RO129982A2 - New 6,8-dichloroquinolones with antimicrobial activity and process for preparing the same - Google Patents
New 6,8-dichloroquinolones with antimicrobial activity and process for preparing the same Download PDFInfo
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- RO129982A2 RO129982A2 ROA201101345A RO201101345A RO129982A2 RO 129982 A2 RO129982 A2 RO 129982A2 RO A201101345 A ROA201101345 A RO A201101345A RO 201101345 A RO201101345 A RO 201101345A RO 129982 A2 RO129982 A2 RO 129982A2
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- Prior art keywords
- piperidinyl
- chloro
- methyl
- quinoline
- ethyl
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- 238000004519 manufacturing process Methods 0.000 title claims abstract 3
- 230000000845 anti-microbial effect Effects 0.000 title abstract description 6
- VUBQYJSQVLEZKD-UHFFFAOYSA-N 6,8-dichloro-1h-quinolin-2-one Chemical class N1C(=O)C=CC2=CC(Cl)=CC(Cl)=C21 VUBQYJSQVLEZKD-UHFFFAOYSA-N 0.000 title 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 8
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims abstract description 5
- -1 3-methyl-piperidinyl Chemical group 0.000 claims abstract 14
- 150000007660 quinolones Chemical class 0.000 claims abstract 12
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract 5
- 239000001257 hydrogen Substances 0.000 claims abstract 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract 3
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000003795 chemical substances by application Substances 0.000 claims abstract 2
- 239000002253 acid Substances 0.000 claims description 4
- LPPMDJJMTYAWBR-UHFFFAOYSA-N C(C)N1C=C(C(C2=CC(=C(C(=C12)Cl)N1CCCC1)Cl)=O)C(=O)O Chemical group C(C)N1C=C(C(C2=CC(=C(C(=C12)Cl)N1CCCC1)Cl)=O)C(=O)O LPPMDJJMTYAWBR-UHFFFAOYSA-N 0.000 claims description 2
- SMFHOAVIRDBOFH-UHFFFAOYSA-N C(C)N1C=C(C(C2=CC(=C(C(=C12)Cl)N1CCCCC1)Cl)=O)C(=O)O Chemical group C(C)N1C=C(C(C2=CC(=C(C(=C12)Cl)N1CCCCC1)Cl)=O)C(=O)O SMFHOAVIRDBOFH-UHFFFAOYSA-N 0.000 claims description 2
- BXQCWCJCKQKONL-UHFFFAOYSA-N C(C)N1C=C(C(C2=CC(=C(C(=C12)Cl)N1CCOCC1)Cl)=O)C(=O)O Chemical group C(C)N1C=C(C(C2=CC(=C(C(=C12)Cl)N1CCOCC1)Cl)=O)C(=O)O BXQCWCJCKQKONL-UHFFFAOYSA-N 0.000 claims description 2
- SRCXRWQLBUAOBB-UHFFFAOYSA-N C(C)N1C=C(C(C2=CC(=C(C=C12)N1CCC(CC1)C)Cl)=O)C(=O)O Chemical group C(C)N1C=C(C(C2=CC(=C(C=C12)N1CCC(CC1)C)Cl)=O)C(=O)O SRCXRWQLBUAOBB-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 239000012038 nucleophile Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 5
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 4
- 229940008406 diethyl sulfate Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 4
- 239000012429 reaction media Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 241001360526 Escherichia coli ATCC 25922 Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical class C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- UXKKFPGAZIINBX-UHFFFAOYSA-N 3-chloro-1h-quinolin-2-one Chemical class C1=CC=C2NC(=O)C(Cl)=CC2=C1 UXKKFPGAZIINBX-UHFFFAOYSA-N 0.000 description 2
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- UDTQUVPXSUZSAS-UHFFFAOYSA-N 3,4-dichloro-1h-quinolin-2-one Chemical class C1=CC=C2C(Cl)=C(Cl)C(=O)NC2=C1 UDTQUVPXSUZSAS-UHFFFAOYSA-N 0.000 description 1
- BFCGHXVOVSHPIC-UHFFFAOYSA-N 6,7-dichloro-4-oxo-1h-quinoline-3-carboxylic acid Chemical compound ClC1=C(Cl)C=C2C(=O)C(C(=O)O)=CNC2=C1 BFCGHXVOVSHPIC-UHFFFAOYSA-N 0.000 description 1
- KOOFIWNKWSWUGO-UHFFFAOYSA-N 6-chloro-1-ethyl-7-morpholin-4-yl-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(Cl)=C1N1CCOCC1 KOOFIWNKWSWUGO-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- KTQRJNZLMUCMBZ-UHFFFAOYSA-N C(C)N1C=C(C(C2=CC(=C(C(=C12)Cl)N1CC(CCC1)C)Cl)=O)C(=O)O Chemical compound C(C)N1C=C(C(C2=CC(=C(C(=C12)Cl)N1CC(CCC1)C)Cl)=O)C(=O)O KTQRJNZLMUCMBZ-UHFFFAOYSA-N 0.000 description 1
- PIEMQNOMDXKNQP-UHFFFAOYSA-N C(C)N1C=C(C(C2=CC(=C(C(=C12)Cl)N1CCC(CC1)C)Cl)=O)C(=O)O Chemical compound C(C)N1C=C(C(C2=CC(=C(C(=C12)Cl)N1CCC(CC1)C)Cl)=O)C(=O)O PIEMQNOMDXKNQP-UHFFFAOYSA-N 0.000 description 1
- MTQQJVQOAYRAOU-UHFFFAOYSA-N C(C)N1C=C(C(C2=CC(=C(C=C12)N1CC(CCC1)C)Cl)=O)C(=O)O Chemical compound C(C)N1C=C(C(C2=CC(=C(C=C12)N1CC(CCC1)C)Cl)=O)C(=O)O MTQQJVQOAYRAOU-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- PMGNGTDFPXCYNP-UHFFFAOYSA-N ethyl 6,7-dichloro-4-oxo-1h-quinoline-3-carboxylate Chemical compound ClC1=C(Cl)C=C2C(=O)C(C(=O)OCC)=CNC2=C1 PMGNGTDFPXCYNP-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Prezenta invenție se refera la derivați 6,8 diclorochinolonici cu activitate antimicrobiana si la procedee de preparare al lor.The present invention relates to 6.8 dichloroquinolone derivatives with antimicrobial activity and processes for their preparation.
