JPS5944355A - 2-azetidinone derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The optically active 2-azetidinone derivative of formula I [R is lower alkyl, (substituted) aryl or (substituted) aralkyl]. EXAMPLE:(4R)-4-Phenylthioazetidin-2-one. USE:Useful as a synthetic intermediate of an antibiotic substance containing beta-lactam ring, e.g. a carbapenem antibiotics such as thienamycin, etc. or monocyclic beta-lactam antibiotic, etc. PROCESS:The compound of formula I can be prepared by reacting the compound of formula II [X is lower alkanoyloxy or (substituted) arylsulfonyl] with the compound of formula III in the presence of cinchonidien in a solvent such as diethyl ether, etc. The amount of cinchonidine is 0.5-3mol, preferably 1-2mol per 1mol of the compound of formula II, and that of the compound of formula IIIis about 1-8mol per 1mol of the compound of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel synthetic intermediates for antibiotics having β-lactam properties, such as carbapenem antibiotics such as chenamycin, and monocyclic β-lactam antibiotics ψC. A general formula that is a body [wherein, R may be lowered to lower alki tv, 1iffi sent, a! The present invention relates to an optically active 2-azetidinone derivative represented by the formula J-/L/Ji% (indicates an optionally substituted aholki/I/group) and a method for producing the same.

In recent years, monocyclic β-octam antibiotics (e.g. l-sulfo-2-azetidinone derivatives) and carbapenem antibiotics (e.g. chenamycin, etc.) have been shown to have antibacterial effects, β-lactamase inhibitory effects, and effectiveness against resistant bacteria. It is attracting attention because of its excellent properties in terms of, etc.

The present inventors have discovered that monocyclic β-lactam antibiotics and
As a result of intensive research into a new method for producing mu-based antibiotics such as chenamycin, we discovered that the general formula [wherein or lower alkanoyloxy radical tiJ: optionally substituted arylsulfony] v group When a compound represented by ] and a compound represented by general formula ] are reacted in the presence of cinchonidine, the substituent at the 4-position represented by They also discovered that the obtained compound (1) is extremely useful as intermediate zero 1 for the industrial production of carbapenem antibiotics, such as chenamycin. As a result of various investigations based on the findings, the present invention was completed.7 Namely, the present invention is characterized by reacting (1) compound [l], (2) compound CI) with compound (II) in the presence of cinchonidine. The present invention relates to a method for producing compound (1).

In the above general formula, the lower alkyl group represented by R is, for example, methyl, ethyl/l/.

Propyl, isopropy/L/, n-butyl, isobuty A
A straight chain or branched lower alkyl/1/ group having 1 to 4 carbon atoms such as /, t-butyμ, etc. is used.

Examples of the aryl group in the optionally substituted aryl group represented by R include phenyl, a-naphthyl, and β-naphthyl.

Examples of the aralkyl group in the optionally substituted aralkyl group represented by R include benzyl, phenethyl, phenylproyl, naphthylethyl, etc. J
A linear or branched lower alkyl/l' group having 1 to 4 carbon atoms with -/L/ substitution is used.

FPf in optionally substituted aryl group represented by R to optionally substituted aralkyl
Examples of substituents include alkyl, alkoxy, pulkenyl, aryl, and aralkyl.

Alkylthio, arylthio, afuruki/Llthio.

alkylsulfonyl, arylsulfony/l/, afurky-sulfonyl, trihalogenoa)v'(/l'e
Hydroquine, halogen, nitro, amino, cyano, carbamoyl, carboxy, acyl, acyloxy, acylamino, hydroxyalkyl, carboxyalkyl, helogenoa μkyl, monomodal sialkylaminoalkyl #
etc. (herein, alkyl is preferably a straight-chain or branched lower alkyl (1 to 6), such as methyl, ethyl, n-]10-pyl,
Irafu0ropyru, n-buty/l/l isobutyl,
5ea-glutyl, tert-butyl, n-bench/
I/, isobenchi/L', 11-hegycyl, isohegicyl, etc. are used, and as the alkoxy, linear or branched low +'t alkoxy having 1 to 6 carbon atoms is preferred.
For example, methoxy, ethoxy, 11-propoxy,
Isopropoxy, n-butoxy, isobutoxy, se
c,-butoxy, t,crt-butoxy, n-pentyloxy, isopentyloxy, ]1-hexyloxy, isohexyloxy, etc. are used, and the halogens used include bromine, chlorine, fluorine, etc. μ is preferably a single chain or U, 11-branched lower ano-kenyl having 2 to 6 carbon atoms, such as vinyl, allyl, isoprobeni/L/, 2-metalino 1/, 2-puteni/L/ , 3-butenyl, etc. are used, and the acyl μ includes, for example, acetyl, gropionyl, n-butyryl, isobutyryl μ, n-pentanoyl 1n-hexanoyl, benzy/L/, 4-hydroxybenzoyl, 4-methoxybenzoyl, phenylacetyl, 4-hydroxyphenylacetyl, 4-methoxyphenylacetyl, 2-thenylcarbonyl, 2-furylcarbonyl, 2-. 4- or 5-thiazolyl acetyl/L', 2- or 3-thhenyl acetyl/L', 2- or 3-furylacetyl, 2
-amino-4 or 5-thiazolyl acetate, etc., and the aryl and aralkyl mentioned above are used).

X is, for example, a lower a〉-norkyloxy group having 2 to 4 carbon atoms such as acetoxy, propionyloxy, or
/sulfonyl, etc.), and as the substituent for the aryls fi/honyl, the same substituents as the optionally substituted av-iv & represented by R are used.

