.

8) Another embodiment relates to the process of any one of embodiments 1) to 7), wherein the process is carried out in the presence of:

a solvent which is a water-miscible ether solvent (in particular dioxane); wherein the water-miscible ether solvent is present in an amount of about 5 to 100 volumes (especially about 10 to 50 volumes, especially about 20 to 40 volumes) relative to the compound of formula (II); and

water, in particular in an amount of about 0.05 to 2 volumes (in particular about 0.1 to 1 volume) relative to the compound of formula (II);

wherein the ratio of water-miscible ether solvent to water is preferably greater than about 10:1 (v/v); especially about 10:1 to 200:1 (v/v); particularly about 20:1 to 100:1 (v/v); specifically about 30:1 to 80:1 (v/v).

9) Another embodiment relates to the process according to embodiment 8), wherein the separation of the formula (I) from the reaction mixture is carried out by solid-liquid separation_K) The amount of water in the reaction mixture is reduced prior to crystallizing the compound of (a); wherein, in particular, the total volume of the reaction mixture is reduced to a volume of about 50% to 80% (in particular about 80% to 90%) of the initial volume (e.g. by evaporation under reduced pressure, or by distillation under atmospheric pressure).

10) Another embodiment relates to the process according to embodiment 9), wherein the separation of the formula (I) from the reaction mixture is carried out by solid-liquid separation_K) Prior to crystallizing the compound of (1), and subsequently proceeding to the step of embodiment 9), additional water-miscible ether solvent is added to the reaction mixture (wherein, in particular, the evaporating volume of the reaction mixture is replaced by about the same volume of the water-miscible ether solvent).

11) Another embodiment relates to a process as in any of embodiments 1) to 10), wherein the formula (I) is separated from the reaction mixture by solid-liquid separation_K) Before crystallizing the compound of (a), the reaction mixture is cooled to a temperature of less than about 50 ℃, in particular about 20 ℃ to 40 ℃.

12) Another embodiment relates to the method of embodiment 11), wherein the cooling of the reaction mixture is achieved in about 2 hours or less than 2 hours, particularly about 1 hour or less than 1 hour.

Although not included in the scope of the method of embodiment 1), the methods of embodiments 1) to 12) are similar and are performed by using an inorganic sodium base (specifically Na)₂CO₃) Instead of the inorganic potash, the process is also suitable for the preparation of crystalline and regioisomerically substantially pure 5-methyl-2- (2H- [1,2, 3)]Triazol-2-yl) -benzoic acid sodium salt.

13) A second aspect of the invention relates to formula (I)_K) Crystalline forms of the compound:

wherein R is¹Represents methoxy and R²Represents hydrogen (i.e., formula (I)_K) The compound of (1) is crystalline 5-methoxy-2- (2H- [1,2, 3)]Triazol-2-yl) -benzoic acid potassium salt); the method is characterized in that:

a) in the X-ray powder diffraction pattern, there are peaks at the following angles of refraction 2 θ: 6.7 °,7.4 °, 15.4 °, 23.3 °, 27.0 °; or

b) In the X-ray powder diffraction pattern, there are peaks at the following angles of refraction 2 θ: 10.8 °, 15.1 °, 25.0 °, 25.9 °, 27.1 °

Or wherein R is¹Represents hydrogen and R²Represents a methyl group (i.e., formula (I)_K) The compound of (1) is crystalline 4-methyl-2- (2H- [1,2, 3)]Triazol-2-yl) -benzoic acid potassium salt); the method is characterized in that:

in the X-ray powder diffraction pattern, there are peaks at the following angles of refraction 2 θ: 5.4 °, 10.7 °, 16.1 °, 21.6 °, 27.0 °.

It is understood that the crystalline forms as in embodiment 13) comprise the respective 2- (2H- [1,2, 3)]Crystalline potassium salts of triazol-2-yl) -benzoic acid derivatives, i.e. of formula (I)_K) Of (a) is a crystalline compound. Additionally, the crystalline forms may include non-coordinating and/or coordinating solvents. Coordinating solvents are used herein as the term for crystalline solvates. Likewise, non-coordinating solvent is used herein as a term for physisorbed or physically coated solvents (according to Pharmaceutical industry)y (R.Hilfiker eds., VCH,2006), chapter 8: polymorphic definition in U.J.Griesser: The Import of Solvates). The crystalline form as in embodiment 13) specifically contains no coordinated water, but may contain non-coordinated water.

