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WO2012152438A1 - Procédé pour la préparation d'ester d'acide de nitrate de composés organiques - Google Patents

Procédé pour la préparation d'ester d'acide de nitrate de composés organiques Download PDF

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Publication number
WO2012152438A1
WO2012152438A1 PCT/EP2012/001990 EP2012001990W WO2012152438A1 WO 2012152438 A1 WO2012152438 A1 WO 2012152438A1 EP 2012001990 W EP2012001990 W EP 2012001990W WO 2012152438 A1 WO2012152438 A1 WO 2012152438A1
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Prior art keywords
nitrate
ester
mmol
cycloalkyl
alcohol
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Annalisa Bonfanti
Laura Storoni
Gael Ronsin
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Nicox SA
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Nicox SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C07B43/02—Formation or introduction of functional groups containing nitrogen of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/02—Preparation of esters of nitric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/127—Preparation from compounds containing pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a one-step process for the preparation of nitrate acid esters and 15 N isotopically labeled nitrate esters of organic compounds.
  • nitric acid esters of organic compounds are known and have been used as important source of nitric oxide and the interest toward this kind of functionality has grown in recent years due to the therapeutic benefits conferred by NO such as vasodilatation and anti-inflammatory activity.
  • nitric acid esters of organic compounds are well known and are usually based on substitution reactions of suitable leaving groups (halogen, triflate, tosyl etc). These leaving groups can be easily prepared from compounds having a free hydroxyl group.
  • WO 95/0983 1 describes a process for the preparation of (S)-naproxen 4-nitrooxy butyl ester whereby naproxen 4-hydroxybutyl ester is halogenated in the presence of PBr 3 . This is followed by reaction of the resulting halogenated ester with silver nitrate.
  • the use of a stoichiometric amount or an excess of silver nitrate to achieve a good yield of the product constitutes an economical drawback for large scale manufacturing of (S -naproxen 4-nitrooxybutyl ester.
  • WO 98/25918 discloses the preparation of aralkyl esters of nitrated cycloaliphatic diols by reaction of an aralkylic acid derivative with the respective mononitrated cycloaliphatic diol.
  • the nitrated alcohols are prepared by nitration of the respective monohalogenated cycloaliphatic diol or by reaction the respective diol with acetic anhydride and nitric acid. No yields are given.
  • WO 2010/070079 discloses a two-steps method for the preparation of dioxa-bicyclooctane nitrate compounds which comprises the preparation of the isoidide-2-thioacetate-5-triflate intermediates followed by the nitration reaction that is carried out using tetrabutylammoniun nitrate.
  • Nighat Afza et al. (Liebigs Annalen der Chemie) disclose a one-pot procedure to synthesize sugar nitrate.
  • the method consists of reacting a mixture of a sugar and trifloromethanesulfonic anhydride in the presence of tetrabutylammonium nitrate and acetonitrile or dichloromethane or dimethylformamide.
  • the present invention provides a process for the preparation of nitrate esters or 15 N isotopically labeled nitrate esters of formula (I)
  • n 0 or 1 ;
  • Y is selected from:
  • each of Yi or Y 2 independently is a straight or branched alkyl chain having 1 to 5 carbon atoms and X is -O-CO-, -CO-0-,- ⁇ -, -NH-, -NH-CO- or -CO-NH-;
  • R is selected from:
  • aryl groups selected from a monocyclic aromatic ring or a bicyclic aromatic system, or an heterocyclic aromatic system comprising one or two rings;
  • the aryl groups can be substituted with one, two or three substituents independently selected from alkyl, alkoxy, alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, halo, cyano, alkylsulfinyl, hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido, alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamido and nitro; preferred aryl groups are: phenyl, pyridyl, napthyl, quinoyl, tetrahydronap
  • a cycloalkyl group selected from a saturated cycloalkyl comprising from 3 to about 10 carbon atoms; the cycloalkyl group can be substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo, alkylsulfinyl, and nitro; preferred cycloalkyl groups are cyclopentyl or cyclohexyl;
  • bridged cycloalkyl selected from a combination of two or more cycloalkyl groups or of a cycloalkyl and a heterocyclic fused via adjacent or non-adjacent atoms;
  • the bridged cycloalkyl can be substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro;
  • preferred bridged cycloalkyl groups are selected from: adamantyl, decahydronapthyl, quinuclidyl, 2,6-dioxabicyclo(3,3,0)octane,
