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WO2001056997A1 - Procede de preparation de derives d'acide piperazique de ce dernier - Google Patents

Procede de preparation de derives d'acide piperazique de ce dernier Download PDF

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Publication number
WO2001056997A1
WO2001056997A1 PCT/EP2001/001159 EP0101159W WO0156997A1 WO 2001056997 A1 WO2001056997 A1 WO 2001056997A1 EP 0101159 W EP0101159 W EP 0101159W WO 0156997 A1 WO0156997 A1 WO 0156997A1
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WIPO (PCT)
Prior art keywords
general formula
process according
piperazic acid
alkyl
tert
Prior art date
Application number
PCT/EP2001/001159
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English (en)
Inventor
Walter Brieden
Colm O'murchu
Original Assignee
Lonza Ag
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 Lonza Ag filed Critical Lonza Ag
Priority to AU2001244122A priority Critical patent/AU2001244122A1/en
Publication of WO2001056997A1 publication Critical patent/WO2001056997A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to a process for preparing piperazic acid or derivatives thereof.
  • the synthesis has been described by K. J. Hale et al. in Tetrahedron 1996, 52(3), 1047-1068.
  • the yield of the reaction described by K. J. Hale was 55-63% and thus is relatively low.
  • piperazic acid derivatives can be prepared in a greater yield compared to the yield obtained in the Hale process by treating a 2,5-dihalopentanoate with a hydrazodicarboxylic acid derivative whereby nucleophihc substitution at both of the halo atoms of the 2,5-dihalopentanoate occurs.
  • the object of the present invention is to provide a process for preparing piperazic acid derivatives of the general formula
  • R 1 is C,_ 20 -alkyl and R 2 is hydrogen, C- ⁇ -alkyl, C, ⁇ -haloalkyl, C,_ 6 -alkoxy, allyloxy, 2,2,2-trichloroethoxy.
  • 2-iodoethoxy optionally substituted phenyl, benzyloxy, 4-methoxy- benzyloxy or 2,4-dimethoxybenzyloxy, which process comprises reacting a 2.5-dihalopentanoate of the general formula
  • R 2 is as defined above.
  • C,_ 20 -alkyl refers to straight chain or branched alkyl groups having 1-20 carbon atoms.
  • straight chain alkyl groups examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, decyl, dodecyl, hexadecyl, heptadecyl and eicosyl.
  • Preferred straight chain hydrocarbon groups are methyl and ethyl.
  • branched alkyl groups include: • alpha branched alkyls such as e. g. isopropyl, 1-methylpropyl, 1-methylbutyl, 1-methyl- pentyl, 1-methylhexyl, 1 -ethylpropyl, 1 -ethylhexyl, 1-propylpentyl, 1 -ethyl heptyl, 1-propyl- hexyl and 1-hexylundecyl;
  • alpha branched alkyls such as e. g. isopropyl, 1-methylpropyl, 1-methylbutyl, 1-methyl- pentyl, 1-methylhexyl, 1 -ethylpropyl, 1 -ethylhexyl, 1-propylpentyl, 1 -ethyl heptyl, 1-propyl- hexyl and 1-hexylundecyl;
  • beta branched alkyls such as e. g. 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethyl- butyl, 2-methylhexyl, 2-ethylpentyl, 2-methylheptyl, 2-ethylhexyl, and 2-propylpentyl; • polybranched alkyls such as e. g.
  • Preferred branched chain alkyl groups are isopropyl and tert-butyl.
  • the alkyl groups are optionally substituted with one or more substituents selected from the group consisting of C- ⁇ -alkoxy, amino, monoalkylamino, dialkylamino, cyano, halo, hydroxy, nitro, phenyl, substituted phenyl and the like.
  • a preferred substituted alkyl group is the benzyl group.
  • C- ⁇ -haloalkyl refers to a straight or branched alkyl group substituted with one or more halo atoms such as e. g. trifluoromethyl.
