JPH09227556A - Isoxazolidine compound and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an isoxazolidine compound useful as a raw material for producing an amino-alcohol compound useful as an intermediate for a carbapenem derivative important as a medicine, an agrochemical, etc., by reacting a specific pyrrolidine derivative with a nitron compound. SOLUTION: This new isoxazolidine compound is shown by formula I (R<1> is H or a hydroxy group-protecting group; R<2> is an amino group-protecting group; R<3> is an alkyl or an aralkyl) e.g. (2S,4R)-N-t-butoxycarbonyl-4-t- butyldimethylsiloxy-2-[(5R)-2-methyl-5-isoxazolidinyl]pyrrolidine, etc.}. The derivative is useful as a raw material for producing an amino-alcohol compound suitable as an intermediate for a carbapenem derivative. The compound is obtained by reacting a pyrrolidine derivative of formula II with a nitron compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an isoxazolidine compound useful as a production intermediate for medicines and agricultural chemicals, and a method for producing the same.

[0002]

2. Description of the Related Art General formula (4)

[0003]

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[In the formula, R ¹ represents a hydrogen atom or a hydroxyl group protecting group, R ⁴ represents a hydrogen atom or an amino group protecting group, and R ⁵ represents a hydrogen atom, an alkyl group or an aralkyl group. ] The amino alcohol compound represented by the above is a compound useful as an intermediate of a carbapenem derivative which is an antibiotic. Conventionally, as a method for synthesizing this compound, JP-A-6-8785 has been used.
As described in Japanese Patent Publication No. 8, a method is known in which a 2-formylpyrrolidine derivative and an acetic acid ester compound are reacted with each other, then converted into an amide compound, and then a reduction reaction is performed.
However, in this manufacturing method, the first reaction step is from -60 to
Unless it was carried out at a low temperature of −78 ° C., a sufficient yield could not be obtained, and the operation was complicated.

[0005]

Therefore, in the production of the above amino alcohol compound, it has been desired to develop a method for producing the amino alcohol compound in a high yield without passing through a reaction step at a low temperature.

[0006] Against the above background, the present invention aims to provide a compound useful as a raw material used in such a method for producing an amino alcohol compound.

[0007]

Means for Solving the Problems The present inventors have intensively studied in view of the above problems. As a result, they have found that the above problems can be solved by utilizing a novel specific isoxazolidine compound, and have completed the present invention.

That is, the present invention provides a compound represented by the general formula (1):

[0009]

[Chemical 6]

[In the formula, R ¹ represents a hydrogen atom or hydroxyl protecting group, R ² represents an amino protecting group, and R ³ represents an alkyl group or an aralkyl group. ] The isoxazolidine compound shown by these.

In the general formula (1), as the hydroxyl-protecting group for R ¹ or the amino-protecting group for R ² , any known protecting group can be used. Preferably, a lower alkoxycarbonyl group having 1 to 5 carbon atoms such as methyloxycarbonyl group and t-butyloxycarbonyl group, for example, 2-iodyloxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group. A lower halogenoalkoxycarbonyl group having 1 to 5 carbon atoms such as benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, and p-nitrobenzyloxycarbonyl group. Group, for example, acyl group such as formyl group, acetyl group, benzoyl group, aralkyl group such as benzyl group and triphenylmethyl group, for example, methyl group, ethyl group, t-butyl group having 1 to 5 carbon atoms Lower alkyl groups such as trimethylsilyl Group, triethylsilyl group, trialkylsilyl group such as t-butyldimethylsilyl group, lower alkylsulfonyl group having 1 to 5 carbon atoms such as methanesulfonyl, arylsulfonyl group such as p-toluenesulfonyl group. is there. Preferably, the carbon number is 1
5 lower alkoxycarbonyl groups, aralkyloxycarbonyl groups, aralkyl groups, trialkylsilyl groups,
It is a lower alkylsulfonyl group having 1 to 5 carbon atoms.

The alkyl group for R ³ is not particularly limited, but a lower alkyl group having 1 to 5 carbon atoms such as a methyl group, an ethyl group and a t-butyl group is preferable. Further, the aralkyl group of R ³ is not particularly limited, but is a benzyl group, p-nitrobenzyl group, α-
Those having 7 to 19 carbon atoms such as methylbenzyl group, diphenylmethyl group and triphenylmethyl group are preferred.

