Duloxetine hydrochloride synthesis

11synthesis methods

Product Name:Duloxetine hydrochloride
CAS Number:136434-34-9
Molecular formula:C18H20ClNOS
Molecular Weight:333.88

The synthesis from Lilly’s group is depicted in Scheme 4. Friedel-Crafts acylation of thiophene (24) by 3- chloropropanoyl chloride (25) with SnCl4 as Lewis acid gave ketone 26 which was then enantioselectively reduced with (R )-1-methyl-3,3-diphenyl-tetrahydropyrrolo[1,2- c][1,3,2]oxazaborole (27) in the presence of borane in THF to give (S)-3-chloro-1-(2-thienyl)-1-propanol (28). Compound 28 was subjected to Finkelstein reaction to give (S)-3-iodio-1-(2-thienyl)-1-propanol which was reacted with methylamine in THF to give compound 29. The alcohol 29 was then used in a nucleophilic displacement reaction with 1-fluoronaphthalene (30) in the presence of sodium hydride in DMA to give duloxetine free base in 88% yield. Finally, the free base was treated with HCl to yield duloxetine hydrochloride (IV).

321-38-0 Synthesis

321-38-0
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$6.00/10g

(S)-3-(MethylaMino)-1-(2-thienyl)-1-propanol

116539-55-0
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$8.00/1g

136434-34-9
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$25.00/10mg

Yield:136434-34-9 93%

Reaction Conditions:

Stage #1:1-Fluoronaphthalene;(S)-3-methylamino-1-(2-thienyl)-1-propanol with sodium hydride in paraffin oil (nujol);dimethyl sulfoxide at 20 - 50;
Stage #2: with hydrogenchloride;acetic acid in Isopropyl acetate at 0 - 15; for 5 h;

Steps:

1
NaH (60 % in paraffin oil, 2.92 g) was suspended in DMSO (75 mL). After mixing of hydride (about 10 minutes) (S)-3-methyl-amino- 1 -(2-thienyl)- 1 -propanol (l Og) at 20 °C was added carefully. Stirring was started slowly and the reaction mixture was heated to 30-40 °C. A solution of F-naphthalene (9 mL) in DMSO (10 mL) was then added dropwise in about 30 minutes. Red-brownish suspension was heated to 40-50 °C for 9 to 18 hours. Heating was stopped, the mixture was cooled to 23 °C and quenched with a slow dropwise addition into ice-cold solution of water (200 mL) and acetic acid (12 mL). It was heated to 20 °C (pH ~ 5-5.5) and hexane (80 mL) was added. After extraction the phases were separated and the aqueous phase was alkalized with 50 % NaOH (12 mL). After complete addition of hydroxide iPrOAc (lOOmL) was added to the aqueous phase and during vigorous stirring the two-phase system was heated to 20 °C. The phases were separated and the aqueous phase was extracted one more time with iPrOAc (100 mL). The combined organic phases were rinsed 2X with water (2 X 80 mL) and treated for 30 minutes in hot with activated carbon. It was hot filtered and the filtrate was cooled. Into the cooled extract acetic acid (5 mL, 15+/-5°C) was added and the product was precipitated slowly with 2.5M HC1 (23 mL) in iPrOAc under vigorous stirring. The white suspension was stirred for 5 hours, cooled to 0-5 °C. It was filtered off and the filtrate was rinsed with iPrOAc. The product was dried in a vacuum drier for 5 hours. Obtained were 16.33 g (84 %) of crude duloxetine chloride (HPLC purity 99.87 %; 99.0 % ee), which was recrystallized from iPrOH. 15.18 g (93 %) of pure product (HPLC purity 99.94 % and 99.9 % ee) were obtained

References:

KRKA, D.D., NOVO MESTO;BOMBEK, Sergeja;MERSLAVIC, Marjo;BENKIC, Primoz;ZAJC, Natalija;VRECER, Franc WO2011/128370, 2011, A1 Location in patent:Page/Page column 21

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132335-46-7 Synthesis