JP2001226370A - Method for producing 4-aminotetrahydropyrane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing 4-aminotetrahydropyran that can produce the objective compound through a simple process under mild conditions in high yield, thus is very suitable as an industrial process. SOLUTION: The objective 4-aminotetrahydropyran derivatives can be produced via an industrially suitable and simple process that can produce the objective 4-aminotetrahydropyran in high yield under mild conditions from the tetrahydropyranyl-4-sulfonate that is readily available by easy synthesis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 4-aminotetrahydropyran derivative from tetrahydropyranyl-4-sulfonate. A 4-aminotetrahydropyran derivative is a compound useful as a synthetic intermediate or a raw material of a medicine, an agricultural chemical, or the like.

[0002]

2. Description of the Related Art Conventionally, as a method for producing a 4-aminotetrahydropyran derivative, for example, a method in which ammonia gas and hydrogen gas are brought into contact with tetrahydropyranyl-4-one in the presence of Raney nickel (Helv. Chim. Acta) ., 47,2
145 (1964)), a method of reacting tetrahydropyranyl-4-one with an amine in the presence of sodium cyanoborohydride (J. Med. Chem., 37 , 565 (1994)), tetrahydropyranyl-4 A method is known in which -one is heated in a mixed solution of water, N, N-dimethylformamide and formic acid (JP-A-11-263764). However, tetrahydropyranyl-4-one is a compound that is relatively difficult to synthesize, and is also a compound that is extremely unstable with respect to a base. Also, the yield of the desired 4-aminotetrahydropyran derivative was low in all cases. On the other hand, J. Org.Chem., 36 , 522
(1971) discloses a method in which 4-chlorotetrahydropyran and ammonium are reacted at 200 ° C. in an autoclave, but has a problem that the reaction conditions are severe and the yield is extremely low.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide an industrially suitable 4-aminotetrahydropyran capable of producing a 4-aminotetrahydropyran derivative in a simple manner under mild conditions by a simple method. The present invention provides a method for producing a derivative.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide tetrahydropyranyl-4-sulfonate and a compound represented by the general formula (1):

[0005]

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(Wherein, R ¹ and R ² each represent a group that does not participate in the reaction. R ¹ and R ² may be combined with each other to form a ring). General formula (2)

[0007]

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(Wherein R ¹ and R ² have the same meanings as described above).

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The starting material tetrahydropyranyl-4-sulfonate used in the reaction of the present invention is obtained, for example, by reacting 3-buten-1-ol with a formaldehyde derivative (for example, formalin) and an organic sulfonic acid. Thus, the compound can be easily synthesized.

The above-mentioned tetrahydropyranyl-4-sulfonate includes tetrahydropyranyl-4-alkylsulfonate such as tetrahydropyranyl-4-methanesulfonate; tetrahydropyranyl-4-benzenesulfonate;
Tetrahydropyranyl-4-arylsulfonates such as tetrahydropyranyl-4-p-toluenesulfonate and tetrahydropyranyl-4-p-bromobenzenesulfonate are exemplified.

The amine used in the reaction of the present invention is
It is represented by the general formula (1). In the general formula (1), R ¹ and R ² are groups that do not participate in the reaction, and may be the same or different, specifically, a hydrogen atom; an alkyl which may have a substituent. A cycloalkyl group, an aralkyl group or an aryl group. Further, R ¹ and R ² may combine to form a ring.

The alkyl group is preferably a compound having 1 to 1 carbon atoms.
10 alkyl groups are preferred, for example, methyl, ethyl, propyl (and its isomers), butyl (and its isomers), pentyl (and its isomers), hexyl (and its isomers) , A heptyl group (and its isomers), an octyl group (and its isomers), a nonyl group (and its isomers), and a decyl group (and its isomers).

The cycloalkyl group is particularly preferably a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

The aralkyl group preferably has 7 carbon atoms.
The aralkyl group of 10 to 10 is preferable, and examples thereof include a benzyl group, a phenethyl group (and its isomer), a phenylpropyl group (and its isomer), and a phenylbutyl group (and its isomer).

The aryl group is preferably a group having 6 to 6 carbon atoms.
Preferred are 14 aryl groups, for example, phenyl, p-
Examples include a tolyl group, a naphthyl group and an anthranyl group.

The above-mentioned alkyl group, cycloalkyl group, aralkyl group or aryl group may have a substituent. Examples of the substituent include at least one selected from a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, and a halogen atom.

Examples of the substituent formed through the carbon atom include an alkyl group such as a methyl group, an ethyl group and a propyl group; an aralkyl group such as a benzyl group; an aryl group such as a phenyl group; and a cyano group.

Examples of the substituent formed through the oxygen atom include a methoxy group, an ethoxy group, a propoxy group,
An alkoxy group such as a butoxy group and a benzyloxy group; an aryloxy group such as a phenoxy group; and an acyloxy group such as an acetyloxy group and a benzoyloxy group.

Examples of the substituent formed through the nitrogen atom include a nitro group and an amino group.

As the halogen atom, a fluorine atom,
Examples include a chlorine atom, a bromine atom and an iodine atom.

The amine used in the reaction of the present invention may be an amine itself, but in the case of an amine having a low boiling point at normal pressure, it is preferably used as an aqueous solution or alcohol solution which is easy to handle. Its concentration is preferably from 1 to 90% by weight, more preferably from 3 to 60% by weight.

The amount of the amine used is preferably from 1 to 60, based on the starting material tetrahydropyranyl-4-sulfonate.
The molar amount is 2 times, more preferably 3 to 40 times.

The reaction of the present invention is carried out in the presence or absence of a solvent. Examples of the solvent used include water; amides such as N, N-dimethylformamide; N, N ′
Ureas such as -dimethylimidazolidinone; methanol,
Alcohols such as ethanol, isopropyl alcohol and t-butyl alcohol; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; methylene chloride;
Halogenated hydrocarbons such as chloroform, dichloroethane and the like can be mentioned, but water and alcohols are more preferable, and water, methanol and ethanol are more preferable.

The amount of the solvent used is preferably 0 to 50 times by weight, more preferably 0 to 20 times by weight, based on the starting material tetrahydropyranyl-4-sulfonate. These solvents may be used alone or in combination of two or more.

The reaction of the present invention is carried out using tetrahydropyranyl-4
-It is preferable to contact the sulfonate and the amine in a liquid phase, for example, by mixing tetrahydropyranyl-4-sulfonate and the amine in an inert gas atmosphere and heating and stirring the mixture under normal pressure or pressure. Done in
The reaction temperature at that time is preferably 40 to 180 ° C, more preferably 50 to 130 ° C.

If necessary, the reactivity may be adjusted by adding an inorganic base or an organic base to the system.

The final product, a 4-aminotetrahydropyran derivative, is separated and purified by a general method such as distillation, recrystallization, and column chromatography after the completion of the reaction.

[0028]

EXAMPLES Next, the present invention will be described specifically with reference to examples, but the scope of the present invention is not limited to these examples.

Reference Example 1 Synthesis of tetrahydropyranyl-4-p-toluenesulfonate In a 200 ml-capacity glass flask equipped with a stirrer, a thermometer and a dropping funnel, 20.0 g (0.28 mol of 3-buten-1-ol) was placed.
l), 10.8 g of 92% by weight paraformaldehyde (manufactured by Mitsui Toatsu Chemicals Co., Ltd.) and 100 ml of toluene were added, and 84.4 g of p-toluenesulfonic acid monohydrate (0.44 mol
l) was slowly added dropwise and reacted at 55 ° C. for 3 hours. After completion of the reaction, 50 ml of a saturated saline solution was added to the obtained reaction solution, and the mixture was extracted three times with 100 ml of ethyl acetate. Next, the organic layer was separated, washed twice with 50 ml of a saturated aqueous solution of potassium carbonate, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 49.4 g of tetrahydropyranyl-4-p-toluenesulfonate having a purity of 93% (area percentage by gas chromatography) as a colorless solid (yield 64%). Physical properties of tetrahydropyranyl-4-p-toluenesulfonate are as follows: CI-MS (m / e); 257 (M + 1) ¹ H-NMR (CDCl ₃ ); 1.7 to 1.9 ppm (4H, m), 2.45 ppm (3H, s),
3.47ppm (2H, m), 3.87ppm (2H, m), 4.69ppm (1H, m), 7.34p
pm (2H, d, J = 8.2Hz) and 7.80ppm (2H, d, J = 8.2Hz).

Example 1 0.57 g (2.1 mm) of 93% pure tetrahydropyranyl-4-p-toluenesulfonate synthesized in Reference Example 1 was placed in a 10 ml stainless steel autoclave equipped with a stirrer and a thermometer.
ol) and 5.6 g (62 mmol) of a 50% by weight aqueous dimethylamine solution (manufactured by Katayama Chemical Co., Ltd.), and reacted at 70 ° C. for 4 hours. After completion of the reaction, the obtained reaction solution was analyzed by high performance liquid chromatography (internal standard method). As a result, 0.18 g (yield 66%) of 4-dimethylaminotetrahydropyran was produced.

Reference Example 2 Synthesis of tetrahydropyranyl-4-methanesulfonate In a 300-ml glass flask equipped with a stirrer, a thermometer, and a dropping funnel, 30.0-buten-1-ol (40.0 g, 0.55 mol
l), 21.6 g (0.66 mol) of 92% by weight paraformaldehyde (manufactured by Mitsui Toatsu Chemicals) and 200 ml of toluene were added, and 85.3 g (0.89 mol) of methanesulfonic acid was stirred under a nitrogen atmosphere.
Was slowly added dropwise and reacted at 55 ° C. for 2 hours. After completion of the reaction, 100 ml of saturated saline was added to the obtained reaction solution, and the mixture was extracted three times with 200 ml of ethyl acetate. Next, the organic layer was separated, washed twice with 50 ml of a saturated aqueous solution of potassium carbonate, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give tetrahydropyranyl-4-86 as a pale yellow solid having a purity of 86% (area percentage by high performance liquid chromatography).
84.3 g of methanesulfonate was obtained (yield 73%). Physical properties of tetrahydropyranyl-4-methanesulfonate are as follows: CI-MS (m / e); 181 (M + 1) ¹ H-NMR (CDCl ₃ ); 1.88 ppm (2H, m), 2.04 ppm (2H, m), 3.04p
pm (3H, s), 3.55ppm (2H, m), 3.95ppm (2H, m), 4.90ppm (1
H, m).

Example 2 The same apparatus as in Example 1 was used, and the purity synthesized in Reference Example 2 was 86%.
1.05 g of tetrahydropyranyl-4-methanesulfonate
(5.0 mmol) and 9.0 g (100 mmol) of a 50% by weight aqueous solution of dimethylamine (manufactured by Katayama Chemical Co., Ltd.) were added and reacted at 90 ° C. for 5 hours. After the completion of the reaction, the obtained reaction solution was analyzed by gas chromatography (internal standard method). As a result, 0.38 g (yield: 59%) of 4-dimethylaminotetrahydropyran was produced.

Example 3 50.0 g (0.24 m 2) of 86% pure tetrahydropyranyl-4-methanesulfonate synthesized in Reference Example 2 was placed in a 500 ml stainless steel autoclave equipped with a stirrer and a thermometer.
ol) and 400.0 g (4.44 mol) of a 50% by weight aqueous solution of dimethylamine (manufactured by Katayama Chemical Co., Ltd.), and reacted at 70 ° C. for 5 hours.
After completion of the reaction, the obtained reaction solution was transferred to a 1000 ml glass flask equipped with a reflux condenser and a cooling trap (cooled to -20 ° C with dry ice / ethanol), and the temperature of the reaction solution was raised to 50 to 110. Unreacted dimethylamine was collected in a cooling trap while stirring at ℃ (the recovered amount of dimethylamine was 130 g). After that, the reaction solution was cooled to room temperature, acidified (pH = 1) by adding 25 ml of concentrated hydrochloric acid, and then washed three times with 100 ml of chloroform. Next, add 8 mol / l to the aqueous layer.
Add 30 ml of aqueous sodium hydroxide to make it basic (pH = 11)
After that, extraction was performed three times with 100 ml of methylene chloride, and the obtained organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and then distilled under reduced pressure (83-85 ° C., 50 mmHg) to obtain 14.6 g of 4-dimethylaminotetrahydropyran having a purity of 99% (area percentage by gas chromatography) as a colorless liquid ( Yield 47%). Physical properties of 4-dimethylaminotetrahydropyran are as follows: CI-MS (m / e); 130 (M + 1) ¹ H-NMR (CDCl ₃ , δ (ppm)); 1.53 (2H, dt, J = 4.8, 11.7Hz),
1.75 (2H, dt, J = 2.1,11.7Hz), 2.25 ~ 2.31 (7H, m), 3.36 (2
H, dt, J = 2.1,11.7Hz) and 4.01 (2H, dt, J = 4.5,11.7Hz).

Comparative Example 1 Tetrahydropyranyl-4 was added to the same reactor as in Example 3.
50.0 g (0.5 mol) of a 50% by weight dimethylamine aqueous solution 18
0.0 g (2.0 mol) and 20 g of 5 wt% Pd / C (9 mmol as palladium atom) were added, and the mixture was reacted at 50 ° C. for 7 hours and further at 70 ° C. for 4 hours under a hydrogen pressure of 0.2 to 0.4 MPa. After completion of the reaction, the obtained reaction solution was cooled to room temperature, and the catalyst was filtered through Celite.
After acidification (pH = 1) by adding 60 ml of concentrated sulfuric acid, 2-butanol
The plate was washed twice with 200 ml and twice with 200 ml of chloroform. Next, 130 g of potassium hydroxide was added to the aqueous layer to make it basic (pH = 11), and then extracted three times with 300 ml of ethyl acetate, and the obtained organic layer was dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure, and then distilled under reduced pressure (83-85 ° C., 50 m
mHg) gave 12.4 g of 4-dimethylaminotetrahydropyran with a purity of 99% (area percentage by gas chromatography) as a colorless liquid (19% yield).

Example 4 In a device similar to that of Example 1, 86% of the purity synthesized in Reference Example 2 was used.
1.05 g of tetrahydropyranyl-4-methanesulfonate
(5.0 mmol) and piperidine 1.28 g (15.0 mmol) were added, and 100
The reaction was performed at ℃ for 4 hours. After the reaction is completed, add 8
The mixture was basified (pH = 11) by adding 1.0 ml of a mol / l aqueous solution of sodium hydroxide and 2.0 ml of water, extracted twice with 30 ml of chloroform, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 0.74 g of 4-piperidinotetrahydropyran having a purity of 82% (area percentage by gas chromatography) as a yellow liquid (yield: 72%). Physical properties of the 4-piperidinophenyl tetrahydropyran, CI-MS (m / e ); 169 (M + 1) 1 H-NMR (CDCl 3, δ (ppm)); 1.42~1.77 (10H, m), 2.37-2.
46 (1H, m), 2.51 (4H, t, J = 5.7Hz), 3.36 (2H, dt, J = 2.4,12.
0 Hz) and 4.01 (2H, dd, J = 4.5,11.1 Hz).

Example 5 50.0 g (0.24 m 2) of 86% pure tetrahydropyranyl-4-methanesulfonate synthesized in Reference Example 2 was placed in a 500 ml stainless steel autoclave equipped with a stirrer and a thermometer.
ol) and a 40% by weight aqueous solution of methylamine (Katayama Chemical Co., Ltd.) 4
00.0 g (5.15 mol) was added and reacted at 70 ° C. for 3 hours. After completion of the reaction, the obtained reaction solution was transferred to a 1000 ml glass flask equipped with a reflux condenser and a cooling trap (cooled to -20 ° C with dry ice / methanol), and the reaction solution was heated to 50 to 110 Unreacted methylamine was collected in a cooling trap while stirring at a temperature of 57 ° C (the amount of methylamine recovered was 57%).
g. ). Thereafter, the reaction solution was cooled to room temperature, and acidified (pH = 1) by adding 25 ml of concentrated hydrochloric acid.
Washed three times with 0 ml. Next, the aqueous layer was basified by adding 40 ml of an 8 mol / l aqueous sodium hydroxide solution (pH = 9), and extracted three times with 100 ml of chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate. After filtration, concentrate under reduced pressure,
Then, 11.0 g of 4-methylaminotetrahydropyran having a purity of 90% (area percentage by gas chromatography) was obtained as a colorless liquid by vacuum distillation (78 to 85 ° C, 50 mmHg) (36% yield). Physical properties of 4-methylaminotetrahydropyran are as follows: CI-MS (m / e); 115 (M + 1) ¹ H-NMR (CDCl ₃ , δ (ppm)); 0.8 to 1.2 (1H, brs), 1.37 (2H, d
t, J = 4.8,11.7Hz), 1.81 to 1.87 (2H, m), 2.44 (3H, s), 2.5
1-2.61 (1H, m), 3.40 (2H, dt, J = 2.4,11.7Hz), 3.98 (2H, d
t, J = 3.6,11.7Hz).

Example 6 The same apparatus as in Example 1 was used, and the purity synthesized in Reference Example 2 was 86%.
0.21 g of tetrahydropyranyl-4-methanesulfonate
(1.0 mmol) and 5.0 mol of 2 mol / l methylamine ethanol solution
(10 mmol) and reacted at 100 ° C. for 5 hours. After the reaction was completed, the obtained reaction solution was analyzed by gas chromatography (internal standard method). As a result, 0.047 g (yield 41%) of 4-methylaminotetrahydropyran was found to have been produced.

