WO2012152438A1 - Process for the preparation of nitrate acid ester of organic compounds - Google Patents

Process for the preparation of nitrate acid ester of organic compounds Download PDF

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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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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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Abstract

The present invention relates to a one-step process for the synthesis of nitric acid esters or 15N isotopically labeled nitrate esters of organic compounds starting from the correspondent alcohols. Formula (I).

Description

PROCESS FOR THE PREPARATION OF NITRATE ACID ESTER OF ORGANIC COMPOUNDS
The present invention relates to a one-step process for the preparation of nitrate acid esters and 15N isotopically labeled nitrate esters of organic compounds.
The 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.
Preparations of 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 PBr3. 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.
Limitation of this method is the isolation of the triflate intermediates which are often very unstable compounds and may not be easily isolated.
A common drawback of the above reported methods is that they involve multi-steps process that is disadvantageous for industrial-scale synthetic preparations.
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.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a one-step process for the preparation of nitric acid esters and 15N isotopically labeled nitrate esters of organic compounds starting from alcohols.
In one aspect the present invention provides a process for the preparation of nitrate esters or 15N isotopically labeled nitrate esters of formula (I)
R-[Y]n-ONO2
(I)
wherein
n is 0 or 1 ;
Y is selected from:
- a straight or branched alkyl chain having 1 to 10 carbon atoms; or
- a group of formula:
- Y,-(X)-Y2- wherein each of Yi or Y2 independently is a straight or branched alkyl chain having 1 to 5 carbon atoms and X is -O-CO-, -CO-0-,-Ο-, -NH-, -NH-CO- or -CO-NH-;
R is selected from:
- P-O- or P-NH- wherein P is a protecting group;
- an aryl group 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, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl;
- 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;
- a 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,
7-oxabicyclo(2,2, l) heptyl, 8-azabicyclo(3,2, l)oct-2-enyl;
n is 1 when R is an aryl group;
said process comprises:
(a) reacting an alcohol of formula (II)
R-[Y]n-OH (II)
wherein n, Y and R are as above defined, with
- an 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, and
- a nitrated salt selected from tetramethylammonium nitrate, tetraethylammonium nitrate, tetrabutylammonium nitrate, 15N- tetraethylammonium nitrate or 15N-tetrabutylammonium nitrate, the preferred nitrate salts are tetraethylammonium nitrate, tetrabutylammonium nitrate or 15N- tetraethylammonium nitrate or 15N-tetrabutylammonium nitrate. in an organic solvent selected from dichloromethane, acetonitrile, tetrahydrofurane, the preferred solvent is dichloromethane, at a temperature from -70°C to - 20°C,
(b) treating the obtained mixture with triflic anhydride at a temperature from -70°C to room temperature.
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;
(c) optionally removing protecting groups
Preferably R is selected from:
- an aryl group 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,
- 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,
- a 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 is 1 when R is an aryl group;
Most preferably R is selected from:
- an aryl group selected from phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl;.
- a cycloalkyl group selected from cyclopentyl or cyclohexyl;
- a bridged cycloalkyl selected from adamantyl, decahydronapthyl, quinuclidyl, 2,6-dioxabicyclo(3,3,0)octane, 7-oxabicyclo(2,2, l) heptyl, 8-azabicyclo(3,2, 1 )oct-2-enyl. 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.
Preferably 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
(a) reacting (S)-4-hydroxybutyl-2-(6-methoxynaphtalen-2yl) propanoate (naproxen 4-hydroxybutyl ester) with
- 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,
- a nitrated salt selected from tetraethylammonium nitrate or tetrabutylammonium nitrate, 15N- tetraethylammonium nitrate or 15N-tetrabutylammonium nitrate, the preferred nitrate salt is tetraethylammonium nitrate,
in an organic solvent selected from dichloromethane, acetonitrile, tetrahydrofurane, the preferred solvent is dichloromethane, at a temperature from -70°C to -20°C
(b) then treating the obtained mixture with triflic anhydride at a temperature from -70°C to room temperature.
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.
(S)-4-nitrooxybutyl-2-(6-methoxynaphtalen-2-yl)propanoate, also known as 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). Naproxen nitrooxybutyl ester is the first of a class of NSAIDs known as cyclooxygenase inhibiting NO donors.
In the molecule of (S)-4-nitrooxybutyl-2-(6-methoxynaphtalen-2- yl)propanoate a primary mononitrate ester and an electron rich aromatic system are present.