In the present invention, the specific examples of the isoxazolidine compound represented by the above general formula (1) are as follows:
S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[(5R) -2-methyl-
5-isoxazolidinyl] pyrrolidine, (2S, 4
R) -N-benzyl-4-t-butyldimethylsiloxy-2-[(5R) -2-methyl-5-isoxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyloxycarbonyl-4- t-butyldimethylsiloxy-2-
[(5R) -2-Methyl-5-isoxazolidinyl]
Pyrrolidine, (2S, 4R) -Nt-butoxycarbonyl-4-methanesulfonyloxy-2-[(5R)-
2-methyl-5-isoxazolidinyl] pyrrolidine,
(2S, 4R) -N-benzyl-4-methanesulfonyloxy-2-[(5R) -2-methyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyloxycarbonyl-4 -Methanesulfonyloxy-2
-[(5R) -2-Methyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -Nt-butoxycarbonyl-4-hydroxy-2-[(5R) -2-methyl-5- Isoxazolidinyl] pyrrolidine, (2S,
4R) -N-benzyl-4-hydroxy-2-[(5
R) -2-Methyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyloxycarbonyl-4-hydroxy-2-[(5R) -2-methyl-5-
Isoxazolidinyl] pyrrolidine, (2S, 4R)-
Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[(5R) -2-benzyl-5-isoxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyl-4-t-. Butyldimethylsiloxy-2-[(5
R) -2-benzyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyloxycarbonyl-4-t-butyldimethylsiloxy-2-[(5R)
-2-Benzyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -Nt-butoxycarbonyl-4
-Methanesulfonyloxy-2-[(5R) -2-benzyl-5-isooxazolidinyl] pyrrolidine, (2
S, 4R) -N-Benzyl-4-methanesulfonyloxy-2-[(5R) -2-benzyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyloxycarbonyl-4- Methanesulfonyloxy-2-
[(5R) -2-Benzyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -Nt-butoxycarbonyl-4-hydroxy-2-[(5R) -2-benzyl-5-iso Oxazolidinyl] pyrrolidine, (2
S, 4R) -N-benzyl-4-hydroxy-2-
[(5R) -2-Benzyl-5-isoxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyloxycarbonyl-4-hydroxy-2-[(5R) -2-benzyl-5-isooxa Zolidinyl] pyrrolidine, (2
S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[(5R) -2-t-butyl-5-isoxazolidinyl] pyrrolidine (2S, 4
R) -N-benzyl-4-t-butyldimethylsiloxy-2-[(5R) -2-t-butyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyloxycarbonyl- 4-t-butyldimethylsiloxy-
2-[(5R) -2-t-butyl-5-isoxazolidinyl] pyrrolidine, (2S, 4R) -Nt-butoxycarbonyl-4-methanesulfonyloxy-2-
[(5R) -2-t-Butyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyl-4-
Methanesulfonyloxy-2-[(5R) -2-t-butyl-5-isooxazolidinyl] pyrrolidine, (2
S, 4R) -N-Benzyloxycarbonyl-4-methanesulfonyloxy-2-[(5R) -2-t-butyl-5-isooxazolidinyl] pyrrolidine, (2S, 4
R) -Nt-butoxycarbonyl-4-hydroxy-
2-[(5R) -2-t-butyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyl-
4-hydroxy-2-[(5R) -2-t-butyl-5
-Isoxazolidinyl] pyrrolidine, (2S, 4R)
-N-benzyloxycarbonyl-4-hydroxy-2
-[(5R) -2-t-Butyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-
[(5S) -2-Methyl-5-isooxazolidinyl]
Pyrrolidine (2S, 4R) -N-benzyl-4-t-butyldimethylsiloxy-2-[(5S) -2-methyl-
5-isoxazolidinyl] pyrrolidine, (2S, 4
R) -N-benzyloxycarbonyl-4-t-butyldimethylsiloxy-2-[(5S) -2-methyl-5-
Isoxazolidinyl] pyrrolidine, (2S, 4R)-
Nt-butoxycarbonyl-4-methanesulfonyloxy-2-[(5S) -2-methyl-5-isoxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyl-4-methanesulfonyloxy- 2-[(5S) -2-
Methyl-5-isooxazolidinyl] pyrrolidine, (2
S, 4R) -N-Benzyloxycarbonyl-4-methanesulfonyloxy-2-[(5S) -2-methyl-5
-Isoxazolidinyl] pyrrolidine, (2S, 4R)
-Nt-butoxycarbonyl-4-hydroxy-2-
[(5S) -2-Methyl-5-isooxazolidinyl]
Pyrrolidine, (2S, 4R) -N-benzyl-4-hydroxy-2-[(5R) -2-methyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyloxycarbonyl-4 -Hydroxy-2-[(5S)
-2-Methyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -Nt-butoxycarbonyl-4
-T-Butyldimethylsiloxy-2-[(5S) -2-
Benzyl-5-isooxazolidinyl] pyrrolidine,
(2S, 4R) -N-benzyl-4-t-butyldimethylsiloxy-2-[(5S) -2-benzyl-5-isoxazolidinyl] pyrrolidine, (2S, 4R) -N-
Benzyloxycarbonyl-4-t-butyldimethylsiloxy-2-[(5S) -2-benzyl-5-isoxazolidinyl] pyrrolidine, (2S, 4R) -Nt-
Butoxycarbonyl-4-methanesulfonyloxy-2
-[(5S) -2-Benzyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyl-4-
Methanesulfonyloxy-2-[(5S) -2-benzyl-5-isoxazolidinyl] pyrrolidine, (2S,
4R) -N-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(5S) -2-benzyl-5-
Isoxazolidinyl] pyrrolidine, (2S, 4R)-
Nt-butoxycarbonyl-4-hydroxy-2-
[(5S) -2-Benzyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyl-4-
Hydroxy-2-[(5S) -2-benzyl-5-isoxazolidinyl] pyrrolidine, (2S, 4R) -N-
Benzyloxycarbonyl-4-hydroxy-2-
[(5S) -2-Benzyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-
[(5S) -2-t-Butyl-5-isooxazolidinyl] pyrrolidine (2S, 4R) -N-benzyl-4-t
-Butyldimethylsiloxy-2-[(5S) -2-t-
Butyl-5-isooxazolidinyl] pyrrolidine, (2
S, 4R) -N-benzyloxycarbonyl-4-t-
Butyldimethylsiloxy-2-[(5S) -2-t-butyl-5-isoxazolidinyl] pyrrolidine, (2
S, 4R) -Nt-butoxycarbonyl-4-methanesulfonyloxy-2-[(5S) -2-t-butyl-
5-isoxazolidinyl] pyrrolidine, (2S, 4
R) -N-benzyl-4-methanesulfonyloxy-2
-[(5S) -2-t-Butyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyloxycarbonyl-4-methanesulfonyloxy-2-
[(5S) -2-t-Butyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -Nt-butoxycarbonyl-4-hydroxy-2-[(5S) -2-t-
Butyl-5-isooxazolidinyl] pyrrolidine, (2
S, 4R) -N-benzyl-4-hydroxy-2-
[(5S) -2-t-Butyl-5-isooxazolidinyl] pyrrolidine, (2S, 4R) -N-benzyloxycarbonyl-4-hydroxy-2-[(5S) -2-t.
-Butyl-5-isooxazolidinyl] pyrrolidine and the like.

The isoxazolidine compound represented by the general formula (1) has optical isomers and stereoisomers based on asymmetric carbons at the 2-position and 4-position of the pyrrolidine ring and the 5-position of the isoxazolidine ring, Although all of these isomers are represented by a single formula for the sake of convenience, the scope of the present invention is not limited thereto, and the present invention includes all of the above isomers. However, considering the efficacy of the carbapenem derivative having this isoxazolidine compound as an intermediate, [(2S, 4R), (5
R)] coordination and [(2S, 4R), (5S)] coordination compounds are preferable, and [(2S, 4R), (5R)] coordination is particularly preferable.

The above pyrrolidine derivative can be confirmed by the following means.

(1) By measuring the ¹ H-nuclear magnetic resonance spectrum, the bonding mode of hydrogen atoms present in the compound can be known. For example, a spectrum of 8 methylene group protons near 2 to 4 ppm and 3 methine group protons near 4 to 5 ppm is shown.

(2) By measuring the infrared absorption spectrum, the characteristic absorption derived from the functional group of the compound can be observed. For example, when R ¹ and R ² are lower alkoxycarbonyl groups having 1 to 5 carbon atoms, the absorption spectrum of the carbonyl group is shown near 1700 cm ^-1 .

In the present invention, the isoxazolidine compound represented by the general formula (1) may be produced by any method. Preferably, the general formula (2)

[0019]

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[In the formula, R ¹ represents a hydrogen atom or a hydroxyl protecting group, and R ² represents an amino protecting group. ] And the general formula (3)

[0021]

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It is preferably produced by reacting with a nitrone compound represented by the formula: wherein R ³ represents an alkyl group or an aralkyl group.

In the present invention, the reaction of the pyrrolidine derivative represented by the general formula (2) and the nitrone compound represented by the general formula (3) is generally carried out in an inert solvent. Examples of the inert solvent include ethers such as diethyl ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride, aromatic hydrocarbons such as benzene, toluene and xylene, such as N, N-dimethylformamide. Examples thereof include organic solvents such as amides, sulfoxides such as dimethyl sulfoxide, and mixed solvents of these organic solvents.

The reaction temperature is not particularly limited, but is usually room temperature to 200 ° C., preferably 40 to 200 ° C.
The reaction time varies depending mainly on the reaction temperature and the kind of the raw material compound, but is 1 hour to 10 hours.

As described above, the isoxazolidine compound represented by the general formula (1) is obtained. The compound may be isolated from the reaction solution by a usual organic chemical technique.
For example, it can be obtained by adding water to the reaction mixture, stirring, extracting with an organic solvent incompatible with water, washing the organic layer with water, and distilling off the solvent. If necessary, the obtained target compound can be purified by a conventional method, for example, silica gel column chromatography.

