JPH0565268A - Azetidinone derivative and production thereof - Google Patents

Abstract

PURPOSE:To provide new compounds useful as an intermediate for synthesis of cephalosporin-based antibiotics. CONSTITUTION:Compounds of formula I (R<1> is H or carboxylic acid-protecting group; Ar is aryl), e.g. p-methoxybenzyl-2-[3-amino-4-(p-toluene) sulfonylthio-2- azetidinon-1-yl]-3-chloromethyl-3-butenoate. The compound of formula I can be produced by reacting a chlorothiazolidineazetidinone derivatice of formula II (R<2> is aryl or aryloxy; R<3>CO is carboxylic acid residue) with an arylsulfinic acid of formula Ar-SO2H in the presence of an acid (e.g. hydrochloric acid) in a lower alcohol (e.g. methanol) at -20-50 deg.C for 30min-10hr. An economical penicillin can be used as the raw material for production.

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 is an important synthetic intermediate for cephalosporin antibiotics, and for example, Japanese Patent Application No. 3-53 filed on the same day by the present applicant. According to the method of the specification (title of the invention: a method for producing a 7-amino-3-chloromethyl-3-cephem derivative), the compound can be easily converted into a cephalosporin derivative (4) as shown in the following reaction formula (A). Is possible.

[Chemical 4] The above compound (4) can be easily converted into various cephalosporin antibiotics by acylating the amino group at the 7-position, substituting the chloromethyl group at the 3-position with an aromatic heterocyclic thiol and further removing the carboxylic acid protecting group. It is known as an important synthetic intermediate that can be converted into a substance, and its industrial utility value is extremely high.

[0003]

2. Description of the Related Art Known analogues of the derivative represented by the general formula (1) according to the present invention include Shigeru Torii et al.
-85894, 59-164771), and all of them are, for example, amino groups as shown in the following formula (5).

[Chemical 5] Is in the form protected by an acyl group. Therefore, the operation of cleaving this acyl group must be performed again in a later step. In the present invention, this is not necessary at all.

[0004]

[Problems to be Solved by the Invention] Using a simple method,
To convert a thiazolidine azetidinone derivative represented by the general formula (2) into a azetidinone derivative represented by the general formula (1) which is a synthetic precursor for obtaining a cephalosporin derivative (4) in high yield. is there.

[0005]

The starting material (2) used in the present invention is a compound which can be easily synthesized from penicillin sulfoxide (6) as shown in the following reaction formula (C).

[Chemical 6] Conversion of compound (6) to (7) is described in R.H. D. G. Coo
per et al. (J. Am. Chem. Soc.,
92 , 2575 (1970)) and the conversion of compound (7) to (9) via (8) by S. J. Ea
gle et al. (Tetrahedron Let
t. , 1978 , 4703). The chlorination reaction from compound (9) to (2) can be carried out according to the method of Japanese Patent Application No. 3- (Tiazolidine azetidinone derivative and its production method) filed on the same day by the applicant. It can be done easily.
In the thiazolidine azetidinone derivative (2),
R ¹ , R ² and R ³ are not particularly limited, but a protecting group generally used in ordinary penicillin-cephalosporin conversion is used. For example, specific examples of R ¹ include a phenylmethyl group, a methyl group, an ethyl group, 2,2,2, such as a benzyl group, a paranitobenzyl group, a paramethoxybenzyl group, a diphenylmethyl group and the like, which may be substituted or unsubstituted. -A lower alkyl group which may contain halogen such as a 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 a hydrogen atom, an alkyl group such as a methyl group, an ethyl group, and an n-butyl group, a phenyl group, a paratoluyl group, a paranitrophenyl group, a parachlorophenyl group, or a substituted or unsubstituted aryl group. Groups and the like. Specific examples of Ar include a phenyl group, a paratoluyl group, a parachlorophenyl group, a paranitrophenyl group, a paramethoxyphenyl group, an aryl group which does not have a substituent such as a 2,4-dinitrophenyl group, and the like. Be done.

