WO2012038979A2 - A process for preparation of ertapenem - Google Patents

A process for preparation of ertapenem Download PDF

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Publication number
WO2012038979A2
WO2012038979A2 PCT/IN2011/000656 IN2011000656W WO2012038979A2 WO 2012038979 A2 WO2012038979 A2 WO 2012038979A2 IN 2011000656 W IN2011000656 W IN 2011000656W WO 2012038979 A2 WO2012038979 A2 WO 2012038979A2
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Prior art keywords
ertapenem
preparation
monosodium
monoprotected
formula
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PCT/IN2011/000656
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French (fr)
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WO2012038979A3 (en
Inventor
Gnanaprakasam Andrew
Veeramani Ganapathy
Shahul Hameed Syed Ibrahim
Murugesan Karthikeyan
Thangavel Sivasamy
Sekar Jeyaraj Michael
Thangavel Arulmoli
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Sequent Anti Biotics Private Limited
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Publication of WO2012038979A2 publication Critical patent/WO2012038979A2/en
Publication of WO2012038979A3 publication Critical patent/WO2012038979A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D477/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a novel process for the preparation of 1 ⁇ -methylcarbapenem antibiotic, Ertapenem of formula I.
  • Ertapenem is a sterile, synthetic, parenteral, l- ⁇ methyl-carbapenem that is structurally related to beta-lactam antibiotics. It is marketed by Merck as Invanz®. It is structurally very similar to Meropenem in that it possesses a l- ⁇ methyl group. Ertapenem is used as antibiotic agent in the treatment of moderate to severe complicated foot infection due to indicated pathogens in diabetic patients without osteomyelitis, and also useful in the treatment of pneumonia, urinary tract infections, intra-abdominal, gynaecological, skin, and soft tissue infections, meningitis, septicaemia and febrile Neutrogena.
  • US patent No. 6,504,027 provides a process for preparing Ertapenem in crystalline form which comprises deprotecting and extracting a polar organic solution containing a crude mono- protected Ertapenem disodium salt with G O alcohol in the presence of ion-pairing reagent followed by adjusting the pH to 5.5, collecting and crystallizing the resultant aqueous phase to produce Ertapenem disodium.
  • This process involves a number of operations like extraction, it is not preferred at industrial scale.
  • the main aspect of the present invention is to provide a process for preparation Ertapenem monosodium comprising: a) condensing the compound of formula II with compound of formula III in presence of a base and a solvent to obtain a monoprotected compound of formula IV or its sodium salt;
  • the another aspect of the present invention is to provide a novel crystalline form of Ertapenem monosodium characterised by having X-ray powder diffraction pattern as given in figure 1 and having a 2 ⁇ peaks at 4.1, 7.14, 9.62, 12.3, 20.43, 22.43, 29.03, 30.65 and 31.8 ⁇ 0.2.
  • the another aspect of the present invention is to provide a novel amorphous form of monoprotected ertapenem acid characterized by X-ray powder diffraction pattern as given in figure 2.
  • the another aspect of the present invention is to provide a novel amorphous form of monoprotected ertapenem monosodium characterized by X-ray powder diffraction pattern as given in figure 3.
  • Figure I X-Ray diffractogram of Ertapenem monosodium of the present invention
  • Figure2 X-Ray diffractogram of monoprotected ertapenem acid of the present invention
  • Figure3 X-Ray diffractogram of monoprotected ertapenem monosodium of the present invention
  • the protective group P selected from group such as allyl, 2,2,2,-trichloroethyl, 2-bromoethyl, benzhydryl, trityl, aryl, trimethylsilyl, triethylsilyl, 4- methoxybenzyl, t-butyl, p-nitrobenzyl and the like, preferably P and P" is selected from P- nitrobenzyl.
  • the solvent used in step (a) is selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, xylene, dichloromethane, 1,2- dichloroethane, ⁇ , ⁇ -dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, N- ethylpyrrolidinone, N-methylpiperidinone, acetonitrile, propionitrile, and mixtures thereof, preferably ⁇ , ⁇ -dimethylformamide; and inorganic base used is selected from diisopropylethylamine (DIPEA), diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), l,8-diazabicyclo[4.3.0.]undec-7-ene (DBU) 1,5- diaza
  • DIPEA diis
  • the monoprotected compound of formula (IV) can be isolated as an acid or a sodium salt, using mixture of ethyl acetate, alcohol and isopropyl ether.
  • the monoprotected acid or its sodium salt was subjected to de-protection to yield Ertapenem monosodium.
