JPH02292255A - Production of optically active beta-lactam compound - Google Patents

Abstract

PURPOSE:To dividedly obtain an antibiotic beta-lactam compound in the form of (+) and (-) modifications by making an optical resolution, using a specific relevant agent, of an optically active isomer mixture of a beta-lactam compound. CONSTITUTION:The objective compound can be obtained by making an optical resolution, using a cellulose tris substituted phenylcarbamate of formula II (X is 1 to 4C lower alkyl or halogen) or an amylose tris substituted phenylcarbamate of formula III (X is 1 to 2C lower alkyl), of a mixture of each optically active isomer for a beta-lactam compound of formula I [R1 and R2 are each H or 1 to 10C alkyl, excluding that R1 is H and R2 is (CH2)2CH3, R1 is CH3 and R2 is CH2CH3, or R1 is CH3 and R2 is (CH2)2CH3]. The beta-lactam compound thus obtained has a broad anti-fungal spectrum against Gram-positive and Gram-negative bacteria.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing an optically active β-lactam compound having an alkyl group at the 31st position and an acetoxy group at the 41st position.

The optically active β-lactam compound produced by the present invention has a highly reactive acetoxy group at the 41-position and is a useful intermediate that can be converted into various derivatives. For example, an optically active substance having an ethyl group or an isoprobyl group at the 31-position of the present invention can be converted into a carpabenem antibiotic by performing a substitution reaction on the acetoxy group at the 41-position.

[Conventional technology]

Among β-lactam antibiotics, carbabenem antibiotics, represented by chenamycin, have a broad antibacterial spectrum, strong antibacterial activity, and penicillins and cephalosporins have long been the main antibiotics. β-
It is an excellent β-lactam antibiotic that has strong resistance to 2-catamase.

However, penicillins and cephalosporins can be easily supplied as pharmaceutical raw materials in large quantities through fermentation, and from these, 6-aminoberisillanic acid (6-rubabenem antibiotics are produced by total synthesis, as their productivity by microorganisms is low). method has become mainstream.

Many methods for synthesizing optically active carpabenem antibiotics have been reported. A typical synthesis method is a method using the optically active skeleton of 6-aminobenicillanic acid (a-APA), as described by C SXarady, J.; S. Amano
tR. A. Reamer, L. M. Weinst
ock, J. A. C. A. 103. 6756(
(1980)) This method uses optically active amino acids, natural sugars, etc. as raw materials. (T.S.Salzm
ann+ FLW: RatcliffelB. G. Ch
ri s tenjlen+F. A. Bouffaa
rd, J. A. C. S. 102. 61 61(
1980) ) [Problems to be Solved by the Invention] There have been no reports or descriptions of a production method for converting the diastereomeric and racemic β-lactam compounds of the present invention into optically active compounds using a chiral column.

The inventors synthesized a β-lactam compound having an alkyl group at the 31-position and an acetoxy group at the 41-position, which was synthesized by the reaction of enol acetate } tocrorosulfonylisocyanate, by a known method, and further synthesized a β-lactam compound having an alkyl group at the 31-position and an acetoxy group at the 41-position. Among the specific cellulose derivatives (listed below) or amylose derivatives (listed below) discovered as a result of intensive research into methods for producing one type of pure optical isomer that can serve as a useful precursor for substances.
The object of the present invention is to provide a method for producing an optically active β-lactam compound by optically resolving the β-lactam compound using the following method.

[Means to solve the problem]

The first aspect of the present invention is to combine each optically active isomer mixture of a β-lactam compound represented by the following general formula (I) with a cellulose tris-substituted phenyl carbamate represented by the following general formula (m) or a β-lactam compound represented by the following general formula (III). This is a method for producing an optically active β-lactam compound in which an optically active β-lactam compound is collected by optical resolution using an amylose tris-substituted phenyl carbamate.

Here, the β-lactam compound has a general formula.

Here R,, R. represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. However, C R, H, R2 (CH
! )z CH,) or C RI C quick- & C Hg
C Hs ) or C RI CH3,R! (Chz
)z CH3) Specific Rt and Rt of typical β-lactam compounds represented by general formula (I) are as shown in Table 1 below.

