WO2006117763A2 - A process for the preparation of doripenem - Google Patents

A process for the preparation of doripenem Download PDF

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Publication number
WO2006117763A2
WO2006117763A2 PCT/IB2006/051398 IB2006051398W WO2006117763A2 WO 2006117763 A2 WO2006117763 A2 WO 2006117763A2 IB 2006051398 W IB2006051398 W IB 2006051398W WO 2006117763 A2 WO2006117763 A2 WO 2006117763A2
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Prior art keywords
formula
protecting group
doripenem
compound
represents hydrogen
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PCT/IB2006/051398
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French (fr)
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WO2006117763A3 (en
Inventor
Neera Tewari
Hashim Nizar Poovanathi Nagoor Meeran
Bishwa Prakash Rai
Vinod George
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Ranbaxy Laboratories Limited
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Publication of WO2006117763A3 publication Critical patent/WO2006117763A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D477/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification

Definitions

  • the present invention provides processes for the preparation of doripenem generally and doripenem in amorphous form.
  • Doripenem exhibits potent, broad and well-balanced antibacterial activity against a wide range of both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.
  • U.S. 5,317,016 provides a process for the preparation of doripenem and its isolation by chromatographic purification and subsequent lyophilization. Similar processes for preparing lyophilized doripenem have also been described in Yasuyoshi Iso et al, J. Antibiot. 1996, 49, 199-209 and Yasuyoshi Iso et al, J. Antibiot. 1996, 49, 478- 484.
  • Yutaka Nishino et al Org. Process Res. Dev. 2003, 7, 846-850 provides a process for the preparation of doripenem by deprotection of the compound of Formula II in the presence of palladium-carbon and magnesium chloride,
  • FORMULA IV in the presence of diisopropylethylamine.
  • the process provides crystalline doripenem by crystallization from 2-propanol.
  • the process also employs the use of inorganic salts for isolation of doripenem, which are difficult to remove and, thus, contaminate the product.
  • U.S. Patent Nos. 6,111,098 and 5,703,243 provide processes for preparing crystalline and amorphous forms of lyophilized doripenem.
  • U.S. Patent Publication No 2003/0153191 provides processes for preparing Type III and Type IV crystals of doripenem.
  • FORMULA HIa wherein P 1 represents a carboxyl protecting group, P 2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR) 2 or OSO 2 R, wherein R represents substituted or unsubstituted C 1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
  • Embodiments of this process may include the deprotection being carried out in the presence of palladium catalyst.
  • a process for the preparation of doripenem of Formula I includes:
  • FORMULA IHa wherein P 1 represents a carboxyl protecting group, P 2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR) 2 or OSO 2 R, wherein R represents substituted or unsubstituted C 1-6 alkyl, aralkyl or aryl, with a thiopyrrolidine of Formula IVa
  • Embodiments of this process may include the deprotection being carried out in the presence of palladium catalyst.
  • Embodiments of the process may include the buffering agent being methylmorpholine and acetic acid. Embodiments of this process also may include the deprotection being carried out in the presence of palladium catalyst.
  • FORMULA Ia wherein P 1 represents hydrogen or a carboxyl protecting group, P 2 represents hydrogen or a hydroxyl protecting group and P 3 represents hydrogen or an amino protecting group.
  • the process includes: a) reacting enol-phosphate of Formula HIb
  • Embodiments of the process may include the secondary amine being selected from the group comprising diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6- tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), 1,8- diazabicyclo[4.3.0]undec-7-ene (DBU) and l,5-diazabicyclo[4.3.0]non-5-ene (DBN).
  • Embodiments of this process also may include the deprotection being carried out in the presence of palladium catalyst.
  • the process includes: a) reacting enol-phosphate of Formula HIb FORMULA HIb wherein P 1 and P 2 are as defined above, with a thiopyrrolidine of Formula IVb
  • Embodiments of this process may include the deprotection being carried out in the presence of palladium catalyst.
  • a process for the preparation of amorphous doripenem includes (a) treating an aqueous solution of doripenem with a water miscible organic solvent, and (b) isolating amorphous doripenem from the reaction mass thereof.
  • Embodiments of the process may include one or more of the following features.
  • the process may include the aqueous solution being a reaction mixture containing doripenem.
  • the water miscible solvent may be selected from the group comprising methanol, ethanol, 1-propanol, 2-propanol, acetone and acetonitrile.
  • a process for the preparation of amorphous doripenem includes: a) reacting enol-phosphate of Formula Ilia FORMULA IHa wherein P 1 represents a carboxyl protecting group, P 2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR) 2 or OSO 2 R, wherein R represents substituted or unsubstituted C 1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
  • Embodiments of the process may include one or more of the following features.
  • step a) may be carried out in the presence of a secondary or tertiary amine.
  • the deprotection may be carried out in the presence of a palladium catalyst or a buffering agent.
  • the buffering agent may be N-methylmorpholine and acetic acid.
  • Figure I depicts comparative powder X-ray diffraction patterns of amorphous doripenem as obtained in Examples 1, 2 and 3.
  • the present inventors have developed a one-pot reaction for the preparation of doripenem.
  • the present process does not involve the isolation of any intermediate, thereby reducing the work-up time as well as the cost of production.
  • the yield of the final product, doripenem is also considerably improved.