The pyrrolidine derivative represented by the general formula (2) used as a raw material in the above production method may be produced by any method. Preferably, the general formula (5)

[0027]

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[In the formula, R ¹ represents a hydrogen atom or a hydroxyl protecting group, and R ² represents an amino protecting group. ] And a general formula (6) (R ⁶ ) ₃ P ⁺ CH ₃ · X ⁻ [In the formula, R ⁶ represents an aryl group and X represents a halogen atom]
It is preferably produced by reacting with a phosphonium salt represented by the formula (1) in the presence of a base.

The aryl group for R ⁶ of the phosphonium salt represented by the general formula (6) is preferably a phenyl group or a dimethylaminophenyl group, and the halogen atom for X is preferably chlorine, bromine or iodine.

The amount of the phosphonium salt is required to be sufficient for the reaction to proceed, but it is usually 1 to 5 mol, preferably 1 to 3 mol per 1 mol of the pyrrolidine derivative (5).

As the base, known bases can be used without limitation, but in consideration of the yield of the target product, n-butyllithium, phenyllithium, sodium methoxide, potassium t-butoxide, sodium amide, sodium hydride. It is preferable to use a strong base such as. The amount of the base is required to be sufficient for the reaction, but it is usually 1 to 5 mol, preferably 1 to 3 mol per 1 mol of the pyrrolidine derivative (5).

In the present invention, the reaction of the pyrrolidine derivative represented by the general formula (5) with the phosphonium salt represented by the general formula (6) is generally carried out in an inert solvent. Examples of the inert solvent include ethers such as diethyl ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride, such as benzene, and the like.
Aromatic hydrocarbons such as toluene and xylene, such as N,
Examples thereof include amides such as N-dimethylformamide, organic solvents such as sulphoxides such as dimethylsulfoxide, and mixed solvents of these organic solvents.

The reaction temperature is not particularly limited, but is usually 0.
~ 100 ° C, preferably 5 ~ 80 ° C. The reaction time varies depending on the reaction temperature and the kind of the starting compound, but is several minutes to 10 hours.

As described above, the pyrrolidine derivative represented by the general formula (2) is obtained. The compound may be isolated from the reaction solution by a usual organic chemical technique. For example,
Water is added to the reaction mixture, the mixture is stirred, extracted with an organic solvent that separates from water, the organic layer is washed with water, and then the solvent is distilled off. If necessary, the obtained target compound can be purified by a conventional method, for example, silica gel column chromatography.

The isoxazolidine compound represented by the general formula (1) of the present invention may be used for any purpose, but is preferably the general formula (4).

[0036]

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[In the formula, R ¹ represents a hydrogen atom or a hydroxyl group protecting group, R ⁴ represents a hydrogen atom or an amino group protecting group, and R ⁵ represents a hydrogen atom, an alkyl group or an aralkyl group. ] It is preferable to use it as a manufacturing raw material of the amino alcohol compound shown by these. That is, the amino alcohol compound of the general formula (4) is obtained by reducing the compound. The reaction proceeds well at room temperature to 100 ° C. Therefore, according to the method of using the isoxazolidine compound represented by the general formula (1) as a raw material, the amino alcohol compound can be obtained with good operability even if the reaction is not performed at a low temperature.

Any known reduction method can be used without limitation as the reduction method of the above-mentioned production method, but a catalyst such as platinum or palladium-carbon is used, and hydrogen at room temperature to 100 ° C. and atmospheric pressure to 10 atm is used. A pressure-based catalytic hydrogen reduction method is preferred. Examples of the solvent used include lower alcohols having 1 to 5 carbon atoms such as methanol and ethanol, organic solvents such as ethers such as tetrahydrofuran and dioxane, and mixed solvents of these organic solvents, or organic solvents thereof. A mixed solvent of a solvent and water is suitable.

In this reduction, the protective group for the hydroxyl group of R ¹ and the protective group for the amino group of R ² of the isoxazolidine compound represented by the general formula (1) to be treated are cleaved to hydrogen atoms during the reduction reaction. In the case of a group that is easily converted, for example, a benzyloxycarbonyl group or a benzyl group, R ¹ and R ⁴ of the resulting amino alcohol compound are usually converted to a hydrogen atom. In addition, the aralkyl group of R ³ of the isoxazolidine compound represented by the general formula (1) which is similarly treated is a group which is easily cleaved during the reduction reaction to be converted into a hydrogen atom,
For example, in the case of a benzyl group, R ⁵ of the resulting amino alcohol compound is usually converted to a hydrogen atom.

The aminoalcohol compound obtained as described above has optical isomers and stereoisomers based on the asymmetric carbons at the 2-position and 4-position of the pyrrolidine ring and the 1-position of the propyl group. Considering the medicinal effect of carbapenem derivatives with the intermediate of [(2S,
4R), (1R)] and [(2S, 4R), (1S)] coordination are preferable, and [(2S, 4R), (1R)] coordination is particularly preferable.

[0041]

The isoxazolidine compound represented by the general formula (1) of the present invention is useful as a raw material for producing an aminoalcohol compound represented by the general formula (4) which is an intermediate of a carbapenem derivative. Then, if this compound is used, the above specific amino alcohol compound can be produced with good operability without requiring a special low temperature reaction step. Therefore, the present invention is extremely useful industrially.

[0042]

EXAMPLES The present invention will be described more specifically with reference to Production Examples and Examples, but the present invention is not limited thereto.

Production Example 1 Triphenylmethylphosphonium bromide (5.36)
g, 15 mmol) of tetrahydrofuran (50 ml)
While stirring at room temperature under nitrogen at room temperature, potassium t-butoxide (1.68 g, 15 mmol) was added,
After stirring for 30 minutes, (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-
A solution of formylpyrrolidine (3.29 g, 10 mmol) in tetrahydrofuran (5 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Water (20 ml) was added to the reaction mixture, the mixture was stirred for 1 hr, concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to give a colorless liquid (2.85 g, yield: 87.0%). The spectral data of this compound is as follows: ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.90 (9H, s): (b), 1.4
7 (9H, s): (c), 1.77 to 2.02 (2H,
m): (d), 3.35 to 3.45 (2H, m):
(E), 4.30 to 4.36 (2H, m): (f),
5.02-5.15 (2H, m): (g), 5.70-
5.80 (1H, m): (h) IR cm ^-1 : 1697 (C = O), 1253 (CH
₃ -Si), 1113 (Si-O), 912 (CH = C
H ₂ ) and (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-vinylpyrrolidine

[0044]

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It was confirmed that

Production Example 2 (2S, 4R) -N-benzyl-4-t-butyldimethylsiloxy-2-formylpyrrolidine (3.19 g, 1)
0 mmol) and the same operation as in Example 1
A colorless liquid (2.68 g, yield: 84.7%) was obtained.