Table 1-ff Cellulose represented by formula CD) or (1)} IJ-substituted phenyl carbamate or amylose tris-substituted phenyl carbamate has the following structural formula.

(X is a lower alkyl group having 1 to 4 carbon atoms (X is an alkyl group having 1 to 2 carbon atoms, or a lower alkyl group such as F or Br, and represents the halogen shown in the table)
(To) The second is the general formula (It
) Cellulose represented by IJS-substituted phenyl carbamate is cellulose tris (4-t-7' tylphenyl carbamate), cellulose tris (3,S-dimethylphenyl carbamate), cellulose tris (phenyl carbamate), cellulose tris ( 4-fluorophenyl carbamate), cellulose tris (4-promophenyl carbamate), cellulose tris (4-}lifluoromethylphenyl carbamate),
There is also a method for producing an optically active β-lactam compound as described in the first article, wherein the amylose tris-converted phenyl carbamate represented by the general formula (transformation) is allulose tris (3,5-dimethylphenyl carbamate).

The cellulose tris-substituted phenyl carbamate or amylose tris-substituted phenyl carbamate used in the present invention is synthesized by reacting a substituted isocyanate with cellulose or amylose.

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

When the chiral stationary phase prepared in this way is used as a column for high performance liquid chromatography, and a solvent system whose polarity is adjusted using various solvents with different polarities is used, it is possible to optically analyze the β-lactam compound that is the raw material of the present invention. The active isomers can be prepared separately.

The chromatogram equipment is a chromatograph (JAS
CO-TRIROTAR It), IJV detection H (.
JASCO-UV-100-1 [ ), Mi Hikari Fr
(JAS CoT) IP-18IC, light source (without filter)) was used. As an example of a method for evaluating optically resolved chromatograms, the results of division are shown in FIG.

The resolved compound (Ib) is a diastereomer,
It is a mixture of four components: (→ body and (he) body of 2nd ence, (+) body and ← body of cis body, and the peak in the chromatogram is 4.
It becomes a book. Note that trans and cis were distinguished by 'HNMR.

The solubility ratio kl. represents the strength of the interaction between the stationary phase and the solute.
and k- are evaluated using the one-pronged equation (lv), and the separation coefficient α representing the asymmetric discrimination ability of the stationary phase is evaluated using the general equation (V). Also, the degree of separation R, which indicates the degree of separation of the peaks, is expressed by the general formula (Vt)
It is evaluated by

tlt j2: Retention time of enantiomer Vi) *w2: Beak width t0: Retention time of a compound that passes through without being adsorbed to the stationary phase (1,3.5-}Lee for non-polar eluent) (The retention time of t-butylbenzene is close to t0.) If there is no separation at all, α is 1, and the larger it is, the better. Normally, if α is 1 or 2 or more, there is a high possibility of complete division. When Rs=1, the peak hemplates slightly overlap, p, t. If it is greater than or equal to zs, almost complete division has been performed.

The β-lactam compound that is the target of optical resolution is produced by reacting enol acetates represented by O, C, ~C, lower alkyl groups with chlorosulfonyl isocyanate, and then reducing the general formula. (In the formula, R, , R. are the same as above) The above reaction formula is as follows.

Here, R,, R2 are the same as above, typically υ in Table 1. As the reducing agent, conventionally used sodium sulfite, sodium sulfite, etc. are used.

There are no restrictions on the method of optically resolving optical isomers of the β-lactam compound using the cellulose tris-substituted phenyl carbamate represented by the general formula (I) or the amylose tris-substituted quenyl carpamate represented by the general formula (I). You can use any method without any problem.

The method for producing a chiram column of cellulose tris-substituted phenyl carbamate represented by the general formula (b) and amylose tris-substituted phenyl carbamate represented by the general formula (@) of the present invention is as follows.

{(a) Pyridine 3 5 ml to cellulose 0.70
3.5-dimethylphenyl isocyaner} 2.
semI! was added and reacted at about 100°C for 21 hours.

Pour the reaction solution into methanol to precipitate the product,
It was filtered through a glass filter and dried under vacuum at 60°C to obtain white crystal cellulose tris(3.5-dimethyl 7-enylcarbamate) f: 2.09 1-obtained*.

