Biapenem

• Molecular FormulaC₁₅H₁₈N₄O₄S
• Average mass350.393 Da

BiapenernCL 186-815LJ C10,627LJ C10627LJC 10627MFCD00864863 [MDL number]omegacinYR5U3L9ZH1

(4R,5S,6S)-3-((6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium-6-yl)thio)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

[4R-[4a,5b,6b(R*)]]-6-[[2-Carboxy-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5 H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt

120410-24-4[RN]

5H-Pyrazolo[1,2-a][1,2,4]triazol-4-ium, 6-[[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-, inner salt [ACD/Index Name]

6-[[(4R,5S,6S)-2-Carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt

7074

(4R,5S,6S)-3-(6,7-Dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium-6-ylsulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

TL8000539UNII:YR5U3L9ZH1UNII-YR5U3L9ZH1биапенем

بيابينام比

阿培南

INDIA CDSCO APPROVED 25 SEPT 2021, BDR PHARMA,  
https://www.cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadCTApprovals/BDR.pdfhttps://medicaldialogues.in/news/industry/pharma/bdr-pharma-gets-dcgi-nod-for-generic-antibiotic-drug-biapenem-82384

Biapenem

CAS Registry Number: 120410-24-4 
CAS Name: 6-[[(4R,5S,6S)-2-Carboxy-6-((1R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt

Additional Names: (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]-triazolium-6-yl)thio]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate

Manufacturers’ Codes: LJC-10627; L-627; CL-186815 
Molecular Formula: C15H18N4O4SMolecular Weight: 350.39

Percent Composition: C 51.42%, H 5.18%, N 15.99%, O 18.26%, S 9.15% 
Literature References: 1-b-methyl-carbapenem antibiotic. Prepn: T. Kumagai et al.,EP289801; eidem,US4990613 (1988, 1991 both to Lederle). Total synthesis: Y. Nagao et al.,J. Org. Chem.57, 4243 (1992). Renal dehydropeptidase stability: M. Hikida et al.,Antimicrob. Agents Chemother.36, 481 (1992). In-vitro antimicrobial spectrum: H. M. Wexler et al.,J. Antimicrob. Chemother.33, 629 (1994); H. Y. Chen, D. M. Livermore, ibid. 949. Clinical pharmacokinetics: M. Nakashima et al.,Int. J. Clin. Pharmacol. Ther. Toxicol.31, 70 (1993). Clinical evaluation: H. Meguro et al.,Jpn. J. Antibiot.47, 903 (1994). 
Properties: Amorphous, pale yellow powder from acetone/water, occurs as hemihydrate. [a]D20 -32.9° (c = 0.5)

.Optical Rotation: [a]D20 -32.9° (c = 0.5)

Therap-Cat: Antibacterial.Keywords: Antibacterial (Antibiotics); ?Lactams; Carbapenems.

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Biapenem (INN) is a carbapenem antibiotic. It has in vitro activity against anaerobes.^[1] 1-β-methyl-carbapenem antibiotic. Approved in Japan in 2001.

syn

CN 110343122

https://patents.google.com/patent/CN110343122B/en

PATENT

EP 168707

EP 289801

JP 02088578

ZA 9100014

EP 533149

CN 1995040

IN 2006DE01555

CN 101121716

IN 2008CH00177

CN 101805359

CN 101851206

CN 101935321

CN 111875622

WO 2018074916

WO 2016059622

US 20150328323

WO 2015151081

WO 2015155753

WO 2015151078

US 20150284416

WO 2015151080

US 20150038726

WO 2014104488

IN 2013MU00181

WO 2014111957

CN 103570750

WO 2014097221

IN 2012CH01371

WO 2013150550

PAPERS

 Journal of Organic Chemistry (1992), 57(15), 4243-9.

Heterocycles (1993), 36(8), 1729-34.

Journal of Antibiotics (1993), 46(12), 1866-82.

e-EROS Encyclopedia of Reagents for Organic Synthesis (2008), 1-3.

Bioorganic & medicinal chemistry letters (2009), 19(17), 5162-5.

