HK1095582B - Method for producing 4-pentafluoride-sulfanyl-benzoylguanidines - Google Patents

Description

Process for preparing 4-pentafluorosulfanylbenzoylguanidines

The invention relates to a method for producing 4-pentafluorosulfanyl benzoylguanidines of the formula I. The compounds of formula I are NHE1 inhibitors and can be used, for example, for the treatment of cardiovascular disorders.

German application 10222192 describes pentafluorosulfanylbenzoylguanidines as NHE1 inhibitors. However, the processes described therein for the preparation of these compounds have low yields, require reagents and reaction conditions which cause great technical complexity or are not suitable for large-scale preparation.

It has now been found that said disadvantages can be avoided by a novel, highly efficient synthesis starting from commercially available 4-nitrophenyl sulphur pentafluoride.

Accordingly, the present invention relates to a process for the preparation of compounds of formula I and salts thereof

Wherein each meaning is:

r1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, NR10R11, -O_p-(CH₂)_n-(CF₂)_o-CF₃Or- (SO)_m)_q-(CH₂)_r-(CF₂)_s-CF₃；

R10 and R11

Independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or-CH₂-CF₃；

m is 0, 1 or 2;

n, o, p, q, r and s

Independently of one another, 0 or 1;

r2 is hydrogen, - (SO)_h)_z-(CH₂)_k-(CF₂)_l-CF₃Alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

h is 0, 1 or 2;

z is 0 or 1;

k is 0, 1, 2, 3 or 4;

l is 0 or 1;

or

R2 is- (CH)₂)_t-a phenyl group or-O-phenyl group,

which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of: -O_u-(CH₂)_v-CF₃Alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃；

t is 0, 1, 2, 3 or 4;

u is 0 or 1;

v is 0, 1, 2 or 3;

or

R2 is- (CH)₂)_w-heteroaryl radical

Which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of: -O_x-(CH₂)_y-CF₃Alkoxy having 1, 2, 3 or 4 carbon atoms and alkyl having 1, 2, 3 or 4 carbon atoms, -SO₂CH₃；

w is 0, 1, 2, 3 or 4;

x is 0 or 1;

y is 0, 1, 2 or 3;

r3 and R4 are in turn,

independently of one another, hydrogen or F;

as depicted in the flow chart of fig. 1, the method includes

Scheme 1

a) Reducing the 4-nitrophenyl sulphur pentafluoride derivative of formula II to an amine of formula III,

b) halogenating the compound of formula III with a halogenating agent at the ortho position with respect to the amino group to obtain a compound of formula IV,

c) replacement of the halogen substituent in the compound of formula IV with substituent R2 using a suitable nucleophile or organoelement compound (organoelement compound), such as an alkylboron compound, if appropriate with catalysis,

d) replacing the amino function in the compound of formula V with a halogen substituent,

e) replacing the halogen substituent in the compound of formula VI with a nitrile functionality,

f) hydrolyzing the nitrile function in the compound of formula VII to a carboxylic acid,

g) converting a carboxylic acid of formula VIII to an acylguanidine of formula I,

wherein in the compounds of the formulae II, III, IV, V, VI, VII and VIII,

r1 to R4 are as defined for formula I, and

x and Y are each independently of the other F, Cl, Br or I.

In one embodiment, this is preferredA compound of formula I, wherein R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, NR10R11, -O-CH₂-CF₃or-SO_m-(CH₂)_r-CF₃Wherein R10 and R11 are each independently of the other hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or-CH₂-CF₃And wherein m is 0, 1 or 2 and R is 0 or 1, particularly preferred are compounds wherein R1 is hydrogen or methyl. In another embodiment, preference is given to compounds of the formula I in which R2 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or-SO_h-(CH₂)_k-CF₃(where h is 0, 1 or 2 and k is 0 or 1), phenyl or-O-phenyl, which are unsubstituted or substituted as described, particular preference being given to compounds in which R2 is hydrogen or methyl.

In another embodiment, compounds of formula I are preferred wherein R3 and R4 are hydrogen.

The process for the preparation of the compounds of the formula I starts in step a (scheme 1) and the compounds of the formula II are converted into compounds of the formula III by known methods which are in principle useful for the reduction of aromatic nitro compounds to aromatic amines. Such methods are described, for example, in r.c. larock, Comprehensive organic transformations: a Guide to Functional Group Preparations, VCHPublishers, New York, Weinheim, 1999, 821-828 and references cited therein.

Subsequently (step b), the compound of formula III is dissolved in an organic solvent a and reacted with a halogenating agent, e.g. a brominating agent. The reaction temperature in this case is generally from-30 ℃ to +150 ℃, preferably from 0 ℃ to 40 ℃. The reaction time is generally from 10min to 20h, depending on the composition of the mixture and the temperature range selected. The reaction mixture obtained can be worked up as follows: the product is subsequently purified by filtration through a layer of silica gel, washing with organic solvent A, removal of the solvent in vacuo and conventional purification methods such as recrystallization, distillation or chromatography.

