JPS6054387A - Thienamycin derivative manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing derivatives of chenamycin or C1, related natural antibiotics such as N-acetylchenamycin. Sulfoxylate the sulfur-containing side chain of mycin
The present invention relates to a production method for converting into a new sulfur C11 [A-group 1111 chain] through substitution of a sulfone intermediate or a sulfone intermediate.

Chenamycin t [Structural formula: 7L11'' has a characteristic structure and particularly strong external activity, and β-lactam I'J''1. It is a biological substance.

B'j , '+Notation C/'': (~da, 1: sea urchin, chenamycin and its N-acetyl derivatives, N-acetyl chenamycin has a unique trans-R configuration in which the hydroxyethyl group at the 6-position Chenamycin and N-acetylchenamycin are structurally characterized by having a
U.S. Pat. No. 3,950,357, issued April 13, 1976; No. 534, published October 21, 1980). Chenamycin can also be obtained by total chemical synthesis, as described, for example, in US Pat. No. 4,234,596, published November 18, 1980. The activity of chenamycin and N-acetyl chenamycin as antibiotics in the treatment of animals and humans and in inanimate systems is fully described in the patent and chemical literature mentioned above.

As indicated above, the production method of the present invention is based on the technology of converting chenamycin or N~acetylchenamycin sulfur-containing side chains into novel sulfur-containing side chains. 3. An important reaction during the production process is the substitution of sulfoxide 7F or sulfone intermediates with 7'H-? 'r is also σ), 1 The method of the present invention is the anti-L1-1r' shown below, 4
"+' VC, J: Ripples are combined: n: l; E is equal to 12 M = I+, alkali metal cation (4) Among the above reaction steps, steps A and B are well-known for β-lactam drugs. Introduction of conventional N-protecting groups (Step A) and carboxyl protecting groups (Step B). Typical N-protecting groups include, for example, p-nitropencyloxycarbonyl, acetyl, trimethylsilyl; Typical carboxyl protecting groups include p-nitrohenzyl and trimethylsilyl.Of course, if N-acetylchenamycin is used as the starting material, the N-protecting group is already in place and step A is unnecessary. In addition, when trimethylsilyl group is used as the N-protecting group and carboxyl protecting group, step A and step B are combined into one. When using trimethylsilyl group, the hydroxyl group in the side chain is also silylated. This is a natural consequence of the chemical reaction and is not a necessary feature for side chain exchange.The common Kp-nitrobenzyl group is the preferred carboxyl protecting group.

Establishing these protecting groups has already been described in the literature.
This is accomplished by the final method.

During the reaction, step C oxidizes the sulfite side chain to the sulfoxide; also to the r1 sulfone.
In bamboo 'li', for example, tetrahydrofuran, 4'lA
Mild agents such as metachloroperbenzoic acid, perbenzoic acid, peracetic acid, sthorium metaperiodate, phenyldichloroiodite, hydrogen peroxide, etc. Treatment with oxidizing agent V? It can be implemented from T. The reaction is about -20
It is carried out at a temperature of 1711'l-+ in a room temperature of 1711'l-+, and is usually completed in 5 minutes to 4 hours.1, generally about 1 mole of oxidizing agent. 11'' to give the sulfoxide intermediate.
of metachloroperbenzoic acid. Using 2 molar equivalents or more of the oxidizing agent gives the corresponding sulfone rather than the sulfoxide.
The sulfones can be used in the process of the invention in the same way as sulfoxides.

Step in the reaction step is to replace the sulfoxide 4 or sulfone side chain with the mercapto reagent H8R3.

Typical mercapto reagent B R3 is phenyl, 2-pyridyl, hensyl, 2-hydroxyethyl, t-butyl,
2-Amino-1,1-dimethylethyl, N,N-dimethylcarhamimidoylmethyl, 2-amino-2-methoxycarbonylethyl, 2-amino-2-carbamoylethyl, 2-aminobutyl, 2-aminol 1 -carbamoylethyl, 2-amino-1-calphokidiethyl, 1-aminomethyl-2-(imidazol-1-yl)ethyl,
2-amino-2-(thiazol-4-yl)ethyl. Such thiols and the N- and carboxy protected derivatives mentioned above are known compounds that are either commercially available or easily prepared by methods already described in the literature. The reaction is carried out with a base such as diisopropylethylamine, triethylamine,
In the presence of 4-dimethylaminopyridine, potassium carbonate, cyasabicycloundecene, etc., the reaction can be carried out from -40°C to room temperature. Two molar equivalents of the reaction vc it thiol are used: 1 molar equivalent of thiol is required to scavenge the sulfenic acid removed from the starting sulfoxide. Suitable substitution reaction 1.2
Two equivalents of thiol are used at 0° C. in dimethylformamide containing diisopropylethylamine.

Finally, step E of the reaction process diagram for the previous R1 is to deprotect the carboxyl group and the protected functional group in the sR'' side chain.
gives the final product. Conveniently, deprotection dtlJ, water, ethanol, dioxane, tetrahydrofuran soil, p
This is achieved by hydrogenating a 1:1+7 buffer solution or a mixed solvent of t, I and activated carbon-adsorbed palladium or platinum oxide in the presence of a 1:1 hydrogenation catalyst.

In some cases (8), the alkali metal salt of the deprotection product can be conveniently generated by adding an alkali metal salt such as sodium bicarbonate to the hydrogenation mixture. When R2 is trimethylsilyl, final deprotection is easily accomplished by mild acidic hydrolysis using an aqueous pH 3-6 buffer with a solvent such as dioxane, ethanol, or tetrahydrofuran. The product is present in the form of an alkali metal salt, but if required can be converted to the free acid by neutralization with a dilute mineral acid.

The optimal conditions under which Applicants intended to practice the invention are illustrated by the following examples.

Example 1. (5R,6S”)-2-phenylthio-6
-[(R)-1-Hydroxyethyl]-1-carbadethiapen-2-em-3-calho Step A, (5R,6S)
-2-[2-(p-nitrohenzyloxycarbonylamino)ethylthio]-6~[(■-1-humanoxyethyl)-1-carbadecithiapen-2-em-3~calphone f'F2 p-nitro benzyl ester water-cooled HzO
Chenamycin (565#V) dissolved in (55 ml)
, purity 94% by ultraviolet absorption, 1.95 mmol) in NaHCO3 (1,68 t).

20 mmol) was diluted with dioxane (45d). The resulting solution was cooled and stirred in a water bath, then diluted with p-nitrobenzyl chloroformate ((i 4'
h'LW, 3 mmol) in dioxane (10 g)
was added dropwise over 11 minutes. Further while cooling 1-7]
After stirring for 0 min, the mixture was neutralized to pH 7 with cold IM.112S 01 and cooled with cold ether (50me
) was extracted. Add cold ethyl acetate (5 (1 ml) to the aqueous layer.
J, (-overlayer (-1 M- with vigorous stirring in a water bath)
11280, and it was set to 1u112.3. Separate the two layers,
The aqueous layer is further ethyl acetate (10mX2 +111)
Extracted with [77. Add the collected ethyl acetate solution to a cold saturated diet j1
aWash with water (;S (l ml), then cool 0.05N
It was completely extracted with Li01r (40me). The aqueous layer was separated, washed with r￥i:rg ethyl (50 m ), partially concentrated under vacuum to remove the organic solvent, and then lyophilized to produce crude (5R,68)-2-(2-p-nitropene). Zyloxycarbonylamino)ethylthio]-6-((I()
-1~human ethethyl]-1-carbadecethiapene-2
Lithium -M-3-carphonate (599 my, 6 s
H) was obtained as a yellow powder.

Dehydrated hexamethylphosphoramide (6.3 ml)
Crude lithium carboxylate (1.3 mmol) and p-nitrohenzyl bromide (7o21N!, 3.25 mmol) dissolved in
The mixture of (mmol) was stirred at room temperature under N2 atmosphere for 2.5 hours. The mixture was diluted with ethyl acetate (100ml), H
,,o (50mg x 5 times), 5% NaHCO3 (50m
1), washed with saturated brine, dehydrated and concentrated under reduced pressure to give a yellow semi-solid. This material was triturated with ethyl acetate and ether and dried in vacuo to produce a product (438 cm.

A total yield of 38%) was obtained as a pale yellow solid.

IRν (nujol, mal): 1776°169
5crn→ (11) 11V (thioxane) λmax: 268 (219
00)++m, 318(14:S(10)nm:'
II NMR (300 Mllz, Me2CO-d6
) δ: 1.05 (TI, l, J=fillz, O
TI), 1.27 (d, 3. J=6.511
7,, ClIC! j, ) , 3.09 (m, 2
．． 5CH2), 3.33(dd, l, J=2.F
i and 6.8I(z, H6), 3.33 (dd.

1, J:8 & 18Hz, Hla), 3.4
5 (m, 2゜(,'H2N), 35'l (d
d, ,1. J=1.0 and 18Hz.

old 1+), 4.1:((ddd, 1.C廿C
T(3), 4.28 (ddd, I, J=2.
5. '8. and 10Hz, N5) 5.28 (
S, 2. NC02CI12), 5.31 and 5
．． 55 (2d, 2°, 1:=1411z, C0
2C112), 6.92 (m, 1.NH).

7.67 (d, 2. J=9 Flz, aryl)
, 7.83 (d, 2..1 = 9 Hz, aryl)
, 8.27 (a, 4. J=!H1z, aryl); M'S, mle 542 (M'-44), 540,5
00. ．． 304 elements)]l' (C2+1 Hpa
N40+o S) Engineering F+iB: (511,6S)
2 [2(p(12) 1-nitropenzyloxycarbonylamino)ethylsulfinyl)-6-[(R)-1-hydroxyethyl]-
1-carbadethiapen-2-em-3-carboxylic acid p-
Nitrobenzyl ester 85% m-chloroperbenzoic acid (415 ■.

2.045 mmol) of CH, mock solution (6.8 ml)
, dehydrated dimethylformamide (6,8 m) of carboxylic acid ester of step A and CH2(A (26,8++/
) was added dropwise over 3 minutes into the stirred suspension. The resulting mixture was stirred at room temperature under N atmosphere.

After 2 minutes, the reaction mixture became a solution. After 5 minutes, the solution was diluted with ethyl acetate (250111/) and diluted with H20 (150
-x twice). The aqueous washes were collected and further washed with ethyl acetate (100+d). The collected organic solvent was diluted with 5% NaHCO3 (159 m/ml) and saturated saline (15 m/ml).
The mixture was washed with 0 mA), dehydrated with Algs O4, filtered with p, and concentrated under reduced pressure. The residue was triturated with ethyl acetate and ether to give the crystalline diastereomeric sulfoxide product (534~,
A yield of 55% was obtained.

Melting point 147-149℃ Titν (nujol, mal): 3450.33
15°178(], l (i95.1520.1347
cm-'tIV (dioxane) λmax: 26
6 (21,300).

