JP2669961B2 - Azetidinone derivatives and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel azetidinone derivative represented by the general formula (1), which has not been published in the literature, and a method for producing the same. The azetidinone derivative represented by the general formula (1) produced by the present invention can be an important synthetic intermediate for cephalosporin antibiotics. That is, as shown in the following reaction route diagram, the azetidinone derivative represented by the general formula (1) is

[0002]

Embedded image Deacetoxy cephalosporin can be synthesized by a number of synthetic routes by appropriately combining a ring closure reaction with a base, a side chain acylation, an N-protecting group introduction reaction, a halogenation of an allyl methyl group, a 3'position substitution reaction and the like. The system as well as cephalosporin antibiotics can be easily synthesized.

As described above, the azetidinone derivative represented by the general formula (1) is important as a synthetic intermediate which can be converted into various cephalosporin antibiotics, and it can be said that it has an extremely high industrial utility value. .

[0004]

2. Description of the Related Art Induction of azetidinone represented by the general formula (1)
As a compound similar to a conductor, there is Shigeru Torii et al.
-134779, 59-164771)
(4) (in the formula, R¹, R^TwoAnd Ar are the same as above. ) And
General formula (5) (wherein R¹, R ^TwoAnd Ar are the same as above
Same. )

[0005]

Embedded image And the present inventors (Japanese Patent Application No. 3-109).
904) (wherein R ¹ and Ar are the same as above).

[0006]

[Chemical 6] Compounds represented by are known. However, as described above, the compound represented by the general formula (1) has a possibility that various synthetic routes can be selected when the cephalosporin compound is synthesized, more than the known compounds. Here, the chemical reaction used for producing the compound represented by the general formula (1) is the following reaction previously found by the present inventors, that is, thiazolidine azetidinone.

[0007]

Embedded image Similar to the conversion reaction from the derivative (7) (wherein R ¹ , R ² and R ³ are the same as above) to the compound represented by the general formula (6) (Japanese Patent Application No. 3-109904), one step Is a very useful reaction in which the thiazolidine ring opening reaction is followed by a sulfonylthio body formation reaction and an acylamide side chain cleavage reaction all at once.

[0008]

As described above, an azetidinone derivative represented by the general formula (1), which is considered to be very useful and versatile as a synthetic intermediate for various cephalosporin antibiotics, is obtained. , A thiazolidine azetidinone derivative represented by the general formula (2) that can be easily obtained from inexpensive penicillin by a simple method.

[0009]

The starting material used in the present invention, a thiazolidineazetidinone derivative represented by the general formula (2), is a penicillin sulfoxide (8) (in the formula, R ¹ and R ² is the same as described above.).

[0010]

Embedded image The conversion of penicillin sulfoxide (8) to thiazoline azetidinone derivative (9) (in the formula, R ¹ and R ² are the same as described above) is carried out by the method described in R. D. G. Cooper et al. (J. Am. Chem. Soc., 92 , 2575).
(1970)) and the conversion of the thiazoline azetidinone derivative (9) to the thiazolidine azetidinone derivative (2) is described by S. et al. J. Method by Eagle et al. (T
etrahedron Lett. , 1978 , 470
3) can be performed.

In the thiazolidine azetidinone derivative (2), R ¹ , R ² and R ³ are not particularly limited, but a protecting group commonly used in ordinary penicillin-cephalosporin chemical conversion is used. For example, specific examples of R ¹ include phenylmethyl group, methyl group, ethyl group, substituted or unsubstituted benzyl group, paranitrobenzyl group, paramethoxybenzyl group, diphenylmethyl group, and the like.
Examples thereof include an alkyl group which may contain a halogen such as a 2,2,2-trichloroethyl group. Specific examples of R ² include a substituted or unsubstituted aryl group such as a phenyl group, a paranitrophenyl group and a parachlorophenyl group, and a substituted or unsubstituted aryloxy group such as a phenoxy group and a parachlorophenoxy group. Etc. can be mentioned. Specific examples of R ³ include an alkyl group which may contain a halogen atom such as a hydrogen atom, a methyl group, an ethyl group, an n-butyl group, a chloromethyl group and a trifluoromethyl group. Specific examples of Ar of sulfinic acid (3) include phenyl group, paratoluyl group,
Paranitrophenyl group, paramethoxyphenyl group, 2,
Substituted or non-substituted aryl groups such as 4-dinitrophenyl group may be mentioned.

In the method of the present invention, the thiazolidine azetidinone derivative (2) is dissolved in a lower alcohol such as methanol or an organic solvent containing it at a concentration of 1 mol / l to 0.01 mol / l, and hydrochloric acid is added thereto. And an acid such as sulfinic acid or a metal salt thereof are added and reacted. The reaction time and reaction temperature are not constant depending on the type of thiazolidine azetidinone compound (2) used, the amount of sulfinic acid (3) used, the concentration of acid, etc., but the reaction temperature is preferably -20 ° C to 50 ° C, and more preferably Is -5 ° C to 20 ° C, and the reaction time is usually 30 minutes to 10 hours to complete the reaction. The sulfinic acid (3) is usually 1.0 to 6.0 times mol, preferably 1.05 mol, with respect to the thiazolidine azetidinone compound (2).
~ 2.0 times the molar amount is used. As the acid to be added, for example, a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid, an organic acid such as trifluoroacetic acid, trifluoromethanesulfonic acid, paratoluenesulfonic acid, or the like is used, and preferably 1% to 20% hydrochloric acid.

