WO2011048583A1 - Process for the preparation of carbapenem compounds - Google Patents

Process for the preparation of carbapenem compounds Download PDF

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Publication number
WO2011048583A1
WO2011048583A1 PCT/IB2010/054827 IB2010054827W WO2011048583A1 WO 2011048583 A1 WO2011048583 A1 WO 2011048583A1 IB 2010054827 W IB2010054827 W IB 2010054827W WO 2011048583 A1 WO2011048583 A1 WO 2011048583A1
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formula
para
compound
process according
nitrobenzyl
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PCT/IB2010/054827
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French (fr)
Inventor
Suresh Kumar Kannapogu
Swargam Sathyanarayana
Rajesh Kumar Thaper
Mohan Prasad
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Ranbaxy Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/008—Preparation of nitrogen-containing organic compounds containing a N-O bond, e.g. nitro (-NO2), nitroso (-NO)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
    • C12P17/184—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system containing a beta-lactam ring, e.g. thienamycin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/01—Carboxylic ester hydrolases (3.1.1)
    • C12Y301/01003—Triacylglycerol lipase (3.1.1.3)

Definitions

  • the present invention relates to a process for the preparation of mono-para- trobenzyl malonate Formula II or its salt.
  • P 3 is hydrogen or a hydroxyl protecting group
  • P i is hydrogen or C 1- alkyl
  • A is selected from a group consisting of:
  • P 2 is hydrogen or an amino protecting group
  • R 2 and R 3 may be same or different and are hydrogen, Ci_ 5 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • Xi O or S
  • the carbapenem compounds of Formula I are generally prepared in the prior art by reacting a compound of Formula VIII with a compound of Formula IX, IX
  • Ri is hydrogen or Ci_ 3 alkyl
  • B is -P(0)(OR) 2 or -S0 2 R, wherein R is substituted or unsubstituted Ci_ 6 alkyl, aralkyl or aryl;
  • P 3 is hydrogen or a hydroxyl protecting group
  • A is as defined in Formula I.
  • the mono-p-nitrobenzyl malonate (PNB-Malonate) of Formula II or its salt is an important intermediate for the preparation of the compound of Formula VIII.
  • U.S. Patent No. 5,516,934 provides a process for the preparation of mono-p- nitrobenzyl malonate by reacting p-nitrobenzyl alcohol with malonic acid in the presence of organic solvent and an acid catalyst and by removing water through azeotropic distillation.
  • Di-p-nitrobenzyl malonate of Formula IV is a major by-product in the processes involving reaction of p-nitrobenzyl alcohol with malonic acid.
  • Japanese Application No. 04-082863 provides a process for the preparation of mono-para-nitrobenzyl malonate by selective hydrolysis of di-para-nitrobenzyl malonate using lipase M-10, lipase F-AP-15, lipase CE-10, lipase P and pig liver esterase.
  • the reaction time of biocatalysis is from 2 to 3 days.
  • the present invention provides for a process for the preparation of mono-para-nitrobenzyl malonate Formula II or its salt
  • Embodiments of this aspect of the invention may include one or more of the following features.
  • the immobilized lipase is lipase A derived from Candida antarctica.
  • the lipase is immobilized on an organic material or an inorganic material, such as silica gel.
  • the hydrolysis is carried out in the presence of a solvent and a buffer.
  • the solvent may be an organic solvent, such as n-hexane, toluene, benzene, chloroform, ethyl acetate or diethyl ether.
  • the buffer may be a phosphate buffer. The hydrolysis is carried out at pH of about 6 to about 9.
  • P 3 is hydrogen or a hydroxyl protecting group
  • P i is hydrogen or Ci_ 3 alkyl
  • A is selected from a group consisting of
  • P 2 is hydrogen or an amino protecting group
  • R 2 and R 3 may be the same or different and are hydrogen, Ci_ 5 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • Xi O or S
  • the compound of Formula I or its stereoisomers, or salts thereof is further subjected to deprotection.
  • the deprotected compound of Formula I is imipenem, meropenem, ertapenem or doripenem.
  • protecting group in the present invention refers to those used in the art and serve the function of blocking the carboxyl, amino or hydroxyl groups while the reactions are carried out at other sites of the molecule.