Se cunosc dervatii substituiti ai acizilor chinolin-3-carboxilici definiți prin structura generala:Substituted dervishes of quinoline-3-carboxylic acids defined by the general structure are known:
in care substituentii au diferite semnificații, care prezintă activitate antibacteriana atat împotriva bacteriilor gram-pozitive cat si a celor gram-negative. [Koga H.; Itoh A.; Murayama S.; J.Med. Chem. ,1980,23, 1358-1363; Jose A.; J. Med. Chem. 1991, 34,78-81]wherein the substituents have different meanings, which exhibit antibacterial activity against both gram-positive and gram-negative bacteria. [Koga H.; Itoh A.; Murayama S.; J.Med. Chem. , 1980,23, 1358-1363; Jose A.; J. Med. Chem. 1991, 34.78-81]
Se cunosc de asemenea dervatii substituiti ai acizilor chinolin-3-carboxilici definiți prin structura generala :Substituted derves of quinoline-3-carboxylic acids defined by the general structure are also known:
in care substituentii au semnificații bine definite si prezintă activitate antibacteriana. [DE 2840910].wherein the substituents have well-defined meanings and exhibit antibacterial activity. [OF 2840910].
Se cunosc de asemenea dervatii substituiti ai acizilor chinolin-3-carboxilici definiți prin structura generala:Substituted derves of quinoline-3-carboxylic acids defined by the general structure are also known:
in care substituentii au semnificații bine definite si prezintă activitate antibacteriana. [Yun Xun Yang, Hui Yuan Guo; Chinese Chemical Letters, 2007,18, 1479-1482]wherein the substituents have well-defined meanings and exhibit antibacterial activity. [Yun Xun Yang, Hui Yuan Guo; Chinese Chemical Letters, 2007,18, 1479-1482]
Prezenta invenție lărgește gama derivatilor cu activitate antimicrobiana cu noi compuși care corespund formulei generale I:The present invention extends the range of derivatives with antimicrobial activity with new compounds corresponding to general formula I:
^2 0 1 1 ’ 0 1 3 4 5^ 2 0 1 1 '0 1 3 4 5
Ο 7 *12* 2011 intensa, timp de 45 de minute, la temperatura menționata mai sus, când are loc si îndepărtarea alcoolului etilic rezultat in urma reacției de condensare. Se răcește la 20°C si se filtrează precipitatul format, care se spala cu acetona si se usucă. Se obțin 105 g ester etilic al aciduluiΟ 7 * 12 * 2011 intense, for 45 minutes, at the temperature mentioned above, when the ethyl alcohol removal resulting from the condensation reaction also takes place. Cool to 20 ° C and filter the formed precipitate, which is washed with acetone and dried. 105 g of ethyl ester of the acid are obtained
6,7-dicloro-4-hidroxi-chinolin-3-carboxilic (p.t.° 310-315°C; randamentul global 87%).6,7-dichloro-4-hydroxy-quinoline-3-carboxylic acid (mp. 310-315 ° C; overall yield 87%).
*H-RMN(dmso-d6, δ ppm, JHz): 8.63(s, 1H, H-2); 8.23(s, 1H, H-5(8)); 7.88(s, 1H, H-8(5)); 4.22(q, 2H, H-12, 7.1); 1.28(t, 3H, H-13, 7.1).* H-NMR (dmso-d6, δ ppm, JHz): 8.63 (s, 1H, H-2); 8.23 (s, 1H, H-5 (8)); 7.88 (s, 1H, H-8 (5)); 4.22 (q, 2H, H-12, 7.1); 1.28 (t, 3H, H-13, 7.1).
FT-IR(solid in ATR, v cm1): 3142m;3088s; 1693vs; 1604s; 1546m; 1516s; 1447m; 1378m; 1359w; 1331w; 1294m; 1266w; 1187m; 1122m; 1108m; 1028w; 966w; 909w; 888w; 860w; 827w; 800m; 756w; 679w; 647w; 620w.FT-IR (solid in ATR, v cm 1 ): 3142m; 3088s; 1693vs; 1604s; 1546m; 1516s; 1447m; 1378m; 1359w; 1331w; 1294m; 1266w; 1187m; 1122m; 1108m; 1028w; 966w; 909w; 888w; 860w; 827w; 800m; 756w; 679w; 647w; 620w.
Puritate ~80%. Amestec cu 5,6-C12.Purity ~ 80%. Mixture with 5.6-C12.
