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Novel preparation of crystalline forms L1 and L2 of L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester Disclosure Number: IPCOM000250258D
Publication Date: 2017-Jun-20
Document File: 3 page(s) / 485K

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Novel preparation of crystalline forms L1 and L2 of L-Valine, (2R,3R,11bR)-



L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-

benzo[a]quinolizin-2-yl ester referred to the following formula :

Disclosed herein are crystalline forms L1 and L2 of L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-

hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester

Crystalline form L1 of L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-

dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester:

L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-

benzo[a]quinolizin-2-yl ester form L1 may be characterized by X-ray powder diffractogram

as depicted in Figure 1.

PXRD method

XRPD analysis was performed on ARL (SCINTAG) powder X-Ray diffractometer model

X’TRA equipped with a solid state detector. Copper radiation of 1.5418 Å was used.

Scanning parameters: range: 2-40 degrees two-theta; scan mode: continuous scan; step size:

0.05°, and a rate of 3deg/min.

1: XRPD pattern of Valbenazine form L1Figure

Sample ID: Analyst: Firas, Sample name: VLB TN-7586+SI, Temp: 25.0°C

Date: 12/06/16 16:43 Step : 0.050° Integration Time: 1.000 sec

Range: 2.000 - 40.000° Cont. Scan Rate: 3.000 [°/min]

Vert. Scale Unit: [CPS]

Horz. Scale Unit: [deg]

2.0 6.0 10.0 14.0 18.0 22.0 26.0 30.0 34.0 38.0






The strong peak at about 28.5° is attributed to silicon powder added as an internal standard.

Main PXRD peaks:

Form L1 is characterized by main XRPD peaks at 6.0, 6.8, 12.0, 13.5, 16.8, 18.1, 19.9, 20.3,

23.9 and 26.4 ± 0.2 °2θ.

Example 1: Preparation of Crystalline form L1 of L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-

hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester

L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-

benzo[a]quinolizin-2-yl ester, di(4-methylbenzenesulfonate) starting material can be prepared

according to methods known from the literature (WO2017075340A1).

L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-

benzo[a]quinolizin-2-yl ester, di(4-methylbenzenesulfonate) (70 g) was mixed with Heptane

(490 ml, 7 vol) at RT followed by dropwise addition of NH4OH solution (25%, 21.25 ml, 1.5

vol). To the obtained heavy slurry mixture, water (245 ml, 3.5 vol) was added and the pH...