GB2114132A - Azetidinone derivatives - Google Patents
Azetidinone derivatives Download PDFInfo
- Publication number
- GB2114132A GB2114132A GB08224128A GB8224128A GB2114132A GB 2114132 A GB2114132 A GB 2114132A GB 08224128 A GB08224128 A GB 08224128A GB 8224128 A GB8224128 A GB 8224128A GB 2114132 A GB2114132 A GB 2114132A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- general formula
- substituent
- acetoxymethyl
- carried out
- 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.)
- Granted
Links
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title claims abstract description 15
- -1 5- methyl-1,3,4-thiadiazol-2-yl Chemical group 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 59
- 238000000034 method Methods 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000741 silica gel Substances 0.000 claims description 10
- 229910002027 silica gel Inorganic materials 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000005949 ozonolysis reaction Methods 0.000 claims description 5
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000006317 isomerization reaction Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- 125000001506 1,2,3-triazol-5-yl group Chemical group [H]N1N=NC([H])=C1[*] 0.000 abstract description 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 abstract description 2
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 abstract description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 2
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 abstract description 2
- 125000006502 nitrobenzyl group Chemical group 0.000 abstract description 2
- 125000006501 nitrophenyl group Chemical group 0.000 abstract description 2
- 125000005633 phthalidyl group Chemical group 0.000 abstract description 2
- 125000003373 pyrazinyl group Chemical group 0.000 abstract description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 235000019256 formaldehyde Nutrition 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 3
- DIOVBHTUHUUROP-UHFFFAOYSA-N acetyloxymethyl 2-oxoacetate Chemical compound CC(=O)OCOC(=O)C=O DIOVBHTUHUUROP-UHFFFAOYSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 150000003952 β-lactams Chemical class 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- DJANLSNABDFZLA-RQJHMYQMSA-N methyl (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound S1C(C)(C)[C@H](C(=O)OC)N2C(=O)C[C@H]21 DJANLSNABDFZLA-RQJHMYQMSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MHSGOABISYIYKP-UHFFFAOYSA-N (4-nitrophenyl)methyl carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(COC(Cl)=O)C=C1 MHSGOABISYIYKP-UHFFFAOYSA-N 0.000 description 1
- ARAIIFFPXFUMGY-AATRIKPKSA-N (E)-4-[(4-nitrophenyl)methoxy]-4-oxobut-2-enoic acid Chemical compound OC(=O)\C=C\C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 ARAIIFFPXFUMGY-AATRIKPKSA-N 0.000 description 1
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
- ZCUXPKHCTGPJBC-UHFFFAOYSA-N COC(=O)C(=C(C)C)N1CCC1=O Chemical compound COC(=O)C(=C(C)C)N1CCC1=O ZCUXPKHCTGPJBC-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- ISILWUCQPACDOX-UHFFFAOYSA-N acetyloxymethyl 2-(2-oxoazetidin-1-yl)-2-(triphenyl-lambda5-phosphanylidene)acetate Chemical compound C(C)(=O)OCOC(=O)C(=P(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1)N1C(CC1)=O ISILWUCQPACDOX-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000005055 short column chromatography Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/88—Compounds with a double bond between positions 2 and 3 and 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
-
- 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
- C07D205/09—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 with a sulfur atom directly attached in position 4
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/568—Four-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
<IMAGE> Azetidinones I (R'=H, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 hydroxyalkyl optionally protected by p.nitrobenzyloxycarbonyl; X=CH2Z or CH2Z'; Z=OH, NH2, NH2COO, OR1 or OCOR1; R1=C1-C4 alkyl; Z'=SH, pyridinium or SR3; R3=C1-C4 alkyl, 5- methyl-1,3,4-thiadiazol-2-yl, 1- methyl-1H-tetrazol-5-yl, 1,2,3-triazol- 5-yl or pyrazinyl; n=0 or 1; Ph=phenyl; R''=H, C1-C4 alkyl, 2,2,2- trichloroethyl, benzyl, acetonyl, p.nitrobenzyl, p.methoxybenzyl, phenyl, p.nitrophenyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl, phthalidyl, -CH(CH3).OCOOC2H5 or -CH2NHCOR2; R2=C1-C4 alkyl, cycloalkyl, aryl; Y=H, C1-C4 alkyl, CN alkoxycarbonyl or CH2Z) are useful as intermediates in the preparation of penem-carboxylic acids and esters, see British Patent Specification No. 2043639
Description
SPECIFICATION
Azetidinone derivatives
The invention relates to azetidinone derivatives and to processes for their preparation.
