U.S. patent application number 10/700679 was filed with the patent office on 2004-07-08 for process for the preparation of cephalosporins.
This patent application is currently assigned to ORCHID CHEMICALS & PHARMACEUTICALS, LTD.. Invention is credited to Deshpande, Pandurang Balwant, Kamma, Ramakrishna, Luthra, Parven Kumar, Sreedhar, Gedi.
Application Number | 20040132995 10/700679 |
Document ID | / |
Family ID | 29287798 |
Filed Date | 2004-07-08 |
United States Patent
Application |
20040132995 |
Kind Code |
A1 |
Deshpande, Pandurang Balwant ;
et al. |
July 8, 2004 |
Process for the preparation of cephalosporins
Abstract
The present invention relates to a process for the preparation
of cephalosporin antibiotics of the formula (I) 1
Inventors: |
Deshpande, Pandurang Balwant;
(Chennai, IN) ; Luthra, Parven Kumar; (Chennai,
IN) ; Kamma, Ramakrishna; (Chennai, IN) ;
Sreedhar, Gedi; (Chennai, IN) |
Correspondence
Address: |
OLIFF & BERRIDGE, PLC
P.O. BOX 19928
ALEXANDRIA
VA
22320
US
|
Assignee: |
ORCHID CHEMICALS &
PHARMACEUTICALS, LTD.
CHENNAI
IN
|
Family ID: |
29287798 |
Appl. No.: |
10/700679 |
Filed: |
November 5, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10700679 |
Nov 5, 2003 |
|
|
|
10207103 |
Jul 30, 2002 |
|
|
|
Current U.S.
Class: |
540/222 ;
540/223 |
Current CPC
Class: |
C07D 501/00
20130101 |
Class at
Publication: |
540/222 ;
540/223 |
International
Class: |
C07D 501/14 |
Foreign Application Data
Date |
Code |
Application Number |
May 3, 2002 |
IN |
338/MAS/2002 |
Claims
1. A process for the preparation of cephalosporin antibiotics of
the formula (I) or its esters, which form prodrug or a counter ion
which forms salt 20wherein R.sub.1 represents hydrogen, trityl,
CH.sub.3, CR.sub.aR.sub.bCOOR.sub.c where R.sub.a and R.sub.b
independently represent hydrogen or methyl and R.sub.c represents
hydrogen or (C.sub.1-C.sub.6)alkyl; R.sub.2 represents hydrogen,
CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2OCOCH.sub.3, CH.dbd.CH.sub.2,
CH.sub.2OCONH.sub.2, 21which comprises: (i) condensing the
activated derivative of the formula (III) 22where X represents
halogen atom such as chlorine or bromine, with silylated derivative
of 7-amino cephalosporin of the formula (XIII) 23wherein R
represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or
diphenylmethyl group and R.sup.2 is as defined above in the
presence of a solvent at a temperature in the range of -50.degree.
C. to 0.degree. C. to produce a compound of formula (XIV), 24where
R.sup.1 is as defined above, (ii) cyclising the compound of formula
(XIV) with thiourea in the presence of solvent and sodium acetate
at room temperature to produce cephalosporin compound of the
formula (XV) 25wherein all symbols are as defined above, (iii)
deesterifying the compound of formula (XV) using
anisole/trifluoroacetic acid, phenol/trifluoroacetic acid, formic
acid in the presence or absence of a solvent at a temperature in
the range of 0.degree. C. to 60.degree. C. to produce a compound of
formula (I) and (iv) converting the compound of formula (I) to its
pharmaceutically acceptable salt or its esters which form
prodrug.
2. The process as claimed in claim 1, wherein the solvent used for
condensation is selected from dichloromethane, ethyl acetate,
tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane,
acetonitrile, DMAc, N,N-dimethylformamide, dialkylethers, water or
mixtures thereof.