325 (eyebrow, 6150) nm' II NMri IHI (1MIIz, DMSO
-da) δ:1.12 (d.

3. J=6.211z, C1f(Jja), 3
．． 04 3.56 (m, 6゜5Cf12.C1r2
．． C112N), 3.60 (dd, IH, J=3.
0 and 5.0117. , IHi), 3.98 (m,
1. CHCH3), 4.26(di, 1.J-:
l, 0 and 9.2Hz, H5), 5.16 (S,
2゜NCO□C112), 5.40 and 5.46 (2d
, 2. J=1411y, C□, C112), 7
．． 61.7.73.8°23 and 8.26 (4(1,8
, J-=8.511z, aryl), 7.78 (
tl 11J 5. :1rrz, NII) ノI] Elementary analysis (c, 1lr-r□o N< Ou S
) Step C: (5R,6S) 2-phenylthio-6
-[(r4 1-Hydroxyethyl]-1-Rubadethiapen-2-em-3-carboxylic acid p-nitrobenzyl ester Step B sulfoxide (15,0 μ, 0.025 mmol) in dehydrated dimethylformamide solution (0 ,20m)
was stirred in a water bath under a cool N2 atmosphere. A solution of N,N-diisopropylethylamine (8.7 μL, 0.05 mmol) and thiophenol (5.1 μt, 0.05 mmol) in dimethylformamide (0.04 M) was added, and the resulting solution was incubated at 0° for 30 min. Stirred. The reaction mixture was diluted with ethyl acetate (3-), H20 (3x3d),
pH 3 phosphate buffer (3 m), 5% NaHCO3 (5 m
1), washed with saturated saline (3g), dehydrated with AIgS04, filtered, and then reduced under reduced pressure to give an oil (18.6 mg). The crude product was chromatographed on silica gel (2,059) using petroleum ether-ethyl acetate 3:1 as eluent. Fractions No. 19-35 were collected and concentrated under reduced pressure to give the phenylthio product (10,4) as an oil.

IRν (CH, false): 3600. 1776, 1
701゜(15) 1525.1332 cm', uv (dioxane) λmax:' 269 (12
, 800).

319 (15,000) nm 10NMR (:100MITz, CDC/s) δ
: 1.30 (d, 3°J”6.3Hz, CII
Cjj3), 1.63 (d, 1. J=4.5Hz
, OH).

2.69 (d, 2. J=9.2Hz, CHt
), 3.11 (dd, 1. J=3 and 6.6Hz
, 116), 4.11 (d t, t, J=3 and 9', 21rz, H5), 4.20 (m, 1.
CHCH8), 5.31 and 5.57 (2d,
211. J-43Hz, C0zCH2), 7.37
-7.64 (m, 5. phenyl), 7.71 and 8
．． 26 (2d.

4, J-=8.611z, aryl) MS mle
: 440 (M), 396 (M-C2H3O), 35
4 (If/l Cn1roOz), 304 (M P
NB)-1 culm 1): (51,68)-2-phenylthio-6-[(I-1-hydroxyethyl]-1-carbadecithiapen-2-em-3-carbo1]C(22ν
A solution (3.6 mg) of the ester of TeI lahitrofuran (Iv, 0.05 mmol) was added to ethanol (1.8 m
) and NaHCO3 (4,2”I.

(16) (0.05 mmol) in deionized water. The resulting solution was preactivated with 10% pd/c (20
) was added to the ethanol mixture (1,8-) and the mixture was stirred vigorously under an H2 atmosphere. After 30 minutes, the mixture was filtered and the F-separated catalyst was H! 0 (10-N twice).

Add aqueous F solution to ethyl acetate (20dX twice), ethyl acetate-
Ether]:1 (40 TIIt), concentrated under reduced pressure to about 6 m and lyophilized to obtain the title compound (13.81 W by ultraviolet absorption) as an off-white, amorphous powder.

IR (Nujol, Maru): 3350 (br).

1755, 1595m-1, uv (HsO) λmax: 303nm' HN
MR (D, O) δ: 1.12 (d, 3. J=
6.2Hz.

C! ! 3CH), 2.66 (dd, 1. J=10
．． 0 and 18Hz.

Hla), 2.80 (dd, 1. J=8.8 and 1
8Hz, Hlb).

3.31 (dd, 1. J=2.5 and 5.9Hz
, H6), 4.08 (dt, 1. J=2.5 and about 9.3 Hz, H5), 4.19 (dq.

IH, J = approx. 6Hz, CH3CH), 7.47.7
(m, 5. phenyl).

Example 2. (5R, 6S) -2(2~Viridilna A
)-6-[(Hammer-1-hydroxyethyl)-1,-carbadecethiapen-2-M-3-carphone overnight] Ni'+iA: (5R,6S) 2 (2-pyrisylthio)-6-C( 101-Hydroxythio2-1-
Carbadecthiapen-2-em-3-sulfonic acid 1)-nitrohensyl ester N,N-diisopropylethylamine (17.4 μt, 0.1 mmol) and 2-mercaptopyridine (I 1.7 h) I/, 0.1 mmol) of dehydrated dimethylformamide mm (0, i me )
sulfoxy l of Example 11-Step 13, which was water-cooled; (
30.1mf.

0.05 mmol) in a dehydrated dimethylformamide bath (V
1 ((1,3+t+e)) was added to the stirring medium.

stomach! The mixed mixture was stirred for 90 min under a N2 atmosphere ()°, diluted with n' + ethyl acid (15 tne), 5% N
It was washed with a11CO3 (15me x 7 times), saturated brine, dehydrated with Na25O1, filtered, and concentrated under reduced pressure. The residue was washed with silica gel (3, Of
) was subjected to column chromatography (approximately 2 fractions/min). Fractions 8-16 were collected and concentrated under reduced pressure to obtain a crystalline product (13.1 to 59%).

IR (Nushor, Maru): 3370.1765°171.0.1675.1510.1340 tyn-
', UV (dioxane) λmax: 323nm
.

'HNMR (300MHz, CDα3) δ: 1.3
4 (d, 3°J=6.0Hz, Cf13CH),
1.66 (d, ]-, J=4.6Hz, 01l).

3.02 (da, i, J=9.0 and 18.81 (
z, Hla), 3.20 (aa, 1. J=3.
0 and 6.6Hz, H6), 3.26 (dd.

1, J=10.0 and 18.8Hz, H], b),
4.25 (m, 2.II5 and CH3CH), 5.
32 and 5.56 (2d, 2. J-13,8Hz,
CO2CH2), 8.55 (d, l, J=8.0Hz
, pyridyl), 7.71. (m, 2.pyridyl)
, 7.71 and 8.27 (2d, 4. J=8.
6Hz, aryl), 8.63(b r d, 1.
J-4,6Hz, pyridyl) MS, m/e: 44
1 (M), 355 (M-C41 (602).

■Procedure B: (5R,6S)-2-(2-pyridylchie J
-) -6-C(■-1-Hydroxyethyl]-1-carbadecethiapen-2-em-3-carphonic acid ester of step A (40.0 mg, 0.091 mmol) in tetrahydrofuran 10% Pd/c ( 0.24.8Tng).
IMX pH 7.1 phosphate buffer (2.8 rn
e) and the mixture in a hydrogen atmosphere IJ chamber? 1 in ilA
．． Stirred for 75 hours. Pass the mixture through lJI, remove 17
The catalyst was washed with deionized water (25 me). The θ-1 solution was dissolved in ethyl acetate (25-X 3 11+1 >
-c ('A: 6+, after th.R pressure IM m,
Column of XAD 2 resin i'c 1-j'[-'
I-ko. The column was heated in a cold room with deionized water, then 1
Bathe in T-r20 containing 0% tetrahydrofuran, 3
．． There were 6 and 17 fractions every 25 minutes. Based on ultraviolet absorption, fraction No. 1 9-3 4-i'f was filtered, concentrated under reduced pressure, and lyophilized to yield compound 11I'1 (Table 9).
3 nyt) with amorphous powder and 12
/child.

UV (II2 0) λmax:, 305nm'
H NMR (300t'i'lT-1'z, I)!
4 0) δ: 1.23 (d, 3, J=6.
2Hz, CH3CH), 2.87 (d, 2, J = 9.6
Hz, CH2).

3,40 (ad, 1, J=2.8 and 5.8Hz
, H6), 4.1 8 (dt, 1, J=2.8
and 9.6Hz, H5), 4.22 (dQ.

1, J=6.2 and H6.2, CH3C! 7.
46, 7.70, 7.90 and 8.54 (4m,
4, pyridyl).

Example 3. (5R,6S)-2-pencylthio-6-
[(5R,6S)-2-Hensylthio-6-[(5R,6S)-2-Hensylthio-6-[
(R)-1-Hydroxyethylcy-1-rubadethiapen-2-em-3-carphonic acid p-nitrobenzyl ester Example 1 Step B sulfoxide (30.Cf.

0.05 mmol) in dehydrated dimethylformamide solution (
0.30+++j) was cooled in a water bath and stirred under N2 atmosphere. N,N-diisopropylethylamine (17
．． 4 μt, o. A solution of dimethylformamide (0.1 mg) and pencil mercaptan (11.7 μt, 0.1 mmol) was added to the sulfoxide solution, and the resulting mixture was stirred at 0° for 45 minutes. 8 times with ethyl acetate (5II+1!),
Wash with 5% NaTlCO3 (5 ml x 7 times), N
After dehydration over a 2 S 04 and filtration, the mixture was concentrated under reduced pressure. The residue (34,1+I+7) was prepared using silica gel (3:3.
59) was subjected to column chromatography (1).The fractions 10-14 were the product l05tng/, :rieh
:53 fractions 7-9 are impure products ((i, (i
1ng), but a shield was further prepared using preparative T■ and C, and the product 5.1■ was further separated into I! It was. The combined yield of crystalline product was 15. fll19 ((j9%).

rrtν (C1r2(], ): 3590.17
72.1695,1518゜1325 tyn-' uv (Shiogijin) λmax: 26],, 31
6nm'H'NMIt (200M'lIz, C
D false) δ: ], 35 (d, 3°J-6,41r
z、CL! , C1r), 1.64 (d, 1. J
=5.0Hz.

CDI), 3. (13(dd, I, J=8.7 and 17.9Hz, Hla).

:3.15 (dd, 1. J=2.8 and 7.0H
z, I(b), 3.29(da, 1. J=9.7
and 17.9Hz, Hlb), 4.10(ABq,
2. J-14,8Hz, 5CH2), 4.20 (
m, 2. N5 and CH3Cdan), 5.25 and 5.
53 (2d, 2H, J-13, 7Hz, CO2C
H2), 7.37 (S, 5H, phenyl).

7.67 and 8.25 (2d, 4. J=8.5H
z, aryl) MS mle: 454 (M), 36
8 (MC4H602), 331 (M-8CH, C6H
,) Step B: (5R,6S)-2-pencylthio-6-[
A tetrahydrofuran solution (3,6-) of (→-1-hydroxyethyl]-1-hydralhadithiapen-2-em-3-sodium carbonic acid ester (22,7)N7,0°05 mmol of step A) was added to ethanol. (1,8 Tnt) and NaHCO3 (4,2”?.

