EP1144378A2 - Process for the preparation of 1,2,3,6-tetrahydro-2,2,6,6-tetraalkylpyridines - Google Patents

Process for the preparation of 1,2,3,6-tetrahydro-2,2,6,6-tetraalkylpyridines

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Publication number
EP1144378A2
EP1144378A2 EP00907490A EP00907490A EP1144378A2 EP 1144378 A2 EP1144378 A2 EP 1144378A2 EP 00907490 A EP00907490 A EP 00907490A EP 00907490 A EP00907490 A EP 00907490A EP 1144378 A2 EP1144378 A2 EP 1144378A2
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EP
European Patent Office
Prior art keywords
formula
process according
compound
water vapour
temperature
Prior art date
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Application number
EP00907490A
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German (de)
French (fr)
Other versions
EP1144378A3 (en
Inventor
Reinhard Sommerlade
Bernd Siebenhaar
Bruno Casagrande
Heinz Steiner
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BASF Schweiz AG
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Ciba Spezialitaetenchemie Holding AG
Ciba SC Holding AG
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Publication of EP1144378A2 publication Critical patent/EP1144378A2/en
Publication of EP1144378A3 publication Critical patent/EP1144378A3/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • 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 present invention relates to a process for the preparation of 2,2,6,6-tetraalkylpiperidin-1- oxyls, such as 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), via the corresponding 1 ,2,3,6- tetrahydro-2,2,6,6-tetraalkylpyridine, which latter is prepared by dehydration in the gas phase from 4-hydroxy-2,2,6,6-tetraalkylpiperidine on a metal oxide or semimetal oxide catalyst in the presence of water.
  • TEMPO 2,2,6,6-tetraalkylpiperidin-1- oxyl
  • Tetraalkylpiperidin-1-oxyl and, in particular, 2,2,6,6-tetramethylpiperidin-1-oxyl are products which have versatile uses and which may be used, for example, as polymerisation inhibitors during the distillation and purification of styrene or acrylates.
  • EP-A-0 866 060 it is even possible to oxidise the olefinically unsaturated compound 1 ,2,3,6-tetrahydro-2,2,6,6-tetramethylpyridine to N-oxyl in the presence of alkaline earth salts or alkaline earth hydroxides without the double bond being attacked.
  • suitable catalysts show a change of pH from 0.5 to 2 units after a certain time.
  • the yield after an induction phase of about 1 week is said to be 70 or 82%.
  • the dehydration is carried out in the presence of water on a metal or metal oxide catalyst, then the full catalytic effect is present from the start and there is no induction period.
  • the acid strength is adjusted in situ by means of the water or water vapour present serving as modifier for the catalyst.
  • the catalyst is continuously purified by the water or the water vapour so that standing times of several thousand hours result without the activity getting any worse.
  • the reaction temperature can even be lowered to below 300° C.
  • This invention provides a simple, efficient, low cost and at the same time ecologically compatible large-scale synthesis, for example for preparing the intermediate 1 ,2,3,6-tetrahydro- 2,2,6,6-tetramethylpyridine from 4-hydroxy-2,2,6,6-tetramethyipiperidine, and thus also a process for the preparation of TEMPO from readily accessible basic substances.
  • the present process for the dehydration of 4-hydroxy-2,2,6,6-tetraalkyipiperidinepiperidine results in a high yield, can be carried out continuously or batchwise and yields the intermediate in high purity.
  • this invention relates to the preparation of a compound of formula I (I), wherein
  • R 1 f R 2 , R 3 and R 4 are each independently of one another C ⁇ -C 4 alkyl; R 5 is H or CH 3 ; and R 6 is H or C C 18 alkyl; from a compound of formula II
  • Alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, dodecyl or octadecyl.
  • the alkyl groups may be linear or branched.
  • R r R is ethyl or propyl and the remaining R to R 4 are methyl.
  • R 6 is preferably hydrogen or C C 4 alkyl, particularly preferably hydrogen.
  • TTMP from 4-hydroxy-2,2,6,6-tetramethylpiperidine is that, which comprises dehydrating
  • Suitable catalysts are Al 2 0 3 - or Si0 2 -gels, Si0 2 -AI 2 0 3 -cogels and also Si0 2 -ZrO 2 , SiO 2 -TiO 2 , Si0 2 -MgO-cogels, or mixtures thereof.
  • Sheet silicates are also suitable, for example bento- nites, montmorillonites, sepiolite as well as natural and synthetic zeolites or also porous glasses.
  • an aqueous solution of the educt may be in the range from 1 % by weight up to the saturation point at the corresponding temperature and pressure.
  • the solutions can be prepared in the temperature range from room temperature up to about 100° C and can then be added to the reactor.
  • an aqueous solution of the educt is advantageously carried out in an about 1 % to about 60 % by weight aqueous solution at the corresponding temperature, particularly advantageously in a 1-15 % by weight solution at room temperature and, very particularly advantageously, in a 5-14 % by weight solution at room temperature.
  • the ratio of water vapour to the compounds of formula II during the addition of the educt is from 1 to 50 mol of water vapour / mol of educt, particularly preferably from 2 to 30 mol of water vapour / mol of educt, most preferably from 5 to 20 mol of water vapour / mol of educt.
  • water vapour may have a temperature from 100° C to 600° C.
  • the range from 200° C to 500° C is preferred and the range from 250° C to 400° C is particularly preferred.
  • the addition to the reactor can be carried out by known methods. Suitable metering pumps and valves are commercially available.
