U.S. patent application number 11/875122 was filed with the patent office on 2008-05-08 for process for the preparation of 7-substituted 3-alkyl-3h-isobenzofuran-1-one derivatives.
This patent application is currently assigned to SYNGENTA CROP PROTECTION, INC.. Invention is credited to Marco PASSAFARO, Thomas RAPOLD, Anita SCHNYDER.
Application Number | 20080108813 11/875122 |
Document ID | / |
Family ID | 4550254 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108813 |
Kind Code |
A1 |
SCHNYDER; Anita ; et
al. |
May 8, 2008 |
PROCESS FOR THE PREPARATION OF 7-SUBSTITUTED
3-ALKYL-3H-ISOBENZOFURAN-1-ONE DERIVATIVES
Abstract
The present invention relates a process for the preparation of a
compound of formula Ia ##STR1## The process includes the step of
reacting a first compound having the formula ##STR2## at elevated
reaction temperature in the presence of sulfur in a nucleophilic
aromatic substitution reaction with an alkali metal sulfide,
disulfide or polysulfide of the formula M.sub.2S.sub.q wherein R is
halogen, R.sub.1SO.sub.2 or (R.sub.1).sub.2NC(X)O; R.sub.1 is
C.sub.1-C.sub.8alkyl, aryl-C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8-haloalkyl or aryl; R.sub.2 is hydrogen,
C.sub.1-C.sub.4alkyl or C.sub.1-C.sub.4haloalkyl, X is O or S; and
wherein M is an alkali metal or hydrogen, and q is 1, 2 or a
fractional number from 1 to 7,
Inventors: |
SCHNYDER; Anita; (Allschwil,
CH) ; PASSAFARO; Marco; (Stein, CH) ; RAPOLD;
Thomas; (Wallbach, DE) |
Correspondence
Address: |
SYNGENTA CROP PROTECTION , INC.;PATENT AND TRADEMARK DEPARTMENT
410 SWING ROAD
GREENSBORO
NC
27409
US
|
Assignee: |
SYNGENTA CROP PROTECTION,
INC.
410 Swing Road
Greensboro
NC
27409
|
Family ID: |
4550254 |
Appl. No.: |
11/875122 |
Filed: |
October 19, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10478020 |
Apr 7, 2004 |
7307175 |
|
|
PCT/EP02/05572 |
May 21, 2002 |
|
|
|
11875122 |
Oct 19, 2007 |
|
|
|
Current U.S.
Class: |
544/319 ;
549/307 |
Current CPC
Class: |
C07D 307/88 20130101;
C07C 63/70 20130101 |
Class at
Publication: |
544/319 ;
549/307 |
International
Class: |
C07D 239/60 20060101
C07D239/60; C07D 307/87 20060101 C07D307/87 |
Foreign Application Data
Date |
Code |
Application Number |
May 22, 2001 |
CH |
954/01 |
Claims
1. A process for the preparation of a compound of formula Ia
##STR23## wherein R.sub.2 is hydrogen, C.sub.1-C.sub.4alkyl or
C.sub.1-C.sub.4haloalkyl, wherein a compound of formula I ##STR24##
wherein R is halogen, R.sub.1SO.sub.2 or (R.sub.1).sub.2NC(X)O;
R.sub.1 is C.sub.1-C.sub.8alkyl, aryl-C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8-haloalkyl or aryl; X is O or S; and R.sub.2 is as
defined above, is reacted at elevated reaction temperature in the
presence of sulfur in a nucleophilic aromatic substitution reaction
with an alkali metal sulfide, disulfide or polysulfide of formula X
M.sub.2S.sub.q (X), wherein M is an alkali metal or hydrogen, and q
is 1, 2 or a fractional number from 1 to 7, with the proviso that
at least one M is an alkali metal, and optionally, when a reagent
of formula X wherein q>1 is used, is worked up reductively and,
after the reaction mixture has been rendered acidic, the desired
target compound of formula Ia is isolated therefrom and optionally
re-isolated in the form of the salt using a strongly basic aqueous
solution.
2. The process according to claim 1, wherein the nucleophilic
aromatic substitution reaction in the compound of formula I with an
alkali metal disulfide, prepared in situ in a solvent from
elemental sulfide and an alkali metal sulfide, is carried out in an
equimolar amount or in an excess of from 2 to 50 mol %, based on
the compound of formula I, and once the pH range of the reaction
mixture has been adjusted to the acid range, the compound of
formula Ia is isolated, optionally after reductive working-up, and
then optionally re-isolated from the organic phase using a strongly
basic aqueous solution.
3. The process according to claim 2, wherein an alcohol, ether,
aromatic hydrocarbon, sulfoxide, amide, ester or water, or a
mixture thereof, is used as solvent.
4. The process according to claim 3, wherein there is used as
solvent ethanol, propanol, butanol, 2-methoxyethanol,
tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide,
N,N-dimethylformamide, 1-methyl-2-pyrrolidone,
N,N-dimethylacetamide, ethyl acetate or water, or a mixture
thereof.
5. The process according to claim 1, wherein the nucleophilic
aromatic substitution reaction is carried out at a reaction
temperature of from -20.degree. to 160.degree. C.
6. The process according to claim 1, wherein the nucleophilic
aromatic substitution reaction is carried out at a pressure of from
1.1 to 100 bar.
7. The process according to claim 1, wherein a phase transfer
catalyst is additionally used, especially a quaternary ammonium
salt, in an amount of from 0.1 to 10 mol %, based on the compound
of formula Ia.
8. The process according to claim 2, wherein there is used as
reducing agent for the reductive working-up diborane, hydrazine or
a phosphine in a sub-stoichiometric amount, in equimolar amount or
in a slight excess of from 5 to 15 mol %, based on the compound of
formula I used.
9. The process according to claim 2, wherein as reducing agent for
the reductive working-up there is used a borohydride in a
sub-stoichiometric amount, based on the compound of formula I
used.
10. The process according to claim 2, wherein the nucleophilic
aromatic substitution reaction in the compound of formula I is
carried out using sodium disulfide, prepared in situ from an
equimolar mixture of sulfur and sodium sulfide, in 2-methoxyethanol
or N,N-dimethylformamide at a reaction temperature of from
80.degree. to 100.degree. C. for 1 hour and, after the addition of
toluene and water, and adjustment of the reaction mixture to the pH
range of from 1 to 5, the compound of formula Ia is extracted with
toluene and then optionally back-extracted from the organic phase
with an aqueous strong base.
11. A process for the preparation of a compound of formula Ia
##STR25## wherein R.sub.2 is hydrogen, C.sub.1-C.sub.4alkyl or
C.sub.1-C.sub.4haloalkyl, wherein a compound of formula III
##STR26## wherein R is halogen, R.sub.1S(O).sub.2 or
(R.sub.1).sub.2NC(X)O; R.sub.1 is C.sub.1-C.sub.8alkyl,
aryl-C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8-haloalkyl or aryl; X is
O or S; and R.sub.3 is C.sub.1-C.sub.5alkyl or
C.sub.1-C.sub.5haloalkyl, is subjected to benzylic lactonisation in
the ortho-position alkyl chain R.sub.3 in the presence of a
free-radical initiator and a halogenating agent, yielding a
compound of formula I ##STR27## wherein R and R.sub.2 are as
defined above, which compound is then reacted at elevated reaction
temperature in the presence of sulfur in a nucleophilic aromatic
substitution reaction with an alkali metal sulfide, disulfide or
polysulfide of formula X M.sub.2S.sub.q (X), wherein M is an alkali
metal or hydrogen, and q is 1, 2 or a fractional number from 1 to
7, with the proviso that at least one M is an alkali metal and
optionally, when a reagent of formula X wherein q>1 is used, is
worked up reductively and, after the reaction mixture has been
rendered acidic, the desired target compound of formula Ia is
isolated therefrom and optionally re-isolated in the form of the
salt using a strongly basic aqueous solution.
