JP3134786B2 - 2-Azabicyclo [3.3.0] octane derivatives, their production and optical resolution of diols or amino alcohols - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a 2-azabicyclo [3.3.0] octane derivative useful as an optical resolving agent and a method for producing the same, and a method for optically resolving diols and amino alcohols using the same. About. The optically active diols and amino alcohols obtained by the method of the present invention are useful as synthetic intermediates for pharmaceuticals, agricultural chemicals, etc., or asymmetric catalysts and their raw materials.

[0002]

2. Description of the Related Art A known method for optically resolving racemic or meso-form diols and amino alcohols is to attach and detach a substituent in the presence of an enzyme or some asymmetric source. Examples of conventional optical resolution of diols and amino alcohols include 2,4-dimethylpentane-1,5
-Enzyme (Pig pancreatic lip)
ase) in the presence of monoacetate (J. Am.
Chem. Soc., 106, 3695 (1984)), cis-aziridine-
Example in which diacetate of 2,3-dimethanol was converted to monoacetate in the presence of an enzyme (Amano P) (Tetrahedron Le
tt., 31, 6663 (1990)) and examples of acetylation or benzoylation of cis-1,2-cyclohexanediol, cis-1,2-cyclopentanediol or meso-hydrobenzoin in the presence of an asymmetric phosphine catalyst. (J. Org.
Chem., 61, 430 (1996)). Further, as an optical resolution method for amino alcohols, a preferential crystallization method by forming a salt with an optically active organic acid is also a frequently used means.

[0003]

However, among the conventional methods, the method using an enzyme is not suitable for mass synthesis because the enzyme to be used is very expensive. Also,
Enzymes are substrate-specific and their generality is not uncommon. Moreover, only one side of the enantiomer can be obtained with high optical purity. In addition, the method using an asymmetric phosphine catalyst has a high asymmetric yield of 68% ee at the highest and is not practical. In addition, there are only three kinds of diols mentioned above, and there is a question about the generality of the substrate. Furthermore, in the preferential crystallization method of amino alcohols with an optically active organic acid, an equal amount of the optically active organic acid is required, and a complicated recrystallization step needs to be repeated, so that a reduction in yield cannot be avoided.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to find a method for inexpensively and in large quantities optical resolution of diols or amino alcohols.
The inventors have found that azabicyclo [3.3.0] octane derivatives are useful as the optical resolving agent, and have completed the present invention. That is, the present invention provides the following 2 represented by Formula 1
-Azabicyclo [3.3.0] octane derivatives. The present invention also relates to an optical resolution method for diols or amino alcohols using the 2-diazabicyclo [3.3.0] octane derivative, and a novel optically active monoacyl-1,2-diol obtained by the method. Kind of offer.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The 2-azabicyclo [3.
3.0] Octane derivatives are represented by the following formula 1.

Embedded image (Wherein, Ar represents an aryl group) The above compound is represented by the following formula 1-A

Embedded image (Wherein Ar is the same as described above) and its enantiomers.

To produce the 2-azabicyclo [3.3.0] octane derivative (1) of the present invention, for example, taking the case of the stereoisomer of formula 1-A as an example, the following formula 2

Embedded image (Where Ar is as defined above) is added to the racemic compound represented by the following formula 3

Embedded image Wherein Ar is the same as above, M is a lithium atom or a magnesium halide such as chloride, bromide,
A compound represented by the following formula 4

Embedded image (Ar is the same as described above) and then debenzylation to give the following formula 5

Embedded image (Ar is the same as above), and then one enantiomer is obtained by a preferential crystallization method by salt formation with an optically active organic acid, and further reacted with 4-chloropyridine in the presence of a base. .

