JP6558910B2 - Optically active triethylenediamine derivative and method for producing the same - Google Patents

Description

  The present invention relates to an optically active triethylenediamine derivative useful as an asymmetric reagent and a method for producing the same.

  Triethylenediamine derivatives are used as organic catalysts due to the strong nucleophilicity of the nitrogen atoms contained, and as bases and ligands due to their strong basicity. Among them, since (hydroxymethyl) triethylenediamine derivatives have asymmetric points in the molecule, their optically active substances are useful as asymmetric reagents such as asymmetric organic catalysts and asymmetric ligands. It is used for Baylis-Hillman reaction (for example, see Non-Patent Document 1) and asymmetric epoxidation (for example, see Non-Patent Document 2). However, the method for preparing the optically active (hydroxymethyl) triethylenediamine derivative requires a multi-step process. In addition, a method for easily synthesizing a racemate of 2- (hydroxymethyl) triethylenediamine has been reported so far (see, for example, Patent Documents 1 and 2), but a method for producing the optically active substance is completely reported. Was not.

Japanese Patent No. 5640332 Japanese Patent No. 5640337

Tetrahedron: Asymmetry, Vol. 6, pp. 1241-1244, 1995 Tetrahedron Letters, 33, 639-642, 1992

  Although the optically active triethylenediamine derivative is useful as an asymmetric reagent, the production method thereof requires many steps and is not an efficient method. The subject of this invention is providing the novel optically active triethylenediamine derivative useful as an asymmetric reagent, and its simple manufacturing method.

  As a result of intensive studies in view of the above problems, the present inventors have carried out an asymmetric acylation reaction of (hydroxymethyl) triethylenediamine in the presence of a vinyl ester derivative and a hydrolase, thereby producing optical activity (hydroxymethyl). The inventors have found that triethylenediamine can be easily produced, and have completed the present invention.

  That is, the present invention relates to the general formula (1)

(In the formula, R ⁵ represents a hydrogen atom or a general formula —C (O) R ^1.
[Wherein, R ¹ represents an alkyl group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 12 carbon atoms. ]
X represents a nitrogen atom or a general formula ≡N ⁺ R ⁶ X ⁻
[Wherein, R ⁶ represents an alkyl group having 1 to 8 carbon atoms, and X represents a halogen atom, an alkyl sulfonate group having 1 to 4 carbon atoms, or a haloalkyl sulfonate group having 1 to 4 carbon atoms. ]
And * represents an asymmetric center. )
It is related with the optically active triethylenediamine derivative represented by these.

  Further, the present invention provides a compound represented by formula (1a)

(Hydroxymethyl) triethylenediamine represented by the general formula (2)

(In the formula, R ¹ represents an alkyl group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 12 carbon atoms, and R ² , R ^3, and R ⁴ are each independently a hydrogen atom. Or represents a C1-C4 alkyl group.)
And a vinyl ester derivative represented by the general formula (1c),

(Wherein R ¹ represents the same meaning as described above, and * represents an asymmetric center.)
An optically active (R or S)-(acyloxymethyl) triethylenediamine represented by formula (1b)

(In the formula, * represents the same meaning as described above.)
It is related with the manufacturing method of optically active (R or S)-(hydroxymethyl) triethylenediamine represented by these.

  Further, the present invention provides a compound represented by the general formula (1c)

(In the formula, R ¹ represents an alkyl group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 12 carbon atoms, and * represents an asymmetric center.)
Solvolysis of optically active (R or S)-(acyloxymethyl) triethylenediamine represented by the formula (1b)

(In the formula, * represents the same meaning as described above.)
It is related with the manufacturing method of optically active (R or S)-(hydroxymethyl) triethylenediamine represented by these.

  Further, the present invention provides a compound represented by the general formula (1f)

Wherein R ⁵ is a hydrogen atom or a general formula —C (O) R ¹
[Wherein, R ¹ represents an alkyl group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 12 carbon atoms. ]
Represents an acyl group, and * represents an asymmetric center. )
An optically active triethylenediamine derivative represented by formula (3):

(In the formula, R ⁶ represents an alkyl group having 1 to 8 carbon atoms, and X represents a halogen atom, an alkyl sulfonate group having 1 to 4 carbon atoms, or a haloalkyl sulfonate group having 1 to 4 carbon atoms.)
And a compound represented by the general formula (1g)

(Wherein R ⁵ , R ⁶ , X and * represent the same meaning as described above.)
It is related with the manufacturing method of optically active triethylenediamine derivative represented by these.

  The optically active triethylenediamine derivative of the present invention can be used as an asymmetric reagent such as an asymmetric organic catalyst or an asymmetric ligand.

  The present invention is described in further detail below.

R ¹ , R ² , R ³ , R ⁴ , R ⁶ and X in this specification will be described.

The alkyl group having 1 to 8 carbon atoms represented by R ¹ and R ⁶ may be linear or branched, and is methyl, ethyl, propyl, isopropyl, butyl, isobutyl. Group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, 2-ethylhexyl group, octyl group and the like.

Examples of the haloalkyl group having 1 to 8 carbon atoms represented by R ¹ include a fluoromethyl group, a chloromethyl group, a bromomethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 1-chloroethyl group, Examples thereof include a 1-fluoroethyl group, a perfluoroethyl group, a 3-chloropropyl group, a 3-chlorobutyl group, a perfluorobutyl group, a perfluorohexyl group, and a perfluorooctyl group.

Examples of the aryl group having 6 to 12 carbon atoms represented by R ¹ include a phenyl group, a naphthyl group, an anthryl group, and a biphenylyl group.

From the viewpoint of good yield, R ¹ is preferably a methyl group.

In view of good yield, R ⁶ is preferably a methyl group.

The alkyl group having 1 to 4 carbon atoms represented by R ² , R ³ and R ⁴ may be either linear or branched, and is a methyl group, ethyl group, propyl group, isopropyl group, butyl Group, isobutyl group, sec-butyl group, tert-butyl group and the like.

In terms of a good yield, R ² , R ³ and R ⁴ are preferably a methyl group or a hydrogen atom, and more preferably a hydrogen atom.

  Examples of the halogen atom represented by X include a chlorine atom, a bromine atom, and an iodine atom.

