KR19990074599A - Novel Method for Preparing Benzylamine Derivatives Using Solid Phase Reaction - Google Patents

Abstract

The present invention relates to chromatography by combining an acid compound and an amine compound bound to Wang resin by combinatorial chemistry using a solid phase reaction by a coupling reaction at room temperature, The present invention relates to a novel process for preparing benzylamine derivatives of the general formula (1) in high purity and high yield in a short time without the need for a post-treatment process such as recrystallization.

In the above formula,

R ₁ represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,

R ₂ represents hydrogen, alkyl, alkoxyalkyl or allyl,

R ₃ represents alkyl, aralkyl, cycloalkyl, isoquinolyl, naphthalene, phenoxyaryl, hydroxyaryl, sulfonylalkyl, bicycloalkyl or alkoxyalkyl, or

R ₂ and R ₃ together with the nitrogen atom to which they are attached represent a 5-7 membered heterocyclic group which may be substituted or unsubstituted and further contain one nitrogen atom.

Description

Novel Method for Preparing Benzylamine Derivatives Using Solid Phase Reaction

The present invention uses only one coupling reaction step of an acid compound and an amine compound bound to Wang resin using combinatorial chemistry using a solid phase reaction. The present invention relates to a novel process for producing benzylamine 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 substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,

R ₂ represents hydrogen, alkyl, alkoxyalkyl or allyl,

R ₃ represents alkyl, aralkyl, cycloalkyl, isoquinolyl, naphthalene, phenoxyaryl, hydroxyaryl, sulfonylalkyl, bicycloalkyl or alkoxyalkyl, or

R ₂ and R ₃ together with the nitrogen atom to which they are attached represent a 5-7 membered heterocyclic group which may be substituted or unsubstituted and further contain one nitrogen atom.

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 (19) 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 20 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 to prepare substituted benzylamine derivatives, such as the compound of Formula 1, to prepare benzylamine 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 acid-bonded acid compound and various amine compounds are reacted at room temperature for one day only in one step. By reacting, it was found that the benzylamine derivative of the formula (1) can be easily prepared, and the present invention was completed.

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

For this purpose, in the present invention, a resin-bonded benzylamine derivative of formula (2) is coupled with an amine derivative of formula (3) to obtain a compound of formula (4), and then the compound of formula (4) By treatment in acetic acid and methylene chloride solvent, the desired compound of formula 1 can be obtained in high purity and high yield:

[Formula 1]

In the above formula,

R ₁ represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,

R ₂ represents hydrogen, alkyl, alkoxyalkyl or allyl,

R ₃ represents alkyl, aralkyl, cycloalkyl, isoquinolyl, naphthalene, phenoxyaryl, hydroxyaryl, sulfonylalkyl, bicycloalkyl or alkoxyalkyl, or

R ₂ and R ₃ together with the nitrogen atom to which they are attached represent a 5-7 membered heterocyclic group which may be substituted or unsubstituted and further contain one nitrogen atom,

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, where these aryl or heteroaryl groups may be optionally substituted by lower alkyl, lower alkoxy or halogen.

The term "5-7 membered heterocyclic group which may be substituted or unsubstituted and may further contain one nitrogen atom" refers to a group consisting of lower alkyl, hydroxy, hydroxyalkyl, alkylcarbonyl and alkylsulfonyl 5-7 membered heterocyclic group, for example pyrrolidinyl, which may be unsubstituted or substituted by one or two substituents selected, which may be saturated or unsaturated and contain one or two nitrogen atoms as ring members , Piperazinyl or hexahydroazinyl.

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 coupled with an amine derivative of formula (3) substituted with R ₂ and R ₃ to obtain a compound of formula (4), and then the compound of formula (4) By treating in roacetic acid and methylene chloride solvent to remove the aqua resin can easily obtain the target 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 coupling reaction of the compound of formula (2) and the amine compound of formula (3) to which the hydrophobic resin is bound 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 room temperature. The reaction time is generally 5 to 24 hours, preferably 7 to 12 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 (4) obtained by this coupling reaction can then be treated with trifluoroacetic acid and a methylene chloride solvent to remove the aqua resin, thereby obtaining the desired compound of formula (1). 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 5 is reacted with 4-nitrophenylchloroformate of formula 6 to produce a compound of formula 7.