The aryl group represented by Ar in the compound of the present invention includes a substituted or unsubstituted phenyl group, naphthyl group, anthracenyl group, phenanthryl group and the like. Of these, a naphthyl group is desirable, and
-A naphthyl group is particularly preferred. Examples of the substituent include a lower alkyl group such as a methyl group, an ethyl group and an isopropyl group, and a halogen atom such as chlorine and bromine. The method for producing the 2-azabicyclo [3.3.0] octane derivative of the present invention will be described more specifically. The compound of formula 2 is known and is known in the art [Tetrahedron Le
tt., 30, 5547 (1989)]. The compound represented by Formula 4 is obtained by reacting the compound represented by Formula 2 (racemic form) with the compound represented by Formula 3 in an organic solvent. An ordinary method is employed for debenzylating the compound represented by the formula 4 to obtain a compound represented by the formula 5, and for example, a method of catalytic hydrogenation in the presence of a palladium carbon catalyst is generally used. In order to optically resolve the obtained compound of the formula 5, a preferential crystallization method using salt formation with an optically active organic acid is used. The optically active organic acids used include, for example, (+)-or (-)-camphorsulfonic acid, (+)-or (-)-mandelic acid,
(+)-Or (-)-methoxytrifluoromethylphenylacetic acid, 2,3: 4,6-di-O-isopropylidene-2
-Keto-L-gulonic acid, among which (+)-or
(−)-Camphorsulfonic acid is particularly preferred. The optically resolved compound of the formula 5 is prepared in an organic solvent in the presence of a base.
Reaction with halogenopyridine affords the desired 2-azabicyclo [3.3.0] octane derivative. As the base used, trimethylamine, triethylamine, tri-
Amine bases such as n-butylamine and pyridine are particularly preferred. As the halogen atom of 4-halogenopyridine, chlorine, bromine and iodine are preferred.

According to the present invention, diols and amino alcohols can be optically resolved by using the 2-azabicyclo [3.3.0] octane derivative (1). That is, when a diol or an amino alcohol is treated with an acylating agent in the presence of, for example, a 2-azabicyclo [3.3.0] octane derivative represented by the formula 1-A or an enantiomer thereof, Since only the optically active substance is acylated and the other optically active substance remains as it is, by separating them, optically active diols or amino alcohols can be obtained. Hereinafter, the method for optical resolution of diols or amino alcohols according to the present invention will be described. These diols and amino alcohols include meso-2,3-butanediol, meso-3,4-hexanediol, meso-4,5-
Octanediol, mixture of 2R, 3S-2,3-pentanediol and its enantiomer, mixture of 2R, 3S-2,3-tridecanediol and its enantiomer, 4R, 5S-2-methyl-8-ethyl- A mixture of 4,5-decanediol and its enantiomer, meso-hydrobenzoin, cis-cyclopropanediol, cis-1,2-cyclobutanediol, cis-1,2-cyclopentanediol, cis-1,
2-cyclohexanediol, cis-1,2-cycloheptanediol, cis-1,2-cyclooctanediol, cis-1,2-cyclononanediol, 1,1′-bi-2-naphthol, 2-hydroxymethyl Pyrrolidine,
2- (hydroxydiphenylmethyl) pyrrolidine, 2-
Hydroxymethylpiperidine, 1-amino-2-propanol, 2-amino-1-propanol and the like can be mentioned. These diols and amino alcohols may be monoacylated or non-acylated. First, the case of optically resolving non-acylated diols or amino alcohols will be described. The diols or amino alcohols are dissolved or suspended in an organic solvent, and the 2-azabicyclo [3.3.0] octane derivative is added thereto. (1-A) or an enantiomer thereof is dissolved, an acylating agent is added in the presence of an amine base, and the mixture is treated by an ordinary method to obtain an optically active non-acylated diol or an amino alcohol and an optically active monoacylated diol or It can be divided into amino alcohols.

Examples of the organic solvent include chlorine solvents such as dichloromethane, hydrocarbon solvents such as hexane, aromatic solvents such as toluene, ether solvents such as diethyl ether and tetrahydrofuran, nitrile solvents such as acetonitrile, N, N, and the like. Non-protic polar solvents such as N-dimethylformamide and dimethyl sulfoxide are exemplified, and among them, aromatic solvents and chlorine solvents are particularly preferable. The amount of the 2-azabicyclo [3.3.0] octane derivative used is 0.3% based on the diol or amino alcohol.
It is preferably from 1 to 50 mol%, particularly preferably from 1 to 15 mol%. Sufficient optical purity can be obtained with 1 mol% or more, but no remarkable improvement in optical purity is observed even when 15 mol% or more is used. As the acylating agent, a general-purpose acylating agent is preferable because it is inexpensive. For example, benzoic anhydride, acetic anhydride, n-pentanoic anhydride, isobutanoic anhydride, carboxylic anhydride such as pivalic anhydride, or benzoic anhydride There are carboxylic acid halides such as acid chloride, benzoic acid bromide, acetic acid chloride, acetic acid bromide, n-pentanoic acid chloride, n-pentanoic acid bromide, isobutanoic acid chloride, and isobutanoic acid bromide. Acid anhydrides are particularly preferred. The amount of the acylating agent to be used is preferably 0.4 to 1.0 equivalent to diol or amino alcohol. Examples of the base used include amine bases such as triethylamine, pyridine, diazabicycloundecene, collidine, 4-N, N-dimethylaminopyridine, and collidine is particularly preferred. The dose of this base is preferably 1.0 to 1.5 equivalents to the diol or amino alcohol. The reaction temperature is preferably as low as possible, particularly preferably from -78 ° C to 50 ° C.

