WO2009064078A1

WO2009064078A1 - Method of preparing intermediates of penem antibiotics

Info

Publication number: WO2009064078A1
Application number: PCT/KR2008/006182
Authority: WO
Inventors: Choong Eui Song; Sang Seop Han
Original assignee: Sungkyunkwan University Foundation For Corporate Collaboration
Priority date: 2007-11-12
Filing date: 2008-10-20
Publication date: 2009-05-22

Abstract

The present invention relates to a method of preparing bicyclic keto esters, which are intermediates for carbapenem-based antibiotics. The method of preparing carbapenem-based antibiotic intermediates according to the present invention has not only the fast reaction rate using co-catalysts and specific reaction solvents which may be allowed to have high activity of rhodium catalysts, but also reduces the amount of expensive rhodium catalysts. Therefore, the present invention is very economical and useful, in industrial aspects.

Description

METHOD OF PREPARING INTERMEDIATES OF

PENEM ANTIBIOTICS

Technical Field

[1] The present invention relates to a method of preparing bicyclic keto esters, which are intermediates for carbapenem-based antibiotics. Background Art

[2] It has been known a reaction in which a bicyclic keto ester compound of Formula 1 is prepared from a diazo compound of Formula 2 below using a rhodium catalyst of Formula 3 below.

[3] [Formula 1]

[5] [Formula 2]

[9] wherein, [10] R and R represent each independently hydrogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynly group, an optionally substituted aryl group, an optionally substituted heterocyclyl group, or - CH(OR )R ,

3 4

[11] where R represents hydrogen, an acyl group, or an alcohol protecting groups, and

[12] R represents an optionally substituted alkyl group, an optionally substituted alkenyl

4 group, an optionally substituted aryl group, or an optionally substituted heterocyclyl group,

[13] R represents a carboxylic acid protecting group,

[14] X represents oxygen atom, or nitrogen atom substituted with an alkyl group, and

[15] R , R , and R represent each independently hydrogen atom or an optionally

5 6 7 substituted alkyl group.

[16] Generally, it is known that when said bicylclic keto ester compound of Formula 1 is prepared by a N-H insertion reaction from said diazo compound of Formula 2, using said rhodium catalyst of Formula 3, which forms a rhodium carbenoid with releasing a diazo group, it can be synthesized in a solvent such as ethyl acetate, benzene, toluene, and tetrahydrofuran (THF) using at least 1 mol% of dirhodium (II) acetate (diazo compound/rhodium catalyst = 100:1 above, in mol ratio). [D. G. Melillo, I. Shinkai, Tetrahedron lett, 1980, 21, 2783; C. P. Mak, C. Mayerl, Tetrahedron Lett, 1983, 24, 347; C. Wenteup, H. W. winter, J. Am. Chem. Soc, 1980, 102, 6161; R. W. Ratcliffe, T. N. Salzmann, Tetrahedron Lett. 1980, 21, 31]

[17] Furthermore, in US Patent No. 4,287,123, a compound, wherein R is a para- nitrobenzyl group, and R is hydrogen, of said compounds of Formula 2 was stirred in toluene as an organic solvent at 80 to 85⁰C for 2.5 hours, using 2.55 mol% of dirhodium (II) tetraacetate [Rh (CH COO) ] (a compound of Formula 2/rhodium

2 3 4 catalyst = 39: 1), to prepare a compound of Formula 1, wherein R is a para-nitrobenzyl group, and R is hydrogen. However, such methods use expensive rhodium catalysts in a large quantity. Thus, it is difficult to industrially apply them.

Disclosure of Invention

Technical Problem [18] In preparing bicyclic keto ester compounds from diazo compounds using a rhodium catalyst, one object of the present invention is to provide a method of preparing the desired compounds economically by improving activity of the rhodium catalyst and outstandingly decreasing its amount. [19] In addition, the other object of the present invention is to provide an improved method of preparing penem intermediates which may be in various optical isomers due to presence of asymmetric carbon atoms in diazo compounds and bicyclic keto ester compounds. Technical Solution

[20] The present invention provides a method of preparing a compound of the following Formula 1 or isomers thereof comprising subjecting a compound of the following Formula 2 to a ring closure reaction, in the presence of a major catalyst of the following Formula 3; and one or more co-catalysts selected from the group consisting of a copper-containing compound and a zinc-containing compound.

[21] [Formula 1]

[23] [Formula 2]

[27] wherein [28] R and R represent each independently hydrogen, an optionally substituted alkyl

1 2 group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted heterocyclyl group, or - CH(OR )R ,

3 4

[29] where R represents hydrogen, an acyl group, or an alcohol protecting group, and [30] R represents an optionally substituted alkyl group, an optionally substituted alkenyl

[31] R represents a carboxylic acid protecting group, [32] X represents oxygen atom, or nitrogen atom substituted with an alkyl group, and [33] R , R , and R represent each independently hydrogen atom or an optionally

5 6 7 substituted alkyl group.

[34] In addition, the present invention provides a method of preparing a compound of the following Formula 1 or isomers thereof from a compound of the following Formula 2 in the presence of a rhodium catalyst of the following Formula 3 and a solvent of the following Formula 4.

[35] [Formula 1]

[37] [Formula 2]

[43] wherein [44] R and R represent each independently hydrogen, an optionally substituted alkyl

3 4

[45] where R represents hydrogen, an acyl group, or an alcohol protecting group, and

[46] R represents an optionally substituted alkyl group, an optionally substituted alkenyl

[47] R represents a carboxylic acid protecting group,

[48] X represents oxygen atom, or nitrogen atom substituted with an alkyl group,

[49] R , R , and R represent each independently hydrogen atom or an optionally

5 6 7 substituted alkyl group, and [50] R represents a C alkyl group.

8 3-6

Advantageous Effects

[51] The present invention has effects which may reduce remarkably not only the amount of the rhodium catalyst by using a copper or zinc catalyst as a co-catalyst, in preparing penem intermediates, but also prepare very economically the desired compounds by increasing efficiency of the rhodium catalyst to improve the reaction rate.

[52] In addition, the present invention has an advantage that rhodium residues can be minimized in the product, in preparing penem-based antibiotic intermediates of Formula 1 which are important in pharmaceutical field. Best Mode for Carrying out the Invention

[53] The present invention relates to a method of preparing a compound of the following

Formula 1 or isomers thereof comprising subjecting a compound of the following Formula 2 to a ring closure reaction, in the presence of a major catalyst of the following Formula 3; and one or more co-catalysts selected from the group consisting of a copper-containing compound and a zinc-containing compound.

[54] [Formula 1]

[56] [Formula 2]

[60] wherein [61] R and R represent each independently hydrogen, an optionally substituted alkyl

3 4

[62] where R represents hydrogen, an acyl group, or an alcohol protecting group, and [63] R represents an optionally substituted alkyl group, an optionally substituted alkenyl

[64] R represents a carboxylic acid protecting group, [65] X represents oxygen atom, or nitrogen atom substituted with an alkyl group, and [66] R , R , and R represent each independently hydrogen atom or an optionally

5 6 7 substituted alkyl group.

[67] Definitions of terms used herein are as follows. [68] The term "alkyl" used herein refers to a radical of a saturated aliphatic group including a straight alkyl group, a branched alkyl group, a cycloalkyl (alicyclic) group, a cycloalkyl group substituted with alkyl and an alkyl group substituted with cycloalkyl. In the preferred embodiment, the straight or branched alkyl has 30 or less carbon atoms (for example, C -C for the straight chain, C -C for the branched

1 30 3 30 chain), and more preferably, 20 or less carbon atoms as its backbone, as long as the number of carbon is not particularly restricted. Similarly, the preferred cycloalkyl has 4 to 10 carbon atoms, and more preferably 5, 6 or 7 carbon atoms in the ring structure.

