WO1997017327A1 - Hydrogen peroxide oxidation of 4-hydroxy-2,2,6,6-tetramethylpiperidine and of a 4-acylamino-2,2,6,6-tetramethylpiperidine - Google Patents

Hydrogen peroxide oxidation of 4-hydroxy-2,2,6,6-tetramethylpiperidine and of a 4-acylamino-2,2,6,6-tetramethylpiperidine Download PDF

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WO1997017327A1
WO1997017327A1 PCT/EP1996/004692 EP9604692W WO9717327A1 WO 1997017327 A1 WO1997017327 A1 WO 1997017327A1 EP 9604692 W EP9604692 W EP 9604692W WO 9717327 A1 WO9717327 A1 WO 9717327A1
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Prior art keywords
tetramethylpiperidine
hydrogen peroxide
hydroxy
oxyl
acylamino
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PCT/EP1996/004692
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French (fr)
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Stephen Daniel Pastor
Andrea R. Smith
Kurt Michael Bessonen
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Ciba Specialty Chemicals Holding Inc.
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Priority claimed from US08/555,823 external-priority patent/US5629426A/en
Priority claimed from US08/555,822 external-priority patent/US5654434A/en
Application filed by Ciba Specialty Chemicals Holding Inc. filed Critical Ciba Specialty Chemicals Holding Inc.
Priority to AU74948/96A priority Critical patent/AU7494896A/en
Publication of WO1997017327A1 publication Critical patent/WO1997017327A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide

Definitions

  • the instant invention pertains to the hydrogen peroxide oxidation of 4-hydroxy-2,2,6,6-tetra- methylpiperidine and of a 4-acy.amino-2,2,6,6-tetramethylpiperidine to the corresponding 4- hydroxy-2,2,6,6-tetrarnethylpiperidine-N-oxyl and 4-acylarnino-2,2,6,6-tetramethylpiperidine- N-oxyl compound using hydrogen peroxide in the absence of any catalyst or with an ammonium or alkali metal carbonate or bicarbonate catalyst.
  • 2,2,6,6-Tetramethylpiperidine and its derivatives are important spin traps for labelling biological molecules. This is illustrated in a number of reviews as follows: J. F. W. Keana, Chemical Reviews, 78, 37 (1978); M. Dagonneau et al., Synthesis, 1984. 895; E. G. Rozantsev et al., Synthesis 1971. 401 ; and E. G. Rozantsev et al., Synthesis, 1971. 190.
  • Such compounds are also disclosed as inhibitors for preventing the premature polymerization of vinyl monomers as seen in United States Patent No. 5,254,760.
  • the instant process differs from that of the Zakrzewski process by using none or only catalytic amounts of carbonate or bicarbonate rather than the large molar excess amount used by Zakrzewski; by running the reaction at elevated temperatures rather than at room temperature; and by achieving very high yields and conversions of product (up to 99%) in a relatively short period of time (hours) rather than the two days needed for the Zakrzewski process.
  • the instant invention pertains to a process for the preparation of 4-hydroxy-2,2,6,6-tetra- methylpiperidine-N-oxyl or a 4-acylamino-2.2,6,6-tetramethylpiperidine-N-oxyl which comprises oxidizing 4-hydroxy-2,2,6,6-tetramethylpiperidine or a 4-acylamino-2,2,6,6-tetramethyl- piperidine with an aqueous hydrogen peroxide solution a) in the absence of any catalyst at a temperature range of 80-99° C or b) in the presence of a catalytic amount of an ammonium or alkali metal carbonate or bicarbonate at a temperature range of 60-99°C
  • One preferred embodiment of the invention is a process for the preparation of a 4-acyl- amino-2,2,6,6-tetramethylpiperidine-N-oxyl which comprises oxidizing a 4-acylaminc-2.2 I 6 I 6-tetramethylpiperidine with an aqueous hydrogen peroxide solution in the
  • Another preferred embodiment is a process for the preparation of 4-hydroxy-2,2,6,6-tetra- methylpiperidine-N-oxyl which comprises oxidizing 4-hydroxy-2,2,6,6-tetramethylpiperidine with an aqueous hydrogen peroxide solution in the presence of a catalytic amount of an ammonium or alkali metal carbonate or bicarbonate at a temperature range of 60-99°C.
