DD203718A5 - PROCESS FOR THE PREPARATION OF 1- (ARYL OR SUBST.-ARYL) AMINO-1-THIOALKANCARBOXYL SALZEN BZW. THE ENCOMPARING CARBOXYTEURS - Google Patents

Abstract

Process for the preparation of 1- (aryl or substituted aryl) amino-1-thioalkanecarboxylate salts or the corresponding carboxy acids. The invention relates to a process for the preparation of 1- (aryl or substituted aryl) amino-1-thialkancarboxylarsalzen or the corresponding Carboxysaeuren, which are suitable for the preparation of 3- (N-aryl-N-acylamino) gamma-butyrothiolaten which are valuable fungicides by reacting the corresponding arylamino-gamma-lactones with thiolate salts to obtain the corresponding arylaminothiolalkanecarboxylate salts which can be hydrolyzed with the corresponding carboxylic acids.

Description

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Field of application of the invention

The invention relates to a process for the preparation of 1- (aryl or substituted aryl) amino-1-thioalkanecarboxylate salts or the corresponding carboxylic acids.

Characteristic of the known technical solutions

3- (N-Aryl-N-acylamino) - / ^ - butyrothiolactones are known compounds having a fungicidal activity and are described for example in BE-PS 871 668. According to this BE-PS, the compounds are prepared via the amination (anilination) of B-halo-δ-butyrothiolactones and subsequent acylation with the corresponding acyl halide.

There is also known a process for preparing such compounds by cleaving the corresponding N-aryl-N-acylaminolactone analogs with a thiolate salt and then treating the resulting (N-aryl-N-acylamino) carboxythioalkane product with phosphorus trichloride to close the ring.

The preparation of certain non-substituted thiolactones is further described by Truce et al. in "Journal of Organic Chemistry", Vol. 28, p. 964 (April 1963).

0 Q ηUT απ j π

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Object of the invention

The aim of the invention is to provide a process for the preparation of 1- (aryl or substituted aryl) amino-1-thioalkanecarboxylate salts or of the corresponding carboxylic acids which are used as intermediates for the preparation of 3- (N-aryl-N-acylamino) - IT- butyrothiolactones are used in the context of the following 3-step process:

(a) contacting a 3- (aryl or substituted arylamino) -butyrolactone or a 5-substituted derivative thereof with a thiolate salt under reactive conditions to obtain the corresponding 1- (aryl or substituted aryl) amino-1 thioalkanecarboxylate salt and acidifying the salt to give the corresponding carboxylic acid,

(b) contacting the product of step (a) with an acyl halide under reactive conditions to obtain the corresponding acylamino derivative and

(c) contacting the product of step (b) with a cyclizing agent which effects esterification of a saturated fatty carboxylic acid with a lower molecular weight primary alcohol to obtain the corresponding 3- (N-aryl or substituted aryl-N-acylamino ) - (- "" - butyrothiolactones or a 5-substituted derivative thereof.

Optionally, the order of steps (b) and (c) may be reversed so that first the intermediate of step (a) is cyclized followed by acylation.

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Explanation of the essence of the invention

The process according to the invention is carried out as follows:

Contacting a 3- (aryl or substituted arylamino) -butyrolactone or a 5-substituted derivative thereof with a thiolate salt under reactive conditions to obtain the corresponding 1- (aryl or substituted aryl) amino-1-thioalkanecarboxylate salt and acidifying the salt to obtain the corresponding carboxylic acid,

This reaction can be represented by the following reaction scheme:

HR ²

Ar - N + M (SR) Ar - N - CH - CH₂-CH-SR | 2J_ _R 2 [I] ^ι

) 5 (B) ^^ C = O

L (A). * V I (I)

(I) + R ¹ CX- (salt or acid) (C)

wherein Ar is aryl or substituted aryl having 1 to 4 substituents selected from fluoro, chloro, bromo, iodo, lower alkyl or lower alkoxy, R is lower alkyl (preferably tertiary butyl), lower alkenyl (preferably allyl) or arylalkyl (preferably benzyl) .

