JPH0639472B2 - Azole derivative - Google Patents

Description

Detailed Description of the Invention

The present invention relates to a novel azole derivative, more specifically the following formula

[0002]

[Chemical 2]

In the formula, A represents C H or N, R ₁ represents a hydrogen atom or an amino protecting group which can be easily split off, R ₂ and R ₃ are the same or different and each is a hydrogen atom,
Lower alkyl group, phenyl group, or a benzyl group or Jifuenirumechiru group, or R ₂ and R ₃ represents a lower alkylene group together, R ₄ represents a water atom or a lower alkyl group, in the compounds represented Regarding

The compound of the above formula (V) has the following formula

[0005]

[Chemical 3]

In the formula, Y represents an acetyl group, a 1-hydroxyethyl group or a 1-fluoroethyl group, R ₁ represents a hydrogen atom or an easily protecting amino protecting group, and R ₂
And R ₃ are the same or different and each represents a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group or a diphenylmethyl group, or R ₂ and R ₃ together represent a lower alkylene group. It is useful as a synthetic intermediate.

A 3-substituted azetidinone derivative, particularly a 3-substituted azetidinone derivative having an S-configuration at the 4-position, is used as an intermediate for the production of various β-lactam antibacterial compounds such as carbapenems and penems. It is useful and various types have been proposed.

The present inventors now use D-mannitol, which is relatively inexpensive, as a starting material, and react a ketalized product of D-glyceraldehyde derived therefrom with diketene in the presence of a certain azole compound. Then, the inventors have found that a 3-substituted-azetidinone derivative having the S-configuration at the 4-position represented by the above formula (I) can be stereoselectively obtained, and completed the present invention.

The compounds of formula (I) proposed by the present invention have already been used as various drugs, especially carbapenam or carbapenem antibiotics, such as carbapenem antibiotics having excellent antibacterial activity and being relatively stable. Known formula

[0010]

[Chemical 4]

It is useful as an intermediate for the synthesis of antibiotics represented by

The term "lower" in the present specification means that the group or compound to which this term is attached has 8 or less carbon atoms, preferably 6 or less carbon atoms.

Further, the "easily leaving amino protecting group" means that it can be hydrolyzed, reduced, oxidized or the like without substantially adversely affecting other parts of the compound to which the amino protecting group is bonded. Those which can be removed from the compound are included, for example, tri (lower alkyl) silyl group such as trimethylsilyl, tert-butyldimethylsilyl, etc .; substituted with one or two lower alkoxy groups such as benzyl, methoxybenzyl, dimethoxybenzyl, etc. A benzyl group which may be substituted; a phenyl group which may be substituted with one or two lower alkoxy groups such as methoxyphenyl and dimethoxyphenyl, and the like.

Further, the "lower alkyl group" may be of a straight chain type or a branched chain type, for example, methyl, ethyl, n-propyl, isopropyl, n.
-Butyl, sec-butyl, isobutyl, tert-butyl groups and the like can be mentioned, and as the "lower alkylene group", those having 4 to 5 carbon atoms such as tetramethylene and pentamethylene are preferable.

In the above formula (I), the hydroxyl group and fluorine atom in the 1-hydroxyethyl and 1-fluoroethyl groups which can be represented by Y can have either S- or R-configuration, but in general, The fluorine atom preferably has the R-configuration.

Thus, the above formula provided by the present invention
Typical examples of the compound (I) are as follows.

(3S, 4S) -3-Acetyl-4-[(4S)
-2,2-Dimethyl-1,3-dioxolan-4-yl]
-1- (4-methoxy) phenyl-2-azetidinone, (3S, 4S) -4-[(4S) -2,2-dimethyl-1,3-
Dioxolan-4-yl] -3-[(1S) -1-hydroxyethyl] -1- (4-methoxy) phenyl-2-azetidinone, (3S, 4S) -4-[(4S) -2,2- Dimethyl-1,3-
Dioxolan-4-yl] -3-[(1R) -1-hydroxyethyl] -1- (4-methoxy) phenyl-2-azetidinone, (3R, 4S) -4-[(4S) -2,2- Dimethyl-1,3-
Dioxolan-4-yl] -3-[(1R) -1-fluoroethyl] -1- (4-methoxy) phenyl-2-azetidinone, (3S, 4S) -3-acetyl-1-benzyl-4- [ (4
S) -2,2-Dimethyl-1,3-dioxolan-4-yl] -2-azetidinone, (3S, 4S) -1-benzyl-4-[(4S) -2,2-dimethyl-1,3 -Dioxolan-4-yl] -3-[(1
S) -1-hydroxyethyl] -2-azetidinone, (3S, 4S) -1-benzyl-4-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -3- [ (1
R) -1-hydroxyethyl] -2-azetidinone, (3R, 4S) -1-benzyl-4-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -3- [ (1
R) -1-Fluoroethyl] -2-azetidinone, (3S, 4S) -3-acetyl-1- (2,4-dimethoxy)
Phenyl-4-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -2-azetidinone, (3S, 4S) -1- (2,4-dimethoxy) phenyl-4-
[(4S) -1,3-dioxolan-4-yl] -3-[(1
S) -1-Hydroxyethyl] -2-azetidinone, (3S, 4S) -1- (2,4-dimethoxy) phenyl-3-
[(1R) -1-hydroxyethyl] -4-[(4S) -2-
Phenyl-1,3-dioxolan-4-yl] -2-azetidinone, (3R, 4S) -1- (2,4-dimethoxy) phenyl-4-
{(2S) -1,4-Dioxospiro [4,5] deca-2-yl} -3-[(1R) -1-fluoroethyl] -2-azetidinone, (3S, 4S) -3-acetyl-1 -(4-methoxy) benzyl-4-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -2-azetidinone, (3S, 4S) -3-[(1S) -1 -Hydroxyethyl]-
1- (4-methoxy) benzyl-4-[(4S) -2-phenyl-1,3-dioxolan-4-yl] -2-azetidinone, (3S, 4S) -4-[(4S) -1, 3-dioxolane-4
-Yl] -3-[(1R) -1-hydroxyethyl] -1-
(4-methoxy) benzyl-2-azetidinone, (3R, 4S) -4-[(4S) -2-ethyl-2-methyl-
1,3-Dioxolan-4-yl] -3-[(1R) -1-
Fluoroethyl] -1- (4-methoxy) benzyl-2-
Azetidinone, (3S, 4S) -3-Acetyl-4-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -1-trimethylsilyl-2-azetidinone, (3S, 4S)- 1-t-butyldimethylsilyl-4-[(4
S) -2,2-Diphenyl-1,3-dioxolane-4-
Iyl] -3-[(1S) -1-hydroxyethyl] -2-azetidinone, (3S, 4S) -4-[(4S) -2,2-dimethyl-1,3-
Dioxolan-4-yl] -3-[(1R) -1-hydroxyethyl] -1-trimethylsilyl-2-azetidinone, (3R, 4S) -1-t-butyldimethylsilyl-3-[(1
R) -1-Fluoroethyl] -4-[(4S) -2-methyl-1,3-dioxolan-4-yl] -2-azetidinone, (3S, 4S) -3-acetyl-1- (2, 4-dimethoxy)
Benzyl-4-[(4S) -2-phenyl-1,3-dioxolan-4-yl] -2-azetidinone, (3S, 4S) -3-Acetyl-4-[(4S) -2,2-diphenyl -1,3-Dioxolan-4-yl] -1- (4
-Methoxy) phenyl-2-azetidinone, (3S, 4S) -3-acetyl-4-[(4S) -1,3-dioxolan-4-yl] -1- (4-methoxy) phenyl-2-azetidinone.

