JPS61210068A - 4-sulfonylazetidinone derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is H or protective group of N of amide; R<2> is OH-protective group; R<3> is alkyl or aryl). EXAMPLE:(+ or -)-3alpha-[(S)-1-t-butyldimethylsilyloxyethyl]-4alpha-phenyl-sulfonyl- 2-azetidi none. USE:Synthetic intermediate for penem derivative of formula VII [R<5> is (substituted) alkyl] having excellent antibacterial activity. PREPARATION:The compound of formula I wherein R<3> is R<3a> can be produced by (1) protecting the amide group of the compound of formula II (R<3a> is aryl) with a protective group by conventional method, (2) treating the obtained compound of formula III (R<1>' is protective group of N of amide) with a base, (3) reacting the obtained enolate anion with acetaldehyde to obtain the compound of formula IV, (4) protecting the OH of the compound by conventional method, (5) oxidizing the resultant compound of formula V with a peracid to obtain the compound of formula VI and (6) removing the protective group with tetrabutylammonium fluoride.

Description

[Detailed Description of the Invention] (1) Purpose of the Invention We investigated a method for synthesizing a penem derivative that has a broad spectrum and exhibits strong antibacterial activity, and 4-sulfonylazethinononone (1) described below is a synthetic method for penem derivatives. discovered that it was an important intermediate, and completed the present invention.

(II) Structure of the Invention The present invention relates to a compound having general formula (1).

In the formula, R1 represents a hydrogen atom, B2 represents a protection fund for an amide nitrogen atom, B2 represents a protection fund for a hydroxyl group, B5f is an alkyl group, and fc represents an alkyl fund.

The protecting group for the amide nitrogen atom of R1 is not particularly limited and may be a widely used protecting group for the amide nitrogen atom, such as a t-butyltmethylsilyl group.

As the protecting group for the hydroxyl group of B2, there is no particular limitation, and it is a widely used protecting group for the hydroxyl group, such as 4-nitropenzyloxycarbonyl or tertiary dimethylsilyl.

The alkyl group of B5 is a lower alkyl group, for example methyl or ethyl. As the aryl group of B3, it is still an aryl group even if it has a substituent, and 9 is phenyl or 7? , (Etrile.

The compound having the formula (1) has various stereoisomers, and the compound having the formula (1) is one of them or a mixture thereof.

A compound in which R3 is an aryl group in formula (1) can be synthesized by Method A shown below.

(1') In the formula, B represents the above-mentioned protecting group for the amide nitrogen atom, and R
2fX indicates agreement with the above, P13a indicates aryl fund, Azetidinone (2) (K, C1a
uss et al.: Ann, Chem, 538 (1974
year) ) amide group.

Compound (3) is protected by a protecting group such as t-butyldimethylsilyl according to a conventional method, and treated with a base such as 't-IJ tium diimpropylamide. The resulting erulate anion is reacted with acetaldehyde. This leads to compound (4). The hydroxyl group of compound (4) is protected according to a conventional method to obtain compound (5), which is oxidized with a peracid such as 3-chloroperzoic acid to obtain compound (6). Then, the protecting group on the amide nitrogen atom of (6) is removed by treatment with tetrabutylammonium heptafluoride to obtain 4-sulfoylazetidunon (1').

A compound in which R5 is an alkyl group in formula (1) can be synthesized using Method B shown below.

(91Qq In the formula, R2 has the same meaning as described above, n3b represents an alkyl group, and R4 represents a protecting group for a carboxyl group, such as an alkyl group such as methyl, ethyl or t-butyl, or a benzyl group). Indicates an aralkyl group.

6-Brompenicillanic acid ester (7) (J, P.

