U.S. patent application number 13/340289 was filed with the patent office on 2012-04-19 for process for the preparation of beta-lactam antibiotic.
This patent application is currently assigned to ORCHID CHEMICALS & PHARMACEUTICALS LIMITED. Invention is credited to Pramod Narayan DESHPANDE, Panchapakesan GANPATHY, Syril Sudhan HENRY, Arvind Atmaram JANGALE, Ram Dattatray KALDATE, Sanjay Nivruti KARALE, Rajendra Janardan SARANGDHAR, Selvakumar SEKAR, Senthilkumar SURULICHAMY.
Application Number | 20120095210 13/340289 |
Document ID | / |
Family ID | 37865315 |
Filed Date | 2012-04-19 |
United States Patent
Application |
20120095210 |
Kind Code |
A1 |
SURULICHAMY; Senthilkumar ;
et al. |
April 19, 2012 |
PROCESS FOR THE PREPARATION OF BETA-LACTAM ANTIBIOTIC
Abstract
The present invention provides a novel process for the
preparation of the meropenem trihydrate of formula (I).
##STR00001##
Inventors: |
SURULICHAMY; Senthilkumar;
(Chennai, IN) ; SEKAR; Selvakumar; (Chennai,
IN) ; DESHPANDE; Pramod Narayan; (Chennai, IN)
; GANPATHY; Panchapakesan; (Chennai, IN) ;
SARANGDHAR; Rajendra Janardan; (Chennai, IN) ; HENRY;
Syril Sudhan; (Chennai, IN) ; KARALE; Sanjay
Nivruti; (Aurangabad, IN) ; JANGALE; Arvind
Atmaram; (Aurangabad, IN) ; KALDATE; Ram
Dattatray; (Aurangabad, IN) |
Assignee: |
ORCHID CHEMICALS &
PHARMACEUTICALS LIMITED
Chennai
IN
|
Family ID: |
37865315 |
Appl. No.: |
13/340289 |
Filed: |
December 29, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11991624 |
Apr 30, 2009 |
|
|
|
PCT/IB2006/002548 |
Sep 15, 2006 |
|
|
|
13340289 |
|
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Current U.S.
Class: |
540/350 |
Current CPC
Class: |
A61P 17/00 20180101;
A61P 15/00 20180101; A61P 13/02 20180101; A61P 31/00 20180101; A61P
31/04 20180101; C07D 477/20 20130101; C07D 477/06 20130101; A61P
11/00 20180101 |
Class at
Publication: |
540/350 |
International
Class: |
C07D 477/20 20060101
C07D477/20 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 15, 2005 |
IN |
1301/CHE/2005 |
Aug 22, 2006 |
IN |
1486/CHE/2006 |
Claims
1. An improved process for preparation of compound of formula (V),
which comprises the steps of: ##STR00009## wherein PNB represents
p-nitrobenzyl and PNZ represents p-nitrobenzyloxycarbonyl i)
reacting the activated compound of formula (III) with mercaptan of
formula (IV) in the presence or absence of base in a water-miscible
organic solvent to yield compound of formula (V); ##STR00010## ii)
quenching the reaction mass from step (i) in water in the presence
or absence of buffer; iii) optionally adjusting the pH of step (ii)
mass to 3.0 to 5.0; and iv) filtering the compound of formula
(V).
2. The process as claimed in claim 1, wherein the base used in step
(i) is selected from organic amines selected from group comprising
diisopropylamine, diisopropylethylamine, triethylamine, pyridine,
4-dimethylaminopyridine, tetramethylguanidine (TMG) or mixtures
thereof.
3. The process as claimed in claim 1, wherein water-miscible
organic solvent used in step (i) is selected from tetrahydrofuran,
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidinone, N-ethylpyrrolidinone, N-methylpiperidinone,
acetonitrile, propionitrile, acetone, ethanol, methanol, isopropyl
alcohol, 1-propanol, methyl ethyl ketone, DMSO or mixtures
thereof.
4. The process as claimed in claim 3, wherein water-miscible
organic solvent is selected from N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidinone; preferably
N,N-dimethylformamide.
5. The process as claimed in claim 1, wherein the buffer used in
step (ii) is selected from dipotassium hydrogen orthophosphate or
potassium dihydrogen orthophosphate.
6. A process as claimed in claim 1, further comprising converting
compound of formula (V) into Meropenem or its hydrate by
deprotection.
