AU2002302882A1 - Process for the preparation of imipenem - Google Patents
Process for the preparation of imipenemInfo
- Publication number
- AU2002302882A1 AU2002302882A1 AU2002302882A AU2002302882A AU2002302882A1 AU 2002302882 A1 AU2002302882 A1 AU 2002302882A1 AU 2002302882 A AU2002302882 A AU 2002302882A AU 2002302882 A AU2002302882 A AU 2002302882A AU 2002302882 A1 AU2002302882 A1 AU 2002302882A1
- Authority
- AU
- Australia
- Prior art keywords
- formula
- imipenem
- mixture
- compound
- base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 title claims description 42
- 229960002182 imipenem Drugs 0.000 title claims description 30
- 238000000034 method Methods 0.000 title claims description 29
- 238000002360 preparation method Methods 0.000 title claims description 16
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 title claims 5
- -1 enol phosphate Chemical class 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- RJXCWYMBQYTWIS-UHFFFAOYSA-N benzyl methanimidate Chemical compound N=COCC1=CC=CC=C1 RJXCWYMBQYTWIS-UHFFFAOYSA-N 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 238000011065 in-situ storage Methods 0.000 claims description 5
- 229930194542 Keto Natural products 0.000 claims description 4
- LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 3
- 239000012736 aqueous medium Substances 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- XWEHFBHUHPIKFI-UHFFFAOYSA-N 2,2-dimethyl-1-(2-methylpropyl)piperidine Chemical compound CC(C)CN1CCCCC1(C)C XWEHFBHUHPIKFI-UHFFFAOYSA-N 0.000 claims description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims 2
- GSOSVVULSKVSLQ-JJVRHELESA-N imipenem hydrate Chemical compound O.C1C(SCCNC=N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 GSOSVVULSKVSLQ-JJVRHELESA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 3
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical group C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- LSNKBVFMXFAUOF-UHFFFAOYSA-N benzyl methanimidate;hydrochloride Chemical compound Cl.N=COCC1=CC=CC=C1 LSNKBVFMXFAUOF-UHFFFAOYSA-N 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 229940097265 cysteamine hydrochloride Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- INYSHFQQWIZFKO-UHFFFAOYSA-N n'-(2-sulfanylethyl)methanimidamide Chemical compound SCCNC=N INYSHFQQWIZFKO-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Description
PROCESS FOR THE PREPARATION OF IMIPENEM
FIELD OF THE INVENTION
The present invention relates to an improved, cost effective and industrially advantageous process for the preparation of imipenem.
BACKGROUND OF THE INVENTION
Imipenem monohydrate of Formula I which is the N-formimidoyl derivative of thienamycin and has the structural Formula I.
FORMULA I
It is the first clinically available member of a new class of β-lactam antibiotics that
possess the carbapenem ring system. Imipenem exhibits an extremely broad spectrum of activity against gram-positive and gram-negative aerobic and anaerobic
species, which is partly due to its high stability in the presence of β-lactamases.
Imipenem was first disclosed in U.S. Patent No. 4,194,047. Several general methods for the preparation of N-methylene derivatives of thienamycin including imipenem have been outlined in U.S. Patent No. 4,194,047 starting from thienamycin. The process for the preparation of imipenem has been found to give the product in low yield and of poor quality due to inherent instability of the starting compound i.e. thienamycin.
1
U.S. Patent No. 4,292,436 provides an alternate method for the preparation of imipenem from bicyclo ketone precursor of Formula II,
FORMULA II
wherein R is a protecting group, comprising activating the keto ester and reacting the activated keto ester with N-formimidoyl-2-aminoethanethiol to obtain carboxyl protected imipenem which gives imipenem after hydrogenation. However, the process gives low yields of the final product (59% in solution and 35% of isolated imipenem monohydrate).
U.S. Patent No. 4,374,772 gives an improved process for preparing imipenem from dilute aqueous solutions of thienamycin using benzylic formimidate reagents. However, the process has the disadvantage of producing at least 5% of dimer bis- thienamycin formamidene along with the desired proudct imipenem.
U.S. Patent No. 4,894,450 uses new reagents - bis (chloro-substituted phenyl) phosphorochloridate to activate the bicycloketone precursor of formula II, wherein R is a protecting group. Subsequent reaction with cysteamine hydrochloride, amidine formation and hydrogenolysis of the ester group gives good yield of imipenem. However, the reagent employed for activation is not available
commercially and its preparation involves a cumbersome multistage purification process.
In light of the above drawbacks in the prior art processes, there is a need for the development of a process for the preparation of imipenem which is convenient to operate on an industrial scale, employs readily and commercially available raw materials and reagents and which process gives substantially pure product in good yield.
SUMMARY OF THE INVENTION
It is an object of the present invention to solve the problems associated with the prior art and provide an efficient process. The process provides obvious benefits with respect to economics and convenience to operate on a commercial scale.
