GB2301354A - Preparation for intermediates for quinolone antibiotics - Google Patents
Preparation for intermediates for quinolone antibiotics Download PDFInfo
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- GB2301354A GB2301354A GB9506905A GB9506905A GB2301354A GB 2301354 A GB2301354 A GB 2301354A GB 9506905 A GB9506905 A GB 9506905A GB 9506905 A GB9506905 A GB 9506905A GB 2301354 A GB2301354 A GB 2301354A
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims description 7
- 239000000543 intermediate Substances 0.000 title abstract description 9
- 239000003242 anti bacterial agent Substances 0.000 title abstract description 6
- 229940088710 antibiotic agent Drugs 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- -1 cyclic amine Chemical class 0.000 claims abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 5
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 claims abstract description 4
- 150000001408 amides Chemical class 0.000 claims abstract description 4
- 150000001412 amines Chemical class 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 3
- 230000002378 acidificating effect Effects 0.000 claims abstract description 3
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 3
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 3
- 150000002690 malonic acid derivatives Chemical class 0.000 claims abstract description 3
- 150000002825 nitriles Chemical class 0.000 claims abstract description 3
- 230000001737 promoting effect Effects 0.000 claims abstract description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 3
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 3
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 claims abstract 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229960003405 ciprofloxacin Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229960001180 norfloxacin Drugs 0.000 description 3
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- IEEHKTFVUIVORU-UHFFFAOYSA-N 2-methylpropanedioyl dichloride Chemical compound ClC(=O)C(C)C(Cl)=O IEEHKTFVUIVORU-UHFFFAOYSA-N 0.000 description 2
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 150000001733 carboxylic acid esters Chemical group 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000000346 malonyl group Chemical group C(CC(=O)*)(=O)* 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 2
- 239000003306 quinoline derived antiinfective agent Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- 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 1
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-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
- HJSCQRDGGJZGJH-UHFFFAOYSA-N 4-chloroquinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(Cl)C(C(=O)O)=CN=C21 HJSCQRDGGJZGJH-UHFFFAOYSA-N 0.000 description 1
- WNNSMMJBBOPPOT-UHFFFAOYSA-N 7-chloro-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound FC1=C(Cl)C=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 WNNSMMJBBOPPOT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 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
- 239000000706 filtrate Substances 0.000 description 1
- DYDNPESBYVVLBO-UHFFFAOYSA-N formanilide Chemical class O=CNC1=CC=CC=C1 DYDNPESBYVVLBO-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000002271 gyrase inhibitor Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- JXYZHMPRERWTPM-UHFFFAOYSA-N hydron;morpholine;chloride Chemical compound Cl.C1COCCN1 JXYZHMPRERWTPM-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000007522 mineralic acids Chemical group 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
Key intermediates in the production of quinolone antibiotics of formula in which R 1 represents a lower alkyl group, a lower aralkyl group, a vinyl or allyl group, a lower hydroxy alkyl group or a lower halogeno-alkyl group, a cyclopropyl group or an aryl group, R 2 represents a substituent displaceable by an amine, and R 3 represents a hydrogen atom or, together R 3 and R 1 represent the group -OCH 2 CH-R 4 , where R 4 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, are obtained by a process comprising the following steps: ```(a) reaction of a compound of the general formula with a malonic acid derivative of the general formula in which R 5 and R 6 each represent a C 1-5 aliphatic group or R 5 and R 6 , together with the nitrogen represent a cyclic amine optionally containing one or more further heteroatoms, and R 7 represents a carboxylic acid ester, amide or nitrile, in the presence of a chlorinating agent capable of promoting a Vilsmeier-Haack reaction to obtain a compound of the general formula and ```(b) hydrolysis of the intermediate of general formula IV under hot aqueous acidic conditions sufficient to form the quinolone and to convert the substituent R 7 into a carboxyl group, to obtain the product of general formula I.
Description
Synthesis of Intermediates for Quinolone Antibiotics
This invention relates to the synthesis of a key intermediate for the preparation of quinolone antibiotics such as norfloxacin and ciprofloxacin, in particular the intermediate used as the starting material for the introduction of the 7-piperazinyl substituent.
