JPH0416460B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing optically active β-arylthioketones, and more particularly to a method for producing optically active β-arylthioketones using a novel base catalyst of (2S,4S)-2-(anilinomethyl)-1-ethyl-4-hydroxypyrrolidine. This invention relates to a method for producing ruthioketone. It is generally known that physiologically active substances such as pharmaceuticals and agricultural chemicals exhibit different physiological effects depending on their enantiomers. Obtaining such compounds with high optical purity has become an important issue from an industrial standpoint as well as for researching their physiological effects. Some β-arylthioketone derivatives are known to have properties such as soil bactericidal activity.
All of these are synthesized as a so-called racemic mixture, which is a mixture of an optically active substance and its isomer in equal amounts. In order to study the physiological effects in detail and to synthesize one of the enantiomers with effective physiological effects, it is necessary to develop a method for synthesizing optically active forms of β-arylthioketones. In particular, for these β-arylthioketones, it is difficult to apply the optical resolution method that has often been used to obtain optically active forms, and highly selective asymmetric synthesis is the only method for obtaining optically active forms. Development is desired. Conventionally, as a method for synthesizing racemic β-arylthioketones, a method is known in which a thiol is added with an α,β unsaturated ketone in the presence of a catalytic amount of an amine. (e.g. U.S. Patent No. 3658909
However, if an optically active amino compound is used as the amine, optically active β-arylthioketones are expected to be synthesized. As such attempts, asymmetric synthesis methods using natural optically active bases such as quinine and cinchonidine have been reported, but the asymmetric yields thereof are not necessarily high. The present invention provides a method for producing an optically active β-arylthioketone by an asymmetric Michael addition reaction of a thiol to a cyclic α,β-unsaturated ketone, which enables high asymmetric induction. As a result of research on optically active catalysts that enable high asymmetric induction, the present inventor discovered that the natural amino acid L
-4-Hydroxyproline is used as a starting material and is an optically active diamino alcohol derivative without racemization (2S,
4S)-2-(anilinomethyl)-1-ethyl-4-
We succeeded in synthesizing hydroxyproline (hereinafter abbreviated as diamino alcohol catalyst). Furthermore, when using this compound as a base catalyst,
The Michael addition reaction of thiols to optically active cyclic α, β-unsaturated ketones proceeds with high asymmetric yield.
We have discovered that optically active β-arylthioketones can be synthesized. The reaction formula is as follows. The present invention was completed based on this knowledge. According to the method of the present invention, an optically active β-arylthioketone can be produced by a simple operation of mixing and stirring a thiol and an unsaturated ketone in the presence of the diamino alcohol catalyst. The reaction temperature can be -40℃ to room temperature, but especially -5
A good asymmetric yield can be obtained if the reaction is carried out at around 10°C. The diamino alcohol catalyst, which serves as an asymmetric source, can be used in an amount of 1 to 100 mol % based on the thiol, but the product can be obtained with a sufficiently good synthesis yield when used in an amount of about 2 mol %. It is preferable to use a solvent during the reaction. As a solvent, any of hydrocarbon solvents such as hexane, aromatic hydrocarbon solvents such as toluene, and ether solvents such as ether and tetrahydrofuran can be used. In this case, β-arylthioketone can be produced with the best asymmetric yield. The method for synthesizing the diamino alcohol catalyst used in the method of the present invention using the natural amino acid L-4-hydroxyproline as a starting material is as follows. 1 L-hydroxyproline () to (2S,
4R)-N-benzyloxycarbonyl-4-hydroxyproline (Z-hydroxyproline)
Synthesis of () L-hydroxyproline (131g, 1.00mol)
Add 30-35% of benzyloxycarbonyl chloride to 1600 ml of an aqueous solution at room temperature with vigorous stirring.
320g toluene solution and 200g sodium bicarbonate
and stir for 4 hours. Additionally, a 30-35% toluene solution of benzyloxycarbonyl chloride
Add 320g and 100g of sodium hydrogen carbonate and stir for 3 hours. After extracting and removing unreacted substances with ether, the pH is adjusted to 2 to 3 with 6N hydrochloric acid under ice cooling. The product is extracted with ethyl acetate, the organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound () as an oil. If left for several weeks, it will crystallize.
The reaction formula is as follows. However, Z:

