JPH0352466B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula [] [In the formula, R ₁ is a hydrogen atom or a hydroxyl group protecting group, R ₂ is a hydrogen atom or an amino group protecting group,
R ₃ represents a hydrogen atom or a carboxyl group protecting group. ] The present invention relates to a novel β-lactam compound represented by the above, a pharmacologically acceptable salt thereof, and a method for producing the same.

In the general formula [], the hydroxyl group-protecting group in R ₁ or the amino group-protecting group in R ₂ is preferably a lower alkoxycarbonyl group such as tert-butyloxycarbonyl, such as 2-ethyloxyiodide. carbonyl, 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 ₃ 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, pivalooxymethyl, 1-lower alkoxycarbonyloxyethyl groups such as 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, e.g. aralkyl groups such as benzyl, P-methoxybenzyl, o-nitrobenzyl, P-nitrobenzyl, benzhydryl groups,
or a phthalidyl group.

The carboxylic acid compound in which R ₃ is a hydrogen atom in the general formula [] can be converted into a pharmacologically acceptable salt form, if necessary. Such salts include salts of inorganic metals such as lithium, sodium, potassium, calcium, magnesium, or ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, triethylammonium, preferably sodium salts and potassium salts. It's salt.

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, and various N-
It is a novel compound having a substituted-2-carbamoylpyrrolidin-4-ylthio group and various o-substituted-2-hydroxyethyl groups at the 6th position.These compounds have strong antibacterial activity and are useful as medicines. The present invention was completed based on the discovery that the compound is an important intermediate for compounds exhibiting antibacterial activity.

The method for producing the compound of the present invention will be described in detail above.

General formula [] [In the formula, R ₄ represents a hydroxyl group-protecting group, and R ₅ represents a carboxyl group-protecting group. ] Reactive ester of alcohol represented by and general formula [In the formula, R ₆ represents a group protecting an amino group. ] By reacting a mercaptan represented by the general formula [ ] in an inert solvent in the presence of a base. [In the formula, R ₄ , R ₅ .R ₆ 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 sulfonate 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., halogenated lower alkanesulfonic acid ester, such as trifluoromethanesulfonic acid ester, diarylphosphoric acid ester, such as diphenylphosphoric acid ester, etc., and halogenated compound. , 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 hydroxyl group-protecting group in R ₄ , the amino group-protecting group in R ₆ , and the carboxyl group-protecting group in R ₅ correspond to each of the above-mentioned protecting groups in R ₁ , R ₂ , and R ₃ , and are suitable protecting groups. A similar example can be given.

Inert solvents used in this reaction include dioxane, dimethylformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, etc., and bases include potassium carbonate, sodium hydrogen carbonate, triethylamine,
Mention may be made of diisopropylamine.

The preferred reaction temperature is -40 to 25°C.

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 [], a hydroxyl protecting group
Removal reaction of R ₄ , removal reaction of amino protecting group R ₆ ,
A β-lactam compound represented by the general formula [] can be obtained by appropriately combining the reactions for removing the carboxyl protecting group R ₅ as necessary.

The method for removing protecting groups varies depending on the type, but
It is removed by generally known methods. For example, a compound in which R ₄ and R ₅ are a halogenoalkoxycarbonyl group or an aralkyloxycarbonyl group in the general formula [], or a compound in which R ₆ is a halogenoalkyl group, an aralkyl group, or a benzhydryl group may be subjected to an appropriate reduction reaction. The protecting group can be removed by. 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. Suitable solvents used in this catalytic reduction reaction include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, acetic acid, or a mixed solvent of these organic solvents and water. The reaction temperature is preferably 0°C to room temperature. Moreover, hydrogen pressure can be carried out under normal pressure or increased pressure.

After the reaction is completed, the resultant can be taken out using ordinary organic chemical methods.

Note that the compound represented by the above general formula [] has optical isomers and stereoisomers based on asymmetric carbon atoms, and all of these isomers are represented by a single formula. The scope of the description of the invention is not limited. However, preferably
Examples include compounds in which the carbon atom at position 5 has R coordination (5R, 6S) and (5R, 6R) coordination. Regarding the 8-position, a compound having R coordination can be selected as a suitable one. When producing isomers having such coordination, corresponding isomers can be used in the starting material compound [].