  • Examples of a carboxyl protecting group include alkyl, alkenyl, aralkyl, and aryl groups.
  • Examples of hydroxyl and amino protecting groups include alkylsilyl, alkoxymethyl, aralkyl, acyl, alkoxycarbonyl, alkenyloxycarbonyl and aralkyloxycarbonyl groups.
  • An aspect of the present invention provides a process for the preparation of mono- para-nitrobenzyl malonate Formula II or its salt
  • Di-para-nitrobenzyl malonate of Formula IV or its salt may be prepared by reacting p-nitrobenzyl alcohol with malonic acid or as a by-product in the preparation of mono-para-nitrobenzyl malonate.
  • Di-para-nitrobenzyl malonate of Formula IV or its salt is hydrolyzed to mono-para-nitrobenzyl malonate or its salt using immobilized lipase.
  • the immobilized lipase may be, for example, lipase A derived from Candida antarctica.
  • the lipase may be immobilized on an organic material, for example, a resin, or an inorganic material, for example, silica gel.
  • the hydrolysis reaction may be carried out in the presence of a solvent and a buffer.
  • the solvent may be water, an organic solvent, or a mixture thereof.
  • the organic solvent may be, for example, n-hexane, toluene, benzene, chloroform, ethyl acetate or diethyl ether.
  • the buffer may be, for example, a potassium phosphate buffer.
  • the hydrolysis may be carried out at pH of about 6 to about 9, for example, about 7 to about 8. The pH may be maintained in above range by further addition of a base such as sodium hydroxide.
  • the suitable temperature for hydrolysis may be about 10°C to about 50°C.
  • the hydrolysis may be completed in about 30 minutes to about 24 hours, for example in about 2 hours to about 5 hours.
  • the hydrolysis may be facilitated by stirring the reaction mixture.
  • the immobilized lipase may be recovered from reaction mixture by filtration or decantation or a combination thereof.
  • the mono-para-nitrobenzyl malonate of Formula II so obtained may be isolated from the reaction mixture by distillation, pH adjustment, layer separation, concentration, filtration or a combination thereof.
  • the mono-para-nitrobenzyl malonate of Formula II is isolated, for example, by concentration and pH adjustment using an acid.
  • the mono-para-nitrobenzyl malonate of Formula II is isolated, for example, as a crystalline solid with a purity of about 99% or above.
  • the mono-para-nitrobenzyl malonate of Formula II may be converted into salt, for example a magnesium salt, by treating with a magnesium source, such as magnesium chloride.
  • P 3 is hydrogen or a hydroxyl protecting group
  • Ri is hydrogen or C 1-3 alkyl
  • A is selected from a group consisting of
  • P 2 is hydrogen or an amino protecting group
  • R 2 and R 3 may be same or different and are hydrogen, Ci_ 5 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • Xi O or S
  • P i is hydrogen or C 1-3 alkyl
  • P 3 is hydrogen or a hydroxyl protecting group
  • Ri is hydrogen or C 1-3 alkyl
  • Pi is para-nitrobenzyl
  • P 3 is hydrogen or a hydroxyl protecting group.
  • the reaction between the compound of Formula III and the compound of Formula II or its salt may be carried out at a temperature in the range of about 10°C to about 80°C, for example, about 20°C to about 40°C.
  • the reaction is carried out for about 10 minutes to about 100 hours, for example, about 1 hour to about 3 hours.
  • the reaction may also be followed by an optional deprotection step by base and/or acid treatment or by
  • the azide may be toluenesulfonylazide, methanesulfonylazide or p- carboxybenzenesulfonylazide.
  • the reaction may be carried out in the presence of a base catalyst.
  • the base catalyst may be triethylamine, pyridine or dimethylamine.
  • the reaction may be carried out at a temperature in the range of about 10°C to about 80°C, for example, about 20°C to about 30°C.
  • the reaction may be carried out for about 1 minute to 100 hours, for example, about 10 minutes to about 30 minutes.
  • the reaction may also be followed by an optional deprotection step by base and/or acid treatment or by
  • the compound of Formula VI may be isolated from the reaction or directly cyclized into the compound of Formula VII without isolation. If isolated, the reaction may be continued further in the same or different organic solvent employed in the previous steps.
