JPH0463878B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel β-lactam compounds or salts thereof, and methods for producing them. For more details, please refer to the general formula [] [In the formula, R ₁ is a hydrogen atom or a hydroxyl group protecting group,
R ₂ represents a hydrogen atom or an amino group-protecting group, R ₃ represents a hydrogen atom or a carboxyl group-protecting group,
_R4 represents a hydrogen atom or a _C1 - _C8 alkyl group. Y is general formula (2) (In the formula, R ₅ and R ₆ are the same or different and are a hydrogen atom, a C ₁ -C ₅ alkyl group, a lower alkenyl, an aryl lower alkyl group, a substituted C ₁ -C ₅ alkyl group,
or represents a pyridyl group, or R ₅ and R ₆
represents an alkylene chain bonded to each other, or represents an alkylene chain via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom, and has a double bond in a 3- to 7-membered ring together with an adjacent nitrogen atom. also represents an unsubstituted or substituted cyclic amino group. ), general formula (3) (In the formula, R ₇ represents a hydrogen atom or a lower alkyl group.) A guanidyl group, a protected or unprotected hydroxyl group, a lower alkoxyl group, an unsubstituted or lower alkyl-substituted hydrazino group, or the general formula (4) − NHOR ₈ (4) (In the formula, R ₈ represents a hydrogen atom, a hydroxyl protecting group, or a lower alkyl group.) ] The present invention relates to novel β-lactam compounds or salts thereof, and methods for producing them. In the above general formula [], various commonly used protecting groups can be used as the protecting group for the hydroxyl group in _R1 or the protecting group for the amino group in _R2 , but preferably, for example, tert-butyloxycarbonyl. lower alkoxycarbonyl group, such as 2-ethyloxycarbonyl iodide, 2,2,2
-halogenoalkoxycarbonyl groups such as trichloroethyloxycarbonyl, e.g. aralkyloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, e.g. trimethylsilyl, tert - a trialkylsilyl group such as butyldimethylsilyl. The carboxyl protecting group for R ₈ is preferably a linear or branched lower alkyl group such as methyl, ethyl, isopropyl, or tert-butyl, such as 2-ethyl iodide, 2-ethyl iodide, or , 2,2-trichloroethyl, lower alkoxymethyl groups such as methoxymethyl, ethoxymethyl, isobutoxymethyl, e.g. acetoxymethyl,
Lower aliphatic acyloxymethyl groups such as propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 1-lower alkoxycarbonyloxyethyl groups such as 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, For example, an aralkyl group such as benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, a benzhydryl group, or a phthalidyl group. Examples of the lower alkyl group for R ₄ include methyl, ethyl, n-propyl, and the like. Regarding Y, when Y is an amino group represented by the general formula (2), R ₅ and R ₆ are the same or different from each other. In R ₅ and R ₆ , examples of C ₁ to C ₅ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.; examples of lower alkenyl groups include C ₃ to C 5 such as propenyl and butenyl; The C ₄ alkenyl group can be replaced with an aryl lower alkyl group such as benzyl, substituted benzyl,
An alkyl group having 1 to 3 carbon atoms substituted with a phenyl group, a substituted phenyl group, a pyridyl group, or a substituted pyridyl group such as phenethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, etc., is substituted with C ₁ -C Examples of the _5- alkyl group include a hydroxyl group, a di- _C1 to _C3 alkylamino group, a carbamoyl group,
_C1 -C3 substituted with a substituent such as a mono- or di-C1- _C3 alkyl-substituted aminocarbonyl group, or a protected or unprotected carboxyl group
The straight chain or branched alkyl group of 5 is replaced by 2-pyridyl, 3-pyridyl and 4
-pyridyl group. R ₅ and R ₅ represent an alkylene chain bonded to each other, or oxygen atom, sulfur atom or C ₁
~ C ₃ When representing an alkylene chain via an alkyl-substituted nitrogen atom and indicating an unsubstituted or substituted cyclic amino group which may have a double bond in a 3- to 7-membered ring together with the adjacent nitrogen atom, , the cyclic amino group includes, for example, an aziridino group, an azetidino group,
Saturated cyclic amino groups such as pyrrolidino, piperidino, etc.; e.g. 3-azabicyclo[3,2,
2] Cyclic amino group having a crosslinked structure such as nonan-3-yl group; unsaturated cyclic amino group such as pyrrolyl group, 3-pyrrolinyl group, etc.; e.g. morpholino group, thiomorpholino group, N-methylpiperazino group Examples include cyclic amino groups having an oxygen atom, a sulfur atom, or an alkyl-substituted nitrogen atom in the ring. Furthermore, examples of the substituent for each cyclic amino group include a C ₁ -C ₃ alkyl group, a carbamoyl group, a mono- or di-C ₁ -
Examples include a C ₃ alkyl-substituted aminocarbonyl group and a hydroxyl group. Examples of unsubstituted or lower alkyl-substituted guanidyl groups include guanidyl groups, and those having 1 to 1 carbon atoms such as methyl, ethyl, n-propyl, and isopropyl.
A guanidyl group substituted with an alkyl group in No. 3 can be mentioned, and more specifically, for example, an N,N'-tetramethylguanidyl group can be mentioned. Examples of lower alkoxyl groups include methoxy,
Examples include alkoxyl groups having 1 to 3 carbon atoms such as ethoxy, n-propoxy, and isopropoxy. Regarding the hydrazino group, for example, hydrazino,
Examples include unsubstituted hydrazino groups such as 2',2'-dimethylhydrazino and trimethylhydrazino, or hydrazino groups substituted with 1 to 3 alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, and isopropyl. . Regarding R ₈ represented by general formula (4),
R ₈ is, for example, a hydrogen atom, a protecting group commonly used as a hydroxyl protecting group, methyl, ethyl, n
- It can be referred to as a _C1 - _C3 alkyl group such as propyl. In addition, when Y is a protected hydroxyl group, examples of the protecting group include those commonly used as carboxyl protecting groups. In the general formula [], -COOR8 or -
A carboxylic acid compound in which the group represented by COY is a carboxyl group can be converted into a pharmacologically acceptable salt form, if necessary. Such salts include lithium, sodium, potassium, calcium,
Examples include salts of inorganic metals such as magnesium, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, and triethylammonium, but sodium salts and potassium salts are preferred. The β-lactam compound represented by the general formula [] of the present invention is carbapenem (1-azabicyclo[3,2,0]hept-2-en-7-one-2
-carboxylic acid) derivatives. Since thienamycin is an antibiotic that exhibits strong antibacterial activity against Gram-positive and Gram-negative bacteria, research on the synthesis of carbapenem derivatives related to thienamycin has been widely developed. As a result of repeated research on the synthesis of carbapenems or penem derivatives, the present inventors found that
Compounds represented by the general formula [ ] that have a substituent easily derived from 4-hydroxyproline as a side chain, that is, a substituted pyrrolidinyl group with a carbonyl group attached with various substituents at the 2-position, have strong antibacterial activity. We have completed the present invention by discovering that this is a compound that is useful as a medicine and is an important intermediate for compounds that exhibit antibacterial activity. The method for producing the compound of the present invention will be described in detail below. General formula [] [In the formula, R ₁ and R ₄ have the same meanings as above, and R ₉ represents a carboxyl group protecting group. ] and the general formula [] [In the formula, R ₂ has the same meaning as above. Y′ is a group represented by the general formula (2), an unsubstituted or lower alkyl-substituted guanidyl group, a hydroxyl group protected with a carboxyl group-protecting group, a lower alkoxyl group, an unsubstituted or lower alkyl-substituted hydrazino group, or the general formula ( 4') -NHOR' ₈ (4') (In the formula, _R'8 represents a hydroxyl protecting group or a lower alkyl group.) ] by reacting with a mercaptan represented by the general formula [ ] in an inert solvent in the presence of a base. [In the formula, R ₁ , R ₂ , R ₄ , R ₉ , and Y' have the same meanings as above. ] A β-lactam compound represented by the following can be produced. Here, the reactive ester of alcohol refers to, for example, substituted or unsubstituted aryl sulfonic acid ester, lower alkanesulfonic acid ester, halogeno lower alkanesulfonic acid ester, or diarylphosphoric acid ester of alcohol [ ], or halogenated Indicates a halide that is an ester with hydrogen. Furthermore, as substituted or unsubstituted arylsulfonic acid esters,
For example, benzenesulfonic acid ester, p-toluenesulfonic acid ester, p-nitrobenzenesulfonic acid ester, p-bromobenzenesulfonic acid ester, etc., and lower alkanesulfonic acid ester include, for example, methanesulfonic acid ester,
Ethanesulfonic acid ester, etc., halogeno lower alkanesulfonic acid ester, such as trifluoromethanesulfonic acid ester, diarylphosphoric acid ester, such as diphenylphosphoric acid ester, etc.; , for example, chlorine, bromine, iodide, etc. Suitable examples of such alcohol reactive esters include p-toluenesulfonic acid ester, methanesulfonic acid ester, and diphenylphosphoric acid ester. The protecting group for the carboxyl group in R ₉ corresponds to the protecting group in R ₃ , and similar examples can be given as suitable protecting groups. Examples of the inert solvent used in this reaction include dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, etc., or a mixture of two or more thereof, and preferred examples include acetonitrile, Dimethylformamide and the like can be mentioned. Bases include sodium carbonate, potassium carbonate, sodium hydride,
Examples include various bases such as potassium hydride, potassium t-butoxide, pyridine, various lutidines, 4-dimethylaminopyridine, triethylamine, and diisopropylethylamine, but organic bases such as diisopropylethylamine are preferred. The amount of base needs to be sufficient for the reaction to proceed sufficiently, and usually 1 to 2 equivalents are used per mole of mercaptan. The raw material mercaptan [] needs to be in an amount sufficient for the reaction to proceed sufficiently, and a large excess amount can be used, but it is usually carried out using 1 to 2 equivalents relative to the compound represented by the general formula []. can. The reaction temperature is carried out in the range of -78℃ to 60℃.
A range of 40°C to 40°C is preferred. In addition, after the reaction is completed, the resultant can be taken out by ordinary organic chemical methods. Next, from the obtained compound represented by the general formula [], the hydroxyl protecting group in R ₁ is removed, the amino group in R ₂ is removed, and the carboxyl group is protected. base R ₉
The β-lactam compound represented by the general formula [] can be obtained by appropriately combining the removal reaction of 1 and the removal reaction of the protecting group on Y' as necessary. The method for removing protecting groups varies depending on the type, but
It is removed by generally known methods. For example, in the above general formula [], the hydroxyl group-protecting group and/or the amino group-protecting group is a halogenoalkoxycarbonyl group, an aralkyloxycarbonyl group, and the carboxyl group-protecting group is a halogenoalkyl group, an aralkyl group, or a benzhydryl group. The protecting group can be removed from the compound by subjecting it to a suitable reduction reaction. 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 an aralkyl group or a benzhydryl group, a catalytic reduction reaction using a catalyst such as platinum or palladium on carbon is suitable. The solvents used in this catalytic reduction reaction include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, acetic acid, or organic modifiers thereof, and water, phosphoric acid, morpholinopropanesulfonic acid, etc. A mixed solvent with a buffer is suitable. The reaction temperature ranges from 0°C to 100°C, but preferably from 0°C to 40°C. Moreover, hydrogen pressure can be carried out under normal pressure or increased pressure. In particular, the protecting group is o-nitrile bezyl group or o
-Nitrobenzyloxycarbonyl groups can also be removed by photoreaction. In addition, after the reaction is completed, the resultant can be taken out by ordinary organic chemical methods. In addition, 5 of the compound represented by the above general formula []
The carbons at the 2'- and 4' _- positions in the 3-position side chain are all asymmetric carbons. Therefore, the compound represented by the general formula [] has optical isomers and stereoisomers based on the asymmetric carbon, and although all of these isomers are represented by a single formula, this The scope of the description of the invention is not limited. However, compounds in which the carbon atom at position 5 has the R coordination, which is the same coordination as that of thienamycin (5R, 6S) or (5R, 6R), can be preferably used. Regarding the 8th place,
Compounds having R coordination can be selected as suitable ones. As for the 4-position, compounds in which the alkyl group R ₄ has a 4R coordination in which the alkyl group R 4 has a β coordination can be mentioned as preferred. Furthermore, there are four types of isomers for the 2'-substituted pyrrolidin-4'-ylthio group, and among them, the preferred three-dimensional configurations are (2'S, 4'S) configuration,
Compounds with (2′R, 4′R) coordination can be mentioned. When producing isomers having such coordination, corresponding isomers can be used in the starting compounds [] and/or []. Compound [], which is a starting compound, can be produced by various methods that have already been reported. Compounds in which R ₄ is a hydrogen atom in the general formula [] are:
For example, the compound itself is known from the following literature, or it can be obtained according to the method described therein. (1) Japanese Patent Application Publication No. 55-27169 (2) Journal of American Chemical
Society (J.Am.Chem.Soc.) Volume 103, No.
pp. 6765-6767 (1981) (3) Journal of Chemical Society
Perkin I (J.Chem.Soc.Perkin I) No. 964~
968 pages (1981) Also Tetrahedron Letters
General formula (a) obtained by the method described in Letters), pages 2298-2296 (1982) or the method described in European Patent Publication No. 70204. [In the formula, R ₁ has the same meaning as above, and Ac represents an acetyl group. ] Using the compound represented by as a raw material, the above-mentioned documents etc.
Compound [] can be synthesized according to the methods described in (1) to (3). Furthermore, European published patent publication no.
General formula (b) obtained by the method described in No. 70204 [In the formula, DAM represents a di-p-anisylmethyl group. ] The compound represented by is subjected to a carbon enrichment reaction such as the Arndt-Einstert reaction, and then the ethenyl group is converted to a 1-hydroxyethyl group by an oxymer cure reaction etc., and if necessary, General formula (c) obtained by combining carboxyl group protection, deprotection reaction, and hydroxyl group protection reaction [In the formula, R ₁ and DAM are as described above. ] Compound [ ] can be obtained from the compound represented by the following according to the method described in JP-A-57-167964. The DAM group on the nitrogen of compound (c) is Ceric ammonium nitrate (Ceric ammonium nitrate).
ammonium nitrate) in an inert solvent such as acetonitrile-water at 10 to 30°C. In that case, carboxyl group protection, deprotection reactions, and hydroxyl group protection reactions are performed as necessary. They can also be combined. In addition, compounds in which R ₄ is an alkyl group in the general formula [] are, for example, Hetero-cycles, Vol. 21, p. 29 (1984),
Alternatively, it can be produced by a known method described in JP-A-58-26887 or in accordance with that method. General formula [V] that can be a raw material compound for a compound in which R ₄ is an alkyl group [In the formula, R ₁ has the same meaning as above, and R ^o ₄ represents a lower alkyl group. ] The compound represented by these can be produced, for example, by the following route. [In the formula, R ^o ₄ has the same meaning as above, R ₁₀ represents a carboxyl group protecting group, and TBDMS represents t-
