JP4561197B2 - Process for producing 5- (4-tetrahydropyranyl) hydantoin and its intermediate - Google Patents

Description

  The present invention relates to a process for producing 5- (4-tetrahydropyranyl) hydantoin and intermediates thereof. 5- (4-Tetrahydropyranyl) hydantoin is a useful compound that can be derived from 4-tetrahydropyranylglycine, which is a raw material and synthetic intermediate for pharmaceuticals and agricultural chemicals.

  Conventionally, as a method for producing 5- (4-tetrahydropyranyl) hydantoin, for example, 4-formyltetrahydropyran is added to an aqueous sodium bisulfite solution, and then ethanol, ammonium carbonate and potassium cyanide are added and reacted. A method is disclosed (for example, see Patent Document 1). However, in this method, since the reaction system is complicated, the reaction operation becomes complicated, and a large amount of highly toxic potassium cyanide must be used. For example, the industrial use of 5- (4-tetrahydropyranyl) hydantoin It was not satisfactory as a manufacturing method.

Japanese National Patent Publication No. 11-500120

  The object of the present invention is to solve the above-mentioned problems, and industrially produce 5- (4-tetrahydropyranyl) hydantoin in a high yield by a simple and safe method (without using a cyanide compound). It is to provide a process for producing a suitable 5- (4-tetrahydropyranyl) hydantoin.

  In view of the above problems, as a result of intensive studies by the present inventors, high yield of 5- (4-tetrahydropyranyl) hydantoin was obtained by a simple and safe method (without using a cyanide compound) by the following method. I found a method that can be manufactured. Furthermore, 5- (4-tetrahydropyranylidene) hydantoin, which is useful as an intermediate for producing the compound, was also found and the present invention was completed.

  That is, the subject of this invention is (A) General formula (1) in presence of a base.

(In the formula, R represents an alkyl group.)
Is reacted with tetrahydropyran-4-one in a solvent to give a compound of formula (2):

A first step of 5- (4-tetrahydropyranylidene) hydantoin (hereinafter referred to as compound (2)) represented by:
(B) The compound (2) is then reduced to give the formula (3)

Solved by a process for producing compound (3), characterized in that it comprises two steps of the second step of 5- (4-tetrahydropyranyl) hydantoin (hereinafter referred to as compound (3)) Is done.

  The subject of the present invention is also the formula (2)

It can also be solved by the compound (2) represented by

  Industrially suitable 5- (4-tetrahydropyranyl) which can produce 5- (4-tetrahydropyranyl) hydantoin in a high yield by a simple and safe method (without using a cyanide compound) according to the present invention. A method for producing hydantoin can be provided.

(A) First Step The first step of the present invention is a step of obtaining compound (2) by reacting compound (1) with tetrahydropyran-4-one in a solvent in the presence of a base.

  The compound (1) used in the first step of the present invention is represented by the general formula (1). In the general formula (1), R is an alkyl group, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. These groups include various isomers.

  Examples of the base used in the first step of the present invention include alkali metal alkoxides such as sodium methoxide and potassium methoxide; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium hydride Alkali metal hydrides such as potassium hydride; alkaline earth metal hydrides such as calcium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate. Preferably, an alkali metal hydroxide is used, more preferably lithium hydroxide, sodium hydroxide, or potassium hydroxide is used. These bases may be anhydrides or hydrates, and may be used alone or in combination of two or more.

  The amount of the base to be used is preferably 1.0 to 10 mol, more preferably 1.0 to 5.0 mol, per 1 mol of tetrahydropyran-4-one.

  The amount of compound (1) used in the first step of the present invention is preferably 1.0 to 10 mol, more preferably 1.0 to 5.0 mol, per 1 mol of tetrahydropyran-4-one.

  The solvent used in the first step of the present invention is not particularly limited as long as it does not inhibit the reaction. For example, water; alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, ethylene glycol, and triethylene glycol Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ureas such as N, N′-dimethylimidazolidinone; sulfoxides such as dimethyl sulfoxide; acetonitrile, propio Nitriles such as nitrile and benzonitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; and aromatic hydrocarbons such as benzene, toluene and xylene, preferably water, alcohols, more preferably Water, methanol, eta Lumpur is used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  The amount of the solvent used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution, but is preferably 1 to 100 g, more preferably 1.1 to 50 g, relative to 1 g of tetrahydropyran-4-one.

