EA002603B1 - Method and reagents for the quantification of solid-phase reactions using fluorine nmr - Google Patents

Abstract

1. A method of quantitating a solid-phase reaction comprising: (a) reacting a solid-phase reaction component or a fluorine-containing solid-phase reaction component with a reactant or fluorine-containing reactant to form a fluorine-containing solid-phase reaction product; (b) obtaining a <19>F NMR spectrum of the fluorine-containing solid-phase reaction product; and (c) comparing the integral corresponding to the fluorine-containing solid-phase reaction product <19>F resonance to the integral corresponding to a standard <19>F resonance. 2. The method according to Claim 1 wherein the <19>F NMR spectra are obtained using magic angle spinning. 3. The method according to Claim 1 wherein the internal standard is a fluorine-containing solid-phase reaction component of the formula wherein is a solid support optionally containing one or more fluorine atoms; L is absent or a linking group optionally containing one or more fluorine atoms, provided that at least one of the components selected from solid support and the linking group contains at least one fluorine atom; and B is a functional group suitable for reaction with a reactant to form a fluorine-containing solid-phase reaction product. 4. The method according to Claim 3 wherein the solid support contains one or more fluorine atoms. 5. The method according to Claim 3 wherein is a solid support; L is a group of formula A is absent or is selected from -C(O)-, -YC(O)-, -SO2-, -NR<7>SO2-, -CHR<7>-, -CHR<7>Y- and -CHR<7>YC(O)(CH2)m-; or when B is halogen, NHP, OW or SO2Z; D is CH or N; P is H or an amine protecting group; W is H, NHP, NPR<9>, NC(O)Cl, C(O)R<9>, C(O)NR<10>R<11>, C(O)OR<9>, SO2R<9> or C(O)-imidazol-1-yl; Y is -O- or-NR<8>-; Z is Cl, OH, ORa or NR<9>R<12>; R<1> is F, or when one of R<16>, R<17>, R<18> and R<19> is F, R<1> is H, alkyl, alkoxy, halogen, CN or NO2; R<2>, R<3> and R<4> are independently H, alkyl, alkoxy, halogen, CN or NO2, or one of R<2>, R and R<4>, taken together with one of R<5> and R<6> and the carbon atoms to which they are attached, define a group of formula R<5> and R<6> are independently -H, alkyl, phenyl or phenyl substituted with one or more substituents selected from alkyl, alkoxy, halogen, nitrile and -NO2; R<7> and R<8> are independently H or alkyl comprising 1 to 4 carbon atoms; R<9> and R<13> are independently aliphatic or aromatic; R<10> and R<11> are independently H, aliphatic or aromatic; R<12> is -CH2R<13>; R<14>, R<15>, R<16>, R<17>, R<18>, R<19>, R<20>, R<21>, R<22> and R<23> are independently selected from H, alkyl, alkoxy, halogen, -CN and -NO2; m is 0 or 1; n is 1-6; and p is 0, 1 or 2. 6. The method according to Claim 5 wherein R<1>, R<2>, R<3> and R<4> are F; and one of R<5> and R<6> is H and the other of R<5> and R<6> is H or 2,4-dimethoxyphenyl. 7. The method according to Claim 6 wherein B is F, OW or SO2Z. 8. The method according to Claim 7 wherein A is phenylene, -C(O)-, -YC(O)-, -SO2-, -NR<7>SO2- or -CHR<7>O-. 9. The method according to Claim 5 wherein the fluorine-containing solid-phase reaction component is selected from 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1%-divinylbenzene) resin, 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl-polystyrene resin, 2,3,5,6-tetrafluorobenzamidomethyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorobenzamidomethyl-4-sulfonylchloride-polystyrene resin, 4-hydroxy-2,3,5,6-tetrafluorobenzoyloxymethyl-polystyrene resin, 2,3,5,6-tetrafluorobenzoyloxymethyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorobenzoyloxymethyl-4-sulfonylchloride-polystyrene resin, 4-hydroxy-2,3,5,6-pentafluorobenzoyl-polystyrene resin, 2,3,5,6-tetrafluorobenzoyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorobenzoyl-4-sulfonylchloride-polystyrene resin, 4-hydroxy-2,3,5,6-tetrafluorophenylsulfonamidomethyl-polystyrene resin, 2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonylchloride-polystyrene resin, N-(4-hydroxy-2,3,5,6-tetrafluorobenzoyl)-piperidinomethyl-polystyrene resin, N-(2,3,5,6-tetrafluorobenzoyl-4-sulfonic acid)-piperidinomethyl-polystyrene resin, N-(2,3,5,6-tetrafluorobenzoyl-4-sulfonyl chloride)-piperidinomethyl-4-polystyrene resin, N-(4-hydroxy-2,3 ,5 ,6-tetrafluorophenylsulfonyl)-piperidinomethyl-polystyrene resin, N-((2,3,5,6-tetrafluorophenyl-4-sulfonic acid)sulfonyl)-piperidinomethyl-polystyrene resin, N-((2,3,5,6-tetrafluorophenyl-4-sulfonylchloride)sulfonyl)-piperidinomethyl-polystyrene resin, 4-hydroxy-2,3,5,6-tetrafluorophenyl-polystyrene resin, 2,3,5,6-tetrafluorophenyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorophenyl-4-sulfonylchloride polystyrene resin, 4-hydroxy-2,3,5,6-tetrafluorophenylsulfonyl-polystyrene resin, 2,3,5,6-tetrafluorophenylsulfonyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorophenylsulfonyl-4-sulfonylchloride-polystyrene resin. 10. The method according to Claim 5 wherein the fluorine-containing solid-phase reaction component is selected from 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-(2',4'-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetra-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl-polystyrene resin, 2,3,5,6-tetrafluorobenzamidomethyl-4-sulfonic acid-polystyrene resin, 2,3,5,6-tetrafluorobenzamidomethyl-4-sulfonylchloride-polystyrene resin, 4-hydroxy-2,3,5,6-pentafluorobenzoyl-polystyrene resin, 2,3,5,6-tetrafluorobenzoyl-4-(sulfonic acid)-polystyrene resin, 2,3,5,6-tetrafluorobenzoyl-4-sulfonylchloride-polystyrene resin, 4-hydroxy-2,3,5,6-tetrafluorophenylsulfonamidomethyl-polystyrene resin, 2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-(sulfonic acid)-polystyrene resin and 2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonylchloride-polystyrene resin. 11. The method according to Claim 5 wherein the fluorine-containing solid-phase reaction component is 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl-polystyrene resin. 12. The method according to Claim 1 wherein the solid-phase reaction component is chloromethylated polystyrene resin and the fluorine-containing reactant is 4-fluorophenol. 13. A fluorine-containing solid-phase reaction component of formula wherein is a solid support containing one or more fluorine atoms; LG is absent or a linking group wherein LG is optionally substituted by one or more fluorine atoms; and B is a functional group suitable for reaction with a reactant to form a fluorine-containing solid-phase reaction product. 14. The fluorine-containing solid-phase reaction component according to Claim 13 which is prepared by polymerizing a mixture comprising at least one fluorine-containing monomer. 15. The fluorine-containing solid-phase reaction component according to Claim 14 wherein the fluorine-containing monomer is 4-fluorostyrene. 16. The fluorine-containing solid-phase reaction component according to Claim 14 which is prepared by polymerizing a mixture of 4-fluorostyrene, 1,4-divinylbenzene and 4-vinylbenzylchloride.

Description

Technical Field of the Invention

This invention relates to the use of ¹⁹ P NMR for the control and quantification of reactions in the solid phase (or solid-phase reactions) and to fluorine-containing solid-phase reagents useful for such application.

BACKGROUND OF THE INVENTION

Solid phase synthesis methods in which the reagent is immobilized on a polymer material that is inert with respect to the reagents and the reaction conditions used, and is also insoluble in the medium used, are an important synthesis tool for the preparation of amides and peptides, as well as for the conversion of various functional groups . A brief description of many techniques or methods for synthesizing peptides in the solid phase can be found in TM publications. 81eg \\ <1st APB TB. Woopd, 8o11b-ryake Reybe 8up! Yek1k, 2 ' ¹ Eb., P1egse Syetua1 So. (Syssado, Gb, 1984); 1. Ms1ep1yyeg. Nogtop1 Рgo! Ёшк апб Рерийбек, уо1. 2, p. 46, Asabetyu Rgekk (No. \ ν Wogk), 1973; and E. A! yeyop apb K.S. 8yerragb, 8o11bryake Rerybe 8up1yek1k: And Rtasyys1 Arrtoasy, 1KB Rgek a! OhGogb Ishuegkyu Rgekk (OhGogb, 1989). Regarding the use of the reaction technique in the solid phase in the preparation of non-peptide molecules, see the publication Le / Po 'S. S., Ace. Siet. Kek., 1978, 11, 327 - 333. The use of polymer reagents in transformations of functional groups is described in the publications of A. Ake1ay apb B.S. 8yetgtd1op, Arriesayop OG Ripsyopai / eb Ro1utegk t Ogdashs 8up! Yek1k, Syet. Keu., 1981, 81, 557-587 and No.T. Rothb apb E.S. Vlokkeu, Röluteg 8irroyeb Keadep! K, Röluteg kirroyeb Ca! A1uk1k, apb Röluteg 8irroyeb SoirNpd Keasyopk, r Prérégaye SjetIyu iktd 8irroyeb Keadep! K, Rögge 21, k2. The use of polymer reagents in oxidative reactions is described in TMD publications. Rhesye! e! A1., 1. Ogd. C1et., 1978, 43, 2618, and S. Sachet e! A1., 1. At. Siet. 8os., 1976, 98, 6737. The use of polymer reagents in halogenation reactions is presented in the publications of B. MD. Mercy! e! A1., 1. Masgoto1. 8s1. C1et., 1977, A-11, 507 and B.S. 8yegppd! Op e! A1., Eig. Ро1ут. 1., 1977, 13, 73. The use of polymer reagents in epoxidation reactions is described in B.M. Rhesye! e! A1., Masgoto1esi1ek, 1975, 8, 130 and S.K. Nutcop e! A1., 1. Siet. 8os. Siet. Sottip., 1974, 1009. The use of polymer reagents in acylation reactions is disclosed in the publications of M.V. 811at1sh e! A1., Those !. ^ her., 1973, 1627 and M.V. 811at1sh e! A1., 1. Siet. 8os. Siet. Sottip., 1974, 619. The use of polymer reagents in Wittig reactions is described in publication 8.U. MsK1p1eu e! A1., 1. Siet. 8os. Siet. Sottip., 1972, 134.

Polymeric reagents have also found wide application in combinatorial synthesis and for obtaining combinatorial libraries (funds).

See publications by R. Ва1кеп1ю111 е! A1., Update. C1. 1p !. Fuck Epd. 1, 1996, 35, 2288 - 2337 and KA. Tyotrkop e! A1., Siet. Keu., 1996, 96, 555-600.

However, the analysis technique for monitoring and quantifying the reactions using polymer reagents is not as well developed as the solid phase reaction methods themselves. Typically, samples are cleaved from a solid support or support and analyzed by conventional means such as TLC, IR and ¹ H NMR. Removing samples from a solid support takes time and may lead to a change in the reaction product. Therefore, analytical methods for the quantitative assessment and control of interconversions of the functional groups of samples associated with the resin are a key issue in the continuation of the development of synthesis methods in the solid phase.

Well-known developments related to the analysis of resin-related samples using fluorine NMR include the use of ¹⁹ P NMR to characterize products resulting from the bonding of fluorinated aromatic compounds with Tep! ACe1 resin (8Upcope e! A1., Te! Taebgop Ε ^ Ι. 1996, 37, 7649); to use ¹⁹ P NMR and ¹⁹ P NMR of the “magic rotation angle” for controlling nucleophilic displacement of a fluorine atom from 4 fluoro-3-nitrobenzamide bound to Rink resin (8yarpo e! a1., Te! tayebgop ΕΜΙ., 1996, 37, 4671) ; for use as linkers of fluorinated analogues of p-hydroxymethylbenzoic acid, 3-4- (hydroxymethylphenyl) alkanoic acid and 4- (hydroxymethyl) phenoxyacetic acid to control solid phase synthesis using ¹⁹ P NMR in the gel phase (8Upcop e! a1., Those! Tayebgop ^ her., 1998, 39, 7193-7196); and to a method for quantitative analysis of resin loading using ¹⁹ P NMR in the gel phase (8! custody e! a1., Tayayebgop Ε ^ Ι., 1998, 39, 4875 - 4878).

SUMMARY OF THE INVENTION

This invention relates to methods for monitoring and quantifying solid-state reactions using solid-phase synthesis reagents, in which one or more fluorine atoms is invariably included as an internal standard, thereby allowing directly to quantify and control the load on the resin and subsequent reactions in the solid phase by ¹⁹ F NMR, obviating the need for further manipulation of the analytical sample, including adding an external standard or the addition ReA tions sample for introducing fluorine atom.

Accordingly, in its main aspect, the present invention relates to a method for quantifying a reaction in a solid phase comprising (a) reacting a solid phase reaction component or a fluorine-containing component of a solid-phase reaction with a reactant or fluorine-containing reagent to obtain a fluorine-containing reaction product in a solid phase;

(b) obtaining a ¹⁹ P NMR spectrum of a fluorine-containing reaction product in a solid phase; and (c) comparing the integral corresponding to the ¹⁹ P resonance of the fluorine-containing reaction product in the solid phase with the integral corresponding to the ¹⁹ P resonance of the standard (reference).

In another aspect, the present invention relates to a fluorine-containing component of a reaction in a solid phase of the formula u-in in which (pp) .. ..

represents a solid carrier containing one or more fluorine atoms;

L0 is absent or represents a linking group, where L0 is optionally substituted with one or more fluorine atoms; and

B represents a functional group suitable for reaction with a reagent to form a fluorine-containing solid-phase reaction product.

In yet another aspect, the present invention relates to a fluorine-containing component of a reaction in a solid phase comprising a known amount of fluorine obtained by reacting a component of a reaction in a solid phase with a quantity of a fluorine-containing reagent.

Brief Description of the Drawings

FIG. 1 represents ¹⁹ P MA8 NMR spectrum

2,3,5,6-tetrafluoro-4-hydroxybenzoic acid.

FIG. 2 represents a ¹⁹ P ML8 NMR spectrum of a 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl-poly (styrene-1% divinylbenzene) resin.

FIG. 3 represents a ¹⁹ P ML8 NMR spectrum of a mixture comprising 3-fluorobenzamide and 4hydroxy-2,3,5,6-tetrafluorobenzamidomethyl copoly (styrene-1% divinylbenzene) resin.

