JP2000198774A - Optically active guanidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful as an asymmetric synthesis reagent capable of selectively producing an optically active compound in high yield. SOLUTION: This new compound is a compound of formula I (R1 and R2 are each an alkyl; R3 is an (OH-contg.) aralkyl or heterocyclic ring; *, denotes an asymmetric carbon atom), e.g. 1,3-bis[(1S)-1-phenylethyl]-2-[(1S)-1- phenylethylimino]imidazolidine. The compound of formula I is obtained, for example, by reaction between a compound of formula II (Z is a halogen) e.g. 2-chloro-1,3-bis[(1S)-1-phenylethyl]imidazolinium chloride) and a primary amine of the formula H2N-R3 [e.g. (S)-α-phenethylamine] in the presence of a base such as triethylamine, wherein it is preferable that either the compound of formula II or the above primary amine is previously dissolved in a solvent such as methylene chloride and the other is gradually dripped into the resulting solution at room temperature or under cooling.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a guanidine derivative useful as an asymmetric synthesis reagent used for selectively producing an optically active compound.

[0002]

2. Description of the Related Art When an organic compound having an enantiomer (enantiomer) is used as a flavor or a food additive, it is known that each of the enantiomers has a different smell and taste. In addition, it is known that the medicinal properties and toxicity of pharmaceuticals differ greatly depending on each isomer, as shown in the examples of thalidomide. Further, in strongly inducing liquid crystals, a decrease in optical purity is considered to cause a significant decrease in function, and a compound having a pure chiral molecular structure is required.

As described above, in the industrial fields such as medicines, agricultural chemicals, flavors, food additives, and electronics, any enantiomer having high optical purity is required.

[0004] In order to produce a compound having high optical purity, it is common and easy to carry out a chemical reaction using an optically active compound as an asymmetric synthesis reagent. Therefore, there is a demand for a cheap and large-scale supply of such optically active compounds.

[0005]

As a method for producing an optically active compound, there is a method in which a racemate obtained by a usual chemical reaction is separated using an optically active resolving agent.

However, in the method using a resolving agent,
Since half of the isomers that cannot be used industrially remain, resources could not be effectively used, which was uneconomical.

[0007] Further, a method of converting only one isomer into a target substance using an enzyme or a biological technique is known. However, this method is limited in applicable compounds and has a low reaction concentration. There was a problem that mass production was difficult.

Accordingly, an object of the present invention is to provide an optically active compound useful as an asymmetric synthesis reagent capable of selectively producing an optically active compound at a high yield.

[0009]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies. As a result, if a novel compound represented by the following general formula (1) is used as an asymmetric synthesis reagent, high enantioselectivity can be obtained. The present inventors have found that the reaction proceeds in a specific manner, and that the optically active compound can be selectively produced at a high yield, and the present invention has been completed.

That is, the present invention provides the following general formula (1)

[0011]

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Wherein R ¹ and R ² are the same or different and each represents an alkyl group, R ³ represents an aralkyl group or a heterocyclic group which may have a hydroxyl group, and * represents the position of the asymmetric carbon. The optically active guanidine derivative represented by the following formula] or a salt thereof is provided.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The bicyclic guanidine derivative of the present invention is represented by the general formula (1). R in the formula
¹ and R ² represent an alkyl group, and preferred examples thereof include a linear or branched alkyl group having 1 to 24 carbon atoms. Specifically, a methyl group, an ethyl group, n-
Propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, i-hexyl, sec-hexyl, t- Hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group,
n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group, n-nonadecyl group, n-eicosyl group, n-docosyl group, Examples thereof include an n-tricosyl group and an n-tetracosyl group. this house,
Those having 1 to 6 carbon atoms are particularly preferred, and those having 1 to 4 carbon atoms are most preferred. Note that R ¹ and R ² may be the same or different.

