| WO/1995/026966 | CEPHALOSPORIN ANTIBIOTICS |
| JP3953274 | How to Synthesize Carbapenem Antibiotics |
| WO/1991/000864 | CARBAPENEM DERIVATIVES |
GEORGE VINOD (IN)
MANE AVINASH SHESHRAO (IN)
MEERAN HASHIM NIZAR POOVANATHI (IN)
PRASAD MOHAN (IN)
TEWARI NEERA (IN)
GEORGE VINOD (IN)
MANE AVINASH SHESHRAO (IN)
MEERAN HASHIM NIZAR POOVANATHI (IN)
PRASAD MOHAN (IN)
| WO1999014218A1 | 1999-03-25 | |||
| WO1998002439A1 | 1998-01-22 |
| US5527793A | 1996-06-18 | |||
| EP0528678A1 | 1993-02-24 | |||
| EP1132379A1 | 2001-09-12 |
KYE J S ET AL: "Synthesis and Biological Properties of New 1beta-Methylcarbapenems", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no. 13, 7 July 1998 (1998-07-07), pages 1607 - 1612, XP004137093, ISSN: 0960-894X
We claim:
1. A process for the preparation of the compound of Formula VI,
FORMULA IV wherein P 1 , R 1 and R 2 are as defined above, and R 3 comprises a thiol protecting group comprising of acetyl or benzoyl, to form the compound of Formula I
FORMULA I wherein P 1 , R 1 and R 2 are as defined above; b) reacting the compound of Formula I with a compound of Formula III,
2. The process of claim 1, wherein the compound of Formula VI is meropenem.
3. The process of claim 1, wherein the compound of Formula VI is ertapenem.
4. The process of claim 1, wherein the thiol compound of Formula TV is treated with acetyl chloride.
5. The process of claims 1, wherein step a) is carried out in the presence of one or more organic solvents comprising one or more of Ci -5 alkanol, aromatic hydrocarbon, halogenated hydrocarbon, ketone, ester, ether or a mixture thereof.
6. The process of claims 1, wherein step a) is carried out under reflux temperature.
7. The process of claims 1, wherein the compounds of Formula I and Formula II are isolated from the reaction mixture prior to step b).
8. The process of claims 1, wherein step b) further comprises deprotection of the compounds of Formula VI and Formula VII. 9. A process for the preparation of the compound of Formula VII,
FORMULA VII wherein P 1 comprises hydrogen or an amino protecting group, P 2 comprises hydrogen or a carboxyl protecting group and P 3 comprises hydrogen or a hydroxyl protecting group, wherein the process comprises: a) forming a reaction mixture by treating the thiol compound of Formula V with one or more of acetyl chloride, silica chloride, thionyl chloride or oxalyl chloride,
|
A PROCESS FOR THE PREPARATION OF CARBAPENEM COMPOUNDS
Field of the Invention
The present invention relates to an improved process for the preparation of carbapenem compounds.
Background of the Invention
Carbapenem compounds are known for their broad and potent antibacterial activity. A large number of derivatives have been synthesized and investigated for clinical efficacy. Meropenem, ertapenem and doripenem are some of the commercially available carbapenem antibiotics available for treating various bacterial infections.
Thiol side chain compounds of Formulae I and II wherein,
FORMULAI FORMULA II
P 1 represents hydrogen or an amino protecting group, and R 1 and R 2 may be hydrogen, Ci- 5 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, are important intermediates in the preparation of carbapenem compounds.
The thiol side chain compounds of the above formulae are further condensed with enolphosphate of Formula III wherein,
P 2 represents hydrogen or a carboxyl protecting group, P 3 represents hydrogen or 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, to obtain respective carbapenem antibiotics.
The thiol side chain compounds of Formulae I and II described above may be prepared by S-deprotection of the compounds of Formulae IV and V respectively,
FORMULA IV FORMULA V
wherein P 1 , R 1 and R 2 are as defined above, and R 3 is a thiol protecting group including one or both of acetyl or benzoyl. U.S. Patent No. 4,943,569 provides a process for the preparation of meropenem, wherein the process involves the reaction between enolphosphate of Formula III, wherein P 2 is p-nitrobenzyl, P 3 is hydrogen and X is diphenoxyphosphoryloxy, and the thiol side chain compound of Formula I, wherein P 1 is p-nitrobenzyloxycarbonyl, and R 1 and R 2 are methyl, followed by deprotection of the protected meropenem intermediate, hi this method, the thiol side chain compound of Formula I, wherein P 1 is p- nitrobenzyloxycarbonyl, and R 1 and R 2 are methyl, is prepared by S-deacetylation of the compound of Formula IV, wherein P 1 is p-nitrobenzyloxycarbonyl, R 1 and R 2 are methyl, and R 3 is acetyl, in the presence of aqueous sodium hydroxide and hydrochloric acid.
