HUP0003125A2 - New solid-phase synthesis methods for the preparation of several analog compounds - Google Patents

Abstract

The subject of the invention is a method for synthesizing several analog compounds in such a way that (a) a solid-phase intermediate is reacted with some cleaving/condensing reagent, whereby a solution-phase condensation product is formed and a solid-phase intermediate remains; (b) the solution phase condensation product formed in step (a) is separated from the solid phase; (c) the intermediate carried on the remaining solid phase is reacted with a cleavage/condensation reagent different from the cleavage/condensation reagent used in step (a), during the formation of a solution-phase condensation product analogous to the solution-phase condensation product formed in step (a); (d) separating the solution phase condensation product from step (c) from the solid phase; and (e) if desired, if an intermediate carried on the remaining solid phase is present, steps (c) and (d) are repeated one or more times, with the application of additional different cleavage/condensing reagents at each repetition, during the formation of additional analogous solution-phase condensation products. HE

Description

ΐΖε-Κ-Κ íUOppr

Ήϊ UX.WKxI^g _290ί uupppqvzg rzo^zmsM

68.597/ZE ^-D-rs ^0003125

PUBLICATION

COPY

A2_

New solid-phase synthesis methods for the preparation of several analogue compounds

The invention relates to chemical syntheses using solid phase methods. Solid phase synthesis methods are used in the preparation of peptides (Merrifield, J. Am. Chem. Soc. 85:2149-2154 (1963)), oligonucleotides (Oligonucleotide Synthesis: A Practical Approach, Gait, ed. IRL Press, Oxford ( 1964)) and small organic molecules (Leznoff, Acc. Chem. Res., 11, 327 (1978); Hermkins, Tetrahedron, 52, 4527-4554 (1996)). Solid-phase synthesis methods can be effectively applied to the combinatorial synthesis of large libraries (Bunin et al., J. Am. Chem. Soc. 114, 10997-10998 (1992)), which libraries themselves are good tools for medicinal chemistry research (U.S. Patent No. 5,506,337; Terrett et al., Tetrahedron, 51, 8135-8173 (1995)).

One advantage of solid-phase methods is that reactions can be carried out using large excesses of reagents, after which the excess reagent can be removed by simple filtration. The solid-phase supported product can then be removed from the solid support with a cleavage reagent, after which the solution-phase product can be separated from the solid phase by filtration. Alternatively, the final reaction step of the solid-phase synthesis can be coupled to a cleavage reaction to yield the final product, followed by the subsequent transfer of the product to the solution phase (Dewitt and Czarnik, Acc. Chem. Res., 29, 114 (1996)). Thus, in general practice, solid-phase synthesis methods yield a single solution-phase product for each aliquot of the solid-phase supported starting material or intermediate.

- from part 2. Methods are needed that allow the production of multiple analogous compounds from an aliquot of a starting material or intermediate supported on a solid phase.

The above and other references mentioned in the specification form part of the invention.

The invention relates to a method for synthesizing several analogous compounds in such a way that:

(a) reacting a solid-phase supported intermediate with a cleaving/condensing reagent, thereby forming a solution-phase condensation product and leaving a solid-phase supported intermediate;

(b) separating the solution-phase condensation product formed in step (a) from the solid phase;

(c) reacting the remaining solid phase supported intermediate with a cleavage/condensation reagent different from the cleavage/condensation reagent used in step (a) to form a solution phase condensation product analogous to the solution phase condensation product formed in step (a);

(d) separating the solution phase condensation product formed in step (c) from the solid phase; and (e) optionally, if a residual solid phase supported intermediate is present, repeating steps (c) and (d) one or more times, each time using a different cleavage/condensation reagent, while forming additional analogous solution phase condensation products.

According to a second embodiment of the invention, the invention provides a method for synthesizing a plurality of analogous compounds by:

(a) reacting a solid phase supported intermediate with a cleavage/condensation reagent, thereby forming a solution phase condensation product and leaving a solid phase supported intermediate;

(b) separating the solution-phase condensation product formed in step (a) from the solid phase;

(c) optionally repeating steps (a) and (b) one or more times, each time using a different cleaving/condensing reagent, while forming additional analogous solution phase condensation products.

