JPH11209345A - Production of intermediate for drug - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an intermediate for synthesis of drugs, e.g. nitrogen monoxide synthesizing enzyme inhibitor, in high yield without needing optical resolution by dehydrating a specific compound. SOLUTION: This compound, shown by formula III or IV, e.g. (-)- N-(methoxybenzyl)-5,6-dehydro-3-methylpiperidone), is obtained by dehydrating a compound shown by formula I or II (R is 4-methoxybenzyl, 3,4- dimethoxybenzyl, p-phenylbenzyl or the like). It is recommended that the dehydration reaction is effected using an acid, e.g. p-toluenesulfonate, at 80 to 120 deg.C in the presence of an inert organic solvent, e.g. benzene.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a pharmaceutical intermediate. For more information, see the equation

[0002]

Embedded image

(R is a 4-methoxybenzyl group, 3,4
-Dimethoxybenzyl, p-phenylbenzyl, triphenylmethyl, p-chlorobenzyl or benzyl. )).

[0004]

The formulas (Ia) and (Ia)
Compounds of formula (b) are useful as nitric oxide synthase inhibitors of formula (A):

[0005]

Embedded image

(In the formula, -R1- represents a 3- or 4-membered carbocyclic ring condensed with the carbon atom at the bonding position to d or e of the piperidine ring or spiro-bonded to the 4-position. , R2 represents C1-6 alkyl, and R3 represents
Represents a C1-6 alkyl, a C2-6 alkenyl, a C2-6 alkynyl or a halogen, and R4 represents a hydrogen atom, an amino-C1-4 alkyl, a carbocyclic ring -C1-4 optionally substituted with an amino-C1-4 alkyl. Represents alkyl,
i represents 0-3, and n represents 0-3. However, a plurality of R2 or R3 may be the same or different. )) (See Japanese Patent Application No. 9-273196).

[0007]

BACKGROUND OF THE INVENTION The compound represented by the formula (A) is compact, but has several asymmetric centers, and requires optical resolution in a usual synthesis method, which is extremely costly and troublesome. There is a problem.

[0008]

2. Description of the Related Art There are several methods for synthesizing a compound represented by the formula (A). This is considered to be the simplest because division is not required.

[0009]

Means for Solving the Problems The present inventors have made the formula (I)
Investigations were repeated to produce the compounds represented by a) and (Ib) in good yield and without the need for optical resolution. As a result, the formula (II)

[0010]

Embedded image

By using the compound represented by the formula (1), the present inventors have found a method for producing the compounds represented by the formulas (Ia) and (Ib) without going through any optical resolution step, and completed the present invention.

[0012]

The present invention relates to a method for producing Formulas (Ia) and (Ib) without optical resolution, as described above. In order to explain the present invention in detail, the following reaction scheme (A) is shown.

[0013]

Embedded image

Each step of the present invention will be described in detail below. Step (a) is a reduction reaction, for example, in an inert organic solvent (THF, diethyl ether, dioxane, dimethoxyethane, diglyme, methylene chloride, etc.), a reducing agent (borane-dimethylsulfide complex, borane-tetrahydrofuran complex, Diborane, borane-pyridine complex, borane-dimethylamine complex, etc.) at -10 to 40 ° C.

Steps (b) and (f) are an amidation reaction, for example, in an inert organic solvent (benzene, toluene, xylene, chlorobenzene, 1,2-dichloroethane, THF, etc.) and a tertiary amine ( In the presence or absence of dimethylaminopyridine, triethylamine, dimethylaniline, pyridine and the like, the amine (4-methoxybenzylamine, 3,4-dimethoxybenzylamine, p-phenylbenzylamine, Phenylmethylamine, p-chlorobenzylamine or benzylamine) and heating to reflux.

Steps (c) and (g) are oxidation and ring closure reactions, for example, in an inert organic solvent (1,2-dichloroethane, methylene chloride, etc.) or without solvent, with a tertiary amine (triethylamine, Using an oxidizing agent (such as dimethyl sulfoxide) in the presence or absence of an activating agent (such as sulfur trioxide-pyridine complex or DCC) in the presence or absence of diisopropylethylamine or the like; Performed at ° C.