  • the sodium salt of formula (IV) is more stable, and easy to handle in industrial point of view.
  • monoprotected compound of formula (IV) or its sodium salt is optionally isolated by quenching the reaction mass from step (i) into a buffer solution selected from dipotassium hydrogen orthophosphate, or potassium dihydrogen orthophosphate, or water and the like followed by extracting the compound in an organic solvent like ethyl acetate, MDC (dichloromethane) preferably in MDC and precipitating the compound of formula (IV) directly from the resultant organic layer or by quenching the organic layer into a solvent selected from hexane, heptane, IPE (diisopropylether), methyl tert-butyl ether and the like or mixtures thereof.
  • the intermediate of formula (IV) can be taken to next stage with or without isolation. Alternatively the intermediate of formula (IV) can be directly precipitated from the buffer solution or water.
  • the deprotection is preferably done by hydrogenolysis.
  • the hydrogenolysis is usually done in presence of a metal catalyst, preferably in presence of hydrogen gas and palladium (Pd/C) catalyst.
  • the solvent for deprotection in step (c) is selected from THF, acetonitrile, dioxane, ethyl acetate, isopropyl alcohol, n-propanol, methanol, dichloromethane, DMF, MDC, aqueous carbonic acid, water or mixtures thereof preferably aqueous MDC and n-propanol .
  • the de-protection of protecting groups can be carried out using a mixture of solvents either in single phase or in biphasic medium.
  • the hydrogenation process can employ employs sodium ion source base such as sodium bicarbonate, sodium hydroxide, and sodium carbonate.
  • the product after completion of hydrogenation, the product was taken into aqueous medium, followed by optionally washing with organic solvents like MDC, butyl acetate, ethyl acetate, toluene, hexane, 1,2-dibromoethane and the like to remove reaction by-products and/or impurities.
  • organic solvents like MDC, butyl acetate, ethyl acetate, toluene, hexane, 1,2-dibromoethane and the like to remove reaction by-products and/or impurities.
  • carbon dioxide gas was purged to the reaction mass.
  • the aqueous layer was subjected to degassing technique to remove the dissolved solvent if required.
  • pH of aqueous layer optionally was adjusted using acid like acetic acid, formic acid, HC1, etc to obtain the compound of formula (I).
  • the pH of aqueous layer containing the Ertapenem monosodium was optional
  • the crystalline form of Ertapenem monosodium is novel and it is characterised by X-ray powder diffraction pattern same as given in figure 1 and having 20 peaks at 4.1, 7.14, 9.62, 12.3, 20.43, 22.43, 29.03, 30.65 and 31.8 ⁇ 0.2.
  • This novel crystalline form of Ertapenem is very stable and the form doesn't change with time for a considerably long time.
  • the crystalline form of Ertapenem monosodium is characterised by having further X-ray powder diffraction 20 peaks at 4.30, 5.09, 7.97, 10.77, 14.26, 15.03, 17.01 18.96, 25.94, 26.48, 27.41, 28.47, 29.87, 32.24, 32.67, 33.09, 33.36, 33.90, 35.41, 36.22, 37.72, 39.83, 42.72, 43.14, 44.67, 46.24 and 49.21 ⁇ 0.2.
  • the monoprotected ertapenem acid and monoprotected ertapenem monosodium are amorphous in nature as shown in figure 2 and figure 3 respectively.
  • the starting material compound of formula (III) is prepared by utilizing technique known in the art.
  • Example 1 The present invention is illustrated with the following non-limiting examples.
  • Example 1 The present invention is illustrated with the following non-limiting examples.
  • Example 1 The present invention is illustrated with the following non-limiting examples.
  • reaction mass was quenched into buffer solution (KH 2 P0 4 in water). The pH was adjusted by using phosphoric acid. The product has been extracted with adding MDC and washed with water. Sodium-2-ethyl Hexanoate was dissolved in methanol and was added into the organic layer. This mixture was quenched in to IPE and precipitated sold was filtered and washed, dried to obtain monoprotected Ertapenem monosodium.
  • the monoprotected ertapenem monosodium (25 g) obtained above was dissolved in MDC and n-propanol at 0°C to 5°C and DM water was added to it.
  • Pd/c was slurryfied in DM H 2 0 and added to it, stirred under H 2 atm at 3°C to 5°C. After the reaction completion Pd/c was filtered and washed with DM H 2 0. Organic layer was separated. The aqueous layer was washed with MDC, treated with Carbon at 0°C -5°C, degaussed and filtered.
