KR100465353B1 - Hydrazine derivatives and processes for the preparation thereof - Google Patents

Abstract

The present invention relates to various and large-scale hydrazine libraries and their preparation, and more particularly, to a hydrazine library by a combination and sharing method according to the molecular combination new technology and a method for easily preparing the same in a short period of time in a solution or solid phase. .

Description

Hydrazine derivatives and processes for preparing the same

The present invention relates to various and large-scale hydrazine libraries and their preparation, and more particularly, various kinds of hydrazine libraries represented by the following structural formula (I) by a combination and sharing method according to the molecular combination new technology, and a solution phase or A method for easily preparing in a short time in the solid phase.

In formula (I), R 1 is hydrogen, alkyl, or substituted or unsubstituted phenyl, naphthyl, or benzyl; R 2 is hydrogen, lower alkyl, or substituted or unsubstituted, phenyl, phenylalkyl, hetero ring, or naphthyl; X is hydrogen, oxygen, or sulfur; n is 0 or 1; Y is substituted or unsubstituted and lower alkylamino, aniline, naphthylmethylamino, vinylamino, propazylamino, lowerdialkylamino, indolinyl, quinolinyl, isoquinolinyl, benzylamino, phenylethylamino, heterocyclic Methylamino, piperazinyl, piperidine, lower alkylphenylamino, halogen, phenyl, naphthyl, pyranyl, or thiophenyl.

The hydrazine derivative represented by the above formula (I) is a kind of similar peptide called azapeptide, which is well known to be able to replace the main skeleton structure of the peptide or is known as an important compound related thereto [Angew. Chem. Int. Ed. Engl. 33 , 1699 (1994); Adv. Drug. Res. 29 , 1 (197)]. Since the hydrazine skeleton of the formula (I) is a structure in which the carbon at the alpha position of the amino acid is substituted with nitrogen, it is easy to prepare a compound having a more diverse structure because there is one more reactive nitrogen function than a normal amino acid. In terms of their steric structure, they have the main characteristic of simulating D- and L-amino acids simultaneously under low energy barrier. In particular, azapeptides are more stable to hydrolytic enzymes in vivo than normal peptide structures, and therefore, anti-cancer agents, osteoporosis treatment agents, antiviral agents, antithrombogenic agents, etc. that target cysteine, aspartyl and serine protease inhibitors It has been used as a leading endogenous endogenous proteases inhibitors [Chem. Rev. 97 , 133 (1997)], used as an alternative compound that mimics the major skeletal structure of peptides with other anti-inflammatory or growth hormone-promoting activity, resulting in improved activity, physical properties and pharmacokinetics compared to the original peptide. It is known to be an important compound that is being studied in depth. Med. Chem. 41 , 3387 (1998).

Hydrazine library refers to a collection of more than hundreds of thousands of various hydrazine compounds, usually produced by mathematical statistical combination and sharing by molecular combination method. The purpose of molecular combinatorial chemistry is to easily produce many compounds with various structures simultaneously in a short time. For example, the number of possible monomers from each of the four monomer compounds is four, but in the case of tetramers, 4 ⁴ = 256 (see Table 1).

Table 1.Comparison of the total number of compounds with increasing monomer

Possible number of monomers Total number of compounds unit Dimer Trimer Tetramer 4 4 16 64 256 20 20 400 8 x 10 ³ 1.6 x 10 ³ 50 50 2,500 1.3 x 10 ⁵ 7.3 x 10 ⁶

As described above, the molecular combination method is a technique that can be produced by increasing the diversity of the polymer exponentially by the combination and sharing method as the type of each possible unit is introduced. This method was achieved by examining how the natural world gives diversity to molecules in vivo and by acquiring techniques to mimic it. The natural world uses this diversity to produce a limited number of amino acids and sugars and to create and distinguish many different genes, or to produce proteins, lipids, and carbohydrates with various physiological activities.

In order to manufacture a variety of compounds using a molecular combination method, which is a natural imitation technology, it is necessary to develop a new manufacturing method technology. For example, new major technologies to be completed include solid or liquid library manufacturing techniques; Separation purification, quantitative analysis and identification analysis techniques; Tag introduction and identification techniques; Scaffold and manufacturing techniques should be developed. Particularly, the development of solid phase manufacturing technology revolutionizes the method of preparing compounds one by one according to the conventional solution phase manufacturing method, and enables the production of hundreds or thousands of compounds at the same time in a short time. [C & EN Fev 7, 20 ( 1994); Angew. Chem. Int. Ed. Engl. 35 , 2288 (1996).

This successful achievement was made possible primarily by taking advantage of the solid phase manufacturing process. For example, identifying and utilizing solid effects in solid phase reactions; Ease of separation and purification; The use of solid phase resins (resins) capable of miniaturization; It is based on the adoption of reaction conditions that enable high yields and, above all, on the development of processes that make use of these advantages. Also in the present invention, through the development of a solid-phase production technology, it was possible to produce hundreds or more kinds of hydrazine derivative represented by the above formula (I) at the same time.

As a method for preparing a hydrazine derivative, a method of introducing azaglutamine using an isocyanate derivative of an amino acid whose C-terminus of the amino acid is supported on a solid phase is known [Int. J. Pepetide Protein Res. 40 , 351 (1992).

However, the preparation of hydrazine derivatives by this method is limited to azaglutamine derivatives and is different from the production method in which the N-terminus, which is a development process pursued by the present invention, is connected to a solid phase support, and is different from the structure of the compound of the present invention. The main skeleton is completely different.

In addition, a method for producing an azapeptide in which amino acids and acyl groups are sequentially introduced using t-butoxycarbonylmethylhydrazine as a skeleton is known [WO 9603982; WO 9630395].

However, this method is only preparation in solution phase and is only a manufacturing method limited to t-butoxycarbonylmethylhydrazine structure. Since N-t-butoxycarbonylamino acid used as a hydrazine protecting group is unstable under acidic conditions, it is already known to be difficult to use for solid phase preparation. Therefore, as a skeleton of N-1- (9-fluorenylmethoxycarbonyl) -N-1- (substituted) hydrazine used in the present invention, a method for preparing a hydrazine derivative through the introduction of a position-selective substituent It is different and not particularly suitable for the preparation of hydrazine derivatives in the solid phase.

In order to quickly and easily prepare a hydrazine library having a large and diverse structure in a solution phase as well as a solid phase, a 9-fluorenylmethoxycarbonyl (Fmoc) protecting group is optionally introduced at the 1-position of a substituted hydrazine group. It is an object to provide a method of making a hydrazine scaffold.

In addition, after the introduction of an amino acid group having a linking group to a protecting group or a solid resin (resin) at the 2-position of the substituted hydrazine using the hydrazine skeleton in which the Fmoc-protecting group was introduced using a combination and sharing method using a molecular combination, the Fmoc- It is an object of the present invention to provide a method for preparing a large number of hundreds of large hydrazine libraries in a short time by deprotecting the protecting group under mild basic conditions and then introducing various substituents back to the 1-position, and providing the hydrazine library thereof.

The present invention relates to a hydrazine library having various structures represented by the following structural formula (I) based on the combination and sharing method according to the molecular combination chemistry and a method for easily preparing the same in a solution phase or a solid phase in a short time.

R 1, R 2, n, X and Y are the same as defined above.

Hereinafter, a method for preparing the hydrazine compound of the present invention will be described in detail.

<Step 1: Production process of N-substituted amino acid>

When R in the general formula (II) is an amine protecting group, an amine group was easily protected by using an amino acid having a commercially available protecting group or a protecting group commonly used in the field of amino acid derivatives. The conventional amine protecting group herein means an amine protecting group which can be easily deprotected, especially under acidic conditions, and t-butoxycarbonyl (t-Boc), triphenylmethyl (Ph ₃ C) and the like are preferable.

In addition, when R in the general formula (II) is a solid resin carbonyl linker, Merifield available as a commercial (Novabiochem Co.) having 4-benzyloxybenzyl alcohol residue on the polymer solid resin. 4-nitrophenylchlorocarba commonly used in accordance with known methods [Tetrahedron Lett., 37 , 937 (1996)] from resins such as Merrifield resin, Wang Resin or TentaGel. As a method using a mate (p-NO 2 PhOCOCl), a method of preparing an activated resin having 4-nitrophenyl carbonate (p-NO 2 PhOCO—) in a solid phase was used.

In addition, in the general formula (II), the amino acid in which R is hydrogen is reacted with a previously prepared activated resin using a silylating agent under an appropriate solvent and basic conditions, and then washed with various solvents to link each amino acid onto a solid resin. Could. The silylating agents used herein include N, O-bistrimethylsilylacetimide (BSA), bistrimethylsilyltrifluoroacetamide (BSTFA) or 1,1,1,3,3,3-hexamethyldisilazane (HMDS ) And chlorotrimethylsilane (TMSCl) or mixtures thereof are possible, with N, O-bistrimethylsilylacetimide (BSA) being particularly preferred. The solvent usable for the solid phase reaction in the present manufacturing process may be acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), dichloromethane, or a polar solvent of a mixed solvent thereof. In the solid phase reaction, solvents such as dichloromethane and dimethylformamide are more preferable in view of swelling, solvation and reactivity. As the base used herein, all of conventional organic bases such as triethylamine (Et ₃ N), dimethylaminopyridine (DMAP) and pyridine can be used. After the reaction, there is a need to wash away the free 4-nitrophenol and remaining excess amino acids, bases, and silylating agents, and in particular, to remove the silylating agent and the remaining trimethylsilyl groups serving as activation and protecting groups. It is sufficiently washed with a solvent such as tetrahydrofuran (THF), dimethylformamide (DMF), dichloromethane and the like containing a methanol solvent having a real group, and capping the solid alcohol residue remaining unreacted after the reaction. Deactivated throughout the process.

