AU2002212591A1 - Process for the preparation of crystalline N-formimidoyl thienamycin monohydrate (imipenem monohydrate) - Google Patents
Process for the preparation of crystalline N-formimidoyl thienamycin monohydrate (imipenem monohydrate)Info
- Publication number
- AU2002212591A1 AU2002212591A1 AU2002212591A AU1259102A AU2002212591A1 AU 2002212591 A1 AU2002212591 A1 AU 2002212591A1 AU 2002212591 A AU2002212591 A AU 2002212591A AU 1259102 A AU1259102 A AU 1259102A AU 2002212591 A1 AU2002212591 A1 AU 2002212591A1
- Authority
- AU
- Australia
- Prior art keywords
- formula
- group
- monohydrate
- alkyl
- imipenem
- 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
- -1 N-formimidoyl thienamycin monohydrate Chemical class 0.000 title claims abstract description 29
- 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 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 17
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims description 17
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 150000003951 lactams Chemical class 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 229960002182 imipenem Drugs 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 150000003335 secondary amines Chemical class 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- 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 claims description 6
- 229940043279 diisopropylamine Drugs 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000011065 in-situ storage Methods 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- LSNKBVFMXFAUOF-UHFFFAOYSA-N benzyl methanimidate;hydrochloride Chemical compound Cl.N=COCC1=CC=CC=C1 LSNKBVFMXFAUOF-UHFFFAOYSA-N 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 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
- 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 3
- GGYVTHJIUNGKFZ-UHFFFAOYSA-N 1-methylpiperidin-2-one Chemical compound CN1CCCCC1=O GGYVTHJIUNGKFZ-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
- BZQAWHMCGZYKMH-UHFFFAOYSA-N 2-aminoethanethiol Chemical compound NCCS.NCCS BZQAWHMCGZYKMH-UHFFFAOYSA-N 0.000 claims description 2
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 claims description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000006184 cosolvent Substances 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims 2
- 229930194542 Keto Natural products 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 125000000468 ketone group Chemical group 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 239000000243 solution Substances 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000000718 methaneimidamido group Chemical group C(=N)N* 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XQQUKAGHLDAJGO-UHFFFAOYSA-N 1-(2,6-dihydroxy-4-methoxyphenyl)hexan-1-one Chemical compound CCCCCC(=O)C1=C(O)C=C(OC)C=C1O XQQUKAGHLDAJGO-UHFFFAOYSA-N 0.000 description 1
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- HZAVSJRAODFHGF-UHFFFAOYSA-N 2-methyl-7-oxohept-2-enoic acid Chemical compound OC(=O)C(C)=CCCCC=O HZAVSJRAODFHGF-UHFFFAOYSA-N 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 238000002441 X-ray diffraction Methods 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
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical group C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- 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
- C07D477/10—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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—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 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a cost effective and commercially viable process for the preparation of crystalline N-formimidoyl thienamycin monohydrate (Imipenem monohydrate) of Formula I.
Description
PROCESS FOR THE PREPARATION OF CRYSTALLINE N-FORMIMIDOYL THIENAMYCIN MONOHYDRATE (IMIPENEM MONOHYDRATE)
FIELD OF THE INVENTION
The present invention relates to a cost effective and commercially viable process for the preparation of crystalline N-formimidoyl thienamycin monohydrate (Imipenem monohydrate) of Formula I:
FORMULA I
BACKGROUND OF THE INVENTION
Imipenem monohydrate, the crystalline monohydrate of N-formimidoyl derivative of thienamycin of Formula I, is the first clinically available member
of a new class of β-lactam antibiotic 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 presence of β-lactamases.