12. A process for the preparation of
7-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-methyl-3H-isobenzofuran-1-one
by reacting 7-thio-3-methyl-3H-isobenzofuran-1-one of formula Ia
prepared according to claim 1 ##STR28## wherein R.sub.2 is methyl,
with a compound of formula VI ##STR29##
13. A process for preparing
7-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-methyl-3H-isobenzofuran-1-one
by reacting 7-thio-3-methyl-3H-isobenzofuran-1-one of formula Ia
prepared according to claim 11. ##STR30## wherein R.sub.2 is
methyl, with a compound of formula VI ##STR31##
14. A compound of formula III ##STR32## wherein R is halogen,
R.sub.1S(O).sub.n or (R.sub.1).sub.2NC(X)O; R.sub.1 is
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl,
aryl-C.sub.1-C.sub.8-alkyl or aryl; n is 0, 1, 2 or 3; X is O or S;
and R.sub.3 is C.sub.2-C.sub.5alkyl or C.sub.1-C.sub.5haloalkyl, or
a salt thereof.
Description
[0001] This application is a divisional of application Ser. No.
10/478,020 filed Apr. 7, 2004, still pending, which is the National
Stage of International Application No. PCT/EP02/05572, filed May
21, 2002, which claims the benefit of Swiss Application No. 954/01,
filed May 22, 2001.
[0002] The present invention relates to a novel process for the
preparation of 7-substituted 3-alkyl-3H-isobenzofuran-1-one
derivatives, to their use as intermediates in the preparation of
byproduct-free 7-thio-3H-isobenzofuran-1-one derivatives, and to
their use as intermediates in the preparation of herbicidal
7-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-methyl-3H-isobenzo-furan-1-one.
[0003] WO 91/05781 describes a process for the preparation of
7-thio-3-methyl-3H-isobenzofuran-1-one. According to that process,
that compound is obtained by rearrangement in three steps starting
from 7-hydroxy-3-methyl-3H-isobenzofuran-1-one according to
Kwart-Newmann via the
7-(N,N-dimethylthiocarbamoyl)oxy-3-methyl-3H-isobenzofuran-1-one
derivative with heating at about 170-200.degree. C. to the
7-(N,N-dimethylcarbamoyl)thio-3-methyl-3H-isobenzofuran-1-one
intermediate and is then subjected to alkaline hydrolysis. Since
the starting material 7-hydroxy-3-methyl-3H-isobenzofuran-1-one
also has to be prepared by a multistep process, that process for
the preparation of 7-thio-3-methyl-3H-isobenzofuran-1-one is
troublesome and unsuitable for commercial synthesis.
[0004] In a further process, starting from 3-nitrophthalic acid the
target compound 7-thio-3-methyl-3H-isobenzofuran-1-one is obtained
in four reaction steps in a yield of about 60%. The latter reaction
sequence consists of introducing a methyl group using
methylmagnesium bromide or malonic acid, reducing a nitro group and
a carbonyl group, and then diazotising the resulting
7-amino-3-methyl-3H-isobenzofuran-1-one in the presence of sodium
hydrogen sulfide.
[0005] Pest Manag Sci. 57, 205-224 (2001) describes further
synthesis processes for the preparation of
7-thio-3-methyl-3H-isobenzofuran-1-one (compound of formula Xc in
FIG. 7 on page 211) in which undesired disulfide byproducts
(compounds of formula Xc' in FIG. 7) are substantially excluded,
e.g. by reduction and simultaneous ring-closure of
2-acetyl-6-nitrobenzoic acid with Raney nickel, diazotisation of
the 7-amino-3-methylphthalide (compound of formula XXa) obtained in
a crude yield of 89.8%, and subsequent thiol formation by treatment
of the corresponding diazonium salt with an alkaline potassium
xanthogenate solution in a crude yield of 87.5% over the last two
reaction steps.
[0006] That process too is unsatisfactory in terms of volumetric
and chemical yields. In addition, the use of xanthogenates as
source of sulfur for the thiol formation gives rise to volatile,
unpleasant-smelling, toxic, sulfur-containing waste products, such
as e.g. COS, CS.sub.2 and H.sub.2S. Moreover, individual reaction
steps, such as e.g. the reduction of 3-nitrophthalic acid
derivatives to the corresponding amines (formation of hydroxylamine
byproducts), have a significant thermal safety risk (TMR (=`time to
maximum rate`)<2 hours). From the standpoint of industrial-scale
preparation processes, these aspects are problematic especially in
ecological terms and in respect of process safety.
[0007] Monatsh. Chem. 123(12), 1125-1134 (1992) describes the
preparation of 7-chlorophthalides methyl- or phenyl-substituted in
the 3-position by ortho-lithiation of 3-chlorobenzanilides with
n-butyllithium, reaction with electrophiles e.g. acetaldehyde, for
the preparation of 7-chloro-3-methyl-phthalides, and subsequent
acid-catalysed cyclisation. As described above in Pest Manag Sci.
57, 205-224, such 7-chloro-3H-isobenzofuran-1-ones can be converted
by treatment with an excess of alkylmercaptides, e.g. sodium
methyl- or ethyl-mercaptide, at temperatures of about
100-130.degree. C. in N,N-dimethylformamide to the desired
7-mercapto-3H-isobenzofuran-1-ones by way of a
7-alkylmercapto-3H-isobenzofuran-1-one intermediate. That process
too is unsuitable for industrial-scale processes because of the
yield, process safety and the formation of unpleasant-smelling
dialkylsulfides and is also uneconomical owing to the cost of the
reagent n-butyllithium.
[0008] Tetrahedron Lett. 36(39), 7089-7092 (1995) and J. Chem.
Soc., Perkin Trans. 1, 1997, 787-793 describe the oxidative,
free-radical-forming, photochemical preparation of lactones at room
temperature starting from o-alkyl aromatic carboxylic acids in the
presence of [bis(tri-fluoroacetoxy)iodo]benzene and iodine
(phenyl-I(O(O)CCF.sub.3).sub.2/I.sub.2) by way of a hypoiodite
species in an organic solvent, such as dichloromethane, and
irradiation with a high-pressure mercury vapour lamp in moderate to
good yields (from 5 to 90%, based on the starting compound) of the
desired lactone, and Tetrahedron Asym. 8, 3765-3774 (1997)
describes the preparation of 3-alkylphthalide derivatives starting
from o-alkyl aromatic carboxylic acids as biocatalysed benzylic
oxidation and lactonisation using microorganisms, such as e.g.
Pseudomonas putida. Neither synthesis process can be carried out on
an industrial scale. Chem. Ber. 38, 3981-3985 (1905) describes a
synthesis variant for the preparation of phthalide derivatives
starting from aromatic ortho-aldehydro acids by means of
nucleophilic addition using Grignard reagents with the formation of
the corresponding alcohol derivatives and subsequent lactonisation
of the same.
[0009] J. Org. Chem. 51, 3849-3858 (1986) and J. Organomet. Chem.
231, 79-90 (1982) describe a further synthesis variant for
3-methylphthalides by the reduction and lactonisation of
2-methylketonecarboxylic acids using sodium borohydride and
ruthenium-triphenyl-phosphine complex and hydrogen
(RuCl.sub.2(PPh.sub.3).sub.3/H.sub.2), respectively, in a
quantitative yield, and a yield of 51%, respectively.
[0010] Tetrahedron Lett. 28(43), 5175-5176 (1987), J. Chem. Soc.
Perkin Trans II, 1983, 595-601, Ind. J. Chem. Sect. B 24, 1202-1203
(1985) and Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.)
31(10), 2041-2046 (1982) describe the preparation of .gamma.- and
.delta.-lactones from alkanecarboxylic acids by oxidation with
oxygen-containing compounds, such as e.g.
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or sodium
persulfate (Na.sub.2S.sub.2O.sub.8), in the presence of catalytic
amounts of copper(II) chloride or nickel(II) chloride, or
cerium(IV) ammonium nitrate
(Ce(NH.sub.4).sub.2(NO.sub.3).sub.6/HNO.sub.3) in a yield of
10-35%.