Examples of amino acids used herein include L-valine (IIa), L-isoleucine (IIb), L-leucine (IIc), L-phenylalanine (IId), L-glycine (IIe), and the like.

<Step 2: manufacturing process of hydrazine skeleton>

In formula (III), R 2 represents hydrogen, lower alkyl, or substituted or unsubstituted phenyl, phenylalkyl, hetero ring, naphthyl and the like, and examples of the hydrazine skeleton (III) prepared and used herein are As follows.

For general and convenient preparation of the hydrazine scaffold of the general formula (III), t-butoxycarbazate (t-BocNHNH ₂ ) and a conventional aldehyde (1) are condensed through a corresponding imine compound ( 2), a hydrazine derivative (3) having t-butoxycarbonyl group (t-Boc) at 2-position of hydrazine was further prepared through reduction reaction, followed by 9-fluorenylmethoxycarbonyl ( Fmoc) a protecting group was further introduced at the 1-position of hydrazine to prepare compound (4) having a Fmoc-protecting group at the 1-position of the hydrazine and a t-Boc-protecting group at the 2-position of the hydrazine, followed by 2-position under acidic conditions. The selective deprotection of only t-Boc-protecting groups resulted in the preparation of hydrazine skeleton (II). Conventional aldehydes here are alkylaldehydes, phenylaldehydes, substituted phenylaldehydes, phenylalkyls, substituted phenylalkyls, naphthylaldehydes, substituted naphthyl, hetero rings, or substituted hetero rings that readily condense with hydrazine derivatives. And the like. Acidic conditions are conditions under which the t-Boc-protecting group can be selectively deprotected while leaving the Fmoc-protecting group intact. Generally, hydrochloric acid or trifluoroacetic acid is converted into dichloromethane or ethyl acetate. A method of mixing and treating with an organic solvent such as was used. Another method of preparing the hydrazine skeleton is to react with 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) directly in a suitable solvent with alkylhydrazine (5) to complete the preparation of the hydrazine skeleton (III). It became.

In order to prepare the amine compound of Structural Formula (2) shown in Step 2, the condensation reaction of t-butoxycarbazate (t-BocNHNH2) with aldehyde (1) is carried out with n-hexane, alcohol or tetra It could be easily prepared under reflux conditions using a conventional organic solvent such as hydrofuran (THF). Reduction reaction conditions for preparing the hydrazine derivative (3) from the imine compound (2) include palladium / carbon (Pd / C) catalytic hydrogen, platinum / carbon (Pt / C) catalytic hydrogen or hydrogen borane-tetrahydrofuran (BH Compound (3) can be easily prepared using conventional methods such as ₃ -THF). The next process involves reacting 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) in the presence of a base in a suitable solvent to introduce a Fmoc group at the 1-position of hydrazine, resulting in an Fmoc-protecting group and 2 at the 1-position. Compound (4) having a t-Boc-protecting group at the -position was prepared. Bases used herein include conventional organic bases such as triethylamine (Et ₃ N) and diisopropylethylamine (i-Pr ₂ NEt). As the solvent used, polar organic solvents such as tetrahydrofuran (THF), dimethylformamide (DMF), dichloromethane and ethyl acetate (EtOAc) can be used.

The hydrazine skeleton of formula (III) was selectively deprotected by selectively deprotecting only the t-Boc protecting group in the 1-position amine group of hydrazine using conventional methods of deprotecting the compound of formula (4) under acidic conditions. The compound was prepared.

<Step 3: Combined amino acid and hydrazine skeleton>

In order to prepare a hydrazine derivative of the general formula (I) in the present invention to prepare a compound of the general formula (IV) from the compound of the general formula (II) and the general formula (III) through a conventional amide bond reaction in solution and solid phase Process. The conventional amide binding reaction here is a method already used in the preparation of peptides, which refers to a process of activating a free acid group and then replacing an amine. Activation methods used herein include active esters such as -OBT, -OSu or -Opfp esters, etc., and these were carried out without being separated and used directly. Catalysts required for this coupling reaction include dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBT), benzotriazol-1-yl Oxytridimethylaminophosphonyl hexafluorophosphonate (BOP), 1- (3-dimethylaminopropyl) -3-methylcarbodiimide (EDAC), etc. can be used. The binding reagent may be used in an amount of 1-10 equivalents, more preferably 2-5 equivalents.

In the above general formulas (IV) and (V), R, R1 and R2 are the same as described above. And the vowels of the target compounds of the general formula (V) obtained here represent hydrazine derivatives obtained according to the manner of combination and sharing in solution and solid phase. For example, in the case of reacting amino acids (five species) of Formula (II) with hydrazine (8 species) of Formula (III), for the same R, the compounds formed are each R1 and There are 5 x 8 = 40 vowels distinguished by R2. Identification of these derivatives obtained here in the solid phase was performed in the state where the protecting group (R) was removed, respectively. That is, each unit of the general formula (IV) on the solid-phase support was identified by comparison with the standard compound of the general formula (IV) prepared in solution after being advantageous under acidic conditions. As the acidic conditions used herein, a solid phase support having a hydroxybenzyl moiety is usually used, for example, hydrochloric acid, trifluoroacetic acid, or a 5-25% water mixture thereof. Or a mixture of organic solvents such as dichloromethane, ethyl acetate, dimethylformamide, or tetrahydrofuran can be used. Particularly preferably, a 5% water-95% trifluoroacetic acid mixed solution is used. It is suitable.

In order to prepare a library of general formula (I) from general formula (IV), a deprotection process of the Fmoc-protecting group of the compound of general formula (IV) is required. Commonly used solution and solid phase deprotection conditions are also useful, for example, using secondary amine bases such as piperidine or the use of tertiary amine bases such as 4-dimethylaminopyridine (DMAP). The solvent used consists of from 5 minutes to 2 hours in polar organic solvents such as dimethylformamide (DMF), dichloromethane, 1-methylmorpholine and ethyl acetate, more preferably 25% -piperi. Dean / dimethylformamide or 2-10% -DMAP / dichloromethane is suitable.

From the deprotected compound (V), a variety of acylating agents, isocyanate (-N = C = O), isothiocyanate (-N = C = S), and the like, both in solution and solid phase, The hydrazine derivatives of (I) can be prepared respectively.

Here, as an acylating agent, normal acylating agents, such as an acyl halide and a carboxylic acid, can be reacted under basic conditions, or both normal active esters, such as -OBT, can be used. In addition, after the introduction of the bromomethyl acyl group as the acylating agent, the hydrazine derivative of the general formula (I) below can be easily prepared by substitution with various amines.

<Step 4: Reaction Step of Bromomethylacylation with Amine>

In the above general formulas (V) and (I), R, R1 and R2 are as described above. Y is substituted or unsubstituted and lower alkylamino, aniline, naphthylmethylamino, vinylamino, propazylamino, lowerdialkylamino, indolinyl, quinolinyl, isoquinolinyl, benzylamino, phenylethylamino, heterocyclic Methylamino, piperazinyl, piperidine, or lower alkylphenylamino. As the solvent used in the step of substituting the amine, any of a conventional polar organic solvent such as tetrahydrofuran, dimethylformamide, or dimethyl sulfoxide (DMSO) can be used. Examples of amines used here are as follows.

And the vowels of the target compounds of general formula (I) obtained here represent hydrazine derivatives obtained according to the manner of combination and sharing in solution and solid phase. Each unit of the formula (I) on the solid support was identified by comparison with the standard compound of the formula (I) prepared in solution after being released under acidic conditions.

<Step 5: Reaction Step with Acylating Agent>

Examples of acyl halides used here are as follows.

Wherein R, R1, R2 are the same as described above, Y represents lower alkyl, halogen or substituted or unsubstituted and represents phenyl, naphthyl, pyranyl, thiophenyl, hetero ring and the like.

When using general formula (V) and iso (thio) cyanate (-NCO, -NCS), the hydrazine derivative containing (thio) urea can be manufactured. As the solvent used herein, conventional polar and nonpolar organic solvents such as benzene, dichloromethane, tetrahydrofuran and dimethylformamide can be used.

<Step 6: Reaction Step with Iso (thio) cyanate>

Examples of iso (thio) cyanate used herein are as follows.

In the above general formula (I), when X is oxygen (X = O), R, R1, R2 are the same as described above, Y is alkylamino, phenylamino, substituted phenylamino, naphthylamino Or substituted naphthylamino.

In the above general formula (I), when X is sulfur (X = S), R, R1, R2 are the same as described above, Y is lower alkylamino, phenylamino, substituted phenylamino, naphthylamino Or substituted naphthylamino and the like.

In addition, the collection of the target compound of general formula (I) obtained here means the hydrazine derivative obtained by the method of combination and sharing in a solution and a solid phase. Each unit of the formula (I) on the solid support was identified by comparison with a standard compound of the formula (I) prepared in solution after being released under acidic conditions. As the acidic conditions used herein, a solid phase support having a 4-hydroxybenzyl moiety is usually separated, for example, using hydrochloric acid, trifluoroacetic acid, or a 5-25% water mixture solution. All methods can be used in combination with organic solvents such as dichloromethane, ethyl acetate, dimethylformamide or tetrahydrofuran, but in particular 5% water-95% trifluoroacetic acid can be used. desirable.

Hereinafter, the hydrazine derivative of the present invention will be described in more detail by dividing into a method of preparing in a solution phase and a method of preparing in a solid phase. However, the present invention is not limited thereto.

First, the method for preparing the hydrazine derivative of the present invention in the solution phase will be described.

