KR20010107078A - Method of preparing 4-alkoxy-2-azetidinone derivative and its optical isomer - Google Patents

Abstract

The present invention relates to a novel process for synthesizing 4-alkoxy-2-azetidinone using novel azetidinone derivatives. By using the preparation method according to the present invention, it is not necessary to additionally use a protecting group, and it is possible to synthesize 4-alkoxy-2-azetidinone in high yield using conventional bases and reactants.

Description

Method of preparing 4-alkoxy-2-azetidinone derivative and its optical isomer

The present invention relates to a method for producing 4-alkoxy-2-azetidinone derivatives and optical isomers thereof, and more particularly, 4-alkoxy-2-azetidinone derivatives and opticals thereof using novel azetidinone derivatives. It relates to a novel production method for synthesizing isomers.

4-alkoxy-2-azetidinone (hereinafter referred to as "4-AlcA") represented by the following formula (2) is used for the synthesis of oxapenem antibiotics or beta-lactamase inhibitors. It is a useful material as an intermediate.

Wherein R ₁ is hydrogen or tert -butyldimethylsilyl group, and R ₂ is an alkyl group having 1 to 6 carbon atoms.

It has conventionally been known that the use of 4-acetoxy-2-azetidinone (hereinafter referred to as "4-AA") as a key intermediate is essential in the synthesis of 4-AlcA. The known synthesis method of 4-AA can be divided as follows.

First, as disclosed in European Patent Publication Nos. 371875, 369691 and 509821, a method is synthesized using a ruthenium catalyst. However, this method has been pointed out as a problem of using expensive ruthenium as a catalyst, complicated reprocessing process for recycling of used ruthenium, and the use of highly toxic and explosive acetaldehyde or peroxide. .

Secondly, there is a method of synthesis using chlorosulphonic isocyanates, as disclosed in EP 167154, 280962 and 372699. This method has also been pointed out as a problem that chlorosulphonic isocyanate is an expensive, highly toxic, and less stable material. In addition, according to this method, in order to maximize the yield ratio of the desired isomer in the mixed product of the isomer, It has the disadvantage that it should be carried out at an extremely low temperature, yield is low, and additional separation step of the desired isomer.

Third, as disclosed in European Patent Publication Nos. 259268 and 290385, chiral intermediates are made using enzymes or chiral boranes, borohydrides, chiral aluminum hydrides, Raney nickel or platinum, and the like Then, 4-AA is synthesized through an isomerization reaction. This method also has the drawback that the enzyme or coenzyme used is expensive and insensitive to moisture or air, resulting in poor stability, and the process is very complicated because isomerization of cyclized intermediates to specific bases results in the synthesis of 4-AA. It has the disadvantage of long and low yield.

In addition, a method of synthesizing 4-AlcA using 4-AA is known. For example, the synthesis method is as follows.

First, as disclosed in Japanese Patent Laid-Open No. 5017432, a method of electrochemically synthesizing after introducing a silyl group at the carbon position 4 is known. However, these methods require the use of expensive reagents called hexamethyldisilazane, the addition and removal of protecting groups, and the increase in production costs and operating costs in industrial applications. It can be pointed out as a problem.

Second, as described in Chem. Pharm. Bull. 1992, 4 0, 1044, Yasuyuki Kita; Tetrahedron Letters , 1991, 32 , 2375, Yasuyuki Kita, a method using an excess tin compound and Lewis acid Can be mentioned. However, these methods require expensive, toxic and unstable reagents such as Lewis acid, highly toxic tin compounds, and very unstable silyltriplates, and additionally require the introduction and removal of protecting groups, and the reaction solvent is also an anhydrous solvent. There is a drawback to using

A third method of refluxing excess hydroxy compounds at very high temperatures for a long time is described in J. Chem. Soc. Perkin Trans I 1983, 1157 , Mario D. Bachi; Synlett 1990, 681, Wataru Nagata; Synlett 1990, 684, Wataru Nagata). However, these methods require environmental pollution, low yields and economical problems caused by the use of excess reagents, additional protective agent introduction and removal processes, and long periods of time at very high temperatures. It is difficult to apply industrialization because of many problems such as the need to respond.