For example, 0.1 to 10mol of the compound of the formula II are dissolved in 1000ml of organic solvent A. For example, for 1mol of compound of the formula II to be halogenated, from 0.8 to 1.2 equivalents of halogenating agent are used.

The term "halogenating agent" means, for example, halogen elements, halogen-amine complexes, cyclic and acyclic N-halogenated amides and imides and ureas, for example r.c. larock, Comprehensive organic transformations: a Guide to Functional Group Preparations, VCHPublishes, New York, Weinheim, 1999, 619 + 628 and references cited therein or M.B. Smith and J.March, March's Advanced Organic Chemistry: reactions, Mechanisms, and Structure, Wiley, New York, 2001, 704-707 and references cited therein, such as for example N-bromosuccinimide, N-chlorosuccinimide, H of HBr₂SO₄Solution or 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione, the latter being capable of transferring 2 bromine atoms per molecule. The term "brominating agent" means, for example, elemental bromine, bromine-amine complexes, cyclic and acyclic N-brominated amides and imides and ureas, such as r.c. larock, Comprehensive Organic Transformations: a Guide to Functional groups precursors, VCH Publishers, New York, Weinheim, 1999, 622-: reactions, Mechanisms, and Structure, Wiley, New York, 2001, 704-707 and references cited therein, such as N-bromosuccinimide, HBr in H₂SO₄Solution or 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione, the latter being capable of transferring 2 bromine atoms per molecule.

The term "organic solvent a" preferably means an aprotic solvent, such as, for example, dichloromethane, chloroform, tetrachloromethane, pentane, hexane, heptane, octane, benzene, toluene, xylene, chlorobenzene, 1, 2-dichloroethane, trichloroethylene or acetonitrile.

Any HX formed in the reaction can be captured by an organic or inorganic base.

In step c, the compound of formula IV is subsequently dissolved in an organic solvent B and reacted with a nucleophilic reagentAgent R2^-Or an elemental compound containing substituent R2 to give a compound of formula V. In this case it is possible to add the base A and to add the catalytic metal salt A.

The reaction temperature in this case is generally from-20 ℃ to +150 ℃, preferably from 30 ℃ to 100 ℃. The reaction time is generally from 0.5h to 20h, depending on the composition of the mixture and the temperature range selected. The reaction mixture obtained can be worked up as follows: the product is subsequently purified by filtration through a layer of silica gel, washing with organic solvent B, removal of the solvent in vacuo and subsequent purification by customary purification methods such as recrystallization, chromatography (e.g.silica gel chromatography), distillation or steam distillation.

For example, 0.1 to 10mol of the compound of the formula IV are dissolved in 1000ml of organic solvent B. For example, for 1mol of starting compound of the formula IV, 0.8 to 3 equivalents of the nucleophile R2 are used^-Or an elemental compound comprising substituent R2.

The term "nucleophile R2^-By "is meant a compound produced by deprotonation of compound R2-H with a strong base, such as an alkyl-or aryl-lithium compound, an organomagnesium compound, an alkoxide, or lithium diisopropylamide.

"organoelement compounds comprising a substituent R2" means, for example, organolithium compounds R2-Li, organomagnesium compounds R2-Mg-Hal (Hal ═ Cl, Br, I), organoboron compounds such as R2-B (OH)₂R2-boronic esters, for example

R2-boronic anhydrides, for example

Or an organozinc compound R2-Zn-Z, wherein Z ═ Cl, Br, I.

The term "base A" means those bases which are used as auxiliary bases in cross-coupling reactions and are mentioned, for example, in A.Suzuki et al, chem.Rev.1995, 95, 2457-2483 or M.Lamaire et al, chem.Rev.2002, 102, 1359-1469 or S.P.Stanforth, Tetrahedron 1998, 54, 263-303 and the references cited therein in each case, for example Na₂CO₃、Cs₂CO₃、KOH、NaOH、K₃PO₄N (ethyl)₃。

The term "organic solvent B" means a protic or aprotic solvent, such as diethyl ether, dimethoxyethane, THF, alcohol, water or mixtures thereof. In one embodiment, a mixture with water is preferred.

