JPH0977761A - Optically active n-sulfinylimine and production of beta-lactam derivative using the compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject derivative expressed by a specific formula, free from substituent on the 3-site of the β-lactam ring and useful for the arbitrary control of the steric structure of the 4-site in high production yield and selectivity. SOLUTION: The objective compound is expressed by formula I (A is phenyl or tolyl; (r) is an alkyl), e.g. 2-methyl-2-(N-p-toluenesulfinyl)iminomethyl-1,3- dioxolan. Preferably, the derivative of formula I is reacted with a metal ester enolate of formula II (Met is lithium, triisopropoxytitanium, diethylaluminum or potassium; R' is an alkyl) to obtain a β-lactam derivative of formula III. The derivative of formula I is produced, e.g. by acetalizing an alkyl ester such as ethyl pyruvate in an alcohol solvent such as ethanol, reducing the ester part, subjecting to acetal exchange with ethylene glycol, converting to an aldehyde and iminating the product.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an N-sulfinyl imine derivative and a method for stereoselectively producing a β-lactam derivative using the same.

[0002]

2. Description of the Related Art Since β-lactam antibiotics have strong antibacterial activity, many methods for producing them have been studied. However, a simple and highly stereoselective reaction is desired because of its usefulness.

Among them, the β-lactam ring which is unsubstituted at the 3-position is widely applied to the synthesis of β-lactam antibiotics by introducing various substituents at the 3-position including induction to clavulanic acid. be able to.

The present inventor selected the metal species of the enolate in the addition reaction of the ester enolate to the optically active imine having an asymmetric source derived from tartaric acid as shown below, thereby selecting the 4-position of the β-lactam ring. It has been reported that the stereochemistry can be controlled arbitrarily (Chem. Let.
t. , 1992, 1349).

[0005]

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[0006]

SUMMARY OF THE INVENTION It is an object of the present invention to obtain a production method in which the 3-position of the β-lactam ring is unsubstituted and the stereochemistry at the 4-position can be arbitrarily controlled.

[0007]

The present invention has the general formula [I]

Embedded image (A represents a phenyl or tolyl group and r represents an alkyl group)
N-sulfinyl imine derivative represented by the formula

[Chemical 6] (Met represents lithium, triisopropoxytitanium, diethylaluminum, potassium, and R ′ represents an alkyl group), and a metal ester enolate represented by the formula is reacted and cyclized. It is a method for producing the represented β-lactam derivative.

[Chemical 7] The β-lactam derivative represented by the general formula [III] is 4S.
In the present invention, this stereochemistry can be arbitrarily controlled. The alkyl group represented by R'and r represents a lower alkyl group such as methyl, ethyl, propyl and butyl, and r is preferably a methyl group and R'is preferably a t-butyl group.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The N-sulfinyl imine derivative of the present invention can be synthesized by the following formula. That is, after alkylating an alkyl ester such as ethyl pyruvate in an alcohol solvent such as ethanol, the ester portion is reduced, and acetal exchange is performed using ethylene glycol. The optically active N-sulfinyl imine can be synthesized by oxidizing the alcohol part to convert it to an aldehyde and then iminoizing it with (-)-(S) -menthyl sulfinate.

[0009]

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The addition reaction of the metal ester enolate to the optically active N-sulfinyl imine is carried out in an atmosphere of an inert gas such as nitrogen or argon. In a polar solvent such as THF or ether, the acetic acid alkyl ester is converted to a metal enolate at −100 to 0 ° C., preferably −78 ° C., and the imine is added dropwise to the β-amino ester of the R form and the S form. . The alkyl of acetic acid alkyl ester is t
The er-butyl group is preferred and its lithium enolate is prepared by adding acetic acid t-butyl ester to lithium diisopropylamide. Other metal enolates such as triisopropoxy titanium, diethylaluminum, potassium can be prepared by transmetallation from lithium enolate.

