KR19990074600A - Novel Process for Preparing Propionamide Derivatives Using Solid Phase Reaction - Google Patents

Abstract

The present invention relates to an amine compound, an aldehyde derivative or a sulfonyl chloride derivative compound bound to Wang resin by combinatorial chemistry using a solid phase reaction in one step at room temperature. The present invention relates to a novel process for preparing propionamide derivatives of the following formula (1) in high purity and high yield in a short time without the need for post-treatment steps such as chromatography and recrystallization.

In the above formula,

R ₁ represents an RCH ₂ -or RSO ₂ -group, where R represents alkyl, or in each case substituted or unsubstituted aryl, heteroaryl or bicycloalkyl,

R ₂ and R ₃ each independently represent hydrogen, alkyl, cycloalkyl, alkoxyalkyl, allyl, isoquinolyl, benzyl, naphthalene, phenoxyaryl, hydroxyaryl, sulfonylalkyl, bicycloalkyl or alkoxyalkyl.

Description

Novel Process for Preparing Propionamide Derivatives Using Solid Phase Reaction

The present invention is a one-step reaction of an amine compound and an aldehyde derivative or sulfonyl chloride derivative compound bound to Wang resin using combinatorial chemistry using a solid phase reaction. The present invention relates to a novel process for producing propionamide derivatives of the general formula (1) in high yield and high purity without the aftertreatment process:

[Formula 1]

In the above formula,

R ₁ represents an RCH ₂ -or RSO ₂ -group, where R represents alkyl, or in each case substituted or unsubstituted aryl, heteroaryl or bicycloalkyl,

R ₂ and R ₃ each independently represent hydrogen, alkyl, cycloalkyl, alkoxyalkyl, allyl, isoquinolyl, benzyl, naphthalene, phenoxyaryl, hydroxyaryl, sulfonylalkyl, bicycloalkyl or alkoxyalkyl.

In general, blood clotting mechanisms involve a number of complex enzymatic reactions, and the final stage involves the conversion of prothrombin to thrombin, which activates platelets and converts fibrinogens to fibrin. It plays an important role in coagulation, in which fibrin is converted into a polymer by a polymerization reaction and crosslinked by activated blood factor XIII to become insoluble thrombi. Thrombin also activates blood factors V and VIII, which accelerate blood coagulation by feedback. Thus, inhibitors of thrombin may act as effective anticoagulants by inhibiting the activation of platelets and preventing the production of fibrin.

Peptides with cleavage sites similar to fibrin, the substrate of thrombin, are three amino acids, D-Phe-Pro-Arg, and derivatives mimicking this structure have been reported to be effective as thrombin inhibitors. These derivatives are compounds in which the C-terminal portion of D-Phe-Pro-Arg is substituted with aldehyde, phosphonate or boronic acid (Trends in Pharm. Sci. 1993, 14, 366-376). However, most of these compounds retain the properties of peptides. Peptide compounds are generally unstable in vivo, cannot be absorbed into organs, and have fast degrading properties. Not suitable Therefore, it is very difficult to develop peptide-based compounds as useful thrombin inhibitors.

Therefore, various studies have recently been made to develop nonpeptidic compounds as thrombin inhibitors. Representative non-peptidic thrombin inhibitors include Argatroban represented by the following formula (18) commercialized in Japan in 1990 (see US Pat. Nos. 4258192 and 4201863).

Agatroban, however, is an arylsulfonyl arginine-based compound, which has excellent efficacy as an injection, but is not active at all for oral administration, and has a disadvantage in that it is prepared only through a complicated synthesis process.

As a compound that improves the disadvantages of the prior art compounds, a compound of the formula (19) has been recently published as a compound having excellent thrombin inhibitory activity, good selectivity to thrombin compared to trypsin, and ultimately improved absorption after oral administration. Patent Application No. 97-7754].