Compound [], which is a starting compound, can be produced by various methods that have already been reported. For example, the compound itself is known from the following literature, or the compound [] 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
Letters), pp. 2293-2296) (1982) or the method described in European Patent Publication No.
General formula (a) obtained by the method described in No. 70204 [In the formula, R ₄ has the same meaning as above, and Ac represents an acetyl group. ] Using the compound represented by as a raw material, the above literature etc. (1)
Compound [] can be synthesized according to the method described in ~(3).

Furthermore, European Patent Publication No. 70204
General formula (b) obtained by the method described in No. [In the formula, DAM represents a di-P-anisylmethyl group. ] The compound represented by is subjected to a carbonization reaction such as the Arndt-Einstert reaction, and then the ethenyl group is converted to a hydroxyethyl group by an oxymer cure reaction etc., and if necessary, the carboxyl group is converted to a hydroxyethyl group. General formula (c) obtained by combining protection, deprotection reaction, and protection reaction of hydroxyl group [In the formula, R ₄ 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.

One of the raw material mercaptans, including those newly synthesized in the present invention, can be produced, for example, by the method shown below.

[In the formula, R ₇ has the same meaning as above, and X represents an alkylcarbonyl group, an arylcarbonyl group, or an aralkyl group. ] Conversion of hydroxyproline (1) to compound (2) can be easily achieved by protection reactions of various known amino acids commonly used in the general formula, for example, S-acyl-4,6-dimethyl -2-Mercaptopyrimidine and the like can be mentioned.

Compound (2) can be converted to compound (3) by various known methods of converting a carboxylic acid into an amide group. Ru.

Compound (3) can be converted to (4) by various known methods of converting a hydroxyl group into a thiol group. This can be achieved by reacting with a suitable sulfur compound. Examples of suitable active esters of hydroxyl groups include halogen atoms, alkanesulfonyloxy groups, and arylsulfonyloxy groups.

Compound (4) can be converted to (5) by various methods such as alkaline hydrolysis, acid treatment, or reduction reaction.

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 has excellent antibacterial activity against a wide range of pathogenic bacteria, including Gram-positive bacteria such as C. pyrogiens and Streptococcus fuecalis, and Gram-negative bacteria such as Escherichia coli, Proteus mirabilis, Selassia marsetuscens, and Pseudomonas aeruginosa. It is a useful compound 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.

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 200 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 may 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 (a group of compounds 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 PNB: P-nitrobenzyl group Ph: phenyl group, Ac: acetyl group MS: methanesulfonyl group Example 1 a) (5RS, 6SR, 8RS)-P-nitrobenzyl-3-(diphenylphosphoryloxy)-6-
(1-P-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]
-Hept-2-en-7-one-2-carboxylate [J. Chem. Soc. Perkin I, p. 964 (1981)] (80 mg) was dissolved in dry acetonitrile (2
ml), diisopropylethylamine (41 mg) was added under ice-cooling in a nitrogen stream, and then [2S,4S]-1-(P-nitrobenzyloxycarbonyl)-2-carbamoyl-4-mercaptopyrrolidine (50 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 preparative thin layer chromatography to give (5RS, 6SR, 8RS)-p-nitrobenzyl-3-[4-(1-P-nitrobenzyloxycarbonyl-2-carbamoyl)pyrrolidinylthio]-6 -(1-P-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,
2,0]hept-2-en-7-one-2-carboxylate (65 mg) was obtained.

