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INTERMEDIATES IN THE PREPARATION OF (R)-6-HYDROXY-8-{1-HYDROXY-2-[2-(4-METHOXYPHENYL)-1,1-DIMETHYLETHYLAMINO]ETHYL}-4H-BENZO[1,4]OXAZIN-3-ONE HYDROCHLORIDE

IP.com Disclosure Number: IPCOM000246935D
Publication Date: 2016-Jul-18

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The IP.com Prior Art Database

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Page 01 of 12

INTERMEDIATES IN THE PREPARATION OF (R)-6-HYDROXY-8-{1-HYDROXY- 2-[2-(4-METHOXYPHENYL)-1,1-DIMETHYLETHYLAMINO]ETHYL}-4H-

BENZO[1,4]OXAZIN-3-ONE HYDROCHLORIDE

    Provided herein are crystalline forms of intermediates in the preparation of (R)6hydroxy8{1hydroxy2[2(4methoxyphenyl)1,1dimethylethylamino]ethyl}4Hbenzo[1,4]oxazin3one hydrochloride.

Crystalline 6-benzyloxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-

ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one hydrochloride (referred to as

compound A):

   Samples of Compound A were prepared according to the process reported in IPCOM000245679D (the isolated hydrochloride salt was recrystallized by dissolution in a trimethylamine/methanol mixture followed by precipitation after addition of 37% HCl at 35/40°C) and were analyzed by X-ray powder diffraction ("XRPD"). Figure 1 present the XRPD of the obtained crystalline form.

Figure 1: XRPD of the crystalline form of Compound A:

The crystalline form of Compound A is characterized by XRPD peaks as provided in the table below ( ± 0.2 deg. 2θ):

Pos. [°2θ]

Intensity (counts)

30000

20000

10000

0

5 10 15 20 25 30 35 40 2Theta (°)

Rel. Int. [%]
6.3 14.14 100.0
7.3 12.05 3.2
9.2 9.61 29.3


10.1 8.79 0.6

d-spacing


[Å]


12.5 7.08 96.9
13.2 6.70 1.7
14.7 6.02 4.3
14.9 5.96 5.4
15.4 5.75 5.8
16.5 5.38 2.7


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17.1 5.18 10.1
18.5 4.81 30.8
18.8 4.72 35.6
19.1 4.65 3.8
19.4 4.58 17.6
19.6 4.54 8.8
20.2 4.39 8.3
20.8 4.27 6.5
21.9 4.06 5.0
22.1 4.01 8.2
22.4 3.96 6.4
22.8 3.89 21.9
23.4 3.80 10.0
23.9 3.72 9.8
24.2 3.67 28.3
24.5 3.63 7.2
25.1 3.54 12.3
25.6 3.49 4.7
25.7 3.47 5.3
26.4 3.38 4.0
26.9 3.32 4.2
27.3 3.26 2.6
27.8 3.21 19.7
28.2 3.17 12.5
28.8 3.10 4.2
29.0 3.08 3.6


29.4 3.04 1.6
29.6 3.01 2.4
30.0 2.98 10.2
30.2 2.95 11.6
30.4 2.94 5.3
30.9 2.90 3.5
31.6 2.83 9.9
31.9 2.80 6.6
32.1 2.78 6.4
32.7 2.74 3.1
33.1 2.71 2.2
33.4 2.68 2.7
33.8 2.65 7.2
34.3 2.62 6.3
34.6 2.59 2.8
34.9 2.57 1.9
35.4 2.53 1.9
35.8 2.51 3.6
35.9 2.51 3.9
36.2 2.48 4.2
37.2 2.41 3.5
38.2 2.35 1.7
38.7 2.32 1.9
39.3 2.29 3.7
39.7 2.27 8.0

Crystalline 6-benzyloxy-8-{2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-acetyl}-

4H-benzo[1,4]oxazin-3-one hydrochloride (referred to as compound B) Form 1:

   Samples of Compound B were prepared according to the process reported in IPCOM000245679D (the hydrochloride salt was obtained by precipitation after addition of 37% HCl to the reaction mixture in DMF/EtOH at 25/30°C) and were analyzed by X-ray powder diffraction ("XRPD"). Figure 2 present the XRPD of crystalline form 1 of compound
B.


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Figure 2: XRPD of crystalline form 1 of Compound B:

Intensity (counts)

15000

10000

5000

0

5 10 15 20 25 30 35 40 2Theta (°)

Crystalline form 1 of Compound B is characterized by XRPD peaks as provided in the table below ( ± 0.2 deg. 2θ):

Pos. [°2θ]

d-spacing
[Å]

Rel. Int. [%]


5.7 15.42 100.0
6.0 14.64 6.2
9.7 9.13 8.6


11.5 7.71 78.5
11.7 7.56 6.6
12.0 7.35 17.0
13.6 6.53 5.0
14.5 6.12 62.4
15.0 5.91 14.0
16.1 5.49 11.4
16.3 5.42 2...