  • the organic solvent may be selected from a group consisting of aliphatic hydrocarbons, for example, hexane, heptane or pentane, halogenated hydrocarbons, for example, dichloromethane or dichloroethane, ethers, for example, diethyl ether, t-butylmethyl ether or tetrahydrofuran, esters, for example, ethyl acetate, propyl acetate, methyl acetate, isopropyl acetate or butyl acetate, aromatic hydrocarbons, for example, toluene, chlorobenzene or xylene, and a mixture thereof.
  • the organic solvent is, for example, dichloromethane.
  • carboxylate for example, rhodium(II)octanoate.
  • the cyclization may be facilitated by heating the reaction mixture up to about 40°C.
  • the reaction may also be followed by an optional deprotection step by base and/or acid treatment or by hydrogenation.
  • Ri is hydrogen or Ci_ 3 alkyl
  • B is -P(0)(OR) 2 or -S0 2 R, wherein R is substituted or unsubstituted Ci_ 6 alkyl, aralkyl or aryl;
  • P 3 is hydrogen or a hydroxyl protecting group.
  • the reaction of the compound of Formula VII with the compound X-B is carried out in the presence of a base.
  • the base may be a secondary amine, for example, diisopropylamine, dicyclohexylamine, 2,2,6, 6-tetramethylethylpiperidine or 1,1,3,3- tetramethylguanidine, or a tertiary amine, for example, diisopropylethylamine, triethylamine or tributylamine.
  • the reaction may be carried out at a temperature of about 15°C or below, for example, at a temperature in the range of about -35°C to about 0°C.
  • the formation of the compound of Formula VIII may be effected by stirring the reaction mixture.
  • the reaction may also be followed by an optional deprotection step by base and/or acid treatment or by hydrogenation.
  • the compound of Formula VIII so obtained is optionally isolated from the reaction mixture.
  • A is as defined in Formula I, in the presence of an organic solvent to obtain the compound of Formula I or its stereoisomers, or salts thereof.
  • the compound of Formula IX may be prepared by the methods available in the prior art, including those described in U.S. Patent Nos. 4,943,569; 4,888,344; 5,478,820; 5,317,016; 4,260,543; and 4,990,613; European Patent No. 0 072 710 Bl; and Yutaka et al, Org. Process. Res. Dev., 7, 649-654 (2003).
  • the reaction may be facilitated by further addition of a base.
  • the base may be a secondary amine, for example, diisopropylamine, dicyclohexylamine, 2,2,6, 6-tetramethylethylpiperidine or 1,1,3,3-tetramethylguanidine, or a tertiary amine, for example, diisopropylethylamine, triethylamine or tributylamine.
  • the reaction may be carried out at a temperature in the range of about -35°C to about 15°C, for example, about -20°C to about 0°C.
  • the reaction may be carried out for about 10 minutes to about 100 hours.
  • the compound of Formula I or its stereoisomers or salts thereof so obtained may be subjected to isolation and/or deprotection.
  • the isolation may be carried out by conventional methods, for example, filtration, concentration, distillation, layer separation, solvent precipitation, reverse osmosis or a combination thereof.
  • the deprotection may be carried out, for example, to remove the para-nitrobenzyl group at Pi, by hydrogenating the compound of Formula I in the presence of a noble metal catalyst, for example palladium - carbon.
  • Hydrogen gas or a compound capable of generating hydrogen gas may be used as a source of hydrogen for deprotection.
  • the deprotected compound of Formula I so obtained is, for example, imipenem, meropenem, ertapenem or doripenem.
  • Di-para-nitrobenzyl malonate (100 g) and toluene (750 ml) were charged into a flask positioned in a water bath. The temperature of water bath was raised to 55°C. After the dissolution of di-para-nitrobenzyl malonate, potassium phosphate buffer (0.1 M, pH 7.5) 250 ml was added to reaction mixture and the pH of 7.5 was maintained. The temperature of water bath was brought down to 45°C and immobilized CalB (Candida antarctica lipase - c-LEcta, Germany; 5 g) was added to reaction mixture. 1 N sodium hydroxide was added drop-wise to reaction mixture to maintain and control the pH at 7.5. The reaction mixture was allowed to stir for 7 hours.
