AU6392196A - Improved process for synthesizing carbapenem intermediates - Google Patents
Improved process for synthesizing carbapenem intermediatesInfo
- Publication number
- AU6392196A AU6392196A AU63921/96A AU6392196A AU6392196A AU 6392196 A AU6392196 A AU 6392196A AU 63921/96 A AU63921/96 A AU 63921/96A AU 6392196 A AU6392196 A AU 6392196A AU 6392196 A AU6392196 A AU 6392196A
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- Prior art keywords
- compound
- formula
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- base
- reactive solvent
- Prior art date
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- Granted
Links
- 238000000034 method Methods 0.000 title claims description 28
- 230000008569 process Effects 0.000 title claims description 22
- 230000002194 synthesizing effect Effects 0.000 title claims description 10
- 239000000543 intermediate Substances 0.000 title description 18
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 8
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- -1 triethylsilyl Chemical group 0.000 claims description 7
- 229940011051 isopropyl acetate Drugs 0.000 claims description 6
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims 4
- 239000000243 solution Substances 0.000 description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 229940041011 carbapenems Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- HDKCVDHYIIKWFM-UHFFFAOYSA-K octanoate;rhodium(3+) Chemical compound [Rh+3].CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O HDKCVDHYIIKWFM-UHFFFAOYSA-K 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 150000008049 diazo compounds Chemical class 0.000 description 2
- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- UQSQSQZYBQSBJZ-UHFFFAOYSA-M fluorosulfonate Chemical compound [O-]S(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-M 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 2
- 229940102001 zinc bromide Drugs 0.000 description 2
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- YKMONJZIUAOVEM-WDSKDSINSA-N 1beta-methylcarbapenem Chemical compound C[C@H]1C=CN2C(=O)C[C@@H]12 YKMONJZIUAOVEM-WDSKDSINSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical group [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- MKDJIADBNUOBJH-UHFFFAOYSA-N octanoic acid;rhodium Chemical compound [Rh].[Rh].CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O MKDJIADBNUOBJH-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- CDXVUROVRIFQMV-UHFFFAOYSA-N oxo(diphenoxy)phosphanium Chemical compound C=1C=CC=CC=1O[P+](=O)OC1=CC=CC=C1 CDXVUROVRIFQMV-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- JQKHNBQZGUKYPX-UHFFFAOYSA-N tris(2,4,6-trimethoxyphenyl)phosphane Chemical compound COC1=CC(OC)=CC(OC)=C1P(C=1C(=CC(OC)=CC=1OC)OC)C1=C(OC)C=C(OC)C=C1OC JQKHNBQZGUKYPX-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
IMPROVED PROCESS FOR SYNTHESIZING CARBAPENEM INTERMEDIATES
BACKGROUND OF THE INVENTION
The present invention is related to an improved synthesis of carbapenem intermediates, and in particular, the following compounds:
wherein R represents hydrogen or methyl and P represents triethylsilyl or trimethylsilyl. Similar such intermediates have been used in the past to synthesize carbapenem antibiotics. However, to date, the synthesis pathway for these antibiotics has required the use of extremely unstable intermediates. Additionally, the syntheses disclosed in the past result in low yields and require numerous separation and purification steps. The intermediates for carbapenem antibiotics described herein are addressed in, e.g., U. S. Pat. No. 4,350,631 issued to Christensen, et aL on September 21 , 1982 and U. S. Pat. No. 4,994,568 issued to Christensen on February 19, 1991. In the process described in each of these patents, a diazo compound of the formula:
is cyclized using a catalyst or irradiation. This generates a mixture of 1-α and 1-β methyl isomers, which in turn requires separation prior to further chemical modification.
Lastly, many of the prior processes of synthesizing carbapenem antibiotics utilize an intermediate of the formula:
which has an active leaving group at position 2, namely the triflate. This compound is extremely unstable, and cannot be utilized in large scale synthesis with an acceptable level of efficiency. As such, one of the objectives of the present invention is to avoid this intermediate.
The present invention overcomes these disadvantages, providing a scheme which avoids unstable intermediates, and in many instances, producing intermediates which are in crystalline form, requiring little or no purification before futher use.