(d) modifying the solid phase supported intermediate to obtain a solid phase supported intermediate analogous to the solid phase supported intermediate used in steps (a)-(c);

(e) reacting the analogous solid phase supported intermediate with a cleaving/condensing reagent to obtain a solution phase condensation product analogous to the solution phase condensation product formed in steps (a) or (c);

(f) separating the solution phase condensation product obtained in step (e) from the solid phase;

(g) if any remaining solid phase supported intermediate is present, optionally repeating steps (e) and (f) one or more times, each time using a different cleaving/condensing reagent, to obtain further analogous solution phase condensation products; and (h) optionally repeating steps (d) to (g) one or more times, to obtain further analogous solution phase condensation products.

According to a third embodiment of the invention, the invention provides a combinatorial library containing a plurality of analogous compounds prepared by the methods of the invention.

- 4 The invention is described in detail below.

The terms used in the specification and claims have the following meanings unless otherwise indicated.

The term alkyl in the 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfinylalkyl, 4-hydroxyphenylsulfonylalkyl, 4-aminosulfonylbenzoylaminoalkyl, and 3-aminosulfonylpropionylaminoalkyl groups means a straight-chain, saturated aliphatic hydrocarbon group having 1-6 carbon atoms.

The term analogous compounds or analogous solution phase condensation products means that said compounds or products are chemically similar to each other in that they are derived from similar starting materials or intermediates, but are chemically different.

The term linking group means a divalent radical which links an intermediate compound to the solid support. According to the invention, in the description and claims, the term linking groups refers to a monovalent precursor radical linked to the solid support. For example, a linking group of the following general formula -

- where SS represents the solid support, represents a 4-hydroxyphenylthioalkyl group, such as, for example, a 4-hydroxyphenylthiomethyl group.

The phrase "if desired" means that the following event or condition may or may not occur; it means that the description includes examples where the event or condition occurs and examples where the event or condition does not occur. For example, the following sentence: if desired, repeat

- 5 - ♦ ·-. .,:

"steps (c) and (d)" means that the relevant steps may or may not occur within the scope of the invention.

The term "residual solid phase supported intermediate" refers to the solid phase supported intermediate that remains unreactedly attached to the solid phase support after the solid phase supported intermediate is subjected to a cleavage/condensation reaction and the resulting solution phase condensation product is separated from the solid phase.

The term substoichiometric amount means a molar amount less than one molar equivalent. Thus, in the specification and claims, with respect to substoichiometric amounts of cleavage/condensation reagents, this means that the molar amount of the reagents present in the reaction medium is a fraction of the molar amount of the intermediate supported on the solid phase present.

The process of the invention relates to the synthesis of multiple analogous compounds by successively treating a solid phase supported intermediate in a manner that results in the formation of a solution phase condensation product and the solid phase supported intermediate remains in an amount sufficient to carry out subsequent cleavage/condensation reactions with other cleavage/condensation reagents.

For example, the process of the invention can be illustrated by the following reaction scheme:

Reaction scheme 1

where SS represents the solid support, X represents a linking group between the solid support and the intermediate supported on the solid phase, Y represents any group capable of initiating a cleavage/condensation reaction, R‘, Ra, Rb and R° represent any non-reactive group and Z is a linking group formed during the condensation reaction.

In the process of the invention, a solid phase supported intermediate of formula 1 is reacted with a suitable cleavage/condensation reagent of general formula R ^a Y in such a way that the solid phase supported intermediate is cleaved from the solid support and simultaneously undergoes a condensation reaction with the cleavage/condensation agent to form a first solution phase condensation product of formula 2(a) and all solid phase supported intermediate remains unreacted. The

- 7 the first solution phase condensation product obtained is separated from the solid phase, the remaining solid phase supported intermediate of formula 1(a) is reacted with a second, different cleavage/condensation reagent of general formula R ^b Y to form a second solution phase condensation product of general formula 2(b); then the second solution phase condensation product is separated from the solid phase. After the separation of the second solution phase condensation product of general formula 1(b), or after any subsequent condensation/cleavage reaction and separation step (1(n)), the remaining solid phase supported intermediate is optionally reacted with a suitable cleavage/condensation reagent of general formula RY to form further analogous solution phase condensation products of general formula 2(n).

