JP4962845B2 - Process for producing optically active cyclic amino alcohol - Google Patents

Description

  The present invention relates to a method for producing an optically active cyclic amino alcohol. Optically active cyclic amino alcohols are useful compounds as pharmaceutical intermediates, agricultural chemical intermediates, liquid crystal materials, and perfumes.

As a method for synthesizing an optically active nitrogen-containing cyclic alcohol characterized by converting a carbon-carbon double bond to a hydroxyl group, a method via a hydroboration reaction is known. For example, synthesis of optically active N-substituted-3-pyrrolidinol by asymmetric hydroboration followed by oxidation using diisopinocinfeylborane synthesized from BH ₃ .S (CH ₃ ) ₂ or the like (Non-patent Document 1). , 2, 3). In addition, as for the optically active N-substituted-3-pyrrolidinol derivative synthesis method, a report example synthesized through an oxidation step after the reaction of these organic boron compounds and a carbon-carbon double bond can be seen (Patent Document 1). No example of adding alcohol after the oxidation reaction is known.
JP 2005-120067 A Journal of Organic Chemistry. , 51, 4296, (1986), Journal of American Chemical Society. , 108.2049 (1986), Heterocycles, 28, 1,283 (1989)

  In any of the above cases, the raw material nitrogen-containing cyclic olefin is oxidized with hydrogen peroxide under basic conditions to obtain the corresponding optically active cyclic amino alcohol. In the case of the attached nitrogen-containing cyclic olefin, it was found that hydrolysis after the oxidation reaction does not proceed sufficiently in normal oxidation treatment, and optically active cyclic amino alcohols such as optically active pyrrolidinol may be obtained only in a low yield. It was.

  An object of the present invention is to provide an industrial production method capable of efficiently obtaining an optically active cyclic amino alcohol having high optical purity in producing an optically active cyclic amino alcohol.

  The present inventors diligently studied a method for producing an optically active cyclic amino alcohol using a nitrogen-containing cyclic olefin as a raw material, and completed the present invention.

That is, the present invention is “the following three steps,
(First step) Optically active dialkylborane and general formula (1)

(Wherein R ¹ and R ² represent an aryl group, which may be the same or different. In the formula, n represents any one of 1 to 3). Reacting olefins,
(Second step) An oxidation step of reacting the reaction solution obtained in the first step with an oxidizing agent,
(Third step) General formula (2) characterized by including a decomposition step of decomposing boric acid triester by adding alcohol to the reaction solution obtained in the second step.

(In the formula, R ¹ and R ² represent an aryl group, and may be the same or different. In the formula, n represents an integer of 1 to 3, and * represents an asymmetric carbon.) Is a process for producing an optically active cyclic amino alcohol represented by

  An optically active cyclic amino alcohol that can be obtained only in a low yield by ordinary oxidation treatment can also be obtained in a high yield and high optical purity.

  The present invention will be described in detail below.

  The production method of the present invention includes the three steps described above.

  The general production of the optically active dialkylborane is carried out as follows. An example using optically active α-pinene is given as an example. After optically active α-pinene is added to tetrahydrofuran, sodium borohydride is subsequently added, and finally trifluoroborane or sulfuric acid is added dropwise to prepare optically active dialkylborane. Such a synthesis method includes optically active bicyclic monoterpenes such as optically active 2-carene, in addition to diisopinocampheylborane using the optically active α-pinene mentioned as an example of optically active dialkylborane. The present invention can also be applied to optically active dialkylboranes such as the optically active bis (2-isocaranyl) borane used.

  When carried out in accordance with the above-described method for synthesizing optically active dialkylborane, dialkylborane is generated in the system via monoalkylborane. At this time, since an equilibrium exists between the monoalkylborane and the dialkylborane, the reaction solution is a mixture of the monoalkylborane and the dialkylborane. It is dialkylborane that exhibits high stereoselectivity, and monoalkylborane has low stereoselectivity.

  When used as an optically active dialkylborane in the present invention, a mixture of dialkylborane, monoalkylborane and borane prepared by the above method can be used as it is.

  Solvents used for the production of optically active dialkylborane include, as specific examples, aliphatic ethers such as tetrahydrofuran, diglyme, dimethoxyethane, triglyme and tetrahydropyran, aromatic ethers such as anisole and ethoxybenzene, hydrocarbons such as benzene and xylene, Examples thereof include halogenated hydrocarbons such as chloroform, dichloromethane, and carbon tetrachloride. Preferred are aliphatic ethers and aromatic ethers, and more preferred are aliphatic ethers.