The spectral data of this compound is as follows: ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.90 (9H, s): (b), 1.7
7-2.47 (3H, m): (c), 3.11-3.4
3 (2H, m): (d), 3.90 to 4.56 (3H,
m): (e), 5.05 to 5.17 (2H, m):
(F), 5.70 to 5.80 (1H, m): (g),
7.20~7.25 (5H, m) :( h ) IR cm -1: 1253 (CH 3 -Si), 1113
(Si-O), 913 a _{(CH = CH 2), (} 2S, 4R) -N- benzyl -4-t-butyldimethylsiloxy-2-vinyl pyrrolidine

[0048]

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It was confirmed that

Production Example 3 (2S, 4R) -N-benzyloxycarbonyl-4-
Using t-butyldimethylsiloxy-2-formylpyrrolidine (3.63 g, 10 mmol), the same operation as in Example 1 was carried out to obtain a colorless liquid (3.11 g, yield: 86.
3%).

The spectral data of this compound is as follows: ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.90 (9H, s): (b), 1.7
7-2.04 (2H, m): (c), 3.35-3.4.
5 (2H, m): (d), 4.25 to 4.36 (2H,
m): (e), 5.02 to 5.15 (4H, m):
(F), 5.70 to 5.80 (1H, m): (g),
7.21 to 7.25 (5H, m): (h) IR cm ^-1 : 1700 (C = O), 1254 (CH
₃ -Si), 1114 (Si-O), 912 (CH = C
A _{H 2), (2S, 4R} ) -N- benzyloxycarbonyl -4-t-butyldimethylsiloxy-2-vinyl pyrrolidine

[0052]

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It was confirmed that

Production Example 4 (2S, 4R) -Nt-butoxycarbonyl-2-formyl-4-hydroxypyrrolidine (2.15 g, 10)
mmol) was used to perform the same operation as in Example 1 to obtain a white solid (1.82 g, yield: 85.7%).

The spectral data of this compound is as follows: ¹ H-NMR (CDCl ₃ ) σ: 1.47 (9H,
s): (a), 1.76 to 2.01 (2H, m):
(B), 3.38 to 3.47 (2H, m): (c),
4.21 to 4.35 (3H, m): (d), 5.02
5.15 (2H, m): (e), 5.70-5.80
(1H, m): (f) IR cm ⁻¹ : 3440 (OH), 1695 (C =
O), 906 (CH = CH ₂ ) and (2S, 4R) -Nt-butoxycarbonyl-4-hydroxy-2-vinylpyrrolidine.

[0056]

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It was confirmed that

Production Example 5 (2S, 4R) -N-benzyloxycarbonyl-2-
Formyl-4-hydroxypyrrolidine (2.49 g, 1
0 mmol) and the same operation as in Example 1
A white solid (2.07 g, yield: 83.8%) was obtained.

The spectral data of this compound are shown by ¹ H-NMR (CDCl ₃ ) σ: 1.76 to 2.02.
(2H, m): (a), 3.35-3.46 (2H,
m): (b), 4.22 to 4.36 (3H, m):
(C), 5.03 to 5.15 (3H, m): (d),
5.71-5.79 (1H, m): (e), 7.20-
7.26 (5H, m): (f) IR cm ⁻¹ : 3438 (OH), 1700 (C =
O), 908 (CH = CH ₂ ) and (2S, 4R) -N-benzyloxycarbonyl-4-hydroxy-2-vinylpyrrolidine.

[0060]

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It was confirmed that

Production Example 6 (2S, 4R) -Nt-butoxycarbonyl-2-formyl-4-methanesulfonyloxypyrrolidine (2.
The same operation as in Example 1 was performed using 93 g, 10 mmol) to give a white solid (2.51 g, yield: 86.4%).
I got

The spectral data of this compound is as follows: ¹ H-NMR (CDCl ₃ ) σ: 1.47 (9H,
s): (a), 1.86 to 2.61 (2H, m):
(B), 3.01 (3H, s): (c), 3.67-.
3.84 (2H, m): (d), 4.25 to 4.55
(1H, m): (e), 5.02 to 5.30 (3H,
m): (f), 5.70-5.80 (1H, m):
(G) IR cm ^-1 : 1693 (C = O), 1361 (S =
O), 1171 (S = O ), 902 (CH = is _{CH 2), (2S, 4R} ) -N-t- butoxycarbonyl-4-methanesulfonyloxy-2-vinyl pyrrolidine

[0064]

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It was confirmed that

Production Example 7 (2S, 4R) -N-benzyloxycarbonyl-2-
The same operation as in Example 1 was carried out using formyl-4-methanesulfonyloxypyrrolidine (3.27 g, 10 mmol) to give a white solid (2.79 g, yield: 85.
9%) was obtained.

The spectral data of this compound is as follows: ¹ H-NMR (CDCl ₃ ) σ: 1.86 to 2.60
(2H, m): (a), 3.02 (3H, s):
(B), 3.66 to 3.84 (2H, m): (c),
4.27 to 4.56 (3H, m): (d), 5.02
5.33 (3H, m): (e), 5.70-5.80
(1H, m): (f), 7.20 to 7.27 (5H,
m): (g) IR cm ^-1 : 1700 (C = O), 1362 (S =
O), 1171 (S = O ), 903 (CH = is _{CH 2), (2S, 4R} ) -N- benzyloxycarbonyl-4-methanesulfonyloxy-2-vinyl pyrrolidine

[0068]

Embedded image

It was confirmed that

Example 1 (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-vinylpyrrolidine (3.27 g, 10 mmol) obtained in Preparation Example 1 and N
A solution of methyl nitrone (0.89 g, 15 mmol) in toluene (60 ml) was stirred at 120 ° C. for 6 hours. After cooling, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate-hexane 2:
Purified and separated in 1), low polarity compound (2.00 g, yield:
51.8%) and highly polar compounds (0.93 g, yield:
(24.1%) colorless liquid was obtained. Of these compounds,
The spectral data of the low-polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.87 (9H, s): (b), 1.4
5 (9H, s): (c), 1.82 to 2.60 (5H,
m): (d), 2.65-2.70 (3H, m):
(E) 3.23 to 3.45 (3H, m): (f),
3.90-4.65 (3H, m): (g) IR cm- ¹ : 1695 (C = O), 1253 (CH
₃ -Si), 1107 (Si-O), which is (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-.
[(5R) -2-Methyl-5-isoxazolidinyl]
Pyrrolidine

[0071]

Embedded image

It was confirmed that

On the other hand, the highly polar compound has spectral data of ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.87 (9H, s): (b), 1.4
5 (9H, s) :( c), 1.95-2.40: (5
H, m): (d), 2.64 (3H, s): (e),
3.20-3.60 (3H, m): (f), 4.20-
4.55 (3H, m): (g) IR cm ^-1 : 1695 (C = O), 1254 (CH
₃ -Si), 1107 (Si-0), and (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[(5S)-.
2-Methyl-5-isooxazolidinyl] pyrrolidine

[0074]

Embedded image

It was confirmed that

Example 2 (2S, 4R) -N-benzyl-4 obtained in Preparation Example 2
The same procedure as in Example 1 was performed using -t-butyldimethylsiloxy-2-vinylpyrrolidine (3.17 g, 10 mmol) to give a low-polarity compound (1.96 g, yield: 5).
2.0%) and a highly polar compound (0.92 g, yield: 2)
4.5%) of a colorless liquid was obtained.