  • the temperature in the reactor is from 225 to 350° C, particularly preferably from 250 to 300° C and, very particularly preferably, from 260 to 290° C.
  • the pressure in the reactor is usually from 500 to 10000 hectopascal, preferably from 1000 - 5000 hectopascal, particularly preferably from 1000 - 2000 hectopascal.
  • a preferred embodiment of the process is that, which comprises carrying out the process continuously by spraying the melt into the reactor and adding water vapour.
  • the catalyst can be placed in the reactor by known methods. In the batch operation it may, for example, be present in slurried form in the solvent, and in the continuous operation it may be fixed in the reactor and flowed through by the educt or water vapour.
  • This invention also relates to a process for the preparation of compounds of formula III
  • TEMPO 2,2,6,6-tetramethylpiperidin-1-oxyl
  • the hydration of the compounds of formula (I), in particular of 1 ,2,3,6-tetrahydro-2,2,6,6- tetramethylpyridine (THTMP), is carried out by methods known per se.
  • the hydration may be carried out, for example, continuously over a nickel catalyst in the gaseous phase.
  • the product to be hydrated does not have to be purified beforehand and may also be added with residual water.
  • Such continuous hydration processes are known to the skilled person and are described in "Katalytician Hydrtechniken im organisch-chemischen Laboratorium, F. Zymalkowski, 1965, Gustav Enke Verlag Stuttgart".
  • Nickel skeleton catalysts usually being used (Ni on AI 2 O 3 - or e.g. SiO 2 substrates).
  • the yield is normally very high and is usually from 96-98%.
  • hydration processes are also known to the skilled person and are described, inter alia, in ⁇ ydrogenation Methods, Paul N. Rylander, 1985, Academic Press".
  • Typical process parameters in the case of batchwise hydration are temperatures in the range from 30-100° C and a hydrogen pressure of about 50 bar, Pd- or Pt-catalysts usually being used which are normally bound to carrier materials.
  • the ratio of educt to catalyst is usually from 50-1000 g/g.
  • the oxidation step C) is known from the literature and has been described with different oxidants, for example tert-butylhydroperoxide or 3-chloroperbenzoic acid. Not least because of costs, H 2 O is particularly suitable as oxidant for use on an industrial scale, as is disclosed, inter alia, in EP-A-0 574 667.
  • other catalysts are used without which the reaction times may take up to several days. Catalysts used are mainly transition metal compounds such as sodium tung- state, ammonium tungstate (e.g. GB 1 199 351 ) or phosphorus tungstic acid (Bull. Soc. Chim. Fr.
  • Tungstates are mostly used in combination with the salt of ethylenediaminetetracetic acid (EDTA).
  • EDTA ethylenediaminetetracetic acid
  • a preferred process is that, in which the oxidation step is carried out in the presence of a dialkylamide.
  • a dialkylamide such as di- methylformamide (DMF)
  • DMF di- methylformamide
  • TMP 2,2,6,6-tetramethylpiperidine
  • Suitable dialkylamides are derived from C ⁇ -C 8 dialkylamides, preferably from C C 4 dialkyl- amides and particularly preferably from dimethylamides or diethylamides.
  • the amides are preferably derived from C C 12 acids; C r C 6 acids are particularly preferred and the dialkylacetamides and dialkylformamides are very particularly preferred.
  • dialkylamides are N,N-dimethylformamide (DMF) and N,N-dimethyl- acetamide. It is preferred to use 1-10 mol %, particularly preferably 2-5 mol %, of the dialkylamide.
  • a particularly preferred process for the preparation of 2,2,6,6-tetramethylpiperidin-1-oxyl comprises hydrating in a first step
  • This invention also relates to the use of dialkylamides when oxidising compounds of formula (la) to compounds of formula (III) with hydrogen peroxide.
  • Another object of this invention is the use of a metal oxide or semimetal oxide catalyst for the catalytic dehydration of compounds of formula (II) in the presence of water or water vapour.
  • Example A1 Dehydration of 4-hvdroxy-2,2,6,6-tetramethylpiperidine to 1.2.3.6-tetrahydro- 2,2,6,6-tetramethylpyridine on a laboratory scale
  • a microreactor is charged with 5 ml of an AI 2 O 3 catalyst.
  • a HPLC pump and a receiver with cold trap are connected to the microreactor.
  • the reactor is heated in an oven to 275-300° C.
  • a 13% by weight aqueous solution (deionised water) of 4-hydroxy- 2,2,6,6-tetramethylpiperidine is added continuously via the pump at 8 ml / hour.
  • the two phases of the product solution are transferred to a 500 ml separating funnel and separated.
  • the aqueous phase is shaken out twice with diethyl ether, the organic phases are combined and the highly volatile products and solvents are stripped off in a rotary evaporator. This yields crude 1 ,2,3,6-tetrahydro-2,2,6,6-tetramethylpyridine in 79% yield in the form of a yellow oil having a purity of 93%.
  • Example A2 semipilot: 4-hydroxy-2.2,6,6-tetramethylpiperidine to 1 ,2,3,6-tetrahvdro-2.2.6.6- tetramethylpyridine
  • the apparatus consists of a heatable cylindrical reaction vessel which is filled with 800 ml of AI 2 O 3 catalyst and heated to 270-280° C.
  • a melt of 4- hydroxy-2,2,6,6-tetramethylpiperidine is added via a heatable feed inlet at 150-400 ml / hour.