SUMMARY OF THE INVENTION
A process of synthesizing a compound of the formula:
B
is disclosed wherein R represents H or methyl and P represents triethylsilyl or trimethylsilyl. The process comprises treating a compound of the formula:
with P-Cl wherein P is as defined above, in the presence of base and a substantially non-reactive solvent to produce:
DETAILED DESCRIPTION OF THE INVENTION
The 1 -β methyl isomer of the diazo compound 1 and the bicyclic ketoester 2 (R = methyl) which are shown above are highly desired and useful as carbapenem intermediates, because 1-β methyl carbapenem antibiotics have a reduced tendency toward biological inactivation by the enzyme dehydropeptidase when administered to a mammalian patient to treat a bacterial infection. Generally, the 1 -β methyl isomer of the final product is more resistant to deactivation than the IH or the 1-α methyl isomer.
The bicyclic ketoester 2 can be further reacted at the 2- position to establish a leaving group, e.g., L, which represents diphenyl phosphate, triflate, tosylate, mesylate, fluorosulfonate, chloride and the like, to form the appropriate activated carbapenem intermediate. The
activated carbapenem intermediate is suitable for coupling to a substituent at position 2, for example, through the use of a palladium catalyst, e.g., Pd2(dba)3*CHCl3, and tris(2, 4, 6- trimethoxyphenyl)phosphine in a suitable solvent. Further details regarding coupling reactions can be obtained from U.S. Patent No. 5,034,384.
In one preferred embodiment of the invention, a compound of formula 3 wherein R represents H or methyl is reacted with P-Cl in the presence of base and a substantially non-reactive solvent to produce a compound of formula 1 :
In a more preferred embodiment of the invention, a compound of formula 3 is reacted with P-Cl wherein P represents triethylsilyl to produce a compound of formula la:
In another more preferred embodiment of the invention, a compound of formula 3 is reacted with P-Cl wherein P represents trimethylsilyl to produce a compound of formula lb:
In another preferred embodiment, a compound of formula 4 wherein R represents H or methyl, is reacted with P-Cl in the presence of base and a substantially non-reactive solvent to produce a compound of formula 2:
In another more preferred embodiment of the invention, a compound of formula 4 is reacted with P-Cl wherein P represents triethylsilyl to produce a compound of formula 2a:
In another more preferred embodiment of the invention, a compound of formula 4 is reacted with P-Cl wherein P represents trimethylsilyl to produce a compound of formula 2b:
2b CO PNB
In another preferred embodiment, the substituted azetidinone is cyclized before protection of the hydroxyethyl side chain. After cyclization, the side chain is protected with P.
As used herein, PNB refers to the protecting group para- nitrobenzyl.
The abbreviation THF refers to tetrahydrofuran.
The abbreviation OAc refers to acetate, CH3C(0)0-. Hence, the solvent ethyl acetate is abbreviated as EtOAc and isopropyl acetate is abbreviated iPrOAc. TES refers to the group triethylsilyl.
TMS refers to the group trimethylsilyl.
Et3N refers to triethylamine. dba refers to dibenzylideneacetone.
Generally, the objects of the present invention are to utilize crystalline intermediates and to avoid unstable intermediates. Additionally, stereospecificity and regiospecific reactions are favored. The following schemes are representative.
SCHEME 1
(Crystalline)
Cyclize B
(Crystalline)
C02PNB χ = |Θavjng group C02PNB (Stable)
Coupling Reaction 2-Substituted Carbapenems
SCHEME 2
B Cyclize
(Crystalline)
(Stable)
(Stable) C°2P N B
2-Substituted Carbapenems
The starting materials for schemes 1 and 2 can be obtained in accordance with U.S. Patent Nos. 4,454,332 (issued on June 12, 1984) and 4,312,871 (issued on January 26, 1982). For each of the schemes noted above, by reacting compound 3 or 4 with P-Cl in the presence of base, stable and even crystalline intermediates are realized. This is an unexpected and suφrising advantage over other processes of synthesizing carbapenems.
