JPH0529229B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel β-lactam compounds and salts thereof that have antibacterial activity or are intermediates for compounds that have antibacterial activity. Since carbapenem compounds such as thienamycin exhibit excellent antibacterial activity, many research groups have conducted research on them, and a large number of carbapenem derivatives have been reported. The present inventors have also carried out extensive research with the aim of finding carbapenem compounds that are excellent as antibacterial agents, and have discovered that the compound represented by the general formula [] has a strong antibacterial effect or can be a precursor thereof.The present invention completed. That is, the present invention is based on the general formula [] [In the formula, R ₁ represents a hydrogen atom or a lower alkyl group, R ₂ represents a hydrogen atom or a protecting group for a carboxy group, R ₀ represents a hydrogen atom or a protecting group for a hydroxyl group, and X represents the general formula (1) (In the formula, R ₃ and R ₄ may be the same or different and represent a hydrogen atom or a lower alkyl group, or R ₃ and R ₄ together represent an alkylene group.) group, general formula (2) -ZCOR ₅ (2) (wherein Z represents a -NH- group or an oxygen atom, R ₅ is an amino group, a lower alkyl-substituted amino group,
Indicates a lower alkoxy group or a lower alkyl group. )
A group represented by general formula (3) (In the formula, R ₆ represents a hydrogen atom or a lower alkyl group.) A group represented by the general formula (4) -CH=N-R ₇ (4) (In the formula, R ₇ is a lower alkyl-substituted amino group, or a lower alkoxy group) or a group represented by general formula (5) (In the formula, R ₈ , R ₉ and R ₁₀ may be the same or different and represent a hydrogen atom or a lower alkyl group.) or X represents an amino group,
A protected amino group, carboxyl group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, cyano group, hydroxyl group, lower alkoxy group, lower alkylthio group or lower alkanesulfonyl group, Y is a hydrogen atom, a protecting group for an amino group, General formula (6) (In the formula, R ₁₁ and R ₁₂ may be the same or different and represent a hydrogen atom or a lower alkyl group.) or a group represented by the general formula (7) (In the formula, R ₂₀ represents a hydrogen atom or a lower alkyl group.) where n represents an integer of 1 to 4. ] The present invention relates to a novel β-lactam compound or a salt thereof, and a method for producing the same. In the general formula [], R ₁ is preferably a hydrogen atom, for example, C ₁ - such as a methyl group or an ethyl group.
_C3 is a lower alkyl group. Examples of the protecting group for the carboxyl group represented by R ₂ include linear or branched lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, and tert-butyl; for example, 2-iodinated halogeno lower alkyl groups such as ethyl, 2,2,2-trichloroethyl,
For example, lower alkoxymethyl groups such as methoxymethyl, ethoxymethyl, isobutoxymethyl,
For example, lower aliphatic acyloxymethyl groups such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonylethyl, etc.
Examples include lower alkoxycarbonyloxyethyl groups, such as aralkyl groups such as benzyl, p-methoxybenzyl, o-nitrobenzyl, and p-nitrobenzyl, benzhydryl groups, and phthalidyl groups. Examples of the protecting group for the hydroxyl group represented by R ₀ include lower alkoxycarbonyl groups such as tert-butyloxycarbonyl, halogenoalkoxy groups such as 2-ethyloxycarbonyl iodide, and 2,2,2-trichloroethyloxycarbonyl. carbonyl groups, such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o
- an aralkyloxycarbonyl group such as nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, e.g. trimethylsilyl,
Examples include trialkylsilyl groups such as tert-butyldimethylsilyl. The case where X is a group represented by general formula (1), (2), (3), (4) or (5) will be explained next. Examples of the lower alkyl group represented by R ₃ and R ₄ in general formula ₍ 1) include C ₁ to _{C 4} lower alkyl groups such as _methyl , ethyl, and propyl groups; When taken together to represent an alkylene group, the alkylene group is bonded to the N-atom,
For example, it forms a 3- to 7-membered ring such as aziridine, azetidine, pyrrolidine, piperazine, etc. The lower alkyl-substituted amino group represented by R ₅ in general formula (2) is, for example, a C ₁ to C ₃ lower alkyl-substituted amino group such as a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, or a lower alkoxy Examples of the group include methyloxy group,
C ₁ - _{C 3} such as ethyloxy group and propyloxy group
The lower alkoxy group is a lower alkyl group,
For example, C ₁ such as methyl group, ethyl group, propyl group, etc.
~ _C3 lower alkyl groups can be mentioned. Examples of the lower alkyl group represented by R ₆ in general formula (3) include C ₁ -C ₃ lower alkyl groups such as methyl and ethyl groups. The lower alkyl-substituted amino group represented by R ₇ in general formula (4) is, for example, a C ₁ to C ₃ lower alkyl-substituted amino group such as a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, or a lower alkoxy Examples of the group include methyloxy group,
C ₁ - _{C 3} such as ethyloxy group and propyloxy group
Examples include lower alkoxy groups. Examples of lower alkyl groups represented by R ₈ , R ₉ and R ₁₀ in general formula (5) include methyl group, ethyl group,
Examples include _C1 - _C4 lower alkyl groups such as propyl groups. In addition, as the protected amino group represented by etc. C ₁ ~
The _C4 lower alkyloxycarbonyl group may be substituted with a substituent such as a benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, or o-nitrobenzyloxycarbonyl group. Examples of the aralkyloxycarbonyl group that may have a lower alkoxy group include C ₁ to _{C 3} such as a methoxy group, an ethoxy group, an n-propyloxy group, and an isopropyloxy group.
Examples of lower alkoxy groups include C ₁ to _{C 3} lower alkylthio groups such as methylthio, ethylthio, and propylthio groups; examples of lower alkanesulfonyl groups include methanesulfonyl, ethanesulfonyl, and propanesulfonyl. Examples include lower alkanesulfonyl groups such as groups. Next, regarding Y in general formula [], the same examples as the above-mentioned amino group protecting group can be used as the lower alkyl group represented by R ₁₁ and R ₁₂ in general formula (6). As a group, for example, a methyl group,
Ethyl group, isopropyl group, n-propyl group, etc.
C ₁ -C ₄ lower alkyl group, etc., and R ₂₀ of general formula (7)
Examples of the lower alkyl group represented by include C ₁ -C ₃ lower alkyl groups such as methyl group, ethyl group, and isopropyl group. The carboxylic acid compound in which R ₂ is a hydrogen atom in the general formula [] can be formed into a salt, particularly a pharmacologically acceptable salt, if necessary. Such salts include salts of inorganic metals such as lithium, sodium, potassium, calcium, and magnesium, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, and triethylammonium, but sodium salts are preferred. and potassium salts. Also, compounds having basicity, such as compounds in which Y is a hydrogen atom or a group represented by general formula (7) in the general formula [], or compounds in which X is an amino group or a group represented by general formula (3). can be in the form of a salt, especially a pharmacologically acceptable salt, if necessary. Such salts include, for example, hydrochloric acid,
Examples include salts with mineral acids such as sulfuric acid. Among the compounds of the present invention represented by the general formula [], preferred compounds are those represented by the general formula [-g] [In the formula, R _1a represents a hydrogen atom or a methyl group, and X _e represents a group represented by the above general formula (1), (2), (3), (4) or (5), or _e is an amino group,
carboxyl group, lower alkoxycarbonyl group,
represents a cyano group, hydroxyl group, lower alkoxy group, lower alkylthio group or lower alkanesulfonyl group, Y _e represents a hydrogen atom, a substituent represented by general formula (6) or a substituent represented by general formula (7), n represents the same meaning as above. ] Compounds represented by these can be mentioned. The method for producing the compound of the present invention will be explained below. (i) General formula [] [In the formula, R ₀ and R ₁ have the same meanings as above, R _2a represents a carboxyl group-protecting group, and Z _a represents a hydroxyl group-reactive ester group. ] The reactive ester of alcohol represented by the general formula [] [Wherein, X _a is the general formula (1), (2), (4) or (5)
or X _a is a protected amino group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, cyano group, hydroxyl group,
It represents a lower alkoxy group, a lower alkylthio group, or a lower alkanesulfonyl group, Y _a represents a protecting group for an amino group or a substituent represented by the general formula (6), and n has the same meaning as above. ] In an inert solvent, a mercapto compound represented by
By reacting in the presence of a base, the general formula [] [In the formula, R ₀ , R ₁ , R _2a , X _a , Y _a and n represent the same meanings as above. ] A β-lactam compound represented by the following can be produced. Examples of the reactive ester of the hydroxyl group represented by Z _a include substituted or unsubstituted arylsulfonic acid esters, lower alkanesulfonic acid esters, halogeno-lower alkanesulfonic acid esters, diarylphosphoric acid esters, and hydrogen halide esters. Examples include halides, which are esters. Further, examples of substituted or unsubstituted arylsulfonic acid ester include benzenesulfonic acid ester, p-
Toluenesulfonic acid ester, p-nitrobenzenesulfonic acid ester, p-bromobenzenesulfonic acid ester, etc., as lower alkanesulfonic acid ester, methanesulfonic acid ester, ethanesulfonic acid ester, etc., as halogeno lower alkanesulfonic acid ester, etc. Examples of diarylphosphoric acid esters include diphenylphosphoric acid esters, and examples of halides include chlorine, bromine, and iodide. . Suitable examples of such alcohol reactive esters include p-toluenesulfonic acid ester, methanesulfonic acid ester, and diphenylphosphoric acid ester. R _2a corresponds to the protecting group for R ₂ above, and examples of such protecting groups include those similar to R ₂ . Examples of the inert solvent used in this reaction include dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, etc.
Suitable examples include acetonitrile and dimethylformamide. Examples of the base include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, t-butoxypotassium, pyridine, dimethylaminopyridine, triethylamine, diisopropylamine, etc., and diisopropylamine is particularly preferred. I can do it. The base must be used in an amount sufficient to allow the reaction to proceed sufficiently, and the reaction can be carried out usually in an amount of 1 to 1.5 equivalents relative to the starting mercaptan compound represented by the general formula []. The raw material mercapto compound represented by the general formula [] needs to be used in an amount sufficient for the reaction to proceed sufficiently, and a large excess amount can be used, but it is usually 1 to 1.5 times the amount of the reactive ester of alcohol [].
This can be done using equivalent amounts. The reaction temperature is carried out in the range of -78℃ to 60℃,
A range of -40°C to 40°C is suitable. In addition, after the reaction is completed, the resultant can be taken out by ordinary organic chemical methods. Next _, from the thus obtained _compound represented by the general _formula , by performing the removal reaction of the carboxyl group protecting group R _2a in an appropriate combination, the general formula [-b] [In the formula, R ₁ and n represent the same meanings as above, and X _b represents a group represented by the above general formula (1), (2), (4) or (5), or X _b represents an amino group. group, carboxyl group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, cyano group, hydroxyl group,
It represents a lower alkoxy group, a lower alkylthio group or a lower alkanesulfonyl group, and Y _b represents a hydrogen atom or a group represented by the above general formula (6). ] A β-lactam compound represented by the following can be produced. Removal of the protecting group varies depending on the type, but it is removed by a generally known method. For example, in the above general formula [], a compound in which the hydroxyl group protecting group in R ₀ and/or the amino group protecting group in X _a and Y _a is a halogenoalkoxycarbonyl group or an aralkyloxycarbonyl group, a carboxyl group protecting group R _2a Compounds in which is a halogenoalkyl group, an aralkyl group or a benzhydryl group can be subjected to a suitable reduction reaction to remove the protecting group. For such a reduction reaction, when the protecting group is a halogenoalkoxycarbonyl group or a halogenoalkyl group, reduction with an organic solvent such as acetic acid, tetrahydrofuran, or methanol and zinc is suitable; In the case of a benzhydryl group, a catalytic reduction reaction using a catalyst such as platinum or palladium-carbon is suitable. Solvents used in this catalytic reduction reaction include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, or acetic acid, or combinations of these organic solvents with water, phosphoric acid, morpholinopropanesulfonic acid, etc. A mixed solvent with a buffer is suitable. The reaction temperature is carried out in a range of 0°C to 100°C, preferably a range of 0°C to 40°C. Moreover, hydrogen pressure can be carried out under normal pressure or increased pressure. Further, when the protecting group is an o-nitrobenzyloxycarbonyl group or an o-nitrobenzyl group, the protecting group can also be removed by photoreaction. (ii) General formula [-c] [In the formula, R ₁ and n represent the same meanings as above, and Y _d represents a substituent represented by general formula (6). ] Compounds represented by and general formula [] [In the formula, R ₂₀ has the same meaning as above, and R ₂₁ represents a lower alkyl group or a benzyl group. ] By reacting the compound represented by or its salt with an acid under alkaline conditions, the general formula [-d] [In the formula, R ₁ , R ₂₀ , n and Y _d have the same meanings as above. ] A β-lactam compound represented by the following can be produced. Examples of R ₂₁ in the compound represented by the above general formula [] include methyl, ethyl, n-propyl,
Examples include lower alkyl groups having 1 to 5 carbon atoms such as isopropyl, n-butyl, and isobutyl, and benzyl groups, with methyl and ethyl being preferred. Examples of salts with acids include salts of hydrohalic acids such as hydrochloric acid, hydrobromic acid, and hydroiodic acid, but salts with hydrochloric acid are preferred. The reaction under alkaline conditions can be carried out at a pH of 8 to 14, preferably around PH9 to 10. Alkaline reagents used in the reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide, sodium carbonate, and potassium carbonate. Among them, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are preferred. Further, this reaction is preferably carried out using water as a solvent, but it can also be carried out in a mixed solvent of water and an organic solvent. Examples of the organic solvent used include alcohols such as methanol, ethanol, and n-propanol, ethers such as tetrahydrofuran and dioxane, dimethylformamide, and acetonitrile.
The reaction can be suppressed or accelerated by cooling or heating as appropriate, but the preferred reaction temperature is 0°C to room temperature. After the reaction is completed, the resultant can be taken out using ordinary organic chemistry methods. A reaction product can be obtained by separating the eluted portion and freeze-drying it. (iii) General formula [-e] [In the formula, R ₁ and n represent the same meanings as above, and X _d represents a group represented by the above general formula (1), (2), (4) or (5), or X _d represents a protected represents an amino group, carboxyl group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, cyano group, hydroxyl group, lower alkoxy group, lower alkylthio group, or lower alkanesulfonyl group. ] Compounds represented by and general formula [] [In the formula, R ₂₀ represents a hydrogen atom or a lower alkyl group, and R ₂₁ represents the same meaning as above. ] By reacting the compound represented by or its salt with an acid under alkaline conditions, the general formula [-f] [In the formula, R ₁ , R ₂₀ , n and X _d have the same meanings as above. ] A β-lactam compound represented by the following can be produced. Examples of salts of the compound represented by the above general formula [] with acids include salts of hydrohalic acids such as hydrochloric acid, bromic hydroxyacid, iodohydric acid, etc., but salts with hydrochloric acid are preferable. It is. The reaction under alkaline conditions can be carried out at a pH of 8 to 14, preferably around PH9 to 10.
Alkaline reagents used in the reaction include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, etc. Alkali metal carbonates can be mentioned, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are preferred. Further, this reaction is preferably carried out using water as a solvent, but it can also be carried out in a mixed solvent of water and an organic solvent. Examples of organic solvents used include alcohols such as methanol, ethanol, and n-propanol, ethers such as tetrahydrofuran and dioxane, dimethylformamide,
Examples include acetonitrile. The reaction can be suppressed or accelerated by cooling or heating as appropriate, and a suitable reaction temperature is 0° C. to room temperature. After the reaction is completed, the resultant can be taken out using ordinary organic chemistry methods. For example, after the reaction mixture is brought to near neutrality, it is subjected to column chromatography using an adsorption resin, etc., to elute the target compound. A reaction product can be obtained by separating the portion and freeze-drying it. The compound represented by the above general formula [] has the following formula As shown in the figure, the 4th and 5th positions of the carbapenem skeleton
Although optical and stereoisomers exist based on the asymmetric carbons in positions 6, 6, and 8, and these isomers are all represented by a single formula for convenience, this provides that the present invention The scope of the description is not limited, and the present invention includes all isomers and isomer mixtures based on each asymmetric carbon atom. However, regarding the steric coordination at the 5th and 6th positions, when R ₁ is a hydrogen atom, the hydrogen atom at the 5th position preferably has an R coordination (5R, 6S), (5R,
6R) coordination compounds include (5S, 6S) coordination compounds and (5S, 6R) coordination compounds in which the carbon atom at position 5 has S coordination when R ₁ is a lower alkyl group. be able to. Regarding the 8-position, a compound having R coordination can be selected as a suitable one. Regarding the 4-position, there are isomers of R-coordination and S-coordination, and R-coordination is preferred. More preferable examples include compounds having (5R, 6S, 8R) coordination and (5R, 6R, 8R) coordination when R ₁ is a hydrogen atom, and compounds having (5R, 6R, 8R) coordination when R ₁ is a lower alkyl group. is (4R, 5S, 6S, 8R) coordination, (6R,
Examples include compounds with 5S, 6R, 8R) coordination. The most suitable coordination compound is the following formula (')
Or, compounds represented by (″) can be mentioned. (In the formula, R ₀ , R ₁ , R ₂ , X, Y and n have the same meanings as above.) When producing an isomer having such coordination, in the starting compound [] and [] Each corresponding isomer can be used. The compound of the present invention represented by the general formula [] is 3
It is a group of novel carbapenem derivatives having various 2-substituted pyrrolidin-4-ylthio groups at the 4-position and a lower alkyl group at the 4-position.These compounds exhibit excellent antibacterial activity and are useful compounds as pharmaceuticals. or are important intermediates for compounds that exhibit these activities. Specific examples of compounds having the above general formula [] in which R ₀ and R ₂ are hydrogen atoms, which can be obtained according to the present invention, include the compounds shown in Table 1 below. In Table 1, Me represents a methyl group, Et represents an ethyl group, Ac represents an acetyl group, and Pr represents a propyl group.