In the above formula,

R ₁ represents substituted or unsubstituted aryl or heteroaryl,

R ₂ and R ₃ each independently represent hydrogen, lower alkyl, cycloalkyl, or in each case substituted or unsubstituted aryl or heteroaryl, or R ₂ and R ₃ are bonded together with the nitrogen atom to which they are attached Substituted or unsubstituted by lower alkyl, carboxyl or carboalkoxy to form a 5 to 8-membered ring containing a nitrogen atom,

The amino methyl group is present at the meta or para position relative to the other substituents of the phenyl ring.

However, since the introduction of the substituents R ₁ , R ₂ and R ₃ in these compounds simply by the classical method requires much time and labor to synthesize the desired compound, a method of easily preparing such derivatives is required. .

Thus, the present inventors have rarely been used in the preparation of substituted propionamide derivatives, such as the compound of Formula 1, to prepare propionamide derivatives by a new and easy method using a solid phase completely different from the conventional methods. Intensive research has been carried out for the purpose, and as a result, by using combinatorial chemistry by the method described in detail below, the amine compound to which the aqua resin is bound and various aldehyde or sulfonyl chloride derivatives in one step reaction The present invention was completed by finding that the propionamide derivative of Formula 1 can be easily prepared by reacting at room temperature for one day.

Accordingly, it is an object of the present invention to provide a method for more economically and effectively preparing propionamide derivatives of formula 1 using combinatorial chemistry using solid phase reactions.

According to this object, in the present invention, a resin-bonded benzylamine derivative of formula (2) is reacted with a sulfonyl chloride derivative of formula (3) or an aldehyde derivative of formula (4) to obtain a compound of formula (5), and then the compound of formula (5) By treatment in trifluoroacetic acid and methylene chloride solvent, the desired compound of formula 1 can be obtained in high purity and high yield:

[Formula 1]

RSO ₂ Cl

RCHO

In the above formula,

R ₁ represents an RCH ₂ -or RSO ₂ -group, where R represents alkyl, or in each case substituted or unsubstituted aryl, heteroaryl or bicycloalkyl,

R ₂ and R ₃ each independently represent hydrogen, alkyl, cycloalkyl, alkoxyalkyl, allyl, isoquinolyl, benzyl, naphthalene, phenoxyaryl, hydroxyaryl, sulfonylalkyl, bicycloalkyl or alkoxyalkyl,

Represents a residue of Wang resin.

As used herein, the term "alkyl" as used to define a substituent of a compound of Formula 1 means straight or branched chain alkyl of 1 to 8 carbon atoms including methyl, ethyl, isopropyl, isobutyl, t-butyl, octyl .

The term "cycloalkyl" means cyclic alkyl of 6 to 8 carbon atoms including cyclopentyl, cyclohexyl and the like.

The term "aryl" refers to a 6-membered monocyclic aromatic group or a 10-membered bicyclic aromatic group, and the term "heteroaryl" refers to 5 to 5 containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur. 6-membered monocyclic aromatic group or 9-membered bicyclic aromatic group, wherein these aryl or heteroaryl groups are unsubstituted or substituted by alkyl, alkoxy, aryl, or halogen, lower alkoxy or nitro Optionally mono- or tri-substituted by aryloxy or arylalkoxy.

Hereinafter, the manufacturing method of the present invention will be described in more detail.

If the above production method according to the present invention represented by the reaction scheme can be represented by the following reaction scheme 1.

According to Scheme 1, first, a compound of formula (2) having a hydrophobic bond is reacted with a sulfonyl chloride derivative of formula (3) or an aldehyde derivative of formula (4) to obtain a compound of formula (5), and then the compound of formula (5) is trifluoro By treating on acetic acid and methylene chloride solvent, the aqua resin can be removed to easily obtain the desired compound of formula (1).

