PL179321B1 - Nowy sposób wytwarzania pochodnych cefemowych PL PL - Google Patents

Nowy sposób wytwarzania pochodnych cefemowych PL PL

Info

Publication number: PL179321B1
Authority: PL; Poland
Prior art keywords: group; formula; amino; hydrogen; solvent
Prior art date: 1994-03-21

Application number

PL94306199A

Other languages

English (en)

Polish (pl)

Other versions

PL306199A1 (en

Inventor

Sung K Kim

Seong N Kim

Woo H Kim

Jong Ch Lim

Hee M Oh

Tae S Kwon

Bong J Park

Original Assignee

Lucky Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1994-03-21

Filing date

1994-12-09

Publication date

2000-08-31

1994-12-09 Application filed by Lucky Ltd filed Critical Lucky Ltd

1995-10-02 Publication of PL306199A1 publication Critical patent/PL306199A1/xx

2000-08-31 Publication of PL179321B1 publication Critical patent/PL179321B1/pl

Links

238000000034 method Methods 0.000 title claims abstract description 41
241000534944 Thia Species 0.000 title claims abstract description 11
239000002253 acid Substances 0.000 title abstract description 10
229930186147 Cephalosporin Natural products 0.000 title description 5
229940124587 cephalosporin Drugs 0.000 title description 5
150000001780 cephalosporins Chemical class 0.000 title description 5
239000002904 solvent Substances 0.000 claims abstract description 29
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 28
239000001257 hydrogen Substances 0.000 claims abstract description 28
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 18
125000006239 protecting group Chemical group 0.000 claims abstract description 18
238000002360 preparation method Methods 0.000 claims abstract description 15
239000002585 base Substances 0.000 claims abstract description 14
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 12
125000001424 substituent group Chemical group 0.000 claims abstract description 12
RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 claims abstract description 11
150000001782 cephems Chemical class 0.000 claims abstract description 11
HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims abstract description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
239000001301 oxygen Substances 0.000 claims abstract description 7
125000005042 acyloxymethyl group Chemical group 0.000 claims abstract description 6
229910052799 carbon Inorganic materials 0.000 claims abstract description 6
150000003839 salts Chemical class 0.000 claims abstract description 5
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
235000019441 ethanol Nutrition 0.000 claims description 23
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
239000000203 mixture Substances 0.000 claims description 19
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 10
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
125000000217 alkyl group Chemical group 0.000 claims description 9
229920006395 saturated elastomer Polymers 0.000 claims description 9
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
229910052757 nitrogen Inorganic materials 0.000 claims description 6
FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
125000005842 heteroatom Chemical group 0.000 claims description 5
229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
235000017550 sodium carbonate Nutrition 0.000 claims description 5
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
229910001413 alkali metal ion Inorganic materials 0.000 claims description 4
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
239000011736 potassium bicarbonate Substances 0.000 claims description 4
229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
235000011181 potassium carbonates Nutrition 0.000 claims description 4
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
229910052701 rubidium Inorganic materials 0.000 claims description 4
125000004434 sulfur atom Chemical group 0.000 claims description 4
239000008096 xylene Substances 0.000 claims description 4
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
150000001298 alcohols Chemical class 0.000 claims description 3
125000000753 cycloalkyl group Chemical group 0.000 claims description 2
229910052740 iodine Inorganic materials 0.000 claims description 2
125000003367 polycyclic group Chemical group 0.000 claims description 2
125000003158 alcohol group Chemical group 0.000 claims 1
150000002431 hydrogen Chemical class 0.000 abstract description 10
125000000623 heterocyclic group Chemical group 0.000 abstract description 6
239000007858 starting material Substances 0.000 abstract description 4
MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract description 3
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 abstract description 3
229910052698 phosphorus Inorganic materials 0.000 abstract description 3
JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 abstract description 3
229910052708 sodium Inorganic materials 0.000 abstract description 3
239000011734 sodium Substances 0.000 abstract description 3
239000000126 substance Substances 0.000 abstract description 3
CZPWVGJYEJSRLH-UHFFFAOYSA-O hydron;pyrimidine Chemical compound C1=CN=C[NH+]=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-O 0.000 abstract description 2
238000004519 manufacturing process Methods 0.000 abstract description 2
125000004437 phosphorous atom Chemical group 0.000 abstract description 2
241000386115 Coras Species 0.000 abstract 1
229910052783 alkali metal Inorganic materials 0.000 abstract 1
150000001340 alkali metals Chemical class 0.000 abstract 1
230000000694 effects Effects 0.000 abstract 1
150000002500 ions Chemical class 0.000 abstract 1
-1 β-lactam compounds Chemical class 0.000 description 85
150000001875 compounds Chemical class 0.000 description 41
238000006243 chemical reaction Methods 0.000 description 39
230000015572 biosynthetic process Effects 0.000 description 26
238000003786 synthesis reaction Methods 0.000 description 24
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 20
239000000243 solution Substances 0.000 description 17
238000003756 stirring Methods 0.000 description 17
238000004128 high performance liquid chromatography Methods 0.000 description 16
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 12
125000002252 acyl group Chemical group 0.000 description 12
125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 11
239000012153 distilled water Substances 0.000 description 11
150000007524 organic acids Chemical class 0.000 description 11
239000012074 organic phase Substances 0.000 description 11
239000000047 product Substances 0.000 description 11
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
239000003054 catalyst Substances 0.000 description 9
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
238000001816 cooling Methods 0.000 description 8
239000002244 precipitate Substances 0.000 description 8
239000011541 reaction mixture Substances 0.000 description 8
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
239000008346 aqueous phase Substances 0.000 description 7
GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 7
229960004261 cefotaxime Drugs 0.000 description 7
238000002844 melting Methods 0.000 description 7
230000008018 melting Effects 0.000 description 7
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
239000003242 anti bacterial agent Substances 0.000 description 5
229940088710 antibiotic agent Drugs 0.000 description 5
239000006227 byproduct Substances 0.000 description 5
150000002148 esters Chemical class 0.000 description 5
230000009257 reactivity Effects 0.000 description 5
229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
235000017557 sodium bicarbonate Nutrition 0.000 description 5
239000007787 solid Substances 0.000 description 5
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
125000005907 alkyl ester group Chemical group 0.000 description 4
125000003277 amino group Chemical group 0.000 description 4
239000007864 aqueous solution Substances 0.000 description 4
150000001721 carbon Chemical group 0.000 description 4
239000013078 crystal Substances 0.000 description 4
JNSGIVNNHKGGRU-JYRVWZFOSA-N diethoxyphosphinothioyl (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetate Chemical compound CCOP(=S)(OCC)OC(=O)C(=N/OC)\C1=CSC(N)=N1 JNSGIVNNHKGGRU-JYRVWZFOSA-N 0.000 description 4
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
239000000706 filtrate Substances 0.000 description 4
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
150000003512 tertiary amines Chemical class 0.000 description 4
125000000335 thiazolyl group Chemical group 0.000 description 4
JKWWAQAPKNSKSX-WAPJZHGLSA-N (2-amino-1,3-thiazol-4-yl) (2Z)-2-methoxyiminoacetate Chemical compound CO\N=C/C(=O)OC1=CSC(N)=N1 JKWWAQAPKNSKSX-WAPJZHGLSA-N 0.000 description 3
HCQABJQZDYSTJH-QFSRMBNQSA-N (6r)-4-acetamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CC(NC(=O)C)S[C@@H]2CC(=O)N21 HCQABJQZDYSTJH-QFSRMBNQSA-N 0.000 description 3
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 3
ADDBAPLLQRBDLT-UHFFFAOYSA-N 2-ethoxyiminoacetic acid Chemical compound CCON=CC(O)=O ADDBAPLLQRBDLT-UHFFFAOYSA-N 0.000 description 3
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
AJUCGEVBFWZUBP-UHFFFAOYSA-N acetic acid trihydroxy(sulfanylidene)-lambda5-phosphane Chemical class C(C)(=O)O.P(=S)(O)(O)O AJUCGEVBFWZUBP-UHFFFAOYSA-N 0.000 description 3
150000008065 acid anhydrides Chemical class 0.000 description 3
238000005917 acylation reaction Methods 0.000 description 3
125000003118 aryl group Chemical group 0.000 description 3
229960002100 cefepime Drugs 0.000 description 3
HVFLCNVBZFFHBT-ZKDACBOMSA-O cefepime(1+) Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-O 0.000 description 3
HJJDBAOLQAWBMH-YCRCPZNHSA-N cefmenoxime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C HJJDBAOLQAWBMH-YCRCPZNHSA-N 0.000 description 3
229960003791 cefmenoxime Drugs 0.000 description 3
NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 3
229960001991 ceftizoxime Drugs 0.000 description 3
VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 3
229960004755 ceftriaxone Drugs 0.000 description 3
HPFKOFNYNQMWEF-UHFFFAOYSA-N chloro-dihydroxy-sulfanylidene-$l^{5}-phosphane Chemical class OP(O)(Cl)=S HPFKOFNYNQMWEF-UHFFFAOYSA-N 0.000 description 3
125000005843 halogen group Chemical group 0.000 description 3
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
150000007530 organic bases Chemical class 0.000 description 3
230000035484 reaction time Effects 0.000 description 3
239000011780 sodium chloride Substances 0.000 description 3
RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 3
RJFPBECTFIUTHB-INEUFUBQSA-N (6r,7r)-7-azaniumyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC=C(C(O)=O)N2C(=O)[C@@H](N)[C@H]21 RJFPBECTFIUTHB-INEUFUBQSA-N 0.000 description 2
YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 2
RXYPXQSKLGGKOL-UHFFFAOYSA-N 1,4-dimethyl-1,4-diazacyclohexane Natural products CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 2
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
125000001931 aliphatic group Chemical group 0.000 description 2
229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
150000008041 alkali metal carbonates Chemical class 0.000 description 2
125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
150000001408 amides Chemical class 0.000 description 2
UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
125000001589 carboacyl group Chemical group 0.000 description 2
239000007795 chemical reaction product Substances 0.000 description 2
239000000460 chlorine Substances 0.000 description 2
238000009833 condensation Methods 0.000 description 2
230000005494 condensation Effects 0.000 description 2
238000001914 filtration Methods 0.000 description 2
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
150000007529 inorganic bases Chemical class 0.000 description 2
229910052943 magnesium sulfate Inorganic materials 0.000 description 2
235000019341 magnesium sulphate Nutrition 0.000 description 2
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
239000003495 polar organic solvent Substances 0.000 description 2
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
229910052717 sulfur Chemical group 0.000 description 2
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
MIHIJWOEDDPOLG-DUXPYHPUSA-N (2e)-2-methoxyiminoacetic acid Chemical compound CO\N=C\C(O)=O MIHIJWOEDDPOLG-DUXPYHPUSA-N 0.000 description 1
NLARCUDOUOQRPB-WTKPLQERSA-N (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid Chemical compound CO\N=C(/C(O)=O)C1=CSC(N)=N1 NLARCUDOUOQRPB-WTKPLQERSA-N 0.000 description 1
125000002861 (C1-C4) alkanoyl group Chemical group 0.000 description 1
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 description 1
125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
JYUXDXWXTPSAEL-UHFFFAOYSA-N 1,4-dioxane;oxolane Chemical compound C1CCOC1.C1COCCO1 JYUXDXWXTPSAEL-UHFFFAOYSA-N 0.000 description 1
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
ORLCYMQZIPSODD-UHFFFAOYSA-N 1-chloro-2-[chloro(2,2,2-trichloroethoxy)phosphoryl]oxybenzene Chemical compound ClC1=CC=CC=C1OP(Cl)(=O)OCC(Cl)(Cl)Cl ORLCYMQZIPSODD-UHFFFAOYSA-N 0.000 description 1
DVDGHRQOLYEZAE-UHFFFAOYSA-N 1-n,1-n,2-n,2-n-tetramethylcyclohexane-1,2-diamine Chemical compound CN(C)C1CCCCC1N(C)C DVDGHRQOLYEZAE-UHFFFAOYSA-N 0.000 description 1
125000006017 1-propenyl group Chemical group 0.000 description 1
125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
MIHIJWOEDDPOLG-UHFFFAOYSA-N 2-methoxyiminoacetic acid Chemical compound CON=CC(O)=O MIHIJWOEDDPOLG-UHFFFAOYSA-N 0.000 description 1
ALNBSBNUZMWFSY-UHFFFAOYSA-N 2-propan-2-yloxyiminoacetic acid Chemical compound CC(C)ON=CC(O)=O ALNBSBNUZMWFSY-UHFFFAOYSA-N 0.000 description 1
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
125000004070 6 membered heterocyclic group Chemical group 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
RAUVAJUJUKPEPW-UHFFFAOYSA-N C(C)ON=CC(=O)OC1=NC(=NS1)N Chemical compound C(C)ON=CC(=O)OC1=NC(=NS1)N RAUVAJUJUKPEPW-UHFFFAOYSA-N 0.000 description 1
LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
150000003855 acyl compounds Chemical class 0.000 description 1
230000002411 adverse Effects 0.000 description 1
230000001476 alcoholic effect Effects 0.000 description 1
125000003545 alkoxy group Chemical group 0.000 description 1
125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
125000001118 alkylidene group Chemical group 0.000 description 1
HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
125000003368 amide group Chemical group 0.000 description 1
230000009286 beneficial effect Effects 0.000 description 1
125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
239000003782 beta lactam antibiotic agent Substances 0.000 description 1
125000003460 beta-lactamyl group Chemical group 0.000 description 1
229910000085 borane Inorganic materials 0.000 description 1
125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
229910052801 chlorine Inorganic materials 0.000 description 1
KMJJJTCKNZYTEY-UHFFFAOYSA-N chloro-diethoxy-sulfanylidene-$l^{5}-phosphane Chemical compound CCOP(Cl)(=S)OCC KMJJJTCKNZYTEY-UHFFFAOYSA-N 0.000 description 1
ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical class OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 1
238000010276 construction Methods 0.000 description 1
125000004093 cyano group Chemical group *C#N 0.000 description 1
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
238000010511 deprotection reaction Methods 0.000 description 1
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
238000004090 dissolution Methods 0.000 description 1
125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
238000000605 extraction Methods 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
229910052736 halogen Inorganic materials 0.000 description 1
150000002367 halogens Chemical class 0.000 description 1
125000002636 imidazolinyl group Chemical group 0.000 description 1
125000002883 imidazolyl group Chemical group 0.000 description 1
238000011065 in-situ storage Methods 0.000 description 1
125000001041 indolyl group Chemical group 0.000 description 1
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
238000002955 isolation Methods 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
125000005956 isoquinolyl group Chemical group 0.000 description 1
125000000842 isoxazolyl group Chemical group 0.000 description 1
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
239000012046 mixed solvent Substances 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
TXXWBTOATXBWDR-UHFFFAOYSA-N n,n,n',n'-tetramethylhexane-1,6-diamine Chemical compound CN(C)CCCCCCN(C)C TXXWBTOATXBWDR-UHFFFAOYSA-N 0.000 description 1
VGIVLIHKENZQHQ-UHFFFAOYSA-N n,n,n',n'-tetramethylmethanediamine Chemical compound CN(C)CN(C)C VGIVLIHKENZQHQ-UHFFFAOYSA-N 0.000 description 1
DMQSHEKGGUOYJS-UHFFFAOYSA-N n,n,n',n'-tetramethylpropane-1,3-diamine Chemical compound CN(C)CCCN(C)C DMQSHEKGGUOYJS-UHFFFAOYSA-N 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
150000002894 organic compounds Chemical class 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
125000001715 oxadiazolyl group Chemical group 0.000 description 1
125000002971 oxazolyl group Chemical group 0.000 description 1
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
150000004714 phosphonium salts Chemical class 0.000 description 1
239000011574 phosphorus Substances 0.000 description 1
125000004193 piperazinyl group Chemical group 0.000 description 1
125000003386 piperidinyl group Chemical group 0.000 description 1
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([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
125000003373 pyrazinyl group Chemical group 0.000 description 1
125000003226 pyrazolyl group Chemical group 0.000 description 1
125000002098 pyridazinyl group Chemical group 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
125000004076 pyridyl group Chemical group 0.000 description 1
125000000714 pyrimidinyl group Chemical group 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
125000001422 pyrrolinyl group Chemical group 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
125000001453 quaternary ammonium group Chemical group 0.000 description 1
125000005493 quinolyl group Chemical group 0.000 description 1
238000000926 separation method Methods 0.000 description 1
229910000077 silane Inorganic materials 0.000 description 1
125000003107 substituted aryl group Chemical group 0.000 description 1
239000011593 sulfur Chemical group 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
RKHXQBLJXBGEKF-UHFFFAOYSA-M tetrabutylphosphanium;bromide Chemical compound [Br-].CCCC[P+](CCCC)(CCCC)CCCC RKHXQBLJXBGEKF-UHFFFAOYSA-M 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
125000001113 thiadiazolyl group Chemical group 0.000 description 1
125000001984 thiazolidinyl group Chemical group 0.000 description 1
125000002769 thiazolinyl group Chemical group 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
150000003573 thiols Chemical class 0.000 description 1
125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
229920001567 vinyl ester resin Polymers 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
239000002132 β-lactam antibiotic Substances 0.000 description 1
229940124586 β-lactam antibiotics Drugs 0.000 description 1
150000003952 β-lactams Chemical class 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- 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)
Cephalosporin Compounds (AREA)

PL94306199A 1994-03-21 1994-12-09 Nowy sposób wytwarzania pochodnych cefemowych PL PL PL179321B1 (pl)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
KR1019940005658A KR0129567B1 (ko)	1994-03-21	1994-03-21	반응성 유기산 유도체로부터 세팔로스포린 화합물의 제조방법

Publications (2)

Publication Number	Publication Date
PL306199A1 PL306199A1 (en)	1995-10-02
PL179321B1 true PL179321B1 (pl)	2000-08-31

Family

ID=19379305

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
PL94306199A PL179321B1 (pl)	1994-03-21	1994-12-09	Nowy sposób wytwarzania pochodnych cefemowych PL PL

Country Status (5)

Country	Link
KR (1)	KR0129567B1 (ro)
MX (1)	MXPA94009625A (ro)
PL (1)	PL179321B1 (ro)
RO (2)	RO113245B1 (ro)
RU (1)	RU2097385C1 (ro)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
KR100967341B1 (ko) *	2008-04-01	2010-07-05	주식회사 이매진	카바페넴 합성 중간체의 제조방법
CN111072592B (zh) *	2019-12-20	2021-07-20	河北合佳医药科技集团股份有限公司	一种氨噻肟酸二聚体的高纯度选择性制备和纯化方法

1994
- 1994-03-21 KR KR1019940005658A patent/KR0129567B1/ko not_active Expired - Lifetime
- 1994-12-07 RO RO96-01614A patent/RO113245B1/ro unknown
- 1994-12-07 RO RO94-01960A patent/RO111682B1/ro unknown
- 1994-12-09 RU RU9494043775A patent/RU2097385C1/ru not_active IP Right Cessation
- 1994-12-09 PL PL94306199A patent/PL179321B1/pl not_active IP Right Cessation
- 1994-12-13 MX MXPA94009625A patent/MXPA94009625A/es active IP Right Grant

Also Published As

Publication number	Publication date
RU94043775A (ru)	1996-09-27
MXPA94009625A (es)	2005-08-24
KR950026881A (ko)	1995-10-16
PL306199A1 (en)	1995-10-02
RU2097385C1 (ru)	1997-11-27
RO113245B1 (ro)	1998-05-29
KR0129567B1 (ko)	1998-04-09
RO111682B1 (ro)	1996-12-30

Legal Events

Date	Code	Title	Description
2015-02-27	LAPS	Decisions on the lapse of the protection rights	Effective date: 20131209

Publication	Publication Date	Title
CS247081B2 (en)	1986-11-13	Production method of cefemderivatives
FI63586B (fi)	1983-03-31	Foerfarande foer framstaellning av 7-beta-(2-oxiimino-2-arylacetamido)-3-(sulfoalkyltetrazol-5-yltiometyl)-3-cefem-4-karboxylsyror med antibakteriell verkan
EP0628561B1 (en)	1997-09-03	Process for preparing cephalosporin compounds from reactive organic acid derivatives
EP0175814B1 (en)	1990-05-23	Process for preparing cephem derivatives
CS247080B2 (en)	1986-11-13	Production method of cefemderivatives
FI83223B (fi)	1991-02-28	Foerfarande foer avlaegsning av syre fraon 7 -acylamino-3-cefem-4-karboxylsyra-1-oxidderivat.
PL179321B1 (pl)	2000-08-31	Nowy sposób wytwarzania pochodnych cefemowych PL PL
KR930007260B1 (ko)	1993-08-04	세팔로스포린 유도체의 제조방법
EP0045717B1 (en)	1985-09-25	New cephalosporin derivatives, their production and their use
EP0791597B1 (en)	2000-07-12	Method for manufacture of cephalosporins and intermediates thereof
GB1582960A (en)	1981-01-21	Chemical synthesis of -lactam derivatives
PL179324B1 (pl)	2000-08-31	Nowa reaktywna tiofosforanowa pochodna kwasu tia(dia) zolooctowegoi sposób jej otrzymywania PL
EP0253507B1 (en)	1994-03-23	Process for the preparation of cephalosporins
EP0246068B1 (en)	1993-12-08	Process for the manufacture of cephalosporin derivatives
KR970005893B1 (ko)	1997-04-21	반응성 유기산 유도체로부터 세팔로스포린 화합물의 제조방법
KR100361829B1 (ko)	2005-08-17	반응성 유기산 유도체로 부터 세프트리악손을 제조하는 방법
KR810000760B1 (ko)	1981-07-02	세팔로스포린 화합물의 제조법
KR100375594B1 (ko)	2003-04-23	티아(디아)졸아세트산의반응성티오포스페이트유도체의신규한제조방법
JPS5951555B2 (ja)	1984-12-14	セフアロスポリン化合物の製造法
KR800001265B1 (ko)	1980-10-26	세팔로스포리의 화합물의 제조법
KR900003562B1 (ko)	1990-05-21	실릴세팔로스포린 화합물의 제조방법
HU192983B (en)	1987-08-28	Process for production of cefem compounds
JPS6150952B2 (ro)	1986-11-06
EP0148004A2 (en)	1985-07-10	Cephalosporin antibiotics