3. The process as claimed in claim 1, wherein the activated
derivative of the compound of formula (III) is an acid halide, a
mixed anhydride, an active ester or an active amide
4. The process as claimed in claim 1, wherein solvent used for
cyclisation in step (ii) is selected from water, tetrahydrofuran,
acetone, acetonitrile, N,N-dimethylformamide,
N,N-dimethylacetamide, dioxane, (C.sub.1-C.sub.3)alcohol or
mixtures thereof.
5. The process as claimed in claim 1, wherein the solvent used for
deesterification in step (iii) is selected from dichloromethane or
dichloroethane.
6. The process as claimed in claim 1, wherein the pharmaceutically
acceptable salt is sodium or hydrochloride.
7. The process as claimed in claim 1, wherein the prodrug ester is
proxetil, axetil, hexetil or pivoxil.
8. A process for the preparation of compound of formula (XIII)
26which comprises; (i) reacting the 7-aminocephalosporin derivative
of the formula (XVI) 27wherein R.sub.3 represents hydrogen,
(C.sub.1-C.sub.4)alkyl, substituted or unsubstituted phenyl or
substituted or unsubstituted phenoxy with R.sub.2--X, wherein X
represents halogen atom and R.sub.2 represents hydrogen, CH.sub.3,
CH.sub.2OCH.sub.3, CH.sub.2OCOCH.sub.3, CH.dbd.CH.sub.2,
CH.sub.2OCONH.sub.2, 28in the presence in an organic solvent and a
base at a temperature in the range of 0.degree. C. to 30.degree. C.
to produce 7-aminocephalosporin derivative of the formula (XVII),
29(ii) deacylating the compound formula (XVII) using
PCl.sub.5/POCl.sub.3/pyridi- ne, PCl.sub.5/pyridine, triphenyl
phosphite/Cl.sub.2 complexes in the presence of an alcohol, at a
temperature in the range of -40.degree. C. to 0.degree. C. to
produce a compound of the formula (XIII) and (iii) isolating the
compound of formula (XIII).
9. The process as claimed in claim 8, wherein the solvent used in
step (i) is selected from tetrahydrofuran, acetone, acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, dioxane,
(C.sub.1-C.sub.3)alcohol or mixtures thereof
10. The process as claimed in claim 8, wherein the base used in
step (i) is selected from sodium acetate, potassium carbonate,
triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO),
1,5-diaza-bicyclo[4,3,0]-non-5-e- ne (DBN),
1,8-diazabicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium
carbonate.
11. A process for the preparation of compound of formula (XIII)
30wherein R.sub.2 represents hydrogen, CH.sub.3, CH.sub.2OCH.sub.3,
CH.sub.2OCOCH.sub.3, CH.dbd.CH.sub.2, CH.sub.2OCONH.sub.2, 31which
comprises; (i) acylating the 7-aminocephalosporin derivative of the
formula (XVIII) 32phenyl acetyl chloride to produce compound of
formula (XIX) 33in the presence of an organic solvent at a
temperature in the range of -20.degree. C. to 30.degree. C., (ii)
esterifying the compound of formula (XIX) using an esterifying
agent in the presence of a solvent and a base at a temperature in
the range of 25.degree. C. to 50.degree. C. to produce a compound
of formula (XX) 34(iii) deacylating the compound of formula (XX)
using PCl.sub.5/POCl.sub.3/pyridine, PCl.sub.5/pyridine, triphenyl
phosphite/Cl.sub.2 complexes in the presence of an alcohol, at a
temperature in the range of -40.degree. C. to 0.degree. C. to
produce a compound of the formula (XIII) and (iv) isolating the
compound of formula (XIII).
12. The process as claimed in claim 11, wherein the solvent used in
step (i) is selected from toluene, xylene, benzene, methylene
dichloride, chloroform, ethyl acetate and the like.
13. The process as claimed in claim 11, wherein the base used in
step (ii) is selected from sodium carbonate, potassium carbonate,
sodium bicarbonate or potassium bicarbonate.