FIG. 4 represents a ¹⁹ P ML8 NMR spectrum of a mixed product resulting from a combination of an aminomethyl resin and 2,3,5,6tetrafluoro-4-hydroxybenzoic acid in the presence of ΌΣΟ and OMAP. FIG. 4 shows ¹⁹ P resonances for 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl copoly (styrene-1% divinylbenzene) resin at approximately -146 and -164 ppm. In addition, the ¹⁹ P spectrum also contains resonances at approximately -140, -144 and -153 ppm, corresponding to the unexpected by-product resulting from the combination of 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl copoly (styrene-1 % divinylbenzene) resin with another molecule of 2,3,5,6tetrafluoro-4-hydroxybenzoic acid to form an ester.

FIG. 4 illustrates the usefulness of the methods described in this invention for detecting and controlling the formation of an undesirable by-product, which thus allows improving the synthesis procedure for maximizing the formation of the desired product 4-hydroxy-2,3,5,6-tetrafluorobenzamido methylsopoli (styrene-1% divinylbenzene) resin.

FIG. 5 represents a ¹⁹ P MA8 NMR spectrum of 4- [1- (4-trifluoromethylphenyl) -2,5-dimethylpyrrol-4-oyl] hydroxy-2,3,5,6-tetrafluorobenzamidomethyl copoly (styrene-1% divinylbenzene) resin.

FIG. 6 represents a ¹⁹ P MA8 NMR spectrum of a reaction mixture consisting of 4-hydroxy-

2.3.5.6- tetrafluorobenzamidomethyl copoly- (styrene-1% divinylbenzene) resin, 1- (4trifluoromethylphenyl) -2,5-pyrrole-4-carboxylic acid (5 equiv.), 4-dimethylaminopyridine (1.5 equiv.) And diisopropylcarbodiimide ( 5 equiv.) And taken after 5, 50 and 100 minutes. After five minutes, G resonances are present at approximately -153 and -172 ppm, corresponding to ¹⁹ P resonances of 4-hydroxy-2,3,5,6tetrafluorobenzamidomethyl copoly (styrene-1% divinylbenzene) resin. After 50 minutes, ¹⁹ P resonances are present at approximately −153 and approximately −172 ppm corresponding to 4-hydroxy

2.3.5.6- tetrafluorobenzamido-methylsopoli (styrene-

1% divinylbenzene) resin, and at approximately 147 and 158 ppm, corresponding to 4- [1 (4-trifluoromethylphenyl) -2,5-dimethylpyrrole-4oyl] hydroxy-2,3,5,6-tet -fluorobenzamidomethyl copoly (styrene-1% divinylbenzene). The spectrum after 100 min consists mainly of ¹⁹ P resonances at -147 and -158 ppm, showing that essentially all 4-hydroxy-2,3,5,6tetrafluorobenzamidomethyl copoly (styrene-1% divinylbenzene) the resin was converted into the product 4- [1 - (4-trifluoromethylphenyl) -2,5-dimethylpyrrol-4-oyl] hydroxy-2,3,5,6-tetrafluorobenzamidomethyl copoly (styrene-1% divinylbenzene) resin.

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms

Used here above and further throughout the description of the invention, the following terms, unless otherwise indicated, should be understood as having the following meanings:

“Solid support or solid support” means a substrate that is inert to the reagents and reaction conditions described herein and is also substantially insoluble in the medium used. Typical examples of solid carriers include inorganic substrates such as kieselguhr, silica gel, and pore-controlled glass; organic polymers including polystyrene, including 1-2% copoly polystyrene-divinylbenzene (in gel form) and 20-40% copolystyrene-divinylbenzene (macroporous form), polypropylene, polyethylene glycol, 5 polyacrylamide, cellulose, etc .; and composite inorganic polymer compositions, such as polyacrylamide, deposited within the matrix from kieselguhr particles. See publication 1.M. 81e \\ 'ah apy ΕΌ. Woopd, Zoyrjake Rerje 8up111SY5. 2 ' ¹ . Her., P1etee Sesh1ea1 So. (Syssado, 1b, 1984).

In addition, the term “solid carrier” includes the solid carrier described above that is attached to yet another inert carrier, such as the pins (pins) described in the Teksisha1 Maiia1, Mi1yrsh ™ 8ROC, Sytoy Tes1to1oshche5 (1995) publication and in the references cited in this publication, which include a removable nozzle based on polyethylene or polypropylene, grafted with a methacrylate copolymer with an introduced functional amino group, and an inert base.

In addition, a “solid carrier” includes polymeric carriers, such as polyethylene glycol carriers, described in publications 1aia e1 a1., Proc. No. 11. Asai. δα. I8A, 92, 64196423 (1995) and δ. Vgiieg, UO 95/16918, which are soluble in many solvents, but can also be precipitated by the addition of a precipitating solvent.

“Binding group” and “linker” means a group through which functional groups suitable for reaction with a fluorine-containing reagent can covalently bind to a solid support. The linking group is essentially inert to the reagents and reaction conditions described in this invention.

"Fluorine-containing solid-phase reaction product" means a product formed as a result of a reaction between a component of a solid-phase reaction and a reagent in which the fluorine-containing solid reaction product includes at least one fluorine atom. The fluorine-containing reaction product in the solid phase is obtained by reacting the fluorine-containing component of the reaction in the solid phase, as defined herein, with a reagent or fluorine-containing reagent, or by reacting the component of the reaction in the solid phase with a fluorine-containing reagent. The fluorine-containing reaction product in the solid phase may contain functional groups suitable for subsequent reactions in the solid phase, in which case subsequent reactions in the solid phase can be quantitated using the methods described in this invention.

“Solid phase reaction component” (or solid phase reaction component) means a solid support as defined herein that contains many reactive sites containing functional groups suitable for reaction with a reactant to form a fluorine-containing reaction product in a solid phase.

"Fluorine-containing component of the reaction in the solid phase" means a component of the solid-phase reaction, as defined in the description, which contains at least one fluorine atom.

"Reagent" means a compound that contains functionality suitable for the formation of a covalent bond with a reaction component in a solid phase to form a fluorine-containing reaction product in a solid phase. In addition to containing functionality suitable for the formation of a covalent bond with the reaction component in the solid phase, the reagent may contain at least one additional functional group suitable for the reaction with additional reagents connected to a solid carrier. The functional group may be protected by a suitable protecting group to avoid interference with the formation of a bond with the reaction component in the solid phase.

“Fluorine-containing reagent” means a reagent as defined herein that contains at least one fluorine atom in addition to functionality suitable for forming a covalent bond with a reaction component in a solid phase, such that a reaction of a fluorine-containing reagent with a solid-phase reaction component or with a fluorine-containing a component of the reaction resulted in the formation of a fluorine-containing reaction product in the solid phase, in which at least one fluorine atom is introduced into the fluorine-containing reaction product in the solid phase through a fluorine-containing reagent.

“Resin load” means a fraction of reactive sites on a solid phase reaction component that reacts with a fluorine-containing reactant to form a fluorine-containing solid-phase reaction product (that is, a fraction of reactive sites that is “loaded” with a fluorine-containing reagent).

“Standard (reference)” refers to a fluorine-containing substance, which, when combined in a known amount with a fluorine-containing solid-phase reaction product, allows one to quantify the formation of a fluorine-containing solid-phase reaction product by comparing the ¹⁹ P integral of the fluorine-containing solid-phase reaction product and ¹⁹ E integrals of the standard. The standard can be either “internal” when the standard is physically included in a known amount in the solid phase reaction component or “external” when a known amount of the fluorine-containing standard compound is added to the sample of the fluorine-containing solid-phase reaction product.

“Rotation at a magic angle” (shady aid1e hrshpd - MA8) represents the NMR method in which a test tube with a sample is oriented at a certain angle to the magnetic field.

Magical angle rotation is used in solid state and gel phase NMR to remove the linear expansion caused by the anisotropy of the chemical shift. The "magic angle" is approximately 54.7 °. For general discussion of MAZ NMR, see Coeshd Publications. B .. It’s interesting to the public; Atepsap Syesh1sa1 8os1e1u. \ Wak1'ppd1op. Bc. 1992 and Yes! A1 .. 1. Sep. Siet .. 1994. 59. 7955 and references cited in these works.

“Protecting group for an amino group” or amino protecting groups means an easily removable group that is known in the art for protecting an amino group from an undesired reaction in the synthesis process and is capable of being selectively removed. The use of Ν-protecting groups to protect groups from undesirable reactions in the synthesis process is well known in the art, and many such protecting groups are known, for example, in T.N. Szhepe apb R.S.M. \ U1k. Rto1esbuye Sgoirk ίη Ogdashs ZupSheyk. 2 ^pb eShop. 1oyp Uyeu & Zopk. Νο \ ν Watk (1991). included in the description for information. Preferred “protecting groups” are acyl, including formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyan; and an acyloxy group, including methoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2.2.2-trifluoroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl (BOC), 1,1-dimethylpropynyloxycarbonylcarbonyl, carbonyloxycarbonyl, carbonyl, benzylcarbonyl, carbonyl, benzyl sulfinyl, p-nitrobenzyloxycarbonyl, 2.4-dichlorobenzyloxycarbonyl, allyloxycarbonyl (A11oc) and the like.

“Carboxylic acid protecting group” and “acid protecting group” means an easily removable group that is known in the art for protecting a carboxylic acid group (—CO ₂ H) from an undesired reaction in the synthesis process and is capable of being selectively removed. The use of carboxylic acid protecting groups is well known in the art, and many such protecting groups are described in the literature, see, for example, T.N. Szhepe apb R.S.M. \ U1k. Rgo1esyue Sgoirk sh Ogdashs ZupSheyk. 2 ^pb ebayup. 1oyp HUPeu & Zopk. No. \ ν Watk (1991). included in the description for information. Examples of carboxylic acid protecting groups include esters such as methoxymethyl, methylthiomethyl, tetrahydropyranyl, benzyloxymethyl, substituted and unsubstituted phenacyl, 2,2,2-trichloroethyl, tert-butyl, cinnamyl, substituted and unsubstituted benzyl, trimethylsilyl, allyl, etc. ., and amides and hydrazides, including Ν.Ν-dimethyl-, 7-nitroindolylhydrazide, Ν-phenylhydrazide, etc. Particularly preferred carboxylic acid protecting groups are tert-butyl and benzyl.

“Hydroxyl protecting group” (or hydroxy protecting group) means an easily removable group that is known in the art for protecting a hydroxyl group from an undesired reaction during synthesis and is capable of being selectively removed. The use of hydroxy protecting groups is well known in the art and many such protecting groups are known, for example, from T.N. Szhepe apb R.S.M. \ U1k. Rto1esbuye Sgirk sh Ogdashs 8up1yek1k. 2 ^pb ebayup. 1oyp \ UPeu & Zopk. No. \ ν Watk (1991). which is included in the description for information. Examples of hydroxy protecting groups include ether groups such as methyl; substituted methyl ethers such as methoxymethyl (MOM). methylthiomethyl (MTM). 2-methoxyethoxymethyl (MEM). bis (2-chloroethoxy) methyl, tetrahydropyranyl (THP). tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, etc .; substituted ethyl ether groups such as 1 ethoxyethyl, 1-methyl-1-methoxyethyl, 2 (phenylselenyl) ethyl, tert-butyl, allyl, benzyl, o-nitrobenzyl, triphenylmethyl, α-naphthyl diphenylmethyl, p-methoxyphenyl diphenylmethyl, 9- (9 -phenyl-10-oxo) -anthranyl (tritylon) and the like; silyl ethers such as trimethylsilyl (TMZ). isopropyl dimethylsilyl; tert-butyldimethylsilyl (TBMZ). tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triisopropylsilyl and the like; ester groups such as formate, acetate, trichloroacetate, phenoxyacetate, isobutyrate, pivaloate, adamantoate, benzoate, 2.4.6trimethylbenzoate and the like; and carbonates such as methyl, 2.2.2-trichloroethyl, allyl, pnitrophenyl, benzyl, p-nitrobenzyl, 3 benzylthiocarbonate, etc.

“Amino acid” means an amino acid selected from the group consisting of natural and unnatural amino acids as defined below.

“Natural amino acid” means an amino acid selected from the group consisting of the following: alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine , aspartic and glutamic acids.

“Unnatural amino acid” means an amino acid for which there is no nucleic acid codon. Examples of unnatural amino acids include, for example, the Ό-isomers of the natural α-amino acids listed above; aminobutyric acid (A1b). 3-aminoisobutyric acid (LAl). Norvaline (Ms). βA1a, 2-aminoadipic acid (Aab). 39 aminoadipic acid (LAB), 2-aminobutyric acid (ABb), γ-aminobutyric acid (CaBa). 6-aminocaproic acid (Acr), 2.4-diaminobutyric acid (Eb), α-aminopimelic acid, trimethylsilylA1a (TM8A), alloisoleucine (a11e), norleucine (L1e), t-bp, citrulline (Ci), ornithine ( 2'-diaminopimelic acid (Orth), 2,3-diaminopropionic acid (Erg), α- or βΝα1. cyclohexyl-A1a (Sya), hydroxyproline, sarcosine (8AG) and the like; cyclic amino acids; --alkylated amino acids, such as OH ^α- methylglycine (MeC1y), N-ethylglycine (E161y) and OH ^α- ethylasparagin (E1A8i); and amino acids in which α-carbon carries two substituents representing side chains.

"Equivalent amino acid" means an amino acid that can be used instead of another amino acid in the peptides according to the invention without any noticeable loss of function. When making such substitutions, the substitution of such amino acids is based on the relative similarity of the substituents representing the side chains, for example, taking into account the size, charge, hydrophilicity, hydropathicity and hydrophobicity, as described here.

“Peptide” and “polypeptide” means a polymer in which the monomers are residues of natural or unnatural amino acids linked to each other via amide bonds. “Peptide skeleton” means a series of amide bonds through which amino acid residues bind. "Amino acid residue" means individual amino acid units included in peptides or polypeptides.

“Aliphatic” means a radical derived from a non-aromatic CH bond by the removal of a hydrogen atom. The aliphatic radical may be further substituted with additional aliphatic or aromatic radicals as defined herein. Typical aliphatic groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkiloksialkil, aralkiloksikarbonilalkil, aralkyl, aralkynyl, aralkiloksialkenil, heteroaralkenyl, heteroaralkyl, geteroaralkiloksialkenil, geteroaralkiloksialkil, geteroaralkinil fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroar Ilheterocyclyl, condensed arylheterocyclenyl, condensed heteroarylheterocyclenyl, etc.

“Aromatic” means a radical derived from an aromatic CH bond through the removal of a hydrogen atom.

“Aromatic” includes both aryl and heteroaryl rings as defined herein. The aryl or heteroaryl ring may be further substituted with additional aliphatic or aromatic radicals as defined herein. Typical aromatic groups include aryl, condensed cycloalkenylaryl, condensed cycloalkylaryl, condensed heterocyclylaryl, condensed heterocyclylaryl, heteroaryl, condensed cycloalkylheteroaryl, condensed cycloalkenyl heteroaryl, condensed heterocyclicheterocycloheterocycloheterocyclo.

