KR100471948B1 - 3-amino-2-mercaptobenzoic acid derivatives and preparation method thereof - Google Patents

Abstract

The following compounds of formula (I) and their disulfides and salts thereof are important intermediate products for the preparation of compounds of formula (III) having microbial and plant immunity:

In the compounds of the general formulas (I) and (III),

X is halogen,

n is 0, 1, 2 or 3,

Z is CN, CO-A or CS-A,

A is hydrogen, halogen, OR ₁ , SR ₂ and N (R ₃ ) R ₄ ,

R ₁ to R ₄ are hydrogen, substituted or unsubstituted open chain saturated or unsaturated hydrocarbon radicals containing up to 8 carbon atoms, substituted or unsubstituted cyclic, saturated containing up to 10 carbon atoms Or unsaturated hydrocarbon radicals, substituted or unsubstituted benzyl or phenethyl, substituted or unsubstituted alkanoyl groups containing up to 8 carbon atoms, substituted or unsubstituted benzoyl groups or substituted or unsubstituted hetero Cyclic radicals; or

R ₃ and R ₄ are 5- or 6-membered substituted or unsubstituted heterocyclic radicals having 1 to 3 heteroatoms 0, S and / or N in combination with the nitrogen atom to which they are attached.

Processes for the preparation of compounds of general formula (I) are described.

Description

3-amino-2-mercaptobenzoic acid derivatives and preparation methods thereof

The present invention relates to compounds of formula (I), disulfides and salts thereof, methods for their preparation, and their use to prepare compounds of formula (III) having microbial and plant immunization actions:

In the compounds of the general formulas (I) and (III),

X is fluorine,

n is 0, 1, 2 or 3,

Z is CN, CO-A or CS-A,

A is hydrogen, OR ₁ , SR ₂ and N (R ₃ ) R ₄ ,

R ₁ to R ₄ are hydrogen, substituted or unsubstituted open chain saturated or unsaturated hydrocarbon radicals containing up to 8 carbon atoms, substituted or unsubstituted cyclic, saturated containing up to 10 carbon atoms Or unsaturated hydrocarbon radicals, substituted or unsubstituted benzyl or phenethyl, substituted or unsubstituted alkanoyl groups containing up to 8 carbon atoms, substituted or unsubstituted benzoyl groups or substituted or unsubstituted hetero Cyclic radicals; or

R ₃ and R ₄ are a 5- or 6-membered substituted or unsubstituted heterocyclic radical having 1 to 3 heteroatoms 0, S and / or N, combined with the nitrogen atom to which they are attached; Except for compounds where n is 0 and Z is CN, CONH ₂ or COOH.

Compounds of formula (I) have one or more basic groups and can therefore form acid addition salts. They are reacted with inorganic acids such as sulfuric acid, phosphoric acid or hydrohalic acid, by reaction with organic carboxylic acids such as acetic acid or oxalic acid, malonic acid, maleic acid, fumaric acid or phthalic acid, and hydroxycarboxylic acids such as ascorbic acid, lactic acid, malic acid. , By reaction with tartaric acid or citric acid, or by reaction with benzoic acid, or by reaction with organic sulfonic acids such as methane- or p-toluenesulfonic acid. Based on the SH group or the acid group on the substituent Z, the compound of formula (I) may form a salt with a base. Salts with suitable bases include metal salts such as alkali metal or alkaline earth metal salts, such as sodium, potassium or magnesium salts, or ammonia or morpholine, piperidine, pyrrolidine, mono-, di- or tri-lower alkylamines. Salts with the same organic amines, such as ethyl-, diethyl-, triethyl- or dimethyl-propyl-amine, or mono-, di- or trihydroxy-lower alkylamines, such as mono-, di- or triethanolamine . Suitably, corresponding internal salts may also be formed.

Unless otherwise defined, the general terms used above and below have the following meanings.

Hydrocarbon radicals are saturated or unsaturated and may be open chains or cyclic or mixtures of open chains and cyclics such as cyclopropylmethyl or benzyl.

Alkyl groups are straight or branched, depending on the number of carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, tertiary butyl, secondary amyl, tertiary amyl, 1-hexyl or 3-hexyl to be.

Unsaturated hydrocarbon radicals are alkenyl, alkynyl or alkeninyl groups having three or more multiple bonds, such as butadienyl, hexatrienyl, 2-penten-4-ynyl.

Alkenyl is understood as straight or branched alkenyl, for example allyl, metalyl, 1-methylvinyl or but-2-en-1-yl. Preference is given to alkenyl radicals of 3 to 4 carbon atom chain lengths.

Alkynyl is straight or branched, depending on the number of carbon atoms, propargyl, but-1-yn-1-yl and but-1-yn-3-yl. Propargyl is preferred.

The cyclic unsaturated hydrocarbon radicals can be aromatic, such as phenyl and naphthyl or nonaromatics such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctadienyl, or partially aromatic such as tetrahydronaphthyl and indane It's work.

Halogen or halo and Hal are fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

Haloalkyl may contain the same or different halogen atoms, such as fluoromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2, 2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trichloroethyl and 3,3,3-trifluoropropyl.

Alkoxy is for example methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, secondary butyloxy and tertiary butyloxy. Preferably methoxy and ethoxy.

Haloalkoxy is, for example, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloro Ethoxy and 2,2-difluoroethoxy

Cycloalkyl is cyclopropyl, ciflobutyl, cyclopentyl or cyclohexyl.

Alkanoyl is straight or branched chain. Examples are formyl, acetyl, propionyl, butyryl, pivaloyl or octanoyl.