The invention provides azetidinone derivatives of the general formula I
wherein n is O or 1, Ph represents a phenyl group, R" represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, a 2,2,2-trichloroethyl, benzyl, acetonyl, p.nitrobenzyl, p.methoxybenzyl, phenyl, p.nitrophenyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl or phthalidyl group or a group of the formula -CH(CH3) . OCOOC2Hs or -CK2NHCOR2 wherein R2 represents an alkyl group having from 1 to 4 carbon atoms or a cycloalkyl or aryl group;X represents a group of the formula CH2Z or CH2Z' wherein Z represents a hydroxy, amino or carbamoyloxy group, or a group of the formula OR, or OCOR, wherein R, represents an alkyl group having from 1 to 4 carbon atoms and Z' represents a mercapto or pyridinium group or a group of the formula SR3 wherein
R3 represents an alkyl group having from 1 to 4 carbon atoms or a 5-methyl-i ,3,4-thiadiazol-2-yl, 1methyl1 H-tetrazol-5-yl, 1 ,2,3-triazol-5-yl or pyrazinyl group; Y represents a hydrogen atom, a lower alkyl, cyano or alkoxycarbonyl group or a group of the formula CH2Z in which Z is as above defined; and R' represents a hydrogen atom or an alkyl, alkoxy, or hydroxyalkyl group, each of which has from 1 to 4 carbon atoms, the alcoholic function of the hydroxyalkyl group being free or protected by a p.nitrobenzyloxycarbonyl group.The 3-substituent may have the - or p-configuration.
3a-substitution is preferred.
Preferred groups which R' may represent are methyl, ethyl, methoxy, 1 -hydroxy-ethyl and 1 (p.nitrobenzyloxycarbonyloxy)-ethyl groups.
The azetidinone derivatives according to the invention are useful as intermediates in the preparation of certain penem-carboxylic acids and esters which have a wide spectrum of antibacterial activity as well as p-lactamase inhibiting activity (see British Patent Specification No. 2043639, from which this Application is divided). It should be pointed out that the stereochemistry at C4 of the compounds according to the invention, as well as that of all the intermediates of their preparation, is the same as in naturally occurring penicillins and cephalosporins.
The invention further provides a process for the preparation of compounds of the general formula
I in which n, R' and R", Y and Ph are as above defined and X represents a group of the formula CH2Z in which Z is as above defined. Such compounds of the general formula I are hereinafter referred to as compounds of the formula (9). The process is illustrated by the following reaction scheme, in which R',
R", Y, Ph, Z and n are as above defined and R represents an alkyl group.
The process comprises condensing, in an inert solvent at elevated temperature, a penicillanic acid
S-oxide ester of the general formula (2) with an acetylenic compound of the general formula ZCH2C=-CY, isomerising the resultant compound of the general formula (3), preferably in basic conditions, and converting the resultant azetidinone derivative of the general formula (4) into one of the general formula (9) by the steps of
(a) ozonolysis of the 1 -substituent of the formula
in solution at reduced temperature, (b) removal of the 1-subsituent of the formula
resulting from step (a) by mild alkaline hydrolysis or by the action of silica gel,
(c) condensation of the 1-unsubstituted azetidinone resulting from step (b) with a glyoxylate of the formula CHO .COOR" by refluxing in a solvent,
(d) chlorination of the 1-substituent of the formula
introduced in step (c) by the action of a chlorinating agent, and
(e) conversion of the 1-substituent of the formula
introduced in step (d) into one of the formula
by reaction with triphenylphosphine, the steps (a) to (e) being carried out in the order given, and the optional step of
(f) reduction of the 4P-(substituted vinylsulphinyl) group by the action of a reducing agent, the step (f) being carried out (if at all) immediately after step (a) or step (e), and if carried out after step (e) then being carried out in acidic conditions.
The reaction sequence (a), (b), (c), (d), (e), (f) is possible when Y is not a strong electron withdrawing group. Then the compound (6, n=1) is surprisingly stable.
The optional reduction step (f) may be carried out using phosphorus tribromide or sodium iodide in 8ethyl chloride as reducing agent.
When R' represents a hydroxyalkyl group in the desired compound of the general formula I, the reaction sequence is preferably carried out with the alcoholic function protected.
Compounds of the general formula I in which R" represents a hydrogen atom can be obtained by hydrolysis of hydrogenolysis of corresponding esterified compounds.