[69] Moreover, the term, alkyl, used over the specification and claims is intended to include both "unsubstituted alkyl" and "substituted alkyl," and the latter refers to an alkyl residue having substituents which substitute hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, halogen, hydroxyl, carbonyl, alkoxyl, esters, phosphoryl, amine, amide, imine, thiol, thioether, thioester, sulfonyl, amino, nitro or organic metal residues. It will be appreciated by one skilled in this field that if appropriate, the residues substituted in hydrocarbon chains can be substituted on themselves. For example, substituents of the substituted alkyl may include ether, thioether, selenoether, carbonyl (including ketone, aldehyde, carboxylate and ester), -CF , -CN, and the like, as well as amine, imine, amide, phosphoryl (including phosphonate and phosphine), sulfonyl (including sulfate and sulfonate) and silyl groups, having substituted and unsubstituted types. Cycloalkyl may be further substituted with alkyl, alkenyl, alkoxy, thioalkyl, aminoalkyl, alkyl substituted with carbonyl, CF , CN, and the like.

[70] The terms, "alkenyl" and "alkynyl," refer to unsaturated aliphatic groups having length and possible substitutions similar to alkyl as described above, but contain one or more double and triple carbon-carbon bonds, respectively.

[71] As long as the number of carbon is not otherwise stated, the term, "lower alkyl" used herein refers to the alkyl group as defined above, but has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 4 carbon atoms, in its backbone structure. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

[72] As used herein, the term, "amino" refers to -NH ; the term, "nitro" -NO ; the term,

"halogen" -F, -Cl, -Br or -I; the term, "thiol" -SH; the term, "hydroxyl" -OH; the term, "sulfonyl" -SO -; the term, "organic metal" metal atoms (for example, mercury, zinc, lead, magnesium or lithium) or metalloid (for example, silicon, arsenic or selenium) directly bonded to carbon atom such as a diphenylmethylsilyl group, and the term, "acyl" -C(O)R, where R refers to alkyl or aryl.

[73] The term, "alkoxy" used herein refers to the defined alkyl group above bonded to oxygen radical. A representative alkoxyl group includes methoxy, ethoxy, propoxy, tert-butoxy, and the like. The "ether" is two hydrocarbons covalently boned by oxygen. Therefore, a substituent of alkyl which makes alkyl into ether is the same as or similar to alkoxyl which may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, - 0-(CH )m-R (wherein, m and R are the same as described above).

2 8 8

[74] The term, "aryl" includes a single or fused cyclic aromatic group having 4 to 10 members which may comprise 0 to 4 hetero atoms, such as benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine. Said aryl group having hetero atoms in the ring structure may be known as "aryl heterocycle." One or more ring positions in the aromatic ring may be substituted with substituents as described above, such as halogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, -CF , or -CN.

[75] The term, "heterocycle" or "heterocyclic group" used herein refers to a ring structure having 4 to 10 members, and more preferably 5 to 7 members, and said ring structure includes 1 to 4 hetero atoms. The heterocyclic group includes pyrrolidine, ojolane, thiolane, imidazole, oxazole, piperidine, piperazine, morpholine. One or more positions in the heterocyclic ring may be substituted with substituents as described above, such as halogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, -CF , or -CN.

[76] The term, "protecting group" used herein refers to a temporary substituent which protects a potentially reactable functional group from the undesired chemical transformation. Examples of such protecting group include esters of carboxylic acids, silyl esters of alcohols, acetals of aldehydes and ketals of ketones. The chemical field of protecting groups has been viewed in a literature (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd Ed.; Wiley: New York, 1991).

[77] The term, "hetero atom" refers to any element other than carbon or hydrogen. The preferred hetero atoms are nitrogen, oxygen, sulfur, phosphorus and selenium.

[78] Definitions of the preferred substituents in said Formulas 1 to 3 are described below, without restricting the scope of the present invention to these, and may be also applied, in the same manner, to various penem-based intermediates which are known in this field.

[79] In said Formulas 1 to 3, R represents -CH(OR )R , where R represents hydrogen; an

2 3 4 3 acyl group; or a silyl group substituted with one or more substituents selected from the group consisting of a C alkyl group, a C alkenyl group, and an acyl group having 5

1-6 2-6 to 10 cyclic members, and [80] R represents, preferably, a C alkyl group, R represents, preferably, a benzyl group

4 1-6 substituted with a C alkenyl group, nitro, a C alkoxy group or a C alkyl group, R ,

2-6 1-6 1-6 5

R , and R represents, preferably, each independently hydrogen atom or C alkyl

6 7 1-20 group unsubstituted or substituted with halogen atoms,X represents, preferably, oxygen atom, and R , R , and R represent hydrogen atom; or preferably, R and R

5 6 7 5 7 represent hydrogen atom, and R represents a C alkyl group.

6 1-12

[81] In addition, said copper-containing compound includes one or more selected from the group consisting of a copper (0) compound, a monovalent copper [Cu(I)] compound and a divalent copper [Cu(II)] compound, and specifically, may use copper powder, CuCl, CuBr, Cu O, Cu(CF SO ), Cu(acac) , CuO, CuBr , Cu(CF SO ) , CuSO

2 3 3 2 2 3 3 2

, or CuCl , and the like, without limitation.

4 2

[82] Said zinc-containing compound includes one or more selected from the group consisting of a zinc (0) compound and a divalent zinc [Zn(II)] compound, and more specifically, may use zinc powder, Zn(acac) , ZnBr , Zn(CF SO ) , ZnSO , or ZnCl ,

2 2 3 3 2 4 2 and the like, without limitation.

[83] Said reaction solvents are not particularly limited, but on using one or more solvents selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and tert-butyl acetate, the amount of rhodium catalysts may be further reduced.

[84] In addition, on using a mixed solvent of ethyl acetate, and one or more selected from the group consisting of n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and tert-butyl acetate among said reaction solvents, the amount of rhodium catalysts may be not only reduced, but also side reactions may be inhibited.

[85] It is advantageous that isomers of compounds of Formulas 1 and 2 in said reaction are compounds of Formulas Ia and 2a, respectively.

[86] [Formula Ia]

[88] [Formula 2a]

[90] wherein [91] R represents hydrogen, an acyl group, or an alcohol protecting group, and R represents a carboxylic acid protecting group.

[92] In addition, it is advantageous that isomers of compounds of Formulas 1 and 2 in said reaction are compounds of Formulas Ib and 2b, respectively.

[93] [Formula Ib]

[95] [Formula 2b]

[97] wherein [98] R represents a C alkyl group, and

1 1-6 [99] R represents a carboxylic acid protecting group. [100] The present invention also relates to a method of preparing a compound of the following Formula 1 or isomers thereof from a compound of the following Formula 2 in the presence of a rhodium catalyst of the following Formula 3 and a solvent of the following Formula 4.

[101] [Formula 1]

[103] [Formula 2]

[109] wherein [HO] R and R represent each independently hydrogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted heterocyclyl group, or - CH(OR )R ,

3 4

[111] where R represents hydrogen, an acyl group, or an alcohol protecting group, and [112] R represents an optionally substituted alkyl group, an optionally substituted alkenyl

[113] R represents a carboxylic acid protecting group, [114] X represents oxygen atom, or nitrogen atom substituted with an alkyl group, [115] R , R , and R represent each independently hydrogen atom or an optionally

5 6 7 substituted alkyl group, and [116] R represents a C alkyl group.

8 3-6

[117] In said reaction, one or more selected from the group consisting of n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate and tert-butyl acetate are preferably used as a solvent.

[118] More preferably, a mixed solvent of ethyl acetate, and one or more selected from the group consisting of n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and tert-butyl acetate is used. Preferred substituents of Formulas 1 to 3 are defined as above.