R is lower alkyl, lower alkoxy, cycloalkyl of 3 to 6 carbon atoms (preferably cyclopropyl), lower epoxyalkyl of 2 to 6 carbon atoms, including one or two epoxy groups, lower alkenyl, lower alkenyloxy, hydroxy lower alkyl (preferably hydroxymethyl), haloalkyl of 1 to 3 halogen substituents and 1 to 6 carbon atoms (de), lower alkoxyalkyl, lower alkylthioalkyl, 'phenylthio-lower alkyl, (preferably phenylthiomethyl), phenoxy-lower alkyl (preferably phenoxy, methyl), substituted phenylthio-lower alkyl (preferably substituted phenylthiomethyl) or substituted phenoxy-lower alkyl (preferably substituted phenoxymethyl) having one or two ring substituents, selected from fluorine, chlorine, bromine, iodine, lower alkyl or lower alkoxy, while

R is hydrogen, chloro, bromo, lower alkyl, phenyl or substituted phenyl having 1 to 2 substituents selected from fluoro, chloro, bromo or lower alkyl, and R is hydrogen or O, wherein

-CR ¹ ''

R is selected from the group of substituents given for R.

M is an inorganic cation, preferably an alkali metal cation, while m is its valence, while X is chlorine or bromine.

- JeT - 5 "

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The process according to the invention can be carried out in an expedient manner in that the corresponding compounds

the formula A having the desired Ar and R substituents is contacted with the thiolate of the formula B, preferably in a suitable organic solvent under reactive conditions.

Typically, this process is carried out at temperatures between about 20 and 200 ^° C., and preferably about 50 to 80 ^° C., for about 1 to 8 hours and preferably for about 1 to 4 hours. Typically, about 1 to 1.5 moles and preferably about 1 to 1.25 moles of the compound of formula B, based on the thiolate content, are employed per mole of the compound of formula A.

rf μ JI & \ L * ^ * L

rl / 11 IXM \ i 1 i

y 4L * 4 * * & ι wv #

When an organic solvent is used, the solvent is generally only a solvent for the reactant A. Suitable inert organic solvents which may be used are, for example, dimethoxyethane, toluene, tetrahydrofuran, dimethylformamide, or the like, and compatible mixtures thereof. Preferably, dimethoxyethane is used as the solvent. Typically, a ratio of about 1 to 3 moles of reactant A per liter of solvent used is maintained.

In general, the best results are obtained when the process is carried out at temperatures between about 50 to 8O ⁰ C, with about 1 to 1.10 moles B are used per mole A in dimethoxyethane.

Suitable thiolates of the formula B which can be used are, for example, alkali metal thiolates, for example sodium 2-methyl-2-propanethiolate, potassium 2-methyl-2-propanethiolate, alkaline earth lithiolates, calcium bis (alkyl thiolates), ammonium thiolates, quaternary amine thiolates, for example, tetramethylammonium thiolate, benzylthiolate, or the like. When alkylmercaptides are used, tertiary alkylmercaptides are preferred to the secondary and primary alkynecaptides in terms of yields, while secondary alkylmercaptides are to be preferred over primary alkylmercaptides. In general, best results are obtained using sodium 2-methyl-2-propanethiolate. In a preferred embodiment, the thiolate salt is prepared in situ via the reaction of the corresponding RSH mercaptan with an alkali metal alkylate, for example, sodium methylate.

The compounds of the formula A are known compounds and can be prepared by known methods, for example by reacting the corresponding aryl or substituted arylamine with the corresponding 3-chloro- or 3-bromobutyrolactone, and this, for example

in U.S. Pat. No. 871,668 and in U.S. Patents 3,933,860 or 4,165,322.

The product of this process step is the corresponding M salt of the acid of formula I. This salt can be freed of any unreacted unreacted compound A), suitably by extraction, since compound A] is generally insoluble in water when the compound (I) is soluble in water.

The salt (I) may then be hydrolyzed by treatment with a weak acid such as acetic acid.

The following terms have the meanings explained, unless stated otherwise. The term "halogen" means fluorine, chlorine, bromine and iodine.

The term "alkyl" means straight-chain and branched alkyl groups. The term "lower alkyl" refers to both straight-chain and branched-chain alkyl groups having a total of 1 to 6 carbon atoms and includes primary, secondary and tertiary alkyl groups.

Typical lower alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-hexyl or the like.