The preparation of compounds of the general formula I in which n, R',R", Y and Ph are as herein defined and X represents a group of the formula CH2Z' in which Z' is as above defined is carried out according to the above process with the additional step of converting the substituent Z into a substituent of Z'. The additional step may be carried out at any stage in the above process after the condensation of the penicillanic acid S-oxide ester (2) with the acetylenic compound ZCH2C=-CY, and is necessary because of the difficulty of condensing the penicillanic acid S-oxide ester (2) directly with an acetylenic compound HSCH2-C=-CY, R,SCH2C=CY or PyCH2-C=-CY in which Py represents a pyridinium ion. This process is also within the scope of the invention.
The starting materials of the general formula (2) in which R' represents a hydrogen atom may be prepared from (5R)-6-aminopenicillanic acid following known procedures (see Cignarella et al., Journal of Organic Chemistry, 27,2668 and Evrard et al., Nature, 201, 1124).
When R' represents an alkyl or hydroxyalkyl group, it can be introduced according to the procedure of Di Ninno et al., Journal of Organic Chemistry 42, 2960 (1 977). When R' represents an alkoxy group, it may be introduced according to the procedures of Hauser et al., Helv. Chem. Acta, 50, 1327 (1967) and Giddings et al., Tetrahedron Letters, 11, 995, (1978). Alternatively compounds of general formula (2) in which R' represents a hydrogen atom can be converted to compounds of the general formula (2) in which R' represents an alkyl or hydroxyalkyl group by introducing the substituent into the 6-position using a strong base, as illustrated in the following Examples.Compounds of the general formula (2) in which R' represents an alkyl or hydroxyalkyl group can also be prepared starting from a suitable ester of penicillanic acid S-oxide, as illustrated in the following Examples. The substitution at the 3-position is stereospecifically directed to the 3-derivatives.
The following Examples illustrate the invention.
Example 1 4p-(1 -acetoxymethyl-3-acetoxy-1 -propenylsulphinyl)-1 -(1 -methoxycarbonyl-2-methyl-allyl)azetidin-2-one
(3): R=CH3; R'=H, Y=CH2O . CO . CH3, Z=OCOCH3
A solution of 2.0 g of methyl penicillanate S-oxide and 2.8 g of butyndiol diacetate in 40 ml of toluene was refluxed for 24 hours. 1.4 g of the title compound was obtained after purification by column chromatosraphy on silica gel eluting with 96:4 by volume dichloromethane:ethyl acetate.
PMR (CDCl3): 2.03 a
2.15 and 2.20 a (two s,2 CH3CO), 2.88 6 (dd, Jgem=14 Hz, Jvic cis=4 Hz, C-3-Ha), 3.38 a (dd, Jgem=1 4 Hz, Jvic trans=2 Hz, C-3-Hp),3.83 a (s, CH3O), 4.88 a (d, Jvic=6 Hz,
4.92 a (broad s, CH2-C=), 4.93-5.33 a (m, =CH2 and
5.32 a (dd, Jvic=4 and 2 Hz, C-4-H), 6.47 8 (t, Jvic=6 Hz,
Example 2 4p-(1 -acetoxymethyl-3-acetoxy.1 -propenylsulphinyl)-1 -(1 -methoxycarbonyl-2-methyl-1 - propenyl)-azetidin-2-one
(4): R=CH3, R'=H, Y=CH2O . CO . CH3, Z=OCOCH3
1.7 g of the compound prepared in Example 1 were dissolved in 80 ml of dichloromethane. 0.5 ml of triethylamine were added and the solution was left for a few hours at room temperature. After evaporating off the solvent, the title compound was obtained in pure form in quantitative yield.
PMR (CDCl3): 2.13 (9H) and 2.32 (3H) 8 (two s,2 CHO and 2 CH3-6=), 2.928 (dd, Jgem=1 5 Hz, Jvic cis=5 Hz, C-3-Ha), 3.38 8 (dd, Jgem=1 5 Hz, Jvic trans=2.5 Hz, C3-HP), 3.82 8 (s,
CH3O) 4.88 8 (d, Jvic=6.5 Hz,
4.92 S (s, CH2-C=), 5.1 5 S (dd, Jvic=5 and 2.5 Hz, C-4-H), 6.508 (t, Jvic 6.5 Hz,
Example 3 4p-( 1 -acetoxymethyl-3-acetoxy-1 -propenylsulphinyl)-1 -methoxyoxalyl-azetidin-2-one
(5): R=CH3, R'=H, Y=CH2O .CO . CH3, ,Z=OCOCH3, n=1
2.0 g of the compound prepared in Example 2 were dissolved in 1 50 ml of dichloromethane and, after cooling to -780C, a flow of ozone in oxygen was bubbled through the solution until a slightly blue colour appeared. The solution was raised to room temperature, shaken with an aqueous solution of sodium pyrosulphite and dried over anhydrous sodium sulphate. The resulting organic phase gave, after evaporation "in vacuo" of the solvent therefrom, 1.4 g of the title compound.
