Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
This is a divisional application of Canadian application 378,121
filed on May 22, 1981.
This invention relates to processes for making intermediates and
those intermediates ~hich may be used for preparing 3-(N-aryl-N-acylamino)-
gamma butyrothiolactones.
3-(N-aryl-N-acylamino)-gamma butyrothiolactones are known com-
pounds having fungicidal activity and are clescribed in Belgian Patent
871,668. In the ~elgian patent, the compo~mds are prepared via the amina-
tion (anilination) of a 3-halo-gamma-butyrothiolactone following by
acylation with the appropriate acyl halide.
A discussion of the preparation of certain unsubstituted thio-
lactones can be Eound in an article by Truce et al appearing in the Journal
of Organic Chemistry, Vol. 28, p. 964 (April 1963).
The present invention relates to an improved process for pre-
paring high yields of 3-(N-aryl-N-acylamino)-gamma thiobutyrolactones. As
part of the improved process, the invention provides for a process for
preparing the compound of formula (II)
o
Il 1
CR Rl2
Ar - N - CH - CH2 - CH - SR
C=O
1R3
wherein Ar is aryl or substituted aryl having from one through four sub-
stituents independently selected from the group consisting of fluoro,chloro, bromo, iodo, lower alkyl and lower alkoxy;
R is lower alkyl~ lower alkenyl, aryl-lower alkyl;
R is lower alkyl, lower alkoxy, cycloalkyl having three through
six carbon atoms, lower epoxyalkyl, lower alkenyl, lower alkenyloxy, hydro-
xymethyl; haloalkyl having one through three halo substituents and from one
through six carbon atoms; lower alkoxyalkyl, lower alkylthioalkyl, phenyl-
thio-lower alkyl, phenoxy-lower alkyl, or substituted phenoxy-lower alkyl
or substituted phenylthio-lower alkyl having one or two ring suhstituents
--1--
.~.
2~
independently selec~ed from ~he group consisting of 1uoro,chloro, bromo,
iodo, lower alkyl, and lower alkoxy;
R is hydrogen, c:hloro, bromo~ lower alkyl, phenyl, substituted
phenyl having one or two ring substituents independently selected from the
group consisting of fluoro, chloro, bromo, iodo, or lower alkyl; and
R3 is hydrogen or the radical
~ o~ 1
-CR
wherein Rl is selected from the same group of substituents as Rl defined
hereinabove;
which process comprises contacting the corresponding compound having the
following formula
Ar - NH - C~ - CH2 - CHR - ~R
C=O
O(M )1/
wherein Ar, R and R2 are as defined above, and Ml is hydrogen or a cation,
and m' is the valence of M ;
with an acyl halide, having the formula
O
Rlcx
wherein X is chloro or bromo and Rl is as defined above, under reactive
conditions thereby yielding the corresponding compound of formula II above.
The present invention also provides for novel intermediates
of formula II.
The overall process to whih the invention relates comprises the
steps of:
(a) contac~ing a 3-~aryl or substituted arylami.no)~gamma-butyro-
lactone or a 5-substituted derivative thereof with a thiolate salt under
reactive conditions to yield tha corresponding 1-~aryl or substituted aryl)
amino l-thio-alkane carbo~ylate salt and acidifying the salt to yield the
t,~:
"
~8;~
corresponding carboxy acid; and
(b) contacting the product of step (a) with an acyl halide under
reactive conditions to yield the corresponding acyl amino derivative; and
(c) contacting the product of step (b) with a cyclizing agent, which
will effect esterification of a saturated fatty carboxylic acid with a low
moleclllar weight primary alcohol, to yield the corresponding 3-(N-aryl
or substituted aryl-N-acylamino)-gamma-butyrothiolactone or 5-substituted
derivative thereof.
The above process can be conveniently schematically represented
by the follo~ing overall reaction equations
H H R2
1 3 4 I I
Ar - N ~ - ~ M(SR)m (1) ~Ar - ~ -,CH - CH2 - CH - SR
~ ~ (B) ,- C = O
O O 5 , I
(A) " OM (I)
~i~ '
.,~ ,.
Q,~C ~ O
CR R2
' ~ Ar - N - CH - CH - CH - SR
(Salt or acid) (C) (2j 1 2
C=O
1R3 (Il)
- 2a -
0 1 o
cycli2ing agent ~ C _ Rl
(II) > Ar ~ N. ~ R2
05 ~ S (III3
wherein Ar is aryl or substituted aryl having from
one through four substituents independently selected from
the group of fluoro, chloro, bromo, iodo, lower alkyl, or
lC lower alkoxy;
R is lower alkyl (preferably t-butyl); lower alkenyl
~preferably allyl) or arylalkyl (preferably benzyl);
Rl is lower alkyl; lower alkoxy; cycloalkyl having
three through six carbon atoms (preferably cyclopropyl);
lower epoxyalkyl having from 2 through 6 carbon atoms
ncluding one or two epoxy groups; lower alkenyl; lower
alkenyloxy; hydroxy-lower alkyl ~preferably hydroxy-
methyl); haloalkyl having one through three halo substitu-
ents and from one through six carbon atoms; lower alkoxy-
alkyl, lower alkylthioalkyl; phenylthio-lower alkyl
(preferably phenylthiomethyl); phenoxy-lower alkyl ~pref-
erably phenoxymethyl~; substituted phenylthio-lower alkyl
(preferably substituted phenylthiomethyl), or substituted
phenoxy-lower alkyl ~preferably substituted phenoxymethyl)
having one or two ring substituents independently selected
from the group of fluoro, chloro, bromo, iodo, lower
alkyl, or lower alkoxy; and
R2 is hydrogen, chloro, bromo, lower alkyl, phenyl or
substituted phenyl having one or two subs~ituents inde-
pendently selected from the group of fluoro, chloro~ bromo
or lower alkyl;
R3 is hydrogen or O
CR
01 wherein Rl is selected from the same group of sub-
stituents as Rl.
