Field of the Invention
The field of the invention relates to pure 7- amino (p-hydroxyphenylglycyl) cephem compounds. The invention also relates to processes for the preparation of pure 7- amino (p-hydroxyphenylglycyl) cephem compounds and pharmaceutical compositions that include the pure 7- amino (p-hydroxyphenylglycyl) cephem compounds.
Background of the Invention
7- amino (p-hydroxyphenylglycyl) cephem compounds such as cefprozil. cefadroxil and cefatrizine are generally prepared by reacting a cephem derivative with a reactive derivative, such as a reactive ester; a reactive amide; and a mixed-acidic anhydride of 4-hydroxyphenylglycine.
British Patent GB 1.240.687 discloses a process involving reacting N-protected 4-hydroxyphenylglycine with ethyl chloroformate to obtain a carbonate derivative, which is acylated with a cephem compound. However, this method gives a product of low purity. A major impurity formed in such a process has the structure of Formula A
(Formula Removed)
FORMULA A
wherein R is a group commonly used at the 3-position in cephalosporins. for example, methyl. 1-propenyl and l,2.3-triazol-5-yl thiomethyl.
It was observed that this impurity is formed by reaction of ethyl chloroformate with the phenolic hydroxyl group under basic reaction conditions employed.
Thus, the present invention provides a process which results in pure 7- amino (p-hydroxyphenylglycyl) cephem compounds. The process of the present invention avoids purification by tedious and cumbersome processes. The process of the present invention reduces the impurity content of the final product, eliminates the costly and time-consuming purification steps.
Summary of the Invention In one general aspect there are provided pure cephem compounds of Formula I,
.(Formula Removed)
FORMULA I
wherein R is a group commonly used at the 3-position in cephalosporins and may include C=alkyl. C2-6alkenyl. C2-6alkynyl. C2-6 alkadienyl. cyclic C2-6 alkyl. aryl.
substituted aryl, heteroaryl. or hcteroaryllhioalkyl . In particular, it may include methyl. 1-propenyl and 1.2.3-triazol-5-yl thiomethyl.
In another general aspect there is provided a process for the preparation of cephem compounds of Formula I.
In another aspect there is provided a pharmaceutical composition and dosage forms containing a therapeutically effective amount of the cephem compounds of Formula I and which may also contain pharmaceutically acceptable carriers, excipients or diluents which are useful for the treatment of bacterial infections.
In another aspect there is provided a method of treating bacterial infections comprising administering to a mammal in need thereof, a therapeutically effective amount of cephem compounds of Formula I as described above.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Detailed Description of the Invention
'f'he inventors have developed a process for the preparation of certain cephem compounds of Formula I.
(Formula Removed)



FORMULA I
wherein R is a group commonly used at the 3-position in cephalosporins and includes C1-6 alkyl. C2-6alkenyl. C2-6 alkynyl. C2-6 alkadienyl. cyclic C3-6alkyl. aryl. substituted aryl. heteroaryl. or heteroarylthioalkyl . In particular, it includes methyl. 1-propenyl and 1.2,3-tria/ol-5-yl thiomethyl. The process comprising:
(i) reactinu a Dane salt of Formula III.
(Formula Removed)

