JPS62277390A - Cephalosporanic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula [X is S, O, SO or SO2; R1 is H or lower alkoxy; R2 is H, (substituted) acyl or (substituted) silyl; R3 is (substituted) carboxyl or carboxyl saltl; R4 is H, halogen, hydroxymethyl, lower alkyl etc.]. EXAMPLE:7beta-Amino-7alpha-methoxy-3-(1H-tetrazol-5-yl)thiomethyl-3-ce phem-4-carbo xylic acid benzhydryl ester. USE:A synthetic intermediate for producing a cephalosporin antibiotic substance such as cefaclor in high yield and purity. PREPARATION:Bis(trimethylsilyl)trifluoroacetamide is added to 7-amino- cephalosporanic acid and themixture is made to react with 4-pyridylthioacetic acid chloride hydrochloride. The pH of the reaction system is adjusted with triethylamine to crystallize the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to the following formula (1 ): 1 (wherein, carboxyl group.

Represents a substituted carboxyl group or a salt of a carboxyl group,
R4 is hydrogen, a halogen atom, a hydroxymethyl group, a lower alkyl group, or a lower alkoxy group.

It represents a pyridyloxymethyl group, an acyloxymethyl group, an allyloxymethyl group, an aryloxymethyl group, or a heterocyclic thiomethyl group with or without a substituent. ] The present invention relates to a novel cephalosporanic acid derivative shown in the following.

Conventional techniques and their problems Conventionally, 3-chloro-7-D-(2-phenylglycinamide)-3-cephem-4-carmenic acid (cefachlor) represented by the following formula (2); 3) 7-[D-α-amino-α-(p-hydroxyphenyl)acetamido-3-methyl-3-cephem-4-carmenic acid (cefadroxil) represented by the following formula (4
) 7β-cyanomethylthioacetamide-7α-
Methoxy-3-((1-methyl-IH-tetrazole-
It is known that 5-yl)thio]methyl-3cephemu-4-cargenic acid (cefmetazole) and the like exhibit excellent antibacterial activity and are useful as cephalosporin antibiotics.

For this reason, various proposals have been made as methods for producing compounds such as the above formulas (2), (3), and (4). It is further desired to develop methods and intermediates that can be obtained with high yield and high purity.

Summary of the invention In view of the above circumstances, the present inventors have developed formulas (2) and (3).
, (4) etc. As a result of intensive research into efficiently producing compounds such as, for example, formula (5) described later,
(7), (9).

α0, R5, fi3), (15), (16), αl,
(21, (21, H, U, fi, etc.) by reacting an acylating agent with an acylating agent and then hydrolyzing this, the above formula (2), ( 3
), (4) and the like can be obtained in high yield and purity. Therefore, by passing the new compound of formula (1) as all intermediates in this way, formula (2)
, (3), and (4) can be efficiently synthesized, leading to the present invention.

The present invention will be explained in more detail below.

Structure of the Invention The novel cephalosylanic acid derivative according to the present invention Vζ has the above-mentioned formula (1), that is, (where X represents sulfur, oxygen, SO or SO□,
R1 represents hydrogen or a lower alkoxy group, R2 represents hydrogen, an acyl group, a substituted acyl group, a silyl group, or a substituted silyl group, and R3 represents a carbyxyl group.

represents a substituted carboxyl group or a salt of a carmexyl group,
R4 is hydrogen, a halodane atom, a droxymethyl group, a lower alkyl group, or a lower alkoxy group.

It represents a pyridyloxymethyl group, an acyloxymethyl group, an allyloxymethyl group, an aryloxymethyl group, or a heterocyclic thiomethyl group with or without a substituent. ).

In addition, here, the lower alkoxy group has 1 to 5 carbon atoms,
In particular, those from 1 to 3 can be mentioned.

Substituted acyl groups include phenylglycine, p-hydroxyphenylglycine, cyanomethylthioacetic acid, (2-
aminothiazol-4-yl)acetic acid, tetrazolylacetic acid, 4-pyridylthioacetic acid or 2-cal? Ki-2-
Examples include groups obtained when reacting with an acylating agent such as (p-hydroxyphenyl)acetic acid or its reactive derivatives at the carboxyl group.

