JPH0687828A - Synthesis of difluoromethyl compound by cyclization - Google Patents

Abstract

PURPOSE:To provide a new 4-piperidinol compound bearing difluoromethyl group promising glucosidase inhibitory activity and excellent anti-HIV activity. CONSTITUTION:The optically active (2R or 2S)-difluoromethyl-(4R or 4S)- piperidinol of formula I (* is asymmetric carbon atom), which can be obtained by the following process: an imine of formula II (R is 1-20C alkyl, 6-20C aryl or 7-20C arylalkyl) and siloxydiene of formula III are put to cycloaddition reaction in the presence of a Lewis acid catalyst (e.g. zinc oxide) to produce an optically active N-substituted-2-difluoromethyl-4-dihydropyridone of formula IV, which is then reduced by sodium borohydride into an optically active N- substituted-2-difluoromethyl-4-piperidinol of formula V, which is then hydrogenated in the presence of Pd-C. The respective compounds of the formulas IV and V are also new compounds.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel optically active (2R
Or 2S) -difluoromethyl- (4R or 4S) -piperidinol, an intermediate for the preparation of said piperidinol and a process for the preparation of said intermediate.

[0002]

2. Description of the Related Art With the global spread of AIDS, there is a strong demand for the development of effective anti-AIDS drugs. Nevertheless, AIDS is a slow virus infection caused by HIV (human immunodeficiency virus), which is the most likely to produce mutant strains, so development is extremely difficult. However, with recent progress in AIDS research, anti-HIV active compounds with various modes of action have been reported.

As one example thereof, 1- having a glucosidase inhibitory action as shown in the following formulas 6 and 7
There are deoxynojirimycin (VI) and (VII).

[0004]

[Chemical 6]

[H.Yoon, SBKing, B.Ganem, Tetrahedr
on Lett. 32, 7199-7202 (1991).)

[0006]

[Chemical 7]

[Tamon Moriya, Tohru Ohtake, Kazuo Matsumoto Chemistry and Biology, 30, 305-313 (1992).]

[0008]

An object of the present invention is to provide a novel 4-piperidinol compound having a difluoromethyl group, and an intermediate useful for producing the compound.

[0009]

As a result of intensive studies, the present inventor has a skeleton similar to 1-deoxynojirimycin (VI) and (VII) shown in Chemical formulas 6 and 7, Found 4-piperidinol having a difluoromethyl group at the 2-position,
The present invention has been completed.

That is, the present invention provides an optically active 2-difluoromethyl-4-piperidinol (I) represented by the formula:
[Hereinafter, abbreviated as piperidinol (I)].

[0011]

[Chemical 8]

[However, in chemical formula 8, * represents an asymmetric carbon. ] The above-mentioned piperidinol (I) has four stereoisomers.
That is, 2R-difluoromethyl-4S-piperidinol [hereinafter, abbreviated as (2R, 4S) -piperidinol (I)], 2R
-Difluoromethyl-4R-piperidinol (hereinafter, (2R, 4
(R) -piperidinol (I) is abbreviated), 2S-difluoromethyl-4S-piperidinol (hereinafter, abbreviated as (2S, 4S) -piperidinol (I)) and 2S-difluoromethyl-4R-piperidinol (hereinafter, ( It is abbreviated as 2S, 4R) -piperidinol (I)].

These four types of piperidinol (I) can be produced by the following method.

That is, an imine (IV) synthesized from a hemiacetal having a difluoromethyl group and a siloxydiene (V) are subjected to a cycloaddition reaction in the presence of a Lewis acid catalyst to give an N-substituted-2-difluoromethyl group. -4-Dihydropyridone (III) is obtained. This dihydropyridone (III)
After separating the 2R and 2S isomers of N, each isomer was reduced with NaBH ₄ (sodium borohydride) to give N-substituted-2-difluoromethyl-4-piperidinol (II) as a diastereomeric mixture. To be Furthermore, after separating this diastereomer mixture, each diastereomer is hydrogenated in the presence of Pd-C (palladium carbon) to obtain the above-mentioned four kinds of optically active piperidinol (I).

The method for producing the four piperidinol (I) compounds will be described in more detail. The imine (IV) is represented by the general formula 9
Is a compound represented by.

[0016]

[Chemical 9]

[However, in the chemical formula 9, R is 1 to 20 carbon atoms.
Alkyl group, aryl group having 6 to 20 carbon atoms or 7 carbon atoms
~ 20 represents an arylalkyl group. The imine (IV) is, for example, difluoroacetaldehyde ethyl hemiacetal (VIII) represented by the formula 10 and R-NH ₂
[However, R is an alkyl group having 1 to 20 carbon atoms, 6 to 20 carbon atoms
Or an arylalkyl group having 7 to 20 carbon atoms. ] And can be obtained.

[0018]

[Chemical 10]

Difluoroacetaldehyde ethyl hemiacetal (VIII), which is a raw material of imine (IV), can be obtained by reducing ethyl difluoroacetate with lithium aluminum hydride and reacting with ethanol.

One equivalent of imine (IV) thus obtained and the formula

[0021]

[Chemical 11]

The siloxydiene (V) represented by
N-substituted-2-difluoromethyl-4-dihydropyridone (III) represented by the general formula 12 by performing cycloaddition reaction with an equivalent amount and a Lewis acid catalyst, hereinafter referred to as dihydropyridone (III) Do] is obtained.