Indicates a butyldimethylsilyl group. ] Compounds (e) and (f) are listed in the Chemical and Pharmaceutical Bulletin (Chem.Pharm.
(3R,4R)-4-acetoxy-3-[(R)
-1-(t-Butyldimethylsilioxy)ethyl]-2-azetidinone (d) was prepared by the method described in JP-A-55-73656, that is, in the presence of diethylaluminum chloride and zinc, using the general formula R ^o ₄ CHX -COOR ₁₀ [wherein R ^o ₄ and R ₁₀ have the same meanings as above, and X represents a halogen atom. ] A mixture is obtained by reacting the halogeno fatty acid ester represented by the following in a solvent such as ethers such as tetrahydrofuran, dioxane, diethyl ether, aromatic hydrocarbons such as benzene and toluene, or in a mixed solvent of these and hexane. can get. Separation and purification of each isomer (e) and (f) can be performed by silica gel chromatography. Compounds (e) and (f) can be induced to compound [] by appropriately combining hydroxyl group, carboxyl group, or nitrogen atom protection and deprotection reactions as necessary. An example of the method for producing the raw material compound [] is shown in the scheme below, and each step will be explained. [In the formula, R ₁ , R ₄ , R ₉ have the same meanings as above,
R ^o ₁ represents a hydroxyl protecting group, and Ph represents a phenyl group. ] From the above-mentioned compound (g), a compound was prepared according to the reaction described in JP-A-57-167964 or the reaction described in Heterocycles, Vol. 14, pp. 1305-1306 (1980). (h) can be obtained. Furthermore, compound (i) can be obtained by reacting compound (h) with a diazotizing agent such as carboxybenzenesulfonazide in the presence of a base, as described in Tetrahedron Letters, pages 31-34 (1980). It can be obtained by Furthermore, compound (j) can be obtained by subjecting compound (i) to a ring-closing reaction in the presence of a metal salt catalyst such as dirhodium tetrakis acetate or by photoreaction. Finally, the starting compound represented by general formula [a] can be obtained by reacting compound (j) with diphenylphosphoryl chloride in an inert solvent in the presence of a base. Normally, in the production of carbapenem derivatives, starting compound [a] is produced from compound (j), and it can be obtained by reacting it with various mercaptans without isolating it as it is, but starting compound [a] ] can also be isolated once and then reacted with a mercaptan derivative [ ] to obtain a compound represented by the general formula [ ]. Optically active reactive ester, e.g. [a]
If desired, it can be obtained in the same manner as the above reaction by using an isomer having the corresponding stereochemistry in the starting material β-lactam derivative (g). On the other hand, raw material mercaptan [ ] can be produced by various methods, but for example, by the method shown below, trans-4-hydroxy-L-proline 1 ~ is used as a raw material compound.
Mercaptan [a] with 2′S coordination, [
b] and [c] can be produced. [In the formula, Y″ has the same meaning as the definition of Y′ excluding the hydroxyl group and lower alkoxy group protected with a carboxyl group protecting group, and R ₁₀ has the same meaning as above. R ₁₁ This represents a protecting group for an amino group, and R ₁₂ represents a protecting group for a thiol group.] Step A This can be easily accomplished by a commonly used reaction for protecting the amino group of various known amino acids. Examples include a method of reacting with arylmethyloxycarbonyl chloride etc. in the presence of carboxylic acid, a method using S-acyl-4,6-dimethyl-2-mercaptopyrimidine etc. Step B Various methods for obtaining an ester from a carboxylic acid. Although known methods are possible, it can be achieved, for example, by reacting carboxylic acid 2~ with various alkyl halides or aralkyl halides in the presence of a base. Step C: Converting a hydroxyl group to a protected thiol group. Various known methods are possible to achieve this, but for example, it can be achieved by deriving a hydroxyl group into an active ester and then reacting it with various thiolating reagents such as thioacetic acid, thiobenzoic acid, trityl mercaptan, etc. in the presence of a base. This step can also be obtained by reacting an alcohol derivative with a thiolating reagent such as thioacetic acid in an inert solvent such as tetrahydrofuran in the presence of triphenylphosphine or diethyl azodicarboxylate. D Process Various known methods for converting an ester into a carboxyl group are possible, such as alkaline hydrolysis, an acid method using trifluoroacetic acid, hydrobromic acid, etc., or a reductive method using zinc. Step E Various known methods for converting a carboxylic acid into an amide group are possible, but for example, the carboxylic acid group is converted into an active ester derivative using a halogenating agent, an acylating agent, etc., and the general formula Y'' is obtained. This is achieved by a method of treating with various amine derivatives represented by H [wherein Y'' has the same meaning as above]. Step F: Various known deprotection methods for ochyl protecting groups are possible. However, for example, when the thiol protecting group is an acyl group, it can be removed by a method such as alkaline hydrolysis.G step Various known oxidation reactions for converting a hydroxyl group into a carbonyl group are possible, but for example, This can be achieved by an oxidation reaction such as chromic acid-sulfuric acid in acetone.H step Various known reduction reactions for converting carbonyl groups into hydroxyl groups are possible, but for example, by treatment with sodium borohydride etc. A mixture of Compounds 3 to 9 and Compounds 9 to which the hydroxyl groups of 3 to sterically differ can be obtained. Although the production ratio of 3~ and 9~ differs depending on the conditions, each compound can be obtained as a single compound by purification such as recrystallization or chromatography. Isomerization of the 4-position hydroxyl group can be achieved through the above steps G and H, but it can also be achieved by a method that involves steps I and J described below. Steps I and J: Alcohol derivatives are reacted with formic acid in an inert solvent such as tetrahydrofuran in the presence of triphenylphosphine and diethyl azodicarboxylate to formyloxy derivatives 13-
This can be achieved by removing the formyl group by a method such as alkaline hydrolysis. K step Various commonly used methods for deprotecting amino groups are possible, including methods using acids such as trifluoroacetic acid and hydrobromic acid, reductive methods using zinc or lithium-liquid ammonium, etc. Alternatively, it can be achieved by catalytic reduction or the like. In addition, when Y in the general formula [] is a protected or unprotected hydroxyl group or a lower alkoxyl group, the raw material mercaptan [] is compound 4- or 10-
can be obtained by subjecting it to step F. In addition, in the production of 2′R mercaptan, cis-4-hydroxy-
It can be produced using D-proline in accordance with the method for producing the 2'S isomer described above, that is, by combining the various reactions described in the production of the 2'S isomer. Among the novel β-lactam compounds of the present invention represented by the above general formula [], compounds in which R ₁ , R ₂ and R ₃ are hydrogen atoms include Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus It exhibits excellent antibacterial activity against a wide range of pathogens, including Gram-positive bacteria such as Coccococcus pyrogens and Streptococcus fuecalis, and Gram-negative bacteria such as Escherichia coli, Proteus mirabilis, Serratia marsetuscens, and Pseudomonas aeruginosa. It is a compound useful as an antibacterial agent. moreover,
It is a unique compound that has excellent antibacterial activity against β-lactamase-producing bacteria. Other compounds of the present invention are important synthetic intermediates for synthesizing compounds exhibiting antibacterial activity as described above. Although the compounds of the present invention differ depending on each compound, they are generally characterized by high physicochemical stability and excellent solubility in water. 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. In addition, the compound of the present invention can be used as Z-7-(L
-amino-2-carboxyethylthio)-2-
It can be administered in combination with a dipeptidase inhibitor such as sodium (2,2-dimethylcyclopropanecarboxamide)-2-heptenoate (compound group described in JP-A-56-81518). 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 tBu: t- Butyl group, Me: methyl group, Et: ethyl group Reference example 1-1 Trans-4-hydroxy-L-proline (6.55 g) and triethylamine (7.5 ml) were dissolved in water (15 g).
ml) and added Sp-nitrobenzyloxycarvinyl-4,6-dimethyl-2 at room temperature.
- A solution of mercaptopyrimidine (15.95 g) in dioxane (85 ml) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours and left overnight. Add 2N to the reaction solution under ice cooling.
Add sodium hydroxide (30ml), extract with ether, and extract the ether layer using sodium hydroxide (20ml).
After washing with , the alkaline aqueous layers were combined, acidified with hydrochloric acid using 2N-hydrochloric acid water (100 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 washed with ethyl acetate while heating to give 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 1-2 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 ( 12.66
mm) 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 evaporated and the residue was crystallized from ether to give trans-1-(p-nitrobenzyloxycarbonyl).
-4-(hydroxy-L-proline-p-methoxybenzyl ester was obtained. mp 83-85℃ IR ^film _nax (cm ^-1 ): 3430, 1735, 1705, 1510, 1340
,
1245, 1160 Reference example 1-3 trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline-p
-Methoxybenzyl ester (8.6 g) and triphenylphosphine (7.86 g) were dissolved in dry tetrahydrofuran (20 ml), and a solution of diethyl azodicarboxylate (5.22 g) in dry tetrahydrofuran (5 ml) was cooled with ice under a nitrogen stream. Drip and leave it as is.
After stirring for 30 minutes, thioacetic acid (2.28 g) was added dropwise, and the mixture was stirred for 1 hour under ice cooling and then for 3 hours at room temperature.
Concentrate the reaction solution. The residue was subjected to silica gel column chromatography to give cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L
-Proline-p-methoxybenzyl ester was obtained. IR ^film _nax (cm ^-1 ): 1740 (sh), 1715, 1520, 1405
,
1343, 1120 NMRδ ( _CDCl3 ): 2.31 (3H, s), 3.79 (3H,
s), 5.10 (2H, s), 5.24 (2H, s), 7.49
(2H, d, J=9.0Hz), 8.18 (2H, d, J=
9.0Hz), Reference example 1-4 cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline-P-
Methoxybenzyl ester (9.76g), anisole (4.32g) with trifluoroacetic acid (35ml)
Stir at room temperature for 30 minutes. It was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain cis-1-
(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline was obtained. mp 107~109℃ IR ^Nujol _nax (cm ^-1 ): 1725, 1685, 1660 (sh), 1340
,
1180, 1110 Reference example 1-5 cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline (180
mg) was dissolved in dry tetrahydrofuran (2 ml), dimethylamine hydrochloride (48 mg), N,N-dimethylaminopyridine (78 mg) and dicyclohexycarbodiimide (152 mg) were added sequentially, and the mixture was stirred overnight. Insoluble materials were removed, the solution was diluted with ethyl acetate, washed successively with dilute hydrochloric acid and water, dried with sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel chromatography to obtain (2S, 4S)-1-(p -nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine was obtained. This compound was prepared by dissolving 200 mg of the raw material carboxylic acid in 1.8 ml of dry methylene chloride, and adding 1 ml of dimethylformamide.
Add dropwise, then add 0.12ml of oxalyl chloride under ice cooling.
was added dropwise, and after stirring at room temperature for 1 hour, the solvent was distilled off. After thoroughly drying the residue under vacuum, it was dissolved in 1 ml of dry tetrahydrofuran, and 1.2 ml of dimethylamine in tetrahydrofuran solution (1M) was added dropwise under ice cooling, followed by stirring for 15 minutes. Add ice water to the reaction solution and extract with EtOAc. It can also be obtained by washing the organic layer in the order of dilute HCl and water, drying and distilling off the solvent. IR ^lilm _nax (cm ^-1 ): 1705, 1650, 1515, 1400, 1340
,
1105 NMRδ ( _CDCl3 ): 2.32 (3H, s), 2.97 (3H,
s), 3.11 (3H, s), 5.21 (2H, s), 8.18
(2H, d, J = 8.5Hz) [α] ³⁰ _D +5.21° (C = 0.379 acetone) Reference example 1-6 cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline (277
mg) in dry methylene chloride (1.5 ml), then oxalyl chloride (0.15 ml) and a catalytic amount of dimethylformamide were added and stirred at room temperature for 1.5 hours.
The solvent of the reaction solution was distilled off, dry benzene was added to the residue, and then the benzene was distilled off to remove the remaining oxalyl chloride. Separately, pyrrole (51 mg) was dissolved in dry tetrahydrofuran (2 ml), a 1.60 mmol/ml n-butyllithium hexane solution (0.47 ml) was added under ice cooling under a nitrogen stream, and the mixture was stirred for 40 minutes. This was added to a solution of the above-mentioned reaction residue dissolved in dry tetrahydrofuran (2 ml) under ice cooling under a nitrogen stream, and the mixture was stirred for 10 minutes. The reaction solution was diluted with methylene chloride, washed with water, dried with salt water, and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(1- pyrrolyl)carbonyl-
4-Acetylthiopyrrolidine was obtained. IR ^CHCl3 _nax (cm ^-1 ): 1710, 1525, 1345, 1278, 1120 NMR δ (CDCl ₃ ): 2.33 (3H, s), 5.28 (2H,
s) 6.85 (2H, d, J=2Hz), 7.51 (2H,
d, J=9Hz) Reference example 1-7 (2S,4S)-1-p-Nitrobenzyloxycarbonyl-2-hydroxycarbonyl-4-acetylthiopyrrolidine (868 mg) was dissolved in dry methylene chloride (3 ml), then oxalyl chloride (0.3 ml) and a catalytic amount of dimethyl Add formamide, stir at room temperature for 1.5 hours, and evaporate the reaction solution.
Dry benzene was added to the residue, and then the benzene was distilled off to remove the remaining oxalyl chloride. on the other hand,
4-Carbomoylperidine (128 mg) was dissolved in dry tetrahydrofuran (3 ml), then bistrimethylsilylacetamide (0.25 ml) was added,
The mixture was stirred for 3 hours under a nitrogen stream. Next, triethylamine (101 mg) was added, and to this was added a solution of the aforementioned reaction residue in dry tetrahydrofuran (3 ml) under ice cooling in a nitrogen stream, and the mixture was stirred for 15 minutes under ice cooling. Methylene chloride was added to the reaction solution, washed with brine, diluted hydrochloric acid, brine, dehydrated water, brine, dried with salt water, and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography.
4S)-1-p-nitrobenzyloxycarbonyl-2-(4-carbamoylpiperidinyl)carbonyl-4-acetylthiopyrrolidine was obtained. IRν ^CHCl3 _nax (cm ^-1 ): 3440, 1695, 1655, 1525,
1350, 1120 NMRδ (CDCl ₃ ): 2.25 (3H, s), 5.21 ((2H,
s), 5.93 (2H, s) 7.52 (2H, d, J=9
Hz), 8.22 (2H, d, J=7Hz) Reference example 1-8 (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4
- Dissolve acetylthiopyrrolidine (40 ml) in methanol (4 ml), add IN-NaOH (0.1 ml),
The mixture was stirred at room temperature for 15 minutes. Then 1N-HCl (0.11ml)
Add and concentrate under reduced pressure. The concentrated solution was diluted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off (2S, 4S).
1-(p-nitrobenzyloxycarbonyl)-2
-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained. IR ^film _nax (cm ^-1 ): 1705, 1650, 1515, 1400, 1340
,
1165, 1105 NMRδ ( _CDCl3 ): 1.90 (1H, d, J = 8Hz),
2.97 (3H, s), 3.08 (3H, s), 5.19 (2H,
s), 7.48 (2H, d, J=9Hz), 8.15 (2H,
d, J=9Hz) The following thioacetates were obtained in the same manner as in Reference Example 1-5 using the corresponding amines.