The above formula (I) when Y represents an acetyl group
The compound of

[0019]

[Chemical 5]

In the formula, R ₁ , R ₂ and R ₃ have the above-mentioned meanings.

[0021]

[Chemical 6]

[0022] In the formula, A represents a C H or N, R ₄ in the presence of an azole compound represented in represents the water atom or a lower alkyl group, the following formula

[0023]

[Chemical 7]

It can be produced by reacting with a diketene represented by:

The reaction of the compound of formula (II) with the diketene of formula (IV) is carried out in the absence of a solvent or preferably in a suitable solvent, for example, a halogenated hydrocarbon such as methylene chloride, chloroform, dichloroethane; ethyl acetate, In ester hydrocarbons such as butyl acetate; ether hydrocarbons such as diethyl ether, tetrahydrofuran, dioxane; etc., generally between about -40 ° C and about 40 ° C, preferably between about -20 ° C and about 25 ° C. It can be performed at temperatures between.

The ratio of the compound of the formula (II) to the diketene of the formula (IV) is not strictly limited and can be varied over a wide range depending on the kind of the compound of the formula (II), the reaction temperature and the like. However, in general, 0.5 to 3 moles of the compound of formula (II) per mole of diketene of formula (IV), preferably 0.1.
It is expedient to use in a proportion of 8 to 1.5 mol.

In addition, the formula (II
Examples of the azole of I) include imidazole, 2-methylimidazole, 4-methylimidazole, 2,4-
Dimethylimidazole, 1,2,4-triazole, 3-
Methyl-1,2,4-triazole, 5-methyl-1,2,
4-triazole, 3,5-dimethyl-1,2,4-triazole and the like can be mentioned, and these azoles are generally 0.5 to 3 mol, preferably 1 to 1 mol of the compound of the formula (II).
It is suitable to use at a ratio of up to 1.5 moles, but when using triazoles, triethylamine, tributylamine, diethylisopropylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, etc. It is necessary to use the above organic base as a reaction aid. The above reaction produces a compound of formula (I) in which Y represents an acetyl group, which compound is reacted by a method known per se, for example, extraction with an organic solvent, crystallization or silica gel column chromatography. It can be easily isolated and purified from the mixture.

Alternatively, when Y represents an acetyl group, the compound of formula (I) is a compound of formula (II) and a compound of formula (II)
The following formula formed by the reaction of I) with an azole compound

[0029]

[Chemical 8]

It can also be prepared by reacting a compound of the formula A, R ₁ , R ₂ , R ₃ and R ₄ having the abovementioned meaning with a diketene of the formula (IV).

The reaction of the compound of formula (V) with the diketene of formula (IV) is generally carried out in a solvent as described above, generally at about -30 ° C.
It can be carried out at a temperature of about 40 ° C, preferably about -20 ° C to about 25 ° C.

The proportion of the compound of the formula (V) used with respect to the diketene of the formula (IV) is not critical and may be varied depending on the type of the compound of the formula (V), the reaction temperature, etc. The compound of the formula (V) is preferably used in an amount of 0.5 to 2 mol, particularly 0.8 to 1 mol, per 1 mol of diketene.

The compound of formula (I) in which Y thus formed represents an acetyl group can be isolated and purified from the reaction mixture by the same means as described above.

The compounds of formula (II) used as starting materials in the reactions mentioned above are known per se,
For example, the following formula

[0035]

[Chemical 9]

Wherein R ₂ and R ₃ have the meanings given above,
The oxidative decomposition of 1,2,5,6-O-diketalized D-mannitol represented by the following formula (for example, using periodic acid or lead tetraacetate)

[0037]

[Chemical 10]

Wherein R ₂ and R ₃ have the meanings given above,
The ketalized product of D-glyceraldehyde represented by

[0039]

Embedded image R ₁ —NH ₂ (VIII) In the formula, R ₁ has the above-mentioned meaning, and can be easily produced by reacting with an amine represented by

On the other hand, the compound of the formula (V) is a novel compound which has not been described in the conventional literatures.
V) in a solvent as described for the reaction of diketene with the formula
It can be produced by reacting a compound of (II) with an azole compound of formula (III). In that case, the reaction temperature is generally about -40 ° C to about 40 ° C, preferably about -20 ° C.
Temperatures between about 25 ° C are suitable. Further, the ratio of the compound of the formula (III) to the compound of the formula (II) is not strictly limited, but in general, 1 mol of the compound of the formula (II) is added to the compound of the formula (III). 5 to 2 mol, preferably 1 to
Conveniently, it is used in a proportion of 1.5 mol. The resulting compound of formula (V) once isolated from the reaction mixture,
It may be reacted with the diketene of the formula (III), or may be directly reacted with the diketene of the formula (III) without isolation.

