ChemicalBook CAS DataBase List Atomoxetine hydrochloride

Atomoxetine hydrochloride synthesis

8synthesis methods

Product Name:Atomoxetine hydrochloride
CAS Number:82248-59-7
Molecular formula:C17H22ClNO
Molecular Weight:291.82

The 3-aryloxy substituent was introduced utilizing a chiral alcohol by either the Mitsunobu reaction or by nucleophilic aromatic displacement. Because of the expense and difficulty of the Mitsunobu reaction on large scale, the commercial process adopts the nucleophilic aromatic substitution method. 3- Chloropropiophenone (37) was asymmetrically reduced with borane and catalytic amount of (S)-oxazaborolidine (8) in THF at 0°C to give chiral alcohol 38 in 99% yield and 94% e.e. The chiral alcohol was further purified by recrystallization to greater than 99% e.e.. Subsequent treatment of chloride 38 with excess dimethylamine (40% in water) in ethanol gave dimethylamine alcohol 39 in 90% yield. Alcohol 39 was then subjected to nucleophilic aromatic displacement in the presence of NaH in DMSO with 1- fluoro-2-(t-butylimino)benzene (41), which was prepared in high yield from 2-fluorobenzaldehyde (40). The displacement product 42 was obtained in 98% yield, and the imine 42 was subsequently hydrolyzed with acetic acid in water at low temperature to give the corresponding aldehyde 43 in 96% yield. Sodium borohydride was employed to reduce aldehyde 43 to alcohol in cold methanol and the intermediate alcohol was converted to chloride 44 with thionyl chloride. Chloride 44 was then reduced with zinc metal under acidic conditions to give methyl adduct 45 in 95% yield and 94% e.e. Finally, phenyl chloroformate and triethylamine was used to transform dimethylamine 45 to monomethyl amine, which was subsequently treated with HCl in EtOAc under reflux to give atomoxetin hydrochloride (IV) in 98% yield and 99% e.e. from 45.

615-37-2 Synthesis

615-37-2
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$5.00/5g

(R)-(+)-3-(N-METHYLAMINO)-1-PHENYL-1-PROPANOL

115290-81-8
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$130.00/2.5mg

82248-59-7
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$14.00/25mg

Yield:82248-59-7 99%

Reaction Conditions:

Stage #1:ortho-methylphenyl iodide;(R)-N-methyl-3-phenyl-3-hydroxypropylamine with potassium carbonate;copper(l) iodide in toluene at 148; for 21 h;Heating / reflux;Ullmann type reaction;
Stage #2: with hydrogenchloride in water; pH=1 - 2
Stage #3: with sodium hydroxide in water; pH=11 - 12

Steps:

5
(R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride:; A 3 -necked 100 ml glass reactor was flushed for 15 min with N₂ and subsequently charged with 15 g (90.8 mmol) of the above mentioned (3R)-methyl-3-hydroxy-3- phenylpropylamine (>99 % ee, chiral HPLC), potassium phosphate (28.9 g, 136.2 mmol) and 1.73 g copper(I)iodide (9.8 mmol, 10 mol-%). 60 ml of toluene was added to the mixture and the suspension was stirred for 5 min. 12.8 ml (100 mmol) of 2-iodotoluene was added and the reaction mixture was heated to reflux for 24 h. After cooling to room temperature, the suspension was filtered and the filter cake was washed with 60 ml of toluene. 75 ml of water was added to the filtrate and the mixture was stirred for 10 min at room temperature. The aqueous phase was brought to pH 1-2 with 30 % HCl and the phases were separated. 60 ml of toluene was added to the aqueous phase and aqueous NaOH was added until pH 12-14 of the aqueous phase was reached. After stirring for EPO 10 min the phases were separated. The organic phase was evaporated under reduced pressure yielding 25 g of an oil.The oil was redissolved in 80 ml of toluene, warmed to 80 °C and 36 g of a 10 % HCl- ethyl acetate solution was added dropwise to the solution. During cooling of the solution a white solid precipitated. After 5 h at room temperature, the suspension was filtered and the residue was dried in vacuum at about 50 °C to yield 22 g (75.4 mmol, 83 %) of (R)- N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride.The (R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride salt was placed in a 100 ml reaction vessel and 55 ml of isopropanol was added. Upon heating to reflux temperature all solids were dissolved. Slow cooling to room temperature gave 18.1 g (82 %) of colorless (R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride (>99 % ee, HPLC).

References:

FERMION OY WO2007/10082, 2007, A1 Location in patent:Page/Page column 18-19

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