C1ayton, J. Chem, 8oc, (C)
2123 (1968)) t-trialkyloxonium tetrafluoroester, followed by treatment with a base such as basic alumina, can lead to compound (8)K. Compounds <8) treated with a Grignard reagent such as methylmagnesium bromide or a noalkylcopper lithium such as dimethylcopper-lithium or with zinc in the presence of a dialkylaluminum halide such as diethylaluminum chloride. In particular, when the erulate anion obtained by this process is reacted with acetaldehyde, compound (9) is obtained. The hydroxyl group of compound (9) is protected according to a conventional method to obtain compound (t), which is oxidized with sodium periodate in the presence of permanganese and potassium to give 4-methylsulfonyl-2-azetidinone (1'). t- can be obtained.

The coordination of the carbon substituted with the hydroxyl group of the main product of compound (9) obtained by this method is S.

This compound is treated with an organic acid such as benzoic acid in the presence of triphenylphosphine and dietherazodilypoxylate, and then hydrolyzed in the presence of a base such as ram methoxide, which inverts the coordination of the hydroxyl group.
Compound (9) with R coordination is obtained.

CIl+) Effects of the Invention The compound having the general formula (1) is disclosed in Japanese Patent Application Laid-open No. 1986-55 shown by the following formula.
Penem derivatives can be obtained using the method described in Japanese Patent No. 153789.

(1') αηCL4
C15 In the formula, I(2, R3 and R4tX have the same meanings as described above, and even if B5 is substituted, it represents an alkyl group.

In the presence of a base such as sodium methoxide, the protection fund of the amide nitrogen atom of compound (1) is removed, and the mercaptan is successfully processed even if it is substituted with 2-ethoxyethyl mercaptan. Treatment with carbon disulfide gives the compound αη. Compound CL2 obtained by reacting compound α and 4-nitropenol glyoxylate ester has R, B,
Methods such as Wood punishment (He1v, Chxm,
Acta, 55408 (1972)), leading to compound (2). When this is heated, penem derivative 4 is obtained, and then the protecting group of compound a4 is removed by a conventional method to obtain penem derivative (T), which has excellent antibacterial activity.
is obtained.

A method for synthesizing Example t-age compound (1) will be specifically shown below.

Example 1 Under nitrogen flow, (±1-4-phenylthio-2-azetinononone (3,0(1) and triethylamine (1,862)
Dimethylformamide (181d) # While stirring under ice cooling, add t-butyldimethylchlorosilane C2,78 to the solution.
? )′Add Ik. Stir for an additional 1.5 hours at the same temperature.
After that, a benzene-hexane mixed solution (1:1.1zomg
) 2 and wash with water. Extracted with Mizutori's penzene-hexane mixed solvent, dried together with the previous solution, and distilled off the solvent to obtain a residue (5,29). Elution was performed to obtain 4.82 mm (yield, 98 mm) of the title compound as an oil.

IR spectrum #v”Q CrIL-1:1759
, 1584ax nmr spectrum (CDC43) δpI'1m: 0
．． 29 (6H, s), 0.95 (9) 1. s), 2.9
5(1)1. dd, J=15,3ya], 3.43(I
H, dd, J = 15.5 Hz), 4.87 (IH.

dd, J=5.3Hz), 7.36(5H,5)3-(
1-Hydroxyethyl]-4-phenylthio-2-azetidinone was added to a tetrahydro 7 run lW solution containing 4,26 mmol of Noritium zoisoderopylamide cooled to -78°C under a nitrogen stream with stirring. -1-(t-Butyldimethylsilyl)-4-phenylthio-2-azetidinone (1,Of) in tetrahydro7rane (2,51j)
Add the solution. After 2 minutes, acetaldehyde (0,30
f) a solution of tetrahydrofuran (2,5+17) containing i,
't' was added, and after 5 minutes, acetic acid (0,51f) was added to terminate the reaction.

