Note: Descriptions are shown in the official language in which they were submitted.
Subject of the present invention is a process for the manufacture of
2-~4'-(benzoxazolyl-2'1-oxy, -kenzothiazolyl-2"-oxy and -kenzimidazolyl-2"-oxy)-
-phenoxy]-alkanecarboxylic acid derivatives of the formula I
(R) ~ /C-O- ~ O C-Z (I)
in which
R is halogen, CF3, N02, CN; aIkyl, alkoxy or alkylthio each having from 1 to 4
carbon atoms;
A is O, S, NH or N-(Cl-C4)-alkyl;
~ is H or (Cl-C4)-alkyl,
Z is a group of the formLlae
O O O O R6 S O
" R ~ ~ p .,
-C-O-R -C-S-R -C-W / 4 , -C-N-N\ 7 , C-NR , CN, -CH2OH, -CH2-O-C-Rg~
2 C N ~ or -CH2-0-S02-R
m is an integer of from 0 to 2
R2 is H, (Cl-C12)-aIkyl optionally substituted with 1 to 6 halogen atoms, prefer-
ably F, Cl, Br, and/or OH, (Cl-C6)-aIkoxy, (Cl-C4)-aIkylthio, (Cl-C6)-aIkoxy-
-(C2-C6)-alkoxy, halo-(Cl-C2)-alkoxy, methoxyethoxyethoxy, (C1-C4)-aIkylamino,
di-(Cl-C4)-alkylamino, phenyl, oxiranyl and/or phenoxy, the latter one optionally
mono- or disubstituted with halogen or (Cl~C4)-alkyl; (C5-&)-cycloaIkyl option-
ally substituted with halogen or methyl; tC3-C6)-alkenyl, halo-(C3-&)-a~enyl or
(C5-C6)-cycloalkenyl; (C3-C4)-aIkinyl optio~ally mono- or disubstituted with
(Cl-C6)-alkyl, phenyl, halogen or (Cl-C2)alkoxy; phenyl optionally mono- to tri-
substituted with (Cl-C4)-alkyl or -aIkoxy, halogen, N02 or CF3; furfuryl, tetra-
hyd-ofurfuryl, a cation equivalent or an organic or inorganic base, or radicals
of the formulae
- 2 -
3~
_ 3 _ ~IO~ 80/F 161
,1 ,1 (C1-C~-alkyl
-CH-COOH, -cI~-coo(C1-C4)alkyl or N=
~H or (c1-c4)-a
R3 is (C1~C6)-alkyl, phenyl-(C1-c2)-alkyl~ the phenyl
5 radical optionally mono- or disubstituted with ~C1-C4)-
alkyl and/or halogen; (C3-C6)-alkenyl or phenyl optionally
mono- or disubstituted wi.th ~C1-C4)-al.kyl and/or halogen;
R4 and R5, being identical or different, each are H,
(C1-C6)-alkyl, hydroxy-~C1-C6)-alkyl, (C5-C6)-cycloal]cyl
10 or phenyl optionally mono- to trisubstituted with (C1-C4)-
alkyl or ~alkoxy, halogen or CE'3; with the proviso that
R4 and R5 together are not phenyl; or togethe.r form a
methylene chain havi.ng 2, 4 or 5 members, where one CH2
group can be substituted by O, NH or N(CE~3);
15 R6 is H or CH3;
R7 is H, CH3 ~ ~2 5
8 i~ El, CH3, C2H5 or phenyl;
Rg is (C1-C6)-alkyl optionally mono- to trisubsti.tutecl w.ith
halogen, cyclopropyl, (C3-C6)-alkenyl, phenyl, (C1-C4)-
20 alkylphenyl or -alkoxyphenyl, halophenyl, trifluoromethyl-
phenyl or nitrophenyl; and
R10 is (C1--C~)-alkyl or phenyl optionally mono-- or di-
substituted with halogen, CF3, NO2 or (C1-C~)-alkyl.; whi.ch
comprises reacting phenols of the formula II
R
HO ~ ~O-CH-Z ~II)
30 with compounds of the formula III
(R)m ~ ~ ( )n 11 (III)
in which
l fj~3~
n is 1 or 2, and
Rll is an aliphaticl cycloaliphatic, araliphatic or aromatic group, in the
presence of an acid binding agent.
