1,1-Dichloroethane → amino-tropane TFA salt

To 8.0 mmol (1.802 g) of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1) in 10 mL of THF, in a 100 mL RBF, was added 1.1 equivalents of benzyl amine (2), neat, along with 480 μL (˜1 equivalent) of glacial acetic acid and 1.3 equivalents of sodium triacetoxyborohydride. The mixture was stirred at room temperature overnight. The crude product mixture was then evaporated to near dryness, acidified with 0.5 N HCl and washed with diethyl ether. The aqueous solution containing the crude product was made basic by 1 N NaOH, extracted into diethyl ether and evaporated to dryness. The product was taken up in methanol and purified by prep HPLC (using a Shimadzu preparative HPLC employing methanol/water and 0.1% trifluoroacetic acid buffer with a Phenomenex Luna, C18, 21 mm×100 mm, 10 μm column at a gradient of 0-50% B (where A=10% HPLC grade methanol/0.1% trifluoroacetic acid/90% HPLC grade water and B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water) and a flow rate of 25 mL/min. over 10 minutes with a 5-10 minute hold) to give the tert-butylcarbamate protected amino tropane (3) as an oily solid (48-79% yield). Post-purification LC/MS data was obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Column I (Phenomenex 10 μm C18, 4.6×30 mm), Solvent system I (gradient of 0-100% B where A=10% HPLC grade methanol/0.1% trifluoroacetic acid/90% HPLC grade water and B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), in 2 minutes with a 1 minute hold at a flow rate of 5 mL/minute. To 4 mmol of amino tropane (3) was added 4.8 mL of dichloroethane (DCE) along with 1.2 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours. The crude product was evaporated to near dryness then diluted with DCE and evaporated again to give a quantitative yield of the amino-tropane TFA salt (4).

1. customPost-purification LC/MS data
2. customwas obtained on a Shimadzu analytical LC /Micromass Platform LC (ESI+) at 220 nm
3. customThe crude product was evaporated
4. additionthen diluted with DCE
5. customevaporated again

ORD record

ord-6346014f0a05467da686976cc5bf2525

Source dataset

uspto-grants-2009_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07541353B2