HRP920486A2 - 4-oxo-azetidine of -2- sulfonic acids and salts, the method for the preparation and use thereof - Google Patents
4-oxo-azetidine of -2- sulfonic acids and salts, the method for the preparation and use thereof Download PDFInfo
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- HRP920486A2 HRP920486A2 HR920486A HRP920486A HRP920486A2 HR P920486 A2 HRP920486 A2 HR P920486A2 HR 920486 A HR920486 A HR 920486A HR P920486 A HRP920486 A HR P920486A HR P920486 A2 HRP920486 A2 HR P920486A2
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- Prior art keywords
- hydrogen
- cooch2c6h4
- phenylacetamido
- methyl
- oxo
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- 238000000034 method Methods 0.000 title claims description 12
- 150000003839 salts Chemical class 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 7
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- -1 phenylacetamido, phenoxyacetamido, phthalimido, 5-methyl-3-o-chlorophenyl-isoxazole-4-carboxamido Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- SXTPCWDEYAMPTR-UHFFFAOYSA-N 4-oxoazetidine-2-sulfonic acid Chemical class OS(=O)(=O)C1CC(=O)N1 SXTPCWDEYAMPTR-UHFFFAOYSA-N 0.000 claims description 7
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 7
- 239000012286 potassium permanganate Substances 0.000 claims description 7
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 7
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000000543 intermediate Substances 0.000 claims description 3
- FIEQMOCSOXENFX-UHFFFAOYSA-N 4-oxoazetidine-2-sulfinic acid Chemical class OS(=O)C1CC(=O)N1 FIEQMOCSOXENFX-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 239000002132 β-lactam antibiotic Substances 0.000 claims description 2
- 229940124586 β-lactam antibiotics Drugs 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 241001465754 Metazoa Species 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 238000011203 antimicrobial therapy Methods 0.000 claims 1
- 125000005544 phthalimido group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000284 extract Substances 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- 239000010410 layer Substances 0.000 description 5
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- SKFSFIDBKDWSJN-MWLCHTKSSA-N (2r,3r)-4-oxo-3-[(2-phenoxyacetyl)amino]azetidine-2-sulfonic acid Chemical compound OS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(=O)COC1=CC=CC=C1 SKFSFIDBKDWSJN-MWLCHTKSSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- FBPINGSGHKXIQA-UHFFFAOYSA-N 2-amino-3-(2-carboxyethylsulfanyl)propanoic acid Chemical compound OC(=O)C(N)CSCCC(O)=O FBPINGSGHKXIQA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- PGOVCEKQTUBQGL-UHFFFAOYSA-N 4-oxo-3-[(2-phenylacetyl)amino]azetidine-2-sulfonic acid Chemical compound OS(=O)(=O)C1NC(=O)C1NC(=O)CC1=CC=CC=C1 PGOVCEKQTUBQGL-UHFFFAOYSA-N 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- MGGABXPAYAOLGW-XYMBCYCGSA-L C(CCC)[N+](CCCC)(CCCC)CCCC.C(CCC)[N+](CCCC)(CCCC)CCCC.C1(=CC=CC=C1)CC(=O)N[C@H]1[C@H](N(C1=O)S(=O)(=O)[O-])S(=O)(=O)[O-] Chemical compound C(CCC)[N+](CCCC)(CCCC)CCCC.C(CCC)[N+](CCCC)(CCCC)CCCC.C1(=CC=CC=C1)CC(=O)N[C@H]1[C@H](N(C1=O)S(=O)(=O)[O-])S(=O)(=O)[O-] MGGABXPAYAOLGW-XYMBCYCGSA-L 0.000 description 1
- FVLJPEZGPSNFTH-HNYBLYFDSA-M C(CCC)[N+](CCCC)(CCCC)CCCC.C1(=CC=CC=C1)CC(=O)N[C@H]1[C@H](NC1=O)S(=O)(=O)[O-] Chemical compound C(CCC)[N+](CCCC)(CCCC)CCCC.C1(=CC=CC=C1)CC(=O)N[C@H]1[C@H](NC1=O)S(=O)(=O)[O-] FVLJPEZGPSNFTH-HNYBLYFDSA-M 0.000 description 1
- FCIVWXCTSVLLGS-ZYHUDNBSSA-N COS(=O)(=O)[C@H]1NC([C@H]1NC(CC1=CC=CC=C1)=O)=O Chemical compound COS(=O)(=O)[C@H]1NC([C@H]1NC(CC1=CC=CC=C1)=O)=O FCIVWXCTSVLLGS-ZYHUDNBSSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- QGTSBTZLEXAYPO-FOKYBFFNSA-M [Na+].C1(=CC=CC=C1)CC(=O)N[C@H]1[C@H](NC1=O)S(=O)(=O)[O-] Chemical compound [Na+].C1(=CC=CC=C1)CC(=O)N[C@H]1[C@H](NC1=O)S(=O)(=O)[O-] QGTSBTZLEXAYPO-FOKYBFFNSA-M 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 1
- 229960003644 aztreonam Drugs 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229940041009 monobactams Drugs 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Oblast tehnike u koju izum spada The technical field to which the invention belongs
Int. Klas.C07D 205/08 Int. Class C07D 205/08
A61K 31/395 A61K 31/395
Izum se odnosi na 4-okso-azetidin-2-sulfonske kiseline i soli, postupke za njihovo dobivanje i upotrebu. The invention relates to 4-oxo-azetidine-2-sulfonic acids and salts, procedures for their preparation and use.
Poznate su brojne monocikličke 4-okso-azetidin-1-sulfonske kiseline i derivati [Chemistry in Britain (1983) 302] među kojima je i značajni beta-laktamski antibiotik aztreonam [Drugs of the Future 8 (1983) 295]. Numerous monocyclic 4-oxo-azetidine-1-sulfonic acids and derivatives are known [Chemistry in Britain (1983) 302], among which is the significant beta-lactam antibiotic aztreonam [Drugs of the Future 8 (1983) 295].
Poznate su također i neke 4-okso-azetidin-2-sulfonske kiseline priređene transformacijom nekih bicikličkih molekula [Angew. Chem. 95 (1983) 912] tako da su oba vodikova atoma u položaju C3 supstituirana. Also known are some 4-oxo-azetidine-2-sulfonic acids prepared by the transformation of some bicyclic molecules [Angew. Chem. 95 (1983) 912] so that both hydrogen atoms in the C3 position are substituted.