Steps (d) and (h) are dehydration reactions, for example, using an inert organic solvent (benzene, toluene, xylene, chlorobenzene, 1,2-dichloroethane, T
HF) at 80 to 120 ° C. using an acid (p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, etc.). Step (e) comprises 1) conversion to an alkali metal salt, 2)
A reduction reaction and 3) a ring closure reaction by lactonization. For example, 1) an alkali (water) with or without an inert organic solvent (methanol, ethanol, propanol, THF, dioxane, etc.) miscible with water. After performing at 0 to 50 ° C. using an aqueous solution of lithium oxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc., 2) inert organic solvent (THF, diethyl ether, dioxane, dimethoxyethane, etc.) Medium, using a reducing agent (lithium borohydride, etc.) at 0-70 ° C., 3) inert organic solvent (benzene, toluene, xylene, chlorobenzene, 1,2-dichloroethane, T
HF) at 80 to 120 ° C. using an acid (p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, etc.).

Each step is preferably performed in an inert gas atmosphere. Further, the steps other than the steps (d) and (h) are preferably performed in an anhydrous state. The compound represented by the formula (II) is commercially available, but can also be produced according to the following reaction step formula (B).

[0019]

Embedded image

In each reaction scheme, the compound used as a starting material is a known compound, or can be easily produced from a known compound by a known method. Other starting materials and each reagent in the present invention are:
They are known per se or can be produced by known methods. In each reaction herein, the reaction product may be purified by conventional purification means, for example, distillation under normal pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, or column chromatography. Or washing,
It can be purified by a method such as recrystallization. Purification may be performed for each reaction, or may be performed after several reactions are completed.

[0021]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. Reference Example 1 Trimethyl 2-methyl-1,1,3-propanetricarboxylate (1)

[0022]

Embedded image

Under a stream of argon, 37 L of methanol was placed in a 100 L reaction vessel, cooled with ice water (internal temperature to 10 ° C.), and stirred. The internal temperature was kept at 40 ° C. or lower, and sodium methoxide 4.2 kg (74 mol ) Was added. After heating the reaction mixture to an internal temperature of 4040 ° C., 11.5 kg of dimethyl malonate (87 mo
l) and 7.4 kg (74 mol) of methyl crotonate
It was added dropwise over a period of minutes. After the completion of the dropwise addition, the mixture was refluxed for 1 to 2 hours.
The reaction mixture is cooled with ice water, and the acetic acid
4.23 L was added and neutralized. The resulting sodium acetate is converted to water about 4.
9 L was added and dissolved. The methanol was distilled off under reduced pressure, and about 24.5 L of ice water and about 15 L of ethyl acetate were added to the residue, followed by stirring for about 5 minutes. After liquid separation, the aqueous layer was ethyl acetate about 10 L
Extract and wash the combined organic layers with water (about 8 LX 1). Wash with saturated saline (about 16 LX 1). Concentrate under reduced pressure and trimethyl
2-methyl-1,1,3-propanetricarboxylate (1)
Was obtained as a crudely purified oily substance in an amount of about 19.2 kg (100% up). The obtained crude oil (1) was used for the next reaction without purification. TLC: UV absorption and color development by color developing solution are undetectable; Mass: (APCI, Pos., 40V) 233 (M + H) +, 201, 169; NMR: (200MHz, CDCl3) δ3.74 (3H, s) , 3.74 (3H,
s), 3.68 (3H, s), 3.46 (1H, d, J = 7.0Hz), 2.83-
2.67 (1H, m), 2.54 (1H, dd, J = 5.0, 15.8Hz), 2.32
(1H, dd, J = 8.4, 15.8Hz), 1.06 (3H, d, J = 6.8Hz). Reference Example 2 Dimethyl 3-methylglutarate (2)

[0024]

