JPS5970663A - Preparation of beta-lactam derivative - Google Patents

Abstract

PURPOSE:To obtain 3-acetyl-2-azetidinone which is a synthetic intermediate for medicines having the antimicrobial action efficiently by easy operation, by reacting diketene with a Schiff base obtained from an aldehyde in an inert solvent in the presence of an imidazole. CONSTITUTION:A Schiff base obtained easily from an aldehyde and an amine, e.g. the Schiff base obtained from di-p-anisylmethylamine and n-butyl glyoxylate, is reacted with diketene in the presence of an imidazole, preferably imidazole or 4-methylimidazole, to give a 3-acetyl-2-azetidinone derivative, e.g. 1-(di-p-anisylmethyl)-3-acetyl-4-n-butyloxycarbonyl-2-azetidinone. USE:A synthetic intermediate for various epsilon-lactam derivatives, e.g. carbapenem derivatives and penem derivatives, which are medicines having antimicrobial action.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 8-acetyl-2-azetidinone derivatives by reacting digetene with a Schiff base obtained from an aldehyde in the presence of imidazoles. .

8-Acetyl-2-azetidinone derivatives (for example, carbapenem derivatives having a 1-hydroxyethyl group at the 6-position, or penem derivatives, etc.) can be useful intermediates in the production of various β-lactam antibacterial agents. Several methods are already known for its production, but all of them require a long number of steps, complicated reaction operations, or require unstable intermediates. Each of them has some difficulties, such as having to go through the following steps.

The present inventors have conducted intensive research to develop a new method for producing 8-acetyl-2-azetidinone derivatives that is easy to operate and efficient. They discovered that the objective could be achieved by carrying out the reaction in the presence of imidazoles, and completed the present invention.

The method of the present invention will be explained in detail below.

The production method of the present invention is a method for obtaining an 8-acetyl-2-azetidinone derivative by reacting ditethene with a suitable Schiff base in an inert solvent in the presence of imidazoles.

Examples of imidazoles used in the reaction include imidazole and various imidazole derivatives such as imidazole substituted with lower alkyl at the 2- or 4-position such as 4-methylimidazole, 2,4-dimethylimidazole, and 2-methylimidazole. However, imidazole or 4-methylimidazole is preferred.

Imidazole can be used in a large excess amount as a catalyst, but from 0.1 to 1.0 molar amount per 1 Schiff base.
It is desirable to use 5 times the molar amount.

Examples of inert solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform,
Halogenated stratified hydrogens such as 1,2-dichloroethane or mixtures thereof are preferred. Ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether, nitriles such as acetonitrile, aliphatic hydrocarbons such as hexane, heptane, cyclohexane, and pentane, dimethylformamide,
Various heating media such as dimethyl sulfoxide or acetate esters such as methyl acetate and ethyl acetate can also be used.

It is possible to suppress or accelerate the reaction by cooling or heating, but the reaction temperature is between -1θ℃ and 1θ℃.
20°C is preferred.

After completion of the reaction, the target compound of this reaction can be taken out by ordinary organic chemical techniques.

By the method of the present invention, β-lactam derivatives having an acetyl group at the 3-position of the β-lactam structure can be obtained, and these include carbapenem derivatives, penem derivatives, etc. (Fβ-lactam derivatives, For example, 'I'etrahedron Letters, 229
8 (1982) d.

As the raw material Schiff base obtained from aldehyde, it is possible to use Schiff bases having various substituents. Derivatives of -γcetyl-2-azetidinone having various 14 substituents at the 2- or 4-position can be produced.

For example, according to the method of the present invention, general formula (I)-1(2 N (1) R.

In the formula C, l(, represents an arylmethyl group, a diarylmethyl group, or an aryl group, and R2 represents a conserved group, thus representing a conserved calhoyl group, a cyclic alkyloxycarbonyl group, or an aryl group. By reacting the Schiff base represented by the following with diketene, a β-lactam attractant represented by the general formula [in the formula, it, and it2 indicate the same laziness as described above] can be obtained. I can do it.