  • Ertapenem monosodium (NS) 50gm was dissolved in water-for-injection(WFI) water in presence of sodium bicarbonate & sodium hydroxide at 2-5°C. The clear filtrate was filtered through 0.2micron and it vial lyophilized.
  • MAP 25 g
  • Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2-carboxamido] benzoic acid hydrochloride were dissolved in DMF at RT. Reaction mass was cooled to -50°C to - 60°C. DBU was added at the same temperature. After completion of the reaction, the reaction mass was quenched into buffer solution (KH2P04 in water). The pH was adjusted by using phosphoric acid. The product was extracted with adding MDC and washed with water . The pH of MDC layer was adjusted to 7.0 -8.0 in presence of water by using Sodium bicarbonate and directly taken for next step.
  • the pH was adjusted with acetic acid in methanol to 4.5-5.0 and crystallized by adding n-propanol. Crystals were filtered off and washed by using chilled Ethanol at - 3°C to -5°C, filtered solid was dried under Vacuum and nitrogen.
  • MAP 25 g
  • Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2-carboxamido] benzoic acid hydrochloride 16 g were dissolved in DMF at RT. Reaction mass was cooled to -50°C to -60°C. DBU was added at the same temperature. After completion of reaction, the reaction mass was quenched into buffer solution ( H 2 P0 in water). The pH was adjusted by using phosphoric acid. The product was extracted with adding MDC and washed with water. This layer directly taken for next stage.
  • the above MDC layer of Monoprotected Ertapenem acid was dissolved in n-propanol at 0°C -5°C and sodium bicarbonate and DM water were added to it.
  • Pd/C was slurryfied in DM H 2 0 and added, stirred under H 2 atmosphere at 3°C-5°C, after the reaction completion Pd/C was filtered and washed with DM H 2 0.
  • the MDC layer was separated.
  • the aqueous layer was washed with MDC, treated with Carbon at 0°C -5°C, degaussed and filtered. It was re-filtered through 0.2 ⁇ filter paper and methanol was added into the aq layer at -3°C to -5°C and then cooled to -20°C.
  • the pH was adjusted with acetic acid in methanol to 4.5-5.0 and crystallized by adding n-propanol. Crystals were filtered off and washed by using chilled Ethanol at -3°C to -5°C, filtered solid was dried under Vacuum and nitrogen.
  • MAP 25 g
  • Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2- carboxamido]benzoic acid hydrochloride were dissolved in DMF at RT. Reaction mass was cooled to -50°C to -60°C. DBU was added at the same temperature. After completion of reaction, reaction mass was quenched into Buffer solution (KH2P04 in water). The pH was adjusted by using phosphoric acid. The product was extracted by adding MDC and washed with water. The MDC layer was added with methanol and methyl tertiarybutyl ether and precipitated the monoprotected ertapenem acid. The precipitated solid was filtered, washed and dried.
  • Monoprotected ertapenem acid 25g was dissolved in MDC and n-propanol at 0°C to 5°C.
  • Sodium bicarbonate and DM H 2 0 were added to it at the same temperature.
  • Pd/c was slurryfied in DM H 2 0 was added to above mass, stirred under H 2 atmosphere at 3°C to 5°C. After the completion of reaction Pd/c was filtered and washed with DM H 2 0 .MDC layer was separated. The aqueous layer was washed with MDC, treated with Carbon at 0°C -5°C, degaussed and filtered.
  • MAP 25 g
  • Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2-carboxamido] benzoic acid hydrochloride were dissolved in DMF at RT. Reaction mass was cooled to -50°C to - 60°C. DBU in 50ml DMF was added at the same temperature. After completion of the reaction, the reaction mass was quenched into buffer solution (KH 2 P0 4 in water). The pH was adjusted by using phosphoric acid. The product was extracted with adding MDC and washed with water . The pH of MDC layer was adjusted to 7.0 -8.0 in presence of water by using Sodium bicarbonate and directly taken for next step.
  • Step-II Preparation of Ertapenem mono sodium NS Monoprotected Ertapenem monosodium was stirred in water, MDC and n-propanol at 0°C - 5°C. Pd/c slurryfied in DM H 2 0 was added to it and stirred under H 2 atm at 3°C-5°C. After the completion of reaction Pd/c was filtered and washed with DM water, organic layer was separated. The aqueous layer was washed with MDC, treated with Carbon at 0°C -5°C, degaussed with EDTA, Sodium dithionite and filtered.