0.05 mmol) in deionized water (2.8 ml). The resulting solution was preactivated with 10% Pd/
c (20 ml) was added to ethanol (1,8 m) and the mixture was stirred vigorously under an atmosphere of H2. After 1 hour, the mixture was filtered and the removed catalyst was washed with deionized water. /75 solution (23) t, washed with 1 ethyl citrate (30me x 3 times), approx.
, 5 ml, -+ concentrated under reduced pressure and lyophilized to give the product (
11,5 mg) was given as an amorphous powder.

■R (Nushor, Mal): 3310.1740°1575 cm-' TJV (1■t O)λmax: 302nm'
IT NMIt (20(I Mrl z, I)20
) δ: 1.15 (d, 3°=T-fi, 4Hz
, C intestine C11), 2.84 (dd, 1., J
=8.8 and 17.811z, T-11,a), 3.
1.5 (dd, 1. J=9.7 and 17.811
7. , old b), 3.22 (d d, 1. J=2
．． 6 and fi, 01Tz, rI6), 4115 (m
, 4. N5.5CH2, CH3C animals), 7.34
(ITI, 5. Phenyl)” 1 soil (5+1,6S)
-2-Humanized xyedylthio-6-[(R)-1-hydroxyethyl] -1-carbadecthiapen-2-em-
3 to culm A: (5R,6S) 2-hydroxyethylthio-6-[(R) -1-hydroxyethylthio-1-carboxythiapen-2-M-3-carphone M+2, -
Nitrohensyl ester (24) N,N-diisobrolethylamine (17,4μt,
o, i mmol) and 2-mercaptoethanol (7
, 0 μt, 0.1 mmol) in dimethylformamide (Q, ] me ) was ice-cooled to form a dehydrated dimethylformamide solution (0.3 m ) of the sulfoxide (30.0 mg, 0.05 mmol) in Example 1 Step B. Added while stirring. The resulting mixture was stirred for 1 h at 0° under N2 atmosphere, then ethyl acetate (6me)
The mixture was diluted with NaHCO3, washed with 5% NaHCO3 (6me x 7 times), dehydrated with Na2SO4, filtered through p, and concentrated under reduced pressure. The residue was triturated with ethyl acetate and ether to obtain the product (8.2q) as off-white crystals. The mother liquor was concentrated under reduced pressure and the residue was chromatographed on silica gel using 5% methanol/ethyl acetate as the eluent.
) was obtained as colorless crystals (melting point 125-129°).

IRν(CO2CH2): 3590.1772.1
517.1-325crn-'UV (dioxane)λ
max: 265.317nm' HNMR (200
MHz, CDα3)δ: 1.32 (d, 3°J
-6,211z, C1l, C11), 1.64 (d
, 1. J=4.8Hz, Cll0II), 1.8
3 (L, 1. J=5.8)Tz, CHzOH)
.

2.98 (m, 2.5CI(z), 3.07 (
dd, 1. J=8.7 and 17.7flz, II
1 +1), 3.15 (dd, 1. J=8.7
and 17.711z, l1la), 3.15 (dd
, IH, J=2.6 and 6.811z, H6),
:(,32(dd, 1. J=9.8 and 17.71
1z, INb), :(,80(q, 2. J=6.
0Hz, CH20H), 4.20 (m, 2.I
H5 and CM3CH), 5.20 and 5.47 (2d
, 2. J=13.7Hz, C0tCHt),
7.62 and 8.19 (2(1,4,J=8.7Hz
, aryl) Step II (5R,68)-2-hydroxyethylthio-6~[(R)-1-hydroxyethyl]
A tetrahydrofuran solution (6.2 m) of -1-carbadethiapene-2-M-3-carboxylic sodium chloride (35.4 M?, 0.087 mmol) in Step A was mixed with ethanol (:1. im) and NaHCOs. (7,
3W.

0.087 mmol) in deionized water (4.9 m). 10% Pd/c pre-reduced to solution
A mixture of (:14.4+1v) in ethanol (3.1 m) was vigorously stirred under H2 atmosphere for 65 min. The mixture was filtered and the removed catalyst was washed with H20. The p solution was washed with ethyl acetate (30 dXa times).

After concentrating under reduced pressure to approximately 3 d, a column of XAD-2 resin (5 (
ld) and eluted with deionized water in a cold room. Appropriate fractions were collected based on ultraviolet absorption, concentrated under reduced pressure, and lyophilized to obtain the product (7,8) as an amorphous powder.

IRI/ (Nujolmaru): 3280 (br
).

1740, 1585 cm-' UV (D, 0) λmax: 298 nm' HN
MR (300MHz, D!O) δ: 1.30 (d
, 3. J=6.4Hz, CH3CH), 3.01
(m, 2.5CHt).

3.18 (dd, 1. J=8.9 and 17.1H
z, Hla).

3.32 (dd, 1. J=9.5 and 17.1H
z, Hlb).

3.42 (dd, 1. J=2.5 and 6.0Hz
, H6), 3.79(t, 2. J=6.2Hz,
CHlOH), 4.24 (m, 2. H5 and CH
8CH) Example 5. (5R,68)-2-(t-butylthio)
-6-[(R)-1-Hydroxyethyl] (27) -1-Carbadethiapen-2-em-3-sulfonic acid sodium salt A (',)R,68)-2-(t-butylthio) -6-[(R)-1-Hydroxyethyl-1-carbadecethiapen-2-em-3-carboxylic acid p-nitrobenzyl ester Example 1-N sulfoxide (101,71+9°0.1 (i While stirring a dehydrated dimethylformamide solution (1.7 mg) of -N,N-diisopropylethylamine (9 mmol) under a 0',N atmosphere, -N,N-diisopropylethylamine (
59 μt, 0.339 mmol) and t-butyl mercaptan (381 μt, 3.38 mmol) were added. The reaction mixture was stirred for 55 min at 0°C under N, then diluted with ethyl acetate (
Diluted with 7-), 1120 (5td x 6 times), 5%
NaHCO3 (5 m), saturated food J-washed with water, Na!
80. It was dehydrated, filtered, and concentrated under reduced pressure. 1IIt left (92
, 7■) was chromatographed on silica gel (10,15f) using ethyl thiacetate/methylene chloride as the elution solvent (4I111!/fraction/min), fraction bundles 17-(28) and 38 were collected, concentrated under reduced pressure, and freeze-dried from benzene to obtain the title compound (4B, 2q) as an amorphous powder.

IRν (CH, false): 3540.1770.17
05.1515゜1320 Sub-1 UV (dioxane) λ""X: 320nm' H
NMR (300MHz, CDC4) δ: 1.37
(d, 3°J=6.7Hz, CH3CH), 1.4
8 (S, 9. t-butyl).

3.16 (dd, 1. J=8.9 and 17.6H
z, Hla).

3.21 (dd, 1. J=2.8 and 6.9Hz
, H6), 3.53 (dd, IH, J=9.7 and 17.6Hz, Hlb), 4.26 (m, 2.H
5 and CH, Cdan), 5.24 and 5.52 (2d.

2, J=14.0Hz, C0ICH,), 7.68
and 8.24 (2d.

4, J=8.5Hz, aryl) MS, m/e: 420 (M), 364 (M
-C4H8) Step B (5R,68)-2-(t-butylthio)-6-((1-t-hydroxyethyl)-1-
Ester of sodium carbadethiapen-2-em-3-ruponate Step A (4o, 1my, 0.095mmol) and 10% Pd/c (19,7vq) in tetrahydro7rane (6,(ime), ethanol) (6,
6m).

A mixture of deionized water (5,5#ll!) containing Na1ICO3 (8,OTni, 0.095 mmol) was added to a Parr shaker to give approximately 2.8 Kylcr.
1 (40 psi) for 225 hours. The mixture was filtered and removed 1. Catalyst stand and deionized water (35 m
Washed with t). Aqueous IJi liquid t” Washed with ether (
35 g x 3 times), then activated carbon (o, 2 oy) and shaking,
After filtering 1) II (i, 7), concentration and lyophilization gave the product (2r=rrl1g) as a shaped powder.

TRν (Nushor Mar): 1740.158
0crn-'TIV (II20) λ”aX: 2
92nm' If NM14 (2(lOMIIz,
D20) δ: 1.29 (d, 3. J(i, 5
II z, C113C old, 1.39(s, 9.t
-butyl).

:1.06 (dd, l, J-8,8 and 17.0
Hz, Hla).

:135 (dd, l, J-9,9 and 17.0
Hz, Hlb), 3.46(rid, l, J=
= -2,7 and 5.8Hz, H6), 4.24 (m
.

2, H5 and CI, CIT) Example (i (5R,6S)-2(3-amino-2-methyl-2-propylthio)-〇-[(R)-1-hydroxyethyl)-1-carpathethiapene- 2-M-3-
Carphonic acid step A (5R,6s)-2-[a-(p-
Example 1 Step B sulfoxide 195.4 mg.

A dehydrated dimethylformamide solution (1,6 TId) of N-(p-nitrobenzyloxycarbonyl)-2-mercapto-2-methylpropylamine (94,5 mmol, 0.332 mmol) was cooled with water. N to where it is stirring.

N-diisopropylethylamine (55 μt.

0.316 mmol) was added. The reaction mixture was stirred at 0° under N2 atmosphere for 1.5 h and diluted with ethyl acetate (30-)
Diluted with HzO (30 tnl x 5 times).

5% NaHCO3 (3 o mt) and saturated saline (3 o mt)
0 (31) me), and was dehydrated with rA:rfl, Na25O, filtered, and concentrated under reduced pressure. Wagyu Homono (168■) is made of 4 sheets using 20% ethyl acetate/1/n methane chloride as the developing solvent. (Chromatography was performed on an L-layer silica gel plate (1 x 20 x 20 cm). The position of the band showing appropriate absorption was determined by ultraviolet absorption, and when it was scraped off and eluted with ethyl acetate, the product (63.7 nl!) was obtained. was given as a colorless solid.

TTeν (Nushor, Maru): 3340.17
65゜1705.15 Seal 5.1: Eye 5 on 'nv
(Shioxane) λmax: 313 (13,90
0) nm' HNMI? (300Mllz, CD
C/! 3) δ: 1. ．． 37 (d, 3°, r-6
,4+(y,, crr3crr), 1.42(S,
6.2CH3), 3.15(dd, 1. J=8.
8 and 18.0Hz, Hla), 3.25 (dd,
1. J”2.6 and 6.4Hz, H6), 3.3
6 (t, 2. J=6.4Hz, Cl72N),
3.41 (dd, 1. J=9.5 and 18.0T
(z, Hlb), 4.26 (m, 2. I(5 and CH3CH).