The remaining solid phase supported intermediate can be generated in any manner that results in an incomplete reaction relative to the amount of solid phase supported intermediate used. For example, an incomplete reaction can be brought to completion by changing the reaction conditions - e.g. reaction temperature or pressure, solvents, etc. - to slow down the reaction rate or limit the reaction times. A common means of generating an incomplete reaction is to use a substoichiometric amount of the cleaving/condensing reagent relative to the amount of solid phase supported intermediate.

Suitable solid supports include polymers (e.g. polystyrene, poly(ethylene glycol) grafted polystyrene, poly(ethylene glycol) grafted polyacrylamide, etc.), cellulose, modified silica gel supports, modified controlled pore glass, etc. Suitable linking groups include chemical functional groups or bonds that are capable of reacting with the cleaving/condensing reagents. For example, suitable linking groups for carboxylic acid intermediates include 4-hydroxyphenylthioalkyl-,

- 8 4-hydroxyphenylsulfinylalkyl, 4-hydroxyphenylsulfonylalkyl, 4-hydroxy-2-nitrophenyl4-hydroxy-3-nitrophenyl and the like, where an ester bond is formed between the intermediate and the linking group; or 4-aminosulfonylbenzoylaminoalkyl, 3-aminosulfonylpropionylaminoalkyl and the like, where an amide bond is formed. Suitable linking agents for the various intermediate compounds are compounds known to those skilled in the art.

Suitable cleavage/condensation reagents include nucleophilic amines, organometallic reagents (e.g., Grignard reagents, organolithium reagents, etc.), alcohols, anilines, phenols, thiols, activated carbon nucleophiles (e.g., beta-ketoesters, beta-diesters, beta-cyanoesters, nitroalkanes, etc.), and the like.

Within the broadest scope of the invention, certain embodiments of the invention are preferred. For example, preferred are processes wherein the remaining solid phase supported intermediate is formed by reacting the solid phase supported intermediate with a substoichiometric amount of a cleaving/condensing reagent. More preferred are processes wherein the solid support is a polymer and the solid phase supported intermediate is a carboxylic acid derivative which, together with the linking group attached thereto, forms an ester or amide bond. Even more preferred is the process wherein the linking group is 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfinylalkyl, 4-hydroxyphenylsulfonylalkyl, 4-hydroxy-2-nitrophenyl, 4-hydroxy-3-nitrophenyl, 4-aminosulfonylbenzoylaminoalkyl, or 3-aminosulfonylpropionylalkyl. Particularly preferred is the process where the cleavage/condensation reagent is an amine or an organometallic reagent, or where the linking group is a 4-aminosulfonylbenzoylaminoalkyl or 3-aminosulfonylpropionylaminoalkyl group and the cleavage/condensation reagent is an alcohol, aniline, thiol or carbon nucleophile. Still further

- 9 The process is more preferred where the solid support is polystyrene or poly(ethylene glycol) or grafted polystyrene. The process is most preferred where the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the cleaving/condensing reagent is an amine.

A process according to the invention, wherein the solid phase supported intermediate forms an ester bond with the linking group and Y is an amino group, is illustrated by the following reaction scheme:

2, reaction scheme

where SS is a solid support and R ² , R ^a , R ^b and R ⁿ are each a non-reactive group.

w z

- 10 The process of the invention, wherein the solid phase intermediate forms an ester bond with the linking group and the cleavage/condensation reagent is an amine, can be carried out under standard acylation reaction conditions, using commonly used separation methods. For example, the cleavage/condensation reaction can be carried out in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, N-methylmorpholine, etc., preferably triethylamine), in a suitable solvent (e.g. 2,6-lutidine, pyridine, toluene, tetrahydrofuran, etc., preferably 2,6-lutidine or pyridine) at a temperature between 0°C and 70°C, preferably at about ambient temperature, for 1-100 hours. The solution phase condensation product can be separated from the solid phase by filtration and washing the solid support with a suitable solvent (such as dichloromethane, methanol, tert-butyl methyl ether, toluene, tetrahydrofuran, diethyl ether, etc.). Certain solid supports (such as polystyrene) swell in the presence of an organic solvent and in such cases the separation can be facilitated by washing the solid support with a solvent that results in high swelling (such as dichloromethane, toluene or tetrahydrofuran) and a solvent that results in low swelling (such as tert-butyl methyl ether, diethyl ether or methanol). The procedures are described in more detail in Examples 3 and 4.