【table】

【table】

【table】

[Table] Reference example 2-1 trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline 3.10
g, 1.10 g of triethylamine was dissolved in 40 ml of dry tetrahydrofuran, and 1.20 g of ethyl chloroformate was dissolved in 10 ml of dry tetrahydrofuran at -25°C to -35°C.
Add the solution dropwise and stir for 50 minutes, then -25℃ to -40℃
10 ml of concentrated ammonia water was added dropwise at ℃. The temperature was gradually raised to room temperature, and after further stirring for 1 hour, the reaction solution was concentrated under reduced pressure. Add 20 ml of water and 50 ml of ether to the residue, collect the white crystals obtained after cooling on ice, wash them sequentially with cold water and cold ether, and dry under reduced pressure to obtain trans-1-(p
-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolinamide was obtained. mp 163.3~164.0℃ IR ^Nujol _nax (cm ^-1 ): 3460, 3370, 3200, 1687,
1640, 1621, 1539, 1341, 1180, 1078 Reference example 2-2 1.89 g of methanesulfonyl chloride was added to a suspension of 2.32 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolinamide and 1.67 g of triethylamine in 40 ml of dry tetrahydrofuran at room temperature.
ml solution was added dropwise, and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure. Add 30 ml of water and 30 ml of ether to the residue, collect the white crystals obtained after cooling with ice, wash them sequentially with cold water and cold ether, and dry under reduced pressure to obtain trans-1-
(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolinamide was obtained. mp 149.5~151℃ IR ^Nujol _nax (cm ^-1 ): 3400, 3225, 1715, 1675,
1520, 1340, 1170, 1135 Reference example 2-3 642 thioacetic acid under a nitrogen stream in a suspension of 374 mg of 50% sodium hydride in 13 ml of dry dimethylformamide.
Add 14 ml of dry dimethylformamide solution of
Stir for 25 minutes at room temperature, add 975 mg of sodium iodide to this solution, and then add a solution of 2.52 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolinamide in 12 ml of dry dimethylformamide. Heated at 70°C for 6 hours. The reaction solution was poured into cold brine and extracted with benzene. The extract was washed successively with a 10% aqueous sodium sulfite solution and brine, dried with mirabilite, and the solvent was distilled off. The resulting crude crystals were heated and washed with a mixed refrigerant of tetrahydrofuran and benzene. cis-1-(p-nitrobenzyloxycarbonyl)-4-thioacetoxy-
L-prolinamide was obtained. mp 168.5~169.5℃ IR ^Nujol _nax (cm ^-1 ): 3350, 3180, 1715, 1690,
1638, 1510, 1330, 1100 [α] ³⁰ _D −23° (c=0.334, DMF) Reference example 2-4 Dissolve (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4-acetylthiopyrrolidine (950 mg) in methanol (95 ml) and add 1N aqueous sodium hydroxide solution (2.59 ml) in an argon stream. was added at room temperature, and the mixture was stirred for 15 minutes. The reaction mixture was neutralized by adding 1N aqueous hydrochloric acid (2.59ml), methanol was distilled off under reduced pressure, and the precipitated crystals were collected and washed with water (2S,
4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4-mercaptopyrrolidine was obtained. mp 158～162℃ Reference example 3-1 A solution of dimethyl sulfoxide (0.35 ml) in dry methylene chloride (1 ml) was added to a solution of oxalyl chloride (0.2 ml) in dry methylene chloride (5 ml) at -60 to -70°C.
ml) was added dropwise, and after 10 minutes, a dry methylene chloride solution (10 ml) of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester (860 mg) was added at -50°C. It was added dropwise and stirred for 15 hours. Next, add triethylamine (1.01g) dropwise and warm to room temperature.
It was diluted with methylene chloride, washed with diluted hydrochloric acid, dried with mirabilite, and the solvent was distilled off. The residue was subjected to silica gel column chromatography to obtain 1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline p- Methoxybenzyl ester IR ^film _nax (cm ^-1 ): 1762, 1740, 1710, 1512, 1345
,
1245, 1155 NMRδ ( _CDCl3 ): 3.78 (3H, s), 3.95 (2H,
s), 5.08 (2H, s), 6.85 (2H, d, J=9
Hz), 8.12 (2H, d, J=9Hz) Reference example 3-2 1-(p-nitrobenzyloxycarbonyl)-
4-Oxa-L-proline p-methoxybenzyl ester (650 mg) was dissolved in ethanol (45 ml) and dissolved in sodium borohydride (86 mg) at room temperature.
Add in two parts. After 30 minutes, it was concentrated under reduced pressure at below 30°C, the concentrated solution was diluted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off. nitrobenzyloxycarbonyl)-4-hydroxy-
L-proline p-methoxybenzyl ester (450 mg) and trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester (190 mg)
I got it. Trans form: IR and NMR were consistent with the spectrum data of the compound of Reference Example 1-2. Cis body: IR ^film _nax (cm ^-1 ): 3400 (br), 1725, 1515
,
1405, 1350, 1250, 1170, 1120 NMRδ ( _CDCl3 ): 3.78 (3H, s), 5.08 (2H,
s), 6.82 (2H, d, J=9Hz), 8.12 (2H,
d, J=9Hz) Reference example 3-3 Using cis-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester (610 mg), trans-1- (p-nitrobenzyloxycarbonyl)
-4-acetylthio-L-proline was obtained. IR ^film _nax (cm ^-1 ): ~3000, 1700, 1515, 1430,
1400, 1345, 1205, 1165 NMRδ ( _CDCl3 ): 2.32 (3H, s), 5.20 (2H, br.
s), 7.42 (2H, d, J=9Hz), 8.12 (2H,
d, J=9Hz) Reference example 3-4 (a) [2S,4R]-1-(p- Nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine (100
mg) was obtained. IR ^neat _nax (cm ^-1 ): 1700, 1655, 1515, 1400, 1340
,
1115 [α] ³⁰ _D +32.8° (C = 0.375, acetone) (b) Thioacetate derivative obtained in (a) above (80 mg)
[2S, 4R] by the same method as Reference Example 1-3
-1-(p-nitrobenzyloxycarbonyl)
-2-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained. IR ^film _nax (cm ^-1 ): 1700, 1650, 1510, 1420, 1400
,
1340, 1120 NMRδ ( _CDCl3 ): 1.77 (1H, d, J = 7Hz),
2.97 (3H, s), 3.16 (3H, s), 5.22 (2H,
s), 8.16 (2H, d, J=8.5Hz) The following thioacetate and mercapta were obtained in the same manner as in Reference Example 3-4 using the corresponding amines.