Exemplul 2: Sinteza acidului l-etil-6,7-dicloro-l,4-dihidro-4-oxo-chinolin-3-carboxilic -6C1QAExample 2: Synthesis of l-ethyl-6,7-dichloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid-6C1QA
0,03 Moli de dietilsulfat(DES) se adauga la un amestec format din 5,72 g (0,02 moli) ester etilic al acidului 6,7-dicloro-4-hidroxi chinolin-3-carboxilic si 108 g 40% hidroxid de sodiu. Amestecul se agita la 20°C timp da 30 min. si apoi la 100°C timp de 30 min. Se mai adauga inca 0,03 moli de dietilsulfat (DES) si se agita in continuare inca o ora. Se răcește masa de reacție la 20°C, se filtrează si se spala cu apa . Se usucă si se purifica din Ν,Ν-dimetilformamida. Se obțin 3,49 g acid l-etil-6,7-dicloro-l,4-dihidro-4-oxo-chinolin-3-carboxilic (p.t. 294,8-296,7°C, randament reacție +purificare 61%).0.03 moles of diethylsulfate (DES) was added to a mixture of 5.72 g (0.02 moles) 6,7-dichloro-4-hydroxy quinoline-3-carboxylic acid ethyl ester and 108 g 40% hydroxide. of sodium. The mixture was stirred at 20 ° C for 30 min. and then at 100 ° C for 30 min. Another 0.03 moles of diethylsulfate (DES) was added and stirred for an additional hour. Cool the reaction to 20 ° C, filter and wash with water. It is dried and purified from Ν, Ν-dimethylformamide. 3.49 g of l-ethyl-6,7-dichloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are obtained (mp 294.8-296.7 ° C, reaction yield + purification 61% ).
’H-NMR(dmso-d6, δ ppm, JHz): 9.06(s, 1H, H-2); 8.42(s, 1H, H-5); 8.41(s, 1H, H-8);H-NMR (dmso-d6, δ ppm, JHz): 9.06 (s, 1H, H-2); 8.42 (s, 1H, H-5); 8.41 (s, 1H, H-8);
4.59(q, 2H, H-17, 7.1); 1.39(t, 3H, H-18, 7.1).4.59 (q, 2H, H-17, 7.1); 1.39 (t, 3H, H-18, 7.1).
13C-NMR(dmso-d6, δ ppm): 176.31(019); 165.47(C-4); 150.33(02); 138.46(Cq); 137.51(Cq); 129.59(0}); 127.11(CH); 125.57(Cq); 120.55(CH); 108.6l(Cq); 49.36(017); 14.61(018). 13 C-NMR (dmso-d6, δ ppm): 176.31 (019); 165.47 (C-4); 150.33 (02); 138.46 (Cq); 137.51 (Cq); 129.59 (0}); 127.11 (CH); 125.57 (Cq); 120.55 (CH); 108.6l (Cq); 49.36 (017); 14.61 (018).
FT-IR(solid in ATR, vcm'1): 3094w; 3038w; 2990w; 1715s; 1599vs; 1547m; 1526m; 1486m; 1456vs; 1437vs; 1382s; 1300m; 1258m; 1219s; 1147m; 1122m; 1090m; 973m; 936s; 909m; 864m; 805m; 771w; 752w; 688w; 666m; 541w.FT-IR (solid in ATR, vcm ' 1 ): 3094w; 3038w; 2990w; 1715s; 1599vs; 1547m; 1526m; 1486m; 1456vs; 1437vs; 1382s; 1300m; 1258m; 1219s; 1147m; 1122m; 1090m; 973m; 936s; 909m; 864m; 805m; 771w; 752w; 688w; 666m; 541w.
Exemplul 3: Sinteza acidului l-etil-6-cloro-7-(4-metil-piperidinil)-l,4-dihidro4-oxo-chinolin-3-carboxilic - PQ 80Example 3: Synthesis of 1-ethyl-6-chloro-7- (4-methyl-piperidinyl) -1,4-dihydro4-oxo-quinoline-3-carboxylic acid - PQ 80
Λτ 2 Ο 1 1 - 0 ΐ 3 4 5 0 7 “,2‘ 2011Λτ 2 Ο 1 1 - 0 ΐ 3 4 5 0 7 “ , 2 '2011
Un amestec format din acid l-etil-6,7-dicloro-l,4-dihidro-4-oxo-chinolin-3-carboxilic (6C1QA) (5,72 g, 0,02 moli), 4-metil-piperidina (9,9 g, 0,1 moli; 12,05 ml) si N,Ndimetilformamida (60 ml) se încălzește sub agitare energica timp de 8 ore la 110-120°C. Sfârșitul regimului de reacție este pus in evidenta prin cromatografie in strat subtirersistem de eluare: tetrahidrofuran :dioxan:amoniac conc. : 20:60:30 (v/v/v), suport Silica gel 60F 254(s-a urmărit dispariția spotului cracteristic acidului l-etil-6,7-dicloro-l,4-dihidro-4-oxo-chinolin-3-carboxilic. Masa de reacție este transvazata in instalația de distilare la vid pentru îndepărtarea solventului si a excesului de 4-metil-piperidina. Reziduu se dizolva intr-o soluție 2N de NaOH, prin încălzire la 60°C. Soluția rezultata se decolorează si se filtrează, si după răcire se aduce la pH 7 cu o soluție 10 % de acid actic. Precipitatul format se filtrează si se spala cu apa. După recristalizare din dimetilformamida se obțin 5 g produs pur (p.t. = 262,5-264,5°C; randament reacție + purificare 70 %).A mixture of l-ethyl-6,7-dichloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (6C1QA) (5.72 g, 0.02 mol), 4-methyl-piperidine (9.9 g, 0.1 mol; 12.05 ml) and N, Ndimethylformamide (60 ml) was heated under vigorous stirring for 8 hours at 110-120 ° C. The end of the reaction regime is highlighted by chromatography in the elution sub-system: tetrahydrofuran: dioxane: ammonia conc. : 20:60:30 (v / v / v), support Silica gel 60F 254 (followed by the disappearance of the spot spot of the l-ethyl-6,7-dichloro-1, 4-dihydro-4-oxo-quinoline-3- acid bacterial spot). The reaction mass is transferred to the vacuum distillation facility to remove the solvent and the excess of 4-methyl-piperidine. The residue is dissolved in a 2N NaOH solution, heated to 60 ° C. The resulting solution is discolored and discolored. filter, and after cooling it is brought to pH 7 with a 10% solution of actic acid. The precipitate formed is filtered and washed with water. 5 g pure product is obtained after recrystallization from dimethylformamide (mp = 262.5-264.5 °). C; reaction yield + purification 70%).