14) Another embodiment relates to a crystalline potassium salt of 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as in embodiment 13); the method is characterized in that:

a. in the X-ray powder diffraction pattern, there are peaks at the following angles of refraction 2 θ: 6.7 °,7.4 °, 8.7 °, 15.4 °, 16.4 °, 20.2 °, 23.3 °, 24.4 °, 27.0 °, 28.1 °; or

b. In the X-ray powder diffraction pattern, there are peaks at the following angles of refraction 2 θ: 8.4 °, 10.8 °, 12.3 °, 15.1 °, 17.5 °, 25.0 °, 25.9 °, 27.1 °, 27.9 °, 28.8 °.

15) Another embodiment relates to a crystalline potassium salt of 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as in embodiment 13); characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 10.8 °, 15.1 °, 25.0 °, 25.9 °, 27.1 ° (in particular at 8.4 °, 10.8 °, 12.3 °, 15.1 °, 17.5 °, 25.0 °, 25.9 °, 27.1 °, 27.9 °, 28.8 °); it has a melting point of about 280 ℃, where melting is accompanied by a decay in the exotherm as determined by differential scanning calorimetry (e.g., by using the method as described herein).

16) Another embodiment relates to a crystalline potassium 4-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoate salt as in embodiment 13); characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 5.4 °, 8.8 °, 10.7 °, 12.0 °, 16.1 °, 21.6 °, 23.3 °, 24.2 °, 27.0 °, 32.6 °.

17) Another embodiment relates to a crystalline potassium 4-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoate salt of embodiment 16); characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 5.4 °, 10.7 °, 16.1 °, 21.6 °, 27.0 ° (in particular at 5.4 °, 8.8 °, 10.7 °, 12.0 °, 16.1 °, 21.6 °, 23.3 °, 24.2 °, 27.0 °, 32.6 °); it has a melting point of about 277 ℃, where melting is accompanied by a decay in the exotherm as determined by differential scanning calorimetry (e.g., by using the method as described herein).

Further disclosed are crystalline forms of the sodium salt of 5-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid; characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 6.5 °, 7.7 °, 11.9 °, 15.3 °, 17.5 °, 19.0 °, 20.1 °, 21.7 °, 23.6 °, 25.6 °.

18) A third aspect of the present invention relates to the method according to any one of embodiments 1) to 12), wherein formula (I)_K) The isolated crystalline compound of (a):

wherein

·R¹Represents methoxy and R²Represents hydrogen; or

·R¹Represents hydrogen and R²Represents a methyl group;

further converted into the respective crystalline 2- (2H- [1,2,3] triazol-2-yl) -benzoic acid derivative (compound of formula (I)):

[ wherein it is understood that for the compounds of formula (I), R¹And R²As previously for formula (I)_K) As defined for the compound]

The process comprises a crystallization step from an acidic aqueous medium.

19) Another embodiment relates to the method of embodiment 18), wherein the method comprises the steps of:

(i) preparing an aqueous alkaline solution comprising a compound of formula (I); in particular by reacting a compound of formula (I)_K) Wherein it is understood that such aqueous medium may be water or an alkaline aqueous medium (such as an aqueous solution of an alkali metal hydroxide, carbonate or bicarbonate)]；

(ii) Crystallizing the compound of formula (I) by acidifying an aqueous alkaline solution comprising the compound of formula (I); and

(iii) isolating the crystalline compound of formula (I) by solid-liquid separation.

Thus, the process of embodiments 18) and 19) involves salt decomposition in an aqueous medium and comprises crystallizing the compound of formula (I) in regioisomerically substantially pure form, in particular in a regioisomeric ratio of greater than 98:2, in particular in regioisomerically pure form.

20) Thus, another embodiment relates to the method of embodiment 18) or 19), wherein the regio-isomeric ratio of the isolated crystalline compound of formula (I); that is to say [ compounds of the formula (I) ]]Is shown in the formula (I)_R) Compound (I)]The ratio of (A) to (B):

at least about 98: 2; wherein in particular the crystalline compound of formula (I) is obtained in regioisomerically pure form.