[Table] Reference example 4-1 Cis-1-p-nitrilebenzyloxycarbonyl-4-hydroxy-D-proline-p-methoxybenzyl ester obtained from cis-4-hydroxy-D-proline in the same manner as in Reference Examples 1-1 and 1-2. (166 mg) and triphenylphosphine (202 mg) were dissolved in dry tetrahydrofuran (1.5 ml) and then formic acid (27 mg) was added.
plus diethyl azodicarboxylate (134mg)
was added under a nitrogen stream at room temperature, and after stirring for 30 minutes, the solvent was distilled off. The residue was purified by silica gel chromatography to give trans-1-p-nitrobenzyloxycarbonyl-4-formyloxy-D-proline-
p-methoxybenzyl ester was obtained. IR ^film _nax (cm ^-1 ): 1720, 1515, 1402, 1342, 1245
,
1165, 1120 NMRδ ( _CDCl3 ): 3.76 (3H, s), 4.50 (2H, t,
J=8Hz), 5.08 (2H, s), 5.15 (2H, ABq,
J=16Hz), 5.41 (1H, m), 7.97 (1H, s) Reference example 4-2 trans-1-p-nitrobenzyloxycarbonyl-4-formyloxy-D-proline-p
-Methoxybenzyl ester (215mg) was dissolved in tetrahydrofuran (1.1ml) and 1N-NaOH water was added.
Add 0.93ml, stir for 10 minutes, dilute with ethyl acetate, and wash with saturated saline. After drying the Glauber's salt, the solvent was distilled off. The residue was purified by thin layer chromatography to give trans-1-p-nitrobenzyloxycarbonyl-4
-Hydroxy-D-proline-p-methoxybenzyl ester was obtained. IR ^film _nax (cm ^-1 ): 3425 (br,) 1735, 1705, 1510
,
1400, 1340, 1240, 1162 NMRδ ( _CDCl3 ): 2.33 (2H, m), 3.58 (2H,
d, J=3.5Hz), 3.73 (3H, s), 5.03 (2H,
s), 5.07 (2H, ABq, J=18Hz), 6.73 (2H,
d, J=9Hz), 6.77 (2H, d, J=9Hz),
8.00 (2H, d, J=8.5Hz), 8.07 (2H, d,
J=8.5Hz) Reference example 4-3 (a) trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-D-proline-p
- using methoxybenzyl ester (110 mg),
[2R,4R]-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine was obtained in the same manner as in Reference Examples 1-3, 1-4 and 1-5. IR ^film _nax (cm ^-1 ): 1705, 1650, 1515, 1435, 1340
,
1115 [α] ³⁰ _D −7.38° (c=0.210, acetone) (b) Thioacetate derivative obtained in (a) above (42 mg)
[2R,
4R]-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained. IR ^film _nax (cm ^-1 ): 1710, 1660, 1525, 1440, 1347
,
1180, 1122 Reference example 4-4 (a) trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-D-proline-p
- using methoxybenzyl ester (110 mg),
[2R,4R]-1-p-nitrobenzyloxycarbonyl-2-carbamoyl-4- was prepared in the same manner as in Reference Examples 1-3, 1-4 and 2-1.
40 mg of acetylthiopyrrolidine was obtained. IR ^film _nax (cm ^-1 ): 1685, 1515, 1400, 1340, 1110 [α] ³⁰ _D +39.6° (c = 0.293, DMF) (b) Thioacetate derivative obtained in (a) above (40 mg)
By the same method as Reference Example 1-8 using
[2R,4R]-1-p-nitrobenzyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine was obtained. IR ^Nujol _nax (cm ^-1 ): 3200, 1710, 1655, 1512,
1340, 1115 Reference example 5-1 (a) Cis-4-hydroxy-D-proline (300
mg) from Reference Examples 1-1, 1-2, 1-3, 1-
By the same method as 4 and 1-5 [2R, 4S]
-1-(p-nitrobenzyloxycarbonyl)
-2-dimethylcarbamoyl-4-acetylthiopyrrolidine (45 mg) was obtained. IR ^film _nax (cm ^-1 ): 1700, 1650, 1520, 1400, 1345
,
1120 [α] ³⁰ _D −29.6° (c=0.215, acetone) (b) Thioacetate derivative obtained in (a) above (30 mg)
[2R, 4S] by the same method as Reference Example 1-8
-1-(p-nitrobenzyloxycarbonyl)
-2-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained. IR ^film _nax (cm ^-1 ): 1710, 1655, 1520, 1430, 1405
,
1347, 1122 The following thiacetates and mercaptans were obtained in the same manner as in Reference Example 5-1 using the corresponding amines.

[Table] Reference example 6-1 trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-L-proline (500mg)
and p-nitrobenzyl bromide (383 mg),
Trans-1- by the same method as Reference Example 1-2
p-nitrobenzyloxycarbonyl-4-hydroxy-L-proline-p-nitrobenzyl ester was obtained. IR ^CHCl _3nax (cm ^-1 ): 3380 (br), 1750, 1705, 1520
,
1425, 1400, 1342, 1160 NMRδ ( _CDCl3 ): 2.20 (3H, m), 3.67 (2H,
d, J=3Hz, 4.60 (2H, t, J=8Hz),
5.15 (2H, s), 5.23 (2H, ABq), 7.47 (4H,
d, J=8.5Hz), 8.15 (4H, d, J=8.5Hz) Reference example 6-2 trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-L-proline-p-nitrobenzyl ester in Reference Examples 1-3 and 1-
Cis-1-p-nitrobenzyloxycarbonyl-4-mercapto-L-proline-p-nitrobenzyl ester was obtained in the same manner as in Example 8. IR ^film _nax (cm ^-1 ): 1700, 1685, 1600, 1510, 1430
,
1400, 1340, 1105 Reference example 6-3 (a) Dissolve cis-1-p-nitrobenzyloxycarbonyl-4-mercapto-L-proline-p-nitrobenzyl ester (115 mg) in dry tetrahydrofuran (3 ml), add triethylamine (30 mg), and cool on ice. Ethyl chloroformate (28.5 mg) was added dropwise, and after stirring for 10 minutes, the mixture was diluted with ethyl acetate, washed successively with dilute hydrochloric acid and water, and dried with mirabilite. The solvent was distilled off to obtain cis-1-p-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline-p-nitrobenzyl ester (133 mg). IR ^film _nax (cm ^-1 ): 1755, 1710, 1610, 1525, 1405
,
1350, 1160, 1015, 850 (b) Add the ester derivative (133 mg) obtained in (a) above to a mixture of tetrahydrofuran and water (1:1) (5 ml).
Dissolve, add 1N-NaOH water (0.26ml),
After stirring at room temperature for 2.5 hours, 1N-HCl (0.3 ml) was added.
Extracted with ethyl acetate, washed with water, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel thin layer chromatography to give cis-1-p-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-
Got proline. IR ^film _nax (cm ^-1 ): 1700, 1520, 1400, 1340, 1165
,
1145 NMRδ ( _CDCl3 ): 1.30 (3H, t, J=7Hz),
4.28 (2H, q, J=7Hz), 5.24 (2H, s),
7.50 (2H, d, J = 9Hz), 8.17 (2H, d, J
=9Hz) Reference example 6-4 (a) Cis-1-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline (72 mg) was dissolved in dry tetrahydrofuran (3 ml), triethylamine (40 mg) was added, and ethyl chloroformate ( After stirring for 15 minutes, methylamine (40%) aqueous solution (1.5 ml) was added dropwise, and the mixture was stirred for an additional 15 minutes. The reaction solution was diluted with ethyl acetate, washed with dilute hydrochloric acid and water, and dried with mirabilite. The solvent was distilled off to obtain [2S,4S]-1-p-nitrobenzyloxycarbonyl-2-methylaminocarbonyl-4-ethoxycarbonylthiopyrrolidine. IR ^Nujol _nax (cm ^-1 ): 3290, 1705, 1660, 1520,
1425, 1405, 1345, 1180, 1160 NMRδ ( _CDCl3 ): 1.30 (3H, t, J=8Hz),
2.80 (3H, d, J = 5Hz), 4.27 (2H, q, J
=8Hz), 5.22 (2H, s), 7.48 (2H, d, J
= 9 Hz), 8.18 (2H, d, J = 9 Hz) (b) The methylaminocarbonyl derivative (82 mg) obtained in (a) above was mixed with a mixture of methanol and water (1:1) (4
ml), add 0.25 ml of 1N-NaOH,
After stirring at room temperature for 30 minutes, add 0.27 ml of 1N-HCl.
Extracted with ethyl acetate, washed with water, dried with mirabilite, and then distilled off the solvent to give [2S, 4S]-1-p-nitrobenzyloxycarbonyl-2-methylaminocarbonyl-
4-Mercaptopyrrolidine was obtained. IR ^Nujol _nax (cm ^-1 ): 3280, 1710, 1650, 1510,
1340, 1165 NMRδ ( _CDCl3 ): 2.79 (3H, d, J = 5Hz),
4.27 (2H, t, J=8Hz), 5.28 (2H, s),
7.50 (2H, d, J = 9Hz), 8.20 (2H, d, J
=9Hz) The following thiocarbonates were obtained in the same manner as in Reference Example 6-4 (a) using the corresponding amines.

