¨
C. Adelwohrer et al.
(11.62 ml, 106.5 mmol) were added. The reaction mixture was O–CH2). Comparison with the non-deuterated product (N-
heated at 1001C overnight. After cooling down, the solids were methylmorpholine N-oxide): reference.12 1H NMR (CDCl3,
filtered off and the solvent was removed in vacuo. The crude 0.1 M): d 3.11 (dd, 2H, N–CHeq), 3.27 (s, 3H, N–CH3), 3.38 (dt,
product was purified by column chromatography, starting with 2H, N–CHax), 3.78 (dd, 2H, O–CHeq), 4.45 (dt, 2H, O–CHax). 13C
EtOAc/n-hexane (v/v 5 1:10). After removal of non-polar by- NMR (CDCl3, 0.1 M): d 61.3 (N–CH3), 61.7 (N–CH2), 66.0 (O–CH2).
products, compound 6 was eluted with EtOAc/n-hexane Microanalysis: calcd. for C5D11NO2 (128.21): C: 46.84, H 8.65;
(v/v 5 1:2). Removal of the solvent provided 6 as a light yellow found: C: 46.75, H 8.88.
liquid (3.88 g, 98%). 1H NMR: d 3.50 (s, 2H, CH2), 7.21–7.29 (m, 5H,
Trideuteroacetic acid isopropyl ester (11): To acetic acid-d4
Ar-H). 13C NMR: d 53.4 (pent, N-CD2, JC,D 5 22 Hz), 63.6 (Ph-CH2), (5.0 g, 4.47 ml, 0.078 mol) and 2-propanol (7 ml, 0.091 mol) was
66.3 (pent, O-CD2, JC,D 5 22 Hz), 127.1 (ArC-4), 128.4 (2C, ArC-3/5), added acidic ion exchanged resin (Dowex 50W, H1 form,
129.2 (2C, ArC-2/6), 137.7 (ArC-1). Comparison with the non- 100–200 mesh, 0.2 g). The mixture was stirred at r.t. for 30 min
1
deuterated product (N-benzyl-morpholine). H NMR: d 2.43 (m, and refluxed for 2 h. After cooling to r.t., the catalyst was filtered
4H, N–CH2), 3.48 (s, 2H, Ph-CH2), 3.70 (m, 4H, O–CH2), 7.24–7.32 off. The mixture was used for the subsequent ammonolysis
(m, 5H, ArH). 13C NMR: d 53.6 (N–CH2), 63.4 (Ph-CH2), 66.9 without purification. NMR data were obtained by a sample
(O–CH2), 127.0 (ArC-4), 128.2 (2C, ArC-3/5), 129.1 (2C, ArC-2/6), purified by distillation over MgSO4. 1H NMR: d 1.23 (d, 6H, 2x
137.7 (ArC-1).
Me), 5.02 (sept., 1H, CH(Me)2). 13C NMR:
d 21.4 (sept.,
JC,D 5 19 Hz, CD3), 22.0 (2x Me), 74.9 (Me2CH–O), 170.5 (COO).
Octadeutero-morpholine hydrochloride (7): N-Benzyl morpho-
line-d8 (3.88 g, 20.94 mmol) was dissolved in methanol (280 ml) Comparison with the non-deuterated product (isopropyl acet-
1
and dichloromethane (150 ml) and Pd/C (2.21 g, 10%) were ate): H NMR: d 1.22 (d, 6H, 2x Me), 2.05 (s, 3H, CH3 in Ac), 4.98
added. The reaction mixture was hydrogenated at ambient (sept., 1H, CH(Me)2). 13C NMR: d 21.8 (Me in Ac), 22.3 (2x Me),
pressure under stirring until N-benzyl morpholine was comple- 75.0 (Me2CH–O), 171.4 (COO).
tely consumed (TLC control). The reaction mixture was filtered
Trideuteroacetamide (12): The crude product obtained accord-
over celite and the remainder was washed extensively with ing to the above procedure was dissolved in ethanol (10 ml),
dichlormethane. The filtrate was concentrated in vacuo, and the cooled to 01C, and dropped into a concentrated aqueous
crude product 7, obtained as off-white solid (2.7 g, 98%), was solution of ammonia (5 ml) at 01C. After stirring for 30 min, the
1
used without further purification. H NMR (D2O, neutralized to mixture was allowed to reach r.t. and was stirred for additional
pH 7 with NaOD): d 3.21 (bs, 2H). 13C NMR (D2O, neutralized to 30 min. The solvents were removed in vacuo at a bath
pH 7 with NaOD): d 46.0 (N–CD2, JC,D 5 22 Hz), 67.4 (O–CD2, temperature of 601C. The remainder, which solidified upon
J
C,D 5 22 Hz). Comparison with the non-deuterated product cooling to r.t., was recrystallized twice from dry acetone to
1
(morpholine hydrochloride). H NMR (D2O, neutralized to pH 7 afford trideuteroacetamide (12, 3.01 g, 62% rel. to 10). 1H NMR: d
with NaOD): 2.05 (s, NH), 2.87 (m, 4H, N–CH2), 3.68 (m, 4H, 4.50 (s, br, NH2). 13C NMR: d 19.6 (sept., JC,D 5 19 Hz, CD3), 171.5
O–CH2). 13C NMR (D2O, neutralized to pH 7 with NaOD): 46.5 (CONH2). Comparison with the non-deuterated product (iso-
1
(N–CH2), 68.1 (O–CH2).