  Next, a specific method for synthesizing diisopinocinfeylborane that is preferably used in that the effect of the present invention is particularly remarkable will be described.

In general, an activator is added to a mixture containing α-pinene and sodium borohydride. Here, the order in which the raw materials are charged is not limited, and α-pinene may be added last. Preferably, the activator is added last, and the property of the mixed solution may be a slurry. good. The addition temperature when adding the activator is preferably 20 ° C to -30 ° C, more preferably -10 ° C to 10 ° C. The stirring temperature after adding the activator is preferably 0 ° C to 30 ° C, more preferably 5 ° C to 25 ° C. The stirring time is preferably 3 hours to 48 hours, more preferably 5 hours to 24 hours.
The optical rotation of α-pinene used in the present invention may be either (+) or (−), and its optical purity is 50% ee. The optical purity is preferably 70% ee. Or more, more preferably 80% ee. That's it. The amount of α-pinene added is preferably at least 4 mole times that of the pyrroline derivative.

  The shape of sodium borohydride used in the present invention is not particularly limited, and various particle sizes from fine powder to granular can be used. The method for adding sodium borohydride is not limited, and may be added after diluting with a solvent, or may be added as it is without diluting. Further, the addition amount of sodium borohydride is preferably 1.5 mol times or more with respect to the pyrroline derivative.

  The activator used in the present invention may be any one that activates sodium borohydride to generate diborane, and is selected from boron halides, mineral acids, sulfonic acids, and alkyl acids. It is preferable to include at least one. Examples include boron halides, mineral acids, and aluminum halides, preferably boron halides, mineral acids, and aluminum halides, and more preferably boron halides.

  Boron halide represents boron trifluoride, boron trichloride, boron tribromide, boron triiodide, and boron trifluoride, boron trichloride and the like are preferable.

  These activators may be used alone or in combination, and may be used as a complex in a solvent. For example, boron trifluoride / dimethyl ether complex, boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex, iodine trifluoride / 1,4-dioxane complex and the like are particularly preferable.

  The addition amount of the activator is preferably 2.0 to 2.4 mol times, more preferably 2.0 to 2.2 mol times with respect to the pyrroline derivative. The upper limit is preferably 2.4 mol times or less because the reaction rate decreases when the amount of the activator is too large.

  Next, the mixed liquid is added to the nitrogen-containing cyclic olefin to be added, but conversely, the mixed liquid may be added to the nitrogen-containing cyclic olefin solution.

  The nitrogen-containing cyclic olefin is the following (1).

(Wherein R ¹ and R ² represent an aryl group, which may be the same or different. In the formula, n represents any one of 1 to 3). Olefin.

As R < ¹ >, R < ² > in the said General formula (1), unsubstituted or polysubstituted aryl groups, such as a phenyl group and a naphthyl group, or heterocyclic rings, such as a tetrahydro pyridyl group, are preferable, and especially a phenyl group is preferable. n represents an integer of 1 to 3 as described above, but 2 is preferable.

  Specific examples of the nitrogen-containing cyclic olefin include 1-diphenylmethyl-1,2-dihydroazet, 1-ditoluylmethyl-1,2-dihydroazetate, 1-dixylylmethyl-1,2-dihydroazetate, 1-dinaphthylmethyl-1,2-dihydroazate, 1-phenylnaphthylmethyl-1,2-dihydroazate, 1-diphenylmethyl-2-pyrroline, 1-ditoluylmethyl-2-pyrroline, 1-dixylmethyl 2-pyrroline, 1-dinaphthylmethyl-2-pyrroline, 1-phenylnaphthylmethyl-2-pyrroline, 1-diphenylmethyl-3-pyrroline, 1-ditoluylmethyl-3-pyrroline, 1-dixylmethyl- 3-pyrroline, 1-dinaphthylmethyl-3-pyrroline, 1-phenylnaphthylmethyl-3-pyrroline, 1-diphenyl Methyl-1,2,3,6-tetrahydropyridine, 1-ditoluylmethyl-1,2,3,6-tetrahydropyridine, 1-dixylmethyl-1,2,3,6-tetrahydropyridine, 1-di Naphthylmethyl-1,2,3,6-tetrahydropyridine, 1-dinaphthylmethyl-1,2,3,6-tetrahydropyridine, 1-phenylnaphthylmethyl-1,2,3,6-tetrahydropyridine, 1- Diphenylmethyl-1,2,3,4-tetrahydropyridine, 1-ditolylmethyl-1,2,3,4-tetrahydropyridine, 1-dixylmethyl-1,2,3,4-tetrahydropyridine, 1- Dinaphthylmethyl-1,2,3,4-tetrahydropyridine, 1-phenylnaphthylmethyl-1,2,3,4-tetrahydropyridine, etc. Preferably, 1-diphenylmethyl-1,2-dihydroazete, 1-diphenylmethyl-2-pyrroline, 1-diphenylmethyl-3-pyrroline, 1-diphenylmethyl-1,2,3,6 -Tetrahydropyridine, 1-diphenylmethyl-1,2,3,4-tetrahydropyridine, 1-phenylnaphthylmethyl-1,2-dihydroazetate, 1-phenylnaphthylmethyl-2-pyrroline, 1-phenylnaphthylmethyl- 3-pyrroline, 1-phenylnaphthylmethyl-1,2,3,4-tetrahydropyridine, 1-phenylnaphthylmethyl-1,2,3,4-tetrahydropyridine.

