JPH0341066A - 2-substituted aminocarbonyl-4-mercaptopyrrolidine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 is H; R2 is H or amino-protecting group; R3 is H, (substituted) lower alkyl, lower alkenyl or aralkyl; R4 is (substitute) alkyl, lower alkenyl or aralkyl; R3 and R4 mutually link to form alkylene chain or represent alkylene chain through O, S, etc., and together with adjacent N, may form 4- to 7-membered cyclic amino]. EXAMPLE:[2S,4S]-1-(p-Nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4- mercaptopyrrolidine. USE:A medicine and synthetic intermediate for penem or carbapenem compounds having excellent antimicrobial activity. PREPARATION:A pyrrolidine derivative expressed by formula II (R5 is acyl, such as acethyl, propionyl, benzoyl or phenylacetyl, or ethoxycarbonyl) is subjected to hydrolytic or solvolytic reaction in the presence of a base, such as NaOH, in a solvent, such as methanol, to afford the compound expressed by formula I.

Description

Detailed Description of the Invention The present invention relates to the general formula CI) [wherein R1 is a hydrogen atom, R2 is a hydrogen atom or a protecting group for an amino group, and R2 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aralkyl group] group, or a substituted lower alkyl group, and R4 is a lower alkyl group, a lower alkenyl group, an aralkyl group, or a substituted lower alkyl group,
Alternatively, R1 and R4 represent an alkylene chain bonded to each other or an alkylene chain via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom, and together with the adjacent nitrogen atom, represent a 4- to 7-membered cyclic amino group.

] It is related with the novel 2-substituted aminocarbonyl-4-mercaptopyrrolidine derivative represented by these.

In the general formula (I), the protecting group for the amino group in R2 is preferably a lower alkoxycarbonyl group such as tert-butyloxycarbonyl, for example 2-
Ethyloxycarbonyl iodide 2.2.2-) Halogenoalkoxycarbonyl groups such as 2-)lichloroethyloxycarbonyl, e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 0-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl aralkyloxycarbonyl groups such as, for example, trialkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl.

Examples of lower alkyl groups in R1 or R4 include lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, and n-butyl, and examples of lower alkenyl groups include 2 carbon atoms such as propenyl and butenyl. -4 alkenyl group, the aralkyl group is, for example, a phenyl group such as benzyl, substituted benzyl, phenethyl, or an alkyl group having 1 to 3 carbon atoms substituted with a substituted phenyl group, and the substituted lower alkyl group is, for example, a hydroxyl group,
Examples include lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, and n-propyl substituted with a di-lower alkylamino group or a carbamoyl group.

Also, alkyl 1.R2 and R4 are bonded to each other. When representing an alkylene chain via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom, and representing a 4- to 7-membered cyclic amino group together with the adjacent nitrogen atom, examples include an azetidino group, a piperidino group, pyrrolidino group,
Examples include a morpholino group, a thiomorpholino group, and an N-methylpiperazino group.

The compound represented by the general formula (1) has optical isomers and stereoisomers based on the asymmetric carbon atoms at the 2- and 4-positions, and for convenience, all of these isomers are represented by a single formula. However, the scope of the present invention is not limited thereby. However, preferably (2S, 4
S) coordination and [2R,4R) coordination compounds.The present inventors have found that the compound of the present invention represented by the general formula CI) is an important synthesis of penem or carbapenem compounds having excellent antibacterial activity. The present invention was completed by discovering that the compound is useful as an intermediate.

Examples of the compound having the general formula (1) obtained by the present invention include the compounds described below.

