Large-scale preparation of 3-methyl-4H-[1,2,4]oxadiazol-5-one, potassium or sodium salt

Article abstract of DOI:10.1021/op0255579

The development of a safe and practical process for the potassium and sodium salts of 3-Methyl-4H-[1,2,4]oxadiazol-5-one 1A and 1B is described. The focus of the report is how the scale-up issues of the original procedure are overcome, in particular, the thermal hazards of the starting material, hydroxylamine, and the intermediate, acetamidoxime 4. The final process was demonstrated multiple times on a 600-L scale with consistent yields (70%) and purities (95%).

Full text of DOI:10.1021/op0255579

Organic Process Research & Development 2002, 6, 896−897
Large-Scale Preparation of 3-Methyl-4H-[1,2,4]oxadiazol-5-one, Potassium or
Sodium Salt
Robert Hett,*,† Ralf Kra¨hmer,† Irene Vaulont,† Kindrick Leschinsky,‡ Jeffrey S. Snyder,‡ and Peter H. Kleine‡
CarboGen Laboratories (Neuland) AG, Neulandweg 5, CH-5502 Hunzenschwil, Switzerland, and Pharmacia Corporation,
DiscoVery Medicinal Chemistry, 700 Chesterfield Parkway, Chesterfield Missouri 63198, U.S.A.
Scheme 1. Oxadiazolones as precursors for amidines
Scheme 2. Original procedure for the synthesis of 1A
Abstract:
The development of a safe and practical process for the
potassium and sodium salts of 3-Methyl-4H-[1,2,4]oxadiazol-
5-one 1A and 1B is described. The focus of the report is how
the scale-up issues of the original procedure are overcome, in
particular, the thermal hazards of the starting material,
hydroxylamine, and the intermediate, acetamidoxime 4. The
final process was demonstrated multiple times on a 600-L scale
with consistent yields (70%) and purities (95%).
Introduction
Oxadiazolones 1, 2 are versatile synthetic intermediates
that serve as precursors and protecting groups for amidines
3, an important class of biologic functionality.1 The conver-
sion to the parent amidines is readily achieved by mild
reductive methods such as Pd/H2 or Zn/AcOH (Scheme 1).
During the course of a recent project a safe and operationally
simple procedure to prepare multikilogram lots of the
potassium salt of 3-Methyl-4H-[1,2,4]oxadiazol-5-one (1A)
was needed (Scheme 2). Compound 1 has been converted
to amidines by methods developed by Moormann et al.2
Table 1. Thermokinetic data
T onset (°C)
(exotherm [J/g]) (heat of fusion [J/g])
melting point (°C)
cmpd
acetamidoxime 4
oxadiazolone-K 1A
oxadiazolone-Na 1B
140 (-1253)
270 (-782)
307 (-750)
130 (202)
264 (158)
278 (128)
product, potassium 3-methyl-4H-[1,2,4]oxadiazol-5-one 1A,
could nevertheless be isolated in high yield and purity by
filtration, up to 50-g scale in the laboratory.
However, the scale-up issues described above led us to
develop an alternative procedure. Further investigations
included thermokinetic analysis by DSC of the intermediate
4 and the final products 1A and 1B (Table 1).
While the final compounds 1A and 1B are relatively stable
