JP2922943B2 - Imidazolidinone derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a compound of the general formula (I) [Wherein, R ¹ is an alkyl group, an alkyl group having a substituent,
An aryl group or a sulfonyl group represented by the formula R ² SO ₂ −, R ² is an alkyl group, an alkyl group or an aryl group having a substituent, R ³ and R ⁴ are different from each other, and have a hydrogen atom, an alkyl group, and a substituent. It represents an alkyl group or an aryl group. The substituent of the alkyl group means a phenyl group which may have one or more substituents selected from an alkyl group, an alkoxy group and a halogen atom. And a salt thereof, and a compound represented by the general formula (II) Wherein, R ^1, R ³ and R ⁴ is as defined above, R ⁵ is an alkyl group, an alkyl group having a substituent, an aryl group, R ⁶
Is a hydrogen atom or a formula Wherein R ⁷ represents an alkyl group and R ⁸ represents a hydrogen atom or a hydroxyl-protecting group. And a salt thereof.

The compounds of the formula (I) and salts thereof are useful as chiral auxiliary in the production of penem antibiotics or carbapenem antibiotics, and of the formula (II)
Is a compound obtained by reacting the compound of the formula (I), and is an important compound as an intermediate for producing the antibiotic.

[Prior Art] As an important intermediate for the production of the above antibiotic, a compound of the formula (III) Are known. (Positions 2 and 3 of the compound are in the S and R configurations, respectively). As a method for producing such an optically active compound in a highly stereoselective manner, a stereoselective aldol condensation method using boron enolates is known. In this method, 2-oxazolidinones (DA Evans) are used as chiral auxiliary agents. JACS (1981) 103 2129
−2131). However, these chiral auxiliaries have the disadvantage that their recovery and reuse are difficult. Further, the above formula (II)
Even when the production intermediate of I) is to be produced, the desired compound cannot be obtained by basic hydrolysis. Therefore, the above-mentioned production method has not been industrially sufficiently satisfactory.

[Problems to be Solved by the Invention] The present inventors have made intensive studies to overcome the conventional disadvantages, and as a result, completed the present invention.

[Constitution of the Invention] The present invention relates to compounds of formulas (I) and (II) and salts thereof.

Examples of the alkyl group in the formulas (I) and (II) include methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, tertiary butyl and the like. Examples of the substituent of the alkyl group include an alkyl group,
One substituent selected from an alkoxy group and a halogen atom
And a phenyl group which may have one or more groups. Examples of the aryl group include phenyl, naphthyl, and the like, which may have one or more substituents selected from an alkyl group, an alkoxy group, and a halogen. Examples of the hydroxyl-protecting group include trialkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group, aralkyl groups such as benzyl group, alkoxyalkyl groups such as methoxymethyl group, and 2-tetrahydropyranyl group. Can be.

The compound represented by the general formula (I) of the present invention can be produced by the following method.

[Wherein R ¹ , R ³ and R ⁴ are the same as above, and R ⁹ represents a hydrogen atom or a carbamate group such as methoxycarbonyl, ethoxycarbonyl, tertiarybutyloxycarbonyl, benzyloxycarbonyl group. The method for producing the compound of the formula (I) differs depending on the type of the substituent R ^{9 in} the formula (IV), and each method will be described below.

In addition, among the raw material compounds of the formula (IV), a novel compound can be produced with reference to a known method [J. Am. Chem. Soc., 82 , 1886 (1960)].

When R ⁹ is a hydrogen atom, the compound represented by the general formula (IV) is used in the presence of phosgene, carbonyldiimidazole, methyl chlorocarbonate, benzyl chlorocarbonate, or urea such as urea, methylurea, or dimethylurea; And triethylamine,
Diisopropylopyramine, 1,8-diazabicyclo [5,4,0]
The compound of formula (I) can be produced by reacting in the presence of a base such as undec-7-ene. or,
The compound is obtained by converting a compound of the formula (IV) to a carbonate such as diethyl carbonate or phenyl carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium carbonate, sodium hydroxide, sodium methylate, sodium ethylate, triethylamine, diisopropylethylamine. The reaction can also be carried out in the presence of a base such as

The reaction is usually carried out without a solvent or an alcohol solvent such as methanol or ethanol, a hydrocarbon solvent such as benzene, toluene or cyclohexane, an ether solvent such as diethyl ether, tetrahydrofuran or dioxane, chloroform, dichloromethane, carbon tetrachloride or the like. 30 minutes to 10 at a temperature of -20 ° C to 200 ° C in a halogenated hydrocarbon solvent
Done for hours.