'H-NMR CDCl3:5=l,02(3H,CH3 piperidina); 1,49 (3H, CH3 etil); 1,55-1,9 (5H, CH si CH2 din piperidina); 2,78 si 3,62 (fiecare 2H, CH2-piperidina) 4,35 (2H, Creții); 6,95 (1H, CH arom.); 8,39 (1H, CH arom.); 8,67 (1H,CH arom)H-NMR CDCl 3 : 5 = 1.02 (3H, CH 3 piperidine); 1.49 (3H, CH 3 ethyl); 1.55-1.9 (5H, CH and CH 2 from piperidine); 2.78 and 3.62 (each 2H, CH2-piperidine) 4.35 (2H, Cre); 6.95 (1H, aromatic CH); 8.39 (1H, CH arom.); 8.67 (1H, CH aroma)
Prin același procedeu au fost preparați următorii compuși:By the same process, the following compounds were prepared:
Exemplul 3a: acidul l-etil-6-cloro-7-(3-metil-piperidinil)-l,4-dihidro-4-oxo-chinolin-3carboxilic (6C1PQ-24) (raport molar acid chinolin carboxilic-heterociclu 1: 5,mediu de reacție •.dimetilformamida, temperatura de reacție 110°C, timp reacție 5,5 ore, p.t. = 216,2-218,4°C, randament reacție + purificare 58%)Example 3a: 1-ethyl-6-chloro-7- (3-methyl-piperidinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (6C1PQ-24) (quinoline carboxylic acid-heterocycle 1 molar ratio: 5, reaction medium • .dimethylformamide, reaction temperature 110 ° C, reaction time 5.5 hours, mp = 216.2-218.4 ° C, reaction yield + purification 58%)
'H-NMR(dmso-d6, δ ppm, 7 Hz): 9.00(s, 1H, H-2); 8.22(s, 1H, H-5); 7.30(s, 1H, H-8); 3.42(m, 4H, H-12-16); 2.83(m, 1H, H-15); 1.81(m, 3H, H-14-15); 1.47(t, 3H, H-18, 7.3); 1.17(q, 1H, H13, 6.4); 1.00(d, 3H, H-20, 6.4).H-NMR (dmso-d6, δ ppm, 7 Hz): 9.00 (s, 1H, H-2); 8.22 (s, 1H, H-5); 7.30 (s, 1H, H-8); 3.42 (m, 4H, H-12-16); 2.83 (m, 1H, H-15); 1.81 (m, 3H, H-14-15); 1.47 (t, 3H, H-18, 7.3); 1.17 (q, 1H, H13, 6.4); 1.00 (d, 3H, H-20, 6.4).
O 1 1-01345O 1 1-01345
7 -12- 2011 13ONMR(dmso-d6, δ ppm, JHz): 175.60(04); 166.11(C-21); 154.98(Cq); 149.31(02);7 -12- 2011 13 ONMR (dmso-d6, δ ppm, JHz): 175.60 (04); 166.11 (C-21); 154.98 (Cq); 149.31 (02);
139.85(Cq); 127.79(05); 127.16(Cq); 121.20(Cq); 108.51(Cq); 108.40(08); 59.00(012);139.85 (Cq); 127.79 (05); 127.16 (Cq); 121.20 (Cq); 108.51 (Cq); 108.40 (08); 59.00 (012);
51.98(017); 49.36(016); 32.58(015); 31.19(013); 25.25(014); 19.30(020); 14.61(018).51.98 (017); 49.36 (016); 32.58 (015); 31.19 (013); 25.25 (014); 19.30 (020); 14.61 (018).
FT-IR(solid in ATR, v cm'1): 3037; 2958; 2927; 2849; 2807; 2722; 1715; 1609; 1535; 1512; 1449; 1385; 1359; 1301; 1269; 1243; 1203; 1117; 1086; 1022; 976; 924; 897; 852; 806; 753; 714; 680; 620; 553;493;436.FT-IR (solid in ATR, v cm ' 1 ): 3037; 2958; 2927; 2849; 2807; 2722; 1715; 1609; 1535; 1512; 1449; 1385; 1359; 1301; 1269; 1243; 1203; 1117 1086; 1022; 976; 924; 897; 852; 806; 753; 714; 680; 620; 553; 493; 436.
Exemplul 3b : acid l-etil-6-cloro-7-morfolinil-l,4-dihidro-4-oxo-chinolin-3-carboxilic (6C1PQ25) (raport molar acid chinolin carboxilic-heterociclu 1:5, temperatura de reacție 110°C,mediu de reacție : dimetilsulfoxid, timp reacție 6 ore, p.t. - 267,1-269,2°C, randament reacție + purificare 80%)Example 3b: 1-ethyl-6-chloro-7-morpholinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (6C1PQ25) (quinoline carboxylic acid-heterocycle 1: 5 molar ratio, reaction temperature 110 ° C, reaction medium: dimethylsulfoxide, reaction time 6 hours, mp - 267.1-269.2 ° C, reaction yield + purification 80%)
1 H-NMR(dmso-d6, δ ppm, JHz): 9.02(s, 1H, H-2); 8.27(s, 1H, H-5); 7.36(s, 1H, H-8); 4.64(q, 2H, H-17, 7.1); 3.85(m, sist. A2B2, 4H, H-13-15); 3.28(m, sist. A2B2, 4H, H-12-16); 1.46(t, 3H, H-18, 7.1). 1 H-NMR (dmso-d6, δ ppm, JHz): 9.02 (s, 1H, H-2); 8.27 (s, 1H, H-5); 7.36 (s, 1H, H-8); 4.64 (q, 2H, H-17, 7.1); 3.85 (m, sist. A 2 B 2 , 4H, H-13-15); 3.28 (m, sist. A 2 B 2 , 4H, H-12-16); 1.46 (t, 3H, H-18, 7.1).