  Examples of the alkyl sulfonate group having 1 to 4 carbon atoms represented by X include a methyl sulfonate group, an ethyl sulfonate group, and a butyl sulfonate group.

  Examples of the haloalkyl sulfonate group having 1 to 4 carbon atoms represented by X include a trifluoromethyl sulfonate group, a pentafluoroethyl sulfonate group, a perfluorobutyl sulfonate group, and the like.

  Next, the manufacturing method of this invention is demonstrated. The production method of the optically active triethylenediamine derivative (1) of the present invention is as shown in the following reaction formula.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , X and * represent the same meaning as described above.)
In step 1, (hydroxymethyl) triethylenediamine (1a) and vinyl ester derivative (2) are contacted in the presence of a hydrolase, and optical activity (R or S)-(hydroxymethyl) triethylenediamine (1b) and optical activity ( R or S)-(acyloxymethyl) triethylenediamine (1c).

  (Hydroxymethyl) triethylenediamine (1a), which is a raw material of Step 1, can be prepared by a method described in the literature (for example, see Patent Literatures 1 and 2). In addition, optically active (R or S)-(hydroxymethyl) triethylenediamine (1b) obtained by the production method of the present invention (Step 1 and Step 2) can also be used.

  As the vinyl ester derivative (2) which is the raw material of Step 1, vinyl acetate, isopropenyl acetate, vinyl propionate, isopropenyl propionate, vinyl butyrate, isopropenyl butyrate, vinyl caproate, isopropenyl caproate, vinyl chloroacetate And isopropenyl chloroacetate, vinyl pivalate, isopropenyl pivalate, vinyl benzoate and the like. These vinyl ester derivatives (2) are commercially available, but can also be prepared by methods described in the literature (Chemical Communications, pages 706-707, 2003). From the viewpoint of good yield, it is preferable to use vinyl acetate or isopropenyl acetate, and it is more preferable to use vinyl acetate.

  Examples of the hydrolase that can be used in Step 1 include lipase, protease, amylase, and the like, and it is preferable to use lipase. Examples of lipases that can be used include Candida cylindracea, Candida rugosa, Penicillium roqueforti, Burkholderia cepalcia, .) And lipases from Aspergillus niger. Examples of the lipase product derived from Candida cilindracea include LipaseOF (trade name: obtained from Meito Sangyo), and Lipase from Candida cylindracea (trade name, obtained from Sigma Aldrich Japan). LipaseAY “Amano” 30G (trade name, obtained from Amano Enzyme), LipaseAYS “Amano” (trade name, obtained from Amano Enzyme) and Lipase from Candida rugosa (trade name, Sigma Aldrich Japan) Available). Lipase® “Amano” (trade name, available from Amano Enzyme) can be mentioned as a lipase product derived from Penicillium roqueforti. Examples of lipase products derived from Burkholderia cepacia include LipasePS “Amano” SD (trade name, obtained from Amano Enzyme) and LipasePS “Amano” IM (trade name, obtained from Amano Enzyme). Examples of the lipase product derived from Alkaligenes sp include LipaseQLM (trade name: obtained from the famous sugar industry) and LipasePL (trade name: obtained from the famous sugar industry). Products derived from Aspergillus niger include Lipase AS “Amano” (trade name, obtained from Amano Enzyme), Sumizyme NSL3000 (trade name, obtained from Shin Nippon Chemical Industry), Lipase A “Amano” 6 (trade name, obtained from Amano Enzyme) Can be mentioned. The hydrolase used in the present invention may be used in a free state or supported on an insoluble carrier.

  The amount of hydrolase used in step 1 is not particularly limited, but is preferably 0.001 to 5 parts by weight with respect to 1 part by weight of (hydroxymethyl) triethylenediamine (1a) from the viewpoint of reaction efficiency. 0.1 to 2 parts by weight is more preferable.

  Although the usage-amount of the vinyl ester derivative (2) used in the process 1 does not have a restriction | limiting in particular, It is preferable to use 1-10 equivalent with respect to (hydroxymethyl) triethylenediamine (1a). More preferably, it is 1 to 5 equivalents.

  In the reaction of Step 1, an acid may be added. The acid that can be used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include acetic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and trifluoroacetic acid. It is preferable to use 1 to 2 equivalents with respect to (hydroxymethyl) triethylenediamine (1a). More preferably, it is 1 equivalent.

  The reaction in Step 1 may be carried out in a solvent, and the solvent that can be used is not particularly limited as long as it is an inert solvent for the reaction, and is appropriately selected according to the desired reaction temperature. For example, ether solvents such as dimethyl ether, diethyl ether, tetrahydrofuran and dioxane, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, carboxylic solvents such as acetic acid and propionic acid, methyl acetate, ethyl acetate, butyl acetate and propion Ester solvents such as ethyl acid, aromatic hydrocarbon solvents such as benzene, toluene, xylene and mesitylene, aromatic halogen solvents such as monochlorobenzene and dichlorobenzene, and aliphatic hydrocarbons such as hexane, heptane, octane and cyclohexane Solvents, aliphatic halogen solvents such as dichloromethane, chloroform, ethylene dichloride, nitrile solvents such as acetonitrile, propionitrile, benzonitrile, etc. can be used. Two of these solvents It is also possible to use a mixture of above. There is no restriction | limiting in particular in the usage-amount of a reaction solvent.

  The reaction in Step 1 can be performed within a temperature range used by those skilled in the art when performing an enzyme reaction. For example, it can be performed at a temperature appropriately selected from the range of 0 to 70 ° C. From the viewpoint of reaction rate and reaction efficiency, room temperature to 50 ° C. is more preferable.

  If necessary, from the solution after the reaction, insoluble matters such as the hydrolase used are filtered off, and optically active (R or S)-(hydroxymethyl) triethylenediamine (1b) and optically active (R or S)-(acyloxymethyl) triethylenediamine (1c) can be isolated and purified. The isolation / purification method is not particularly limited, and may be a general method such as solvent extraction, distillation, silica gel column chromatography, preparative thin layer chromatography, preparative liquid chromatography, or the like. Optically active (R or S)-(hydroxymethyl) triethylenediamine (1b) and optically active (R or S)-(acyloxymethyl) triethylenediamine (1c) can be isolated and purified.