Fourth, as disclosed in US Pat. Nos. 4,288,95 and 4293555, a method using mercuriacetate and hydrochloric acid gas. However, this method requires the use of highly toxic and environmentally contaminating reagents such as mercuria acetate, the use of hydrochloric acid gas, which is a type of poison gas, and the difficulty in treating wastewater. This addition is pointed out as a problem.

Fifth, as disclosed in European Patent Publication No. 474038, a method of using chlorine gas. However, this method has been pointed out that the use of chlorine gas, which is a type of poison gas, and additionally requires the introduction and removal of the protecting group.

Sixth, there is a method through multi-step reaction with excess base as disclosed in US Pat. Nos. 5,108,747,568,876,509,6899,5998612, European 548790,18305. However, this method requires the use of extremely strong bases such as butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, etc. in excess of very low temperatures and solvents using anhydrous solvents, sulfide intermediates at 4-AA. There is a problem that can be synthesized only after a very large number of steps, such as making and then passing through a halogenated intermediate, low yield, and additionally the introduction and removal of the protecting group is required.

As such, in the synthesis of conventional 4-AlcA, the method of using 4-AA as an intermediate is due to various problems such as difficulty in handling the reagents and reactants used in the method or problems in industrial application. The demand for improvement was increasing.

Meanwhile, 4-AA is also a key intermediate used to synthesize 1-β-alkylazetidinone (1-BMA), which is useful as an intermediate in the synthesis of carbapenem antibiotics. In this regard, the present inventors have already proposed through the Republic of Korea Patent Application No. 2000-17011 for a useful new material that can be used in place of 4-AA in the synthesis of 1-BMA.

That is, according to the Korean Patent Application No. 2000-17011, an azetidinone derivative represented by Chemical Formula 1 and a method of synthesizing 1-BMA using the same are introduced in detail.

Wherein X is a halogen element and R ₁ is hydrogen or tert -butyldimethylsilyl group.

More specifically, according to the present invention, at least one of an alkali metal acetate, an alkali metal carbonate or an alkali metal bicarbonate, a halogenated reagent such as a chlorolation reagent, a bromination reagent or an iodide reagent, and a compound represented by the following Chemical Formula 3 Introducing a method for preparing an azetidinone derivative represented by Chemical Formula 1 comprising the step of reacting at least one organic base of an inorganic base or a pyridine compound, quinoline or imidazole.

Wherein R ₁ is hydrogen or tert -butyldimethylsilyl group.

The present inventors have conducted many studies and experiments on the possibility that the novel compound represented by the formula (1) can be used as a useful intermediate material that can replace 4-AA in the synthesis of 4-AlcA. It became.

The technical problem to be achieved by the present invention is to provide a method of using a novel and useful intermediate material that can replace the conventional 4-AA in the synthesis of 4-AlcA.

Another technical object of the present invention is to provide a method for economically and efficiently producing 4-AlcA or its optical isomers from the novel and useful intermediate materials.

The technical problems of the present invention, the step of reacting the azetidinone derivative represented by the formula (1) with R ₂ OH or R ₂ OM (where M is an alkali metal) in the presence of any catalyst in any solvent It is achieved through a method for producing a 4-alkoxy-2-azetidinone derivative represented by the formula (2) and the optical isomer thereof

[Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2, X is a halogen element, R ₁ is hydrogen or tert -butyldimethylsilyl group, R ₂ is an alkyl group having 1 to 6 carbon atoms.

According to the present invention, chlorine, bromine or iodine is preferable as the halogen element, and methyl, ethyl, normal propyl, isopropyl, normal butyl, sec -butyl, tert -butyl, normal pentyl, or normal hexyl are preferable as the alkyl. In addition, the alkali metal is preferably lithium, sodium or potassium.

The method for synthesizing 4-AlcA derivatives and optical isomers thereof from the azetidinone derivative represented by Formula 1 of the present invention specifically includes the following reaction steps.