The compo~mds of the formula I are known for example from German
Offenlegungsschriften Nos. 2,640,730; 2,914,300 and 3,018,003. They are
distinguished by an excellent herbicidal effect especially against weed grasses.It is known that the compounds of the formula I can be prepared for
example by reaction of corresponding phenols of the formula II with 2-halobenz-
oxazoles, 2-halobenzothiazoles and 2-halobenzimidazoles of the formula IV
(R) ~ \ ~ Hal (IV)
(Hal = Cl or ~r). However, this reaction has the disadvantage of requiri.ng
relatively long reaction times ~except if oxazole is used as reactant). For
exaTnple, in the reaction of 2-(4'-hydroxyphenoxy)-propionic acid ethyl ester
with 2-chlorobenzothiazole and potassium carbonate as base additive in
acetonitrile, an 88.5 % yield of Z-[4'-(benzothiazol-2"-yl-oxy)-phenoxy]-
propionic acid ethyl ester is obtained after refluxing for 30 hours. Because
of these relatively drastic reaction conditions, paTtial saponification of the
ester group Z in the phenol compound II and the final products I occurs with
formation of the corresponding carboxylic acids. Under the above reaction
conditions, irreversible alterations of the substituent Z of the other compoundsof the formulae I and II cannot be excluded, either.
In principle, all compounds of the formula I can be prepared
according to the process of the invention. Preferably, the process is used for
the manufacture of compounds of the formula I where
R is F, Cl, Br, CF3 or N02 in 6-position,
-4-
;9f3~
5 - HOE 80/F 161
m is 0 or 1,
R1 is methyl and
Z is -COOR2.
When using optically active 2-(4'-hydroxyphenoxy)-
; 5 alkanecarboxylic acid esters of the formula II as starting
substances, optically active ~inal products as descrihed
for example in German OffenleguncJsschrift No. 2,758,002
are obtained.
Irhe phenols of the ~ormula IX are known from the
10 literature (for example J. Org~ Chem. 39, 214 (1974)) orcan be prepared in ar1alogy to known processes. The
compounds of the formula III can be manufactured according
to known processes, for example from the corresponding 2~
mercartobenzoxazoles or 2-mercaptohenzothiazoles by alkyla-
15 tiOI1 and su~se~uent oxidation with potassium permanganate,hydrogen pero~ide or organic peracids (see J. Chem. Soc.
1949, 3311; Eur. 3. Med. Chem. 1378, 171; J. Heterocycl.
Chem. 13, 491 (1976); Chem Pharm. Bull. 17, 1958 (1969)).
Because of the importance of the compounds I as plant
20 protecting agents, an improved manufacturing process was
in great demand. The process of the invention avoids the
disadvantages described above; after a relatively short
reaction time it supp]:ies the compounds of the formula I
with high yields and in good purity, without adversely
25 affecting the functional groups present in the radical Z.
This was surprising and not to he expected from the state
o~ the art. Although the reaction of 2-alkylsulfonylbenzo-
thiazole derivatives with aliphatic alcohols, primary or
secondary amines or CH-acidic compounds is known (see J.
30 Chem. Soc. 1~49, 3311; J. Heterocycl. Chem. 13, 491 (1976);
Eur. J. Med. Chem. 1978, 171), corresponding reactions with
phenols so ar have not been described.
In principle~the radical R11 may be any aliphatic,
cycloaliphatic, araliphatic or aromatic radical; advantageous-
35 ly, however, startin~ substances are used in which Rl1 islow molecular weigl1t alkyl, alkenYl, alkoxyalk~yl or carb-
- `
G'&~
alkoxyalkyl, or phenyl or benzyl, because such compounds are easy and cheap to
obtain. Examples are: 2-methylsulfonyl-benzothiazole or -benzoxazole, 2-
ethylsulfonyl-benzothiazole or -benzoxazole, 6-chloro-2-methylsulfonylbenzo-
thiazole or -benzoxazole, 6-bromo-2-methylsulfonyl-benzothiazole, 6-chloro-2-
methylsulfinyl-benzothiazole, ethyl(benzothiazol-2-y])-sulfonyl acetate,
methyl~6-chlorobenzothiazol-2-yl)-sulfonyl acetate or 6-chloro-2-phenylsulfonyl-
benzothiazole or -benzoxazole.
In the reaction of the invention, the nucleofuge -S(O)n-Rll group is
replaced by the deprotonated phenol component. By contrast, when 6-chloro-2-
methylsulfonylbenzothiazole is reacted with a phenol of the formula II with
addition of potassium carbonate, potassium methylsulfinate is obtained in nearly
quantitative yield, in addition to the intended compound I and potassium
bicarbonate. The molar ratio of the reactants II and III is not critical and may
be varied within wide limits. Since, however, separation of unreacted starting
material requires additional operations, equimolar amounts or an excess of up to
10 % of compound II at most are preferabl~ used.
The process of the invention may be carried out in the presence or
absence of solvents, preferably however in the presence of a solvent inert
under the reaction conditions. Preferably polar aprotic solvents are used, for
example acid amides such as dimethyl formamide, dimethyl acetam:ide or N-
methylpyrrolidone, furthermore dimethyl sulfoxide, nitriles such as acetonitrile
or propionitrile, ketones such as acetone, methylethylketone or methyliso-
butylketone, ethers such as tetrahydrofuran or dioxan, or aromatic or aliphatic
hydrocarbons such as chlorobenzene or cyclohexane.
