CA1182464A - Process for preparing 3-(n-aryl-n-acylamino)-gamma- butyrothiolate - Google Patents
Process for preparing 3-(n-aryl-n-acylamino)-gamma- butyrothiolateInfo
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Abstract
ABSTRACT
Intermediates, and processes for their preparation, usful in the preparation of 3-(N-aryl-N-acylamino)-gamma-butyrothiolactone fungicides.
The intermediates are prepared by cleaving the corresponding arylamino-gamma-lactone with a thiolate salt to yield the corresponding arylamino-thiol-alkane carboxylate salt, hydrolyzing the salt and then acylating to yield the desired. N-acyl-N-arylamino intermediate product. This intermediate may then be cyclized to yield the fungicide named above.
Intermediates, and processes for their preparation, usful in the preparation of 3-(N-aryl-N-acylamino)-gamma-butyrothiolactone fungicides.
The intermediates are prepared by cleaving the corresponding arylamino-gamma-lactone with a thiolate salt to yield the corresponding arylamino-thiol-alkane carboxylate salt, hydrolyzing the salt and then acylating to yield the desired. N-acyl-N-arylamino intermediate product. This intermediate may then be cyclized to yield the fungicide named above.
Description
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
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 .~.
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
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 .~.
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 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
' ~ 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
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 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
' ~ 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 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.
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 ~8~
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 ~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.
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.
.
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 ;4 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.
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 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.
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.
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;
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.
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 ~8~
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 ~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.
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.
.
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 ;4 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.
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 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.
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.
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;
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.
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.
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.
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;
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.
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.
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.
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound having the formula 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, R1 is lower alkyl, lower alkoxy, cycloalkyl, having three through six carbon atoms, lower epoxyalkyl, lower alkenyl, lower alkenyloxy, hydroxy-methyl; 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 substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, lower alkyl, and lower alkoxy;
R2 is hydrogen, chloro, 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 wherein R1' is selected from the same group of substituents as R1 defined hereinabove.
R is lower alkyl, lower alkenyl, aryl-lower alkyl, R1 is lower alkyl, lower alkoxy, cycloalkyl, having three through six carbon atoms, lower epoxyalkyl, lower alkenyl, lower alkenyloxy, hydroxy-methyl; 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 substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, lower alkyl, and lower alkoxy;
R2 is hydrogen, chloro, 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 wherein R1' is selected from the same group of substituents as R1 defined hereinabove.
2. The compound of Claim 1 wherein R is selected from the group consisting of t-butyl, allyl, and benzyl.
3. A process for preparing the compound of Claim 1 which comprises contacting the corresponding compound having the formula wherein Ar, R and R2 are as defined in Claim 1 and M1 is hydrogen or a cation, and m' is the valence of M1;
with an acyl halide, having the formula wherein X is chloro or bromo and R1 is as defined in Claim 1, under reactive conditions thereby yielding the corresponding compound of Claim 1.
with an acyl halide, having the formula wherein X is chloro or bromo and R1 is as defined in Claim 1, under reactive conditions thereby yielding the corresponding compound of Claim 1.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16245380A | 1980-06-23 | 1980-06-23 | |
| US162,453 | 1980-06-23 | ||
| US20086480A | 1980-10-27 | 1980-10-27 | |
| US200,864 | 1980-10-27 | ||
| CA000378121A CA1156664A (en) | 1980-06-23 | 1981-05-22 | Process for preparing 3-(n-aryl-n-acylamino)-gamma- butyrothiolate |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000378121A Division CA1156664A (en) | 1980-06-23 | 1981-05-22 | Process for preparing 3-(n-aryl-n-acylamino)-gamma- butyrothiolate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1182464A true CA1182464A (en) | 1985-02-12 |
Family
ID=27167064
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000422478A Expired CA1182464A (en) | 1980-06-23 | 1983-02-25 | Process for preparing 3-(n-aryl-n-acylamino)-gamma- butyrothiolate |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1182464A (en) |
-
1983
- 1983-02-25 CA CA000422478A patent/CA1182464A/en not_active Expired
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