The compound of formula (I) in which Y represents an acetyl group produced as described above can be converted to the 1-hydroxymethyl group by reducing the acetyl group. When Y represents an acetyl group, the reduction of the compound of formula (I) is generally carried out by ether hydrocarbons such as diethyl ether, tetrahydrofuran and dimethoxyethane; alcohol hydrocarbons such as ethanol and methanol; aromatic hydrocarbons such as benzene and toluene. In a solvent such as a system hydrocarbon, for example, sodium borohydride, lithium borohydride, lithium aluminum hydride, magnesium trifluoroacetate-diisopropylamine-borane,
Tri-sec-butylboron hydride, lithium (L-selectride), potassium tri-sec-butylboron hydride,
It can be carried out using a reducing agent such as diisobutylaluminium hydride (DIBAL). By selecting this reducing agent, for example, lithium borohydride, 1S-hydroxyethyl group is obtained when L-selectride is used, and also diisobutylaluminium hydride (DIBAL), magnesium trifluoroacetate-diisopropylamine is obtained. -When borane is used, a 1R-hydroxyethyl group is obtained.

The above-mentioned reduction reaction depends on the type of reducing agent used, but is generally -78 ° C to 40 ° C, preferably -78 ° C to
It can be carried out at a temperature of 25 ° C. Although the amount of the reducing agent used is not critical, it is generally 0.5 to 1 mol of the compound of the formula (I) when Y represents an acetyl group.
It is suitable to use it in a proportion of 10 mol, preferably 1 to 4 mol.

The thus obtained compound of formula (I) in which Y represents a 1-hydroxyethyl group is then fluorinated to give the corresponding compound of formula (I) in which Y represents a 1-fluoroethyl group. can get. The fluorination of the compound of formula (I) in which Y represents a 1-hydroxyethyl group is carried out according to a method known per se, for example, using diethylaminosulfate trifluoride (DAST), Chingpongmatsuk et al., Heterocycles. ) 19 , 1399
(1982) or the Ishikawa reagent (hexafluoropropene-diethylamine mixed reagent), whereby S- at the 1-hydroxyethyl group can be obtained.
The OH of the configuration is stereoselectively substituted with the F of the R-configuration to give the corresponding compound of formula (I) when Y represents a 1R-fluoroethyl group.

The following formula thus obtained

[0045]

[Chemical 12]

In the formula, R ₁ , R ₂ and R ₃ have the above-mentioned meanings, and the compounds represented by the following formula A can be converted into the antibiotic of formula (A).

[0047]

[Chemical 13]

[0048]

[Chemical 14]

[0049]

[Chemical 15]

In the above reaction formula, R ₁₁ represents an amino protecting group which can be easily removed.

The hydrolysis of the compound of formula (I-1) in which R ₁ represents an easily leaving amino protecting group is carried out according to a method known per se, for example by mixing the compound with an acetic acid-water mixed solution at about 25. It can be carried out by treating at a temperature of from 60 to 60 ° C.

Oxidation of the resulting compound of formula (1) is usually carried out in a solvent such as benzene, toluene, tetravitrofuran, tetrahydrofuran-water, dimethoxyethane-water, water-containing methanol, water-containing ethanol or the like, for example, periodic acid,
It can be carried out using an oxidizing agent such as sodium metaperiodate or lead tetraacetate. In addition, the above-mentioned oxidation reaction is generally between about -10 ° C and about 50 ° C, preferably about 0 ° C to about 25 ° C.
It can be carried out at temperatures between.

The amount of the oxidant used is not strictly limited and may be varied depending on the kind of the oxidant used and the like, but generally 0.5 to 1 mol of the compound of the formula (1) is used.
It is preferably used in a proportion of 5 mol, preferably 1 to 1.5 mol.

This gives the compound of the formula (2) which is then subjected to the diones oxidation or KMnO ₄ -t-Bu.
It can be converted into compounds of formula (3) by subjecting to oxidation with a reagent of _{OH-5% NaH 2 PO 4} . The above-mentioned Djones oxidation or the oxidation using the above-mentioned reagent is a method known per se, for example, DJ Hart.
Tetrahedron Letters
s) 26 , 5493 (1985) and Atsushi Abiko (Atsus)
hi Abiko) et al., Tetrahedron Letters (Tetrahedr
on Letters) 27 , 4537 (1980).

The compound of formula (3) thus obtained can then be converted to the compound of formula (4) by oxidatively decarboxylation using lead tetraacetate. This oxidative decarboxylation is also a method known per se, for example, PJ Reider et al., Tetrahedron Letters 23 , 2293 (1982).
It can be performed according to the method described in. The 1-position amino-protecting group of the compound of formula (4) to be produced is subjected to a suitable deamination-protecting group reaction depending on the kind of the amino-protecting group [for example, an acid when R ₁₁ is a tri (lower alkyl) silyl group]. By hydrolysis, when R ₁₁ is an unsubstituted or substituted benzyl group, hydrogenolysis, and when R ₁₁ is a p-methoxyphenyl or o, p-dimethoxyphenyl group, suitable elimination by oxidation] It is also possible to lead to the compound of (5). In the case of a trimethylsilyl group, it may be used in the next reaction without deprotection.

The steps from the compound of formula (5) to the compound of formula (A) can be produced using the following reagents and according to the methods described in the following documents.

[0057] Reagents

[0058]

[Chemical 16]

Document 1) W. Flitsch et al., Tetrahedron Letters 23 , 229
7 (1982) 2) DG Melillo et al., Tetrahedron Letters 21 , 2
783 (1980) The antibiotic of formula (A) produced as described above has a wide range and excellent antibacterial activity and is stable against renal dehydropeptidase, and is extremely useful as an antibacterial agent.