PMR (CDCl3): 2.05 and 2.08 S (two s, 2CH3CO), 3.03 8 (dd, Jgem=1 7 Hz, Jvic cis=5.5 Hz, C-3
Ha), 3.508 (dd, Jgem=1 7 Hz, Jvic trans=3 Hz, C-3-Hp), 3.90 8 (s, CH3O), 4.82 (d,
Jvic=6.5Hz,
4.90 8 (s, CH2-C=), 5.32 8 (dd, Jvic=5.5 and 3 Hz, C-4-H), 6.47 8 (t, Jvic=6.5 Hz,
IR (CH2CI2): 1830 cm-' ss-lactam C=O 1750 cm-l esters C=O
1715 cm-l amide C=O
Example 4 4ss-(1 -acetoxymethyl-3-acetoxy- 1 -propenylthio)-1 -methoxy-oxa lyl-azetidi n-2-one (5):R=CH3, R'=H, Y=CH2O . CO . CH3, Z=OCOCH3, n=O
A solution of 1.4 g of the compound prepared in Example 3 in 10 ml of anhydrous dimethylformamide was cooled to --25 C and 0.9 ml of phosphorus tribromide were added. After 10 minutes the mixture was diluted with ethyl acetate and washed twice with a saturated solution of sodium bicarbonate. After drying the solution over anhydrous sodium sulphate and evaporating the solvent therefrom, 0.9 g of the title compound were obtained.
PMR (CDCl3): 2.07 S (s, 2CH3CO), 3.17 8 (dd, Jgem=1 9 Hz, Jvic trans=3.5 Hz, C-3-H), 3.65 8 (dd, Jgem=1 9 Hz, Jvic cis=5 Hz, C-3-Ha), 3.90 8 (s, CH3O), 4.73 8 (d, Jvic=6.5 Hz,
4.88 8 (broad s, CH2-0=), 5.52 S (dd, Jvic=5 and 3.5 Hz, C-4-H), 6.25 8 (t, Jvic=6.5 Hz,
IR (CHCl3): 1815 cm-' ss-lactam C=O
1745 cm-' esters C=O
1710cm-1 amide C=O
Example 5 4ss-(1 -acetoxymethyl-3-acetoxy-1 -propenylth io)-azetidin-2-one
(6):R'=H, Y=CH2O. CO . CH3, Z=OCOCH3, n=O
1.5 g of the compound prepared in Example 4 were dissolved in 100 ml of methanol and a few grams of silica gel were added under stirring. After one hour the silica gel was filtered off and the methanolic solution evaporated to give 0.8 g of the title compound.
PMR (CDCl3): 2.25 8 (s, 2CH3CO), 2.98 8 (dd, Jgem=1 5 Hz, Jvic trans=2 Hz, C-3-Hss),3.48 8 (dd, Jgem=1 5 Hz, Jvic cis=4.5 Hz, C-3-Ha), 4.78 8 (d, Jvic=7 Hz,
4.87 (s, CH2-C=), 5.03 8 (dd, Jvic=4.5 and 2 Hz, C-4-H), 6.02 S (t, Jvic=7 Hz,
7.13 S (broad, N-H).
IR (CHCl3): 1770 cm-1 ss-lactam C=O 1740 cm-' esters C=O.
Example 6 4p -ecetoxymethyl-3-acetoxy-l -propenylsulphinyl)-acetidin-2-one (6): R'=H, Y=CH2O. CO . CH3, Z=OCOCH3, n=1
0.800 g of the compound prepared in Example 3 were dissolved in 80 ml of methanol and a few grams of silica gel were added under stirring. After one hour the silica gel was filtered off and the solvent was evaporated off. 0.5 of the title compound were obtained.
PMR (CDCl3): 2.138(s, 2CH3CO),3.0-3.38 (m, 2 protons at C-3), 4.70# (m, C-4-H), 4.888 (d,
Jvic=6 Hz,
4.93 8 (s, CH2-C=), 6.53 8 (t, Jvic=6 Hz,
7.23 8 (s, NH).
IR (CHCl3): 1790 cm-1 p-lactam C=O 1745 cm-' esters C=O.