21) Another embodiment relates to the process according to any one of embodiments 18) to 20), wherein the crystallization step [ corresponding to step (ii) as in embodiment 19) ] is performed at a temperature of about 30 ℃ to 60 ℃, preferably at a temperature of about 40 ℃ to 55 ℃, in particular at about 40 ℃ to 50 ℃.

22) Another embodiment relates to a process according to any one of embodiments 18) to 21), wherein the crystalline compound of formula (I) is isolated by solid-liquid separation [ corresponding to step (iii) as in embodiment 19) ]; wherein the solid-liquid separation is carried out at a temperature of about 10 ℃ to 50 ℃, in particular at a temperature of about 20 ℃ to 45 ℃, particularly preferably about 30 ℃ to 40 ℃.

23) Another embodiment relates to the method according to any one of embodiments 18) to 22), wherein step (ii) of the crystallization step [ corresponds to embodiment 19 ]]Previously, step (I) of contacting an aqueous solution of the compound of formula (I) [ e.g. according to embodiment 19 ] with an aqueous solution of the compound of formula (I): by contacting the compound of formula (I)_K) Obtained by dissolving the compound in an aqueous medium]The following steps are carried out:

a) a filtration step (e.g., using standard filtration techniques; or standard filtration techniques and additionally filtration via activated carbon); and/or

b) A washing step comprising at least two liquid-liquid separation sequences, wherein the compound of formula (I) is first extracted into an organic water-immiscible solvent; and subsequently extracted from the organic water-immiscible solvent into an aqueous alkaline solution; wherein the basic aqueous solution is subsequently used in the crystallization step [ corresponding to step (ii) of embodiment 19) ] of the process according to any one of embodiments 18) to 21).

Such washing steps comprising a sequence of liquid-liquid separations according to variant b) of embodiment 23) refer, for example, to the following steps:

(b1) acidifying an aqueous alkaline solution comprising a compound of formula (I), for example as obtained according to step (I) of embodiment 19); and extracting the compound of formula (I) into an organic non-water miscible solvent such as, in particular, tert-butyl methyl ether (TBME);

(b2) optionally washing the organic phase obtained in step (b1) with an aqueous acidic solution, such as an aqueous solution of a mineral acid, in particular sulfuric acid or hydrochloric acid; and

(b3) extracting the compound of formula (I) from the organic phase obtained in step (b1) or (b2) into an alkaline aqueous medium, such as an alkali metal hydroxide or carbonate solution, in particular an aqueous sodium or potassium hydroxide solution; wherein the basic aqueous solution is subsequently used in the crystallization step [ step (ii) corresponding to embodiment 19) ] as in any one of embodiments 18) to 21).

24) Another embodiment relates to the process according to any one of embodiments 18) to 23), wherein in the crystallization step [ corresponding to step (ii) of embodiment 19) ] an aqueous mineral acid is used to acidify the aqueous basic solution [ wherein such aqueous mineral acid is in particular aqueous sulfuric acid (in particular about 10% to 30% aqueous sulfuric acid; specifically about 20% aqueous sulfuric acid); or an aqueous hydrochloric acid solution (specifically, an aqueous hydrochloric acid solution of about 10% to 32%, specifically, an aqueous hydrochloric acid solution of about 32) ].

25) Another embodiment relates to the process according to any one of embodiments 18) to 24), wherein in the crystallization step [ corresponding to step (ii) of embodiment 19) ] the pH of the acidic aqueous solution is below about 4, in particular below about 3, in particular between about 1 and 3.

26) Another embodiment relates to the process of any one of embodiments 18) to 25), wherein during the crystallization step [ corresponding to step (ii) of embodiment 19) ], seeding crystals are added to the aqueous mixture; wherein the pH of the mixture upon addition of the seeding crystals is about 6 or less than 6, in particular about 4 to 3.

Although not included in the scope of the method of embodiment 18), the methods of embodiments 18) through 26) are similar and substantially pure 5-methyl-2- (2H- [1,2, 3) by self-crystallization and regioisomerism]Triazol-2-yl) -benzoic acid sodium salt instead of formula (I)_K) Starting from the compounds, the process is also suitable for preparing crystalline and regioisomeric substantially pure 5-methyl-2- (2H- [1,2, 3)]Triazol-2-yl) -benzoic acid.