After returning the reaction solution to room temperature, benzene-hexane=1
=1 Mixed solvent (501d) was added, washed with water, the organic layer was separated and dried, the solvent was distilled off, and the remaining residue was washed with silicage/
Column chromatography using I/(42)t- (eluent: benzene:ethyl acetate = 5:1) yields 1.23f of the crude title compound. This was further subjected to liquid chromatography using Rover Column B (Merck) (elution solvent: chloroform:ethyl acetate = 10:
According to the order of separation and elution by 1), 3α4α
1' FIS isomer 393 rrq (yield: 34ti) and 3α4β1'S-isomer 31011Ig (yield,
27%) as an oil and the 3α4β1′R isomer 390w1i (yield, 34≠) as crystals. When the latter is recrystallized from hexane, it becomes acicular crystals, melting point 66-69.
Give ℃.

IR, X pek) /l/ NijigRuLs crtt-
', 3 (24α1'BS body: 35 (10, 1740
, 1581: 3 (:E4βl' 8 bodies: 3450 (
br) 1738 * l 581: vKB”c
IrL-' *ax 3α4β1' R form: 335υ, 1720 nmr spectrum (CDCt, )δppm + 3α4α1'E
S body 20, +12 (6H, s), 0.73 (9H, s)
, 1.10 (3E.

d, J=6Hz), 2.61 (IH, br, d
, J==3Hz), 3.31(IH,t, J=5Hz
), ~4.0 (IH, m), 4.81 (IH, d, J-
58z), 7.11 (5H, s): 3α4βI's body 20, 02 (6H, s), 0.70 (9H.

S), 0.90 (3H, d, J=6Hz), 1.77 (
1) 1°br, d, J=5Hz), 2.87(IH, d
d, J=6.2Hz), 3.76 (IH, m), 4.
51 (LH, d, J = 2Hz), 7.11 (5B, m
)? 3α4β1'R body: 0.02 (6H,s), 0.7
2(,9H,s), 0.78(3H,d.

J=7Hz), 2. t17 (IH, br, s), 2.8
5 (LH.

dd, J=4.5.2Hz), ~3.8(IH,m),
4,71 (1B, d, J=2Hz), ~7.1 (5H
, m) Mass spectrum m/e (for any isomer) 2228(M-3C6B5):21+3(2
28-H2O); 141 under non-nitrogen stream, (car 1-(t-butyldimethylsilyl)
-3α-(1-hydroxyethyl)-4α-phenylthio-2-azetizonone (6221 qL!: N,N-tumethylformamide (3,5
mz) Add t-butyldimethylchlorosilane (587
W)'t-Add and stir for 2 hours.

A mixed solvent of benzene-hexane=1:1 was added to the reaction solution, washed with water, dried, and the solvent was distilled off to leave a residue of silica gel (1:1).
(1) Column chromatography using i (elution bath agent,
Benzene:chloroform=5:1) to obtain the title compound 8.
05119 (yield.

97) is obtained as an oily substance.

