JPH0649679B2 - Azetidinone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] (In the formula, R ² is an aralkyl group.) The present invention relates to an azetidinone derivative.

The azetidinone derivative represented by the general formula (I) of the present invention can be led to a carbapenem β-lactam antibiotic such as thienamycin. The carbapenem β-lactam antibiotics show excellent antibacterial activity against almost all bacteria including Pseudomonas aeruginosa, its strength is far greater than that of conventional drugs, and β-lactamase stability is also excellent. Therefore, it is a group of substances with great expectations as a β-lactam antibiotic of the IV generation.

[Conventional technology]

Carbapenem-based β-lactam antibiotics have low productivity due to fermentation, and industrially they have no choice but to rely on chemical synthesis. This can be said to be completely different from conventional penicillin and cephalosporin antibiotics.

To date, various carbapenem β-lactam antibiotics are in the clinical stage, but as the synthetic intermediates that form the basis of these compounds, the general formula (In the formula, R ³ and R ⁴ are protecting groups.) Β-
It is a well-known fact among those skilled in the art that it is a lactam.

Conventionally, as a method for producing the β-lactam represented by the general formula (II), 1) a monocyclic β- having a side chain at the 4-position by utilizing asymmetric synthesis with an optically active amino acid or an enzyme.
A method of constructing a lactam ring and then introducing a side chain at the 3-position, 2) β-lactam after selectively constructing an asymmetric carbon corresponding to the 3-position, 4-position, 1'position by using a special means A method for forming a ring and 3) a method for constructing a monocyclic β-lactam having a 3-position side chain from L-threonine, optically active penicillin, etc., and then introducing a 4-position side chain are known [Masayuki Shibuya , Journal of Organic Synthetic Chemistry, 41 , 62 (1983)].

[Problems to be solved by the invention]

However, the method of 1) above is relatively difficult to introduce a side chain into the 3-position and is not suitable for large-scale synthesis, and is difficult to adopt as an industrial production method. Although the method 2) is an industrially adopted method, it has a drawback that it requires a long manufacturing process and includes optical division. Further, the above method 3) has a drawback that the number of manufacturing steps is long although the desired product can be obtained with an optically active substance. Very recently, a short-step synthetic method using optically active 3-hydroxybutyric acid was announced [J. Am. Chem. Soc., 106 , 4819 (1984); Chem. Lett., 1927 (19).
84); Chem. Lett., 651 (1985); Tet. Lett., 26 , 937 (1985); Te
t. Lett., 26 , 1523 (1985)], but it is unsatisfactory in terms of stereoselectivity and yield. Among synthetic compounds having optically active 3-hydroxybutyric acid as a starting material, a compound represented by the following formula (III) can be mentioned as a particularly applicable synthetic intermediate. In the existing synthetic method, the desired compound represented by the above formula (III) is a by-product, and the undesired stereoisomer represented by the above formula (IV) is highly selectively produced. Therefore, in order to induce carbapenem antibiotics such as thienamycin, an extremely complicated step of epimerization at the 3-position is required [J. Am. Chem. Soc., 106 , 4819 (1984); Chem. Lett. , 1
927 (1984); Chem. Lett., 651 (1985)]. Further, these synthetic methods of the formulas (III) and (IV) consist of an aldol-type condensation between the following formula (V) and the following formula (VI), (In the formula, R is a methyl group or an alkyl group.) In the above reaction, trimethylsilyl is essential as a protecting group for N, and it is said that the reaction does not proceed with other protecting groups.

As a result of intensive studies to solve the above problems, the present inventor has found that the azetidinone derivative represented by the general formula (I) of the present invention is highly selectively produced from optically active hydroxybutyric acid. From the azetidinone derivative represented by the general formula (I), it is possible to lead to a synthetic intermediate of the β-lactam compound represented by the general formula (II) without requiring an extremely complicated step of epimerization at the 3-position, The present invention has been completed.

[Means for solving problems]

The azetidinone derivative represented by the general formula (I) of the present invention has the general formula (VII) (In the formula, R ¹ is an alkyl group or an aryl group, and R ² is an aralkyl group.) The thiol ester moiety of the β-N-substituted aminothiol ester represented by the formula is hydrolyzed,
Then triphenylphosphine and 4, in acetonitrile
It is produced by heating under reflux in the presence of 4'-dipyridyl disulfide.

The β-N-substituted aminothiol ester represented by the general formula (VII), which is a raw material, is prepared by reacting the general formula in the presence of a tertiary amine. (In the formula, R ¹ is an alkyl group or an aryl group.) And a β-hydroxythiol ester represented by the general formula (In the formula, R and R ′ are an alkyl group or a cycloalkyl group, and can form a ring together with the boron bonded together). Then, the resulting reaction mixture is reacted. Prepared by reacting an imine represented by the general formula R ² —N═CH—C≡C—SiMe ₃ — (X) (wherein R ² is an aralkyl group) and then treating with hydrogen peroxide. can do. The reaction does not proceed when R ^{2 in the} general formula (X) is a trimethylsilyl group.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples.

