JP2004099609A - Method for producing optically active 7-amino-5-azaspiro[2.4]heptane - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing optically active 7-amino-5-azaspiro[2.4]heptane with high optical purity in a high yield. <P>SOLUTION: This method for producing the 7-amino-5-azaspiro[2.4]heptane comprises reacting a compound expressed by formula (1) (R<SP>1</SP>is H or an amino-protecting group) with a compound expressed by formula: R<SP>2</SP>-NH<SB>2</SB>(R<SP>2</SP>is H, an amino-protecting group or an imino-protecting group) in the presence of an acid to produce a compound expressed by formula (2), and hydrogenating the produced compound in the presence of an asymmetric catalyst. When R<SP>2</SP>of the compound expressed by formula (2) is the protecting group having an asymmetric carbon, the protecting group is, if desired, removed after hydrogenation of the compound. <P>COPYRIGHT: (C)2004,JPO

Description

The present invention relates to a method for producing optically active 7-amino-5-azaspiro [2.4] heptane, which is a raw material for synthesizing an antibacterial compound.

Optically active 7-amino-5-azaspiro [2.4] heptane is useful as an intermediate for producing an antibacterial compound (see Patent Documents 1 and 2). As a synthesis method, a split crystallization method using racemic amines and an optically active acid has been proposed (see Patent Documents 3 and 4). However, this method does not require one of the optically active isomers, and requires measures such as a racemization reaction (see Patent Documents 5 and 6) in order to utilize the unnecessary isomer.
JP-A-2-231475 JP-A-5-221947 JP-A-4-149174 JP-A-7-224033 JP-A-4-342565 JP-A-7-233146

In recent years, there have been many reports on asymmetric synthesis methods using asymmetric metal complexes as catalysts, and have realized higher efficiency of organic synthesis reactions. Accordingly, development of an asymmetric synthesis method of an optically active spiroamine compound has been desired.
An object of the present invention is to provide a method for producing optically active 7-amino-5-azaspiro [2.4] heptane using asymmetric synthesis.

Accordingly, the present inventors have conducted various studies, and as a result, the ketone compound represented by the formula (1) was used as a raw material, and an amine compound was reacted therewith in the presence of an acid to produce an imine compound represented by the formula (2). Reduction in the presence of a catalyst, or when the protecting group has an asymmetric carbon atom, conversion to an optically active compound by reduction, and furthermore, when this has a protecting group, deprotection enables high-yield optical yield. It was found that active 7-amino-5-azaspiro [2.4] heptane (formula (4)) was obtained, and the present invention was completed.

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

(Wherein, R ¹ represents a hydrogen atom or an amino-protecting group) in a compound represented by the formula R ² —NH ₂ (wherein R ² represents a hydrogen atom or an amino group or an imino group) in the presence of an acid. A compound represented by the formula (2):

(Wherein the same. R ¹ and R ² are each independently a) a compound represented by the formula MX _m L _n (wherein, M is the Periodic Table 8-10 transition metals, X is hydrogen An atom, a halogen atom, an alkoxy group, an alkenyl group or an aryl group, L represents an optically active phosphine ligand, m represents an integer of 0 to 6, and n represents an integer of 1 to 6). Formula (3) obtained by reduction in the presence of a homogeneous catalyst

(Wherein, R ¹ and R ² are each independently the same as described above), wherein the optically active compound represented by the formula (4) is optionally deprotected.

And a process for producing an optically active compound represented by the formula:
When R ² has an asymmetric carbon atom, the corresponding compound represented by the formula (2) is reduced by ordinary reduction, for example, catalytic hydrogenation or hydride ion instead of reduction in the presence of an asymmetric catalyst. , Preferably by reduction with a hydride ion, followed by deprotection, to provide a method for producing a compound represented by the formula (4).

Furthermore, the present invention provides a method for producing the compound represented by the formula (2) and the compounds represented by the formulas (2) to (4) and (6).

According to the production method of the present invention, an optically active 7-amino-5-azaspiro [2.4] heptane having high optical purity and high optical purity can be produced by using a catalytic amount of an asymmetric source or an asymmetric protecting group. Further, the compound of the formula (2) is useful as an intermediate for producing an antibacterial compound.

The optically active 7-amino-5-azaspiro [2.4] heptane (4) of the present invention is produced by the following reaction route.

(In the formula, R ¹ , R ² , M, X, L, m and n are the same as described above.)
When R ² is a protecting group (R ³ ) for an amino group or imino group having an asymmetric carbon atom, it may be produced by the following reaction route.

(In the formula, R ¹ and R ³ are the same as described above.)

Here, when R ¹ and R ² are protecting an amino group or an imino group, the protecting group includes a t-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, and a 2,2,2-trichloroethoxycarbonyl group. Aralkyloxycarbonyl groups such as alkoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group and paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, t-butyroyl group, pivaloyl group and benzoyl group And aralkyl groups such as an benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group and a paramethoxybenzyl group, among which aralkyl groups are preferred. ¹ and R ² simultaneously It is preferably a jyl group.