 IP.com Journal (2014), 14(12A), 1-3

IP.com Journal (2014), 14(10A), 1-2.

Bioorganic & medicinal chemistry (2013), 21(18), 5841-50.

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PATENT

https://patents.google.com/patent/WO2014097221A1/esBiapenem is chemically known as 6-[[2(4R,5S,6S)-carboxy-6-[(lR)- hydroxy ethyl] -4-methyl-7-oxo- 1 -azabicyclo [3.2.0]hept-2-en-3 -yljthio] 6,7-dihydro-5H- pyrazolo[l,2-a][l,2,4]triazol-4-ium inner salt, and is represented by Formula 1. It is indicated for the treatment of bacterial infection and sepsis.

Formula 1U.S. Patent No. 4,866,171, in Example 6, discloses the purification of biapenem using chromatography and/or lyophilization techniques. This patent also describes a process for the conversion of amorphous biapenem into a crystalline form by dissolving the amorphous biapenem in water while heating, followed by cooling, then washing the obtained crystals with a 50% aqueous ethanol solution.U.S. Patent No. 5,241,073 describes a process for the purification of biapenem involving column chromatography and crystallization with ethanol.U.S. Patent No. 5,286,856 describes a process for the crystallization of biapenem from an aqueous solution, comprising maintaining the temperature of the aqueous solution from eutectic temperature (-10°C to -2°C) to a temperature lower than 0°C, followed by lyophilization.The Journal of Organic Chemistry, 63(23):8145-8149 (1998) describes the purification of biapenem involving resin chromatography.The present invention provides an alternate process for the purification of biapenem that avoids making use of tedious techniques like chromatography and lyophilization. At the same time, it results in a high yield and high purity of the final product. Advantageously, the crystalline biapenem of this invention can be directly isolated from the reaction mixture. Further, the process of the present invention involves fewer steps, is easily scalable, and industrially advantageous.EXAMPLESExample 1 : Purification of BiapenemBiapenem (12 g) was added into water (300 mL) at 65°C, stirred for 5 minutes, and cooled to 30°C within 10 minutes. Enoantichromos carbon (0.6 g) was added to the reaction mixture and stirred for 10 minutes to 15 minutes at 25°C to 30°C. The reaction mixture was filtered through a hyflo bed and washed with water (36 mL). The filtrate obtained was passed through a 0.45 micron filter, and its pH was adjusted to 5.5 using 5% aqueous sodium hydroxide solution at 10°C to 15°C. Acetone (336 mL) was added to the reaction mixture at 5°C to 10°C. The resultant slurry was stirred for 3 hours at 5°C to 10°C, filtered, and the obtained solid was washed with acetone (60 mL). The solid was dried under reduced pressure (720 mmHg) at 30°C to 35°C to obtain the title product as white crystals.Yield: 84%HPLC Purity: 99.87% Example 2: Purification of BiapenemBiapenem (18 g) was added into water (450 mL) at 65°C, stirred for 5 minutes, and cooled to 30°C within 10 minutes. Enoantichromos carbon (0.9 g) was added to the reaction mixture and stirred for 30 minutes at 25°C to 30°C. The reaction mixture was filtered through a hyflo bed and washed with water (54 mL). The filtrate obtained was passed through a 0.45 micron filter and its pH was adjusted to 4.9 using 5% aqueous sodium hydroxide solution at 10°C to 15°C. Acetone (504 mL) was added to the reaction mixture at 10°C to 15°C. The resultant slurry was stirred for 3 hours at 5°C to 10°C, filtered, and the obtained solid was washed with acetone (90 mL). The solid was dried under reduced pressure (720 mmHg) at 35°C to 40°C to obtain the title product as white crystals.Yield: 81.77%HPLC Purity: 99.80% 
PATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013150550

The present invention relates to an improved process for the preparation of carbapenem antibiotic; more particularly relates to the preparation of Ertapenem monosodium salt of formula (I) having purity greater than 98.5% and having pharmaceutically acceptable level of residual solvent and palladium content.

