WO2004039776A2 - A process for the preparation of benzyl 2-oxo-4- (heteroaryl) dithio-alpha-isoprenyl-1- azetidineazetate derivatives - Google Patents

A process for the preparation of benzyl 2-oxo-4- (heteroaryl) dithio-alpha-isoprenyl-1- azetidineazetate derivatives Download PDF

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WO2004039776A2
WO2004039776A2 PCT/IB2003/004860 IB0304860W WO2004039776A2 WO 2004039776 A2 WO2004039776 A2 WO 2004039776A2 IB 0304860 W IB0304860 W IB 0304860W WO 2004039776 A2 WO2004039776 A2 WO 2004039776A2
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formula
compound
solvent
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ethyl acetate
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WO2004039776A3 (en
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Pandurang Balwant Deshpande
Palanisamy Senthilkumar Udayampalayam
Sanjay Nivrutti Karale
Jayaraman Kannappan
Andrew Gnanaprakasam
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Orchid Chemicals & Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

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  • the present invention relates to a process for the preparation of azetidine derivatives. More particularly, the present invention relates to a process for the preparation of azetidine derivatives of the formula (I).
  • the compound of formula (I) is useful an intermediate for the preparation of tazobactam, an antibiotic of formula (II).
  • Tazobactam is chemically known as 2 ⁇ -methyl-2 ⁇ -(l,2,3-triazol-l-yl)- methylpenam-3 ⁇ -carboxylate- 1,1 -dioxide. It is an orally effective penicillin antibiotic having a broad spectrum of antibacterial activity against both gram positive and gram-negative organisms and is disclosed in US Patent No.
  • X represents chlorine atom or bromine atom and R represents hydrogen atom or penicillin carboxy-protecting radical, and a process for its preparation comprising reacting a compound of the formula (IV) wherein R is as defined above with a chlorinating reagent or brominatitig reagent.
  • R- is as defined above and R is a substituted or unsubstituted heterocyclic group with a nitrogen-containing heterocyclic compound of the formula
  • the objective of the present invention is to develop a simple and commercially viable process for the preparation of tazobactam of the formula (I)* Summary of the Invention
  • the present invention provides a process for the preparation of azetidine derivatives of the formula (I)
  • R represents substituted benzyl
  • R- represents a heteroaryl ring, which comprises the steps of : i) halogenating the compound of formula (VI) using a halogenating agent in the presence of metal nitrite and solvent to obtain compound of formula
  • the substituent on the benzyl is selected nitro, methoxy, phenyl, halogen and the like.
  • the halogenation is carried out using metal nitrite such as sodium nitrite or potassium nitrite
  • the halogenating agent used is selected from bromine, chlorine, Br 2 /HBr, I 2 /HI, C1 2 /HC1.
  • the solvent used for halogenation of compound of formula (VI) is selected from methylene dichloride, ethylene dichloride, ethylene chloride, toluene, chloroform, ethyl acetate, water and the like or a mixture thereof.
  • the dihalo compound of formula (VII) is extracted into the aqueous phase by adjusting the pH using alkali/alkaline earth metal hydroxides, carbonates, or oxides such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, calcium oxide and the like.
  • the dehalogenation of compound of formula (VII) is carried out in the presence of magnesium, iron, Pd/C using base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like; either in a biphasic medium comprising water and a water-immiscible organic solvent selected from ethyl acetate, methylene dichloride, ethylene dichloride and the like while adjusting the pH or in a homogeneous medium like methanol, ethanol and the like.
  • base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like
  • a biphasic medium comprising water and a water-immiscible organic solvent selected from ethyl acetate, methylene dichloride, ethylene dichloride and the like while adjusting the pH or in a homogeneous medium like methanol, ethanol and the like.
  • esterification of compound of formula (VIII) is carried out using esterifying agents such as p- methoxybenzyl bromide, p-methoxybenzyl chloride, p-nitrobenzyl bromide, p- nitrobenzyl chloride, o-chlorobenzyl chloride, benzyl bromide and the like in the presence of a solvent selected from methylene dichloride, N,N- dimethylformamide, N-methylpyrrolidone, acetonitrile, dioxane, tetrahydrofuran, diglyme, ethyl acetate, N,N-dimethylacetamide, water and the like or mixtures thereof.