When the protecting group R ² of the amino group is a protecting group R ³ having an asymmetric carbon atom, reduction may be carried out in the presence of an asymmetric catalyst to produce the optically active compound (3). The optically active compound (6) may be produced by addition or reduction with a hydride ion, preferably by a hydride ion, followed by deprotection to produce the optically active compound (4).
In this case, R ³ preferably has a specific configuration, and specifically,

(In the formula, R ^a , R ^b and R ^c are different groups from each other and include a phenyl group, a benzyl group, and a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, Or at least one group selected from the group consisting of an alkoxy group, a halogen atom and a nitro group may be present as a substituent.), A hydrogen atom and an alkyl group having 1 to 4 carbon atoms. Selected from the group consisting of
The group represented by is preferred.
R ^a , R ^b , and R ^c are different from each other and represent a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-chlorophenyl group, a 4-nitrophenyl group, More preferably, it is a group selected from the group consisting of a 4-dichlorophenyl group, a 2,4-dinitrophenyl group, a 3,5-dichlorophenyl group, a 3,5-dinitrophenyl group and a naphthyl group.

R ³ further includes (R) -α-methylbenzyl group ((R) -1-phenylethyl group), (S) -α-methylbenzyl group ((S) -1-phenylethyl group), R) -1-phenylpropyl group, (S) -1-phenylpropyl group, (R) -1-phenyl-2- (p-tolyl) ethyl group, (S) -1-phenyl-2- (p- (Tril) ethyl group, (R) -1- (1-naphthyl) ethyl group, (S) -1- (1-naphthyl) ethyl group, (R) -1- (4-methoxyphenyl) ethyl group, (S ) -1- (4-methoxyphenyl) ethyl group, (R) -1- (4-chlorophenyl) ethyl group, (S) -1- (4-chlorophenyl) ethyl group, (R) -1- (4- Nitrophenyl) ethyl group, (S) -1- (4-nitrophenyl) ethyl group, (R) -1- ( , 4-dichlorophenyl) ethyl group, (S) -1- (2,4-dichlorophenyl) ethyl group, (R) -1- (2,4-dinitrophenyl) ethyl group, (S) -1- (2 4-dinitrophenyl) ethyl group, (R) -1- (3,5-dichlorophenyl) ethyl group, (S) -1- (3,5-dichlorophenyl) ethyl group, (R) -1- (3,5 A -dinitrophenyl) ethyl group or a (S) -1- (3,5-dinitrophenyl) ethyl group is preferred, and a (R) -α-methylbenzyl group ((R) -1-phenylethyl group) is particularly preferred. preferable.

Hereinafter, each reaction step will be described.
Preparation of Compound of Formula (2) The compound of formula (2) is prepared by reacting the compound of formula (1) with an amine compound represented by R ² —NH ₂ in the presence of an acid.
As the acid, either a Bronsted acid or a Lewis acid can be used. Examples of the Bronsted acid include sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like, and examples of the Lewis acid include boron trifluoride, aluminum trichloride, and antimony pentafluoride. preferable. The amount of the acid to be used may usually be in the range of 1/1000 to 1 mol, preferably 1/100 to 1/2 mol, particularly preferably 1/10 mol, relative to the compound of the formula (1).
It is preferable to use a solvent for this reaction, and there is no particular limitation as long as it is inert to the reaction.Aromatic hydrocarbons, ethers, amides, and others, ethyl acetate and the like can be used. Aromatic hydrocarbons such as benzene and toluene are preferred. The reaction temperature varies depending on the type of acid and the solvent used, but may be in the range of room temperature to the boiling point of the solvent.

Production of Optically Active Compound of Formula (3) The optically active compound of formula (3) is produced by reducing the compound of formula (2) in the presence of an asymmetric catalyst.
Asymmetric catalyst used in this reaction has the formula _{MX m L n (M, X} , L, m and n are as defined above) represented by the periodic table 8-10 transition metal complex and an optically active phosphine Is reacted in a solvent and isolated or used as is. Here, iridium, rhodium, ruthenium, and the like are preferable as transition metals of Groups 8 to 10 of the periodic table. The amount of the asymmetric catalyst to be used may be in the range of 1/1000 to 1/2 mole, preferably 1/100 to 1/5 mole, especially 1/10 mole relative to the compound of the formula (2). preferable.

Group 8-10 transition metal complexes include chloro (1,5-cyclooctadiene) iridium dimer, bis (1,5-cyclooctadiene) iridium, tetrafluoroborate, chloro (1,5-cyclooctadiene) Rhodium dimer, bis (1,5-cyclooctadiene) rhodium tetrafluoroborate, bis (1,5-cyclooctadiene) rhodium, trifluoromethanesulfonate, chloro (norbornadiene) rhodium dimer, bis (norbornadiene) rhodium tetrafluoro Borate, bis (norbornadiene) rhodium perchlorate, dichloro (1,5-cyclooctadiene) ruthenium, p-cymeneruthenium chloride dimer, benzene ruthenium chloride dimer, etc. Be, but especially chloro (1,5-cyclooctadiene) iridium dimer are preferred.