In spectrum ν"HCt5cm-': 1738.
1580ax nmr spectrum AI (CT)CLs) 'ppm
-1' S isomer (main component) 20.02 (6H, s)
, 0.20 (6H, s), 0.98 (18H, s), 1
．． 43 (3H, d, J=7Hz), 3.63 (IH, d
d, J=8.5e5.5Hz), ~4.4 (I H,
m), 5.06 (IH, d, J=5.5Hz), 7.4
1(5)1. s): 1'R isomer (main component 3): 0
．． 14 (6H, a), 0.25 (6H, s), 0.99
(18H, a), 1.47 (3H, d, J=7Hz),
3.59 (IH, dd, J=5.5°3Hz)
, ~4.4 (1)1, m), 5.19 (IE
, d, J=5.5Hz), 7.41 (5H, s) Mass spectrum/l/m/e: 436 (M"-C
I(3), 394(M”-C4H,), 342(M”
-3C6H5)3α-(1-t-butyldimethylsilyloxyethyl)-4α-phenylsulfonyl-2-7zetidinone(gradient-1-(t-butyldimethylsilyl)-3α-(1
-t-butyldimethylsilyloxyethyl)-4α-phenylthio-2-azetidinone (525ffl, acetylacetone manganese salt (15■), sodium acetate (
trihydrate, 145■) and 40% peracetic acid (1,097M)
, and ethyl acetate (1 omz) was stirred for 5 hours under water cooling. Then, after diluting with ethyl acetate, hydrogen sulfite was added at the same temperature. An aqueous gold solution was added to decompose excess peracid. The organic layer is separated, washed with dilute If water, washed with water, and then dried. The emollient was distilled off and the residue 570η was subjected to preparative thin layer chromatography (developing solvent: benzene: ethyl acetate = 8:
1) to give 3.4-cis-1'R isomer 95η (yield, 17%) and 3.4-cis-1'S isomer 3
14 to (yield, 56 cm) All obtained as oily substances・IE (spectrum y""+5 crIL-': 3
,4-cis-1'Rax isomer: 1763.1581:3,4-cis-1'
S isomer: 1767.1581 nmr spectrum/I/(CDC4,)δppm,
3.4-cis-l'R isomer: 0.10 (6H,
s), 0.20 (6H, s), 0.90 (9H, S),
1.04 (9B, s), 1.46 (3H.

(1, J = 7) 1z), 3.82 (IH, t, J = 6H
z), 4.7 (IH, m), 5.04 (IH, d, J=
6Hz), 7.6-8.3 (5H, m): 3+4-ci
s-1's isomer 20, (+5(6H,s), 0.19
(6H,s), 0.83 (9H.

8), 0.95 (3H, d, J=6Hz), 0.96 (
9H.

S), 3.55 (LH, dd, J=9,6Ez), 4.
32 (IH, m), 4.87 (IH, d, J=6Hz)
, 7.6-8.2 (5H, m) Mass spectrum m/e (for any isomer):
468 (M”-CH), 426 (M”-C4H2
), 342 (M-802C6H5), 199 Example 2 -2-Azetidinone Under a nitrogen atmosphere, (thl-1-(t-butyldimethylsilyl)-3α-((S)-1-t-butyldimethylsilyloxyethyl ]-4α-phenylsulfonyl-2-azetidinone (364η) in tetrahydrofuran (1,87
M) Tetrabutylammonium fluoride (
227W) and acetic acid (104η) in a tetrahydrofuran (0,51) bath. After stirring at the same temperature for 1 hour and 15 minutes, the reaction solution was completely diluted with ethyl acetate, and washed successively with aqueous sodium bicarbonate and water. After drying the organic layer, the solvent was distilled off, leaving a residue of 270W.
This is separated by preparative thin layer chromatography (developing solvent: benzene:ethyl acetate = 1:1) to obtain the desired product 187cm (yield: 68cm). Recrystallization is performed using a mixed solvent of ethanol and hexane to obtain prismatic crystals having a melting point of 120.5 to 134°C.

IR ratio νnujo1cm-': 3190.3
080.

ax 1778.1580 nmr spectrum/I/ (CDC+5) δppm: 0
．． 07(6)1. s), 0.91 (9H, s), 1.4
1 (3H, d, J, = 6Hz), 3.58 (1
day, dd, J==10.5Hz), 4.68 (LH.

a, J==5Hz), 4.80 (IH, m), 7.18
(IH.

br,s), 7.6-8.2 (,5H,m) Example 3 Tedinone Same as (3) of Example 1, factor-1-(t-butyldimethylsilyl)-3α-C(8- 1-hydroxyethyl]-
Processing of 4β-phenylthio-2-azetidinone yielded 9
The title compound is obtained as an oil at 3%.