Heterocyclic radicals refer to 5- or 6-membered aromatic and non-aromatic rings having heteroatoms N, 0 and / or S. Unsubstituted or substituted benzo groups may be fused to heterocyclic radicals bonded to the rest of the molecule. Examples of heterocyclic groups include pyridyl, pyrimidinyl, imidazolyl, thiazolyl, 1,3,4-thiadiazolyl, triazolyl, thienyl, furanyl, pyrrolyl, morpholinyl, oxazolyl and Corresponding partially or fully hydrogenated rings. Examples of heterocyclic groups having fused benzo groups are quinolyl, isoquinolyl, benzooxazolyl, quinoxalinyl, benzothiazolyl, benzimidazolyl, indolyl and indolinyl.

Compounds of general formula (III) having microbial and plant immunization functions and methods for their preparation are known, for example, from EP-A-313 512. The process described here involves many reaction steps, some of which are complex and inadequate in yield, making them unsuitable for production on an industrial scale. Therefore, there has been a need for a method for industrially advantageous synthesis of such compounds.

Compounds of formula (I) according to the invention enable the production of compounds of formula (III) as shown in equation (1). This synthesis is characterized by the ease of precursor procurement, the use of conventional reactants and excellent yields without the isolation of intermediate products. The present invention also relates to the above synthesis method.

In the general formula of Equation 1, X, n and Z are as defined in formula (1) and T is hydrogen, C ₁ -C ₁₂ alkyl, in particular C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl.

Precursors of general formula (V) can be obtained industrially or can be prepared by known methods, for example by reducing the corresponding nitro compound.

Specifically, the reaction step can be carried out as follows:

(1) in the presence of SCN-T / such as methyl isothiocyanate / inert solvent / if needed acid or base; Or SCN salts.

(2) oxidizing agents such as SO ₂ CL ₂ or Br ₂ or H ₂ SO ₄ / bromide or Cl ₂ .

(3) an aqueous strong base such as potassium hydroxide solution, preferably in an inert atmosphere.

Reactions (1), (2) and (3) are described in the literature:

Org. Synthesis, Coll. Volume III, page 76;

J. Het. Chem. Volume 17, page 1325 (1980);

US-5,374,737.

Ukrain.Khim.Zhur. Volume 22, 363, 1956; Chem. Abstr. 22, 4358b (1957).

(3a) Diazolation / H ₃ PO ₂ (Synth. Comm.Vol. 10, page 167, 1980)

(4) Diazolation with cyclization using nitrous acid (= HONO) or inorganic or organic nitrites such as sodium nitrite or isoamyl nitrite (such as EP A 313,512).

(4a) hydrazine / ethanol or basic hydrolysis, or as in 4)

(Synth. Comm. Volume 10, page 167, 1980).

(4b) Zn / acid or Fe / acid (Heterocyclic Compounds, Volume 7, p. 541 p.); Or H ₂ / catalyst.

(5) Converting a COOH group to a Z group (wherein Z is as defined in formula (I)) can be carried out by a known method as shown in equation (3).

Preferred compounds of formula (I) are as follows:

(1) Z is CN, CO-A or CS-A;

A is OR ₁ , SR ₂ and N (R ₃ ) R ₄ ,

R ₁ , R ₂ and R ₃ are hydrogen; Unsubstituted or from 1 to 5 halogen atoms, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, phenoxy, benzyloxy C ₁ -C ₄ acyloxy, benzoyloxy, hydroxyl, nitro, cyano, C ₁ -C ₄ alkanoyl, benzoyl, carboxyl, C ₁ -C ₄ alkoxycarbonyl, benzyloxycarbonyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino or heterocyclic C ₁ -C ₈ alkyl substituted by; C ₃ -C ₆ alkenyl unsubstituted or substituted by 1 to 5 halogen atoms; C ₃ -C ₆ alkynyl; C ₃ -C ₆ cycloalkyl; C ₁ -C ₄ alkanoyl; The phenyl ring is unsubstituted or substituted by halogen, hydroxy, C ₁ -C ₄ alkyl, halogeno-C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, halogeno-C ₁ -C ₂ alkoxy or nitro Phenyl, benzyl or phenethyl substituted three to three times; Or naphthyl, benzoyl or heterocyclic, unsubstituted or substituted one to three times by halogen, C ₁ -C ₂ alkyl, halogenomethyl or nitro in the same or different ways; or

R ₄ is hydrogen, C ₁ -C ₆ alkyl, phenyl or benzyl, or

R ₃ and R ₄ may combine with the nitrogen atom to which they are attached to form a 5- to 6-membered ring having 1 to 2 heteroatoms O, S and / or N, wherein the rings are unsubstituted or identical A compound of formula (I) substituted one or two times with halogen, C ₁ -C ₃ alkyl or C ₁ -C ₂ alkoxycarbonyl in different ways.

(2) X is fluorine; n is 0 or 1; Z is CN or CO-A; A is OR ₁ , SR ₂ , or N (R ₃ ) R ₄ .

(3) n is 0 or 1; Z is CN or CO-A;

A is OR ₁ or SR ₂ ; In addition

R ₁ and R ₂ are hydrogen; C ₁ -C ₆ alkyl unsubstituted or substituted by 1 to 3 halogen atoms, C ₃ -C ₆ cycloalkyl or C ₁ -C ₂ alkoxy; C ₃ -C ₄ alkenyl unsubstituted or substituted by 1 to 3 halogen atoms; C ₃ -C ₄ alkynyl; C ₃ -C ₆ cycloalkyl or phenyl ring is unsubstituted or halogen, hydroxyl, C ₁ -C ₄ alkyl, halogeno-C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, halogeno-C _1- C ₂ alkoxy or phenyl, benzyl or phenethyl, substituted once or twice by nitro.