Accordingly, the present invention relates to an improved process for the preparation of imipenem of sufficient purity and high yield starting from the bicyclo ketone precursor of formula II, wherein R is a protecting group.
In particular, the present invention relates to a process for the preparation of imipenem of Formula I
comprising: FORMULA I
a) activating a keto ester compound of Formula II,
FORMULA II
wherein R is a protecting group, with a phosphorohalidate derivative of Formula VI,
FORMULA VI
wherein X is a halogen atom and R' is aryl, in the presence of a base and a catalytic amount of a dialkylaminopyridine, to obtain enol phosphate compound of Formula
FORMULA III wherein R and R' have the same meaning as defined above,
b) reacting the enol phosphate intermediate of Formula III, in situ with 2- aminoethanethiol or an acid addition salt thereof to get thienamycin ester of Formula IV,
FORMULA IV
wherein R has the same meaning as defined above, c) reacting thienamycin ester of Formula IV in situ with benzyl formimidate or an acid addition salt thereof in the presence of a base to get carboxyl protected imipenem of Formula V,
FORMULA V
wherein R has the same meaning as defined above, and d) hydrogenating the carboxyl protected imipenem of formula V in an aqueous medium to obtain imipenem.
The reactions at steps a) and c) are preformed in the presence of a base which may be a secondary amine or a tertiary amine. Examples of secondary amines include diisopropylamine, dicyclohexylamine, 2,2,6,6-
tetramethylethylpiperidine (TMP) and 1 ,1 ,3,3-tetramethylguanidine (TMG). Examples of suitable tertiary amines include diisopropylethylamine, triethylamine and tributylamine.
The presence of a catalytic amount of dialkylaminopyridine at step a) prevents the formation of impurity of formula VII,
FORMULA VII
The impurity of Formula VII is formed in substantial quantities (14-15% by HPLC) by side reaction of the hydroxymethyl group at the 6-position of the carbapenem.
Dialkylaminopyridines are used in catalytic amounts, preferably in the range of about 0.5 to 2% w/w relative to the keto ester of Formula II. For the purpose of the present invention, dialkylaminopyridine includes pyridine substituted at the 2- or 4- position. Examples of such dialkylamino substituents include N,N-dimethylamino, N,N-diethylamino, N,N-dicyclohexylamino, N-cyclohexyl-N-methylamino, 1- pyrrolidinyl, 1-piperidinyl and mixture(s) thereof.
The protecting group R in the compound of Formula II is any carboxylic acid protecting group which may be easily removed by hydrogenation, such as benzyl, p- nitrobenzyl or methoxymethyl.
In the compound of Formula VI, X is a halogen atom which may be chloro, bromo or iodo. Particularly preferred is chloro. R' in the compound of Formula VI is aryl, preferably phenyl, which may be substituted.
Compounds of Formula II, VI and benzylformimidate or its acid addition salts may be obtained by methods known in the art.
The reaction at step a) is carried out in an organic solvent such as N, N- dimethyl acetamide (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidone
(NMP), ethylacetate, dichloromethane, tetrahydrofuran, or mixture(s) thereof.
Preferably a mixture of dichloromethane and any of the solvents chosen from DMAc,
DMF or NMP is used. The reaction at step b) is carried out at a temperature of from about -50 to -759C, preferably at about -60 to -759C.
Steps a), b) and c) are performed in situ, thus the solvent and the base are common to the three steps. Additional amount of the base is added to facilitate the reaction at step c).
Acid addition salts of 2-aminoethanethiol and benzylformimidate used at steps b) and c) respectively may be the same or different and may arise from either organic or inorganic acids. Examples of such salts include hydrochloride, hydrobromide, hydroiodide, sulfate, methanesulfonate, benzenesulfonate, fumarate, tartrate, thiocyanate, tosylate, phosphate, picrate, succinate, pivalate, benzoate,
acetate and citrate salts. Particularly preferred are the hydrochloride salts of both 2- aminoethanethiol and benzylformimidate.
The hydrogenation step d) is carried out after suitable aqueous work up of the reaction mixture from step c). Preferably, a lower alcohol is added to the obtained aqueous solution of compound V and hydrogenation carried out at a pH of about 7 to 8 in the presence of N-methylmorpholine buffer. Examples of lower alcohols which may be added include methanol, ethanol, isopropanol and propanol. The hydrogenation may be carried out using any of the metal cataylsts such as platinum oxide, platinum / carbon, palladium hydroxide and palladium/carbon.
Imipenem is obtained as a solution after hydrogenation and filtration of the catalyst. Imipenem may then be isolated from the solution in the usual manner by lyophilization and/or crystallization methods known in the art but is preferably crystallized by the method described in the patent application filed concurrently herewith.
DETAILED DESCRIPTION OF THE INVENTION
In the following section one preferred embodiment is descπbed by way of example to illustrate the process of the invention. However, it is not intended in any way to limit the scope of the present invention.