Next, the present invention will be described more specifically by way of examples.

Reference Example N- (4-methoxy) phenyl-{[(4S) -2,2-dimer
Tyl-1,3-dioxolan-4-yl] methane} imine
Manufacturing of

[0062]

[Chemical 17]

1,2,5,6-O-diisopropylidene-
D-mannitol 5 g (19 mmol) was added to methanol 24 ml.
Dissolved in 5% sodium hydrogencarbonate aqueous solution under ice cooling,
Add 7.75 ml, metaperiodic acid 5.865 g and water 3
2.8 ml were combined and added. The mixture was stirred at the same temperature for 1 hour. The insoluble matter in the reaction solution was filtered off, the filtrate was extracted three times with methylene chloride, the combined extracts were washed with saturated brine and then dried over anhydrous sodium sulfate. After drying, anhydrous sodium sulfate was filtered off and the filtrate was concentrated to give 1,2-O.
-Isopropylidene-D-glyceraldehyde was obtained. At this time, the solvent was distilled off without heating, and only methylene chloride was distilled off. Then, the yield of 0.8 equivalents of anisidine was dissolved in weighed benzine, and the solution was stirred under nitrogen atmosphere for 1,2.
To the benzene solution of -O-isopropylidene-D-glyceraldehyde was added an appropriate amount of anhydrous sodium sulfate, and the mixture was stirred overnight. After the reaction, anhydrous sodium sulfate was filtered off, and the filtrate was concentrated to give the title compound (7.2 g, 80 g).
% Yield.

¹ H-NMR (CDCl ₃ )

[0065]

[Chemical 18]

[0066]

[0067]

EXAMPLES Example 1 1-{[(4S) -2,2-dimethyl-1,3-dioxolane
-4-yl]-(4-methoxy) phenylimino} methylyl
Manufacture of midazole

[0068]

[Chemical 19]

N- (4-methoxy) phenyl-{[(4S)
-2,2-Dimethyl-1,3-dioxolan-4-yl]
30 mg (0.13 mmol) of methane} imine was dissolved in 1 ml of anhydrous methylene chloride, and 8.7 mg of imidazole (0.13 mmol, 1e)
q. ) Was added at room temperature, reacted at the same temperature for 5 minutes under a nitrogen atmosphere, concentrated to dryness, and 1-{[(4S) -2,2-dimethyl-
1,3-Dioxolan-4-yl]-(4-methoxy) phenylimino} methylimidazole was obtained quantitatively.

¹ H-NMR (CDCl ₃ ) δ (ppm) = 1.45, 1.47, 1.53, 1.60 (6
H, m

[0071]

[Chemical 20]

[0072] 6.40-6.95 (4H, m, Ar- H ), 7.03 (2H, m, H
-4 & H-5), 7.60, 7.68 (1H, s, H-2) Example 2 1-{[(4S) -2,2-dimethyl-1,3-dioxolane
-4-yl]-(4-methoxy) phenylimino} methyl-
Production of 1,2,4-triazole

[0073]

[Chemical 21]

N- (4-methoxy) phenyl-{[(4S)
-2,2-Dimethyl-1,3-dioxolan-4-yl]
30 mg (0.13 mmol) of methane} imine was dissolved in 1 ml of anhydrous methylene chloride, and 8.97 mg (0.1%) of 1,2,4-triazole was dissolved.
13 mmol) at room temperature and reacted at the same temperature for 10 minutes under a nitrogen atmosphere and then concentrated to dryness to give 1-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl]-. (4-Methoxy) phenylimino} methyl-1,2,4-triazole was obtained quantitatively.

¹ H-NMR (CDCl ₃ )

[0076]

[Chemical formula 22]

4.22 to 4.90 (3H, m, H-4 ', H-
5'a, H-5'b),

[0078]

[Chemical formula 23]

6.66 to 7.05 (4H, m, Ar- H ), 8.1
0- (1H, s, H-3), 8.25,8.30 (1H, s, H-5) Example 3 (3S, 4S) -3-Acetyl-4-[(4S) -2,2-di
Methyl-1,3-dioxolan-4-yl] -1- (4-
Production of (methoxy) phenyl-2-azetidinone

[0080]

[Chemical formula 24]

1-{[(4S) -obtained according to Example 1
2,2-Dimethyl-1,3-dioxolan-4-yl]-
(4-Methoxy) phenylimino} methylimidazole 6.
45 g (21.3 mmol) was dissolved in 40 ml of anhydrous methylene chloride, and 2.45 ml (31.
95 mmol) was added. After stirring at the same temperature for 30 minutes, returning to room temperature and stirring for 150 minutes, the reaction solution was poured into a mixed solution of methylene chloride and 0.5N hydrochloric acid containing ice, washed, and washed again with 0.5N hydrochloric acid. After (total: 0.5 ml hydrochloric acid 65 ml x
(Twice), washed with a saturated saline solution, and dried with Glauber's salt. Glauber's salt was removed by filtration and purified by silica gel column chromatography (toluene → toluene / ethyl acetate = 50/1 → 3
(0/1 → 20/1 → 15/1), 4.60 g of the title compound was obtained with a yield of 67.6%.

