Process for stereoselective preparation of 4-acetoxyazetidinones

Technical Field

The present invention relates to a process for stereoselective preparation of (3R,4R)-4-acetoxy-3- { [( 1 'R)- 1 '-t-butyldimethylsilyloxy] ethyl }-2-azetidinone (I) (here-in-after, abbreviated as "4- acetoxyazetidinone") which is a useful intermediate for preparing carbapenem and penem type β -lactam antibiotics.

In the formula, Ri represents a lower alkyl group, and OAc represents acetoxy group.

Background Art

The 4-acetoxyazetidinones represented by general formula (I), a useful intermediate for carbapenem and penem type antibiotics, are known compounds which are produced by three Japanese companies (Kanega Fuchi, Suntory-Nippon Soda and Takasago) in a magnificent amount every year. The synthetic processes are illustrated in short by the following reaction schemes.

- Process of Kanega Fuchi [Japanese Patent No. 92-1 12867, EP-Ai- 167154]

OH O

( 3_?) -methy l - bu t yrate

- Process of Suntory-Nippon Soda [J. Chem. Soc. Chem. Commun., 662(1991)]

( 3 ?) -bu tane-1 , 3-d i o !

Process of Takasago [EP-A ₂ -371875( 1990)]

In the formulas, TBDMS represents t-butyldimethylsilyl group, and TMS represents trimethylsilyl group.

Though the three processes have industrialized and succeeded in mass production of the compound, they involves various common problems in that the cost of starting material is very high and the overall yield is still low in spite of using advanced industrial technique.

A process for preparing azetidinone derivatives starting from L- threonine has been disclosed by Shiozaki et al. [Tetrahedron, Vol. 40, pl795] According to the disclosure, (2S,3R)-2-bromo- 3-hydroxy-

butyric acid (Formula A) synthesized starting from L-threonine was reacted with alkyl-N-(aryl or substituted benzyl) glycinate in the presence of a coupling agent (such as 1,3-dicyclohexylcarbodiimide; DCC) to give hydroxybromoamide compound of general formula (B). Then the compound (B) was reacted with equivalent amount of alkali metallic strong base (such as lithium hexamethyldisilazide; LiHMDS) to obtain the epoxyamide of general formula (V), which was then reacted with equivalent amount of alkali metallic strong base to give trans-azetidinone of general formula (IV) by β -lactam ring formation. The process is illustrated by Scheme 1 below.

Scheme 1

L-threonιne ( A)

LiHMDS

( I V) (V)

In the formula, R ² represents a CM lower alkyl group, and R ³ represents aryl group, or substituted benzyl group, particularly 4- methoxyphenyl group or 2,4-dimethoxybenzyl, as a β -lactam protective group.

Alternatively, the compound (V) can be prepared by a process developed by the present inventors et al. First, L-threonine is converted

to (2R,3R)- epoxybutyric acid (VII) by the use of a known procedure [Tae-sub Hwang et al., Korean Patent Laid-Open No. 96-41 161]; and the compound (VII) is reacted with N- arylalkylglycinate synthesized from an aryl amine and an alkyl haloacetate by a mixed anhydride process or an active ester process to obtain (2R,3R)-N- (alkyloxycarbonyl)methyl-N-aryl-2,3-epoxybutyric amide (here-in-after, referred to as "epoxyamide").

Scheme 2

/.- threon i ne

( VI I ) ( VI )

(V)

In the formulas, R ² and R ³ are defined as above.

Disclosure of the Invention The present inventors have found that the compound represented by general formula (V) prepared from L-threonine, which can be abundantly supplied from the nature, is a useful intermediate for the synthesis of azetidinone derivatives, and developed an improved process for preparing the object compound of the present invention represented by general formula (I) starting from the compound (V), to complete the invention.

The object of the present invention is to provide a process for economically preparing the compound represented by general formula (I)

with a high yield.