The hydrophobic resin bound to the compound of Formula 2 used as a starting material in this reaction has excellent properties as a leaving group, and is manufactured and marketed by various companies (eg, Advanced ChemTech, Novabiochem, etc.). The reaction of the compound of Formula _{2 to} which the hydrophobic resin is bound and the sulfonyl chloride derivative of Formula 3 may yield a compound of Formula 1 wherein R ₁ is RSO ₂ . This reaction is carried out in a solvent in the presence of an acid binder. Examples of bases that can be used as acid binders in this reaction include triethylamine, diisopropylethylamine, DBU (1,8-diazabicyclo [5.4.0] undes-7-ene), and the like. Preferably triethylamine is used. Any solvent may be used as long as it is an organic solvent that does not adversely affect the reaction. For example, dimethylformamide, dimethyl sulfoxide (DMSO), methylene chloride, N, N-dimethylacetamide and the like are used. Most preferably the solvent used is methylene chloride.

The reaction temperature is not particularly limited, and in general, the reaction is carried out under cooling to warming, preferably at 25 ° C. The reaction time is generally 5 to 24 hours, preferably 7 to 12 hours.

On the other hand, the reaction of the aqua resin-bonded compound of Formula 2 with an aldehyde derivative of Formula 4 yields a compound of Formula 1 wherein R ₁ is RCH ₂ . This reaction is preferably carried out in a solvent using sodium cyanoborohydride (NaBH ₃ CN), acetic acid, sodium trimethoxyborohydride (NaBH (OAc) ₃ ), and the like. As the solvent used for this purpose, any organic solvent which does not adversely affect the reaction can be used, for example, N, N-dimethylacetamide (DMA), dimethylformamide and the like are used. Most preferably the solvent used is N, N-dimethylacetamide.

The reaction temperature is not particularly limited, and in general, the reaction is carried out under cooling to warming, preferably at 25 ° C. The reaction is generally suitable for 24 hours.

After the reaction is completed, it is only necessary to remove the excess solvent by washing several times with solvents such as methylene chloride and methanol without any need for additional post-treatment.

The compound of formula (5) obtained by the reaction of the compound of formula (2) with the compound of formula (3) or (4) can be subsequently treated with trifluoroacetic acid and a methylene chloride solvent to remove the aqua resin to obtain the desired compound of formula (1). have. That is, this reaction is preferably performed by, for example, mixing trifluoroacetic acid (TFA) and methylene chloride in a ratio of 1: 1 (volume ratio), then adding to the compound of formula 4, stirring for about 30 minutes, and then filtering. Can be. In this way, only the desired compound of formula 1 is present in the solution obtained by filtration.

Since the process of the present invention as described above is carried out by a combinatorial chemical reaction using a solid phase, a yield of almost 100% is achieved without performing conventional post-treatment methods such as chromatography and recrystallization. The desired compound of formula 1 can be obtained.

The compound of formula 2 used as a starting material in the method of the present invention according to Scheme 1 may be prepared by a series of methods as follows.

That is, first, the aqua resin of formula 6 is reacted with 4-nitrophenylchloroformate of formula 7 to produce a compound of formula 8.

In the above formula, Represents a residue of the aqua regia

The reaction can be represented by the following scheme 2.

As shown in Scheme 2, the aqua resin 6 and 4-nitrophenylchloroformate 7 are first reacted to obtain a compound (8) bound to the aqua resin. This reaction is generally preferably carried out in the presence of N-methylmorpholine and a methylene chloride solvent. The reaction is preferably carried out at 0 ° C. to room temperature for one day.

Additionally, 2- (trimethylsilyl) ethanol of formula 9 is reacted with 4-nitrophenylchloroformate of formula 7 to produce a compound of formula 10.

[Formula 7]

The reaction can be represented by the following scheme 3.

As shown in Scheme 3, 2- (trimethylsilyl) -ethanol (9) is reacted with 4-nitrophenylchloroformate in a solvent such as acetonitrile in the presence of an acid acceptor, for example triethylamine, to Obtain the compound. This reaction is preferably carried out at a temperature of 0 ° C.

Thereafter, the compound of formula 11 is reacted with an amine compound of formula 12 substituted with R ₂ and R ₃ to obtain a compound of formula 13, and the compound of formula 13 is acid hydrolyzed to remove a protecting group to remove the compound of formula 14 After obtaining, the compound of formula 14 is reacted with the silyl compound of formula 10 obtained in Scheme 3 to obtain a silyl-protected compound of formula 15, and then the compound of formula 15 is reduced to give a compound of formula 16 .