Embedded image

In a reaction vessel, 2-methyl-1,1,3-propanetricarboxylate (1) 19 kg (74 mol), water 1.7 L, DMF
56 L, charged with 3.76 kg (89 mol) of lithium chloride,
The reaction was carried out at 137 ° C for about 3 to 4 hours.
% After confirming that the temperature has become below 30%
Cooled down to: After stirring the reaction mixture in about 110 L of ice water, about 22.9 L of 2N HCl was added thereto at an internal temperature of about 20 L.
The pH was adjusted to 4 to 5 while maintaining the temperature at or below ℃. Extracted with n-hexane / ethyl acetate (3/1) (about 25 LX 4), combined organic layers, washed with saturated sodium bicarbonate water (about 20 LX 1), washed with water (about 20 LX 1), and washed with saturated saline (about 20 LX 1). ). After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure to obtain about 11 to 12 L of a crude oil. By precision distillation, 7.92 kg (61.4%, based on methyl crotonate) of dimethyl 3-methylglutarate (2) was obtained as a colorless oil. TLC: UV absorption and color development by color developing solution are undetectable; Mass: (APCI, Pos., 20V) 175 (M + H) +, 143; NMR: (200MHz, CDCl3) δ 3.65 (6H, s), 2.51- 2.14
(5H, m), 1.00 (3H, d, J = 6.4Hz). Reference Example 3 Methyl (R) -3-methylglutarate ((+)-3)

[0026]

Embedded image

50 L of water was placed in a 200 L plastic container, and 871 g (5.0 mol) of dipotassium hydrogen phosphate was dissolved. Then, about 93 mL (1.6 mol) of phosphoric acid was added to adjust the pH to 7. While stirring, dimethyl 3-methyl glutarate
(2) 7.5 kg (43.1 mol) of porcine liver esterase (PL
E) After adding 250,000 units, add sodium bicarbonate
3.62 kg (43.1 mol) of a 50 L solution of water was added (pH = 7.8
2). After stirring at room temperature for about 26 hours, confirm the completion of the reaction by gas chromatography (compound (2) is 0.5% or less).
About 30 kg of sodium chloride was added to the reaction mixture to dissolve it, and about 10 L of ethyl acetate was added and stirred.
The insoluble matter derived from it was separated by filtration. Transfer the reaction mixture to a 300 L reaction vessel, add about 40 L of ethyl acetate, and stir 2N
Adjust pH to 4 by adding about 19.6 L of HCl little by little, and add about 5
After stirring for minutes and liquid separation, about 25 L of ethyl acetate was added to the aqueous layer, about 3.6 L of 2N HCl was added, and the mixture was stirred for about 5 minutes. After liquid separation, combine the organic layers and wash with saturated saline (about 10 LX
1), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give methyl (R) -3-methylglutarate ((+)-
3) was obtained as a colorless oil (6.38 kg, 92.4%). TLC: Rf = 0.39 (n-Hexane / AcOEt, 1/1); Mass: (APCI, Neg., 40V) 159 (MH) +, 127; NMR: (200MHz, CDCl3) δ 10.50-6.50 (1H, br ), 3.67
(3H, s), 2.57-2.19 (5H, m), 1.05 (3H, d, J = 6.2H
z). Example 1 Methyl (R) -5-hydroxy-3-methylpentanoate
(Four)

[0028]

Embedded image

Under a nitrogen stream, 2.83 kg (17.7 mol) of methyl (R) -3-methylglutarate (3) and dehydrated THF were added to the reaction vessel.
17.7 L was added, and the mixture was cooled with ice water and stirred. Internal temperature is 10
When the temperature falls below ℃, the borane dimethyl sulfide complex 2.
9.70 L (19.7 mol) of a 0M THF solution was added dropwise, and the mixture was stirred for 15 minutes. Then, the ice water bath was changed to a water bath (about 20 ° C.) and stirred. Although the internal temperature gradually increased, the mixture was stirred while maintaining the temperature at 35 ° C or lower, and then stirred at 25 to 30 ° C for about 1 hour after the temperature rose. After confirming the completion of the reaction by TLC, the mixture was cooled with ice water, and when the internal temperature became 10 ° C. or lower, 11.1 L of water was carefully added dropwise. After completion of the dropwise addition, THF was distilled off under reduced pressure. To the residue were added 10 L of water, 10 L of ethyl acetate, and 4.7 kg of sodium chloride, and the mixture was stirred for about 5 minutes to separate the layers.
L x 1, 6 L x 1). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give methyl (R) -5-hydroxy-3-methylpentanoate (4)
2.51 kg (97%) as a pale yellow oil. The title compound (4) having the following physical data was used for the next reaction without purification. TLC: Rf = 0.51 (n-Hexane / AcOEt, 1/1); Mass: (APCI, Pos., 20V) 147 (M + H) +, 129, 115; NMR: (200MHz, CDCl3) δ 3.68 (3H , s), 3.68 (2H,
t, J = 6.5Hz), 3.20-2.60 (1H, br), 2.42-2.06 (3H, m),
1.67-1.47 (2H, m), 0.99 (3H, d, J = 6.4Hz). Example 2 (R) -N- (4-methoxybenzyl) -5-hydroxy-3-methylvaleramide (5)

[0030]

Embedded image

In a reaction vessel, 1780 g (12.2 mol) of methyl (R) -5-hydroxy-3-methylpentanoate (4), toluene 2
Charge 5 L and add 4-methoxybenzylamine with stirring.
After the addition of 1800 mL (13.9 mol), the reaction mixture was heated and refluxed for 1.5 hours (the internal temperature at the start of reflux was about 110
℃, about 105 ℃ after 1.5 hours). About 12.5 L of toluene containing a low-boiling fraction was distilled off from the reaction mixture, and about 1.5
Reflux for 4 hours, and 125 mL of 4-methoxybenzylamine (1.9 m
ol) and refluxed for about another hour. After confirming the completion of the reaction by TLC, toluene was distilled off under reduced pressure.The residue was diluted with 25 L of ethyl acetate, and 1N hydrochloric acid (5 L x 2)
Then, the mixture was washed with saturated saline (4 L), and the combined washings were extracted with ethyl acetate (4 L × 3 times). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give (R) -N- (4-methoxybenzyl) -5-hydroxy-3-methylvaleramide (5) as a pale yellow wax. 3.11 as a solid
kg (100% up). Title compound having the following physical data
(5) was used for the next reaction without purification. TLC: Rf = 0.40 (n-Hexane / AcOEt, 1/1); Mass: (APCI, Pos., 40V) 252 (M + H) +, 136, 121; NMR: (200MHz, CDCl3) δ 7.24-7.14 (2H, m), 6.90-
6.81 (2H, m), 6.03 (1H, br), 4.36 (2H, d, J = 5.6Hz),
3.79 (3H, s), 3.72-3.59 (2H, m), 2.99 (1H, br), 2.
29-2.01 (3H, m), 1.59-1.46 (2H, m), 0.97 (3H, d, J
= 6.6Hz). Example 3 (R) -N- (4-methoxybenzyl) -6-hydroxy-3-methylpiperidone (6)

[0032]