  The optically active (R or S)-(hydroxymethyl) triethylenediamine (1b) obtained by the reaction in Step 1 can be used again as (hydroxymethyl) triethylenediamine (1a), which is the raw material in Step 1. By repeating the production method of the present invention, optically active (R or S)-(hydroxymethyl) triethylenediamine having high optical purity can be obtained.

  Step 2 is a method for producing optically active (R or S)-(hydroxymethyl) triethylenediamine (1b) by solvolysis of optically active (R or S)-(acyloxymethyl) triethylenediamine (1c). .

  Methods for solvolysis include methods known to those skilled in the art (for example, Protective Groups in Organic Synthesis 3rd. Ed., PMGM Wuts & TW Greene, John Wily & Sons, Inc, pp. 369-453). 1999).

  The reaction in Step 2 is a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium cyanide, basic anion exchange resin (Amberlite, Amberjet), hydrochloric acid, sulfuric acid, trifluoroacetic acid or p-toluenesulfone. By carrying out the reaction in a solvent such as toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, methanol, ethanol, acetic acid, water or a mixed solvent thereof in the presence of an acid such as an acid, optical activity ( R or S)-(hydroxymethyl) triethylenediamine (1b) can be obtained.

  The amount of the base used in the reaction of Step 2 is not particularly limited, but it is preferably 1 to 10 equivalents based on the optically active (R or S)-(acyloxymethyl) triethylenediamine (1c). More preferably, it is 1 to 5 equivalents.

  The amount of acid used in the reaction of Step 2 is not particularly limited, but it is 0.01 to 10 equivalents based on optically active (R or S)-(acyloxymethyl) triethylenediamine (1c). preferable. More preferably, it is 0.1-5 equivalent.

  The reaction in step 2 can be performed within the temperature range used by those skilled in the art when performing a solvolysis reaction. For example, it can be performed at a temperature appropriately selected from the range of 0 to 120 ° C. From the viewpoint of reaction rate and reaction efficiency, room temperature to 100 ° C is more preferable.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but it may be a general purpose method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

  The obtained optically active (R or S)-(hydroxymethyl) triethylenediamine (1b) can be used again as (hydroxymethyl) triethylenediamine (1a) which is the raw material of Step 1.

  Step 3 is a method for producing an optically active triethylenediamine derivative (1d) by reacting an optically active (R or S)-(hydroxymethyl) triethylenediamine (1b) with an alkyl halide or an alkylsulfonate (3). It is.

  A commercially available alkyl halide or alkyl sulfonate (3) used in Step 3 can be used.

  The alkyl halide or alkylsulfonate (3) used in Step 3 is used in an amount of 0.5 to 1.5 equivalents based on the optically active (R or S)-(hydroxymethyl) triethylenediamine (1b). It is preferable. More preferably, it is 0.7-1.2 equivalent.

  The reaction in Step 3 may be performed in a solvent, and a solvent that can be used is not particularly limited as long as it is an inert solvent for the reaction, and is appropriately selected according to a desired reaction temperature. For example, ether solvents such as dimethyl ether, diethyl ether, tetrahydrofuran and dioxane, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, carboxylic solvents such as acetic acid and propionic acid, methyl acetate, ethyl acetate, butyl acetate and propion Ester solvents such as ethyl acid, aromatic hydrocarbon solvents such as benzene, toluene, xylene and mesitylene, aromatic halogen solvents such as monochlorobenzene and dichlorobenzene, and aliphatic hydrocarbons such as hexane, heptane, octane and cyclohexane Solvents, aliphatic halogen solvents such as dichloromethane, chloroform, ethylene dichloride, nitrile solvents such as acetonitrile, propionitrile, benzonitrile, etc. can be used. Two of these solvents It is also possible to use a mixture of above. There is no restriction | limiting in particular in the usage-amount of a reaction solvent.

  The reaction in Step 3 can be performed at a temperature appropriately selected from the range of 0 to 120 ° C. From the viewpoint of reaction rate and reaction efficiency, room temperature to 100 ° C is more preferable.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but it may be a general purpose method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

  Step 4 is a process for producing an optically active triethylenediamine derivative (1e) by reacting an optically active (R or S)-(acyloxymethyl) triethylenediamine (1c) with an alkyl halide or an alkylsulfonate (3). It is.

  A commercially available alkyl halide or alkyl sulfonate (3) used in Step 4 can be used.

  The alkyl halide or alkyl sulfonate (3) used in Step 4 is used in an amount of 0.5 to 1.5 equivalents relative to the optically active (R or S)-(acyloxymethyl) triethylenediamine (1c). It is preferable. More preferably, it is 0.7-1.2 equivalent.

  The reaction in Step 4 may be performed in a solvent, and a solvent that can be used is not particularly limited as long as it is an inert solvent for the reaction, and is appropriately selected according to a desired reaction temperature. For example, ether solvents such as dimethyl ether, diethyl ether, tetrahydrofuran and dioxane, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, carboxylic solvents such as acetic acid and propionic acid, methyl acetate, ethyl acetate, butyl acetate and propion Ester solvents such as ethyl acid, aromatic hydrocarbon solvents such as benzene, toluene, xylene and mesitylene, aromatic halogen solvents such as monochlorobenzene and dichlorobenzene, and aliphatic hydrocarbons such as hexane, heptane, octane and cyclohexane Solvents, aliphatic halogen solvents such as dichloromethane, chloroform, ethylene dichloride, nitrile solvents such as acetonitrile, propionitrile, benzonitrile, etc. can be used. Two of these solvents It is also possible to use a mixture of above. There is no restriction | limiting in particular in the usage-amount of a reaction solvent.

  The reaction in Step 4 can be performed at a temperature appropriately selected from the range of 0 to 120 ° C. From the viewpoint of reaction rate and reaction efficiency, room temperature to 100 ° C is more preferable.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but it may be a general purpose method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

  EXAMPLES Next, although an Example and a reference example demonstrate this invention further in detail, this invention is not limited to these.

