JPH0813828B2 - Novel β-lactam compound and method for producing the same - Google Patents

Description

The present invention relates to a novel β-lactam compound having a hydroxyethyl group having a hydroxyl group protected at the 3-position and a silyl ether group at the 4-position, and a novel β-lactam compound thereof. Regarding manufacturing method.

The novel β-lactam compound according to the present invention has a highly reactive silyl ether group at the 4-position and is a useful intermediate which can be converted into various derivatives. For example, by performing a substitution reaction on the 4-position silyl ether group of the present compound, a carbapenem-based β represented by thienamycin known as a fourth-generation β-lactam antibiotic, etc.
-3- (1-hydroxyethyl) useful as a synthetic intermediate for lactam antibiotics and penem β-lactam antibiotics
A -4-acetoxyazetidin-2-one derivative can be obtained (for example, Raider et al., Tetrahedron Letters, Vol. 23, page 2293 (1982), and Yoshida et al., Chemical and Pharmacological Butylene (Chem. Pha
rm.Bull.), 29, 2899 (1981)].

(Prior Art and Problems) The present inventors have already applied for a patent for a β-lactam compound having a silyl ether group at the 4-position and a method for producing the same.
61-18791). The present inventors have conducted further studies, found a novel β-lactam compound having a silyl ether group at the 4-position and a method for synthesizing the same, and completed the present invention.
The details will be described below.

(Means for Solving Problems and Effects) The present invention provides a compound represented by the general formula (I) (In the formula, R ¹ is a hydroxyl protecting group, R ² , R ³ and R ⁴ are C _{1 to} C ₆ lower alkyl groups or aralkyl groups, R ⁵ is a substituted phenyl group, a phenyl group, an aralkyl group, a lower alkyl group. The present invention relates to a novel β-lactam compound represented by As R ¹ which is an O-protecting group for the hydroxyethyl group at the 3-position in the general formula (I), R ¹ is represented by the general formula (I
I) (In the formula, R ⁶ , R ⁷ , and R ⁸ represent a C _{1 to} C ₆ lower alkyl group.)
A trialkylsilyl group represented by: tert-butyldimethylsilyl group, triisopropylsilyl group, isopropyldimethylsilyl group, isobutyldimethylsilyl group, dimethyl- (1,2-dimethylpropyl) silyl group, dimethyl- (1,1 , 2-Trimethylpropyl) silyl group, tert-butyl group, benzyl group, trichloroethoxycarbonyl group, tert-butoxycarbonyl group or p
-Nitrobenzyloxycarbonyl group and the like, but preferably stable during the reaction, and further tert-butyldimethylsilyl group, isopropyldimethylsilyl group, dimethyl- (1,1,1, which can be selectively deprotected by acid treatment.
2-trimethylpropyl) silyl group or dimethyl-
A (1,2-dimethylpropyl) silyl group is preferred.

R ² , R ³ , and R ⁴ of the β-lactam compound (I) are C _{1 to} C ₆ lower alkyl groups such as methyl, ethyl, isobutyl, and 1,1,2 trimethylpropyl, or benzyl group, p-nitro. The same or different groups can be selected from aralkyl groups such as benzyl group, but R ² = R ³ = R ⁴ = methyl is most preferable.

When these substituents are used, the desired configuration of the β-lactam compound at the 3-position and the 4-position is a trans form, and the configuration at the 3-position of the β-lactam ring is desirable (R). It is easy to become a body. General formula (I)
Regarding the three-dimensional structure of β-lactam represented by, three asymmetric carbons are present, and eight kinds of stereoisomers can be produced, but preferably 3- (R) and 4- (R) And the configuration of the asymmetric carbon in the O-protected hydroxyethyl group is (R).

 Next, the manufacturing method will be described.

Regarding the synthesis of a β-lactam compound having an O-protected hydroxyethyl group at the 3-position and a silyl group at the 4-position, the present inventors have summarized the reaction between an enol silyl ether and chlorosulfonyl isocyanate. Target β-
Having found that a lactam ring can be formed and filed an application (Japanese Patent Application Laid-Open No. 61-18791), the present inventors have made further detailed investigations and found that instead of chlorosulfonyl isocyanate, p-toluenesulfonyl isocyanate and benzenesulfonyl isocyanate were used. By using a substituted phenyl such as nato and p-chlorobenzenesulfonyl isocyanate, phenyl, aralkyl, and lower alkyl sulfonyl isocyanate, β- which is stable and not unstable as when chlorosulfonyl isocyanate is used is used. A lactam compound is obtained. Further, they have found that the reaction is mild and that the target β-lactam compound can be obtained in a high yield, and the present invention has been completed.