First, according to one embodiment of the present invention, the preparation method of the present invention includes the step of reacting an azetidinone derivative represented by Formula 1 in the presence of a catalytic amount of R ₂ OM in R ₂ OH. . In this reaction step, R ₂ OH simultaneously serves as a reaction solvent and as a reactant to provide R ₂ O- groups.

Secondly, according to another embodiment of the present invention, the preparation method of the present invention, reacting the azetidinone derivative represented by the formula (1) with an equivalent of R ₂ OM in an R ₂ OH solvent or a general solvent Steps. Here, the general solvent is not particularly limited as long as it is a solvent commonly used in chemical reactions such as ethyl acetate, normal hexane, acetone, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, benzene, toluene, and xylene. Do not. In this reaction step, R ₂ OM acts as a reactant to provide a R ₂ O- group.

Third, according to another embodiment of the present invention, the preparation method of the present invention, the azetidinone derivative represented by the formula (1), in R ₂ OH, the catalytic amount of R ₃ OM (where R ₃ is And an alkyl group having 1 to 6 carbon atoms different from R ₂ . In this reaction step, the R ₂ OH solvent serves both as a reaction solvent and as a reactant to provide a R ₂ O- group.

In addition, the three reaction steps according to an embodiment of the present invention is preferably carried out at a reaction temperature of -20 to 80 ℃, preferably 0 to 30 ℃.

If the reaction temperature is less than -20 ℃, the viscosity of the solvent is increased so that the stirring efficiency is not good due to the characteristics of the alcohol solvent when using the alcohol solvent as in the present invention, the reaction efficiency is low, while the reaction temperature is 80 ℃ When exceeded, the defect that the β-lactam ring of the β-lactam compound is easily broken and the reaction by-products are increased is inevitable.

That is, using the production method of the present invention it is possible to economically and efficiently obtain 4-AlcA from the azetidinone derivative represented by the formula (1).

The novel azetidinone derivative represented by the general formula (1) according to the present invention has a high electronegativity at the N atom of β-lactam and a halogen group (X group) having a stronger leaving group than acetate has been introduced. The hydrogen of adjacent carbons is more activated, that is, the acidity (acidity) is increased to easily prepare an intermediate that can easily proceed to the subsequent reaction even if not necessarily a strong base. In addition, the N atom of β-lactam reacts without protecting group, and thus, the N atom of β-lactam has a problem of attaching a protecting group to react and removing the protecting group again after completion of the reaction. In contrast, the novel azetidinone derivative represented by Chemical Formula 1 according to the present invention has a halogen atom attached to the N atom and acts as a kind of protecting group so that it is easily released after the reaction. The process can be omitted.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by the following Examples.

<Production example>

(3S) -N -Chloro-3- [ (R) -One'- tert -Butyldimethylsilyloxyethyl] -2-azetidinone

(3S) -3- [(R) -1'- tert - butyldimethylsilyloxy ethyl] -2-azetidinone 60 g (0.26 mol) sodium acetate and 23 g (0.28 mol) was dissolved in the ethanol in 100 ㎖ . 38 g (0.28 mol) of N -chlorosuccinimide was added thereto at room temperature, followed by stirring for 6 hours. Then, 100 ml of water was added and extracted with 300 ml of hexane (300 ml × 3). Hexane was removed from the extracted solution under reduced pressure to obtain an oil product, which was then separated and purified using silica gel-packed column chromatography using a mixed solution of ethyl acetate and hexane in a volume ratio of 1: 1. (3S) obtained in the form of a clear oil product -N - Chloro -3- [(R) -1'- tert - butyldimethylsilyloxy ethyl] -2-azetidinone was 68 g, the yield was 98%.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.08 (s, 6H), 0.86 (s, 9H), 1.20 (d, 3H, J = 6.2 Hz), 3.36 (q, 1H, J = 3.0 Hz), 3.56 (m, 1 H), 3.66 (m, 1 H), 4.26 (m, 1 H)

<Example 1>

(3R, 4R) -4-methoxy-3- [ (R) -One'- tert -Butyldimethylsilyloxyethyl] -2-azetidinone

