JP2002255933A - Method for producing optically active 7-amino-5- azaspiro[2.4]heptane - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an optically active 7-amino-5- azaspiro[2.4]heptane which is a raw material for synthesizing antibacterial compounds. SOLUTION: This method for producing the 7-amino-5-azaspiro[2.4]heptane is characterized by reacting a compound represented by formula (1) (R<1> is H or an amino-protecting group) with a compound represented by the formula: R<2> -NH2 (R<2> is H or an amino-protecting group) in the presence of an acid, hydrogenating the produced compound represented by formula (2) (R<1> and R<2> are each independently the same as described above) in the presence of an asymmetric catalyst, and, if desired, removing the protecting group. The highly optically pure 7-amino-5-azaspiro[2.4]heptane having a high optical purity can be produced using a catalytic amount of the asymmetric source in a high yield.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD 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 antibacterial compounds.

[0002]

2. Description of the Related Art Optically active 7-amino-5-azaspiro [2.4] heptane is useful as an intermediate for producing an antibacterial compound (JP-A-2-231475, JP-A-5-231475).
221947). As a synthesis method thereof, a split crystallization method using racemic amines and an optically active acid has been proposed (JP-A-4-149174, JP-A-7-224).
No. 033). However, this method does not require one of the optically active isomers, and it is necessary to take measures such as a racemization reaction (JP-A-4-342565, JP-A-7-233146) in order to utilize the unnecessary isomer. there were.

[0003]

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

[0004]

The inventors of the present invention have conducted various studies and found that a ketone compound represented by the formula (1) was used as a raw material, and this was reacted with an amine compound in the presence of an acid to form a compound represented by the formula (2). An imine compound is produced and then reduced with hydrogen in the presence of an asymmetric catalyst to convert the compound into an optically active compound, and when this has a protective group, it is deprotected, so that the optically active 7-amino- It was found that 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)

[0006]

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[0007] (In the formula, R ^1. Indicating a hydrogen atom or a protective group for an amino group) into the compound represented by, in the presence of an acid, wherein R ² -NH ₂ (wherein, R ² is a hydrogen atom or an amino A compound represented by the formula (2):

[0008]

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(Wherein R ¹ and R ² are each independently the same as defined above) by the formula MX _m L _n (wherein M
Is a transition metal of Groups 8 to 10 of the periodic table, 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, and m and n are each an integer of 0 to 6 Is shown. ) In the presence of an asymmetric catalyst represented by the formula (3)

[0010]

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(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.

[0012]

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[0013] It is intended to provide a method for producing an optically active compound represented by the formula: The present invention also provides a method for producing the compound represented by the formula (2) and the compounds represented by the formulas (2) to (4).

[0014]

DETAILED DESCRIPTION OF THE INVENTION The optically active 7-amino- of the present invention.
5-Azaspiro [2.4] heptane (4) is produced by the following reaction route.

[0015]

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(Wherein R ¹ and R ² are the same as above)

When R ¹ and R ² are amino groups, the protective groups include t-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl and 2,2,2-trichloroethoxycarbonyl. Alkoxycarbonyl groups such as, benzyloxycarbonyl group, aralkyloxycarbonyl groups such as paramethoxybenzyloxycarbonyl group and paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group,
t-butyroyl group, acyl groups such as pivaloyl group and benzoyl group, benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, aralkyl groups such as paranitrobenzyl group and paramethoxybenzyl group, and the like.
Among these, an aralkyl group is preferred, and it is particularly preferred that R ¹ and R ² are simultaneously a benzyl group. Less than,
A description will be given for each reaction step.

Preparation of the 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. Boron trifluoride is particularly preferred. The amount of the acid used may usually be in the range of 1/1000 to 1 mole, preferably 1/100 to 1/2 mole, and particularly preferably 1/10 mole relative to the compound of the formula (1). It is preferable to use a solvent for the reaction, and there is no particular limitation as long as the solvent is inert to the reaction. Aromatic hydrocarbons such as benzene and toluene are preferred. The reaction temperature is
Although it depends on the kind of the acid and the solvent used, it may be carried out within a range from room temperature to the boiling point of the solvent.

Preparation of Optically Active Compound of Formula (3) The optically active compound of formula (3) is produced by catalytic reduction of the compound of formula (2) in the presence of an asymmetric catalyst. Asymmetric catalyst used in this reaction is represented by MX _m L _n, periodic table 8
A reaction product of a group 10 transition metal complex and an optically active phosphine in a solvent is isolated or used as it 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 used is 1/1000 to 1/100 with respect to the compound of the formula (2).
It may be in the range of 2 moles, preferably 1/100 to 1/5.
A 1-fold mole, particularly a 1 / 10-fold mole, is preferred.

Examples of the transition metal complexes of Groups 8 to 10 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 tetrafluoroborate, bis (norbornadiene) rhodium perchlorate, dichloro (1,5-cyclooctadiene) ruthenium, p-cymene ruthenium chloride dimer, benzene ruthenium chloride dimer, etc. However, chloro (1,5-cyclooctadiene) iridium dimer is particularly preferred.

The 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, 3
R-2,3-o-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane: DIOP, 2S, 3S- and 2R, 3R-2,3-
Bis (diphenylphosphino) butane: CHIRAPH
OS, 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: BPP
FOH, 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 can be used, but tol-BINAP is particularly preferred.

[0022]

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As the asymmetric catalyst, iridium- (tol
-BINAP) is preferred.