[Table] The following mercaptans were obtained in the same manner as in Reference Example 1-8 or 6-4(b).

【table】

【table】

【table】

[Table] Reference example 8-1 (a) Same method as in Reference Example 1-1 using trans-4-hydroxy-L-proline (10 g) and S-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (23.2 g) trans-1-(p-methoxybenzyloxycarbonyl)-4-hydroxy-L-pyrroline was obtained. IR ^film _nax (cm ^-1 ): 3400 (br), 1692, (109) 1430
,
1355, 1245, 1170, 1122 NMRδ ( _CDCl3 ): 2.23 (2H, m), 3.73 (3H,
s), 5.00 (2H, s), 6.78 (2H, d, J=9
Hz), 7.20 (2H, d, J = 9Hz) (b) Using the proline derivative (0.57g) obtained in (a) above and benzylamine (0.215g), Reference Example 2-
Trans-1-p-methoxybenzyloxycarbonyl-4-hydroxy-L-benzylprolinamide was obtained in the same manner as in Example 1. IR ^Nujol _nax (cm ^-1 ): 3375, 3300, 1665, 1248,
1165, 1120, 1025 NMRδ ( _CDCl3 ): 3.76 (3H, s), 4.35 (4H,
m), 4.96 (2H, s), 6.79 (2H, d, J=9
Hz), 7.20 (5H, s) (c) Benzylprolinamide obtained in (b) above (0.5
g) in the same manner as in Reference Example 1-3 to prepare [2S,4S]-1-p-methoxybenzyloxycarbonyl-2-benzylaminocarbonyl-
4-Acetylthiopyrrolidine was obtained. IR ^Nujol _nax (cm ^-1 ): 3280, 1690, 1675, 1240 NMR δ (CDCl ₃ ): 2.27 (3H, s), 3.82 (3H,
s), 4.42 (2H, d, J=6Hz), 5.05 (2H,
s), 6.87 (2H, d, J=8Hz), 7.23 (2H,
d, J=8Hz), 7.28 (5H, s) Reference example 8-2 (a) [2S,4S]-1-p-methoxybenzyloxycarbonyl-2-benzylaminocarbonyl-4-acetylthiopyrrolidine (177 mg) and anisole (86 mg) were dissolved in 0.5 ml of trifluoroacetic acid and stirred at room temperature for 30 minutes. did. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous sodium bicarbonate and water, and dried with sodium sulfate. The solvent was distilled off, the residue was subjected to silica gel thin layer chromatography, and [2S, 4S]-
2-benzylaminocarbonyl-4-acetylthiopyrrolidine was obtained. IR ^film _nax (cm ^-1 ): 3325, 1690, 1510, 1400, 1350
,
1120, 950 NMRδ ( _CDCl3 ): 2.28 (3H, s), 3.83 (2H,
m), 4.42 (2H, d, J=6Hz), Reference example 9-1 1-(di-p-anisylmethyl)-3-ethenyl-4-carboxymethyl-2-azetidinone is 1
-(di-p-anisylmethyl)-3-ethenyl-4
- From carboxy-2-azetidinone JP-A-1983-
It was obtained in a similar manner to the method described in Publication No. 222089. IR ^neat _nax (cm ^-1 ): ~3000, 1700, 1612, 1510,
1300, 1180, 1030, 820 NMRδ (CDCl ₃ ): 2.35 (2H, d, J = 6Hz)
3.73 (6H, s), 5.80 (1H, s), 6.78 (4H,
d, J=9.0Hz), 7.08 (4H, d, J=9.0Hz) Reference example 9-2 1-(Di-p-anisylmethyl)-3-ethenyl-4-carboxymethyl-2-azetidinone (2.3 g) was dissolved in dry dimethylformamide (50 ml), triethylamine (1.5 ml) was added, then p-methoxybenzyl Chloride (1.3 g) was added dropwise, stirred at 70°C for 3 hours, diluted with ethyl acetate and ether, washed sequentially with dilute hydrochloric acid and water, dried with mirabilite,
By evaporation of the solvent and silica gel chromatography, 1-(di-p-anisylmethyl)-3-ethenyl-4-p
-methoxybenzyloxycarbonylmethyl-2
-Azetidinone was obtained. IR ^film _nax (cm ^-1 ): 1750, 1612, 1510, 1250, 1175
,
1033 NMRδ ( _CDCl3 ): 2.36 (2H, d, J = 6.5Hz),
3.72 (6H, s), 3.75 (3H, s), 4.83 (2H,
s), 5.78 (1H, s) Reference example 9-3 1-(di-p-anisylmethyl)-3-ethenyl-4-pmethoxybenzyloxycarbonylmethyl-2-azetidinone (2.85 g)
1-(J-p) in the same manner as described in 99463
-anisylmethyl)-3-(1-hydroxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone (2.6 g) was obtained. IR ^film _nax (cm ^-1 ): 3430, 1730, 1615, 1510, 1247
,
1178, 1030, 820 NMRδ ( _CDCl3 ): 1.23 (3H, d, J = 6.5Hz),
2.42 (2H, d, J=7Hz), 3.77 (9H, s)
4.95 (2H, s), 5.78 (1H, s) Reference example 9-4 1-(di-p-anisylmethyl)-3-(1-hydroxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone (2.6
Dissolve g) in dry methylene chloride (15 ml) and add 4-
Dimethylaminopyridine (1.22g) was added, and p-nitrobenzyl chloroformate (1.3g) was added under ice cooling.
A solution of g) in dry methylene chloride (7 ml) was added dropwise,
After stirring at room temperature for 1 hour, methylene chloride and water were added.
The methylene chloride layer was mixed with 1N hydrochloric acid, water, 5% sodium bicarbonate solution,
1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-p-methoxybenzyloxycarbonyl Methyl-2-azetidinone (2.2g) was obtained. IR ^film _nax (cm ^-1 ): 1755, 1610, 1510, 1350, 1245
,
1175, 1030 NMRδ ( _CDCl3 ): 1.35 (3H, d, J = 6.5Hz),
2.40 (2H, d, J=6.5Hz), 3.09 (1H, dd,
J = 2.5 and 6Hz), 3.73 (6H, s), 3.77
(3H, s), 4.91 (2H, s), 5.18 (2H, s),
5.71 (1H, s) Reference example 9-5 1-(di-p-anisylmethyl)-3-(1-p
-Nitrobenzyloxycarbonyloxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone (2.2g) was dissolved in dry methylene chloride (20ml), m-dimethoxybenzene (0.88g), and trifluoroacetic acid (2.5g). ml) was added, stirred at room temperature for 4 hours, the solvent was distilled off, and the oily residue was purified using silica gel chromatography.
Anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-carboxymethyl-2-azetidinone (1.75 g) was obtained. IR ^film _nax (cm ^-1 ): ~3000, 1745, 1615, 1510,
1250, 1180, 1035 NMRδ (CDCl ₃ ): 1.35 (3H, d, J = 6.5Hz),
2.35 (2H, d, J = 6.5Hz), 3.10 (1H, m),
3.73 (6H, s), 5.16 (2H, s), 5.75 (1H,
s), 6.73 (4H, d, J=9Hz), 7.46 (2H,
d, J=9Hz), 8.10 (2H, d, J=9Hz) Reference example 9-6 1-(di-p-anisylmethyl)-3-(1-p
-nitrobenzyloxycarbonyloxyethyl)-4-carboxymethyl-2-azetidinone (0.8 g) was dissolved in dry methylene chloride (20 ml),
Add N-methylmorpholine (0.17 ml) to this. Next, the mixture was cooled to −10° C. or lower, and ethyl chloroformate (0.15 ml) was added dropwise, followed by stirring for 30 minutes. Separately, t-butyl-(p-nitrobenzyl)malonate (0.81 g) was dissolved in dry tetrahydrofuran (15 ml), and sodium hydride (50% purity) (0.14 g) was added under ice-cooling and nitrogen flow. Stirred for 30 minutes. This solution was added dropwise to the previously prepared mixed acid anhydride solution at -10°C or lower, and stirred for 1 hour. The temperature was raised to room temperature, the reaction solution was concentrated under reduced pressure,
Dilute the concentrate with cold water and ethyl acetate to 1N-
Wash with hydrochloric acid and water, and dry with mirabilite. The solvent was distilled off, the residue was purified by silica gel chromatography, and 1-
(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4
-[3-t-butoxycarbonyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone was obtained. IR ^film _nax (cm ^-1 ): 1750, 1610, 1510, 1345, 1250 NMR δ (CDCl ₃ ): 1.38 (9H, s), 3.75 (6H,
s), 5.17 (4H, s), 5.77 (1H, br, s),
6.77 (4H, d, J=8.5Hz), 7.45 (4H, d,
J=9Hz), 8.15 (4H, d, J=9Hz) Reference example 9-7 1-(di-p-anisylmethyl)-3-(1-p
-nitrobenzyloxycarbonyloxyethyl)-4-[3-t-butoxycarbonyl-3-
(p-Nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone (2.3 g) was dissolved in dry methylene chloride (120 ml), trifluoroacetic acid (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with aqueous sodium bicarbonate and water, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography to give 1-(di-p-anisylmethyl)-3-
(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-3-oxopropyl]-2-azetidinone was obtained. IR ^film _nax (cm ^-1 ): 1748, 1720 (sh), 1610, 1510
,
1345, 1250 NMRδ ( _CDCl3 ): 1.41 (3H, d, J = 6.5Hz),
2.61 (2H, d, J=6.5Hz), 3.27 (2H, s)
3.76 (6H, s), 5.77 (1H, s), 6.82 (4H,
d, J=9Hz), 7.47 (2H, d, J=9Hz),
7.58 (2H, d, J = 9Hz), 8.20 (4H, d, J
=9Hz) Reference example 9-8 1-(di-p-anisylmethyl)-3-(1-p
-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone in the same manner as described in JP-A-58-222089. -Nitrobenzyl-5,6-trans-3-(diphenylphosphorine)-6-(1-p-
(nitrobenzyloxycaronyloxyethyl)
-1-Azabicyclo[3,2,0]hept-2-
En-7-one-2-carboxylate was obtained. IR ^film _nax (cm ^-1 ): 1780, 1745, 1585, 1517, 1480
,
1345, 1295, 1255, 1180, 1158, 965 NMRδ ( _CDCl3 ): 1.46 (3H, d, J = 6.5Hz),
3.24 (2H, br, d, J = 8.5Hz), 3.40 (1H,
dd, J = 3.0 and 8.5Hz), 5.42 (2H, s),
5.32 (2H, ABq, J=13Hz), 7.28 (10H, s)
7.53 (4H, d, J=8.5Hz), 8.14 (2H, d,
J = 8.5Hz), 8.23 (2H, d, J = 8.5Hz) Also (3R, 4S)-1-(di-p-anisylmethyl)-3-ethenyl-4-carboxy-2-azetidinone [specific optical rotation] α] ²² _D = +63.3° (c = 0.12,
By using (CHCl ₃ )], (5R, 6S, 8R)
-p-nitrobenzyl-3-(diphenylphosphoryloxy)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]-hept-2-en-7-one -2
-carboxylate was obtained. Reference example 10-1 20 ml of dry tetrahydrofuran was added to 1.33 g (20 mM) of activated zinc, and then a 15% n-hexane solution (8.8 ml) of diethylaluminium chloride was added under ice-cooling and nitrogen flow, and (3R, 4R)- 4