The raw material compound (general formula CI) brown Schiff base can be easily synthesized from the corresponding aldehyde and amine by a commonly used known method (therefore, the Schiff base obtained in this way can be simply synthesized). Let go or Ha4
4 (can be subjected to reaction with diketene).

Next, R1 and the λ chamber in the above equation will be described in detail.

In R, l, examples of the arylmethyl group include benzyl group, substituted benzyl group, etc., examples of the diarylmethyl group include unsubstituted or substituted diphenylmethyl group, and examples of the aryl group include Examples include phenyl group and substituted phenyl group. Furthermore, the substituted benzyl group includes a benzyl group substituted with a lower alkoxyl group having 1 to 8 carbon atoms such as a P-methoxybenzyl group and a 2,4-dimethoxybenzyl group, and a nitro group such as a P-nitrobenzyl group. Examples of the substituted diphenylmethyl group include diphenylmethyl groups substituted with a lower alkoxyl group having 1 to 8 carbon atoms such as di-P-anisylmethyl group, and directly substituted phenyl groups. Examples of the group include a phenyl group substituted with a lower alkoxyl group having 1 to 8 carbon atoms such as P-methoxyphenyl group.

In k2, the protecting group for the carboxyl group is a commonly used protecting group, such as a lower alkyl group, a mono- or diaryl lower alkyl group, an aryl group, a substituted lower alkyl group, and the like. Here, examples of lower alkyl groups include linear or branched lower alkyl groups having 1 to 5 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, and t-butyl group. Examples of the mono- or diaryl lower alkyl group include benzyl group, P-methoxybenzyl group, 2,4-dimethoxybenzyl group, P-nitrobenzyl group, 0-nitrobenzyl group, diphenylmethyl group, di-P-anisylmethyl group. Examples of aryl groups include unsubstituted or substituted mono- or diphenylmethyl groups with lower alkoxyl groups having 1 to 8 carbon atoms or nitro groups, such as ≠
Examples of substituted lower alkyl groups include unsubstituted or substituted phenyl groups such as phenyl and P-nitrophenyl groups, such as 2,2,2-trichloroethyl group and 2-iodoethyl group. Examples include a lower alkyl group having 1 to 8 carbon atoms substituted with a lower alkoxyl group having 1 to 8 carbon atoms substituted with a halogen atom, and the like.

Furthermore, in R1, a cyclic alkyloxycarbonylcarbonyl group, norbornyloxycarbonyl group, etc.
Examples of the aryl group include a phenyl group or a phenyl group substituted with a lower alkoxyl group having 1 to 8 carbon atoms such as a P-methoxyphenyl group.

In the compound represented by the above general formula obtained by the method of the present invention, 8-acetyl group! There are two steric relationships, cis and trans, and stereoisomers exist, but the trans isomer can be obtained with selectivity. In addition, the acetyl group! The substituted carbons at the 8th and 4th positions are asymmetric carbons, and optical isomers exist.

Furthermore, the general formula obtained by the method of the present invention [wherein R,
has the same meaning as above. ] In the β-lactam compound represented by
The production ratio of (s)-derivatives is such that the menthyl group is
By using an optically active menthyl group such as a 1-(-)-menthyl group, a 4-(Sl- derivative can be obtained as the main product, although it varies depending on the reaction conditions, the type of R1 substituent, etc.).

As mentioned above, the method of the present invention provides effective 8-acetyl-
A 2-azetidinone derivative and a method for producing the same are provided.

Next, the present invention will be further explained with reference to Examples, but the present invention is of course not limited to these in any way.

In addition, in the following examples, the following abbreviations are made.

