JPS61243079A - 1-(alxoxycarbonylalkyl)-4-(2-furyl)-3-substituted-2-azetidinone and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is Cl, -NH2 or -N3; R<2> is H, phenyl or Cl when R<1> is Cl, and R<2> is H when R1 is -NH2 or -N3; R<3> is 1-3C alkyl; n is 1 or 2). EXAMPLE:3,3-Dichloro-1-ethoxycarbonylmethyl-4-(2-furyl)-2-azetidinone. USE:Intermediate for producing 3-[2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetamido]-2-azetidinone derivative, etc., having excellent antibacterial activity. PREPARATION:The compound of formula I can be produced preferably by reacting the acetyl chloride derivative of formula II (R<4> is Cl or -N3; R<5> is H, phenyl or Cl when R<4> is Cl, and is H when R<4> is -N3) with an organic amine, especially a 1-3C alkylamine, and reacting the resultant ketene of formula III with the Schiff base of formula IV.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides 3-(2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide]-2 having excellent antibacterial properties. The present invention relates to 1-(alkoxycarbonylalkyl)-4-(2-furyl)-3-substituted-2-azetidinone, which is an intermediate for producing -azetidinone derivatives, etc., and a method for producing the same.

[Conventional technology]

Conventionally, the (2+2) cycloaddition reaction between ketene and a compound having a carbon-carbon double bond has been known for a long time, but the (2+2) addition reaction to a carbon-nitrogen double bond has not been carried out very often. do not have. In particular, there are fewer reports on reactions using Schiff bases as compounds with carbon-nitrogen double bonds, and ketenes include diphenylketene, ketoketenes such as dimethylketene, methoxyketenes, and aldoketenes such as P-nitrophenylketene. Most of the examples are Among these, those using ketoketene are described, for example, by Mukherjee et al. (A, K,
Mukerjee et al.) % Synthesis (
Synthesis)-1975, 547゜Fitton et a'1., Journal on Chemical Society Perkin Trans.
in Trans, )1.1977.1450. Tomimatsu et al., Chemical and Pharmaceutical Bulletin (Chem.

Parm, Bull, ), 24.2532 (197
6).

and those using aldoketenes are described in, for example, Mukherjee et al. (A, K.

Mukerjee et al.) Tetrahedron (T
etrahedron), 34.1731 (197
8), Ya Sames (P, G.

Sammes), Chemical Review (Chem,
Rev.) ■, 1 (1976).

Furthermore, the synthesis of 2-azetidinone derivatives using chlorine-containing haloketenes was described by Fitton et al. (A, O).

Fitton et al.), Journal of
Chemical Society Perkin Trans (J, C
hem.

Soc, Perkin Trans,) 1.19
77.1450゜F, Duran et al.
al, ), Tetrahedron Letter (Tetra
hedron Lett,) 1970.245,
and Nelson (D, A, Nelson), Tetrahedron Le
tt, ), 1971.2543. As reported by the authors, Kato et al.

Kato et al.), Chemical Pharmace.
Technical Bulletin (Chem, Pharm, Bu
ll, ), 31.2899 (1983), Kato et al.
'l', Kato et al.), Journal of Heterocyclic Chemistry (J, Hete
rocyclic Chem, ), 1, 407 (1
984), Kato et al.

et al.), Chemical Pharmaceutical
Bulletin (Chem, Pharm, Bull)
, 32.4149 (1984).

On the other hand, when azidoketene is used, an azide is introduced at the 3-position of the 2-azetidinone derivative produced, and it is expected that a valuable reaction intermediate will be obtained. However, there are few examples regarding this reaction with azidoketene, and Bose et al.
Tetrahedron) 23.4769 (196
7), with a compound having a carbon-nitrogen double bond (
2+ 2) The production of 2-azetidinone by a cycloaddition reaction has only been reported.

Compounds with a carbon-nitrogen double bond used in this reaction are limited to benzylideneaniline derivatives and 3-(allyliminomethyl)chromone, which use haloketene with chlorine, and those which use azidoketene. It was limited to benzylideneaniline derivatives and ethyl N-phenylformimidate.

[Problem that the invention seeks to solve]

The present invention provides intermediates useful for producing 3-(2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido)-2-azetidinone derivatives having excellent antibacterial properties, and the production thereof. The purpose is to provide a method.

[Means for solving problems]

The present invention combines the above reaction with furfural, glycine and β-
Expanding the reaction with the Schiff base obtained from the lower alkyl ester of alanine, 2 has excellent antibacterial properties.
- This was made based on the knowledge that useful intermediates for producing azetidinone derivatives can be obtained.

That is, the present invention provides general formula (I): (wherein, R1 is chlorine, NHz or -N, and R
When ' is chlorine, R2 is hydrogen, a phenyl group or chlorine, and when R1 is -NH or -N3, R2 is hydrogen. R3 is an alkyl group having 1 to 3 carbon atoms, and n is 1 or 2. ) 1-(Alkoxycarbonylalkyl)-4-(2-furyl)-3-substituted-2-azetidinone is provided.