Reference example 1 5.91 g (50 mmol) of methyl 3-hydroxybutyrate and 3.74 g (55 mmol) of imidazole were dissolved in 20 m of DMF, and 8.29 g (55 mmol) of t-butyldimethylsilyl chloride was dissolved in this.
Was added several times. After stirring for 30 minutes at room temperature,
Ice water was added, and the mixture was extracted 3 times with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This concentrate is distilled (62-68 ℃ / 5
mmHg) and 10.51 g of methyl (-)-3-t-butyldimethylsilyloxybutyrate were obtained. Yield 91%.

TLC: 0.4 (hexane: diethyl ether 20: 1). IR: (neat) 1735 cm ^-1 . NMR: δ 0.03,0.06 (each 3H; s), 0.85 (9H; s), 1.20 (3H; d J = 5), 2.42 (2H; m), 3.75 (3H; s), 4.25 (1H; m ). MS: 115,133,159 [M- (Me + COOMe)], 175 [M-Bu], 217 [M-Me]. ▲ [α] ²⁰ _D ▼ -31.75 ° (c = 1.94, CHCl ₃ ). Reference example 2 3.58 g (15.4 mmol) of methyl (-)-3-t-butyldimethylsilyloxybutyrate was dissolved in 30 m of methanol, 30 m of 1N potassium hydroxide was added, and the mixture was stirred for 15 hours. Most of the methanol was distilled off, acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3.18 g of (-)-3-t-butyldimethylsilyloxybutyric acid. Yield 95%.

TLC: 0.2 (hexane: diethyl ether 20: 1). IR: (neat) 1710 cm ^-1 . NMR: δ 0.09 (6H; s), 0.88 (9H; s), 1.20 (3H; d J = 6), 2.46 (2H; d J = 6), 4.27
(1H; dt J = 6,6). MS: 110,137,197,218 [M]. ▲ [α] ²⁰ _D ▼ -12.50 ° (c = 0.96, chloroform). Reference example 3 (−)-3-t-Butyldimethylsilyloxybutyric acid 3.18
g (19.2mmol), thiophenol 2.26m (22mmol)
After dissolving in 100 m of methylene chloride, 4.53 g (22 mmol) of N, N'-dicyclohexylcarbodiimide was added thereto. After stirring at room temperature for 2 hours and filtering, the filtrate is concentrated and distilled (110-116 ° C / 0.3 mmHg) to give (-)-3-
5.00 g (yield 83%) of t-butyldimethylsilyloxybutyric acid phenylthioester was obtained.

TLC: 0.3 (hexane: diethyl ether 20: 1). IR (neat) 1710 cm ^-1 . NMR: δ 0.07 (6H; s), 0.91 (9H; s), 1.22 (3H; d J = 5), 2.61, 2.87 (each 1H; dd J = 15,7), 4.34 (1H; m), 7.41 (5H; s). MS: 115,159 [M- (Me + COSPh)], 253 [M-Bu], 295 [M-Me]. ▲ [α] ²⁰ _D ▼ −65.91 ° (c = 0.98, CHCl ₃ ). Reference example 4 3.26 g (10.4 mmol) of (−)-3-t-butyldimethylsilyloxybutyric acid phenylthioester was added to acetic acid: THF:
50 m of water (3: 1: 1) was added, and the mixture was stirred at 50 ° C for 24 hours. This was concentrated and distilled (128-130 ° C./0.8 mmHg) to obtain 1.91 g of (−)-3-hydroxybutyric acid phenylthioester and a yield of 94%.

