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Process and solid state forms of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate and salts thereof

IP.com Disclosure Number: IPCOM000250080D
Publication Date: 2017-May-29
Document File: 6 page(s) / 264K

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Process and solid state forms of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-

1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate and salts thereof

Described hereinafter synthesis of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-

methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate (also named

4-[2-Amino-6-[(1R)-1-[4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl]- 2,2,2-trifluoroethoxy]-4-

pyrimidinyl]-L-phenylalanine ethyl ester), referred to herein as Compound 1.

Also described are solid state forms of Compound 1; hippurate salt of Compound 1 and

intermediates in their synthesis.

Crystalline form of Compound 1

Figure 1:

* The peak at 28.48°belongs to Silicon

Main PXRD peaks: 8.5, 11.7, 13.8, 15.2, 16.9, 19.1, 20.8, 21.4, 23.5 and 24.0 degrees two theta

± 0.2 degrees two theta

5 10 15 20 25 30 35 2Theta (°)

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Amorphous form of Compound 1

Figure 2:

Amorphous form of hippurate salt of Compound 1

Figure 3:

5 10 15 20 25 30 35 2Theta (°)

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Crystalline form of (R)-4-chloro-6-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-

trifluoroethoxy) pyrimidin-2-amine; intermediate A in the synthesis of Compound 1

Figure 4:

Main PXRD peaks: 9.8, 10.5, 13.0, 16.4, 17.8, 19.7, 21.0, 24.6, 27.3 degrees two theta ± 0.2

degrees two theta

Crystalline form of (S)-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-

yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic

acid, intermediate B in the synthesis of Compound 1

Figure 5:

5 10 15 20 25 30 35 2Theta (°)

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Main PXRD peaks: 6.8, 8.4, 8.7, 10.4, 10.8, 11.4, 16.4, 16.8, 19.2, 20.6 degrees two theta ± 0.2

degrees two theta

X-ray powder diffraction method:

Sample after being powdered in a mortar and pestle is applied directly on a silicon plate holder.

The X-ray powder diffraction pattern was measured with Philips X'Pert PRO X-ray powder

diffractometer, equipped with 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 described peak positions were determined using silicon powder as an internal standard in an

admixture with the sample measured. The position of the silicon (Si) peak was corrected to silicone

theoretical peak: 28.45 degrees two theta and the positions of the measured peaks were corrected

respectively.

Example 1: (R)-4-chloro-6-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)

pyrimidin-2-amine (Intermediate A)

(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (15 g, 51,6 mmol)...