[0011] Tetrahedron Lett. 29(1), 85-88 (1988) describes the
preparation of .gamma.-lactones from .gamma.-arylbutyric acids via
halogenation with bromine in the presence of the free-radical
initiator .alpha.,.alpha.'-azoisobutyronitrile in carbon
tetrachloride in a yield of 53%.
[0012] J. Org. Chem. 45, 2365-2368 (1980) describes the
palladium(0)-catalysed carbonylation of isolated methyl-, methoxy-,
halo- and nitro-substituted arenediazonium tetrafluoroborates in
acetonitrile in the presence of sodium acetate and carbon monoxide
in yields of from 28 to 86%, and J. Chem. Soc., Perkin Trans. 1,
1998, 407-410 describes the palladium(II)-catalysed carbonylation
of isolated bisarenediazonium tetrafluoroborate salts in methanol
at room temperature and normal pressure in yields of from 76 to
93%, based on the diazonium salt. WO 96/19443 discloses a process
for the preparation of aromatic o-sulfo-carboxylic acids by means
of diazotisation of the corresponding aniline-2-sulfonic acids and
subsequent palladium(II)-catalysed carbonylation of the diazonium
salt formed, with or without isolation of that diazonium salt.
[0013] Whilst the preparation of sulfides by the reaction of
halides with mercaptides, xanthates, thiourea, alkali metal
sulfides or alkali metal disulfides (the latter being prepared in
situ from alkali metal sulfides and sulfur) are well-documented
standard processes, as described e.g. in J. Org. Chem. 56,
3728-3729 (1991), J. Am. Chem. Soc. 68, 498 (1946), Gazz. Chim.
Ital. 110, 301-303 (1980), Org. Synth., Coll. Vol. III, 86-87 and
Chem. Pharm. Bull. 33, 5184-5189 (1985), they are all unsuitable
for industrial-scale batches, because:
a) the reagents used are too expensive, such as e.g. the use of
sodium borohydride for the reductive working-up of disulfide
derivatives,
b) the resulting product yields and product purities are
unsatisfactory for industrial-scale preparation processes,
c) the amount of di- and poly-sulfides formed is too great, and
d) the reproducibility cannot be guaranteed.
[0014] The problem of the present invention is to overcome those
disadvantages and provide a technically simpler process suitable
for industrial-scale processes that is associated with little
outlay in terms of apparatus.
[0015] It has now been found, surprisingly, that
3-alkyl-3H-isobenzofuran-1-one derivatives substituted specifically
in the 7-position can readily be prepared with high product yield,
product purity and selectivity, in an economically and ecologically
especially advantageous manner, avoiding the disadvantages of the
processes described above, from inexpensive and readily accessible
starting compounds, such as e.g. aniline derivatives, using
technically simple, reproducible and safe process conditions by way
of only three or four reaction steps, by diazotising
2,6-disubstituted aniline derivatives, carbonylating the resulting
diazonium salt in the presence of catalysts and cyclising the
resulting benzoic acid derivative in the presence of a halogenating
agent and a free-radical initiator to form the corresponding
lactone derivative. That lactone derivative is then used in a
further, fourth reaction step for a nucleophilic aromatic
substitution reaction with sulfides and a subsequent, specific
purification step at a controlled pH range for the preparation of
byproduct-free 7-thio-3H-isobenzofuran-1-one, which can be used
directly e.g. for the preparation of herbicides according to EP-B-0
447 506. In that process, careful attention is given to the
critical factors and crucial reaction parameters in all the
reaction steps including working-up, such as e.g. the choice of
solvents, acids, bases and buffer systems, the water content in the
reaction mixture, the pH range, the reaction temperature, the
charging procedure for the palladium complex, pressure and reaction
time.
[0016] The present invention accordingly relates to a process for
the preparation of 7-substituted 3-alkyl-3H-isobenzofuran-1-ones of
formula I ##STR3## wherein R is halogen, R.sub.1O,
R.sub.1S(O).sub.n or (R.sub.1).sub.2NC(X)O; R.sub.1 is
C.sub.1-C.sub.8alkyl, aryl-C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8haloalkyl or aryl; n is 0, 1, 2 or 3; X is O or S;
and R.sub.2 is hydrogen, C.sub.1-C.sub.4alkyl or
C.sub.1-C.sub.4haloalkyl, in which process, in a solvent, (1) an
aniline derivative of formula IV ##STR4## wherein R is as defined
above, and R.sub.3 is C.sub.1-C.sub.5alkyl or
C.sub.1-C.sub.5haloalkyl, is diazotised in the presence of a
mineral acid to form the corresponding diazonium salt of formula II
##STR5## wherein R and R.sub.3 are as defined above, A.sup.m- is an
anion such as e.g. PF.sub.6.sup.-, BF.sub.4.sup.-, HSO.sub.4.sup.-,
SO.sub.4.sup.2-, CH.sub.3(C.sub.6H.sub.4)SO.sub.3.sup.-,
CH.sub.3SO.sub.3.sup.-or (Zn(II)Cl.sub.3).sup.-, and m is 1 or 2,
(2) the resulting diazonium salt of formula II is carbonylated in
the presence of a catalyst, CO and optionally a buffer, to form a
benzoic acid derivative of formula III ##STR6## wherein R and
R.sub.3 are as defined above, and (3) the benzoic acid derivative
of formula III is then subjected to benzylic lactonisation in the
ortho-position alkyl chain R.sub.3 in the presence of a
free-radical initiator and a halogenating agent.
[0017] The compounds of formula I prepared according to the
invention are used as starting compounds in the preparation of
compounds of formula Ia ##STR7## wherein R.sub.2 is as defined for
formula I, by reacting a compound of formula I ##STR8## wherein R
is halogen, R.sub.1SO.sub.2 or (R.sub.1).sub.2NC(X) O; and X,
R.sub.1 and R.sub.2 are as defined for formula I, with the reagent
of formula X M.sub.2S.sub.q (X), wherein M is an alkali metal or
hydrogen, and q is 1, 2 or a fractional number from 1 to 7, with
the proviso that at least one M is an alkali metal (halogen-sulfide
exchange; Reaction scheme 3).
[0018] The compounds of formulae I and Ia may be in the form of
optical isomers and mixtures of isomers depending on the
substituents R/R.sub.1 and/or R.sub.2. Unless enantiomerically pure
starting materials are used, the compounds of formulae I and Ia in
the processes described above are generally obtained in the form of
racemates or diastereoisomeric mixtures, which can optionally be
separated on the basis of physicochemical properties according to
known methods, such as e.g. fractional crystallisation after salt
formation with optically pure bases or metal complexes or by
chromatographic processes, such as e.g. high pressure liquid
chromatography (HPLC) on acetylcellulose.
[0019] In the present invention, the compounds of formulae I and Ia
are to be understood as including both the enriched and optically
pure forms of the stereoisomers in question and the racemates or
diastereoisomers. Where there is no specific reference to the
individual optical antipodes, the racemic mixtures under the given
formula are to be understood as being those obtained in the
preparation process according to the invention.
[0020] The present invention includes also the salts that can be
formed by the compounds of formulae Ia and III.
[0021] For example, owing to their acidity, compounds of formulae
Ia and III can readily be converted in the presence of bases
(proton acceptors) into the corresponding salts (e.g. with metal
ions or ammonium cations). Any customary proton acceptor can be
used as base. Such salts are, for example, alkali metal salts, such
as e.g. sodium and potassium salts; alkaline earth metal salts,
such as e.g. calcium and magnesium salts; ammonium salts, that is
to say unsubstituted ammonium salts and mono- or poly-substituted
ammonium salts, such as e.g. triethylammonium and methylammonium
salts, or salts with other organic bases or other cations, such as
e.g. sulfonium or phosphonium cations. Sulfonium cations are, for
example, tri(C.sub.1-C.sub.4alkyl)sulfonium cations, which can be
obtained from the corresponding alkali metal salts e.g. by
conversion into different salts using, for example, a cation
exchanger. Of the alkali metal hydroxides and alkaline earth metal
hydroxides as salt formers, special mention may be made, for
example, of the hydroxides of lithium, sodium, potassium, magnesium
and calcium, but especially those of sodium and potassium. Suitable
ammonium salt formers are described, for example, in WO 97/41112.