¹ H-NMR (CDCl ₃ )

[0083]

[Chemical 25]

[0084]

[Chemical formula 26]

[0085] H-5'a), 3.70 (3H , s, OCH 3), 4.05
(1H, dd, J = 6.5Hz, J = 9.0Hz, H-5'b), 4.
12 (1H, d, J = 2.5Hz, H-3), 4.4 to 4.6 (2
H, m, H-4 ', H-4), 6.75 (2H, d, J = 9.
0Hz, H-3 ", H-5"), 7.22 (2H, d,
J = 9.0Hz, H-2 ", H-6") [Α] _D ^22.5 = -87.3 ° (c = 1, CHCl ₃ ) Example 4 (3S, 4S) -3-Acetyl-4-[(4S) -2,2-dimethyl-
1,3-Dioxolan-4-yl] -1- (4-methoxy) phenyl
Production of le-2-azetidinone

[0086]

[Chemical 27]

1-{[(4S) -obtained according to Example 2
2,2-Dimethyl-1,3-dioxolan-4-yl]-
30 mg (0.1 mmol) of (4-methoxy) phenylimino} methyl-1,2,4-triazole was dissolved in anhydrous methylene chloride, and 13.9 μl (0.1 mmo) at −20 ° C. under nitrogen atmosphere.
l, 1 eq.) of triethylamine was added, and 11.5 μl (0.
(15 mmol, 1.5 eq.) Was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into a mixture of methylene chloride and 0.5N hydrochloric acid with ice, extracted, washed, and washed again with 0.5N hydrochloric acid. , Washed with saturated saline, dried with sodium sulfate, purified by silica gel column chromatography (see above),
3.1 mg of the title compound was obtained with a yield of 10%, the physicochemical properties of which were in agreement with those of the compound obtained in Example 3.

Example 5(3S, 4S) -3-[(1S) -1-Hydroxyethyl] -4-
[(4S) -2,2-Dimethyl-1,3-dioxolan-4-yl]
Preparation of -1- (4-methoxy) phenyl-2-azetidinone

[0089]

[Chemical 28]

(3S, 4S) -3-Acetyl-4-[(4S) -2,
2-Dimethyl-1,3-dioxolan-4-yl] -1- (4-methoxy) phenyl-2-azetidinone 300 mg (0.94 m
(mol) was dissolved in 5.5 ml of anhydrous tetrahydrofuran,
1.13 ml (1.13 mmol, 1.2 eq.) Under nitrogen atmosphere at 70 ° C
L-Selectride of was added dropwise and stirred at the same temperature for 1 hour, and then 0.135 ml (2.37 mmol, 2.1 eq.) Of acetic acid was added. After stirring for 5 minutes, extract with 30 ml of ethyl acetate,
The extract was washed twice with 10 ml of saturated saline solution, once with 15 ml of saturated aqueous sodium hydrogen carbonate solution and once again with 10 ml of saturated saline solution, and dried with sodium sulfate. Glauber's salt was removed by filtration and purified by silica gel column chromatography (toluene → toluene / ethyl acetate = 5/1 → 3/1 → 2/1) to obtain 264.0 mg of the title compound, yield 87.5%. Obtained in. The (1R) -1-hydroxyethyl compound at the 3-position, which is an isomer of the compound, was not obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm) = 1.29 to 1.38 (9 H, m,

[0091]

[Chemical 29]

[0092] _{CH-C H 3), 2.49} (1H, d, J = 3.
6Hz, OH), 3.19 (1H, dd, J = 2.1Hz, J =
5.1Hz, H-3), 3.72 (3H, s, OCH 3), 3.
62 ~ (1H, dt, J = 3.5Hz, J = 7.5Hz, H-
4 '), 6.79 (2H, d, J = 9.5Hz, H-3 "and H-5"), 7.28 (2H, d, J = 9.5Hz, H-2 "
And H-6 ") ^{_{[α] D 23 = -60.7 °}} (c = 1, CHCl 3).

Example 6 (3S, 4S) -3-[(1R) and (1S) -1-hydroxy]
Ethyl-4-[(4S) -2,2-dimethyl-1,3-dioxola
N-4-yl] -1- (4-methoxy) phenyl-2-azetidi
Non production

[0094]

[Chemical 30]

(3S, 4S) -3-Acetyl-4-[(4S) -2,
2-Dimethyl-1,3-dioxolan-4-yl] -1- (4-methoxy) phenyl-2-azetidinone 50.3 mg (0.16)
mmol) in 1.6 ml of anhydrous tetrahydrofuran, and diisobutylaluminum hydrate (DIBAL) 240
μl (0.24 mmol, 1.5 eq.) under nitrogen atmosphere was -70.
The mixture was added dropwise at 0 ° C and stirred for 30 minutes or longer. After the reaction was completed, 29.3 μl (0.51 mmol) of acetic acid was added at the same temperature to stop the reaction and 2
It was extracted with 0 ml of ethyl acetate. The extract was washed once with a saturated saline solution, further washed once with a saturated sodium hydrogencarbonate aqueous solution, washed again with a saturated saline solution, dried with mirabilite, filtered out to remove mirabilite, and subjected to silica gel column chromatography. Purified by E (toluene → toluene / ethyl acetate = 5/1 → 3/1 → 2/1, CH ₂ Cl ₂ charge) 32
mg of (3S, 4S) -3-[(1R) and (1S) -1-hydroxy] ethyl-4-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -1 A-(4-methoxy) phenyl-2-azetidinone mixture was obtained with a yield of 64%. The ratio of the (1R) form to the (1S) form in this mixture was about 3: 1.

¹ H-NMR (CDCl ₃ ) δ (ppm) = 1.28 to 1.50 (9 H, m,

[0097]

[Chemical 31]

[0098] _{CH-C H 3), 2.12~2.40} (1H,
m, OH), 3.10 (2 / 3H, dd, J = 2.5Hz, J =
6.0 Hz, 1R H-3), 3.18 (1 / 3H, dd,
J = 2.5 Hz, J = 6.0 Hz, 1S body H-3), 3.7
_{0 (3H, s, OCH 3} ), 3.71 ), 6.79 (2H, d, J = 9Hz, H-3 ", H-
5 "), 7.28 (2H, d, J = 9Hz, H-2", H-
6 ″) Example 7-1 (3R, 4S) -3-[(1R) -1-fluoroethyl] -4-[(4
S) -2,2-Dimethyl-1,3-dioxolan-4-yl] -1-
Preparation of (4-methoxy) phenyl-2-azetidinone

[0099]

[Chemical 32]

(3S, 4S) -3-[(1S) -1-Hydroxyethyl] -4-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -1- (4 -Methoxy) phenyl-2-azetidinone (87.9 mg, 0.27 mmol) was dissolved in anhydrous methylene chloride (1.5 ml), and the mixture was mixed with hexafluoropropene-diethylamine (Ishikawa reagent) at 0 ° C under a nitrogen atmosphere.
8 μl (0.18 mmol) was added dropwise. The reaction solution was returned to 15 ° C, stirred for 40 minutes, and cooled to 0 ° C after completion of the reaction.
20 ml of H7.4 phosphate buffer was added and stirred for 5 minutes. After that, extract with methylene chloride (20 ml once, 10 m
The organic layer was washed with saturated saline and dried with sodium sulfate. Glauber's salt was filtered off and purified by silica gel column chromatography (toluene → toluene / EtOAc = 20 /
1 → 15/1 → 10/1 → 5/1 → 3/1), and the title compound was obtained in a yield of 56.1 mg, 64.3%.