According to the present invention, a process for preparing the compound (I) through a 5-step process starting from the compound represented by general formula (V) is provided, as illustrated in Scheme 3. First, an epoxyamide (V) is reacted with an alkali metallic strong base, and the product, without further purification, is treated with t- butyldimethylchlorosilane to give silyl ester azetidinone (IV) in a one-pot reaction. The alkyl ester group of silyl ester azetidinone (IV) thus obtained is hydrolyzed and treated with an acid to obtain (3S,4S)-3- { [(l'R)- -t- butyldimethylsilyloxy ] ethyl } - 4 - carboxy - 1 - aryl - 2 - azetidinone represented by general formula (III) (here-in-after, abbreviated as "4-carboxyazetidinone") as a free acid form. The free acid group of the 4-carboxyazetidinone (III) is stereoselectiveiy acetoxylated to synthesize (3R,4R)-4- acetoxy-3-{ [( rR)-l '-t- butyldimethylsilyloxy]ethyl}-l-aryl-2-azetidinone of general formula (II) (here-in-after, abbreviated as "aryl-4-acetoxyazetidinone". The protective group for β -lactam ring, the aryl group, is then selectively deprotected by ozonolysis to give 4-acetoxyazetidinone represented by general formula (I).

Scheme 3

step 3

In the formula, R ¹ , R ² , R ³ and OAc arc defined as above.

Now, the process according to the present invention is described step by step, in more detail.

When an epoxyamide of general formula (V) is treated with a strong base of alkali metal type, a C3-C4 bond formation (azetidinone formation) occurs stereoselectiveiy to give an alkali metal salt compound. To the alkali metal salt compound, without further purification, a trialkylhalosilane is added in situ, to synthesize a silyl ester azetidinone of general formula (IV). Step 1 and Step 2 are a process performed in a one-pot reaction. Though the azetidinone formation and hydroxy group protecting reaction are reported by Shiozaki as mentioned above, the present invention provides a more economic and simple process as the reactions are carried out in an one-pot reaction in the present invention, while the reactions have been performed in two steps in the known process. Thus, the overall yield is greatly increased in the invention. The alkali metallic strong bases which may be used in the step include lower alkyl lithiums such as methyl lithium and n-butyl lithium; alkali metal alkoxides such as lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; alkali metal amides such as lithium amide, sodium amide, lithium hexamethyldisilazide, lithium diisopropylamide and lithium dicyclohexylamide; alkali metal hydride such as sodium hydride and potassium hydride; and mixtures of alkali metal and DMSO such as sodium Dimsylate and lithium Dimsylate. Preferably, lithium hexamethyldisilazide in an amount of 1 to 3 equivalents is used. The reaction temperature is selected between -30 ^° C to room temperature in order to inhibit the production of diastereomers as far as possible. As a reaction solvent, dichloromethane or tetrahydrofuran may be preferably used. The step 2 is performed in situ by adding trialkylhalosilane derivative to the product of step 1 , to obtain the silyl ester azetidinone of

general formula (IV). Trialkylhalosilane derivatives are fully described in the literature ["Protective Groups in Organic Synthesis", 2nd ed.; John Wiley & Sons: New York, USA( 1991 )]. In particular, t- butyldimethylchlorosilane was preferably used so as to minimize the side reactions and to improve the yield and stability of the product. According to the reaction, the epoxyamide (V) is treated with a strong base such as lithium amide or the like to produce an anion at a -carbon position adjacent to the ester group, and the anion attacks C2-position of the epoxide by SN2 mode to form an azetidinone ring. In such a reaction, diastereomers are usually produced, however, the inventors confirmed by using 300 MHz 'H-NMR and high performance liquid chromatography, that only the desirable stereoisomer having trans configuration is produced according to the present invention.

In Step 3, the silyl ester azetidinone of general formula (IV) is treated by means of saponifi cation in the presence of alkali metal hydroxide and then acidification to obtain the 4-carboxyazetidinone of general formula (III) as free acid form. As the alkali metal hydroxide, sodium hydroxide or potassium hydroxide (KOH) may be used. It is preferable to use sodium hydroxide in an amount of 1 to 2 equivalents, with an economic viewpoint. The reaction temperature may be selected between room temperature and reflux temperature unless there occurs particular side reactions. While, as a polar organic solvent, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, methanol, ethanol, isopropanol or butanol may be used, most effective result was obtained by using methanol as a solvent. When the hydrolysis is performed by the use of alkali metal hydroxide, the product is obtained as a metallic salt form, which, without separation from the reaction mixture, is acidified with hydrochloric acid or sulfuric acid to obtain 4- carboxyazetidinone (III) as a desired free acid form. The Step 4 is a process to introduce an acetoxy group at C4- position by a stereoselective acetoxylation of the 4-carboxyazetidinone of general formula (III). As an oxidant which can oxidize the free acid at