(1) 2-Methylaminocarbonyl-4-mercaptopyrrolidine (2) 2-ethylaminocarbonyl-4-mercaptopyrrolidine (3) 2-n-propylaminocarbonyl-4-mercaptopyrrolidine (4) 2-isopropylaminocarbonyl- 4-mercaptopyrrolidine (5) 2-n-butylaminocarbonyl-4-mercaptopyrrolidine (6) 2-isobutylaminocarbonyl-4-mercaptopyrrolidine (7) 2-dimethylaminocarbonyl-4-mercaptopyrrolidine (8) 2- Diethylaminocarbonyl-4-mercaptopyrrolidine (9) 2-di-n-butylaminocarbonyl-4-mercaptopyrrolidine (10) 2-diisopropylaminocarbonyl-4-
Mercaptopyrrolidine (11) 2-di-n-butylaminocarbonyl-4-
Mercaptopyrrolidine (12) 2-diisobutylaminocarbonyl-4-mercaptopyrrolidine (13) 2-ethylmethylaminocarbonyl-4-mercaptopyrrolidine (14) 2-n-butylmethylaminocarbonyl-4-
Mercaptopyrrolidine (15) 2-n-butylethylaminocarbonyl-4-
Mercaptopyrrolidine (16) 2-(2-hydroxylethyl)aminocarbonyl-4-mercaptopyrrolidine (17) 2-(3-hydroxylpropyl)aminocarbonyl-4-mercaptopyrrolidine (18) 2-(2-hydroxylpropyl)amino Carbonyl-4-mercaptopyrrolidine (19) 2-(2-hydroxy-l-methylethyl)aminocarbonyl-4-mercapto-pyrrolidine (20) 2-(2-dimethylaminoethyl)aminocarbonyl-4-mercaptopyrrolidine (21 ) 2-(2-diethylaminoethyl)aminocarbonyl-4-mercaptopyrrolidine (22) 2-(3-dimethylaminopropyl)aminocarbonyl-4-mercaptopyrrolidine (23) (24) (25) (26) 2-( 3-diethylaminopropyl)aminocarbonyl-4-mercaptopyrrolidine 2-(2-dimethylaminoethyl)ethylaminocarbonyl-4-mercapto-pyrrolidine 2-(2-diethylaminoethyl)ethylaminocarbonyl-4-mercapto-pyrrolidine 2-( 2-Carbamoylmethyl)aminocarbonyl-4
-Mercaptopyrrolidine (27) 2-(2-carbamoylethyl)aminocarbonyl-4
-Mercaptopyrrolidine (28) 2-benzylaminocarbonyl-4-mercaptopyrrolidine (29) (30) (31) 2-(2-hydroxylethyl)methylaminocarbonyl-4-mercaptopyrrolidine 2-(2-hydroxylethyl)ethyl Aminocarbonyl-4-mercaptopyrrolidine 2-(2-dimethylaminoethyl)methylaminocarbonyl-4-mercaptopyrrolidine 32) 2-Benzylmethylaminoerbonyl-4-mercaptopyrrolidine (33) 2-Benzylethylaminocarbonyl-4-
Mercaptopyrrolidine (34) 2-(1-azetidinocarbonyl)-4-mercaptopyrrolidine (35) 2-(1-pyrrolidinocarbonyl)-4-mercaptopyrrolidine (36) 2-(1-piperidinocarbonyl)- 4-Mercaptopyrrolidine (37) 2-(1-morpholinocarbonyl)-4-mercaptopyrrolidine (38) 2-(1-thiomorpholinocarbonyl)-4-
Mercaptopyrrolidine (39) 2-(1-N-methylpiperazinocarbonyl)-4-mercaptopyrrolidine (40) 2-(1-N-ethylpiperazinocarbonyl)
-4-Mercaptopyrrolidine As mentioned above, stereoisomers exist in this exemplified compound, and although a single name has been given, this is not intended to be limiting in any way. However, as a preferred option (
Examples include those having 2S, 43) and (2R, 4R) coordinations.

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

(In the formula, R2, R1 and R4 have the same meanings as above, R
1 represents an acyl group such as acetyl, propionyl, benzoyl, or phenylacetyl, or an ethoxycarbonyl group. ) by subjecting the pyrrolidine derivative represented by formula (I) to a hydrolysis reaction or solvolysis reaction.
-Substituted aminocarbonyl-4-mercaptopyrrolidine derivatives can be produced by this reaction: sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, lithium methoxide, lithium ethoxide, sodium hydrogen carbonate, sodium carbonate, It is carried out in the presence of a base such as potassium carbonate.

Inert solvents used in this reaction include organic solvents such as methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane, acetone, and methylene chloride, mixed solvents of these organic solvents, water, and mixed solvents of the aforementioned organic solvents and water. I can list the following.

Although the reaction temperature is not particularly limited, it is preferably carried out within a range of -20°C to 40°C in order to suppress side reactions.