Example 1 Preparation of N-1- (9-Fluorenylmethoxycarbonyl) -N-1-methylhydrazine

The reaction solution in which methylhydrazine (0.53 ml, 10 mmol) and diisopropylethylamine (1.92 ml, 11 mmol) was dissolved in dichloromethane (30 ml) was cooled to 0 ° C. To this solution was slowly added 9-fluorenylmethyl chloroformate (2.85 g, 11 mmol) and stirred for 30 minutes at the same temperature. The reaction solution was washed with water and saturated brine, dried and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.38 g, 8.9 mmol) as a white solid.

¹ H NMR (CDCl ₃ ; δ): 3.17 (s, 3H), 4.10-4.30 (m, 3H), 4.45 (d, 2H), 7.30-7.80 (m, 8H)

IR (KBr; cm ^-1 ): 3339, 1782, 1615

Melting Point (℃): 80-82

Example 2 Preparation of N-1- (9-Fluorenylmethoxycarbonyl) -N-1-benzylhydrazine

Step 1) Preparation of N-1- (t-butoxycarbonyl) -N-2-benzylidenehydrazone

After tert-butylcarbazate (13.67 g, 103 mmol) was dissolved in n-hexane (100 ml), benzaldehyde (9.58 ml, 94 mmol) was added dropwise to the reaction solution at room temperature and refluxed for 1 hour. After cooling the reaction mixture to room temperature, the resulting white solid was filtered and dried under reduced pressure to give the title compound (22 g, 91 mmol).

¹ H NMR (CDCl ₃ ; δ): 1.48 (s, 9H), 7.36-7.62 (m, 5H), 7.98 (s, 1H), 10.85 (br, 1H)

IR (KBr; cm ^-1 ): 3239, 3024, 1684, 1520

Melting Point (℃): 184-186

Step 2) Preparation of N-1- (t-butoxycarbonyl) -N-2-benzylhydrazine

10% of the catalytic amount after dissolving N-1- (t-butoxycarbonyl) -N-2-benzylidenehydrazone (13 g, 59 mmol) in step 1) in tetrahydrofuran (200 ml) -Palladium / Carbon (Pd / C; 1 g) was added and stirred for 30 minutes under hydrogen pressure of about 40 psi. The reaction solution was filtered through celite and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (10.8 g, 48.6 mmol).

¹ H NMR (DMSO-d ₆ ; δ): 1.38 (s, 9H), 3.85 (d, 2H), 4.70 (d, 1H), 7.2-7.3 (m, 5H), 8.2 (br, 1H)

IR (KBr; cm ^-1 ): 3239, 2925, 1687, 1521

Melting Point (℃): 170-173

Step 3) Preparation of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine

The title compound (4.0 g, 9 mmol) using N-1- (t-butoxycarbonyl) -N-2-benzylhydrazine (2.2 g, 10 mmol) instead of methylhydrazine in the same manner as in Example 1. Obtained.

¹ H NMR (CDCl ₃ ; δ): 1.42 (s, 9H), 4.25 (m, 1H), 4.40-4.80 (m, 4H), 6.30 br, H), 7.20-7.80 (m, 13H)

IR (KBr; cm ^-1 ): 3310, 2974, 1727, 1678

Melting Point (℃): 114-117

Step 4) Preparation of N-1- (9-fluorenylmethoxycarbonyl) -N-1-benzylhydrazine

Step 1) N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine (3.7 g, 8.3 mmol) was added to dichloromethane ( 30 ml) and cooled to 0 ° C. Trifluorovinelic acid (20 ml) was slowly added to this solution and stirred for 30 minutes at the same temperature. After distilling the reaction solution under reduced pressure, the residue was diluted with dichloromethane (100 ml) and the solution was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dehydrated with magnesium sulfate (MgSO 4) and distilled under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.1 g, 6.1 mmol).

¹ H NMR (CDCl ₃ ; δ): 4.0 (br, 2H), 4.2 (m, 1H), 4.4-4.6 (m, 4H), 7.0-7.7 (m, 13H)

IR (KBr; cm ^-1 ): 3310, 2974, 1727, 1678

Melting Point (℃): 114-117

Example 3. Preparation of N-1- (9-fluorenylmethoxycarbonyl) -N-1- (1-naphthylmethyl) hydrazine

Step 1) Preparation of N-1- (t-butoxycarbonyl) -N-2- (1-naphthylmethylidene) hydrazone

The title compound (16.5 g, 61 mmol) was obtained by using naphthylaldehyde (8.7 ml, 64 mmol) instead of benzaldehyde in the same manner as in step 1) of Example 2.

¹ H NMR (CDCl ₃ ; δ): 1.48 (s, 9H), 7.56-8.02 (m, 6H), 8.62 (s, 1H), 8.78 (d, 2H), 10.98 (br, 1H)

IR (KBr; cm ^-1 ): 3262, 2979, 1694, 1518

Melting Point (℃): 160-163

Step 2) Preparation of N-1- (t-butoxycarbonyl) -N-2- (1-naphthylmethyl) hydrazine

N-1- (t-butoxycarbonyl) -N instead of N-1- (t-butoxycarbonyl) -N-2-benzylidenehydrazone in the same manner as in step 2) of Example 2 2- (1-naphthylmethylidene) hydrazone (14 g, 52 mmol) was used to give the title compound (11.8 g, 43 mmol).

¹ H NMR (DMSO-d ₆ ; δ): 1.40 (s, 9H), 4.3 (d, 2H), 4.75 (br, 1H), 7.38-7.92 (m, 6H), 8.2-8.3 (m, 2H)

IR (KBr; cm ^-1 ): 3361, 2922, 1696, 1541

Melting Point (℃): 118-120

Step 3) Preparation of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (1-naphthylmethyl) hydrazine

In the same manner as in Example 1, using N-1- (t-butoxycarbonyl) -N-2- (1-naphthylmethyl) hydrazine (2.7 g, 10 mmol) instead of methylhydrazine, the title compound ( 4.8 g, 9.7 mmol) was obtained.

¹ H NMR (CDCl ₃ ; δ): 1.45 (s, 9H), 4.25 (m, 1H), 4.40-5.00 (m, 4H), 6.38 (br, 1H), 7.20-7.95 (m, 15H)

IR (KBr; cm ^-1 ): 3238, 2924, 1723

Melting Point (℃): 55-58

Step 4) Preparation of N-1- (9-fluorenylmethoxycarbonyl) -N-1- (1-naphthylmethyl) hydrazine

N-1 instead of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in step 4) of Example 2 The title compound using-(t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (1-naphthylmethyl) hydrazine (4.7 g, 9.5 mmol) (2.9 g, 7.4 mmol) was obtained.

¹ H NMR (CDCl ₃ ; δ): 4.0-4.2 (m, 3H), 4.5 (d, 2H), 4.9 (s, 2H), 7.1-8.1 (m, 15H)

IR (KBr; cm ^-1 ): 3339, 1701

Melting Point (℃): 77-80

Example 4 Preparation of N-1- (9-Fluorenylmethoxycarbonyl) -N-1-piperonylhydrazine

Step 1) Preparation of N-1- (t-butoxycarbonyl) -N-2-piperonylidenehydrazone

Piperonal (8.8 ml, 67 mmol) was used instead of benzaldehyde in the same manner as in step 1) of Example 2 to obtain the title compound (14.1 g, 53 mmol).

¹ H NMR (CDCl ₃ ; δ): 1.45 (s, 9H), 6.05 (s, 2H), 6.9-7.2 (m, 3H), 7.95 (s, 1H), 10.78 (br, 1H)

Step 2) Preparation of N-1- (t-butoxycarbonyl) -N-2-piperonylhydrazine

N-1- (t-butoxycarbonyl) -N instead of N-1- (t-butoxycarbonyl) -N-2-benzylidenehydrazone in the same manner as in step 2) of Example 2 2-Piperonylidenehydrazone (14.1 g, 53 mmol) was used to give the title compound (6 g, 23 mmol).

¹ H NMR (DMSO-d ₆ ; δ): 1.45 (s, 9H), 3.90 (s, 2H), 5.95 (s, 1H), 6.75-6.85 (s, 3H)

Step 3) Preparation of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-piperonylhydrazine

In the same manner as in Example 1, using the title compound (8 g, 16) using N-1- (t-butoxycarbonyl) -N-2-piperonylhydrazine (5 g, 19 mmol) instead of methylhydrazine. mmol).

¹ H NMR (DMSO-d ₆ ; δ): 1.40 (s, 9H), 4.3 (d, 2H), 4.75 (br, 1H), 7.38-7.92 (m, 6H), 8.20-8.30 (m, 2H)

IR (KBr; cm ^-1 ): 3361, 2922, 1696, 1541

Step 4) Preparation of N-1- (9-fluorenylmethoxycarbonyl) -N-1-piperonylhydrazine

N-1 instead of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in step 4) of Example 2 -(t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-piperonylhydrazine (4.7 g, 9.5 mmol) to give the title compound (2.9 g, 7.4 mmol) was obtained.

¹ H NMR (CDCl ₃ ; δ): 3.9 (br, 2H), 4.2-4.4 (m, 3H), 4.6 (d, 2H), 5.9 (s, 2H), 6.5-6.8 (m, 3H), 7.3 -7.9 (m, 8H)

Example 5 Preparation of N-1- (9-Fluorenylmethoxycarbonyl) -N-1- (4-methoxybenzyl) hydrazine

Step 1) Preparation of N-1- (t-butoxycarbonyl) -N-2- (4-methoxybenzylidene) hydrazone

In the same manner as in step 1) of Example 2, 4-methoxybenzaldehyde (10 g, 73 mmol) was used instead of benzaldehyde to obtain the title compound (18.2 g, 66 mmol).