Description
[0001] This is a Division of application Ser. No. 11/991,624 filed
Apr. 30, 2009, which in turn is a National Phase of
PCT/IB2006/002548 filed Sep. 15, 2006, which claims priority of
Indian Applications No. 1301/CHE/2005 filed Sep. 15, 2005 and No.
1486/CHE/2006 filed Aug. 22, 2006. The disclosure of the prior
applications is hereby incorporated by reference herein in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention provides an improved process for the
preparation of the compound of formula (I) or its hydrate in a pure
form.
##STR00002##
[0003] The present invention further provides an improved process
for the preparation of compound of formula (V) in amorphous form,
which is an important intermediate in the preparation of Meropenem
of formula (I)
##STR00003##
wherein PNB represents p-nitrobenzyl group and PNZ represents
(p-nitrobenzyloxycarbonyl group.
BACKGROUND OF THE INVENTION
[0004] Meropenem is a broad spectrum, beta-lactamase-resistant,
carbapenem antibiotic for parenteral administration. The compound
of the formula (I) is generically known as meropenem and is used as
antibiotic agent in the treatment of pneumonia, urinary tract
infections, intra-abdominal, gynaecological, skin, and soft tissue
infections, meningitis, septicemia and febrile neutropenia. In USA
it is sold under the trade name of MERREM.RTM. I.V. (meropenem for
injection). MERREM is a sterile, pyrogen-free, synthetic, broad
spectrum, carbapenem antibiotic for intravenous administration, and
chemically known as
(4R,5S,6S)-3-[[(3S,5S)-5-(dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-
-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic
acid trihydrate. In view of the importance of the compound of the
formula (I), several synthetic procedures to prepare the compound
have been reported.
[0005] U.S. Pat. No. 4,888,344 provides crystalline Meropenem
trihydrate along with non-toxic carbonate composition. According to
this patent, Meropenem was obtained by deprotecting the protecting
groups of the penultimate compound by hydrogenation as per the
following scheme.
##STR00004##
[0006] U.S. Pat. No. 4,943,569 claims Meropenem and process for its
preparation. This patent utilizes buffer like morpholinoalkyl
sulfonic acid (MOPS) or its salt during deprotection stage. The
description also discloses that the penultimate intermediate
(diprotected Meropenem) of Meropenem can be isolated by
organochemical means.
[0007] According to the above said patents, Meropenem trihydrate
was obtained by subjecting the aqueous reaction mass obtained after
the deprotection of protecting group, to reverse osmosis (if
required), followed by adding water-miscible organic solvent such
as ethanol, iso-propanol, acetone, tetrahydrofuran (THF), dioxane,
acetonitrile, etc.
[0008] IN 198820 provide a method for the preparation of Meropenem
wherein biphasic solvent system such as Water-THF-Ethyl acetate was
utilized for deprotection (where R' is allyloxycarbonyl). After
deprotection of the protecting groups, the aqueous layer was
subjected to crystallization of meropenem trihydrate by the
addition of THF.
[0009] WO2006/035300 A2 describes a process for preparing
Meropenem. This patent publication describes the use of biphasic
solvent system for the deprotection step resulting in Meropenem,
which is similar to the teachings given in U.S. Pat. No. 4,943,569,
where ethyl acetate was added after the hydrogenation to remove
organic impurity, and obvious over our Indian patent, 198820. Even
though U.S. Pat. No. 4,943,569 teaches the isolation of
penultimate, which is not necessary as mentioned, "After completion
of the reaction, the reaction product (i.e formula (V)) can be
isolated by usual organochemical means"; WO2006/035300A2
publication claims a process for preparing Meropenem trihydrate in
which the penultimate compound of formula (V) was not isolated.
Similarly, U.S. Pat. No. 4,888,344, which teaches "when the
catalytic hydrogenation is carried out in a water-containing
organic solvent, the filtrate obtained by filtration of the
reaction mixture for removal of the catalyst may be subjected to
distillation for evaporation of the organic solvent. In such case,
Compound A (Meropenem trihydrate) can be crystallized out directly
from the resultant aqueous concentrate. Thus, crystalline Compound
A is obtainable without separation and isolation of non-crystalline
Compound A, for instance, by column chromatography or
lyophilization", claims a direct process for preparing Meropenem
trihydrate in which the crystallization is done directly after
deprotection.