  • esterifying agents such as p- methoxybenzyl bromide, p-methoxybenzyl chloride, p-nitrobenzyl bromide, p- nitrobenzyl chloride, o-chlorobenzyl chloride, benzyl bromide and
  • the oxidation of compound of formula (IX) in step (iv) is carried out using peracetic acid, rri- chloroperbenzoic acid, H 2 O 2 , trifluoroperacetic acid, magnesium monoperoxyphthalate and the like in the presence of solvent selected from methylene dichloride, ethylene dichloride, chloroform, toluene, N,N- dimethylformamide, N-methylpyrrolidone, ethyl acetate, acetic acid, N,N- dimethylacetamide, acetone and the like or mixtures thereof.
  • solvent selected from methylene dichloride, ethylene dichloride, chloroform, toluene, N,N- dimethylformamide, N-methylpyrrolidone, ethyl acetate, acetic acid, N,N- dimethylacetamide, acetone and the like or mixtures thereof.
  • the ring opening of compound of the formula (X) step (v) is carried out using a mercaptan selected from 2-mercaptobenzothiazole, 2-mercaptobenzooxazole, 2- mercaptobenzimidazole, 2-mercapto-5-methylterazole in the presence of a solvent selected from 1,4-dioxane, toluene, xylene, chlorobenzene and the like.
  • a solvent selected from 1,4-dioxane, toluene, xylene, chlorobenzene and the like.
  • the heteroaryl ring represented by R- is selected from 2-mercaptobenzothiazole, 2- mercaptobenzooxazole, 2-mercaptobenzimidazole or 2-mercapto-5- methyltetrazole.
  • the aqueous layer was extracted with MDC (2 x 100 ml).
  • the MDC layer was separated and used as such in the next step.
  • water 150 ml
  • Aqueous layer was separated and to the organic layer sodium hydroxide solution was added to adjust the pH again.
  • the aqueous layer was separated and combined with the main aqueous layer.
  • the pH of the combined aqueous layer was adjusted with dil.HCl to 4.0 - 4.5.
  • To this magnesium powder (45 g) was added while maintaining the pH at 4.0- 4.5 with dil HC1. After completion of the reaction, the reaction mixture was cooled and filtered.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a process for the preparation of azetidine derivatives. More particularly, the present invention relates to a process for the preparation of azetidine derivatives of the formula (I), wherein R represents substituted benzyl; R1 represents a heteroaryl ring; X represents halogen atom.

Description

A PROCESS FOR THE PREPARATION OF AZETIDINE
DERIVATIVES
Field of the Invention
The present invention relates to a process for the preparation of azetidine derivatives. More particularly, the present invention relates to a process for the preparation of azetidine derivatives of the formula (I).
Figure imgf000002_0001
The compound of formula (I) is useful an intermediate for the preparation of tazobactam, an antibiotic of formula (II).
Figure imgf000002_0002
Background of the Invention
Tazobactam is chemically known as 2α-methyl-2β-(l,2,3-triazol-l-yl)- methylpenam-3α-carboxylate- 1,1 -dioxide. It is an orally effective penicillin antibiotic having a broad spectrum of antibacterial activity against both gram positive and gram-negative organisms and is disclosed in US Patent No.
4,562,073.
US patent No. 4,496,484 discloses compounds of formula (III)
Figure imgf000002_0003
wherein X represents chlorine atom or bromine atom and R represents hydrogen atom or penicillin carboxy-protecting radical, and a process for its preparation comprising reacting a compound of the formula (IV)
Figure imgf000003_0001
wherein R is as defined above with a chlorinating reagent or brominatitig reagent.