Examples of amines suitable for ammonium salt formation that come
into consideration are ammonia and also primary, secondary and
tertiary C.sub.1-C.sub.18alkylamines, and heterocyclic amines.
Especially suitable are, for example, trimethylamine,
triethylamine, tri-n-propylamine, triiso-propylamine,
triisobutylamine, pyridine, 5-ethyl-2-methylpyridine and
morpholine. More especially suitable are trimethylamine and
triethylamine. In the above definitions, halogen is to be
understood as being fluorine, chlorine, bromine or iodine,
preferably fluorine, chlorine or bromine.
[0022] The alkyl groups appearing in the substituent definitions
are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, isobutyl and tert-butyl, and also the pentyl, hexyl,
heptyl and octyl isomers.
[0023] Haloalkyl groups preferably have a chain length of from 1 to
6 carbon atoms. Haloalkyl is, for example, fluoromethyl,
difluoromethyl, difluorochloromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, dichlorofluoromethyl,
trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl,
2-chloroethyl, 2,2-difluoroethyl, 2,2-dichloroethyl,
2,2,2-trichloroethyl or pentafluoroethyl, preferably
trichloromethyl, difluoromethyl, difluorochloromethyl,
trifluoromethyl or dichloro-fluoromethyl.
[0024] Aryl in the definition of the radical R.sub.1 is .alpha.- or
.beta.-naphthyl, especially phenyl, it being possible for those
aromatic rings to carry one or more identical or different
substituents, such as e.g. halogen, nitro, cyano,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy,
C.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4haloalkyl. The same applies
also to arylalkyl in the definition of the radical R.sub.1.
Corresponding meanings can be assigned also to the substituents in
composite definitions of R, such as e.g. alkoxy, haloalkoxy,
arylalkyl, aryloxy, arylthio, arylsulfonyl, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, haloalkylthio,
haloalkylsulfinyl, haloalkylsulfonyl, haloalkylsulfonyloxy,
arylalkylthio, arylalkylsulfinyl and arylalkylsulfonyl.
[0025] A.sup.m- in the diazonium salt of formula II denotes a mono-
(m=1) or di-valent (m=2) anion and according to the definition
includes e.g. PF.sub.6.sup.-, BF.sub.4.sup.-, HSO.sub.4.sup.-,
SO.sub.4.sup.2-, CH.sub.3(C.sub.6H.sub.4)SO.sub.3.sup.-,
CH.sub.3SO.sub.3.sup.-and (Zn(II)Cl.sub.3).sup.-, preferably
PF.sub.6.sup.-and BF.sub.4.sup.-.
[0026] THE reagent of formula X, M.sub.2S.sub.q, is, when both M
are alkali metals and q is 1, an alkali metal sulfide, such as e.g.
sodium sulfide (Na.sub.2S), potassium sulfide (K.sub.2S), lithium
sulfide (Li.sub.2S) or sodium potassium sulfide (NaKS); when one M
is an alkali metal and the second M is hydrogen and q is 1, the
reagent of formula X is an alkali metal hydrosulfide, such as e.g.
sodium hydrosulfide (NaHS) or potassium hydrosulfide (KHS); when
both M are alkali metals and q is 2, the reagent of formula X is an
alkali metal disulfide, such as e.g. sodium disulfide
(Na.sub.2S.sub.2), potassium disulfide (K.sub.2S.sub.2) or sodium
potassium disulfide (NaKS.sub.2), and finally when one M is an
alkali metal and the second M is hydrogen and q is 2, the reagent
of formula X is an alkali metal hydrodisulfide, such as e.g. sodium
hydrodisulfide (NaHS.sub.2) or potassium hydrodisulfide
(KHS.sub.2). For higher values of q, the reagent M.sub.2S.sub.q of
formula X denotes compounds such as, for example, Na.sub.2S.sub.4
or mixtures prepared in situ from lower alkali metal sulfides and
sulfur. The definition of M.sub.2Sq also includes mixtures of lower
and higher alkali metal sulfides. The nucleophilic species are then
e.g. NaS.sup.-, HS.sup.-, NaS.sub.2.sup.-and HS.sub.2.sup.-. The
process according to the invention is especially suitable for the
preparation of compounds of formula I wherein R is chlorine or
bromine, especially chlorine.
[0027] The process according to the invention is also especially
suitable for the preparation of compounds of formula I wherein
R.sub.2 is CH.sub.3.
[0028] The process according to the invention is also especially
suitable for the preparation of compounds of formula I wherein R is
chlorine and R.sub.2 is CH.sub.3.
[0029] The preparation of compounds of formula I by way of three
reaction steps (Steps (1), (2) and (3)) and the use thereof in a
derivatisation step by means of a nucleophilic aromatic
substitution reaction with the reagent of formula X M.sub.2S.sub.q
(X) (reaction step 41 halogen-sulfide exchange) to form compounds
of formula Ia will be explained in greater detail in the following
Reaction schemes 1, 2 and 3. ##STR9## ##STR10## ##STR11##
[0030] In the first Step (1) in Reaction scheme 1, the
diazotisation of the aniline derivative of formula IV is carried
out advantageously in a solvent and in the presence of a 20 to 120%
excess of a mineral acid, based on the diazotisation reagent, at
reaction temperatures in the range of from -5.degree. to 25.degree.
C.
[0031] As diazotisation reagent there may be used the customary
nitrites, such as, for example, alkali metal nitrites, dinitrogen
trioxide (N.sub.2O.sub.3) or organic nitrites, preferably sodium
nitrite, potassium nitrite, N.sub.2O.sub.31 tert-butyl nitrite or
pentyl nitrite in equivalent amounts or in a slight excess of from
3 to 10% molar equivalents, based on the aniline derivative of
formula IV.
[0032] Suitable solvents for the diazotisation in Step (1) are
C.sub.1-C.sub.4-carboxylic acids, nitrites, ethers, amides,
carbonates, alcohols or water, or mixtures thereof, for example
acetic acid, propionic acid, acetonitrile, tetrahydrofuran,
dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA),
1-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI),
propylene carbonate, isoamyl alcohol, n-pentanol, isopropanol,
n-propanol, tert-butanol, n-butanol, ethanol, methanol or water, or
mixtures thereof. Preference is given to acetic acid, acetonitrile,
alcohols and water.
[0033] Suitable mineral acids for the diazotisation reaction in
Step (1) are preferably sulfuric acid, hydrochloric acid, nitric
acid and hydrobromic acid.
[0034] The catalysts that come into consideration for the
carbonylation of the diazonium salts of formula II in Step (2)
(Matsuda carbonylation, Reaction scheme 1) are generally
palladium(II) and palladium(0) complexes. Examples of such
palladium complexes are palladium(II) dihalides, palladium(II)
acetate, palladium(II) sulfate, palladium(II) acetylacetonate,
bis-hydridopalladium(II) tetrahalides (H.sub.2PdCl.sub.4),
bis(alkali metal)palladium(II) tetrahalides,
cis,cis-1,5-cyclooctadiene-palladium(II) dihalides,
bis(acetonitrile)- and bis(benzonitrile)-palladium(II) dihalides,
bis(dibenzylideneacetone)palladium(0) (Pd.sub.2(dba).sub.3),
[Pd(.eta..sub.3-C.sub.3H.sub.5)Cl].sub.2,
[Pd(n.sub.3-Me-C.sub.3H.sub.4)Cl].sub.2, [Pd
(.eta..sub.3-C.sub.3H.sub.5)(acac)].sub.2,
bis(triphenylphosphine)palladium(II) dihalides and
tetrakis(triphenylphosphine)palladium(II) dihalides.
