EP1406882A1

EP1406882A1 - Supported condensation reactants and method for the production thereof

Info

Publication number: EP1406882A1
Application number: EP02740723A
Authority: EP
Inventors: Ralf Wischnat; Joachim Rudolph
Original assignee: Bayer Chemicals AG
Current assignee: Bayer Chemicals AG
Priority date: 2001-06-29
Filing date: 2002-06-17
Publication date: 2004-04-14
Also published as: DE10131294A1; JP2005506314A; WO2003002546A1

Abstract

The invention relates to novel supported condensation reactants of formula (I) and to the use thereof as peptide coupling reactants. The invention also relates to a method for the production of said reactants, to the intermediate products required for said method and to a method for the production of said intermediate products.

Description

Supported condensation reagents and process for their preparation

The present invention relates to new supported condensation reagents and their use as peptide coupling reagents, processes for their preparation and intermediates required in this process and processes for their

Manufacturing.

Condensation reagents such as carbodiimides are often used in carrying out chemical reactions in which the components react with the escape of water. With the chemical

Reactions can be, for example, Mitsunobu reactions, amide syntheses or peptide syntheses. The use of carbodiimides as a condensation reagent (= peptide coupling reagent) has long been known, in particular for peptide synthesis. The formation of various active esters for the racemization-free synthesis of

Peptides have been used in the past (Nakajima et al .; Tetrahedron; 44; 3; 1988; 721, Hinterding et al., Chem. Europ. J .; 5; l; 1999; 227).

Since the use of carbodiimides may result in soluble ureas which then have to be removed from the reaction mixture in a complex manner, already supported carbodiimides such as, for example, supported l-ethyl-3- (3-dimethylaminopropyl) carbodiimide have been developed (GM Weinshenker et al. Org. Synth ., Coll. Vol. VI, 1988, 951; M. Desai, et al., Tetrahedron Letters, 48, 1993, 7685). The ureas formed during the reaction thus remain on a solid phase and are therefore simple, e.g. by filtration to remove from the reaction mixture.

Heterocyclic, highly active peptide coupling reagents such as hydroxybenzotriazole (HOBt) and derivatives such as TBTU have also been synthesized on the solid phase. (Chinchilla et al, Tetrahedron Letters, 41, 2000, 2463). Supported peptide coupling reagents represent a further development, which can be reactivated in the course of the reaction. For example, Dendrinos et al., Chem. Commun. 1998, 499, the use of polymer-bound HOBt in the synthesis of amides, it being possible for the polymer-bound HOBt to be used again for the amide synthesis after several washing steps. A disadvantage of this process, however, is the fact that the reactivation can only be used for selected reactions and that carbodiimides in soluble form must be added as further condensing agents. This creates urea during the reaction, which cannot be removed by filtration.

There was therefore a need for improved reactivatable, supported condensation reagents which can be used in particular in peptide synthesis.

Surprisingly, it has now been found supported compounds of the formula (I)

in which

R ^{1 represents} methyl, ethyl, n-propyl, isopropyl, oxide ion, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, p-methylphenylsulfonyl or benzyl optionally substituted by halogen, nitro, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy .

R ^{2 represents} C _r C ₈ alkyl, C _r C ₈ alkenyl, C _r C ₈ alkynyl or phenyl, where the said radicals optionally carry at least one substituent from the series halogen, nitro and C 1 -C 4 -alkyl, for Hydroxy, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, p-methylphenylsulfonyl, for optionally by halogen, nitro, Cι-C ₈ alkyl, C _{j-C4-haloalkyl,} C1-C4 alkylsulfonyl, Cι-C4-alkoxy, C1-C4

Alkoxycarbonyl, C -C4-haloalkoxycarbonyl, C 1 -C4 alkylcarbonyloxy or Cι-C4-haloalkylcarbonyloxy substituted phenyl, for benzyl optionally substituted by halogen, nitro, Ci-Q-alkyl or Cι-C4-alkoxy or for optionally substituted by halogen, -Cι -C4-alkyl or -CC-C4-haloalkyl substituted pyrrolyl, thienyl, naphthyl, or benzothiophenyl,

A represents a divalent radical from the series SO2, CO and CH2,

B represents an atom or a group of atoms,

Shark represents halogen,

X "for chloride, bromide, iodide, hydrogen sulfate, Vz equivalent of sulfate, sulfate, antimony hexachloride (SbCl-g), methanesulfonate (mesylate), trifluoromethane sulfonate (triflate), p-toluenesulfonate (tosylate), tetrafluorobluoroborate, tetrahydrofluoroborate, tetrahydrofluoroborate, tetrahydrofluoroborate, tetrahydrofluoroborate, tetrahydrofluoroborate, tetrahydrofluoroborate, tetrahydrofluoroborate, tetrahydrofluoroborate, tetrahydrofluoroborate, tetrahydrofluoroborate, tetrahydrofluoroborate, tetrafluoroborate,

POL stands for a polymeric carrier.

The new compounds of formula (I) according to the invention are particularly suitable as condensing agents, very particularly for use in peptide synthesis as peptide coupling reagents.