  • potassium phosphate buffer 0.1 M, pH 7.5
  • immobilized CalB Candida antarctica lipase - c-LEcta, Germany; 5 g
  • reaction mixture was filtered to recover the enzyme and dried overnight in a dessicator under vacuum in the presence of phosphorus pentaoxide.
  • toluene and water layers were separated and toluene layer was concentrated under vacuum to obtain para-nitrobenzyl alcohol (38 g).
  • the pH of water layer was adjusted to 2.0 with 6N hydrochloric acid at 0°C to 5°C to facilitate the crystallization of mono-para- nitrobenzyl malonate. Crystalline mono-para-nitrobenzyl malonate was filtered and dried under vacuum at 50°C.

Abstract

The present invention relates to a process for the preparation of mono-para- nitrobenzyl malonate Formula (II) or its salt.

Description

PROCESS FOR THE PREPARATION OF CARBAPENEM COMPOUNDS
Field of the Invention
The present invention relates to a process for the preparation of mono-para- trobenzyl malonate Formula II or its salt.
Figure imgf000002_0001
FORMULA II
Background of the Invention
A large number of carbapenem compounds have been prepared and investigated for clinical efficacy. Meropenem, ertapenem, doripenem, impenem and biapenem are some of the carbapenem compounds available in the market for treating various bacterial infections. The processes for preparing carbapenem compounds of Formula I and their intermediates are described in several prior art references including U.S. Patent Nos.
5,424,422; 4,833,167; 5,104,984; 5,574,152; 5,587,474; 5,260,438; 5,414,081; 6,867,297; 5,792,861; 5,578,722; 5,973,142; 6,080,854; 6,340,751; 6,858,727; 5,231,179; 6,011,150; 5,703,234; 5,580,976; 5,493,018; 4,683,296; 5,442,057; 6,162,911; 5,731,431; 4,918,184; and 5,075,437; PCT Publication No. WO 02/020476, EP Patent No. 0 300 657 Bl;
European Application Nos. 0 444 889 Al; 0 836 607 Al; Japanese Patent Nos. 2510860; 2592110; 2902178; 3219833; 3388874; 3479720; 3761096; 3080417; and 3467265;
Japanese Publication Nos. 07-005590; 63-112558; 02-178262; 04-117382; 04-368365; 04- 368386; 06-065195; 2002-338572; 08-081439; 08-325261; 08-311092; 09-031054; 09- 316071; 2000-044537; 07-013058; 09-031075; 2000-044587; 2003-026680; 10-077263; 2003-277390; 2000-007676 A2; Yutaka et al, Org. Process Res. Dev., 7, 846-850 (2003), Sunagawa et al., J. Antibiot., (Tokyo), 43(5), 519-532 (1990), and Haruki et al.,
Heterocycles, 36, 145-159 (1995).
Figure imgf000003_0001
FORMULA I
wherein:
Pi is para-nitrobenzyl;
P3 is hydrogen or a hydroxyl protecting group; P i is hydrogen or C1- alkyl; and
A is selected from a group consisting of:
a)
Figure imgf000003_0002
b)
Figure imgf000003_0003
c)
Figure imgf000003_0004
d)
Figure imgf000004_0001
wherein,
P2 is hydrogen or an amino protecting group;
R2 and R3 may be same or different and are hydrogen, Ci_5 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; and
Xi is O or S,
or its stereoisomers, or salts thereof.
The carbapenem compounds of Formula I are generally prepared in the prior art by reacting a compound of Formula VIII with a compound of Formula IX, IX
Figure imgf000005_0001
FORMULA VIII wherein:
Ri is hydrogen or Ci_3 alkyl;
B is -P(0)(OR)2 or -S02R, wherein R is substituted or unsubstituted Ci_6 alkyl, aralkyl or aryl;
Pi para-nitrobenzyl;
P3 is hydrogen or a hydroxyl protecting group; and
A is as defined in Formula I.
There are several multi-step synthetic routes available in the prior art for preparing the compound of Formula VIII via various azetidinone intermediates. For example, U.S. Patent No. 4,350,631 provides the following process for the preparation of the compound of Formula VIII.