Next, the case where the monoacylated diol or amino alcohol is optically resolved will be described. Examples of the monoacylated diol or amino alcohol include the isobutyrate, pivalate, benzoate, 4-methoxybenzoate, 4-N, N-dimethylaminobenzoate and the like of the diol or amino alcohol, and particularly preferably N, N- It is dimethylaminobenzoate or 4-methoxybenzoate. In the case of monoacylated amino alcohols, either the hydroxyl group or the amino group may be acylated. Further, in the case of amino alcohols, in addition to the above acyl group, the amino group may be a usual protecting group, for example, t-
Those protected with a butyloxycarbonyl group are likewise preferred. By treating these monoacylated diols or amino alcohols in the same manner as in the case of the non-acylated product, optically active monoacylated diols or amino alcohols and optically active diacylated diols or amino alcohols can be separated. As the organic solvent, a chlorine-based solvent such as dichloromethane, a hydrocarbon-based solvent such as hexane, an aromatic solvent such as toluene, an ether-based solvent such as diethyl ether and tetrahydrofuran,
Examples thereof include nitrile solvents such as acetonitrile, and aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide. Among them, aromatic solvents and chlorine solvents are particularly preferable.

2-Azabicyclo [3.3.0] used
The amount of the octane derivative (1-A) or its enantiomer is from 0.1 to 50 relative to the diol or amino alcohol.
mol% is preferred, and particularly preferably 1 to 15 mol.
%. Sufficient optical purity can be obtained with 1 mol% or more, but no remarkable improvement in optical purity is observed even when 15 mol% or more is used. As the acylating agent, the same as those in the case of the non-acylated compound can be mentioned, but the amount used is
The amount is preferably 0.4 to 0.9 equivalent based on the monoacylated diol or amino alcohol. If it is 0.9 equivalent or more, the yield of the remaining monoacyl compound having high optical purity is extremely low, which is not preferable. Examples of the base used include amine bases such as triethylamine, pyridine, diazabicycloundecene, collidine, 4-N, N-dimethylaminopyridine, and collidine is particularly preferred. The amount used is preferably 1.0 to 1.5 equivalents to the monoacylated diol or amino alcohol.
The reaction temperature is preferably as low as possible, particularly preferably-
78 ° C to 50 ° C.

Among the optically active substances obtained by the above method,
Optically active monoacylated diols include novel compounds. Thus, the present invention also provides a novel optically active monoacyl-1,2-diol derivative represented by the following formula 8 or an enantiomer thereof.

Embedded image (Wherein, R ¹ and R ² represent a linear or branched alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted aryl group, and R ¹ and R ² are combined to form a ring X represents a dimethylamino group or a methoxy group) Examples of the monoacyl-1,2-diols include various diols, for example, meso-2,3-butanediol and meso-3,4-hexane. Diol, meso-4,5-octanediol, a mixture of (2R, 3S) -2,3-pentanediol and its enantiomer, a mixture of (2R, 3S) -2,3-tridecanediol and its enantiomer, (4R, 5S) -2
-Methyl-8-ethyl-4,5-decanediol and a mixture of its enantiomers, meso-hydrobenzoin, cis-cyclopropanediol, cis-1,2-cyclobutanediol, cis-1,2-cyclopentanediol, Cis-
Monoacyl compounds such as 1,2-cyclohexanediol, cis-1,2-cycloheptanediol, cis-1,2-cyclooctanediol, and cis-1,2-cyclononanediol are included. Examples of the acyl include acyl of 4-dimethylaminobenzoic acid and 4-methoxybenzoic acid. To produce a racemic monoacyl-1,2-diol derivative, when X is a dimethylamino group, an equimolar amount of 4-N, N-dimethylaminobenzoic acid with the above diol is used in the presence of a dehydrating condensing agent. A method of reacting under the following conditions is generally used, and when X is a methoxy group, a method of reacting the diol with an equimolar amount of 4-methoxybenzoic halide in the presence of a base is generally used,
You are not limited to those methods.

[0013]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. Example 1 8β-hydroxy-8α- (β-naphthylmethyl) -2
Synthesis of-(4-pyridyl) -2-azabicyclo [3.3.0] octane (compound represented by the following formula 8a)

Embedded image (1) Synthesis of 8β-hydroxy-8α- (β-naphthylmethyl) -2-benzyl-2-azabicyclo [3.3.0] octane (a compound represented by the following formula 6) (racemic form).