Preferred substituents or preferred ranges of the radicals present in the formulas listed above and below are defined below: R ¹ preferably represents methyl, ethyl, n-propyl, oxide ion, methylsulfonyl, ethylsulfonyl or optionally fluorine and / or chlorine, methyl, ethyl, n- or i-propyl, trifluoromethyl, methoxy, ethoxy or n- or i- propoxy substituted benzyl.

R ² preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl L isobutyl or optionally fluorine and / or chlorine, methyl, ethyl, n- or i-propyl, methoxy, ethoxy or n - or i-propoxy substituted benzyl or phenyl.

A preferably represents SO2, CO or CH2,

B preferably represents a divalent radical from the series NH, N-C2-C4-

Alkyl, O and S

Shark preferably stands for CI or Br

X "preferably stands for bromide, 5 equivalents of sulfate, sulfate, SbCl" g, mesylate, triflate, tosylate, tetrafluoroborate, tetraphenylborate or hexafluorophosphate.

R ¹ particularly preferably represents methyl, ethyl, methylsulfonyl, ethylsulfonyl or benzyl optionally substituted by fluorine and / or chlorine.

R particularly preferably represents methyl, ethyl, n-propyl, n-butyl or optionally substituted by fluorine and / or chlorine, methyl or ethyl

Phenyl.

A particularly preferably represents SO2 or CO,

B particularly preferably represents NH, N -CC-C4-alkyl, preferably N-CH3 or

NC ₂ H ₅ or for O Shark particularly preferably stands for Br

X- particularly preferably represents bromide, ^1A equivalent of sulfate, sulfate or tetrafluoroborate.

R ¹ very particularly preferably represents methyl, ethyl, n-propyl or i-propyl

R ² very particularly preferably represents methyl or ethyl.

A very particularly preferably stands for SO2

B stands especially for NH or OH,

X "very particularly preferably stands for tetrafluoroborate.

According to the invention, preference is given to the compounds of the formula (I) in which there is a combination of the meanings listed above as preferred.

According to the invention, particular preference is given to the compounds of the formula (I) in which there is a combination of the meanings listed above as being particularly preferred.

According to the invention, very particular preference is given to the compounds of the formula (I) in which a combination of those listed above as being particularly preferred

Meanings exist.

The preferred ranges corresponding to the corresponding anions X "apply to the cations. The general definitions or explanations of residues or explanations listed above or in preferred areas can be combined with one another, that is to say also between the respective areas and preferred areas. They apply accordingly to the end products as well as to the preliminary and intermediate products.

The compounds of the formula (I) according to the invention are preferably obtained by binding new intermediates of the formula (II) which are likewise according to the invention

in which

R ² and shark have one of the meanings given above,

A ^{1 represents} a radical from the series SO ₂ R ³ , COR ³ and CH ₂ R ⁴ , where

R ^{3 represents} OH, OC _r C ₄ alkyl or halogen and

R4 stands for OH, SH, CI, Br or I,

obtained on a polymeric support POL-B ¹ and subsequent alkylation, wherein

B ^{1 stands} for a reactive group which reacts with Al in a chemical reaction, preferably for a group from the

Series NH ₂ , NH-C ₁ -C ₄ alkyl, OH, SH, CI and Br.

Preferred intermediates according to the invention of the formula (II) are those in which A ^{1 represents} a radical SO R ³ , where R ^{3 represents} F, CI, Br or I. Especially preferred intermediates of formula (II) are those in which A ^{1 represents} a radical SO ₂ R ³ , where R ^{3 represents} F, CI, Br or I and R ^{2 represents} C _r C ₈ alkyl, C _r C ₈ - Alkenyl, -CC ₈ -alkynyl, benzyl or phenyl, the said radicals optionally carrying at least one substituent from the series halogen, nitro and C ₁ -C -alkyl.

Further preferred intermediates according to the invention of the formula (II) are those in which A ^{1 represents} a COR ³ radical, where R ^{3 represents} OH or O-C 1 -C ₄ -alkyl. Particularly preferred intermediates according to the invention of the formula (II) are those in which A ^{1 represents} a COR ³ radical, where R ^{3 represents} OH or OC ₁ -C ₄ -

Alkyl is and R ^{2 is} C _r C ₈ alkyl, C _r C ₈ alkenyl, C _r C ₈ alkynyl, benzyl or phenyl, the said radicals optionally having at least one substituent from the series halogen, nitro and C 1 -C Wear ₄ alkyl.

Further preferred intermediate products of the formula (II) according to the invention are those in which A ^{1 represents} a radical CH ₂ R ⁴ , where R ^{4 represents} OH, SH, CI, Br or I. Particularly preferred intermediates of the formula (II) according to the invention are those in which A ^{1 is} a CH ₂ R radical, R ^{4 is} OH, SH, CI, Br or I and R ^{2 is} C _r C ₈ alkyl, C _r C ₈ alkenyl, C _r C ₈ alkynyl, benzyl or phenyl, the radicals mentioned optionally carrying at least one substituent from the series halogen, nitro and C ₁ -C ₄ alkyl.

Particularly preferred intermediates according to the invention of the formula (II) are those in which A ^{1 represents} the radical SO ₂ CI. Very particularly preferred intermediates of the formula (II) according to the invention are those in which A ^{1 is} for the

The radical SO ₂ Cl is and R ^{2 is} C _r C ₈ -alkyl, C _r C ₈ -alkenyl, C _r C ₈ -alkynyl, benzyl or phenyl, the said radicals optionally having at least one substituent from the series halogen, nitro and C 1 -C ₄ alkyl wear.

