JPH08176155A - Production of 2-alkyl-substituted carbapenem derivative - Google Patents

Abstract

PURPOSE: To easily and effectively obtain a 2-alkyl-substituted carbapenem derivative useful as a β-lactam antibiotic substance under mild reaction condition by directly introducing a substituted alkyl group at a specific site of a carbapenem skeleton. CONSTITUTION: The objective derivative of formula R-R' [R is a carbapenem skeleton; R' is an (un)substituted alkyl bonded to the 2-site of the skeleton], e.g. p-methoxybenzyl (5R,6S)-2-[3-(p-methoxybenzyloxycarbonyl)amino-prop-1- yl]-6-[(1R)-1-(triethylsilyloxy)ethyl]carbapen-2-em-3-carboxylate is produced by reacting (A) a carbapenem compound of formula R-Z having an eliminable substituent Z on the 2-site (preferably Z is a halogeno-lower alkanesulfonic acid group) with (B) an alkylborane-type compound of formula (X and Y are each an organic residue) in an organic solvent in the presence of a palladium catalyst [preferably dichlorobis(acetonitrile)palladium(II)].

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention provides a carbapenem compound by directly introducing a substituted alkyl group at the 2-position to give a 2-
The present invention relates to a method for producing an alkyl-substituted carbapenem derivative.

[0002]

Various compounds are known as carbapenems, which are a type of β-lactam antibiotics. For example, imipenem, meropenem, meropenem mesylate and urea are known (JP-A-60-
19787, Japanese Patent Laid-Open No. 60-233076). These are those in which an S substituent is introduced at the 2-position of the carbapenem skeleton.

Conventionally, in order to introduce a C substituent at the 2-position of the carbapenem skeleton, a method of indirectly introducing it through several steps has been used. For example, Tetrahedron Lett. , 2
6 , p.89 (1985), a C substituent group is constructed in the initial stage of synthesis, and then a carbapenem skeleton is synthesized through several steps. This method requires a large number of steps, so
It is inefficient as a reaction for introducing a position C substituent. There are few examples of the method of directly introducing the C substituent into the 2-position of the carbapenem skeleton.

For example, Thomas A. Rano et al., Tetrahedron
Lett. , Vol. 31, No. 20, p. 2853 (1990), a carbapenem compound β-ketoester is reacted with trifluoromethanesulfonic anhydride (abbreviated as Tf ₂ O),
Carbapenem 2-position to the leaving group trifluoromethane sulfonic acid groups of the backbone (-OSO ₂ CF _3: -OTf and abbreviated) to form enol triflate ester which was introduced, then the presence of a palladium catalyst, aryl trimethyltin A method of reacting (ArSnMe ₃ ) to introduce an aryl group at the 2-position of a carbapenem compound is disclosed. However, the organotin reagent used in this method has a practical problem because it contains toxic tin. N. Yasud
a et al., Tetrahedron Lett. , Vol. 34, No. 20, p. 3211 (1
993), a β-ketoester form of a carbapenem compound is reacted with trifluoromethanesulfonic anhydride to form an enol triflate ester form in which a leaving group —OTf group is introduced at the 2-position of the carbapenem skeleton, and then palladium In the presence of a catalyst, aryldihydroxyborane (Ar
B (OH) ₂ ) is reacted to introduce an aryl group at the 2-position of the carbapenem compound.

JP-A-3-223285 discloses a method of introducing a methyl group into the 2-position of the carbapenem skeleton, but this method also uses a tin reagent.

[0006] As described above, a general method having practicality for directly introducing various substituted alkyl groups into the 2-position of a carbapenem compound has not been known. The carbapenem compound having a substituted alkyl group at the 2-position can be used as an intermediate for pharmaceuticals such as antibacterial agents.

Therefore, there is a demand for a method of simply and effectively introducing a substituted alkyl group into the 2-position of a carbapenem compound.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems of the prior art, while effectively maintaining the configuration at the 1-position while maintaining the configuration at the 1-position and effectively changing the position to the 2-position of the carbapenem skeleton. By directly introducing a substituted alkyl group,
An object of the present invention is to provide a method for simply and effectively producing a 2-alkyl-substituted carbapenem derivative useful for producing various carbapenem derivatives.

[0009]

The present invention provides the formula (I):

[0010]

Embedded image

(Wherein R is a carbapenem skeleton,
R'is a substituted or unsubstituted alkyl group, which is bonded to the 2-position of the carbapenem skeleton), and is a method for producing a 2-alkyl-substituted carbapenem derivative represented by the formula (II):

[0012]

[Chemical 9]

A carbapenem compound represented by the formula (wherein R has the same meaning as in formula (I)) substituted with a leaving group Z at the 2-position, and a formula (III):

[0014]

[Chemical 10]

(In the formula, R'is a substituted or unsubstituted alkyl group and is bonded to boron through a carbon atom of the alkyl group; X and Y are each independently an organic residue. , Or together to form a monocyclic or polycyclic carbocycle, which carbocycle may contain a heteroatom or may have a substituent). And a reaction in the presence of a palladium catalyst in an organic solvent.

In a preferred embodiment, the leaving group Z
Is a halogeno lower alkane sulfonic acid group or a halogeno sulfonic acid group.

In another preferred embodiment, the leaving group Z is --OSO ₂ CF ₃ .

In another preferred embodiment, R ′ of the alkylborane type compound (III) is represented by the formula (IIIA):

[0019]

[Chemical 11]

Wherein R ⁴ and R ⁵ are each independently hydrogen or an organic residue, or they together form a carbocycle, which carbocycle may optionally contain a heteroatom. It may have a group).

In another preferred embodiment, the above 2-
The alkyl-substituted carbapenem derivative has the formula (I-1):

[0022]

[Chemical 12]

Wherein R ¹ is hydrogen or an organic residue, R ² is hydrogen, a lower alkyl or a lower alkoxy group, R ³ is an optionally protected carboxyl group, R ⁴ and R ⁵ has the same meaning as in formula (IIIA)).

In another preferred embodiment, the palladium catalyst is dichlorobis (acetonitrile) palladium (II), tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris ( Dibenzylideneacetone) dipalladium (0), palladium acetate (II), dichlorobis (triphenylphosphine) palladium (II),
Group consisting of dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II), dichloro [1,2-bis (diphenylphosphino) ethane] palladium (II), and chloroallylpalladium (II) dimer Selected from.

In another preferred embodiment, the above formula (I
X and Y in II) are alkylene which together form a monocyclic or polycyclic ring.

In another preferred embodiment, the alkylborane type compound (III) has the formula (IV):

[0027]

[Chemical 13]

A 1-olefin compound of the formula (V) wherein R ⁴ and R ⁵ have the same meanings as in formula (IIIA)

[0029]

Embedded image

It can be obtained by reacting with an organic borane reagent represented by the formula (wherein X and Y have the same meaning as in formula (III)).

The meanings of the abbreviations in this specification are shown below.

Ac: acetyl Boc: t-butoxycarbonyl Bu: butyl Et: ethyl Me: methyl Ph: phenyl PMB: p-methoxybenzyl Tf: -SO ₂ CF _{3 In the} present specification, the preferred range of each group is as follows. Is the street.

The "lower alkyl" has 1 to 6 carbon atoms, and examples of such an alkyl group include methyl, ethyl,
Examples include n-propyl, iso-propyl, n-butyl, t-butyl, pentyl and hexyl. The carbon number of this lower alkyl is preferably 1 to 4. The most preferred lower alkyl is methyl or ethyl.

The term "aryl" means a monocyclic or polycyclic aromatic group such as phenyl or naphthyl. “Aralkyl” means the above lower alkyl substituted with the above aryl.

The above "lower alkyl", "aryl",
All of the "aralkyl" may be substituted with halogen, nitro, optionally protected hydroxy, optionally protected amino, or a substituent which does not adversely influence the reaction.

The following formula (I):

[0037]

[Chemical 15]

In the 2-alkyl-substituted carbapenem derivative represented by R, R is a carbapenem skeleton. This R
May have substituents at each position which may be used in the carbapenem compound. R'is attached to the 2-position of the carbapenem skeleton.

In the present specification, each position of the carbapenem skeleton conventionally follows the numbering shown below.

[0040]

Embedded image

R'is a substituted or unsubstituted alkyl group, and is represented by the following formula (IIIA):

[0042]

[Chemical 17]

It is shown by.

The 2-alkyl-substituted carbapenem derivative of the above formula (I) is preferably the following formula (I-1):

[0045]

Embedded image

It is shown by. Here, R ¹ is hydrogen or an organic residue, and this organic residue is 6 of the carbapenem compound.
Any substituent can be used at the position, for example,
Examples thereof include a hydroxy-substituted lower alkyl or lower alkoxy group which may be protected. R ² is hydrogen, a lower alkyl or a lower alkoxy group and the like. R ³ is an optionally protected carboxyl group. R ⁴ and R ⁵ are each independently hydrogen or an organic residue. Alternatively, R ⁴ and R ⁵ may together form a carbocycle, which carbocycle may contain heteroatoms and may be substituted.