14. The process as claimed in claim 11, wherein the esterifying
agent is selected from diphenyl diazomethane, alkyl halide,
p-methoxybenzyl chloride, p-nitrobenzyl chloride.
15. The process as claimed in claim 11, wherein the solvent used
for esterification is selected from methylene dichloride,
chloroform, ethyl acetate, toluene, water, tetrahydrofuran,
acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide
N,N-dimethylacetamide, dioxane, (C.sub.1-C.sub.3)alcohol or
mixtures thereof.
16. A process for the preparation of compound of formula (XIII)
35wherein R.sub.2 represents hydrogen, CH.sub.3, CH.sub.2OCH.sub.3,
CH.sub.2OCOCH.sub.3, CH.dbd.CH.sub.2, CH.sub.2OCONH.sub.2,
36comprising esterifying the compound of the formula (XVIII)
37using an esterifying agent in the presence of a solvent and
base.
17. The process as claimed in claim 16, wherein the solvent used is
selected from tetrahydrofuran, acetone, acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, dioxane,
(C.sub.1-C.sub.3)alcohol or mixtures thereof.
18. The process as claimed in claim 16, wherein the base used is
selected from sodium acetate, potassium carbonate, triethylamine,
1,4-diazabicyclo-[2,2,2]-octane (DABCO),
1,5-diazabicyclo[4,3,0]-non-5-en- e (DBN),
1,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium
carbonate.
19. An intermediate of the formula (XIV) 38wherein X represents
halogen atom such as chlorine or bromine; R represents
p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group; R.sub.2
represents hydrogen, CH.sub.3, CH.sub.2OCH.sub.3,
CH.sub.2OCOCH.sub.3, CH.dbd.CH.sub.2, CH.sub.2OCONH.sub.2, 39
Description
[0001] This application is a continuation in part of pending U.S.
application Ser. No. 10/207,103 filed on Jul. 30, 2002.
FIELD OF THE INVENTION
[0002] The present invention relates to a process for the
preparation of cephalosporin antibiotics of the formula (I) 2
[0003] wherein R.sub.1 represents hydrogen, trityl, CH.sub.3,
CR.sub.aR.sub.bCOOR.sub.c where R.sub.a and R.sub.b independently
represent hydrogen or methyl and R.sub.c represents hydrogen or
(C.sub.1-C.sub.6)alkyl; R.sub.2 represents CH.sub.3,
CH.sub.2OCH.sub.3, CH.sub.2OCOCH.sub.3, CH.dbd.CH.sub.2, 3
BACKGROUND OF THE INVENTION
[0004] EP 0030294 discloses a process for the preparation of
compound of cephalosporin antibiotic as given in scheme 1: 4
[0005] wherein R represents hydrogen atom or a readily hydrolysable
ester group and X represents one of the groups 5
[0006] EP patent 0 842 937 discloses a process for the preparation
of compound of cephalosporin antibiotic as given in scheme 2: 6
[0007] wherein R is 7
[0008] WO 00/63214 discloses a process for the preparation of
cephalosporins by condensation of carboxy ester intermediate with
silylated thiourea. 8
[0009] wherein X and R.sub.1 are substituents useful in
cephalosporin chemistry and R.sub.E is hydrogen, a negative charge
or together with the COO-- group to which R.sub.E is attached is an
ester, Y is halogen; R' is hydrogen or silyl and R" is silyl;
R'.sub.E is silyl or together with the COO-- group to which R.sub.E
is attached is an ester.
[0010] This patent publication discloses an alternate process,
which involves the desilylation of compound of formula (II) and
then condensation of desilylated compound with thiourea.
[0011] WO 02/083634 discloses a process for the preparation of
cefpodoxime of formula (XII), as shown in scheme 3 below: 9
[0012] wherein R is hydrogen or silyl group and R' is silyl group
or COOR' is a carboxylic acid salt; X is halogen. The process
comprises reacting the compound of formula (IX) with compound of
formula (III) and desilylating the compound of formula (X) and
cyclizing the desilylated compound with thiourea to produce
cefpodoxime acid of formula (XII).