[Formula 10]

In the above formula,

R ₂ and R ₃ are the same as defined in Formula 1,

P represents a conventional amino protecting group such as benzyloxycarbonyl, allyloxycarbonyl, t-butoxycarbonyl or trityl group and the like.

This reaction can be represented by the following reaction scheme 4 together with representative reaction conditions.

As shown in Scheme 4, first, the coupling reaction between the compound of Formula 9 and the amine compound of Formula 12 is carried out using a coupling reagent in the presence of 1-hydroxybenzotriazole. Known coupling reagents that can be used for this purpose include dicyclohexylcarbodiimide (DCC), 3-ethyl-3 '-(dimethylamino) -propylcarbodiimide (EDC), bis- (2-oxo-3 Oxazolidinyl) -phosphinic acid chloride (BOP-Cl), diphenylphosphoryl azide (DPPA), and the like, but are not limited to these. In this reaction, 3-ethyl-3 '-(dimethylamino) -propylcarbodiimide (EDC) is particularly preferably used as coupling agent in the presence of 1-hydroxybenzotriazole.

This coupling reaction is also preferably carried out in a solvent in the presence of a base. Examples of bases that can be used for this purpose include triethylamine, diisopropylethylamine, DBU (1,8-diazabicyclo [5.4.0] undes-7-ene) and the like, most preferably Triethylamine is used. Any solvent may be used as long as it is an organic solvent that does not adversely affect the reaction. For example, dimethylformamide, dimethyl sulfoxide (DMSO), methylene chloride, N, N-dimethylacetamide and the like are used. Most preferably the solvent used is dimethylformamide. The reaction temperature is not particularly limited, and in general, the reaction is carried out under cooling to warming, preferably at 25 ° C. The reaction is generally suitable for 24 hours.

The compound of formula 13 thus obtained is subjected to acid hydrolysis by treatment with trifluoroacetic acid in methylene chloride to remove the protecting group to give the compound of formula 14. The obtained compound of formula 14 is reacted with the silyl compound of formula 10 obtained according to the method shown in Scheme 3 to obtain a compound of formula 15. This reaction is preferably carried out using dimethoxyaminopyridine (DMAP) under reflux in a solvent such as acetonitrile in the presence of a base such as triethylamine. The silyl-protected compound of formula 15 obtained is then reacted for one day in a methanol solvent in the presence of palladium on carbon (Pd / C) and concentrated hydrochloric acid to reduce the cyano group to an aminomethyl group. To obtain.

The compound of formula (16) obtained according to the reaction of Scheme 4 is subsequently reacted with the resin compound of formula (8) obtained in Scheme 2 to obtain a resin-bonded compound of formula (17), wherein the silyl protecting group from the compound of formula (17) By removal it is possible to obtain the compound of formula 2 which is necessary as a starting material in the process of the invention.

[Formula 8]

[Formula 16]

In which R ₂ , R ₃ and Is as defined above.

The above reaction can be represented by the following reaction scheme 5 together with representative reaction conditions.

As shown in Scheme 5, the compound of Formula 8 and the compound of Formula 16 are coupled to obtain a compound of Formula 17. This reaction can be carried out using a coupling reagent in the presence of 1-hydroxybenzotriazoles. Known coupling reagents which can be used for this purpose include DIEA (diisopropylethylamine), dicyclohexylcarbodie Mead (DCC), 3-ethyl-3 '-(dimethylamino) -propylcarbodiimide (EDC), bis- (2-oxo-3-oxazolidinyl) -phosphinic chloride (BOP-Cl), diphenyl Phosphoryl azide (DPPA) and the like, but are not limited thereto. Particularly preferred in the present reaction is DIEA as coupling agent in the presence of 1-hydroxybenzotriazole.

This reaction is carried out in the presence of a solvent. Any organic solvent which does not adversely affect the reaction can be used. For example, dimethylformamide, methylene chloride, N, N-dimethylacetamide, and the like are used. Most preferably, a mixed solvent of dimethylformamide and methylene chloride is used.