[0010] WO2005/118586 A1 claims crystalline penultimate compound of
formula (V) and a process for preparing this intermediate.
According to this publication this intermediate is crystallized out
either from concentrating the mother liquor in alkyl alkanoate such
as ethyl acetate or by the addition of anti-solvent such as
cyclohexane or heptane to the mother liquor in ethyl acetate. Since
this patent describes the use of multiple solvent systems, the
processes are not commercially viable from industrial point of view
owing to multiple solvent recoveries, adding further the cost of
production.
[0011] As per U.S. Pat. No. 4,888,344 in example 1, Meropenem is
dissolved in water, where upon small amount of meropenem crystals
formed and further addition of acetone yielded meropenem
trihydrate. Since the sterile preparation requires complete
dissolution for sterile filtration, this technique is not found
attractive.
[0012] With our continued research for developing a process for the
preparation of compound of formula (I) as sterile product, we have
come up with a process, which is not only commercially viable, but
also involves simple techniques such as crystallizations, isolation
of the penultimate of formula (V) avoiding multiple solvents. None
of the prior art suggests or teaches the techniques of the present
invention.
OBJECTIVES OF THE INVENTION
[0013] The main objective of the present invention is to provide a
simple and commercially viable process for the preparation of
compound of the formula (I) as sterile product in pure form.
[0014] Another objective of the present invention is to provide a
simple and commercially viable process for the preparation of
compound of the formula (I), which avoids chromatographic
techniques.
[0015] Yet another objective of the present invention is to provide
a simple and commercially viable process for the preparation of
compound of the formula (V), which avoids multiple solvent
systems.
SUMMARY OF THE INVENTION
[0016] Accordingly, the present invention provides a process for
the preparation of Meropenem trihydrate of formula (I), which
comprises the steps of: [0017] (a) dissolving Meropenem or its
trihydrate in water in the presence or absence of water-miscible
organic solvent and in the presence of base, [0018] (b) optionally
filtering through micron filter, [0019] (c) adjusting pH to 4.0 to
7.0 using acid, and [0020] (d) optionally adding solvent to
precipitate the Meropenem trihydrate of formula (I).
##STR00005##
[0021] The present invention further provides an improved process
for preparation of compound of formula (V), which comprises the
steps of:
##STR00006## [0022] (1) reacting the activated compound of formula
(III) with mercaptan of formula (IV) in the presence or absence of
base in a water-miscible organic solvent, [0023] (2) precipitating
the compound of formula (V) obtained in step (1) by mixing the
reaction mass from step (1) with water in the presence or absence
of buffer, [0024] (3) optionally adjusting the pH to 3.0 to 5.0,
[0025] (4) filtering the compound of formula (V).
[0026] In another embodiment of the present invention there is
provided an improved process for preparation of compound of the
formula (I), the said process comprising the steps of: [0027] (i)
activating the compound of formula (II) using an activating reagent
in the presence or absence of base and solvent to produce compound
of formula (III), [0028] (ii) reacting the activated compound of
formula (III) with mercaptan of formula (IV) in the presence or
absence of base and solvent to yield compound of formula (V),
[0029] (iii) deprotecting the compound of formula (V) by catalytic
hydrogenation to yield compound of formula (I), and [0030] (iv)
optionally converting the compound of formula (I) into sterile
compound of formula (I).
[0031] The process is shown in Scheme-I as given below:
##STR00007##
DRAWINGS OF THE INVENTION
[0032] FIG. 1: PXRD of amorphous form of diprotected meropenem
intermediate of compound of formula (V).
DETAILED DESCRIPTION OF THE INVENTION
[0033] In an embodiment of the present invention, the base used in
step (a) is selected from ammonia, sodium hydroxide, sodium
carbonate, potassium carbonate, diethylamine, diisopropylamine,
triethylamine, diisopropylethylamine, sodium bicarbonate, potassium
bicarbonate, sodium acetate, sodium-2-ethyl hexanoate, sodium
lactate and the like, preferably ammonia and water-miscible organic
solvents used in step (a) is selected from acetone, methanol,
ethanol, isopropanol, 1-propanol, THF, acetonitrile or mixtures
thereof.
[0034] In another embodiment of the present invention, the acid
used in step (c) is elected from HCl, formic acid, oxalic acid,
acetic acid, methane sulfonic acid, sulfuric acid, phosphoric acid,
trifluoroacetic acid and the like, preferably formic acid.