The term "catalytic metal salt A" means in particular Pd and Ni catalysts, such as those used in Suzuki and Negishi reactions and for example those described in A.Suzuki et al, chem.Rev.1995, 95, 2457-2483 or M.Lamaire et al, chem.Rev.2002, 102, 1359-1469 or S.P.Stanforth, Tetrahedron 1998, 54, 263 or G.C.Fu et al, J.Am.chem.Soc.2001, 123, 10099 or G.C.Fu et al, J.Am.chem.Soc.2002, 124, 13662 and references cited therein in each case, including ligands added, such as Pd (OAc)₂、PdCl₂(dppf) or Pd₂(dba)₃。

In step d, the compound of formula V is subsequently converted to a compound of formula VI by a diazo-halogenation process using a diazo-halogenating agent, for example using a diazo-brominating agent such as those described for other aromatic amines for replacement of the amine functionality with a halogen functionality, see for example m.b. smith and j.march, March's Advanced Organic Chemistry: reactions, mechanics, and Structure, Wiley, New York, 2001, 935-936 or R.C. Larock, Comprehensive Organic Transformations: a Guide to Functional groups precursors, VCH Publishers, New York, Weinheim, 1999, 678-679 and references cited therein, for example, by the Sandmeyer or Gattermann reaction. Methods of m.doyle et al, j.org.chem.1977, 42, 2426 or s.oae et al, fill.chem.soc.jpn.1980, 53, 1065 are preferred.

In step e, the compound of formula VI is reacted with a cyanating agent, for example with the addition of a catalytic metal salt B, in a solvent C. The reaction temperature is generally 20 ℃ to 200 ℃, preferably 80 ℃ to 150 ℃. The reaction time is generally from 1h to 20h, depending on the composition of the mixture and the temperature range selected. The reaction mixture obtained can be filtered off with suction through a layer of silica gel or kieselguhr, and the filtrate can be worked up by extraction with water. After evaporation of the solvent in vacuo, the compound of formula VII is purified by conventional purification methods such as recrystallization, silica gel chromatography, distillation or steam distillation.

For example, 0.1 to 10mol of the compound of the formula VI are dissolved in 1000ml of organic solvent C. For example, 1 to 10 equivalents of cyanating agent are used for 1mol of compound of the formula VI to be reacted.

The term "cyanating agent" is intended to mean, for example, alkali metal cyanide or Zn (CN)₂Alone or in admixture with metallic zinc, preferably in the form of zinc powder.

The term "organic solvent C" preferably means an aprotic polar solvent, such as for example DMF, dimethylacetamide, NMP, DMSO.

The term "catalytic metal salt B" means in particular Pd and Ni catalysts, such as those used in Suzuki reactions and for example A.Suzuki et al, chem.Rev.1995, 95, 2457 2483 or M.Lamaire et al, chem.Rev.2002, 102, 1359-1469 or S.P.Stanforth, Tetrahedron 1998, 54, 263 and those described in the documents cited therein, for example PdCl₂(dppf)、Pd(OAc)₂、Pd₂(dba)₃。

The resulting compound of formula VII is then hydrolyzed in step f to the carboxylic acid of formula VIII, for example in the presence of a base. This can be carried out by methods known to the skilled worker for the hydrolysis of aromatic nitriles, for example r.c. larock, Comprehensive Organic Transformations: a Guide to functional Group Preparations, VCH Publishers, New York, Weinheim, 1999, 1986-: reactions, Mechanisms, and Structure, Wiley, New York, 2001, 1179-.

The carboxylic acid of formula VIII is then subsequently converted to an acylguanidine of formula IX in step g. For this purpose, the carboxylic acid is converted into an activated acid derivative, such as a carbonyl halide, preferably carbonyl chloride; esters, preferably methyl ester, phenyl ester, phenylthio ester, methylthio ester, 2-pyridylthio ester; or a nitrogen heterocycle, preferably 1-imidazolyl. The esters and nitrogen heterocycles are advantageously obtained in a manner known to the skilled worker from the base phosgene which can be prepared in a manner known per se from the base carboxylic acid, for example using thionyl chloride.

In addition to phosgene, it is also possible to prepare other activated acid derivatives in a known manner directly from the basic benzoic acid class, for example by treatment with gaseous HCl in methanol to prepare methyl esters, by treatment with carbonyldiimidazoles to prepare N-acylimidazoles, by treatment with Cl-COOC in an inert solvent in the presence of triethylamine₂H₅Or tosyl chloride treatment, and the use of Dicyclohexylcarbodiimide (DCC) or of O- [ (cyano (ethoxycarbonyl) methylene) amino group]1, 1, 3, 3-tetramethyluronium tetrafluoroborate ("TOTU") to activate benzoic acids. Many suitable methods for preparing activated carboxylic acid derivatives are described in the literature m.b. smith and j.march, March's Advanced Organic Chemistry: reactions, mechanics, and Structure, Wiley, New York, 2001, 506-: a Guide to Functional groups precursors, VCH Publishers, New York, Weinheim, 1999, 1941-1949.