As the group represented by R ⁴ and R ⁵ alone or together, for example, a substituent bonded to the S atom at the 2-position of a known carbapenem antibacterial agent can be used. For example, a substituted or unsubstituted lower alkyl group; a substituted or unsubstituted cycloalkyl group; a substituted or unsubstituted 5 to 8 membered aryl group; a substituted or unsubstituted nitrogen atom, oxygen atom and / or sulfur atom containing 3 to 8 Membered alicyclic heterocyclic group or condensed cyclic group thereof; 3- to 8-membered aromatic or non-aromatic heterocyclic group containing substituted or unsubstituted nitrogen atom, oxygen atom and / or sulfur atom or condensed ring group thereof And so on. Substituents for these groups include, for example, lower alkyl groups;
Lower alkenyl group (for example, C _2-6 alkenyl group (vinyl, butenyl, propenyl, etc.)); cycloalkyl group (for example, C _3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl); an aryl group (e.g., phenyl, C _{6 -10} aryl groups such as naphthyl, the aryl group further hydroxyl, C _1-4 alkyl group (methyl, ethyl, etc.), C _1-4 alkoxy group (methoxy, ethoxy, etc. )
A lower alkenoyloxycarbonylamino group; an aromatic heterocyclic group (for example, a 5- to 6-membered aromatic group containing 1 to 4 heteroatoms such as nitrogen atom, oxygen atom, and sulfur atom) Heterocyclic groups (furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
Isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,
2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl)); nitrogen atom, oxygen atom , 1- to 5-membered heteroatoms such as sulfur atoms, etc., containing 1 to 5 5- or 6-membered aromatic heterocycles or benzene rings fused with 1 or 2 nitrogen atoms, oxygen atoms, 1 to 5 heteroatoms such as sulfur atoms 2 Cyclic or tricyclic aromatic condensed heterocyclic group (benzofuranyl, isobenzofuranylbenzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, Benzothiazolyl, 1,2-benzisothiazolyl, 1
H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenazinyl, phenazinyl. Inyl, thianthrenyl, phenatoridinyl, phenatorolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo
[1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo
[1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4 -Triazolo [4,3-b] pyridazinyl, etc.); Non-aromatic heterocyclic group (for example, 4- to 6-membered non-aromatic heterocyclic group containing 1 to 3 hetero atoms such as nitrogen atom, oxygen atom, sulfur atom) (Oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.); amino group; mono- or di-lower alkylamino group (for example, methylamino, ethylamino, mono- or di-C _1-6 alkylamino group), such as dimethylamino; tri (lower alkyl) ammonium group (e.g., trimethylammonium, triethylammonium, triprolidine Tri C _1-6 alkyl ammonium group, such as Le ammonium);
Imino lower alkylamino group; amidino group; guadinino group; acyl group (for example, C _1-6 alkanoyl group such as formyl, acetyl, propionyl); carbamoyl group;
Mono- or di-lower alkylcarbamoyl group (e.g., methylcarbamoyl, ethylcarbamoyl, mono- or di-C _1-6 alkylcarbamoyl group such as dimethylcarbamoyl); thiocarbamoyl group; a sulfamoyl group; a mono- or di-lower alkylsulfamoyl group (e.g. , A mono- or di-C _1-6 alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl); an optionally protected sulfamoylamino group; a carboxyl group; A carboxyamino group; a lower alkoxycarbonyl group (for example,
C _1-6 such as methoxycarbonyl and ethoxycarbonyl
Alkoxycarbonyl group); aralkyloxycarbonyl group; hydroxyl group; lower alkoxy group (for example, C _1-6 alkoxy group such as methoxy and ethoxy); lower alkenyloxy group (for example, C _2-6 such as allyloxy and 2-butenyloxy) Alkenyloxy group); cycloalkyloxy group (for example, C _3-7 cycloalkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy), aralkyloxy group (for example, benzyloxy, C _{7- 10} aralkyl group) such as phenethyloxy; aryloxy group (e.g., phenoxy,
C _6-10 aryloxy groups such as naphthyloxy);
Mercapto group; lower alkylthio group (for example, C _1-6 alkylthio group such as methylthio, ethylthio); aralkylthio group (for example, C _7-10 aralkylthio group such as benzylthio, phenethylthio); arylthio group (for example, phenylthio, C _6-10 arylthio groups such as naphthylthio); sulfo groups; cyano groups; azido groups; nitro groups;
Nitroso group; oxo group; thioxo group; halogeno group (eg,
Fluorine, chlorine, bromine, etc.) and the like. further,
The hydroxy group, amino group, carboxy group and the like in the above substituents may be protected by a known protecting group. R
⁴ and R ⁵ may be the same or different.

The above-mentioned preferred 2-alkyl-substituted carbapenem derivative (I-1) is synthesized, for example, according to the following reaction scheme 1.

[0049]

[Chemical 19]

The leaving group Z is introduced at the 2-position of the 2-oxocarbapenem derivative to form the compound (II-1).
In the presence of a palladium catalyst in (II-1), an alkylborane type compound having a desired substituted alkyl group to be introduced (III-1)
To give a 2-alkyl-substituted carbapenem derivative (I
-1) is obtained. Here, R ¹ , R ² and R ³ have the same meaning as in formula (I-1), and R ⁴ and R ⁵ have the same meaning as in formula (IIIA).

In the production method of the present invention, the above formula (II-1)
Examples of the leaving group Z are, for example, a substituted or unsubstituted arylsulfonic acid group, lower alkanesulfonic acid group, halogeno lower alkanesulfonic acid group, halogenosulfonic acid group, dialkylphosphoric acid group, diarylphosphoric acid group, halogeno group. , An alkylsulfinyl group, an arylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group and the like are used. Examples of the arylsulfonic acid group include benzenesulfonic acid group, p-toluenesulfonic acid group, p-
Examples thereof include a nitrobenzene sulfonic acid group and a p-bromobenzene sulfonic acid group. Examples of the lower alkanesulfonic acid group include a methanesulfonic acid group and an ethanesulfonic acid group. Examples of the halogeno lower alkane sulfonic acid group include trifluoromethane sulfonic acid group. Examples of the halogenosulfonic acid group include a fluorosulfonic acid group. Examples of the dialkyl phosphate group include a diethyl phosphate group. Examples of the diaryl phosphate ester include a diphenyl phosphate group.
Examples of the halogeno group include chlorine, bromine and iodine. Examples of the alkylsulfinyl group include methylsulfinyl and the like. The arylsulfinyl group includes phenylsulfinyl and the like. Examples of the alkylsulfonyl group include methylsulfonyl and the like. Examples of the arylsulfonyl group include p-toluenesulfonyl. Examples of the suitable leaving group Z include a halogeno lower alkane sulfonic acid group and a halogeno sulfonic acid group, and more preferably a trifluoromethane sulfonic acid group is used.

The carbapenem compound (II-1) substituted in the 2-position with the leaving group Z used in the above reaction is prepared by reacting a 2-oxocarbapenem compound with an amine in an organic solvent (dichloromethane, tetrahydrofuran, acetonitrile, toluene, etc.). In the presence of compounds (N, N-diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, etc.), react with an acid anhydride (anhydrous trifluoromethanesulfonic acid, anhydrous fluorosulfonic acid, etc.) that can introduce the leaving group Z Can be obtained.

The palladium catalyst usable in the reaction of the above scheme 1 is preferably a catalyst in which the valence of palladium is 0 or 2, and examples thereof include dichlorobis (acetonitrile) palladium (II) and tetrakis (triphenylphosphine). Palladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), palladium acetate (II), dichlorobis (triphenylphosphine) palladium (II), dichloro [1,1 '-Bis (diphenylphosphino) ferrocene] palladium (II), dichloro [1,2-
Bis (diphenylphosphino) ethane] palladium (I
Examples thereof include I) and chloroallyl palladium (II) dimer, but are not particularly limited. Further, the palladium catalyst can be a palladium salt such as chloride, bromide, iodide, sulfate, perchlorate, acetylacetone salt. Alternatively, palladium can be used in combination with a suitable ligand. Examples of suitable ligands include triphenylphosphine, triethylphosphine,
Tri-n-propylphosphine, tri-iso-propylphosphine, tri-n-butylphosphine, dimethylphenylphosphine, diethylphenylphosphine, di-n-propylphenylphosphine, di-iso-propylphenylphosphine, di-n-butyl Phenylphosphine, triphenylphosphine, tri (ortho-tolyl) phosphine, tri (para-tolyl) phosphine, tri (para-methoxyphenyl) phosphine, tricyclopentylphosphine,
Monodentate ligands such as tricyclohexylphosphine, tri-2-furylphosphine, tri-2-thienylphosphine,
And 1,3-bis-diphenylphosphinopropane, 1,4
-Phosphine ligands such as bidentate ligands such as bis-diphenylphosphinobutane and diphenylphosphinoferrocene, phosphites such as trimethylphosphite, triethylphosphite, tri-iso-propylphosphite and triphenylphosphite Examples include ligands. Suitably, the palladium catalyst is dichloro [1,1'-
Bis (diphenylphosphino) ferrocene] palladium (II), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and chloroallylpalladium (II) dimer.