13ONMR(dmso-d6, δ ppm): 175.61(04); 165.34(021); 153.01(Cq); 148.89(CH-2); 13 ONMR (dmso-d6, δ ppm): 175.61 (04); 165.34 (021); 153.01 (Cq); 148.89 (CH-2);
138.72(Cq); 126.90(05); 125.91(Cq); 120.66(Cq); 107.86(C-8); 65.67(013-15); 50.53(012-138.72 (Cq); 126.90 (05); 125.91 (Cq); 120.66 (Cq); 107.86 (C-8); 65.67 (013-15); 50.53 (012-
16); 48.55(017); 13.89(018).16); 48.55 (017); 13.89 (018).
FT-IR(solid in ATR, v cm’1): 3035; 2971; 2947; 2904; 2865; 1724; 1609; 1514; 1466; 1438; 1384; 1337; 1294; 1237; 1191; 1111; 1062; 995; 950; 912; 865; 842; 805; 750; 713; 686; 625; 552; 490; 453; 426.FT-IR (solid in ATR, v cm ' 1 ): 3035; 2971; 2947; 2904; 2865; 1724; 1609; 1514; 1466; 1438; 1384; 1337; 1294; 1237; 1191; 1111; 1062; 995; 950; 912; 865; 842; 805; 750; 713; 686; 625; 552; 490; 453; 426.
Exemplul 3c : acid l-etil-6-cloro-7-piperidinil-l,4-dihidro-4-oxo-chinolin-3-carboxilic (6C1PQ32) (raport molar acid chinolin carboxilic-heterociclu 1:5, temperatura de reacție 110°C, mediu de reacție dimetilformamida, timp reacție 8 ore, p.t. = 234,4-236,4 randament reacție + purificare 53%)Example 3c: l-ethyl-6-chloro-7-piperidinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (6C1PQ32) (quinoline carboxylic acid-heterocycle molar ratio 1: 5, reaction temperature 110 ° C, dimethylformamide reaction medium, reaction time 8 hours, mp = 234.4-236.4 reaction yield + purification 53%)
‘H-NMRidmso-dâ, δ ppm, JHz): 8.97(s, 1H, H-2); 8.20(s, 1H, H-5); 7.28(s, 1H, H-8); 4.58(q, 2H, H-17, 7.1); 3.18(m, 4H, 2H-20, 2H-24); 1.72(bs, 4H, 2H-21, 2H-23); 1.62(bs, 2H, H-22); 1.42(t, 3H, H-18, 7.1).H-NMRidmso-dâ, δ ppm, JHz): 8.97 (s, 1H, H-2); 8.20 (s, 1H, H-5); 7.28 (s, 1H, H-8); 4.58 (q, 2H, H-17, 7.1); 3.18 (m, 4H, 2H-20, 2H-24); 1.72 (bs, 4H, 2H-21, 2H-23); 1.62 (bs, 2H, H-22); 1.42 (t, 3H, H-18, 7.1).
(λ“2 Ο 1 1 - Ο 1 3 4 5(λ “2 Ο 1 1 - Ο 1 3 4 5
O 7 -12- 2011 13C-NMR(dmso-d6, δ ppm): 176.01(C-4); 165.75(019); 154.61(09); 148.99(02); 139.16(0O 7 -12- 2011 13 C-NMR (dmso-d6, δ ppm): 176.01 (C-4); 165.75 (019); 154.61 (09); 148.99 (02); 139.16 (0
9);9);
127.04(05); 120.41(03); 107.90(08); 107.73(010); 51.84(020, 024); 48.86(017); 25.44(021, 023); 23.49(022); 14.17(018).127.04 (05); 120.41 (03); 107.90 (08); 107.73 (010); 51.84 (020, 024); 48.86 (017); 25.44 (021, 023); 23.49 (022); 14.17 (018).
FT-IR(solid in ATR, v cm’1): 3O35w; 2990w; 295 lm; 2937m; 2917m; 2842w; 1722vs; 1608s; 1513s; 1486m; 1462vs; 1443vs; 1388m; 1373s; 1340m; 1297m; 1256m; 1240vs; 1197sm; 1091m; 1061m; 1032m; 985m; 949m; 914w; 899m; 863m; 843w; 823w; 805m; 750w; 687m; 528w.FT-IR (solid in ATR, v cm ' 1 ): 3O35w; 2990w; 295 lm; 2937m; 2917m; 2842w; 1722vs; 1608s; 1513s; 1486m; 1462vs; 1443vs; 1388m; 1373s; 1340m; 1297m; 1256m; 1240vs; 1197sm; 1091m; 1061m; 1032m; 985m; 949m; 914w; 899m; 863m; 843w; 823w; 805m; 750w; 687m; 528w.