M is an inorganic cation, preferably an alkali metal
cation, and m corresponds to its valence.
05 Step 1 of the process can be conveniently con-
dùcted by contacting the appropriate compound of formula A
having the desired Ar and R2 substituent with the thiolate
of formula B~ preferably in a suitable organic solvent
under reactive conditions.
Typically, this process i5 conducted at tempera~
tures in the range of about from 20 to 200C preferably
about from 50 to 80C for about from 1 to 8 hours prefer-
ably about from 1 t-o 4 hours. Typically, about from 1 to
1.5 mols r preferably about from 1 to 1.25 mols of compound
of formula B ~based on the thiolate content) are used per
mol of compound of formula A.
Where an organic solvent is used, the solvent is
generally only a solvent for reactant A. Suitable inert
oryanic solvents which can be used include~ or example,
dimethoxyethane~ toluene, tetrahydrofuran, dimethyl
formamide and the like and compatible mixtures thereof.
Preferably dimethoxyethane is used as the solvent. Typi-
cally, a liquid medium ratio o about from 1 to 3 mols of
reactant A per liter of solvent is used.
Generally, best results are obtained by conduct-
ing the process at temperatures in the range of about from
50 to B0C using about from 1 to 1.10 mol of B per mol of
A in dimethyoxyethane.
Suitable thiolates of formula B which can be
3~ used include, for example, alkali metal thiolates e.~.,
sodium 2-methyl-2-propanethiolate r potassium 2-methyl-2-
propanethiolat.e; alkali earth thiolates, calcium
bis(alkylthiolate)~ ammonium thiolates; quaternary amine
thiolates, e.g. tetramethylammonium, benzylthiolate and
the like. Generally, best results are obtained using
--5--
01 sodium 2-methyl-2-propanethiola~e. In a preferred embodi-
ment, the thiola~e salt is prepared in situ via the reac-
tion of the corresponding ~SH mercaptan with an alkali
metal alkoxide ~e.g., sodium methoxide).
o5 The compounds of formula A are known compounds
and can be prepared by known procedures, including, for
example, via the reaction of the corresponding aryl or
substituted aryl amine with the corresponding 3-chloro or
3-bromobutyrolactone, as, for example, described in
Belgian Patent 871,668; U.S. Patent 3,933,860 or U.S.
Patent 4,165,322.
The product of step 1 is the corresponding M
salt of the acid of ormula I. Before conducting the
second step of the present process it is very much pre-
ferred to remove any unreacted compound (A) from the reac-
tion product. This can be conveniently effected by
extraction since compound (A) is generally insoluble in
water whereas compound (I) is soluble in water.
Salt (I) can then be reacted with the acyl
chloride (C) according to step 2 of the present invention
or preferably is first hydrolyzed to the acid (formula I)
via treatment with a weak acid such as acetic acid.
If desired, the hydrolysis can generally be conducted in
situ. The acid treatment affords an economic advantage,
and in some instances also produces a cleaner (purer)
acylation reaction product than is obtained by direct
acylation of the salt (I). An economic advantage is
afforded because the acid (e.g., acetic acid) is substan-
tially less expensive than the acyl chloride (C). Thus,
where the salt ~I~ is acylated directly, two mols of acyl
chloride is stoichiometrically re~uired per mol of salt
(I). By first hydrolyzing the salt (I), one of these acyl
chloride mols is replaced with a less expensive mol of
acid.
--6
Ol In the second step of the process, the salt of
formula I or its acid is contacted with the appropriate
acyl chloride o formula C under reactive conditions
preferably in an inert organic solvent and optionally in
05 the presence of an organic scavenger base, under reactive
conditions. We have found that this process step arfords
very high yields of the product of formula II. The acyl-
ated product of formula II urther performs better in the
cyclizing reaction (step 3) than does the corresponding
secondary amine; probably due to the protection of the
free NH with an acyl group. The product is generally a
mixture of the l-carboxy acid, and its anhydride ~i.e.,
~ .
R3 is CRl )
depending upon the relative mol ratio of reactants.
This process is typically conducted at tempera-
tures in the range of about from 0 to 120C for about from
1 to 8 hours where a scavenger base is used. Lower ~em-
peratures are preferably used typically about from 0 to
25C. Where a scavenger base i5 not used then higher
temperatures are used, typically about from 80 to 120C;
to drive off the hydrogen chloride byproduct as a gas.