TLC: 0.35 (hexane: diethyl ether 1: 1). IR (neat) 3440, 1705 cm ^-1 . NMR: δ 1.20 (3H; d J = 6), 2.82 (2H; d J =
6), 3.0 (1H; br.s), 4.22 (1H; m), 7.36 (5H; s). MS: 110 [PhSH], 137 [COSPh], 196 [M]. ▲ [α] ²⁰ _D ▼ -42.25 ° (c = 1.42, CHCl ₃ ). Reference example 5 3-trimethylsilyl-2-propinal 1.51 g (12.0
mmol), benzylamine 1.31m (12.0mmol) 10m
The mixture was stirred in diethyl ether for 30 minutes, and the solvent was evaporated under reduced pressure. This residue was distilled under reduced pressure (oil bath temperature 120 ℃ -130 ℃ / 1m
Immine obtained immediately was used in the following reaction. (−)-3-Hydroxybutyric acid phenyl thioester
1.963 g (10.0 mmol) was dissolved in 40 m of methylene chloride, and diisopropylethylamine 4.00 m (2
3.0 mmol) and 5.94 g (22.0 mmol) of 9-BBN triflate were added. Temperature rises to -25 ℃ over 1 hour, -30 ℃ to -20 ℃
After stirring for 1 hour at 40 ° C., a 40 m methylene chloride solution of the imine prepared above was added dropwise to this over the course of about 20 minutes at the same temperature.
The temperature was raised to room temperature over 1.5 hours, and the mixture was further stirred for 1 hour. After cooling the reaction solution to −35 ° C. to −40 ° C., a mixed solution of phosphate buffer (pH 7.0) 60 m, methanol 60 m, and 31% hydrogen peroxide solution 30 m was added over about 20 minutes. After heating to 0 ° C over 30 minutes and stirring vigorously at room temperature for 1 hour, the mixture was extracted twice with methylene chloride, and the extract was washed with saturated saline,
The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by a silica gel column (C-300; developing solvent hexane: diethyl ether 3: 2), and 3-benzylamino-2- (1-hydroxyethyl) -5-trimethylsilyl-4-pentynoic acid phenylthioester 2.054
g was obtained. Yield 50%.

TLC: 0.41 (hexane: diethyl ether 3: 2). IR: (neat) 3400,2160,1700cm ^-1 . NMR: δ 0.23 (3H; s), 1.25 (3H; d J = 7), 2.92 (1
H; t J = 6), 3.6 to 3.8 (2H; m), 4.03 (1H; d J = 1
2), 4.3 (1H; m), 7.30 (5H; s), 7.39 (5H; s). MS: 151,216,302 [M ⁺ -SPh], 4.12 [M ⁺ +1]. Example 1 3-benzylamino-2- (1-hydroxyethyl)-
Dissolve 2.054 g (5.0 mmol) of 5-trimethylsilyl-4-pentynoic acid phenylthioester in 40 m of THF,
3 m of potassium hydroxide N was added, and the mixture was stirred at room temperature for 3 hours. This was neutralized with 2N hydrochloric acid and extracted 6 times with ethyl acetate while salting out. The extract is dried over anhydrous magnesium sulfate,
Concentrated. To this concentrated solution was added 250 m of acetonitrile, and 1.57 g (6.0 mmol) of triphenylphosphine was added.
With vigorous stirring under heating and reflux, 2,2'-dipyridyl disulfide 1.32 g (6.0 mmol) of acetonitrile 50
The m solution was added dropwise over 40 minutes. After heating and refluxing for another hour, the reaction solution is concentrated and purified twice with 50 g of silica gel chromatography (developing solvent methylene chloride → diethyl ether) and 50 g of silica gel chromatography (developing solvent hexane: diethyl ether 1: 4). 801 mg of trans form of 1-benzyl-4-ethynyl-3- (1-hydroxyethyl) -2-azetidinone
62 mg of cis form was obtained. As a sample for analysis of the trans form, a sample obtained by recrystallization from diethyl ether was used.

Trans form TLC: 0.75 (diethyl ether). mp.134 ° C. IR: (chloroform) 3450,1745 cm ^-1 . NMR: δ1.24 (3H; d J = 6), 2.42 (1H; d J =
1), 2.7 (1H; br.s), 3.28 (1H; ddJ = 5,2.5) 4.1
(3H; m), 4.37 (1H; d J = 15), 7.29 (5H; s). MS: 132,186,211,229 [M ⁺ ]. Anal: C ₁₄ H ₁₅ O ₂ N calculated value C, 73.34%; H, 6.59%; N, 6.11% Measured value C, 73.45%; H, 6.54%; N, 6.10% ▲ [α] ²⁰ _D ▼ -20.45 ° (c = 1.00, chloroform). Cis TLC: 0.56 (diethyl ether). IR: (chloroform) 3500,1750 cm ^-1 . NMR: δ1.36 (3H; d J = 6), 2.68 (1H; d J =
2), 2.7 (1H; br.s), 3.27 (1H; dd J = 5,6).
4.2 (3H; m), 4.76 (1H; d J = 15), 7.38 (5H; s). MS: 150,187,205,229 [M ⁺ ]. ▲ [α] ²⁰ _D ▼ -58.82 ° (c = 1.22, chloroform). Reference example 6 206 mg (0.90 mmol) of 1-benzyl-4 (S) -ethynyl-3- (S)-[1 (R) -hydroxyethyl] -2-azetidinone obtained in Example 1 in 3 m
Of tert-butyldimethylsilyl chloride (180 mg, 1.2 mmol) and imidazole (82 mg, 1.2 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with diethyl ether, water was added, and the mixture was extracted 3 times with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. This was purified by 10 g of silica gel column chromatography (developing solvent hexane: diethyl ether 2: 1).
8 mg of 1-benzyl-4 (S) -ethynyl-3 (S)-[1 (R)
-T-Butyldimethylsilyloxyethyl] -2-azetidinone was obtained. Yield quantitative.