Embedded image 22.8 g (0.16 mol) of β-methylnaphthalene was dissolved in 200 ml of tetrahydrofuran, cooled to 0 ° C., an equal amount of n-butyllithium was added, and the mixture was stirred for 5 hours. After adding 8.6 g (0.04 mol) of the compound represented by the formula 2 at 0 ° C. and stirring for 2 hours, the unreacted lithium reagent is crushed with a small amount of water, extracted with dichloromethane, washed with a saturated saline solution, and washed with an organic solvent. The layer was dried over anhydrous sodium sulfate. filtration,
After concentration, the residue was purified by silica gel column chromatography (hexane / diethyl ether = 75: 25). The yield was 11.9 g, and the yield was 83%. ¹ H-NMR (200 MHz, CDCl ₃ , TMS) δppm: 1.20-2.00 (m, 6
H), 2.20-2.90 (m, 4H), 2.9-3.1 (m, 3H), 3.35 (d, 1
H, J = 15.0Hz), 3.85 (d, 1H, J = 15.0Hz), 7.00-7.90
(m, 12H)

(2) Synthesis of 8β-hydroxy-8α- (β-naphthylmethyl) -2-azabicyclo [3.3.0] octane (compound represented by the following formula 7) (racemic form)

Embedded image 12.96 g of the compound obtained in the above (1) was dissolved in 100 ml of methanol, and 1.92 ml of acetic acid and 20% Pd (O
H) Catalytic hydrogenation was performed by adding 1.2 g of _2- C. After completion of the reaction, the reaction solution was filtered, and methanol was distilled off under reduced pressure. A 1N aqueous solution of sodium hydroxide was added, extracted with dichloromethane, washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration, 9.3 g of a compound represented by the formula 7 was obtained. The crude yield was 96%. ¹ H-NMR (200 MHz, CDCl ₃ , TMS) δppm: 1.38-1.62 (m, 2
H), 1.62-1.88 (m, 4H), 2.57-2.90 (m, 5H), 3.03 (d,
1H, J = 13.0Hz), 3.50 (d, 1H, J = 8Hz), 7.41-7.49
(m, 3H), 7.68-7.82 (m, 4H).

(3) Optical resolution of the compound represented by the formula (7) 4.75 g (0.018 mol) of the compound obtained in the above (2)
l) and 4.13 g of (-)-camphorsulfonic acid (0.0
18mol) was dissolved in isopropyl alcohol and recrystallized three times to obtain 2.23 g of a salt. The salt was added to a 1N aqueous solution of sodium hydroxide, stirred well, extracted with dichloromethane, washed with saturated saline, and dried over anhydrous sodium sulfate. Filtration, concentration, optically pure (+)
-8β-hydroxy-8α- (β-naphthylmethyl)-
1.10 g of 2-azabicyclo [3.3.0] octane was obtained. Some of them were converted to N-benzoyl and analyzed by Daicel's Chiral Pack AS.
It was 00% ee. [α] _D ²⁰ + 14.32 ° (c 1.019, CHCl ₃ )

(4) Synthesis of compound represented by formula 8a 1.10 g (4.1 mmol) of the compound obtained in the above (3)
l) was dissolved in 15 ml of dimethylsulfoxide, 2.33 g (20.5 mmol) of 4-chloropyridine and tri-n
After adding 1.95 ml of -butylamine and stirring at 150 ° C overnight, dimethylsulfoxide and tri-n-butylamine were distilled off under reduced pressure. A 1N aqueous solution of sodium hydroxide was added to the residue, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography (chloroform: methanol: triethylamine = 95: 5: 0.5). The yield was 541 mg and the yield was 40%. ¹ H-NMR (400 MHz, CDCl ₃ , TMS) δppm: 1.56-1.59 (m, 2
H), 1.81-1.88 (m, 3H), 2.08-2.17 (m, 1H), 2.30 (br
s, 1H), 2.90-2.91 (m, 1H), 3.03 (d, 1H, J = 14.0H
z), 3.20 (d, 1H, J = 14.0Hz), 3.97 (d, 1H, J = 8.0
Hz), 6.37 (d, 2H, J = 6.4Hz), 7.43-7.48 (m, 3H),
7.73 (s, 1H), 7.78-7.84 (m, 3H), 8.02 (d, 2H, J =
6.4Hz).