OBJECTIVES OF THE INVENTION
[0013] The primary objective of the invention is to provide a new
method for the preparation of cephalosporin antibiotics of the
formula (I), which would be easy to implement in commercial
scales.
SUMMARY OF THE INVENTION
[0014] Accordingly, the present invention provides a process for
the preparation of cephalosporin antibiotics of the formula (I) or
its esters, which form prodrug or a counter ion which forms salt
10
[0015] wherein R.sub.1 represents hydrogen, trityl, CH.sub.3,
CR.sub.aR.sub.bCOOR.sub.c where R.sub.a and R.sub.b independently
represent hydrogen or methyl and R.sub.c represents hydrogen or
(C.sub.1-C.sub.6)alkyl; R.sub.2 represents hydrogen, CH.sub.3,
CH.sub.2OCH.sub.3, CH.sub.2OCOCH.sub.3, CH.dbd.CH.sub.2,
CH.sub.2OCONH.sub.2, 11
[0016] which comprises:
[0017] (i) condensing the activated derivative of the formula (III)
where X represents halogen atom such as chlorine or bromine, with
silylated derivative of 7-amino cephalosporin of the formula (XIII)
wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or
diphenylmethyl group in the presence of a solvent at a temperature
in the range of -50.degree. C. to 0.degree. C. to produce a
compound of formula (XIV), where R is as defined earlier,
[0018] (ii) cyclising the compound of formula (XIV) with thiourea
in the presence of solvent and sodium acetate at room temperature
to produce cephalosporin compound of the formula (XV) wherein R is
as defined earlier,
[0019] (iii) deesterifying the compound of formula (XV) using
anisole/trifluoroacetic acid, phenol/trifluoroacetic acid, formic
acid in the presence or absence of a solvent at a temperature in
the range of 0.degree. C. to 60.degree. C. to produce a compound of
formula (I) and
[0020] (iv) converting the compound of formula (I), to its
pharmaceutically acceptable salt or its esters which form
prodrug.
[0021] The process is shown in Scheme-4 below 12
[0022] In yet another embodiment of the present invention, there is
provided a process for the preparation of compound of formula
(XIII) 13
[0023] which comprises:
[0024] (i) reacting the 7-aminocephalosporin derivative of the
formula (XVI) wherein R.sub.3 represents hydrogen,
(C.sub.1-C.sub.4)alkyl, substituted or unsubstituted phenyl or
substituted or unsubstituted phenoxy with R.sub.2--X, wherein X
represents halogen atom and R.sub.2 is as defined earlier in the
presence in an organic solvent and a base at a temperature in the
range of 0.degree. C. to 30.degree. C. to produce
7-aminocephalosporin derivative of the formula (XVII),
[0025] (ii) deacylating the compound formula (XVII) using
PCl.sub.5/POCl.sub.3/pyridine, PCl.sub.5/pyridine, triphenyl
phosphite/Cl.sub.2 complexes in the presence of an alcohol, at a
temperature in the range of -40.degree. C. to 0.degree. C. to
produce a compound of the formula (XIII) and
[0026] (iii) isolating the compound of formula (XIII).
[0027] The process is shown in Scheme-5 below 14
[0028] In yet another embodiment of the present invention, there is
provided a process for the preparation of compound of formula
(XIII) 15
[0029] which comprises:
[0030] (i) acylating the 7-aminocephalosporin derivative of the
formula (XVIII) phenyl acetyl chloride to produce compound of
formula (XIX) in the presence of an organic solvent at a
temperature in the range of -20.degree. C. to 30.degree. C.,
[0031] (ii) esterifying the compound of formula (XIX) using an
esterifying agent in the presence of a solvent and a base at a
temperature in the range of 25.degree. C. to 50.degree. C. to
produce a compound of formula (XX)
[0032] (iii) deacylating the compound of formula (XX) using
PCl.sub.5/POCl.sub.3/pyridine, PCl.sub.5/pyridine, triphenyl
phosphite/Cl.sub.2 complexes in the presence of an alcohol, at a
temperature in the range of -40.degree. C. to 0.degree. C. to
produce a compound of the formula (XIII) and
[0033] (iv) isolating the compound of formula (XIII).