Generally, about from 2 to 2.5 mol, preferably about from
2 to 2.2 mol of acyl chloride 5C) is used per mol of reac-
tant I ~salt3 and about half this amount of acyl chloride
when the acid formula I is used (i.e. 3 about from 1.0 to
1.5~ preferably about from 1.0 to 1.10 mol of acyl
chloride per mol of I acid)~
Suitable inert organic solvents which can be
used include, for example, methylene chloride, ethyl
acetate, dimethoxymethane~ benzene and the like and com-
patible mixtures thereof. Where the reaction is conducted
in the presence of an organic scavenger base, to react
01 ~ith the hydrogen chloride byproduct, suitable scavenger
bases which can be used include1 for example, triethyl-
amine, pyridine, 2,6-lutidine, sodium carbonate and the
like.
05 The acyl chlorides (C) are known compounds
and can be prepared by known procedures or obvious modifi-
cations thereof (e.g., substitution of appropriate sub-
strates, sol~ents, etc.).
The last step of the process is preferably
effected by contacting the compound of formula II with a
suitable cyclizing agent, preferably in a suitable inert
organic solvent, under reactive conditions~
- Typically, this process is conducted at tempera-
tures in the range of about from 0 to reflux, preferably
above about 5~C for about from 1/4 hour to 2 hours prefer-
ably about from 1/4 to 1 hour. Generally, about from 1 to
5 mols, preferably about from 2 to 2.5 mols of reactant II
are used per mol of cyclizing agent. Optimum temperatures
and ratios of cyclizing agents will vary with the
particular cyclizing agent, for example, where sulfuric
acid is used as the cyclizing agent only a relatively
small amount is preferably used. Where~ for example,
phosphorus trichloride is used as the cyclizing agent, it
is preferred to use abou~ from ~ to 2.5 mols of reactant
II per mol of phosphorus trichloride.
Also, since water is formed as a byproduct, it
is preferred to conduct the reaction under conditions
which remove water from the reaction system, for example,
by distillation or the use of cyclizing reagents, etc.
3~ which combine with water.
Suitable inert organic solvents which can be
used include, for example, methylene chloride, ethyl ace-
tate, benzene, 1,2-dimethoxyethane, and the like and com-
patible mixtures thereof Typically, a solvent ratio of
:~82~
01 about from 0.5 to 3 mols of rea~tant II per liter of
solvent is used.
A very broad range of cycli~ing agents can be
used. These reagents can be deEined as reagents which
05 will effect the esterification of a saturated fatty car-
boxylic acid upon contact o the acid with a low molecularweight primary alcohol. Suitable cyclizing agents which
can be used, include, for example, carboxylic acid anhy-
drides, e.g. acetic anhydride, phthalic anhydride, acyl
chlorides, e.g. acetyl chloride, benzoyl chloride; tri
chloroacetic acid; p-toluene sulfonic acid; monoalkyl
dehydrogen phosphites; e.g. decyl dihydrogen phosphite;
boron trifluoride etherate; sulfonic acid type ion
exchange resins; phosphorus trichloride, phosphorus tri-
bromide, phosphoric acid, thionyl chloride, phosphorus
pentachloride, sulfuric acid, phosgene, oxalyl chloride,
carboxylic acids and the like, and compatible mixtures
thereof.
Very good results are obtained by conducting the
~ process using about from 2 to 2.5 mol of reactant II per
mol of phosphorus trichloride in methylene chloride at
temperatures in the range of about from 5 to 15C. Good
results are also obtained by using acetic acid with a
small amount of sulfuric acid as the cyclizing agent at
reflux.
In each of the above process steps, unless
otherwise specified, it is preferred to separate the
respective products oE formulas I and II before conducting
the next process step. Also, with the exception of the
hydrolysis of the salt (I) to its acidl it is generally
~referred to conduct the present process under substan-
tially anhydrous conditionsa The respec~ive products
of formulas I~ II, and III can be separated ~rom the
respective product reaction mixtures by any suitable puri-
fication procedure such as, for example, evaporation,
~z~
extraction, crystallizations, chromatography, distillationand the like~ Specific illustrations of suitable separation
and purification procedures are illustra-ted in the examples
set forth hereinbelow; however, it should be apprecia-ted
that other suitable procedures could also be used.
It should also be appreciated tha-t where typical
reaction conditions (e.g., temperatures, mol ratios, reac-
tion times, etc.) have been given, that conditions both
above and below these ranges can also be used, though
generally less conveniently or with poor economics. Also,
optimum reaction conditions (e.g., temperatures, solvents,
reaction times) can vary with the particular reactants,
concentrations, etc., used but can be obtained by routine
experimentation.
As used herein, the following terms have the
following meanings, unless expressly stated to the con-
trary.
The term "halo" refers to the group of fluoro,
chloro, bromo and iodo.
The term "alkyl" refers to both straigllt- and
branched-chain alkyl groups. The term "lower alkyl" reers
to both straight- and branched-chain alkyl groups having a
total from one through six carbon atoms and includes pri-
mary, secondary and teritary alkyl groups. Typical lower
alkyls include, for example, methyl, ethyl, n-propyl,
isopropyl, n-butyl, t-butyl, n-hexyl and the like.
The term l'alkoxy" refers to the radical R'0-
wherein R' is alkyl.