  • superheated water vapour of 280° C is added to the melt shortly before entry into the reaction tube.
  • a condenser with a product receiver. Separation of the phases results in crude 1 ,2,3,6-tetrahydro-2,2,6,6- tetramethylpyridine in a 73-80% yield and having a content of > 85%.
  • Example A3 Dehydration of 4__hvdroxy-2.6-diethyl-2,3,6-trimethylpiperidine to 1.2.3.6- tetrahydro-2,6-diethyl-2,3.6-trimethylpyridine on a laboratory scale
  • a microreactor is charged with 5 ml of a AI 2 O 3 catalyst.
  • a HPLC pump and a receiver with cold trap are connected to the microreactor.
  • the reactor is heated in an oven to 275-300 °C.
  • a 10% by weight aqueous solution (deionised water) of 4-hydroxy-2,6- diethyl-2,3,6-trimethylpiperidine is continuously added via the pump at 4 ml/h.
  • the two phases of the product solution are transferred into a 250 ml separating funnel and separated. Further working up is carried out as described in Example A1.
  • the 1 ,2,3,6-tetrahydro-2,6-diethyl-2,3,6-trimethylpyridine content of the organic phase is 83%.
  • Example A4 Dehydration of 4-hvdro ⁇ y-1.2.2.6,6-pentamethylpiperidine to 1 ,2,3,6-tetrahvdro- 1.2.2,6,6-pentamethylpyridine on a laboratory scale
  • a microreactor is charged with 5 ml of a Al 2 0 3 catalyst.
  • a HPLC pump and a receiver with cold trap are connected to the microreactor.
  • the reactor is heated in an oven to 260-280 °C.
  • a 4% by weight aqueous solution (deionised water) of 4-hydroxy- 1 , 2,2,6, 6-pentamethylpiperidine is continuously added via the pump at 6 ml/h.
  • the two phases of the product solution are transferred to a 250 ml separating funnel and separated. Further working up is carried out as described in Example A1.
  • the 1 ,2,3,6-tetrahydro-1 ,2,2,6,6-pentamethylpyridine content of the organic phase is about 37 %.
  • Example A5 Dehydration of 4-hvdroxy-1.2.2.6.6-pentamethylpiperidine (HPMP) to 1 ,2.3.6- tetrahvdro-1 ,2,2,6,6-pentamethylpyridine on a laboratory scale
  • a microreactor is charged with 5 ml of a Al 2 0 3 catalyst.
  • a HPLC pump, a heatable feed inlet and metering device and a receiver with cold trap are connected to the microreactor.
  • the reactor is heated in an oven to 260-280°C. At this temperature, 8 ml of deionised water and 0.5 g of a 4-hydroxy-1 ,2,2,6,6-pentamethylpiperidine melt per hour are added continuously.
  • the two phases of the product solution are transferred to a 250 ml separating funnel and separated. Further working up is carried out as described in Example A1.
  • the 1 ,2,3,6-tetrahydro-1 ,2,2,6,6-pentamethylpyridine content of the organic phase is about 48 %.
  • a microreactor is charged with 5 ml of a Ni/NiO-AI 2 0 3 catalyst.
  • a HPLC pump and a receiver with cold trap are connected to the microreactor.
  • the reactor is heated in an oven to 250° C in a N 2 stream (50ml/minute). When that temperature is reached, increasing amounts of hydrogen are admixed to the N 2 stream until the proportion of hydrogen is 100%. Subsequently, the temperature is elevated for 30 minutes to 350° C and then lowered to 100° C. At this temperature, the THTMP of Example A1 is added in an amount of 4.2 ml/h via the pump. At the same time hydrogen is added at a rate of 50 ml/minute. The reaction is completed quantitatively at 110-130° C.
  • Example B2 Hydration of 1.2,3.6-tetrahvdro-2,6-diethyl-2,3.6-trimethylpyridine to 2.6-diethyl- 2.3,6-trimethylpiperidine (DETMP) on a laboratory scale
  • a microreactor is charged with 5 ml of a Ni/NiO- AI 2 O 3 catalyst.
  • a HPLC pump and a receiver with cold trap are connected to the microreactor.
  • the reactor is heated in an oven to 250 °C in a N 2 stream (50 ml/min). When that temperature is reached, increasing amounts of hydrogen are admixed to the N 2 stream until the proportion of hydrogen is 100%. Subsequently, the temperature is elevated for 30 minutes to 350°C and then lowered to 100°C.
  • the 1 ,2,3,6-tetrahydro-2,6-diethyl-2,3,6-trimethylpyridine of Example A3 is then added in an amount of 4 ml/h via the HPLC pump.
  • hydrogen is added at a rate of 50 ml/min.
  • the reactor temperature rises to 120 - 130 °C. The reaction is almost quantitative and the entire DETMP yield is virtually 100%.
  • Example B3 Hydration of 1.2,3,6-tetrahvdro-1.2.2,6.6-pentamethylpyridine to 1 ,2.2.6.6- pentamethylpyridine (PMP) on a laboratory scale
  • a microreactor is charged with 5 ml of a Ni/NiO- AI 2 O 3 catalyst.
  • a HPLC pump and a receiver with cold trap are connected to the microreactor.
  • the reactor is heated in an oven and in a N 2 stream (50 ml/min) to 250 °C. When that temperature is reached, increasing amounts of hydrogen are admixed to the N 2 stream until the proportion of hydrogen is 100%. Subsequently, the temperature is elevated for 30 minutes to 350°C and then lowered to 100°C.