: DAM n-Butyl group : n-Bu Phenyl group : Ph P-methoxyphenyl group (p-anisyl group) 2Ani
s [Example 1] G-P-anisylmethylamine 2.48f (lomM)
, n-butyl glyoxylate 1.78 f (12mM
) was dissolved in toluene (96 g/), subjected to azeotropic dehydration to produce Schiff base, added toluene equivalent to the distilled amount, and added 0.68 t (l OmM) of imidazole.
Digetene 1.01F (12mM) in toluene (
8041/ ) solution was added dropwise over 2 hours and stirred for 15 minutes. The reaction solution was poured into cold diluted hydrochloric acid, extracted with toluene, and then diluted with 2N
-Washing with hydrochloric acid, saturated saline, saturated sodium bicarbonate, and saturated saline;
The l-
(di-P-anisylmethyl)-8-acetyl-4-n-
Butyloxycarbonyl-2-azetidinone 8.86F
(88%).

m, P,: 92.5-94.0°C IRnu”1 (m-1): 1765.1740,171
2゜ax 1612.1255, 1026.818NMRδ(CD
CIs): 0.60-1.80 (7H, m)
, 2.28(8)1. s), 8.77(6)1. s)
, 8.77-4.15. (2)(.

m), 4.17 (LH, d, J=2Hz), 4.40 (
IH.

d, J=2H2), 5.78(l)1. s), 6.60
~7.40 (gH, m), p, p, m.

[Example 2] DAM di-P-anisylmethylamine 248q (1mM), n-butyl glyoxylate 178++y (1,2tnM
) was dissolved in toluene (12 m/), azeotropically dehydrated to produce a Schiff base, and the same amount of toluene as the distilled amount was added.
Add 4-methylimidazole s2q (1mM) and
Digetene lol (1,2 mM) 0)) at °C
/l/x7 (0.5 yttl) solution was added dropwise over 20 minutes and stirred for 8 hours. The reaction solution was poured into cold diluted hydrochloric acid, extracted with toluene, and the extract was mixed with 2N hydrochloric acid, saturated saline,
After washing with a saturated aqueous sodium bicarbonate solution and a saturated saline solution and drying with sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting oil was separated and purified by silica gel thin layer chromatography to obtain 1-(di-P-anisylmethyl)-8-acetyl- 240 μm (65%) of 4-n-butyloxycarbonyl-2-azetidinone was obtained.

I K , NMR was the same as that obtained in [Example 1].

[Example 8] G-P-anisylmethylamine 24819 (1mM),
Glyoxyl n-butyl 178 ml? (1,2m
M ) was dissolved in 7 (12+wt), azeotropically dehydrated to produce a Schiff base, and the same amount of toluene as the distilled base was added to give 2-methylimidazo-/I/82mg.
(l tnM ) and diketene 101η (
1,2m M) /L/ x 7 (0,5ml
) The solution was added dropwise over 20 minutes, stirred for 2 hours, and then added for 60 minutes.
The mixture was stirred at 80°C for 1 hour and then at 80°C for 1 hour. By performing post-treatment and separation and purification in the same manner as described in [Example 2], l-(di-P-anisylmethyl)-8-acetyl-4-n-butyloxycarbonyl-2-azetidinone 24+v(5 %) was obtained.

IR and NMR were the same as those obtained in [Example 1].

[Example 4] G-P-anisylmethylamine 1.118F (4,f,
), glyoxylic acid-1-(published-menthyl 1.
058f (4.6mM) was dissolved in toluene # (4B / ), azeotropically dehydrated to produce Schiff base, added with the same amount of toluene as the distillation apparatus, and imidazole 818! (4,6mM) and dikete 74.646f (5,5mM) of toluene (14
*t) The solution was added dropwise over 2 hours and stirred. By post-treating and separating and purifying the reaction solution in the same manner as described in [Example 1], 1-(di-P-anisylmethyl)-8-
Acetyl-4-e-←)-menthyloxycarbonyl-2l)-8-acetyl-4-e-(-)-menthyloxycarbonyl-2-azetidinone is n-hexane-
By performing fractional recrystallization with carbon tetrachloride solvent, 4-(
It was possible to separate 81 compounds, (O8,48)-1-(di-p-7nisylmethyl)-8-acetyl-4-#-(-
)-menthyloxycarbonyl-2-azetidinone was obtained.

Iris u, p: 99-100°C IRnujol (crll-'): 176B, 17B
9, 1712.161B.

ax 1510.1242.1088.818.