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 (5) and 4-nitrophenylchloroformate (6) are first reacted to obtain a compound (7) 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.

Also separately, 2- (trimethylsilyl) ethanol of formula 8 is reacted with 4-nitrophenylchloroformate of formula 6 to produce a compound of formula 9.

[Formula 6]

The reaction can be represented by the following scheme 3.

As shown in Scheme 3, 2- (trimethylsilyl) -ethanol (8) 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 10 is esterified to give methyl propionate methyl ester of formula 11, the acid hydrolysis of the ester compound of formula 11 to remove the protecting group to give the compound of formula 12, After reacting with the silyl compound of formula 9 obtained in Scheme 3 to obtain a silyl-protected compound of formula 13, the compound of formula 13 is reduced to give a compound of formula 14.

[Formula 9]

In the above formula,

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, for example, the compound of formula 10 is first esterified by reacting with methane iodide and potassium carbonate in the presence of a solvent such as dimethylformamide to obtain the propionic acid methyl ester compound of formula 11. Thereafter, the compound of formula 11 is treated with trifluoroacetic acid in methylene chloride and acid hydrolyzed to remove the protecting group to give the compound of formula 12. The obtained compound of formula 12 is reacted with the silyl compound of formula 9 obtained according to the method shown in Scheme 3 to obtain a compound of formula 13. 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 resulting silyl-protected compound of formula 13 is subsequently reacted for one day in 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 give a compound of formula 14 do.

The compound of formula 14 obtained according to the reaction of Scheme 4 is subsequently reacted with the resin compound of formula 7 obtained in Scheme 2 to obtain a resin-bonded compound of formula 15, wherein the silyl protecting group is Is removed to obtain a compound of formula 16, and the compound of formula 16 is reacted with a sulfonylchloride derivative of formula 17 to obtain a compound of formula 18, followed by demethylation to obtain a compound of formula 2 as a starting material in the process of the present invention. Can be obtained.

[Formula 7]

[Formula 14]

In which R ₁ and Is as defined in Formula 1 and 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 7 and the compound of Formula 14 are coupled to obtain a compound of Formula 15. 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.

The reaction is carried out in the presence of a solvent, and any organic solvent which does not adversely affect the reaction can be used, for example, dimethylformamide, methylene chloride, N, N-dimethylacetamide, dimethyl sulfoxide, and the like. 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 5 to 24 hours, preferably 7 to 12 hours.

The compound of formula 15 thus prepared is subsequently reacted with tetrabutylammonium fluoride (nBu ₄ NF) in a solvent such as tetrahydrofuran to remove the silyl protecting group to obtain a compound of formula 16, The compound is reacted with a sulfonylchloride derivative of formula 17 having a R ₁ group in a dimethylformamide solvent in the presence of triethylamine to give a compound of formula 18. The obtained compound of formula 18 can subsequently be deesterified to produce a compound of formula 2 used as starting material in the process of the invention. To this end, the compound of formula 18 is treated with lithium hydroxide (LiOH) in a solvent. In this reaction, any solvent may be used as long as it does not adversely affect the reaction. Preferably, a mixed solvent of tetrahydrofuran and water is used.

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 benzylamine derivative compounds which may be prepared according to the process of the invention may be mentioned the following compounds:

<1> (s) -3- (4-aminomethyl-phenyl) -1- (2-methyl-pyrrolidinyl) -2- (naphthalene-2-sulfonylamino) -propionamide

<2> (s) -3- (4-aminomethyl-phenyl) -1- (3-hydroxy-pyrrolidinyl) -2- (naphthalene-2-sulfonylamino) -propionamide

<3> (s) -3- (4-aminomethyl-phenyl) -1- (4-hydroxy-piperidinyl) -2- (naphthalene-2-sulfonylamino) -propionamide

<4> (s) -3- (4-aminomethyl-phenyl) -1- (4-acetyl-piperazinyl) -2- (naphthalene-2-sulfonylamino) -propionamide

<5> (s) -3- (4-aminomethyl-phenyl) -1- (3-hydroxy-piperidinyl) -2- (naphthalene-2-sulfonylamino) -propionamide