IR ^film _nax (cm ^-1 ): 1775, 1740, 1690, 1510, 1340, 1250, NMR δ (CDCl ₃ ): 1.47 (3H, d, J = 6.5Hz) 3.20 (2H, br, d, J = 8.5Hz ) 5.24 (4H, s) 5.16 and 5.44 (2H, ABq, J = 13Hz) 7.46 (2H, d, J = 9.0Hz) 7.52 (2H, d, J = 9.0Hz) 7.60 (2H, d, J = 9.0 Hz) 8.13 (2H, d, J = 9.0Hz) 8.15 (2H, d, J = 9.0Hz) 8.19 (2H, d, J = 9.0Hz) b) (5RS, 6SR, 8RS) -P-nitrobenzyl- 3-[4-(1-P-nitrobenzyloxycarbonyl-2-carbamoyl)pyrrolidinylthio]-6-(1-P-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept -2-en-7-one-
2-carboxylate (20 mg) was dissolved in tetrahydrofuran (2.1 ml), morpholinopropanesulfonic acid buffer (PH = 7.0 2.1 ml) and platinum oxide (6 mg) were added, and the mixture was heated under a hydrogen pressure of 3.5 atm.
Hydrogenated for hours. After passing through the catalyst, tetrahydrofuran was removed under reduced pressure to remove the precipitated insoluble materials, and the liquid was subjected to polymer chromatography (CHP-20P). From the portion eluted with water, (5RS, 6SR, 8RS)- 3-[4-(2-carbamoyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,
0] hept-2-en-7-one-2-carboxylic acid was obtained.

UVλ ^H2O _{nax on} : 297 NMRδ (D ₂ O): 1.24 (3H, d, J = 7.0Hz)
2.15 (2H, m) 2.97 (2H, t, J = 7.0Hz) 4.19 (2H, dd, J = 6.0 and 8.0Hz) 4.42 (1H, dt, J = 3.0 and 8.5Hz) IRKBr maxcm ^-1 : 3400, 1750, 1682, 1580 Also (5R, 6S, 8R)-P-nitrobenzyl-
3-(diphenylphosphoryloxy)-6-(1-
P-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]-hept-
2-en-7-one-2-carboxylate (75
(5R, 6S, 8R, 2′S, 4′S)-P-nitrobenzyl-3-[4-[1-P-nitrobenzyloxycarbonyl-2 -carbamoyl)pyrrolidinylthio]
-6-(1-P-nitrobenzyloxycarbonylethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (42 mg) was obtained.

IR ^Nujol _nax (cm ^-1 ): 3420, 1785, 1742, 1710, 1677, 1510, 1342, 1255 mp138~142℃ [α] ³⁰ _D +44.4° (c=0.105, DMF) Furthermore (5R, 6S, 8R),2′S,4′S)-P-nitrobenzyl-3-[4-(1-P-nitrobenzyloxycarbonyl-2-carbamoyl)pyrrolidinylthio]-6-(1-P-nitrobenzyl oxycarbonylethyl)-1-azabicyclo[3,2,
0] Hept-2-en-7-one-2-carboxylate (20 mg) was treated in the same manner as in b) above to obtain (5R, 6S, 8R, 2′S, 4′S)-3-[4 -(2-carbamoyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]
Hept-2-en-7-one-2-carboxylic acid was obtained.

UVλ ^H2O _{nax on} : 295 IR ^KBr _nax (cm ^-1 ): 1752, 1687, 1595, 1385 NMR δ (D ₂ O): 1.24 (3H, d, J = 6.5Hz), 2.0 ~ 2.15 (1H, m), 2.83~2.98 (1H, m), 3.17 (2H, d, J=9Hz), 3.32~3.42 (2H,
m), 3.71~3.80 (1H, m), 3.98 (1H, quintet, J=7Hz), 4.13~4.32 (1H, m), 4.41 (1H,
t, J=8.5Hz) [α] ³⁰ _D −25° (c=0.05, H ₂ O) Example 2 a) (5R,6S,8R)-P-nitrobenzyl-
3-(diphenylphosphoryloxy)-6-(1
-P-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0)-hept-2-en-7-one-2-carboxylate (152 mg) and [2S,4R)-1-P- Using nitrobenzyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine (72 mg),
By the same method as in Example 1(a) (5R, 6S,
8R, 2′S, 4′R)-P-nitrobenzyl-3-
[4-(1-P-nitrobenzyloxycarbonyl-2-carbamoyl)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 ): 1775, 1745, 1700, 1520, 1345, 1260, 1130 NMR δ (CDCl ₃ ): 1.48 (3H, d, J = 6.5Hz), 3.22 (2H, br, d, J = 9.0Hz) 5.26 (4H,
s), 5.25 and 5.46 (2H, ABq, J = 14Hz), 7.50, 7.54 and 7.60 (each2H, d, J = 9.0Hz), 8.18 (4H, d, J = 9.0Hz), 8.21 (2H, d, J=9.0Hz) α] ²⁹ _D +37.3゜c=0.244, acetone) b) (5R, 6S, 8R, 2'S, 4'R) -P-nitrobenzyl-3-[4-(1- P-nitrobenzyloxycarbonyl-2-carbamoyl)pyrrolidinylthio]-6-(1-P-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one -2-carboxylate (32 mg) was used in the same manner as in Example 1(b) (5R, 6S, 8R,
2′S,4′R)-3-[4-(2-carbamoyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-azabicyclo[3,2,0]hept-2-ene-7 -one-2-carboxylic acid was obtained.