[Formula] (same below) Yield: 80% NMR: (δ, CDCl ₃ ) 2.0-2.3 (m, 2H), 3.5 (S, 2H), 4.2-4.6
(m, 2H), 5.0 (S, 2H), 7.1 (S, 5H) IR; (neat, cm ^-1 ) 3400, 1580, 1500, 770, 700 [α] ²³ _D : −77.8° (C0.97 , CHCl ₃ ) Melting point: 102-104°C 2 (S)-N-benzyloxycarbonyl-4
-Oxoproline (Z-oxoproline) ()
Synthesis of Z-hydroxyproline () (8.1g, 29m
ml), dropwise added 31 ml of 8N chromic acid solution over 5 minutes to 450 ml of special grade acetone solution under ice-cooling and vigorous stirring. After stirring for 30 minutes, add 6 ml of methanol.
was slowly added dropwise to the reaction solution, the trivalent chromium compound was removed using Celite, and the solution was diluted with ethyl acetate. This is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound () above as crystals. When this crystal is further purified by silica gel column chromatography (methylene chloride-acetic acid (95:5)), the compound () is obtained as white crystals. The reaction formula is as follows. Yield: 90% NMR: (δ, _CDCl3 ) 2.6-3.0 (m, 2H), 3.9
(S, 2H), 4.6-5.0 (q, 1H, J=5Hz),
5.1 (S, 2H), 7.2 (S, 5H) IR: (KBr disk, cm ^-1 ) 3450, 1750, 1710, 1650, 1590, 1495, 765,
705 [α] ²⁶ _D : +5.3° (C1.01, CHCl ₃ ) Melting point: 96-98°C 3 (2S, 4S)-N-benzyloxycarbonyl-
Synthesis of 4-hydroxyproline (Z-allohydroxyproline) () Z-oxoproline () (1.11g, 4.22m
2 ml of an aqueous solution of sodium borohydride (0.642 g, 17.0 mmd) was slowly added dropwise to a 30 ml methanol solution of md) under ice cooling, and the mixture was stirred for 2 and a half hours. The reaction solution was diluted with ethyl acetate, and 6N hydrochloric acid was added under ice-cooling to adjust the pH to 2. Methanol was removed by concentration, and the product was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained oil is crystallized and recrystallized from ethyl acetate-petroleum ether (4:1) to obtain the above compound () as white crystals. The reaction formula is as follows. Yield: 80% NMR: (δ, _CDCl3 ) 2.0-2.4 (m, 2H), 3.5 (S, 3H), 4.1-4.5
(m, 1H), 5.0 (S, 2H), 7.2 (S, 5H) IR: (KBr disk, cm ^-1 ) Melting point: 108.5-109.5℃ 4 (2S, 4S)-4-acetoxy-N-benzyloxy Synthesis of carbonylproline () Under an argon atmosphere, acetic anhydride (6.50 g, 63.7 mmol) and pyridine (13 ml, 161 mmol) were added to a 50 ml suspension of the above compound (10.8 g, 40.8 mmol) in acetonitrile. becomes a solution. A catalytic amount of 4-dimethylaminopyridine was added to the mixture, and the mixture was stirred at room temperature for 6 hours. Concentrate the reaction solution, dilute with ethyl acetate, and adjust the pH to 2 by adding 2N hydrochloric acid. The aqueous layer is saturated with salt, the product is extracted with ethyl acetate, the organic layer is washed with saturated brine, and then extracted with a 4% aqueous sodium bicarbonate solution. After washing the aqueous layer with ethyl acetate, add 6N hydrochloric acid to adjust the pH to 2, extract with ethyl acetate, wash the organic layer with saturated brine, and dry over anhydrous sodium sulfate. The oil obtained by concentrating this is dissolved in benzene, further heptane is added and concentrated under reduced pressure to obtain the above compound () as crystals. The reaction formula is as follows. Yield: 59% NMR: (δ, _CDCl3 ) 1.9 (S, 3H), 2.2-2.5 (m, 2H), 3.6-3.7
(m, 2H), 4.3-4.7 (m, 1H), 5.1 (S,
3H), 10.5 (S, 1H) IR: (KBr disk, cm ^-1 ) 1740, 1700, 1680, 1580, 1500, 770, 700 [α] ²⁷ _D : −58.7° (C1.03, CHCl ₃ ) Melting point : 107-108℃ Elemental analysis: Actual value C58.76%; H5.49%; N4.47% Calculated value C58.63%; H5.57%; N4.56% 5 (2S, 4S)-4-acetoxy Synthesis of -N-benzyloxycarbonylproline anilide () Under an argon atmosphere, a THF 40ml solution of the above compound (9.10g, 29.6mmol) and N-methylmorpholine (3.00g, 29.6mmol) was added to -40
The mixture was cooled to -50°C, and pivaloyl chloride (3.31 g, 29.6 mml) was slowly added dropwise thereto while stirring, then the temperature was gradually raised and the mixture was stirred at -15°C for 1 hour. After cooling to -40°C to -50°C again and slowly adding aniline (2.77 g, 29.7 mmol) dropwise,
Gradually raise the temperature and stir at room temperature for 4 hours. Concentrate the reaction solution, add ethyl acetate and concentrate again.
The THF was removed and the residue was dissolved in ethyl acetate.
This is washed successively with saturated brine, ice-cooled 1N hydrochloric acid, saturated brine, 4% aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether (3:2)) to obtain the above compound () as white crystals. The reaction formula is as follows. Yield: 75% NMR: (δ, _CDCl3 ) 1.9 (S, 3H), 2.0-2.7 (m, 2H), 3.4-3.7
(m, 2H), 4.3~4.6 (dd, 1H, J ₁ = 3Hz, J ₂
=9Hz), 5.1 (S, 3H), 6.9~7.5 (m, 5H),
7.2 (br, S, 5H) IR: (KBr disk, cm ^-1 ) 3350, 1720, 1680, 1590, 1490, 750, 690 [α] ²⁷ _D : −65.4° (C1.01, CHCl ₃ ) Melting point: 87.0-93.5℃ Elemental analysis: Actual value C66.16%; H5.80%; N7.30% Calculated value C65.96%; H5.80%; N7.33% 6 (2S, 4S)-4-acetoxyproline Synthesis of anilide () Compound () (8.23 g, 21.7 mmol)
10% Pd-C (836 mg) in 60 ml of methanol solution of
and stirred under hydrogen atmosphere (1 atm) overnight. The catalyst is separated using Celite, and the liquid is concentrated under reduced pressure to obtain the above compound (). The reaction formula is as follows. Yield: 100% NMR: (δ, CDCl ₃ ) 1.8 (S, 3H), 2.3 (dd, J ₁ = 6 Hz, J ₂ = 3 Hz,
2H), 2.6-2.7 (broad, 1H), 3.0-3.4 (m,
2H), 3.9 (t, J=6Hz, 1H), 5.1~5.3
(m, 1H), 6.9-7.7 (m, 5H), 9.5-9.8
(broad, 1H) IR: (KBr disk, cm ^-1 ) 3350, 1720, 1660, 750, 690 Melting point: 64-72℃ Elemental analysis: Actual value C62.91%; H6.65%; N11.19% Calculation Value C62.89%; H6.50%; N11.28% 7 Synthesis of (2S, 4S)-4-acetoxy-1-acetylprolineanilide () Under an argon atmosphere, the above compound (2.42 g, 9.76 mmol) ) in 5 ml of methylene chloride, a solution of acetic anhydride (1.12 g, 11.0 mmol) in 9 ml of pyridine, and a catalytic amount of 4-(dimethylamino)
Add pyridine and stir at room temperature overnight. The reaction solution is diluted with 20 ml of methylene chloride, washed successively with 1N hydrochloric acid, saturated brine, 4% aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystals (2.83 g, ~100%) were purified by basic alumina thin layer chromatography (benzene-methanol (96:4)) to give the above () as white crystals. The compound is obtained. The reaction formula is as follows. Yield: 90% (2.55 g) NMR: (δ, _CDCl3 ) 1.8-3.0 (m, 2H), 1.8 (S, 0.6H), 2.0 (S,
2.4H), 2.1 (S, 0.6H), 2.2 (S, 2.4H), 3.5
~3.9 (m, 2H) 4.4 ~ 4.6 (dd, 0.2H, J ₁ = 9
Hz, J ₂ = 3Hz), 4.7-4.9 (dd, 0.8H, J ₁ = 9
Hz, J ₂ = 3Hz), 5.1-5.4 (m, 1H), 6.9-7.7
(m, 5H), 8.6~8.8 (broad, 0.2H), 9.3~