Further, particularly preferred intermediates according to the invention are those in which A ^{1 represents} a radical SO ₂ R ³ , where R ^{3 represents} F, CI, Br or I or those wherein A ^{1 represents} a COR ³ radical, where R ^{3 represents} OH or OC _r C ₄ alkyl, or those in which A ^{1 represents} a CH ₂ R radical, where R ^{4 represents} OH, SH, CI, Br or I is and R ^{2 is} methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or optionally by fluorine and / or chlorine, methyl, ethyl, n- or i-propyl, methoxy, ethoxy or n- or i-propoxy substituted benzyl or phenyl.

The intermediates of the formula (II) according to the invention are preferably obtained from compounds of the formula (III)

in which R ² and shark have one of the meanings given above, prepared by processes known per se (Lateef et al., Rocz. Chem. 46, 1972, 1647; Lee et al., J Heterocycl. Chem. 22, 1985, 1621 ; Erlenmeyer et al., He / v. Chim. Acta 28, 1945, 985; Balli et al., He / v. Chim. Acta; 59; 1976, 155).

For their part, compounds of the formula (III) are preferably obtained by compounds of the formula (IV)

in which

R ^{2 has} one of the meanings given above,

with hydrogen halide in the presence of a diluent and then the hydrogen halide from the compound of the formula (V) initially obtained

wherein

R ² and shark have one of the meanings given above.

The Nerbindungen of formula (IV) are known and / or can be prepared by methods known per se (see for example Schantl et al., Synth. Commun. 28, 1998, 1451-1462).

A preferred process for the preparation of compounds of formula (III) is

Cyclization of compounds of formula (IV) with hydrogen halide in the presence of a diluent.

Certain aprotic organic solvents and any mixtures thereof can be considered as diluents. Examples include: Alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloro, trichloroethane or carbon tetrachloride; Ethers, such as diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether or anisole. It is preferred to use methylene chloride, chloroform, 1,2-dichloroethane, diethyl or tert-butyl methyl ether, particularly preferably methylene chloride.

The cyclization is carried out per mol of a compound of the formula (IV) 2.0 to

10 mol, preferably 2.1 to 7 mol of hydrogen halide and 0.5 to 5 1, preferably 1 to 3 1, of diluent. The cyclization is carried out with the exclusion of moisture. This can be ensured, for example, by using commercially available dry diluents or by using the generally customary drying methods, by continuing to use dry hydrogen halide and / or by using a frozen gas trap and / or a drying tower with a suitable desiccant or a gas scrubbing device such as a Wash bottle with concentrated sulfuric acid, conducts.

The cyclization is advantageously carried out in such a way that the compound of the formula (IV) is preferably initially introduced into the diluent and then the

Initiates hydrogen halide under temperature control and good distribution. The exothermic reaction is generally carried out at a temperature of -30 to + 40 ° C, preferably at -15 to + 30 ° C. It is particularly advantageous to keep the temperature at the introduction of hydrogen halide between 0 and + 10 ° C. and then to react and crystallize at room temperature for up to 15 h. The resulting compound of formula (V) can then be conveniently obtained by a solid-liquid separation method such as filtering off or centrifuging.

To release the compounds of formula (III) from the compounds of

Formula (V) are suitable for weaker acid acceptors. Organic and inorganic bases are suitable for this. These preferably include alkali metal carbonates or bicarbonates, such as sodium, potassium or ammonium carbonate, sodium bicarbonate or potassium bicarbonate, and tertiary amines, such as trimethylamine, triethylamine, tributylamine, N, N-dimethylaniline, N, N-dimethylbenzylamine, Pyridine, N-methylpiperidine, N-methylmo holin, N, N-dimethylamino-pyridine, diazabicyclooctane (DABCO), diazabicyclonones (DBN) or diazabicyclo- undecene. Sodium bicarbonate or potassium bicarbonate are preferred.

The release of the compounds of formula (HI) from the compounds of

Formula (V) can be done in the same without a previous drying step Diluents such as cyclization take place. For this purpose, it is advantageous to wash off with a little diluent when separating the hydrohalide in order to largely remove the excess hydrogen halide. The compounds of the formula (V) are suspended in the diluent (generally 0.8 to 31 per mol of hydrohalide) and the base is then added. An aqueous solution of an inorganic base, such as, for example, sodium bicarbonate solution, is preferably used. The concentration is not critical. It is preferable to use more concentrated to saturated solutions. 1.0 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, of base are used per mole of hydrohalide. The neutralization is generally carried out at a temperature of from -20 to + 30 ° C, preferably at -5 to + 10 ° C.

The compounds of the formula (III) are isolated by the customary methods of organic chemistry. Phase separation is preferably carried out and the organic phase is distilled. You can do one before distillation

Carry out drying with a drying agent such as magnesium or sodium sulfate, calcium chloride, silica gel or molecular sieve.