[0023]

[Chemical 12]

[However, in Chemical formula 12, R is a carbon number of 1 to 20
Alkyl group, aryl group having 6 to 20 carbon atoms or 7 carbon atoms
~ 20 represents an arylalkyl group, * represents an asymmetric carbon. The obtained dihydropyridone (III) is N-substituted-2R-difluoromethyl-4-dihydropyridone [hereinafter abbreviated as 2R-dihydropyridone (III)] and N-substituted-2S-difluoromethyl-4- It is a 1: 1 mixture with dihydropyridone [hereinafter abbreviated as 2S-dihydropyridone (III)]. When the substituent R is an optically active group such as (R) or (S) -methylbenzyl group (α-phenethyl group), the asymmetric carbon is not only in the 2-position of the dihydropyridone ring but also in the substituent R. Also present, dihydropyridone (III) results in a 1: 1 mixture of diastereomers.

The Lewis acid catalyst used in the above reaction is
Examples thereof include ZnCl ₂ , BF _3, TiCl _3, AlCl _{3, and} ZnBr ₂ , and among them, ZnCl ₂ (zinc chloride) is most suitable. The Lewis acid catalyst may be used in an amount of 1.0 to 1.1 equivalents based on imine (IV).

Further, the above reaction is carried out by using tetrahydrofuran
(THF), methylene chloride, in a reaction solvent such as dioxane,
The reaction may be performed at a reaction temperature of 5 to 100 ° C, preferably 15 to 30 ° C for 3 to 8 hours.

Dihydropyridone (II obtained by the above reaction
The 2R and 2S forms of I) are easily separated by silica gel column chromatography when the substituent R is an optically active group such as (R) or (S) -methylbenzyl group (α-phenethyl group). can do. When the substituent R is not an optically active group, it may be separated by high performance liquid chromatography using an optical column or the like.

Next, 2R-dihydropyridone (III) and 2S-dihydropyridone (III) obtained above are reduced with NaBH ₄ (sodium borohydride) to give a general formula from 2R-dihydropyridone (III). N-substituted-2R-
Difluoromethyl-4-piperidinol (II) is obtained, 2
From S-dihydropyridone (III)
N-substituted-2S-difluoromethyl-4-piperidinol (II) is obtained.

[0029]

[Chemical 13]

[In Chemical Formula 13, R is a carbon number of 1 to 20]
Alkyl group, aryl group having 6 to 20 carbon atoms or 7 carbon atoms
~ 20 represents an arylalkyl group, * represents an asymmetric carbon. ] The above N-substituted-2R-difluoromethyl-4-piperidinol (I
I) is N-substituted-2R-difluoromethyl-4R-piperidinol [hereinafter abbreviated as (2R, 4R) -N-substituted piperidinol (II)] and N-substituted-2R-difluoromethyl-4S-piperidinol [hereinafter , (2R, 4S) -N-substituted piperidinol (II)]].

Further, the above N-substituted-2S-difluoromethyl-4
-Piperidinol (II) is N-substituted-2S-difluoromethyl
-4R-piperidinol [hereinafter abbreviated as (2S, 4R) -N-substituted piperidinol (II)] and N-substituted-2S-difluoromethyl-4
It is an approximately 2: 3 diastereomeric mixture with S-piperidinol [hereinafter abbreviated as (2S, 4S) -N-substituted piperidinol (II)].

The above reaction is carried out in the presence of NaBH ₄ (sodium borohydride) in an alcohol-based reaction solvent such as ethanol, methanol or propyl alcohol at a reaction temperature of 0 to 50 ° C., preferably 0 to 25 ° C. Allow to react for ~ 24 hours. Separation of the diastereomer mixture as a reaction product may be carried out by column chromatography on silica gel.

Then, the N-substituted- (2R or
2S) -Difluoromethyl- (4R or 4S) -piperidinol (II)
Is hydrogenated in the presence of Pd-C (palladium carbon), the four optically active piperidinol (I) represented by the above formula 8 can be obtained.

That is, (2R, 4R) -N-substituted piperidinol
From (II), (2R, 4R) -piperidinol (I) is obtained, and (2R, 4R) -piperidinol (I) is obtained.
4S) -N-substituted piperidinol (II) gives (2R, 4S) -piperidinol (I), which is (2S, 4R) -N-substituted piperidinol (I).
From (I), (2S, 4R) -piperidinol (I) is obtained, and from (2S, 4S) -N-substituted piperidinol (II), (2S, 4S)-
Piperidinol (I) is obtained.

In the above reaction, palladium carbon may be used in a ratio of 0.05 g per 1 mmol of N-substituted piperidinol (II). In addition, the above reaction is performed using tetrahydrofuran (THF), diethyl ether, dioxane, N, N-
In a reaction solvent such as dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), methanol, ethanol,
The reaction may be performed at a reaction temperature of 5 to 80 ° C, preferably 15 to 30 ° C for 20 to 24 hours. The reaction product may be purified by column chromatography on silica gel.

Further, in the above reaction, the substituent R of the N-substituted piperidinol (II) represented by the general formula 13 may be one that can be easily cleaved by reduction.
(R) or (S) -methylbenzyl group (α-phenethyl group),
Benzyl group, p-methoxyphenyl group and the like, (R)
Alternatively, the (S) -methylbenzyl group (α-phenethyl group) is particularly preferable.

[0037]

Industrial Applicability According to the present invention, it is possible to provide 4-piperidinol [piperidinol (I)] which is a novel optically active compound and has a difluoromethyl group at the 2-position. In addition, the dihydropyridone newly provided by the present invention
(III) and N-substituted piperidinol (II) are important intermediates for producing the above-mentioned piperidinol (I), and the compound (I
The final objective compound of the present invention, the above-mentioned piperidinol (I), could be easily produced by way of II) and (II).