The US patents namely US 5,478,820 and US 5,856,321 disclose various processes for preparing Ertapenem and its sodium salt. Example 12 of US 5,478,820 discloses a process in which the Ertapenem was isolated using column purification followed by freeze-drying technique. According to Example-4 of this patent disodium salt of Ertapenem was prepared by dissolving crude product in water using NaHCO₃, followed by purification using column chromatography and subsequent lyophilization.

US 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 of formula

wherein P represents protecting group and X represents charge balancing group like sodium

with C4.10 alcohol in the presence of ion-pairing reagent followed by adjusting the pH of the aqueous layer to 5.5 and crystallizing using methanol and 1-propanol to produce a crystalline compound; this patent process involves operations like

multiple extractions which is cumbersome in plant and said operation affects the overall yield.

US 7,145,002 provides a process for producing Ertapenem or its sodium salt and/or its solvate in crystalline form. This patent states (refer para 3, lines 31-41) that contact of Ertapenem sodium with water and alcoholic solvents results in the formation of crystalline solvates. The processes reported in examples- 1 & 2 provide crystalline Ertapenem monosodium which is isolated from a mixture of methanol, 1-propanol and water followed by washing with aqueous isopropyl alcohol which results in the formation of crystalline solvate of Ertapenem sodium. Applicant found the Ertapenem monosodium obtained according to this process contain higher amount of residual solvent and palladium content.

US 7,022,841 provide a process for reducing the levels of organic solvents in Ertapenem to pharmaceutically acceptable levels. This patent discloses (Refer para 1, lines 52-60) that Ertapenem sodium obtained from water/alcohol mixture according to US 7, 145,002 becomes amorphous when water content of the solid is reduced and further the organic solvent present in the solid is not readily removed. In view of this drawback, this patent provides a process wherein the water content of Ertapenem sodium is maintained between 13-25% during the washing and drying process. This patent further discloses that (Refer para 9, lines 6-14) the washing of Ertapenem sodium can be carried out using anhydrous solvents which results in the formation of amorphous solid, which is then dried using hydrated nitrogen by increasing the water content of the solid. Due to the hygroscopic and unstable nature of Ertapenem sodium when in contact with water, the above processes result in more degradation of Ertapenem. The patent further discloses in example 5 that the degradation of Ertapenem sodium is more when it takes more time for drying.

Further this patent requires repetitive washing and control of moisture content to get the desired results.

For isolation of Ertapenem sodium from the reaction mass, all the above discussed prior art patents utilize methanol and 1-propanol as crystallization solvent. The filtration of Ertapenem sodium formed by using these solvents or their mixture takes longer time duration and subsequent drying for the removal of residual solvent also takes several hours due to occlusion of solvent into Ertapenem sodium. During these operations the Ertapenem sodium degrades an results in the formation of many impurities such as several dimers, methanolysis impurity etc., and hence the reported processes is not suitable to manufacture Ertapenem sodium on commercial scale with purity greater than 98.5% and with pharmaceutically acceptable level of residual solvent content.

Methanolysis impurity Dimer-I

Dimer-II

Further the applicant found that Ertapenem monosodium isolated by following the process reported in prior art was having palladium content above the pharmaceutically acceptable level. Hence the process reported in prior art is not suitable on manufacturing scale where maintaining stringent technological condition is cumbersome and involves higher operating cost.

Thus all the reported processes suffer in terms of one or more of the following facts:

^■ Filtration time of Ertapenem sodium takes several hours.

^■ Drying time takes several hours due to occlusion of solvent and nature of the solid.

^■ Stringent technological condition is required for maintenance of moisture content during washing & drying operation.

■ Palladium content is found to be higher (greater than 25 ppm) which is not acceptable for pharmaceutical products.

■ The isolated Ertapenem sodium is having higher amount of residual solvents.

■ The purity is reduced over to several hours of filtration & drying.

With our continued research for developing a process for the preparation of Ertapenem monosodium of formula (I) to overcome the above mentioned drawbacks, we surprisingly found that when esters of organic acid were used as solvents in place of 1-propanol, the solid obtained was easily filterable with less cycle time. Further the washing with hydrocarbon solvents containing 0-75% alcoholic solvent followed by drying results in Ertapenem having residual solvent content well below the pharmaceutically acceptable levels. The use of thiourea, thiosemicarbazide or their N-substituted derivatives in the presence of organic solvents during isolation brings down the palladium content to pharmaceutically acceptable level.