-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone
(1) A solution of 1.49g (5.2mM) and benzyl-α-bromopropionate 3.73g (15.3mM) dissolved in 13.3ml of dry tetrahydrofuran was added dropwise over 30 to 40 minutes, and then stirred for an additional hour. Under ice cooling, 2.8 ml of pyridine was added, followed by 13.2 ml of water, 26.5 ml of ethyl acetate and 13.2 ml of 1N hydrochloric acid, and the mixture was filtered over Celite. The liquid was washed with water, the organic layer was dried with sodium sulfate, the solvent was distilled off, and the resulting oily residue was subjected to silica gel column chromatography to obtain 4-(1-benzyloxycarbonyl)ethyl-3-[(R)- A mixture of 1-(t-butyldimethylsilyloxy)ethyl]-2-acetidinone was obtained. Separation of isomers is 1.5%
This was achieved by Rover column chromatography (silica gel) eluting with isopropanol/n-hexane to give (2a) and (2b) as oils. Isomer (2a) NMRδ ( _CDCl3 ): 0.06 (6H, s), 0.87 (9H,
s), 1.08 (3H, d, J=6.5Hz), 1.18 (3H,
d, J=7.0Hz), 3.91 (1H, dd, J=2.2 and 5.5Hz), 4.17 (2H, q, J=6Hz), 5.12
(2H, s), 7.35 (5H, s) Isomer (2b) IR ^film _nax (cm ^-1 ): 1755, 1460, 1377, 1252, 1100
,
835 NMRδ ( _CDCl3 ): 0.06 (6H, s), 0.87 (9H,
s), 1.16 (3H, d, J=6.5Hz), 1.19 (3H,
d, J=7.0Hz), 3.71 (1H, dd, J=2 and 10Hz), 5.14 (2H, s), 7.35 (5H, s) Reference example 10-2 4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(t-butyl-dimethylsilyloxy)ethyl]-2-azetidinone (2a) (200
mg) was dissolved in dry dimethylformamide (2 ml), triethylamine (126 mg) was added, and then t
-Butyldimethylsilyl chloride (151 mg) was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, dried with sodium sulfate, and purified by silica gel chromatography to obtain 4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(t-butyldimethylsilyloxy). ) ethyl]-1-(t-butyldimethylsilyl)-2-azetidinone (3a) was obtained. IR ^film _nax (cm ^-1 ): 1750, 1465, 1325, 1255, 835 Reference example 10-3 4-(1-benzyloxycarbonyl)ethyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(t-butyldimethylsilyl)-2-azetidinone (184 mg) was dissolved in methanol 4
ml and stirred with 10% palladium-carbon (20 mg) under normal pressure hydrogen gas for 2 hours. The catalyst was removed, the liquid was concentrated under reduced pressure, and 4-(1-carboxy)
Ethyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(t-butyldimethylsilyl)-2-azetidinone (4a) was obtained. IR ^film _nax (cm ^-1 ): 1740, 1465, 1330, 1255, 1043
,
337 Reference example 10-4 4-(1-carbonyl)ethyl-3-[(R)-1
-(t-butyldimethylsilyloxy)ethyl-
From 1-(t-butyldimethylsilyl)-2-azetidinone (170 mg) (4a), (4R, 5R,
6S, 8R)-p-nitrobenzyl-4-methyl-6
-(1-hydroxyethyl)-1-azabicyclo[3,2,0]-hepto-3,7-dione-2-carboxylate (5a) was obtained. IR ^film _nax (cm ^-1 ): 3450 (br), 1770 (sh), 1750
,
1605, 1520, 1350, 1217, 1180 Example 1-1 (a) (5R, 6S, 8R)-p-nitrobenzyl-3
-(diphenylphosphoryloxy-6-(1-p
-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (122 mg) was dissolved in dry acetonitrile (3 ml) and placed on ice in a nitrogen stream. Add diisopropyl elamine (31mg) to the sample, then [2S,4S]-1
-p-nitrobenzyloxycarbonyl-2-
Dimethylaminocarbonyl-4-mercaptopyrrolidine (60 mg) was added, and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water,
It was dried over magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography to give (5R, 6S, 8R, 2′S, 4′S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2- dimethylaminocarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-
1-Azabicyclo[3,2,0]hept-2-
En-7-one-2-carboxylate (95
mg) was obtained. IR ^film _nax (cm ^-1 ): 1780, 1745, 1705, 1650, 1605
,
1515, 1342, 1257 NMRδ ( _CDCl3 ): 1.49 (3H, d, J = 6Hz),
2.99 (3H, s), 3.11 (3H, s), 5.25 (4H,
s), 5.23 and 5.46 (2H, ABq, J=14
Hz), 7.53 (4H, d, J = 8.5Hz), 7.62 (2H,
d, J=8.5Hz), 8.18 (6H, d, J=8.5Hz) [α] ²⁸ _D +7.7° (c=0.303, acetone) (b) (5R, 6S, 8R, 2′S, 4 'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)pyrrolidinylthio]-6-(1-p-nitrobezyloxycarbonyloxyethyl) -1-
Dissolve azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (95 mg) in dioxane (20 ml) and add morpholinopropanesulfonic acid buffer (PH = 7.0, 10 ml) and platinum oxide (35 mg). ) was added and hydrogenated for 6.5 hours under a hydrogen pressure of 3.5 atm. After passing through the catalyst, the dioxane was distilled off under reduced pressure, the residual liquid was washed with ethyl acetate, the aqueous layer was again distilled off the organic solvent under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P). From the part eluted with water (5R, 6S, 8R,
2′S, 4′S)-3-[4-(2-dimethylaminocarbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0] hept-2-en-7-one-2-carboxylic acid was obtained. UV ^H2O _{nax o} m: 297 IR ^KBr _nax cm ^-1 : 1755, 1627, 1393, 1252, 1130 NMR δ (D ₂ O): 1.25 (3H, d, J = 6.4Hz),
1.81-1.96 (1H, m), 2.96 (3H, s), 3.03
(3H, s), 3.14~3.20 (3H, m), 3.31~3.41
(2H, m), 3.62-3.72 (1H, m), 8.90-4.00
(1H, m), 4.14-4.26 (2H, m), 4.63 (1H,
t, J=8.5Hz) Example 1-2 (a) (5R, 6S, 3R)-p-nitrobenzyl-3
-(diphenylphosphoryloxy)-6-(1-
p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (129 mg) and [2S,4R]-1-p-nitrobenzyl Oxycarbonyl-2-dimethylaminecarbonyl-4-mercaptopyrrolidine (67
(5R, 6S, 8R, 2'S, 4'R)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyl (oxycarbonyl-2-dimethylaminocarbonyl)
pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-
7-one-2-carboxylate (40 mg) was obtained. IR ^film _nax (cm ^-1 ): 1775, 1745, 1705, 1650, 1520
,
1440, 1345, 1260, 1130 NMRδ (CDCl ₃ ): 1.48 (3H, d, J = 6Hz),
2.96 (3H, s), 3.12 (3H, s), 5.22 (4H,
s), 7.44, 7.50 and 7.58 (2H, d, J respectively
= 8.5Hz), 8.17 (6H, d, J = 8.5Hz) [α] ²⁷ _D +31.1° (c = 0.193, acetone) (b) (5R, 6S, 8R, 2′S, 4′R) -p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1
-Azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (40mg)
by the same method as in Example 1-1(b) (5R,
6S, 8R, 2′S, 4′R)-3-[4-(2-dimethylaminocarbonyl)pyrrolidinylthio]-6-
(1-Hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-
2-carboxylic acid was obtained. UV ^H2O _{nax o} m: 297 Example 1-3 (a) (5R, 6S, 8R)-p-nitrobenzyl-3
-(diphenylphosphoryloxy)-6-(1-
p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (61 mg) and [2R,4S]-1-p-nitrobenzyl Oxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (31 mg)
(5R, 6S, 8R, 2'R, 4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxy carbonyl-2-dimethylaminocarbonyl)
pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-
7-one-2-carboxylate (37 mg) was obtained. IR ^film _nax (cm ^-1 ): 1775, 1745, 1705, 1650, 1520
,
1400, 1345, 1260, 1130 NMRδ ( _CDCl3 ): 1.49 (3H, d, J = 6.5Hz),
2.98 (3H, s), 3.16 (3H, s), 5.27 (4H,
s), 5.19 and 5.47 (2H, ABq, J=14
Hz), 7.50, 7.55, 7.64 (2H, d, J = 8.5 respectively)
Hz), 8.20 (4H, d, J = 8.5Hz), 8.22 (2H,
d, J=8.5Hz) [α] ²⁹ _D +26.8° (c=0.243, acetone) (b) (5R, 6S, 8R, 2′R, 4′S)-p-nitrobenzyl-3-[ 4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1
-Azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (37mg)
by the same method as in Example 1-1(b) (5R,
6S, 8R, 2′R, 4′S)-3-[4-(2-dimethylaminocarbonyl)pyrrolidinylthio]-6-
(1-Hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-
2-carboxylic acid was obtained. UV ^H2O _{nax o} m: 297 Example 1-4 (a) (5R, 6S, 8R)-p-nitrobenzyl-3
-(diphenylphosphoryloxy)-6-(1-
p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (76 mg) and [2R,4R]-1-p-nitrobenzyl Oxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (39
(5R, 6S, 8R, 2'R, 4'R)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyl Benzyloxycarbonyl-2-dimethylaminocarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1
-Azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (35mg)
I got it. IR ^film _nax (cm ^-1 ): 1775, 1745, 1705, 1650, 1520
,
1440, 1342, 1260, 1120 NMRδ ( _CDCl3 ): 1.49 (3H, d, J = 6.5Hz),
2.98 (3H, s), 3.09 (3H, s), 5.25 (4H,
s), 5.26 and 5.44 (2H, ABq, J=14
Hz), 8.20 (6H, d, J = 8.5Hz) [α] ³⁰ _D +23.3° (c = 0.329, acetone) (b) (5R, 6S, 8R, 2'R, 4'R) - p -Nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1
-Azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (35mg)
by the same method as in Example 1-1(b) (5R,
6S, 8R, 2′R, 4′R)-3-[4-(2-dimethylaminocarbonyl)pyrrolidinylthio]-6-
(1-Hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-
2-carboxylic acid was obtained. UV ^H2O _{nax o} m: 297 Example 2 (a) (4R, 5R, 6S, 8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)-
1-Azebicyclo[3,2,0]hept-3,
7-Dione-2-carboxylate (53 mg) was dissolved in dry acetonitrile (5 ml) and diisopropylethylamine (57