27) A fourth aspect of the present invention is directed to a crystalline form of the compound of formula (I):

wherein R is¹Represents methoxy and R²Represents hydrogen (i.e. the compound of formula (I) is crystalline 5-methoxy-2- (2H- [1,2, 3)]Triazol-2-yl) -benzoic acid);

a) characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 5.7 °, 11.5 °, 17.2 °, 21.3 °, 25.0 °; or

b) Characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 11.4 °, 12.3 °, 15.5 °, 21.3 °, 23.6 °;

or wherein R is¹Represents hydrogen and R²The compound representing methyl (i.e. formula (I) is crystalline 4-methyl-2- (2H- [1,2, 3)]Triazol-2-yl) -benzoic acid);

characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 6.2 °, 12.5 °, 15.1 °, 18.8 °, 25.2 °.

It is to be understood that the crystalline forms as in embodiment 27) comprise the respective crystalline 2- (2H- [1,2,3] triazol-2-yl) -benzoic acid derivatives, i.e. the respective crystalline compounds of formula (I). Additionally, the crystalline forms may include non-coordinating and/or coordinating solvents. Coordinating solvents are used herein as the term for crystalline solvates. Likewise, non-coordinating solvents are used herein as a term for physisorbed or physically coated solvents (according to The polymorphic definition in Pharmaceutical Industry (R.Hilfiker eds., VCH,2006), Chapter 8: U.J.Griisser: The Import of Solvates). The crystalline form as in embodiment 27) specifically does not contain coordinated water, but may contain, for example, non-coordinated water.

28) Another embodiment relates to crystalline 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as in embodiment 27); characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 5.7 °, 11.5 °, 16.0 °, 17.2 °, 18.9 °, 19.7 °, 21.3 °, 23.7 °, 25.0 °, 27.9 °.

29) Another embodiment relates to crystalline 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as in embodiment 27); characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 5.7 °, 11.5 °, 17.2 °, 21.3 °, 25.0 ° (in particular at 5.7 °, 11.5 °, 16.0 °, 17.2 °, 18.9 °, 19.7 °, 21.3 °, 23.7 °, 25.0 °, 27.9 °); it has a melting point of about 80 ℃ as determined by differential scanning calorimetry (e.g., by using a method as described herein).

30) Another embodiment relates to crystalline 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as in embodiment 27); characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 11.4 °, 12.3 °, 14.6 °, 15.5 °, 21.3 °, 23.1 °, 23.6 °, 24.8 °, 25.6 °, 29.9 °.

31) Another embodiment relates to crystalline 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as in embodiment 27); characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 5.7 °, 11.5 °, 17.2 °, 21.3 °, 25.0 ° (in particular at 11.4 °, 12.3 °, 14.6 °, 15.5 °, 21.3 °, 23.1 °, 23.6 °, 24.8 °, 25.6 °, 29.9 °); as determined by differential scanning calorimetry (e.g., by using the methods as described herein), which has a melting point of about 130 ℃ - & 131 ℃.

32) Another embodiment relates to crystalline 4-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as in embodiment 27); characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 6.2 °, 11.3 °, 12.5 °, 13.3 °, 15.1 °, 17.0 °, 17.8 °, 18.8 °, 22.6 °, 25.2 °.

33) Another embodiment relates to crystalline 4-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as in embodiment 27); characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 6.2 °, 12.5 °, 15.1 °, 18.8 °, 25.2 ° (specifically at 6.2 °, 11.3 °, 12.5 °, 13.3 °, 15.1 °, 17.0 °, 17.8 °, 18.8 °, 22.6 °, 25.2 °); it has a melting point of about 125 ℃ as determined by differential scanning calorimetry (e.g., by using a method as described herein).

Further disclosed are crystalline forms of 5-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid; characterized by the presence of peaks in the X-ray powder diffraction pattern at the following angles of refraction 2 θ: 11.8 °, 13.0 °, 13.9 °, 16.6 °, 21.1 °, 21.9 °, 23.3 °, 23.8 °, 26.6 °, 28.0 °. The crystalline form has a melting point of about 173 ℃, as determined by differential scanning calorimetry (e.g., by using a method as described herein).