The Ertapenem or its sodium salt can be prepared according the processes provi

(I)

P’ and P” represent carboxylic protecting groups and X is H or Na

Scheme-1

The present invention is illustrated with the following examples, which should not be construed to limit the scope of the invention.

Example- I

Preparation of Ertapenem monosodium of formula (I)

Step-I:

To a stirred solution of p-nitrobenzyl (4R,5S,6S)-3-(diphenyloxy)phosphoryloxy-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (compound II) (100 g) and (2S,4S)-2-[[(3-carboxyphenyl) amino]carbonyl]-4-mercapto-l-(4-nitrobenzyl)pyrrolidinecarboxylate (compound III) (75 g) in N,N-dimethylformamide was added Ν,Ν-diisopropylethylamine at -30 to -40° C and stirred. The reaction mass, after completion of the reaction, was quenched with a mixture of phosphate buffer solution-ethyl acetate and the pH was adjusted to 5 – 6 with phosphoric acid. The organic layer was separated, washed with water and subjected to carbon treatment. To the organic layer containing the compound of formula (IV) (wherein P’ and P” refers to p-nitrobenzyl), a solution of sodium 2-ethylhexanoate (42 g in 500 mL methanol) was added and taken to next step as such. (If required the compound of formula (IV) is isolated either as sodium salt or as free acid by following the process reported in prior art and taken further)

Step-II:

To the Step-I organic layer containing the compound of formula (IV) (wherein P’ and P” refers to p-nitrobenzyl & X is Na), 3-(N-morpholino)propanesulfonic acid solution was added and subjected to hydrogenation using palladium on carbon at 8- 10° C with 9-10 kg hydrogen pressure. The reaction mass, after completion of reaction, was filtered to remove palladium on carbon. To the filtrate, thiourea (5 g) and tetrahydrofuran were added and stirred. The aqueous layer was separated and treated with carbon and neutral alumina at 10-15° C while degassing and filtered. The filtrate was added to methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with a mixture of cyclohexane: ethanol (200 ml) and dried under vacuum. Yield: 46 g; Purity by HPLC: 98.93%; Palladium content: 1.8 ppm by ICP MS

The HPLC purity of Ertapenem monosodium was checked using the following parameters

Column : Zorbax Eclipse plus C8, (50 mm x 4.6 mm), 1.8μ).

Mobile phase : Ammoniam acetate buffer: Acetonitile: water

Detector : UV at 250 nm

Flow rate : 0.5 mL/min

Run time : 45 min.

Example- II

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and subjected to hydrogenation using palladium on carbon at 8-10° C with 9-10 kg hydrogen pressure. The reaction mass, after completion of reaction, was filtered and the filtrate was treated with thiourea and 2-methyltetrahydrofuran and the layers separated. The aqueous layer was treated with carbon & neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with cyclohexane (200 ml) and

dried under vacuum. Yield: 44 g; Purity by HPLC: 98.84%; Palladium content: 0.93 ppm by ICP MS

The term ICP MS method refers to the inductively coupled plasma mass spectrometry. The following parameter was used to determine the content of palladium.

The carbapenem was digested in a closed vessel system in presence of reagents Nitric acid, Hydrogen peroxide and Hydrochloric acid by using Microwave reaction system with microwave radiation power 1200 Watts. The digested sample was introduced into inductively coupled plasma mass spectrometer by help of Peltier cooled spray chamber. The sample aerosol is getting atomized then ionized in the argon plasma. The ionized Palladium was estimated by using Quadrupole mass detector. The sample was quantified against NIST traceable reference standards at mass number ! 05.