In the method of the present invention, the thiazolidine azetidinone derivative (2) is dissolved in an organic solvent containing a lower alcohol such as methanol at a concentration of 1 mol / 1 to 0.01 mol / 1, and then dissolved in hydrochloric acid or the like. The acid and arylsulfinic acid or its metal salt are added and reacted. The reaction temperature and reaction time are not constant depending on the type of thiazolidine azetidinone derivative (2) used, but the reaction temperature is preferably -20 to 50 ° C, more preferably -5 to 25 ° C, and the reaction time is The reaction is usually completed in 30 minutes to 10 hours. The arylsulfinic acid (3) is generally used in an amount of 1.0 to 5.0 times, preferably 1.05 to 1.20 times the mol of the thiazolidine azetidinone derivative (2).
As the acid to be added, for example, mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, organic acids such as trifluoroacetic acid and paratoluenesulfonic acid, and the like are used, and preferably 1 to 20% methanol-hydrochloric acid. The amount of the acid added is usually 0.1 to 20 times mol, preferably 5 to 10 times mol, of the thiazolidine azetidinone derivative (2).

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. Organic solvents used by mixing with the lower alcohol include acetone, ketones such as methyl ethyl ketone, acetonitrile, nitriles such as butyronitrile, diethyl ether, Diisopropyl ether, tetrahydrofuran,
Ethers such as 1,4-dioxane, nitromethane, dichloromethane, chloroform, 1,2-dichloroethane, halogenated hydrocarbon solvents such as carbon tetrachloride, aromatic solvents such as benzene, toluene and chlorobenzene, ethyl acetate, formic acid Examples thereof include esters such as methyl and amides such as dimethylformamide and dimethylacetamide.

The compound of the present invention thus produced is easily isolated and purified by a conventional separation means.

[0009]

【Example】

 Example 1 p-methoxybenzyl 2- (3-amino-4- (p-
Toluene) sulfonylthio-2-azetidinone-1-i
) -3-Chloromethyl-3-butenoate (1a)
(R¹= P-methoxybenzyl, Ar = p-toluyl)
Compound (2a) (R¹= P-methoxybenzyl, R^Two=
Phenyl, R^Three= Hydrogen) 500 mg of methylene chloride 1.
Dissolve in a mixture of 5 ml and 10 ml of methanol, and under ice cooling
6N-hydrochloric acid 1 ml and paratoluenesulfinic acid 166
mg was added and reacted at room temperature for 4 hours. The reaction solution is
Pour into a mixture of 50 ml of ethylene and 50 ml of water, and after separating,
The layers were further extracted with 10 ml of methylene chloride and merged.
The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to dryness.
It was The residue is reverse phase C₁₈(Nacalai Tesque Cosmo Seal
75C₁₈Column chromatography using OPN, 50g)
Purify with Raffy (acetonitrile-water 3: 2),
Compound (la) 428 mg (84%) as a pale yellow syrup
Got as.¹ H-NMR (CDCl_Three) Δ 1.78 (bs, 2H, NH_Two), 2.44
(S, 3H, SO_TwoC₆H_FourCH_Three), 3.80 (s,
3H, CH_TwoC₆H_FourOCH_Three), 4.07 (s, 2
H, CH_TwoC₆H_FourOCH_Three), 4.63 (d, 1H,
J = 4.5 Hz, β-lactam), 4.93, 5.0
7, 5.37 (each s, each 1H, CH(COOCH_TwoC₆
H_FourOCH_Three) C (CH_TwoCl) = CH ₂ ), 5.10
(D, 1H, J = 10.8Hz, CH_TwoCl), 5. I
7 (d, 1H, J = 10.8Hz, CH_TwoCl), 5.
53 (d, 1H, J = 4.5 Hz, β-lactam),
6,89 (d, 2H, J = 9.0Hz, CH_TwoC₆H_Four
OCH_Three), 7.28 (d, 2H, J = 9.0 Hz, C
H_TwoC₆H_FourOCH_Three), 7.33 (d, 2H, J =
8.4Hz, SO_TwoC₆H_FourCH_Three), 7.77 (d,
2H, J = 8.4Hz, SO_TwoC₆H_FourCH_Three  IR 3400, 3340, 1775,
1740, 1335, 1145 cm^-1