Substituted silyl groups include trimethylchlorosilane, triethylchlorosilane, propyldimethylchlorosilane,
Inbutyldimethylchlorosilane, octyldimethylchlorosilane, octadecylmethylchlorosilane, triprobylchlorosilane, tributylchlorosilane, tar
t-Gtylddimethylchlorosilane, tert-butyldiphenylchlorosilane, triphenylchlorosilane, phenyldimethylchlorosilane, RI00methyldimethylchlorosilane, 3-chloropropyldimethylchlorosilane, 1,2-bis(dimethylchlorosilyl)ethane, 1.
1,3.3-tetramethyl-1,3-dichlorosilane,
1.3-) chlorotetraisopropyldisiloxane,
Hexamethyldisiladene, 1,3-divinyl-1,1,
3,3-tetramethyldisiladene, 1,1,3.3-tetramethyldisiladene, 1,3-bis(chloromethyl)
1.1,3.3-tetramethyldisiladene, trimethylsilyldimethylamine, trimethylsilyldiethylamine, anilinotrimethylsilane, bis(,dimethylamino)dimethylsilane, bis(dimethylamine)methylsilane, trimethylsilylimidazole, N,O-bis( trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N,N'-bis(trimethylsilyl)urea, N-trimethylsilylacetamide, N-methyl-N-)dimethylsilylacetamide, N- Methyl-N-(trimethylsilyl)trifluoroacetamide, trimethylsilyltrifluoromethanesulfonate, tert-butyldimethylsilyl-
Examples include groups obtained when a silylating agent is reacted with trifluoromethanesulfonate, N,0-bis(trimethylsilyl)-sulfonate, trimethyliodosilane, aryltrimethylsilane, vinyltrimethylsilane, and ethynyltrimethylsilane. It will be done.

Substituted carboxyl groups include phenyl-substituted methyl groups, tsrt-butyl groups, jert-amyl groups, whose hydrogen atoms have or do not have a substituent group on the benzene nucleus, such as benzhydryl group, benzyl group, p-methoxybenzyl group. tert lower a-lower alkyl group, alkoxymethyl group such as noroxymethyl group, methoxymethyl group, phenacyl group with or without a substituent on the benzene nucleus such as p-romphenacil group, tricumylethyl group, etc. Examples include those substituted with an image-retaining group such as a polyhero-noethyl group, or a silyl group similar to the above-mentioned silyl group.

Carboxyl group salts include sodium, potassium,
Alkali metal salts such as lithium, or trimethylbenolamine, noethylbenolamine, dimethylcyclohexylamine, soethylcyclohexylamine, noisoprobylamine, norchlorhexylamine, tert-butylamine, tert-octylamine, methylbiyridine, Examples include addition salts such as amine salts of ethylpiperidine, benzylamine, 2-aminoethanol, jetanolamine, and the like.

Examples of the halodane atom include CL r Br r F and the like.

Examples of the lower alkyl group include those having 1 to 5 carbon atoms, particularly 1 to 3 carbon atoms.

Examples of the acyloxymethyl group include a carbamoyloxymethyl group and an acetoxymethyl group.

Examples of the aryloxymethyl group include a benzoyloxymethyl group.

As a heterocyclic thiomethyl group with or without all substituents, 2-(1,3,5-triazolo)thiomethyl, 5
-Methyl-1,3,4-thianoazolyl-2-thiomethyl, (1-methyl-IH-tetrazol-5-yl)thiomethyl, (1,2,3-triazol-5-yl)thiomethyl, (1-(2 -trimethylaminoethyl)-1H
-tetrazol)-5-yl)] monocyclic 5- or 6-membered thiomethyl group containing a sulfur or nitrogen atom, such as thiomethyl.

The compound of the present invention represented by the above-mentioned formula (1) has the above-mentioned (2)
), (3), (4) It is suitably used as an intermediate raw material in the production of various cephalosporin antibiotics such as compounds of formulas.

In this case, various cephalosporin antibiotics can be obtained by reacting the compound of formula (1) with the following acylating agent and the like. For example, the 7-(N-trimethylsilylamino)cephalosporanic acid trimethylsilyl ester of the present invention represented by the following formula (5) is reacted with 4-pyridylthioacetic acid or its reactive derivative at the carboxylic group represented by the following formula (6). Cephapirin can be obtained by making K.

Cefazolin can be obtained by reacting the compound of the present invention represented by the following formula (7) with tetrazolylacetic acid or its reactive derivative in the carboxyl group represented by the following formula (8).

The present invention compound represented by the following formula (9) or the present invention compound represented by the following formula αQ, and (2-aminothiazol-4-yl)acetic acid represented by the following formula α or a reactive derivative thereof in the carboxyl group. By reacting, ce7othium hydrochloride can be obtained.