5.22 (S, 2. NCO2CH2), 5.27
and 5.53 (2d, 2. J=13.711Z,
co2cn2), 5.63 (t, 1. J=6.
411z, Nlυ, 7.5:3.7.68.8.25
(4d, 8H, J=(32) 8.5Hz, aryl) MS, m/e: 570 (M CHsCHO)l:
(5R,68)-2-(3-amino-2-methyl-2
-propylthio)-6-[(R)-1-hydroxyethyl]-1-carbadecethiapen-2-em-3-carphonic acid ester of Step A (38,4■, 0.063 mmol) in tetrahydrofuran (3,4 ) of 10% pd/c (38,2'ng) previously reduced to solution. IM
Pi 7.1 phosphate buffer (1,8++d) was added. The resulting mixture was stirred at room temperature under H2 atmosphere for 105 minutes. The catalyst was separated and washed with H20 (15 m/). The aqueous p-liquid was washed with ether (20rrt x 3 times), about 2-
After concentrating under reduced pressure to
X 20z) (5treak). Determine the desired band by ultraviolet absorption, scrape it off, and dilute it with acetonitrile-water 4
:1 (5 m6 x 4 times). The eluate was H2O(2
5rn! , ) and washed with hexane (15mXa times)
After concentration under reduced pressure and lyophilization, a product (2.8 m?) was obtained as an amorphous powder.

TRν (Nushor Maru): 3370.176
5゜1 fioo cm -' uv (+120) λmax: 280 nm'
HNMR (200Mllz, I)20)δ: 1.2
9 (d, 3°, L-6,5]Tz, Cll3Ct
l), -1,45(S, 3.CH3), 1.46
(S, 3. C1l, ), 3.08 (AB[l,
2. J=14.7Hz, CH2N), 3.15
(d, 2., L-9, 3Hz, CHz), 3.
52 (dd, l, J'-29 and (i, 0]1z
, Tl6), 4. ．． 27 (m, 2゜115 and C
If, CII).

Example 7. (5 patches 6S)-2(N,N-dimethylcalhamimidoylmethylthio)-6-[(IQ--1-
Hydroxyethyl]-1-carhaththiopen-2-em-3-carphonic acid Step A: (5rt, 6s)-2-ethylthio-6-[(16-1-hydroxyethylcal1
- 2-M-3-carphonic acid p-nitrohensyl ester N2 atmosphere (10-r(3R,5R,6S)-2-oxo-6-4(1-1-hydroxyethyl)-1 -Carbadethiapenam-3-carphonic acid p-nitropenyl ester (2792nrg.

0.802 mmol) in dehydrated acetonitrile solution,
N-diisopropylethylamine (152 μt, 0
．． 873 mmol) and diphenylchlorophosphate (176 μt, 0.849 mmol) were added. The resulting bath liquid was stirred at 0° for 5 minutes. Furthermore, N,N-diisopropylethylamine (152 μff, '0.873
mmol) and ethanethiol (148 μt, 2.0
mmol) was added to the reaction mixture. The mixture was placed under N2 at 0°
The mixture was stirred for 6.25 hours, during which time a large amount of colorless precipitate formed. Filter the product (~, cold acetonitrile (
6-) and cold ethyl acetate (3 ml), and drying under vacuum, 226.8~ was obtained as colorless crystals.

Melting point 180-183° (decomposition) IRν (nujol mal): 3410.177
5゜1687 cm-' (35) TJV (TJV) λmax: 267 (
1,0,1,00).

319 (11,1101) nm' II NMR (:S 110 Mll 7.,
C1,)(!3) δ: 1.34. (ty:
l,,+7. :Day 1z, CJjlCI+21. 1
．． 37 (d, 3. J=6.3117,, C4L
:+C11), 2.88(m, 2. CH, +C tan,
), 3.12 (d d, I, J 8. (i and 17
．． 711z, l1la), 3.21 (II d, I,
J2. li and 7. Old IZ, 1■6), 3.33
(dd.

1, , L.41.7 and 17.7. lIz, l1l
b), 4.26 (m, 2°II5 and Cl11C!
5.26 and 5.53 (2d, 2°J-141
rz, C(12cl12), 7.68 and 8.25
(2d.

4, J-8,511z, aryl) MS, ITI,
10: :192(M), 348(MC21(40
), 306 (MC4Hp 02 ) Dingseij 11 : (51L + 6 S ) −2
-ethylsulfinyl-6-[(R)-1-troxyethyl]-1-carbadethiapene-2-em-3-hydroxysulfonic acid 1)-nitrohensyl ester 1 1 1″A 1 methyl thioate 2.9 (19,5+g, 0.05 mmol) in dehydrated dimethylformamide solution (11,5 me
) ((1 dehydrated methylene chloride (1.0 ml) (3
6), cooled in a water bath, and stirred under N2 atmosphere. 85
% m-chloroperbenzoic acid (1,2,2rt1g.

0.06 mmol) of methylene chloride (0,5-) was added dropwise to the solution over 3 minutes. After stirring for 30 min at 0°, the solution was diluted with methylene chloride, H20 (3 times),
5% NaHCO3, I (20, washed with saturated saline,
Dehydrated with MgSO4 and filtered.

When the solvent was distilled off under reduced pressure, a diastereomeric mixture (19.2 mq) of crude sulfoxide was obtained as a pale yellow oil.

IRν (film): 3400.1782.17
23゜1520, 1325 on-' UV (dioxane) λmax: 268.325 (
) ii) nm' HNMR (200MHz, CD(A
) δ: 1.35 (m, 6゜CH3CH and CH
3CH2), 2.95 (m, 2.5OCH2).

3.39 (m, 1. H6), 415 (m, 1
．． CH3CH).

4.42 (m, 1. H5) Yu1 engineering: (5R,'6S)-2-(N,N-dimethylcarhamimidoylmethylthio)-6-[(R)-1-
The sulfoxide (0,046 mmol) produced by hydroxyethyl]-1-carbabutiapene-2-nimo-3-carboxylic acid N2 atmosphere 1. Cool in a tri-ice-carbon tetrachloride bath. To this sulfoxide lf'1''8't, 87 μi of N,N-diisopropylethylamine (1 (15 mmol)) and N,N-dimethylcarhamimidoyl Methyl mercaptan (7,1 Inl, 0.(14(i mmol)) in dehydrated dimethyl sulfoginate solution (0,1, me) was added and the resulting solution was stirred for 10 minutes at t, l-2rr. Ether (8me) was added to the shellfish and the mixture was shaken.

Ether layer & J 44. +77 (5R, 6S)
2=(N,N--dimethylrubamimidoylmethylthio)-6-[(T◇-1-hydroxyethyl]-1-carbadithiapen-2-em-3-hydroxysulfonic acid p-nitrohensyl ester in oil form The residue was separated by decantation, and the ester C1 and Et20 (3 mg
Washed twice).

The oily residue of the crude ester was dissolved in tetrahydrofuran (1.8 m
A) and 0.1M pH 7 potassium phosphate buffer (1,4
m) and H2 using 10% Pd/c (13■).
Hydrogenation was carried out at 1 atm. After stirring for 60 minutes, the catalyst (1
3~) was added and hydrogenation was continued. After a total of 120 minutes,
The mixture was filtered and the catalyst was washed with deionized H20 (2 x 3η). The aqueous p-liquid was ethyl acetate (5me
RPS-F TLC after washing with
It was adsorbed onto the pre-adsorption layer of a plate (0.25 mm x 20 x 20 on). Plates were placed in 10% ethanol/in a cold room.
Developed with water (~) The ultraviolet and visible absorption bands of R40,26 were injected with acetonitrile-water 4:1 (5dX 4 times).The solution was diluted with deionized water (10'm),
The mixture was washed with hexane (10 ml x 4 times), concentrated under reduced pressure over approximately 1 hour, and lyophilized to give the product (1.7 mm, determined by ultraviolet absorption) as an amorphous powder.

UV (R20) λmax: 293nm (39)' LI N'MR (2110Mf1z, DpO)
δ: 1.29 (d, 3°J-6,4H2,C-
jl+c11), 3.12 (m, 2. CH2)-
:3.18 (S, 3. NCTl, ), 3.31
(S, 3. NCH3).

3.45 (dtl, 1. J-2,6 and 6.0H
z, H6), 4.01(S, 2.5CI421.4
．． 23 (m, 2.R5 and CH3CH).

(40) Example 8 (5R,6S)-2-(2-amino-2-methyloxycarbonylethylthio)-6”4 (R)-
1-Hydrobovine diethyl]-1-carbadethiapene-2-
Step A: 3-mercapto 2-(p-nitrobenzyloxycarbonylamino)propionic acid methyl ester. , 5.83 mmol) of NaHCO3 (1,40 f?) into a mixture of ether (125+nJ) and water (16 ml).

An aqueous solution (16 mg) of 16.7 mmol) was added. p
-ditropencyl chloroformate (1,39f, 6
．． 45 mmol) in ether (52 ml) was added dropwise to the vigorously stirred reaction mixture over a period of 1 hour.

After another 20 minutes, the two layers were separated and the ether layer was 0.2
'5N'.H (J!) followed by extraction with saturated Na (:l! solution). Each aqueous layer was backwashed with ether.

When the dyed ether layer is dehydrated, filtered, and concentrated, the crystalline residue is removed by Iiλ-1.When washed with ether, the product (
+, 55 f, 84.7%) was obtained.

Melting point 87-88° +Cl1r -l.

rn νmaXcm , 2540, 1745, 1690
°N M Rδ (CD C/3): 1.40 (t,
1)I.

J=9Hz, H8-), 3.03 (d d, 2H.

J=5 and 91h, 5CfTz ), 3.82 (
S.

3 If, C02CII3), 4.7 (1(m, I
H, N CH-CO2), 5.25 (S, 2H,
CH2-Ar).

5.8 (br, III, NH), 7.55 and 8,
25 (d each, 2" each + J = 8 Hz, aromatic proton) Step n: (5R,6s)-2-(2-(p-nitrobenzyloxycarbonylamino)ethylsulfonyl)
-6-1: (R)-1-Hydroxyedyl]-1-carbadethiapen-2-emu: 3-carboxylic acid p-nitropencyl ester Example 1 Step A carboxylic acid 59μ, 0.1 mmol) m- in a cold (0°) tetrahydrofuran solution (3-) of
Perbenzoic acid (44 μm, 0.22 mmol) was added and the mixture was stirred at O0 under N2 for 0.5 h and further Na2
After addition of HPO4 (35+V), the mixture was stirred at room temperature for 7 hours.

The reaction mixture was diluted with ethyl acetate, washed with 5% NaHCO3 and saturated Naα solution, dried with AIgS04, filtered,
Concentration gave the sulfone (79■) as a pale yellow oil. The crude product was used in the next step without further purification.