Example 2 p-Methoxybenzyl 2- (3-amino-4-benzenesulfonylthio-2-azetidinone-1-yl) -3
-Chloromethyl-3-butenoate (1b) (R ¹ = paramethoxybenzyl, Ar = phenyl)

Compound (2b) (R¹= P-methoxyben
Jill, R^Two= Phenyl, R^Three= Hydrogen) Chloride 500 mg
Dissolved in a mixture of 1.5 ml of methylene and 4 ml of methanol
Then, under ice cooling, 1N-hydrogen chloride / methanol 6 ml and benz
213mg sodium sodium sulfinate dihydrate
And reacted at room temperature for 3 hours. Perform the same operation as in Example 1.
No, compound (1b) 443 mg (87%)
Got it as a lop.¹ H-NMR (CDCl_Three) Δ 1.80 (bs, 2H, NH_Two), 3.80
(S, 3H, CH_TwoC₆H_FourOCH_Three), 4.05
(S, 2H, CH_TwoC₆H_FourOCH_Three), 4.63
(D, 1H, J = 4.5 Hz, β-lactam), 4.9
2, 5.01, 5.33 (each s, each 1H, CH(COO
CH_TwoC₆H_FourOCH_Three) C (CH_TwoCl) = C
H ₂ ), 5.09 (d, 1H, J = 10.8Hz, CH
_TwoCl), 5. I6 (d, 1H, J = 10.8Hz, C
H_TwoCl), 5.55 (d, 1H, J = 4.5Hz, β
-Lactam), 6,89 (d, 2H, J = 9.0Hz,
CH_TwoC₆H_FourOCH_Three), 7.28 (d, 2H, J =
9.0Hz, CH_TwoC₆H_FourOCH_Three), 7.51-
7.89 (5H, m, SO_TwoC₆H₅  IR 3400, 3340, 1775,
1740, 1335, 1145 cm^-1

Example 3 p-Methoxybenzyl 2- (3-amino-4-benzenesulfonylthio-2-azetidinone-1-yl) -3
-Chloromethyl-3-butenoate (1b) (R ¹ = p
- methoxybenzyl, Ar = phenyl) Compound ^(2c) (R 1 = p- ^{methoxybenzyl, R} 2 =
Phenyl, R ³ = methyl) 1.0 g methylene chloride 3 m
Dissolve in a mixed solution of 1 and 8 ml of methanol and 1N- under ice cooling.
Hydrogen chloride / methanol (12 ml) and sodium benzenesulfinate dihydrate (450 mg) were added, and the mixture was reacted at room temperature for 12 hours. The same operation as in Example 1 was performed to obtain 797 mg (82%) of the compound (1b).

[0013]

Industrial Applicability The azetidinone derivative represented by the general formula (1) according to the present invention undergoes an important synthetic intermediate of various cephalosporin antibiotics through the above reaction formula (A) which is the method of the present inventors. It can be easily converted to the body (4). In this respect, the present invention has a great utility value in the pharmaceutical manufacturing industry, and since inexpensive penicillin can be used as a raw material, it is considered that the present invention can greatly contribute to the reduction of the manufacturing cost of various cephalosporin antibiotics.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Katsuharu Iinuma 760, Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Ken Nishibata 760, Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Co., Ltd. Pharmaceutical Research Institute

Claims (4)

[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, and Ar represents a substituted or unsubstituted aryl group.) An azetidinone derivative represented by the following formula. 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 an organic solvent containing a lower alcohol in the presence of an acid. (In the formula, R ² represents a substituted or non-substituted aryl group or a substituted or non-substituted aryloxy group, R ³ CO represents a carboxylic acid residue, and R ¹ is the same as above.) A thiazolidineazetidinone derivative represented by the general formula (3) (In the formula, Ar is the same as the above.) The manufacturing method of the azetidinone derivative represented by General formula (1) of Claim 1 obtained by making it react with arylsulfinic acid. 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 with sulfinic acid in which Ar is paratoluyl or phenyl in the general formula (3).