The term "alkoxy" refers to the radical R ¹ O-, where R ^{1 is} alkyl.

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The term "lower alkoxy" includes alkoxy groups having 1 to 6 carbon atoms, for example, methoxy, ethoxy, tert-butoxy, hexoxy or the like.

The term "lower epoxyalkyl" refers to epoxyalkyl groups of 2 to 6 carbon atoms, for example, one or two oxy groups. Such groups are, for example, 1,2-epoxypropyl (ie, CH- ^ CH ^ - ^ CH-); 2,4-epoxypentyl (ie, '', 4'-methyloxetanylmethyl; CH 1 1 -CH 2 CH ₃ CH ₂ -CH ₂ -CH 2 -); 1,2,4,5-diepoxyhexyl (ie, CH ₃ -CH ₃ -) CH- CH ₂ -CH ^ - ^ CH-) or the like

The term "hydroxy-lower alkyl" includes groups of the formula HOR ¹ wherein R ^{1 is} lower alkyl. Mention may be made, for example, hydroxymethyl, 3-hydroxypentyl, 2-hydroxyethyl or the like.

The term "lower alkoxyalkyl" refers to R'OR "-, wherein R ¹ O is lower alkoxy and R" is lower alkyl.

The term "lower alkylthioalkyl" refers to the radical R ¹ SR "-, wherein R ¹ and R" independently represent lower alkyl. Typical lower alkylthioalkyl groups are, for example, methylthiomethyl or 4-tert-butylthiohexyl.

The term "alkenyl" refers to unsaturated alkyl groups having one double bond and includes both straight-chain and branched alkenyl groups.

The term "lower alkenyl" refers to alkenyl groups of 2 to 6 carbon atoms. Typical lower alkenyl groups are, for example, allyl, eut-3-enyl, 2-methylpent-4-enyl or the like.

The term "lower alkenyloxy" embraces the groups of the formula R 0 - wherein R is lower alkenyl.

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The term "lower alkenyloxyalkyl" includes groups of the

5 5

Formula R OR ¹ - where R is lower alkenyl and R ^{1 is} lower alkyl. Typical lower alkenyloxyalkyl groups are, for example, allyloxymethyl, 2- (but-3-enyloxy) hexyl or the like.

The term "aryl" includes aryl groups having 6 to 12 carbon atoms, for example, phenyl and naphthyl.

The term "phenoxy-lower alkyl" refers to groups of the formula Ph-O-R'-, wherein Ph is phenyl and R ^{1 is} lower alkyl. Examples are phenoxymethyl, phenoxyhexyl, 5-phenoxy-3-methylpentyl or the like.

The term "phenylthio-lower alkyl" refers to groups of the formula Ph-SR ¹ -, wherein Ph is phenyl and R 'is lower alkyl. Mention may be made, for example, phenylthiomethyl, phenylthioethyl, 4-phenylthio-1-methylbutyl or the like.

The term "substituted phenoxy lower alkyl" refers to groups of the formula Ph'-O-R'-, wherein R 'is lower alkyl and Ph ^{1 is} a phenyl group having 1 to 2 substituents independently selected from the group consisting of fluoro, Chloro, bromo, iodo, lower alkyl and lower alkoxy. Typical substituted phenoxy lower alkyl groups are, for example, 4-fluorophenoxymethyl, 2-iodo-5-bromo phenoxymethyl, 2- (2,5-dimethylphenoxyethyl, 4- (2-methoxy-4-chlorophenoxy) -1-methylbutyl or the like.

The term "substituted phenylthio-lower alkyl" refers to groups of the formula Ph'-S-R'-, wherein R ^{1 is} lower alkyl and Ph 'is a phenyl group having 1 or 2 substituents independently selected from the group consisting of fluoro, Chloro, bromo, iodo, lower alkyl or lower alkoxy. Typical substituted phenylthio-lower alkyl groups are, for example, 4-fluorophenyl

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thiomethyl, 2-iodo-5-bromophenylthiomethyl, 2- (2,5-dimethylphenylthio) ethyl, 4- (2-hexoxy-4-chlorophenylthio) -1-methylbutyl or the like.

The term "unsubstituted fatty acid" refers to carboxylic acids of the formula R'COOH where R 'is an alkyl group having 1 to 20 carbon atoms.