  • the 1 ,2,3,6-tetrahydro-1 ,2,2,6,6-pentamethylpyridine (organic phase of Examples A4/A5) is then added in an amount of 4 ml/h via the HPLC pump. At the same time hydrogen is added at a rate of 50 ml/min.
  • the reactor temperature rises to 110 - 120 °C.
  • the reaction is almost quantitative and the entire PMP yield is practically 100%.
  • TMP 2,2,6,6-tetramethylpiperidine
  • N,N,-dimethylformamide (0.11 mol).
  • the mixture is heated, with stirring, to 70-80°C and then 263.6 g (2.3 mol) of 35% hydrogen peroxide are added dropwise over 4 hours such that the temperature of the reaction mixture does not ex- ceed 85°C.
  • the pH of the reaction mixture falls in the course of the addition from about 8.3 to about 6.2 and the reaction mixture turns an intense dark red.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

This invention relates to a process for the preparation of a compound of formula (I), wherein R1, R2, R3 and R4 are each independently of one another C1-C4alkyl; R5 is H or CH3; and R6 is H or C1-C18alkyl; from a compound of formula II, which comprises dehydrating the compound of formula (II) either a1) in the form of an aqueous solution or suspension, or a2) in the form of an atomised melt together with water vapour at a temperature of above 150° C on a metal oxide or semimetal oxide catalyst. This invention also relates to a process, in which the compounds of formula I are hydrated and then oxidised to the corresponding N-oxyls.

Description

Process for the preparation of 2,2,6,6-tetraalkylpiperidin-1-oxyl via 1 ,2,3,6-tetrahvdro- 2.2,6.6-tetraalkylpyridine
The present invention relates to a process for the preparation of 2,2,6,6-tetraalkylpiperidin-1- oxyls, such as 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), via the corresponding 1 ,2,3,6- tetrahydro-2,2,6,6-tetraalkylpyridine, which latter is prepared by dehydration in the gas phase from 4-hydroxy-2,2,6,6-tetraalkylpiperidine on a metal oxide or semimetal oxide catalyst in the presence of water. Other objects of this invention are the use of a metal oxide or semimetal oxide catalyst for the dehydration of 4-hydroxy-2,2,6,6-tetraalkylpiperidines and the use of a dialkylamide during the oxidation to the corresponding N-oxyl.
Tetraalkylpiperidin-1-oxyl and, in particular, 2,2,6,6-tetramethylpiperidin-1-oxyl, are products which have versatile uses and which may be used, for example, as polymerisation inhibitors during the distillation and purification of styrene or acrylates.
They are usually obtained from the corresponding amine through oxidation.
The synthesis of N-oxyls through oxidation of the corresponding secondary amines is known from the literature and has been described with different oxidants. In EP-A-0 157 738, for example, the oxidation is carried out using organic peroxides. In J. Org. Chem. 39 (1947), 2356-2360, 3-chlorobenzoic acid is used as suitable oxidant. Hydrogen peroxide in combination with different catalysts is also suitable as oxidant. This is disclosed, inter alia, in GB 1 199 351 or in EP-A-0 574 667. According to EP-A-0 866 060 it is even possible to oxidise the olefinically unsaturated compound 1 ,2,3,6-tetrahydro-2,2,6,6-tetramethylpyridine to N-oxyl in the presence of alkaline earth salts or alkaline earth hydroxides without the double bond being attacked.
While the oxidation step has been thoroughly investigated and can be carried out economically on an industrial scale, the provision of the intermediates has not yet been satisfactorily solved. In particular when starting from 4-hydroxy-2,2,6,6-tetramethylpiperidine, which is readily available on an industrial scale, the dehydration step to 1 ,2,3,6-tetrahydro-2,2,6,6- tetramethylpyridine is a process step which can only be satisfactorily carried out with high excess of concentrated sulfuric acid [E. Fischer, Chem. Ber. 16, 1604 (1883)]. However, disposing of large amounts of acid is ecologically problematical. EP-A-0 894 790 describes a process in which the dehydration is carried out at elevated temperature in the gas phase on a solid acid catalyst. This is carried out at temperatures of above 300° C and the educt is led over the catalyst at this temperature without further additives.
When sodium hydroxide solution is added, suitable catalysts show a change of pH from 0.5 to 2 units after a certain time. The yield after an induction phase of about 1 week is said to be 70 or 82%.
Surprisingly, it has now been found that it is possible to carry out a gas phase dehydration of 4-hydroxy-2,2,6,6-tetraalkylpiperidines to 1 ,2,3,6-tetrahydro-2,2,6,6-tetraalkylpyridines on a metal or metal oxide catalyst in the presence of water or water vapour with excellent results.
If the dehydration is carried out in the presence of water on a metal or metal oxide catalyst, then the full catalytic effect is present from the start and there is no induction period. The acid strength is adjusted in situ by means of the water or water vapour present serving as modifier for the catalyst. The catalyst is continuously purified by the water or the water vapour so that standing times of several thousand hours result without the activity getting any worse.
The reaction temperature can even be lowered to below 300° C.
This invention provides a simple, efficient, low cost and at the same time ecologically compatible large-scale synthesis, for example for preparing the intermediate 1 ,2,3,6-tetrahydro- 2,2,6,6-tetramethylpyridine from 4-hydroxy-2,2,6,6-tetramethyipiperidine, and thus also a process for the preparation of TEMPO from readily accessible basic substances.