[0034] The process is shown in Scheme-6 below 16
[0035] In still another embodiment of the present invention the
compound of formula (XIII), can be prepared by a process, which
comprises esterifying the compound of the formula (XVIII) using an
esterifying agent in the presence of a solvent and base.
[0036] The process is as shown in Scheme-7 below 17
[0037] wherein R represents lower alkyl, p-methoxybenzyl,
p-nitrobenzyl or diphenylmethyl group and R.sup.2 is as defined
above.
[0038] In another embodiment of the present invention, there is
provided a new intermediate of the formula (XIV) 18
[0039] wherein X represents halogen atom such as chlorine or
bromine; R represents p-methoxybenzyl, p-nitrobenzyl or
diphenylmethyl group; R.sub.2 represents hydrogen, CH.sub.3,
CH.sub.2OCH.sub.3, CH.sub.2OCOCH.sub.3, CH.dbd.CH.sub.2,
CH.sub.2OCONH.sub.2, 19
DETAILED DESCRIPTION OF THE INVENTION
[0040] In yet another embodiment of the present invention, the
condensation of compound of formula (III) with (XIII) is performed
by using the activated derivative of formula (III) in the presence
of a solvent selected from dichloromethane, ethyl acetate,
tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane,
acetonitrile, DMAc, N,N-dimethylformamide, dialkylethers, water or
mixtures thereof.
[0041] The compound of formula (III) is activated as acid halides,
mixed anhydrides, active esters, active amides. The acid halides
are acid chlorides or acid bromides. The mixed anhydrides are
anhydrides of the compounds of formula (III) with pivaloyl
chloride, ethyl chloroformate, benzyl chloroformate.
[0042] In yet another embodiment of the present invention, the
silylation of 7-amino cephalosporin of the formula (XIII) is
carried out using silylating agent selected from
hexamethyldisilazane (HMDS), trimethylchlorosilane (TMCS),
trimethylsilyl iodide (TMSI), N,O-bis-(trimethylsilyl)-acetamide
(BSA), methyltrimethylsilyltrifluoroac- etamide (MSTFA),
N,O-bistrimethylsilyltrifiuoroacetamide (BSTFA),
methyldichlorosilane, dimethyldichlorosilane,
diphenyldichlorosilane, N-methylsilylacetamide (MSA),
bistrimethylsilylurea and the like.
[0043] In yet another embodiment of the present invention, the
cyclisation of compound of (XIV) is carried out using solvents
selected from water, tetrahydrofuran, acetone, acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, dioxane,
(C.sub.1-C.sub.3)alcohol and the like or mixtures thereof.
[0044] In still another embodiment of the present invention the
deesterification of compound of formula (XV) is carried out using
anisole/trifluoroacetic acid, phenol/trifluoroacetic acid, formic
acid in the absence or presence of dichloromethane, dichloroethane
as a solvent.
[0045] In another embodiment of the present invention, the
pharmaceutically acceptable salt is sodium or hydrochloride.
[0046] In yet another embodiment of the present invention the
prodrug ester is proxetil, axetil, hexetil, pivoxil and the
like.
[0047] In another embodiment of the present invention, the solvent
used for reacting the compound of formula (XVI) in step (i) of
scheme-5 is selected from tetrahydrofuran, acetone, acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, dioxane,
(C.sub.1-C.sub.3)alcohol or mixtures thereof, in the presence of a
base selected from sodium acetate, potassium carbonate,
triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO),
1,5-diazabicyclo[4,3,0]-non-5-en- e (DBN),
1,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium
carbonate.