Optically active phosphines include S- and R-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl: BINAP, S- and R-2,2'-bis (di-p-tolylphosphino) -1,1'-Binaphthyl: tol-BINAP, 2S, 4S- and 2R, 4R-N- (tert-butoxycarbonyl) -4- (diphenylphosphino) -2-[(diphenylphosphino) methyl] pyrrolidine: BPPM, 2S, 3S- and 2R, 3R-2,3-o-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane: DIOP, 2S, 3S- and 2R, 3R- 2,3-bis (diphenylphosphino) butane: CHIRAPHOS, 2S, 4S- and 2R, 4R-2,3-bis (diphenylphosphino) pentane: BDPP, 5S, 6S- and 5R, 6R-5,6-bis (diphenylphosphino) -2-norbornene: NORPHOS, R-1- [S-1 ', 2-bis (diphenylphosphino) ferrocenyl] ethyl alcohol And its stereoisomer: BPPFOH, S-1- [R-2- (diphenylphosphino) ferrocenyl] ethyldicyclohexylphosphine and its stereoisomer: JOSIPHOS, 1,2-bis [(2R, 5R) -2,5 -Diethylphosphorano] ethane and its stereoisomer: Et-BPE, 1,2-bis [(2R, 5R) -2,5-diethylphosphorano] benzene and its stereoisomer: Et-DUPHOS Although it can be used, tol-BINAP is particularly preferred.

と し て As the asymmetric catalyst, iridium- (tol-BINAP) is preferable.

溶媒 A solvent is preferably used in this reaction, and alcohols, aromatic hydrocarbons, ethers, halogenated hydrocarbons and the like can be used, and a preferable one may be selected. A mixed solvent obtained by combining two or more of the above solvents may be used. The hydrogen pressure may be in the range of normal pressure to 100 atm, preferably in the range of 30 to 50 atm. The reaction temperature may be in the range of -78 ° C to the boiling point of the solvent, preferably in the range of -30 ° C to -10 ° C. In addition, in this reaction, the chemical yield and the asymmetric yield may be improved by adding an iodide such as potassium iodide, an amine such as benzylamine, or an ammonium salt such as tetra-n-butylammonium borohydride.

When R ² is a protecting group (R ³ ) for an amino group or an imino group having an asymmetric carbon atom, the compound of the formula (5) is reduced by a usual catalytic hydrogenation or hydride ion to obtain a compound represented by the formula (5). The compound of 6) may be produced.

The catalyst used for the reduction by catalytic hydrogenation is not particularly limited as long as it is usually used, but a platinum catalyst such as a platinum carbon catalyst, a palladium catalyst such as a palladium carbon catalyst, a nickel catalyst, Examples thereof include cobalt-based catalysts and transition metal-based catalysts belonging to Groups 8 to 10 of the periodic table such as iridium, rhodium, and ruthenium. Of these, platinum-based catalysts, particularly platinum-carbon catalysts, are preferred.
Further, the reducing agent serving as a hydride ion source used in the reduction by hydride ions is not particularly limited as long as it is a commonly used one, but a metal borohydride such as sodium borohydride or lithium borohydride, Aluminum hydrides such as lithium aluminum hydroxide or sodium dihydrobismethoxyethoxyaluminate; borane-based reducing agents such as diborane; Of these, metal borohydride, particularly sodium borohydride, is preferred. If the reduction by catalytic hydrogenation is compared with the reduction by hydride ions, the reduction by catalytic hydrogenation produces 4-ethylpyrrolidin-3-yl-amines having a cyclopropane ring opened, thereby producing a drug. When high purity is required as in the case of an intermediate, reduction with a hydride ion is particularly preferred.

The compound of the formula (6) produced at this time may be an inorganic acid salt such as a hydrochloride, a sulfate or a nitrate, or an organic acid such as a carboxylate such as an oxalate, a tartrate or a mandelate which is not optically active. The use of a salt is preferred because purification is easy and the optical purity can be increased, and a hydrochloride is particularly preferred.

Preparation of Optically Active Compound of Formula (4) The compound of the formula (4) is a compound of the formula (3) or (6) wherein R ¹ , R ² and / or R ³ is an amino- or imino-group protecting group. Is produced by reducing this in the presence of a metal catalyst.
As the metal catalyst, a palladium-based catalyst such as palladium carbon, palladium hydroxide, and palladium-barium sulfate is preferable.
It is preferable to use a solvent for this reaction, and there is no particular limitation as long as it is inert to the reaction. However, alcohols, aromatic hydrocarbons, ethers, amides, water, others, and ethyl acetate are used. What is necessary is just to select a preferable thing.
The hydrogen pressure can be increased from normal pressure to 100 atm, preferably from normal pressure to 50 atm.
The reaction temperature varies depending on the type of acid and the solvent used, but may be in the range of room temperature to the boiling point of the solvent.

Here, the pathway for asymmetric reduction after the preparation of the imine compound is shown. However, by treating the compound (1) and an amine compound, an acid, and an asymmetric catalyst in a hydrogen atmosphere at once, these are reduced. Can also be carried out.

7-Amino-5-azaspiro [2.4] heptane produced by the production method of the present invention is a salt of an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, or an organic acid such as a substituted carboxylic acid or a substituted sulfonic acid. Is also good.