【table】

【table】

【table】

【table】

【table】

【table】

【table】

[Table] As mentioned above, stereoisomers exist in the compounds illustrated in Table 1, and the exemplified compounds include all isomers. However, the preferred carbapenem skeletons are (4R, 5S, 6S, 8R), (4R, 5S, 6R,
8R) coordination.
As for the pyrrolidinylthio group which is a substituent at the 3-position, preferred examples include those having the coordination represented by the following formula.

【formula】

[Formula] (In the formula, X, Y and n represent the same meanings as above.) The compound [] which is a raw material compound is a carbon atom [] [In the formula, R ₀ , R ₁ and R _2a have the same meanings as above. ] For example, benzenesulfonyl chloride, p-toluenesulfonyl chloride,
Substituted or unsubstituted arylsulfonylating agents such as p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, and p-bromobenzenesulfonyl chloride; lower classes such as methanesulfonic anhydride, methanesulfonyl chloride, and ethanesulfonyl chloride; Alkanesulfonylating agents, such as trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, halogeno-lower alkanesulfonylating agents, such as diarylphosphonylating agents, such as diphenyl chlorophosphate, or, for example, triphenylphosphine dichloride, triphenyl Treatment in the presence of a halogenating agent such as phosphine dibromide or oxalyl chloride and a base such as triethylamine, diisopropylethylamine or N-dimethylaminopyridine in an inert solvent such as methylene chloride, acetonitrile, dimethylformamide or tetrahydrofuran. It can be manufactured by The compound represented by the above general formula [] can be prepared by a known method, for example, when R ₁ is a hydrogen atom, (1) JP-A-55-27169 (2) Journal of American Chemical Society ( J.Am.Chem.Soc), vol. 103,
Pages 6765-6767 (1981) (3) Journal of Chemical Society
J.Chem.Perkin I, p.964~
(p. 968) 1981), when R ₁ is a lower alkyl group, (4) Heterocycles, Vol. 21,
Pages 29 to 40 (1984) (5) JP-A-58-26887 (6) It can be produced by the method described in JP-A-60-104088. On the other hand, the raw material mercaptan compound () can be produced from trans-4-hydroxy-L-proline or cis-4-hydroxy-D-proline by various methods. The novel β-lactam compound represented by the general formula [] according to the present invention includes Staphylococcus aureus, Staphylococcus epidermides, Streptococcus pyrodiens, Streptococcus fuecalis, Escherichia coli, Proteus・It has excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria such as S. mirabilis, Serratia marsetuscens, and Pseudomonas aeruginosa, and is particularly useful as an antibacterial agent that shows extremely excellent antibacterial activity against Gram-negative bacteria, or It is useful as an important synthetic intermediate in producing such antibacterial agents. Carbapenem compounds such as thienamycin are known to be unstable in vivo, especially to dehydropeptidase-I (DHP-I) localized in the kidney, but the compounds of the present invention, especially those in which R ₁ is β- One of its characteristics is that compounds with methyl groups are more stable against DHP-I, although the degree of stability differs depending on each compound.
Some of the compounds of the invention are extremely stable to DHP-I. The administration form for using the compound of the present invention as an antibacterial agent to treat bacterial infections includes, for example, oral administration in tablets, capsules, powders, syrups, etc., or parenteral administration in intravenous injection, intramuscular injection, rectal administration, etc. An example is administration. The dosage varies depending on symptoms, age, body weight, dosage form, number of administrations, etc., but is usually about 100 to 3000 mg per day for adults.
Administer in one or several doses. The amount can be reduced or increased as necessary. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is of course not limited to these in any way. The meanings of the abbreviations used in the following Examples and Reference Examples are as follows. PNZ: p-nitrobenzyloxycarbonyl group PMZ: p-methoxybenzyloxycarbonyl group PMB: p-methoxybenzyl group PNB: p-nitrobenzyl group Ph: phenyl group Ac: acetyl group Ms: methanesulfonyl group Ts: p-toluene Sulfony group TBDMS: tert-butyldimethylsilyl group Me: methyl group Et: ethyl group t-Butert-butyl group Example 1 a) (4R,5R,6S,8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)
-1-azabicyclo[3.2.0]-hept-3,7
-dione-2-carboxylate (511 mg) was dissolved in dry acetonitrile (3.1 ml), diisopropylamine (154
mg), then diphenylchlorophosphate (317
After stirring at the same temperature for 1 hour, diisopropylethylamine (154 mg) was added, followed by [2R,4S)-1-p-nitrobenzyloxycarbonyl -2-Methylaminocarbonylmethyl-4-mercaptopyrrolidine (420 mg) was added,
The mixture was stirred at -20 to -30°C for 1 hour. The reaction solution was diluted with a solvent of ether-dichloromethane (4:1), washed with water, washed with an aqueous monopotassium phosphate solution, dried with magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography. Purify (4R, 5S, 6S, 8R, 2′R, 4′R)
-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-methylaminocarbonylmethylpyrrolidine)-4-ylthio]
-4-methyl-6-(1-hydroxyethyl)-
1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (453 mg) was obtained. IR ^CHCl3 _nax cm ^-1 : 1762, 1700, 1655, 1520, 1403,
1343, 1212; NMRδ (CDCl ₃ ): 1.27 (3H, d, J = 2Hz),
1.34 (3H, d, J = 6.2Hz), 2.76 (3H, d,
J=4.6Hz), 5.21 (2H, s), 5.47 (1H,
d, J=13.6Hz), 6.94 (1H, bs), 8.18
(4H, d, J = 8.8Hz); b) (4R, 5S, 6S, 8R, 2′R, 4′S)-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2 -methylaminocarbonylmethylpyrrolidine)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate ( 45 mg) was dissolved in tetrahydrofuran (21 ml) and hydrogenated under morpholinopropanesulfonic acid buffer (PH 7.0, 14 ml) and normal hydrogen pressure for 1 hour at room temperature.
10% palladium-carbon (549
mg) was added and hydrogenated at room temperature for 3 hours under normal pressure of hydrogen. After passing through the catalyst, tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with dichloromethane, and the organic solvent was distilled off from the aqueous layer again under reduced pressure.
The residual liquid was subjected to polymer chromatography (CHP-
(4R, 5S, 6S, 8R,
2′R,4′S)-3-[(2-methylaminocarbonylmethylpyrrolidine)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept -2-en-7-one-2-carboxylic acid was obtained. UV ^H2O _nax nm: 298; IR ^KBr _nax cm ^-1 : 1748, 1650, 1585, 1380, 1250; NMR δ (D ₂ O): 1.19 (3H, d, J = 7Hz), 1.27
(3H, d, J=6Hz), 2.72 (3H, s),
2.79 (2H, d, J=7Hz), 3.44 (1H, dd,
J = 2.6Hz and 6Hz), 4.19 (1H, d, J
= 2.6Hz). Example 2 a) (4R,5R,6S,8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)
-1-azabicyclo[3.2.0]-hept-3,7
-dione-2-carboxylate (98 mg) was dissolved in dry acetonitrile (1 ml), diisopropylethylamine (39
mg), then diphenyl chlorophosphate (81
After stirring at the same temperature for 1 hour, diisopropylethylamine (35 mg) was added, followed by diisopropylethylamine (35 mg), followed by 2R,4S]-1-p-nitrobenzyloxycarbonyl. - Add a solution of 2-(dimethylaminocarbonylmethyl)-4-mercaptopyrrolidine (99 mg) in dry acetonitrile (1 ml) and -
Stirred at 20 to -30°C for 1 hour. The reaction solution was diluted with a solvent of ether-dichloromethane (4:1), washed with water, washed with an aqueous monopotassium phosphate solution, dried with magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography. Purify (4R, 5S, 6S, 8R, 2′R, 4′S)
-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylmethylpyrrolidine)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[ 3.2.0〕-Hept-2
-en-one-2-carboxylate (88 mg) was obtained. IR ^CHCl _3nax cm ^-1 : 1770, 1690, 1690, 1520, 1400,
1345, 1105; NMRδ (CDCl ₃ ): 1.28 (3H, d, J = 6.8Hz),
1.36 (3H, d, J=7Hz), 5.22 (2H, s),
5.49 (1H, d, J = 13.9Hz), 8.21 (4H,
d, J = 8.8Hz). b) (4R,5S,6S,8R,2′S,4′S)-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylmethylpyrrolidine)-4-ylthio ]-4-
Methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hept-2-en-7-one-2-carboxylate (83 mg) was dissolved in tetrahydrofuran (3.7 ml), and morpholinopropane was dissolved in tetrahydrofuran (3.7 ml). Sulfonic acid buffer (Hz7.0, 2.4
ml) and hydrogen at normal pressure for 1 hour at room temperature, washed with water, 10% palladium-carbon (101 mg) was added, and hydrogenated under hydrogen at normal pressure for 3 hours at room temperature. After passing through the catalyst, tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with dichloromethane, the organic solvent was distilled off from the aqueous layer again under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P). From the part eluted with 1% tetrahydrofuran aqueous solution (4R, 5S, 6S,
8R,2′R,4′S)-3-[(2-dimethylaminocarbonylmethylpyrrolidine)-4-ylthio]-
4-methyl-6-(1-hydroxyethyl)-1
-Azabicyclo[3.2.0]-hept-2-ene-
7-one-2-carboxylic acid was obtained. UV _H2Onax nm: 296; IR _KBrnax cm ^-1 : 1752, 1630, 1390, 1260, 1148; NMR δ (D ₂ O): 1.20 (3H, d, J = 6.9Hz),
1.27 (3H, d, J = 6.3Hz), 2.91 (3H,
s), 3.02 (3H, s). Example 3 a) (4R,5R,6S,8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)
-1-azabicyclo[3,2,0]-hept-
3,7-dione-2-carboxylate (101
mg) in dry acetonitrile (1.5 ml),
Diisopropylethylamine (37 mg), then diphenylchlorophosphate (77 mg) in dry acetonitrile (0.8 ml) under ice cooling in a nitrogen stream.
After adding a solution of and stirring at the same temperature for 1 hour, -
Cool to 35 °C and diisopropylethylamine (40
mg), then [2R,4S]-1-p-nitrobenzyloxycarbonyl-2-(2-dimethylaminocarbonylethyl)-4-mercaptopyrrolidine (117 mg) in dry acetonitrile (1 ml).
A solution of was added thereto, and the mixture was stirred at -20 to -30°C for 1 hour.
The reaction solution was mixed with ether-dichloromethane (4:1).
After washing with water, washing with an aqueous monopotassium phosphate solution, washing with water, drying with magnesium sulfate, evaporating the solvent, and purifying the residue by silica gel thin layer chromatography, (4R, 5S, 6S, 8R,
2′R,4′S)-p-nitrobenzyl-3-[(1-
p-nitrobenzyloxycarbonyl-2-
(2-dimethylaminocarbonylethylpyrrolidine)-4-ylthio]-4-methyl-6-(1
-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-
Carboxylate (90 mg) was obtained. IR ^CHCl3 _nax cm ^-1 : 1763, 1700, 1625, 1518, 1400,
1343; NMRδ (CDCl ₃ ): 1.26 (3H, d, J = 7.9Hz),
1.35 (3H, d, J = 6.4Hz), 2.91 (3H,
s), 2.95 (3H, s) 5.21 (2H, s), 5.48
(1H, d, J = 13.6Hz), 8.20 (4H, d, J
= 8.8Hz). b) (4R, 5S, 6S, 8R, 2′R, 4′S)-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-(2-dimethylaminocarbonylethylpyrrolidine)- 4-ylthio]
-4-methyl-6-(1-hydroxyethyl)-
1-azabicyclo[3,2,0]-hept-2
-en-7-one-2-carboxylate (90
mg) in tetrahydrofuran (4 ml),
Morpholinopropanesulfonic acid buffer (PH7.0,
2.7 ml) and 10% palladium, which was hydrogenated at room temperature under normal hydrogen pressure for 1 hour and washed with water.
Carbon (109 mg) was added and hydrogenated under normal hydrogen pressure for 3 hours at room temperature. After passing through the catalyst, tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with dichloromethane, the organic solvent was distilled off from the aqueous layer again under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P). From the part eluted with 1% tetrahydrofuran aqueous solution (4R,
5S, 6S, 8R, 2′R, 4′S)-3-[(2-(2-dimethylaminocarbonylethyl)pyrrolidine)
-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0]-hept-2-en-7-one-2-carboxylic acid was obtained. UV _H2Onax nm: 298; IR _KBrnax cm ^-1 : 1757, 1620, 1385, 1260, 1145; NMR δ (D ₂ O): 1.18 (3H, d, J = 7.3Hz),
1.26 (3H, d, J = 6.3Hz), 2.90 (3H,
s), 3.03 (3H, s). Example 4 a) (4R,5R,6S,8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)
-1-azabicyclo[3.2.0]-hept-3,7
-Dione-2-carboxylate (78 mg) was dissolved in dry acetonitrile (1 ml), diisopropylethylamine (29
mg), then diphenylchlorophosphate (59
After stirring at the same temperature for 1 hour, diisopropylethylamine (35 mg) was added, followed by [2R,4S]-1-p-nitrobenzyloxy. Carbonyl-2-(2-methylaminocarbonylethyl)-4-mercaptopyrrolidine (72mg)
Add a solution of dry acetonitrile (1 ml) of
The mixture was stirred at -20 to -30°C for 1 hour. The reaction solution was diluted with a solvent of ether-dichloromethane (4:1), washed with water, washed with an aqueous monopotassium phosphate solution, dried with magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography. Purify (4R, 5S, 6S, 8R, 2′R, 4′S)
-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-(2-methylaminocarbonylethyl)pyrrolidine)-4-
ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (68 mg) was obtained. IR _CHCl3nax cm ^-1 : 1767, 1695, 1518, 1400, 1341; NMR δ (Me ₂ CO-d ₆ ): 1.27 (3H, d, J = 5.9
Hz), 1.28 (3H, d, J=7Hz), 2.68 (3H,
d, J = 4.6Hz), 5.26 (2H, s). b) (4R,5S,6S,8R,2′R,4′S)-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-methylaminocarbonylethylpyrrolidine)-4-ylthio ]-4-Methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (68 mg) in 25% dimethylformamide/tetrahydrofuran (2.8