US patent No. 4,898,939 discloses process for preparing a 2β- substituted-methylpenicillin compound of the formula (V)
Figure imgf000003_0002
wherein --N Y is an optionally substituted heterocyclic group containing 2 to 4 nitrogen atoms as the hetero atom in the ring structure, and Rt is a penicillin carboxyl protecting group, the process comprising reacting an azetidinonedisulfide compound of the formula (I)
Figure imgf000003_0003
wherein R- is as defined above and R is a substituted or unsubstituted heterocyclic group with a nitrogen-containing heterocyclic compound of the formula
wherein --N Y is as defined above in the presence of a metal compound.
Objective of the Invention
The objective of the present invention is to develop a simple and commercially viable process for the preparation of tazobactam of the formula (I)* Summary of the Invention
Accordingly, the present invention provides a process for the preparation of azetidine derivatives of the formula (I)
Figure imgf000004_0001
wherein R represents substituted benzyl; R- represents a heteroaryl ring, which comprises the steps of : i) halogenating the compound of formula (VI) using a halogenating agent in the presence of metal nitrite and solvent to obtain compound of formula
(VII) wherein X represents halogen atom, ii) dehalogenating the compound of formula (VII ) to obtain compound of formula (VIII), iii) esterifying the compound of formula (VIII) using an esterifying agent in the presence of a solvent at a temperature in the range of 10 to 50 °C to produce a compound of formula (IX) wherein R represents substituted benzyl group, iv) oxidizing the compound of formula (IX) using an oxidizing agent in the presence of a solvent at a temperature in the range of -30 °C to 30 °C to a compound of formula (X) and v) opening the penam ring of the formula (X) using a mercaptan in the presence of a solvent at a temperature in the range of 80 °C to 150 °C to produce a compound of formula (I) where Rt represents a heteroaryl ring and all other symbols are as defined above,
The process is shown in Scheme -1 below :
Figure imgf000005_0001
Scheme -1
Detailed Description of the Invention
In an embodiment of the present invention, the substituent on the benzyl is selected nitro, methoxy, phenyl, halogen and the like.
In an embodiment of the present invention, the halogenation is carried out using metal nitrite such as sodium nitrite or potassium nitrite
In an embodiment of the present invention, the halogenating agent used is selected from bromine, chlorine, Br2/HBr, I2/HI, C12/HC1. In an embodiment of the present invention, the solvent used for halogenation of compound of formula (VI) is selected from methylene dichloride, ethylene dichloride, ethylene chloride, toluene, chloroform, ethyl acetate, water and the like or a mixture thereof.
In yet another embodiment of the present invention, the dihalo compound of formula (VII) is extracted into the aqueous phase by adjusting the pH using alkali/alkaline earth metal hydroxides, carbonates, or oxides such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, calcium oxide and the like. In an embodiment of the present invention, the dehalogenation of compound of formula (VII) is carried out in the presence of magnesium, iron, Pd/C using base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like; either in a biphasic medium comprising water and a water-immiscible organic solvent selected from ethyl acetate, methylene dichloride, ethylene dichloride and the like while adjusting the pH or in a homogeneous medium like methanol, ethanol and the like.
In yet another embodiment of the present invention the esterification of compound of formula (VIII) is carried out using esterifying agents such as p- methoxybenzyl bromide, p-methoxybenzyl chloride, p-nitrobenzyl bromide, p- nitrobenzyl chloride, o-chlorobenzyl chloride, benzyl bromide and the like in the presence of a solvent selected from methylene dichloride, N,N- dimethylformamide, N-methylpyrrolidone, acetonitrile, dioxane, tetrahydrofuran, diglyme, ethyl acetate, N,N-dimethylacetamide, water and the like or mixtures thereof.
In yet another embodiment of the present invention the oxidation of compound of formula (IX) in step (iv) is carried out using peracetic acid, rri- chloroperbenzoic acid, H2O2, trifluoroperacetic acid, magnesium monoperoxyphthalate and the like in the presence of solvent selected from methylene dichloride, ethylene dichloride, chloroform, toluene, N,N- dimethylformamide, N-methylpyrrolidone, ethyl acetate, acetic acid, N,N- dimethylacetamide, acetone and the like or mixtures thereof.