Next, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

Example 1
Synthesis of N-benzyl-N- (5-benzyl-5-azaspiro [2.4] hept-7-ylidene) amine 5-benzyl-5-azaspiro [2.4] heptan-7-one (1 g), benzyl To a solution of the amine (642 mg) in benzene (10 mL) was added a boron trifluoride / ether solution (0.1 mL), and a Dean-Stark reflux condenser was attached, followed by heating under reflux for 4 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography and developed with n-hexane: ethyl acetate = 2: 1 to obtain 952 mg of the title compound as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.85 (dd, J = 3.0, 5.1 Hz, 2H), 1.18 (dd, J = 3.0, 5.1 Hz, 2H), 2.83 (s, 2H), 3.39 (s, 2H) ), 3.73 (s, 2H), 4.39 (s, 2H), 7.18-7.38 (m, 10H).

Examples 2 to 8
Asymmetric reduction of N-benzyl-N- (5-benzyl-5-azaspiro [2.4] hept-7-ylidene) amine [Ir (COD) Cl] ₂ (30.9 mg) in ethanol (4.5 mL) R-tol-BINAP (67.9 mg) was added to the solution, and the mixture was stirred at room temperature for 2 hours to prepare a catalyst. An autoclave was charged with a solution of N-benzyl-N- (5-benzyl-5-azaspiro [2.4] hept-7-ylidene) amine (290 mg) in ethanol (4.5 mL) and the prepared catalyst solution, and hydrogen pressure was set to 30. The mixture was stirred at atmospheric pressure at -10 ° C for 63 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography and developed with chloroform: methanol = 10: 1 to obtain N-benzyl-N- (5-benzyl-5-azaspiro [2.4] heptane. 187 mg of -7-yl) amine were obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.35-0.42 (m, 1H), 0.51-0.64 (m, 2H), 0.86-0.91 (m, 2H), 2.56 (dd, J = 8.9, 43.6 Hz), 2.55 (dd, J = 4.0,4.0Hz, 1H), 3.00-3.10 (m, 2H), 3.64 (d, J = 8.6Hz, 2H), 3.71 (dd, J = 13.2,43.6Hz, 2H), 7.10- 7.36 (m, 10H).
The optical purity and conversion of the obtained amine were analyzed by liquid chromatography.
Column: CHIRALPAK AD-RH (manufactured by Daicel Chemical Industries, Ltd.)
Developing solvent: acetonitrile: phosphate buffer (pH 7.0) = 2: 3 (volume ratio)
Flow rate: 1.0 mL / min

Table 1 shows the results of the same reaction performed with different ligands, solvents and additives.

Example 9
7-amino-5-azaspiro [2.4] heptane dihydrochloride N-benzyl-N- (5-benzyl-5-azaspiro [2.4] heptan-7-yl) amine [170 mg, 53% ee ( S)] To a suspension of 5% Pd-C (17 mg) in toluene (2 mL) was added concentrated hydrochloric acid (0.58 mL), and the mixture was stirred under a hydrogen atmosphere for 5 hours. After removing the catalyst by filtration, the filtrate was allowed to cool, isopropyl alcohol (5 mL) was added, and the mixture was stirred for 3 hours. The precipitate was collected by filtration to obtain 177 mg of the known title compound as white crystals.
A part of the obtained amine was acylated with 3,5-dinitrobenzoyl chloride by the method described in JP-A-4-149174, and the optical purity was measured by liquid chromatography. As a result, 53% ee was obtained. The absolute configuration was S-form.

Example 10
(1) Synthesis of 5-benzyl-5-azaspiro [2.4] hept-7-ylidene- (1R) -1-phenylethylamine 5-benzyl-5-azaspiro [2.4] heptan-7-one (21 (R) -1-phenylethylamine (13.6 g) and acetic acid (1.20 g) were added to a toluene (100 mL) solution of 0.3 g), and the mixture was heated to reflux while dehydrating. Acetic acid (1.20 g, 1.20 g, 1.80 g) was added every hour, and the mixture was heated under reflux for a total of 4 hours. The reaction solution was allowed to cool, washed with a saturated aqueous solution of sodium hydrogen carbonate, and then the solvent was distilled off under reduced pressure to obtain 35.4 g of the title compound as a red-brown oil. 109.9%
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.76-0.86 (m, 2H), 1.14-1.19 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H), 2.73 (d, J = 9.0 Hz , 1H), 2.79 (d, J = 9.0Hz, 1H), 3.19 (d, J = 15.0Hz, 1H), 3.48 (d, J = 15.0Hz, 1H), 3.68 (s, 2H), 4.30 (q , J = 6.6Hz, 1H), 7.15-7.33 (m, 10H).

(2) Synthesis of 5-benzyl-5-azaspiro [2.4] hept-7-yl- (1R) -1-phenylethylamine (i) 5% Pt-C (6.4 g) in ethanol (50 mL) To the suspension, a solution of 5-benzyl-5-azaspiro [2.4] hept-7-ylidene- (1R) -1-phenylethylamine (35.4 g) in ethanol (50 mL) was added, and the mixture was heated at 45 ° C. under a hydrogen atmosphere. Stir for 44 hours. Pt-C was filtered, and the filtrate was concentrated under reduced pressure to obtain 32.2 g of the title compound as a reddish brown oil. 91.5% 7S: 7R = 97: 3
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.29-0.36 (m, 1H), 0.52-0.65 (m, 2H), 0.88-0.94 (m, 1H), 1.25 (d, J = 6.6 Hz, 3H) , 2.22 (dd, J = 9.1,6.2Hz, 1H), 2.46 (d, J = 9.0Hz, 1H), 2.52 (d, J = 9.0Hz, 1H), 2.91 (dd, J = 9.1,6.2Hz, 1H), 3.05 (t, J = 6.2Hz, 1H), 3.47 (d, J = 12.6Hz, 1H), 3.58 (d, J = 12.6Hz, 1H), 3.66 (q, J = 6.6Hz, 1H) , 7.19-7.27 (m, 10H).

