JPS604190A - Preparation of cephalosporin derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate of antibacterial agent, etc., economically in an industrial scale, by reacting a specific cephem-4-carboxylic acid compound with halogenated alkyl carboxylate or carbonate, and eliminating the protecting group from the product. CONSTITUTION:The objective compound of formula III is produced by dispersing the compound of formula I [A is amino or (substituted) benzylideneimino] (e.g. 7beta-amino-3-methoxymethyl-3-cephem-4-carboxylic acid) in a solvent such as N,N- dimethylacetamide, reacting with the compound of formula II (R<1> is H or lower alkyl; R<2> is lower alkyl or lower alkoxy; X is halogen) (e.g. 1-iodoethyl isopropylcarbonate) in the presence of a base such as diisopropylamine, and removing benzylidene group when A is benzylideneimino.

Description

Detailed Description of the Invention The present invention is based on the general formula (wherein 11 represents a hydrogen atom or a lower alkyl group)
12 represents a lower alkyl group or a lower alkoxy group.

) and relates to a new method for producing cephalosporin derivatives and acid addition salts thereof, more specifically compounds having the general formula (wherein A represents an amino group or a benzylideneimino group with or without a substituent). In the presence of a base, the general formula (wherein R1 and R2 have the same meanings as described above, and X represents a rogone atom) is obtained. ), and when A is a benzylidene imino group, the benzylidene group is eliminated.
The present invention relates to a method for producing a compound having 1) and an acid addition salt thereof.

In the above formula, R1 preferably represents a hydrogen atom or a methyl group, and R2 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isodityl, tert-butyl, and tert-butyl.
A linear or branched alkyl group having 1 to 4 carbon atoms such as butyl, methoxy, ethoxy, n-
It represents a linear or branched alkoxy group having 1 to 4 carbon atoms, such as glopoxy, incytoxy, n-butoxy, incytoxy, (8)-butoxy, and tart-cytoxy, and A is an amine group or benzylidene group. It represents an unsubstituted or substituted benzylideneimino group such as imino or salicylideneimino, and X represents a halodane atom such as bromine or iodine.

In general, the conventional method for producing such compounds of the present invention involves acylating the 7-position of the cephalosporin skeleton, then esterifying carbic acid at the 4-position, and then cleaving the acyl group by an iminoether method using phosphorus pentachloride or the like. It was carried out as follows. According to the method of the present invention, the desired product can be easily obtained without requiring complicated operations such as cleavage of acyl groups with phosphorus pentachloride.

In carrying out the method of the present invention, the general formula (II
) can be reacted with a compound having the general formula (-) in the presence of a base, which can be carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction, but for example, fatty acid dialkylamides such as dimethylformamide and dimethylacetamide, or these together with sochloromethane,
A mixed solvent with an organic solvent such as methanol is preferred. Suitable bases used in the reaction are organic bases such as triethylamine, twinpropylamine, tart-octylamine, dimethyl-benzylamine, and dicyclohexylamine. The reaction temperature is usually around -10°C to room temperature, and the reaction time is usually 30 minutes to 2 hours, although it varies depending on the reaction temperature, reaction reagent (type of music, etc.).

In the compound obtained by this esterification reaction, when substituent A represents a benzylidene amino group, the benzylidene group can be removed according to a conventional method. As an elimination reagent for that purpose, there is no particular limitation as long as it regenerates the diamino group, such as a Schiff base compound, but preferred examples include Girard T reagent, phenylhydrazine or its hydrochloride, acetelhydrazone, benzoylhydrazine, Examples include organic bases such as aniline and toluidine, and acid addition salts thereof such as acetic acid or oxalic acid.

After the reaction is completed, the target compound (1) of this reaction can be collected from the reaction mixture according to a conventional method.

For example, it can be obtained by extracting the reaction mixture with an organic solvent such as ethyl acetate, washing the organic solvent layer with water, and drying. The target compound thus obtained can be prepared, if necessary, by conventional methods, such as hydrochloride, hydrobromide, benzenesulfone TIN salt, p-)luenesulfonate, α-L<iiβ-naphthalenesulfonic acid. It can be purified as an acid addition salt such as a salt.

The object compound (1) of the present invention is useful as a raw material for pharmaceuticals having antibacterial activity. For example, an oral cephalosporin compound as described in JP-A-57-59894 can be produced using the present compound (1) as an intermediate.

Next, the manufacturing method of the present invention will be explained in more detail with reference to Examples.

Example 1 7β-amino-3-methoxymethyl-3-cephem-4
- 5.0 l of carboxylic acid was suspended in 50 - of N,N-dimethylacetamide, cooled to below 5°C in an ice-water bath, and while stirring, 3.4 - of diimpropylamine was added, followed by 2.5 ml of benzaldehyde. Add and continue stirring for 30 minutes, resulting in a clear solution.