  • the instant invention carries out the deprotection in a biphasic system.
  • Deprotection in a biphasic system offers several advantages. First, the by-products and coloring impurities remain in the organic layer whereas deprotected doripenem is present in the aqueous layer. Second, the isolation of doripenem from the aqueous layer becomes easy as the removal of impurities present in the organic layer is facilitated by layer separation.
  • the use of a buffer in the present invention offers further advantages in terms of cost and availability and eliminates the need for reagents such as magnesium chloride.
  • the buffer system also serves as a means for carrying out the reaction at a pH of about 7.
  • the present inventors have also observed that the inclusion of a secondary amine in the coupling reaction between enolphosphate and the aminomethylpyrrolidine intermediate enhances the rate of reaction compared to that observed when tertiary amines are used in the same reaction for preparing doripenem. This also minimizes the reaction time and makes the process industrially preferable.
  • the present inventors have further observed that when the coupling reaction between enolphosphate and the aminomethylpyrrolidine intermediate is carried out at a temperature of -10 0 C or less, the reaction is faster and complete conversion is noticed within an hour. This leads to improved time cycle and process economics, and further reduces the impurities present in the final product.
  • the present invention further provides a novel process for the preparation of amorphous doripenem by solvent precipitation.
  • amorphous doripenem By employing the present process it is possible to isolate amorphous doripenem directly from the reaction mixture without the use of lyophilization, column chromatography or reverse osmosis. This further helps in improving the time cycle and process economics.
  • the present process avoids the use of inorganic salts during isolation of doripenem and thus the contamination of these salts in the final product is avoided.
  • protecting group in the present invention refers to those used in the art that 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, but not limited to, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 alkenyl, optionally substituted C7-Q 9 aralkyl, optionally substituted C 6 -C 12 aryl, optionally substituted C 1 -C 12 amino, optionally substituted C 3 -C 12 hydrocarbonated silyl, optionally substituted C 3 -C 12 hydrocarbonated stannyl, and a pharmaceutically active ester forming group.
  • hydroxyl and amino protecting groups include, but not limited to, lower alkylsilyl groups, lower alkoxymethyl groups, aralkyl groups, acyl groups, lower alkoxycarbonyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups.
  • a first aspect of the present invention provides a process for preparation of doripenem of Formula I
  • FORMULA I which comprises a) reacting enol-phosphate of Formula Ilia
  • FORMULA IHa wherein P 1 represents a carboxyl protecting group, P 2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR) 2 or OSO 2 R, wherein R represents substituted or unsubstituted C 1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
  • a second aspect of the present invention provides a process for preparation of doripenem of Formula I
  • FORMULA I which comprises a) reacting enol-phosphate of Formula Ilia
  • FORMULA IHa wherein P 1 represents a carboxyl protecting group, P 2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR) 2 or OSO 2 R, wherein R represents substituted or unsubstituted C 1-6 alkyl, aralkyl or aryl, with a thiopyrrolidine of Formula IVa
  • a third aspect of the present invention provides a process for preparation of doripenem of Formula I
  • FORMULA I which comprises a) reacting enol-phosphate of Formula Ilia
  • FORMULA IHa wherein P 1 represents a carboxyl protecting group, P 2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR) 2 or OSO 2 R, wherein R represents substituted or unsubstituted C 1-6 alkyl, aralkyl or aryl, with a thiopyrrolidine of Formula IVa
  • a fourth aspect of the present invention provides a process for preparation of a compound of Formula Ia
  • a fifth aspect of the present invention provides a process for preparation of a compound of Formula Ia
  • Enol-phosphate and thiopyrrolidine can be prepared by processes reported in the prior-art as mentioned earlier. Enolphosphate is added to a mixture containing thiopyrrolidine in an organic solvent, and the resultant reaction mass is cooled to a temperature of -10 0 C or less. A secondary amine is added to this reaction mass.
  • the amine is selected from the group comprising diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6, 6-tetramethylpiperidine (TMP), 1,1,3,3- tetramethylguanidine (TMG), l,8-diazabicyclo[4.3.0]undec-7-ene (DBU) and 1,5- diazabicyclo[4.3.0]non-5-ene (DBN) optionally in a drop-wise manner while maintaining the temperature at -10 0 C or less. After stirring the reaction mass for less than 10 hours to effect the coupling reaction, it is poured into a mixture of water immiscible organic solvent and water.
  • DIPA diisopropylamine
  • DCHA dicyclohexylamine
  • TMP 2,2,6, 6-tetramethylpiperidine
  • TMG 1,1,3,3- tetramethylguanidine
  • DBU 1,1,3,3- tetramethylguanidine
  • DBU 1,1,3,3
  • an aqueous buffer is added to the organic layer containing the condensed product and the resultant biphasic mass is hydro genated using a noble metal catalyst.
  • a noble metal catalyst Preferably N-methylmorpholine and acetic acid are used as a buffer and palladium is used a noble metal catalyst.
  • hydrogen gas or a compound capable of generating hydrogen gas can be used as a source of hydrogen.
  • the aqueous layer containing the product is washed with an organic solvent and doripenem can be isolated from the aqueous layer by conventional methods.
  • a sixth aspect of the present invention provides a process for preparation of amorphous doripenem which comprises (a) treating an aqueous solution of doripenem with a water miscible organic solvent, and (b) isolating amorphous doripenem from the reaction mass thereof.
