KR0149070B1 - Method for preparing 4-acetoxyagetidinone derivatives - Google Patents

Abstract

The 4-carboxyzecidinone N-substituent of Structural Formula (I) was electrochemically reacted by applying a direct current to an electrode in the presence of an electrolyte selected from the group consisting of alkali metal salts and amine bases of acetic acid in a mixed solvent of acetic acid and an organic solvent. Then, a method of stereoselectively synthesizing 4-acetoxyazetidinone of formula (II) by one-way reaction by adding only an appropriate amount of water without separating the reaction product and then flowing a direct current under the same conditions to deprotect the aryl group Is provided.

Wherein R ¹ represents a trialkylsilyl group; R ² represents an aryl group.

According to the production method of the present invention, 4-acetoxyazetidinone is obtained in one-way reaction by electrochemical reaction, thus overcoming the problem of environmental stigma with cost reduction; The advantages of easy industrialization, simple manufacturing process and high yield are provided.

Description

Stereoselective preparation of 4-acetoxyazetidinone derivatives

The present invention provides (3S, 4S) -4-carboxy-3 [VII (1'R) -1'-trialkylsilyloxy｝ ethyl] -1-arylazetidin-2-one represented by general structural formula (I). (Hereinafter abbreviated as 4-carboxyxazetidinone N-substituent) (3R, 4R) -4-aceoxy-3- [VII () of structural formula (II), which is an important intermediate of carbapenem and penem-based lactam antibiotics 1'R) -1'-trialkylsilyloxy｝ ethyl] azetidin-2-one (hereinafter abbreviated as 4-acetoxyazetidinone) is stereoselectively subjected to electrochemical one pot oxidation. It relates to a manufacturing method.

In which R ¹ represents a trialkylsilyl group, in particular a t-butyldimethylsilyl group, as a protecting group of a hydroxy group; R ² represents an aryl group as an amino protecting group.

4-acetoxyazetidinone of the above formula (II) is a known compound and is an important intermediate of carbapenem and phenom β-lactam antibiotics, and one of the important steps in the synthesis method is β-lactam ring formation reaction. In addition to the nitrogen source of the β-lactam ring, a method of introducing a p-anisidine derivative as a protecting group is widely used.

In the method for preparing the compound of formula (II), J. Am. Chem. Soc., Georg et al., P1129, 1987, prepared 4-carboxyxazetidinone N-substituents in the presence of acetic acid in the presence of acetic acid via a chiral pool molecule as shown in the following scheme. Oxidation reaction with lead acetate (Pb (OAc) ₄ ) to replace the free acid with acetoxy and then deprotection of the aryl group with ceric ammonium nitrate (CAN) to produce the 4-acetoxyazetidinone.

However, in the above manufacturing process, the yield is good in the deprotection process using CAN, but an excessive amount (more than 3 equivalents) of CAN must be used, and since the CAN has a large molecular weight (548), a large amount of CAN can be industrialized. Not only is it uneconomical as it is needed, and a large amount of heavy metal waste is generated, which poses a problem of heavy metal treatment.

According to the above method, a large amount of heavy metal (Pb (OAc) ₄ ) is also used in the step of introducing the acetoxy group. Due to these problems, industrialization of the process is almost impossible.

Accordingly, the present inventors have focused on the production method of 4-acetoxyazetidinone using an electrochemical oxidation method using a safe and low-cost reagent to solve the problems of the conventional manufacturing method as described above.

The preparation of the azetidinone compound using the two-step electrochemical oxidation reaction is already known, and the contents thereof are briefly described as follows. That is, US Patent No. 4834846 (1987) discloses a method for deprotecting an aryl group by using anodized oxidation with a perchlorate salt of a beta-lactam ring compound protected with phenyl or a substituted phenyl group. US Pat. No. 49,522,88 (1989) describes a process for preparing 4-acyloxyazetidinone from 4-carboxyazetidinone via an electrical oxidation reaction in the presence of a C _1-8 organic acid and corresponding salts. The bar is represented by the reaction scheme as follows.

(Wherein R ¹ represents a C ₁ -C ₆ alkoxy group and R ² represents hydrogen or a C ₁ -C ₆ alkoxy group.)

