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

IP.com Disclosure Number: IPCOM000250301D
Publication Date: 2017-Jun-25
Document File: 4 page(s) / 197K

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

trimethylpentan-1-amine hydrochloride

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

(referred to herein as Compound 2) is an intermediate in the synthesis of 3-((2R,3R)-

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

Compound 2 can be prepared as an HCl salt, which can be later converted to

Compound 1.

Example 1:

Step a): preparation of Compound 2:

ZnCl2 (13.6 g, 0.099 mol) and 1,2-dimethoxyethane (76 mL) were charged into 500

mL round-bottom flask, equipped with Argon flow and cooled to 0 °C. To the

prepared suspension, NaBH4 (8.27 g, 0.219 mol) was added portion wise while

keeping the reaction temperature at 0-5 °C. Reaction mixture was allowed to warm up

to ambient temperature and stirred for 20 h to form Zn(BH4)2.

(2S,3S)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (referred to

herein as Compound 4) (5 g, 0.019 mol), ZnCl2 (4.07 g, 0.029 mol) and

dichloromethane (100 mL) were charged into 250 mL round-bottom flask, inertised

with Ar, stirred at ambient temperature for 10 min and then cooled to -10 °C. To the

prepared suspension, a solution of SOCl2 (1.73 mL, 0.024 mol) in dichloromethane

(50 mL) was added drop wise over 35 minutes while keeping the reaction temperature

at -10 to -5 °C. The reaction mixture was stirred for next 90 minutes when complete

conversion to (2S,3S)-3-chloro-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine

(referred to herein as Compound 3) was observed.

A previously prepared suspension of Zn(BH4)2 in 1,2-dimethoxyethane was

cooled to -10 °C and reaction mixture of freshly prepared compound 3 was added

drop wise over 45 minutes while keeping the reaction temperature at -10 to -5 °C.

Reaction mixture was allowed to warm up to ambient temperature and stirred for 20 h

when complete conversion to amine-borane complex was observed. Reaction mixture

was cooled to -10 °C and quenched with slow drop wise addition of saturated NH4Cl

(150 mL). White precipitate of inorganic salts was filtered off and layers were

separated. Water layer was extracted with one more portion of dichloromethane (100

mL). Organic layers were combined, dried at anhydrous Na2SO4 and evaporated to

2

dryness yielding 3.86 g of amine–borane complex which was dissolved in methanol

(50 mL) and refluxed for 20 h .

Methanol was evaporated to dryness. Remaining oil was dissolved in

dichloromethane (50 mL), 5% HCl solution (30 mL) was added and mixture was

stirred for 15 minutes. Layers were separated and water layer was extracted one more

time with dichloromethane (50 mL) at pH 1. Organic layers were combined, dried at

anhydrous Na2SO4 and evaporated to dryness yielding 3.39 g of ((2R,3R)-3-(3-

methoxyphenyl)-N,N,2-trimethylpentan-1-amine hydrochloride, i.e. compound 2 –

HCl salt.

Yield: 63 %

HPLC purity: 88.75 area % (0.11 area % (2R,3S)-diastereomer(

UPLC/MS: MH+ 236,1

1 H NMR (400 MHz, DMSO-d6): δ/ppm: 7.24 (t, J=7.88 Hz, 1H), 6.7...