An improved process for the production of a 7- amino(p-hydroxyphenylglycyl) cephem compounds of is provided.
7- amino(p-hydroxyphenylglycyl) cephem compounds such as cefatrizine, cefadroxil and cefprozil are generally prepared by reacting a cephem derivative with a reactive derivative of 4hydroxyphenylglycine such as: a reactive ester; a reactive amide; and a mixed-acidic anhydride.
British Patent GB 1,240,687 disclosed a process involving reacting N-protected 4-hydroxyphenylglycine with ethyl chloroformate to obtain a carbonate derivative to be acylated with a cephem compound. However, this method gives a product of low purity. A major impurity formed in such procedures has the structure of Formula A, as shown in the accompanied drawings, wherein R is a group commonly used at the 3-position in cephalosporins. It was observed that this impurity is formed by reaction of ethylchloroformate with the phenolic hydroxyl group under basic reaction conditions.
An improved process for the production of a cephem compound of Formula I, as shown
in the accompanied drawings, wherein R is a group commonly used at the 3-position in
cephalosporins is provided, which comprises :
i) reacting a Dane salt of Formula III, as shown in the accompanied drawings, wherein R' is C^ alkyl and IvT is an alkali metal cation, with a lower alkyl chloroformate in the presence of an amine, and an acid selected from the group consisting of methanesulfonic acid, sulfuric acid, formic acid and acetic acid, to obtain a mixed carboxylic acid anhydride of Formula IV, as shown in the accompanied drawings; and ii) reacting the mixed carboxylic acid anhydride with a silylated derivative of the 7-amino-ceph-3-em-4-carboxylic acid of Formula II, wherein R is as defined above,
to obtain the cephem compound of Formula I.

Presence of a small amount of an acid selected from the group consisting of methanesulfonic acid, sulfuric acid, formic acid and acetic acid in the production of the mixed anhydride minimizes the formation of impurity of Formula B, as shown in the accompanied drawings, wherein R is a group commonly used at the 3-position in cephalosporins, in the step ii) reaction.
Thus, compounds of Formula I, wherein R is a group commonly used at the 3-position in cephalosporins, having less than 0.5% by weight of the impurity of Formula B, wherein R is the same as above are provided. In some particular examples compounds of Formula I, wherein R is a group commonly used at the 3-position in cephalosporins, having less than 0.1% by weight, or having less than 0.05% by weight of the impurity of Formula B, wherein R is the same as above are provided.
Particular examples of R group in the compound of Formula I include methyl, 1-propenyl and 1,2,3-triazol-5-yl thiomethyl.
The process is useful for the preparation of a wide variety of 7- amino(p-hydroxyphenylglycyl) -cephalosporins, e.g., cefatrizine, cefadroxil, or cefprozil, in good yield and purity.
Examples of Dane salts of Formula III suitable for the production include sodium or potassium D-N-(1-methoxycarbonylpropen-2-yl)amino-p-hydroxyphenyl- acetate, and sodium or potassium D-N-(1-ethoxycarbonyl- propen-2-yl)-amino-p-hydroxyphenylacetate.
Examples of alkyl chloroformates include ethyl chloroformate and methyl chloroformate.
Examples of amines present as a catalyst for mixed carboxylic acid anhydride formation include N-methyl morpholine, N,N-dimethyl benzyl amine, pyridine, picoline, and lutidine.

The mixed anhydride may be prepared in a solvent conventionally used such as a halogenated hydrocarbon, e.g. dichoromethane, dichloroethylene; a ketone e.g. acetone, methyl isobutyl ketone; an ester e.g. ethyl acetate, isopropylacetate; an ether e.g. tetrahydrofuran, dioxane; a nitrile e.g. acetonitrile; or an aromatic hydrocarbon e.g. toluene; and a co-solvent such as an organic amide. Organic amide is selected from formamide, acetamide, N,N-dimethyl formamide, N-methylacetamide, N,N-dimethylacetamide and N-methylpyrrolidone.
The formation of the mixed carboxylic acid anhydride may be carried out at temperatures, from about -80°C to about 50°C, or from about -50°C to about 5°C.
The product of step i) is generally a solution or a suspension of the mixed carboxylic acid anhydride, which can be used further as such. If desired this anhydride may be maintained between step i) and step ii) at from about -60°C to about -20°C.
The 7-amino-ceph-3-em-4-carboxylic acid of Formula II may be silylated with silylation agents in a solvent inert under the reaction conditions. Examples of silylation agents include mono- or bissilylated amides, such as N,0-bis-(trimethylsilyl)acetamide (BSA), N-methyl-N-trimethylsilyl-acetamide (MSA); silylated ureas, such as N,N'-bis-(trimethylsilyl)-urea (BSU); or silazanes, such as 1 1 3,3,3- hexamethyldisilazane (HMDS), in combination with a halosilane such as trimethylchlorsilane, dimethyldichlorosilane, or an amine, such as triethylamine, tert.octylamine.
The solvents used for mixed anhydride preparation above may be used for silylation of the 7-amino-ceph-3-em-4-carboxylic acid, and also for the step ii) reaction.
Suitable reaction temperatures for the step ii) may be from about -60°C to room temperature, or from about -40°C to about -10°C.
The reaction mixture of the step ii) may be worked up in conventional manner. The substituted vinyl group may be split by hydrolysis in aqueous acid.

The suspension of silylated 7-APCA was added to the above mixed anhydride at -65 to - 70°C and further stirred for 60 minutes at -40 to -45°C. The temperature was raised to -20 to -25°C and further stirred for 90 minutes. A mixture of water (170ml) and 35% hydrochloric acid (35 ml) was added to the reaction mixture and stirred for 15 minutes at 0 to 5°C. The aqueous layer was diluted with dimethylformamide(700ml) and acetone (150 ml), and pH of the mixture adjusted to 6.5 with 25% ammonia solution. The mixture was stirred at 20-25°C for 2 hours and the separated solid was filtered. The solvate was washed dimethylformamide (100 ml) followed by acetone and dried at 40°C to yield 98g of cefprozil as dimethyl formamide (1.5 mole) solvate.
m/c by KF = 0.25%, HPLC purity =99.58%, DMF content (by GC) = 18.2% Impurity of formula B (R = 1-propenyl, Alkyl = ethyl) = 0.05% (by HPLC)
Above cefprozil dimethyl formamide solvate was converted to crystalline Cefprozil as monohydrate by the procedure reported in US 4694079.
Example-2
Cefadroxil
7-amino-3-desacetoxy-3-cephem-4-carboxylic acid (7-ADCA, 50g) was added to methylene chloride (300ml). 1,1,3,3-hexamethylsilazane (26g), chlorotrimethylsilane (18.7g) and imidazole (0.5g) were added. The reaction mixture was refluxed for 3-4 hours and then cooled to 0 to 5°C.
Potassium (D)-N-(1-methyoxycarbonyl-propen-2-yl)-a-amino-p-hydroxyphenyl acetate (Dane salt, 79g) was added to methylene chloride (300ml) and dimethylformamide (200ml) and stirred at -40 to -45°C. N-methylmorpholine (0.47g) and methanesulfonic acid (1.12 g) were added followed by ethylchloroformate (29.5g) and stirred for about 90 minutes at -35 to -40°C. It was then cooled to -65 to -70°C.

The suspension of silylated 7-ADCA was added to the above mixed anhydride at -65 to - 70°C and further stirred for 60 minutes at -40 to -45°C. The temperature was raised to -20 to -25°C and further stirred for 90 minutes. A mixture of water (170ml) and 35% hydrochloric acid (35 ml) was added to the reaction mixture and stirred for 15 minutes at 0 to 5°C. The aqueous layer was diluted with dimethylformamide (700ml) and acetone (150 ml), and pH of the mixture adjusted to 6.5 with 25% ammonia solution. The mixture was stirred at 20-25°C for 2 hours and the separated solid was filtered. The solvate was washed dimethylformamide (100 ml) followed by acetone and dried at 40°C to yield 105g of cefadroxil as dimethyl formamide (1.5 mole) solvate.
m/c by KF = 0.48%, HPLC purity =99.24%, DMF content (by GC) = 22.8% Impurity of formula B (R = methyl, Alkyl = ethyl) = 0.08% (by HPLC)
Above cefadroxil dimethyl formamide solvate was converted to white crystalline solid Cefadroxil monohydrate by the procedure reported in US 4504657.

WE CLAIM:
1. A process for the production of a cephem compound of Formula I, as shown in the
accompanied drawings, wherein R is a group commonly used at the 3-position in
cephalosporins, which comprises:
i) reacting a Dane salt of Formula III, as shown in the accompanied drawings, wherein R1 is C1-4 alkyl and M+ is an alkali metal cation, with a lower alkyl chloroformate in the presence of an amine, and an acid selected from the group consisting of methanesulfonic acid, sulfuric acid, formic acid and acetic acid, to obtain a mixed carboxylic acid anhydride of Formula IV, as shown in the accompanied drawings; and
ii) reacting the mixed carboxylic acid anhydride with a silylated derivative of the 7-amino-ceph-3-em-4-carboxylic acid of Formula II, wherein R is as defined above,
to obtain the cephem compound of Formula I.
2. The process according to claim 1, wherein the R group in the compound of Formula I
is selected from the group consisting of methyl, 1-propenyl and 1,2,3-triazol-5-yl
thiomethyl.
3. The process according to claim 1, wherein the Dane salt used in step i) is selected
from the group consisting of sodium or potassium D-N-(1-methoxycarbonylpropen-2-
yl)amino-p-hydroxyphenyl- acetate, and sodium or potassium D-N-(1-ethoxycarbonyl-
propen-2-yl)-amino-p-hydroxyphenylacetate
4. The process according to claim 1, wherein the alkyl chloroformates is selected from
ethyl chloroformate and methyl chloroformate.

5. The process according to claim 1, wherein the amine is selected from the group consisting of N-methyl morpholine, N,N-dimethyl benzyl amine, pyridine, picoline, and lutidine.
10. The process according to claim 1, wherein steps i) is performed in a solvent
selected from the group consisting of a halogenated hydrocarbon, a ketone, an ester,
an ether, a nitrile and an aromatic hydrocarbon.
11. The process according to claim 10, wherein the solvent is selected from the group
consisting of dichloromethane, dichloroethylene, acetone, methyl isobutyl ketone, ethyl
acetate, isopropylacetate, tetrahydrofuran, dioxane, acetonitrile and toluene.

12. The process according to claim 1, wherein the steps i) is carried out at
temperatures, from about -80°C to about 50°C.
13. The process according to claim 12, wherein the steps i) is carried out at
temperatures, from about -50°C to about 5°C.

14. The process according to claim 10, wherein a co-solvent is used.
15. The process according to claim 14, wherein the co-solvent is selected from the
group consisting of formamide, acetamide, N,N-dimethyl formamide, N-
methylacetamide, N.N-dimethylacetamide, and N-methylpyrrolidone.
16. The process according to claim 1, wherein steps ii) is performed in a solvent
selected from the group consisting of a halogenated hydrocarbon, a ketone, an ester,
an ether, a nitrile and an aromatic hydrocarbon.
17. The process according to claim 16, wherein the solvent is selected from the group
consisting of dichloromethane, dichloroethylene, acetone, methyl isobutyl ketone, ethyl
acetate, isopropylacetate, tetrahydrofuran, dioxane, acetonitrile and toluene.

18. The process according to claim 1, wherein the steps ii) is carried out at
temperatures, from about -60°C to about 25°C.
19. The process according to claim 18, wherein the steps ii) is carried out at
temperatures, from about -40°C to about -10°C.
20. The process according to claim 1, wherein silylation of the 7-amino-ceph-3-em-4-
carboxylic acid of Formula II is carried out with a silylation agent selected from the
group consisting of mono- or bissilylated amides, silylated ureas, andsilazanes, in
combination with a halosilane or an amine.
21. The process according to claim 21, wherein the silylation agent is selected from the
group consisting of N,0-bis-(trimethylsilyl)acetamide (BSA), N-methyl-N-trimethylsilyl-
acetamide (MSA), N,N'-bis-(trimethylsilyl)-urea (BSD), and 1 1 3,3,3-
hexamethyldisilazane (HMDS),

22. The process according to claim 20, wherein the halosilane is selected from
trimethylchlorsilane and dimethyldichlorosilane.
23. The process according to claim 20, wherein the amine is selected from
triethylamine, and tert.octylamine.
24.The process for preparing 7-amino(p-hydroxyphenylglycyl) cephem compounds of formula I, as herein described and illustrated by the examples herein, herein