The amount of the palladium catalyst used varies depending on the reaction conditions to be carried out and is not particularly limited, but it is preferable to use a smaller amount from the economical point of view.
On the other hand, in terms of reaction kinetics, it is preferable to use a relatively large amount. Generally, it is preferred to use 0.1 mol% to 100 mol% of the substrate, preferably 1 mol% to 30 mol%.

The alkylborane-type compound (III-1) having a substituted alkyl group to be introduced can be prepared by reacting an organic borane reagent (V) such as monoalkylborane or dialkylborane with 1- (1) as shown in the following reaction scheme. It can be prepared by a conventional method by reacting an olefin compound (IV) (Andrew Pelter et al. "Chapter 3: Preparation of Hydroboration and Organoborane ", Borane Reagents , p.165).
-235, Academic Press, 1988).

[0056]

Embedded image

In the above organic borane reagent (V), X and Y are alkylborane type compounds (I) and carbapenem compounds (I).
When reacting with I), a group that is less likely to be rearranged than the substituted alkyl group to be introduced may be used, and a bulky alkyl group or a bicycloalkyl group is preferable. For example, 9
-Borabicyclo [3.3.1] nonane (9-BBN), 1,1,2-trimethylpropylborane (alias: thexylborane), bis (2,4,6-trimethylphenyl) borane (alias: dimesitylborane), 4,4 , 6-trimethyl-1,3,2-dioxaborinane, 1,3,2-benzodioxaborole, dithiaborane,
Catechol borane, dimethoxy borane and the like,
Preferred is 9-borabicyclo [3.3.1] nonane.

The organic borane reagent (V) is, for example, Borane Re
According to the method described in agents , p.165-235, Academic Press, 1988, etc., for example, alkene or cycloalkadiene is reacted with borane (BH ₃ ) to obtain dialkylborane or bicyclic dialkylborane.

In Scheme 2 above, the organoborane reagent
As the 1-olefin compound (IV) to be reacted with (V),
3 to 8 containing a substituted or unsubstituted 1-olefin, a substituted or unsubstituted methylenecycloalkane, a substituted or unsubstituted methylenecycloalkene, a substituted or unsubstituted nitrogen atom, an oxygen atom and / or a sulfur atom.
Member methylene non-aromatic heterocyclic compounds and the like.

The reaction of Scheme 1 above is carried out in a suitable organic solvent. Examples of the organic solvent include dimethylformamide, tetrahydrofuran, dimethylsulfoxide, acetonitrile, dioxane, N-methylpyrrolidone and the like.

In this reaction, it is preferable to add potassium phosphate, potassium carbonate, triethylamine or the like as an additive.

The reaction temperature is -50 to 160 ° C, preferably -20 to 80 ° C.

The reaction time varies depending on the reaction conditions such as raw materials and reaction reagents, but is several minutes to several tens hours, and preferably 30 minutes to 4 hours.

In the present invention, the carbapenem skeleton 2 can be effectively treated under mild reaction conditions (reaction temperature, reaction time, etc.).
Substituted alkyl groups can be introduced directly at positions. At this time, the configuration at the 1-position of the carbapenem skeleton is maintained.

The 2-alkyl-substituted carbapenem derivative thus obtained is useful, for example, as various antibacterial compounds or synthetic intermediates thereof.

[0066]

EXAMPLES The present invention will be described below with reference to reference examples and examples.

Organoborane reagent used in the method for producing a 2-alkyl-substituted carbapenem derivative (I) of the present invention
The 1-olefin compound (IV) to be reacted with (V) is synthesized by a usual method. Reference Examples 1 (Scheme 3), Reference Examples 2 (Scheme 4), Reference Examples 3 (Scheme 5), Reference Examples 4 (Scheme 6) below are examples of synthesizing the above 1-olefin compound (IV) and intermediates thereof. And Reference Example 5 (Scheme 7).

Reference Example (Reference Example 1)

[0069]

[Chemical 21]

(A) N- (p-methoxybenzyloxycarbo
Nyl) -2-propenylamine (2) Allylamine (1) (5g) and triethylamine (14.6ml) in methylene chloride (200ml) under nitrogen atmosphere and ice-cooled Sp
-Methoxybenzyloxycarbonyl-4,6-dimethyl-2-
After adding mercaptopyrimidine (31.98g), about 5 at room temperature.
Stir for hours. The reaction solution was concentrated under reduced pressure, water-ethyl acetate was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers are combined, saturated aqueous sodium hydrogen carbonate solution,
The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. Purification by silica gel column chromatography gave the title compound (2) (14.5 g, yield: 75%) as a colorless liquid. The data of IR, ¹ H-NMR and elemental analysis of this compound are shown below.

IR (CHCl ₃ ): 3442, 1714 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 3.70-3.90 (m, 5H), 4.62-4.88 (br, 1
H), 5.05 (s, 2H), 5.07-5.25 (m, 2H), 5.72-5.96 (m, 1
H), 6.89 (d, 2H, J = 8.6Hz), 7.31 (d, 2H, J = 8.6Hz) Elemental analysis: Calculated as C ₁₂ H ₁₅ NO ₃ (%): C, 65.14; H, 6.83; N, 6.33 Found (%): C, 64.80; H, 6.87; N, 6.38.

(Reference example 2)

[0073]

[Chemical formula 22]

(A) 1-tert-butoxycarbonyl-4- (R) -hi
Droxy-L-proline (4) 4- (R) -hydroxy-L-proline (3) (300 g) in methanol (1
(500 ml) solution, under ice cooling, an aqueous solution of sodium hydroxide (94.35 g) (570 ml), di-tert-butyl dicarbonate (549.29 g).
Methanol (366 ml) solution was sequentially added, and the mixture was stirred at room temperature for about 3 hours. The reaction solution was concentrated under reduced pressure to remove methanol and then the aqueous layer was washed with toluene. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure to give the title compound (4) (506.4 g, yield: 96%) as a colorless powder. The data of IR, ¹ H-NMR and elemental analysis of this compound are shown below.

IR (CHCl ₃ ): 3394, 1724, 1685 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 1.43 (s, 9H X 2/3), 1.46 (s, 9H X 1
/ 3), 1.96-2.14 (m, 1H), 2.18-2.36 (m, 1H), 3.36-3.60
(m, 2H), 4.23-4.45 (m, 2H); Elemental analysis: Calculated as C ₁₀ H ₁₇ NO ₅ (%): C, 51.94; H, 7.41; N, 6.06 Measured value (%): C, 51.87; H, 7.33; N, 6.08.

(B) 1-tert-butoxycarbonyl-4-oxo
-L-proline (5) 1-tert-butoxycarbonyl-4-obtained in Reference Example 2- (a)
(R) -Hydroxy-L-proline (4) (20 g) in ethyl acetate (280 m
l) To the solution, under ice cooling, saturated aqueous sodium metaperiodate solution (495 ml) and ruthenium oxide (11.5 mg) were sequentially added,
The mixture was stirred at room temperature for about 6 hours. The reaction solution was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, washed with ether, and the title compound (5) (13.3
g, yield: 67%) was obtained as a colorless powder. I of this compound
The data of R, ¹ H-NMR and elemental analysis are shown below.

IR (CHCl ₃ ): 1765, 1724, 1699 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 1.46 (s, 9H), 2.45-2.64 (m, 1H), 2.
97-3.21 (m, 1H), 3.68-3.97 (m, 2H), 4.60-4.79 (m, 1
H); Elemental analysis: Calculated as C ₁₀ H ₁₅ NO ₅ (%): C, 52.40; H, 6.6
0; N, 6.11 Found (%): C, 52.05; H, 6.5
1; N, 6.08.

(C) 1-tert-butoxycarbonyl-4-methyl
-L-proline (6) in a nitrogen atmosphere, in a solution of methyltriphenylphosphonium bromide (51.43 g) in tetrahydrofuran (400 ml), -7
N-Butyllithium (1.69M hexane solution, 77.4ml) at 8 ℃
After adding, the temperature was naturally raised to room temperature. A solution of 1-tert-butoxycarbonyl-4-oxo-L-proline (5) (10 g) obtained in Reference Example 2- (b) in tetrahydrofuran (70 ml) was added to the reaction solution, and the mixture was heated under reflux overnight. did. After cooling, water, saturated aqueous sodium hydrogen carbonate solution and ether were added, the aqueous layer was separated, and the organic layer was extracted with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, washed with ether, acidified with concentrated hydrochloric acid, and extracted with ether. The ether layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the crude title compound (6) (9.9 g) as a pale yellow substance. The data of IR, ¹ H-NMR and elemental analysis of this compound are shown below.