“Acyl” means an H — CO— or alkyl — CO group in which the alkyl group is as defined herein. Preferred acyls contain lower alkyl. Typical acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.

“Acylamino” represents an acyl group in which acyl is as defined herein.

“Alkenoyl” means an alkenyl-CO— group in which alkenyl is as defined herein.

"Alkenyl" means a straight or branched aliphatic hydrocarbon group comprising from 2 to about 15 carbon atoms, which contains at least one carbon-carbon double bond. Preferred alkenyl groups contain from 2 to about 12 carbon atoms; more preferred alkenyl groups contain from 2 to about 4 carbon atoms. An alkenyl group is optionally substituted with one or more alkyl groups as defined herein. Typical alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

“Alkenylene” means a divalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond. Typical alkenylenes include —CH = CH—, —CH ₂ CH = CH—, C (CH ₃ ) = CH—, —CH ₂ CH = CHCH ₂ -, and the like.

“Alkenyloxy—” means an alkenyl-O-group in which the alkenyl group is as defined herein. Typical alkenyloxy groups include allyloxy or 3-butenyloxy.

“Alkoxy—” means an alkyl-O-group in which the alkyl group is as defined herein. Typical alkoxy groups include methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, heptoxy and

etc.

“Alkoxyalkylenyl” means an alkyl-Alkylene group in which alkyl and alkylene are as defined herein. Typical alkoxyalkylenyl groups include methoxyethyl, ethoxymethyl, nbutoxymethyl and cyclopentylmethoxyethyl.

“Alkoxyalkoxy” means an alkyl-Alkylene-O-group. Typical alkoxyalkoxy groups include methoxymethoxy, methoxyethoxy, ethoxyethoxy, and the like.

“Alkoxycarbonyl” means an ester group; that is, an alkyl-O — CO — group in which alkyl is as defined herein. Typical alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like.

“Alkoxycarbonylalkyl” means an alkylO-CO-alkylene group in which alkyl and alkylenyl are as defined herein. Typical alkoxycarbonylalkyl groups include methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl and the like.

“Alkyl” means an aliphatic hydrocarbon group, which may be straight or branched, having from about 1 to 20 carbon atoms in the chain. Preferred alkyl groups contain from 1 to about 12 carbon atoms in the chain. The term “branched” means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkyl chain. The term “lower alkyl” means alkyl with about 1-4 carbon atoms in a chain, which may be straight or branched. Alkyl may be substituted by one or more “substituents of the alkyl group”, which may be the same or different and include halogen, cycloalkyl, hydroxy, alkoxy, amino, carbamoyl, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkyloxycarbonyl or heteroaralkyloxycarbonyl. Typical alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, npropyl, isopropyl, n-butyl, tert-butyl, npentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl and pyridylmethyloxy.

"Alkylene" means a straight or branched divalent hydrocarbon chain with

1-20 carbon atoms. Alkylene may be substituted with one or more substituents of the alkyl group as defined herein. Preferred alkylene groups are lower alkylene groups containing from 1 to about 4 carbon atoms. Typical examples of alkylene groups include methylene, ethylene, etc.

“Alkylsulfinyl” means an alkyl-8O group in which the alkyl group is as defined above. Preferred alkylsulfinyl groups are those in which the alkyl group is lower alkyl.

“Alkylsulfonyl” means an alkyl-8O ₂ group in which the alkyl group is as defined herein. Preferred alkylsulfonyl groups are those in which the alkyl group is lower alkyl.

“Alkylsulfonylcarbamoyl” means an alkyl-8O ₂ —MH — CO— group in which the alkyl group is as defined herein. Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is lower alkyl.

“Alkylthio” means an alkyl-8-group in which the alkyl group is as defined herein. Preferred alkylthio groups are those in which the alkyl group is lower alkyl. Typical alkylthio groups include methylthio, ethylthio, isopropylthio, heptylthio and the like.

"Alkynyl" means a straight or branched aliphatic hydrocarbon group with 2 to about 15 carbon atoms, which contains at least one triple carbon-carbon bond. Preferred alkynyl groups contain from 2 to 12 carbon atoms. More preferred alkynyl groups contain from 2 to 4 carbon atoms. "Lower alkynyl" means alkynyl with about 2-4 carbon atoms. An alkynyl group may be substituted with one or more substituents of an alkyl group as defined herein. Typical alkynyl groups include ethynyl, propynyl, n-butynyl,

2-butynyl, 3-methylbutynyl, n-pentynyl, heptinyl, octinyl, decynyl, etc.

“Alkynylene” refers to a divalent group obtained by removing two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing a carbon-carbon triple bond. Typical alkynylene groups include —CH ^ CH—, CH — CH — CH ₂ -. -CH CH-CH (CH ₃ ) - and the like.

“Alkynyloxy” means an alkynyl group in which the alkynyl group is as defined herein. Typical alkynyloxy groups include propynyloxy,

3- butynyloxy and the like.

“Alkynyloxyalkyl” means an alkynyl-alkylene group in which alkynyl and alkylenyl are as defined herein.

"Amidino" or "amidine-" means a group of the formula

in which B ²⁴ represents hydrogen; B ²⁶ O ₂ C—, where B ²⁶ represents hydrogen, alkyl, aralkyl or heteroaralkyl; At ²⁶ O-;

K ²⁶ C (O) -; cyano; alkyl; nitro; or amino, and K ^{25 is} selected from hydrogen, alkyl, aralkyl, heteroaralkyl.

“Amino” means a group of the formula Υ ¹ Υ ² Ν-, in which Υ ¹ and Υ ² independently represent hydrogen; acyl or alkyl; or Υ ¹ and Υ, ² taken together with the nitrogen atom through which Υ ¹ and Υ ^{2 are} connected, form a 4-7 membered azaheterocyclyl. Typical amino groups include amino (Η ₂ Ν-), methylamino, dimethylamino, diethylamino, and the like.

“Aminoalkyl” means an aminoalkylene group in which amino and alkylene are as defined herein. Typical aminoalkyl groups include aminomethyl, aminoethyl, dimethylaminomethyl and the like.

“Aralkenyl” means an arylalkenylene group in which aryl and alkenylene are as defined herein. Preferred aralkenyls contain a lower alkenylene moiety. A typical aralkenyl group is 2-phenethenyl.

“Aralkyloxy” means an aralkyl-Ogroup in which aralkyl is as defined herein. Typical aralkoxy groups include benzyloxy, naphth-1ylmethoxy, naphth-2-ylmethoxy, and the like.

“Aralkyloxyalkyl” means an aralkyl-alkylene group in which aralkyl and alkylene are as defined herein. A typical aralkoxyalkyl group is benzyloxyethyl.

“Aralkyloxycarbonyl” means an aralkyl O — CO— group in which aralkyl is as defined herein. A typical aralkoxycarbonyl group is benzyloxycarbonyl.

“Aralkoxycarbonylalkyl” means an aralkoxycarbonylalkylene group in which aralkoxycarbonyl and alkylene are as defined herein. Typical aralkoxycarbonylalkyls include benzyloxycarbonylmethyl, benzyloxycarbonylethyl.

“Aralkyl” means an arylalkylene group in which aryl and alkylene are as defined herein. Preferred aralkyls contain a lower alkylene group. Typical aralkyl groups include benzyl, 2-phenethyl, naphthylenemethyl and the like.

“Aralkyloxyalkenyl” means an aralkylO-alkenylene group in which aralkyl and alkenylene are as defined herein. A typical aralkyloxyalkenyl group is 3-benzyloxyallyl.

“Aralkylsulfonyl” means an aralkyl ₈ O ₂ group in which aralkyl is as defined herein.

“Aralkylsulfinyl” means an aralkyl8O group in which aralkyl is as defined herein.

“Aralkylthio” means an aralkyl-8-group in which aralkyl is as defined herein. A typical aralkylthio group is benzylthio.

"Aroyl" means an aryl-CO group in which aryl has the meanings defined in the description. Typical aroyl groups include benzoyl, naphth-1-oyl and naphth-2-oyl.

“Aryl” means an aromatic monocyclic or polycyclic ring system with about 6-14 carbon atoms, preferably with 6-10 carbon atoms. Aryl is optionally substituted with one or more “ring system substituents”, which may be the same or different and have the meanings defined in the description. Typical aryl groups include phenyl and naphthyl.

“Aralkynyl” means an arylalkynylene group in which aryl and alkynylene are as defined herein. Typical aralkynyl groups include phenylacetylenyl and 3-phenylbut-2-ynyl.

“Aryldiazo” means an aryl-H = N-group in which aryl has the meanings defined in the description. Typical aryl diazo groups include phenyldiazo and naphthyldiazo.

“Arylcarbamoyl” means an aryl-LHCO group in which aryl has the meanings defined in the description.

“Carbamyl” means a group of formula Υ ^! Υ ² Ν№-, in which Υ ¹ and Υ ² have the meanings defined in the description. Typical carbamyl groups include carbamyl- (H ^ CO-), dimethylaminocarbamoyl (Me ^ CO-), and the like.

"Condensed arylcycloalkenyl" means a radical derived from condensed aryl and cycloalkenyl, as defined herein by the removal of a hydrogen atom from the cycloalkenyl moiety. Preferred fused arylcycloalkenyls are groups in which aryl is phenyl and cycloalkenyl consists of about 5-6 ring atoms. The fused arylcycloalkenyl is optionally substituted with one or more ring system substituents, wherein “ring system substituent” is as defined herein. Typical condensed arylcycloalkenyl groups include 1,2-dihydronaphthylene, indene and the like, in which the bond with the main part is via a non-aromatic carbon atom.

“Condensed cycloalkenylaryl” means a radical derived from condensed arylcycloalkenyl, as defined herein, by removing a hydrogen atom from the aryl moiety. Typical condensed cycloalkenylaryls are the groups defined in the description for condensed arylcycloalkenyl, except that the bond with the main part is via an aromatic carbon atom.

“Condensed arylcycloalkyl” means a radical derived from condensed aryl and cycloalkyl as defined herein by removing a hydrogen atom from the cycloalkyl moiety. Preferred fused arylcycloalkyls are groups in which aryl is phenyl and cycloalkyl consists of about 5-6 ring atoms. Condensed arylcycloalkyl is optionally substituted with one or more ring system substituents, wherein “ring system substituent” is as defined herein. A typical condensed arylcycloalkyl includes 1,2,3,4tetrahydronaphthyl and the like, in which the bond with the main part is via a non-aromatic carbon atom.

“Condensed cycloalkylaryl” means a radical derived from a condensed arylcycloalkyl as defined herein by removing a hydrogen atom from the aryl moiety. Typical condensed cycloalkylaryls are the groups described for the condensed arylcycloalkyl radical, except that the bond with the main moiety is via an aromatic carbon atom.

"Condensed arylheterocyclenyl" means a radical derived from condensed aryl and heterocyclenyl as defined herein by removing the hydrogen atom from the heterocyclenyl moiety. Preferred fused arylheterocyclenyls are groups in which aryl is phenyl and heterocyclenyl consists of about 5-6 ring atoms. The prefix "aza", "oxa" or "thia" before the heterocyclyl part of the condensed arylheterocyclenyl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The fused arylheterocyclenyl is optionally substituted with one or more ring system substituents, wherein “ring system substituent” is as defined herein. The nitrogen or sulfur atom of the heterocyclenyl moiety of the condensed arylheterocyclenyl is optionally oxidized to the corresponding Ν-oxide, 8-oxide or 8.8 dioxide. Typical condensed arylheterocyclenyls include 3H-indolinyl, 1H-2oxoquinolyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, and the like. the main part is through a non-aromatic carbon atom.

“Condensed heterocyclenylaryl” means a radical derived from a condensed arylheterocyclenyl as defined herein by removing a hydrogen atom from the aryl moiety. Typical fused heterocyclenylaryls are the groups described herein for a fused arylheterocyclenyl radical, except that the bond with the main moiety is via an aromatic carbon atom.

“Condensed arylheterocyclyl” means a radical derived from condensed aryl and heterocyclyl, as defined herein, by removing a hydrogen atom from the heterocyclyl moiety. Preferred fused arylheterocyclyls are groups in which aryl is phenyl and heterocyclyl consists of about 5-6 ring atoms. The prefix "aza", "oxa" or "thia" before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The fused arylheterocyclyl is optionally substituted with one or more ring system substituents, where the “ring system substituent” is as defined herein. The nitrogen or sulfur atom of the heterocyclyl portion of the condensed arylheterocyclyl is optionally oxidized to the corresponding окс-oxide, 8-oxide or 8.8 dioxide. Typical preferred condensed arylheterocyclyl ring systems include indolinyl, 1,2,3,4tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2, 3-dihydroisoindolyl, 2, 3-dihydrobenz [1] isoindolyl, 1,2,3,3 , 4-tetrahydrobenz [d] isoquinolinyl, etc., in which the bond with the main part is via a non-aromatic carbon atom.

“Condensed heterocyclylaryl” means a radical derived from a condensed arylheterocyclyl, as defined herein, by removing a hydrogen atom from the heterocyclyl moiety. Typical preferred fused heterocyclyl ring systems are the groups described for fused arylheterocyclyl, with the difference that the bond with the main moiety is via an aromatic carbon atom.

“Carboxy” means a HO (O) C group (ie, a carboxylic acid group).

“Carboxyalkyl” means HO (O) alkylene group in which alkylene is as defined herein. Typical carboxyalkyls include carboxymethyl and carboxyethyl.

“Cycloalkyloxy” means a cycloalkyl-O— group in which cycloalkyl is as defined herein. Typical cycloalkyloxy groups include cyclopentyloxy, cyclohexyloxy and the like.

“Cycloalkyl” means a non-aromatic mono- or polycyclic ring system with about 3-10 carbon atoms, preferably 5-10 carbon atoms. Preferred cycloalkyl rings contain about 5-6 ring atoms. Cycloalkyl is optionally substituted with one or more "ring system substituents" which may be the same or different and have the meanings defined in the description. Typical monocyclic cycloalkyls include cyclopentyl, cyclohexyl, cycloheptyl and the like. Typical polycyclic cycloalkyls include 1-decalin, norbornyl, adamantyl and the like.

“Cycloalkenyl” means a non-aromatic mono- or polycyclic ring system with about 3-10 carbon atoms, preferably about 5-10 carbon atoms, which contains at least one carbon-carbon double bond. Preferred cycloalkylene rings contain about 5-6 ring atoms. Cycloalkenyl is optionally substituted with one or more “ring system substituents”, which may be the same or different and have the meanings defined in the description. Typical monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. A typical polycyclic cycloalkenyl is norbornylenyl.