34) Another aspect of the invention relates to a process according to any one of embodiments 18) to 26), wherein the crystalline compound of formula (I), which is crystalline 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid under this particular condition, in particular crystalline 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as in embodiment 28) or 29), is further converted into the compound (S) - (2- (5-chloro-4-methyl-1H-benzo [ d ] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2, 3-triazol-2-yl) phenyl) methanone; or a pharmaceutically acceptable salt thereof. Also, the present invention relates to the use of crystalline 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid (especially as in embodiment 28) or 29)) for the preparation of (S) - (2- (5-chloro-4-methyl-1H-benzo [ d ] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2, 3-triazol-2-yl) phenyl) methanone; or a pharmaceutically acceptable salt thereof.

Such transitions as in embodiment 34) are described in particular in WO2013/182972, WO2015/083071, WO2015/083070 and WO2015/083094, the references of which are incorporated herein in their entirety. In particular, the crystalline 5-methoxy-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid is coupled with (S) -5-chloro-4-methyl-2- (2-methylpyrrolidin-2-yl) -1H-benzo [ d ] imidazole (e.g., under standard amide coupling conditions), to produce (S) - (2- (5-chloro-4-methyl-1H-benzo [ d ] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2, 3-triazol-2-yl) phenyl) methanone, which is an orexin receptor antagonist.

Alternatively, such a multi-step transition may comprise the steps of: coupling 5-methoxy-2- (2H-1,2, 3-triazol-2-yl) benzoic acid with (S) -2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride under standard amide coupling conditions to yield (S) -1- (5-methoxy-2- (2H-1,2, 3-triazol-2-yl) benzoyl) -2-methylpyrrolidine-2-carboxylic acid methyl ester, which is further converted to (S) - (2- (5-chloro-4-methyl-1H-benzo [ d ] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2, 3-triazol-2-yl) phenyl) methanone or its hydrochloride salt (wherein the further transformation comprises the following: the order of hydrolysis, coupling of the carboxylic acid with 4-chloro-3-toluene-1, 2-diamine hydrochloride, and cyclization).

For the avoidance of doubt, substituents of the benzimidazole moiety may be attached ortho to the bridgehead atom (i.e. attached in positions 4 and/or 7) and/or meta to the bridgehead atom (i.e. attached in positions 5 and/or 6). It is understood that two ortho and two meta positions, respectively, are considered equivalent. For example, it is understood that the group 5-chloro-4-methyl-1H-benzimidazol-2-yl represents the same group as 6-chloro-7-methyl-3H-benzimidazol-2-yl, and its tautomeric form 5-chloro-4-methyl-3H-benzimidazol-2-yl/6-chloro-7-methyl-1H-benzimidazol-2-yl is contemplated.

35) Another aspect of the invention relates to a method according to any one of embodiments 18) to 26), wherein in this particular case is crystalline 4-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid, in particular crystalline compounds of formula (I) which are crystalline 4-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid as in embodiment 32) or 33) are further converted into the compound (4-methyl-2- [1,2,3] triazol-2-yl-phenyl) - [ (R) -3- (3- [1,2,3] triazol-2-yl-benzyl) -morpholin-4-yl ] -methanone.

Such multi-step transformations as in embodiment 35) are described in particular in WO2013/068935, the reference of which is incorporated herein in its entirety.

In particular, the crystalline 4-methyl-2- (2H- [1,2,3] triazol-2-yl) -benzoic acid is coupled (e.g., under standard amide coupling conditions) with (R) -3- (3- (2H- [1,2,3] triazol-2-yl) benzyl) morpholine (intermediate a15 of WO 2013/068935) to produce (4-methyl-2- [1,2,3] triazol-2-yl-phenyl) - [ (R) -3- (3- [1,2,3] triazol-2-yl-benzyl) -morpholin-4-yl ] -methanone, which is an orexin receptor antagonist.

Where used in the plural form of a compound, salt, pharmaceutical composition, disease or the like, such plural form is also intended to mean a single compound, salt or the like.

For the avoidance of any doubt, as long as one of the above embodiments mentions "in the X-ray powder diffraction pattern, a peak at the following refraction angle 2 θ", the X-ray powder diffraction pattern is obtained by using combined Cu ka 1 and ka 2 radiation (and no K α 2 exfoliation); and it should be understood that the accuracy of the 2theta values provided herein is within +/-0.1-0.2 deg.. Notably, when specifying the angle of refraction 2 θ (2theta) for a peak in the embodiments of the invention and in the claims, a given 2theta value is understood to mean that value minus 0.2 ° to that value plus the 0.2 ° interval (2theta +/-0.2 °); and preferably the value minus 0.1 deg. to the value plus the 0.1 deg. interval (2theta +/-0.1 deg.).