[0035] The palladium complexes are prepared ex situ or optionally,
in the case of ligand-carrying complexes, such as e.g.
triphenylphosphinepalladium(II) complexes, also in situ. Examples
of preferred palladium(0) and palladium(II) catalysts prepared ex
situ or in situ are PdCl.sub.2, PdBr.sub.2, H.sub.2PdCl.sub.4 (in
the form of a solution in hydrochloric acid), Na.sub.2[PdCl.sub.4],
Li.sub.2[PdCl.sub.4], K.sub.2[PdCl.sub.4], Pd(acac).sub.2,
PdCl.sub.2(COD) (=PdCl.sub.2(cis,cis-1,5-cyclooctadiene)),
PdCl.sub.2(AcCN).sub.2, PdCl.sub.2(PhCN).sub.2,
PdCl.sub.2(PPh.sub.3).sub.2, PdCl.sub.2(PPh.sub.3).sub.4 and
Pd(PPh.sub.3).sub.4.
[0036] Such palladium complexes are known and have been described
many times in the literature, such as e.g. in J. Am. Chem. Soc.
121, 4369-4378 (1999), EP-A-0 564 406, EP-A-0 646 590 and
`Palladium Reagents and Catalysts`, Editor J. Tsuji, John Wiley
& Sons, 1995.
[0037] The palladium catalysts are used in an amount of from 0.1 to
5.0 mol %, preferably from 0.25 to 1.00 mol %, based on the
compound of formula II.
[0038] Suitable solvents for the carbonylation in Step (2) are the
same as those listed for the diazotisation in Step (1). Generally,
directly before the carbonylation reaction, from 0 to 10
equivalents of water, based on the compound of formula IV, are
metered in or an excess of water is reduced using carboxylic acid
anhydrides, such as e.g. acetic anhydride (Examples P2 and P3).
[0039] The palladium-catalysed carbonylation reaction of the
diazonium salt of formula II in Step (2) is carried out at a CO
pressure of from 1 to 100 bar and at reaction temperatures of from
-20.degree. to 60.degree. C., preferably in a pressurised vessel
(autoclave).
[0040] The two Steps (1) and (2), the diazotisation and
carbonylation in Reaction scheme 1, can be carried out, in
principle, according to two different variants:
[0041] a) as a two-step reaction with isolation of the
intermediately formed, stable diazonium salt of formula II
##STR12## wherein R, R.sub.3, A.sup.m- and m are as defined for
formula I, or
[0042] b) preferably as a single-step reaction without isolation of
the intermediately formed diazonium salt of formula II ##STR13##
wherein R, R.sub.3, A.sup.m- and m are as defined for formula I,
with the result that the diazotisation of the aniline derivative of
formula IV and the palladium-catalysed carbonylation reaction of
the compound of formula II in Steps (1) and (2) are carried out as
a continuous process, that is in the same reaction vessel and
solvent system as a one-pot reaction.
[0043] When selecting one of the two variants a) or b), in addition
to considering the stability of the diazonium salt of formula II,
the reactants present in the reaction mixture must also be taken
into account and must be matched according to the process variant
in question in order to avoid possible secondary reactions and thus
a reduction in yield. Critical factors are, for example, the
selection of the solvent or solvent mixture, of the nitrite reagent
as potential catalyst poison and of the mineral acid, e.g. sulfuric
acid as opposed to hydrochloric acid, and the buffering of excess
mineral acid, for example with acetates, the water content in the
reaction mixture, and the nature of the palladium catalyst and its
charging procedure, especially the sequence of the addition of CO
and the metering of the palladium complex into the reaction
mixture. In addition, the reaction parameters, such as e.g. the
reaction temperature and the CO pressure in the system, may be
critical to the manner in which each reaction proceeds.
[0044] Accordingly, prior to the catalytic carbonylation of the
diazonium salt of formula II in Step (2) the mineral acid in the
reaction mixture is advantageously buffered with a buffer system,
preferably using an alkali metal acetate, for example sodium
acetate.
[0045] Once the diazotisation is complete, excess nitrite reagent
present in the reaction mixture is destroyed in customary manner
known to the person skilled in the art, for example by adding
sulfamic acid (Examples P2 and P3) until nitrite is no longer
detectable (nitrite detection using KI paper moistened with 1 N
aqueous hydrochloric acid solution) and the reaction mixture so
treated is prepared for the subsequent palladium-catalysed
carbonylation step, which is preferably carried out in the same
reaction vessel.
[0046] In the case of the two-step variant a), with isolation of
the diazonium salt of formula i, the following aqueous base
systems, for example, are suitable for the subsequent carbonylation
reaction: alkali metal, alkaline earth metal and ammonium salts of
acetates, propionates, butyrates, benzoates and stearates, and of
carbonates, for example lithium, sodium, potassium, calcium, barium
and ammonium acetate, propionate and benzoate, and lithium, sodium,
potassium, calcium, barium, magnesium, ammonium and
(C.sub.1-C.sub.18alkyl).sub.3NH salts of carbonates.
[0047] In an especially preferred variant of Steps (1) and (2)
according to the invention, the diazotisation of the aniline
derivative of formula IV (Step (1)) is carried out using an
equivalent amount of sodium nitrite in the presence of a 25% excess
of sulfuric acid, based on the nitrite, and acetic acid as solvent,
and the subsequent palladium-catalysed carbonylation reaction (Step
(2)) is carried out using Pd.sub.2(dba).sub.3CHCl.sub.3 at a CO
pressure of from 2 to 10 bar and a reaction temperature of from
20.degree. to 60.degree. C. in the same reaction vessel as a
one-pot reaction.
[0048] In Step (3) in Reaction scheme 2, the treatment with the
halogenating reagent and subsequent or simultaneous ring-closure
reaction (lactonisation) of the benzoic acid derivative of formula
III are advantageously carried out using halogen, preferably
chlorine or bromine, using hypohalite, preferably hypochlorite or
hypobromite, or using sulfuryl halide, preferably sulfuryl chloride
or sulfuryl bromide, in a solvent, such as e.g. a chlorinated
hydrocarbon, a C.sub.1-C.sub.4-carboxylic acid or water, or a
mixture thereof, and in the presence of a free-radical initiator,
such as e.g. .alpha.,.alpha.'-azoisobutyronitrile or benzoyl
peroxide.
[0049] The halogenating reagent is advantageously used in an amount
of from 1 to 2 molar equivalents, based on the benzoic acid
derivative of formula III.
[0050] The solvents especially suitable for Step (3) are, for
example, chlorinated hydrocarbons, for example tetrachloroethylene,
chloroform, dichloromethane, chlorobenzene and dichloro-benzene,
carboxylic acids, for example acetic acid or propionic acid, or
water, or mixtures thereof, the reaction temperature being from
-20.degree. to 160.degree. C. and the reaction pressure being from
1 to 100 bar.
[0051] In an especially preferred variant of Step (3) according to
the invention, the treatment with the halogenating reagent and the
ring-closure reaction of the compound of formula III are carried
out with from 1 to 1.3 molar equivalents of bromine, based on the
compound of formula III, in chlorobenzene at reaction temperatures
of from 80.degree. to 100.degree. C. and at normal pressure in the
presence of .alpha.,.alpha.'-azoisobutyronitrile as free-radical
initiator.
[0052] For good selectivity and in order to carry out the reaction
in Step (3) efficiently, the choice of the solvent, the amount of
halogenating reagent and of free-radical initiator and the purity
of the starting compound of formula III, and the reaction
parameters, such as temperature and duration of the reaction, are
critical in order as far as possible to suppress over-oxidation and
the formation of halides, such as e.g. phenyl nuclear halides and
alkyl halides (R.sub.2). Excess halogenating and oxidising agents
can be rendered inactive in the course of a working-up process, for
example using an alkali metal thiosulfate, for example using sodium
thiosulfate (Example P4).