Imipenem was initially obtained by lyophilization technique as disclosed in US Patent No. 4,194,047. An alternate process of freeze crystallization or
lyophilization has been reported by M. Connolly et. al in J. Pharm. Sci, 85, 174-175 (1996). However, lyophilized product so obtained is often found to be largely amorphous which is thermodynamically unstable. A crystalline monohydrate form of imipenem is disclosed in US Patent No. 4,260,543, which is obtained by crystallization of a lyophilized sample of imipenem and was found to have unexpected stability in the solid state over the lyophilized form (amorphous form). However, it is reported that the changes in lyophilization conditions can change the degree of crystallinity of the final product. Crystallinity is of interest in the study of lyophilized imipenem because crystalline imipenem is more thermodynamically stable than amorphous or disordered imipenem. Processes of obtaining crystalline imipenem as described in the prior art requires specialized equipment such as freeze dryer or a lyophilizer which renders it unattractive at a commercial scale and also do not produce the product having consistent degree of crystallinity.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a cost effective and commercially viable process for producing highly pure thermally stable crystalline imipenem monohydrate having uniform degree of crystallinity directly from an aqueous solution obtained from the reaction mixture without involving lyophilization at any stage.
More particularly, the present invention relates to a process for the preparation of crystalline N-formimidoyl thienamycin monohydrate (imipenem monohydrate) of Formula I which comprises
(a) activating a eto ester compound of Formula II
FORMULA II
wherein p is hydrogen or a protecting group, in the presence of a suitable secondary amine, in a suitable N-substituted lactam or N, N- disubstituted amide as a solvent, optionally in combination with an inert organic solvent to obtain an activated keto ester of Formula III
FORMULA
wherein X is OP(O)(OR)2 or OS(O) 2R and R is Cm alkyl, d-6 alkaryl, aryl or perfluoro C1-6 alkyl. The term alkyl refers to a straight or branched chain and when of sufficient size, may be cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl and cyclopropyl methyl. The term aryl refers to aromatic rings including phenyl, substituted phenyl and naphthyl. Aryl groups may be substituted with one to three substitutents independently selected from a halogen, alkyl and halogenated lower alkyl group, wherein alkyl has the same meaning as defined above.
The protecting group p may be any of the readily removable carboxyl protecting groups. Preferably, p can be selected from the group consisting of benzyl, p-nitrobenzyl and methoxymethyl.
The suitable secondary amine is selected from the group consisting of diisopropylamine, dicyclohexylamine, 2,2,6,6- tetramethylethyl piperidine (TMP) and 1 ,1 ,3,3-tetramethylguanide (TMG).
The suitable N-substituted lactam is selected from the group consisting of N-methyl-pyrrolidone (NMP), N-ethyl-pyrrolidone (NEP), N-methyl piperidinone and 1 ,3-dimethyl 3,4,5, 6-tetrahydro-2(H) pyrimidinone (DMPH). The suitable N, N-disubstituted amide is selected from the group consisting of dimethylformamide (DMF), dimethylacetamide (DMAc) and optional inert organic solvent is preferably tetrahydrofuran. The reaction is carried out at a temperature ranging between -20 to -70SC. The compound of Formula II may be prepared using methods known in the art.
(b) Reacting the activated keto ester of Formula III, in situ with 2-aminoethanethiol (cysteamine) or with its salt in the presence of a secondary amine in N-substituted lactam or N, N-disubstituted amide at a temperature ranging from -809C to -409C to get thienamycin ester of Formula IV
FORMULA IV
wherein p, N-substituted lactam and N, N-disubstituted amine have the same meanings as defined above.
(c) Reacting thienamycin ester of Formula IV, in situ with benzyl formimidate hydrochloride (C6H5CH2θCH=NH2 +CI") in the presence of a secondary amine in N-substituted lactam or N, N- disubstituted amide to get amidine carboxylate ester (blocked N - formimidoyl thienamycin) of Formula V
FORMULA V
wherein p, N-substituted lactam and N, N-disubstituted amide have the same meanings as defined above.
(d) Hydrogenation of the blocked N-formimidoyl thienamycin of Formula V to get imipenem and the solution containing the reaction mixture is subjected to dianion chromatography, followed by crystallization in the presence of a suitable alcohol or a ketone as a co-solvent to yield highly pure crystalline N-formimidoyl thienamycin monohydrate (imipenem monohydrate). Suitable alcohol and ketone may be selected from ethanol, isopropanol, acetone and methyl isobutyl ketone.
DETAILED DESCRIPTION OF THE INVENTION
In the following section one preferred embodiment is described by way of example to illustrate the process of this invention. However, these are not intended in any way to limit the scope of the present invention.