ml), hydrogenated with morpholinopropanesulfonic acid buffer (PH7.0, 1.4 ml) and hydrogen at normal pressure at room temperature for 1 hour, and washed with water.
% palladium-carbon (83 mg) was added and hydrogenated under atmospheric hydrogen pressure for 3 hours at room temperature. After passing through the catalyst, the tetrahydrofuran is distilled off under reduced pressure, the residual liquid is washed with dichloromethane, the organic solvent is distilled off from the aqueous layer again under reduced pressure, and the residual liquid is subjected to polymer chromatography (CHP-20P). and 1
(4R, 5S, 6S, 8R, 2′R, 4′S)-3-[2
-(2-methylaminocarbonylethylpyrrolidine)-4-ylthio]-4-methyl-6-(1
-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-
Carboxylic acid was obtained. UV ^H2O _nax nm: 299; IR ^KBr _nax cm ^-1 : 1751, 1640, 1592, 1382, 1253; NMR δ (D ₂ O): 1.19 (3H, d, J = 7.3Hz),
1.27 (3H, d, J = 6.3Hz), 2.71 (3H,
s), 3.44 (1H, dd, J = 1.7Hz and 5.9Hz). Example 5 a) (4R,5R,6S,8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)
-1-azabicyclo[3.2.0]-hept-3,7
- Dione-2-carboxylate (144 mg) was dissolved in dry acetonitrile (2 ml), diisopropylethylamine (45 mg) was dissolved in dry acetonitrile (2 ml) in a nitrogen stream and cooled with ice, followed by a solution of diphenylchlorophosphate (93 mg) in dry acetonitrile (1 ml). was added and stirred at the same temperature for 1 hour, then cooled to -35°C and diisopropylethylamine (49mg),
Then (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-hydroxymethyl-4-
Add a solution of mercaptopyrrolidine (117 mg) in dry acetonitrile (1 ml) and heat at -20 to -30°C.
The mixture was stirred for 1 hour. The reaction solution was diluted with a solvent of ether-dichloromethane (4:1), washed with water, washed with an aqueous phosphate-potassium solution, dried with magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography. Refined,
(4R,5S,6S,8R,2′S,4′S)-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-hydroxymethylpyrrolidine)-4-ylthio]-4- Methyl-6-(1-
hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-
Carboxylate (136 mg) was obtained. IR ^neat _nax cm ^-1 : 172, 1695, 1518, 340, 1210; NMR δ (CDCl ₃ ): 1.27 (3H, d, J = 6.4Hz),
1.33 (3H, d, J = 5.7Hz), 5.22 (2H,
s), 5.46 (1H, d, J = 13.9Hz), 8.18
(4H, d, J = 8.6Hz). b) (4R, 5S, 6S, 8R, 2′S, 4′S)-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-hydroxymethyl)-
4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (136 mg) was dissolved in tetrahydrofuran (6 ml).
I grinned. On the other hand, 10% palladium-carbon (165 mg) was hydrogenated in advance with morpholinopropanesulfonic acid buffer (PH7.0, 4 ml) and under normal hydrogen pressure at room temperature for 1 hour, and then washed with water.
This was added to the above tetrahydrofuran solution and hydrogenated under normal hydrogen pressure at room temperature for 3 hours. After passing through the catalyst, tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with dichloromethane, the organic solvent contained in the aqueous layer was distilled off under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P). From the part eluted with 1% tetrahydrofuran aqueous solution (4R, 5S, 6S, 8R, 2′S, 4′S)
-3-[(2-hydroxymethylpyrrolidine)-
4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid was obtained. UV ^H2O _nax nm: 298; IR ^KBr _nax cm ^-1 : 1748, 1585, 1386, 1252; NMR δ (D ₂ O): 1.20 (3H, d, J = 7.3Hz),
1.27(3H)d, J=6.3Hz). Example 6 a) (5R,6S,8R)-p-nitrobenzyl-
3-(diphenylphosphoryloxy)-6-(1
-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3.2.0]hept-
2-en-7-one-2-carboxylate (182 mg) was dissolved in dry acetonitrile (2 ml), diisopropylethylamine (34 mg) was added under ice cooling in a nitrogen stream, and then [2R,4S]-1
-p-nitrobenzyloxycarbonyl-2-
Dimethylaminocarbonylmethyl-4-mercaptopyrrolidine (88 mg) was added, and the mixture was stirred for 15 minutes. The reaction solution was diluted with a solvent of ether-dichloromethane (4:1), washed with water, and diluted with phosphoric acid.
The residue obtained by washing with an aqueous potassium solution, drying with magnesium sulfate, and evaporating the solvent was purified by silica gel thin layer chromatography to obtain (5R, 6S, 8R,
2′R,4′S)-p-nitrobenzyl-3-[(1-
p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylmethylpyrrolidine)-
4-ylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (137 mg) was obtained. IR ^CHCl _3nax cm ^-1 : 1780, 1743, 1700, 1630, 1517,
1255; NMRδ (CDCl ₃ ): 1.49 (3H, d, J = 6.4Hz),
2.92 (6H, s), 5.22 (2H, s), 5.26 (2H,
s), 5.46 (1H, d, J = 13.9Hz), 8.22
(6H, d, J = 8.1Hz). b) (5R, 6S, 8R, 2′R, 4′S)-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylmethylpyrrolidine)-4-ylthio]- 6-(1
morpholinopropanesulfonic acid After hydrogenation at room temperature for 1 hour under a buffer solution (PH7.0, 3.4 ml) and normal hydrogen pressure, 10% palladium-carbon (164 mg) washed with water was added and hydrogenated at room temperature for 4 hours under normal hydrogen pressure. did. After passing through the catalyst, tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with dichloromethane, the organic solvent was distilled off from the aqueous layer again under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P). Tokoro, 1
(5R, 6S, 8R, 2′R, 4′S)-3-[(2-
dimethylaminocarbonylmethylpyrrolidine)
-4-ylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]hepeto-2-
En-7-one-2-carboxylic acid was obtained. UV ^H2O _nax nm: 298; IR ^KBr _nax cm ^-1 : 1752, 1620, 1580, 1380, 1240,
1140; NMRδ (D ₂ O): 1.26 (3H, d, J = 6.3Hz),
2.91 (3H, s), 3.02 (3H, s). Example 7 a) (5R,6S,8R)-p-nitrobenzyl-
3-(diphenylphosphoryloxy)-6-(1
-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3.2.0]hept-
2-en-7-one-2-carboxylate (167 mg) was dissolved in dry acetonitrile (2.5 ml), diisopropylethylamine (54 mg) was added under ice cooling in a nitrogen stream, and then [2R, 4S]
-1-p-nitrobenzyloxycarbonyl-
2-Aminocarbonylmethyl-4-mercaptopyrrolidine (85 mg) was added, and the mixture was stirred for 15 minutes. The reaction solution was diluted with a solvent of ether-dichloromethane (4:1), washed with water, washed with an aqueous monopotassium phosphate solution, washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography (5R, 6S,
8R, 2′R, 4′S)-p-nitrobenzyl-3-
[(1-p-nitrobenzyloxycarbonyl-
2-aminocarbonylmethylpyrrolidine)-4
-ylthio]-6-(1-p-nitrobenzyloxylcarbonyloxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (60 mg) was obtained. IR ^Nujol _nax cm ^-1 : 1775, 1740, 1690, 1670 (sh),
1510, 1340; NMRδ (DMSO-d ₆ ); 1.34 (3H, d, J = 6.2
Hz), 5.23 (2H, s), 5.30 (2H, s), 6.82
(1H, bs), 8.21 (6H, d, J = 8.8Hz). b) (5R, 6S, 8R, 2′R, 4′S)-p-nitrobenzyl-3-[(1-p-nitrobenzyloxycarbonyl-2-aminocarbonylmethylpyrrolidine)-4-ylthio]-6 -(1-p-nitrobenzyloxycarbonyloxyethyl)
-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (60mg)
was dissolved in tetrahydrofuran (13 ml) and dimethylformamide (0.5 ml), and hydrogenated at room temperature for 1 hour under morpholinopropanesulfonic acid buffer (PH 7.0, 1.2 ml) and atmospheric hydrogen pressure.
10% palladium-carbon (73
mg) was added and the catalyst was hydrogenated under atmospheric hydrogen pressure for 4 hours at room temperature. After that, tetrahydrofuran and dimethylformamide were distilled off under reduced pressure, the residual liquid was washed with dichloromethane, the organic solvent was distilled off from the aqueous layer again under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P).
(5R, 6S, 8R, 2′R, 4′S)-3-[(2
-aminocarbonylmethylpyrrolidine)-4-
[ylthio]-6-(1-hydroxyethyl)-1
-Azabicyclo[3.2.0]hept-2-ene-
7-one-2-carboxylic acid was obtained. UV ^H2O _nax nm: 298; IR ^KBr _nax cm ^-1 : 1743, 1670, 1590, 1400, 1260; NMR δ( _D2O ): 1.2 (3H, d, J=6.3Hz). Example 8 (5R, 6S, 8R, 2′S, 4′S)-p-nitrobenzyl-3-[(1-dimethylaminocarbonyl-2-
p-Nitrobenzyloxycarbonylaminomethylpyrrolidine)-4-ylthio]-6-(1-p-
(nitrobenzyloxycarbonyloxyethyl)
-1-Azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (100 mg) was dissolved in tetrahydrofuran (10 ml), and morpholinopropanesulfonic acid buffer (PH7.0, 8.5 ml) and After hydrogenation at room temperature for 1 hour under normal hydrogen pressure,
Washed with excess water. 10% palladium-carbon (121
mg) and hydrogenated at room temperature for 4 hours under normal hydrogen pressure. After passing through the catalyst, the liquid was cooled to 0°C.
While adjusting the pH to 8.5 with 1N-NaOH, benzylformimidate hydrochloride (200 mg) was added, and after stirring for 10 minutes while maintaining the pH at 8.5 at the same temperature, tetrahydrofuran was distilled off from the reaction solution under reduced pressure to remove the residual liquid. was washed with dichloromethane, and the remaining organic solvent was distilled off from the aqueous layer under reduced pressure. When the residual liquid was subjected to polymer chromatography (CHP-20P), from the part eluted with a 1% aqueous tetrahydrofuran solution,
(5R,6S,8R,2′S,4′S)-3-[(1-dimethylaminocarbonyl-2-formamidinomethylpyrrolidine)-4-ylthio]-6-(1-hydroxyethyl)-1- Azabicyclo [3.2.0] Hept-
2-en-7-one-2-carboxylic acid was obtained. UV ^H2O _nax nm: 298; IR ^KBr _nax cm ^-1 : 1752, 1580, 1494, 133, 1240; NMR δ (D ₂ O): 1.25 (3H, d, J = 6.3Hz),
2.83 (6H, s) 7.78 (1H, s). Example 9 (5R, 6S, 8R, 2′S, 4′S)-p-nitrobenzyl-3-[(1-dimethylaminocarbonyl-2-
p-Nitrobenzyloxycarbonylaminomethylpyrrolidine)-4-ylthio]-6-(1-p-
(nitrobenzyloxycarbonyloxyethyl)
-1-Azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (100 mg) was dissolved in tetrahydrofuran (10 ml), and morpholinopropanesulfonic acid buffer (PH7.0, 8.5 ml) and After hydrogenation at room temperature for 1 hour under normal hydrogen pressure, 10% palladium-carbon (121 mg) washed with water was added, and hydrogenation was carried out under normal hydrogen pressure at room temperature for 4 hours. After passing through the catalyst, the liquid was cooled to 0°C, and while adjusting the pH to 8.5 with 1N-NaOH, ethyl acetimidate hydrochloride (250 mg) was added, and the mixture was stirred for 1 hour while maintaining the pH at 8.5 at the same temperature. ,
Tetrahydrofuran was distilled off from the reaction solution under reduced pressure, the residual liquid was washed with dichloromethane, and from the aqueous layer under reduced pressure,
The remaining organic solvent was distilled off. When the residual liquid was subjected to polymer chromatography (CHP-20P), (5R, 6S, 8R, 2'S, 4'S)-3-[(1-dimethylamino carbonyl-2-acetamidinomethylpyrrolidin)-4-ylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]
Hept-2-en-7-one-2-carboxylic acid was obtained. UV ^H ₂ ^O _nax nm: 299; IR ^KBr _nax cm ^-1 : 1756, 1590, 1500, 1395; NMR δ (D ₂ O): 1.26 (3H, d, J = 6.3Hz),
2.20 (3H, s), 2.84 (3H, s), 2.85 (3H,
s) Example 10 (4R, 5S, 6S, 8R, 2'R, 4'S) -3- [(2-
dimethylaminocarbonylmethylpyrrolidine)-
4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid (15 mg)
morpholinopropanesulfonic acid buffer (PH7.0,
15 ml), cooled to 0°C, added 4N sodium hydroxide solution dropwise to adjust the pH to 9.0, added benzylformimidate hydrochloride (100 mg), added 4N sodium hydroxide solution, and adjusted the pH to 9.0. maintain it,
After stirring for 10 minutes, 1N hydrochloric acid was added dropwise to adjust the pH to 7.6, the reaction solution was washed with dichloromethane, the dichloromethane remaining in the aqueous layer was distilled off under reduced pressure, and the remaining solution was subjected to polymer chromatography (CHP-20P). (6R, 5S, 6S, 8R, 2'R, 4'S)-3
-[(1-formimino-2-dimethylaminocarbonylmethylpyrrolidine)-4-ylthio]-4-
Methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid was obtained. UV ^H ₂ ^O _nax nm: 298; IR ^KBr _nax cm ^-1 : 1745, 1700, 1625, 1590, 1385; NMR δ (D ₂ O): 1.21 (3H, d, J = 7.3Hz),
1.28 (3H, d, J = 6.6Hz), 2.93 (3H,
s), 3.06 (3H, s), 7.99 (1H, s). Example 11 (4R, 5S, 6S, 8R, 2′R, 4′S)−3−{[2−
(1-pyrrolidinecarbonylmethyl)pyrrolidine]
-4-ylthio}-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid (10
mg) in morpholinopropanesulfonic acid buffer (PH
7.0, 15 ml), cooled to 0℃, added 4N sodium hydroxide solution dropwise to adjust the pH to 9.0, added ethyl acetimidate hydrochloride (100 mg) in 4 portions, and added 4N water each time. After adding sodium oxide solution dropwise to maintain the pH at 9.0 and stirring for 2 hours, the reaction solution was subjected to polymer chromatography (CHP-
(4R, 5S, 8R, 2′R,
4′R)-3-{[1-acetimino-2-(1-pyrrolidinecarbonylmethyl)pyrrolidine]-4-ylthio}-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0 ]-Hept-2-
En-7-one-2-carboxylic acid was obtained. UV ^H ₂ ^O _nax nm: 298; IR ^KBr _nax cm ^-1 : 1750, 1685 (sh), 1610, 1450,
1380, 1255; NMRδ (D ₂ O): 1.19 (3H, d, J = 7.3Hz),
1.28 (3H, d, J = 6.6Hz), 2.20 (3H,
s). The compounds shown in Tables 2 and 3 below can be obtained by the same method as in the above examples.

