KR890001284B1 - Process for preparing cephalosporin derivatives - Google Patents

Abstract

Title compds. (I)[R=(tetrazol-1-yl)methane, etc.; M=H, diphenyl methane, earth metals; X=(5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl, etc. were prepd.. Thus, 36g 6-nitrobenzotriazole was dissolved in 300ml anhyd. THF and 28ml triethyl amine. The mixt. was cooled, treated with 21.6ml N,N-dimethyl-sulfamoyl chloride, and stirred for 12hr. Tri-ethylamine.HCl was removed, concd., treated with n-Hexane, stood up at 0 ≰C for 3hrs, and washed with petroleum ether to give 53g 1-dimethylsulfamoyl-6-nitrobenzo triazole.

Description

Method for preparing cephalosporin derivatives by a novel acylation method

The present invention relates to a new process for the preparation of compounds of the general formula (I)

[In Formula (I), R is a (tetrazol-1-yl) methane group, a Cin-methoxyiminoyl- (furyl-2-yl) methane group, a Cin-methoxyiminoyl-(2-aminothiazole -4-yl) methane group, D-α-amino-α- (4-hydroxyphenyl) methane group or D-α-t-butoxy carbonylamino-α- (4-hydroxyphenyl) methane group , M represents a hydrogen atom or an alkaline earth metal or represents a diphenylmethane group, X represents a (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl group, a carbamoyloxymethyl group, (2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-triazin-3-yl) thiomethyl group or (1,2,3-triazol-4-yl) thiomethyl group. ]

The preparation method of the present invention is characterized by preparing a compound of formula (I) by condensing a compound of formula (IV) with an organic acid of formula (III) using a condensing agent of formula (II) It is done.

(Wherein R has the same meaning as described above and in some cases R represents an α-amino acid derivative in which an α-amine group is protected by a t-butoxycarbonyl group)

(In the formula, M and X have the same meaning as described above. However, in some cases, M may represent a diphenylmethyl group.)

As a method of acylating the amine group of β-lactam, an acid chloride method for producing an acylated β-lactam by converting an organic acid into an acyl halide and then reacting with a β-lactam, and then acting with a β-lactam after converting an organic acid into an anhydride The mixed anhydride method for producing acylated β-lactam is widely used. This acylation method sometimes has side reactions and violent reactions, which makes the reaction process difficult. Therefore, recently, an active ester method in which acylation reaction proceeds in high yield even under mild conditions has been widely developed.

That is, the organic acid is activated esterified using N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxybenzotriazole and dicyclohexylcarbodiimide, and then β-lactam reaction is performed. This is the method for producing a misfired β-lactam.

In particular, an active esterification method using 1-hydroxybenzotriazole has been widely developed because 1-hydroxybenzotriazole acts as an excellent leaving group as compared to other active ester methods. This is because it accelerates the substitution reaction. This method of active esterification using 1-hydroxybenzotriazole is dibenzotriazolyl carbonate, 1-force, which is simple to operate from the classical method of using dicyclohexylcarbodiimide as a method of preparing the active ester. Various developments have been made up to the manner of using oxybenzotriazole, 1-alkylsulfonyloxybenzotriazole and the like. For example, as disclosed in British Patent No. 2,098,216, German Patent No. 3,316,798, Tetrahedron Letters 1985, 1341, J. Org Chem., 1985, 50, 273, J. Antibiotics, 1986, 39,119, etc. The advantages of being gentle and yielding well are shown. However, this active esterification method has a disadvantage that it sometimes requires a long reaction time, and also has the disadvantage that some active esterification condensing agents are not stable and difficult to store at room temperature for a long time.

The present invention is to compensate for the disadvantages of the existing condensing agent to develop a new type of condensing agent which is very stable and very stable at the same time, using this condensing agent can be produced in the cephalosporin derivative in high yield under mild conditions It's about a new way.

타입으로 결합하고 있으며 비교적 안정하다고 알려져 있으며, 여기에서 Z는 할로겐 원자이거나 알콕시기를 나타낸다.The condensation agent of formula (II) of the present invention is a new sulfamoyloxybenzotriazole which is not known at all as a new condensing agent of sulfamoyl type. Compounds having sulfamoyl groups are not well-known forms of compounds because they have not been studied much compared to sulfone compounds or sulfinyl compounds. The structural characteristics of sulfamoyl compounds are as follows.

It is known to be bonded in a type and relatively stable, in which Z represents a halogen atom or an alkoxy group.

When the present invention is represented by the reaction scheme as follows.

(In the above scheme, R, M, X are as described above.)