[119] In accordance with the present invention, the major catalyst of Formula 3 may be used in an amount of 0.1 mol% (compound of Formula 2: compound of Formula 3 = 1000: 1, in mole ratio) or less, preferably 0.05 mol% or less, more preferably 0.03 mol% or less, and most preferably from 0.001 mol% or more to 0.02 mol% or less, based on the compound of Formula 2.

[120] In addition, the amount of the co-catalyst is not particularly limited, but it may be used in an amount of 0.1 mol% (compound of Formula 2: co-catalyst = 1000: 1, in mole ratio) or more, preferably 0.2 mol% or more, and more preferably from 0.3 mol% or more to about 30 mol% or less, based on the compound of Formula 2.

[121] To study a method for minimizing the amount of the rhodium catalyst in said ring closure reaction, a reaction for preparing compounds of Formulas Ia and Ib from compounds of Formulas 2a and 2b via the following reaction schemes 1-1 and 1-2 has been selected and researched herein The present invention may be applied, via representative reaction schemes 1-1 and 1-2 below, to a method of preparing compounds of Formula 1 from said general compounds of Formula 2 as well as the method of preparing compounds of Formulas Ia and Ib.

[ 122] [Reaction Scheme 1 - 1 ]

[124] [Formula 2a] [Formula Ia] [125] In said Formula Ia, Formula 2a and Reaction Scheme 1-1, R is a benzyl group substituted with C alkenyl, or para-substituted with a nitro group, a C alkoxy group

1-4 or a C alkyl group as a carboxylic acid protecting group.

1-6

[126] [Reaction Scheme 1-2]

[128] [Formula 2b] [Formula Ib] [129] In said Formula Ib, Formula 2b and Reaction Scheme 1-2, R is a benzyl group substituted with C alkenyl, or para-substituted with a nitro group, a C alkoxy group

1-4 or a C alkyl group as a carboxylic acid protecting group.

1-6

[130] [Formula 3 a]

[132] wherein, R , R , R are hydrogen atom, a C ~C alkyl group, or an alkyl group substituted with fluorine.

[133] As a method for minimizing the amount of the rhodium catalyst of Formula 3, a reaction of Reaction Scheme 1-1 herein has been carried out. That is, the reaction of Reaction Scheme 1-1 has beens carried out from the compound of Formula 2a, wherein R is para-nitrobenzyl, in a reaction solvent of ethyl acetate, n-propyl acetate, i- propyl acetate or n-butyl acetate in the presence of each of i) 0.01 mol% (Formula 2a/rhodium catalyst = 10000:1) of dirhodium (II) tetraacetate [Rh (CH COO) ], ii) 0.5

2 3 4 mol% of Cu-powder having copper (0); and iii) 0.01 mol% (Formula 2a/rhodium catalyst. 10000:1) of dirhodium (II) tetraacetate [Rh (CH COO) ] and 0.5 mol% of Cu-

2 3 4 powder having copper (0) (particle size: 1-5 μm) as a catalyst, with stirring under heat and reflux, and the results are arranged in the following Table 1. [134] As shown in the results of Table 1 below, it has been identified that the reaction is completed in case of using a rhodium catalyst and a copper catalyst together, it does not almost proceed in case of using only a copper catalyst, and it proceeds by about 20% only, in case of using only a rhodium catalyst. Such results prove that on using the rhodium catalyst and the copper catalyst at the same time, the observed catalyst activity increases remarkably. That is, in light of the above results, the preferred method in preparing the compound of Formula 1 via Reaction Scheme 1 is to use the rhodium catalyst of Formula 3 and the copper catalyst at the same time.

[135] In addition, as seen in the results of Table 1, the inventors have found that the solvents affect highly reaction rate and purity of products. On carrying out the reaction of Reaction Scheme 1-1 by using the compound of Formula 2a, the rhodium catalyst in 10,000: 1 and 0.5 mol% of copper powder, it has been found that while the time of completing the reaction in a solvent of ethyl acetate is 3 hours, 40 minutes in n-propy acetate, 2 hours in isopropyl acetate using the rhodium catalyst in the same amount, and the reaction in n-butyl acetate is completed in only 40 minutes, but the side reaction proceeds largely.

[136] Therefore, all general organic solvents, such as benzene, toluene, and tetrahydrofuran, having a boiling point of 50 ~ 13O⁰C, are possible as solvents for Reaction Scheme 1-1, but it is preferably methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and the like, and more preferably, ethyl acetate and n-propyl acetate.

[137] In addition, the inventors have identified whether the synergistic effect of catalyst activity is a phenomenon to be generally observed, even though other copper compounds, such as monovalent or divalent copper compounds, except for copper (0) are used. In preparing compounds of Formula Ia, the reaction of Reaction Scheme 1-1 has been carried out by using propyl acetate as a reaction solvent, and 0.5 mol% of, monovalent copper, CuCl, CuBr, Cu O, Cu(CF SO ), or of, divalent copper, Cu(acac) ,

2 3 3 2

CuO, CuSO , CuBr , Cu(CF SO ) , and the like and 0.01 mol% (Formula 2a/rhodium

4 2 3 3 2 catalyst = 10000:1) of dirhodium (II) tetraacetate [Rh (CH COO) ] at the same time.

2 3 4

As a result, as seen in the results of Table 2 below, all the reactions have been completed. [138] Therefore, it has been identified that copper (0), monovalent, and divalent copper compounds may serve as a copper co-catalyst. However, it is preferred to use copper powder having copper (0), since it is relatively inexpensive, easily removable through filtering process after reaction and reusable. [139] In addition, to identify whether the synergistic effect of catalyst activity on using the copper co-catalyst is a phenomenon to be generally observed, even though other rhodium catalysts of Formula 3 are used, the reaction of Reaction Scheme 1-1 has been carried out by using propyl acetate as a reaction solvent, and 0.01 mol% of dirhodium (II) perfluorotetradecanoate [Rh [CO (CF ) CF ] } or dirhodium (II) octanoate [Rh

2 2 2 12 3 4 2

[CO (CH ) CH )] } and 0.5 mol% of copper powder at the same time in preparing compounds of Formula Ia. As a result, as shown in Table 3 below, it has been identified that both reactions of two cases are completed.

[140] Therefore, it has been identified that when the copper co-catalyst is used, the reaction rate is highly enhanced, regardless of the structures of rhodium catalysts of Formula 3. While any rhodium catalyst of Formula 3 in preparing compounds of Formula 1 is unrelated herein, the most inexpensive dirhodium (II) tetraacetate [Rh (CH COO) ] is

2 3 4 more preferably used.

[141] In addition, the reaction of Reaction Scheme 1 - 1 in a reaction solvent of propyl acetate has been carried out herein by using 0.5 mol% (Formula 2a/copper catalyst, 200: 1) of copper powder which is industrially applied with more ease, with decreasing the amount of rhodium (II) acetate. As a result, as shown in Table 4, by using the copper co-catalyst, the amount of rhodium could be reduced to 0.002 mol%, over 0.1 ~ 1 mol% (prior art). On carrying out the reaction of Reaction Scheme 1-1 by using 0.0022 mol% of rhodium (II) acetate as a rhodium catalyst, the time of completing the reaction is 4.5 hours. Thus, by using the copper catalyst together in Reaction Scheme 1, the amount of rhodium catalyst of Formula 3 could be remarkably reduced.

[142] In addition, to identify whether said synergistic effect of catalyst activity is a phenomenon to be generally observed regardless of structures of Formula 1 in preparing compounds of Formula 1 from compounds of Formula 2, the reaction of Reaction Scheme 1-2 herein has been further carried out. On proceeding the reaction of the compound, wherein R in Reaction Scheme 1-2 is a para-nitrobenzyl group, by using propyl acetate as a reaction solvent, and 0.5 mol% of copper powder having copper (0) and 0.01 mol% of dirhodium (II) tetraacetate [Rh (CH COO) ] at the same

2 3 4 time, it has been identified that the reaction is completed in only 1 hour, and the reaction of the compound, wherein R in Reaction Scheme 1-2 is an allyl group is completed in only 50 minutes.