【table】

【table】

【table】

【table】

【table】

【table】

【table】

【table】

[Table] Reference example 1 Trans-4-hydroxy-L-proline (6.55 g) and triethylamine (7.5 ml) were dissolved in water (15 g).
ml) and added Sp-nitrobenzyloxycarbonyl-4,6-dimethyl-2 at room temperature.
- A solution of mercaptopyridine (15.95 g) in dioxane (35 ml) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours and left overnight. Add 22N sodium hydroxide (30ml) to the reaction mixture under ice cooling, extract with ether, wash the ether layer with 1N sodium hydroxide (20ml), combine the alkaline aqueous layers, and add 2N hydrochloric acid (100ml).
ml) and extracted with ethyl acetate. The ethyl acetate layer was sequentially washed with 2N hydrochloric acid, dried with sodium sulfate, and the solvent was distilled off. The resulting crude crystals were purified by repulping with ethyl acetate to obtain trans
-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline was obtained. mp: 134.3~135.5℃; IR ^Nujol _nax (cm ^-1 ): 3300 (br), 1738, 1660, 1605
，
1520, 1340, 1205, 1172, 1070, 965. Reference example 2 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline (15.0 g) and triethylamine (13.5 ml) were dissolved in dry dimethylformamide (150 ml), and p-methoxybenzyl chloride was dissolved under a nitrogen stream. (12.66
ml) was added dropwise and stirred at 70°C for 10 hours. The reaction solution was diluted with ethyl acetate (500ml), washed with water, dried with mirabilite,
The solvent was distilled off and the residue was crystallized from ether to give trans-1-(p-nitrobenzyloxycarbonyl)-
4-Hydroxy-X-proline-p-methoxybenzyl ester was obtained. mp: 83~85℃; IR ^neat _nax (cm ^-1 ): 3430, 1735, 1705, 1510, 1340
，
1245, 1160. The p-methoxybenzyl ester derivatives shown in Table 4 below were obtained in the same manner as above using the corresponding carboxylic acid derivatives.