IR (CHCl ₃ ): 1721, 1693 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 1.43 (s, 9H X 2/5), 1.49 (s, 9H X 3
/ 5), 2.60-3.14 (m, 2H), 4.06 (br-d, 2H, J = 11.4Hz), 4.
34-4.58 (m, 1H), 5.03 (br-s, 2H).

(D) 1-tert-butoxycarbonyl-2- (S) -di
Methylcarbamoyl-4-methylenepyrrolidine (7) Under nitrogen atmosphere, 1-tert-butoxycarbonyl-4-methylene-L-proline (6) (2.45 g) obtained in Reference Example 2- (c) in methylene chloride ( 50 ml) solution at −20 ° C. with triethylamine (1.8 ml).
ml) and isobutyl chloroformate (1.54 ml), and add about 1
Stir for hours. Further, dimethylamine hydrochloride (1.76 g) and triethylamine (4.5 ml) were added, and the mixture was stirred under ice cooling for about 2 hours. The reaction solution was added to 1N hydrochloric acid-ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate.
The organic layers were combined, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over magnesium sulfate. The solvent was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound (7) (1.08 g, yield: 39%).
Was obtained as a pale yellow oil. The data of IR, ¹ H-NMR and elemental analysis of this compound are shown below.

IR (CHCl ₃ ): 1686, 1654 cm ^-1 ; ¹ H-NMR (CDCl ₃ ) d: 1.41 (s, 9H X 1/3), 1.47 (s, 9H X 2
/ 3), 2.40-2.60 (m, 1H), 2.81-3.03 (m, 1H), 2.95 (s, 3H
X 2/3), 2.97 (s, 3H X 1/3), 3.06 (s, 3H X 1/3), 3.08
(s, 3H X 2/3), 3.99-4.31 (m, 2H), 4.71 (dd, 1H X 1 /
3, J = 9.4, 3.3Hz), 4.85 (dd, 1H X 2/3, J = 9.4, 3.3Hz),
4.92-5.07 (m, 2H); HR-MS: C ₁₃ H ₂₃ N ₂ O ₃ [M + H] ⁺ ; Calculated value: 255.1708,
Found: 255.1709.

(Reference Example 3)

[0083]

[Chemical formula 23]

(A) 1-tert-butoxycarbonyl-2- (S) -hi
Droxymethyl-4-methylenepyrrolidine (8) under nitrogen atmosphere, 1-tert-butoxycarbonyl-4-methylene-L-proline (6) (2.8 g) obtained in Reference Example 2- (c) in tetrahydrofuran (25 ml) To the solution was added triethylamine (3.43 ml) and ethyl chloroformate (1.77 ml) at -20 ° C,
Stir for about 30 minutes. The reaction solution was filtered, and the filtrate was added to an aqueous solution (50 ml) of sodium borohydride (1.4 g) under ice cooling,
Stir for 1 hour. The reaction solution was added to water-ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification by silica gel column chromatography gave the title compound (8) (1.67 g, yield: 64%) as a colorless oil. The IR and ¹ H-NMR data of this compound are shown below.

IR (CHCl ₃ ): 3378, 1672 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 1.48 (s, 9H), 2.15-2.85 (m, 2H), 3.
60 (t, 2H, J = 5.3Hz), 3.81-4.30 (m, 3H), 4.98 (br-s, 2
H).

(B) 1-tert-butoxycarbonyl-2- (S)-[N
-(tert-Butyloxycarbonyl) -N-sulfamoylami
Nomethyl] -4-methylenepyrrolidine (9) 1-te obtained in Reference Example 3- (a) was cooled with ice under a nitrogen atmosphere.
rt-Butoxycarbonyl-2- (S) -hydroxymethyl-4-methylenepyrrolidine (8) (1.27 g) in tetrahydrofuran (25 m
l) in the solution, (tert-butoxycarbonyl-sulfamoyl)
After sequentially adding amine (1.40 g), triphenylphosphine (1.56 g) and diethylazodicarboxylate (0.938 ml), the mixture was stirred at room temperature for about 5 hours. The reaction solution was added to water-ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Purify by silica gel column chromatography to give the title compound (9) (2.06
g, yield: 88%) was obtained as a colorless powder. I of this compound
The data of R, ¹ H-NMR and elemental analysis are shown below.

IR (CHCl ₃ ): 3362, 3190, 1708, 1673 cm
^-1 ; ¹ H-NMR (CDCl ₃ ) d: 1.43 (s, 9H), 1.51 (s, 9H), 2.13 (d,
1H, J = 15.2Hz), 2.60-2.81 (m, 1H), 3.49-3.90 (m, 3
H), 4.02-4.20 (m, 1H), 4.50-4.68 (m, 1H), 5.05 (br-s,
2H), 5.18 (br-s, 2H); Elemental analysis: Calculated as C ₁₆ H ₂₉ N ₃ O ₆ S (%): C, 49.09; H, 7.47; N, 10.73; S, 8.1
9 Found (%): C, 48.86; H, 7.35; N, 10.67; S, 8.0
9.

(Reference Example 4)

[0089]

[Chemical formula 24]

(A) 1-tert-butoxycarbonyl-3-hydro
Xypyrrolidine (11) 3-hydroxypyrrolidine (10) (5.32 g) in methylene chloride (80
ml) solution at room temperature with di-tert-butyl dicarbonate (13.3
A solution of 3 g) in methylene chloride (40 ml) was added dropwise, and the mixture was stirred for about 1.5 hours. The reaction solution was added to water-methylene chloride, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined, washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification by silica gel column chromatography gave the title compound (11) (11.21 g, yield: 98%) as a colorless powder. The data of IR, ¹ H-NMR and elemental analysis of this compound are shown below.

IR (CHCl ₃ ): 3398, 1677 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 1.46 (s, 9H), 1.84-2.23 (m, 2H), 2.
64-3.03 (br, 1H), 3.26-3.56 (m, 4H), 4.44 (br-s, 1
H); Elemental analysis: Calculated as C ₉ H ₁₇ NO ₃ (%): C, 57.73; H, 9.15; N, 7.48 Measured value (%): C, 57.49; H, 9.00; N, 7.47.

(B) 1-tert-butoxycarbonyl-3-oxo
Pyrrolidine (12) Under a nitrogen atmosphere, add oxalyl chloride to a solution of dimethyl sulfoxide (9.1 ml) in methylene chloride (100 ml) at -78 ° C.
(5.59 ml) was added, and the mixture was stirred for about 30 minutes. A solution of 1-tert-butoxycarbonyl-3-hydroxypyrrolidine (11) (10 g) obtained in Reference Example 4- (a) in methylene chloride (50 ml) was added to the reaction solution, and the mixture was stirred for about 1 hour, and then triethylamine was added. (22.3 ml)
Was added and the mixture was further stirred for about 1 hour. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution-ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. Combine the organic layers,
After washing with saturated saline and drying with magnesium sulfate,
The solvent was distilled off under reduced pressure. Purification by silica gel column chromatography gave the title compound (13) (9.61 g, yield: 97%) as a colorless powder. The IR, ¹ H-NMR and MS data of this compound are shown below.

IR (CHCl ₃ ): 1759, 1691 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 1.49 (s, 9H), 2.59 (t, 2H, J = 8.1H
z), 3.75 (s, 2H), 3.78 (t, 2H, J = 8.1Hz); HR-MS: as C ₉ H ₁₅ NO ₃ ; calculated value: 185.1051, measured value:
185.1061.

(C) 1-tert-butoxycarbonyl-3-methyl
N-pyrrolidine (13) under a nitrogen atmosphere, methyltriphenylphosphonium bromide (51.81 g) in tetrahydrofuran (250 m) solution, -78
N-Butyllithium (1.61M hexane solution, 81.9ml) at ℃
After adding, the mixture was stirred for about 2 hours. In the reaction solution, Reference Example 4-
A solution of 1-tert-butoxycarbonyl-3-oxopyrrolidine (12) (8.14 g) obtained in (b) in tetrahydrofuran (70 ml) was added, and the mixture was heated under reflux for about 4 hours. After cooling, the mixture was added to water-methylene chloride, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification by silica gel column chromatography gave the title compound (13) (6.43 g, yield: 80%) as a colorless liquid. The IR, ¹ H-NMR and MS data of this compound are shown below.