NMI-δ(CsDe+): 0.50-1.96(
19)1. m), 1.94 (8H.

S), 8.88 (6H=S)*4.00 (IH, d, J
=2Hz)4.75(IH,d,J=/!Hri,4
．． 40-5.05 (11-1゜m), 5.90 (LH,
S), 6.60-7.60 (8H, m) p, p, m.

In addition, by crystallizing the furnace liquid in the n-hexane-carbon tetrachloride section (8K).

4K)-1-(di-p-7nisylmethyl)-8-acetyl-4-g-(-1-menthyloxyca, rubonyl-2-azetidinone) was obtained.

m, P,: 128-125°C IRnu"'(cIn-'): 1770t1740.1
71B, 1606-ax・1506.1241.1202.1028.822
NMRδ (CsCI+): 0.50-1.95 (19H
, m), 1.98 (8H.

S), 8.28 (8B, S), 8.80 (8H, S),
4.12 (IH, d, J = 2) 1g), 4.75 (IH
*'-J=2'').

4.40-4.85 (lH, m)', 5.94 (IH,
S).

6, fSO~7.50 (8f(,m), P, P
, m.

[Example 5] G-P-anisylmethylamine 248 (1 mM), n-butyl glyoxylate t7smp 1.2 mM))
/I/ F (7Hl), azeotropically dehydrated to produce a Schiff base, added the same amount of toluene as the distilled amount, and imidazole 84111! (0.5mM) and 50
A solution of diketene l 014 (1.2mM) (7)) toluene (5.5g1) was added dropwise to the mixture over 2 hours at 0.degree. C., and the mixture was further stirred for 1.8 hours. The reaction solution was post-treated and separated and purified in the same manner as described in [Example 2] to obtain 1-(di-P-anisylmethyl)-8-acetyl-4-n-butyloxycarbonyl-2-azetidinone 856. ■ (81%) was obtained.

(IR and NMR were the same as those obtained in [Example 1].) [Example 6] Di-P-anisylmethylamine 243μ (1mM), n-butyl glyoxylate 17811% + ( 1,2mM)
was dissolved in toluene (7 Mt), azeotropically dehydrated to produce a Schiff base, added with the same amount of toluene as the distilled amount, added with imi')''/-ru'1tQ (0, LmM), and heated at 50°C.
101 mg (1,2 mM) of diketene in toluene (5,
5 ml of solution was added dropwise over 2 hours and stirred for 8 hours. By post-treating the reaction solution in the same manner as described in [Example 2] and separating and purifying it, ■-(di-P-anisylmethyl)
-8-acetyl-4-n-butyloxycarbonyl-2
-Azetidinone 268% (60%) was obtained.

(IEL and NMR were the same as those obtained in [Example 1].) The following compounds can be obtained by the same method as shown in [Example 1].

In addition, "amount" in the "Raw material compound" column refers to the following:
The corresponding amines (R1-NH,) and aldehydes (R,-CHo) used to generate Schiff bases, respectively.
) indicates the amount of -'t.

Hand pillow correction helmet (spontaneous) December 27, 1980 Commissioner of the Patent Office Kazuo Chikusugi Tono 1, Matter 1'1 Indication 1980 Patent Application No. 180268 2 Name of the invention β-lactano, production of derivatives Law: 3. Relationship with IT I'L Patent applicant Representative name of Sumitomo Chemical Co., Ltd., 5-15 Kitahama, Higashi-ku, Osaka (2+19)
Takeshi Kamigata 4, agent contact 5'1. i” I!: L, (06)22111
-34045, hlt iL object clear ♀ Ill li+ Detailed description of the invention column 6゜ Contents of amendment Detailed rock No. 2/L page Example 14ζ
Compound 1'< z (, t11') r-C0 in column J
Let 0An i sJ be r-COOMe nJ.