There are numerous methods of cyclizing the diazo intermediates noted above to produce the bicyclic ketoester 2 or 4. The preferred method of cyclization involves a reaction in the presence of a rhodium catalyst, such as rhodium acetate or rhodium octanoate. Likewise, when activating the bicyclic ketoester 2 at position two, the anhydride L2O or the halide L-Cl can be combined with the bicyclic ketoester in the presence of a nitrogen containing base and in a substantially non-reactive solvent to produce the activated carbapenem 5. The activated carbapenem 5, with the appropriate group L at position 2, can then be coupled to an appropriate substituent according to the procedures set forth in U. S. Pat. No. 5,034,384. Carbapenems which can be synthesized in accordance with the process described herein are disclosed, and the groups which are appropriate for such attachment, can be found, e.g., in U.S. Pat. No. 5,034,384. The preferred substantially non-reactive solvents used herein are dimethylformamide, tetrahydrofuran (THF), isopropyl acetate, ethyl acetate and methylene chloride. Most preferably, mixtures thereof are used.
The preferred base used in the processes described herein is imidazole.
The nitrogen containing bases for use in the activating reaction with L2O or L-Cl include triethylamine, diisopropylethylamine and diisopropylamine.
Preferred values for L include the sulfonate leaving groups, such as trifluoromethanesulfonate (triflate), methanesulfonate (mesylate), toluenesulfonate (tosylate) and fluorosulfonate, the phosphonic acid residues, such as diphenylphosphonate and the halide leaving groups, such as chloride, bromide or iodide. Most preferred are triflate (OTf), flurorosulfonate (OSO2F), mesylate (OMs), diphenyl phosphate and tosylate (OTs).
EXAMPLE ONE
Compound Ja (7.8 g.) and imidazole (3.4 g.) are dissolved in ethyl acetate (70 mL, sieve dried) and the solution is stirred for 10 min. at room temperature. The solution is cooled and trimethylsilyl chloride (3.57 mL) is added while maintaining the temperature at -10 to -1 °C. A white-yellow suspension formed.
The suspension is allowed to warm to room temperature and stirred at room temperature for 1.5 hrs. Pour into phosphate buffer (0.0 IM, 80 mL, pH 6.8). Separate phases and wash the organic phase with aq. NaHCθ3 solution (saturated, 40 mL). Dry over Na2Sθ4. Filter and evaporate the filtrate to dryness. Load the filtrate onto a flash silica column (40 cm diam x 180 cm high), packed in 30% EtOAc and hexane (+ 0.025% E13N). Fractions 18 - 55 contained compound lc
EXAMPLE TWO
A 250 mL 3 -neck flask equipped with a N2 inlet, a thermocouple probe, and a dropping funnel was charged with THF (20 mL; KF < 80 μg/mL), isopropy lacetate (IPAC; 90 mL; KF < 80 μg/mL), compound 3α (15 g; 38.4 mmol) and imidazole (4.7 g; 69.0 mmol). The slurry was stirred at room temperature for 10 minutes until dissolution
was complete (KF < 140 μg/mL). The solution was maintained at 18-22
°C as TESC1 (9.0 mL; 53.6 mmol) was added slowly over 100 minutes.
After the addition was completed, the batch was aged at 20 °C for 2 hr.
The reaction mixture was assayed by HPLC. The starting material should be less than 0.15 area % at 245 nm.
Reaction mixture was quenched into a mixture of heptanes
(30 mL) and 0.01 M phosphate buffer (100 mL; pH 6.8) at room temperature. After 30 minutes of stirring at room temperature, the organic layer was separated. The organic layer was washed twice with 0.01 M phosphate buffer (pH 6.8; 100 mL each).
The organic layer was concentrated to about 35 mL at 18 -
20°C/1 10 - 80 mm Hg (GC showed 6.3 v/v % heptanes). Heptanes (30 mL) was slowly added during further concentration at 18 - 20°C/1 10 - 80 mm Hg keeping the volume at about 40 mL. After crystallization took place, additional heptane (90 mL) was added slowly at room temperature and the suspension was aged at
20°C for 1 hr then 0°C for 1 hr.
The crystals were filtered and washed (slurry then displacement) with a mixture of IPAC and heptane (3 : 97 v/v; lOOmL), and then dried under a nitrogen stream. The product (18 g; 93 % yield;
99.6 area %.) was obtained as a white crystalline solid.
EXAMPLE THREE
Starting from compound 3b, using the procedure set forth in Example One, compound le is obtained.