¹ H NMR (CDCl ₃ ; δ): 1.5 (s, 9H), 3.9 (s, 2H), 6.9 (d, 2H), 7.6 (d, 2H), 7.8 (br, 1H), 7.9 (br, 1H )

Step 2) Preparation of N-1- (t-butoxycarbonyl) -N-2- (4-methoxybenzyl) hydrazine

N-1- (t-butoxycarbonyl) -N instead of N-1- (t-butoxycarbonyl) -N-2-benzylidenehydrazone in the same manner as in step 2) of Example 2 2- (4-methoxybenzylidene) hydrazone (18.2 g, 73 mmol) was used to give the title compound (16.6 g, 66 mmol).

¹ H NMR (CDCl ₃ ; δ): 1.45 (s, 9H), 3.90 (s, 3H), 3.95 (s, 2H), 6.10 (br, 1H), 6.90-7.30 (m, 4H)

Step 3) Preparation of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (4-methoxybenzyl) hydrazine

In the same manner as in Example 1, using N-1- (t-butoxycarbonyl) -N-2- (4-methoxybenzyl) hydrazine (8.3 g, 33 mmol) instead of methylhydrazine, the title compound ( 14.2 g, 30 mmol) was obtained.

¹ H NMR (CDCl ₃ ; δ): 1.40 (s, 9H), 3.90 (s, 3H), 4.25 (d, 1H), 4.4-4.8 (m, 4H), 6.3 (br, 1H), 7.2-7.8 (m, 12H)

Step 4) Preparation of N-1- (9-fluorenylmethoxycarbonyl) -N-1- (4-methoxybenzyl) hydrazine

N-1 instead of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in step 4) of Example 2 The title compound using-(t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (4-methoxybenzyl) hydrazine (14.2 g, 30 mmol) (8.4 g, 22.5 mmol) was obtained.

¹ H NMR (CDCl ₃ ; δ): 3.2-3.5 (br, 2H), 3.9 (s, 3H), 4.25 (t, 1H), 4.4 (s, 2H), 4.6 (d, 2H), 6.8 (d , 2H), 7.0 (m, 2H), 7.3-7.8 (m, 8H)

Example 6 Preparation of N-1- (9-Fluorenylmethoxycarbonyl) -N-1- (4-tolylmethyl) hydrazine

Step 1) Preparation of N-1- (t-butoxycarbonyl) -N-2- (4-tolylmethylidene) hydrazone

In the same manner as in step 1) of Example 2, 4-tolylaldehyde (9.8 ml, 83 mmol) was used instead of benzaldehyde to obtain the title compound (15.7 g, 66 mmol).

¹ H NMR (CDCl ₃ ; δ): 1.5 (s, 9H), 2.35 (s, 3H), 7.15 (d, 2H), 7.55 (d, 2H), 7.8 (br, 1H), 7.9 (br, 1H )

Step 2) Preparation of N-1- (t-butoxycarbonyl) -N-2- (4-tolylmethyl) hydrazine

N-1- (t-butoxycarbonyl) -N instead of N-1- (t-butoxycarbonyl) -N-2-benzylidenehydrazone in the same manner as in step 2) of Example 2 The title compound (15.7 g, 66 mmol) was obtained using 2- (4-tolylmethylidene) hydrazone (19.4 g, 83 mmol).

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 2.3 (s, 3H), 3.8 (s, 2H), 4.6 (s, 1H), 7.0-7.2 (m, 4H), 8.2 (br , 1H)

Step 3) Preparation of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (4-tolylmethyl) hydrazine

The title compound (13.8) using N-1- (t-butoxycarbonyl) -N-2- (4-tolylmethyl) hydrazine (7.9 g, 33 mmol) instead of methylhydrazine in the same manner as in Example 1. g, 30 mmol) was obtained.

¹ H NMR (CDCl ₃ ; δ): 1.45 (s, 9H), 2.40 (s, 3H), 4.30 (d, 2H), 4.40-4.80 (m, 4H), 6.40 (br, 1H), 7.00-7.80 (m, 12H)

Step 4) Preparation of N-1- (9-fluorenylmethoxycarbonyl) -N-1- (4-tolylmethyl) hydrazine

N-1 instead of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in step 4) of Example 2 -(t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (4-tolylmethyl) hydrazine (13.8 g, 30 mmol) to give the title compound ( 5.7 g, 15.8 mmol) was obtained.

¹ H NMR (CDCl ₃ ; δ): 2.4 (s, 3H), 3.8 (br, 2H), 4.3 (t, 1H), 4.5 (s, 2H), 4.6 (d, 2H), 7.0-7.8 (m , 12H)

Example 7 Preparation of N-1- (9-fluorenylmethoxycarbonyl) -N-1- (2-naphthylmethyl) hydrazine

Step 1) Preparation of N-1- (t-butoxycarbonyl) -N-2- (2-naphthylmethylidene) hydrazone

The title compound (16.5 g, 61 mmol) was obtained by using 2-naphthylaldehyde (8.7 ml, 64 mmol) instead of benzaldehyde in the same manner as in step 1) of Example 2.

¹ H NMR (CDCl ₃ ; δ): 1.48 (s, 9H), 7.56-8.02 (m, 6H), 8.62 (s, 1H), 8.78 (d, 2H), 10.98 (br, 1H)

Step 2) Preparation of N-1- (t-butoxycarbonyl) -N-2- (2-naphthylmethyl) hydrazine

N-1- (t-butoxycarbonyl) -N instead of N-1- (t-butoxycarbonyl) -N-2-benzylidenehydrazone in the same manner as in step 2) of Example 2 The title compound (14.2 g, 52 mmol) was obtained using -2- (2-naphthylmethylidene) hydrazone (17.6 g, 65 mmol).

¹ H NMR (DMSO-d ₆ ; δ): 1.45 (s, 9H), 3.9 (s, 2H), 5.95 (s, 1H), 6.75-6.85 (s, 3H)

Step 3) Preparation of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (2-naphthylmethyl) hydrazine

The title compound (7.0 g, 26 mmol) was used in the same manner as in Example 1 using N-1- (t-butoxycarbonyl) -N-2- (2-naphthylmethyl) hydrazine (7.0 g, 26 mmol) instead of methylhydrazine. 11.5 g, 23 mmol) was obtained.

¹ H NMR (CDCl ₃ ; δ): 1.40 (s, 9H), 4.30 (d, 2H), 4.75 (br, 1H), 7.38-7.92 (m, 6H), 8.20-8.30 (m, 2H)

IR (KBr; cm ^-1 ): 3361, 2922, 1696, 1541

Step 4) Preparation of N-1- (9-fluorenylmethoxycarbonyl) -N-1- (2-naphthylmethyl) hydrazine

N-1 instead of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in step 4) of Example 2 The title compound using-(t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (2-naphthylmethyl) hydrazine (11.5 g, 23 mmol) (7.4 g, 18.8 mmol) was obtained.

¹ H NMR (CDCl ₃ ; δ): 3.9 (br, 2H), 4.2-4.4 (m, 3H), 4.6 (d, 2H), 5.9 (s, 2H), 6.5-6.8 (m, 3H), 7.25 -7.9 (m, 8H)

Example 8 Preparation of N-1- (9-Fluorenylmethoxycarbonyl) -N-2- (1,4-benzodioxane-6-ylmethyl) hydrazine

Step 1) Preparation of N-1- (t-butoxycarbonyl) -N-2- (1,4-benzodioxane-6-ylmethylidene) hydrazone

1,4-benzodioxane-6-carboxyaldehyde (13.1 g, 80 mmol) was used instead of benzaldehyde in the same manner as in step 1) of Example 2, to obtain the title compound (19.5 g, 70 mmol).

¹ H NMR (CDCl ₃ ; δ): 1.42 (s, 9H), 4.25 (s, 4H), 6.85 (d, 1H), 7.05 (d, 2H), 7.95 (s, 1H), 10.78 (br, 1H )

Step 2) Preparation of N-1- (t-butoxycarbonyl) -N-2- (1,4-benzodioxane-6-ylmethyl) hydrazine

N-1- (t-butoxycarbonyl)-in place of N-1- (t-butoxycarbonyl) -N-2-benzylidenehydrazone in the same manner as in step 2) of Example 2) The title compound (16.8 g, 60 mmol) was obtained using N-2- (1,4-benzodioxane-6-ylmethylidene) hydrazone (19.5 g, 70 mmol).

¹ H NMR (DMSO-d ₆ ; δ): 1.5 (s, 9H), 4.25 (s, 2H), 6.8 (d, 2H), 7.2 (m, 2H), 7.7 (s, 1H), 7.85 (br , 1H)

Step 3) of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (1,4-benzodioxane-6-ylmethyl) hydrazine Produce

In the same manner as in Example 1, N-1- (t-butoxycarbonyl) -N-2- (1,4-benzodioxane-6-ylmethyl) hydrazine (8.4 g, 30 mmol) was used instead of methylhydrazine. To give the title compound (13.6 g, 27 mmol).

¹ H NMR (CDCl ₃ ; δ): 1.50 (s, 9H), 4.20 (s, 6H), 4.40-4.65 (m, 3H), 6.60 (br, 1H), 6.80 (d, 2H), 7.10-7.8 (m, 9H), 8.3 (s, 1H)

Step 4) Preparation of N-1- (9-fluorenylmethoxycarbonyl) -N-2- (1,4-benzodioxane-6-ylmethyl) hydrazine

N-1 instead of N-1- (t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in step 4) of Example 2 -(t-butoxycarbonyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (1,4-benzodioxan-6-ylmethyl) hydrazine (13.6 g, 27 mmol) To obtain the title compound (8.2 g, 20.3 mmol).