Example 7 4l3-(1 -acetoxymethyl-3-acetoxy-1 -propenylthio)-1 1 -acetoxymethoxycarbonyl- -hydroxymethyl)-azetidin-2-one
(7): R'=H, R"=Y=CH2O. CO. CH3, Z=OCOCH3, n=O 0.7 g of acetoxymethyl glyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate) were dissolved in 30 ml of benzene and the resulting solution was refluxed for 20 minutes through a
Dean-Stark apparatus. After cooling to 500--60 C, 0.7 g of the compound prepared in Example 5 dissolved in 10 ml of benzene were added and the resulting solution was refluxed for 2 hours. The title compound was obtained in almost quantitative yield and can be used as crude mixture for the next step. A pure sample was obtained by preparative TLC, for analytical purposes.
PMR (CDCl3): 2.07 S (5, 3CH3CO), 2.97 8 (dd, Jgem=1 8 Hz, Jvic trans=2 Hz, C-3-H), 3.40 S (dd, Jgem=1 8 Hz, Jvic cis=4 Hz, C-3-Ha), 4.70 8 (d, Jvic=6 Hz,
4.77 S (s, CH2-C=), 5.0-5.48 (m, C-4-H) and
5.77 a (s, -COO-CH2-OCO-), 6.12 8 (t, Jvic=6 Hz,
Example 8 4ss-(1 -acetoxymethyl-3-acetoxy-l -propenylthio)-1 1 -acetoxy-methoxycarbonyl)-l -chloromethyl)-azetidin-2-one
(8):R'=H, R"=Y=CH,O;-O . CH3, Z=OCOCH3, n=O
0.6 g of the compound prepared in Example 7 dissolved in 1 5 ml of tetrahydrofuran were cooled to 0 C.0.115 ml of pyridine and 0.104 ml of thionyl chloride were added and the mixture was left under stirring for 10 minutes. The insoluble material was filtered off and the solution was evaporated "in vacuo" at room temperature to give the title compound in high yield. A sample was purified on preparative TLC for analytical purposes, but the crude mixture can be used without purification for the next step.
PMR (CDCl3): 2.14# (s, 3CH3CO), 3.108 (dd, Jgem=1 5.5 Hz, Jvic trans=2 Hz, C-3-H), 3.558 (dd, Jgem=1 5.5 Hz, Jvic cis=5 Hz, C-3-Ha), 4.77 8 (d, Jvic=6.5 Hz,
4.83 8 (s, CH2-C=), 5.4-5.9 8 (m, C-4-H) and -N-CHCI-COO-), 5.88 S (s-COO- CH2-OCO-), 6.13 8 (t, Jvic=6.5 Hz,
Example 9 4ss-(1 -acetoxymethyl-3-acetoxy-1 -propenylthio)-1-(1 -acetoxymethoxycarbonyl-1 -triphenylphosphoranylidenemethyl)azetidin-2-one
(9): R'=H, R"=X=Y=CH20 . CO .CH3, Z=OCOCH3, n=O
A solution of 0.430 g of the compound prepared in Example 8 in 5 ml of tetrahydrofuran and 5 ml of dioxan containing 0.520 g of triphenylphosphine and 0.08 ml of pyridine was stirred overnight at 500 C. The resulting phosphorane was purified by column chromatography on silica gel eluting with 70:30 by volume dichloromethane:ethyl acetate. 0.400 g of the title compound was obtained.
PMR (CDCl3): 2.05 S (s, 3CH3CO), 4.70 S (d, Jvic=6.5 Hz,
4.73 8 (s, CH2-C=), 5.77 8 (s, -COOH2-OCO-), 5.90 S (t, Jvic=6.5 Hz,
7.1-8.0# (m, 3C6H5).
Example 10 4P'-(1 -acetoxymethyl-3-acetoxy-1 -propenylthio)-1-(1 -p.nitrobenzyloxycarbonyl-l -hydroxymethyl)-azetidin-2-one
(7): R'=H, R"=p.NO2. C6H4. CH2, Y=CH2O . CO . CH3, Z=OCOCH3, n=O
The title compound was obtained following the procedure described in Example 7, using pnitrobenzyl glyoxylate (freshly prepared by ozonolysis of p-nitrobenzyl fumarate) instead of acetoxymethyl glyoxylate. Quantitative yield.
PMR (CDCl3) 8:2.1(s, 6H, 2.8-3.7 (m, 2H); 4.7 4.9 (m, 5H); 5.1-5.6 (m, 2H); 5.2 (m, 1 H);
6.1 (m, 1 H); 7.5-8.3 (m, 4H).