  • C- ⁇ -alkoxy refers to C- ⁇ -alkyl-O- groups having from 1 to 6 carbon atoms. Preferred alkoxy groups include e. g. methoxy, ethoxy, propoxy, isopropoxy, ( «-)butoxy, tert-butoxy, sec-butoxy, (w-)pentyloxy, ( ⁇ -)hexyloxy, 1 ,2-dimethylbutoxy, and the like.
  • the phenyl group is optionally substituted with one or more substituents selected from C- ⁇ -alkyl, C, ⁇ -alkoxy, hydroxy, nitro, chloro, fluoro, trichloromethyl and trifluoromethyl.
  • halo refers to fluorine, chlorine, bromine, and iodine.
  • the -COR 2 moieties may also be regarded as amino protective groups.
  • amino protective group is generally known in the art and relates to groups which are suitable for protecting an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions of the molecule. Examples of such groups are, in particular, C,_ 6 -alkanoyl such as e. g. formyl, acetyl, propionyl, butyryl; C- ⁇ -alkoxycarbonyl such as e. g. methoxycarbonyl, ethoxycarbonyl; tert-butoxycarbonyl (Boc); Aryl-C- ⁇ -alkoxycarbonyl such as e.g.
  • benzyloxycarbonyl also called “CBZ” or simply “Z”
  • CBZ benzyloxycarbonyl
  • other known groups such as e.g. allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl.
  • the reaction of the 2,5-dihalopentanoate (II) with the hydrazine derivative (III) of the above process is effected in the presence of a base.
  • a base Any base suitable to perform the nucleophihc disubstitution reaction will suffice.
  • Examples for a suitable base are NaH, KH, LiH, ⁇ -butyl- lithium, tert-butyllithium, phenyllithium, lithium diisopropylamide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide sodium hexamethyldisilazide, NaOH or KOH.
  • Preferred bases are NaH and rc-butyllithium.
  • the base is preferably added in an amount somewhat greater than the stoichiometric amount of two equivalents.
  • the base may be added or prepared in situ.
  • the molar ratio of the 2,5-dihalopentanoate (II) to the hydrazine derivative (III) is preferably 1.0 to 1.2, a ratio of 1.03 to 1.1 being especially preferred.
  • aprotic solvent examples include tetrahydrofuran, dimethylsulfoxide, N-N-dimethylpropyleneurea (DMPU), diethyl ether, methyl tert-butyl ether, diisopropyl ether, N,N-dimethylformamide, N-methylpyrrolidone, toluene or a mixture of two or more of the foregoing solvents.
  • DMPU N-N-dimethylpropyleneurea
  • DMPU N-N-dimethylpropyleneurea
  • diethyl ether diethyl ether
  • methyl tert-butyl ether diisopropyl ether
  • N,N-dimethylformamide N-methylpyrrolidone
  • toluene or a mixture of two or more of the foregoing solvents.
  • the above process is carried out at a temperature in the range of -30 to 40 °C, most preferably at room temperature.
  • the product i. e. the compound of the general formula I may be recovered by known methods such as extraction, distillation or chromatography.
  • a preferred compound of the formula I is a compound wherein R 1 is ethyl and R 2 is ethoxy.
  • Said preferred compound can be prepared by adding diethyl hydrazodicarboxylate to a solution of ethyl 2,5-dibromopentanoate in the presence of ⁇ aH.
  • Compounds of the formula II which are preferably dibromo compounds can be prepared using methods known in the art, for example from ⁇ -valerolactone as described by W. A. J. Starmans et al. in Tetrahedron 1998, 54, 4991-5004 or by bromination of 5-bromopentanoic acid as described by R. Merchant et al. in J. Am. Chem. Soc. 1927, 49, 1828-1831.
  • the compound of the formula III wherein R 2 is hydrogen can easily be prepared by reacting hydrazine with formic acid C. ⁇ -alkyl ester.
  • the compound of the formula III wherein R 2 is methyl, ethoxy or phenyl is commercially available, for example at Aldrich or Fluka.