Embedded image

To a solution of 20 g (80.0 mmol) of (R) -N- (4-methoxybenzyl) -5-hydroxy-3-methylvaleramide (5) in 160 mL of dimethyl sulfoxide was added 44 mL (320 mmol) of triethylamine with stirring. After the addition, the mixture is cooled in a cold water bath, and when the internal temperature becomes 20 ° C or lower, a suspension of 25 g (36.6 mol) of sulfur trioxide-pyridine complex in 20 mL of dimethyl sulfoxide is maintained at 30 ° C or lower. Added slowly. After the addition of the sulfur trioxide-pyridine complex suspension, the mixture is stirred at 15 to 20 ° C for 30 minutes. After confirming the completion of the reaction by TLC, the reaction mixture was ice-water 950 m
And add 50 g of salt and 400 mL of ethyl acetate to add
Stir for 3 minutes. After separation, the aqueous layer was washed with ethyl acetate (200 mL
x 3). The organic layer was washed with 2N-hydrochloric acid (150 mL), saturated saline 150 mL, saturated aqueous sodium bicarbonate 150 mL, saturated saline 150 mL
And dried over about 7 g of anhydrous magnesium sulfate. Then, add 5 g of silica gel (Merck 7734) and add
After stirring for 5 minutes, the mixture was filtered and concentrated under reduced pressure (aspirator, bath temperature: about 40 ° C.). The concentrate obtained as a solid is n-
After adding 70 mL of a mixed solvent of hexane / ethyl acetate = 2/1 and stirring for about 10 minutes to wash the crystals, the crystals are collected by suction filtration and mixed with a mixed solvent of n-hexane / ethyl acetate = 5/1. The crystals were washed with 50 mL. The obtained crystals were dried under reduced pressure (pump, no heating) to give 11.3 g (57.3%) of the title compound (6) having the following physical data. Shape: white powder; TLC: Rf = 0.64 (AcOEt); Mass: (APCI, Pos., 20V) 250 (M + H) +; NMR: (200MHz, CDCl3) δ 7.26-7.18 (2H, m), 6.89 -
6.80 (2H, m), 5.02-4.90 (2H, m), 4.32 (1H, d, J = 14.
6Hz), 3.79 (3H, s), 2.71-2.54 (2H, m), 2.44-2.20
(1H, m), 2.09-1.86 (2H, m), 1.47 (1H, ddd, J = 3.6,
12.8, 13.6 Hz), 1.01 (3H, d, J = 6.6 Hz); specific rotation [α] D: +118.1 (c = 0.97, MeOH). Example 4 (-)-N- (4-methoxybenzyl) -5,6-dehydro-3-methylpiperidone ((-)-7)

[0034]

Embedded image

(R) -N- (4-methoxybenzyl) -6-
Hydroxy-3-methylpiperidone (6) 1071 g (4.3 mo
l) and 24 L of toluene, 24.5 g (0.13 mol) of p-toluenesulfonic acid monohydrate was added with stirring, and the water generated in the reaction system was heated by azeotropic distillation with toluene. After the distillation was continued for 30 minutes, the mixture was cooled with water. After confirming the completion of the reaction by TLC, pyridine 1 was added to the reaction mixture.
2.6 mL (0.16 mol) was added, toluene was distilled off under reduced pressure, and the concentrate was washed with about 2 L of toluene. After adding and drying 30 g of anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel (BW-235): 15 kg, elution solvent: toluene / ethyl acetate = 7/1, 240 L) to give the title compound ((-)-7 having the following physical data). ) As a colorless oil (919.7 g, containing 92.5%, about 4% wt toluene). TLC: Rf = 0.59 (n-Hexane / AcOEt, 1/2); Mass: (APCI, Pos., 40V) 232 (M + H) +, 124, 121; NMR: (200MHz, CDCl3) δ 7.23-7.13 (2H, m), 6.90-
6.81 (2H, m), 5.96 (1H, dd, J = 1.6, 7.8Hz), 5.03 (1
H, ddd, J = 1.0, 4.0,7.6Hz), 4.61 (2H, dd, J = 15.0, 1
7.2Hz), 3.79 (3H, s), 2.70-2.48 (2H, m), 2.38-2.22
(1H, m), 1.05 (3H, d, J = 6.8 Hz); specific rotation [α] D: -88.6 (c = 0.89, MeOH). Example 5 (R) -4-methyltetrahydro-2H-pyran-2-one
(8)

[0036]

