JPH057392B2 - - Google Patents

Description

[Detailed description of the invention] [Industrial field of application] The present invention relates to the general formula (In the formula, R ¹ is an alkyl group or an aryl group,
R ² is an aralkyl group. ) expressed as β−N
- Substituted aminothiol ester and method for producing the same.

β-N represented by the general formula () of the present invention
-Substituted aminothiol esters can lead to carbapenem β-lactam antibiotics such as thienamycin. Carbapenem β-lactam antibiotics exhibit excellent antibacterial activity against almost all bacteria, including Bacillus aeruginosa, and their strength is much greater than that of conventional drugs, and they also have excellent β-lactamase stability. Therefore, it is a group of substances that has great expectations as a next-generation β-lactam antibiotic.

[Conventional technology]

Currently, carbapenem β-lactam antibiotics have low productivity through fermentation, and industrially they have 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 the synthetic intermediates that form the basis of these compounds are based on the general formula It is a well-known fact among those skilled in the art that it is a β-lactam represented by the formula (wherein R ³ and R ⁴ are protecting groups).

Conventionally, methods for producing β-lactams represented by the above general formula () include (1) asymmetric synthesis using optically active amino acids or enzymes to produce a monocyclic β-lactam ring having a side chain at the 4-position; (2) Using special means to selectively construct asymmetric carbons corresponding to the 3-, 4-, and 1-positions, and then form a β-lactam ring. (3) A method of constructing a monocyclic β-lactam having a side chain at the 3-position from L-threonine, optically active penicillin, etc., and then introducing a side chain at the 4-position [Masayuki Shibuya, organic Journal of the Society of Synthetic Chemistry, 41 , 62
(1983)].

[Problem that the invention seeks to solve]

However, method 1) is relatively difficult to introduce a side chain into the 3-position, is unsuitable for large-scale synthesis, and is difficult to employ as an industrial production method. Also, the above
Although method (2) is an industrially adopted method, it has the disadvantage that the manufacturing process is long and includes optical resolution. Furthermore, the method (3) above has the disadvantage that although the desired product can be obtained as an optically active substance, the number of manufacturing steps is long. Very recently, a short-step synthesis method using optically active 3-hydroxybutyric acid was announced [J.Am.Chem.Soc., 106 , 4819 (1984); Chem.
Lett., 1927 (1984); Chem. Lett., 651 (1985);
Tet.Lett., 26 , 937 (1985); Tet.Lett., 26 , 1523
(1985)], but it is unsatisfactory in terms of stereoselectivity and yield.

As a result of intensive studies to solve the above problems, the present inventors have discovered that the β-N-substituted aminothiol ester compound represented by the general formula () of the present invention has a β-N-substituted aminothiol ester compound represented by the general formula () The present invention was completed by discovering that the present invention is an excellent intermediate for the synthesis of lactam compounds.

[Means for solving problems]

β-N represented by the general formula () of the present invention
-Substituted aminothiol esters, in the presence of a tertiary amine, have the general formula (In the formula, R ¹ is an alkyl group or an aryl group.) and the general formula (In the formula, R and R ¹ are an alkyl group or a cycloalkyl group, and can be combined to form a ring together with bonded boron.) Then, the resulting reaction mixture is Produced by reacting an imine represented by the general formula R ² -N=CH-C≡C-SiMe ₃ -() (in the formula, R ² is an aralkyl group) and then treating with hydrogen peroxide. It is something.

β-Hydroxythioester represented by the general formula () is a compound that can be easily obtained by protecting the hydroxyl group of β-hydroxycarboxylic acid, followed by dehydration condensation with the corresponding mercaptan, and then deprotection ( (See reference example below). Examples of the β-hydroxythioester represented by the general formula () include S-phenyl-3(R)-hydroxybutanethioate, S-t-butyl-3(R)-
Hydroxybutanethioate, S-ethyl-3(R)
-Hydroxybutanethioate, S-sec-butyl-3(R)-hydroxybutanethioate, S-n
-Propyl-3(R)-hydroxybutanethioate, S-isopropyl-3(R)-hydroxybutanethioate, etc. can be used. On the other hand, boron compounds represented by the general formula () are industrially easily available, such as 9-borabicyclo[3.3.1]nonyltrifluoromethanesulfonate, dicyclopentyltrifluoromethanesulfonyloxyboron, di-n-butyltrifluoromethane. Sulfonyloxyboron and the like can be used.