Example 2 Optical Resolution of Nt-Butyloxycarbonyl-2-hydroxymethylpiperazine 103 mg of the racemate of the title compound under a stream of argon
(0.48 mmol), 8.3 m of the compound of formula 8a
g (94% ee, 5 mol%) was dissolved in 3 ml of carbon tetrachloride, 0.063 ml (0.48 mmol) of collidine was added, and then 0.056 ml (0.34 mm) of isobutanoic anhydride was added.
ol) and stirred at 0 ° C. for 4.5 hours. Add 0.
1N Hydrochloric acid was added, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, and then dried over anhydrous sodium sulfate. After filtration and concentration, the product was purified by preparative thin-layer chromatography (hexane / ethyl acetate = 1/1) to obtain 25 mg (24%) of optically active Nt-butyloxycarbonyl-2-hydroxymethylpiperazine, and 85 mg of Nt-butyloxycarbonyl-2-hydroxymethylpiperazine isobutyrate (60 mg
%). The optical purity of the obtained optically active form of the title compound was 74% ee according to HPLC analysis of the benzoyl form.
Met. It has the following physical properties. ¹ H-NMR (200 MHz, CDCl ₃ , TMS) δppm: 1.45 (s, 9H), 1.
60 (m, 6H), 2.40 (m, 2H), 2.85 (m, 1H), 3.60 (dd, 1
H, J = 15.0, 5.0Hz), 3.70 (m, 1H), 3.95 (m, 1H),
4.3 (m, 1H).

Example 3 Optical resolution of cis-2- (4-N, N-dimethylaminobenzoyloxy) cyclopentanol 124 mg of the racemic title compound under a stream of argon.
(0.50 mmol) and the compound 8.a of the formula 8a.
6 mg (5 mol%) was dissolved in 3 ml of toluene, 0.066 ml (0.50 mmol) of collidine was added, and then 0.058 ml (0.35 mmol) of isobutanoic anhydride was added, followed by stirring at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by preparative thin-layer chromatography (hexane / ethyl acetate = 1/1) to give the title compound (1S, 2).
R) -form, that is, (1S, 2R) -cis-2- (4-N,
29 mg (23%) of (N-dimethylaminobenzoyloxy) cyclopentanol and (1R, 2S) -cis-
2- (4-N, N-dimethylaminobenzoyloxy)
97 mg (61%) of cyclopentanol isobutyrate
I got The optical purity of the (1S, 2R) form of the obtained title compound was 97% ee according to HPLC analysis. It has the following physical properties. [α] _D ²⁰ -10.03 ゜ (c 1.375, CHCl ₃ ) ¹ H-NMR (200 MHz, CDCl3, TMS) δppm: 1.55-2.08 (m, 6
H), 2.30 (brs, 1H), 3.04 (s, 6H), 4.28 (dd, 1H, J =
9.9, 5.1Hz), 5.13 (dd, 1H, J = 11.7, 5.1Hz), 6.64
(d, 2H, J = 9.2Hz), 7.92 (d, 2H, J = 9.2Hz)

Example 4 Optical resolution of cis-2- (4-N, N-dimethylaminobenzoyloxy) cyclohesanol 132 mg of the racemic compound of the title compound under a stream of argon
(0.50 mmol) and the compound 8.a of the formula 8a.
6 mg (5 mol%) was dissolved in 3 ml of toluene, 0.066 ml (0.50 mmol) of collidine was added, and then 0.058 ml (0.35 mmol) of isobutanoic anhydride was added, followed by stirring at room temperature for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by preparative thin-layer chromatography (hexane / ethyl acetate = 1/1) to give the title compound (1
R, 2S) form, that is, (1R, 2S) -cis-2- (4
-N, N-dimethylaminobenzoyloxy) cyclohexanol 29 mg (22%) and (1S, 2R)-
97 mg of cis-2- (4-N, N-dimethylaminobenzoyloxy) cyclohexanol isobutyrate (5 mg
8%). The optical purity of the (1R, 2S) form of the obtained title compound was 100% ee according to HPLC analysis. It has the following physical properties. [α] _D ²⁰ −6.78 ゜ (c 1.375, CHCl ₃ ) ¹ H-NMR (200 MHz, CDCl ₃ , TMS) δppm: 1.35-2.02 (m, 8
H), 2.16 (brs, 1H), 3.05 (s, 3H), 3.95 (m, 1H), 5.1
7 (dt, 1H, J = 7.4, 2.9Hz), 6.66 (d, 2H, J = 9.2H
z), 7.93 (d, 2H, J = 9.2Hz)

