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Crystalline intermediates of 5-[[[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propanoyl]-[(1S)-1-(5-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid

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Publication Date: 2015-Jul-26
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Crystalline intermediates of 5-[[[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propanoyl]-[(1S)-1-(5-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid

(S)-methyl 2-methoxy-5-(((1-(4-phenyl-1H-imidazol-2-yl)ethyl)amino)methyl)benzoate hydrochloride salt (referred to as Compound 1), methyl 5-(((S)-2-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoate, hydrochloride salt (referred to as Compound 2), and 5-(((S)-2-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoic acid (referred to as Compound 3) are intermediates in the synthesis of 5-[[[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propanoyl]-[(1S)-1-(5-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid (reffered to as Compound A)

Disclosed hereinafter are solid state forms of Compound 1, Compound 2 and Compound 3.

Compound 1 crystalline form

Figure 1. PXRD pattern of crystalline Compound 1:

Main PXRD peaks:  6.1, 7.2, 8.9, 12.2, 13.3, 13.8, 15.9, 16.6, 17.8, 19.4, 22.5, 23.1, 24.0, 26.1, 26.8, 27.7, 30.8 and 36.1 ± 0.2 °2θ


Figure 2. FTIR spectrum of crystalline Compound 1:

Compound 2 crystalline form

Figure 3. PXRD pattern of crystalline Compound 2:

Main PXRD peaks: 6.6, 7.3, 8.3, 10.0, 10.6, 11.8, 12.4, 13.1, 13.5, 14.7, 15.5, 16.5, 16.9, 18.1, 18.6, 19.3, 20.1, 20.4, 21.2, 24.1, 25.0, 26.6, 28.3 and 31.3 ± 0.2 °2θ.


Figure 4. FTIR spectrum of crystalline Compound 2:

Compound 3 crystalline form

Figure 5. PXRD pattern of crystalline Compound 3:

Main PXRD peaks: 3.9, 6.8, 7.8, 9.9, 10.4, 11.4, 12.0, 13.8, 14.9, 15.7, 16.4, 16.8, 17.1, 18.0, 19.4, 20.2, 21.8, 22.4, 22.7, 23.2, 23.7, 24.2, 25.1, 25.7, 26.9, 27.5, 27.8, 28.6, 29.9, 30.2, 31.8 and 33.3  ± 0.2 °2θ.

Figure 6. FTIR spectrum of crystalline Compound 3:

Compound 3 amorphous form

Figure 7. PXRD pattern of amorphous Compound 3:


Figure 8. FTIR spectrum of amorphous Compound 3:

Experimental:

PXRD method:

After being powdered using mortar and pestle, samples were applied directly on a silicon plate holder. The X-ray powder diffraction pattern was measured with a Philips X'Pert PRO X-ray powder diffractometer, equipped with a Cu irradiation source = 1.54184 Ǻ (Ǻngström), X’Celerator (2.022º 2θ) detector. Scanning parameters: angle range: 3-40 deg., step size 0.0167, time per step 37 s, continuous scan. The accuracy of peak positions was defined as +/- 0.2 degrees due to experimental differences like instrumentations and sample preparations.

FTIR method:

Instrument: Nicolet 6700 FT-IR spectrometer

Sample preparation: Sample was prepared as KBr pellet. Empty sample compartment was used for background spectrum acquisition.

Scanning parameters

The spectra were scanned between: 4000-400 cm-1

All the spectra were measured in 16 scans

Resolution: 4.0 cm-1


Preparation examples

Preparation of crystalline (S)-methyl 2-meth...