“Cycloalkenyl” means a divalent saturated carbocyclic group containing about 4-8 carbon atoms. Preferred cycloalkenyl groups include 1,2-, 1,3- or 1,4-cis or transcyclohexanylene.

“Diazo” means the divalent -Ν = radical.

"Ethylene" means —CH = CH— group.

“Halogen” means fluoro, chloro, bromo or iodo.

“Heteroaralkenyl” means a heteroarylalkenylenyl group in which heteroaryl and alkenylene are as defined herein. Preferred heteroaralkenyls contain a lower alkenylene moiety. Typical heteroaralkenyl groups include 4-pyridylvinyl, thienylethenyl, pyridylethenyl, imidazolylethenyl, pyrazinylethenyl, etc.

“Heteroaralkyl” means a heteroarylalkylenyl group in which heteroaryl and alkylenyl are as defined herein. Preferred heteroaralkyls contain a lower alkylenyl group. Typical heteroaralkyl groups include thienylmethyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, etc.

“Heteroaralkyloxy” means a heteroaralkyl-O— group in which heteroaralkyl is as defined herein. A typical heteroaralkyloxy group is 4-pyridylmethyloxy.

“Heteroaralkyloxyalkenyl” means a heteroaralkyl-O-alkenylene group in which heteroaralkyl and alkenylene are as defined herein. A typical heteroaralkyloxyalkenyl group is 4pyridylmethyloxyallyl.

“Heteroaralkyloxyalkyl” means a heteroaralkyl-O-alkylene group in which heteroaralkyl and alkylene are as defined herein. A typical heteroaralkyloxyalkyl group is 4-pyridylmethyloxyethyl.

“Heteroaralkynyl” means a heteroarylalkynylene group in which heteroaryl and alkynylene are as defined herein. Preferred heteroaralkynyls contain a lower alkynylene moiety. Typical heteroaralkinyl groups include pyrid-3-acetylenyl, quinoline-3-acetylenyl, 4-pyridylethynyl, etc.

“Heteroaroyl” means a heteroaryl-CO group in which heteroaryl is as defined herein. Typical heteroaroyl groups include thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, pyridinoyl, etc.

“Heteroaryl” means an aromatic monocyclic or polycyclic ring system of about 5-14 ring atoms, preferably about 5-10 ring atoms, in which one or more atoms in the ring system are other than carbon, for example nitrogen, oxygen or sulfur. Preferred heteroaryls contain about 5-6 ring atoms. “Heteroaryl” may also be substituted with one or more “ring system substituents”, which may be the same or different and have the meanings defined in the description. The prefix "aza", "oxa" or "thia" before heteroaryl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The nitrogen atom of heteroaryl can be oxidized to the corresponding Ν-oxide. Typical heteroaryls include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxylazinazylazinazyl -a] pyridine, imidazo [2,1-b] thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, benzodiinazoleazole, azidazoinazido .

“Heteroaryldiazo” means a heteroaryl ^ = ^ group. in which heteroaryl has the meanings defined in the description.

"Condensed heteroarylcycloalkenyl" means a radical derived from condensed heteroaryl and cycloalkenyl as defined herein by removing a hydrogen atom from the cycloalkenyl moiety. Preferred fused heteroarylcycloalkenyls are groups in which heteroaryl and cycloalkenyl each contain about 5-6 ring atoms. The prefix “aza”, “oxa” or “thia” before heteroaryl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The fused heteroarylcycloalkenyl is optionally substituted with one or more ring system substituents, where the “ring system substituent” is as defined herein. The nitrogen atom of the heteroaryl portion of the condensed heteroarylcycloalkenyl is optionally oxidized to the corresponding Ν oxide. Typical condensed heteroarylcycloalkenyls include 5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl, 4,5-dihydrobenzoxazolyl, and with the main part via a non-aromatic carbon atom.

“Condensed cycloalkenylheteroaryl” means a radical derived from a condensed heteroarylcycloalkenyl as defined herein by removing a hydrogen atom from the heteroaryl moiety. Typical fused cycloalkenylheteroaryl groups are those defined for fused heteroarylcycloalkenyl, except that the bond with the main moiety is via an aromatic carbon atom.

“Condensed heteroarylcycloalkyl” means a radical derived from condensed heteroaryl and cycloalkyl as defined herein by removing a hydrogen atom from the cycloalkyl moiety. Preferred fused heteroarylcycloalkyls are groups in which heteroaryl consists of about 5-6 ring atoms, and cycloalkenyl of about 5-6 ring atoms. The prefix "aza", "oxa" or "thia" before heteroaryl means that at least a nitrogen, oxygen or sulfur atom is present as a ring atom. The fused heteroarylcycloalkyl is optionally substituted with one or more ring system substituents, where the “ring system substituent” is as defined herein. The nitrogen atom of the heteroaryl moiety of the condensed heteroarylcycloalkyl is optionally oxidized to the corresponding окс-oxide. Typical condensed heteroarylcycloalkyls include 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8 tetrahydroisoquinolyl, 5,6,7,8-tetrahydroquino xalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7 tetrahydro - 1H-benzimidazolyl, 4,5,6,7-tetrahydrobenzoxazolyl, 1H-4-oxa-1,5-diazanaphthalen-2 -onyl, 1,3-dihydroimidazole- [4,5] pyridin-2-onyl and t .p. in which the bond with the main part is via a non-aromatic carbon atom.

"Condensed cycloalkylheteroaryl" means a radical derived from a condensed heteroarylcycloalkyl as defined herein by removing a hydrogen atom from the heteroaryl moiety. Typical fused cycloalkylheteroaryls are groups defined for fused heteroarylcycloalkyl with the difference that the bond with the main moiety is via an aromatic carbon atom.

"Condensed heteroarylheterocyclenyl" means a radical derived from condensed heteroaryl and heterocyclenyl, as defined herein, by removing a hydrogen atom from the heterocyclenyl moiety. Preferred fused heteroarylheterocyclenyls are groups in which the heteroaryl moiety is comprised of about 5-6 ring atoms, and the heterocyclenyl moiety is about 5-6 ring atoms. The prefix "aza", "oxa" or "thia" before heteroaryl or heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The fused heteroarylheterocyclenyl is optionally substituted with one or more ring system substituents, where the “ring system substituent” is as defined herein. The nitrogen atom of the heteroaryl portion of the condensed heteroarylheterocyclenyl is optionally oxidized to the corresponding окс-oxide. The nitrogen or sulfur atom of the heterocyclenyl portion of the condensed heteroarylheterocyclenyl is optionally oxidized to the corresponding Ν-oxide, 8-oxide or 8.8-dioxide. Typical condensed heteroarylheterocyclenyls include 7,8-dihydro [1,7] naphthyridinyl, 1,2-dihydro [2,7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyridyl, 1,2- dihydro -1,5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl, 1,2-dihydro-1,7-naphthyridinyl, 1,2-dihydro-1,8-naphthyridinyl, 1,2-dihydro 2,6-naphthyridinyl and the like, in which the bond with the main part is via a non-aromatic carbon atom.

“Condensed heterocyclenylheteroaryl” means a radical derived from a condensed heteroarylheterocyclenyl as defined herein by removing a hydrogen atom from the heteroaryl moiety. Typical fused heterocyclenylheteroaryl groups are those described for fused heteroarylheterocyclenyl with the difference that the bond with the main moiety is via an aromatic carbon atom.

“Condensed heteroaryl heterocyclyl” means a radical derived from condensed heteroaryl and heterocyclyl as defined herein by removing a hydrogen atom from the heterocyclyl moiety. Preferred fused heteroaryl heterocyclyls are groups in which heteroaryl consists of about 5-6 ring atoms and heterocyclyl is about 5-6 ring atoms. The prefix "aza", "oxa" or "thia" before the heteroaryl or heterocyclenyl part of the condensed heteroaryl hetero cyclic means that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The fused heteroaryl heterocyclyl is optionally substituted with one or more ring system substituents, where the “ring system substituent” has the meanings defined in the description. The nitrogen atom of the heteroaryl moiety of the condensed heteroarylheterocyclyl is optionally oxidized to the corresponding окс-oxide. The nitrogen or sulfur atom of the heterocyclyl portion of the fused heteroaryl heterocyclyl is optionally oxidized to the corresponding Ν-oxide, 8-oxide or 8.8 dioxide. Typical condensed heteroaryl heterocyclyls include 2,3-dihydro1H-pyrrole [3,4-b] -quinolin-2-yl, 1,2,3,4-tetrahydrobenz [b] [1,7] naphthyridin-2-yl, 1, 2,3,4-tetrahydrobenz [b] [1,6] naphthyridin-2-yl, 1,2,3,4-tetrahydro-9H-pyrido [3,4-b] indol-2-yl, 1,2 , 3,4tetrahydro-9H-pyrido [4,3-b] indol-2-yl, 2,3-dihydro-1H-pyrrolo [3,4-b] indol-2-yl, 1H-2,3,4 5tetrahydroazepino [3,4-b] indol-2-yl, 1H-2,3,4,5tetrahydroazepino [4,3-b] indol-3-yl, 1H-2,3,4,5tetrahydroazepino [4,5 B] indol-2-yl, 5,6,7,8 tetrahydro [1,7] naphthyridinyl, 1,2,3,4-tetrahydro [2,7] naphthyridyl, 2,3-dihydro [1,4] dioxino [2,3-b] pyridyl, 2,3-dihydro [1,4] dioxino [2,3b] pyr idyl, 3,4-dihydro-2H-1-oxa- [4,6] diazanaphthalenyl, 4,5,6,7-tetrahydro-3H-imidazo [4,5-c] pyridyl, 6,7-dihydro [5 , 8] diazanaphthalenyl,

1,2,3,4-tetrahydro - [1,5] naphthyridinyl, 1,2,3,4tetrahydro [1,6] naphthyridinyl, 1,2,3,4-tetrahydro [1,7] naphthyridinyl, 1,2 , 3,4-tetrahydro [1,8] naphthyridinyl, 1,2,3,4-tetrahydro [2,6] naphthyridinyl and the like, in which the bond with the main part is via a non-aromatic carbon atom.

“Condensed heterocyclylheteroaryl” means a radical derived from a condensed heteroarylheterocyclyl, as defined herein, by removing a hydrogen atom from the heteroaryl moiety. Typical fused heterocyclyl heteroaryl groups are those described for fused heteroaryl heterocyclyl, with the difference that the bond with the main moiety is via an aromatic carbon atom.

“Heteroarylsulfonylcarbamoyl” means heteroaryl-8O ₂ ^ H — CO— group in which heteroaryl is as defined herein.

“Heterocyclenyl” means a non-aromatic monocyclic or polycyclic ring system of about 3-10 ring atoms, preferably about 5-10 ring atoms, where one or more atoms in the ring system is (are) atom (s) of element (s) other than ) from carbon, for example by nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond. Preferred heterocyclenyl rings contain about 5-6 ring atoms. The prefix "aza", "oxa" or "thia" before heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. Heterocyclenyl may optionally be substituted with one or more ring system substituents, where “ring system substituent” is as defined herein. The nitrogen or sulfur atom of heterocyclenyl is optionally oxidized to the corresponding окс-oxide, 8-oxide or 8.8-dioxide. Typical monocyclic azaheterocyclenyl groups include 1,2,3,4tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3 -pyrrolinyl, 2-imidazolinyl, 2pyrazolinyl and the like. Typical oxaheterocyclenyl groups include 3,4-dihydro-2Npiran, dihydrofuranyl, fluorodihydrofuranyl and the like. A typical polycyclic oxaheterocyclenyl group is 7oxabicychenyl [2.2.1]. Typical monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, etc.

“Heterocyclyl” means a non-aromatic saturated monocyclic or polycyclic ring system of about 3-10 ring atoms, preferably 5-10 ring atoms, in which one or more of the atoms in the ring system is (are) the atom (s) of an element (s) other than (s) from carbon, for example, nitrogen, oxygen or sulfur atoms. Preferred heterocyclyls contain about 5-6 ring atoms. The prefix "aza", "oxa" or "thia" before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom is present, respectively, as ring atoms. Heterocyclyl is optionally substituted with one or more ring system substituents, which may be the same or different and have the meanings defined in the description. The nitrogen or sulfur atom of the heterocyclyl is optionally oxidized to the corresponding oxide, 8-oxide or 8.8-dioxide. Typical monocyclic heterocyclic rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and the like.

“Heterocyclylalkyl” means a heterocyclylalkylene group in which heterocyclyl and alkylene are as defined herein. Preferred heterocyclylalkyls contain a lower alkylene moiety. A typical heteroaralkyl group is tetrahydropyranylmethyl.

“Heterocyclylalkyloxyalkyl” means a heterocyclylalkyl-O-alkylene group in which heterocyclylalkyl and alkylene are as defined herein. A typical heterocyclylalkyloxyalkyl group is tetrahydropyranylmethyloxymethyl.

"Heterocyclyloxy" means a heterocyclyl-O-group in which heterocyclyl has the meanings defined in the description. Exemplary heterocyclyloxy include hinuklidiloksi, pentametilensulfidoksi, tetrahydropyranyloxy, tetragidrotiofeniloksi, pyrrolidinyloxy, tetrahydrofuranyloxy, 7oksabitsiklo [2.2.1] -geptaniloksi, gidroksitetragidropiraniloksi, hydroxy-7oksabitsiklo [2.2.1] geptaniloksi etc.

“Hydroxyalkyl” means an alkyl group, as defined herein, substituted with one or more hydroxyl groups. Preferred hydroxyalkyls contain lower alkyl. Typical hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

o ”II ₊ “ Ν-oxide ”means ^{= Ν} “ group.

“Phenoxy” means a phenyl-O-group in which the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.

“Phenylene” means an α-phenyl group in which the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.

“Phenylthio” means a phenyl-8-group in which the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.

“Pyridyloxy” means a pyridyl group in which the pyridyl ring is optionally substituted with one or more ring system substituents as defined herein.

“Substituent ring system” means an attached substituent that optionally replaces hydrogen in an aromatic or non-aromatic ring system. Ring system substituents are selected from the group consisting of aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aryloxy arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroalkylthio, cycloalkyl, cycloalkenyl, amyridinoamino, arylazino carbamyl and sulfamyl.

When the ring system is saturated or partially saturated, the “ring system substituent” further includes methylene (H ₂ C =), oxo (0 =) and thioxo group (8 =).

“Sulfamyl” means a group of the formula Υ ¹ Υ ² Ν 8Ο2-, in which Υ ¹ and Υ ² have the meanings given in the description. Typical sulfamyl groups are aminosulfamoyl (Η2Ν8Ο ₂ -) and dimethylaminosulfamoyl (Μο ₂ Ν80 ₂ -).

