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EP1532101A1 - Verfahren zur herstellung von monoalkylaminoketonen - Google Patents

Verfahren zur herstellung von monoalkylaminoketonen

Info

Publication number
EP1532101A1
EP1532101A1 EP03790843A EP03790843A EP1532101A1 EP 1532101 A1 EP1532101 A1 EP 1532101A1 EP 03790843 A EP03790843 A EP 03790843A EP 03790843 A EP03790843 A EP 03790843A EP 1532101 A1 EP1532101 A1 EP 1532101A1
Authority
EP
European Patent Office
Prior art keywords
formula
compounds
acid
preparation
compound
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Withdrawn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
EP03790843A
Other languages
German (de)
English (en)
French (fr)
Inventor
Kai Fabian
Claus-Peter Niesert
Joachim Kralik
Karl-Heinz GLÜSENKAMP
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.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=31502148&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1532101(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1532101A1 publication Critical patent/EP1532101A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings

Definitions

  • the invention relates to monoalkylaminoketones of the formula I.
  • R1 is an unsubstituted or mono- or polysubstituted by R 3 and / or R 4 , saturated, unsaturated or aromatic carbocyclic or heterocyclic radical, R 2 alkyl having 1-20 C atoms,
  • R 3 , R 4 each independently of one another are H, alkyl or alkoxy having 1-20 C atoms, aryl, aryloxy or COOR 2 , F, Cl, Br, OH, CN, NO 2 , N (R 2 ) 2 or NHCOR 2
  • R 1 and R 2 have the meaning given above, in the presence of an alkylamine of the formula R 2 NH 2 wherein R 2 has the meaning indicated above.
  • the compounds of formula II are preferably as
  • Methyl, p-toluene or benzenesulfonic acid, perchloric, sulfuric or phosphoric acid are suitable.
  • the hydrochlorides are particularly preferred
  • the invention in particular enables the synthesis of precursors of optically active S-monoalkylaminopropanols, which can be used as starting compounds in the production of medicaments, e.g. Antidepressants.
  • the invention was therefore based on the object of finding a production process for the compounds of the formula I or their salts and in particular for the compound Ia or their salts which can be used in particular as intermediates in the synthesis of medicaments and which has the disadvantages mentioned above does not have.
  • bases Ib and Ic that can be released by bases are:
  • alkyl has 1 to 20, preferably 1 to 6, in particular 1, 2, 3 or 4, carbon atoms.
  • Alkyl preferably means methyl or ethyl, furthermore propyl, isopropyl, further also butyl, isobutyl, sec-butyl or tert-butyl.
  • R 1 is preferably an aromatic carbocyclic or heterocyclic radical which is unsubstituted or substituted by R 3 and / or R 4.
  • This radical can be mono- or polynuclear and is preferably mono- or dinuclear, but in particular mononuclear.
  • R 1 is particularly preferably unsubstituted.
  • R 1 is a carbocyclic radical, this radical is preferably, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl.
  • R 1 is a heterocyclic radical, preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5- Isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1,2 , 3-triazol-1-, - 4- or -5-yl, 1, 2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazole -4- or -5-yl, 1, 2,4-oxadiazol-3- or -5-yl, i, 3,4-thiadiazol-2- or -5-yl, 1, 2,4-thiadiazol-3 - or -5-yl,
  • Metallocenes such as Ferrrocenes, especially acetylferrocene can be used.
  • the heterocyclic radicals can also be partially or completely hydrogenated.
  • a heterocyclic radical z. B also 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3- furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, - 3-, -4- or -5- pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4- imidazolyl, 2,3-dihydro-1-, - 2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-
  • heterocyclic radicals mentioned can additionally be substituted by R 3 and / or R 4 .