UV ^H2O _{nax on} : 298 Example 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 (121 mg) and [2R,4S)-1-P- Using nitrobenzyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine (57 mg),
By the same method as in Example 1(a) (5R, 6S,
8R, 2′R, 4′S)-P-nitrobenzyl-3-
[4-(1-P-nitrobenzyloxycarbonyl-2-carbamoyl)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 ): 1775, 1750, 1700, 1520, 1345, 1260, 1180 NMR δ (CDCl ₃ ): 1.48 (3H, d, J = 6.5Hz, 3.26 (2H, br, d, J = 9.0 Hz), 5.25 (4H, s), 5.18 and 5.46 (2H, ABq, J=14
Hz), 7.49, 7.53 and 7.62 (each2H, d, J = 8.5Hz), 8.17 (4H, d, J = 8.5Hz), 8.19 (2H, d, J = 8.5Hz) [α] ²⁵ _D +43.7゜(c=0.353, acetone) b) (5R, 6S, 8R, 2′R, 4′S)-P-nitrobenzyl-3-[4-(1-P-nitrobenzyloxycarbonyl-2-carbamoyl) Using pyrrolidinylthio]-6-(1-P-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylate (95 mg), By the same method as in Example 1(b) (5R, 6S, 8R,
2′R,4′S)-3-[4-(2-carbamoyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-azibicyclo[3,2,0]hept-2-ene-7 -one-2-carboxylic acid was obtained.

UV ^H2O _{nax on} : 297 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 (53 mg) and [2R,4R]-1-P- Using nitrobenzyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine (25 mg),
By the same method as in Example 1(a) (5R, 6S,
8R, 2′R, 4′R)-P-nitrobenzyl-3-
[4-(1-P-nitrobenzyloxycarbonyl-2-carbamoyl)pyrrolidinylthio]-
6-(1-P-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,
0] hept-2-en-7-one-2-carboxylate (45 mg) was obtained.

IR ^film _nax (cm ^-1 ): 1780, 1745, 1700, 1610, 1520, 1400, 1350, 1260, 1120 NMR δ (CDCl ₃ ): 1.48 (3H, d, J = 6Hz), 3.19 (2H, d, J =9Hz), 3.44(1H, dd, J
= 2.5 and 7.5Hz), 5.25 (4H, s), 5.23 and 5.42 (2H, ABq, J = 14Hz),
7.47, 7.52 and 7.60 (each2H, d, J = 8.5Hz), 8.16 (4H, d, J = 8.5Hz), 8.19 (2H, d, J = 8.5Hz) [α] ³² _D +57.6° (c =0.279, acetone) b) (5R,6S,8R,2′R,4′R)-P-nitrobenzyl-3-[4-(1-P-benzyloxycarbonyl-2-carbamoyl)pyrrolidinylthio] -6-(1-P-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[3,2,0]hept-2-en-7-one-
(5R, 6S, 8R, 2′R,
4′R-3-[4-(2-carbamoyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1
-Azabicyclo[3,2,0]hept-2-en-7-one-2-carboxylic acid was obtained.