C4-position and introduce an acetoxy group thereto, lead oxide (Pb3θ ), lead tetraacetate [Pb(OAc)4], mercuric acetate [Hg(OAc)2], cupric acetate [Cu(OAc)2] or thallium acetate [Tl(OAc). ] may be used. Better results have been obtained when using lead oxide in an amount of 1 to 3 equivalents in the presence of acetic acid, or lead tetraacetate of 1 to 3 equivalents. As a reaction solvent, acetonitrile, dimethylformamide, methanol, dimethyl sulfoxide, acetic acid or acetic anhydride may be employed. Among these, acetic acid may be preferably used alone or with dimethylformamide. As the reaction is exothermic, the rapid elevation of the temperature may cause side-reactions, thereby it is essential to add lead oxide or lead tetraacetate in properly small portions. Unless a certain side reaction occurs, the reaction is preferably performed at a temperature range between 0 ^° C and 80 ^° C .

The Step 5 is to effectively remove the aryl group, particularly p- methoxyphenyl group among the protective groups, in order to prepare 4- acetoxyazetidinone of general formula (I). In other words, a variety of oxidation processes are applied on the aryl-4-azetidinone of general formula (II) to remove aryl group so as to obtain desired 4- acetoxyazetidinone (I). The oxidation process included in the step is a known technique from the literature written by Green et al. ["Protective Groups in Organic Synthesis", 2nd ed.; John Wiley & Sons: New York, USA( 1991 )] on page 400. The conventional deprotecting techniques described in the literature may be usually applied. As the protective groups are usually removed in the final reactive step, they are sometimes needless from the viewpoint of the overall synthetic steps. However, they must be considered carefully because they can avoid the possibility of side reactions to increase the total reaction yield. The properties of the protective group to be used depend upon the properties of the functional groups thereof. As the common knowledge concerning the protective groups is essential to any organic chemists, it is not necessary to explain or define protective groups and deprotection thereof in the specification. However, described herein is the deprotection process, in

connection with Step 5, in which the aryl group, particularly p- methoxyphenyl group (a protective group for β -lactam ring) from aryl- 4-acetoxyazetidinone of general formula (II) is removed. The removal of p-methoxyphenyl group, the protective group for β -lactam, in Step 5 is mainly performed through an oxidation reaction by generating oxygen. As an oxidant, ceric ammonium nitrate, potassium permanganate, sodium bichromate, 2,3-dichloro-5,6- dicyano- l ,4-benzoquinone (DDQ) or ozone may be used. Good results could be also obtained by modifying the electrochemical oxidation developed by the present inventors et al. Preferable oxidants used in Step 5 include ceric ammonium nitrate or ozone. Preferable solvents include dioxane, tetrahydrofuran, hexane, ethyl acetate, acetonitrile, dimethyl formamide, dichloromethane, chloroform, carbon tetrachloride, acetic acid, methanol and ethanol. In case of using ceric ammonium nitrate as an oxidant, best result could be obtained by using a mixed solvent of acetonitrile and water. In case of using ozone as an oxidant, the reaction was preferably performed by using methanol as a single solvent, at a relatively low temperature at -40 to 10 ^° C . The removal of p-methoxyphenyl group by using electrochemical oxidation has been already known [Abramson et al., US Patent No. 4834846]. However, according to the present invention, the known technique has been enhanced by applying an electrochemical oxidation to the azetidinone compound (II) containing acetoxy group at C4-position by using an amorphous carbon electrode, which is available at a low cost, to give high yield of 4-acetoxyazetidinone (I). All work-up procedures of the steps according to the present invention are carried out by using conventional procedures. If necessary, the product can be purified by recrystallization or column chromatography to obtain pure reaction product for analysis. The progress of the reactions of the present invention could be checked by thin layer chromatography (TLC). For more precise separation and determination of proportions, high performance liquid chromatography

(HPLC) was employed. The resultant product of each step was identified by nuclear magnetic resonance (NMR) spectrum, mass analysis, or the like. Optical rotation was measured for the compounds having stereochemical structure. The characteristic aspects and advantages of the present invention is summarized as follows : First, it is economically beneficial because the objective compound, 4-acetoxyazetidinone of general formula (I) is stereoselectiveiy obtained by a short reactive steps (5 steps) starting from compound of general formula (V) synthesized from L-threonine which can be abundantly supplied from the nature : Second, the overall yield has been increased by performing the C. -Gt azetidinone ring formation under various stereoselective reaction conditions to find the best reaction condition out : Third, the environmental pollution resulted from the prior art can be avoided by performing the removal of p-methoxyphenyl group, a protective group for azetidinone ring, by the use of ozone, and the acetoxylation using electrochemical oxidation reaction also is an advanced synthetic technique to minimize the pollution, although this reaction can be carried out with known oxidation agent. Thus, the present invention provides economic advantages as well as high synthetic yield.