That is, the general formula (III) (In the formula, R ¹ represents a hydroxyl protecting group, and R ² , R ³ and R ⁴ represent C _{1 to} C ₆ lower alkyl groups, phenyl groups or aralkyl groups.)
The enol silyl ethers represented by the general formula (I
V) R ⁵ —SO ₂ —NCO (IV) (wherein, R ⁵ represents a substituted phenyl group, a phenyl group, an aralkyl group, a lower alkyl group) and a compound represented by the general formula (I) (In the formula, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as the above), and a method for producing a β-lactam compound is described.

 The reaction method of the present invention is shown below.

Reaction formula 1 The R ⁵ -SO ₂ NCO used in the present invention has R ⁵ substituted phenyl,
Commercially available products corresponding to phenyl, aralkyl and lower alkyl can be used.

Examples of the raw material enol silyl ethers in this reaction include 3-tert-butyldimethylsilyloxybut-1-ynyltrimethylsilyl ether and 3-tert-
Butyldimethylsilyloxybute-1-nyldimethylisobutylsilyl ether, 3-tert-butyldimethylsilyloxybute-1-yl-tert-butyldimethylsilyl ether, 3-tert-butyldimethylsilyloxybute-1
-Nyl-tert-butylmethylphenyl silyl ether,
3-tert-butyldimethylsilyloxy-but-1-ynyl-tert-butyldiphenyl silyl ether, 3-dimethyl- (1,1,2-trimethylpropyl) silyloxybute-
1-nyltrimethylsilyl ether, 3-dimethyl-
(1,2-dimethylpropyl) silyloxybute-1-nyltrimethylsilyl ether, 3-dimethylisopropylsilyloxybute-1-nyltrimethylsilyl ether,
3-Dimethylisopropylsilyloxybute-1-nyl-
tert-butyl dimethyl silyl ether, 3-acetoxy bute-1-nyl trimethyl silyl ether, 3-acetoxy bute-1-nyl-tert-butyl dimethyl silyl ether, 3-acetoxy bute-1-nyl-tert-butyl diphenyl silyl ether, 3- tert-butoxy-bute
1-nyltrimethylsilyl ether, 3-tert-butoxybute-1-nyl-tert-butyldimethylsilyl ether, 3-tert-butoxybute-1-nyl-tert-butyldiphenylsilyl ether, 3-benzyloxycarbonyloxybute- 1-nyltrimethylsilyl ether,
3-benzyloxycarbonyloxybute-1-nyl-
tert-Butyldimethylsilyl ether, 3-benzyloxycarbonyloxybut-1-ynyl-tert-butyldiphenyl ether, 3-p-nitrobenzyloxycarbonyloxybut-1-enyltrimethylsilyl ether, 3-p-nitro Benzyloxycarbonyloxybut-1-ynyl-tert-butyldimethylsilyl ether,
3-p-nitrobenzyloxycarbonyloxybute-
1-nyl-tert-butyldiphenylsilyl ether, 3
-O-nitrobenzyloxycarbonyloxybute-1
-Nyltrimethylsilyl ether, 3-o-nitrobenzyloxycarbonyloxybut-1-ynyl-tert-butyldimethylsilyl ether, 3-o-nitrobenzyloxycarbonyloxybut-1-ynyl-tert-butyldiphenylsilyl Although ether and the like can be adopted, preferably 3-tert-butyldimethylsilyloxybute-1-yltrimethylsilyl ether, 3-dimethyl- (1,1,2
-Trimethylpropyl) silyloxybute-1-nyltrimethylsilyl ether, 3-dimethyl- (1,2-dimethylpropyl) silyloxybute-1-nyltrimethylsilyl ether, 3-dimethylisopropylsilyloxybute-1-yltrimethylsilyl ether. These raw materials can be synthesized from 3-hydroxybutyric acid ester according to the following reaction formula 2.

Reaction formula 2 In the β-lactam compound (I) of the compound of the present invention,
The configuration of the O-protected hydroxyethyl group of the 3-position side chain is preferably the (R) -configuration, for which an optically active 3
The β-lactam formation reaction represented by the reaction formula 1 may be carried out using an optically active enol silyl ether compound obtained by using (R) -hydroxy-butyric acid ester.