The preferred intermediates of the formula (II) according to the invention, in which A ^{1 represents} a radical SO ₂ R ³ , where R ^{3 represents} F, CI, Br or I and the particularly preferred intermediates of the formula (II), in which A ^{1 represents} a Radical SO ₂ R ³ , where R ^{3 is} F, CI, Br or I and R ^{2 is} C _r C ₈ alkyl, C _r C ₈ alkenyl, C _r C ₈ alkynyl, benzyl or phenyl, where the radicals mentioned optionally carry at least one substituent from the series halogen, nitro and C ₁ -C ₄ -alkyl are preferably obtained by reacting compounds of the formula (III)

in which R ² and shark have one of the meanings given above, with sulfonating agents. For example, as in Ludwig et al., Collect. Czech. Chem. Commun. 49, 5, 1984, 1182 and Heumann et al., Chem. Ber. 15, 1882, 1118.

Are the compounds of formula (III) to the particularly preferred intermediates of formula (II) according to the invention, wherein A ¹ for the rest

SO2CI, converted by chlorosulfonation, is preferably used as the sulfonating agent thionyl chloride, sulforyl chloride, chlorosulfonic acid or mixtures of the aforementioned reagents. The sulfonating agents are used in excess or in equimolar amounts based on the compounds of the formula (III). It is preferred to work in a diluent such as toluene or dichloroethane. Polar aprotic solvents such as dimethylformamide can also be used as diluents. It is further preferred to use chlorosulfonic acid or thionyl chloride as the diluent. Mixtures of the aforementioned reagents or diluents are also suitable as the reaction medium. The procedure is preferably such that the compound of the formula (III) is reacted with one of the aforementioned reagents at from 20 ° C. to 150 ° C. The product is worked up by crystallization, distillation or chromatography, depending on the physical state of the product.

The particularly preferred intermediates according to the invention of the formula (II), in which A ^{1 represents} the radical SO2CI, are preferably the preferred intermediates according to the invention of the formula (II), in which A ^{1 represents} the radical SO2R ³ , where R ^{3 is} F, Br or I is made. For this purpose, the particularly preferred intermediates of the formula (II) according to the invention are carried out, in which A ^{1 represents} the radical SO2CI, preferably by generally customary processes using anhydrous HBr, HI or HF, as described, for example, in Lukaschewitsch, Dokl. Akad. NaukSSSR 103, 1955, 627 or Chem. Abstr., 1956, 5556.

The conversion of the particularly preferred intermediates according to the invention of the formula (II) in which A ^{1 represents} SO2CI to the preferred inventive Intermediates of formula (II), wherein A ^{1 stands} for Sθ ₂ Br, are further preferably carried out by hydrolysis and subsequent Mitsunobu reaction, as described, for example, in Kataoka et al., Synthesis 4, 1998, 423.

The likewise preferred intermediates of the formula (II) according to the invention, in which A ^{1 represents} a COR ³ radical, where R ^{3 represents} OH or O-C 1 -C ₄ -alkyl and the particularly preferred intermediates according to the invention, in which A ^{1 represents} a COR radical ³ stands for R ³ for OH or OC _r C ₄ alkyl and R ^{2 stands} for C _r C ₈ alkyl, C 1 -C ₈ alkenyl, C 1 -C ₈ alkynyl, benzyl or phenyl, the radicals mentioned optionally at least one substituent from the series

Halogen, nitro and Ci-C-rAlkyl are preferably from 2-bromo-5-halothiazoles, such as in Kaye et al. J Chem. Soc. Perlün Trans. 1, 1981, 2335.

Here, 2-bromo-5-halothiazoles with the help of suitable

Metallating reagents, preferably n-butyllithium, metallized and then reacted with solid CO ₂ . The metalation reaction is preferably carried out under protective gas at temperatures from -80 to -40 ° C. in a diluent, particularly preferably in hydrocarbons, very particularly preferably in hexane. The reaction mixture is after the

Metalation reaction implemented with solid CO ₂ , for this purpose the reaction mixture is preferably added to solid CO ₂ or to a mixture of solid CO ₂ and a diluent, preferably diethyl ether. The reaction product is preferably isolated by extraction.

The likewise preferred intermediates of the formula (II) according to the invention, in which A ^{1 represents} a COR ³ radical, where R ^{3 represents} OH or O-C 1 -C ₄ -alkyl and the particularly preferred intermediates according to the invention, in which A ^{1 represents} a COR radical ³ stands for R ³ for OH or OC _r C ₄ alkyl and R ^{2 stands} for C _r C ₈ alkyl, C - [- C ₈ alkenyl, Ci-Cs-alkynyl, benzyl or phenyl, where the said Residues optionally at least one substituent from the series Halogen, nitro and C1-C4-alkyl can in turn be used by methods known per se in further preferred intermediates according to the invention of the formula (II) in which A ^{1 is} CH ₂ R ⁴ , where R ^{4 is} OH, SH, CI, Br or I stands, are transferred.

For example, the reduction of compounds of the formula (II) in which A ^{1 represents} a radical COOH or COO-Ci-CrAlkyl, preferably as in Lee et al., J Heterocycl. Chem. 22, 1985, 1621-1630. Metal hydrides such as sodium borohydride or lithium aluminum hydride are preferably used as reducing agents. Ethers such as tetrahydrofuran or diethyl ether are preferably used as solvents. Other preferred solvents are polar protic solvents such as alcohols, for example ethyl alcohol. It is preferred to work at temperatures from -10 ° C to 100 ° C. The product is usually worked up by hydrolysis and extraction of the products with organic solvents such as ethyl acetate, dichloromethane or hexane.