[0011]

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In this reaction, the metal species of the metal enolate,
By selecting the reaction solvent, the stereochemistry of the obtained β-amino ester can be controlled, and the production ratio of the R isomer and the S isomer can be changed. This ratio can also be changed by adding hexamethylphosphoric triamide to the solvent.

The β-amino ester is treated with trifluoroacetic acid or the like to remove the asymmetric source and hydrolyze the ester portion to obtain the corresponding amino acid. Cyclization of this amino acid with triphenylphosphine-dipyridyl disulfide (Ohno method) can lead to β-lactam. Through this asymmetric removal and cyclization, the stereochemistry of the initial β-aminoester is retained and the S-form β-aminoester can be induced to the 4-position S-form β-lactam.

[0014]

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[0015]

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
The compound was identified by NMR, IR and HPLC.

Example 1 (Synthesis of 2-methyl-2- (Np-toluenesulfinyl) iminomethyl-1,3-dioxolane)

[0017]

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Synthesis of Ethyl Pyruvate Diethyl Acetal In a 300 ml wide-necked eggplant type flask, ethyl pyruvate 20 was added.
g (172 mmol), triethyl orthoformate 56 g
(376 mmol) and 84 ml of ethyl alcohol were added, the mixture was cooled to 0 ° C., 15 drops of concentrated sulfuric acid was added, and the temperature was raised to room temperature for reaction. After stirring for 3 hours, the mixture was cooled in an ice bath and potassium carbonate was added for neutralization. Salts were removed by filtration through Celite and washed with diethyl ether. After concentration with a rotary evaporator, filtration through Celite again and concentration were performed to obtain a crude product. Acetal was obtained by distillation under reduced pressure. Yield 32.7 g (172 mmol) Yield 100% ¹ H-NMR (60 MHz, CCl ₄ ) δ 1.05-1.53 (m, 12H) 3.5 (q, 4H, J = 7.0 Hz) 4. 16 (q, 4H, J = 7.0 Hz) IR (neat) cm ⁻¹ 2980, 1740, 1280, 1130, 1040 Boiling point 70-83 ° C. (15 mmHg)

Synthesis of 2,2-diethoxy-1-propanol 4.53 g of lithium aluminum hydride was placed in a 300 ml three-necked eggplant-shaped flask which was heated, dried under reduced pressure and purged with argon.
(120 mmol) was added. After installing a dropping funnel with a 100 ml side tube, cool with an ice bath and add tetrahydrofuran (TH
F) 60 ml was added slowly. 55 ml of THF solution of 15 g (79 mmol) of ethyl pyruvate diethyl acetal was slowly added dropwise using a dropping funnel with a side tube,
The reaction was carried out overnight while slowly raising the temperature to room temperature.
After cooling in an ice bath, saturated sodium sulfate aqueous solution 34.7 ml
The reaction was stopped with. The mixture was filtered through Celite, washed with ethyl acetate, and concentrated with a rotary evaporator to obtain a crude product. A colorless oily product was obtained by distillation under reduced pressure. Yield 11.4 g (77 mmol) Yield 95% ¹ H-NMR (60 MHz, CCl ₄ ) δ 1.05-1.53 (m, 10H) 3.3-3.7 (m, 6H) IR (neat) cm ^-1 3460, 2950, 1240, 1160, 1060,
960,840 Boiling point 75-82 ° C (30mmHg)

2-hydroxymethyl-2-methyl-
Synthesis of 1,3-dioxolane 22 g (148 mmol) of 2,2-diethoxy-1-propanol and ethylene glycol 12.
5 g (201 mmol), benzene 300 ml, and a catalytic amount of p-toluenesulfonic acid were added, and the mixture was heated and refluxed for a whole day and night to react. After cooling with an ice bath, neutralize with sodium carbonate,
It was filtered through Celite and washed with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and then concentrated by a rotary evaporator to obtain a crude product. A colorless oily product was obtained by distillation under reduced pressure. Yield 12.9 g (109 mmol) Yield 74% ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.40 (s, 3H) 2.39 (br, 1H) 3.57 (d, 2H, J = 5. 6 Hz) 4.05 (s, 4H) IR (neat) cm ^-1 3400, 2880, 1720, 1380, 1050,
850 Boiling point 80-96 ° C (30 mmHg)