[143] As an alternative method for minimizing the amount of rhodium catalyst of Formula 3, the reactions of Reaction Schemes 1-1 and 1-2 herein have been carried out. That is, the reactions of Reaction Schemes 1-1 and 1-2 have been carried out from the compounds of Formulas 2a and 2b, wherein R is para-nitrobenzyl, in a reaction solvent of ethyl acetate, n-propyl acetate, or n-butyl acetate in the presence of each of i) 0.02 mol% (Formula 2a/rhodium catalyst = 5000: 1, in mole ratio) of dirhodium (II) tetraacetate, ii) 0.25 mol% of zinc chloride having divalent zinc; iii) 0.02 mol% of dirhodium (II) tetraacetate and 0.25 mol% of zinc chloride having divalent zince, iv) 0.02 mol% of dirhodium (II) tetraacetate and 0.25 mol% of zinc bromide having divalent zinc, and v) 0.02 mol% of dirhodium (II) tetraacetate and 0.25 mol% of zinc powder as a catalyst, with stirring under heat and reflux for 1 hour, and the results have been arranged in the following Tables 6 and 7, respectively.

[144] As shown in the results of Tables 6 and 7 below, the reaction has been completed in case of using a rhodium catalyst and a divalent zinc catalyst together, a yield of 70 to 73% has been obtained in case of using zinc powder together, but the reaction has not almost proceeded in case of using only a zinc catalyst, and a yield of 51 to 55% has been obtained in case of using only a rhodium catalyst. Such results prove that on using the rhodium catalyst and the zinc catalyst at the same time, the observed catalyst activity increases remarkably. That is, in light of the above results, the preferred method in preparing the compound of Formula 1 via Reaction Scheme 1 is to use the rhodium catalyst of Formula 3 and the zinc catalyst of Formula 4 at the same time. More preferably, it is to use a rhodium catalyst and a divalent zinc compound together.

[145] In addition, as seen in the results of Table 6 below, the inventors have found that the solvents affect highly reaction rate and purity of products. On carrying out the reaction of Reaction Scheme 1-1 by using the compound of Formula 2a, the rhodium catalyst in 5,000: 1 and 0.25 mol% of zinc chloride, the time of completing the reaction in a solvent of ethyl acetate is 1 hour, but 30 minutes in n-propyl acetate, and the reaction in n-butyl acetate, using the rhodium catalyst in the same amount, is completed in only 35 minutes. Therefore, all general organic solvents, such as benzene, toluene, and tetrahydrofuran, having a boiling point of 50 ~ 13O⁰C, are possible as solvents for Reaction Scheme 1, but it is preferably methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and the like, and more preferably, ethyl acetate and n-propyl acetate. In addition, to identify whether the synergistic effect of catalyst activity on using the zinc co-catalyst is a phenomenon to be generally observed, even though other rhodium catalysts of Formula 3 are used, the reactions of Reaction Schemes 1-1 and 1-2 have been carried out by using ethyl acetate as a reaction solvent, and 0.02 mol% of dirhodium (II) octanoate and 0.25 mol% of zinc chloride having divalent zinc at the same time in preparing compounds of Formulas Ia and Ib. As a result, as shown in Table 8 below, it has been identified that both reactions of two cases are completed.

[146] The reactions of Reaction Schemes 1-1 and 1-2 have been carried out, with varying reaction solvents. That is, the reactions of Reaction Schemes 1-1 and 1-2 have been carried out from the compounds of Formulas 2a and 2b, wherein R is para-nitrobenzyl, in ethyl acetate, the interior temperature of which is 70 to 75⁰C; and n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, and tert-butyl acetate, the interior temperature of which are 90 to 100⁰C, in the presence of 0.025 mol% (Formula 2a/rhodium catalyst = 4000: 1, in mole ratio) of dirhodium acetate of Formula 3 as a catalyst, with stirring, and the results of Reaction Schemes 1-1 and 1-2 have been arranged in the following Tables 9 and 10, respectively.

[147] As shown in Tables 9 and 10 below, on decreasing the amount of rhodium catalyst to 0.025 mol%, the reaction in n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and tert-butyl acetate has been completed in only 40 to 60 minutes, but the reaction in the previously known toluene and ethyl acetate has been completed no longer after at least 24 hours of the reaction time and identified that the compound at the early reaction remains. That is, in light of the above results, the preferred solvent in preparing compounds of Formula 1 via Reaction Scheme 1 is n- propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate or mixed solvents thereof and other mixed organic solvents comprising the same. Mode for the Invention

[148] The present invention is explained in more detail, with reference to the following examples. However, the examples illustrate the aspects of the present invention, and are not intended to restrict the scope of the present invention.

[149] <Comparative Example 1>

[150] 4.26 g (11.32 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 0.5 mg (0.00113 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] were added to 42.7

2 3 4 mL of ethyl acetate, and the mixture was stirred with maintaining a reaction temperature at 8O⁰C. After carrying out the reaction for 3 hours, the reaction solution was concentrated, the conversion ratio was calculated via Proton Nuclear Magnetic Resonance Spectroscopy, and the results were represented in Table 1.

[151] <Comparative Example 2>

[152] 4.74 g (12.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 4 mg (0.063 mmol) of Cu powder catalyst were added to 47.6 rnL of ethyl acetate, and the mixture was stirred with maintaining a reaction temperature at 8O⁰C. After carrying out the reaction for 3 hours, the reaction solution was concentrated, the conversion ratio was calculated via Proton Nuclear Magnetic Resonance Spectroscopy, and the results were represented in Table 1.

[153] <Example 1.1>

[154] 6.81 g (18.1 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 0.8 mg (0.00181 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 5.8 mg

2 3 4

(0.0913 mmol) of Cu powder catalyst were added to 68.32 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 8O⁰C. The reaction was completed in 3 hours, in case of Example 1.1. The reaction solution was concentrated to 13 mL, and hexane and toluene were added by 26 mL, respectively, to the concentrated reaction solution, and the mixture was stirred at O⁰C for 2 hours, and filtered off to obtain 5.35 g (85%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester as a product. The results were represented in Table 1.

[155] <Example 1.2>

[156] 6.81 g (18.1 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 0.8 mg (0.00181 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 5.8 mg

2 3 4

(0.0913 mmol) of Cu powder catalyst were added to 68.32 mL of n-propyl acetate, and the mixture was stirred with maintaining the reaction temperature at 100⁰C. The reaction was completed in only 40 minutes. The reaction solution was concentrated to 13 mL, and hexane and toluene were added by 26 mL, respectively, to the concentrated reaction solution, and the mixture was stirred at O⁰C for 2 hours, and filtered off to obtain 5.67 g (90%)of(5RS,

[157] 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester as a product. The results were represented in Table 1.

[158] <Example 1.3>

[159] 6.81 g (18.1 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 0.8 mg (0.00181 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 5.8 mg

2 3 4

(0.0913 mmol) of Cu powder catalyst were added to 68.32 mL of isopropyl acetate, and the mixture was stirred with maintaining the reaction temperature at 9O⁰C. The reaction was completed in only 2 hours. The reaction solution was concentrated to 13 rnL, and hexane and toluene were added by 26 rnL, respectively, to the concentrated reaction solution, and the mixture was stirred at O⁰C for 2 hours, and filtered off to obtain 4.49 g (80%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester as a product. The results were represented in Table 1.