The compound of the present invention represented by the following formula (6) or the following formula (6) COOCR (
The compound of the present invention represented by C6H5)2H and p- represented by the following formula α→
Cefatridine can be obtained by reacting with hydroxyphenylglycine or a reactive derivative thereof at the carbuxyl group, which can then be reacted with propylene glycol under certain conditions to obtain cefatridine propylene glycol.

The following formula α→ coos t (CH3).

The above (
2) Cefaclor of formula can be obtained.

In this case, new compounds shown in the following formulas (18m) to (18X) can be mentioned as reactive derivatives of the carboxyl group of phenylglycine, and these (18
Cefaclor can be favorably produced by reacting the novel compounds of formulas m) to (18K) with the compound of the present invention of formula (1). In addition, the following (18m) ~ (18:E)
In the compound of the formula, the NH2 group is appropriately protected as necessary.

That is, as the above derivative, as the active amide, H'
Examples of active esters include novel compounds such as Co2Me H.

Ryo New compounds such as

The present invention compound represented by the following formula α9coos i (CHs)s or the present invention compound represented by the following formula (7), and p-hydroxyphenylgrine represented by the following formula (Jl) or its cal? By reacting the xyl group with a reactive derivative, cefadroxil of the formula (3) can be obtained.

In this case, the following (22a
) to (22K), and by reacting these novel compounds of formulas (22a) to (22X) with the compound of the present invention of formula (1),
Cefadroxil can be produced successfully.

In addition, in the compounds of the following formulas (22m) to (22K), the NH2 group is appropriately protected as necessary.

That is, as the above derivative, as the active amide, H and L
J2M1! Examples of the active ester include novel compounds such as H RN H2, and active esters include novel compounds such as U i2.

The following ceremony OCR.

...The compound of the present invention represented by @ or the following formula (c)...
(Incorporated) and the compound of the present invention, which is water-weird with the following formula 4NCCH25CH2COOH... (e) Cyanomethylthioacetic acid or its carcinol? By reacting with a reactive derivative in the xyl group, the above (
4) Cefmetazole of formula can be obtained.

Here, the cyanomethylthioacetic acid of the formula (1) can be produced, for example, by reacting tosylglycolic acid with sodium cyanomethylthiothio, cyanomethylthiolithium, or the like (see reaction section below).

→NCCH25CH2COOH... Prisoner (However,
M represents hydrogen or an alkali metal such as sodium or lithium. ] In this case, the following (26m) to (26
)C) New compounds shown in formula (1) can be mentioned, and these new compounds of formula (26&) to (26X) and formula (1) can be mentioned.
By reacting with the compound of the present invention, cefmetazole can be successfully produced.

That is, as the above derivative, as the active amide, HCo
□Me ph ph NCCH2SCH2CON (J
Examples of active esters include novel compounds such as """ (lbm) or -7, and active esters include novel compounds such as OCCH28CH2CN 0=CCH2SCH2CN.

The following formula OCR.

・・・・・・ The compound of the present invention represented by (Foundation) or the compound of the present invention represented by the following formula (c) and 2-cartoxy-2- represented by the following formula Latamoxef can be obtained by reacting it with (p-hydroxyphenyl)acetic acid or its reactive derivative in the carboxylic group, and various other cephalosporin antibiotics can also be obtained in the same manner. be.

As described in detail of the invention, the novel hepphalosporanic acid derivative of the formula (1) according to the present invention has the following compounds: (2), (3) s
It is effectively used as an intermediate in the production of compounds of formula (4), etc., and these (2), (3)? The compound of formula (4) etc. can be obtained with high efficiency.

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

[Example 1] 2.7211 of 7-aminocephalosporanic acid was suspended in 501 dK of anhydrous methylene chloride, and bis(trimethylsilyl)
Add 5.148.9Y of trifluoroacetamide and stir at room temperature for 30 minutes. Next, the mixture was cooled to KO', 2.6881 of 4-pyridylthioacetic acid chloride hydrochloride was added, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. After that, the solvent was distilled off under reduced pressure, a mixture of methanol 104 and water 50M was added, and while cooling and stirring, triethylamine was added and the pH was adjusted to 3.
Adjust to 1 and analyze. The crystals were separated, washed with acetone, and dried under reduced pressure to obtain 7-(4-pyridylthioacetamide).
] Cephalosporanic acid 4. Obtain OIF. Yield 94.8
% [Example 2] α-diphenylmethoxycardenyl-α-p-hydroxyphenyl vinegar W11.27. F is anhydrous methylene chloride 15
Dissolve in 11 Ll Triethylamine 0.41 at Qo
5d and 0.2551d of oxalyl chloride are added and stirred for 15 minutes.

