JPH07107045B2 - Process for producing optically active β-lactam compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for producing various optically active β-lactam compounds which are precursors of β-lactam antibiotics such as carbapenem, carbapenum, carbacephem, carbacepham and oxapenam. It is about.

[Conventional technology]

β-lactam antibiotics are important drugs having antibacterial activity against various bacteria such as Gram-positive bacteria and Gram-negative bacteria.

As a method for producing penicillin, cefalosporin, etc., which have been the mainstream of conventional antibiotics, a culture method using bacteria has already been established. Carbapenem, a new type of antibiotic, carbapenam has extremely strong antibacterial activity,
It is expected that it will be replaced by penicillin and cefalosporin in the future, but its skeleton is extremely unstable, and there are drawbacks such as low productivity by bacteria. Therefore, the synthetic method is mainly used. I was crying.

[Problems to be Solved by the Invention]

Many methods for producing an optically active β-lactam compound by synthesis have been reported. (PHBentley, E, Hunt, J.
CSPerkin, JCSPerkin I, 2222 (1980) K.Clauss, DG
rimm, G.Prossel, Liebigs Ann.Chem., 539 ~ 560 (197
4)) However, these are methods of using a natural optically active substance such as a penicillin skeleton and an L-aspartic acid derivative as a raw material [Paul J. Reider and Edword JJ Crabowski, Tetrahed.
ron Letters, Vol.23, No.22, 2293-2296 (1982)] and a method by asymmetric synthesis, [Y. Nagao, et.al., J. Am. Chem. Soc., 108, 4673-4675 (198
6)] No method has been reported for producing an optically active β-lactam compound from a racemic raw material by optical resolution.

The present inventors have synthesized racemic β-lactam compounds represented by the following general formulas (1) to (8) by using racemic 4-acetoxy-2-azetidine as a starting material to synthesize carbapenem, carbapenam, carbacephem, As a result of earnest research on a method for collecting one pure optical isomer which is a useful precursor such as carbacepham and oxapenum, a specific cellulose derivative [1] I or a specific amylose derivative [II] described below is used. Thus, it was found that the optically active β-lactam compound of the present invention can be produced, and the present invention was completed.

[Means for Solving the Problems]

In the present invention, a mixture of optically active isomers of racemic β-lactam compounds represented by the following general formulas (1) to (8) is used as a cellulose tri-substituted fluoropolymer having a structural unit represented by the following general formula [I]. The present invention provides a process for producing an optically active β-lactam compound, which is obtained by optical resolution using an amylose tri-substituted phenyl carbamate having a structural unit represented by the following general formula [II].

(X represents a lower alkyl group having 1 to 2 C atoms.) (X is the same as in [I]) The cellulose tri-substituted phenyl carbamate derivative or amylose tri-substituted carbamate derivative used in the present invention is synthesized by reacting a substituted phenyl isocyanate with cellulose or amylose.

Cellulose tri-substituted phenyl carbamates used in the present invention include cellulose tris (phenyl carbamate), cellulose tris (3,5-dimethylphenyl carbamate), and cellulose tris (4-t-butyl phenyl carbamate), As the amylose tri-substituted phenyl carbamate, there is amylose tris (3,5-dimethylphenyl carbamate).

To further explain the production method of the present invention, the cellulose tri-substituted phenyl carbamate represented by the general formula [I] or the amylose tri-substituted phenyl carbamate represented by the general formula [II] is supported on porous spherical silica gel,
This is packed in a column and used as a chiral stationary phase for high performance liquid chromatography.

When the chiral stationary phase thus prepared is used as a column for high performance liquid chromatography and a solvent system in which polarities are adjusted by using solvents having different polarities is used, an optically active isomer can be resolved.

As described above, the optical isomer of the β-lactam compound is optically resolved by using the cellulose tri-substituted phenyl carbamate represented by the general formula [I] or the amylose tri-substituted phenyl carbamate represented by the general formula [II]. Any specific method may be used without any limitation. Also, the optical isomers resolved by the method of the present invention are collected by conventional methods.

The present invention will be described below with reference to examples.

Example 1 Porous spherical silica gel surface-treated with 3-aminopropyltriethoxysilane (particle size 10 μ, pore size 1000-4000)
Cellulose tris (3,5-dimethylphenyl carbamate) was loaded on 25% by weight in Å) and packed into a chromatographic tube [250 x 4.6 mm (inner diameter)] by the slurry method to prepare a chiral column.

Chromatographic equipment JASCO TRIROTAR II (Chromatograph: JASCO), JASCO UVDIC-100-III (UV detector: 245m
m), JASCO DIP-181C (light meter) was used.

Hexane / 2-propanol = (80/20) as an eluent, a solution of a compound [(2)-(a)] having a diazoketoester group in the side chain (concentration 1 to 5% by weight) 10 μl
Was passed through the above chiral column at 25 ° C and a flow rate of 0.5 ml / min.
The obtained optical resolution chart is shown in FIGS.

Similarly, a chiral column prepared by using the cellulose tri-substituted phenyl carbamate represented by the general formula [I] or the amylose tri-substituted phenyl carbamate represented by the general formula [II] is similarly used to perform the optical resolution chart. 1, FIG. 1-2, and FIG. 1-4 were obtained. Similarly, using the compound [(2)-(b)], the optical resolution chart is shown in FIG.
4, FIG. 2-2, FIG. 2-3, and FIG. 2-4 were obtained. Figure 3-1, Figure 3-2, Figure 3-3, Figure 3-4 using compound [(2)-(c)], Figure 4 using compound [(2)-(d)] -1, FIG. 4-2, and FIG. 4-3 were obtained.