Further purification can be carried out by generally customary methods by distillation, crystallization or by chromatography.

The intermediates of the formula (II) according to the invention are converted into supported intermediates of the formula (VI) which are likewise according to the invention,

embedded image in which

R ^{2 represents} Cj-Cs-alkyl, C -Cs-alkenyl, C ^ Cg-alkynyl or phenyl, where the said radicals optionally carry at least one substituent from the series halogen, nitro and C1-C4-alkyl, for hydroxyl, methylsulfonyl , Ethylsulfonyl, phenylsulfonyl, p-methylphenylsulfonyl, for optionally by halogen, nitro, -CC ₈ -alkyl, -C-C ₄ -haloalkyl, C1-C4- alkylsulfonyl, -C-C4-alkoxy, Cι-C4-haloalkoxy, C1-C4-

Alkoxycarbonyl, Cι-C4-haloalkoxycarbonyl, Cι-C4-alkylcarbonyloxy or Cι-C4-haloalkylcarbonyloxy substituted phenyl, for optionally substituted by halogen, nitro, Cι ~ C4-alkyl or Cι-C4-alkoxy or for optionally by halogen, Cι- C4-alkyl or Ci-Q-haloalkyl substituted pyrrolyl, thienyl, naphthyl, or benzothiophenyl,

A represents a divalent radical from the series SO2, CO or CH2,

B represents an atom or a group of atoms,

Shark represents halogen,

POL stands for a polymeric carrier.

Preferred substituents or preferred ranges of the radicals present in the formulas listed above and below are defined below:

R ² preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or optionally fluorine and / or chlorine, methyl, ethyl, n- or i-propyl, methoxy, ethoxy or n- or i-Propoxy substituted benzyl or phenyl.

A preferably represents SO ₂ , CO or CH ₂ ,

B preferably represents a divalent radical from the series NH, N-C1-C4-alkyl, O and S. Hal preferably stands for CI or Br

R ² particularly preferably represents methyl, ethyl, n-propyl, n-butyl or phenyl optionally substituted by fluorine and / or chlorine, methyl or ethyl.

A particularly preferably represents SO2 or CO,

B particularly preferably represents NH, NC 1-C4-alkyl, preferably N-CH3 and NC ₂ H ₅ or O

Shark particularly preferably stands for Br

R ² very particularly preferably represents methyl or ethyl.

A very particularly preferably stands for SO2

B stands especially for NH or OH.

According to the invention, preference is given to the compounds of the formula (VI) in which one

A combination of the meanings listed above as preferred is present.

According to the invention, particular preference is given to the compounds of the formula (VI) in which there is a combination of the meanings listed above as being particularly preferred.

According to the invention, very particular preference is given to the compounds of the formula (VI) in which there is a combination of the meanings listed above as being particularly preferred. The general definitions or explanations of residues or explanations listed above or in preferred areas can be combined with one another, that is to say also between the respective areas and preferred areas.

For the preparation of the supported intermediates of the formula according to the invention

(IV) intermediates of the formula (II) are reacted with functionalized polymeric supports POL-B ¹ , where B ^{1 stands} for a reactive group which reacts with A ¹ in a chemical reaction. B ¹ is preferably a reactive group from the series SH, OH, NH ₂ , HC ^ C ^ AJkyl, CI and Br.

The polymeric supports POL are polymeric supports known to the person skilled in the art, as are usually used in solid-phase synthesis. It is preferably a polymeric carrier from the polystyrene series, preferably crosslinked with divinylbenzene, polyacrylamide and polyethylene glycol. The polymeric carrier POL is preferably made of a polymeric backbone and tethered thereto spacers, which carries as a spacer between the part of the polymeric carrier, wherein the reactive group B ¹ and act the polymeric backbone. Longer hydrocarbon groups are preferably suitable as spacers. Polymeric supports in which the reactive group B ^{1 is} attached to a methylene unit are particularly preferred.

Preferred functionalized polymeric supports POL-B ¹ are polystyrenes crosslinked with divinylbenzene, which carry a group from the series SH, OH, NH ₂ , NH-C _r C ₄ -alkyl, CI and Br as reactive groups. The loading of the polymeric carrier with the reactive groups is preferably 0.1 to 2 mmol / g polymeric carrier. The particle size of the polymeric carrier is preferably 100-500 mesh, particularly preferably 200-400 mesh.

To produce the supported intermediate products of the formula (rV) according to the invention, the procedure is preferably such that the functionalized polymeric support

POL-B ^{1 is presented} in a diluent. The right one Diluent depends on the polymeric carrier. It is advantageous if the polymeric carrier is present in the swollen state. If a preferred polystyrene crosslinked with divinylbenzene is used as the polymeric support, dichloromethane, tetrahydrofuran, dimethylformamide or hydrocarbons are preferably used as diluents. The invention

Intermediates of formula (II) are preferably used in excess, based on the reactive groups of the polymeric carrier. 1.5 to 3 equivalents of intermediates of the formula (II), based on the reactive groups of the polymeric carrier, are particularly preferably used. The reaction is preferably carried out in the presence of an acid scavenger. A base, particularly preferably a base from the series of tert-amines such as triethylamine or pyridine, strong bases such as DBU and metal hydrides such as NaH are particularly preferably used as acid scavengers. Working up takes place according to methods known to the person skilled in the art, such as washing the polymeric carrier and filtration (see, for example, Pop et al., J

Org. Chem. 62, 1997, 2594).

The supported intermediates of formula (VI) according to the invention are converted into the compounds of formula (I) according to the invention by processes known per se. For this purpose, the procedure described below is preferred:

(A) Compounds of the formula (1-1) are obtained

in which

R, 1, r R2 A, B, Hai and POL have one of the meanings given above, and X ^{1- represents} chloride, bromide, iodide, hydrogen sulfate, V∑ equivalent sulfate, sulfate, SbCl-g, methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate,

if compounds of the formula (VI)

in which

R ² A, B, Hai and POL have one of the meanings given above,

with alkylation reagents of formula (VII)

R ^! -X '(VII), in which

R ^{1 has} one of the meanings given above, and

X 'represents chlorine, bromine, iodine, sulfoxy, ¹ A equivalent of sulfate, sulfate, SbCl " ₆ , methylsulfonyloxy, trifluorosulfonyloxy or toluenesulfonyloxy,

in the presence of a diluent.

(B) Compounds of the formula (1-2) are obtained

in which

R ¹ , R ² A, B, Hai and POL have one of the meanings given above, and

X "- stands for tetrafluoroborate, tetraphenylborate or hexafluorophosphate,

if compounds of the formula (VI)

in which

R ² A, B, Hai and POL have one of the meanings given above,

with alkylation reagents of formula (VIII)

in which

R ¹ and X "- have the meaning given above,

in the presence of a diluent, or if compounds of the formula (1-1) are used and the anion X '"is replaced with tetrafluoroborohydroic acid, tetraphenylborohydric acid or hexafluorophosphoric acid or an anion exchanger loaded with these acids for an anion with the abovementioned meaning of X" " ,

The diluents used for the reactions (A) and (B) are preferably dichloromethane, dichloroethane, dimethylformamide or toluene. to Workup is preferably first filtered and then washed with various solvents. Dichloromethane, tetrahydrofuran, dimethylformamide and hydrocarbons are particularly suitable as solvents for this.

The supported compounds of the formula (I) according to the invention can preferably be used as condensation reagents, particularly for the formation of an amide bond between a carboxylic acid or a carboxylic acid derivative and an amine, very particularly preferably in peptide synthesis. The supported compounds according to the invention not only show excellent properties as condensation reagents, but they can also be reactivated by simple measures, so that they can be used as condensation reagents in a new reaction.

The use of the supported compounds of the formula (I) as condensation reagents to form an amide bond is also according to the invention. For this purpose, a carboxylic acid or a carboxylic acid derivative is reacted with an amine in the presence of the supported compounds (I) according to the invention. The reaction is preferably carried out in the presence of an auxiliary base, particularly preferably in the presence of a tertiary amine such as diisopropylamine. The reaction is preferably carried out in the presence of a diluent, particularly preferably in the presence of hydrocarbons such as hexane or

Halogenated hydrocarbons such as dichloromethane. Further preferred diluents are polar aprotic diluents such as dimethylformamide. The reaction is preferably carried out at temperatures from -10 to 60 ° C. For working up, the product is preferably filtered first and the product is isolated by removing the diluent from the filtrate.

The supported compounds according to the invention can be reactivated by simple measures, so that they can be reacted as

Condensation reagents can be used. The reactivation will preferably with halogenating agents, such as in Hantzsch, Chem. Ber. 60, 1927, 2544 or Beyer, Chem. Ber. 89, 1956, 107. Preferred halogenating agents are POCI3, POBr3, SOCI2, PCI3, PCI5, PBr3 or PCI5. The halogenating agents are preferably used in molar ratios in equimolar amounts, based on the compounds of the formula (I), preferably in a diluent such as, for example, toluene or dichloromethane. It is also possible to carry out the reactivation without diluent in one of the halogenating agents mentioned or in mixtures of the halogenating agents mentioned. The temperature of the reactivation reaction is preferably 20 to 120 ° C. For purification, filtration is preferably carried out; the supported compounds of the formula (I) according to the invention are preferably washed with one or more organic solvents, for example dichloromethane or hexane, and then dried. The supported compounds of the formula (I) according to the invention can then be used as condensation reagents in further reactions.

Further details emerge from the examples below, without the invention being restricted thereby.

Examples

Example 1 Synthesis of 2-chloro-4-ethyl-5-chlorosulfonylthiazole

At room temperature, 170 g (758 mmol) of 2-chloro-4-ethylthiazole are introduced into a mixture of 670.79 g (5.758 mol) of chlorosulfonic acid and 685.17 g (5.758 mol) of thionyl chloride so that 30 ° C. is not exceeded. When the addition is complete, the mixture is heated to reflux until the reaction is complete. The mixture is cooled to room temperature and all volatile constituents are distilled off in a water jet vacuum (20 mbar). The residue is taken up in 300 ml of dichloromethane and washed 4 times with 300 ml of water each time. It is dried over MgSO4 and the solvent is distilled off on a rotary evaporator. The residue is fractionally distilled in a high vacuum at 0.9 mbar.