Among these compounds, the spectrum data of the low polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 0.05 (6H,
s): (a), 0.89 (9H, s): (b), 1.8
6 to 2.40 (6H, m): (c), 2.69 (3H,
d): (d), 3.05 to 3.28 (3H, m):
(E), 3.50 (1H, d): (f), 4.16-
4.28 (3H, m): (g), 7.23 to 7.31
(5H, m) :( h) IR cm -1: 1253 (CH 3 -Si), 1113
(Si-O). From the above results, this compound is (2S, 4
R) -N-Benzyl-4-t-butyldimethylsiloxy-2-[(5R) -2-methyl-5-isoxazolidinyl] pyrrolidine

[0078]

Embedded image

It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 0.05 (6H,
s): (a), 0.89 (9H, s): (b), 1.7
4 to 2.60 (6H, m): (c), 2.67 (3)
H, s): (d), 3.05 to 3.45 (4H, m):
(E), 4.06 to 4.37 (3H, m): (f),
7.21~7.34 (5H, m) :( g ) IR cm -1: 1253 (CH 3 -Si), 1113
(Si-O). From the above results, this compound is (2S, 4
R) -N-benzyl-4-t-butyldimethylsiloxy-2-[(5S) -2-methyl-5-isoxazolidinyl] pyrrolidine

[0081]

[Chemical 21]

It was confirmed that

Example 3 (2S, 4R) -N-benzyloxycarbonyl-4-t-butyldimethylsiloxy-2-obtained in Preparation Example 3
Using vinylpyrrolidine (3.61 g, 10 mmol), the same operation as in Example 1 was carried out, and the low polar compound (2.
21 g, yield: 52.6%) and highly polar compounds (1.
02 g, yield: 24.4%) of a colorless liquid was obtained.

Among these compounds, the spectrum data of the low polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.89 (9H, s): (b), 1.8
3 to 2.58 (5H, m): (c), 2.64 to 2.7
0 (3H, m): (d), 3.22 to 3.45 (3H,
m): (e), 3.92-4.65 (3H, m):
(F), 5.10 (2H, s): (g), 7.21
7.25 (5H, m): (h) IR cm ^-1 : 1700 (C = O), 1253 (CH
₃ -Si) and 1113 (Si-O). From the above results, this compound is (2S, 4
R) -N-benzyloxycarbonyl-4-t-butyldimethylsiloxy-2-[(5R) -2-methyl-5-
Isoxazolidinyl] pyrrolidine

[0085]

Embedded image

It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.88 (9H, s): (b), 1.9
4 to 2.40 (5H, m): (c), 2.65 (3
H, s): (d), 3.20 to 3.61 (3H, m):
(E), 4.19 to 4.55 (3H, m): (f),
5.10 (2H, s): (g), 7.21 to 7.24
(5H, m): (h) IR cm ^-1 : 1700 (C = O), 1254 (CH
₃ -Si) and 1113 (Si-O). From the above results, this compound is (2S, 4
R) -N-benzyloxycarbonyl-4-t-butyldimethylsiloxy-2-[(5S) -2-methyl-5-
Isoxazolidinyl] pyrrolidine

[0088]

Embedded image

It was confirmed that Example 4 Using (2S, 4R) -Nt-butoxycarbonyl-4-hydroxy-2-vinylpyrrolidine (2.13 g, 10 mmol) obtained in Production Example 4, the same operation as in Example 1 was performed. The low polarity compound (1.43 g, yield: 5)
2.5%) and highly polar compound (0.67 g, yield: 2)
A colorless liquid (4.7%) was obtained.

Among these compounds, the spectrum data of the low-polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 1.45 (9H,
s): (a), 1.80 to 2.61 (5H, m):
(B), 2.65-2.71 (3H, m): (c),
3.24-3.47 (4H, m): (d), 3.90-
4.65 (3 H, m): (e) IR cm ⁻¹ : 3440 (OH), 1695 (C =
O). From the above results, this compound is (2S, 4
R) -Nt-butoxycarbonyl-4-hydroxy-
2-[(5R) -2-methyl-5-isooxazolidinyl] pyrrolidine

[0091]

Embedded image

It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 1.45 (9H,
s): (a), 1.94 to 2.41 (5H, m):
(B), 2.65 (3H, s): (c), 3.20 ~.
3.60 (4H, m): (d), 4.20 to 4.55
(3H, m): (e) IR cm ⁻¹ : 3440 (OH), 1695 (C =
O). From the above results, this compound is (2S, 4
R) -Nt-butoxycarbonyl-4-hydroxy-
2-[(5S) -2-methyl-5-isooxazolidinyl] pyrrolidine

[0094]

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It was confirmed that

Example 5 Using (2S, 4R) -N-benzyloxycarbonyl-4-hydroxy-2-vinylpyrrolidine (2.47 g, 10 mmol) obtained in Production Example 5, the same procedure as in Example 1 was carried out. The operation was carried out to obtain a low-polarity compound (1.62 g, yield: 5
3.0%) and a highly polar compound (0.67 g, yield: 2)
A colorless liquid (4.8%) was obtained.

Among these compounds, the spectrum data of the low-polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 1.80 to 2.60
(5H, m): (a), 2.65 to 2.70 (3H,
m): (b), 3.25 to 3.46 (4H, m):
(C), 3.90-4.66 (3H, m): (d),
5.10 (2H, s): (e), 7.20 to 7.26
(5H, m): (f) IR cm ⁻¹ : 3438 (OH), 1700 (C =
O). From the above results, this compound is (2S, 4
R) -N-benzyloxycarbonyl-4-hydroxy-2-[(5R) -2-methyl-5-isoxazolidinyl] pyrrolidine

[0098]

Embedded image

It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 1.95 to 2.40.
(5H, m): (a), 2.65 (3H, s):
(B) 3.21 to 3.60 (4H, m): (c),
4.21 to 4.56 (3H, m): (d), 5.10.
(2H, s): (e), 7.20 to 7.25 (5H,
m): (f) IR cm ⁻¹ : 3438 (OH), 1700 (C =
O). From the above results, this compound is (2S, 4
R) -N-benzyloxycarbonyl-4-hydroxy-2-[(5S) -2-methyl-5-isoxazolidinyl] pyrrolidine

[0101]

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It was confirmed that

Example 6 Using the (2S, 4R) -Nt-butoxycarbonyl-4-methanesulfonyloxy-2-vinylpyrrolidine (2.91 g, 10 mmol) obtained in Preparation Example 6, Example 1 was used. Perform the same operation as in 1.
g, yield: 53.8%) and highly polar compounds (0.88)
g, yield 25.2%) was obtained as a colorless liquid.

