JPH06135928A - Production of azetidinone derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound important as a synthetic intermediate for medicines such as a beta-lactam-based antimicrobial agent in good yield by directly reacting a azetidinone derivative used as a raw material with an alcohol or a thiol compound in the presence of a copper compound. CONSTITUTION:An azetidinone derivative of formula I [OR1 is protected OH; R2 is alkyl or (substituted)aromatic] is made to react with an alcohol compound or a thiol compound of formula II (X is O or S; R3 is alkyl, alkenyl, aralkyl or aryl) in the presence of a copper compound to provide the objective 4- substituted azetidinone derivative of formula III [e.g. (3R,4R)-3-[(R)-1-(tert.- butyldimethylsilyloxy)ethyl]-4-aryloxy-2-azetidinone]. As the copper compound, copper (I) oxide or copper (II) oxide is preferably used. This method is industrially advantages because reactional process is shortened.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an azetidinone derivative, which is important as a pharmaceutical synthesis intermediate such as a β-lactam antibacterial agent.

[0002]

PRIOR ART General formula (3)

[Chemical 4] (Wherein OR ₁ represents a protected hydroxyl group, X represents an oxygen atom or a sulfur atom, and R ₃ represents a substituted or unsubstituted alkyl group, alkenyl group, aralkyl group or aryl group). Is mainly used as a synthetic intermediate for β-lactam antibacterial agents (eg, Nagata).
et al., Heterocycles, 1977, 7 , 839 (1977) and Tetra
hedron Letters, 1979 , 4287. Etc. are exemplified). Recently, in fields other than antibacterial agents, for example, human
It has been reported that the leukocyte elastase is involved in the treatment of lung diseases (Hagmann et al., Bioo
rganic and Medicinal Chemistry Letters, 1 , 545 (1
991)).

The desired azetidinone derivative represented by the general formula (3) has been converted to the general formula (1).

[Chemical 5] (Wherein OR ₁ has the same meaning as described above, and R ₂ represents an alkyl group or a substituted or unsubstituted aromatic group), when a azetidinone derivative represented by the general formula (1) It was necessary to oxidize the sulfide group of the azetidinone derivative represented by the formula (3) to convert it to a sulfone group having a good elimination property, or to substitute it with an acyloxy group or the like.

The conversion of the azetidinone derivative represented by the general formula (1) into a sulfone body is carried out by using a peracid (Yo
shida et al., Chem. Pharm. Bull., 29 , 2899 (1981))
However, the conversion to the acyloxy form is carried out by using a mercury compound (Yoshida et al., Chem. Pharm. Bull., 29 , 2
899 (1981)) is known, but it is difficult to adapt it to practical production in terms of safety and toxicity.

Regarding the conversion to the acyloxy form, a useful method recently using a copper compound (Japanese Patent Laid-Open No. 3-16305)
7) has been reported, and significant improvements have been made in practical use. However, there is no report on a method of directly converting the azetidinone derivative represented by the general formula (1) into the azetidinone derivative represented by the general formula (3).

[0006]

The method for directly converting the azetidinone derivative represented by the general formula (1) into the azetidinone derivative represented by the general formula (3) is carried out by conversion into a sulfone body or an acyloxy body. Compared to the method described above, if one step is shorter and a simple operation can be performed with good yield,
It becomes a useful practical tool. Therefore, the present inventors have conducted a study on a method of directly converting an azetidinone derivative represented by the general formula (1) into an azetidinone derivative represented by the general formula (3), and arrived at the present invention.

[0007]

The present invention is based on the general formula (1)

[Chemical 6] (Wherein OR ₁ and R ₂ have the same meanings as described above), and an azetidinone derivative represented by the general formula (2)

[Chemical 7] By reacting an alcohol compound or a thiol compound represented by the formula (wherein X and R ₃ have the same meaning as described above) in the presence of a copper compound in an organic solvent.

[Chemical 8] (Wherein OR ₁ , X and R ₃ have the same meanings as described above) 4
A method for producing a position-substituted azetidinone derivative.