¹ H-NMR (CDCl ₃ )

[0102]

[Chemical 33]

[0103]

[Chemical 34]

(3H, dd, J = 6Hz, J = 24Hz, CH
_{F-C H 3), 3.19} (1H, ddd, J = 2.4Hz, J =
7.5Hz, J = 16.5Hz, H-3), 3.62 (3H,
_{s, OCH 3), 3.6~4.0 (} 3H, m, H-4, H-5
a ', H-5b') 4.31 (1H, dt, J = 2.4Hz, J =
6.0 Hz, H-4 ') 4.74 (1H, ddq, J = 46.5)
Hz, J = 7.5Hz, J = 6.0Hz, C H F-CH 3),
6.58 (2H, d, J = 9Hz, H-3 ", H-5"),
7.03 (2H, d, J = 9Hz, H-2 ", H-6") [α] _D ^22.5 = -76.4 ° (c = 1, CHCl ₃ ).

Example 7-2(3R, 4S) -3-[(1R) -1-fluoroethyl] -4-[(4
S) -2,2-Dimethyl-1,3-dioxolan-4-yl] -1-
Preparation of (4-methoxy) phenyl-2-azetidinone
Law)

[0106]

[Chemical 35]

(3S, 4S) -3-[(1S) -1-Hydroxyethyl] -4-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -1- (4 -Methoxy) phenyl-2-azetidinone (151.8 mg, 0.47 mmol) in anhydrous methylene chloride (3)
9 ml of diethylaminosulfur-trifluoride (DAST) at a temperature of -50 ° C under nitrogen atmosphere.
(0.71 mmol, 1.5 eq.) Was added dropwise. After stirring for 1 hour,
After the reaction solution was poured into a mixed solution of saturated sodium hydrogen carbonate aqueous solution and methylene chloride containing ice to decompose excess DAST,
The organic layer was washed with saturated brine and purified by silica gel column chromatography (toluene → toluene / EtO).
Ac = 20/1 → 15/1 → 10/1 → 5/1 → 3 /
1), 71.2 mg of the title compound was obtained with a yield of 46.9%. The physicochemical properties of this product were the same as those obtained in Example 7-1.

Example 8 (3R, 4S) -4-[(1S) -1,2-dihydroxyethyl]-
3-[(1R) -1-fluoroethyl] -1- (4-methoxy) phenyl
Production of Nyl-2-azetidinone

[0109]

[Chemical 36]

(3R, 4S) -3-[(1R) -1-Fluoroethyl] -4-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -1- (4 127.3 mg (0.39 mmol) of -methoxy) phenyl-2-azetidinone was dissolved in 10.4 ml of a mixed solution of acetic acid: water = 4: 1 and reacted at 40 ° C for 14 hours.
After completion of the reaction, the mixture is concentrated and purified by silica gel column chromatography (toluene → toluene / EtOAc = 2 /
(1 → 1/1 → 1/2 → 1/3, charged with methylene chloride) to give the title compound (104.3 mg, yield 94.5%).

NMR (CDCl ₃ ) δ (ppm) = 1.42 (3H, dd, J = 7.2Hz, J = 24.
_{6Hz, CHF-C H 3)} , 2.85 (1H, t, J = 6.0
Hz, 2'-OH), 3.30 (1H, m, H-3), 3.55
(2H, m, H-5'a, H-5'b), 3.70 (3H, s,
_{OCH 3), 4.04~4.15 (2H,} m, H-4, H-
4 '), 4.87 (1H, ddq, J = 7.2Hz, J = 48.
0Hz, J = 5.4Hz, C H F-CH 3), 6.73 (2
H, d, J = 9.3 Hz, H-3 ", H-5"), 7.20
(2H, d, J = 9.3Hz, H-2 ", H-6") [α] _D ²² = -63.4 ° (c = 1.19, CHCl ₃ ) Example 9 (3R, 4S) -3-[(1R) -1-fluoroethyl] -4
-Formyl-1- (4-methoxy) phenyl-2-azeti
Zinone production

[0112]

[Chemical 37]

(3R, 4S) -4-[(1S) -1,2-dihydroxyethyl] -3-[(1R) -1-fluoroethyl]
-1- (4-methoxy) phenyl-2-azetidinone 4
7.5 mg (0.17 mmol) of tetrahydrofuran (THF)
Dissolve in 0.8 ml and under period of nitrogen, periodic acid 48.4 mg
(0.21 mmol, 1.25 eq.) Dissolved in 1 ml THF is added. After completion of the reaction, the mixture was extracted with 30 ml of ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium sulfite and saturated saline, and then purified by silica gel column chromatography (toluene → toluene / toluene /
EtOAC = 3/1 → 2/1 → 1/1 → 1/2 → 1/3 methylene chloride) The title compound was obtained in an amount of 26.0 mg in a yield of 61.0%.