[0048] In another embodiment of the present invention, the
acylation of compound of formula (XVIII) in step (i) of scheme-6 is
carried out in the presence of solvent selected from toluene,
xylene, benzene, methylene dichloride, chloroform, ethyl acetate
and the like.
[0049] In another embodiment of the present invention, the
esterification of compound of formula (XIX) in step (ii) of
scheme-6 is carried out using esterifying agents such as diphenyl
diazomethane, alkyl halide, p-methoxybenzyl chloride, p-nitrobenzyl
chloride and a solvent selected from methylene dichloride,
chloroform, ethyl acetate, toluene, water, tetrahydrofuran,
acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide
N,N-dimethylacetamide, dioxane, (C.sub.1-C.sub.3)alcohol or
mixtures thereof, in the presence of catalytic quantities of
iodine. The reaction is carried out in the presence of base such as
sodium carbonate, potassium carbonate, sodium bicarbonate,
potassium bicarbonate and the like.
[0050] In another embodiment of the present invention, the solvent
used for reaction in scheme-7 is selected from tetrahydrofuran,
acetone, acetonitrile, N,N-dimethylformamide,
N,N-dimethylacetamide, dioxane, (C.sub.1-C.sub.3)alcohol or
mixtures thereof, in the presence of a base selected from sodium
acetate, potassium carbonate, triethylamine,
1,4-diazabicyclo-[2,2,2]-octane (DABCO),
1,5-diazabicyclo[4,3,0]-non-5-en- e (DBN),
1,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium
carbonate.
[0051] The substituent on R.sub.3 in Scheme-5 is selected from
methyl, methoxy, nitro or halogen atom.
[0052] In yet another embodiment of the present invention, the
product obtained in any of the reactions may be used in next step
without isolation.
[0053] The present invention is provided by the examples below,
which are provided by way of illustration only and should not be
considered to limit the scope of the invention.
EXAMPLE-1
[0054] Step I
[0055] Preparation of
7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxy- lic Acid
[0056] 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid (7-AMCA)
(100 gm) was reacted with N,O-bis silyl acetamide (103.9 gm) in
presence of methylene dichloride (300 mL) at RT for 1 hour under
nitrogen atmosphere. The silylated mass was cooled to -10 to
-15.degree. C. To this phenyl acetyl chloride (95 gm) was added
over 30 minutes, and stirred for 1 hour. After completion of the
reaction, chilled water (1000 mL) was added at -10 to -15.degree.
C., distilled off methylene chloride under vacuum at 10-12.degree.
C. for 30 minutes. Filtered the product and washed with isopropyl
ether (1000 mL) and dried under vacuum 40-45.degree. C. till to get
the title compound (123 g, purity 95%).
[0057] Step II
[0058] Preparation of
7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxy- lic Acid
p-methoxy Benzyl Ester
[0059] p-Methoxy benzyl chloride (66 g) was stirred with sodium
iodide (41.4 g) in presence of dimethyl sulfoxide (200 mL) for 1
hour at 25-30.degree. C. To this
7-phenylacetamido-3-methoxymethyl-3-cephem-4-car- boxylic acid (100
gm) obtained in step I and sodium bicarbonate (35.3 g) was added
and stirred for 25-30.degree. C. for 5-7 hours. After completion of
the reaction, the reaction mass was cooled to 20.degree. C. and
added DM water (2.5 L) containing sodium thiosulphate (10 gm). The
reaction mixture was stirred for 30 min. at 25-30.degree. C.,
filtered the product and washed with DM water (500 mL). Finally
stirred the product with methanol (600 mL) at -5.degree. C. and
filtered, dried the product under vacuum 40-45.degree. C. till
moisture less than 2% to get the title compound (120 gm, purity
96%).