【table】

【table】

IR ^neat _nax cm ^-1 : 1740, 1702, 1523, 1405, 1345 IR ^neat _nax cm ^-1 : 1732, 1697, 1515, 1393, 1342. Reference example 3 Trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-L-proline-p-methoxybenzyl ester (49 g) was dissolved in dry tetrahydrofuran (300 ml), triethylamine (33 ml) and 4-dimethylaminopyridine (9.59 g)
g) and benzoyl chloride (33.2g).
After refluxing for an hour, tetrahydrofuran was distilled off.
The residue was diluted with ethyl acetate, washed with water, washed with dilute hydrochloric acid,
Washing with water, washing with sodium bicarbonate, washing with water, drying with sodium sulfate, the solvent was distilled off, the residue was crystallized from ether, and trans-1
-p-nitrobenzyloxycarbonyl-4-benzoyloxy-L-proline-p-methoxybenzyl ester was obtained. IR ^Nujol _nax cm ^-1 : 1740, 1716, 1703, 1608, 1516,
1343. Reference example 4 trans-1-p-nitrobenzyloxycarbonyl-4-benzoyloxy-L-proline-
Anisole (12.8 ml) was added to p-methoxybenzyl ester (61.3 g), then trifluoroacetic acid (70 ml) was added, and after stirring at room temperature for 30 minutes, the trifluoroacetic acid was distilled off and ethyl acetate was added to the residue. Next, add sodium bicarbonate solution to collect the precipitated crystals, dissolve them in methanol, and add 6N hydrochloric acid to adjust the pH.
= 1, ethyl acetate was added, washed with water, dried with mirabilite, and the solvent was distilled off to give trans-1-p-nitrobenzyloxycarbonyl-4-benzoyloxy-L.
- Obtained proline. IR ^CHCl3 _nax cm ^-1 : 1720, 1610, 1527, 1436, 1350,
1275, 1114. The carboxylic acid derivatives shown in Table 5 below were obtained by the same method as above using the corresponding p-methoxybenzyl ester derivatives.

[Table] Reference example 5 Trans-1-p-nitrobenzyloxycarbonyl-4-benzoyloxy-L-proline (43.1 g) was dissolved in dry tetrahydrofuran (86 ml), triethylamine (12.2 g) was added, and the mixture was heated at -10 to -15°C in a nitrogen stream. Ethyl chloroformate (13.0
g) was added dropwise, and after stirring at the same temperature for 15 minutes, the reaction solution was filtered, and the solution was added to a solution of sodium borohydride (7.68 g) in water (78 ml) at 0°C. After stirring for an hour, the reaction solution was diluted with ethyl acetate, washed with water, washed with diluted hydrochloric acid, washed with water, added aqueous sodium bicarbonate to the ethyl acetate layer, separated the precipitated crystals, washed the ethyl acetate layer with water, dried sodium sulfate, and removed the solvent. Distillation gave (2S,4R)-1p-nitrobenzyloxycarbonyl-2-hydroxymethyl-4-benzoyloxy-pyrrolidine. IR ^CHCl3 _nax cm ^-1 : 1720, 1530, 1435, 1352, 1280,
1115. Reference example 6 Dissolve (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-hydroxymethyl-4-benzoyloxypyrrolidine (32.06 g) in dry pyridine (64 ml), add p-toluenesulfonyl chloride (28.02 g), After stirring at room temperature for 12 hours, water was added to the reaction solution, extracted with a solvent of ether-dichloromethane (4:1), washed with brine, diluted hydrochloric acid, washed with brine, washed with sodium bicarbonate, washed with sodium chloride, dried with sodium sulfate, and the solvent was distilled off. The residue was crystallized from ether to obtain (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-p-toluenesulfonyloxymethyl-4-benzoyloxypyrrolidine. IR ^CHCl3 _nax cm ^-1 : 1700, 1518, 1342, 1265, 1172,
1090. Reference example 7 (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-p-toluenesulfonyloxymethyl-4-benzoyloxypyrrolidine (35.82
g) in methyl ethyl ketone (90 ml), added sodium iodide (19.29 g), and refluxed for 1 hour. The reaction solution was filtered and the solvent was distilled off.
The residue was dissolved in ethyl acetate, washed with water, washed with sodium hypochlorite, washed with water, dried with sodium sulfate, and then the solvent was distilled off to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-iodomethyl-4- Benzoyloxypyrrolidine was obtained. IR ^Nujol _nax cm ^-1 : 1710, 1515, 1394, 1275, 1115. Reference example 8 (2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-iodomethyl-4-benzoyloxypyrrolidine (5.24 g) was dissolved in dry dimethylformamide (26 ml), sodium cyanide (539 mg) was added thereto, and the mixture was heated at room temperature. After stirring for 24 hours at
Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried with sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (2R, 4R).
-1-p-nitrobenzyloxycarbonyl-2
-cyanomethyl-4-benzoyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 2250, 1715, 1605, 1520, 1400,
1345, 1275, 1110. Reference example 9 (2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-cyanomethyl-4-benzoyloxypyrrolidine (3.0 g) was dissolved in acetic acid (10 ml) and concentrated hydrochloric acid (10 ml), and after refluxing for 3 hours, the solvent was distilled. The residue was dissolved in water (4 ml) and then diluted with 1N
-NaOH (25 ml) was added, and p-nitrobenzyloxycarbonyl chloride (1.53
A solution of ether (6 ml) and tetrahydrofuran (2 ml) from g) was added, and after stirring at the same temperature for 30 minutes, the reaction solution was separated and the aqueous layer was PHed with 6N-HCl.
= 1, extracted with ethyl acetate, washed with water, dried with Glauber's salt, and then distilled off the solvent to obtain (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-carboxymethyl-4-hydroxypyrrolidine. IR ^Nujol _nax cm ^-1 : 1690, 1603, 1517, 1460, 1200,
1116. Reference example 10 (2R,4R)-1-p-Nitrobenzyloxycarbonyl-2-p-methoxybenzyloxycarbonylmethyl-4-hydroxypyrrolidine (1.40 g) was dissolved in dry tetrahydrofuran (7 ml) and triphenylphosphine ( Then, diethyl azodicarboxylate (783 mg) was added at 0°C, and after stirring at the same temperature for 30 minutes, thioacetic acid (342 mg) was added, and after stirring for 1 hour, the reaction solution was diluted with ethyl acetate. The solvent was distilled off, the residue was purified by silica gel column chromatography, and (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-p- Methoxybenzylcaroxybonylmethyl-4-acetylthiopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1700, 1605, 1510, 1400, 1343,
1240. The thioacetate derivatives shown in Table 6 below were obtained in the same manner as above using the corresponding alcohols.

【table】

【table】

IR ^neat _nax cm ^-1 : 1725 (sh), 1686, 1515, 1407,
1342, 1242. Reference example 11 Anisole (330 mg) was added to (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-p-methoxybenzyloxycarbonylmethyl-4-acetylthiopyrrolidine (810 mg), and then trifluoroacetic acid (4 ml) was added. After stirring at room temperature for 30 minutes, trifluoroacetic acid was distilled off, and the residue was purified by silica gel thin layer chromatography to obtain (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-carboxymethyl-4. - Acetylthiopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1690, 1602, 1517, 1400, 1342,
1108. Reference example 12 (2R,4S)-1-p-Nitrobenzyloxycarbonyl-2-carboxymethyl-4-acetylthiopyrrolidine (125 mg) was dissolved in dry dichloromethane (1 ml), and oxalyl chloride (0.1 ml) and a catalytic amount of After adding dimethylformamide and stirring at room temperature for 2 hours, the solvent was distilled off, the residue was dissolved in dry benzene, and the benzene was distilled off. After repeating this operation twice, the residue was dissolved in dry dichloromethane (2 ml), This was heated to 0°C in a nitrogen stream.
dimethylamine (45 mg) in dry dichloromethane (1.5 ml) and dry tetrahydrofuran (0.2 ml)
After stirring at the same temperature for 30 minutes, the reaction solution was washed with water, diluted hydrochloric acid, water, sodium bicarbonate, water,
After drying the sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography to obtain (2R,4S)-
1-p-nitrobenzyloxycarbonyl-2-
Dimethylaminocarbonylmethyl-4-acetylthiopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1700, 1635, 1518, 1398, 1342,
1100. By the same method as above, (2R,4S)-1-p
-(2R,4S)-1-p-nitrobenzyloxycarbonyl-2-(2-dimethylaminocarbonylethyl)-4-acetylthiopyrrolidine is obtained from nitrobenzyloxycarbonyl-2-carboxyethyl-4-acetylthiopyridine. Ta. IR ^neat _nax cm ^-1 : 1690, 1630, 1515, 1400, 1346,
1110. Reference example 13 (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylmethyl-4-acetylthiopyrrolidine (100 mg) was dissolved in methanol (3 ml) and heated at room temperature in a nitrogen stream.
After adding 1N-NaOH (0.24 ml) and stirring at the same temperature for 15 minutes, 1N-HCl (0.24 ml) was added and the solvent was distilled off. (2R,4S)-1-p
-Nitrobenzyloxycarbonyl-2-dimethylaminocarbonylmethyl-4-mercaptopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1700, 1640, 1520, 1400, 1345,
1100. The mercaptan derivatives shown in Table 7 below were obtained by the same method as above using the corresponding thioacetate derivatives.

【table】

【table】

IR ^CHCl _3nax cm ^-1 : 1695, 1585, 1470, 1362, 1320. Reference example 14 (2R,4S)-1-p-Nitrobenzyloxycarbonyl-2-carboxymethyl-4-acetylthiopyrrolidine (82 mg) was dissolved in dry tetrahydrofuran (1.5 ml) and triethylamimine (33
mg), then added ethyl chloroformate (35 mg) at -10 to -15°C in a nitrogen stream, stirred at the same temperature for 30 minutes, cooled to -40°C, and cooled to 29% (w/w) ammonia aqueous solution ( After stirring at -30 to -40℃ for 30 minutes, dilute hydrochloric acid was added to the reaction solution to make it acidic.
Ethyl acetate was added, washed with water, washed with sodium bicarbonate, washed with water, dried with mirabilite, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography to obtain (2R,4S)-1.
-p-nitrobenzyloxycarbonyl-2-amino-carbonylmethyl-4-acetylthiopyrrolidine was obtained. IR ^CHCl3 _nax cm ^-1 : 1705, 1603, 1518, 1395, 1342,
1260, 1105. The amide derivatives shown in Table 8 below were obtained in the same manner as above using the corresponding carboxylic acids.