The reaction of the activated carboxylic acid derivative with guanidine is preferably carried out in a manner known per se in an aprotic or aprotic polar organic solvent using a free guanidine base or guanidine chloride in the presence of a base. In this respect, conditions which have proven suitable for the reaction of methyl benzoate-based compounds with guanidine are: methanol, isopropanol or THF, at a reaction temperature of 20 ℃ to the boiling point of these solvents. Most of the reactions of the activated carboxylic acid derivative with the salt-free guanidine are advantageously carried out in aprotic solvents such as THF, dimethoxyethane, dioxane. However, water may also be used as solvent in the reaction with guanidine when a base such as NaOH is used.

If phosgene is used as the carboxylic acid derivative, it is advantageous to add an acid scavenger, for example in the form of excess guanidine, in order to bind the hydrohalic acid.

For the preparation of compounds of formula I wherein R2 is hydrogen, the synthesis may be carried out without performing steps b and c.

For the preparation of compounds in which R2 ═ - (SO)_h)_z-(CH₂)_k-(CF₂)_l-CF₃Wherein h is 1 or 2, as described above, wherein R2 is- (SO)_h)_z-(CH₂)_k-(CF₂)_l-CF₃Wherein h is 0, which is subsequently converted to the desired compound of formula I by known oxidation reactions.

The reaction mixture can be worked up after each of the process steps a), b), c), d), e), f) and g) or after two or more process steps. However, the synthesis of the compounds of the formula I by the process of the invention can also be carried out in two or more successive process steps without isolation of the compounds of the formulae III, IV, V, VI, VII or VIII obtained in each process step, in which case a work-up after each process step is not necessary. Work-up and, if desired, purification of the product is carried out by customary methods such as extraction, pH separation, chromatography or crystallization and customary drying.

The starting compounds of formula II are commercially available or can be prepared by methods described in the literature or known to the skilled person or analogously thereto, for example as described in Bowden, r.d., Comina, p.j., Greenhall, m.p., Kariuki, b.m., Loveday, a., Philip, d.tetrahedron 2000, 56, 5660.The functional groups in the starting compounds may also be present in protected form or in precursor form, which may then be converted into the desired groups in the compounds of formula I prepared by the process of the present invention. Suitable protecting group techniques are known to the skilled person. For example, where R1 is NH₂NH in the compound of formula II₂The groups may be present in protected form by acetyl, trifluoroacetyl or trityl groups, which are then deprotected.

Another aspect of the invention relates to novel compounds of formulas V, VI, VII and VIII.

Accordingly, the present invention relates to 4-pentafluorothio-substituted compounds of the formula X

Wherein each meaning is:

r1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, NR10R11, -O_p-(CH₂)_n-(CF₂)_o-CF₃Or- (SO)_m)_q-(CH₂)_r-(CF₂)_s-CF₃；

R10 and R11

Independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or-CH₂-CF₃；

m is 0, 1 or 2

n, o, p, q, r and s

Independently of one another, 0 or 1;

r6 is- (SO)_h)_z-(CH₂)_k-(CF₂)_l-CF₃Alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by fluorine atoms;

h is 0, 1 or 2;

z is 0 or 1;

k is 0, 1, 2, 3 or 4;

l is 0 or 1;

or

R6 is- (CH)₂)_t-a phenyl group or-O-phenyl group,

which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of: -O_u-(CH₂)_v-CF₃Alkoxy having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms and-SO₂CH₃；

t is 0, 1, 2, 3 or 4;

u is 0 or 1;

v is 0, 1, 2 or 3;

or

R6 is- (CH)₂)_w-heteroaryl radical

Which is unsubstituted or substituted by 1, 2 or 3 radicals selected from the group consisting of: -O_x-(CH₂)_y-CF₃Alkoxy having 1, 2, 3 or 4 carbon atoms and alkyl having 1, 2, 3 or 4 carbon atoms, -SO₂CH₃；

w is 0, 1, 2, 3 or 4;

x is 0 or 1;

y is 0, 1, 2 or 3;

r3 and R4 are in turn,

independently of one another, hydrogen or F;

and salts thereof.

In one embodiment, preference is given to compounds of the formula X in which R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, NR10R11, -O-CH₂-CF₃or-SO_m-(CH₂)_r-CF₃Wherein R10 and R11 are each independently of the other hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or-CH₂-CF₃And wherein m is 0, 1 or 2 and R is 0 or 1, particularly preferred are compounds wherein R1 is hydrogen or methyl. In another embodiment, compounds of formula X are preferred wherein R6 is hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms or-SO_h-(CH₂)_k-CF₃(where h is 0, 1 or 2 and k is 0 or 1), phenyl or-O-phenyl, which are unsubstituted or substituted as described, particular preference being given to compounds in which R6 is hydrogen or methyl, for example hydrogen. In another embodiment, compounds of formula X are preferred wherein R6 is F, Cl, Br or I, especially Br. In another embodiment, compounds of formula X are preferred wherein R3 and R4 are hydrogen.