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 15N-derivatives of active drugs. 15N-derivatives of active drugs are stable isotope labeled substrates which are important for the evaluation of in vivo NO metabolism. 15N-derivatives of active drugs cannot be prepared from alcohols by the classic nitration with HNO3 and Ac2O because fuming 15N-HNO3 is not commercially available. Applying the method of the present invention, using 15N-Bu NNO3; preparing and using 15N-Bu4NNO3 or 15N-Et4NNO3; enantiopure labeled nitrate can be directly prepared from easily accessible enantiopure alcohols, without any protection/deprotection or activation steps, otherwise not avoidable with known methodology employing 15N nitrate salts. Examples
Nitration of alcohols having an electron rich aromatic ring
Example 1
Synthesis of 3-methoxyphenethyl nitrate (Compound la)
A dry 50 mL round bottom flask containing 3-methoxyphenetyl alcohol
(228 mg, 152.19 mg/mmol, 1.5 mmol), 2,6-di-tert-butyl-4-methylpyridine (462 mg, 205.35 mg/mmoli 2.25 mmol) and tetraethylammonium nitrate (346 mg, 192.26 mg/mmol, 1.8 mmol) in dichloromethane (15 mL) was cooled to -70°C and maintained at this temperature with stirring during the dropwise addition of a solution of triflic anhydride (300 μΐ,, 282.14 mg/mmol, d=1.71 g/mL, 1.8 mmol) in dichloromethane (5 mL). On completion of the addition, the 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 H2O. 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%.
Ή NMR (300 MHz, CDC13) δ 7.54 - 6.57 (m, 4H), 4.66 (t, J = 7.1 , 2H), 3.83 (s, 3H), 3.02 (t, J = 7.1, 2H).
Example 2
Synthesis of 3-(4-methoxyphenyl)propyl nitrate (Compound 2a)
A. Synthesis of 3-(4-methoxyphenyl)propyl alcohol
To a stirred solution of 3-(4-hydroxyphenyl)-l-propanol in Ethanol, K2CO3 was added and the reaction was stirred at room temperature for 4 days. Ethanol was evaporated and the residue partitioned between dichloromethane and H2O. The aqueous layer was extracted with dichloromethane, the organic phase dried over anhydrous sodium sulfate and concentrated. The crude material was purified over silica gel eluting with EtOAc/n-Hexane, gradient: from 15% to 90% in 8 CV (percentage of EtOAc), to give 3529 mg of 3-(4- methoxyphenyl)propyl alcohol, yield: 80%. Ή NMR (300 MHz, CDC13) δ 7.23 - 6.75 (m, 4H), 3.81 (s, 3H), 3.69 (t, J = 6.4, 2H), 2.79 - 2.56 (m, 2H), 1.97 - 1.77 (m, 2H), 1.28 (t, J = 7.1 , 1 H).
B. Synthesis of 3-(4-methoxyphenyl)propyl nitrate
Title compound was synthesized following the procedure of Example 1 except that 3-(4-methoxyphenyl)propyl alcohol was used instead of 3-methoxyphenethyl alcohol.
lH NMR (300 MHz, CDC13) δ 7.12 (m, 2H), 6.87 (m, 2H), 4.45 (t, J = 6.5, 2H), 3.82 (s, 3H), 2.74 - 2.66 (m, 2H), 2.04 (dq, J = 8.5, 6.6, 2H).
Example 3
Synthesis of l-(naphthalene-l-yl)ethyl nitrate (Compound 3a)
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.
!H NMR (300 MHz, CDC13) δ 8.10 - 7.77 (m, 3H), 7.64 - 7.36 (m, 4H), 4.97 - 4.64 (m, 2H), 3.53 (dd, J = 9.2, 5.7, 2H).
Example 4
Synthesis of 4-bromophenethyl nitrate (compound 4a)
Title compound was synthesized following the procedure of Example 1 except that 4-bromophenethyl alcohol was used instead of 3-methoxyphenethyl alcohol.
Ή NMR (300 MHz, CDC13) δ 7.54 - 7.06 (m, 4H), 4.64 (t, J = 6.9, 2H), 3.00 (t, J - 6.9, 2H).
Example 5
Synthesis of 3-bromophenethyl nitrate (compound 5a)
Title compound was synthesized following the procedure of Example 1 except that 3-bromophenethyl alcohol was used instead of 3-methoxyphenethyl alcohol.
Ή NMR (300 MHz, CDC13) δ 7.56 - 7.09 (m, 4H), 4.65 (t, J = 6.9, 2H), 3.02 (t, J - 6.9, 2H).
Example 6
Synthesis of 3-(pyridi-3-yl)propyl nitrate (compound 6a)
Title compound was synthesized following the procedure of Example 1 except that 3-(pyridi-3-yl)propyl alcohol was used instead of 3-methoxyphenethyl alcohol.