[160] <Example 1.4> [161] 6.81 g (18.1 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 0.8 mg (0.00181 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 5.8 mg

2 3 4

(0.0913 mmol) of Cu powder catalyst were added to 68.32 mL of n-butyl acetate, and the mixture was stirred with maintaining the reaction temperature at 12O⁰C. The reaction was completed in only 40 minutes. The reaction solution was concentrated to 13 mL, and hexane and toluene were added by 26 mL, respectively, to the concentrated reaction solution, and the mixture was stirred at O⁰C for 2 hours, and filtered off to obtain 4.03 g (71%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester as a product. The results were represented in Table 1.

[162] [Reaction Scheme 1-1]

[164] [Formula 2a] [Formula Ia]

[165] wherein, R is a para-nitrobenzyl group.

[166] Table 1 [Table 1]

Comparison of reactivity according to rhodium and copper catalysts in the N-H insertion reaction of Reaction Scheme 1-1

[167] In the above table, [1] is a conversion ratio determined using Proton Nuclear Magnetic Resonance Spectroscopy.

[168] <Example 2.1>

[169] 5.5 g (14.6 rrrrcl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, Formula 2a, and 0.7 mg (0.00158 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 7.2 mg

2 3 4

(0.073 mmol) of copper chloride (I) [CuCl(I)] catalyst were added to 65 mL of n- propyl acetate and stirred with maintaining the reaction temperature at 11O⁰C. After reaction of the mixture for 40 minutes, the results were represented in Table 2. 3.66 g (72%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0] heptane- 2-carboxylic acid p-nitrobenzyl ester as a product was obtained by a separation method via chromatography.

[170] <Example 2.2>

[171] 5.5 g (14.6 rrrrcl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, Formula 2a, and 0.7 mg (0.00158 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 10.5 mg

2 3 4

(0.073 mmol) of copper bromide (I) [CuBr(I)] catalyst were added to 65 mL of n- propyl acetate and stirred with maintaining the reaction temperature at 11O⁰C. After reaction of the mixture for 40 minutes, the results were represented in Table 2. 3.92 g (77%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0] heptane- 2-carboxylic acid p-nitrobenzyl ester as a product was obtained by a separation method via chromatography.

[172] <Example 2.3>

[173] 5.5 g (14.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, Formula 2a, and 0.7 mg (0.00158 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 7 mg

2 3 4

(0.073 mmol) of copper oxide (I) [Cu 0(I)] catalyst were added to 65 mL of n-propyl acetate and stirred with maintaining the reaction temperature at 11O⁰C. After reaction of the mixture for 1 hour, the results were represented in Table 2. 3.56 g (70%) of (5RS, 6RS)-6-[(RS)- l-hydroxyethyl]-3,7-dio?D- l-azabicyclo[3.2.0] heptane- 2-carboxylic acid p-nitrobenzyl ester as a product was obtained by a separation method via chromatography.

[174] <Example 2.4>

[175] 5.5 g (14.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, Formula 2a, and 0.7 mg (0.00158 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 15.5 mg

2 3 4

(0.073 mmol) of copper (I) trifluoromethanesulfonate [Cu(CF SO )] catalyst were added to 65 mL of n-propyl acetate and stirred with maintaining the reaction temperature at 11O⁰C. After reaction of the mixture for 40 minutes, the results were represented in Table 2. 4.07 g (80%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester as a product was obtained by a separation method via chromatography.

[176] <Example 2.5>

[177] 5.5 g (14.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, Formula 2a, and 0.7 mg (0.00158 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 19.3 mg

2 3 4

(0.073 mmol) of bis(acetylacetonato)Cu(II) [Cu(acac) ] catalyst were added to 65 mL of n-propyl acetate and stirred with maintaining the reaction temperature at 11O⁰C. After reaction of the mixture for 30 minutes, the results were represented in Table 2. 4.17 g (82%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0] heptane-2-carboxylic acid p-nitrobenzyl ester as a product was obtained by a separation method via chromatography.

[178] <Example 2.6>

[179] 5.5 g (14.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, Formula 2a, and 0.7 mg (0.00158 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 5.8 mg

2 3 4

(0.073 mmol) of copper oxide (II) [CuO(II)] catalyst were added to 65 mL of n-propyl acetate and stirred with maintaining the reaction temperature at 11O⁰C. After reaction of the mixture for 30 minutes, the results were represented in Table 2. 4.32 g (85%) of (5RS, 6RS)-6-[(RS)- l-hydroxyethyl]-3,7-dio?D- l-azabicyclo[3.2.0] heptane- 2-carboxylic acid p-nitrobenzyl ester as a product was obtained by a separation method via chromatography.

[180] <Example 2.7>

[181] 5.5 g (14.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, Formula 2a, and 0.7 mg (0.00158 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 16.3 mg

2 3 4

(0.073 mmol) of copper bromide (II) [CuBr (H)] catalyst were added to 65 mL of n- propyl acetate and stirred with maintaining the reaction temperature at 11O⁰C. After reaction of the mixture for 30 minutes, the results were represented in Table 2. 4.07 g (80%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0] heptane- 2-carboxylic acid p-nitrobenzyl ester as a product was obtained by a separation method via chromatography.

[182] <Example 2.8>

[183] 5.5 g (14.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, Formula 2a, and 0.7 mg (0.00158 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 26.4 mg

2 3 4

(0.073 mmol) of copper (II) trifluorcmethanesulfonate [Cu(CF SO ) ] catalyst were added to 65 mL of n-propyl acetate and stirred with maintaining the reaction temperature at 11O⁰C. After reaction of the mixture for 40 minutes, the results were represented in Table 2. 3.97 g (78%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester as a product was obtained by a separation method via chromatography.

[184] <Example 2.9>

[185] 5.5 g (14.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, Formula 2a, and 0.7 mg (0.00158 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 11.7 mg

2 3 4

(0.073 mmol) of copper sulfate(II) [CuSO (H)] catalyst were added to 65 mL of n-

4 propyl acetate and stirred with maintaining the reaction temperature at 11O⁰C. After reaction of the mixture for 2 hours, the results were represented in Table 2. 4.07 g (80%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0] heptane- 2-carboxylic acid p-nitrobenzyl ester as a product was obtained by a separation method via chromatography.

[186] <Example 2.10> [187] 5.5 g (14.6 nrrol) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, Formula 2a, and 0.7 mg (0.00158 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 9.8 mg

2 3 4

(0.073 mmol) of copper chloride (II) [CuCl (H)] catalyst were added to 65 mL of n- propyl acetate and stirred with maintaining the reaction temperature at 11O⁰C. After reaction of the mixture for 40 minutes, the results were represented in Table 2. 4.17 g (82%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0] heptane- 2-carboxylic acid p-nitrobenzyl ester as a product was obtained by a separation method via chromatography.

[188] [Reaction Scheme 1-1]

[190] [Formula 2a] [Formula 1] [191] wherein, R is a para-nitrobenzyl group. [192] Table 2 [Table 2]

Reaction of Reaction Scheme 1-1 using 0.5 mol% of copper catalysts and 0.01 mol% of Rh₂(OAc)₄ catalyst together

[193] <Example 3.1> [194] 2.42 g (6.43 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 1.9 mg (0.00064 mmol) of dirhodium (II) perfluorotetradodecanoate [Rh [CO (CF ) CF ] ]

2 2 2 12 3 4 catalyst and 2.1 mg (0.032 mmol) of Cu powder catalyst were added to 68.32 mL of n- propyl acetate, and the mixture was stirred with maintaining the reaction temperature at 11O⁰C. After reaction of it for 8 hours, the reaction solution was concentrated to 5 mL, and hexane and toluene were added by 10 mL, respectively, to the concentrated reaction solution, and the mixture was stirred at O⁰C for 2 hours, and filtered off. 1.904 g (89%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0] heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product. The results were represented in Table 3.