Example 5 Optical resolution of cis-2- (4-N, N-dimethylaminobenzoyloxy) cycloheptanol 142 mg of the racemic compound of the title compound under a stream of argon
(0.50 mmol) and the compound 8.a of the formula 8a.
6 mg (5 mol%) was dissolved in 3 ml of toluene, 0.066 ml (0.50 mmol) of collidine was added, and then 0.058 ml (0.35 mmol) of isobutanoic anhydride was added, followed by stirring at room temperature for 3.8 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by preparative thin-layer chromatography (hexane / ethyl acetate = 1/1) to give the title compound (1
R, 2S) form, that is, (1R, 2S) -cis-2- (4
-N, N-dimethylaminobenzoyloxy) cycloheptanol 28 mg (20%) and (1S, 2R)-
Cis-2- (4-N, N-dimethylaminobenzoyloxy) cycloheptanol isobutyrate 105 mg
(59%). (1R, 2) of the obtained title compound
S) The optical purity of the compound was 93% ee according to HPLC analysis. It has the following physical properties. [α] _D ²⁰ +8.43 ゜ (c 1.095, CHCl ₃ ) ¹ H-NMR (200 MHz, DCCl ₃ , TMS) δppm: 1.40-1.90 (m, 7
H), 2.05-2.15 (m, 1H), 2.60 (brs, 1H), 3.05 (s, 6
H), 4.05 (m, 2H), 5.20 (m, 2H), 6.65 (d, 2H, J =
9.0Hz), 7.90 (d, 2H, J = 9.0Hz)

Example 6 Optical Resolution of cis-2- (4-N, N-dimethylaminobenzoyloxy) cyclootanol Under a stream of argon, 96 mg of a racemic form of the title compound was obtained (0.1 mg).
33 mmol) and 5.7 m of the compound of formula 8a
g (5 mol%) was dissolved in toluene (3 ml), collidine (0.044 ml, 0.33 mmol) was added, and isobutanoic anhydride (0.038 ml, 0.23 mmol) was added, followed by stirring at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by preparative thin-layer chromatography (hexane / ethyl acetate = 3/2) to give an optically active form of the title compound, ie, optically active cis-2- (4-N, N-dimethylaminobenzoyl). 34 mg of (oxy) cyclooctanol (2
1%) and 100 mg (56%) of optically active cis-2- (4-N, N-dimethylaminobenzoyloxy) cyclooctanol isobutyrate. According to HPLC analysis, the optical purity of the obtained optically active compound of the title compound was 92%.
% Ee. It has the following physical properties. [α] _D ²⁰ +14.79 (c 0.91, CHCl ₃ ) ¹ H-NMR (200 MHz, CDCl ₃ , TMS) δppm: 1.60-2.20 (m, 1
2H), 3.03 (s, 6H), 4.07 (m, 1H), 5.26 (dt, 1H, J =
9.0, 2.2Hz), 6.64 (d, 2H, J = 9.1Hz), 7.91 (d, 2
(H, J = 9.1Hz)

Example 7 Optical resolution of a mixture of (2R, 3S) -3- (4-N, N-dimethylaminobenzoyloxy) -2-butanol and its enantiomer 121 mg (0.51 mm) of the title mixture under a stream of argon.
ol) and 8.8 mg (5 m
ol%) was dissolved in 3 ml of toluene, and collidine 0.06 was dissolved.
After adding 7 ml (0.50 mmol), 0.059 ml (0.35 mmol) of isobutanoic anhydride was added, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration,
The product was purified by preparative thin-layer chromatography (hexane / ethyl acetate = 1/1) to give 19 mg of an optically active form of the title compound, ie, optically active 3- (4-N, N-dimethylaminobenzoyloxy) -2-butanol. (16%) and its enantiomer, isobutyrate compound 107 mg (70 mg).
%). The optical purity of the obtained optically active substance of the title compound was 92% ee according to HPLC analysis. It has the following physical properties. [α] _D ²⁰ -7.52 ゜ (c 0.780, CHCl ₃ ) ¹ H-NMR (200 MHz, CDCl ₃ , TMS) δppm: 1.23 (d, 3H, J
= 6.5Hz), 1.32 (d, 3H, J = 6.6Hz), 2.28 (brs, 1H),
3.04 (s, 6H), 3.99 (dq, 1H, J = 6.6, 3.1Hz), 6.65
(d, 2H, J = 9.1Hz), 7.92 (d, 2H, J = 9.1Hz)