Figure imgf000006_0001
Magnesium salt
Figure imgf000006_0002
Similar synthetic routes for preparing the compound of Formula VIII are also described in U.S. Patent Nos. 4,499,278; 4,360,684; 4,312,871; 4,282,148; 4,273,709; and 4,262,010.
As represented in the above synthetic route, the mono-p-nitrobenzyl malonate (PNB-Malonate) of Formula II or its salt, is an important intermediate for the preparation of the compound of Formula VIII.
Figure imgf000007_0001
FORMULA II
U.S. Patent No. 5,516,934 provides a process for the preparation of mono-p- nitrobenzyl malonate by reacting p-nitrobenzyl alcohol with malonic acid in the presence of organic solvent and an acid catalyst and by removing water through azeotropic distillation. Di-p-nitrobenzyl malonate of Formula IV is a major by-product in the processes involving reaction of p-nitrobenzyl alcohol with malonic acid.
Figure imgf000007_0002
FORMULA IV
Japanese Application No. 04-082863 provides a process for the preparation of mono-para-nitrobenzyl malonate by selective hydrolysis of di-para-nitrobenzyl malonate using lipase M-10, lipase F-AP-15, lipase CE-10, lipase P and pig liver esterase. The reaction time of biocatalysis is from 2 to 3 days.
Summary of the Invention
In one general aspect, the present invention provides for a process for the preparation of mono-para-nitrobenzyl malonate Formula II or its salt,
Figure imgf000008_0001
FORMULA II
wherein the process includes, hydrolyzing di-para-nitrobenzyl malonate of Formula IV or its salt
Figure imgf000008_0002
FORMULA IV
using immobilized lipase.
Embodiments of this aspect of the invention may include one or more of the following features. For example, the immobilized lipase is lipase A derived from Candida antarctica. The lipase is immobilized on an organic material or an inorganic material, such as silica gel.
The hydrolysis is carried out in the presence of a solvent and a buffer. The solvent may be an organic solvent, such as n-hexane, toluene, benzene, chloroform, ethyl acetate or diethyl ether. The buffer may be a phosphate buffer. The hydrolysis is carried out at pH of about 6 to about 9.
The mono-para-nitrobenzyl malonate Formula II or its salt is further converted into a compound of Formula I
Figure imgf000009_0001
FORMULA I
wherein:
Pi is para-nitrobenzyl;
P3 is hydrogen or a hydroxyl protecting group; P i is hydrogen or Ci_3 alkyl; and
A is selected from a group consisting of
a)
Figure imgf000009_0002
b)
Figure imgf000009_0003
c)
Figure imgf000009_0004
d)
Figure imgf000010_0001
wherein,
P2 is hydrogen or an amino protecting group;
R2 and R3 may be the same or different and are hydrogen, Ci_5 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; and
Xi is O or S,
or its stereoisomers, or salts thereof.
The compound of Formula I or its stereoisomers, or salts thereof is further subjected to deprotection. The deprotected compound of Formula I is imipenem, meropenem, ertapenem or doripenem.
Detailed Description of the Invention
The term "protecting group" in the present invention refers to those used in the art and serve the function of blocking the carboxyl, amino or hydroxyl groups while the reactions are carried out at other sites of the molecule. Examples of a carboxyl protecting group include alkyl, alkenyl, aralkyl, and aryl groups. Examples of hydroxyl and amino protecting groups include alkylsilyl, alkoxymethyl, aralkyl, acyl, alkoxycarbonyl, alkenyloxycarbonyl and aralkyloxycarbonyl groups.
An aspect of the present invention provides a process for the preparation of mono- para-nitrobenzyl malonate Formula II or its salt,
Figure imgf000011_0001
FORMULA II
wherein the process includes hydrolyzing di-para-nitrobenzyl malonate of Formula IV or its salt
Figure imgf000011_0002
FORMULA IV
using immobilized lipase.
