JPS6046117B2 - Method for producing cephalosporin derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a cephalexin compound of formula (■) above that is useful as an antibiotic, and a method for purifying a useful intermediate.

In the production of cephalexin, N-protected D-phenylglycine or its carboxylic acid active derivative and 7-ADC are used.
The above formula (I
), namely N-protected cephalexin, is obtained.

This N-protected cephalexin necessarily contains N-protected D-phenylglycine and is in crude form. When the crude N-protected cephalexin thus obtained is subjected to the deprotection step without purification, it is possible to remove D-phenylglycine present in the deprotected product, cephalexin of formula (■). It becomes very difficult and essentially the purity of the obtained cephalexin is very low.
For these reasons, the present inventor has developed a solution by treating crude N-protected cephalexin (containing N-protected D-phenylglycine as an impurity) with dibenzylamine in a solution to form a dibenzylamine salt. It was recognized that dibenzylamine salt separates from impurities and precipitates from the above, and that it can be further separated and purified to obtain highly pure N-protected cephalexin in a highly selective manner in high yield, and that this N-protected cephalexin can be obtained in a highly selective manner in a high yield. It was found that the final product produced by subjecting to the deprotection step does not contain D-phenylglycine and is obtained with high purity, and based on this, the present invention was completed.
The present invention provides a dibenzylamine salt of a compound of formula (1) by reacting dibenzylamine (abbreviated as DBA) to a crude product of a compound represented by the following formula (in which R is a protecting group for an amino group). is formed, separated and purified, the compound of formula (1) is liberated from the dibenzylamine salt, and then the protecting group R is removed from the compound, that is, cephalexin. Provided is a method for producing cephalexin with high purity.

Note that the dibenzylamine (DBA) salt of compound (1) itself is a new substance. The compound (1
), R represents β-lactam and a known protecting group for an amino group that can be removed without affecting the amide bond at the 7-position; typical examples include benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group , t-
Butoxycarbonyl group, diphenylmethoxycarbonyl group, t-pentyloxycarbonyl group, β,β,β-trichloroethoxycarbonyl group, β,β,β-tribromoethoxycarbonyl group, 2,4-dinitrophenoxycarbonyl group, p- Nitrobenzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl group, trityl group, bis(p-methoxyphenyl)methyl group, o-nitrophenylsulfenyl group , p-nitrophenylsulfenyl group, formyl group, and the like.
These protecting groups can be removed from the compound of formula (1) without affecting the β-lactam and the 7-position amide bond by methods commonly used in the field of peptide chemistry. In this method, the DBA salt formation reaction is carried out in an inert solvent from 0 to
The reaction is carried out by treating the crude compound (1) with DBA at 50°C, preferably 10 to 20°C.

The inert solvent used in this step may be ethers such as ethyl ether or isopropyl ether, ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or esters such as ethyl acetate or butyl acetate, or several solvents. It can be used as a mixed solvent. In the formation of dibenzylamine (DBA) salt, the amount of DBA that acts on compound (1) may be 1 to 2 moles, and the amount of DBA actually used is
It is preferable to add 1.1 to 1.5 mol to 1). The generated dibenzylamine salt precipitates from the reaction solution, but the impurities remain dissolved and can be separated and purified.

For example, the dibenzylamine salt is collected by filtration. When the dibenzylamine salt of compound (1) thus formed and collected is treated with hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, etc., it is decomposed to produce compound (1) in the form of a free acid. By extracting this product with an organic solvent such as ethyl acetate, butyl acetate, or methyl isobutyl ketone to remove dibenzylamine itself, it is quantitatively converted and regenerated into the free acid form of compound (1). I can do it. This regeneration step is preferably carried out at a temperature of 0 to 5 DEG C., and the extraction should be carried out carefully to completely remove dibenzylamine. Compound (1) thus regenerated
The step of removing the protecting group R from a highly purified product to generate compound (■) is simply a step of deprotecting the group, and the means of deprotection is generally known in the field of peptide chemistry. As you can see, there are various methods depending on the type of protecting group, but
The method must not affect the β-lactam and the 7-position amide bond.

For example, when a t-butoxycarbonyl group is present on compound (1) as a protecting group R, it can be deprotected by treatment with an acid such as trifluoroacetic acid, formic acid, or hydrochloric acid. Cephalexin obtained by the method of the present invention is
That is, compound (1) produced without going through DBA salt.
) has extremely high purity and does not contain D-phenylglycine derived from unreacted raw materials compared to cephalexin produced by immediately subjecting it to the deprotection step without purification at the crude product stage. .