  • the compound of the formula III wherein R 2 is other than hydrogen can be prepared by known methods such as e.g. described in the following references: L. A. Carpino and P. j. Crowely in Organic Syntheses, Coll. Vol. V, page 160; J. M. Mellor and R. ⁇ . Pathirana, J. Chem. Soc. Perkin Trans. 1 1984, 753-759; H. B ⁇ shagen and J. Ullrich Chem. Ber. 1961, 92, 1478.
  • the -CO-R 2 groups of the compound of formula I may be detached from the nitrogen atom by treatment with a base. Furthermore, under these conditions hydrolysis of the ester function (-COOR 1 ) occurs. This reaction is preferably carried out under heating to reflux in the presence of a base such as for example in the presence of a hydroxide of an alkali metal, preferably in the presence of KOH.
  • Piperazic acid is obtained in the form of its alkali metal salt which may be recovered by known methods, such as e. g. extraction.
  • the aqueous solution obtained together with salts are purified by extraction of neutral and basic components with e. g. methylene chloride.
  • the alkali salt of piperazic acid may easily be converted into free piperazic acid by methods known in the art.
  • the alkali salt of piperazic acid may also be reacted in a further additional step with a chloroformate of the general formula
  • R 3 is C- ⁇ -alkyl, allyl, 2,2,2-trichloroethyl, 2-iodoethyl, benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, to give a compound of the general formula
  • this additional step is carried out by adding the chloroformate (V) to an aqueous solution of the salt of piperazic acid in the presence of a base as an acid acceptor.
  • a base as an acid acceptor.
  • This kind of reaction is known in the art and for example described by C. E. Adams et al. in Synth. Commun. 1988, 18(1 ), 2225-2231. It may be carried out with the solution obtained by base treatment of the piperazic acid derivative (I) without isolating the alkali salt of piperazic acid (IV).
  • benzyl chloroformate is especially preferred.
  • the compounds of formula V are known and commercially available.
  • the amount of the chloroformate (V i is usually 0.7 to 1.4 mol based on 1 mol of the alkali salt of piperazic acid.
  • the reaction with the chloroformate (V ) is usually conducted in an aqueous solvent, and an aprotic solvent such as one of those listed above can be added to the aqueous reaction solution.
  • the reaction temperature of this step is usually -10 to 50 °C, preferably 0 to 20 °C.
  • the aqueous and the organic phase are separated, the aqueous phase is acidified to afford crystals of the desired N ⁇ substituted piperazic acid.
  • the piperazic acid derivatives of formula I contain a center of asymmetry and can, therefore, exist in racemic or optically active form.
  • the invention includes within its scope the resolution of racemates which can be carried out according to known methods.
  • the compounds of the general formula I are valuable intermediates for the preparation of pharmacologically active molecules.
  • the aqueous solution obtained in the preceding example was cooled to 10-15 °C and was treated in two parallel streams, with 2 N NaOH (247 ml) and with a solution of benzyl chloroformate (79.9 g, 95%> pure, 0.44 mol) in toluene (247 ml) over a period of 30 min, while maintaining the pH at 10-1 1 and agitating rapidly.
  • the pH may be adjusted with additional 2 N HCl or with 2 N NaOH.
  • After a further 2 hours stirring at 10 °C the phases were separated and the aqueous phase washed with toluene (2x250 ml).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de dérivés d'acide pipérazique représentés par la formule générale (I), dans laquelle R1 représente C¿1-20?-alkyle et R?2¿ représente un hydrogène, C¿1-6?-alkyle, C1-6-haloalkyle, C1-6-alcoxy, allyloxy, 2,2,2,-trichloroéthoxy, 2-iodoéthoxy, éventuellement un phényle, benzyloxy, 4-méthoxybenzyloxy ou 2,4-diméthoxybenzyloxy substitué. Ce procédé consiste à faire réagir un 2,5-dihalopentanoate représenté par la formule générale (II): CH2X-CH2-CH2-CH2X-COOR?1¿, dans laquelle X représente un Br ou un Cl et R1 représente un élément décrit ci-dessus, en présence d'une base avec un dérivé d'hydrazine représenté par la formule générale (III): R2CONH-NHCOR2, dans laquelle R2 représente un élément décrit ci-dessus. L'invention concerne également un procédé de préparation de sels alcalins d'acide pipérazique et des dérivés d'acide pipérazique représentés par la formule générale (VI), dans laquelle R3 représente C¿1-6?-alkyle, allyle, 2,2,2-trichloroéthyle, 2-iodoéthyle, benzyle, 4-méthoxybenzyle ou 2,4-diméthoxybenzyle.
PCT/EP2001/001159 2000-02-04 2001-02-02 Procede de preparation de derives d'acide piperazique de ce dernier WO2001056997A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001244122A AU2001244122A1 (en) 2000-02-04 2001-02-02 Process for preparing piperazic acid derivatives thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP00102420.7 2000-02-04
EP00102420 2000-02-04
US20393600P 2000-05-12 2000-05-12
US60/203,936 2000-05-12

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028449A1 (fr) * 2003-06-26 2005-03-31 Honeywell Specialty Chemicals Seelze Gmbh Procede ameliore de fabrication d'acides hexahydropyridazine-3-carboxyliques 1,2-disubstitues et leurs esters
CN100404516C (zh) * 2004-02-13 2008-07-23 大连绿源药业有限责任公司 六氢哒嗪三羧酸酯的制备方法
WO2012049646A1 (fr) 2010-10-12 2012-04-19 Ranbaxy Laboratories Limited Procédé de préparation d'un intermédiaire de cilazapril
CN102898328A (zh) * 2012-10-26 2013-01-30 山东师范大学 偶氮二甲酸二乙酯及其中间体的合成方法
CN109651189A (zh) * 2019-01-31 2019-04-19 上海应用技术大学 一种苯甲酰腙类神经氨酸酶抑制剂及其制备方法和用途
CN109776354A (zh) * 2019-01-04 2019-05-21 上海应用技术大学 一种二羟基苯甲酰腙类神经氨酸酶抑制剂及其制备和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994011353A1 (fr) * 1992-11-12 1994-05-26 University College London PROCEDE DE PREPARATION DES DERIVES DES ACIDES (3R)- et (3S)-PIPERAZIQUES

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994011353A1 (fr) * 1992-11-12 1994-05-26 University College London PROCEDE DE PREPARATION DES DERIVES DES ACIDES (3R)- et (3S)-PIPERAZIQUES

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HALE K J ET AL: "Enantioselective Synthesis of (3R)- and (3S)-Piperazic Acids. The Comparative Unimportance of DMPU Mediated Retro-Hydrazination", TETRAHEDRON,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 52, no. 3, 15 January 1996 (1996-01-15), pages 1047 - 1068, XP004104575, ISSN: 0040-4020 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028449A1 (fr) * 2003-06-26 2005-03-31 Honeywell Specialty Chemicals Seelze Gmbh Procede ameliore de fabrication d'acides hexahydropyridazine-3-carboxyliques 1,2-disubstitues et leurs esters
CN100404516C (zh) * 2004-02-13 2008-07-23 大连绿源药业有限责任公司 六氢哒嗪三羧酸酯的制备方法
WO2012049646A1 (fr) 2010-10-12 2012-04-19 Ranbaxy Laboratories Limited Procédé de préparation d'un intermédiaire de cilazapril
CN102898328A (zh) * 2012-10-26 2013-01-30 山东师范大学 偶氮二甲酸二乙酯及其中间体的合成方法
CN102898328B (zh) * 2012-10-26 2014-12-24 山东师范大学 偶氮二甲酸二乙酯及其中间体的合成方法
CN109776354A (zh) * 2019-01-04 2019-05-21 上海应用技术大学 一种二羟基苯甲酰腙类神经氨酸酶抑制剂及其制备和应用
CN109651189A (zh) * 2019-01-31 2019-04-19 上海应用技术大学 一种苯甲酰腙类神经氨酸酶抑制剂及其制备方法和用途

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