  Example-1

To 2- (hydroxymethyl) triethylenediamine (14.2 g, 100 mmol) was added dichloromethane (200 mL), acetic acid (5.7 mL, 100 mmol), LipasePL (16 g), vinyl acetate (9.2 mL, 100 mmol), and at room temperature. Stir. After 14 hours, it was confirmed by NMR that the reaction ratio was 5: 1 [2- (acetoxymethyl) triethylenediamine: 2- (hydroxymethyl) triethylenediamine]. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. To the obtained crude product, THF (120 mL) and Amberlyst A21 (40 g) were added and stirred for 2 hours, followed by filtration and concentration under reduced pressure. Water (100 mL) was added to the resulting crude product, and the mixture was extracted with a chloroform-methanol (4: 1) mixed solvent (500 mL × 4). The organic layer was concentrated under reduced pressure to obtain (S) -2- (acetoxymethyl) triethylenediamine (10.1 g). The aqueous layer was azeotroped with toluene, and methanol (20 mL) and Amberlite IRA400 (OH ⁻ ) (7 g) were added to the resulting crude product and stirred. After 2 hours, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain (R) -2- (hydroxymethyl) triethylenediamine (1.8 g, 13%).

  To the obtained (R) -2- (hydroxymethyl) triethylenediamine (1.8 g, 12.7 mmol), dichloromethane (26.4 mL), acetic acid (726 μL), LipasePL (910 mg), vinyl acetate (1.46 mL) And stirred at room temperature. After 21 hours, it was confirmed by NMR that the reaction ratio was 3: 1 [2- (acetoxymethyl) triethylenediamine: 2- (hydroxymethyl) triethylenediamine]. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. To the obtained crude product, THF (12 mL) and Amberlyst A21 (4 g) were added and stirred for 2 hours, followed by concentration under reduced pressure. Water (50 mL) was added to the obtained crude product, and the mixture was extracted and washed with a mixed solvent of chloroform-methanol (4: 1) (200 mL × 4).

The aqueous layer was azeotroped with toluene, and methanol (3 mL) and Amberlite IRA400 (OH ⁻ ) (3 g) were added to the resulting crude product and stirred. After 2 hours, filtration was performed and vacuum concentration was performed. Then, it was washed with ethyl acetate, filtered, and concentrated under reduced pressure to obtain (R) -2- (hydroxymethyl) triethylenediamine (300 mg, 17%, 88% ee). Optical purity and absolute configuration correspond to reacting the resulting 2- (hydroxymethyl) triethylenediamine with (S) -α-methoxy-α- (trifluoromethyl) phenylacetic acid ((S) -MTPA). The MTPA ester was determined by comparison with the product of Reference Example-7.

(R) -2- (hydroxymethyl) triethylenediamine: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.54 (dd, J = 10.0, 12.2 Hz, 1 H), 3.50 (dd, J = 4.8, 12.2 Hz, 1H), 2.97-2.86 (m, 4H), 2.86-2.76 (m, 3H), 2.76-2.62 (m, 2H), 2.58 (m, 1H), 2.20 (m, 1H).

(S) -2- (acetoxymethyl) triethylenediamine: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.20 (dd, J = 8.6 Hz, 11.9 Hz, 1H), 4.07 (dd, J = 5.5 Hz, 11.9 Hz, 1H), 3.08 (m, 1H), 3.02-2.91 (m, 3H), 2.91-2.80 (m, 1H), 2.80- 2.71 (m, 2H), 2.71-2.61 (m, 3H), 2.39 (ddd, J = 1.9 Hz, 7.5 Hz, 13.1 Hz, 1H), 2.09 (s , 3H).

  Example-2

2- (hydroxymethyl) triethylenediamine (2.84 g, 20 mmol), chloroform (40 mL), acetic acid (1.14 mL, 20 mmol), LipasePS “Amano” IM (1.92 g), vinyl acetate (3.68 mL, 40 mmol) ) Was added and stirred at room temperature. After 45 hours, NMR confirmed that the reaction ratio was 2: 1 [2- (acetoxymethyl) triethylenediamine: 2- (hydroxymethyl) triethylenediamine]. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. Then, THF (24 mL) and Amberlyst A21 (8 g) were added to the reaction crude product and stirred. After 2 hours, filtration was performed and vacuum concentration was performed. Water (20 mL) was added, and the mixture was extracted and washed with a mixed solvent of chloroform-methanol (4: 1) (100 mL × 4). The organic layer was concentrated under reduced pressure to obtain (R) -2- (acetoxymethyl) triethylenediamine (1.7 g). The aqueous layer was azeotroped with toluene, and methanol (4 mL) and Amberlite IRA400 (OH ⁻ ) (1.4 g) were added to the resulting crude product and stirred. After 2 hours, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain (S) -2- (hydroxymethyl) triethylenediamine (984 mg, 35%).

The obtained (S) -2- (hydroxymethyl) triethylenediamine (984 mg, 6.97 mmol) was mixed with chloroform (13.9 mL), acetic acid (398 μL, 7.0 mmol), LipasePS “Amano” IM (953 mg), acetic acid. Vinyl (1.28 mL, 13.9 mmol) was added and stirred at room temperature. After 45 hours, NMR confirmed that the reaction ratio was 6: 1 [2- (acetoxymethyl) triethylenediamine: 2- (hydroxymethyl) triethylenediamine]. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. Thereafter, THF (8.3 mL) and Amberlyst A21 (2.8 g) were added to the reaction crude product and stirred. After 2 hours, filtration was performed and vacuum concentration was performed. Water (15 mL) was added, and the mixture was extracted and washed with a mixed solvent of chloroform-methanol (4: 1) (100 mL × 4). The aqueous layer was azeotroped with toluene, and methanol (3 mL) and Amberlite IRA400 (OH ⁻ ) (300 mg) were added to the resulting crude product and stirred. After 2 hours, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain (S) -2- (hydroxymethyl) triethylenediamine (95 mg, 10%, 78% ee).

