KR-102961844-B1 - Method for preparing amino diaryl ether and amino diaryl ether hydrochloride salt

Abstract

The present invention relates to a method for preparing a compound of formula (I) described herein, comprising the step of reducing the compound of formula (II) described herein using hydrogen in the presence of a palladium catalyst and a polar, aprotic solvent or a solvent that is a C3-C10 alcohol: Chemical formula (I) Chemical formula (II) The present invention also relates to hydrochloride salts and monohydrochloride salts of the compound of formula (I) described in this specification, and methods for preparing the same.

Inventors

• 바우어 마이클
• 한 우베
• 밥퍼트 에르하르트

Assignees

• 셀레스티아 바이오테크 아게

Dates

Publication Date

20260507

Application Date

20190620

Priority Date

20180621

Claims (20)

1. A compound of formula (IIa) is reduced to hydrogen in the presence of a palladium catalyst and a polar, aprotic solvent or a C3-C10 alcohol to form a compound of formula (Ia), and A method comprising reacting a compound of formula (Ia) with less than 1.5 molar equivalents of hydrochloric acid to form a monohydrochloride salt of the compound of formula (Ia). Method for preparing a monohydrochloride salt of a compound of chemical formula (Ia): Chemical formula (Ia) Chemical formula (IIa)
2. In paragraph 1, A method for manufacturing the above palladium catalyst being palladium on activated carbon.
3. In paragraph 1 or 2, A method of manufacturing in which the above palladium catalyst is present in an amount of less than 7 mol%.
4. In paragraph 1, A method of preparation in which the solvent is selected from 2-propanol, acetone, 2-butanone, 3-methyl-2-butanone, cyclohexanone, acetonitrile, chlorobenzene, methylene chloride, chloroform, trichloroethane, ethylene chloride, benzaldehyde, sulfolane, ethyl acetate, propyl acetate, amyl acetate, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, diethyl carbonate, propylene carbonate, ethylene carbonate, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, and mixtures thereof.
5. A method of manufacturing according to claim 1, wherein the solvent is ethyl acetate.
6. A manufacturing method according to claim 1, further comprising the step of contacting a compound of formula (Ia) with activated charcoal.
7. A manufacturing method according to claim 1, further comprising the step of crystallizing the monohydrochloride salt.
8. In claim 1, the compound of the above formula (IIa) is, A method of preparation obtained by a method comprising the step of reacting a compound of formula (IIIa) with a compound of formula (IVa); and optionally crystallizing a starting material of formula (IIa): Chemical formula (IIIa) Chemical formula (IVa) In the above formula, Cl is the leaving group.
9. Monohydrochloride salt of the compound of chemical formula (Ia): Chemical formula (Ia)
10. A monohydrochloride salt according to claim 9, characterized by having a melting point of 173 °C.
11. A pharmaceutical formulation comprising a monohydrochloride salt according to claim 9 or 10 for use in the treatment and/or prevention of cancer.
12. Monohydrochloride salt of paragraph 9 or 10 that is intended for use in the treatment and/or prevention of cancer.
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Description