  • Also preferred is a process for the preparation of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N- oxyl or of a 4-acylamino-2,2,6,6-tetramethylpiperidine-N-oxyl which comprises oxidizing 4-hydroxy-2,2,6,6-tetramethylpiperidine or a 4-acylamino-2,2,6,6-tetramethyl- piperidine with an aqueous hydrogen peroxide solution in the absence of any catalyst at a temperature range of 80-99°C.
  • the aqueous hydrogen peroxide is 30-50 % by weight hydrogen peroxide; most preferably 50 % by weight hydrogen peroxide.
  • alkali metal salts including cesium and rubidium, preferably the alkali metal is sodium, potassium or lithium, most preferably sodium.
  • catalysts found useful in the instant process are sodium carbonate, lithium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate and ammonium carbonate.
  • the preferred amount of catalyst is from 0.05 to 0.3 mole % of catalyst based on the starting 4-hydroxy-2,2,6,6-tetramethylpiperidine or 4-acylamino-2,2,6,6-tetramethyl- piperidine.
  • a preferred temperature range for the process is 80-95° C for the oxidation of a 4-acyl- amino-2,2,6,6-tetramethylpiperidine and 85-95° C for the oxidation of 4-hydroxy-2,2,6,6- tetramethylpiperidine when a catalyst is present.
  • the oxidation is run most preferably at a temperature of 90-99°C.
  • a preferred embodiment of the process involves adding the hydrogen peroxide continuously over a 2-4 hour period to the reaction mixture.
  • the acyl group is the monoacyl radical obtained by removal of the OH from a monocar- boxilic aliphatic, cycloaliphatic, aryl or aralkanoic acid. Since the starting compound should most conveniently be soluble in water, clearly the lower alkanoic C ⁇ -C 6 acyl groups such as for example acetyl or propionyl are preferred. Since the acyl group is not involved in this oxidation reaction, its exact nature is not critical to the instant process.
  • acylamino is acetamido
  • the instant process may optionally have a metal passivator or chelator present.
  • the EDTA type chelators such as ethylenediaminetetraacetic acid disodium salt are particularly suited since they remove trace amounts of iron or other metals encountered during manufacturing processes without interfering with the catalyst system. Iron or other metals may decompose the hydrogen peroxide unless removed by such a chelator.
  • Any excess hydrogen peroxide may be destroyed using catalytic quantities of platinum or palladium on charcoal.
  • any excess hydrogen peroxide may be destroyed facilely by the addition of sodium sulfite at an elevated pH (using sodium hydroxide) followed by the addition of acid for neutralization.
  • the N-oxyl compound may be isolated by using rotary evaporation of the water solvent under vacuum or other conventional means.
  • the oxidation of the starting material to the corresponding N-oxyl using hydrogen peroxide proceeds without a catalyst, but is perceptibly slower than with a catalyst.
  • the advantages of the instant process besides the clear environmental benefits, are a slightly better conversion with time and a quicker initiation of the oxidation reaction.
  • the initiation of the reaction without catalyst is variable, leading to different levels of hydrogen peroxide built up in the reaction mixture. This can result in a strong exotherm at the initiation of the reaction which may cause difficulty in any scaled-up reaction.
  • This is overcome by use of the instant catalyst which leads to a quicker onset of reaction, a somewhat higher conversion and a more reproducible and convenient process.
  • Example 7 When the procedure of Example 7 is repeated using 1.5 equivalents of 50 % aqueous hydrogen peroxide at 80°C, the conversion to the desired N-oxyl product after seven hours is 97.1 % as determined by GLC.
  • Example 7 When the procedure of Example 7 is repeated using 2 equivalents of 50 % hydrogen peroxide at 80°C without any EDTA disodium salt passivator or chelator present, the conversion to the desired N-oxyl product after seven hours is 99.4 % as determined by GLC.
  • the N-oxyl compound is obtained in a conversion of 99.8 % as determined by GLC analysis.
  • Example 10 When the sodium carbonate catalyst used in Example 10 is replaced with an equivalent amount of cesium carbonate, the N-oxyl title compound is obtained in a conversion of 99.5% as determined by GLC analysis.

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  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

An environmentally friendly process is described for the preparation of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl or of a 4-acylamino-2,2,6,6-tetramethylpiperidine-N-oxyl by the carbonate-mediated hydrogen peroxide oxidation of 4-hydroxy-2,2,6,6-tetramethylpiperidine or of a 4-acylamino-2,2,6,6-tetramethylpiperidine. The reaction can also be run in the absence of any catalyst.