Furthermore, chloroform (872 μL), acetic acid (25 μL, 0.44 mmol), LipasePS “Amano” IM (43 mg), acetic acid were added to the obtained (S) -2- (hydroxymethyl) triethylenediamine (62 mg, 0.436 mmol). Vinyl (80 μL, 0.87 mmol) was added and stirred at room temperature. After 26 hours, further vinyl acetate (80 μL, 0.87 mmol) was added and stirred for 24 hours. It was confirmed by NMR that the reaction ratio was 0.6: 1 [2- (acetoxymethyl) triethylenediamine: 2- (hydroxymethyl) triethylenediamine]. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. Thereafter, THF (1 mL) and Amberlyst A21 (176 mg) were added to the reaction crude product and stirred. After 2 hours, filtration was performed and vacuum concentration was performed. Water (10 mL) was added, and the mixture was extracted and washed with a mixed solvent of chloroform-methanol (4: 1) (33 mL × 4). The aqueous layer was azeotroped with toluene, and methanol (1 mL) and Amberlite IRA400 (OH ⁻ ) (82 mg) were added to the resulting crude product and stirred. After 2 hours, filtration was performed and the filtrate was concentrated under reduced pressure. The mixture was washed with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to obtain (S) -2- (hydroxymethyl) triethylenediamine (32 mg, 52%, 88% ee). Optical purity and absolute configuration correspond to reacting the resulting 2- (hydroxymethyl) triethylenediamine with (S) -α-methoxy-α- (trifluoromethyl) phenylacetic acid ((S) -MTPA). The MTPA ester was determined by comparison with the product of Reference Example-7.

(S) -2- (hydroxymethyl) triethylenediamine: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.54 (dd, J = 10.0, 12.2 Hz, 1 H), 3.50 (dd, J = 4.8, 12.2 Hz, 1H), 2.97-2.86 (m, 4H), 2.86-2.76 (m, 3H), 2.76-2.62 (m, 2H), 2.58 (m, 1H), 2.20 (m, 1H).

(R) -2- (acetoxymethyl) triethylenediamine: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.20 (dd, J = 8.6 Hz, 11.9 Hz, 1H), 4.07 (dd, J = 5.5 Hz, 11.9 Hz, 1H), 3.08 (m, 1H), 3.02-2.91 (m, 3H), 2.91-2.80 (m, 1H), 2.80- 2.71 (m, 2H), 2.71-2.61 (m, 3H), 2.39 (ddd, J = 1.9 Hz, 7.5 Hz, 13.1 Hz, 1H), 2.09 (s , 3H).

  Example-3

To 2- (hydroxymethyl) triethylenediamine (14.2 g, 100 mmol) was added methylene chloride (200 mL), acetic acid (5.70 mL, 100 mmol), LipasePL (16.2 g), vinyl acetate (9.2 mL, 100 mmol). And stirred at room temperature. After 5 hours, it was confirmed by NMR that the reaction ratio was 0.8: 1.0 [2- (acetoxymethyl) triethylenediamine: 2- (hydroxymethyl) triethylenediamine]. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. Then, THF (100 mL) and Amberlyst A21 (40 g) were added to the reaction crude product and stirred. After 2 hours, filtration was performed and vacuum concentration was performed. Water (100 mL) was added, and the mixture was extracted with a chloroform-methanol (4: 1) mixed solvent (500 mL × 4). The extract was dried over sodium sulfate and concentrated under reduced pressure to obtain (S) -2- (acetoxymethyl) triethylenediamine (7.9 g, 43%). Methanol (34 mL) and Amberlite IRA-400 (OH ⁻ ) (11.9 g) were added to the obtained product, and the mixture was stirred at 50 ° C. After 2 hours, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain (S) -2- (hydroxymethyl) triethylenediamine (6.1 g, 99%, 36% ee).

To the obtained (S) -2- (hydroxymethyl) triethylenediamine (6.1 g, 43 mmol), methylene chloride (86 mL), acetic acid (2.45 mL, 43 mmol), LipasePL (6.9 g), vinyl acetate (4 0.0 mL, 43 mmol) was added and stirred at room temperature. After 25 hours, it was confirmed by NMR that the reaction ratio was 0.9: 1.0 [2- (acetoxymethyl) triethylenediamine: 2- (hydroxymethyl) triethylenediamine]. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. Then, THF (43 mL) and Amberlyst A21 (17.2 g) were added to the reaction crude product and stirred. After 2 hours, filtration was performed and vacuum concentration was performed. Water (43 mL) was added, and the mixture was extracted with a mixed solvent of chloroform-methanol (4: 1) (215 mL × 4). The extract was dried over sodium sulfate and concentrated under reduced pressure to obtain (S) -2- (acetoxymethyl) triethylenediamine (3.2 g, 40%). Methanol (13.6 mL) and Amberlite IRA-400 (OH ⁻ ) (4.76 g) were added to the obtained product, and the mixture was stirred at 50 ° C. After 2 hours, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain (S) -2- (hydroxymethyl) triethylenediamine (2.4 g, 40%, 54% ee).

To the obtained (S) -2- (hydroxymethyl) triethylenediamine (2.4 g, 17 mmol), methylene chloride (34 mL), acetic acid (980 μL, 17 mmol), LipasePL (2.8 g), vinyl acetate (1.6 mL). , 17 mmol) and stirred at room temperature. After 5 hours, it was confirmed by NMR that the reaction ratio was 0.8: 1.0 [2- (acetoxymethyl) triethylenediamine: 2- (hydroxymethyl) triethylenediamine]. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. Thereafter, THF (17 mL) and Amberlyst A21 (6.9 g) were added to the reaction crude product and stirred. After 2 hours, filtration was performed and vacuum concentration was performed. Water (17.2 mL) was added, and the mixture was extracted with a chloroform-methanol (4: 1) mixed solvent (86 mL × 4). The extract was dried over sodium sulfate and concentrated under reduced pressure to obtain (S) -2- (acetoxymethyl) triethylenediamine (1.4 g, 43%). Methanol (5.8 mL) and Amberlite IRA-400 (OH ⁻ ) (2.0 g) were added to the obtained product, and the mixture was stirred at 50 ° C. After 2 hours, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain (S) -2- (hydroxymethyl) triethylenediamine (1.0 g, 99%, 75% ee).

To the obtained (S) -2- (hydroxymethyl) triethylenediamine (1.0 g, 7.3 mmol), methylene chloride (14.6 mL), acetic acid (421 μL, 7.3 mmol), LipasePL (240 mg), vinyl acetate (688 μL, 7.3 mmol) was added and stirred at room temperature. After 25 hours, it was confirmed by NMR that the reaction ratio was 0.9: 1.0 [2- (acetoxymethyl) triethylenediamine: 2- (hydroxymethyl) triethylenediamine]. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. Then, THF (7.3 mL) and Amberlyst A21 (3.0 g) were added to the reaction crude product and stirred. After 2 hours, filtration was performed and vacuum concentration was performed. Water (7.4 mL) was added, and the mixture was extracted with a chloroform-methanol (4: 1) mixed solvent (37 mL × 4). The extract was dried over sodium sulfate and concentrated under reduced pressure to obtain (S) -2- (acetoxymethyl) triethylenediamine (560 mg, 40%). Methanol (2.3 mL) and Amberlite IRA-400 (OH ⁻ ) (800 mg) were added to the obtained product, and the mixture was stirred at 50 ° C. After 2 hours, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain (S) -2- (hydroxymethyl) triethylenediamine (400 mg, 99%, 83% ee).

