GB2071102A - Synthesis of optically active functionalised azetidinones - Google Patents
Synthesis of optically active functionalised azetidinones Download PDFInfo
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- GB2071102A GB2071102A GB8113352A GB8113352A GB2071102A GB 2071102 A GB2071102 A GB 2071102A GB 8113352 A GB8113352 A GB 8113352A GB 8113352 A GB8113352 A GB 8113352A GB 2071102 A GB2071102 A GB 2071102A
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- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title claims description 29
- 230000015572 biosynthetic process Effects 0.000 title description 4
- 238000003786 synthesis reaction Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- -1 alkyl radical Chemical group 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 15
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 125000003368 amide group Chemical group 0.000 claims abstract description 4
- 150000005840 aryl radicals Chemical group 0.000 claims abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000005544 phthalimido group Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- DDROIUOHXRYUCB-GXSJLCMTSA-N [(2R,3R)-3-(1,3-dioxoisoindol-2-yl)-4-oxoazetidin-2-yl] acetate Chemical compound C(C)(=O)O[C@@H]1[C@H](C(N1)=O)N1C(C=2C(C1=O)=CC=CC2)=O DDROIUOHXRYUCB-GXSJLCMTSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 1
- 125000003431 oxalo group Chemical group 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- 150000003952 β-lactams Chemical group 0.000 abstract description 12
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 abstract description 3
- 229930182555 Penicillin Natural products 0.000 abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 229940049954 penicillin Drugs 0.000 abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 238000007248 oxidative elimination reaction Methods 0.000 abstract description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 abstract 1
- 239000000470 constituent Substances 0.000 abstract 1
- 238000006317 isomerization reaction Methods 0.000 abstract 1
- 125000003452 oxalyl group Chemical group *C(=O)C(*)=O 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WPWHSFAFEBZWBB-UHFFFAOYSA-N 1-butyl radical Chemical compound [CH2]CCC WPWHSFAFEBZWBB-UHFFFAOYSA-N 0.000 description 1
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- DDROIUOHXRYUCB-ONGXEEELSA-N [(2S,3R)-3-(1,3-dioxoisoindol-2-yl)-4-oxoazetidin-2-yl] acetate Chemical compound C(C)(=O)O[C@H]1[C@H](C(N1)=O)N1C(C=2C(C1=O)=CC=CC2)=O DDROIUOHXRYUCB-ONGXEEELSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N carbon tetrachloride Substances ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- HLYQCKQJQXJXKV-KBXCAEBGSA-N methyl 2-[(2R,3R)-2-acetyloxy-3-(1,3-dioxoisoindol-2-yl)-4-oxoazetidin-1-yl]-3-methylbut-2-enoate Chemical compound COC(=O)C(=C(C)C)N1C([C@@H]([C@H]1OC(C)=O)N1C(C=2C(C1=O)=CC=CC2)=O)=O HLYQCKQJQXJXKV-KBXCAEBGSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000004296 sodium metabisulphite Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001131 transforming effect Effects 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
- C07D205/085—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 nitrogen atom directly attached in position 3
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Novel 3R, 4S and 3R, 4R epimers of the general formula: <IMAGE> useful as intermediates in the preparation of beta-lactam structures can be obtained by reacting a penicillin having the formula: <IMAGE> where R is H or a protected amino or protected amido group, R1 is an alkyl radical having 1-6 carbon atoms, or an aryl radical or a heterocyclic residue and A is an alkyl radical having 1-6 carbon atoms, with a compound R1COOH in the presence of trimethyl phosphite to give a mixture of 3R, 4S and 3R 4R epimers of the general formula: <IMAGE> The latter mixture can be separated into its constituent epimers which can then be converted into the respective intended compound of formula XX by successive isomerisation of the olefinic bond, oxidative cleavage of the olefinic bond to give an oxamide and hydrolitic removal of the oxalyl group, or these successive steps can be applied to said mixture to give a mixture of the intended 3R, 4S and 3R, 4R epimers which are then separated from each other.