  • R 1 particularly preferably denotes phenyl or 2-thienyl.
  • R 2 is preferably methyl, ethyl, n-propyl or isopropyl, but especially methyl.
  • R 3 and R 4 independently of one another preferably denote H, methyl, in particular H.
  • Aryloxy preferably means e.g. Phenyloxy, o-, m- or p-tolyloxy, o-, m- or p-hydroxyphenyloxy, o-, m- or p-methoxyphenyloxy, o-, m- or p-fluorophenyloxy.
  • Aryl preferably means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl.
  • the process according to the invention is simple, the compound of the formula II preferably being dissolved or suspended in a solvent such as water, alcohol, ether, saturated or aromatic halogenated or halogen-free hydrocarbons or mixtures thereof.
  • a solvent such as water, alcohol, ether, saturated or aromatic halogenated or halogen-free hydrocarbons or mixtures thereof.
  • the mixture is strongly acidified by adding a strong acid such as hydrochloric acid or sulfuric acid.
  • a corresponding acid addition salt of the alkylamine of the formula R 2 NH 2 can be added to the solution or suspension of the compounds of the formula II.
  • the pH of the solution is then increased to about pH 2-7.5, preferably pH 4-7, in particular pH 5.2 to 6.8, by adding an alkylamine of the formula R 2 NH 2 , and the reaction mixture is further 1 to 24 h, preferably 5 - 10 h at 0 ° to 200 ° C, preferably at 10 ° C-100 ° C and in particular at 30X- 90 ° C, whereby the compounds of formula I or their salts are obtained.
  • a one-pot process for the preparation of the compounds of the formula I is preferred, in which initially known processes, in particular FF FF, JH Burckhalter, J. Am. Chem. Soc. 1942, 64, 451-454, the compound of formula II is prepared.
  • This is preferably a mixture of a formaldehyde source, such as paraformaldehyde or trioxane, with a corresponding alkylammonium salt of the formula R 2 NH 2 * HX, where HX is a strong acid, such as hydrogen halide, especially hydrogen chloride or sulfuric acid, with a ketone of formula III and one
  • the reaction time of this reaction is generally between a few hours and 14 days, the reaction temperature between 0 ° C. and 200 ° C., normally between 10 ° C. and 130 ° C., preferably between 20 ° C. and 100 ° C. and especially between 30 ° C and 90 ° C.
  • the compounds of the formula II generally precipitate out of the reaction mixture as a solid after the reaction. Then the pH of the previously strongly acidic, the
  • Reaction mixture containing compounds of the formula II, without further isolation of this compound by adding an alkylamine of the formula R 2 NH 2 to about pH 2-7.5, preferably pH 5-6, and the reaction mixture for a further 1 to 24 h, preferably 5-10 h heated to 0 ° to 200 ° C, preferably to 10 ° C-100 ° C and in particular to 30 ° C-90 ° C, whereby the compounds of formula I are obtained.
  • work is preferably carried out under increased pressure, preferably between 1 and 50 bar, in particular between 2 and 10 bar.
  • Trioxane is particularly suitable as a formaldehyde source.
  • Suitable acids for the process according to the invention are, in particular, inorganic acids, preferably non-oxidizing inorganic acids.
  • a process for the preparation of compounds of the formula I characterized in that the pH for the conversion of the compounds of the formula II to the compounds of the formula I by adding an alkylamine of the formula R 2 NH 2 to about pH 2-7.5 is set.
  • Process for the preparation of compounds of the formula I characterized in that the reaction of the compounds of the formula II to the compounds of the formula I is carried out at 0 ° to 200 ° C, preferably under increased pressure, in particular from 2 to 50 bar.
  • Process for the preparation of compounds of the formula characterized in that the compound of the formula II is first obtained by reacting a mixture of a formaldehyde source with a corresponding alkylammonium salt and a ketone of the formula III in the presence of a strong acid, and the so obtained
