Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-22
2001-12-11
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S132000, C544S133000, C540S603000, C546S210000, C546S272400
Reexamination Certificate
active
06329528
ABSTRACT:
FIELD OF THE INVENTION
This invention provides new synthetic procedures and intermediates for preparing insecticidal 3-(substituted phenyl)-5-thienyl or furyl)-1,2,4-triazoles.
BACKGROUND OF THE INVENTION
U.S. patent application Ser. No. 09/048,601, filed Mar. 26, 1998, incorporated herein by reference, discloses a series of highly active new insecticides. Although that patent application discloses suitable laboratory methods for preparation of the compounds, a need exists for a commercially applicable manufacturing process.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing compounds of the formula (1)
wherein
Ar is substituted phenyl;
Y is O or S;
R
3
is selected from H, halo, lower alkyl, (C
7
-C
21
) straight or branched chain alkyl, hydroxy, lower alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, lower alkenyl, lower alkynyl, haloalkenyl, CN, NO
2
, COR
6
, CO
2
R
6
, CON(R
6
)
2
, (C
3
-C
6
) cycloalkyl, S(O)
m
R
6
, —OSO
2
R
6
, SCN, —(CH
2
)
n
R
6
, —CH═CHR
6
, —C≡CR
6
, —(CH
2
)
q
OR
6
—(CH
2
)
q
SR
6
, —(CH
2
)
q
NR
6
R
6
, —O (CH
2
)
q
R
6
, —S (CH
2
)
q
R
6
, —NR
6
(CH
2
)
q
R
6
,
pyridyl, substituted pyridyl, isoxazolyl, substituted isoxazolyl, naphthyl, substituted naphthyl, phenyl, substituted phenyl, thienyl, substituted thienyl, pyrimidyl, substituted pyrimidyl, pyrazolyl, or substituted pyrazolyl;
R
4
and R
5
are independently H, halo, lower alkyl, lower alkoxy, haloalkyl, haloalkoxy, CN, CO
2
R
6
, CON(R
6
)
2
, or S(O)
m
alkyl, or
if R
4
and R
5
are attached to adjacent carbon atoms, they may join to form a 5 or 6 member saturated or unsaturated carbocyclic ring which may be substituted by 1 or 2 halo, lower alkyl, lower alkoxy or haloalkyl groups;
R
6
is H, lower alkyl, haloalkyl, lower alkenyl, lower alkynyl, phenyl, or substituted phenyl;
m is 0, 1, or 2;
n is 1 or 2;
p is an integer from 2 to 6; and
q is 0 or 1;
which comprises the steps of:
(a) reacting a compound of formula (2)
wherein Ar is as defined in formula (1) and R
7
is lower alkyl, or an acid addition salt thereof, with an acid chloride of the formula (3)
wherein Y, R
3
, R
4
, and R
5
are as defined in formula (1), in an inert organic solvent the presence of an organic or inorganic base to produce the adduct-intermediate of formula (4)
wherein Ar, Y, R
3
, R
4
, and R
5
are as defined in formula (1) and R
7
is lower alkyl; and
(b) optionally isolating said adduct intermediate, and
(c) reacting said adduct-intermediate with methyl hydrazine to produce the compound of formula (1).
Adduct-intermediates of formula (4) are novel compounds, and they are an important aspect of the invention.
Adduct-intermediates that are preferred based on desirable properties of the final products they may be used to produce are those of formula
wherein
R
1
and R
2
are independently F or Cl;
R
3
, R
4
, and R
5
are independently H, CH
3
, Cl or Br; and
R
7
is lower alkyl.
Most preferred adduct intermediates are those of formula (4a) wherein R
1
is Cl, R
2
is F, R
7
is CH
3
, and:
(a) R
3
, R
4
, and R
5
are each Cl;
(b) R
3
and R
4
are each Br and R
5
is H; or
(c) R
3
is CH
3
, R
4
is Cl or Br, and R
5
is H.
In another of its aspects, the invention provides the methyl sulfate salt of a compound of the formula
DETAILED DESCRIPTION OF THE INVENTION
Throughout this document, all temperatures are given in degrees Celsius, and all percentages are weight percentages unless otherwise stated.
The term “lower alkyl” refers to (C
1
-C
6
) straight hydrocarbon chains and (C
3
-C
6
) branched and cyclic hydrocarbon groups.
The terms “lower alkenyl” and “lower alkynyl” refer to (C
2
-C
6
) straight hydrocarbon chains and (C
3
-C
6
) branched hydrocarbon groups containing at least one double or triple bond, respectively.
The term “lower alkoxy” refers to —O-lower alkyl.
The terms “halomethyl” and “haloalkyl” refer to methoxy and lower alkyl groups substituted with one or more halo atoms.