When R ⁹ is a carbamate group, a compound represented by the general formula (IV) is converted into a hydrocarbon solvent such as benzene, toluene, and cyclohexane; an ether solvent such as diethyl ether, tetrahydrofuran, and dioxane; dimethylformamide, dimethyl sulfoxide;
-80 ° C in the presence of a base such as sodium hydride, potassium hydride, lithium hydride, n-butyllithium, lithium diisopropylamide, sodium hexamethyldisilazane in an aprotic polar solvent such as hexamethylphosphoric triamide The compound of formula (I) can be produced by reacting at a temperature of about to room temperature for 30 minutes to 10 hours.

A method for producing the compound of the formula (II) from the compound of the formula (I) obtained as described above will be described below.

The preparation method of the compound of the formula (II) varies depending on various substituents R ⁶ , and each preparation method will be described below.

(Wherein R ¹ , R ³ , R ⁴ and R ⁵ are as defined above) The compound of formula (I) is converted to β-methylthiopropionyl chloride, β-ethylthiopropionyl chloride, β-phenylthiopropionyl chloride, β- R ⁵ SCH ₂ COX (X represents a halogen atom) such as benzylthiopropionyl chloride or β- (4-paramethoxybenzyl) thiopropionyl chloride and an alkali such as lithium hydride, sodium hydride, potassium hydride and the like. Metal hydride, methyl lithium,
alkyl or aryl lithium compounds such as n-butyl lithium, phenyl lithium, sodium, lithium,
The compound of formula (IIa) can be produced by reacting in an organic solvent in the presence of a base such as an alkali metal such as potassium. Examples of the solvent include diethyl ether, tetrahydrofuran, dioxane, ether solvents such as 1,2-dimethoxyethane, benzene, toluene, hexane, hydrocarbon solvents such as cyclohexane, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide. Such aprotic polar solvents and mixtures of these solvents can be mentioned. The reaction is usually performed at a temperature of -80C to room temperature for 30 minutes to 10 hours. After completion of the reaction, the desired compound of the formula (II
The compound of a) can be isolated.

(Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ⁷ are the same as described above). And the reaction in the presence of a tertiary amine to produce a compound of the formula (IIb). Examples of the boronant triflate include dibutyl boron triflate, dipropyl boron triflate, diethyl boron triflate, diisopropyl boron triflate, diisobutyl boron triflate, dicyclohexyl boron triflate, dicyclopentyl boron triflate and 9-borabicyclo [3,
3,1] nonyl triflate and the like. As the tertiary amine, triethylamine, diisopropylethylamine, diisopropylmethylamine, 1-
Ethyl piperidine, 1-methylmorpholine, 1-ethylpyrrolidine, 1,4-diazabicyclo [2,2,2] octane,
1,5-diazabicyclo [5,4,0] unde-5-cene and 1,1
5-diazabicyclo [4,3,0] no-5-ene and the like can be mentioned. Examples of the solvent that does not participate in the reaction include halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, and ethers such as tetrahydrofuran and diethyl ether. The amount of the boronant triflate to be used is generally 1.1 times the molar amount of the compound of the formula (IIa). Furthermore, the amount of the tertiary amine to be used is usually 1.3 times the mol of the compound of the formula (IIa). The compound of the formula (V) may be used in a molar excess with respect to the compound of the formula (IIa). The reaction is usually performed at -80 ° C to 0 ° C for 1 to 5 hours.

In the compounds of formula (IIb), the substituents HO and R ⁵ -SC
H ₂ is one having a configuration as described below are preferred from the stereospecificity of the antibiotics of the final desired product.

The method for producing the compound of formula (IIb) having these two configurations will be described below.

(Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ⁷ are the same as described above) That is, the compound of the formula (V) is a compound of the formula (IIa) wherein R ⁴ is a hydrogen atom (IIa ′) The compound of formula (IIb ') can be produced by reacting in the same manner as in the above.

On the other hand, to produce the compound of formula R ³ is a hydrogen atom in the formula (II a) The compound of (V) (II a ") and the the formula by reacting in the same manner (II b") it can.

(Wherein, R ⁸¹ represents a hydroxyl-protecting group, and R ¹ , R ³ , R ⁴ , R ⁵ , R ⁷
Is the same as described above. By protecting the hydroxyl group of the compound of the formula (IIb), a compound of the formula (IIc) wherein R ⁸ in the formula (II) is a protecting group for a hydroxyl group can be produced. The method for producing the compound varies depending on the kind of the protecting group, and examples thereof include the following.

(1) In the case of a tri-lower alkylsilyl group The compound of the formula (IIb) is reacted with a tri-lower alkylsilyl chloride in a solvent not involved in the reaction in the presence of a base such as imidazole, 4-dimethylaminopyridine and triethylamine for several hours at room temperature. By reacting for several days, the formula (II
In c), a compound wherein R ⁸¹ is a tri-lower alkylsilyl group can be produced. Examples of the solvent include dimethylformamide, tetrahydrofuran, dichloromethane and the like. The tri-lower alkylsilyl chloride is usually used in an equimolar amount to 3 times, preferably 1.5 times, the molar amount of the compound of the formula (IIb). The base is usually of the formula (II
It is used in an amount of 2 to 5 moles relative to the compound of b).

(2) In the case of an aralkyl group By reacting the compound of the formula (IIb) with aralkyl bromide or aralkyl chloride in a solvent not involved in the reaction in the presence of a base such as sodium hydride or silver oxide at 0 ° C. to room temperature for several hours. A compound in which R ⁸¹ is an aralkyl group in the formula (IIc) can be produced. Examples of the solvent include dimethylformamide, dimethylsulfoxide, tetrahydrofuran and the like. The base and silver oxide are usually used in an amount of 1 to 2 moles compared to the compounds of the formula (IIb). The aralkyl bromide and aralkyl chloride are usually used in a molar amount of 1 to 2 times the compound of the formula (IIb).

(3) In the case of a lower alkoxyalkyl group The compound of the formula (IIb) is reacted with a lower alkoxyalkyl chloride in a solvent not involved in the reaction in the presence of a base such as sodium hydroxide or diisopropylamine at 0 ° C. to room temperature for several hours to
By reacting all day and night, a compound in which R ⁸¹ is a lower alkoxyalkyl group in the formula (IIc) can be produced. Examples of the solvent include tetrahydrofuran, dimethoxyethane, methylene chloride and the like. The lower alkoxyalkyl chloride is usually used in an amount of 1 to 2 moles compared to the compounds of the formula (IIb). The base is of the formula (IIb)
Is usually used in a molar amount of 1 to 2 times the amount of the compound.

(4) In the case of a tetrahydropyranyl group The compound of the formula (IIb) is reacted for several hours at room temperature in the presence of an acid catalyst such as tosylic acid or pyridinium tosylic acid in a solvent which does not participate in the reaction with dihydropyran.
In c), a compound wherein R ⁸¹ is a tetrahydropyranyl group can be produced. Examples of the solvent include methylene chloride and n-hexane. Dihydropyran is usually used in a molar amount of 1 to 2 times the amount of the compound of the formula (IIb).

In the above reactions (1) to (4), when the compound of the formula (IIb ′) or (IIb ″) is used as a raw material, the configuration of the hydroxyl group and the substituent represented by the formula R ⁵ SCH ₂ is generated. It can also be retained in objects.

The production of the target penem or carbapenem antibiotic from the compound produced as described above may be carried out as follows.

… Penem or carbapenem antibiotics (wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ⁸¹ are the same as above) That is, the compound of formula (IIc) is converted to lithium hydroxide, sodium hydroxide The compound of formula (VI) can be produced by hydrolysis with an alkali such as potassium hydroxide.

The β-lactam compound of the formula (VII) can be obtained by reacting the obtained compound of the formula (VI) in the same manner as in the production method disclosed in JP-A-62-70353.

The compound is disclosed in JP-A-62-70353, JP-A-56-11619.
No. 4, Tetrahedron Letters 23 , 2293-2296 (198
2), Tetrahedron Letters 21 , 2783-2786 (1980), Ch
Pharm. Bull., 29 , 2899-2909 (1981) and the like can be used as appropriate to combine them with the appropriate penem or carbapenem antibiotics.

[Effect of the Invention] The compound of the formula (I) of the present invention is excellent in releasability and handling in the reaction and excellent as an asymmetric auxiliary.
In addition, the compound of the formula (II) of the present invention is an excellent intermediate for producing a penem or carbapenem antibiotic derived from the compound of the formula (I). Antibiotics can be produced in a short number of steps and with good reactivity.