The reaction between the β-hydroxythiol ester represented by the general formula () and the boron compound represented by the general formula () needs to be carried out in the presence of a tertiary amine. Examples of the tertiary amine include diisopropylethylamine, troethylamine, trimethylamine, and tributylamine, but it is preferable to use diisopropylethylamine in order to carry out the reaction efficiently.

This reaction is carried out in a solvent. Examples of solvents include halogenated hydrocarbon solvents such as methylene chloride, chloroform, and 1,2-dichloroethylene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and dimethoxyethane (DME);
Aromatic hydrocarbons such as toluene and xylene can be used.

The reaction normally proceeds smoothly at a temperature ranging from -78°C to room temperature. The reaction mixture obtained by the above reaction is reacted with the imine represented by the above general formula (). Examples of the imine represented by the above general formula () include N-3-trimethylsilipropynylidenebenzylamine, N-3-trimethylsilipropynylidenebenzylamine, -trimethylsilylpropynylidene-p-methoxyanisidine, N-3-trimethylsilylpropynylidene-o-methoxyanisidine, N-3-trimethylsilylpropynylidene-p-methoxybenzylamine, etc. can be used.

The solvent used in the reaction with the imine is the same as that used in the reaction between the β-hydroxythiol ester and the boron compound.

The reaction proceeds easily between -78°C and room temperature.

In the present invention, a β-N-substituted aminothiol ester represented by the above general formula () is obtained by reacting an imine and then treating it with hydrogen peroxide. A 30% aqueous solution of hydrogen peroxide is usually used. The amount of hydrogen peroxide used is 1 to 50 equivalents based on the β-hydroxythiol ester. During the hydrogen peroxide treatment, it is desirable to cool the reaction solution to -25°C to room temperature.

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

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

TLC: 0.4 (hexane:diethyl ether 20:1). IR: (neat) 1735cm ^-1 . NMR: δ0.03, 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 Dissolve 3.58 g (15.4 mmol) of methyl (-)-3-t-butyldimethylsilyloxybutyrate in 30 ml of methanol and add 30 ml of 1N potassium hydroxide.
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 obtain 3.18 g of (-)-3-t-butyldimethylsilyloxybutyric acid.

Yield 95% TLC: 0.2 (hexane:diethyl ether 20:1). IR: (neat) 1710 cm ^-1 . NMR: δ0.09 (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 3.18g (19.2mmol), thiophenol 2.26ml
(22 mmol) was dissolved in 100 ml of methylene chloride and added with N,N'-dicyclohexylcarbodiimide.
4.53g (22mmol) was added. After stirring at room temperature for 2 hours, the filtrate was concentrated and distilled (110-116℃/
0.3 mmHg), 5.00 g (yield: 83%) of (-)-3-t-butyldimethylsilyloxybutyric acid phenylthioester was obtained.

TLC: 0.3 (hexane:diethyl ether 20:1). IR (neat) 1710cm ^-1 . NMR: δ0.07 (6H; s), 0.91 (9H; s), 1.22
(3H; d J=5), 2.61, 2.87, (each 1H;
dd J=i5, 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-t-Butyldimethylsilyloxybutyric acid phenylthioester 3.26g (10.4mmol)
Add 50 ml of acetic acid:THF:water (3:1:1) to
Stirred at 50°C for 24 hours. By concentrating and distilling this (128-130℃/0.8mmHg), (-)
-3-hydroxybutyric acid phenylthioester
Obtained 1.91 g, yield 94%.