Prema nama dostupnim podacima o stanju tehnike, 4-okso-azetidin-2-sulfonske kiseline i soli koje su predmet ovog izuma, postupci za njihovo dobivanje, kao i njihova upotreba, nisu poznati. According to the information available to us on the state of the art, 4-oxo-azetidine-2-sulfonic acid and salts that are the subject of this invention, the procedures for their preparation, as well as their use, are not known.
Predmet ovog izuma je priprava novih 4-okso-azetidin-2-sulfonskih kiselina i soli opće formule I The subject of this invention is the preparation of new 4-oxo-azetidine-2-sulfonic acids and salts of the general formula I
[image] [image]
gdje radikali imaju značenje: where the radicals have the meaning:
R = fenilacetamido, fenoksiacetamido, ftalimido, 5-metil-3-o-klorfenil-izoksazolil-4-karboksamido R = phenylacetamido, phenoxyacetamido, phthalimido, 5-methyl-3-o-chlorophenyl-isoxazolyl-4-carboxamido
R1 = vodik, natrij, tetrabutilamonij, R1 = hydrogen, sodium, tetrabutylammonium,
R2 = vodik, SO2O-+NBu4-n. (CH3)2C=C-COOCH3, R2 = hydrogen, SO2O-+NBu4-n. (CH3)2C=C-COOCH3,
(CH3)2C=C-COOCH2-C6H4-pNO2, (CH3)2C=C-COOCH2-C6H4-m-CH3 (CH3)2C=C-COOCH2-C6H4-pNO2, (CH3)2C=C-COOCH2-C6H4-m-CH3
Daljnji predmet ovog izuma je postupak za pripravu novih 4-okso-azetidin-2-sulfonskih kiselina i soli opće formule I, gdje radikali imaju značenje kako je navedeno, a koji se mogu pripraviti reakcijom 4-okso-azetidin-2-sulfinskih kiselina i derivata opće formule II A further object of this invention is a process for the preparation of new 4-oxo-azetidine-2-sulfonic acids and salts of the general formula I, where the radicals have the meaning as stated, which can be prepared by the reaction of 4-oxo-azetidine-2-sulfinic acids and derivatives of the general formula II
[image] [image]
gdje radikali imaju značenje: where the radicals have the meaning:
R = fenilacetamido, fenoksiacetamido, ftalimido, 5-metil-3-o-klorfenil-izoksazolil-4-karboksamido R = phenylacetamido, phenoxyacetamido, phthalimido, 5-methyl-3-o-chlorophenyl-isoxazolyl-4-carboxamido
R1 = vodik, metil, R1 = hydrogen, methyl,
R2 = (CH3)2C=C-COOCH3, (CH3)2C=C-COOCH2-C6H4-pNO2, R2 = (CH3)2C=C-COOCH3, (CH3)2C=C-COOCH2-C6H4-pNO2,
(CH3)2C=C-COOCH2-C6H4-m-CH3 (CH3)2C=C-COOCH2-C6H4-m-CH3
s kalijevimpermanganatom ili m-klorperbenzojevom kiselinom (m-CPBA) ili vodikovim peroksidom u kiselom vodeno-organskom mediju, kod uobičajenih reakcijskih uvjeta uz molarne odnose i način izolacije kako je navedeno u primjerima. U pojedinim slučajevima moguće je izolirati sulfonate kao intermedijere i hidrolizirati ih s organskim ili anorganskim bazama do sulfonskih kiselina odnosno soli. Pojedine sulfonske kiseline su izolirane u obliku alkalijskih ili amonijskih soli uobičajenim postupcima priprave i izolacije. with potassium permanganate or m-chloroperbenzoic acid (m-CPBA) or hydrogen peroxide in an acidic aqueous-organic medium, under usual reaction conditions with molar ratios and method of isolation as specified in the examples. In some cases, it is possible to isolate sulfonates as intermediates and hydrolyze them with organic or inorganic bases to sulfonic acids or salts. Individual sulfonic acids are isolated in the form of alkaline or ammonium salts by the usual preparation and isolation procedures.
Daljnji predmet ovog izuma se odnosi na upotrebu ovih spojeva kao korisnih intermedijera u sintezama novih beta-laktamskih analogona posebno monobaktama i karbapenema. A further subject of this invention relates to the use of these compounds as useful intermediates in the synthesis of new beta-lactam analogs, especially monobactams and carbapenems.
Daljnji predmet ovog izuma se odnosi na upotrebu ovih spojeva kao aktivnih komponenti u farmaceutskim preparatima koji imaju antimikrobnu aktivnost. A further subject of this invention relates to the use of these compounds as active components in pharmaceutical preparations having antimicrobial activity.
Primjer 1 Example 1
(2R, 3R) 3-Ftalimido-1-(1'-p-nitrobenziloksikarbonil-2'-metil-prop-1'-enil)-4-okso-azetidin-2-sulfonska kiselina (2R, 3R) 3-Phthalimido-1-(1'-p-nitrobenzyloxycarbonyl-2'-methyl-prop-1'-enyl)-4-oxo-azetidine-2-sulfonic acid
a) Metil ester 3-ftalimido-1-(1'-p-nitrobenziloksikarbonil-2'-metil-prop-1'-enil)-4-okso-azetidin-2-sulfinske kiseline (1230 mg, 2.33 mmol) se otopi u EtoAc (30 ml) i H2O (12 ml) doda 0.3 ml 80 %-tne octene kiseline i kod +5 °C dokapa u vremenu od 80 minuta 14 ml vodene otopine KMnO4 (560 mg, 3.5 mmol). Doda se voda (30 ml), dokapa 30 % H2O2 (~7ml) do nestanka boje. Organski sloj odvojen, dodana otopina NaHCO3 (250 mg, 3 mmol) u vodi i miješano kod 50 °C. Upareno u vakuumu do krutog ostatka, otopljeno u vodi i propušteno preko Dowex-a 50. Eluat liofiliziran. Zaostalo 941 mg (76.3 %) pahuljastog ostatka. a) 3-phthalimido-1-(1'-p-nitrobenzyloxycarbonyl-2'-methyl-prop-1'-enyl)-4-oxo-azetidine-2-sulfinic acid methyl ester (1230 mg, 2.33 mmol) was dissolved in EtoAc (30 ml) and H2O (12 ml) add 0.3 ml of 80% acetic acid and add 14 ml of aqueous KMnO4 solution (560 mg, 3.5 mmol) over a period of 80 minutes at +5 °C. Add water (30 ml), add 30% H2O2 (~7ml) until the color disappears. Separated the organic layer, added a solution of NaHCO3 (250 mg, 3 mmol) in water and stirred at 50 °C. Evaporated in vacuo to a solid residue, dissolved in water and passed over Dowex 50. Eluate lyophilized. 941 mg (76.3 %) of fluffy residue remained.
Rf 0.51 (EtoAc : HAc : H2O = 10:2:1); Rf 0.51 (EtoAc : HAc : H2O = 10:2:1);
IR(KBr) 3700-3200 bm, 1790 s, 1770 s, 1725 vs, 1520 m, 1395 s, 1350 m, 1215 m, 1040 w cm-1 IR(KBr) 3700-3200 bm, 1790 s, 1770 s, 1725 vs, 1520 m, 1395 s, 1350 m, 1215 m, 1040 w cm-1
1H NMR (DMSO-d6) δ: 2.33 (s, 2 CH3), 4.81 (d, C4H, J 5.4 Hz), 4.97 (s, SO2OH+HOH), 5.44 (d, C3H, J 5.4Hz), 5.50 (s, OCH2), 7.81 i 8.35 (2d, C6H4NO2) 7.97 (s, C6H5) ppm 1H NMR (DMSO-d6) δ: 2.33 (s, 2 CH3), 4.81 (d, C4H, J 5.4 Hz), 4.97 (s, SO2OH+HOH), 5.44 (d, C3H, J 5.4Hz), 5.50 ( s, OCH2), 7.81 and 8.35 (2d, C6H4NO2) 7.97 (s, C6H5) ppm
b) Metil ester 3-ftalimido-1-(1'-p-nitrobenziloksikarbonil-2'-metil-prop-1'-enil)-4-okso-azetidin-2-sulfonske kiseline (480 mg, 0,88 mmol) se otopi u metilenkloridu (10 ml), doda trietilamin (200 mg, 1.98 mmol) i miješa 4 sata kod +5 °C. Upari se do suha; ostatak se otopi u vodi i propusti preko Dowex-a 50. Eluat se liofilizira nakon čega zaostaje pahuljasti produkt identičan opisanom u postupku a). b) Methyl ester of 3-phthalimido-1-(1'-p-nitrobenzyloxycarbonyl-2'-methyl-prop-1'-enyl)-4-oxo-azetidine-2-sulfonic acid (480 mg, 0.88 mmol) is dissolved in methylene chloride (10 ml), triethylamine (200 mg, 1.98 mmol) is added and stirred for 4 hours at +5 °C. Evaporate to dryness; the rest is dissolved in water and passed through Dowex 50. The eluate is lyophilized, after which a fluffy product identical to that described in procedure a) remains.
Primjer 2 Example 2
2R,3R) 3-Fenilacetamido-1-(1'-p-nitrobenziloksikarbonil-2'-metil-prop-1'-enil)-4-okso-azetidin-2-sulfonska kiselina 2R,3R) 3-Phenylacetamido-1-(1'-p-nitrobenzyloxycarbonyl-2'-methyl-prop-1'-enyl)-4-oxo-azetidine-2-sulfonic acid
a) Metil ester 3-fenilacetamido-1-(1'-p-nitrobenziloksikarbonil-2'-metil-prop-1'-enil)-4-okso-azetidin-2-sulfinska kiselina (400 mg, 0.78 mmol) se otopi u metilenkloridu (15 ml) i mravljoj kiselini (1.3 ml) i doda kod RT 30 %-tni vodikov peroksid (4.8 ml). Reakcijska smjesa se miješa 2 sata kod 40 °C nakon čega se doda metilenklorid (20 ml) i voda (15 ml). Organski ekstrakt se odvoji, ispere s H2O (1 x 15 ml), suši (Na2SO4), filtrira i upari do suha u vakumu. Ostatak se otopi u etilacetatu (10 ml) doda trietilamin (100 mg, 1 mmol) miješa kod RT 1.5 sati. Upari se u vakumu, ostatak otopi u vodi (10 ml), propusti preko Dowex-a 50 i liofilizira. Zaostaje 213 mg (52.6 %) sirovog produkta koji kristalizira iz etilacetata. a) Methyl ester 3-phenylacetamido-1-(1'-p-nitrobenzyloxycarbonyl-2'-methyl-prop-1'-enyl)-4-oxo-azetidine-2-sulfinic acid (400 mg, 0.78 mmol) is dissolved in methylene chloride (15 ml) and formic acid (1.3 ml) and add 30% hydrogen peroxide (4.8 ml) at RT. The reaction mixture was stirred for 2 hours at 40 °C, after which methylene chloride (20 ml) and water (15 ml) were added. The organic extract is separated, washed with H2O (1 x 15 ml), dried (Na2SO4), filtered and evaporated to dryness under vacuum. The residue is dissolved in ethyl acetate (10 ml), triethylamine (100 mg, 1 mmol) is added and stirred at RT for 1.5 hours. It is evaporated under vacuum, the residue is dissolved in water (10 ml), passed through Dowex 50 and lyophilized. 213 mg (52.6 %) of the crude product, which crystallizes from ethyl acetate, remains.
t.t. 164-166 °C d.p. 164-166 °C
Rf 0.58 (CH2Cl2 : CH3OH = 4:1) Rf 0.58 (CH2Cl2 : CH3OH = 4:1)
IR(KBr): 3700 - 3150 bm, 3360 s, 1765 s, 1755 s, 1710 m, 1680 m, 1660 m, 1520 s, 1350 s, 1220 vs, 1040 s cm-1 IR(KBr): 3700 - 3150 bm, 3360 s, 1765 s, 1755 s, 1710 m, 1680 m, 1660 m, 1520 s, 1350 s, 1220 vs, 1040 s cm-1
1H NMR (DHSO-d6) δ: 2.04 (s, CH3), 2.18 (s, CH3), 3.52 (s, CH2CO), 4.59 (d, C2H, J 5.4 Hz), 5.33 (s, O-CH2), 5.37 (q, C3H, J 5.4 i 10.1 Hz), 6.44 (bs, SO2OH), 7.27 (s, C6H5), 7.67 i 8.23 (2d, C6H4-NO2, J 8.6 Hz) i 8.0 (d, NHCO, J 10.1 Hz) ppm 1H NMR (DHSO-d6) δ: 2.04 (s, CH3), 2.18 (s, CH3), 3.52 (s, CH2CO), 4.59 (d, C2H, J 5.4 Hz), 5.33 (s, O-CH2), 5.37 (q, C3H, J 5.4 and 10.1 Hz), 6.44 (bs, SO2OH), 7.27 (s, C6H5), 7.67 and 8.23 (2d, C6H4-NO2, J 8.6 Hz) and 8.0 (d, NHCO, J 10.1 Hz) ppm
b) Metil ester 3-fenilacetamido-1-(1'-p-nitrobenziloksikarbonil-2-metil-prop-1'-enil)-4-okso-azetidin-2 sulfonska kiselina (240 mg, 0.45 mmol) se otopi u metilenkloridu (5 ml); doda se trietilamin (68 mg, 0.67 mmol) i miješa reakcijska otopina 1 sat. Upari se u vakumu, ostatak se otopi u vodi (10 ml), propusti preko Dowexa-50 i liofilizira. Zaostaje identičan produkt kao što je dobiven u postupku a). Prinos: 180 mg (77.8 %). b) Methyl ester 3-phenylacetamido-1-(1'-p-nitrobenzyloxycarbonyl-2-methyl-prop-1'-enyl)-4-oxo-azetidin-2 sulfonic acid (240 mg, 0.45 mmol) is dissolved in methylene chloride (5 ml); triethylamine (68 mg, 0.67 mmol) was added and the reaction solution was stirred for 1 hour. It is evaporated under vacuum, the residue is dissolved in water (10 ml), passed through Dowex-50 and lyophilized. The identical product as obtained in procedure a) remains behind. Yield: 180 mg (77.8 %).
Primjer 3 Example 3
(2R, 3R) 3-Fenilacetamido-4-okso-azetidin-2-sulfonska kiselina natrijska sol (2R, 3R) 3-Phenylacetamido-4-oxo-azetidine-2-sulfonic acid sodium salt
Metil ester 3-fenilacetamido-1-(1'-p-nitrobenziloksikarbonil-2'-metil-prop-1'-enil)-4-okso-azetidin-2-sulfinske kiseline (3.00 g, 5.82 mmol) otopi se u etilacetatu (40 ml), ohladi na temperaturu 0°C, doda 80 %-tna octena kiselina (40 ml) i dokapa uz miješanje vodena otopina kalij permanganata (75 ml, 18.98 mmol) u vremenu od 40 minuta i nastavi miješanje još 20 minuta. Dokapa se 30 %-tna otopina H2O2 (2,5 ml) kod čega se izgubi boja permanganata. 3-Phenylacetamido-1-(1'-p-nitrobenzyloxycarbonyl-2'-methyl-prop-1'-enyl)-4-oxo-azetidine-2-sulfinic acid methyl ester (3.00 g, 5.82 mmol) was dissolved in ethyl acetate (40 ml), cool to a temperature of 0°C, add 80% acetic acid (40 ml) and add, while stirring, an aqueous solution of potassium permanganate (75 ml, 18.98 mmol) over a period of 40 minutes and continue stirring for another 20 minutes. A 30% solution of H2O2 (2.5 ml) is added, during which the color of the permanganate is lost.
Doda se etilacetat (50 ml) i natrij klorid do zasićenja vodene otopine i miješa na sobnoj temperaturi 30 minuta. Organski ekstrakt se odvoji, a vodeni sloj se ekstrahira s etilacetatom (40 ml). Organski ekstrakti se spoje, suše (Na2SO4), filtriraju i upare do suha u vakuumu. Ostatku se doda etilacetat; suspenzija se miješa 2 sata kod +5 °C i kristal se odsiše. Prinos 640 mg (35.9 %). Add ethyl acetate (50 ml) and sodium chloride until the aqueous solution is saturated and stir at room temperature for 30 minutes. The organic extract was separated and the aqueous layer was extracted with ethyl acetate (40 ml). The organic extracts are combined, dried (Na2SO4), filtered and evaporated to dryness under vacuum. Ethyl acetate is added to the residue; the suspension is stirred for 2 hours at +5 °C and the crystal is filtered off with suction. Yield 640 mg (35.9 %).
t.t. = 205-207°C d.p. = 205-207°C
Rf = 0.61 (n-BuOH : HAc : H2O =4:1:1) Rf = 0.61 (n-BuOH : HAc : H2O =4:1:1)
IR(KBr): 3310 m, 3325 m, 1760 vs, 1640 s, 1525 s, 1260 s, 1205 s, 1070 s cm-1 IR(KBr): 3310 m, 3325 m, 1760 vs, 1640 s, 1525 s, 1260 s, 1205 s, 1070 s cm-1
1H NMR (DMSO-d6) δ: 3.59 (s, CH2CO), 4.39 (d, C2H, J 5.0 Hz), 5.40 (q, C3H, J 5.0 i 10.2 Hz), 7.38 (s, C6H5), 7.93 (d, NHCO, J 10.2 Hz), 8.88 (bs, N1H) ppm. 1H NMR (DMSO-d6) δ: 3.59 (s, CH2CO), 4.39 (d, C2H, J 5.0 Hz), 5.40 (q, C3H, J 5.0 and 10.2 Hz), 7.38 (s, C6H5), 7.93 (d , NHCO, J 10.2 Hz), 8.88 (bs, N1H) ppm.
Rač.: Na 7,51 %; Nađ.: Na 7.68 %. Ratio: At 7.51 %; Found.: At 7.68 %.
Primjer 4 Example 4
(2R, 3R) 3-fenilacetamido-4-okso-azetidin-2-sulfonska kiselina tetrabutilamonijeva sol (2R, 3R) 3-phenylacetamido-4-oxo-azetidine-2-sulfonic acid tetrabutylammonium salt
Natrijeva sol 3-fenilacetamido-4-okso-azetidin-2-sulfonske kiseline (100 mg, 0.33 mmol) i Sodium salt of 3-phenylacetamido-4-oxo-azetidine-2-sulfonic acid (100 mg, 0.33 mmol) and
tetrabutilamonijhidrogensulfat (120 mg, 0.35 mmol) se otope u smjesi CH2Cl2 (10 ml) i H2O (10 ml) i miješaju 2 sata kod sobne temperature. tetrabutylammonium hydrogen sulfate (120 mg, 0.35 mmol) was dissolved in a mixture of CH2Cl2 (10 ml) and H2O (10 ml) and stirred for 2 hours at room temperature.
Organski ekstrakt se odvoji; vodeni dio se ekstrahira s CH2Cl2 (2 x 10 ml). Spojeni organski ekstrakti se suše (Na2SO4), filtriraju i upare u vakuumu. Zaostaje 100 mg (57.6 %) produkta. The organic extract is separated; the aqueous portion is extracted with CH2Cl2 (2 x 10 ml). The combined organic extracts are dried (Na2SO4), filtered and evaporated in vacuo. 100 mg (57.6 %) of the product remains behind.
Rf 0.58 (CH2Cl2 : CH3OH = 4:1) Rf 0.58 (CH2Cl2 : CH3OH = 4:1)
IR (KBr): 3325 w, 2960 s, 2880 m, 1770 vs, 1680 s, 1520 m, 1225 s, 1200 s, cm-1 IR (KBr): 3325 w, 2960 s, 2880 m, 1770 vs, 1680 s, 1520 m, 1225 s, 1200 s, cm-1
1H NMR (CDCl3) δ: 1.03-1.54 (28 H, m), 3.12 - 3.30 (8 H, m), 3.59 (s, CH2CO), 4.58 (d, C2H, J 5.3 Hz), 5.63 (q, C3H, J 5.3 i 10.5 Hz), 7.30 (s, C6H5), 7.76 (d, CONH, J 10.0 Hz), 8.20 (d, N1H, J 8.0 Hz) ppm. 1H NMR (CDCl3) δ: 1.03-1.54 (28 H, m), 3.12 - 3.30 (8 H, m), 3.59 (s, CH2CO), 4.58 (d, C2H, J 5.3 Hz), 5.63 (q, C3H , J 5.3 and 10.5 Hz), 7.30 (s, C6H5), 7.76 (d, CONH, J 10.0 Hz), 8.20 (d, N1H, J 8.0 Hz) ppm.
Primjer 5 Example 5
(2R, 3R) 3-fenilacetamido-4-oksoazetidin-1,2-di-sulfonska kiselina di tetrabutilamonijeva sol (2R, 3R) 3-phenylacetamido-4-oxoazetidine-1,2-di-sulfonic acid di tetrabutylammonium salt
Metilni ester (2R, 3R) 3-fenilacetamido-4-oksoazetidin-2-sulfonske kiseline (160 mg, 0.54 mmol) doda se u smjesu piridin sumportrioksid kompleksa (85 mg, 0.54 mmol) i trietilamina (0.12 ml) u metilenkloridnu (10 ml). Reakcijska otopina se miješa 2 sata na sobnoj temperaturi u struji dušika i izlije na 1 M otopinu KH2PO4 (10 ml). Vodeni dio se izdvoji, ispere s metilenkloridom (10 ml) i miješa s otopinom tetrabutilamonijhidrogensulfata (180 mg, 0.54 mmol) u metilen kloridu (30 ml) 2 sata kod sobne temperature. Organski ekstrakt se odvoji, a vodeni sloj se ispere s metilen kloridom (2x10 ml). Spojeni organski ekstrakti se suše (Na2SO4), filtriraju i upare. Zaostaje 140 mg produkta (30.6 %). (2R, 3R) 3-Phenylacetamido-4-oxoazetidine-2-sulfonic acid methyl ester (160 mg, 0.54 mmol) was added to a mixture of pyridine sulfur trioxide complex (85 mg, 0.54 mmol) and triethylamine (0.12 ml) in methylene chloride (10 ml). The reaction solution was stirred for 2 hours at room temperature under a stream of nitrogen and poured onto a 1 M solution of KH2PO4 (10 ml). The aqueous part is separated, washed with methylene chloride (10 ml) and mixed with a solution of tetrabutylammonium hydrogen sulfate (180 mg, 0.54 mmol) in methylene chloride (30 ml) for 2 hours at room temperature. The organic extract is separated, and the aqueous layer is washed with methylene chloride (2x10 ml). The combined organic extracts are dried (Na2SO4), filtered and evaporated. 140 mg of product (30.6%) remains behind.
Rf = 0.56 (CH2Cl2 : MeOH = 4:1) Rf = 0.56 (CH2Cl2 : MeOH = 4:1)
IR NMR (CH2Cl2): 3400 w, 2920 s, 2850 s, 1775 s, 1675 s, 1510 m, 1220 s, 885 s, cm-1 IR NMR (CH2Cl2): 3400 w, 2920 s, 2850 s, 1775 s, 1675 s, 1510 m, 1220 s, 885 s, cm-1
1H NMR (CDCl3) δ: 1.00-1.65 (56 H, m), 3.13-3.23 (16 H, m), 3.56 (s, CH2CO), 4.54 (d, C2H, J 5.0), 5.60 (q, C3H, J 5.0 i 10.3 Hz), 7.27 (s, C6H5), 7.73 (d, CONH, J 10.3 Hz) ppm 1H NMR (CDCl3) δ: 1.00-1.65 (56 H, m), 3.13-3.23 (16 H, m), 3.56 (s, CH2CO), 4.54 (d, C2H, J 5.0), 5.60 (q, C3H, J 5.0 and 10.3 Hz), 7.27 (s, C6H5), 7.73 (d, CONH, J 10.3 Hz) ppm
Primjer 6 Example 6
(2R, 3S) 3-Fenilacetamido-4-oksoazetidin-2-sulfonska kiselina tetrabutilamonijeva sol (2R, 3S) 3-Phenylacetamido-4-oxoazetidine-2-sulfonic acid tetrabutylammonium salt
Metil ester(2R, 3S) 3-fenilacetamido-1-(1'-p-nitrobenziloksikarbonil-2'-metil-prop-1'-enil)-4-okso-azetidin-2-sulfinske kiseline (515 mg, 1 mmol) otopi se u EtoAc (10 ml) ohladi na (temperaturu 0 °C, doda 80 %-tna otopina HAc (6.8 ml) i dokapava 4 %-tna otopina KMnO4 (11.8 ml, 3 mmol) uz snažno miješanje za vrijeme od 1 sata. Zatim se dokapa 30 %-tna otopina H2O2 do obezbojenja reakcijske otopine. Methyl ester (2R, 3S) 3-phenylacetamido-1-(1'-p-nitrobenzyloxycarbonyl-2'-methyl-prop-1'-enyl)-4-oxo-azetidine-2-sulfinic acid (515 mg, 1 mmol ) was dissolved in EtoAc (10 ml), cooled to (temperature 0 °C, 80% HAc solution (6.8 ml) was added and 4% KMnO4 solution (11.8 ml, 3 mmol) was added dropwise with vigorous stirring for 1 Then a 30% solution of H2O2 is added drop by drop until the reaction solution becomes colorless.
Doda se EtoAc (20 ml) i NaCl do zasićenja vodene otopine i miješa još 30 min na sobnoj temperaturi. Organski ekstrakt se odvoji, a vodeni sloj se još jednom ekstrahira s EtoAc (20 ml). Spojeni organski ekstrakti se suše (Na2SO4), filtriraju i upare do suha. Dodatkom EtoAc-MeOH nastaje suspenzija koja se profiltrira, a dobiveni talog se otopi u vodi (10 ml) i propusti preko Dowex-a 50. Dobivena vodena otopina (20 ml) miješa se 2 sata s tetrabutilamonijhidrogensulfatom u CH2Cl2 (20 ml) (170 mg, 0.5 mmol) Organski ekstrakt se odvoji, a vodeni sloj se ekstrahira s CH2Cl2 (2x10 ml). Spojeni organski ekstrakti se suše (Na2SO4), filtriraju i upare. Prinos:94mg(18%) Add EtoAc (20 ml) and NaCl until the aqueous solution is saturated and stir for another 30 min at room temperature. The organic extract was separated and the aqueous layer was extracted once more with EtoAc (20 ml). The combined organic extracts are dried (Na2SO4), filtered and evaporated to dryness. Addition of EtoAc-MeOH creates a suspension which is filtered, and the resulting precipitate is dissolved in water (10 ml) and passed through Dowex 50. The resulting aqueous solution (20 ml) is stirred for 2 hours with tetrabutylammonium hydrogen sulfate in CH2Cl2 (20 ml) (170 mg, 0.5 mmol) The organic extract is separated, and the aqueous layer is extracted with CH2Cl2 (2x10 ml). The combined organic extracts are dried (Na2SO4), filtered and evaporated. Yield: 94mg (18%)
Rf = 0.51 (CH2Cl2: MaOH = 4:1) Rf = 0.51 (CH2Cl2: MaOH = 4:1)
IR(KBr): 3320 w, 2950 s, 2920 s,1765 s, 1675 s, 1520 m, 1220 s, 1190 s cm-1 IR(KBr): 3320 w, 2950 s, 2920 s, 1765 s, 1675 s, 1520 m, 1220 s, 1190 s cm-1
Primjer 7 Example 7
(2R, 3R) 3-Fenoksiacetamido-4-okso-azetidin-2-sulfonska kiselina (2R, 3R) 3-Phenoxyacetamido-4-oxo-azetidine-2-sulfonic acid
Metilni ester 3-fenoksiacetamido-1-(1'-metiloksikarbonil-2'-metil-prop-1'-enil)-4-oksoazetidin-2-sulfinske kiseline (4,1 g, 10 mmol) se otopi u etilacetatu (100 ml) i 80 %-tnoj octenoj kiselini (40 ml) i kod 0 °C dokapa 4 %-tna vodena otopina KMnO4 (150 ml, 6 g, 38 mmol) u trajanju od 60 minuta. Reakcijska suspenzija se miješa još 60 minuta na 0 °C. Doda se voda (20 ml), dokapa 30 % H2O2 (5 ml) do nestanka boje. Organski sloj se odvoji, suši nad Na2SO4 i upari pod sniženim pritiskom do krutog ostatka. Zaostaje 3,9 g krutine na koju se doda metanol (30 ml), miješa 60 minuta i krutina odvoji filtracijom. Prinos: 0,96 g (32 %) 3-Phenoxyacetamido-1-(1'-methyloxycarbonyl-2'-methyl-prop-1'-enyl)-4-oxoazetidine-2-sulfinic acid methyl ester (4.1 g, 10 mmol) was dissolved in ethyl acetate (100 ml) and 80% acetic acid (40 ml) and at 0 °C a 4% aqueous solution of KMnO4 (150 ml, 6 g, 38 mmol) is added for 60 minutes. The reaction suspension was stirred for another 60 minutes at 0 °C. Water (20 ml) is added, and 30% H2O2 (5 ml) is added drop by drop until the color disappears. The organic layer is separated, dried over Na2SO4 and evaporated under reduced pressure to a solid residue. 3.9 g of solid remains, to which methanol (30 ml) is added, stirred for 60 minutes and the solid separated by filtration. Yield: 0.96 g (32 %)
T. t. 225-230 °C (raspad); Rf = 0,45 (n- BuOH : HAc : H2O =4:1:1) T.t. 225-230 °C (decomposition); Rf = 0.45 (n- BuOH : HAc : H2O =4:1:1)
IR(KBr): 3330-3315 m, 1750 vs, 1655 s, 1595 m, 1525 m, 1495 m, 1245-1195 s, 1060 s, 750cm-1 IR(KBr): 3330-3315 m, 1750 vs, 1655 s, 1595 m, 1525 m, 1495 m, 1245-1195 s, 1060 s, 750cm-1
1H NMR (DMSO-d6) d: 4.31 (d,C2H, J 4.98 Hz), 4.50 (s, OCH2), 5.35 (q, C3H, J 4.98 Hz i 9.96 Hz), 7.02-7.40 (m, C6H5O), 8.58 (d, NH-CO. J 9.96 Hz) i 8.82 (s, N1H) ppm. 1H NMR (DMSO-d6) d: 4.31 (d, C2H, J 4.98 Hz), 4.50 (s, OCH2), 5.35 (q, C3H, J 4.98 Hz and 9.96 Hz), 7.02-7.40 (m, C6H5O), 8.58 (d, NH-CO. J 9.96 Hz) and 8.82 (s, N1H) ppm.
Primjer 8 Example 8
(2R, 3R) 3-Fenoksiacetamido-1-(1'-metiloksikarbonil-2'-metil-prop-1'-enil)-4-okso-azetidin-2-sulfonska kiselina (2R, 3R) 3-Phenoxyacetamido-1-(1'-methyloxycarbonyl-2'-methyl-prop-1'-enyl)-4-oxo-azetidine-2-sulfonic acid
Matičnica nakon izolacije krutine u postupku opisanom u primjeru 7. se upari pod sniženim pritiskom do krutog ostatka. Doda se metanol (5 ml) i aceton (30 ml) i miješa 60 minuta. Krutina se odvoji filtracijom., otopi se u vodi (10 ml) i propusti preko Dowex-a 50. Eluat se liofilizira. Prinos: 1,32 g (32 %) After isolating the solid in the procedure described in example 7, the mother liquor is evaporated under reduced pressure to a solid residue. Methanol (5 ml) and acetone (30 ml) were added and stirred for 60 minutes. The solid is separated by filtration, dissolved in water (10 ml) and passed through Dowex 50. The eluate is lyophilized. Yield: 1.32 g (32 %)
Rf = 0.70 (n- BuOH : HAc : H2O = 4:1:1) Rf = 0.70 (n- BuOH : HAc : H2O = 4:1:1)
IR(KBr): 3350 (m), 1780 (s), 1705 (s), 1600 (w), 1540 (m), 1500 (m), 1440 (m), 1390 (w), 1230 (s), 1035 (m) cm-1 IR(KBr): 3350 (m), 1780 (s), 1705 (s), 1600 (w), 1540 (m), 1500 (m), 1440 (m), 1390 (w), 1230 (s), 1035 (m) cm-1
1H NMR (DMSO-d6) δ: 2.11 (s, CH3), 2.28 (s, CH3), 3.82 (s, -OCH3), 4.67 (s, OCH2), 4.7 (d, C2H, J 5.6 Hz), 5.37 (s, SO2OH + HOH), 5.57 (q, C3H, J 5.6 Hz i 8.8 Hz), 7.02-7.52 (m, C6H5O) i 8.83 (d, NH, J 8.8 Hz) ppm 1H NMR (DMSO-d6) δ: 2.11 (s, CH3), 2.28 (s, CH3), 3.82 (s, -OCH3), 4.67 (s, OCH2), 4.7 (d, C2H, J 5.6 Hz), 5.37 (s, SO2OH + HOH), 5.57 (q, C3H, J 5.6 Hz and 8.8 Hz), 7.02-7.52 (m, C6H5O) and 8.83 (d, NH, J 8.8 Hz) ppm
Primjer 9 Example 9
(2R, 3R) 3-Fenoksiacetamido-4-okso-azetidin-2-sulfonska kiselina tetrabutilamonijska sol (2R, 3R) 3-Phenoxyacetamido-4-oxo-azetidine-2-sulfonic acid tetrabutylammonium salt
(2R, 3R) 3-Fenoksiacetamido-4-okso-azetidin-2-sulfonska kiselina (0.3 g, 1 mmol) otopi se u vodi (10 ml), doda se tetrabutilamonijskihidrogensulfat (0,34 g; 1 mmol) i metilen klorid (10 ml). Smjesa se miješa na sobnoj temperaturi 3 sata. Organski sloj se odvoji, ispere s vodom (10 ml) i upari pod sniženim pritiskom. Prinos: (0.39g, 72%) (2R, 3R) 3-Phenoxyacetamido-4-oxo-azetidine-2-sulfonic acid (0.3 g, 1 mmol) is dissolved in water (10 ml), tetrabutylammonium hydrogen sulfate (0.34 g; 1 mmol) and methylene chloride are added (10 ml). The mixture is stirred at room temperature for 3 hours. The organic layer is separated, washed with water (10 ml) and evaporated under reduced pressure. Yield: (0.39g, 72%)
Rf = 0.80 (CH2Cl2 : MeOH = 4:1) Rf = 0.80 (CH2Cl2 : MeOH = 4:1)
IR (parafinsko ulje): 3350-3110 (m), 3000-2850 (s), 1680 (s), 1600 (w), 1530 (m), 1495 (s), 1460 (m), 1380 (m), 1225 (vs), 1185 (s), 1060 (s), 1010 (m) cm-1 IR (paraffin oil): 3350-3110 (m), 3000-2850 (s), 1680 (s), 1600 (w), 1530 (m), 1495 (s), 1460 (m), 1380 (m), 1225 (vs), 1185 (s), 1060 (s), 1010 (m) cm-1
Anal. C27H47N2O6S (541.736): Anal. C27H47N2O6S (541.736):
izračunato: C 59.84; H 8.74; N 7.76; S 5.92 calculated: C 59.84; H 8.74; N 7.76; With 5.92
nađeno: C 59.81; H 9.98; N7.81; S 5.06 found: C 59.81; H 9.98; N7.81; With 5.06
1H NMR (DMSO-d6) δ: 1.00-1.84 (m, 28 H), 3.20-3.5 (m, 8H), 4.46 (d, C2H, J 5.3 Hz), 4.62 (s. OCH2), 5.47 (q, C3H, J 5.3 Hz i 10.25 Hz), 7.02-7.53 (m, C6H5O), 8.7 (d, NHCO, J 10.25 Hz) i 8.95 (s, N1H) ppm 1H NMR (DMSO-d6) δ: 1.00-1.84 (m, 28 H), 3.20-3.5 (m, 8H), 4.46 (d, C2H, J 5.3 Hz), 4.62 (s. OCH2), 5.47 (q, C3H, J 5.3 Hz and 10.25 Hz), 7.02-7.53 (m, C6H5O), 8.7 (d, NHCO, J 10.25 Hz) and 8.95 (s, N1H) ppm
Primjer 10 Example 10
(2R, 3R) 3-(3'-O-klorfenil-5'-metil-izoksazol-4'-karboksamido)-1-(1'-m-metil-benzil-oksikarbonil-2'-metil-prop-1'-enil)-4-okso-azetidin-2-sulfonska kiselina (2R, 3R) 3-(3'-O-chlorophenyl-5'-methyl-isoxazole-4'-carboxamido)-1-(1'-m-methyl-benzyl-oxycarbonyl-2'-methyl-prop-1 '-enyl)-4-oxo-azetidine-2-sulfonic acid
a) Metilen ester 3-(3'-o-klorfenil-5'-metil-izoksazol-4'-karboksamido)-1-(1'-m-metilbenziloksikarbonil-2'-metil-prop-1'-enil)-4-okso-azetidin-2-sulfinske kiseline (703 mg, 1,2 mmola) se otopi u CHCl3 (8 ml) i otopini uz miješanje doda otopina m-klorperbenzojeve kiseline (414 mg; 2.4 mmola) u CHCl3 (5 ml). Reakcijska smjesa se miješa na sobnoj temperaturi 10 sati, obradi sa zasićenom vodenom otopinom NaHCO3 (10 ml) i vodom. Organski sloj se upari pod sniženim pritiskom do pjenaste krutine. Kromatografijom na koloni silikagela pomoću otapala metilenklorid i metanol, izolirano je 438 mg (65,4 %) odgovarajuće sulfonske kiseline sa Rf 0.42 (CH2Cl2 : McOH = 4:1); tt. 178-82 °C. a) Methylene ester 3-(3'-o-chlorophenyl-5'-methyl-isoxazole-4'-carboxamido)-1-(1'-m-methylbenzyloxycarbonyl-2'-methyl-prop-1'-enyl)- 4-oxo-azetidine-2-sulfinic acid (703 mg, 1.2 mmol) was dissolved in CHCl3 (8 ml) and a solution of m-chloroperbenzoic acid (414 mg; 2.4 mmol) in CHCl3 (5 ml) was added to the solution with stirring. . The reaction mixture was stirred at room temperature for 10 hours, treated with saturated aqueous NaHCO3 solution (10 ml) and water. The organic layer is evaporated under reduced pressure to a foamy solid. Chromatography on a silica gel column using methylene chloride and methanol as solvents isolated 438 mg (65.4%) of the corresponding sulfonic acid with Rf 0.42 (CH2Cl2 : McOH = 4:1); tt. 178-82 °C.
IR -(KBr): 3700-3150 bs, 1780 s, 1660 s, 1610 m, 1530 m, 1400 w, 1295 w, 1220 vs, 1040 m, 770 m cm -1 IR -(KBr): 3700-3150 bs, 1780 s, 1660 s, 1610 m, 1530 m, 1400 w, 1295 w, 1220 vs, 1040 m, 770 m cm -1
1H NMR-spektar (CDCl3) δ: 1.62 i 1.82 (2s, (CH3)2), 2.04 (s, CH3-izoksazol), 2.31 (s, CH3-Ph), 2.71 (s, b SO3H), 4.40 (d, J 6 Hz, C2H), 4.48 (s, CH2), 4.89 (dd, J 6 i 8 Hz, C3H). 6.04 (d, J 8 Hz, NH), 6.18-6.31 (m, Ph), 6.40-6.62 (m, Ph-izoksazol). 1H NMR spectrum (CDCl3) δ: 1.62 and 1.82 (2s, (CH3)2), 2.04 (s, CH3-isoxazole), 2.31 (s, CH3-Ph), 2.71 (s, b SO3H), 4.40 (d , J 6 Hz, C2H), 4.48 (s, CH2), 4.89 (dd, J 6 and 8 Hz, C3H). 6.04 (d, J 8 Hz, NH), 6.18-6.31 (m, Ph), 6.40-6.62 (m, Ph-isoxazole).
b) Priredi se otopina metilnog estera 3-(3'-o-klorfenil-5'-metil-izoksazol-4'-karboksamido)-1-(1' -m-metilbenziloksikarbonil-2'-metil-prop-1'-enil)-2-okso-azetidin-4-sulfinske kiseline (1.85 g; 3 mmola) u octenoj kiselini (26 ml), doda H2O2 (6.6 ml; 60 mmol) i miješa na sobnoj temperaturi 15 sati. Reakcijska smjesa se izlije na hladnu vodu (100 ml) i nastala otopina neutralizira (pH ~5) dodatkom krute NaHCO3, te ekstrahira s metilenkloridom (2 x 100 ml). Organski ekstrakti se sakupe i upare pod sniženim pritiskom do pjenaste krutine. Kromatografijom na koloni silikagela pomoću smjese otapala metilenklorid i metanol izolirano 1.160 g (77,5 %) spoja identičnog s produktom dobivenim u postupku a). b) Prepare a solution of methyl ester 3-(3'-o-chlorophenyl-5'-methyl-isoxazole-4'-carboxamido)-1-(1'-m-methylbenzyloxycarbonyl-2'-methyl-prop-1'- enyl)-2-oxo-azetidine-4-sulfinic acid (1.85 g; 3 mmol) in acetic acid (26 ml), added H2O2 (6.6 ml; 60 mmol) and stirred at room temperature for 15 hours. The reaction mixture is poured into cold water (100 ml) and the resulting solution is neutralized (pH ~5) by the addition of solid NaHCO3, and extracted with methylene chloride (2 x 100 ml). The organic extracts are collected and evaporated under reduced pressure to a foamy solid. Chromatography on a silica gel column using a solvent mixture of methylene chloride and methanol isolated 1,160 g (77.5 %) of a compound identical to the product obtained in procedure a).
c) Otopina metilnog estera 3-(3'-o-klorfenil-5'-metil-izoksazol-4'-karboksamido)-1-(1'-m-metil-benziloksikarbonil-2'-metil-prop-1'-enil)-2-okso-azetidin-4-sulfinske kiseline (1.030 g; 1.8 mmola) u etilacetatu (10 ml), se doda octena kiselina (1.2 ml). Otopini se uz miješanje, na temperaturi + 10 °C dokapava 4 %-tna vodena otopina KMnO4 do ružičaste boje. Dodatkom H2O2 otopina se obezboji i slojevi odijele. Nakon pranja s zasićenom otopinom NaHCO3 i vodom, organski se dio upari pod sniženim pritiskom do guste skoro bezbojne tekućine. Odvajanjem pojedinih komponenata na koloni silikagela pomoću smjese otapala metilenklorid i metanol izolirano je 180 mg (21 %) supstance identične priređenoj u postupku a). c) Methyl ester solution 3-(3'-o-chlorophenyl-5'-methyl-isoxazole-4'-carboxamido)-1-(1'-m-methyl-benzyloxycarbonyl-2'-methyl-prop-1'- enyl)-2-oxo-azetidine-4-sulfinic acid (1.030 g; 1.8 mmol) in ethyl acetate (10 ml), acetic acid (1.2 ml) was added. A 4% aqueous solution of KMnO4 is added dropwise to the solution while stirring at a temperature of + 10 °C until it turns pink. By adding H2O2, the solution is decolored and the layers are separated. After washing with saturated NaHCO3 solution and water, the organic part is evaporated under reduced pressure to a thick almost colorless liquid. By separating individual components on a silica gel column using a mixture of methylene chloride and methanol solvents, 180 mg (21 %) of a substance identical to that prepared in procedure a) was isolated.
Claims (13)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HR920486A HRP920486A2 (en) | 1991-02-12 | 1992-09-25 | 4-oxo-azetidine of -2- sulfonic acids and salts, the method for the preparation and use thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU25091 | 1991-02-12 | ||
| HR920486A HRP920486A2 (en) | 1991-02-12 | 1992-09-25 | 4-oxo-azetidine of -2- sulfonic acids and salts, the method for the preparation and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP920486A2 true HRP920486A2 (en) | 1994-08-31 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR920486A HRP920486A2 (en) | 1991-02-12 | 1992-09-25 | 4-oxo-azetidine of -2- sulfonic acids and salts, the method for the preparation and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| HR (1) | HRP920486A2 (en) |
-
1992
- 1992-09-25 HR HR920486A patent/HRP920486A2/en not_active Application Discontinuation
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