The term "lower alkoxy" refers -to alkoxy groups
~0 having from one through six carbon atoms and inclucles, for
example, methoxy, ethoxy, t-butoxy, hexoxy and the like.
_ g _
~i82 ~6
--10~
01 The term "lower epoxyalkyl" refers to epoxyalkyl
groups having from two through six carbon atoms including
one or two epoxy groups. Such groups include, for exam-
ple,
05 ~0\
1,2-epoxypropyl ~i.e., CH3~CH - CH- ~; 2,4-epoxypentyl
~i.e., 4 -methyloxetanylmethyl; CH3-CH-CH~-CH-CH2- );
1,2,4,5-diepoxyhexyl (i.e. CH3-CH - CH~CH2-CH - CH~~ and
the like
The term "hydroxy lower alkyl" refers to the
group having the formula HOR' wherein R' is lower alkyl
and includes, for example, hydroxymethyl, 3 hydroxypentyl,
2-hydroxyethyl and the like.
The term "lower alkoxyalkyl" refers to the radi-
cal R'OR"- wherein R'O is lower alkoxy and R" is lower
alkyl.
The term "lower alkylthioalkyl" refers to the
r~dical R'SR"- wherein R' and R" are independently lower
alkyl. Typical lower alkylthioalkyl groups include, for
example, methylthiomethyl, 4-t-butylthiohexyl.
The term "alkenyl" refers to unsaturated alkyl
groups having a double bond and includes bo~h straight
and branched-chain alkenyl groupsO
The term "lower alkenyl" re~ers to alkenyl
groups having two through six carbon atoms. Typical lower
alkenyl groups include, for example, allyl~ but-3-enyl, 2-
methylpent-4-enyl and the like.
The term "lower alkenyloxy" refers to groups
having the formula R50~ wherein R5 is lower alkenyl.
The ~erm "lower alkenyloxyalkyl" refers to
groups having the formula R50R'- wherein R5 is lower
alkenyl and R' is ~ower al~yl. Typical lower alkenyloxy-
alkyl groups include, for example, allyloxymethyl; 2-(but-
3~enyloxy)hexyl; and the like.
~1 The term "aryl" referc; to aryl groups having six
through twelve carbon atoms and includes, for example,
phenyl and naphthyl~
The term "phenoxy-lower alkyl" refers to groups
05 having the formula Ph-O-R'- wherein Ph is phenyl and Rl is
lower alkyl and includes, for example, phenoxymethyl,
phenoxyhexyl, 5~phenoxy-3-methylpentyl and the like.
The term "phenylthio-lower alkyl" refers to
~roups having the formula Ph-S-R'- wherein Ph is phenyl
and R' is lower alkyl and includes, for examplel phenyl-
thiomethyl, phenylthioethyl/ 4-phenylthio-1-methylbutyl-
and the like.
The term "substituted phenoxy-lower alXyl"
refers to groups having the formula Ph'-O-R'- wherein R'
is lower alkyl and Ph' is a phenyl group having one or two
substituents independently selected from the group of
fluoro, chloro, bromo, iodo, lower alkyl and lower
alkoxyn Typical substituted phenoxy-lower alkyl groups
incl~de, for example, 4-fluorophenoxymethyl; 2-iodo-5-
bromophenoxymethyl; 2-(2,5-dimethylphenoxy)ethyl; ~-(2-
methoxy-4-chlorophenoxy)-1-methylbutyl) and the like.
The term "substituted phenylthio-lower alkyl"
.refers to groups having the formula Ph'-S-R' wherein Ri
is lower alkyl and Ph' i5 a phenyl group having one or two
substituents independently selected from the group o
fluoro, chloro, bromo/ iodo, lower alkyl and lower
alkoxy. Typical substituted phenylthi.o~lower alkyl groups
include, for example, 4-fluorophenylthiomethyl; 2-iodo-5-
bromophenylthiomethyl; 2-(2,5-dimethylphenylthio)ethyl; 4-
~2-hexoxy-4-chlorophenylthio~-1-methylbutyl and the like.
The term "unsubstituted fatty acid'l refers to
carboxylic acids having the formula R'COOH wherein R' is
an alkyl group having rom 1 through 20 carbon atoms.
The term "low molecular weight primary alcohol"
refers to a primary alcohol having a molecular weight
below about 70, such as for example methanol, ethanol, and
the like.
As be:Eore mentioned, the products of formula III
are useful for controlling fungi, particularly plant fungal
infections; see Belgium Patent No. 871,668. For example,
the compounds have been applied as fungicides against fungal
diseases such as downy mildews, e.g., Plasmopara viticola
~grapes) and Peronospora parasitica (cabbage and collard),
late blights, e.g., hytophthora infestans (tomatoes
and potatoes~, and crown and root rots, e.g., P _tophthora.
These compounds are particularly useful fungi-
cides because they cure certain types of established fungal
infections. This permits economical use of the fungicides
of application Serial No. 378,121, because they need not be
applied to plants unless fungal infection actually occurs.
Thus, a preventative program of applying fungicides against
potential fungal infection is not necessary.