(Ii) A solution of 5-benzyl-5-azaspiro [2.4] hept-7-ylidene- (1R) -1-phenylethylamine (2.48 g) in methanol (12 mL) under ice-cooling was treated with sodium borohydride ( 614 mg) and stirred at room temperature for 2 hours. After confirming the disappearance of the raw materials, the reaction solution was ice-cooled, acetone was added and the mixture was stirred, and then the reaction solution was concentrated under reduced pressure. Water and toluene were added to the residue, and after stirring, the organic layer was separated. Toluene was added to the aqueous layer, and after stirring and extraction, the organic layer was separated. All organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.84 g of the title compound as a reddish brown oil. 74.9% 7S: 7R = 94: 6
Column: TSK-gel ODS-80TM 4.6 × 150mm
Oven: 40 ° C, Det .: UV220 nm, Flow: 1.0 mL / min
Mobile phase: 0.5M Phosphate Buffer (pH 2.4) / MeOH = 85/15
Retention time: 7R = 6.4 min, 7S = 13.8 min

(Iii) To a toluene solution (79.6 g) of 5-benzyl-5-azaspiro [2.4] heptan-7-one (60.0 g) was added (1R) -1-phenylethylamine (43.35 g) and acetic acid ( 14.32 g) was added thereto, and the mixture was heated under reflux for 4 hours while being dehydrated. The reaction solution was allowed to cool under a nitrogen atmosphere, and a saturated aqueous solution of sodium hydrogen carbonate (90 mL) was added. After stirring for 30 minutes, the mixture was allowed to stand and separated to obtain an organic layer. The organic layer was further washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in that order, and then the solvent was distilled off under reduced pressure to give 5-benzyl-5-azaspiro [2.4] hept-7-ylidene- (1R). 107.1 g of -phenylethylamine were obtained as a reddish brown oil. To another reaction vessel, under ice-cooling, methanol (270 mL) and sodium borohydride (11.28 g) were added, and subsequently, the above-mentioned 5-benzyl-5-azaspiro [2.4] hept-7-ylidene- ( A solution of (1R) -1-phenylethylamine (107.1 g) in methanol (90 mL) was added dropwise, and the mixture was stirred at room temperature for 12.5 hours. The reaction solution was ice-cooled, a 28% aqueous sodium hydroxide solution (90 mL) and water (180 mL) were sequentially added, and the mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. Toluene (270 mL) and water (270 mL) were added to the residue, and the mixture was stirred and allowed to stand. The resulting organic layer was washed with a 5% aqueous sodium hydroxide solution (120 mL) and water (120 mL) in that order, and then the solvent was removed. By distilling off under reduced pressure, 104.9 g of the title compound was obtained as a reddish brown oil. The yield of the 7S form by HPLC quantification was 73.3 g, 80.2%. 7S: 7R (HPLC area ratio) = 89.1: 10.9
Column: YMC-Pack ODS-AM AM-311 6.0 × 100mm
Oven: 40 ℃, Det,: UV220nm, Flow: 1.0mL / min
Mobile phase: 0.02M Phosphate Buffer (pH7.0) / MeCN = 1/1
Retention time: 7S = 18.0 min, 7R = 21.7 min

(3) Synthesis of 5-azaspiro [2.4] hept- (7S) -7-ylamine 5-benzyl-5-azaspiro [2.4] hept- (7S) -7-yl- (1R) -1- To a solution of phenylethylamine (2.58 g: 97.0% de) in toluene (5 mL) was added 1N HCl (10 mL) and a 10% Pd-C catalyst (0.15 g: NE type, 57% wet), and the mixture was added with 45 to 45%. Stirred at 50 ° C. for 18 hours. Pd-C was filtered, the filtrate was separated, the aqueous layer was separated, and concentrated under reduced pressure. 2-propanol was added to the residue, and the mixture was concentrated under reduced pressure to obtain 1.53 g of the title compound as pale yellow crystals. 84.4% ee
¹ H-NMR (300 MHz, D ₂ O) δ: 0.77-0.94 (3H, m), 0.97-1.06 ( ¹ H, m), 3.07 (1 H, d, J = 12.0 Hz), 3.46-3.56 (2 H, m ), 3.63 (1H, dd, J = 7.5,3.0Hz), 3.92 (1H, dd, J = 13.5,7.5Hz).