IR (CHCl ₃ ): 1682 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 1.47 (s, 9H), 2.55 (br-t, 2H, J = 6.9
Hz), 3.37-3.55 (br, 2H), 3.92 (br-s, 2H), 4.91-5.02
(m, 2H); HR- MS: as C ₁₀ H ₁₇ NO _2; Calculated: 183.1258, Found: 183.1256.

(Reference Example 5)

[0097]

[Chemical 25]

(A) Di-tert-butylhydrazodicarboxy
Rate (15) tert-Butylcarbazate (14) (25 g) of 2-propanol (1
(00 ml) solution, di-tert-butyl dicarbonate (49.54 g)
2-propanol (20 ml) solution of was added dropwise at room temperature and stirred for about 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved in benzene (150 ml), petroleum ether (300 ml) was added, and the crystals were collected by filtration. Wash with petroleum ether to give the title compound (15) (41.75 g,
Yield: 95%) was obtained as a colorless powder. IR of this compound, ¹ H
-NMR and elemental analysis data are shown below.

IR (CHCl ₃ ): 3420, 1727 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 1.48 (s, 18H), 6.05-6.35 (br, 2H); Elemental analysis: C ₁₀ H ₂₀ N Calculated as ₂ O ₄ (%): C, 51.71; H, 8.68; N, 12.06 Measured value (%): C, 51.62; H, 8.51; N, 12.03.

(B) 1,2-di (tert-butoxycarbonyl) -4-
Methylenepyrazolidine (16) Di-tert-butylhydrazodicarboxylate (15) (5 g) obtained in Reference Example 5- (a) in dimethylformamide (100 ml)
The solution was treated with sodium hydride (ca.
%, 947 mg) was added and the mixture was stirred for about 1 hour. 3-chloro in the reaction solution
After adding 2-chloromethyl-1-propene (3.74 ml), add about 1
Stirred for hours. Further, sodium hydride (947 mg) was added, and the mixture was stirred for 30 minutes, then the reaction solution was warmed to about 90 ° C and stirred for 4 hours. After allowing to cool, the reaction solution was added to water-ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Purify by silica gel column chromatography to give the title compound (16) (5.1
2 g, yield: 84%) was obtained as a colorless powder. I of this compound
The data of R, ¹ H-NMR and elemental analysis are shown below.

IR (CHCl ₃ ): 1691 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 1.48 (s, 18H), 3.84 (br-d, 2H, J = 15
Hz), 4.44 (br-d, 2H, J = 15Hz), 5.07 (quint, 2H, J = 2.4
Hz); Elemental analysis: Calculated as C ₁₄ H ₂₄ N ₂ O ₄ (%): C, 59.14; H, 8.51; N, 9.85 Measured value (%): C, 58.86; H, 8.48; N, 9.95.

Next, Reference Example 6 below shows a synthesis example of a carbapenem compound in which a leaving group trifluoromethanesulfonic acid group is introduced at the 2-position.

(Reference Example 6)

[0104]

[Chemical formula 26]

(A) (3S, 4R) -4- (3-diazo-3-p-methoxy
Benzyloxycarbonyl-2-oxo-propyl) -3-[(1
R) -1-Hydroxyethyl] -azetidin-2-one (17a) Y. Ueda et al . , Can. J. Chem. , 62 , p . 2936 (1984) according to the method described in (3S, 4R) -4. -Acetoxy-3-[(1R) -1- (te
rt-Butyldimethylsilyloxy) ethyl] -azetidine-2-
4-methoxybenzyl 2-diazo-3-oxo-butyrate was reacted with on and then deprotected to synthesize the PMB ester form (17a) of the title compound as a pale yellow foam. The IR, ¹ H-NMR and MS data of this compound are shown below.

IR (CHCl ₃ ): 3404, 2140, 1754, 1712, 16
41 cm _-1 ; ¹ H-NMR (CDCl ₃ ) d: 1.32 (d, 3H, J = 6.3Hz), 2.88 (dd, 1
H, J = 7.5, 2.4Hz), 2.91-3.04 (br, 1H), 3.15-3.37 (m,
2H), 3.82 (s, 3H), 3.97 (dt, 1H, J = 6.9, 2.4Hz), 4.10-
4.23 (m, 1H), 5.21 (s, 2H), 6.06-6.19 (br, 1H), 6.91
(d, 2H, J = 8.7Hz), 7.32 (d, 2H, J = 8.7Hz). HR-MS: As C ₁₇ H ₁₉ N ₃ O ₆ Na [M + Na] ⁺ ; Calculated value: 384.117
1, Found: 384.1175. (b) (3S, 4R) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1
-Methyl-3-diazo-3-p-methoxybenzyloxycarbo
Nyl -2-oxo-propyl] -azetidin- 2-one (17b) S. Uyeo et al., Tetrahedron Lett. , 32 , p . 2143 (1991) described (3S, 4R) -4-[(3R)- 1-buten-3-yl] -3-[(1R) -1-
(tert-Butyldimethylsilyloxy) ethyl] -azetidine-
Starting from 2-one, H. Fliri et al., J. Org. Chem. ,
50 , p.3438 (1985), according to (3S, 4R) -3-[(1R) -1- (te
rt-Butyldimethylsilyloxy) ethyl] -4-[(1R) -1-carboxyethyl] -azetidin-2-one followed by DH Sh
The PMB ester form (17b) of the title compound was synthesized as a colorless powder according to the method of ih et al., Heterocycles , 21 , p. 29 (1984). The data of IR, ¹ H-NMR and elemental analysis of this compound are shown below.

IR (CHCl ₃ ): 3476, 3402, 2142, 1755, 17
10, 1638 cm ^-1 ; ¹ H-NMR (CDCl ₃ ) d: 1.21 (d, 3H, J = 6.6Hz), 1.30 (d, 3H,
J = 6.2Hz), 2.62-2.74 (br, 1H), 2.85-2.94 (m, 1H), 3.
69-3.88 (m, 2H), 3.82 (s, 3H), 4.03-4.21 (m, 1H), 5.21
(s, 2H), 6.06-6.20 (br, 1H), 6.91 (d, 2H, J = 8.8Hz),
7.32 (d, 2H, J = 8.8Hz). Elemental analysis: Calculated as C ₁₈ H ₂₁ N ₃ O ₆ (%): C, 57.59; H, 5.64; N, 11.19 Measured value (%): C, 57.63 H, 5.70; N, 11.08.

(C) (3S, 4R) -4- (3-diazo-3-p-methoxy
Benzyloxycarbonyl-2-oxo-propyl) -3-[(1
R) -1- (Triethylsilyloxy) ethyl] -azetidine-2-o
(18a) (3S, 4R) -4- (3-diazo-3-p-methoxybenzyloxycarbonyl-2-oxo-propyl) -obtained in Reference Example 6- (a)
3-[(1R) -1-hydroxyethyl] -azetidin-2-one (17a)
To a solution of (8.19 g) in dimethylformamide (50 ml) was ice-cooled in a nitrogen atmosphere, triethylchlorosilane (5.7 ml) and imidazole (3.09 g) were added, and the mixture was stirred for 30 minutes. Reaction solution 1
The mixture was added to 0% aqueous phosphoric acid solution-ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. Combine the organic layers, 10
% Phosphoric acid aqueous solution, saturated sodium hydrogen carbonate aqueous solution, saturated saline solution in that order, and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure. Purification by silica gel column chromatography gave the title compound (18a) (10.12 g, yield: 94%) as a colorless oil. The data of IR, ¹ H-NMR and elemental analysis of this compound are shown below.

IR (CHCl ₃ ): 3408, 2138, 1755, 1711, 16
46 cm ^-1 ; ¹ H-NMR (CDCl ₃ ) d: 0.59 (q, 6H, J = 8.0Hz), 0.94 (t, 9H,
J = 8.0Hz), 1.23 (d, 3H, J = 6.0Hz), 2.85 (dd, 1H, J = 5.
4, 2.4Hz), 2.99 (dd, 1H, J = 18.0, 10.0Hz), 3.40 (dd,
1H, J = 18.0, 3.3Hz), 3.82 (s, 3H), 4.00 (dt, 1H, J = 9.
6, 2.7Hz), 4.19 (quint, 1H, J = 6.0Hz), 5.21 (s, 2H),
6.02 (br-s, 1H), 6.91 (d, 2H, J = 8.7Hz), 7.31 (d, 2H,
J = 8.7Hz). Elemental analysis: Calculated as C ₂₃ H ₃₃ N ₃ O ₆ Si (%): C, 58.08; H, 6.99; N, 8.83 Measured value (%): C, 58.04; H, 6.99; N, 8.83.

