GB2104893A - Azetidinone derivatives - Google Patents
Azetidinone derivatives Download PDFInfo
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- GB2104893A GB2104893A GB08224130A GB8224130A GB2104893A GB 2104893 A GB2104893 A GB 2104893A GB 08224130 A GB08224130 A GB 08224130A GB 8224130 A GB8224130 A GB 8224130A GB 2104893 A GB2104893 A GB 2104893A
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- general formula
- methyl
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- ch2z
- azetidinone derivative
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- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title claims abstract description 40
- -1 p-nitro- benzyloxycarbonyl Chemical group 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 238000006317 isomerization reaction Methods 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 10
- 150000002148 esters Chemical class 0.000 abstract description 4
- 125000001506 1,2,3-triazol-5-yl group Chemical group [H]N1N=NC([H])=C1[*] 0.000 abstract description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 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 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 2
- 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 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 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 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 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
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 235000019256 formaldehyde Nutrition 0.000 description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-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
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000006519 CCH3 Chemical group 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 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
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 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 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000005055 short column chromatography Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 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
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- 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 and their isomers II (R=alkyl; R'=H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl optionally protected by p-nitro- benzyloxycarbonyl; X=CH2Z or CH2Z'; Z=OH, NH2, NH2COO, OR1; R1=C1-C4 alkyl; Z'=SH, pyridinium or SR3; R3=C<1>-C4alkyl, 5-metyl-1,3,4- thiadiazol-2-yl, 1-methyl-1H-tetrazol- 5-yl, 1,2,3-triazol-5-yl or pyrazinyl; Y=H, lower alkyl, CN, alkoxycarbonyl, CH2Z) are useful as intermediates in the preparation of penem-carboxylic acids and esters, see British Patent Specification No. 2043639 from which this Application is divided. The azetidinones I and II and their preparation from penicillanic acid S- oxide esters are claimed.
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 and their isomers of the general formula II
wherein R represents an alkyl group; 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;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 5methyl1 ,3,4-thiadiazol-2-yl, l-methyl-l H-tetrazol-5-yl, 1,2,3triazol-5-yl or pyrazinyl group; and Y represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, a cyano or alkoxycarbonyl group or a group of the formula CH2Z wherein Z is as above defined. The 3-substituent may have the a- or ,B-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 a p-lactamase inhibiting activity (see British Patent Specification No. 2043639, from which this Application is divided). It should be pointed out that the stereo-chemistry at C4 of the compounds according to the invention is the same as in naturally occurring penicillins and cephalosporins.
The azetidinone derivatives of the general formulae I and II in which R, R' and Y are as above defined and X represents a group of the formula CH2Z in which Z is as above defined are hereinafter denoted as the azetidinone derivatives (3) and the azetidinone derivatives (4) respectively. The remaining azetidinone derivatives of the general formula I and II, that is those in which R, R' and Y are as above defined and X represents a group of the formula CH2Z' in which Z' is as above defined, are hereinafter denoted as the azetidinone derivatives (5) and the azetidinone derivatives (6) respectively.
The azetidinone derivatives (3) may be prepared by a process comprising condensing, in an inert solvent at elevated temperature, a penicillanic acid S-oxide ester of the general formula (2)
wherein R and R' are as above defined with an acetylenic compound of the general formula ZCH2C=CY wherein Y and Z are as above defined.
The azetidinone derivatives (4) may be prepared according to the above process with the additional step of isomerising the azetidinone derivative (3). This isomerization is preferably carried out in basic conditions.
The azetidinone derivatives (5) may be prepared by converting the substituent Z in an azetidinone derivative (3) prepared by the above process into a substituent Z' as above defined. The azetidinone derivatives (6) may be prepared by converting the substitutent Z in an azetidinone derivative (4) prepared by the above process into a substituent Z' as above defined or by isomerising an azetidinone derivative (5), preferably in basic conditions. The conversion of the substituent Z into a substituent Z' is necessary because of the difficulty of condensing the pencillanic acid S-oxide ester (2) directly with an acetylenic compound HSCH2-C=-CY, R3SCH2-C=-CY or PyCH2-C=-CY in which Py represents a pyridinium ion.
When R' represents a hydroxyalkyl group in the desired compound of the general formula I or II, the reaction sequence is preferably carried out with the alcoholic function protected.
All the processes described are within the scope of the invention. They are illustrated by the following reaction scheme.
The starting materials of the general formula (2) in which R' represents a hydrogen atom may be prepared from (5R)-6-aminopeniciííanic acid following known procedures (see FIGNARELLA et al.,
Journal of Organic Chemistry, 27,2668 and EVRARD et al., Nature, 201, 1124).
