WO1994017074A1 - Process for the manufacture of a tricyclic compound - Google Patents

Process for the manufacture of a tricyclic compound Download PDF

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Publication number
WO1994017074A1
WO1994017074A1 PCT/EP1994/000147 EP9400147W WO9417074A1 WO 1994017074 A1 WO1994017074 A1 WO 1994017074A1 EP 9400147 W EP9400147 W EP 9400147W WO 9417074 A1 WO9417074 A1 WO 9417074A1
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WO
WIPO (PCT)
Prior art keywords
compound
process according
formula
amino
methyl
Prior art date
Application number
PCT/EP1994/000147
Other languages
English (en)
French (fr)
Inventor
Martin Karpf
Rene Trussardi
Original Assignee
Pfizer Inc.
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.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to CA002153984A priority Critical patent/CA2153984C/en
Priority to KR1019950702906A priority patent/KR100256461B1/ko
Priority to EP94905666A priority patent/EP0680482B1/en
Priority to DE69402412T priority patent/DE69402412T2/de
Priority to AU59696/94A priority patent/AU688301B2/en
Priority to US08/492,039 priority patent/US5892040A/en
Publication of WO1994017074A1 publication Critical patent/WO1994017074A1/en
Priority to GR970400856T priority patent/GR3023195T3/el