with onset temperatures well above operating temperatures,
the intermediate 4 showed a prohibitively high exotherm with
an onset temperature of 140 °C.4 These data suggested
decreasing the reaction temperature from 75 to 80 °C to
below 40 °C and not to concentrate the solution for the
isolation of 4, but rather to telescope it with the next step.
In addition it is well established that handling of hydroxyl-
amine free base can be a dangerous enterprise5 at elevated
temperatures and in the presence of metal ions.
First Campaign Procedure. With these scale-up issues
in mind, the following procedure for the first production
campaign was designed. The temperature during liberation
of hydroxylamine free base was decreased to 0-5 °C to
minimize decomposition of hydroxylamine.5,6 Filtration of
Discussion
The starting point for our scale-up work was a procedure
based on the synthesis published by Harsa´nyi et al.3 This
two-step procedure (Scheme 2) describes first the liberation
of hydroxylamine free base from the hydrochloride using
sodium ethylate in ethanol and then filtration to remove the
resulting sodium chloride, followed by heating the filtrate
at reflux with 1 equiv of acetonitrile. The acetamidoxime 4
was isolated as a solid in yields of 40-50% by concentrating
the solution to dryness. The second step of the procedure
involved treatment of a suspension of the acetamidoxime in
diethyl carbonate with solid potassium tert-butoxide. This
concentrated reaction mixture was troublesome as the reac-
tion was very exothermic and heterogeneous. In fact, stirring
became very difficult upon formation of large lumps. The
* To whom correspondence should be addressed. E-mail: roberthett@
carbogen.com.
† CarboGen Laboratories (Neuland) AG.
‡ Pharmacia Corporation.
(1) Bolton, R. E.; Coote, S. J.; Finch, H.; Lowdon, A.; Pegg, N.; Vinader, M.
V. Tetrahedron Lett. 1995, 36, 4471.
(2) Moormann, A. E.; Wang, J. L.; Palmquist, K. E.; Promo, M. A.; Snyder,
J. S.; Scholten, J. A.; Leschinsky, K. L.; Sikorski, J. A.; Webber, R. K.
3-Methyl-4H-[1,2,4]-oxadiazol-5-one: A Synthon and Protecting Group
for the Methyl Amidine. Publication in preparation.
(3) Taka´cs, K.; Harsa´nyi, K. Chem. Ber. 1970, 103, 2330; Mindl, J.; Kavalek,
J.; Strakova, H.; Sterba, V. Collect. Czech. Chem. Commun. 1999, 64, 1641.
(4) A commonly accepted rule in the industry recommends an operation
temperature of at least 100 °C below the observed onset temperature of
unacceptably high exotherms.
(5) A very good collection of safety data on hydroxylamine free base is found
on the BASF Website, http://www.basf.dk/en/produkte/chemikalien/
anorganika/anorg_spezial/hydroxyl_fb/hafb_sucess.htm.
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Vol. 6, No. 6, 2002 / Organic Process Research & Development
10.1021/op0255579 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/10/2002

