CH667458A5 - METHOD FOR PRODUCING CEPHEMIC DERIVATIVES. - Google Patents

Description

DESCRIPTION The invention relates to a process for the preparation of β-lactam derivatives of the general formula which act as antibiotics:

20th

25th

I2N (/

> \

- ç -C— NH-

\

OCH-

p-

COOR1

(I)

with a compound of the general formula:

-H

R

(IV)

wherein R3 represents a benzotriazolyl, pyridyl, succinimidyl or phthalimidyl group and n = 1 or 2, in the presence of an organic amine to give a corresponding reactive ester of the general formula:

0— R "

(V)

OCH-;

Ko M

COOR1

wherein R1 and R: have the meaning given, acylated in the presence of an organic reaction solvent.

2. The method according to claim 1, characterized in that in the preparation of the reactive ester of formula (V) as an organic reaction solvent N, N-dimethylformamide, N, N-dimethylacetamide and / or N-methyl-2- pyrrolidone used.

3. The method according to claim 1, characterized in that one carries out the esterification at room temperature for 10-15 h.

in which mean:

30 R1 is a hydrogen atom or an alkali metal and

R2 represents a hydrogen atom, an acetoxymethyl group or a 5- or 6-membered heterocyclic radical which is bonded via a thiomethyl group -CH2S- and is optionally substituted by a short-chain alkyl group and has at least 35 one nitrogen atom.

There are already a wide variety of processes for producing antibiotics from the β-lactam series. According to these methods, antibiotics of the β-lactam series are generally obtained by condensation of a 7-aminodeoxycephalospo-4o ranoic acid (7-ADCA) or 7 aminocephalosporanoic acid (7-ACA) derivative with a reactive derivative of an organic acid with formation of a peptide bond (between two reactants). In a typical known process for the preparation of an acyl compound of the formula (I), in an organic acid of the formula:

wherein R3 has the meaning given, esterified and the compound of the formula (V) obtained with a compound of the general formula:

50 -J /

k2N— \

CC, OH

(II)

\

(III)

OCH-

55 hanging amine residue introduced a protective group easily removable by an acid, whereupon the organic acid into a reactive derivative, e.g. an acid chloride, a reactive ester or a reactive amide, a mixture of the acid anhydride and the like. is transferred. 60 Methods for the preparation of a compound of formula (I) via acid chlorides of a compound of formula (II) are described in JP-OS 52-102 096, 53-34 795, 53-68 796, 54-52 096 and 54-157 596 and GB-PS 2 025 933 known. These processes usually consist of protecting the amino group bonded to the orange 65 acid of the formula (II) by means of a protective group, protecting the protected acid with thionyl chloride (SOCl2) phosphorus pentachloride (PC15), phosphorus oxychloride (POCl3) and the like. the like to the corresponding acid

3rd

667 458

implement chloride, acylate and then remove the amino protecting group to obtain a compound of formula (I).

However, a disadvantage of these processes is that the entire reaction has to be carried out under drastic conditions and that the acid chloride intermediate is unstable.

Processes for preparing a compound of the formula (I) via the reactive derivatives of the organic acid of the formula (II) are known from JP-OS 52-102 293, 54-95 593 and 56-152 488. According to the teachings of these references, the organic acid of the formula (II) is converted into the corresponding 2-pyridine thioester, 2-benzothiazole ester or 1-hydroxybenzotriazole ester and this is then acylated to a compound of the formula (I). A disadvantage of these processes is that undesired side reactions which occur in the course of the ester preparation can lead to a poor yield and the acylation takes a long time to complete.

The processes using the acid amide or a mixture of the acid hydride of the organic acid of the formula (II) also have similar disadvantages (as described).

Consequently, when the known processes are carried out, it is necessary, first, before they are acylated, for conversion into the corresponding acid chloride, the corresponding reactive ester or the corresponding reactive amide and the like. protect the amine group of the organic acid of the formula (II) by means of a protective group, then acylate the intermediate with 7-ADCA or 7-ACA and finally remove the protective group from the acylated compound.

It has now surprisingly been found that the yield and purity of the end product can be increased if the amino group of the organic acid of the formula (II) is not protected.

The invention was based on the object of specifying an economical and convenient (than previously) feasible new process for preparing a compound of the formula (I) in higher yield and greater purity.

The invention thus relates to a process for the preparation of a β-lactam derivative of the general formula (I), in which the various radicals have the meaning given, which is characterized in that an organic acid of the formula:

0

/ N

C - C - OH

wherein R3 has the meaning given, esterified and the ester obtained with a compound of the general formula:

HoN

10th

(III)

COOR-1

wherein R1 and R2 have the meaning given, in the presence of an organic reaction solvent to give a β-lactam derivative or cephem derivative of the general formula:

HoN

20th

(I)

where R1 and R2 have the meaning given, to -25.

The process according to the invention can be represented by the following reaction scheme:

Reaction scheme:

(II)

\

30th

35

40

45

50

0

• I

C -OH

(II)

OCH.

O

R3-04-è - ^ O -R3 (IV)

V

(V)

OCH-

with an esterifying agent of the general formula: O

t »o

O- R

55

(IV)

wherein R3 represents a benzotriazolyl, pyridyl, succinimidyl or phthalimidyl group and n = 1 or 2, in the presence of an organic amine to form a reactive 60 acid ester of the formula:

H2N ^

X,

J -'- y

COOR

(III)

C— C- "

(V)

65

Kl

C C - HN

II N

\

\

OCH,

OOOR1

OCH-j

(I)

667 458

It follows from the reaction scheme that the amino group of the organic acid of the formula (II) need not be protected when the process according to the invention is carried out. The esterification reaction to obtain the reactive ester of the formula (V) according to the reaction scheme can generally be carried out in the presence of an organic reaction solvent.

Suitable organic solvents for this purpose are, for example, N, N-dimethylformamide, N, N-dimethyl-acetamide, N-methyl-2-pyrrolidone, dichloromethane, 1,2-di-chloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane and the like ., preferably N, N-dimethylformamide and N, N-dimethylaeetamide. The esterification must be carried out under the basic conditions created by a weak organic amine. Amine bases suitable for esterification are, for example, pyridine, triethylamine, N, N-dimethylaniline, N, N-dimethylaminopyridine, isopropylamine and the like.

The ratio of organic acid of formula (II) and base to the esterifying agent of formula (IV) should preferably be 1.2 equivalents or equimolar. The reaction is usually carried out at room temperature and provides the reactive ester of the formula (V) quantitatively 10-15 h after its onset. The ester of formula (V) can be precipitated if the reaction mixture is poured into water all at once. The amount of water required for this purpose should preferably be about 20 to 30 times the amount of solvent used.

The following acylation of the ester of formula (V) with a compound of formula (III) can be carried out in a mixed solvent of a basic solution and an organic solvent. Bases suitable for preparing the basic solution are, for example, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine. Sodium hydroxide, sodium carbonate, potassium carbonate, aqueous ammonia and the like, preferably sodium hydrogen carbonate. Organic solvents suitable for preparing the solution mixture are, for example, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dioxane and the like, preferably acetonitrile, tetetrahydrofuran and N, N-dimethylformamide. When carrying out the acylation, the organic solvent selected in each case is first introduced into a basic solution of a compound of the formula (III), whereupon the reactive ester obtained in crystalline form is added to the mixture obtained. The whole is then stirred at room temperature for 6-8 hours. The reaction is quantitative. After the reaction has ended, the organic solvent is removed by distillation in vacuo, whereupon the pH of the separately obtained aqueous layer is adjusted to the respective isoelectric point in order to precipitate the compound of the formula (I). The amounts of water and solvent required for this purpose are preferably about 20 to 30 times the amount of starting material of the formula (III). The ratio of water to solvent used is preferably 1: 1 or 1: 2. The pH of the aqueous basic solution is preferably 7.0 to 7.5.

The previous explanations show that when the method according to the invention is carried out

1. it is not necessary to protect the amino group of the organic acid of the formula (II) and then to remove the amino protecting group,

2. it becomes possible to use an easy-to-use stable esterification agent (acylating agent).

3. it is possible to carry out all reaction steps at room temperature, and

4. It is possible to simply isolate the end product from an aqueous solution after the overall conversion has ended.

According to the invention, the production of the cephem compounds in question can thus both simplify the process stages and reduce the analog costs in comparison with the known processes, which is why the process according to the invention can be addressed as economically valuable.

The following examples are intended to illustrate the invention in more detail.

Production process for an output compound 1:

36 ml of trichloromethyl chloroformate are added to a suspension of 82 g of 1-hydroxybenzotriazole in 400 ml of toluene, and the mixture is heated to reflux temperature for 2.5 h. The precipitate formed is filtered off, washed with 150 ml of toluene and dried, 71 gl, 1 '- (carbonyldioxy) -dibenzotri-azole having an mp (with decomposition) of 150 ° C. and an IR spectrum (KBr , cm-1) can be obtained at 1800.

Production process for a starting compound 2:

A suspension of 27.3 g of 1-hydroxybenzotriazole in 300 ml of toluene is mixed with 8.6 ml of oxalychloride, whereupon the mixture obtained is heated to reflux temperature for 3 hours and then cooled in an ice bath. The precipitate which has precipitated out is filtered off, yielding 21.7 gl, l'-dibenzotriazole oxalate with an mp (with decomposition) of 158-160 C and an IR spectrum (KBr, cm-1) at 1725 in 67% yield .

example 1

A solution of 2.0 g of 2- (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetic acid in 35 ml of N, N-dimethylformamide is mixed with 0.8 ml of pyridine and the mixture is stirred for 10 minutes. After the addition of 6.0 g of l, l '- (cabonyldioxy) dibenzotriazole, the mixture is stirred for 12 hours at room temperature and then slowly poured into 600 ml of water to precipitate out a precipitate. After the reaction solution has been stirred for 1 hour, the precipitate is filtered off and dried, 3.2 g of 2- (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetic acid benzotriazole ester being obtained in 95% yield as a reactive ester.

IR spectrum (KBr, cm "1): 1780 (β-lactamcarbonyl).

Nuclear Magnetic Resonance Spectrum (DMSO-df „5): 4.0 (3H, s, -OCH3), 7.18 (1H, s, thiazole proton), 7.21 (2H, s, -NH2) and 7.7- 8.25 (4H, m, benzotriazole).

Example 2

Example 1 is repeated, but using 32 ml of N, N-dimethylacetamide instead of the N, N-dimethylformamide. 2.95 g of 2- (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetic acid-benzotriazole ester, mp 141-143 C, are obtained in 93% yield.

Example 3

Example 1 is repeated, but 40 ml of N-methyl-2-pyrrolidone are used instead of the N, N-dimethylformamide. 2.5 g of 2- (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetic acid-benzotriazole ester, mp 141-143 C., are obtained in 91% yield.

Example 4

A suspension of 2.72 g of 7-aminocephalosporanic acid in 40 ml of water is mixed with 2.0 g of sodium hydrogen carbonate

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

667 458

The mixture is stirred for 15 minutes until a solution is obtained. To. 40 ml of acetonitrile are added, the mixture is cooled to 10 ° C. and 3.18 g of one of the 2- (2-aminothiazol-4-yl) -2-syn ~ methoxyiminoacetic acid benzotriazolesters of Examples 1, 2 or 3 are then added. The reaction mixture is then stirred at room temperature for 6 hours until a clear solution is obtained (end product of the reaction). The acetonitrile is evaporated in vacuo from the solution, whereupon the aqueous layer obtained is mixed with 40 ml of water and then adjusted to a pH of 4.0 with 2N-HCl. After stirring for 1 hour, the precipitate is filtered off. The filtrate is saturated with sodium chloride and then treated with 80 ml of ethyl acetate. When the mixture is adjusted to a pH of 2.5 with vigorous stirring, white crystals precipitate out. These are filtered off and dried, yielding 4.22 hg of 7 - {[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamino j-cephalosporanic acid («cefotaxime») in 93% yield .

IR spectrum (KBr, cm-1) - '1780 (β-lactam carbonyl).

Nuclear Magnetic Resonance Spectrum (D20 / NaHC03, 8): 2.08 (3H, s,

O

II

-C-CHa), 3.53 (2H, d, C, -H), 4.02 (3H, s, -OCH3), 4.84 (2H, d, -S-CH2), 5-2 ( 1H, d, C6-H), 5.83 (1H, d, Cr-H) and 6.97 (1H, s, thiazole proton).

Example 5

Example 4 is repeated, but 40 ml of tetrahydrofuran are used instead of the acetonitrile. 4.13 g of 7 - {[2- (2-aminothiazol-4-yl) -2-syn-mathoxyimino] acetamido) cephalosporanic acid are obtained in 91% yield.

Example 6

A suspension of 2.72 g of 7-aminocephalosporanic acid in 40 ml of water and 20 ml of N, N-dimethylformamide is mixed with 2.0 g of sodium hydrogen carbonate, and the whole is stirred for 10 minutes at room temperature until a solution is obtained. The solution is then cooled to 10 ° C. and with 3.18 g of one of the 2- (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetic acid benzotriazolesters of Examples 1, 2 or 3 in 20 ml of N, N-dimethylformamide within Crosslinked for 10 minutes.

Thereafter, the reaction mixture was stirred at 10 ° C for 1 hour and then at room temperature for 3 hours to allow the reaction to proceed to completion. The reaction mixture is now extracted twice with 80 ml of ethyl acetate in order to remove the N, N-dimethylformamide fractions therefrom. The aqueous layer obtained is then saturated with sodium chloride. After cooling to 5 C, the pH of the mixture is adjusted to 4.0 with 2N-HCl and then filtered to remove insoluble constituents. When the pH of the filtrate is adjusted to 2.5, a white precipitate is obtained. After stirring for 2 hours, the precipitate is filtered off from the mixture, washed with a small amount of water and dried, 3.99 g of 7 - {[2 - (- aminothiazol-4-yl) -2-syn. In 88% yield -methoxy-imino] -acetamido j-cephalosporanic acid can be obtained.

Example 7

A suspension of 3.28 g of 7-amino- [3- (1-methyl-1H-te-trazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid in 35 ml of water is mixed with 2.0 g Sodium bicarbonate was added and the whole was stirred at room temperature for 20 minutes until a solution was obtained. After adding 40 ml of acetonitrile and cooling to 10 ° C., 3.81 g of 2- (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetic acid-rebenzotriazole ester are added to the mixture. The reaction mixture is now

Stirred for 5 hours until a clear solution is obtained (end product of the reaction). To remove the acetonitrile, the solution is evaporated in vacuo. The resulting aqueous layer is mixed with a further 40 ml of water and adjusted to a pH of 3.8 using 2N-HCl. After stirring for 1 hour, the crystals formed are filtered off. The filtrate is saturated with NaCl and adjusted to a pH of 2.7 with 2N-HC1, a crystalline precipitate being formed. After 10 2 hours of stirring at 5 ° C, the precipitate formed. filtered off, with 4.65 g of the desired product 7 - ([2- (2-aminothiazol-4-yl) -2-syn-methoxy-iminoj-acetamido) -3 - [(1 -methyl- 1 H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid ("cefmenoxime") can be obtained 15.

IR spectrum (KBr, cm "" '): 1780 (ß-lactamcarbonyl).

Nuclear Magnetic Resonance Spectrum (D? Q / NaHC03, 5): 3.84 (2H, d, C, -H), 4.01 (3H, s, -OCH3), 4 ~ 05 (3H, s,> N-CH3) , 5.02 (IH, d, C6-H), 5.77 (1H, d, C7-H) and 7.01 (1H, s, thiazole-20 proton).

Example 8

Example 7 is repeated, but the acetonitrile is replaced by 40 ml of ethyl acetate. In this way, 4.60 g of 7- | [2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] -acetamino | -3 - [(I -methyl-1 H- tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid.

Example 9

30 A suspension of 3.28 g of 7-amino- [3- (1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid in 40 ml of water and 20 ml of N, N- Dimethylformamide is mixed with 2.0 g of sodium bicarbonate, then the mixture was stirred at room temperature for 10 minutes until a solution was obtained and finally cooled to 10 ° C. A further solution of 3.81 g of 2- (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetic acid-benzotriazole ester in 20 ml of N, N-dimethylformamide is then added to the solution obtained within 10 min Completion of the reaction 40 is first stirred at 10 C for 1 h and then at room temperature for 4 h. After extracting the reaction mixture twice with 80 ml of ethyl acetate to remove the N, N-dimethylformamide components and saturating the aqueous layer obtained with sodium chloride, the solution 45 is cooled to 5 ° C., adjusted to a pH of 4.0 and finally filtered to give insoluble substances Remove substances. The filtrate is adjusted to a pH of 2.5 with 2N-HC1, a white precipitate separating out. After the mixture has been stirred for 2 hours, the precipitate 50 is filtered off, washed with a small amount of water and dried, 4.19 g of 7- | [2- (2-aminothiazol-4-yl) -2- in 82% yield. syn-methoxyimino] -acetamido | -3 - [(lmethyl-1 H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid.

55

Example 10

A suspension of 3.71 g of 7-amino-3- (2,5-dihydro-2-methyl-6-hydroxy-5-oxo ~ as-triazin-3-yl) thiomethyl-3-ce-phem-4 -carboxylic acid in 40 ml of water and 30 ml of tetrahydro-60 furan is treated with 2.7 g of sodium bicarbonate to produce a clear solution at a pH of 8.0 to 8.2. After adding 3.81 g of 2- (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetic acid benzotriazole ester, the reaction mixture is stirred at 5 C for 1 h, then warmed to 25 C 65 and continued for 5 h to complete the reaction . The reaction mixture is then evaporated in vacuo to remove the tetrahydrofuran. The evaporation residue is 30 ml

667 458

6

Water was added, the mixture was cooled to 5 ° C., adjusted to pH 4.2 with 2N-HCl and stirred for 30 minutes. The reaction mixture is then filtered to remove insoluble substances. The filtrate is saturated with sodium chloride and adjusted to a pH of 2.9 to 3.0 with 2N-HCl, a precipitate being formed. The mixture is then continued at a certain pH for 2 hours and the precipitate which has separated out is removed by filtration. The precipitate is dried, 4.7 g of 7- | [2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] -acetamido | -3- | [(2,5- dihydro-6-methoxy-2-methyl-5-oxo-as-triazin-3-yl) thio] -methyl j-3-cephem-4-carboxylic acid ("ceftriaxone") can be obtained.

IR spectrum (KBr, cm- '): 1780 (β-lactam carbonyl).

Nuclear Magnetic Resonance Spectrum (Di0 / NaHC03, S): 3.2 (2H, d, C -.- H), 3.62 (3H, s, N-CH,), 3 ~ 95 (3H, s, -OCH3), 4.21 (2H, d, -S-CH :-) 5.17 (1H, d, C6-H), 5.72 (1H, d, Cj-H) and 6.95 (1 H, s, Thizole hydrogen).

Example 11

Example 10 is repeated, but the tetrahydrofuran is replaced by 40 ml of acetonitrile. This gives 4.5 g of 7- | [2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido | -3- ([(2,5-dihydro-6 -hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] -methyl} -3-ce-phem-4-carboxylic acid.

Example 12

A suspension of 1.88 g of 7-amino-3-cephem-4-car-bonic acid in 20 ml of water and 20 ml of tetrahydrofuran is mixed with 2.0 g of sodium bicarbonate, a solution being obtained. This is cooled to 5 C and 3.18 g of 2- (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetic acid benzotriazole ester are then added within 10 min. The reaction mixture is then stirred at 5 C for 1 h and at 25 C for 2 h to complete the reaction. After evaporation of the reaction mixture in vacuo to remove the tetrahydrofuran fractions, 15 ml of water are added to the evaporation residue, the mixture is cooled to 5 ° C., adjusted to pH 4.2 with 2N-HCl and stirred for 30 minutes. Then the reaction mixture is filtered to remove insoluble substances. The filtrate is saturated with sodium chloride and adjusted to a pH of 2.8 with 2N-HCl. After stirring for 2 hours in an ice bath at a certain pH, the mixture is filtered. The filter residue is washed with water saturated with sodium chloride and then with cooled water and dried, with 3.48 g of 15 7 - {[2- (2-aminothiazol-4-yl) methoxyimino] acetamido) in 91% yield. 3-cephem-4-carboxylic acid («ceftizoxime») can be obtained.

IR spectrum (KBr, cm-1): 1780 (β-lactamcarbonyl).

Nuclear magnetic resonance spectrum (DMSO-d6, S): 3.60 62H, broad s), 3.84 (3H, s), 5.12 (1H, d, J-5Hz), 5.84 (1H, dd, J = 5Hz), 20 6.52 (1H, s), 6.76 (1H, s), 7.26 (2H, broad s) and 9.65 (1H, d, J = 8Hz).

Example 13

Example 12 is repeated, but the Tetrahy-25 drofuran is replaced by 20 ml of acetone. This gives 3.4 g of 7- | [(2-aminothiazol-4 -) - methoxyimino] acetamido j-3-cephem-4-carboxylic acid in 90% yield.

Example 14

Example 6 is repeated, but the tetrahydrofuran used in Example 12 is replaced by N, N-dimethylformamide. This gives 3.26 g of 7 - ([(2-aminothiazol-4-yl) -methoxy-imino] -acetami-do j-3-cephem-4-carboxylic acid in an 86% yield.

C.

Claims (4)

667 458 2nd PATENT CLAIMS 1. Process for the preparation of cephem derivatives of the general formula: 0 (I) 10th in which mean: R1 is a hydrogen atom or an alkali metal and R: a hydrogen atom, an acetoxymethyl group or a 5- or 6-membered heterocyclic radical with one, two or more nitrogen atoms, optionally substituted by a thiomethyl group -CH2S-, substituted by a short-chain alkyl group characterized that you have an organic acid of the formula: l 0 II c- C -OH (II) \ OCH- 4. The method according to claim 1, characterized in that is used in the esterification as the organic amine pyridine, triethylamine, N, N-dimethylaniline, N, N-dimethylaminopyridine and / or isopropylamine. 5. The method according to claim 1, characterized in that acetonitrile, tetrahydrofuran, ethyl acetate, acetone, N, N-dimethylformamide, N, N-dimethylacetamide and / or dioxane are used as the reaction solvent in the acylation. 6. The method according to claim 1, characterized in that one carries out the acylation in the presence of a base consisting of sodium hydrogen carbonate, potassium hydrogen carbonate and / or triethylamine. 15