propyl acetate): H NMR: d 2.04 (s, 3H, Me), 4.25 (s, br, NH2). 13C
N-methyl morpholine N-oxide-d11 (9): Hydrochloride 7 (2.70 g, NMR: d 20.3 (Me), 170.9 (CONH2).
20.52 mmol) was dissolved in formic acid-d2 (5.00 g) and
Nona-adeutero-N,N-dimethylacetamide (14): Deutero-parafor-
paraformaldehyde-d2 (1.00 g) was added to the solution. The maldehyde (0.11 mol, 3.52 g) was dissolved in 40 ml of warm
reaction mixture was refluxed overnight. After cooling, formic acid (601C), and acetamide (3.0 g, 0.048 mol) was added.
10% aqueous NaOH was added (pH 5 10, control!), and the The mixture was refluxed for 24 h and fractionated under
aqueous phase was extracted with dichloromethane repeatedly. vacuum. The fraction containing mainly the desired product was
At least 10 extractions were necessary to bring the redistilled under normal pressure to give neat DMAc-d9 (14,
N-methylmorpholine quantitatively into the organic phase. 1.95 g, 0.02 mol, 42% rel. to 12). For NMR data see below.
The combined organic extracts were dried over MgSO4, the
Bis(trideuteromethylamine)– carbon dioxide complex (17): In a
solvent was removed, and an aliquot was taken for NMR stainless steel autoclave with Teflon coating, ammonium
analysis. To the crude product remainder, aqueous hydrogen carbonate (7.81 g, 0.1 mol), tetradeuteromethanol (7.21 g,
peroxide (30%, 4.65 g) was added at 01C, and the mixture 8.12 ml) and acidic aluminum oxide (15.0 g) was heated to
was stirred for overnight at r.t. The remaining peroxide 3501C for 3 h under stirring. Even though the vessel contained
was destroyed by activated MgO2. The solids were filtered no liquids at the temperature used, efficient agitation of the
and washed with ethanol. The filtrate was concentrated in alumina was crucial to complete the reaction within the time
vacuo, the oily remainder was further dried in vacuo for 5 days. used. The vessel was cooled to r.t. and carbon dioxide was
After sublimation in a Kugelrohr apparatus at 1201C in high introduced until a pressure of 5 bar was reached. After stirring
vacuum, compound 9 was obtained as white powder (1.9 g, for 10 min at r.t., the vessel was heated to 801C and the gases
72%).
slowly expanded into a trap cooled to about À101C by a ice/
N-trideuteromethyl-octadeuteromorpholine (8): 13C NMR: d 45.4 NaCl mixture. After reaching atmospheric pressure, the auto-
(sept., N–CD3, JC,D 5 18 Hz), 55.1 (pent, 2C, N–CD2, JC,D 5 22 Hz) clave was purged with a stream of nitrogen under stirring to
66.4 (pent, O–CD2, JC,D 5 22 Hz). Comparison with the non- desorb residual products from the alumina. In the cooling trap
deuterated product (N-methylmorpholine). 1H NMR (CDCl3, a colorless liquid condensed. The liquid was transferred into a
0.1 M): d 2.32 (s, 3H, N–CH3), 2.41 (‘t’, 4H, N–CH2), 3.71 (‘t’, 4H, flask and redistilled at a bath temperature of 801C and a
O–CH2). 13C NMR (CDCl3 0.1 M): d 46.4 (N–CH3), 55.5 (2C, N–CH2), condenser temperature of 01C to afford bis(trideuteromethyl-
66.9 (2C, O–CH2).
amine)–carbon dioxide complex (17, 7.50 g, 56% rel. to 15). It
N-trideuteromethyl octadeutero-morpholine N-oxide (9): 1H should be pointed out again that this procedure is not a
NMR (CDCl3, 0.1 M): d 3.72 (bs, H2O). 13C NMR (CDCl3, 0.1 M): d conventional distillation but a decomposition/reformation of a
60.6–61.4 (m, 3C, N–CH3, N–CH2), 65.2 (pent, 2C, JC,D 5 22 Hz, liquid addition complex of two gaseous components.
J. Label Compd. Radiopharm 2008, 51 28–32
Copyright r 2008 John Wiley & Sons, Ltd.