When used as fungicides, the compounds are
applied in fungicidally effective amounts to fungi and/or
their habitats, such as vegetative hosts and nonvegetative
hosts, e.g., animal products. The amount used will, of
course, depend on several factors such as the host, the
type of fungus and the particular compound applied. As
with most pesticidal compounds, the compounds are not
usually applied full strength, but are generally incorpo-
rated with conventional, biologically inert extenders or
carriers normally employed for facilitating dispersion of
active fungicidal compounds, recognizing that the formu-
lation and mode of application may affect ~he activity of
the fungicide. Thus, the compounds may be so formulated
and applied as granules, as powdery dusts, as wettable
powders, as emulsifiable concentrates, as solutions, or as
- 12 -
~8~
-13-
01 any of several other kno~m types of formulations, depend-
ing on the desired mode of application.
Wettable powders are in the form of finely
divided particles which disperse readily in water or other
S dispersant. These compositions normally contain rom
about 5-80% funyicide, and the rest inert material, which
includes dispersing agents, emulsifying agents and wetting
agents. The powder may be applied to the soil as a dry
dust or preferably as a suspension in water. Typical
carriers include fuller's earth, kaolin clays, silicas,
and other highly absorbent, wettable, inorganic diluents.
Typieal wetting, dispersing or emulsifying agents include
for example: the aryl and alkylaryl sulfonates and their
sodium salts, alkylamide sulfonates, including fatty
methyl taurides, alkylaryl polyether alcohols, sulfated
higher alcohols and polyvinyl alcohols; polyethylene
oxides, sulfonated animal and vegetable oils; sulfonated
petroleum oils, fatty acid esters of polyhydric alcohols
and the ethylene oxide addition products of such esters;
and the addition products of long-chain mercaptans and
ethylene oxide. Many other types of useful surace-active
agents are available in commerce. The surface active
agent, when used, normally eomprises from 1% to 15~ by
weight of the fungicidal composition~
Dusts are freely flowing admixtures of the
active fungicide with finely divided solids such as talc,
natural elays, kieselguhr, pyrophyllite, chalk, diatoma-
ceous earths, calcium phosphates, ealcium and magnesium
. carbonates, sulfur, lime, floursr and other organic and
3~ inorganic solids which act as dispersants and carriers for
the toxicant. These finely divided solids have an average
particle size of less than about 50 microns. A typieal
dust formulation contains 75% silica and 25~ of the toxi-
cant.
~1 Useful liquid concentrates include the emulsifi-
able concentrates, which are homogeneous liquid or paste
compositions which are readily dispersed in water or other
dispersant, and may consist entirely of the fungicide with
05 a liquid or solid emulsifing ayent, or may also contain a
liquid carrier such as xylene, heavy aromatic naph~has,
isophorone, and other nonvolatile organic solvents. For
application, these concentrates are dispersed in water or
other liquid carrier, and are normally applied as a spray
lQ to the area to be ~reated.
Other useful formulations for fungicidal appli-
cations include simple solutions of the active fungicide
in a dispersant in~which it is completely soluble at the
desired concentration, such as acetone, alkylated naph-
thalenes, xylene, or other organic solvents. Granular
formulations, wherein the fungicide is carried on rela-
tively coarse particles, are of particular utility for
aerial distribution or for penetration of cover-crop
car.opy. Pressurized sprays, typically aerosols wherein
the active ingredient is dispersed in finely divided form
as a result of vaporization of a low~boiling dispersant
solvent carrier, such as the Freons, may also be used.
All of those techniques for formulating and applying Eun-
gicides are well known in the art.
The optimum percentages by weight of the fungi-
cide (active compound) may vary according to the manner in
which the composition is to be applied and the particular
~ype of formulationt but in general comprise 0.5 to 95% by
weight of the fun~icidal composition.
The fungicidal compositions may be formulAted
and applied with other active ingredients, including other
funqicides, insecticides, nematocides, bactericides, plant
growth regulators, fertilizers, etc.
A further understanding of the invention can be
had from the ollowing non-limiting examples. Also, as
* Trade Mark
used hereinabove and below, unless expressly stated to -the
contrary, all temperatures ranges reEer to the Celsius system
and the term "ambient" or "room" tempera-ture reEers to about
20~C-25~C. The term percent (or "%" refers to weight percent>
and the term "mol" or "mols" refers to gram mols. The term
"equivalent" refers to an amount of reagent equal in mols to
mols of the preceding or succeeding reactant recited in the
preparation or example in terms of mols or finite weight or vol-
ume. Also, unless expressly stated to the contrary, racemic mix-
tures and/'or diastereomeric mixtures are used as starting materials,
and correspondingly racemic mixtures and/or diastereomeric mixtures
are obtained as products. Where necessary, examples are repeated
to provide sufficient quantities of starting materials for subse-
quent preparations and examples. The abbreviation E. A. refers to
elemental analysis, for both calcuiated and found values in weight
percent.
Where given proton-magnetic resonance spectrum (p.m.r.)
are determined at 60 mHz, and signals are assigned as singlets (s),
broad singlets (bs), doublets (d), double doublets (dd), triplets
(t)~ double triplets (dt), quartets (q) and multiplets (m).
EXAMPLE I
This example illustrates process step (1) above and the
preferred op-tional hydrolysis of the salt (I) to its acid.