Among these compounds, the spectrum data of the low-polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 1.45 (9H,
s): (a), 1.90 to 2.60 (5H, m):
(B), 2.65 to 2.70 (3H, m): (c),
3.01 (3H, s): (d), 3.25 to 3.84
(3H, m): (e), 3.90 to 4.55 (2H,
m): (f), 5.02 to 5.30 (1H, m):
(G), IR cm ⁻¹ : 1693 (C═O), 13
It was 61 (S = O) and 1171 (S = O). From the above results, this compound is (2S, 4R) -Nt-
Butoxycarbonyl-4-methanesulfonyloxy-2
-[(5R) -2-Methyl-5-isooxazolidinyl] pyrrolidine

[0105]

Embedded image

It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 1.45 (9H,
s): (a), 1.95 to 2.40 (5H, m):
(B), 2.65 (3H, s): (c), 3.01 (3
H, s): (d), 3.20-3.85 (3H, m):
(E), 4.20 to 4.55 (2H, m): (f),
5.01 to 5.30 (1H, m): (g), IR c
m- ¹ : 1693 (C = O), 1361 (S = O), 1
171 (S = O). From the above results, this compound was confirmed to be (2S, 4R) -Nt-butoxycarbonyl-4-methanesulfonyloxy-2-[(5S) -2-
Methyl-5-isooxazolidinyl] pyrrolidine

[0108]

Embedded image

It was confirmed that

Example 7 Using (2S, 4R) -N-benzyloxycarbonyl-4-methanesulfonyloxy-2-vinylpyrrolidine (3.25 g, 10 mmol) obtained in Preparation Example 7,
The same operation as in Example 1 was carried out to give the low-polarity compound (2.04
g, yield: 53.1%) and highly polar compounds (0.96)
g, yield: 25.0%) to obtain a colorless liquid.

Among these compounds, the spectrum data of the low polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 1.90 to 2.60.
(5H, m): (a), 2.65-2.70 (3H,
m): (b), 3.02 (3H, s): (c), 3.2
5 to 3.85 (3H, m): (d), 3.90 to 4.5
6 (2H, m): (e), 5.01 to 5.30 (3H,
m): (f), 7.20 to 7.25 (5H, m) I
R cm ⁻¹ : 1700 (C = O), 1361 (S =
O) and 1171 (S = O). From the above results, this compound was confirmed to be (2S, 4R) -N-benzyloxycarbonyl-4-methanesulfonyloxy-2-
[(5R) -2-Methyl-5-isoxazolidinyl]
Pyrrolidine

[0112]

Embedded image

It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 1.95 to 2.42
(5H, m): (a), 2.65 (3H, s):
(B), 3.02 (3H, s): (c), 3.21-
3.86 (3H, m): (d), 4.20 to 4.55
(2H, m): (e), 5.01 to 5.30 (3H,
m): (f), 7.20 to 7.25 (5H, m):
(G) IR cm ^-1 : 1700 (C = O), 1361 (S =
O), 1171 (S = O). From the above results, this compound is (2S, 4
R) -N-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(5S) -2-methyl-5-isoxazolidinyl] pyrrolidine

[0115]

Embedded image

It was confirmed that

Example 8 (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-vinylpyrrolidine (3.27 g, 10 mmol) obtained in Preparation Example 1 and N
A solution of benzyl nitrone (2.03 g, 15 mmol) in toluene (60 ml) was stirred at 120 ° C. for 6 hours. After cooling, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate-hexane 2:
Purified and separated in 1) to give a low polarity compound (2.46 g, yield:
53.2%) and highly polar compounds (1.16 g, yield:
25.2%) of a colorless liquid was obtained. Of these compounds,
The spectral data of the low-polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.89 (9H, s): (b), 1.4
5 (9H, s): (c), 1.80 to 2.60 (5H,
m): (d), 3.23 to 3.45 (3H, m):
(E), 3.90 to 4.65 (5H, m): (f),
7.20 to 7.25 (5H, m): (g) IR cm ^-1 : 1695 (C = O), 1254 (CH
₃ -Si), 1107 (Si-O), which is (2S, 4R) -2-[(5R)-.
2-Benzyl-5-isooxazolidinyl] -Nt-
Butoxycarbonyl-4-t-butyldimethylsiloxypyrrolidine

[0118]

Embedded image

It was confirmed that

On the other hand, the highly polar compound has spectral data: ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.89 (9H, s): (b), 1.4
5 (9H, s) :( c), 1.95-2.40: (5
H, m): (d), 3.20 to 3.60 (3H, m):
(E), 4.00 to 4.55 (5H, m): (f),
7.20 to 7.25 (5H, m): (g) IR cm ^-1 : 1695 (C = O), 1254 (CH
₃ -Si), 1107 (Si-0) and (2S, 4R) -2-[(5S) -2-benzyl-5-isoxazolidinyl] -Nt-butoxycarbonyl-4-t. -Butyldimethylsiloxypyrrolidine

[0121]

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It was confirmed that

Example 9 (2S, 4R) -N-benzyloxycarbonyl-4-t-butyldimethylsiloxy-2-obtained in Preparation Example 3
Using vinylpyrrolidine (3.61 g, 10 mmol), the same operation as in Example 8 was carried out to obtain the low polar compound (2.
66 g, yield: 53.7%) and highly polar compounds (1.
A colorless liquid (21 g, yield: 24.4%) was obtained.

Among these compounds, the spectrum data of the low polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.89 (9H, s): (b), 1.8
5 to 2.58 (5H, m): (c), 3.22 to 3.4
5 (3H, m): (d), 3.90 to 4.65 (5H,
m): (e), 5.10 (2H, s): (f), 7.2
1 to 7.25 (10 H, m): (g) IR cm ⁻¹ : 1700 (C═O), 1253 (CH
₃ -Si) and 1113 (Si-O). From the above results, this compound is (2S, 4
R) -2-[(5R) -2-Benzyl-5-isooxazolidinyl] -N-benzyloxycarbonyl-4-t
-Butyldimethylsiloxypyrrolidine

[0125]

Embedded image

It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.89 (9H, s): (b), 1.9
4 to 2.40 (5H, m): (c), 3.20 to 3.
60 (3H, m): (d), 3.98 to 4.55 (5
H, m): (e), 5.10 (2H, s): (f),
7.21 to 7.25 (10H, m): (g) IR cm ^-1 : 1700 (C = O), 1254 (CH
₃ -Si) and 1113 (Si-O). From the above results, this compound is (2S, 4
R) -2-[(5S) -2-Benzyl-5-isooxazolidinyl] -N-benzyloxycarbonyl-4-t
-Butyldimethylsiloxypyrrolidine

[0128]

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It was confirmed that

Example 10 Using (2S, 4R) -Nt-butoxycarbonyl-4-hydroxy-2-vinylpyrrolidine (2.13 g, 10 mmol) obtained in Production Example 4 and in the same manner as in Example 8. The low polarity compound (1.84 g, yield: 5)
3.0%) and highly polar compound (0.85 g, yield: 2)
4.5%) of a colorless liquid was obtained.