9.6 (broad, 0.8H) IR: (methylene chloride solution cell, cm ^-1 ) 1730, 1680, 1590, 1490, 1220, 1180 [α] ²⁵ _D : −115° (C1.01, CH ₂ Cl ₂ ) 8 Synthesis of (2S,4S)-2-(anilinomethyl)-1-ethyl-4-hydroxypyrrolidine () Under an argon atmosphere, the above compound () was added to a suspension of lithium aluminum hydride (490mg, 12.9mmol) in 5ml of THF. 545mg, 1.89mmol)
A 25 ml solution of THF was added dropwise under ice cooling, and the mixture was heated under reflux for 18 hours. Under ice-cooling, a saturated aqueous solution of sodium sulfate is added to stop the reaction, the resulting white precipitate is separated, and the liquid is dried over anhydrous sodium sulfate and concentrated. The residue was subjected to basic alumina thin layer chromatography (benzene-methanol (93:
When the oily substance obtained by purification by 7)) is purified by distillation, the above compound () is obtained as a colorless and transparent oily substance. The reaction formula is as follows. Yield: 80%, (333 mg) NMR: (δ, _CDCl3 ) 1.1 (t, J = 8 Hz, 3H), 1.5-1.9 (m,
1H), 2.1-2.5 (m, 3H), 2.5-3.0 (m,
2H), 3.0-3.3 (m, 4H), 4.1-4.5 (m,
2H), 6.5~7.3 (m, 5H) IR: (neat, cm ^-1 ) 3375, 1600, 1500, 750, 695 [α] ²³ _D : -58.1° (C1.03, EtOH) Boiling: 150~170 °C/2mmHg (bath temperature) Elemental analysis: Actual value C70.90% H9.37% N12.54% Calculated value C70.87% H9.15% N12.72% Production of optically active β-arylthio or β-alkylthioketone An example of the method follows. Example 1 (Asymmetric Michael addition of benzenethiol to 2-cyclohexenone) Under an argon atmosphere, benzenethiol (440 mg,
4 mmol) in 25 ml toluene and 2-cyclohexenone (440 mg, 5 mmol and (2S,4S)-2-
25 ml of a toluene solution containing (anilinomethyl)-1-ethyl-4-hydroxypyrrolidine (hereinafter referred to as diamino alcohol catalyst) (20 mg, 0.08 mmol) is mixed at -5°C and stirred for 5 days.
The reaction solution was mixed with 1N hydrochloric acid (5 ml x 3) and saturated saline (5 ml).
× 1), 1N sodium hydroxide aqueous solution (5 ml × 3),
Wash sequentially with saturated brine (5 ml x 1) and dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel thin layer chromatography (hexane-ethyl acetate) to obtain optically active 3.
-Phenylthiocyclohexanone was obtained. Yield: 685 mg (83%) NMR: (δ, _CDCl3 ) 1.2-2.8 (m, 8H), 3.1-3.7 (m, 1H), 9.0-
9.5 (m, 5H) IR: (neat, cm ^-1 ) 1710, 1580, 1480, 750, 700 [α] ²¹ ₅₇₇ : +55.6°, [α] ²¹ ₃₆₅ : +497° (C2.00
, benzene) Boiling point: 150-170°C/1 mmHg (bath temperature) The results of a reaction conducted in a similar manner to this are as follows.

【table】

【table】

【table】

[Table] The compounds obtained in each of the above examples are effective as insecticides and fungicides for agricultural products and soil. As described above, the method of the present invention has the excellent effect of easily obtaining an optically active substance with high selectivity.

Claims (1)

[Claims] 1 In the presence of (2S, 4S)-2-(anilinomethyl)-1-ethyl-4-hydroxypyrrolidine, the formula
Arylthiol having the structural formula represented by (1) R- _C6H4- ( _CH2 )n-SH (1) where R represents lower alkyl, _lower alkoxy or halogen, and n represents 0 or 1. An optically active β-arylthioketone having a structural formula represented by formula (2), which is characterized by subjecting it to an asymmetric Michael addition reaction on a cyclic α, β-unsaturated ketone consisting of a 4- to 8-membered ring. Here, R represents lower alkyl, lower alkoxy or halogen, n represents 0 or 1, and m represents an integer of 1 to 5. manufacturing method.