Procedural amendment filed June 1, 1982 1 Case description 1980 Patent application No. 180268 2 Title of invention Process for producing β-lactam derivatives 3 Address of person making the amendment Address related to the case Osaka 5-chome Kitahama, Higashi-ku, tnPlace name (209
) Sumitomo Chemical Co., Ltd. Representative Takeshi Hijikata 4, Agent Tomoji Address 5-15-5 Kitahama, Higashi-ku, Osaka, "Detailed Description of the Invention" column 6 of the specification to be amended, Contents of the amendment (1) ) On page 4 of the specification, lines 14 to 17, ``For example...
·····can. ” is corrected as follows.

[For example, the compound of formula (1) obtained by the method of the present invention can be led to the compound of formula (5) by the following synthetic route.

(1) (2) (4)
(5) [In the formula, 几 represents a carboxyl group-protecting group or a ring alkyl group, DAM
represents a di-p-ayucylmethyl group, and Y represents a hydrogen atom or a hydroxyl group-protecting group. ] The reduction of the carbonyl group of the acetyl compound (1) can be carried out according to various methods generally used for reducing a carbonyl group to a hydroxyl group.

Hydrolysis of the ester group of compound (2) is generally carried out according to well-known methods.

For example, the reaction can be carried out by reacting compound (2) with caustic soda in a solvent such as methanol or tetrahydrofuran in the presence of water at 0 to 40°C.

A method for converting carboxylic acid (3) into ester (4) is, for example, Tetrahedron Letter 11+ 22
98 (1982) and the like. Alternatively, the acetyl compound (1) can be converted into a compound (2).
The reaction can also be carried out according to the method described in the above-mentioned literature.

Compound (4) can be converted to compound (5) in various ways, but for example, in acetonitrile-water, 1
C!eric ammonium nitrate at 5 to 85°C.
), it is possible to achieve the DAM removal reaction, and the method described in JP-A-57-11962 can be applied.

The hydroxyl group of compound (4) is protected by a known method with various hydroxyl protecting groups such as p-nitrobenzyloxycarbonyl and t-butyldimethylleryl, and then the above-mentioned de-D
It is also possible to perform an AM reaction.

Compound (5) can be prepared by known methods such as the above (7).
Tetrahedron Letters, 229B
(1982), carbapenem derivatives such as chenamycin can be obtained according to the method described in (1982). ”(2)
Following the last line of page 24 of the specification, the following addition is made:

[[Reference Example 1]. □ (88,48)-1-(di-p-ayucylmethyl)-8
-acetyl-4-1-(-) = menthyloxycarbonyl-2-azetidinone (27 m) of isopropanol (
Sodium borohydride (2 hits) in 0,6 ynt) solution
A solution of (0.1 ml) in water was added at room temperature and stirred for 10 minutes.

The reaction solution was diluted with saturated brine and ethyl acetate, washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, dried, and the solvent was distilled off. The residual liquid was purified by thin layer silica gel chromatography to give (88,48)-1-(di-p-ayucylmethyl)-8-(1-hydroxyethyl)-4-1-(
-)-menthyloxycarbonyl-2-azetidinone (
28 mg) was obtained.

High performance liquid chromatography analysis (column: Lichr
osorb 8I-60, developing solution: 5% isopropano-
The ratio of 5-(R) monomer to 5-(s) monomer in the 1F+ monomer (1F+1 complex) was about 8:5.

TTCzs I 几 (m-'): 17B5.1600.15
00゜ax 1g50.1168.1022 Also, (88,48)-1-(di-p-ayucylmethyl)-8-acetyl-4-t-(c)-menthyloxycarbonyl-2-azetidinone is known in the literature. Method(
Tetrahedron Letters, 229B
(1982)), the reaction was carried out according to (88
,48,5R)-1-(di-p-ayucylmethyl)-8
-(1-Hydroxyethyl)-4-1-θ-menthyloxycarbonyl-2-azetidinone was obtained as the main product.

1240, 11721 NMRa (Oj)Cl3): 0.5-2.0
(191, m).

4.07 (IH, dJ-8Hz), 4.1-4.9 (
2H.

m), 5.80 (IH, s), 6.7-7.
4(8H,m)p,p,m.