After the reaction is complete, the resultant can be taken out using conventional organic chemistry techniques. For example, it can be obtained by neutralizing the reaction mixture with an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, extracting with an organic solvent that separates from water, washing with water, and then distilling off the solvent.

The raw material pyrrolidine derivative (II) can be produced by various methods, but for example, by the method shown below, pyrrolidine having a 2S coordination can be produced using trans-4-hydroxy-L-proline as a raw material compound. Derivative (IIa), (IIb] or (I[c)
can be manufactured.

(IIa) (IIb) (Irb) [wherein R3, R4 and Rs have the same meanings as above. R1 represents an amino group-protecting group, and R7 represents a carboxyl group-protecting group. ] Step A can be easily achieved by a commonly used amino group protection reaction of various known amino acids,
For example, a method of reacting with arylmethyloxycarbonyl chloride etc. in the presence of a base, or a method of reacting with S-acyl-4
, 6-dimethyl-2-mercaptopyrimidine, and the like.

Step B: Various known methods for obtaining an ester from a carboxylic acid are possible; for example, in the presence of a base, a carboxylic acid
This can be achieved by reacting with various alkyl halides or aralkyl halides.

Step C: Various known methods are possible for converting a hydroxyl group into a protected thiol group; for example, after derivation of a hydroxyl group into an active ester form, various thiolating reagents such as thioacetic acid, thiobenzoic acid, trityl mercaptan, etc. and a base are used. This can be achieved by reacting in the presence of

This step can also be obtained by reacting an alcohol derivative with a thiolating reagent such as thioacetic acid in the presence of triphenylphosphine and diethyl azodicarboxylate in an inert solvent such as tetrahydrofuran.

Step D Various known methods for converting esters into carboxyl groups are possible; for example, alkaline hydrolysis, an acid method using trifluoroacetic acid, hydrobromic acid, etc., or a reductive method using zinc. can.

Step C Various known methods are possible for converting carboxylic acid into an amide group, but for example, converting a carboxylic acid group into an active ester derivative using a halogenating agent, an acylating agent, etc.
This is achieved by a method of treating an amine represented by the general formula.

Step F Various known oxidation reactions for converting hydroxyl groups into carbonyl groups are possible, and this can be achieved, for example, by oxidation reactions such as chromic acid-sulfuric acid in acetone.

Step C Various known reduction reactions for converting carbonyl groups into hydroxyl groups are possible, but for example, by treating with sodium borohydride etc., a mixture of compounds with different steric hydroxyl groups can be obtained. .

Incidentally, the production ratio of these and tanning differs depending on the conditions, or each compound can be obtained as a single compound by purification such as recrystallization or chromatography.

Isomerization of the hydroxyl group at the 4-position can be achieved through the steps F and C described above, or it can also be achieved through the steps H and (2) described below.

H・■Step The alcohol derivative is reacted with formic acid in an inert solvent such as tetrahydrofuran in the presence of triphenylphosphine and diethyl azodicarboxylate to form a formyloxy derivative, and then formyloxy derivative is obtained by a method such as alkaline hydrolysis. J step can be achieved by removing the group. Various commonly used and well-known deprotection methods for amine groups are possible, such as methods using acids such as trifluoroacetic acid or hydrobromic acid, This can be achieved by a reductive method using halium-liquid ammonia or the like, or by catalytic reduction.

In addition, the production of the 2R-form pyrrolidine derivative (II) was carried out in accordance with the method for producing the 2S-form described above using cis-4-hydroxy-D-proline as a raw material, that is, the various reactions described in the production of the 23-form were carried out. The compound CI) of the present invention obtained by the above methods can be produced by combining penem or carbapenem compounds with excellent antibacterial activity by the method shown in the reaction formula below [in the formula, R, , R, , R, and R1 have the same meaning as above. R1 represents a hydroxyl protecting group.

] 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: I) -methoxybenzyloxycarbonyl group PMB: p-methoxybenzyl group PNB: p-nitrobenzyl group Ph: phenyl group AC=acetyl group tBu: t-butyl group Me =Methyl group Et: Ethyl group Reference example 1-1 PNZ trans-4-hydroxy-L-proline (6°55g
), triethylamine (7,51d) and water (15yrt
5-p-nitropenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (15.95 g) was dissolved in dioxane (35 rnI
) solution was added dropwise and stirred at room temperature for 1.5 hours, -
I installed it at night. Add 2N-sodium hydroxide (
Add 3Lxj') and extract with ether, IN the ether layer
- After washing with sodium hydroxide (20-), the alkaline aqueous layers were combined, acidified using 2N-hydrochloric acid (100rd), and extracted with ethyl acetate. The ethyl acetate layer was diluted with 2N-
The crude crystals obtained were washed successively with hydrochloric acid, dried with sodium sulfate, and the solvent was distilled off. The resulting crude crystals were purified by repulping with ethyl acetate to obtain trans
p-Nitropenzyloxycarbonyl>-4-hydroxy-L-proline was obtained.

m, p, 134.3-135.5℃IR,,,cm
-' (Nujol): 3300 (br), 1738
．． 1660°16α5.1520.1340.1205
゜1172, 1070.965 Reference Example 1-2 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline (15, Og)) ethylamine (13,5J) was dissolved in dry dimethylformamide (150rILl) ), p-methoxybenzyl chloride (12.66ml) was added dropwise under a nitrogen stream,
The mixture was stirred at 70°C for 10 hours. The reaction solution was diluted with ethyl acetate (50
The residue was crystallized from ether to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline-p-methoxybenzyl ester. Ta.

m, p, 83-85°C IR,, cr' (film): 3430.173
5.1705.1510°1340, 1245.116
0 Reference Example 1-3 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-proline-p-methoxybenzyl ester (8.6 g) and triphenylphosphine (7.86 g) were dissolved in dry tetrahydrofuran ( 201nl
) in dry tetrahydrofuran (5.22 g) and cooled in water under a nitrogen stream.
-) The solution was added dropwise and stirred for 30 minutes, then thioacetic acid (2.28 g) was added dropwise, stirred for 1 hour under water cooling, then stirred at room temperature for 3 hours, and the reaction solution was concentrated. The residue was subjected to silica gel column chromatography to give cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L
-Proline-p-methoxybenzyl ester was obtained.

[R,,,cr'(film): 1740(sh)
, 1715.1520°1405, 1348. 1
12O MR δ (CDC1,): 2.31 (3H, S), 3.79 (3H, s),
5, 10 (28, s), 5.24 (2H, s), 7.4
9 (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)
) was stirred with trifluoroacetic acid (35rILl) for 30 minutes at room temperature. The residue was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline.

m, p, 107-109°C IR,, cm-' (Nujol): 1725.16
85.1660 (sh).

1340, 1180.1110 Reference Example 1-5 Nyl)-4-acetylthio-L-proline (180■)
was dissolved in dry tetrahydrofuran (2rd), dimethylamine hydrochloride (48■), N,N-dimethylaminepyridine (78■), dicyclohexylcarbodiimide (
152■) were added one after another, and the mixture was stirred overnight. Insoluble materials were removed by filtration, the filtrate 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.

[R,, cm-' (film): 1705.16
50. 1515. 1400°1340, 11l1 05N δ (CDCIs): 2.32 (3H
, s), 2.97 (3H, s), 3, 11 (3H, S)
, 5.21 (2B, s), 8, 18 (2H, d, J
=8.5Hz)(α)! '+5.21' (c
=0.379 T sen) The following thioacetates were obtained in the same manner as in Reference Example 1-5 using the corresponding amines.

Reference Example 2-1 Oxalyl chloride (0.2 ml) in dry methylene chloride (5-) solution at -60 to -70'C dimethyl sulfoxide (0.35 ml) in dry methylene chloride solution (1-)
After 10 minutes, a dry methylene chloride solution of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester (860 μm) was added dropwise to and stirred for 05 minutes.Next, triethylamine (1,01
g) was added dropwise, warmed to room temperature, diluted with methylene chloride,
Washing with dilute hydrochloric acid water, drying with Glauber's salt, evaporation of the solvent, and subjecting the residue to silica gel column chromatography to obtain 1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline p-methoxybenzyl ester rR,, cm -'(film): 1762. 1
740. 1710. 1512°1345, 124
5. 1155 NMRδ (CDC12): 3.78 (3H
, s), 3.95 (2H, s), 5.08 (2H, s)
, 6.85 (2H, d, J=9H2), 8.12 (2
H, d, J = 9H2) Reference Example 2-2 NZ 1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline p-methoxybenzyl ester (
650 ■) in ethanol (45 mj'), and sodium borohydride (86 ■) was added in two portions at room temperature. After 30 minutes, it was concentrated under reduced pressure below 300℃, the concentrated solution was diluted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off.The residue was subjected to silica gel column chromatography to obtain cis-l- carbonyl)-4-
Hydroxy-L-proline p-methoxybenzyl ester and trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-purine p-methoxybenzyl ester were obtained.