In yet another embodiment of the present invention the ring opening of compound of the formula (X) step (v) is carried out using a mercaptan selected from 2-mercaptobenzothiazole, 2-mercaptobenzooxazole, 2- mercaptobenzimidazole, 2-mercapto-5-methylterazole in the presence of a solvent selected from 1,4-dioxane, toluene, xylene, chlorobenzene and the like. In an embodiment of the present invention the heteroaryl ring represented by R- is selected from 2-mercaptobenzothiazole, 2- mercaptobenzooxazole, 2-mercaptobenzimidazole or 2-mercapto-5- methyltetrazole.
In yet another embodiment of the present invention, there is provided a process for the preparation of tazobactam of formula (II)
Figure imgf000007_0001
from azetidine derivatives of the formula (I)
The following examples are provided by way of illustration only and should not be limited to construe the scope of the invention.
Example 1
Preparation of p-nitrobenzyl 2-oxo-4-(benzothiazol-2-yl)dithio-α- isopropenyl-1-azetidine acetate Step (ϊ)
Preparation of sodium 2,2-dimethyl-penam-3-carboxyIate Into a round-bottomed flask containing DM water (174 ml) at 0-5 °C, methylene dichloride (MDC) (1000 ml) was added under stirring. To this, bromine (129.5 g) was added followed by and sodium nitrite solution (64 g in 120 ml water). To this reaction mass, 6-APA (100 g)_at -8 to 0 °C was added over a period of 90-120 min. and stirred for 30 min at the same temperature. An aqueous solution of sodium metabisulfite (42.75 g) was added to the reaction mixture, stirred and separated the layers. The aqueous layer was extracted with MDC (2 x 100 ml). The MDC layer was separated and used as such in the next step. To the MDC layer, water (150 ml) was added and the pH adjusted to 7.0 - 7.5 using sodium hydroxide solution. Aqueous layer was separated and to the organic layer sodium hydroxide solution was added to adjust the pH again. The aqueous layer was separated and combined with the main aqueous layer. The pH of the combined aqueous layer was adjusted with dil.HCl to 4.0 - 4.5. To this magnesium powder (45 g) was added while maintaining the pH at 4.0- 4.5 with dil HC1. After completion of the reaction, the reaction mixture was cooled and filtered. The pH of the filtrate was lowered and added sodium chloride (96 g) and ethyl acetate (300 ml) under string. The aqueous layer was separated and extracted with ethyl acetate (2 x 300 ml). To the combined ethyl acetate layers, activated carbon was added and stirred for 30 min. at 3-8 °C. Filtered, washed with ethyl acetate and added sodium 2-ethylhexanoate solution (55 g in 150 ml ethyl acetate) at 0-5 °C in 30 to 45 min. The temperature was raised and filtered the reaction mass, washed with ethyl acetate and dried under vacuum at RT to yield the title compound (81 g, > 99%).
Step (if)
Preparation of 2,2-dimethyIpenam-3α-carboxylic acid p-nitrobenzyl ester To a solution of sodium 2,2-dimethylpenam-3α-carboxylate (65 g) in DMAc (270 ml), p-nitrobenzyl bromide (67.5 g) was added and stirred at for 36 hrs. The progress of the reaction was monitored by HPLC. Isopropyl ether (370 ml) was added at RT in 30-40 min and cooled to 0-5 °C. DM water (300 ml) was added at 2-5 °C and temperature raised to RT and stirred for 30 min filtered, washed with water followed by isopropyl ether and dried to yield the title compound (100 g). Purity 99% by HPLC.