In the general formula (1), the aralkyl group represented by R ³ includes a phenylalkyl group (preferably an alkyl group having 1 to 5 carbon atoms), an α-naphthylalkyl group (an alkyl group having 1 carbon atom). To 5 are preferable). Of these, a phenylmethyl group, a phenylethyl group, a phenylpropyl group, a naphthylmethyl group, and a naphthylethyl group are preferred. The aralkyl group may have a hydroxyl group, and particularly preferably has an hydroxyl group in the alkyl group portion. Specifically, 1
-Benzyl-2-hydroxyethyl group, 1-phenylethyl-2-hydroxyethyl group, 1-phenylpropyl-2-hydroxyethyl group, 1-naphthylmethyl-2-
A hydroxyethyl group, a 1-naphthylethyl-2-hydroxyethyl group and the like.

The heterocyclic group represented by R ³ may be either saturated or unsaturated. Examples of the heteroatom constituting the heterocyclic ring include one or more of a nitrogen atom, an oxygen atom and a sulfur atom. . Examples thereof include a pyridyl group, a pyrrolyl group, a furanyl group, an oxazolyl group, a thienyl group, a thiazolyl group, a purinyl group, a quinolinyl group and the like, with a pyridyl group being particularly preferred.

The configuration of the two asymmetric carbon atoms of the guanidine derivative represented by the general formula (1) may be either S or R, but is preferably the same.

The compound (1) of the present invention can be produced, for example, according to the following reaction formula.

[0018]

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[Wherein R ¹ , R ² , R ³ and * represent the same as above, X, Y and Z each represent a halogen atom;
B represents a base]

That is, N- (α-phenylalkyl) halogenoacetamide (4) is obtained by condensing α-phenylalkylamine (2) and halogenoacetylhalogenide (3) in the presence of a base. α-Phenylalkylamine (5) was combined with the resulting N-
(Α-phenylalkyl)-(α-phenylalkyl)
The aminoacetamide (6) is reduced using lithium aluminum hydride (7) or the like to obtain a diamine (8), which is reacted with thiophosgene (9) in the presence of a base (10) to close the ring to form a cyclic thiourea (11). And reacting it with a halogenating agent to obtain an iminium salt, to which a primary amine (13)
Is reacted in the presence of a base to obtain the guanidine derivative (1) of the present invention.

Hereinafter, the above reaction will be described step by step. (1) Step 1 An N- (α-phenylalkyl) halogenoacetamide (4) is obtained by condensing an optically active α-phenylalkylamine (2) and a halogenoacetylhalogenide (3) in the presence of a base. Can be The reaction is methylene chloride,
Α-Phenylalkylamine (2) and a base are dissolved in a suitable solvent such as toluene, and halogenoacetylhalogenide (3) is slowly added dropwise thereto at room temperature or under cooling. The base used for the reaction includes triethylamine, tributylamine, N,
Organic bases such as N-dimethylaniline and pyridine; and inorganic bases such as anhydrous potassium carbonate and anhydrous sodium hydrogen carbonate. Since the α-phenylalkylamine (2) used here has an asymmetric carbon, there are R-forms, S-forms, and mixtures thereof. Such a configuration is based on the guanidine derivative (1) as a final product. Held until That is, α-phenylalkylamine (2) having a configuration according to the configuration of the desired guanidine derivative (1) is used.

(2) Step 2 In step 2, N- (α-phenylalkyl) -halogenoacetamide (4) is condensed with α-phenylalkylamine (5) to form N- (α-phenylalkyl)-
This is a step of obtaining (α-phenylalkyl) aminoacetamide (6). This reaction is carried out in an inert solvent such as toluene, benzene, chloroform or tetrahydrofuran in the presence of a base under heating or at room temperature. Examples of the base used in the reaction include organic bases such as triethylamine, tributylamine and pyridine, and inorganic bases such as anhydrous potassium carbonate and anhydrous sodium hydrogen carbonate. The α-phenylalkylamine (5) used herein has an asymmetric carbon atom, and thus has an R-form, an S-form and a mixture. Such a configuration is limited to the guanidine derivative (1) as a final product. Will be retained. That is, α-phenylalkylamine (5) having a configuration corresponding to the configuration of the desired guanidine derivative (1) is used.

