Preparation of arthropodicidal oxadiazines

Details Preparation of arthropodicidal oxadiazines Preparation of arthropodicidal oxadiazines

2000-05-09

2001-05-15

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S029000, C560S053000

Reexamination Certificate

active

06232489

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention pertains to the preparation of arthropodicidal oxadiazines and intermediates therefor.
Arthropodicidal oxadiazines are disclosed in WO 9211249 and WO 9319045. However, preparative methods for these compounds must be improved for economic commercial operation. Accordingly, the present invention provides a convenient route to preferred arthropodicidal oxadiazines.
SUMMARY OF THE INVENTION
The present invention pertains to a process for preparing a compound of Formula I which is racemic or enantiomerically enriched at chiral center *
wherein R
1
is F, Cl, or C
1
-C
3
fluoroalkoxy, and R
2
is C
1
-C
3
alkyl, comprising: (a) reacting a compound of Formula II, optionally enantiomerically enriched at *,
with the compound of Formula III in the presence of an acid catalyst
H
2
N—NHR
3
  III
to form-a compound of Formula IV
wherein R
3
is a protecting group such as CO
2
CH
2
(C
6
H
5
) and the like;
(b) reacting the compound of Formula IV with di(C
1
-C
3
alkoxy)methane in the presence of a Lewis acid to form a compound of Formula V
(c) hydrogenating the compound of Formula V to form a compound of Formula VI
(d) reacting the compound of Formula VI with the compound of Formula VII
to form a compound of Formula I having substantially the same absolute configuration as the compound of Formula II.
The present invention further pertains to a process for preparing a compound of Formula f enantiomerically enriched at chiral center * comprising Steps a-d wherein the compound of Formula II in Step a is enantiomerically enriched at * with the same configuration as the desired compound of Formula I.
The present invention further pertains a process for preparing a compound of Formula I enantiomerically enriched at chiral center * comprising Steps a-d and further comprising
(i) reacting para-substituted phenylacetyl halide with ethylene in the presence of Lewis acid to produce compounds of Formula VII
(ii) reacting VIII with peroxyacid to produce compounds of Formula IX
(iii) reacting IX with C
1
-C
3
alcohol in the presence of acid catalyst to produce compounds of Formula X
(iv) reacting X with base to produce compounds of Formula XI
and
(v) reacting XI with hydroperoxide in the presence of chiral base to produce enantiomerically enriched II;
wherein
enantiomerically enriched II from step v is reacted in step a and wherein R
1
and R
2
are as previously defined.
The present invention further pertains to the individual process steps a, b, c and d and to multi-step processes a, b; a, b, c; b, c; b, c, d; and c, d.
The present invention further pertains to the single process step v for preparing enantiomers of Formula II from compounds of Formula XI; the five-step i-v process to prepare compounds of Formula II; the four-step i-iv process for the preparation of compounds of Formula XI from para-substituted phenylacetyl halide; the two-step i-ii process to prepare compounds of Formula IX; the single process step ii to prepare compounds of Formula IX; and, the two-step ii-iii process to prepare compounds of Formula X.
The present invention further pertains to (+) enantiomers of compounds of Formula II:
wherein
R
1
is selected from the group F, Cl and C
1
-C
3
fluoroalkoxy, and R
2
is C
1
-C
3
alkyl, which compounds are substantially pure (+) enantiomers.
The present invention further pertains to racemic and enantiomerically enriched compounds of Formulae IV, V and VI:
wherein
R
1
is F, Cl, or C
1
-C
3
fluoroalkoxy, R
2
is C
1
-C
3
alkyl, and R
3
is CO
2
CH
2
(C
6
H
5
).
The present invention farther pertains to the compound of Formula VII.
The present invention further pertains to compounds of Formulae IX and X
wherein
R
1
is selected from the group F, Cl and C
1
-C
3
fluoroalkoxy, and R
2
is C
1
-C
3
alkyl.
In the above definitions, the term “halide” means fluoride, chloride, bromide or iodide. The term “C