Yield of 2-chloro-4-ethyl-5-chlorosulfonylthiazole: 116.7 g (61.1%) Boiling point: 59 - 64 ° C (0.9 mbar) MS (CI): m / z = 245 (Cl ₃₅ ), 247 (Cl ₃₇ ) 1H-NMR (CDC1 ₃ , 400 MHz): δ = 2.45 (t, 3H, CH ₃ ), 3.65 (q, 2H, CH ₂ ).

Example 2

Synthesis of polymer-bound 2-chloro-4-ethyl-5-aminomethylsulfonylthiazole

25 g (67.50 mmol) aminomethyl resin AM (200-400 mesh, suspension in dichloromethane, content approx. 50%), 2% DVB, 2.7 mmol / g (Novabiochem) is placed in 100 ml dichloromethane and at room temperature 19.94 g (81 mmol) of 2-chloro-4-ethyl-5-chlorosulfonylthiazole were added. At this suspension are at

Room temperature 8.2 g (81.0 mmol) triethylamine added so that 25 ° C does not be crossed, be exceeded, be passed. The mixture is stirred at room temperature for 3 h and the polymer-bound thiazole is suctioned off. For purification, it is washed successively twice with 100 ml of dichloromethane and dimethylformamide and then dried in a drying cabinet at 40 ° C.

Elemental analysis: N: calculated: 5.2%, found 5.0%. CI: calculated: 6.0%, found 6.2%

Claims

Patentansprtiche

1. Compounds of formula (I)

in which

R ^{1 represents} methyl, ethyl, n-propyl, isopropyl, oxide ion, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, p-methylphenylsulfonyl or benzyl which is optionally substituted by halogen, nitro, C1-C4-alkyl or C1-C4-alkoxy,

R ^{2 stands} for C _r C ₈ alkyl, C _r C ₈ alkenyl, C _r C ₈ alkynyl or phenyl, the radicals mentioned optionally being at least one

Bear substituents from the series halogen, nitro and C 1 -C 4 -alkyl, for hydroxyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, p-methylphenylsulfonyl, for optionally by halogen, nitro, C 1 -C ₈ -alkyl, C _r C ₄ -haloalkyl, C _r C ₄ -alkylsulfonyl, C _r C ₄ -alkoxy, Cι-C4-haloalkoxy, Ci-Cψ-alkoxycarbonyl, C1-C4-

Halogenalkoxycarbonyl, -C-C4-alkylcarbonyloxy or C1-C4-haloalkylcarbonyloxy substituted phenyl, for benzyl optionally substituted by halogen, nitro, Cι-C4-alkyl or Cι-C4-alkoxy or for optionally substituted by halogen, Cι-C4-alkyl or Ci C4-haloalkyl substituted pyrrolyl, thienyl, naphthyl, or

Benzothiophenyl stands,

A represents a divalent radical from the series SO2, CO or CH ₂ , B represents an atom or a group of atoms,

Shark represents halogen,

X "for chloride, bromide, iodide, hydrogen sulfate, ^X A equivalent of sulfate,

Sulfate, antimony hexachloride (SbCl-g), methanesulfonate (mesylate), trifluoromethanesulfonate (triflate), p-toluenesulfonate (tosylate), tetrafluoroborate, tetraphenylborate or hexafluorophosphate is and

POL stands for a polymeric carrier.

2. Compounds of formula (I) according to claim 1, wherein

R ¹ for methyl, ethyl, n-propyl, oxide ion, methylsulfonyl, ethylsulfonyl or for optionally by fluorine and / or chlorine, methyl, ethyl, n- or i-propyl, trifluoromethyl, methoxy, ethoxy or n- or i- Propoxy substituted benzyl,

R ² for methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or for optionally by fluorine and / or chlorine, methyl, ethyl, n- or i-propyl, methoxy, ethoxy or n- or i-propoxy-substituted benzyl or phenyl,

A represents SO ₂ , CO or CH ₂ ,

B for a divalent radical from the series NH, N-C1-C4-alkyl, O and

S stands

Shark stands for CI or Br and X- stands for bromide, ^I A equivalent of sulfate, sulfate, SbCk ₆ , mesylate, triflate, tosylate, tetrafluoroborate, tetraphenylborate or hexafluorophosphate.

3. Compounds of formula (I) according to claim 1, wherein POL is a polymeric carrier from the series polystyrene, polyacrylamide and polyethylene glycol.

4. Process for the preparation of compounds of formula (I-1)

in which

R 1, r R> 2 A, B, shark and POL have the meaning given in claim 1, and

X'- represents chloride, bromide, iodide, hydrogen sulfate, ^X A equivalent of sulfate, sulfate, SbC "lg, methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate,

by reacting compounds of formula (VI) according to claim 16 with

Alkylation reagents of formula (VII)

R ^! -X '(VII) in which

R ^{1 has} the meaning given in claim 1 and X 'represents chlorine, bromine, iodine, sulfoxy, Vz equivalent of sulfate, sulfate, SbCl ^_ ₆ , methylsulfonyloxy, trifluorosulfonyloxy or toluenesulfonyloxy,

in the presence of a diluent.