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • the present invention relates to a new process for the manufacture of a tricyclic compound, i.e. a pyrido[3,2,1-ij]-1,3,4-benzoxadiazine derivative of the formula
  • the compound of formula I, 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl- 1-piperarinyl)-7-oxo-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid and its pharmaceutically acceptable salts are antibacterially active and useful as effective ingredients in antibacterial agents. They are described in European Patent Specification No. 259 804 together with a process for their manufacture. The process described therein is unpracticable for large scale manufacture, however, in that a multi ⁇ tep process is used which requires high temperatures and untechnical reagents (e.g. 0-(2,4-dinitrophenyl)- hydroxylamine for amination involves danger of explosion) resulting in low over-all yields.
  • a multi ⁇ tep process is used which requires high temperatures and untechnical reagents (e.g. 0-(2,4-dinitrophenyl)- hydroxylamine for a
  • the present invention provides a practical process for manufacturing the compound of formula I in superior yields. Starting from the acid chloride of 2,3,4,5-tetrafluorobenzoic acid, the process can be depicted by the following flow sheet (Scheme I).
  • R represents alkyl of from one to four carbon atoms, preferably methyl or ethyl
  • NR 1 R 2 is N,N'-(dicyclohexyl)amino, N-methyl- N'-benzyl-amino or 4-methyl-piperazinyl
  • M is the cation of an alkali metal hydroxide
  • the wavy line ( ) indicates two stereospecific possibilities.
  • 2,3,4,5-Tetrafluorobenzoic acid chloride VII is converted to the acylated malonic ester VIII via a metal salt of a malonic acid ester, preferably via the magnesium salt of diethyl malonate.
  • the so-obtained acylated malonic acid ester VIII is subjected to acidic hydrolysis, preferably by refluxing with a sulfonic acid, such as p- toluene sulfonic acid in aqueous medium, to yield the monoester IX.
  • a sulfonic acid such as p- toluene sulfonic acid in aqueous medium
  • Said monoester IX is converted to the alkoxyacrylic acid ester IVa by refluxing with a trialkyl orthoformate (preferably triethyl
  • an organic solvent which is preferably acetic acid anhydride.
  • the alkoxyacrylic acid IVa is reacted with N-amino-N-methyl- formamide in an inert organic solvent, preferably toluene at about room temperature to yield product V.
  • Compound V is cyclized to the 1-(N-methylformamido)-quinoline derivative VI by heating the reaction solution, preferably up to reflux temperature, preferably in the presence of a base, such as a lower trialkyl- amine, e.g. triethyiamine, or an alkali metal carbonate, e.g. sodium carbonate.
  • a base such as a lower trialkyl- amine, e.g. triethyiamine, or an alkali metal carbonate, e.g. sodium carbonate.
  • the compound VI is reacted with N-methylpiperazine to yield the substitution product III, preferably at reflux temperature in the same solvent as the previous reaction and under the same basic conditions.
  • Compound III is reacted with an alkali metal hydroxide, preferably potassium hydroxide, in an aqueous medium at about 80°C to 120°C, preferably reflux, for about 20 to 100 hours.
  • an alkali metal hydroxide preferably potassium hydroxide
  • a fluorine/hydroxy exchange is effected in position 8, which goes to practical completion by utilizing at least about 10 mol equivalents of alkali metal hydroxide and increasing the reaction time to about 70 to 100 hours.
  • the alkali metal hydroxide is preferably present in a concentration of about 10 to 20% by weight of the aqueous solution.
  • the 1-(N-methylamino)-quinoline derivative II obtained in this manner is cyclized to the desired end product I, viz. 9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6- carboxylic acid, by treatment with formic acid and formaldehyde, preferably with an excess of both of 85% aqueous formic acid and 25-50% aqueous formaldehyde.
  • the end product is obtained as formiate salt, which is neutralized to the corresponding carboxylic acid form by means of an aqueous base, such as aqueous sodium hydroxide or aqueous ammonia.
  • an aqueous base such as aqueous sodium hydroxide or aqueous ammonia.
  • 2,3,4,5-Tetrafluorobenzoic acid VII is acylated (via its acid chloride) with the aminoacrylic ester X in the presence of a base, preferably a tertiary amine, e.g. triethyiamine, in an inert organic solvent, preferably toluene at elevated temperature, preferably reflux.
  • a base preferably a tertiary amine, e.g. triethyiamine
  • an inert organic solvent preferably toluene at elevated temperature, preferably reflux.
  • the so obtained intermediate IVb is reacted with N-amino-N-methylformamide in an inert organic solvent, preferably toluene at about room temperature to yield the condensation product V.
  • 2,3,4,5-Tetrafluorobenzoic acid VII is reacted (via its acid chloride) with the 3-(formylmethylhydrazono)-propionic ester XI and a magnesium lower alkanolate, e.g. magnesium ethylate, in an inert organic solvent, such as ethyl acetate, at low temperature, preferably in the range of 0-10°C, followed by acidification, e.g. with formic acid, to yield compound V.
  • a magnesium lower alkanolate e.g. magnesium ethylate
  • an inert organic solvent such as ethyl acetate
  • the resulting green viscous solution was stirred for 30 min at 0°C and then treated in the course of 1 hour with a solution of 200 ml of concentrated sulfuric acid (3.7 mol) mixed with 3200 ml of ice water (deionized), keeping the temperature at 0°C.
  • the two-phase mixture was transferred to an extraction vessel, mixed with 5000 ml of water (deionized) and extracted.
  • the aqueous phase was transferred for extraction to a second, then to a third extraction vessel, each containing 4000 ml, in total 8000 ml, of toluene.
  • the aqueous phase was discarded and the 3 organic layers were consecutively washed with 2 portions of 3000 ml, in total 6000 ml, of water (deionized).
  • the aqueous layers were discarded, the organic layers combined and evaporated in a rotary evaporator first at 50°/16 torr, then dried at 50o/ 2 torr to give as a crude product 2648 g (98%) of 22 as a yellowish liquid. This material was used in the next step without further purification.
  • the brown residue was evaporated in a rotary evaporator first at 70°C/10 torr, then at 70°C/0.1 torr to yield a crude product 3426 g (93%) of 24 as a brown liquid.
