JP4899385B2 - Method for producing 3-aminomethyloxetane compound - Google Patents

Description

  The present invention relates to a novel process for producing 3-aminomethyloxetane compounds such as 3-substituted-3-aminomethyloxetane. A 3-aminomethyl oxetane compound is a compound useful as a raw material for synthesis or an intermediate for pharmaceuticals, agricultural chemicals, resins and the like.

  Examples of a method for producing a 3-aminomethyloxetane compound such as 3-substituted-3-aminomethyloxetane include 3-methyl-3-p-toluenesulfonyloxymethyloxetane and 3-methyl-obtained from phthalimide potassium salt. A method for obtaining 3-methyl-3-aminomethyloxetane in a yield of 81% (based on phthalimide form) by reacting 3-phthalimidomethyloxetane with excess hydrazine and then decomposing excess hydrazine with Raney neckel is known. (Non-Patent Documents 1 and 2). In addition, a method for obtaining 3-phenyl-3-aminomethyloxetane in the same manner from 3-phenyl-3-phthalimidomethyloxetane is also known (Non-patent Document 3).

However, these methods not only require a decomposition step in order to decompose excess hydrazine, but also require a special reaction reagent or catalyst in the phthalimidization and hydrazine decomposition steps. As a result, it was disadvantageous both in terms of process and economy. Furthermore, in the latter method, the yield (phthalimide body basis) was as low as 54%.
Chem. Commun. 43 (1998) J. et al. Org. Chem. , 65, 2253 (2000) Tetrahedron, 58, 7065 (2002)

  This invention solves the said problem, and makes it a subject to provide the industrially suitable manufacturing method of 3-aminomethyl oxetane compounds, such as 3-substituted- 3-aminomethyl oxetane. That is, the present invention provides a process- and economically advantageous 3-aminomethyloxetane compound capable of obtaining a 3-aminomethyloxetane compound in a high yield by a simple method using a general reaction reagent. It is an object to provide a manufacturing method.

  An object of the present invention is to produce a 3-aminomethyloxetane compound represented by the general formula (2) by reacting a raw material oxetane compound represented by the general formula (1) with ammonia. It is solved by the process for producing aminomethyloxetane compounds. In the formula, R represents a substituent not involved in the reaction, and X represents a leaving group.

  In the invention, the leaving group X is preferably a halogen atom or an organic sulfonyloxy group, more preferably a chlorine atom, a bromine atom, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group. R is preferably an alkyl group. Furthermore, in the said invention, it is preferable to use ammonia water as ammonia.

  According to the present invention, the above problems can be solved and an industrially suitable process for producing a 3-aminomethyloxetane compound such as 3-substituted-3-aminomethyloxetane can be provided. That is, the method for producing the 3-aminomethyloxetane compound of the present invention is advantageous in terms of process and economy, and a 3-substituted-3-aminomethyloxetane or the like can be produced by a simple method using a general reaction reagent. The 3-aminomethyloxetane compound can be obtained in high yield.

Hereinafter, the present invention will be described in detail.
In the raw material oxetane compound represented by the general formula (1), R is a substituent not involved in the reaction, for example, an alkyl group (preferably having 1 to 10 carbon atoms; a methyl group, an ethyl group, a propyl group, a butyl group, Pentyl group, hexyl group, heptyl group, etc.), aralkyl group (preferably 7-10 carbon atoms; benzyl group, phenethyl group, phenylpropyl group, etc.), aryl group (preferably 6-12 carbon atoms; phenyl group, tolyl group) , Xylyl group, naphthyl group, anthryl group, etc.), alkoxyl group (preferably having 1 to 10 carbon atoms; methoxy group, ethoxy group, etc.), amino group, nitro group, carboxyl group, cyano group and the like. Among them, an alkyl group, an aralkyl group, and an aryl group are preferable, but an alkyl group is more preferable, and a methyl group and an ethyl group are particularly preferable. These substituents include various isomers, and other substituents (alkyl group, aralkyl group, aryl group, alkoxyl group, amino group, nitro group, carboxyl group, cyano group, etc.) can be used unless they are involved in the reaction. The carbon chain may contain an unsaturated bond such as a double bond or a heteroatom such as oxygen, nitrogen, or sulfur.