  The first step of the present invention is performed, for example, by a method of mixing the compound (1), tetrahydropyran-4-one, a base and a solvent and reacting them with stirring. The reaction temperature at that time is preferably −10 to 100 ° C., more preferably 0 to 50 ° C., and the reaction pressure is not particularly limited.

  In addition, although the compound (2) is obtained by the first step of the present invention, it can be obtained by a general method such as neutralization, extraction, filtration, concentration, recrystallization, crystallization, column chromatography after the reaction is completed. Isolated and purified.

(B) 2nd process The 2nd process of this invention is a process of reducing a compound (2) and obtaining a compound (3).

  The second step of the present invention is not particularly limited as long as it is a method capable of reducing a double bond, but it is preferable to perform it in a hydrogen atmosphere in the presence of a metal catalyst.

  The metal catalyst preferably contains at least one metal atom selected from the group consisting of palladium, platinum, rhodium and nickel. Specifically, for example, palladium / carbon, palladium / barium sulfate, palladium hydroxide / Examples thereof include platinum, platinum / carbon, platinum sulfide / carbon, palladium-platinum / carbon, platinum oxide, rhodium / carbon, and Raney nickel. In addition, you may use these metal catalysts individually or in mixture of 2 or more types.

  The amount of the metal catalyst used is preferably 0.0005 to 0.5 mol, more preferably 0.001 to 0.1 mol, based on 1 mol of the compound (2), in terms of metal atoms.

  The amount of hydrogen used in the second step of the present invention is preferably 1 to 20 mol, more preferably 1.1 to 5 mol, per 1 mol of compound (2).

  The second step of the present invention is desirably performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, t-butyl alcohol, ethylene glycol, triethylene glycol; Ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone; Ureas such as N, N'-dimethylimidazolidinone; Acetonitrile Nitriles such as propionitrile and benzonitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; and aromatic hydrocarbons such as benzene, toluene and xylene, preferably water, alcohols, More preferred Water, methanol, ethanol and n-propyl alcohol are used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  The amount of the solvent used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution, but is preferably 1.0 to 100 g, more preferably 1.1 to 50 g, relative to 1 g of compound (2).

  The second step of the present invention is performed, for example, by a method of mixing the compound (2), a metal catalyst and a solvent and reacting them in a hydrogen gas atmosphere while stirring. The reaction temperature at that time is preferably 0 to 200 ° C., more preferably 5 to 180 ° C., and the reaction pressure is preferably 0.1 to 10 MPa, more preferably 0.1 to 3 MPa.

  In addition, compound (3) is obtained by the second step of the present invention, and this is carried out by a general method such as neutralization, extraction, filtration, concentration, recrystallization, crystallization, column chromatography after the completion of the reaction. Isolated and purified.

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

Reference Example 1 (Compound 1; Synthesis of 5-diethylphosphonohydantoin)
While adding hydantoin 200 g (2.0 mol) and acetic acid 800 ml to a glass reactor having an internal volume of 2000 ml equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel, the liquid temperature was maintained at 83 to 85 ° C. Then, 352 g (2.2 mol) of bromine was slowly added dropwise and reacted at the same temperature for 30 minutes. Next, 339 g (2.0 mol) of triethyl phosphite was slowly added dropwise while maintaining the liquid temperature at 40 to 45 ° C., and reacted at the same temperature for 2 hours while stirring. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and then the concentrate was added to 800 ml of diethyl ether and stirred at 5 ° C. for 1 hour. The precipitated solid was filtered to obtain 191.1 g of 5-diethylphosphonohydantoin as white crystals (isolation yield: 40%).
The physical properties of 5-diethylphosphonohydantoin were as follows.