TLC: 0.35 (hexane: diethyl ether 1:
1). IR: (neat) 3440, 1705 cm ^-1 . NMR: δ1.20 (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 ). Example 1 3-trimethylsilyl-2-propynal 1.51
g (12.0 mmol), benzylamine 1.31 ml (12.0 m
mol) in 10 ml of diethyl ether for 30 minutes, and the solvent was distilled off under reduced pressure. This residue was distilled under reduced pressure (oil bath temperature: 120°C to 130°C/1 mmHg), and the resulting imine was immediately used in the following reaction. 1.963g of (-)-3-hydroxybutyric acid phenylthioester
(10.0 mmol) was dissolved in 40 ml of methylene chloride, -
4.00 ml of diisopropylethylamine (23.0
mmol), 9-BBN triflate 5.94g (22.0m
mol) was added.

Raise the temperature to -25℃ over 1 hour, then -30℃ to -20℃.
After stirring for 1 hour at ℃, the previously prepared imine 40
ml methylene chloride solution was added dropwise thereto over about 20 minutes at the same temperature. Raise the temperature to room temperature over 1.5 hours,
The mixture was further stirred for 1 hour. The reaction solution was heated to −35°C to −40°C.
After cooling to ℃, 60ml of phosphate buffer (PH7.0),
A mixed solution of 60 ml of methanol and 30 ml of 31% hydrogen peroxide was added over about 20 minutes. The temperature was raised to 0° C. over 30 minutes, and after stirring vigorously for 1 hour at room temperature, extraction was performed twice with methylene chloride, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated solution was purified with a silica gel column (C-300; developing solvent: hexane: diethyl ether 3:2) to obtain 3-benzylamino-2-(1-hydroxyethyl)-5-trimethylsilyl-4-pentate phenylthioester 2.054 I got g. Yield 50%.

TLC: 0.41 (hexane: diethyl ether 3:2) IR: (neat) 3400, 2160, 1700 cm ^-1 . NMR: δ0.23 (9H; s), 1.25 (3H; d J = 7),
2.92 (1H; t J = 6), 3.6-3.8 (2H; m),
4.03 (1H; d J = 12), 4.3 (1H; m), 7.30
(5H;s), 7.39(5H;s). MS: 151, 216, 302 [M ⁺ −SPh], 412 [M ⁺ +1]. Reference example 5 2.054 g (5.0 mmol) of 3-benzylamino-2-(1-hydroxyethyl)-5-trimethylsilyl-4-pentinoic acid phenylthioester was added to 40
ml of THF, 3 ml of 4N potassium hydroxide was added, and the mixture was stirred at room temperature for 3 hours. This was neutralized with 2N hydrochloric acid and extracted six times with ethyl acetate while salting out. The extract was dried over anhydrous magnesium sulfate and concentrated.
Add 250 ml of acetonitrile to this concentrated solution, add 1.57 g (60 mmol) of triphenylphoshine,
While heating under reflux and stirring vigorously, a solution of 1.32 g (6.0 mmol) of 2,2'-dipyridyl disulfide in 50 ml of acetonitrile was added dropwise over 40 minutes. After further heating under reflux for 1 hour, the reaction solution was concentrated and
Purification was performed twice using 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) to obtain 1-benzyl-4-ethynyl-3- (1-
801 mg of trans isomer and 62 mg of cis isomer of hydroxyethyl)-2-azetidinone were obtained. The sample for analysis of the trans isomer was obtained by recrystallization from diethyl ether.

Trans-isomer TLC: 0.75 (diethyl ether) mp: 134℃. 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; dd J=
5.2.5), 4.1 (3H; m), 4.73 (1H; d J = 15),
7.29 (5H;s). MS: 132, 186, 211, 229 [M ⁺ ]. Anal: Calculated values as C ₁₄ H ₁₅ O ₂ N C 73.34%, H 6.59%, N 6.11% Measured values 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 The trans isomer obtained in Reference Example 5, that is, 1-
Benzyl-4(S)-ethynyl-3(S)-[1(R)-hydroxyethyl]-2-azetidinone 206mg (0.90m
mol) in 3 ml of dimethylformamide,
To this, t-butyldimethylsilyl chloride
180mg (1.2mmol), imidazole 82mg (1.2mmol)
mol) and stirred at room temperature overnight. After diluting the reaction solution with diethyl ether, water was added and extracted three times with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. This was purified by 10 g of silica gel column chromatography (developing solvent: hexane: diethyl ether 2:1), and 318 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) 1750cm ^-1 .