As is apparent from FIGS. 1 to 4, the β-lactam compound (2) can be obtained by using any chiral column according to the optical resolution of the present invention.
It was found that the derivative of (1) was divided into (+)-form (right-handed) and (-)-form (left-handed) optically active isomers.

Example 2 A compound of the formula (3) is used in the same manner as in Example 1 by using several kinds of cellulose tri-substituted phenyl carbamate represented by the general formula [I] or amylose tri-substituted phenyl carbamate represented by the general formula [II]. It was found that each column was resolved into (+) isomer (right-handed) and (-) isomer (left-handed) optically active isomers. The results are shown in FIGS. 5-1 and 5-2 as optical resolution charts.

Example 3 The racemic β-lactam compound (4) was subjected to optical resolution using cellulose tris (3,5-dimethylphenyl carbamate) as a chiral stationary phase and hexane / 2 propanol = (80/20) as an eluent. As a result, as shown in FIG. 6A, the product was resolved into (+) isomer (right-handed) and (−) isomer (left-handed) optically active isomers.

Similarly, using a chiral column prepared with amylose tris (3,5-dimethylphenyl carbamate), β
-Lactam compound (4) in hexane / 2-propanol =
When (95/5) was split as an eluent, the results shown in FIG. 6-2 were obtained as an optical resolution chart.

Examples 4 to 8 Formulas [(1)-(a), (1)-(b)], (5)-
A racemic β-lactam compound represented by (8) is used as a eluent using a chiral column prepared from cellulose tris (3,5-dimethylphenyl carbamate) or amylose tris (3,5-dimethylphenyl carbamate). Optical resolution was performed using hexane / 2-propanol = (95 / 5-80 / 20) and hexane / ethanol = (80 / 20-70 / 30). The results are shown as optical resolution charts in FIG. 7 [compound (5)], FIG. 8-1 [compound (1)-(a)], and FIG.
2 [compound (1)-(b)], FIG. 9-1, FIG. 9-2 [compound (6)], FIG. 10 [compound (7)] and FIG. 11-1, FIG.
It is shown in 11-2 [Compound (8)].

As is clear from FIGS. 7 to 13, it was found that any compound was resolved into optically active isomers. It was also clarified that a more preferable division pattern can be obtained by adjusting the polarity of the eluent with 2-propanol or ethanol.

〔The invention's effect〕

The present invention relates to various optically active β-lactam compounds used as optically active precursors of β-lactam antibiotics having broad antibacterial activity against Gram-positive and Gram-negative bacteria, and racemic β-lactam compounds. Optically active isomerization of (+) form (right-handed) and (-) form (left-handed) of β-lactam compound by optical resolution using cellulose tri-substituted phenyl carbamate or amylose tri-substituted phenyl carbamate. It has been successfully manufactured by optically dividing it into a body, which is an epoch-making invention never seen before.

[Brief description of drawings]

1-1, 1-2, 1-3, 1-4, 2-1,
2-2, 2-3, 2-4, 3-1, 3-2,
FIG. 3-3, FIG. 3-4, FIG. 4-1, FIG. 4-2, and FIG. 4-3 are optical resolution charts of the racemic β-lactam compound (2) described in Example 1, respectively. 1 and FIG. 5-2 are optical resolution charts of the racemic β-lactam compound (3) described in Example 2, and FIGS. 6-1 and 6-2 are the racemic β of the racemic compound described in Example 3. -Optical resolution charts of lactam compound (4), respectively, and Figs. 7-1 and 7-
2 is a racemic β-lactam compound (5), FIG. 8-1 is a racemic β-lactam compound (1)-(a), FIG.
2 is a racemic β-lactam compound (1)-(b), FIGS. 9-1 and 9-2 are racemic β-lactam compounds (6), and FIG. 10 is a racemic β-lactam compound (7). ),
11-1 and 11-2 are diagrams of the optical resolution charts of the racemic β-lactam compound (8) described in Examples 4 to 8, respectively. (+) Is the right-handed optically active isomer (-) is the left-handed optically active isomer

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07D 498/04 102 A

Claims (2)

[Claims] 1. A mixture of optically active isomers of racemic β-lactam compound derivatives represented by the following general formulas (1) to (8) having a structural unit represented by the following general formula [I]. A method for producing an optically active β-lactam compound, which comprises performing optical resolution using cellulose tri-substituted phenyl carbamate or amylose tri-substituted phenyl carbamate having a structural unit represented by the following general formula [II]. (Here, X represents a lower alkyl group having 1 to 2 C atoms) (Same as X: [I]) 2. A cellulose tri-substituted phenyl carbamate having a structural unit represented by the general formula [I] is cellulose tris (phenyl carbamate), cellulose tris (3,5-dimethylphenyl carbamate), cellulose tris (4-). t-butyl carbamate), and the amylose tri-substituted phenyl carbamate represented by the general formula [II] is amylose tris (3,5-dimethylphenyl carbamate). -A method for producing lactam compounds.