The compound of the present invention is, for example, a Schiff base represented by the general formula (■): and R in the general formula (■):
4 is chlorine or -N3, and when R4 is chlorine, R5
is hydrogen, a phenyl group or chlorine, and when R4 is -N3, R5 is hydrogen.

The compound of the present invention is produced by the above method, but since the ketene represented by the general formula (III) is a highly reactive and unstable compound, the general formula (■): O (in the formula, R4 and R5 has the same meaning as above.) and an organic amine, especially an alkyl (1 to 3 carbon atoms) amine, are reacted in a reaction system to produce the above ketene, and this and the general formula (n ) is preferably reacted with a ship base represented by

Among the 2-azetidinone derivatives represented by formula (I), those in which R1 is chlorine and R2 is hydrogen, a phenyl group, or chlorine are examples of the Schiff base of formula (II) and the anhydride of triethylamine. An anhydrous benzene solution of the acetyl chloride (R4 is chlorine, R5 is hydrogen, phenyl group or chlorine) derivative of formula (IV) is added to the benzene solution under stirring under water cooling.
It is obtained by adding gradually and reacting at room temperature for 1 to 3 hours.

Further, in formula (I), when R1 is -N3 and R'' is hydrogen, for example, acetyl chloride of formula (IV) (R' is -N !, R' is hydrogen) in anhydrous methylene chloride is gradually added under stirring under salt-ice cooling, and the mixture is reacted at room temperature for 1 to 3 hours.

Furthermore, in formula (I), when R1 is NH2 and R'' is hydrogen, when R1 is N3 and R'' is hydrogen, in methanol,
It is obtained by catalytic reduction of hydrogen gas in the presence of Pd-C for 1 to 3 hours.

The raw material Schiff base was prepared by Kato et al.
al,), Chemical and Pharmaceutical Bulletin (Chem, Pharm, Bull,)
, 31.538 (1983).

〔Effect of the invention〕

The present invention provides a useful intermediate for producing 2-azetidinone derivatives having biological activity. That is, 2-methoxy-2-(2-amino-
After dehydration condensation of 4-thiazolyl)acetic acid, ozone oxidation,
By photolysis (cleavage of the furan ring) and then ring-closing reaction between furan and methylene, 3-(2-(2
-amino-4-thiazolyl)-2-(methoxyimino)
Acetamide]2-azetidinone derivatives can be obtained. More specifically, the reaction is shown below.

Z=Q Engineering Z
The final 2-azetidinone derivative obtained here is disclosed in JP-A-55-108872 and Takatani et al., Journal of the Chemical Society of Japan 1.
981 (5), p. 785-804, and it is described that this material has excellent antibacterial properties.

Next, the present invention will be explained with reference to Examples, but the present invention is not limited thereto.

Example 1: 3.3-dichloro-1-ethoxycarbonylmethyl-4-(2-furyl)-2-azetidinone [
Synthesis of Compound I] The following reaction was performed. That is, 3.62 g (0.02 mol) of ethyl N-furfurylidene glycinate and 3.03 g (0.03 mol) of triethylamine.
Anhydrous benzene (100ml) solution was cooled with ice (5-1
0”C) 11 dichloroacetyl chloride under stirring 3.54
g (0,024 mol) of anhydrous benzene (LOML)
The solution was added dropwise over a period of 20 minutes. After the dropwise addition was completed, the mixture was stirred at room temperature for 30 minutes. Triethylamine hydrochloride was removed by filtration, and the solvent was distilled off under reduced pressure. The residue (7.21 g') was subjected to silica gel column chromatography (silica gel 15
0 g) and eluted with hexane-ethyl acetate (5:1) to obtain a yellow oil [Compound (1)]. Yield is 0.95
g (yield 16%).

Physical property value: IR (CHCI:I): 1795.1740cm
-'.

'H-NMR (CDC13'') δ: 5.12 (s, L
H,2-azetidinone 4-H).

High resolution MS m/z: Ct+II++C1g
NOn(M”) Calculated value: 291.0063° Actual value: 291.0040° Example 2 2-3-chloro-1-ethoxycarbonylethyl-4-(2-furyl)-2-azetidinone [Compound ■]
Synthesis of following reaction: That is, N-furfuryridine-2-
Ethoxycarbonylethylamine 3.90 g (0,0
2 mol) and triethylamine 3.03 g (0.03
mol) in anhydrous benzene (100 ml) was cooled with water (5-
10°C) under stirring, dichloroacetyl chloride 2.71
A solution of g (0,024 mol) in anhydrous benzene (10 ml) was added dropwise over a period of 20 minutes.