Further, piperidinol (I) is expected to have a glucosidase inhibitory action and an excellent anti-HIV action in view of the similarity in chemical structure to 1-deoxynojirimycin. Furthermore, since the above piperidinol (I) has a difluoromethyl group, it is expected to be used as an antifungal agent. Furthermore, the piperidinol (I) is expected to be used as an optically active site of a ferroelectric liquid crystal.

[0039]

EXAMPLES Examples of the present invention will be described in detail below.

In each Example, commercially available reagents were used without purification, and the infrared spectrum was JASC.
KB using an O A-102 spectrometer or JASCO FT / IR-5000 spectrometer
r Measured by the tablet method. The nuclear magnetic resonance (NMR) spectrum was measured by ¹ H-NMR of 200 MHz or 500 MHz, ¹⁹ F-NMR of 470 MHz or 500 MHz and ¹³ C-NMR of 50 MHz, and the yield was shown as isolated. .

(Preparation of 2,2-difluoroethylidene-α-phenethylamine (4a), (4b)) Difluoroacetaldehyde ethyl hemiacetal was prepared according to the following procedure.

A 1.0M solution of lithium aluminum hydride dissolved in THF at -78 ° C was added to a solution prepared by mixing 20 mL (200 mmol) of ethyl difluoroacetate and 30 mL of dry ether.
50 mL (50 mmol) was added. After stirring at that temperature for 3 hours, 5.0 mL of 95% ethanol was added and the temperature was returned to room temperature.
The mixture was poured into ice water containing 15 mL of concentrated sulfuric acid and extracted with ether. After the extract was dried over anhydrous magnesium sulfate, the solvent was removed and the remaining oily substance was purified by distillation to give difluoroacetaldehyde ethyl hemiacetal (bp: 45-47 ° C (27 mmHg)) with the following identification data. Obtained in 60%.

¹ H-NMR (CDCl ₃ ); δ: 1.26 (3H, t, J _{H, H} = 7.1 Hz), 3.2-3.4 (1H, br), 3.
63 (1H, dq, J _{H, H} = 7.1,9.6Hz), 3.91 (1H, dq, J _{H, H} =
7.1,9.6Hz), 4.70 (1H, ddd, J _{H, H} = 2.4,5.7,8.0Hz),
5.60 (1H, ddd, J _{H, H} = 2.7Hz, J _{H, F} = 54.9,55.5Hz) ¹³ C-NMR (CDCl ₃ ); δ: 15.05,64.55,93.77 (dd, J = 26.3,29.2Hz) , 113.40
(t, J = 241Hz) ¹⁹ F-NMR (CDCl ₃ ); δ: 25.15 (ddd, J _{F, H} = 7.6,55.7Hz, J _{F, F} = 291Hz), 3
0.11 (ddd, J _{F, H} = 6.1,54.9Hz) IR (cm ^-1 ); 3400 (OH) C ₄ H ₈ O ₂ F ₂ ； Next, to a solution of R-(+)-α-phenethylamine (3.6 g, 30.0 mmol) in toluene was added 3.78 g (30.0 mmol) of difluoroacetaldehyde ethyl hemiacetal at 0 ° C. 1 at ℃
Stir for hours. After removing water and ethanol under reduced pressure, the remaining oily substance was purified by distillation to give R-(+)-2,2-difluoroethylidene-α-phenethylamine (4a) having a yield of 85 Obtained in%.

When S-(-)-α-phenethylamine was used in place of R-(+)-α-phenethylamine to carry out the same reaction as described above, S-(-)-2 showing the following identification data was obtained. 2,2-Difluoroethylidene-α-phenethylamine (4b) was obtained.

(R-(+)-2,2-difluoroethylidene-α-
Identification data of phenethylamine (4a)) ¹ H-NMR (CDCl ₃ ); δ: 1.540 (d, J = 6.68Hz), 4.493 (qd, J = 6.88Hz), 6.0
17 (td, J = 54.95,5.29Hz), 7.2-7.4 (m), 7.679 (dtd,
J = 5.21,2.08,0.81Hz) ¹³ C-NMR (CDCl ₃ ); δ: 153.88 (t, J = 32.0Hz), 142.81 (s) 128.69 (s)
127.50 (s) 126.58 (s) 113.07 (t, J = 238.4Hz), 69.11
(s) 24.02 (t, J = 1.4Hz) ¹⁹ F-NMR (CDCl ₃ ); δ: 38.88 (ddd, J = 329.60,54.93,4.58Hz), 39.56 (dd
d, J = 329.60,54.93,4.57Hz) IR (cm ^-1 ); 1390 (C = N) [α] _D ¹⁹ ; +90.82 ° (c = 1.064 g / 100mL; MeOH) (S-(-) Identification data of -2,2-difluoroethylidene-α-phenethylamine (4b)) ¹ H-NMR (CDCl ₃ ); δ: 1.540 (d, J = 6.68Hz), 4.493 (qd, J = 6.88Hz), 6.0
17 (td, J = 54.95,5.29Hz), 7.2-7.4 (m), 7.679 (dtd,
J = 5.21,2.08,0.81Hz) ¹³ C-NMR (CDCl ₃ ); δ: 153.88 (t, J = 32.0Hz), 142.81 (s) 128.69 (s)
127.50 (s) 126.58 (s) 113.07 (t, J = 238.4Hz), 69.11
(s) 24.02 (t, J = 1.4Hz) ¹⁹ F-NMR (CDCl ₃ ); δ: 38.88 (ddd, J = 329.60,54.93,4.58Hz), 39.56 (dd
d, J = 329.60,54.93,4.57Hz) IR (cm ^-1 ); 1390 (C = N) [α] _D ²² ; -70.43 ° (c = 0.72 g / 100mL; CHCl ₃ ) Example 1: N- ((R) -Methylbenzyl)-(2R or 2S) -difluoromethyl-4-dihydropyridone (3a), (3b)

