EP0215902A1 - Procede de preparation de 4-amino quinolines - Google Patents

Procede de preparation de 4-amino quinolines

Info

Publication number
EP0215902A1
EP0215902A1 EP19860902141 EP86902141A EP0215902A1 EP 0215902 A1 EP0215902 A1 EP 0215902A1 EP 19860902141 EP19860902141 EP 19860902141 EP 86902141 A EP86902141 A EP 86902141A EP 0215902 A1 EP0215902 A1 EP 0215902A1
Authority
EP
European Patent Office
Prior art keywords
mixture
formula
compound
piperazine
gal
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP19860902141
Other languages
German (de)
English (en)
Inventor
John M. Mccall
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
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 Upjohn Co filed Critical Upjohn Co
Publication of EP0215902A1 publication Critical patent/EP0215902A1/fr
Withdrawn legal-status Critical Current

Links

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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms

Definitions

  • the present invention provides a novel means for preparing a known pharmacological agent.
  • the present invention provides a novel means of preparing 1[(4-fluorophenyl)sulfonyl]-4-[4-[[7(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
  • This compound is disclosed and claimed in U.S. Patent 4,167,567. This compound is known to be useful as an antihypertensive agent, and is currently under development at The Upjohn Company. This compound has the USAN name "losulazine”.
  • U.S. Patent 4,167,567 discloses a process for preparing 1[(4-fluorophenyl)sulfonyl]-4-[4-[[7(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
  • the present invention particularly provides:
  • a process for preparing a compound of the Formula C-7, or a pharmacologically acceptable acid addition salt thereof which comprises reacting a compound of the Formula C-5, or a pharmacologically acceptable acid addition salt thereof, with a compound of the Formula C-6 to yield the Formula C-7 compound.
  • salts include the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate, and the like. These salts may be in hydrated form.
  • the present invention provides a novel means to prepare losulazine.
  • the prior art process employs the 4-chloro-7-trifluoromethyl quinoline, the most expensive compound used in the preparation of losulazine, in the first step of the process, as seen by Chart A.
  • This reagent is very expensive, and while the reaction proceeds in high yield, when the remaining steps of the process are performed, the yield of the final product from this starting material becomes relatively low. In other words, this process is not efficient in terms of 7-trifluoro- methyl-4-chloroquinoline.
  • Another means of preparing this compound, as disclosed in the prior art is that set forth in Chart B. Once again, the yield based on the expensive starting material is low.
  • the present invention provides a novel means for employing 4-chloro-7-trifluoromethyl-quinoline in the last step, thereby obtaining a substantial yield of final product based on this reagent.
  • Two means of obtaining the compound of the Formula II are set forth on Chart C. As can be seen, both of these procedures ultimately employ the process of the present invention as the last step.
  • the Formula C-5 compound (1-(4-aminobenzoyl)-4-(4-fluorophenyl)sulfonyl piperazine) is prepared from the 4-aminobenzoyl piperazine compound (Formula C-3A) by treating it with p-fluorobenzene sulfonyl chloride.
  • the Formula C-3 p-nitrobenzoyl piperazine is treated with p-fluorobenzene sulfonyl chloride to yield the Formula C-4 compound (4-[4-fluorobenzenesulfonyl]-1-[4-nitrobenzoyl]- piperazine) which is then hydrogenated by known means (e.g., using hydrogen gas with a platinum oxide or palladium-on-carbon catalyst to yield the Formula C-5 compound.
  • known means e.g., using hydrogen gas with a platinum oxide or palladium-on-carbon catalyst
  • the solution is basified by known means (e.g., using an aqueous wash of sodium hydroxide, tertiary organic amine bases like triethylamine, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate).
  • a co-solvent may be added (e.g., ethanol, methanol, n-propanol, and n-butanol).
  • reaction will proceed in any of the following as the sole reaction solvent: chloroform, methylene chloride, 1,2-dichloroethane, the alcohols named above, dimethylformamide (DMF) or dimethylsulfoxide
  • the preferred solvent for the reaction is a mixture of two solvents because, surprisingly, the product formed is more soluble in such solvent mixture than it is in a comparable volume of either solvent alone, thus the preferred solvent is a mixture of two solvents: one co-solvent selected from the chlorinated hydrocarbon solvents chloroform, methylene chloride and 1,2-dichloroethane; the other co-solvent selected from the group of alcohols methanol, ethanol, n-propanol and n-butanol.
  • the ratio (volume/volume) of the chlorinated hydrocarbon solvent: alcohol solvent can vary from 11 to 10:1, preferably it is about 2:1 to 5:1.
  • the chloroform-ethanol mixture is preferred because: (1) the chloroform is sufficiently high boiling to allow a beneficial reaction rate; and (2) the ethanol apparently reacts with the 4-chloro- 7-trifluoromethylquinoline reactant more slowly than e.g., methanol does.
  • the product may be recrystall i zed from toluene, ethyl acetate, benzene , dioxane , diethyl ether or tetrahydrofuran, (after dissolving it in the original reaction solvents ) as described more fully in Example 2.
  • Glacial acetic acid tank farm 40 gal
  • the autoclave is charged with 18.0 g of Platinum oxide and the solution is stirred under 50 psig of hydrogen until the required 3 molar equivalents of hydrogen is absorbed. Whenever the solution reaches 35° C , the stirrer is stopped and the mixture is cooled to 25° C before resuming the agitation.
  • the mixture is filtered through Solka Floe on a sparkler filter collecting the filtrate in a 50-gal glass-lined wash tank.
  • the autoclave is rinsed and the mixture filtered with 2.0 gal of glacial acetic acid.
  • Steps 1-3 are repeated with 4.77 kg of 4-[4-fluorobenzenesulfonyl)- 1-[4-nitrobenzoyl]piperazine combining the f iltrates and washes from both runs in the 50-gal wash tank.
  • the mixture is chilled to 20° C with cold water.
  • the distillate is diluted with 30 gal of absolute methanol and discarded.
  • step 8 The crystals from step 8 are collected on a grounded stainless steel filter (the filtrate is saved) , the crystals are rinsed with 3.0 gal of ethyl acetate and dried on the filter.
  • the crystals are assayed by TLC (Analtech GF, 6% methanol/methylene chloride-uv).
  • the crystals contained two major components (Rf-0.43, 85%; Rf-0.31, 15%).
  • the crystalline product is collected by filtration through a stainless steel filter.
  • the filter cake is rinsed with 3.0 gal of ethyl acetate.
  • the filtrate is concentrated to about 3 gal and 3 gal of ethyl acetate are blown into the hot solution.
  • the mixture is cooled and the crystals are collected by filtration, and the crystals are rinsed with ethyl acetate. The filtrate is discarded. The crystals are dried in a vacuum oven at 50° C, wt. 450 g (5%).
  • TLC (Analtech GF, 6% methanol/methylene chloride, uv) analysis shows the first crop >99.9% one spot; second crop >98% one spot.
  • Example 1 1 -C ( 4-fluorophenyl)sulfonyl]-4-[4-[[7(trifluoromethyl )- 4-quinolinyl]amino]phenyl]benzoyl piperazine monohydrochloride hemi hydrate Refer to Chart C (conversion of C-5 to C-7) .
  • Procedure 1 From a grounded drum, 256 liters of chloroform are drawn into the 100 gallon vessel , which is maintained under nitrogen.
  • the sodium hydroxide solution is added to the chloroform suspension through the port all at once.
  • the pH of the aqueous portion is monitored , and is basified via the addition of more sodium hydroxide if necessary .
  • the layers are then separated.
  • the chloroform (lower ) layer is separated into the 200 gal wash tank.
  • the aqueous layer is discarded after pH is adj usted to 7.
  • the organic layer is washed with 187 l of water .
  • the organic (lower) layer is drawn into the second 100 gallon vessel which is clean and dry.
  • the aqueous layer is monitored for the presence of residual starting material by TLC . When no significant starting material is present , the pH is adj usted to 6.5-8.5 and the material is discarded.
  • the TLC assay is performed with Analtech GF plates , using 6% methanol/-methylene chloride , developed with ultraviolet light (uv) .
  • anhydrous hydrogen chloride is prepared by bubbling gaseous hydrogen chloride into 900 ml of pre-weighed absolute ethanol until 58.4 g have been absorbed.
  • the ethanolic hydrogen chloride solution is then drawn into the reaction mixture. Beware of corrosive hydrogen chloride fumes .
  • the hot reaction mixture is assayed by treating a sample with a few drops of 10% sodium hydroxide solution.
  • the organic portion is analyzed by TLC comparing with the starting material and the product , using Analtech GF plates , and 6% methanol/methyl ene chloride and developing with ultraviolet light .
  • the reaction i is approximately 95% complete , the mixture is concentrated under reduced pressure to about 22 2, ( 6.0 gal) .
  • the chloroform distillate is discarded.
  • the mixture is chilled to 18° C with cold water cooling.
  • the crystalline filter cake is dried in a vacuum oven at 50° C.
  • TLC analysis Analtech GF, 6% methanol/methylene chloride, u.v. shows one spot with an Rf value of 0.51.
  • reaction vessel is re-inerted with nitrogen 75 % of methanol is drawn into the vessel from a grounded drum through a Sethco filter.
  • a Sethco (in-line) filter is used to remove any find articulate matter.
  • the filtrate should have no appreciable quantity of desired product remaining therein.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