After the dropwise addition was completed, the mixture was stirred at room temperature for 3 hours. Triethylamine hydrochloride was removed by filtration, and the solvent was distilled off under reduced pressure. Residue (
6,33g) was subjected to silica gel column chromatography (
The mixture was applied to silica gel (150 g) and eluted with hexane-ethyl acetate (4:1) to give a yellow oil [Compound (1)]. The yield was 0.67 g (yield 12%).

Physical property value: IR (CHCli): 1770.1730cm-
'.

'HNMR (CDC1i) δ: 4.63 (d, IH
, J=2Hz, 2-azetidinone 3-H), 4.8
2 (d.

IH, J = 2Hz, 2-azetidinone 4-H).

High resolution MS m/z: C, 2H14CINO4,
(M”) Calculated value: 271.0609° Actual value: 271.0610° Example 3: 3-azido-1-ethoxycarbonylethyl-4-(2-furyl)-2-azetidinone [Compound ■]
Synthesis of following reaction: That is, a solution of 3.62 g (0.02 mol) of ethyl N-furfuryritine glycinate and 2.02 g (0.02 mol) of triethylamine in 100 ml of anhydrous methylene chloride was cooled with salt-water (-15 mol).
~-10°C) under stirring, azidoacetyl chloride 2.39
10 m of anhydrous methylene chloride containing g (0.02 mol)
1 solution was added dropwise. After completion of the dropwise addition, the mixture was returned to room temperature, stirred for 1 hour, and washed with water (100ml x 3). Thereafter, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue (4.90 g) was subjected to silica gel column chromatography (100 g of silica gel) and eluted with hexane-ethyl acetate (4:1) to obtain a dark yellow oil [Compound (1)].

The yield was 3.32 g (yield 63%).

Physical property value: Elemental analysis C item H+ ZN404 Calculated value: C50,0
0; H4,58° Actual value: C49,78; H4,37° IR (CHClz): 2100.1775.19
35 am-'.

'HNMR (CDCI+) δ: 4.90 (d,
IH,J=5H2,2-azetidinone 3-H),
5.15 (d.

I HSJ=5Hz, 2-azetidinone 4-H).

High resolution MS m/2: CzH+zNzOn
(M''-Nz) Calculated value: 236.0798° Actual value: 236.0798° Example 4: 3-Amino-1-ethoxycarbonylethyl-4-(2-furyl)-2-azetidinone [Compound ■]
Synthesis of following reaction: That is, 23 g of Pd-CO was added to 20 ml of methanol solution containing 2.20 g (8.3 mmol) of 3-azido-1-ethoxycarbonylethyl-4(2-furyl)-2-azetidinone [compound m], Catalytic reduction was carried out by passing hydrogen gas through it for 2 hours while shaking. Thereafter, Pd-C was removed by filtration, and the solvent was distilled off under reduced pressure. The residue (1.74 g) was subjected to silica gel column chromatography (60 g of silica gel) and eluted with ethyl acetate-methanol (100:1) to obtain a dark yellow oil [Compound (1)]. Yield: 0.98g (yield 49%)
Met.

Physical property value: Elemental analysis CIIH + aNzOa (4) Calculated value: C
155,45; H, 5,92; N, 11.76° Actual value 20, 55.17; H, 5,83; N, 11.76° IR (CIICh): 1760.1740 cm
-'.

'H-NMR (CDC13) δ: 4.55 (d, I
H, J=5Hz, 2-azetidinone 3-H), 5.0
3 (d.

IH, J-5Hz, 2-azetidinone 4-H).

Claims (3)

[Claims] (1) General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (I) (In the formula, R^1 is chlorine, -NH_2 or -N_3, and when R^1 is chlorine , R^2 is hydrogen, phenyl group or chlorine, and when R^1 is -NH_2 or -N_3,
R^2 is hydrogen. R^3 is an alkyl group having 1 to 3 carbon atoms, and n is 1 or 2. ) represented by 1-(
alkoxycarbonylalkyl)-4-(2-furyl)
-3-substituted-2-azetidinone. (2) General formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) (In the formula, R^3 is an alkyl group having 1 to 3 carbon atoms, and n
is 1 or 2. ) Schiff base represented by and general formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(III) (In the formula, R^4 is chlorine or -N_3, and R^4 is chlorine In the case, R^5 is hydrogen, phenyl group or chlorine,
When R^4 is -N_3, R^5 is hydrogen. ) General formula (IV) characterized by the reaction with ketene represented by When N_3 and R^1 is chlorine, R^2 is hydrogen, phenyl group or chlorine, and when R^1 is -NH_2 or -N_3,
R^2 is hydrogen. R^3 has the same meaning as above. ) 1-(alkoxycarbonylalkyl)-
A method for producing 4-(2-furyl)-3-substituted-2-azetidinone. (3) Haloketene represented by the general formula (III) is reacted with the general formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(V) (In the formula, R^4 and R ^5 has the same meaning as above.) Claim No. 5 is produced by the reaction of an acetyl chloride derivative represented by
The manufacturing method described in section 2).