Example- III

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction, was filtered and the filtrate was treated with thiourea and tetrahydrofuran and the layers separated. The aqueous layer was separated and treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with a mixture of toluene: ethanol (200 ml) and dried under vacuum. Yield: 42 g; Purity by HPLC: 99.03%

Example- IV

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction was filtered and the filtrate was treated with thiosemicarbazide and tetrahydrofuran and the layers separated. The aqueous layer was treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C followed by the addition of ethyl acetate and stirred. The solid obtained was filtered, washed with a mixture of cyclohexane: ethanol (200 ml) and dried under vacuum. Yield: 41 g; Purity by HPLC: 99.13%; Palladium content: 1.71 ppm by ICP MS

Example- V

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and subjected to hydrogenation using palladium on carbon at 8-10° C with 9-10 kg hydrogen pressure. The reaction mass, after completion of reaction, was filtered and the filtrate was treated with thiourea and 2-methyltetrahydrofuran and the layers separated. The aqueous layer was treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, a mixture of ethyl acetate containing 10% methyl acetate was added and stirred. The solid obtained was

filtered, washed with cyclohexane:ethanol and dried under vacuum. Yield: 40.5 g; Purity by HPLC: 98.77%; Palladium content: 1.43 ppm by ICP MS

Example-VI

(V ) (V I )

The diprotected Meropenem of formula (V) (where P and P’ were p-nitrobenzyl) was dissolved in tetrahydrofuran and 3-(N-morpholino)propanesulfonic acid buffer and hydrogenated using palladium on carbon at 9-10 kg hydrogen pressure. The mass was filtered and the filtrate was washed with ethyl acetate. The aqueous layer was treated with thiourea and 2-methyltetrahydrofuran. The aqueous layer was separated, treated with carbon and degassed. The carbon was filtered off and acetone was added to the filtrate to crystallize Meropenem trihydrate of formula (VI). The product was filtered and washed with aq. acetone and dried under vacuum to get Meropenem trihydrate. Purity: 99.8%; Pd content: 0.08 ppm

Reference example-I:

Preparation of Ertapenem monosodium of formula (I)

To Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction, was filtered. The filtrate was treated with thiourea and tetrahydrofuran and the layers separated. The aqueous layer was treated with carbon and neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5.5-5.7 using aqueous acetic acid. To the mass ethyl acetate was added and stirred. The solid obtained was filtered, washed with ethanol (5 * 100 ml) and dried under vacuum. Yield: 31 g; Purity by HPLC: 96.76%

Reference example-II:

Preparation of Ertapenem monosodium of formula (I)

To the Step-I reaction mass , as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction was filtered and the layers separated. The aqueous layer was treated with carbon and neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5.5-5.7 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with a mixture of cyclohexane: ethanol and dried under vacuum. Yield: 43 g; Purity by HPLC: 98.6%; Palladium content: 35.8 ppm by ICP MS.

Reference example-HI:

Preparation of Ertapenem monosodium of formula (I)

To the Step-I reaction mass as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction, was filtered and the layers separated. The aqueous layer was treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with 1-propanol at -5° C and the pH was adjusted to 5.5-5.7 using aqueous acetic acid. To the mass methanol and 1-propanol were added and stirred. The solid obtained was filtered, washed with ethanol and dried under nitrogen atmosphere in vacuum. Yield: 25 g; Purity by HPLC: 97 %.: palladium content: 38.2 ppm

The following tables illustrate the advantages of the present invention over prior art process:

Table-I: Comparison of present process with prior art process

The crystallization and washing method disclosed in US 7,022,841 was followed.

The above table indicates that the use of ethyl acetate as crystallization solvent results with improved yield and high purity with less filtration and drying time thereby increasing the productivity significantly on manufacturing scale. Further the use of thiourea or thiosemicarbazide as reagents in the present process results in the pharmaceutically acceptable level of palladium content.

Table-II: Comparison of solvents for washing Ertapenem monosodium

The above table indicates that the use of hydrocarbon solvents containing 0-75% of alcoholic solvent helps in washing to remove the residual solvent content in shorter duration and with single run wash. On the other hands the use of ethanol alone results in Ertapenem monosodium having less yield and purity requiring repetitive washing.