Among these compounds, the spectrum data of the low polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 1.45 (9H,
s): (a), 1.80 to 2.62 (5H, m):
(B), 3.24 to 3.48 (4H, m): (c),
3.90-4.65 (5H, m): (d), 7.20-
7.25: (e) IR cm ⁻¹ : 3440 (OH), 1695 (C =
O). From the above results, this compound is (2S, 4
R) -2-[(5R) -2-Benzyl-5-isooxazolidinyl] -Nt-butoxycarbonyl-4-hydroxypyrrolidine

[0132]

Embedded image

It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 1.45 (9H,
s): (a), 1.93 to 2.41 (5H, m):
(B), 3.20 to 3.60 (4H, m): (c),
3.98 to 4.55 (5H, m): (d), 7.20 to
7.25: (e) IR cm ⁻¹ : 3440 (OH), 1695 (C =
O). From the above results, this compound is (2S, 4
R) -Nt-butoxycarbonyl-4-hydroxy-
2-[(5S) -2-benzyl-5-isooxazolidinyl] pyrrolidine

[0135]

Embedded image

It was confirmed that

Example 11 Using (2S, 4R) -N-benzyloxycarbonyl-4-hydroxy-2-vinylpyrrolidine (2.47 g, 10 mmol) obtained in Production Example 5, the same procedure as in Example 8 was carried out. The operation was performed to obtain a low-polarity compound (2.01 g, yield: 5
2.6%) and highly polar compounds (0.92 g, yield: 2)
A colorless liquid (4.0%) was obtained.

Among these compounds, the spectrum data of the low polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 1.80 to 2.60
(5H, m): (a), 3.24 to 3.46 (4H,
m): (b), 3.90-4.66 (5H, m):
(C), 5.10 (2H, s): (d), 7.20 ~.
7.25 (10 H, m): (e) IR cm ⁻¹ : 3438 (OH), 1700 (C =
O). From the above results, this compound is (2S, 4
R) -2-[(5R) -2-benzyl-5-isooxazolidinyl] -N-benzyloxycarbonyl-4-hydroxypyrrolidine

[0139]

Embedded image

It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 1.95 to 2.40.
(5H, m): (a), 3.20 to 3.60 (4H,
m): (b), 4.01 to 4.56 (5H, m):
(C), 5.10 (2H, s): (d), 7.20 ~.
7.25 (10 H, m): (e) IR cm ⁻¹ : 3438 (OH), 1700 (C =
O). From the above results, this compound is (2S, 4
R) -2-[(5S) -2-Benzyl-5-isooxazolidinyl] -N-benzyloxycarbonyl-4-hydroxypyrrolidine

[0142]

Embedded image

It was confirmed that

Example 12 Using the (2S, 4R) -Nt-butoxycarbonyl-4-methanesulfonyloxy-2-vinylpyrrolidine (2.91 g, 10 mmol) obtained in Preparation Example 6, Example 8 was used. The same operation as described in (2.27)
g, yield: 53.4%) and highly polar compounds (1.05)
g, yield: 24.8%) to obtain a colorless liquid.

Among these compounds, the spectrum data of the low polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 1.45 (9H,
s): (a), 1.90 to 2.63 (5H, m):
(B), 3.01 (3H, s): (c), 3.25 to.
3.85 (3H, m): (d), 3.90 to 4.55
(4H, m): (e), 5.02 to 5.30 (1H,
m): (f), 7.20 to 7.25 (5H, m):
(G) IR cm ^-1 : 1693 (C = O), 1361 (S =
O), 1171 (S = O). From the above results, this compound is (2S, 4
R) -2-[(5R) -2-Benzyl-5-isoxazolidinyl] -Nt-butoxycarbonyl-4-methanesulfonyloxypyrrolidine

[0146]

Embedded image

It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 1.45 (9H,
s): (a), 1.95 to 2.40 (5H, m):
(B), 3.01 (3H, s): (c), 3.20-
3.85 (3H, m): (d), 4.01 to 4.55
(4H, m): (e), 5.01 to 5.30 (1H,
m): (f), 7.20 to 7.25 (5H, m):
(G) IR cm ^-1 : 1693 (C = O), 1361 (S =
O), 1171 (S = O). From the above results, this compound is (2S, 4
R) -2-[(5S) -2-Benzyl-5-isoxazolidinyl] -Nt-butoxycarbonyl-4-methanesulfonyloxypyrrolidine

[0149]

Embedded image

It was confirmed that

Example 13 Using the (2S, 4R) -N-benzyloxycarbonyl-4-methanesulfonyloxy-2-vinylpyrrolidine (3.25 g, 10 mmol) obtained in Preparation Example 7,
The same operation as in Example 8 was carried out to give the low polarity compound (2.43)
g, yield: 52.9%) and highly polar compound (1.14)
g, yield: 24.7%) to obtain a colorless liquid.

Among these compounds, the spectrum data of the low polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 1.90 to 2.63
(5H, m): (a), 3.02 (3H, s):
(B), 3.25 to 3.85 (3H, m): (c),
3.90 to 4.56 (4H, m): (d), 5.01
5.30 (3H, m): (e), 7.20 to 7.25
(10H, m): (f) IR cm ^-1 : 1700 (C = O), 1361 (S =
O), 1171 (S = O). From the above results, this compound is (2S, 4
R) -2-[(5R) -2-benzyl-5-isoxazolidinyl] -N-benzyloxycarbonyl-4-methanesulfonyloxypyrrolidine

[0153]

Embedded image

It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 1.95 to 2.43
(5H, m): (a), 3.02 (3H, s):
(B), 3.20 to 3.86 (3H, m): (c),
4.01 to 4.55 (4H, m): (d), 5.01
5.30 (3H, m): (e), 7.20 to 7.25
(10H, m): (f) IR cm ^-1 : 1700 (C = O), 1362 (S =
O), 1171 (S = O). From the above results, this compound is (2S, 4
R) -2-[(5S) -2-Benzyl-5-isooxazolidinyl] -N-benzyloxycarbonyl-4-methanesulfonyloxypyrrolidine

[0156]

Embedded image

It was confirmed that

Example 14 (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-vinylpyrrolidine (3.27 g, 10 mmol) obtained in Preparation Example 1 and N
-T-butyl nitrone (1.52 g, 15 mmol)
(60 ml) in toluene was stirred at 120 ° C. for 6 hours. After cooling, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate-hexane 2:
Purified and separated in 1), low polarity compound (2.30 g, yield:
53.8%) and highly polar compounds (1.05 g, yield:
A colorless liquid (24.6%) was obtained. Of these compounds,
The spectral data of the low-polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.87 (9H, s): (b), 1.1
5 (9H, S) :( c), 1.45 (9H, s):
(D), 1.83 to 2.60 (5H, m): (e),
3.21 to 3.45 (3H, m): (f), 3.90 to
4.65 (3H, m) :( g ) IR cm -1: 1695 (C = O), 1253 (CH 3 -S
i) 1107 (Si-O), which is (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-.
[(5R) -2-t-butyl-5-isoxazolidinyl] pyrrolidine

[0159]

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It was confirmed that

On the other hand, the highly polar compound has spectral data of ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.87 (9H, s): (b), 1.1
5 (9H, s) :( c), 1.45 (9H, s):
(D), 1.95 to 2.42: (5H, m): (e),
3.20-3.60 (3H, m): (f), 4.20-
4.55 (3H, m): (g) IR cm ^-1 : 1695 (C = O), 1254 (CH
₃ -Si), 1107 (Si-0), and (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[(5S)-.
2-t-butyl-5-isooxazolidinyl] pyrrolidine

[0162]

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It was confirmed that

Example 15 Using (2S, 4R) -Nt-butoxycarbonyl-4-hydroxy-2-vinylpyrrolidine (2.13 g, 10 mmol) obtained in Preparation Example 4 and in the same manner as in Example 14. The low polarity compound (1.67 g, yield:
53.2%) and highly polar compounds (0.76 g, yield:
A colorless liquid (24.3%) was obtained.