Preferred Embodiments

In a preferred aspect of the invention, ¹⁹ P NMR spectra are obtained at a magic angle of rotation.

To calculate the amount of reagents for use in subsequent reactions and to optimize subsequent chemistry, it is necessary to determine the loading of the fluorine-containing solid-phase reaction product.

The loading of the fluorine-containing solid-phase reaction product / gram (α) is calculated by the formula 1 _ χΐ, <2, ^and m, in which

1 _G is the integral corresponding to the resonance of a fluorine-containing solid-phase reaction product;

x is the number of equivalent P atoms in the standard compound;

y is the number of equivalent P atoms in the reference compound;

1, is the resonance integral of the standard;

Oh, - the amount of standard in moles;

M _g is the mass of resin in grams.

In another preferred aspect of the invention, the calculation of the solid-state reaction is carried out using an external standard.

To determine the resin load using an external standard, a known amount of a fluorine-containing standard compound is added as an external standard to a precisely defined amount of a fluorine-containing solid-phase reaction product, which is then swelled in an appropriate solvent. Suitable fluorine-containing standard compounds include any non-reactive soluble fluorinated material. A preferred fluorine-containing standard compound is 3-fluorobenzamide (3PB).

^{The 19} P spectrum of this system consists of well distinguishable resonances corresponding to a fluorine-containing standard compound and a fluorine-containing component of the solid-state reaction. A simple calculation according to Formula 1 using the integral values for the ¹⁹ P signals of the fluorine-containing standard compound and the fluorine-containing component of the solid-state reaction and known quantities of the fluorine-containing standard compound and the fluorine-containing component of the solid-state reaction present in the sample gives the resin loading amount.

The load of the fluorine-containing component of the solid-state reaction / gram (α), determined using ¹⁹ P NMR using an external standard, was checked by comparing the values of α using other methods, such as elemental analysis.

In another preferred aspect of the invention, the quantification of the solid-state reaction is carried out using an internal standard comprising the fluorine-containing component of the solid-state reaction defined in the description.

Determination of the load on the resin using the internal standard is carried out, as described above, by comparing the integrals ¹⁹ P resonance (s) of the fluorine-containing component of the solid-state reaction with the ¹⁹ P resonance (s) of the fluorine-containing product of the solid-phase reaction.

The preferred internal standard for use in the method of this invention are the fluorine-containing components of the solid-state reaction of formula I

in which represents a solid carrier, optionally containing one or more fluorine atoms;

B is absent or represents a linking group, optionally containing one or more fluorine atoms, provided that at least one of the solid support and the linking group contains at least one fluorine atom; and

B represents a functional group suitable for reaction with a reagent to form a fluorine-containing solid-phase reaction product.

Fluorine-containing components of the solid-state reaction of the formula I, including a solid support and a fluorine-containing linking group, are obtained by reacting a component of the solid-phase reaction, as defined in the description, with a fluorine-containing subcell.

A fluorine-containing subcell is a compound that contains at least one fluorine atom, functionality suitable for the formation of a covalent bond with a solid-phase reaction component, and at least one additional functional group suitable for reaction with a reagent to form a solid-phase fluorine product reactions. The additional functional group (s) (s) may be protected (s) by a suitable protecting group to avoid interference with the formation of a bond with the solid phase reaction component.

Typical solid-phase reaction components suitable for reaction with a fluorine-containing subcell to form a fluorine-containing component of the solid-state reaction include polystyrene, aminomethyl polystyrene, Merrifield resin (chloromethylated polystyrene), hydroxymethyl resin, acid resin Ktpk'a-2-benzyl-4-benzyl-4-benzyl-4-benzyl-4-benzyl-4-benzyl-4-benzyl-2-benzyl-4-benzyl-4-benzyl-4-benzyl-4-benzene ), Vanga resin (\ Uapd) (p-benzyloxybenzyl alcohol resin), MVNA resin (p-methylbenzhydrylamine resin), VNA resin (benzhydrylamine resin), Rinka resin (4- (2 ', 4'-dimethoxyphenyl) aminemetin phenoxy resin) and the like. Fluorine-containing components of a solid-state reaction in which a solid support contains one or more fluorine atoms is represented in the description by formula II θ-cz- _c in which represents a solid support containing one or more fluorine atoms;

BC is absent or represents a linking group, optionally substituted with one or more fluorine atoms; and

B represents a functional group suitable for reaction with a reagent to form a fluorine-containing solid-phase reaction product.

The fluorine-containing components of the solid-phase reaction of formula II are prepared by polymerization using known methods so as to incorporate one or more fluorine-containing monomers into a solid support. Typical fluorine-containing monomers include 4 fluorostyrene, 4-trifluoromethylstyrene and the like.

Preferred fluorine-containing components of the solid-state reaction of formula II are obtained by polymerization of a mixture of 4 fluorostyrene, 1,4-divinylbenzene and 4vinylbenzyl chloride.

Another preferred internal standard for use in the method of the present invention is a fluorine-containing solid-phase reaction component obtained by reacting a certain amount of a solid-phase reaction component with a certain amount of a fluorine-containing reagent, so that a known amount of fluorine is introduced into the fluorine-containing component of the solid-phase reaction.

In a preferred aspect, the fluorine-containing component of the solid-state reaction is obtained by reacting the component of the solid-phase reaction with about 0.05-0.4 molar equivalents of the fluorine-containing reagent.

Typical fluorine-containing reagents suitable for reaction with a solid phase reaction component to obtain a fluorine-containing solid phase reaction component include bis (2,2,2 trifluoroethyl) amine, 3,5-bis (trifluoromethyl) benzoyl chloride, 4-fluorobenzoyl chloride, 4-fluorobenzylamine, 4- fluorobenzene sulfonyl chloride, 4-fluorobenzaldehyde, 4-fluorophenyl chloroformate, 3-fluorophenyl isocyanate, 4-fluorophenyl isothiocyanate, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, 4- (trifluoromethyl) benzyl amide-4 (trifluoromethyl) 4-trifluoromethyl-4-trifluoromethyl-4-trifluoromethyl-4-trifluoromethyl lift trimethyl) phenylisocyanate, 4- (trifluoromethyl) thiophenol, 1H, 1H, 2H, 2H-perfluorodecyldimethylchlorosilane, 2,2,2-trifluoroethanesulfonyl chloride, 2,2,2-trifluoroethanol, 4-fluorophenol, 4-fluorobenzoic acid, 1,2- epoxy-3-fluoropropane, 4-fluoro-4-hydroxybenzophenone, 2-fluoro-4-hydroxybenzoic acid, 2-fluoro-4-hydroxybenzyl alcohol, 2 fluoro-4-hydroxybenzyl chloride and the like. A preferred fluorine-containing reagent is 4-fluorophenol.

Typical solid-phase reaction components suitable for reaction with a fluorine-containing reagent to form a fluorine-containing component of the solid-phase reaction include polystyrene, aminomethyl polystyrene, Merrifield resin (chloromethylated polystyrene), hydroxymethyl resin, Rink acid resin (4-benzyloxydimethyl-2 '), Wang resin (p-benzyloxybenzyl alcohol resin), MVNA resin (p-methylbenzhydrylamine resin), BHA resin (benzhydrylamine resin), Rink resin (4- (2 ', 4'-dimethoxyphenyl Rhos-aminomethyl) phenoxy mole), etc. A preferred solid phase reaction component is Merrifield resin.

More preferred fluorine-containing components of the solid-state reaction for use as internal standards according to the method of the present invention have the formula III,

represents a solid carrier;

B represents a group of the formula

A is missing or selected from

□ represents CH or Ν;

P represents H or an amino protecting group;

Ψ represents H, ΝΗΡ, ΝΡΚ ⁹ , ^ (O) C1, C (O) I ⁹ , C (O ^ I ¹⁰ I ^H , C (O) OA ⁹ , 8O ₂ I ⁹ or C (O) imidazole-1 -il;

Υ represents —O— or —ΝΚ ⁸ -;

Ζ is C1, OH, or RP _and ΝΚ ⁹ Κ ^12;

I ¹ represents P or when one of I ¹⁶ , 171819 1

I, I and I represent P, I represents H, alkyl, alkoxy, halogen, CΝ or ΝΘ ₂ ;

I ² , I ³ and I ⁴ independently represent H, alkyl, alkoxy, halogen, CΝ or ΝΘ ₂ , or one of I ¹ , I ² and I ⁴ , taken together with one of I ⁵ and I ⁶ and carbon atoms, to to which they are attached form a group of the formula

I ⁵ and I ⁶ independently represent —H, alkyl, phenyl or phenyl substituted with one or more substituents selected from alkyl, alkoxy, halogen, nitrile and —ΝΘ ₂ ;

I ⁷ and I ⁸ independently represent H or lower alkyl;

I ⁹ and I ¹³ independently represent an aliphatic or aromatic group;

I ¹⁰ and I ¹¹ independently represent an aliphatic or aromatic group;

I ¹² represents —CH ₂ I ¹³ ;

I ¹⁴ , I ¹⁵ , I ¹⁶ , I ¹⁷ , I ¹⁸ , I ¹⁹ , I ²⁰ , I ²¹ , I ²² and I ^{23 are} independently selected from H, alkyl, alkoxy, halogen, ^ Ν and -ΝΘ ₂ ;

t is 0 or 1;

η is 1-6; and p is 0, 1 or 2.

The preparation of the fluorine-containing components of the solid-phase reaction of formula III for use according to the method of the present invention is described in Schemes 1-10 below. The preparation and use of fluorine-containing components of the solid-phase reaction of formula III in which B represents ΘΝΗΡ or ΘΝΡΚ ⁹ in the preparation of aldehydes, ketones, oximes, amines and hydroxamic acids is described in PCT / i897 / 23920, which is incorporated herein by reference. Obtaining and using fluorine-containing components of the solid-phase reaction of formula III, in which B represents (G or 8Ο2Ζ, where represents hydrogen, No. (O) C1, C (O) I ⁹ , C (O ^ I ¹⁰ I ^P , C (O) OIA ⁹ , 8O2IA ⁹ or C (O) -imidazol-1-yl, in the preparation of amides, peptides, hydroxamic acids, amines, urethanes, carbonates, carbamates, sulfamides and α-substituted carbonyl compounds, is described in application for US Patent No. 60 / 090558, filed June 24, 1998, which is included in this description for information.

Obtaining a solid-phase reaction component of the formula

-C (O) -, -US (O) -, -8Ο ₂ -, -νκ ⁷ ο2-, -sya ⁷ -, -sya ⁷ yy and CHNY ⁷ US (O) (CH2) t-;

B represents halogen, ΝΗΡ, (W or

8Ο2Ζ;

shown in diagram 1

Scheme 1

® K ² , K ³ , K ⁴ and K ⁷ have the meanings defined in the description.

According to the above scheme 1, amino resin 1 or hydroxy resin 4 is combined with a 4-hydroxyfluorobenzoic acid derivative 2 in a suitable organic solvent such as dichloromethane, DMF, DMSO or THF to obtain 4-hydroxyfluorine-containing components of the solid-state reaction 3 or 4 hydroxyfluorobenzoyloxylamine in the range of about 2 to 24 hours, depending on the amino resin and the 4-hydroxyfluorobenzoic acid derivative to be combined, the activating agent, the solvent, and the temperature. The combination is carried out at a temperature of from about -10 to 50 ° C, preferably at about room temperature. The carboxylic acid moiety is activated by a suitable activating agent, such as isopropyl chloroformate in the presence of метил-methylpiperidine, diisopropylcarbodiimide (E1C) in the presence of 1-hydroxybenzotriazole (HOBT), diisopropylcarbodiimide (O1C) in the presence of 4-dimethylamino-2-amino-2-aminopyridine oxazolidinyl) phosphonium chloride (BOP-C1) in the presence of triethylamine, 2- (1H-benzotriazole1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTi) in the presence of diisopropylethylamine, Ν-hydroxysuccinimide in the presence of Ν.Ν'-dimethyloxyhexyl a (OSS), etc.

A preferred amino resin 1 for the preparation of the 4-hydroxyfluorobenzamidoside resin of the present invention is aminomethyl polystyrene. Depending on the particle size (75-250 mesh), aminomethyl polystyrene has a loading (filling) interval of from about 0.5 to 1.2 mmol / g and from about 0.1 to 0.5 mmol / g, respectively. Aminomethyl polystyrene having a particle size of 75 mesh is preferred.

A preferred hydroxy resin 4 is hydroxymethyl resin.

In a preferred method for producing 4-hydroxyfluorobenzamide resin 3, a mixture of a derivative of 4-hydroxyfluorobenzoic acid 2, aminomethyl polystyrene, diisopropylcarbodiimide (O1C) and 4-dimethylaminopyridine (OMAP) in anhydrous DMF is stirred for approximately 3 hours, then it is washed for more than 4 hours. solvents and dried.

Obtaining a solid-phase reaction component of the formula

where Ό, p, K ² , K ³ and K ⁴ take the values defined in the description, presented in scheme 2.

Scheme 2

As shown in Scheme 2 above, the combination of an azacycloalkyl resin 6 with a 4-hydroxyfluorobenzoic acid derivative (compound 2) provides 4-hydroxyfluorobenzoylazacycloalkyl resin (compound 7). The combination is carried out using the reagents and conditions described in scheme 1 above. A preferred azacycloalkyl resin is (piperidinomethyl) polystyrene, described herein as ®iE (piperidinomethyl) polystyrene

Obtaining a solid-phase reaction component of the formula

E

where A represents —C (O) -, and B represents T, OH, 8O ₃ H or 8O ₂ Cl, as shown in Scheme 3.

Scheme 3

As shown in Scheme 3, Friedel-Kraft polystyrene acylation with 4 fluorofluorobenzoyl chloride derivative 8 in the presence of a Lewis acid, such as TeC1 ₃ , 8iC1 ₄ or A1C1 ₃ , in a suitable organic solvent provides 4-fluorofluorobenzoyl resins (compound 9). The interaction of 9 with hydroxide provides 4-hydroxyfluorobenzoyl resins (compound 10).

In a preferred aspect, the polystyrene is acylated with the 4-fluorofluorobenzoyl chloride derivative 8 in the presence of A1C13 in nitrobenzene to give 4 fluorofluorobenzoyl resins (compound 9). 9 in a mixture of 31 water / cyclohexane is treated with sodium hydroxide and tetrabutylammonium hydrosulfate according to the procedure described in the publication ReMtap e! A1., b. Ogd. Sc., 56 (26), 7350-7354 (1991), to obtain 4-hydroxyfluorobenzoyl resins (compound 10).