Example 11 4P-(1 -acetoxymethyl-3-acetoxy-1 -propenylthio)-1-(1 -p.nitrobenzyloxycarbonyl-l -chloromethyl)-azetidin-2-one
(8): R'=H, R"=p.NO2 . C. H4. CH2, Y=CH2O . CO. CH3, Z=OCOCH3,n=O The title compound was obtained following the procedure described in Example 8, but using the compound prepared in Example 10 instead of that prepared in Example 7.
PMR (CDCl3) S: 2.1 (s, 6H 2.8-3.7 (m, 2H); 4.7--4.9 (m, 4H); 5.2-5.4 (m, 1 H); 5.4 (m, 2H); 6.1-6.3 (m, 2H); 7.5-8.4 (m, 4H).
Example 12 4P-(1 -acetoxymethyl-3-acetoxy-l -propenylthio)-1-(1 -p.nitrobenzyloxycarbonyl-l -triphenyl phosphoranylidenemethyl)-azetidin-2-one (9): R'=H, R"=p.NO2C6H4. CH2, Y=CH2. O. CO . OH3, Z=OCOCH3, n=O
The title compound was obtained following the procedure described in Example 9, but using the compound prepared in Example 11 instead of that prepared in Example 8.
Example 13 methyl 6-(1 -hydroxyethyl)-3-penicillanate
To a solution of 2.2 g of methyl penicillanate in 30 ml of anhydrous tetrahydrofuran, a slight excess of lithium diisopropylamide was added at -780C under nitrogen. An excess of acetaldehyde was dropped in and the mixture was stirred for 5 minutes. The reaction was then quenched with a trace of acetic acid; the mixture was poured into water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulphate and evaporated "in vacuo" to give 0.8 g of the title compound.
Example 14 methyl 6-( I -p-nitrnbenzyloxycarbonyloxyethyl)-3-penicillanate 1.2 g of methyl 6-(1 -hydroxyethyl)-3-penicillanate, prepared as described in Example 13, were dissolved in 40 ml of tetrahydrofuran cooled two 7800 and treated with one equivalent of butyl lithium.
1.2 equivalents of p-nitrobenzyloxycarbonyl chloride were added to the mixture. After 30 minutes at --78 C, the reaction mixture was left at room temperature for 60 minutes, poured into water and extracted with dichloromethane. 1.4 g of the title compound were obtained after drying over anhydrous sodium sulphate and evaporating off the solvent.
Example 15 methyl 6-( I -p-nitrobenzyloxycarbonyloxyethyl-3-penicillanate-S-oxide (2): R=CH3,
1.8 g of methyl 6-[1-p-nitrobenzyloxycarbonyloxyethyl]-3-penicillanate, prepared as described in
Example 14, were dissolved in 50 ml of dichloromethane and treated at OOC with 1.5 equivalents of mchloroperbenzoic acid. The organic phase was shaken with a saturated solution of sodium bicarbonate, extracted, dried over anhydrous sodium sulphate and evaporated: 1.4 g of the expected sulphoxide were obtained.
Example 16 4p-(1 -acetoxymethyl-3-acetoxy-1 -propenylsulphinyl)-3-(1 -p-nitrobenzyloxycarbonyloxyethyl)-1 (1 -methoxycarbonyl-2-methyl-allyl)-acetidin-2-one
A solution of 2.0 g of the compound prepared in Example 1 5 and 2.4 g of butyndiol diacetate in 50 ml of toluene was refluxed for 24 hours. The trapped compound was then purified by silica gel column chromatographyeluting with 9:1 by volume dichloromethane:ethyl acetate. 1.1 g of the title compound were obtained.
Example 17 4P-(1 -acetoxymethyl-3-acetoxy-1 -propenylsulphinyl )-3-(1 -p-nitrobenzyloxycarbonyloxyethyl )-1 (1 -methoxycarbonyl-2-methyl-1 -propenyl)-azetidin-2-one
1.3 g of the compound prepared in Example 1 6 were dissolved in 80 ml of dichloromethane. 0.3 ml of triethylamine were added and the mixture was left at room temperature for 2 hours. The title compound was obtained in pure form in quantitative yield by evaporating off the solvent.
Example 18 4p-(1 -acetoxymethyl-3-acetoxy-1 -propenylsulphinyl)-3-(1 -p-nitrobenzyloxycarbonyloxyethyl)-1 methoxyoxalyl-azetidin-2-one
A solution of 1.1 g of the compound prepared in Example 17 in 100 ml of dichloromethane was cooled to --780C. Ozone in oxygen was then bubbled through the solution until a blue colour appeared.