The definitions provided herein are intended to apply consistently to formulas (I) and (I)_K) And is applicable to the methods as defined in any one of embodiments 1) to 35), and mutatis mutandis throughout the specification and claims, unless a definition providing a broader or narrower definition is explicitly stated otherwise. It is to be fully understood that the termsThe definitions or preferred definitions of (a) are defined and the respective term(s) can be substituted independently (and in combination with) any definition or preferred definition of any or all other term(s) as defined herein.

The term "solid-liquid separation" refers to conventional solid-liquid separation techniques well known to those of ordinary skill in the art (see, e.g., Perry's Chemical Engineers' Handbook, 7 th edition, Perry, R.H.; Green, D.W. McGraw-Hill 1997). Specifically, the term includes techniques such as filtration, centrifugation, and gravity sedimentation; in particular filtration.

The term "liquid-liquid extraction" refers to conventional liquid-liquid extraction or washing techniques well known to those of ordinary skill in the art (see, e.g., Perry's Chemical Engineers' Handbook, 7 th edition, Perry, R.H.; Green, D.W.McGraw-Hill 1997). In particular, the term includes washing or extraction techniques using precipitators, swirlers, centrifuges, mixing precipitators, all types of continuous contact devices; and (3) distillation: batch and continuous distillation; and supercritical fluid separation techniques.

Unless used with respect to temperature, the term "about" preceding the value "X" in the present application refers to a range extending from 10% of X minus X to 10% of X plus X, and preferably to a range extending from 5% of X minus X to 5% of X plus X (where it is to be fully understood that values below 0%, respectively above 100%, do not apply). If the term about is placed before a range, then the respective ranges will apply to both values in the range. In the specific case of temperature, the term "about" placed before the temperature "Y" refers in the present application to the interval extending from the temperature Y minus 10 ℃ to Y plus 10 ℃; and preferably, at a temperature of at least 30 ℃, means an interval extending from Y minus 5 ℃ to Y plus 5 ℃; or in the case of a temperature below 30 ℃ the interval extending from Y minus 2 ℃ to Y plus 2 ℃.

Whenever the terms "between" or "to" are used to describe a numerical range, it is understood that the endpoints of the specified ranges are explicitly included in the range. For example: if a temperature range is described between 40 ℃ and 80 ℃ (or 40 ℃ to 80 ℃), this means that the endpoints 40 ℃ and 80 ℃ are included in the range; or if a variable is defined as an integer between 1 and 4 (or 1 to 4), this means that the variable is an integer of 1,2,3 or 4.

The expression w/w% refers to the percentage by weight compared to the total weight of the composition considered. If not explicitly indicated, the value% is to be understood as w/w%. The expression in relation to the ratio (wt/wt) refers to the weight ratio of the two components considered. Likewise, the expression v/v refers to the volume ratio of the two components considered. Likewise, the expression a/a% refers to the purity with respect to the area under the curve (i.e., the integral) in the chromatogram, preferably the UV absorbance is measured. The expression "volume" denotes the volume (in L of, for example, solvent) per weight (in kg of, for example, reactants). For example, 10 volumes means 10 liters (solvent) per kg (reactant).

The term "enriched" in the context of the present invention is understood to mean in particular, for example when used in the context of regioisomers/enantiomers or diastereomers, that the individual regioisomers/enantiomers/diastereomers are present in the explicitly stated ratios (as the case may be corrected: purity); in general, they are present in a ratio of at least 70:30, in particular at least 80:20 and especially at least 90:10 (corrected for practical reasons: purity of 70%/80%/90%) relative to the respective other regioisomers/enantiomers/diastereomers. Preferably, the term refers to the respective substantially pure regioisomers/enantiomers/diastereomers.

The term "substantially", for example when used in terms such as "substantially pure", is understood in the context of the present invention to mean in particular that the respective stereoisomer/composition/compound etc. is present in an amount of at least 90%, in particular at least 95% and in particular at least 98% by weight of the respective pure regioisomer/stereoisomer/composition/compound etc. The term "pure" when used in the context of a certain regioisomer or enantiomer or diastereoisomer is understood in the context of the present invention to mean that the respective other regioisomer or enantiomer/diastereoisomer is below 1% (in particular undetectable) as measured by the same analytical means such as in particular HPLC/LC-MS (in this case it is understood that% refers to a/a% as measured in particular by HPLC/LC-MS).

