KR19980018089A - Stereoselective Preparation of Transazetidinone - Google Patents

Abstract

The present invention relates to (3S, 4S) -3-[(1'R) -1'-hydroxyethyl] -4-alkoxycarbonyl-alkyl-2-, an important intermediate of carbapenem and penem-based lactam antibiotics. The present invention relates to a method for stereoselectively preparing azetidinone.

The target compound of the present invention has the features and advantages to obtain a high synthetic yield with excellent economy.

Description

Stereoselective Preparation of Transazetidinone

The present invention relates to (3S, 4S) -3-[(1'R) -1'-hydroxyethyl] -4-alkoxy of the following general formula (I), which is an important intermediate of carbapenem and penem-based lactam antibiotics The present invention relates to a method for stereoselectively preparing carbonyl-2-azetidinone (hereinafter, abbreviated as transazetidinone) using L-threonine, which is an α-amino acid which is abundant in nature, as a starting material.

(Wherein R ¹ represents a lower alkyl group having _{1 to 4} carbon atoms, and R ² represents an aryl group or substituted benzyl, in particular 4-methoxyphenyl group, 2,4-dimethoxybenzyl, in the β-lactam ring protecting group.)

The transazetidinone of general formula (I), which is the target substance of the present invention, is a known compound and its preparation method has been reported by Shiozaki et al. (Tetrahedron, Vol. 40, p. 1795). Introducing:

As shown in Scheme 1, (2S, 3R) -bromo-3-hydroxy-butyric acid of the following structural formula (A) synthesized with L-threonine as a starting material is alkyl-N- (aryl or substituted benzyl Reaction of glycinate with a coupling reagent (e.g., 1,3-dicyclohexylcarbodiamide; DCC) to prepare a hydroxybromoamide compound of the general formula (I) When reacted with a strong base (e.g., lithium hexamethyldisilazide; LiHMDS), an epoxyamide of the following general formula (IV) is obtained, and when treated with the same amount of an alkali metal strong base, C ₃ -C ₄ β-lactam ring formation reaction is performed. It arises and the transazetidinone of the following general formula (I) is synthesize | combined. The transazetidinone (I) thus obtained can also be prepared with silyl esterazetidinone of the general formula (C) by protecting the free hydroxyl group with t-butyldimethylchlorosilane in the presence of a tertiary amine if necessary.

Scheme 1

Wherein R ¹ and R ² are as defined above and TBDMS represents a t-butyldimethylsilyl group.

However, the present inventors were able to find out the following problems based on the reproducibility experiment based on the preparation method. First, the removal of by-products (DCU, etc.) generated when performing the condensation reaction using 1,3-dicyclohexylcarbodiimide It was not easy and the yield was lower than the reported yield when the compound (b) was epoxidized with the equivalent of lithium hexamethyldisilazide, and secondly, a considerable amount of C ₃ -C ₄ β-lactam ring formation reaction was observed. Separation was difficult due to the generation of stereoisomers, and since the third synthesis step was difficult and complicated, serious side reactions occurred in the synthesis process of Formula (I), resulting in a decrease in yield.

The present inventors have completed the present invention as a result of research efforts to solve the problems of the conventional manufacturing method as described above.

In the present invention, the overall yield is higher than that of the conventional manufacturing method for stereoselectively preparing the desired compound, transazetidinone (I), using L-threonine, an inexpensive α-amino acid, which is present in abundance in nature, as a starting material. It is an object of the present invention to provide a new manufacturing method that solves the problems of known manufacturing methods.

Hereinafter, the present invention will be described in more detail by schematizing the reaction schemes for each synthesis step, as shown in Scheme 2 below.

Scheme 2

Wherein R ¹ and R ² are as defined above.

First, L-threonine is used to obtain (2R, 3R) -epoxybutyl acid of formula (II), which is reacted with N-arylalkylglycinate of formula (III) synthesized from arylamine and alkyl haloacetate. (2R, 3R) -N- (alkyloxycarbonyl) methyl-N-aryl-2,3-epoxybutylamide (hereinafter abbreviated as epoxyamide) of the above general formula (IV) and thus synthesized A stereoselective azetidinone cyclization reaction of the compound of (IV) affords the transazetidinone of the general formula (I).