Best Mode for Carrying out the Invention

The present invention is described in more detail with reference to the Examples. It should be noted that the scope of the present invention is not restricted to those Examples.

Example V. (3S,4S)-3-{[(rR)-r-t-Butyldimethylsilyioxyjethyl}-4- ethoxycar bonyI-l-p-methoxyphenyI-2-azetidinone

Lithium amide (2.5 g, 0.1 mol) was suspended in THF (40 ml) under nitrogen atmosphere, and hexamethyldisilazane (12.5 ml, 0.15 mol) was added thereto. After heating under reflux for 3 hours, the reaction mixture was chilled to -10 ^° C . Epoxyamide (V) (20.5 g, 0.07 mol) was

dissolved in THF (200 ml) and the solution chilled to -30 ^° C . The Lithium hexamethyldisilazide solution prepared above was added thereto under nitrogen atmosphere, and the reaction mixture was stirred for 30 minutes at the same temperature. When the starting material, epoxyamide (V), was completely disappeared, t- butyldimethylchlorosilane (15 g, 0.1 mol) was slowly added to the mixture as maintaining the temperature at -10 ^° C , and the reaction temperature was slowly raised to room temperature. The mixture was stirred for 3 hours at the same temperature. After the completion of the reaction, the reaction was quenched by using dilute hydrochloric acid. The reaction mixture was then diluted with dichloromethane (500 ml). The separated organic layer was dried over an appropriate amount of anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give crude title compound. The crude product was purified by a short column chromatography (eluent: EA/Hex = 1/7) to obtain pure title compound (20.8 g, 73%) as pale yellow oil. 'H-NMR(300MHz, CDCh) δ ; 0.03(6H, d, J=16Hz), 0.74(9H, s), 1.24 - 1.28(6H, m), 3.27(1 H, t, J=2.7Hz), 3.76(3H, s), 4.21(2H, m), 2.33(1H, m), 4.54( 1H, d, J=2.4Hz), 6.83(2H, d, J=10Hz), 7.22(2H, d, J=10Hz)ppm.

Example 2^ (3S,4S)-3-{[(l ^, R)-l ^, -t-Butyldimethylsilyloxy]ethyl}-4- carboxy-l-p-methoxyphenyl-2-azetidinone

To a solution of silyl ester azetidinone (IV) (20 g, 49 mmol) in methanol (150 ml), lN-NaOH (73.5 ml, 73.5 mmol) was added dropwise, and the mixture stirred at room temperature for 10 hours. After completion of the saponification, the reaction solvent was concentrated by 70% of the overall volume. After adding water (200 ml) to dilute the mixture, the resultant mixture was washed by ethyl acetate (500 ml). To the separated water layer, water (200 ml) and acetone (50 ml) was added to dilute the mixture again, and the resulting mixture was acidified (pH

π

3.5) with 1N-HC1, to give crystalline solid. After filtering under reduced pressure and drying, the title compound ( 17.8 g, 96%) was obtained as pale yellow powder. The compound thus obtained is relatively pure, so that it may be used in the next step without further purification. In order to obtain sample for analysis, it was recrystallized from methanol to give pure title compound. 'H-NMR(300MHz, CDCb) δ ; 0.03(6H, d, J=l 8Hz), 0.73(9H, s), 1.28(3H, d, J=6.3Hz), 3.39(1 H, t, J=2.5Hz), 3.78(3H, s), 4.38(1H, m), 63(1H, d, J=2.5Hz), 6.87(2H, d, J=10Hz), 7.26(2H, d, J-10Hz)ppm.