7β-amino-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-5-oxazothia-
3-cephem-4-carboxylic acid benzhydryl ester 0.509. Bis(trimethylsilyl)acetamide 0.407 in anhydrous methylene chloride 20rILl solution containing F
．． 9 and stir at room temperature.

After 30 minutes, the reaction solution was added dropwise while cooling to O'',
After stirring at the same temperature for about 30 minutes and then stirring at room temperature for 2 hours, the reaction solution was distilled off under reduced pressure. Add 40ml of ethyl acetate to the residue and add carbonate.) Wash sequentially with an aqueous solution of IJum, water, dilute hydrochloric acid, water and saturated brine, dry over magnesium sulfate, and concentrate under reduced pressure. The residue was purified by silica del chromatography to give 7β-(α-nophenylmethoxyrudenyl-α-p-hydroxyphenylacetamide)-7α-
Methoxy-3-(1-methyltetrazol-5-yl)
Thiomethyl-1-oxazothia-3-cephem-4-cargenic acid benzhydryl ester 0.7011 is obtained.

Yield: 82.4 [Example 3] The formula below... OCR.

......(a) The present compound 7β-amino-7α-methoxy-3-(1)I-tetrazol-5-yl)thiomethyl-3-cephem-4-carpinic acid benzhydryl ester is By dissolving it in anhydrous methylene chloride and reacting it with amine and trimethylsilyltrifluoromethanesulfonate under water cooling or at room temperature,
The compound of the present invention of formula (c) is obtained.

Next, the compound of formula (c) produced by the above reaction is NM
Confirmed by R. That is, the compound of the above formula (1) was dissolved in methylene chloride, diisopropylethylamine and trimethylsilyltrifluoromethanesulfonate were added thereto under water cooling, and after stirring, the reaction solution was measured by NMR, and the 7-amino group was A trimethylsilylation peak was observed at 0.196 ppm.

[Example 4] 0.81' of 7β-amino-7α-methoxy-3-(IH-tetrazol-5-yl)thiomethyl-3-cephem-4-cargenic acid benzhydryl ester was dissolved in 3211 L of methylene chloride. , 70.251 of ethyl diisopropylamide and 0.361 of trimethylsilyltrifluoromethanesulfo+-) were added under ice-cooling and stirring, and 1 was added at room temperature.
The solution was stirred for an hour, cooled again on ice, 0.22 g of triethylamine was added, and then cyanmethylthioacetyl N
, N-bis[2-oxo-3-oxazolidinylphosphorodiamidi) 0.69811 is added. Stirring at room temperature completes the reaction.

The reaction solution was washed once with water, twice with an aqueous potassium hydrogen sulfate solution, and once again with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to give 7β-cyanmethylthioacetamide-7α-methoxy-3-( 1-Methyl-IH-tetrazol-5-ylcothiomethyl-3-cephem-4-
Calgenic acid pendzquidryl ester is obtained.

The ester group of this 7β-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-IH-tetrasol-5-yl)thiomethyl-3-cephem-4-cargenic acid benzhydryl ester was added with trifluoroacetic acid-anisole. 7β-cyanmethylthioacetamide-7α-methoxy-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-
Calzenic acid (cefmetazole) is obtained.

[Example 5] 7β-amino-7α-methoxy-3-(1-methyl-I
H-tetrazol-5-yl) thiomethyl-3-cephem-4-calgen benzhydryl ester (2.1 g) was dissolved in 80 d of methylene chloride, and under stirring under water cooling, 0.62 y of ethyldiisopropylamine + ) 'J memethi Add 0.89 g of silyl trifluoromethanesulfone,
Stir for 1 hour at room temperature.

Then cool and add 2.42.9 of N,N-damethylaniline, followed by 0.42.9 of N,N-damethylaniline, followed by 0.95% of cyanmethylthioacetyl chloride.
Add 72.9.

After stirring at the same temperature for 1 hour, the reaction solution was washed twice with IN hydrochloric acid, once with water, and once with an aqueous solution of 5% hydrogen carbonate. Next, after drying over anhydrous magnesium sulfate, the solvent was distilled off to give 7β-cyanomethylthioacetamide-7.
α-methoxy-3-(1-methyl-IH-tetrazol-5-ylcothiomethyl-3-cephem-4-cargenic acid benzhydryl ester is obtained.
The analysis results by MH are shown below.

・Nuclear magnetic resonance frequency δppm (CDCl2)3
．． 40(4H, - double line, NCCH25CH2CO-)3
．． 45(3I(,-double line,-QC)I3)3.75(2
H, quartet, 2nd position CH,) 3.82 (3) I, - doublet,
Tetrazole N-OH,) 4.30 (2H, quartet, 3
position CH25-) 4.98 (IH, - double line, 6th position H) 6.95 (IH, - double line, C00CHPh2) 7.3
5 (LH, - heavy line, coocH (c6 ships 5] 2) this 7β-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-IH-tetrasol-b-yl)
The ester group of thiomethyl-3-cephem-4-cargenic acid diphenylmethyl ester was removed with trifluoroacetic acid-anisole to give 7β-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-IH-tetrazole-5- yl)thiomethyl-3-cephem-4-caldenic acid (cefmetazole) is obtained. The analysis results for this compound are shown below.

・Nuclear magnetic resonance spectrum δppm (heavy acetone) 3
．． 50 (3H, - double line, 7th position OCR,) 3.60 (2H
,-double line, NCCH25 or -5cu2co)3
．． 5-3.7C2H, quartet, 2nd position I (2) 3.70 (
2H, - heavy line, NCCH25 or -5CI (2Co
) 3.98 (3H, - double line, N-CH,) 4.3~
4.6 (2H, quartet, 3rd position -CH2S-)5.10
(LH, - double line, H at position 6) [Example 6] 7β-amino-7α-methoxy-3-(1-methyl-I
H-tetrazol-5-ylcothiomethyl-3-cephem-4-caldenic acid R-hydryl ester 0.84.
9 was dissolved in 20 m of dry DMF, and 0.25 I of ethyldiimprobylamine and 0.31 l of trimethylsilyl triple olomethane sulfone were added thereto under stirring while cooling with water, and the mixture was stirred at room temperature for 1 hour.

This solution was cooled on ice again, and 3-(cyanomethylthioacetyl)-1,3-thiazolidine-2-thio 70.45N
Add and stir for 1 hour.

Add the reaction solution to water, collect the precipitate with F, and dry it to obtain 7β-7.
7-methylthioacetamide 7α-methoxy-3-(
1-Methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-cargenic acid benzhydryl ester is obtained.

The ester group of this 7β-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-IH-tetrazol-5-ylcothiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester) was
Elimination with anisole gave 7β-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4.
- Obtain carbic acid (cefmetazole).

[Example 7] A suspension of 7-amino-3-chloro-3-cephem-4-cargenic acid benzhydryl ester 0.4I in dry acetonitrile 15a/1 was stirred at room temperature while bis(trimethylsilyl)acetamide 0.407 Add .9 and stir at the same temperature for 30 minutes.

Add 0.248.9 of N-(phenylglycylamido-imidazole) to this solution and stir at room temperature for 2 hours.The reaction solution was distilled off under reduced pressure, and the residue was 301111 ethyl acetate.
Add and remove insoluble matter. IJ
Wash sequentially with umum aqueous solution, water, dilute hydrochloric acid, water, and saturated saline,
After drying with magnesium sulfate, concentrate under reduced pressure. The residue was purified by silica del column chromatography to %7-[
D-α-phenylglycylamide]-3-chloro-3-
Cephem-4-cargenic acid penzhydryl ester is obtained in high yield.

Then, this 7-(D-α-phenylglycylamide)
The ester group of -3-chloro-3-cephem-4-carmenic acid diphenylmethyl ester was removed with trifluoroacetic acid-anisole and 7-(D-α-7enylglycylamide)-3-chloro-3- Cephem-4-carbic acid (
Obtain (Self End Crawl).

Claims (1)

[Claims] 1. The following formula (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(1) (However, X represents sulfur, oxygen, SO or SO_2,
R_4 represents hydrogen or a lower alkoxy group, R_2 represents hydrogen, an acyl group, a substituted acyl group, a silyl group, or a substituted silyl group, R_3 represents a carboxyl group substituted with a carboxyl group or a salt of a carboxyl group, R_4 represents hydrogen,
halogen atom, hydroxymethyl group, lower alkyl group,
It represents a lower alkoxy group, a pyridyloxymethyl group, an acyloxymethyl group, an allyloxymethyl group, an aryloxymethyl group, or a heterocyclic thiomethyl group with or without a substituent. ) Cephalosporanic acid derivatives.