U.S. Patent No. 5,478,820 provides a similar process for the preparation of ertapenem. The thiol group of the compound of Formula IV, wherein P 1 is p- nitrobenzyloxycarbonyl, R 1 is hydrogen, R 2 is 3-allyloxycarbonylphenyl, and R 3 is acetyl, is deprotected in the presence of 1 M sodium hydroxide.
YatakaNishino et al., Org. Process Res. Dev. 2003, 7(6), 846-850, provides a process for the preparation of doripenem, where the thiol group of the compound of
Formula V, wherein each P 1 independently represents p-nitrobenzyloxycarbonyl or t- butyloxycarbonyl, and R 3 is acetyl, is S-deacetylated in the presence of 98% sulfuric acid.
Similar processes for the preparation of carbapenem compounds have also been provided in U.S. Patent No. 4,888,344, U.S. Patent No. 5,122,604, Sunagawa M., et al., J. Antibiot (Tokyo), 1990, 43(5), 519-532, Yasuyoshi Iso et al, J. Antibiot (Tokyo), 1996, 49(2), 199-209, and Haruki M., et al., Heterocycles, 1995, 36, 145-159.
The prior art processes involve the preparation of thiol side chain compounds of Formulae I and II by S-deacylation using strong basic or acidic conditions. Such reaction conditions also require a considerable amount of strong base or acid for neutralization of the reaction mixture. Carbapenem ring systems are sensitive to both acidic or basic conditions, and therefore exposure to such conditions generally result in reduced yields and increased impurity levels. However, there remains a need for novel processes that avoid the above problems.
Summary of the Invention
In one general aspect there is provided a process for the preparation of the compound of Formula VI,
FORMULA VI wherein P 1 includes hydrogen or an amino protecting group, P 2 includes hydrogen or a carboxyl protecting group, P 3 includes hydrogen or a hydroxyl protecting group, and R 1 and R 2 include one or more of hydrogen, C 1-5 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The process includes the steps of: a) treating the thiol compound of Formula IV with one or more of acetyl chloride, silica chloride, thionyl chloride or oxalyl chloride,
FORMULA IV wherein P 1 , R 1 and R 2 are as defined above, and R 3 includes a thiol protecting group including acetyl or benzoyl, to form the compound of formula I
FORMULA I wherein P 1 , Ri and R 2 are as defined above; b) reacting the compound of Formula I with a compound of Formula III,
Embodiments of the process may include one or more of the following features. For example, the compound of Formula VI may be meropenem or ertapenem.
Thiol compound of Formula IV may be treated with acetyl chloride. Step a) may be carried out in the presence of one or more organic solvents including Cr 5 alkanol, aromatic hydrocarbon, halogenated hydrocarbon, ketone, ester and ether. Step a) may be carried out under stirring and under reflux temperature.
The compounds of Formula I and Formula II are isolated from the reaction mixture prior to step b). Step b) may further include deprotection of the compounds of Formula VI and Formula VII.
In another general embodiment, there is provided a process for the preparation of the compound of Formula VII,
Embodiments of the process may include one or more of the following features. For example, the compound of Formula VII may be doripenem.
The thiol compound of Formula V may be treated with acetyl chloride and step a) may be carried out in the presence of one or more organic solvents. The one or more organic solvents maybe C 1 -S alkanol, aromatic hydrocarbon, halogenated hydrocarbon, ketone, ester, ether or mixtures thereof. For example, suitable organic solvents may be a Cr 5 alkanol.
Step a) may be carried out under stirring and under reflux temperature. The compounds of Formula I and Formula II may be isolated from the reaction mixture prior to step b). Step b) may include the deprotection of the compounds of Formula VI and Formula VII. This deprotection may be carried out in the presence of palladium carbon
and an aqueous buffer or the deprotection may be carried out in the presence of non- nucleophilic buffer and in biphasic solvent system.
Detailed Description of the Invention
It has been found that the S -deprotection of a thiol side chain compound can be carried out in the presence of one or more of acetyl chloride, silica chloride, oxalyl chloride or thionyl chloride. The present method employs only a catalytic quantity of these chloride compounds and does not require the addition of a base or an acid for neutralization. Thus the present process provides final carbapenem compounds with improved purity and good yield.