Description

Hydrogen Peroxide Oxidation of 4-Hvdroxy-2.2.6.6-Tetramethylpiperidine and of a 4-
Acylamino-2.2.6.6-Tetramethylpiperidine
The instant invention pertains to the hydrogen peroxide oxidation of 4-hydroxy-2,2,6,6-tetra- methylpiperidine and of a 4-acy.amino-2,2,6,6-tetramethylpiperidine to the corresponding 4- hydroxy-2,2,6,6-tetrarnethylpiperidine-N-oxyl and 4-acylarnino-2,2,6,6-tetramethylpiperidine- N-oxyl compound using hydrogen peroxide in the absence of any catalyst or with an ammonium or alkali metal carbonate or bicarbonate catalyst.
Background of the Invention
2,2,6,6-Tetramethylpiperidine and its derivatives are important spin traps for labelling biological molecules. This is illustrated in a number of reviews as follows: J. F. W. Keana, Chemical Reviews, 78, 37 (1978); M. Dagonneau et al., Synthesis, 1984. 895; E. G. Rozantsev et al., Synthesis 1971. 401 ; and E. G. Rozantsev et al., Synthesis, 1971. 190.
Such compounds are also disclosed as inhibitors for preventing the premature polymerization of vinyl monomers as seen in United States Patent No. 5,254,760.
The oxidation of 4-subst'rtuted 2,2,6,6-tetramethylpiperidines to the corresponding N-oxyl derivatives is known to occur by a number of different processes. United States Patent No. 4,665,185 describes using tert-butyl hydroperoxide with transition metal catalysts. G. Sosnovsky et al., Z. Naturforsch. 21tj, 1376 (1976); J. Zakrzewski, J. Prakt. Chem., 32Z, 101 1 (1985) and E. G. Rozantsev et al., Synthesis, 1971. 190 each teach the use of hydrogen peroxide with sodium tungstate catalyst. United States Patent No. 5,416,215 teaches the use of hydrogen and selected divalent metal salts. M. E. Brik, Tetrahedron Letters, 26, 5519 (1995) teaches the oxidation of secondary amines to nitroxides using Oxone® (potassium peroxomonosulfate) in aqueous buffered solutions.
E. J. Rauckman et al., Syn. Communications 5(6), 409 (1975) describe inter alia the oxidation of secondary amines to nitroxides using catalytic amounts of sodium tungstate in the presence of acetonitrile, methanol, hydrogen peroxide and sodium bicarbonate at room temperature for two days to give the oxyl compound in a yield of 85%. The required presence of the known sodium tungstate catalyst clearly differentiates the Rauckman process from the instant process where no sodium tungstate is present.
J. Zakrzewski, J. prakt. Chem., 22Z(6), 1011 (1985) does teach that 30% hydrogen peroxide in the presence of sodium carbonate gives the oxyl compound in a yield of 73%. The Zakrzewski reaction is run at room temperature (there is an exotherm requiring system cooling) and uses a large (three molar) excess of sodium carbonate for a two-day period. This large excess of sodium carbonate is clearly not a catalytic amount.
The instant process differs from that of the Zakrzewski process by using none or only catalytic amounts of carbonate or bicarbonate rather than the large molar excess amount used by Zakrzewski; by running the reaction at elevated temperatures rather than at room temperature; and by achieving very high yields and conversions of product (up to 99%) in a relatively short period of time (hours) rather than the two days needed for the Zakrzewski process.
It is clear that the instant process involves the use of an environmentally safe and friendly catalyst and avoids the presence of transition metals in waste waters. Sodium bicarbonate and sodium carbonate are easily handled, are economically inexpensive and cause no adverse environmental conditions. The instant process also gives the desired N-oxyl compounds in high yields and conversions without the use for costly and environmentally hazardous transition metals or divalent metal ions.
Detailed Disclosure
The instant invention pertains to a process for the preparation of 4-hydroxy-2,2,6,6-tetra- methylpiperidine-N-oxyl or a 4-acylamino-2.2,6,6-tetramethylpiperidine-N-oxyl which comprises oxidizing 4-hydroxy-2,2,6,6-tetramethylpiperidine or a 4-acylamino-2,2,6,6-tetramethyl- piperidine with an aqueous hydrogen peroxide solution a) in the absence of any catalyst at a temperature range of 80-99° C or b) in the presence of a catalytic amount of an ammonium or alkali metal carbonate or bicarbonate at a temperature range of 60-99°C One preferred embodiment of the invention is a process for the preparation of a 4-acyl- amino-2,2,6,6-tetramethylpiperidine-N-oxyl which comprises oxidizing a 4-acylaminc-2.2I6I6-tetramethylpiperidine with an aqueous hydrogen peroxide solution in the presence of a catalytic amount of an ammonium or alkali metal carbonate or bicarbonate at a temperature range of 70-99° C.