<6> (s) -3- (4-aminomethyl-phenyl) -1- (4-methylsulfonyl-piperazinyl) -2- (naphthalene-2-sulfonylamino) -propionamide

<7> (s) -3- (4-aminomethyl-phenyl) -1- (3,5-dimethyl-piperidinyl) -2- (naphthalene-2-sulfonylamino) -propionamide

<8> (s) -3- (4-aminomethyl-phenyl) -1- [2- (2-hydroxy-ethyl) -piperidinyl] -2- (naphthalene-2-sulfonylamino) -propion Amide

(9) (s) -3- (4-aminomethyl-phenyl) -1-hexahydroazinyl-2- (naphthalene-2-sulfonylamino) -propionamide

<10> (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2- (naphthalene-2-sulfonylamino) -propionamide

(11) (s) -3- (4-aminomethyl-phenyl) -N-isopropyl-N-methyl-2- (naphthalene-2-sulfonylamino) -propionamide

(12) (s) -3- (4-aminomethyl-phenyl) -N, N-dimethyl-2- (naphthalene-2-sulfonylamino) -propionamide

(13> (s) -3- (4-aminomethyl-phenyl) -N-isopropyl-2- (naphthalene-2-sulfonylamino) -propionamide

(14) (s) -3- (4-aminomethyl-phenyl) -N-benzyl-N-methyl-2- (naphthalene-2-sulfonylamino) -propionamide

<15> (s) -3- (4-aminomethyl-phenyl) -2- (naphthalene-2-sulfonylamino) -1-pyrrolidinyl-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) -1- (2-methyl-pyrrolidinyl) -2- (naphthalene-2-sulfonylamino) -propionamide

20 mg of an acid compound to which aqua resin is bonded, that is, a compound of Formula 2 wherein R ₁ represents a naphthalene group, is 3.5 equivalents of 2-methylpyrrolidine, 3.5 equivalents of 1-hydroxybenzotriazole, 3-ethyl-3'- The mixture was stirred in 2 ml of dimethylformamide (DMF) solvent with 3.5 equivalents of (dimethylamino) -propylcarbodiimide (EDC) and 3.5 equivalents of triethylamine for one day. After the reaction was completed, the reaction mixture was filtered to remove the excess DMF solvent, and the product was washed three times with 10 ml of methylene chloride and 10 ml of methanol, followed by 1 ml of trifluoroacetic acid and 1 methylene chloride solvent. ML was added together, stirred for 30 minutes, filtered to remove the aqua resin, and trifluoroacetic acid and methylene chloride were removed by evaporation from the remaining filtrate to obtain the title compound in a yield of 70%.

MS (FAB): 452 (M ⁺ + H ⁺ )

Example 2

Synthesis of (s) -3- (4-aminomethyl-phenyl) -1- (3-hydroxy-pyrrolidinyl) -2- (naphthalene-2-sulfonylamino) -propionamide

The reaction was carried out according to the same method as Example 1 using 20 mg of the compound of formula 2 wherein R ₁ represents a naphthalene group and 3.5 equivalents of 3-hydroxypyrrolidine to give the title compound in a yield of 75%.

MS (FAB): 440 (M ⁺ + H ⁺ )

Example 3

Synthesis of (s) -3- (4-aminomethyl-phenyl) -1- (4-hydroxy-piperidinyl) -2- (naphthalene-2-sulfonylamino) -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 ₁ represents a naphthalene group and 3.5 equivalents of 4-hydroxypiperidine to give the title compound in a yield of 70%.

MS (FAB): 468 (M ⁺ + H ⁺ )

Example 4

Synthesis of (s) -3- (4-aminomethyl-phenyl) -1- (4-acetyl-piperazinyl) -2- (naphthalene-2-sulfonylamino) -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 ₁ represents a naphthalene group and 3.5 equivalents of piperazin-1-yl-ethanone to obtain the title compound in a yield of 79%. .

MS (FAB): 495 (M ⁺ + H ⁺ )

Example 5

Synthesis of (s) -3- (4-aminomethyl-phenyl) -1- (3-hydroxy-piperidinyl) -2- (naphthalene-2-sulfonylamino) -propionamide

The reaction was carried out according to the same method as Example 1 using 20 mg of the compound of formula 2 wherein R ₁ represents a naphthalene group and 3.5 equivalents of 3-hydroxypiperidine, to give the title compound in a yield of 69%.