EXAMPLE FOUR
To a solution of 3b (245 mg) in a mixture of THF ( 1 mL) and EtOAc (2 mL) was added imidazole (80 mg) and TESCl (0.15 mL) at room temperature. After stirring for 2 hrs, the reaction mixture was diluted with hexanes (3 mL) and washed with phosphate buffer (pH 7.0; 6 mL) twice. The organic layer was dried over MgS04 and concentrated to give crude If, which was further purified by silica gel column chromatography using a mixture of hexanes and EtOAc (3 : 2 to 1 : 1 ) to give pure 7/(310 mg).
EXAMPLE FIVE
Compound Id (16.0 kg), rhodium octanoate (0.123 kg), anhydrous zinc bromide (71 g), and dry dichloromethane (63.42 L; KF < lOOμg/mL) are charged to a dry reactor. The solution is deoxygenated with three vacuum/nitrogen-fill cycles, then heated to reflux under nitrogen for 90 min to give a solution of Compound 2d.
EXAMPLE SIX
Starting from compound lc, using the procedure set forth in
Example Five, compound 2c is obtained.
EXAMPLE SEVEN
OoPNB
TESCl Imidazole
A solution of Compound 3α (1.1 g) in methylene chloride (4 mL) was heated under reflux with zinc bromide (10 mg) and rhodium octanate (10 mg) for 4 hours. The solution containing Compound 4α was cooled down to -78 °C. To this solution was added a mixture of triethylsilyl chloride (0.65 mL) and imidazole (285 mg) at -78 °C. After aged for 1 hr at -78 °C. The reaction mixture was slowly warmed up to 0
°C. From NMR and HPLC analysis, the solution contained mainly Compound 2d.
EXAMPLE EIGHT
A solution of If (291 mg) in methylene chloride (5 mL) is heated with 10 mg of rhodium octanoate dimer at 30°C for 3 hrs. The reaction mixture was concentrated under reduced pressure to give crude 2f (260 mg).
EXAMPLE NINE
Starting from compound le, using the procedure set forth in Example Eight, the TMS protected intermediate 2e is obtained.
EXAMPLE TEN
To a solution of 4α (0.97 g) and imidazole (343 mg) in a mixture of THF (5 mL) and EtOAc (5 mL) was slowly added TESCl (0.66 mL) at room temperature. After stirring for 2 hrs, the reaction mixture was diluted with 10 mL of EtOAc and washed with phosphate buffer (pH 7.0; 15 mL) twice. The organic layer was dried over MgS04, concentrated under reduced pressure to give crude 2f (1.235 g).
Claims (13)
- WHAT IS CLAIMED IS:A process of synthesizing a compound of the formula:COoPN Bwherein R represents H or methyl and P represents triethylsilyl or trimethylsilyl comprising treating a compound of the formula:Bwith P-Cl wherein P is as defined above, in the presence of base and a substantially non-reactive solvent to produce:B
- 2. A process of synthesizing a compound of the formula:wherein R represents H or methyl, comprising treating a compound of the formula:with triethylsilyl chloride in the presence of base and a substantially non¬ reactive solvent to produce
- 3. A process in accordance with claim 1 wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.
- 4. A process in accordance with claim 3 wherein the base is imidazole.
- A process of synthesizing a compound of the formula:Bwherein R represents H or methyl, comprising treating a compound of the formula:Bwith triethylsilyl chloride in the presence of a nitrogen containing base and a substantially non-reactive solvent to produce:B
- 6. A process in accordance with claim 5 wherein the substantially non -reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.
- 7. A process in accordance with claim 6 wherein the base is imidazole.
- 8. A process of synthesizing a compound of the formula:wherein R represents H or methyl, comprising treating a compound of the formula:with trimethylsilyl chloride in the presence of base and a substantially non-reactive solvent to produce
- 9. A process in accordance with claim 8 wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.
- 10. A process in accordance with claim 9 wherein the base is imidazole.
- 1 1. A process of synthesizing a compound of the formula:wherein R represents H or methyl, comprising treating a compound of the formula:with trimethylsilyl chloride in the presence of base and a substantially non-reactive solvent to produce:COoPNB
- 12. A process in accordance with claim 11 wherein the substantially non-reactive solvent is dimethylformamide, tetrahydrofuran, isopropyl acetate, ethyl acetate or methylene chloride.
- 13. A process in accordance with claim 12 wherein the base is imidazole.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US58595P | 1995-06-28 | 1995-06-28 | |
US000585 | 1995-06-28 | ||
GB9602921 | 1996-02-13 | ||
GBGB9602921.0A GB9602921D0 (en) | 1996-02-13 | 1996-02-13 | Improved process for synthesizing carbapenem intermediates |
PCT/US1996/010783 WO1997001564A1 (en) | 1995-06-28 | 1996-06-24 | Improved process for synthesizing carbapenem intermediates |
Publications (2)
Publication Number | Publication Date |
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AU6392196A true AU6392196A (en) | 1997-01-30 |
AU696543B2 AU696543B2 (en) | 1998-09-10 |
Family
ID=26308678
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Application Number | Title | Priority Date | Filing Date |
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AU63921/96A Ceased AU696543B2 (en) | 1995-06-28 | 1996-06-24 | Improved process for synthesizing carbapenem intermediates |
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EP (1) | EP0836607A1 (en) |
JP (1) | JPH11513979A (en) |
KR (1) | KR19990028406A (en) |
CN (1) | CN1193322A (en) |
AR (1) | AR002507A1 (en) |
AU (1) | AU696543B2 (en) |
BR (1) | BR9609338A (en) |
CA (1) | CA2224439A1 (en) |
CZ (1) | CZ419097A3 (en) |
EA (1) | EA199800096A1 (en) |
HU (1) | HUP9903016A3 (en) |
SK (1) | SK176597A3 (en) |
WO (1) | WO1997001564A1 (en) |
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US8841444B2 (en) | 2008-07-30 | 2014-09-23 | Ranbaxy Laboratories Limited | Process for the preparation of carbapenem compounds |
WO2011048583A1 (en) | 2009-10-23 | 2011-04-28 | Ranbaxy Laboratories Limited | Process for the preparation of carbapenem compounds |
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Publication number | Priority date | Publication date | Assignee | Title |
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US4683301A (en) * | 1982-04-08 | 1987-07-28 | Bristol-Myers Company | Carbapenem antibiotics |
JP2675625B2 (en) * | 1989-01-12 | 1997-11-12 | 鐘淵化学工業株式会社 | Method for producing enol silyl ether compound |
NZ234411A (en) * | 1989-07-18 | 1991-05-28 | Merck & Co Inc | Preparation of 2-diazo-3-silyloxy-3-butenoate esters |
DE3934100A1 (en) * | 1989-10-12 | 1991-04-18 | Bayer Ag | METHOD FOR PRODUCING 0-SILYLATED HYDROXYL COMPOUNDS AND THE USE THEREOF FOR PRODUCING ISOCYANATES HAVING ESTER GROUPS |
-
1996
- 1996-06-18 AR ARP960103190A patent/AR002507A1/en unknown
- 1996-06-24 AU AU63921/96A patent/AU696543B2/en not_active Ceased
- 1996-06-24 CA CA002224439A patent/CA2224439A1/en not_active Abandoned
- 1996-06-24 CZ CZ974190A patent/CZ419097A3/en unknown
- 1996-06-24 BR BR9609338A patent/BR9609338A/en unknown
- 1996-06-24 HU HU9903016A patent/HUP9903016A3/en unknown
- 1996-06-24 KR KR1019970709722A patent/KR19990028406A/en not_active Application Discontinuation
- 1996-06-24 SK SK1765-97A patent/SK176597A3/en unknown
- 1996-06-24 EP EP96923404A patent/EP0836607A1/en not_active Withdrawn
- 1996-06-24 CN CN96196325A patent/CN1193322A/en active Pending
- 1996-06-24 WO PCT/US1996/010783 patent/WO1997001564A1/en not_active Application Discontinuation
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CN1193322A (en) | 1998-09-16 |
MX9800041A (en) | 1998-08-30 |
SK176597A3 (en) | 1998-07-08 |
HUP9903016A2 (en) | 2000-03-28 |
KR19990028406A (en) | 1999-04-15 |
AR002507A1 (en) | 1998-03-25 |
CZ419097A3 (en) | 1998-07-15 |
EA199800096A1 (en) | 1998-08-27 |
JPH11513979A (en) | 1999-11-30 |
WO1997001564A1 (en) | 1997-01-16 |
AU696543B2 (en) | 1998-09-10 |
CA2224439A1 (en) | 1997-01-16 |
EP0836607A1 (en) | 1998-04-22 |
HUP9903016A3 (en) | 2000-04-28 |
BR9609338A (en) | 1999-05-11 |
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