To the obtained (S) -2- (hydroxymethyl) triethylenediamine (400 mg, 2.9 mmol), methylene chloride (5.8 mL), acetic acid (168 μL, 2.9 mmol), LipasePL (96 mg), vinyl acetate (275 μL). , 2.9 mmol), and stirred at room temperature. After 25 hours, it was confirmed by NMR that the reaction ratio was 0.7: 1.0 [2- (acetoxymethyl) triethylenediamine: 2- (hydroxymethyl) triethylenediamine]. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. Thereafter, THF (2.9 mL) and Amberlyst A21 (1.2 g) were added to the reaction crude product and stirred. After 2 hours, filtration was performed and vacuum concentration was performed. Water (2.96 mL) was added, and the mixture was extracted with a chloroform-methanol (4: 1) mixed solvent (15 mL × 4). The extract was dried over sodium sulfate and concentrated under reduced pressure to give (S) -2- (acetoxymethyl) triethylenediamine (160 mg, 30%). Methanol (1 mL) and Amberlite IRA-400 (OH ⁻ ) (240 mg) were added to the obtained product, and the mixture was stirred at 50 ° C. After 2 hours, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain (S) -2- (hydroxymethyl) triethylenediamine (120 mg, 99%, 90% ee). Optical purity and absolute configuration correspond to reacting the resulting 2- (hydroxymethyl) triethylenediamine with (S) -α-methoxy-α- (trifluoromethyl) phenylacetic acid ((S) -MTPA). The MTPA ester was determined by comparison with the product of Reference Example-7.

  Example-4

  To a solution of (R) -2- (hydroxymethyl) triethylenediamine (142 mg, 1 mmol) in ethyl acetate (3.3 mL) was added methyl iodide (114 mg, 0.8 mmol) at 0 ° C., and the mixture was stirred for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The reaction crude product was decanted with ethyl acetate and chloroform to obtain (R) -2- (hydroxymethyl) -4-methyltriethylenediamine iodide (157 mg, 70%).

¹ H-NMR (400 MHz, DMSO-d6) δ 4.90 (dd, J = 4.8, 6.7 Hz, 1H), 3.55-3.43 (m, 2H), 3.37 (s, 1H ), 3.25-3.20 (m, 3H), 3.20-3.10 (m, 3H), 3.10-3.00 (m, 3H), 2.95 (s, 3H), 2.81 (s, 1H).

  Example-5

  To a solution of (S) -2- (acyloxymethyl) triethylenediamine (142 mg, 1 mmol) in ethyl acetate (3.3 mL) was added methyl trifluoromethanesulfonate (90.5 μL, 0.8 mmol) at 0 ° C. Stir for hours. The reaction solution was filtered, and the resulting solid was further washed with chloroform. The obtained washing solution was concentrated under reduced pressure to obtain (R) -2- (acyloxymethyl) -4-methyltriethylenediamine triflate (66 mg, 27%).

¹ H-NMR (400 MHz, DMSO-d6) δ 4.25 (dd, J = 7.8, 11.7 Hz, 1H), 4.01 (dd, J = 5.3, 11.7 Hz, 1H), 3 .48-3.38 (m, 2H), 3.28-3.14 (m, 4H), 3.14-3.02 (m, 3H), 3.13-2.86 (m, 5H) , 2.03 (s, 3H).

¹⁹ F-NMR (376 MHz, DMSO-d6) δ-77.8 (s, 3F).

  Reference Example-1

  (R) -piperazin-2-ylcarboxylic acid dihydrochloride (100 mg, 0.492 mmol) is dissolved in water (1 mL) and 1,4-dioxane (1.6 mL), and the pH is adjusted with 50% sodium hydroxide solution. = 11. Then, benzyl chloroformate (140 μL, 0.984 mmol) was added dropwise and stirred at room temperature. After 1 hour, the reaction solution was returned to pH = 11 again, benzyl chloroformate (20 μL, 0.14 mmol) was added dropwise, and the mixture was stirred for 30 minutes. The reaction solution was washed with diethyl ether, and then the aqueous layer was adjusted to pH = 2 and extracted with ethyl acetate. The obtained organic layer was concentrated under reduced pressure to obtain (R) -1,4-bis (benzyloxycarbonyl) piperazin-2-ylcarboxylic acid (145 mg, 73%).

[Α] _D ²² = + 10.0 ° (C 0.174, CHCl ₃ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.36-7.32 (m, 10H), 5.21-5.17 (m, 4H), 4.80-4.62 (m, 2H), 4 .12-3.88 (m, 2H), 3.38-3.10 (m, 2H), 2.99-2.87 (m, 1H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 172.7 (1C), 156.3-155.3 (m, 2C), 136.1 (1C), 136.0 (1C), 128.56 (4C) , 128.3 (1C), 128.2 (1C), 128.0 (4C), 68.0 (1C), 67.8 (1C) 54.3 (0.5C), 53.8 (0. 5C), 44.5 (0.5C), 44.3 (0.5C), 43.1 (1C), 41.2 (0.5C), 40.8 (0.5C).

  In a similar manner, (S) -piperazin-2-ylcarboxylic acid dihydrochloride (4.0 g) was converted to (S) -1,4-bis (benzyloxycarbonyl) piperazin-2-ylcarboxylic acid (5.8 g, 73 %).

  Reference example-2

BH ₃ -THF (713 μL, 0.68 mmol) was slowly added dropwise to a THF solution of (R) -1,4-bis (benzyloxycarbonyl) piperazin-2-ylcarboxylic acid (129 mg, 0.32 mmol) under an argon atmosphere. did. Thereafter, the temperature was raised to 50 ° C. and stirred for 4 hours. After the reaction, the temperature was returned to room temperature, methanol (76 μL) was added dropwise, and the mixture was heated to reflux for 1 hour. Thereafter, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1, Rf = 0.13) to give (R) -1,4-bis (benzyloxy). Carbonyl) piperazin-2-ylmethanol (88 mg, 73%) was obtained.