Di-para-nitrobenzyl malonate of Formula IV or its salt may be prepared by reacting p-nitrobenzyl alcohol with malonic acid or as a by-product in the preparation of mono-para-nitrobenzyl malonate. Di-para-nitrobenzyl malonate of Formula IV or its salt is hydrolyzed to mono-para-nitrobenzyl malonate or its salt using immobilized lipase. The immobilized lipase may be, for example, lipase A derived from Candida antarctica. The lipase may be immobilized on an organic material, for example, a resin, or an inorganic material, for example, silica gel. The hydrolysis reaction may be carried out in the presence of a solvent and a buffer. The solvent may be water, an organic solvent, or a mixture thereof. The organic solvent may be, for example, n-hexane, toluene, benzene, chloroform, ethyl acetate or diethyl ether. The buffer may be, for example, a potassium phosphate buffer. The hydrolysis may be carried out at pH of about 6 to about 9, for example, about 7 to about 8. The pH may be maintained in above range by further addition of a base such as sodium hydroxide. The suitable temperature for hydrolysis may be about 10°C to about 50°C. The hydrolysis may be completed in about 30 minutes to about 24 hours, for example in about 2 hours to about 5 hours. The hydrolysis may be facilitated by stirring the reaction mixture.
The immobilized lipase may be recovered from reaction mixture by filtration or decantation or a combination thereof. The mono-para-nitrobenzyl malonate of Formula II so obtained may be isolated from the reaction mixture by distillation, pH adjustment, layer separation, concentration, filtration or a combination thereof. The mono-para-nitrobenzyl malonate of Formula II is isolated, for example, by concentration and pH adjustment using an acid. The mono-para-nitrobenzyl malonate of Formula II is isolated, for example, as a crystalline solid with a purity of about 99% or above. The mono-para-nitrobenzyl malonate of Formula II may be converted into salt, for example a magnesium salt, by treating with a magnesium source, such as magnesium chloride.
Mono-para-nitrobenzyl malonate Formula II or its salt is further converted into a compound of Formula I:
Figure imgf000012_0001
FORMULA I
wherein:
para-nitrobenzyl; P3 is hydrogen or a hydroxyl protecting group; Ri is hydrogen or C1-3 alkyl; and
A is selected from a group consisting of
a)
b)
Figure imgf000013_0001
c)
Figure imgf000013_0002
d)
Figure imgf000013_0003
e)
Figure imgf000013_0004
f)
Figure imgf000014_0001
wherein,
P2 is hydrogen or an amino protecting group;
R2 and R3 may be same or different and are hydrogen, Ci_5 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; and
Xi is O or S,
or its stereoisomers, or salts thereof, according to the methods, for example, those described in U.S. Patent Nos. 4,350,631; 4,499,278; 4,360,684; 4,312,871; 4,282,148; 4,273,709; 4,262,010; and PCT Publication Nos. WO 2007/029084, and 2007/004028; and Indian Application Nos. 1808/DEL/2008, 1555/DEL/2006, and 2505/DEL/2007.
Mono-para-nitrobenzyl malonate of Formula II or its salt, for example, magnesium salt, is reacted with a compound of Formula III:
Figure imgf000014_0002
FORMULA III
wherein:
P i is hydrogen or C1-3 alkyl; and
P3 is hydrogen or a hydroxyl protecting group,
to obtain a compound of Formula V
Figure imgf000015_0001
FORMULA V
wherein,
Ri is hydrogen or C1-3 alkyl;
Pi is para-nitrobenzyl; and
P3 is hydrogen or a hydroxyl protecting group.
The reaction between the compound of Formula III and the compound of Formula II or its salt may be carried out at a temperature in the range of about 10°C to about 80°C, for example, about 20°C to about 40°C. The reaction is carried out for about 10 minutes to about 100 hours, for example, about 1 hour to about 3 hours. The reaction may also be followed by an optional deprotection step by base and/or acid treatment or by
hydrogenation.
The compound of Formula V so obtained is reacted with an azide to obtain a compound of Formula VI,
Figure imgf000015_0002
FORMULA VI
wherein Pi, P3 and Ri are as defined in Formula V.