  X is a leaving group, for example, halogen atom (chlorine atom, bromine atom, iodine atom, etc.), organic sulfonyloxy group (methanesulfonyloxy group, ethanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group) Group, p-toluenesulfonyloxy group, etc.). Among them, a chlorine atom, a bromine atom, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group are preferable, and a methanesulfonyloxy group is particularly preferable.

  Examples of the raw material oxetane compound represented by the general formula (1) include 3-methyl-3-methanesulfonyloxymethyloxetane, 3-ethyl-3-methanesulfonyloxymethyloxetane, and 3-methyl-3-p-toluenesulfonyl. Oxymethyloxetane, 3-ethyl-3-p-toluenesulfonyloxymethyloxetane, 3-chloromethyl-3-methyloxetane, 3-chloromethyl-3-ethyloxetane, 3-bromomethyl-3-methyloxetane, 3-bromomethyl Specific examples include -3-ethyloxetane.

  The raw material oxetane compound represented by the general formula (1) can be synthesized by a known method. For example, 3-ethyl-3-methanesulfonyloxymethyloxetane can be obtained by reacting 3-ethyl-3-hydroxymethyloxetane and methanesulfonyl chloride (see Reference Example 1 of the present application), and 3-methyl-3- p-Toluenesulfonyloxymethyloxetane can be obtained by reacting 3-methyl-3-hydroxymethyloxetane and p-toluenesulfonyl chloride (see Reference Example 2 of the present application). Also, 3-chloromethyl-3-ethyloxetane can be synthesized from 3-ethyl-3-methanesulfonyloxymethyloxetane and triethylamine hydrochloride (see Reference Example 3 of the present application).

  As ammonia, any of ammonia water, liquid ammonia, and ammonia gas can be used, and ammonia dissolved in a solvent described later may be used. Among these, ammonia water is preferable because it is general and can be used easily. At this time, the concentration of ammonia in the gas or solution is not particularly limited. However, when a reaction solvent is used, it is sufficient that a necessary amount of ammonia is dissolved within the range of the solvent use amount. In this case, 28% by mass aqueous ammonia is preferable. The amount of ammonia used is preferably in the range of 1 to 100 mol, more preferably 1.1 to 50 mol, and particularly preferably 10 to 50 mol with respect to 1 mol of the oxetane compound represented by the general formula (1). In addition, when using ammonia water as ammonia, since the water becomes a reaction solvent described later, it is not necessary to add a reaction solvent in particular, and it is only necessary to add a necessary amount of water within the range of the amount of reaction solvent used. Good.

  In the reaction of the raw material oxetane compound represented by the general formula (1) with ammonia, the reaction temperature is preferably 0 to 200 ° C., more preferably 5 to 180 ° C., particularly 50 to 120 ° C., and the reaction pressure is usually It is preferably a pressure or a pressure.

  The reaction is performed by, for example, a method of mixing the raw material oxetane compound and ammonia and reacting them with stirring. At this time, a reaction solvent can be used as necessary, and the amount used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution. It is preferably in the range of 0 to 50 g, particularly 2 to 15 g.

  The reaction solvent is not limited as long as it does not inhibit the reaction. Water, alcohols (methanol, ethanol, isopropyl alcohol, t-butyl alcohol, methoxyethanol, ethoxyethanol, butoxyethanol, etc.), nitriles (acetonitrile, propionitrile) , Benzonitrile, etc.), amides (N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), ureas (N, N′-dimethylimidazolidinone, etc.), sulfoxides (dimethyl sulfoxide) Etc.) and sulfones (sulfolane etc.). Among these, water and alcohols (particularly methanol) are preferable, but water is particularly preferable.

  According to the reaction of the present invention, a 3-aminomethyl oxetane compound such as 3-aminomethyl-3-methyl (or ethyl) oxetane is generated corresponding to the raw material oxetane compound. It is isolated and purified by a general method such as filtration, neutralization, extraction, concentration, distillation, column chromatography and the like.

  Next, the present invention will be specifically described with reference to examples.

[Reference Example 1; Synthesis of 3-ethyl-3-methanesulfonyloxymethyloxetane]
To a glass flask having an internal volume of 2000 ml equipped with a stirrer, a thermometer and a dropping funnel, 232.2 g (2.0 mol) of 3-ethyl-3-hydroxymethyloxetane, 243.0 g (2.4 mol) of triethylamine and 1000 ml of toluene Then, 252.0 g (2.2 mol) of methanesulfonyl chloride was slowly added while maintaining the liquid temperature at 5 to 10 ° C., and the reaction was allowed to proceed with stirring at the same temperature for 3 hours and at room temperature for 3 hours.

  After completion of the reaction, the reaction solution was washed (water 500 ml × twice), the aqueous layer was extracted (toluene 500 ml), and the entire organic layer (this organic layer + the previous organic layer) was washed (saturated aqueous sodium bicarbonate 500 ml and saturated sodium chloride). 500 ml of water). Next, the obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to distill off the solvent. The obtained residue was vacuum-dried to obtain 306.6 g of 3-ethyl-3-methanesulfonyloxymethyloxetane. According to gas chromatography analysis, the purity of the product was 84.0% by mass and the isolated yield was 78.9%. In addition, the thing in the said parenthesis was used for the washing | cleaning solvent and the extraction solvent.

The physical property values of the product were as follows.
(A) CI-MS (m / e): 195 (M + 1)
(B) ¹ H-NMR (CDCl ₃ , δ (ppm)): 0.94 (3H, t, J = 7.3 Hz), 1.81 (3H, q, J = 7.3 Hz), 3.07 (3H, s), 4.42 to 4.48 (4H, m)

Reference Example 2 Synthesis of 3-methyl-3-p-toluenesulfonyloxymethyl oxetane
In a glass flask having an internal volume of 500 ml equipped with a stirrer, thermometer, dropping funnel and reflux condenser, 51.0 g (0.5 mol) of 3-methyl-3-hydroxymethyloxetane, 300 ml of toluene and p-toluenesulfonyl chloride After adding 114.4 g (0.60 mol), it cooled to 0 degreeC, stirring. Next, 51.4 g (0.65 mol) of pyridine was added dropwise at the same temperature, and the reaction was performed at the same temperature for 4 hours and at 50 ° C. for 5 hours.

  After completion of the reaction, the reaction solution is concentrated, the concentrated solution is extracted (ethyl acetate 200 ml + water 200 ml), the aqueous layer is extracted (ethyl acetate 200 ml), and the entire organic layer (this organic layer + the previous organic) is washed (water 100 ml). Next, the obtained organic layer was concentrated and 200 ml of heptane was added, and then the precipitated white crystals were collected by filtration and dried to obtain 70.2 g of 3-methyl-3-p-toluenesulfonyloxymethyloxetane ( Yield 54.8%).

The physical properties of the product were as follows: (a) CI-MS (m / e): 257 (M + 1)
(B) ¹ H-NMR (CDCl ₃ , δ (ppm)): 1.30 (3H, s), 2.46 (3H, s), 4.11 (2H, s), 4.30-4. 38 (4H, m), 7.35 to 7.39 (2H, m), 7.79 to 7.82 (2H, m)

[Reference Example 3; Synthesis of 3-chloromethyl-3-ethyloxetane]
To a glass flask having an internal volume of 1000 ml equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, 38.0 g (0.5 mol) of 3-ethyl-3-hydroxymethyloxetane, 300 ml of acetonitrile and 61.0 g of triethylamine ( 0.61 mol) was added and the mixture was cooled to 0 ° C. with stirring. Next, 63 g (0.55 mol) of methanesulfonyl chloride was dropped at the same temperature and reacted for 3 hours, and then the temperature was raised to room temperature, 200 ml of methanol was added, and the mixture was stirred at 50 ° C. for 5 hours.