The term "low molecular weight primary alcohol" refers to a primary alcohol having a molecular weight within about 70, such as methanol, ethanol, or the like.

The following examples illustrate the invention without limiting it. Unless otherwise indicated, all temperatures are to ⁰ C. The terms "ambient temperature" or "room temperature" mean a temperature of about 20 to 25 ^° C. The term "%" means wt% and the term "mol" stands for gramol. The term "equivalent" indicates an amount of the reagent equivalent in moles to the moles of the preceding or succeeding reactant indicated in a preparation or use example as moles or finite weight or volume. Unless otherwise stated, racemic mixtures and / or diastereomeric mixtures are used as starting materials and corresponding racemic mixtures and / or diastereomeric mixtures are obtained as products. If necessary, examples are repeated to provide sufficient quantities of starting materials for subsequent production methods and methods of use. The abbreviation EA stands for "elemental analysis, both for the calculated and found values (in% by weight).

ΑΛ

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The protoninagnetic resonance spectra (ΡΓ.Ρ.) are determined at 60 mHz and the signals are singlets (bs), broad singlets (bs), doublets (d) , double doublets (dd), triplets (t), double triplets (dt) , Quartet (q) and multiplet (m).

Embodiment ·

This example illustrates the process according to the invention as well as the hydrolysis of the salt (I) to its acid.

In carrying out this example, 15 ml of anhydrous dimethoxyethane are mixed with 1.98 g (0.022 mol) of 2-methyl-2-propanethio, 1.08 g (0.02 mol) of sodium methylate. The mixture is refluxed for 1 h, then cooled to room temperature and mixed with 4.10 g (0.02 mol) of 3- (2,6-dimethylphenyl-amino) -p-butyroiactone. The resulting mixture is refluxed for one-quarter hour, after which approximately 0.2 g of sodium methyiate is added and the reflux is continued for a further h. After this time, the mixture is cooled, whereupon 20 ml of ice water are added. The mixture is then extracted with toluene and the residual aqueous phase is acidified to pH 6 with glacial acetic acid and extracted with methylene chloride. The methylene chloride extract is then washed three times with water, dried over magnesium sulfate and evaporated to give 2.80 g of 1-carboxy-1- (2,6-dimethyl-phenyl-amino) -3-tert-butyithiopropane in the form of a viscous oil become.

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By the same method, but using the corresponding lactone starting materials instead of 3- (2,6-dimethylphenylamino) -butyrolactone, the following compounds are prepared:

1-carboxy-1- (2,3,6-trimethylphenylamino) -3-tert-butylthiopropan,

1-carboxy-1- (2-methoxy-6-methylphenylamino) -3-tert-butylthiopropane and 1-carboxy-1-naphthylamino-3-tert-butylthiopropane.

Following the same procedure, but instead of preparing the thiolate in situ, the thiolate salts potassium allyl thiolate, ammonium benzylthiolate and sodium naphthylthiolate are reacted directly with each of the butyrolactone starting materials as mentioned above to give the corresponding thioethylene, thiobenzene and thionaphthalene analogs of each of the obtained above products.

Claims (4)

-% - 244216 3 invention claim 1. A process for the preparation of a compound of the formula Ar -NH .C CH-R ² / ν wherein Ar is aryl or substituted aryl having 1 to 4 substituents independently selected from the group consisting of fluorine, chlorine, bromine, iodine, lower alkyl or lower alkoxy, and R 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 or lower alkyl, characterized in that 2442 1 6 3 (a) a compound of the formula Ar NH CH CH ₉ II ₂ C CH-R ^Z
° 0 where Ar and R. have the meanings given above, is contacted with a thiolate salt under reactive conditions, and (b) reacting the product produced in step (a) with a reagent capable of esterifying a saturated fatty carboxylic acid upon contact with a low molecular weight primary alcohol. 2. The method according to item 1, characterized in that the product of step (a) before step (b) is converted into the acid. 3. The method according to item 2, characterized in that the thiolate salt used is 2-methyl-2-propanethiolate and the reagent of step (b) used is phosphorus trichloride. 4. The method according to item 3, characterized in that Ar is 2,6-dimethyl phenyl.