EXAMPLE 1
PREPARATION OF CRYTALLINE IMIPENEM MONOHYDRATE
Step 1 - Preparation of (5R, 6S) p-Nitrobenzyl-3-(diphenylphosphono)-6-[(1 R)- 1 -hydroxyethyl]-1 -azabicyclo[3.2.0] hept-2-ene-7-one-2-caφoxylate
To a solution of p-nitrobenzyl (5R, 6S)p-Nitrobenzyl-6[(1 R)-1 - hydroxyethyl]-1 -azabicyclo[3.2.0]-heptan-3,7-dione-2-carboxylate (20. Og,
57mmol) in a mixture of tetrahydrofuran and 1 ,3-dimethyl-3,4,5,6-tetrahydro (2H) pyrimidinone (160 ml; 1 :1 v/v) was added diisopropylamine (7.0g, 69mmol) at -25 to -30QC followed by diphenylchlorophosphate (17.0g, 63mmol). The mixture was stirred for 40-45 min. at -10 to -15QC and used in the next step without isolation of the enol phosphate intermediate.
Step II - Preparation of (5R.6S) p-Nitrobenzyl-3-[(2-aminoethyl)thio]-6-[(1 R)-1- 10 hydroxyethyl]-1 -azabicyclo [3.2.0] hept-2-ene-7-one-2-carboxylate
The reaction mixture from Step I was cooled to -75eC. A solution of cysteamine (2-aminoethanethiol) hydrochloride (7.2g, 63mmol) in 1 ,3- dimethyl-3,4,5,6-tetrahydro (2H) pyrimidinone (70ml) and diisopropylamine (7.0g, 69 mmol) was added at -75 to -50eC in 10 min. The reaction mixture 15 thus obtained was further stirred at -40eC to -45SC for about 1 hr and was used as such without its isolation.
Step III - Preparation of (5R.6S) p-Nitrobenzyl-3-[2- [(iminomethyl)amino]ethyl]thio]-6-[(1 R)-1 -hydroxyethyl]-1 - azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylate
20. The reaction mixture from Step II was cooled to -45SC, and diisopropylamine (8.7g, 86mmol) was added followed by benzylformimidate hydrochloride (12.8g, 74.6mmol). The resulting mixture was stirred at -45 to -
402C for about 30 minutes and then at -20 to -159C for about 1 hour 30 minutes. Tetrahydrofuran (200ml) was added at -20 to -15QC and diisopropylamine salts were filtered off from the reaction mixture. The filtrate contained the N-formamidoyl thienamycin PNB ester.
Step IV - Preparation of [5R- [5α, 6α (R*)]]-6-(1-hydroxyethyl)-3-[[2-
[(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyIo[3.2.0]hept-2-ene-2- carboxylic acid
The filtrate from Step III containing PNB-N-formimidoyl thienamycin was poured into a mixture of water (400ml), N-methylmorpholine (18g), isopropyl alcohol (200ml) at 0-5sC and at pH of about 7.0. The reaction mixture was then hydrogenated over at 3-4 kg of hydrogen pressure at 5- 10 C. The reaction mixture was filtered, extracted with methylene chloride (2 x 300ml) and the aqueous layer was separated. The aqueous layer was concentrated to 200ml by distillation under reduced pressure. The concentrated solution was purified by dianion chromatography using water as an eluent. The fractions containing the desired product were combined and concentrated either under reduced pressure or using plain membrane type reverse osmosis techniques to a volume of 50ml. The concentrated solution was then cooled to 0-5eC and isopropyl alcohol (25ml) was added to it. It was further stirred for 40-45 min at the same temperature. Another lot of isopropyl alcohol (25ml) was added and stirring continued for about 1 hour at 0-5QC. The crystalline precipitate obtained was filtered, washed with isopropyl alcohol and acetone (2 x 10ml) and dried to yield 4.0g of crystalline N-formimidoyl thienamycin.
X-ray diffraction pattern (Figure 1) shows peaks characteristic of crystalline form of imipenem monohydrate as obtained per US Patent No. 4,260,543; Purity by HPLC = 99.23%.