[0060] Step III
[0061] Preparation of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic
Acid p-methoxy Benzyl Ester
[0062] To a suspension of PCl.sub.5 (6.5 gm) in MDC (100 mL),
pyridine (2.5 gm) was added under ice cooling and the resulting
suspension was stirred at this temperature for 30 minutes. To this
7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid
p-methoxy benzyl ester (10 g) obtained in step II was added at
below 0.degree. C. After stirring at 0.degree. C. for 90-120 min,
the reaction mixture was cooled to -40.degree. C. To the cooled
mixture pre-cooled methanol (30 mL, 3 volumes) was added below
-10.degree. C. for 30 minutes. After being stirred at 0.degree. C.
for 30 minutes, the mixture was concentrated at 45.degree. C. to
get residue. This residue was triturated with water (10 mL), EtOAc
(40 mL) and isopropyl ether (IPE) (40 mL). The resulting
precipitate was collected by filtration, washed with IPE and dried
to get the title compound (6.5 gm, >98%).
[0063] Step IV
[0064] Preparation of
7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]--
3-methoxymethyl-3-cephem-4-carboxylic Acid p-methoxy Benzyl
Ester
[0065] To a suspension of
7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl
ester (10 g), in MDC (50 mL, 5 volumes) obtained in step III, BSA
(10 g) was added at 30.degree. C. for 30 minutes. After stirring at
30.degree. C. for 50-60 minutes solution was cooled to -30.degree.
C.
[0066] Meanwhile in another flask to a suspension of PCl.sub.5
(7.89 g) in MDC (50 mL, 5 volumes),
4-chloro-2(Z)-methoxyimino-3-oxo-butyric acid chloride (6.759) was
added in four lots at 0 to -10.degree. C. The resulting clear
solution was added to the above silylated solution at -30 to
-20.degree. C. for 10-15 minutes time. After being stirred for
another 15 minutes at same temperature, chilled water (100 ml, 5
volumes) was added for 5 minutes time. Concentrated the separated
organic layer at 40-45.degree. C. to get residue, which is
triturated, with IPE (100 mL) to get the title compound (9.0 gm,
90%).
[0067] Step V
[0068] Preparation of
7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-- 3
methoxymethyl-3-cephem-4-carboxylic Acid p-methoxy Benzyl Ester
[0069] To a mixture of THF (50 mL) and water (50 mL),
7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]-3-methoxymethyl-3-cep-
hem-4-carboxylic acid p-methoxy benzyl ester (10 g) obtained in
step IV was added at 30.degree. C. To this thiourea (1.74 g) and
sodium acetate (7.8 gm) at 30.degree. C. was added and the
resulting solution was stirred at 30.degree. C. for 8-10 hours.
After extracting the mixture with methylene dichloride (MDC) (100
mL), the resulting MDC layer was concentrated at 40.degree. C. to
get residue. This residue was crystallized with MDC-IPE (1:5)
mixture to get the title compound (9.5 g, 90%).
[0070] Step VI
[0071] Preparation of
7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]--
3-methoxymethyl-3-cephem-4-carboxylic Acid (Cefpodoxime Acid)
[0072] Addition of trifluoro acetic acid (20.75 g) to a stirred
solution of phenol (125 mL) and
7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido-
]-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester
obtained in step V (50 gm) at 40.degree. C. over 20-30 minutes. The
reaction mixture was maintained at 40-45.degree. C. for 2-4 hours.
Monitored the reaction by HPLC. After completion of the reaction,
the reaction mixture was cooled to 25-30.degree. C. and chilled
water (250 mL), ethyl acetate (250 mL) was added and adjusted the
pH to 7.3-7.5 with 25% Na.sub.2CO.sub.3 solution (90 mL) at
20.degree. C. Stirred and separated the layers and extracted the
aqueous layer with ethyl acetate (250 mL) and separated the layers.
Adjusted the pH to 5.8 with 10% H.sub.2SO.sub.4 solution and
charged carbon (10 gm), sodium dithionite (0.35 gm), and stirred
the reaction mixture for 1 hour. Filtered and washed with water (50
mL). Adjusted the pH to 2.8 with 10% H.sub.2SO.sub.4 solution at
20-25.degree. C. and stirred the reaction mixture at 5.degree. C.
for 3 hours. Filtered the product and washed with chilled acetone
(-5 to -10.degree. C., 100 mL) and suck dried to get the title
compound (20 gm, purity>98%).
