EP1532100A1 - Verfahren zur enfantioselektiven hydrierung von aminoalkoholen - Google Patents

Verfahren zur enfantioselektiven hydrierung von aminoalkoholen

Info

Publication number
EP1532100A1
EP1532100A1 EP03790842A EP03790842A EP1532100A1 EP 1532100 A1 EP1532100 A1 EP 1532100A1 EP 03790842 A EP03790842 A EP 03790842A EP 03790842 A EP03790842 A EP 03790842A EP 1532100 A1 EP1532100 A1 EP 1532100A1
Authority
EP
European Patent Office
Prior art keywords
formula
compounds
alkyl
preparation
chiral
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Withdrawn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
EP03790842A
Other languages
German (de)
English (en)
French (fr)
Inventor
Joachim Kralik
Kai Fabian
Christoph Mürmann
Norbert Schweickert
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
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1532100A1 publication Critical patent/EP1532100A1/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Withdrawn legal-status Critical Current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
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/5027—Polyphosphines

Definitions

  • the invention relates to a process for the enantioselective production of amino alcohols of the formula I.
  • R 1 is an unsubstituted or mono- or polysubstituted by R and / or R 4 , saturated, unsaturated or aromatic carbocyclic or heterocyclic radical, alkyl having 1-20 C atoms or H,
  • R 3 , R 4 each independently of one another are H, alkyl or alkoxy having 1-20 carbon atoms, aryl, aryloxy or COOR 2 , F, Cl, Br, OH, CN, N0 2) N (R 2 ) 2 or NHCOR 2 and n 0, 1, 2 or 3
  • R 1 , R 2 and n have the meaning given above, in the presence of a non-racemic catalyst, characterized in that the catalyst is a transition metal complex in which the transition metal with a chiral diphosphine ligand A
  • R b , R ö R 7 and R 8 each independently of one another are H, alkyl or alkoxy having 1-20 C atoms, aryl, aryloxy or F, Cl, Br, N (R 2 ) 2 or NHCOR 2
  • R 11 H alkyl or alkoxy with 1-20 C atoms, aryl, aryloxy or S0 3 Na, COOR 12 , F, Cl, N (R 12 ) 2 or
  • R 12 alkyl with 1-20 C atoms or H
  • R 5 and R 6 , R 6 and R 7 and R 7 and R 8 together also have the meaning
  • ⁇ may have
  • Ph is phenyl, o-, m- or p-methylphenyl or dimethylphenyl, is complexed.
  • R 9 and R 10 preferably signify
  • Ph has the meaning given above and X, H, alkyl, O (alkyl), Cl, or F and R 'alkyl O (alkyl) or F.
  • Compounds of the formula A3 in which Ph is phenyl, X, H and R 'OCH 3 are particularly preferred.
  • Preferred compounds of formula A are symmetrical.
  • the compounds of formula II are preferably used as acid addition salts, in particular the acid addition salts of strong acids such as e.g. Hydrohalic acid, methyl, p-toluene or benzenesulfonic acid, perchloric, sulfuric or phosphoric acid but also acetic acid, formic acid or propanoic acid are suitable. Acid addition salts with sulfuric acid or the hydrochlorides of the compounds of the formula II are particularly preferred.
  • the acid addition salts of the compounds of the formula II are obtained, from which the free bases are released by adding a strong base such as alkali metal carbonate or hydroxide leaves.
  • the invention therefore relates in particular to a process for preparing the optically active forms, and also the salts, hydrates and solvates, for example alcoholates, of the compounds of the formula I, in particular of the compounds of the formula I, in which n is 1.
  • the invention preferably enables the synthesis of optically active, aryl-substituted 3-monoalkylaminopropanols, which are suitable as precursors in the production of antidepressants.
  • the desired enantiomer of 3-methylamino-1- (2-thienyl) -1-propanol can naturally be obtained in a maximum of 50% yield by cleavage of the racemic alcohol (e.g. analogous to Chirality 2000, 12, 26 or EP 650965).