  • n 1 when R is an aryl group
  • said process comprises:
  • n, Y and R are as above defined, with
  • organic base selected from: 2,6-di-tert-butyl-4-methylpyridine, sym-collidine, 2,6-lutidine, pyridine or triethylamine
  • preferred organic bases are 2,6-ditert-butyl-4-methylpyridine, sym-collidine or 2,6-lutidine
  • nitrated salt selected from tetramethylammonium nitrate, tetraethylammonium nitrate, tetrabutylammonium nitrate, 15 N- tetraethylammonium nitrate or 15 N-tetrabutylammonium nitrate
  • the preferred nitrate salts are tetraethylammonium nitrate, tetrabutylammonium nitrate or 15 N- tetraethylammonium nitrate or 15 N-tetrabutylammonium nitrate.
  • an organic solvent selected from dichloromethane, acetonitrile, tetrahydrofurane
  • the preferred solvent is dichloromethane, at a temperature from -70°C to - 20°C
  • the molar ratio base / alcohol (II) is from 1.3 to 1.5.
  • the molar ratio nitrated salt/ alcohol (II) is from 1 to 1.2.
  • the molar ratio triflic anhydride /alcohol (II) is from 1 to 1.2;
  • R is selected from:
  • aryl groups selected from a monocyclic aromatic ring or a bicyclic aromatic system, or an heterocyclic aromatic system comprising one or two rings;
  • the aryl groups can be substituted with one, two or three substituents independently selected from alkyl, alkoxy, alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, halo, cyano, alkylsulfinyl, hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido, alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamido and nitro,
  • cycloalkyl group selected from a saturated cycloalkyl comprising from 3 to about 10 carbon atoms; the cycloalkyl group can be substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo, alkylsulfinyl, and nitro,
  • bridged cycloalkyl selected from a combination of two or more cycloalkyl groups or of a cycloalkyl and a heterocyclic fused via adjacent or non-adjacent atoms;
  • the bridged cycloalkyl can be substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro,
  • n 1 when R is an aryl group
  • R is selected from:
  • - an aryl group selected from phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl;
  • cycloalkyl group selected from cyclopentyl or cyclohexyl
  • Suitable protecting groups P are those known in the art, for example as described in T. W. Greene "Protecting groups in organic synthesis” Harvard University Press, 1980.
  • the molar ratio base / alcohol (II) is from 1.3 to 1 .5, the molar ratio nitrated salt/ alcohol (II) is from 1 to 1.2, and the molar ratio triflic anhydride /alcohol (II) is from 1 to 1 .2.
  • the organic base is preferably 2,6-ditert-butyl-4-methylpyridine and the nitrate salt is tetraethylammonium nitrate and the solvent is dichloromethane.
  • Another embodiment relates to a process for the synthesis of (S)-4-nitrooxybutyl-2-(6-methoxynaphtalen-2yl)propanoate which comprises
  • an organic base selected from: 2,6-di-tert-butyl-4-methylpyridine, sym-collidine, 2,6-lutidine, pyridine or triethylamine, the preferred base is 2,6-ditert-butyl-4-methylpyridine,
  • nitrated salt selected from tetraethylammonium nitrate or tetrabutylammonium nitrate, 15 N- tetraethylammonium nitrate or 15 N-tetrabutylammonium nitrate, the preferred nitrate salt is tetraethylammonium nitrate,
  • an organic solvent selected from dichloromethane, acetonitrile, tetrahydrofurane, the preferred solvent is dichloromethane, at a temperature from -70°C to -20°C
  • the molar ratio base/(S)-4-hydroxybutyl-2-(6-methoxynaphtalen-2yl) propanoate is from 1.3 to 1.5
  • the molar ratio nitrated salt/(5)-4-hydroxybutyl-2-(6- methoxynaphtalen-2yl) propanoate is from 1 to 1.2.
  • the molar ratio triflic anhydride/(S)-4-hydroxybutyl-2-(6- methoxynaphtalen-2yl) propanoate is from 1 to 1.2.
  • Naproxen nitrooxybutyl ester is a nitric oxide releasing derivative of naproxen which is a drug belonging to the class of the non steroidal antiinflammatory drugs (NSAIDs).
  • NSAIDs non steroidal antiinflammatory drugs
  • Naproxen nitrooxybutyl ester is the first of a class of NSAIDs known as cyclooxygenase inhibiting NO donors.
  • the process of the present invention has several advantages than the known methods, such as in the presence of electron rich aromatic group this procedure affords mainly nitration of the alcohol instead of nitration on the ring, when the starting material is a chiral secondary alcohol the reaction proceeds with complete retention of configuration of the carbon atom moreover this method allows to easily prepare 15 N-derivatives of active drugs.
  • 15 N-derivatives of active drugs are stable isotope labeled substrates which are important for the evaluation of in vivo NO metabolism.
  • 15 N-derivatives of active drugs cannot be prepared from alcohols by the classic nitration with HNO 3 and Ac 2 O because fuming 15 N-HNO 3 is not commercially available.
