KR100205769B1 - Stereoselective preparation method of transazetidinone - Google Patents

Abstract

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

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-alkoxycarb of the following general formula (I), which is an important intermediate of carbapenin and penem-based lactam antibiotics The present invention relates to a method for stereoselectively preparing carbonyl-2-azetidinone (hereinafter abbreviated as transazetidinone) as a starting material using L-threonine, which is an α-amino acid which is abundant in nature.

Wherein R ¹ represents a lower alkyl group which is C _1-4 , and R ² represents an aryl group or a substituted benzyl, in particular 4-methoxyphenyl group, 2,4-dimethoxybenzyl, in the β-lactam ring protecting group. )

Transazetidinone of the 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 Equation 1, (2S, 3R) -2-bromo-3-hydroxy-butyric acid of the following structural formula (A) synthesized with L-threonine as starting material is alkyl-N- (aryl or substituted Benzyl) glycinate in the presence of a coupling reagent (e.g., 1,3-dicyclohexylcarbodiimide; DCC) to prepare a hydroxybromoamide compound of the general formula (I) Reaction with an alkali metal strong base (e.g., lithium hexamethyldisilazide; LiHMDS) yields an epoxyamide of the general formula (IV), which is then treated with an equivalent amount of an alkali metal strong base to form a C ₃ -C ₄ β-lactam ring. The reaction occurs to synthesize a transazetidinone of the general formula (I). 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 drawbacks as a result of reproducibility experiments based on the preparation method. First, removal of by-products (such as DCU) generated during the condensation reaction using 1,3-dicyclohexylcarbodiimide It was not easy and the yield was lower compared to the reported yield when the compound (b) was oxidized with an equivalent amount of lithium hexamethyldisilazide, and a second amount of C ₃ -C ₄ β-lactam ring formation reaction. Separation was difficult due to the generation of stereoisomers, and the third synthesis step was difficult and complicated, and 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.

The present invention has a high overall yield compared to the conventional production method for the stereoselective preparation of the desired compound, transazetidinone (I), using L-threonine, which is an inexpensive α-amino acid, abundantly present in nature, as a starting material, An object of the present invention is 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.

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-epoxybutyluramide (hereinafter abbreviated as epoxyamide) of the general formula (IV) and thus synthesized When the compound of (IV) is subjected to stereoselective azetidinone cyclization reaction, the transazetidinone of the general formula (I) is obtained.

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 steric 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 filed details in Korean [Hwang Tae-seop et al., Korean Patent Publication No. 96-41161], but the present invention 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 1 to 10 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, especially chloro atoms, was caused by the chloro anion produced by hydrochloric acid. (C1 ^-) additional becomes the (2S, 3R) -2- chloro-3-hydroxy-butyl acid synthesis without the supply of reagent, in situ conditions at 1 to 10 equivalents of sodium hydroxide, by acting as a nucleophilic (nucleophile) reagent 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. Then, 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 then concentrated under reduced pressure. The relatively pure (2R, 3R)- Epoxybutyl acid is a drawing 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 may be used in the present invention. The alkyl halo acetates were methylchloroacetate, methylbromoacetate, ethylchloroacetate, ethlobromoacetate, ethyl iodine acetate, n-propylchloroacetate, n-propylbromoacetate, n-butylchloroacetate, n Butyl bromoacetate, isopropylchloroacetate, isopropyl bromoacetate, t-butylchloroacetate or t-butylbromoacetate Sites 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 the reaction, not participating in the reaction under reaction conditions, or EH, which does not lower the reactivity and minimizes side reactions. Hydrocarbons such as hydrocarbons, ether compounds such as diethyl ether and tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, 1,2-dichloroethane and chloroform, esters such as methyl acetate and ethyl acetate, acetonitrile and toluene , N, N-dimethylformamide and lower alcohols such as methanol and ethanol, and the like, and dehalogenating agents, i.e., tertiary organic compounds such as n-butyllithium, lithium amide, sodium amide, sodium hydride, and the like. Alkali metal hydroxides, such as amines, ammonium hydroxide, caustic soda, potassium hydroxide, etc. are used However, in this synthesis step, the best results were obtained when triethylamine was used alone as an organic solvent and a dehalogenating agent without using an inert organic solvent, and preferably 2 to 6 equivalents of triethylamine was used. . Although reaction temperature is not specifically limited, Room temperature to reflux temperature is common.

In the present invention, step 3 is obtained by using the amide bond coupling reagent of (2R, 3R) -epoxybutyl acid (II) and N-arylalkylglycinate (III) obtained in step 1 and step 2, respectively. As the step of synthesizing the epoxyamide compound of IV), the amide coupling methods that can be generally applied to the present reaction include an acid halide method, a mixed anhydride method, an active ester method, and the like. In this synthesis step, however, the mixed anhydride method was found to increase the yield under moderate reaction conditions with minimal reaction. Ethylchloroformate, isopropylchloroformate, isobutylchlororoformate 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 ethylchloroformene are used. The organic solvent used is preferably dichloromethane, chloroform or ethyl acetate among the above-mentioned inert organic solvents, and triethylamine, which is used as a scavenger for removing the generated hydrochloric acid (HCI), 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 reported by Shiozaki et al., But is superior in terms of economics and industrialization. It is a step of synthesizing the transazetidinone of the general formula (I) in 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 acid can be halides of amphoteric or transition elements such as zinc, manganese, tin, titanium, aluminum, or boron. Among these, ZncL ₂ ZnBr ₂ has excellent results. Secondary amines are dimethylamine, diene. Deamine, dicyclopentylamine, dicyclohexylamine, hexamethyldisilazane and the like can be used, but it is particularly preferable to use hexamethyldisilazane as a catalyst. Herein, the catalyst amount means that 0.01 to 0.9 equivalent is used. 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 respects compared to the known technology. According to the first known technology, only 61% yield was obtained using 1 equivalent of expensive lithium hexamethyldisilazide (LiHMDS). The yield was greatly improved by using the equivalent LiHMDS and the catalytic amount of ZnBr ₂ , and also by using the commercially widely used inexpensive lithium amide (LiNH ₂ ) as the main base and the catalytic amount of hexamethyldisilazane. Excellent results were obtained at. 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 kinematic control in a 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-HC1 and adding 20 g (0.15 mol) of L-threonine to completely dissolve it, 18.2 g of NaNO ₂ was added in small portions over 5 hours while maintaining the reaction temperature at 5 to 10 ° C. The internal temperature of the reaction temperature was cooled to 0 ° C. and 40% NaOH solution was slowly added dropwise, stirred at room temperature for 15 hours, acidified with 6N-HC1 (pH 20.) while inhibiting the reaction temperature rise, and ethyl acetate After extracting twice with 400ml, 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, CDC13) 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 to 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 mol) of p-anisidine was dissolved in 100 ml of triethylamine, and 23.3 ml (0.22 mol) of ethylchloroacetate was added while maintaining an internal temperature of 50 占 폚 and stirred for 30 minutes under reflux conditions. After the reaction was completed, the temperature inside the reaction was gradually lowered, and 500 ml of water / methanol (2/1) solution was added thereto and stirred vigorously to yield pale yellow crystals. The solid thus produced was filtered under reduced pressure and dried in vacuo to afford the title compound as a tan.

H-NMR (300 MHz, CDC13) 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 to 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 DP 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 added. It 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 after rmXSKS. The organic layer was added, washed successively with 5% NaHCO 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 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.

H-NMR (300 MHz, CDC13) 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, doublet, J = 10 Hz) ppm.

[Examples 14 to 21: Preparation of (2R, 3R) -N- (ethoxycarbonyl) metal-N-p-methoxyphenyl-2,3-epoxybutylacrylamide]

The reaction was carried out based on Example 13 using 1 equivalent of (2R, 3R) -epoxybutylic acid and applying various coupling methods to give 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, ZnBr2.3 g (10 mmol) was added, the reaction solution was cooled to -10 DEG C, 80 ml (80 mol) of 1 mol-lithium hexamethyldisilazide Millimol) was added dropwise quickly 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 solution and saturated brine, and concentrated under reduced pressure. The title compound is obtained. The residue was purified by short column chromatography (CHCl / acetone = 20/1) to obtain 17.2 g (86%) of the title compound as pale yellow needles.

H-NMR (300 MHz, CDC13) 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, doublet, J = 10 Hz) ppm.

[Method B]

Dissolve 20 g (68 mmol) of epoxyamide (IV) in 400 ml of CHCl in the presence of nitrogen, add 3.1 g (136 mmol) of lithium amide and 1.6 ml (7.48 mmol) of hexamethyldisilazane, then add 1 ml of ethanol at the start of reflux. Then reflux for 5 hours. After the reaction was completed, the reaction 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 is C _1~4) represents a lower alkyl group, R ² represents an aryl group or a substituted benzyl protecting group of the β- lactam ring.) The process according to claim 1, wherein the azetidinone cyclization reaction is carried out using alkali metal amides and catalytic amount of Lewis acid or alkali metal amides and catalytic amount of secondary amines. A 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. The process according to claim 3, wherein the compound of formula (II) is obtained by reacting L-threonine with an acid and a 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.