Compound (1) has the nitrogen atom at the 1st position of the azetidinone skeleton with the general formula %) (wherein, Xl, represents isopropyl/l/ group]
It may be maintained with l' nails. In the above general formula (A), the lower alkyl JN represented by Xl,)(2) is
Date is methyl, chloromethyl, ethyl, chloroethyl, n-propyl, isopropy/l/, n-butyl, t
A lower alkyl group having 1 to 4 carbon atoms which may be substituted with halogen such as ert-butyl is used, and as a lower anotoxy group, a methoxy group, an ethoxyoxy group, etc. are used.

In compound (1), it is useful as a raw material for a substance at the 4th position on the β-octum ring.

Compound CI,1 can be produced by reacting compound (1) and CI) in the presence of polyconidine. In this reaction, cinchonidine is usually used in an amount of about 0.5 to 3 moles, preferably 1 to 2 moles, per 17 μm of the compound. Also, usually thio-7+/compound (1)
is used in an amount of about 2 to 8 mol, preferably about 2 to 6 mol, per 1 mol of compound CI). The reaction is usually carried out using a solvent. Examples of solvents include esters such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; esters such as ethyl acetate and butyl acetate; Ketones such as acetone, methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, xylene, hydrocarbons such as pentane, hexane, heptane, cyclopentane, cyclohexane, nitrile/L' such as acetonitrile alcohols such as methanol, ethanol, isopropanol, t-buty/L'7/L'co/L', hydrogen halides such as dichloromethane, chloroform, carbon tetrachloride, carbon disulfide , thiophene, pyridine, etc. are used. The reaction temperature of this reaction is about -30 to 150°C, preferably i, t: about -10=100t. Reaction time varies depending on the solvent used in the reaction, reaction temperature, etc., but generally the reaction is completed in a few hours to several weeks.

The optical yield of this reaction is about 40 to 80%.

The resulting compound (1) can be purified by means of separation lees production methods known per se, such as solvent extraction, crystallization, recrystallization, adsorption, or partition chromatography.

The raw material compounds C, H) for this reaction are 1ib Either one body or one body can be used.

To further explain the above optical yield, for example, when using the enantiomer of compound (1), the optically active form of general formula CI) as the target product has a yield of 140 to 100 of its enantiomer.
~110 stereoselectively produced. The reaction solution containing the optically active form [I] obtained in this way may be directly subjected to the primary reaction, or CI) may be separated from its enantiomer by a method known per se, and then subjected to a pyrolysis reaction. It's okay. For example, the optical purity can be further increased by known means such as recrystallization, and then subjected to the next reaction.

The formula t4a of compound (1) is compound [I] and the general formula % () [wherein, XI, X2, and X3 have the same meanings as above, Y
represents a reactive group to be eliminated], the desired silyl 1/derivative can be produced.

In the above general formula (l), the leaving reactive group represented by Y includes, for example, N-()!Jmethylsilyl)trifluoroacetimidoyloxy group, N-()lymethylsilyl)acetimidoyloxynail, Halogeno, acylamino groups such as formylamino, acetylamino, propionylamino, butyrylamino, trifluoroacetylamino, amino such as (trimethylsilyl)amino, (chloromethyldimethylsilyl)amino, lower alkyl/L/( tM prime number 1
to 4) amino groups, such as N, N-dimethylamino, N-chloromethy/l/-N-dimethylamino, N,
N-diethylamino, N, N-dipropylamino, N-
N such as methyl-N-ethylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino,
N-dilower a/kyl (1 to 4 carbon atoms) amino group, imidazoyl, etc.; cyclic group is used.

Compound CB) is 1 for raw material compound [l] and (1).
About 3 times the mole amount is used. The reaction is generally carried out in an inert solvent. A suitable inert solvent is, for example, tetrahydrofuran. Dichloromethane, chloroform, dichloroethane, acetonitrile, ethyl acetate, etc. are used. Schiff still prefers to carry out this reaction under anhydrous conditions.
If necessary, this is carried out in the presence of a deoxidizing agent such as an organic tertiary amine such as triethylamine, dimethylaniline, pyridine, quinoline, lutidine, or N-ethylpiperazine.

Thus, from the optically active compounds CI)-j and shiso shiri)v derivatives, novel and useful compounds [j'l ) or its silyl derivative can be produced.

That is, from the optically active compound CI) or its sil/1/derivative, the compound (Vl)t or its Si! The J/L' derivative is produced by reacting the compound [1] or its silyl derivative with acetaldehyde in the presence of a base, oxidizing the obtained compound [■] to form a metal compound [V], and converting this into a metal compound [V]. Subject to a reduction reaction, or ■ Compound [l] or its sh! I) Compound (V) obtained by acetylating its β-octam ring 3 (r'L) from the v derivative by the method described below.
J: In the reaction of □ [1■] CI) → l) carried out by subjecting the body to a reduction reaction, acetaldehyo i4J
%fiZi(, al 0075, I; 30tE, x<?
-80 to 0 centigrade is preferred.

Examples of the base used in this reaction include (eg, alkylsililithiums such as methyllithium, butyllithium, and 5ec-butyllithium, allyllithiums such as phenyllithium and naphthyllithium, lithium diisopropylamide, lithium hexamethyl Amine lithium salts such as dishiwozan are used. Among these, lithium diisopropylamide, phenyl lithium, etc. are clever. 'l;? 1 base per 1 mole of I-isomer
rlj [Q usually about 1 to 24 equivalents, preferably 2.5
A period of about 3 to 3 days is used. This reaction is carried out in a solvent for -R'Z. As the solvent, a solvent inert to the reaction is suitable, such as ethers such as diethyl ether, dimethyl ether, tetrahydrofuran, and dioxane.