[0046]

[Chemical 14]

Zinc chloride in a system substituted with nitrogen at room temperature
0.80 g (5.9 mmol) was dissolved in 50 mL of THF. Preliminarily prepared R-(+)-2,2-difluoroethylidene-α-phenethylamine (4a) 1.08 g (5.9 mmol) and 1-methoxy
-3-Trimethylsiloxy-1,3-butadiene (5) 1.51g
(8.8 mmol) was added and the mixture was stirred for 3 hours. Then, water was added to the system, the mixture was extracted with ethyl acetate, the extract was dried over magnesium sulfate, and the solvent was removed by an evaporator. Then, N-[(R) -methylbenzyl] -2-difluoromethyl-4-dihydropyridone was obtained with a yield of 83%,
At this time, the production ratio of the two diastereomers was 1: 1.

When this was separated by column chromatography on silica gel (developing solvent; hexane / ethyl acetate = 1/3), the isolation yield of the two diastereomers was diastereomer (3a) [N-[( R) -Methylbenzyl]-(2R)-
Difluoromethyl-4-dihydropyridone] is 40%, diastereomer (3b) [N-[(R) -methylbenzyl]
-(2S) -Difluoromethyl-4-dihydropyridone] is 43%
Met. The identification data of each diastereomer is shown below.

(Identification data for diastereomer (3a)) ¹ H-NMR (CDCl ₃ ); δ: 1.68 (3H, d, J _{H, H} = 6.84 Hz), 2.55 (1H, d, J _{H, H)} = 1
7.3Hz), 2.79 (1H, ddd, J _{H, H} = 2.20,7.57,17.3Hz), 3.
58 (1H, m), 4.65 (1H, q, J _{H, H} = 7.08Hz), 5.13 (1H, d
d, J _{H, H} = 0.73,7.57Hz), 5.97 (1H, dt, J _{H, H} = 6.59Hz,
J _{H, F} = 55.9Hz), 7.2-7.4 (Ar-H), 7.48 (1H, dd, J _{H, H} =
0.98,7.57Hz) ¹³ C-NMR (CDCl ₃ ); δ: 21.29 (s), 34.39 (t, J = 3.8Hz), 58.49 (t, J = 23.
8Hz), 62.93 (t, J = 1.6Hz), 99.52 (s), 113.09 (t, J
= 246.6Hz), 125.77 (s), 128.39 (s), 129.28 (s),
142.21 (s), 147.89 (s), 188.58 (s) ¹⁹ F-NMR (CDCl ₃ ); δ: 34.91 (ddd, J _{F, H} = 7.4,54.93 Hz, J _{F, F} = 288 Hz), 3
5.50 (ddd, J _{F, H} = 9.16,54.9Hz) IR (cm ^-1 ); 1650 (C = O) [α] _D ¹⁹ ＋ 523.70 ° (c = 1.070 g / 100mL; MeOH) (diastereo) Identification data of mer (3b)) ¹ H-NMR (CDCl ₃ ); δ: 1.64 (3H, d, J _{H, H} = 7.08Hz), 2.44 (1H, dt, J _{H, H} =
1.22,17.6Hz), 2.71 (1H, dd, J _{H, H} = 7.57,17.3Hz),
3.83 (1H, m), 4.71 (1H, q, J _{H, H} = 6.83Hz), 4.96 (1H, d
d, J _{H, H} = 0.73,7.56Hz), 5.97 (1H, dt, J _{H, H} = 6.59Hz,
J _{H, F} = 55.9Hz), 6.90 (1H, dd, J _{H, H} = 1.22,7.81Hz),
7.2-7.4 (Ar-H) ¹³ C-NMR (CDCl ₃ ); δ: 21.29 (t, J = 1.1Hz), 35.22 (dd, J = 2.2,4.9Hz), 5
7.92 (dd, J = 22.1,25.8Hz), 63.10 (s), 99.93 (s),
113.56 (dd, J = 245.2,247.8Hz), 128.10 (s), 129.23
(s), 129.65 (s), 139.21 (s), 150.73 (s), 189.3
0 (s) ¹⁹ F-NMR (CDCl ₃ ); δ: 35.10 (ddd, J _{F, H} = 12.2,56.5 Hz, J _{F, F} = 288 Hz), 3
6.96 (ddd, J _{F, H} = 7.63,54.9 Hz) IR (cm ^-1 ); 1650 (C = O) [α] _D ¹⁸ ; −236.07 ° (c = 0.716 g / 100 mL; MeOH) Example 2: N-[(S) -methylbenzyl]-(2R or 2S) -difluoromethyl-4-dihydropyridone (3c), (3d)

[0050]

[Chemical 15]

Zinc chloride in a system substituted with nitrogen at room temperature
0.80 g (5.9 mmol) was dissolved in 50 mL of THF. 1.08 g (5.9 mmol) of S-(-)-2,2-difluoroethylidene-α-phenethylamine (4b) and 1-methoxy
-3-Trimethylsiloxy-1,3-butadiene (5) 1.51g
(8.8 mmol) was added and the mixture was stirred for 3 hours. Then, water was added to the system, the mixture was extracted with ethyl acetate, the extract was dried over magnesium sulfate, and the solvent was removed by an evaporator. Then, N-[(S) -methylbenzyl] -2-difluoromethyl-4-dihydropyridone was obtained with a yield of 63%,
At this time, the production ratio of the two diastereomers was 1: 1.7.