7.
5F! - was added, stirred for 1.5 hours, and Norard T reagent 7.
Add a solution of 01 dissolved in 100rnl of methanol,
Stir for an additional 40 minutes. Then, the mixture is concentrated under reduced pressure to distill off methanol. Add 100 ml of ethyl acetate to the residue and wash twice with 60 ml of 18% brine and 20 ml of 18% brine to obtain more ethyl acetate from the aqueous layer. Dissolve this in 50rnl of ethyl acetate, add 50ml of water, add 6N HCl while stirring to adjust the - to 1.8, and add salt to precipitate crystals.

When washed with ethyl acetate and dried, 2.59-
One of the title compounds was obtained as a hydrochloride.

Melting point 186-188°C (decomposed) nmr spectrum (CD, OD) δ: 1.30 Doublet (6I (, J = 6Hz) 1.57
Double line (3H, J = 6 Hz) 3.37 - Double line (
3H) 3.7〇 - Heavy line (2H) 4.40 - Heavy line (2H) 5.13 , 5.30 Four weights (2H, d, d, J
=5Hz)6.93 Quadruple (! H, J=6Hz
) The furnace liquor from which this hydrochloride was removed in the furnace was separated, the ethyl acetate layer was taken, and the layer was washed with 5% sodium bicarbonate water and then with water.
p-) Add 2.5 I of luenesulfonic acid and dissolve, once concentrate to dryness under reduced pressure, add ethyl acetate and leave to stand to precipitate crystals. This was collected in a furnace, washed with ethyl acetate, and dried to obtain p-)luenesulfonate of the other epimer of the title compound 3.71.

Melting point 182-183.5°C (decomposed) nmr spectrum (CD, OD) δ: 1.27 Doublet (6H, J = 6Hz) 1.53
Double M (3H, J = 6 Hz) 2.37-Double (3
H) 3.37-double (3H) 3.67-double (2H) 4.33-double (2H) 5.13, 5.27 quartet (2H, d, d, J
=5Hz)6.87 41st line (II(,J =6Hz
) 7.23, 7.73 quartet (4HIA2B2.
J=9Hz) Example 2 7β-amino-3-methoxyphthyl-3-cephem-4
-carboxylic acid5. Qy- was suspended in N,N-dimethylacetamide 5o-, cooled to below 5°C in an ice water bath, and while stirring, tert-octylamine 4.3- was added and dissolved, and 1-iodoethyl isopropyl chloride was added. - Pone) 7
．． Add 4F and continue stirring for 2 hours. Then ethyl acetate 1
00- and working up as in Example 1 gives 6.01 of the title compound of Example 1; working similarly as in Example 1 gives the hydrochloride 2.1? and p-toluenesulfonate 3.0
g- was obtained.

Example 3 7β-amino-3-methoxymethyl-3-cephem-4
- 2.44f of carboxylic acid was suspended in 25g of trimethylacetamide under water cooling, and 1.4f of diisopropylamine was suspended in 25g of dimethylacetamide. Add and dissolve IP, add 1.2 td of benzaldehyde and stir for 30 minutes, then add 3.15 td of hivaloyloxymethyl iodide.
Add P and stir at 3°C for 1 hour and 30 minutes. Then, a solution of 3.4F Girard T reagent dissolved in 50fItt of methanol is added and stirred for 1 hour. Methanol was distilled off under reduced pressure, 60% of ethyl acetate was added to the residue, and 30% of 18% brine was added.
7! After washing twice with , it was concentrated under reduced pressure, and the residue was purified using benzene:ethyl acetate (1:1). 48-Double line (2■) 4.23-g@(2H) 4.63, 4.87 Quadruple line (2H, d, d, J
=5Hz) 5.80-duplex (2H) Example 4 Piparoyloxymethyl iodide of Example 3 3.1
Iodomethyl inglovir car is substituted for 5f) 3
．． 2i, reacted in the same manner as solvent, benzene:ethyl acetate 1:1) nmr spectrum (CDCA, ) δ
: 1.30 Double line (2H, J=6 Hz) 3.31-
Heavy line (3H) 3.51-Double line (2H) 4.71, 4.98 VfAX ray (2H, d, d,
J=5Hz) 5.83-double line (2K) Example 5 In place of the piparoyloxymethyl iodide of Example 3, iodomethylethyl car was used as a nate nmr spectrum #
(CDCA3) δ: 1.32 triplet (3H, J=7Hz
) 3.26-double line (3H) 3.50-double line (3■) 4.16 Quadruple line (2H, J=7Hz) 4.67, 4
．． 85 Quadruple (2H, d, d, J=5Hz) 5
．． 80-Double line (2H) Patent applicant: Sankyo Co., Ltd. Agent Patent attorney: Shoji Kashide

Claims (1)

[Scope of Claims] In the presence of a base, a compound having the general formula (wherein A represents an amine group or a benzylideneimino group with or without a substituent) is treated with the general formula (wherein R1 is a hydrogen atom). or lower alkyl group
B2 represents a lower alkyl group or a lower alkoxy group,
A general formula (wherein R1 and R2 are the same as those described above) is reacted with a compound having @) where X represents a halodane atom, and when A is a benzylidene imino group, the benzylidene group is eliminated. A process for producing a cephalosporin derivative and an acid addition salt thereof having the following.