(4) According to another process, the compound of formula (I) can be prepared according to equation 2 via the corresponding benzodithiazolium salt (VI) or hydroxybenzodithiazole (VII) (Houben-Weyl, E8d). , Heteroarene [Heteroarenes] III, Part 4; see below on page 2, and below on page 59).

(a) sulfur halides such as S ₂ Cl ₂ or SCl ₂ (preferably an aniline derivative (V) is converted to the corresponding hydrochloride) in an inert solvent such as acetic acid at 0-120 ° C. (J. Org. Chem 30, 2763, J. Het.Chem 3, 518, same book 5, 1149).

(b1) H ₂ O / or H ₂ O / NaOAC (0-50 ° C.) (Khim. Get. Soed. (9), 1205 (1979); Synth. Comm. 23 , 263).

(b2) H ₂ O / 20 to 100 ° C. (J. Am. Chem. Soc. 68, 1594, (with or without a base such as sodium bicarbonate, sodium carbonate or diluted alkali metal or alkaline earth metal hydroxides or oxides) 1946)).

(C) sulfur dihalide (such as SCl ₂ ), thionyl halide (SOCl ₂ ), -20 to 100 ° C. (J. Het. Chem. 3, 518),

(d) S (0) L ₂ , where L is a leaving group such as halogen, imidazol-1'-yl or 1,2,4-triazol-1-yl, such as thionyldiimidazole or SOCl ₂ ,- 30 to 100 ° C., inert solvent (J. Org. Chem. 30, 2763 (1965))

Benzodithiazolium salts (VI) and (VII) are described under suitable conditions without isolation (J. Chem. Soc. 1970, 2250, Houben Weyl E8d, Heteroarene [Heteroarenes] III, Part 4, page 59 or below, in particular see page 93 or below). Reaction in place under)) yields benzothiadiazole (III) or (IIIa).

(a) chlorinating agents such as SOCl ₂ or COCl ₂ ;

(b) MA (III), wherein M is hydrogen, Li ⁺ , Na ⁺ , K ⁺ , 1 / 2Mg ²⁺ or quaternary ammonium ions and A is as defined in formula (I);

(c) thionating agents, such as phosphorus pentasulfide or 4-methoxyphenylthiophosphonic acid cyclodithio anhydride ("Roweson reagent");

(d) NH ₃ ;

(e) dehydrating agents such as SOCl ₂ or COCl ₂ ;

(f) reduction with hydrogen / catalyst or reduction with hydrogenation complexes such as LiAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ .

The above reactions can be carried out in the manner originally known, for example in the absence or usually in the presence of a suitable solvent or diluent or mixture thereof, and the reaction can also be carried out with cooling at room temperature as required or sealed under reduced pressure if necessary. In a vessel, under inert gas atmosphere and / or anhydrous conditions, it can be carried out while heating to a temperature in the boiling point range of about -80 ° C to the reaction medium, preferably about -20 ° C to about + 170 ° C. The diazotization reaction, ie, reacting the primary amine with nitrous acid or with inorganic or organic nitrite is preferably carried out at -20 ° C to + 30 ° C.

Leaving groups are, for example, fluorine, chlorine, bromine, iodine; C ₁ -C ₈ alkylthio such as methylthio, ethylthio or propylthio; C ₁ -C ₈ alkanoyloxy such as acetoxy; (Halogeno) -C ₁ -C ₈ alkanesulfonyloxy such as methanesulfonyloxy, ethanesulfonyloxy or trifluoromethanesulfonyloxy; Or substituted or unsubstituted phenylsulfonyloxy such as benzenesulfonyloxy or p-toluenesulfonyloxy; Imidazolyl, triazolyl, hydroxyl or water, preferably chlorine, bromine, iodine and P-toluenesulfonyloxy.

Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides, alkanolates, carbonates, dialkylamides or dialkylsilylamides, alkylamines, alkylenediamines, unalkylated or N-alkylated saturated or unsaturated cyclos Alkylamines, basic heterocyclic compounds, ammonium hydroxide and carbocyclic amines. Examples include sodium hydroxide, hydrides, amides, methanolates and carbonates, potassium tert-butanolate and carbonates, lithium diisopropylamides, potassium bis (trimethylsilyl) amides, calcium hydrides, triethylamine, triethylenediamine, cyclohexyl Amines, N-cyclohexyl-N, N-dimethylamine, N, N-diethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, N-methylmorpholine, benzyl-trimethyl-ammonium hydroxide and 1 , 8-diazabicyclo [5.4.0] undec-5-ene (DBU).

The reactants can be reacted with one another, ie without addition of solvent or diluent, such as in a melt. However, it is advantageous to add inert solvents or diluents or mixtures thereof. Examples of such solvents or diluents are aromatic, aliphatic and cycloaliphatic and halogenated hydrocarbons such as benzene, toluene, xylene, chlorobenzene, bromobenzene, petroleum ether, hexane, cyclohexane, methylene chloride, chloroform, dichloroethane or trichloro ethane; Ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran or dioxane; Ketones such as acetone or methyl ethyl ketone: alcohols such as methanol, ethanol, propanol, butanol, ethylene glycol or glycerol; Esters such as ethyl acetate or butyl acetate; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone or hexamethyl phosphate triamide; Nitriles such as acetonitrile; And sulfoxides such as dimethyl sulfoxide. Excess bases such as triethylamine, pyridine, N-methylmorpholine or N, N-diethylaniline can also be used as solvents or diluents. The reaction can be carried out in an organic solvent such as methylene chloride or toluene in the presence of a phase aqueous catalyst such as sodium hydroxide solution in the presence of a phase transfer catalyst and a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate. Typical reaction conditions can be seen from the examples.