  • a process for the preparation of compounds of the formula I characterized in that the pH of the strongly acidic reaction mixture containing the compounds of the formula II without further isolation of the compound of the formula II by adding an alkylamine of the formula R 2 NH 2 to about pH 2-7.5 is increased and the mixture is then heated.
  • reaction mixture containing the compounds of the formula II is heated to 10 ° C. to 100 ° C. after the addition of an appropriate alkylamine.
  • the process according to the invention is particularly suitable for the preparation of the ketones 3-methylamino-1-phenyl-1-propanone or 3-methylamino-1- (2-thienyl) -1-propanone, which are advantageous to the active substances duloxetine, fluoxetine, tomoxetine and Have LY227942 processed further.
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • Some of the compounds of the formula II are known; the unknown compounds can easily be prepared analogously to the known compounds.
  • Suitable solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme), optionally also mixtures of the solvents mentioned with one another or mixtures with water.
  • Hydrocarbons such as hexane, petroleum ether, benzen
  • a base of the formula I, in particular Ib, can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon, sulfonic or Sulfuric acids, e.g.
  • Salts with physiologically unacceptable acids for example picrates, can be used for the isolation and / or purification of the compounds of the formula I.
  • compounds of the formula I with bases for example sodium or potassium hydroxide or carbonate
  • bases for example sodium or potassium hydroxide or carbonate
  • compounds of the formula I with bases can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
  • the invention furthermore relates to the use of the compounds of the formula I as intermediates for the synthesis of medicaments.
  • Corresponding drugs are mentioned, for example, in Synlett, 689-690, 1991.
  • the invention furthermore relates to the use of the compounds of the formula I as intermediates for the synthesis of medicaments which have effects on the central nervous system.
  • customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, separated off, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization. Rf values on silica gel.
  • a mixture of 49 g of trioxane, 111 g of methylammonium chloride, 162.2 g of acetylthiophene and 12 g of 37% hydrochloric acid in 176 ml of ethanol and 44 ml of water is heated under reflux for 17 hours. 17.6 g of methylamine solution (40% in water) are then added and the mixture is heated to 65-84 ° C. for 7 h. Then the reaction mixture is allowed to cool to room temperature, 23.7 g of 37% hydrochloric acid are added and the mixture is cooled to below 0.degree. The precipitated crystals are suction filtered, washed with acetone and then dried, whereby the desired ketone is obtained.
  • a mixture of 113 kg trioxane, 621 kg methylammonium chloride, 400 kg acetylthiophene and 35 kg 37% hydrochloric acid in 783 kg ethanol is heated to reflux for 19 h.
  • the mixture is then diluted with 992 kg of ethanol, 36 kg of methylamine solution (40% in water) are added and the mixture is refluxed for 4 h.
  • the reaction mixture is first allowed to cool to room temperature and cooled to 5 ° C. for 48 h.
  • the precipitated crystals are separated off, suspended with 994 kg of ethanol at 68 ° C. and separated off again and at 50 ° C. i. Vak. dried to constant weight. 363 kg of pure product are obtained.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Furan Compounds (AREA)
EP03790843A 2002-08-27 2003-08-01 Verfahren zur herstellung von monoalkylaminoketonen Withdrawn EP1532101A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10240026 2002-08-27
DE10240026A DE10240026A1 (de) 2002-08-27 2002-08-27 Verfahren zur Herstellung von Monoalkylaminoketonen
PCT/EP2003/008514 WO2004020391A1 (de) 2002-08-27 2003-08-01 Verfahren zur herstellung von monoalkylaminoketonen

Publications (1)

Publication Number Publication Date
EP1532101A1 true EP1532101A1 (de) 2005-05-25

Family

ID=31502148

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03790843A Withdrawn EP1532101A1 (de) 2002-08-27 2003-08-01 Verfahren zur herstellung von monoalkylaminoketonen

Country Status (15)

Country Link
US (1) US7579484B2 (pt)
EP (1) EP1532101A1 (pt)
JP (1) JP4593275B2 (pt)
KR (1) KR101017885B1 (pt)
CN (1) CN100368384C (pt)
AU (1) AU2003260348B2 (pt)
BR (1) BR0313796A (pt)
CA (1) CA2497028A1 (pt)
DE (1) DE10240026A1 (pt)
HK (1) HK1081532A1 (pt)
MX (1) MXPA05002117A (pt)
PL (1) PL373599A1 (pt)
RU (1) RU2340595C2 (pt)
WO (1) WO2004020391A1 (pt)
ZA (1) ZA200502457B (pt)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4546242B2 (ja) 2002-07-09 2010-09-15 ロンザ アーゲー Ｎ−モノ置換β−アミノアルコールの製造方法
DE10302595A1 (de) 2003-01-22 2004-07-29 Basf Ag 3-Methylamino-1-(2-thienyl)-1-proganon, seine Herstellung und Verwendung
CN103214452B (zh) * 2013-05-07 2014-08-06 浙江丽晶化学有限公司 N-甲基-3-羟基-3-（2-噻吩基）-丙胺的制备方法
CN109134427B (zh) * 2018-10-24 2020-06-30 浙江乐普药业股份有限公司 一种3-甲氨基-1-(2-噻吩基)-1-丙酮盐酸盐的合成方法
CN114790146B (zh) * 2022-05-19 2024-03-29 河南省科学院高新技术研究中心 一种3-(甲基氨基)-1-芳香基丙酮的制备方法

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US3859305A (en) * 1970-03-10 1975-01-07 Degussa Indole aminoketones
DE2017468A1 (en) * 1970-04-11 1971-11-04 Deutsche Gold- U. Silber-Scheideanstalt, Vorm. Roessler, 6000 Frankfurt Phenylalkylaminoalkyl-pyrazoles antiphlogistic
DE2063901A1 (en) * 1970-12-28 1972-07-20 Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler, 6000 Frankfurt Phenylalkylaminoalkylthiazoles - as antiphlogistics
DE2353873A1 (de) * 1973-10-26 1975-05-07 Inst Toxikologii Beta-ketoderivate der linearen und cyclischen beta-phenylaethylamine, deren salze und verfahren zu deren herstellung
DD122967A1 (de) * 1975-07-10 1976-11-12 Lothar Luecke Hylamin-derivate
US4948813A (en) 1987-11-30 1990-08-14 E. I. Du Pont De Nemours And Company Benzylketone phospholipase A2 inhibitors
US5075339A (en) * 1989-07-28 1991-12-24 Du Pont Merck Pharmaceutical Company Benzylketone phospholipase A2 inhibitors
CA2022462A1 (en) * 1989-08-04 1991-02-05 Akira Matsubara Aminoketone derivatives and use thereof
AU658134B2 (en) * 1989-12-28 1995-04-06 Virginia Commonwealth University Sigma receptor ligands and the use thereof
JPH0570412A (ja) * 1991-09-13 1993-03-23 Fuji Yakuhin Kogyo Kk 光学活性なβ−アミノアルコールの製造方法
EP0571685A1 (en) * 1992-05-27 1993-12-01 Novo Nordisk A/S Aryloxyheteroarylpropylamines, their preparation and use
ATE224366T1 (de) 1997-10-31 2002-10-15 Hoffmann La Roche D-prolinderivate
JP2000264867A (ja) * 1999-03-18 2000-09-26 Nippon Shokubai Co Ltd 有機アミド化合物およびその製造法
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Also Published As

Publication number Publication date
ZA200502457B (en) 2005-10-25
WO2004020391A1 (de) 2004-03-11
CN100368384C (zh) 2008-02-13
US7579484B2 (en) 2009-08-25
AU2003260348B2 (en) 2009-09-03
MXPA05002117A (es) 2005-05-23
KR20050059104A (ko) 2005-06-17
JP4593275B2 (ja) 2010-12-08
RU2005108974A (ru) 2005-10-27
CA2497028A1 (en) 2004-03-11
AU2003260348A1 (en) 2004-03-19
CN1678564A (zh) 2005-10-05
JP2005536557A (ja) 2005-12-02
HK1081532A1 (en) 2006-05-19
RU2340595C2 (ru) 2008-12-10
PL373599A1 (en) 2005-09-05
KR101017885B1 (ko) 2011-03-04
BR0313796A (pt) 2005-09-27
US20060122405A1 (en) 2006-06-08
DE10240026A1 (de) 2004-03-11

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