Suitable acid binding agents are the usual organic bases, for
example tertiary amines such as triethylamine, and especially inorganic
bases such as alkali metal carbonates
31f~3
(Na2C03, K2C03). Ihey are used in at least equimolar amounts (relative to II),
or in an exoe ss of frcm 5 to 20 ~.
rme prooe ss is advantageously carried out as follows: The compound of
the formula II is heated with the basic compound in a solvent first to reaction
temperature, thus forming at least in part the salt of the compound II. Subse-
quently the heterocyclic compound of the formula III, optionally dissolved in
the same solvent, is added, and the batch is stirred at elevated temperature
until the reaction is complete. The reactants may also be introduced into the
reactor in another order.
m e reaction temperature may be varied within a wide range of fram 20
to 160C. Preferably it is between 40 and 85C, optionally at the boiling point
of the solvent used. me reaction time depends on the tem~erature, the solvent
used and the ratio of II to III; it is reduced with rising temperature and in-
creasing excess of II. me reaction is generally complete after 20 minutes to 8
hours. It is advantageous although not necessary to carry it out u~der a protec-
tive gas; nitrogen being preferred as inert gas.
After completion of the reaction the salt formed is separated by filtra-
tion and the solvent is distilled off. If necessary, excess II is removed by
basic extraction.
2Q me compounds of the formula I obtained may be further purified by dis-
tillation or chromatography; hcwever, because of the high purity degree of the
products, this operation generally can be omitted.
The follcwing examples illustrate the invention.
EXAMPIES OF PREPAR~TION
Example 1
2-[4'-(6"-chlorokenzothiazol-2"-yl-oxy)-pheno~y]-propionic acid ethyl_ester
21 g (0.1 mol) of 2-(4'-hydroxyphenoxy)-propionic acid ethyl ester were
~ ~ `
~ 3~ ~ ~
refluxed for 1 1/2 hours with 16.6 g (0.12 mol) of potassium carbonate in 150 cc
of aoe tonitrile. 24.75 g (0.1 mol) of 6-chloro-2-methylsulfonyl-benzothiazole
dissolved in 100 cc of aoe tonitrile were added, and the batch was refluxed for a
further 5 hours. The hot solution was filtered off frcm the salt portion and the
solvent was distilled off. me remaining residue was dissolved in 200 cc of
toluene, the solution was washed se~eral times with dilute NaHQ03 solu-tion, and
dried over Na2SO4. After having distilled off the toluene, 37 g (98 ~ of theory)
of 2-[4'-(6"-chlorobenzothiazol-2"-yl-oxy)-phenoxy]-propionic acid ethyl ester,
m.p. 54 & were obtained.
Cl S~ ~ O-CH-COOC2H5
me salt residue (weight after drying: 21.85 g) was extracted several times with
hot ethanol. After evaporation of the extracts, 11.3 g (97 % of th.) of potas-
sium methylsulfinate were obtained.
In analogous manner, there were obta med:
Exam~
32.2 y (94 % of th.) of 2-[4'-(benzothiazol-2"-yl-oxy)-phenoxy~-pro-
pionic acid ethyl ester having a boiling point of 201-204C/0.13 mbar
~ ~ O ~ ~O-CH-COOC2H5
after a reaction time of 6 hours with the use of 31 g (Ool mol) of 2-phen~l~
sulfonyl-benzothiazole.
Exa~lple 3
30.5 g (84 % of th.) of 2-[4'-(6"-chlorobenzothiazol-2"-yl-oxy)-
-p~enoxy]-propionic acid methyl ester having a boiling point of 226-228C/0.13
mbar
-- 8 --
3~6~
Cl \\r 0 ~ H3
after a reaction time of 6 hours with the use of 19.6 g tO.l mol) of 2-(4'-
hydroxyphenoxy)-propionic acid methyl ester and 23.2 g (0.1 mol) of 6-chloro-2-
methylsulfinylbenzothiazole.
Exam~le 4
,.
31.8 g (88.6 % of th.) of 2-[4'-(6'-chlorobenzoxazol-2"-yl-oxy)-phenoxy]-
propionic acid ethyl ester having a boiling point of 81 - 82C
C~ >-- ~ O-CHCOOC2H5
after a reaction time of 30 minutes with the use of 23.2 g (0.1 mol) of
6-chloro-2-methylsulfonyl-benzoxazole.
Example 5
36.5 g (94 ~ of th.) of D-(*~-2-~4-(6-chlorobenzothiazol-2-yl-oxy)-phenoxy]-
-propionic acid ethyl ester having a melting point of 53C and [o~]20 of 30.2
(c = lm, chloroform)
Cl ~ ~ O-CU-COOC2~15
after a reaction time of 6 hours with the use of 21 g (0.1 mol) of D-(*)-2-
(4'-hydroxyphenoxy)-propionicacid ethyl ester and 26~2 g (0.1 mol) of 6-chloro-
- 2-ethylsulfonylbenzothiazole.
,
;'-
" ' ' :