Example 7 The same apparatus as in Example 1 was used, and the purity synthesized in Reference Example 2 was 86%.
0.21 g of tetrahydropyranyl-4-methanesulfonate
(1.0 mmol) and 5.0 ml of 2 mol / l ammonia ethanol solution (1
0 mmol) and reacted at 130 ° C. for 10 hours. After completion of the reaction, the obtained reaction solution was analyzed by gas chromatography (internal standard method), and as a result, 0.083 g (yield: 83%) of 4-aminotetrahydropyran was generated. Then, it was concentrated under reduced pressure to obtain 0.020 g of 4-aminotetrahydropyran having a purity of 99% (area percentage by gas chromatography) as a pale yellow liquid. The physical properties of 4-aminotetrahydropyran were CI-MS (m / e); 102 (M + 1) ¹ H-NMR (CDCl ₃ , δ (ppm)); 1.31 to 1.45 (4H, m), 1.74 to 1.8
0 (2H, m), 2.80 ~ 2.90 (1H, m), 3.39 (2H, dt, J = 2.4,12.6H
z), 3.95 (2H, dt, J = 3.3, 11.4 Hz).

Example 8 In a device similar to that of Example 1, 93% of the purity synthesized in Reference Example 1 was used.
Of tetrahydropyranyl-4-p-toluenesulfonate 1.3
8 g (5.0 mmol) and 3.18 g (26.0 mmol) of benzylmethylamine
Was added and reacted at 70 ° C. for 4 hours and further at 90 ° C. for 5 hours. After the completion of the reaction, the obtained reaction solution is concentrated under reduced pressure, and silica gel column chromatography (filler: Wakogel C-20)
0 (manufactured by Wako Pure Chemical Industries), developing solvent: chloroform / methanol
(= 9/1 (volume ratio))) and purified to 90 as a pale yellow liquid.
% (Area percentage by high performance liquid chromatography)
0.72 g of 4-benzylmethylaminotetrahydropyran was obtained (70% yield). Physical properties of 4-benzylmethylaminotetrahydropyran are as follows: CI-MS (m / e); 206 (M + 1) ¹ H-NMR (CDCl ₃ , δ (ppm)); 1.61 to 1.84 (4H, m), 2.20 (3H,
s), 2.56-2.69 (1H, m), 3.32-3.41 (2H, m), 3.58 (2H,
s), 4.02 to 4.68 (2H, m), 7.22 to 7.36 (5H, m).

Example 9 The same apparatus as in Example 1 was used, and the purity synthesized in Reference Example 2 was 86%.
1.05 g of tetrahydropyranyl-4-methanesulfonate
(5.0 mmol) and 1.61 g (15.0 mmol) of N-methylaniline were added and reacted at 100 ° C. for 4 hours. After completion of the reaction, the resulting reaction solution was added with an 8 mol / l aqueous solution of sodium hydroxide 1.0 ml and water 2.0 ml.
After the mixture was basified by adding thereto, the mixture was extracted twice with 30 ml of chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene / ethyl acetate (= 3/1 (volume ratio))). Thus, 0.16 g of 4-N-methylanilinotetrahydropyran having a purity of 99% (area percentage by high performance liquid chromatography) was obtained as a red liquid (yield: 17%). Physical properties of 4-N-methylanilinotetrahydropyran are as follows: CI-MS (m / e); 192 (M + 1) ¹ H-NMR (CDCl ₃ , δ (ppm)); 1.66 to 1.92 (4H, m ), 2.79 (3H,
s), 3.47 (2H, dt, J = 2.1, 11.7 Hz), 3.77 to 3.86 (1H, m), 4.
06 (2H, dd, J = 4.8,11.7Hz), 6.73 (1H, t, J = 7.2Hz), 6.82 (2
H, d, J = 8.1 Hz) and 7.21 to 7.23 (2H, m).

[0041]

Industrial Applicability According to the present invention, 4-aminotetrahydropyran derivatives can be produced from tetrahydropyranyl-4-sulfonate, which is easy to synthesize, by a simple method under mild conditions in a high yield. A method for producing a 4-aminotetrahydropyran derivative can be provided.

Continued on the front page (72) Inventor Minoru Nishimura 9-3-1 Uenonakacho, Ube-shi, Yamaguchi F-term (reference) 4C062 AA15

Claims (1)

[Claims] (1) Tetrahydropyranyl-4-sulfonate and a compound of the general formula (1) (In the formula, R ¹ and R ² represent groups that do not participate in the reaction. Further, R ¹ and R ² may combine to form a ring.)
Wherein the compound is reacted with an amine represented by the general formula (2): (Wherein, R ¹ and R ² have the same meanings as described above).