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 (10)
1. A process for the preparation of crystalline N-formimidoyl thienamycin monohydrate (imipenem) of Formula I
FORMULA I which comprises
(a) activating a keto ester compound of Formula II
FORMULA II
wherein p is hydrogen or a protecting group, in the presence of a suitable secondary amine, in a suitable N-substituted lactam or N, N-disubstituted amide as a solvent, optionally in combination with an inert organic solvent to obtain a compound of Formula III
FORMULA III
ιu wherein x is OP(O)(OR)2 or OS (O)2 R and R is Cm alkyl, Cι-6 alkaryl, aryl or perfluoro Ci-e alkyl; the term alkyl refers to a straight or branched chain and when of sufficient size, may be cyclic, preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl, preferred cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl and cyclopropyl methyl; the term aryl refers to aromatic rings including phenyl, substituted phenyl and naphthyl, aryl groups may be substituted with one to three substituents independently selected from halogen, alkyl and halogenated lower alkyl group, wherein alkyl has the same meaning as defined above,
(b) reacting the activated keto ester of Formula III in situ with 2-aminoethanethiol (cysteamine) or its salt in the presence of a secondary amine in a N-substituted lactam or N, N-disubstituted amide as a solvent to get thienamycin ester of Formula IV
FORMULA IV
wherein p, n-substituted lactam and N, N-disubstituted amine, have the same meaning as defined above,
I I (c) reacting thienamycin ester of Formula IV, in situ with benzyl formimidate hydrochloride in the presence of a secondary amine in a N-substituted lactam or N, N-disubstituted amide to get amidine carboxylate ester (blocked N-formimidoyl thienamycin) of Formula V
FORMULA V wherein p, N-substituted lactam and N, N-disubstituted amine, have the same meaning as defined above,
(d) hydrogenating the blocked N-formimidoyl thienamycin of Formula V, to yield N-formimidoyl thienamycin (imipenem) in a solution and subjecting the solution containing the reaction mixture to dianion chromatography followed by crystallization in the presence of an alcohol or a ketone co- solvent to yield highly pure crystalline N-formimidoyl monohydrate (imipenem monohydrate) of Formula I.
2. The process of claim 1 wherein protecting group p is selected from the group consisting of benzyl, p-nitrobenzyl and methoxymethyl.
3. The process of claim 1 wherein the suitable secondary amine is selected from the group consisting of diisopropylamine, dicyclohexyl amine, 2,2,6,6-tetramethylethyl piperidine (TMP) and 1 ,1 ,3,3-tetramethylguanide (TMG).
4. The process of claim 1 wherein N-substituted lactam or N, N-disubstituted amide is used alone or in combination with an inert solvent.
5. The process in accordance with claim 4 wherein N- substituted lactam is selected from the group consisting of N-methyl pyrrolidone (NMP), N-ethylpyrrolidone (NEP), N-methylpiperidone and 1 ,3-dimethyl-3,4,5,6-tetrahydro(2H) pyrimidinone.
6. The process in accordance with claim 4 wherein suitable N, N-disubstituted amide is selected from the group consisting of dimethylformamide (DMF) and dimethylacetamide (DMAc).
7. The process of claim 4 wherein inert solvent is tetrahydrofuran.
8. The process of claim 4 wherein a mixture of 1 ,3-dimethyl- 3,4,,5,6-tetrahydro-2(H) pyrimidinone and tetrahydrofuran is used as a^ solvent.
9. The process according to claim 1 wherein alcohol is selected from the group consisting of ethanol and isopropyl alcohol.