Among these compounds, the spectrum data of the low polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 1.15 (9H,
s): (a), 1.45 (9H, s): (b), 1.8
0 to 2.63 (5H, m): (c), 3.22 to 3.4
7 (4H, m): (d), 3.90 to 4.65 (3H,
m): (e) IR cm ^-1 : 3440 (OH), 1695 (C =
O). From the above results, this compound is (2S, 4
R) -Nt-butoxycarbonyl-4-hydroxy-
2-[(5R) -2-t-butyl-5-isooxazolidinyl] pyrrolidine

[0166]

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It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 1.15 (9H,
s): (a), 1.45 (9H, s): (b), 1.9
5 to 2.40 (5H, m): (c), 3.20 to 3.6
0 (4H, m): (d), 4.20 to 4.55 (3H,
m): (e) IR cm ^-1 : 3440 (OH), 1695 (C =
O). From the above results, this compound is (2S, 4
R) -Nt-butoxycarbonyl-4-hydroxy-
2-[(5S) -2-t-butyl-5-isooxazolidinyl] pyrrolidine

[0169]

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It was confirmed that

Example 16 Using the (2S, 4R) -Nt-butoxycarbonyl-4-methanesulfonyloxy-2-vinylpyrrolidine (2.91 g, 10 mmol) obtained in Preparation Example 6, Example 14 was used. The same operation as described above is performed to obtain a low-polarity compound (2.11).
g, yield: 54.0%) and highly polar compounds (0.95)
g, yield 24.3%) to obtain a colorless liquid.

Among these compounds, the spectrum data of the low polarity compound is ¹ H-NMR (CDCl ₃ ) σ: 1.15 (9H,
s): (a), 1.45 (9H, s): (b), 1.9
0 to 2.60 (5H, m): (c), 3.01 (3H,
s): (d), 3.25 to 3.85 (3H, m):
(E), 3.90 to 4.55 (2H, m): (f),
5.01 to 5.30 (1H, m): (g), IR c
m- ¹ : 1693 (C = O), 1361 (S = O), 1
171 (S = O). From the above results, this compound was confirmed to be (2S, 4R) -Nt-butoxycarbonyl-4-methanesulfonyloxy-2-[(5R) -2-
t-Butyl-5-isooxazolidinyl] pyrrolidine

[0173]

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It was confirmed that

The spectral data of the highly polar compound is ¹ H-NMR (CDCl ₃ ) σ: 1.15 (9H,
s): (a), 1.45 (9H, s): (b), 1.9
5 to 2.40 (5H, m): (c), 3.01 (3H,
s): (d), 3.20 to 3.85 (3H, m):
(E), 4.20 to 4.55 (2H, m): (f),
5.01 to 5.30 (1H, m): (g) IR cm ^-1 : 1693 (C = O), 1361 (S =
O), 1171 (S = O). From the above results, this compound is (2S, 4
R) -Nt-butoxycarbonyl-4-methanesulfonyloxy-2-[(5S) -2-t-butyl-5-isoxazolidinyl] pyrrolidine

[0176]

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It was confirmed that

Example 17 (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-obtained in Example 1
[(5R) -2-Methyl-5-isoxazolidinyl]
5% Palladium-carbon catalyst (0.2 g) was added to a solution of pyrrolidine (2.0 g, 5.2 mmol: low polarity compound) in ethanol (50 ml), and the mixture was stirred at room temperature for 24 hours under hydrogen at normal pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give a pale yellow liquid (1.95 g, yield: 97.0%).

The spectral data of this compound is as follows: ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.87 (9H, s): (b), 1.4
9 (9H, s) :( c), 1.50 (2H, m):
(D), 1.80 to 2.05 (2H, m): (e),
2.41 (3H, s): (f), 2.78 to 2.90
(2H, m): (g), 3.18 to 3.45 (4H,
m): (h), 3.83 to 4.05 (2H, m):
(I), 4.40 (1H, m): (j) IR cm ⁻¹ : 3438 (OH), 1695 (C =
_{O), 1252 (CH 3 -Si} ), 1108 (Si-
O). From the above results, this compound is (2S, 4
R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[(1R) -1-hydroxy-3
-(N-methylamino)] propylpyrrolidine

[0180]

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It was confirmed that

Example 18 (2S, 4R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-obtained in Example 1
[(5S) -2-Methyl-5-isooxazolidinyl]
The same operation as in Example 17 was carried out using pyrrolidine (2.0 g, 5.2 mmol: highly polar compound) to obtain a pale yellow liquid (1.94 g, yield: 96.8%).

The spectral data of this compound is as follows: ¹ H-NMR (CDCl ₃ ) σ: 0.06 (6H,
s): (a), 0.87 (9H, s): (b), 1.4
9 (9H, s) :( c), 1.60 (2H, m):
(D), 1.80 to 2.05 (2H, m): (e),
2.43 (3H, s): (f), 2.78 to 2.92
(2H, m): (g), 3.30 to 4.42 (7H,
m): (h) IR cm ^-1 : 3438 (OH), 1695 (C =
_{O), 1252 (CH 3 -Si} ), 1108 (Si-
O). From the above results, this compound is (2S, 4
R) -Nt-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[(1S) -1-hydroxy-3
-(N-methylamino)] propylpyrrolidine

[0184]

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It was confirmed that

Examples 19 to 45 Using the isoxazolidine compounds obtained in Examples 2 to 16, the same operation as in Example 17 was carried out to obtain the products shown in Table 1. The yield is shown in Table 1.

[0187]

[Table 1]

[0188]

[Table 2]

[0189]

[Table 3]

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display area // (C07D 413/04 207: 12 261: 02)

Claims (3)

[Claims] 1. A compound of the general formula (1) [In the formula, R ¹ represents a hydrogen atom or a hydroxyl group protecting group, R ² represents an amino group protecting group, and R ³ represents an alkyl group or an aralkyl group. ] The isoxazolidine compound shown by these. 2. A compound of the general formula (2) [In the formula, R ¹ represents a hydrogen atom or a hydroxyl-protecting group, and R ² represents an amino-protecting group. ] The pyrrolidine derivative represented by the general formula (3) [In the formula, R ³ represents an alkyl group or an aralkyl group. ] The nitrone compound shown by these is made to react, The manufacturing method of the isoxazolidine compound of Claim 1 characterized by the above-mentioned. 3. An isoxazolidine compound according to claim 1, which is reduced by the general formula (4): [In the formula, R ¹ represents a hydrogen atom or a hydroxyl group, R ⁴ represents a hydrogen atom or an amino group, and R ⁵ represents a hydrogen atom, an alkyl group or an aralkyl group. ] The manufacturing method of the amino alcohol compound shown by these.