It is preferable to use a solvent for this reaction.
Alcohols, aromatic hydrocarbons, ethers, halogenated hydrocarbons and the like can be used, and preferred ones may be selected. Further, 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.

Preparation of Optically Active Compound of Formula (4) When R ¹ and / or R ² of the compound of formula (3) is an amino-protecting group, the compound of formula (4) is converted to hydrogen. ,
It is produced by reduction in the presence of a metal catalyst. As the metal catalyst, palladium carbon, palladium hydroxide,
Palladium-based catalysts such as palladium-barium sulfate are preferred. 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.

Although the route for asymmetric reduction after the preparation of the imine compound is shown here, it is necessary to treat the compound (1) and an amine compound, an acid and an asymmetric catalyst in a hydrogen atmosphere. These reactions can be performed all at once.

7-amino-produced by the process of the present invention
5-Azaspiro [2.4] heptane may be in the form of a salt such as an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid, or an organic acid such as substituted carboxylic acids and substituted sulfonic acids.

[0028]

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] heptane-7
To a solution of -one (1 g) and benzylamine (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 = 3.0,5.1Hz, 2H), 2.83 (s, 2H), 3.39 (s, 2H), 3.73 (s, 2
H), 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 ) Was added to a solution of R-tol-BINAP (67.9) in ethanol (4.5 mL).
mg) and stirred at room temperature for 2 hours to prepare a catalyst.
The autoclave was charged with N-benzyl-N- (5-benzyl-
A solution of 5-azaspiro [2.4] hept-7-ylidene) amine (290 mg) in ethanol (4.5 mL) and the prepared catalyst solution were charged, and a hydrogen pressure of 30 atm.
Stirred for 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 give N-benzyl-
187 mg of N- (5-benzyl-5-azaspiro [2.4] heptan-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 = 8.9,43.6Hz), 2.55 (dd, J
= 4.0,4.0Hz, 1H), 3.00-3.10 (m, 2H), 3.64 (d, J = 8.6Hz, 2
H), 3.71 (dd, J = 13.2, 43.6 Hz, 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) 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 when the ligand, the solvent and the additive were changed.

[0032]

[Table 1]

Example 9 7-Amino-5-azaspiro [2.4] heptane dihydrochloride N-benzyl-N- (5-benzyl-5-azaspiro [2.4] heptane-7-yl) amine [ 170 mg, 5
[3% 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 for 5 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate is 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% e was obtained. .
e. The absolute configuration was S-form.

[0034]

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. Further, the compound of the formula (2) is useful as an intermediate for producing an antibacterial compound.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Toshifumi Akiba 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo F-term in Tokyo Research & Development Center, Daiichi Pharmaceutical Co., Ltd. 4C204 AB20 BB04 CB10 DB31 EB02 FB01 GB01 4G069 AA06 BA27A BA27B BC65A BC69A BC70A BC71A BC74A BC74B BE03A BE04A BE04B BE26A BE27A BE27B BE37A BE37B BE46A BE46B CB57 4H006 AA02 AC80 AC81 4H039 CA71 CB30

Claims (11)

[Claims] 1. The following formula (1) (Wherein R ¹ represents a hydrogen atom or an amino-protecting group) in the presence of an acid in the presence of a compound represented by the formula R ^2-
A compound represented by NH ₂ (wherein R ² represents a hydrogen atom or an amino-protecting group) is reacted to obtain a compound of the formula (2) (Wherein R ¹ and R ² are each independently the same as described above), and a compound represented by the formula MX _m L _n (where M is the periodic table 8)
Group X to X transition metals, X represents a hydrogen atom, a halogen atom, an alkoxy group, an alkenyl group or an aryl group, L represents an optically active phosphine ligand, and m and n each represent an integer of 0-6. ) In the presence of an asymmetric catalyst represented by
The obtained formula (3) (Wherein, R ¹ and R ² are each independently the same as defined above), wherein the compound represented by the formula (4) is optionally deprotected. A method for producing an optically active compound represented by the formula: ^2. The amino-protecting group for R ¹ and R ² is an alkoxycarbonyl group, an aralkyloxycarbonyl group,
The method for producing an optically active compound according to claim 1, which is 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. 4. The method according to claim ^1, wherein R ¹ and R ² are benzyl groups.
4. The method for producing an optically active compound according to any one of items 3 to 3. 5. The following formula (2): (Wherein, R ¹ and R ² each independently represent a hydrogen atom or an amino-protecting group). 6. The compound according to claim 5, wherein the amino-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 an aralkyl group. 8. The method according to claim 5, wherein R ¹ and R ² are benzyl groups.
A compound according to any one of claims 1 to 7. 9. The following formula (1) (Wherein R ¹ represents a hydrogen atom or an amino-protecting group) in the presence of an acid in the presence of a compound represented by the formula R ^2-
Reacting a compound represented by NH ₂ (wherein R ² represents a hydrogen atom or a protecting group for an amino group), characterized by the following formula (2): (Wherein, R ¹ and R ² are each independently the same as described above). 10. The following formula (2) (Wherein R ¹ and R ² each independently represent a hydrogen atom or an amino-protecting group).
_m L _n (wherein, M is a transition metal of Groups 8 to 10 of the periodic table, 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 and wherein n is an integer of 0 to 6), wherein hydrogen reduction is carried out in the presence of an asymmetric catalyst represented by the following formula (3): (Wherein R ¹ and R ² are the same as described above). 11. The following formula (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 not simultaneously a hydrogen atom). ,
Formula (4) characterized by deprotection Production method of optical activity represented by