JPH0357105B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new cefem derivative and a method for producing the same, and more particularly to a cefem compound that is a new synthetic intermediate useful for synthesizing a cephalosporin antibiotic having a methoxy group at the 7-position, and its production method. Regarding the manufacturing method.

Cefamycin antibiotics are found in nature as a group of cephalosporin antibiotics that have a methoxy group at the 7-position, and are known to exhibit excellent antibacterial properties due to their structural feature of having a methoxy group at the 7-position. Since its introduction, a large number of 7-methoxycephalosporin derivatives have been synthesized. On the other hand, many new methods for chemically introducing a methoxy group into the 7-position of the cefem nucleus have been studied.

Some of these new derivatives have been evaluated as excellent antibacterial agents and are used in actual medical treatment as chemotherapeutic agents. Therefore, the method of chemically introducing a methoxy group into the 7-position of the cephalosporin bone core (especially the cephalosporin core) is extremely important industrially, and many methods have been proposed so far. For example, the following methods are available.

(1) 7 (or 6)-acylaminocephalosporin (or penicillin) in the presence of a strong base.
The so-called acylimine method (J.Am.Chem.Soc. 95 , 2401) involves reacting with a positive halogen compound such as butyl hypochlorite to form the corresponding acylimino compound, and adding methanol to this.
(1973)).

(2) 7 produced by introducing the amino group at the 7 (or 6) position into a Schiff base and reacting with a strong base.
The so-called carbanion method involves reacting the corresponding carbanion at the (or 6) position with methanethiosulfonate or a positive halogen compound to form a 7 (or 6)-methylthio form or -halo form, and then substituting this into a methoxy group with methanol. (J.Org.Chem., 38 , 943 (1973)).

(3) 3,5-di-t at the 7 (or 6) position amino group
- A methoxy introduction method in which methanol is added to the imine after oxidizing Schiff's base with butyl-4-hydroxybenzaldehyde to a quinone imine (Te-trahedron letters., 1975.2705).

(4) After iminohalogenation of α-halo or α,α-dihaloacetamidocephalosporin (or penicillin) or its vinylogue, the iminoether derived by substitution with methanol is 1,4-deactivated. A method of forming a vinylimine compound with hydrogen halide and adding methanol to the 1,4-position (Tetrahedron letters.
1976.1307).

(5) A method of oxidizing 7 (or 6)-sulfenamide cephalosporin (or penicillin) to the corresponding sulfenimine form and adding methanol to this [J.Am.Chem.Soc., 99 , 5505
(1977)].

(6) diazotizing the amino group at the 7 (or 6) position,
A method characterized by an addition reaction of an azide compound such as a halogenated azide to this [J.Am.Chem.
Soc., 94 , 1408 (1972)], etc.

However, each of the above-mentioned methods has the following drawbacks and difficulties, and therefore is difficult to be satisfied as an industrial method, and there is a demand for the development of an even better method.

Since method (1) uses a strong oxidizing agent, it has the disadvantage that oxidation by-products are likely to be produced when there is a side chain that is easily oxidized, especially a side chain that contains a sulfide bond. Methods (1), (2), and (4) require special reaction conditions such as extremely low temperatures (-78℃) and are susceptible to cleavage of β-lactam rings such as lithium methoxide. The disadvantage is that a strong base must be used. In addition, methods (3) and (5) involve a heterogeneous reaction using a large excess of metal oxide (solid) as an oxidizing agent, but this heterogeneous reaction is difficult to implement on an industrial scale. There are drawbacks such as difficulty in controlling homogeneous reactions. In addition, method (6) has drawbacks such as low yield because the addition of the azide compound is not stereospecific, and the reaction route is long and complicated.

The first object of the present invention is to provide an extremely useful intermediate compound for producing 7-methoxycephalosporin derivatives.

A second object of the present invention is to provide a method for producing the intermediate compound.

The cefem derivative found by the present inventors and useful as an intermediate compound is a new compound and is represented by the following formula ().

