15. There is a dispute as to the reaction mechanisms and products formed in Shiokawa example 5.
Specifically, Shiokawa argues that the process recited in example 5 would lead to the inherent
formation of a 1,3,5-oxadiazine intermediate compound, i.e. a compound of Shiokawa formula (III)
where Z is CH -O-CH and E is N-R . Yet, Shiokawa example 5 is directed to the “preparation of an2 2 2
intermediate compound” having the formula:
(SX 2003, example 5, col. 17, lines 26-35, i.e., a compound of Shiokawa formula (III) where Z is
CH -N(OCH )-CH and E is NH). Example 5 specifically states that:
2 3 2
A mixture consisting of nitroguanidine (10 g), methoxyamine hydrochloride (9.6
g), 75% paraformaldehyde (11.5 g), toluene (80 ml) and a catalytic amount of
concentrated hydrochloric acid was subjected to heating under reflux for three hours,
while the water was removed therefrom. Under reduced pressure, the solvent[2]
contained in the mixture was distilled off to obtain white crystals of the hydrochloride of
5-methoxy-2-nitroimino-hexahydro-1,3,5-triazine (16.2 g) having a melting point from
o o
160 to 170 C.
(SX 2003, example 5, lines 36-46, emphasis added to highlight reactants and removal of water).
Nowhere does Shiokawa ‘146 mention the formation of a 1,3,5-oxadiazine intermediate compound, let
Depicted on p. 247 of Petersen “Synthesis of Cyclic Ureas by "-Ureidoalkylation” (SX 2051)2
is a reaction of a 1,3,5-oxadiazine compound and a hydrochloride salt of a methyl amine. This reaction
is depicted as forming hexahydro-1,3,5-triazine, water and HCl. Shiokawa, having relied upon the
Petersen reference, fails to sufficiently explain why such a reaction would not occur in example 5 of the
‘146 patent. Moreover, if such a reaction does occur in example 5, Shiokawa has failed to sufficiently
explain why the removal of the water from the process of example 5 of the ‘146 patent would not drive
the reaction toward the 1,3,5-triazine and away from the 1,3,5-oxadiazine.
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