Trans form: IR and NMR were consistent with the spectral data of the compound of Reference Example 1-2.

Cis form: [R,,, Cm-' (film): 340
0(br), 1725°1515, 1405.135
0. 1250°1170, 112O NMRδ (CDCIg): 3.78 (3H, s)
,5,08(2)(,s),6.82(2H,d,J
=9Hz), 8.12(2)1. d, J=9Hz) Reference Example 2-3 cis-1-(p-nitrobenzyloxycarbonyl)-
Reference Examples 1-3 and 1 were prepared using 4-hydroxy-L-proline p-methoxybenzyl ester (610).
ILax cm-' (f+1m) NMR δ (CDC13): ~3000. 1700. +515. 1430
1400, 1345. 1205. 1165:
2.32 (3H, S), 5.20 (2H, br.

S), 7. '42 (2H, d, J=9Hz), 8.
12 (2H, d, J=9Hz) Reference example 3-1 Reference example 1-1 from cis-4-hydroxy-D-proline
and cis-1-p-nitropenzyloxycarbonyl-4-hydroxy-D- obtained by the same method as 1-2.
Proline-p-methoxybenzyl ester (166■)
and triphenylphosphine (202 ■) were dissolved in dry tetrahydrofuran (1,5 mt'), then formic acid (2
Add 7■). Furthermore, diethyl azodicarbonate) (
134■) was added at room temperature under a nitrogen stream, and after stirring for 30 minutes, the solvent was distilled off. The residue was purified by silica gel chromatography to obtain trans-1-p-nitrobenzyloxycarbonyl-4-formyloxy-D-proline-p-methoxybenzyl ester.

IR=,, am-'(film): 1720.1
515.1402.1342゜1245, 1165.1
120°NMRδ (CDCh): 3.76 (3H, s)
, 4.50 (2H, t, J atmosphere 8Hz), 5.08 (2
8, s), 5, 15 (2H, ABq, J=16Hz), 5.41
(IH, m), 7.97 (IH, s) Reference Example 3-2 NZ NZ trans-t-p-nitropenzyloxy carbonyl-4-formyloxy-D-proline-p-methoxybenzyl ester (215 ) to tetrahydrofuran (1,
1d), I N -Na0H (0,93d)
After stirring for 10 minutes, the mixture was diluted with ethyl acetate and washed with saturated brine. After drying the Glauber's salt, the solvent was distilled off. The residue was purified by thin layer chromatography to give trans-t-p-nitrobenzyloxycarbonyl-4-hydroxy-D-proline-p
-Methoxybenzyl ester was obtained.

[R,, cm-' (film): 3425 (br
), 1735.1705°1510, 1400.13
40.1240°162 NMRδ (CDCIg): 2.33 (2H, m
), 3, 58 (2H, d, J=3.5Hz), 3, 7
3 (3H, s), 5.03 (2H, s), 5, 07 (2
H,ABq, J=18Hz), 6,73(2H,d,
J=9)1z), 6, 77(2H,d, J=9)1
z), 8, 00 (2H, d, J=8.5Hz), 8.
07 (2H, d, J=8.5Hz) Reference example 4-1 trans-t-p-nitrobenzyloxycarbonyl-
Reference Example 1-2 using 4-hydroxydi-L-proline (500 ■) and p-nitrobenzyl bromide (383 ■)
trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-L-proline-p by the same method as
-Nitrobenzyl ester was obtained.

rR,,lIcm-'(CHC1*): 3380(b
r), 1750.1705°1520, 1425.1
400.1342゜16O NMRδ (CDCIs) + 2.20 (3H, m
), 3.67 (2H, d, J = 3Hz), 4.60 (2
H, 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 4-2 Trans-t-p-nitrobenzyloxycarbonyl-
4-Hydroxy-L-proline-p-nitrobenzyl ester was converted to cis-1-p-nitrobenzyloxycarbonyl-4 in the same manner as in Reference Example 1-3 and Example 1.
-Mercapto-L-proline-p-nitrobenzyl ester was obtained.