Table-IH: Effect of different reagent in reduction of palladium content

Reagent : thiourea, thiosemicarbazide or its N-substituted derivatives

Advantages of the process of the present invention:

> The use of ester of an organic acid for the crystallization of Ertapenem sodium results in fast filtration and reduced cycle time, thereby increasing the productivity.

> Washing of Ertapenem sodium with hydrocarbon solvent optionally containing alcohol results in improved physical nature of Ertapenem sodium resulting in reduced washing and drying time thereby avoid the degradation of Ertapenem and providing Ertapenem sodium with purity greater than 98.5% by HPLC.

Use of thiourea, thiosemicarbazide or their N-substituted derivatives in the process results in Ertapenem sodium having pharmaceutically acceptable level of palladium content.

PATENT

https://patents.google.com/patent/WO2002057266A1/enEXAMPLE

PNB = p-nitrobenzyl

Ia’A hydrogenator is charged with 63 g of 10% Pd on carbon catalyst (dry weight) in 1.8 L of water. The vessel is placed under hydrogen then vented and placed under nitrogen. Sodium hydroxide (68 g, 50%) is charged adjusting the pH to about 7.5 with carbon dioxide.The enol phosphate (170 g) and the thiol (86 g) are dissolved in 1.3^‘L of N- ethylpyrrolidinone (NEP). The mixture is cooled to below -40°C and 1,1,3,3- tetramethylguanidine (109 g) is added. After 3 hours, the reaction mixture is quenched into the hydrogenator at below 15°C adjusting the pH to about 8 with carbon dioxide. The vessel is placed under hydrogen. When the reaction is complete, the hydrogen is vented and the reaction mixture is treated with activated carbon and filtered. The filtrate is extracted with iso-amyl alcohol containing diphenylphosphoric acid (240 g) and 50% NaOH (44 g). The resulting aqueous solution is further extracted with iso-amyl alcohol to give an aqueous solution containing at least 90 mg/mL of the product. Both extractions are performed using two CINC centrifugal separators set in series for countercurrent extraction. The pH is adjusted to 5.5 with acetic acid. The product is crystallized by adding equal volumes of methanol and 1- propanol at below -5°C and isolated by filtration. The solid is washed with a mixture of 2-propanol and water (85: 15 v/v) then dried to yield a compound of formula la’.While certain preferred embodiments of the invention have been described herein in detail, numerous alternative embodiments are contemplated as falling within the scope of the appended claims. Consequently the invention is not to be limited thereby.

Patent Citations

Publication numberPriority datePublication dateAssigneeTitleUS4866171A1987-04-111989-09-12Lederle (Japan), Ltd.(1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio-6-[R-1-hydroxyethyl]-1-methyl-carbapenum-3-carboxylateUS5241073A1990-10-121993-08-31Lederle (Japan)Process for preparing (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo [1,2-a][1,2,4]triazolium-6-yl)]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate and starting materials thereofUS5286856A1991-09-201994-02-15Takeda Chemical Industries, Ltd.Production of crystalline penemWO2002057266A1 *2001-01-162002-07-25Merck & Co., Inc.Improved process for carbapenem synthesisWO2009047604A1 *2007-10-082009-04-16Orchid Chemicals & Pharmaceuticals LimitedProcess for the preparation of carbapenem antibioticCN102268025A *2011-07-152011-12-07海南美兰史克制药有限公司一种比阿培南化合物及其制法

References

1. ^ Aldridge KE, Morice N, Schiro DD (April 1994). “In vitro activity of biapenem (L-627), a new carbapenem, against anaerobes”. Antimicrob. Agents Chemother. 38 (4): 889–93. doi:10.1128/aac.38.4.889. PMC 284564. PMID 8031067.

External links

• (in Japanese) Omegacin

ClinicalTrials.gov

NIPH Clinical Trials Search of Japan

/////////BIAPENEM, TL8000539, UNII:YR5U3L9ZH1, UNII-YR5U3L9ZH1, биапенем, بيابينام ,比阿培南 , Biapenern, CL 186-815, CL 186815, L 627, LJC 10627, Omegacin, Antibacterial, Antibiotics, Lactams, Carbapenems, ind 2021, india 2021, approvals 2021

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