NMR: δ0.06, 0.09 (each 3H; s), 0.86 (9H;
s), 1.24 (3H; d J=6), 2.43 (1H; d
J=2), 3.27 (1H; dd J=3, 2.5), 4.2
(3H; m), 4.70 (1H; d J=15), 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) and quinoline
0.015 ml and 1.5 ml of petroleum ether were added, and to this was added 1.5 mg of Lindlar catalyst. Stir vigorously at room temperature for 12 hours under hydrogen atmosphere. Filter the reaction solution,
The filtrate was concentrated, 2 ml of petroleum ether and 3 mg of Lindlar's catalyst were added, and the reaction was further carried out under a hydrogen atmosphere for 36 hours. The reaction solution was subjected to 10 g of silica gel column chromatography (developing solvent benzene: methylene chloride 1:1) to obtain a semi-reduced product containing the raw material,
It was used in the following reaction without further purification.
Dissolve the semi-reduced product containing the raw material in 2 ml of THF, and add 1.1 ml of 9-BBN THF solution (0.6M) in an ice bath.
(0.63 mmol) and stirred in an ice bath for 1 hour.
Furthermore, 0.5 ml (0.3
mmol) and stirred in an ice bath for 2 hours and at room temperature for 1 hour. Add 0.56 ml (2.3 mmol) of 4N sodium hydroxide and 0.4 ml of 31% hydrogen peroxide solution to this reaction solution in an ice bath.
ml and stirred at room temperature for 1 hour. The reaction solution was diluted with diethyl ether, water was added, and extracted three times with diethyl ether. The extract was washed with a dilute aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. This was subjected to 10g silica gel column chromatography (developing solvent diethyl ether:hexane 3:1 → 5:1).
to give 70 mg of 1-benzyl-3(S)-[1(R)-
t-Butyldimethylsilyloxyethyl]-4(R)
-(2-hydroxyethyl)-2-azetidinone was obtained.

Yield 64%.

TLC: 0.3 (diethyl ether:hexane 3:
1) IR: (chloroform) 3460, 1740cm ^-1 . NMR: 0.03, 0.07 (each 3H; s), 0.87 (9H;
s), 1.26 (3H; 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 Sodium hydride (50% oily) 13mg (0.26m
mol), add 1 ml of THF and 0.6 ml of dimethylformamide, and add 1-benzyl-3(S)- to this in an ice bath.
[1(R)-t-butyldimethylsilyloxyethyl]
Add 2 ml of THF solution of 64 mg (0.18 mmol) of -4(R)-(2-hydroxyethyl)-2-azetidinone,
Stir for 10 minutes. Add this to 0.03ml of benzyl bromide.
(0.25 mmol) was added and stirred at room temperature overnight. Water was added to the reaction solution, extracted three 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)-t-butyldimethylsilyloxyethyl]-
46 mg of 2-azetidinone was obtained. Yield 58%. This one is based on the literature (T.Iimori and M.Shibasaki
Tetrahedron Lett. 26 , 1523 (1985) It is completely identical to the above compound and is efficiently converted to thienamycin.

〔Effect of the invention〕

β-N represented by the general formula () of the present invention
- Substituted aminothiol ester forms a β-lactam ring, then protects the hydroxyl group, partially reduces the triple bond,
The hydroboration reaction leads to the optically active β-lactam represented by the general formula () in a short process and in good yield, and therefore can become an excellent useful synthetic intermediate.

Claims (1)

[Claims] 1. General formula β-N-substituted aminothiol ester represented by (wherein R ¹ is an alkyl group or an aryl group, and R ² is an aralkyl group). 1 In the presence of a tertiary amine, the general formula β-hydroxythiol ester represented by and the general formula The reaction mixture is then reacted with an imine represented by the general formula R ² -N=CH-C≡C-SiMe ₃ , and then treated with hydrogen peroxide. , general formula A method for ^producing a β- ^N -substituted aminothiol ^ester represented by ,
Together they can form a ring with the bound boron. ).