Another preferred embodiment is a process for the preparation of 4-hydroxy-2,2,6,6-tetra- methylpiperidine-N-oxyl which comprises oxidizing 4-hydroxy-2,2,6,6-tetramethylpiperidine with an aqueous hydrogen peroxide solution in the presence of a catalytic amount of an ammonium or alkali metal carbonate or bicarbonate at a temperature range of 60-99°C.
Also preferred is a process for the preparation of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N- oxyl or of a 4-acylamino-2,2,6,6-tetramethylpiperidine-N-oxyl which comprises oxidizing 4-hydroxy-2,2,6,6-tetramethylpiperidine or a 4-acylamino-2,2,6,6-tetramethyl- piperidine with an aqueous hydrogen peroxide solution in the absence of any catalyst at a temperature range of 80-99°C.
Preferably the aqueous hydrogen peroxide is 30-50 % by weight hydrogen peroxide; most preferably 50 % by weight hydrogen peroxide.
While any of the alkali metal salts may be used including cesium and rubidium, preferably the alkali metal is sodium, potassium or lithium, most preferably sodium.
Specific catalysts found useful in the instant process are sodium carbonate, lithium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate and ammonium carbonate.
The preferred amount of catalyst is from 0.05 to 0.3 mole % of catalyst based on the starting 4-hydroxy-2,2,6,6-tetramethylpiperidine or 4-acylamino-2,2,6,6-tetramethyl- piperidine. A preferred temperature range for the process is 80-95° C for the oxidation of a 4-acyl- amino-2,2,6,6-tetramethylpiperidine and 85-95° C for the oxidation of 4-hydroxy-2,2,6,6- tetramethylpiperidine when a catalyst is present.
Suφrisingly in view of the formidable prior art touting the need for exotic catalysts for this reaction to take place, the oxidation to the N-oxyl compound also occurs in good yield and conversion without any catalyst at all.
When no catalyst is used, the oxidation is run most preferably at a temperature of 90-99°C.
A preferred embodiment of the process involves adding the hydrogen peroxide continuously over a 2-4 hour period to the reaction mixture.
The acyl group is the monoacyl radical obtained by removal of the OH from a monocar- boxilic aliphatic, cycloaliphatic, aryl or aralkanoic acid. Since the starting compound should most conveniently be soluble in water, clearly the lower alkanoic Cι-C6acyl groups such as for example acetyl or propionyl are preferred. Since the acyl group is not involved in this oxidation reaction, its exact nature is not critical to the instant process.
Most preferred is a process, wherein acylamino is acetamido.
The instant process may optionally have a metal passivator or chelator present. The EDTA type chelators such as ethylenediaminetetraacetic acid disodium salt are particularly suited since they remove trace amounts of iron or other metals encountered during manufacturing processes without interfering with the catalyst system. Iron or other metals may decompose the hydrogen peroxide unless removed by such a chelator.
The course of the reaction is monitored by GLC (Gas Liquid Chromatography) to determine the conversion of the N-H to N-oxyl compound. In theory 1.5 equivalents of hydrogen peroxide are needed to oxidize one equivalent of the starting material to the corresponding N-oxyl compound. Preferred is an amount of aqueous hydrogen peroxide from 1.5 to 2 equivalents per equivalent of a 4-acylamino-2,2,6.6-tetramethylpiperidine or 4-hydroxy-2,2,6,6-tetramethyl- piperidine, when a catalyst is used and 1 ,5 to 4 equivalents in the absence of any catalyst.
Any excess hydrogen peroxide may be destroyed using catalytic quantities of platinum or palladium on charcoal.
Alternatively, any excess hydrogen peroxide may be destroyed facilely by the addition of sodium sulfite at an elevated pH (using sodium hydroxide) followed by the addition of acid for neutralization.
The N-oxyl compound may be isolated by using rotary evaporation of the water solvent under vacuum or other conventional means.
The oxidation of the starting material to the corresponding N-oxyl using hydrogen peroxide proceeds without a catalyst, but is perceptibly slower than with a catalyst. The advantages of the instant process, besides the clear environmental benefits, are a slightly better conversion with time and a quicker initiation of the oxidation reaction. The initiation of the reaction without catalyst is variable, leading to different levels of hydrogen peroxide built up in the reaction mixture. This can result in a strong exotherm at the initiation of the reaction which may cause difficulty in any scaled-up reaction. This is overcome by use of the instant catalyst which leads to a quicker onset of reaction, a somewhat higher conversion and a more reproducible and convenient process.
The following examples are for illustrative purposes.
Example 1
4-Acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl
To a solution of 14.95 g (0.08 mol) of 4-acetamido-2,2,6,6-tetramethylpiperidine, 0.08 g (0.2 mmol) of ethylenediaminetetraacetic acid disodium salt dihydrate and 0.01 g (0.1 mmol) of ammonium carbonate in 10 g of deionized water at 92°C. is added over a one-hour period using a syringe pump 24 ml (0.392 mol) of 50% hydrogen peroxide. The reaction mixture is stirred for 18 hours. The conversion to 4-acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl is 97.5% as determined by GLC analysis. Example 2
4-Acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl
A solution of 15.15 g (0.08 mol) of 4-acetamido-2,2,6,6-tetramethylpiperidine, 0.08 g (0.2 mmol) of ethylenediaminetetraacetic acid disodium salt dihydrate and 0.01 g (0.094 mmol) of anhydrous sodium carbonate in 10 ml of distilled water is heated to 90°C. To the resultant mixture is added over a two-hour period using a syringe pump 24 ml (0.392 mol) of 50% hydrogen peroxide. Upon completion of the slow addition of the hydrogen peroxide, the conversion to 4-acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl is 99.2% as determined by GLC analysis.
Example 3
4-Acetamido-2,2,6,6-tetramethyipiperidine-N-oxyl
A solution of 15.19 g (0.08 mol) of 4-acetamido-2,2,6,6-tetramethylpiperidine, 0.08 g (0.2 mmol) of ethylenediaminetetraacetic acid disodium salt dihydrate and 0.01 g (1.19 mmol) of sodium bicarbonate in 10 ml of distilled water is heated to 90°C. To the resultant mixture is added over a one-hour period using a syringe pump 24 ml (0.392 mol) of 50% hydrogen peroxide. The conversion to 4-acetamidc-2,2,6,6-tetramethylpiperidine-N-oxyl is 96.8% as determined by GLC analysis.
Example 4
4-Acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl
A solution of 15.03 g (0.08 mol) of 4-acetamido-2,2,6,6-tetramethylpiperidine and 0.08 g (0.2 mmol) of ethylenediaminetetraacetic acid disodium salt dihydrate in 10 ml of distilled water is heated to 90°C. To the resultant mixture is added over a one-hour period using a syringe pump 24 ml (0.392 mol) of 50% hydrogen peroxide. The conversion to 4-acetamido- 2,2,6,6-tetramethylpiperidine-N-oxyl is 99.0% as determined by GLC analysis. The results of Examples 1-4 are summarized in table 1. Table 1
Reaction Conc% Percent
Example Temp. °C H?Og Conversion Catalyst
1 92 50 97.5 (NH4)2C03
90 50 99.2 Na2CO3
90 50 96.8 NaHCOa
90 50 99.0 None
Example 5
4-Hydroxy-2.2,6,6-tetramethylpiperidine-N-oxyl
To a solution of 100 g (0.636 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine in 80 g of deionized water at 80°C is added over a four-hour period using a syringe pump 86.4 g (1.27 mol) of 50% hydrogen peroxide. The reaction mixture is stirred for 3 additional hours. The conversion to 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl is 99.4% as determined by GLC analysis.
Example 6
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
A solution of 126.78 g (0.81 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine and 0.74 g (0.002 mol) of ethylenediaminetetraacetic acid disodium salt dihydrate in 100 ml of distilled water is heated to 70°C. To the resultant mixture is added over a two-hour period using a syringe pump 160 ml (2.61 mol) of 50% hydrogen peroxide. The temperature of the reaction mixture is increased to 95-99°C over the first 20 minutes of the addition of the hydrogen peroxide and then the reaction mixture is maintained at that temperature till all the hydrogen peroxide is added. Upon completion of the slow addition of hydrogen peroxide, the conversion to 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl is 99.1% as determined by GLC analysis.
Example 7
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
To a solution of 100 g (0.636 mol) of 4-hydroxy-2,2.6,6-tetramethylpiperidineI 0.29 g of ethylenediaminetetraacetic acid disodium salt dihydrate and 0.14 g (1.3 mmol) of anhydrous sodium carbonate in 80 g of deionized water at 60°C. is added over a four-hour period using a syringe pump 130 g (1.91 mol) of 50% hydrogen peroxide. The reaction mixture is stirred for 18 hours. The conversion to 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl is 99.2% as determined by GLC analysis.
Example 8
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
A solution of 126.17 g (0.80 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine, 0.74 g of ethylenediaminetetraacetic acid disodium salt dihydrate and 0.09 g (1.0 mmol) of anhydrous sodium bicarbonate in 100 ml of distilled water is heated to 70°C. To the resultant mixture is added over a two-hour period using a syringe pump 160 ml (2.61 mol) of 50% hydrogen peroxide. The temperature of the reaction mixture is raised to 95-98°C over the first 25 minutes of the addition of the hydrogen peroxide and then the reaction mixture is maintained at that temperature. Upon completion of the slow addition of the hydrogen peroxide, the conversion to 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl is 99.1% as determined by GLC analysis.
Example 9
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
A solution of 126.91 g (0.81 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine, 0.72 g of ethylenediaminetetraacetic acid disodium salt dihydrate and 0.09 g (1.0 mmol) of lithium carbonate in 100 ml of distilled water is heated to 70°C. To the resultant mixture is added over a two-hour period using a syringe pump 240 ml (2.35 mol) of 30% hydrogen peroxide. The temperature of the reaction mixture is raised to 90-94°C over the first 25 minutes of the addition of the hydrogen peroxide and then the reaction mixture is maintained at that temperature. Upon completion of the slow addition of the hydrogen peroxide, the conversion to 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl is 91.2% as determined by GLC analysis.
Example 10
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
A solution of 126.17 g (0.80 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine, 0.77 g of ethylenediaminetetraacetic acid disodium salt dihydrate and 0.12 g (1.0 mmol) of anhydrous sodium carbonate in 100 ml of distilled water is heated to 70°C. To the resultant mixture is added over a two-hour period using a syringe pump 240 ml (3.92 mol) of 50% hydrogen peroxide. The temperature of the reaction mixture is raised to 95-98°C over the first 25 minutes of the addition of the hydrogen peroxide and then the reaction mixture is maintained at that temperature. Upon completion of the slow addition of the hydrogen peroxide, the conversion to 4-hydroxy-2,2,6.6-tetramethylpiperidine-N-oxyl is 98.8% as determined by GLC analysis.
Example 11
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
A solution of 126.17 g (0.80 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine, 0.77 g of ethylenediaminetetraacetic acid disodium salt dihydrate and 0.12 g (1.0 mmol) of anhydrous sodium carbonate in 100 ml of distilled water is heated to 75°C. To the resultant mixture is added over a five-hour period using a syringe pump 480 ml (4.70 mol) of 30% hydrogen peroxide. The temperature of the reaction mixture is raised to 91 °C over the first 25 minutes of the addition of the hydrogen peroxide and then the reaction mixture is maintained at 85- 90°C. Upon completion of the slow addition of the hydrogen peroxide, the conversion to 4- hydroxy-2.2,6,6-tetramethy.piperidine-N-oxyl is 98.9% as determined by GLC analysis. Example 12
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
A solution of 126.75 g (0.81 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine, 0.73 g of ethylenediaminetetraacetic acid disodium salt dihydrate and 0.12 g (1.0 mmol) of anhydrous sodium carbonate in 100 ml of distilled water is heated to 68°C. To the resultant mixture is added over a six-hour period using a syringe pump 480 ml (4.70 mol) of 30% hydrogen peroxide. The temperature of the reaction mixture is raised to 80°C over the first 20 minutes of the addition of the hydrogen peroxide and then the reaction mixture is maintained at 80°C. Upon completion of the slow addition of the hydrogen peroxide, the conversion to 4- hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl is 90.8% as determined by GLC analysis.
The results of Examples 7-12 are summarized in table 2.