In the β-lactam ring formation reaction by the reaction of enol silyl ethers and isocyanates, the configuration of β-lactam to be produced differs depending on the type of silyl ether group, and carbapenem-based β-lactam antibiotics represented by thienamycin. Desirable 3 (R), 4 in the synthesis of
To obtain the β-lactam compound (I) having the (R) configuration, the silyl ether group is a trimethylsilyl group, tert-butyldimethylsilyl group, isopropyldimethylsilyl group, dimethyl- (1,1,2-trimethylpropyl) silyl group. Etc. are suitable. Further, for R ¹ which is a hydroxyl-protecting group of enol silyl ethers, tert-butyldimethylsilyl group, isopropyldimethylsilyl group, dimethyl- (from the point of considering the above stereochemistry and good reactivity with isocyanate, A 1,1,2-trimethylpropyl) silyl group and a dimethyl- (1,2-dimethylpropyl) silyl group are preferred.

The reaction between enol silyl ether and isocyanate is
It can be carried out without solvent or using an organic solvent which is inert to methylene chloride, chloroform, toluene, cumene n-hexane, ethyl ether and other isocyanates and enol silyl ethers. The reaction temperature at this time can be selected in the range of -40 ° C to the boiling point of the solvent used, but it is preferably achieved by dropping an isocyanate into the enol silyl ether solution in the temperature range of -20 ° C to + 50 ° C. it can. The molar ratio of the enol silyl ether and the isocyanate may be about 1: 1 and the equimolar ratio. After completion of the reaction, the reaction solution is concentrated under reduced pressure and recrystallized as it is, or water is added to the reaction solution and the desired β-lactam compound is extracted with an organic solvent such as ethyl acetate or n-hexane, and sulfuric acid is added. After drying with a dehydrating agent such as magnesium, the solvent is distilled off under reduced pressure to obtain a β-lactam compound having an O-protected hydroxyethyl group at the 3-position and a silyl ether group at the 4-position. it can.

(Examples) Next, the present invention will be described in more detail with reference to Examples.
The invention is not limited to only these examples.

Example 1 (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-p-toluenesulfonyl-
Synthesis of 4-trimethylsilyloxyazetidin-2-one (3R) -3-tert-butyldimethylsilyloxybute-
To 3.06 g of 1-nyl-trimethylsilyl ether, 1.60 ml of tosyl isocyanate was added at room temperature under N ₂ flow. After stirring at room temperature for 10 hours, the reaction solution became a pale yellow solid.
After adding about 3 ml of hexane to dissolve most solids,
Crystallize at about 10 ° C. After crystal precipitation, the solution was removed to give (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-p-toluenesulfonyl-4-trimethylsiloxyazetidine-2- On 2.
0 g was obtained as colorless crystals. Physical properties were as follows.

▲ [α] ²⁰ _D ▼ = -6.6 ° (c = 0.16, toluene) ¹ H-NMR (90 MHz, CDCl ₃ ) δ (ppm): 0.01 (3H, s),
0.08 (3H, s), 0.27 (9H, s), 0.87 (9H, s), 1.24 (3
H, d), 2.46 (3H, s), 2.95 (1H, m), 4.20 (1H, m),
5.88 (1H, d), 7.36 (2H, d), 7.91 (2H, d) Example 2 (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-p -Toluenesulfonyl-
Synthesis of 4-trimethylsilyloxyazetidin-2-one (3R) -3-tert-butyldimethylsilyloxybute-
To 3.64 g of 1-nyl-trimethylsilyl ether, 1.97 ml of tosyl isocyanate was added at room temperature under N ₂ flow. 0 ° C
After stirring for 10 hours, the reaction solution became a pale yellow solid.
50 ml of n-hexane was added and dissolved, washed twice with 50 ml of water and then dried over anhydrous magnesium sulfate. After that, concentration under reduced pressure gave 5.5 g of a pale yellow oily substance. When this product was analyzed by NMR, (3R, 4R) -3-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-p-toluenesulfonyl-4-trimethylsiloxyazetidin-2-one was identified. It was the main product.

Example 3 (3R, 4R) -3-[(R) -1-dimethyl- (1,1,2-
Synthesis of (trimethylpropyl) silyloxyethyl] -1-p-toluenesulfonyl-4-trimethylsilyloxyazetidin-2-one (3R) -3-dimethyl- (1,1,2-trimethylpropyl) silyloxybute-1- Nyl-trimethylsilyl ether (1.0 g) (mixture of trans isomer and cis isomer in a ratio of 12: 1) was added to 5 ml of chloroform, and tosyl isocyanate (0.65 g) was added over 10 minutes at room temperature under N ₂ stream. After reacting at room temperature for 8 hours, the mixture was extracted with 10 ml of water and 20 ml of hexane and dried over magnesium sulfate. The solvent was distilled off by concentration under reduced pressure to obtain 1.3 g of a crude product mainly containing the desired β-lactam.