Example 11
(1) Synthesis of 5-benzyl-5-azaspiro [2.4] hept-7-yl- (1R) -1-phenylethylamine hydrochloride 5-benzyl- produced in (2) (i) of Example 10 To a solution of 7.17 g (7S: 7R = 97: 3) of crude 5-azaspiro [2.4] hept-7-yl- (1R) -1-phenylethylamine in toluene (21 mL) was added water (35 mL) and concentrated water. Hydrochloric acid (4.0 mL) was added and stirred. The aqueous layer was separated, 28% sodium hydroxide (7.0 mL) was added, extracted with toluene (20 mL × 2), and the combined toluene layers were concentrated under reduced pressure. The obtained residue was dissolved in 2-propanol (12 mL), concentrated hydrochloric acid (3.4 mL) was added, and the mixture was stirred for 30 minutes. The solvent was concentrated under reduced pressure, and 2-propanol (20 mL) was added to the obtained residue. By suspension washing, 2.83 g of the title compound was obtained as pale yellow crystals. 7S: 7R = 99.9: 0.1
Column: TSK-gel ODS-80TM 4.6 × 150mm
Oven: 40 ° C, Det .: UV220 nm, Flow: 1.0 mL / min
Mobile phase: 0.5M Phosphate Buffer (pH 2.4) / MeOH = 85/15
Retention time: 7R = 6.4 min, 7S = 13.8 min

(2) Synthesis of 5-azaspiro [2.4] hept- (7S) -ylamine 5-benzyl-5-azaspiro [2.4] hept- (7S) -7-yl- (1R) -1-phenylethylamine (0.30 g: 99.8% de) was dissolved in 1N HCl (2.0 mL), and a 10% Pd-C catalyst (0.15 g: NE type, 57% wet) was added. Stir at 50 ° C. for 15 hours. Pd-C was filtered, the filtrate was concentrated under reduced pressure, 2-propanol was added to the residue, and the mixture was concentrated under reduced pressure to obtain 0.17 g of the title compound as pale yellow crystals. 99.2% ee

Example 12
Synthesis of 5-benzyl-5-azaspiro [2.4] hept-7-yl- (1R) -1-phenylethylamine dihydrochloride 5-benzyl-5-azaspiro synthesized in Example 10 (2) (iii) [2.4] Hept-7-yl (1R) -1-phenylethylamine (104.0 g, containing 72.7 g of 7S-form) was dissolved in acetone (600 mL) 6 and cooled with ice. Under ice-cooling and stirring, concentrated hydrochloric acid (49.8 mL) was added dropwise, and after stirring for 2 hours under ice-cooling, the precipitated crystals were collected by filtration to obtain 86.1 g of the title compound as pale yellow crystals. The 7S isomer by HPLC quantification was 83.0 g, yield 92.2%, 99.6% de.
Column: YMC-Pack ODS-AM AM-311 6.0 × 100mm
Oven: 40 ° C, Det .: UV220 nm, Flow: 1.0 mL / min
Mobile phase: 0.02M Phosphate Buffer (pH 7.0) / MeOH = 1/1
Retention time: 7R body = 18.0 min, 7S body = 21,7 min

Example 13
(1) (i) 5-benzyl-5-azaspiro [2.4] hept-7-ylidene- (1R) -1-phenylethylamine (3.00 g) was dissolved in ethanol (15 mL), and 5% Pt was added. -C (1.5 g, ethanol was added to a 50% wet body, and decantation was performed three times) was added, and the mixture was stirred at 40 to 45 ° C in a hydrogen atmosphere for 16.5 hours. The Pt-C was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.77 g of 5-benzyl-5-azaspiro [2.4] hept-7-yl- (1R) -1-phenylethylamine as an orange-yellow oil. .

(Ii) 5-Benzyl-5-azaspiro [2.4] hept-7-yl- (1R) -1-phenylethylamine (2.77 g) was dissolved in acetone (12.5 mL) and cooled with ice. Under ice-cooling and stirring, concentrated hydrochloric acid (1.5 mL) was added dropwise, and after stirring under ice-cooling for 1.5 hours, the precipitated crystals were collected by filtration and 5-benzyl-5-azaspiro [2.4] hept-7. 2.42 g of -yl- (1R) -1-phenylethylamine dihydrochloride was obtained as pale yellow crystals.

(Iii) 5-benzyl-5-azaspiro [2.4] hept-7-yl- (1R) -1-phenylethylamine dihydrochloride (1.5 g) was dissolved in methanol (4.5 mL), and 10% Pd-C (NE type, 50% wet) was added, and the mixture was stirred at 40 to 45 ° C for 5 hours under a hydrogen atmosphere. After Pd-C was filtered and the filtrate was concentrated under reduced pressure, water (3 mL) and activated carbon (0.15 g) were added to the residue, and the mixture was stirred at room temperature for 1 hour. After filtering the activated carbon, the filtrate was concentrated under reduced pressure, 2-propanol (3 mL) was added to the residue, and the mixture was concentrated under reduced pressure. Crystals obtained by adding 2-propanol (4.5 mL) and water (0.45 mL) to the residue and stirring under ice-cooling for 2 hours are filtered, and 5-azaspiro [2.4] hept- (7S) is obtained. 0.50 g of -7-ylamine was obtained as white crystals (crystal 1-1). 99.8% ee. The mother liquor was concentrated under reduced pressure, 2-propanol (1.5 mL) was added to the residue, and the mixture was stirred for 2 hours under ice-cooling. The resulting crystals were filtered and 5-azaspiro [2.4] hept- (7S) -7 was obtained. 0.08 g of -ylamine was obtained as pale yellow crystals (crystal 1-2).