[195] <Example 3.2> [196] 6.81 g (18.1 rrrrøl) of (3RS, 4RS)-diazo-3-[l(RS)-hydroxyethyl]- ,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 1.4 mg (0.00181 rrrrøl) of dirhodium (II) octanoate [Rh [CO (CH ) CH ] ] catalyst and 5.8

2 2 2 6 3 4 mg (0.0913 mmol) of Cu powder catalyst were added to 68.32 mL of n-propyl acetate, and the mixture was stirred with maintaining the reaction temperature at 11O⁰C. After reaction of it for 1 hour, the reaction solution was concentrated to 13 mL, and hexane and toluene were added by 26 mL, respectively, to the concentrated reaction solution, and the mixture was stirred at O⁰C for 2 hours, and filtered off. 5.67 g (90%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product. The results were represented in Table 3.

[197] [Reaction Scheme 1-1]

[199] [Formula 2a] [Formula Ia]

[200] wherein, R is a para-nitrobenzyl group.

[201] Table 3 [Table 3]

Reaction of Reaction Scheme 1-1 using 0.5 mol% of copper powder catalysts and 0.01 mol% Of Rh₂(OAc)₄ catalyst together

[202] <Example 4.1>

[203] 18.9 g (50.21 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 0.8 mg (0.00181 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 16 mg

2 3 4

(0.251 mmol) of Cu powder catalyst were added to 227 mL of n-propyl acetate, and the mixture was stirred with maintaining the reaction temperature at 11O⁰C. After reaction of it for 4 hours, the reaction solution was concentrated to 38 mL, and hexane and toluene were added by 76 mL, respectively, to the concentrated reaction solution, and the mixture was stirred at O⁰C for 2 hours, and filtered off. 14.85 g (85%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product. The results were represented in Table 4.

[204] <Example 4.2>

[205] 15.8 g (41.8 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 0.4 mg (0.0009 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 13.3 mg

2 3 4

(0.209 mmol) of Cu powder catalyst were added to 189 mL of n-propyl acetate, and the mixture was stirred with maintaining the reaction temperature at 11O⁰C. After reaction of it for 4.5 hours, the reaction solution was concentrated to 31 mL, and hexane and toluene were added by 62 mL, respectively, to the concentrated reaction solution, and the mixture was stirred at O⁰C for 2 hours, and filtered off. 12.81 g (88%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0] heptane- 2-carboxylic acid p-nitrobenzyl ester was obtained as a product. The results were represented in Table 4. [206] [Reaction Scheme 1-1]

[208] [Formula 2a] [Formula Ia] [209] wherein, R is a para-nitrobenzyl group. [210] Table 4 [Table 4]

Reaction of Reaction Scheme 1-1 using 0.5 mol% of copper powder catalysts and Rh2(OAc)4 catalyst together

[211] <Example 5.1> [212] 6.67 g (22.6 rrrrøl) of (3S,4R)-3-[(R)-l-hydroxyethyl] -

4-[(R)- l-methyl-3-diazo-3-allyloxycarbonyl-2-ox)propyl-2-azetidinone, of Formula 2b, and 1 mg (0.00226 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst

2 3 4 and 7.2 mg (0.113 mmol) of Cu powder catalyst were added to 102.3 mL of n-propyl acetate, and the mixture was stirred with maintaining the reaction temperature at 11O⁰C. After reaction of it for 1 hour, the yield was identified by a separation method via chromatography. The results were represented in Table 5, and 5.32 g (88%) of allyl (lR,3R,5R,6S)-6-[(R)-l-hydroxyethyl]-l-methyl-2-ox)carbapenem-3-carboxylate was obtained.

[213] <Example 5.2> [214] 8.82 g (22.6 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

4-[(lR)-l-methyl-3-diazo-3-p-nitrobenzylcarbonyl-2-ox)propyl]2-azetidinone, of Formula 2b, and 1 mg (0.00226 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ]

2 3 4 catalyst and 7.2 mg (0.113 mmol) of Cu powder catalyst were added to 102.3 mL of n- propyl acetate, and the mixture was stirred with maintaining the reaction temperature at 11O⁰C. After reaction of it for 50 minutes, the yield was identified by a separation method via chromatography. The results were represented in Table 5, and 7.45 g (91%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl] - 4-methyl-3,7-diox> l-azabicyclo[3.2.0.]heptane-2-carboxylate was obtained. [215] [Reaction Scheme 1-2]

[217] [Formula 2b] [Formula Ib]

[218] wherein, R is a para-nitrobenzyl group or C alkenyl group. [219] Table 5 [Table 5]

Reaction of Reaction Scheme 1-1 using 0.5 mol% of copper powder catalysts and 0.01 mol% of Rli₂(OAc)₄ catalyst together

[220] In the above table, [1] represents that R is a C alkenyl group, and [2] represents that R is a para-nitrobenzyl group.

[221] <Comparative Example 3> [222] 8.5 g (22.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 2 mg (0.00452 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] were added to 85 mL

2 3 4 of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, the reaction solution was concentrated, and 4.02 g (51%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product by a separation method via chromatography. The results were represented in Table 6 below.

[223] <Comparative Example 4> [224] 8.5 g (22.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 7.7 mg (0.0565 mmol) of zinc chloride (ZnCl ) were added to 85 rnL of ethyl acetate, and the

2 mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, the results were represented in Table 6 below.

[225] <Example 6.1>

[226] 8.5 g (22.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 2 mg (0.00452 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 7.7 mg

2 3 4

(0.0565 mmol) of zinc chloride (ZnCl ) catalyst were added to 85 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, the reaction solution was concentrated to 17 mL, and 34 mL of hexane and 34 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 7.24 g (92%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product. The results were represented in Table 6 below.

[227] <Example 6.2>

[228] 8.5 g (22.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 2 mg (0.00452 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 12.7 mg

2 3 4

(0.0565 mmol) of zinc bromide (ZnBr ) catalyst were added to 85 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, the reaction solution was concentrated to 17 mL, and 34 mL of hexane and 34 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 7.4 g (94%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product. The results were represented in Table 6 below.

[229] <Example 6.3>

[230] 8.5 g (22.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 2 mg (0.00452 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 3.7 mg

2 3 4

(0.0565 mmol) of zinc powder catalyst were added to 85 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, followed by filtering off the zinc powder, the reaction solution was concentrated to 17 mL, and 34 mL of hexane and 34 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 5.51 g (70%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0] heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product. The results were represented in Table 6 below.

[231 ] <Example 6.4>

[232] 8.5 g (22.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 2 mg (0.00452 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 7.7 mg

2 3 4

(0.0565 mmol) of zinc chloride (ZnCl ) catalyst were added to 85 mL of n-propyl acetate, and the mixture was stirred with maintaining the reaction temperature at 95 to 100⁰C. After reaction of it for 30 minutes, the reaction solution was concentrated to 17 mL, and 34 mL of hexane and 34 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 7.32 g (93%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product. The results were represented in Table 6 below.

[233] <Example 6.5>

[234] 8.5 g (22.6 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 2 mg (0.00452 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst and 7.7 mg

2 3 4

(0.0565 mmol) of zinc chloride (ZnCl ) catalyst were added to 85 mL of n-butyl acetate, and the mixture was stirred with maintaining the reaction temperature at 95 to 100⁰C. After reaction of it for 35 minutes, the reaction solution was concentrated to 17 mL, and 34 mL of hexane and 34 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 6.69 g (85%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product. The results were represented in Table 6 below. [235] Table 6 [Table 6]

Comparison of reactivity according to rhodium and zinc catalysts in the N-H insertion reaction of Reaction Scheme 1-1

[236] <Comparative Example 5>

[237] 8.82 g (22.6 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

4-[(lR)-l-methyl-3-diazo-3-p-nitrobenzylcarbonyl-2-ox)propyl]2-azetidinone, of Formula 2b, and 2 mg (0.00452 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ]

2 3 4 were added to 88 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, the reaction solution was concentrated, and 4.5 g (55%) of (3S,4R)-3-[(lR)-l-hydroxyethyl] - 4-[(1R)- l-methyl-3-diazo- 3-p-nitrobenzylcarbonyl-2-ox)propyl]2-azetidinone, of Formula Ib, was obtained as a product by a separation method via chromatography. The results were represented in Table 7 below.