Next, in the oxidation reaction to (IV)-(V), as an oxidizing agent,
Usually, chromic acid-based oxidizing agents are advantageously used. As the chromic acid-based oxidizing agent, chromic anhydride, potassium dichromate, sodium dichromate, tertiary butyl, etc. are used. The oxidizing agent used is compound Q4,
For 1 mole of IJ (IV l) or its silyl ■ conductor, ya! Use excess oxidant.

This reaction is usually carried out using a solvent. Here, lysine, dimethylpho/l/1. Amide etc. are used.

These solvents may be used in combination if necessary.
Oxidation in sunny weather? The reaction force q' will disappear in about 30 minutes to 24 hours for f'jX, although it varies depending on the reaction temperature and the reaction temperature.

The reaction of the father (11-(V)) is carried out by reacting the compound [l'3 or its silyl nFj #; body with an N-' acetyl nitrogen-containing heterocyclic compound in the presence of C. N-acetyl-containing ζ (as a heterocyclic compound, for example, N-acetylpiracy/l/
, N-acetylimidazole, N-acetylbenzotriazole, 4-lower alkyl (N-acetyl nitrogen-containing 5-
(J-membered heterocyclic compounds are used.

The amount of the N-acetyl heterocyclic compound used in this reaction is about 1 to 4 mol (v1 preferably about 2 to 3 mol) per 1 mol of the compound []] star or its silyl derivative. In the presence of wood ash and ai bases, fi
I will be beaten. As the base 7 used, for example, the above (1
) to l) The salt h(s) used in the reaction (1, 2, etc.) is j111, usually 1 to 4 times, preferably 2 to 3 times 1 generation culm.

This reaction is usually carried out in a solvent. Examples of the solvent include diethyl ether.

Diisopropylene, 11/ether, ethylene glycol dimethyl ade, tetrohydrofone. Ethers such as dioxane, dimethylformamide, etc. are used.
Among these solvents, tetrohydrofuran, dioxane, etc. are suitable.

Compound [V] subjected to u+W MW by such a method
Alternatively, the silyl compound can be converted into the compound (Vl) by subjecting it to a reduction reaction (=J).

J used in this reaction ([d as the radical side, for example, lithium borohydride, sodium borohydride.

Triisobutylboron hydride 9'thium, hydride! J
- sec. - Lithium butyl boron, hydrogenated tri-13ec - butyl boron potassium, water hydrated tri-Be
c-butylboumi(]sodium, lithium tridiamylboron hydride, potassium tridiamylborohydride, etc. 1.J4 complexes, e.g. il: ) I
Tri-low H. methinoamine-borane, diisoprobipanoamine-borane, etc. Jjt alkyl (1 carbon number
and 4) amine borane (iM::tθ) ice borohydrides, etc. are used. Among these, sodium borohydride, tri-butyl borohydride, and sodium borohydride.

Diisoprobylamine-borane and the like are preferred. In the reaction, approximately 1 to 5 mo/L' of the q element is used per mole of compound (V). The reaction is usually carried out in a solvent.

Examples of solvents include diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether,
Ethylene glycol diethyl ether, tetrahydrofuran, dioxannat ether yv#L methanol, ethano-μ, isoprono? Nord=fuqhan, butanol,
Alcohol solvents such as tert-butano-μ, pyridine, water, etc. are used, and these solvents are usually used alone, but they can be mixed as appropriate, and furthermore, methylene chloride,
A suitable mixture of halogenated hydrocarbons such as carbon tetrachloride may be used. The reaction temperature is about -40 to 100C, usually about -io to 40C and about 7y.

The reaction time varies depending on the reducing agent, solvent, and reaction temperature used in the reaction, but is generally about 30 minutes to 3 days, preferably about 1 to several hours.

In addition, compound [11] or its! J/L' derivative 3
Position Hydroxyl group bonding part of hydroxyethyl group (1st position)
The isomers ((1,R)-1-hydroxyethyl form and (Is)-1-hydroxyethyl form) can be separated from each other by, for example, chromatography, but these two Among the isomers of (IS)
-1-Hydroxyethyl form can be obtained, for example, by treating it with triphenylphosphine and diethyl azocarboxylate in formic acid to invert the steric configuration to obtain 0-hoA/miA/(IR)-1-hydroxyethyl form. It can also be converted to the (IR)-1-hydroxyethyl form by subjecting it to a so-called elemental value reaction to obtain a derivative, and then subjecting the 0-form μ form to a dehopmylation reaction (tetrahedron). Letters, No. 18, pp. 1619-1622 (1973
).

The triphenylphosphine claw used in the Kimitsunobu reaction is about 2 to 3 times mofi per mole of the raw material, and the diethylazocarboxylate and Higi f'i'H moth used is about 2 to 10 times mole per mole of the raw material. A magnification of approximately 7 times is suitable. Furthermore, formic acid can be added in large excess and used as a solvent. Generally, the reaction is carried out in a solvent, for example, ethers such as tetrohydrofuran, dioxane, etc. are used. Reaction ff! The degree is usually in the range of 0 to 8 (1), preferably in the range of 2 () to 30.
It takes about 24 hours. 51 was subjected to a deformylation reaction tri,
This is carried out by a method known per se, for example by reacting methanol with hydrochloric acid or the like. Reaction humidity is -20~・6
The temperature is about 0°C, preferably about -5 to 30°C, and the reaction time is 3
05) By protecting the hydroxy μ of the ethyl/I/ group with silyl)v, %% and subjecting it to an oxidation reaction, it is possible to lead to the known middle starting material compound of enamycin [■].

1 [where x', X2. X3. R has the same meaning as above]
. Compound (Vl) to Sanko! The J/l/ conversion reaction can be carried out in the same manner as the silino-1 conversion reaction of compound (1). The silyl/L/derivative of the compound CVl) can be led to the silyl compound (Vi[) through an oxidation reaction (=J).