The present invention relates to the following production method, wherein the substituents in the following reaction formulas (1) to (6) are as defined in equation (1).

(1) A general formula comprising reacting a compound of formula (II) with an aqueous strong base to obtain a compound of formula (Ia) or a salt thereof, and then reacting it further to produce a compound of formula (I) ( Process for the preparation of the compound of I) or salt thereof.

(2) a compound of formula (Ia) comprising reacting a compound of formula (II) with an aqueous strong base, in particular a potassium hydroxide solution or a sodium hydroxide solution, at a temperature of 120 to 150 ° C. and a pressure of 1 to 5 bar, or Method for preparing the salt thereof.

(3) a) reacting a compound of general formula (II) with an aqueous strong base to produce a compound of general formula (Ia) or a salt thereof;

b1) converting the compound of general formula (Ia) to the compound of general formula (IIIa) by diazotization with nitrous acid or organic or inorganic nitrite and then to the compound of general formula (III) if necessary; or

b2) the following general formula comprising the conversion of a compound of formula (Ia) to a compound of formula (I) followed by diazotization with nitrous acid or organic or inorganic nitrite Process for the preparation of the compound of III).

(4) The compound of formula (II) is reacted with an aqueous strong base to form a compound of formula (Ia) or a salt thereof, and then without isolation, by diazotization using nitrous acid or organic or inorganic nitrite, Process for preparing a compound of formula (IIIa) comprising converting directly to a compound:

The first reaction step is carried out in potassium hydroxide or a salt thereof at a pressure of 120 to 170 ° C. and 1 to 5 bar, and the diazotization is carried out using sodium nitrite.

(5) A process for preparing the compound of formula (I), comprising hydrolyzing the compound of formula (VI) under neutral or basic conditions.

(6) reacting a compound of general formula (V) with a SCN-T or SCN salt in a solvent, if necessary in the presence of an acid or a base, and then reacting the resulting compound of general formula (IV) with an oxidizing agent such as SO ₂ Cl ₂ or A process for preparing a compound of formula (II) or a salt thereof comprising reacting with Br ₂ or H ₂ SO ₄ / bromide or Cl ₂ to produce a compound of formula (II):

Preferably, C ₁ -C ₆ alkyl isothiocyanates, especially methyl isothiocyanate, are used in the first reaction step; Suitable solvents include carboxylic anhydrides such as formic acid and acetic acid; Alcohols such as ethanol and isopropanol, ketones, ethers and halogenated hydrocarbons. The two reaction steps are preferably carried out in the same solvent, such as in acetic acid, without isolation of the compound of formula (IV).

The present invention also relates to the intermediates of the following general formulas (II) and (IV) or salts thereof:

In the food,

X is fluorine,

n is 0, 1, 2 or 3,

T is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl;

Z is CN, CO-A or CS-A,

A is hydrogen, halogen, OR ₁ , SR ₂ and N (R ₃ ) R ₄ ,

R ₁ to R ₄ are hydrogen, substituted or unsubstituted open chain saturated or unsaturated hydrocarbon radicals containing up to 8 carbon atoms, substituted or unsubstituted cyclic, saturated with 10 or more carbon atoms, or Unsaturated hydrocarbon radicals, substituted or unsubstituted benzyl or phenethyl, substituted or unsubstituted alkanoyl groups containing up to 8 carbon atoms, substituted or unsubstituted benzoyl groups or substituted or unsubstituted heterocycles Is a click radical; or

R ₃ and R ₄ are 5- or 6-membered substituted or unsubstituted heterocyclic radicals having 1 to 3 heteroatoms O, S and / or N in combination with the nitrogen atom to which they are attached; In addition

Provided that compounds of formulas (II) and (IV) wherein Z is COOH or COOC ₂ H ₅ , n is 0 and T is hydrogen (Ukrain, Khim. Zhur. Volume 22, 363, 1956) Chem. Abstr. 22, 4358b, 1957).

n is 0 or 1;

T is hydrogen or C ₁ -C ₆ alkyl;

Z is CN or CO-A,

A is OR ₁ , SR ₂ or N (R ₃ ) R ₄ ,

R ₁ to R ₄ are preferably compounds of the general formulas (II), (IV) and (VI) as defined above, in particular

A is OR ₁ or SR ₂ ; In addition

R ₁ and R ₂ are hydrogen, unsubstituted or C ₁ -C ₆ alkyl, unsubstituted or substituted with 1 to 3 halogen atoms, C ₃ -C ₆ cycloalkyl or C ₁ -C ₂ alkoxy C ₃ -C ₄ alkenyl, C ₃ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl by three halogen atoms, or the phenyl ring is unsubstituted or halogen, hydroxyl, C ₁ -C ₄ alkyl General formula (II) which is phenyl, benzyl or phenethyl substituted once or twice by halogeno-C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, halogeno-C ₁ -C ₂ alkoxy or nitro , Compounds of (IV) and (VI), in particular n is 0; T is hydrogen or methyl;

Z is CO-A; A is OR ₁ ; In addition

R ₁ is hydrogen, unsubstituted or C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl substituted by 1 to 3 halogen atoms or C ₁ -C ₂ alkoxy, or the phenyl ring is unsubstituted or Phenyl substituted once or twice by halogen, hydroxy, C ₁ -C ₄ alkyl, halogeno-C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, halogeno-C ₁ -C ₂ alkoxy or nitro Preference is given to compounds of the formulas (II), (IV) and (VI) which are benzyl or phenethyl.