Method for preparing amino diaryl ether and amino diaryl ether hydrochloride salt The present invention relates to a method useful for preparing an amino diaryl ether of formula (I), in particular 6-(4-( tert -butyl)phenoxy)pyridine-3-amine (formula (Ia)). The present invention further relates to a method useful for preparing a hydrochloride salt of a compound of formula (I), in particular a monohydrochloride salt of a compound of formula (I), and a monohydrochloride salt of said compound of formula (I), in particular 6-(4-( tert -butyl)phenoxy)pyridine-3-amine (formula (Ia)). The compound of formula (I) can be prepared using the method disclosed in WO2013/093885 as a modulator of the Notch signaling pathway, which is useful for the treatment and/or prevention of cancer, particularly for the treatment and/or prevention of Notch-dependent cancer. The method disclosed in WO2013/093885 has the disadvantages that (i) the compound of formula (I) obtained by the method is contaminated by the catalyst used, and (ii) the compound of formula (I) is further contaminated by by-products due to the occurrence of side reactions. These disadvantages affect, for example, the physical appearance and solubility of the compound of formula (I) and further affect manufacturing steps such as grinding. Consequently, the method described in WO2013/093885 is not suitable for the large-scale production of pharmaceutical-grade compounds of formula (I). Therefore, it would be advantageous to develop an alternative or improved method for preparing the compound of formula (I) that does not exhibit some or all of these disadvantages. The present invention is described in detail below with reference to the accompanying drawings: Figure 1 shows the differential scanning calorimetry thermogram (DSC) of the monohydrochloride salt of the compound of formula (Ia), namely 6-(4-( tert -butyl)phenoxy)pyridine-3-amine monohydrochloride. The DSC thermogram indicates that 6-(4-( tert -butyl)phenoxy)pyridine-3-amine monohydrochloride exhibits a melting point accompanied by an onset of 170.9 °C and a peak at 173.4 °C. Figure 2 shows the DSC thermogram of the compound of formula (Ia), namely 6-(4-( tert -butyl)phenoxy)pyridine-3-amine. The DSC thermogram indicates the melting point of the compound of formula (Ia), accompanied by an onset at 90.8 °C and a peak at 92.0 °C. Figure 3 shows the X-ray powder diffraction (XRPD) diffractogram of the monohydrochloride salt of the compound of formula (Ia), namely, 6-(4-( tert -butyl)phenoxy)pyridine-3-amine monohydrochloride. Figure 4 shows the HPLC chromatogram of the compound of formula (Ia), namely 6-(4-( tert -butyl)phenoxy)pyridine-3-amine (purity: 99.9%), obtained by the method of the present invention (see Example 3A). FIG. 5 shows a reference HPLC chromatogram of the compound of formula (Ia), namely 6-(4-( tert -butyl)phenoxy)pyridine-3-amine, obtained by the method described in WO2013/093885 (Example 2). FIG. 6 shows the DSC thermal analysis of a substance (Example 5) obtained by reacting 6-(4-( tert -butyl)phenoxy)pyridine-3-amine (chemical formula (Ia)) with hydrochloric acid in an amount exceeding 1.5 molar equivalents. The DSC thermal analysis shows that the substance does not exhibit a distinct melting point, which suggests that at least two species exist. The present invention is described and illustrated in more detail below. definition The term "approximately" refers to +/- 10% of a given measurement. The term "polar, aprotic solvent" refers to a solvent that does not contain acidic hydrogen (Morrison and Boyd, Organic Chemistry 3rd Edition, 31 (1974)) and exhibits polarity according to the E T (30)-scale between about 36 kcal/mol and about 49 kcal/mol (C. Reichardt, Chem. Rev. 1994 , 94, 2319-2358; C. Reichardt, G. Schaefer, Liebigs Ann . 1995 , 1579-1582; R. Eberhardt, S. Loebbecke, B. Neidhart, C. Reichardt, Liebigs Ann. /Recueil 1997 , 1195-1199; C. Reichardt, Green Chem. 2005 , 7, 339-351; (VG Machado, RI Stock, C. Reichardt, Chem. Rev. 2014 , 114, 10429-10475.) refers to a solvent. The interaction of proton donation or proton acceptance is usually greatest when the atom attached to the proton is nitrogen or oxygen. This behavior contributes to hydrogen bonding. Generally, the strength of hydrogen bonding increases as the acidity of the proton-donor increases and as the basicity of the proton-acceptor increases. A polar, aprotic solvent suitable for use in the present invention is a solvent that does not contain acidic or basic functional groups and does not decompose into an acid or base, including but not limited to ketones, nitriles, substituted aromatics, such as halogenated aromatics, amides, sulfoxides, alkyl carbonates, chlorinated aliphatic, aromatic aldehydes, sulfones, esters, etc. Polar, aprotic solvents preferred for use in the present invention include, but are not limited to, acetone, 2-butanone, 3-methyl-2-butanone, cyclohexanone, acetonitrile, chlorobenzene, methylene chlori