PREPARATION OF IMIPENEM Example 1 Step a) - Preparation of enol phosphate intermediate
A solution of p-nitrobenzyl (3R, 5R, 6S)-2oxo-6-[(1 R)-1-hydroxyethyl)] carbapenem-3-carboxylate (30g) was dissolved in a mixture of N, N- dimethylacetamide (300ml) and dichloromethane (150ml). The solution was cooled to -55°-C and 4-(dimethylamino)pyridine (0.17g) was added followed by diisopropylethylamine (26.7g). The mixture was stirred for 5 min. at -55SC and then a solution of diphenylchlorophosphate (25.4g) in dichloromethane (30ml) was added dropwise at -55 to -45SC. The reaction mixture thus obtained was stirred further for 30 minutes to obtain the enol phosphate ester.
Step b) - Preparation of thienamycin ester
The reaction mixture from step a) was further cooled to -70 to -75eC and a solution of 2-aminoethanethiol hydrochloride (12g) in N,N-dimethylacetamide (60ml) was added in 10 min at -75 to -60QC. The reaction mixture was stirred for another 60 min. to produce p-nitrobenzyl ester of thienamycin.
Step c) - Preparation of p-nitrobenzyl ester of imipenem To the above reaction mixture from step b), was added diisopropylethylamine
(16.0g) and benzyl formimidate hydrochloride (20.0g) at -50 to -55SC. The reaction mixture was maintained for about one and a half hour at the same temperature. The temperature was then raised to -209C in 20-30 min and the reaction mixture stirred for 20-30 min at this temperature to obtain the imipenem ester.
Step d) - Preparation of imipenem
The above clear solution of step c) was poured into a mixture of water (300ml), isopropanol (150ml) and N-methylmorpholine (26g) maintained at 5-109C and the pH of the solution adjusted to 7.0 to 7.5. The solution was hydrogenated at 3-4 kg pressure for 2.5 hour at 10-259C over palladium / carbon. The mixture was filtered and assayed for imipenem (80%, as determined by HPLC).
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.
Claims (12)
1. A process for the preparation of imipenem of Formula
FORMULA I comprising :
a) activating a keto ester compound of Formula II,
FORMULA II
wherein R is a protecting group with a phosphorohalidate of Formula VI
o xo — p — OR'
I OR
FORMULA VI
wherein X is a halogen atom and R' is aryl, in the presence of a base and a catalytic amount of a dialkylaminopyridine to obtain enolphosphate compound of Formula III,
FORMULA in
wherein R and R' have the same meaning as defined above, b) reacting the enol phosphate intermediate of Formula III, in situ with 2- aminoethanethiol or an acid addition salt thereof to get thienamycin ester of Formula IV,
FORMULA IV
wherein R has the same meaning as defined above, c) reacting thienamycin ester of Formula IV in situ with benzyl formimidate or an acid addition salt thereof in the presence of a base to get carboxyl protected imipenem of Formula V,
FORMULA V wherein R has the same meaning as defined above, and d) hydrogenating the carboxyl protected imipenem of formula V in an aqueous medium to obtain imipenem.
2. The process of claim 1 wherein the dialkylaminopyridine is 4- (dimethylamino)pyridine.
3. The process of claim 1 wherein the base used at step a) and step c) is a secondary amine or a tertiary amine.
4. The process of claim 3 wherein said base is selected from the group consisting of diisopropylamine, dicyclohexylamine, 2,2,6,6-tetramethyl ethylpiperidine (TMP), 1 ,1 ,3,3-tetramethylguanidine(TMG), diisopropylethylamine, triethylamine, tπ'butylamine, and mixture(s) thereof.
5. The process of claim 1 wherein the protecting group R is benzyl, p-nitrobenzyl or methoxymethyl in the compound of Formula II.
6. The process of claim 1 wherein the reaction at step a) is performed in an organic solvent.
7. The process of claim 6 wherein said organic solvent is selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylformamide, N- methylpyrrolidone, ethyl acetate, dichloromethane, tetrahydrofuran, and mixture(s) thereof.
8. The process of claim 6 wherein the reaction at step a) is performed in a mixture of dichloromethane and one of the solvents selected from N,N- dimethylacetamide, N, N-dimethyl formamide and N-methylpyrrolidone.
9. The process of claim 1 wherein the reaction at step b) is performed at a temperature of from about -60 to -75SC.
10. The process of claim 1 wherein R' is phenyl in the compound of Formula III.
11. The process of claim 1 wherein the hydrogenation at step d) is carried out in an aqueous medium comprising a mixture of water and a lower alcohol.
12. The process of claim 11 wherein the lower alcohol is selected from the group consisting of methanol, ehtanol, isopropanol, and propanol.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN594/DEL/01 | 2001-05-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2002302882A1 true AU2002302882A1 (en) | 2002-12-03 |
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