Examples of the oxidizing agent used include permanganate salts such as potassium permanganate and barium permanganate.
．． 11Φammonium, aromatic acid, percarbonate (r acid, monoperphthalic acid, r
Organic peracids such as o-chlor J1.9 benzoic acid, hydrogen peroxide, and oxidizing agents such as ruthenium tetrachloride are destroyed. The water reaction is carried out using a 1iT1 normal solvent, where the solvent and 1. In this case, water, acetic acid, acetone, tertiary chloride, etc. are used singly or in combination. In addition, when using permanganate with an oxidizing agent, 1i
It is advantageous to use inorganic acids such as IR, acids, acetic acid, or black vinegar.The reaction temperature is about -30 to 50°C, preferably about -10 to 30°C. Although it varies depending on the type of reaction and reaction temperature, generally it takes 30 minutes to 24 minutes.
It takes about an hour.

The compound (Vil) thus obtained can be converted into compound [IX] to produce chenamycin according to the authority shown below. The method for producing chenamycin from compound [1x] is, for example, Tetra, hedron Letters 2.
3.2875 (1982), etc.

1 (Vi't) The amount of Grignard lv reagent used is [
The reaction is carried out in a solvent such as ether, detohydrofuran, etc. at a molar ratio of ~1.5 times to 'fW]. The reaction temperature is about 0 to 40°C. A reaction time of about 1 to 5 hours is sufficient.

To obtain compound [1] from compound [■1], the above [
1] silylation reaction is used.

Compounds [1v] to (iX') etc. obtained in this way can be produced into thin rice grains by means known per se, such as extraction, crystallization, recrystallization, adsorption or partition chromatography. I can do it.

The content of the present invention will be explained in detail below with reference to contracts and examples, and reference ff1l.

The following symbols used in the 9-step example have the following meanings.

S; singlet d string doublet dd i double doublet dddi ) ripple doublet ti) rip l/sito m; matif 0 let q; cultit qd i double cultit quint H clinet br 〼 Wide range of examples/ (4R)-4 -Phenylthioazetidin-2-one 4-phenyls! lefonylazetidin-2-one 7,1
0'! (0,99 ramol) in benzene 20
mllclIi% and cinchonidine (Wako Pure Pharmaceutical Shiba Co., Ltd.).

(a) '7 = -t to, 2° (c = t, 04
, C2H50H), 585,4M', 1.9
9mmo1. , 2 Touo), Chi, t 7 Enru (54
7.2 parts, 4.97 mol, 5 equivalents) was added thereto, and the mixture was heated under an argon atmosphere for 186.5 hours at 11f. The reaction solution was diluted with benzene (ZOOM/), insoluble matters were removed, and the residue obtained by distilling off the reaction solution under reduced pressure was subjected to silica gel column chromatography (Silijke fL/609).
,oil! -'F-/L': Ethyl acetate/l/=2:1
Elution at ~1:1). Obtained 4-phenylthioazetidin-2-one 159.4q (yield 89,
(5%) is ('')V = +54.1' (c = 1.Ol
, C[1C13). (Optical curvature * 52%) The 4-phenylthioazetidin-2-one ((abbreviated as shi)) produced by the above reaction (1) is optically purified by recrystallization. Then a spike was formed.

C(l J % = + !55. Oo(c= O-
95, CHCl3) ↓ Add 132.7# to benzene 1.・The mixture was dissolved once, and cyclobequinone was added in a well where it became slightly cloudy, and the mixture was left at room temperature and further left at 6°C. Obtained/nickel crystals (colorless b57 flakes 84, 9'6
', m p 59, 5° to 74°C) 9 is Cn]
'l = + 17.3° (c = i, 27, CHC
13), and the mother r+ was 1IFi4M
↓ 37.5 da (mp58~
60t:) is Ca]'i = +, L(12,7°(c
=0.75, CHCl3).

Other solvents (acid, methanol, ether)
Even in Petroleum Ete/L/), [a] 2 pups = 1,400~
In the case of recrystallization at an angle of 60°, the material in the mother liquor was optically more pure than that in the case of precipitation as crystals.

However, [α)2. In recrystallization (ether/L/dipetroleum ether) of ↓ without l=+80 to 90°, the crystal had higher purity.

('')'''# = +59.8° (c = 0.92, C
7.58g of HCl3) was recrystallized from ethyl acetate, resulting in crystal h 974mf, (α)'% = +1.0
° (c=i, 03, CHCl3) was obtained, the mother liquor was purified by silica gel column chromatography, and crystals s, z
xg(Cα]I-4-61,7°, (c=0.83.
CHCl3)) was obtained. The ↓ obtained from the mother liquor was again recrystallized from ethyl acetate, giving 1.349 CCU of crystals.
7.7° (c=Q, 91.

CHCl3)] and the mother liquor gave 4.689.

When the upper layer obtained from the mother liquor is recrystallized from ether-petroleum ether μ, the crystallized layer is 2.891(α)%5=-1-95
．． 9° (c=t, 30, Crec13)) and 11.33 g ((α) Sweet + 88
．． 3° ((1=1.54, CHCl3)) was obtained. When the crystals obtained as crystals are further recrystallized from ether-petroleum ether, [α] Kan = +105.1° (c = 0
．． 65, cIIc13) was precipitated as crystals.

(m D L-body, m p 72 'C+ end size - Len der Hemi -yw (Ann,) 197.4.5
39) Pan-p, 58-60°C Infrared absorption spectrum (Engineering R) (CHCl3)Cnl' 3430.
1775 nuclear magnetic resonance spectrum (NMR) (CHCl3. internal standard, tetramethylsilane (TMS)) a: 7.80-7.26 (m, 5
H), 6.64 (br, I H), 5.02
(d d d , l IT , J =4.812-4
.