[Α] _D ²² = + 21.9 ° (C 0.200, CHCl ₃ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.37-7.33 (m, 10H), 5.18-5.11 (m, 4H), 4.32-3.87 (m, 4H), 3 68-3.45 (m, 2H), 3.19-2.89 (m, 3H).

¹³ C-NMR (400 MHz, CDCl ₃ ) δ 156.2-155.1 (m, 2C), 136.2 (2C), 128.6 (2C), 128.6 (2C), 128.3 (1C) , 128.2 (1C), 128.0 (4C), 67.6 (2C), 60.4-58.3 (m, 1C), 52.5 (1C), 43.9-43.1 ( m, 2C), 39.6 (1C).

  In a similar manner, (S) -1,4-bis (benzyloxycarbonyl) piperazin-2-ylcarboxylic acid (5.8 g) was converted to (S) -1,4-bis (benzyloxycarbonyl) piperazin-2-yl. Methanol (4.0 g, 72%) was obtained.

  Reference example-3

  To a dichloromethane solution (10 mL) of (R) -1,4-bis (benzyloxycarbonyl) piperazin-2-ylmethanol (384 mg, 1.0 mmol), 4-dimethylaminopyridine (122 mg, 1 mmol), triethylamine (167 μL, 1.2 mmol) and tert-butyldiphenylchlorosilane (312 μL, 1.2 mmol) were added, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1, Rf = 0.42) to obtain (R) -1,4-bis. (Benzyloxycarbonyl) piperazin-2-ylmethyl tert-butyldiphenylsilyl ether (563 mg, 90%) was obtained.

[Α] _D ²² = + 11.8 ° (C 0.200, CHCl ₃ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.65-7.55 (m, 4H), 7.43-7.37 (m, 2H), 7.37-7.24 (m, 14H), 5 .22-5.06 (m, 3H), 4.97 (m, 1H), 4.40-4.18 (m, 2H). 4.09-3.77 (m, 2H), 3.77-3.60 (m, 2H), 3.09 (dd, J = 4.3 Hz, 13.6 Hz, 1H), 3.07-2 .93 (m, 2H) 1.00 (s, 9H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 156.2-155.8 (m, 2C), 136.9 (2C), 136.1 (4C), 133.7 (1C), 133.7 (1C) , 130.3 (1C), 130.3 (1C), 129.0 (4C), 128.6 (2C), 128.5 (2C), 128.5 (2C), 128.3 (2C), 128.3 (2C), 68.0 (2C), 60.8 (1C), 53.1 (1C), 43.9 (1C), 43.3 (1C), 40.1 (1C), 27 .2 (3C), 19.7 (1C).

  In a similar manner, (S) -1,4-bis (benzyloxycarbonyl) piperazin-2-ylmethanol (4.0 g) was converted to (S) -1,4-bis (benzyloxycarbonyl) piperazin-2-ylmethyl. Tert-butyldiphenylsilyl ether (5.4 g, 84%) was obtained.

  Reference example-4

  To a solution of (R) -1,4-bis (benzyloxycarbonyl) piperazin-2-ylmethyl tert-butyldimethylsilyl ether (563 mg, 0.9 mmol) in ethanol (9 mL) was added palladium carbon (143 mg) followed by hydrogen. Under atmosphere and stirred vigorously at room temperature. After 2 hours, the reaction was stopped under an argon atmosphere. The reaction solution was filtered through Celite to remove palladium on carbon. Thereafter, the filtrate was concentrated under reduced pressure to obtain (R) -piperazin-2-ylmethyl tert-butyldiphenylsilyl ether (32 mg, quantitative).

[Α] _D ²² = −2.9 ° (C 0.200, CHCl ₃ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.67-7.63 (m, 4H), 7.45-7.36 (m, 6H), 3.58 (dd, J = 4.7 Hz, 10. 1 Hz, 1H), 3.51 (dd, J = 7.4 Hz, 10.1 Hz, 1H), 3.01 (d, J = 11.2 Hz, 1H), 2.95-2.82 (m, 4H) ), 2.82-2.70 (m, 1H), 2.43 (dd, J = 11.2 Hz, 11.4 Hz, 1H), 1.05 (s, 9H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 136.1 (2C), 136.1 (2C), 134.0 (1C), 133.9 (1C), 130.3 (2C), 128.3 (4C) ), 77.8 (1C), 66.9 (1C), 58.2 (1C), 47.3 (1C), 47.3 (1C), 27.5 (3C), 19.8 (1C) .

  In a similar manner, (S) -1,4-bis (benzyloxycarbonyl) piperazin-2-ylmethyl tert-butyldiphenylsilyl ether (5.4 g) was converted to (S) -piperazin-2-ylmethyl tert-butyldiphenylsilyl. Ether (3.0 g, quantitative) was obtained.

  Reference Example-5

Under an argon atmosphere, a solution of (R) -piperazin-2-ylmethyl tert-butyldiphenylsilyl ether (1.97 g, 5.55 mmol) in toluene (18.5 mL), triethylamine (1.7 mL, 12.4 mmol) and 1 , 2-dibromoethane (478 μL, 5.64 mmol) was added, and the mixture was heated and stirred at 110 ° C. After 24 hours, the temperature was returned to room temperature, and the reaction solution was filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (CHCl _{3 /} MeOH = 10/1, Rf = 0.4), and (R) -2-[(tert-butyldiphenyl). Silyloxy) methyl] triethylenediamine (442 mg, 21%) was obtained.

[Α] _D ²² = + 45.5 ° (C 0.200, CHCl ₃ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.68-7.65 (m, 4H), 7.45-7.36 (m, 6H), 3.79 (dd, J = 1.1 Hz, 6. 08 Hz, 2H), 2.98-2.91 (m, 2H), 2.91-2.77 (m, 3H), 2.72-2.63 (m, 5H), 2.55 (dd, J = 8.1 Hz, 13.0 Hz, 1H), 1.06 (s, 9H).