When R' represents a lower alkyl or hydroxyalkyl group, it can be introduced according to the procedure of Di Ninno et al., Journal of Organic Chemistry 42, 2960 (1977). When R' represents a lower 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 a lower 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 a lower 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 6-position is stereospecifically directed to the 6aderivatives.
The following Examples illustrate the invention.
Example 1 4p-(1 -acetoxymethyl-3-acetoxy- 1 -propenylsulphinyl)-1 -(1 -methoxycarbonyl-2-methyl-aIlyI)- azetidin-2-one (3): R=CH R'=H, Y=CH20.CO.CH3, Z=OCOCH3 A solution of 2.0 g of methyl penicillinate 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 chromatography on silica gel eluting with 96:4 by volume dichloromethane: ethyl acetate.
PMR (CDCl3): 2.03 a (s,
2.15 and 2.20 a (two s,2 CH3CO), 2.88 8 (dd, Jgem=1 4Hz, Jvic cis=4 Hz, C-3-Ha, 3.38 8 (dd, Jgem=1 4Hz, Jvic trans=2Hz, C--33-Hss),3.83 8 (s, CH3O),
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 CH3CO and 2
2.92 8 (dd, Jgem=1 5Hz, Jvic cis=5Hz, C--3--Hα), 3.38 8 (dd, Jgem=1 5Hz, Jvic trans=2.5Hz, C--3--Hss), 3.82 S (s, CH3O) 4.88 8 (d, Jvic=6.5Hz,
4.92 8 (s, CH2-C=), 5.15 8 (dd, Jvic=5 and 2.5Hz, C--4--H), 6.50 8 (t, Jvic 6.5Hz,
Example 3 4ss-(1 -hydroxymethyl-vinylsulphinyl)-1 -(1 -methoxycarbonyl-2-methyl-allyl)-azetidin-2-one
(3):R=CH3,R'=Y=H, Z=OH
4 g of methyl pencillanate S-oxide were dissolved in 1 5 ml of toluene and refluxed with 1 5 ml of propargyl alcohol for 8 hours. After evaporating off the solvent in vacuo, the residue was purified by short column chromatography on silica gel, eluting with dichloromethane: ethyl acetate (1:1 by volume).
2.8 g of the title compound were obtained.
PMR (CDCl3) 8:1.96 (bs, 3H,
2.91 and 3.35 (dd, 2H, J=2Hz, 5Hz, 15Hz, CO--CH2-CH-S); 3.78 (s, 3H, COOCH3); 4.36 (bs, 2H, CH2OH);
Example 4 4p-(1 -hydroxymethyl-vinylsulphinyl)-1 -(1 -methoxywarbonyl-2-methyl-1 -propenyl )-azetidin-2-one
(4): R=CH3, R'=Y=H, Z=OH 3.0 g of the compound- prepared in Example 3 were dissolved in 100 ml of dichloromethane and left at room temperature for a few hours. After evaporating the solvent from the solution, the residue consisted of the title compound in pure form.Quantitative yield
PMR (CDCI,)G: 2.08 (s, 3H,
2.18 (s, 3H, =C-CH3); 2.7-3.6 (m, J=2Hz, 16Hz, COCN2-CH-S); 3.78 (s, 3H,
COOCH3); 4.35 (s, 2H, CH2OH); 5.32 (m, 1 H, CH-S); 5.90 (bs, 2H, =CH2).
Example 5 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 6 methyl 6-( 1 -p-nitrobenzyloxycarbonyloxyethyl )-3-penici lianate 1.2 g of methyl 6-(1 -hydroxyethyl)-3-penicillanate, prepared as described in Example 5, were dissolved in 40 ml of tetrahydrofuran cooled to -780C and treated with one equivalent of butyl lithium.
1.2 equivalents of p-n itrobenzyloxyca rbonyi chloride were added to the mixture. After 30 minutes at -780C, 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 7 -methyl 6-( 1 -p-nitrobenzyloxyearbonyloxyethyl )-3-penici lXanate-S-oxide (2): R=CH3,
1.8 g of methyl 6-[1 -p-nitrobenzyloxycarbonyloxyethyl]-3-penicillanate, prepared as described in
Example 6, were dissolved in 50 ml of dichloromethane and treated at O C 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 8 3-( 1 -acetoxymethyl-3-acetoxy-1 -propenylsulphinyl)-3-( 1 -p-nitrobenzyloxycarbonyloxyethyl)-1 (1 -methoxy-carbonyl-2-methyl-allyl)-azetidin-2-one (3): R=CH3,
A solution of 2.0 g of the compound prepared in Example 7 and 2.4 g of butyndiol diacetate in 50 m of toluene was refluxed for 24 hours. The trappped compound was then purified by silica gel column chromatography eluting with 9:1 by volume dichloromethane: ethyl acetate. 1.1 g of the title compound were obtained.