■Process C: (5R,6S)-2-(2-methoxycarbonyl-2-p-nitropenzyloxylponylaminoethylthio)-6-[(R)-1-hydroxyethyl]
-1-carbadethiapen-2-em-3-carboxylic acid p
-(5R,6s)-2-42-(p-nitrobenzyloxycarbonylamino)ethylsulfonyl)-6 of nitrobenzyl ester step B
-[(R)-1-human 1koxyethyl]-1-carbadecthiapen-2-em-; u-carboxylic acid p-nitrobenzyl ester (6i9Tng, 0.10 mmol) and the naol of Step A (33,5μ, 0.11 mmol)
A solution of diisopropylethylamine (12.9 mg, 0.10 mmol) in acetonitrile (0.5 m) was added to the stirred acetonitrile (3 td) and tetrahydrofuran (3 me) solution at -55 ° under argon, and the mixture was Stir for 10 min, cool in water and mix with 1-1 phosphate buffer (p+17) (:((1+ne)).

The extract was washed with phosphate buffer (3 + 1 + rre) and cold saturated Naα bath solution (30 mg).
I was dehydrated. Filtration, concentration in vacuo, followed by trituration with ether gave 33.8 cm (52%) of the product.

TRV A:, 12cm': 1775M5. m
ee: 644 (M+) 2nd step D: (5R,6S)-2-(2-amino-2-
methoxycarbonylethylthio)-6-[(R)-1-
[Hydroxyethyl]-1-carbadecethiapen-2-em-3-carboxylic acid (33, omy, 0.051 mmol) and 10% Pb/C (34) in dioxane (4,
1-), ethanol (3,4me), H20 (2,4me),
ml), 1 M-K2T(PO4(0.06ml
) The mixture was subjected to catalytic hydrogenation at room temperature and 4 atm for 1 hour. The reaction mixture was filtered and the catalyst was washed with a small amount of water. The filtrate and washings were collected, washed with ether (151 nt x 5), and the aqueous layer was lyophilized. Dissolve the residue in water, XAD-2
Column chromatography [(20X210mm),
The mixture was sequentially eluted with water and a 5% tetrahydrofuran bath solution. Fractions were detected by ultraviolet absorption.

The fractions eluted with 5% tetrahydrofuran solution were lyophilized to give the product (5.2 ml, 30%).

KBr 1: 1750 IRνmaxcm NMR (D20) δ: 1.25 (d, 3H, J-6
Hz, Cg H3), 3.1 3.3 (m+
3 H) +34, ;U 6 (nt, 2N),
3.82 (S, 3H.

C02CH3), 4.1, 4. +((m, 3H
) , 4.80 (u o D ) Example 9 (5R,68)-2-((2-amino-2-
Carbamoyl)ethylthio]-6-[(Ie)-1-hydroxyethyl]-1-Process A: 3-Mercapto-2
-(p-nitropenzyloxylponylamino)-propyN2 L-2-amino:woomercaptopropionamide hydrochloride 1 (47 (l) stirred at 0'C
■, : mmol) of ether (80 ml) and Tl2
NaHCO3 (756■, 9
mmol) of H20 solution (s mt ) was added. An ether solution (20 ml) of p-nitrobenzyl chloroformate (711 mmol) was added dropwise over 1 hour to the reaction mixture which was being vigorously stirred at room temperature.

Next, add tetrahydrofuran (2 (l ml)),
The mixture was stirred for 30 minutes. The organic solvent layer was completely separated, and the aqueous layer was extracted with ethyl acetate. The collected organic solvent layer was 0.25N
Washed with HC/, then saturated NaCl solution-C. The extract was dehydrated (Na25O4) and concentrated under reduced pressure. Knead the residue with ether to obtain the product as a powder (56511!, 70%)
was obtained and used in the next reaction without further purification.

T. N. Martin et al., J. Med. Chem, Vol. 10, 1172.
Page (1967) KBr-1・IR, Vmaxcm, 1690.166ONMR
δ(DMS O-d,): 2.75-2.95(m,
2 H,5CI(2) ,4.05 4.25 (m
.

I H, 5CH2Cl), 5.26 (S, 2H,
CH2Ar), 7.2o and 7.52 (each Dry, each 2H, CONH2),' 7.67 and 8.30
(Each d.

2H, J=9Hz each, 4 aromatic protons) Step B
: (5R,68)-2-[(2-carbamoyl-2-
p-Nitropenzyloxy(luponylamino)ethylthio)-6-4(R)-1-hydroxyethyl]-1-carbadethiapen-2-em-3-carboxylic acid p-nitropencyl ester N2 Stir at -10° below Example 8 Step B sulfone ((i 2119.0.1 mmol)) in acetonitrile (3 ml) and tetrahydrofuran (2 ml)
The thiol from Step A (30 µ, 0.11 mmol) and diisopropylethylamine (13 µ, 0.10 mmol) were added to the solution, and stirring was continued at the same temperature for 1 hour. Ethyl acetate was added to the reaction mixture and the ethyl acetate layer was washed with pH 7 phosphate buffer and then saturated Naα solution.

The extract was dehydrated (Ama 804) and then concentrated under reduced pressure. The syrupy residue was needled and washed with ethyl acetate to give the product (23 mg, 30Y).

KRr −+・TRVmaxcm, 1775, 1720, 1680°NMRδ (DMSO-da): 1. I 4 (d.

:(r(, J = 1i Hz, CH3), 3.9
0 4.05(m, I II, -CIf N R
), 4.10-4.30 (m, 2H, C5H and C
3-H), 5.22(S, 2H,0CH2Ar
), 5.32 and 5.48 (each d, each I H, J
= 15 Hz, OCH2Ar) MS, mle:
629 (M+).

■Process C: (5R,68)-2-C(2-amino-2-
Ester of step B (43q)
v dioxane (6g), ethanol (0,5 m), deionized water (3,5 mg), IM K2HPO4 (0
, 1 ml) and 10% pb/c (solq) was subjected to catalytic hydrogenation at room temperature and 4 atm for 1 hour. After cooling the reaction mixture to below 5°, the catalyst was filtered off and deionized water (3
11dX3 times). The separated aqueous layer was washed with ether (10 dXS times). Lyophilization of the aqueous layer yielded a yellow powder, which was subjected to XAD-2 column chromatography (20X50
0■), the product (10q, 45%) becomes ■! II
I'm tired.

TIL V""cut': 1760. 16
70. 1600ax IJ V λ”Onm : 297 aX N M It δ(2(10M H7, containing internal standard 1)20 ) : 1.28 (d , 3H,
J=6Hz.

C113), 2. ! 1-: 381 m, 4
H, CIH2 and -sc2), 3.42 (77
+1 1 H+ Ca-1f), :(,74(t, IH
, J=6Hz, 5CII'2 C,QN -) , □
1.1/I-4,31(m, 2H.

C5-,II and C,II), 4.8(1(HDO)
.

11 real examples + 11 (5R, fis) -2-, (2-amidanotylthio)-6-r: (R)'-hydro+cyenalthio]-1-carbade'thiapen-2-em-:
U-carboxylic acid 41i4 A: 2 (Tl-nitropenyloxycar-1-nyl)amylafuthanethiol 4-enal-2-deacylidinethione (500ml.:
A 111-X compound of 4 mm chloride and 20% Hα(lOmZ) was heated at 165° for 15 hours in a 1R blue seal, and the reaction mixture was washed with chloroform and concentrated under reduced pressure to give 2-aminobutanaol hydrochloride. The salt was given as a yellow solid and used in the reaction without further purification. In a stirred mixture of 2-aminobutanethiol hydrochloride (440 mg, 3.13 mmol), ether (80 ml) and water (15+f) of NaHCO3 (790 mg) in water (1
5rnl) solution was added at 0°. Remove the water bath and add p-nitropenzyloxytriponyl chloride (740 μm, 343 mmol) to the vigorously stirred reaction mixture.
A dehydrated ether solution (30ml) was added over 1 hour. After another 20 minutes, the two layers were separated, and the organic bath layer was washed with 0.25NHα and saturated saline, and the organic bath layer was washed with MgSO
4 and concentrated under reduced pressure to give a semi-solid residue, which was purified by preparative 'I' LC (chloroform) to produce thiol products (23 (1-, 26 crabs) as colorless solids,
A melting point of 58-61° was obtained.

"Br-1: 1690, 1600, 1510゜IR
νmax cm 1340° (51) N M Rδ (CI) (7!3): 0.96 (
t, 3H.

J = 8 frZ, -CH□C 3), 1.30
(,t,IH.

, j=8 l(z, -5T-r), 1.58 (
m, -CH2C11+(), 2.7 5 1 dd
, , 2H9J = 5 and 8 Hz.

5CII2) , 3.76 (m, I H, CHN −)
.

-1,! 15 (m, III, -NH), 5.24
(S.

2 If, --CjT2Ar), 7.55 and 8.27 (each d, each 2 jl, , T=9 H
z, aromatic proton) MS, w/e: 28/I (M+, 10 (1%)
.

X'l-le-he-clap (L, R, C1a, p
p) and Hsieh-Goubru-Watzien (J, W
,Wat,ien),,J,A,m,CI
+em, Soc, , Volume 7 F2, i4.90° (1st year 1953).

Step +1: (5R,6S) 2 (2p-21/[1pencyloxycarponylaminobutylnao) -+i-
(, (rt) 1-hydroxyethyl) -, -1-
Example 1 (5
2) Step B sulfoxide (120 mmol, 0.2 mmol) was added to tetrahydrofuran (4 ml), CH3CN (3 m7
dimethyl sulfoxide (01-) cold solution (-40°
), the thiol from Step A (99 Tng, 0.35 mmol) and diisopropylethylamine (02M acetonitrile solution: 1.95 ml, 0.39 mmol) were added in small amounts. The reaction mixture was diluted with ethyl acetate, washed with phosphate buffer (pH, 7) and saturated saline, and homogenized in SO4.
After dehydration and concentration under reduced pressure, a pale yellow oil was obtained. When the oily product is triturated with ether, a colorless solid product (88■, 7
2%) was obtained.

Melting point 1j5-. 155°IRνKB"cm': 1770.1710 (shoulder).

aX 69O NMRδ (CD0g): 0.98 (t, 3T(
.

J=8Hz, -CH2CH3), 1.38 (d
, 3H.

J-7Hz + Cg H3) + L5 1.9
(77+ 1-CH2CH3), 2.85-3. ．．
60 (, m, 5 H, C+.

1” + CI2!!) + 4.25 (m+
2 H+ C5-I1 and (J:CB-!(), 5
．． 25 (S, 2H, -C 2C+: 11.+N1)
2I+)+! i, 27. 5.55 (AB-q
.