Step (iii) Preparation of 2,2-dimethylpenam-3α-carboxyIic acid 1-oxide p- nitrobenzyl ester
A solution of 2,2-dimethylpenam-3α-carboxylic acid p-nitrobenzyl ester (100 g) in methylene dichloride (360 ml) was cooled to -10 °C. To this solution, peracetic acid (80 ml) was added at -10 °C in 60-70 min. After the reaction was over, DM water (125 ml) was added and the organic layer separated. The aqueous layer was extracted with MDC (400 ml) at 0-5 °C, and washed with 5% sodium chloride solution (210 ml). The pH of the organic layer was adjusted to 6.0-6.5 using sodium bicarbonate and stirred for 15 min. The aqueous layer was separated and extracted with MDC (100 ml) at 0-5 °C. The organic layers were combined and washed with 5% sodium chloride solution. The organic layer was charcoalized, concentrated under vacuum to remove methylene chloride and treated with isopropyl ether. The product obtained was filtered and dried under vacuum to yield the title compound (100 g, purity: 98% by HPLC).
Step (W)
Preparation of p-nitrobenzyl 2-oxo-4-(benzothiazol-2-yl)dithio-α- isopropenyl-1-azetidineacetate A solution of 2,2-dimethylpenam-3α-carboxylic acid 1-oxide p-nitrobenzyl ester (100 g) in toluene (1.4 L) was refluxed in a Dean-Stark apparatus with 2- mercaptobenzothiazole (100 g). After completion of the reaction, the solvent distilled off under vacuum, treated with isopropyl ether, filtered, washed with isopropyl ether and dried under vacuum to yield the title compound (125 g, purity 95% by HPLC).
Example 2
Preparation of sodium 2,2-dimethylpenam-3-carboxylate
Step (ϊ) Preparation of 6,6-dibromopenicillanic acid
Into a 2L round-bottomed flask containing DM water (100 ml) at 0-3 °C, hydrogen bromide (30 ml, 47-49% solution), and bromine (48 ml) were added followed by a solution of sodium nitrite 0-3 °C. To this reaction mass, a clear solution of 6-APA (prepared by dissolving 6-APA (100 g) in water and adding hydrogen bromide to get clear solution) and sodium nitrite solution were added at 0-2 °C over a period of 90-120 min. and stirred for 45 min at 4-6 °C. To this stirred reaction mixture, water (500ml) and aqueous solution of sodium metabisulfite (50 ml) were added and stirred for 20 min at 8 °C. The crystallized material was filtered, washed with water and dried under vacuum to yield the title compound (145 g, purity 97.5%).
Preparation of sodium 2,2-dimethylpenam-3-carboxylate
To a cold mixture of 6,6-dibromopenicillanic acid (140 g) in water (250 ml) sodium carbonate solution was added at 0-5 °C to adjust the pH to 5.6-5.8 to get clear solution (if not clear adjusted the pH with HC1 to 5-5.6). To this magnesium powder (20 g) was added while maintaining the pH at 3-8 °C in 60-90 min. The pH was adjusted to 4-4.5 and stirred for 90-120 min. The pH was adjusted to 4.0-4.5 with HC1 solution at 3-8 °C and added magnesium powder (25 g) slowly while maintaining the pH at 4-4.5 with HC1 at 3-8 °C and stirred for 60-90 min. . Filtered the reaction mass and washed with water and cooled to 0-5 C. Adjusted the pH to 2-2.5 with HC1 and added sodium chloride and stirred for 15 min. To this ethyl acetate was added and separated the aqueous layer and extracted with ethyl acetate (250 ml x 2). To the combined the ethyl acetate layers, activated carbon was added and stirred for 30 min. at 3-8 C. Filtered, washed with ethyl acetate and added sodium 2-ethyl hexanoate solution (57 g in 150 ml ethyl acetate). The temperature was raised and filtered the reaction mass, washed with ethyl acetate and dried under vacuum at RT to yield the title compound (70 g, purity 99% by HPLC).