The azide may be toluenesulfonylazide, methanesulfonylazide or p- carboxybenzenesulfonylazide. The reaction may be carried out in the presence of a base catalyst. The base catalyst may be triethylamine, pyridine or dimethylamine. The reaction may be carried out at a temperature in the range of about 10°C to about 80°C, for example, about 20°C to about 30°C. The reaction may be carried out for about 1 minute to 100 hours, for example, about 10 minutes to about 30 minutes. The reaction may also be followed by an optional deprotection step by base and/or acid treatment or by
hydrogenation.
The compound of Formula VI so obtained is cyclized to obtain a compound of Formula VII,
Figure imgf000016_0001
FORMULA VII
wherein Pi, P3 and Ri are as defined in Formula V. The compound of Formula VI may be isolated from the reaction or directly cyclized into the compound of Formula VII without isolation. If isolated, the reaction may be continued further in the same or different organic solvent employed in the previous steps. The organic solvent may be selected from a group consisting of aliphatic hydrocarbons, for example, hexane, heptane or pentane, halogenated hydrocarbons, for example, dichloromethane or dichloroethane, ethers, for example, diethyl ether, t-butylmethyl ether or tetrahydrofuran, esters, for example, ethyl acetate, propyl acetate, methyl acetate, isopropyl acetate or butyl acetate, aromatic hydrocarbons, for example, toluene, chlorobenzene or xylene, and a mixture thereof. The organic solvent is, for example, dichloromethane. The cyclization of the compound of Formula VI is carried out by treating the compound of Formula VI with a metal catalyst optionally in the presence of zinc halide. The metal catalyst may be a rhodium
carboxylate, for example, rhodium(II)octanoate. The cyclization may be facilitated by heating the reaction mixture up to about 40°C. The reaction may also be followed by an optional deprotection step by base and/or acid treatment or by hydrogenation.
The compound of Formula VII so obtained is reacted with a compound X-B, wherein B is -P(0)(OR)2 or -S02R, wherein R is substituted or unsubstituted Ci_6 alkyl, aralkyl or aryl, and X is halogen, to obtain a compound of Formula VIII,
Figure imgf000017_0001
FORMULA VIII
wherein:
Ri is hydrogen or Ci_3 alkyl;
B is -P(0)(OR)2 or -S02R, wherein R is substituted or unsubstituted Ci_6 alkyl, aralkyl or aryl;
Pi is para-nitrobenzyl, and
P3 is hydrogen or a hydroxyl protecting group.
The reaction of the compound of Formula VII with the compound X-B is carried out in the presence of a base. The base may be a secondary amine, for example, diisopropylamine, dicyclohexylamine, 2,2,6, 6-tetramethylethylpiperidine or 1,1,3,3- tetramethylguanidine, or a tertiary amine, for example, diisopropylethylamine, triethylamine or tributylamine. The reaction may be carried out at a temperature of about 15°C or below, for example, at a temperature in the range of about -35°C to about 0°C. The formation of the compound of Formula VIII may be effected by stirring the reaction mixture. The reaction may also be followed by an optional deprotection step by base and/or acid treatment or by hydrogenation. The compound of Formula VIII so obtained is optionally isolated from the reaction mixture.
The compound of Formula VIII is reacted with a compound of Formula IX,
HS-A
FORMULA IX
wherein A is as defined in Formula I, in the presence of an organic solvent to obtain the compound of Formula I or its stereoisomers, or salts thereof. The compound of Formula IX may be prepared by the methods available in the prior art, including those described in U.S. Patent Nos. 4,943,569; 4,888,344; 5,478,820; 5,317,016; 4,260,543; and 4,990,613; European Patent No. 0 072 710 Bl; and Yutaka et al, Org. Process. Res. Dev., 7, 649-654 (2003). The reaction may be facilitated by further addition of a base. The base may be a secondary amine, for example, diisopropylamine, dicyclohexylamine, 2,2,6, 6-tetramethylethylpiperidine or 1,1,3,3-tetramethylguanidine, or a tertiary amine, for example, diisopropylethylamine, triethylamine or tributylamine. The reaction may be carried out at a temperature in the range of about -35°C to about 15°C, for example, about -20°C to about 0°C. The reaction may be carried out for about 10 minutes to about 100 hours. The compound of Formula I or its stereoisomers or salts thereof so obtained may be subjected to isolation and/or deprotection. The isolation may be carried out by conventional methods, for example, filtration, concentration, distillation, layer separation, solvent precipitation, reverse osmosis or a combination thereof. The deprotection may be carried out, for example, to remove the para-nitrobenzyl group at Pi, by hydrogenating the compound of Formula I in the presence of a noble metal catalyst, for example palladium - carbon. Hydrogen gas or a compound capable of generating hydrogen gas may be used as a source of hydrogen for deprotection. The deprotected compound of Formula I so obtained is, for example, imipenem, meropenem, ertapenem or doripenem.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE
Preparation of Mono-Para-Nitrobenzyl Malonate:
Di-para-nitrobenzyl malonate (100 g) and toluene (750 ml) were charged into a flask positioned in a water bath. The temperature of water bath was raised to 55°C. After the dissolution of di-para-nitrobenzyl malonate, potassium phosphate buffer (0.1 M, pH 7.5) 250 ml was added to reaction mixture and the pH of 7.5 was maintained. The temperature of water bath was brought down to 45°C and immobilized CalB (Candida antarctica lipase - c-LEcta, Germany; 5 g) was added to reaction mixture. 1 N sodium hydroxide was added drop-wise to reaction mixture to maintain and control the pH at 7.5. The reaction mixture was allowed to stir for 7 hours. The reaction mixture was filtered to recover the enzyme and dried overnight in a dessicator under vacuum in the presence of phosphorus pentaoxide. After the recovery of the enzyme from the reaction mixture, toluene and water layers were separated and toluene layer was concentrated under vacuum to obtain para-nitrobenzyl alcohol (38 g). The pH of water layer was adjusted to 2.0 with 6N hydrochloric acid at 0°C to 5°C to facilitate the crystallization of mono-para- nitrobenzyl malonate. Crystalline mono-para-nitrobenzyl malonate was filtered and dried under vacuum at 50°C.
Yield: 58 g
Purity (by HPLC): 99.83%
Moisture content: 0.14%

Claims

claim:
A process for the preparation of mono-para-nitrobenzyl malonate Formula II or its salt,
Figure imgf000020_0001
FORMULA II
wherein the process comprises, hydrolyzing di-para-nitrobenzyl malonate of Formula IV or its salt
FORMULA IV
using immobilized lipase.
2. A process according to claim 1, wherein the immobilized lipase is lipase A derived from Candida antarctica.
3. A process of according to claim 1, wherein the lipase is immobilized on an organic material or an inorganic material.
4. A process of according to claim 3, wherein the lipase is immobilized on a resin or silica gel.
5. A process according to claim 1, wherein the hydrolysis is carried out in the presence of a solvent and a buffer.
6. A process according to claim 5, wherein the solvent comprises an organic solvent.
7. A process according to claim 6, wherein the organic solvent comprises n-hexane, toluene, benzene, chloroform, ethyl acetate or diethyl ether.
8. A process according to claim 5, wherein the buffer comprises a phosphate buffer.
9. A process according to claim 1, wherein the hydrolysis is carried out at pH of about 6 to about 9.
10. A process according to claim 1, wherein mono-para-nitrobenzyl malonate Formula II or its salt is further converted into a compound of Formula I
Figure imgf000021_0001
FORMULA I
wherein:
Pi is para-nitrobenzyl;
P3 is hydrogen or a hydroxyl protecting group;
P i is hydrogen or C1-3 alkyl; and
A is selected from a group consisting of
a)
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0003
Figure imgf000022_0004
Figure imgf000022_0005
R2 and R3 may be the same or different and are hydrogen, C1-5 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; and
Xi is O or S,
or its stereoisomers, or salts thereof.
11. A process according to claim 10, wherein the compound of Formula I or its
stereoisomers, or salts thereof is subjected to deprotection.
12. A process according to claim 11, wherein the deprotected compound of Formula I is imipenem, meropenem, ertapenem or doripenem.
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CN103540622A (en) * 2013-09-29 2014-01-29 南京工业大学 Method for enzymatic synthesis of mono-4-nitrobenzyl malonate
CN111019980A (en) * 2019-12-16 2020-04-17 牡丹江医学院 Efficient biosynthesis method of mono-p-nitrobenzyl malonate

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