When this was separated by column chromatography on silica gel (developing solvent; hexane / ethyl acetate = 1/3), the isolation yields of the two diastereomers were diastereomers (3c) [N-[( S) -Methylbenzyl]-(2R)-
Difluoromethyl-4-dihydropyridone] is 24%, diastereomer (3d) [N-[(S) -methylbenzyl]
-(2S) -Difluoromethyl-4-dihydropyridone] is 40%
Met. The identification data of each diastereomer is shown below.

(Identification data of diastereomer (3c)) ¹ H-NMR (CDCl ₃ ); δ: 1.64 (3H, d, J _{H, H} = 7.08 Hz), 2.44 (1H, dt, J _{H, H)} =
1.22,17.6Hz), 2.71 (1H, dd, J _{H, H} = 7.57,17.3Hz),
3.83 (1H, m), 4.71 (1H, q, J _{H, H} = 6.83Hz), 4.96 (1H, d
d, J _{H, H} = 0.73,7.56Hz), 5.97 (1H, dt, J _{H, H} = 6.59Hz,
J _{H, F} = 55.9Hz), 6.90 (1H, dd, J _{H, H} = 1.22,7.81Hz),
7.2-7.4 (Ar-H) ¹³ C-NMR (CDCl ₃ ); δ: 21.29 (t, J = 1.1Hz), 35.22 (dd, J = 2.2,4.9Hz), 5
7.92 (dd, J = 22.1,25.8Hz), 63.10 (s), 99.93 (s),
113.56 (dd, J = 245.2,247.8Hz), 128.10 (s), 129.23
(s), 129.65 (s), 139.21 (s), 150.73 (s), 189.3
0 (s) ¹⁹ F-NMR (CDCl ₃ ); δ: 35.10 (ddd, J _{F, H} = 12.2,56.5 Hz, J _{F, F} = 288 Hz), 3
6.96 (ddd, J _{F, H} = 7.63,54.9Hz) IR (cm ^-1 ); 1650 (C = O) [α] _D ¹⁹ ; −475.95 ° (c = 1.074 g / 100mL; CHCl ₃ ) (diastereo) Identification data of mer (3d)) ¹ H-NMR (CDCl ₃ ); δ: 1.68 (3H, d, J _{H, H} = 6.84Hz), 2.55 (1H, d, J _{H, H} = 1
7.3Hz), 2.79 (1H, ddd, J _{H, H} = 2.20,7.57,17.3Hz), 3.
58 (1H, m), 4.65 (1H, q, J _{H, H} = 7.08Hz), 5.13 (1H, d
d, J _{H, H} = 0.73,7.57Hz), 5.97 (1H, dt, J _{H, H} = 6.59Hz,
J _{H, F} = 55.9Hz), 7.2-7.4 (Ar-H), 7.48 (1H, dd, J _{H, H} =
0.98,7.57Hz) ¹³ C-NMR (CDCl ₃ ); δ: 21.29 (s), 34.39 (t, J = 3.8Hz), 58.49 (t, J = 23.
8Hz), 62.93 (t, J = 1.6Hz), 99.52 (s), 113.09 (t, J
= 246.6Hz), 125.77 (s), 128.39 (s), 129.28 (s),
142.21 (s), 147.89 (s), 188.58 (s) ¹⁹ F-NMR (CDCl ₃ ); δ: 34.91 (ddd, J _{F, H} = 7.4,54.93 Hz, J _{F, F} = 288 Hz), 3
5.50 (ddd, J _{F, H} = 9.16,54.9Hz) IR (cm ^-1 ); 1650 (C = O) [α] _D ¹⁹ ； + 332.73 ° (c = 0.302 g / 100mL; CHCl ₃ ) Example 3: N-[(S) -methylbenzyl]-(2R) -difluoromethyl- (4S or 4R) -piperidinol (2a), (2b)

[0054]

[Chemical 16]

N-[(S) -methylbenzyl]-(2R) -difluoromethyl-4-dihydropyridone (3c) prepared in Example 2
0.45 g (1.8 mmol) was dissolved in 5 mL of ethanol and the temperature was kept at 0 ° C. Sodium borohydride 0.13 there
g (3.6 mmol, 8 eq) was slowly added, and the mixture was brought to room temperature and stirred for 5 hours. Then, ethanol was removed by an evaporator, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was removed by an evaporator. Then, N-[(S) -methylbenzyl]-(2R) -difluoromethyl-4-piperidinol was obtained with a yield of 93%, and the production ratio of the two diastereomers was [the diastereomer (2a) ]: [Diastereomer
(2b)] = 1.5: 1.

When this was separated by column chromatography on silica gel (developing solvent; hexane / ethyl acetate = 2/1), the isolation yield of each diastereomer was found to be diastereomer (2a) [N-[(S ) -Methylbenzyl]-(2R) -difluoromethyl- (4S) -piperidinol] is 56%, and the diastereomer (2b) (N-[(S) -methylbenzyl]-(2R)-
Difluoromethyl- (4R) -piperidinol] was 37%. The identification data of each diastereomer is shown below.

(Identification data for diastereomer (2a)) ¹ H-NMR (CDCl ₃ ); δ: 1.37 (3H, d, J _{H, H} = 6.59 Hz), 1.6-1.7 (1H, s), 1 .
7-1.8 (4H, m), 2.76 (1H, dtt, J _{H, H} = 0.97,2.69,13.18
Hz), 2.88 (1H, dt, J _{H, H} = 3.41,13.43Hz), 3.29 (1H,
m), 3.9-4.0 (1H, m), 5.95 (ddd, J _{H, H} = 3.91Hz, J
_{H, F} = 55.67,56.64Hz) ¹³ C-NMR (CDCl ₃ ); δ: 21.80 (s), 32.63 (d, J = 7.1Hz), 39.52 (s), 4
2.24 (s), 59.39 (s), 65.71 (t, J = 5.3Hz), 121.46
(t, J = 234.0Hz), 127.07 (s), 128.25 (s), 128.48
(s) ¹⁹ F-NMR (CDCl ₃ ); δ: 37.97 (ddd, J _{H, H} = 21.36Hz, J _{F, H} = 56.46Hz, J _{F, F} = 2
83.82Hz), 40.97 (ddd, J _{H, H} = 10.68Hz, J _{F, H} = 54.93Hz,
J _{F, F} = 283.82Hz) IR (cm ^-1 ); 3400 (OH) [α] _D ²⁰ ; + 12.62 ° (c = 0.436 g / 100mL; MeOH) (identification data for diastereomer (2b)) ¹ H-NMR (CDCl ₃ ); δ: 1.41 (3H, d, J _{H, H} = 6.84Hz), 1.6-1.7 (1H, s), 1.
7-1.8 (4H, m), 2.45 (1H, ddd, J _{H, H} = 4.15,5.37,12.94
Hz), 2.958 (1H, m), 3.06 (1H, ddd, J _{H, H} = 3.18,9.2
8,12.70Hz), 3.9-4.0 (1H, m), 4.13 (1H, quin, J _{H, H} =
7.08Hz) 6.32 (1H, ddd, J _{H, H} = 5.61,55.18Hz, J _{H, F} = 5
7.62Hz) ¹⁹ F-NMR (CDCl ₃ ); δ: 34.73 (ddd, J _{F, H} = 9.16,54.93 Hz, J _{F, F} = 283.82H
z), 41.40 (ddd, J _{F, H} = 10.68,57.99Hz, J _{F, F} = 283.82H
z) IR (cm ⁻¹ ); 3400 (OH) [α] _D ²² ; −2.61 ° (c = 0.324 g / 100 mL; CHCl ₃ ). Example 4: N-[(R) -methylbenzyl]-(2S ) -Difluoromethyl- (4S or 4R) -piperidinol (2c), (2d)

[0058]

[Chemical 17]

N-[(R) -methylbenzyl]-(2S) -difluoromethyl-4-dihydropyridone (3b) prepared in Example 1
0.45 g (1.8 mmol) was dissolved in 5 mL of ethanol and the temperature was kept at 0 ° C. Sodium borohydride 0.13 there
g (3.6 mmol, 8 eq) was slowly added, and the mixture was brought to room temperature and stirred for 5 hours. Then, ethanol was removed by an evaporator, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was removed by an evaporator. Then, N-[(R) -methylbenzyl]-(2S) -difluoromethyl-4-piperidinol was obtained with a yield of 72%, and the production ratio of the two diastereomers was [the diastereomer (2c) ]: [Diastereomer
(2d)] = 1: 1.5.

When this was separated by column chromatography on silica gel (developing solvent; hexane / ethyl acetate = 2/1), the isolation yield of each diastereomer was diastereomer (2c) [N-[(R ) -Methylbenzyl]-(2S) -difluoromethyl- (4R) -piperidinol] is 43%, and the diastereomer (2d) (N-[(R) -methylbenzyl]-(2S)-
Difluoromethyl- (4S) -piperidinol] was 29%. The identification data of each diastereomer is shown below.