  In the first step of the present invention, the optically active dialkylborane and the nitrogen-containing cyclic olefin are reacted in a solvent. Specific examples of the solvent used in the first step include tetrahydrofuran, diglyme, dimethoxyethane, triglyme, tetrahydropyran. And aliphatic ethers such as anisole and ethoxybenzene, hydrocarbons such as benzene and xylene, and halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride. Preferred are aliphatic ethers and aromatic ethers, and more preferred are aliphatic ethers.

  In addition, you may use the reaction system containing the solvent used for the synthesis | combination of optically active dialkyl borane as it is for the 1st process.

  The addition temperature of the nitrogen-containing cyclic olefin in the first step is preferably −10 ° C. to 20 ° C., more preferably −5 ° C. to 10 ° C. The stirring time after adding the nitrogen-containing cyclic olefin is preferably 30 minutes to 3 hours, more preferably 1 hour to 2 hours.

  Next, the second step of the present invention will be described.

  In the second step, the reaction solution obtained in the first step is oxidized with an oxidant to produce boric acid triester (oxidation step). As a specific example of the oxidant used in this oxidation step, excess Examples thereof include hydrogen oxide, perbenzoic acid, oxygen, oxone and the like, preferably hydrogen peroxide, perbenzoic acid and peracetic acid, more preferably hydrogen peroxide. In the step of reacting the oxidizing agent, it is preferable to add the oxidizing agent after making the reaction solution obtained by adding the nitrogen-containing cyclic olefin alkaline, specifically, the pH value is larger than 7, more preferably 8 That's it. Usually, the amount of the oxidizing agent used is preferably 6 equivalents or more with respect to the nitrogen-containing cyclic olefin.

  The temperature for the oxidation reaction in the second step is preferably from 0 ° C to 30 ° C, more preferably from 0 ° C to 20 ° C. The stirring time after adding the oxidizing agent is preferably 0.5 hours to 3 hours, more preferably 1 to 2 hours.

  Thus, trialkyl borane oxidation reaction using a peroxide produces a trialkyl borate ester. In general, water present in the system causes hydrolysis of boric acid trialkyl ester to give boric acid and an optically active cyclic amino alcohol.

  However, the present inventors have found that in the case of the nitrogen-containing cyclic olefin represented by the above formula (1), the corresponding optically active nitrogen-containing cyclic amino alcohol can be obtained only in a low yield. Therefore, in this invention, the process which decomposes | disassembles boric acid triester by adding alcohol to the reaction liquid (oxidation reaction liquid) obtained by the oxidation reaction which is the said 2nd process as a 3rd process is performed. Thereby, an optically active cyclic amino alcohol can be obtained with a very high yield. The reason why the yield of the optically active cyclic amino alcohol is remarkably improved by performing the third step in this way is not clear, but if the third step is not performed, the corresponding trialkyl borate and water are sufficiently mixed. However, it was considered that the use of alcohol, which is an organic compound having a hydroxyl group, facilitates miscibility with the boric acid trialkyl ester and causes sufficient solvolysis.