Reaction of 4-gidroksiftorbenzoilsmoly (Compound 10) 8 o ₃ ^- equivalent such as potassium metabisulfite in the presence of a base in a suitable organic solvent such as dichloromethane, dichloroethane or chloroform provides 11 compounds fluorobenzoyl-4-sulfonic acid resin. Typical examples of bases include diisopropylethylamine, pyridine, triethylamine, methylpiperidine and the like. The reaction of compound 11 (fluorobenzoyl-4-sulfonic acid resin) with an acid chloride such as chlorosulfonic acid, thionyl chloride, oxalyl chloride and the like, in an inert organic solvent, provides compound 12-5,6 trifluorobenzoyl-4-sulfonyl chloride resin .

Obtaining a solid-phase reaction component of the formula

where B represents P or OH, shown in scheme 4.

Scheme 4 ₇ ® / = Γ = ν ^κ2 (8 Y — ΝΗΡ ⁷ + C1-5 — C 5-one ----- О amino resin pZ

As shown in Scheme 4, the reaction of amino resin 1 with compound 13-4-hydroxyfluorophenylsulfonyl chloride, in the presence of a base such as метил-methylmorpholine, pyridine, collidine, triethylamine or diisopropylethylamine, in a suitable organic solvent such as dichloromethane, dichloroethane R, dioxane, ΌΜΤ, provides the connection 14 - 4-hydroxyfluorophenylsulfonamide resin. The reaction is preferably carried out in dichloromethane in the presence of collidine.

Alternatively, amino resin 1 is reacted with compound 15-4 fluorofluorophenyl sulfonyl chloride as described above, to give compound 16-4 fluorofluorophenyl sulfonamide resin, which is converted to the desired 4-hydroxyfluorophenyl sulfonamide resin (compound 14) as described in Scheme 3 above.

Obtaining a solid-phase reaction component of the formula

where B represents P, OH, 8O ₃ H or 8O ₂ C1, shown in scheme 5.

Scheme 5

polystyrene 17 (? Ηθ-Β (ΟΗ) ₂ .

H ⁴ 19

B = Br, C1.1

As shown in Scheme 5, bromination of polystyrene, for example using Br ₂ in the presence of TeC1 ₃ , T1 (OAc) ₃ or BT ₃ , provides brominated polystyrene (compound 17). Metal halide exchange, for example, using an alkyl lithium reagent such as n-butyllithium in benzene or ΤΜΕΌΆ; trimethyl borate addition; and acidification provides obtaining polystyrene styrene acid (compound 18). A combination of 18 with a fluorophenyl halide (compound 19) using the Suzuki conditions (catalytic amount of Pb (0), basic conditions; see publications RhepeNe e! A1., Tebberbop Be !!., 1994, 35, 9177 and Brno ! a1., b. Ateg Cet. 8oc., 1996, 118, 6331) provides 4-fluorofluorophenyl polystyrene (compound 20). The conversion of 20 to 4-hydroxyfluorophenyl polystyrene (compound 21), fluorophenyl-4-sulfonic acid polystyrene (compound 22) or fluorophenyl-4-sulfonyl chloride-polystyrene (compound 23) is carried out as described in scheme 3 above.

Obtaining a solid-phase reaction component of the formula

where B represents P or OH, shown in scheme 6.

Scheme 6

As shown in Scheme 6 above, the reaction of thiopolystyrene with a trifluorophenylbenzene derivative (compound 24) leads to the formation of a difluorophenylthiopolystyrene derivative (compound 25). The reaction is preferably carried out in a suitable solvent, such as toluene, dioxane, ΌΜΡ or BM8O, in the presence of a base, preferably catalytic pyridine or Ν methylmorpholine. The conversion of 25 to 4-hydroxyfluorophenylthiopolystyrene (compound 26) is carried out as described in Scheme 3 above. Oxidation of 26, for example, using mchlorobenzoic acid (b-siBiOb7O1c ac1bMSPBA), provides 4-hydroxyfluorophenylsulfonyl-polystyrene 27. Obtaining a solid-phase reaction component of the formula

where ®, B and P take the values defined in the description, presented in scheme 7.

According to the above scheme 7, the polymer hydroxysmol (compound 28) is converted to the polymeric ид-hydroxyphthalimidosin resin (compound 29) by combination with Ν-hydroxyphthalimide under Mitsunobu’s conditions (see the publication MBzipo O., 8unche818 1981, 1); the conversion of a hydroxyl group to a leaving group, such as mesylate, followed by nucleosubstitution with hydroxyphthalimide; or by reacting a polymer hydroxy resin with гидрок-hydroxyphthalimide in the presence of an acid such as benzenesulfonic acid. Removal of the phthalimido group using known methods, such as treatment with hydrazine 29 or, preferably, methylamine, provides a fluorine-containing component of the solid-state reaction 30, in which P represents N.

For example, a combination of compound 28 with β-hydroxyphthalimide is carried out in the presence of diisopropylazodicarboxylate and triphenylphosphine in DMF. Then the protection of the phthalimidogroup is removed by methylaminolysis in THF at approximately 40 ° C.

The introduction of protection for an amino group, such as benzyl, using reagents and reaction conditions known in the art, provides a fluorine-containing component of the solid-phase reaction 31, in which P represents a protective group of the amino group.

In some examples, an attempt to introduce certain protecting groups for an amino group into the fluorine-containing component of the solid-state reaction 30 removes the protection of the Ν atom. This deprotection is prevented by selective monoprotection of compound 30 with the protective group P ′ to form a mono-protected fluorine-containing reaction component in solid phase 32, followed by the introduction of a protective group P to form a Ν, Ν -disolated fluorine-containing component of the solid-state reaction 33 and selective removal of P ′. A preferred protecting group P 'is allyloxycarbonyl, which is selectively cleaved in the presence of additional protecting groups for the amino group with Pb (O).

An alternative method for preparing the solid-state reaction component 31 is shown in Scheme 8.

Scheme 8

According to the above scheme 8, the reaction component in the solid phase 30 is combined with a Ν, Ν -disubstituted hydroxylamine (compound 34), where P and P 'represent protecting groups for the amino groups, with the formation of a Ν, Ν -disapplied fluorine-containing component of the solid-state reaction

35. The amino group protecting group P ′ is then selectively removed to form the “protected fluorine-containing component of the solid-state reaction 31.

In a preferred embodiment of the synthesis described in Scheme 8, P is benzyl and P 'is allyloxycarbonyl. Selective removal of the allyloxycarbonyl protecting group is carried out by treating tetrakis (triphenylphosphine) with Palladium (0).

The Ν, Ν-dis-protected hydroxylamine 34 is obtained by sequentially introducing the protective groups P and P 'into the O-protected hydroxylamine of the formula H ^ OP ² , where P ² represents a protecting group of the hydroxyl group. A preferred hydroxyl protecting group is alkyl. The amino protecting groups P and P ′ are then introduced using reagents and reaction conditions well known in the field of organic synthesis. For example, the reaction of O-tert-butylhydroxylamine with allyloxychloroformate results in the formation of Ν-allyloxycarbonyl-O-tert-butylhydroxylamine, which is then reacted with benzyl bromide to form Ν-οοιβπ'ι-ли allyloxycarbonyl-O-tert-butylamine. Treatment of ^ benzyl ^ -allyloxycarbonyl-O-tert-butylhydroxylamine with trifluoroacetic acid yields Ν-οοιβπ'ι-Ν-allyloxycarbonylhydroxylamine.

Obtaining a solid-phase reaction component of the formula

presented in diagram 9

Scheme 9

@4Ζ ^ _ο ύΗ- ^ ^{ονΗ2 N}

According to the above scheme 9, a polymer chloromethyl resin such as chloromethyl polystyrene (36, Merrifield resin) is reacted with 4-hydroxyfluorobenzoic acid (compound 37) in the presence of a base to form 4 carboxyfluorophenoxymethyl resin (compound 38). The reduction of the carboxylic acid group, for example, using IL1H ₄ , diisobutylaluminum hydride or BH ₃ -THE, provides 4-hydroxymethyl fluorophenoxymethyl resin (compound 39). The conversion of 39 into a hydroxyphthalimidosin resin (compound 40) followed by removal of the phthalimido group, as described in Scheme 7 above, provides a fluorine-containing component of the reaction in solid phase 41.

Obtaining a solid-phase reaction component of the formula

Pattern 10

According to the above scheme 10, the polymer chloromethyl resin (compound 36) is reacted with ketone 42 in the presence of a base, as described in scheme 9 above, with the formation of 4- (2 ', 4'-dimethoxyphenylcarbonyl) fluorophenoxymethyl resin (compound 43). The reduction of carbonyl, for example, using NIV ₄ , provides 4- (hydroxymethyl-2 ′, 4′-dimethoxyphenyl) fluorophenoxymethyl resin (compound 44). The conversion of 44 to hydroxyphthalimidosinum 45 followed by removal of the phthalimidogroup, as described in Scheme 7 above, provides a solid-phase reaction component 46.

Even more preferred components of the solid-state reaction for use according to the method of the present invention have the formula II, where K ¹ , K ² , K ³ and K ⁴ represent E; and one of K ⁵ and K ⁶ represents hydrogen, and the other of K ⁵ and K ⁶ represents H or 2,4-dimethoxyphenyl.

Other even more preferred solid phase reaction components for use according to the method of the present invention are of formula II, wherein K ¹ , K ² , K ³ and K ⁴ are E; one of K ⁵ and K ⁶ represents hydrogen, and the other of K ⁵ and K ⁶ represents hydrogen or 2,4 dimethoxyphenyl; and B represents E, OR or 8Ο2Ζ.

Other even more preferred solid phase reaction components for use according to the method of the present invention are of formula II, wherein K ¹ , K ² , K ³ and K ⁴ are E; one of K ⁵ and K ⁶ represents hydrogen, and the other of K ⁵ and K ⁶ represents hydrogen or 2,4-dimethoxyphenyl; B represents E, OR or δΟ ₂ Ζ; and A represents phenylene, —C (O) -, —US (O) -, —8O2—, —N ^ 802—, or —CH ⁷ O—.

presented in diagram 10.

Typical examples of even more preferred components of the solid state reaction include, but are not limited to: 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl copoly (styrene-1% divinylbenzene) resin, which is described in the description as

4- (O-methylhydroxylamine) -2,3,5,6tetrafluorophenoxymethyl copoly (styrene-1% divinylbenzene) resin, presented in the description as

HER

4- (2 ', 4'-dimethoxyphenyl-O-methylhydroxylamine) -2,3,5,6-tetrafluorophenoxymethyl copoly (styrene-1% divinylbenzene) resin, described in the description as

HER .

4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl polystyrene resin, described as

2,3,5,6-tetrafluorobenzamidomethyl-4sulfonic acid-polystyrene resin, described in the description as

2,3,5,6-tetrafluorobenzamidomethyl-4sulfonyl chloride polystyrene resin described in the description as

4-hydroxy-2,3,5,6-tetrafluorobenzoyloxymethyl polystyrene resin, described in the description as

2,3,5,6-tetrafluorobenzoylmethyl-4sulfonic acid-polystyrene resin, described in the description as

2,3,5,6-tetrafluorobenzoylmethyl-4-sulfonyl chloride polystyrene resin, described in the description as

4-hydroxy-2,3,5,6-pentafluorobenzoyl polystyrene resin, described in the description as

2,3,5,6-tetrafluorobenzoyl-4-sulfonic acid-polystyrene resin,

2,3,5,6-tetrafluorobenzoyl-4-sulfonyl represented in polystyrene chloride resin, description of how

4-hydroxy-2,3,5,6-tetrafluorophenylsulfonamidomethyl polystyrene resin described in the description as

2,3, 5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonic acid-polystyrene resin, described in the description as

2,3, 5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonyl chloride polystyrene resin, described in the description as

X- (4-hydroxy-2,3,5,6-tetrafluorobenzoyl) piperidinomethyl polystyrene resin described herein as

Ν- (2,3,5,6-tetrafluorobenzoyl-4-sulfonic acid) -piperidinomethyl-polystyrene resin, described in the description as

About e

No. (2,3,5,6-tetrafluorobenzoyl-4-sulfonyl chloride) -piperidinomethyl-4-polystyrene resin, described in the description as

E No. (4-hydroxy-2,3,5,6-tetrafluorophenylsulfonyl) -piperidinomethyl polystyrene resin, described in the description as

E No. ((2,3,5,6-tetrafluorophenyl-4-sulfonic acid) sulfonyl) piperidinomethyl polystyrene resin, described in the description as

e.

No. ((2,3,5,6-tetrafluorophenyl-4-sulfonyl chloride) sulfonyl) piperidinomethyl polystyrene resin described in the description as

Ε

4-hydroxy-2,3,5,6-tetrafluorophenyl polystyrene resin described in the description as

HER

2.3.5.6 - tetrafluorophenyl-4-sulfonic acid-polystyrene resin, described in the description as ^p \ ^p CEU — C 9 — C # ~ ^5OzH

HER ;

2.3.5.6-tetrafluorophenyl-4-sulfonyl chloride polystyrene resin, described in the description as

4-hydroxy-2,3,5,6-tetrafluorophenylsulfonyl polystyrene resin, described herein as

2,3,5,6-tetrafluorophenylsulfonyl-4sulfonic acid-polystyrene resin, described in the description as

HER

2,3,5,6-tetrafluorophenylsulfonyl-4sulfonyl chloride polystyrene resin described in the description as

HER

Even more preferred components of the solid state reaction for use according to the method of the present invention have the formula I, wherein B ¹ , B ² , B ³ and B ⁴ are E; one of B ⁵ and B ⁶ is hydrogen, and the other of B ⁵ and B ⁶ is 2,4-dimethoxyphenyl; and A represents phenylene, —C (O) -, —US (O) -, —8O2—, —BW ⁷ 8O2—, or STB ⁷ O—.

Typical examples of more preferred solid phase reaction components include:

4-carboxy-2,3,5,6-tetrafluorophenoxymethyl copolymer styrene-1% divinylbenzene resin;

4- (O-methylhydroxylamine) -2,3,5,6-tetrafluorophenoxymethyl copolymer styrene-1% divinylbenzene resin;

4- (2 ', 4'-dimethoxyphenyl-O-methylhydroxylamine) -2,3,5,6-tetrafluorophenoxymethyl copolymer styrene-1% divinylbenzene resin;

4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl polystyrene resin;

2.3.5.6-tetrafluorobenzamidomethyl-4-sulfonic acid-polystyrene resin;

2.3.5.6-tetrafluorobenzamidomethyl-4sulfonyl chloride polystyrene resin;

4-hydroxy-2,3,5,6-pentafluorobenzoyl polystyrene resin;

2.3.5.6-tetrafluorobenzoyl-4-sulfonic acid-polystyrene resin;

2.3.5.6-tetrafluorobenzoyl-4-sulfonyl chloride polystyrene resin;

4-hydroxy-2,3,5,6-tetrafluorophenylsulfonamidomethyl polystyrene resin;

2.3.5.6-tetrafluorophenylsulfonamidomethyl-4-sulfonic acid-polystyrene resin; and

2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonyl chloride polystyrene resin.