(Identification data for diastereomer (2c)) ¹ H-NMR (CDCl ₃ ); δ: 1.36 (3H, d, J _{H, H} = 6.59 Hz), 1.7 (4H, m), 2.64
(2H, m), 2.89 (1H, dt, J _{H, H} = 4.39,13.68Hz), 3.32
(1H, m), 4.0 (1H, m), 4.01 (1H, q, J _{H, H} = 6.59Hz),
5.91 (1H, ddd, J _{H, H} = 3.91Hz, J _{F, H} = 55.42,56.40Hz) ¹³ C-NMR (CDCl ₃ ); δ: 20.07 (s), 30.88 (s), 32.14 (s), 42.09 (d, J
= 1.1Hz), 53.92 (t, J = 21.0Hz), 59.42 (s), 65.64
(d, J = 2.1Hz), 121.83 (t, J = 95.9Hz), 127.07 (s), 1
28.51 (s), 140.70 (s) ¹⁹ F-NMR (CDCl ₃ ); δ: 39.73 (ddd, J _{H, H} = 19.84 Hz, J _{F, H} = 56.46,285.34 _H
z), 42.44 (ddd, J _{H, H} = 10.68Hz, J _{F, H} = 56.46,285.34H
z) IR (cm ^-1 ); 3400 (OH) [α] _D ²⁰ ; + 1.62 ° (c = 0.436 g / 100mL; MeOH) (identification data for diastereomer (2d)) ¹ H-NMR (CDCl ₃ ); δ: 1.34 (3H, d, J _{H, H} = 13.41Hz), 1.5 (1H, s), 1.7
(2H, m), 1.8 (2H, m), 2.37 (1H, dq, J _{H, H} = 3.67,12.70
Hz), 2.72 (1H, dq, J _{H, H} = 3.42,11.96Hz), 3.11 (1H, d
q, J _{H, H} = 4.88,15.48Hz), 3.89 (1H, dq, J _{H, F} = 10.50Hz,
J _{H, H} = 3.91Hz), 4.14 (1H, q, J _{H, H} = 6.60Hz), 6.26
(1H, ddd, J _{H, H} = 5.37Hz, J _{H, F} = 55.17,56.88Hz), 7.2-
7.5 (5H, m) ¹³ C-NMR (CDCl ₃ ); δ: 15.45 (s), 32.14 (dd, J = 2.2, 6.0Hz), 32.76
(s), 56.33 (t, J = 21.6Hz), 57.98 (d, J = 1.2Hz), 66.72
(s), 116.43 (dd, J = 242.6,245.2Hz), 126.81 (s),
127.29 (s), 128.25 (s), 144.89 (s) ¹⁹ F-NMR (CDCl ₃ ); δ: 34.33 (ddd, J _{H, H} = 10.68Hz, J _{F, H} = 54.93Hz, J _{F, F} = 2
85.34Hz), 38.60 (ddd, J _{H, H} = 10.68Hz, J _{F, H} = 57.98Hz,
J _{F, F} = 285.34 Hz) IR (cm ⁻¹ ); 3400 (OH) [α] _D ¹⁹ ; −16.48 ° (c = 0.951 g / 100 mL; MeOH) Example 5: (2S) -difluoromethyl- ( 4R or 4S) -piperidinol (1a), (1b) Palladium carbon (Pd-C) 0.13 g was suspended in 5 mL of THF, and N-[(R) -methylbenzyl]-(2S prepared in Example 4 was suspended therein. ) -Difluoromethyl- (4R) -piperidinol (2c)
Was added in an amount of 0.050 g (0.18 mmol). The mixture was stirred at room temperature under a hydrogen stream for 24 hours. Then, the palladium carbon was removed by filtration, and the solvent was removed by an evaporator. Purification by silica gel column chromatography (developing solvent; ethyl acetate) shows the following identification data (2S)
-Difluoromethyl- (4R) -piperidinol (1a) 0.024
g (0.15 mmol) was obtained. The yield was 83%.

Further, instead of N-[(R) -methylbenzyl]-(2S) -difluoromethyl- (4R) -piperidinol (2c), N-
[(R) -Methylbenzyl]-(2S) -difluoromethyl- (4S)-
When the reaction similar to the above is performed using piperidinol (2d), the following identification data is shown (2S) -difluoromethyl- (4S).
-Piperidinol (1b) was obtained.

(Identification data for diastereomer (1a)) ¹ H-NMR (CDCl ₃ ); δ: 1.25 (1H, q, J _{H, H} = 11.2 Hz), 1.40 (1H, ddt, J _{H, H)}
= 4.40,12.5Hz), 1.75 (OH, s), 1.97 (1H, dddd, J _{H, H}
= 2.44,4.88,4.88,12.2Hz), 2.08 (1H, ddt, J _{H, H} = 2.1
9,4.15,12.0Hz), 2.66 (1H, dt, J _{H, H} = 2.69,12.5Hz),
2.90 (1H, ddddd, J _{H, H} = 2.68,4.88,10.5,11.0,11.0Hz),
3.17 (1H, dt, J _{H, H} = 3.42,12.2Hz), 3.70 (1H, tt, J
_{H, H} = 4.39,11.0Hz), 5.63 (1H, dt, J _{H, H} = 4.81Hz, J
_{H, F} = 56.64Hz) ¹³ C-NMR (CDCl ₃ ); δ: 34.62 (t, J = 2.8Hz), 35.3 (s), 39.76 (s), 56.
96 (t, J = 22.6Hz), 67.98 (s), 117.53 (t, J = 243Hz) ¹⁹ F-NMR (CDCl ₃ ); δ: 38.73 (ddd, J _{F, H} = 10.68,56.46Hz, J _{F , F} = 287Hz),
40.83 (ddd, J _{F, H} = 10.68,56.46Hz) IR (cm ^-1 ); 3300 (OH) [α] _D ²⁰ -16.49 ° (c = 0.320 g / 100mL; CHCl ₃ ) (Diastereomer ( Identification data of 1b)) ¹ H-NMR (CDCl ₃ ); δ: 1.56 (1H, ddd, J _{H, H} = 2.68,11.5,13.7Hz), 1.68 (1
H, m), 1.73 (1H, ddd, J _{H, H} = 2.93,4.63,13.9Hz), 1.8
1 (1H, ddd, J _{H, H} = 3.42,4.89,13.4Hz), 2.89 (1H, dt, J
_{H, H} = 3.66,12.2Hz), 3.08 (1H, dt, J _{H, H} = 3.90,11.7H
z), 3.31 (1H, ddddd, J _{H, H} = 2.93,4.63,11.2,11.2,11.2
Hz), 4.25 (1H, dt, J _{H, H} = 2.93,2.93Hz), 5.59 (1H, dt,
J _{H, H} = 4.88Hz, J _{H, F} = 56.64Hz) ¹³ C-NMR (CDCl ₃ ); δ: 33.26 (dd, J = 2.9,4.1Hz), 34.62 (s), 43.81
(s), 42.50 (t, J = 21.9Hz), 63.39 (d, J = 4.1Hz), 116.8
2 (t, J = 242Hz) ¹⁹ F-NMR (CDCl ₃ ); δ: 38.59 (ddd, J _{F, H} = 10.68,56.46Hz, J _{F, F} = 287Hz),
40.32 (ddd, J _{F, H} = 10.68,56.46Hz) IR (cm ^-1 ); 3300 (OH) [α] _D ²⁰ -13.14 ° (c = 0.283 g / 100mL; CHCl ₃ ) The (2R) -difluoromethyl- (4R) -piperidinol prepared in Example 3 by the method of
[(S) -Methylbenzyl]-(2R) -difluoromethyl- (4R)-
N-[(S)-was obtained from piperidinol and (2R) -difluoromethyl- (4S) -piperidinol was prepared in Example 3.
Methylbenzyl]-(2R) -Difluoromethyl- (4S) -piperidinol. The identification data is shown below.