FORMULA III
wherein R' is C1-4 alkyl and M+ is an alkali metal cation.
with a lower alkyl chloroform ate in the presence of an amine. and an acid, to obtain a mixed carboxylic acid anhydride of Formula IV. and
(Formula Removed)
FORMULA IV
(ii) reacting the mixed carhoxylic acid anhydride with a silylated derivative of the 7-amino-ceph-3-em-4-carboxylic acid of Formula II,
(Formula Removed)
FORMULA II
wherein R is C1-6 alkyl. C2-6 alkenyl. C2 6 alkynyl. C2-6 alkadienyl, cyclic C3-6 alkyl. aryl. substituted aryl. heteroaryl. or heteroarylthioalkyl.
to obtain the cephem compound of Formula I.
In general, the preparation of the mixed anhydride is carried out in the presence of a small amount of an acid to minimize the formation of impurity of Formula B, in the step ii) reaction.
(Formula Removed)
FORMULA B
wherein R is a group commonly used at the 3-position in cephalosporins. and includes CK, alkyl. C2-6 alkenyl. C2-6 alkynyl. C2-6alkadienyl. cyclic C3-6alkyl. aryl. substituted aryl. heteroaryl. or heteroarylthioalkyl.
The process is useful for the preparation of a wide variety of 7- amino(p-hydroxyphenylglycyl) -cephalosporins. for example, cefalrizine. cefadroxil. orcelprozil. in good yield and purity.
Examples of Dane salts of Formula III 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 chlorotbrmate.
Hxamples of amines present as a catalyst for mixed carhoxylic acid anhydride formation include N-methyl morpholine, N.N-dimethyl benzyl amine. pyridine. picoline, and lutidine.
The mixed anhydride may be prepared in one or more solvents, including, for example, halogenated hydrocarbon, ketone. ester, ether, nitrile. aromatic hydrocarbon, amide and mixtures thereof. Examples of chlorinated hydrocarbons include dichoromethane and dichloroethylene: Examples of ketones include acetone and methyl isobutyl ketone; Examples of ester include ethyl acetate and isopropylacetate; Examples of ether include tetrahydrofuran and dioxane; a nitrile includes acetonitrile; Examples of aromatic hydrocarbon include toluene. A suitable co-solvent may be used with a solvent, for example amide. A suitable amide includes one or more of formamide. acetamide. N.N-dimethyl formamide. N-methylacetamide. N.N-dimethylacetamide and N-methylpyrrolidone. Mixtures ol'all of these solvents are also contemplated.
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 obtained as a solution or a suspension of the mixed carboxylic acid anhydride, and can be further used as such. If desired, this anhydride may be maintained at from about -60°C to about -2()°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.
The 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 a conventional manner. The substituted vinyl group may be split by hydrolysis in aqueous acid.
The final product may he isolated in a conventional manner, for example by adjusting the pH of the reaction mixture. The product of formula I can be obtained in a very high purity, for example above 98%.
The 7-amino-ceph-3-em-4-carboxylic acid of Formula II may be prepared in accordance with any of the known methods (see U.S. Patent Nos. 3,867,380; 3 489,752 and 4.520.022).
The Dane salt of Formula III may be obtained from commercial sources or prepared by methods well known in the art.
Thus, compounds of Formula I having less than 0.5% by weight of the impurity of Formula B can be obtained. In particular, compounds of Formula I having less than 0.1% by weight of the impurity of Formula B. or less than 0.05% can be obtained.
The resulting cephem compounds of Formula I may be formulated into ordinary dosage forms such as. for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
'fhe compositions include dosage forms suitable for oral and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, as well as liquid suspensions. Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and are not intended to limit the scope of the invention. Although the examples are directed to the cefprozil and cefdroxil. the principles described in these examples can be applied to other cephem compounds.
Example 1 C'efpro/il
7-amino-3-(propen-l-yl)-3-cephem-4-carboxylic acid (7-APCA. 50g) was added to methylene chloride (300ml). 1.1.3.3-hexamethylsilazane (25g). chlorotrimethylsilane (17.5g) 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-(l-methyoxycarbonyl-propen-2-yl)-a-amino-p-hydroxyphenyl acetate (Dane salt. 71g) was added to methylene chloride (300ml) and dimethylformamide (200ml) and stirred at -40 to -45T. N-methylmorpholine (0.42g) and methanesulfonic acid (1.0 g) were added followed by ethylchloroformale (28.2g) and stirred for about 90 minutes at -35 to -40T. It was then cooled to -65 to -70°C.
The suspension of silylated 7-APCA was added to the above mixed anhydride at -65 to - 70T 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 (1 70ml) 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 pi 1 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.
Moisture content by KF = 0.25%; HPLC purity =99.58%; DMF content (by GC) =
J.2%
Impurity of formula B (R = 1-propenyl. Alkyl = ethyl) = 0.05% (by HPLC)
Above cefprozil dimethyl formamide solvate was converted to crystalline cefprozil monohydrate by the procedure reported in U.S. Patent No. 4.694.079.
Example 2 Cel'adroxil
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-(l-melhyoxycarbonyl-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 -45T. N-methylmorpholine (0.47g) and melhanesulfonic acid (1.1 2 g) were added followed by ethylchlorofonnate (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 -25T and further stirred for 90 minutes. A mixture of water (1 70ml) 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 dimethylibrmamide (70()ml) and acetone (150 ml), and pi 1 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 dimethylibrmamide (100 ml) followed by acetone and dried at 40°C to yield 105g of cefadroxil as dimethyl formamide (1.5 mole) solvate.
Moisture content by KF = 0.48%: HPLC purity =99.24%; DMF content (by GC) =
22.8%
Impurity of formula B (R = methyl. Alky] - ethyl) = 0.08% (by HPLC)
Above cefadroxil dimethyl formamide solvate was converted to white crystalline solid cefadroxil monohydrate by the procedure reported in U.S. Patent No. 4.504.657.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

WE CLAIM:
1. A process for the production of a cephem compound of Formula I,

(Formula Removed)
Wherein R is C1-6 alkyl. C2-6 alchemy. C2-6 alkvnvl. C2-6 alkadienyl. Cyclic C 3-6 , alkyl. aryl.
substituted aryl. heteroaryl. or heteroarylthioalkyl. the process comprising:
i) reactinu a Dane salt of Formula 111
.(Formula III Removed)
FORMULA III
wherein R1 is C1-4 alkyl and M+ is an alkali metal cation, with a lower
alkyl chlorotbrmate in the presence of an amine. and an acid, to obtain a mixed carboxvlie acid anhydride of Formula IV.
(Formula IV Removed)

FORMULA IV
wherein R' is as defined above and alkyl is methyl or ethyl, and
ii) reacting the mixed carboxvlie acid anhydride with a silylated derivative of the 7-amino-ceph-3-em-4-carboxylic acid of Formula II,

FORMULA II
(FORMULA REMOVED)
wherein R is as defined above,
to obtain the cephem compound of Formula I.
2. The process of claim 1. wherein the R group is methyl. 1-propenyl and 1.2,3-
tria/ol-5-yl thiomethyl.
3. The process of claim 1. wherein the Dane salt used in step i) is selected from the
group consisting of sodium or potassium D-N-(l-methoxycarbonylpropen-2-yl)amino-p-
hydroxyphenyl- acetate, and sodium or potassium D-N-( 1-ethoxycarbonyl- propen-2-yl)-
amino-p-hydroxyphenylacctate. the alkyl chloroformate is ethyl chloroformate or methyl
chlorotbrmate and the amine is selected from the group consisting of N-methyl
morpholine. N.N-dimethyl benzyl amine. pyridine, picoline, and lutidine.
4. The process of claim 1. wherein step i) is performed in a solvent.
5. The process of claim 4. wherein the solvent comprises one or more of a
halogcnated hydrocarbon, ketone. ester, ether, nitrile. aromatic hydrocarbon or mixtures
thereof
6. The process of claim 1. wherein the step i) is carried out at temperature from about
-HOT to about SOT.
7. The process of claim 4. wherein a co-solvent is used.
8. The process of claim 7. wherein the co-solvent is selected from the group
consisting of Ibrmamide. aeetamide. N.N-dimethyl formamide. N-methylacetamide. N.N-
dimethylacetamide. and N-methylpyrrolidone.
9. The process of claim 1. wherein the step ii) is performed in a solvent.
10. The process of claim 9. wherein the solvent comprises one or more of halogenated
hydrocarbon, ketone. ester, ether, nitrile. aromatic hydrocarbon, or mixtures thereof
11. The process of claim 1. wherein the step ii) is carried out at temperatures from
about -60T to about 25T.
12. The process of claim 1, wherein the 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, and silazanes, in combination
with a halosilane or an am inc.
13. The process of claim 12. wherein the silylation agent is selected from the group
consisting of N.()-bis-(trimelhylsilyl)acetamide (BSA). N-methyl-N-trimethylsilyl-
acelamide (MSA). N.N'-bis-(trimethylsilyl)-urea (BSU), and 1,1. 3.3.3-
hexamethyldisilazane (HMDS), halosilane is trimethvlchlorsilane and
dimethyldichlorosilane and the amine comprises one or more of triethylamine, and
tert.octylamine.
14. Compounds of Formula I.


(Formula IV Removed)
FORMULA I
wherein R is C1-6 alkyl. C2-6 alkenyl. C2-6alkynyl. C2_6 alkadienyl, cyclic C3-6alkyl, aryl,
substituted aryl, heteroaryl. or heteroarylthioalkyl. having less than 0.5% by weight of the impurity of Formula B.
(Formula B Removed)
FORMULA B
wherein R is as defined above.
15. The compound of claim 14. wherein the R group is methyl, 1-propenyl and 1.2.3-triazol-5-yl thiomethvl.
16. The compound of claim 14. wherein the impurity of Formula B is less than 0.1% by weight.
17. The compound of claim 16. wherein the impurity of Formula-B is less than 0.05% by weight.
18. The compound of claim 14 or 15. wherein the alkyl group in the impurity of Formula B is methyl or ethyl.
lc). A pharmaceutical composition comprising the compound of claim 14 or 15 optionally together with pharmaceutically acceptable carriers, excipients or diluents.
20. A pharmaceutically acceptable composition comprising a pharmaceutically acceptable effective amount of a compound according to claim 14 or 15 with a pharmaceutically acceptable carrier for treating bacterial infections.