(3) Step 3 Step 3 is to reduce the amide group to obtain the diamine (8)
This is the reaction to obtain The reduction reaction is carried out in an aprotic solvent such as tetrahydrofuran, 1,4-dioxane, diethyl ether or the like using lithium aluminum hydride or the like as the reducing agent (7) for several hours to several tens of hours at room temperature or under heating. Done by

(4) Step 4 In step 4, a ring-closing reaction is carried out by reacting thiophosgene (9) with diamine (8) in the presence of base (10).
This is a reaction for obtaining a cyclic thiourea (11). Examples of the base used here include organic bases such as triethylamine, tri-n-butylamine and N-methylmorpholine, and inorganic bases such as potassium carbonate and sodium carbonate. The reaction is carried out by dissolving the diamine (8) and the base (10) in an aprotic solvent such as methylene chloride, chloroform, and benzene, and dropping thiophosgene into the solution.

(5) Step 5 By reacting the thiourea (11) with a halogenating agent, an iminium salt (12) is obtained. Examples of the halogenating agent used here include oxalyl halide, phosphorus trihalide, phosphorus pentahalide, phosphorus oxyhalide, phosgene, trichloromethylchloroformate, triphosgene and the like. The reaction is preferably carried out by dissolving thiourea (11) and a halogenating agent in a suitable solvent such as toluene, and reacting at room temperature or under heating for several hours to several tens of hours. The iminium salt (12) obtained here may be isolated, but can be used in the next step 6 without isolation.

(6) Step 6 The guanidine derivative (1) of the present invention is obtained by reacting the iminium salt (12) with the primary amine (13) in the presence of the base (10). In addition, primary amine (1
3) may be an optical isomer. Examples of the base used herein include organic bases such as triethylamine, tributylamine, dimethylaniline, and pyridine; and inorganic bases such as potassium carbonate and sodium carbonate.The primary amine used in the reaction may be used as the base. it can. Reaction is iminium salt (12) or primary amine (13)
It is preferable to dissolve either of them in an appropriate solvent such as benzene, acetonitrile, methylene chloride or the like, and slowly add the other dropwise at room temperature or under cooling.

The compound (1) of the present invention can be used as an asymmetric synthesis reagent in various asymmetric synthesis reactions. For example,
The asymmetric epoxidation reaction using the compound of the present invention as a catalyst can be carried out according to the following reaction formula.

[0028]

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[Wherein R ⁴ and R ⁵ represent organic groups] That is, enone (14) and t-butyl peroxide (15) are each equivalent to one equivalent and a catalytic amount of the compound of the present invention (1) in toluene, If the reaction is carried out at around room temperature in an inert solvent such as chloroform or methylene chloride, the epoxidation reaction proceeds enantioselectively, and the desired optically active epoxy compound (16) can be easily obtained. This epoxy compound (16) can be led to pharmaceuticals and agricultural chemicals according to a conventional method. In addition, (1) used as a catalyst in the above reaction can be reused without particularly requiring a purification operation. Here, the organic group represented by R ⁴ and R ⁵ may be any of an aliphatic group and an aromatic group.

[0030]

According to the present invention, when the compound of the present invention is used as an asymmetric synthesis reagent, an optically active compound can be produced selectively and at a high yield.

[0031]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples and Production Examples, but the present invention is not limited thereto.

Production Example 1 Production of N-[(S) -1-phenylethyl] chloroacetamide Chloroacetyl chloride 2 in 200 ml of methylene chloride
0.00g (0.18 mol) was dissolved therein, and 21.43 g (0.18 mol) of (S) -phenethylamine was added thereto under ice cooling.
l) and 17.89 g (0.18 mol) of triethylamine
Of methylene chloride was slowly added dropwise, and after the completion, stirring was continued at room temperature for 35 minutes. Subsequently, a diluted hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The crystals obtained by evaporating the solvent under reduced pressure
After washing with -hexane, 32.93 g (yield 94%) of the title compound was obtained.

