EP1268366A2 - Modifizierung der selektivität bei der oxidation von stickstoff-enthaltenden organischen verbindungen - Google Patents

Modifizierung der selektivität bei der oxidation von stickstoff-enthaltenden organischen verbindungen

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Publication number
EP1268366A2
EP1268366A2 EP01929478A EP01929478A EP1268366A2 EP 1268366 A2 EP1268366 A2 EP 1268366A2 EP 01929478 A EP01929478 A EP 01929478A EP 01929478 A EP01929478 A EP 01929478A EP 1268366 A2 EP1268366 A2 EP 1268366A2
Authority
EP
European Patent Office
Prior art keywords
protic solvent
solvent
oxidation
nitrogen
reaction
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.)
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Application number
EP01929478A
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English (en)
French (fr)
Inventor
Patrick Bernardelli
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.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
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Filing date
Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1268366A2 publication Critical patent/EP1268366A2/de
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B41/00—Formation or introduction of functional groups containing oxygen
    • C07B41/02—Formation or introduction of functional groups containing oxygen of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B33/00—Oxidation in general

Definitions

  • Cytochromes P450 the main enzymes involved in the biotransformation of drugs, catalyze oxidation reactions. It is very interesting, from an economic point of view, to try to predict in vi tro which metabolites will result from the biotransformation of a compound.
  • many drugs contain nitrogen groups that can be metabolized to iV derivatives oxidized by these monooxygenase enzymes. These N-oxidized products are generally easily synthesizable by conventional oxidation methods (reaction with peracids, for example).
  • the invention makes it possible to solve this technical problem by implementing a process, carried out under mild conditions and using a protic solvent or co-solvent, the properties of which make it possible to orient the chemoselectivity of the reaction d 'oxidation.
  • the invention makes it possible in particular to avoid the instability problems which can arise from the use of salts of the compound to be oxidized, but also to avoid racemization and / or degradation of the starting products and / or of the oxidation products and / or reagents, which characterize the use of strong acids.
  • the present invention therefore relates to a process for chemoselective oxidation of an organic compound comprising several oxidizable groups including at least one nitrogen group.
  • the method comprises bringing an organic compound to be oxidized into contact with a reaction mixture comprising an oxidant in a protic solvent, a good donor of hydrogen bonds, optionally accompanied by an inert and aprotic solvent.
  • the protic solvent is capable of forming a bond hydrogen with a nitrogen group of the compound to be oxidized, and therefore to limit the oxidation of this nitrogen group, thus promoting the oxidation of other functional groups of the compound to be oxidized.
  • the process then consists in recovering the products resulting from the oxidation reaction.
  • the present invention also relates to a process for the chemoselective oxidation of an organic compound comprising several oxidizable groups including at least one nitrogen group.
  • the method includes contacting said organic compound with a reaction mixture comprising an oxidant and a protic solvent.
  • the protic solvent is capable, in said reaction medium, of forming a hydrogen bond, with one or more nitrogen groups of said organic compound, without resulting in the complete protonation of said nitrogen group (s), and therefore of limiting the oxidation of this or these (these) nitrogen groups, thus promoting the oxidation of other functional groups of the compound to be oxidized.
  • the process then consists in recovering the products resulting from the oxidation reaction.
  • the method of the invention can be used in metabolism studies. It in fact makes it possible to change the proportion of the various products obtained at the end of the oxidation of an organic compound of which one wants to know the potential metabolites, and in particular to increase the obtaining of oxidation products which are difficult to obtain. by conventional oxidation conditions. It can also make it possible to obtain additional metabolites and therefore to change the nature of the products obtained at the end of the oxidation reaction.
  • the process of the invention has the consequence of limiting the oxidation of one or more nitrogen groups present in an organic compound in favor of other less reactive functional groups present in the same organic compound.
  • the process of the invention makes it possible to obtain a proportion of N-oxidized products relative to the totality of the products resulting from the reaction of between 0 and 50%. More particularly, the process of the invention makes it possible to obtain a proportion of N-oxidized products relative to the totality of the products resulting from the reaction of between 0 and 20%, 0 and 15% or 0 and 5%.
  • This process includes the use of an oxidant and a protic solvent, a good donor of hydrogen bonds, characterized by a high ⁇ parameter.
  • the parameters ⁇ and ⁇ allow respectively to measure the capacity of a molecule to give a hydrogen bond and the capacity of a molecule to accept a hydrogen bond (for more details, see the following reference: Abraham, Michael H.
  • the protic solvent is therefore chosen so that the formation of hydrogen bonds, between a hydrogen of the solvent (hydrogen bond donor) and the non-nitrogen bonding electron doublet (hydrogen bond acceptor) of the nitrogen group of the organic compound, do not result in complete protonation of said nitrogen group.