1H NMR (300 MHz, CDC13) δ 8.47 (dd, J = 4.9, 1.3, 2H), 7.51 (ddd, J =
7.8, 2.2, 1.7, 1H), 7.23 (ddd, J = 7.8, 4.8, 0.6, 1H), 4.46 (t, J = 6.4, 2H), 2.79 - 2.68 (m, 2H), 2.06 (ddt, J = 7.5, 6.5, 5.7, 2H).
Example 7
Synthesis of (E)-4-(nitrooxy)butyl 3-(furan-2-yl)acrylate (compound 7a)
A. Synthesis of (E)-4-(hydroxy)butyl 3-(furan-2-yl)acrylate
To a stirred solution of 1,4-butandiol (425 μΐ,, 90.12 mg/mmol, d=1.014, 4.78 mmol), ED AC (1081 mg, 191.71 mg/mmol, 5.64 mmol) and DMAP (53 mg, 122.17 mg/mmol, 0.43 mmol) in dichloromethane (80 mL) a solution of 3-(2-uryl)acrylic acid (600 mg, 138.12 mg/mmol, 4.34 mmol) in dichloromethane (20 mL) was added dropwise and the resulting solution was stirred overnight. The solvent was evaporated and the crude material purified over silica gel eluting with EtOAc/n-Hexane, gradient: 1 CV at 30%, from 30% to 100% in 10 CV, at 100% for 1 CV (percentage of EtOAc), to give 440 mg of (E)-4-(hydroxy)butyl 3-(furan-2-yl)acrylate, yield: 48%.
1H NMR (300 MHz, CDC13) δ 7.50 (dd, J = 1.2, 0.6, 1H), 7.44 (d, J = 15.8, 1H), 6.63 (d, J = 3.4, 1H), 6.49 (dd, J = 3.4, 1.8, 1H), 6.33 (d, J = 15.7, 1H), 4.25 (t, J = 6.4, 2H), 3.73 (t, J = 6.3, 2H), 1.90 - 1.64 (m, 4H) B. Synthesis of (E)-4-(nitrooxy)butyl 3-(furan-2-yl)acrylate
Title compound was synthesized following the procedure of Example 1 except that (E)-4-(hydroxy)butyl 3-(furan-2-yl)acrylate was used instead of
3-methoxyphenethyl alcohol.
Ή NMR (300 MHz, CDC13) δ 7.54 - 7.49 (m, 1H), 7.45 (d, J = 15.7,
1H), 6.64 (d, J = 3.4, 1H), 6.49 (dd, J = 3.4, 1.8, 1H), 6.32 (d, J = 15.7, 1H),
4.53 (t, J = 6.2, 2H), 4.26 (t, J = 6.2, 2H), 1.98 - 1.74 (m, 4H).
Example 8: comparative example
Synthesis of 3-methoxyphenethyl nitrate (Compound la)
Compound la was synthesized according to the one-pot procedure described by Nighat Afza et al.; Liebigs Ann. Chem. (10), 1929-34; 1985)
A dry 100 mL round bottom flask containing 3-methoxyphenethyl alcohol (1.5 mmol), dry pyridine (3.075 mmol) and tetrabuthylammonium nitrate (3 mmol) in dichloromethane (45 mL) and dimethylformamide (3 mL) was cooled to -50°C and maintained at this temperature with stirring while a solution of triflic anhydride (3 mmol) in dichloromethane (30 mL) was added dropwise. On completion of the addition, the reaction mixture was allowed to warm to room temperature and then warmed at 40°C for 20 h. Thereafter the solution was cooled and 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: 1 CV at 0%, from 0% to 50% in 7 CV, at 50% for 1 CV (percentage of EtOAc), to give 71 mg of product 3-methoxyphenethyl nitrate, yield: 24%.
1H NMR (300 MHz, CDC13) δ 7.54 - 6.57 (m, 4H), 4.66 (t, J = 7.1 , 2H), 3.83 (s, 3H), 3.02 (t, J = 7.1, 2H).
Example 9: comparative example
Synthesis of 3-methoxyphenethyl nitrate (Compound la)
Compound la was synthesized using acetyl nitrate as the nitrating agent.
To a stirred solution of Ac2O (0.91 mmol) in 3 mL dichloromethane at -50°C, was added fuming HNO3 (1.05 mmol), followed by of 3-methoxyphenethyl alcohol (0.65 mmol) dissolved in 0.5 mL of dichloromethane. The reaction was stirred at -50°C for 1 h and then allowed to reach room temperature. The reaction mixture was poured into 15 mL of ice water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and the solvent removed in vacuo. No evidence of the formation of the product was found. The isolated subproducts were a mixture of dinitrated products both on the ring and on the alcohol.