【table】

[Table] Reference example 15-1 (2R,4S)-1-p-Nitrobenzyloxycarbonyl-2-carboxymethyl-4-acetylthiopyrrolidine (153 mg) was dissolved in dry tetrahydrofuran (2 ml) and triethylamine (61
mg), then added ethyl chloroformate (65 mg) at -10 to -15°C in a nitrogen stream, stirred at the same temperature for 30 minutes, cooled to -40°C, and added 30% methylamine ethanol solution (414 mg). After stirring at -20 to -30°C for 1 hour, the reaction solution was made acidic with dilute hydrochloric acid, ethyl acetate was added, washed with water, washed with sodium bicarbonate, washed with water, dried with Glauber's salt, the solvent was distilled off, and the residue was separated into a thin layer of silica gel. Purified by chromatography to produce (2R,4S)-1-p
-Nitrobenzyloxycarbonyl-2-methylaminocarbonylmethyl-4-mercaptopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1700, 1642, 1515, 1458, 1350. Reference example 15-2 (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-carboxymethyl-4-acetylthiopyrrolidine was subjected to the same reaction as in Reference Example 15-1, and (2R,4S)-1-p- Nitrobenzyloxycarbonyl-2-(1-pyrrolidinecarbonylmethyl)-4-mercaptopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1700, 1615, 1520, 1430, 1356,
1107. Reference example 16 (2R,4S)-1-p-Nitrobenzyloxycarbonyl-2-carboxymethyl-4-acetylthiopyrrolidine (148 mg) was dissolved in dry dichloromethane (2 ml), and oxalyl chloride (0.2 ml) and a catalytic amount of After adding dimethylformamide and stirring at room temperature for 2 hours, the solvent was distilled off, the residue was dissolved in dry benzene, and the benzene was distilled off.
After repeating this operation twice, the residue was dissolved in dry dichloromethane (2 ml), and this was added to a solution of methanol (125 mg) and triethylamine (81 mg) in dry dichloromethane (1 ml) under ice-cooling in a nitrogen stream. After stirring for 2 hours, the reaction solution was mixed with water,
Washing with diluted hydrochloric acid and drying with Glauber's salt and distilling off the solvent gave (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-methoxycarbonylmethyl-
4-Acetylthiopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1736, 1710, 1522, 1406, 1352,
1160. Reference example 17 (2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-iodomethyl-4-benzoyloxypyrrolidine (5.24 g) was dissolved in dry dimethylformamide (21 ml), phthalimide potassium salt (2.22 g) was added, and the mixture was heated at 90°C. After stirring for 6 hours with
Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried with mirabilite, the solvent was distilled off, and the residue was purified by silica gel column chromatography (2S, 4R).
-1-p-nitrobenzyloxycarbonyl-2
-phthalimidoylmethyl-4-benzoyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1775, 1720, 1605, 1522, 1346,
1275. Reference example 18 (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-phthalimidoylmethyl-4-benzoyloxypyrrolidine (490 mg) was dissolved in ethanol (20 ml), and hydrazine monohydrate (432 mg) was dissolved in ethanol (20 ml).
was added, and after refluxing for 30 minutes, the reaction solution was filtered.
The solvent of the liquid was evaporated, the residue was dissolved in dry tetrahydrofuran (3 ml), trichloroacetyl isocyanate (212 mg) was added, and after stirring at room temperature for 3 hours, the solvent was evaporated, and the residue was purified by silica gel thin layer chromatography. (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-trichloroacetylaminocarbonylaminomethyl-4-benzoyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1710, 1600, 1517, 1440, 1270,
1110. Reference example 19 (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-trichloroacetylaminocarbonylaminomethyl-4-benzoyloxypyrrolidine (431 mg) was dissolved in methanol (10 ml),
Add 1N aqueous sodium hydroxide solution (1.48ml),
After stirring at room temperature for 1.5 hours, 1N hydrochloric acid (1.48 ml)
was added, methanol was distilled off, the residue was dissolved in dichloromethane, washed with water, dried with mirabilite, the solvent was distilled off, the residue was purified by silica gel thin layer chromatography, and (2S,4R)-1-p- Nitrobenzyloxycarbonyl-2-aminocarbonylaminomethyl-4-hydroxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1665, 1596, 1510, 1425, 1336,
1103. Reference example 20-1 (2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-phthalimidoylmethyl-4-benzoyloxypyrrolidine (105 mg) was dissolved in ethanol (2 ml), and hydrazine monohydrate (14
After refluxing for 30 minutes, the reaction solution was filtered, the solvent was distilled off, the residue was dissolved in tetrahydrofuran (2 ml), and triethylamine (115
After stirring at room temperature for 1 hour, the reaction solution was diluted with ethyl acetate, washed with water, washed with dilute hydrochloric acid, washed with water, washed with sodium bicarbonate, washed with water, and dried with sodium sulfate.The solvent was distilled off. The residue was purified by silica gel thin layer chromatography to obtain (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylaminomethyl-4-benzoyloxypyrrolidine. IR ^neat _nax cm ^-1 : 1710, 1640, 1530, 1345, 1275,
1110. Reference example 20-2 (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-phthalimidoylmethyl-4-benzoyloxypyrrolidine was treated in the same manner as in Reference Example 20-1, and (2S,4R)-1-p- Nitrobenzyloxycarbonyl-2-ethoxycarbonylmethyl-4-benzoyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1705, 1515, 1400, 1345, 1270,
1100. Reference example 20-3 (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-phthalimidoylmethyl-4-benzoyloxypyrrolidine was treated in the same manner as in Reference Example 20-1, and (2S,4R)-1-p- Nitrobenzyloxycarbonyl-2-acetylaminomethyl-4-benzoyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1705, 1520, 1400, 1345, 1275,
1110. Reference example 21 (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylaminomethyl-4-benzoyloxypyrrolidine (145
mg) in methanol (2.4 ml) and add 1N
-NaCH (0.32 ml) was added and stirred at room temperature for 30 minutes, then 1N-HCl (0.32 ml) was added, methanol was distilled off, dichloromethane was added to the residue, washed with water, dried with Glauber's salt, and the solvent was distilled off. , the residue was purified by silica gel thin layer chromatography to obtain (2S,4R)-
1-p-nitrobenzyloxycarbonyl-2-
Dimethylaminocarbonylaminomethyl-4-hydroxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1690, 1632, 1530, 1410, 1345,
1110. The alcohol derivatives shown in Table 9 below were obtained in the same manner as above using the corresponding benzoic acid esters.

【table】

【table】

[Table] Reference example 22 (2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-hydroxymethyl-4-benzoyloxypyrrolidine (1.09 g) was dissolved in dry dimethylformamide (16.5 ml), imidazole (0.46 g) was added, then tert. -Butyldimethylsilyl chloride (0.49g) was added, and after stirring at room temperature for 2 hours, the reaction solution was diluted with ethyl acetate, washed with water, dried with magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography. Purification was performed to obtain (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-tert-butyldimethylsilyloxymethyl-4-benzoyloxypyrrolidine. IR ^neat _nax cm ^-1 : 1710, 1520, 1400, 1340, 1265,
1108. Reference example 23 (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-tert-butylmethylsilyloxymethyl-4-acetylthiopyrrolidine (0.85g)
was dissolved in methanol (8.5 ml) and 6N-HCl (0.85
ml) and stirred at room temperature for 2.5 hours, the reaction solution was diluted with ethyl acetate, washed with water, dried with magnesium sulfate, the solvent was distilled off, and the residue was crystallized from ether (2S,4S)-1- p-nitrobenzyloxycarbonyl-2-hydroxymethyl-4-acetylthiopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1695, 1520, 1430, 1402, 1343,
1110. Reference example 24 (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-hydroxymethyl-4-acetylthiopyrrolidine (100 mg) was added to dry ethyl acetate (3
ml), added trichloroacetyl isocyanate (0.05 ml) under ice-cooling in a nitrogen stream, and stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with sodium bicarbonate, washed with water, and dried with mirabilite. The solvent was distilled off to obtain (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-trichloroacetylaminocarbonyloxymethyl-4-acetylthiopyrrolidine. IR ^neat _nax cm ^-1 : 1722, 1680, 1602, 1400, 1335,
1250, 1102. Reference example 25 (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-trichloroacetylaminocarbonyloxymethyl-4-acetylthiopyrrolidine (121 mg) was dissolved in methanol (5.8 ml) and 1N-NaOH ( After stirring at the same temperature for 40 minutes, 1N-HCl (0.45 ml) was added, the solvent was distilled off, the residue was dissolved in dichloromethane, washed with water, dried with Glauber's salt, and the solvent was distilled off ( 2S,
4S)-1-p-nitrobenzyloxycarbonyl-2-aminocarbonyloxymethyl-4-mercaptopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1715, 1603, 1512, 1398, 1360,
1098. Reference example 26 (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-hydroxymethyl-4-acetylthiopyrrolidine (78 mg) was added to dry pyridine (1 ml).
4-dimethylaminopyridine (135mg)
was added, then dimethylaminocarbonyl chloride (119 mg) was added, and after stirring at 90 to 100°C for 20 hours, water was added to the reaction solution, extracted with ethyl acetate, and the ethyl acetate layer was mixed with water, dilute hydrochloric acid, water, sodium bicarbonate solution, After washing with water in order and drying the sodium sulfate, the solvent was distilled off (2S, 4S).
-1-p-nitrobenzyloxycarbonyl-2
-dimethylaminocarbonyloxymethyl-4-
Acetylthiopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1700, 1515, 1393, 1340, 1185,
1100. NMRδ (CDCl ₃ ): 2.23 (3H, s), 2.89 (6H.s),
5.23 (2H, s). Reference example 27 Triethylamine (21 ml) was added to a solution of trans-4-hydroxy-L-proline (13.1 g) in water (55 ml), followed by a solution of 2-p-methoxybenzyloxycarbonylthio-4,6-dimethylpyrimidine (33.44 g). After adding a solution of dimethylformamide (55 ml) and stirring at room temperature for 12 hours,
Water was added to the reaction solution, washed with ethyl acetate, and then the aqueous layer was heated to 0°C and the pH was adjusted to 2 with cold 5N-HCl.
The extract was extracted with ethyl acetate, washed successively with diluted hydrochloric acid and saturated brine, dried with sodium sulfate, and then the solvent was distilled off to obtain trans-1-p-methoxybenzyloxycarbonyl-4-hydroxy-L-proline. IR ^neat _nax cm ^-1 : 1670, 1435, 1350, 1240, 1168. Reference example 28 trans-1-p-methoxybenzyloxycarbonyl-4-hydroxy-L-proline (5.0
Dissolve g) in methanol (50 ml) and tetrahydrofuran (50 ml), add an ethereal solution of diazomethane under ice-cooling until no more nitrogen is generated, and leave at room temperature overnight to evaporate the solvent. -p-methoxybenzyloxycarbonyl-4-hydroxy-L-proline methyl ester was obtained. IR ^neat _nax cm ^-1 : 1748, 1695, 1518, 1438, 1360,
1250, 1175. Reference example 29 Trans-1-p-methoxybenzyloxycarbonyl-4-hydroxy-L-proline methyl ester (5.18 g) was dissolved in dry dimethylformamide (52 ml), followed by triethylamine (3.79 g) and then tert-butyldimethylsilyl chloride ( After stirring at room temperature for 3 hours, water was added to the reaction solution, extracted with ethyl acetate, washed with water, washed with diluted hydrochloric acid, washed with water, dried with Glauber's salt, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. The resulting product was purified by E to obtain trans-1-p-methoxybenzyloxycarbonyl-4-tert-butyldimethylsilyloxy-L-proline methyl ester. IR ^neat _nax cm ^-1 : 1750, 1710, 1517, 1415, 1355,
1250, 1115. The t-butyldimethylsilyl ether derivatives shown in Table 10 below were obtained in the same manner as above using the corresponding alcohols.

[Table] Reference example 30 Trans-1-p-methoxybenzyloxycarbonyl-4-tert-butyldimethylsilyloxy-L-proline methyl ester (5.64 g) was dissolved in dry tetrahydrofuran (56.4 ml) and sodium borohydride (1.01 g) was dissolved in a nitrogen stream. and lithium iodide (3.52 g) were added, and after refluxing for 1 hour, water was added to the reaction solution, extracted with ethyl acetate, washed with water,
After drying Glauber's salt, the solvent was distilled off and (2S,4R)-1-
p-methoxybenzyloxycarbonyl-2-hydroxymethyl-4-tert-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1670, 1504, 1420, 1405, 1240,
1100. The alcohol derivatives shown in Table 11 below were obtained by the same method as above using the corresponding methyl ester derivatives.