Synthesis of 2-formyl-2-methyl-1,3-dioxolane A 500 ml three-necked flask dried under reduced pressure was replaced with argon, and 150 ml of methylene chloride was added. 19 ml (220 mmol) of oxalyl chloride was slowly added using a syringe, and after cooling to −78 ° C., 20 ml (280 mmol) of dimethyl sulfoxide was slowly added dropwise using a syringe. 1 while gradually raising the temperature to -40 ° C
Stir for hours. 2-hydroxymethyl 2-methyl-1,
A solution of 11 g (110 mmol) of 3-dioxolane in 100 ml of methylene chloride was slowly added dropwise with a syringe. After stirring for 1 hour, 106 ml (760 mmol) of triethylamine was added, and the temperature was gradually raised to room temperature. It was cooled using an ice bath and water was added until the triethylamine hydrochloride was completely dissolved. It was extracted with chloroform, dried over sodium sulfate, and then concentrated by a rotary evaporator to obtain a crude product. A colorless oily product was obtained by distillation under reduced pressure. Yield 5.4 g (46.5 mmol) Yield 49% ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.43 (s, 3H) 3.95-4.15 (m, 4H) 9.35 (s, 1H) IR (neat) cm ^-1 3300, 2900, 1740, 1380, 1050 Boiling point 62-68 ° C (42 mmHg)

Synthesis of 2-Methyl-2- (Np-toluenesulfinyl) iminomethyl-1,3-dioxolane In a 100 ml two-necked eggplant type flask under an argon atmosphere, T was placed.
3 ml of HF was added and the mixture was cooled to 0 ° C. Hexamethyldisilazane 7.2 ml (34 mmol) was added, and 1.61N n-butyllithium hexane solution 21.1 ml (34
(mmol) was slowly added dropwise to prepare lithium hexamethyldisilazide. Raise to room temperature, 3
After stirring for 0 minutes, the mixture was cooled to -78 ° C. (-)-(S)-
Menthyl-p-toluenesulfinate 5.0 g (17
A solution of 20 mmol of THF) in 20 ml of THF was slowly added.
After gradually warming to room temperature, the mixture was stirred for 2 hours. It was cooled using an ice bath, diluted with ethyl acetate, and 20 ml of distilled water was added. It was rapidly extracted with ethyl acetate, dried over sodium sulfate, and then concentrated by a rotary evaporator. After completely removing the solvent with a vacuum pump, 12 ml of THF was added and the mixture was cooled to 0 ° C. 2-formyl-2-methyl-1,3-
Dioxolane 3.9 g (34 mmol) in THF 12 m
1 solution was added, and cesium fluoride 5.2 g (34 mmo
l) was added. The reaction was carried out for 5 hours while gradually raising the temperature to room temperature. The reaction was stopped with a phosphate buffer solution and extracted with ethyl acetate. After drying over sodium sulfate, the product was concentrated by a rotary evaporator to obtain a crude product. The product was isolated and purified by silica gel column chromatography treated with a phosphate buffer solution to obtain a yellow oily product. Yield 2.0 g (7.9 mmol) Yield 47% ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.55 (s, 3H) 2.40 (s, 3H) 3.92-4.07 (m, 4H) 7.29 (d, 2H, J = 7.92 Hz) 7.55 (d, 2H, J = 8.25 Hz) 8.02 (s, 1H) IR (neat) cm ^-1 2900, 1630, 1180 , 1100, 1040,
860,810 [α] _D ²³ +286.3 (c0.50, CHCl ₃ ).