Description
SPECIFICATION
Synthesis of optically active functionalised azetidinones
This invention relates to new azetidinones being compounds having any of the Formulae Ill and IV depicted herein and to processes for preparing those compounds. In particular, the invention relates to a multi-stage process for preparing from certain penicillin derivatives compounds of Formula Ill or IV which are of particular use in the preparation of beta-lactam compounds. Reference herein to compounds of various formulae designated by Roman numerals refers to the formulae of those numbers depicted herein under the heading "Synthetic Diagram" which also shows diagrammatically the routes by which one structure can be obtained from another.It is to be noted that the formulae are arranged in two columns and that the left hand column formulae are of 3R, 4S stereochemical structure and those in the right hand column are of 3R, 4R structure. The system of numbering of the ring structure of the compounds of formulae I to IV and VII to Xis shown in formula
In the British Patent Application No. 48064/77 in the name of the present applicants a novel procedure for transforming penicillin ester derivatives into functionalized azetidinones of definite stereochemistry (namely 3S,4S), which have proved to be useful intermediates for the synthesis of classical and non-classical beta-lactam structures, has been disclosed.
In parent Patent Application 7912034 from which the present Application has been divided, there is described and claimed new azelidinones having the formula:
and new azetidinones having the formula
wherein in each formula R is H or a protected amino or amido group or halogen; COOA is a carboxyclic group or an ester or salt thereof; and R1 is a lower alkyl radical (as herein defined), an aryl radical or a heterocyclic residue.
The protected amino or amido group is conveniently a phthalimido, benzamido, phenylacetamido or phenoxyacetamido group, for example (C6H5)3 CNH, C6H5 CONH, C6H5CH2 CONH, C6HSOCH2 CONH or
In group COOA, A is conveniently a lower alkyl radical. The term "lower alkyl radical" as used herein means an alkyl radical having from 1 to 6 carbon atoms, for example a methyl, ethyl, propyl or butyl radical.
Where R1 is a lower alkyl, a phenyl or other aryl radical or a heterocyclic residue, it can be a substituted radical or residue as the case may be. Examples of substituted aryl radicals of particular interest are halogen-substituted radicals, for instance mono-or other chloro-substituted phenyl radicals.
Compounds of formulae I or II can be obtained as an epimeric mixture by treatment of a penicillin compound of formula VI with a compound of formula R1 COOH, where R1 has the appropriate meaning.
Compounds (i) and (II) may be subsequently reduced to the simpler new azetidinones of general formula (III) and respectively (IV), which are the subject of the present Application,
wherein Rand R1 have the above meanings. Compounds (III) and (IV) are also useful intermediates for the synthesis of classical and non classical compounds having ss-lactam structures.
Compounds of formula (III) can be prepared by a process in which 6-epi-penicillin derivatives of general formula (Vl) (R.D.G. Cooper et al., J.Am.Chem. Soc.,91, 1528(1969) wherein R has the above meaning and
COOA is here any acid-stable ester group, are heated (normally at 60-800C) with a weak carboxylic acid R1
COOH, wherein R1 has the above meaning, in the presence of trimethylphosphite (TMP) in a suitable solvent for example benzene, dichloromethane, chloroform, tetrahydrofuran, hexamethyl-phosphotriamide, dioxane, dimethyl, formamide and their mixtures to give a separable mixture of two epimeric azetidinones of formula (I) and (II) respectively.
Treatment of compounds (I) with a weak base in an aprotic solvent affords the conjugated esters (VII).
The weak base is conveniently a tertiary amine, for example triethylamine. An example of a suitable aprotic solvent is methylene chloride.
The compounds of formula VII can be transformed into the simpler azetidinones (III) by an oxidative cleavage of the olefinic bond to give the corresponding oxamide compound of formula IX followed by hydrolitic removal of the ozalyl (-CO-COOA) group in the resulting oxamide (IX) (J.H.C. Nayler et al., J.C.S.
Chem.Comm., 1972229 and J.S.C. Perkin 1, 1976,447 R.D.G.Cooper et al. J. Amer Chem.Soc.94 (1972).
By means of similar treatment compounds (II) can be transformed into the simpler azetidinones (IV) via the conjugated esters (VIII) and the oxamides (X).
Alternatively, the aforementioned set of reactions may be carried out on a mixture of the compounds
having formulae (I) and (ill); the two resulting azetidinones (Ill) and (IV) can then be separated at the end of the reaction by suitable means, for example, fractional crystallization.
The various aspects of the invention are illustrated by the following Examples 4 and 7, Examples 1 to 3, 5 and 6,8 and 9 being included to illustrate preparation of compounds used in the preparation of compounds
Ill and IV.