¹ H NMR (CDCl ₃ ; δ): 3.8 (br, 2H), 4.2 (m, 5H), 4.4 (s, 2H), 4.55 (d, 2H), 6.6 (br, 1H), 7.3-7.8 (m , 9H)

Example 9 Preparation of N-1- (N-t-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-methylhydrazine

N-1- (9-fluorenylmethoxycarbonyl) -N-1-methylhydrazine (1.0 g, 3.7 mmol) and triethylamine (2.9 ml, 5.6 mmol) of Example 1 were diluted with dichloromethane (5 ml). ) And Nt-butoxycarbonyl-L-glycine (0.78 g, 4.5 mmol) and 1-hydroxybenzotriazole (HOBT; 0.61 g, 4.5 mmol) in a reaction solution dissolved in dimethylformamide (5 ml). And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDAC-HCl; 0.96 g, 5 mmol) were added sequentially at room temperature. The solution was stirred at room temperature for 3 hours. The reaction solution was washed with water and saturated brine, dehydrated with sodium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.0 g, 2.4 mmol).

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 3.2 (m, 3H), 3.6 (br, 1H), 4.3 (m, 1H), 4.5 (m, 2H), 7.2-7.8 (m , 8H)

IR (KBr; cm ^-1 ): 3330, 2924, 1695

Melting Point (℃): 37

Example 10 Preparation of N-1- (N-t-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine

N-1- (9-fluorenylmethoxycarbonyl) -N of Example 2 instead of N-1- (9-fluorenylmethoxycarbonyl) -N-1-methylhydrazine in the same manner as in Example 9 -1-Benzylhydrazine (1.05 g, 3 mmol) was used to obtain the title compound (0.8 g).

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 3.5-3.8 (m, 2H), 4.2 (m, 1H), 4.4-4.7 (m, 4H), 4.9 (s, 1H), 5.1 (s, 1H), 7.2-8.0 (m, 13H)

IR (KBr; cm ^-1 ): 3275, 2968, 1674

Melting Point (℃): 72-75

Example 11 of N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (1-naphthylmethyl) hydrazine Produce

N-1- (9-fluorenylmethoxycarbonyl) -N of Example 3 instead of N-1- (9-fluorenylmethoxycarbonyl) -N-1-methylhydrazine in the same manner as in Example 9 -1- (1-naphthylmethyl) hydrazine (1.45 g, 3.7 mmol) was used to give the title compound (1.36 g).

¹ H NMR (CDCl ₃ ; δ): 1.3 (s, 9H), 3.4 (m, 2H), 4.2 (m, 1H), 4.6 (m, 4H), 5.1 (s, 1H), 7.2-7.8 (m , 15H)

Example 12 Preparation of N-1- (N-t-butoxycarbonyl-L-phenylalaninyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-methylhydrazine

In the same manner as in Example 9, N-t-butoxycarbonyl-L-phenylalanine (1.19 g, 4.5 mmol) was used instead of N-t-butoxycarbonyl-L-glycine to obtain the title compound (1.04 g).

¹ H NMR (CDCl ₃ ; δ): 1.39 (s, 9H), 3.05 (s, 5H), 4.2 (m, 1H), 4.4 (m, 2H), 5.0 (s, 2H), 7.2-7.8 (m , 15H)

IR (KBr; cm ^-1 ): 3275, 2968, 1674

Example 13. Preparation of N-1- (N-t-butoxycarbonyl-L-phenylalaninyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine

N-t-butoxycarbonyl-L-phenylalanine (1.19 g, 4.5 mmol) was used instead of N-t-butoxycarbonyl-L-glycine in the same manner as in Example 10 to obtain the title compound (1.0 g).

¹ H NMR (CDCl ₃ ; δ): 1.3 (s, 9H), 3.0 (s, 2H), 4.2-5.0 (m, 6H), 7.2-7.8 (m, 18H)

Example 14 of N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (1-naphthylmethyl) hydrazine Produce

In the same manner as in Example 11, N-t-butoxycarbonyl-L-phenylalanine (1.47 g, 5.55 mmol) was used instead of N-t-butoxycarbonyl-L-glycine to obtain the title compound (1.3 g).

¹ H NMR (CDCl ₃ ; δ): 1.3 (s, 9H), 3.0 (s, 2H), 4.2-5.0 (m, 6H), 7.2-7.8 (m, 20H)

Example 15 Preparation of N-1- (N-t-butoxycarbonyl-L-valinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-piperonylhydrazine

Nt-butoxycarbonyl-L- in the same manner as in Example 9 in place of Nt-butoxycarbonyl-L-glycine and N-1- (9-fluorenylmethoxycarbonyl) -N-1-methylhydrazine Valine (0.65 g, 3 mmol) and N-1- (9-fluorenylmethoxycarbonyl) -N-1-piperonylhydrazine of Example 4 were used to obtain the title compound (0.4 g). .

¹ H NMR (CDCl ₃ ; δ): 0.9 (m, 6H), 1.4 (s, 9H), 3.9 (m, 1H), 4.2-4.6 (m, 5H), 5.1 (m, 1H), 5.95 (s , 2H), 6.6-6.9 (m, 3H), 7.2-7.8 (m, 8H)

Example 16 Preparation of N-1- (N-t-butoxycarbonyl-L-glycinyl) -N-2-benzylhydrazine

N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine (0.37 g, 0.7 mmol) of Example 10 Was dissolved in dichloromethane (5 ml) and piperidine (0.11 ml, 1.1 mmol) was added slowly at room temperature. After stirring for 2 hours, the reaction solution was washed with water and saturated brine, dehydrated and concentrated, and purified by column chromatography to obtain the title compound (0.03 g).

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 3.2-3.8 (m, 2H), 4.3 (d, 2H), 5.3 (br, 1H), 7.2-7.8 (m, 5H)

Example 17 Preparation of N-1- (N-t-butoxycarbonyl-L-valinyl) -N-2-piperonylhydrazine

Example instead of N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in Example 16 15 N-1- (Nt-butoxycarbonyl-L-valinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-piperonylhydrazine (0.4 g, 0.7 mmol) Was used to obtain the title compound (0.1 g).

¹ H NMR (CDCl ₃ ; δ): 0.9 (m, 6H), 1.39 (s, 9H), 2.0 (m, 1H), 3.8 (m, 3H), 5.4 (s, 2H), 6.7-6.8 (m , 3H), 7.7 (br, 1H)

Example 18 Preparation of N-1- (N-t-butoxycarbonyl-L-phenylalaninyl) -N-2-benzylhydrazine

Example instead of N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in Example 16 N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine (0.5 g, 0.8 mmol) of 13 was used. To give the title compound (0.2 g).

¹ H NMR (CDCl ₃ ; δ): 1.35 (s, 9H), 3.0 (m, 2H), 3.8 (m, 1H), 4.2-4.7 (m, 2H), 5.1 (d, 1H), 5.4 (m , 1H), 7.0-7.7 (m, 10H)

Example 19 Preparation of N-1- (N-t-butoxycarbonyl-L-glycinyl) -N-2- (1-naphthylmethyl) hydrazine

Example instead of N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in Example 16 11 N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (1-naphthylmethyl) hydrazine (0.65 g , 1.2 mmol) was used to give the title compound (0.27 g).

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 3.7 (d, 2H), 4.4 (s, 2H), 5.05 (br, 1H), 5.8 (br, 1H), 7.2-8.2 (m , 7H), 8.6 (br, 1H)

Example 20 Preparation of N-1- (N-t-butoxycarbonyl-L-phenylalaninyl) -N-2- (1-naphthylmethyl) hydrazine

Example instead of N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in Example 16 14. N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2- (1-naphthylmethyl) hydrazine (0.6 g, 0.9 mmol) to give the title compound (0.1 g).

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 3.0 (m, 2H), 4.0 (m, 1H), 4.45 (d, 2H), 4.8-5.1 (m, 2H), 7.2-8.0 (m, 7H), 8.2 (m, 1H)

Example 21 Preparation of N-1- (N-t-butoxycarbonyl-L-phenylalaninyl) -N-2-methylhydrazine

Example instead of N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in Example 16 Using N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-methylhydrazine (0.5 g, 0.97 mmol) of 12 To give the title compound (0.1 g).

¹ H NMR (CDCl ₃ ; δ): 1.3 (s, 9H), 2.8 (m, 2H), 3.0 (s, 3H), 3.6 (br, 1H), 5.4 (br, 1H), 7.0-7.2 (m , 5H)

Example 22. Preparation of N-1- (N-t-butoxycarbonyl-L-glycinyl) -N-2-methylhydrazine

Example instead of N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-benzylhydrazine in the same manner as in Example 16 N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (9-fluorenylmethoxycarbonyl) -N-2-methylhydrazine (0.5 g, 1.2 mmol) of 9 was used To give the title compound (0.1 g).

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 3.1 (s, 3H), 3.8 (m, 2H), 5.4 (br, 1H)

Example 23 Preparation of N-1- (L-phenylalaninyl) -N-2- (2-methoxyethylaminoacetyl) -N-2- (1-naphthylmethyl) hydrazine

Step 1) Preparation of N-1- (N-t-butoxycarbonyl-L-phenylalaninyl) -N-2- (bromoacetyl) -N-2- (1-naphthylmethyl) hydrazine

N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (1-naphthylmethyl) hydrazine (0.6 g, 1.43 mmol) and triethylamine (0.22 ml, 1.6 from Example 20) mmol) was dissolved in dichloromethane (10 ml) and the reaction solution was cooled to 0 ° C. Bromoacetyl bromide (0.14 ml, 1.6 mmol) was slowly added to the solution and stirred for 30 minutes at the same temperature. The reaction solution was washed with water and saturated brine, dehydrated and distilled under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.5 g).