  • the crude product was used in the next step without further purification.
  • step b) The beige, dense pulp resulting from step b) was treated with 35.0 ml of 1-methylpiperazine (0.312 mol) and the reaction mixture was heated to reflux for 6 hours. After the addition of 8.8 ml of 1-methylpiperazine (0.078 mol) the brown reaction mixture was heated to reflux for 2 hours, then cooled to about 40°C and evaporated in a rotary evaporator to dryness at 16 torr. The brown, sticky residue was taken up in 275 ml of water (deionized), neutralized to pH 7 by careful addition of ca. 55 ml of 3N hydrochloric acid and extracted with 400 ml of methylene chloride.
  • the organic phase was washed with 2 portions of 150 ml, in total 300 ml, of half concentrated brine and the 3 aqueous phases were extracted consecutively with 3 portions of 125 ml, in total 375 ml, of methylene chloride.
  • the combined organic phases were dried over ca. 20 g of sodium sulfate and filtered.
  • the filter cake was washed with ca. 120 ml of methylene chloride, and the combined filtrates were evaporated in a rotary evaporator at 50°C/16 torr.
  • the beige crystals obtained were suspended in 460 ml of methyl t-butyl ether and vigorously stirred at room temperature overnight.
  • the suspension was filtered, the filter cake was washed with 2 portions of ca. 125 ml, in total ca. 250 ml, of methyl t-butyl ether and dried at 50°C/0.02 torr to give 43.5 g (68%) of 36 as slightly beige crystals.
  • Step 4) Preparation of ethyl 6,8-difluoro- 1 -4-dihydro-1-(N-methylformamido)- 7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylate (11)
  • Step 5 Preparation of 6-fluoro-1,4-dihydro-8-hvdroxy-1-(methylamino)-7-(4- methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (12)
  • step 4 The crude product (232.0 g) of step 4) containing 11 was transferred to a 2 litre steel reactor equipped with a steel mechanical stirrer, a thermocouple, a descending Liebig condenser and an inert gas supply using
  • step 6 To the dark brown reaction mixture of step 6) containing 12 340 ml of 85% formic acid (ca. 7.5 mol) were added dropwise during 5 minutes without exceeding a temperature of 50°C. In the temperature range of 40-50°C
  • the suspension was cooled to room temperature, stirred for 1 hour, filtered, and the filter cake was washed with 3 portions of 60 ml, in total 180 ml, of ethanol to yield after drying at 50°C/35 torr overnight as the product 77.71 g (43% relative to 6) of 1 as yellow crystals of m.p. 265-268°C (dec).
  • reaction mixture was allowed to cool to 60-65°C and filtered through a glass filter funnel with intense suction.
  • the filter cake was washed with 2 portions of 100 ml, in total 200 ml, of toluene and the combined filtrates containing 6 were directly used for step 5).
  • Step 7) Preparation of ethyl 6,8-difluoro-1 ,4-dihydro-1-(N-methylforma- mido)-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxyIate (11 )
  • step 7 The crude product (264.8 g) of step 7) containing 11 was transferred to a 2 litre steel reactor equipped with a steel mechanical stirrer, a thermocouple, a descending Liebig condenser and an inert gas supply using
  • Step 10 Preparation of 9-fl ⁇ oro-2,3-dihydro-3-methyl-10-(4-methyl-1-pipera- zinyl)-7-oxo-7H-pyrido[ 3,2,1-ij][4,1,2]benzoxadiazine-6-carboxylic acid (1.
  • step 9 To the dark brown reaction mixture of step 9) containing 12 340 ml of 85% formic acid (ca. 7.5 mol) were added dropwise during 5 minutes without exceeding a temperature of 50°C. In the temperature range of 40-45°C
  • the combined extracts were filtered through a glass fibre filter to remove small amounts of insoluble by-products, and the dark brown filtrate was evaporated in a rotary evaporator at 50°C/20 torr to dryness to yield 100.7 g of brown crystals.
  • the crystals were taken up in 400 ml of ethanol and the resulting slurry was stirred for 1 hour at 0-5°C, filtered, and the filter cake was washed with 100 ml of ethanol to yield after drying at 50°C/30 mbar overnight 67.3 g of crude 1 as yellow crystals.
  • This crude material was suspended in a mixture of 670 ml of ethanol, 335 ml of toluene and 335 ml of water (deionized) and heated to reflux. From the clear yellow solution formed 670 ml of a solvent mixture was distilled off whereby the temperature rose from 72-79°C and a yellow precipitation was formed. The suspension was cooled to room temperature, stirred for 1 hour, filtered, and the filter cake was washed with 3 portions of 60 ml, in total with 180 ml of ethanol to yield after drying at 50°C/30 mbar overnight as the product 60.40 g (33% relative to 2) as yellow crystals of m.p. 261-265°C (dec).
  • the yellowish oil (13.7 g) was taken up in 30 ml of dichloromethane, washed with 50 ml of water and subsequently twice with each 7.5 ml of half-saturated brine.
  • the aqueous extracts were washed twice with each 15 ml of dichlormethane, the organic phases united, dried over magnesium sulphate, filtered and evaporated at 47°C/20 torr.
  • the crystalline, beige residue (6.1 g) was suspended in 40 ml of tert.-butylmethyl ether, vigorously digested for 50 min., the crystals filtered, washed twice with each 10 ml of tert.-butylmethyl ether and dried at 45°C/13 torr.
  • the residual crystalline slurry was taken up in 100 ml of methylene chloride and 250 ml of deionized water, intensely shaken, the phases separated and the aqueous phase extracted 3 times with each 30 ml, totally 90 ml, of methylene chloride.
  • the united organic extracts were dried over 10 g sodium sulphate and evaporated at 40°C/40 torr.
  • the brown oily residue (25.0 g) was dissolved in 130 ml of ethanol with heating. Crystallization was started by slow stirring after removal of the heating source (about 0.5 hours) and terminated by ice/water cooling after 3 hours. The resulting crystals were filtered off and dried for 15 hours at 50°C/40 torr.
  • the phases were separated and the aqueous phase extracted 3 times with each 20 ml, totally 60 ml, of methylene chloride.
  • the united organic extracts were washed with 50 ml of deionized water, dried over 4 g of sodium sulphate and the solvent evaporated off at 40°C/40 torr. There remained 21.05 g of light brown crystals, which were digested in 20 ml of ethanol for 2 hours with ice/water cooling, filtered off and dried for 14 hours at 50°C/40 torr.