5. Process for the preparation of compounds of formula (1-2)

in which

1

R, R A, B, shark and POL have the meaning given in claim 1 and

X "- stands for tetrafluoroborate, tetraphenylborate or hexafluorophosphate,

by reacting compounds of the formula (VI) according to claim 16 with alkylating reagents of the formula (VIII)

(R ^! ) 3-O ⁺ X "- (VIII), in which

R ¹ and X "- have the meaning given above,

in the presence of a diluent.

6. Process for the preparation of compounds of formula (1-2) by using compounds of formula (II) and exchange of the anion X'- with tetrafluoroborohydric acid, tetraphenylborohydric acid or Hexafluorophosphoric acid or an anion exchanger loaded with these acids for an anion with the meaning of X "- according to claim 5.

7. Use of compounds according to claim (I) as

Condensation reagents, preferably as peptide coupling reagents.

8. Use of compounds according to claim 1 (I) in peptide synthesis

9. Compounds of formula (II)

in which

R ² is C _r C ₈ - alkyl, C _r C ₈ alkenyl, C _r is C ₈ alkynyl or phenyl, where the radicals mentioned may optionally carry at least one substituent selected from halogen, nitro and C1-C4 alkyl, for Hydroxy, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, p-methylphenylsulfonyl, optionally by halogen, nitro, Cι ~

C ₈ alkyl, C _r C4 haloalkyl, C ₁ -C ₄ alkylsulfonyl, C _r C ₄ alkoxy, Cι-C4 haloalkoxy, Cι-C4-alkoxycarbonyl, C1-C4-

Halogenalkoxycarbonyl, -C-C4-alkylcarbonyloxy or C ₁ -C4 ~ haloalkylcarbonyloxy substituted phenyl, optionally substituted by halogen, nitro, C1-C4-alkyl or Cι-C4-alkoxy

Benzyl or pyrrolyl, tbienyl, naphthyl or benzothiophenyl which is optionally substituted by halogen, C 1 -C 4 -alkyl or 0 ^ - C4-haloalkyl, Hal stands for halogen,

R ^{3 represents} OH, OC _r C ₄ alkyl or halogen and

R ^{4 stands} for OH, SH, CI, Br or I.

10. Compounds of formula (II) according to claim 9, wherein A ^{1 is} a radical SO ₂ R ³ , wherein R ^{3 is} F, CI, Br or I.

11. Compounds of formula (II) according to claim 9, wherein A ^{1 is} a radical COR ³ , wherein R ^{3 is} OH or OC _r C ₄ alkyl.

12. Compounds of formula (II) according to claim 9, wherein A ^{1 is} a radical

CH ₂ R ⁴ is where R ^{4 is} OH, SH, CI, Br or I.

13. A process for the preparation of compounds according to claim 10, by chlorosulfonation of compounds of formula (III)

in which R ² and shark have the meaning given in claim 9, and, in the event that R ^{3 is} F, Br or I, subsequent reaction of the resulting product with anhydrous HBr, HI or HF.

14. A process for the preparation of compounds according to claim 11, by reacting compounds of the formula (III)

in which R ^{2 has} the meaning given in Claim 9 and shark stands for Br, by metallization and subsequent reaction with solid CO2.

15. A process for the preparation of compounds according to claim 12, by reduction of compounds according to claim 11.

16. Compounds of the formula (VI)

in which

R ² for -CC ₃ -A Ikyl, Ci-C keny] l, Ci-C », where the radicals mentioned optionally carry at least one substituent from the series halogen, nitro and Cι-C4-alkyl, for hydroxyl, methylsulfonyl, ethylsulfonyl , Phenylsulfonyl, p-methylphenylsulfonyl, for optionally by halogen, nitro, Cj-Cg-AlkyL, C _r C ₄ -haloalkyl, C _r C ₄ -alkylsulfonyl, C _r C ₄ -alkoxy,

C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4

Halogenalkoxycarbonyl, -C-C4-alkylcarbonyloxy or C1-C4-haloalkylcarbonyloxy substituted phenyl, for benzyl optionally substituted by halogen, nitro, C _j -C4-alkyl or Cι-C alkoxy or for optionally substituted by halogen, C1-C4-alkyl or C. _j -

C4-haloalkyl substituted pyrrolyl, thienyl, naphthyl, or benzothiophenyl, A represents a divalent radical from the series SO ₂ , CO and

B represents an atom or a group of atoms,

Shark represents halogen, and

POL stands for a polymeric carrier.

17. Compounds of formula (VI) according to claim 16, wherein

A represents a divalent radical from the series SO ₂ , CO and CH ₂ ,

B for a divalent radical from the series NH, NC ₁ -C ₄ - alkyl, O and

S stands, and

Shark stands for CI or Br.

18. A process for the preparation of compounds of formula (VI) according to claim 16 and 17 by reacting compounds of formula (II) according to claim 9 with polymeric carriers POL-B ¹ , wherein

B ^{1 represents} a reactive group which reacts with A ¹ in a chemical reaction, and

POL stands for a polymeric carrier.

9. The method according to claim 18, characterized in that polymeric carriers POL-B ¹ are used, wherein

B ^{1 is} a reactive group from the series SH, OH, NH ₂ , NH-C ₁ -C ₄ alkyl, CI and Br and

POL stands for a polymeric carrier from the series polystyrene, polyacrylamide and polyethylene glycol.