Scheme 3. Developed process for the synthesis of 1B
sodium chloride was postponed to a later stage of the process,
when all hydroxylamine was consumed. The reaction tem-
perature for the next step was lowered from reflux to 20 °C
to avoid decomposition of hydroxylamine and to stay well
below the onset temperature of decomposition of 4. To
compensate for the lower conversion rates, acetonitrile was
added in excess rather than just in stoichiometric amounts.3
This change also improved safety, as it decreased the
likelihood of hydroxylamine decomposition.
downstream chemistry, due to improved solubility (Scheme
3).
Summary
Due to the thermal potential of 4, telescoping was
preferred over isolation. However, dark-colored byproducts
were observed upon addition of diethyl carbonate and
potassium tert-butylate, presumably due to the presence of
acetonitrile. Weaker bases, such as potassium carbonate, did
not initiate the ring-closing reaction. Thus, a solvent ex-
change of acetonitrile to methanol/diethyl carbonate was
carried out by adding diethyl carbonate, followed by continu-
ous addition of methanol and removal of acetonitrile to
maintain a constant volume, whereby a potential adiabatic
temperature increase, caused by decomposition of 4, would
not reach the boiling point of the reaction mixture.7 When
the acetonitrile was reduced to levels of 10%, the base-
induced cyclization step occurred without colored byprod-
ucts. Running the last step in methanol avoided the hetero-
geneous nature of the original procedure and also improved
the temperature control of this exothermic reaction step. A
final solvent exchange to 2-propanol furnished crystallized
1A as high-quality material in yields of 60%.
Second Campaign Procedure. Further improvements to
the process were straightforward and focused on increasing
throughput. To this end the free-basing procedure of hy-
droxylamine salt was omitted and commercially available
aqueous hydroxylamine free base (50 wt %) used instead.
This change saved two unit operations, that is, the liberation
of the free base in ethanol and the filtration step. It also
increased conversion rate due to a higher concentration of
acetonitrile. The water was removed after formation of 4
during the solvent-exchange process to diethyl carbonate and
methanol. Potassium tert-butoxide, the base for the cycliza-
tion, was replaced by a solution of sodium methylate in
methanol, which was less expensive and, because it was
purchased as a solution, simplified handling. This procedure
generated the product as the sodium salt 1B, which showed
similar safety characteristics, but behaved superiorly in the
A safe and practical process for the potassium and sodium
salts of 3-Methyl-4H-[1,2,4]oxadiazol-5-one 1A and 1B has
been developed. This process was demonstrated multiple
times on a 600-L scale with consistent yields (70%) and
purities (95%).
Experimental Section
To a 640-L glass-lined reactor, charged with acetonitrile
(170 L), was added hydroxylamine (50% aq, 15 L, 240 mol)
over 15 min at 20-25 °C. After the mixture stirred at 20-
25 °C for 24 h, hydroxylamine was undetectable (TLC SiO2,
CH2Cl2, MeOH, NEt3 70:30:1, 1% ninhydrin in EtOH,
Rf(NH2OH) ) 0.17, Rf(4) ) 0.24). The reaction mixture was
analysed by GC for the content of 4 to assess the amount of
sodium methoxide necessary (typically 210 mol of 4 were
formed). Diethyl carbonate (217 L) was added to the reaction
mixture followed by distillation of 190 L of acetonitrile/water
at 30 °C, at 90-110 mbar. Methanol (312 L) was added as
the distillate was removed. At the end of the distillation
process the reaction mixture was analysed by GC for
acetonitrile (less than 10%). Sodium methoxide in methanol
(5.4 M, 40 L, 216 mol) was added over a period of 30 min
at 10-15 °C. After addition was complete, the reaction
mixture was heated to 67-70 °C and stirred for 5 h (TLC
see above). The reaction mixture was concentrated at 50-
60 °C to a volume of 50-60 L at 100 mbar and diluted
with 2-propanol (167 L). The suspension was heated to 67-
70 °C, stirred at that temperature for 1 h, and cooled to 0-5
°C, and stirring continued for 12 h. The suspension was
filtered or centrifuged and dried at 40 °C and 25 mbar to
give 1B (20.7 kg, 70%) as a white solid. The purity was
determined by NMR (using hydroquinone as internal stan-
dard) to be 95%.
1H NMR (400 MHz, DMSO): δ 1.85 ppm (s); 13C NMR
(100 MHz, DMSO): δ 13.00, 166.42, 173.91 ppm.
IR (ATR): ν ) 1624, 1535, 1416, 1362, 1227, 1088,
1069, 1020, 951, 905, 824, 786 cm-1.
Anal. Calcd for for C3H3N2NaO2 (122.06): C 29.52, H
2.48, N 23.0; Na 18.84; found: C 29.03, H 2.54, N 22.60;
Na 18.60
(6) As an additional safety precaution, water was filled in the feed vessels for
a safety quench, in case of an unexpected thermal event during the liberation
of hydroxylamine free base.
(7) Acetamidoxime 4 decomposes with a release in energy of 1253 J/g. A rough
estimate using an average heat capacity of 2 J/g K for organic solvents
with a minimum dilution of 1:12 calculated to an adiabatic temperature
rise of 52 °C. After diethyl carbonate is added, 4 is rapidly consumed into
an open-chain precursor of 1A, which appears to be less reactive towards
thermal decompostion. DSC analysis on reaction mixtures after the addition
of diethyl carbonate never showed significant exotherms.
Received for review June 6, 2002.
OP0255579
Vol. 6, No. 6, 2002 / Organic Process Research & Development
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