The invention also relates to 4-pentafluorothio-substituted compounds of formula XI

Wherein each meaning is:

r1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, NR10R11, -O_p-(CH₂)_n-(CF₂)_o-CF₃Or- (SO)_m)_q-(CH₂)_r-(CF₂)_s-CF₃；

R10 and R11

Independently of one another, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or-CH₂-CF₃；

m is 0, 1 or 2

n, o, p, q, r and s

Independently of one another, 0 or 1;

r2 is hydrogen, F, Cl, Br, I, - (SO)_h)_z-(CH₂)_k-(CF₂)_l-CF₃Or an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms;

h is 0, 1 or 2;

z is 0 or 1;

k is 0, 1, 2, 3 or 4;

l is 0 or 1;

r3 and R4 are in turn,

independently of one another, hydrogen or F;

r7 is CN;

and salts thereof.

In one embodiment, preference is given to compounds of the formula XI in which R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, methoxy, ethoxy, NR10R11, -O-CH₂-CF₃or-SO_m-(CH₂)_r-CF₃Wherein R10 and R11 are each independently of the other hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or-CH₂-CF₃And wherein m is 0, 1 or 2 and R is 0 or 1, particularly preferred are compounds wherein R1 is hydrogen or methyl. In another embodiment, preference is given to compounds of formula XI wherein R2 is hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms or-SO_h-(CH₂)_k-CF₃Wherein h is 0, 1 or 2, k is 0 or 1, particularly preferably wherein R2 is hydrogen or methyl, e.g. hydrogenationA compound (I) is provided. In another embodiment, preference is given to compounds of formula XI in which R2 is F, Cl, Br or I, especially Br.

In another embodiment, preference is given to compounds of formula XI wherein R3 and R4 are hydrogen.

If the substituents R1, R2, R3, R4 and R6 contain one or more asymmetric centers, they may, independently of one another, have the S or R configuration. The compounds may be present as optical isomers, diastereomers, racemates or as mixtures thereof in all ratios.

The present invention includes all tautomeric forms of the compounds of formula I.

The alkyl group may be linear or branched. This also applies when they carry substituents or occur as substituents of other radicals, for example in fluoroalkyl radicals or alkoxy radicals. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl (═ 1-methylethyl), n-butyl, isobutyl (═ 2-methylpropyl), sec-butyl (═ 1-methylpropyl), tert-butyl (═ 1, 1-dimethylethyl), n-pentyl, isopentyl, tert-pentyl, neopentyl and hexyl. Preferred alkyl groups are methyl, ethyl, n-propyl and isopropyl. One or more, for example 1, 2, 3, 4 or 5, hydrogen atoms in the alkyl group may be replaced by fluorine atoms. Examples of such fluoroalkyl groups are trifluoromethyl, 2, 2, 2-trifluoroethyl and pentafluoroethyl. The substituted alkyl group may be substituted at any position.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. One or more, for example 1, 2, 3 or 4, hydrogen atoms in the cycloalkyl group may be replaced by fluorine atoms. Substituted cycloalkyl groups may be substituted at any position.

The phenyl group may be unsubstituted or substituted once or more than once, for example once, twice or three times, by identical or different radicals. If the phenyl group is substituted, it preferably has one or two identical or different substituents. The same applies to substituted phenyl groups in phenylalkyl or phenoxy groups and the like. The substituents in the monosubstituted phenyl radicals may be in the 2-, 3-or 4-position. The disubstituted phenyl groups may be substituted in the 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5-position. The substituents in the trisubstituted phenyl group may be in the 2, 3, 4-position, 2, 3, 5-position, 2, 4, 6-position, 2, 3, 6-position or 3, 4, 5-position. Heteroaryl is an aromatic ring compound in which one or more ring atoms is an oxygen atom, a sulfur atom, or a nitrogen atom, for example 1, 2, or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, or a combination of different heteroatoms. Heteroaryl groups may be attached through all positions, such as the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position. Heteroaryl groups may be unsubstituted or substituted one or more times, for example one, two or three times, by the same or different radicals. The same applies to heteroaryl groups in the radical of heteroarylalkyl and the like. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and cinnolinyl.