Example 3 Preparation of sodium 2,2-dimethylpenam-3-carboxylate Step (i Preparation of 6,6-dibromopenicillanic acid
Into a 2L round-bottomed flask containing DM water (100 ml) at 0-3 °C, hydrogen bromide (30 ml, 47-49% solution), and bromine (48 ml) were added followed by a solution of sodium nitrite 0-3 °C. To this reaction mass, a clear solution of 6-APA (100 g) and sodium nitrite solution were added at 0-2 °C over a period of 90-120 min. and stirred for 45 min at 4-6 °C. To this stirred reaction mixture, water (500ml) and aqueous solution of sodium metabisulfite (50 ml) were added and stirred for 20 min at 8 °C. The crystallized material was filtered, washed with water and dried under vacuum to yield the title compound (145 g, purity 97.5%). Step (if)
Preparation of sodium 2,2-dimethylpenam-3-carboxylate To a cold mixture of 6,6-dibromopenicillanic acid (140 g) in water (850 ml) sodium carbonate solution was added at 0-5 °C to adjust the pH to 7.0 - 7.5 to get clear solution. To this sodium bicarbonate (65 g) was added and stirred for 20 min. and hydrogenated using Pd/C (8 g) and stirred for 3 to 4 hrs. After completion of the reaction, the reaction mass was filleted and washed with water. Adjusted the pH to 2-2.5 with HC1 and added sodium chloride and stirred for 15 min. To this ethyl acetate was added and separated the aqueous layer and extracted with ethyl acetate (250 ml x 2). To the combined the ethyl acetate layers, activated carbon was added and stirred for 30 min. at 3-8 °C. Filtered, washed with ethyl acetate and added sodium 2-ethylhexanoate solution (57 g in 150 ml ethyl acetate) at 0-5 °C in 30 to 45 min. The temperature was raised and filtered the reaction mass, washed with ethyl acetate and dried under vacuum at RT to yield the title compound (67 g, purity 98% by HPLC).

Claims

Claims :
1. A process for the preparation of azetidine derivatives of the formula (I)
Figure imgf000013_0001
wherein R represents substituted benzyl; R- represents a heteroaryl ring, which comprises the steps of : i) halogenating the compound of formula (VI)
Figure imgf000013_0002
using a halogenating agent in the presence of metal nitrite and solvent to obtain compound of formula (VII)
Figure imgf000013_0003
wherein X represents halogen atom, ii) dehalogenating the compound of formula (VTI ) to obtain compound of formula (VIII),
Figure imgf000013_0004
iii) esterifying the compound of formula (Vffl) using an esterifying agent in the presence of a solvent at a temperature in the range of 10 to 50 °C to produce a compound of formula (LX)
Figure imgf000013_0005
wherein R represents substituted benzyl group, iv) oxidizing the compound of formula (LX) using an oxidizing agent in the presence of a solvent at a temperature in the range of -30 °C to 30 °C to a compound of formula (X)
Figure imgf000014_0001
and v) opening the penam ring of the formula (X) using a mercaptan in the presence of a solvent at a temperature in the range of 80 °C to 150 °C to produce a compound of formula (I) where R- represents a heteroaryl ring and all other symbols are as defined above.
2. ■ The process as claimed in claim 1, the substituent on the benzyl is selected nitro, methoxy, phenyl, halogen and the like.
3. The process as claimed in claim 1, the halogenation is carried out using metal nitrite selected from sodium nitrite or potassium nitrite.
4. The process as claimed in claim 1, the halogenating agent is selected from bromine, chlorine, Br2/HBr, I2/HI or C12 HC1.
5. The process as claimed in claim 1, the solvent used for halogenation is selected from methylene dichloride, ethylene dichloride, ethylene chloride, toluene, chloroform, ethyl acetate, water or a mixture thereof.
6. The process as claimed in claim 1, the dehalogenation of compound of formula (VII) is carried out in the presence of magnesium, iron, Pd/C using base selected from sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate.
7. The process as claimed in claim 1, the esterifying agent is selected from p-methoxybenzyl bromide, p-methoxybenzyl chloride, p-nitrobenzyl bromide, p-nitrobenzyl chloride, o-chlorobenzyl chloride or benzyl bromide.
8. The process as claimed in claim 1, the solvent used for esterification is selected from methylene dichloride, N,N-dimethylformamide, N- methylpyrrolidone, acetonitrile, dioxane, tetrahydrofuran, diglyme, ethyl acetate, N,N-dimethylacetamide, water or mixtures thereof.