IR spectrum ν0 gate'5: 1743.15810
π nllIr spectrum (cDct3) δppm: 0.
01 (6H, s), 0.05 (6B,, s), 0.6
3 (9H, s), 0.75 (3H.

d, J=6Hz), 0.77(9H,s), 2.92(
IH.

t, J=3Hz), ~3.9(IH,m), 4.86(
IH.

d, J==zHz), 7.1-7.4 (5H, m)
Mass spectrum m/e: 394 (M”-C4H,
), 342(M''-3C6H5) -azetidinone ((trans)-1-(t-
Butyldimethylsilyl)-3α-((8-1-t-butyldimethylsilyloxyethyl)-4β-phenylthio-2-azetidinone is treated to obtain the desired product as crystals with a yield of 81%. Methanolic recrystallization and melting point 116~
Colorless prismatic crystals at 116.5°C are obtained.

More Spectpy v”JolcrIL-’: 17
59# 1582ax ntnr spectrum/l/ (CDC2,) δppm: 0
．． 01(6)1. s), 0.41 (6H, a), 0.4
5 (3B, d, J=7Hz), 0.86 (9
H, s), 1.09 (9H, s), 3.32 (1) 1°t, J = 2.5 Hz), ~4.2 (LH, m), 4.7
4(II(.

d, J=2.5Hz), 7.6-8.2 (5H, m
) Example 4 2-Azetidinone Same as in Example 2, ((1)-1-(t-butyltmethylsilyl)-3α-[(1-t-butyltmethylsilyloxyethyl)- 4β-phenylsulfonyl-
2-Azetidinone lla [Crystalline target product is obtained in a yield of 83%. The product is recrystallized in a hexane-methanol mixed solvent to obtain colorless needle crystals with a melting point of 145.5 to 146.5°C.

From spectrum Shinnuj01sono-1=5180.30
90°ax 1773.1737 nmr spectrum (CDCt5) δppm: 0.00
(6H, s), 0.81 (9H, s), 1.09 (3H
, d, J=7Hz), 3.41(IH,t, J=2Hz
), 4.27 (I H, m), 4.70 (I H, d
, J = 2Hz), 6.7(1)1. br, s),
7.6-8.2 (5H, m) Example 5 (1) (38,4E)-3-bromo 1-(l-
Methoxycardani-2-methyl-1-f Ropeni J,
P. Clayton's method (J. Chem, 8o
c, (C12123 (1969)) Synthesized methyl 6α-bromopenicillanate (8,56
To a nitromethane solution (61 ml) of P) was added trimethylochinium tetrafluorogelate (4,52f) under water cooling in a nitrogen stream. Reaction solution '1 (stir for 10 minutes and then keep at 5°C for 48 hours. Add nitromethane (60ml) to the reaction solution to dissolve the precipitate. Add carbonate powder to this solution) IJum (11.3f) t - Add and stir at room temperature for 2 hours. Ethyl acetate was added to this solution, washed with water, diluted hydrochloric acid, and cold 1 water, and dried, and all the solvent was distilled off.

The residue was treated with alumina (WoelmB, activity
The title compound (5,96S
) is obtained as a powder.

mI) 55-6°C (recrystallized with isopropyl ether/hexane) nmr spectrum (CDCt,) δppm: 2.00 (
3H,s).

2.16 (3H, s), 2.27 (3H, s), 3.8
0 (3H.

8), 4.85 (IH, d, J = 2Hz), 5.13 (
IH.

d, J=2Hz) (2) (38,4B)-3-(1-hydroxyethyl)-1-(1-methoxycardani-2-methyl-1
-fropenyl)-4-methylthio-2-azetidinone CO□CH3 Active zinc (C, El, Eauaer and D,
S. Breslow.

“Organic 5ynthesis”, Co1
1. Vol, [1, ed, by E,C.