Production Example 2 Production of N-[(S) -1-phenylethyl]-[(S) -1-phenylethyl] aminoacetamide N-[(S) -1-phenylethyl] chloroform in 300 ml of toluene 32.93 g of acetamide (0.17mo
l), 20.17 g of (S) -α-phenethylamine
(0.17 mol) and 16.84 g of triethylamine
(0.17 mol), and the mixture was heated under reflux for 7 hours. After cooling down,
The desired product was extracted with a dilute aqueous hydrochloric acid solution, and after removing the toluene layer, the aqueous layer was extracted with chloroform. The extract was washed with an aqueous solution of potassium carbonate and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to give the title compound.
31 g (yield 77%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, d, J = 7.7 Hz),
1.43 (3H, d, J = 7.0Hz), 1.67 (1H, bs), 3.18 (2H, s), 3.71 (1
(H, q, J = 7.0Hz), 5.11 (1H, m), 7.23-7.43 (8H, m)

Production Example 3 N, N'-bis [(S) -1-
Preparation of phenylethyl] ethylenediamine 7.14 g (188 mmol) of lithium aluminum hydride and N-[(S) -1 in 300 ml of tetrahydrofuran
-Phenylethyl]-[(S) -1-phenylethyl]
17.66 g (63 mmol) of aminoacetamide was added and 6
Heated at 0 ° C. for 25 hours. After cooling, the reaction solution was dropped into a saturated aqueous solution of sodium sulfate, and after completion, insoluble crystals were removed by filtration.
Next, the filtrate was extracted with methylene chloride, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel chromatography (solvent: chloroform / methanol) to obtain 10.79 g (yield: 64%) of the title compound. Obtained.

Production Example 4 Production of 1,3-bis [(S) -1-phenylethyl] -2-thiooxoimidazolidin N, N'-bis [(S) -1 in 110 ml of methylene chloride
-Phenylethyl] ethylenediamine 10.79 g (4
0.26 mmol) and 8.13 g of triethylamine (8
0.52 mmol) and 4.63 g of thiophosgene under ice cooling.
A solution of (40.26 mmol) in 20 ml of methylene chloride was slowly added dropwise, and after the completion, stirring was continued for another 3 hours. Then, water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The solvent was distilled off under reduced pressure, and 14.61 g of the obtained crystals were purified by silica gel chromatography (solvent: chloroform / methanol) to give 10.53 g of the title compound. (84% yield).

¹ H-NMR (CDCl ₃ ) δ: 1.53 (6H, d, J = 7.0 Hz),
3.01-3.11 (2H, m), 3.26-3.39 (2H, m), 6.18 (2H, q, J = 7.0H
z), 7.23-7.40 (8H, m)

Production Example 5 Production of 2-chloro-1,3-bis [(S) -1-phenylethyl] imidazolinium chloride 1,114-ml 1,3-bis [(S) -1-phenylethyl] imidazolinium chloride 5.70 g of -2-thioxoimidazolidine
(18.39 mmol) and oxalyl chloride 2.80
g (22.06 mmol) was added and the mixture was heated at 70 ° C. for 24 hours. After cooling, the precipitated crystals were collected by filtration and washed with toluene to obtain 5.11 g (yield: 80%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.77 (6H, d, J = 7.0 Hz),
3.89-3.97 (2H, m), 4.27-4.35 (2H, m), 5.33 (2H, q, J = 7.0H
z), 7.31-7.45 (8H, m),