Example 2 (addition reaction of 2-methyl-2- (Np-toluenesulfinyl) iminomethyl-1,3-dioxolane with lithium enolate of t-butyl acetate)

[0024]

[Chemical 12]

A THF solution 1 of 242.8 mg (2.4 mmol) of diisopropylamine was placed in a 30 ml two-necked eggplant type flask heated and dried under reduced pressure at -78 ° C. under an argon atmosphere.
Lithium diisopropylamide was prepared by adding 5 ml and 1.47 ml (2.4 mmol) of a 1.63N n-butyllithium hexane solution. T-Butyl acetate 275.
15 ml of a THF solution containing 3 mg (2.37 mmol) was slowly added, and the mixture was stirred for 30 minutes to obtain a lithium enolate. Hexamethylphosphoric triamide 430m
g (2.4 mmol) was added and stirred for 30 minutes. -78 ° C
After cooling to 2-methyl-2- (N-p-toluenesulfinyl) iminomethyl-1,3-dioxolane 200 mg
A solution of (0.79 mmol) in THF (15 ml) was slowly added dropwise, and the reaction was allowed to proceed for 6 hours while raising the temperature to 0 ° C. The reaction was stopped with a phosphate buffer solution and extracted with ethyl acetate. After drying over sodium sulfate, the product was concentrated by a rotary evaporator to obtain a crude product. Isolation and purification was carried out by silica gel thin layer chromatography treated with a phosphate buffer solution to obtain a colorless oily product as a mixture of diastereomers. The diastereomeric ratio was determined by high performance liquid chromatography analysis using a Hibar column. Yield 197 g (0.53 mmol) Yield 68% 3R: 3S = 2: 98 (96% de) 3S body ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.26 (s, 3H) 1.46 (s, 9H) 2.40 (s, 3H) 2.53 (dd, 1H, J = 7.0, 15.0 Hz) 2.65 (dd, 1H, J = 5.5, 15.5 Hz) 3.81- 3.99 (m, 5H) 4.63 (d, 1H, J = 9.5Hz) 7.28 (d, 2H, J = 9.5Hz) 7.61 (d, 2H, J = 8.5Hz) IR (neat) cm ⁻¹ 3900, 2975, 1730, 1360, 1140,
1080 retention time 22.8 minutes 3R body ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.41 (s, 3H) 1.43 (s, 9H) 2.40 (s, 3H) 2.53 (d, 2H, J = 6.3 Hz) 3.90-3.98 (m, 5H) 4.64 (d, 1H, J = 8.9 Hz) 7.29 (d, 2H, J = 7.9 Hz) 7. 62 (d, 2H, J = 8.3Hz) IR (neat) cm ^-1 Same as 3S body, retention time 15.9 minutes

Examples 3 and 4 The same experiment as in Example 2 was conducted using THF alone and diethyl ether alone as the solvent. The results are shown in Table 1.

Example 5 Diisopropylamine 48.8 was placed in a 30 ml two-necked eggplant type flask heated and dried under reduced pressure at -78 ° C under an argon atmosphere.
3 mg of THF solution of mg (0.48 mmol), 1.6
1N n-butyllithium hexane solution 0.3 ml
(0.48 mmol) was added to prepare lithium diisopropylamide. T-Butyl acetate 55.1 mg (0.
47 mmol) in THF (3 ml) was added slowly,
Lithium enolate was obtained by stirring for 30 minutes.
Titanium enolate was prepared by adding 0.47 ml (0.47 mmol) of 1.0 N titanium triisopropoxide hexane solution and stirring for 30 minutes to perform metal exchange. It was cooled to -78 ° C, and 2-methyl-2- (N-
3 ml of a THF solution of 40 mg (0.18 mmol) of p-toluenesulfinyl) iminomethyl-1,3-dioxolane was slowly added dropwise, and the reaction was allowed to proceed for 6 hours while raising the temperature to 0 ° C. The reaction was stopped with a phosphate buffer solution, filtered through Celite, and then extracted with ethyl acetate. After drying over sodium sulfate, the product was concentrated by a rotary evaporator to obtain a crude product. Isolation and purification was carried out by silica gel thin layer chromatography treated with a phosphate buffer solution to obtain a colorless oily product as a mixture of diastereomers. The diastereomeric ratio was determined by high performance liquid chromatography analysis using a Hibar column. Yield 51.4 g (0.14 mmol) Yield 89% 3R: 3S = 96: 4 (92% de)