The solution was shaken with an aqueous solution of sodium pyrosulphite and dried over anhydrous sodium sulphate. 0.5 g of the title compound were obtained after evaporation off of the solvent.
Example 19 4ss-(1 -acetoxymethyl-3-acetoxy-1 -propenylthio)-3-(l -p-nitrobenzyloxycarbonyloxyethyl)-1 methoxyoxalyl-azetidin-2-one
A solution of 0.8 g of the compound prepared in Example 18 in 1 5 ml of anhydrous dimethylformamide was cooled to --200C and 0.6 ml of phosphorus tribromide were added. The reaction mixture was diluted with ethyl acetate after 10 minutes and washed twice with a solution of sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate and the solvent was then evaporated off giving 0.4 g of the title compound.
Example 20 4p-(1 -acetoxymethyl-3-acetoxy-l -propenylthio)-3-(1 -p-nitrobenzyloxycarbonyloxyethyl)- azetidin-2-one
1.2 g of the compound prepared in Example 1 9 were dissolved in methanol and 2 g of silica gel were added to the solution. After 60 minutes the insoluble matter was filtered off and the organic phase was evaporated: a short column chromatography afforded 0.4 g of the title compound.
Example 21 4P-( -acetoxymethyl-3-acetoxy-1 -propenylthio)-3-(1 -p-nitrobenzyloxycarbonyloxyethyl)-1 -(1 acetoxymethoxycarbonyl-l -hydroxymethyl)-azetidin-2-one
0.6 g of the compound prepared in Example, dissolved in 30 ml of benzene, and 0.6 g of acetoxymethyl glyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate), were refluxed together. The reaction was completed after two hours. The condensation product can be used for the next step without further purification.
Example 22 4p-(1 -acetoxymethyl-3-acetoxy-1 -propenylthio)-3-(1 -p-nitrobenzyloxycarbonyloxyethyl )-1 -(1 - acetoxym ethoxycarbonyl-l -chloromethyl)-azetidin-2-one
0.5 g of the compound prepared in Example 21 were dissolved in 12 ml of anhydrous tetrahydrofuran and cooled to ooh. 1.1 Equivalents of pyridine and 1.1 equivalents of thionyl chloride were added and the mixture was left under stirring for 10 minutes. The insoluble matter was filtered off and the solvent was evaporated off at room temperature to give the title compound in nearly quantitative yield. The product can be used without further purification for the next step.
Example 23 4,B-(1 -acetoxymethyl-3-acetoxy-1 -propenylthio)-3-( 1 -p-nitrobenzyloxycarbonyloxyethyl)-1 (acetoxymethoxycarbonyl-1 -triphenylphosphoranylidenemethyl)-azetidin-2-one
A solution of 0.760 g of the compound prepared in Example 22 in 10 ml of tetrahydrofuran and 10 ml of dioxan was stirred overnight at 500C with 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine. The phosphorane was purified by silica gel column chromatography, eluting with 70:30 by volume dichloromethane:ethyl acetate. 0.480 g of the title compound were obtained.
Claims (8)
1. An azetidinone derivative having the general formula I as herein defined.
2. 4P-(1 -acetoxymethyl-3-acetoxy- 1 -propenylthio)-1 -(1 -acetoxymethoxycarbonyl- 1 -triphenylphosphoranylidenemethyl)-azetidin-2-one.
3. 4p-(1 -acetoxymethyl-3-acetoxy- 1 -propenylthio)- 1 -( 1 -(1 -p.nitro-benzyloxycarbonyl- 1 -triphenyl- phosphosphora nylidenemethyl)-azetidin-2-one.
4. 4P-(1 -acetoxymethyl-3-acetoxy- 1 -propenylthio)-3-( 1 -p.nitrobenzyloxycarbonyloxyethyl)-l - (acetoxymethoxy-carbonyl- 1 -triphenylphosphoranylidenemethyl)-azetidin-2-one.