(The acyl group represents an alkoxycarbonyl group of C ₁ -C ₈ organic acid.)

However, when the 4-acetoxyazetidinone of the structural formula (II) is prepared from the 4-carboxyazetidinone N-substituent of the group (I) by the above production method, the following problems occur.

First, since the electrochemical deprotection method of 4-carboxiazetidinone N-substituent is not mentioned in the above document, it was not easy to elucidate the problem, so the present inventors experienced a serious side reaction as a result of reproducibility experiments according to the preparation method. The target compound could not be obtained.

Second, according to the method for preparing 4-acetoxyazetidinone N-substituent by electrically introducing acetoxy group, separating and purifying them, and then electrically deprotecting the aryl group to prepare the compound of formula (II), Since it needs to proceed in two stages, a separate electrolyte is required, which causes a cost increase during industrialization, and has a disadvantage in that post-treatment is complicated and yield is lowered.

Third, perchlorate salt was used as an electrolyte in the deprotection process of the aryl group. Since such electrolytes have some solubility in organic solvents, there is room for improvement because there is a disadvantage to pay attention to safety in mass synthesis. .

Accordingly, the present inventors have developed a method capable of overcoming the disadvantages of the prior art as a result of research efforts to solve the problems in the conventional manufacturing method as described above.

Hereinafter, the present invention will be described in more detail as follows.

The present invention provides a suitable amount of direct current in the presence of an alkali metal salt of acetic acid or an amine base such as triethylamine, using 4-carboxyazetidinone N-substituent of formula (I) as a starting material and acetic acid and an organic solvent as a mixed solvent. After passing through an appropriate anode and cathode, without adding a reaction product, only an appropriate amount of water was added, and then a direct current was flowed under the same conditions to deprotect the aryl group, and 4-acetoxyazetidinone of formula (II) as a compound Stereoselective synthesis is represented by the reaction scheme as follows.

In the formula, R ¹ is a conventional trialkylsilyl group as a protecting group of a hydroxy group, and R ² represents an aryl group as an amino protecting group.

Examples of the trialkylsilyl group acting as a hydroxy protecting group include trimethylsilyl, diphenyl-t-butylsilyl, triethylsilyl, triphenylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, and the like, among which t-butyldimethyl Silyl groups are most stable and preferred during the reaction run.

As a specific example of the aryl group which acts as an amino protecting group, the phenyl group in which 1 or 2 positions were substituted by a linear or branched C _1-6 alkoxy group is preferable, and p-methoxyphenyl group is especially preferable.

As the alkali metal salt of acetic acid, sodium or potassium salt is suitable and the amount of use is 0.2 to 10 equivalents.

As the amine bases that can be used in the method of the present invention, secondary or tertiary amines are preferable, and 5 equivalents or more of triethylamine, 1,8-diazabicyclo [5,4,0] -7-undecene Or pyridine, diethylamine, piperidine, cyclohexylamine, etc. may be used, but most preferably triethylamine is used.

As an organic solvent used with acetic acid, an organic solvent which can dissolve all the compounds used, does not participate in the reaction or decreases the reactivity under the reaction conditions, and minimizes side reactions is preferable. Preferably, acetonitrile and propane nitrile are used. Preference is given to polar organic solvents such as, dimethylformamide and tetradrafurfuran.

The proportion and the amount of the mixed solvent may be appropriately changed depending on the amount of the starting material, the amount of the electrolyte used as the additive, and the amount of electricity.

The reaction proceeds by flowing an electric current through a suitable electrode. The cathode used is chemically inert, such as a starting material, an intermediate intermediate product, a reaction product, and can remove electrons from the starting material. Platinum, palladium, palladium or various types of carbon electrodes, ie, graphite, felt, or RVC (Reticulated Vitreous Carbon) may be used as the conductive material that does not cause side reactions due to Platinum or various types of carbon electrodes are suitable below.

Suitable anodes serve as electron sources, but they are chemically inert and do not cause side reactions due to self-ionization. They also contain a wider variety of materials than cathodes, such as stainless steel, platinum, palladium, and various types of carbon electrodes. Although it does not affect the reaction yield, the platinum or carbon electrode is preferable.