[0053] The yields of isolated product of formula I in all three
Steps (1), (2) and (3) are generally >70% of theory (depending
on the solvent and acid used, the optimum water content, the
charging procedure for the palladium catalyst, the nature and
amount of halide and purity of the starting materials) with the
final product having a purity of >90%.
[0054] The starting compounds of formula IV in Reaction scheme 1
are known e.g. from DE-A-2 405 479 and Ann. Chem. 424, 255
(1921).
[0055] All the reagents used, such as diazotisation agents,
palladium(II) and palladium(0) catalysts, phosphine ligands and
free-radical initiators, are also known or can be prepared
according to known processes.
[0056] The compounds of formula III ##STR14## wherein R is halogen,
R.sub.1S(O).sub.n or (R.sub.1).sub.2NC(X)O; R.sub.1 is
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl,
aryl-C.sub.1-C.sub.8-alkyl or aryl; n is 0, 1, 2 or 3; X is O or S;
and R.sub.3 is C.sub.2-C.sub.5alkyl or C.sub.1-C.sub.5haloalkyl,
and salts thereof are novel. They make a significant contribution
in structural terms to the preparation of the lactones of formulae
I and Ia and have been developed especially for the process
according to the invention.
[0057] Preferred compounds of formula III are those wherein R is
halogen or R.sub.1S(O).sub.2 and R.sub.3 is ethyl.
[0058] The compounds of formula I ##STR15## wherein R is fluorine,
bromine, iodine, R.sub.1S(O).sub.n or (R.sub.1).sub.2NC(X)O;
R.sub.1 is C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8-haloalkyl,
aryl-C.sub.1-C.sub.8alkyl or aryl; n is 0 1, 2 or 3; X is O or S;
and R.sub.2 is hydrogen, C.sub.1-C.sub.4alkyl or
C.sub.1-C.sub.4haloalkyl, are also novel. They make a substantial
contribution in structural terms to the preparation of the lactones
of formula Ia and have been developed especially for the use
according to the invention.
[0059] Preferred compounds of formula I are those wherein R is
bromine or R.sub.1SO.sub.2 and R.sub.2 is methyl.
[0060] The present invention accordingly relates also to the
compounds of formulae I and III.
[0061] The present invention accordingly relates also to the use of
compounds of formula I in the preparation of
7-thio-3H-isobenzofuran-1-one derivatives of formula Ia ##STR16##
wherein R.sub.2 is hydrogen, C.sub.1-C.sub.4alkyl or
C.sub.1-C.sub.4haloalkyl, wherein a compound of formula I ##STR17##
wherein R is halogen, R.sub.1SO.sub.2 or (R.sub.1).sub.2NC(X)O; X
is O or S; R.sub.1 is C.sub.1-C.sub.8alkyl,
aryl-C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl or aryl; and
R.sub.2 is as defined above, is reacted at elevated reaction
temperature in the presence of sulfur in a nucleophilic aromatic
substitution reaction with an alkali metal sulfide, disulfide or
polysulfide of formula X M.sub.2S.sub.q (X), wherein M is an alkali
metal or hydrogen, and q is 1, 2 or a fractional number from 1 to
7, with the proviso that at least one M is an alkali metal
(halogen-sulfide exchange; Reaction scheme 3), and optionally, when
a reagent of formula X wherein q>1 is used, is worked-up
reductively and, after the reaction mixture has been rendered
acidic, the desired target compound of formula Ia is isolated
therefrom and optionally re-isolated in the form of the salt using
a strongly basic aqueous solution.
[0062] As alkali metal sulfides or disulfides of formula X for the
nucleophilic aromatic substitution reaction (halogen-sulfide
exchange) in the compound of formula I, it is possible to use, for
example, sodium sulfide (Na.sub.2S), potassium sulfide (K.sub.2S),
lithium sulfide (Li.sub.2S), sodium potassium sulfide (NaKS),
sodium disulfide (Na.sub.2S.sub.2), sodium potassium disulfide
(NaKS.sub.2), and also alkali metal hydrosulfides and alkali metal
hydrodisulfides, for example sodium hydrosulfide (NaHS), potassium
hydrosulfide (KHS) and sodium hydrodisulfide (NaHS.sub.2) (Reaction
scheme 3), the disulfides preferably being prepared in situ in a
solvent, such as e.g. an amide, for example DMF, from elemental
sulfur and an alkali metal sulfide, e.g. sodium sulfide,
analogously to the manner described, e.g. in Gazz. Chim. Ital. 110,
301 (1980), J. Am. Chem. Soc. 68, 498 (1946) and Chem. Pharm. Bull.
33, 5184 (1985).
[0063] The alkali metal sulfides and disulfides of formula X are
advantageously used in equimolar amounts or in an excess of from 2
to 50 mol %, based on the compound of formula I. After adjustment
of the pH range of the reaction mixture to the acid range,
preferably to the pH range of from 1 to 5, the desired compound of
formula Ia can be isolated, optionally after reductive working-up
when q is 2 in the compound of formula X that is used (disulfides),
and then optionally re-isolated from the organic phase using a
strongly basic aqueous solution (Example P6).
[0064] Solvents suitable for the nucleophilic aromatic substitution
of the compounds of formula I are generally, for example, alcohols,
ethers, aromatic hydrocarbons, sulfoxides, amides, esters or water,
or mixtures thereof, for example ethanol, propanol, butanol,
2-methoxyethanol, tetrahydrofuran, dioxane, toluene, dimethyl
sulfoxide, N,N-dimethylformamide, 1-methyl-2-pyrrolidone,
N,N-dimethylacetamide, ethyl acetate or water, or mixtures thereof.
The nucleophilic aromatic substitution of the compounds of formula
I is carried out at a reaction temperature of from -20.degree. to
160.degree. C., preferably from 80.degree. to 100.degree. C., and
at normal pressure (1 bar) or in a sealed system at an elevated
pressure of from 1.1 to 100 bar. Optionally, it is possible
additionally to add phase transfer catalysts, especially quaternary
ammonium salts, such as e.g. tetraalkylammonium halides, for
example tetrabutylammonium chloride and tricaprylomethylammonium
chloride (aliquat), as solubilisers between the dissolved starting
material of formula I and the disulfide, which may have been
prepared in situ, which has the effect of accelerating the
reaction. Further phase transfer catalysts suitable for the above
nucleophilic aromatic substitution reaction are described, for
example, in Synthesis 1973, 441-456 and in Angew. Chem., Int. Ed.
EngI. 13, 170-179 (1974). Such phase transfer catalysts are used in
amounts of from 0.1 to 10 mol %, especially from 0.5 to S mol %,
based on the compound of formula Ia.
[0065] A further characteristic of the use, according to the
invention, of compounds of formula I is the purification step for
the compounds of formula Ia, which follows the nucleophilic
aromatic substitution, which purification step offers great
advantages for industrial-scale processes because complicated
separation and purification steps can be avoided and the outlay in
terms of apparatus can be reduced.
[0066] For that purpose, the reaction mixture rendered
aqueous-organic following the nucleophilic aromatic substitution
reaction or obtained in that form from a phase transfer-catalysed
reaction procedure is adjusted to an acidic pH range of from 1 to 5
with aqueous acid, that acidic reaction mixture is optionally
worked-up reductively, and the product is extracted with organic
solvents, such as e.g. aromatic hydrocarbons, for example toluene,
or ethers, for example THF or dioxane, and the product taken up in
the organic phase is optionally re-isolated with an aqueous strong
base, preferably in the pH range of from 12 to 14, such as e.g. an
alkali metal hydroxide. The compound of formula Ia is thus obtained
in the form of a salt in an aqueous solution e.g. as an alkali
metal, alkaline earth metal or ammonium salt (Example P6). Suitable
reducing agents for the reductive working-up of resulting di- and
poly-sulfides are, for example, diborane, hydrazine and phosphines,
which are used in sub-stoichiometric amounts, in equimolar amounts
or in a slight excess of from 5 to 15 mol %, based on the compound
of formula I used.