[0035] In yet another embodiment of the present invention, the
solvent used in step (d) is selected from THF, acetone, methyl
ethyl ketone, methanol, isopropanol, 1-propanol, ethanol and the
like or mixtures thereof, preferably THF.
[0036] In one more embodiment of the present invention, the
starting material, non-sterile Meropenem or its trihydrate is
prepared by utilizing the process given in our Indian patent,
198820 or by utilizing the process according to our present
invention or by any conventional methods.
[0037] In still another embodiment, the present invention can be
used for the purification of Meropenem trihydrate to achieve highly
pure Meropenem trihydrate by performing steps (a), (c) and (d).
[0038] In another embodiment of the present invention, the base
used in step (1) is an organic amine selected from
diisopropylamine, diisopropylethylamine, triethylamine, pyridine,
N,N-dimethylaminopyridine, N,N-diethylaminopyridine,
tetramethylguanidine (TMG) and the like or mixture thereof.
[0039] In still another embodiment of the present invention,
water-miscible organic solvent used in step (1) is selected from
tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidinone, N-ethylpyrrolidinone, N-methylpiperidinone,
acetonitrile, propionitrile, acetone, ethanol, methanol, isopropyl
alcohol, 1-propanol, methyl ethyl ketone, DMSO and other such
organic solvents known in the art or mixture thereof.
[0040] In yet another embodiment of the present invention, the
diprotected compound of the formula (V) is precipitated from the
reaction medium by mixing the reaction mass into water or buffer
solution or vice versa followed by filtering the solid obtained
thereof. Optionally the pH of the reaction mass in step (3) was
adjusted to the pH in the range of 3.0 to 5.0 and more specifically
3.6 to 4.2 using acid such as sulphuric acid, hydrochloric acid and
the like. The compound thus isolated is in amorphous form.
Alternatively the compound of formula (V) is used further in situ
for the preparation of compound of formula (I) thereby avoids the
need of isolation. The filtered compound of formula (V) is taken to
further steps either as a wet or dry material.
[0041] In another embodiment of the present invention, the
activating group represented by X in formula (III) is selected from
diphenyl phosphate, 2,4-dichlorodiphenyl phosphate, diethyl
thiophosphate, tosylate, mesylate and the like preferably diphenyl
phosphate and the activating reagent used in step (i) is selected
from diphenyl chlorophosphate, 2,4-dichlorodiphenylchloro
phosphate, diethyl chlorothiophosphate, p-toluenesulphonyl
chloride, methanesulphonyl chloride.
[0042] In another embodiment of the present invention, the base
used in step (i) or (ii) is selected from diisopropylamine,
ethyldiisopropylamine, triethylamine, pyridine,
N,N-dimethylaminopyridine, N,N-diethylaminopyridine and the like or
the mixtures thereof. If a mixture of base was employed then one of
the bases can be used in catalytic amount over the other.
[0043] In still another embodiment of the present invention, the
solvent used in step (i) or (ii) is selected from diethyl ether,
tetrahydrofuran, toluene, xylene, dichloromethane,
1,2-dichloroethane, N,N-dimethylformamide, dimethylacetamide,
N-methylpyrrolidinone, N-ethylpyrrolidinone, N-methylpiperidinone,
acetonitrile, propionitrile, and other such organic solvents known
in the art or mixtures thereof.
[0044] Accordingly, this invention also provides a common process
for isolation of compound of formula (III) or (V) which comprises
quenching the reaction mass obtained into a buffer solution
selected from dipotassium hydrogen orthophosphate, potassium
dihydrogen orthophosphate, and the like followed by extracting the
compound in an organic solvent like ethyl acetate, MDC
(dichloromethane), THF and the compound of formula (III) or (V) was
precipitated as white to off-white solid or paste in a crystalline
or amorphous forms or as a foamy solid using hexane or IPE
(diisopropylether) or methyl tert-butyl ether.
[0045] In one more embodiment of the present invention, the solvent
used in the deprotection stage in step (iii) is selected from THF,
dioxane, ethyl acetate, isopropyl alcohol, dichloromethane, DMF, or
mixtures thereof and water, and catalyst employed for reduction is
selected from platinum oxide, Pd/C, Pt/C and the like.