  • MAP 25 g
  • Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2-carboxamido] benzoic acid hydrochloride were dissolved in DMF at RT. Reaction mass was cooled to -50°C to - 60°C. DBU was added at the same temperature. After completion of the reaction, the reaction mass was quenched into buffer solution (KH 2 PO 4 in water). The pH was adjusted by using phosphoric acid. The product was extracted with adding MDC and washed with water . The pH of MDC layer was adjusted to 7.0 -8.0 in presence of water by using Sodium bicarbonate and directly taken for next step.
  • the pH was adjusted with acetic acid in methanol to 4.5-5.0 and crystallized by adding n-propanol at -20°C. Crystals were filtered off and washed by using chilled Acetone at -3°C to -5°C, filtered solid was dried under Vacuum and nitrogen.

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Abstract

The present invention relates to a novel process for the preparation of 1 β- methylcarbapenem antibiotic, Ertapenem of formula I. The process comprises isolation of monoprotected Ertapenem acid or its monosodium salt and further deprotection to obtain Ertapenenm monosodium.

Description

A Process for Preparation of Ertapenem
FIELD OF INVENTION
The present invention relates to a novel process for the preparation of 1 β-methylcarbapenem antibiotic, Ertapenem of formula I.
Figure imgf000003_0001
BACKGROUND OF THE INVENTION
Ertapenem is a sterile, synthetic, parenteral, l-β methyl-carbapenem that is structurally related to beta-lactam antibiotics. It is marketed by Merck as Invanz®. It is structurally very similar to Meropenem in that it possesses a l-β methyl group. Ertapenem is used as antibiotic agent in the treatment of moderate to severe complicated foot infection due to indicated pathogens in diabetic patients without osteomyelitis, and also useful in the treatment of pneumonia, urinary tract infections, intra-abdominal, gynaecological, skin, and soft tissue infections, meningitis, septicaemia and febrile Neutrogena.
A number of synthetic processes are reported for the preparation of Ertapenem. US patent 5,478,820 describes a process for preparation of Ertapenem where it is isolated by using column purification as well as freeze-drying technique. This patent also describes a process of preparation of disodium salt of Ertapenem by dissolving crude product in water using NaHC03, followed by purification using column chromatography and subsequent lyophilisation.
US patent No. 6,504,027 provides a process for preparing Ertapenem in crystalline form which comprises deprotecting and extracting a polar organic solution containing a crude mono- protected Ertapenem disodium salt with G O alcohol in the presence of ion-pairing reagent followed by adjusting the pH to 5.5, collecting and crystallizing the resultant aqueous phase to produce Ertapenem disodium. This process involves a number of operations like extraction, it is not preferred at industrial scale.
These processes are not attractive for industrial scale production because they involve chromatographic purification in certain stages for purification. The present inventors has developed a process which is more practical, efficient, cost effective and which removes lot of impurity to yield a highly pure product without doing column chromatographic purification.
SUMMARY OF THE INVENTION
Accordingly, the main aspect of the present invention is to provide a process for preparation Ertapenem monosodium comprising: a) condensing the compound of formula II with compound of formula III in presence of a base and a solvent to obtain a monoprotected compound of formula IV or its sodium salt;
b) optionally isolating monoprotected compound of formula IV or its sodium salt;
c) deprotecting the monoprotected compound of formula IV or its sodium salt in a solvent in presence or absence of a buffer and in presence or absence of a sodium ion source; and d) extracting the product with optional pH adjustment to obtain Ertapenem of formula I or its monosodium salt.
The above process is illustrated in below scheme:
Figure imgf000004_0001
MONOPROTECTED
Where P Is a protecting group
Figure imgf000004_0002
Ertapenem The another aspect of the present invention is to provide a novel crystalline form of Ertapenem monosodium characterised by having X-ray powder diffraction pattern as given in figure 1 and having a 2Θ peaks at 4.1, 7.14, 9.62, 12.3, 20.43, 22.43, 29.03, 30.65 and 31.8±0.2.
The another aspect of the present invention is to provide a novel amorphous form of monoprotected ertapenem acid characterized by X-ray powder diffraction pattern as given in figure 2.
The another aspect of the present invention is to provide a novel amorphous form of monoprotected ertapenem monosodium characterized by X-ray powder diffraction pattern as given in figure 3.
Brief Description of the Diagram/Figure
Figure I : X-Ray diffractogram of Ertapenem monosodium of the present invention Figure2: X-Ray diffractogram of monoprotected ertapenem acid of the present invention Figure3: X-Ray diffractogram of monoprotected ertapenem monosodium of the present invention
DETAIL DESCRIPTION OF THE INVENTION
In an embodiment of the present invention, the protective group P selected from group such as allyl, 2,2,2,-trichloroethyl, 2-bromoethyl, benzhydryl, trityl, aryl, trimethylsilyl, triethylsilyl, 4- methoxybenzyl, t-butyl, p-nitrobenzyl and the like, preferably P and P" is selected from P- nitrobenzyl.
