Organic Process Research & Development
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cooled below 40 °C over 30 min. The solvent was distilled under
reduced pressure (by rotary evaporator) until reaching about
one-third of the original volume. EtOAc (700 mL) was added
and the mixture stirred at 10À15 °C for 10 min. The solids were
filtered and washed with EtOAc (2 Â 200 mL). The filtrate was
washed with 20% brine (2 Â 150 mL) and with saturated brine
(75 mL). The organic layer was dried with sodium sulfate (120 g),
filtered, and concentrated under reduced pressure to approxi-
mately 200 mL. The crude product solution was sampled for
HPLC analysis and used directly in the next step. HPLC analysis
indicated 94.2% purity.
(200 mL) was added and the solution concentrated again to
approximately 100À125 mL. Toluene was added to a final volume
of approximately 350 mL. A purified sample of 11, obtained from
silica gel chromatography, solidified upon standing overnight at
1
ambient temperature; MS (ESI) m/z 333 [M + 1]+. H NMR
(CDCl3) 1.43 (s, 18 H), 2.71À2.77 (m, 1 H), 3.17À3.26 (m,
2 H), 3.50À3.58 (m, 2 H), 3.71 (s, 3 H), 5.22 (s, 2 H).
tert-Butyl 2-(3-Ethyl-1,2,4-oxadiazol-5-yl)propane-1,
3-diyldicarbamate (12). Propionamide Oxime. Propionitrile
(55.0 g, 0.998 mol) was combined with MeOH (440 mL) and
the solution brought to reflux. A solution of 50% aqueous
hydroxylamine (50.7 g, 0.768 mol) was added dropwise over
20 min. The mixture was refluxed for 8 h, cooled, and partially
concentrated under vacuum. The residue was co-evaporated
with toluene (300 mL). Co-evaporation was repeated with
additional toluene (300 mL), and the resulting oil was dried for
16 h under high vacuum (<1 mbar) at ambient temperature to
56.8 g of oil which solidified upon cold storage. MS (ESI) m/z
89 [M + 1]+. 1H NMR (DMSO-d6) 1.01 (t, 3H), 1.96 (q, 2H),
5.29 (s, 2H), 8.68 (s, 1H).
Methyl 3-Amino-2-(aminomethyl)propanoate Dihydro-
chloride (10). Product solution containing 9 in EtOAc (0.385
mol theoretical) was concentrated to about 175 mL (yellow oil)
and treated with MeOH (300 mL). The solution was transferred
to a Parr bottle containing 36.0 g of wet 10% Pd/C and HOAc
(600 mL). The mixture was hydrogenated for 15 h at 38 °C,
starting at 50 psi hydrogen pressure. The mixture, upon cooling,
was filtered through Celite and washed with MeOH (4 Â
100 mL). The filtrate was concentrated at 30 mbar pressure with
the bath at 45 °C, until no more distillate collected. The residue
was treated with ACN (1 L) and concentrated to remove HOAc.
The co-evaporation was then repeated with additional ACN (1 L).
The residue was dissolved in MeOH (500 mL), cooled below
15 °C, and treated slowly (dropwise) with conc. HCl (95 mL),
keeping the temperature below 26 °C. The mixture was con-
centrated until the distillate stopped collecting (30 mbar, 45 °C
bath temp). The HCl exchange cycle was repeated, again with
MeOH (500 mL) and conc. HCl (95 mL), and the batch was
concentrated until the distillate stopped collecting. The residue
was taken up in ACN (500 mL) and concentrated to remove
water. The residue was treated with another portion of ACN
(500 mL) and concentrated until the distillate stopped collect-
ing. The residue was taken up in MeOH (400 mL) and refluxed
for about 15 min to dissolve solids. The heat was turned off, and
the solution was treated slowly with EtOAc (400 mL). Solids
formed as the mixture cooled; stirring was continued at ambient
temperature overnight. Solids were collected and washed with
cold EtOAc/MeOH (75:25, 200 mL) and then with EtOAc
(200 mL). The solids were dried for 18 h at ambient temperature
under high vacuum (<1 mbar) to 54.8 g of white solid. The
mother liquors were condensed, and a second crop of solids was
obtained from MeOH (100 mL, hot) and EtOAc (100 mL). The
second crop dried to 4.0 g of white solid. The total yield was 58.8
g (74.5% for two steps). MS (ESI) m/z 133 [M + 1]+. 1H NMR
(DMSO-d6) 3.05À3.25 (m, 5 H), 3.70 (s, 3 H), 8.37 (bs, 6H).