mg) and then diphenyl chlorophosphate (43 mg) and stirred for 2.5 hours [2S, 4S]
-1-p-nitrobenzyloxycarbonyl-
2-dimethylaminocarbonyl-4-mercaptopyrrolidine (57 mg) was added, and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off.
The residue was purified by silica gel thin layer chromatography to give (4R, 5R, 6S, 8R, 2′S, 4′S)-p
-Nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azebicyclo[3,2 ,0]hept-2-ene-7-
One-2-carboxylate (35 mg) was obtained. IR ^film _nax (cm ^-1 ): 1760, 1705, 1645, 1520, 1402
,
1342, 1135, 1110 NMRδ ( _CDCl3 ): 1.30 (3H, d, J = 7.0Hz),
1.35 (3H, d, J=6.5Hz), 2.99 (3H, s),
3.02 (3H, d, J=15Hz), 5.21 (2H, s),
5.20 and 5.43 (2H, ABq, J=14Hz), 7.51
(2H, d, J = 8.5Hz), 7.64 (2H, d, J =
8.5Hz), 8.20 (4H, d, J = 8.5Hz) (b) (4R, 5R, 6S, 8R, 2′S, 4′S)-p-nitrobenzyl-3-[4-(1-p -nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)pyrrolidinylthio]-4-methyl-6
-(1-hydroxyethyl)-1-azebicyclo[3,2,0]hept-2-en-7-one-
2-carboxylate (25 mg) was dissolved in tetrahydrofuran (1.9 ml) and ethanol (0.3 ml), and this solution was hydrogenated for 1 hour under normal hydrogen pressure in morpholinopropanesulfonic acid buffer (PH = 7.0, 1.9 ml). After that, 10% palladium on carbon (30 mg), which had been filtered and washed with water, was added and hydrogenated at room temperature for 3 hours under hydrogen pressure. After passing through the catalyst, tetrahydrofuran and ethanol were distilled off under reduced pressure, the residual liquid was washed with ethyl acetate, the aqueous layer was again distilled off the organic solvent under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P). 4R, 5R, 6S, 8R, 2′S,
4′S)-3-[4-(2-dimethylaminocarbonyl)pyrrolidinylthio]-4-methyl-6-(1
-hydroxyethyl)-1-azabicyclo[3,
2,0]hept-2-en-7-one-2-carboxylic acid was obtained. UV ^H2O _{nax o} m: 296 NMRδ (D ₂ O): 1.21 (3H, d, J = 7.0Hz),
1.29 (3H, d, J = 6.5Hz), 1.92 (1H, m),
2.99 (3H, s), 3.06 (3H, s) Example 3 (a) (4R, 5R, 6S, 8R)-p-nitrobenzyl-4-methyl-6-(1-hydroxyethyl)-
1-Azebicyclo[3,2,0]hept-3,
7-dione-2-carboxylate (61 mg) was dissolved in dry acetonitrile (6 ml) and diisopropylethylamine (72
mg), then diphenyl chlorophosphate (55 mg) and stirred for 2.5 hours [2S, 4S]
-1-p-nitrobenzyloxycarbonyl-
Add 2-(1-pyrrolidinylcarbonyl-4-mercaptopyrrolidine (77 mg)) and add 1
Stir for hours. Dilute the reaction solution with ethyl acetate,
After washing with water, it was dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography to obtain (4R, 5R, 6S, 8R, 2′S,
4′S)-p-nitrobenzyl-3-(1-p-nitrobenzyloxycarbonyl-2-(1-pyrrolidinylcarbonyl)pyrrolid-4-ylthio]-4--methyl-6-(1-hydroxy Ethyl)-1-azabicyclo[3,2,0]-hept-2-en-7-one-2-carboxylate (51 mg) was obtained. IR ^film _nax (cm ^-1 ): 1760, 1710, 1640, 1525, 1440
,
1350, 1210, 1110 NMRδ (CDl ₃ ): 1.30 (3H, d, J = 7.0Hz),
1.34 (3H, d, J=6.5Hz), 5.21 (2H, s),
5.20 and 5.44 (2H, ABq, J=14Hz), 7.50
(2H, d, J=8.5Hz), 7.64 (2H, d, J=
8.5Hz), 8.20 (4H, d, J = 8.5Hz) (b) (4R, 5R, 6S, 8R, 2′S, 4′S)-p-nitrobenzyl-3-[1-p-nitrobenzyl Oxycarbonyl-2-(1-pyrrolidinylcarbonyl)pyrrolidin-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7
-one-2-carboxylate (50mg) was mixed with tetrahydrofuran (3.9ml) and ethanol (0.6ml).
ml), to this solution was hydrogenated in morpholinopropanesulfonic acid buffer (PH = 7.0, 3.9 ml) under normal hydrogen pressure at room temperature for 1 hour, and then 10% palladium on carbon (60 mg), which had been washed with water, was added. Hydrogenation was carried out under normal hydrogen pressure for 4.5 hours at room temperature. After passing through the catalyst, tetrahydrofuran and ethanol were distilled off under reduced pressure, the residual liquid was washed with ethyl acetate, the aqueous layer was again distilled off the organic solvent under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P). From the part eluted with 2% tetrahydrofuran aqueous solution (4R, 5R,
6S, 8R, 2′S, 4′S)-3-[2-(1-pyrrolidinylcarbonyl)pipolidin-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 o} m: 297 NMRδ (D ₂ O): 1.20 (3H, d, J = 7.0Hz),
1.28 (3H, d, J = 6.5Hz), 1.95 (6H, m),
3.46 (6H, m), 3.72 (1H, dd, J=6.5 and 12Hz), 4.02 (1H, quintet, J=6.5Hz) Example 4 (a) (5R, 6S, 8R)-p-nitrobenzyl-3
-(diphenylphosphoryloxy)-6-(1-
p-Nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (172 mg) was dissolved in dry acetonitrile (2.3 ml) and placed on ice under a stream of nitrogen. Diisopropylenalamine (59 mg) in dry acetonitrile (0.7 mg) under cooling.
ml) solution, then [2S,4S]-1-p
-nitrobenzyloxycarbonyl-2-(3
A solution of -pyrrolinyl-1-carbonyl-4-mercaptopyrrolidine (94 mg) in dry acetonitrile (1 ml) was added and the mixture was stirred for 15 minutes.
The reaction solution was diluted with ether, washed with water, the insoluble matter in the ether layer was dissolved in methylene chloride, and the ether layer was dried with magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography to give (5R, 6S, 8R, 2′S, 4′S)-p-
Nitrobenzyl-3-{4-[1-p-nitrobenzyloxycarbonyl-2-(3-pyrrolinyl-1-carbonyl)]pyrrolidinylthio}-6
-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,
0] hept-2-en-7-one-2-carboxylate (182 mg) was obtained. IR ^CHCl3 _nax (cm ^-1 ): 1780, 1745, 1708, 1660,
1623, 1606, 1520, 1342 NMRδ ( _CDCl3 ): 1.49 (3H, d, J = 6.2Hz),
5.26 (4H, s), 8.18 (6H, d, J = 8.8Hz) (b) (5R, 6S, 8R, 2′S, 4′S)-p-nitrobenzyl-3-{4-[1- p-Nitrobenzyloxycarbonyl-2-(3-pyrrolinyl-1-carbonyl)]pyrrolidinylthio}-6-(1-p
-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (182 mg) was dissolved in tetrahydrofuran (12.6 ml) and ethanol (2 ml). Add morpholinopropanesulfonic acid buffer (PH7.0, 12.6) to this solution.
ml) at room temperature and pressure under hydrogen pressure for 1 hour, 10% palladium-carbon (219 mg) filtered and washed with water was added, and hydrogenation was carried out at room temperature under hydrogen pressure and normal pressure for 7 hours. After passing through the catalyst, tetrahydrofuran and ethanol are distilled off under reduced pressure, the residual liquid is washed with ethyl acetate, 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 from the part eluted with 2% tetrahydrofuran (5R, 6S,
8R, 2′S, 4′S)-3-{4-[2-(3-pyrroline-1-carbonyl)pyrrolidinylthio}-6
-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-
2-carboxylic acid was obtained. UV ^H2O 〓 _{nax o} m: 298 IR ^KBr _nax (cm ^-1 ): 1755, 1640, 1595, 1450, 1380,
1245 NMRδ (D ₂ O): 1.26 (3H, d, J = 6.4Hz),
3.18 (1H, dd, J=2.1 and 9.0Hz), 3.77
(1H, dd, J = 7.0 and 12.0Hz), 5.89 (2H,
br, s) Example 5 (a) (5R, 6S, 8R)-p-nitrobenzyl-3
-(diphenylphosphoryloxy)-6-(1-
p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (68 mg) and [2S,4S]-1-p-nitrobenzyl Oxycarbonyl-2-carbamoylmethylaminocarbonyl-4-mercaptopyrrolidine (33 mg) was treated in the same manner as in Example 1-1(a), and the resulting crystalline (5R, 6R, 8R, 2'S,
4′S)-p-nitrobenzyl-3-[4-(1-p
-Nitrobenzyloxycarbonyl-2-carbamoylmethylaminocarbonyl)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7 -on-
2-carboxylate (61 mg) was obtained by filtration. IR ^Nujol _nax (cm ^-1 ): 3445, 3300, 1790, 1745,
1710, 1670, 1635, 1510, 1345, 1270 NMRδ ( _CDCl3 ): 1.50 (3H, d, J = 6.5Hz),
5.23 (4H, s), 7.50 (4H, d, J=8.5Hz),
8.21 (6H, d, J = 8.5Hz) mp184-189℃ (decomposition) (b) (5R, 6S, 8R, 2'S, 4'S)-p-nitrobenzyl-3-[4-(1- p-Nitrobenzyloxycarbonyl-2-carbamoylmethylaminocarbonyl)pyrrolidinylthio]-6-(1-p
-Nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (30 mg) was dissolved in tetrahydrofuran (3.1 ml)-dimethylformamide (1 ml). , add morpholinopropanesulfonic acid buffer (PH
7.0, 3.1 ml) at room temperature and pressure for 1 hour under hydrogen pressure, filtered and water-washed 10% palladium-carbon (37 mg) was added, and hydrogenation was carried out under hydrogen pressure at room temperature for 5 hours. After passing through the catalyst, tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with methylene chloride, the organic solvent was distilled off from the aqueous layer under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P) to produce water. (5R, 6S, 8R, 2′S, 4′S)
-3-[4-(2-carbamoylmethylaminocarbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0] hept-2-en-7-one-2-carboxylic acid was obtained. UV ^H2O _{nax o} m: 300 IR ^KBr _nax (cm ^-1 ): 1745, 1665, 1590, 1390, 1220,
1180, 1040 NMRδ (D ₂ O): 1.26 (3H, d, J = 6.6Hz),
1.86 (1H, m), 3.20 (2H, dd, J = 7.5 and 14.7Hz), 3.38 (1H, dd, J = 3.0 and 6.7
Hz), 4.02 (1H, t, J=9.0Hz) The following compound was obtained from the corresponding mercaptan derivative.