IR,, cm-' (film): 1700.16
85.1600.1510°1430, 1400.13
40.1105 Reference Example 4-3 a) Cis-t-p-nitrobenzyloxycarbonyl-4-mercapto-L-7'loline-p-nitrobenzyl ester (115) was dissolved in dry tetrahydrofuran (3
-), added triethylamine (30 µ), and added dropwise ethyl chloroformate (28,5 µ) under water cooling.
After stirring for 0 minutes, dilute with ethyl acetate, wash sequentially with dilute hydrochloric acid and water, and dry with sodium sulfate. The solvent was evaporated and cis-1-p-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline-p-nitrobenzyl ester (13
3■) was obtained.

IR,, cm-' (film): 1755.17
10.1610.1525°1405, 1350.11
60.1015゜50 b) Dissolve the ester derivative (133■) obtained in a) above in a tetrahydrofuran-water (1:1) mixture (5-), add IN-NaOH (0.26rIdl), and stir at room temperature. After stirring for 2.5 hours, I N -MCI (0,3-)
Then, extract with ethyl acetate, wash with water, dry with sodium sulfate, and evaporate the solvent.

The residue was subjected to silica gel thin layer chromatography.
1-p-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline was obtained.

IR,,,cr'(film): 1700.152
0.1400.1340°1165, 1145 NMRδ (CDCIg): 1.30 (3H, t
, J=7Hz), 4, 28(2H,q, J=7H2
), 5, 24 (2H, s), 7, 50 (2H, d, J=9Hz), 8, 17 (2H
, d, J=9Hz) Reference Example 4-4 Cis-1-p-nitrobenzyloxycarbonyl-4-
Ethoxycarbonylthio-L-proline (72■) was dissolved in dry tetrahydrofuran (3-), triethylamine (40■) was added, ethyl chloroformate (41■) was added dropwise under water cooling, and after stirring for 15 minutes, methyl Amine (40
%) aqueous solution (1.5 mN) was added dropwise and 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.

[R,,,am-'(Nujol): 3290.17
05.1660.1520°1425, 口05.1
345.1180°160: 1.30 (3H, t, J-8H2), 2, 80 (3
H, d, J=5H2), 4, 27(2H, q, J=
8Hz), 5, 22 (2H, S), 7, 48 (2H, d, J=9H2), 8, 18 (2H
, d, Jf9Hz) The following thiocarbonates were obtained in the same manner as in Reference Example 4-4 using the corresponding amines.

NMRδ (CDCIg) Reference Example 5 a) Trans-4-hydroxy-L-proline (10g
) and 5-p-methoxybenzyloxycarbonyl-4,
6-dimethyl-2-mercaptopyrimidine (23.2g
) in the same manner as in Reference Example 1-1.
1-(p-methoxybenzyloxycarbonyl)-4-
Hydroxy-L-proline was obtained.

IR,,,Cm-'(film): 3400(br), 1692. 1430°1355, 1245. 1170. 1122:
2.23 (2H, m), 3.73 (3H, s), 5, 0
0 (2H, S), 6.78 (2H, d, J=9Hz)
, 7.20 (2H, d, J=9Hz) and NMR δ (CDCh) b) Using the above a) benzylamine (0,215 g), Reference Example 2-1
Trans-1-p-methoxybenzyloxycarbonyl-4-hydroxy-L-benzylprolinamide was obtained in the same manner as above.

[R-,, cm-' (Nujol): 3375.33
00.1665. 1248°1165, 1120.
1010 25Nδ (CDCI2): 3.76 (3H,s
), 4.35 (4N, m), 4.96 (2H, s),
6.79 (2H, d, J=9Hz), 7.20 (5H
,5) C) Benzylprolinamide obtained in b) above (0.5g
) and in the same manner as in Reference Example 1-3 (2S, 4
S)-1-p-methoxybenzyloxycarbonyl-2
-Benzylaminocarbonyl-4-acetylthiopyrrolidine was obtained.