In the compound of formula (VI), Hal is preferably chlorine.

Manufacturing Example

Example 1: 3-Amino-2-mercapto-benzoic acid (Ia1)

28.9 g of potassium hydroxide (85%) dissolved in 38 ml of water was added dropwise over 3.5 minutes to 3.5 g of methyl-2-amino-benzothiazole-7-carboxylate in 38 ml of dioxane under nitrogen atmosphere. Stirring and cooling with ice ensured that the internal temperature did not exceed 25 ° C. Thereafter, the mixture was refluxed at a bath temperature of 140 ° C. and at the end of the reaction, the internal temperature was increased to 170 ° C. and dioxane was distilled off using a desending condenser. The mixture was cooled to 0 ° C. and then filtered under nitrogen atmosphere and the residue was washed with 30 ml of ice water. The title compound was isolated from the filtrate by acidification to pH 5.5, cooled and stirred at a maximum temperature of 0 ° C., extracted with ethyl acetate / tetrahydrofuran (8: 2) and washed with concentrated sodium chloride solution. Because of the risk of forming disulfide, the potassium salt (potassium 3-amino-2-mercapto-benzoate) in the filtrate was reacted directly.

Example 2: Benzo-1,2,3-thiadiazole-7-carboxylic acid

The filtered aqueous solution of the potassium salt of 3-amino-2-mercapto-benzoic acid obtained by hydrolyzing 17.6 mmol of methyl 2-aminobenzothiazole-7-carboxylate was concentrated at a maximum temperature of 0 ° C. under a nitrogen atmosphere. Acidify with 31.6 ml of sulfuric acid, then stir and cool thoroughly, then add a solution of 1.28 g (18.6 mmol) of sodium nitrite in 3.4 ml of water dropwise at a maximum of 10 ° C below the surface and add the mixture for 4 hours. Stirred. In the meantime, the temperature increased to about 25 ℃. The precipitate formed was filtered off, washed with ice water, dissolved in tetrahydrofuran, treated with activated charcoal and the mixture was filtered over a small amount of silica gel. After evaporation of the filtrate, 2.64 g (88%, 2 steps) of the crude title compound having a melting point of 232 to 233 ° C was obtained. HPLC analysis showed at least 83% of the title compound and about 8-17% of the isomeric benzo-1,2,3-thiadiazole-5-carboxylic acid. Recrystallization from dioxane affords the pure title compound with a melting point of 239 to 240 ° C.

Example 3: benzo-1,2,3-thiadiazole-7-carbonyl chloride

290 g of benzo-1,2,3-thiadiazole-7-carboxylic acid are suspended in 1.6 liter of toluene, 3.5 ml of dimethylformamide and 129 ml of thionyl chloride are added and the mixture is heated at 80-90 ° C. After stirring, the suspension was made into a solution with gas evolution. Upon completion of this reaction, the solution was cooled and filtered over a small amount of hyflo, the residue was washed with toluene and the filtrate was evaporated. 297 g (93%) of crude acid chloride which can be reacted directly were obtained.

Example 4: S-methyl benzo-1,2,3-thiadiazole-7-thiocarboxylate

210 ml of triethylamine and 2.1 g of 4-dimethylaminopyridine were added to a solution in which 60.7 g (1.26 mol) of methylmercaptan was dissolved in 1450 ml of methylene chloride at 0 ° C. 250.1 g (1.26 mol) of the acid chloride solution dissolved in 1.2 liter of methylene chloride was added while cooling at a temperature of 0 to 5 ° C. and the mixture was stirred at room temperature for 3 hours. Ice water was added, the aqueous phase was extracted with methylene chloride and the combined organic extracts were washed with water, dried over sodium sulfate, dried over a small amount of silica gel and evaporated. 236 g (89%) of S-methyl benzo-1,2,3-thiadiazole-7-thiocarboxylate having a melting point of 132-134 ° C was obtained.

Example 5: Methyl 3-amino-benzoate

130 ml (1.78 moles) of thionyl chloride were added dropwise to 500 ml of methanol and stirred while cooling to -5 ° C and the mixture was stirred thoroughly at 0 ° C for 15 minutes. 70 g (0.5 mol) of solid 3-amino-benzoic acid were introduced at the same temperature and the mixture was stirred for 15 minutes, heated and the resulting solution was left overnight at 70 ° C. After evaporation ethyl acetate and ice water were added to the residue and the pH was brought to 7.5 by adding saturated sodium bicarbonate solution. The product was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and evaporated. 69.8 g (92.2%) of pure methyl ester were obtained in the form of an oil which crystallized upon standing. Melting point 37-38 ° C.

Example 6: Methyl 3-thioureido-benzoate

11. 3 g of methyl 3-aminobenzoate are introduced into the reaction vessel as a solution in 75 ml of chlorobenzene, and 2.07 ml of concentrated sulfuric acid (96%) is added dropwise at -5 ° C to 0 ° C over 15 minutes. Then stirred for 5 minutes. 6.8 g of sodium thiocyanate were then introduced in small portions at up to 0 ° C. and the mixture was stirred for a further 15 minutes. 0.2 ml of 15-crown-5 was added and the mixture was stirred at a water bath temperature of 100 ° C. for 10 hours and then cooled to precipitate a precipitate formed and washed three times with water. 13.5 g (85.9%) of the title compound were obtained having a melting point of 171 to 172 ° C.