¹ H-NMR of (3R, 4R, 5R) form (90 MHz, CDCl ₃ ) δ (pp
m) is as follows.

0.02 (6H, s), 0.08 (9H, s), 0.72 (6H, s), 0.75 (6
H, d), 1.12 (3H, d), 1.48 (1H, m), 2.46 (3H, s),
2.85 (1H, dd), 4.09 (1H, m), 5.30 (1H, d), 7.36 (2
H, d), 7.91 (2H, d) Example 4 (3R, 4R) -3-[(R) -Dimethyl- (1,2dimethylpropyl) silyloxyethyl] -1-p-toluenesulfonyl-4- Synthesis of Trimethylsilyloxyazetidin-2-one (3R) -3-Dimethyl- (1,2dimethylpropyl) silyloxybute-1-nyl-trimethylsilyl ether 1.
0 g (mixture of trans-form and cis-form ratio of 12: 1) was added to 5 ml of chloroform, and 0.68 g of tosyl isocyanate was added over 10 minutes at room temperature under N ₂ stream. After reacting at 30 ° C for 10 hours,
After extraction with 10 ml of water and 20 ml of hexane, the extract was dried over magnesium sulfate. The solvent was distilled off by concentration under reduced pressure to obtain 1.4 g of a crude product mainly containing the desired β-lactam.

¹ H-NMR of (3R, 4R, 5R) form (90 MHz, CDCl ₃ ) δ (pp
m) is as follows.

0.01 (6H, s), 0.30 (9H, s), 0.85 (10H, m), 1.24 (3
H, d), 1.80 (1H, m), 2.45 (3H, s), 2.95 (1H, m),
4.20 (1H, m), 5.87 (1H, d), 7.37 (2H, d), 7.92 (2
H, d) Example 5 Synthesis of (3R, 4R) -3-[(R) -dimethyl- (isopropyl) silyloxyethyl] -1-p-toluenesulfonyl-4-trimethylsilyloxyazetidin-2-one 1.0 g of (3R) -3-dimethyl- (isopropyl) silyloxybute-1-nyl-trimethylsilyl ether (a mixture of trans isomer and cis isomer in a ratio of 12: 1) was added to 5 m of chloroform.
In addition to l, 0.76 g of tosyl isocyanate at room temperature under N ₂ flow
Added over 10 minutes. After reacting at room temperature for 10 hours, the mixture was extracted with 10 ml of water and 20 ml of hexane, and dried over magnesium sulfate. The solvent was distilled off by concentration under reduced pressure to obtain 1.4 g of a crude product mainly containing the desired β-lactam.

¹ H-NMR of (3R, 4R, 5R) form (90 MHz, CDCl ₃ ) δ (pp
m) is as follows.

0.07 (6H, s), 0.92 (7H), 1.22 (3H, d), 2.46 (3H,
s), 2.84 (1H, dd), 4.06 (1H, m), 5.21 (1H, d), 7.
35 (2H, d), 7.92 (2H, d) Example 6 1-Benzenesulfonyl-3-[(R) -1-tert-
Synthesis of butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidin-2-one (3R) -3-tert-butyldimethylsilyloxybute-
1.06 g of 1-nyl-trimethylsilyl ether was dissolved in 4 ml of chloroform, and 0.57 ml of benzenesulfonyl isocyanate was added dropwise under N ₂ atmosphere under ice cooling. After stirring at room temperature for 24 hours, the solvent was evaporated to give (3R, 4R) -1-benzenesulfonyl-3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidine- 2-one and (3S, 4S) -1-benzenesulfonyl-3-[(R) -1-tert-butyldimethylsilyloxyethyl] -4-trimethylsilyloxyazetidine-2
1.92 g of a mixture containing 5.5-one of on was obtained. ¹ H-NMR (90 MHz, CDCl ₃ ) δ (ppm): (3R, 4R) form: 0.
01 (3H, s), 0.08 (3H, s), 0.27 (9H, s), 0.86 (9H, s)
s), 1.21 (3H, d), 2.9 (1H, m), 4.2 (1H, m), 5.90
(1H, d), 7.5 to 8.1 (5H, m) (3S, 4S) body: 0.01 (3H, s), 0.08 (3H, s), 0.27 (9
H, s), 0.86 (9H, s), 1.21 (3H, d), 2.9 (1H, m), 4.
2 (1H, m), 5.69 (1H, d), 7.5-8.1 (5H, m) Example 7 3-[(R) -1-tert-butyldimethylsilyloxyethyl] -1- (4-chlorobenzenesulfonyl ) -4
-Trimethylsilyloxyazetidin-2-one synthesis (3R) -3-tert-butyldimethylsilyloxybute-
0.93 g of 1-nyl-trimethylsilyl ether was dissolved in 4 ml of chloroform, and 0.5 ml of 4-chlorobenzenesulfonyl isocyanate was added under N ₂ atmosphere. After reacting for 24 hours at room temperature and distilling off the solvent under reduced pressure, 3-[(R)
-Tert-butyldimethylsilyloxyethyl] -1- (4
-Chlorobenzenesulfonyl) -4-trimethylsilyloxyazetidin-2-one mainly containing crude product
1.72 g was obtained, which was (3R, 4R) :( 3S, 4S) = 5: 1. ¹ H-NMR (90 MHz, CDCl ₃ ) δ (ppm): (3R, 4R) form: 0.
01 (3H, s), 0.08 (3H, s), 0.27 (9H, s), 0.87 (9H, s)
s), 1.23 (3H, d), 2.9 (1H, m), 4.2 (1H, m), 5.94
(1H, d), 7.52 (2H, d), 7.95 (2H, d) (3S, 4S) body:
0.01 (3H, s), 0.08 (3H, s), 0.27 (9H, s), 0.87 (9
H, s), 1.23 (3H, d), 2.9 (1H, m), 4.2 (1H, m), 5.7
0 (1H, d), 7.52 (2H, d), 7.92 (2H, d)