9. The process as claimed in claim 1, the oxidation is carried out using peracetic acid, m-chloroperbenzoic acid, H2O2, frifluoroperacetic acid or magnesium monoperoxyphthalate.
10. The process as claimed in claim 1, the solvent used for oxidation is selected from methylene dichloride, ethylene dichloride, chloroform, toluene, N,N-dimethylformamide, N-methylpyrrolidone, ethyl acetate, acetic acid, N,N-dimethylacetamide, acetone or mixtures thereof.
11. The process as claimed in claim 1, the mercaptan used in step (v) is selected from 2-mercaptobenzothiazole, 2-mercaptobenzooxazole, 2- mercaptobenzimidazole or 2-mercapto-5-methylterazole.
12. The process as claimed in claim 1, the solvent used in reaction step (v) is selected from 1,4-dioxane, toluene, xylene or chlorobenzene.
13. The process as claimed in claim 1, the heteroaryl ring represented by Ri is selected from 2-mercaptobenzothiazole, 2-mercaptobenzooxazole, 2- mercaptobenzimidazole or 2-mercapto-5-methyltetrazole.
14. A process for the preparation of tazobactam of formula (II)
Figure imgf000015_0001
from azetidine derivatives of the formula (I) prepared according to the process claimed in any of claims 1 to 13.
PCT/IB2003/004860 2002-11-01 2003-10-31 A process for the preparation of benzyl 2-oxo-4- (heteroaryl) dithio-alpha-isoprenyl-1- azetidineazetate derivatives WO2004039776A2 (en)

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US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
US8906898B1 (en) 2013-09-27 2014-12-09 Calixa Therapeutics, Inc. Solid forms of ceftolozane
US8968753B2 (en) 2013-03-15 2015-03-03 Calixa Therapeutics, Inc. Ceftolozane-tazobactam pharmaceutical compositions
US9044485B2 (en) 2013-03-15 2015-06-02 Calixa Therapeutics, Inc. Ceftolozane antibiotic compositions
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
CN109305977A (en) * 2018-11-28 2019-02-05 齐鲁天和惠世制药有限公司 A kind of preparation method of Tazobactam Sodium
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
CN110357903A (en) * 2019-08-28 2019-10-22 河北恒百药业有限公司 A kind of synthetic method of tazobactam
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US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
US9925196B2 (en) 2013-03-15 2018-03-27 Merck Sharp & Dohme Corp. Ceftolozane-tazobactam pharmaceutical compositions
US8968753B2 (en) 2013-03-15 2015-03-03 Calixa Therapeutics, Inc. Ceftolozane-tazobactam pharmaceutical compositions
US9044485B2 (en) 2013-03-15 2015-06-02 Calixa Therapeutics, Inc. Ceftolozane antibiotic compositions
US9320740B2 (en) 2013-03-15 2016-04-26 Merck Sharp & Dohme Corp. Ceftolozane-tazobactam pharmaceutical compositions
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US11278622B2 (en) 2013-03-15 2022-03-22 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US10420841B2 (en) 2013-03-15 2019-09-24 Merck, Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US10933053B2 (en) 2013-09-09 2021-03-02 Merck Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US8906898B1 (en) 2013-09-27 2014-12-09 Calixa Therapeutics, Inc. Solid forms of ceftolozane
CN109305977A (en) * 2018-11-28 2019-02-05 齐鲁天和惠世制药有限公司 A kind of preparation method of Tazobactam Sodium
CN110357903A (en) * 2019-08-28 2019-10-22 河北恒百药业有限公司 A kind of synthetic method of tazobactam
CN110357903B (en) * 2019-08-28 2020-09-04 河北恒百药业有限公司 Synthetic method of tazobactam acid
CN110590703A (en) * 2019-10-14 2019-12-20 清华大学 Green synthesis method of rubber vulcanization accelerator dibenzothiazyl disulfide

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