[0046] The starting material used in the present invention is
prepared by utilizing the process available in the literature, or
by utilizing the process given in Heterocycles 1984, 21, 29 as per
the scheme depicted below:
##STR00008##
[0047] Accordingly the starting material of the present invention
is prepared as follows: The compound of formula (C),
(3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-3-p-nitrobenzyloxycarbon-
yl-2-oxopropyl]-2-azetidine-2-one (which is prepared by treating
azetidinone carboxylic acid with Mg salt of malonic acid mono
p-nitrobenzyl ester in the presence of carbonyldiimidazole at
25-30.degree. C., followed by quenching the reaction mass to water
containing ammonium chloride, and extracting the product using
ethyl acetate and treating the ethyl acetate layer with
hydrochloric acid solution followed by quenching ethyl acetate
layer to ether to afford compound of formula (C)) was converted
into compound of formula (D) using 4-dodecylbenzenesulphonylazide
in the presence of solvent like acetonitrile, hexane and an organic
base like TEA, the compound of formula (D) was isolated from the
reaction mass by treating the reaction mass with hexane and buffer
solution followed by extracting into organic solvent like ethyl
acetate or MDC. The conversion of compound of formula (D) into
compound of formula (II) is carried out by using rhodium salt
preferably rhodium octanoate and optionally in the presence of
Lewis acid such as zinc halide preferably zinc iodide or zinc
bromide.
[0048] The foregoing technique has been found to be attractive from
commercial, technological and ecological perspective. The technique
given in the present invention can also be extended to the
preparation of other penems like Panipenem, doripenm, Ertapenem and
the like by simply replacing the corresponding mercaptan. The
penems thus obtained according to present invention can also be
administered in the conventional methods. The conventional
pharmaceutical composition may also contain one or more of the
following: chelating agent such as EDTA; or buffering agent like
citric acid; or amino acids like arginine; or sodium carbonate,
potassium carbonate, sodium bicarbonate, potassium bicarbonate and
the like. It has been found that in the presence of EDTA or citric
acid or both increase the stability and solubility of the
conventional pharmaceutical composition of Meropenem, Panipenem,
Doripenm, Ertapenem, Imipenem, Aztreonam, Faropenem, Biapenem or
its salts, hydrates and solvates.
[0049] The present invention is further illustrated by the
following examples that are not intended as a limitation of the
scope of the invention.
Example 1
Preparation of Sterile Meropenem Trihydrate
[0050] Into a cold suspension of non-sterile Meropenem trihydrate
(100 g) in water (750 mL) ammonia solution was added drop-wise till
clear solution was obtained. The clear solution was subjected to
carbon treatment followed by micron filtration (series of micron
filtrations with numbers 5.0, 1.2 and 0.2.mu.) in sterile area and
pH of filtrate was adjusted to approximately 5 to 6 using aqueous
formic acid. THF was added to the resultant mass. The solid
obtained was filtered, washed with aqueous tetrahydrofuran, and
dried to yield the title compound in pure form. (Purity:
99.00-99.88%; water content: 11.4 to 13.4%).
Example 2
Preparation of Meropenem Trihydrate
[0051] Into a suspension of non-sterile Meropenem trihydrate (100
g) in water (750 mL) ammonia solution was added drop-wise till
clear solution was obtained. To the clear solution, EDTA, sodium
hydrosulfite were added then subjected to carbon treatment followed
and pH of filtrate was adjusted to approximately 5 to 6 using
aqueous formic acid. THF was added to the resultant mass. The solid
obtained was filtered, washed with aqueous tetrahydrofuran, and
dried to yield the title compound in pure form. (Purity:
99.40-99.81%; water content: 11.54 to 13.40%).
Advantages:
[0052] The procedure given in U.S. Pat. No. 4,888,344 is not
suitable for sterile preparation as Meropenem does not remain in
solution long enough to perform sterile filtration in sterile area.
As meropenem trihydrate is administered as an injectable solution,
the present invention provides a solution to prepare sterile
Meropenem trihydrate. Also the present invention provides a
purification process to obtain highly pure compound.