(88,48,5R)-1-(di-P-anisylmethyl)-8-(1-hydroxyethyl)-4-1-(c)-
Menthyloxycarbonyl-2-azetidinone (30~
) was dissolved in tetrahydrofura:/ (0.9rnt) and methanol (0.46rnt), and after dropwise addition of IN-sodium hydroxide (0.06mt), the mixture was stirred at room temperature for 4 hours.

Neutralize with IN-hydrochloric acid, concentrate the reaction solution, dilute with ether, add IN-sodium hydroxide (0.1 mL),
Extracted with water. Write the extracted aqueous layer, IN-hydrochloric acid (0.12m
(88,48,5B)-
1-(di-p-ayucylmethyl)-8-(1-hydroxyethyl)-4-carboxyl-2-azetidinone (2
2sv) obtained □ 1515.1805.1250.1177°1080,
885 NMR, 9 (CDCzs>: 1.22 (8H, dJ
=6Hz), 8.18 (IH, m), 8.72 (6H
, s ), 4.10 (IH, dJ=2Hz), 5.7
5 (141, s) p, p, m.

[Reference Example 8] 0PNB (8-8) Step (is, 4S, 5R)-1-(di-p-ayucylmethyl)-8-(1-hydroxy)-4-carboxyl-2-
Azetidinone (4.0g), potassium acetate (1.0g)
Dimethylformamide (20ml) Solution R:
At 40°C, lead tetraacetate (5.8f) was added in several portions and stirred for 1 hour. After adding ethylene glycol and stirring for several minutes, the reaction solution was diluted with saturated brine and ethyl acetate, filtered to remove insoluble matter, extracted with ethyl acetate, washed with water, dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was isolated and purified by silica gel column chromatography to obtain (8
R,4几,5R)-1-(di-p-ayucylmethyl)-
B-(1-hydroxyethyl)-4-acetoxy-2-
Obtain azetidinone (8,289) uCts L max Ccm-1): 1752118571
1802.1242.1174.1028.958NM
几(CDCz, a): 1,26 (8H, dJ=6.
511z), 1.90 (, IH, s) 8.07 (IH,
broad, dJ=6.5Hz), 8.78(6H,s
), 4.07 (IH.

m), 5.88 (IH, broad, s), 5.88
(LH.

broad, s) p, p, m.

Light intensity [α9 product 2+ 26.0° (c=0.04,
CHCza') (8-b) Step (8R,4R,5R)-1-(di-p-ayucylmethyl)-8-(1-hydroxyethyl)-4-acetoxy-
2-Azetidinone (1,0y) in methylene chloride (5 ml)
>Dissolve H't Cool on ice, and dissolve 4-dimethylaminopyridine (0
A solution of p-nitrobenzylchloropormate (0.77f'') in methylene chloride (5ml) was added dropwise, and after stirring for 1 hour, toluene (25ml) was added. The furnace solution was sequentially washed with 2N hydrochloric acid and saturated brine, dried with sodium sulfate, and the solvent was distilled off.

The obtained residue was isolated and purified by silica gel column chromatography to obtain (3 liters, 4R, 5R)-
1-(di-p-ayucylmethyl)=8-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone (1,2F) was obtained t:1 158B, 1020.850,818. 785NMB,
δ (OHOza): 1.42 (8H, dJ=6Hz
).

1.85 (8H, s), 8.28 (IH, dJ=6H
2).

8.78 (6H, s+, 5.22 (21 (, s).

5.87 (IH, s), 6.11 (IH, s) p, p,
m.

Specific luminous intensity [α] Wa→・40.5° (c=0.88,
CIICts) [Reference Example 4] H (4-8) Step (81, 4R,, 5R) -1-(di-p-ayucylmethyl)-8-(1-p-nitrobenzyloxycarbonyloxyethyl)-4 -acetoxy-2-acetidinone (0,75F) in 10% water-acetonitrile (10ml)
) Add sulfur ammonium nitrate (Ceri) to the solution.
c ammonium n1trate) (1,59
A 10% water-acetonitrile (5 ml) solution of g') was added dropwise at room temperature, and the mixture was stirred for 80 minutes. Sodium sulfite (
After adding and stirring a 0,05f)0') aqueous solution (1, Fi mL), the reaction solution was diluted with saturated brine and extracted with ethyl acetate. After washing the extract with saturated aqueous sodium bicarbonate and saturated brine, drying with mirabilite and distilling off the solvent, the residue was isolated and purified by silica gel column chromatography to obtain (8R, 4R)
,5R') -8-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone (0,421>).