Exemplul 3d : acid l-etil-6-cloro-7-pirolidinil-l,4-dihidro-4-oxo-chinolin-3-carboxilic (6C1PQ35) (raport molar acid chinolin carboxilic-heterociclu 1:5, temperatura de reacție 80-90°C, mediu de reacție: dimetilformamida, timp reacție 5 ore, p.t. = 312,3-315,5°C, randament reacție + purificare 75%)Example 3d: l-ethyl-6-chloro-7-pyrrolidinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (6C1PQ35) (quinoline carboxylic acid-heterocycle molar ratio 1: 5, reaction temperature 80 -90 ° C, reaction medium: dimethylformamide, reaction time 5 hours, mp = 312.3-315.5 ° C, reaction yield + purification 75%)
’H-NMR(dmso-d6, δ ppm, JHz): 8.89(s, IH, H-2); 8.14(s, IH, H-5); 6.83(s, IH, H-8); 4.52(q, 2H, H-17, 7.1); 3.66(m, 4H, H-20, H-23); 1.97(m, 4H, H-21, H-22); 1.42(t, 3H, H-18, 7.1).H-NMR (dmso-d6, δ ppm, JHz): 8.89 (s, IH, H-2); 8.14 (s, IH, H-5); 6.83 (s, IH, H-8); 4.52 (q, 2H, H-17, 7.1); 3.66 (m, 4H, H-20, H-23); 1.97 (m, 4H, H-21, H-22); 1.42 (t, 3H, H-18, 7.1).
FT-IR(solid in ATR, v cm'1): 3057m; 2929s; 2846m; 1708s; 1614vs; 1558m; 1530m; 1510s; 1467vs; 1442s; 1402s; 1344sm; 1273m; 1252m; 1217m; 1177m; 111 lm; 1095m; 1027m;995m; 933w; 873w; 809m; 748w; 649m.FT-IR (solid in ATR, v cm ' 1 ): 3057m; 2929s; 2846m; 1708s; 1614vs; 1558m; 1530m; 1510s; 1467vs; 1442s; 1402s; 1344sm; 1273m; 1252m; 1217m; 1177m; 111 lm; 1095m; 1027m, 995m; 933w; 873w; 809m; 748w; 649m.
Exemplul 4: acid l-etil-6-cloro-7-morfolinil-8-cloro—4-oxo-l,4-dihidro-chinolin-3-carboxilic 6C1PQ-28Example 4: 1-ethyl-6-chloro-7-morpholinyl-8-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid 6C1PQ-28
Peste o soluție de acid l-etil-6-cloro-7-morfolinil-l,4-dihidro-4-oxo-chinolin-3-carboxilic (6C1PQ-25) (1,68 g; 0,005 moli) in cloroform (150 ml), se picura, sub agitare la temperatura camerei, clorura de sulfuril (2,07 g; 0,015 moli; 1,14 ml), după care, se mai agita masa de reacție inca 30 minute la aceeași temperatura. Soluția cloroformica de acid l-etil-6-cloro-7-morfolinil-8cloro-l,4-dihidro-4-oxo-chinolin-3-carboxilic se spala cu 2x200 ml apa, se usucă pe sulfat de sodiu anhidru, si se concentrează. Peste reziduu se adauga 50 ml metanol pentru precipitarea produsului .Se obțin 1,52 g produs pur (spot cromatografic unitar; p.t.0 213,9-216,7°C; randament -81,9%).Over a solution of l-ethyl-6-chloro-7-morpholinyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (6C1PQ-25) (1.68 g; 0.005 mol) in chloroform (150 ml), sulfuryl chloride (2.07 g; 0.015 mol; 1.14 ml) is dripped at room temperature, followed by stirring for another 30 minutes at the same temperature. The chloroform solution of l-ethyl-6-chloro-7-morpholinyl-8-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was washed with 2x200 ml of water, dried over anhydrous sodium sulfate, and dried. concentrated. To the residue was added 50 ml of methanol to precipitate the product .It is obtained 1.52 g of pure product (single spot by chromatography, for 0 213.9 to 216.7 ° C; yield -81.9%).
^-2011-01345^ -2011 to 01,345
7 -12- 20117-12 December 2011
’H-NMRCdmso-dâ, δ ppm, JHz): 8.92(s, 1H, H-2); 8.22(s, 1H, H-5); 4.80(m, 2H, H-17, 7.1); 3.78(m, 4H, H-21, H-23); 3.33(m, 4H, H-20, H-24); 1.40(t, 3H, H-18, 7.1).'H-NMRCdmso-dâ, δ ppm, JHz): 8.92 (s, 1H, H-2); 8.22 (s, 1H, H-5); 4.80 (m, 2H, H-17, 7.1); 3.78 (m, 4H, H-21, H-23); 3.33 (m, 4H, H-20, H-24); 1.40 (t, 3H, H-18, 7.1).
13ONMR(dmso-d6, δ ppm): 175.70(04); 165.00(019); 152.98(02); 150.40(09); 138.54(0 7); 130.76(06); 125.81 (C-5); 124.60(010); 108.61(03); 66.64(021, 023); 52.97(017); 50.19(020, 024); 15.47(018). 13 ONMR (dmso-d6, δ ppm): 175.70 (04); 165.00 (019); 152.98 (02); 150.40 (09); 138.54 (0 7); 130.76 (06); 125.81 (C-5); 124.60 (010); 108.61 (03); 66.64 (021, 023); 52.97 (017); 50.19 (020, 024); 15.47 (018).
FT-IR(solid in ATR, v cm’1): 3046w; 2981m; 2948w; 2913w; 2834m; 1716vs; 1610vs; 1547m; 1491vs; 1430vs; 1367m; 1290w; 1258m; 1236m; 1113s; lOOOm; 928s; 860w; 835m; 803m; 761m; 607w.FT-IR (solid in ATR, v cm ' 1 ): 3046w; 2981m; 2948w; 2913w; 2834m; 1716vs; 1610vs; 1547m; 1491vs; 1430vs; 1367m; 1290w; 1258m; 1236m; 1113s; lOOOm; 928S; 860w; 835m; 803m; 761m; 607w.