Then, 25% of cellulose tris (3.5-dimethylphenyl carbamate) was supported on porous spherical silica gel (particle size 7/irrL, pore size 4000A) 3.0i whose surface was treated with 3-aminopropyltriethoxysilane, Length 25σ, inner diameter 0.46C by slurry filling method
A Chiram column was prepared by filling a II1 chromatography tube.

Similarly, cellulose tris (4-t-butylphenyl carbamate), cellulose tris (phenyl carbamate), cellulose tris (4-fluorophenyl carbamate), and cellulose tris (4-promophenyl carbamate) represented by general formula (II) Enylcarpame-}) and cellulose tris(4-}lifluoromethylphenylcarbamate) were synthesized.

Porous spherical silica gel (particle size 77m or IQ) surface-treated with 3-aminoprobyltriethoxysilane
t1n, hole diameter 4000A) above -1! Le 0-7. A chiral column U8 was prepared by carrying 25% by weight of tris-substituted phenyl carbamate and filling a chromatography tube with a length of 25 mm and an inner diameter of 0.46 txt by a slurry filling method.

←) 35m of pyridine and 0.72m of amylose, 3.
2.86 μl of 5-dimethylphenylinocyanate was added and reacted at about 100° C. for 24 hours. The reaction solution was poured into methanol to precipitate the product, filtered through a glass filter, and vacuum dried at 60°C to form white crystals of amylose tris (3.5-dimethylphenyl carbamate).
1.70,} was obtained.

and porous spherical silica gel surface-treated with 3-aminobutyltriethoxysilane (particle size 77 m, pore size 400
0 people) a. A chiral column was prepared by loading cellulose tris (3.5-dimethylphenylcarbamate) in an amount of 25% by weight on O/, and filling a chromatography tube with a length of 25 necks and an inner diameter of 0.464 by a slurry packing method.

〔Example〕

Example 1 Hexane-2-derobanol (90:10)t-
1. A solution of Compound Ia in Table 1 above (concentration 5 to 5) as syneresis.
10% by weight) from 5pl to 2fil to the detector UV (23
0 nm), 25°C, flow rate o. sml/min or 1.0
Cellulose tris[!7enyl carbamate expressed by the general formula (W) was passed through a kyzyl column at m/Ain. ) were calculated.The results are shown in Table 2.

The trans form of compound Ia is cellulose tris (phenyl carbamate), cellulose tris (4-(4-fluorophenyl carbamate)), cellulose tris (4-promophenyl carbamate), cellulose (4-}lifluoromethylphenyl carpamate) It was.

Examples 2 to 4 Compounds Ib and Idl Ig were optically resolved in the same manner as in Example 1 using columns of cellulose tris-substituted phenyl carbamates represented by several general formulas (■), and the resulting chromatograms were Solubility ratio <Q.), separation coefficient (α),
Each value of the degree of separation (Rs) was determined. The results are also shown in Table 2.

The trans isomer of compound Ib is cellulose tris(3.5-
By using a column of cellulose tris-substituted heptadylcarpamate represented by the general formula (2) other than dimethylphenyl carbamate), it was completely resolved into optically active isomers of the (+) and (c) forms. The trans isomer of compound Id was completely resolved into the optically active isomers ←) and (c) by using a cellulose tris-substituted 7-enyl carbamate column coated with general 2Φ).

Compound G was completely resolved by the use of cellulose tris(4-fluorophenyl carbamate), cellulose tris(4-promophenyl carbamate), cellulose (4-}'J fluoromethylphenyl carbamate) columns.

Example 5 Hexane-2-probanol (90:10) fg
A solution of compound Ia + Ib + I + L Ig (concentration 5-10 Jusha 96) was added as m solution from 5) 1l to 'IJ) 11
detector (UV 23oytm), 25°C, flow rate o. s
It was passed through a Kiram column of amylose tris (3.5-dimethyl phenyl carbamate) at yB/min. The obtained chromatogram shows the solubility ratio Qc'+), the separation coefficient (α
) and the degree of separation (R3) were determined. The results are shown in Table 3.

The cis isomers of compounds Ib and Id, which were not resolved by the cellulose tris-substituted phenyl carbamate column represented by the general formula (r1), are amylose tris (a.S
- dimethyl phenyl carbamate) was completely resolved into the optically active isomers of the (→ and ←) forms by using a force column.