[0067] Suitable reducing agents are also borohydrides, which are
advantageously used in sub-stoichiometric amounts of, for example,
from 0.1 to 0.2 molar equivalent, based on the compound of formula
I used.
[0068] The reductive working-up is carried out at reaction
temperatures of from 0.degree. to 80.degree. C., preferably from
10.degree. to 40.degree. C.
[0069] In an especially preferred variant of the use according to
the invention of compounds of formula I, the nucleophilic aromatic
substitution reaction in the compound of formula I is carried out
using sodium disulfide, prepared in situ from an equimolar mixture
of elemental sulfur and sodium sulfide, in 2-methoxyethanol or
N,N-dimethylformamide (DMF) as solvent at a reaction temperature of
from 80.degree. to 100.degree. C. for 1 hour and, after the
addition of toluene and water, adjustment of the reaction mixture
with acid to a pH range of from 1 to 5, extraction of the compound
of formula Ia with toluene and then optionally back-extraction of
the compound of formula Ia from the toluene phase with an aqueous
strong base. As acid for adjusting the reaction mixture to a pH
range of from 1 to 5 there comes into consideration especially an
aqueous solution of a mineral acid, such as e.g. sulfuric or
hydrochloric acid.
[0070] As aqueous strong base for the back-extraction of the
compound of formula Ia (in the form of the salt) from the organic
phase there comes into consideration especially an aqueous solution
of a hydroxide, such as e.g. an alkali metal hydroxide, for example
sodium hydroxide solution, with preference being given to the use
of a 30% sodium hydroxide solution. The desired target compound of
formula Ia is then in the form of a salt dissolved in water, which
can readily be separated out by concentration of the water phase.
The yields of isolated product of formula Ia from the
halogen-sulfide exchange reaction are generally >90% of theory
(depending on the solvent used, the amount and ratio of alkali
metal sulfide/sulfur, the nature and purity of the halide starting
material, the duration of the reaction and the method of
working-up) with the final product having a purity of >99%.
[0071] The present invention relates also to the use of compounds
of formula III in the preparation of 7-thio-3H-isobenzofuran-1-one
derivatives of formula Ia ##STR18## wherein R.sub.2 is hydrogen,
C.sub.1-C.sub.4alkyl or C.sub.1-C.sub.4haloalkyl, wherein a
compound of formula III ##STR19## wherein R is halogen,
R.sub.1S(O).sub.2 or (R.sub.1).sub.2NC(X)O; R.sub.1 is
C.sub.1-C.sub.8alkyl, aryl-C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8-haloalkyl or aryl; X is O or S; and R.sub.3 is
C.sub.1-C.sub.5alkyl or C.sub.1-C.sub.5haloalkyl, is subjected to
benzylic lactonisation in the ortho-position alkyl chain R.sub.3 in
the presence of a free-radical initiator and a halogenating agent,
yielding a compound of formula I ##STR20## wherein R and R.sub.2
are as defined above, which compound is then reacted at elevated
reaction temperature in the presence of sulfur in a nucleophilic
aromatic substitution reaction with an alkali metal sulfide,
disulfide or polysulfide of formula X M.sub.2S.sub.q (X), wherein M
is an alkali metal or hydrogen, and q is 1, 2 or a fractional
number from 1 to 7, with the proviso that at least one M is an
alkali metal (halogen-sulfide exchange), and optionally, when a
reagent of formula X wherein q>1 is used, is worked up
reductively and, after the reaction mixture has been rendered
acidic, the desired target compound of formula Ia is isolated
therefrom and optionally re-isolated in the form of the salt using
a strongly basic aqueous solution.
[0072] For the use of compounds of formula III in the preparation
of compounds of formula Ia, the preferred meanings are the same as
those already given above.
[0073] The process according to the invention differs from known
processes in that:
1) reduction of a nitro compound is not necessary and therefore
there is no formation of hydroxylamine, which would adversely
affect the thermal safety,
2) there is no reaction with butyllithium, which is expensive and
unfavourable for process safety, as described, e.g. in Monatsh.
Chem. 123(12), 1125 (1992),
3) the number of toxic starting compounds and reagents is reduced
(only CO in Step (2) and the halogenating reagents in Step (3) are
toxic),
4) readily accessible and inexpensive starting compounds are
used,
5) the lactonisation is achieved in a single step and in high
yields,
6) the reaction sequence to obtain the desired target compound of
formula I is reduced by one reaction step,
7) in respect of Steps (1) and (2) (diazotisation and
carbonylation), the reaction can be designed as a one-pot
reaction,
8) the method of working-up is simple and effective,
9) the number of volatile, unpleasant-smelling, toxic waste
products is reduced, and
10) the overall yields are higher, simultaneously combined with a
high degree of product purity, e.g. in respect of the target
compound of formula Ia.
[0074] The advantages of the present process compared with known
processes are accordingly:
[0075] 1) its particular suitability for industrial-scale
applications with a substantially better waste outcome, e.g. in
respect of volatile, sulfur-containing byproducts when using
xanthogenates, as in e.g. Pest. Manag Sci. 57, 205-224 (2001), and
the small amount of disulfides formed,
2) the high thermal safety of the process,
3) the great variety in its reaction media and reaction
conditions,
4) its avoidance of complicated separation and purification
steps,
(5) the possibility of using the formed diazonium salt of formula
II further directly in a one-pot process without changing the
solvent, thus reducing solvent wastes and the outlay in terms of
apparatus,
6) the high volumetric concentration of the reactants,
7) its high product yields and product purities,
8) its large number of suitable palladium catalysts,
9) its use of catalysts that are either commercially available or
can be prepared readily in situ from commercial palladium salts,
such as e.g. palladium(II) chloride solution (20%), and the
appropriate ligands, and
10) its reproducibility.
[0076] The 7-thio-3H-isobenzofuran-1-one derivatives prepared
according to the invention are used especially as intermediates in
the preparation of
7-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-methyl-3H-isobenzofuran-1-one
by reacting 7-thio-3-methyl-3H-isobenzofuran-1-one of formula Ia
##STR21## wherein R.sub.2 is methyl, advantageously in an inert
organic solvent, such as e.g. an ether, ketone, nitrite or amide,
for example tetrahydrofuran, butanone, acetonitrile or
N,N-dimethylformamide (DMF), at temperatures of from 0.degree. to
160.degree. C., with a compound of formula VI ##STR22## as
described, for example, in EP-B-0 447 506.
[0077] The following Examples illustrate the process according to
the invention further.
EXAMPLE P1
Preparation of 2-chloro-6-ethyl-benzoic acid
[0078] 3.60 g (21.2 mmol) of 2-chloro-6-ethylaniline and 2.70 g
(26.5 mmol) of sulfuric acid (96%) in 100 ml of acetic acid are
introduced into a reaction vessel and the clear, colourless
solution is cooled to 10.degree. C. At that temperature, a solution
of 1.46 g (21.2 mmol) of sodium nitrite in 8 ml of water is slowly
added in the course of 15 minutes. When a diazo colour test, e.g.
using dimethylaniline-coated indicator paper, is positive and a
colour spot test, e.g. using KI indicator paper moistened with 1 N
aqueous hydrochloric acid solution, is negative, the reaction
mixture is transferred to a glass autoclave and rinsed with 20 ml
of acetic acid. The autoclave is flushed out three times with
nitrogen at a temperature of 10.degree. C. and then flushed out
three times with CO at 7.degree. C. 55 mg of
Pd.sub.2(dba).sub.3CHCl.sub.3 (0.053 mmol) in 2 ml of acetic acid
are then metered in using a cannula, a CO pressure of 6.3 bar is
applied and the reaction mixture is stirred overnight at 20.degree.
C.