The protected hydroxyl group represented by OR ₁ is tert-butyldiphenylsilyloxy group, te
rt-butyldimethylsilyloxy group, dimethylcumylsilyloxy group, dimethylthexylsilyloxy group, triisopropylsilyloxy group, paranitrobenzyloxycarbonyloxy group, paramethoxybenzyloxycarbonyloxy group, allyloxycarbonyloxy group, Examples thereof include acetoxy group, benzoyloxy group, tetrahydropyranyloxy group and the like.

The group represented by R ₂ is not particularly limited, but is a methyl group, an ethyl group, a propyl group or a butyl group, which is considered to be easily available and can be manufactured at a low cost according to the reports so far. lower alkyl group of C ₁ -C ₄ and a phenyl group, an alkylphenyl group or an alkoxyphenyl group with a lower alkyl group of C ₁ -C _4, an aromatic group such as a halophenyl group are exemplified.

Preferred examples of the group represented by R ₃ include:
C such as methyl group, ethyl group, propyl group, butyl group
Alkyl group of ₁ -C _4, an alkenyl group of C ₃ -C _6, such as allyl, benzyl groups, C such as an aralkyl group or a phenyl group C ₇ -C _11, such as phenylethyl
_6- C ₁₀ aryl groups are mentioned, each group being 1
Or more C ₁ -C ₄ alkyl groups, C ₃ -C ₆
Alkenyl group, C ₇ -C ₁₁ aralkyl group, C ₆ -C
₁₀ aryl groups, C ₁ -C ₁₁ acyl groups, hydroxyl groups, C ₁
It may be substituted with a heterocycle such as a -C ₁₀ alkoxy group, a C ₂ -C ₁₁ alkoxycarbonyl group or a furyl group.

Usually, the reaction is carried out by a hydrocarbon solvent such as benzene or toluene, a chlorine solvent such as methylene chloride or chloroform, a nitrile solvent such as acetonitrile, acetone,
A ketone-based solvent such as methyl vinyl ketone, an ether-based solvent such as diethyl ether or tetrahydrofuran, or an ester-based solvent such as ethyl acetate is used alone or as a mixture, and the azetidinone derivative represented by the general formula (1) is used. In the presence of about 1 to 4 equivalents of the copper compound, about 1 to 3 equivalents of the alcohol compound or thiol compound represented by the general formula (2) and the azetidinone derivative represented by the general formula (1) are treated. It can be done by

As the copper compound, cuprous oxide or cupric oxide is preferable, and the reaction temperature is the type of alcohol compound or thiol compound represented by the general formula (2) to be used,
Although it depends on the kind of the azetidinone derivative represented by the general formula (1) and the like, it is preferably in the range of 0 to 100 ° C., and preferably room temperature to
It is in the range of 100 ° C.

For the treatment after the reaction, for example, the insoluble matter is filtered, the filtrate is concentrated, and then purified by a means such as column chromatography to easily obtain the desired product in a pure form. It can also be obtained by adding a low polar solvent such as pentane or hexane to the filtrate obtained by filtering the insoluble matter, filtering the precipitated insoluble matter, washing the organic layer with water, drying and concentrating. The crude product obtained by this method can be used in the next reaction without purification, but can be purified by recrystallization or column chromatography if necessary.

[0014]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 (3R, 4R) -3-[(R) -1- (tert-butyl)
Didimethylsilyloxy) ethyl] -4-allyloxy
2-Synthesis of azetidinone

(1) (3S, 4R) -3-[(R) -1
-(Tert-Butyldimethylsilyloxy) ethyl]
-4-phenylthio-2-azetidinone (85 mg,
Acetonitrile (0.5 ml), toluene (1 ml) and cuprous oxide (36 mg, 0.25 mmol) were added to 0.25 mmol) and the mixture was stirred with a 1M concentration of allyl alcohol solution in acetonitrile (0.5 ml, 0.5 mmol). 90 to 10
The mixture was stirred at 0 ° C for 24 hours. After cooling, the insoluble material was filtered off, and after concentration, the residue was purified by silica gel column chromatography (solvent: n-hexane: ethyl acetate = 6: 1) to give the title compound as a colorless solid, 58 mg (80.6%). Obtained.