In the context of the present invention, the term "consisting essentially of …" is to be understood as meaning in particular that the respective composition amounts to at least 90% by weight, in particular at least 95% by weight, in particular at least 98% by weight and preferably 100% by weight (i.e. in the sense of "consisting of …") of the respective composition in the amounts explicitly stated in the respective embodiments.

According to the invention, the formulae (I) and (I)_K) Can be produced by or analogously to the processes given in the above embodiments 1) to 12) and 18) to 26) or in the experimental section below. The following examples are provided to further illustrate the invention. These examples should not be construed as limiting the invention in any way.

Experimental part

Commercially available starting materials were used as is without further purification. All temperatures given are internal temperatures and are stated in ° c. The compound may be characterized as¹H-NMR (400MHz) or¹³C-NMR (100MHz) (Bruker; chemical shifts given in ppm relative to the solvent used; multiplets: s ═ singlet, d ═ doublet, t ═ triplet, p ═ quintet, hex ═ hexamer, hept ═ heptaplex, m ═ multiplet, br ═ broad, coupling constants given in Hz); the internal standard used for quantitative NMR was 1, 4-dimethoxybenzene; or by LC-MS, t_RGiven in minutes.

LC-MS method 1: waters iClass, thermal MSQ plus and DAD

LC-MS method 2: agilent G1956B, G1312B and DAD

X-ray powder diffraction analysis

In a reflection modeUsing CuK under (coupled 2 theta/theta)_aX-ray powder diffraction patterns were collected on a Bruker D8 advanced X-ray diffractometer of a radiation operated Lynxeye detector. Typically, the X-ray tube is operated at 40kV/40 mA. A 0.02 deg. (2theta) step size and a 76.8 second step time are applied over a 3-50 deg. scan range of 2 theta. The divergence slit was set to a fixed 0.3. The powder was slightly pressed into a silicon single crystal sample holder with a depth of 0.5mm and the sample was rotated in its own plane during the measurement. Diffraction data was reported using combined Cu ka 1 and ka 2 radiation (and no ka 2 stripping). The accuracy of the 2theta values as provided herein is within +/-0.1-0.2 deg., which is typically the case for conventionally recorded X-ray powder diffraction patterns.

Differential scanning calorimetry

DSC data were collected on a Mettler Toledo STAR System (DSC822e module, measurement unit with ceramic sensor and STAR software version 13) with 34 position autosampler. The energy and temperature of the instrument were calibrated using the identified indium. During the measurement, a nitrogen purge of 20mL/min was maintained on the sample.

For salt, typically 1-5mg of the sample is weighed into a Mettler Toledo 40 microliter aluminum pan that is automatically pierced and placed in a furnace. A heating rate of 4 ℃/min is applied in the range of 20 ℃ to 500 ℃.

For acids, typically 1-5mg of the sample is weighed into a T ü v S ü d (Switzerland) M20 high pressure pan which is hermetically sealed and placed manually in a furnace, a heating rate of 4 ℃/min is applied in the range of 20 ℃ to 400 ℃.

The melting point is reported as the peak temperature.

Abbreviations (as used herein or described above):

aq. containing water

atm atmospheric pressure

eq. equivalent

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EtOAc ethyl acetate

Ex. examples

Figure of Fig

GC-MS gas chromatography mass spectrometry

h hours

HPLC high performance liquid chromatography

IPC in-Process control

iPrMgCl isopropyl magnesium chloride

LC-MS liquid chromatography mass spectrometry

M accurate mass (e.g. for LC-MS)

min minute (minute)

MHz

min Minute (Minute)

MP melting Point

MS Mass Spectrometry

Normal state of N

NMR nuclear magnetic resonance

¹H-NMR proton nuclear magnetic resonance

org. organic

RT Room temperature

TBME Tert-butyl methyl Ether

TFA trifluoroacetic acid

THF tetrahydrofuran

t_RResidence time

sat, saturation

soln. solution

UV ultraviolet ray

% a/a area% (purity of area%)