EXAMPLE 1 (3R,4S)- I-(lcl-methaxycarb onyl-2-methylprop-2-enyl)-4-acetoxy-3-(phthalimido)azetidin-2-one and (3R,4RJ- 1 (1α-methoxycarbonyl-2-methylprop-2-enyl)-4-acetoxy-3(phthalimido)azetidin-2-one
A mixture of 6-epi-6-phthalimido methyl penicillinate sulphoxide (5.922 g, 15.75 mmole) glacial acetic acid (60 ml) and trimethylphosphite (15 ml, 120 mmole) in benzene (500 ml) was refluxed during 17 hrs. The cooled solution was washed with saturated NaCI solution (3x200 ml), saturated NaHCO3 solution (3x 100 ml), saturated NaCI solution (1 x 100 ml) and with water to which few mls of conc. H202 were added to destroy excess of TMP.The organic phase was dried on Na2SO4 and concentrated in vacuo to yield a residue containing two products which were separated by column chromatography on silica gel.
Elution with 15% ethyl acetate-benzene afforded (3R,4R)- 1-(1α-methoxy-carbonyl-2-methyl-prop-2-enyl)-4- acetoxy-3(phthalimido)azetidin-2-one as a white foam in 24% yield.
P.M.R. (CDCl3 b): 1.94 (s, CH3-C=C); 2.10(s, CH3-CO); 3.80 (s, COOCH3); 4.98,5.10 and 5.12 (s, C=CH2, and
exocyclic C-H); 5.28 and 6.54 (d, J = 1.5 cps, ss-lactam protons); 7.72 (br, aromatic
protons).
I.R. (CHCl3, cm-1), 1785, 1750, 1730.
Elution with 20% ethyl acetate-benzene afforded (3R,4S)- 1-(1α-methoxy-carbonyl-2-methyl-prop-2-enyl)-4- acetoxy-3(phthalimido)azetidin-2-one as a white foam in 49% yield.
P.M.R. (CDCI3 b): 1.95 (s, CH3-C=C); 1.95 (s, CH3-CO); 3.78 (s, COOCH3); 4.78, 5.09 and 5.14 (s, C=CH2 and
exocyclic C-H); 5.53 and 6.27 (d, J = 4.5 cps, ss-lactam protons); 7.71 (br, aromatic
protons).
I.R. (CHCl3, cm-1): 1795, 1745, 1730.
EXAMPLE 2 (3R,4R)-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-acetoxy-3-(phthalimido)azetidin-2-one.
A solution of (3R,4R)-1-(1α-methoxycarbonyl-2-methyl-prop-2-enyl)-4-acetoxy-3(phthalimido)azetidin-2-one (1.35 g, 3.5 mmole) dissolved in methylene chloride (50 ml) was treated with few drops of triethylamine.
After standing overnight, the solvent was evaporated in vacuo to yield the title compound quantitatively as white crystals (MeOH-Et20).
P.M.R. (CDCI3, b): 2.09 (s, CH3-CO); 2.09 and 2.29
3.82 (s, COOCH3); 5.38 and 6.51 (d, J = 2.0
cps, p-lactam protons); 7.75 (m, aromatic protons).
m.p.; 113-5 C.
[a]D: + 58.5 (CHCl3).
EXAMPLE 3 (3R,4R)- 1-methyloxalyl-4-acetoxy-3(phthalimido)azetidin-2-one.
(3R,4R)-1 -(1 -methoxycarbonyl-2-methyl prop-1 -enyl)-4-acetoxy-3(phthalimido) azstidin-2-one (1.45 g, 3.32 mmole) dissolved in methylene chloride (300 ml) was cooled down to -78 C and treated with a stream of O3 till saturation of the solvent occurred. An excess of sodium metabisulphite was added and the stirred mixture was allowed to reach room temperature naturally. Enough water to dissolve the salt was added, the organic phase was separated, washed with saturated NaCI solution (3x100 ml) and dried (Na2SO4). The solvent was evaporated in vacuo to give the title compound as white crystals (Et2O) in quantitative yield.
P.M.R. (CDC13, 6): 2.16(s, CH2-CO); 3.95 (s, COOCH3); 5.45 and 6.72 (d, J = 2.0 cps, ss-lactam protons); 7.80
(br, aromatic protons).
EXAMPLE 4 (3R,4R)-4-acetoxy-3(phthalimido)azetidin-2-one.
