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(R)(-)alpha1-[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3-Benzenedimethanol hydrochloride process related impurities

IP.com Disclosure Number: IPCOM000029577D
Publication Date: 2004-Jul-08
Document File: 6 page(s) / 143K

Publishing Venue

The IP.com Prior Art Database

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(R)(-)α1-[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3- Benzenedimethanol hydrochloride process related impurities

Process related impurities are strictly connected to solvent (Methanol) used in the (R)(-)α1- [[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3-Benzenedimethanol.(D)-Dibenzoyltartrate salt precipitation, purification and to the resolving agent used. They are as follows:


1) α1-[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-3-methoxymethyl-1-benzenemethanol (SLB-prim-OMe)

The impurity has the following chemical structure:

HO

H 3CO

OH

H N

SLB-prim-OMe

SLB-prim-OMe is the reaction product of (R)(-)α1-[[(1,1-Dimethylethyl)amino]methyl]-4- hydroxy-1,3-Benzenedimethanol hydrochloride benzylic alcohol with methanol in presence of hydrochloric acid during the transformation of the dibenzoyltartrate to (R)(-)α1-[[(1,1- Dimethylethyl)amino]methyl]-4-hydroxy-1,3-Benzenedimethanol hydrochloride. The same impurity forms in high quantity (5-10% in area) when (R)(-)α1-[[(1,1- Dimethylethyl)amino]methyl]-4-hydroxy-1,3-Benzenedimethanol.(D)-Dibenzoyltartrate salt is dried at 55-60°C for 12-15 hrs.

SLB-prim-OMe is detected in (R)(-)α1-[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3- Benzenedimethanol hydrochloride by the HPLC method described below, and eluted at RRT =
1.88
. It was identified by NMR and elemental analysis. It was prepared together other two impurities (at RRT = 1.42 and RRT = 2.38) by reaction of (R)(-)α1-[[(1,1- Dimethylethyl)amino]methyl]-4-hydroxy-1,3-Benzenedimethanol hydrochloride with methanol in presence of anhydrous hydrochloric acid. It has been isolated by silica gel column and crystallized.

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Its maximum amount in crude (R)(-)α1-[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3- Benzenedimethanol hydrochloride is 0.07% and 0.05 in pure (R)(-)α1-[[(1,1- Dimethylethyl)amino]methyl]-4-hydroxy-1,3-Benzenedimethanol hydrochloride. For this impurity, the following information was obtained from SciFinder, performing an exact structure search:
Registry Number: 18910-70-8
Formula: C 14H23NO3

CA Index Name: Benzenemethanol, α-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-3-

             (methoxymethyl)- (9CI) Other Names: Benzyl alcohol, α-[(tert-butylamino)methyl]-4-hydroxy-3-

(methoxymethyl)- (8CI)

-- Properties --

Calculated

Property Value Condition Note Bioconc. Factor 1 pH 1 (1) ACD Bioconc. Factor 1 pH 4 (1) ACD Bioconc. Factor 1 pH 7 (1) ACD Bioconc. Factor 1 pH 8 (1) ACD Bioconc. Factor 1 pH 10 (1) ACD Boiling Point 402.2±40.0 °C Press: 760.0 (1) ACD

Torr Enthalpy of Vap. 68.89±3.0 kJ/mol (1) ACD Flash Point 197.0±49.2 °C (1) ACD H acceptors 4 (1) ACD H donors 3 (1) ACD Koc 1 pH 1 (1) ACD Koc 1 pH 4 (1) ACD Koc 1 pH 7 (1) ACD Koc 4.40 pH 8 (1) ACD Koc 17.5 pH 10 (1) ACD logD -2.16 pH 1 (1) ACD logD -2.16 pH 4 (1) ACD logD -1.22 pH 7 (1) ACD

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logD -0.31 pH 8 (1) ACD logD 0.29 pH 10 (1) ACD logP 0.937±0.335 (1) ACD Molar Solubility Very So...