The terms “halomethoxy” and “haloalkoxy” refer to methyl and lower alkoxy groups substituted with one or more halo atoms.
The term “alkoxyalkyl” refers to a lower alkyl group substituted with a lower alkoxy group.
The terms “substituted naphthyl”, “substituted thienyl,” “substituted pyrimidyl,” “substituted pyrazolyl,” “substituted pyridyl,” and “substituted isoxaxolyl” refer to the ring system substituted with one or more groups independently selected from halo, halo (C
1
-C
4
) alkyl, CN, NO
2
, (C
1
-C
4
) alkyl, (C
3
-C
4
) branched alkyl, phenyl, (C
1
-C
4
) alkoxy, or halo (C
1
-C
4
) alkoxy.
The term “substituted phenyl” refers to a phenyl group substituted with one or more groups independently selected from halo, (C
1
-C
10
) alkyl, branched (C
3
-C
6
) alkyl, halo (C
1
-C
7
) alkyl, hydroxy (C
1
-C
7
) alkyl, (C
1
-C
7
) alkoxy, halo (C
1
-C
7
) alkoxy, phenoxy, phenyl, NO
2
, OH, CN, (C
1
-C
4
) alkanoyl, benzoyl, (C
1
-C
4
) alkanoyloxy, (C
1
-C
4
) alkoxycarbonyl, phenoxycarbonyl, or benzoyloxy.
The term “substituted benzenesulfonyl” refers to p-chlorobenzenesulfonyl and p-toluenesulfonyl.
Unless otherwise indicated, when it is stated that a group may be substituted with one or more substituents selected from an identified class, it is intended that the substituents may be independently selected from the class.
Alkyl benzthioimidates of formula (2) are known in the literature. They are preferably used in the present invention as an acid addition salt. For example, tetrafluoroboric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide, or the like, may be used. The methyl sulfate salt is preferred.
Thioimidates are readily available through alkylation of the corresponding thioamides which are themselves commercially available or can be made from the amide (
Phosphorus Sulfur
(1985), 25(3), 297-305) or nitrile (
Chem.-Ztg.
(1980), 104(12), 365-7;
J. Chem. Soc.
(1952), 742;
Can. J. Chem.
(1985), 63, 3075).
Reaction of the acid chloride (3) and the imidate (2) to give the adduct (4) can generally be accomplished in any inert solvent with any organic or inorganic base.
Reaction of compounds of formula (4) with methyl hydrazine gives the desired triazoles, generally in good yield and with a high degree of regiospecificity. An example of a previous application of a similar process is given in Synthesis, 483 (1983). In regard to regiospecificity, the undesired possible coproducts are the 5-(substituted phenyl)-3-thienyl or furyl isomers of the desired 3-(substituted phenyl)-5-thienyl or furyl-1,2,4-triazoles.
Compounds of formula (1) can also be made starting with an alkyl benzimidate, as illustrated in the following comparative example. It has been found, however, that the process of the invention, utilizing alkyl benzthioimidates, provides significantly better yields.
Comparative Example 1
Briefly, the reaction of ethyl 2-fluoro-6-chlorobenzimidate (5) with 3,4,5-trichloro-2-thienoyl chloride (3a) was performed in toluene using triethylamine as an acid scavenger. The presumed intermediate (6) which was not isolated, then reacted with methyl hydrazine 3 hr at reflux to give 1-methyl-3-(2-chloro-6-fluoro)phenyl-5-(3,4,5-trichloro-2-thienyl)-1H-1,2,4-triazole (1a) in 35% yield. The following paragraphs describe each step of the synthesis in greater detail.
A. 2-chloro-6-fluorobenzamide
The procedure of R. Balicki and L. Kaczmarek,
Syn. Comm.,
23, 3149 (1993)was used. Into a 1 L round bottom flask equipped with a magnetic stirrer was added acetone (60 mL), water (60 mL) , 2-chloro-6-fluorobenzonitrile (14.5 g, 93.5 mmol), urea (22.5 g, 374 mmol), 30% hydrogen peroxide (42.4 g, 374 mmol), and potassium carbonate (1.3 g, 9.0 mmol). The resulting slurry was stirred at room temperature overnight. Additional portions of urea (11.2 g, 30% hydrogen peroxide (41 g), acetone (30 mL) and potassium carbonate (0.63 g) were added and the mixture was allowed to stir for an additional 2 hr. Additional portions of urea (11.2 g, 30% hydrogen peroxide (41 g), acetone (30 mL) and potassium carbonate (0.63 g) were again added and the mixture was allowed to stir ov
Ash Mary L.
Hull, Jr. John W.
Pearson Norman R.
Podhorez David E.
Romer Duane R.
Corvin Carl D.
Dow AgroSciences LLC
Morris Patricia L.
Stuart Donald R.
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