Table 2 β-lactam compounds derived from cellulose tris-substituted phenyl carbamate derivatives K (Ia, Ib + Id
, Ig) Optical resolution i: Eluent hexane-2-globanol (90:10) Flow rate a) 0.5 m//mi
n b) I. Oml'/min Table 3 β-lactam compounds (Ia, Ib. Id.
Optical resolution of Ig) [Effect of the invention] The present invention provides various optically active β -lactam compounds and K at position 31! An optically active β-lactam compound having an l substituent can be converted into a diastereomeric or racemic β-lactam compound.
From the lactam compound, cellulose tris-substituted heptadyl carpamate or amylose tris-substituted phenyl carbamate was used to prepare the ← and ← forms of β-lactam compounds, respectively.
) was successfully produced by optical resolution of the optically active isomer K. This is an unprecedented and revolutionary invention.

[Brief explanation of the drawing]

FIG. 1 is a chromatogram showing the optical resolution of 4-acetoxy-3-ethyl-2-azetidinone (Ib) using amylose tris (3,5-dimethyl 7-enyl carbamate) of the present invention. Ll, F }Lance peak CI, Ct Sys peak Patent applicant Toyo Kasei Kogyo Co., Ltd. Manual amendment (voluntary) July 7, 1999 Recommended Zu Trans 1. 2. 3. Display of the case 1999 Patent title No. 1-115677 Name of the person who amends the manufacturing method of an optically active β-lactam compound Relationship to the case Patent applicant retention period (min 1 5. Subject of amendment 6) Contents of the amendment (1) On page 4, line 13, “chemistry together” was corrected to “chemistry based on.” (2) On page 5, line 1, “J.A.C.A. 103. 6756 (1980)
) J r J. A. C. S. 103.6765(
1981) Corrected page 5, line 3 r (T.S.) J to rcT. N. ) Correction to J i41 to page 6th line “R5” corrected to rRsj (51 12th page 6th line from the bottom [cellulose 0.70 J to [cellulose oy7ogJ
[6] Page 15, line 1, "2 mel" was changed to [zoplJkC correction t7) Page 15, line 2, column 2, column 3, column 4, column 5, column 6 in table 2, page 15. column,
Column 7, all rKrJs are corrected to “k′l” (8) In Table 2, (1) Line 5 (Id), column 3, line 2, α term “t.so
Correct J to [1.09 J (■) 6m in line 3 (Ia)
In line l, α term “1.01” was corrected to “1.61” +91 rk in the first vertical line “K1” in table 3 on page 19
Corrected to '+'

Claims (1)

[Scope of Claims] 1. A mixture of each optically active isomer of the β-lactam compound represented by the general formula (I) is converted into a cellulose tris-substituted phenyl carbamate represented by the following general formula (II) or the following general formula (III) Optically active β, which is obtained by optical resolution using an amylose tris-substituted phenyl carbamate having a structural unit represented by
- A method for producing a lactam compound. Here, β-lactam compounds are represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I). Here, R_1 and R_2 represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. However, [R_1H, R_2(CH_
2)_2CH_3] or [R_1CH_3, R_2CH
_2CH_3] or [R_1CH_3, R_2(CH_
2) Except for the case of _2CH_3]. The cellulose tris-substituted phenyl carbamate represented by general formula (II) or the amylose tris-substituted phenyl carbamate represented by general formula (III) has the following structural formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (Here, X represents a lower alkyl group with 1 to 4 carbon atoms, or a halogen such as F or Br.) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (Here, x represents a lower alkyl group having 1 to 2 carbon atoms.) 2. The cellulose tris-substituted phenyl carbamate represented by the general formula (II) according to claim 1 is a cellulose tris (4-t -butylphenyl carbamate), cellulose tris (3,5-dimethylphenyl carbamate), cellulose tris (phenyl carbamate), cellulose tris (4-fluorophenyl carbamate), cellulose tris (4-bromophenyl carbamate), cellulose tris (4-bromophenyl carbamate) -trifluoromethylphenyl carbamate) and the amylose tris-substituted phenyl carbamate represented by general formula (III) is amylose tris (3,5-dimethylphenyl carbamate). Method for producing lactam compounds.