Browse Prior Art Database

Process for preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine or its hydrochloride salt

IP.com Disclosure Number: IPCOM000250420D
Publication Date: 2017-Jul-13
Document File: 5 page(s) / 234K

Publishing Venue

The IP.com Prior Art Database

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 30% of the total text.

Process for preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-

1-amine or its hydrochloride salt

(2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine (referred to

herein as Compound 2) or its hydrochloride salt (referred to herein as Compound 2-

HCl) may be used as intermediates in the synthesis of 3-((2R,3R)-1-(dimethylamino)-

2-methylpentan-3-yl)phenol (referred to herein as Compound 1).

Disclosed herein are processes for preparation of Compound 2 and Compound

2-HCl, and their conversion to Compound 1.

Example 1:

Step a) Preparation of Compound 2

A solution of (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-yl

2,2,2-trifluoroacetate (referred to herein as Compound 3a, 1g, 2.879 mmol) in

isopropanol (IPA, 10V) was charged into autoclave. Palladium 10% on activated

carbon (50 % wetted), (0.16 g) and ammonium formate (1.81 g; 28.79 mmol) were

added to the solution. The reaction mixture was stirred at 80 °C for 16 hours. The

reaction mixture was then cooled to room temperature and filtrated. The obtained

solution was concentrated. The obtained residue was dissolved in dichloromethane

(DCM, 20 ml) and brine (15 ml) and then water (5 ml) was added. The pH was

corrected from 2.5 to 11.50 by the addition of 10% NaOH. The layers were separated;

then organic layer was dried over anhydrous Na2SO4 and evaporated to dryness

yielding 490 mg (72,3 %) of (2R,3R)-3-(3-methoxyphenyl) -N,N,2-

trimethylpentan-1-amine (2).

HPLC purity 86.96 area % (diastereomer LTQL)

UPLC/MS MH+ 236,1

Step b) Preparation of Compound 1

Compound 2 (0.44 g; 1.869 mmol) was dissolved in cold methansulfonic acid

(MsOH, 2.24 ml). L-methionine was added (0.422 g) and the reaction mixture was

heated to 80 °C, and was stirred for 16 hours. The reaction mixture was then cooled to

room temperature and dissolved in Ethyl acetate (22 ml) and water (22 ml). The

obtained two phase system was cooled to +10 °C and the pH measured was 0.3. The

pH was corrected by the addition of 10% NaOH to 11 and stirred for 1 hour at room

temperature. The layers were separated and the aqueous layer was extracted with

Ethyl acetate (1x22 ml). The organic layers were combined and washed with water,

dried at anhydrous Na2SO4 and evaporated to dryness yielding 0,40 g of 3-((2R,3R)-

1-(dimethylamino)-2-methylpentan-3-yl)phenol (1, 96 % yield).

Example 2:

Step a) Preparation of Compound 2

A solution of compound 3 (1g, 2.879 mmol) in absolute ethanol (EtOH, 10V)

was charged into autoclave. Palladium 10% on activated carbon (50 % wetted) (0.16

g), ammonium formate (0.18 g; 2.879 mmol) and formic acid (0.326 ml, 8.637 mmol)

were added. The obtained reaction mixture was stirred at 80 °C for 20 hours. The

reaction mixture was then cooled to room temperature and filtrated. The obtained

solution was concentrated. The residue was dissolved in DCM (20 ml) and brine (15

ml) and water (5 ml) were added. The pH was corrected from 2.0 to 11.50 by the

addition of 10% NaOH. The layers were separa...