1
-C
3
alkyl” indicates straight chain or branched alkyl with 1, 2 or 3 carbon atoms and means methyl, ethyl, n-propyl or isopropyl. The term “C
1
-C
3
alkoxy” means methoxy, ethoxy, n-propoxy or isopropoxy. The term “C
1
-C
3
fluoroalkoxy” means methoxy, ethoxy, n-propoxy or isopropoxy partially or ally substituted with fluorine atoms and includes, for example, CF
3
O and CF
3
CH
2
O. The term “C
1
-C
3
alcohol” means methyl, ethyl, n-propyl or isopropyl alcohol.
Preferred compounds of Formulae IV, V and VI are those where R
2
is methyl and R
1
is chlorine, CF
3
O or CF
3
CH
2
O. Most preferred are
phenylmethyl[5-chloro-2,3-dihydro-2-hydroxy-2-(methoxycarbonyl)-1H-inden-1-ylidene]hydrazinecarboxylate (designated IVa);
4a-methyl 2-(phenylmethyl)-7-choroindeno[1,2-e][1,3,4]oxadiazine-2,4a(3H, SH)-dicarboxylate (designated Va); and methyl 7-chloro-2,5-dihydroindeno[1,2-e][1,3,4]oxadiazine4a(3H)-carboxylate (designated VIa).
Preferred compounds of Formulae II, IX and X are those wherein R
2
is methyl and R
1
is chlorine, bromine, CF
3
O or CF
3
CH
2
O. Most preferred are
(+)methyl 5-chloro-1,3 -dihydro-2-hydroxy-1-oxo-2H-indene-2-carboxylate (designated (+)IIa);
2-carboxy-5-chlorobenzenepropanoic acid (designated IXa); and
methyl 5-chloro-2-(methoxycarbonyl)benzenepropanoate (designated Xa).
DETAILED DESCRIPTION OF THE INVENTION
One aspect of this invention pertains to a process for preparing compounds of Formula I comprising four steps, a-d, typically operated as follows.
Step a) forms IV by reacting II (prepared for example from substituted indanone, such as 5-chloro-1-indanone, as described in detail in WO 9211249) with about a molar equivalent of III in the presence of acid catalyst such as p-toluenesulfonic, sulfuric or acetic acid, optionally in an inert solvent such as methanol, isopropanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane and the like. Typical reaction conditions include temperatures of about 40° to 120° C., preferably 65° to 85° C., for about 0.5 to 25 h. Compound IV can be recovered by standard methods such as filtration, optionally after dilution of the reaction mixture with water. Alternatively, IV can be extracted with solvent and used directly in the next reaction step without isolation.
Step b) forms V by reacting IV with di(C
1
-C
3
alkoxy)methane such as dimethoxymethane or diethoxymethane in the presence of a Lewis acid, optionally in an inert solvent such as dichioromethane, 1,2-dichloroethane, chiorobenzene, &agr;,&agr;,&agr;-trifluorotoluene and the like. The di(C
1
-C
3
alkoxy)methane can be in molar excess. Lewis acids include P
2
O
5
, BF
3
and SO
3
, which generally require 0.9 to 4.0 molar equivalents (relative to V) for best results; further included are metal (especially scandium, ytterbium, yttrium and zinc) trifluoromethanesulfonates, which can be used in about 0.1 to 0.5 molar equivalents relative to V. The most preferred Lewis acids for this step are P
2
O
5
and SO
3
; the SO
3
may be in the form of a complex such as DMF.SO
3
(DMF is dimethylformamide). Typical reaction conditions include temperatures of about 20° to 150° C., preferably 50° to 60° C., and pressures of about 100 to 700 kPa preferably 100 to 300 kPa, for about 0.5 to 48 h. It is preferable to continuously remove the byproduct C
1
-C
3
alcohol by distillation during the reaction when non-sacrificial Lewis acid such as a rare-earth trifluoromethanesulfonate is employed. Compound V can be recovered by standard methods such as filtration and used without further purification in the next reaction step. Alternatively, when metal trifluoromethanesulfonates are employed as the Lewis acid, V can be recovered by concentrating the reaction mass, optionally diluting with an inert, water-immiscible solvent such as ethyl acetate, washing with water to remove the metal trifluoromethanesulfonates, concentrating the organic phase and inducing V to crystallize from same, optionally by adding a suitable solvent such as aqueous methanol, nexane and the like.
Step c) forms VI by reacting V with hydrogen from a hydrogen source or p

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