(2) (3S, 4R) -3-[(R) -1
-(Tert-Butyldimethylsilyloxy) ethyl]
-4-phenylthio-2-azetidinone (85 mg,
Acetonitrile (0.5 ml), toluene (1 ml) and cupric oxide (20 mg, 0.25 mmol) were added to 0.25 mmol) and the mixture was stirred with 1 M allyl alcohol solution (0.5 ml, 0.5 mmol) in acetonitrile. 90 to 10
The mixture was stirred at 0 ° C for 48 hours. After cooling, insoluble matter was filtered off, and after concentration, the residue was subjected to silica gel thin layer chromatography (solvent: n
Purification with -hexane: ethyl acetate = 4: 1) gave 11 mg (15.4%) of the title compound as a colorless solid.

IR (KBr) cm ^-1 : 3186,292
9, 1773, 1728, 1257, 1094. NMR
(CDCl ₃ ) δ: 0.06 and 0.07 (each
3H, s, -Si (C H 3) 2), 0.87 (9H,
_{s, -SiC (C H 3)} 3), 1.26 (3H, d, J
_{= 6.6Hz, C H 3 CH-} OSi), 3.05 (1
H, d, J = 4.0 Hz, C3-H), 4.05-4.
08 (2H, m, -OC H 2 CH = CH 2), 4.12
_{-4.21 (1H, m, CH 3} C H -OSi), 5.1
1 (1H, s, C4-H), 5.23 (1H, d, J =
_{10.6Hz, -OCH 2 CH = C H} 2), 5.33
(1H, dd, J = 1.3Hz and 17.2Hz,
_{-OCH 2 CH = C H 2)} , 5.86-6.00 (1
_{H, m, -OCH 2 C H} = CH 2), 6.37 (1H,
brs, NH ).

Example 2 (3R, 4R) -3-[(R)-(1-tert-butyl)
Didimethylsilyloxy) ethyl] -4-phenyloxy
Synthesis of Ci-2-azetidinone

(3S, 4R) -3-[(R) -1- (t
ert-Butyldimethylsilyloxy) ethyl] -4-
Phenylthio-2-azetidinone (84 mg, 0.25
mmol) in acetonitrile (1 ml), toluene (1 ml),
Cuprous oxide (36 mg, 0.25 mmol) was added and the mixture was stirred.
Add phenol (48 mg, 0.5 mmol) to 70-8
The mixture was stirred at 0 ° C for 5 hours. After completion of the reaction, insoluble matter was filtered off, and after concentration, the residue was purified by silica gel thin layer chromatography (solvent: n-hexane: ethyl acetate = 4: 1) to obtain 57 mg (71%) of the title compound as a colorless solid. Obtained.

IR (KBr) cm ^-1 : 3094,296
7,1778,1495,1232,1181,104
0. NMR (CDCl ₃ ) δ: 0.08 and 0.09
(Each 3H, s, -Si ( C H 3) 2), 0.8
8 (9H, s, -SiC ( C H 3) 3), 1.27 (3
H, d, J = 5.9 Hz, C H ₃ CH-OSi), 3.
31-3.34 (1H, m, C3-H), 4.23-
_{4.31 (1H, m, CH 3} C H -OSi), 5.72
(1H, s, C4-H), 6.45 (1H, brs, N
H ), 6.89-7.38 (5H, m, -OC
₆ H ₅ ).

Example 3 (3R, 4R) -3-[(R) -1- (tert-butyl)
Didimethylsilyloxy) ethyl] -4-benzyloxy
Synthesis of Ci-2-azetidinone

(3S, 4R) -3-[(R) -1- (t
ert-Butyldimethylsilyloxy) ethyl] -4-
Phenylthio-2-azetidinone (85 mg, 0.25
mmol) to acetonitrile (0.5 ml), toluene (1 m
l) and cuprous oxide (36 mg, 0.25 mmol) are added, and a 1 M benzyl alcohol solution in acetonitrile (0.5 ml, 0.5 mmol) is added with stirring to 90-100 ° C.
The mixture was stirred for 17.5 hours. After completion of the reaction, insoluble matter is filtered off,
After concentration, the residue was purified by silica gel thin layer chromatography (solvent: n-hexane: ethyl acetate = 4: 1),
54 mg (64%) of the title compound was obtained as a colorless solid.