A particularly preferred solid phase reaction component is 4-hydroxy-

2,3,5,6-tetrafluorobenzamidomethyl polystyrene resin.

The use of ¹⁹ E NMR for the quantification and control of the preparation of a fluorine-containing activated ester product of a solid-phase reaction of the formula

HER

shown in diagram 11

Scheme 11

ζδ) -ΝΗΚ ⁷ + but ₂ amino resins 1

As shown in Scheme 11 above, the first step in the preparation of the fluorine-containing activated ester component of the solid phase reaction consists of loading the aminomethyl resin 1 with a 4-hydroxyfluorobenzoic acid derivative 2, as described in Scheme 1 above. The loading level of amino resin 1 is determined as described above.

The second step in the preparation of the fluorine-containing activated ester component of the solid-state reaction 36 is the reaction of the 4-hydroxyfluorine-containing component of the reaction in solid phase 3 with a carboxylic acid (compound of formula K ⁹ CO2N). The reaction time is in the range of from about 2 to about 24 hours, depending on the nature of the 4-hydroxyfluorinated component of the solid-state reaction 3, carboxylic acid (compound K ⁹ CO2N), solvent, reaction temperature and activating agent. The reaction is preferably carried out using diisopropylcarbodiimide (1E1C) in the presence of catalytic 4-dimethylaminopyridine (ΌΜΑΡ) in a suitable solvent, such as benzene, dichloromethane, dichloroethane, dioxane, THF or DMF, at approximately room temperature for approximately 18 hours. An anhydrous solvent is preferred DMF. The fluorinated activated ester component of the solid phase reaction 36 is then washed with a suitable organic solvent or solvents to remove excess reagents.

The coupling reaction described above leads to a shift to a weak field of ¹⁹ P resonances of the fluorine-containing activated ester component of the solid-state reaction 36 with respect to the 4-hydroxy-fluorine-containing activated ester component of the solid-state reaction 3. Therefore, the loading of the carboxylic acid (compound K ⁹ C0 ₂ H) can be determined by comparing the relative integral 19t values of P resonances corresponding to the activated ester and phenolic moieties. These measurements depend on the amount of resin and the total volume of the sample.

Similarly, subsequent reactions carried out on the fluorine-containing activated ester component of the solid-state reaction 36 can be calculated using the methods described above. For example, the fluorine-containing activated ester component of the solid-state reaction 36 can undergo cleavage under the action of an amine of the formula ΝΗΚ ²⁴ Κ ²⁵ , where K ²⁴ and K ²⁵ represent hydrogen, an aliphatic or aromatic group, with the formation of an amide of the formula 37 and with the concomitant regeneration of the 4-hydroxy fluorine-containing activated ester component of the solid-phase reaction 3, as shown in scheme 12.

Pattern 12

The quantitative coupling of the reaction described in Scheme 12 above is carried out by comparing the relative integral values of P resonances corresponding to the fluorine-containing activated ester component of the solid-state reaction 36 and the 4-hydroxyfluorine-containing component of the solid-state reaction 3.

Similarly, the progress of a solid-state reaction in time can be controlled by obtaining a ¹⁹ P NMR spectrum of the reaction mixture and controlling the disappearance of P resonances corresponding to the fluorine-containing component of the solid-state reaction.

Solid phase synthesis methods are extremely useful in the preparation of peptides. Peptide synthesis on solid supports usually involves the construction of a peptide from amino acids with a terminal carboxyl or C-group, in which an amino acid with a C-terminal group and a protected α-amino group is attached to a solid phase polymer. The protective group of the nitrogen atom is then cleaved and the next amino acid, also Ν-protected, is attached via a peptide bond to the α-amino group of the amino acid attached to a solid support, as described above. The deprotection cycle from the previous acid and the addition of an additional amino acid are repeated until the peptide is complete. Any reactive amino acid side chains are protected by chemical groups that can withstand the addition and removal of the Ν ^α protection, but can be removed at the end of the synthesis.

The yield of any coupling reactions used in the peptide synthesis described above was previously determined by cleaving the peptide sample from the resin, purifying the peptide and calculating the yield. Using the ¹⁹ P method described in this invention, the yield 19 is determined by simply comparing the P resonances of the starting component and the product — the peptide associated with the resin at each stage of the synthesis.

It should be understood that this invention encompasses all appropriate combinations of specific and preferred groups that are mentioned in the description.

The foregoing description can be better understood by referring to the following examples, which are presented for illustration and are not intended to limit the scope of the present invention.

P NMR

Unless otherwise indicated, ¹⁹ P NMR experiments are performed on a Wapap IpEur1i8 spectrometer operating at a ¹⁹ P frequency of 470.228 MHz. ¹ H nanoprobe (paporophilic) is tuned to a ¹⁹ P frequency. Usually, spectra are obtained with a delay-impulse-acquisition sequence repeated for ηΐ non-stationary processes. The usual spectrum width is 100,000 Hz, and chemical shifts are determined relative to COCO ₃ using the frequency of the transmitter. Spectra are obtained using a nanoprobe in which the sample is oriented at a magic angle (54.7 °) relative to the magnetic field, and the sample rotates at a speed of 100 to 1500 Hz. Samples are obtained by swelling a precisely weighed sample (2-3 mg) of the fluorine-containing reaction product in the solid phase in approximately 40 μl of deuterated dimethylformamide (DMF). When an external standard is used for analysis, it is usually added to a dry resin in a sample tube. The external standard is preferably 3-fluorobenzamide, in which case 20 μl of a 0.125 M deuterated DMF solution is added to the dry resin in a sample tube.

Example 1

Obtaining resin composition 4-hydroxy-

2,3,5,6-tetrafluorobenzamidomethyl copolymer styrene-1% divinylbenzene

About p

RChLLN

O R O R

R

About p

To a stirred suspension of aminomethyl polystyrene (0.82 mmol / g, 800 g, 656 mmol) in DMF (8 L), a solution of 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid (234 g, 984 mmol) in DMF ( 1 L), a solution of 1-hydroxybenzotriazole (133 g, 984 mmol) in DMF (250 ml) and diisopropylcarbodiimide (124 g, 984 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was filtered and the resin was washed with DMF (1 x 1 L; 5 x 2 L), THF (3 x 2 L; 2 x 3 L) and CH ₂ Cl ₂ (3 x 3 L). After that, the resin is dried in air in pallets for 2 days.

Then the resin (995 g) was added to the mixture of piperidine (125 ml) and DMF (6 L). DMF (2 L) was added to facilitate stirring and the mixture was stirred for 1 hour. Then the mixture was filtered, the resin was washed with DMF (10 x 500 ml) and dried in vacuo.

The resin was suspended in DMF (4 L), a solution of 2M HC1 (750 ml) in DMF (2 L) was added and the mixture was stirred for 0.5 h. Then the resin was filtered, washed with DMF (10 L) and THF (10 L) and dried overnight in vacuo at room temperature.

Example 2

Obtaining resin composition 2,3,4,5,6pentafluorobenzoyl copolymer styrene-1% divinylbenzene

about r

To a mixture of a copolymer of styrene and 1% divinylbenzene (100-200 mesh, 10 g) and pentafluorobenzoyl chloride (25 g) in nitrobenzene (250 ml), A1Cl ₃ (1.0 M in nitrobenzene, 38 ml) was added and the reaction mixture was stirred at 60 ° C. within 18 hours. The reaction mixture was poured into a mixture of DMF (30 ml), concentrated HCl (20 ml) and ice (80 g). The mixture is stirred for 30 minutes, filtered and the resin washed with a mixture of DMF-H ₂ O (3: 1) until the wash solution is colorless. After that, the resin was washed with warm DMF and a mixture of dichloromethane-methanol (2: 1) (6 x) and dried in vacuum. ¹⁹ P NMR δ -146.5 (2P), -157 (1P), -165.5 (2P).

Example 3

Obtaining resin composition 4-hydroxy-

2,3,5,6-pentafluorobenzoyl copolymer styrene-1% divinylbenzene

R

About p

The resin indicated in the title is obtained by treating a resin with the composition 2,3,4,5,6pentafluorobenzoyl copolymer styrene-1% divinylbenzene in a mixture of water / cyclohexane with sodium hydroxide and tetrabutylammonium hydrosulfate, as described in the publication Her Eshap e! A1., E Ogd. Sc., 56 (26), 7350-7354 (1991).

Example 4

Obtaining resin composition 2,3,5,6tetrafluorobenzoyl-4-sulfonic acid copolymer styrene-1% divinylbenzene p

about r

A mixture of resin composition 2,3,4,5,6pentafluorobenzoyl copolymer styrene-1% divinylbenzene (325 mg) obtained according to the method of example 2, dichloromethane (3 ml), H ₂ O (1 ml), triethylamine (1.2 ml) and potassium metabisulfite (560 mg) was stirred for 3 days. Then the resin is washed with dichloromethane (6 x) and dried in vacuum at 40 ° C. ¹⁹ G NMR δ -142 (2G), -147 (2P).

Example 5

Obtaining a resin composition 2,3,5,6tetrafluorobenzoyl-4-sulfonyl chloride-copolymer styrene-1% divinylbenzene

E

About e

A resin composition of 2,3,5,6-tetrafluorobenzene-4sulfonic acid-styrene-1% divinylbenzene copolymer (300 mg) obtained in Example 4 was subjected to swelling in carbon tetrachloride (3 ml) and chlorosulfonic acid (1 ml) was added. The reaction mixture was stirred for 24 hours, then the reaction was quenched with acetic acid. The resin is filtered, washed with dichloromethane (6 x) and ether (4 x) and dried in vacuum at 40 ° C. ¹⁹ P NMR δ -142 (2G), -146.5 (2G).

Example 6

Obtaining a resin composition 2,3,4,5,6pentafluorophenylsulfonamidomethyl copolymer styrene-1% divinylbenzene

E

Aminomethyl polystyrene (1 g, 1.2 mmol) is swelled in dichloromethane and 2,4,6-collidine (0.475 ml, 3.6 mmol) is added and

2.3.4.5.6-pentafluorophenylsulfonyl chloride (1.44 mmol). The reaction mixture was stirred for 5 hours and the resin was filtered off, washed with dichloromethane (6 x) and dried in vacuo at 40 ° C.

Example 7

Obtaining resin composition 4-hydroxy-

2.3.5.6- pentafluorophenylsulfonamidomethyl copolymer styrene-1% -divinylbenzene

The title resin was prepared according to the method of Example 3, with the difference that a resin of 2,3,4,5,6-pentafluorobenzoyl copolymer styrene-1% divinylbenzene was replaced with a resin of 2,3, 4,5,6-pentafluorophenyl sulfonamidomethyl copolymer styrene-1% -divinylbenzene obtained as in example 1.

Example 8

4-Carboxy-2,3,5,6-tetrafluorophenoxymethyl copolymer styrene-1% divinylbenzene.

p e

Merrifield resin (2 mmol / g, 600 mg, 1.2 mmol) is swelled in anhydrous DMF (20 ml). 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid hydrate (2.28 g, 10 mmol) and cesium carbonate (3.26 g, 10 mmol) are added, the reaction mixture is heated to 85 ° C and kept at this temperature for 12 hours with moderate stirring. The reaction mixture is filtered, and the 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl copolymer styrene-1% divinylbenzene is washed with DMF (5 x), 20% aqueous DMF (5 x), THF (5 x) and dichloromethane and dried over nights in a vacuum. IR (microscope, cm ^-1 ):

1640 (C = O); ¹⁹ g NMR (nanoprobe) -144.4 ppm, -160.2 ppm.

Example 9

Determination of aminomethyl resin loading with 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid (TGR) using ¹⁹ g NMR

The loading of the resin with the composition 4-hydroxy-2,3,5,6tetrafluorobenzamidomethyl copolymer styrene 1% divinylbenzene is determined by obtaining a ¹⁹ G NMR spectrum of a sample consisting of a mixture of 3 fluorobenzamide and 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl copolymer styrene-1% divinylbenzene . The integrals of ¹⁹ G resonances corresponding to 3-fluorobenzamide and a resin composition of 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl copolymer styrene-1% divinylbenzene are measured and, using formula 1, the resin loading is calculated.

^{A 19} G NMR spectrum was obtained at room temperature on a Wapap IpuP1iz spectrometer operating at 470.23 MHz. The spectrometer is equipped with a single carbon proton nanoprobe (§ § е е р го го № №))))) tuned to ¹⁹ G. The sample is prepared by accurately weighing (2-4 mg) the resin in the sample tube. 20 microliters of a 0.125 M solution of 3-fluorobenzamide in 67-dimethylformamide (Satbpbde 1so1ore8) are added to the suspended resin, then an amount of 67 dimethylformamide sufficient to fill the sample tube (total solvent volume is approximately 40 microliters).

The loading of 4 resin samples of the composition 4hydroxy-2,3,5,6-tetrafluorobenzamidomethyl copolymer styrene-1% divinylbenzene obtained using the binding conditions described above is determined using ¹⁹ G NMR and analysis by burning, the results are presented in the table. As shown in the table, there is a perfect match between the resin loading values determined using ¹⁹ G NMR and the loading values determined using combustion analysis.

Table. Determination of aminomethyl resin loading with 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid (TGR) using ¹⁹ g NMR

Sample Connection Conditions Resin loading (mmol TTR / g resin) ¹⁹ g NMR Combustion analysis one Initial loading of aminomethyl resin 0.82 mmol / g 0.83 0.87 2 As in example 1; initial loading of aminomethyl resin 0.39 mmol / g 0.27 0.28 3 As in example 1, the initial loading of aminomethyl resin of 0.47 mmol / g 0.35 0.35 4 As in example 1, except that 20% HC1 in DMF is used instead of 2Ν HC1 / DMF; initial loading of aminomethyl resin 0.47 mmol / g 0.35 0.38

Example 10

General method for preparing activated ester polymer derivatives of a resin of 2,3,5,6-tetrafluorobenzamidomethyl copolymer styrene-1% divinylbenzene

Ε E

O Ε O E

Samples of 4-hydroxy-2,3,5,6tetrafluorobenzamidomethyl copolymer styrene-1% divinylbenzene (0.47 mmol / g) were weighed into each of 40 Jones tubes (1ope 1bb) with a volume of 20 ml placed in a test tube rack and in DMF (4 ml), diisopropylcarbodiimide (ΌΣΟ; 0.186 ml, 5 equiv.) and 4 dimethylaminopyridine (ΌΜΆΡ, 43 mg, 1.5 equiv. (1 ml of the initial solution obtained by dissolving 1720 mg ΌΜΆΡ in 40 ml of DMF) are added to each tube) . The combination carboxylic acid (5 eq.) Is added and the tripod is vibrated overnight at room temperature. The tube stand is removed from the screen and the resin samples are filtered into two baths of 20. Resin samples are washed with DMF (5 x 5 ml), THF (5 x 5 ml) and CH ₂ Cl ₂ (5 x 5 ml) and dried overnight at 35 ° C.