ABXX centered on 1.01(z), 3.15
'(2, T=15.4, 4.+3, 2.4
, 1.41(z) Quality hk analysis (Mass) m/ei 181.180+ 1
79 (λi゛'), tto.

70 (b?3.FIe) M” C, calculated value for H2WO4 179.0405 Actual value 179.0383 [α] Amase+105.1' (c=0.65.CHCl3
) 5 Example λ (4R)-4-Phenylthioazetidin-2-one 4-acetoxyazeti
To this was added 7.39 d of cinchonidine and 6.5 d of thiophenol, and under an argon atmosphere at room temperature for 210 hours (pressing Nψ1).The reaction solution was filtered under reduced pressure, and
The surface was filtrated under reduced pressure, and the resulting residue was purified with silica gel Kawa 11.
When thickened by chromatography (silica gel, 130f7: eluent: vinegar r1 ethyl-petroleum ether (l:4)), the title compound 4!11, '77 g (yield 79%)
was gotten.

[α)25=42.2°(C=1.04, CHCl
3) 1) Theo Akebono reference example/ (4R)-x-(t-butyldimethyA/siri/I/)=
4-phenylthioazetidin-2-one (4R)-4-
Phenylthioazetidin-2-one518. ! F%'
(2,9(i'm5-c+↓-) in dimethylpho/l/
imidazole (DIAF), dissolved in 1 g/
394.7Q (5,80mmo:l-,2 equivalent), t
-butyldimethylsilinoto chloride 873.9r da (
Add 5.80 mmol, 2 equivalents) under argon atmosphere,
After stirring at room temperature for 2 hours, t-butyldimethylsilyl chloride (2,2 equivalents) was added, and the reaction was stirred overnight. Approximately 100g of needles and 10n of water were added to the liquid and pressed into a stopper, and the ether layer was separated.The ether layer was diluted with water and saturated saline.
After washing and drying over anhydrous magnesium sulfate, the ether was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (silicage/I/25S, vinegar "1 (ethyl/I/: petroleum ether=1Nia)" to give the title compound 792.9r!I (yield 93. 3 each ≦) was obtained as a colorless oil.

ER (CI (CI3) cm 12955.2930.
1735°1300. 1256. 1168,842
,822N M R (CDCl2.TMS) δ; 7
．． '38(brr+, 5H)+4.93(dd, IH9
J=5-0+3.0Hz).

ABX centered at 326 (2Ii, , T=16.0.
5.0°3.0Hz), 1.01 (8,9H), 0.2
8 (s, 3H).

0.08 (F!, 3H) Mass m/ei 295+ 294.293 ()J
+), 184°42 1.1+C□5H23NO8iS calculated value i 2
93.1269 Actual 1 Law A Direction 293- 1256 [α] 枦--164.3° (cmt, 54, CH
Cl3) Reference example λ (4R)-1-(t-butyldimethylsiliIL/)-3
-(1-hydroxyethyl)v) -4-phenylthioazetidin-2-one and (3R,4R)-1-(t-
Butyldimethylsilyl/)-3-((IR)-1-hydroxyethylcy4-phenylthioazetidine-2-
5 tons of freshly distilled tetrahydrofuran (THF')
l-Butyllithium-hexane solution (1,53M solution fs'i, 1°7 units/13 equivalents M) and diisopropylamine (267°I
n'! (4R)- to lithium diisopropylamide (L])
1-(t-butyldimethyl/silyl)-4-phenylthioazetidin-2-one (254Q, 0.87mm
A THF (5*t) solution of 1 ml) was added at 7 el, and the container was further washed with 2 vats of THF' and added to the reaction solution.

After stirring for 30 minutes under the same conditions, freshly distilled acetoano 1/dehyde (197 V, 5.Z equivalent) was added for 10 minutes.
After wiping for 1 minute, a saturated aqueous solution of ammonium chloride was added at -78"C to stop the reaction. After warming the reaction solution to room temperature, extraction was carried out with ethyl chloride for 30m
rx3), there is ILj place A at 11! I Wash with Japanese salt water for 6 days,
Subsequently, after drying with anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound (mixture) crude product 31.9.6.
*I got t. From this product, (38,4R)-1,-(t-butyldimethylsilyl)-3-[(11-1- Hydroxyethyl #)-4-phenylthioa 98.2 units (yield 67.8
%) was obtained as a colorless oil.

m, p, 93-93, 5'C (recrystallized from ether-petroleum ether) I R (CHCl3)cnf' 3430.173
8. 1300°125B, 842.822 N M R (CDCl2.TMS) δ B 7.66 ~
7.20 (ro, 5H), 5.00 (d, IH,
J=2.0Hz), 4.14(m, H(), 3.19(
dd, IH, J=4.0.2.0Hz), 2.42(b
r, IH), 1.10 (d, 3H, J=7.0Hz).

1.00 (s, 9H), 0.30 (S, 6H) MasS
, m/e 339. 33L 337 (M+),
228°210, 142 Calculated value for Toke CF upper 2F NO2SIS;
337.1531 Actual measurement value + 337.1548 Elemental content 4IT' value C□7H, C as No2SiS
HN Total - IVft (9.4cio, 51 8.07
4.15 Tue A1 (1 value (@10.45 7.98
4.16 [α] yearst, 7' (cmt, 24
．． CHCl3) (4'l+ 3゜(3S,4R)-1-(t-butyldimethylsilyl)-
3-acety/L/-4-phenylthioazetidine-2-
(4R)-t-(t-butyldimethylsili/l/)-3
-(1-Hydroxyethyl)-4-phenylthioazetidin-2-one 50.6 dF (0.15 mmol) was dissolved in 2rt+i methylene chloride, and heated in an argon atmosphere with a stream of room temperature. Sephite while doing (&545゜]oo
After adding Collins reagent (233'5', 6 equivalents) and stirring vigorously for 30 minutes, Collins reagent (336, 311 &, 8.7 equivalents ↓) was added, and 1
At +7411'li', it was stirred. Methy chloride 1/20
After adding about 1 liter and about 1 liter of Florisil and stirring for 30 minutes, the reaction solution was filtered through a short column of Florisil, and the column was further washed with methylene chloride (about 200 */liter).