The reaction scheme of the present invention will be described in detail as follows. First, in the synthesis step 1, the a-amino group of L-threonine is diazotized by nitrous acid generated during the reaction and is substituted with a halogen atom without inversion of stereo alignment. Thereafter, the halohydrin is converted to the epoxide by a strong base and acidified again so that (2R, 3R) -epoxybutyl acid of the general formula (II) is prepared in a one-pot reaction in one reaction tube. As the present invention, the present inventors have already applied for domestic patents [Hwang Tae-seop et al., Korean Patent Publication No. 96-41161], but the details are included in the present invention, the prior synthesis method was performed more efficiently and economically. As a reagent capable of generating nitrous acid in the reaction solution of step 1, sulfuric acid and sodium nitrite (NaNO ₂ ), sulfuric acid and potassium nitrite, hydrochloric acid and sodium nitrite or hydrochloric acid and potassium nitrite may be used. In particular, the use of 2 to 10 equivalents of normal hydrochloric acid and 1 to 8 equivalents of sodium nitrite was more efficient in the generation of nitrous acid, and the supply of halogen atoms, in particular chloro atoms, resulted in chloro anions produced by hydrochloric acid. (C1 ^-) the nucleophilic (nucleophile) without additional reagent in a reagent supply (2S, 3R) -2- chloro-3-hydroxy-butyl becomes acid is synthesized, 1 to 10 equivalents in the in situ condition caustic soda by acting The epoxidation takes place immediately after treatment with, in which case cooling to 0 ° C. to room temperature is preferred in order to catch initial heat generation. The reaction solution is acidified with an excess of acid, that is, hydrochloric acid or sulfuric acid, extracted with a general inert organic solvent, and the organic solvent is concentrated under reduced pressure to obtain (2R, 3R)- Epoxybutyl acid is a production step obtained in high yield.

In step 2 of the present invention, N-arylalkylglycinate of general formula (III) is reacted by reacting arylamine and alkylhaloacetate with a dehalogenating agent in the presence of an organic solvent or using a dehalogenating agent alone without an organic solvent. As the preparing step, the arylamines used in the synthesis may be aniline, p-anisidine, 2,4-dimethoxyaniline, 3,4-dimethoxyaniline, etc., but p-anisidine was used in the present invention. The alkyl halo acetates include methyl chloro acetate, methyl bromo acetate, ethyl chloro acetate, ethyl bromo acetate, ethyl iodine acetate, n-propylchloro acetate, n-propyl bromoacetate, n-butylchloro acetate, n- Butylbromoacetate, isopropylchloroacetate, isopropylbromoacetate, t-butylchloroacetate or t-butylbromoacetate The agent or the like can be used, but in the present invention was used to select the ethyl chloroacetate. As used herein, the term 'inert organic solvent' refers to an organic solvent capable of dissolving all compounds participating in a reaction, not participating in a reaction under reaction conditions or reducing reactivity, and minimizing side reactions, such as hexane or benzene. Ether compounds such as hydrocarbons, diethyl ether, tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, 1,2-dichloroethane, chloroform, esters such as methyl acetate, ethyl acetate, acetonitrile, toluene, N, N-dimethylformamide and lower alcohols such as methanol and ethanol, and the like, and dehalogenation agents, i.e., alkali such as n-butyllithium, lithiumamide, sodium amide, sodium hydride, potassium hydride, etc. Tertiary organic amines such as metal bases, triethylamine, pyridine, DBN, DBU, etc., ammonium hydroxide Alkali metal hydroxides such as sodium hydroxide, caustic soda, potassium hydroxide and the like can be used. However, the best results were obtained when triethylamine was used alone as an organic solvent and a dehalogenation agent without using an inert organic solvent. Preferably, 2 to 6 equivalents of triethylamine are used. Although reaction temperature is not specifically limited, Room temperature to reflux temperature is common.

In step 3 of the present invention, (2R, 3R) -epoxybutyl acid (II) and N-arylalkylglycinate (III) obtained in steps 1 and 2, respectively, are prepared using an amide bond coupling reagent. In the step of synthesizing the epoxyamide compound of IV), the amide coupling methods that can be generally applied to the reaction include an acid halide method, a mixed anhydride method or an active ester method. In this synthesis step, however, the mixed anhydride method was found to increase the yield under moderate reaction conditions with minimal side reactions. Ethylchloroformate, isopropylchloroformate, isobutylchloroformate and the like may be used as the activator used in the mixed anhydride method, but in the present invention, the best results are obtained when 1 to 3 equivalents of ethylchloroformate are used. The organic solvent used is preferably dichloromethane, chloroform or ethyl acetate among the above-mentioned inert organic solvents, and triethylamine, as a scavenger for removing hydrochloric acid (HCl) generated, Tertiary amines such as pyridine, N, N-dimethylaminopyridine, N-methylmorpholine, bicyclic amines (DBN, DBU, etc.) may be used, among which triethylamine or N-methylmorpholine is 1 to It is preferable to use 5 equivalents, and it is preferable to carry out reaction temperature at -40 degreeC to room temperature.