[238] <Comparative Example 6>

[239] 8.82 g (22.6 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

4-[(lR)-l-methyl-3-diazo-3-p-nitrobenzylcarbonyl-2-ox)propyl]2-azetidinone, of Formula 2b, and 7.7 mg (0.0565 mmol) of zinc chloride (ZnCl 2 ) were added to 88 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, the results were represented in Table 7 below.

[240] <Example 7.1>

[241] 8.82 g (22.6 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

2 3 4 catalyst and 7.7 mg (0.0565 mmol) of zinc chloride (ZnCl 2 ) catalyst were added to 88 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, the reaction solution was concentrated to 18 mL, and 36 mL of hexane and 36 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 7.62 g (93%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl]-4-methyl-3,7-diox)-l-azabicyclo[3.2.0.]heptane-2- carboxylate, of Formula Ib, was obtained as a product. The results were represented in Table 7 below.

[242] <Example 7.2>

[243] 8.82 g (22.6 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

2 3 4 catalyst and 12.7 mg (0.0565 mmol) of zinc bromide (ZnBr ) catalyst were added to 88 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, the reaction solution was concentrated to 18 mL, and 36 mL of hexane and 36 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 7.53 g (92%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl]-4-methyl-3,7-diox)-l-azabicyclo[3.2.0.]heptane-2- carboxylate, of Formula Ib, was obtained as a product. The results were represented in Table 7 below.

[244] <Example 7.3>

[245] 8.82 g (22.6 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

2 3 4 catalyst and 3.7 mg (0.0565 mmol) of zinc powder catalyst were added to 88 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, the reaction solution was concentrated to 18 mL, and 36 mL of hexane and 36 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 5.98 g (73%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl] -4-methyl-3,7-diox)-l-azabicyclo[3.2.0.]heptane-2-carboxylate, of Formula Ib, was obtained as a product. The results were represented in Table 7 below.

[246] Table 7 [Table 7]

Comparison of reactivity according to rhodium and zinc catalysts in the N-H insertion reaction of Reaction Scheme 1-2

[247] <Example 8.1> [248] 8.5 g (22.6 rrrrcl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 3.5 mg (0.00452 rrrrcl) of dirhodium (II) octanoate {Rh [CO (CH ) CH )] } catalyst and 7.7

2 2 2 6 3 4 mg (0.0565 mmol) of zinc chloride (ZnCl ) catalyst were added to 85 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, the reaction solution was concentrated to 17 mL, and 34 mL of hexane and 34 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 7.4 g (94%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product. The results were represented in Table 8 below.

[249] <Example 8.2> [250] 8.82 g (22.6 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

4-[(lR)-l-methyl-3-diazo-3-p-nitrobenzylcarbonyl-2-ox)propyl]2-azetidinone, of Formula 2b, and 3.5 mg (0.00452 mmol) of dirhodium (II) octanoate {Rh [CO (CH )

2 2 2 6

CH )] } catalyst and 7.7 mg (0.0565 mmol) of zinc chloride (ZnCl ) catalyst were

3 4 2 added to 88 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 75 to 77⁰C. After reaction of it for 1 hour, the reaction solution was concentrated to 18 mL, and 36 mL of hexane and 36 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 7.45 g (91%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl]-4-methyl-3,7-diox)-l-azabicyclo[3.2.0.]heptane-2- carboxylate, of Formula Ib, was obtained as a product. The results were represented in Table 8 below.

[251] Table 8 [Table 8]

Reaction of Reaction Schemes 1-1 and 1-2 using 0.25 mol% of zinc chloride catalyst and 0.02 mol% of^" rhodium catalyst together

[252] <Comparative Example 7> [253] 3.4 g (9.04 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 1 mg (0.00226 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] were added to 40 mL

2 3 4 of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 70 to 75⁰C. After reaction of it for 24 hours, the reaction solution was concentrated, and 2.20 g (70%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl] - 3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product by a separation method via chromatography.

[254] <Comparative Example 8> [255] 3.4 g (9.04 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 1 mg (0.00226 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] were added to 40 mL

2 3 4 of toluene, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 24 hours, the reaction solution was concentrated, and 2.27 g (72%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0] heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product by a separation method via chromatography.

[256] <Example 9.1>

[257] 3.4 g (9.04 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 1 mg (0.00226 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst were added to

2 3 4

40 mL of n-propyl acetate, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 40 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 2.9 g (92%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product.

[258] <Example 9.2>

[259] 3.4 g (9.04 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 1 mg (0.00226 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst were added to

2 3 4

40 mL of isoropyl acetate, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 40 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 2.87 g (91%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product.

[260] <Example 9.3>

[261] 3.4 g (9.04 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 1 mg (0.00226 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst were added to

2 3 4

40 mL of n-butyl acetate, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 40 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 2.8 g (89%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product.

[262] <Example 9.4>

[263] 3.4 g (9.04 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 1 mg (0.00226 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst were added to

2 3 4

40 rnL of isobutyl acetate, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 40 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 2.83 g (90%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product.

[264] <Example 9.5>

[265] 3.4 g (9.04 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 1 mg (0.00226 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst were added to

2 3 4

40 mL of sec-butyl acetate, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 40 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 2.77 g (88%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product.

[266] <Example 9.6>

[267] 3.4 g (9.04 rrrrøl) of (3RS, 4RS)-α-diazo-3-[l(RS)-hydroxyethyl] - β,2-diox)-4-azetidinebutanoic acid p-nitrobenzyl ester, of Formula 2a, and 1 mg (0.00226 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ] catalyst were added to

2 3 4

40 mL of tert-butyl acetate, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 40 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 2.87 g (91%) of (5RS, 6RS)-6-[(RS)-l-hydroxyethyl]-3,7-diox)-l-azabicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester was obtained as a product.

[268] Table 9 [Table 9]

Comparison of reactivity according to reaction solvents in the N-H insertion reaction of Reaction Scheme 1-1

[269] <Comparative Example 9> [270] 3.54 g (9.04 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

4-[(lR)-l-methyl-3-diazo-3-p-nitrobenzylcarbonyl-2-ox)propyl]2-azetidinone, of Formula 2b, and 1 mg of dirhodium (II) tetraacetate [Rh (CH COO) ] were added to

2 3 4

40 mL of ethyl acetate, and the mixture was stirred with maintaining the reaction temperature at 70 to 75⁰C. After reaction of it for 24 hours, the reaction solution was concentrated, and 2.33 g (71%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl] - 4-methyl-3,7-diox)-l-azabicyclo[3.2.0.]heptane-2-carboxylate was obtained as a product by a separation method via chromatography.

[271] <Comparative Example 10> [272] 3.54 g (9.04 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

2 3 4

40 mL of toluene, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 24 hours, the reaction solution was concentrated, and 2.29 g (70%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl] - 4-methyl-3,7-diox)-l-azabicyclo[3.2.0.]heptane-2-carboxylate was obtained as a product by a separation method via chromatography.

[273] <Example 10.1> [274] 3.54 g (9.04 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] - 4-[(lR)-l-methyl-3-diazo-3-p-nitrobenzylcarbonyl-2-ox)propyl]2-azetidinone, of Formula 2b, and 1 mg (0.00226 mmol) of dirhodium (II) tetraacetate [Rh (CH COO) ]

2 3 4 were added to 40 rnL of n-propyl acetate, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 40 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 3.01 g (92%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl]-4-methyl-3,7-diox)-l-azabicyclo [3.2.0.] heptane- 2-carboxylate was obtained as a product.