Example 10
Synthesis of (5)-4-nitrooxybutyl-2-(6-methoxynaphtaIen-2yl) propanoate (Compound 8a)
A. Synthesis of (S)-4-hydroxybutyl-2-(6-methoxynaphtalen-2-yl) propanoate
A dry 100 mL round bottom flask containing 1,4-butanediol (294 L, 90.12 mg/mmol, d=1014, 3.31 mmol) in dichloromethane (40 mL) was stirred while ED AC (1269 mg, 191.71 mg/mmol, 6.62 mmol) and DMAP (162 mg, 122.17 mg/mmol, 1.32 mmol) were added. On completion of the addition, a solution of (S)-2-(6-Methoxy-2-naphtyl) propionic acid (762 mg, 230.27 mg/mmol, 3.31 mmol) in dichloromethane (20 mL) was slowly added dropwise and the resulting solution was stirred overnight. The solvent was removed in vacuo and the crude material was purified over silica gel eluting with EtOAc /n-Hexane gradient: at 20% 1 CV, from 20% to 50% in 10 CV (percentage of EtOAc), to give 500 mg of (S) 4-hydroxybutyl-2-(6- Methoxynaphtalen-2-yl) propanoate, yield: 50%.
XH NMR (300 MHz, CDC13) δ 7.83 - 7.55 (m, 3H), 7.42 (d, J = 8.4, 1H), 7.15 (d, J = 10.9, 2H), 4.13 (t, J = 6.4, 2H), 3.93 (s, 3H), 3.87 (q, 7.2, 1H), 3.56 (s, 2H), 1.77 - 1.63 (m, 2H), 1.60 (d, J = 7.1 , 3H), 1.51 (m, 2H), 1 .28 (t, J = 6.7, 1H).
B. Synthesis of (S)-4-nitrooxybutyl-2-(6-methoxynaphtalen-2-yl) propanoate
A dry 100 mL round bottom flask containing (S) 4-hydroxybutyl-2-(6-
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) and tetraethylammonium nitrate (381 mg, 192.26 mg/mmol, 1.98 mmol) in 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 μΐ,, 282.14 mg/mmol, d=l .71 g/mL, 1.98 mmol) in dichloromethane ( 10 mL). On completion of the addition, the 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 H2O. 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: 2 CV at 0%, from 0% to 40% in 10 CV (percentage of EtOAc) to give 372 mg of (S)-4-nitrooxybutyl-2-(6-methoxynaphtalen-2-yl) propanoate, yield: 65%.
1H NMR (300 MHz, CDC13) δ 7.82 - 7.61 (m, 3H), 7.41 (d, J = 8.4, 1H),
7.16 (d, J = 1 1.9, 2H), 4.34 (d, J = 5.9, 2H), 4.12 (d, J = 5.6, 2H), 3.94 (s, 3H), 3.86 (dd, J = 14.3, 7.2, 1H), 1.68 (d, J = 1.9, 4H), 1.60 (d, J = 7.3, 4H).
The yield of the nitrate products and the yield of the isolated subproduct nitrated on the ring of examples 1- 10 are summarized in Table 1. The results show that nitrate esters were obtained with high yields (54%-88%) and that the process mainly affords nitration of the alcohol instead of nitration on the ring, whereas the one-pot procedure known from literature mainly affords nitration of the alcohol instead of nitration on the ring.
Figure imgf000015_0001
Nitration of secondary alcohols
Example 1 1
Preparation of trans l-Methyl-2-nitrooxy-cyclohexane (compound
9a)
A dry 50 mL round bottom flask containing trans-2-methylcyclohexenol
( 1.5 mmol), 2,6-di-tert-butyl-4-methylpyridine (2.25 mmol) and tetraethylammonium nitrate ( 1.8 mmol) in dichloromethane (15 mL) was cooled to -70°C and maintained at this temperature with stirring while a solution of triflic anhydride (1.8 mmol) in dichloromethane (5 mL) was added dropwise. On completion of the addition, the 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: 5 CV at 0%, from 0% to 10% in 3 CV, at 10% for 1 CV (percentage of EtOAc), to give 80 mg of trans- l-Methyl-2-nitrooxy-cyclohexane, yield: 77%. Purity higher than 99%, determined by HPLC.
1H NMR (300 MHz, CDC13) 6 4.62 (td, J = 10.2, 4.2, 1H), 2.21 - 2.07 (m, 1H), 1.95 - 1.76 (m, 2H), 1.74 - 1.56 (m, 2H), 1.50 - 1.09 (m, 4H), 1.06 (d, J = 6.5, 3H).