(D) (3S, 4R) -4-[(1R) -1-methyl-3-diazo
-3-p-methoxybenzyloxycarbonyl-2-oxo-p
Ropil] -3-[(1R) -1- (triethylsilyloxy) ethyl] -a
Zetidin-2-one (18b) (3S, 4R) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-methyl-3 obtained in Reference Example 6- (b) A solution of -diazo-3-p-methoxybenzyloxycarbonyl-2-oxo-propyl] -azetidin-2-one (17b) (30g) in dimethylformamide (150ml) was cooled with ice under a nitrogen atmosphere, and triethylchlorosilane was added.
(20.1 ml) and imidazole (10.88 g) were added, and the mixture was stirred for 30 minutes. The reaction solution was added to 10% aqueous phosphoric acid solution-ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with 10% aqueous phosphoric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. After purified by silica gel column chromatography, solidified from hexane-ether to give the title compound (18b) (34.89 g, yield: 89%) as a colorless powder. The data of IR, ¹ H-NMR and elemental analysis of this compound are shown below.

IR (CHCl ₃ ): 3404, 2138, 1755, 1709, 16
45 cm ^-1 ; ¹ H-NMR (CDCl ₃ ) d: 0.59 (q, 6H, J = 8.0Hz), 0.94 (t, 9H,
J = 8.0Hz), 1.16 (d, 3H, J = 6.8Hz), 1.21 (d, 3H, J = 6.2H
z), 2.91-2.99 (m, 1H), 3.77-4.02 (m, 2H), 3.82 (s, 3
H), 4.17 (dq, 1H, J = 6.2, 4.8Hz), 5.20 (s, 2H), 5.82-
5.94 (br, 1H), 6.91 (d, 2H, J = 8.8Hz), 7.31 (d, 2H, J =
Elemental analysis: Calculated as C ₂₄ H ₃₅ N ₃ O ₆ Si (%): C, 58.87; H, 7.20; N, 8.58 Measured value (%): C, 58.94; H, 7.23; N, 8.57.

(E) p-methoxybenzyl (5R, 6S) -2-oxy
So-6-[(1R) -1- (triethylsilyloxy) ethyl] carbape
Nam-3-carboxylate (19a) (3S, 4R) -4- (3- obtained in Reference Example 6- (c) under a nitrogen atmosphere.
Diazo-3-p-methoxybenzyloxycarbonyl-2-oxo-propyl) -3-[(1R) -1- (triethylsilyloxy) ethyl] -azetidin-2-one (18a) and rhodium (II) acetate dimer A (0.5 mol%) benzene solution was heated to reflux for about 30 minutes. After cooling, the mixture was concentrated under reduced pressure to obtain a crude title compound, 2-keto compound (19a) as a pale yellow oily substance. IR of this compound
And ¹ H-NMR data are shown below.

(19a) IR (CHCl ₃ ): 1764 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.60 (q, 6H, J = 7.8Hz), 0.95 (t, 9H,
J = 7.8Hz), 1.30 (d, 3H, J = 6.3Hz), 2.40 (dd, 1H, J = 19.
0, 7.5Hz), 2.85 (dd, 1H, J = 19.0, 7.2Hz), 3.11 (dd, 1
H, J = 6.3, 2.0Hz), 3.81 (s, 3H), 4.08 (dt, 1H, J = 7.2,
2.0Hz), 4.28 (quint, 1H, J = 6.3Hz), 4.67 (s, 1H), 5.
12 and 5.14 (ABq, 2H, J = 12.0Hz), 6.89 (d, 2H, J = 8.7H
z), 7.29 (d, 2H, J = 8.7Hz). (f) p-methoxybenzyl (1S, 5R, 6S) -1-methyl-2-o
Xo-6-[(1R) -1- (triethylsilyloxyloxy) ethyl]
Carbapenam-3-carboxylate (19b ) was obtained in Reference Example 6- (d) in the same manner as in Reference Example 6- (e) (3S, 4).
R) -4-[(1R) -1-Methyl-3-diazo-3-p-methoxybenzyloxycarbonyl-2-oxo-propyl] -3-[(1R) -1- (triethylsilyloxy) ethyl] -Azetidin-2-one (18b)
From the above, the title compound (19b) was also obtained as a pale-yellow oil. The IR and ¹ H-NMR data of this compound are shown below.

(19b) IR (CHCl ₃ ): 1763 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.60 (q, 6H, J = 8.0Hz), 0.95 (t, 9H,
J = 8.0Hz), 1.18 (d, 3H, J = 7.8Hz), 1.29 (d, 3H, J = 6.2H
z), 2.75 (quint, 1H, J = 7.8Hz), 3.19 (dd, 1H, J = 6.2,
2.4Hz), 3.81 (s, 3H), 4.19 (dd, 1H, J = 7.8, 2.4Hz),
4.28 (quint, 1H, J = 6.2Hz), 4.64 (s, 1H), 5.13 (s, 2
H), 6.89 (d, 2H, J = 8.8Hz), 7.29 (d, 2H, J = 8.8Hz). (G) p-methoxybenzyl (5R, 6S) -6-[(1R) -1- ( Trier
Tylsilyloxy) ethyl] -2-trifluoromethanesulfo
Nyloxycarbapene-2-em-3-carboxylate (20
a) The crude p-methoxybenzyl (5) obtained in Reference Example 6- (e)
R, 6S) -2-oxo-6-[(1R) -1- (triethylsilyloxy) ethyl] carbapenamu-3-carboxylate (19a) in methylene chloride solution under nitrogen atmosphere at -78 ° C under N, N-diisopropylethylamine (1.2 equivalents) and trifluoromethanesulfonic anhydride (Tf ₂ O: 1.1 equivalents) were added successively, and the mixture was stirred for about 30 minutes. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution-ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to obtain a crude triflate of the title compound (20a) as a pale yellow oil. The IR and ¹ H-NMR data of these compounds are shown below.

(20a) IR (CHCl ₃ ): 1793, 1726 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.59 (q, 6H, J = 8.0Hz), 0.94 (t, 9H,
J = 8.0Hz), 1.25 (d, 3H, J = 6.3Hz), 3.03-3.21 (m, 2H),
3.27 (dd, 1H, J = 5.4, 3.0Hz), 3.80 (s, 3H), 4.16-4.28
(m, 2H), 5.25 (s, 2H), 6.87 (d, 2H, J = 8.7Hz), 7.36
(d, 2H, J = 8.7Hz). (h) p-methoxybenzyl (1S, 5R, 6S) -1-methyl-6-[(1
R) -1- (Triethylsilyloxy) ethyl] -2-trifluoro
Methanesulfonyloxycarbapene-2-em-3-carbox
Sylate (20b) Similarly to Reference Example 6- (g), p-methoxybenzyl (1S, 5R, 6S) -1-methyl-2-oxo-6-[(obtained in Reference Example 6- (f) was used. 1R)-
1- (triethylsilyloxyloxy) ethyl] carbapenamu-
The title compound (20b) was also obtained as a pale yellow oil from 3-carboxylate (19b).

(20b) IR (CHCl ₃ ): 1787, 1727 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.59 (q, 6H, J = 8.0Hz), 0.94 (t, 9H,
J = 8.0Hz), 1.24 (d, 3H, J = 6.4Hz), 1.26 (d, 3H, J = 7.2H
z), 3.33 (dq, 1H, J = 11.0, 7.2Hz), 3.35 (dd, 1H, J = 6.
0, 3.4Hz), 3.80 (s, 3H), 4.24 (quint, 1H, J = 6.0Hz),
4.27 (dd, 1H, J = 11.0, 3.4Hz), 5.21 and 5.29 (ABq, 2
H, J = 11.9Hz), 6.88 (d, 2H, J = 8.8Hz), 7.37 (d, 2H, J =
8.8 Hz). Example Compounds having a leaving group at the 2-position obtained as described above
(20a) or (20b) and an organoborane reagent and an alkylborane type compound obtained from a 1-olefin compound (2, 7, 9, 13, 16), a 2-alkyl-substituted carbapenem derivative (21a, 21b, Examples of synthesizing 22, 23, 24, 25, 26, 27) are shown in Examples 1 to 6.

[0117]

[Chemical 27]

Example 1 p-Methoxybenzyl (5R, 6S) -2- [3- (p-methoxybenzyl)
Luoxycarbonyl) amino-prop-1-yl] -6-[(1R) -1
-(Triethylsilyloxy) ethyl] carbapene-2-em-3-
Carboxylate (21a) N- (p-methoxybenzyloxycarbonyl) -2-propenylamine (2) (600 mg) obtained in Reference Example 1 under nitrogen atmosphere
In tetrahydrofuran solution under ice-cooling, 9-borabicyclo
[3,3,1] nonane (9-BBN; 0.5M tetrahydrofuran solution,
After adding (1.5 equivalents), the mixture was stirred at room temperature for about 2 hours. The reaction solution was ice-cooled again, and the crude p-methoxybenzyl (5R, 6S) -6-[(1R) -1- (triethylsilyloxy) ethyl] -2- obtained in Reference Example 6- (g) was obtained. A solution of trifluoromethanesulfonyloxycarbapene-2-em-3-carboxylate (20a) (1.5 equivalent) in tetrahydrofuran was added, and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) chloride (1
(0 mol%) and 2N-sodium hydroxide aqueous solution (1 equivalent) were sequentially added, and then the mixture was heated to about 60 ° C. and stirred. Allow the reaction solution to cool and water
The mixture was added to ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over magnesium sulfate. Concentrate the solvent under reduced pressure,
Purification by silica gel column chromatography gave the desired title compound (21a) (1.5 g, yield: 85%) as a colorless oil. The IR and ¹ H-NMR data of this compound are shown below.