[275] <Example 10.2>

[276] 3.54 g (9.04 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

2 3 4 were added to 40 mL of isopropyl acetate, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 50 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 2.95 g (90%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl]-4-methyl-3,7-diox)-l-azabicyclo [3.2.0.]heptane-2-carboxylate was obtained as a product.

[277] <Example 10.3>

[278] 3.54 g (9.04 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

2 3 4 were added to 40 mL of n-butyl acetate, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 45 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 2.98 g (91%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl]-4-methyl-3,7-diox)-l-azabicyclo [3.2.0.] heptane- 2-carboxylate was obtained as a product.

[279] <Example 10.4>

[280] 3.54 g (9.04 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

2 3 4 were added to 40 rnL of isobutyl acetate, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 45 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 2.78 g (85%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl]-4-methyl-3,7-diox)-l-azabicyclo [3.2.0.] heptane- 2-carboxylate was obtained as a product.

[281] <Example 10.5>

[282] 3.54 g (9.04 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

2 3 4 were added to 40 mL of sec-butyl acetate, and the mixture was stirred with maintaining the reaction temperature at 90 to 100⁰C. After reaction of it for 50 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 2.92 g (89%) of p-nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl]-4-methyl-3,7-diox)-l-azabicyclo [3.2.0.]heptane-2-carboxylate was obtained as a product.

[283] <Example 10.6>

[284] 3.54 g (9.04 rrrrøl) of (3S,4R)-3-[(lR)-l-hydroxyethyl] -

2 3 4 were added to 40 mL of tert-butyl acetate, and the mixture was stirred with mai ntaining the reaction temperature at 90 to 100⁰C. After reaction of it for 55 minutes, the reaction solution was concentrated to 6.8 mL, and 13.6 mL of hexane and 13.6 mL of toluene were added to the concentrated reaction solution. The mixture was stirred at O⁰C for 2 hours, and the resulting white solid product filtered. 2.95 g (90%) of p- nitrobenzyl (4S,5R,6S)-6-[(lR)-hydroxyethyl]-4-methyl-3,7-diox)-l-azabicyclo [3.2.0.]heptane-2-carboxylate was obtained as a product. [285] Table 10 [Table 10]

Comparison of reactivity according to reaction solvents in the N-H insertion reaction of Reaction Scheme 1-2

Claims

[1] A method of preparing a compound of the following Formula 1 or isomers thereof comprising subjecting a compound of the following Formula 2 to a ring closure reaction, in the presence of a major catalyst of the following Formula 3; and one or more co-catalysts selected from the group consisting of a copper- containing compound and a zinc-containing compound: [Formula 1]

wherein

R and R represent each independently hydrogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted heterocyclyl group, or -CH(OR )R ,

3 4 where R represents hydrogen, an acyl group, or an alcohol protecting group, and R represents an optionally substituted alkyl group, an optionally substituted

4 alkenyl group, an optionally substituted aryl group, or an optionally substituted heterocyclyl group, R represents a carboxylic acid protecting group,

X represents oxygen atom, or nitrogen atom substituted with an alkyl group, and

R , R , and R represent each independently hydrogen atom or an optionally

5 6 7 substituted alkyl group.

[2] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 1, characterized in that R represents -CH(OR )R ,

2 3 4 where R represents hydrogen; an acyl group; or a silyl group substituted with one or more substituents selected from the group consisting of a C alkyl group,

1-6 aC alkenyl group, and an aryl group having 5 to 10 cyclic members, and

2-6

R represents a C alkyl group.

4 1-6

[3] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 1, characterized in that R represents a C alkenyl group, nitro, a C alkoxy group or a benzyl group

2-6 1-6 substituted with a C alkyl group.

1-6

[4] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 1, characterized in that R , R , and R represent each independently hydrogen atom or a C alkyl group

5 6 7 1-20 unsubstituted or substituted with halogen. [5] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 1, characterized in that said copper-containing compound is one or more selected from the group consisting of a copper (0) compound, a monovalent copper [Cu(I)] compound and a divalent copper [Cu(II)] compound. [6] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 5, characterized in that said copper-containing compound is one or more selected from the group consisting of copper powder, CuCl, CuBr, Cu O, Cu(CF SO ), Cu(acac) , CuO,

2 3 3 2

CuBr , Cu(CF SO ) , CuSO , and CuCl .

2 3 3 2 4 2

[7] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 1, characterized in that said zinc-containing compound is one or more selected from the group consisting of a zinc (0) compound and a divalent zinc [Zn(II)] compound. [8] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 7, characterized in that said zinc-containing compound is one or more selected from the group consisting of zinc powder, Zn(acac) , ZnBr , Zn(CF SO ) , ZnSO , and ZnCl .

2 2 3 3 2 4 2

[9] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 1, characterized in that

X represents oxygen atom. [10] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 9, characterized in that

R , R , and R represent hydrogen atom; or

5 6 7

R and R represent hydrogen atom, and R represents a C alkyl group.

5 7 6 1-12

[11] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 1, characterized in that the major catalyst of Formula 3 is used in an amount of 0.1 mol% (compound of Formula 2: compound of Formula 3 = 1000: 1, in mole ratio) or less, based on the compound of Formula 2.

[12] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 1, characterized in that the co-catalyst is used in an amount of 0.1 mol% (compound of Formula 2: co- catalyst = 1000: 1, in mole ratio) or more, based on the compound of Formula 2.

[13] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 1, characterized in that it uses as a reaction solvent one or more selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and tert-butyl acetate.

[14] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 1, characterized in that the isomers of compounds of Formulas 1 and 2 are compounds of Formulas Ia and 2a, respectively. [Formula Ia]

[Formula 2a]

wherein

R represents hydrogen, an acyl group, or an alcohol protecting group, and R represents a carboxylic acid protecting group.

[15] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 1, characterized in that the isomers of compounds of Formulas 1 and 2 are compounds of Formulas Ib and 2b, respectively.

[Formula Ib]

wherein

R represents a C alkyl group, and

1 1-6

R represents a carboxylic acid protecting group.

[16] A method of preparing a compound of the following Formula 1 or isomers thereof from a compound of the following Formula 2 in the presence of a rhodium catalyst of the following Formula 3 and a solvent of the following Formula 4:

wherein

4 alkenyl group, an optionally substituted aryl group, or an optionally substituted heterocyclyl group,

R represents a carboxylic acid protecting group, X represents oxygen atom, or nitrogen atom substituted with an alkyl group, R , R , and R represent each independently hydrogen atom or an optionally

5 6 7 substituted alkyl group, and R represents a C alkyl group.

8 3-6

[17] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 16, characterized in that the solvent is one or more selected from the group consisting of n-proyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and tert- butyl acetate. [18] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 16, characterized in that the solvent is a mixed solvent of etyl acetate and one or more selected from the group consisting of n-proyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and tert-butyl acetate. [19] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 16, characterized in that

R represents -CH(OR )R ,

1-6 a C alkenyl group, and an aryl group having 5 to 10 cyclic members, and

2-6

R represents a C alkyl group.

4 1-6

[20] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 16, characterized in that R represents a C alkenyl group, nitro, a C alkoxy group or a benzyl group

2-6 1-6 substituted with a C alkyl group.

1-6

[21] The method of preparing a compound of Formula 1 or isomers thereof according to Claim 16, characterized in that the catalyst of Formula 3 is used in an amount of 0.1 mol% (compound of Formula 2: compound of Formula 3 = 1000: 1, in mole ratio) or less, based on the compound of Formula 2.