¹ H-NMR (CDCl ₃ ) δ (ppm) = 1.49 (3H, dd, J = 6.0 Hz, J = 24)
_{Hz, CHF-C H 3)} , 3.35 (1H, ddd, J = 2.7
Hz, J = 5.7 Hz, J = 21 Hz, H-3), 3.72
(3H, s, OCH ₃ ), 4.40 (1H, dd, J = 2.7H
z, J = 3.0 Hz, H-4) 5.0 (1H, ddq, J = 46.
2Hz, J = 5.7Hz, J = 6.0Hz, C H F-C
_{H 3), 6.75 (2H,} d, J = 9Hz, H-3 ', H-
5 '), 7.12 (2H, d, J = 9Hz, H-2', H-
6 '), 9.65 (1H, d, J = 3Hz, CHO) [Α] _D ²² = -118.9 ° (C = 1, CHCl ₃ ). Example 10 (3R, 4S) -4-carboxy-3-[(1R) -1-ph
Luoroethyl] -1- (4-methoxy) phenyl-2-a
Zetidinone production

[0115]

[Chemical 38]

(3R, 4S) -3-[(1R) -1-fluoroethyl] -4-formyl-1- (4-methoxy) phenyl-2-azetidinone 40.6 mg (0.16 mmol) in 1 ml
Dissolve in tert-butanol, add 0.64 ml of pH 6.7 phosphate buffer, 0.96 ml of 1M potassium permanganate.
Was added at room temperature and stirred for 45 minutes. After completion of the reaction, 4 ml of saturated aqueous sodium sulfite solution was added under ice cooling and the mixture was stirred.
The pH was adjusted to 2-3 with 1N hydrochloric acid. It was extracted twice with 25 ml of ethyl acetate, and the organic layer was washed with saturated saline. The saline layer was re-extracted with ethyl acetate, combined with the previous organic layer, dried over Glauber's salt, filtered off with Glauber's salt and concentrated to give 45.6 m of the title compound.
g, quantitatively obtained.

[0117]¹H-NMR (CDCl₃) δ (ppm) = 1.32 (3H, dd, J = 6.3Hz, J = 24)
Hz, CHF-CH ₃) 3.32 (1H, ddd, J = 3Hz,
J = 4.8 Hz, J = 25.2 Hz, H-3), 3.58 (3
H, s, OCH₃), 4.38 (1H, d, J = 3Hz, H-
4) 4.95 (1H, ddq, J = 4.8Hz, J = 48H
z, J = 6.3Hz, CHF-CH₃), 6.73 (2H,
d, J = 9Hz, H-3 ', H-5'), 7.08 (2H,
d, J = 9Hz, H-2 ', H-6'), 8.72 (1H,
s, COOH)[Α]_D ^{twenty two}= -84.6 ° (c = 1.0, CH₃OH) Example 11(3R, 4R) and (3R, 4S) -4-acetoxy-3-
[(R) -1-fluoroethyl] -1- (p-methoxy) phenyl
Production of enyl-2-azetidinone

[0118]

[Chemical Formula 39]

(3R, 4S) -4-carboxy-3-[(R) -1
-Fluoroethyl] -1- (p-methoxy) phenyl-2-azetidinone 65 mg (0.24 mmole), lead tetraacetate 216 mg (0.2
49mmole), acetic acid 0.2ml, dimethylformamide 0.6
The mixed solution of ml was reacted at 65 ° C. for 15 minutes. The reaction mixture was poured into ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was dissolved in benzene, adsorbed on a silica gel column (7 g) and eluted with benzene, benzene / ethyl acetate (50/1), (40/1) and (20/1). In the elution section, silica gel TLC developed with benzene / ethyl acetate (3/1) was used to collect the sections showing UV absorption at Rf values of 0.75 and 0.57, and concentrated under reduced pressure to obtain 7 mg of the target compound, cis and trans, respectively. , 43 mg were obtained (total yield 73
%). These compounds could be crystallized from benzene-n-hexane.

Physicochemical properties of cis compound Melting point 156-160 ° C. [α] _D ²² + 42.7 ° (c = 0.62, CHCl ₃ ). NMR (CDCl ₃ ) δ; 1.60 (3H, dd, J = 24.0 and 6.0Hz, CH ₃
-CHF) 2.17 (3H, s, OAc) 3.68 (1H, m, H-3) 3.70 (3H, s, OMe) 5.17 (1H, m, CH 3 -C H F) 6.83 (1H, d, J = 6.0Hz, H-4)

[0121]

[Chemical 40]

[0122] Physicochemical Properties mp 121-123.5 ° C. trans compound [α] ^{_{D 22 -51.4 ° (c = 1.013}} , CHCl 3) NMR (CDCl ₃ ) δ; 1.55 (3H, d, J = 24.0 & 6.5Hz, CH ₃ -C
HF) 2.10 (3H, s, OAc) 3.40 (1H, ddd, J = 1.5 & 5.0 & 24.5Hz, H
-3) 3.79 (3H, s, OMe) 5.07 (1H, ddq, H = 48.0 & 5.0 & 6.5Hz, CH
_{3 -C H F-) 6.62 (1H} , d, J = 1.5Hz, H-4)

[0123]

[Chemical 41]

Example 12 (3R, 4R) -4-acetoxy-3-[(R) -1-fur
Production of Oroethyl] -2-azetidinone

[0125]

[Chemical 42]

(3R, 4R) -4-acetoxy-3-
30 mg (0.11 mmole) of [(R) -1-fluoroethyl] -1- (p-methoxy) phenyl-2-azetidinone was dissolved in 1.5 ml of acetonitrile and cooled with ice to give 175.5 mg of seric ammonium nitrate ( A solution of 0.32mmole) 1.
5 ml was gradually added dropwise.

After reacting for 25 minutes at the same temperature, the reaction solution was poured into 50 ml of ethyl acetate and washed with a 5% aqueous sodium hydrogen carbonate solution. The washing solution was extracted again with ethyl acetate, and the organic layers were combined and washed once with a 10% sodium thiosulfate aqueous solution, a 5% sodium hydrogen carbonate aqueous solution, and a saturated saline solution.

The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 15 mg of the title compound (yield 81
%).

This compound was crystallized from benzene-n-hexane.