It is manufactured through the preparation (3S) -N - Chloro -3- [(R) -1'- tert - butyldimethylsilyloxy ethyl] -2-azetidinone 10 g (0.037 mol) in 20 mL of methanol After melting in to lower the temperature of the solution to 0 ℃. 0.76 mL (1 mol%) of sodium methoxide (0.5 M in methanol) was slowly added thereto at 0 ° C. and stirred for 30 minutes. Next, 20 mL of water was added, followed by extraction three times with 30 mL of methylene chloride. (30 mL × 3) The methylene chloride solution was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure to obtain the target compound (3R, 4R). ) -4-methoxy -3- [(R) -1'- tert - butyldimethylsilyloxy ethyl] -2-azepin dinon tea to give a 9.64 g of a 98% yield.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.06 (s, 6H), 0.90 (s, 9H), 1.24 (d, 3H, J = 6.3 Hz), 3.01 (dd, 1H, J = 4.2, 1.1 Hz ), 3.35 (s, 3H), 4.19 (qd, 1H, J = 6.3, 4.2 Hz), 4.99 (d, 1H, J = 1.3 Hz), 6.60 (brs, 1H)

IR (neat, cm ^-1 ): 3405, 1760, 1084

<Example 2>

(3R, 4R) -4-methoxy-3- [ (R) -One'- tert -Butyldimethylsilyloxyethyl] -2-azetidinone

Through the same method as in Example 1, except that 18.95 mL (0.037 mol) of sodium methoxide (2 M in methanol) was added, the target compound (3R, 4R) -4-methoxy-3- [ ( R) 9.64 g of -1' -tert-butyldimethylsilyloxyethyl] -2-azetidinone were obtained in a yield of 98%.

<Example 3>

(3R, 4R) -4-methoxy-3- [ (R) -One'- tert Synthesis of -butyldimethylsilyloxyethyl] -2-azetidinone

Except for adding 0.76 mL (1 mol%) of lithium methoxide (0.5 M in methanol) through the same method as in Example 1, the target compound (3R, 4R) -4-methoxy-3- [ (R) -1'- tert - butyldimethylsilyloxy ethyl] -2-azepin dinon tea to give a 9.54 g of a 97% yield.

<Example 4>

(3R, 4R) -4-methoxy-3- [ (R) -One'- tert -Butyldimethylsilyloxyethyl] -2-azetidinone

Through the same method as Example 1, except that 0.76 mL (1 mol%) of potassium methoxide (0.5 M in methanol) was added, the target compound (3R, 4R) -4-methoxy-3- [ (R) -1'- tert - butyldimethylsilyloxy ethyl] -2-azetidinone to give 9.35 g of a 95% yield.

Example 5

(3R, 4R) -4-ethoxy-3- [ (R) -One'- tert -Butyldimethylsilyloxyethyl] -2-azetidinone

In place of methanol, using the same procedure as in Example 1 except for the use of ethanol in the desired compound of (3R, 4R) -4- Ethoxy -3- [(R) -1'- tert - butyldimethylsilyl Oxyethyl] -2-azetidinone was obtained in 99% yield.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.06 (s, 6H), 0.93 (s, 9H), 1.23 (dd, 3H, J = 6.8 Hz), 1.26 (dd, 3H, J = 6.4 Hz), 2.99 (dd, 1H, J = 4.2, 1.1 Hz), 3.55 (q, 2H, J = 6.8 Hz), 4.12 (qd, 1H, J = 6.4, 4.2 Hz), 5.02 (d, 1H, J = 1.1 Hz ), 6.53 (brs, 1H)

<Example 6>

(3R, 4R) -4-normal propoxy-3- [ (R) -One'- tert -Butyldimethylsilyloxyethyl] -2-azetidinone

(3R, 4R) -4- Normalpropoxy -3-[ (R) -1'- tert -butyl, a target compound, in the same manner as in Example 1, except that normal propanol was used instead of methanol. Dimethylsilyloxyethyl] -2-azetidinone was obtained in 96% yield.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.06 (s, 6H), 0.93 (s, 9H), 0.95 (t, 3H, J = 9.3 Hz), 1.20 (d, 3H, J = 6.3 Hz), 1.55 (m, 2H), 2.99 (dd, 1H, J = 4.3, 1.1 Hz), 3.84 (m, 2H), 4.42 (qd, 1H, J = 4.3, 6.2 Hz), 5.10 (d, 1H, J = 1.1 Hz), 6.34 (brs, 1 H)

<Example 7>

(3R, 4R) -4-isopropoxy-3- [ (R) -One'- tert Synthesis of Butyldimethylsilyloxyethyl] -2-azetidinone

Except for using isopropanol instead of methanol, the same compound as in Example 1 was used to obtain the target compound (3R, 4R) -4-isopropoxy-3-[ (R) -1'- tert - butyldi Methylsilyloxyethyl] -2-azetidinone was obtained in 93% yield.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.06 (s, 6H), 0.93 (s, 9H), 1.20, 1.21, 1.25 (each d, 9H, J = 6.5 Hz), 2.99 (dd, 1H, J = 4.3, 1.1 Hz), 3.76 (heptet, 1H, J = 6.5 Hz), 4.16 (qd, 1H, J = 4.3, 6.5 Hz), 5.10 (d, 1H, J = 1.1 Hz), 6.34 (brs, 1H )

<Example 8>

(3R, 4R) -4-normal-butoxy-3- [ (R) -One'- tert -Butyldimethylsilyloxyethyl] -2-azetidinone

(3R, 4R) -4-Normalbutoxy-3-[ (R) -1'- tert -butyl, a target compound, in the same manner as in Example 1, except that normalbutanol was used instead of methanol. Dimethylsilyloxyethyl] was obtained in a yield of 91%.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.06 (s, 6H), 0.93 (s, 9H), 0.95 (t, 3H, J = 9.3 Hz), 1.20 (d, 3H, J = 6.3 Hz), 1.41 (m, 4H), 2.99 (dd, 1H, J = 4.3, 1.1 Hz), 3.85 (m, 2H), 4.41 (qd, 1H, J = 4.2, 6.2 Hz), 5.10 (d, 1H, J = 1.1 Hz), 6.34 (brs, 1 H)

Example 9

(3R, 4R) -4- sec -Butoxy-3- [ (R) -One'- tert -Butyldimethylsilyloxyethyl] -2-azetidinone

Except for using sec -butanol instead of methanol, the same compound as in Example 1 was used as the target compound (3R, 4R) -4- sec -butoxy-3- [ (R) -1′- tert -Butyldimethylsilyloxyethyl] -2-azetidinone was obtained in 91% yield.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.06 (s, 6H), 0.93 (s, 9H), 0.95 (d, 6H, J = 9.3 Hz), 1.21 (d, 3H, J = 6.0 Hz), 1.72 (m, 1H), 2.99 (dd, 1H, J = 3.0, 1.1 Hz), 3.45 (m, 2H), 4.17 (qd, 1H, J = 6.1, 3.2 Hz), 5.32 (d, 1H, J = 1.1 Hz), 6.24 (brs, 1 H)

<Example 10>

(3R, 4R) -4- tert -Butoxy-3- [ (R) -One'- tert -Butyldimethylsilyloxyethyl] -2-azetidinone

In the same manner as in Example 1, except that tert -butanol was used instead of methanol, the target compound (3R, 4R) -4- tert -butoxy-3- [ (R) -1'- tert -Butyldimethylsilyloxyethyl] was obtained in a yield of 90%.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.06 (s, 6H), 0.93 (s, 9H), 1.21 (d, 3H, J = 6.0 Hz), 1.25 (s, 9H), 2.99 (dd, 1H, J = 3.0, 1.1 Hz), 4.19 (qd, 1H, J = 6.0, 3.0 Hz), 5.32 (d, 1H, J = 1.1 Hz), 6.24 (brs, 1H)

<Example 11>

(3R, 4R) -4-normal-pentyl-3- [ (R) -One'- tert -Butyldimethylsilyloxyethyl] -2-azetidinone

In the same manner as in Example 1, except for using normalpentyl alcohol instead of methanol, the target compound (3R, 4R) -4-normalpentyl-3-[ (R) -1′- tert -butyl Dimethylsilyloxyethyl] -2-azetidinone was obtained in 92% yield.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.06 (s, 6H), 0.93 (s, 9H), 0.97 (t, 3H, J = 9.1 Hz), 1.20 (d, 3H, J = 6.3 Hz), 1.46 (m, 6H), 2.99 (dd, 1H, J = 4.3, 1.1 Hz), 3.87 (m, 2H), 4.41 (qd, 1H, J = 4.3, 6.1 Hz), 5.10 (d, 1H, J = 1.1 Hz), 6.34 (brs, 1 H)

<Example 12>

(3R, 4R) -4-normal hexyl-3- [ (R) -One'- tert -Butyldimethylsilyloxyethyl] -2-azetidinone

Except for using normal hexyl alcohol instead of methanol, the same compound as in Example 1 was used as the target compound (3R, 4R) -4- normalhexyl -3-[ (R) -1′- tert -butyl Dimethylsilyloxyethyl] -2-azetidinone was obtained in 90% yield.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.06 (s, 6H), 0.93 (s, 9H), 0.97 (t, 3H, J = 9.3 Hz), 1.20 (d, 3H, J = 6.3 Hz), 1.43 (m, 6H), 2.99 (dd, 1H, J = 4.3, 1.1 Hz), 3.91 (m, 2H), 4.41 (qd, 1H, J = 4.2, 6.2 Hz), 5.10 (d, 1H, J = 1.1 Hz), 6.34 (brs, 1 H)

As described above, according to the present invention, by using a novel azetidinone derivative as a key intermediate, 4-AlcA, which is an intermediate of an oxapene antibiotic or a beta-lactamase inhibitor, can be economically and efficiently synthesized. We can provide a way. By using the preparation method according to the present invention, it is not necessary to additionally use a protecting group, and 4-AlcA can be synthesized in high yield using conventional bases and reactants.

Claims (6)

Wherein the azetidinone derivative represented by Formula 1 is reacted with R ₂ OH or R ₂ OM, wherein M is an alkali metal, in the presence of any catalyst in any solvent 4-Alkoxy-2-azetidinone derivatives and methods for producing the optical isomers thereof. [Formula 1] [Formula 2] In Chemical Formulas 1 and 2, X is a halogen element, R ₁ is hydrogen or tert -butyldimethylsilyl group, R ₂ is an alkyl group having 1 to 6 carbon atoms. The 4-alkoxy-2-azeti according to claim 1, wherein the reaction step is a step of reacting the azetidinone derivative represented by Formula 1 in the presence of a catalytic amount of R ₂ OM in R ₂ OH. Dinon derivatives and methods for producing the optical isomers thereof. The method of claim 1, wherein the reaction step is characterized in that the step of reacting the azetidinone derivative represented by the formula (1) with an equivalent amount of R ₂ OM in a R ₂ OH solvent or a general solvent, 4-alkoxy-2 Azetidinone derivatives and optical isomers thereof. The method of claim 3, wherein the general solvent is at least one selected from the group consisting of ethyl acetate, normal hexane, acetone, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, benzene, toluene and xylene Characterized in that the 4-alkoxy-2-azetidinone derivatives and optical isomers thereof. The method of claim 1, wherein the reaction step is an azetidinone derivative represented by Formula 1, in R ₂ OH, a catalytic amount of R ₃ OM, wherein R ₃ is an alkyl group having 1 to 6 carbon atoms different from R ₂ A method for producing a 4-alkoxy-2-azetidinone derivative and its optical isomer, characterized in that the step of reacting in the presence of). The method for producing a 4-alkoxy-2-azetidinone derivative and its optical isomer according to any one of claims 1 to 5, wherein the reaction is performed at -20 to 80 ° C.