(2) (i) Under ice-cooling, methanol (9 mL) and sodium borohydride (0.75 g) were added, and 5-benzyl-5-azaspiro [2.4] hept- used in (1) (i) was added. A solution of 7-ylidene (1R) -1-phenylethylamine (3.00 g) in methanol (6 mL) was added dropwise, and the mixture was stirred at room temperature for 15.5 hours. Acetone (1 mL) was added to the reaction solution, and after stirring for 30 minutes, the reaction solution was concentrated under reduced pressure, water (12 mL) and toluene (12 mL) were added to the residue, and the mixture was stirred and allowed to stand for separation to obtain an organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.86 g of 5-benzyl-5-azaspiro [2.4] hept-7-yl- (1R) -1-phenylethylamine as an orange-yellow oil. Obtained.

(Ii) 5-benzyl-5-azaspiro [2.4] hept-7-yl- (1R) -1-phenylethylamine (2.86 g) was dissolved in acetone (12.5 mL) and cooled with ice. Under ice-cooling and stirring, concentrated hydrochloric acid (1.5 mL) was added dropwise, and after stirring under ice-cooling for 1.5 hours, the precipitated crystals were collected by filtration and 5-benzyl-5-azaspiro [2.4] hept-7. 2.27 g of -yl- (1R) -1-phenylethylamine dihydrochloride was obtained as pale yellow crystals.

(Iii) 5-benzyl-5-azaspiro [2.4] hept-7-yl- (1R) -1-phenylethylamine dihydrochloride (1.5 g) was dissolved in methanol (4.5 mL), and 10% Pd-C (NE type, 50% wet) was added, and the mixture was stirred at 40 to 45 ° C for 5 hours under a hydrogen atmosphere. After Pd-C was filtered and the filtrate was concentrated under reduced pressure, water (3 mL) and activated carbon (0.15 g) were added to the residue, and the mixture was stirred at room temperature for 1 hour. After filtering the activated carbon, the filtrate was concentrated under reduced pressure, 2-propanol (3 mL) was added to the residue, and the mixture was concentrated under reduced pressure. 2-Propanol (4.5 mL) and water (0.45 mL) were added to the residue, and the mixture was stirred under ice-cooling for 2 hours. The resulting crystals were collected by filtration, and 5-azaspiro [2.4] hept- (7S 0.50 g of -7-ylamine as white crystals was obtained (crystal 2-1). 99.8% ee. The mother liquor was concentrated under reduced pressure, 2-propanol (1.5 mL) was added to the residue, and the mixture was stirred for 2 hours under ice-cooling. The resulting crystals were filtered and 5-azaspiro [2.4] hept- (7S) -7 was obtained. 0.11 g of -ylamine was obtained as pale yellow crystals (crystal 2-2).

Table 2 shows the optical purity and HPLC quantification results of the obtained crystals 1-1 and 1-2 and crystals 2-1 and 2-2. In Table 2, ND indicates that it was not detected.
Column: CAPCELLPAK C18 SG120-5 4.6 × 250mm
Oven: 40 ° C, Det .: UV254 nm, Flow: 1.2 mL / min
Mobile phase: A mixture of 0.76 g of p-toluenesulfonic acid monohydrate added with 1000 mL of water, dissolved and added with 20 mL of acetonitrile Retention time: A = 9.3 min, B = 13.1 min, C = 14.4 min

From Table 2, it can be seen that in the case of the reduction with hydride ions as compared with the catalytic reduction, there is less by-product of the ring-opened form of the cyclopropane ring.

Claims (24)

The following equation (1)

(In the formula, R ¹ represents a hydrogen atom or a protecting group of an amino group.) The compound represented by, in the presence of an acid, wherein R ² -NH ₂ (wherein, R ² is a protective hydrogen atom or an amino group A compound represented by the formula (2):

(Wherein the same. R ¹ and R ² are each independently a) a compound represented by the formula MX _m L _n (wherein, M is the Periodic Table 8-10 transition metals, X is hydrogen An atom, a halogen atom, an alkoxy group, an alkenyl group or an aryl group, L represents an optically active phosphine ligand, m represents an integer of 0 to 6, and n represents an integer of 1 to 6). Formula (3) obtained by reduction in the presence of a homogeneous catalyst

(Wherein R ¹ and R ² are each independently the same as described above), wherein the compound represented by the formula (4) is optionally deprotected.

A method for producing an optically active compound represented by the formula: The method for producing an optically active compound according to claim 1, wherein the protecting group for the amino group or imino group of R ¹ and R ² is an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group or an aralkyl group. ^{3. The} method for producing an optically active compound according to claim ^1, wherein R ¹ and R ² are aralkyl groups. Process for producing an optically active compound according to any one of claims 1 to 3 R ¹ and R ² is a benzyl group. The following equation (2)

(Wherein R ¹ and R ² each independently represent a hydrogen atom or an amino- or imino-protecting group). The compound according to claim 5, wherein the amino or imino protecting groups for R ¹ and R ² are each independently an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group or an aralkyl group. 7. The compound according to claim 5, wherein R ¹ and R ² are aralkyl groups. The compound according to claim 5, wherein R ¹ and R ² are a benzyl group. The following equation (1)

(Wherein R ¹ represents a hydrogen atom or an amino-protecting group) to a compound represented by the formula R ³ —NH ₂ (wherein R ³ is an amino having an asymmetric carbon atom) in the presence of an acid. And a protecting group for the imino group.), And the resulting compound of the formula (5)

(Wherein R ¹ and R ³ are the same as described above), and the compound represented by the formula (6)

(Wherein R ¹ and R ³ are the same as described above), wherein the compound represented by the formula (4) is optionally deprotected.