Melting point 98.5-102 ° C. [α] _D ²² + 116.8 ° (c = 1.0, CHCl ₃ ). 1745 (ester CO) NMR (CDCl ₃ ) δ; 1.50 (3H, dd, J = 6.5 & 24.0Hz, CH ₃ −
CHF) 2.13 (3H, s, COCH ₃ ) 3.40 (1H, ddd, J = 1.5 & 5.5 & 24.0Hz, H
-3) 5.00 (1H, dqiunt, J = 48.0 & 6.5Hz, CH ₃ −
C H F-) 5.90 (1H, d, J = 1.5Hz, H-4) 6.85 (1H, br, NH) Example 13 4 - [(3R, 4R) -3 - ( (R ) -1-Fluoroethyl)
-2-Oxoazetidin-4-yl] -2-diazo-3
Of 2-oxobutyric acid p-nitrobenzyl ester

[0131]

[Chemical 43]

(3R, 4R) -4-acetoxy-3-
[(R) -1-fluoroethyl] -2-azetidinone 2
After dissolving 0 mg (0.11 mmole) in 1 ml of methylene chloride and cooling with ice, 36 mg (0.11 mmole) of zinc iodide was added. To this mixture at 0 ° C. was added 96 mg of p-nitrobenzyl 2-diazo-3- (trimethylsilyl) oxy-3-butenoate (0.
A solution of 29 mmole) in methylene chloride (1 ml) was slowly added dropwise over 13 minutes.

The reaction solution was stirred at 0 ° C. for 20 minutes and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate.

The residue obtained by distilling off the solvent was adsorbed on 6 g of silica gel using a small amount of methylene chloride and developed in the order of benzene / acetone (10/1) (8/1) (5/1).
When the fractions having UV absorption at Rf 0.36 were collected on TLC using benzene / acetone (3/1) as a developing system in the eluate and dried under reduced pressure, 27 mg (yield 62%) of the title compound was obtained. .

Physicochemical properties of this compound Melting point 90-92 ° C. [α] _D ²² + 41.8 ° (c = 1.25, methanol) 1760 (β-lactam CO), 1710 (ketone CO), 1520,1345 (nitro).

[0136] _{NMR (CDCl 3) δ; 1.44} (3H, dd, J = 24.0 and 6.5 Hz, C H
_3- CHF-) 2.8-3.2 (1H, m, H-3) 3.02 (1H, dd, J = 18.0 and 9.0Hz,

[0137]

[Chemical 44]

3.67 (1H, dd, J = 18.0 and 4.5)
Hz,

[0139]

[Chemical formula 45]

4.02 (1H, ddd, J = 9.0, 4.5 and 2.3Hz, H-4), 4.93 (1H, dqunit, J = 48.0)
And _{6.5Hz, CH 3 C H -F -} ), 5.38 (2H, s, benzyl), 6.30 (1H, br, NH), 7.56 (2H, d, J
= 9.0 Hz, Ar), 8.28 (2 H, d, J = 9.0 Hz, A
r).

Example 14 (3R, 4S) -4-acetoxy-3-[(R) -1-fluor
Preparation of [Rhoethyl] -2-azetidinone

[0142]

[Chemical formula 46]

(3R, 4S) -4-acetoxy-3-
27 mg (0.096 mmole) of ((R) -1-fluoroethyl) -1- (p-methoxy) phenyl-2-azetidinone was dissolved in 1.0 ml of acetonitrile and then cooled with ice, and 132 mg of ceric ammonium nitrate was prepared. 1.0 ml of an aqueous solution of 24 mmole) was slowly added dropwise.

After reacting for 30 minutes at the same temperature, the reaction solution was poured into ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted again with ethyl acetate, and the organic layers were combined and washed successively with 10% aqueous sodium thiosulfate solution, 5% aqueous sodium hydrogen carbonate solution and saturated brine.

After drying with anhydrous sodium sulfate, the solvent was distilled off to obtain 15 mg of the title compound (yield 89%).

[0146] 1780 (β-lactam CO), 1735 (ester CO).

[0147] _{NMR (CDCl 3) δ; 1.55} (3H, dd, J = 6.0 and 24.0Hz, C H
₃ CHF-), 2.17 (3H, s, COCH ₃ ), 3.58 (1
_{H, dddd, J 3, NH} = 2.0, J 3. 4 = 4.5, J 3, C H F =
9.3, J ₃ , F = 13.8Hz, H-3), 5.13 (1H, dd
q, J = 6.0, 9.3 and 48.0Hz, CH ₃ C H F
-), 6.02 (1H, d, J = 4.5Hz, H-4), 6.80
(1H, br, NH).

Example 15 4-[(3R, 4R) -3-((R) -1-fluoroethyl)
-2-Oxoazetidin-4-yl] -2-diazo-3
Of 2-oxobutyric acid p-nitrobenzyl ester

[0149]

[Chemical 47]

(3R, 4S) -4-acetoxy-3-
[(R) -Fluoroethyl] -2-azetidinone 15 mg
(0.086 mmole) was dissolved in 1 ml of methylene chloride, cooled with ice, and 28 mg (0.087 mmole) of zinc iodide was added. To this mixture at 0 ° C p-nitrobenzyl 2-diazo-3- (trimethylsilyl) oxy-3-butenoate 72 mg (0.21 m
A methylene chloride solution (0.5 ml) was slowly added dropwise over 10 minutes.

The reaction solution was kept at 0 ° C. for 10 minutes and then at room temperature for 2 minutes.
Stir for hours. The reaction mixture was diluted with ethyl acetate and washed successively with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine. After drying with anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by preparative TLC (developing system benzene / acetone 3/1) to give 13.7 mg of the title compound.
(Yield 42%) was obtained.

The physicochemical properties of the obtained compound are shown in Example 1.
It was exactly the same as that obtained in 3.

Claims (1)

[Claims] 1. The formula: In the formula, A represents C H or N, and R ₁ is a phenyl which may be substituted with a lower alkoxy group.
It represents Le group, R ₂ and R ₃ are identical or different, each lower alkyl group a to I Table, in the compound represented.