2 Ll, J == l /Illz, -C
See 2 C6'H4NO2P) +7.55.8.2
Fi (each d, Taniya 2H, J = 9tlz, Yoshizai: Group 1'' tons 4 pieces), 7.7, 8.26 (each d, each 2
H, J = 9 Hz, 4 aromatic protons) MS, mlc () I l (M, 1 n 0%
)2 "Undesired C: (5R, 6S) -2-(2-aminophonalthio)-6-[(R) -1-hydroxyenal]-1-carbadithiapen-2-enynisdel of culm B (30■, 0.0488mm monol hot TIKF
(5Me), EtOH (2rnl).

rr20 (2ml!), dioxane (0.5me
) and 0, j M IVIOPs buffer lf* (+
) II 7.1, 2 ml) pto,
Catalytic hydrogenation was carried out in the presence of (a o r〃g) at room temperature and atmospheric pressure for 15 hours.

The catalyst was filtered 12 times, washed with cold H20, the collected aqueous layer was washed with cold ether, briefly concentrated under reduced pressure to remove the remaining organic solvent, and washed with Hz0 and 5% tetrahydrofuran solution. It was subjected to column chromatography with XAD-2 eluted in sequence. Continuous ultraviolet absorption (maximum 29
The product was fractionated with detection at 7 mm) and the collected fractions were lyophilized to obtain the product (55 μm, 37.6%).

KBr −r・IRνmaXcm, 176O NMRδ(P2O): 0.94, 0.95 (one pair of t
', 3 H, J = 8 Hz, -CH2CH3
, DL-mixture origin), 1.22 (d, 3H, J=7
Hz, C9H3), 1.71 (m, 2H, -C2C
T(3), 2.8-3.05 (m, 2 H, c, □
-H).

3.1-3.4 (m, 4 H, C, -T (2, q and CII -H2), 3.37 (d d, I H,
J = 4 and 7 Hz.

Cs H), 4.18 (m, 2H,, Cs H and C
8-■).

Examples] 1 (5R,68)-2-((2-amino-
1-carbamoyl)-ethylthio]-6-((R) -
+ 7-Hydroxienal]-1-Carbadithiapene-
2-M-3-carboxylic acid ■ Culm A:; 2-promol of 3-amino-2-(p-methoxybenzylthio)propionic acid; 3-aminopropionic acid hydrobromide'
(750 mg, 3 mmol) of H20 i & (1,2
II+/) in an IN-NaOH solution (3+++l
) and neutralized with p-methoxybenzyl-mercaptan ('I6 (1 mg, 3 mmol) and Na01
A H20 solution (187 ηe) of 1 (24 (l ff 1 g, 6 mol)) was added at room temperature with constant stirring.

After 17 hours, 4'l'',!I'l: Add 1 hembin to the reaction mixture and dilute the aqueous layer for the entirety of the aqueous layer. The precipitate was collected to give the product (1 to 55.3 cells).

NMRδ (fl, 2 NNa 01) ):, 2.
70-3.00 (tn, 2H, CH2), 3
．． 2f5 (t, IH, J=6 Llz, CI), 3
．． 8.0 (S, jH.

5CII2Ar) , :(,86(S, 3H,O
CH3・).

6.97 and 736 (each d, each 2H2J-9Hz
, 4 aromatic protons) A, 5chobere and H, Braur, Ann
, Vol. 542, p. 274 (1939) ■Procedure B: 3-p-nitrobenzyloxycarbonylamino-2=p-methoxypencyl-3-amino-2-
(p-methoxybenzylthio)propionic acid (680■
, 283 mmol), acetonitrile (20rnI,
H20 (10-), Na HCO3 (5'7 oy
An acetonitrile bath solution (2 ml!) of p-nitropenzyloxytriponyl chloride (61 (HM'+ 2.83 mmol)) was added dropwise to a stirring mixture of p-nitropenzyloxytriponylchloride (61 (HM'+ 2.83 mmol)) at O-5°. 1. After stirring for 30 minutes,
Ether and water were added to the reaction mixture. The separated aqueous layer was acidified with 0.5N Hα and extracted with ethyl acetate. The extract was washed with saturated brine, dried over Na2SO4, and concentrated. The residue is triturated with isopropyl ether to give the product (84
0 Ki, 71%).

NMRδ(CD(1/3): 3.30-3.70(
m, 3TT, 0C113), 3.85 (S, 2H.

5CH2Ar ), 5.16 (S, 2H,0CH
2Ar), 5.4(1-5,63(m, IH, NH).

6.82 and 7.25 (d each, 2H each, J=9H
z, 4 aromatic protons), 7.45 and 8.15 (
d each, 2H each, J=9Hz, 4 aromatic protons)
.

Step C: :3- p-Nitrobenzyloxycarbonylamino-2-p-methoxybenzylthiopropionate methylnisder 3-p-nitrobenzyloxycarbonylamino-2-
p-methoxybenzylthiopropion N! <420■,
1 mmol) and acetyl chloride (1 (l O■, 1.1 mmol) in dehydrated tetrahydrofuran solution (5 m/) i-
While stirring at 1o°, triethylamine (]001!
l! .

1 mmol) was added. After stirring at 50° for 30 minutes, methanol was added to the reaction mixture and concentrated.

The residue was dissolved in ethyl acetate, washed at Hz0, dried over Na804, and concentrated to give a quantitative product.

NMRδ (CDαa): 3.30-3.65 (m, 3
H), 3.73 and 3.76 (S.

3H, OCH3 and C02CH3), 3.80(
S, 2H,5CH2Ar), 5.16 (S, 2
H,0CH2Ar), 6.82.7.25.7.4
5 and 8.15 (d each, 2H each, J=9Hz.

(8 aromatic protons) Step D: 3-p-Nitrobenzyloxycarbonylamino-2-p-methoxybenzylthiopropionamide Step C ester (434 μ, 1 mmol) Tetrahydrofuran (S-), ammonium hydroxide (t Om/
), a mixture of methanol (lod) e40-50°
The mixture was stirred for 17 hours.

The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over Na 2 So 4 and concentrated. The residue was subjected to chromatography on silica gel (10 liters) using chloroform-methanol (98:2 V/V) to obtain the product (180119°/I3!6) as a powder, each point 1/13.
It turned out to be -145°.

NMRδ(co(l!3-nMso-c+s): 3,
:(5-3,6(1(m, 3H), 3.76
(S.

Ko()I, 0CII3), 3.78 (S, 2H
, 5CH2Ar), 5.211 (S, 2H, 0CH
2Ar).

6.56 (brs, 2H, NH2), 7.03 (hr
S, l Tl, N1f), 6.81, 7.25°754 and 8.17 (each d, each 2H, J=911z
, 8 aromatic protons) Engineering 4￥E: : (-p-nitrobenzyloxycarbonylamino-2-mercaptopropiolea 1: Moderate propionamide (3009° (1,72 mmol), anisole (227 capes).

2.1 mmol), a mixture of trifluoroacetic acid (S-)'
Proboscis h: Hetrifluoromethanesulfonic acid (5 drops) was added while stirring under room temperature.

After 30 minutes, ethyl acetate and water were added to the reaction mixture, and the separated organic solvent layer was washed with NILHCO31'# solution and saturated brine, dried over Na2SO4, and concentrated. When the residue was kneaded with tetrahydrofuran-needle, a product (190
, 88%) was obtained.

NMRδ (CDα3-DMSO-do): 3.30-3
．． 60 (m, 3H), 5.20 (S.

2H,0CH2Ar), 6.96 (brs, IH
).

7.45' (brs, 2H), 7.57 and 8.22 (
d each, 2H each, J=9Hz, 4 aromatic protons)
.

Step F: (5R,6S)-2-(1-carbamoyl-
2-p-nitrobenzyloxycarbonylaminoethylthio)-6-(: (R)-1-hydroxyethyl]-
1-Rubadethiaben-2-em-3-carboxylic acid p-
Nitrobenzyl Ester The sulfoxide of Example 1, Step H (150 mm, 0.25 milliliters) was stirred at -50 degrees under argon, and the thiol of -50 degrees Celsius (150 wIf).

05 mmol) of detrahydrofuran (8-), acetonitrile (Hme), dimethyl sulfoxide ((1
, 5we) '#i/ffl was treated with diisopropylethylamine (:43 Ml, (1.25 mmol)) in an acetonitrile bath (+ me) for 1 night (+me). At the same temperature; after stirring for -SO minutes, Dilute the mixture with ethyl acetate, 0, FiNIF (Z and wash with water, Na2
Dehydrated with SO4 and condensed (7).Residue HPLC
The product (1:(0+J#, 83%)
was gotten.

K11r −+ ・TRνmaXcm, 1775, 1710°168
O N M It δ(CDrZ3) : 1.32 (d
, 3H.

J=6)1z, C113), 3.18-3.
75 (m.

51■), 3.98 4.38 (tn, 3H)
, 5.23 (S, 211,0CH2Ar), 5.26
and 555 (each d, 211.J=15Hz, 0CH
2Ar).

6.2 (1-6, 60 (m, 3H), 7.55 and 771 (each d, each 211.J = 9 Hz, 4 aromatic protons), 8.25 (d, 4H, J = 9 Hz) ,
(4 aromatic protons) HPLC: Column: Microbond Pack 〇 1g (μ
mBondapak C+s) l Solvent: MeCN
-H20 (1: l V/V), flow rate: 3 m 11 min.

Holding time: 8.5 minutes Step G: (5R,68)-2-((2-amino-1-
carbamoyl)ethylthio)-6-((Ril-hydroxyethyl)-1-ester of step F (130,0
．． 21 mmol), pto, (13otIIg), dioxane (13m/), ethanol (1.3ml), H
z0 (10 go), I M K 2 HP O4 (0,2
The mixture of 2-) was subjected to catalytic hydrogenation at room temperature at 4 atm for 2 hours, and then cooled to below 5°. Remove catalyst by filtration Hz
Washed with 0. The filtrate and washing liquid were collected, washed with ether, and concentrated under reduced pressure. The resulting aqueous residue was subjected to Diaion (I) TTP-20 column chromatography (20×200 mm) with continuous ultraviolet absorption detection and elution with water and 5% tetrahydrofuran.

Lyophilization of the fraction eluted with water yields the product (251#
I7+: 8%) was obtained.

1(Br': 1760, 1680°I Tt νl1laX c7n +5410c@' II V λmax (r120): 293 nm
NMRδ(D20): 1.27 (d, 3H.

J = 611z, C113), 3. , I 0
3.80 (m.

5 H), 4. (1(1-4,10(7M, IH),
4.18-4.3 (1(m, 2H), 4.80
(HDO).

Example 12 (5R,6S)-2-(2-amino-1-
Carboxy)ethylthio-6-[(R)-1-hydroxyethyl]-1-carbadeche 8A: 3-(p-nitrobenzyloxycarbonyl7mino)-2-(p-methoxybenzylthio)propionic acid p-nitrobeso Dyl ester Example 111 Nizo ii A acid (946, 4 mmol), acetonitrile (30 ml), water (2-), N
A mixture of aHCO3 (840”f, 10 mmol) was added to 0
A solution of p-nitropenzyloxytriponyl chloride (8621 ng, 4 mmol) in acetonitrile (5-) was added dropwise to the mixture while stirring at -5°. After stirring for 30 minutes,
Ether and water were added to the reaction mixture. The separated aqueous layer was acidified with 0.5 N Hα and extracted with ethyl acetate.