IR,, cm-' (Nujol): 3280.16
90.1675.124ONMRδ(CDCI3)
: 2.27 (3H, s), 3.82 (3H, s),
4, 42 (2H, d, J=6Hz), 5, 05 (2H
, S), 6.87 (2H, d, J=8H2), 7.2
3 (2M, d, J=8H2), 7, 28 (5H, s
) Example 1 (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine (40 ml) was dissolved in methanol (4 ml), and IN-NaOH (0 , 1d) at room temperature for 15 minutes
! Stirred. Then lN-1(C1(0,11mj')
and concentrated under reduced pressure. The concentrated solution was diluted with ethyl acetate, washed with water, dried with mirabilite, and the solvent was distilled off to give 2S, 4S)-1-(p
-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained.

IR,, cm"" (film) + 1705.16
50. 1515.1400°1340, 1165.1
1l1 05Nδ (CDC1*): 1.90 (IH, d
,,I'8Hz), 2,97(3H,S), 3.08(
3H,S), 5, 19(2)1. S), 7.48 (2
H, d, J=9H2), 8.15(2H, d, J=
9H2) Example 2 a) trans-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline (180■)
(2S, 4R
]-1-Cp-nitrobenzyloxycarbonyl)-2
-Dimethylaminoka Jv.

Bonyl-4-acetylthiopyrrolidine (100 .mu.) was obtained.

IR,, cm-' (film): 1700.16
55.1515.1400°1340, 1115 [α] Color' + 32.8° (c = 0.375, acetone) b) Thioacetate derivative obtained in a) above (80
(23,4R)-1 by the same method as in Example 1.
-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained.

[R,, cm-' (film): 1700. 1
650. 1510.1420°MR δ (CDC12') 1400, 1340. 1120: 1.77 (lH, d, J=7H2), 2, 97C
3H,S), 3.16(3)(,S), 5,22(2H
, S'), 8, 16 (2H, d, J: 8.5 Hz) Example 3 a) Trans-1-p-nitrobenzyl-bovine dicarbonyl-4-hydroxy-D-proline-p-methoxybenzyl ester (110 ), using Reference Example 1-3,
By the same method as 1-4 and 1-5 (2R, 4R)
-tp-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine was obtained.

rR,, cm-' (film): 1705.16
50.1515.1435°1340, 1115 (α) if' 7. ．． 38° (c = 0.2to
, acetone) b) [2R
94R)-1-p-nitrobenzyloxycarbonyl-
2-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained.

IR,,,cn+-'(film): 1710.
1660.1525.1440゜1347, 1180
．． 1122 Example 4 a) From cis-4-hydroxy-D-proline (300■), (2R, 4S)-1-(p
-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine (45■
) was obtained.

[R,, cm-' (film): 1700.16
50.1520.1400° 1345, 1120 [α) g”-29,6° (c = 0.215, acetone) b) Thioacetate derivative obtained in a) above (30
(2R,4S)-1 by the same method as in Example 1.
-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyl-4-mercaptopyrrolidine was obtained.

IR,, cm-' (film): 1710. 1
655.1520. 1430゜Example 5 (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-methylaminocarbonyl-4-ethoxycarbonylthiopyrrolidine (82■) was dissolved in methanol:water (l
21) Dissolve the mixture (4 mt') and add I N -NaOH (
After stirring at room temperature for 30 minutes,
N-HCl (0.27d) was added, extracted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off [2S4S)-1-p.
-Nitrobenzyloxycarbonyl-2-methylaminocarbonyl-4-mercaptopyrrolidine was obtained.

IR,,,cr'(Nujol): 3280.171
0.1650. 15101340, 1165 NMRδ (CDCI: 2.79 (3H, d,
J=5Hz), 4, 27(2H,t, J=8Hz),
5, 23 (2H, s), 7.50 (2H, d, J=9
Hz), 8.20 (2H, d, J=9H2) The following mercaptan was obtained in the same manner as in Example 1 or Example 5.

cS Example 1 7 a) (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-benzylaminocarbonyl-4-
Acetylthiopyrrolidine (177■) and anisole (8
6) was dissolved in trifluoroacetic acid (0.5d) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous sodium bicarbonate and water, and dried with sodium sulfate. Remove the solvent,
The residue was subjected to silica gel thin layer chromatography (2
S,4S]-2-benzylaminocarbonyl-4-acetylthiopyrrolidine was obtained.