In another embodiment of the present invention, the solvent used in step (a) is selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, xylene, dichloromethane, 1,2- dichloroethane, Ν,Ν-dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, N- ethylpyrrolidinone, N-methylpiperidinone, acetonitrile, propionitrile, and mixtures thereof, preferably Ν,Ν-dimethylformamide; and inorganic base used is selected from diisopropylethylamine (DIPEA), diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), l,8-diazabicyclo[4.3.0.]undec-7-ene (DBU) 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), N-methylpyrrolidine, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate, and the like preferably 1,8- diazabicyclo[4.3.0.]undec-7-ene (DBU). The condensation reaction may optionally contain bases like N,N-dimethylaminopyridine, Ν,Ν-diethylamino pyridine to avoid impurity formation.
In another embodiment of the present invention the monoprotected compound of formula (IV) can be isolated as an acid or a sodium salt, using mixture of ethyl acetate, alcohol and isopropyl ether. The monoprotected acid or its sodium salt was subjected to de-protection to yield Ertapenem monosodium. The sodium salt of formula (IV) is more stable, and easy to handle in industrial point of view.
In another embodiment, monoprotected compound of formula (IV) or its sodium salt is optionally isolated by quenching the reaction mass from step (i) into a buffer solution selected from dipotassium hydrogen orthophosphate, or potassium dihydrogen orthophosphate, or water and the like followed by extracting the compound in an organic solvent like ethyl acetate, MDC (dichloromethane) preferably in MDC and precipitating the compound of formula (IV) directly from the resultant organic layer or by quenching the organic layer into a solvent selected from hexane, heptane, IPE (diisopropylether), methyl tert-butyl ether and the like or mixtures thereof. The intermediate of formula (IV) can be taken to next stage with or without isolation. Alternatively the intermediate of formula (IV) can be directly precipitated from the buffer solution or water.
In yet another embodiment of the present invention, the deprotection is preferably done by hydrogenolysis. The hydrogenolysis is usually done in presence of a metal catalyst, preferably in presence of hydrogen gas and palladium (Pd/C) catalyst. The solvent for deprotection in step (c) is selected from THF, acetonitrile, dioxane, ethyl acetate, isopropyl alcohol, n-propanol, methanol, dichloromethane, DMF, MDC, aqueous carbonic acid, water or mixtures thereof preferably aqueous MDC and n-propanol . The de-protection of protecting groups can be carried out using a mixture of solvents either in single phase or in biphasic medium. If required, the hydrogenation process can employ employs sodium ion source base such as sodium bicarbonate, sodium hydroxide, and sodium carbonate.
In yet another embodiment of the present invention, after completion of hydrogenation, the product was taken into aqueous medium, followed by optionally washing with organic solvents like MDC, butyl acetate, ethyl acetate, toluene, hexane, 1,2-dibromoethane and the like to remove reaction by-products and/or impurities. After hydrogenation, optionally carbon dioxide gas was purged to the reaction mass. The aqueous layer was subjected to degassing technique to remove the dissolved solvent if required. Further depending on the requirement, pH of aqueous layer optionally was adjusted using acid like acetic acid, formic acid, HC1, etc to obtain the compound of formula (I). In yet another embodiment of the present invention, the pH of aqueous layer containing the Ertapenem monosodium was optionally reduced to 5 followed by quenching in to an alcohol yielding the compound of formula (I) as monosodium.
In yet another embodiment of the invention the crystalline form of Ertapenem monosodium is novel and it is characterised by X-ray powder diffraction pattern same as given in figure 1 and having 20 peaks at 4.1, 7.14, 9.62, 12.3, 20.43, 22.43, 29.03, 30.65 and 31.8±0.2. This novel crystalline form of Ertapenem is very stable and the form doesn't change with time for a considerably long time.
In yet another embodiment of the invention the crystalline form of Ertapenem monosodium is characterised by having further X-ray powder diffraction 20 peaks at 4.30, 5.09, 7.97, 10.77, 14.26, 15.03, 17.01 18.96, 25.94, 26.48, 27.41, 28.47, 29.87, 32.24, 32.67, 33.09, 33.36, 33.90, 35.41, 36.22, 37.72, 39.83, 42.72, 43.14, 44.67, 46.24 and 49.21±0.2.
In yet another embodiment of the invention the monoprotected ertapenem acid and monoprotected ertapenem monosodium are amorphous in nature as shown in figure 2 and figure 3 respectively.
In still further embodiment of the present invention, the starting material compound of formula (III) is prepared by utilizing technique known in the art.
Advantage of the process of the present invention: a) The use of monoprotected intermediate of Ertapenem gives higher yield 0.5w/w to 0.6w/w as compared to 0.2w/w to 0.3w/w obtained in prior art.
b) Hydrogenation using MDC gives faster layer separation & adds to the yield.
c) The present process avoids hydrogenation work up as described in innovator patent.
d) The present process avoids purification of final compound to obtain a purity of more than 98% whereas the prior art processes need a purification to achieve this purity.
e) Avoid consumption of more palladium carbon
The present invention is illustrated with the following non-limiting examples. Example 1:
Step-I : Preparation of monoprotected Ertapenem monosodium
1 -Azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, 3-[(diphenoxyphosphinyl)oxy]-6-( 1 - hydroxyethyl)-4-methyl-7-oxo-,(4-nitrophenyl)methyl ester, [4R-[4a,5b,6b(R*)]] (MAP) (25 g) and Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2-carboxamido]benzoic acid hydrochloride were dissolved in DMF at RT. Reaction mass was cooled to -50°C to -60°C. DBU was added at the same temperature. After completion of the reaction, the reaction mass was quenched into buffer solution (KH2P04 in water). The pH was adjusted by using phosphoric acid. The product has been extracted with adding MDC and washed with water. Sodium-2-ethyl Hexanoate was dissolved in methanol and was added into the organic layer. This mixture was quenched in to IPE and precipitated sold was filtered and washed, dried to obtain monoprotected Ertapenem monosodium.
Yield -32g; purity:98%
Step-II: Preparation of Ertapenem mono sodium NS
The monoprotected ertapenem monosodium (25 g) obtained above was dissolved in MDC and n-propanol at 0°C to 5°C and DM water was added to it. Pd/c was slurryfied in DM H20 and added to it, stirred under H2 atm at 3°C to 5°C. After the reaction completion Pd/c was filtered and washed with DM H20. Organic layer was separated. The aqueous layer was washed with MDC, treated with Carbon at 0°C -5°C, degaussed and filtered. It was re-filtered through 0.2 μ filter paper and methanol was added into the aqueous layer at -3°C to -5°C and then cooled to -20°C. The pH was adjusted with acetic acid in methanol to 4.5-5.0 and crystallized by adding n-propanol. Crystals were filtered off and washed by using chilled Ethanol at -3°C to -5°C, filtered solid was dried under Vacuum and nitrogen.
YIELD 12.5 g; purity: 98%; M/C: 10 to 16%
Step-Ill : Preparation of Ertapenem Sterile
Ertapenem monosodium (NS) 50gm was dissolved in water-for-injection(WFI) water in presence of sodium bicarbonate & sodium hydroxide at 2-5°C.The clear filtrate was filtered through 0.2micron and it vial lyophilized.
Yield =50 g; purity: 97%
Example 2:
Step-I: Preparation of monoprotected Ertapenem monosodium
MAP (25 g) and Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2-carboxamido] benzoic acid hydrochloride were dissolved in DMF at RT. Reaction mass was cooled to -50°C to - 60°C. DBU was added at the same temperature. After completion of the reaction, the reaction mass was quenched into buffer solution (KH2P04 in water). The pH was adjusted by using phosphoric acid. The product was extracted with adding MDC and washed with water .The pH of MDC layer was adjusted to 7.0 -8.0 in presence of water by using Sodium bicarbonate and directly taken for next step.
Step-II: Preparation of Ertapenem mono sodium NS
Monoprotected Ertapenem monosodium was stirred in water, MDC and n-propanol at 0°C - 5°C. Pd/c slurryfied in DM H20 was added to it and stirred under H2 atm at 3°C-5°C. After the completion of reaction Pd/c was filtered and washed with DM water, organic layer was separated. The aqueous layer was washed with MDC, treated with Carbon at 0°C -5°C, degaussed and filtered. It was re-filtered through 0.2 μ filter paper and methanol was added into the aq layer at -3°C to -5°C and then cooled to -20°C. The pH was adjusted with acetic acid in methanol to 4.5-5.0 and crystallized by adding n-propanol. Crystals were filtered off and washed by using chilled Ethanol at - 3°C to -5°C, filtered solid was dried under Vacuum and nitrogen.