The reaction temperature is not particularly limited and generally the reaction is carried out under cooling to warming, preferably at room temperature. The reaction time is generally suitable for 7 to 12 hours.

The compound of formula (17) thus prepared is subsequently reacted with tetrabutylammonium fluoride (nBu ₄ NF) in a solvent such as tetrahydrofuran to remove the silyl protecting group of Compounds can be prepared.

In the reaction according to Scheme 5, since each reaction is performed in the solid phase, it is only necessary to remove the excess solvent by washing several times with solvents such as methylene chloride and methanol after performing the reaction, without the need for a separate post-treatment process.

Representative propionamide derivative compounds that may be prepared according to the methods of the invention may be mentioned the following compounds:

<1> (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2-[(naphthalen-2-ylmethyl) -amino] -propionamide

<2> (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2-[(naphthalen-1-ylmethyl) -amino] -propionamide

<3> (s) -3- (4-aminomethyl-phenyl) -2-[(biphenyl-4-ylmethyl) -amino] -N-cyclopentyl-N-methyl-propionamide

<4> (s) -3- (4-aminomethyl-phenyl) -2-[(benzo [1,3] dioxol-5ylmethyl) -amino] -N-cyclopentyl-N-methyl-propionamide

<5> (s) -3- (4-aminomethyl-phenyl) -2- (4-benzyloxy-benzylamino) -N-cyclopentyl-N-methyl-propionamide

<6> (s) -3- (4-aminomethyl-phenyl) -2- [4- (4-chloro-benzyloxy) -benzylamino] -N-cyclopentyl-N-methyl-propionamide

<7> (s) -3- (4-aminomethyl-phenyl) -2- (4-benzyloxy-3-methoxy-benzylamino) -N-cyclopentyl-N-methyl-propionamide

<8> (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-2- [3-methoxy-4- (4-nitro-benzyloxy) -benzylamino] -N-methyl- Propionamide

(9) (s) -3- (4-Aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2- (4-phenoxy-benzylamino) -propionamide

<10> (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-2- [3- (4-methoxy-phenoxy) -benzylamino] -N-methyl-propionamide

(11) (s) -3- (4-Aminomethyl-phenyl) -N-cyclopentyl-2- [4- (1,1-dimethyl-propyl) -benzenesulfonylamino] -N-methyl-propionamide

(12) (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2- (4-propyl- benzenesulfonylamino) -propionamide

(13) (s) -3- (4-Aminomethyl-phenyl) -N-cyclopentyl-2- (2,4,6-triisopropyl-benzenesulfonylamino) -propionamide

(14) (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-2- (octane-1-sulfonylamino) -propionamide

(15) (s) -3- (4-aminomethyl-phenyl) -2-camposulfonylamino-4-cyclopentyl-N-methyl-propionamide

The invention is illustrated in more detail by the following examples. However, these Examples are only for illustrating the present invention, the present invention is not limited to these.

Example 1

Synthesis of (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2-[(naphthalen-2-ylmethyl) -amino] -propionamide

An amine compound to which Wang resin is bound, that is, 20 mg of a compound of formula 2 wherein R ₂ is methyl and R ₃ represents cyclopentyl is ₂ -naphthaldehyde in ₃ ml of N, N-dimethylacetamide (DMA) solvent. After reacting 3.5 equivalents and 0.1 ml of 1% acetic acid at 25 ° C. for 5 hours, 3.5 equivalents of NaBH ₃ CN was added thereto, and the mixture was stirred for one day. After the reaction was completed, the excess DMA solvent was removed and washed three times with 10 ml of methylene chloride and 10 ml of methanol, and then, together with 1 ml of trifluoroacetic acid and 1 ml of methylene chloride, the mixture was added together. After stirring for a minute, the filtrate was removed by filtration, and trifluoroacetic acid and methylene chloride were removed by evaporation from the remaining filtrate to obtain the title compound in a yield of 50%.