The condensing agent of formula (ll) was prepared quantitatively by reacting N, N-dimethylsulfamoylchloride and 6-nitro-1-hydroxybenzotriazole at room temperature in the presence of a suitable organic base. As a solvent for this reaction, aprotic organic solvents such as tetrahydrofuran, ethyne ether, dimethylformamide, acetonitrile, dichloromethane and chloroform are preferable, and pyridine, triethylamine and the like are suitable as organic bases.

Compounds of formula (V) are prepared by reacting a condensing agent of formula (II) with an organic acid of formula (III) under a suitable base, with or without separating the compound of formula (V). The compound of formula (I) is prepared by reacting with the compound of (IV). That is, the compound of the general formula (I) can be easily prepared by condensing the organic acid of the general formula (III) with the compound of the general formula (IV) under a suitable base such as a condensing agent of the structural formula (II).

Suitable solvents for this reaction include dimethyl acetamide, diethylformamide, acetonitrile, dimethyl sulfoxide, N-methylpyrrolidine and the like, and tributylamine and triethylamine as bases. Organic bases, such as pyridine, are preferable. This condensation reaction is completed within 3 hours and the reaction temperature is very convenient because the manufacturing process is simplified to room temperature and the reaction operation is simple. When using 1- (N, N-dimethylsulfamoyl) oxybenzotriazole or 6-trifluoromethyl-1- (N, N-dimethylsulfamoyloxy) benzotriazole, similar to the condensing agent of formula (II), The acylation reaction of the desired condensation reaction does not proceed at room temperature. This fact indicates that sulfamoyl groups are quite stable, so that an electron attracting group must be present in the benzotriazole ring to activate the reactivity. To illustrate. It is believed that the compound of formula (II) of the present invention has a nitro group in the 6-position to activate the reactivity.

The advantages of the present invention are as follows.

First, the manufacturing process is very short because only the desired condensation reaction occurs independently without protecting the functional groups of the reactants.

Second, the isolation method of the target is very simple.

Third, the reaction time is short and the reaction conditions are mild.

Fourth, the yield of the target product is appropriate.

Fifth, the condensing agent is very stable and can be stored for a long time at room temperature.

Hereinafter, the present invention will be described in more detail with reference to the following examples, which are not intended to limit the scope of the present invention.

Example 1

Preparation of 1- (N, N-dimethylsulfamoyloxy) -6-nitrobenzotriazole

6-nitrobenzotriazole (36 g) is dissolved in anhydrous tetrahydrofuran (300 ml) and triethylamine (28 ml). When the solution is pink, it is cooled with ice water and 21.6 ml of N, N-dimethylsulfamoylchloride is slowly added dropwise over 15 minutes. The reaction is stirred at room temperature for 12 hours and the resulting triethylamine hydrochloride is filtered off.

The filtrate was concentrated under reduced pressure, followed by slight addition of normal-hexane to give pale yellow crystals. After standing at 0 ° C. for 3 hours, it is filtered and washed with petroleum ether. 53 g (92%) of 1-dimethylsulfamoyl-6-nitrobenzotriazole are obtained.

Melting Point: 80-81 ℃

IR (KBr): 1535,1420,1400,1350,1290,1180cm ^-1

IH NMR (DMSO-d ₆ δ; 8.7 (5, 1H), 8.4 (m, 2H), 3.0 (s, 6H)

Example 2

Preparation of 2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetic acid 6-nitrobenzotriazol-1-yl ester

Dissolve 2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacet (2 g) in N, N-dimethylformamide (30 ml). 1- (N, N-dimethylsulfamoyloxy) -6-nitrobenzotriazole (2.87 g) is added. Triethylamine (1.4 ml) was slowly added to the reaction, followed by stirring at room temperature for 3 hours. Remove about 15 ml of solvent under vacuum and slowly concentrate the concentrate into iced water (150 ml). After stirring for another 1 hour, the solid obtained by filtration was dried in vacuo to obtain 3.4 g (94%) of active ester of 6-nitrobenzotriazole.

Melting Point: 173-174 ℃

IR (KBr): 1830,1610,1520,1340cm ^-1

1 H NMR (DMSO-d ₆ ): δ 8.52 (s, 1H), 8.15 (d, 2H), 6.95 (s, 1H), 3.55 (s, 3H)

Example 3

7-[[2- (2-aminothiazol-4-yl) -2-cin-methoxyimino] acetamido] -3-[(2,5-dihydro-6-hydroxy-2-methyl Preparation of -5-oxotriazin-3-yl) thiomethyl] -3-cepem-4-carboxylic acid

Method I

7- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetic acid (4 g) and 1- (N, N-dimethylsulfamoyloxy) -6-nitro-benzotriazole (5.8 g) Was dissolved in triethylamine (2.8 ml) and N, N-dimethylformamide (30 ml), and then dissolved in N, N-dimethylformamide (30 ml), and then in N, N-dimethylformamide (35 ml). 7-amino-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxotriazin-3-yl) thiomethyl] -3-cepem-4-carboxylate hydrochloride dissolved (8.16 g) is slowly added dropwise. After the reaction was stirred for about 30 minutes, triethylamine (2.8 ml) was slowly added dropwise. After stirring for 2 hours, the solvent is removed under vacuum and the residue is poured slowly into saturated brine (100 ml). After adjusting to pH 3.5, it is left at 0 degreeC for 1 hour, and is filtered. The solid obtained by filtration is wash | cleaned with cooling water (10 ml), and suspended in ethyl acetate (30 ml). Stir well for 30 minutes, filter, and wash again with acetone (20 ml) to give 9.6 g (89.4%) of the basic desired compound.

IR (KBr): 1780cm ^-1

NMR (NaHCO ₃ -D ₂ O): 6.95 (s, 1H), 5.72 (d, IH), 5.18 (d, 1H), 4.21 (d, 2H), 3.95 (s, 3H), 3.61 (s, 3H ), 3.19 (d, 2H)

Method II

2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetic acid 6-nitrobenzotriazol-1-yl ester (0.8 g) and 7-amino-3- prepared from Example 2 [(2,5-Dihydro-6-hydroxy-2-methyl-5-oxotriazin-3-yl) thiomethyl] -3-cef-4-carboxylate hydrochloride (0.8 g) was added N, N Dissolve in dimethylformamide (30 ml), add triethylamine (0.28 ml) with good stirring and stir the reaction further for 7 hours. The solvent is removed in vacuo and the residue is slowly added to saturated brine (30 ml) to form a solid. Stir for 30 minutes and leave at 0 ° C. for 1 hour. The resulting solid is filtered, washed with cold water (5 ml) and then suspended in ethyl acetate (10 ml). After 30 minutes of further stirring and filtration, washing with acetone (3 ml) gave 1 g (90%) of the title compound.

Example 4

Of 7- (1- (1H) -tetrazolylacetamido) -3- [2- (5-methyl-1,3,4-thiadiazolyl) thiomethyl] -3-cepem-4-carboxylic acid Produce.

Dissolve 1H-tetrazol acetic acid (2.56 g) in N, N-dimethylformamide (30 ml) and add 1- (N, N-dimethylsulfamoyloxy) -6-nitro-benzotriazole (5.8 g). Triethyl amine (2.8 ml) was added thereto, stirred at room temperature for 30 minutes, and again 7-amino-3- [2- (5-methyl-1,3,4-thiadiazolyl) thiomethyl] -3-cefem. 4-carboxylic acid (6.8 g) is added. Stir at room temperature for 3 hours and remove solvent by midstream in vacuo.

20 ml of isopropanol is added to the residue and stirred well to form a solid. 20 ml of dichloromethane was further added, stirred, and left to stand at 0 ° C for 1 hour. The resulting solid is filtered and washed with ethyl acetate (5 ml). Recrystallization of the obtained solid with a small amount of water-soluble acetone affords 6.6 g (73%) of the title compound.

Melting Point: 197-200 ℃

1 H NMR (CF ₃ COOH): δ 8.2 (d, 1H), 5.8 (m, 3H), 5.4 (d, 1H), 4.7 (s, 2H), 3.8 (s, 2H), 3.1 (s, 3H)

IR (KBr): 1770,1715,1670,1555cm ^-1

Example 5

Preparation of 3-carbamoyloxymethyl-7- [2-methoxyimino-2- (furyl-2-yl) acetamido] -3-cefe-4-carbonyl acid

Method 1

7-amino-3-carbamoyloxymethyl-3-cepem-4-carboxylic acid diphenylmethyl ester (4.4 g) with 2-cin-methoxyimino-2- (furyl-2-yl) acetic acid (1.7 g) is dissolved in N, N-dimethylformamide (30 ml) and 1- (N, N-dimethylsulfamoyloxy) -6-nitrobenzotriazole (2.87 g) is added. Triethylamine (1.4 ml) was added thereto, stirred at room temperature for 3 hours, and then the solvent was distilled off under vacuum. After cooling the residue to 0 ° C., anisole (5 ml) was added at the same temperature. Trifluoroacetic acid (20 ml) was added dropwise to the mixture, followed by shaking well for 15 minutes. Again trifluoroacetic acid was removed under reduced pressure, and ethyl acetate ester (15m1) was added to the residue. After stirring for 15 minutes, the suspension was filtered, and the solid obtained by filtration was washed with a 1: 1 mixed solution of ethyl acetate and ethyl ether (10 ml). Again washed with ethyl ether (10m1) to obtain 3.6g of the target compound.

Yield 3.6 g (80%)

IR (KBr): 1752,1710,1665,1625,1600cm ^-1

1 H NMR (DMSO-d ₆ ): δ 7.9 (d, 1H), 6.8-6.7 (m, 2H), 5.7 (m, 1H), 5.1 (d, 1H), 4.8 (q, 2H), 4.0 (s , 3H), 3.4 (q, 2H).

Method II

7-amino-3-carbamoyloxymethyl-3-cepem-4-carboxylic acid (2.65 g) and 2-cin-methoxyimino-2- (furyl2-yl) acetic acid (1.7 g) were added to N, It is dissolved in N-dimethylformamide (30 ml) and 1- (N, N-dimethylsulfamoyloxy) -7-nitrobenzotriazole (2.88 g) is added. Triethylamine (2.8 ml) was slowly added dropwise to the reaction, followed by stirring at room temperature for 3 hours, and the solvent was removed by vacuum distillation. The residue is suspended in ethyl acetate ester (20 ml) and the resulting solid is filtered. The filtered solid was washed with ethyl ether (10 ml) and dried under vacuum to obtain 3.8 g of the target compound.

Yield 85%

Example 6

7- [D-α-amino-α- (4-hydroxyphenyl) acetoamido] -3-[(1,2,3-tria-4-yl) thiomethyl] -3-cepem-4- Preparation of 1,2-propylene glycolate of carboxylic acid

D-α-t-butoxycarbonylamino-α- (4-hydroxyphenyl) acetic acid (2.6 g) and 1- (N, N-dimethylsulfamoyloxy) -6-nitrobenzotriazole (2.9 g) Was dissolved in N, N-dimethylformamide (25m1), triethylamine (2.8 ml) was added dropwise, followed by stirring for 30 minutes.

Again, 7-amino-3-[(1,2,3-triazol-4-yl) thiomethyl] -3-cepem-4-carboxylic acid (3.0 g) was added to the reaction solution and room temperature for 3 hours. Stir in The solvent is removed by vacuum distillation and 99% formic acid (100 ml) is added to the residue. After stirring for 3 hours, the formic acid was removed by distillation under reduced pressure, and the obtained residue was treated with 100 ml of 75% propylene glycol, and then adjusted to pH 1.5-1.7.

Activated carbon (0.5 g) is added to this solution, which is stirred for 30 minutes and then filtered. The filtrate was adjusted to pH 4.5 with triethylamine to give a white solid which was filtered off and washed with 75% propylene glycol (10 ml) and acetone (7 ml). The resultant solid was dried for 20 hours at 50 ° C. in vacuo to yield 4.2 g (83%) of the title compound.

Melting Point: 182- l84 ℃

IH NMR (DMSO-HCl): δ 8.0 (s, IH), 6.7-7.6 (m, 4H), 5.7 (d, IH), 4.9-5.2 (m, 2H), 3.2-4.2 (m, 7H), 1.1 (d, 3 H).

IR (KBr, cm ^-1 ) 1780,1705,1570,1515

Claims (3)

Represented by the following general formula (I) characterized by condensation of an organic acid of the following general formula (III) with a compound of the following general formula (IV) in the presence of a suitable base using a condensing agent of the following structural formula (ll) Method for preparing the compound.

(Wherein R is a (tetrazol-1-yl) methane group, shin-methoxyiminoyl- (furyl-2-yl) methane group, shin-methoxyiminoyl-(2-aminothiazole-4 -Yl) methane group, D-α-amino-α (4-hydroxyphenyl) methane group or D-α-t-butoxycarbonylamino-α- (4-hydroxyphenyl) methane group, and M is Represents a hydrogen atom or an alkaline earth metal or represents a diphenylmethane group X represents (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl group, carbamoyloxymethyl group, (2,5-di Hydro-6-hydroxy-2-methyl-5-oxo-triazin-3-yl) thiomethyl group or (1,2,3-triazol-4-yl) thiomethyl group. The method according to claim 1, wherein the condensing agent of formula (II) is a condensing agent prepared by reacting N.N-dimethylsulfamoyl halide with 6-nitro-1-hydroxybenzotriazole. The process according to claim 1, wherein the compound of the following structural formula (V) which is an active ester produced as an intermediate is not isolated.

(R is as described above.)