The quinolone antibiotics, a very important alternative to p-lactams, tetracyclines and aminoglycosides, operate as DNA gyrase inhibitors against all types of
Gram-negative bacteria. Typical compounds include norfloxacin, ciprofloxacin and ofloxacin (formulae A, B and C)
In each case the synthesis involves the introduction of the heterocyclic group (usually piperazinyl or 4-methyl-piperazinyl) at the 7-position, by displacement of an appropriate leaving radical, generally a halogen atom such as chlorine or an alkylsulfonyl group (see, for example, US-A-4 146 719, US-A-4 292 317, 4 670 444 and EP-B-0047005).
The main synthesis of this type of intermediate, the
Bayer synthesis, is shown in scheme 1
CH2(CO2Etk, Mg(OEtk ii Ho iii HC(OEth,AclO iv
v Base wi piperane Scheme 1
This long and costly synthesis starts with an expensive starting material and thus results in high drug costs.
There is thus a need for a cheaper simpler synthesis of the key intermediate which is, nevertheless, high yielding and regiospecific.
The use of a modified Vilsmeier reaction in the preparation of quinolines is disclosed in Synthesis, 1986, 76-78. In particular, by the interaction of an
N-substituted formanilide, phosphoryl chloride and a malonyl ester chloride (to serve as an electrophilic alkene precursor), a 4-chloro-quinolinium-3- carboxylate is produced which is readily transformed into a 4-quinolone by boiling in aqueous acid or by action of a base (scheme 2)
Scheme 2
While this short, high yielding reaction might appear useful for application to the synthesis of quinolone antibiotics, problems arise when the initial anilide is asymmetric. Thus, 3-chloro-4-fluoroaniline is readily converted into 3-chloro-4-fluoro-N-ethylformanilide by the action of triethyl orthoformate and a catalytic amount of sulfuric acid.However, this unsymmetrically substituted formanilide is capable of cyclizing either ortho- or para- to the chloro substituent and on treatment with methyl malonyl chloride and phosphoryl chloride as in the prior art process, the reaction yields equal quantities of the two possible cyclization products. Thus, not only is the yield of the required product no more than about 40%, but it would be necessary to separate it from an equal amount of the unwanted byproduct.
It has now been recognised that appropriate substitution of the malonyl reagent can provide a reaction which yields only the required isomer.
According to the invention there is thus provided a process for the preparation of a compound of the general formula
in which R1 represents a lower alkyl group, a lower aralkyl group, a vinyl or allyl group, a lower hydroxy alkyl group or a lower halogeno-alkyl group, a cyclopropyl group or an aryl group;R represents a substituent displaceable by an amine e. g. a chlorine or bromine atom or alkylsulfonyl group; and R3 represents a hydrogen atom or, together R3 and R1 represent the 4 4 group -OCH2CH-R , where R represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; comprising the following steps:
(a) reaction of a compound of the general formula
in which R1, R2 and R3 are as defined for formula I, with a malonic acid derivative of the general formula
in which R5 and R6 each represent an aliphatic group with up to 5 carbon atoms or R5 and R6, together with the nitrogen represent a cyclic amine optionally containing one or more further heteroatoms, and R7 represents a carboxylic acid ester, amide or nitrile, in the presence of a chlorinating agent capable of promoting a Vilsmeier-Haack reaction, e. g. phosphorus oxychloride, to obtain a compound of the general formula
in which R1 R2 R3 and R7 are as defined above, and
(b) hydrolysis of the intermediate of general formula IV under hot aqueous acidic conditions sufficient to form the quinolone and to convert the substituent R into a carboxyl group, to obtain the product of general formula I.
It will be seen that the invention lies in the use of a compound of formula III in which the amide group -CONR 5R6 has the effect of inhibiting the cyclization to the position ortho to the substituent
R2 and instead facilitates cyclization at the position para to R3. While we do not wish to be bound by theory, it may be proposed that the amide group -CONR5R6 exerts some steric control because of interaction with R2. It is preferred that the amide is cyclic and it is especially preferred that R5 and
R6, together with the nitrogen, represent a morpholino group.
The groups R1 and R3 will be chosen depending on the quinolone antibiotic to be prepared from the compound formula I. The prior art patents US-A-4 292 317,
US-A-4 670 444 and EP-B-0047005 all disclose a range of such substituents. R1 preferably represents an ethyl group (for norfloxacin), a cyclopropyl group (for ciprofloxacin) or R1 and R3 together preferably represent a -OCH2C (CH3)H- group (for ofloxacin).
The substituent R2 which comprises a leaving radical displaceable by an amine is conventionally a chlorine atom.
The malonic derivative of formula III is preferably a malonic ester amide, where R7 represents a carboxylic acid ester, in particular a lower alkyl ester such as the methyl or ethyl ester.
As indicated above, R5 and R6, together with the intervening nitrogen preferably represent a nitrogen heterocycle which, for reasons of effectiveness and economy is preferably a morpholino group. Thus, a compound of choice is methyl malonyl morpholide.
The chlorinating agent is an inorganic acid chloride, preferably phosphorous oxychloride, but alternatively phosphorus pentachloride, phosgene or thionyl chloride may be used. The reaction is conveniently effected in an excess of the acid chloride (where liquid) as a solvent, or alternatively in the present of an inert solvent or diluent such as a halogenated hydrocarbon, e. g. 1, 2-dichloroethane. The reaction is effected at an elevated temperature, e.g. 80-120-C, and is then quenched by cooling and addition to an excess of ice and water.
The hydrolysis in step (b) can easily be achieved by heating the aqueous system, e. g. at reflux, the product being isolated by filtration of the cooled system.
The compound of the formula II, where R3 represents an hydrogen atom, is conveniently obtained by reaction of the corresponding aniline of formula V
in which R2 is as defined above, R3 is hydrogen and
R1 is a lower alcohol group, with a trialkyl orthoformate and a catalytic amount of an acid such as sulfuric acid. For the compound where R1 represents a cyclopropyl group, the aniline of formula V should first be N-cyclopropylated, for example by reaction with 1-chloro-1-ethoxycyclopropane, and the product subsequently formylated, e. g. by reaction with formic acid and acetic anhydride.
For a compound of formula V where R1 and R3 together form an oxyalkylene bridge, the general technique of
EP-B-0047005 may be used, followed by N-formylation as described above.
The products of general formula I may be treated as conventional in this art in order to prepare the required quinolone antibiotic, by a reaction to displace the substituent R with the heterocyclic amine of choice, e. g. piperazine, 3-methyl-piperazine, 4-methylpiperazine, 4-ethyl-piperazine etc. using reaction conditions known per se.
The following examples illustrate the invention.
Example 1
Preparation of methyl malonyl morpholide
Morpholine (8.OOg), 0.09mop) in anhydrous diethyl ether (40 ml) was stirred at 0 C in an ice bath. Methyl malonyl chloride (5.44g, 0.04mol) in anhydrous diethyl ether (20 ml) was added carefully over a 1/4h period. A vigorous reaction occurred producing a white precipitate of morpholine hydrochloride. When addition was complete the solution was stirred at room temperature for 10 minutes and the white precipitate was removed by filtration. The filtrate was evaporated to give the crude product as a yellow oil.Kugelruhr distillation (185-C, 4.0 mm/Hg) gave a colourless liquid. (5.70g, 76% infra red absorption spectrum [gBr] (may.' cm 1739 (C-O), 1643 (C=O), 1440 (C=O); nuclear magnetic resonance spectrum (CDCl3, 270 MHz) 8 ppm: 6. 35 (6H, m), 3. 71 (3H, s), 3.40 (4H, m).
Example 2
Preparation of 3-chloro-4-fluoro-N-ethyl formanilide
In a two necked round bottomed flask fitted with a 15 cm
Vigreux column packed with glass helices and provided with heated jacket and magnetic stirrer was placed 3-chloro-4-fluoroaniline (14.5g, 0.1 ml), triethyl orthoformate (22. 2g, 0. 15mol) and conc. sulfuric acid (0. 4g). This was heated to 115-120-C in an oil bath.
Over a one and a half hour period ethanol (approx. 10 ml) was collected. The oil bath temperature was gradually raised to 175'C in a 30 minute period and maintained at this temperature for a further 60 minutes. In this time a small amount of distillate was collected. After allowing to cool somewhat, the Vigreux column was removed and the remaining brown oil was distilled under reduced pressure.After a small forerun (approx. 3 ml) the product was collected (180'C/2mm Hg) as a pale yellow, low melting point solid, (15.2g, 75.68) m.p 34-36 C; (Found: C, 53. 68; H, 4. 56; N, 6. 94%. C9H9NOClF requires C, 53. 61; H, 4. 50; N, 6. 95%). vmax(KBr, cm 2980, 1685, 1505, 1251; EH (acetone d6) 1.21 (3H, superimposed triplets), 8.46 (2H, superimposed quartets), 7. 64 (2H,m), 7.45 (1H, dd) 3. 94 (1H,s).