MS (FAB): 468 (M ⁺ + H ⁺ )

Example 6

Synthesis of (s) -3- (4-aminomethyl-phenyl) -1- (4-methylsulfonyl-piperazinyl) -2- (naphthalene-2-sulfonylamino) -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 ₁ represents a naphthalene group and 3.5 equivalents of 1-methanesulfonyl-piperazine to obtain the title compound in a yield of 60%.

MS (FAB): 531 (M ⁺ + H ⁺ )

Example 7

Synthesis of (s) -3- (4-aminomethyl-phenyl) -1- (3,5-dimethyl-piperidinyl) -2- (naphthalene-2-sulfonylamino) -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 ₁ represents a naphthalene group and 3.5 equivalents of 3,5-dimethyl-piperidine to give the title compound in a yield of 64%. .

MS (FAB): 480 (M ⁺ + H ⁺ )

Example 8

Synthesis of (s) -3- (4-aminomethyl-phenyl) -1- [2- (2-hydroxy-ethyl) -piperidinyl] -2- (naphthalene-2-sulfonylamino) -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 ₁ represents a naphthalene group and 3.5 equivalents of 2- (2-hydroxyethyl) piperidine to give the title compound in a yield of 59%. Obtained.

MS (FAB): 496 (M ⁺ + H ⁺ )

Example 9

Synthesis of (s) -3- (4-aminomethyl-phenyl) -1-hexahydroazinyl-2- (naphthalene-2-sulfonylamino) -propionamide

The reaction was carried out according to the same method as Example 1 using 20 mg of the compound of formula 2 wherein R ₁ represents a naphthalene group and 3.5 equivalents of hexahydroazepine to obtain the title compound in a yield of 79%.

MS (FAB): 466 (M + H)

Example 10

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

The reaction was carried out according to the same method as Example 1 using 20 mg of a compound of formula 2 wherein R ₁ represents a naphthalene group and 3.5 equivalents of N-methyl-N-cyclopentylamine, to obtain the title compound in a yield of 78%. .

MS (FAB): 466 (M ⁺ + H ⁺ )

Example 11

Synthesis of (s) -3- (4-aminomethyl-phenyl) -N-isopropyl-N-methyl-2- (naphthalene-2-sulfonylamino) -propionamide

The reaction was carried out according to the same method as Example 1 using 20 mg of a compound of formula 2 wherein R ₁ represents a naphthalene group and 3.5 equivalents of N-methyl-N-isopropylamine, to obtain the title compound in a yield of 74%. .

MS (FAB): 440 (M ⁺ + H ⁺ )

Example 12

Synthesis of (s) -3- (4-aminomethyl-phenyl) -N, N-dimethyl-2- (naphthalene-2-sulfonylamino) -propionamide

The reaction was carried out according to the same method as Example 1 using 20 mg of the compound of formula 2 wherein R ₁ represents a naphthalene group and 3.5 equivalents of N, N-dimethylamine, to give the title compound in a yield of 70%.

MS (FAB): 412 (M + H)

Example 13

Synthesis of (s) -3- (4-aminomethyl-phenyl) -N-isopropyl-2- (naphthalene-2-sulfonylamino) -propionamide

The reaction was carried out according to the same method as Example 1 using 20 mg of the compound of formula 2 wherein R ₁ represents a naphthalene group and 3.5 equivalents of N-isopropylamine, to give the title compound in a yield of 77%.

MS (FAB): 426 (M ⁺ + H ⁺ )

14 to implementation

Synthesis of (s) -3- (4-aminomethyl-phenyl) -N-benzyl-N-methyl-2- (naphthalene-2-sulfonylamino) -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 ₁ represents a naphthalene group and 3.5 equivalents of N-benzyl-N-methylamine to give the title compound in a yield of 79%.