Example 3
Preparation of Meropenem Trihydrate
Step (i)
Preparation of
(4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-1-hydroxyethyl]-4-methyl-7--
oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylicacid-(4-nitrophenyl)methyl
ester (III)
[0053] To the solution of
(4R,5R,6S)-4-methyl-6-[(R)-1-hydroxyethyl]-1-azabicyclo[3.2.0]hept-3,7-di-
one-2-carboxylic acid (4-nitrophenyl)methyl ester of formula (II)
(100 g) in acetonitrile (500 mL) at -10.degree. C. were added
N-ethyldiisopropylamine (54 g) and diphenylchlorophosphate (82 g)
and stirred at -10.degree. C. After completion of the reaction, the
resultant mass was quenched into the mixture containing dipotassium
hydrogen orthophosphate buffer and ethyl acetate and stirred for 15
min. The ethyl acetate layer was separated and washed with
phosphate buffer. Diisopropyl ether was added to the ethyl acetate
layer and stirred for an hour. The precipitated solid was filtered
and dried to yield the title compound (75 g, purity 98%).
Step (ii)
Preparation of
(4R,5S,6S,8R,2'S,4'S)-p-Nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-di-
methylaminocarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabic-
yclo[3.2.0]-hept-2-en-7-one-2-carboxylate (V)
[0054] To a solution of
(4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-1-hydroxyethyl]-4-methyl-7--
oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
(4-nitrophenyl)methyl ester in acetonitrile (1660 mL) were added
(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylamino-4-mercapt-
opyrrolidine (66 g) and N-ethyldiisopropylamine (36 mL) at
-15.degree. C. and stirred under nitrogen atmosphere. After
completion of the reaction, the resultant mass was quenched into
ethyl acetate containing dipotassium hydrogen orthophosphate and
stirred for 15 min. The ethyl acetate layer was distilled out
completely under vacuum. The residue was dissolved in ethyl acetate
and stirred. To the precipitated mass was added diisopropylether
and stirred for an hour. The solid was filtered and dried to yield
the title compound (110 g, Purity: 98%).
Step (iii)
(a). Preparation of
(4R,5S,6S,8R,2'S,4'S)-3-[4-(2-Dimethylaminocarbonyl)
pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]hept-2-e-
n-7-one-2-carboxylic acid (Meropenem trihydrate)
[0055]
(4R,5S,6S,8R,2'S,4'S)-p-Nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbony-
l-2-dimethylaminocarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1--
azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (100 g) obtained
from Step (ii) was dissolved in ethyl acetate, tetrahydrofuran
(1000 mL), water (1000 mL) and 10% palladium-carbon (200 g) were
added thereto, and introduced hydrogen therein at room temperature
under a hydrogen pressure by maintaining a pH in the range of about
3.5. After completion of the reaction, the catalyst was removed by
filtration, and the filtrate was washed with water; the aqueous
layers were separated, and washed with ethyl acetate. The aqueous
layer was treated with carbon, and the filtrate was poured into
excess THF. The solid obtained was filtered and dried to yield the
title compound (38 g; Purity 98-99.5%).
(b). Preparation of Meropenem Trihydrate
[0056]
(5R,6S,8R,2'S,4'S)-p-Nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-
-dimethylamino
carbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo-
[3,2,0]hept-2-ene-2-carboxylate (50 g) was taken in THF (500 mL)
then stirred to get clear solution and water (500 mL) was added
thereafter. The reaction mass was subjected to hydrogenation with
10% palladium on carbon (50 g) for 2-3 h at 25-30.degree. C. with
9-10 kg hydrogen pressure. After hydrogenation, ethyl acetate (500
mL) was added to the reaction mixture. The palladium-carbon was
filtered off and the organic layer separated. The aqueous layer was
extracted into ethyl acetate. Then the aqueous layer was
charcoalised followed by degassing to remove traces of ethyl
acetate. Carbon was filtered off and washed with water. To the
aqueous layer, excess THF was added slowly at to precipitate
Meropenem trihydrate. The product was filtered and washed with
aqueous THF to afford the title compound (19 g) as off-white
crystals with 98% purity.
Example 4
(a). Preparation of Meropenem Trihydrate
[0057] To a solution of
(4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-1-hydroxyethyl]-4-methyl-7--
oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
(4-nitrophenyl)methyl ester (50 g) in acetonitrile (500 mL) was
added
(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylamino-4-mercapt-
opyrrolidine (33 g) and N-diisopropylethylamine (14 g) at
-15.degree. C. and stirred. After the reaction was over, the
reaction mixture was quenched in phosphate buffer solution. The
product was extracted into ethyl acetate and washed with water. The
organic layer was subjected to carbon treatment, filtered off and
evaporated under vacuum to get thick paste (foam nature). To the
thick paste was added ethyl acetate and THF to get clear solution
followed by water. The reaction mass was subjected to hydrogenation
with 10% palladium on carbon for 2-3 h at 25-30.degree. C. with
9-10 kg pressure of hydrogen. The palladium carbon was filtered off
and the organic layer separated. The aqueous layer was charcoalised
followed by degassing to remove the ethyl acetate, filtered and the
carbon bed washed with water. To the aqueous layer was added excess
THF to precipitate the product. The product was filtered, washed
with aqueous THF and dried to afford the title compound (22 g) as
off-white crystals.