Heteroaryl is in particular 2-or 3-thienyl, 2-or 3-furyl, 1-, 2-or 3-pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 1, 2, 3-triazol-1-, -4-or-5-yl, 1, 2, 4-triazol-1-, -3-or-5-yl, 1-or 5-tetrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 1, 2, 3-oxadiazol-4-or-5-yl, 1, 2, 4-oxadiazol-3-or-5-yl, 2, 3-oxadiazol-or-5-yl, 1, 3, 4-oxadiazol-2-or-5-yl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 1, 3, 4-thiadiazol-2-or-5-yl, 1, 2, 4-thiadiazol-3-or-5-yl, 1, 2, 3-thiadiazol-4-or-5-yl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 1-, 2-, 4-or 5-benzimidazolyl, pyridyl, pyrazinyl, pyridazin, 1-, 3-, 4-, 5-, 6-or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7-or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7-or 8-phthalazinyl. Also included are the corresponding N-oxides of these compounds, i.e., for example, 1-oxo-2-, 3-or 4-pyridyl.

Particularly preferred heteroaromatic radicals are 2-or 3-thienyl, 2-or 3-furyl, 1-, 2-or 3-pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 3-or 4-pyridyl, 2-or 3-pyrazinyl, 2-, 4-, 5-or 6-pyrimidinyl and 3-or 4-pyridazinyl.

The compounds of formula I may be isolated in the form of salts. Salts are obtained by reaction with acids or bases using conventional methods. Examples of suitable acid addition salts in this connection are halides, especially the hydrochloride, hydrobromide, lactate, sulphate, citrate, tartrate, acetate, phosphate, methanesulphonate, benzenesulphonate, p-toluenesulphonate, adipate, fumarate, gluconate, glutamate, glycerophosphate, maleate, benzoate, oxalate, pamoate and trifluoroacetate salts, with pharmaceutically acceptable salts being preferred in the case of the preparation of the active ingredient. If the compounds contain acidic groups, they can form salts with bases, for example alkali metal salts, preferably sodium or potassium salts, or ammonium salts, for example salts with ammonia or organic amines or amino acids. They may also be in the form of zwitterions.

List of abbreviations:

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

dba dibenzylidene acetone

OAc acetate

M.p. melting Point

MTB Tert-butyl methyl Ether

NMP N-methyl-2-pyrrolidone

dppf 1, 1' -bis- (diphenylphosphino) -ferrocene

THF tetrahydrofuran

Experimental part

Example 1:

a) 4-aminophenyl sulfur pentafluoride

A solution of tin (II) chloride (1465g, 7.73mol) in concentrated (32%) aqueous HCl was heated to 80 ℃ with stirring and then 4-nitrophenyl sulphur pentafluoride (584g, 2.344mol) was introduced in 8 portions over 1h under ice cooling. During this time, the internal temperature was maintained below 100 ℃. Subsequently, the mixture was stirred at an internal temperature of 85 ℃ for 1.5h and then cooled to 45 ℃ over another 1 h. A mixture of ice (12kg), NaOH (2kg) and dichloromethane (1.5L) was prepared and added to the reaction mixture with vigorous stirring. Separating the phases, extracting the aqueous phase with dichloromethane 3 times, 1L each time, combining the organic phases, and adding Na₂SO₄Dried and evaporated in vacuo. 510g (99%) of 4-aminophenylsulfur pentafluoride are obtained as yellowish crystalline powder, m.p.63-65 ℃ (Bowden, R.D., Comina, P.J., Greenhall, M.P., Kariuki, B.M., Loveday, A., Philip, D.tetrahedron 2000, 56, 3399: 57-59 ℃).

¹H-NMR 400 MHz，CDCl₃：δ＝3.99(bs，2H)，6.61(d，J＝9Hz，2H)，7.52(d，J＝9Hz，2H)ppm。

b) 4-amino-3-bromophenyl-sulfur pentafluoride

4-Aminophenylsulfur pentafluoride (510g, 2.327mol) was dissolved in methylene chloride (7L), the solution was cooled to 5 ℃ and 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione (326g, 1.14mol) was introduced in several portions under ice-cooling while stirring, so that the internal temperature was maintained at 3 to 8 ℃ (about 1 h). The mixture was then stirred and warmed to room temperature for 1h without external cooling. The mixture was filtered through a bed of silica gel (volume about 1L), washed with dichloromethane (5.5L) and the filtrate was evaporated in vacuo. About 700g of a red-brown crystalline substance was obtained, which was dissolved in n-heptane (600ml) at 60 ℃ and then crystallized in a refrigerator at 4 ℃. Suction filtration gave 590g (85%) of 4-amino-3-bromophenyl-sulfur pentafluoride as brownish crystals m.p.59-59.5 ℃.