The term "protecting group," as used herein, refers to protecting groups known in the art and serve the function of blocking carboxyl, amino or hydroxyl groups while the reactions are carried out at other sites of the molecule. Carboxyl protecting groups may include one or more of optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 alkenyl, optionally substituted C 7 -C 19 aralkyl, optionally substituted C 6 -C 12 aryl, optionally substituted Ci-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 may include one or more of lower alkylsilyl groups, lower alkoxymethyl groups, aralkyl groups, acyl groups, lower alkoxycarbonyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups.
A first embodiment of the present invention provides a process for the preparation of the compound of Formula VI,
and R 2 are hydrogen, C 1-5 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein the process comprises: a) treating the thiol compound of Formula IV with one or more of acetyl chloride, silica chloride, thionyl chloride or oxalyl chloride,
FORMULA IV wherein P 1 , Ri and R 2 are as defined above, R 3 is a thiol protecting group one or both of acetyl or benzoyl, to form the compound of formula I
FORMULA I wherein Pi, R 1 and R 2 are as defined above; b) reacting the compound of Formula I with a compound of Formula III,
Enol-phosphate of Formula III and the thiol side chain of Formula IV may be prepared by processes reported in the abovementioned prior-art . The thiol side chain of Formula IV may be treated with a catalytic quantity of acetyl chloride, silica chloride, thionyl chloride or oxalyl chloride in the presence of one or more organic solvents comprising one or more of a C 1-5 alkanol, an aromatic hydrocarbon, a halogenated hydrocarbon, a ketone, an ester, an ether or mixtures thereof. The deprotection of the thiol group may be affected by heating the reaction mixture at reflux temperature or by stirring the reaction mixture for sufficient time. The S-deprotected thiol side chain of Formula I may optionally be isolated from the reaction mixture by layer separation and subsequent concentration.
The S-deprotected thiol side chain of Formula I or a reaction mixture comprising the same, and enolphosphate of Formula III may be dissolved in one or more organic solvents and the resultant reaction mixture may be cooled to a temperature less than or equal to about 0 0 C. The reaction mixture may be stirred in the presence of one or more organic bases for a sufficient time at the same temperature to effect the coupling reaction. The reaction mixture is subsequently hydrogenated using a palladium catalyst in a biphasic system in presence of a non nucleophilic buffer that includes morpholinopropanesulphonic acid and morpholinoethanesulphonic acid or an aqueous buffer comprising N-methylmorpholine.
After completion of the reaction, the solid product may be isolated from the aqueous layer, washed with one or more organic solvents and dried to obtain the compound of Formula VI.
A second embodiment of the present invention provides a process for the preparation of the compound of Formula VII,
wherein Pi represents hydrogen or an amino protecting group, P 2 represents hydrogen or a carboxyl protecting group and P 3 represents hydrogen or a hydroxyl protecting group.
The process includes the steps of: a) treating the thiol compound of Formula V with one or more of acetyl chloride, silica chloride, thionyl chloride or oxalyl chloride,
c) isolating the compound of Formula VII from the reaction mass thereof.
Enol-phosphate of Formula III and thiol side chain of Formula V may be prepared by processes reported in the abovementioned prior-art. The thiol side chain of Formula V may be treated with a catalytic quantity of one or more of acetyl chloride, silica chloride, thionyl chloride or oxalyl chloride in the presence of one or more organic solvents.
Suitable organic solvents may be one or more of a Ci -5 alkanol, an aromatic hydrocarbon, a halogenated hydrocarbon, a ketone, an ester, an ether or mixtures thereof. The thiol group is deprotection by heating the reaction mixture at reflux temperature or by stirring the reaction mixture for sufficient time. The S-deprotected thiol side chain of Formula II may optionally be isolated from the reaction mixture by layer separation and subsequent concentration. The S-deprotected thiol side chain of Formula II or a reaction mixture comprising the same, and enolphosphate of Formula III are dissolved in one or more organic solvents and the resultant reaction mixture is cooled to a temperature less than or equal to about O 0 C. The reaction mixture is stirred in the presence of one or more organic bases for a sufficient time at the same temperature to effect the coupling reaction. The reaction mixture is subsequently hydrogenated using a palladium catalyst in a biphasic system in presence of a non nucleophilic buffer. The non nucleophilic buffer may be one or more of morpholinopropanesulphonic acid and morpholinoethanesulphonic acid or an aqueous buffer that includes N-methylmorpholine. After completion of the reaction, the solid product may be isolated from the aqueous layer, washed with one or more organic solvents and dried to obtain the compound of Formula VII.
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 included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.