MS (FAB): 415 (M ⁺ + H ⁺ )

Example 2

Synthesis of (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2-[(naphthalen-1-ylmethyl) -amino] -propionamide

The reaction was carried out according to the same method as in Example 1 using 20 mg of a compound of formula 2 wherein R ₂ represents methyl and R ₃ represents cyclopentyl and 3.5 equivalents of 1-naphthaldehyde to give the title compound in a yield of 55%. Obtained.

MS (FAB): 415 (M ⁺ + H ⁺ )

Example 3

Synthesis of (s) -3- (4-aminomethyl-phenyl) -2-[(biphenyl-4-ylmethyl) -amino] -N-cyclopentyl-N-methyl-propionamide

The reaction was carried out in the same manner as in Example 1 using 20 mg of the compound of formula 2 wherein R ₂ represents methyl and R ₃ represents cyclopentyl and 3.5 equivalents of 4-biphenylcarboxaldehyde to give 60% of the title compound. Obtained in yield.

MS (FAB): 442 (M ⁺ + H ⁺ )

Example 4

Synthesis of (s) -3- (4-aminomethyl-phenyl) -2-[(benzo [1,3] dioxol-5ylmethyl) -amino] -N-cyclopentyl-N-methyl-propionamide

The reaction was carried out according to the same method as in Example 1 using 20 mg of a compound of Formula 2 and 3.5 equivalents of piperonal, wherein R ₂ represents methyl and R ₃ represents cyclopentyl to give the title compound in a yield of 66%. .

MS (FAB): 410 (M ⁺ + H ⁺ )

Example 5

Synthesis of (s) -3- (4-aminomethyl-phenyl) -2- (4-benzyloxy-benzylamino) -N-cyclopentyl-N-methyl-propionamide

The reaction was carried out in the same manner as in Example 1 using 20 mg of the compound of formula 2 and 3.5 equivalents of 4-benzyloxybenzaldehyde, wherein R ₂ represents methyl and R ₃ represents cyclopentyl to give the title compound in a yield of 50%. Obtained.

MS (FAB): 472 (M ⁺ + H ⁺ )

Example 6

Synthesis of (s) -3- (4-aminomethyl-phenyl) -2- [4- (4-chloro-benzyloxy) -benzylamino] -N-cyclopentyl-N-methyl-propionamide

The reaction was carried out according to the same method as in Example 1 using 20 mg of a compound of formula 2 and 3.5 equivalent of 4- (4-chlorobenzyloxy) benzaldehyde, wherein R ₂ represents methyl and R ₃ represents cyclopentyl. Obtained in 54% yield.

MS (FAB): 506 (M ⁺ + H ⁺ )

Example 7

Synthesis of (s) -3- (4-aminomethyl-phenyl) -2- (4-benzyloxy-3-methoxy-benzylamino) -N-cyclopentyl-N-methyl-propionamide

The reaction was carried out according to the same method as in Example 1 using 20 mg of a compound of formula 2 wherein R ₂ represents methyl and R ₃ represents cyclopentyl and 3.5 equivalents of 4-benzyloxy-3-methoxybenzaldehyde. Obtained in a yield of 51%.

MS (FAB): 502 (M ⁺ + H ⁺ )

Example 8

of (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-2- [3-methoxy-4- (4-nitro-benzyloxy) -benzylamino] -N-methyl-propionamide synthesis

The reaction was carried out according to the same method as Example 1 using 20 mg of a compound of formula 2 wherein R ₂ represents methyl and R ₃ represents cyclopentyl and 3.5 equivalents of 3-methoxy-4- (4-nitrobenzyloxy) benzaldehyde The title compound was obtained in 45% yield.

MS (FAB): 547 (M ⁺ + H ⁺ )

Example 9

Synthesis of (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2- (4-phenoxy-benzylamino) -propionamide

The reaction was carried out in the same manner as in Example 1 using 20 mg of the compound of formula 2 and 3.5 equivalents of 4-phenoxybenzaldehyde, wherein R ₂ represents methyl and R ₃ represents cyclopentyl to give the title compound in a yield of 52%. Obtained.

MS (FAB): 458 (M ⁺ + H ⁺ )

Example 10

Synthesis of (s) -3- (4-Aminomethyl-phenyl) -N-cyclopentyl-2- [3- (4-methoxy-phenoxy) -benzylamino] -N-methyl-propionamide

The reaction was carried out according to the same method as Example 1 using 20 mg of a compound of formula 2 and 3.5 equivalents of 3- (4-methoxyphenoxy) benzaldehyde, wherein R ₂ represents methyl and R ₃ represents cyclopentyl. Was obtained in 49% yield.

MS (FAB): 488 (M ⁺ + H ⁺ )

Example 11

Synthesis of (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-2- [4- (1,1-dimethyl-propyl) -benzenesulfonylamino] -N-methyl-propionamide

An amine compound with Wang resin, ie, 20 mg of the compound of formula 2 wherein R ₂ is methyl and R ₃ represents cyclopentyl is dissolved in 3 ml of methylene chloride solvent and 4- (1,1-dimethyl-propyl) 3.5 equivalents of benzenesulfonylchloride and 3.5 equivalents of triethylamine were added and stirred for one day. After the reaction was completed, the excess methylene chloride solvent was removed and washed three times with 10 ml of methylene chloride and 10 ml of methanol, followed by adding 1 ml of trifluoroacetic acid and 1 ml of methylene chloride, followed by stirring for 30 minutes. After filtrating to remove the aqua resin, trifluoroacetic acid and methylene chloride were removed by evaporation from the remaining filtrate to give the title compound in a yield of 65%.

MS (FAB): 486 (M ⁺ + H ⁺ )

Example 12

Synthesis of (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2- (4-propyl-benzenesulfonylamino) -propionamide

The reaction was carried out according to the same method as in Example 11 using 20 mg of the compound of formula 2 and 3.5 equivalent of 4-propyl-benzenesulfonylchloride, wherein R ₂ represents methyl and R ₃ represents cyclopentyl to give 70% of the title compound. Obtained in the yield.

MS (FAB): 458 (M ⁺ + H ⁺ )

Example 13

Synthesis of (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-2- (2,4,6-triisopropyl-benzenesulfonylamino) -propionamide

The reaction was carried out according to the same method as Example 11 using 20 mg of a compound of formula 2 wherein R ₂ represents methyl and R ₃ represents cyclopentyl and 3.5 equivalents of 2,4,6-triisopropyl-benzenesulfonylchloride To give the title compound in a yield of 67%.

MS (FAB): 539 (M ⁺ + H ⁺ )

14 to implementation

Synthesis of (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-2- (octane-1-sulfonylamino) -propionamide

The reaction was carried out according to the same method as in Example 11 using 20 mg of a compound of formula 2 wherein R ₂ represents methyl and R ₃ represents cyclopentyl and 3.5 equivalents of octane-1-sulfonylchloride to give the title compound of 73%. Obtained in yield.

MS (FAB): 452 (M ⁺ + H ⁺ )

Example 15

Synthesis of (s) -3- (4-aminomethyl-phenyl) -2-camposulfonylamino-4-cyclopentyl-N-methyl-propionamide

The reaction was carried out according to the same method as in Example 11 using 20 mg of a compound of formula 2 wherein R ₂ represents methyl and R ₃ represents cyclopentyl and 3.5 equivalents of camphorsulfonylchloride to obtain the title compound in a yield of 57%. It was.

MS (FAB): 490 (M ⁺ + H ⁺ )

As described above, the present invention relates to a method for preparing a propionamide derivative represented by the following Chemical Formula 1 by combinatorial chemistry using a solid phase reaction, and an acid compound attached to a Wang resin and various amine compounds. The reaction was carried out at room temperature and then the excess solvent was removed, washed several times with methanol and methylene chloride, etc., followed by separating the target compound bound to the resin. According to the method of the present invention, a high-purity propionamide derivative compound which does not require post-treatment steps such as chromatography and recrystallization in a short time can be produced in high yield. Therefore, the present invention is a very economical and effective method for preparing propionamide derivative compounds.

Claims (7)

The resin-bonded benzylamine derivative of formula (2) is reacted with a sulfonylchloride derivative of formula (3) or an aldehyde derivative of formula (4) to obtain a compound of formula (5), and then the compound of formula (5) is mixed with trifluoroacetic acid and a methylene chloride solvent. Process for preparing propionamide derivative of formula 1 characterized in that the treatment in the phase: [Formula 1] [Formula 2] [Formula 3] RSO ₂ Cl [Formula 4] RCHO [Formula 5] In the above formula, R ₁ represents an RCH ₂ -or RSO ₂ -group, where R represents alkyl, or in each case substituted or unsubstituted aryl, heteroaryl or bicycloalkyl, R ₂ and R ₃ each independently represent hydrogen, alkyl, cycloalkyl, alkoxyalkyl, allyl, isoquinolyl, benzyl, naphthalene, phenoxyaryl, hydroxyaryl, sulfonylalkyl, bicycloalkyl or alkoxyalkyl, Represents a residue of Wang resin. A process according to claim 1, wherein the reaction of the compound of formula 2 with the compound of formula 3 is carried out in a solvent in the presence of an acid acceptor. 3. The process according to claim 2, wherein triethylamine is used as the acid acceptor and methylene chloride is used as the solvent. The method of claim 1, wherein the reaction of the compound of Formula 2 with the compound of Formula 4 is carried out using sodium borocyanohydride (NaBH ₃ CN) and acetic acid in a solvent. The method according to claim 4, wherein N, N-dimethylacetamide is used as the solvent. The method of claim 1, wherein the reaction of the compound of Formula 2 with the compound of Formula 3 or 4 is carried out at room temperature for 24 hours. A compound according to claim 1, wherein (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2-[(naphthalen-2-ylmethyl) -amino] -propionamide, (s ) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2-[(naphthalen-1-ylmethyl) -amino] -propionamide, (s) -3- (4-amino Methyl-phenyl) -2-[(biphenyl-4-ylmethyl) -amino] -N-cyclopentyl-N-methyl-propionamide, (s) -3- (4-aminomethyl-phenyl) -2- [(Benzo [1,3] dioxol-5ylmethyl) -amino] -N-cyclopentyl-N-methyl-propionamide, (s) -3- (4-aminomethyl-phenyl) -2- (4 -Benzyloxy-benzylamino) -N-cyclopentyl-N-methyl-propionamide, (s) -3- (4-aminomethyl-phenyl) -2- [4- (4-chloro-benzyloxy) -benzyl Amino] -N-cyclopentyl-N-methyl-propionamide, (s) -3- (4-aminomethyl-phenyl) -2- (4-benzyloxy-3-methoxy-benzylamino) -N-cyclo Pentyl-N-methyl-propionamide, (s) -3- (4-aminomethyl-phenyl) -N-cycle Pentyl-2- [3-methoxy-4- (4-nitro-benzyloxy) -benzylamino] -N-methyl-propionamide, (s) -3- (4-aminomethyl-phenyl) -N-cyclo Pentyl-N-methyl-2- (4-phenoxy-benzylamino) -propionamide, (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-2- [3- (4-meth Methoxy-phenoxy) -benzylamino] -N-methyl-propionamide, (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-2- [4- (1,1-dimethyl-propyl ) -Benzenesulfonylamino] -N-methyl-propionamide, (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2- (4-propyl-benzenesulfonylamino ) -Propionamide, (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-2- (2,4,6-triisopropyl-benzenesulfonylamino) -propionamide, (s) -3- (4-Aminomethyl-phenyl) -N-cyclopentyl-2- (octane-1-sulfonylamino) -propionamide and (s) -3- (4-aminomethyl-phenyl) -2-cam Fosulfonylamino-4-cyclopentyl-N-methyl-propion Characterized in that producing a propionamide derivative of the general formula (I) selected from the group consisting of draw.