Synthetic Approach for Discovery and Development of Novel Rice Herbicide, Pyriminobac-methyl.

Abstract

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.

7‐(4,6‐Dimethoxypyrimidinyl)oxy‐ and ‐thiophthalides as novel herbicides: Part 1. CGA 279 233: a new grass‐killer for rice

“…Overall both the (−)‐( S ) and the (+)‐( R ) forms of 37 showed about the same level of herbicidal activity relative to the racemate 37 . The relative lack of importance of the chirality is not yet clear, but the existence of a broad variety of the ortho ‐substituent Q throughout the series of compounds A has been widely documented 1–10. Similar observations of the lack of importance of chirality have been made earlier on the enantiomers of 5‐(2‐chloro‐4‐trifluoromethylphenoxy)‐3‐methylphthalide 65.…”

“…In contrast, the 6‐acylbenzoates IX are easily available by well‐documented procedures from protected 3‐alkylcarbonylphenols26–28 and then re‐esterified to the more stable phthalide forms II and IIc (R 4 = OR). We observed that, in general, all the ketal esters II , IIb , IIc and IA (R 4 = OR) are far less sensitive to acid‐ or base‐catalysed hydrolysis than the corresponding ortho ‐acetyl salicylates IX, IXa and their 6‐acyl‐pyrimidin‐2‐ylthiosalicylate derivatives A ′ that can undergo self‐catalysed rearrangement merely on standing to give the corresponding phthalide forms II , IIb , IIc and IA (R 4 = alkoxy) 8. 9, 27 The 6‐acylsalicylic acids IX (R = H) and the free acid derivatives A ′ (Figs 1 and 3; R = H) are generally isolated as the corresponding 3‐hydroxyphthalide forms IVb , IVc , II (R 4 = OH) and IA (R 4 = OH), as was shown by Finkelstein et al 29 for 3,7‐dihydroxy‐3‐methylphthalide II (R 3 = Me, R 4 = OH).…”

“…A class of novel (4,6‐dimethoxypyrimidin‐2‐yl)oxysalicylates1–3 and their corresponding thiosalicylic acid analogues4 of the general structure A (Fig 1)5 were reported by Kumiai, leading to the development of KIH‐2031 (Q = Cl, X = S, R = Na) for use in cotton,6 KIH‐2023 (Q = 2‐(4,6‐dimethoxypyrimindinyl)oxy, X = O, R = Na)3 and later of KIH‐6127 (Q = C(Me)NOMe, X = O, R = Me),7, 8 a pro‐pesticidal oxime‐ether derivative of the acyl compound A ′ (X = O, R 3 = R = Me),7–9 for use in rice. Common to this new class of highly active (4,6‐dimethoxypyrimidinyl)oxybenzoate and ‐thiobenzoate herbicides is the existence of an easily hydrolysable carboxylic ester function COOR in the ortho ‐position to the 4,6‐dimethoxypyrimidinyl moiety.…”

Design, Synthesis, and Structure‐Activity Relationship (SAR) Studies of Ketone‐Isobenzofuranone Hybrid Herbicides

“…[14][15][16][17] In terms of phytotoxicity, there are many reports showing that natural and synthetic isobenzofuranones are plant growth inhibitors (Scheme 1). [18 -28] Phenoxyphthalide and its amino-, oxy-, and thio-derivatives; [20,23,26] chrycolide and rubralides, [22,25] cryphonectric acid [19] and its oxycyclohexenyl derivatives; [27] dihydroxy phthalide; [21] butylidene phthalide; [29] isobenzofuranimines; [18] and 4,7-methanoisobenzofuran-1(3H)-one, [24,27] are among those. Overall, the phytotoxicity level of these compounds depends on applied concentrations and chemical structures as well as tested species.…”

Synthesis and herbicidal activity against barnyard grass of novel diarylmethanone O‐(2,6‐bis((4,6‐dimethoxypyrimidin‐2‐yl)oxy)benzoyl)oximes

“…pyrithiobac, pyriminobac, bispyribac, pyriftalid and pyribenzoxim. All five were developed in the 1990s, and are used to prevent and remove broadleaf weeds in cotton, barnyard grass in rice, Kentucky bluegrass in creeping shears, annual bluegrass and large horsetail, among others. However, long‐term use of these herbicides makes the problem of their resistance increasingly serious .…”