Example 11

Monitoring the formation of a product of composition 4 [1 - (4-trifluoromethylphenyl) -2,5-dimethylpyrrol4-oyl] hydroxy-2,3,5,6-tetrafluorobenzamidomethyl copolymer styrene-1% divinylbenzene using ¹⁹ G NMR

here from the reaction at selected time periods and obtaining ¹⁹ G NMR of the aliquot spectrum. As reaction Г proceeds, resonances corresponding to the initial 4-hydroxy

The 2,3,5,6-tetrafluorobenzamidomethyl copolymer styrene-1% divinylbenzene is replaced with ¹⁹ G resonances of the corresponding product of the composition 4- [1- (4-trifluoromethylphenyl) -2,5-dimethylpyrrol-4-oyl] oxy-2,3, 5 , 6-tetrafluorobenzamidomethyl copolymer styrene-1% divinylbenzene. ¹⁹ G NMR spectra obtained after 5, 50 and 100 minutes show that after 5 minutes the reaction mixture consists entirely of the starting resin; after 50 minutes, from approximately equal amounts of the starting resin and the activated ester polymer product; and after 100 minutes, almost entirely from the activated ester polymer product. An accurate calculation of the reaction course for a given period of time is obtained by integrating Г resonances of the initial resin and the product — activated ester resin.

Example 12

General procedure for the cleavage of activated ester derivatives of resins of the composition 2,3,5,6-tetrafluorobenzamidomethyl copolymer styrene-1% divinylbenzene under the action of amines

Ε E

The required number of activated ester derivatives of the resin composition

The 2,3,5,6-tetrafluorobenzamidomethyl styrene-1% divinylbenzene copolymer is placed in the desired receiver, i.e. 96 cell plate; reaction flasks, tubes, etc.

The stock solution in DMF of the desired amine is obtained in the desired capacity. Using any suitable means, that is, using a pipette or automatic device, the desired amount of the amine stock solution is transferred to the reaction vessels with the resin. The amount of amine to be added is usually 0.8 equivalents of resin (in mmoles). The reaction vessels were stirred for approximately 3 days. The mixture of reaction vessels is then removed with a pipette or with an automatic filtering device through any suitable device, such as Johns Copez filter tubes (NigNop 1 & 6) or through a filter plate Po1u1! 11gop1sz. These techniques allow the free resin to be stored on the filtration device, allowing the reaction liquid to pass into a collection vessel, such as a test tube or 96 cell plate. The filtrate was then evaporated to dryness using any suitable device, such as TiBoOas; Zauap! or the Jenevac vaporizer (Oepeuas Euaroga! og). This process will give targeted

The combination of the resin composition 4-hydroxy2,3,5,6-tetrafluorobenzamidomethyl copolymer styrene-1% -divinylbenzene and 1- (4-trifluoromethylphenyl) -2,5-pyrrole-4-carboxylic acid according to the method of example 10 is controlled using ¹⁹ G NMR by isolation of alik49 a compound in the form of an amide in a form suitable for biological testing. In the case of amines, which may be Ν-protected as BOC derivatives, etc., or in the presence of tert-butyl ether groups, they can be removed by treating the final protected amide product with a mixture of trifluoroacetic acid in methylene chloride in the presence of traces of water.

Example 13. Obtaining a fluorine-containing solid carrier.

450 ml of deionized water, 4.5 g of polyvinylpyrrolidone and 0.5 g of azoisobutyronitrile are charged into a 1 L cylindrical reactor. The reactor is well purged with nitrogen gas. The mixture is stirred for 30 minutes at 200 rpm using a Teflon mixer, then styrene (24 ml), 4-fluorostyrene (11.4 ml), 1,4-vinylbenzene (0.6 ml) and 4-vinylbenzyl chloride ( 13.8 ml). The mixture is again stirred for one hour at room temperature at a speed of 305 rpm./min, then heated to 80 ° C and maintained at this temperature for 18 hours to complete the polymerization reaction. After cooling, the resin is washed with water (1.5 L), methanol (1.0 L) and dimethylformamide (2 x 500 ml) and dried in vacuum. Elemental analysis of the polymer resin yields 7.41% C1 and 3.22% G. The IR spectrum of the resin shows: 1266 cm ^-1 (-CH ₂ C1 \\ ^; hell) and 1223 cm ^-1 (SG-elongated).

Example 14. Obtaining a fluorine-containing solid carrier by modifying the previously obtained resin.

Merrifield resin (2 mmol / g, 1.0 g, 2.0 mmol) is swelled in anhydrous dimethylformamide (25 ml). A solution of 4 fluorophenol (0.7 mmol, 78 mg) and sodium hydroxide (0.75 mmol, 0.75 ml of a 1.0 N aqueous solution) in 3 ml of dimethyl sulfoxide is added, the reaction mixture is heated to 80 ° C and maintained at this temperature for with moderate stirring for 30 hours. After cooling, the resin is washed successively with dimethylformamide (2 x 25 ml), 2% aqueous HC1 in dimethylformamide (1 ml in 9 ml of dimethylformamide; 25 ml), dimethylformamide (2 x 25 ml) and, finally, CH2C12 (2 x 25 ml). The product is dried in vacuo, then stored at -5 ° C until use.

Claims (16)

CLAIM 1. A method for quantifying a solid-state reaction, comprising (a) reacting a solid-phase reaction component or a fluorine-containing solid-phase reaction component with a reagent or fluorine-containing reagent to obtain a fluorine-containing solid-phase reaction product; (b) obtaining a ¹⁹ E NMR spectrum of a fluorine-containing solid-phase reaction product; and (c) comparing the integral corresponding to the ¹⁹ E resonance of the fluorine-containing solid-phase reaction product with the integral corresponding to the 19 resonance of the internal standard. 2. The method according to claim 1, where ¹⁹ E NMR spectra were obtained by rotation under a magic angle. 3. The method according to claim 1, where the internal standard is a fluorine-containing component of a solid-phase reaction of the formula where (!) Represents a solid carrier, optionally containing one or more fluorine atoms; B is absent or represents a linking group, optionally containing one or more fluorine atoms, provided that at least one component selected from a solid support and a linking group contains at least one fluorine atom; and B represents a functional group suitable for reacting with a reagent to form a fluorine-containing solid-phase reaction product. 4. The method according to claim 3, where the solid carrier contains one or more fluorine atoms. 5. The method according to p. 3, where ® represents a solid carrier; B represents a group of the formula A is missing or selected from -С (О) -, -СУ (О) -, -8О2-, -ΝΚ ⁷ 8Θ2-, СНК ⁷ -, -СНК ⁷ У- and -СНК ⁷ CSS (O) (СН2) _t -; B represents halogen, ΝΠΡ, ΘΨ or 8Ο2Ζ; Ό represents CH or Ν; P represents H or an amino protecting group; represents H, ΝΙΙΡ, ΝΡΚ ⁹ , ^ (O) C1, C (O) K ⁹ , C (O) NK ¹⁰ K ^P , C (O) OK ⁹ , 8O ₂ K ⁹ or -C (O) -imidazole- 1-yl; Υ represents —O— or —ΝΚ ⁸ -; Ζ represents C1, OH, OK _a or ΝΚ ⁹ Κ ¹² ; K ¹ represents G or, when one of K ¹⁶ , K ¹⁷ , K ¹⁸ and K ¹⁹ represents G, K ¹ represents H, alkyl, alkoxy, halogen, CN or NΟ ₂ ; K ² , K ³ and K ⁴ independently represent H, alkyl, alkoxy, halogen, CN or NΟ ₂ , or one of K ² , K and K ⁴ together with one of K ⁵ and K ⁶ and the carbon atoms to which they are attached form a group of the formula K ⁵ and K ⁶ independently represent —H, alkyl, phenyl or phenyl substituted with one or more substituents selected from alkyl, alkoxy, halogen, nitrile and —ΝΟ ₂ ; K ⁷ and K ⁸ independently represent H or alkyl containing from 1 to 4 carbon atoms; K ⁹ and K ¹³ independently represent a group of an aliphatic or aromatic series; K ¹⁰ and K ¹¹ independently represent H, an aliphatic or aromatic group; K ¹² represents —CH ₂ K ¹³ ; K ¹⁴ , K ¹⁵ , K ¹⁶ , K ¹⁷ , K ¹⁸ , K ¹⁹ , K ²⁰ , K ²¹ , K ²² and K ^{23 are} independently selected from H, alkyl, alkoxy, halogen, —ΌΝ and —ΝΟ ₂ ; t is 0 or 1; η is 1-6; and p is 0, 1 or 2. 6. The method according to claim 5, where K ¹ , K ² , K ³ and K ⁴ represent P; and one of K ⁵ and K ⁶ represents H, and the other of K ⁵ and K ⁶ represents H or 2,4 dimethoxyphenyl. 7. The method according to claim 6, where B represents P, SZ or 8Ο ₂ Ζ. 8. The method according to claim 7, where A represents phenylene, -C (O) -, -US (O) -, -8Ο ₂ -, -ΝΕ ^ Οζ or -СИК ^ -. 9. The method according to claim 5, where the fluorine-containing component of the solid-phase reaction is selected from the following compounds: resins of 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl- (styrene-1% divinylbenzene) copolymer; resins of 4- (O-methylhydroxylamine) -2,3,5,6tetrafluorophenoxymethyl- (styrene-1% divinylbenzene) copolymer; resins of 4- (2 ', 4'-dimethoxyphenyl-O-methylhydroxylamine) -2,3,5,6-tetrafluorophenoxymethyl- (styrene-1% divinylbenzene) copolymer; resins of 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl polystyrene; resins 2,3,5,6-tetrafluorobenzamidomethyl 4- (sulfonic acid) -polystyrene; resins 2,3,5,6-tetrafluorobenzamidomethyl 4-sulfonyl chloride polystyrene; 4-hydroxy-2,3,5,6-tetrafluorobenzoyloxymethyl polystyrene resins; resins 2,3,5,6-tetrafluorobenzoyloxymethyl-4- (sulfonic acid) -polystyrene; resins 2,3,5,6-tetrafluorobenzoyloxy methyl-4-sulfonyl chloride polystyrene; resins of 4-hydroxy-2,3,5,6-pentafluorobenzoyl polystyrene; resins 2,3,5,6-tetrafluorobenzoyl-4- (sulfonic acid) -polystyrene; 2,3,5,6-tetrafluorobenzoyl-4-sulfonyl chloride polystyrene resins; 4-hydroxy-2,3,5,6-tetrafluorophenylsulfonamidomethyl polystyrene resins; resins 2,3,5,6-tetrafluorophenylsulfonamidomethyl-4- (sulfonic acid) -polystyrene; resins of 2,3,5,6-tetrafluorophenylsulfonamidomethyl-4-sulfonyl chloride polystyrene; gums - - (4-hydroxy-2,3,5,6-tetrafluorobenzoyl) -piperidinomethyl polystyrene; resins \ - (2,3> 5,6-tetrafluorobenzoid-4sulfonic acid) -piperidinomethyl polystyrene; gums - - (2,3,5,6-tetrafluorobenzoyl-4sulfonyl chloride) -piperidinomethyl-4-polystyrene; gums - - (4-hydroxy-2,3,5,6-tetrafluorophenylsulfonyl) piperidinomethyl polystyrene; resins \ - ((2,3,5,6-tetrafluorophenyl-4sulfonic acid) -sulfonyl) piperidinomethyl polystyrene; resins \ - ((2,3,5,6-tetrafluorophenyl-4sulfonyl chloride) -sulfonyl) piperidinomethyl polystyrene; resins of 4-hydroxy-2,3,5,6-tetrafluorophenyl polystyrene; resins 2,3,5,6-tetrafluorophenyl-4- (sulfonic acid) -polystyrene; 2.3.5.6-tetrafluorophenyl-4-sulfonyl chloride polystyrene; resins of 4-hydroxy-2,3,5,6-tetrafluorophenylsulfonyl polystyrene; resins 2,3,5,6-tetrafluorophenylsulfonyl 4- (sulfonic acid) -polystyrene; resins of 2,3,5,6-tetrafluorophenylsulfonyl 4-sulfonyl chloride polystyrene. 10. The method according to claim 5, where the fluorine-containing component of the solid-phase reaction is selected from the following components: resins of 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl- (styrene-1% divinylbenzene) copolymer; resins of 4- (O-methylhydroxylamine) -2,3,5,6tetrafluorophenoxymethyl- (styrene-1% divinylbenzene) copolymer; resins of 4- (2 ', 4'-dimethoxyphenyl-O-methylhydroxylamine) -2,3,5,6-tetrafluorophenoxymethyl- (styrene - 1% divinylbenzene) copolymer; resins of 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl polystyrene; resins 2,3,5,6-tetrafluorobenzamidomethyl 4- (sulfonic acid) -polystyrene; resins 2,3,5,6-tetrafluorobenzamidomethyl 4-sulfonyl chloride polystyrene; resins of 4-hydroxy-2,3,5,6-pentafluorobenzoyl polystyrene; 2.3.5.6-tetrafluorobenzoyl-4- (sulfonic acid) -polystyrene; 2,3,5,6-tetrafluorobenzoyl-4-sulfonyl chloride polystyrene resins; 4-hydroxy-2,3,5,6-tetrafluorophenylsulfonamidomethyl polystyrene resins; resins 2,3,5,6-tetrafluorophenylsulfonamidomethyl-4- (sulfonic acid) -polystyrene; and resins 2,3,5, 6-tetrafluorophenylsulfonamidomethyl-4-sulfonyl chloride polystyrene. 11. The method according to claim 5, where the fluorine-containing component of the reaction in the solid phase is a resin of 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl polystyrene. 12. The method according to claim 1, where the solid-phase reaction component is a resin of chloromethylated polystyrene and the fluorine-containing reagent is 4-fluorophenol. 13. A fluorine-containing component of a solid-phase reaction of the formula where (ep) O is a solid support containing one or more fluorine atoms, HS is absent or represents a linking group, where HS is optionally substituted with one or more fluorine atoms; and B represents a functional group suitable for reaction with a reagent to form a fluorine-containing solid-phase reaction product. 14. The fluorine-containing component of the solid-state reaction according to item 13, which is obtained by polymerization of a mixture comprising at least one fluorine-containing monomer. 15. The fluorine-containing component of the solid-state reaction according to 14, where the fluorine-containing monomer is 4-fluorostyrene. 16. The fluorine-containing component of the solid-state reaction according to 14, which is obtained by polymerization of a mixture of styrene, 4-fluorostyrene, 1,4-divinylbenzene and 4-vinylbenzyl chloride.