¹ H-NMR (DMSO-d ₆ , δ); 1.25 (6H, t, J = 7.1 Hz), 4.06 to 4.13 (4H, m), 4.76 (1H, dd, J = 14.4,1.2 Hz), 8.41 ( 1H, brs), 10.91 (1H, brs)
CI-MS (m / e); 237 (M + 1)

Example 1 (Compound (2); Synthesis of 5- (4-tetrahydropyranylidene) hydantoin)
After adding 92 g (0.39 mol) of 5-diethylphosphonohydantoin synthesized in Reference Example 1, 460 ml of ethanol and 138 ml of water to a glass reactor having an internal volume of 1000 ml equipped with a thermometer, a stirrer and a dropping funnel, 16.3 g (0.39 mol) of lithium hydroxide monohydrate was added. Next, 30 g (0.3 mol) of tetrahydropyran-4-one was slowly added dropwise and reacted at the same temperature for 3 hours while stirring. After completion of the reaction, the reaction solution was concentrated, 195 ml (0.39 mol) of 2 mol / l hydrochloric acid was added to the concentrate, and the mixture was stirred at 5 ° C. for 1 hour. The precipitated solid was filtered, and the solid was washed with 120 ml of water to obtain 46.3 g of 5- (4-tetrahydropyranylidene) hydantoin as white crystals (isolated yield: 85%).
5- (4-Tetrahydropyranylidene) hydantoin is a novel compound represented by the following physical property values.

¹ H-NMR (DMSO-d ₆ , δ); 2.32 (2H, t, J = 5.7 Hz), 2.91 (2H, t, J = 5.7 Hz), 3.59 to 3.66 (4H, m), 9.87 (1H, brs), 10.92 (1H, brs)
CI-MS (m / e); 183 (M + 1)
¹³ C-NMR (DMSO-d ₆ , δ); 27.5, 29.7, 67.0, 67.7, 123.2, 125.6, 153.8, 164.8

Example 2 (Compound (3); Synthesis of 5- (4-tetrahydropyranyl) hydantoin)
25 g (0.14 mol) of 5- (4-tetrahydropyranylidene) hydantoin synthesized in Example 1 and 5 mass% palladium / carbon in a stainless steel pressure-resistant container having an internal volume of 300 ml equipped with a thermometer, a stirrer and a reflux condenser. (50% water-containing product) 2.5 g (0.59 mmol as palladium atom) and 150 ml of ethanol were added, and the mixture was reacted at 115 to 125 ° C. for 4 hours with stirring in a hydrogen atmosphere (0.6 to 0.8 MPa). After completion of the reaction, 100 ml of N, N-dimethylformamide was added and stirred at 50 ° C. The reaction solution was filtered and then concentrated under reduced pressure. After adding 250 ml of water to the concentrate, the mixture was stirred at 5 ° C. for 1 hour. The precipitated crystals were filtered to obtain 19.3 g of 5- (4-tetrahydropyranyl) hydantoin as white crystals (isolation yield: 77%).
The physical properties of 5- (4-tetrahydropyranyl) hydantoin were as follows.

¹ H-NMR (DMSO-d ₆ , δ); 1.24 to 1.58 (4H, m), 1.87 to 1.94 (1H, m), 3.21 to 3.32 (2H, m), 3.82 to 3.94 (3H, m), 7.98 (1H, brs), 10.63 (1H, brs)
CI-MS (m / e); 185 (M + 1)
¹³ C-NMR (DMSO-d ₆ , δ); 26.0, 28.4, 36.5, 61.5, 66.4, 66.7, 157.6, 174.9

  The present invention relates to a process for producing 5- (4-tetrahydropyranyl) hydantoin and intermediates thereof. 5- (4-Tetrahydropyranyl) hydantoin is a useful compound that can be derived from 4-tetrahydropyranylglycine, which is a raw material and synthetic intermediate for pharmaceuticals and agricultural chemicals.

Claims (1)

In the presence of a base, general formula (1):

(Wherein R is as defined in claim 1).
Wherein the compound (1) represented by the formula (2) is reacted with tetrahydropyran-4-one in a solvent:

The manufacturing method of 5- (4-tetrahydro pyranilidene) hydantoin (compound (2)) shown by these.