10. The process according to claim 1 wherein ketone is selected from the group consisting of acetone and methyl isobutyl ketone.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN983/DEL/2000 | 2000-11-03 | ||
| IN983DE2000 IN191798B (en) | 2000-11-03 | 2000-11-03 | |
| PCT/IB2001/002069 WO2002036594A1 (en) | 2000-11-03 | 2001-11-05 | Process for the preparation of crystalline n-formimidoyl thienamycin monohydrate (imipenem monohydrate) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2002212591A1 true AU2002212591A1 (en) | 2002-05-15 |
Family
ID=11097114
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002212591A Abandoned AU2002212591A1 (en) | 2000-11-03 | 2001-11-05 | Process for the preparation of crystalline N-formimidoyl thienamycin monohydrate (imipenem monohydrate) |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US7078534B2 (en) |
| EP (1) | EP1334105B1 (en) |
| JP (1) | JP2004525084A (en) |
| KR (1) | KR20030059812A (en) |
| CN (1) | CN100445284C (en) |
| AT (1) | ATE322495T1 (en) |
| AU (1) | AU2002212591A1 (en) |
| BG (1) | BG107852A (en) |
| CA (1) | CA2427762C (en) |
| DE (1) | DE60118593D1 (en) |
| DK (1) | DK1334105T3 (en) |
| EA (1) | EA006442B1 (en) |
| EE (1) | EE200300206A (en) |
| ES (1) | ES2261494T3 (en) |
| IN (1) | IN191798B (en) |
| MX (1) | MXPA03003916A (en) |
| PT (1) | PT1334105E (en) |
| WO (1) | WO2002036594A1 (en) |
| ZA (1) | ZA200303338B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| OA12608A (en) | 2001-05-18 | 2006-06-08 | Ranbaxy Lab Ltd | Process for the isolation of crystalline imiponem. |
| AP1511A (en) * | 2001-05-18 | 2005-12-20 | Ranbaxy Laboratories Ltd | Process for the isolation of crystalline imipenem. |
| ES2328117T3 (en) * | 2001-05-18 | 2009-11-10 | Ranbaxy Laboratories Limited | PROCESS FOR THE PREPARATION OF IMIPENEM. |
| WO2003016312A1 (en) * | 2001-08-13 | 2003-02-27 | Eisai Co., Ltd. | Process for preparation of carbapenem antibiotics |
| JP2005509037A (en) * | 2001-11-16 | 2005-04-07 | ランバクシー ラボラトリーズ リミテッド | Crystalline imipenem production method |
| US6537985B1 (en) | 2001-11-30 | 2003-03-25 | Phoenix Scientific, Inc. | Antibiotic formulation and a method of making this formulation |
| KR100667373B1 (en) * | 2003-12-09 | 2007-01-10 | 주식회사 중외제약 | New manufacturing method of imipenem |
| KR100848752B1 (en) * | 2006-11-10 | 2008-07-25 | 제일약품주식회사 | Thienamycin Solvent Compound and Manufacturing Method Thereof |
| KR100848751B1 (en) * | 2006-11-10 | 2008-07-25 | 제일약품주식회사 | Method of making imipenem |
| EP2209787A4 (en) * | 2007-10-08 | 2011-08-03 | Orchid Chemicals & Pharm Ltd | Process for the preparation of carbapenem antibiotic |
| CN108623598A (en) * | 2018-05-21 | 2018-10-09 | 重庆天地药业有限责任公司 | A kind of preparation method of Imipenem intermediate and Imipenem |
| CN111413427A (en) * | 2020-04-08 | 2020-07-14 | 苏州和合医学检验有限公司 | Method for measuring imipenem content in blood plasma by ultrafiltration pretreatment high performance liquid chromatography |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4194047A (en) * | 1975-11-21 | 1980-03-18 | Merck & Co., Inc. | Substituted N-methylene derivatives of thienamycin |
| US4260543A (en) * | 1978-07-03 | 1981-04-07 | Merck & Co., Inc. | Crystalline N-formimidoyl thienamycin |
| JP3048196B2 (en) | 1991-06-20 | 2000-06-05 | 第一製薬株式会社 | Carbapenem derivatives |
| BR9206590A (en) | 1991-10-01 | 1995-04-25 | Procter & Gamble Pharma | Process for obtaining quinolonyl antimicrobial lactams |