Example 12
Preparation of cis l-Methyl-2-nitrooxy-cyclohexane (compound
10a)
A dry 50 mL round bottom flask containing Cis-2-methylcyclohexanol (300 mg, 2.58 mmol), 2,6-di-tert-butyl-4-methylpyridine (796 mg, 3.87 mmol)) and tetraethylammonium nitrate (596 mg, 3.1 mmol)) in dichloromethane (15 mL) was cooled to -70°C and maintained at this temperature with stirring while a solution of triflic anhydride (51 1 ί, 3.1 mmol)) in dichloromethane (5 mL) was added dropwise. On completion of the addition, the 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.
Ή NMR (300 MHz, CDC13) δ 5.12 (d, J = 2.5, 1H), 2.10 - 1.83 (m, 2H), 1.78 - 1.23 (m, 7H), 1.02 (d, J = 7.0, 3H).
Example 13
Preparation of (lR,2S,5R)-2-isopropyl-5-methylcyclohexyl nitrate (compound 11a) by using tetraethylammonium nitrate
A dry 50 mL round bottom flask containing (-) - Menthol (300 mg, 156.27 mg/mmol, 1.92 mmol), 2,6-di-tert-butyl-4-methylpyridine (591 mg, 205.35 mg/mmoli, 2.88 mmol) and tetraethylammonium nitrate (442 mg, 192.26 mg/mmol 2.3 mmol) in dichloromethane (18 mL) was cooled to -70°C and maintained at this temperature with stirring while a solution of triflic anhydride (380 μί, 282.14 mg/mmol, d=1.71 g/mL 2.3 mmol) in dichloromethane (6 mL) was added drop wise. On completion of the addition, the 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 H2O. 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 6 CV, at 10% for 3 CV (percentage of EtOAc), to give 243 mg of (lR,2S,5R)-2-isopropyl-5- methylcyclohexyl nitrate, yield: 63%. Purity higher than 99%, determined by HPLC. Ή NMR (300 MHz, CDC13) δ 4.89 (td, J = 1 1.0, 4.3, 1H), 2.22 - 2.10 (m, 1H), 2.10 - 1.94 (m, 1H), 1.87 - 1.65 (m, 2H), 1.66 - 1.40 (m, 2H), 1.26 - 1.02 (m, 2H), 1.02 - 0.87 (m, 7H), 0.84 (t, J = 5.0, 3H).
Example 14
Preparation of (lR,2S,5R)-2-isopropyl-5-methylcyclohexyl nitrate
(compound 11a) by using tetrabutylammonium nitrate
A dry 50 mL round bottom flask containing (-)-Menthol (300 mg, 156.27 mg/mmol, 1.92 mmol), 2,6-di-tert-butyl-4-methylpyridine (591 mg, 205.35 mg/mmoli, 2.88 mmol) and Bu4NNO3, (700 mg, 304.48 mg/mmol, 2.3 mmol) in dichloromethane (18 mL) was cooled to -70°C and maintained at this temperature with stirring while a solution of triflic anhydride (380 μL·, 282.14 mg/mmol, d=1.71 g/mL 2.3 mmol) in dichloromethane (6 mL) was added dropwise. On completion of the addition, the 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 H2O. 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%.
Ή NMR (300 MHz, CDC13) δ 4.89 (td, J = 1 1.0, 4.3, 1H), 2.22 - 2.10
(m, 1H), 2.10 - 1.94 (m, 1H), 1.87 - 1.65 (m, 2H), 1.66 - 1.40 (m, 2H), 1.26 - 1.02 (m, 2H), 1.02 - 0.87 (m, 7H), 0.84 (t, J = 5.0, 3H). Purity higher than 99%, determined by HPLC.
Example 15
Preparation of (lS,2S,5R)-2-isopropyI-5-methyIcyclohexyl nitrate nome chimico (Compound 12a)
A dry 50 mL round bottom flask containing (+)-Neomenthol (260 μί, 156.27 mg/mmol, d=0.899 g/mL, 1.5 mmol), 2,6-di-tert-butyl-4-methylpyridine (462 mg, 205.35 mg/mmol, 2.25 mmol) and tetraethylammonium nitrate (346 mg, 192.26 mg/mmol, 1.8 mmol) in dichloromethane ( 18 mL) was cooled to -70°C and maintained at this temperature with stirring while a solution of triflic anhydride (300 μί, 282.14 mg/mmol, d=1.71 g/mL 1.8 mmol) in dichloromethane (6 mL) was added drop wise. On completion of the addition, the 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 H2O. 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%.
