CN1297542C - Process for preparation of 6-fluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid derivatives - Google Patents
Process for preparation of 6-fluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid derivatives Download PDFInfo
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- CN1297542C CN1297542C CNB2003101254897A CN200310125489A CN1297542C CN 1297542 C CN1297542 C CN 1297542C CN B2003101254897 A CNB2003101254897 A CN B2003101254897A CN 200310125489 A CN200310125489 A CN 200310125489A CN 1297542 C CN1297542 C CN 1297542C
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- Prior art keywords
- fluoro
- dihydro
- methyl
- carboxylic acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 4
- 238000000034 method Methods 0.000 title claims 2
- KCEJQAATYWQMMQ-UHFFFAOYSA-N 6-fluoro-4-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=C(F)C=C2C(=O)C(C(=O)O)=CNC2=C1 KCEJQAATYWQMMQ-UHFFFAOYSA-N 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- IPTLKMXBROVJJF-UHFFFAOYSA-N azanium;methyl sulfate Chemical compound N.COS(O)(=O)=O IPTLKMXBROVJJF-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 150000008366 benzophenones Chemical class 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- FAKJFAMIABOKBW-UHFFFAOYSA-N 1-(2,4-dichloro-5-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC(F)=C(Cl)C=C1Cl FAKJFAMIABOKBW-UHFFFAOYSA-N 0.000 abstract 1
- JFMGBGLSDVIOHL-UHFFFAOYSA-N 6-fluoro-1-(4-fluorophenyl)-7-(4-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1 JFMGBGLSDVIOHL-UHFFFAOYSA-N 0.000 abstract 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 9
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- -1 carbostyril compound Chemical class 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BDJZCCWUSOZUQG-UHFFFAOYSA-N 2,4-dichloro-1-fluorobenzene Chemical compound FC1=CC=C(Cl)C=C1Cl BDJZCCWUSOZUQG-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N carbostyril Natural products C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-N methyl sulfate Chemical class COS(O)(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-N 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the preparation of 6-fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid derivative, such as difloxacin hydrochloride. In an important step, 2, 4-dichloro-5-fluoroacetophenone and dimethyl sulfate or derivants are synthesized, and a proper solvent is selected to combine four steps of reactions of cyclization, hydrolyzation, etc. into two steps without separation; thereby, the yield is raised, and the cost is obviously reduced.
Description
Technical field is a carbostyril compound.
Records such as its synthetic method of background technology such as EP 0 131 839, but exist synthesis step long, yield is low, shortcomings such as cost height.
Summary of the invention is at above-mentioned shortcoming, concentrate on studies, the derivative of at first having invented with inexpensive methyl-sulfate replaces expensive triethyl orthoformate, methylcarbonate to replace expensive diethyl carbonate, and two step reactions are lumped together operation, reduce operation steps and equipment, improved yield and reduced cost.The second, selected suitable solvent, the 5th step cyclization, hydrolysis reaction lump together without separation, yield is improved, thereby reduced cost significantly.
Reaction equation is as follows:
(in following formula: R
1The expression methyl; R
2Be phenyl, the 4-fluorophenyl.R
3Be piperazinyl, the N methyl piperazine base.)
Embodiment 1
2,4-two chloro-5-fluoro acetophenones
With 2,4 dichloro fluorobenzene 23.9g (0.145mol) and anhydrous AlCl
348.3g (0.36mol) drop in the reaction flask, under agitation drip new distillatory AcCl 13.5ml (0.22mol), rate of addition is no more than 40 ℃ with interior temperature and is advisable, and drips off the back and stirs 1.5h down in synthermal, stirs 2h in 120～125 ℃ again.In the impouring 150g trash ice, place.Divide oil-yielding stratum, water layer extracts with chloroform 50ml * 3.Organic layer merges, with anhydrous Na
2SO
4Dry.Filled column with 22 * 2.5cm separates organic layer, and after first normal pressure reclaimed chloroform, 90～94 ℃/0.27kPa fraction was collected in decompression, got colourless liquid 2,4-two chloro-5-fluoro acetophenone 24g (80%).Put the refrigerator overnight after fixing, filter, dry in the vacuum drier, get white crystals, 32.5～34.5 ℃ of mp.
Embodiment 2
α-(2,4-two chloro-5-fluorobenzoyl)-β-(4-fluoroanilino) methyl acrylate
NaH 10g with 54% and (MeO)
2CO 19g and toluene 190ml drop in the reaction flask, stir and heating, when interior temperature reaches 50 ℃, begin to drip 2,4-two chloro-5-fluoro acetophenone 20g, and about 20min drips off.Be warming up to backflow 1h after dripping off, be cooled to below 10 ℃, drip the mixture (derivative of methyl-sulfate is N-methoxyl group methylene radical-N, N-diformazan ammonium methyl-sulfate) of methyl-sulfate 27g and DMF16g, stirring reaction 2h.Be warming up to 85 ℃ of stirring reaction 1h.Add water stratification, tell organic layer, organic layer under agitation adds para-fluoroaniline 11g in room temperature, stirring reaction 1h.Condensation, layering leaches solid, dry α-(2,4-two chloro-5-fluorobenzoyl)-β-(4-fluoroanilino) the methyl acrylate 30.6g that gets.
Embodiment 3
7-chloro-6-fluoro-1-is to fluorophenyl-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
With α-(2,4-two chloro-5-fluorobenzoyl)-β-(4-fluoroanilino) methyl acrylate 70g and dimethylbenzene 520ml drop in the reaction flask, stirs also heating, when interior temperature reaches 70 ℃, begin to drip 60% NaH 11g and the mixture of chlorobenzene 60ml, about 2h drips off.In synthermal restir 10h down.Add less water, add 15% NaOH solution 115g again, be warming up to backflow 2h, cold slightly, with 30% hydrochloric acid and pH 1～3, placement is spent the night, and filters washing, dry 7-chloro-6-fluoro-1-is to fluorophenyl-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid 53.5g, yield 87.9%.
Embodiment 4
6-fluoro-1-is to fluorophenyl-7-(4-methyl isophthalic acid-piperazinyl)-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid hydrochloride
To fluorophenyl-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid 33.5g is dissolved among the DMSO 120ml with 7-chloro-6-fluoro-1-, in 90 ℃ of adding N methyl piperazine 30ml, in 110 ℃ of stirring reaction 5h.The pressure reducing and steaming solvent.Add dehydrated alcohol 150ml, stirring and refluxing 10min, room temperature is placed and is spent the night, and leaches solid, washes with small amount of ethanol.This solid is put into there-necked flask, add distilled water, under agitation be adjusted to pH 3, add gac 1.5g, backflow 0.5h, filtered while hot with 30% hydrochloric acid in 70～80 ℃.The filtrate room temperature is placed and is spent the night, filters, and washing, drying gets crystallization 6-fluoro-1-to fluorophenyl-7-(4-methyl isophthalic acid-piperazinyl)-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid hydrochloride 33.5g.Its content of high effective liquid chromatography for measuring is 99.08%.
Claims (1)
1, the represented 6-fluoro-1 of a kind of preparation formula (I), the method of 4-dihydro-4-Oxoquinoline-3-carboxylic acid derivative, the derivative of the methyl-sulfate that the benzophenone derivatives that its feature comprises formula (II) expression and formula (III) are represented is that the mixture of methyl-sulfate and DMF is N-methoxyl group methylene radical-N, the reaction that N-diformazan ammonium methyl-sulfate carries out:
In formula: R
1The expression methyl; R
2Be phenyl, the 4-fluorophenyl; R
3Be piperazinyl, the N methyl piperazine base.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2003101254897A CN1297542C (en) | 2003-12-28 | 2003-12-28 | Process for preparation of 6-fluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2003101254897A CN1297542C (en) | 2003-12-28 | 2003-12-28 | Process for preparation of 6-fluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1634891A CN1634891A (en) | 2005-07-06 |
| CN1297542C true CN1297542C (en) | 2007-01-31 |
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ID=34845143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2003101254897A Expired - Fee Related CN1297542C (en) | 2003-12-28 | 2003-12-28 | Process for preparation of 6-fluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1297542C (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4730000A (en) * | 1984-04-09 | 1988-03-08 | Abbott Laboratories | Quinoline antibacterial compounds |
| CN1247865A (en) * | 1998-07-28 | 2000-03-22 | 辉瑞产品公司 | Prepn. of quinolone and 1,8-diaza-naphthalenone carboxylic acid |
-
2003
- 2003-12-28 CN CNB2003101254897A patent/CN1297542C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4730000A (en) * | 1984-04-09 | 1988-03-08 | Abbott Laboratories | Quinoline antibacterial compounds |
| CN1247865A (en) * | 1998-07-28 | 2000-03-22 | 辉瑞产品公司 | Prepn. of quinolone and 1,8-diaza-naphthalenone carboxylic acid |
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| Publication number | Publication date |
|---|---|
| CN1634891A (en) | 2005-07-06 |
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