The method reported previously (Part I) was employed to prepare a variety of novel 6-acylsalicylates as key intermediates. 6-Acylpyrimidin-2-yl salicylates (2-acyl-6-[(4,6-disubstituted pyrimidin-2-y1)oxylbenzoate derivatives: Type l), the closely related phthalide compounds (3-alkyl-7-[(4,6-dimethoxypyrimidin-2-yl)oxy]phthalide derivatives : Type 2) and the ketal derivatives of 2-acyl-6-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoates (Type 3) were synthesized and their herbicidal activities measured. Methyl 2-acetyl-6-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoate gave excellent control of barnyard grass with a promising profile as a prototype rice herbicide.
The crystal structure of the major isomer of KIH-6127 was investigated
by X-ray crystallographic
techniques. The solid state structure and its conformation were
confirmed as the E form. Thus
KIH-6127 is mainly consistent with methyl
2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-[1-E-(methoxyimino)ethyl] benzoate (compound 1: Table ).
Further modifications of the iminoxy moiety to
introduce a variety of haloalkyl, haloalkenyl, and others were made,
and the Z isomers of several
derivatives were prepared. The physicochemical properties of these
derivatives were measured,
including their log P and K
d values.
We tested their herbicidal activity against barnyard grass
and
their phytotoxicity to transplanted rice in flooded paddy conditions.
We also studied the role of the
iminoxy moiety, on the basis of the hypothesis that the difference in
the E/Z configurations of the
iminoxy moiety determines their biological activity. However,
clear differences in the herbicidal
activities were not observed between these isomer groups. Each
Z isomer was more hydrophilic
than its E counterpart. To investigate this finding
more intensively in a single E/Z pair, the
surface
area of each E/Z isomer of KIH-6127 was
calculated from the X-ray data for the KIH-6127 E
form.
The Z conformation of the iminoxy moiety appears to
take a more compact molecular conformation,
resulting in the Z isomer having more hydrophilic surface
area than the corresponding E isomer.
QSAR studies focused on the iminoxy moiety. Both pre- and
post-emergence activities of the
compounds were well correlated with the square of the log P
value for both configurations of the
iminoxy moiety. In other words, these configurations merely
contributed to the activity by way of
their hydrophilicity. The difference between optimum log
P values for pre- versus post-emergence
indicated that the optimum compound is more lipophilic for pre- than
for post-emergence activity.
Phytotoxity against rice also correlated well with the
K
d value. Thus stronger soil adsorption
of
the compounds provides higher safety for rice. On the basis of
those QSAR studies, compound 1
was selected as the optimal compound for development as a commercial
herbicide.
Keywords: Methyl
2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-[1-E-(methoxyimino)ethyl]
benzoate; KIH-6127; Pyriminobac-methyl; herbicide; barnyard grass; ALS;
QSAR
A novel synthesis of methyl 6-acetylsalicylate as a key synthetic intermediate for methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-[l-(methoxyimino) ethyllbenzoate (KIH-6127) was studied, and directed at 6-substituted pyrimidin-2-yl salicylate herbicides and their analogues. Three synthetic approaches were successful: a modification of the Sandmeyer reaction of 6-acetylanthranilate (Method A), a direct ring-opening reaction of 3-methylphthalide using potassium permangamate and magnesium nitrate (Method B), and a regioselective ortholithiation of the protected 3-hydroxyacetophenone (Method C). These methods were applicable for the synthesis of various 6-acyl salicylates.
A novel synthesis of methyl 6‐acetylsalicylate as a key synthetic intermediate for methyl 2‐[(4,6‐dimethoxypyrimidin‐2‐yl)oxy]‐6‐[1‐(methoxyimino)ethyl]benzoate (KIH‐6127) was studied, and directed at 6‐substituted pyrimidin‐2‐yl salicylate herbicides and their analogues. Three synthetic approaches were successful: a modification of the Sandmeyer reaction of 6‐acetylanthranilate (Method A), a direct ring‐opening reaction of 3‐methylphthalide using potassium permangamate and magnesium nitrate (Method B), and a regioselective ortho‐lithiation of the protected 3‐hydroxyacetophenone (Method C). These methods were applicable for the synthesis of various 6‐acyl salicylates.
A novel synthesis of methyl 6-acetylsalicylate, a key intermediate directed at 6-substituted pyrimidin-2-yl-salicylate herbicides (PS) and their analogues, was studied. Three synthetic approaches were successful. Among them , a regioselective ortholithiation method was the most promising, and was applied for the synthesis of various 6-acylsalicylates and for the commercial synthetic method of Pyriminobac-methyl as well. Using methyl 6-acylsalicylate, 6-acyl pyrimidin-2-yl-salicylates (6-acyl PS) , their acetal analogues and the close related phthalide analogues were synthesized and their herbicidal activities were evaluated. Among them , the compounds such as methyl 2-acetyl-6-[ ( 4 , 6dimethoxypyrimidin-2-y1)oxy] benzoate gave excellent control of barnyard grass, but had unacceptable injury against rice. In order to reduce rice crop injury while keeping herbicidal activity, further extensive synthetic modification of 6-acyl PS was then examined by the introduction of an oximino group. QSAR study was carried out by examining their herbicidal activity against barnyard grass in paddy rice at various growth stages, including pre-emergence.Finally, Pyriminobac-methyl was found to be the most promising candidate and the industrial synthetic scheme was accomplished by modification of the regioselective ortholithiation method. Recently , Pyriminobac-methyl (Prosper(R) was developed for the commercial herbicide and launched to the market.
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