The crude product 46.5Mf obtained by distilling off methylene chloride under reduced pressure was subjected to silica gel column chromatography = (
Shirikage/L'49. Petroleum etherμ: ethyl acetate/L/-
4:1) to give the title compound 43.4π! (Yield 86
．． 3%).

I R(CHCl3) cm 12955.2930.
1,745°1708, 1635. 1617. 1
285. 1160.840°821,807 NMR(Or)C13,TMS)δ: 7.60~
7.16 (m, 5H), 5.35 (d, IH, J=2
．． 2Hz), 4.25(d, IH1J=2.2Hz),
2.24 (s, 3H), 0.98 (s, 9H), o, 3
o(8,61 λKass m/eH337,336,335(M+
), 320°278, 2261 1421 115.
Calculated value for 73 (ba, se) M+C□7H25NO2SSi; 335.1375 Actual value 5335.1
372 [α] Xi = -65.1° (cm2.55.CHCl3)
Reference example Kyu (33,,4R)-1-(t-butyldimethylsilicon/l
/)-3-((iR)-1-hydroxyethyl]-4-
Phenylthioazetidin-2-one and (3s, 4R)
-x-(t-butyldimethylsilyl)-3-((Is)
628. 2'EI (1,89 mmol)
was dissolved in methanol/l/l OH under argon atmosphere.
While stirring at 78°C, water-accumulated sodium boronate (71
, ITigT ]-, 88m+nol) and -781
E for 20 minutes, then the cooling bath was removed and the mixture was stirred for 5 minutes. The mixture was cooled again to -78°C, and acetic acid and saturated ammonium chloride aqueous solution were added to stop the reaction. After the reaction solution was warmed to room temperature, methanol was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (mixture) of the title compound as an oil. This item is Kafumu Chromatogwofi (Shirikage/I/63
Refined with g2 petroleum ether/I/:ether-5:1) and processed with low aspiration (3S, 4R)-1-
(t-buty/l/trimethylsilyl)-3-1(iS)
280.9 rtry of -1-hydroxyethylcou-4-phenyltimeazeticin-2-one (yield 44.4%)
>, as a fuction with high +x properties (38, 4R)
-1-(1-butyldimethylsilyl)-3-((IR)
-1-hydroxyethylcou-4-phenylthioazetidin-2-one at 34. gtny (yield 5.1), and a mixture of both at 222.5r':(1 (yield 3582%)
) was obtained. The mixture was again partitioned by silica gel column chromatography and the former fJZ 64.3'Q', the latter 1], 0.3119, and a mixture thereof 20.
2!7! I got /.

X R(CHCl3)cm': U375.
1735N M R (CHCl3.TMS) δj 7
．． 62-7.12 (m, 5H), 4.80 (d, IH,
J=2.2Hz), 4.00(m, 1B), 3.20(
dd, IH, J=5.6, 2.2Hz), 2.35(b
r, IH), 1.20 (d, 3H, J=6-2Hz),
0.97 (s, 9H), 0.29 (s, 6H) Maas
m/e 339. 338. 337 (M+),
313°228.210 + M +I C,, calculated value i for H28NO2SiS
338.1610 Actual value; 338.1590 [α) D=-75,4° (a-=1.29, cHc
13) Reference example (3s, 4l-3-((tl-x-hydroxyethyl~)
-4-phenylthioazetidin-2-one (3S,4R)-1-(t-butyldimethylsilyliv
)-1-((IR)-i-human aquiche+*)-4-phenylthioazetidin-2-one 111°4W(0,3
3rnmol) of methanol-1v (MeOH) (5d)
The solution was dissolved in a bath, 0.5 g of 1 O*HC1 (W/W) was added thereto, and the mixture was stirred at room temperature for 4 hours. After terminating the reaction by adding a saturated aqueous sodium hydrogen carbonate solution, methanol under pressure was distilled off, and the resulting residue was extracted with ethyl acetate. The alimentary layer was washed with water and saturated brine, dried over anhydrous magnesium, and then concentrated under reduced pressure to obtain the title compound 6.
5.2111f (yield ss, s%) was obtained. The product was used in the next reaction without purification.

IR(CHCl3)Cm-13420,3400,1
76ON M R (CDCl2.TMS) δ; 7.
62-7.20 (m, 5H), 6.23 (br, IH)
, 5.09 (d, IH, J-2,0Hz), 4.26 (
qd, IH, J'=6.4. '4.0Hz), 3.13
(dd, 11 (, J=4.0, 2.0H2), 1.19
(d, 3H.