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Oncology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Quinoline Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/EP1994/000147 1993-01-23 1994-01-19 Process for the manufacture of a tricyclic compound WO1994017074A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA002153984A CA2153984C (en) 1993-01-23 1994-01-19 Process for the manufacture of a tricyclic compound
KR1019950702906A KR100256461B1 (ko) 1993-01-23 1994-01-19 삼환 화합물의 제조 방법
EP94905666A EP0680482B1 (en) 1993-01-23 1994-01-19 Process for the manufacture of a tricyclic compound
DE69402412T DE69402412T2 (de) 1993-01-23 1994-01-19 Verfahren zur herstellung von einer tricyclischen verbindung
AU59696/94A AU688301B2 (en) 1993-01-23 1994-01-19 Process for the manufacture of a tricyclic compound
US08/492,039 US5892040A (en) 1993-01-23 1994-01-19 Process for the manufacture of a tricyclic compound
GR970400856T GR3023195T3 (en) 1993-01-23 1997-04-21 Process for the manufacture of a tricyclic compound.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP93101031.8 1993-01-23
EP93101031 1993-01-23

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WO1994017074A1 true WO1994017074A1 (en) 1994-08-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0647644A1 (de) * 1993-09-02 1995-04-12 Bayer Ag Aktibakteriell wirksame Pyrido 1,2,3-d,e 1,3,4 Benzoxadiazinderivate
WO2011061292A1 (en) * 2009-11-19 2011-05-26 Krka, Tovarna Zdravil, D.D., Novo Mesto A process for a preparation of marbofloxacin and intermediate thereof

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CN101020647B (zh) * 2007-02-14 2011-03-30 杭州师范学院 一种β-环丙胺基丙烯酸(酯)的合成方法
CN102060860B (zh) * 2011-01-07 2013-04-10 宁波美诺华药业股份有限公司 一种马波沙星的制备方法
CN102617595A (zh) * 2012-03-23 2012-08-01 江西华士药业有限公司 氟喹诺酮类抗菌药马波沙星的制备方法
CN107383058B (zh) * 2017-08-28 2019-07-26 海门慧聚药业有限公司 马波沙星的制备
CN107522718B (zh) * 2017-09-14 2019-11-08 浙江国邦药业有限公司 一种马波沙星的合成方法
CN114249749B (zh) * 2022-01-08 2024-03-22 天象生物药业邢台有限责任公司 一种马波沙星甲酸盐的转化方法
CN116987096B (zh) * 2023-08-06 2025-07-01 石家庄学院 一种马波沙星的制备方法

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0647644A1 (de) * 1993-09-02 1995-04-12 Bayer Ag Aktibakteriell wirksame Pyrido 1,2,3-d,e 1,3,4 Benzoxadiazinderivate
US5508278A (en) * 1993-09-02 1996-04-16 Bayer Aktiengesellschaft Pyrido[1,2,3-D,E] [1,3,4]benzoxadiazine derivatives
WO2011061292A1 (en) * 2009-11-19 2011-05-26 Krka, Tovarna Zdravil, D.D., Novo Mesto A process for a preparation of marbofloxacin and intermediate thereof
EP2332916A3 (en) * 2009-11-19 2011-08-03 Krka Tovarna Zdravil, D.D., Novo Mesto A process for a preparation of marbofloxacin and intermediate thereof
EA021239B1 (ru) * 2009-11-19 2015-05-29 Крка, Товарна Здравил, Д.Д., Ново Место Способ получения марбофлоксацина и его промежуточного соединения

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CA2153984A1 (en) 1994-08-04
CN1053907C (zh) 2000-06-28
EP0680482B1 (en) 1997-04-02
EP0680482A1 (en) 1995-11-08
ES2100695T3 (es) 1997-06-16
TW266208B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1995-12-21
GR3023195T3 (en) 1997-07-30
DE69402412T2 (de) 1997-07-10
AU5969694A (en) 1994-08-15
AU688301B2 (en) 1998-03-12
US5892040A (en) 1999-04-06
JPH08502756A (ja) 1996-03-26
JP2809509B2 (ja) 1998-10-08
ZA94433B (en) 1995-07-21
KR100256461B1 (ko) 2000-05-15
ATE151075T1 (de) 1997-04-15
NZ261106A (en) 1997-06-24
DE69402412D1 (de) 1997-05-07
CA2153984C (en) 2008-08-05
CN1116849A (zh) 1996-02-14
DK0680482T3 (da) 1997-05-05

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