IR (KBr) cm ^-1 : 3160,292
9, 1766, 1720, 1099, 836. NMR
(CDCl ₃ ) δ: 0.03 and 0.05 (each
3H, s, -Si (C H 3) 2), 0.63 (9H,
_{s, -SiC (C H 3)} 3), 1.24 (3H, d, J
_{= 5.9Hz, C H 3 CH-} OSi), 3.09 (1
H, d, J = 4.0 Hz, C3-H), 4.12-4.
_{20 (1H, m, CH 3} C H -OSi), 4.54-
4.64 (1H, m, -C H 2 C 6 H 5), 5.17
(1H, s, C4-H), 6.38 (1H, brs, N
H), 7.27-7.39 (5H, m , -CH 2 C 6 H
₅ ).

Example 4 (3R, 4R) -3-[(R) -1- (tert-butyl)
Didimethylsilyloxy) ethyl] -4- (ethoxyca)
Synthesis of Lubonyl) methyloxy-2-azetidinone

(3S, 4R) -3-[(R) -1- (t
ert-Butyldimethylsilyloxy) ethyl] -4-
Phenylthio-2-azetidinone (85 mg, 0.25
mmol) to acetonitrile (0.5 ml), toluene (1 m
l), cuprous oxide (36 mg, 0.25 mmol), and a solution of methyl glycolate 1M in acetonitrile (0.5 ml, 0.5 mmol) with stirring is added at 90 to 100 ° C.
It was stirred for 18 hours. After completion of the reaction, insoluble matter was filtered off, and after concentration, the residue was purified by silica gel column chromatography (solvent: n-hexane: ethyl acetate = 4: 1) to give 57 mg (68.7%) of the title compound as a colorless solid. )Obtained.

IR (KBr) cm ^-1 : 3330,295
7, 1759, 1377, 1123, 836. NMR
(CDCl ₃ ) δ: 0.06 and 0.07 (each
3H, s, -Si (C H 3) 2), 0.87 (9H,
_{s, -SiC (C H 3)} 3), 1.26-1.32 (6
_{H, m, C H 3 CH} -OSi and-OCH 2 C
_{H 3), 3.07-3.09 (1H,} m, C3-H),
_{4.11-4.27 (5H, m, CH 3} C H -OSi,
_{-OCH 2 C H 3 and-OC} H 2 CO), 5.15
(1H, s, C4-H), 6.71 (1H, brs, N
H ).

Example 5 (3S, 4R) -3-[(R) -1- (tert-butyl)
Didimethylsilyloxy) ethyl] -4- (methoxyca)
Synthesis of Rubonyl) methylthio-2-azetidinone

(1) (3S, 4R) -3-[(R) -1
-Tert-butyldimethylsilyloxy) ethyl]-
4-phenylthio-2-azetidinone (169 mg,
0.5 mmol) in acetonitrile (1 ml), toluene (1
ml) and cuprous oxide (72 mg, 0.5 mmol) were added and stirred, and methyl thioglycolate (50 μl, 0.56 mmo
l) was added and the mixture was stirred at 70 ° C. for 6 hours. After completion of the reaction, insoluble matter was filtered off, and after concentration, the residue was subjected to silica gel column chromatography (solvent: n-hexane: ethyl acetate = 3:
Purified in 1), 140 m of the title compound as a colorless solid
g (83.8%) was obtained.

(2) (3S, 4R) -3-[(R) -1
-Tert-butyldimethylsilyloxy) ethyl]-
4-phenylthio-2-azetidinone (85 mg, 0.
Acetonitrile (0.5 ml), toluene (1 ml) and cupric oxide (20 mg, 0.25 mmol) were added to 25 mmol), and the mixture was stirred with a 1 M methylthioglycolate solution in acetonitrile (0.5 ml, 0.5 mmol). 90 plus
The mixture was stirred at 100 ° C for 21 hours. After completion of the reaction, insoluble matter was filtered off, and after concentration, the residue was purified by silica gel thin layer chromatography (solvent: n-hexane: ethyl acetate = 4: 1) to give 70 mg (84%) of the title compound as a colorless solid. Obtained.