YIELD = 13 g; Purity=98%; M/C: 10 to 16%
Example 3:
Step-I: Preparation of monoprotected Ertapenem acid
MAP (25 g) and Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2-carboxamido] benzoic acid hydrochloride (16 g) were dissolved in DMF at RT. Reaction mass was cooled to -50°C to -60°C. DBU was added at the same temperature. After completion of reaction, the reaction mass was quenched into buffer solution ( H2P0 in water). The pH was adjusted by using phosphoric acid. The product was extracted with adding MDC and washed with water. This layer directly taken for next stage.
Step-II: Preparation of Ertapenem mono sodium NS
The above MDC layer of Monoprotected Ertapenem acid was dissolved in n-propanol at 0°C -5°C and sodium bicarbonate and DM water were added to it. Pd/C was slurryfied in DM H20 and added, stirred under H2 atmosphere at 3°C-5°C, after the reaction completion Pd/C was filtered and washed with DM H20. The MDC layer was separated. The aqueous layer was washed with MDC, treated with Carbon at 0°C -5°C, degaussed and filtered. It was re-filtered through 0.2 μ filter paper and methanol was added into the aq layer at -3°C to -5°C and then cooled to -20°C. The pH was adjusted with acetic acid in methanol to 4.5-5.0 and crystallized by adding n-propanol. Crystals were filtered off and washed by using chilled Ethanol at -3°C to -5°C, filtered solid was dried under Vacuum and nitrogen.
YIELD = 13.3 g; Purity=98% ; M/C: 10 to 16% Example 4:
Step-I: Preparation of monoprotected Ertapenem acid
MAP (25 g) and Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2- carboxamido]benzoic acid hydrochloride were dissolved in DMF at RT. Reaction mass was cooled to -50°C to -60°C. DBU was added at the same temperature. After completion of reaction, reaction mass was quenched into Buffer solution (KH2P04 in water). The pH was adjusted by using phosphoric acid. The product was extracted by adding MDC and washed with water. The MDC layer was added with methanol and methyl tertiarybutyl ether and precipitated the monoprotected ertapenem acid. The precipitated solid was filtered, washed and dried.
Yield : 30g; Purity=98%
Step-II: Preparation of Ertapenem mono sodium NS
Monoprotected ertapenem acid (25g) was dissolved in MDC and n-propanol at 0°C to 5°C. Sodium bicarbonate and DM H20 were added to it at the same temperature. Pd/c was slurryfied in DM H20 was added to above mass, stirred under H2 atmosphere at 3°C to 5°C. After the completion of reaction Pd/c was filtered and washed with DM H20 .MDC layer was separated. The aqueous layer was washed with MDC, treated with Carbon at 0°C -5°C, degaussed and filtered. It was re- filtered through 0.2 μ filter paper and methanol was added into the aqueous layer at -3°C to -5°C and then cooled to -20°C. The pH was adjusted with acetic acid in methanol to 4.5-5.0 and crystallized by adding n-propanol. Crystals were filtered off and washed by using chilled Ethanol at -3°C to -5°C, filtered solid was dried under Vacuum and nitrogen.
Yield= 12.5 g; Purity=98%; M/C: 10 to 16%
Example 5:
Step-I: Preparation of monoprotected Ertapenem monosodium
MAP (25 g) and Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2-carboxamido] benzoic acid hydrochloride were dissolved in DMF at RT. Reaction mass was cooled to -50°C to - 60°C. DBU in 50ml DMF was added at the same temperature. After completion of the reaction, the reaction mass was quenched into buffer solution (KH2P04 in water). The pH was adjusted by using phosphoric acid. The product was extracted with adding MDC and washed with water .The pH of MDC layer was adjusted to 7.0 -8.0 in presence of water by using Sodium bicarbonate and directly taken for next step.
Step-II: Preparation of Ertapenem mono sodium NS Monoprotected Ertapenem monosodium was stirred in water, MDC and n-propanol at 0°C - 5°C. Pd/c slurryfied in DM H20 was added to it and stirred under H2 atm at 3°C-5°C. After the completion of reaction Pd/c was filtered and washed with DM water, organic layer was separated. The aqueous layer was washed with MDC, treated with Carbon at 0°C -5°C, degaussed with EDTA, Sodium dithionite and filtered. It was re-filtered through 0.2 μ filter paper and methanol was added into the aq layer cooled to 30C to -50C. The pH was adjusted with acetic acid in methanol to 4.5-5.0 and crystallized by adding n-propanol at -20°C. Crystals were filtered off and washed by using chilled aqueous Ethanol at -3°C to -5°C, filtered solid was dried under Vacuum and nitrogen.