Example 8 Optical resolution of cis-2- (4-methoxybenzoyloxy) cyclopentanol Racemic compound of the title compound (118 mg) under a stream of argon.
(0.50 mmol) and the compound 8.a of the formula 8a.
6 mg (5 mol%) was dissolved in 3 ml of toluene, 0.066 ml (0.50 mmol) of collidine was added, and then 0.058 ml (0.35 mmol) of isobutanoic anhydride was added, followed by stirring at room temperature for 2.8 hours. The reaction mixture was added with 0.1N hydrochloric acid, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by preparative thin-layer chromatography (hexane / ethyl acetate = 3/2) to give the (1S, 2R) -form of the title compound, ie, (1S, 2R) -cis-
31 mg (26%) of 2- (4-methoxybenzoyloxy) cyclopentanol and 96 mg (63%) of (1R, 2S) -cis-2- (4-methoxybenzoyloxy) cyclopentanol isobutyrate were obtained. The optical purity of the (1S, 2R) form of the obtained title compound was determined by HPLC.
According to analysis, it was 79% ee. It has the following physical properties. [α] _D ²⁰ -8.02 ゜ (c 1.366, CHCl ₃ ) ¹ H-NMR (200 MHz, CDCl ₃ , TMS) δppm: 1.59-2.11 (m, 6
H), 2.19 (brs, 1H), 3.86 (s, 3H), 4.30 (dd, 1H, J =
9.7, 5.2Hz), 5.21 (dd, 1H, J = 9.7, 4.6Hz), 6.93
(d, 2H, J = 9.1Hz), 8.00 (d, 2H, J = 9.1Hz)

Example 9 Optical resolution of cis-2- (4-methoxybenzoyloxy) cyclohexanol 116 mg of the racemic form of the title compound under a stream of argon
(0.50 mmol) and the compound 8.a of the formula 8a.
6 mg (5 mol%) was dissolved in 3 ml of toluene, 0.066 ml (0.50 mmol) of collidine was added, and then 0.058 ml (0.35 mmol) of isobutanoic anhydride was added, followed by stirring at 0 ° C. for 2 hours. The reaction mixture was added with 0.1N hydrochloric acid, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by preparative thin-layer chromatography (hexane / ethyl acetate = 3/2) to give the (1R, 2S) -form of the title compound, ie, (1R, 2S) -cis-
31 mg (27%) of 2- (4-methoxybenzoyloxy) cyclohexanol and (1S, 2R) -cis-
91 mg (62%) of the 2- (4-methoxybenzoyloxy) cyclohexanol isobutyrate compound were obtained.
The optical purity of the obtained optically active form of the title compound was determined by HPLC.
Analysis showed 94% ee. It has the following physical properties. [α] _D ²⁰ -10.94 ゜ (c 1.413, CHCl ₃ ) ¹ H-NMR (200 MHz, CDCl ₃ , TMS) δppm: 1.41-2.03 (m, 8
H), 2.14 (brs, 1H), 3.86 (s, 3H), 3.92-3.97 (m, 2
H), 5.20 (dt, 2H, J = 7.6, 3.0Hz), 6.94 (d, 2H, J =
9.0Hz), 8.02 (d, 2H, J = 9.0Hz)

Example 10 Optical Resolution of cis-2- (4-methoxybenzoyloxy) cycloheptanol 131 mg of the racemic compound of the title compound under a stream of argon
(0.50 mmol) and the compound 8.a of the formula 8a.
6 mg (5 mol%) was dissolved in 3 ml of toluene, 0.066 ml (0.50 mmol) of collidine was added, and then 0.058 ml (0.35 mmol) of isobutanoic anhydride was added, followed by stirring at 0 ° C. for 5 hours. The reaction mixture was added with 0.1N hydrochloric acid, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by preparative thin-layer chromatography (hexane / ethyl acetate = 3/2) to give the (1R, 2S) -form of the title compound, ie, (1R, 2S) -cis-
41 mg (31%) of 2- (4-methoxybenzoyloxy) cycloheptanol and (1S, 2R) -cis-
100 mg (60%) of 2- (4-methoxybenzoyloxy) cycloheptanol isobutyrate were obtained. The optical purity of the (1R, 2S) form of the obtained title compound is HPL
According to C analysis, it was 79% ee. It has the following physical properties. [α] _D ²⁰ +2.79 ゜ (c 1.655, CHCl ₃ ) ¹ H-NMR (200 MHz, DCCl ₃ , TMS) δppm: 1.46-2.15 (m, 1
0H), 2.52 (brs, 1H), 3.86 (s, 3H), 4.07 (m, 1H), 5.
23 (dt, 1H, J = 8.3, 2.3Hz), 6.93 (d, 2H, J = 8.5H
z), 8.00 (d, 2H, J = 8.5Hz)