Nouveau procédé de préparation d'agents pharmacologiques connus utiles dans le traitement de l'hypertension et correspondant à la formule C-7.
EP19860902141 1985-03-13 1986-03-11 Procede de preparation de 4-amino quinolines Withdrawn EP0215902A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US71134285A 1985-03-13 1985-03-13
US711342 1985-03-13

Publications (1)

Publication Number Publication Date
EP0215902A1 true EP0215902A1 (fr) 1987-04-01

Family

ID=24857712

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19860902141 Withdrawn EP0215902A1 (fr) 1985-03-13 1986-03-11 Procede de preparation de 4-amino quinolines

Country Status (4)

Country Link
EP (1) EP0215902A1 (fr)
JP (1) JPS62502339A (fr)
ES (1) ES8707187A1 (fr)
WO (1) WO1986005489A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69835430T2 (de) 1997-05-30 2007-03-08 Takeda Pharmaceutical Co. Ltd. Sulfonamidderivate, ihre herstellung und verwendung
CA2317017A1 (fr) 1998-02-05 1999-08-12 Takeda Chemical Industries, Ltd. Derives de sulfamide, leur procede de production et leur utilisation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4025629A (en) * 1974-01-07 1977-05-24 The Upjohn Company P-(trifluoromethylquinolylamino)benzamides, pharmaceutical dosage forms and method of treatment
US4159331A (en) * 1978-05-05 1979-06-26 The Upjohn Company Antihypertensive 4-aminoquinolines
US4167567A (en) * 1978-05-05 1979-09-11 The Upjohn Company Antihypertensive 4-aminoquinolines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8605489A1 *

Also Published As

Publication number Publication date
ES552937A0 (es) 1987-08-01
WO1986005489A1 (fr) 1986-09-25
JPS62502339A (ja) 1987-09-10
ES8707187A1 (es) 1987-08-01

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Inventor name: MCCALL, JOHN, M.