Example 9 4P-( 1 -acetoxymethyl-3-acetoxy-1 -propenylsulphinyl)-3-( I -p-nitrobenzyloxycarbonyloxyethyl)-1 (1 -methoxycarbonyl-2-methyl-1 -propenyl)-azetidin-2-one (4): R=CH3,
Y=CH2O . CO .C0.CH3,Z=0C0CH 1.3 g of the compound prepared in Example 8 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.
Claims (14)
1. An azetidinone derivative having the general formula I as defined herein or an isomer thereof having the general formula II as defined herein.
2.4p-(1 -acetoxymethyl-3-acetoxy- 1 -propenylsulphinyl)-1 -(1 -methoxycarbonyl-2-methyl-allyl)azetidin-2-one.
3. 4P-(1 -acetoxymethyl-3-acetoxy-1 -propenylsulphinyl)-1 -(1 -methoxycarbonyl-2-methyl-1 propenyl)-azetidin-2-one.
4. 4/3-( 1 -hydroxymethyl-vinylsulphinyl)-1 -(1 -methoxycarbonyl-2-methyl-allyl)-azetidin-2-one.
5. 4P-( 1 -hydroxymethyl-vinylsu Iphinyl)- 1 -(1 -methoxycarbonyl-2-methyl- 1 -propenyl)-azetidin-2one.
6. 4P-( 1 -acetoxymethyl-3-acetoxy-1 -propenylsulphinyl)-3-(1 -p-nitrobenzyloxycarbonyl- oxyethyl)- 1 -(1 -methoxycarbonyl-2-methyl-allyl)-azetidin-2-one.
7. 4p-( 1 -acetoxymethyl-3-acetoxy- 1 -propenylsulphinyl)-3-( 1 -p-nitrobenzyloxycarbonyl- oxyethyl)- 1 -(1 -methoxycarbonyl-2-methyl- 1 -propenyl)-azetidin-2-one.
8. A process for the preparation of an azetidinone derivative having the general formula I wherein
R, R' and Y are as defined herein and X represents a group of the formula CH2Z wherein Z is as defined herein, the process comprising condensing, in an inert solvent at elevated temperature, a penicillanic acid S-oxide ester of the general formula (2) as defined herein with an acetylenic compound of the general formula ZCH2C=--CY wherein Y and Z are as defined herein.
9. A process for the preparation of an azetidinone derivative having the general formula II wherein
R, R' and Y are as defined herein and X represents a group of the formula CH2Z wherein Z is as defined herein, the process comprising isomerising an azetidinone derivative prepared according to claim 8.
10. A process according to claim 9 in which the isomerization is carried out in basic conditions.
11. A process for the preparation of an azetidinone derivative having the general formula I wherein R, R' and Y are as defined herein and X represents a group of the formula CH2Z' wherein Z' is as defined herein, the process comprising converting the substituent Z in an azetidinone derivative prepared according to claim 8 into a substituent Z' as defined herein.
1 2. A process for the preparation of an azetidinone derivative having the general formula II wherein R, R' and Y are as defined herein and X represents a group of the formula CH2Z' wherein Z' is as defined herein, the process comprising converting the substituent Z in an azetidinone derivative prepared according to claim 9 or claim 10 into a substituent Z' as defined wherein.
13. A process for the preparation of an azetidinone derivative having the general formula II wherein R, R' and Y are as defined herein and X represents a group of the formula CH2Z' wherein Z' is as defined herein, the process comprising isomerising an azetidinone derivative prepared according to claim 11.
14. A process according to claim 1 3 in which the isomerisation is carried out in basic conditions.
1 5. A process according to claim 8, the process being substantially as described herein with reference to any of Examples 1,3 or 8.
1 6. A process according to claim 9, the process being substantially as described herein with reference to any of Examples 2, 4 or 9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08224130A GB2104893B (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 | ||
| GB08224130A GB2104893B (en) | 1979-02-24 | 1982-08-23 | Azetidinone derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2104893A true GB2104893A (en) | 1983-03-16 |
| GB2104893B GB2104893B (en) | 1983-07-27 |
Family
ID=27260677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08224130A Expired GB2104893B (en) | 1979-02-24 | 1982-08-23 | Azetidinone derivatives |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2104893B (en) |
-
1982
- 1982-08-23 GB GB08224130A patent/GB2104893B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2104893B (en) | 1983-07-27 |
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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 |