Hereinafter, the present invention will be further described with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 5.0 g of N- (benzyloxycarbonyl) -L-valine
Was dissolved in 100 ml of methylene chloride, and at 0 ° C., 3.75 g of paratoluenesulfonamide, 4.20 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.24 g of dimethylaminopyridine were added, and the mixture was stirred at room temperature for 3 hours. . The reaction solution was diluted with methylene chloride and washed with 1M hydrochloric acid, water, and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
g was obtained. This was dissolved in 100 ml of tetrahydrofuran,
At 100 ° C., 100 ml of a 1N solution of diboron-tetrahydrofuran was slowly added. The reaction solution was heated to 40 ° C and stirred for 4 hours, then cooled to 0 ° C again, and methanol was added.

The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography, and developed using a mixture of hexane and ethyl acetate (2/1, v / v). 3.58 g of a body was obtained. This is dimethylformamide 60m
Then, 1.83 g of 60% sodium hydride was added at 0 ° C., and the mixture was stirred for 2 hours. After methanol was added to the reaction solution, the solvent was distilled off under reduced pressure. After the residue was extracted with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and a mixture of hexane and ethyl acetate (3/1, v /
The mixture was developed using x) to obtain 1.54 g of an oily N-methoxycarbonyl compound from the main elution portion. 30m of tetrahydrofuran
1.6 g of potassium tert-butoxide dissolved in 1 l was added, and the mixture was stirred for 1 hour and heated under reflux for 30 minutes. The reaction solution was cooled to 0 ° C., acetic acid and water were added, and tetrahydrofuran was distilled off under reduced pressure. The residue was extracted with chloroform, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 10 ml of tetrahydrofuran and carbonyldiimidazole 79
5 mg was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with methylene chloride, and the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with isopropyl ether to obtain 570 mg of (4S) -4-isopropyl-1-paratoluenesulfonyl-2-imidazolidinone as a white solid.

Mp _{160-161 ℃ [α] D +89.2 (} C1.1, CHCl 3) IR (KBr) 3400,3200,1720,1350,1165cm -1. 1 H-NMR (CDCl 3) δ7.90 (d, J = 8.3Hz, 2H), 7.31 (d, J
= 8.3Hz, 2H), 5.89 (bs1H), 3.98 (m, 1H), 3.47 (m, 2
H), 2.43 (s, 3H), 1.60 (m, 1H), 0.88 (d, J = 6.6Hz, 3
H), 0.86 (d, J = 6.6 Hz, 3H). ¹³ C-NMR (CDCl ₃ ) δ155.7,144.6,135.9,129.6,128.2,5
5.1,48.2,32.8,21.6,17.8,17,6. Example 2 25 g of N- (benzyloxycarbonyl) -L-valine
Was dissolved in methylene chloride (300 ml), and aniline (10 ml) was added at 0 ° C.
21 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1.2 g of 4-dimethylaminopyridine
g was added and stirred for 2.5 hours. The crystals precipitated from the reaction solution are collected by filtration, washed with 1 M hydrochloric acid and water, and washed with anilide 28.
g was obtained. Dissolve 10 g of this in 120 ml of tetrahydrofuran, and at 0 ° C. boron-tetrahydrofuran 1 M solution 150 ml
Was gradually added. The reaction solution was stirred at room temperature for 18 hours, cooled to 0 ° C., and 100 ml of methanol was added dropwise over 1 hour. The reaction solution was stirred at the same temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was dissolved in 100 ml of chloroform, 100 ml of a 1N sodium hydrogen sulfate solution was added, and the mixture was stirred for 20 minutes, and then the organic layer was separated. The organic layer was washed with saturated saline and water, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and developed using a mixture of petroleum ether and ethyl acetate (10/1, v / v) to obtain 5.8 g of a reduced form. This was dissolved in 120 ml of dimethylformamide, and 2.24 g of 60% sodium hydride was added at 0 ° C., followed by stirring for 1 hour. After acetic acid and methanol were added to the reaction solution, the solvent was distilled off under reduced pressure. Dissolve the residue in chloroform,
Washed with water, saturated aqueous sodium bicarbonate and saturated saline. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, developed using a mixture of petroleum ether and ethyl acetate (2/1, v / v) to give (4S)- 2.83 g of 4-isopropyl-1-phenyl-2-imidazolidinone was obtained.

Mp 113-114 ℃ _[α] D -137 ° _{(C1.1, CHCl 3) IR (} KBr) 3230,1690,1600,1410,1310,1250cm -1. 1 HNMR (CDCl 3) δ7.61~7.02 ( m, 5H), 5.30 (bs, 1H),
3.95 (m, 1H), 3.55 (m, 2H), 1.70 (m, 1H), 0.99 (d, J =
6.6Hz, 3H), 0.95 (d , J = 6.6H 2, 3H). ¹³ C NMR (CDCl ₃ ) δ 159.7, 140.9, 128.8, 122.4, 118.0, 55.
1,49.2,33.4,18.0,17.8. Example 3 N- (benzyloxycarbonyl) -L-valine 18.3
g in 150 ml of methylene chloride and thiazolidine-
9.6 g of 2-thione, 15.4 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.9 g of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 4 hours. After the reaction solution was washed with 1N sodium hydrogen sulfate and saturated saline, the solvent was distilled off under reduced pressure to obtain 32.1 g of a yellow oily substance. Dissolve this in 150 ml of tetrahydrofuran and add 4
20 ml of a 0% aqueous methylamine solution was added. When the reaction solution became clear, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography containing about 5% (w / w) silver nitrate and developed using a mixed solution of chloroform and ethyl acetate (2/1, v / v) to obtain 18.2 g of an amide white solid
I got Of these, 5.28 g was dissolved in 100 ml of tetrahydrofuran, 100 ml of a 1M solution of boron-tetrahydrofuran was gradually added, and the mixture was stirred at room temperature for 22 hours. After adding methanol to the reaction solution and stirring for 18 hours, the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography, and developed using a mixture of hexane and ethyl acetate (2/1, v / v) to obtain 1.93 g of a reduced form. Of these, 810 mg is dissolved in dimethylformamide 20 ml, and 60% sodium hydride 400 m
g was added and stirred at 0 ° C. for 1 hour. After methanol was added to the reaction solution, the solvent was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, developed with ethyl acetate, and developed with (4S) -4-isopropyl-1-methyl-2-methyl.
280 mg of a white solid of imidazolidinone were obtained.

Mp 103-103.5 ℃ _[α] D +129 ° _{(C0.94, CHCl 3) IR (} KBr) 3250,2950,1700,1660,1490,1260cm -1 1 HNMR (CDCl 3) δ4.50 (bs, 1H) , 3.60−3.00 (m, 3H),
2.76 (s, 3H), 1.60 (m, 1H), 0.92 (d, J = 6.6Hz, 3H), 0.
88 (d, J = 6.6 Hz, 3H). Example 4 282 mg of (4S) -4-isopropyl-1-paratoluenesulfonyl-2-imidazolidinone was dissolved in 4 ml of tetrahydrofuran, and a 1.5 M hexane solution of n-butyllithium was added at -80 ° C. Further, 0.2 ml of 3- (phenylthio) -propionic chloride was added, and the mixture was stirred for 30 minutes. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, tetrahydrofuran was distilled off under reduced pressure. The aqueous solution was extracted with methylene chloride, and the organic layer was dried over sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and developed using a mixture of hexane and ethyl acetate (3/1, v / v) to develop (4S) -3- [1-oxo-3- (phenylthio). Propyl] -4-isopropyl-1-paratoluenesulfonyl-2-imidazolidinone 383 mg was obtained. ¹ H NMR (CDCl ₃ ) δ 7.91 (d, J = 8.3 Hz, 2H), 7.39-7.22
(M, 7H), 4.24 (m, 1H), 3.90-3.56 (m, 2H), 3.17 (s, 4
H), 2.45 (S, 3H), 2.30 (m, 1H), 0.91 (d, J = 7Hz, 3H),
0.74 (d, J = 7 Hz, 3H). HRMS Calcd for C ₂₂ H ₂₆ N ₂ O ₄ S ₂ : 446.1334. Found: 446.1331. Example 5 (4S) -4-Isopropyl-1-phenyl-2-imidazolidinone 500 mg was dissolved in tetrahydrofuran 10 ml, and n-butyl was dissolved. 1.70 ml of lithium 1.5M hexane solution is -80
At 0 ° C., 0.52 g of 3- (phenylthio) propionic chloride was further added, and the mixture was stirred for 30 minutes. The reaction solution is
After stirring for 5 minutes at room temperature for 15 minutes, a saturated aqueous solution of ammonium chloride was added. After distilling off tetrahydrofuran under reduced pressure, a mixture of ethyl acetate and petroleum ether (1/1, v / v)
Extracted using. The organic layer was washed with saturated saline and water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and developed using a mixture of toluene and acetone (100/1, v / v) to give oily (4S) -3- [1-oxo-3- (phenylthio) Propyl] -4-isopropyl-1-phenyl-2-imidazolidinone was obtained in an amount of 520 mg. _{^{1 HNMR (CDCl 3) δ7.76-7.16 (}} m, 10H), 4.46 (m, 1H),
3.91 (t, J = 9 Hz, 1H), 3.56 (dd, J = 3.9 Hz, 1H), 3.46-
3.14 (m, 4H), 2.16 (m, 1H), 0.96 (d, J = 7Hz, 3H), 0.86
(D, J = 7Hz, 3H). HRMS Calcd for C ₂₁ H ₂₄ N ₂ O ₂ S: 368.1559. Found: 368.1539. Example 6 Dissolve 200 mg of (4s) -4-isopropyl-1-methyl-2-imidazolidinone in 4 ml of tetrahydrofuran,
At 70 ° C., a 1.5 M hexane solution of n-butyllithium was added. Further, 3- (phenylthio) propionic chloride
0.26 ml was added and stirred for 30 minutes. The reaction solution is
After stirring for minutes, a saturated aqueous ammonium chloride solution was added, and tetrahydrofuran was distilled off under reduced pressure. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline and water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and developed using a mixed solution of hexane and ethyl acetate (2/1, v / v). 230 mg of oily (4S) -3- [1-oxo-3- (phenylthio) propyl] -4-isopropyl-1-methyl-2-imidazolidinone was obtained. _{^{1 HNMR (CDCl 3) δ7.40-7.14 (}} m, 5H), 4.30 (m, 1H), 3.
70-3.0 (m, 6H), 2.84 (s, 3H), 2.35 (m, 1H), 0.89 (d,
(J = 7Hz, 3H), 0.78 (d, J = 7Hz, 3H). HRMS Calcd for C ₁₆ H ₂₂ N ₂ O ₂ S: 306.1402. Found: 306.1411. Example 7 (4S) -3- [1-oxo-3- (phenylthio) propyl] -4-isopropyl-1-paratoluenesulfonyl Dissolve 345 mg of 2-imidazolidinone in 5 ml of methylene chloride, add dibutylboron triflate (1 M solution in methylene chloride, 0.94 ml) and 0.17 ml of triethylamine at -78 ° C under an argon atmosphere, stir for 2 hours, and then stir at 0 °
Stir for 15 minutes. Cool to -78 ° C and acetaldehyde 0.08ml
Was added and stirred for 1 hour. The mixture was further stirred at 0 ° C. for 1 hour, 1M sodium hydrogen sulfate solution was added, and the mixture was extracted with a mixture of hexane and ethyl acetate (1/1, v / v). The organic layer was washed with saturated saline and water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and a mixture of hexane and ethyl acetate (3/1, v / v)
And (4S) -3-[(2S, 3R) -1-
251 mg of oxo-2-[(phenylthio) methyl] -3-hydroxybutyl] -4-isopropyl-1-paratoluenesulfonyl-2-imidazolidinone were obtained. The purity of this compound was 99% by HPLC.

Melting point 119-120 ° C ¹ H NMR (CDCl ₃ ) δ 7.90 (d, J = 8.3H ₂ , 2H), 7.39-7.25
(M, 7H), 4.31 (m, 2H), 4.05 (m, 1H), 3.74 (m, 2H), 3.
4-3.1 (m, 2H), 2.46 (s, 3H), 2.40-2.15 (m, 2H), 1.1
5 (d, J = 6.1 Hz, 3H), 0.92 (d, J = 7 Hz, 3H), 0.76 (d, J =
7Hz, 3H). _{.. HRMS Calcd for C 24 H} 30 N 2 O 5 S 2: 490.1596 Found: 490.1608 Example 8 (4S) -3- [1-oxo-3- (phenylthio) propyl] -4-isopropyl-1-phenyl - Dissolve 138 mg of 2-imidazolidinone in 5 ml of methylene chloride and dibutylborontriflate (1M
Methylene chloride solution, 0.42 ml) and triethylamine 0.
After adding 08 ml and stirring for 1 hour, the mixture was stirred at 0 ° C. for 15 minutes.
After cooling to −78 ° C., 0.15 ml of 10 ml of a methylene chloride solution containing 1.77 g of acetaldehyde was added and stirred for 1 hour. 0 ° C
The mixture was further stirred for 1 hour, 1M sodium hydrogen sulfate was added, and the mixture was extracted with a mixed solution of hexane and ethyl acetate (1/1, v / v). The organic layer was washed with saturated saline and water, and then concentrated under reduced pressure. The residue was dissolved in 10 ml of diethyl ether, and the solution was dissolved in phosphate buffer (pH
7) 2 ml and 1 ml of 30% aqueous hydrogen peroxide were added, and the mixture was stirred at 0 ° C. for 1 hour. Water was added to the reaction solution, and the mixture was extracted with a mixture of hexane and ethyl acetate (1/1, v / v). The organic layer was washed with saturated aqueous sodium hydrogen carbonate, saturated saline, and water, and then dried over sodium sulfate.
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and developed with a mixed solution of hexane and ethyl acetate (3/1, v / v) to give oily (4S) -3-[(2S, 3R)
-1-oxo-2-[(phenylthio) methyl] -3-
[Hydroxybutyl] -4-isopropyl-1-phenyl-2-imidazolidinone 73 mg was obtained. _{^{1 HNMR (CDCl 3) δ7.65-7.15 (}} m, 10H), 4.80-4.50 (m,
2H), 4.20 (m, 1H), 3.90 (t, J = 9.3 Hz, 1H), 3.60-3.18
(M, 3H), 2.96 (bs, 1H), 2.50 (m, 1H), 1.24 (d, J = 6.5
Hz, 3H), 0.97 (d, J = 7 Hz, 3H), 0.89 (d, J = 7 Hz, 3H). _{HRMS Calcd for C 23 H 28 N} 2 O 3 S:. 412.1821 Found:. 412.1814 Example 9 (4S) -3- [1-oxo-3- (phenylthio) propyl] -4-isopropyl-1-methyl-2 -Dissolve 195 mg of imidazolidinone in 4 ml of methylene chloride and dibutylborontriflate (1 M in methylene chloride, 0.70 ml) and 0.13 ml of triethylamine at -78 ° C under an argon atmosphere.
After adding 1 ml and stirring for 1 hour, the mixture was stirred at 0 ° C. for 15 minutes.
After cooling to −78 ° C., 0.05 ml of acetaldehyde was added and stirred for 1 hour. The mixture was further stirred at 0 ° C. for 1 hour, 1M sodium hydrogen sulfate solution was added, and the mixture was extracted with hexane and ethyl acetate (1/1, v / v). The organic layer was washed with saturated saline and water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, developed with hexane and ethyl acetate (1/1, v / v) to give an oily (4S)-
93 mg of 3-[(2S, 3R) -1-oxo-2-[(phenylthio) methyl] -3-hydroxybutyl] -4-isopropyl-1-methyl-2-imidazolidinone was obtained.
The purity of the compound was 96% by HPLC. ¹ H NMR (CDCl ₃ ) δ 7.40-7.20 (m, 5H), 4.69-4.36 (m, 2
H), 4.12 (m, 1H), 3.53-3.07 (m, 4H), 2.85 (s, 3H),
2.40 (m, 1H), 1.22 (d, J = 6.6Hz, 3H), 0.91 (d, J = 7Hz,
3H), 0.83 (d, J = 7 Hz, 3H). _{.. HRMS Calcd for C 18 H} 26 N 2 O 3 S: 350.1657 Found: 350.1664 Example 10 (4S) -3 - [(2S, 3R)-1-oxo-2 - [(phenylthio) methyl] -3- Hydroxybutyl] -4-
Dissolve 100 mg of isopropyl-1-paratoluenesulfonyl-2-imidazolidinone in 2 ml of dimethylformamide and add tertiary dibutyldimethylsilyl chloride at 0 ° C.
mg and dimethylaminopyridine 41 mg were added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water and extracted with methylene chloride. The organic layer was washed with saturated saline and water, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a mixture of hexane and ethyl acetate (1/1 /
1,4 / v) and white crystals of (4S) -3-[(2S, 3R)
-1-oxo-2-[(phenylthio) methyl] -3-
(Tertiary butyldimethyl) silyloxy] butyl-4-
120 mg of isopropyl-1-paratoluenesulfonyl-2-imidazolidinone were obtained.

Melting point 99-102 ° C ¹ H NMR (CDCl ₃ ) δ 7.90 (d, J = 8.3 Hz, 2H), 7.38-7.20
(M, 7H), 4.40-3.64 (m, 5H), 3.26 (m, 2H), 2.45 (s, 3
H), 1.09 (d, J = 6.1 Hz, 3H), 0.91 (d, J = 7 Hz, 3H), 0.81
(S, 9H), 0.73 (d, J = 7 Hz, 3H) Reference Example 1 (4S) -3-[(2S, 3R) -1-oxo-2-[(phenylthio) methyl] -3- (third Grade butyldimethyl)
(Silyloxy) butyl-4-isopropyl-1-paratoluenesulfonyl-2-imidazolidinone (35 mg) was dissolved in tetrahydrofuran (2 ml), and 1N lithium hydroxide aqueous solution (0.09 m
l was added and stirred at room temperature for 1 day. 0.09 ml of 1N hydrochloric acid was added to the reaction solution, and tetrahydrofuran was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, the residue was subjected to preparative thin-layer chromatography, developed with a mixture of hexane and ethyl acetate (2/1, v / v), and developed as oily (2S, 3R) -2-[(phenylthio) methyl ] -3-[(tert-butyldimethyl) silyloxybutyric acid (compound A) 17.4 mg and (4S) -4-isopropyl-1-paratoluenesulfonyl-2-imidazolidinone 11.7 mg were obtained.

¹ H NMR (CDCl ₃ ) of Compound A; δ: 7.32 to 7.20 (m, 5H), 4.20 (m, 1H), 3.50 to 3.00 (m, 2
H), 2.85-2.60 (m, 1H), 1.20 (d, J = 6.1 Hz, 3H), 0.86
(S, 9H), 0.09 (s, 3H), 0.06 (s, 3H). In addition, it was manufactured using a chiral auxiliary such as Evans (4S)
-3- [1-oxo-3- (phenylthio) propyl]
-4-isopropyl-2-oxazolidinone in Example 7
And 10 were reacted in the same manner as in (4S) -3-[(2
(S, 3R) -1-oxo-2-[(phenylthio) methyl]
When (-3- (tert-butyldimethyl) silyloxy] butyl-4-isopropyl-2-oxazolidinone was reacted under the same conditions as above, the reaction did not proceed at all, and only the raw material was recovered.

Reference Example 2 p-Anisyl alcohol was dissolved in tetrahydrofuran, and n-butyllithium was added at -10 ° C. This reaction solution was prepared using an asymmetric auxiliary such as embass (4S)-
3-[(2S, 3R) -1-oxo-2-[(phenylthio) methyl] -3- (tert-butyldimethyl) silyloxy] butyl-4-isopropyl-2-oxazolidinone or the chiral auxiliary of the present invention (4S) -3 manufactured using
-[(2S, 3R) -1-oxo-2-[(phenylthio)
Methyl] -3- (tert-butyldimethyl) silyloxy] butyl-4-isopropyl-1-paratoluenesulfonyl-2-imidazolidinone in tetrahydrofuran was added dropwise at the same temperature. After stirring at the same temperature for 3 hours and at room temperature for 2 hours, the reaction was stopped with a saturated aqueous solution of ammonium chloride, and the solvent was distilled off under reduced pressure. After extraction with methylene chloride, drying and purification using a silica gel column, p-methoxybenzyl [(2S, 3R) -2-[(phenylthio) methyl] -3
-(Tert-butyldimethyl) silyloxy] butyrate was obtained. The yields of p-methoxybenzyl ester obtained when Evans or the chiral auxiliary of the present invention were used are shown in the following table, respectively.

As is clear from the above table, when the asymmetric auxiliary of the present invention was used, the desired p-methoxybenzyl ester was obtained in a much higher yield than when Evans was used. Therefore, it was confirmed that the chiral auxiliary of the present invention has a far superior elimination property as compared with that of Evans.

────────────────────────────────────────────────── (5) References JP-A-60-155161 (JP, A) U.S. Pat. No. 4,196,297 (US, A) Biochemical Pharmacology, 28 (8), 1313-18 (1979) Tetrahedron Letters, 30 (13), 1679-82 (1989) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 233/34 C07D 233/38

Claims (2)

(57) [Claims] (1) General formula [Wherein, R ¹ is an alkyl group, an alkyl group having a substituent,
Aryl group, or a group of the formula R ² SO ₂ - sulfonyl group represented by, R ² is an alkyl group, an alkyl group or an aryl group having a substituent, R ³ and R ⁴ are different and represent a hydrogen atom, an alkyl group, a substituent An alkyl group or an aryl group. The substituent of the alkyl group means a phenyl group which may have one or more substituents selected from an alkyl group, an alkoxy group and a halogen atom. And a salt thereof. 2. The general formula [Wherein, R ¹ is an alkyl group, an alkyl group having a substituent,
Aryl group, or a group of the formula R ² SO ₂ - sulfonyl group represented by, R ² is an alkyl group, an alkyl group or an aryl group having a substituent, R ³ and R ⁴ are different and represent a hydrogen atom, an alkyl group, a substituent R ⁵ is an alkyl group, an alkyl group having a substituent, an aryl group, R ⁶ is a hydrogen atom or a formula Wherein R ⁷ represents an alkyl group and R ⁸ represents a hydrogen atom or a hydroxyl-protecting group. And a salt thereof.