Claims (19)

[Claims] 1. A general formula (I) (In the formula, R ¹ is a hydroxyl protecting group, R ² , R ³ and R ⁴ are C _{1 to} C ₆ lower alkyl groups, phenyl groups or aralkyl groups, and R ⁵ is a substituted phenyl group, lower alkyl group or aralkyl group. , Which represents a phenyl group). 2. R ¹ is a general formula (II). (In the formula, R ⁶ , R ⁷ , and R ⁸ represent a C _{1 to} C ₆ lower alkyl group.)
The compound according to claim 1, which is represented by: 3. The compound according to claim 2, wherein R ¹ is a t-butyldimethylsilyl group. 4. The compound according to claim ^{1, wherein} R ¹ is an isopropyldimethylsilyl group. 5. The compound according to claim 1, wherein R ¹ is a dimethyl- (1,1,2-trimethylpropyl) silyl group. 6. The compound according to claim 1, wherein R ¹ is a dimethyl- (1,2-dimethylpropyl) silyl group. 7. The compound according to claim 1, wherein R ² , R ³ and R ⁴ are methyl groups. 8. The compound according to claim 1, wherein R ⁵ is a tolyl group. 9. A method according to claim 1, wherein R ⁵ is a phenyl group.
The compound according to the item. 10. The compound according to claim 1, wherein R ⁵ is a chlorophenyl group. 11. General formula (III) (Wherein R ¹ represents a hydroxyl-protecting group, R ² , R ³ and R ⁴ represent a C _{1 to} C ₆ lower alkyl group, a phenyl group or an aralkyl group) and an enol silyl ether represented by the general formula ( IV) R ⁵ —SO ₂ —NCO (IV) (R ⁵ represents a substituted phenyl group, a phenyl group, an aralkyl group, a lower alkyl group) and a compound represented by the general formula (I) (In the formula, R ¹ is a hydroxyl protecting group, R ² , R ³ and R ⁴ are C _{1 to} C ₆ lower alkyl groups, phenyl groups or aralkyl groups, R ⁵ is a substituted phenyl group, phenyl group, aralkyl group, Which represents a lower alkyl group). 12. R ¹ is a general formula (II). (In the formula, R ⁶ , R ⁷ , and R ⁸ represent a C _{1 to} C ₆ lower alkyl group.)
The manufacturing method according to claim 11, which is represented by: 13. The production method according to claim 11, wherein R ¹ is an isopropyldimethylsilyl group. 14. The production method according to claim 11, wherein R ¹ is a dimethyl- (1,1,2-trimethylpropyl) silyl group. 15. The method according to claim 11, wherein R ¹ is a dimethyl- (1,2-dimethylpropyl) silyl group. 16. The process according to claim 11, wherein R ² , R ³ and R ⁴ are methyl groups. 17. The method according to claim 11, wherein R ⁵ is a tolyl group.
The manufacturing method described in the item. 18. A compound according to claim 1, wherein R ⁵ is a phenyl group.
Manufacturing method described in item 11. 19. The process according to claim 11, wherein R ⁵ is a chlorophenyl group.