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 2.8-3.0 (m, 2H), 3.5-4.0 (m, 2H), 4.2 (t, 1H), 4.5 (br, 1H), 5.0 (m, 2H), 7.0-8.2 (m, 12H), 8.1 (br, 1H)

Step 2) Preparation of N-1- (L-phenylalaninyl) -N-2- (2-methoxyethylaminoacetyl) -N-2- (1-naphthylmethyl) hydrazine

N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (bromoacetyl) -N-2- (1-naphthylmethyl) hydrazine (0.31 g) and tree of step 1) To the reaction solution in which ethylamine (0.46 mmol) was dissolved in dichloromethane (5 ml), 2-methoxyethylamine (0.45 mmol) dissolved in dimethyl sulfoxide (2 ml) was slowly added at room temperature, and the mixture was kept at the same temperature for 6 hours. Stirred. The reaction solution was washed with water and saturated brine, dried and distilled under reduced pressure. The residue was purified by silica gel column chromatography to obtain amine-containing N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (2-methoxyethylaminoacetyl) -N-2 After obtaining-(1-naphthylmethyl) hydrazine, it was dissolved in dichloromethane (4 ml) again, trifluoroacetic acid (1 ml) was added at room temperature, and it stirred for 2 hours. The reaction solution was removed by distillation under reduced pressure, and the solvent and trifluoroacetic acid were dissolved in dichloromethane, washed with saturated sodium bicarbonate and water, and the title compound (0.3 g) was obtained by dehydration and vacuum drying.

¹ H NMR (CDCl ₃ ; d): 3.0 (m, 2H), 3.2-3.5 (m, 7H), 4.4 (m, 1H), 4.6 (m, 2H), 5.0 (d, 2H), 5.8 (d , 1H), 7.2-8.2 (m, 12H)

Example 24 Preparation of N-1- (L-phenylalaninyl) -N-2- (2-cyclopropylaminoacetyl) -N-2-benzylhydrazine

Step 1) Preparation of N-1- (N-t-butoxycarbonyl-L-phenylalaninyl) -N-2- (bromoacetyl) -N-2-benzylhydrazine

N-1 of Example 18 instead of N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (1-naphthylmethyl) hydrazine in the same manner as in step 1) of Example 23 The title compound (30 mg) was obtained using-(Nt-butoxycarbonyl-L-phenylalaninyl) -N-2-benzylhydrazine (30 mg, 0.11 mmol).

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 3.0 (m, 2H), 3.6-3.9 (m, 2H), 4.1 (m, 1H), 4.3-4.6 (m, 2H), 5.0 (m, 1 H), 7.0-7.5 (m, 10 H)

Step 2) Preparation of N-1- (L-phenylalaninyl) -N-2- (2-cyclopropylaminoacetyl) -N-2-benzylhydrazine

N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (bromoacetyl) -N-2- (1-naphthylmethyl) in the same manner as in step 2) of Example 23 N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (bromoacetyl) -N-2-benzylhydrazine (0.3) in place of hydrazine and 2-methoxyethylamine g) and cyclopropylamine were used to obtain the title compound (0.2 g).

¹ H NMR (CDCl ₃ ; d): 0.2-0.7 (m, 4H), 2.6 (m, 1H), 3.0 (m, 2H), 3.4-3.8 (m, 4H), 4.5 (m, 2H), 7.0 -7.5 (m, 10H)

Example 25 Preparation of N-1- (L-phenylalaninyl) -N-2- (2-thiophenmethylaminoacetyl) -N-2- (1-benzylmethyl) hydrazine

N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (bromoacetyl) -N-2-benzylhydrazine (0.3 g) prepared in step 1) of Example 24 The title compound (0.2 g) was obtained in the same manner as in step 2) of Example 23 using offenmethylamine.

¹ H NMR (CDCl ₃ ; δ) 3.0-3.6 (m, 5H), 3.9 (m, 2H), 4.5 (m, 3H), 7.2-8.2 (m, 12H)

Example 26 Preparation of N-1- (L-Glycinyl) -N-2- (2-furfurylaminoacetyl) -N-2- (1-naphthylmethyl) hydrazine

Step 1) Preparation of N-1- (N-t-butoxycarbonyl-L-glycinyl) -N-2- (bromoacetyl) -N-2- (1-naphthylmethyl) hydrazine

N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (1-naphthylmethyl) hydrazine (0.27 g, 0.27 in Example 19) in the same manner as in step 1) of Example 23 mmol) was used to obtain the title compound (0.31 g).

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 3.6 (d, 2H), 3.8-4.0 (m, 4H), 5.0 (br, 1H), 7.3-8.0 (m, 7H)

Step 2) Preparation of N-1- (L-glycinyl) -N-2- (2-furfurylaminoacetyl) -N-2- (1-naphthylmethyl) hydrazine

N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (bromoacetyl) -N-2- (1-naphthylmethyl) in the same manner as in step 2) of Example 23 Hydrazine and furfurylamine were used to obtain the title compound (0.3 g).

¹ H NMR (CDCl ₃ ; δ) 3.1-3.6 (m, 4H), 3.7 (m, 2H), 4.3 (m, 2H), 6.2 (m, 2H), 7.1-8.0 (m, 9H)

Example 27 Preparation of N-1- (L-Glycinyl) -N-2- (2-isobutylaminoacetyl) -N-2-benzylhydrazine

Step 1) Preparation of N-1- (N-t-butoxycarbonyl-L-glycinyl) -N-2- (bromoacetyl) -N-2-benzylhydrazine

In the same manner as in step 1) of Example 23, using N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2-benzylhydrazine (0.3 g, 0.81 mmol) of Example 16. The title compound (0.3 g) was obtained.

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 3.4-3.6 (m, 2H), 3.9 (m, 2H), 4.2-4.8 (m, 2H), 7.2-7.8 (m, 5H) , 7.9 (d, 1H)

Step 2) Preparation of N-1- (L-glycinyl) -N-2- (2-isobutylaminoacetyl) -N-2-benzylhydrazine

N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (bromoacetyl) -N-2-benzylhydrazine and isobutylamine in the same manner as in step 2) of Example 23 To give the title compound (0.1 g).

¹ H NMR (CDCl ₃ ; δ) 0.8-1.6 (m, 7H), 3.0 (m, 2H), 3.7-4.0 (m, 4H), 4.6 (m, 2H), 7.1-7.4 (m, 5H)

Example 28 Preparation of N-1- (L-Glycinyl) -N-2- (a-methylbenzylamineaminoacetyl) -N-2- (1-naphthylmethyl) hydrazine

N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (bromoacetyl) -N-2- (1-naphthylmethyl) hydrazine and a-methyl prepared in Example 26 Using the benzylamine to give the title compound (0.2 g) in the same manner as in step 2) of Example 23.

¹ H NMR (CDCl ₃ ; δ) 1.4 (m, 3H), 3.0-3.8 (m, 5H), 4.5 (m, 2H), 5.0 (m, 1H), 7.2-8.0 (m, 12H)

Example 29 Preparation of N-1- (L-phenylalaninyl) -N-2- (1,2,3,4-tetrahydroisoquinolin-1-ylacetyl) -N-2-methylhydrazine

Step 1) Preparation of N-1- (N-t-butoxycarbonyl-L-phenylalaninyl) -N-2- (bromoacetyl) -N-2-methylhydrazine

In the same manner as in Step 1) of Example 23, using N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2-methylhydrazine (0.1 g, 0.34 mmol) prepared in Example 21 To give the title compound (0.2 g).

¹ H NMR (CDCl ₃ ; δ): 1.4 (s, 9H), 2.8-3.2 (m, 5H), 3.8 (m, 3H), 4.8 (m, 1H), 5.5 (d, 1H), 7.1-7.4 (m, 5H)

Step 2) Preparation of N-1- (L-phenylalaninyl) -N-2- (1,2,3,4-tetrahydroisoquinolin-1-ylacetyl) -N-2-methylhydrazine

N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (bromoacetyl) -N-2-methylhydrazine and 1,2, in the same manner as in step 2) of Example 23; 3,4-tetrahydroisoquinoline was used to obtain the title compound (0.1 g).

¹ H NMR (CDCl ₃ ; δ) 2.6-3.3 (m, 7H), 3.7 (m, 2H), 4.4-4.6 (m, 5H), 5.2 (m, 2H), 7.0-7.4 (m, 9H)

Example 30 Preparation of N-1- (L-valinyl) -N-2- (1- (2-ethoxyphenyl) piperazin-4-ylacetyl) -N-2-piperonylhydrazine

Step 1) Preparation of N-1- (N-t-butoxycarbonyl-L-valinyl) -N-2- (bromoacetyl) -N-2-piperonylhydrazine

N-1- (Nt-butoxycarbonyl-L-valinyl) -N-2-piperonylhydrazine (0.1 g, 0.27 mmol) prepared in Example 17 in the same manner as in Step 1) of Example 23 Was used to obtain the title compound (30 mg).

¹ H NMR (CDCl ₃ ; δ): 0.95 (m, 5H), 1.45 (s, 9H), 2.10 (m, 1H), 3.70-3.90 (m, 5H), 4.85 (d, 1H), 5.95 (s , 2H), 6.75 (m, 3H), 8.00 (s, 1H)

Step 2) Preparation of N-1- (L-valinyl) -N-2- (1- (2-ethoxyphenyl) piperazin-4-ylacetyl) -N-2-piperonylhydrazine

N-1- (Nt-butoxycarbonyl-L-valinyl) -N-2- (bromoacetyl) -N-2-piperonylhydrazine and 1- in the same manner as in step 2) of Example 23 (2-ethoxyphenyl) piperazine was used to give the title compound (0.1 g).