【table】

[Table] Reference example 31-1 a) (2S,4R)-1-p-methoxybenzyloxycarbonyl-2-hydroxymethyl-4-
Using tert-butyldimethylsilyloxypyrrolidine (4.83 g) and the same method as in Reference Example 6, (2S,4R)-1-p-methoxybenzyloxycarbonyl-2-toluenesulfonyloxymethyl-4-tert-butyl Dimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1700, 1505, 1402, 1354, 1240,
1166. b) Using the tosylate derivative (6.52 g) obtained in a) above, (2S,4R)-1-p-methoxybenzyloxycarbonyl-2-iodomethyl-4-tert was prepared in the same manner as in Reference Example 7.
-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1700, 1512, 1405, 1353, 1248,
1100. c) The iodine derivative obtained in b) above (5.99
g) using the same method as Reference Example 17,
(2S,4R)-1-p-methoxybenzyloxycarbonyl-2-phthalimidoylmethyl-4
-tert-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1757, 1715, 1510, 1390, 1245,
1111. Reference example 31-2 (2S,4R)-1-p-methoxybenzyloxycarbonyl-2-phthalimidoylmethyl-4-
Tert-butyldimethylsilyloxypyrrolidine (1.63 g) was dissolved in ethanol (31 ml), hydrazine monohydrate (626 mg) was added, and after refluxing for 30 minutes, the reaction solution was filtered, and the solvent was distilled off to form a residue. was dissolved in dry dichloromethane (15 ml), triethylamine (291 mg) was added in a nitrogen stream, and then p-nitrobenzyloxycarbonyl chloride (620 mg) was dissolved in dry dichloromethane (3 ml) under ice cooling.
After adding a solution of and stirring at the same temperature for 1 hour, the reaction solution was washed with water, diluted hydrochloric acid, water, sodium bicarbonate, water,
After drying Glauber's salt, the solvent was distilled off and the residue was purified by silica gel column chromatography (2S,
4R)-1-p-methoxybenzyloxycarbonyl-2-p-nitrobenzyloxycarbonylaminomethyl-4-tert-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1720, 1690 (sh), 1517, 1345,
1245, 1112. Reference example 322 (2S,4R)-1-p-methoxybenzyloxycarbonyl-2-p-nitrobenzyloxycarbonylaminomethyl-tert-butyldimethylsilyloxypyrrolidine (850 mg) was dissolved in methanol (8.5 ml), and 6N-HCl ( After stirring at room temperature for 30 minutes, ethyl acetate was added to the reaction solution, washed with water, dried with sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain (2S, 4R)-1. -p-methoxybenzyloxycarbonyl-2-p-nitrobenzyloxycarbonylaminomethyl-4-hydroxypyrrolidine was obtained. IR ^CHCl _3nax cm ^-1 : 1720 (sh), 1680, 1510, 1410,
1342, 1225. The alcohol derivatives shown in Table 12 below were obtained in the same manner as above using the corresponding t-butylmethylsilyl ether derivatives.

【table】

[Table] Reference example 33 Anisole (216 mg) was added to (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-p-nitrobenzyloxycarbonylaminomethyl-4-acetylthiopyrrolidine (500 mg), and then trifluoroacetic acid (4 ml) was added. After stirring at room temperature for 1 hour, trifluoroacetic acid was distilled off, the residue was dissolved in dichloromethane, washed with sodium bicarbonate, water, and dried with sodium sulfate, then the solvent was distilled off, the residue was dissolved in tetrahydrofuran (4 ml), and triethylamine (152 mg) was added. and dimethylaminocarbonyl chloride (141 mg) were added, and after stirring at room temperature for 30 minutes, ethyl acetate was added to the reaction mixture, washed with water, washed with dilute hydrochloric acid, washed with water, washed with sodium bicarbonate, washed with water, dried with sodium sulfate, and the solvent was distilled off to remove the residue. Purification by silica gel thin layer chromatography gave (2S,4S)-1-dimethylaminocarbonyl-2-p-nitrobenzyloxycarbonylaminomethyl-4-acetylthiopyrrolidine. IR ^neat _nax cm ^-1 : 1720, 1695 (sh), 160, 1510,
1446, 1240. Reference example 34-1 (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-hydroxymethyl-4-acetylthiopyrrolidine (200 mg) was dissolved in dry tetrahydrofuran (2 ml), and methyl isocyanate (0.168 ml) was added thereto for 10 hours. After refluxing, the reaction solution was concentrated, and the residue was purified by silica gel thin layer chromatography to obtain (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-methylaminocarbonyloxymethyl-4-acetylthiopyrrolidine. I got it. IR ^neat _nax cm ^-1 : 1702, 1521, 1402, 1350, 1258,
1110. Reference example 34-2 (2S,4S)-1-p-Nitrobenzyloxycarbonyl-2-hydroxymethyl-4-acetylthiopyrrolidine (300 mg) was added to dry pyridine (1.5
ml), add acetic anhydride (1.5 ml) to this,
After stirring at room temperature for 5 hours, water was added to the reaction solution and extracted with ether. The ether layer was washed with brine, diluted hydrochloric acid, brine, sodium bicarbonate, and brine. After drying with sodium sulfate, the solvent was distilled off (2S, 4S). )-1-p-nitrobenzyloxycarbonyl-2-acetoxymethyl-
4-Acetylthiopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1735, 690, 1512, 1390, 1340,
1225. Reference example 34-3 (2S,4S)-1-p-Nitrobenzyloxycarbonyl-2-hydroxymethyl-4-acetylthiopyrrolidine (177 mg) was dissolved in dry dichloromethane (2 ml), and triethylamine (76 mg) was dissolved in dry dichloromethane (2 ml).
Dissolve ethyl chloroformate (81 mg) and 4-dimethylaminopyridine (61 mg) under ice-cooling in a nitrogen stream.
After stirring at the same temperature for 3.5 hours, the reaction solution was washed with water, diluted hydrochloric acid, water, sodium bicarbonate, and water in order, and after drying with sodium sulfate, the solvent was distilled off (2S, 4S)-1-
p-nitrobenzyloxycarbonyl-2-ethoxycarbonyloxymethyl-4-acetylthiopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1740, 1702, 1520, 1400, 1343,
1248. Reference example 35 Dimethyl malonate (660 mg) was added to a suspension of 50% sodium hydride (180 ml) in dry dimethylformamide (12.5 ml) under a stream of nitrogen and the solution was stirred for 15 min at room temperature.
After stirring for a minute, (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-iodomethyl-4
After adding -tert-butyldimethylsilyloxypyrrolidine (1.34 g) and stirring at room temperature for 15 hours, 1N-hydrochloric acid (3.75 ml) was added to the reaction mixture, water was further added, and extraction with ethyl acetate was performed. After drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain (2S,4R)-1-p.
-nitrobenzyloxycarbonyl-2-(2,
2-dimethoxycarbonylethyl)-4-tert-
Butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1755, 1710, 1527, 1400, 1350,
1258. By the same method as above, (2S,4R)-1-benzyloxycarbonyl-2-iodomethyl-4
-tert-butyldimethylsilyloxypyrrolidine (2S,4R)-1-benzyloxycarbonyl-2-(2,2-dimethoxycarbonylethyl)-
4-t-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1735, 1700, 1430, 1403, 1342. Reference example 36 (2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-(2,2-dimethoxycarbonylethyl)-4-tert-butyldimethylsilyloxypyrrolidine (1.04 g) was dissolved in methanol (6 ml) and heated to room temperature. After adding 4N aqueous sodium hydroxide solution (3 ml) and stirring at the same temperature for 1.5 hours, 6N aqueous hydrochloric acid (6 ml) and then tetrahydrofuran (5 ml) were added to the reaction solution, and after stirring at room temperature for 2 days, the reaction solution Water and then aqueous sodium bicarbonate were added to make it alkaline, the aqueous layer was washed with ether, the aqueous layer was brought to pH 1 with hydrochloric acid, extracted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off. )-1-p
-nitrobenzyloxycarbonyl-2-(2-
Carboxyethyl)-4-hydroxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1710, 1610, 1524, 1435, 1410,
1352. Reference example 37 Dissolve (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-iodomethyl-4-benzoyloxypyrrolidine (1.05 g) in dimethylformamide (10 ml), and add 15% methyl mercaptan sodium salt aqueous solution (1.40 g) to this solution. After stirring for 30 minutes at room temperature in a nitrogen stream, ethyl acetate was added to the reaction mixture, washed with water, dried with sodium sulfate, and the solvent was distilled off.
The residue was purified by silica gel thin layer chromatography to obtain (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-methylthiomethyl-4-benzoyloxypyrrolidine. IR ^neat _nax (cm ^-1 ) 1700, 1597, 1518, 1392, 1339,
1263. Reference example 38 (2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-methylthiomethyl-4-benzoyloxypyrrolidine (330mg) was dissolved in dry chloroform (3.3ml), and m-chloroperbenzoic acid (385mg) was dissolved in this. After adding and refluxing for 6 hours, ether was added to the reaction solution, washed with sodium bicarbonate water, brine, dried with sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography to obtain (2S,4R)-
1-p-nitrobenzyloxycarbonyl-2-
Methylsulfonylmethyl-4-benzoyloxypyrrolidine was obtained. IR ^nujol _nax (cm ^-1 ): 1719, 1692, 1518, 1450,
1345, 1299. Reference example 39 (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-hydroxymethyl-4-acetylthiopyrrolidine (354 mg) in dichloromethane (30 mg)
ml) was added with a diazomethane diethyl ether solution prepared by a conventional method under ice-cooling, then a catalytic amount of boron trifluoride-ether complex was added, and after stirring at the same temperature for 5 minutes, the reaction solution was diluted with brine. The solution was washed with sodium bicarbonate and brine, dried over magnesium sulfate, the solvent was distilled off, the residue was purified by silica gel thin layer chromatography, and (2S,4S)-1- p-nitrobenzyloxycarbonyl-2-methoxymethyl-4-acetylthiopyrrolidine was obtained. IR ^neat _nax (cm ^-1 ): 1700, 1685, 1516, 1392, 1340
，
1100. Reference Example 40 The methanesulfonic acid derivatives shown in Table 13 below were obtained by following the method described in Reference Example 6, using the corresponding alcohol and replacing p-toluenesulfonyl fluoride with methanesulfonyl chloride. It was done.

【table】

[Table] Reference Example 41 The iodine compounds shown in Table 14 below were obtained by treating a methanesulfonic acid derivative according to the method described in Reference Example 7.