IR (CHCl ₃ ): 3442, 1772, 1710 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.59 (q, 6H, J = 8.0Hz), 0.94 (t, 9H,
J = 8.0Hz), 1.26 (d, 3H, J = 6.0Hz), 1.57-1.74 (m, 2H),
2.58-2.69 (m, 2H), 2.81 (d, 2H, J = 9.0Hz), 3.05 (dd, 1
H, J = 6.6, 2.7Hz), 3.04-3.19 (m, 2H), 3.78 (s, 3H),
3.80 (s, 3H), 4.06 (dt, 1H, J = 9.0, 2.7Hz), 4.18 (quin
t, 1H, J = 6.3Hz), 5.03 (s, 2H), 5.00-5.15 (br, 1H),
5.16 and 5.21 (ABq, 2H, J = 12.3Hz), 6.86 (d, 2H, J = 8.
7Hz), 6.88 (d, 2H, J = 8.7Hz), 7.31 (d, 2H, J = 8.7Hz),
7.36 (d, 2H, J = 8.7Hz). (Example 2) p-methoxybenzyl (1S, 5R, 6S) -2- [3- (p-methoxybeta)
N-dioxycarbonyl) amino-prop-1-yl] -1-me
Chill-6-[(1R) -1- (triethylsilyloxy) ethyl] carba
Pen-2-em-3-carboxylate (21b) By the same method as in Example 1, the N- (p obtained in Reference Example 1
-Methoxybenzyloxycarbonyl) -2-propenylamine (2) (190 mg) and p-methoxybenzyl (1S, 5R, 6S) -1-methyl-6-[(1R ) -1- (Triethylsilyloxy) ethyl] -2-trifluoromethanesulfonyloxycarbapene-2-em-3-carboxylate (20b) and the title compound (21b) (346 mg, yield: 60%) as colorless Obtained as an oil. The IR, ¹ H-NMR and MS data of this compound are shown below.

IR (CHCl ₃ ): 3438, 1765, 1709 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.58 (q, 6H, J = 8.0Hz), 0.94 (t, 9H,
J = 8.0Hz), 1.10 (d, 3H, J = 7.4Hz), 1.26 (d, 3H, J = 6.2H
z), 1.45-1.83 (m, 2H), 2.04-2.24 (m, 1H), 2.80-3.30
(m, 4H), 3.16 (dd, 1H, J = 6.6, 3.0Hz), 3.78 (s, 3H),
3.80 (s, 3H), 4.07 (dd, 1H, J = 10.2, 3.0Hz), 4.20 (qui
nt, 1H, J = 6.4Hz), 4.86-5.08 (br, 1H), 5.03 (s, 2H),
5.16 and 5.21 (ABq, 2H, J = 12.2Hz), 6.86 (d, 2H, J = 8.
8Hz), 6.88 (d, 2H, J = 8.8Hz), 7.31 (d, 2H, J = 8.8Hz),
7.37 (d, 2H, J = 8.8Hz). HR-MS: as C ₃₆ H ₅₀ N ₂ O ₈ SiNa [M + Na] ⁺ ; calculated: 689.3.
232, Found: 689.3238.

Example 3 p-Methoxybenzyl (1S, 5R, 6S) -2-[[(2S, 4S) -1- (te
rt-Butoxycarbonyl) -2-dimethylcarbamoyl-pyro
Lydin-4-yl] methyl] -1-methyl-6-[(1R) -1- (triethyl
Lucillyloxy) ethyl] carbapene-2-em-3-carboxy
Rate (22) Obtained in Reference Example 2- (d) by the same method as in Example 1.
1-tert-butoxycarbonyl-2- (S) -dimethylcarbamoyl-4-methylenepyrrolidine (7) (130 mg) to give the title compound (2
2) (229 mg, yield: 64%) was obtained as a colorless oil. The IR, ¹ H-NMR and MS data of this compound are shown below.

IR (CHCl ₃ ): 1769, 1683, 1655 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.59 (q, 6H, J = 7.8Hz), 0.94 (t, 9H,
J = 7.8Hz), 1.10 (d, 3H, J = 7.2Hz), 1.26 (d, 3H, J = 6.2H
z), 1.39 (s, 9H X 1/2), 1.45 (s, 9H X 1/2), 1.45-1.7
5 (m, 1H), 1.98-2.46 (m, 3H), 2.88-3.23 (m, 4H), 2.98
(s, 3H), 3.04 (s, 3H X 1/2), 3.09 (s, 3H X 1/2), 3.56
-3.85 (m, 1H), 3.80 (s, 3H), 4.01-4.30 (m, 2H), 4.41-
4.66 (m, 1H), 5.10-5.29 (m, 2H), 6.89 (d, 2H, J = 8.6H
z), 7.39 (d, 2H, J = 8.6Hz). HR-MS: C ₃₇ H ₅₇ N ₃ O _{8 As} SiNa [M + Na] ⁺ ; Calculated value: 722.3
809, Found: 722.3808.

Example 4 p-Methoxybenzyl (1S, 5R, 6S) -2-[[(2S, 4S) -1- (te
rt-Butoxycarbonyl) -2- [N- (tert-butoxycarbonyl
) -N-Sulfamoylaminomethyl] pyrrolidin-4-i
Lu] methyl] -1-methyl-6-[(1R) -1- (triethylsilyloxy
Si) ethyl] carbapene-2-em-3-carboxylate (23) p-methoxybenzyl (1S, 5R, 6S) -2-[[(2S, 4R) -1- (te
rt-Butoxycarbonyl) -2- [N- (tert-butoxycarbonyl
) -N-Sulfamoylaminomethyl] pyrrolidin-4-i
Lu] methyl] -1-methyl-6-[(1R) -1- (triethylsilyloxy
Si) ethyl] carbapene-2-em-3-carboxylate (2
4) By the same method as in Example 1, 1-tert-butoxycarbonyl-2- (S)-[N- (tert-butoxycarbonyl) -N-sulfamoyl obtained in Reference Example 3- (b) was used. Aminomethyl] -4-methylenepyrrolidine (9) (500 mg) to the title compound (23) (high-polar isomer: 525 mg, yield: 49%) and (24) (low-polar isomer: 134 mg, yield) : 13%) was obtained as a colorless oil. The data of IR, ¹ H-NMR and elemental analysis of these compounds are shown below.

[Highly polar isomer] IR (CHCl ₃ ): 3360, 3188, 1769, 1710, 1668 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.59 (q, 6H, J = 8.0Hz) , 0.94 (t, 9H,
J = 8.0Hz), 1.12 (d, 3H, J = 7.5Hz), 1.27 (d, 3H, J = 6.0H
z), 1.42 (s, 9H), 1.51 (s, 9H), 1.40-1.70 (m, 1H), 2.
08-2.35 (m, 3H), 2.63-2.80 (m, 1H), 3.03 (dd, 1H, J = 1
0.2, 7.5Hz), 3.10-3.25 (m, 1H), 3.18 (dd, 1H, J = 6.2,
3.0Hz), 3.49-3.63 (m, 1H), 3.67-3.83 (m, 2H), 3.80
(s, 3H), 4.12 (dd, 1H, J = 10.2, 3.0Hz), 4.21 (quint,
1H, J = 6.2Hz), 4.32-4.51 (m, 1H), 5.16 and 5.22 (ABq,
2H, J = 12.2Hz), 6.11 (br-s, 2H), 6.89 (d, 2H, J = 8.7H
z), 7.39 (d, 2H, J = 8.7Hz). Elemental analysis: Calculated as C ₄₀ H ₆₄ N ₄ O ₁₁ SSi (%): C, 57.39; H, 7.71; N, 6.69; S, 3.83 Measured Value (%): C, 57.47; H, 7.70; N, 6.39; S, 3.7
6.