Prin același procedeu au fost preparați următorii compuși:By the same process, the following compounds were prepared:
Exemplul 4a : acid l-etil-6-cloro-7-(3-metil-piperidinil)-8-cloro-4-oxo-l,4-dihidro-chinolin-3carboxilic 6C1PQ-30 (p.t. = 190,3-192,2°C, randament 60%)Example 4a: 1-ethyl-6-chloro-7- (3-methyl-piperidinyl) -8-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid 6C1PQ-30 (pt = 190.3-192 , 2 ° C, 60% yield)
’H-NMR(CDCI3+tfa, δ ppm, JHz): 8.59(s, 1H, H-2); 8.32(s, 1H, H-5); 4.62(q, 2H, H-17, 7.1); 3.20-2.80(m, 4H, H-20, H-24); 1.95-1.80(m, 3H, H-22, H-23); 1.48(t, 3H, H-18, 7.1); 0.85(d, 3H, H-25, 6.3).H-NMR (CDCl 3 + tfa, δ ppm, JHz): 8.59 (s, 1H, H-2); 8.32 (s, 1H, H-5); 4.62 (q, 2H, H-17, 7.1); 3.20-2.80 (m, 4H, H-20, H-24); 1.95-1.80 (m, 3H, H-22, H-23); 1.48 (t, 3H, H-18, 7.1); 0.85 (d, 3H, H-25, 6.3).
13ONMR(CDCl3+tfa, δ ppm): 176.65(04); 165.43(019); 152.92(07); 151.41(02); 139.24(0 6); 132.46(08); 127.12(Cq); 126.87(05); 125.24(Cq); 109.52(Cq); 59.13(020); 53.51 (017); 51.59(024); 32.79(022); 31.69(023); 26.14(021); 19.20(025); 15.86(018). 13 ONMR (CDCl 3 + tfa, δ ppm): 176.65 (04); 165.43 (019); 152.92 (07); 151.41 (02); 139.24 (0 6); 132.46 (08); 127.12 (Cq); 126.87 (05); 125.24 (Cq); 109.52 (Cq); 59.13 (020); 53.51 (017); 51.59 (024); 32.79 (022); 31.69 (023); 26.14 (021); 19.20 (025); 15.86 (018).
FT-IR(solid in ATR, v cm'1): 3050m; 2925s; 2840m; 1717vs; 1610vs; 1547s; 1492vs; 1433vs; 1404vs; 1381s; 1357s; 1281m; 1263m; 1240m; 1210m; 1192m; 1144w; 1119w; 1090m; 1068w; 1022w; 973w; 923m; 85 lw; 834w; 801m; 714m.FT-IR (solid in ATR, v cm ' 1 ): 3050m; 2925s; 2840m; 1717vs; 1610vs; 1547s; 1492vs; 1433vs; 1404vs; 1381s; 1357s; 1281m; 1263m; 1240m; 1210m; 1192m; 1144w; 1119w; 1090m; 1068w; 1022w; 973w; 923m; 85 lw; 834w; 801m; 714m.
Exemplul 4b : acid l-etil-6-cloro-7-(4-metil-piperidinil)-8-cloro-4-oxo-l,4-dihidro-chinolin-3carboxilic Q-87 (p.t. = 152,3-154,9°C, randament 78%)Example 4b: 1-ethyl-6-chloro-7- (4-methyl-piperidinyl) -8-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid Q-87 (pt = 152.3-154 , 9 ° C, yield 78%)
(^-20 11-0 1345 0 1 -12’ 2011(^ -20 11-0 1345 0 1 -12 '2011
’H-NMR(DMSO-d6„ δ ppm, JHz): 8.97(s, 1H, H-2); 8.31(s, 1H, H-5); 5,l(q, 2H, H-17, 7.1); 3.62 (2H, H-20, H-24); 3.48 (m, 1H, H-20); 3.39 (m, 1H, H-24); 2,48-2,52(m,4H,H-21,H-22), l,43(m, 3H, H-23); 1.4l(t, 3H, H-18, 7.1); l,24(d, 3H, H-25, 6.5).H-NMR (DMSO-d6 "δ ppm, JHz): 8.97 (s, 1H, H-2); 8.31 (s, 1H, H-5); 5, l (q, 2H, H-17, 7.1); 3.62 (2H, H-20, H-24); 3.48 (m, 1H, H-20); 3.39 (m, 1H, H-24); 2.48-2.52 (m, 4H, H-21, H-22), l, 43 (m, 3H, H-23); 1.4l (t, 3H, H-18, 7.1); l, 24 (d, 3H, H-25, 6.5).
FT-IR(solid in ATR, v cm’1): 3059; 2948; 1728; 1612; 1554; 1489; 1456; 1417; 1388; 1339;1293; 1255; 1236; 1211; 1172; 1149; 1116; 1085; 1044; 927; 838; 807; 771; 721.FT-IR (solid in ATR, v cm ' 1 ): 3059; 2948; 1728; 1612; 1554; 1489; 1456; 1417 1388; 1339, 1293; 1255; 1236; 1211; 1172; 1149; 1116; 1085; 1044; 927; 838; 807; 771; 721.