¹ H NMR (CDCl ₃ ; δ) 0.8-1.9 (m, 9H), 1.45 (s, 9H), 2.1 (m, 1H), 2.8 (m, 4H), 3.0-3.4 (m, 6H), 3.8 ( m, 1H), 4.1 (q, 3H), 4.5-5.0 (m, 2H), 6.0 (s, 2H), 5.7-7.0 (m, 7H)

Example 31 Preparation of N-1- (L-Glycinyl) -N-2- (1- (benzylaminoacetyl) -N-2-methylhydrazine

N-1- (Nt-butoxycarbonyl-L-glycinyl) -N-2- (bromoacetyl) -N-2-methylhydrazine and benzylamine were used in the same manner as in Step 2) of Example 23. To give the title compound (0.3 g).

¹ H NMR (CDCl ₃ ; δ) 3.0 (m, 2H), 3.2-3.8 (m, 4H), 4.6 (m, 2H), 5.3 (m, 2H), 7.1-7.5 (m, 5H)

Example 32. Preparation of N-1- (L-phenylalaninyl) -N-2- (allylaminoacetyl) -N-2- (1-naphthylmethyl) hydrazine

N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (bromoacetyl) -N-2- (1-naphthylmethyl) in the same manner as in step 2) of Example 23 Hydrazine and allylamine were used to obtain the title compound (0.2 g).

¹ H NMR (CDCl ₃ ; δ) 3.0 (m, 2H), 2.9-3.2 (m, 4H), 4.1 (m, 1H), 4.8-5.0 (m, 4H), 5.6 (m, 3H), 6.9- 7.9 (m, 12H)

Example 33. of N-1- (L-phenylalaninyl) -N-2- (4-acetyl-4-phenylpiperidin-1-ylacetyl) -N-2- (1-naphthylmethyl) hydrazine Produce

N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (bromoacetyl) -N-2- (1-naphthylmethyl) in the same manner as in step 2) of Example 23 The title compound (0.2 g) was obtained using hydrazine and 4-acetyl-4-phenylpiperidine.

¹ H NMR (CDCl ₃ ; δ) 1.85 (s, 3H), 2.0 (m, 2H), 2.3 (m, 2H), 2.7 (m, 2H), 3.1 (m, 2H), 3.6 (d, 2H) , 5.2 (m, 2H), 5.6 (m, 1H), 7.2-8.1 (m, 12H)

Example 34 Preparation of N-1- (L-phenylalaninyl) -N-2- (benzylaminoacetyl) -N-2-methylhydrazine

In the same manner as in Step 2) of Example 23, N-1- (Nt-butoxycarbonyl-L-phenylalaninyl) -N-2- (bromoacetyl) -N-2-methylhydrazine and benzylamine were used. To give the title compound (0.3 g).

¹ H NMR (CDCl ₃ ; δ) 2.8-3.0 (m, 5H), 3.4 (s, 2H), 3.7 (s, 2H), 3.9 (s, 6H), 4.8 (m, 1H), 5.3 (d, 1H), 6.9-7.3 (m, 8H)

In addition, a method for producing the hydrazine compound of the present invention in the solid phase will be described.

Example 35. Preparation of Amino Acids Attached to a Solid Phase Support

Step 1) 4-Benzyloxybenzyl alcohol Polyethylene resin (wang resin; 2 g, 0.9 mmol / g) is suspended by adding 30 ml of dichloromethane. After shaking vigorously for about 1 minute using a stirrer, pressure was applied with nitrogen to push the solvent out, and the resin was filtered. 30 ml of dichloromethane was further added and suspended, followed by addition of N-methylmorpholine (0.2 mL, 1.8 mmol) and 4-nitrophenylchloroformate (1.8 mmol). The mixture was shaken at room temperature for 18 hours and then the resin was filtered off. The filtered resin was washed sequentially with dimethylformamide, methanol and dichloromethane and then dried in vacuo to yield a bright yellow 4-nitrophenyl carbonate carbonate resin compound (2.1 g).

IR (KBr) 1656 cm ^-1 .

Resin substitution capacity by elemental nitrogen analysis = 0.72 mmol / g.

Step 2) Put 6 equivalents of each amino acid (4.3 mmol), N, O-bis (trimethylsilyl) acetamide (BSA; 2.6 ml), and dimethylformamide (7.4 ml) into a stoppered tube. After a little heat is dissolved. The above solution was added to a mixture of resin (1 g, 0.72 mmol / g) and dimethylaminopyridine (DMAP, 257 mg) prepared in step 1) in a 50 ml polypropylene container, and then using a stirrer. Shaking vigorously at room temperature for 48 hours. The reaction mixture was filtered, the filtered resin was added to a mixed solution of methanol and dimethylformamide (1: 1), shaken for 30 minutes, the resin was filtered again, washed with dimethylformamide and dichloromethane, and dried A yellow resin was obtained. Examples of the amino acid used here are the same as described in <Step 1>.

Example 36. Preparation of a compound in which N-1- (substituted) hydrazine was introduced into an amino acid attached to a solid phase support.

Step 1) Each of the amino acids (0.5 g) attached to the solid-phase support of Example 35 was suspended by addition of dimethylformamide (5 ml), followed by eight types of N-1 prepared in Examples 1-8. -(9-fluorenylmethoxycarbonyl) -N-1- (substituted) hydrazine (4 equiv), 1-hydroxybenzotriazole (HOBT, 4 equiv) and diisopropylcarbodiimide (DIC, 4 equiv ) Was added. The mixture was vigorously shaken at room temperature for 18 hours. Each resin was filtered, washed with dimethylformamide, methanol, and dichloromethane and dried to give N-1- (9-fluorenylmethoxycarbonyl) -N-1 to the amino acid attached to the solid support. 40 kinds (5-type X 8 types) of the resin compound (IV) to which-(substituted) hydrazine were bound were obtained, respectively. Examples of N-1- (9-fluorenylmethoxycarbonyl) -N-1- (substituted) hydrazine used herein are the same as those described in <Step 2>.

1-hydroxybenzotriazole (HOBT) and diisopropylcarbodiimide (DIC) and reaction used here for N-1- (9-fluorenylmethoxycarbonyl) -N-1- (substituted) hydrazine Yield according to HPLC analysis of 40 kinds of resin compounds according to conditions is as follows.

Binding reagent equivalent weight Yield (purity%) Reaction time HOBT / DIC 4 > 90 24 HOBT / DIC 4 90-95 48 HOBT / PyBOP / DIPEA 4 > 90 24 HOBT / PyBOP / DIPEA 4 > 90 48 HOBT / PyBOP / DMAP 2 <10 24 HOBT / PyBOP / DMAP 2 <10 48

Step 2) 40 kinds of each resin compound attached to the solid-phase support prepared in step 1) are dissolved in dimethylformamide (5 ml), and a 25% piperidine (1 ml) solution is added and shaken vigorously for 1 hour. . The resin was filtered off, washed with dimethylformamide and dichloromethane, and then dried to dry the N-1- (substituted) hydrazine to the amino acid attached to the N- (9-fluorenylmethoxycarbonyl deprotected solid phase support. Each of the 40 compounds of the title compound (V) desired in combination was obtained, thus, an example of a resin compound prepared by a combination and sharing method is as follows.

IIIa IIIb IIIc IIId IIIe IIIf IIIg IIIh IIa Va-a Va-b Va-c Va-d Va-e Va-f Va-g Va-h IIb Vb-a Vb-b Vb-c Vb-d Vb-e Vb-f Vb-g Vb-h IIc Vc-a Vc-b Vc-c Vc-d Vc-e Vc-f Vc-g Vc-h IId Vd-a Vd-b Vd-c Vd-d Vd-e Vd-f Vd-g Vd-h IIe Ve-a Ve-b Ve-c Ve-d Ve-e Ve-f Ve-g Ve-h

Example 37 Preparation of Compound Incorporating Bromoacetyl Group into N-1- (Substituted) hydrazine Attached to Solid Phase Support

To the resin prepared in Example 36 was added a 0.6 M dimethylformamide solution of bromoacetic acid and 0.6 M diisopropylcarbodiimide (DIC) solution dimethylformamide. The mixture was vigorously stirred at room temperature for 18 hours using a shaker, after which the resin was filtered and washed with dimethylformamide and dichloromethane. The same amount of 0.6M bromoacetic acid solution and 0.6M diisopropylcarbodiimide (DIC) solution were added again, and it stirred for 3 hours at room temperature repeatedly. The resin was filtered, washed with dimethylformamide, methanol, and dichloromethane and dried to give 40 title compounds, respectively.

HPLC analysis: 20 mg of the title resin compound was taken, treated in 95% trifluoroacetic acid solution for about 30 minutes, concentrated, and confirmed by HPLC and NMR analysis.

Example 38 Preparation of N-1- (Amino Acid Substitution) -N-2- (Substitution) -N-2- (Aminomethylcarbonyl Substitution) hydrazine

Step 1) Each resin prepared in Example 37 was aliquoted into a container of about 20 mg for each kind, and 0.5-0.7 ml of amine having a concentration of 0.5-2.0 M was added in order. After plugging and shaking for 4 hours at room temperature, the resin was filtered, washed with dimethylformamide, methanol, and dichloromethane, and dried to obtain the title compound attached to the solid support. Here, examples of R1, R2, Y and the amine used are the same as those described in <Step 4>.