  After completion of the reaction, the reaction solution is concentrated, the concentrated solution is extracted (ethyl acetate 200 ml + water 100 ml), the aqueous layer is extracted (ethyl acetate 100 ml), and the entire organic layer (this organic layer + the previous organic layer) is washed ( 100 ml of water). Next, the obtained organic layer was concentrated, and 23.2 g (0.545 mol) of lithium chloride and 200 ml of methanol were added to 105.7 g of this concentrated liquid and stirred for 5 hours at room temperature, followed by reaction at 60 ° C. for 6 hours. It was.

  After completion of the reaction, the reaction solution is cooled and filtered, the filtrate is concentrated, the concentrate is extracted (ethyl acetate 200 ml + water 100 ml), the aqueous layer is extracted (ethyl acetate 100 m), the entire organic layer (this organic layer + the previous layer) The organic layer) was washed (100 ml of water). Next, after the obtained organic layer was concentrated, 44.2 g of 3-chloromethyl-3-ethyloxetane was obtained by distillation (3.5 kPa, 79 to 80 ° C.) (yield 65.4%). According to gas chromatographic analysis, the purity of this product was 99.6% in area percentage.

The physical property values of the product were as follows.
(A) CI-MS (m / e): 135 (M + 1)
(B) ¹ H-NMR (CDCl ₃ , δ (ppm)): 0.90 (3H, t, J = 7.4 Hz), 1.85 (2H, q, J = 7.4 Hz), 3.79 (2H, s), 4.42 (4H, s)

Reference Example 4 Synthesis of 3-bromomethyl-3-ethyloxetane
The reaction was performed in the same manner as in Reference Example 3 except that lithium chloride was replaced with lithium bromide monohydrate 57.1 (0.545 mol) and the distillation conditions after the reaction were changed to 2.0 kPa / 75 to 80 ° C. The product was isolated and produced to obtain 65.1 g of 3-bromomethyl-3-ethyloxetane (yield 72.0%). According to gas chromatographic analysis, the purity of this product was 99.0% as an area percentage.

The physical property values of the product were as follows.
(A) CI-MS (m / e): 180 (M + 1), 183 (M + 1)
(B) ¹ H-NMR (CDCl ₃ , δ (ppm)): 0.88 (3H, t, J = 7.6 Hz), 1.87 (2H, q, J = 7.6 Hz), 3.69 (2H, s), 4.40 (4H, m)

[Example 1; Production of 3-aminomethyl-3-ethyloxetane]
In a pressure-resistant reactor having an internal volume of 1000 ml equipped with a stirrer, a thermometer, and a pressure gauge, 89.0 g (385 mmol) of 3-ethyl-3-methanesulfonyloxymethyloxetane obtained in Reference Example 1 and 28% by mass aqueous ammonia 703g (11.55mol) was added and it was made to react at 80-90 degreeC for 6 hours, stirring.

  After completion of the reaction, the reaction solution was cooled to room temperature, 30.8 g (385 mmol) of a 50 mass% sodium hydroxide aqueous solution and 135 g of sodium chloride were added, and the mixture was stirred for 30 minutes. When the reaction solution was analyzed by gas chromatography, 41.1 g of 3-aminomethyl-3-ethyloxetane was produced (yield 93%). Next, 15 g of tetraethylenepentamine was added to the residue obtained by extracting the reaction solution (2-butanol 300 ml × 3 times) and concentrating the organic layer under reduced pressure, followed by distillation (200 to 400 kPa, 75 to 85 ° C. ) Gave 34.8 g of 3-aminomethyl-3-ethyloxetane (isolation yield 78%). According to gas chromatographic analysis, the purity of this product was 99% in area percentage.