IR,,,cl'(film): 3325.169
0.1510.1400°1350, 1120.95O NMRδ (CDCI2): 2.28 (3H, s
), 3.83 (2H, m), 4.42 (2H, d, J=
6H2), 7.32(5H,5) b) The thioacetate derivative (40■) obtained in a) above was subjected to the same treatment as in Example 1 to obtain (2S,4S]-2-benzylaminocarbonyl- 4-Mercaptopyrrolidine was obtained.

tR,, cm-' (film): 3250.16
85.1610.1510°132 Reference Example 6 -3-(diphenylphosphoryloxy-6-(1-p-
Nitrobenzyloxycarbonyloxyethyl)-1-
Azabicyclo(3,2,0)-hebuto-2-en-7-
On-2-carboxylate (122■) was dissolved in dry acetonitrile (3mi'), diisopropylethylamine (31■) was added under water cooling in a nitrogen stream, and then (2S,4S)-1-p-nitropenzyl Oxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (60 μ) 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 obtain 5R, 6S, 8R, 3'
3.5'5)-p-nitrobenzyl-3-(3-(1-
p-nitrobenzyloxycarbonyl-5-dimethylaminocarbonyl)pyrrolidinylthio)-6-(1-p-
Nitrobenzyloxycarbonyloxyethyl)-1-
Azabicyclo(3,2,0)-hept-2-ene-7-
One-2-carboxylate (95■) was obtained.

IR,, cm-' (film): 1780.17
45.1705.1650°1605, 1515.13
42.1257NMRδ (CDCI+):
1.49 (3H, d, J=6Hz), 2,99 (3H,
s), 3.11 (3H, S), 5, 25 (48, S),
5.23 and 5, 46 (2H, ABq, J=14H
z), 7, 53 (4H, d, J=8.5Hz), 7,
62 (2H, d, J=8.5Hz), 8, 18 (6H
, d, J=8.5Hz) [α) g”+ 7.7° (
c ~0.303, acetone)b) (5R,6S
, 8R,3'3.5'S) -p-nitrobenzyl-
3-(3-(1-p-nitrobenzyloxycarbonyl-5-dimethylaminocarbonyl)pyrrolidinylthio)
-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo(3,2,O)hept-
2-en-7-one-2-carboxylate (95 mg
) in dioxane (20rnl) and morpholinopropane sulfonic acid buffer (pH=7.0, 10rnl)
and platinum oxide (35cm) and heated under a hydrogen pressure of 3.5 atm.
, hydrogenated for 5 hours. After filtering the catalyst, dioxane was distilled off under reduced pressure, the residual liquid was washed with ethyl acetate, the organic solvent was distilled off from the aqueous layer again under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P). From the part eluted with water (5R, 6S, 8R3″S, 5’5)-3-(3
-(5-dimethylaminocarbonyl)pyrrolidinylthio)-6-(1-hydroxyethyl)-1-azabicyclo[3,20]hept-2-en-7-one-2-carboxylic acid was obtained.

UV--g nm (HJ) [Lax cm-' (KBr) = 297 + 1755. 1627. 1393. 1252
゜130: 1.25 (3H, d, J = 6.4Hz), 1, 8
1-1.96 (IH, III), 2, 96 (3H, S)
, 3.03 (3H, S), 3, 14-3.20 (3H,
m), 3.31-3.41 (2H, m), 3, 62-3.72 (IH, m), 3, 90-4.00 (IH, m), 4, 14-4.26 ( 2H, m), 4.63 (IH, t, J・8.5Hz) NMRδ (D2
0)

Claims (1)

[Claims] General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R_1 is a hydrogen atom, R_2 is a hydrogen atom or a protecting group for an amino group, and R_3 is a hydrogen atom , a lower alkyl group, a lower alkenyl group, an aralkyl group, or a substituted lower alkyl group, and R_4 is a lower alkyl group, a lower alkenyl group, an aralkyl group, or a substituted lower alkyl group, or R_3 and R_4 are alkylene chains bonded to each other. Alternatively, it represents an alkylene chain via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom, and represents a 4- to 7-membered cyclic amino group together with the adjacent nitrogen atom. 2-substituted aminocarbonyl-4-mercaptopyrrolidine derivative represented by