The current density is appropriately 0.5 to 30 mA / cm ³ , and the reaction temperature is appropriate to 0 ° C. to room temperature.

When the reaction was carried out while observing the progress of the reaction by thin layer chromatography, when the starting material disappeared and 4-acetoxyazetidinone N-substituent was formed, the aryl group was deprotected when electrolyzed under the same conditions by adding more than 10 equivalents of water. do.

When the electrolysis is completed, the organic solvent is concentrated under reduced pressure, partitioned into water and an organic solvent which is not mixed with water such as ethyl acetate, diethyl ether, dichloromethane, chloroform, etc., and then extracted from the organic layer using conventional methods, that is, solvent extraction, After the product was separated using recrystallization or silica gel column chromatography, the structure was confirmed by nuclear magnetic resonance (NMR) spectrum and mass spectrometry, and the photoluminescence ([a] _D ) was measured by a conventional method.

This method of the present invention is prepared by replacing the conventional chemical method using expensive and dangerous reagents with the electrochemical oxidation method using a safe and low-cost reagent compared to the conventional manufacturing methods. Overcoming the problem of environmental pollution with cost reduction; Second, to facilitate industrialization by using sodium acetate, potassium acetate or conventional organic bases as electrolytes; It is possible to industrially advantageously produce 4-acetoxyazetidinone by improving the overall yield and simplifying the manufacturing process by advancing the well-known manufacturing method, which has been separated and proceeded in two steps, in one pot. There is a characteristic.

In order that the present invention may be more easily understood, the preparation of representative compounds will be described in detail with reference to Examples, but the present invention is not limited to the following Examples.

Example 1

(3R, 4R) -4-acetoxy-3-'[(1'R) -1'-t-butyldimethylsilyloxy]

Preparation of ethyl quazetidin-2-one

570 mg (3S, 4S) -4-carboxy-3-'[(1'R) -1'-t-butyldimethylsilyloxy] ethyl'-1- (4-methoxyphenyl) azetidin-2-one 1.5 mmol) and 31 mg (0.25 equivalents) of sodium acetate are dissolved in 45 ml of a mixed solvent of acetic acid and acetonitrile (mix ratio ¼). The platinum cathode and anode are connected to a potentiostat and immersed in an undivided electrolysis cell containing the solution. Until the starting material disappears at room temperature, 50mA current is passed for 2 hours at a current density of 3.8mA / cm ³ , and 10ml of water is added to electrolyze under the same conditions for 5 hours. The solvent is concentrated under reduced pressure, and the obtained residue is partitioned into water and ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the organic layers were combined and washed with 10% aqueous sodium sulfite solution (Na ₂ S ₂ O ₃ ), saturated aqueous sodium bicarbonate solution and saturated brine. The residue obtained by drying with a forget-me-not and concentrated under reduced pressure was separated by silica gel column chromatography to give 289 mg (yield 67%) of the white pure title compound.

EXAMPLES 2-7

Preparation of (3R, 4R) -4-acetoxy-3-'[1'R) -1'-t-butyldimethylsilyloxy] ethylzeazetidin-2-one

570 mg of (3S, 4S) -4-carboxy-3-｛[(1'R) -1'-t-butyldimethylsilyloxy] ethyl｝ -1- (4-methoxyphenyl) azetidin-2-one The reaction was carried out in the same manner as in Example 1 using different concentrations of sodium acetate and different current densities as starting materials and under the conditions listed in Table 1 to give the pure title compound.

The reaction conditions and the yield of the product are as shown in Table 1 below.

[Examples 8-11]

Preparation of (3R, 4R) -4-acetoxy-3 '[(1'R) -1'-t-butyldimethylsilyloxy] ethylzeazetidin-2-one

570 mg of (3S, 4S) -4-carboxy-3-'[(1'R) -t-butyldimethylsilyloxy] ethyl'-1- (4-methoxyphenyl) azetidin-2-one and potassium acetate 36.5 Dissolve in 45 ml of acetonitrile mixed solvent (mix ratio 1/4) in excess of mg (0.25 equiv). The reaction was carried out in the same manner as in Example 1 using a platinum cathode and an anode to give 280 mg of the title compound in a yield of 65%.