  Therefore, in the present invention, the yield of optically active amino alcohol is improved by adding an alcohol to the solution oxidized in the second step to decompose the boric acid triester. This solvolysis proceeds more efficiently when carried out under heating conditions, and the effect of improving the yield becomes remarkable.

Furthermore, the effect that optical purity improves by performing this process is also show | played.
Specifically, it can be performed as follows. That is, after performing the second step by oxidizing with peroxide, alcohol is further added to the oxidation reaction solution and heated. The alcohol used may be an aliphatic alcohol or an aromatic alcohol. Specific examples thereof include aliphatic alcohols such as methanol, ethanol and isopropanol, and aromatic alcohols such as phenol and benzyl alcohol. Preferably, methanol, ethanol and isopropanol are used.

  Further, the amount of alcohol used after reacting with the oxidizing agent is usually preferably 3 mol times or more, more preferably 4 mol times or more with respect to the nitrogen-containing cyclic olefin. The upper limit is preferably 5 mol times or less from the viewpoint of productivity.

  Moreover, the temperature at the time of alcohol addition is not particularly limited, but is preferably 20 ° C. or higher, more preferably 40 ° C. or higher, further preferably 50 ° C. or higher in terms of hydrolyzing the boric acid triester. is there. The upper limit is preferably 60 ° C. or less from the viewpoint of suppressing the rapid temperature increase of the reaction accompanying the addition of alcohol.

  The resulting nitrogen-containing optically active amino alcohol is represented by the general formula (2)

(Wherein R ¹ and R ² represent an aryl group, and may be the same or different. In the formula, n represents any one of 1 to 3, and * represents an asymmetric carbon). Specific examples include 1-diphenylmethyl-2-azetidinol, 1-ditoluylmethyl-2-azetidinol, 1-dixylmethyl-2-azetidinol, 1-dinaphthylmethyl-2-azetidinol, 1-diphenylmethyl-3. -Azetidinol, 1-ditoluylmethyl-3-azetidinol, 1-dixylmethyl-3-azetidinol, 1-dinaphthylmethyl-3-azetidinol, 1-diphenylmethyl-2-pyrrolidinol, 1-ditoluylmethyl-2- Pyrrolidinol, 1-dixylmethyl-2-pyrrolidinol, 1-dinaphthylmethyl-2-pyrrolidinol, 1- Phenylmethyl-3-pyrrolidinol, 1-ditoluylmethyl-3-pyrrolidinol, 1-dixylylmethyl-3-pyrrolidinol, 1-dinaphthylmethyl-3-pyrrolidinol, 1-diphenylmethyl-2-piperidinol, 1-ditoluyl Methyl-2-piperidinol, 1-dixylmethyl-2-piperidinol, 1-dinaphthylmethyl-2-piperidinol, 1-diphenylmethyl-3-piperidinol, 1-ditolylmethyl-3-piperidinol, 1-dixylmethyl -3-piperidinol, 1-dinaphthylmethyl-3-piperidinol, 1-diphenylmethyl-4-piperidinol, 1-ditoluylmethyl-4-piperidinol, 1-dixylmethyl-4-piperidinol, 1-dinaphthylmethyl- 4-piperidinol, 1-phenylnaphthylmethyl-azetidinol, 1-phenylnaphthylmethyl-3-azetidinol, 1-phenylnaphthylmethyl-2-pyrrolidinol, 1-phenylnaphthylmethyl-3-pyrrolidinol, 1-phenylnaphthylmethyl-2-piperidinol, 1- Examples thereof include phenylnaphthylmethyl-3-piperidinol, 1-phenylnaphthylmethyl-4-piperidinol, and preferably 1-diphenylmethyl-2-azetidinol, 1-diphenylmethyl-3-azetidinol, 1-diphenylmethyl-2 -Pyrrolidinol, 1-diphenylmethyl-3-pyrrolidinol, 1-diphenylmethyl-2-piperidinol, 1-diphenylmethyl-3-piperidinol, 1-diphenylmethyl-4-piperidinol.

  Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

  Here, a synthesis example of optically active 1-diphenylmethyl-3 (S) -pyrrolidinol by 1-diphenyl-3-methylpyrroline is shown.

