JPH0776226B2 - New manufacturing method of cephalosporin antibiotics - Google Patents

Description

Detailed Description of the Invention

[0001]

This invention relates to formula (I)

[Chemical 8] [Wherein R ₁ is hydrogen, alkyl, phenol, carboalkoxyalkyl, acyl or carboxyalkyl, R ₂ is hydrogen, pivaloyloxymethyl or a carboxy protecting group, R ₃ is a 5-membered nitrogen-, oxygen- or sulfur-containing complex A ring (this ring may be substituted with amino or azide), R ₄ is hydrogen, acetoxy, carbamoyloxy or —S—Y (wherein Y is an optionally substituted heterocycle)] Meaning]].

[0002]

The compounds of formula (I) are described, for example, in West German Patent Publication No. 2223.
No. 375, No. 2556736, No. 2702501
No. 2,707,565, No. 2,715,385, No. 2,992,036, and many other patents, as well as known useful cephalosporin antibiotics disclosed in other publications. This type of antibiotic is characterized by the presence of an oximino group on the 7-acylamide side chain that binds to the cephalosporin nucleus. The oximino group can have a syn or anti configuration,
It is already known that the syn isomer is more preferred.

The heterocycle of R ₃ preferably has one or more oxygen and / or sulfur atoms as heteroatoms. However, it may also have one or more nitrogen heteroatoms. Suitable heterocycles include
Furyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl and oxadiazolyl are exemplified. The heterocycle may be unsubstituted as described above or may be substituted by amino or azide, preferably amino. Preferably, the heterocycle of R ₃ is thiazolyl,
It is preferably substituted by amino.

A particularly preferred group of the above syn isomers is of formula (Ia)

[Chemical 9] [Wherein R ₁ , R ₂ and R ₄ have the above-mentioned meanings].

In these structures R ₄ can be hydrogen. It may also be carbamoyloxy. However, acetoxy or -S-Y are preferred. Suitable heterocycles represented by Y are well known, for example from the many publications mentioned above. Examples of preferred heterocycles include thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, triazolylpyridyl, purinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl or triazinyl. These heterocycles may be unsubstituted or substituted, for example with up to 3 groups. Suitable substituents include C _1-4 alkyl, C _1-4 alkoxy, halogen, trihalo-C _1-4 alkyl, hydroxy, oxo, mercapto, amino, carboxy, carbamoyl, di- (C _1-4 ) alkyl. Examples are amino, carboxymethyl, carbamoylmethyl, sulfomethyl and methoxycarbonylamino. Heterocyclic moieties which are mentioned in the prior art as being particularly preferred are tetrazolyl, especially 1-methyl-1H-.
Tetrazol-5-yl, and triazinyl, especially 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-6-hydroxy-2- Methyl-5-oxo-as-triazin-3-yl or 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazine-
3-yl is exemplified. Preferably R ₄ is acetoxy,
1-methyl-1H-tetrazol-5-yl or 2,
5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl.

In these structures, R ₁ may be hydrogen. It may also be C _1-4 alkyl, preferably C _1-2 alkyl, especially methyl. Suitable phenalkyl groups include phen-C _1-4 alkyl, especially benzyl. R ₁ may also be carboalkoxyalkyl, such as carbo (C _1-2 ) alkoxy (C _1-4 ) alkyl, especially carbo (C _1-4 ) alkoxymethyl (eg carboethoxymethyl). Suitable acyl group is C
Examples are _2-5 alkanoyl or C _1-4 alkoxycarbonyl. R ₁ may also be carboxyalkyl, especially carboxy-C _1-4 alkyl (eg carboxymethyl).

As is well known in the cephalosporin field, the compounds are free acids (R ₂ = H) or salts thereof, such as salts of alkali metals or alkaline earth metals,
It may preferably be in the form of an alkali metal salt such as sodium salt. On the other hand, the compounds may be in the form of esters, for example pivaloyloxymethyl ester (R ₂ = pivaloyloxymethyl). Other carboxy protecting groups represented by R ₂ are well known and include acetoxymethyl, 1-acetoxyethyl, 1-ethoxycarbonyloxyethyl, 5-indanoyl or preferably hexanoylmethyl, phthalidyl, carboethoxymethoxymethyl or 3-carbethoxy-1-acetonyl is exemplified.