As the organic solvent, a lower alcohol alone or a mixed solvent containing at least one lower alcohol is used. Specific examples of the lower alcohol include methanol, ethanol, n-butanol and the like, preferably methanol. As the organic solvent used as a mixture with a lower alcohol, acetone, methyl ethyl ketone, ketones such as 2-butanone, acetonitrile, nitriles such as butyronitrile, diethyl ether, diisopropyl ether, tetrahydrofuran, ethers such as 1,4-dioxane, Dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and other halogenated hydrocarbon solvents, benzene, toluene, chlorobenzene and other aromatic hydrocarbon solvents, ethyl acetate, methyl formate and other esters, dimethylformamide, diethyl Examples thereof include amides such as acetamide.

The compound of the present invention thus produced can be easily isolated and purified by a conventional separation means. Examples will be given below.

[0015]

【Example】

Example 1 p-methoxybenzyl 2- (3-amino-4- (p-
Toluenesulfonylthio) -2-azetidinone-1-yl) -3-methyl-3-butenoate (1a) (R ¹ =
p- methoxybenzyl, Ar = p- tolyl) compound (2a) (R ¹ = p- methoxybenzyl, R ² =
Phenyl, R ³ = hydrogen) 500 mg was added to methylene chloride 3.
It was dissolved in a mixed solution of 5 ml and 4.5 ml of methanol, 1N hydrogen chloride-methanol 1 ml and sodium p-toluenesulfinate 372 mg were added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour.
The reaction was performed for 2 hours. The reaction solution was poured into a mixed solution of 50 ml of methylene chloride and 50 ml of water, the layers were separated, and the aqueous layer was further extracted with 10 ml of methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was reversed-phase C ₁₈ (Nacalai Tesque Cosmo Seal 75C ₁₈ OPN, 50 g)
Column chromatography using (acetonitrile-
Purified with water 3: 2), compound (1a) 443 mg
(86.9%) was obtained as a pale yellow syrup.

¹ H-NMR (CDCl ₃ ) δ 1.71 (bs, 2H, NH ₂ ) 1.78 (s, 3H, C (= CH ₂ ) CH ₃ ) 2.46 (s, 3H, SO ₂ C ₆ H ₄ CH ₃ ) 3.82 (s, 3H, CH ₂ C ₆ H ₄ OC H ₃ ) 4.62 (d, 1H, J = 4.3 Hz, β-lactam) 4.68, 4 .73, 4.92 (each s, each 1H, C H (COOR ¹ ) C (= C H ₂ ) C
_{H 3) 5.07 (d, 1H} , J = 12.1Hz, C H 2 C 6 H
₄ OCH ₃ ) 5.14 (d, 1H, J = 12.1 Hz, C H ₂ C ₆ H
₄ OCH ₃ ) 5.56 (d, 1H, J = 4.3 Hz, β-lactam) 6.89 (d, 2H, J = 8.7 Hz, CH ₂ C ₆ H ₄
OCH ₃ ) 7.27 (d, 2H, J = 8.7 Hz, CH ₂ C ₆ H ₄
OCH ₃ ) 7.33 (d, 2H, J = 8.4 Hz, SO ₂ C ₆ H ₄
CH ₃ ) 7.78 (d, 2H, J = 8.4Hz, SO ₂ C ₆ H ₄
CH ₃ )

Example 2 p-Methoxybenzyl 2- (3-amino-4-benzenesulfonylthio-2-azetidinone-1-yl) -3
- methyl-3- butenoate (1b) (R ¹ = p- methoxybenzyl, Ar = phenyl) Compound (2a) (R ¹ = p- methoxybenzyl, R ² =
Phenyl, R ³ = hydrogen) 2.0 g, methylene chloride 4 ml
And 30 ml of methanol were dissolved, and 30 ml of 1N hydrogen chloride-methanol and 1.67 g of sodium benzenesulfinate dihydrate were added under ice cooling, and the mixture was reacted at the same temperature for 9 hours. The same operation as in Example 1 was carried out to give the compound (1
b) 1.63 g (82.1%) was obtained as a pale yellow syrup.