The reaction yield of the produced 1-diphenylmethyl-3 (S) -pyrrolidinol was calculated by the internal standard method using high performance liquid chromatography under the analysis conditions described below.
Column: CAPCELL PAK C18 (SG120) 5 μm 150 mm * 4.6 mmφ (Shiseido)
Mobile phase: A 5.0 mM sodium dodecyl sulfate aqueous solution (pH 2.20, adjusted with phosphoric acid) / B: acetonitrile composition: A / B = 65/35 (v / v) (20 minutes)
A / B = 65/35 (v / v) → 50/50 (v / v) (10 minutes)
A / B = 50/50 (v / v) (10 minutes)
A / B = 50/50 (v / v) → A / B = 65/35 (v / v) (5 minutes)
A / B = 65/35 (v / v) (10 minutes)
Flow rate: 1.0 ml / min
Temperature: 30 ° C
Detector: UV (210 nm)
Retention time: 1-diphenylmethyl-3-pyrrolidinol 22.2 minutes
1-diphenylmethyl-3-pyrroline 29.0 minutes

The optical purity of the produced 1-diphenylmethyl-3 (S) -pyrrolidinol was calculated from the ratio of S form to R form using high performance liquid chromatography under the analysis conditions described below.
Column: CAPCELL PAK C18 (SG120) 5 μm 250 mm * 4.6 mmφ (Shiseido)
Mobile phase: 0.03% aqueous ammonia (pH 4.5; adjusted with acetic acid) / methanol = 41/59 (v / v)
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detector: UV (234 nm)

(Reference example)
The 1-diphenylmethyl-3-pyrroline used in the present invention was obtained by synthesis and the method is as follows.

Synthesis of cis-1,4-dichlorobutene To a 10 L four-necked flask equipped with a dropping funnel and a thermometer, 2670.0 g of toluene and 320.0 g of pyridine (= 4.04 mol, 0.40 mol times) were charged. Thereto was added 2526.0 g (= 21.11 mol, 2.08 mol times) of thionyl chloride so that the temperature in the system was 5 to 12 ° C. Subsequently, cis-1,4-butenediol (890 g, 10.11 mol) was added dropwise so that the temperature in the system was 5 to 12 ° C. After completion of the dropwise addition, the mixture was stirred at 5 ° C. for 2 hours, then heated to 50 ° C. and stirred for 6 hours. The reaction solution was concentrated, and the resulting solution was separated into two layers. The upper layer of this liquid was separated. The upper toluene layer contained 1122 g of cis-1,4-dichlorobutene (yield 88.7% 8.97 mol).

Synthesis of 1-diphenylmethyl-3-pyrroline To a 10 L flask equipped with a dropping funnel and a thermometer, 790.6 g of toluene, benzhydrylamine (2622.0 g, 14.32 mol) and water 419.02 were mixed, and cis A toluene solution (1090.2 g) of -1,4-dichlorobutene (561.8 g, 4.49 mol) was added dropwise at 40 ° C. over 1.5 h. Subsequently, 742 g (= 8.90 mol, 1.98 mol times) of a 48% NaOH aqueous solution was added and stirred at 60 ° C. for 10 hours. Subsequently, 2558.8 g of toluene and 1610.7 g of water were mixed, and 964.9 g of 35% hydrochloric acid was charged. Crystals precipitated in the reaction solution. The mother liquor and crystals were separated by centrifugation. The aqueous layer was separated from the toluene layer and aqueous layer of the mother liquor. When the toluene layer was concentrated, 829.3 g of 1-diphenylmethyl-3-pyrroline was contained in the concentrated solution (yield 78.4%, 3.52 mol).

Example 1
A 200 ml three-necked flask equipped with a dropping funnel and a thermometer was charged with 76.4 g of tetrahydrofuran, followed by 23.0 g of α-pinene (91% ee optical purity) (= 0.17 mol, 4.01 mol times). 2.39 g (= 0.06 mol, 1.50 mol times) of sodium borohydride was added and stirred. At an internal temperature of 4 to 6 ° C., 12.1 g (= 0.08 mol, 2.02 mol times) of a trifluoroborane / diethyl ether complex was added dropwise over 20 minutes, returned to room temperature, and raised to 25 ° C. for 17 hours. Stir. Then, it was set to 0-2 degreeC, 1-diphenylmethyl-3-pyrroline (10.06g, 0.04mol) was added, and it stirred at 0-2 degreeC for 1 hour. The conversion rate of 1-diphenylmethyl-3-pyrroline in the reaction for 1 hour was 99.4%. To this reaction solution, 13.4 g (= 0.16 mol, 3.82 mol times) of 48% aqueous sodium hydroxide solution was added. Subsequently, 31.78 g (= 0.28 mol, 6.67 mol times) of 30% hydrogen peroxide solution is added dropwise to the reaction solution, but at this time, it is added dropwise over 1 hour so that the temperature inside the system does not rise to 15 ° C. or higher. did. Subsequently, 4.09 g (= 0.13 mol, 3.04 mol times) of methanol was added, and the mixture was heated to 50 ° C. and stirred for 1 hour. At this time, the yield of 1-diphenylmethyl-3 (S) -pyrrolidinol was 91.1% (9.69 g, 0.04 mol), and the optical purity was 76.0% ee.