In this example, 15 ml of anhydrous dimethoxyethane was
admixed with 1.98 (0.022 mol) of 2-methyl-2-propanthiol and l.O~g
~0.02 mol) of sodium methoxide. The mixture was refluxed for 1
hour, then cooled to room temperature and 4.10g (0.02 mol) of 3-
(2,6-dimethylphenylamino)-gamma-butyrolactone was added. The
resulting mixture was refluxed for 1-1/4 'nours! then about 0.2g of
sodium methoxide was added and the refluxing continued for
- 15 -
~32~
-16~
01 another hour. At the end of this time, the mixture was
cooled and 20 ml of ice water was added. The mixture was
then extracted ~ith toluene and the remaining aqueous
phase then acidified with glacial acetic acid to pH 6 and
05 extracted with methylene chloride. The methylene chloride
extract was then washed three times with water r dried over
magnesium sulfate and evaporated affording 2.809 of 1-
carboxy-1-(2,6-dimethylphenylamino)-3-t-butylthiopropane
as a viscous oil.
1~ Similarly, by following the same procedure but
using the corresponding lactone starting materials in
place of 3-(2,6~dimethylphenylamino)-gamma-butyrolactone,
the following compounds are respectively prepared:
l-carboxy-1-(2,3,6-trimethylphenylamino)3-t-butyl-
thiopropane;
l-carboxy-l-(2-methoxy-6-methylphenylamino)3-t-bu-tyl-
thlopropane; and
l-carboxy-l-naphthylamino-3-t-butylthiopropane.
Similarly, by following the same procedure but
in place o~ preparing the thiolate in situ, the thiolate
salts potassium allylthiolate, ammonium benzylthiolate,
and sodium naphthylthiolate are respectively reacted
directly with each of the butyrolactone starting materials
used above to yield the corresponding thioethylene, thio-
benzene, and thionaphthylene analogs of each of the above
products.
EXAMPLE 2
This example illustrates the second step of the
present process.
In this example l.lg (0.0037 mol) of l-carboxy-
1-(2,6-dimethylphenylamino)-3-t-~utyl-thiopropane was
dissolved in 10 ml of methylene chloride containing 0O56g
(0.0554 mol) of triethylamine. The mixture was cooled to
O~C and 0O44g (0.0041 mol) of methoxyacetyl chloride was
dropwise admixed therewith and the resulting mixture
stirred at O-C for 10 minutes. The mixture was then warmed to room
temperature or 30 minutes and then poured into ice water. The methy-
lene chloride phase was extracted, washecl once wi-th aqueous hydro-
chloric acid, twice wi-th water, and then dried over magnesium sulfate
and evaporated afording ].3g of 1-carboxy-1-[N-(2,6-dimethylphenyl)-N-
methoxyacetamido]-3-t-butylthiopropane, containing a small amount of 1-
methoxyacetyloxycarbonyl derivative as an oil. The conversion obtained
for this step based on the carboxy starting material was about 95%.
Similarly, by following the same procedure but respectively
using each of the products of Example 1 as starting materials, the
corresponding methoxyacetamido derivatives of formula (II) are respec-
ti-vely prepared.
Similarly, by following the same procedure but respectively
replacing methoxyacetyl chloride with chloroacetyl chloride, cyclo-
propyl carbonyl chloride, benzoyl chloride and 2,3-epoxybutyryl chloride,
corresponding chloroacetamido, cyclopropylamido, benzoylamido and 2,3-
epoxybutyramido analogs of each of the above compounds are respectively
prepared.
EXAMPLE 3
.
This example illustrates the third step of the present process.
In this example, 1.7g (0.0046 mol) of the l-carboxy-l-[N-
(2,6-dimethylphenyl)-N-methoxyacetamido]-3-t-butylthiopropane product
prepared according to Example 2 hereinabove was dissolved in 10 ml of
anhyd-rous methylene chloride. The mixture was then cooled -to O~C and
0.317g (0.0023 mol) of phosphorus trichloride was admixed therewith.
The mixture was stirred at 0C for 20 minutes and then warmed to room
$emperature and stirred for 1 hour at room temperature and then quenched
by the addition of ice. The solution was then decanted to eliminate a
small amount of solids precipitate which had formed. The methylene
- 17 -
;4
-18-
01 chloride phase was then removed and washed sequentially
with water, 5% weight aqueous sodium carbonate, twice with
water, 1 N. aqueous hydrochloric acid then twice more with
water. The washed mixture was then dried over magnesium
05 sulfate and evaporated affording l.Og of 3-(N-methoxy-
acetyl-N-2,6-dimethylphenylamino~-gamma-~utyrothiolactone
as a oil. The oil was then crystallized from isopropyl
alcohol. The infrared spectra and proton magnetic
resonance spec~ra of the crystalline product was obtained
and was found to be identical to the spectra of a control
sample of 3-(N-methoxyacetyl-N-2,6-dimethylphenylamino)-
gamma-butyrothiolactone.
Similarly, by following the same procedure but
using the corresponding products of Example 2 as starting
materials the corresponding butyrothiolactone derivatives
are respectively prepared.
EXAMPLE 3A
This example illustrates the third step of the
present process using a different cyclizing agent than
used in Example 3.