  • the process of the invention therefore makes it possible to orient the chemioselectivity of the reaction, which makes it possible to limit the N-oxidation of nitrogen groups present in the starting compound and thus promotes the oxidation of other functional groups.
  • the compound to be oxidized such as carbon-hydrogen bonds or carbon-carbon double bonds.
  • This type of chemoselectivity can be called N- chemoselectivity.
  • the process of the invention makes it possible, for example, to promote the hydroxylation of carbon-hydrogen bonds of an organic compound having one or more nitrogen groups.
  • nitrogen group or nitrogen derivative are used here to denote any functional group comprising a nitrogen, and more particularly amines (primary, secondary and tertiary), amides, imines, nitriles and heterocycles, aromatic or not, optionally substituted , including at least one nitrogen atom.
  • the organic compound to be oxidized contains one or more nitrogen groups chosen from the functional groups listed above.
  • the organic compound to be oxidized contains a nitrogen group chosen from the functional groups listed above.
  • the oxidation reaction according to the process of the invention can be carried out in the presence of a catalyst, in particular in the presence of a metalloporphyrin, a compound which makes it possible to mimic the biotransformations undergone by a drug in a biological system.
  • the formation of a hydrogen bond between a nitrogen group of the compound to be oxidized and the protic solvent can lead to nitrogen protonation.
  • This nitrogen protonation or ionization is preferably partial.
  • partial protonation is meant a proportion of organic compound to be oxidized in which the nitrogen group or groups are protonated by the protic solvent, relative to the same non-protonated compound, less than 80%, 50%, 20%, 10% or 1% .
  • the protic solvent used in the process of the invention is capable, in the reaction medium, of forming a hydrogen bond, with one or more nitrogen groups of the organic compound to be oxidized, without leading to complete protonation of the said nitrogen group (s).
  • the protic solvent used in the process of the invention is a very weak Brônsted acid protic solvent, capable, in the reaction medium, of forming a hydrogen bond, with one or more nitrogen groups of the organic compound to be oxidized.
  • very weak Brônsted acid protic solvent is preferably understood to mean a solvent characterized by a pKa greater than or equal to 9.
  • protic solvent capable of forming a hydrogen bond is intended to mean a solvent which gives good hydrogen bonds. This solvent which is a good hydrogen bond donor is advantageously characterized by a high parameter ⁇ .
  • a high parameter ⁇ will be greater than 0.43. In a particularly preferred manner, a high parameter ⁇ will be greater than or equal to 0.55.
  • the protic solvent is moreover very polar and / or weakly nucleophilic.
  • the preferred solvent is very polar and weakly nucleophilic.
  • This solvent must be protic, very weakly acid in the sense of Brônsted (pKa> 9) and have a high ⁇ parameter, that is to say be a good donor of hydrogen bonds.
  • the protic solvent can be an alcohol such as, for example, isopropanol or tert-butyl alcohol (or 2-methyl-2-propanol).
  • the solvent is preferably a fluorinated alcohol such as for example 2-fluoroethanol, 2, 2, 2-trifluoroethanol,
  • the preferred protic solvent is hexafluoroisopropanol because it is an extremely powerful hydrogen bond donor
  • the protic compound of the process of the invention can be used as a single solvent or as a co-solvent in the reaction medium.
  • the reaction medium When the protic compound is used as co-solvent, the reaction medium then contains another solvent, the main solvent, inert and aprotic, which reacts neither with the reagents nor with the products of the reaction.
  • the protic compound also offers, by virtue of its properties, the advantage of facilitating the dissolution of the product to be oxidized in the main solvent.
  • the amount of protic co-solvent used generally represents from 1 to 30% equivalent by volume relative to the main solvent. Preferably, 10% is used.
  • the protic compound making it possible to vary the selectivity of the reaction is used as a single solvent, without main solvent, it allows in this case both the dissolution of the reactants and the chemoselectivity of the oxidation reaction.
  • the total amount of solvent is calculated to obtain a solution whose concentration of starting material is between 0.05 M and 0.5 M.
  • concentration of starting material is preferably approximately 0.1 M.
  • the total amount of solvent comprises the main solvent and the protic co-solvent if the protic compound is used as the co-solvent or the protic solvent alone if the protic compound is used as the sole solvent.
  • protic compound as sole solvent or as co-solvent, the quantity and the nature of the protic compound to be used are parameters which a person skilled in the art can easily determine by routine experiments.
  • the main solvent is chosen so that it reacts neither with the starting material, nor with the products of the reaction.
  • An inert, aprotic solvent is preferred which does not interfere with the oxidation reaction.
  • This main solvent can itself be composed of a combination of several solvents.
  • the main solvent can be a polyhalogenated aliphatic solvent such as 1, 1, 2-trichloro- 1, 2, 2-trifluoroethane or dichloromethane, a solvent polyhalogenated aromatic such as 1,2-dichlorobenzene, 1,2,4-trichlorobenzene, pentafluorobenzene or trifluorotoluene.
  • Tri luorotoluene is the preferred main solvent because it can dissolve many different organic compounds while having a low reactivity under oxidation conditions.
  • oxidizing agents can be used in the process of the invention. Indeed, the nature of the oxidizing agent is not a limiting factor in the course of an oxidation reaction according to the method of the invention. Those skilled in the art can choose the appropriate oxidizing agent from the wide variety of oxidizing agents available.
  • oxidizing agents meta-chloroperbenzoic acid, magnesium monoperoxyphthalate, dimethyldioxyrane and potassium monopersulfate.
  • the oxidant can be iodosylbenzene, also called iodosobenzene, an aqueous hydrogen peroxide solution of 30 to 45%, an anhydrous source of water oxygenated such as sodium percarbonate, urea-hydrogen peroxide complex or the like, potassium monopersulfate, sodium hypochlorite, tert-butyl hydroperoxide, cumene hydroperoxide, meta chloroperbenzoic acid and magnesium monoperoxyphthalate.
  • Preferred oxidants include iodosylbenzene, any source of hydrogen peroxide, or potassium monopersulfate.
  • Hydrogen peroxide is more effective in the presence of a co-catalyst such as imidazole, ammonium acetate, N-hexylimidazole, amine N-oxides, acetate of tetrabutylammonium, tert-butyl pyridine, pyridine, 4-methylpyridine, and 2,4,6-trimethyl-pyridine.
  • a co-catalyst such as imidazole, ammonium acetate, N-hexylimidazole, amine N-oxides, acetate of tetrabutylammonium, tert-butyl pyridine, pyridine, 4-methylpyridine, and 2,4,6-trimethyl-pyridine.
  • the oxidants cited in the following reference can also be used in the process of the invention: "State of the art in the development of biomimetic oxidation catalysts" A Rocha Gonsalves, AM; Pereira, MMJ Mol. Catal.
  • metalloporphyrins are described in international patent application WO 96/08455.
  • the term metalloporphyrin used above designates porphyrins of formula (I):
  • RI, R2 and R3 each independently represent a hydrogen atom or an electronegative group such as Cl, F, Br, S03Na or an equivalent group,
  • R4, R5, R6, R7, R8, R9, RIO and R11 each independently represent a hydrogen atom or a group electronegative like Cl, F, Br, N02, CN, S03Na or an equivalent group,
  • R12 is Cl, acetate or an equivalent group
  • M is chosen from the group formed by iron, manganese, chromium, ruthenium, cobalt, copper and nickel.
  • Mn (TPFPP) Cl which corresponds to the compound of formula (I) above in which M is manganese, RI, R2 and R3 are fluorine, R4, R5, R6, R7, R8, R9, RIO and R11 are hydrogen, and R12 is chlorine.
  • iron tetra- (pentafluorophenyl) porphyrin abbreviated here Fe (TPFPP) Cl, which corresponds to the compound of formula (I) above in which M is iron, RI, R2 and R3 are fluorine, R4, R5, R6, R7, R8, R9, RIO and R11 are hydrogen, and R12 is chlorine;
  • manganese tetra- (2,6-dichlorophenyl) orphyrin here abbreviated as Mn (TDCPP) Cl, which corresponds to the compound of formula
  • iron tetra- (2,6-dichlorophenyl) porphyrin here abbreviated as Fe (TDCPP) Cl, which corresponds to the compound of formula (I) above in which M is iron, RI is chlorine, R2, R3, R4, R5, R6, R7, R8, R9, RIO and R11 are hydrogen, and R12 is chlorine;
  • iron tetra- (2,6-dichlorophenyl) -octachloroporphyrin here abbreviated as Fe (TDCPC1 8 P) Cl, which corresponds to the compound of formula (I) above in which M is iron, RI is chlorine, R2 and R3 are hydrogen, R4, R5, R6, R7, R8, R9,
  • RIO and R11 are chloride, and R12 is chlorine; the compound Mn ((Cl 2 Ph) 4 (N0 2 ) P) C1, which corresponds to the compound of formula (I) above in which M is manganese, RI is chloride, R4 is N02, R2, R3, R5 , R6, R7, R8, R9, RIO, and R11 are hydrogen, and R12 is chlorine; the compound Mn ((Cl 2 Ph) 4 (N0 2 ) 2 P) Cl, which corresponds to the compound of formula (I) above in which M is manganese, RI is chlorine, R5 and R6 are N02, R2, R3, R4, R7, R8, R9, RIO and R11 are hydrogen, and R12 is chlorine.
  • the amount of metalloporphyrin used varies from 0.5 to 10 mol% and is preferably about 1 mol% relative to the starting product.
  • the reaction temperature is between -20 ° C and 100 ° C, preferably between -10 ° C and 40 ° C.
  • the duration of the reaction varies between a few minutes and 2 hours.
  • the progress of the reaction can be monitored by analytical techniques such as thin layer chromatography or HPLC.
  • the reaction is stopped when the oxidation reaction reaches a plateau from which no transformation of the starting compound is no longer observed.
  • Mass spectra are recorded on a Micromass Platform LC spectrometer in positive electrospray.
  • FIGURE 1 A first figure.
  • the reaction is checked one hour after addition by analyzing by HPLC a sample composed of 10 ⁇ L of reaction mixture, 10 ⁇ L of a 10 mM solution of internal standard in 1: 1 methanol / acetonitrile and 980 ⁇ L of a 1: 1 solution methanol and acetonitrile.
  • the structure of the internal standard is as follows:
  • the sample is injected onto a Kromasil 5C18 250x4.6 mm column and eluted at 1 ml / min with a gradient of acetonitrile and methanol in water (oven temperature 25 ° C, UN 240 nm): min% MeOH % CH 3 C ⁇ % H 2 0
  • the starting product 1 has a retention time of 42.7 min and the internal standard of 44.6 min.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Steroid Compounds (AREA)
  • Pyridine Compounds (AREA)
EP01929478A 2000-03-29 2001-03-22 Modifizierung der selektivität bei der oxidation von stickstoff-enthaltenden organischen verbindungen Withdrawn EP1268366A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0003991A FR2807032B1 (fr) 2000-03-29 2000-03-29 Modification de la chimioselectivite lors de l'oxydation de composes organiques azotes
FR0003991 2000-03-29
PCT/EP2001/003635 WO2001072667A2 (fr) 2000-03-29 2001-03-22 Modification de la chimioselectivite lors de l'oxydation de composes organiques azotes

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Publication Number Publication Date
EP1268366A2 true EP1268366A2 (de) 2003-01-02

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EP01929478A Withdrawn EP1268366A2 (de) 2000-03-29 2001-03-22 Modifizierung der selektivität bei der oxidation von stickstoff-enthaltenden organischen verbindungen

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US (1) US6878821B2 (de)
EP (1) EP1268366A2 (de)
JP (1) JP2003528834A (de)
AR (1) AR033975A1 (de)
AU (1) AU2001256240A1 (de)
BR (1) BR0109551A (de)
CA (1) CA2404392A1 (de)
FR (1) FR2807032B1 (de)
MX (1) MXPA02009668A (de)
WO (1) WO2001072667A2 (de)

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JP5036532B2 (ja) * 2004-04-08 2012-09-26 アルメテオン、インコーポレイテッド 血液凝固疾患治療のための物質およびその方法
JP2007284415A (ja) * 2006-03-10 2007-11-01 Daicel Chem Ind Ltd アミド又はラクタムの製造法
US9543758B1 (en) * 2013-11-22 2017-01-10 Sprint Communications Company L.P. Adaptive battery power distribution to remote radio heads in long term evolution (LTE) networks

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US3901879A (en) * 1973-07-27 1975-08-26 Hoffmann La Roche 2-(2-hydroxyethylthio)-2,3-dihydro-5-phenyl-1h-1,4-benzodiazepines
US5760216A (en) * 1994-09-15 1998-06-02 Abbott Laboratories Use of synthetic metalloporphyrins for preparation and prediction of drug metabolites
US6103892A (en) * 1998-04-08 2000-08-15 The Trustees Of Columbia University In The City Of New York Catalyst that oxidizes steroids and other substrates with catalytic turnover
CN1367769A (zh) 1999-08-10 2002-09-04 沃尼尔·朗伯公司 催化有机化合物氧化的方法

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FR2807032A1 (fr) 2001-10-05
JP2003528834A (ja) 2003-09-30
AR033975A1 (es) 2004-01-21
AU2001256240A1 (en) 2001-10-08
US6878821B2 (en) 2005-04-12
CA2404392A1 (fr) 2001-10-04
WO2001072667A2 (fr) 2001-10-04
BR0109551A (pt) 2003-06-10
MXPA02009668A (es) 2003-03-10
FR2807032B1 (fr) 2003-04-18
US20030176723A1 (en) 2003-09-18
WO2001072667A3 (fr) 2001-12-13

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