Example 7: Methyl 2-aminobenzothiazole-7-carboxylate

8.4 g of methyl 3-thioureido-benzoate is suspended in 120 ml of chlorobenzene and 2.2 ml of bromine in 30 ml of chlorobenzene is added with stirring at 0 ° C. over 1 hour while stirring the mixture. Stir to room temperature. It was then maintained at 70 ° C. for 4 hours and then cooled to add a small amount of diethyl ether and the precipitate was filtered off, mixed with 70 ml of aqueous sodium bicarbonate solution, filtered again and washed with water. 7.7 g (88%) of crude product were obtained having a melting point of 231 to 232 ° C. HPLC analysis showed an isomer methyl 2-amino-benzothiazole-5-carboxylate content of 8-18% in addition to at least 83% pure title compound. Suspended and heated with ethyl acetate at 70 ° C., then cooled to 30 ° C. and filtered to give the pure title compound with a melting point of at least 250 ° C.

When the reaction was carried out in acetic acid (instead of chlorobenzene), the content of the unwanted isomer methyl 2-amino-benzothiazole-5-carboxylate was about 5%.

Example 8: Direct preparation of benzo-1,2,3-thiadiazole-7-carboxylic acid from methyl 2-aminobenzothiazole-7-carboxylate

1.3 kg of methyl 2-aminobenzothiazole-7-carboxylate are kept in 3.5 kg of KOH 50% for 4 hours at 120 ° C./1 to 2 bar and then the mixture is quenched with aqueous hydrochloric acid at 0-5 ° C. temperature. Neutralized. An aqueous 40% sodium nitrite solution was added to the solution at 0 ° C to + 10 ° C, and the precipitated product was washed with filtration and dried. 1.03 kg of benzo-1,2,3-thiadiazole-7-carboxylic acid having a melting point of 230 to 233 ° C. was obtained (91% of theory over two steps).

Example 9: Direct preparation of benzo-1,2,3-thiadiazole-7-carboxylic acid from 2-methylamino-benzothiazole-7-carboxylic acid

A suspension of 150 g 2-methylaminobenzothiazole-7-carboxylic acid (92.7%) and 596 g 47% KOH was kept in an autoclave at 155 ° C./1.7 to 1.8 bar for 12 hours and then at 20-25 ° C. Purification by filtration. The filtrate was added dropwise to 635 g of 37% hydrochloric acid and 50 ml of methanol was added. 200 g of 30% aqueous sodium nitrite solution was added dropwise to a suspension of -10 ° C to -5 ° C and the mixture was allowed to react completely at -5 ° C to 0 ° C for 2 hours. Aspiration filtration and washing with water gave 112 g of crude benzo-1,2,3-thiadiazole-7-carboxylic acid having a melting point of 260-262 ° C. HPLC analysis shows a pure title compound content of 90-93%.

Example 10 Preparation of 3-Amino-2-mercaptobenzoic Acid

1.3 g of methyl 2-amino-7-methoxycarbonylbenzoate was introduced into 3.4 g of potassium hydroxide solution 50% under nitrogen atmosphere and with stirring and the mixture was maintained at 120 ° C. for 12 hours in a bomb tube. It was then cooled and 50% of 1.3 g potassium hydroxide solution was added under inert atmosphere and the mixture was maintained at 150 ° C. for 4 hours. After cooling, the mixture was added dropwise to dilute sulfuric acid at an inert atmosphere at a temperature of 0 ° C. to pH 5.5. The precipitate formed was filtered and washed with ice water. After drying under high vacuum, the title compound is obtained having a melting point of 255 to 258 ° C., which contains traces corresponding to disulfide based on the mass spectrum.

Example 11: Preparation of 3- (N'-Methy-thioureido) -benzoic acid

A mixture of 279.6 g 3-amino-benzoic acid, 164.1 g methyl isothiocyanate and 1000 g 100% acetic acid was heated to 80-85 ° C. This temperature increased to 95-100 ° C. over 20 minutes without heating, forming a clear solution in which the product slowly crystallized. This suspension was kept at 90-100 ° C. for 2 hours, then cooled to 15-20 ° C., suction filtered and the material on the suction filter was washed with acetic acid. 404 g of the title compound were obtained. Purity 99.5%, melting point: 190-91 ° C., decomposition. Yield: 95.7% of theory

Example 12 Preparation of 2-Methylamino-benzothiadiazole-7-carboxylic Acid

A solution of 163 g bromine and 50 g 100% acetic acid was added dropwise over 2 h to 212 g 3- (N′-methylthioureido) -benzoic acid and 500 g 100% acetic acid suspension at 45-50 ° C. . The mixture was heated to 90-100 ° C. over 2.5 hours and allowed to react for 2 hours until gas evolution was complete. 150 g of acetic acid was distilled off at 80-85 ° C. under reduced pressure, then 200 g of water was added and the mixture was brought to pH 2 by dropwise addition of 30% sodium hydroxide. Suction filtration at 70-80 ° C. and washing with water afforded 179.2 g of the title compound. Melting point:> 330 ° C. HPLC analysis shows 3-4% isomer 2-methylamino-benzothiazole-5-carboxylic acid content in addition to 94.6% of the title compound. Yield: 81.5% of theory