In this example, a solution containing 0.24g of
sulfuric acid, 4 ml of tol~ene and 6 ml of acetic acid
were added to 2.35 m mol of 1-carboxyl-1-[N-(2,6-dimethyl-
phenyl)-N-methoxyacetamido]-3-t-butylthiopropaneO The
mixture was then heated at reflux (about 110C) fc,r 2
hours and then cooled and washed twice with 10 ml of
water. (A small amount of methylene chloride was added to
prevent solids from precipitating out during washing.)
The washed mixture was then evaporated to dryness at 50C
affording 3.65g of 3-~N-methoxy-acetyl-N-2,6 dimethyl-
phenylamino)-gamma-butyrothiolactone as a solid. The
water washings were combined and extracted with methylene
chloride. The methylene chloride extract was ev~porated
--19--
01 to dryne~s affording an additional 0.27g of 3-(N-methoxy-
acetyl)-N-2,6-dimethylphenylamino)-gamma-butyrothiolactone
as a solid.
Similarly, by following the same procedure but
05 using the corresponding products of Example 2 as starting
materials, the corresponding butyrothiolactone derivatives
are respectively prepared.
EXAMPLE 4
Examples 4-6 illustrate the present process
lQ wherein the salt (I) is directly acylated without prior
conversion to the acid.
In this example, 9.5g (0.1 mol) of 2-methyl-2-
propanthiol was added to a stirred slurry containing 6 of
sodium methoxid2 10.1 mol) in 70 ml of anhydrous 1,2-di-
methoxyethane at room temperature. The resulting mixture
was stirred at room temperature for about 30 minutes
(resulting in the production of sodium 2-methyl-2 propane-
~hiolate) and then 20.5g (0.1 mol) of 3-(2,6 dimethyl-
phenylamino)-gamma butyrolactone was added. The mixture
~as then heated at reflux until the slurry became a clear
solution [about one hour~. me solution was evaporated to
remove solvent and byproduct methanol a-ffording sodium 1-
(2,6-dimethylphenylamino)-1-(2-t-butylthioethyl) acetate
(I) as a residue.
Similarly, by following the same procedure but
using the corresponding 3-aryl or substituted arylamino-
gamma-butyrolactone starting materialsS the following
compounds are respectively prepared: -
sodium l-(phenylamino)-1-(2-t-butylthioethyl) ace-
tate;
sodium 1-(4-fluorophenylaminoj 1-~2-t-butylthioethyl)
acetate;
sodium l-(2-iodophenylamino)-1-(2-t-butylthi~ethyl)
acetate;
~20-
01 sodium 1-(2r6-dichlorophenylamino)-1-(2-t-butylthio-
ethyl) acetate;
sodium 1-(2-methoxyphenylamino~ (2-t-butylthio-
ethyl) acetate;
05 sodium 1-(2-methyl-4 pentylphenylamino)-1-(2-t-butyl-
thioethyl) acetate;
sodium 1-(2,5-dibromophenylamino)~ 2-t-butylthio-
ethyl) acetate;
sodium 1-~2-methyl-3-chlorophenylamino) 1-(2-t-butyl-
thioethyl) acetate;
Similarly, by following the same procedure but
respectively replacing the in situ prepared sodium 2-
methyl-2-propanethiolate with potassium
hex-4-enylthiolate, calcium di(methylthiolate) and
ammonium benzylthiolate, the corresponding analog salts of
each of the above products are respectively prepared.
EXAMPLE 5
In this example, the sodium 1-(2,6-dimethyl-
phenylamino)-1-(2-t-butylthioethyl) acetate (I) residue
from Example 4, was redissolved in 250 ml of dimethoxy
ethane and heated to reflux. 7.5g (0.1 mol) of N,N-di-
methylformamide was then added followed by the addition of
9.5 g (0.1 mols) of acryloyl chloride at which time the
solution became light brown. The mixture was cooled to
room temperature and another 7 5g (0.1 mol) of N,N-di-
methylformamide was then added followed by the addition of
another 9.5g (0.1 mols) of acryloyl chloride. The mixture
was then refluxed for 1-1/2 hours and then evaporated
under vacuum to remove solvent. The residue was slurried
3~ with diethyl ether, filtered over diatomaceous earth and
evaporated affording acrylic-l-[N-(2,6-dimethylphenyl)-N-
acryloylamino]-1-(2-t-butylthioethyl) acetic acid anhy-
dride as the residue.
01 Similarly, by following the same procedure using
the corresponding products of Example 4 as starting mater-
ials, the following compounds are respectively prepared:
acrylic-l(N-phenyl~N-acryloylamino)-1-(2-t-butyl-5 thioethyl acetic acid anhydride;
acrylic-l-[N-(4-fluorophenyl)-N-acryloylamino]-2-t-
butylthioethyl acetic acid anhydride;
acrylic-l-[N-(2,6-dichlorophenyl)-N-acryloylamino]-2-
t-butylthioethyl acetic acid anhydride;
acrylic-1-[N-(2 methoxyphenyl)-N-acryloylamino]-2-t-
butylthioethyl acetic acid anhydride;
acrylic-l-[N-(2-methyl-4-pentylphenyl)-N-acryloyl-
amino]-2-t-butylthioethyl acetic acid anhydride;
acrylic-l-[N-(2,6-dibromophenyl)-N-acryloylamino]-2-5 t-butylthioethyl acetic acid anhydride; and
acrylic-l-[N-(2-methyl-3-chlorophenyl)-N-acryloyl-
amino]-2-t-butylthioethyl acetic acid anhydride.