¹H-NMR 400 MHz，CDCl₃：δ＝4.45(bs，2H)，6.72(d，J＝9Hz，1H)，7.49(dd，J1＝9Hz，J2＝2.5Hz，1H)7.81(d，J＝2.5Hz，1H)ppm。

C₆H₅BrF₅NS (298.07): calcd for C24.18, H1.69, N4.70; found C24.39, H1.45, N4.77.

c) 4-amino-3-methylphenyl sulfur pentafluoride

Mixing Cs₂CO₃A mixture of (794g, 2.7mol), dimethoxyethane (2L), water (300ml) and trimethylboroxocyclohexene (boroxine) (50% in THF, 225g, 0.9mol) was heated to 70 deg.C and PdCl was added₂(dppf)×CH₂Cl₂(37g, 45mmol), a solution of 4-amino-3-bromophenyl sulfur pentafluoride (270g, 0.9mol) in dimethoxyethane (400ml) was added dropwise over 2h while the reaction mixture was heated to reflux. It was then heated under reflux for a further 3h, then cooled to room temperature and treated with MTB etherDiluted (500ml), filtered through a column of silica gel (14X 7cm, 70-200 μm) and washed with MTB ether (2500 ml). The filtrate was evaporated in vacuo. 490g of a black semicrystalline material are obtained which are subjected to steam distillation. A total of 5.5L of condensate was collected, from which crystals of product were isolated. The condensate was extracted 3 times with MTB ether, the organic phases were combined and Na was added₂SO₄Dried and evaporated in vacuo. 4-amino-3-methylphenyl-pentafluoride (181g, 76%) was obtained as colorless crystals at m.p.65-66 ℃.

¹H-NMR 400 MHz，CDCl₃：δ＝2.18(s，3H)，3.92(bs，2H)，6.60(d，J＝8.5Hz，1H)，7.40(dd，J₁＝8.5Hz，J₂＝2.5Hz，1H)，7.43(d，J＝2.5Hz，1H)ppm

C₇H₈F₅NS (233.20): calcd for C36.05, H3.46, N6.01; found C36.43H 3.30N 6.09.

d) 4-bromo-3-methylphenyl sulfur pentafluoride

Tert-butyl nitrite (90% pure, 37ml, 280mmol) was reacted with CuBr₂A mixture (35.8g, 160mmol) in acetonitrile (260ml) was cooled to 5 ℃ and a solution of 4-amino-3-methylphenyl sulfur pentafluoride (30.9g, 132.5mmol) in MTB ether (140ml) was added dropwise at 5-8 ℃ over 1h while stirring and cooling with ice. After about 2min nitrogen evolution began. The mixture was then allowed to warm to room temperature over 1h with stirring, and ice (250g), 26% NH were added₃A mixture of aqueous solution (50ml) and MTB ether (250ml) was stirred for 10 min. The phases were separated, the aqueous phase was extracted 3 times with MTB ether (150ml each), the organic phases were combined and shaken once with 400ml of water. With Na₂SO₄The organic phase was dried and evaporated to give 39g of 4-bromo-3-methylphenylsulfpentafluoride as a red-brown oil¹H-NMR contaminated with 8 mol% of 4, 5-dibromo-3-methylphenyl sulfur pentafluoride, butWas used without further purification. The yield was 89% based on 90% purity. For combustion analysis, the samples were purified by silica gel chromatography (35-70 μm, heptane).

¹H-NMR 400 MHz，CDCl₃：δ＝2.47(s，3H)，7.43(dd，J₁＝9Hz，J₂3Hz, 1H), 7.62(m, 2H) ppm. Signal of 4, 5-dibromo-3-methylphenyl sulfur pentafluoride (contaminant): 2.56(s, 3H), 7.56(d, J ═ 2.5Hz, 1H), 7.85(d, J ═ 2.5Hz, 1H).

C₇H₆BrF₅S (297.09): calcd for C28.30, H2.04; found C28.42, H1.78.

e) 4-cyano-3-methylphenyl sulfur pentafluoride

4-bromo-3-methylphenylsulfpentafluoride (136.4g, 80% purity, 0.367mol), Zn (CN) under stirring and nitrogen blanketing₂A mixture of (72.8g, 0.62mol) and Zn powder (7.2g, 0.11mol) in dimethylacetamide (900ml) and water (40ml) was heated to 125 ℃ and PdCl was added₂(dppf)×CH₂Cl₂(32.7g, 40 mmol). After stirring at 125 ℃ for 1 hour, PdCl was added again₂(dppf)×CH₂Cl₂(16.3g, 20mmol) and Zn powder (3.6g, 55mmol), and stirring was continued at 125 ℃ for 2 h. The mixture was then cooled to room temperature, diluted with N-heptane (400ml), and 5N NH was added₄Aqueous Cl (250ml) and water (450ml) with vigorous stirring for 15 min. The mixture was filtered with suction through a layer of celite, the phases were separated and the aqueous phase was extracted 2 times with n-heptane (200 ml). The combined organic phases were shaken with water (450ml) and MgSO₄Dried and evaporated in vacuo. The resulting black residue was dissolved in 200ml of n-heptane, filtered and evaporated again in vacuo. 78g of a dark brown liquid are obtained which is purified by column chromatography on silica gel (7X 55cm, 60-200. mu.m, n-heptane/dichloromethane 4:1 to 3: 2). The first fraction obtained was 6.5g4Bromo-3-methylphenyl sulfur pentafluoride (precursor) as a yellowish liquid, then 71.1g (80%) of 4-cyano-3-methylphenyl sulfur pentafluoride as a pale yellow oil.