Exemplul 4c : acid l-etil-6-cloro-7-piperidinil-8-cloro-4-oxo-l,4-dihidro-chinolin-3-carboxilicExample 4c: 1-ethyl-6-chloro-7-piperidinyl-8-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
6C1PQ-33 (p.t. = 214,6-216,3°C, randament 76%)6C1PQ-33 (mp = 214.6-216.3 ° C, 76% yield)
6CIPQ 33 ‘H-NMR(DMSO-d6„ δ ppm, JHz): 8.89(s, 1H, H-2); 8.19(s, 1H, H-5); 4,77(q, 2H, H-17, 7.1);6CIPQ 33 'H-NMR (DMSO-d6' δ ppm, JHz): 8.89 (s, 1H, H-2); 8.19 (s, 1H, H-5); 4.77 (q, 2H, H-17, 7.1);
3.6 (m,4H, H-20, H-24); 2,53(bs,4H, H-21,; 2,5 (bs,2H,H-22); l,4(t,3H,H-18)3.6 (m, 4H, H-20, H-24); 2.53 (bs, 4H, H-21,; 2.5 (bs, 2H, H-22); l, 4 (t, 3H, H-18)
FT-IR(solid in ATR, v cm’1): 3057; 2933; 2848; 1723; 1612; 1552; 1489; 1454; 1424; 1346; 1301;1252; 1234; 1158; 1117; 1094; 1023; 992; 928; 860; 801; 768.FT-IR (solid in ATR, v cm -1 ): 3057; 2933; 2848; 1723; 1612; 1552; 1489; 1454; 1424; 1346; 1301, 1252; 1234; 1158; 1117 1094; 1023; 992; 928; 860; 801; 768.
Exemplul 4d : acid l-etil-6-cloro-7-pirolidinil-8-cloro-4-oxo-l,4-dihidro-chinolin-3-carboxilic 6C1PQ-30 (p.t. = 200-203,3°C, randament 67%)Example 4d: 1-ethyl-6-chloro-7-pyrrolidinyl-8-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid 6C1PQ-30 (mp = 200-203.3 ° C, yield 67%)
6CIPQ-36 c\- 2 O 1 1 O 1 3 4 56CIPQ-36 c \ - 2 O 1 1 O 1 3 4 5
O 7 -12- 2011 'H-NMR(CDCl3+tfa, δ ppm, JHz): 9.07(s, 1H, H-2); 8.62(s, 1H, H-5); 5.02(q, 2H, H-17, 7.1);O 7 -12- 2011 'H-NMR (CDCl 3 + tfa, δ ppm, JHz): 9.07 (s, 1H, H-2); 8.62 (s, 1H, H-5); 5.02 (q, 2H, H-17, 7.1);
3.58(m, 4H, H-20, H-23); 2.99(m, 4H, H-21, H-22); 1.66(t, 3H, H-18, 7.1).3.58 (m, 4H, H-20, H-23); 2.99 (m, 4H, H-21, H-22); 1.66 (t, 3H, H-18, 7.1).
l3C-NMR(CDCl3+tfa, δ ppm): 175.94(04); 169.81(019); 153.64(02); 144.21(Cq); 137.98(0 7); 136.09(09); 127.29(05); 126.96(03); 108.08(010); 95.22(08); 55.82(020, 023); 48.13(017); 42.76(021, 022); 16.37(018). l3 C-NMR (CDCl 3 + tfa, δ ppm): 175.94 (04); 169.81 (019); 153.64 (02); 144.21 (Cq); 137.98 (0 7); 136.09 (09); 127.29 (05); 126.96 (03); 108.08 (010); 95.22 (08); 55.82 (020, 023); 48.13 (017); 42.76 (021, 022); 16.37 (018).
FT-IR(solid in ATR, v cm1): 3063w; 3000w; 2938w; 2890w; 2843w; 1716vs; 1606s; 1553m; 1492m; 1481m;1461s; 1429vs; 1382m; 1366m; 1350m; 1329m; 1257m; 1204m; 1173m; 1118m; 1065s; 1035m; 926m; 842m; 806m; 710w; 670m..FT-IR (solid in ATR, v cm 1 ): 3063w; 3000W; 2938w; 2890w; 2843w; 1716vs; 1606s; 1553m; 1492m; 1481m; 1461s; 1429vs; 1382m; 1366m; 1350m; 1329m; 1257m; 1204m; 1173m; 1118m; 1065s; 1035m; 926m; 842m; 806m; 710W; 670m ..
In scopul determinării proprietății antimicrobiene pe care o pot avea clorochinolonele , s-a recurs la metoda dilutiilor seriate in vederea stabilirii unei concentrații minime inhibitorii (CMI) si a tipului de de acțiune pe care acestea le au fata de tulpini bacteriene test, frecvent întâlnite in tehnologiile farmaceutice (activitate bactericida-CMB).S-a determinat CMI în bulion MuellerHinton, utilizandu-se metoda microdiluțiilor. Tulpinile test față de care s-a făcut testarea sunt Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 si Pseudomonas aeruginosa ATCC 9027.In order to determine the antimicrobial properties that chloroquinolones can have, the dilution method was used in order to establish a minimum inhibitory concentration (CMI) and the type of action that they have against the test bacterial strains, commonly encountered in pharmaceutical technologies. (bactericidal activity-CMB). CMI was determined in MuellerHinton broth, using the microdilution method. The test strains tested were Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 9027.
Tabel : Activitatea antimicrobiana „in vitro” a clorochinolonelorTable: "In vitro" antimicrobial activity of chloroquinolones
Dintre compușii testați, compusul 6C1PQ 28 prezintă activitate antibacteriană mai intensa față de E. Coli ATCC 25922 (CMI 1,28 pg/mL), si fata de S.aureus ATCC29223 (CMI 1,28 pg/mL).Of the compounds tested, compound 6C1PQ 28 exhibits more antibacterial activity compared to E. coli ATCC 25922 (CMI 1.28 pg / mL), and to S.aureus ATCC29223 (CMI 1.28 pg / mL).
(>‘20 11-0 1345(> '20 11-0 1345
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