Horning, John Wiley and 5
ons+ Inc., New York.

p4o8 (1955) and prepared by the second son method (7), 625nwi) and noethylaluminum chloride (
15 cm of hexane bath liquid, 6.68 ml) of tetrahydro7ran (15 ml) was added with stirring at 15-20°C.
Over 0 minutes, azetidinone (1,961) obtained in Example 5 (1) and distilled acetaldehyde (84
Add a tetrahydrofuran (20+nx) bath solution of 3rf9). After stirring for 1 hour, ethyl acetate and water were added to the reaction mixture. All insoluble matter was removed, the organic layer was washed with water, dried, and distilled off to obtain a crude product, which was obtained by column chromatography on all-silica gel (3 (J f )) (chloroform/ethyl acetate = maize ~
%) to 1.04f of the title compound (l S/ I B
= '/i mixture) is obtained.

IR spectrum kV#, Aicm-': 3450
, 1760.171ONMB spectrum (spectrum of king product) (cDct,) δppm: 1.3r
l(3H, d, J=6H2), 1.93(,3H.

S), 2.05 (3H, s), 2.15 (3H, s),
3.14 (IH, dd, J=-6,3Hz), 3°72
(3H, s), 4.12 (IH, m), 4.92 (IH
, d, J=3Hz) oxyethyl) -1-(1-methoxyrubbony) Compound obtained in (2) of Example 5 (]
S/IB = 4/1 mixture, 105tv), triphenylphosphine (201■), benzoic acid (94~) at 2
M was dissolved in tetrahydrofuran, and the mixture was gradually added to a solution of azonocargenic acid soethyl ester (1341η) in tetrahydrofuran (component 1) at 20° C. over 10 minutes, and stirring was continued for 1.5 hours. Distill the solvent,
Dissolve the residue in a mixed bath solution (3 times) of benzene-ethyl acetate = 6 = 1, leave it in a cool place, separate the precipitated crystals, and P
The title compound 1191 was separated by liquid gold thin layer chromatography (developing agent, benzene:ethyl acetate = 5:1).
ng (yield, 82%) as an oil. The city is 1
It is a mixture of S/IB=1/4.

IR spectrum 11QcIrL-': 1765
, 1720.

aX 1380.1360.1270 nmr spectrum (cryct5) δI) 1) ml Main component (IFI coordination): I, 49 (3H, d, J = 6Hz
), 1.95 (3H, s), 2, (+3 (3H, s),
2.17 (3H, s), 3.33 (IH.

dd, J=7.3H3), 3.74(3H,s),5.
14(IH, d, J=3Hz), 5.6 :((IH,
dq, J=7°6Hz), 7.54 (3H, m),
8.10 (2H, m): Subcomponent (18 coordination): 1.5
2 (3H, d, J=6Hz), 1.95 (3B, s),
2.03 (3H, s), 2.17 (3H.

S), 3. :33 (IH, dd, J=7.3Hz), 3
．． 74 (3H, s), 4.96 (IH, d, J=3Hz
), 5.63 (IH, dq, J=7.6Hz), 7.5
4(3H,m), 8.10(2H,m) (4) (38,4B)-3-(1-hydroxyethyl J-1-(1-methoxycarbonyl-2-methyl-
1-propenyl)-4-methylthio-2-7zethinonone 02CH5 (38,4R)-3(1-benzoyloxyethyl)-
1-(1-methoxycardani-2-methyl-1-propenyl)-4-methylthio-2-azetidinone (18/
A mixture of IFl = 1/4, 91η) was dissolved in total methanol, and sodium (7,179) was dissolved in methanol (0
, 65 tnl) was added to the solution at () 0 and then stirred at room temperature (18''~20'C) for 5 hours. After the reaction was completed, it was made slightly acidic with acetic acid and ethyl acetate (20ml) was added. and wash with water.

After drying and peeling, the solvent is distilled off. The resulting residue was subjected to preparative thin layer chromatography using silica gel ([tl bath, benzene:ethyl acetate = 2:1]). This one is nmr spectrum area IF1. It is a mixture of Is coordinations and its Kitamoto is f14 versus l. Obtain 50q (yield, 74.4%) as an oil.

IFI Spect A/v49 (yl-': 345
0 (br) + 1750+nmr spectrum (cp
cz5) δppm l main component (ll'l coordination): 1.2
6 (3H, d, J=6Hz), 1.93 (3H
, s), 2.05 (3H, s), 2.15 (3H, s)
, 3.10 (IH.

dd, J=6, 3Hz), 3.72(3H,s
), 4.23 (IH, dq, J=6.6Hz), 5.0
3 (IH, d.

J=3Hz): By-product (Is coordination): 1.29 (3H,
a.

J = 6Hz), 1.93 (3H, s), 2.05 (3H
, s), 2.15 (3H, s), 3.10 (IH, dd
, J=6.3Hz), 3.72(3H,s), 4.23
(IH, dq, J=6.6Hz), 4.90 (IH
, d, J=3Hz) (3R,4h)-3[1-hydroxyethyl]-1-(
l-Methoxycarbonyl-2-methyl-1-flopenyl)-4-methylthio-2-azetidine 7 (Is/I
A mixture of R=l/4, 100η), 4-trimethylaminopyridine (89~) was bathed in total methylene chloride 3me, and p-nitrobensoloxycarbonyl chloride (157■)f, methylene chloride ( 2M) at 0°C, and stirred at the same temperature for 1 minute and then at room temperature for 1 hour. After the reaction is complete, add methylene chloride and
Wash with water. After drying, the solvent is distilled off. The nine oils obtained were subjected to preparative thin-field chromatography using all-silica gel (developing solvent, benzene:ethyl acetate = 5:1).
) was purified to give the title compound 1481! (Yield, 89
%) as an oil. Motoichi GX I S/I B=
It is a 1/4 mixture.

IFI Spect/'I'! Afim-': 176
5 (br,) + 1725nmr spectrum (CDC
4) δppm l main component (IR coordination) = 1.50 (3
H, d, J = 6Hz), 2.00 (3H, a)
, 2.10 (3H, s), 2.22 (3) 1. s), 3
．． 50 (IH.

dd, J=7.3Hz), 3.70 (3H, s), 5.
02 (IP, d, J=3Hz), 5.22 (2H, s)
,5.30(IE(,m),7.60(2H,d,J=
9Hz), 8.30 (2H1d, J=9H2); Subcomponent (Is coordination): 1.5+1 (3H,d, J=6Hz
), 2.00(:(H, +9), 2.10(3H, s
), 2.22 (s, 3B), 3.30 (IH, d
d.

J, = 7, 3Hz), 3.70 (3H, s), 4.
94 (IH.

d, J=3Hz), 5.22(2H,s), 5.30(
IH.

m), 7.60 (2H, d, J=9Hz), 8
．． 30(2)1°d, J=9Hz) -Azethisonone CO□CH3 Compound obtained in Example 5-(2) (I S/I B=
Diethyl azodihydrugexylate (338119) was added to a solution of liphenylphosphine (5031q) and benzoic acid (23411 g) in tetrahydrofuran (5 components) for 10 minutes with stirring at 20°C. of tetrahydro7rane (2,51M
) Add the solution. Stirring was continued for 1.5 hours, the bath medium of the reaction solution was distilled off, and the residue was diluted with benzene/ethyl acetate = 6/1 (
7mj), the bath liquid is cooled, and the insoluble matter is removed in an oven. The residue obtained by distilling off the solvent of F'/[ was subjected to column chromatography on silica gel (109) (benzene/
A crude benzoate compound is obtained by applying the mixture to ethyl acetate (10/1). Methanol (
Add sodium methoxide (IM methanol f8 solution 1.671111) to the solution (3 mJ) and stir at room temperature for 5 hours. Add a small amount of acetic acid to the reaction solution, then add ethyl acetate and wash with water. The organic layer was dried and distilled off, and the resulting residue was subjected to column chromatography (hexane/acetone = 2/1) on silica gel (10t) to obtain the title compound (Is/
IB=1/4, 247W) is obtained.

nmr spectrum (nmr spectrum of main product) (C
DC25) δppm: 1.26 (3H, d, J=6Hz
), 1.93 (,3B, s), 2.05 (3H, s),
2.15 (:(H.

S), 3.10 (1B, dd, J=6.3Hz), 3.
72 (3H, s), 4.23 (LH, m), 5. t)
5 (IH.

d, J = 3Hz) methylsilyloxy)ethyl)-1-(1-methoxycarbonyl-2-,7'thyl-1-7'lovenyl)-4-
Methylthio-2-azetidinone Compound obtained in Example 5 (2) (I S/I R=4/1 mixture, 1.5
9t) of N,N-trimethylformamide (t,5rtt
The t>m solution is treated with imidazole (0,5Sl) and t-butyldimethylchlorosilane (1,05f) at room temperature for 3 hours. Add benzene to the reaction solution, wash with water, if, after drying,
The residue obtained by distilling off the solvent was total silica gel (3+l
The title compound (Is/IFt=
4/1 mixture, 2. O2) is obtained.

nmr spectrum (nmr spectrum of main product) (C
DC2ρδppm: 0.10 (6H, s), 0.84
(9H.

S), 1.28 (3H, d, J=6Hz), 1.92 (
3H.

S), 2.05 (3H, s), 2.16 (3H, s),
3.20 (IH, dd, J=5.3Hz), 3.71 (
3H, s), 4.23 (IH, m), 4.96 (1B
, d, J=3Hz) Toxicarbonyl-2-
methyl-1-7'ropenyl)-4-methylthio-2-azetidinone LJ 2 Ufl 5 Compound obtained in Example 5 (6) (I S/I R=
1/4.

5.69f), imidazole (2,54F), and t-butyltmethylchlorosilane (5,331F) in N,N-tmethylformamide (lloTILl) bath fit - reaction and treatment in the same manner as in (7) of Example 5 Do you want to do that? , the title compound (IS/IB=1/4 mixture, 7.95f) is obtained.

nmr spectrum (ntnr spectrum of main product) (
CDCl2) δI) pm: 0.10 (6H, s), 0.
84 (9E.

S), 1.23 (3H, d, J=6Hz), 1.92 (
3H.

S), 2.05 (3H, s), 2.16 (3H, s),
3.05 (IH, dd, J=5.3Hz), 3.71 (
3H, s), 4.23 (1 day, m), 5.09 (IH
, d, J=3Hz) Rusulfonyl-2-azetinonone Compound obtained in (8) of Example 5 (IS/IB=
A mixture of 1/4, 2t8wli) of sodium periodate (600μ) and potassium permanganate (8μ) in a phosphate buffer fi (0.1M, pH 7.1, 20n/) and acetone (20ml) Soak in the mixture. Stir this solution overnight at room temperature. After removing the insoluble matter kP and distilling off the a7ton of Pfi, the mixture is saturated with common salt and extracted with benzene. Column chromatography (benzene/[
1 ethyl = 10/l). The obtained crystals were recrystallized from a mixed solvent of benzene/hexane to obtain the desired product (93
) is obtained as needle crystals.

mp 102-103℃ [α), +3.5u (c=0.48, tetrahydrofuran) KBr -1・IR spectrum ν engineering, 3320.1790゜a
x nmr spectrum (CDCl2) δppm: 0.0
9 (6H, S), 0.87 (9H,,s), 1.
26 (3H, d, J=6Hz), 2.97 (3H, s)
, 3.58 (IH, m), 4.35 (lH, m), 4.
75 (3H, d, J=2.5Hz), 7.1 (IH,
br, )

Claims (1)

[Claims] General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 represents a hydrogen atom or an amide nitrogen atom protecting group, R^2 represents a hydroxyl group protective group, ^3 represents an alkyl group or an aryl group].