Step 4 of the present invention is a synthesizing step that shows the same technology and context as known by Shiozaki et al., But is superior in terms of economics and industrialization. It is a step of synthesizing transazetidinone of general formula (I) in a high yield by using Lewis acid or by using an alkali metal amide and a catalytic amount of secondary amines. As the alkali metal amines used herein, lithium amide, sodium amide, lithium hexamethyldisilazide, lithium diisopropylamide, lithium dicyclohexylamide, and the like can be used. Lewis acids may be halides of amphoteric or transition elements such as zinc, manganese, tin, titanium, aluminum, or boron. Among these, ZnCl ₂ and ZnBr ₂ have excellent results. Secondary amines are dimethylamine, Diethylamine, dicyclopentylamine, dicyclohexaneamine, hexamethyldisalazan and the like can be used, but it is particularly preferable to use hexamethyldisilazane as a catalyst. Dichloromethane or THF may be used as the inert organic solvent used in step 4, and the reaction temperature is preferably in the range of -20 ° C to reflux temperature. The fourth step of the present invention shows strengths in several aspects compared to the known technique. According to the first known technique, only 61% yield was obtained by using 1 equivalent of expensive lithium hexamethyldisilazide (LiHMDS). using the equivalent of LiHMDS and a catalytic amount of ZnBr ₂ in stylized significantly improve the yield, and also in the synthesis cost level by acting an inexpensive lithium amide (LiNH ₂₎ which are widely used commercially as a main base and using hexamethyldisilazane catalytic amount Excellent results were obtained. Second, also in the reaction yield, step 4 of the present invention, the reaction yield is 86% or 84%, the yield is significantly improved compared to 61% of the known technology. Third, in comparison with the front of the reactor, the known technique generates a considerable amount of unwanted isomers by thermodynamic control in THF solvent, but the method of the present invention generates isomers by performing kinetic control in CH ₂ Cl ₂ solvent. There is an advantage that eliminated fundamentally.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 Preparation of (2R, 3R) -Epoxybutylic Acid

After cooling 90 ml of 7,5N-HCl, 20 g (0.15 mol) of L-threonine was completely dissolved therein, 18.2 g of NaNO ₂ was added in small portions over 5 hours while maintaining the reaction temperature at 5 to 10 ° C. After cooling the internal temperature of the reaction temperature to 0 ℃ and slowly added dropwise 40% NaOH solution and stirred for 15 hours at room temperature, acidified with 6N-HCl (pH 2.0) while inhibiting the increase of the reaction temperature and 400ml of ethyl acetate After extracting twice, the combined organic layers were dried over 10 g of forget-me-not and concentrated under reduced pressure to obtain 14.3 g (90%) of a relatively pure title compound. This was used for the next reaction without further purification.

¹ H-NMR (300 MHz, CDCl ₃ ) δ; 1.44 (3H, d, J = 5.33 Hz), 3.38 (1H, m),

3.57 (1H, d, J = 4.72 Hz), 9-10 (acid-H, brs) ppm.

[a] _D = -10.2 (c = 0.5, MeOH)

Examples 2-6: Preparation of (2R, 3R) -Epoxybutylic Acid

The reaction was carried out in the same manner as in Example 1 using 1 equivalent of L-threonine as a starting material, and the title compound was obtained in the yield shown in Table 1 below.

Example 7 Preparation of Ethyl N-p-methoxyphenyl Glycinate

20 g (0.16 mole) of p-anisidine was dissolved in 100 ml of triethylamine, and 23.3 ml (0.22 mole) of ethylchloroacetate was added while maintaining an internal temperature of 50 占 폚 and stirred for 30 minutes under reflux conditions. After completion of the reaction, the temperature inside the reaction is slowly lowered and vigorously stirred with 500 ml of water / methanol (2/1) solution to form pale yellow crystals. The solid thus produced was filtered under reduced pressure and dried in vacuo to afford the title compound as a tan.

¹ H-NMR (300 MHz, CDCl ₃ ) δ; 1.26 (3H, t, J = 7.2 Hz), 3.74 (3H, s), 3.86 (2H, s), 4.23 (2H, m), 6.6 (2H, d, J = 10 Hz), 6.78 (2H, d, J = 10 Hz) ppm.

Examples 8-12: Preparation of Alkyl N-p-methoxyphenyl Glycinate

When 1 equivalent of p-anisidine and 1.33 equivalent of alkyl halo acetate were used, the title compound was obtained in the following yield under various reaction conditions shown in Table 2 below.