J=6.4Hz) Mass m/e: 223(M+), 142M
+C Yo IH13; 'Calculated value i for JO2S 223
．． 0667 Actual measurement value i 223.0661 Elemental analysis value CHN as C engineering, H engineering 3 No 2 s Calculated value (@纂 59.18. 5.87. 6.28 Actual #J value (9);, 59.03. 5 .89. 6.
291α]2o5=+64.4°(Cm0.65,
CHCl3) Reference example (3S, 4R)-3-1c(IR)-1-formi7leoxyethyl]-4-phenylthioazetidin-2-one (3S, 4R)-1-(t-butyldimethylsilyl) death)
-3-((is)-1-hydroxyethyl]-4-phenylthioazetidin-2-one 417.7'y(1,
24mtool),)su71m=7'phosphine1.
63 g (6,21 mu+ol, 5 ml) of formic acid (purified by distillation) was dissolved in anhydrous tetrahydrofuran (THF) at room temperature under an argon atmosphere and stirred.
．． , bp=40~43℃/55 +n1+J
ig, 373.6”g, 13.] 2 mmol, 6
．． 5 equivalents) was added, and 1.08 g of diethyl azodicarboxylate ((5,21 nonol, 5 equivalents) was added dropwise over 20 minutes. The reaction did not occur and proceeded gradually, and after the completion of the dropwise addition 4.5 g The mixture was stirred for an hour and concentrated under reduced pressure.The residue was purified by column chromatography (silica gel).
0 Q, petroleum ether/shi:ether=4:l)
The title compound was purified at 323.0+ as a yellow oil.
, we obtained Q'. Based on the NMR spectrum, this product contains fewer impurities that are thought to be derived from diethyl azodicarboxylate:
! Although it contained λ, it was used in the next reaction without further purification.

IR(CHCl3)c+n-13425,1770,
1'725°1600, 118O N M R (CDCl2.TMS) δi 7.98 (
S, IH), 7.54-7.28 (m, 5H), 6.6
0 (br, IH), 5.40 (quint, IH, J=
6.2Hz), 5.00 (d, IH, J=2.4Hz)
, 3.24 (dd, IH, J=6.2.2.4Hz),
1-. 39 (d, 3H, J=6.2Hz) Ma, ss rn/p; 253.252. 251
D(+), 205゜42 λ + Cl2H Calculated value to be carved into 3N03S; 251゜0616 Actual law value i 251-05! J6 t9 Example Z (3S,4R)-3-((IR)-1-hydroxyethyl]-4-phenythioazetidin-2-one previously obtained (38,4R)-3-((IR) 323.0q of -1-formyloxyethyl, :]-]4-phenylthioazetidine-2one was dissolved in 30 ml of methanol, and 1 g of 10% I (C1 (W/W)) was added thereto at room temperature.
Stir for 5 hours. After stopping the reaction with a saturated sodium bicarbonate aqueous solution, methanol was distilled off under reduced pressure, and the residue was extracted with ethyl acetate.

Wash layer 1 with saturated saline 1. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, 274.71 rl of the title compound was obtained.
R, Mass, (rt) 1) is a reference example! The data were in complete agreement with the data obtained for the compound.

Reference example and (3s,4R)-3-((1R)-t-(t,-butyldimethylsilyloxyethyl/l/))-4-phenylthioazetidin-2-one (3S,4R)-3 -((IR)-1-human V1 xyethyl]-4-phenylthioazetidin-2-one 298
．． 1~(1,31m+nol) was dissolved in DMF'0.5Pl, and imidazole 2G7.3"f (3,93mm
ol, 3 equivalents), t-butyldimethylsilyl chloride 5
91.7#I (3.93 mmol, 3 equivalents) was added, and the mixture was stirred at room temperature for 3 hours under an argon atmosphere. After the reaction was completed, 150 d of ether and 10 ml of water were added and the mixture was heated for 102 minutes. The two layers were separated, and the organic layer was washed with water and saturated brine, and then dried over 171q aqueous magnesium silicate solution. The title was obtained by distilling off the ether under reduced pressure.

The compound was obtained as a colorless powder. This product was used in the next reaction without purification.

Engineering R (C [013) cnl l 3420.176O
NMR(CDcI3.T)As) δ;7.3B
(bηs, 51().

6.42 (br, LH), 5.1) 6 (d, IH, J=
2.0Hz).

425(m+IH)+3-OJ(m+l
kI) + 1. , ]-9(d + 3H, J=6
．． 0flz), 0.92(s, 9H), 0.05(q,
6H) 1 Ma, ss mle; 338+ 3370.4+
L 33Ci128f) + 36 (M""Bu) Total M value i for C13H□6NO2SiS 280.0827 Actual value; 280.0825 Reference example (38, 4R) -3-f" (, LR) -1-(t - Butyldimethylsilylleokishetti/I/ ) -4
-Phenis/l'honylazetidin-2-one (3s
,4p,)-3-((IR)-1--(t-butyldimethylsilyloxyethyl)v))-4-furyγ/,enylthioazetidine-2-5a1mn]o1) C
m-chloroperbenzoic acid () 1 was dissolved in 1210 ml VL of H2 and stirred for 4'i° under an argon atmosphere.
'1.4''V (3,34tt+mol, 2.5
I added ``Toko'' and did a 10-minute denhai. During the saturated phase, add 4p)l of 16fc acid sodium water i'd solution and 4pl of saturated sodium carbonate ice water bath solution for 20 minutes)'! After stirring, CH
The water extracted with 2 Cl2 was washed with 1 water solution of 1 sodium hydrogen phosphate (and 1 water of Japanese food JiX),
(J) (water M jM' (dry with magnesium; ¥:u,
A crude product was obtained by condensation under reduced pressure. Column chromatography (silica gel 40q1 petroleum goude/v
The mixture was made viscous with ethyl=3:1) to obtain the compound 240.1+. This has optical activity shifts i1~g, 6 tris(3-(
heptafluoropropylhydroA dimethylene)-d-
It was found to be optically pure by 1 fill NMR determination using conflated coeuropium (au(hfc)3).

ip, 170~t 7t't: (ether-petroleum ether/L/) I R (CHCL3) cm 13420.2
951.2930°2850.1785, 11.50,
84ON M R (CDCl2.TMS) δi 7.
98 (dd, 2H, J=7.2, 2.0Hz),
7.90-7.54 (+m, 3H), 6.34 (br,
l'H), 4.83 (d, iH, J=1.911).

4.29(qd, H(, J=6.5, 2.3H2
), 3.44 (dd, IH, J=2.3, 1.9Hz
), 1.13 (d, 3I[, J=6.5Kz), 0.8
5(s, 9H), Q, (151?- and 0.02(R.