A method for producing an optically active compound represented by the formula: (10) The production method according to the above (9), wherein the reduction of the compound represented by the formula (5) is reduction with a hydride ion. 11. The production method according to claim 10, wherein the reduction with hydride ions is a reduction using a reducing agent selected from metal borohydride, aluminum metal hydride and a borane-based reducing agent. The following equation (5)

(Wherein, R ¹ represents a protecting group for a hydrogen atom or an amino group, and R ³ represents a protecting group for an amino group or an imino group having an asymmetric carbon atom). R ³ is given by

(R ^a , R ^b and R ^c are different groups from each other and include a phenyl group, a benzyl group and a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, It may have one or more substituents selected from the group consisting of an alkoxy group, a halogen atom and a nitro group as one or more substituents.), A hydrogen atom and an alkyl group having 1 to 4 carbon atoms. Is the group of choice.)
The compound according to claim 12, which is a group represented by the formula: R ³ is given by

(R ^a , R ^b and R ^c are different groups, and each represents a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-chlorophenyl group, a 4-nitrophenyl Group, 2,4-dichlorophenyl group, 2,4-dinitrophenyl group, 3,5-dichlorophenyl group, 3,5-dinitrophenyl group, and naphthyl group.)
14. The compound according to claim 12, which is a group represented by the formula: R ³ is a (R) -α-methylbenzyl group ((R) -1-phenylethyl group), (S) -α-methylbenzyl group ((S) -1-phenylethyl group), (R)- 1-phenylpropyl group, (S) -1-phenylpropyl group, (R) -1-phenyl-2- (p-tolyl) ethyl group, (S) -1-phenyl-2- (p-tolyl) ethyl Group, (R) -1- (1-naphthyl) ethyl group, (S) -1- (1-naphthyl) ethyl group, (R) -1- (4-methoxyphenyl) ethyl group, (S) -1 -(4-methoxyphenyl) ethyl group, (R) -1- (4-chlorophenyl) ethyl group, (S) -1- (4-chlorophenyl) ethyl group, (R) -1- (4-nitrophenyl) Ethyl group, (S) -1- (4-nitrophenyl) ethyl group, (R) -1- (2,4-dichloro Phenyl) ethyl group, (S) -1- (2,4-dichlorophenyl) ethyl group, (R) -1- (2,4-dinitrophenyl) ethyl group, (S) -1- (2,4-dinitro) group Phenyl) ethyl group, (R) -1- (3,5-dichlorophenyl) ethyl group, (S) -1- (3,5-dichlorophenyl) ethyl group, (R) -1- (3,5-dinitrophenyl) 15) The compound according to any one of claims 12 to 14, which is an ethyl group or a (S) -1- (3,5-dinitrophenyl) ethyl group. The compound according to any one of claims 12 to 14, wherein R ³ is (R) -α-methylbenzyl group ((R) -1-phenylethyl group). The compound according to any one of claims 12 to 16, wherein R ¹ is an aralkyl group. The compound according to any one of claims 12 to 16, wherein R ¹ is a benzyl group. The following equation (1)

(Wherein, R ¹ represents a hydrogen atom or an amino-protecting group) in a compound represented by the formula R ² —NH ₂ (wherein R ² represents a hydrogen atom or an amino group or an imino group) in the presence of an acid. A compound represented by the formula (2):

(Wherein, R ¹ and R ² are each independently the same as described above). The following equation (2)

(Wherein R ¹ and R ² each independently represent a hydrogen atom or a protecting group for an amino group or an imino group), and a compound represented by the formula: MX _m L _n (where M is a periodic table 8) X is a hydrogen atom, a halogen atom, an alkoxy group, an alkenyl group or an aryl group, L is an optically active phosphine ligand, m is an integer of 0 to 6, n is 1 to 6 Wherein the reduction is carried out in the presence of an asymmetric catalyst represented by the formula (3):

(Wherein, R ¹ and R ² are the same as described above). The following equation (5)

(Wherein, R ¹ represents a hydrogen or amino-protecting group, and R ³ represents an amino or imino-protecting group having an asymmetric carbon atom). Equation (6)

(Wherein R ¹ and R ³ are the same as described above). 22. The method according to claim 21, wherein the reduction is reduction with a hydride ion. 23. The production method according to claim 22, wherein the reduction with hydride ions is a reduction with a reducing agent selected from a metal borohydride, a metal aluminum hydride, and a borane-based metal. The following equation (3)

(Wherein, R ¹ and R ² each independently represent a hydrogen atom or a protecting group for an amino group, provided that R ¹ and R ² are simultaneously a hydrogen atom). Formula (4) characterized by deprotecting

A method for producing an optically active compound represented by the formula: