GB2144120A - Azetidinyl acetic acid esters - Google Patents
Azetidinyl acetic acid esters Download PDFInfo
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- GB2144120A GB2144120A GB08415800A GB8415800A GB2144120A GB 2144120 A GB2144120 A GB 2144120A GB 08415800 A GB08415800 A GB 08415800A GB 8415800 A GB8415800 A GB 8415800A GB 2144120 A GB2144120 A GB 2144120A
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- SVDWECPQUANQNC-UHFFFAOYSA-N 2-(azetidin-1-yl)acetic acid Chemical class OC(=O)CN1CCC1 SVDWECPQUANQNC-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000005977 Ethylene Substances 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 150000001408 amides Chemical group 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- -1 Heterocyclic acetic acid esters Chemical class 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 229910001868 water Inorganic materials 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002250 absorbent Substances 0.000 description 5
- 230000002745 absorbent Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 description 4
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 2
- 229910052684 Cerium Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- ZMIGMASIKSOYAM-UHFFFAOYSA-N cerium Chemical compound [Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce] ZMIGMASIKSOYAM-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000006567 deketalization reaction Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 2
- 235000019394 potassium persulphate Nutrition 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- FJYIJQVYYCUVMU-UHFFFAOYSA-N 1-[(2,4-dimethoxyphenyl)methyl]-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxoazetidine-2-carboxylic acid Chemical compound COC1=C(CN2C(C(C2=O)C2(OCCO2)C)C(=O)O)C=CC(=C1)OC FJYIJQVYYCUVMU-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- LVXHNCUCBXIIPE-UHFFFAOYSA-L disodium;hydrogen phosphate;hydrate Chemical compound O.[Na+].[Na+].OP([O-])([O-])=O LVXHNCUCBXIIPE-UHFFFAOYSA-L 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- FDNAPBUWERUEDA-UHFFFAOYSA-N silicon tetrachloride Chemical compound Cl[Si](Cl)(Cl)Cl FDNAPBUWERUEDA-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 229940126572 wide-spectrum antibiotic Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Novel diastereomers of the Formula I <IMAGE> which are useful as intermediates in the preparation of thienamyan, are prepared in a process which comprises removing the ethylene ketal group from a compound of the general Formula III <IMAGE> [wherein R<1> is hydrogen or (as an amide protecting group) a phenyl or benzyl group optionally substituted by one or more methoxy group(s)] and reducing the new compound of the general Formula <IMAGE> thus obtained.
Description
SPECIFICATION
Heterocyclic acetic acid esters
This invention relates to new heterocyclic acetic acid esters and a process for the preparation thereof. More particularly the invention is directed to new diastereomers of the Formula I
and a process for their preparation.
The new diastereomers of the Formula I are useful as intermediates in the preparation of thienamycin, a well-known antibiotic.
Thienamycin is a wide-spectrum antibiotic, the microbiological process for the preparation thereof is described in US patent 3,950,357 and the latest synthesis of the said antibiotic is disclosed in European patent No. 62,840.
It has been found that the compounds of the Formula I can be prepared by simple reaction steps, through new intermediates and with high yields from compounds disclosed in our earlier
Hungarian patent application Ser. No. 4014/81. The said compounds correspond to the general Formula Ill
(wherein R' stands for a hydrogen atom or as amide protecting group a phenyl or benzyl group optionally substituted by one or more methoxy group(s)]. The compound of the general Formula
Ill is subjected to deketalization, the compound of the general Formula II
thus obtained (wherein R' is as stated above) is reduced, the amide protecting group, if present, is removed. Thus the new pair of diastereomers of the Formula I is obtained which can be separated into the components thereof by chromatography, if desired.
From the diastereomers of the Formula I the benzhydryl group can be removed by catalytic hydrogenation to yield the corresponding azetidinyl acetic acid derivative. The latter and its transformation into thienamycin is disclosed in European patent specification No. 62,840.
The present invention is directed to a process for the preparation of new diastereomers of the
Formula I which comprises removing the ethylene ketal group from a compound of the general
Formula Ill [wherein R' stands for a hydrogen atom or as an amide protecting group for a phenyl or benzyl group optionally substituted by one or more methoxy group(s)] and reducing the new compound of the general Formula II thus obtained (wherein R1 has the same meaning as stated above) and isolating the product thus obtained-if desired after removal of the amide protecting group--and if desired separating the pair of diastereomers thus obtained into the components thereof.
According to the process of the present invention a compound of the general Formula Ill is used as starting material.
The new compounds of the general Formula Ill are claimed in our Hungarian patent applications Nos. 4013/81 and 4014/81, the process for the preparation thereof is disclosed in the Examples of the present specification as well.
The ethylene ketal group can be removed from the compounds of the general Formula Ill with the aid of an acid. For this purpose a sulfonic acid (e.g. p-toluene sulfonic acid), a silyl halide (e.g. a silyl halide formed from a mixture of sodium iodide and silicium tetrachloride or sodium iodide and trimethyl silicium chloride) or a mineral acid (preferably perchloric acid) can be used.
The deketalization reaction can be carried out in a suitable organic solvent, preferably in the mixture of ketone (e.g. acetone) or a chlorinated hydrocarbon and acetonitrile.
The reaction mixture is then neutralized and the new compound of the general Formula II thus obtained is isolated, if desired.
According to a further feature of the present invention there are provided new compounds of the general Formula II and a process for the preparation thereof.
ihe compounds of the general Formula II are reduced. The reduction can be preferably accomplished with a complex metal hydride, particularly with an alkali-[tetrahydroborate-(lll)].
If compounds of the general Formula Ill are used as starting material in which R1 is hydrogen, the pair of diastereomers of the Formula I is directly obtained after reduction.
If compounds of the general Formula Ill are used as starting material, in which R' is an amide protecting group, the said amide protecting group is removed after reduction. The said protecting group can be removed with the aid of an oxidizing agent. Thus the dimethoxy-benzyl group can be removed with an oxidizing agent of the peroxydisulfate type, the methoxy-phenyl group by using simultaneously a cerium(lV)salt and an acid, while the amino-phenyl protecting group with the aid of a cerium(lV)salt and an acid or by using chrome trioxide in glacial acetic acid.
The pair of diastereomers thus obtained can be separated into the components thereof, if desired. This step is carried out preferably by chromatographical methods. As absorbent preferably silikagel (Kieselgel PF254+366) and as eluent a 7:3 mixture of benzene and acetone can be used.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to the said Examples.
Example 1 Benzhydryl-f(2 RS, 3 SR)-3-1 (AS and SR)-hydroxyethyl]-4-oxo-2-azetidinyl-acetate) A mixture of 4.89 g (10,0 millimoles) of benzhydryl-{(2 RS, 3 SR)-1-(2,4-dimethoxy-benzyl) 3-r1 (AS and SR)-hydroxyethyl]-4-oxo-2-azetidinyl-acetate}, 10.81 g (40,0 millimoles) of potassium peroxy disulfate (K2S208), 28,65 g (80,0 millimoles) of sodium hydrogen phosphate (Na2HPO4.12 H2O), 56,0 ml of acetonitrile and 21,0 ml of water is heated to boiling under stirring for 3 hours. The reaction mixture is cooled, filtered and the filtrate is separated. The aqueous layer of the filtrate is extracted three times with 50 ml of ethyl acetate each.The organic layers are united, extracted with a 10% aqueous sodium carbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residual oil is worked-up by means of chromatography (absorbent: Kieselgel G, eluting solvent: a 7:1 mixture of dichloromethane and acetone).
Thus 1,73 g of the desired mixture are obtained, yield: 51%.
IR(KBr): 3400, 3250, 1755, 1735 cam~'.
1H-NMR(CDCI3): 81 .18-1.32 dd (3H); 2.20-3.00 m (1H + 2H + + 1H); 3.65-4.28 m (1H + 1H); 6.1 s H); 6.9 s (1 H); 7.30 s (10H).
The starting material can be prepared as follows:
a) To a suspension of 41,2 g (0,109 mole) of transethyl-C1 -(2,4-dimethoxy-benzyl)-3-(2- methyl-1 ,3-dioxolane-2-yl)-4-oxo-2-azetidine-carboxylate] (this compound is disclosed in laidopen Hungarian patent application No. 2263/80 and corresponds to the general Formula VI,
wherein Z is ethyl and R stands for dimethoxy-benzyl) and 50 ml of ethanol a solution of 5,21 g (0,1 30 mole) of sodium hydroxide in 60 ml of water is added under stirring and external cooling with icecold water and the mixture is stirred until a clear solution is formed (about 20 minutes). To the solution 100 ml of water are added and the mixture is extracted with 100 ml of ether.The aqueous phase is acidified with concentrated hydrochloric acid to pH 1 and extracted quickly once with 100 ml and twice with 50 ml of dichloromethane each. The dichloromethane solution is dried over magnesium sulfate, filtered and the filtrate is evaporated.
The residual oil is recrystallized from a mixture of toluene and petrolether. Thus 35 g of transl (2,4-di methoxy-benzyl)-3-(2-methyl- 1 , 3-dioxolane-2-yl)-4-oxo-2-azetidine-carboxylic acid are obtained, yield 92%. This compound corresponds to the general Formula VI (Z is hydrogen and R stands tor dimethoxybenzyl). Mp.: 117-118 C (toluene).
Analysis: for the Formula C,7H2,NO7 (351.35) calculated: C% = 58.11; H% = 6.03; N% = 3.99; found: C% = 58.17; H% = 6.30; N% = 4.24.
IR(KBr): 3500-2500, 2900, 1760, 1720 cm~'.
1H-NMR(CDCl3): 81.39 (s, 3H), 3,50 (d, 1 H, J = 2.5 Hz), 3.77 (s, 3H), 3.79 (s, 3H), 3.86 (d, 1 H, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4.56 (d, 2H, JAB= 15Hz), 6.44 (m, 2H) + 7.15 (d, 1 H, J = 1 OHz), 7.58 (broad, s, 1 H).
b) To a solution of 17.6 g (50 millimoles) of transl -(2,4-dimethoxy-benzyl)-3-(2-methyl-l ,3- dioxolane-2-yl)-4-oxo-2-azetidine-carboxylic acid (prepared according to Example 1 a) in 1 50 ml of anhydrous tetrahydrofurane 7.3 ml (52.5 millimoles) of triethyl amine are added and thereafter to the mixture 5.0 ml (52.5 millimoles) of ethyl chloroformate are added under ice cooling. The reaction mixture is cooled to - 1 5'C and stirred at this temperature for 20 minutes, whereupon the triethyl amine salt precipitated at this temperature under argon is filtered off. To the filtrate a solution of 1 50 millimoles of diazo methane and 230 ml of cold diethyl ether is added.The solution is stirred and allowed to warm to room temperature, whereupon after 2 hours the mixture is evaporated to dryness. The brown viscouse mass is dissolved in 20 ml of benzene and subjected to column chromatography (absorbent: 1 50 g of
Kieselgel 60, diameter: 0,063-0,200 mm; eluent: a 7:2 mixture of benzene and acetone). Thus 12,0 g of trans4-(diazo-acetyl)- 1 -(2, 4-dimethoxy-benzyl)-3-(2-methyl- 1, 3-dioxalane-2-yl)-2-azetidinone are obtained, yield 64%. This compound corresponds to the general Formula V,
(wherein R is dimethoxybenzyl).
Analysis: for the Formula C18H21N306 (375.37) calculated: C% = 57.59; H% = 5.64; found: C% = 57.78; H% = 5.39.
IR(KBr): 2900, 2110, 1760 cm-'.
c) A mixture of 2,25 g (6 millimoles) of trani4-(diazo-acetyl)-1-(2,4-dimethoxy-benzyl)-3-(2- methyl-1 ,3-dioxolan-2-yl)-2-azetidinone, 100 ml of peroxide-free tetrahydrofurane and 50 ml of water is irradiated in a Pyrex apparatus equipped with an immersing lamp under argon for about 4 hours with a high pressure mercury vapour lamp (HPK 125). The solution is evaporated to 50 ml in vacuo and the residue is diluted with water to 1 30 ml. To the aqueous solution 2.4 ml of a 10% aqueous sodium hydroxide solution are added. The alkaline solution is extracted three times with 20 ml of dichloromethane each and the aqueous layer is acidified with concentrated hydrochloric acid to pH = 2. The acidic solution is extracted three times with 20 ml of dichloromethane each.The extract is dried over magnesium sulfate, filtered and the filtrate is evaporated to dryness. The residue is crystallized from ether and filtered.
Thus 1,82 g of [trnns 1 -(2, 4-dimethoxy-benzyl)-3-(2-methyl- 1 , 3-dioxolan-2-yI)-4-oxo-2-azetid nyl]-acetic acid are obtained, yield 83%.
This compound corresponds to the general Formula IV
(R is dimethoxybenzyl).
Mp.: 1 24'C (ether).
Analysis: for the Formula C,8H23NO7 (365,37): calculated: C% = 59.17; H% = 6.34; N% = 3.83; found: C% = 59.22; H% = 6.49; N% = 4.07.
IR(KBr): 3500-2300, 2900, 1730, 1700 cm~'.
d) To a solution of 5.48 g (15 millimoles) of [trans-1-(2,4-dimethoxy-benzyl)-3-(2-methyl-1 ,3- dioxolan-2-yI)-4-oxo-2-azetidinylj-acetic acid prepared according to Example 1 c) in 50 ml of dichloromethane 3,05 g (15.75 millimoles) of diphenyl diazomethane are added at room temperature under stirring. After the nitrogen evolution has stopped, the residual diphenyl diazomethane is decomposed by adding some drops of acetic acid. The solution is evaporated to dryness and the residue (6.77 g) is isolated.
e) 5,31 g (10,0 millimoles) of the residue obtained according to Example 1d) (consisting of benzhydryl-(2 RS, 3 SR)-[ 1 -(2,4-dimethoxy-benzyl)-3-(2-methyl-l , 3-dioxolane-2-yl)-4-oxo-2-azeti- dinyl]-acetatej are dissolved in 100 ml of anhydrous acetone and the solution is cooled to oec, whereupon 2.0 ml (24.0 millimoles) of 70% perchloric acid are added. The reaction mixture is stirred for 45 minutes under ice cooling whereupon 2.20 g of (2.64 millimoles) of sodium hydrogen carbonate are added and the mixture is stirred for further 10 minutes.The suspension is evaporated in vacuo without heating, the residue is dissolved in 60 ml of methanol, whereupon 0.370 g (10.0 millimoles) of sodium-[tetrahydridoborate-(lll)] is added under icecooling and stirring. The reaction takes about an hour. The mixture is acidified with acetic acid to pH 7 and the methanol is distilled off. The residue is dissolved in 100 ml of dichloromethane and extracted twice with 25 ml of water each and with 25 ml of a saturated aqueous sodium chloride solution. The organic layer is dried over magnesium sulfate and evaporated. Thus 3.00 g of benzhydryl- ((2 RS, 3 SR)-1 -(2,4-d i rethoxy-benzyl)-3-l 1 -(RS and SR)-hydroxyethyl]-4-oxo-2- azetidinyl-acetate) mixture is obtained, yi'eld 61%.
IR(KBr): 3400, 1725 cm ~ ' . * 1H-NMR (CDCl3, S): 1.06-1.24 dd (3H); 2.20-3.06 m (1 H + 1 H + 2H); 3.55-3.95 m (3H + 3H + 1 H + 1 H); 3.95-4.10 m (2H); 6.36-6.50 m (2H); 6.90 s (1 H); 7.05-7.40 m (10H+ 1H).
Example 2 Benzhydryl- ((2 RS, 3 SR)-3-C1-(RS and SR)-hydroxyethyl]-4-oxo-2-azetidinyl-acetate} 0.381 g (1.0 millimole) of benzhydryl-{(2 RS, 3 SA)-(3-(2-methyl-1 ,3-dioxolan-2-yl)-4-oxo-2- acezitidinyl]-acetate) are dissolved in 10 ml of acetone and to the solution 0.2 ml (2.3 mi!limoles) of 70% aqueous perchloric acid is added under ice cooling, whereupon after 45 minutes 0.20 9 (2.4 millimoles) of sodium hydrogen carbonate is added. The mixture is stirred for 5 minutes and evaporated to dryness in vacuo as cold.The residue is suspended in 10 ml of anhydrous methanol, whereupon 0.038 g (1.0 millimole) of sodium borohydride (NaBH4) is added under ice cooling and stirring, the mixture is stirred for 3 hours, cooled, neutralized with cold acetic acid and evaporated to dryness. The residue is suspended in dichloromethane, extracted with water, the dichloromethane solution is dried over magnesium sulfate and purified by chromatography (absorbent: Kieselgel PF 254, eluent: a 7:1 mixture of dichloromethane and acetone). Thus 0.25g of the desired product is obtained, yield 74%. The physical constants of the product thus obtained are identical with those of the compound prepared according to
Example 1.
The starting material can be prepared as follows:
To a solution of 5.48 g (15 millimoles) of [transi -(2,4-dimethoxy-benzyl)-3-(2-methyl-1 ,3- dioxolan-2-yl)-4-oxo-2-azetidinyl]-acetic acid prepared according to Example 1 c) and 50 ml of dichloromethane 3.05 g (15.75 millimoles) of diphenyl diazomethane are added under stirring at room temperature. After the nitrogen evolution has ceased the.residual diphenyl diazomethane is decomposed by adding a few drops of acetic acid. The solution is evaporated to dryness and the residue (6.77 g) is dissolved in 84 ml of acetonitrile. To the solution 16.20 g (60 millimoles) of potassium peroxy disulfate (K2S208), 21.60 g (120 millimoles) of disodium hydrogen phosphate monohydrate (Na2HPO4.H20) and 54 ml of water are added, the mixture is intensively stirred for 4 hours, heated to boiling and cooled.The cold reaction mixture is filtered and the layers of the filtrate are separated. The aqueous phase is extracted three times with 30 ml of ethyl acetate each. The united organic phases are dried over magnesium sulfate, filtered and the filtrate is evaporated. The residue is dissolved in benzene and the solution is worked-up by a chromatographical method (absorbent: Kieselgel 60, diameter: 0.050-0.200 mm; eluent: a 7:2 mixture of benzene and acetone). Thus 2.68 g of benzhydryl-(2 RS, 3 SA)-(3-(2-methyl- 1,3-dioxolan-2-yl)-4-oxo-2-azetidinyl]-acetate are obtained, yield: 47%.
Mp.: 130"C(ethanol) Analysis: for the Formula C22H23NOs (387.41) calculated: C% = 69.27; H% = 6.08; N% = 3.67; found: C% = 69.15; H% = 6.20; N% = 3.55.
IR(KBr): 3250, 2900, 1760, 1740cm-1.
'H-NMR(CDCI3): 51.39 s (3H), 2.63 dd (2H, j = 4.4 Hz) and 2.89 dd (2H, J = 9.1 Hz), 3.97 m (5H), 6.12 s (1H), 6.9 s (1H), 7.28 s (10H).
The product prepared according to Example 1 or 2 can be converted into the (2 RS, 3 SR)-3 1-(SR)-hydrnxyethyIl-4-oxo-2-azetidinyl-acetic acid as follows. (The latter compound is an intermediate of thienamycin and disclosed in European patent specification No. 62 840).
A mixture of 0.339 g (1.0 millimole) of benzhydryl-(2 RS, 3 SR)-(3-C1 (RS and SR) hydroxyethyl]-2-azetidinyl)-acetate, 0.03 g of a 10% palladium/charcoal catalyst and 15 ml of anhydrous ethanol is stirred under hydrogen until the hydrogen consumption stops (about 6 hours). The catalyst is filtered off, the filtrate is evaporated in vacuo in the cold. The residue is treated with ether, decanted and the residue is dried. Thus 0.121 g of (2 RS, 3 SR)-3-[1 (SR)hydroxyethyl]-4-oxo-2-azetidinyl-acetic acid are obtained, yield: 70%.
IR(KBr): 3400, 3250, 1740-1660 cm-l.
'H-NMR(CDCI3 + DMSO): S1.25 d (3H, J = 6Hz); 2.58 d (2H, J = 6Hz); 2.9 dd (1 H, J = 5.3
Hz and J = 2.3 Hz); 3.7-4.2 m (1 H + 1 H).
Claims (9)
1. New diastereomers of the Formula I.
2. Process for the preparation of new diastereomers of the Formula I
which comprises removing the ethylene ketal group from a compound of the general Formula Ill
[wherein R' stands for a hydrogen atom or as an amide protecting group for a phenyl or benzyl group optionally substituted by one or more methoxy group(s)] and reducing the new compound of the general Formula II
thus obtained (wherein R' has the same meaning as stated above) and isolating the product thus obtained-if desired, after removal of the amide protecting group--and, if desired, separating the pair of diastereomers thus obtained into the components thereof.
3. Process according to Claim 2, which comprises splitting off the ethylene ketal group with a mineral acid.
4. Process according to Claim 2 or 3, which comprises splitting off the ethylene ketal group in the presence of a ketone.
5. Process according to Claim 2, which comprises carrying out reduction with a complex metal hydride.
6. Process according to Claim 2, which comprises removing the amide protecting group with an oxidizing agent.
7. New compounds of the general Formula II (wherein Rç has the same meaning as stated in
Claim 2).
8. A process according to claim 2, substantially as hereinbefore described with reference to any of the Examples.
9. A compound of the formula I when prepared by a process according to any of claims 2 to 6 and 8.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU832218A HU188913B (en) | 1983-06-23 | 1983-06-23 | Process for producing new azetidinyl-acetic acid esters |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8415800D0 GB8415800D0 (en) | 1984-07-25 |
| GB2144120A true GB2144120A (en) | 1985-02-27 |
| GB2144120B GB2144120B (en) | 1987-01-21 |
Family
ID=10958351
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08415800A Expired GB2144120B (en) | 1983-06-23 | 1984-06-21 | Azetidinyl acetic acid esters |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS6056955A (en) |
| AT (1) | AT383118B (en) |
| AU (1) | AU560544B2 (en) |
| BE (1) | BE899936A (en) |
| CA (1) | CA1215715A (en) |
| CH (1) | CH661269A5 (en) |
| DE (1) | DE3423069A1 (en) |
| ES (1) | ES533664A0 (en) |
| FI (1) | FI842515A (en) |
| FR (1) | FR2549052B1 (en) |
| GB (1) | GB2144120B (en) |
| GR (1) | GR81634B (en) |
| HU (1) | HU188913B (en) |
| IT (1) | IT1196155B (en) |
| LU (1) | LU85424A1 (en) |
| NL (1) | NL8401978A (en) |
| PL (1) | PL142079B1 (en) |
| SE (1) | SE8403349L (en) |
| ZA (1) | ZA844724B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2173192A (en) * | 1985-03-27 | 1986-10-08 | Richter Gedeon Vegyeszet | Azetidinone derivatives |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59222696A (en) * | 1983-05-31 | 1984-12-14 | ハウス食品工業株式会社 | Method and device for discharging drain |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS604814B2 (en) * | 1978-03-03 | 1985-02-06 | 協和醗酵工業株式会社 | 2-azetidinone derivative and method for producing the same |
| PT71553B (en) * | 1979-07-23 | 1981-12-14 | Merck & Co Inc | Process for the preparation of thienamycin and intermediates |
| US4287123A (en) * | 1980-01-14 | 1981-09-01 | Merck & Co., Inc. | Synthesis of thienamycin via (3SR, 4RS)-3-((RS)-1-acyloxyethyl)-2-oxo-4-azetidineacetate |
| JPS57167964A (en) * | 1981-04-09 | 1982-10-16 | Toyama Chem Co Ltd | Preparation of (4r)-3-substituted-4-(substituted or unsubstituted carboxymethyl)-2-azetidinone derivative |
-
1983
- 1983-06-23 HU HU832218A patent/HU188913B/en not_active IP Right Cessation
-
1984
- 1984-06-18 BE BE1/11041A patent/BE899936A/en not_active IP Right Cessation
- 1984-06-20 PL PL1984248312A patent/PL142079B1/en unknown
- 1984-06-20 CH CH2982/84A patent/CH661269A5/en not_active IP Right Cessation
- 1984-06-21 SE SE8403349A patent/SE8403349L/en not_active Application Discontinuation
- 1984-06-21 GR GR75076A patent/GR81634B/el unknown
- 1984-06-21 LU LU85424A patent/LU85424A1/en unknown
- 1984-06-21 FR FR8409757A patent/FR2549052B1/en not_active Expired
- 1984-06-21 IT IT8421534A patent/IT1196155B/en active
- 1984-06-21 AU AU29745/84A patent/AU560544B2/en not_active Ceased
- 1984-06-21 ZA ZA844724A patent/ZA844724B/en unknown
- 1984-06-21 GB GB08415800A patent/GB2144120B/en not_active Expired
- 1984-06-21 JP JP59126537A patent/JPS6056955A/en active Pending
- 1984-06-21 FI FI842515A patent/FI842515A/en not_active Application Discontinuation
- 1984-06-22 DE DE3423069A patent/DE3423069A1/en not_active Withdrawn
- 1984-06-22 CA CA000457319A patent/CA1215715A/en not_active Expired
- 1984-06-22 NL NL8401978A patent/NL8401978A/en not_active Application Discontinuation
- 1984-06-22 AT AT0202784A patent/AT383118B/en not_active IP Right Cessation
- 1984-06-22 ES ES533664A patent/ES533664A0/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2173192A (en) * | 1985-03-27 | 1986-10-08 | Richter Gedeon Vegyeszet | Azetidinone derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| ES8600236A1 (en) | 1985-10-01 |
| LU85424A1 (en) | 1986-02-18 |
| PL142079B1 (en) | 1987-09-30 |
| GB2144120B (en) | 1987-01-21 |
| HUT34441A (en) | 1985-03-28 |
| PL248312A1 (en) | 1985-07-16 |
| SE8403349D0 (en) | 1984-06-21 |
| AU2974584A (en) | 1985-01-03 |
| GR81634B (en) | 1984-12-11 |
| AT383118B (en) | 1987-05-25 |
| SE8403349L (en) | 1984-12-24 |
| IT8421534A0 (en) | 1984-06-21 |
| AU560544B2 (en) | 1987-04-09 |
| CH661269A5 (en) | 1987-07-15 |
| HU188913B (en) | 1986-05-28 |
| FI842515A0 (en) | 1984-06-21 |
| BE899936A (en) | 1984-10-15 |
| CA1215715A (en) | 1986-12-23 |
| IT1196155B (en) | 1988-11-10 |
| ES533664A0 (en) | 1985-10-01 |
| ZA844724B (en) | 1985-02-27 |
| ATA202784A (en) | 1986-10-15 |
| FR2549052B1 (en) | 1987-12-04 |
| FI842515A (en) | 1984-12-24 |
| DE3423069A1 (en) | 1985-01-10 |
| JPS6056955A (en) | 1985-04-02 |
| NL8401978A (en) | 1985-01-16 |
| GB8415800D0 (en) | 1984-07-25 |
| FR2549052A1 (en) | 1985-01-18 |
| IT8421534A1 (en) | 1985-12-21 |
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Legal Events
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| PCNP | Patent ceased through non-payment of renewal fee |