Similarly, by following the same procedure but
in place of acryloyl respectively using acetyl chloride;
dichloroacetyl chloride; hydroxyacetyl chloride; methoxy-
acetyl chloride; methylthioacetyl chloride; phenylthio-
acetyl; phenoxyacetyl; 2,6-dimethylphenylacetyl chloride;
4-ethoxyphenylacetyl chloride and 2,3-epoxybutyryl
chloride the corresponding diacyl derivatives of each of
the above compounds are respectively prepared, for
example:
acetic-l-[N-~2/6-dimethylphenyl)-acetamido]-2-t-bu-
tylthioethyl acetic acid anhydride;
dichloroacetic~ N-phenyl-dichloroacetamido)-2-t-0 butylthioethyl acetic acid anhydride;
hydroxyacetic-1-[N-(4-fluorophenyl)-hydroxyacet-
amido]-2-t-butylthioethyl acetic acid anhydride;
methoxyacetic-l-lN-(2,6-dimethylphenyl)-methoxyacet-
amido]-2-t butylthioethyl acetic acid anhydride;
-22-
01 methylthioacetic-1-[N-(2,6-dichlorophenyl)-methyl-
thioacetamido]-2-t-butylthioethyl acetic acid anhydride;
phenylthioacetic-l-[N-(2-methoxyphenyl)-phenylthio-
acetamido]-2-t-butylthioethyl acetic acid anhydride;
05 phenoxyacetic-1-[N-(2-methy1-4-pentylphenyl)-phenoxy-
acetamido]-2-t-butylthioethyl acetic acid anhydride;
(2,6-dimethylphenyl)acetic-1-[N-(2,6-dibromophenyl)-
~2r6-dimethylphenyl)acetamido]-2-t-butylthioethyl acetic
acid anhydride;
(4-ethoxyphenyl)acetic-1-[N-(2-methyl-3-chloro-
phenyl)-(4-ethoxyphenyl)acetamido]-2-t-butylthioethyl
acetic acid anhydride;
2,3-epoxybutyric-1-[N-(2,6-dimethylphenyl)-2,3-epoxy-
butyramide] 2-t-butylthioethyl acetic anhydride, etc.
EXAMPLE 6
In this example, the l-acrylic-1-[N-(2,6-di-
methylphenyl)-N-acryloylamino~-2-t-butylthioethyl acetic
; acid anhydride residue from Example 5, was mixed with 200
ml of dimethoxyethane and then 42g (0.3 mol) of phosphor-
ous chloride was slowly added. The resulting mixture was
cooled to about 8~C and then stirred at room temperature
overnight (about 12 hours). Thin layer chromographic
analysis of a small sample of this showed the presence of
some unreacted starting materials (i.e., the butylthio-
propane derivative) and two other products. The reaction
mixture was then heated at reflux for 24 hours and then
evaporated to remove solvent. The residue was dissolved
in methylene chloride and washed with saturated sodium
bicarbonate to neutraliæe acidic components and then
washed with water and dried over magnesium sulfate. The
methylene chloride was then removed by evaporation
dffording an oily residueO The oily residue was then
chromatographed over 250g of silica gel sequentially
eluting with petroleum ether; 95% petroleum ether and
ethyl ether; 90% petroleum ether and ethyl ether, 75%
-23~
01 petroleum ether and ethyl ether. The silica gel column
was then further eluted with 50% petroleum ether and ethyl.
ether affording about 3g of 3-(N-acryloyl-N-2,6-phenyl-
amino)-gamma-butyrothiolactone.
05 Similarly, by following tne same procedure, the
products of Example 5 are respectively converted to the
corresponding gamma-butyrothiolactone derivatives, for
example:
3 (N-acryloyl-N-2,6-dichlorophenylamino)-gamma-buty-
rothiolactone;
3-[N-acryloyl-N-(2-methyl-3-chlorophenyl)-amino]-
gamma-butyrothiolactone;
3-~N-dichloroacetyl-N-phenylamino) gamma-butyrothio-
lactone;
3-(N methoxyacetyl-N-2',6'-dimethylphenylamino)-
gamma-butyrothiolactone;
3-(N-phenylthioacetyl-N-2'-methoxyphenylamino)-gamma-
butyrothiolactone;
3-[N-(2,6-dimethylphenyl)acetyl]-N-(2,6-dibromo-
phenyl)-amino]-gamma-butyrothiolactone;
3-[N-(2,3-epoxybutyryl)-N-(2,6-dimethylphenyl)amino~-
gamma-butyrothiolactone; etc.
EXAMPLE 7
In this example, the procedures of Examples 2
and 5 are repeated but using the corresponding acyl bro-
mides in place of the acyl chloride. Samples of theresulting products of formula II are ~hen respectively
converted to the corresponding compounds of formula III by
applying the procedure of Example 3 and the procedures of
Example 3A-
Obviously, many modifications and variations ofthe invention, described hereinabove and below in the
claims, can be made without departing from the essence and
scope thereof.