The extract was washed with saturated brine, dehydrated with Na2S04, and concentrated under reduced pressure. A gummy residue, p-nitrobenzyl bromide (864 mm, 4 mmol), triethylamine (400 mmol),
■.

4 mmol) was dissolved in ethyl acetate (30 m/m), and the mixture was heated under reflux for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water. The separated organic solvent layer is Na 2 S
Dehydrated with O4 and concentrated under reduced pressure. The residue was chromatographed on silica gel (40f) using chloroform,
The raw material (2,13r, 96%) was given as an oil.

NMRδ (CDC13): 3.50 3.70
(m.

3 II), 3.76 (S, 3H, OCH3)
, 3BO(S, 211.5CTf2Ar), 5
．． 17 and 526 (each S, each 2 f (, OCHz
Ar x 2 pieces).

682 and 7.21 (respectively d, valley 2H, J=9Llz
, aromatic powder (4 pieces per ton), 7.47.

7.41, 8.16 and 8.20 (each d, each 2H
.
'2.1? , 3.78 mmol), anisole (
1,2+/, III mol), trifluoroacetic acid (7 m
Stir the mixture of e) at room temperature.
'IJII did it. After stirring for 30 minutes, ethyl acetate and H20f were added to the reaction mixture, and the organic solvent layer was separated. minutes! i+ll I~ The organic solvent layer was washed with NaI (CO3 solution and saturated saline, dehydrated with Na2SO4, and dehydrated with E□
, contraction 1-. The resulting residue was chromatographed on silica gel (120P) using chloroform to yield the product (1.6f).

97%) was obtained.

NMRδ (CDα3): 2.13 (d, IH.

J = 9 Hz, SH), 3.50-3.86
(n.

3H), 5.22 and 5.30 (S each, 2H each, O
CH2Ar X 2. □ pieces), 7.50, 7.55°8.20 and 823 (each d, each 2H, J=9 Hz
, 8 aromatic protons) Step C: (5R96S)-2-(1-p-nitrobenzyloxycarbony, 2-p-nitrobenzyloxycarbonylaminoethylthio i64m(R)-1-hydro-main diethyl ]-1-carbadethiapene-2-M-3
-carboxylic acid p-nitropencyl ester Example 1 sulfoxide Nsomy of step B, o3 mmol), thiol of step B (26
0 mg, 0.6 mmol) of tetrahydrofuran (1
(1me), acetonitrile (10mA), dimethylsulfonate (0,57111!) solution Rk was added diisopropylethylamine (40mf, 0.3mmol) in acetonitrile (Ime). After stirring at the same temperature for 20 minutes, the mixture was diluted with ethyl acetate and then 1/(
, (washed with 1,5N IT C,l and water, Na2SO4
It was dehydrated and reduced to 1/M. The residue is purified by FrPT,C to produce the product (+7 (1〃1@, 7/
I%) was obtained.

[+r−+− T Rν. 4. lX 17501.1720゜6m N M Rδ(CI)C61): 1.36 (d,
3I(.

J = 6 IIZ, CII3), 3.00-3.
83 (m.

5 sr ), 4.1 (1-/I30 (m, 3H
), 5.23 and 5.2 [1 (Tani S, respectively 2H, 0
CH2Ar x 2), 537 and 5.56 (d, 2 respectively)
H.

J=15Hz, 1) CH2Ar ), 7.52 (d
, 4T (, J = 911z, ′) 1 apricot 4 protons), 7, 68 (d, 2 If, J =
9Hz, aromatic proton 2 flail), 8.
24 (d, 6 H, J = 9 Hz.

1) lJ-r group proton (ii solid) II l” L C: Column; Micro Honda Pack-CB (/l-1(on+1apakcB) (7,8X
300 coral), solvent: Me CN Hz 0 (3:
2 v/v), flow rate: 3 m 11 minutes, retention time: 122 minutes Step D: Ri(5R,6S)-2-(2-amino-1-carboxy)ethylthio-6-C(R)-1- Hydroxyethyl io 1-carbadethiapen-2-em-3-carboxylic acid Step C ester (170 mg + 0.22 mmol)
, ptO2 (20omg), dioxane (17ml), ethanol (1,7ml), Hz0 (12m/), I
A mixture of M K2HP 04 (0.23 me ) was subjected to catalytic hydrogenation at room temperature and 4 atm for 1.5 hours, and then cooled to below 5°. The catalyst was filtered off and washed with water. The collected filtrate and washing liquid were washed with ether and concentrated under reduced pressure. The resulting aqueous residue was subjected to Diaion HP-20 column chromatography (20×250 mm) using continuous ultraviolet inhalation detection and Hz0. The desired product eluted at Hz 0, the presence of the product in aqueous solution led to an ultraviolet absorption maximum at 296 nm (NH2O
However, it was not possible to supplant and dry 1.2 without decomposing a considerable amount.

Example 1 Co3(5R,6S) -2-[1-Aminomethyl-2-(imidazol-1-yl)ethylthio]-
AM-imidazole-1-
yl-2-1-chloro-2-hydroxy-3-phthalimidoylpropane''+ (9,59f, 0.04 mol)
and imidazole (20.4f, 0.3 mol) was heated with stirring at 100° for 2 hours.

After heating at 110-115° for 6 hours without further stirring, the reaction mixture was cooled and diluted with water. I41
The precipitate is collected by filtration and dried to produce the product ((i,
939, 63.9%) was obtained as a powder.

Melting point 205-208゜KBr - Lid IRνmaXcm, 3450,3] 1 0゜(OH
):] 760. ] 700 (C-(1)NMRδ
(DMSO-b6)': 3.4-3.7(m, 2H
, -CH2-phthalimide).

4.0 (m, 3H, CHCH2-imidazole), 6
．． 84, 7.15 and 757 (each S.

IH, imidazole ring proton), 7.84 (s,
4H, phthalimide ring proton) Chess Gabriel (
S., Gabriel) et al., Ber.

Vol. 50, p. 822 (1971) Step B: 1-imidazol-1-yl-2-hydroxy-3-(p-nitrobenzyloxyphthalimidoylpropane of Step A (350 μ, 13 mmol) and 20 Hα
The mixture was heated to reflux for 4 hours and cooled. The obtained crystals were filtered and washed with water. The filtrate and washings were combined and concentrated to give an oily residue. Oily residue, H20 (15rn!
), NaHCO3'(1,51).

Cold mixture of acetone trile (10yd) (2-; 3°)
Hep-nitrobenzyloxycarbonyl chloride (36
4-, 1.3X], 3 mmol) of acetonitrile bath was added and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated and extracted with a 1" Roborum. The organic solvent layer was washed with water, dehydrated with Na2S04, and concentrated to give an oily residue, which was diluted with chloroform-ethanol (9:
IV/V) on silica gel (10f). When the solvent is removed, the solid is f8t,
Recrystallization from chloroform-ether gave the product (18
1 to 435π) were obtained as crystals.

KBr −+・ T　RνmaXcm　, 3280 (OH).

1720 (C=0) N　M　Rδ(DMso-as):　3.0　<m.

2IT, -CH2-NH'-CO-), 3.7-4.0
(m, :3 If, -CH(OH)-CH2-imidazole), 5.16 (S, 3H, CH2-o CO
-N n -), 6.85, 7.15 and 7.5 (each brs, each IH, imidazole ring proton), 7.
58 and 8.22 (d, 21 ■ each.

J = 9 Hz, -C6H4-p -N 02 )
.

Step C: 1-Imidazol-1-yl-2-p-toluenesulfonyloxy-3-(p-nitrobenzyloxycarbonylamino)propane Step B imidazolylpropane (48 mf.

015 mmol), 4-dimethylaminopyridine (28
■, O,]5X1.5 mmol), methylene chloride (4t
nl), p' toluenesulfonyl chloride (4
0■, 0. ]5X], 4 mmol) at room temperature.
Stir for hours. Furthermore, 4-dimethylaminopyridine (7
1, 0.057 mmol) and p-toluenesulfonyl chloride (10 , 0.053 mmol) were added to the reaction mixture and stirring was continued for a further 20 hours at room temperature. After removing the solvent, the resulting residue was chromatographed on silica gel (51) using chloroform and chloroform-ethanol (19: IV/V). The fraction eluted with chloroform-ethanol (1≦) was concentrated to give the product (57-80%) as a colorless oil.

NMRδ (CI) αa): 2.42 (S, 3H.

CI■3), 3.2-:(,6(m, 2 H, PNZ
-IIN-C1rz), 4Al -4,2(m, 2
H, -CIT2-imidazole), 4.6-5.0 (m
.

I)1, -CII-0-Ts), 5.1
4 (S.

2N, -CH2QCO-), 5.85(t, III
, J = 6Hz, -NTT-CO), 6.7
7 and (i, 92 (S, imidazole protons at IH, C4 and C5 positions, respectively), 7.1-7.67 (m.

7 II, CII:I C61r4 S 02-,
-C6H4-NO2 ortho proton, imidazole proton at position 02), 8.19 (d, 2H, J-〇
) fz , -C6114-N 02 meta position proton)
.

Two [rods]: 1-imidazol-1-yl-2-(p-
Toluenesulfonyl (methoxybenzylthio)-3-(p-nitrobenzyloxycarbonylamino)purargon in lower step C, t-t-cypropane (475 µ, 1 mmol), p-methoxybenzylmercaptan (351 µ).

Add diazabicycloundecene (3.28 mmol) to a stirring solution (8 ml) in chloroform at room temperature.
04#IF, 2 mmol) in a chloroform bath solution (2 mg
) was added. The mixture was heated to reflux for 4 hours and cooled. The reaction mixture was washed with water, dried over Na2SO4 and concentrated to give a residue which was chromatographed on silica gel (15r) with chloroform and chloroform-ethanol (19: ] V/V). The fractions eluted with chloroform-ethanol (19:1) were concentrated to give the product (386W, 84.6%) as an oil.

NMRδ (CDαa): 3.2 3.4 (m.

2 H, P N Z HN CH2), 3.4 3.
6(m, 2HISCH2-Ar), 3.73
(S, 3H, 0CH3), 3.9-4.2 (m.

3H, -8-CH-CH2-imidazole), 5.1
5 (S, 2 II, -0CH2-Ar), 6.05
(t, l II, J=6) rz, N) 1), 6.7-7
．． 7 (m, 9] 1.C604-OCH3, imidazole and p-21~low〇6H4- meta position proton),)
! , 12 (d, 2H, J=9Hz, p-nitro-C6
Step E: 1-imidazol-1-yl-2-mercapto-3-(p-nitrobenzyloxycarbonylamino)propane [Step I) product (393'mg, 0.86 mmol) , anisole (279++y, 0.96X3 mmol), trifluoroacetic acid (7 ml), trifluoromethanesulfonic acid (10 drops, approx. 250 ~) at room temperature.
The mixture was stirred for 0 minutes and cooled in a water bath. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic solvent layer was washed with water and N
Drying over a2SO4 and concentration gave a residue which was subjected to chromatography on silica gel (+5f). The fraction eluted with chloroform-ethanol (19: ] V/V) was concentrated to yield the product (220 μ, 76%).
was obtained as an oil.

NMRδ (CDCl, 3): 3.2 3.7 (m
.

3H, PNZ-NH-CH2-CH-8H).

4.05-4.3 (m, 2H, -CH2-imidazole), 5.22 (S, 2H, -0CH2-Ar),
6.03 (br, LH, NH), 7.04 (m, 2H
, imidazole ring protons at C4 and C5 positions), 7.
3 7.7 (m, 3H, imidazole ring proton at C2 position and proton at meta position of p-NO2-C6H4-),
8.20 (d.

2 H, J = 9 Hz, p N O2C6H4
- ortho-position proton) Step F: (5R,6S)-2-[:2- (imidazol-1-yl)-1-(p-nitrobenzyloxycarbonylaminomethyl)ethylthio]-6-((R) −
1-Hydroxyethyl]-1-carbadethiapene-2-
Em-3-carboxylic acid p-nitrobenzyl ester Stirring under argon -40'--50' Example 1 Work vl! Mouth Sulho Beef Shito (181■.

()3 mmol) of acetonitrile (9-), tetrahydrofuran (9 ml), dimethyl sulfoxide (0
, 6me ) solution of the thiol of step E (2(12+9.
0.6 mmol) dissolved in tetrahydrofuran (3me
) and diisopropylethylamine (39~, 0.3
A solution of 1 mmol) in tetrahydrofuran (1 me) was added continuously.

After stirring for 25 minutes, the reaction mixture was diluted with ethyl acetate, IM
K r (21) o4, saturated saline, 1/15 M phosphate buffer (+) II 7. Wash in sequence with (1), Na
Dehydrated with 2SO4. Removal of the solvent gave an oily residue, which was mixed with benzene-acetone (1:lV/V), acetone, chloroform-methanol (9°I V/V).
) was subjected to silica gel (5IiI) chromatography. The fractions eluted with chloroform-methanol (9:1) were concentrated to give an oil. Remaining lh
The product (28) was obtained as a powder by kneading it with an isopropyl needle. The residue obtained by concentrating the fraction washed out with acetone was purified by rechromatography on the above-mentioned silica gel (5v) to obtain the product (94 tq).

Yield 1221 g (61!
DCla): 1.33 (d, 3H.

J = 6 Hz', CH3), 2.8-4.6 (m,
approximately 10H), 5.24 (S, 2H, -0CH2Ar
).

5.4 (q, 2H, J=14 Hz, -CH2Ar
).

7.0-7.9 (m, about 7H, imidazole and 4 aromatic protons), 8.26 (d, 4)I.

J = 9 Hz, 4 aromatic protons).

Step a: (5R,6S)-2-[1-aminomethyl-
2-(imidazol-1-yl)ethylthio)-6-[
(R11-Hydroxyethyl)-1'-rubadethiapen-2-em ester of Step F (120 my, 0.1
8 mmol), dioxane (14 m), ethanol (1
,4m), H,O(xly), IM- to 2HP O4
(0,2tne) and Pt02 (120v) was subjected to catalytic hydrogenation at room temperature at 4 atm for 2 hours, and then cooled to below 5°. The catalyst was removed by filtration and washed with cold water. The collected filtrate and washing liquid were washed with ether and concentrated under reduced pressure. The resulting aqueous residue lh (approximately 17 kg) was subjected to Djaion Hp-20 column chromatography (60 m/) using water and 5π tetrahydrofuran with continuous ultraviolet absorption detection.

The fractions eluted with 5% tetrahydrofuran were lyophilized to give the product (18y, 28%) as a pale yellow powder.

IR '4 cm': 1760 UV　λ　(Hz0): 296nm ax NMRδ (D20): 1.2:1i (d, 3H.

J=6Hz, CH3), 2.1-3.8 (m, 5
H), 3.8-4.3 (m, 3H), 4.3-4
．． 6 (m.

21 (, -CH2-imidazole), 7.07 and 7
, 10 (each S, each %■, imidazole), 7.2
6 and 7.30 (each S, each %H, imidazole),
7.83 and 7.88 (each S, each 'H, imidazole).

Example 14 (5R,6S)-2-[2-amino-2-
(thiazol-4-yl)ethylthio]-6-((R1
1-Hydroxyethynoly 1-carbathiapen-2-em-3-cal Step A: 2-p-nitrobenzyloxycarbonylamino-2-(thiazole-4-inoalvone 2-p-nitrobenzyloxycarbonylamino-
IdBH4 (64, 2.95 mmol) was added to a stirring tetrahydrofuran solution (10 m) of the benzyl ester of 2-(thiazol-4-yl)ethanethiol <26011F, 0.59 mmol) at room temperature. .

After stirring for 1 hour, the mixture was diluted with water and placed in an ice-water bath.
．． The mixture was made acidic with 5 N Hα, and the organic solvent layer was concentrated under reduced pressure. The separated oily layer was extracted with ethyl acetate, and the organic solvent layer was washed with water, dried over M2SO4, and concentrated. The residue is on the website
Purification by LC gave the product (78 l, 39%) with an oil (44).

N IVI it δ (CDCe3): 1.27
(t, IH.

J = 811z, 5IT), 2.8-3.4 (m,
2 H.

Cl12s H), 5Al5.4 (m, I H,
CH-), 5.24, (s, 2H, C00CH2Ar
), 5.95 (d, I Tl, J=9 Hz,
NH'), 7.27 ((1, l H, J=2Hz,
f-azole 5-TI), 7.5.1 (d,
2 H, J = 9 Hz.

aromatic proton), 8.22 (d, 2H, J=9 T
(z, C1. aromatic proton), 8.81 (d, IH,
,,I = 2 Ilz, Thiasole 2-H)HI)
T, C column - Nucleosil
)5 Cl820mmX 30cm Solvent=CH3C1N:Hz0(3:1)l#i, Speed=
6. Oml 1 minute retention time - 188 minutes = 47 B: (511, 6S) -2-C2-
p -nitrobenzyloxycarbonylamino-2-(
thiazol-4-yl)ethylthio]-6-[1R11
Example 1 The sulfoxide of Step B (69 mg, .0.12 mmol) and the sulfoxide of Step A with stirring at -50° under argon Thiol (7s my, 0.23 mmol) in acetonitrile (3me), tetrahydrofuran (
31n! ), a solution of diisopropylethylamine in THF (0.5 rnl) and acetonitrile (0.5 ml) was added to a solution of dimethyl sulfoxide (5 drops). The mixture was stirred at the same temperature for 15 minutes and diluted with ethyl acetate. Wash the diluted mixture with 9.5NHα and water, M9SO.

It was dehydrated and concentrated. The residue was purified by HPLC to give the product (57cm, 74%) as a colorless powder.

IRνmaXcm, 1770. ] 725°171
O NMRδ (CDαg): 1.37 (d, 3H.

J = li Irz, , C, )-13), 3.0
-3.6 (m, 5 H.

21+-Hz and 6-H), 4.1-4.4 (y
y+, 2 H, 5-H and 8-■),! 5.0-52
(m,, I H, CH-), 52. s('s, 2H,”
COOCHz Ar), 5.39. , (ABq, 2
H.

J=I411z, 1:(')OCH2Ar),
5.90 (d.

0.5 tr, J = 81 (z, NH), 5.94
(d, 05Ii, J = 8 Hz, '+N
H, ), 7. ．． 30'(S, IH.

Thiazole 5-H), 7.53 (d, 2H, J=
Hz, aromatic proton), 7.67 (d.

2 If', J = 9frz, aromatic proton)
, '13.25 (d, 2 If, J=9 Hz,
aromatic proton), 8.27 < d, 21-1.
．． 1 = 9 Hz, aromatic proton), 8.85 (S
, IH, thiazole 2-II) If PLC: column-nucleosil (Nucle
osil)5C,1,82,0,amX:30
crn solvent-CH5CN-Hz0 (3:1) flow =
, 6.0 me/se.

1st If time [sui, 719 minutes].

Step C: (5R,68)-2-[2-amino-2-(
thiazol-4-yl)-ethylthio]-6-[, (R
il-hydroxyethynolyl-carpathethyapene-
Ester of 2-M-3-carboxylic acid Step B (50 mg, 0.075 mmol), P
t02 (40~), dioxane (5-), water (3),
Ethanol (0.5 td), IM K 2 HP
A mixture of O4 (0.1 ml) was subjected to catalytic hydrogenation at room temperature and 4 atm for 1.5 hours. The catalyst was filtered off and washed with cold water. The filtrate and washing liquid were collected and concentrated under reduced pressure to remove the organic solvent. The aqueous layer was washed with ethyl acetate, approx. 207! concentrated to. The residue is continuously detected by ultraviolet absorption and mixed with water (180n!).
It was subjected to Diaion Hp-720 column chromatography (1.8 cm x 1 5 cm) eluting with π-tetrahydrofuran (80n!).

Lyophilization of the fractions eluted with 5% tetrahydrofuran yields the product (13~).

48%) was obtained as a powder.

K B r −+ ・1760.1580TRνIn
aXCm N M Rδ (+)20): 1.25 (d, 3
H.

J = 611z, CH3), 2.6-3.1 (m, 2
H.

1 112) ,,'(,23,6(m,3 H,S
CH2 and 6-If), 3. ! l 9 (rn
, I H, 5-H), 4.1 '3 (771,11-
1, 8-14), 7.65 (d.

(1,5H, J==2 Hz, Deazol 5-H),
7.7 (1(d, (1,5'11. J=2 H
z, thiazole 5-1r), 9. I O(d,
] H, J = 2 Hz.

Deazol 2-u) tr v λ (If 20) °2.97 r+ma
X

Claims (1)

[Claims] 1. Structural formula [wherein M is hydrogen or an alkali metal cation; R3 is phenyl, 2-pyridyl, benzyl, 2-hydroxyethyl, t-butyl, 2-amino-1 , l-dimethylethyl, N,N-dimethylrubamimitoylmethyl, 2-amino-2-methoxycarbonylethyl, 2-
Amino-2-carbamoylethyl, 2-aminobutyl,
2-amino-1-carbamoylethyl, 2-amino-1
-carboxyethinomer 1-aminomethyl-2-(imidazol-1-yl)ethyl, 2-amino-2-(thiazol-4-yl)ethyl] (a) Structural formula: [wherein n is 1 or 2: R1 is an N-protecting group; A manufacturing method characterized by: producing a compound having the structural formula: b) removing a protecting group by reacting the following: 2, R' is cal)-nitropencyloxycarbonyl and R2 is p-nitropencyl! III. The manufacturing method according to claim 1.