  • An aqueous solution of doripenem can be a reaction mixture resulting from any process for the preparation of doripenem known in the art.
  • the aqueous solution of doripenem can also be prepared by dissolving in water doripenem of any polymorphic form known to the person skilled in the art.
  • the aqueous solution of doripenem obtained from the previous aspects of the present invention can also be used for the preparation of amorphous doripenem.
  • the water miscible solvent is selected from the group comprising methanol, ethanol, 1-propanol, 2-propanol, acetone and acetonitrile.
  • the resultant mixture is stirred for sufficient time to effect complete precipitation.
  • the stirring is carried out preferably at a temperature that is less than about 25°C.
  • the precipitate so obtained is further washed with the same or different organic solvent, or a mixture thereof to get amorphous doripenem.
  • a seventh aspect of the present invention provides a process for preparation of amorphous doripenem which comprises: a) reacting enol-phosphate of Formula Ilia FORMULA IHa wherein P 1 represents a carboxyl protecting group, P 2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR) 2 or OSO 2 R, wherein R represents substituted or unsubstituted C 1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
  • Enol-phosphate and thiopyrrolidine can be prepared by processes reported in the prior-art as mentioned earlier.
  • Enolphosphate is added to a mixture containing thiopyrrolidine in an organic solvent at about 0 0 C.
  • a secondary or tertiary amine optionally in a drop-wise manner so as to control the temperature between -5°C and 25°C. After stirring the reaction mass for a sufficient time to effect the coupling reaction, it is poured into a mixture of water immiscible organic solvent and water.
  • an aqueous buffer is added to the organic layer containing the condensed product, and the resultant biphasic mass is hydro genated using a noble metal catalyst.
  • hydrogen gas or a compound capable of generating hydrogen gas can be used as a source of hydrogen.
  • the aqueous layer comprising the product is added to a water miscible organic solvent at ambient temperature conditions.
  • the water miscible solvent is selected from the group comprising of methanol, ethanol, 1-propanol, 2-propanol, acetone and acetonitrile.
  • the reaction mixture so obtained is stirred for sufficient time to effect complete precipitation, filtered and washed to yield amorphous doripenem.
  • Powder XRD of the samples were determined by using X-Ray Diffractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A 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. EXAMPLES
  • the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The organic layer was separated and added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (500 ml) containing N-methylmorpholine and acetic acid (pH 6.5 to 7.0). The biphasic reaction mass was then hydrogenated for 3 hours under pressure at about 25°C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer was separated. The analysis of the aqueous layer by HPLC showed the formation of doripenem in 85% yield.
  • the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The pH was adjusted to 2.5 to 3.0 and the organic layer was separated. The organic layer so obtained was added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (300 ml) containing N-methylmorpholine and acetic acid (pH 6.0 to 7.0). The biphasic reaction mass was then hydrogenated for 3 to 4 hours under pressure at 10 0 C to 20 0 C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer (350 ml) was separated.
  • the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The pH was adjusted to 2.5 to 3.0 and the organic layer was separated. The organic layer so obtained was added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (300 ml) containing N-methylmorpholine and acetic acid (pH 6.0 to 7.0). The biphasic reaction mass was then hydrogenated for 3 to 4 hours under pressure at 10° to 20 0 C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer (350 ml) was separated.
  • the aqueous layer was then added to isopropyl alcohol (3.5 L) at 20° to 25°C in 15 to 20 minutes. After stirring at 0° to 5°C for 60 minutes, the reaction mixture was filtered and washed with isopropyl alcohol followed by acetone to yield the title compound.
  • the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The pH was adjusted to 2.5 to 3.0, and the organic layer was separated. The organic layer so obtained was added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (300 ml) containing N-methylmorpholine and acetic acid (pH 6.0 to 7.0). The biphasic reaction mass was then hydrogenated for 3 to 4 hours under pressure at 10° to 20 0 C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer (350 ml) was separated.
  • aqueous layer was then added to methanol (3.5 L) at 20° to 25°C in 15 to 20 minutes. After stirring at 0° to 5°C for 60 minutes, the reaction mixture was filtered and washed with methanol followed by acetone to yield the title compound.

Abstract

The present invention provides processes for the preparation of doripenem of formula (I) and for the preparation of doripenem in amorphous form.

Description

A PROCESS FOR THE PREPARATION OF DORIPENEM
Field of the Invention
The present invention provides processes for the preparation of doripenem generally and doripenem in amorphous form.
Background of the Invention
(4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)amino]methyl]-3-pyrrolidinyl]thio]-6- [(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, commonly known as doripenem of Formula I is a synthetic, broad- spectrum, carbapenem antibiotic.
Figure imgf000002_0001
FORMULA I
Doripenem exhibits potent, broad and well-balanced antibacterial activity against a wide range of both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.
U.S. 5,317,016 provides a process for the preparation of doripenem and its isolation by chromatographic purification and subsequent lyophilization. Similar processes for preparing lyophilized doripenem have also been described in Yasuyoshi Iso et al, J. Antibiot. 1996, 49, 199-209 and Yasuyoshi Iso et al, J. Antibiot. 1996, 49, 478- 484.