(3R,4R)-1-methyloxalyl-4-acetoxy-3(phthalimido)azetidin-2-one (1.18 g, 3.29 mmole) dissolved in methanol (30 ml) was treated with a catalytic amount of sodium methoxide. After few hours the resulting precipitate was filtered off, the filtrate was evaporated in vacuo and the residue triturated with Et2O and MeOH to afford more crystals. The combined precipitates were washed with cold ether and dried. The title compound was obtained in quantitative yield.
P.M.R. (CDCl3, #): 2.14 (s, CH3-CO); 5.38 and 6.16 (d, J = 1.5 cps, p-lactam protons); 6.92 (br, N-H); 7.77 (br,
aromatic protons).
I.R. (CHCI3, cm-1): 3430; 1805; 1780; 1730.
185-7 C.
[cdo = + 55) (CHCI3).
EXAMPLE 5 (3R,4S)-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-acetoxy-3(phthalimido)azetidin-2-one.
The title compound was obtained as white crystals (MeOH-ET2O) in quantitative yield with a procedure similar to that given in Example 2.
P.M.R. (CDCl3, #): 1.94 (s, CH3-C=O); 2.26 and 2.30
3.81 (s, COOCH3); 5.64 and 6.42 (d, J =
4.0 cps, ss-lactam protons); 7.75 (br, aromatic protons).
m.p.: 138- 140 [α]D: -24.5 (CHCl3).
EXAMPLE 6 (3R,4S)- 1-methyloxalyl-4-acetoxy-3Kphthalimido)azetidin-2-one.
The title compound was obtained as white crystals (Et2O) in quantitative yield with a procedure similar to that given in Example 3.
P.M.R. (CDCI3, #): 1.95 (s, CH3-CO); 3.92 (s, COOCH3); 5.71 and 6.79 (d, J = 5.0 cps, ss-lactam protons); 7.77
(br, aromatic protons).
EXAMPLE 7 (3R,4S)-4-acetoxy-3(phthalimido)azetidin-2-one.
The title compound was obtained as white crystals (MeOH-Et2O) in quantitative yield with a procedure similar to that given in Example 4.
P.M.R. (CDCl3, #): 1.97 (s, CH3-CO); 5.51 and 6.02 (d, J = 4.0 cps, ss-lactam protons); 7.75 (br, aromatic
protons).
I.R. (CHCI3, cm-1): 3420, 1805, 1750, 1730.
m.p.: 155-7 C [α]D: -133 (CHCl3)
EXAMPLE 8 (3R,4S)-1-(1α-methoxycarbonyl-2-methylprop-2-enyl)-4-(4-chloro)benzoyloxy-3(phthalimido)azetidin-2-one and (3R,4R)- l-( 1α-methoxycarbonyl-2-methylprop-2-enyl)-4-(4-chloro)benzoyloxy-3(phthalimido)azetidin-2- one.
A mixture of 6-epi-6-phthalimido methyl penicillinate sulphoxide (3.5 g, 9.3 mmole), 4-chlorobenzoic acid (10 g, 64.5 mmole) and trimethylphsphite (5 ml, 42 mmole) in benzene (110 ml) and tetrahydrofuran (40 ml) was refluxed during 20 hours. The reaction was then worked up as described in Example 1 to give a residue containing two products which were separated by column chromatography on silica gel.
Elution with 5% ethyl acetate-benzene afforded {3R,4R)-1-rZa-methoxycarbonyl-2-methylprop-2-enyl)-4-r4 chloro)benzoyloxy-3(phthalimido)azetidin-2-one as a white foam in 38% yield.
P.M.R. (CDCl3 #): 1.94 (s, CH3-C=C); 3.80 (s, COOCH3); 5.02 and 5.10 (s, C=CH2 and exocyclic C-H); 5.41 and
6.79 (d, J = 2.0 cps, ss-lactam protons); 7.28 - 7.90 (m, aromatic protons).
Same eel vents afforded, subsequently, (3R,4S)-1-(1α-methoxycarbonyl-2-methylprop-2-enyl)-4-(4- chloro)benzoyloxy-3(phthalimido)azetidin-2-one as a white foam in 42% yield.
P.M.R. (CDCI3, s): 1.96 (S, CH3-CH=C); 3.75 (s, COOCH3); 4.88 and 5.10 (s, C=CH2 and exocyclic C-H); 5.70
and 6.58 (d, J = 4.0 cps, ss-lactam protons); 7.12 - 7.90 (m, aromatic protons).