Cat IR (3'): 8800. 17'14'.

Ma! 1745.1602.1844.1258°1029.
848 NMR (C!DOza): 1.45 (8H, dJ
=6.0Hz).

2.09 (8H, lI), 8.87 (IH, ddJ=1
．． 2 and 6.0Hz), 5.25 (2H, tJ=26
Hz).

5.87(In, dJ=1.2Hz L 6.96(I
H.

broad, s) p, p, m.

2 Specific luminous intensity [α), +86.6° (c=0.09,
C! HOLs) (4-b) Step 5% palladium carbon CBOO-) was dissolved in ethanol (5%
mL, )-water (5 ml) under a hydrogen atmosphere for 80 minutes and washed with water.

(81,4R,5R)-8-(1-
P-nitrobenzyloxycarbonyloxyethyl)-
A solution of 4-acetoxy-2-acetidinone (8,0Of) in ethanol (80d) was added, and the mixture was stirred for 2 hours under a hydrogen atmosphere.
The residue was subjected to silica gel column chromatography (
8 liters.

4R,5R)-8-(1-hydroxyethyl)-4-acetoxy-2-acetidinone (0.90 (lF)) was obtained.

HCt8 fR (m-'): 2980.1760.1862°ax 1220.1025 NMRa (C1025N: 1.80 (8H, dJ=5
Hz).

2.12 (8H, s), 8.17 (IH, ddJ=2
and 5Hz'), 8.4-8.8 (IH,
broad, s).

4.17 (IH, dqJ=5 and 6Hz).

5.88 (IH, dJ=2Hz), 7.117 (IH
.

broad, s) p, p, m, J Above procedure supplement + E r! f (Spontaneous) November 7, 1980 1, Indication of the case 1988 Patent 1 Patent No. 180268 2, Name of the invention Process for producing β-lactam derivatives 8, Relationship with the person making the amendment Patent issue 1 Address: 5-15 Kitahama, Higashi-ku, Osaka Name (20
9＞Sumitomo Chemical Co., Ltd. Representative Hijikata
4. Agent Address: Sumitomo Chemical Co., Ltd., 5-15 Kitahama, Higashi-ku, Osaka Name: Patent Attorney (8597) Moroishi Hikaru Apparatus f061220-3404 5. "Detailed Explanation of Seimei" column of the specification to be amended 6. Same amendments (11. Procedural amendments submitted on May 2, 1981, No. 5)
In the line [[Reference Example 1] J is corrected as follows: "[Example 15] (Men [dl indicates d-...-menthyl group]] Di-P-anisylmethylamine 2487#) , d-(1)-menthyl glyoxylate (23°), diketene (1
l-(di-
p-Ayucylmethyl)-3-acetyl-4-d-menthyloxycarbonyl-2-azetidinone (891mg)
I got it. High +, lft liquid chromatography () f
The ratio of 4S body to 4S body in PLC) is approximately 2:3. Note that NMN showed a spectrum similar to that obtained in Example 1.

[Example 16 ip D-P-anisylmethylamine 248 m (1mM) and 1
-(7)-(2,4-dichloroIL/7,.

Imidazole 68'f (1mM) was dissolved in dry toluene (12ml) and azeotropically dehydrated to form a Schiff base, and the same amount of dry toluene was added to imidazole 68'f ( Add 1mM),
Dike 5-7 (1011η) was dissolved in dry toluene (2 ml
) was added dropwise at 50° C. over 20 minutes, and the mixture was stirred at the same temperature for 1 hour. Dry brine was added to the reaction mixture, followed by extraction with toluene, washing with water, drying with mirabilite, distilling off the solvent, and purifying the residue by silica gel chromatography to obtain two isomers 898■ and 93■.