Yutaka Nishino et al, Org. Process Res. Dev. 2003, 7, 846-850 provides a process for the preparation of doripenem by deprotection of the compound of Formula II in the presence of palladium-carbon and magnesium chloride,
Figure imgf000003_0001
FORMULA II wherein the compound of Formula II is prepared by condensing enolphosphate of Formula III
Figure imgf000003_0002
FORMULA III with N-PNZ-protected aminomethylpyrrolidine of Formula IV
Figure imgf000003_0003
FORMULA IV in the presence of diisopropylethylamine. The process provides crystalline doripenem by crystallization from 2-propanol. The process also employs the use of inorganic salts for isolation of doripenem, which are difficult to remove and, thus, contaminate the product.
U.S. Patent Nos. 6,111,098 and 5,703,243 provide processes for preparing crystalline and amorphous forms of lyophilized doripenem. U.S. Patent Publication No 2003/0153191 provides processes for preparing Type III and Type IV crystals of doripenem.
Summary of the Invention
In one general aspect there is provided a process for the preparation of doripenem of Formula I. The process includes:
Figure imgf000004_0001
FORMULA I a) reacting enol-phosphate of Formula Ilia
Figure imgf000004_0002
FORMULA HIa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
Figure imgf000005_0001
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get a compound of Formula Ha,
Figure imgf000005_0002
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above; b) deprotecting the compound of Formula Ha; and c) isolating doripenem from the reaction mass thereof, wherein the compound of Formula Ha is not isolated from the reaction mixture.
Embodiments of this process may include the deprotection being carried out in the presence of palladium catalyst. In another general aspect there is provided a process for the preparation of doripenem of Formula I. The process includes:
Figure imgf000006_0001
FORMULA I a) reacting enol-phosphate of Formula Ilia
Figure imgf000006_0002
FORMULA IHa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, with a thiopyrrolidine of Formula IVa
Figure imgf000006_0003
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get compound of Formula Ha,
Figure imgf000007_0001
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above; b) deprotecting the compound of Formula Ha, in a biphasic system comprising aqueous and water-immiscible solvents; and c) isolating doripenem from the reaction mass thereof.
Embodiments of this process may include the deprotection being carried out in the presence of palladium catalyst.
In another general aspect there is provided a process for the preparation of doripenem of Formula I. The process includes:
Figure imgf000007_0002
FORMULA I a) reacting enol-phosphate of Formula Ilia
Figure imgf000008_0001
FORMULA IHa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, with a thiopyrrolidine of Formula IVa
Figure imgf000008_0002
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get compound of Formula Ha,
Figure imgf000008_0003
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above; b) deprotecting the compound of Formula Ha in the presence of a buffering agent; and c) isolating doripenem from the reaction mass thereof.
Embodiments of the process may include the buffering agent being methylmorpholine and acetic acid. Embodiments of this process also may include the deprotection being carried out in the presence of palladium catalyst.
In another general aspect there is provided a process for the preparation of a compound of Formula Ia.
Figure imgf000009_0001
FORMULA Ia wherein P1 represents hydrogen or a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and P3 represents hydrogen or an amino protecting group. The process includes: a) reacting enol-phosphate of Formula HIb
Figure imgf000009_0002
FORMULA HIb wherein P1 and P2 are as defined above, with a thiopyrrolidine of Formula IVb
Figure imgf000010_0001
FORMULA IVb wherein P3 is as defined above, in the presence of a secondary amine.
Embodiments of the process may include the secondary amine being selected from the group comprising diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6- tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), 1,8- diazabicyclo[4.3.0]undec-7-ene (DBU) and l,5-diazabicyclo[4.3.0]non-5-ene (DBN). Embodiments of this process also may include the deprotection being carried out in the presence of palladium catalyst.
In another general aspect there is provided a process for preparation of a compound of Formula Ia
Figure imgf000010_0002
FORMULA Ia wherein P1 represents hydrogen or a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and P3 represents hydrogen or an amino protecting group. The process includes: a) reacting enol-phosphate of Formula HIb
Figure imgf000011_0001
FORMULA HIb wherein P1 and P2 are as defined above, with a thiopyrrolidine of Formula IVb
Figure imgf000011_0002
FORMULA IVb wherein P3 is as defined above, at a temperature of about -100C or less.
Embodiments of this process may include the deprotection being carried out in the presence of palladium catalyst.
In another general aspect there is provided a process for the preparation of amorphous doripenem. The process includes (a) treating an aqueous solution of doripenem with a water miscible organic solvent, and (b) isolating amorphous doripenem from the reaction mass thereof.
Embodiments of the process may include one or more of the following features. For example, the process may include the aqueous solution being a reaction mixture containing doripenem. The water miscible solvent may be selected from the group comprising methanol, ethanol, 1-propanol, 2-propanol, acetone and acetonitrile.
In another general aspect there is provided a process for the preparation of amorphous doripenem. The process includes: a) reacting enol-phosphate of Formula Ilia
Figure imgf000012_0001
FORMULA IHa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
Figure imgf000012_0002
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get a compound of Formula Ha,
Figure imgf000012_0003
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above; b) deprotecting the compound of Formula Ha in a biphasic system comprising aqueous and water-immiscible solvents; c) treating the aqueous layer of the reaction mixture with a water miscible organic solvent; and d) isolating amorphous doripenem from the reaction mass thereof.
Embodiments of the process may include one or more of the following features. For example, step a) may be carried out in the presence of a secondary or tertiary amine. The deprotection may be carried out in the presence of a palladium catalyst or a buffering agent. The buffering agent may be N-methylmorpholine and acetic acid.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Brief Description of the Drawings
Figure I depicts comparative powder X-ray diffraction patterns of amorphous doripenem as obtained in Examples 1, 2 and 3.
Detailed Description of the Invention The present inventors have developed a one-pot reaction for the preparation of doripenem. The present process does not involve the isolation of any intermediate, thereby reducing the work-up time as well as the cost of production. By following the present process, the yield of the final product, doripenem, is also considerably improved.
The instant invention carries out the deprotection in a biphasic system. Deprotection in a biphasic system offers several advantages. First, the by-products and coloring impurities remain in the organic layer whereas deprotected doripenem is present in the aqueous layer. Second, the isolation of doripenem from the aqueous layer becomes easy as the removal of impurities present in the organic layer is facilitated by layer separation. The use of a buffer in the present invention offers further advantages in terms of cost and availability and eliminates the need for reagents such as magnesium chloride. The buffer system also serves as a means for carrying out the reaction at a pH of about 7.
The present inventors have also observed that the inclusion of a secondary amine in the coupling reaction between enolphosphate and the aminomethylpyrrolidine intermediate enhances the rate of reaction compared to that observed when tertiary amines are used in the same reaction for preparing doripenem. This also minimizes the reaction time and makes the process industrially preferable.
The present inventors have further observed that when the coupling reaction between enolphosphate and the aminomethylpyrrolidine intermediate is carried out at a temperature of -100C or less, the reaction is faster and complete conversion is noticed within an hour. This leads to improved time cycle and process economics, and further reduces the impurities present in the final product.
The present invention further provides a novel process for the preparation of amorphous doripenem by solvent precipitation. By employing the present process it is possible to isolate amorphous doripenem directly from the reaction mixture without the use of lyophilization, column chromatography or reverse osmosis. This further helps in improving the time cycle and process economics. The present process avoids the use of inorganic salts during isolation of doripenem and thus the contamination of these salts in the final product is avoided. The term "protecting group" in the present invention refers to those used in the art that 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, but not limited to, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 alkenyl, optionally substituted C7-Q9 aralkyl, optionally substituted C6-C12 aryl, optionally substituted C1-C12 amino, optionally substituted C3-C12 hydrocarbonated silyl, optionally substituted C3-C12 hydrocarbonated stannyl, and a pharmaceutically active ester forming group. Examples of hydroxyl and amino protecting groups include, but not limited to, lower alkylsilyl groups, lower alkoxymethyl groups, aralkyl groups, acyl groups, lower alkoxycarbonyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups.
A first aspect of the present invention provides a process for preparation of doripenem of Formula I
Figure imgf000015_0001
FORMULA I which comprises a) reacting enol-phosphate of Formula Ilia
Figure imgf000015_0002
FORMULA IHa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
Figure imgf000015_0003
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get a compound of Formula Ha,
Figure imgf000016_0001
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above, b) deprotecting the compound of Formula Ha, c) isolating doripenem from the reaction mass thereof, wherein the compound of Formula Ha is not isolated from the reaction mixture.
A second aspect of the present invention provides a process for preparation of doripenem of Formula I
Figure imgf000016_0002
FORMULA I which comprises a) reacting enol-phosphate of Formula Ilia
Figure imgf000016_0003
FORMULA IHa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, with a thiopyrrolidine of Formula IVa
Figure imgf000017_0001
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get the compound of Formula Ha,
Figure imgf000017_0002
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above b) deprotecting the compound of Formula Ha in a biphasic system that includes aqueous and water-immiscible solvents, and c) isolating doripenem from the reaction mass thereof A third aspect of the present invention provides a process for preparation of doripenem of Formula I
Figure imgf000018_0001
FORMULA I which comprises a) reacting enol-phosphate of Formula Ilia
Figure imgf000018_0002
FORMULA IHa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, with a thiopyrrolidine of Formula IVa
Figure imgf000018_0003
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get compound of Formula Ha,
Figure imgf000019_0001
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above b) deprotecting the compound of Formula Ha in the presence of a buffering agent, and c) isolating doripenem from the reaction mass thereof.
A fourth aspect of the present invention provides a process for preparation of a compound of Formula Ia
Figure imgf000019_0002
FORMULA Ia wherein P1 represents hydrogen or a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and P3 represents hydrogen or an amino protecting group, comprising a) reacting enol-phosphate of Formula HIb
Figure imgf000020_0001
FORMULA HIb wherein P1 and P2 are as defined above, with a thiopyrrolidine of Formula IVb
Figure imgf000020_0002
FORMULA IVb wherein P3 is as defined above, in the presence of a secondary amine.
A fifth aspect of the present invention provides a process for preparation of a compound of Formula Ia
Figure imgf000020_0003
FORMULA Ia wherein P1 represents hydrogen or a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and P3 represents hydrogen or an amino protecting group, comprising a) reacting enol-phosphate of Formula HIb
Figure imgf000021_0001
FORMULA HIb wherein P1 and P2 are as defined above, with a thiopyrrolidine of Formula IVb
Figure imgf000021_0002
FORMULA IVb wherein P3 is as defined above, at a temperature of about -100C or less.
Enol-phosphate and thiopyrrolidine can be prepared by processes reported in the prior-art as mentioned earlier. Enolphosphate is added to a mixture containing thiopyrrolidine in an organic solvent, and the resultant reaction mass is cooled to a temperature of -100C or less. A secondary amine is added to this reaction mass. The amine is selected from the group comprising diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6, 6-tetramethylpiperidine (TMP), 1,1,3,3- tetramethylguanidine (TMG), l,8-diazabicyclo[4.3.0]undec-7-ene (DBU) and 1,5- diazabicyclo[4.3.0]non-5-ene (DBN) optionally in a drop-wise manner while maintaining the temperature at -100C or less. After stirring the reaction mass for less than 10 hours to effect the coupling reaction, it is poured into a mixture of water immiscible organic solvent and water.
Following the separation of layers, an aqueous buffer is added to the organic layer containing the condensed product and the resultant biphasic mass is hydro genated using a noble metal catalyst. Preferably N-methylmorpholine and acetic acid are used as a buffer and palladium is used a noble metal catalyst. For this purpose of hydrogenation, hydrogen gas or a compound capable of generating hydrogen gas can be used as a source of hydrogen.
After completion of the reaction, the aqueous layer containing the product is washed with an organic solvent and doripenem can be isolated from the aqueous layer by conventional methods.
A sixth aspect of the present invention provides a process for preparation of amorphous doripenem which comprises (a) treating an aqueous solution of doripenem with a water miscible organic solvent, and (b) isolating amorphous doripenem from the reaction mass thereof. An aqueous solution of doripenem can be a reaction mixture resulting from any process for the preparation of doripenem known in the art. The aqueous solution of doripenem can also be prepared by dissolving in water doripenem of any polymorphic form known to the person skilled in the art. The aqueous solution of doripenem obtained from the previous aspects of the present invention can also be used for the preparation of amorphous doripenem. The water miscible solvent is selected from the group comprising methanol, ethanol, 1-propanol, 2-propanol, acetone and acetonitrile.
After treating the aqueous solution of doripenem with a water miscible organic solvent, the resultant mixture is stirred for sufficient time to effect complete precipitation. The stirring is carried out preferably at a temperature that is less than about 25°C. The precipitate so obtained is further washed with the same or different organic solvent, or a mixture thereof to get amorphous doripenem.
A seventh aspect of the present invention provides a process for preparation of amorphous doripenem which comprises: a) reacting enol-phosphate of Formula Ilia
Figure imgf000023_0001
FORMULA IHa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
Figure imgf000023_0002
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get a compound of Formula Ha,
Figure imgf000023_0003
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above, b) deprotecting the compound of Formula Ha in a biphasic system comprising aqueous and water-immiscible solvents, c) treating the aqueous layer of the reaction mixture with a water miscible organic solvent, and d) isolating amorphous doripenem from the reaction mass thereof.
Enol-phosphate and thiopyrrolidine can be prepared by processes reported in the prior-art as mentioned earlier. Enolphosphate is added to a mixture containing thiopyrrolidine in an organic solvent at about 00C. To this reaction mass is added a secondary or tertiary amine optionally in a drop-wise manner so as to control the temperature between -5°C and 25°C. After stirring the reaction mass for a sufficient time to effect the coupling reaction, it is poured into a mixture of water immiscible organic solvent and water.
Following the separation of layers, an aqueous buffer is added to the organic layer containing the condensed product, and the resultant biphasic mass is hydro genated using a noble metal catalyst. For this purpose hydrogen gas or a compound capable of generating hydrogen gas can be used as a source of hydrogen. After completion of the reaction, the aqueous layer comprising the product is added to a water miscible organic solvent at ambient temperature conditions. The water miscible solvent is selected from the group comprising of methanol, ethanol, 1-propanol, 2-propanol, acetone and acetonitrile. The reaction mixture so obtained is stirred for sufficient time to effect complete precipitation, filtered and washed to yield amorphous doripenem.
Powder XRD of the samples were determined by using X-Ray Diffractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A 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. EXAMPLES
EXAMPLE l: Preparation of Doripenem
A mixture of 4-nitrobenzyl(2S,4S)-4-(acetylthio)-2-{[(aminosulfonyl)(tert- butoxy carbony^aminojmethyljpyrrolidine-l-carboxylate (53.5 g) and concentrated sulfuric acid (25 g) in methanol (250 ml) was refluxed for 3 hours, followed by cooling to about 25°C. A mixture of ethylacetate (400 ml) and water (400 ml) was added to the reaction mixture. The organic layer was separated and the aqueous layer was re-extracted with ethylacetate (200 ml). The combined organic layer was washed twice with 5% w/v aqueous sodium chloride solution and concentrated under reduced pressure to give a concentrate containing 4-nitrobenzyl (2S,4S)-2-{ [(aminosulfonyl)amino]methyl}-4-mercaptopyrrolidine-l- carboxylate. N,N-dimethylformamide (250 ml) was added to the concentrate followed by the addition of enolphosphate (50 g) at about 25°C. The resulting solution was cooled to - 400C and diisopropylamine (11 g) was added to this solution drop wise under stirring while maintaining the temperature at -40° to -35°C. After stirring for 1 hour at the same temperature, the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The organic layer was separated and added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (500 ml) containing N-methylmorpholine and acetic acid (pH 6.5 to 7.0). The biphasic reaction mass was then hydrogenated for 3 hours under pressure at about 25°C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer was separated. The analysis of the aqueous layer by HPLC showed the formation of doripenem in 85% yield.
EXAMPLE 2: Preparation of Amorphous Doripenem
A mixture of 4-nitrobenzyl(2S,4S)-4-(acetylthio)-2-{ [(aminosulfonyl)(tert- butoxy carbonyl)amino]methyl}pyrrolidine-l-carboxylate (53.5 g) and concentrated sulfuric acid (25 g) in methanol (250 ml) were refluxed for 3 hours, followed by cooling to about 25°C. The reaction mixture was poured into a mixture of methylene chloride (500 ml) and water (500 ml). The organic layer was separated and washed with water (2 X 500 ml) and concentrated under reduced pressure to give a concentrate containing 4-nitrobenzyl (2S,4S)-2-{ [(aminosulfonyl)amino]methyl}-4-mercaptopyrrolidine-l-carboxylate. The concentrate so obtained was dissolved in N,N-dimethylformamide (50 ml) and added to enolphosphate (50 g) dissolved in N,N-dimethylformamide (200 ml), at 00C to 5°C, followed by drop wise addition of diisopropylethylamine (15.1 g) at the same temperature. After stirring for 18 hours at 00C to 5°C, the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The pH was adjusted to 2.5 to 3.0 and the organic layer was separated. The organic layer so obtained was added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (300 ml) containing N-methylmorpholine and acetic acid (pH 6.0 to 7.0). The biphasic reaction mass was then hydrogenated for 3 to 4 hours under pressure at 100C to 200C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer (350 ml) was separated. The aqueous layer was then added to absolute ethanol (3.5 L) at 200C to 25°C in 15 to 20 minutes. After stirring at 00C to 5°C for 60 minutes, the reaction mixture was filtered and washed with absolute ethanol followed by acetone to yield the title compound.
Yield: 2O g Purity (HPLC): 95%
EXAMPLE 3: Preparation of Amorphous Doripenem
A mixture of 4-nitrobenzyl(2S,4S)-4-(acetylthio)-2-{ [(aminosulfonyl)(tert- butoxy carbonyl)amino]methyl}pyrrolidine-l-carboxylate (53.5 g) and concentrated sulfuric acid (25 g) in methanol (250 ml) were refluxed for 3 hours, followed by cooling to about 25°C. The reaction mixture was poured into a mixture of methylene chloride (500 ml) and water (500 ml). The organic layer was separated and washed with water (2 X 500 ml) and concentrated under reduced pressure to give a concentrate containing 4-nitrobenzyl (2S,4S)-2-{ [(aminosulfonyl)amino]methyl}-4-mercaptopyrrolidine-l-carboxylate. The concentrate so obtained was dissolved in N,N-dimethylformamide (50 ml) and added to enolphosphate (50 g) dissolved in N,N-dimethylformamide (200 ml) at 0° to 5°C, followed by drop wise addition of diisopropylethylamine (15.1 g) at the same temperature. After stirring for 18 hours at 0° to 5°C, the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The pH was adjusted to 2.5 to 3.0 and the organic layer was separated. The organic layer so obtained was added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (300 ml) containing N-methylmorpholine and acetic acid (pH 6.0 to 7.0). The biphasic reaction mass was then hydrogenated for 3 to 4 hours under pressure at 10° to 200C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer (350 ml) was separated. The aqueous layer was then added to isopropyl alcohol (3.5 L) at 20° to 25°C in 15 to 20 minutes. After stirring at 0° to 5°C for 60 minutes, the reaction mixture was filtered and washed with isopropyl alcohol followed by acetone to yield the title compound.
Yield: 2O g
EXAMPLE 4: Preparation of Amorphous Doripenem
A mixture of 4-nitrobenzyl(2S,4S)-4-(acetylthio)-2-{ [(aminosulfonyl)(tert- butoxy carbonyl)amino]methyl}pyrrolidine-l-carboxylate (53.5 g) and concentrated sulfuric acid (25 g) in methanol (250 ml) were refluxed for 3 hours, followed by cooling to about 25°C. Into the reaction mixture was poured a mixture of methylene chloride (500 ml) and water (500 ml). The organic layer was separated and washed with water (2 X 500 ml) and concentrated under reduced pressure to give a concentrate containing 4-nitrobenzyl (2S,4S)-2-{ [(aminosulfonyl)amino]methyl}-4-mercaptopyrrolidine-l-carboxylate. The concentrate so obtained was dissolved in N,N-dimethylformamide (50 ml) and added to enolphosphate (50 g) dissolved in N,N-dimethylformamide (200 ml) at 0° to 5°C, followed by drop wise addition of diisopropylethylamine (15.1 g) at the same temperature. After stirring for 18 hours at 0° to 5°C, the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The pH was adjusted to 2.5 to 3.0, and the organic layer was separated. The organic layer so obtained was added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (300 ml) containing N-methylmorpholine and acetic acid (pH 6.0 to 7.0). The biphasic reaction mass was then hydrogenated for 3 to 4 hours under pressure at 10° to 200C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer (350 ml) was separated. The aqueous layer was then added to methanol (3.5 L) at 20° to 25°C in 15 to 20 minutes. After stirring at 0° to 5°C for 60 minutes, the reaction mixture was filtered and washed with methanol followed by acetone to yield the title compound.
Yield: 1O g EXAMPLE 5: Preparation of Amorphous Doripenem
Doripenem (10 g) was dissolved in water (100 ml) and the resultant solution was poured into ethanol (1 L) at 20-250C. The reaction mixture was cooled to 0-50C and filtered. The filtered product was dried to obtain the title compound.
Yield: 9.09 g Purity (HPLC): 97%

Claims

WE CLAIM:
1. A process for preparation of doripenem of Formula I, the process comprising:
Figure imgf000029_0001
FORMULA I a) reacting enol-phosphate of Formula Ilia
Figure imgf000029_0002
FORMULA IHa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
Figure imgf000029_0003
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get a compound of Formula Ha,
Figure imgf000030_0001
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above; b) deprotecting the compound of Formula Ha; and c) isolating doripenem from the reaction mass thereof, wherein the compound of Formula Ha is not isolated from the reaction mixture.
2. A process for the preparation of doripenem of Formula I, the process comprising:
Figure imgf000030_0002
FORMULA I a) reacting enol-phosphate of Formula Ilia
Figure imgf000030_0003
FORMULA IHa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, with a thiopyrrolidine of Formula IVa
Figure imgf000031_0001
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get compound of Formula Ha,
Figure imgf000031_0002
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above; b) deprotecting the compound of Formula Ha, in a biphasic system comprising aqueous and water-immiscible solvents; and c) isolating doripenem from the reaction mass thereof.
3. A process for the preparation of doripenem of Formula I, the process comprising:
Figure imgf000031_0003
FORMULA I a) reacting enol-phosphate of Formula Ilia
Figure imgf000032_0001
FORMULA IHa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, with a thiopyrrolidine of Formula IVa
Figure imgf000032_0002
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get compound of Formula Ha,
Figure imgf000032_0003
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above; b) deprotecting the compound of Formula Ha in the presence of a buffering agent; and c) isolating doripenem from the reaction mass thereof.
4. A process as claimed in claim 3 wherein the buffering agent comprises N- methylmorpholine and acetic acid.
5. A process for preparation of a compound of Formula Ia
Figure imgf000033_0001
FORMULA Ia wherein P1 represents hydrogen or a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and P3 represents hydrogen or an amino protecting group, the process comprising: a) reacting enol-phosphate of Formula HIb
Figure imgf000033_0002
FORMULA HIb wherein P1 and P2 are as defined above, with a thiopyrrolidine of Formula IVb
Figure imgf000034_0001
FORMULA IVb wherein P3 is as defined above, in the presence of a secondary amine.
6. A process as claimed in claim 5 wherein the secondary amine is selected from the group comprising diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6- tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), 1,8- diazabicyclo[4.3.0]undec-7-ene (DBU) and l,5-diazabicyclo[4.3.0]non-5-ene (DBN).
7. A process for preparation of a compound of Formula Ia
Figure imgf000034_0002
FORMULA Ia wherein P1 represents hydrogen or a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and P3 represents hydrogen or an amino protecting group, the process comprising: a) reacting enol-phosphate of Formula HIb
Figure imgf000034_0003
FORMULA HIb wherein P1 and P2 are as defined above, with a thiopyrrolidine of Formula IVb
Figure imgf000035_0001
FORMULA IVb wherein P3 is as defined above, at a temperature of about -100C or less.
8. A process as claimed in any one of claims 1, 2, 3, 5 and 7 wherein the deprotection is carried out in the presence of palladium catalyst.
9. A process for preparation of amorphous doripenem, the process comprising: a) treating an aqueous solution of doripenem with a water miscible organic solvent, and b) isolating amorphous doripenem from the reaction mass thereof.
10. A process as claimed in claim 9, wherein the aqueous solution comprises a reaction mixture containing doripenem.
11. A process as claimed in claim 9, wherein the water miscible solvent is selected from the group comprising methanol, ethanol, 1-propanol, 2-propanol, acetone and acetonitrile.
12. A process for preparation of amorphous doripenem, the process comprising: a) reacting enol-phosphate of Formula Ilia
Figure imgf000035_0002
FORMULA IHa wherein P1 represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
Figure imgf000036_0001
FORMULA IVa wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get a compound of Formula Ha,
Figure imgf000036_0002
FORMULA Ha wherein P1, P2, P3 and P4 are as defined above; b) deprotecting the compound of Formula Ha in a biphasic system comprising aqueous and water-immiscible solvents; c) treating the aqueous layer of the reaction mixture with a water miscible organic solvent; and d) isolating amorphous doripenem from the reaction mass thereof.
13. A process as claimed in claim 12, wherein step a) is carried out in the presence of a secondary or tertiary amine.
14. A process as claimed in claim 12, wherein the deprotection is carried out in the presence of a palladium catalyst.
15. A process as claimed in claim 12, wherein the deprotection is carried out in the presence of a buffering agent.
16. A process as claimed in claim 15, wherein the buffering agent comprises N- methylmorpholine and acetic acid.
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