Particularly preferred compounds are of formula (Ib)

[Chemical 10] [Wherein R ′ ₄ is acetoxy, 1-methyl-1H-tetrazol-5-yl or 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3.
-Meaning yl] and salts thereof.

The compound of formula (Ib) is cefotaxime (C
efotaxim, R _'4 = acetoxy), SCF-1365
(R _'4 = 1- methyl -1H- tetrazol-5-yl)
And Ceftriaxone (Ro13-9)
904) (R _'4 = 2,5- dihydro-6-hydroxy -
2-Methyl-5-oxo-as-triazin-3-yl) as the sodium salt (Cefotaxim and SCE-13).
65) or the compound known in the form of the disodium salt (Ceftriaxone).

As mentioned above, the compounds of formula (I) are generally known and various production methods have been proposed. As one of the methods, the corresponding 7-aminocephalosporanic acid derivative (which may be protected) is represented by the formula (A):

[Chemical 11] [In the formula, R ₁ and R ₃ have the above-mentioned meanings] A method of acylating with a reactive derivative of the acid can be mentioned.

Among the various reactive derivatives that have been proposed are active esters. For the preparation of the syn isomer of formula (I), the reactive derivative of the acid of formula (A) must also be in the form of the syn isomer in the highest possible purity, the syn configuration of which in the subsequent step In particular, it should be as unaffected as possible in the acylation process. In the various reactive derivatives that have been proposed hitherto, particularly the active esters, the syn configuration is slightly unstable during production or use, so that the production of the anti isomer is increased, and as a result, the yield of the desired syn isomer is increased. There was a disadvantage of causing a decrease.

Another drawback that occurs in the preparation of the preferred compounds of formula (Ia) is that in practice it is necessary to protect the amino substituents of the side chain thiazolyl ring before the acylation step. Otherwise, a competitive reaction will occur,
It results in a significant reduction in the yield of the final product. However, introducing a suitable protecting group prior to the acylation step and removing it afterwards generally reduces the yield and purity of the desired final product, as well as extra reaction time, energy,
It involves labor and costs.

[0013]

The present invention provides the desired syn isomers in high purity and yield, in particular of formula (I
It provides a method by which the syn isomer of a) can be obtained in high purity and yield without the need to protect the amino substituent of the side chain thiazolyl ring.

More specifically, the present invention provides a process for preparing the syn isomer of formula (I) and salts thereof, said process comprising formula (II)

[Chemical 12] Wherein R ₁ is as defined above, R ′ ₃ is a 5-membered nitrogen, oxygen or sulfur containing heterocycle, which ring may be substituted with amino, protected amino or azide.

[Chemical 13] Is a 5- or 6-membered heterocycle (this ring may have 1 or 2 other heteroatoms selected from oxygen, nitrogen and sulfur in addition to the nitrogen atom, and may be substituted). Or optionally condensed to a benzene ring which may itself be substituted], a syn isomer of a compound represented by the formula (III)

[Chemical 14] [Wherein R ₂ and R ₄ are as defined above, R ₅ is hydrogen or an amino-protecting group], and the resulting product is optionally deprotected and, if necessary, A correspondingly obtained R ₂ is a process consisting of converting a compound of hydrogen to its salt or vice versa.

The above process is carried out in an inert organic solvent such as chlorinated hydrocarbons (eg methylene dichloride) or ethers (eg ethyl acetate), or a mixture of such solvent and water. Is appropriate. The reaction temperature is -40 to + 60 ° C, especially -15 to + 25 ° C, especially 0.
-20 ° C is suitable, and the reaction time is typically 0.5-
You can change between 48 hours. Suitably the reactants of formula (II) or formula (III) are used in stoichiometric equivalents. It is also suitable to use an excess of up to 25% of the compound of formula (II).