The solid phase supported intermediates used in the processes of the invention can be prepared by methods known in the art. For example, solid phase supported intermediates that form an ester bond with the linking group, where the linking group is a 4-hydroxyphenylthioalkyl group, can be prepared by reacting a suitable carboxylic acid or active ester (e.g., a carboxylic acid halide), or a protected derivative thereof, with a suitable 4-hydroxyphenylthioalkyl polystyrene. The reaction can be carried out using a suitable coupling reagent (e.g., diisopropylcarbodiimide,

- I I benzotriazol-1-yloxy-tris-pyrrolidino-phosphonium-hexafluoro-phosphate (PyBOP°), bromo-tris-pyrrolidino-phosphonium-hexafluoro-phosphate, O-benzotriazole-N,N,N;N'-tetramethyl-uronium-hexafluoro-phosphate, N,N,N;N'-tetramethyl-fluoro-formamidinium-hexafluoro-phosphate, etc.), in the presence of a suitable base (e.g. triethylamine, N methyl-morpholine, diisopropylethylamine, etc.) and a suitable catalyst (e.g. 4-dimethyl-amino-pyridine, 1-hydroxy-benzotriazole, 1-hydroxy-7-aza-benzotriazole, etc.), at a temperature between 20 and 60°C, preferably at approximately ambient temperature, and for a reaction time of 10 to 100 minutes. The reaction is described in detail in Examples 1 and 2.

The methods of the invention can also be carried out with other solid supports, and the intermediates supported on the solid support can also be prepared with other solid supports and linking groups in a manner well known in the literature and obvious to those skilled in the art.

An alternative way of carrying out the process according to the invention is illustrated by the following reaction scheme:

Reaction scheme 3

In an alternative embodiment of the process of the invention, a solid-phase supported intermediate is reacted in any manner that produces a first solution-phase condensation product and leaves a portion of the solid-phase supported intermediate unreacted, then the first solution-phase condensation product is separated from the remaining solid-phase supported intermediate, the remaining solid-phase supported intermediate is modified to produce a second solid-phase supported intermediate (Figure 3), and then the second solid-phase supported intermediate is reacted with a cleaving/condensing reagent to produce an analogous solution-phase condensation product of general formula 4(a).

Example 1

4-(4-Methoxybenzoylaminoacetoxy)phenylthiomethylpolystyrene

The preparation of a solid phase supported intermediate is described below, where the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the intermediate is 4-methoxybenzoylaminoacetic acid.

A mixture of 160 mg (0.91 mmol) of tert-butoxycarbonylaminoacetic acid and 145 μΙ (0.93 mmol) of diisopropylcarbodiimide in 2 ml of dichloromethane was mixed to give a slurry. The slurry was mixed with 236 mg (1.23 meq/g) of 4-hydroxyphenylthiomethylpolystyrene, 290 μΙ (2.09 mmol) of triethylamine and a few crystals of 4-dimethylaminoU. :::·Η.::- J pyridine. The mixture was vortexed and allowed to stand at ambient temperature for 1 hour. It was then filtered and the solid residue was washed three times with dichloromethane and then methanol, yielding 4-tert-butoxycarbonylaminoacetoxyphenylthiomethylpolystyrene.

The resulting 4-tert-butoxycarbonylaminoacetoxyphenylthiomethylpolystyrene was treated with a 50:48:2 (v/v) dichloromethane/trifluoroacetic acid/anisole mixture for 0.5 h at ambient temperature. The mixture was then filtered and the solid residue was washed three times alternately with dichloromethane and then with methanol to give 4-aminoacetoxyphenylthiomethylpolystyrene.

A mixture of 135 mg (0.91 mmol) of 4-methoxybenzoic acid and excess thionyl chloride was heated under reflux for 5 min. The excess thionyl chloride was removed in vacuo to give crude 4-methoxybenzoyl chloride. The crude 4-methoxybenzoyl chloride was dissolved in 2 mL of dichloromethane and the solution was added to a mixture of 4-aminoacetoxyphenylthiomethylpolystyrene and excess triethylamine. The mixture was vortexed and allowed to stand at ambient temperature for 0.5 h. It was then filtered and the solid residue was washed three times with dichloromethane and then methanol to give 4-(4-methoxybenzoylaminoacetoxy)phenylthiomethylpolystyrene.

