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WO1997005879A1 - Reductions au moyen d'hydrures - Google Patents

Reductions au moyen d'hydrures Download PDF

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Publication number
WO1997005879A1
WO1997005879A1 PCT/US1996/002614 US9602614W WO9705879A1 WO 1997005879 A1 WO1997005879 A1 WO 1997005879A1 US 9602614 W US9602614 W US 9602614W WO 9705879 A1 WO9705879 A1 WO 9705879A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydride
contacting
lithium
reduced
aluminum
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.)
Ceased
Application number
PCT/US1996/002614
Other languages
English (en)
Inventor
John F. Engel
Eric J. Granger
Philip F. Sims
James A. Schwindeman
Robert S. Wedinger
Terry L. Rathman
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.)
FMC Corp
Original Assignee
FMC Corp
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 FMC Corp filed Critical FMC Corp
Priority to EP96906645A priority Critical patent/EP0789573A4/fr
Priority to AU49970/96A priority patent/AU4997096A/en
Publication of WO1997005879A1 publication Critical patent/WO1997005879A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023—Preparation; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • This process concerns the use of certain alkali aluminum hydrides in the reduction of organic functional groups.
  • reducing agents available for organic synthesis.
  • sodium borohydride, borane, lithium aluminum hydride and hydrogen are all employed to perform reductions industrially.
  • Lithium aluminum hydride (LiAIH 4 ) is a powerful reducing agent, soluble in organic solvents.
  • This reagent has found wide utility in organic synthesis, due to its reducing power.
  • a wide variety of functional groups are reduced with this reagent, including aldehydes, ketones, esters, amides, epoxides, nitriles and imides.
  • the expense of lithium aluminum hydride prevents its wider industrial employment.
  • the present invention describes less expensive alternatives for organic functional group reductions, using in situ generated alkali hydride reducing agents.
  • One method involves the metathesis of sodium aluminum hydride (NaAIH ) with lithium chloride to form lithium aluminum hydride and sodium chloride (equation 1).
  • Another method is the hydrogenation of a mixture of lithium (or lithium hydride) and aluminum to generate lithium aluminum hydride (equations 2 and 3).
  • equations 1-3 There are several others variations of equations 1-3 as well as from aluminum chloride and alkali salts and hydrides (equations 4 and 5). It should be noted that preparations of lithium aluminum hydride are never targeted for the preparation of a mixed alkali aluminum hydride such as a mixture of lithium and sodium aluminum hydrides.
  • the present invention overcomes these difficulties. It has been discovered that unfiltered solutions of lithium aluminum hydride (equations 1 to 5) are capable of reduction.
  • the yields with the in situ reduction protocol are essentially identical to the yields obtained when the reduction is performed with filtered lithium aluminum hydride solution. Further, all functional groups that are typically reduced with filtered lithium aluminum hydride are reduced with the unfiltered lithium aluminum hydride solutions.
  • Work-up of the reduction reaction and isolation of the reduced product involves employment of the standard procedure used for commercial lithium aluminum hydride. The inorganic by-products are most often removed by filtration or become part of any aqueous phase that may be present.
  • (+/-) trans 3-ethoxycarbonyl-4-(4 - fluorophenyl)-N-methyl-piperidine-2,6-dione or (+/-) trans 3- methoxycarbonyl-4-(4'-fluorophenyl)-N-methyl-piperidine-2,6-dione with unfiltered lithium aluminum hydride afforded (+/-) ?ra ⁇ s-4-(4'-fluorophenyl)- 3-hydroxymethyl-N-methylpiperidine in essentially the same yields and with similar impurity profiles as with commercial LiAIH 4 .
  • reductions can be accomplished with sodium aluminum hydride when its activity is modified with va ⁇ ous additives.
  • sodium aluminum hydride NaAIH
  • NaAIH sodium aluminum hydride
  • the additive lithium chloride
  • sodium aluminum hydride could be mixed with sodium aluminum hydride in order to produce a resulting hydride that performed as well as sodium aluminum hydride with the additive, lithium aluminum hydride, or lithium aluminum hydride alone.
  • LiCl can be reacted with NaAIH 4 in stoichiometric amounts to form lithium aluminum hydride (equation 1), which is then separated from the by-product, NaCl, prior to use.
  • equation 1 lithium aluminum hydride
  • NaCl sodium hydride
  • LiCl can be added in less than stoichiometric amounts and the NaCl is not separated from the resulting hydride. This invention shows that this filtration is unnecessary.
  • the additives can be added at various times during the entire reduction. Although NaAIH 4 without additives may be less reactive in some cases, it is superior due to the high cost of LiAIH 4 . Reductions of functional groups, especially imides, employing NaAIH 4 with the appropriate additives gave identical results as obtained when using the more costly, commercial LiAIH .
  • (+/-) trans 3-ethoxycarbonyl-4-(4'- fluorophenyl)-N-methyl-piperidine-2,6-dione afforded (+/-) frans-4-(4'-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and with similar impurity profile as with commercial LiAIH 4 .
  • inorganic or organic additives can be added to either reduction protocol to aid the reduction.
  • These additives can be employed in 0.01 equivalents up to and including 5 equivalents.
  • useful additives which can be used in combination as well, include, but are not limited to LiCl.
  • Example 6 Reduction of ( ⁇ )-Tra ⁇ s-3-Ethoxycarbonyl-4-(4'-Fluorophenyl)-N- Methylpiperidin-2,6-Dione with NaAIH4/LiAIH 4
  • NaAIH4/LiAIH 4 0.22 mol
  • toluene/THF under argon is added (+/-) trans -3-ethoxycarbonyl-4-(4'- fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) in THF holding the temperature below 15 °C. After addition is complete, the reaction is allowed to warm to room temperature.
  • LiCl (0.11 mol) in THF.
  • LiCl can be added to the reactor prior to the addition of NaAIH or after the addition of the substrate, (+/-) trans 3- ethoxycarbonyl- -(4'-fluorophenyl)-N-methyl-piperidine-2,6-dione.
  • (+/-) trans 3-ethoxycarbonyl-4-(4'-fluorophenyl)-N-methyl-piperidine-2, 6- dione (0.083 mol) is added in THF (65 ml) holding the temperature below 15 °C. After addition is completed, reaction is allowed to warm to room temperature.
  • LiCl (0.11 mol) in THF.
  • LiCl can be added to the reactor prior to the addition of NaAIH 4 or after the addition of the substrate.
  • N-methylsuccinimide (0.083 mol) in THF is added holding the temperature below 15 °C.
  • the reaction is allowed to warm to room temperature. After 30 minutes at room temperature reaction is heated to > 40 °C for 2 hr. The reaction is then cooled to ⁇ 5 °C and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15 °C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne un procédé de réduction de groupes fonctionnel organiques, en particulier des imides, à l'aide d'hydruroaluminate de lithium non filtré préparé à partir d'hydrure de sodium et d'aluminium, ou hydruroaluminate de lithium ou hydrure de sodium non filtré, préparé à partir des éléments, qui peuvent être utilisés directement dans la réduction subséquente du substrat. Si nécessaire pour améliorer le rendement, on peut ajouter d'autres additifs à l'hydrure de sodium et d'aluminium. Les agents de réduction à l'hydrure non filtrés, préparés in-situ, sont utilisés directement pour la réduction d'un substrat dans un solvant organique. Généralement, ce procédé, permet de réduire le nombre d'étapes de filtration, de rendre les filtrations plus fiables, et de réduire la manipulation de grands volumes de solvants éthérés nécessaires à la préparation de l'agent de réduction.
PCT/US1996/002614 1995-08-03 1996-02-28 Reductions au moyen d'hydrures Ceased WO1997005879A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP96906645A EP0789573A4 (fr) 1995-08-03 1996-02-28 Reductions au moyen d'hydrures
AU49970/96A AU4997096A (en) 1995-08-03 1996-02-28 Reductions using hydrides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US185795P 1995-08-03 1995-08-03
US60/001,857 1995-08-03