As mentioned above, for the preparation of compounds (and their salts) in which R ₂ is hydrogen, it is preferred that the carboxylic acid group of the starting material of formula (III) be protected. Suitable protecting groups are well known and are not limited to those mentioned above as possible definitions of R ₂ but also silyl ester protecting groups,
Particularly included is a trimethylsilyl protecting group, which can be introduced, for example, by reaction of N, O-bis-trimethylsilylacetamide with a free acid.

The 7-amino group of the starting material of formula (III) may also be protected as described above. Suitable protecting groups are well known and include, for example, silyl protecting groups such as the trimethylsilyl group, which groups can be introduced simultaneously when, for example, protecting the carboxylic acid group.

When the desired product R ₃ has an amino substituent on the heterocycle, the corresponding starting material of formula (II) may have this amino substituent either in free or protected form. Good. As mentioned above, protection is generally not required.
If nonetheless protection is desired, it may be achieved in the usual manner, and suitable protecting groups are well known.

After the reaction of the compounds of formula (II) and formula (III),
The subsequent deprotection step can be performed by a usual method. Similarly, the interconversion of the free acid (R ₂ = H) and its salts can be achieved by known methods. The product obtained can be isolated and purified by conventional methods.

The process of the invention therefore uses heterocyclic amides as the reactive derivative of the acid of formula (A). Surprisingly, it has been found that these amides can be prepared and used with virtually complete retention of the -C = N-syn configuration geometry. Furthermore, it was found that the amides do not self-react when an amino group is present in the heterocycle of these amides. Therefore, protection of this amino group is not necessary in the subsequent acylation (but of course it is not excluded if protection is of course desirable for some reason).

The syn isomer of formula (II) is new. In it

[Chemical 15] The type of ring is not limiting and factors such as the ease of formation and availability of starting materials determine the preferred compound. However, preferably the ring means 2-thioxopyridin-1-yl-2-thioxobenzothiazolin-3-yl. Preferred compounds of formula (II) correspond to the preferred end products, namely formula (IIa) and formula (IIb).

[Chemical 16] [Wherein R ₁ and

[Chemical 17] Is a syn isomer represented by the above meaning].

The syn isomer of formula (II) has the formula (IV)

[Chemical 18] It can be produced by appropriately amidating the syn isomer represented by the formula [wherein R ₁ and R ′ ₃ are as defined above]. Amidation can be carried out, for example, by using

[Chemical 19] [In the formula, two groups

[Chemical 20] Are the same and have a 5- or 6-membered heterocycle (which may have, in addition to the nitrogen atom, one or two other heteroatoms selected from oxygen, nitrogen and sulfur, and which may also be substituted. Or optionally fused to a benzene ring which may itself be substituted)].

The reaction is preferably carried out in the presence of tri (lower alkyl)-or tri (aryl) -phosphine or phosphite, especially triphenylphosphine.
The reaction temperature is, for example, −30 to + 50 ° C., particularly −20 to +2.
It may be 5 ° C, preferably -5 to + 5 ° C. The reaction is preferably carried out in an inert, non-hydroxy containing organic solvent (eg, a chlorinated hydrocarbon such as methylene chloride).
If a compound of formula (II) in which R ₃ is a protected amino-substituted heterocycle is desired, the amino protecting group can, of course, be introduced before or after the reaction.

[0024]

The syn isomer of formula (I) is a generally known antibiotic as mentioned above. In particular, the compound is tested in vitro as a serial dilution test, for example at a temperature of 0.01 to 50 μg / ml, and, for example, 0.1 to 100 mg / kg.
As shown in in vivo studies in mice at doses of (animal weight), a wide range of strains such as Staphylococcus aureus, Streptococcus pyrogenes
s), Streptococcus faecalis (Streptococcu
s faecalis), E. coli, Proteus vulgaris, Proteus mirabilis, Proteus
Morgani (Proteus morganii), Shigela disenteria (Shigelladysenteria), Shigella sonei (Shigel)
la sonnei), Shigella flexn
eri), Alcaligenes faculis
ecalis), Klebsiella aero
genes), Klebsiella pne
umoniae), Serata marcesce
ns), Salmonella Heidelberg
delberg), Salmonella typhimurium (Salmonella)
typhimurium), Salmonella enteritidis (Salmo)
nella enteritidis) and as an antibacterial agent against Neuseria gonorrhoae.

Therefore, the above compounds are useful as antibiotics having activity against bacteria. In this application,
The dose will, of course, vary with the compound used, the mode of administration and the treatment desired. However, in general, a daily dose of 1-6 g
Suitably 2 to 2 per day in divided doses of about 0.25 to about 3 g.
Satisfactory results are obtained when administered four times or as a specific formulation.

Compounds in which R ₂ is hydrogen may be used in the form of the free acid or a physiologically acceptable salt thereof, which salt is as active as the free acid. Examples of suitable salts include alkali metal salts and alkaline earth metal salts, particularly alkali metal salts such as sodium salts. The above compound can be mixed with a conventional pharmaceutically acceptable diluent or carrier and, if necessary, other excipients, and can be administered in the form of a capsule or injectable preparation.

The process and intermediate (II) of the present invention are similar to the process and intermediate of EP 37380. However, firstly, the intermediate (I
I) is prepared by substantially the same method described in the European application above and is isolated as substantially pure, and secondly, those intermediates which are amides are
It is surprising that it acts effectively as a reactive derivative of an acid of formula (IV) to obtain the desired product of formula (I).

The invention especially relates to a process for the preparation of compound (I) which comprises a compound of formula (II) which is substantially pure or at least a mixture thereof (for example a mixture with a compound of formula II of the above mentioned European application). , A mixture of compounds of formula (II) according to the invention which occupy at least 60%, preferably 70%, more preferably 80% and most preferably 90%.

[0029]

EXAMPLES Next, the present invention will be described with reference to examples. The temperature is indicated in degrees Celsius.

Example 1 7-{[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido} cephalosporanic acid [cefotaxime]. 2.72 g of 7-aminocephalosporanic acid are suspended in 50 ml of methylene dichloride. 3.5 ml of N, O-bis- (trimethylsilyl) acetamide are added and the mixture is stirred at room temperature until a clear solution is obtained. 3 [2-
3.5 g of (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetyl] benzothiazoline-2-thione are added and the mixture is stirred for 15 hours at 35-40 ° C. The solution is then extracted with 2 g of KHCO ₃ and 40 ml of water and the phases are separated by filtration. The aqueous phase is extracted at pH 2 with a mixture of ethyl acetate / n-butanol (8/2) and the aqueous phase is saturated with (NH ₄ ) ₂ SO ₄ before phase separation. The organic phase is Na
It is washed twice with 100 ml of Cl solution and evaporated to dryness. The crystalline residue is shaken with 100 ml of diethyl ether, filtered,
Wash with ether to give the title product. mp 205
C (decomposition), yield 4.2 g (92% of theory based on the pure syn isomer).

Example 2: 7-{[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido} -3-{[2,5-dihydro-6-hydroxy-2-] Methyl-5-oxo-as-triazine-3-
Il] thiomethyl} -3-cephem-4-carboxylic acid [ceftriaxone]. In a similar manner to that of Example 1, the title compound is obtained in pure form, using approximately equivalent amounts of the appropriate starting materials. mp 1
20 ° C (decomposition).

Example 3: 7-{[(2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido} -3- (1-methyl-1H-tetrazole-5-
Il) thiomethyl-3-cephem-4-carboxylic acid (S
CE1365). In a similar manner to that of Example 1 using approximately equivalent amounts of the appropriate starting materials, the title compound is obtained.

Example 4: 3- [2- (2-Aminothiazol-4-yl) -2-syn-methoxyiminoacetyl] benzothiazoline-2-thione [Compound (II)]. 2- (2-aminothiazol-4-yl) -2-syn-
10.1 g of methoxyiminoacetic acid, 20.3 g of bis (benzothiazol-2-yl) disulfide and 0.16 g of benzyltributylammonium bromide are suspended in 100 ml of anhydrous acetone at room temperature under a completely dry nitrogen atmosphere. The suspension is then triphenylphosphine 1
Mix with 6 g in small amounts at -5 ° C. Triethylamine (5.1 g) is added dropwise over 30 minutes, and then the temperature is raised to room temperature. The mixture was stirred at room temperature for 3 hours, cooled to -5 ° C,
Filter and wash with ice cold acetone. The crude product is recrystallized from tetrahydrofuran and dried to give a golden product. Decomposition point 274 °

IR spectrum: 3400 (st), 32
40 (m, s), 3100 (m), 2940 (w), 1
722 (st), 1600 (vst), 1533 (vs
t), 1460 (vst), 1370 (st), 131
5,1305 (vst, sh), 1280 (st), 1
230 (vst), 1185 (w), 1150 (st,
sh), 1120 (w), 1080 (m), 1045
(M), 1020 (w), 985 (st), 940
(M), 880 (w), 865 (vw), 850
(W), 840 (w), 790 (w), 750, 740
(St, sh).

The teachings of the present invention further enable the following: (B) Formula (IV)

[Chemical 21] [Wherein R ₁ and R ′ ₃ have the above meanings], the syn isomer of the compound is appropriately amidated,
Process for producing the syn isomer of formula (II). (B) Amidation is performed by the formula (V)

[Chemical formula 22] [In the formula, two groups

[Chemical formula 23] Are the same and have a 5- or 6-membered heterocycle (which may have, in addition to the nitrogen atom, one or two other heteroatoms selected from oxygen, nitrogen and sulfur, and which may also be substituted. Or optionally fused to a benzene ring which may itself be substituted]]. (C) Syn isomer of formula (II). (D) Formula (IIa)

[Chemical formula 24] [Wherein R ₁ and

[Chemical 25] Is a compound represented by the above meaning]. (E) Formula (IIb)

[Chemical formula 26] [In the formula,

[Chemical 27] Is a compound represented by the above meaning]. (F) 3- [2- (2-aminothiazol-4-yl)
2-Syn-methoxyiminoacetyl] benzothiazoline-2-thione.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 501/36 114 7602-4C // A61K 31/545 ADZ

Claims (4)

[Claims] 1. Formula (I): [Wherein R ₁ is hydrogen, alkyl, phenol, carboalkoxyalkyl, acyl or carboxyalkyl, R ₂ is hydrogen, pivaloyloxymethyl or a carboxy protecting group, R ₃ is a 5-membered nitrogen-, oxygen- or sulfur-containing complex A ring (this ring may be substituted with amino or azide), R ₄ is hydrogen, acetoxy, carbamoyloxy or —S—Y (wherein Y is an optionally substituted heterocycle)] A compound of formula (II) embedded image and a pharmaceutically acceptable salt thereof. Wherein R ₁ is as defined above, R ′ ₃ is a 5-membered nitrogen, oxygen or sulfur containing heterocycle, which ring may be substituted by amino or azide, Is a 5- or 6-membered heterocycle (this ring may have 1 or 2 other heteroatoms selected from oxygen, nitrogen and sulfur in addition to the nitrogen atom, and may be substituted). Or optionally condensed to a benzene ring which may itself be substituted], the syn isomer of the compound of formula (III) [Wherein R ₂ and R ₄ are as defined above, R ₅ is hydrogen or an amino-protecting group], and the resulting product is optionally deprotected and, if necessary, A method characterized in that the correspondingly obtained compound of R ₂ is hydrogen is converted into its salt or vice versa. 2. Formula (Ia): The method according to claim 1, which is for producing a syn isomer of the compound represented by: and a pharmaceutically acceptable salt thereof. 3. Formula (Ib): [Wherein R ′ ₄ is acetoxy, 1-methyl-1H-tetrazol-5-yl or 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-
The method according to claim 1, which is for producing a syn isomer of a compound represented by the formula: and a pharmaceutically acceptable salt thereof. 4. In the syn isomer of formula (III): The method according to any one of claims 1 to 3, wherein is 3-oxobenzothiazolin-2-yl.