Example 1 1,3-bis [(1S) -1-
Preparation of phenylethyl] -2-[(1S) -1-phenylethylimino] imidazolidine 0.52 g (4.30 mmol) of (S) -α-phenethylamine and 0.2 ml of triethylamine in 20 ml of methylene chloride.
87 g (8.60 mmol) were dissolved, and 2-chloro-1,3-bis [(1S) -1-phenylethyl] imidazolinium chloride (1.50 g, 4.30 mmol) was added little by little to the solution. Thereafter, stirring was continued for another hour. A diluted hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, isopropyl ether was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated crystals were collected by filtration and washed with isopropyl ether. The obtained crystals were dissolved in methanol, and the mixture was made strongly alkaline with an aqueous sodium hydroxide solution, and then extracted with methylene chloride. The extract was washed with ion-exchanged water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 1.32 g (yield 77%) of the title compound as a viscous oil.

[0041] [α] ^{_{D 23 = -152.10 ° (c =}} 1.00, CHCl 3) IRν max neat cm -1: 1640 UVλ max MeOH nm: 207.2 (ε34000)

¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, bs), 1.50 (3
(H, d, J = 6.6Hz), 2.73-2.81 (2H, m), 2.85-2.92 (2H, m), 4.9
8 (1H, q, J = 6.6Hz), 5.33 (2H, bs), 7.22-7.40 (15H, m)

¹³ C-NMR (CDCl ₃ ) δ: 15.29, 28.13, 40.13,
52.52, 55.55, 125.73, 126.17, 126.82, 127.26, 127.9
5, 128.17, 142.12, 149.13, 152.89 MS (FAB): m / z = 398 (M + 1 ⁺ )

Example 2 1,3-bis [(1S) -1-
Preparation of phenylethyl] -2-[(1R) -1- (1-naphthyl) ethylimino] imidazolidine (R) -1- (1-naphthyl) in 30 ml of methylene chloride
1.01 g (5.90 mmol) of ethylamine and 1.19 g (11.81 mmol) of triethylamine were dissolved, and 2-chloro-1,3-bis [(1S) -1-phenylethyl] imidazolinium chloride 2 was dissolved therein. .06g
(5.09 mmol) was added little by little, and after the completion, stirring was further continued for 1 hour. Thereafter, the same operation as in Example 1 was performed to obtain 2.16 g (yield: 82%) of the title compound.

Melting point: 114.9-115.2 ° C. [α] _D ²⁶ = −312.22 ° (c = 1.00, CHCl ₃ ) IRν _max ^KBr cm ⁻¹ : 1650 UVλ _max ^MeOH nm: 225.6 (ε94800), 283.2 (ε8000)

¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, d, J = 7.1 Hz),
1.60 (3H, d, J = 6.2Hz), 2.63--2.99 (4H, m), 5.67 (1H, q, J = 6.
2Hz), 7.17-7.22 (10H, m), 7.37-7.51 (3H, m), 7.67 (1H, d,
J = 8.1Hz), 7.81 (1H, d, J = 7.7Hz), 8.04 (1H, d, J = 7.1Hz),
8.22 (1H, d, J = 8.3Hz)

¹³ C-NMR (CDCl ₃ ) δ: 16.09, 27.67, 40.25,
52.61, 123.16, 123.37, 124.91, 125.40, 125.86, 126.
46, 126.81, 127.25, 127.99, 128.83 130.36, 133.90, 144.82, 153.38

Example 3 1,3-bis [(1S) -1-
Phenylethyl] -2-[(1R) -1-benzyl-2
-Hydroxyethylimino] imidazolidine 0.65 g (4.30 mmol) of (R) -phenylalaninol and 0.2 ml of triethylamine in 20 ml of methylene chloride.
87 g (8.60 mmol) were dissolved, and 2-chloro-1,3-bis [(1S) -1-phenylethyl] imidazolinium chloride (1.50 g, 4.30 mmol) was added little by little to the solution. Thereafter, stirring was continued for another hour. Less than,
The same operation as in Example 1 was performed to obtain 1.35 g of the title compound.
(73% yield).