(b). Preparation of Meropenem Trihydrate
[0058] To a solution of
(4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-1-hydroxyethyl]-4-methyl-7--
oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
(4-nitrophenyl)methyl ester (50 g) in acetonitrile (500 mL) was
added
(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylamino-4-mercapt-
opyrrolidine (33 and N-ethyldiisopropylamine (14 g) at -15.degree.
C. and stirred. After the reaction was over, the reaction mixture
was quenched in phosphate buffer solution. The product was
extracted into ethyl acetate and washed with water. The organic
layer was subjected to carbon treatment, filtered off and
evaporated by vacuum to get the thick paste. To the thick paste was
added THF then stirred to get clear solution and water was added
thereafter. The reaction mass was subjected to hydrogenation with
10% palladium on carbon (50 g) with 9-10 kg hydrogen pressure.
After the hydrogenation, ethyl acetate (500 mL) was added to
reaction mixture. The palladium carbon was filtered off and the
organic layer separated. The aqueous layer was extracted with ethyl
acetate then separated. Then aqueous layer was charcoalised
followed by degassing to remove ethyl acetate. Carbon was filtered
off and washed with water. To the aqueous layer, excess THF was
added to precipitate Meropenem trihydrate. The product was filtered
and washed with aqueous THF to afford the title compound (22 g) as
off-white crystals with 98% purity.
(c). Preparation of Meropenem Trihydrate
[0059] To a solution of
(4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-1-hydroxyethyl]-4-methyl-7--
oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
(4-nitrophenyl)methyl ester (50 g) in acetonitrile (500 mL) were
added
(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylamino-4-mercapt-
opyrrolidine (33 g) and N-ethyldiisopropylamine (14 g) at
-15.degree. C. and stirred. After the reaction was over, the
reaction mixture was quenched in phosphate buffer solution. The
product was extracted into ethyl acetate and washed with water. The
organic layer was subjected to carbon treatment, filtered off and
evaporated under vacuum to give
(4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-di-
methylaminocarbonyl)
pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2--
en-7-one-2-carboxylate (amorphous in nature). To this was added THF
and stirred to get clear solution followed by water (900 mL). The
reaction mass subjected to hydrogenation with 10% palladium on
carbon (50 g) for 2-3 h at 25-30.degree. C. with 9-10 kg pressure
of hydrogen. After hydrogenation was added ethyl acetate (500 mL).
Then palladium carbon was filtered off and the organic layer
separated. The aqueous layer was extracted with ethyl acetate then
separated. Then the aqueous layer was charcoalised followed by
degassing to remove ethyl acetate, filtered and washed with water.
To the aqueous layer was added aqueous THF. The product was
filtered, washed with aqueous THF and dried to afford the title
compound (21.5 g) as off white crystals with 98% purity.
(d). Preparation of Meropenem Trihydrate
[0060] To a solution of
(4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-1-hydroxyethyl]-4-methyl-7--
oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
(4-nitrophenyl)methyl ester (50 g) in acetonitrile (500 mL) was
added
(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylamino-4-mercapt-
opyrrolidine (32 g) and N-ethyldiisopropylamine (14 g) at
-15.degree. C. and stirred. After the reaction was over, the
reaction mixture was quenched in phosphate buffer solution. The
product was extracted with ethyl acetate and washed with water. The
organic layer was subjected to carbon treatment, filtered off and
evaporated under vacuum to get thick paste. To the thick paste was
added ethyl acetate and THF to get clear solution followed by
water. This solution was washed with brine solution and the layers
separated. To the reaction mass, water was added and subjected to
hydrogenation with 10% palladium on carbon. The palladium carbon
was filtered off and the organic layer separated. The aqueous layer
was subjected to carbon treatment, filtered and washed with water.
To the aqueous layer was added excess acetone to precipitate the
product. The product was filtered, washed with aqueous acetone and
dried to afford the title compound (22 g) as off white
crystals.