Example 2
A 200 ml three-necked flask equipped with a dropping funnel and a thermometer was charged with 75.7 g of tetrahydrofuran, followed by 27.3 g (= 0.20 mol, 4.82 mol times) of α-pinene (91% ee optical purity). 2.39 g (= 0.06 mol, 1.50 mol times) of sodium borohydride was added and stirred. At an internal temperature of 4 to 6 ° C., 12.0 g (= 0.08 mol, 2.00 mol times) of a trifluoroborane / diethyl ether complex was added dropwise over 20 minutes, returned to room temperature, and raised to 25 ° C. for 17 hours. Stir. Then, it was set to 0-2 degreeC, 1-diphenylmethyl-3-pyrroline (10.02g, 0.04mol) was added, and it stirred at 0-2 degreeC for 1 hour. The conversion rate of 1-diphenylmethyl-3-pyrroline in the reaction for 1 hour was 99.1%. To this reaction solution, 10.85 g (= 0.13 mol, 3.10 mol times) of a 48% aqueous sodium hydroxide solution was added. Subsequently, 30.92 g of 30% hydrogen peroxide solution (= 0.27 mol, 6.42 mol times) is added dropwise.
At this time, it was added dropwise over 1 hour so that the temperature in the system did not rise to 15 ° C. or higher. Subsequently, 4.16 g (= 0.13 mol, 3.10 mol times) of methanol was added, and the mixture was heated to 50 ° C. and stirred for 1 hour. At this time, the yield of 1-diphenylmethyl-3 (S) -pyrrolidinol was 90% or more, and the optical purity was 84.3% ee.

Example 3
A 200 ml three-necked flask equipped with a dropping funnel and a thermometer was charged with 52.71 g of tetrahydrofuran, followed by 34.67 g of α-pinene (optical purity 91% ee) (= 0.25 mol, 6.06 mol times). 2.39 g (= 0.063 mol, 1.50 mol times) of sodium borohydride was added and stirred. Trifluoroborane / diethyl ether complex (12.06 g) (= 0.09 mol, 2.05 mol times) was added dropwise over 20 minutes at an internal temperature of 4 to 6 ° C., and the temperature was returned to room temperature and raised to 25 ° C. for 20 hours. Stir. Subsequently, the temperature was set to −12 ° C., 1-diphenylmethyl-3-pyrroline (10.03 g, 0.04 mol) was added in 5 minutes, and the mixture was stirred at −12 ° C. for 1 hour. The conversion rate of 1-diphenylmethyl-3-pyrroline in the reaction for 1 hour was 99.9%. To this reaction solution, 10.68 g (= 0.13 mol, 3.10 mol times) of 48% aqueous sodium hydroxide solution was added. Subsequently, 31.14 g of 30% hydrogen peroxide solution (= 0.28 mol, 6.67 mol times) was added dropwise, and at this time, the solution was added dropwise over 1 hour so that the temperature in the system did not rise to 15 ° C. or higher. Subsequently, 4.61 g (= 0.14 mol, 3.33 mol times) of methanol was added, and the mixture was heated to 50 ° C. and stirred for 2.5 hours. At this time, the yield of 1-diphenylmethyl-3 (S) -pyrrolidinol was 83.4% (8.88 g, 0.04 mol), and the optical purity was 84.5% ee.