Example 13: Preparation of 2-methylamino-benzothiazole-7-carboxylic acid without separation of intermediate product (one pot reaction)

A solution of 39.2 g of methyl isothiocyanate and 50 g of 100% acetic acid was added dropwise over 75 minutes to a suspension of 70 g of 3-amino-benzoic acid and 250 g of 100% acetic acid at 75-80 ° C. A solution was formed temporarily where 3- (N'-methylthioureido) -benzoic acid slowly precipitated in crystalline form. The mixture was allowed to react completely for 2 hours, then cooled to 50 ° C. and 81.5 g of bromine and 50 g of 100% acetic acid were added dropwise at 45-50 ° C. over 2 hours. The mixture was heated to 90-100 ° C. over 2 hours and the reaction was allowed to proceed completely until gas evolution was complete for 2 hours. After 160 g of acetic acid was distilled off under reduced pressure at 75 to 80 ° C., 200 g of water was added to the residue, 67 g of 30% sodium hydroxide solution was added dropwise, and the mixture was suction filtered at 75 to 80 ° C. to retain the residue. Water was washed with water to give 73 g of product. Melting point> 330 ° C. HPLC analysis showed 97% title compound content and 0.7% isomer 2-methylamino-benzothiazole-5-carboxylic acid content. Yield: 68% of theory.

Example 14 Methyl 3-amino-2-mercaptobenzoate

Hydrogenation of a solution of 1 g of methyl benzo-1,2,3-thiadiazole-7-carboxylate in 40 ml of dioxane over 0.5 g of palladium / charcoal (5%) at an initial pressure of 150 bar at 160 ° C I was. After complete reaction of the starting material the catalyst was filtered off and washed with dioxane and the filtrate was evaporated to avoid contact with air and the residue was purified on silica gel (hexane / ethyl acetate (6: 4)). The title compound having a melting point of 174 to 175 ° C. was obtained by the above process.

The compounds listed in the following table can be prepared in a manner similar to the method described in the above examples.

Claims (18)