[Table] Reference example 42 Dissolve (2R,4R)-1-benzyloxycarbonyl-2-(2,2-dimethoxycarbonyl)ethyl-4-t-butyldimethylsilyloxypyrrolidine (18 g) in methanol (180 ml), then 1N-sodium hydroxide. After adding an aqueous solution (36 ml) and stirring at room temperature for 18 hours, 1N aqueous hydrochloric acid (36 ml) was added to the reaction mixture, the solvent was distilled off, the residue was diluted with ethyl acetate, washed with brine, dried with sodium sulfate, and the solvent was distilled off. ,
(2R,4R)-1-benzyloxycarbonyl-2
-(2-carboxy-2-methoxycarbonylethyl)-4-t-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1732, 1710, 1680, 1420, 1350. Reference example 43 Dissolve (2R,4R)-1-benzyloxycarbonyl-2-(2-carboxy-2-methoxycarbonylethyl)-4-t-butyldimethylsilyloxypyrrolidine (18.0 g) in dry dimethyl sulfoxide (90 ml), After stirring at ℃ for 3 hours, the reaction solution was added to ice water, extracted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off to give (2R,4R)-1-benzyloxycarbonyl-2-(2-methoxycarbonylethyl). -4-t-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1740, 1705, 1410, 1358, 1258. Reference example 44 Using (2R,4R)-1-benzyloxycarbonyl-2-(3-iodopropyl)-4-t-butyldimethylsilyloxypyrrolidine (3.03g), the same method as in Reference Example 1-8 (2R,
4R)-1-benzyloxycarbonyl-2-(3
-cyanopropyl)-4-t-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 2250, 1705, 1415, 1358, 1255,
1112. Reference example 45 (2R,4R)-1-Benzyloxycarbonyl-2-(3-cyanopropyl)-4-t-butyldimethylsilyloxypyrrolidine (1.69 g) in a solution of 5% palladium-carbon (338 mg) in ethanol (34 ml). was added and catalytically reduced for 2 hours at room temperature and pressure, the catalyst (v) was distilled off and the solvent was distilled off (2R,
4R)-2-(3-cyanopropyl)-4-t-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 2245, 1460, 1250, 1080. Reference example 46 (2R,4R)-2-(3-cyanopropyl)-4
4N-sodium hydroxide (7 ml) was added to a solution of -t-butyldimethylsilyloxypyrrolidine (1.02 g) in dioxane (22 ml) and water (15.5 ml).
After refluxing for 2 hours, the reaction solution was neutralized with 6N hydrochloric acid, the solvent was distilled off, the residue was dissolved in water (10 ml), triethylamine (0.98 ml) was added, and the mixture was further stirred for 2 hours.
-(p-nitrobenzyloxycarbonylthio-
Add a solution of 4,6-dimethylpyrimidine (1.67 g) in dimethylformamide (20 ml) and stir at room temperature for 5 minutes.
After stirring for an hour, the reaction solution was diluted with ethyl acetate,
Next, wash with saline, diluted hydrochloric acid, and saline in this order.
Glauber's salt was dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain (2R,4R)-1
-(p-nitrobenzyloxycarbonyl)-2-
(3-cyanopropyl)-4-hydroxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 2250, 1700, 1520, 1402, 1345. Reference example 47 (2R,4R)-1-(p-nitrobenzyloxycarbonyl)-2-(3-cyanopropyl)-4-
Reference example 1 using hydroxypyrrolidine (353mg)
-9, (2R,4R)-1-(p
-nitrobenzyloxycarbonyl-2-(3-
Carboxypropyl)-4-hydroxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1700, 1608 (sh), 1518, 1402,
1343. Reference example 48 A solution of oxalyl chloride (0.32 ml) in dry dichloromethane (7.9 ml) in a nitrogen stream from -45°C to -
Dry dimethyl sulfoxide (0.56 ml) was added at 56°C, and after stirring at the same temperature for 20 minutes, (2R,4R)-1-
Benzyloxycarbonyl-2-(3-hydroxypropyl)-4-t-butyldimethylsilylpyrrolidine (1.30g) in dry dichloromethane (6.2g)
ml) at -50°C to -60°C, stirred at the same temperature for 15 minutes, and then added triethylamine (2.2 ml) at -50°C.
The mixture was added at ~-60°C, and after the addition was returned to room temperature, the reaction solution was washed with brine, diluted hydrochloric acid, and brine in that order, dried with sodium sulfate, and the solvent was distilled off to give (2R,4R)-1-benzyloxycarbonyl-2- (2-formylethyl)-4-t
-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1703, 1413, 1359, 1255, 1110. By the same method as above, (2R,4R)-1-p
-Nitrobenzyloxycarbonyl-2-hydroxyethyl-4-t-butyldimethylsilyloxypyrrolidine (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-formylmethyl-
4-t-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1723 (sh), 1703, 1520, 1400,
1342. Reference example 49 Dissolve t-butyloxycarbonylmethyltriphenylphosphonium bromide (2.15g) in dichloromethane (40ml), and add saturated sodium bicarbonate solution (30ml) to this solution.
ml), stirred at room temperature for 5 minutes, separated the dichloromethane layer, dried mirabilite, separated the mirabilite, and added (2R,4R)-1-benzyloxycarbonyl-2 to the liquid.
A solution of -(2-formylethyl)-4-t-butyldimethylsilyloxypyrrolidine (1.29 g) in dichloromethane (30 ml) was added, refluxed for 30 minutes, the solvent was distilled off, and the residue was purified by silica gel column chromatography. 2R,4R)-1-benzyloxycarbonyl-2-(3-t-butoxycarbonylmethylidenepropyl)-4-t-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 702, 1649, 1408, 1363, 1148. Reference example 50 (2R,4R)-1-Benzyloxycarbonyl-2-(3-t-butoxycarbonylmethylidenepropyl-4-t-butyldimethylsilyloxypyrrolidine (1.17 g) in a solution of 5% palladium- Add carbon (350mg),
After catalytic hydrogenation at normal temperature and pressure for 3 hours, the catalyst was separated and the solvent was distilled off to give (2R,4R)-2-(4-t-
Butoxycarbonylbutyl)-4-t-butylmethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1730, 1460, 1365, 1250, 1147. Reference example 51 (2R,4R)-2-(4-t-Butyloxycarbonylbutyl)-4-t-butyldimethylsilyloxypyrrolidine (770 mg) was dissolved in tetrahydrofuran (7 ml), and 2-p-nitrobenzyloxycarbonylthio-4 ,6-dimethylpyrimidine (719 mg) was added and stirred at room temperature for 2 hours.
The reaction solution was diluted with ethyl acetate, washed sequentially with brine, diluted hydrochloric acid, and brine, dried with sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography.
(2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(4-t-butyloxycarbonylbutyl-4-t-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1730 (sh ), 1712, 1528, 1402,
1350. Reference example 52 (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-(4-t-butyloxycarbonylbutyl-4-acetylthiopyrrolidine (493mg)
Dissolve in trifluoroacetic acid (2.5 ml) and stir at room temperature.
After stirring for 15 minutes, the trifluoroacetic acid was distilled off.
(2R,4S)-1-p-nitrobenzyloxycarbonyl-2-(4-carboxybutyl)-4-acetylthiopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1702, 1520, 1002, 1343. Reference example 53 Triethylamine (150 mg) was added to a solution of (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-(2-carboxyethyl)-4-acetylthiopyrrolidine (323 mg) in dry dimethylformamide (3.3 ml), Next, p-nitrobenzyl bromide (324 mg) was added, and the solution was stirred at room temperature for 3.5 min.
After stirring for an hour, water was added to the reaction solution, followed by extraction with ethyl acetate, washing with sodium bicarbonate, washing with water, washing with dilute hydrochloric acid, washing with water, drying with sodium sulfate, evaporating the solvent, and purifying the residue by silica gel chromatography (2R, 4S). 1-p-nitrobenzyloxycarbonyl-2-(2-p-
nitrobenzyloxycarbonylethyl)-4-
Acetylthiopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1732, 1697, 1515, 1393, 1342. Reference example 54 A solution of (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-carboxymethyl-4-acetylthiopyrrolidine (218 mg) in dry tetrahydrofuran (2.2 ml) was added with 1,1'-dimethylhydrazine (63 mg) and N , N'-dicyclohexylcarbodiimide (159 mg) was added, and after stirring at room temperature for 3 hours, the reaction solution was filtered, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography to obtain (2R,4S)- 1-p-Nitrobenzyloxycarbonyl-2-[(1,4-dimethylhydrazinocarbonylmethyl-4-acetylopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1700, 1660, 1515, 1418, 1340. Reference Example 55 (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-carboxymethyl-4-hydroxypyrrolidine (5.39 g) in dry methanol (54
ml) was added with concentrated sulfur (0.9 ml), and after refluxing for 4 hours, 1N aqueous sodium hydroxide solution was added to the reaction mixture to neutralize, and the solvent was distilled off. Ethyl acetate was added to the residue, and the mixture was washed with water. After drying the sodium sulfate, the solvent was distilled off.
(2S,4R)-1-p-nitrobenzyloxycarbonyl-2-methoxycarbonylmethyl-4-hydroxy was obtained. IR ^neat _nax cm ^-1 : 1740, 1708, 1528, 1440, 1348. Similarly to the above reference example, (2R, 4R)-1-
p-nitrobenzyloxycarbonyl-2-(2
-methoxycarbonylethyl)-4-hydroxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1730, 1688, 1523, 1352. Reference example 56 (2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-formylmethyl-4-t-butyldimethylsilyloxypyrrolidine (423 mg) was added to a solution of 1,1-dimethylhydrazine (65 mg) in ethanol (2 ml) at room temperature. ) and stirred at the same temperature for 15 minutes, then added ethyl acetate to the reaction solution, washed with water,
After drying Glauber's salt, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography to obtain (2R,4R)-
1-p-nitrobenzyloxycarbonyl-2-
(2-dimethylhydrazonoethyl)-4-t-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1713, 1528, 1405, 1348. Reference example 57 Methoxyamine hydrochloride (124 mg) in water (4 ml)
Add sodium acetate (244 mg) to the solution at room temperature,
Then (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-formylmethyl-4-t-butyldimethylsilyloxypyrrolidine (418 mg)
Add a solution of ethanol (5 ml) and incubate at the same temperature for 30
After stirring for a minute, the reaction solution was diluted with ethyl acetate,
After washing with water, washing with sodium bicarbonate, and drying with sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography to produce (2R,4R)-1-p-nitrobenzyloxy-2-(2-methoxyiminoethyl). -4-t-
Butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1705, 1523, 1400, 1343. Reference example 58 (2R,4S)-1-p-Nitrobenzyloxycarbonyl-2-(2-acetoxyethyl)-4-acetylthiopyrrolidine (204 mg) was dissolved in methanol (5 ml), and then 1N-
Add aqueous sodium hydroxide solution (1 ml) and stir at the same temperature for 30 minutes.
ml) was added, then diluted with ethyl acetate, washed with brine 5 times, dried with mirabilite, the solvent was distilled off, and the residue was purified by silica chromatography.
(2R,4S)-1-p-nitrobenzyloxycarbonyl-2-(2-hydroxyethyl)-4-mercaptopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1690, 1522, 1432, 1408, 1348. Similarly to the above reference example, (2R,4S)-1-p
-nitrobenzyloxycarbonyl-2-(3-
Hydroxypropyl)-4-mercaptopyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1695, 1522, 1433, 1410, 1350. Reference example 59 (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-hydroxyethyl)-4t-
Butyldimethylsilyloxypyrrolidine (900mg)
was dissolved in dry pyridine (2.25 ml), then acetic anhydride (2.25 ml) was added at room temperature, and after stirring at the same temperature for 1 hour, the reaction solution was diluted with ether, and then dissolved in brine, dilute hydrochloric acid, brine, and sodium bicarbonate solution. , saline solution, dried mirabilite, the solvent was distilled off, and (2R,4R)-
1-p-nitrobenzyloxycarbonyl-2-
(2-acetoxyethyl)-4-t-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1739, 1005, 1522, 1408, 1350. Similarly to the above reference example, (2R, 4R)-1-p
-nitrobenzyloxycarbonyl-2-(3-
Acetoxypropyl)-4-t-butyldimethylsilyloxypyrrolidine was obtained. IR ^neat _nax cm ^-1 : 1739, 1712, 1522, 1401, 1345.

[Claims]

1 M (hfa) ₂・1,2-DME, where M is
Mg or Zn, hfa is 1, 1, 1, 5, 5,
A complex compound which is 5-hexafluoro-2,4-pentanedionate and 1,2-DME is a neutral 1,2-dimethoxyethane ligand. 2. The complex compound according to claim 1, wherein M is Mg. 3. The complex compound according to claim 1, wherein M is Zn. 4 M (hfa) ₂・1,2-DME, where M is
Mg or Zn, hfa is 1, 1, 1, 5, 5,
5-hexafluoro-2,4-pentanedionate, and 1,2-DME is a neutral 1,2-dimethoxyethane ligand. Thing M
(hfa) _{2.H 2} O with the ligand 1,2-DME.

Claims (1)

(In the formula, R ₃ and R ₄ may be the same or different and represent a hydrogen atom or a lower alkyl group, or R ₃ and R ₄ together represent an alkylene group.) group, general formula (2) -ZCOR ₅ (2) (wherein Z represents a -NH- group or an oxygen atom, R ₅ is an amino group, a lower alkyl-substituted amino group,
Indicates a lower alkoxy group or a lower alkyl group. ), a group represented by general formula (3) (In the formula, R ₆ represents a hydrogen atom or a lower alkyl group.) A group represented by the general formula (4) -CH=N-R ₇ (4) (In the formula, R ₇ represents a lower alkyl-substituted amino group or (lower alkoxy group) or general formula (5) (In the formula, R ₈ , R ₉ and R ₁₀ may be the same or different and represent a hydrogen atom or a lower alkyl group.) or X represents an amino group,
A protected amino group, carboxyl group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, cyano group, hydroxyl group, lower alkoxy group, lower alkylthio group or lower alkanesulfonyl group, Y is a hydrogen atom, a protecting group for an amino group, General formula (6) (In the formula, R ₁₁ and R ₁₂ may be the same or different and represent a hydrogen atom or a lower alkyl group.) or a group represented by the general formula (7) (In the formula, R ₂₀ represents a hydrogen atom or a lower alkyl group.) where n represents an integer of 1 to 4. ] A β-lactam compound or a salt thereof. 2 A compound represented by the general formula [] is a compound represented by the general formula []
−α〕 [In the formula, R _1a represents a hydrogen atom or a lower alkyl group, and X _c represents the general formula (1) Group represented by general formula (2) −ZCOR ₅ (2) Group represented by general formula (3) A group represented by the general formula (4) -CH=N-R ₇ (4) or a group represented by the general formula (5) or X _c is an amino group,
Carboxy group, lower alkoxycarbonyl group, cyano group, hydroxyl group, lower alkoxy group, lower alkylthio group or lower alkanesulfonyl group, Y _c is a hydrogen atom, general formula (6) A group represented by or general formula (7) Indicates a group represented by ] The β-lactam compound and its salt according to claim 1, which is a compound represented by: