The present invention provides a process for the preparation of Doripenem.
(4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)amino]methyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-
hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid,
commonly known as doripenem of Formula I is a synthetic, broad-spectrum, carbapenem antibiotic.
(Formula Removed)
Doripenem exhibits potent, broad and well-balanced antibacterial activity against a wide range of both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.
US Patent No. 5,317,016 provides a process for the preparation of doripenem. Similar processes for preparing doipenem 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 compound of Formula II in the presence of palladium-carbon and magnesium chloride,
(Formula Removed)
wherein the compound of Formula II is prepared by condensing enolphosphate of Formula III
(Formula Removed)
with N-PNZ-protected aminomethylpyrrolidine of Formula IV
(Formula Removed)
in the presence of diisopropylethylamine.
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. Firstly, the by-products and coloring impurities remain in the organic layer whereas deprotected doripenem is present in aqueous layer. Secondly, the isolation of doripenem from aqueous layer becomes easy as the removal of impurities present in 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 of reagents like 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 observed that the inclusion of a secondary amine in the coupling reaction between enolphosphate and aminomethylpyrrolidine intermediate enhances the rate of reaction than observed when tertiary amines are used in the same reaction for preparing doripenem. It minimizes the reaction time and makes the process industrially preferable.
The present inventors have further observed that when the coupling reaction between enolphosphate and aminomethylpyrrolidine intermediate is carried out at a temperature less than 0°C, the reaction is faster and complete conversion is noticed within an hour. This leads to improved time cycle and process economics. It further reduces the impurities present in the final product.
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, but not limited to, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 alkenyl, optionally substituted C7-C19 aralkyl, optionally substituted C6-C12 aryl, optionally substituted C1-C12 amino, optionally substituted C3-Ci2 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
(Formula Removed)
which comprises
a) reacting enol-phosphate of Formula IlIa
(Formula Removed)
wherein PI represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(0)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
(Formula Removed)
wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get a compound of Formula I la,
(Formula Removed)
wherein P1, P2, P3 and P4 are as defined above,
b) deprotecting the compound of Formula I la,
c) isolating doripenem from the reaction mass thereof,
characterized by the fact that the compound of Formula I la is not isolated from the reaction mixture.
A second aspect of the present invention provides a process for preparation of doripenem of Formula I
(Formula Removed)
which comprises
a) reacting enol-phosphate of Formula IlIa
(Formula Removed)
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
(Formula Removed)
wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get compound of Formula lla,
(Formula Removed)
wherein P1, P2, P3 and P4 are as defined above
b) deprotecting the compound of Formula I la, in a biphasic system comprising of
aqueous and water-immiscible solvents,
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
(Formula Removed)
which comprises
a) reacting enol-phosphate of Formula IlIa
(Formula Removed)
wherein PI 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
(Formula Removed)
wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get compound of Formula lla,
(Formula Removed)
wherein P1, P2, P3 and P4 are as defined above
b) deprotecting the compound of Formula lla in the presence of a buffering agent,
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 la
(Formula Removed)
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 IIIb
(Formula Removed)
wherein PI and P2 are as defined above, with a thiopyrrolidine of Formula IVb
(Formula Removed)
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 la
(Formula Removed)
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 IIIb
(Formula Removed)
wherein P1 and P2 are as defined above, with a thiopyrrolidine of Formula IVb
(Formula Removed)
wherein P3 is as defined above, at a temperature of -10°C 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 -10°C or less. To this reaction mass is added an amine selected from the group comprising of diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (IMP), 1,1,3,3-tetramethylguanidine (TMG), 1,8-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°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 a 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 hydrogenated 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 containing the product is washed with an organic solvent and from this doripenem can be isolated by conventional methods.
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 1
PREPARATION OF DORIPENEM
A mixture of 4-nitrobenzyl(2S,4S)-4-(acetylthio)-2-{[(aminosulfonyl)(tert- butoxy
carbonyl)amino]methyl}pyrrolidine-1-carboxylate (53.5 g) and concentrated sulfuric
acid (25 g) in methanol (250 ml) were refluxed for 3 hours, followed by cooling to
ambient temperature. To the reaction mass was added a mixture of ethylacetate (400
ml) and water (400 ml). The organic layer was separated and the aqueous layer was
reextracted 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-1-carboxylate. N,N-
dimethylformamide (250 ml) was added to the concentrate followed by the addition of enolphosphate (50 g) at ambient temperature. The resulting solution was cooled to -40°C and diisopropylamine (11 g) was added to this solution drop wise under stirring while maintaining the temperature -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 ambient temperature. 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.

WE CLAIM:
1. A process for preparation of doripenem of Formula I
(Formula Removed)
which comprises
a) reacting enol-phosphate of Formula Ilia
(Formula Removed)
wherein PI represents a carboxyl protecting group, P2 represents hydrogen or a hydroxyl protecting group and X represents OP(0)(OR)2 or OS02R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl with a thiopyrrolidine of Formula IVa
(Formula Removed)
wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get a compound of Formula lla,
(Formula Removed)
wherein P1, P2, P3 and P4 are as defined above,
b) deprotecting the compound of Formula lla,
c) isolating doripenem from the reaction mass thereof,
characterized by the fact that the compound of Formula lla is not isolated from the reaction mixture.
2. A process for preparation of doripenem of Formula I
(Formula Removed)
which comprises
a) reacting enol-phosphate of Formula IlIa
(Formula Removed)
wherein PI 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
(Formula Removed)
wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get compound of Formula Ma,
(Formula Removed)
wherein P1, P2, P3 and P4 are as defined above
b) deprotecting the compound of Formula Ma, in a biphasic system comprising of
aqueous and water-immiscible solvents,
c) isolating doripenem from the reaction mass thereof.
3. A process for preparation of doripenem of Formula I
(Formula Removed)
which comprises
a) reacting enol-phosphate of Formula Ilia
(Formula Removed)
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
(Formula Removed)
wherein P3 represents hydrogen or an amino protecting group and P4 represents an amino protecting group, to get compound of Formula lla,
(Formula Removed)
wherein P1, P2, P3 and P4 are as defined above
b) deprotecting the compound of Formula Ha in the presence of a buffering
agent,
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 la
(Formula Removed)
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 IIIb
(Formula Removed)
wherein P1 and P2 are as defined above, with a thiopyrrolidine of Formula IVb
(Formula Removed)
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 a
group comprising of diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (IMP), 1,1,3,3-tetramethylguanidine (TMG), 1,8-diazabicyclo[4.3.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
7. A process for preparation of a compound of Formula la
(Formula Removed)
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 IIIb
(Formula Removed)
wherein P1 and P2 are as defined above, with a thiopyrrolidine of Formula IVb
(Formula Removed)
wherein P3 is as defined above, at a temperature of -10°C or less.
8. A process as claimed in claims 1, 2, 3, 5 and 7 wherein the deprotection is carried out in presence of palladium catalyst.