2, Example

4-{3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxy}-phenylthiomethylpolystyrene

The preparation of a solid phase supported intermediate is described below, where the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the intermediate is 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionic acid.

- 14 A mixture of 409 mg (2.15 mmol) of 3-tert-butoxycarbonylaminopropionic acid and 360 μΙ (2.3 mmol) of diisopropylcarbodiimide in 10 mL of dichloromethane was mixed to form a slurry. The slurry was mixed with 1.02 g (0.75 meq/g) of 4-hydroxyphenylthiomethylpolystyrene, 70 mg (0.64 mmol) of 4-dimethylaminopyridine, and 0.6 mL (5.5 mmol) of N-methylmorpholine. Nitrogen gas was bubbled through the mixture at ambient temperature for 2 hours. This was then filtered and the solid residue was washed three times alternately with dichloromethane and then methanol, yielding 4-(3-tert-butoxycarbonylaminopropionyloxy)phenylthiomethylpolystyrene.

The resulting 4-(3-tert-butoxycarbonylaminopropionyloxy)phenylthiomethylpolystyrene was treated with a 50:48:2 (v/v) dichloromethane/trifluoroacetic acid/anisole mixture for 0.5 h at ambient temperature, then filtered, and the solid residue was washed three times alternately with dichloromethane and then methanol, yielding 4-aminopropionyloxyphenylthiomethylpolystyrene.

A mixture of 4-aminopropionyloxyphenylthiomethylpolystyrene, 0.67 g (2.5 mmol) 2-(4-dimethylaminophenylazo)benzoic acid, 1.35 g (2.6 mmol) PyBOP ⁰ and PyBOP°, and 0.67 mL (6.1 mmol) N-methylmorpholine in 25 mL N,N-dimethylformamide (DMF) was allowed to stand for 3 h. The mixture was then filtered and the solid residue was washed twice with DMF, then alternately with dichloromethane and methanol until the washings were colorless. The mixture was then filtered and the solid residue was dried under vacuum to give 4-{3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxy}-phenylthiomethylpolystyrene.

Example 3 N-Benzyl-2-(4-methoxybenzoylamino)acetamide, N [2-(3,4-dimethoxyphenyl)ethyl]-2-(4-methoxybenzoylamino)acetamide and N-(2-dimethylaminoethyl)-2-(4-methoxybenzoylamino)acetamide

Below, three batches of solution phase condensation products are prepared from a single batch of solid phase supported intermediate.

Step 1

A mixture of 4-(4-methoxybenzoylaminoacetoxy)phenylthiomethylpolystyrene prepared according to Example 1, (5 μΙ (45.8 μmol) benzylamine and (15 μΙ (0.11 mmol) triethylamine in 2 ml 2,6-lutidine was allowed to stand for 4 hours. It was then filtered and the solid phase was washed once with dichloromethane and then three times with methanol. The combined filtrate and washings were concentrated by evaporation to give N-benzyl-2-(4methoxybenzoylamino)acetamide.

Step 2

A mixture of the remaining 4-(4-methoxybenzoylaminoacetoxy)phenylthiomethylpolystyrene obtained in step 1, (5μΙ (29.6 μmol) 2-(3,4-dimethoxyphenyl)ethylamine and 20 μΙ (0.14 mmol) triethylamine in 2 ml 2,6-lutidine was allowed to stand for approximately 12 hours. It was then filtered and the solid residue was washed three times alternately with dichloromethane and then with methanol. The combined filtrate and washings were concentrated by evaporation to give 8.8 mg (24.4 pmol) N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(4-methoxybenzoylamino)acetamide.

Step 3

A mixture of the remaining 4-(4-methoxybenzoylaminoacetoxy)phenylthiomethylpolystyrene obtained in step 2, 4 μΙ (36.4 μmol) of 2, 2-dimethylaminoethylamine and 35 μΙ (0.25 mmol) of triethylamine in 2 ml of 2,6-lutidine was allowed to stand for approximately 12 hours,

- 16 then filtered and the solid residue was washed three times alternately with dichloromethane and methanol. The combined filtrate and washings were concentrated by evaporation to give 16.8 mg (60.1 mmol) of crude N-(2-dimethylaminoethyl)-2-(4-methoxybenzoylaminoacetamide.