Example 3: (3R,4R)-4-Acetoxy-3-{((l'R) -l'-t-butyldimethyl silyloxy]ethyl}-l-p-methoxyphenyl-2-azetidinone (Method A) To a mixed solution of dimethylformamide and acetic acid (3/1 , 300 ml), 4-carboxyazetidinone (III) (15 g, 39.5 mmol) was added. Tetravalent lead acetate (24.5 g, 55.3 mmol) was then added thereto, and the reaction mixture was stirred for 2 hours while maintaining the reaction temperature at 60 ^° C . To the reaction mixture, a mixed solution of ethyl acetate and n-hexane (1/1 , 800 ml), and brine (500 ml) were added. After stirring 30 minutes at room temperature, insoluble materials were filtered off. The separated organic layer was washed with brine (400 ml), 10% sodium bicarbonate solution (400 ml) and brine (400 ml), sequentially, and concentrated under reduced pressure. The residue was purified by a short column chromatography (eluent: EA/Hex = 1/6) to obtain pure title compound (14.9 g, 96%) as brown oil. Η-NMR(300MHz, CDCh) δ ; 0.03(6H, d, J=18Hz), 0.75(9H, s), 1.32(3H, t, J=6.37Hz), 2.13(3H, s), 3.20(1H, dd, J=0.7 and 2.8Hz), 2.79(3H, s), 4.29(1H, m), 6.64(1H, s), 6.87(2H, d, J=10Hz), 7.33(2H, d, J=10Hz)ppm.

(Method B)

4-Carboxyazetidinone (III) (15 g, 39.5 mmol) was dissolved in glacial acetic acid (100 ml). To the solution, Pb3θ4 (29.4 g, 43 mmol) was added in small portions at the reaction temperature of 60 °C . Because the reaction is the exothermic, the reaction temperature slowly rose. After the addition of Pb3θ was completed, the reaction mixture was vigorously stirred for 30 minutes. When the reaction was completed, a small amount of ethylene glycol was added, and the solvent removed by evaporation under reduced pressure. The reaction mixture was worked-up as the procedure described in (Method A) to obtain the title compound (14.4 g, 94%).

Example 4: (3R,4R)-4-Acetoxy-3-{[(l'R)-r t-butyldimethyI silyloxy] ethy l}-2-azetidinone (Method A)

Aryl-4-acetoxyazetidinone (II) (26 g, 66 mmol) was dissolved in methanol (500 ml). The internal temperature of the reactor was lowered to -20 ^° C , and the reaction was performed for 3 hours with slowly incorporating ozone. After the reaction was completed, 10% solution of Na2S2θ3 and thiourea were added sequentially, and the resultant mixture was vigorously stirred for 30 minutes at room temperature. Then, the reaction mixture was concentrated to have a volume of 1/3 of the initial volume of the mixture. The concentrate was chilled to -10 ^° C to produce white crystalline powder. The powder was filtered, dried and recrystallized from n-hexane to obtain pure 4-acetoxyazetidinone (I) ( 18.1 1 g, 85%) as white crystals.

Η-NMR(300MHz, CDCh) δ ; 0.01(6H, s), 0.80(9H, s),

1.19(3H, d, J=6.4Hz), 2.04(3H, s), 3.12(1H, dd, J=3.4 and 1.3Hz), 4.16(1H, m), 5.77(1H, s), 6.63(amide-H, brs)ppm. [ ff ]D = + 51.8 ° ( c=1.0, CHCh )

(Method B)

To a 0.1 M solution (45 ml) of lithium perchlorate in mixed solvent of acetonitrile and distilled water ( 10: 1 ), aryl-4-acetoxyazetidinone (II) (349 mg, 1 mmol) was added and dissolved. The mixture was poured in a non-dividable electrolysis vessel with connecting an amorphous carbon anode and an cathode plate, and a Ag/Ag" reference electrode to a Potentiostat (EG & G 273). Under 1.8 V constant voltage, the mixture was electrolysed until all the starting material disappeared. After removing the organic solvent by evaporation under reduced pressure, the residue was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium sulfite solution and saturated brine sequentially, and evaporated under reduced pressure. The residue was purified by a short column chromatography (eluent: EA/Hex = 1/4) to obtain pure 4- acetoxyazetidinone (1) (220 mg, 76%) as white crystals.

(Method C)

Aryl-4-acetoxyazetidinone (II) (5 g, 12.7 mmol) was dissolved in acetonitrile (100 ml). After chilling the solution to -15 ^° C , a solution of ceric ammonium nitrate (34.8 g, 63.5 mmol) dissolved in water (150 ml) was added dropwise. The resultant mixture was stirred for 30 minutes. After the completion of the reaction, the mixture was extracted from ethyl acetate (300 ml), and the organic layer was washed with each 200 ml of water, 10% Na2Sθ3 solution, 10% NaHCθ3 solution and saturated brine, sequentially, and then concentrated under reduced pressure. The obtained brown residue was recrystallized from n-hexane to give 4- acetoxyazetidinone (I) (3.1 g, 89%) as white crystalline powder.