(Identification data for (2R) -difluoromethyl- (4R) -piperidinol) ¹ H-NMR (CDCl ₃ ); δ: 1.56 (1H, ddd, J _{H, H} = 2.68,11.5,13.7 Hz), 1.68 (1
H, m), 1.73 (1H, ddd, J _{H, H} = 2.93,4.63,13.9Hz), 1.8
1 (1H, ddd, J _{H, H} = 3.42,4.89,13.4Hz), 2.89 (1H, dt, J
_{H, H} = 3.66,12.2Hz), 3.08 (1H, dt, J _{H, H} = 3.90,11.7H
z), 3.31 (1H, ddddd, J _{H, H} = 2.93,4.63,11.2,11.2,11.2
Hz), 4.25 (1H, dt, J _{H, H} = 2.93,2.93Hz), 5.59 (1H, dt,
J _{H, H} = 4.88Hz, J _{H, F} = 56.64Hz) ¹³ C-NMR (CDCl ₃ ); δ: 33.26 (dd, J = 2.9,4.1Hz), 34.62 (s), 43.81
(s), 42.50 (t, J = 21.9Hz), 63.39 (d, J = 4.1Hz), 116.8
2 (t, J = 242Hz) ¹⁹ F-NMR (CDCl ₃ ); δ: 38.59 (ddd, J _{F, H} = 10.68,56.46Hz, J _{F, F} = 287Hz),
40.32 (ddd, J _{F, H} = 10.68,56.46Hz) IR (cm ^-1 ); 3300 (OH) [α] _D ²² ; +14.93 ° (c = 0.688 g / 100mL; CHCl ₃ ) ((2R) Identification data of -difluoromethyl- (4S) -piperidinol) ¹ H-NMR (CDCl ₃ ); δ: 1.25 (1H, q, J _{H, H} = 11.2Hz), 1.40 (1H, ddt, J _{H, H}
= 4.40,12.5Hz), 1.75 (OH, s), 1.97 (1H, dddd, J _{H, H}
= 2.44,4.88,4.88,12.2Hz), 2.08 (1H, ddt, J _{H, H} = 2.1
9,4.15,12.0Hz), 2.66 (1H, dt, J _{H, H} = 2.69,12.5Hz),
2.90 (1H, ddddd, J _{H, H} = 2.68,4.88,10.5,11.0,11.0Hz),
3.17 (1H, dt, J _{H, H} = 3.42,12.2Hz), 3.70 (1H, tt, J
_{H, H} = 4.39,11.0Hz), 5.63 (1H, dt, J _{H, H} = 4.81Hz, J
_{H, F} = 56.64Hz) ¹³ C-NMR (CDCl ₃ ); δ: 34.62 (t, J = 2.8Hz), 35.3 (s), 39.76 (s), 56.
96 (t, J = 22.6Hz), 67.98 (s), 117.53 (t, J = 243Hz) ¹⁹ F-NMR (CDCl ₃ ); δ: 38.73 (ddd, J _{F, H} = 10.68,56.46Hz, J _{F , F} = 287Hz),
40.83 (ddd, J _{F, H} = 10.68,56.46Hz) IR (cm ^-1 ); 3300 (OH) [α] _D ²² ＋ 13.68 ° (c = 0.384 g / 100)
mL; CHCl ₃ )

Claims (5)

[Claims] 1. 2-Difluoromethyl-4 represented by the formula 1
-Piperidinol. [Chemical 1] [However, in Chemical formula 1, * represents an asymmetric carbon. ] 2. An N-substituted-2-difluoromethyl-4-piperidinol represented by the general formula 2. [Chemical 2] [In Chemical Formula 2, R represents an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms or an arylalkyl group having 7 to 20 carbon atoms, and * represents an asymmetric carbon atom. ] 3. An N-substituted-2-difluoromethyl-4-dihydropyridone represented by the general formula 3. [Chemical 3] [In Chemical Formula 3, R represents an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms or an arylalkyl group having 7 to 20 carbon atoms, and * represents an asymmetric carbon atom. ] 4. An imine represented by the general formula 4 and a formula 5
The method for producing N-substituted-2-difluoromethyl-4-dihydropyridone according to claim 3, wherein the siloxydiene represented by the formula (5) is subjected to a cycloaddition reaction in the presence of a Lewis acid catalyst. [Chemical 4] [In Chemical Formula 4, R represents an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, or an arylalkyl group having 7 to 20 carbon atoms. ] [Chemical 5] 5. The production method according to claim 4, wherein the Lewis acid catalyst is zinc chloride.