Embedded image

Methyl (R) -3-methylglutarate
((+)-3) A 0.2 mol / L aqueous solution of lithium hydroxide was added to (36 g, 224.8 mmoL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, the mixture was concentrated, toluene (150 mL × 3) was added thereto, and the mixture was azeotropically dried, and dried under reduced pressure to obtain white crystals. Then, under argon atmosphere, T
HF (300 mL) was added and lithium borohydride (10.8 g,
A suspension of 495.9 mmoL) and THF (100 mL) was added dropwise over about 1 hour. After completion of the dropwise addition, the mixture was stirred at 50 ° C. for 3 hours. After the reaction is completed, slowly add methanol (70 mL) and add 50 mL
Stirred at 30 ° C. for 30 minutes. After concentrating the reaction solution, water (200 mL)
Was added, and 6N hydrochloric acid (150 mL) was added to adjust the pH to 2, followed by extraction with ethyl acetate (200 mL × 6). The organic layer was dried over anhydrous magnesium sulfate, concentrated, and then concentrated by adding p-toluenesulfonic acid monohydrate (430 mg) and benzene (150 mL) to obtain 40 g as a crude product. Was. Purification by silica gel column was performed to obtain some data, and the title compound (8) having the following physical data was obtained. TLC: Rf 0.49 (n-hexane: ethyl acetate = 1: 1); NMR: (CDCl3, 200MHz) δ 4.48-4.38 (1H, m), 4.33-4.
20 (1H, m), 2.85-2.60 (1H, m), 2.20-1.85 (2H, m),
1.65-1.46 (1H, m), 1.07 (3H, d, J = 6.6 Hz); MS: (APC
I, Pos. 20V) 115 (M) +. Example 6 (S) -N- (4-methoxybenzyl) -5-hydroxy-3
-Methylvaleramide (9)

[0038]

Embedded image

Under an argon atmosphere, (R) -4-methyltetrahydro-2H-pyran-2-one (8) (40 g, 224.8
mmoL), toluene (418 mL), p-methoxybenzylamine
(35 mL, 269.7 mmoL) was heated to reflux for 1 hour. After completion of the reaction, the mixture was filtered through celite and concentrated. 2N hydrochloric acid (200 mL) was added to the obtained residue, and ethyl acetate (300 mL) was added.
mL × 5). The obtained organic layer was dried over anhydrous magnesium sulfate, and concentrated to give the title compound (9) (54 g) having the following physical data. TLC: Rf 0.28 (ethyl acetate); NMR: (CDCl3, 200MHz) δ 7.21 (2H, d, J = 8.8 Hz), 6.
87 (2H, d, J = 8.8 Hz), 5.84 (1H, brs), 4.38 (2H, d,
J = 5.6 Hz) 3.80 (3H, s), 3.70-3.60 (2H, m), 2.30-2.0
5 (3H, m), 1.60-1.50 (2H, m), 0.99 (3H, d, J = 6.6 H
z); MS: (APCI, Pos. 20V) 121, 252 (M) +. Example 7 (S) -N- (4-methoxybenzyl) -6-hydroxy-3
-Methylpiperidone (10)

[0040]

Embedded image

(S) -N- (4-methoxybenzyl) -5-hydroxy-3-methylvaleramide (9) (53.9 g, 21
Dimethylsulfoxide (431 mL) and triethylamine (149 mL, 1072 mmol) were added to the mixture and cooled to 15 ° C.
g, 535.9 mmoL) in dimethylsulfoxide (60 mL) was added slowly, and the mixture was stirred at 15 ° C for 30 minutes. After completion of the reaction, the reaction solution was poured into ice water (2 L), and ethyl acetate (300
mL × 5). The organic layer was washed with 2N hydrochloric acid (200 mL), saturated saline (200 mL), saturated aqueous sodium bicarbonate (200 mL), and saturated saline.
(200 mL), dried over anhydrous magnesium sulfate, and concentrated to precipitate white crystals. A mixed solvent of n-hexane / ethyl acetate = 2/1 was added to the obtained crystals in 1
After adding 50 mL and stirring for about 10 minutes to wash the crystals, the crystals were collected by suction filtration and washed with a mixed solvent of n-hexane / ethyl acetate = 5/1. The obtained crystals were dried under reduced pressure to give the title compound (10) (23 g) having the following physical data. TLC: Rf 0.45 (ethyl acetate); NMR: (CDCl3, 200MHz) δ 7.23 (2H, d, J = 8.8 Hz), 6.
85 (2H, d, J = 8.8 Hz), 4.95 (1H, d, J = 14.2 Hz), 5.00
-4.88 (1H, m), 4.34 (1H, d, J = 14.2 Hz), 3.79 (3H,
s), 2.70-2.52 (1H, m), 2.40-2.18 (1H, brs), 2.10-
1.80 (2H, m), 1.65-1.36 (2H, m), 1.00 (3H, d, J = 6.
MS: (APCI, Pos. 20V) 121, 252 (M) +; Specific rotation: [α] D -168.13 (c 0.95, MeOH). Example 8 (R) -N- (4-methoxybenzyl) -5,6-dehydro-
3-methylpiperidone ((+)-7)

[0042]

Embedded image

(S) -N- (4-methoxybenzyl) -6-hydroxy-3-methylpiperidone (10) (11 g, 44.0
mmoL), toluene (200 mL) and p-toluenesulfonic acid monohydrate (130 mg, 0.69 mmoL) were added, and the mixture was stirred at 80 ° C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and concentrated.
Toluene (50 mL), pyridine (0.06 m
L) and concentrate, silica gel column chromatography (Merck 7734, 110 g, n-hexane / ethyl acetate = 5/1)
The title compound ((+)-
7) (10.2 g) was obtained. TLC: Rf 0.58 (n-hexane: ethyl acetate = 1: 1); NMR (CDCl3, 200MHz) δ 7.17 (2H, d, J = 8.8 Hz), 6.8
4 (2H, d, J = 8.8 Hz), 5.96 (1H, dd, J = 7.7, 1.5 Hz),
5.03 (1H, dd, J = 7.7, 3.4 Hz), 4.61 (2H, d, J = 2.6 H
z), 3.79 (3H, s), 2.70-2.50 (2H, m), 2.40-2.15 (1
H, m), 1.05 (3H, d, J = 6.8 Hz); MS: (APCI, Pos. 20V) 124, 232 (M) +; Specific rotation: [α] D +84.53 (c 0.92, MeOH) .

Claims (5)

[Claims] (1) Formula (1) (Wherein, R represents a 4-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a p-phenylbenzyl group, a triphenylmethyl group, a p-chlorobenzyl group or a benzyl group). A formula characterized by subjecting to a dehydration reaction (Wherein, R represents the same meaning as described above). 2. The formula: (Wherein R has the same meaning as described in claim 1). The compound represented by the formula (1) is subjected to an oxidation reaction and a ring-closure reaction, respectively, to obtain the resulting compound. (Wherein R has the same meaning as described above), wherein each of the compounds is subjected to a dehydration reaction. (Wherein, R represents the same meaning as described above). 3. The formula: Are subjected to an amidation reaction to obtain the resulting compound of the formula (Wherein R has the same meaning as described in claim 1). The compound represented by the formula (1) is subjected to an oxidation reaction and a ring-closure reaction, respectively, to obtain the resulting compound. (Wherein R has the same meaning as described above), wherein each of the compounds is subjected to a dehydration reaction. (Wherein R has the same meaning as described above). 4. The formula: The compounds of the formulas are each subjected to a reduction reaction and the resulting formula Are subjected to an amidation reaction to obtain the resulting compound of the formula (Wherein R has the same meaning as in claim 1). The compound represented by the formula (1) is subjected to an oxidation reaction and a ring-closure reaction, respectively, to obtain the resulting compound. (Wherein R has the same meaning as described above), wherein each of the compounds is subjected to a dehydration reaction. (Wherein R represents the same meaning as described above). 5. The formula: Are subjected to 1) a conversion reaction to an alkali metal salt, 2) a reduction reaction, and 3) a lactonization reaction, respectively, to obtain a compound represented by the following formula: Are subjected to an amidation reaction to obtain the resulting compound of the formula (Wherein R has the same meaning as in claim 1). The compound represented by the formula (1) is subjected to an oxidation reaction and a ring-closure reaction, respectively, to obtain the resulting compound. Wherein R represents the same meaning as described above, wherein each of the compounds is subjected to a dehydration reaction. (Wherein R represents the same meaning as described above).