¹H-NMR 400 MHz，CDCl₃：δ＝2.65(s，3H)，7.71(m，3H)ppm。

f) 2-methyl-4-pentafluorosulfanylbenzoic acid

A mixture of 4-cyano-3-methylphenyl-sulfur pentafluoride (41.2g, 169.4mmol), NaOH (20.4g, 510mmol) and water (60ml) in ethylene glycol (160ml) was heated to 130 ℃ and stirred at this temperature for 4 h. It was then cooled to room temperature, diluted with MTB ether (150ml) and water (250ml) and the mixture was filtered with suction. The filtrate phases were separated, the aqueous phase was acidified with concentrated aqueous HCl and the precipitated solid was filtered off with suction. 41.1g (93%) 2-methyl-4-pentafluorosulfanylbenzoic acid are obtained as colorless crystals m.p.138-139 ℃.

¹H-NMR 400 MHz，DMSO-d₆：δ＝2.60(s，3H)，7.81(dd，J₁＝8.5Hz，J₂＝2Hz，1H)，7.89(d，J＝2Hz，1H)，7.97(d，J＝8.5Hz，1H)，13.43(bs，1H)ppm。

C₈H₇F₅O₂S (262.20): calcd for C36.65, H2.69; found C36.85, H2.59.

g) 2-methyl-4-pentafluorosulfanylbenzoylguanidine

2-methyl-4-pentafluorosulfanylbenzoic acid (77.5g, 295mmol) was suspended in toluene (300ml), thionyl chloride (36ml, 0.5mol) and 5 drops of DMF were added and the mixture was heated at reflux for 2h with stirring. The filtrate was then filtered off with suction, evaporated in vacuo, and the residue taken up 2 times in toluene (100 ml each) and evaporated in vacuo each time. 78.8g of the acid chloride were obtained as a light brown liquid and used further without purification.

Guanidine hydrochloride (172g, 1.8mol) was added to a solution of NaOH (84g, 2.1mol) in water (600ml) and the mixture was cooled to-3 ℃. Then, a solution of the crude acid chloride in dichloromethane (600ml) was added dropwise over 1h while stirring and ice-cooling. The mixture is stirred at room temperature for a further 30min, and the precipitated solid is then filtered off with suction, washed with dichloromethane and dried in vacuo at room temperature. 74.3g (87%) of 2-methyl-4-pentafluorosulfanylbenzoylguanidine are obtained as beige-coloured crystals m.p.183-183.5 ℃.

¹H-NMR 400 MHz，CD₃OD：δ＝2.51(s，3H)，4.84(bs，5H)，7.62(m，2H)，7.65(s，1H)ppm。

C₉H₁₀F₅N₃OS (303.26): calcd for C35.65, H3.32, N13.86; found C35.69, H3.18, N14.04.

Claims (4)

1. A process for the preparation of a compound of formula I,

wherein each meaning is:

r1 is hydrogen;

r2 is alkyl having 1, 2, 3 or 4 carbon atoms;

r3 and R4 are independently from each other hydrogen or F;

the method comprises

a) Reducing the 4-nitrophenyl sulphur pentafluoride derivative of formula II to an amine of formula III,

b) halogenating the compound of formula III with a halogenating agent at the ortho position with respect to the amino group to obtain a compound of formula IV,

c) replacing the halogen substituent in the compound of formula IV with substituent R2 using an organoelement compound comprising substituent R2, wherein the organoelement compound comprising substituent R2 refers to organolithium compound R2-Li, organomagnesium compound R2-Mg-Hal, organoboron compound or organozinc compound;

d) replacing the amino function in the compound of formula V with a halogen substituent,

e) replacing the halogen substituent in the compound of formula VI with a nitrile functionality,

f) hydrolyzing the nitrile function in the compound of formula VII to a carboxylic acid,

g) converting a carboxylic acid of formula VIII to an acylguanidine of formula I,

wherein in the compounds of the formulae II, III, IV, V, VI, VII and VIII,

r1 to R4 are as defined for formula I, and

x and Y are each independently of the other F, Cl, Br or I,

optionally converting the obtained compound of formula I into a salt thereof.

2. The method of claim 1, wherein the organoelement compound comprising substituent R2 is an alkyl boron compound.

3. The process according to claim 1, wherein steps a), b), c), d), e), f) and g) are carried out continuously or discontinuously, independently of one another.

4. The method of claim 1, wherein step c) is carried out catalytically.