EXAMPLE 9 (3R,4S)-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-(4-chloro)benzoyl-oxy-3(phthalimido)azetidin-2-one.
The title compounds was obtained as white crystals (Et2O-CCl4) in quantitive yield with a procedure similar to that given in Example 2.
P.M.R. (CDCl3 a): 2.27
3.83 (s, COOCH3); 5.76
and 6.70 (d, J = 4 cps, ss-lactam protons); 7.12 - 7.90 (m, aromatic protons).
m.p.. 215-8 C.
[α]D: -32 (CHCl3)
SYNTHETIC DIAGRAM
Claims (15)
1. A compound of the formula Ill or IV depicted herein, in which R is H or a protected amino or amido group or halogen; COOA is a carboxylic group or an ester or salt thereof; and R1 is a lower alkyl radical (as herein defined), an aryl radical or a heterocylic residue.
2. A compound according to Claim 1, in which R is phthalimido.
3. A compound according to Claim 1, in which R is (C6H5)3CNH, CONH C6H5CH2CONH or C6H5
OCH2CONH.
4. A compound according to Claim 1,2 or 3, in which R1 is a substituted lower alkyl or a substituted aryl radical or a substituted heterocyclic residue.
5. A compound according to Claim 1, 2 or 3 in which R1 is a chloro-substituted phenyl radical.
6. A compound according to Claim 4, in which R1 is a chloro-substituted phenyl radical.
7. A compound according to Claim 6, in which R1 is p-chloro-phenyl.
8. (3R,4S)-4-acetoxy-3(phthal imido)azetidin-2-one.
9. (3R,4R)-4-acetoxy-3(phthalimido)azetidin-2-one.
10. A process for the preparation of a compound of formula Ill or IV depicted herein, in which R and R1 are as defined in Claim 1, in which a compound of formula IX or X respectively where Rand R1 are as defined in
Claim 1, and A is a lower alkyl radical (as herein defined) is hydrolised to remove the oxalyl (-CO-COOA) group of the compound of formula IX or X.
11. A process according to Claim 10, substantially as described herein.
12. A process for preparing a compound as claimed in Claim 1, substantially as described in Example 7 or 4, respectively.
13. A compound of formula Ill or IV obtained by the process of Claim 10, 11 or 12.
14. A process for preparing a compound of formula Ill or IV depicted herein, in which R and R, are as defined in Claim 1, in which a compound of formula VI in which R is as defined in Claim 1 and A is a lower alkyl radical (as herein defined) is reacted with a weak carboxylic acid of formula R1COOH, where R1 is as defined in Claim 1, and with trimethyl-phosphite in an organic solvent to produce a mixture of two epimeric compounds of formula I and II which is then treated with a weak base in an aprotic solvent to produce a mixture of two epimeric compounds of formula VII and VIII which is then oxidized at the olefinic bond to produce a mixture of two epimeric compounds for formula IX and X which is then hydrolised to produce a mixture of two epimeric compounds of formula Ill and IV respectively, and the desired compound of formula lil or IV is separated from the remainder of the last mentioned mixture.
15. A compound of formula III or IV obtained by the process of Claim 14.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB502378 | 1978-02-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2071102A true GB2071102A (en) | 1981-09-16 |
| GB2071102B GB2071102B (en) | 1982-10-20 |
Family
ID=9788293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8113352A Expired GB2071102B (en) | 1978-02-08 | 1979-04-05 | Synthesis of optically active functionalised azetidinones |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS54115366A (en) |
| BE (1) | BE873271A (en) |
| DE (1) | DE2901993A1 (en) |
| GB (1) | GB2071102B (en) |
| IT (1) | IT1203686B (en) |
-
1979
- 1979-01-02 BE BE192730A patent/BE873271A/en not_active IP Right Cessation
- 1979-01-19 DE DE19792901993 patent/DE2901993A1/en not_active Withdrawn
- 1979-01-25 JP JP811179A patent/JPS54115366A/en active Pending
- 1979-02-07 IT IT19960/79A patent/IT1203686B/en active
- 1979-04-05 GB GB8113352A patent/GB2071102B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IT7919960A0 (en) | 1979-02-07 |
| BE873271A (en) | 1979-05-02 |
| GB2071102B (en) | 1982-10-20 |
| DE2901993A1 (en) | 1979-08-09 |
| IT1203686B (en) | 1989-02-15 |
| JPS54115366A (en) | 1979-09-07 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |