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WO2006038872A1 - Nouveau procede pour la preparation d'acide phosphinique - Google Patents

Nouveau procede pour la preparation d'acide phosphinique Download PDF

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Publication number
WO2006038872A1
WO2006038872A1 PCT/SE2005/001472 SE2005001472W WO2006038872A1 WO 2006038872 A1 WO2006038872 A1 WO 2006038872A1 SE 2005001472 W SE2005001472 W SE 2005001472W WO 2006038872 A1 WO2006038872 A1 WO 2006038872A1
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Prior art keywords
compound
formula
alkyl
process according
cyclic
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Ceased
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PCT/SE2005/001472
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English (en)
Inventor
Panagiotis Ioannidis
Maths Nilsson
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AstraZeneca AB
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AstraZeneca AB
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Publication of WO2006038872A1 publication Critical patent/WO2006038872A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/20—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters

Definitions

  • the present invention is directed to a new process for a regio- and stereoselective synthesis of ⁇ -halo- ⁇ -amino esters and ⁇ -halo- ⁇ -amino amides.
  • GABAe-receptor agonists as well as methods of making said compounds are disclosed in WO 98/ 11885 Al and in WO 01/ 42252 Al.
  • GABA B receptor agonists are being described as being of use in the treatment of central nervous system (CNS) disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome (IBS) and as prokinetic and anti-tussive agents.
  • CNS central nervous system
  • IBS irritable bowel syndrome
  • GABA B receptor agonists have also been disclosed as useful in the treatment of emesis (WO 96/11680, A2) and, as mentioned above, in the inhibition of transient lower oesophageal sphincter relaxations, TLOSR (WO 98/11885, Al).
  • EP 0356128, Al describes the use of the specific compound (3-aminopropyl) methyl phosphinic acid, as a potent GABA B receptor agonist, in therapy.
  • EP 0181833, Al discloses substituted 3-aminopropyl phosphinic acids (or more correctly 3-aminopropyl phosphonous acids having very strong affinities towards GABA B receptor sites.
  • EP 0399949, Al discloses derivatives of (3-aminopropyl)methyl phosphinic acid that are described as potent GABA B receptor agonists. These compounds are stated to be useful as muscle relaxants.
  • EP 0463969, Al, and FR 2722192, A are both applications related to 4- aminobutanoic acid derivatives having different heterocyclic substituents at the ⁇ -carbon of the butyl chain.
  • Synthesis of ⁇ -halo- ⁇ -amino esters has been disclosed by Gani et al. (J. Chem. Soc. Chem. Commun., 16, 1983, 898-900, Gani; Hitchcock, Young).
  • the synthesis described herein is a single step reaction performed by reaction between (N-dibenzyl)-(2-amino-3-hydroxy)- propionic acid and (diethylamino)sulphur trifluoride (a compound as hereinafter is called DAST).
  • DAST is a thermally unstable compound and has risks when handed in bulk quantities.
  • the present invention provides a new process for large-scale halogenation i.e. for large- scale preparation of ⁇ -halo- ⁇ -amino esters or ⁇ -halo- ⁇ -amino amides.
  • the reaction is a regioselective synthesis as well as a stereoselective synthesis of the ⁇ -halo- ⁇ -amino ester and ⁇ -halo- ⁇ -amino amide.
  • the compound obtained by the process can be further processed to corresponding ⁇ -halo- ⁇ -amino acids.
  • One object of the present invention is to provide a process enabling the different reaction steps to be performed in a consecutive order, thus avoiding the time-consuming step of isolation, separation and filtration of the product after each reaction steps. This provides a more environmentally friendly process provided, as less amounts of, for example, solvents are needed for the process.
  • a further object of the present invention is to provide a process suitable for full-scale preparation with reactants that are easier and safety to handle, in comparison with DAST as this reactant is a thermally unstable compound.
  • the present invention is a step- wise reaction for synthesising a compound of formula I:
  • A is O or N
  • R is a Ci- C ⁇ alkyl, optionally substituted by an aryl or a heteroaryl;
  • R and R are each and independently a C ⁇ - Cio alkyl, optionally substituted or interrupted by an aryl or a heteroaryl; and X is selected from F, Cl, Br, or I.
  • the reaction is a halogenation procedure comprising the consecutive sequence of following reactions: a) di-N-alkylation of ⁇ -amino- ⁇ -hydroxy-ester, or of ⁇ -halo- ⁇ -hydroxy-amide; b) formation of a leaving group on the alcohol function; and c) halogenation.
  • reaction sequence comprises the following steps: a) reacting compound of formula II
  • A represents O or N
  • R is as defined above;
  • R and R are each and independently C ⁇ - C ⁇ Q alkyl, optionally substituted by aryl, heteroaryl,
  • Z is selected from Cl, Br, I; the reaction is hereinafter referred to "di-N-alkylation reaction", a reaction to provide a compound of formula III
  • Step b transforming the alcohol to a leaving group Y, to give a compound of formula IV
  • A represents O or N;
  • R represents a Cj- Cg alkyl, optionally substituted with aryl, heteroaryl;
  • R and R each independently represents Cj- Cio alkyl, optionally substituted by aryl, heteroaryl;
  • Y represents the leaving group
  • Step c reacting compound of formula IV with a halogen source to give the compound of formula I.
  • This compound is an intermediate in the process for synthesis of, for example alkyl phospinic acids.
  • the starting material to be used for the synthesis of compounds of formula I according to the process provided by the present invention are commercial available, for example from Sigma-Aldrich.
  • Ci-C ⁇ o alkyl as used throughout this specification includes linear, branched or cyclic C J-C jo alkyl.
  • Examples of C]-C ⁇ Q alkyl include, but are not limited to methyl, ethyl, propyl, n-propyl, isopropyl, cyclopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, hexyl and cyclohexyl.
  • cyclic C3-C6 alkyl as used throughout this specification means a cyclic alkyl having from 3 to 6 carbon atoms in the ring.
  • Examples of cyclic C 3 -C 6 alkyl are cyclic propyl, cyclic butyl, cyclic pentyl, and cyclic hexyl.
  • cyclic C3-C6 heteroalkyl as used throughout this specification means a cyclic alkyl which one or more of the from 3 to 6 in the ring are elements other than carbon, such as N, S and O.
  • aryl as used throughout this specification means an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphtyl.
  • heteroaryl as used throughout this specification means an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
  • the term "leaving group”, denoted Y in the compound of formula IV, can be formed by reaction of III with a reagent suitable for the suitable for the present reaction which can be selected from a group consisting of mesylate (-0802CHs) 5 tosylate - OSO 2 (C 6 H 4 ) CH 3) Inflate (-OSO 2 CF 3 ), nosylate (-OSO 2 (C 6 H 4 ) CH 3 ).
  • a reagent suitable for the suitable for the present reaction which can be selected from a group consisting of mesylate (-0802CHs) 5 tosylate - OSO 2 (C 6 H 4 ) CH 3) Inflate (-OSO 2 CF 3 ), nosylate (-OSO 2 (C 6 H 4 ) CH 3 ).
  • reagents are commercial available in their respectively chloride or/and anhydride form.
  • the invention is not restricted to the leaving groups mentioned above.
  • halogene source denotes any compound abel to donate a halide, such compounds can be selected from the group comprising potassium halide, tetraalkyl ammoniumhalide or pyridine hydrohalide.
  • the halide used is selected from fluoride, chloride, bromide, and iodide.
  • Non-limiting examples of halogene source are triethyl amine trihydrofluoride, potassium fluoride, tetrabutyl arnmoniumfluoride, pyridine hydrofluoride, triethyl amine hydrochloride, trimethyl amine hydrochloride, potassium chloride, tetrabutyl ammoniumchloride, and pyridine hydrochloride.
  • the group of halogenating agents is not restricted to these mentioned.
  • Suitable solvent for the reaction sequence is selected from the group comprising toluene, methyl ⁇ -o-butylketone, ethylacetate, acetonitrile, or an equivalent solvent, or mixture thereof.
  • the reaction is performed as stepwise reaction wherein the different step follows in a consecutive order, thus, without isolation of the intermediates.
  • One object of the present invention is to provide a process for the production of ⁇ -halo- ⁇ - amino esters with high enantioselective excess.
  • the process of the invention can be stereoselective and more than 98 % enantiomeric excess (%ee) can be achieved. Also when production on larger scale, i.e. of volumes equal or larger than 50 1, high enantiomeric excess is achieved.
  • the stereoselectivity of the reaction can be obtained by specific selection of reactants, for example by coupling a sterically hindered group such as benzyl- group to enantiomerically pure (>99 %ee) methyl-(2-amino-3-hydroxy)-propionic acid.
  • a further object of the invention is to provide a process for the production of a compound of formula I wherein X represents fluorine or chlorine and Rj represents methyl.
  • the procedure is regioselective, it is possible to provide the desired isomer in a ratio of 15- 20: 1.
  • the process according to the present invention provides a good yield, i.e. 80 % or higher and reduced production time when performed on larger scale.
  • the compound of formula I may be further processed, even without isolation, for example, by reduction of the ester functionality forming the corresponding alcohol.
  • This reaction is suitable performed by sodium borohydride using polyethylene glycol 400 (PEG) as solvent (Santaniello, Ferraboschi, Fiecchi, Grisenti, Manzocchi, J.Org. Chem. 1987, 52, pp. 671- 4).
  • PEG polyethylene glycol 400
  • toluene or tetrahydrofuran
  • This also enabled an easy extractive work-up procedure with water.
  • Step l Di-N-alkylation 943 g NaHC ⁇ 3 (11.2 mol, 4.5 eq.) and 841 g benzylbromide (4.86 mol, 2 eq.) were dispensed in 2.8 L acetonitrile/water 5:2 mixture and heated to 50 0 C. 400 g of L-Serine- methylester x HCl (2.54 mol, 1.02 eq) was added slowly. The reaction mixture was heated over night (13 hours) and then cooled to 18 0 C. HPLC showed 96 % conversion to methyl N 5 N dibenzylserinate. The inorganic salts were filtered off and washed with 500 mL toluene. IL toluene and 500 mL water were added to the filtrate, the layers were separated after 15 minutes stirring (two clear phases).
  • Step 2 Transforming of alcohol to a leaving group - mesylation
  • reaction mixture was cooled to 6° C. 280 g triethyl amine (2.74 mol, 1.1 eq) was charged followed by slow addition (Ih 15 min) of 318 g mesyl chloride (2.74 mol, 1.1 eq) diluted in 200 mL toluene. The addition was exothermic, temperature was raised to 15 0 C. +99 % conversion was achieved after 35 minutes (HPLC). 2L water was charged at 10 0 C followed by 150 g Na 2 CC>3 (s) and 300 mL toluene.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau procédé destiné à synthétiser un composé de formule (I), dans laquelle A représente O ou N, R1 représente un alkyle C1-C6, R2 et R3 représentent chacun indépendamment alkyle C1-C10, éventuellement substitué ou interrompu par alkyle C3-C6 cyclique, hétéroalkyle C3-C6 cyclique, aryle ou hétéroaryle, et X est choisi parmi F, Cl, Br ou I, au moyen d'une opération d'halogénation comprenant la séquence consécutive de réactions suivantes: (a) une diénalkylation, (b) la formation d'un groupe partant sur la fonction alcool, et (c) une halogénation. L'invention concerne également les composés pouvant être obtenus au moyen de ce procédé.
PCT/SE2005/001472 2004-10-08 2005-10-05 Nouveau procede pour la preparation d'acide phosphinique Ceased WO2006038872A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0402461-8 2004-10-08
SE0402461A SE0402461D0 (sv) 2004-10-08 2004-10-08 New process

Publications (1)

Publication Number Publication Date
WO2006038872A1 true WO2006038872A1 (fr) 2006-04-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009286779A (ja) * 2008-04-28 2009-12-10 Central Glass Co Ltd α−フルオロ−β−アミノ酸類の製造方法
JP2010285350A (ja) * 2009-06-09 2010-12-24 Central Glass Co Ltd ２−フルオロアクリル酸エステルの製造方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1052265A1 (fr) * 1998-01-30 2000-11-15 Ajinomoto Co., Inc. Procede servant a preparer des derives de nucleosides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1052265A1 (fr) * 1998-01-30 2000-11-15 Ajinomoto Co., Inc. Procede servant a preparer des derives de nucleosides

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] SIMONSSON ROGER.: "Synthesis of 14C labelled AZD-3355.", accession no. stn Database accession no. (2004:859374) *
GANI D ET AL: "Stereochemistry of the Metabolism of the DNA Base Thymine and the Drug 5-Fluorouracil.", J CHEM SOC CHEM COMMUN., 1983, pages 898 - 900, XP002994999 *
PANKIEWICZ, KRZYSZTOF W.: "A Synthesis of 9-(2-Deoxy-2-fluoro-Beta-D-arabinofuranosyl)adenine and Hypoxanthine. An Effect of C3'-Endo to C2'-Endo Conformational Shift on the Reaction Course of 2'-Hydroxyl Group with DAST1.", J ORG CHEM., vol. 57, 1992, pages 553 - 559, XP002107309 *
SOMEKH L ET AL: "Facile Stereospecific Synthesis of alpha-Fluoro-Beta-Amino Acids.", J AM CHEM SOC., vol. 104, 1982, pages 5836 - 5837, XP002994997 *
SYNTHESIS AND APPLICATIONS OF ISOTOPICALLY LABELLED COMPOUNDS, PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUM 8TH., 1 June 2003 (2003-06-01) - 5 June 2003 (2003-06-05), pages 33 - 36 *
TAKAMATSU S ET AL: "9-(2,3-Dideoxy-2-fluoro-Beta-D-threo-pentofuranosyl)-adenine (FddA) via a Purine3'-Deoxynucleoside.", J ORG CHEM., vol. 66, 2001, pages 7469 - 7477, XP002994998 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009286779A (ja) * 2008-04-28 2009-12-10 Central Glass Co Ltd α−フルオロ−β−アミノ酸類の製造方法
EP2246322A4 (fr) * 2008-04-28 2011-09-14 Central Glass Co Ltd Procédé de production d acides -fluoro- -aminés
US8217196B2 (en) 2008-04-28 2012-07-10 Central Glass Company, Limited Process for producing α-fluoro-β-amino acids
JP2010285350A (ja) * 2009-06-09 2010-12-24 Central Glass Co Ltd ２−フルオロアクリル酸エステルの製造方法

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