Example 12

Preparation of (3R, 4R) -4-acetoxy-3-'[(1'R) -1'-t-butyldimethylsilyloxy]｝ ethylazetidin-2-one

570 mg of (3S, 4S) -4-carboxy-3-'[(1'R) -1'-t-butyldimethylsilyloxy] ethyl'-1- (4-methoxyphenyl) azetidin-2-one Dissolve 31 mg (0.25 equivalents) of sodium acetate in 45 ml of a mixture of acetic acid and acetonitrile (mixture ratio ¼), using a carbon electrode as the cathode and anode, and supply a current of 50 mA in an undivided electrolysis cell. Density 3mA / cm After 3 hours, add 10 ml of water and electrolyze for 5 hours under the same conditions. The residue obtained by concentrating the solvent under reduced pressure is partitioned between radish and ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the organic layers were combined and washed with 10% aqueous sodium sulfite solution (NaSO), saturated aqueous sodium bicarbonate solution and saturated brine. The residue obtained by drying after concentration under reduced pressure with forget-me-not was separated by silica gel column chromatography to obtain 280 mg of a white, pure title compound in a yield of 65%.

Example 13

Preparation of (3R, 4R) -4-acetoxy-3-'[(1'R) -1'-t-butyldimethylsilyloxy] ethylzeazetidin-2-one

570 mg of (3S, 4S) -4-carboxy-3-'[(1'R) -1'-t-butyldimethylsilyloxy] ethyl'-1- (4-methoxyphenyl) azetidin-2-one Dissolve 31 mg (0.25 equivalents) of sodium acetate in a mixture of acetic acid and acetonitrile (mixture ratio¼). When the RVC carbon electrode was used as a cathode and an anode, and the reaction was performed in the undivided electrolysis call as in Example 1, 285 mg of the title compound was obtained in a yield of 66%.

Example 14

Preparation of (3R, 4R) -4-acetoxy-3-[(1'R) -1'-t-butyldimethylsilyloxy] ethylazetidin-2-one

In this embodiment, (3S, 4S) -4-carboxy-3-[(1'R) -1'-t-butyldimethylsilyloxy] ethyl-1 is used as a method of using triethylamine as an organic pressure group as an electrolyte. 570 mg of-(4-methoxyphenyl) azetidin-2-one is dissolved in 40 ml of a mixed solvent of acetic acid and acetonitrile (mixture ratio 1/1), and 1 ml of triethylamine is added thereto. The platinum cathode and anode are connected to a potentiostat and immersed in an undivided electrolysis cell containing the solution. 50mA current until the starting material disappears at room temperature After 4 hours, add 10ml of water and electrolyze for 5 hours under the same conditions. The solvent is concentrated under reduced pressure, and the obtained residue is partitioned into water and acetate. The aqueous layer was extracted again with ethyl acetate, and the organic layers were combined and washed with 10% aqueous sodium sulfite solution (NaSO), saturated aqueous sodium bicarbonate solution and saturated brine. The residue obtained by drying with forget-me-not and concentrated under reduced pressure was separated by silica gel column chromatography to give 267 mg of the pure title compound as a yield of 62%.

Claims (8)

The 4-carboxyazetidinone N-substituent of the following formula (I) is electrochemically reacted by applying a direct current to an electrode in the presence of an electrolyte selected from the group consisting of alkali metal salts and amine bases of acetic acid in a mixed solvent of acetic acid and an organic solvent. After the addition of a suitable amount of water without separation of the reaction product after the reaction, a direct current is applied under the same conditions to deprotect the aryl group by the method to stereoselectively synthesize 4-acetoxyazetidinone of formula (II). In the formula, R ¹ represents a trialkylsilyl group; R ² represents an aryl group. A process according to claim 1 wherein R ¹ is t-butyldimethylsilyl. The process according to claim 1 or 2, wherein R ² is methoxyphenyl. The process according to claim 1, wherein the organic solvent is acetonitrile. The process according to claim 1, wherein 0.2 to 10 equivalents of sodium acetate or potassium acetate are used as the electrolyte. The process according to claim 1, wherein triethylamine is used as the electrolyte. The method according to claim 1, wherein at least 10 equivalents of water is used in the dearylation reaction. The method according to claim 1, wherein a platinum or carbon electrode is used as the electrode.