Purity higher than 99.9%, determined by HPLC. lH NMR (300 MHz, CDC13) δ 5.39 (d, J = 2.4, 1H), 2.12 (ddd, J = 14.7, 5.9, 3.5, 1H), 1.91 - 1.58 (m, 4H), 1.32 - 1.07 (m, 3H), 1.04 - 0.83 (m, 10H).
Example 16
Preparation of (lR,2S,5R)-2-isopropyl-5-methylcyclohexyI nitrate (compound 11a)
A dry 100 mL round bottom flask containing (-)-Menthol (500 mg, 156.27 mg/mmol, 3.2 mmol), base 2,6-Lutidine (559 μΐ,, 107.16 mg/mmol, d=0.92, 4.8 mmol) and tetraethylammonium nitrate (442 mg, 192.26 mg/mmol 3.84 mmol) in dichloromethane (30 mL) was cooled to -70°C and maintained at this temperature with stirring while a solution of triflic anhydride (634 μί, 282.14 mg/mmol, d=1 .71 g/mL 3.84 mmol) in dichloromethane ( 10 mL) was added dropwise. On completion of the addition, the 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 H2O. 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.
!H NMR (300 MHz, CDC13) δ 4.89 (td, J = 1 1.0, 4.3, 1H), 2.22 - 2.10
(m, 1H), 2.10 - 1.94 (m, 1H), 1.87 - 1.65 (m, 2H), 1.66 - 1.40 (m, 2H), 1.26 - 1.02 (m, 2H), 1.02 - 0.87 (m, 7H), 0.84 (t, J= 5.0, 3H).
Example 17
Preparation of (lR,2S,5R)-2-isopropyl-5-methylcyclohexyl nitrate (compound 11a)
A dry 100 mL round bottom flask containing (-)-Menthol (500 mg, 156.27 mg/mmol, 3.2 mmol), Sym Collidine (636 121.18 mg/mmol, d=0.914, 4.8 mmol) and tetraethylammonium nitrate (442 mg, 192.26 mg/mmol 3.84 mmol) in dichloromethane (30 mL) was cooled to -70°C and maintained at this temperature with stirring while a solution of triflic anhydride (634 iL, 282.14 mg/mmol, d=1.71 g/mL 3.84 mmol) in dichloromethane (10 mL) was added dropwise. On completion of the addition, the 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 H2O. 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.
1H NMR (300 MHz, CDC13) 5 4.89 (td, J = 1 1.0, 4.3, 1H), 2.22 - 2.10
(m, 1H), 2.10 - 1.94 (m, 1H), 1.87 - 1.65 (m, 2H), 1.66 - 1.40 (m, 2H), 1.26 - 1.02 (m, 2H), 1.02 - 0.87 (m, 7H), 0.84 (t, J = 5.0, 3H).
The yield of the nitrate esters of examples 1 1-15 are summarized in Table 2. The results show that nitrate esters were obtained with high yields and that the process mainly leads to nitration of the secondary alcohols with complete retention of configuration.
Figure imgf000021_0001
Nitration of primary or secondary alcohols to obtain I5N-nitrates derivatives in the presence of protecting groups
Example 18
Synthesis of Bu4N15N03
To a stirred solution of Ag15NO3 (4000 mg, 170.87 mg/mmol,
23.4 mmol) in CH3CN (150 mL), Bu4NCl (6500 mg, 277.93 mg/mmol, 23.4 mmol) was added and the mixture stirred at room temperature for 2 hours. The precipitate was filtrated and the residue concentrated to obtain 6844 mg of white solid, yield: 96%.
Example 19
Synthesis of Et4N15N03
To a stirred solution of Ag15NO3 (1.70 g, 10 mmol) in CH3CN (30 mL), Et4NBr (2.1 g, 10 mmol) was added and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (30 mL) was then added, the precipitate was filtrated and the residue concentrated to obtain 1.81 g of the desired compound as a white solid, yield: 94%.
Example 20
Preparation of 4-(15N-nitroxy)butyl 4-nitrobenzoate (compound
13a)
A dry 100 mL round bottom flask containing 4-hydroxybutyl
4-nitrobenzoate ( 1.77 g, 7.4 mmol), 2,6-di-tert-butyl-4-methylpyridine (1.67 g, 8.14 mmol, 1.1 eq) and tetrabutylammonium 15N-nitrate (1.5 g, 7.76 mmol, 1.05 eq) in dry dichloromethane (40 mL) was cooled to -70°C and maintained at this temperature with stirring while a solution of triflic anhydride (1.28 mL, 7.76 mmol, 1.05 eq) in dichloromethane (5 mL) was added dropwise. 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. The filtrate was evaporated in vacuo and 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 70/30 during 12 CV) gave compound as a yellow solid (1.90 g, 90%).