A compound of formula (I) or a disulfide or salt thereof: In the food, X is fluorine, n is 0, 1, 2 or 3; Z is CN, CO-A or CS-A, A is hydrogen, OR ₁ , SR ₂ and N (R ₃ ) R ₄ , R ₁ to R ₄ are hydrogen, substituted or unsubstituted open chain saturated or unsaturated hydrocarbon radicals containing up to 8 carbon atoms, substituted or unsubstituted cyclic, saturated containing up to 10 carbon atoms Or unsaturated hydrocarbon radicals, substituted or unsubstituted benzyl or phenethyl, substituted or unsubstituted alkanoyl groups containing up to 8 carbon atoms, substituted or unsubstituted benzoyl groups or substituted or unsubstituted hetero Cyclic radicals; or R ₃ and R ₄ are a 5- or 6-membered substituted or unsubstituted heterocyclic radical having 1 to 3 heteroatoms 0, S and / or N, combined with the nitrogen atom to which they are attached; Except for compounds where n is 0 and Z is CN, CONH ₂ or COOH. The method of claim 1, Z is CN, CO-A or CS-A; A is OR ₁ , SR ₂ or N (R ₃ ) R ₄ ; R ₁ , R ₂ and R ₃ are hydrogen; Unsubstituted or from 1 to 5 halogen atoms, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, phenoxy, benzyloxy C ₁ -C ₄ acyloxy, benzoyloxy, hydroxy, nitro, cyano, By C ₁ -C ₄ alkanoyl, benzoyl, carboxy, C ₁ -C ₄ alkoxycarbonyl, benzyloxycarbonyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino or heterocyclic Substituted C ₁ -C ₈ alkyl; C ₃ -C ₆ alkenyl unsubstituted or substituted by 1 to 5 halogen atoms; C ₃ -C ₆ alkynyl; C ₃ -C ₆ cycloalkyl; C ₁ -C ₄ alkanoyl; The phenyl ring is unsubstituted or substituted by halogen, hydroxy, C ₁ -C ₄ alkyl, halogeno-C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, halogeno-C ₁ -C ₂ alkoxy or nitro Phenyl, benzyl or phenethyl substituted three to three times; Or naphthyl, benzoyl or heterocyclic, unsubstituted or substituted one to three times by halogen, C ₁ -C ₂ alkyl, halogenomethyl or nitro in the same or different ways; or R ₄ is hydrogen, C ₁ -C ₆ alkyl, phenyl or benzyl, or R ₃ and R ₄ may combine with the nitrogen atom to which they are attached to form a 5- to 6-membered ring having 1 to 2 heteroatoms O, S and / or N, wherein the rings are unsubstituted or identical Compounds substituted once or twice by halogen, C ₁ -C ₃ alkyl or C ₁ -C ₂ alkoxycarbonyl in different ways. The method of claim 2, n is 0 or 1; Z is CN or CO-A; A is OR ₁ , SR ₂ or N (R ₃ ) R ₄ , wherein R ₁ to R ₄ are compounds as defined in claim 2, The method of claim 3, wherein n is 0 or 1; Z is CN or CO-A; A is OR ₁ or SR ₂ ; In addition R ₁ and R ₂ are hydrogen; C ₁ -C ₆ alkyl unsubstituted or substituted by 1 to 3 halogen atoms, C ₃ -C ₆ cycloalkyl or C ₁ -C ₂ alkoxy; C ₃ -C ₄ alkenyl unsubstituted or substituted by 1 to 3 halogen atoms; C ₃ -C ₄ alkynyl; C ₃ -C ₆ cycloalkyl or phenyl ring unsubstituted or halogen, hydroxyl, C ₁ -C ₄ alkyl, halogeno-C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, halogeno-C _1- C ₂ alkoxy or phenyl, benzyl or phenethyl, substituted once or twice by nitro. Formula (I) comprising reacting a compound of Formula (II) with an aqueous strong base to produce a compound of Formula (Ia) or a salt thereof and further reacting to produce a compound of Formula (I) Method for the preparation of a compound or salt thereof: In the food, X, n and Z are as defined in general formula (I), T is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl. A process for preparing a compound of formula (Ia) or a salt thereof, comprising reacting a compound of formula (II) with an aqueous strong base . Wherein X, n and Z are as defined in formula (I) and T is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl. The method of claim 6 wherein potassium hydroxide solution or sodium hydroxide solution is used as the base. The method of claim 6, wherein the reaction is carried out at 1 to 5 bar, 120 to 150 ° C. 8. a) reacting a compound of formula (II) with an aqueous strong base to produce a compound of formula (Ia) or a salt thereof, b1) converting the compound of general formula (Ia) to the compound of general formula (IIIa) by diazotization with nitrous acid or organic or inorganic nitrite and then to the compound of general formula (III) if necessary; or b2) the following general formula comprising the conversion of a compound of formula (Ia) to a compound of formula (I) followed by diazotization with nitrous acid or organic or inorganic nitrite Process for the preparation of the compound of III). In the food, X, n and Z are as defined in general formula (I), T is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl. The compound of formula (II) is reacted with an aqueous strong base to form a compound of formula (Ia) or a salt thereof, and then directly into the compound of formula (IIIa) by diazotization with nitrous acid or organic or inorganic nitrite without isolation. Process for preparing a compound of formula (IIIa) comprising converting to: In the food, X, n and Z are as defined in general formula (I), T is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl. The process of claim 10, wherein the first reaction step is carried out in potassium hydroxide solution at 1-5 bar, 120-170 ° C. and the diazotization reaction is carried out using sodium nitrite. A process for preparing a compound of formula (I) comprising hydrolyzing a compound of formula (VI) under neutral or basic conditions. In the food, X, n and Z are as defined in general formula (I). Reacting a compound of formula (V) with an SCN-T or SCN salt in a solvent, if desired in the presence of an acid or a base, and then reacting the resulting compound of formula (IV) with an oxidizing agent such as SO ₂ Cl ₂ or Br ₂ or A process for preparing a compound of formula (II) or a salt thereof comprising reacting with H ₂ SO ₄ / bromide or Cl ₂ to produce a compound of formula (II). Wherein X, n, Z and T are as defined in claim 6. The process of claim 13 wherein methyl isothiocyanate is used in the first reaction step and Br ₂ is used in the second reaction step, and the two reaction steps are carried out in anhydrous carboxylic acid without isolation of the compound of general formula (IV). Method carried out. A compound of formula (II): In the food, X is fluorine, n is 0, 1, 2 or 3; T is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl; Z is CN, CO-A or CS-A, A is hydrogen, halogen, OR ₁ , SR ₂ and N (R ₃ ) R ₄ , R ₁ to R ₄ are hydrogen, substituted or unsubstituted open chain saturated or unsaturated hydrocarbon radicals containing up to 8 carbon atoms, substituted or unsubstituted cyclic, saturated containing up to 10 carbon atoms Or unsaturated hydrocarbon radicals, substituted or unsubstituted benzyl or phenethyl, substituted or unsubstituted alkanoyl groups containing up to 8 carbon atoms, substituted or unsubstituted benzo diols or substituted or unsubstituted Heterocyclic radical; or R ₃ and R ₄ are a 5- or 6-membered substituted or unsubstituted heterocyclic radical having 1 to 3 heteroatoms 0, S and / or N, combined with the nitrogen atom to which they are attached; Provided that compounds in which Z is COOH or COOC ₂ H ₅ , n is 0 and T is hydrogen are excluded. The method of claim 15, n is 0 or 1; T is hydrogen or C ₁ -C ₆ alkyl; Z is CN or CO-A, A is OR ₁ , SR ₂ or N (R ₃ ) R ₄ , R ₁ to R ₄ are as defined in claim 2. The method of claim 16, A is OR ₁ or SR ₂ , R ₁ and R ₂ are hydrogen; C ₁ -C ₆ alkyl unsubstituted or substituted by 1 to 3 halogen atoms, C ₃ -C ₆ cycloalkyl or C ₁ -C ₂ alkoxy; C ₃ -C ₄ alkenyl unsubstituted or substituted by 1 to 3 halogen atoms; C ₃ -C ₄ alkynyl: C ₃ -C ₆ cycloalkyl; Or the phenyl ring is unsubstituted or by halogen, hydroxyl, C ₁ -C ₄ alkyl, halogeno-C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, halogeno-C ₁ -C ₂ alkoxy or nitro Compound which is phenyl, benzyl or phenethyl substituted once or twice. The method of claim 17, n is 0; T is hydrogen or methyl; Z is CO-A; A is OR ₁ ; In addition C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or phenyl ring, wherein R ₁ is hydrogen, unsubstituted or substituted by 1 to 3 halogen atoms or C ₁ -C ₂ alkoxy, is unsubstituted or halogen , Phenyl once or twice substituted by hydroxyl, C ₁ -C ₄ alkyl, halogeno-C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, halogeno-C ₁ -C ₂ alkoxy or nitro, Benzyl or phenethyl.