Example 5
(a). Preparation of Meropenem Trihydrate
[0061] To a solution of
(4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-1-hydroxyethyl]-4-methyl-7--
oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
(4-nitrophenyl)methyl ester (50 g) and
(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylamino-4-mercapt-
opyrrolidine (33 g) in N,N-dimethylformamide (250 mL) was added
slowly diisopropylethylamine (14 g) at -40 to -10.degree. C. and
stirred for 2-3 h. The reaction mass was then added slowly to the
phosphate buffer to isolate the solid product. The pH was then
adjusted to 3.8 to 4.0 using sulphuric acid at 5-10.degree. C. then
stirred for an hour. The isolated
(4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-di-
methylaminocarbonyl)
pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]hept-2-e-
n-7-one-2-carboxylate (V) was filtered and washed with water.
[0062] The isolated wet product was dissolved in THF (550 mL), then
water (400-450 mL) added and the pH adjusted to 3.8 to 4.5 using
sulphuric acid solution. The reaction mass was subjected to
hydrogenation with 10% palladium on carbon (55 g) at 25-30.degree.
C. with 9-10 kg pressure of hydrogen. The palladium-carbon was
filtered off and the filtrate washed with ethyl acetate. The
aqueous layer was charcoalised. To the aqueous filtrate was added
slowly cold THF. The product was filtered and washed with aqueous
THF to afford the title compound (22.0 g) as off white crystal.
(b). Preparation of Meropenem Trihydrate
[0063] To a solution of
(4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-1-hydroxyethyl]-4-methyl-7--
oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
(4-nitrophenyl)methyl ester (50 g) and
(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylamino-4-mercapt-
opyrrolidine (33 g) in N,N-dimethylformamide (250 mL) was added
slowly diisopropylethylamine (14 g) at -40 to -10.degree. C. then
stirred for 2-3 h. The reaction mass was then added slowly to the
phosphate buffer to isolate the solid product. The pH was adjusted
3.8 to 4.0 using sulphuric acid at 5-10.degree. C. and stirred for
an hour. The product was filtered and washed with water. The
product was then dried to result in amorphous diprotected meropenem
of compound formula (V) (FIG. 1).
[0064] The isolated wet product was dissolved in THF (550 mL), then
water (400-450 mL) added and the pH adjusted to 3.8 to 4.5 using
sulphuric acid solution. The reaction mass was subjected to
hydrogenation with 10% palladium on carbon (55 g) at 25-30.degree.
C. with 9-10 kg pressure of hydrogen. The palladium-carbon was
filtered off and the filtrate washed with ethyl acetate. The
aqueous layer was charcoalised. To the aqueous filtrate was added
slowly cold acetone. The product was filtered and washed with
aqueous acetone to afford the title compound (23.5 g) as off-white
crystal.
(c). Preparation of Meropenem Trihydrate
[0065] To a solution of
(4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-1-hydroxyethyl]-4-methyl-7--
oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
(4-nitrophenyl)methyl ester (50 g) and
(2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylamino-4-mercapt-
opyrrolidine (33 g) in N,N-dimethylformamide (250 mL) was added
slowly diisopropylethylamine (14 g) at -40 to -10.degree. C. and
stirred for 2-3 h. The reaction mass was added slowly to the water
at 3 to 10.degree. C. to isolate the solid product. The pH was then
adjusted to 3.8 to 4.0 using sulphuric acid at 5 to 10.degree. C.
and stirred for an hour. The product was filtered and washed with
water.
[0066] The isolated wet product was dissolved in THF (550 mL), then
water (400-450 mL) added. The reaction mass was subjected to
hydrogenation with 10% palladium on carbon (55 g) at 25-30.degree.
C. with 9-10 kg pressure of hydrogen. The palladium-carbon was
filtered off and the filtrate washed with ethyl acetate. The
aqueous layer was charcoalised. To the aqueous filtrate was added
slowly cold THF. The product was filtered and washed with aqueous
THF to afford the title compound (22.0 g) as off white crystal.
Advantages:
[0067] The known process described in literature for the isolation
of compound of formula (V) involves the usage of ethyl acetate or
ethyl acetate/heptane or hexane or IPE. The present invention
obviates the use of multiple solvent, and hence economically
advantageous over the existing process. Also the present process
obviates the risk involved in the recovery of solvent by
distillation. The present invention provides a simple isolation
technique for the compound of formula (V).
* * * * *