The physical property values of the product were as follows.
(A) CI-MS (m / e): 116 (M + 1)
(B) ¹ H-NMR (CDCl ₃ , δ (ppm)): 0.89 (3H, t, J = 7.6 Hz), 1.30 (1H, brs), 1.71 (2H, q, J = 7.6 Hz), 2.93 (2H, s), 4.39 (4H, s)

[Example 2; Production of 3-aminomethyl-3-ethyloxetane]
To a pressure-resistant reactor having an internal volume of 50 ml equipped with a stirrer, a thermometer and a pressure gauge, 1.0 g (5.15 mmol) of 3-ethyl-3-methanesulfonyloxymethyloxetane and 9.4 g (155 mmol) of 28% by mass aqueous ammonia were added. ) And reacted at 60 to 70 ° C. for 6 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by gas chromatography. As a result, 540 mg of 3-aminomethyl-3-ethyloxetane was produced (yield 92%).

Example 3 Production of 3-aminomethyl-3-methyloxetane
In the same reactor as in Example 2, 5.12 g (20.0 mmol) of 3-methyl-3-p-toluenesulfonyloxymethyl oxetane obtained in Reference Example 2 and 36.5 g (600 mmol) of 28% by mass aqueous ammonia. Was added and reacted at 100-110 ° C. for 12 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by gas chromatography. As a result, 1.72 g of 3-aminomethyl-3-methyloxetane was produced (yield 85%).

The physical property values of the product were as follows.
(A) CI-MS (m / e): 102 (M + 1)
(B) ¹ H-NMR (CDCl ₃ , δ (ppm)): 1.28 (3H, s), 1.30 to 1.60 (1H, brs), 2.89 (2H, s), 4. 38 (2H, d, J = 5.9 Hz), 4.44 (2H, d, J = 5.9 Hz)

Example 4 Production of 3-aminomethyl-3-ethyloxetane
To the same reactor as in Example 2, 1.35 g (10.0 mmol) of 3-chloromethyl-3-ethyloxetane obtained in Reference Example 3 and 18.2 g (300 mmol) of 28% by mass aqueous ammonia were added and stirred. The reaction was carried out at 100 to 110 ° C. for 6 hours. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by gas chromatography. As a result, 1.0 g of 3-aminomethyl-3-ethyloxetane was produced (yield 87%).

Example 5 Production of 3-aminomethyl-3-ethyloxetane
To the same reactor as in Example 2, 1.81 g (10.0 mmol) of 3-bromomethyl-3-ethyloxetane obtained in Reference Example 4 and 18.2 g (300 mmol) of 28 mass% aqueous ammonia were added and stirred. The reaction was carried out at 100 to 110 ° C. for 6 hours. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by gas chromatography. As a result, 1.03 g of 3-aminomethyl-3-ethyloxetane was produced (yield 89%).

  According to the present invention, a 3-aminomethyloxetane compound such as 3-aminomethyl-3-methyl (or ethyl) oxetane can be produced in a high yield by an industrially suitable production method. Such a 3-aminomethyl oxetane compound is a useful compound as a raw material for synthesis or an intermediate for pharmaceuticals, agricultural chemicals, resins and the like.

Claims (5)

A process for producing a 3-aminomethyloxetane compound represented by the general formula (2) by reacting a raw material oxetane compound represented by the general formula (1) with ammonia, and using ammonia water as ammonia. A method for producing a 3-aminomethyloxetane compound, which is characterized. (In the formula, R represents a substituent not involved in the reaction, and X represents a leaving group.)

The process for producing a 3-aminomethyloxetane compound according to claim 1, wherein the leaving group X is a halogen atom or an organic sulfonyloxy group. The method for producing a 3-aminomethyloxetane compound according to claim 1, wherein the leaving group X is a chlorine atom, a bromine atom, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group. The process for producing a 3-aminomethyloxetane compound according to claim 1, wherein R is an alkyl group. The manufacturing method of the 3-aminomethyl oxetane compound as described in any one of Claims 1-4 whose reaction temperature is 50-120 degreeC.