Table 2
Reaction Conc% Percent
Example Temp. °C Conversion Catalyst
60 50 99.2 Na∑COs
8 95-98 50 99.1 NaHCOg
9 95-98 30 91.2 Li2CO3
10 95-98 50 98.8 Na2CO3
11 85-90 30 98.9 Na2CO3
12 80 30 90.8 Na CC3 Example 13
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
When the procedure of Example 7 is repeated using 1.5 equivalents of 50 % aqueous hydrogen peroxide at 80°C, the conversion to the desired N-oxyl product after seven hours is 97.1 % as determined by GLC.
Example 14
4-Hydroxy-2,2,6,6-tetramethylpiperidιne-N-oxyl
When the procedure of Example 7 is repeated using 2 equivalents of 50 % hydrogen peroxide at 80°C without any EDTA disodium salt passivator or chelator present, the conversion to the desired N-oxyl product after seven hours is 99.4 % as determined by GLC.
Example 15
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
When the sodium carbonate catalyst used in Example 10 is replaced with an equivalent amount of potassium carbonate, the N-oxyl compound is obtained in a conversion of 99.8 % as determined by GLC analysis.
Example 16
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
To a solution of 126.34 g (0.80 mol) of 4-hydroxy-2,2,6.6-tetramethylpiperidine, 0.75 g of ethylenediaminetetraacetic acid disodium salt dihydrate (0.002 mol) and 0.10 g (1.0 mmol) of ammonium carbonate in 100 g of deionized water at 70°C. is added over a four-hour period using a syringe pump 160 g (2.61 mol) of 50% hydrogen peroxide. The temperature initially rises to 94°C, but then falls to 87°C. The reaction mixture is stirred overnight at a temperature of 78-87°C. The conversion to 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl is 99.8% as determined by GLC analysis.
Example 17
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
When the sodium carbonate catalyst used in Example 10 is replaced with an equivalent amount of cesium carbonate, the N-oxyl title compound is obtained in a conversion of 99.5% as determined by GLC analysis.
Example 18
4-Hydroxy-2,2,6,6-tetrarnethylpiperidine-N-oxyl
When the sodium carbonate catalyst used in Example 7 is replaced with an equivalent amount of ammonium bicarbonate, the N-oxyl title compound is obtained in excellent conversion.
Example 19
4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl
To a solution of 126.0 g (0.80 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine, 0.37 g of ethylenediaminetetraacetic acid disodium salt dihydrate (0.001 mol) and 0.18 g (1.7 mmol) of sodium carbonate in 100 g of deionized water at 80°C. is added over a three-hour period 110 g (1.62 mol) of 50% hydrogen peroxide. The reaction mixture is held at 80°C for four hours. The residual hydrogen peroxide is reduced by adding 40 g (0.317 mol) of solid sodium sulfite at 70°C and adjusting the pH to about 12 using 50% aqueous sodium hydroxide solution. The product is isolated after neutralization of the mixture with acetic acid and sodium sulfate solution. The yield of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl is 96%. It is clear that the instant process gives the desired N-oxyl compounds in excellent conversion in the presence of an ammonium or alkali metal carbonate or bicarbonate catalyst using hydrogen peroxide or even in the absence of any catalyst at all. This process affords the desired N-oxyl end product without the concomitant undesired heavy metal catalyst waste products which are environmentally hazardous. The by-products of the instant process such as water and the use of simple ammonium or alkali metal carbonate or bicarbonate catalysts do not present any severe pollution problems in waste water streams.

Claims

WHAT IS CLAIMED IS:
1. A process for the preparation of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl or a 4- acylamino-2,2,6,6-tetramethylpiperidine-N-oxyl which comprises oxidizing 4-hydroxy-2,2,6,6-tetramethylpiperidine or a 4-acylamino-2,2,6,6-tetramethyl- piperidine with an aqueous hydrogen peroxide solution a) in the absence of any catalyst at a temperature range of 80-99° C or b) in the presence of a catalytic amount of an ammonium or alkali metal carbonate or bicarbonate at a temperature range of 60-99°C.
2. A process for the preparation of a 4-acylamino-2,2,6,6-tetramethylpiperidine-N-oxyl according to claim 1 which comprises oxidizing a 4-acylamino-2,2,6,6-tetramethylpiperidine with an aqueous hydrogen peroxide solution in the presence of a catalytic amount of an ammonium or alkali metal carbonate or bicarbonate at a temperature range of 70-99° C.
3. A process for the preparation of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl according to claim 1 which comprises oxidizing 4-hydroxy-2,2,6,6-tetramethylpiperidine with an aqueous hydrogen peroxide solution in the presence of a catalytic amount of an ammonium or alkali metal carbonate or bicarbonate at a temperature range of 60-99°C.
4. A process for the preparation of a 4-acylamino-2,2,6,6-tetramethylpiperidine-N-oxyl according to claim 1 which comprises oxidizing a 4-acylamino-2,2,6,6-tetramethylpiperidine with an aqueous hydrogen peroxide solution in the absence of any catalyst at a temperature range of 80-99°C.
5. A process for the preparation of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl according to claim 1 which comprises oxidizing 4-hydroxy-2,2,6,6-tetramethylpiperidine with an aqueous hydrogen peroxide solution in the absence of any catalyst at a temperature range of 80-99°C.
6. A process according to claim 1 wherein the alkali metal is sodium, potassium or lithium.
7. A process according to claim 6 wherein the alkali metal is sodium.
8. A process according to 1 wherein the catalyst is sodium carbonate, lithium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate or ammonium carbonate.
9. A process according to claim 1 wherein the amount of catalyst is from 0.05 to 0.3 mole % of catalyst based on the starting 4-hydroxy-2,2,6,6-tetramethylpiperidine or 4-acylamino- 2,2,6,6-tetramethylpiperidine.
10. A process according to claim 1 wherein the aqueous hydrogen peroxide is 30-50 % by weight hydrogen peroxide.
11. A process according to claim 1 wherein the hydrogen peroxide is added continuously over a 2 to 4 hour-period to the reaction mixture.
12. A process according to claim 1 wherein a metal passivator is additionally present.
13. A process according to claim 12 wherein the metal passivator is ethylenediaminetetra¬ acetic acid disodium salt.
14. A process according to claim 1 wherein the amount of aqueous hydrogen peroxide is from 1.5 to 4 equivalents per equivalent of 4-acylamino-2,2,6,6-tetramethylpiperidine or 4- hydroxy-2,2,6,6-tetramethylpiperidine.
15. A process according to claim 1 , wherein acylamino is acetamido.
PCT/EP1996/004692 1995-11-09 1996-10-29 Hydrogen peroxide oxidation of 4-hydroxy-2,2,6,6-tetramethylpiperidine and of a 4-acylamino-2,2,6,6-tetramethylpiperidine WO1997017327A1 (en)

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US08/555,823 US5629426A (en) 1995-11-09 1995-11-09 Carbonate-mediated hydrogen peroxide oxidations of 4-hydroxy-2,2,6,6-tetramethylpiperidine
US08/555,823 1995-11-09
US08/555,822 US5654434A (en) 1995-11-09 1995-11-09 Hydrogen peroxide oxidation of 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine
US08/555,822 1995-11-09
US1706796P 1996-05-01 1996-05-01
US60/017,067 1996-05-01

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EP1375457A1 (en) * 2002-06-25 2004-01-02 Bayer Aktiengesellschaft One-pot process for the preparation of functionalized alkoxyamines
JP2011219382A (en) * 2010-04-06 2011-11-04 Dai Ichi Kogyo Seiyaku Co Ltd Method for manufacturing n-oxyl compound
JP2011219381A (en) * 2010-04-06 2011-11-04 Dai Ichi Kogyo Seiyaku Co Ltd Method for producing n-oxyl compound
CN108569996A (en) * 2017-12-29 2018-09-25 江苏富比亚化学品有限公司 A kind of synthetic method of high-efficiency polymerization inhibitor 701

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002527425A (en) * 1998-10-13 2002-08-27 チバ スペシャルティ ケミカルズ ホールディング インコーポレーテッド Method for synthesizing 4-substituted N-[(alk-2-en-1-yl) oxy]-and N-aralkyloxy-2,2,6,6-tetraalkylpiperidine
EP1375457A1 (en) * 2002-06-25 2004-01-02 Bayer Aktiengesellschaft One-pot process for the preparation of functionalized alkoxyamines
JP2011219382A (en) * 2010-04-06 2011-11-04 Dai Ichi Kogyo Seiyaku Co Ltd Method for manufacturing n-oxyl compound
JP2011219381A (en) * 2010-04-06 2011-11-04 Dai Ichi Kogyo Seiyaku Co Ltd Method for producing n-oxyl compound
CN108569996A (en) * 2017-12-29 2018-09-25 江苏富比亚化学品有限公司 A kind of synthetic method of high-efficiency polymerization inhibitor 701

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