Example 4: N-Butyl-3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide, N-allyl-3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide, N-(3-methoxypropyl)-3-[2-(4-dimethylaminophenylazo)benzoylamino)propionamide and N-(2,2-diphenylethyl)-3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide

Below, five batches of solution phase condensation products are prepared from a single batch of solid phase supported intermediate.

Step 1

A mixture of 111 mg of 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxyphenylthiomethylpolystyrene prepared according to Example 2, 0.05 ml (0.36 mmol) of triethylamine and 5 μΙ (50.6 μmol) of butylamine in 0.95 ml of pyridine was allowed to stand for 1.5 hours at ambient temperature, then filtered and the solid residue was washed alternately with dichloromethane and methanol, or dichloromethane and tert-butyl methyl ether, until the washings became colorless. The combined filtrate and washings were concentrated and the residue was purified by flash chromatography using 95:5 chloroform:methanol as eluent to give 7.6 mg (19.2 μmol) of N-butyl-3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide.

¹⁷ ' ί.ί. *** V·· ^: Η NMR: 9.54 (t, 1Η, NH); 8.32 (d, 1Η, ArH); 7.82 (d, 2H, ArH); 7.80 (d, 1H, ArH); 7.46 (m, 2H, ArH); 6.79 (d, 1H, ArH), 6.18 (t, 1H, NH); 3.80 (q, 2H, CH ₂ ); 3.12 (q, 2H, CH ₂ ); 3.12 (s, 3H, CH ₃ ); 2.56 (t, 2H, CH ₂ ); 1.33 (m, 2H, CH 2 ); 1.18 (m, 2H, CH ₂ ); 0.75 (t, 3H, CH ₃ ).

ESMS (M+H) calcd: 396, found: 396.1.

Step 2

The remaining 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxyphenylthiomethyl polystyrene obtained in step 1, (0.05 ml (0.36 mmol) triethylamine and (5 μΙ (66.6 pmol) allylamine were mixed in 0.95 ml pyridine and allowed to stand for 1.5 hours at ambient temperature. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and methanol or dichloromethane and tert-butyl methyl ether until the washings became colorless. The combined filtrate and washings were concentrated and the residue was purified by flash chromatography using a 95:5 chloroform/methanol mixture as eluent. In this way, 5.2 mg (13.7 pmol) N Allyl-3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide is obtained.

¹ H NMR: 9.57 (t, 1 H NH); 8.32 (d, 1H, ArH); 7.82 (d, 2H, ArH); 7.80 (d, 1H, ArH); 7.46 (m, 2H, ArH); 6.79 (d, 1H, ArH); 6.02 (t, 1H, NH); 5.70 (m, 1H, =CH); 5.03 (m, 2H, =CH 2 ); 3.80 (m, 4H; CH ₂ ); 3.13 (s, 3H, CH ₃ ); 2.60 (t, 2H, CH ₂ ), ESMS (M+H) calcd: 380.2, found: 380.1.

Step 3

A mixture of the remaining 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxyphenylthiomethylpolystyrene obtained in step 2, (0.05 mL, 0.36 mmol) triethylamine and 5 μΙ (49 pmol) 3-methoxypropylamine in 0.95 mL pyridine was allowed to stand at ambient temperature for 1.5 h. The mixture was then filtered and the solid residue was

The mixture was washed alternately with dichloromethane and methanol or dichloromethane and tert-butyl methyl ether until colorless washings were obtained. The filtrate and washings were concentrated and the residue was purified by flash chromatography using a 95:5 chloroform/methanol mixture as eluent. In this way, 7.9 mg (19.2 μmol) of N-(3-methoxypropyl)-3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide was obtained.

¹ H NMR: 9.55 (t, 1 H, NH); 8.32 (d, 1H, ArH); 7.82 (d, 2H, ArH); 7.80 (d, 1H, ArH); 7.46 (m, 2H, ArH); 6.79 (d, 1H, ArH); 6.31 (t, 1H, NH); 3.80 (q, 2H, CH ₂ ); 3.27 (m, 4H, CH ₂ ); 3.12 (s, 3H, CH ₃ ); 3.12 (s, 3H, CH 2 ); 2.55 (t, 2H, CH ₂ ); 1.62 (5°, 2H, CH ₂ ). ESMS (M+H) calculated: 412.2, found: 412.1.