EXAMPLE-2
[0073] Step I
[0074] Preparation of
7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]--
3-methoxymethyl-3-cephem-4-carboxylic Acid p-methoxy Benzyl
Ester
[0075] To a suspension of PCl.sub.5 (6.5 gm) in MDC (100 mL),
pyridine (2.5 gm) was added under ice cooling and the resulting
suspension was stirred at this temperature for 30 minutes. To this
7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid
p-methoxy benzyl ester (10 g) obtained in step II was added at
below 0.degree. C. After stirring at 0.degree. C. for 90-120 min,
the reaction mixture was cooled to -40.degree. C. To the cooled
mixture pre-cooled methanol (30 mL, 3 volumes) was added below
-10.degree. C. for 30 minutes. After being stirred at 0.degree. C.
for 60 minutes, the mixture temperature was taken to -20.degree. C.
and charged 20 ml of water below -10.degree. C. The pH of the mass
is adjusted to 4-4.5 by adding 25% of sodium carbonate solution (40
ml) keeping the temperature below -5.degree. C. The temperature of
the reaction mass is raised to 30.degree. C. in 30-40 min. The
layers were separated and to the organic layer was added
Bis-(trimethylsilyl)urea (BSU) 8.5 g. The mass was stirred for 2-3
Hrs at 30.degree. C.
[0076] The mixture was cooled to -30.degree. C. Meanwhile in
another flask to a suspension of PCl.sub.5 (6.5 g) in MDC (50 mL, 5
volumes), 4-chloro-2(Z)-methoxyimino-3-oxo-butyric acid (5.6 g) was
added in four lots at 0 to -10.degree. C. The resulting clear
solution was added to the above silylated solution at -30 to
-20.degree. C. for 10-15 minutes time. After being stirred for
another 15 minutes at same temperature, chilled water (100 m, 10
volumes) was added in 5-10 minutes. The temperature of the mass was
raised to 30.degree. C. over a period of 30-40 min. The layers were
separated and the organic layer was treated with sodium carbonate
solution to bring its pH to 5.8-6.2. Again the layers were
separated and the organic layer was concentrated at 40-45.degree.
C. under vacuum to get residue, which is triturated, with IPE (100
mL) to get the title compound (8.0 gm, purity>85%)
[0077] Step II
[0078] Preparation of
7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]--
3-methoxymethyl-3-cephem-4-carboxylic Acid (Cefpodoxime Acid)
[0079] To a mixture of THF (50 mL) and water (50 mL),
7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]-3-methoxymethyl-3-cep-
hem-4-carboxylic acid p-methoxy benzyl ester (10 g) obtained in
step III was added at 30.degree. C. To this thiourea (1.74 g) and
sodium acetate (7.8 gm) at 30.degree. C. was added and the
resulting solution was stirred at 30.degree. C. for 8-10 hours.
After extracting the mixture with methylene dichloride (MDC) (100
mL), the resulting MDC layer was concentrated at 40.degree. C. to
get residue. To this residue was added phenol (25 mL) at
40-45.degree. C. Trifluoro acetic acid (4.2 g) was added to the
above mixture in 20-25 min at 40-45.degree. C. The reaction mass
was stirred for 4-5 Hrs and finally poured into a mixture of ethyl
acetate (50 ml) and water (50 ml). The pH of the reaction mass was
adjusted to 8.5 with 25% sodium carbonate solution at 30.degree. C.
The layers were separated. The aqueous layer was again washed with
50 ml of ethyl acetate. Finally the aqueous layer is treated with
charcoal (1.0 g), charcoal is filtered off and to the clear
filtrate dilute sulfuric acid is added to bring the pH to 2.6-2.8.
The mixture was cooled to 5.degree. C. and product was collected by
filtration and washed with acetone (3.0 g, purity>98%).
* * * * *