Example 3
Reaction of 3-chloro-4-fluoro-N-ethylforrnanilide, methyl malonyl morpholide and POC13 in a 1. 1 to 1. 0 molar ratio
To a stirred solution of 3-chloro-4-fluoro-N-ethyl formanilide (0. 63g, 3. 12 mmol) in POCl3 (5ml) was added methyl malonyl morpholide (0. 50g, 2. 67 mmol) with
POCl3 washings (lml). The resulting solution was stirred in an oil bath at 100-C over a 12 hour period during which the colour changed from pale yellow to brown. After this time the reaction mixture was allowed to cool to room temperature whereupon it was poured onto a solution of ice and water (300 ml) and vigorously stirred. The resulting pale yellow solution was then boiled for one and a half hours and then allowed to cool to room temperature. The product, 7-chloro-1-ethyl-6fluoroquinolin-4-one 3-carboxylic acid, was collected by filtration as a white solid (5. 10g, 70. 8%).
Recrystallised from acetic acid/acetonitrile m.p 279 C, may (KBr, cm1) 3058, 1718, s, 1691, s, 1616, m, 1465; #H (CF3CO2D) 2.05 (3H, t, J 7.29), 5. 18 (2H, q, J 7.29), 8.66 (2H, overlapping d, JF57.8 and F85 9), 9. 69 (1H, s).
Claims (3)
1. A process for the preparation of a compound of the general formula
in which R represents a lower alkyl group, a lower aralkyl group, a vinyl or allyl group, a lower hydroxy alkyl group or a lower halogeno-alkyl group, a cyclopropyl group or an aryl group, R2 represents a substituent displaceable by an amine, and R3 represents a hydrogen atom or, together R3 and R represent the group -OCH2CH-K , where R4 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms comprising the following steps::
(a) reaction of a compound of the general formula
in which R1, R2 and R3 are as defined for formula I, with a malonic acid derivative of the general formula
in which R5 and R6 each represent an aliphatic group with up to 5 carbon atoms or R5 and R6, together with the nitrogen represent a cyclic amine optionally containing one or more further heteroatoms, and R7 represents a carboxylic acid ester, amide or nitrile, in the presence of a chlorinating agent capable of promoting a Vilsmeier-Haack reaction to obtain a compound of the general formula
in which K 1, R2 R3 and R7 are as defined above, and
(b) hydrolysis of the intermediate of general formula IV under hot aqueous acidic conditions sufficient to form the quinolone and to convert the substituent R7 into a carboxyl group, to obtain the product of general formula I.
2. A process according to Claim 1 in which R2 represents a chlorine or bromine atom or a methanesul fonyl group.
3. A process according to claim 1 or claim 2 in which said chlorinating reagent is phosphorus oxychloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9506905A GB2301354A (en) | 1995-04-04 | 1995-04-04 | Preparation for intermediates for quinolone antibiotics |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9506905A GB2301354A (en) | 1995-04-04 | 1995-04-04 | Preparation for intermediates for quinolone antibiotics |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9506905D0 GB9506905D0 (en) | 1995-05-24 |
| GB2301354A true GB2301354A (en) | 1996-12-04 |
Family
ID=10772456
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9506905A Withdrawn GB2301354A (en) | 1995-04-04 | 1995-04-04 | Preparation for intermediates for quinolone antibiotics |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2301354A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6316618B1 (en) | 1998-02-24 | 2001-11-13 | Samsung Electronics Co., Ltd. | Process for preparing (-)pyridobenzoxazine carboxylic acid derivatives |
| CN104163797A (en) * | 2014-05-14 | 2014-11-26 | 遵义医学院 | Synthetic method of 4-hydroxy-1,2,3,4-tetrahydroquinoline |
-
1995
- 1995-04-04 GB GB9506905A patent/GB2301354A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6316618B1 (en) | 1998-02-24 | 2001-11-13 | Samsung Electronics Co., Ltd. | Process for preparing (-)pyridobenzoxazine carboxylic acid derivatives |
| CN104163797A (en) * | 2014-05-14 | 2014-11-26 | 遵义医学院 | Synthetic method of 4-hydroxy-1,2,3,4-tetrahydroquinoline |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9506905D0 (en) | 1995-05-24 |
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