Examples 6 and 7 The same experiment as in Example 5 was carried out by adding diethylaluminum enolate and potassium enolate instead of titanium enolate. The results are shown in Table 1.

[0029]

[Table 1]

Example 8 (cyclization reaction)

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De-asymmetric source and hydrolysis of 3- (2-methyl-1,3-dioxolanyl) -3- (p-toluenesulfinylamino) -tert-butyl 3- (p-toluenesulfinylamino) propionate 3- ( 2-Methyl-1,3-dioxolanyl) -3- (p-toluenesulfinylamino)
197 mg (0.53 mmo) of a diastereomeric mixture of t-butyl propionate (3R: 3S = 2: 98).
1) was placed in a 30 ml eggplant-shaped flask, cooled in an ice bath, 5.5 ml of trifluoroacetic acid was added, and the mixture was stirred for 15 minutes. A crude product was obtained by concentrating with a rotary evaporator and drying under reduced pressure with a vacuum pump. Purification using an ion exchange resin (Dowex H) gave white crystals. Yield 65 mg (0.37 mmol) Yield 70% ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.24 (s, 3H) 1.31 (s, 9H) 2.48-2.78 (m, 2H) 3.67-3.69 (m, 1H) 3.88-4.00 (m, 4H)

3-amino-3- (2-methyl-1,3)
Cyclization of -dioxolanyl) propionic acid to β-lactam In a 30 ml two-necked eggplant type flask, 3-amino-3- (2-
Methyl-1,3-dioxolanyl) propionic acid 9.0
mg (0.051 mmol) was added and the atmosphere was replaced with argon. Acetonitrile (1.25 ml) was added, and triphenylphosphine (16.0 mg, 0.061 mmol) and dipyridyl disulfide (13.4 mg, 0.061 mmol) were added.
Was added and the mixture was kept at 55-60 ° C. and reacted for 11 hours. After cooling to room temperature, saturated aqueous sodium chloride solution was added and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the product was concentrated by a rotary evaporator to obtain a crude product. The product was obtained by isolation and purification by silica gel thin layer chromatography treated with a phosphate buffer solution. Yield 4.6 mg (0.029 mmol) Yield 58
% ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.32 (s, 3H) 2.82-3.01 (m, 2H) 3.71-3.73 (m, 1H) 3.92-4. 06 (m, 4H) IR (solution cell) cm ^-1 3400, 1760, 1350, 950 [α] _D ²³ -35.7 (c0.28, CHCl ₃ )

[0033]

INDUSTRIAL APPLICABILITY In the addition reaction of the optically active N-sulfinyl imine and the ester enolate of the present invention, by appropriately selecting the metal species of the enolate, the solvent and the additive, a good yield and high selectivity can be achieved. Both diastereomers of β-aminoester can be optionally synthesized. Further, this β-amino ester can be induced to β-lactam by removing an asymmetric source and cyclizing.

Claims (2)

[Claims] 1. A compound of the general formula [I] (A represents a phenyl or tolyl group and r represents an alkyl group)
An N-sulfinyl imine derivative represented by: 2. N represented by the general formula [I] according to claim 1.
-Sulfinyl imine derivatives and the general formula [II] (Met represents lithium, triisopropoxytitanium, diethylaluminum, potassium, and R ′ represents an alkyl group), and a metal ester enolate represented by the formula is reacted and cyclized. A method for producing the represented β-lactam derivative. Embedded image