!H NMR (300 MHz, CDC13) δ 8.33 - 8.24 (m, 2H), 8.24 - 8.15 (m, 2H), 4.59 - 4.49 (m, 2H), 4.43 (t, J = 5.9, 2H), 2.02 - 1.85 (m, 4H).
Preparation of 4-hydroxybutyl 15N-nitrate
To a stirred solution of compound 13a (1.9 g, 6.66 mmol) in a 1/1 mixture of tetrahydrofuran / ethanol (30 mL) cooled to 0°C was added a 1M solution of NaOH (10 mL, 1.5 eq) and the reaction was stirred at this temperature for 2 h. The reaction was diluted with water and ethyl acetate and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient n-hexane/ethyl acetate 70/30 to n-hexane/ethyl acetate 50/50 during 10 CV) to give compound 13b as a colorless oil (0.72 g, 79%).
1H NMR (300 MHz, CDC13) δ 4.51 (td, J = 6.5, 2.8, 2H), 3.71 (dd, J = 1 1.2, 6.1, 2H), 1.90-1.80 (m, 2H), 1.75 - 1.62 (m, 2H), 1.30 (bs, 1H).
Example 21
Preparation of (5S)-5,6-bis(15N-nitrooxy)hexyl benzoate (compound 14a)
A dry 50 mL round bottom flask containing (5S)-5,6-dihydroxyhexyl 4- nitrobenzoate (0.566 g, 2.0 mmol, e.e.= 95%), 2,6-di-tert-butyl-4- methylpyridine (0.904 g, 4.4 mmol, 2.2 eq) and tetraethylammonium 15N-nitrate (0.8 g, 4.2 mmol, 2.1 eq) in dry dichloromethane (20 mL) was cooled to -70°C and maintained at this temperature with stirring while a solution of triflic anhydride (0.66 mL, 4.0 mmol, 1.0 eq) in dichloromethane (5 mL) was added dropwise. The 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. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient n-hexane/ethyl acetate 85/15 to n-hexane/ethyl acetate 75/25 during 10 CV) gave compound 14 a as a colorless oil (0.604 g, 85%, e.e.= 95%).
1H NMR (300 MHz, CDC13) δ 8.32 (d, J = 8.6, 2H), 8.22 (d, J = 8.6, 2H), 5.33 (m, 1H), 4.78 (dd, J = 12.9, 2.7, 1H), 4.59 - 4.48 (m, 1H), 4.42 (t, J = 6.3, 2H), 1.96 - 1.78 (m, 4H), 1.76 - 1.58 (m, 2H).
Preparation of (2S)-6-hydroxy-2-(1 N-nitrooxy)hexyl 15N-nitrate
To a stirred solution of compound 14a (0.604 g, 1.61 mmol) in a mixture of tetrahydrofuran / ethanol (10 mL /3 mL) cooled to 0°C was added a 2M solution of NaOH (1.05 mL, 1.3 eq) and the reaction was stirred at this temperature for 2 h. The reaction was diluted with water and ethyl acetate and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient n-hexane/ethyl acetate 60/40 to n-hexane/ethyl acetate 40/60 during 10 CV) to give compound 14b as a colorless oil (0.276 g, 76%).
1H NMR (300 MHz, CDC13) 5 5.38 - 5.23 (m, 1H), 4.77 (d, J = 12.9, 1H), 4.56 - 4.42 (m, 1H), 3.69 (t, J = 5.6, 2H), 1.89 - 1.72 (m, 2H), 1.72 (m, 5H). Example 22
Preparation of tert-butyl 2-(15N-nitrooxy)ethyIcarbamate (compound 15a)
A dry 50 mL round bottom flask containing tert-butyl 2-hydroxyethylcarbamate (0.8 g, 5.0 mmol), 2,6-di-tert-butyl-4- methylpyridine (1.15 g, 5.5 mmol, 1.1 eq) and tetraethylammonium 15N-nitrate (0.96 g, 5.25 mmol, 1.05 eq) in dry dichloromethane (20 mL) was cooled to -70°C and maintained at this temperature with stirring while a solution of triflic anhydride (0.86 mL, 5.5 mmol, 1.1 eq) in dichloromethane (5 mL) was added dropwise. 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 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%).
Ή NMR (300 MHz, CDC13) δ 4.80 (bs, 1H, NH), 4.53 (m, 2H), 3.48 (dd, J = 10.6, 5.3, 2H), 1.45 (s, 9H).
Preparation of 2-aminoethyl 15N-nitrate hydrochloride
To a solution of tert-butyl 2-(15N-nitrooxy)ethylcarbamate (0.270 g, 1.31 mmol) in dry dichloromethane cooled to 0°C was added a 4M solution of hydrochloric acid in dioxane (0.66 mL, 2 eq). After 16 h at room temperature, diethylether was added and the precipitate was collected. The title compound was isolated as a white solid (0.164 g, 89%).
1H NMR (300 MHz, DMSO) δ 8.36 (bs, 3H), 4.75 (dd, J = 8.2, 5.2, 2H), 3.16 (t, J = 5.2, 2H).
The yield of the 15N-nitrate esters of examples 20-22 are summarized in Table 3. The results show that nitrate esters were obtained with high yields and that the process allowed to obtain the nitration of secondary alcohols with complete retention of configuration and is compatible with sensitive protecting groups.
Figure imgf000026_0001

Claims

1. A process for the preparation of nitrate esters or 15N isotopically labeled nitrate esters of formula (I)
R-[Y]n-ONO2
(I)
wherein
n is 0 or 1 ;
Y is selected from:
- a straight or branched alkyl chain having 1 to 10 carbon atoms; or
- a group of formula:
- Y (X)-Y2- wherein each of Yi or Y2 independently is a straight or branched alkyl chain having 1 to 5 carbon atoms and X is -O-CO-, -CO-0-,-Ο-, -NH-, -NH- CO- or -CO-NH-;
R is selected from:
- P-O- or P-NH- wherein P is a protecting group;
- an aryl group 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,
- 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,
- a 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 is 1 when R is an aryl group;
said process comprises:
(a) reacting an alcohol of formula (II)
R-[Y]n-OH (II)
wherein n, Y and R are as above defined, with
- an organic base selected from: 2,6-di-tert-butyl-4-methylpyridine, sym-collidine, 2,6-lutidine, pyridine or triethylamine, and
- a nitrated salt selected from tetramethylammonium nitrate, tetraethylammonium nitrate, tetrabutylammonium nitrate,
15N- tetraethylammonium nitrate or 15N-tetrabutylammonium nitrate,
in an organic solvent selected from dichloromethane, acetonitrile, tetrahydrofurane, at a temperature from -70°C to - 20°C,
(b) treating the obtained mixture with triflic anhydride at a temperature from -70°C to room temperature;
(c) optionally removing protecting groups
2. A process according to claim 1 wherein R is selected from: - an aryl group 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,
- 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,
- a 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 is 1 when is an aryl group;
3. A process according to claim 1 or 2 wherein
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.
4. A process according to claim 1-3 wherein the organic base is 2,6-ditert- butyl-4-methylpyridine, the nitrate salt is tetraethylammonium nitrate and the solvent is dichloromethane.
5. A process according to any of claims 1-4 wherein R is selected from:
- an aryl group selected from phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl;.
- a cycloalkyl group selected from cyclopentyl or cyclohexyl;
- a bridged cycloalkyl selected from adamantyl, decahydronapthyl, quinuclidyl, 2,6-dioxabicyclo(3,3,0)octane, 7-oxabicyclo(2,2, l ) heptyi, 8- azabicyclo(3,2, l)oct-2-enyl.
6. A process according to any of claims 1 -4 wherein the alcohol of formula (II) is (S)-4-hydroxybutyl-2-(6-methoxynaphtalen-2yl) propanoate.
7. A process according to claim 1 wherein the alcohol of formula (II) is 4- hydroxybutyl 4-nitrobenzoate
- the organic base is 2,6-di-tert-butyl-4-methylpyridine and
- the nitrated salt is tetrabutylammonium 15N-nitrate.
8. The process according to claim 7 further comprising the step of removing the hydroxyl protecting group.
9. A process according to claim 1 wherein the alcohol of formula (II) is tert-butyl 2-hydroxyethylcarbamate (0.8 g, 5.0 mmol),
- the organic base is 2,6-di-tert-butyl-4-methylpyridine and
- the nitrated salt is tetraethylammonium 15N-nitrate.
10. The process according to claim 9 further comprising the step of removing the amino protecting group.
1 1. A process according to claim 1 wherein the alcohol of formula (II) is (5S)-5,6-dihydroxyhexyl 4-nitrobenzoate,
- the organic base is 2,6-di-tert-butyl-4-methylpyridine and
- the nitrated salt is tetraethylammonium 15N-nitrate.
12. The process according to claim 1 1 further comprising the step of removing the hydroxyl protecting group.
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CN115043731A (en) * 2022-05-20 2022-09-13 上海大学 3-halogenated-butyl-3-alkene-1-nitrate compound and preparation method thereof
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CN114436846A (en) * 2022-01-12 2022-05-06 上海师范大学 A kind of nitrate group transfer reagent and its preparation method and application
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