Example 11 Optical Resolution of cis-2- (4-methoxybenzoyloxy) cyclooctanol 139 mg of the racemic title compound under an argon stream.
(0.50 mmol) and the compound 8.a of the formula 8a.
6 mg (5 mol%) was dissolved in 3 ml of toluene, 0.066 ml (0.50 mmol) of collidine was added, and then 0.058 ml (0.35 mmol) of isobutanoic anhydride was added, followed by stirring at 0 ° C. for 5.7 hours. . The reaction mixture was added with 0.1N hydrochloric acid, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by preparative thin-layer chromatography (hexane / ethyl acetate = 3/2) to give an optically active form of the title compound, ie, optically active cis-2- (4-methoxybenyloxy) cyclooctanol. 42mg
(31%) and optically active cis-2- (4-methoxybenyloxy) cyclooctanol isobutyrate 9
4 mg (59%) were obtained. The optical purity of the obtained optically active form of the title compound was 71% ee according to HPLC analysis. It has the following physical properties. [α] _D ²⁰ +11.10 ゜ (c 1.405, CHCl ₃ ) ¹ H-NMR (200 MHz, CDCl ₃ , TMS) δppm: 1.49-2.20 (m, 1
2H), 2.39 (brs, 1H), 3.86 (s, 3H), 4.07 (m, 1H), 5.
29 (dt, 1H, J = 9.1, 2.2Hz), 6.93 (d, 2H, J = 9.0H
z), 8.00 (d, 2H, J = 9.0Hz)

[0027]

By using the 2-azabicyclo [3.3.0] octane derivative of the present invention, optically active diols or amino alcohols can be produced in large quantities at low cost. In addition, since the compound of the present invention can easily obtain its enantiomer, both enantiomers of diols and amino alcohols can be obtained.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI C07C227 / 34 C07C227 / 34 229/60 229/60 // C07M 7:00 (58) Field surveyed (Int.Cl. ⁷ C07D 401/04 C07B 53/00 C07B 57/00 350 C07C 67/48 C07C 69/92 C07C 227/34 C07C 229/60 C07M 7:00 CA (STN) REGISTRY (STN)

Claims (10)

(57) [Claims] (1) The following formula (1): (Ar represents an aryl group) 2-azabicyclo [3.3.0] octane derivative. 2. The 2-azabicyclo [3.3.0] octane derivative according to claim 1, wherein Ar in the formula 1 is a β-naphthyl group. 3. The following formula 2 In the racemic form of the compound represented by the following formula 3, (Ar represents an aryl group, M represents a lithium atom or a magnesium halide), and the compound represented by the following formula 4 (Ar represents an aryl group), which is debenzylated to give the following formula 5 (Ar represents an aryl group), and then one enantiomer is obtained by preferential crystallization by salt formation with an optically active organic acid, and further reacted with 4-halogenopyridine in the presence of a base. Formula 1-A characterized by the following: And a process for producing a 2-azabicyclo [3.3.0] octane derivative represented by the formula: 4. A racemic mixture of a diol or an amino alcohol is treated with an acylating agent in the presence of a catalytic amount of a compound represented by the formula 1-A or an enantiomer thereof to convert one of the optically active compounds into an acyl group. An optical resolution method for diols or amino alcohols, which comprises separating the other optically active diol or amino alcohol which is not acylated. 5. A method of treating a mono-acylated racemic mixture of a diol or aminoalcohol with an acylating agent in the presence of a catalytic amount of a compound of formula 1-A or an enantiomer thereof to produce one of the optics. An optical resolution method for diols or amino alcohols, which comprises acylating the active form and separating the other non-acylated optically active monoacylated diol or amino alcohol. 6. The monoacylated diol or amino alcohol is a diol or amino alcohol 4-N, N-dimethylaminobenzoate or 4-methoxybenzoate selected from alkanediol, cycloalkanediol and azacycloalkylmethanol. An optical resolution method for a diol or an amino alcohol according to claim 5. 7. The method for optical resolution of diols or amino alcohols according to claim 4, wherein the acylating agent is a carboxylic anhydride. 8. The method for optical resolution of diols or amino alcohols according to claim 4, wherein the acylating agent is isobutanoic anhydride. 9. The amino alcohol of claim 5, wherein the amino group is protected with a t-butyloxycarbonyl group.
Or the optical resolution method for amino alcohols according to 8. 10. The method for optical resolution of a diol or amino alcohol according to claim 4, wherein the diol or amino alcohol is a 1,2-substituted diol or amino alcohol.