| HUT65301A (en) | 1992-09-09 | 1994-05-02 | Sankyo Co | New method for preparing of carbapenem- and penem-carbonacid-derivatives with antibacterial activity |
| US5245069A (en) * | 1992-10-27 | 1993-09-14 | Merck & Co., Inc. | Process for the preparation of bis(aryl)-phosphorohalidates |
| US5872250A (en) * | 1997-07-30 | 1999-02-16 | Merck & Co., Inc. | Process for synthesizing carbapenem antibiotics |
-
2000
- 2000-11-03 IN IN983DE2000 patent/IN191798B/en unknown
-
2001
- 2001-11-05 EE EEP200300206A patent/EE200300206A/en unknown
- 2001-11-05 JP JP2002539352A patent/JP2004525084A/en not_active Withdrawn
- 2001-11-05 EA EA200300520A patent/EA006442B1/en not_active IP Right Cessation
- 2001-11-05 EP EP01980805A patent/EP1334105B1/en not_active Expired - Lifetime
- 2001-11-05 ES ES01980805T patent/ES2261494T3/en not_active Expired - Lifetime
- 2001-11-05 MX MXPA03003916A patent/MXPA03003916A/en active IP Right Grant
- 2001-11-05 DK DK01980805T patent/DK1334105T3/en active
- 2001-11-05 CN CNB018207154A patent/CN100445284C/en not_active Expired - Fee Related
- 2001-11-05 KR KR10-2003-7006118A patent/KR20030059812A/en not_active Withdrawn
- 2001-11-05 WO PCT/IB2001/002069 patent/WO2002036594A1/en not_active Ceased
- 2001-11-05 AT AT01980805T patent/ATE322495T1/en active
- 2001-11-05 AU AU2002212591A patent/AU2002212591A1/en not_active Abandoned
- 2001-11-05 DE DE60118593T patent/DE60118593D1/en not_active Expired - Lifetime
- 2001-11-05 US US10/415,633 patent/US7078534B2/en not_active Expired - Fee Related
- 2001-11-05 PT PT01980805T patent/PT1334105E/en unknown
- 2001-11-05 CA CA002427762A patent/CA2427762C/en not_active Expired - Fee Related
-
2003
- 2003-04-30 ZA ZA200303338A patent/ZA200303338B/en unknown
- 2003-05-27 BG BG107852A patent/BG107852A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2427762C (en) | 2009-10-20 |
| CN1481384A (en) | 2004-03-10 |
| CN100445284C (en) | 2008-12-24 |
| EA200300520A1 (en) | 2003-10-30 |
| EP1334105B1 (en) | 2006-04-05 |
| EE200300206A (en) | 2003-10-15 |
| JP2004525084A (en) | 2004-08-19 |
| ZA200303338B (en) | 2004-03-09 |
| US20040054167A1 (en) | 2004-03-18 |
| PT1334105E (en) | 2006-08-31 |
| DE60118593D1 (en) | 2006-05-18 |
| MXPA03003916A (en) | 2004-01-29 |
| ES2261494T3 (en) | 2006-11-16 |
| EP1334105A1 (en) | 2003-08-13 |
| ATE322495T1 (en) | 2006-04-15 |
| KR20030059812A (en) | 2003-07-10 |
| BG107852A (en) | 2004-01-30 |
| EA006442B1 (en) | 2005-12-29 |
| US7078534B2 (en) | 2006-07-18 |
| CA2427762A1 (en) | 2002-05-10 |
| WO2002036594A1 (en) | 2002-05-10 |
| DK1334105T3 (en) | 2006-08-14 |
| IN191798B (en) | 2004-01-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1334105B1 (en) | Process for the preparation of crystalline n-formimidoyl thienamycin monohydrate (imipenem monohydrate) | |
| US20120095210A1 (en) | Process for the preparation of beta-lactam antibiotic | |
| CA2461565C (en) | Process for making carbapenem compounds | |
| AU2002341747A1 (en) | Process for making carbapenem compounds | |
| US20020095034A1 (en) | Imipenem production process | |
| US7241885B2 (en) | Process for the isolation of crystalline imipenem | |
| KR100667373B1 (en) | New manufacturing method of imipenem | |
| KR100286083B1 (en) | Process for the preparation of imipenem | |
| JP2003183282A (en) | Carbapenem compounds | |
| KR100848751B1 (en) | Method of making imipenem | |
| AU2002302887A1 (en) | Process for the isolation of crystalline imipenem |