¹³ C-NMR (100 MHz, CDCl ₃ ) δ 135.6 (4C), 133.4 (1C), 133.3 (1C), 129.7 (2C), 127.7 (4C), 65.5 (1C) ), 56.0 (1C), 50.6 (1C), 49.9 (1C), 47.1 (1C), 46.3 (1C), 42.4 (1C), 26.8 (3C) 19.2 (1C).

  In a similar manner, (S) -piperazin-2-ylmethyl tert-butyldiphenylsilyl ether (3.0 g) to (S) -2-[(tert-butyldiphenylsilyloxy) methyl] triethylenediamine (500 mg, 20% )

  Reference Example-6

((R) -2-[(tert-butyldiphenylsilyloxy) methyl] triethylenediamine (207 mg, 0.541 mmol) was dissolved in a 10% sodium hydroxide methanol solution (3.1 mL), and the mixture was heated to reflux for 2 hours. After completion of the reaction, the reaction solution was washed with hexane, and the reaction solution was concentrated under reduced pressure.The crude product was dissolved in THF (1.8 mL), 4M-HCl (135 μL, 0.541 mmol) was added, and the mixture was stirred for 30 minutes. Thereafter, the reaction solution was filtered, the obtained solid was dissolved in methanol (2 mL), Amberlite IRA400 (OH ⁻ ) (207 mg) was added and stirred, and after 1 hour, filtration was performed and the filtrate was concentrated. (R) -2- (hydroxymethyl) triethylenediamine (17 mg, 22%) was obtained.

[Α] _D ²² = 71.8 ° (C 0.200, MeOH).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.59 (dd, J = 10.0 Hz, 10.6 Hz, 1 H), 3.50 (dd, J = 4.5 Hz, 10.6 Hz, 1 H), 3. 0-2.87 (m, 4H), 2.87-2.75 (m, 3H), 2.75-2.65 (m, 2H), 2.65-2.52 (m, 1H), 2.25-2.17 (m, 2H).

  By the same method, (S) -2- (hydroxymethyl) triethylenediamine (71 mg, 38%) was obtained from (S) -2-[(tert-butyldiphenylsilyloxy) methyl] triethylenediamine (500 mg).

[Α] _D ²¹ = −74.9 ° (C 0.21, MeOH).

  Reference Example-7

  Under an argon atmosphere, p-tosyl chloride (19.4 mg, 0.10 mmol) and (S) -α-methoxy-α- (trifluoromethyl) phenylacetic acid (20 mg, 0.085 mmol) in acetonitrile (1 mL) and N-methylimidazole (20 μL, 0.256 mmol) was added in an ice bath. After stirring for 30 minutes, (R) -2- (hydroxymethyl) triethylenediamine (12.1 mg 0.085 mmol) was added, and the mixture was stirred at 0 to 5 ° C. for 3 hours.

After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (CHCl _{3 /} MeOH = 9/1, Rf = 0.3). [(R) -1,4-diazabicyclo [2,2,2] oct-2-ylmethyl] = (S) -α-methoxy-α- (trifluoromethyl) phenylacetic acid ester (27%, 90%) Obtained.

[(R) -1,4-diazabicyclo [2,2,2] oct-2-ylmethyl] = (S) -α-methoxy-α- (trifluoromethyl) phenyl acetate: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.57-7.55 (m, 2H), 7.43-7.37 (m, 3H), 4.52 (dd, J = 7.64, 11.3, 1H), 4. 18 (dd, J = 6.36 Hz, 11.3 Hz, 1H), 3.56 (s, 3H), 3.09-3.03 (m, 1H), 2.95-2.74 (m, 4H) ), 2.73-2.57 (m, 5H), 2.39-2.34 (m, 1H).

¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-71.65 (s, 3F).

  Similarly, from (RS) -2- (hydroxymethyl) triethylenediamine, [(RS) -1,4-diazabicyclo [2,2,2] oct-2-ylmethyl] = (S) -α-methoxy-α- (Trifluoromethyl) phenyl acetate was obtained.

  NMR spectrum measured and NMR spectrum of [(R) -1,4-diazabicyclo [2,2,2] oct-2-ylmethyl] = (S) -α-methoxy-α- (trifluoromethyl) phenylacetate [(S) -1,4-diazabicyclo [2,2,2] oct-2-ylmethyl] = (S) -α-methoxy-α- (trifluoromethyl) phenyl acetate ester The NMR spectrum of was assigned.

[(S) -1,4-diazabicyclo [2,2,2] oct-2-ylmethyl] = (S) -α-methoxy-α- (trifluoromethyl) phenyl acetate: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.57-7.55 (m, 2H), 7.43-7.37 (m, 3H), 4.60 (dd, J = 7.64 Hz, 11.3 Hz, 1H), 4. 26 (dd, J = 6.36 Hz, 11.3 Hz, 1H), 3.57 (s, 3H), 3.09-3.03 (m, 1H), 2.95-2.74 (m, 4H) ), 2.73-2.57 (m, 5H), 2.39-2.34 (m, 1H).

¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-71.54 (s, 3F).

The ¹⁹ F-NMR of the esterified product of (R) -2- (hydroxymethyl) triethylenediamine and (S) -MTPA has a peak at −71.65 ppm, and (S) -2- (hydroxymethyl) tri ¹⁹ F-NMR of the esterified product of ethylenediamine and (S) -MTPA has a peak at −71.54. Therefore, the optical purity of 2- (hydroxymethyl) triethylenediamine can be calculated by reacting with (S) -MTPA to convert to the corresponding ester, and measuring ¹⁹ F-NMR of the esterified product.

Claims (1)

Formula (1a)
(Hydroxymethyl) triethylenediamine represented by the general formula (2)
(In the formula, R ¹ represents an alkyl group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 12 carbon atoms, and R ² , R ^3, and R ⁴ are each independently a hydrogen atom. Or represents a C1-C4 alkyl group.)
A vinyl ester derivative represented by the general formula (1c), wherein the hydrolase selected from LipasePL and LipasePS “Amano” IM is contacted
(Wherein R ¹ represents the same meaning as described above, and * represents an asymmetric center.)
An optically active (R or S)-(acyloxymethyl) triethylenediamine represented by formula (1b)
(In the formula, * represents the same meaning as described above.)
The manufacturing method of optically active (R or S)-(hydroxymethyl) triethylenediamine represented by these.