[0079] After the pressure has been released, 25 ml of a 1 N aqueous
sodium hydroxide solution are added and the resulting suspension is
filtered. The orange-brown filtrate is adjusted to pH 2 with
sulfuric acid and extracted three times with 40 ml of toluene each
time. The combined organic phases are washed three times with 40 ml
of water each time, dried over sodium sulfate and concentrated by
evaporation under reduced pressure using a rotary evaporator. The
crude yield is 3.24 g with a target compound content of 70%
according to HPLC. The pure yield of the desired target compound
after purification by means of vacuum distillation (b.p.
130-135.degree. C./10.01 mbar) is 2.24 g (57% of theory).
EXAMPLE P2
Preparation of 2-chloro-6-ethyl-benzoic acid
[0080] 3.60 g (21.2 mmol) of 2-chloro-6-ethylaniline in 60 ml of
acetic acid is introduced into a reaction vessel and the clear,
colourless solution is cooled to 6.degree. C. At that temperature,
3.64 g (22.7 mmol) of a 43% aqueous sodium nitrite solution are
added and then, in the course of 15 minutes, a solution of 4.32 g
(42.4 mmol) of sulfuric acid (96%) in 7 ml of acetic acid is added
dropwise. The resulting dark-red solution is then stirred for 30
minutes. When a diazo colour test, for example using
dimethylaniline-coated indicator paper, is positive and a colour
spot test, e.g. using KI indicator paper moistened with aqueous 1 N
hydrochloric acid solution, is negative, 15 mg of sulfamic acid are
added and then, at a temperature of 10.degree. C., 8.7 ml (91.6
mmol) of acetic anhydride are added. The reaction mixture is then
transferred to a glass autoclave and rinsed with 20 ml of acetic
acid. At a temperature of 20.degree. C. the autoclave is flushed
out three times with nitrogen and then flushed out three times with
CO. 220 mg of Pd.sub.2(dba).sub.3CHCl.sub.3 (0.212 mmol) in 5 ml of
acetic acid are then metered in using a cannula at a CO pressure of
1 bar, then a CO pressure of 8 bar is applied and the reaction
mixture is stirred overnight at 45.degree. C. When the pressure has
been released, the resulting suspension is filtered and the acetic
acid filtrate is concentrated by evaporation under reduced pressure
using a rotary evaporator; 1 M aqueous hydrochloric acid solution
is added to the organic phase that remains and extraction is
carried out three times with toluene. The combined organic phases
are evaporated under reduced pressure using a rotary evaporator,
yielding 4.43 g of crude product with a target compound content of
75% according to HPLC. Purification by means of vacuum distillation
(b.p. 130-135.degree. C./0.01 mbar) yields 3.31 g (yield 85% of
theory) of the desired target compound.
EXAMPLE P3
Preparation of 2-chloro-6-ethyl-benzoic acid
[0081] 3.60 g (21.2 mmol) of 2-chloro-6-ethylaniline in 24 ml of
acetic acid are introduced into a reaction vessel and the clear,
colourless solution is cooled to 11.degree. C. At that temperature,
3.25 g (31.8 mmol) of sulfuric acid (96%) are added and then, in
the course of 15 minutes, 3.64 g (22.7 mmol) of a 43% aqueous
sodium nitrite solution are added. The resulting dark-red solution
is then stirred for 30 minutes. When a diazo colour test, e.g.
using dimethylaniline-coated indicator paper, is positive and a
colour spot test, e.g. using KI indicator paper moistened with
aqueous 1 N hydrochloric acid solution, is negative, 15 mg of
sulfamic acid are added and then, at a temperature of 10.degree.
C., 8.7 ml (91.6 mmol) of acetic anhydride are added. The reaction
mixture is then transferred to a glass autoclave and rinsed with 6
ml of acetic acid. At a temperature of 20.degree. C. the autoclave
is flushed out three times with nitrogen and then three times with
CO. 220 mg of Pd.sub.2(dba).sub.3CHCl.sub.3 (0.212 mmol) in 3 ml of
acetic acid are metered in using a cannula at a CO pressure of 1
bar, then a CO pressure of 8 bar is applied and the reaction
mixture is stirred for 5 hours at 45.degree. C. When the pressure
has been released, the resulting suspension is filtered and the
acetic acid filtrate is concentrated by evaporation under reduced
pressure using a rotary evaporator; 1 M aqueous hydrochloric acid
solution is added to the organic phase that remains and extraction
is carried out three times with toluene. The combined organic
phases are evaporated under reduced pressure using a rotary
evaporator, yielding 3.72 g of crude product with a target compound
content of 75% according to HPLC. Purification by means of vacuum
distillation (b.p. 130-135.degree. C./0.01 mbar) yields 2.12 g
(yield 55% of theory) of the desired target compound.
EXAMPLE P4
Preparation of 7-chloro-3-methyl-3H-isobenzofuran-1-one
[0082] 5.00 g (0.027 mol) of 2-chloro-6-ethylbenzoic acid in 120 ml
of chlorobenzene are introduced into a reaction vessel and heated
to 90.degree. C. 0.1 g of .alpha.,.alpha.'-azoisobutyronitrile is
then added, followed by 5.04 g (0.03154 mol) of bromine in 25 ml of
chlorobenzene, which is metered in in the course of 10 minutes. The
reaction mixture is then stirred for 1 hour at 90.degree. C. to
complete the reaction. After the reaction mixture has cooled to
20.degree. C./, it is washed with 50 ml of sodium thiosulfate
solution (0.1 mol), the organic phase is dried over sodium sulfate
and the solvent evaporated off under reduced pressure using a
rotary evaporator. The desired target compound is obtained in a
yield of 6.1 g and a purity of about 74% (corresponding to 90% of
theory).
EXAMPLE P5
Preparation of 7-thio-3-methyl-3H-isobenzofuran-1-one
[0083] 5.70 g of 7-chloro-3-methyl-3H-isobenzofuran-1-one is
introduced into a reaction vessel together with 1.30 g of sulfur
and 5.40 g of sodium sulfide in 30 ml of DMF, the mixture is heated
to 90.degree. C. and left to react for 1 hour. Once all the
starting material has reacted, the reaction mixture is cooled to
20.degree. C., 50 ml of toluene and 30 ml of water are added and
the mixture is adjusted to a pH of 3. The resulting suspension is
filtered over Hyflo and the organic phase is separated from the
two-phase mother liquor. The organic phase is then extracted with
50 ml of aqueous sodium hydroxide solution. The desired target
compound is obtained in the form of the sodium salt in a yield of
4.3 g (80% of theory).
EXAMPLE P6
Preparation of 7-thio-3-methyl-3H-isobenzofuran-1-one
[0084] 15 g of 2-methoxyethanol are introduced into a 200 ml
reaction vessel and, together with 1.9 g of
7-chloro-3-methyl-3H-isobenzofuran-1-one, 1.8 g of sodium sulfide
and 0.43 g of sulfur, are heated to 110.degree. C. After 6 hours'
reaction time, the mixture is cooled to 20.degree. C. and a mixture
of 20 ml of water and 1 ml of 12% sodium borohydride solution is
added. After being left to stand for 5 minutes, 20 ml of toluene
are added and the pH value of the reaction mixture is adjusted to
from 1 to 1.5 with hydrochloric acid. The organic phase is
separated off and then extraction is carried out twice with 10 ml
of aqueous sodium hydroxide solution. The desired target compound
is obtained in the form of the sodium salt in a yield of 80% as a
2.8% aqueous solution.
EXAMPLE P7
Preparation of 7-thio-3-methyl-3H-isobenzofuran-1-one
[0085] The reaction is started analogously to the manner described
above in Example P5. Working-up of the desired target compound is
carried out reductively by means of extraction from an acid medium,
separation of the organic phase and treatment thereof with 5 mol %
triphenyl-phosphine. Back-extraction of the reaction mixture with
25 ml of sodium hydroxide solution yields the desired target
compound in the form of the sodium salt in an aqueous solution in a
yield of 82%.
* * * * *