TLC: 0.36 (diethyl ether: hexane 1: 2). IR: (chloroform) 1750 cm ^-1 . NMR: δ 0.06, 0.09 (each 3H; s), 0.86 (9H; s), 1.24
(3H; d J = 6), 2.43 (1H; d J = 2), 3.27 (1H; d
d J = 3,2.5), 4.2 (3H; m), 4.70 (1H; d J = 1
5), 7.34 (5H; s). MS: 242,286 [M ⁺ -Bu], 328 [M ⁺ -Me]. ▲ [α] ²⁰ _D ▼ -11.62 ° (c = 1.00, chloroform). Reference example 7 1-benzyl-4 (S) -ethynyl-3 (S)-[1 (R) -t
-Butyldimethylsilyloxyethyl-]-2-azetidinone (103 mg, 0.30 mmol) was added with quinoline (0.015 m) and petroleum ether (1.5 m), and Lindlar's catalyst (1.5 mg) was added thereto. The mixture was vigorously stirred for 12 hours at room temperature under a hydrogen atmosphere. The reaction solution is filtered, the filtrate is concentrated, petroleum ether 2 m,
Add 3 mg of Lindlar catalyst and add 36 more under hydrogen atmosphere.
Reacted for hours. The reaction solution was subjected to 10 g of silica gel column chromatography (developing solvent benzene: methylene chloride 1:
In 1), the semi-reduced form containing the starting material was obtained and used in the following reaction without further purification. The semi-reduced material containing the raw material was dissolved in 2 m of THF, and the solution of 9-BBN in THF (0.6
M) 1.1 m (0.63 mmol) was added, and the mixture was stirred in an ice bath for 1 hour, then 9-BBN in THF (0.6 M) 0.5 m (0.3 mmol) was added.
Was added, and the mixture was stirred in an ice bath for 2 hours and at room temperature for 1 hour. 0.56m (2.3m) of 4N sodium hydroxide was added to this reaction solution in an ice bath.
mol) and 0.4% of 31% hydrogen peroxide water were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with diethyl ether, water was added, and the mixture was extracted 3 times with diethyl ether. The extract was washed with dilute aqueous sodium hydrogen thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. This was purified by 10 g of silica gel column chromatography (developing solvent diethyl ether: hexane 3: 1 → 5: 1) and 70 mg of 1-benzyl-3 (S)-[1 (R) -t-butyldimethylsilyloxy. Ethyl] -4 (R)-(2-hydroxyethyl) -2-azetidinone was obtained. Yield 64%.

TLC: 0.3 (diethyl ether: hexane 3: 1). IR: (chloroform) 3460,1740 cm ^-1 . NMR: 0.03,0.07 (each 3H; s), 0.87 (9H, s), 1.26 (3
H; d J = 6), 1.8 (2H; m). 2.8 (1H; br.s), 3.02
(1H; dd J = 2,8), 3.6 (3H; m), 4.2 (2H; m),
4.61 (1H; d J = 15), 7.3 (5H; s). MS: 306 [M ⁺ -Bu], 348 [M ⁺ -Me]. ▲ [α] ²⁰ _D ▼ -1.09 ° (c = 1.20, chloroform). Reference example 8 THF to 13 mg (0.26 mmol) of sodium hydride (50% oily)
1m and dimethylformamide 0.6m were added, and 1-benzyl-3 (S)-[1 (R) -t-bityldimethylsilyloxyethyl] -4 (R)-(2-hydroxyethyl was added thereto under an ice bath. ) -2-Azetidinone 64 mg (0.18 mmol) THF2
m solution was added and stirred for 10 minutes. Benzyl bromide
0.03 m (0.25 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted 3 times with diethyl ether, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. This was purified by 10 g of silica gel column chromatography (developing solvent hexane: diethyl ether 1: 1), and 1-benzyl-4 (R)-(2-benzyloxyethyl) -3 (S)-[1 (R) 46 mg of -t-butyldimethylsilyloxyethyl] -2azetidinone was obtained (yield 58%).

This is a document (T. Iimori and M. Shibasaki Tetrahe
dron Lett. 26 , 1523 (1985)), which is in perfect agreement with the above compound and is efficiently converted to thienamycin.

〔The invention's effect〕

The azetidinone derivative represented by the general formula (I) of the present invention is subjected to partial reduction of triple bond and then hydroboration reaction to give an optically active β represented by the general formula (II).
It can be easily introduced into lactams in short steps, and thus can be excellent and useful synthetic intermediates.

Claims (1)

[Claims] 1. A general formula An azetidinone derivative represented by: (wherein R ² is an aralkyl group).