6H) Magp mle j 369 (M+), 354
．． 317! , 228(M+-tBtl) C13H
□, calculated value for 3NO4SSi + 312.07
21 Loss 1 + Hat I γ Ding ¥ 31.2.07013 Elemental Analysis I
l+lI0□711217NO4SSi binding CHN measurement [(@ delirium 55.29. 7.38
．． 3.78 Actual value (store; 55.', 36.
7.31. 3.73(a) Sweet=-11,oo(cmo
, 91, CI (C13) spring example/θ (3S, 4R)-3-C(JR)-t-(t-butyldimethylsilyloxyethyl/L/))-4-10 vinylazetidine-2- Attach a reflux condenser and place metallic magnesium (55 to 10 equivalents) and a catalytic amount of mercuric chloride in a 20 flask.
After heating and drying with a dryer while reducing the pressure with a vacuum pump, dry with argon gas.

Anhydrous ether) V 6 Pe was added thereto, stirred thoroughly, and then propargyl bromide 320.4"9 (t
11N) was added and reacted at room temperature. After the intense reaction is completed, it is cooled to -18tE and
2 at was added. (38,4R)-3-C(IR)-
1-(t-butyldimethylsilyloxyethyl/v))-
4-Phenylsulfonylazetidin-2-one 98°8
1″9 (0,27+nmol) anhydrous T tT F
This solution γf (2) was added dropwise from the dropping funnel to the glass test chamber prepared above, and the dropping funnel was further washed with THF'1 and this washing solution was also added to the reaction solution. 118
℃ for 1'i, 'J'l'' for 5 min, and then pressed on one side for 30 min at 0°C. After stopping the reaction by adding saturated ammonium chloride aqueous solution at 0°C, the crude product was Extracted with ethyl torate (3 (3×3). Extracted with 1.'1.
1.11 1'-'e with Japanese salt solution, rinse with anhydrous (iijf
After drying with magnesium chloride and condensation, 125.8m+i"Q of phase-forming acid was obtained. Column chromatography (silica gel 309.petroleum ether/': f'
The compound 64.7 was obtained as colored crystals (yield: 90.5%).

sum, p, 119.6-120.5°C (ether-petroleum ether/L/) I R(CHCl3)cnr 13430.332 (1
,2930°1760, 1140.838 NMR(CDCl2.TMS)δ; 5.94
(br, lH).

4.23 (qd, IH, J=6.0, 5.0Hz), 3
．． 89 (dt.

IH, J-7, 0, 2, 0Hz), 2.93 (dd, I
H, J = 2.0.5.0Hz), 2.56 (dd, 2H
, J=5.0,2. (lHz), 2.06(t, IH,
J=2. QHz), 1.24 (d, 3H, J=7.0H
z), 0.90 (e, 9H), 0.09 (s, 6H) M
ass m/eH269, 268, 267 (M+),
211゜210, 166, 75 (M++1) C Yo4 [1 word for I26N02S1 Sanzihaku; 268.1732 cusp value delusion
268.1753 Elemental analysis 1α CHN calculation as C engineering 4H25NO2Si [(@; 62.87. 9.42. 5.24
Actual value (@; (I2.99. 9.40. 5.1
4(/7) ,,=-4,2°(Q=4.53,
CHCl,, ) Reference example // (3S,4R)-1-(t,-butyldimethylsilyl)
-3-((IR)-1-(t-p1-iv dimethylsilicon/L/O6-cieg)v)]]4-provinyla! Tidin-2-one (3S,4R)-3-((:1.R)-t-(t-butyldimethylsilyl))-4-10 Vinylazetidin-2-one 430 places q(0, 16 mmo1.
) to D), 4F' 0.1++/l:ON,
Triethylamine 72.6QC sail 72m+l] o1. , 4
, 5 equivalents IMI) + t-butyldimethylsilyl chloride ((32 mmol, 2 equivalents)) was added, the reaction was left for 14.5 hours, and further triethylamine 7
2.6')'I and t-butyldimethylsilyl chloride 4
8.5lll? P was added and stirred for 1 hour. After adding 30 g of ether and 10 g of water to the reaction solution and stirring, the ether layer was separated. ! :It's L. The water was further extracted with ether. The combined ether) vu was washed with saturated water, dried over anhydrous magnesium oxide, and concentrated under reduced pressure to obtain a crude product. The title compound 48.7F7!7 (yield: 80. (1 example)) was prepared using ethyl vinegar and ethyl chloride (15:1).

Engineering R (CHCl3) (・+++ ” 332
0. 2950. 2925°2850, 1738.
1255.839N M R (CDCl2.TMS)
δ+ 4.22 (qd, IH,,'l'=6.5,4.
0Hz), 3.80(dcM, l[(, J=6.5
,4. +1.2.5Hz), 3.09(dd, In,,
T=4.5.2.5Hz), 2.58(m, 2H), 2
．． 06 (t, If-1, J=2..5Rr,), 1.2
5 (cl, 3H, J=6.5Hz), 0.98 (s, 9
1 (), 0.90 (8, 9H), 0.25 (s, 6H)
, old) 9 (s.

3H), 0.07(F3.31()

Claims (1)

[Claims] 1. Represented by the general formula [wherein R represents a lower alkyl/L/ group, an optionally substituted ary/l/ group, or an optionally substituted aralkyl group] Optically active 2-azetidinone derivative. 2. Compounds represented by the general formula [wherein, optionally a v-/L/ group or B-substituted aralkyl) V
1. A method for producing an optically active 2-azetidinone derivative represented by the general formula [wherein R is the same as above, with the α meaning], which is characterized by reacting a group [representing a group] with cinchonidine in the presence of cinchonidine.