Example 13: Preparation of (2R, 3R) -N- (ethoxycarbonyl) methyl-N-p-methoxyphenyl-2,3-epoxy butyrylamide

14.3 g (0.1 mol) of (2R, 3R) -epoxybutylic acid was dissolved in 300 ml of chloroform, cooled to -30 ° C, 20 ml (0.18 mol) of N-methylmorpholine was added, and 17.4 ml (0.18 mol) of ethylchloroformate. Was slowly added dropwise and stirred vigorously for 30 minutes. 29.2 g (0.14 mol) of ethyl Np-methoxyphenyl glycinate synthesized in Example 7 was added to the solution and the reaction temperature was raised to room temperature, followed by stirring for 10 hours. The reaction was terminated. The organic layer was added, washed successively with 5% NaHCO ₃ and saturated brine, dried over forget-me-not and concentrated under reduced pressure to yield 45 g of impure title compound. 45 g of the impurity title compound thus obtained was purified by column chromatography (EA / Hex = 1/2) to obtain 34.5 g (84%) of the title compound as a pure pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ; 1.27 (3H, t, J = 7.2 Hz), 1.42 (3H, d, J = 5.4 Hz), 3.05 (1H, m), 3.30 (1H, d, J = 4.5 Hz), 3.83 (3H, s), 4.14 (1H, d, J = 17.1 Hz), 4.19 (2H, q, J = 7.2 Hz), 4.66 (1H, d, J = 17.1 Hz), 6.95 (2H, d, J = 10 Hz), 7.29 (2H , d, J = 10 Hz) ppm.

Examples 14-21: Preparation of (2R, 3R) -N- (ethoxycarbonyl) methyl-N-p-methoxyphenyl-2,3-epoxybutylarylamide

The reaction was carried out based on Example 13 using 1 equivalent of (2R, 3R) -epoxybutylic acid and various coupling methods to obtain the title compound in the yield shown in Table 3.

Example 22 Preparation of (3S, 4S) -3-[(1'R) -1'-hydroxyethyl] -4-ethoxycarbonyl-1-p-methoxyphenyl-2-azetidinone

(Method A)

20 g (68 mmol) of epoxyamide (IV) was dissolved in 300 ml of THF in the presence of nitrogen, 2.3 g (10 mmol) of ZnBr ₂ were added, the reaction solution was cooled to -10 DEG C and 80 ml (1 mol-lithium hexamethyldisilazide). 80 mmol) was added drop wise and the reaction temperature was gradually raised to 0 ° C. and the reaction was terminated by adding an appropriate amount of dilute hydrochloric acid, diluted with 600 ml of dichloromethane. The organic layer was separated, washed with 10% NaHCO ₃ solution and saturated brine, and concentrated under reduced pressure. This gives an impure title compound. The residue was purified by short column chromatography (CH ₂ Cl ₂ / acetone = 20/1) to give 17.2 g (86%) of the title compound as a slightly yellow needle.

¹ H-NMR (300 MHz, CDCl ₃ ) δ; 1.27 (3H, t, J = 7.2 Hz), 1.39 (3H, d, J = 6.4 Hz), 2.51 (1H, d, J = 4.5 Hz), 3.36 (1H, dd, J = 2.5 and 4.0 Hz), 3.77 (3H, s), 4.27 (2H, m), 4.35 (1H, m), 4.57 (1H, d, J = 2.5 Hz), 6.85 (2H, d, J = 10 Hz), 7.23 (2H, d, J = 10 Hz) ppm.

(Method B)

20 g (68 mmol) of epoxyamide (IV) was dissolved in 400 ml of CH ₂ Cl _{2 in the} presence of nitrogen, and 3.1 g (136 mmol) of lithium amide and 1.6 ml (7.48 mmol) of hexamethyldisilazane were added to reflux. 1 ml of ethanol was added thereto and then refluxed for 5 hours. After the reaction was completed, the process was carried out in the same manner as the post-treatment method of (A) to obtain 14.4 g (84%) of the pure title compound.

Claims (5)

A process for producing a compound of formula (I) by subjecting a compound of formula (IV) to a stereoselective azetidinone cyclization reaction. (Wherein R ¹ represents a lower alkyl group having _{1 to 4} carbon atoms, and R ² represents an aryl group or substituted benzyl in a β-lactam ring protecting group.) The process according to claim 1, wherein the azetidinone cyclization reaction is carried out using alkali metal amides and catalytic amounts of Lewis acid or alkali metal amides and catalytic amount of secondary amines. The process according to claim 1, wherein the compound of formula (IV) is obtained by reacting a compound of formula (II) with a compound of formula (III). Wherein R ¹ and R ² are as defined above. 4. A process according to claim 3, wherein the compound of formula (II) is obtained by reacting L-threonine with an acid and nitrite. 4. A process according to claim 3, wherein the compound of formula (III) is obtained by reacting an arylamine with an alkylhaloacetate with a dehalogenating agent.