¹ H-NMR (CDCl ₃ ) δ 1.63 (bs, 2H, NH ₂ ) 1.70 (s, 3H, C (= CH ₂ ) CH ₃ ) 3.82 (s, 3H, CH) _{2 C 6 H 4 OC H 3} ) 4.64 (d, 1H, J = 4.5Hz, β- lactam) 4.69,4.90 (each s, 2H, 1H, C H (COO
R ¹ ) C (= C H ₂ ) CH ₃ ) 5.08 (d, 1H, J = 10.8 Hz, C H ₂ C ₆ H
₄ OCH ₃ ) 5.17 (d, 1H, J = 10.8Hz, C H ₂ C ₆ H
₄ OCH ₃ ) 5.58 (d, 1H, J = 4.5 Hz, β-lactam) 6.90 (d, 2H, J = 9.0 Hz, CH ₂ C ₆ H ₄
OCH ₃ ) 7.28 (d, 2H, J = 9.0 Hz, CH ₂ C ₆ H _{4
OCH 3) 7.52-7.69 (m, 3H} , SO 2 C 6 H 5) 7.88-7.93 (m, 2H, SO 2 C 6 H 5)

Example 3 Preparation of Compound (1b) Compound (2b) (R ¹ = p-methoxybenzyl, R ² =
Phenyl, R ³ = methyl) 1.0 g methylene chloride 3 m
It is dissolved in a mixed solution of 1 and 15 ml of methanol and 1N under ice cooling.
12 ml of hydrogen chloride-methanol and 870 mg of sodium benzenesulfinate dihydrate were added, and the mixture was reacted at room temperature for 2 hours. The same operation as in Example 1 was carried out to give the compound (1
b) 779 mg (81.0%) was obtained.

Example 4 Preparation of Compound (1b) Compound (2c) (R ¹ = p-methoxybenzyl, R ² =
Phenoxy, R ³ = hydrogen) 1.0 g, methanol 10 m
Dissolve in 1 and under ice cooling 1N hydrogen chloride-methanol 12 ml
And sodium benzenesulfinate dihydrate 870mg
Was added and reacted at room temperature for 2 hours. The same operation as in Example 1 was carried out to obtain 448 mg (46.6%) of compound (1b).
I got

Example 5 Preparation of Compound (1a) Compound (2c) (R ¹ = p-methoxybenzyl, R ² =
Phenoxy, R ³ = methyl) 1.0 g methanol 10
Dissolve in 1 ml of 1N hydrogen chloride-methanol 12m under ice cooling.
1 and 950 mg of sodium p-toluenesulfinate were added and reacted at the same temperature for 12 hours. The same operation as in Example 1 was carried out to obtain 561 mg (56.7) of the compound (1a).
%).

Example 6 Preparation of Compound (1a) Compound (2d) (R ¹ = p-methoxybenzyl, R ² =
Phenoxy, R ³ = methyl) 1.0 g methanol 10
Dissolve in 1 ml of 1N hydrogen chloride-methanol 12m under ice cooling.
1 and 980 mg of sodium p-toluenesulfinate were added, and the mixture was reacted at the same temperature for 12 hours. The same operation as in Example 1 was carried out to obtain 497 mg (51.7) of the compound (1a).
%).

[0023]

INDUSTRIAL APPLICABILITY The azetidinone derivative represented by the general formula (1) according to the present invention is a useful and versatile compound which can be easily chemically converted into various cephalosporin antibiotics through various reaction routes as described above. It is a large synthetic intermediate. In this respect, it is considered that the present invention has a great utility value in the pharmaceutical manufacturing industry, and can use inexpensive penicillin as a raw material, and thus can greatly contribute to reduction of the manufacturing cost of cephalosporin antibiotics.

 ───────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Katsuharu Iinuma 760 Shiokaoka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Inside the Pharmaceutical Research Institute, Meiji Seika Co., Ltd. Yasushi Tominaga Examiner, Pharmaceutical Research Institute, Inc.

Claims (4)

(57) [Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ represents a hydrogen atom or a carboxylic acid protecting group,
Ar represents a phenyl group, a paratoluyl group, a paranitrophenyl group, a paramethoxyphenyl group, or a 2,4-dinitrophenyl group. ) Azetidinone derivative represented by. 2. An azetidinone derivative in which R ¹ is paramethoxybenzyl and Ar is paratoluyl or phenyl in the general formula (1) of claim 1. 3. A compound represented by the general formula (2): embedded image in the presence of an acid in a lower alcohol or an organic solvent containing a lower alcohol. (In the formula, R ² represents a phenyl group, a paranitrophenyl group, a parachlorophenyl group, a phenyl group, a phenoxy group, a parachlorophenoxy group, R ³ CO represents a carboxylic acid residue, and R ¹ represents a hydrogen atom or a carboxylic acid residue. An acid protecting group is shown) and a thiazolidine azetidinone derivative represented by the general formula (3): (Wherein Ar represents a phenyl group, a paratoluyl group, a paranitrophenyl group, a paramethoxyphenyl group, or a 2,4-dinitrophenyl group), which is obtained by reacting with an arylsulfinic acid. A method for producing an azetidinone derivative represented by the general formula (1). 4. A thiazolidine azetidinone in which R ¹ is paramethoxybenzyl, R ² is phenyl and R ³ is a hydrogen atom or methyl in an organic solvent containing methanol-hydrochloric acid. Derivatives and claim 3
The method for producing an azetidinone derivative represented by the general formula (1) according to claim 1, which is obtained by reacting sulfinic acid in which Ar is paratoluyl or phenyl in the general formula (3).