Step 4

A mixture of the remaining 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxyphenylthiomethylpolystyrene obtained in step 3, (0.05 ml (0.36 mmol) triethylamine and 5.5 mg (25.3 μmol) 2,2-diphenylethylamine in 0.95 ml pyridine was allowed to stand for 1.5 h at ambient temperature. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and methanol or dichloromethane and tert-butyl methyl ether until colorless washings were obtained. The filtrate and washings were concentrated and the residue was purified by flash chromatography using a 95:5 chloroform/methanol mixture as eluent. In this way, 4.1 mg (7.9 μmol) N-(2,2-diphenylethyl)-3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide is obtained.

¹ H NMR: 9.43 (t, 1 H, NH); 8.32 (d, 1H, ArH); 7.82 (d, 2H, ArH); 7.80 (d, 1H, ArH); 7.46 (m, 2H, ArH); 6.79 (d, 1H, ArH); 5.77 (t, 1H, NH); 5.33 (t, 1H, CH); 3.99 (t, 2H, CH ₂ ); 3.76 (q, 2H, CH ₂ ); 3.07 (s, 3H, CH ₃ ); 2.20 (t, ZH, CH ₂ ), ESMS (M+H) calcd: 520.3, found: 520.3.

Step 5

A mixture of the remaining 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxyphenylthiomethylpolystyrene obtained in step 3, 0.05 mL (0.36 mmol) triethylamine and 50 μΙ (0.51 mmol) butylamine in 0.95 mL pyridine was allowed to stand at ambient temperature for 1.5 h. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and methanol or dichloromethane and tert-butyl methyl ether until colorless washings were obtained. The filtrate and washings were concentrated and the residue was purified by flash chromatography using a 95:5 chloroform/methanol mixture as eluent. In this way, 66.2 mg (170 pmol) of N-butyl-3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide are obtained. ¹ H NMR: 9.54 (t, 1 H, NH); 8.32 (d, 1H, ArH); 7.82 (d, 2H, ArH); 7.80 (d, 1H, ArH); 7.46 (m, 2H, ArH); 6.79 (d, 1H, ArH); 6.18 (t, 1H, NH); 3.80 (q, 2H, CH ₂ ); 3.12 (q, 2H, CH ₂ ); 3.12 (s, 3H, CH 2 ); 2.56 (t, 2H, CH ₂ ); 1.33 (m, 2H, CH ₂ ); 1.18 (m, 2H, _CH2 ); 0.75 (t, 3H, _CH3 ), ESMS: (M+H) calcd: 396.2, found: 396.1.

Claims (13)