EXAMPLE 1 PREPARATION OF MEROPENEM: a) Preparation of 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4- mercaptopyrrolidine-1-carboxylate
4-Nitrobenzyl (25',45)-4-(acetylthio)-2-[(dimethylammo)carbonyl]pyrrolidin e- 1 - carboxylate (50 g) was suspended in methanol (250 mL), followed by the addition of acetyl chloride (10 g). The reaction mixture was stirred for 5 hours at about 25 0 C and then added to a mixture of methylene chloride (500 mL) and water (500 mL). The organic layer was collected and washed with water (250 mL). The organic layer was concentrated and the residue was recrystallized with isopropylalcohol to obtain the title compound.
Yield: 80 %
PMR (CDCl 3 ) Data: 8.15 (d, 2H), 7.50 (d, 2H), 5.21 (s, 2H), 4.62 (m, IH), 4.70 (m, IH), 4.06 (t, IH), 3.41 (t, IH), 3.26 (t, 2H), 3.10 (s, 3H), 2.90 (s, 3H), 2.72 (t, IH) and 1.88 (IH, br) b) Preparation of 4-nitrobenzyI (2S,4S)-2-[(dimethylamino)carbonyl]-4- mercaptopyrrolidine-l-carboxylate
4-Nitrobenzyl (2 1 S',45)-4-(acetylthio)-2-[(dimethylamino)carbonyl]pyrrolidine - 1 - carboxylate (50 g) was suspended in methanol (250 mL), followed by the addition of acetyl chloride (5 g). The reaction mixture was refluxed for 2.5 hours followed by cooling to about 25 0 C and then added to a mixture of methylene chloride (500 ml) and water (500 mL). The organic layer was collected and washed with water (250 mL). The organic layer was concentrated and the residue was recrystallized with isopropylalcohol to obtain the title compound. Yield: 70 %
PMR (CDCl 3 ) Data: 8.15 (d, 2H), 7.50 (d, 2H), 5.21 (s, 2H), 4.62 (m, IH), 4.70 (m, IH), 4.06 (t, IH), 3.41 (t, IH), 3.26 (t, 2H) 5 3.10 (s, 3H), 2.90 (s, 3H), 2.72 (t, IH) and 1.88 (IH, br) c) Preparation of meropenem: The 4-nitrobenzyl (4i?,5i?,65)-3-[(diρhenoxyρhosρhoryl)oxy]-6-[(li?)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2 -carboxylate (50 g) and 4- nitrobenzyl (2iS',4 J S)-2-[(dimethylamino)carbonyl]-4-mercaptopyrrolidme-l-carbox ylate (30 g) obtained from step a) or from step b) were dissolved in a mixture of N 5 N- dimethylformamide (200 mL) at about 25 0 C. The solution was then cooled to -45 0 C followed by dropwise addition of diisopropylethylamine (11 g) under stirring while
maintaining the temperature between -50 to -45 0 C. After stirring the reaction mixture for about 1 hour, it was poured into a mixture of ethyl acetate (500 niL) 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 about 7.0). The above biphasic reaction mass was hydrogenated for 3 hours under pressure at 20-25 0 C. After completion of the reaction, the mixture was filtered and the aqueous layer was separated. The aqueous layer was concentrated by reverse osmosis and tetrahydrofuran was added to the condensate at a temperature of about 5-10 0 C. The resultant mixture was stirred for about 5 hours to obtain the title compound as a trihydrate. Yield: 21.6 g
EXAMPLE 2 PREPARATION OF DORIPENEM a) Preparation of 4-nitrobenzyl (2S,4S)-2-{ [(aminosulfonyl)amino] methyl}-4- mercaptopyrrolidine-1-carboxylate 4-Nitrobenzyl (2S,4S)-4-(acetylthio)-2- { [(aminosulfonyl)(tert-butoxy carbonyl)amino]methyl} pyrrolidine- 1-carboxylate (56 g) was suspended in methanol (250 mL), followed by the addition of acetyl chloride (4.13 g). The reaction mixture was refluxed for 2 hours and the completion of the reaction was monitored by thin layer chromatography. After the completion of the reaction, the reaction mixture was cooled to about 25 0 C and poured into a mixture of dichloromethane (500 mL) and water (500 mL). The organic layer was collected, washed with water and concentrated to obtain the title compound.
Yield: 50 g b) Preparation of doripenem: N,N-Dimethylformarnide (250 mL) was added to the concentrate obtained from step a) followed by the addition of enolphosphate (50 g) at about 25 0 C. The resulting solution was cooled to -40 0 C and diisopropylethylamine (11 g) was added to this solution drop wise under stirring while maintaining the temperature at between about -40 0 C to -35 0 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 an aqueous buffer (500 mL)
containing N-methylmorpholine and acetic acid (pH 6.5 to 7.0). The triphasic reaction mass was then hydrogenated for 3 hours under pressure at about 25 0 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 the title compound in an 85 % yield.