Anal. Calcd for C5H14Cl2N2O2 (205.08): C 29.28; H 6.88; Cl
34.57; N 13.66. Found: C 29.64; H 6.87; Cl 34.17; N 13.42.
Methyl 3-(tert-Butoxycarbonylamino)-2-((tert-butoxycar-
bonylamino)methyl)propanoate (11). The diamine HCl 10
(58.6 g, 0.285 mol) was stirred vigorously with 95% EtOH
(600 mL) and treated with sodium bicarbonate (72.0 g, 0.857
mol) and di-tert-butyl dicarbonate (127.8 g, 0.585 mol). A rinse
with 95% EtOH (285 mL) completed the transfer of solids. The
mixture was stirred vigorously for 3 h at 45À48 °C. The mixture
was condensed to about 200 mL, resulting in a thick, free-flowing
slurry. EtOAc (700 mL) was added and the mixture extracted
with D.I. water (580 mL). The organic layer was washed with
water (290 mL) followed by saturated brine (290 mL), dried over
sodium sulfate, and filtered. The organic solution was concen-
trated to approximately 200 mL. The crude product was taken
directly to the next step. In preparation for the next step, toluene
Oxadiazole Formation. The toluene solution of N-Boc-methyl
ester 11 (0.285 mol theoretical) was combined with crude pro-
pionamide oxime (62.7 g, 0.71 mol) and the mixture further
diluted with additional toluene to a total volume of about
580À600 mL. The reaction vessel was fitted with a DeanÀStark
trap and condenser. Potassium carbonate (177.7 g, 1.285 mol)
was charged and the reaction heated to reflux with vigorous
stirring for 5 h. The mixture was extracted with D.I. water
(370 mL) and EtOAc (315 mL). The organic layer was washed
with 5% citric acid (2 Â 160 mL), followed by saturated sodium
bicarbonate solution (160 mL) and finally with saturated brine
(160 mL). The organic layer was dried (sodium sulfate), filtered,
and concentrated to about 90 g of oil. The crude product was
used directly in the next step. A pure sample was obtained from
silica gel chromatography (25% EtOAc/hexane); MS (ESI) m/z
371 [M + 1]+.1HNMR(CDCl3) 1.30À1.34 (m, 3H), 1.44 (s, 18 H),
2.72À2.78 (m, 2 H), 3.33 (m, 4 H), 3.74À3.78 (m, 1 H), 7.26
(s, 2 H).
2-(3-Ethyl-1,2,4-oxadiazol-5-yl)propane-1,3-diamine Dihy-
drochloride (13). Crude 12 (N-Boc oxadiazole, approximately
90 g) was taken up in EtOH (630 mL), stirred at ambient
temperature, and treated slowly with conc. HCl (140 mL) over
15 min. The temperature increased to 34 °C during the addition.
The mixture was warmed to 45À50 °C for 4.5 h then cooled
below 25 °C. Toluene (700 mL) was added, and the mixture was
concentrated under reduced pressure to about one-fourth the
volume. The residue was treated with EtOAc (810 mL), causing a
precipitate to form. The mixture was allowed to stand overnight
at ambient temperature and then was stirred vigorously at 5 °C
for 30 min. The solids were collected by filtration, washed with
EtOAc, and dried for 20 h under vacuum. The mother liquors
were condensed and co-evaporated with EtOH (150 mL), and a
second crop of product was obtained from EtOH/EtOAc. The
first crop produced 41.61 g of white solid; the second crop
provided 5.27 g of white solid. Total yield was 46.88 g (67.6% for
three steps). MS (ESI) m/z 171 [M + 1]+. 1H NMR (CD3OD)
1.32À1.36 (m, 3H), 2.81À2.83 (m, 2 H), 3.49À3.51 (m, 4 H),
3.90À3.96 (m, 1 H).
3-Ethyl-5-(1,4,5,6-tetrahydropyrimidin-5-yl)-1,2,4-oxadiazole
Hydrochloride (MCD-386, 7). Oxadiazole diamine HCl, 13
(45.88 g, 0.189 mol), was treated with triethyl orthoformate
(94.4 mL, 0.567 mol) and EtOH (460 mL). The mixture was
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dx.doi.org/10.1021/op2001996 |Org. Process Res. Dev. 2011, 15, 1344–1347