Step 2) 20 mg of the title resin compound was taken, treated in 95% triplefuroacetic acid solution for about 30 minutes, concentrated, and confirmed by HPLC and NMR analysis. Examples of each compound obtained show the following yields (%).

Unit: yield (%)

R2 Y One 2 3 4 5 6 8 9 17 19 20 IIIa 70 50 52 88 53 73 90 75 61 66 75 IIIb 58 53 53 65 58 59 24 41 47 52 63 IIIc 57 51 49 59 62 53 64 43 9 47 52 IIId 57 58 53 61 59 62 55 44 54 48 64 IIIe 48 45 45 46 49 46 63 39 44 50 43 IIIf 46 54 43 55 64 34 47 43 46 53 60 IIIg 63 60 60 65 64 59 54 47 56 53 60 IIIh 57 41 57 59 58 59 49 42 53 50 60

Unit: yield (%)

R2 Y One 2 3 4 5 6 8 9 13 17 19 20 IIIb 78 67 68 68 67 71 60 53 50 75 64 75 IIIc 70 64 62 70 64 68 62 54 71 64 58 70 IIId 75 67 70 66 69 63 40 76 72 72 71 69 IIIe 58 63 63 63 60 62 35 51 61 68 64 76 IIIf 70 64 57 64 59 68 53 50 74 67 54 62 IIIg 69 69 69 68 51 67 65 56 78 67 59 71 IIIh 76 67 60 72 62 66 59 53 57 68 60 74

Unit: yield (%)

R2 Y One 2 3 4 5 6 8 9 13 17 19 20 21 23 24 25 28 IIIb 82 77 81 64 71 67 70 59 93 69 75 81 79 74 76 90 35 IIIc 75 93 82 84 77 78 65 62 84 86 74 85 76 73 78 86 74 IIId 82 80 82 84 77 78 76 60 81 75 77 86 81 77 82 91 83 IIIe 30 78 68 76 71 66 36 65 81 72 69 81 73 77 90 92 81 IIIf 70 64 57 64 59 68 53 50 74 67 54 62 74 62 70 69 74 IIIg 78 88 88 84 73 78 75 60 86 73 75 69 77 72 71 74 60 IIIh 84 81 77 80 78 87 76 63 73 90 75 84 76 63 67 85 78

Unit: yield (%)

R2 Y One 2 3 4 5 6 8 9 13 17 19 20 21 23 25 27 30 IIIb 69 62 71 62 62 65 58 49 52 65 53 48 61 53 37 64 60 IIIc 69 63 62 62 63 62 59 48 56 37 55 51 67 54 65 60 48 IIId 62 45 66 62 67 76 57 50 70 48 62 92 64 88 53 30 69 IIIe 53 58 54 58 66 57 88 65 59 61 51 61 53 69 92 64 45 IIIf 39 43 42 56 39 55 43 40 37 51 53 57 53 44 69 56 48 IIIg 53 53 57 62 60 56 67 41 89 58 60 72 53 59 81 62 57 IIIh 56 56 66 46 66 59 49 57 69 63 54 66 31 62 73 57 62

Unit: yield (%)

R2 Y One 2 3 4 5 6 8 9 13 17 19 20 21 23 25 29 31 IIIb 76 81 41 68 83 77 64 55 62 80 80 93 76 46 80 52 69 IIIc 77 76 39 71 72 73 65 60 87 91 79 88 74 54 84 60 83 IIId 67 80 44 78 83 87 75 61 74 91 97 72 87 82 92 74 82 IIIe 76 91 46 68 71 76 68 58 56 71 89 73 76 55 81 56 90 IIIf 74 79 47 76 72 77 75 63 79 80 79 88 76 76 78 71 94 IIIg 73 82 38 82 79 77 80 61 72 86 91 93 88 80 93 68 80 IIIh 81 84 47 75 85 66 75 65 80 86 86 95 85 88 80 73 88

Example 39 Preparation of N-1- (Amino Acid Substitution) -N-2- (Substitution) -N-2- (Substituted Acyl) hydrazine

Step 1) Each resin prepared in Example 36 is aliquoted into a container of about 20 mg of each kind and suspended in 0.7 ml of dichloromethane, respectively. To this was added 3 equivalents of acyl chloride dichloromethane solution and triethylamine each at a concentration of 0.1-0.2M. After closing the stopper and shaking for 4 hours at room temperature, the resin was filtered, washed with dimethylformamide, methanol, and dichloromethane, and dried to obtain the title compound attached to the solid support. Here, examples of R1, R2, Y and the acyl chloride used are the same as those described in <Step 5>.

Step 2) Each 20 mg of the title resin compound was taken, treated for 30 minutes in a 95% trifluoroacetic acid solution and concentrated to obtain the title compounds. Examples of the respective compounds obtained by HPLC and NMR analysis showed the following yields.

Y One 2 3 4 5 6 7 8 9 10 11 12 yield(%) 83 49 88 76 47 79 59 78 53 96 87 64

Y One 2 3 4 5 6 7 8 9 10 11 12 yield(%) 73 69 70 68 40 58 59 73 78 47 60 50

Y One 2 3 4 5 6 7 8 9 10 11 12 yield(%) 81 71 77 63 50 49 71 79 80 53 41 68

Example 40 Preparation of N-1- (Amino Acid Substituted) -N-2- (Substituted) -N-2- (Substituted (thio) ureido) hydrazine

Step 1) Each resin prepared in Example 36 is aliquoted into a container of about 20 mg of each kind and suspended in 0.7 ml of dichloromethane, respectively. To this was added 3 equivalents of substituted-iso (thio) cyanate dichloromethane solution each at a concentration of 0.1-0.2M. After closing the stopper and shaking for 4 hours at room temperature, the resin was filtered, washed with dimethylformamide, methanol, and dichloromethane, and dried to obtain the title compound attached to the solid support. Here, R1, R2, Y and the substituted-iso (thio) cyanate examples used are the same as those described in <Step 6>.

Step 2) Each 20 mg of the title resin compound was taken, treated for 30 minutes in a 95% trifluoroacetic acid solution and concentrated to obtain the title compounds. Confirmed by HPLC and NMR analysis, the examples of each compound obtained showed the following yields.

Y One 2 3 4 5 yield(%) 89 80 79 59 63

Y One 2 3 4 5 yield(%) 31 56 67 48 51

Y One 2 3 4 5 yield(%) 45 24 69 48 65

The method for preparing a hydrazine library according to the present invention can be easily produced in a short time at the same time in a solid phase by using a hydrazine skeleton of the formula (III) that can introduce amino acids and various substituents bound to the solid phase resin In addition, the method of isolating the compound is simple, so it is necessary to secure a variety of drug screening agents and to identify the leading substances and optimize them. Useful and effective for preparing compounds.

Especially. By developing a manufacturing method that can be applied to not only the solid phase but also in the solution phase, all of the advantages are secured, and thus, various hydrazine libraries can be manufactured in a short time using the solid phase library manufacturing method.

Claims (7)

delete N-1- (9-fluorenylmethoxycarbonyl) -N-1- (substituted) -hydrazine of the following formula (I) characterized by binding a substituent capable of bonding an N-substituted amino acid and an amine Process for preparing hydrazine derivatives: In formula (I), R 1 is hydrogen, alkyl, or substituted or unsubstituted phenyl, naphthyl, or benzyl; R 2 is hydrogen, C _1-4 alkyl, or substituted or unsubstituted, phenyl, phenylalkyl, hetero ring, or naphthyl; X is hydrogen, oxygen, or sulfur; n is 0 or 1; Y is substituted or unsubstituted as C _1-4 alkylamino, aniline, naphthylmethylamino, vinylamino, propazylamino, C _1-4 dialkylamino, indolinyl, quinolinyl, isoquinolinyl, benzylamino, Phenylethylamino, heterocyclicmethylamino, piperazinyl, piperidine, C _1-4 alkylphenylamino, halogen, phenyl, naphthyl, pyranyl, or thiophenyl. The method for producing a hydrazine derivative according to claim 2, wherein the N-substituted amino acid is an N-substituted amino acid bonded to a solid support having a hydroxy functional group. The method for preparing a hydrazine derivative according to claim 3, wherein the solid support is bonded to a linker. The N-1- (9-fluorenylmethoxycarbonyl) -N-1- (substituted) -hydrazine is N-1- (t-butoxycarbonyl) -N-2- (substituted) N-1- (9-fluorenylmethoxycarbonyl) -N-1 prepared by reacting 9-fluorenylmethoxycarbonyl chloride with) -hydrazine and then selectively removing only t-butoxycarbonyl group A method for producing a hydrazine derivative, which is-(substituted) -hydrazine. A hydrazine derivative of formula (I) prepared by combining a substituent which may be bonded to N-substituted amino acid and amine to N-1- (9-fluorenylmethoxycarbonyl) -N-1- (substituted) -hydrazine : In formula (I), R 1 is hydrogen, alkyl, or substituted or unsubstituted phenyl, naphthyl, or benzyl; R 2 is hydrogen, C _1-4 alkyl, or substituted or unsubstituted, phenyl, phenylalkyl, hetero ring, or naphthyl; X is hydrogen, oxygen, or sulfur; n is 0 or 1; Y is substituted or unsubstituted as C _1-4 alkylamino, aniline, naphthylmethylamino, vinylamino, propazylamino, C _1-4 dialkylamino, indolinyl, quinolinyl, isoquinolinyl, benzylamino, Phenylethylamino, heterocyclicmethylamino, piperazinyl, piperidine, C _1-4 alkylphenylamino, halogen, phenyl, naphthyl, pyranyl, or thiophenyl. delete