【table】 \

HN
MRδ( _CDCl3 ): 1.48(3H,d,J=6.5Hz),2.73(3H,


HHH CH ₃
s),3.21(2H,d,J=9Hz),5.25(4H,
/

−N
s),5.25and5.43(2H,ABq,each J=
\

H
14Hz), 7.50, 7.54 and 7.62 (each



2H,d,J=8.5Hz),8.20(6H,d,J=



8.5Hz)


UV
λ ^H2O _nax nm: 297

8 PNZ PNZ PNB CH ₃
IRν ^Nujol _nax (cm ⁻¹ ): 1770,1740,1700,1
510,1340,
/

CH
1255
／ ＼

−N CH ₃ N
MRδ( _CDCl3 ): 1.08(3H,d,J=6.5Hz),1.11(3H,d,
\

H
J=6.5Hz),1.48(3H,d,J=6Hz),


HHH CH ₃
3.18(2H,br,d,J=9Hz),5.25(4H,
/

CH
s),5.26and5.44(2H,ABq,J=14
／ ＼

-N CH ₃
Hz), 7.50, 7.54 and 7.62 (respectively
\

H
2H,J=9Hz),8.20(6H,d,J=8.5Hz)


UV
λ ^H2O _nax nm: 296

9 PNZ PNZ PNB CH ₂ CH=CH ₂
IRν ^Nujol _nax (cm ⁻¹ ): 3275,1782,1740,1
700,1650,
/

−N
1515,1340,1260
\

HN
MRδ( _CDCl3 ): 1.48(3H,d,J=6.5Hz),3.18(2H,


HHH CH ₂ CH ₂ CH ₃
br,d,J=9Hz),5.24(4H,s),5.25
/

−N
and 5.45(2H,ABq,J=14Hz),7.50,
\

H
7.53 and 7.62 (2H, d, J = 8.5 respectively


HHH CH ₂ CH=CH ₂
Hz),8.19(6H,d,J=8.5Hz)
/

−N NMR
δ(D ₂ O): 1.0(3H,t,J=7.5Hz),1.23(3H,d,J=
\

H
7Hz)


UV
λ ^H2O _nax nm: 298



N.M.
Rδ(D ₂ O): 1.27(3H,d,J=7Hz),5.68(3H,m)




UV
λ ^H2O _nax nm: 298

【table】 /

−N
1250
\

HN
MRδ( _CDCl3 ): 1.49(3H,d,J=6.5Hz),4.42(2H,d,


HHH CH ₂ Ph
J=7.0Hz),5.25(4H,s),5.27and
/

−N
5.43(2H,ABq,J=14Hz),7.27(5H,
\

H
s), 7.54, 7.62, 8.21 and 8.22 (each



2H,d,J=8.5Hz)


UV
λ ^H2O _nax nm: 297

13 PNZ PNZ PNB CH ₂ Ph I
Rν ^neat _nax (cm ⁻¹ ): 1780,1750,1715,1660,1
525,
/

−N
1442,1350,1265,1122
\

_CH3
NMRδ( _CDCl3 ): 1.48(3H,d,J=6.5Hz),2.92(3H,


HHH CH ₂ Ph
s),4.56(2H,d,J=5Hz),5.25(4H,
/

−N
s),8.19(6H,d,J=9Hz)
\

_CH3
UVλ ^H2O _nax nm: 297

14 PNZ PNZ PNB IR
ν ^Nujol _nax (cm ⁻¹ ): 1790,1745,1714,165
2,1605,

1520,1347
m.
p.179−182℃ (decomposition)
UV
λ ^H2O _nax nm: 299,266,260

IR
ν ^KBr _nax (cm ⁻¹ ): 1745,1590,1490,1210,1090,9
Ten
N.M.
Rδ(D ₂ O): 1.26(3H,d,J=6.3Hz),1.99(1H,m),

2.80(1H,m),3.36(1H,dd,J=2.7 and
HHH
and 6.0Hz),3.58(1H,dd,J=7.0 and

12.0Hz),3.86(1H,m),4.51(2H,d,J＝

4.4Hz),7.82(1H,dt,J=1.8 and

7.7Hz),8.42(1H,m)






15 PNZ PNZ PNB CH ₂ CH ₂ N(CH ₃ ) ₂
IRν ^neat _nax (cm ⁻¹ ): 1775,1745,1700,166
0(sh),
/

−N
1515,1345,1260
\

HN
MRδ( _CDCl3 ): 1.47(3H,d,J=6.5Hz),2.24(3H,


HHH CH ₂ CH ₂ N(CH ₃ ) ₂
s),2.27(3H,s),5.25(4H,s),7.49,

/

−N
7.53 and 7.62 (2H, d, J = 8.5 respectively
\

H
Hz),8.20(6H,d,J=8.5Hz)


UV
λ ^H2O _nax nm: 297

【table】 /

−N
and 5.45(2H,ABq,J=13.5Hz),
\

_CH3
7.49, 7.51 and 7.63 (2H, d, J respectively



=8.5Hz),8.19(4H,d,J=8.5Hz),



8.21(2H,d,J=8.5Hz)


UV
λ ^H2O _nax nm: 297

19 PNZ PNZ PNB CH ₂ CH ₂ CH ₂ COOPNB
IRν ^neat _nax (cm ⁻¹ ): 1770,1730,1695,1650
,1600,
/

−N
1505,1340
\

HN
MRδ( _CDCl3 ): 1.48(3H,d,J=6.5Hz),5.25(4H,


HHH CH ₂ CH ₂ CH ₂ COOH
s),7.62(2H,d,J=8.6Hz),8.20

/

−N
(6H,d,J=8.6Hz)
\

HU
Vλ ^H2O _nax nm: 297

20 PNZ PNZ PNB CH ₂ CONHCH ₃
IRν ^Nujol _nax (cm ⁻¹ ): 1795,1747,1
712,1640,1608,
/

−N
1517,1350,1275
\

H m
.p.167−169℃ (decomposition)


HHH CH ₂ CONHCH ₃
UVλ ^H2O _nax nm: 300

/

−NIR
ν ^KBr _nax (cm ⁻¹ ): 1752,1650,1590,1388.1255,1
150
\

HN
MRδ( _D2O ): 1.26(3H,d,J=6.3Hz),2.71(3H,s),



2.93(1H,q,J=7.4Hz),3.88(2H,s)
21 PNZ PNZ PNB CH ₂ CON(CH ₃ ) ₂
IRν ^Nujol _nax (cm ⁻¹ ): 1800,1750,17
07,1675,1650,
/

−N
1610,1520,1350,1280
\

H m
.p.196−199℃ (decomposition)


HHH CH ₂ CON(CH ₃ ) ₂
UVλ ^H2O _nax nm: 299

/

−NIR
ν ^KBr _nax (cm ⁻¹ ): 1750,1640,1590,1380,1250,1
145
\

HN
MRδ( _D2O ): 1.26(3H,d,J=6.3Hz),2.92(3H,s),



3.03(3H,s),3.19(2H,dd,J=6.3 and



and 9.2Hz),3.51(1H,dd,J=7.4 and



12Hz),4.12(2H,s)
22 PNZ PNZ PNB CH ₃ I
Rν ^Nujol _nax (cm ⁻¹ ): 1795,1750,1700,16
80,1655,


｜
1610,1525,1350


CHCONH ₂
mp168−170℃ (decomposition)
/

-NIR
ν ^KBr _nax (cm ⁻¹ ): 1745,1665,1590,1390,1180,1
037
\

HU
Vλ ^H2O _nax nm: 300



HHH CH ₃



｜



CHCONH ₂

/

−N

\

H

【table】 /

−N
1524,1345
\

_CH3
NMRδ( _CDCl3 ): 1.48(3H,d,J=6.4Hz),3.19(3H,


HHH CH ₂ CONH ₂
s),5.17(2H,s),5.24(2H,s),8.19
/

−N
(6H,d,J=8.6Hz)
\

_CH3
UVλ ^H2O _nax nm: 300



IR
ν ^KBr _nax (cm ⁻¹ ): 1750,1654,1590,1395,1250,1
060


N.M.
Rδ(D ₂ O): 1.26(3H,d,J=6.3Hz),2.95(3H,s),



3.21(2H,dd,J=2.2 and 9.0Hz),



3.38(1H,dd,J=2.2 and 5.5Hz)
26 PNZ PNZ PNB CH ₂ CONHCH ₃ I
Rν ^CHCl3 _nax (cm ⁻¹ ): 1778,1743,1685,16
60,1605,
/

−N
1520,1340
\

_CH3
NMRδ( _CDCl3 ): 1.48(3H,d,J=6.2Hz),2.72(3H,d,


HHH CH ₂ CONHCH ₃
J=5Hz),3.19(3H,s),5.22(2H,s),
/

−N
5.25(2H,s),8.22(6H,d,J=8.8Hz)
\

_CH3
UVλ ^H2O _nax nm: 300



IR
ν ^KBr _nax (cm ⁻¹ ): 1750,1640,1585,1382,1250,1
125


N.M.
Rδ(D ₂ O): 1.26(3H,d,J=6.3Hz),2.73(3H,s),



3.09(3H,s),3.39(1H,q,J=2.6Hz)
27 PNZ PNZ PNB CH ₂ CON(CH ₃ ) ₂
IRν ^neat _nax (cm ⁻¹ ): 1778,1745,1705,1650,
1605,
/

−N
1520,1345
\

_CH3
NMRδ( _CDCl3 ): 1.49(3H,d,J=6.2Hz),2.93(3H,


HHH CH ₂ CON(CH ₃ ) ₂
s), 2.99(3H,s), 3.10 and 3.15
/

−N
(3H,s),5.25(4H,s),8.21(6H,d,J
\

_CH3
=8.4Hz)


UV
λ ^H2O _nax nm: 297



IR
ν ^KBr _nax (cm ⁻¹ ): 1760,1650,1500,1380,1240,1
130
28 PNZ PNZ PNB IR
ν ^neat _nax (cm ⁻¹ ): 1778,1750,1705,1650,15
18,

1430,1345,1258
N.M.
Rδ( _CDCl3 ): 1.49(3H,d,J=6.5Hz),2.25(3H,

s),2.31(4H,s),5.25(4H,s),5.21
HHH
and 5.46(2H,ABq,J=13.5Hz),

7.53(4H,d,J=8.5Hz),7.62(2H,d,

J=8.5Hz),8.20(6H,d,J=8.5Hz)
UV
λ ^H2O _nax nm: 298

【table】

【table】

【table】

【table】 /

−N−N IR
ν ^KBr _nax (cm ⁻¹ ): 1763,1660,1590,1380,1240,1
060
\

_CH3NM
Rδ(D ₂ O): 1.26(3H,d,J=6.6Hz),2.50(3H,s),



2.52(3H,s),2.92(3H,s),3.18(2H,q,



J=4.3Hz)

【table】

【table】

【table】

【table】

【table】

【table】

【table】

【table】

【table】

[Table] The following compounds can be synthesized by methods similar to those shown in the examples above.

【table】

【table】

【table】

【table】

【table】

【table】

【table】

【table】

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ is a hydrogen atom or a hydroxyl group protecting group,
R ₂ represents a hydrogen atom or an amino group-protecting group, R ₃ represents a hydrogen atom or a carboxyl group-protecting group,
R ₄ represents a hydrogen atom. Y is a general formula (In the formula, R ₅ represents a hydrogen atom and R ₆ represents a pyridyl group.) A group represented by the general formula (In the formula, R ₇ is a hydrogen atom or a lower alkyl group.) A guanidyl group, an unsubstituted or lower alkyl-substituted hydrazino group, or a general formula -NHOR ₈ (In the formula, R ₈ is a hydrogen atom or a hydroxyl group. represents a protecting group or a lower alkyl group). ] A β-lactam compound or a salt thereof. 2. The β-lactam compound or salt thereof according to claim 1, wherein R ₁ , R ₂ and R ₃ are hydrogen atoms.