UV ^H2O _{nax on} : 297 Reference example 1 trans-4-hydroxy-L-proline 6.55
g, dissolve 7.5 ml of triethylamine in 15 ml of water,
A solution of 15.95 g of S-P-nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine in 35 ml of dioxane was added dropwise to this at room temperature.
The mixture was stirred at room temperature for 1.5 hours and left overnight.
Add 30 ml of 2N sodium hydroxide to the reaction solution under ice cooling, extract with ether, wash the ether layer with 20 ml of 1N sodium hydroxide, and combine the alkaline aqueous layers.
The mixture was acidified with hydrochloric acid using 100 ml of 2N-hydrochloric acid water, and this was 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.
(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline was obtained.

mp134.3～135.5℃ IR ^Nujol _nax (cm ^-1 ): 3300 (br), 1738, 1660, 1605, 1520, 1340, 1205, 1172, 1070, 965 Reference example 2 1-(P-nitrobenzyloxycarbonyl)-
Dissolve 3.10 g of 4-hydroxy-L-proline and 1.10 g of triethylamine in 40 ml of dry tetrahydrofuran, and dissolve ethyl chloroformate at -25°C to -35°C.
A solution of 1.20 g of dry tetrahydrofuran in 10 ml was added dropwise, and after stirring for 50 minutes, 10 ml of concentrated aqueous ammonia was added dropwise at -25°C to -40°C. 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 with ice, wash them sequentially with cold water and cold ether, and dry under reduced pressure to obtain 1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline. Obtained amide.

mP163.3～164.0℃ IR ^Nujol _nax (cm ^-1 ): 3460, 3370, 3200, 1687, 1640, 1621, 1539, 1341, 1180, 1078 Reference example 3 1-(P-nitrobenzyloxycarbonyl)-
2.32 g of 4-hydroxy-L-prolinamide, 1.67 g of triethylamine in dry tetrahydrofuran
Methanesulfonyl chloride at room temperature in 40ml suspension
A solution of 1.89 g of dry tetrahydrofuran in 10 ml was added dropwise, and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure. 30 ml of water and 0 ml of ether were added to the residue, and the resulting white crystals were collected after cooling on ice, washed successively with cold water and cold ether, and dried under reduced pressure to give 1-(P-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-
L-prolinamide was obtained.

mp149.5～151℃ IR ^Nujol _nax (cm ^-1 ): 3400, 3225, 1715, 1675, 1520, 1340, 1170, 1135 Reference example 4 Thioacetic acid under a nitrogen stream in a suspension of 374 mg of 50% sodium hydride in 13 ml of dry dimethylformamide.
A solution of 642 mg of dry dimethylformamide in 14 ml was added and stirred at room temperature for 25 minutes. To this solution was added 975 mg of sodium iodide and then 2.52 g of 1-(P-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolinamide. A 12 ml solution of dry dimethylformamide was added thereto, and the mixture was heated and stirred at 70°C for 6 hours. Pour the reaction solution into cold brine, extract with benzene,
The extract was sequentially washed with a 10% aqueous sodium sulfite solution and brine, dried with mirabilite, and the solvent was distilled off. The resulting crude crystals were purified by pulp using a mixed solvent of tetrahydrofuran and benzene to obtain cis-1-(P-nitrobenzyloxycarbonyl). )-4-thioacetoxy-L
- Prolinamide was obtained.

mP168.5～169.5℃ IR ^Nujol _nax (cm ^-1 ): 3350, 3180, 1715, 1690, 1638, 1510, 1330, 1100 [α] ³⁰ _D −23° (c=0.334, DMF) Reference example 5 [2S,4S]-1-(P-nitrobenzyloxycarbonyl)-2-carbamoyl-4-acetylthiopyrrolidine (950 mg) was dissolved in methanol (95 ml), and 1N aqueous sodium hydroxide solution (2.59 ml) was added in an argon stream. was added at room temperature, and the mixture was stirred for 15 minutes. A 1N aqueous hydrochloric acid solution (2.59 ml) was added to the reaction solution to neutralize it, methanol was distilled off under reduced pressure, and the precipitated crystals were collected and washed with water to obtain [2S,
4S]-1-(P-nitrobenzyloxycarbonyl)-2-carbamoyl-4-mercaptopyrrolidine was obtained.

mP158～162℃ Reference example 6 a) [2S,4R]-1-(P-nitrobenzyloxycarbonyl)-2- was prepared using trans-4-hydroxy-L-proline (350 mg) in the same manner as in Reference Examples 1, 2, 3, and 4. Carbamoyl-4-acetylthiopyrrolidine (132mg)
I got it.

IR ^film _nax (cm ^-1 ): 3300 (br), 1700 (sh), 1685, 1512, 1430, 1400, 1345, 1175, 1115 [α] ³⁰ _D +7.36° (c = 0.625, acetone) b) Using the thioacetate derivative (100 mg) obtained in a) above, [2S,4R]-1-(P-nitrobenzyloxycarbonyl)-2-carbamoyl-4-mercaptopyrrolidine was obtained in the same manner as in Reference Example 5. Ta.

IR ^film _nax (cm ^-1 ): 1700, 1685, 1515, 1435, 1400, 1342, 1118 NMRδ (CDCl ₃ ): 2.26 (1H, d, J = 7Hz), 5.22 (2H, s) Reference example 7 a) [2R,4S]-1-P-nitrobenzyloxycarbonyl-2-carbamoyl-4 was obtained from cis-4-hydroxy-D-proline (300 mg) in the same manner as in Reference Examples 1, 2, 3, and 4.
-Acetylthiopyrrolidine (82mg) was obtained.

IR ^film _nax (cm ^-1 ): 1705 (sh), 1685, 1520, 1425,
1402, 1342, 1122 [α] ³⁰ _D −6.92° (C = 0.665, acetone) b) Thioacetate derivative obtained in a) above (66
mg) in the same manner as in Reference Example 5 to obtain [2R,4S)-1-P-nitrobenzyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine.

IR ^CHCl3 _nax (cm ^-1 ): 1695 (sh), 1682, 1515, 1395, 1340, 1115 Reference example 8 a) [2R,4R]-1-P-nitrobenzyloxycarbonyl-2-carbamoyl- was prepared using trans-4-hydroxy-D-proline (250 mg) in the same manner as in Reference Examples 1, 2, 3, and 4. 4-acetylthiopyrrolidine (40 mg) 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) using the same method as in Reference Example 5 [2R,
4R]-1-P-nitrobenzyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine was obtained.

IR ^Nujol _nax (cm ^-1 ): 3200, 1710, 1655, 1512, 1340, 1115.

Claims (1)

[Claims] 1. General formula [] [In the formula, R ₁ is a hydrogen atom or a hydroxyl group protecting group, R ₂ is a hydrogen atom or an amino group protecting group,
R ₃ represents a hydrogen atom or a carboxyl group protecting group. ] A β-lactam compound represented by these and a pharmacologically acceptable salt thereof. 2. The β-lactam compound and its pharmacologically acceptable salt according to claim 1, wherein R ₁ , R ₂ and R ₃ are hydrogen atoms. 3 General formula [] [In the formula, R ₁ is a hydrogen atom or a hydroxyl group protecting group, R ₂ is a hydrogen atom or an amino group protecting group,
R ₃ represents a hydrogen atom or a carboxyl group protecting group. ] In producing the β-lactam compound represented by the general formula [] [In the formula, R ₄ represents a hydroxyl group-protecting group, and R ₅ represents a carboxyl group-protecting group. ] Reactive ester of alcohol represented by and general formula [In the formula, R ₆ represents a protecting group for an amino group. ] The mercaptan represented by is reacted in the presence of a base to form the general formula [] [In the formula, R ₄ , R ₅ , and R ₆ have the same meanings as above. ] Produce a β-lactam compound represented by R ₁ ,
When a β-lactam compound in which R ₂ and/or R ₃ is a hydrogen atom is desired, a reaction for removing the carboxyl group protecting group R ₅ and a hydroxy protecting group
A β-lactam compound represented by the above general formula [] characterized in that a reaction for removing R ₄ and a reaction for removing an amino group protecting group R ₆ are carried out in appropriate combinations as necessary, and its pharmacologically acceptable β-lactam compound. A method of manufacturing salt.