Patent claims 1. A method for synthesizing compounds, comprising: (a) reacting a solid-phase supported intermediate with a cleavage/condensation reagent such that a solution-phase condensation product is formed and the remaining solid-phase supported intermediate is available; and (b) separating the solution-phase condensation product formed in step (a) from the solid phase. 2. The process according to claim 1, characterized in that the condensation/cleavage reaction of step (a) is carried out by reacting the intermediate supported on the solid phase with a substoichiometric amount of the cleavage/condensation reagent. 3. The method according to claim 2, characterized in that a polymer is used as the solid support, and the intermediate supported on the solid phase forms an ester or amide bond with the linking group. 4. The method according to claim 3, characterized in that the linking group is 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfinylalkyl, 4-hydroxyphenylsulfonylalkyl, 4-hydroxy-2-nitrophenyl, 4-hydroxy-3-nitrophenyl, 4-aminosulfonylbenzoylaminoalkyl or 3-aminosulfonylpropionylaminoalkyl, and the cleaving/condensing reagent is an amine or an organometallic compound. 5. The method according to claim 4, characterized in that the linking group is also a 4-aminosulfonylbenzoylaminoalkyl or 3-aminosulfonylpropionylaminoalkyl group, and an alcohol, aniline, thiol or carbon nucleophile is used as the cleaving/condensing reagent. 6. The method according to claim 4, characterized in that polystyrene or polyethylene glycol grafted polystyrene is used as the solid support. 7. The process according to claim 6, characterized in that polystyrene is used as the solid support, 4-hydroxyphenylthiomethyl is used as the linking group, and an amine is used as the cleaving/condensing reagent. 8. A method for synthesizing a plurality of analogous compounds, comprising (a) reacting a solid phase supported intermediate with a cleavage/condensation reagent in such a manner that a solution phase condensation product is formed and the remaining solid phase supported intermediate is available; and (b) separating the solution phase condensation product obtained in step (a) from the solid phase; (c) reacting the remaining solid phase supported intermediate with a cleavage/condensation reagent different from the cleavage/condensation reagent used in step (a) to form a solution-phase condensation product analogous to the solution-phase condensation product formed in step (a); (d) separating the solution phase condensation product obtained in step (c) from the solid phase; and (e) optionally, if there is a residual solid phase supported intermediate present, repeating steps (c) and (d) one or more times, each time using a different cleaving/condensing reagent, while forming further analogous solution phase condensation products. 9. The process of claim 8, wherein the remaining solid phase supported intermediate is prepared by reacting the solid phase supported intermediate with a substoichiometric amount of a cleavage/condensation reagent. ΊΊ • · «·· «*· ···* • ··· ·· · · 10. A method for synthesizing a plurality of analogous compounds, comprising (a) reacting a solid phase supported intermediate with a cleavage/condensation reagent in such a manner that a solution phase condensation product is formed and a remaining solid phase supported intermediate is available; and (b) separating the solution phase condensation product obtained in step (a) from the solid phase; (c) optionally repeating steps (a) and (b) one or more times, each time using a different cleaving/condensing reagent, while forming analogous solution phase condensation products; (d) modifying the remaining solid phase supported intermediate to form a solid phase supported intermediate analogous to the solid phase supported intermediate used in steps (a)-(c); (e) reacting the analogous solid phase supported intermediate with a cleaving/condensing reagent to form a solution phase condensation product analogous to the solution phase condensation product(s) formed in steps (a) or (c); (f) separating the solution phase condensation product obtained in step (e) from the solid phase; (g) optionally, if a residual solid phase supported intermediate is present, repeating steps (e) and (f) one or more times, each time using a different cleaving/condensing reagent, to form further analogous solution phase condensation products; and (h) optionally, repeating steps (d) to (g) one or more times, to form further analogous solution phase condensation products. 11. The process of claim 10, wherein the remaining solid phase supported intermediate is prepared by reacting the solid phase supported intermediate with a substoichiometric amount of a cleavage/condensation reagent. 12. A combinatorial library of multiple analog compounds, wherein the analog compounds are prepared by the following process: (a) reacting a solid phase supported intermediate with a cleavage/condensation reagent in such a way that a solution phase condensation product is formed and the remaining solid phase supported intermediate is available; (b) separating the solution phase condensation product obtained in step (a) from the solid phase; (c) reacting the remaining solid phase supported intermediate with a different cleavage/condensation reagent than that used in step (a) to form a solution phase condensation product analogous to the solution phase condensation product formed in step (a); (d) separating the solution phase condensation product obtained in step (c) from the solid phase; and (e) optionally, if there is a residual solid phase supported intermediate present, repeating steps (c) and (d) one or more times, each time using a different cleavage/condensation reagent, while forming further analogous solution phase condensation products. 13. A combinatorial library of multiple analog compounds, wherein the analog compounds are prepared by a method suitable for synthesizing multiple analog compounds, by the following process: (a) reacting a solid-phase supported intermediate with a cleavage/condensation reagent in such a way that a solution-phase condensation product is formed and a remaining solid-phase supported intermediate is available; (b) separating the solution phase condensation product obtained in step (a) from the solid phase; (c) optionally repeating steps (a) and (b) one or more times, each time using a different cleaving/condensing reagent, while forming analogous solution phase condensation products; (d) modifying the remaining solid phase supported intermediate to form a solid phase supported intermediate analogous to the solid phase supported intermediate used in steps (a)-(c); (e) reacting the analogous solid phase supported intermediate with a cleaving/condensing reagent to form a solution phase condensation product analogous to the solution phase condensation product(s) formed in steps (a) or (c); (f) separating the solution phase condensation product obtained in step (e) from the solid phase; (g) optionally, if a residual solid phase supported intermediate is present, repeating steps (e) and (f) one or more times, each time using a different cleaving/condensing reagent, to form further analogous solution phase condensation products; and (h) optionally, repeating steps (d) to (g) one or more times, to form further analogous solution phase condensation products. The authorized person