5. A process for the preparation of an azetidinone derivative having the general formula I wherein
R, R", Y, and Ph and n are as herein defined and X represents a group of the formula CH2Z wherein Z is as herein defined, the process comprising condensing, in an inert solvent at elevated temperature, a penicillanic acid S-oxide ester of the general formula (2) as herein defined with an acetylenic compound of the general formula ZCH2CsCY wherein Y and Z are as herein defined, isomerising the resultant compound of the general formula (3) as herein defined and converting the resultant azetidinone derivative of the general formula as herein defined into one of the general formula as herein defined by the steps of (a) ozonolysis of the 1-substituent of the formula
in solution at reduced temperature, (b) removal of the 1 -substituent of the formula
resulting from step (a) by mild alkaline hydrolysis or by the action of silica gel, (c) condensation of the 1-unsubstituted azetidinone resulting from step (b) with a glyoxylate of
the formula CHO .COOR" wherein R" is as herein defined by refluxing in a solvent, (d) chlorination of the 1 -substituent of the formula
introduced in step (c) by the action of a chlorinating agent, and (e) conversion of the 1-substituent of the formula
introduced in step (d) into one of the formula
by reaction with triphenylphosphine, the steps (a) to (e) being carried out in the order given, and the optional step of
(f) reduction of the 4P-(substituted vinylsulphinyl) group by the action of a reducing agent, the
steps (f) being carried out (if at all) immediately after step (a) or step (e), and if carried out
after step (e) then being carried out in acidic conditions.
6. A process for the preparation of an azetidinone derivative having the general formula I wherein
R, R", Y, Ph and n as herein defined and X represents a group of the formula CH2Z' wherein Z' is as herein defined, the process being as defined in claim 5 with the additional step of converting the substituent Z into a substituent Z' as herein defined, the additional step being carried out at any stage in the process after the condensation of the penicillanic acid S-oxide ester with the acetylenic compound.
7. A process according to claim 5 or claim 6 in which the isomerisation is carried out in basic conditions.
8. A process according to claim 5, the process being substantially as described herein with reference to Examples 1 to 5 and 7 to 9 or to Examples 1 6 to 23.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08224128A GB2114132B (en) | 1979-02-24 | 1982-08-23 | Azetidinone derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7906634 | 1979-02-24 | ||
| GB7932591 | 1979-09-20 | ||
| GB08224128A GB2114132B (en) | 1979-02-24 | 1982-08-23 | Azetidinone derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2114132A true GB2114132A (en) | 1983-08-17 |
| GB2114132B GB2114132B (en) | 1984-01-18 |
Family
ID=27260675
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08224128A Expired GB2114132B (en) | 1979-02-24 | 1982-08-23 | Azetidinone derivatives |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2114132B (en) |
-
1982
- 1982-08-23 GB GB08224128A patent/GB2114132B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2114132B (en) | 1984-01-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1095026A (en) | Cyclization to form cephem ring and intermediates therefor | |
| US4631150A (en) | Process for the preparation of penems | |
| IE49407B1 (en) | Antibacterial agents and beta-lactamase inhibitors | |
| KR950013767B1 (en) | Chiral azetidinone derivatives and method for preparing them | |
| JPH0557980B2 (en) | ||
| EP0146730B1 (en) | Process for the production of penems | |
| US3872086A (en) | Certain disulfide derivatives of 2-azetidinones | |
| DE3382761T2 (en) | Process for the production of penem compounds. | |
| US4089956A (en) | 7-Acylamino-8-oxo-3-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid derivatives and bactericidal compositions and use thereof | |
| KR840000865B1 (en) | Process for preparing -lactam-containing antibacterial agents | |
| US4024152A (en) | 4-Dithio-3-imido-azetidin-2-ones | |
| EP0008514A1 (en) | Beta-lactam anti-bacterials, compositions containing them and a process for their preparation | |
| US4008230A (en) | Process for preparing 3-hydroxy cephalosporins | |
| GB2114132A (en) | Azetidinone derivatives | |
| CA1076125A (en) | Intermediates for cephalosporin analogues | |
| JPH04330075A (en) | Preparation of bicyclic beta-lactam | |
| PL172378B1 (en) | Method of obtaining novel 4-substituted azetidinones | |
| IE49408B1 (en) | Azetidinone derivatives | |
| US4554103A (en) | Preparation of 4-acyloxyazetidinones from acyl nitrates and penams | |
| Cainelli et al. | β-Lactams from ester enolates and N-TMSimines: Enantioselective synthesis of (6R, 7S)-1β-3-dimethyl-3-isocephem | |
| KR810001820B1 (en) | Process for preparing cephem derivatives | |
| GB2116167A (en) | Azetidinone derivatives | |
| US4187375A (en) | Process for preparing oxazine ring compounds | |
| NL8002843A (en) | PENICILLINS. | |
| RU2175971C2 (en) | Method of preparing 2-halogenmethyl penems and 2-azitidinone derivatives as intermediate compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| PE20 | Patent expired after termination of 20 years |
Effective date: 20000218 |