Their IR and NMR data were as follows.

Isomer 1 1458.185B, 1168.101022Nδ(C
eDs): 1.12 (8H, dJ=6.6Hz)1
．． 92(3H,s), 8.87(If(,dJ=2.2
Hz), 4.75(10,dJ-2,2Hz)p
-p, tn ・isomer 2 852 NMR δ (in eDs): 1.14 (8f (, dJ = 6
．． 4Hz), 1.89 (8H, s), 8.92 (LH,
dJ=2.4tiz), 4.81(18, dJ=2.4
Hz) P ・p, m ・ [Example 17] Z) G-P-anisylmenalamine (243■) 1' = -
(+) -1-Phenylethylgly□5 oxylate (L 96 mg) was dissolved in toluene (12 Wl),
After azeotropic dehydration to produce Schiff's base, add toluene (by reflux), add imidazole (68 ml), and dropwise add a solution of diketene (7 nq) in toluene (2 ml) over 20 minutes at 50°C. Stirred at 7°C for 1 hour.

(sS, 4s)-
1-(di-P-anisylmethyl)-3-acetyl-4-
(Ryo-(+)-phenylethyloxycarbonyl)-2
-azetidinone (3s4my) and (31'!-, 4R)
I tree (l 1 8...l) I ha) tko.

For l of the (35,45) body, the NMR data is 43 as follows.

1845.1168.1010 18Nδ (C61's): 1.21 (81-1, d, I
-6,6Hz), 1.84 (8H,i), 8.94 (
ill, dJ=2.2Hz), 4.78 (dJ
= 2.202), P - P ・1n ・ (3 and 4) bodies, NMR data were as follows.

165 NMR, δ(CsDe): 1.16 (8)1.
d, l=6.6Hz), 1.79(81(,S), 8
．． 80(if-1, dJ=2.2f(z), 4.76(
Eye 1, d J = 2,211 z・)p threat p,
m b) Same #l as in fl 9 a) using S-(-1,-t-phenylethylglyoxylate instead of R-(+)-t-phenylethylglyoxylate)
) I (Carry out the reaction Ic J: I'), (8S
, 45) -1-(di-p-ayucylmethyl)-3-acetyl-4-(5-(-)-t-phenylethyloxycarbonyl)-2-azetidinone and (3+t, 4
A mixture of Iζ) was obtained. NMR showed NMk similar to that obtained with R-() integral, Sono+WtJ "Teha(8
The ratio of S, 4S) and (8R,4K) bodies is 1:3.
Met.

The following compounds were obtained in the same manner as in [Example 1].

In addition, "glyoxylate acid" and "amic acid" in the table
(OHC-coOR,) is the corresponding glyoxyre used to generate the Schiff base, respectively.
b and 144 of Ami 7 (R1-NH2) are shown.

〔note〕

(The lik spectrum data in Table 11 is llLmax
(r:Wl-").

(2) In the NMR spectrum data in the table, the cal-dift is shown in δ value (ppm), and the unit of coupling constant (J value) is shown in Hz.

Note that if no solvent is specified, heavy benzene (C5
This is data measured in Ds).

(81*l, *2, etc. have the following meanings.

*1 Production ratio of two isomers determined from NMR data *1 Production ratio of isomers 1 and 5 determined from NMR data *4: Production ratio of isomers determined from NMR data *4: Production ratio of isomers determined from NMR data The production ratio of the 5 isomers has not been determined. 0 (4) Isomer 1 represents the main product, and isomer 2 represents the by-product.

(6) ..., (-) and (mo) in R and Q of the table are,
Both represent the optical rotation of the compound represented by R, OH = 2
6”)J is r'5.25(2H,s)J.

that's all

Claims (1)

[Claims] (1) A method for producing an 8-acetyl-2-azetidinone derivative, which comprises reacting digetene with a Schiff base obtained from an aldehyde in the presence of an imidazole.