The method of the present invention will be explained below using Examples, but the present invention is not limited thereto. Example (a) 7β-(4)-α-t-butoxycarbonyla”
Minnow α-phenylacetamide)-3-methyl-3-
Generation of cefhemu 4-carboxylic acid, dibenzylamine salt.

3.86 J of lithium salt of D-α-t-butoxycarbonylaminophenyl acetate is dissolved in 40 ml of DMF and dried by concentrating to 20 ml under 2 reduced pressure.

This solution was cooled on ice, and a (g) α solution of anhydrous sulfuric acid and a dimethylformamide mixture (SO3/DMF) (see Japanese Patent Application No. 1971-60235) (a). 1y1m1) Add 12mt. Then stir twice. Add this solution to 7-amino-3
- Methyl; 2.14 Da of 3-cephemu-4-carboxylic acid was suspended in 50 ml of water, solubilized to pH 7.5 with a saturated aqueous solution of sodium hydrogen carbonate, and the solution maintained at a temperature of 5 to 10°C was stirred. While doing so, add about 1 drop. PH is maintained at 7.5-8.0. After dropping, use the same PHL at the same temperature. After continued stirring, 50 ml of water was added to saturate with salt, and 100 ml of ethyl acetate was added to give a 10%
pH2 with hydrochloric acid. O, and insoluble matter was removed by filtration.
Separate the ethyl acetate layer and extract the aqueous layer with 50 TnL of ethyl acetate to incorporate the organic layer. Dilute the organic layer with saturated saline solution 100%
mL twice, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.6q of residue. 20 mL of a 1:1 mixture of ethyl acetate and ether was added to dissolve the residue, and 1.1 dibenzylamine 8T was added with stirring. The generated DBA salt precipitated out, and was filtered out, washed with a small amount of ethyl acetate, and recrystallized from a mixed solvent of ethyl acetate nimethanol 15:1. 5.
The title compound was obtained as 85 g of white needles.

Mp. l53℃ (decomposition) [α] D=+49.4 (methanol, C=0.036) UV: λMeOH, max26
3mμ, H1%, 1cm107.6IR (Nujiyoru)
3350cm-1 (NH) 17600-1 (β-1ac
Iam) 1660cm-1 (urethane) NMR
: (DMSO-(16,TMS,60MHz)1.4
0(S,9H,t-Bu)1.93(S,3ll,CH
3) 3.26 (Q, 2H, 2nd position CH2) 3.95 (S,
4H, CH2) 4.90 (D, lH, 6th position H) 5
．． 35 (D, lH, NH) 5.53 (Q, lH, 7th position H
)7.

26-7.33 (15H, phenyl) (b) 7
β-(D-α-amino-α-phenylacetamide)-
Formation of 3-methyl-3-cefemu-4-carboxylic acid.

The product of the previous section (a), that is, 7-β(-D-α-t-
Suspend 2 g of dibenzylamine salt of butoxycarbonylamino-α-phenylacetamide)-3-methyl-3-cephemu-4 monocarboxylic acid in 20 ml of ethyl acetate, and suspend 2 g of dibenzylamine salt of ethyl acetate.
0ml and cooled 50% citric acid to pH 3. It was set as O.

Separate the ethyl acetate layer and add 20ml of ethyl acetate to the aqueous layer.
Add t and extract, add ethyl acetate and add 20ml of saturated saline.
The free acid was obtained from the dibenzylamine salt by washing with T twice, drying with anhydrous magnesium sulfate, and distilling off the solvent. Add 10ml of methylene chloride to the residue, dissolve it, and add 5ml of concentrated hydrochloric acid.
After stirring at room temperature for 1 hour, 20 ml of ice water was added and the aqueous layer was separated, and triethylamine was added to the aqueous layer under cooling to adjust the pH to 4.5 and precipitate. After stirring for about 1 hour, the solids were collected by filtration and washed with a small amount of water. 1
．． The title compound was obtained as 16 g of white crystals.

Claims (1)

[Claims] Primary formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (in the formula, R is a protecting group for an amino group), which is obtained by reacting dibenzylamine with a crude product of the compound represented by , forming a dibenzylamine salt of the compound of formula (I), separating and purifying this,
The following formula ▲Mathematical formula, chemical formula, table, etc.▼ is characterized by liberating the compound of formula (I) in the form of a free acid from this dibenzylamine salt, and then removing the protecting group R from the compound. A method for producing cephalexin represented by (II).