Example 4
A 200 ml three-necked flask equipped with a dropping funnel and a thermometer was charged with 49.3 g of tetrahydrofuran, followed by 27.5 g of α-pinene (91% ee optical purity) (= 0.20 mol, 4.82 mol times). 2.39 g (= 0.063 mol, 1.50 mol times) of sodium borohydride was added and stirred. At an internal temperature of 4 ° C., 11.95 g (= 0.084 mol, 2.00 mol times) of a trifluoroborane / diethyl ether complex was added dropwise over 20 minutes, and the mixture was returned to room temperature and stirred for 18 hours while raising the temperature to 25 ° C. . Subsequently, the temperature was set to −12 to −10 ° C., 1-diphenylmethyl-3-pyrroline (10.02 g, 0.042 mol) was added in 5 minutes, and the mixture was stirred at −12 ° C. for 1 hour. The conversion rate of 1-diphenylmethyl-3-pyrroline in the reaction for 1 hour was 99.4%. To this reaction solution, 11.98 g (= 0.143 mol, 3.42 mol times) of a 48% sodium hydroxide aqueous solution was added. Subsequently, 30.97 g of hydrogen peroxide 30% (= 0.273 mol, 6.51 mol times) is added dropwise to the reaction solution, but at this time, it is added dropwise over 1 hour so that the temperature inside the system does not rise to 15 ° C. or higher. did. Subsequently, 4.09 g (= 0.127 mol, 3.04 mol times) of methanol was added, and the mixture was heated to 50 ° C. and stirred for 1 hour. At this time, the yield of 1-diphenylmethyl-3 (S) -pyrrolidinol was 86.8% (9.24 g, 0.036 mol), and the optical purity was 86.9% ee.

Comparative Example 1
A 200 ml three-necked flask equipped with a dropping funnel and a thermometer was charged with 76.4 g of tetrahydrofuran, followed by 23.0 g of α-pinene (91% ee optical purity) (= 0.17 mol, 4.01 mol times). 2.39 g (= 0.06 mol, 1.50 mol times) of sodium borohydride was added and stirred. At an internal temperature of 4 ° C., 12.1 g (= 0.08 mol, 2.02 mol times) of a trifluoroborane / diethyl ether complex was added dropwise over 20 minutes, and the mixture was returned to room temperature and stirred for 18 hours while raising the temperature to 25 ° C. . Subsequently, the temperature was set to −12 to −10 ° C., 1-diphenylmethyl-3-pyrroline (10.06 g, 0.04 mol) was added in 5 minutes, and the mixture was stirred at 0 to 2 ° C. for 1 hour. The conversion rate of 1-diphenylmethyl-3-pyrroline in the reaction for 1 hour was 99.4%. To this reaction solution, 13.4 g (= 0.16 mol, 3.82 mol times) of 48% aqueous sodium hydroxide solution was added. Subsequently, 31.78 g (= 0.28 mol, 6.67 mol times) of 30% hydrogen peroxide water is added dropwise to the reaction solution at −12 to −10 ° C. At this time, the temperature of the system is raised to 15 ° C. or higher. The solution was added dropwise over 1 hour. At this time, the yield of 1-diphenylmethyl-3 (S) -pyrrolidinol was 60.4% (6.40 g, 0.03 mol), and the optical purity was 70.3% ee.

Comparative Example 2
A 200 ml three-necked flask equipped with a dropping funnel and a thermometer was charged with 75.7 g of tetrahydrofuran, followed by 27.3 g (= 0.20 mol, 4.82 mol times) of α-pinene (91% ee optical purity). 2.39 g (= 0.06 mol, 1.50 mol times) of sodium borohydride was added and stirred. At an internal temperature of 4 ° C., 12.0 g (= 0.08 mol, 2.00 mol times) of a trifluoroborane / diethyl ether complex was added dropwise over 20 minutes, and the mixture was returned to room temperature and stirred for 18 hours while raising the temperature to 25 ° C. . Subsequently, 1-diphenylmethyl-3-pyrroline (10.02 g, 0.04 mol) was added in 5 minutes, and the mixture was stirred at -12 ° C for 1 hour. The conversion rate of 1-diphenylmethyl-3-pyrroline in the reaction for 1 hour was 99.1%. To this reaction solution, 10.85 g (= 0.13 mol, 3.10 mol times) of a 48% sodium hydroxide aqueous solution was added over 5 minutes. At this time, the temperature of the solution rose to -8 ° C. Subsequently, 30.92 g of 30% hydrogen peroxide solution (= 0.27 mol, 6.42 mol times) is added dropwise to the reaction solution at −12 ° C., but at this time, the temperature in the system should not be raised to 15 ° C. or higher. The solution was added dropwise over 1 hour. At this time, the yield of 1-diphenylmethyl-3 (S) -pyrrolidinol was 56.0% (5.93 g, 0.04 mol), and the optical purity was 78.9% ee.

Comparative Example 3
A 200 ml three-necked flask equipped with a dropping funnel and a thermometer was charged with 52.71 g of tetrahydrofuran, followed by 34.67 g of α-pinene (optical purity 91% ee) (= 0.25 mol, 6.06 mol times). 2.39 g (= 0.063 mol, 1.50 mol times) of sodium borohydride was added and stirred. At an internal temperature of 4 ° C., 12.06 g (= 0.09 mol, 2.05 mol times) of a trifluoroborane / diethyl ether complex was added dropwise over 20 minutes, and the mixture was returned to room temperature and stirred for 18 hours while raising the temperature to 25 ° C. . Subsequently, 1-diphenylmethyl-3-pyrroline (10.03 g, 0.04 mol) was added in 5 minutes, and the mixture was stirred at -12 ° C for 1 hour. The conversion rate of 1-diphenylmethyl-3-pyrroline in the reaction for 1 hour was 99.9%. To this reaction solution, 10.68 g (= 0.13 mol, 3.10 mol times) of 48% aqueous sodium hydroxide solution was added. Subsequently, 31.14 g of 30% hydrogen peroxide solution (= 0.28 mol, 6.67 mol times) was added dropwise to the reaction solution, but this was added dropwise over 1 hour so that the temperature inside the system did not rise to 15 ° C. or higher. did. At this time, the yield of 1-diphenylmethyl-3 (S) -pyrrolidinol was 51.3% (8.88 g, 0.04 mol), and the optical purity was 82.3% ee.

Comparative Example 4
A 200 ml three-necked flask equipped with a dropping funnel and a thermometer was charged with 49.3 g of tetrahydrofuran, followed by 27.5 g of α-pinene (91% ee optical purity) (= 0.20 mol, 4.82 mol times). 2.39 g (= 0.06 mol, 1.50 mol times) of sodium borohydride was added and stirred. At an internal temperature of 4 ° C., 11.95 g (= 0.08 mol, 2.00 mol times) of a trifluoroborane / diethyl ether complex was added dropwise over 20 minutes, and the mixture was returned to room temperature and stirred for 18 hours while raising the temperature to 25 ° C. . Subsequently, the temperature was set to −12 to −10 ° C., and 1-diphenylmethyl-3-pyrroline (10.02 g, 0.04 mol) was stirred at −12 to −10 ° C. for 1 hour. The conversion rate of 1-diphenylmethyl-3-pyrroline in the reaction for 1 hour was 99.4%.

  To this reaction solution, 11.98 g (= 0.14 mol, 3.42 mol times) of a 48% sodium hydroxide aqueous solution was added. Subsequently, 30.97 g of hydrogen peroxide 30% (= 0.273 mol, 6.51 mol times) is added dropwise to the reaction solution, but at this time, it is added dropwise over 1 hour so that the temperature inside the system does not rise to 15 ° C. or higher. did. At this time, the yield of 1-diphenylmethyl-3 (S) -pyrrolidinol was 49.2% (5.21 g, 0.02 mol), and the optical purity was 79.8% ee.

Claims (4)

The next three steps,
(First step) Optically active dialkylborane and general formula (1)

(Wherein R ¹ and R ² represent an aryl group, which may be the same or different. In the formula, n represents any one of 1 to 3). Reacting the olefin in a solvent;
(2nd process) The oxidation process which produces | generates boric acid triester by making the reaction liquid obtained at the 1st process oxidize with an oxidizing agent,
(3rd process) General formula (2) characterized by including the decomposition | disassembly process which adds alcohol to the oxidation reaction liquid obtained at the 2nd process, and decomposes | disassembles boric acid triester.

(In the formula, R ¹ and R ² represent an aryl group, and may be the same or different. In the formula, n represents an integer of 1 to 3, and * represents an asymmetric carbon.) The manufacturing method of optically active cyclic amino alcohol represented by these. 2. The method for producing an optically active cyclic amino alcohol according to claim 1, wherein the optically active dialkylborane used in the first step is diisopinocinfeylborane. The method for producing an optically active cyclic amino alcohol according to claim 1 or 2, wherein the alcohol used in the third step is an aliphatic alcohol having 1 to 4 carbon atoms. The optically active cyclic amino according to any one of claims 1 to 3 , wherein the amount of alcohol used in the third step is 3 mol times or more based on the nitrogen-containing cyclic olefin used in the first step. Alcohol production method.