IR (KBr) cm ^-1 : 3148,294
9, 2927, 2856, 1760, 1470, 143
8, 1409, 1371, 1318, 1287, 124
8,1201,1178,1150,1134,110
6,1061,965,892,782. NMR (CD
Cl ₃ ) δ: 0.07 and 0.08 (each 3
H, s, -Si (C H 3) 2), 0.88 (9H, s,
_{-SiC (C H 3) 3)} , 1.24 (3H, d, C H 3
CH-OSi), 3.11 (1H, m, C3-H),
3.36 (2H, s, -SC H 2 CO 2), 3.75
_{(3H, s, -CO 2 C} H 3), 4.26 (1H, m,
CH3C H -OSi), 4.92 (1H , d, J = 2.
0 Hz, C4-H), 6.31 (1H, brs, N
H ).

Example 6 (3S, 4R) -3-[(R) -1- (tert-butyl)
Didimethylsilyloxy) ethyl] -4-triphenyl
Synthesis of methylthio-2-azetidinone

(3S, 4R) -3-[(R) -1- (t
ert-Butyldimethylsilyloxy) ethyl] -4-
Phenylthio-2-azetidinone (169 mg, 0.5
acetonitrile) (0.9 ml), toluene (0.
9 ml) and cuprous oxide (50 mg, 0.35 mmol) were added, and the mixture was stirred with triphenylmethylmercaptan (158 m).
g, 0.57 mmol) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, insoluble matter was filtered off, and after concentration, the residue was purified by silica gel column chromatography (solvent: n-hexane: ethyl acetate = 8: 1) to obtain 192 mg (76%) of the title compound as a colorless solid. It was

IR (KBr) cm ^-1 : 1764. NMR
(CDCl ₃ ) δ: 0.51 and 0.59 (each
3H, s, -Si (C H 3) 2), 0.78 (9H,
_{s, -SiC (C H 3)} 3), 1.25-1.37 (3
_{H, m, C H 3 CH} -OSi), 3.16 (1H, t,
J = 2.6 Hz, C3-H), 4.19-4.31 (1
H, m, CH3C H -OSi) , 4.41 (1H, br
s, NH ), 4.59 (1H, d, J = 3.3Hz, C
4-H), 7.22-7.43 (9H , m, -C (C 6
_{H 5) 3), 7.43-7.59 (} 6H, m, -C (C
₆ H ₅ ) ₃ ).

[0035]

EFFECTS OF THE INVENTION According to the present invention, the yield is obtained by reacting the alcohol or thiol compound directly with the copper compound without converting the sulfide group SR ₃ of the compound of the general formula (1). Since the azetidinone derivative represented by the general formula (3) can be produced well, the reaction step can be shortened as compared with the conventional method, which is industrially extremely advantageous.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tetsuo Shimamoto 1-1-1, Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka Suntory Ltd. Biomedical Research Institute (72) Takuro Yoshida Chiyoda-cho, Tomaku-gun, Gunma Prefecture 2716 Akaiwa Kurakake 1 Suntory Co., Ltd. Pharmaceutical Center (72) Inventor Hiromitsu Iwata 5-27-7 Nandaidai, Takatsuki City, Osaka Prefecture

Claims (3)

[Claims] 1. A compound represented by the general formula (1): (Wherein OR ₁ represents a protected hydroxyl group, R ₂ represents an alkyl group or a substituted or unsubstituted aromatic group), and an azetidinone derivative represented by the general formula (2): (Wherein X represents an oxygen atom or a sulfur atom, R ₃ represents a substituted or unsubstituted alkyl group, alkenyl group, aralkyl group or aryl group), an alcohol compound or a thiol compound represented by the presence of a copper compound General formula (3) characterized by carrying out a lower reaction (Wherein OR ₁ , X and R ₃ have the same meanings as described above) 4
A method for producing a position-substituted azetidinone derivative. 2. The alcohol compound or thiol compound represented by the general formula (2), wherein R ₃ is an allyl group, a phenyl group, a benzyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, or a trityl group. 1. The production method according to 1. 3. The method according to claim 1, wherein the copper compound is cuprous oxide or cupric oxide.