[Low polar isomer] IR (CHCl ₃ ): 3360, 3188, 1
768, 1711, 1672 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.60 (q,
6H, J = 8.0 Hz, 0.95 (t, 9H,
J = 8.0 Hz), 1.11 (d, 3H, J =
7.2 Hz), 1.27 (d, 3H, J = 6.0)
Hz), 1.42 (s, 9H), 1.50
(S, 9H), 1.40-1.70 (m, 2H),
2.14 (dd, 1H, J = 13.8, 6.0
Hz), 2.37-2.54 (m, 1H), 2.
97 (dq, 1H, J = 10.2, 7.2 Hz),
3.00-3.23 (m, 2H), 3.17 (d
d, 1H, J = 6.2, 3.0 Hz), 3.3
7-3.70 (m, 3H), 3.80 (s, 3
H), 4.11 (dd, 1H, J = 10.2,
3.0 Hz), 4.22 (quint, 1H, J
= 6.2 Hz), 4.28-4.41 (m, 1
H), 5.14 and 5.25 (ABq, 2
H, J = 12.0 Hz, 6.13 (br-s,
2H), 6.88 (d, 2H, J = 8.7 Hz),
7.38 (d, 2H, J = 8.7 Hz). Elemental analysis: Calculated as C ₄₀ H ₆₄ N ₄ O ₁₁ SSi (%): C, 57.39; H, 7.71; N, 6.69; S, 3.83 Measured value (%): C, 57.45; H, 7.62; N, 6.41; S, 3.6
1.

Example 5 p-Methoxybenzyl (5R, 6S) -2-[(R)-[1- (tert-butoxy)
Cycarbonyl) pyrrolidin-3-yl] methyl] -6-[(1R) -1-
(Triethylsilyloxy) ethyl] carbapene-2-em-3-
Carboxylate (25) p-methoxybenzyl (5R, 6S) -2-[(S)-[1- (tert-butoxy)
Cycarbonyl) pyrrolidin-3-yl] methyl] -6-[(1R) -1-
(Triethylsilyloxy) ethyl] carbapene-2-em-3-
Carboxylate (26) Obtained in Reference Example 4- (c) by a method similar to Example 1.
1-tert-butoxycarbonyl-3-methylenepyrrolidine (13)
(100 mg) to the title compound (25) (highly polar isomer: 125 mg,
Yield: 37%) and (26) (low polar isomer: 113 mg, yield:
34%) was obtained as a colorless oil. The IR, ¹ H-NMR and MS data of these compounds are shown below.

[High polar isomer] IR (CHCl ₃ ): 1773, 1710, 1679 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.59 (q, 6H, J = 7.8Hz), 0.94 (t , 9H,
J = 7.8Hz), 1.27 (d, 3H, J = 6.3Hz), 1.40-1.80 (m, 1H),
1.46 (s, 9H), 1.81-1.97 (m, 1H), 2.18-3.01 (m, 6H),
3.02-3.12 (m, 1H), 3.14-3.31 (m, 1H), 3.31-3.60 (m, 2
H), 3.80 (s, 3H), 4.01-4.14 (m, 1H), 4.19 (quint, 1H,
J = 6.3Hz), 5.16 and 5.23 (ABq, 2H, J = 12.2Hz), 6.88
(d, 2H, J = 8.7Hz), 7.37 (d, 2H, J = 8.7Hz). HR-MS: As C ₃₃ H ₅₀ N ₂ O ₇ SiNa [M + Na] ⁺ ; Calculated value: 637.3
283, Found: 637.3287.

[Low polarity isomer] IR (CHCl ₃ ): 1772, 1710, 1679 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.59 (q, 6H, J = 7.8Hz), 0.94 (t , 9H,
J = 7.8Hz), 1.27 (d, 3H, J = 6.3Hz), 1.40-1.64 (m, 1H),
1.46 (s, 9H), 1.82-1.97 (m, 1H), 2.18-2.38 (m, 1H),
2.70-2.98 (m, 3H), 2.82 (d, 2H, J = 6.2Hz), 3.01-3.11
(m, 1H), 3.14-3.31 (m, 1H), 3.33-3.58 (m, 2H), 3.80
(s, 3H), 4.01-4.14 (m, 1H), 4.19 (quint, 1H, J = 6.3H
z), 5.17 and 5.21 (ABq, 2H, J = 12.3Hz), 6.88 (d, 2H,
J = 8.7Hz), 7.37 (d, 2H, J = 8.7Hz). HR-MS: as C ₃₃ H ₅₀ N ₂ O ₇ SiNa [M + Na] ⁺ ; calculated: 637.3
283, Found: 637.3288.

Example 6 p-Methoxybenzyl (1S, 5R, 6S) -2-[[N, N-bis (tert
-Butoxycarbonyl) pyrazolidin-4-yl] methyl] -1-
Methyl-6-[(1R) -1- (triethylsilyloxy) ethyl] calc
Vapene-2-em-3-carboxylate (27) Obtained in Reference Example 5- (b) by a method similar to that in Example 1.
The title compound (27) (3.41 g, yield: 66%) was obtained as a colorless oil from 1,2-di (tert-butoxycarbonyl) -4-methylenepyrazolidine (16) (2 g). The IR, ¹ H-NMR and MS data of these compounds are shown below.

IR (CHCl ₃ ): 1769, 1710, 1686 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) d: 0.59 (q, 6H, J = 8.0Hz), 0.94 (t, 9H,
J = 8.0Hz), 1.09 (d, 3H, J = 7.2Hz), 1.26 (d, 3H, J = 6.0H
z), 1.98-2.15 (m, 1H), 2.43-2.61 (m, 1H), 2.76-3.64
(m, 5H), 3.16 (dd, 1H, J = 6.6, 3.0Hz), 3.74-4.16 (m,
2H), 3.80 (s, 3H), 4.21 (quint, 1H, J = 6.3Hz), 5.16 an
d 5.23 (ABq, 2H, J = 12.3Hz), 6.88 (d, 2H, J = 8.7Hz), 7.
38 (d, 2H, J = 8.7Hz). HR-MS: C ₃₈ H ₅₉ N ₃ O _{9 As} SiNa [M + Na] ⁺ ; Calculated value: 752.39
14, Found: 752.3913.

The 1-olefin compound (IV) used in each of the above-mentioned examples, the 2-alkyl-substituted carbapenem derivative (I) obtained therefrom and the yield thereof are shown in Table 1 below.

[0132]

[Table 1]

The compounds (21a), (22), (2
3), (26) and (27) are precursors of various antibacterial compounds as shown below.

[0134]

[Chemical 28]

[0135]

As described above, according to the present invention, a substituted alkyl group can be directly introduced directly to the 2-position of the carbapenem skeleton under mild reaction conditions, and the configuration at the 1-position is maintained. Therefore, 2-alkyl-substituted carbapenem derivatives useful for preparing various carbapenem derivatives can be simply and effectively produced.

Claims (8)

[Claims] 1. Formula (I): (In the formula, R is a carbapenem skeleton, R ′ is a substituted or unsubstituted alkyl group,
A 2-alkyl-substituted carbapenem derivative represented by the formula (II): A carbapenem compound represented by the formula (wherein R has the same meaning as in formula (I)) and substituted at the 2-position with a leaving group Z; (In the formula, R ′ is a substituted or unsubstituted alkyl group and is bonded to boron through a carbon atom of the alkyl group; X and Y are each independently an organic residue, or together. To form a monocyclic or polycyclic carbocyclic ring, which may have a heteroatom or may have a substituent). A method comprising reacting in the presence of a palladium catalyst in a solvent. 2. The method according to claim 1, wherein the leaving group Z is a halogeno lower alkane sulfonic acid group or a halogeno sulfonic acid group. 3. The leaving group Z is —OSO ₂ CF ₃ .
The method according to claim 2. 4. R ′ of the alkylborane type compound (III) has the formula (IIIA): (In the formula, R ⁴ and R ⁵ are each independently hydrogen or an organic residue, or they together form a carbocycle,
This carbocycle may contain a heteroatom or may have a substituent), The method according to any one of claims 1 to 3. 5. The 2-alkyl-substituted carbapenem derivative has the formula (I-1): (In the formula, R ¹ is hydrogen or an organic residue, R ² is hydrogen,
A lower alkyl or lower alkoxy group, R ³ is an optionally protected carboxyl group, and R ⁴ and R ⁵ have the same meanings as in formula (IIIA)). The method described in any one of. 6. The palladium catalyst is dichlorobis (acetonitrile) palladium (II), tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium ( 0), palladium acetate (II), dichlorobis (triphenylphosphine) palladium (II), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II), dichloro [1,2-bis (diphenylphos) Fino) ethane] palladium (II), and the method according to any one of claims 1 to 5, selected from the group consisting of chloroallyl palladium (II) dimers. 7. The X of the alkylborane type compound (III)
The method according to any one of claims 1 to 5, wherein and Y are alkylene which together form a monocyclic or polycyclic ring. 8. The alkylborane type compound (III) is
Formula (IV): (Wherein R ⁴ and R ⁵ have the same meanings as in formula (IIIA)) and a 1-olefin compound represented by formula (V): The method according to claim 7, which is obtained by reacting with an organic borane reagent represented by the formula: wherein X and Y have the same meaning as in formula (III).