The present process for the dehydration of 4-hydroxy-2,2,6,6-tetraalkyipiperidinepiperidine results in a high yield, can be carried out continuously or batchwise and yields the intermediate in high purity.
In one of its aspects, this invention relates to the preparation of a compound of formula I (I), wherein
R1 f R2, R3 and R4 are each independently of one another Cι-C4alkyl; R5 is H or CH3; and R6 is H or C C18alkyl; from a compound of formula II
which comprises dehydrating the compound of formula (II) either a1) in the form of an aqueous solution or suspension, or a2) in the form of an atomised melt together with water vapour at a temperature of above 150° C on a metal oxide or semimetal oxide catalyst.
C C18Alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, dodecyl or octadecyl. The alkyl groups may be linear or branched.
In a preferred embodiment of this invention, at least one of RrR is ethyl or propyl and the remaining R to R4 are methyl.
R6 is preferably hydrogen or C C4alkyl, particularly preferably hydrogen.
A preferred process for the preparation of 1 ,2,3,6-tetrahydro-2,2,6,6-tetramethylpyridine
(THTMP) from 4-hydroxy-2,2,6,6-tetramethylpiperidine is that, which comprises dehydrating
4-hydroxy-2,2,6,6-tetramethylpiperidine either a1 ) in the form of an aqueous solution or suspension, or a2) in the form of an atomised melt together with water vapour at a temperature of above 150° C on a metal oxide or semimetal oxide catalyst. Suitable catalysts are Al203- or Si02-gels, Si02-AI203-cogels and also Si02-ZrO2, SiO2-TiO2, Si02-MgO-cogels, or mixtures thereof. Sheet silicates are also suitable, for example bento- nites, montmorillonites, sepiolite as well as natural and synthetic zeolites or also porous glasses.
It is preferred to use AI2O3, Si02, SiO2-AI203 cogels, sheet silicates or zeolites, particularly preferably AI2O3 and Si02-Al203 cogels.
For the dehydration process it is particularly important that a certain amount of water is added in addition to the educt. This addition of water can be carried out in different ways and depends on the type of reactor (continuous or batchwise operation) and on the chosen type of addition of the educt (aqueous solution or melt).
Instead of a solution it is also possible to use a suspension which contains undissolved proportions of the educt in slurried form.
If an aqueous solution of the educt is prepared, it may be in the range from 1 % by weight up to the saturation point at the corresponding temperature and pressure. The solutions can be prepared in the temperature range from room temperature up to about 100° C and can then be added to the reactor.
The addition of, for example, an aqueous solution of the educt is advantageously carried out in an about 1 % to about 60 % by weight aqueous solution at the corresponding temperature, particularly advantageously in a 1-15 % by weight solution at room temperature and, very particularly advantageously, in a 5-14 % by weight solution at room temperature.
Expressed in molar amounts, the ratio of water vapour to the compounds of formula II during the addition of the educt is from 1 to 50 mol of water vapour / mol of educt, particularly preferably from 2 to 30 mol of water vapour / mol of educt, most preferably from 5 to 20 mol of water vapour / mol of educt.
If water vapour is added, it may have a temperature from 100° C to 600° C. The range from 200° C to 500° C is preferred and the range from 250° C to 400° C is particularly preferred. The addition to the reactor can be carried out by known methods. Suitable metering pumps and valves are commercially available.
The temperature in the reactor is from 225 to 350° C, particularly preferably from 250 to 300° C and, very particularly preferably, from 260 to 290° C.
Depending on the temperature, the corresponding pressure is obtained in the reactor. The pressure in the reactor is usually from 500 to 10000 hectopascal, preferably from 1000 - 5000 hectopascal, particularly preferably from 1000 - 2000 hectopascal.
A preferred embodiment of the process is that, which comprises carrying out the process continuously by spraying the melt into the reactor and adding water vapour.
The catalyst can be placed in the reactor by known methods. In the batch operation it may, for example, be present in slurried form in the solvent, and in the continuous operation it may be fixed in the reactor and flowed through by the educt or water vapour.
This invention also relates to a process for the preparation of compounds of formula III
which comprises hydrating in a first step
A) a compound of formula (II), wherein R6 is hydrogen, either a1) in the form of an aqueous solution or suspension, or a2) in the form of an atomised melt together with water vapour at a temperature of above 150° C on a metal oxide or semimetal oxide catalyst, hydrating the resulting compound of formula (I) in a second step
B) continuously or batchwise in the presence of a hydration catalyst and oxidising the resulting hydrated product of formula (la) (la) in a third step
C) with an oxidant to a compound of formula (III).
A preferred process for the preparation of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) is that, which comprises hydrating in a first step
A) 4-hydroxy-2,2,6,6-tetramethylpiperidine either a1) in the form of an aqueous solution or suspension, or a2) in the form of an atomised melt together with water vapour at a temperature of above 150° C on a metal oxide or semimetal oxide catalyst, hydrating the resulting 1 ,2,3,6-tetra- hydro-2,2,6,6-tetramethylpyridine (THTMP) in a second step
B) continuously or batchwise in the presence of a hydration catalyst and oxidising the resulting 2,2,6,6-tetramethylpiperidine in a third step
C) with an oxidant to 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO).
The hydration of the compounds of formula (I), in particular of 1 ,2,3,6-tetrahydro-2,2,6,6- tetramethylpyridine (THTMP), is carried out by methods known per se. The hydration may be carried out, for example, continuously over a nickel catalyst in the gaseous phase. The product to be hydrated does not have to be purified beforehand and may also be added with residual water. Such continuous hydration processes are known to the skilled person and are described in "Katalytische Hydrierungen im organisch-chemischen Laboratorium, F. Zymalkowski, 1965, Ferdinand Enke Verlag Stuttgart".
Continuous hydrations over nickel catalysts are typically carried out in the temperature range from about 90-150° C, nickel skeleton catalysts usually being used (Ni on AI2O3- or e.g. SiO2 substrates). The yield is normally very high and is usually from 96-98%.
It is also possible to carry out the hydration batchwise, for example in the presence of a Pd/C or Pt/C catalyst. Such hydration processes are also known to the skilled person and are described, inter alia, in Ηydrogenation Methods, Paul N. Rylander, 1985, Academic Press". Typical process parameters in the case of batchwise hydration are temperatures in the range from 30-100° C and a hydrogen pressure of about 50 bar, Pd- or Pt-catalysts usually being used which are normally bound to carrier materials. The ratio of educt to catalyst is usually from 50-1000 g/g.
As already mentioned above, the oxidation step C) is known from the literature and has been described with different oxidants, for example tert-butylhydroperoxide or 3-chloroperbenzoic acid. Not least because of costs, H2O is particularly suitable as oxidant for use on an industrial scale, as is disclosed, inter alia, in EP-A-0 574 667. In the processes known in the state of the art, other catalysts are used without which the reaction times may take up to several days. Catalysts used are mainly transition metal compounds such as sodium tung- state, ammonium tungstate (e.g. GB 1 199 351 ) or phosphorus tungstic acid (Bull. Soc. Chim. Fr. 11 , 3273 (1965)), but titanium-containing compounds (EP 488 403) or alkaline earth metal salts (EP 0 866 060) are also used. Tungstates are mostly used in combination with the salt of ethylenediaminetetracetic acid (EDTA).
A preferred process is that, in which the oxidation step is carried out in the presence of a dialkylamide.
Surprisingly, it has been found that an addition of 1-20 mol % of a dialkylamide, such as di- methylformamide (DMF), substantially accelerates the oxidation of 2,2,6,6-tetraalkylpiperi- dines with hydrogen peroxide. In this manner e.g. 2,2,6,6-tetramethylpiperidine (TMP) is completely reacted to TEMPO already after a few hours. Without addition of DMF, however, a substantial proportion of TMP remains unreacted even after a 24 hour reaction time.
Suitable dialkylamides are derived from Cι-C8dialkylamides, preferably from C C4dialkyl- amides and particularly preferably from dimethylamides or diethylamides.
The amides are preferably derived from C C12acids; CrC6acids are particularly preferred and the dialkylacetamides and dialkylformamides are very particularly preferred.
Particularly suitable dialkylamides are N,N-dimethylformamide (DMF) and N,N-dimethyl- acetamide. It is preferred to use 1-10 mol %, particularly preferably 2-5 mol %, of the dialkylamide.
A particularly preferred process for the preparation of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) comprises hydrating in a first step
A) 4-hydroxy-2,2,6,6-tetramethylpiperidine either a1) in the form of an aqueous solution or suspension, or a2) in the form of an atomised melt together with water vapour at a temperature of above 150° C on a metal oxide or semimetal oxide catalyst, hydrating the resulting 1 ,2,3,6-tetrahydro-2,2,6,6-tetramethylpyridine (THTMP) in a second step
B) continuously or batchwise in the presence of a hydration catalyst and oxidising the resulting 2,2,6,6-tetramethylpiperidine in a third step
C) with an oxidant to 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) in the presence of a dialkylamide.
This invention also relates to the use of dialkylamides when oxidising compounds of formula (la) to compounds of formula (III) with hydrogen peroxide.
Another object of this invention is the use of a metal oxide or semimetal oxide catalyst for the catalytic dehydration of compounds of formula (II) in the presence of water or water vapour.
The following Examples illustrate the invention.
A) Examples of dehydration
Example A1 : Dehydration of 4-hvdroxy-2,2,6,6-tetramethylpiperidine to 1.2.3.6-tetrahydro- 2,2,6,6-tetramethylpyridine on a laboratory scale
A microreactor is charged with 5 ml of an AI2O3 catalyst. A HPLC pump and a receiver with cold trap are connected to the microreactor. The reactor is heated in an oven to 275-300° C. At this temperature, a 13% by weight aqueous solution (deionised water) of 4-hydroxy- 2,2,6,6-tetramethylpiperidine is added continuously via the pump at 8 ml / hour. At 6-20 hour intervals the two phases of the product solution are transferred to a 500 ml separating funnel and separated. The aqueous phase is shaken out twice with diethyl ether, the organic phases are combined and the highly volatile products and solvents are stripped off in a rotary evaporator. This yields crude 1 ,2,3,6-tetrahydro-2,2,6,6-tetramethylpyridine in 79% yield in the form of a yellow oil having a purity of 93%.
Example A2 semipilot: 4-hydroxy-2.2,6,6-tetramethylpiperidine to 1 ,2,3,6-tetrahvdro-2.2.6.6- tetramethylpyridine
The apparatus consists of a heatable cylindrical reaction vessel which is filled with 800 ml of AI2O3 catalyst and heated to 270-280° C. At the head is a inlet through which a melt of 4- hydroxy-2,2,6,6-tetramethylpiperidine is added via a heatable feed inlet at 150-400 ml / hour. In another feed inlet, superheated water vapour of 280° C is added to the melt shortly before entry into the reaction tube. At the outlet of the reactor located at the bottom is a condenser with a product receiver. Separation of the phases results in crude 1 ,2,3,6-tetrahydro-2,2,6,6- tetramethylpyridine in a 73-80% yield and having a content of > 85%.
Example A3: Dehydration of 4__hvdroxy-2.6-diethyl-2,3,6-trimethylpiperidine to 1.2.3.6- tetrahydro-2,6-diethyl-2,3.6-trimethylpyridine on a laboratory scale
A microreactor is charged with 5 ml of a AI2O3 catalyst. A HPLC pump and a receiver with cold trap are connected to the microreactor. The reactor is heated in an oven to 275-300 °C. At this temperature, a 10% by weight aqueous solution (deionised water) of 4-hydroxy-2,6- diethyl-2,3,6-trimethylpiperidine is continuously added via the pump at 4 ml/h. At 10-20 h intervals, the two phases of the product solution are transferred into a 250 ml separating funnel and separated. Further working up is carried out as described in Example A1. The 1 ,2,3,6-tetrahydro-2,6-diethyl-2,3,6-trimethylpyridine content of the organic phase is 83%.
Example A4: Dehydration of 4-hvdroχy-1.2.2.6,6-pentamethylpiperidine to 1 ,2,3,6-tetrahvdro- 1.2.2,6,6-pentamethylpyridine on a laboratory scale
A microreactor is charged with 5 ml of a Al203 catalyst. A HPLC pump and a receiver with cold trap are connected to the microreactor. The reactor is heated in an oven to 260-280 °C. At this temperature a 4% by weight aqueous solution (deionised water) of 4-hydroxy- 1 , 2,2,6, 6-pentamethylpiperidine is continuously added via the pump at 6 ml/h. At 10-20 h intervals, the two phases of the product solution are transferred to a 250 ml separating funnel and separated. Further working up is carried out as described in Example A1. The 1 ,2,3,6-tetrahydro-1 ,2,2,6,6-pentamethylpyridine content of the organic phase is about 37 %.
Example A5: Dehydration of 4-hvdroxy-1.2.2.6.6-pentamethylpiperidine (HPMP) to 1 ,2.3.6- tetrahvdro-1 ,2,2,6,6-pentamethylpyridine on a laboratory scale
A microreactor is charged with 5 ml of a Al203 catalyst. A HPLC pump, a heatable feed inlet and metering device and a receiver with cold trap are connected to the microreactor. The reactor is heated in an oven to 260-280°C. At this temperature, 8 ml of deionised water and 0.5 g of a 4-hydroxy-1 ,2,2,6,6-pentamethylpiperidine melt per hour are added continuously. At 10-20 h intervals, the two phases of the product solution are transferred to a 250 ml separating funnel and separated. Further working up is carried out as described in Example A1. The 1 ,2,3,6-tetrahydro-1 ,2,2,6,6-pentamethylpyridine content of the organic phase is about 48 %.
B) Examples of hydration
Example B1 : Hydration to 2,2,6,6-tetramethylpiperidine
A microreactor is charged with 5 ml of a Ni/NiO-AI203 catalyst. A HPLC pump and a receiver with cold trap are connected to the microreactor. The reactor is heated in an oven to 250° C in a N2 stream (50ml/minute). When that temperature is reached, increasing amounts of hydrogen are admixed to the N2 stream until the proportion of hydrogen is 100%. Subsequently, the temperature is elevated for 30 minutes to 350° C and then lowered to 100° C. At this temperature, the THTMP of Example A1 is added in an amount of 4.2 ml/h via the pump. At the same time hydrogen is added at a rate of 50 ml/minute. The reaction is completed quantitatively at 110-130° C. The entire yield of 2,2,6,6-tetramethylpiperidine, obtained in the form of a colourless liquid, is practically 100%. Example B2: Hydration of 1.2,3.6-tetrahvdro-2,6-diethyl-2,3.6-trimethylpyridine to 2.6-diethyl- 2.3,6-trimethylpiperidine (DETMP) on a laboratory scale
A microreactor is charged with 5 ml of a Ni/NiO- AI2O3 catalyst. A HPLC pump and a receiver with cold trap are connected to the microreactor. For activation, the reactor is heated in an oven to 250 °C in a N2 stream (50 ml/min). When that temperature is reached, increasing amounts of hydrogen are admixed to the N2 stream until the proportion of hydrogen is 100%. Subsequently, the temperature is elevated for 30 minutes to 350°C and then lowered to 100°C. The 1 ,2,3,6-tetrahydro-2,6-diethyl-2,3,6-trimethylpyridine of Example A3 is then added in an amount of 4 ml/h via the HPLC pump. At the same time, hydrogen is added at a rate of 50 ml/min. The reactor temperature rises to 120 - 130 °C. The reaction is almost quantitative and the entire DETMP yield is virtually 100%.
Example B3: Hydration of 1.2,3,6-tetrahvdro-1.2.2,6.6-pentamethylpyridine to 1 ,2.2.6.6- pentamethylpyridine (PMP) on a laboratory scale
A microreactor is charged with 5 ml of a Ni/NiO- AI2O3 catalyst. A HPLC pump and a receiver with cold trap are connected to the microreactor. For activation, the reactor is heated in an oven and in a N2 stream (50 ml/min) to 250 °C. When that temperature is reached, increasing amounts of hydrogen are admixed to the N2 stream until the proportion of hydrogen is 100%. Subsequently, the temperature is elevated for 30 minutes to 350°C and then lowered to 100°C. The 1 ,2,3,6-tetrahydro-1 ,2,2,6,6-pentamethylpyridine (organic phase of Examples A4/A5) is then added in an amount of 4 ml/h via the HPLC pump. At the same time hydrogen is added at a rate of 50 ml/min. The reactor temperature rises to 110 - 120 °C. The reaction is almost quantitative and the entire PMP yield is practically 100%.
C) Example of oxidation
Example C1 : Preparation of 2.2.6.6-tetramethylpiperidin-1-oxyl (TEMPO)
A 1 litre multinecked flask, equipped with propeller agitator, reflux condenser, dropping funnel and pH electrode, is charged with 166.7 g (1.18 mol) of 2,2,6,6-tetramethylpiperidine (TMP) of Example B1 and with 8.3 g of N,N,-dimethylformamide (0.11 mol). The mixture is heated, with stirring, to 70-80°C and then 263.6 g (2.3 mol) of 35% hydrogen peroxide are added dropwise over 4 hours such that the temperature of the reaction mixture does not ex- ceed 85°C. The pH of the reaction mixture falls in the course of the addition from about 8.3 to about 6.2 and the reaction mixture turns an intense dark red. After the addition is complete, stirring is continued for another 3 hours at 80°C to complete the reaction. The course of the reaction is observed via gas chromatography. Towards the end of the stirring time, hardly any TMP can be found; the TEMPO content is about 95% and the content of intermediate N-hydroxy-2,2,6,6-tetramethylpiperidine is at most 2.5%. The reaction mixture is saturated with about 85 g of sodium chloride and is left standing for phase separation. The bottom yellow aqueous phase is then separated and the oily product is recrystallised from water. Drying in a vacuum drying oven at room temperature yields 94 g of TEMPO (60% of theory) in the form of dark red crystals having a content of >99.5%.

Claims

What is claimed is
1. A process for the preparation of a compound of formula I
(I), wherein
Rι, R2, R3 and R4 are each independently of one another CrC alkyl; R5 is H or CH3; and R6 is H or CrC18alkyl; from a compound of formula II
which comprises dehydrating the compound of formula (II) either a1) in the form of an aqueous solution or suspension, or a2) in the form of an atomised melt together with water vapour at a temperature of above 150° C on a metal oxide or semimetal oxide catalyst.
2. A process according to claim 1 , wherein at least one of RrR4 is ethyl or propyl and the remaining Ri to R4 are methyl.
3. A process according to claim 1 , wherein R6 is hydrogen or Cι-C alkyl.
4. A process according to claim 1 , for the preparation of I ^.S.β-tetrahydro^^.e.e-tetra- methylpyridine (THTMP) from 4-hydroxy-2,2,6,6-tetramethylpiperidine.
5. A process according to claim 1 , wherein the metal oxides or semimetal oxides are Al203, SiO2, Si02-Al203 gels or cogels, sheet silicates or zeolites.
6. A process according to claim 1 , wherein the ratio of water vapour to the compound of formula II during the addition of the educt is from 1 to 50 mol of water vapour per mol of educt.
7. A process according to claim 1 , wherein the temperature in the reactor is from 225 to 350° C.
8. A process according to claim 1 , wherein the pressure in the reactor is from 1000 to 5000 hectopascal.
9. A process according to claim 1 , which comprises carrying out the process continuously by spraying the melt in the reactor and adding water vapour.
10. A process for the preparation of compounds of formula III
R R (Ml).
3 N , ^R 1. o. which comprises hydrating in a first step
A) a compound of formula (II), wherein R6 is hydrogen, either a1) in the form of an aqueous solution or suspension, or a2) in the form of an atomised melt together with water vapour at a temperature of above 150° C on a metal oxide or semimetal oxide catalyst, hydrating the resulting compound of formula (I) in a second step
B) continuously or batchwise in the presence of a hydration catalyst and oxidising the resulting hydrated product of formula (la)
(la) in a third step
C) with an oxidant to a compound of formula (III).
11. A process according to claim 10 for the preparation of 2,2,6,6-tetramethylpiperidin-1-oxyI (TEMPO), which comprises hydrating in a first step A) 4-hydroxy-2,2,6,6-tetramethylpiperidine either a1) in the form of an aqueous solution or suspension, or a2) in the form of an atomised melt together with water vapour at a temperature of above 150° C on a metal oxide or semimetal oxide catalyst, hydrating the resulting 1 ,2,3,6-tetra- hydro-2,2,6,6-tetramethylpyridine (THTMP) in a second step
B) continuously or batchwise in the presence of a hydration catalyst and oxidising the resulting 2,2,6,6-tetramethylpiperidine in a third step
C) with an oxidant to 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO).
12. A process according to claim 10, which comprises carrying out the oxidation step in the presence of a dialkylamide.
13. Use of a metal oxide or semimetal oxide catalyst for the catalytic dehydration of compounds of formula (II) in the presence of water or water vapour.
14. Use of dialkylamides when oxidising the hydrated compounds of formula (la) to compounds of formula (III) with hydrogen peroxide.
EP00907490A 1999-02-05 2000-01-31 Process for the preparation of 1,2,3,6-tetrahydro-2,2,6,6-tetraalkylpyridines Withdrawn EP1144378A3 (en)

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