  • reaction mixture was stirred at -70°C for 2 h, and then allowed to warm to room temperature over a period of 2 h.
  • the reaction mixture was washed with H 2 O.
  • the organic phase was dried over anhydrous sodium sulfate and the solvent removed in vacuo.
  • the crude material was purified over silica gel eluting with EtOAc/n-Hexane, gradient: 1 CV at 0%, from 0% to 40% in 10 CV, at 40% for 1 CV (percentage of EtOAc), to give 159 mg of 3-methoxyphenethyl nitrate, yield: 54%.
  • Example 2 Title compound was synthesized following the procedure of Example 1 except that 1 -(naphthalene- l-yl)ethyl alcohol was used instead of 3-methoxyphenethyl alcohol.
  • Example 8 comparative example
  • Example 9 comparative example
  • Compound la was synthesized using acetyl nitrate as the nitrating agent.
  • Methoxynaphtalen-2-yl) propanoate 500 mg, 302.27 mg/mmol, 1.65 mmol
  • 2,6-di-tert-butyl-4-methylpyridine 493 mg, 205.35 mg/mmol, 2.48 mmol
  • tetraethylammonium nitrate 381 mg, 192.26 mg/mmol, 1.98 mmol
  • dichloromethane 30 mL
  • was cooled to -70°C and maintained at this temperature with stirring during the dropwise addition of a solution of triflic anhydride (327 ⁇ ,, 282.14 mg/mmol, d l .71 g/mL, 1.98 mmol) in dichloromethane ( 10 mL).
  • reaction mixture was stirred at -70° C for 2 h, then allowed to warm to room temperature over a period of 2 h.
  • the reaction mixture was washed with water.
  • the organic phase was dried over anhydrous sodium sulfate and the solvent removed in vacuo.
  • the crude material was purified over silica gel eluting with EtOAc/n-Hexane gradient: at 0% 2 CV, from 0% to 20% in 3 CV, at 20% 3 CV to give 258 mg of cis-l-Methyl-2-nitrooxy- cyclohexane, yield: 62%. Purity higher than 99%, determined by HPLC.
  • reaction mixture was stirred at -70° C for 2 h, and then allowed to warm to room temperature over a period of 2 h.
  • the reaction mixture was washed with H 2 O.
  • the organic phase was dried over anhydrous sodium sulphate and the solvent removed in vacuo.
  • the crude material was purified over silica gel eluting with Acetone/n- Hexane, gradient: at 0% for 2 CV, from 0% to 20% in 3 CV, at 30% for 3 CV (percentage of Acetone, to give 299 mg of compound 11a, yield: 77%.
  • reaction mixture was stirred at -70° C for 2 h, then allowed to warm to room temperature over a period of 2 h.
  • the reaction mixture was washed with H 2 O.
  • the organic phase was dried over anhydrous sodium sulfate and the solvent removed in vacuo.
  • the crude material was purified over silica gel eluting with EtOAc/n-Hexane, gradient: from 0% to 10% in 3 CV, at 10% for 3 CV (percentage of EtOAc), to give 200 mg of (l S,2S,5R)-2-isopropyl-5- methylcyclohexyl nitrate, yield: 66%. d.e. 99%.
  • reaction mixture was stirred at -70° C for 2 h, and then allowed to warm to room temperature over a period of 2 h.
  • the reaction mixture was washed with H 2 O.
  • the organic phase was dried over anhydrous sodium sulphate and the solvent removed in vacuo.
  • the crude material was purified over silica gel eluting with Acetone/n- Hexane, gradient: at 0% for 2 CV, from 0% to 20% for 3 CV, at 20% for 3 CV (percentage of Acetone), to give 373 mg of compound 1 1a, yield: 58%. Purity higher than 99%, determined by HPLC.
  • reaction mixture was stirred at -70° C for 2 h, and then allowed to warm to room temperature over a period of 2 h.
  • the reaction mixture was washed with H 2 O.
  • the organic phase was dried over anhydrous sodium sulphate and the solvent removed in vacuo.
  • the crude material was purified over silica gel eluting with Acetone/n-Hexane, gradient: at 0% for 2 CV, from 0% to 20% for 3 CV, at 20% for 3 CV (percentage of Acetone), to give 358 mg of compound 1 1a, yield: 56%. Purity higher than 99%, determined by HPLC.
  • the reaction mixture was stirred at -70° C for 1 h, then allowed to warm to 0°C over a period of 1 h and then quenched by the addition of water.
  • the organic phase was separated and washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo.
  • the crude material was taken in diethylether (20 mL) and the solid formed was filtered off, washed with cold diethylether.
  • reaction mixture was stirred at -70°C for 1 h, then quenched by the addition of a solution of ammonium chloride.
  • the organic phase was separated and washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo.
  • reaction mixture was stirred at -70° C for 1 h, then allowed to warm to 0°C over a period of 1 h and then quenched by the addition of an aqueous solution of ammonium chloride.
  • the organic phase was separated and washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo.
  • the residue purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient n-hexane/ethyl acetate 90/10 to n-hexane/ethyl acetate 60/40 during 10 CV) gave compound 15a as a colorless oil (0.53 g, 51%).

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé en une étape pour la synthèse d'esters d'acide nitrique ou d'esters de nitrate marqués par isotope 15N de composés organiques à partir des alcools correspondants. Formule (I).
PCT/EP2012/001990 2011-05-11 2012-05-09 Procédé pour la préparation d'ester d'acide de nitrate de composés organiques Ceased WO2012152438A1 (fr)

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EP11165613 2011-05-11

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10017457B2 (en) 2014-03-07 2018-07-10 Corning Incorporated Continuous synthesis of isooctyl nitrate in a flow reactor
CN114436846A (zh) * 2022-01-12 2022-05-06 上海师范大学 一种硝酸酯基转移试剂及其制备方法和应用
CN115043731A (zh) * 2022-05-20 2022-09-13 上海大学 一种3-卤代-丁-3-烯-1-硝酸酯类化合物及其制备方法
CN115461321A (zh) * 2020-04-22 2022-12-09 帝斯曼知识产权资产管理有限公司 制备α,ω-烷二醇单硝酸酯的方法

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WO1998025918A1 (fr) 1996-12-12 1998-06-18 Hoechst Marion Roussel Esters analgesiques, anti-inflammatoires et anti-thrombotiques d'alcools cycloaliphatiques nitres
JP2001002626A (ja) * 1999-04-19 2001-01-09 Sankyo Co Ltd 硝酸エステル体の製造法
WO2007137980A1 (fr) * 2006-05-29 2007-12-06 Nicox S.A. Composés hétérocycliques nitrés en tant qu'antagonistes de récepteur de l'endothéline
WO2008075152A1 (fr) * 2006-12-15 2008-06-26 Pfizer Products Inc. Inhibiteurs de l'anhydrase carbonique de type triazoles
EP2048129A1 (fr) * 2007-10-12 2009-04-15 Lonza Ag Procédé pour la préparation de nitrates organiques
WO2009106470A2 (fr) * 2008-02-26 2009-09-03 Nicox S.A. Antagonistes vis-à-vis des récepteurs de l'angiotensine ii
WO2009106471A2 (fr) * 2008-02-26 2009-09-03 Nicox S.A. Nouveaux dérivés bloquant les récepteurs de l'angiotensine ii
WO2009149053A2 (fr) * 2008-06-02 2009-12-10 Dr. Reddy's Laboratories Ltd. Procédé de fabrication de naproxcinod et dispersion solide de naproxcinod
WO2010070079A1 (fr) 2008-12-19 2010-06-24 Lacer, S.A. Nouveau procédé stéréospécifique pour préparer des composés de nitrate de dioxa-bicyclo-octane
WO2011012400A2 (fr) * 2009-07-28 2011-02-03 Nicox S.A. Naproxène libérant de l'oxyde nitrique

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CN114436846A (zh) * 2022-01-12 2022-05-06 上海师范大学 一种硝酸酯基转移试剂及其制备方法和应用
CN114436846B (zh) * 2022-01-12 2024-03-26 上海师范大学 一种硝酸酯基转移试剂及其制备方法和应用
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