MS (FAB): 474 (M ⁺ + H ⁺ )

Example 15

Synthesis of (s) -3- (4-aminomethyl-phenyl) -2- (naphthalene-2-sulfonylamino) -1-pyrrolidinyl-propionamide

The reaction was carried out according to the same method as Example 1 using 20 mg of a compound of formula 2 wherein R ₁ represents a naphthalene group and 3.5 equivalents of pyrrolidine to give the title compound in a yield of 81%.

MS (FAB): 438 (M ⁺ + H ⁺ )

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

Claims (6)

Coupling a resin-bonded benzylamine derivative of formula (2) with an amine derivative of formula (3) to obtain a compound of formula (4), which is then treated in a trifluoroacetic acid and methylene chloride solvent To prepare a benzylamine derivative of formula 1: [Formula 1] [Formula 2] [Formula 3] [Formula 4] In the above formula, R ₁ represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, R ₂ represents hydrogen, alkyl, alkoxyalkyl or allyl, R ₃ represents alkyl, aralkyl, cycloalkyl, isoquinolyl, naphthalene, phenoxyaryl, hydroxyaryl, sulfonylalkyl, bicycloalkyl or alkoxyalkyl, or R ₂ and R ₃ together with the nitrogen atom to which they are attached represent a 5-7 membered heterocyclic group which may be substituted or unsubstituted and further contain one nitrogen atom, Represents a residue of Wang resin. The method of claim 1, wherein the coupling reaction is carried out using 1-hydroxybenzotriazole and 3-ethyl-3 '-(dimethylamino) -propylcarbodiimide as coupling agents. The method of claim 2 wherein the coupling reaction is carried out in a solvent in the presence of a base. 4. A process according to claim 3, characterized in that triethylamine is used as the base and dimethylformamide is used as the solvent. The method of claim 1 wherein the coupling reaction is carried out at room temperature for 24 hours. A compound according to claim 1, wherein (s) -3- (4-aminomethyl-phenyl) -1- (2-methyl-pyrrolidinyl) -2- (naphthalene-2-sulfonylamino) -propionamide, (s ) -3- (4-aminomethyl-phenyl) -1- (3-hydroxy-pyrrolidinyl) -2- (naphthalene-2-sulfonylamino) -propionamide, (s) -3- (4- Aminomethyl-phenyl) -1- (4-hydroxy-piperidinyl) -2- (naphthalene-2-sulfonylamino) -propionamide, (s) -3- (4-aminomethyl-phenyl) -1 -(4-acetyl-piperazinyl) -2- (naphthalene-2-sulfonylamino) -propionamide, (s) -3- (4-aminomethyl-phenyl) -1- (3-hydroxy-pipepe Ridinyl) -2- (naphthalene-2-sulfonylamino) -propionamide, (s) -3- (4-aminomethyl-phenyl) -1- (4-methylsulfonyl-piperazinyl) -2- (Naphthalene-2-sulfonylamino) -propionamide, (s) -3- (4-aminomethyl-phenyl) -1- (3,5-dimethyl-piperidinyl) -2- (naphthalene-2-sul Ponylamino) -propionamide, (s) -3- (4-aminomethyl-phenyl) -1- [2- (2-hydro Oxy-ethyl) -piperidinyl] -2- (naphthalene-2-sulfonylamino) -propionamide, (s) -3- (4-aminomethyl-phenyl) -1-hexahydroazinyl-2- (Naphthalene-2-sulfonylamino) -propionamide, (s) -3- (4-aminomethyl-phenyl) -N-cyclopentyl-N-methyl-2- (naphthalene-2-sulfonylamino) -propion Amide, (s) -3- (4-aminomethyl-phenyl) -N-isopropyl-N-methyl-2- (naphthalene-2-sulfonylamino) -propionamide, (s) -3- (4- Aminomethyl-phenyl) -N, N-dimethyl-2- (naphthalene-2-sulfonylamino) -propionamide, (s) -3- (4-aminomethyl-phenyl) -N-isopropyl-2- ( Naphthalene-2-sulfonylamino) -propionamide, (s) -3- (4-aminomethyl-phenyl) -N-benzyl-N-methyl-2- (naphthalene-2-sulfonylamino) -propionamide and (s) -3- (4-aminomethyl-phenyl) -2- (naphthalene-2-sulfonylamino) -1-pyrrolidinyl-propionamide selected from the group consisting of Characterized in that producing the derivatives.