  • the invention was therefore based on the object of finding a production process for compounds which can be used in particular as intermediates in the synthesis of medicaments and which do not have the disadvantages mentioned above.
  • radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 9 , R 10 , R 11 and R 12 , Q, Y and Z and the index m and n have the meanings given in the formulas I, II, A and B, unless expressly stated otherwise. If there are multiple occurrences within a formula, the meanings of the individual radicals are independent of one another.
  • alkyl has 1 to 20 carbon atoms, 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 comes, for example
  • 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 denote H, methyl, in particular H.
  • R 5 and R are preferably H, alkyl, Oalkyl, Cl or F.
  • R 7 and R 8 are preferably H.
  • R 1 is preferably H or methyl, especially methyl.
  • R 12 is preferably methyl or ethyl.
  • n is preferably 0 or 1, in particular 1.
  • m is preferably 1.
  • Aryloxy preferably means, for example, phenyloxy, o-, m- or p-tolyloxy, o-, m- or p-hydroxyphenyloxy, o-, m- or p-methoxyphenyloxy, o-, m- or p-fluorophenyloxy.
  • Aryl 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.
  • the chiral ligands of the formula A are preferably used.
  • Ph means phenyl, 2-, 3- or 4-methylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl.
  • Ph is preferably phenyl, 4-tolyl or 3,5-dimethylphenyl, 4-tolyl being particularly preferred.
  • Y preferably denotes P (C (CH 3 ) 3) 2.
  • Z preferably means H.
  • Q is preferably P (phenyl) 2 .
  • Chiral ligands of the formula B are preferred, in which Z is H and YP (C (CH 3 ) 3) 2. Also preferred are ligands of the formula B in which Z is P (phenyl) 2 and Y is OH.
  • ligands of the formula B with the following combinations of the radicals Q and Y:
  • Q PPh 2 ;
  • Y P (tert-butyl) 2
  • Q P (cyclohexyl) 2 ;
  • the process according to the invention is particularly suitable for the preparation of the alcohols (S) -3-methylamino-1-phenyl-1-propanol or (S) -3-methylamino-1- (2-thienyl) -1-propanol, which are advantageous to the Allow active ingredients Duloxetine, Fluoxetine, Tomoxetine and LY227942 to be processed further.
  • the compounds of the formula I have one or more chiral centers and can therefore exist in various stereoisomeric forms.
  • Formula I encompasses all of these forms.
  • enantioselective preparation defines a process that as a reaction product usually contains a mixture containing a compound of the formula IA
  • the compounds of the formula II can be hydrogenated with the enantiomerically pure rhodium-phosphine complexes containing the phosphines A or B to give enantiomerically pure or enantiomerically enriched compounds of the formula I.
  • the invention also relates to a process for the preparation of the compounds of the formula I, characterized in that the chiral, non-racemic catalyst is an enantiomerically enriched transition metal complex containing one or more metals or their salts selected from the group rhodium, Iridium, ruthenium and palladium. Transition metal complexes containing rhodium or rhodium salts are particularly preferably used.
  • Transition metal salts containing sulfate, chloride, methanesulfonate, toluenesulfonate, hexachloroantimonate, hexafluoroantmonate or trifluoromethanesulfonate as an anion are particularly preferred.
  • Enantiomerically pure transition metal complexes are preferably used.
  • enantiomerically pure denotes above and below an enantiomeric purity of> 90% ee, preferably> 92% ee and in particular> 99% ee.
  • the (R) - or (S) -enantiomer of the ligand in the catalyst is obtained in excess.
  • the ligands are particularly preferred:
  • Toi means 4-methylphenyl.
  • (S) -TolBINAP is particularly preferred.
  • rhodium complexes contain one of the following anions
  • 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.
  • Suitable solvents are e.g. Water, 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 PEG, ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone, methyl ethyl ketone or butanone; Amides such as acetamide, di
  • a process is particularly preferred in which hydrogenation is carried out in the presence of one or more alcohols, in particular methanol.
  • the reaction time of the enantioselective hydrogenation is, depending on the conditions used, between a few minutes and 14 days, the reaction temperature between 0 and 200 ° C, usually between 10 and 150 ° C, preferably between 20 and 130 ° C and in particular between 20 and 70 ° C ,
  • the catalyst / substrate ratio is usually between 1: 10000 and 1:20, preferably between 1: 5000 and 1:50, particularly preferably between 1: 2000 and 1: 100.
  • the response time is then e.g. between 0.1 and
  • the hydrogenation is preferred carried out under 1-250 bar hydrogen pressure, preferably at 3-210 bar, in particular between 120 and 200 bar.
  • the reactions are preferably carried out under oxygen-free reaction conditions.
  • the invention furthermore relates to the use of the compounds of the formula I as intermediates for the synthesis of medicaments.
  • Corresponding drugs are described, for example, in J. Labeled Compd. Radio Pharm. 1995, 36 (3), 213.
  • 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.
  • Example 2 In a steel autoclave, 8.23 g of 3-methylamino-1- (2-thienyl) -1-propanone are added to 5.3 mg of bis (1,5-cyclooctadiene) dirhodium (l) dichloride and 17.2 mg (S) - (-) - 2,2'Bis (di-p-tolylphosphino) -1, 1'-binaphthyl and 50 ml of methanol and 50 ml of toluene were added to this mixture. After the reactor has been closed, the reactor is freed of oxygen by repeated flushing with nitrogen and then hydrogen.
  • the reactor is charged with 55 bar of hydrogen and heated to 50 ° C. The course of the reaction is followed by the pressure drop in the autoclave. After 15 hours, sales are complete.
  • the desired alcohol is obtained with an enantiomeric excess of 92.8% ee.
  • the oily residue obtained according to Example 2 is taken up in 300 ml of water, extracted 3 times with 250 ml of dichloromethane each time and the organic phase is discarded. Then the aqueous phase is again mixed with 250 ml of dichloromethane, brought to pH 14 with 41.0 g of 32% sodium hydroxide solution and the phases are separated. The organic phase is freed from the solvent.
  • the oil obtained is dissolved at 55 ° C. in 320 g of an MTB ether / toluene mixture, mixed with 2.5 g of activated carbon and filtered hot. After slowly opening the almost colorless solution
  • the autoclave is heated to 50 ° C. and after this temperature has been reached, the internal pressure is set to 120 bar of hydrogen. After 7 hours, the hydrogen uptake stops, the reaction is stopped and the reaction solution is analyzed. Product sales: 98%; Enantiomeric excess in the product: 94%.
  • the autoclave is heated to 50 ° C and after reaching this temperature, the internal pressure is set to 60 bar hydrogen. After 8 hours, the uptake of hydrogen stops, the reaction is stopped and the reaction solution is analyzed. Product sales:> 99%; Enantiomeric excess in the product: 92%.
  • EXAMPLE 6 16.46 g (80 mmol) of 3-methylamino-1- (2-thienyl) -1-propanone are weighed out in a steel autoclave, 75 ml of methanol are added and the mixture is rendered inert by pressing 7 bar of nitrogen 3 times and then releasing the pressure , 5.2 mg (0.011 mmol) of bis (1,5-cyclooctadiene) dirhodium (l) dichloride and 15.2 mg (0.022 mmol) of (S) - TolBINAP are weighed into a Schlenk tube and dissolved in 15 ml of toluene under argon , This solution is cannulated into the autoclave in a nitrogen countercurrent transferred.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP03790842A 2002-08-27 2003-08-01 Verfahren zur enfantioselektiven hydrierung von aminoalkoholen Withdrawn EP1532100A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10240025 2002-08-27
DE10240025 2002-08-27
PCT/EP2003/008513 WO2004020389A1 (de) 2002-08-27 2003-08-01 Verfahren zur enfantioselektiven hydrierung von aminoalkoholen

Publications (1)

Publication Number Publication Date
EP1532100A1 true EP1532100A1 (de) 2005-05-25

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ID=31969008

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03790842A Withdrawn EP1532100A1 (de) 2002-08-27 2003-08-01 Verfahren zur enfantioselektiven hydrierung von aminoalkoholen

Country Status (14)

Country Link
US (1) US7488833B2 (ru)
EP (1) EP1532100A1 (ru)
JP (1) JP4589724B2 (ru)
KR (1) KR101017884B1 (ru)
CN (1) CN100526290C (ru)
AU (1) AU2003260347B2 (ru)
BR (1) BR0313795A (ru)
CA (1) CA2496883C (ru)
HK (1) HK1081531A1 (ru)
MX (1) MXPA05002114A (ru)
PL (1) PL373650A1 (ru)
RU (1) RU2340594C2 (ru)
WO (1) WO2004020389A1 (ru)
ZA (1) ZA200502458B (ru)

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WO2002038532A1 (fr) * 2000-11-09 2002-05-16 Mitsui Chemicals, Inc. Derive d'amine optiquement actif et methode de synthese
DE10302595A1 (de) * 2003-01-22 2004-07-29 Basf Ag 3-Methylamino-1-(2-thienyl)-1-proganon, seine Herstellung und Verwendung
EP2044049A2 (en) 2006-07-03 2009-04-08 Ranbaxy Laboratories Limited Process for the preparation of enantiomerically pure salts of n-methyl- 3 -( 1-naph-thaleneoxy)- 3 - (-2-thienyl) propanamine
EP2329013B1 (en) 2008-08-27 2015-10-28 Codexis, Inc. Ketoreductase polypeptides for the production of a 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine
WO2010025287A2 (en) 2008-08-27 2010-03-04 Codexis, Inc. Ketoreductase polypeptides for the production of 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine
KR101046434B1 (ko) * 2008-10-24 2011-07-05 한국화학연구원 이미드화 반응용 촉매와 이 촉매를 이용한 폴리이미드의 제조방법
JP2012518653A (ja) * 2009-02-24 2012-08-16 グラクソ グループ リミテッド ケトンの立体選択的水素化
JPWO2011118625A1 (ja) * 2010-03-24 2013-07-04 住友精化株式会社 光学活性なｎ−モノアルキル−３−ヒドロキシ−３−アリールプロピルアミン化合物の製造方法
SI2558455T1 (sl) 2010-04-13 2017-12-29 Krka, D.D., Novo Mesto Sinteza duloksetina in/ali njegovih farmacevtsko sprejemljivih soli
DK2426116T3 (da) 2010-08-30 2013-09-08 Saltigo Gmbh Fremgangsmåde til fremstilling af (S)-3-N-methylamino-1-(2-thienyl)-1-propanol
CN105085372B (zh) * 2014-05-12 2018-11-16 上海交通大学 手性γ-氨基醇类化合物的制备方法
CN107021884B (zh) * 2017-04-27 2019-12-24 武汉凯特立斯科技有限公司 通过Ir/f-amphox催化α-氨基酮高效合成手性1,2-氨基醇的方法
CN115838342B (zh) * 2021-09-18 2024-07-26 凯特立斯（深圳）科技有限公司 一种不对称催化氢化氨基酮的方法
CN115872905B (zh) * 2021-09-29 2024-08-09 凯特立斯（深圳）科技有限公司 一种拉罗替尼中间体的制备方法
CN116102464A (zh) * 2021-11-10 2023-05-12 凯特立斯（深圳）科技有限公司 一种不对称氢化制备氨基醇的方法及其应用

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Also Published As

Publication number Publication date
WO2004020389A1 (de) 2004-03-11
JP2005536556A (ja) 2005-12-02
CA2496883C (en) 2011-03-08
KR101017884B1 (ko) 2011-03-04
MXPA05002114A (es) 2005-05-23
US20050261514A1 (en) 2005-11-24
BR0313795A (pt) 2005-07-12
ZA200502458B (en) 2005-10-10
RU2340594C2 (ru) 2008-12-10
KR20050058451A (ko) 2005-06-16
CA2496883A1 (en) 2004-03-11
PL373650A1 (en) 2005-09-05
JP4589724B2 (ja) 2010-12-01
AU2003260347A1 (en) 2004-03-19
RU2005108973A (ru) 2005-11-20
US7488833B2 (en) 2009-02-10
AU2003260347B2 (en) 2009-06-18
HK1081531A1 (en) 2006-05-19
CN100526290C (zh) 2009-08-12
CN1678562A (zh) 2005-10-05

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