The viscous oil [α] ^{_{D 26 = -109.08 ° (c =}} 1.00, CHCl 3) IRν max neat cm -1: 1635 UVλ max MeOH nm: 208.0 (ε30000)

¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, J = 6.6 Hz),
1.43 (3H, d, J = 7.1Hz), 2.63 (1H, dd, J = 8.3 and 13.5Hz),
2.96-3.04 (2H, m), 3.10 (1H, dd, J = 6.0 and 13.5Hz), 3.56
-3.63 (2H, m), 3.98 (1H, dd, J = 6.1 and 8.1Hz), 4.12 (1H, m
t, J = 8.1Hz), 5.23 (1H, q, J = 7.1Hz), 5.33 (1H, bs), 7.17-
7.31 (15H, m)

¹³ C-NMR (CDCl ₃ ) δ: 17.10, 24.15, 42.42,
44.41, 46.79, 55.10, 57.99, 65.13, 71.89, 126.51, 1
26.78, 126.94, 127.20, 128.19, 128.29, 128.36, 128.
46, 129.44, 138.24, 141.19, 145.56, 161.78 MS (FAB): m / z = 428 (M + 1 ⁺ )

Example 4 1,3-bis [(1S) -1-
Preparation of phenylethyl] -2- (4-pyridylimino) imidazolidine 200 mg of 4-aminopyridine in 20 ml of chloroform
(2.10 mmol) and 420 mg of triethylamine (4.
20 mmol) was dissolved therein, and 610 mg (1.75 mmol) of 2-chloro-1,3-bis [(1S) -1-phenylethyl] imidazolinium chloride was added little by little.
After the completion, stirring was further continued at room temperature for 4.5 hours. Thereafter, the same operation as in Example 1 was performed to obtain 420 mg of the title compound (yield: 6).
5%).

Viscous oil [α] _D ²⁵ = -165.88 ° (c = 1.00, CHCl ₃ ) IRν _max ^neat cm ^-1 : 1615, 1585 UVλ _max ^MeOH nm: 207.2 (ε22900), 296.8 (ε16000)

¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, d, J = 7.1 Hz),
2.88-3.01 (2H, m), 3.16-3.28 (2H, m), 5.16 (2H, q, J = 7.1H
z), 6.78 (2H, dd, J = 1.5 and 4.8Hz), 7.24-7.36 (10H, m),
8.26 (2H, dd, J = 1.5 and 4.8Hz),

¹³ C-NMR (CDCl ₃ ) δ: 15.24, 39.47, 51.97,
116.44, 127.20, 127.54,128.51, 140.03, 149.44, 15
6.15, 158.04

Reference Example Epoxidation reaction of chalcone

[0057]

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192 mg (70%, 1.49 mmol) of t-butyl peroxide was dissolved in 10 ml of toluene, anhydrous sodium sulfate was added, and the mixture was filtered to remove water.
31 mg (0.15 mmol) of chalcone and 1,3-bis [(1S) -1-phenylethyl] -2-[(1S) were added to the filtrate.
-1-phenylethylimino] imidazolidine 12 mg
(3 × 10 ⁻⁵ mol) and the mixture was stirred at room temperature for 24 hours. Then, the reaction solution was subjected to silica gel chromatography (solvent:
The residue was purified with n-hexane / ethyl acetate) to obtain 3 mg of 1,3-diphenyl-2,3-epoxy-1-propanone. This compound was analyzed by HPLC (column: CHIRAL
CEL OD, mobile phase: n-hexane: isopropanol = 40: 1) and the ratio of 2S, 3R: 2R, 3S was 60:40.

Claims (1)

[Claims] 1. The following general formula (1): Wherein R ¹ and R ² are the same or different and represent an alkyl group, R ³ represents an aralkyl group or a heterocyclic group which may have a hydroxyl group, and * represents the position of an asymmetric carbon. An optically active guanidine derivative or a salt thereof represented.