[In the formula, R ¹ is a hydrogen atom or a group -A-B (where A is an oxygen atom or a sulfur atom, and B is at least one hetero group selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom) a substituted or unsubstituted heterocyclic group containing atoms as ring members; or a substituted or unsubstituted carbamoyl group; R ² represents a hydrogen atom or a protecting group for a carboxyl group; R ³ represents a lower alkyl Represents a group; R ⁴
represents a lower alkyl group or a phenyl group. ] Note that examples of the substituent that the heterocyclic group which is one embodiment of B constituting R ¹ may have include a lower alkyl group, an aminoalkyl group, a carboxylalkyl group, a sulfoalkyl group, and the like. Specific examples of such heterocyclic groups include 1H-tetrazol-5-yl group, 1-methyl-tetrazol-5-yl group, 1-carboxymethyl-1H
-tetrazol-5-yl group, 2-carboxymethyl-1H-triazol-5-yl group, 1-sulfoethyl-1H-tetrazol-5-yl group,
2-carboxymethyl-1-methyl-1H-triazol-5-yl group, 4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,
Examples include 4-triazylyl-3-yl group, pyridiniummethyl group, triazolyl group, thiadiazolyl group, and the like. B may be a substituted or unsubstituted carbamoyl group, and the substituted carbamoyl group includes, for example, a mono-substituted carbamoyl group and a di-substituted carbamoyl group substituted with an alkyl group.

Furthermore, R ² is a hydrogen atom or a protecting group for a carboxyl group, and as a protecting group for a carboxyl group, a protecting group commonly used in the field of penicillin and cephalosporin is used, such as a tert-butoxy group. . Further, as the halogen atom for ^R5 , chlorine, bromine, and iodine are generally used.

The above-mentioned compound of the present invention () can be produced according to the following reaction route.

(In the above formula, R ¹ , R ² , R ³ and R ⁴ have the above-mentioned meanings, and R ⁵ represents a halogen atom.) Hereinafter, the method for producing the compound of the present invention ( ) will be described according to the above formula. I will explain in detail.

That is, aldehyde R ³ R ⁴ R ⁵ CCHO (wherein R ³ , R ⁴ and R ⁵ have the above-mentioned meanings) or a reagent equivalent thereto is added to the 7-aminocephem compound (),
By reacting in a conventional manner, the corresponding Schiff base () can be obtained.

Next, an appropriate acid scavenger is applied to the obtained Schiff base () to efficiently dehydrohalogenate it, and an imine compound, which is a new cefem derivative represented by the general formula (), is produced. Obtained in good yield. Acid scavengers used here include solid deoxidizers such as alumina, silica gel, zeolites (such as molecular sieves), basic resins; pyridine, triethylamine, triethylenediamine, diazabicyclononene (DBN), diaza Organic tertiary amines such as bicycloundecene (DBU); metal alkoxides such as lithium methoxide and potassium t-butoxide; metal amides such as lithium diisopropylamide; metal hydrides such as sodium hydride, sodium bicarbonate, and borax. Examples include basic inorganic salts such as. Among these, particularly suitable is alumina.

As described in detail above, the steps from the compound of formula () to the cefem derivative of formula () according to the present invention are carried out under mild conditions using an inert solvent. The compound of formula (), which is an intermediate product, may be isolated and proceed to the next step, but the reaction may also be proceeded continuously without isolation.

The above Cefem derivative () according to the present invention is
By treating with methanol in the presence or absence of an acid catalyst under very mild conditions as shown below, for example at 0° C., 7- of the formula () can be obtained. Methoxy
It can be converted to Schiff base with high selectivity and good yield.

[In the formula, R ¹ , R ² , R ³ and R ⁴ have the above-mentioned meanings. ] The obtained Schiff base compound () is either hydrolyzed and then acylated by reacting with acyl chloride (R ⁶ COCl), or directly acylated with acyl chloride (R ⁶ COCl) and then hydrolyzed. By doing the following formula (): [In the above formula, R ¹ and R ² have the same meanings as above,
R ⁶ represents alkyl, haloalkyl, aralkyl, etc. ] 7-acylamino-7-methoxy-3 represented by
- Can lead to cefem compounds. Based on this reaction, useful antibiotics (The Journal
of Antibiotics, 554 (1976), patent application 1976
-123159, reference) can be induced.

Furthermore, the cefem derivative represented by the formula () can be converted into the compound of the formula () in one step by adding methanol in the presence of a Lewis acid and a methyl orthoester.

Examples of Lewis acids include boron trifluoride/ether complex, titanium tetrachloride, and zinc chloride.
In addition, examples of methyl orthoesters include trimethylborate, tetramethylorthotitanoate,
Examples include aluminum trimethoxide, tetramethylorthosilicate, trimethylorthoformate, tetramethylorthocarbonate, methyltrimethylsilyl ether, and lithium methoxide. Furthermore, when the reaction is carried out in the presence of methyl orthoesters, methanol is not necessarily required.

By using an acyl chloride, the compound of formula () can be converted into a compound of formula (), which can further be converted into a useful antibiotic as described above.

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

Example 1 7-(2'-methyl-1'-propenylimino)-
3-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (1) 7-β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (4.95 g, 10.0 mmol) in methylene chloride (70 ml)
To the solution is added a solution of 2-chloro-2-methylpropanal (1.17 g, 11.0 mmol) in methylene chloride (5 ml) under ice cooling, followed by anhydrous magnesium sulfate (5 g). After stirring for 1.5 hours at room temperature,
The reaction solution was filtered, the filtrate was concentrated to dryness under reduced pressure,
7β-(2'-chloro-2'-methylpropylideneamino)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid benzhydryl ester (5.84g)
I got it.

(2) The Schiff base obtained in (1) was dissolved again in methylene chloride (200 ml) without isolation and purification, and under ice cooling, alumina (activity level -) (120 g) was added and stirred for 1 hour. The alumina was removed by filtration, concentrated under reduced pressure, and the resulting crystals were recrystallized from dimethyl sulfoxide (30 ml) to give the title compound (2.16 g,
(Yield 139%) was obtained as pale yellow crystals.

mp215°−218° (decomposition) NMR (CDCl ₃ ) δppm: 1.90 (3H, s), 2.05
(3H, broad s), 3.70 (2H, broad s), 3.82
(3H, s), 4.17 (1H, d, J=14Hz), 4.46
(1H, d, J=14Hz), 5, 27 (1H, s), 6.60
(1H, broad s), 6.96 (1H, s), 7.1~7.7
(10H, m) IR (KBr tablet method) cm ^-1 : 1765, 1710 MS (FD): 546 (M ⁺ ) Reference example 1 7-bromoacetylamino-7-methoxy-
3-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (1) 7-(2'-methyl-1'-propenylimino)-
3-(1-Methyl-1H-tetrazol-5-yl)-4-carboxylic acid benzhydryl ester (200 mg, 0.366 mmol) in methylene chloride (10 ml)
Methanol (5 ml) and p-
Toluenesulfonic acid (4 mg) was added. After stirring for 3 hours under ice cooling, Girard T reagent (200 mg,
A solution of 1.19 mmol) in methanol (4 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Next, the reaction solution was concentrated to half its volume under reduced pressure, 30 ml of ice water was added, and the mixture was extracted with ethyl acetate (30 ml, twice). The ethyl acetate layer was washed with ice water (30 ml, twice) and dried over anhydrous magnesium sulfate to give 7-amino-
An ethyl acetate solution of 7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester was obtained.

(2) The ethyl acetate solution obtained in (1) was concentrated to 10 ml under reduced pressure, 30 ml of ethyl acetate was added thereto, and the solution was concentrated again to 5 ml under reduced pressure. -20 to this solution
dimethylaniline (0.070 ml,
0.55 mmol) followed by bromoacetyl bromide (0.050 ml, 0.55 mmol). The reaction solution,
After stirring for 10 minutes under ice cooling, add ice water (30 ml),
Extracted with ethyl acetate (50ml). The ethyl acetate layer was diluted with ice-cooled saturated aqueous potassium hydrogen sulfate solution (20%
ml, 3 times), ice water (20 ml), ice-cooled saturated aqueous sodium bicarbonate solution (20 ml), and saturated brine (20 ml), and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was isolated and purified by silica gel thin layer chromatography to obtain the title compound (139 mg, yield 59%) as a white foam. (Rf value: 0.70, benzene:ethyl acetate=1:1).

Reference example 2 7-bromoacetylamino-7-methoxy-
3-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (1) 7-(2'-methyl-1'-propenylimino)-
3-(1-Methyl-1H-tetrazol-5-yl)-4-carboxylic acid benzhydryl ester (200 mg, 0.366 mmol) in methylene chloride (10 ml)
Trimethylborate (1 ml) was added to the solution under ice cooling.
Boron trifluoride ether complex (0.050 ml) and methanol (0.5 ml) were added sequentially. below freezing,
After stirring for 2 hours, the reaction solution was added to a mixture of saturated aqueous sodium hydrogen carbonate solution (20 ml) and ice (20 g), and extracted with ethyl acetate (30 ml). The organic layer was washed with saturated brine (20 ml) and dried over anhydrous magnesium sulfate to obtain an ethyl acetate-methylene chloride solution of 7-amino-7-methoxy-3-cephem-4-carboxylic acid benzhydryl ester. .

(2) The solution obtained in (1) was treated in the same manner as in Example 2 (2) to obtain the title compound (127 mg, yield: 53%) as a white foam.

Example 2 7-(2'-phenyl-1'-propenylimino)
-3-(1-methyl-1H-tetrazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (1) 7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (2.97 g, 6.00 mmol) in methylene chloride (60 ml)
2-chloro-2-phenylpropanal (1.11 g, 6.60 mmol) was added to the solution under ice cooling, followed by anhydrous magnesium sulfate (6 g). After stirring at room temperature for 2 hours, the reaction solution was filtered and 7β
-(2'-chloro-2'-phenylpropylideneamino)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-
A methylene chloride solution of carboxylic acid benzhydryl ester was obtained.

(2) Add more methylene chloride to the methylene chloride solution obtained in (1) to make a total volume of 200 ml. This solution was cooled to -20℃ and alumina (activity ~)
(120g) and stirred at the same temperature for 1 hour. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography.
(Using 200 g of silica gel and eluting with methylene chloride.) The fractions containing the target product (Rf value: 0.65, benzene: ethyl acetate = 5:1) were combined and concentrated, and the title compound as yellow crystals was extracted with 1' -1.46g (40%) was obtained as a mixture of E and Z. mp152~160°
(Decomposition) NMR (CDCl ₃ ), δppm: 2.50 (3H, broad
s), 3.77 (2H, broad s), 3.85 (3H,
s), 4.19 (1H, d, J = 14Hz), 4.49 (1H,
d, J=14Hz), 5.33+5.43 (1H), 6.98
(1H, s), 7.05-8.00 (16H, m) IR (KBr tablet method) cm ^-1 : 1765, 1710 Reference example 3 7-(bromoacetyl)amino-7-methoxy-3-(1-methyl-1H -tetrazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (1) 7-(2'-phenyl-1'-propenylimino)
-3-(1-methyl-1H-tetrazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (90.0 mg,
0.148 mmol) in methylene chloride (5 ml),
Methanol (1 ml) and p-toluenesulfonic acid (1 mg) were added under ice cooling, and the mixture was stirred for 45 minutes.
The reaction solution was added to an ice-cooled saturated aqueous sodium hydrogen carbonate solution (20 ml), and extracted with methylene chloride (20 ml). The methylene chloride layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was dissolved in ethyl acetate (2 ml), a solution of Girard T reagent ((carboxymethyl)trimethylammonium chloride hydrazide) (100 mg, 0.600 mmol) in methanol (3 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was added to ice water (20ml) and extracted with ethyl acetate (2x20ml).

The ethyl acetate layer was washed with ice water (20 ml x 2), dried over anhydrous magnesium sulfate, concentrated to 2 ml, and extracted with 7-amino-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl. An ethyl acetate solution of -3-cephem-4-carboxylic acid benzhydryl ester was obtained.

(2) The amino ester solution obtained in (1) was bromoacetylated in the same manner as in Example 4 to obtain the title compound (43 mg, yield: 45%).

Reference example 4 7-(bromoacetyl)amino-7-methoxy-3-(1-methyl-1H-tetrazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (1) 7-(2'-methyl-1'-propenylimino)-
3-(1-methyl-1H-tetrazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (200mg,
Methanol (1 ml) was added to a solution of 0.366 mmol) in methylene chloride (10 ml), and then titanium tetrachloride (0.040 ml, 0.37 mmol) was added dropwise at -78°C. After stirring at the same temperature for 2 hours, the reaction mixture was poured into an ice-cooled saturated aqueous sodium carbonate solution (20 ml) and extracted with methylene chloride (2x20 ml). The methylene chloride layer was washed with ice water (20 ml x 2), dried over anhydrous magnesium sulfate, and concentrated to 5 ml.
Add 30 ml of ethyl acetate and concentrate again to 5 ml.
Add Girard T reagent ((carboxymethyl)trimethylammonium chloride hydrazide) (200 mg, 1.20 mmol) to this solution in methanol (5 ml).
The solution was added and stirred at room temperature for 30 minutes. Add the reaction solution to ice water (20ml) and add ethyl acetate (2x20ml)
Extracted with. The ethyl acetate layer was diluted with ice water (20 ml x 2
After washing with 5 times) and drying with anhydrous magnesium sulfate,
Concentrate to ml, 7-amino-7-methoxy-3
An ethyl acetate solution of -(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester was obtained.

Reference example 5 7-(bromoacetyl)amino-7-methoxy-3-(1-methyl-1H-tetrazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (1) 7-(2'-methyl-1-propenylimino)-
3-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (200 mg,
Methanol (1 ml) was added to a solution of 0.366 mmol) in methylene chloride (10 ml), and then boron trifluoride ether complex (0.050 ml,
0.37 mmol) was added dropwise. After stirring at the same temperature for 2 hours, the reaction solution was poured into ice-cooled saturated aqueous sodium carbonate solution (20 ml), and methylene chloride (20 ml
2 times). The methylene chloride layer was washed with ice water (20 ml x 2), dried over anhydrous magnesium sulfate, and concentrated to 5 ml. ethyl acetate 30ml
was added and concentrated again to 5 ml, and a solution of Girard T reagent ((carboxymethyl)trimethylammonium chloride hydrazide) (200 mg, 1.20 mmol) in methanol (5 ml) was added, followed by stirring at room temperature for 30 minutes. The reaction solution was added to ice water (20ml) and extracted with ethyl acetate (2x20ml). The ethyl acetate layer was washed with ice water (20 ml x 2), dried over anhydrous magnesium sulfate, and concentrated to 5 ml to give 7-amino-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl- An ethyl acetate solution of 3-cephem-4-carboxylic acid benzhydryl ester was obtained.

(2) The solution of the amino ester obtained in (1) was bromoacetylated in the same manner as in Example 4 to obtain the title compound (142 mg, yield: 60%).

Claims (1)

[Claims] Linear formula [In the formula, R ¹ is a hydrogen atom or a group -AB (where A is an oxygen atom or a sulfur atom, and B is at least one heterozygous group selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. a substituted or unsubstituted heterocyclic group containing atoms as ring members; or a substituted or unsubstituted carbamoyl group; R ² represents a hydrogen atom or a protecting group for a carboxyl group; R ³ represents a lower alkyl group represents;
R ⁴ represents a lower alkyl group or a phenyl group] A cefem derivative represented by the following. Quadratic equation [In the formula, R ¹ is a hydrogen atom or a group -AB (where A is an oxygen atom or a sulfur atom, and B is at least one heterozygous group selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. R ² represents a hydrogen atom or a protecting group for a carboxyl group; R ³ represents a lower alkyl group; Representation; R ⁴
represents a lower alkyl group or a phenyl group;
R ⁵ represents a halogen atom] is treated with an acid scavenger using the following formula: (In the formula, R ¹ to ^{R 4} are the same as above.) A method for producing a cefem derivative represented by the following. 3. The method according to claim 2, wherein the acid scavenger is alumina, an organic tertiary amine, a metal alkoxide, a metal amide, a metal hydride, or a basic inorganic salt. Quaternary formula [In the formula, R ¹ is a hydrogen atom or a group -AB (where A is an oxygen atom or a sulfur atom, and B is at least one heterozygous group selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. a substituted or unsubstituted heterocyclic group containing atoms as ring members; or a substituted or unsubstituted carbamoyl group; R ² represents a hydrogen atom or a protecting group for a carboxyl group. formula: (In the formula, R ³ represents a lower alkyl group; R ⁴ represents a lower alkyl group or phenyl group; R ⁵ represents a halogen atom) by reacting with an aldehyde represented by the following formula: (In the formula, R ¹ to R ⁵ are the same as above.) This compound is then treated with an acid scavenger to form the following formula: (In the formula, R ¹ to ^{R 4} are the same as above.) A method for producing a cefem derivative, which is characterized by obtaining a compound represented by the following formula.