YIELD = 13.5 g, ; Purity=98%; M/C: 10 to 16%
Example 6:
Step-I: Preparation of monoprotected Ertapenem monosodium
MAP (25 g) and Ertapenem side chain -[(2S,4S)-4-Mercaptopyrrolidine-2-carboxamido] benzoic acid hydrochloride were dissolved in DMF at RT. Reaction mass was cooled to -50°C to - 60°C. DBU was added at the same temperature. After completion of the reaction, the reaction mass was quenched into buffer solution (KH2PO4 in water). The pH was adjusted by using phosphoric acid. The product was extracted with adding MDC and washed with water .The pH of MDC layer was adjusted to 7.0 -8.0 in presence of water by using Sodium bicarbonate and directly taken for next step.
Step-II: Preparation of Ertapenem mono sodium NS
Monoprotected Ertapenem monosodium was stirred in water, MDC and n-propanol at 0°C - 5°C. Pd/c slurryfied in DM H20 was added to it and stirred under H2 atm at 3°C-5°C. After the completion of reaction Pd/c was filtered and washed with DM water, organic layer was separated. The aqueous layer was washed with MDC, treated with Carbon at 0°C -5°C, degaussed with EDTA, Sodium dithionite and filtered. It was re-filtered through 0.2 μ filter paper and methanol was added into the aq layer cooled to 3°C to -5°C. The pH was adjusted with acetic acid in methanol to 4.5-5.0 and crystallized by adding n-propanol at -20°C. Crystals were filtered off and washed by using chilled Acetone at -3°C to -5°C, filtered solid was dried under Vacuum and nitrogen.
YIELD = 13.5 g; Purity=98%; M/C: 10 to 16%

Claims

We claim:
1. A process for preparation Ertapenem monosodium of formula I comprising:
Figure imgf000012_0001
I
a) condensing the compound of formula II with compound of formula III in presence of a base and a solvent to obtain a monoprotected compound of formula IV or its sodium salt;
Figure imgf000012_0002
Where P is a protecting group
b) optionally isolating monopro or its sodium salt;
Figure imgf000012_0003
c) deprotecting the monoprotected compound of formula IV or its sodium salt in a solvent in presence or absence of a buffer and in presence or absence of a sodium ion source; and d) extracting the product with optional pH adjustment to obtain Ertapenem of formula I or its monosodium salt.
2. A process for preparation of ertapenem monosodium according to claim 1 wherein, the solvent for the deprotection in step (c) is selected from THF, acetonitrile, dioxane, ethyl acetate, isopropyl alcohol, n-propanol, methanol, dichloromethane, DMF, MDC, aqueous carbonic acid, water or mixtures thereof preferably aqueous MDC and n-propanol.
3. A process for preparation of ertapenem monosodium according to claim 1 wherein, the deprotection is carried out in presence of a metal catalyst preferably Pd/C.
4. A process for preparation of ertapenem monosodium according to claim 1 wherein, the solvent for condensation in step (a) is selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, xylene, dichloromethane, 1,2-dichloroethane, N,N- dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, N-ethylpyrrolidinone, N- methylpiperidinone, acetonitrile, propionitrile, and mixtures thereof, preferably N,N- dimethylformamide;
5. A process for preparation of ertapenem monosodium according to claim 1 wherein, the base for condensation in step (a) is selected from the group consisting of diisopropylethylamine (DIPEA), diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6- tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), 1,8- diazabicyclo[4.3.0.]undec-7-ene (DBU) l,5-diazabicyclo[4.3.0]non-5-ene (DBN), N- methylpyrrolidine, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate, and the like preferably l,8-diazabicyclo[4.3.0.]undec-7-ene (DBU).
6. A process for preparation of ertapenem monosodium according to claim 1 wherein, the pH adjustment in step (d) is carried out using acetic acid in methanol.
7. A crystalline form of Ertapenem monosodium characterised by X-ray powder diffraction pattern same as given in figure 1 and having 2Θ peaks at 4.1, 7.14, 9.62, 12.3, 20.43, 22.43, 29.03, 30.65 and 31.8±0.2.
8. An amorphous form of monoprotected ertapenem acid.
9. An amorphous form of monoprotected ertapenem monosodium.
PCT/IN2011/000656 2010-09-24 2011-09-22 A process for preparation of ertapenem WO2012038979A2 (en)

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