Publications (1)

Publication Number Publication Date
WO1997005879A1 true WO1997005879A1 (fr) 1997-02-20

Family

ID=21698146

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/002614 Ceased WO1997005879A1 (fr) 1995-08-03 1996-02-28 Reductions au moyen d'hydrures

Country Status (3)

Country Link
EP (1) EP0789573A4 (fr)
AU (1) AU4997096A (fr)
WO (1) WO1997005879A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998013319A1 (fr) * 1996-09-24 1998-04-02 Fmc Corporation Nouvelles compositions de reduction et leurs procedes de fabrication
US6444190B2 (en) 1995-08-03 2002-09-03 Fmc Corporation Reduction compositions and processes for making the same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4902801A (en) * 1985-08-10 1990-02-20 Beecham Group Plc. Process for preparing aryl-piperidine carbinols and novel intermediates used in the process
US5258517A (en) * 1992-08-06 1993-11-02 Sepracor, Inc. Method of preparing optically pure precursors of paroxetine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4902801A (en) * 1985-08-10 1990-02-20 Beecham Group Plc. Process for preparing aryl-piperidine carbinols and novel intermediates used in the process
US5258517A (en) * 1992-08-06 1993-11-02 Sepracor, Inc. Method of preparing optically pure precursors of paroxetine

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CASREACT on STN, Chemical Abstracts Service, (Columbus, OH), 115:91342, GYOUNG, Y.S. et al., "A Convenient Procedure for the Conversion of Tertiary Amides to the Corresponding Alcohols with Lithium Aluminum Hydride", Reaction (1) of 2; & J. KOREAN CHEM. SOC., 35(3), 1991. *
CASREACT on STN, Chemical Abstracts Service, (Columbus, OH), 120:8801, ABRAHAM, J. et al., "Steroids and Related Studies. Part 90. Certain New Azasteroidal Bisquaternary Neuromuscular Blockers", Reaction (2) of 16; & EUR. J. MED. CHEM., 28(3), 1993. *
CASREACT on STN, Chemical Abstracts Service, (Columbus, OH), 123:286279, ARITSUKA, M. et al., "Preparation of Alkenysilanes from Alkenychlorosilanes", Reaction (1) of 1; & JP,A,07 173 173 (MITSUI TOATSU CHEMICALS) 11 July 1995. *
J. MED. CHEM., 05 August 1994, Vol. 37, No. 16, MACOR, J.E. et al., "5-((3-Nitropyrid-2-yl)amino)indoles: Novel Serotonin Agonist with Selectivity for the 5-HT1D Receptor. Variation of the C3 Substituent on the Indole Template Leads to Increased 5-HT1D Receptor Selectivity", pages 2509-2512. *
See also references of EP0789573A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6444190B2 (en) 1995-08-03 2002-09-03 Fmc Corporation Reduction compositions and processes for making the same
WO1998013319A1 (fr) * 1996-09-24 1998-04-02 Fmc Corporation Nouvelles compositions de reduction et leurs procedes de fabrication

Also Published As

Publication number Publication date
EP0789573A1 (fr) 1997-08-20
EP0789573A4 (fr) 1998-04-29
AU4997096A (en) 1997-03-05

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