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EP1699770A1 - Method for the synthesis of exocyclic derivatives of cycloalkyl-hydrazines and exocyclic derivatives of heterocycloalkyl-hydrazines - Google Patents

Method for the synthesis of exocyclic derivatives of cycloalkyl-hydrazines and exocyclic derivatives of heterocycloalkyl-hydrazines

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Publication number
EP1699770A1
EP1699770A1 EP04816423A EP04816423A EP1699770A1 EP 1699770 A1 EP1699770 A1 EP 1699770A1 EP 04816423 A EP04816423 A EP 04816423A EP 04816423 A EP04816423 A EP 04816423A EP 1699770 A1 EP1699770 A1 EP 1699770A1
Authority
EP
European Patent Office
Prior art keywords
hydrazine
solution
exocyclic
heterocycloalkyl
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04816423A
Other languages
German (de)
French (fr)
Inventor
Henri Delalu
Cécile COLAS-DURICHE
Jacques Berthet
Philippe Leurent
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Safran Ceramics SA
Universite Claude Bernard Lyon 1
Original Assignee
Centre National de la Recherche Scientifique CNRS
Isochem SAS
Universite Claude Bernard Lyon 1
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Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS, Isochem SAS, Universite Claude Bernard Lyon 1 filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP1699770A1 publication Critical patent/EP1699770A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/30—Nitrogen atoms non-acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • the present invention relates to a new process for the synthesis of exocyclic cycloalkyl hydrazine derivatives and exocyclic heterocycloalkyl hydrazine derivatives.
  • Cycloalkyl hydrazine derivatives and exocyclic heterocycloalkyl hydrazines, in particular N-aminopiperidine, are very frequently used as intermediates in the manufacture of medicaments.
  • a second method consists of a nitrosation of piperidine followed by a chemical hydrogenation (LiAlH 4 ) or catalytic (Zn / AcOH) of the nitrose derivative (1-nitrosopiperidine) (Allen & Hanburys Ltd. (1965), 74, 3693-4 ).
  • the nitrosed compound must be purified by distillation.
  • This method leads to fairly good yields (75%).
  • the product resulting from the first stage must be handled with great care because of its toxicity (highly carcinogenic compound), which poses industrial problems of exploitation.
  • the use of LiAlH 4 imposes the absence of traces of water, sealed reactors and anhydrous solvents (diethyl ether), which has the effect of increasing the risks of ignition of the reaction mixture.
  • Patent EP 0277267 describes a process for the continuous synthesis of N-amino aza-3 bicyclo [3,3,0] octane, characterized in that a solution of ammonium hydroxide and chloride is reacted ammonium with an aqueous solution of sodium hypochlorite at a temperature between -15 ° C and -7 ° C in an alkaline medium, and then reacting the monochloramine thus formed with aza-3 bicyclo [3 , 3.0] octane, in a two-phase medium in a suitable reactor fitted with a coaxial stirrer with fins, at a temperature between 30 ° C and 90 ° C and in an alkaline medium, then separated from the rammoniac reaction medium and then the aza-3 bicyclo [3,3,0] octane which has not reacted by distillation to recycle it, and then a concentrated solution of N-amino aza-3 bicyclo [3 is isolated by demixing) 3.0]
  • reaction solution After formation of N-amino aza-3 bicyclo [3,3,0] octane and cooling, the reaction solution undergoes degassing to remove ammonia and 3-amino bicyclo [3,3,0] octane which does not unreacted is separated from the reaction medium by simple distillation under atmospheric pressure and at a temperature of about 90 to 100 ° C. Under these conditions, the amine is obtained in the form of an aqueous solution concentrated to 30% in aza-3 bicyclo [3,3,0] octane. This solution is recycled.
  • the inventors have now discovered a new process for the synthesis of exocyclic cycloalkyl hydrazine derivatives and exocyclic heterocycloalkyl hydrazine derivatives, in particular N-aminopiperidine.
  • This process implemented in continuous is partly based on a transposition of the Raschig process, and it consists in preparing the monochloramine by action of sodium hypochlorite on ammonia at low temperature, and then in making the monochloramine thus produced act on a heterocyclic amine in medium homogeneous or, depending on the temperature, in a heterogeneous medium, then to extract the hydrazine formed.
  • the starting amine is recycled, then if necessary reinjected directly onto the monochloramine without any additional treatment.
  • exocyclic cycloalkyl-hydrazine derivative (s) and the exocyclic heterocycloalkyl-hydrazine derivative (s) may be designated by the term "hydrazine (s)".
  • the expression “exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine” should read “exocyclic cycloalkyl-hydrazine derivative or exocyclic heterocycloalkyl-hydrazine derivative”.
  • the hetero cyclic amine (s) may be designated by the term "amine (s)”.
  • the present invention thus relates to a process for the synthesis of exocyclic cycloalkylhydrazine derivatives and exocyclic heterocycloalkyl-hydrazine derivatives, characterized in that it comprises the following successive steps: a) synthesizing the cycloalkyl-hydrazine derivative or heterocycloalkyl - exocyclic hydrazine in a suitable reactor by reacting in an alkaline medium and at a temperature between 30 and 60 ° C a monochloramine with a heterocyclic amine; then b) demixing the solution obtained following step a) into an organic phase and an aqueous phase by adding anhydrous sodium hydroxide under cooling so that the temperature does not exceed the boiling point of the compounds; and c) if necessary, isolating, by distillation of the organic phase thus obtained, the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine.
  • exocyclic cycloalkyl-hydrazine or exocyclic heterocycloalkyl-hydrazine derivative is advantageously of formula (I) in which one of the carbon atoms of the ring is optionally replaced by a heteroatom chosen from a nitrogen or oxygen atom, RI and R2, identical or different, represent a hydrogen atom or a C ⁇ -C 6 alkyl radical or RI and R2 together form a C 3 -C 8 cycloalkyl and n is 1 to 3.
  • the exocyclic cycloalkyl-hydrazine or heterocycloalkyl-hydrazine derivative is even more advantageously chosen from the group consisting of N-aminopiperidine, N-aminomorpholine, N-amino-2,6-dimethyl-piperidine, N-aminopyrrolidine , N-aminoazepine, N-amino-4-methyl-piperazine.
  • the reactor of step a) is advantageously placed under an inert atmosphere, in particular under an argon or nitrogen sweep.
  • Said suitable reactor of step a) is advantageously a stirred tabular reactor.
  • the tubular reactor makes it possible to avoid contact between the nascent hydrazine and the monochloramine and thus it makes it possible to avoid an oxidation-reduction reaction between these two reactants.
  • the reaction front moves along the tube and the hydrazine is no longer in contact with the monochloramine injected at the base of the reactor.
  • the concentration of hydroxyl ions in the reaction medium of step a) is between 0.3 and 0.8 mol.l "1.
  • the ratio of the molar concentrations of the amine heterocyclic on the monochloramine must advantageously be greater than or equal to 4 and less than or equal to 10.
  • the reaction time is variable and depends on the temperature at which the reaction is carried out and on the ratio of the concentrations of the reactants. in the case of the synthesis of N-aminopiperidine and in the range of concentration ratios given, the reaction time is of the order of 20 seconds to 2 minutes at 25 ° C. and of the order of 4 seconds to 30 seconds at 60 ° C.
  • the monochloramine is made alkaline before step a) in a mixer by adding a solution of a strong base such as sodium hydroxide so that the mass content of hydroxide sodium is between 2 and 6%.
  • Said mixer is advantageously maintained at a temperature between -10 and 5 ° C.
  • the reaction of monochloramine with the heterocyclic amine is thus advantageously carried out in the presence of an aqueous solution of sodium hydroxide when hot.
  • the concentration of sodium hydroxide in the reaction medium is approximately 0.3 mol.L "1.
  • the sodium hydroxide concentration must not be too high otherwise the reaction mixture risks demixing by salting out.
  • a reactor of the agitated piston reactor type would then have to be used During the hydrazine synthesis reaction, hydrochloric acid is also formed, but any local protonation of the amine during mixing must be avoided in order to avoid the formation of a substituted chloramine.
  • piperidine protonated by hydrochloric acid can react with monochloramine to form 1-chloropiperidine, which can then react with hydroxyl ions to form the 2,3,4,5-tetrahydropyridine, which then risks trimerizing.
  • the alkalinization of monochloramine that is to say the addition of a strong base such as sodium hydroxide, thus makes it possible to neutralize the acid formed.
  • the amount of strong base added must be sufficient to neutralize all the acid formed.
  • the rate of formation of hydrazine increases with the alkalinity of the medium, which is not the case for the rate of degradation reactions, such as for example the oxidation of incipient hydrazine by chloramine .
  • the amount of anhydrous sodium hydroxide added is such that the mass content of sodium hydroxide is between 10 and 35%, preferably approximately equal to 30%.
  • the medium demixes into two phases, one of which concentrates the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine formed in the light phase (organic phase).
  • This sodium hydroxide treatment makes it possible, by demixing, to remove the water present in the reaction medium and to extract the salts and, where appropriate, the ammonia in the lower phase (aqueous phase).
  • the temperature of the demixing medium of step b) must not exceed 80 ° C.
  • the heterocyclic amine is introduced, in step a), in the form of an anhydrous heterocyclic amine.
  • the monochloramine, advantageously alkalized, and the anhydrous heterocyclic amine are advantageously introduced simultaneously into the reactor.
  • the addition rates of the heterocyclic amine and of the monochloramine are such that the ratio of the molar concentrations of the anhydrous heterocyclic amine to the monochloramine is advantageously between 4 and 10, the limits being able to be included.
  • Part of the synthesis reaction of the cycloalkyl-hydrazine derivative and exocyclic heterocycloalkyl-hydrazine can be carried out in a heterogeneous medium.
  • step b makes it possible to demix the medium into two phases, one of which, the upper phase or the organic phase concentrates almost all of the organics, namely the exocyclic cycloalkyl-hydrazine or heterocycloalkyl-hydrazine derivative and the heterocyclic amine.
  • Step c) then advantageously comprises the following successive steps: i) isolating the heterocyclic amine which has not reacted and a concentrated solution of exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine by distillation of the organic phase obtained following step b); then ii) if necessary, rectify by distillation under reduced pressure said concentrated solution of the derivative of cycloalkyl-hydrazine and of exocyclic heterocycloalkyl-hydrazine.
  • step i) the distillation is advantageously carried out in a single distillation column under atmospheric or reduced pressure, depending on the boiling temperature of the starting amine.
  • a concentrated heterocyclic amine solution or, where appropriate, a heterocyclic water-amine azeotropic solution until the water is used up is collected at the top of the column, followed by the anhydrous heterocyclic amine.
  • the anhydrous heterocyclic amine thus recovered can be reinjected directly into the reactor of step a) where the synthesis of hydrazine takes place.
  • the heterocyclic amine obtained in the form of a concentrated solution or an azeotropic solution with water can be recovered, then optionally reinjected after an appropriate treatment.
  • step i) rectification under reduced pressure, advantageously around 115 mm of Hg, of the product obtained at the bottom of the column in step i) makes it possible to collect the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine with a higher titer at 99%, advantageously greater than 99.9%.
  • Said exocyclic cycloalkyl-hydrazine or heterocycloalkyl-hydrazine derivative must then be stored under an inert atmosphere, such as under argon for example, so as to avoid any oxidation reaction with oxygen.
  • This variant of the invention is particularly advantageous in the context of a batch preparation of the exocyclic cycloalkyl-hydrazine derivative or exocyclic heterocycloalkyl-hydrazine derivative.
  • the heterocyclic amine is introduced, in step a), in the form of a concentrated aqueous solution of heterocyclic amine or of an azeotropic water-heterocyclic amine solution.
  • Step a) is then carried out in a homogeneous or heterogeneous medium (in the case of a very heavy amine).
  • the concentrated aqueous solution of heterocyclic amine may be in the form of a heterocyclic water-amine azeotrope.
  • the monochloramine, advantageously alkalized, and the heterocyclic amine solution are advantageously introduced simultaneously into the reactor.
  • the addition rates of the concentrated aqueous solution of heterocyclic amine, or of the azeotropic water-heterocyclic amine solution, and of the monochloramine are such that the ratio of the molar concentrations of the heterocyclic amine solution to the monochloramine is advantageously understood. between 4 and 10, the terminals may be included.
  • the reaction mixture can optionally undergo one or more degassing step (s) to remove the ammonia contained in said mixture.
  • the method comprises the following steps: i ') eliminating the ammonia present in the solution obtained following step a ) by stripping; then ii ') isolating a solution comprising the exocyclic hetero-cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine formed and a concentrated solution of unreacted heterocyclic amine, or if necessary a heterocyclic azeotropic water-amine solution which n 'has not reacted, by distillation of the solution obtained following step i') under atmospheric or reduced pressure at a temperature between 50 and 180 ° C; and iii ') reinjecting into the reactor of step a) said concentrated or azeotropic aqueous solution of heterocyclic amine obtained following step ii').
  • the expression “stripping” is understood to mean the elimination of a very volatile product, in this case ammonia, by
  • reaction solution containing hydrazine, recovered in step ii '), is then treated by adding a strong base, such as sodium hydroxide (step b)).
  • a strong base such as sodium hydroxide
  • This operation allows the separation of the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine in an organic phase, having a titer between 70 and 90% hydrazine, depending on the organic character of the hydrazine molecule.
  • the concentrated solution of hydrazine thus obtained can be used directly or distilled under reduced pressure (step c)).
  • the amine is recycled during the distillation step ii '), without entraining the hydrazine and at a temperature below the boiling point of the amine, which avoids its thermo-degradation.
  • the amine Given the absence of traces of hydrazine in the aqueous solution containing the heterocyclic amine, optionally in the form of an azeotrope, it can be injected, without additional treatment, directly at the stage reactor a), where hydrazine is formed.
  • This variant of the invention is particularly advantageous in the context of a continuous preparation of the exocyclic cycloalkyl-hydrazine derivative or exocyclic heterocycloalkyl-hydrazine derivative.
  • the process according to the present invention therefore allows not only the synthesis of the cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine exocyclic continuously, without the formation of any toxic intermediate, but it also allows the obtaining of said hydrazine with little cost Student.
  • the classic Raschig synthesis generally requires a large excess of amine, which constitutes a considerable drawback when the amines used as raw material for the preparation of the corresponding hydrazines have a very high cost.
  • the process of the present invention thanks to the recovery and recycling of a concentrated solution of heterocyclic amine, optionally in the form of an azeotrope, makes it possible to obtain the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine corresponding with a very low cost compared to other known methods.
  • the isolation of the amine in the form of an aqueous solution, optionally azeotropic, at relatively low temperature also constitutes another originality as well as a considerable economic advantage of the process according to the invention.
  • the monochloramine introduced in step a) is advantageously prepared according to a process comprising the following successive steps: ci) preparing an aqueous solution of sodium hypochlorite having a chlorometric degree of between 36 and 100 ° optionally by dilution of a solution d hypochlorite having a chlorometric degree of between 100 and 120 °; then ⁇ ) reacting a solution of ammonium hydroxide and ammonium chloride with the aqueous solution of sodium hypochlorite obtained following step d), in a weakly alkaline medium, at a temperature between -15 and -7 ° C, to form said monochloramine.
  • weakly alkaline medium is understood to mean a medium whose pH value is approximately 10 ⁇ 1.
  • the molar ratio of ammonium hydroxide and ammonium chloride / aqueous solution of sodium hypochlorite is advantageously between 2.5 and 3, the limits being included.
  • the molar ratio of chloride ammom 'um / ammonium hydroxide is advantageously between 0.1 and 1.75, the limits included, more preferably it is about 0.65.
  • step ⁇ In the case where the chlorinated reagent used in step ⁇ ) is obtained by dilution of a high titer hypochlorite solution at 100-120 ° chlorometric, this dilution has the advantage of reducing the content of sodium chloride. This environmentally friendly treatment allows cooling of the bleach solution, without risk of crystallization down to -15 ° C.
  • Example 1 gives, without limitation, a detailed description of the implementation of the method of the invention, the method of which the block diagram is shown in FIG. 1.
  • CD1 distillation column n ° 1
  • CD2 distillation column n ° 2
  • Example 2 gives, without implied limitation, a detailed description of the implementation of the method of the invention, the method of which the principle diagram is represented in FIG. 2.
  • N-amino-piperidine 3' Water solution + NH 3 + NaCl + NaOH
  • EXAMPLE 1 Preparation of the N-amino piperidine continuously
  • the monochloramine solution obtained above (2 liters) is made alkaline by continuous introduction of a concentrated solution of sodium hydroxide (0.37 liter at 30% by weight) within a double jacket mixer M kept at low temperature between -9 ° C and -11 ° C. Homogenization is ensured by magnetic drive.
  • N-aminopiperidine is carried out in a single-phase medium in a stirred tubular reactor (R2), under scanning of argon or nitrogen.
  • the NH 2 CI / NaOH mixture obtained (2.37 liters) and the piperidine solution (2.36 liters at 66% by weight) are introduced simultaneously (under argon or nitrogen) continuously into the reactor R2 with an adequate flow rate for have a piperidine to monochloramine molar ratio of approximately 8 and a titer of sodium hydroxide in the reaction medium at the end of the reaction equal to 0.3 mol.L "1.
  • the reaction temperature is maintained at approximately 55 ° C.
  • reaction mixture After 30 seconds of reaction, the reaction mixture then undergoes a degassing operation to remove the ammonia contained in the solution
  • the reaction solution is first of all freed from the ammonia by stripping (distillation column CD1, recovery is obtained at the head about 62 g of ammonia) then about 4.6 kg of the ammonia-free solution are distilled at 92.2 ° C. at atmospheric pressure (CD2 distillation column) to remove the unreacted amine, piperidine.
  • CD2 distillation column atmospheric pressure
  • the piperidine is obtained at the top of the column in the form of an aqueous solution of composition of approximately 66% by weight in amine (approximately 2 kg). This solution is then recycled and immediately re-injected into R2, without additional treatment ( Figure 1: dotted arrow).
  • the reaction solution containing the hydrazine (recovered at the bottom of the CD2 column, approximately 2.7 kg) is treated by addition of solid sodium hydroxide under cooling and under scanning of argon, to separate the N - aminopiperidine in an organic phase titrating nearly 70 to 80% hydrazine at 80 ° C.
  • the mass titer of anhydrous soda injected is preferably between 15 and 30% by weight.
  • This organic phase is thus recovered, titrating nearly 92% of hydrazine and an aqueous phase comprising water and the salts (NaCl, NaOH).
  • the concentrated solution of hydrazine (organic phase) can then be used directly or distilled under reduced pressure (CD3 distillation column).
  • N-aminopiperidine After distillation under reduced pressure, N-aminopiperidine is obtained with a degree of purity greater than 99.5%. The hydrazine yield relative to the piperidine consumed is greater than 92%.
  • the reaction fluid from RI (2 liters) with a titer greater than 1 mol.L "1 in monochloramine is introduced into a mixer M fed continuously by a 30% sodium hydroxide solution (flow rate of 1.75 mL / min).
  • a thermostatic jacket allows the temperature in the mixer to be set at -10 ° C.
  • the synthesis of N-aminopiperidine is carried out by means of an agitated tubular agitator R2 and under scanning of argon.
  • the alkalized monochloramine (2.35 liters), coming from the enclosure of the mixture M, and the amino reagent are introduced simultaneously at the base of the reactor by means of metering pumps.
  • the present variant is characterized in that an amount of hydroxide of hydroxide is added to the homogeneous reaction liquor (4.04 liters). sodium between 13 and 30% under cooling so that the temperature does not exceed 60 ° C.
  • N-aminopiperidine then requires two successive stages: recovery of the piperidine which has not reacted by distillation of the organic phase at atmospheric pressure under argon. concentrated amine solution at 66% by weight (1 ") at a temperature from 92.2 ° C until the water is used up, then about 600 g of anhydrous piperidine (1 ') at a temperature of 105 ° C (distillation column CD1').

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Abstract

The invention relates to a method for the synthesis of exocyclic derivatives of cycloalkyl-hydrazines and exocyclic derivatives of heterocycloalkyl-hydrazines. The invention is characterised in that the method comprises a step consisting in demixing a solution containing said synthesised derivative, by reacting a heterocyclic amine with monochloramine, in an organic phase and an aqueous phase with the addition of anhydrous sodium hydroxide. According to the invention, the starting amine which has not reacted is collected and reused directly without any additional treatment. The inventive method can also be used to obtain the corresponding exocyclic heterocycloalkyl-hydrazine or cycloalkyl-hydrazinederivative derivative at a low cost compared to that of other known methods.

Description

Procédé de synthèse de dérivés de cycloalkyl-hydrazines exocycliques et de dérivés d'hétérocycloalkyl-hydrazines exocycliquesProcess for the synthesis of exocyclic cycloalkyl hydrazine derivatives and exocyclic heterocycloalkyl hydrazine derivatives

La présente invention concerne un nouveau procédé de synthèse de dérivés de cycloalkyl-hydrazines exocycliques et de dérivés d'hétérocycloalkyl-hydrazines exocycliques.The present invention relates to a new process for the synthesis of exocyclic cycloalkyl hydrazine derivatives and exocyclic heterocycloalkyl hydrazine derivatives.

Les dérivés de cycloalkyl-hydrazines et d'hétérocycloalkyl-hydrazines exocycliques, notamment la N-aminopipéridine, sont utilisés très fréquemment comme intermédiaires dans la fabrication de médicaments.Cycloalkyl hydrazine derivatives and exocyclic heterocycloalkyl hydrazines, in particular N-aminopiperidine, are very frequently used as intermediates in the manufacture of medicaments.

A l'heure actuelle, les méthodes de synthèse de dérivés de cycloalkyl-hydrazines et d'hétérocycloalkyl-hydrazines exocycliques décrites dans la littérature scientifique font appel à l'urée et aux nitrosamines. Dans le cas de la synthèse de la N-aminopipéridine par exemple, une première méthode de synthèse réalisée en trois étapes consiste à préparer la 1-pipéridyl urée suivie d'une oxydation par Phypochlorite de sodium. La l-pipéridyl-3-chlorourée formée est ensuite transformée en N-aminopipéridine sous l'action d'une solution concentrée en soude (R. Ohme, H. Preuschhof, J. Prakt. Chem. 312, 349 (1970)). Une seconde méthode consiste en une nitrosation de la pipéridine suivie d'une hydrogénation chimique (LiAlH4) ou catalytique (Zn/AcOH) du dérivé nitrosé (1-nitrosopipéridine) (Allen & Hanburys Ltd. (1965), 74, 3693-4). Dans tous les cas, le composé nitrosé doit être purifié par distillation. Cette méthode conduit à d'assez bons rendements (75%). Cependant, le produit issu de la première étape doit être manipulé avec beaucoup de précautions à cause de sa toxicité (composé hautement cancérogène), ce qui pose industriellement des problèmes de mise en exploitation. De plus, l'utilisation de LiAlH4 impose l'absence de traces d'eau, de réacteurs étanches et de solvants anhydres (éther diéthylique), ce qui a pour effet d'augmenter les risques d'inflammation du mélange réactionnel.At present, the methods of synthesis of cycloalkyl-hydrazine derivatives and exocyclic heterocycloalkyl-hydrazines described in the scientific literature use urea and nitrosamines. In the case of the synthesis of N-aminopiperidine for example, a first method of synthesis carried out in three stages consists in preparing 1-piperidyl urea followed by oxidation with sodium hypochlorite. The 1-piperidyl-3-chlorourea formed is then transformed into N-aminopiperidine under the action of a concentrated solution of sodium hydroxide (R. Ohme, H. Preuschhof, J. Prakt. Chem. 312, 349 (1970)). A second method consists of a nitrosation of piperidine followed by a chemical hydrogenation (LiAlH 4 ) or catalytic (Zn / AcOH) of the nitrose derivative (1-nitrosopiperidine) (Allen & Hanburys Ltd. (1965), 74, 3693-4 ). In all cases, the nitrosed compound must be purified by distillation. This method leads to fairly good yields (75%). However, the product resulting from the first stage must be handled with great care because of its toxicity (highly carcinogenic compound), which poses industrial problems of exploitation. In addition, the use of LiAlH 4 imposes the absence of traces of water, sealed reactors and anhydrous solvents (diethyl ether), which has the effect of increasing the risks of ignition of the reaction mixture.

D'autre part, il est reconnu que pour la préparation des différentes hydrazines, on fait souvent appel à la réaction dite de « Raschig » qui consiste à synthétiser la monochloramine par réaction de l'ammoniac sur une solution d'hypochlorite de sodium et ensuite faire réagir la monochloramine formée sur une aminé pour obtenir l'hydrazine correspondante. Ce procédé nécessite deux étapes distinctes, la première réalisée à froid pour la synthèse de la monochloramine et la deuxième réalisée à chaud, pendant laquelle est effectuée la synthèse proprement dite de l'hydrazine. Par ailleurs, la monochloramine doit se trouver en présence d'un excès suffisant d'aminé dans les solutions intermédiaires de manière à éviter des réactions secondaires de dégradation, et par la suite le procédé exige des quantités très importantes de solutions à traiter.On the other hand, it is recognized that for the preparation of the various hydrazines, use is often made of the so-called "Raschig" reaction which consists in synthesizing monochloramine by reaction of ammonia on a solution of sodium hypochlorite and then reacting the monochloramine formed on an amine to obtain the corresponding hydrazine. This process requires two separate steps, the first carried out cold for the synthesis of monochloramine and the second carried out hot, during which the actual synthesis of hydrazine is carried out. Furthermore, the monochloramine must be in the presence of a sufficient excess of amine in the intermediate solutions so as to avoid secondary degradation reactions, and subsequently the process requires very large quantities of solutions to be treated.

Cependant, ce procédé ne peut pas être appliqué pour la préparation de toutes les alkyl- et hétéroalkyl- hydrazines exocycliques et surtout pas pour la préparation d'hydrazines organiques, thermodégradables à température d'ébullition élevée. En particulier, le traitement des solutions de synthèse nécessite l'extraction de l'eau puis de l'aminé, ce qui exige des opérations onéreuses.However, this process cannot be applied for the preparation of all exocyclic alkyl- and heteroalkyl-hydrazines and especially not for the preparation of organic hydrazines, thermodegradable at high boiling temperature. In particular, the treatment of synthetic solutions requires the extraction of water and then of the amine, which requires expensive operations.

Le brevet EP 0277267 décrit un procédé de synthèse en continu du N-amino aza-3 bicyclo [3,3,0] octane, caractérisé en ce que l'on fait réagir une solution d'hydroxyde d'ammonium et de chlorure d'ammonium avec une solution aqueuse d'hypochlorite de sodium à une température comprise entre -15°C et -7°C en milieu alcalin, et ensuite, que l'on fait réagir la monochloramine ainsi formée avec l'aza-3 bicyclo [3,3,0] octane, en milieu biphasique dans un réacteur approprié muni d'un agitateur coaxial à ailettes, à une température comprise entre 30°C et 90°C et en milieu alcalin, puis que l'on sépare du milieu réactionnel rammoniac et ensuite l'aza-3 bicyclo [3,3,0] octane qui n'a pas réagi par distillation pour le recycler, puis que l'on isole par démixtion une solution concentrée de N-amino aza-3 bicyclo [3,3,0] octane par addition d'hydroxyde de sodium au milieu réactionnel, et que l'on purifie l'hydrazine ainsi obtenue, si on le désire, par distillation.Patent EP 0277267 describes a process for the continuous synthesis of N-amino aza-3 bicyclo [3,3,0] octane, characterized in that a solution of ammonium hydroxide and chloride is reacted ammonium with an aqueous solution of sodium hypochlorite at a temperature between -15 ° C and -7 ° C in an alkaline medium, and then reacting the monochloramine thus formed with aza-3 bicyclo [3 , 3.0] octane, in a two-phase medium in a suitable reactor fitted with a coaxial stirrer with fins, at a temperature between 30 ° C and 90 ° C and in an alkaline medium, then separated from the rammoniac reaction medium and then the aza-3 bicyclo [3,3,0] octane which has not reacted by distillation to recycle it, and then a concentrated solution of N-amino aza-3 bicyclo [3 is isolated by demixing) 3.0] octane by addition of sodium hydroxide to the reaction medium, and the hydrazine thus obtained is purified, if desired, by distillation.

Après formation de N-amino aza-3 bicyclo [3,3,0] octane et refroidissement, la solution réactionnelle subit un dégazage pour éliminer l'ammoniac et l'amino-3 bicyclo [3,3,0] octane qui n'a pas réagi est séparé du milieu réactionnel par simple distillation sous pression atmosphérique et à une température environ 90 à 100°C. Sous ces conditions, l'aminé est obtenue sous forme d'une solution aqueuse concentrée à 30% en aza-3 bicyclo [3,3,0] octane. Cette solution est recyclée.After formation of N-amino aza-3 bicyclo [3,3,0] octane and cooling, the reaction solution undergoes degassing to remove ammonia and 3-amino bicyclo [3,3,0] octane which does not unreacted is separated from the reaction medium by simple distillation under atmospheric pressure and at a temperature of about 90 to 100 ° C. Under these conditions, the amine is obtained in the form of an aqueous solution concentrated to 30% in aza-3 bicyclo [3,3,0] octane. This solution is recycled.

Les inventeurs ont maintenant découvert un nouveau procédé de synthèse de dérivés de cycloalkyl-hydrazines exocycliques et de dérivés d'hétérocycloalkyl-hydrazines exocycliques, notamment de la N-aminopipéridine. Ce procédé mis en œuvre en continu est en partie basé sur une transposition du procédé Raschig, et il consiste à préparer la monochloramine par action de l'hypochlorite de sodium sur l'ammoniac à base température, et ensuite à faire agir la monochloramine ainsi produite sur une aminé hétérocyclique en milieu homogène ou, selon la température, en milieu hétérogène, puis à extraire l'hydrazine formée. L'aminé de départ est recyclée, puis le cas échéant réinjectée directement sur la monochloramine sans aucun traitement supplémentaire.The inventors have now discovered a new process for the synthesis of exocyclic cycloalkyl hydrazine derivatives and exocyclic heterocycloalkyl hydrazine derivatives, in particular N-aminopiperidine. This process implemented in continuous is partly based on a transposition of the Raschig process, and it consists in preparing the monochloramine by action of sodium hypochlorite on ammonia at low temperature, and then in making the monochloramine thus produced act on a heterocyclic amine in medium homogeneous or, depending on the temperature, in a heterogeneous medium, then to extract the hydrazine formed. The starting amine is recycled, then if necessary reinjected directly onto the monochloramine without any additional treatment.

Dans le cadre de la présente invention, on pourra désigner, dans un souci de simplification, le ou les dérivés de cycloalkyl-hydrazines exocycliques et le ou les dérivés d'hétérocycloalkyl-hydrazines exocycliques par le terme « hydrazine(s) ».In the context of the present invention, for the sake of simplification, the exocyclic cycloalkyl-hydrazine derivative (s) and the exocyclic heterocycloalkyl-hydrazine derivative (s) may be designated by the term "hydrazine (s)".

Au sens de la présente invention, l'expression « dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazines exocyclique » doit se lire « dérivé de cycloalkyl- hydrazine exocyclique ou dérivé d'hétérocycloalkyl-hydrazine exocyclique ». D'une manière similaire, on pourra désigner la(les) amine(s) hétéro cyclique(s) par le teπne « amine(s) ».Within the meaning of the present invention, the expression “exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine” should read “exocyclic cycloalkyl-hydrazine derivative or exocyclic heterocycloalkyl-hydrazine derivative”. Similarly, the hetero cyclic amine (s) may be designated by the term "amine (s)".

La présente invention concerne ainsi un procédé de synthèse de dérivés de cycloalkyl- hydrazines exocycliques et de dérivés d'hétérocycloalkyl-hydrazines exocycliques caractérisé en ce qu'il comprend les étapes successives suivantes : a) synthétiser le dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl- hydrazine exocyclique dans un réacteur approprié en faisant réagir en milieu alcalin et à une température comprise entre 30 et 60°C une monochloramine avec une aminé hétérocyclique ; puis b) démixter la solution obtenue suite à l'étape a) en une phase organique et une phase aqueuse par l'ajout d'hydroxyde de sodium anhydre sous refroidissement afin que la température ne dépasse pas la température d'ébullition des composés ; et c) le cas échéant, isoler, par distillation de la phase organique ainsi obtenue, le dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique. Le dérivé de cycloalkyl-hydrazine exocyclique ou d'hétérocycloalkyl-hydrazine exocyclique est avantageusement de formule (I) dans laquelle un des atomes de carbone du cycle est éventuellement remplacé par un hétéroatome choisi parmi un atome d'azote ou d'oxygène, RI et R2, identiques ou différents, représentent un atome d'hydrogène ou un radical alkyle en Cι-C6 ou RI et R2 forment ensemble un cycloalkyle en C3-C8 et n vaut 1 à 3.The present invention thus relates to a process for the synthesis of exocyclic cycloalkylhydrazine derivatives and exocyclic heterocycloalkyl-hydrazine derivatives, characterized in that it comprises the following successive steps: a) synthesizing the cycloalkyl-hydrazine derivative or heterocycloalkyl - exocyclic hydrazine in a suitable reactor by reacting in an alkaline medium and at a temperature between 30 and 60 ° C a monochloramine with a heterocyclic amine; then b) demixing the solution obtained following step a) into an organic phase and an aqueous phase by adding anhydrous sodium hydroxide under cooling so that the temperature does not exceed the boiling point of the compounds; and c) if necessary, isolating, by distillation of the organic phase thus obtained, the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine. The exocyclic cycloalkyl-hydrazine or exocyclic heterocycloalkyl-hydrazine derivative is advantageously of formula (I) in which one of the carbon atoms of the ring is optionally replaced by a heteroatom chosen from a nitrogen or oxygen atom, RI and R2, identical or different, represent a hydrogen atom or a Cι-C 6 alkyl radical or RI and R2 together form a C 3 -C 8 cycloalkyl and n is 1 to 3.

Le dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique est encore plus avantageusement choisi dans le groupe constitué par la N-aminopipéridine, la N-aminomorpholine, la N-amino-2,6-diméthyl-pipéridine, la N-aminopyrrolidine, la N-aminoazépine, la N-amino-4-méthyl-pipérazine. Le réacteur de l'étape a) est avantageusement placé sous atmosphère inerte, notamment sous balayage d'argon ou d'azote. Ledit réacteur approprié de l'étape a) est avantageusement un réacteur tabulaire agité. Le réacteur tubulaire permet d'éviter un contact entre l'hydrazine naissante et la monochloramine et ainsi il permet d'éviter une réaction d'oxydo-réduction entre ces deux réactifs. Le front réactionnel se déplace le long du tube et l'hydrazine n'est plus en contact avec la monochloramine injectée à la base du réacteur.The exocyclic cycloalkyl-hydrazine or heterocycloalkyl-hydrazine derivative is even more advantageously chosen from the group consisting of N-aminopiperidine, N-aminomorpholine, N-amino-2,6-dimethyl-piperidine, N-aminopyrrolidine , N-aminoazepine, N-amino-4-methyl-piperazine. The reactor of step a) is advantageously placed under an inert atmosphere, in particular under an argon or nitrogen sweep. Said suitable reactor of step a) is advantageously a stirred tabular reactor. The tubular reactor makes it possible to avoid contact between the nascent hydrazine and the monochloramine and thus it makes it possible to avoid an oxidation-reduction reaction between these two reactants. The reaction front moves along the tube and the hydrazine is no longer in contact with the monochloramine injected at the base of the reactor.

Selon une variante avantageuse de l'invention, la concentration en ions hydroxyles dans le milieu de réaction de l'étape a) est comprise entre 0,3 et 0,8 mol.l"1. Le rapport des concentrations molaires de l'aminé hétérocyclique sur la monochloramine doit avantageusement être supérieur ou égal à 4 et inférieur ou égal à 10. Le temps de réaction est variable est dépend de la température à laquelle s'effectue la réaction et du rapport des concentrations des réactifs. Par exemple, dans le cas de la synthèse de la N-aminopipéridine et dans la gamme des rapports de concentrations donnée, le temps de réaction est de l'ordre de 20 secondes à 2 minutes à 25°C et de l'ordre de 4 secondes à 30 secondes à 60°C.According to an advantageous variant of the invention, the concentration of hydroxyl ions in the reaction medium of step a) is between 0.3 and 0.8 mol.l "1. The ratio of the molar concentrations of the amine heterocyclic on the monochloramine must advantageously be greater than or equal to 4 and less than or equal to 10. The reaction time is variable and depends on the temperature at which the reaction is carried out and on the ratio of the concentrations of the reactants. in the case of the synthesis of N-aminopiperidine and in the range of concentration ratios given, the reaction time is of the order of 20 seconds to 2 minutes at 25 ° C. and of the order of 4 seconds to 30 seconds at 60 ° C.

Selon un mode avantageux de la présente invention, la monochloramine est alcalinisée préalablement à l'étape a) dans un mélangeur par ajout d'une solution d'une base forte telle que l'hydroxyde de sodium de telle sorte que le titre massique en hydroxyde de sodium soit compris entre 2 et 6%. Ledit mélangeur est avantageusement maintenu à une température comprise entre -10 et 5°C. La réaction de la monochloramine avec l'aminé hétérocyclique s'effectue ainsi avantageusement en présence d'une solution aqueuse d'hydroxyde de sodium à chaud. A la fin de la réaction de synthèse du dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique, c'est-à-dire en sortie du réacteur de l'étape a), la concentration en hydroxyde de sodium dans le milieu réactionnel est d'environ 0,3 mol.L"1. La concentration en soude ne doit pas être trop élevée sinon le mélange réactionnel risque de démixter par relargage. En cas de relargage, il faudrait alors faire intervenir un réacteur du type réacteur piston agité. Lors de la réaction de synthèse de l'hydrazine, de l'acide chlorhydrique est également formé, or il faut éviter toute protonation locale de l'aminé au moment du mélange afin d'éviter la formation d'une chloramine substituée. Par exemple, dans le cas de la synthèse de la N-aminopipéridine, la pipéridine protonée par l'acide chlorhydrique (pipéridinium) peut réagir avec la monochloramine pour former la 1-chloropipéridine, qui peut alors réagir avec les ions hydroxyles pour former la 2,3,4,5-tetrahydropyridine, qui risque ensuite de se trimériser. L'alcalinisation de la monochloramine, c'est-à-dire l'ajout d'une base forte telle que la soude, permet ainsi de neutraliser l'acide formé. La quantité de base forte ajoutée doit être suffisante pour neutraliser tout l'acide formé. De plus, la vitesse de formation de l'hydrazine augmente avec l'alcalinité du milieu, ce qui n'est pas le cas pour la vitesse des réactions de dégradation, telles que par exemple l'oxydation de l'hydrazine naissante par la chloramine.According to an advantageous embodiment of the present invention, the monochloramine is made alkaline before step a) in a mixer by adding a solution of a strong base such as sodium hydroxide so that the mass content of hydroxide sodium is between 2 and 6%. Said mixer is advantageously maintained at a temperature between -10 and 5 ° C. The reaction of monochloramine with the heterocyclic amine is thus advantageously carried out in the presence of an aqueous solution of sodium hydroxide when hot. At the end of the synthesis reaction of the exocyclic cycloalkyl-hydrazine or heterocycloalkyl-hydrazine derivative, that is to say at the outlet of the reactor in step a), the concentration of sodium hydroxide in the reaction medium is approximately 0.3 mol.L "1. The sodium hydroxide concentration must not be too high otherwise the reaction mixture risks demixing by salting out. In the case of salting out, a reactor of the agitated piston reactor type would then have to be used During the hydrazine synthesis reaction, hydrochloric acid is also formed, but any local protonation of the amine during mixing must be avoided in order to avoid the formation of a substituted chloramine. , in the case of the synthesis of N-aminopiperidine, piperidine protonated by hydrochloric acid (piperidinium) can react with monochloramine to form 1-chloropiperidine, which can then react with hydroxyl ions to form the 2,3,4,5-tetrahydropyridine, which then risks trimerizing. The alkalinization of monochloramine, that is to say the addition of a strong base such as sodium hydroxide, thus makes it possible to neutralize the acid formed. The amount of strong base added must be sufficient to neutralize all the acid formed. In addition, the rate of formation of hydrazine increases with the alkalinity of the medium, which is not the case for the rate of degradation reactions, such as for example the oxidation of incipient hydrazine by chloramine .

Lors de l'étape b), la quantité d'hydroxyde de sodium anhydre ajoutée est telle que le titre massique en hydroxyde de sodium soit compris entre 10 et 35%, de préférence environ égal à 30%. Dans ces conditions, le milieu démixte en deux phases dont l'une concentre le dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique formé dans la phase légère (phase organique). Ce traitement à l'hydroxyde de sodium permet par démixtion d'éliminer l'eau présente dans le milieu réactionnel et d'extraire les sels et le cas échéant l'ammoniac dans la phase inférieure (phase aqueuse). Dans le cas de la synthèse de la N-aminopipéridine par exemple, la température du milieu de démixtion de l'étape b) ne doit pas dépasser 80°C. Selon une première variante avantageuse de l'invention, l'aminé hétérocyclique est introduite, à l'étape a), sous forme d'une aminé hétérocyclique anhydre. La monochloramine, avantageusement alcalinisée, et l'aminé hétérocyclique anhydre sont de manière avantageuse introduites simultanément dans le réacteur. Les débits d'addition de l'aminé hétérocyclique et de la monochloramine sont tels que le rapport des concentrations molaires de l'aminé hétérocyclique anhydre sur la monochloramine soit avantageusement compris entre 4 et 10, les bornes pouvant être incluses. Une partie de la réaction de synthèse du dérivé de cycloalkyl-hydrazine et d'hétérocycloalkyl-hydrazine exocyclique peut être effectuée en milieu hétérogène. L'ajout d'hydroxyde de sodium anhydre lors de l'étape b), avantageusement de telle sorte que le titre massique en hydroxyde de sodium soit compris entre 15 et 35 %, permet de démixter le milieu en deux phases dont l'une, la phase supérieure ou la phase organique, concentre la quasi-totalité des organiques, à savoir le dérivé de cycloalkyl-hydrazines ou d'hétérocycloalkyl-hydrazine exocyclique et l'aminé hétérocyclique.During step b), the amount of anhydrous sodium hydroxide added is such that the mass content of sodium hydroxide is between 10 and 35%, preferably approximately equal to 30%. Under these conditions, the medium demixes into two phases, one of which concentrates the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine formed in the light phase (organic phase). This sodium hydroxide treatment makes it possible, by demixing, to remove the water present in the reaction medium and to extract the salts and, where appropriate, the ammonia in the lower phase (aqueous phase). In the case of the synthesis of N-aminopiperidine for example, the temperature of the demixing medium of step b) must not exceed 80 ° C. According to a first advantageous variant of the invention, the heterocyclic amine is introduced, in step a), in the form of an anhydrous heterocyclic amine. The monochloramine, advantageously alkalized, and the anhydrous heterocyclic amine are advantageously introduced simultaneously into the reactor. The addition rates of the heterocyclic amine and of the monochloramine are such that the ratio of the molar concentrations of the anhydrous heterocyclic amine to the monochloramine is advantageously between 4 and 10, the limits being able to be included. Part of the synthesis reaction of the cycloalkyl-hydrazine derivative and exocyclic heterocycloalkyl-hydrazine can be carried out in a heterogeneous medium. The addition of anhydrous sodium hydroxide during step b), advantageously so that the mass titer in sodium hydroxide is between 15 and 35%, makes it possible to demix the medium into two phases, one of which, the upper phase or the organic phase concentrates almost all of the organics, namely the exocyclic cycloalkyl-hydrazine or heterocycloalkyl-hydrazine derivative and the heterocyclic amine.

L'avantage de ce traitement permet, en une seule étape, d'éliminer 80 à 90% en poids de l'eau présente dans le milieu réactionnel, selon le caractère organique (nombre d'atomes de carbones) des molécules d'aminé et d'hydrazine, et d'extraire l'ammoniac avec les sels dans la phase inférieure (phase aqueuse). L'étape c) comprend alors avantageusement les étapes successives suivantes : i) isoler l'aminé hétérocyclique qui n'a pas réagi et une solution concentrée de dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique par distillation de la phase organique obtenue suite à l'étape b) ; puis ii) le cas échéant, rectifier par distillation sous pression réduite ladite solution concentrée du dérivé de cycloalkyl-hydrazine et d'hétérocycloalkyl-hydrazine exocyclique.The advantage of this treatment makes it possible, in a single step, to remove 80 to 90% by weight of the water present in the reaction medium, depending on the organic nature (number of carbon atoms) of the amine molecules and hydrazine, and extracting the ammonia with the salts in the lower phase (aqueous phase). Step c) then advantageously comprises the following successive steps: i) isolating the heterocyclic amine which has not reacted and a concentrated solution of exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine by distillation of the organic phase obtained following step b); then ii) if necessary, rectify by distillation under reduced pressure said concentrated solution of the derivative of cycloalkyl-hydrazine and of exocyclic heterocycloalkyl-hydrazine.

Lors de l'étape i), la distillation s'effectue avantageusement dans une colonne de distillation unique sous pression atmosphérique ou réduite, en fonction de la température d'ébullition de l'aminé de départ. Dans un premier temps, on recueille en tête de colonne une solution concentrée d'aminé hétérocyclique ou le cas échéant une solution azéotropique eau-amine hétérocyclique jusqu'à épuisement de l'eau, puis l'aminé hétérocyclique anhydre. L'aminé hétérocyclique anhydre ainsi récupérée peut être réinjectée directement dans le réacteur de l'étape a) où a lieu la synthèse de l'hydrazine. L'aminé hétérocyclique obtenue sous forme de solution concentrée ou de solution azéotropique avec l'eau peut être récupérée, puis éventuellement réinjectée après un traitement approprié. Le cas échéant, une rectification sous pression réduite, avantageusement vers 115 mm de Hg, du produit obtenu en pied de colonne à l'étape i) permet de recueillir le dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique avec un titre supérieur à 99%, avantageusement supérieur à 99,9%. Ledit dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique doit ensuite être stocké sous atmosphère inerte, tel que sous argon par exemple, de manière à éviter toute réaction d'oxydation par l'oxygène.During step i), the distillation is advantageously carried out in a single distillation column under atmospheric or reduced pressure, depending on the boiling temperature of the starting amine. Firstly, a concentrated heterocyclic amine solution or, where appropriate, a heterocyclic water-amine azeotropic solution until the water is used up, is collected at the top of the column, followed by the anhydrous heterocyclic amine. The anhydrous heterocyclic amine thus recovered can be reinjected directly into the reactor of step a) where the synthesis of hydrazine takes place. The heterocyclic amine obtained in the form of a concentrated solution or an azeotropic solution with water can be recovered, then optionally reinjected after an appropriate treatment. If necessary, rectification under reduced pressure, advantageously around 115 mm of Hg, of the product obtained at the bottom of the column in step i) makes it possible to collect the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine with a higher titer at 99%, advantageously greater than 99.9%. Said exocyclic cycloalkyl-hydrazine or heterocycloalkyl-hydrazine derivative must then be stored under an inert atmosphere, such as under argon for example, so as to avoid any oxidation reaction with oxygen.

Cette variante de l'invention est particulièrement avantageuse dans le cadre d'une préparation en batch du dérivé de cycloalkyl-hydrazine exocyclique ou d'hétérocycloalkyl-hydrazine exocyclique.This variant of the invention is particularly advantageous in the context of a batch preparation of the exocyclic cycloalkyl-hydrazine derivative or exocyclic heterocycloalkyl-hydrazine derivative.

Selon une seconde variante avantageuse de l'invention, l'aminé hétérocyclique est introduite, à l'étape a), sous forme d'une solution aqueuse concentrée d'aminé hétérocyclique ou d'une solution azéotropique eau-amine hétérocyclique. L'étape a) s'effectue alors en milieu homogène ou hétérogène (dans le cas d'une aminé très lourde).According to a second advantageous variant of the invention, the heterocyclic amine is introduced, in step a), in the form of a concentrated aqueous solution of heterocyclic amine or of an azeotropic water-heterocyclic amine solution. Step a) is then carried out in a homogeneous or heterogeneous medium (in the case of a very heavy amine).

En fonction de l'aminé considérée, la solution aqueuse concentrée d'aminé hétérocyclique peut être sous la forme d'un azéotrope eau-amine hétérocyclique. La monochloramine, avantageusement alcalinisée, et la solution d'aminé hétérocyclique sont de manière avantageuse introduites simultanément dans le réacteur. Les débits d'addition de la solution aqueuse concentrée d'aminé hétérocyclique, ou de la solution azéotropique eau-amine hétérocyclique, et de la monochloramine sont tels que le rapport des concentrations molaires de la solution d'aminé hétérocyclique sur la monochloramine soit avantageusement compris entre 4 et 10, les bornes pouvant être incluses. Lors de l'étape a), le mélange réactionnel peut le cas échéant subir une ou plusieurs étape(s) de dégazage pour éliminer l'ammoniac contenu dans ledit mélange. Dans cette seconde variante de l'invention, suite à l'étape a) et préalablement à l'étape b), le procédé comprend les étapes suivantes : i') éliminer l'ammoniac présent dans la solution obtenue suite à l'étape a) par stripping ; puis ii') isoler une solution comprenant le dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique formé et une solution concentrée d'aminé hétérocyclique qui n'a pas réagi, ou le cas échéant une solution azéotropique eau-amine hétérocyclique qui n'a pas réagi, par distillation de la solution obtenue suite à l'étape i') sous pression atmosphérique ou réduite à une température comprise entre 50 et 180°C ; et iii') réinjecter dans le réacteur de l'étape a) ladite solution aqueuse concentrée ou azéotropique d'aminé hétérocyclique obtenue suite à l'étape ii'). Au sens de la présente invention, on entend par l'expression « stripping » l'élimination d'un produit très volatil, en l'occurrence l'ammoniac, par simple chauffage du mélange.Depending on the amine considered, the concentrated aqueous solution of heterocyclic amine may be in the form of a heterocyclic water-amine azeotrope. The monochloramine, advantageously alkalized, and the heterocyclic amine solution are advantageously introduced simultaneously into the reactor. The addition rates of the concentrated aqueous solution of heterocyclic amine, or of the azeotropic water-heterocyclic amine solution, and of the monochloramine are such that the ratio of the molar concentrations of the heterocyclic amine solution to the monochloramine is advantageously understood. between 4 and 10, the terminals may be included. During step a), the reaction mixture can optionally undergo one or more degassing step (s) to remove the ammonia contained in said mixture. In this second variant of the invention, following step a) and prior to step b), the method comprises the following steps: i ') eliminating the ammonia present in the solution obtained following step a ) by stripping; then ii ') isolating a solution comprising the exocyclic hetero-cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine formed and a concentrated solution of unreacted heterocyclic amine, or if necessary a heterocyclic azeotropic water-amine solution which n 'has not reacted, by distillation of the solution obtained following step i') under atmospheric or reduced pressure at a temperature between 50 and 180 ° C; and iii ') reinjecting into the reactor of step a) said concentrated or azeotropic aqueous solution of heterocyclic amine obtained following step ii'). For the purposes of the present invention, the expression “stripping” is understood to mean the elimination of a very volatile product, in this case ammonia, by simple heating of the mixture.

La solution réactionnelle contenant l'hydrazine, récupérée à l'étape ii'), est ensuite traitée par ajout d'une base forte, telle que la soude (étape b)). Cette opération permet la séparation du dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique dans une phase organique, ayant un titre compris entre 70 et 90% en hydrazine, selon le caractère organique de la molécule d'hydrazine. Suivant les spécifications d'emploi, la solution concentrée de l'hydrazine ainsi obtenue peut être utilisée directement ou distillée sous pression réduite (étape c)). Le recyclage de l'aminé, lors de l'étape de distillation ii'), s'effectue sans entraînement de l'hydrazine et à une température inférieure au point d'ébullition de l'aminé, ce qui évite sa thermo-dégradation. Compte tenu de l'absence de traces d'hydrazine dans la solution aqueuse contenant l'aminé hétérocyclique, éventuellement sous la forme d'un azéotrope, celle-ci peut être injectée, sans traitement supplémentaire, directement au niveau du réacteur de l'étape a), où se forme l'hydrazine.The reaction solution containing hydrazine, recovered in step ii '), is then treated by adding a strong base, such as sodium hydroxide (step b)). This operation allows the separation of the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine in an organic phase, having a titer between 70 and 90% hydrazine, depending on the organic character of the hydrazine molecule. According to the specifications for use, the concentrated solution of hydrazine thus obtained can be used directly or distilled under reduced pressure (step c)). The amine is recycled during the distillation step ii '), without entraining the hydrazine and at a temperature below the boiling point of the amine, which avoids its thermo-degradation. Given the absence of traces of hydrazine in the aqueous solution containing the heterocyclic amine, optionally in the form of an azeotrope, it can be injected, without additional treatment, directly at the stage reactor a), where hydrazine is formed.

Cette variante de l'invention est particulièrement avantageuse dans le cadre d'une préparation en continu du dérivé de cycloalkyl-hydrazine exocyclique ou d'hétérocycloalkyl-hydrazine exocyclique. Le procédé selon la présente invention permet donc non seulement la synthèse du dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique en continu, sans formation d'aucun intermédiaire toxique, mais il permet aussi l'obtention de ladite hydrazine avec un coût peu élevé. En effet, la synthèse classique de Raschig nécessite en général un grand excès d'aminé, ce qui constitue un inconvénient considérable quand les aminés utilisées comme matière première pour la préparation des hydrazines correspondantes ont un coût très élevé. Le procédé de la présente invention, grâce à la récupération et au recyclage d'une solution concentrée d'aminé hétérocyclique, éventuellement sous la forme d'un azéotrope, permet l'obtention du dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique correspondant avec un coût très peu élevé par rapport aux autres procédés connus. L'isolement de l'aminé sous forme d'une solution aqueuse, éventuellement azéotropique, à relativement basse température constitue aussi une autre originalité ainsi qu'un avantage économique considérable du procédé selon l'invention.This variant of the invention is particularly advantageous in the context of a continuous preparation of the exocyclic cycloalkyl-hydrazine derivative or exocyclic heterocycloalkyl-hydrazine derivative. The process according to the present invention therefore allows not only the synthesis of the cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine exocyclic continuously, without the formation of any toxic intermediate, but it also allows the obtaining of said hydrazine with little cost Student. Indeed, the classic Raschig synthesis generally requires a large excess of amine, which constitutes a considerable drawback when the amines used as raw material for the preparation of the corresponding hydrazines have a very high cost. The process of the present invention, thanks to the recovery and recycling of a concentrated solution of heterocyclic amine, optionally in the form of an azeotrope, makes it possible to obtain the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine corresponding with a very low cost compared to other known methods. The isolation of the amine in the form of an aqueous solution, optionally azeotropic, at relatively low temperature also constitutes another originality as well as a considerable economic advantage of the process according to the invention.

La monochloramine introduite à l'étape a) est avantageusement préparée selon un procédé comprenant les étapes successives suivantes : ci) préparer une solution aqueuse d'hypochlorite de sodium ayant un degré chlorométrique compris entre 36 et 100° éventuellement par dilution d'une solution d'hypochlorite ayant un degré chlorométrique compris entre 100 et 120° ; puis β) faire réagir une solution d'hydroxyde d'ammonium et de chlorure d'ammonium avec la solution aqueuse d'hypochlorite de sodium obtenue suite à l'étape d), en milieu faiblement alcalin, à une température comprise entre -15 et -7°C, pour former ladite monochloramine.The monochloramine introduced in step a) is advantageously prepared according to a process comprising the following successive steps: ci) preparing an aqueous solution of sodium hypochlorite having a chlorometric degree of between 36 and 100 ° optionally by dilution of a solution d hypochlorite having a chlorometric degree of between 100 and 120 °; then β) reacting a solution of ammonium hydroxide and ammonium chloride with the aqueous solution of sodium hypochlorite obtained following step d), in a weakly alkaline medium, at a temperature between -15 and -7 ° C, to form said monochloramine.

Au sens de la présente invention, on entend par l'expression milieu « faiblement alcalin » un milieu dont la valeur de pH est d'environ ÎO±I.For the purposes of the present invention, the expression “weakly alkaline” medium is understood to mean a medium whose pH value is approximately 10 ± 1.

Le rapport molaire solution d'hydroxyde d'ammonium et de chlorure d'ammonium/solution aqueuse d'hypochlorite de sodium est avantageusement compris entre 2,5 et 3, les bornes étant incluses. Le rapport molaire chlorure d'ammom'um/hydroxyde d'ammonium est avantageusement compris entre 0,1 et 1,75, les bornes étant incluses, plus avantageusement il est d'environ 0,65.The molar ratio of ammonium hydroxide and ammonium chloride / aqueous solution of sodium hypochlorite is advantageously between 2.5 and 3, the limits being included. The molar ratio of chloride ammom 'um / ammonium hydroxide is advantageously between 0.1 and 1.75, the limits included, more preferably it is about 0.65.

Dans le cas où le réactif chloré mis en œuvre à l'étape ά) est obtenu par dilution d'une solution d'hypochlorite haut titre à 100-120°chlorométrique, cette dilution présente l'avantage de diminuer de 40% la teneur en chlorure de sodium. Ce traitement, favorable pour l'environnement, permet un refroidissement de la solution d'eau de Javel, sans risque de cristallisation jusqu'à -15°C.In the case where the chlorinated reagent used in step ά) is obtained by dilution of a high titer hypochlorite solution at 100-120 ° chlorometric, this dilution has the advantage of reducing the content of sodium chloride. This environmentally friendly treatment allows cooling of the bleach solution, without risk of crystallization down to -15 ° C.

L'exemple 1 donne, à titre non limitatif, une description détaillée de la mise en œuvre du procédé de l'invention, procédé dont le schéma de principe est représenté figure 1.Example 1 gives, without limitation, a detailed description of the implementation of the method of the invention, the method of which the block diagram is shown in FIG. 1.

Signification des abréviations utilisées :Meaning of the abbreviations used:

RI : réacteur 1 M : mélangeur R2 : réacteur 2RI: reactor 1 M: mixer R2: reactor 2

CD1 : colonne de distillation n°l CD2 : colonne de distillation n°2CD1: distillation column n ° 1 CD2: distillation column n ° 2

CD3 : colonne de distillation n°3CD3: distillation column n ° 3

1 : solution de pipéridine1: piperidine solution

2 : N-amino-pipéridine2: N-amino-piperidine

3 : Solution eau+NaCl+NaOH 4 : résidus3: Water + NaCl + NaOH solution 4: residues

L'exemple 2 donne, à titre non limitatif, une description détaillée de la mise en œuvre du procédé de l'invention, procédé dont le schéma de principe est représenté figure 2.Example 2 gives, without implied limitation, a detailed description of the implementation of the method of the invention, the method of which the principle diagram is represented in FIG. 2.

Signification des abréviations utilisées :Meaning of the abbreviations used:

RI : réacteur 1 M : mélangeur R2 : réacteur 2 CD 1 ' : colonne de distillation n° 1 'RI: reactor 1 M: mixer R2: reactor 2 CD 1 ': distillation column n ° 1'

CD2' : colonne de distillation n°2'CD2 ': distillation column n ° 2'

1 ' : pipéridine anhydre1 ': anhydrous piperidine

1 " : solution de pipéridine à 66% en poids (azéotrope eau-pipéridine)1 ": 66% by weight piperidine solution (water-piperidine azeotrope)

2' : N-amino-pipéridine 3' : Solution eau+NH3+NaCl+NaOH EXEMPLE 1 : Préparation de la N-amino pipéridine en continu2 ': N-amino-piperidine 3': Water solution + NH 3 + NaCl + NaOH EXAMPLE 1 Preparation of the N-amino piperidine continuously

Toutes les quantités indiquées correspondent à une unité en régime et sont rapportées à un litre d'hypochlorite injecté. Un litre d'une solution d'hypochlorite de sodium élaborée par dilution de 50% d'une solution d'hypochlorite de haut titre (100 à 120°chlorométrique, soit [NaOCl]*=2,14 mol.L"1 ; [NaCl]=0,85 mol.L"1) et un litre de solution ayant une concentration en ammoniac de 3,60 mol.L"1 et en chlorure d'ammonium de 2,38 mol.L"1 sont introduits en continu dans un réacteur agité (RI) à raison de 5 mL.min"1 chacun (soit 6 g/min de solution d'hypochlorite à 48°chlorométrique et 5,05 g/min du mélange ammoniacal NH3 + NH4C1).All the quantities indicated correspond to a unit in regime and are related to a liter of hypochlorite injected. One liter of a sodium hypochlorite solution prepared by diluting 50% of a high titer hypochlorite solution (100 to 120 ° chlorometric, ie [NaOCl] * = 2.14 mol.L "1 ; [ NaCl] = 0.85 mol.L "1 ) and a liter of solution having an ammonia concentration of 3.60 mol.L " 1 and ammonium chloride of 2.38 mol.L "1 are continuously introduced in a stirred reactor (RI) at a rate of 5 mL.min "1 each (ie 6 g / min of hypochlorite solution at 48 ° chlorometric and 5.05 g / min of the ammoniacal mixture NH 3 + NH 4 C1).

La température au sein du réacteur est maintenue entre -8°C et -11°C, et le pH de la réaction est voisin de 10. A la sortie de RI, on obtient une solution de monochloramine de titre supérieur à 1 mol.L"1, ce qui correspond à un rendement proche de 100% par rapport à Phypochlorite de sodium.The temperature inside the reactor is maintained between -8 ° C and -11 ° C, and the pH of the reaction is close to 10. At the outlet of RI, a solution of monochloramine with a title greater than 1 mol.L is obtained. "1 , which corresponds to a yield close to 100% compared to sodium hypochlorite.

A la sortie de RI, la solution de monochloramine obtenue ci-dessus (2 litres) est alcalinisée par introduction en continu d'une solution concentrée d'hydroxyde de sodium (0,37 litre à 30% en poids) au sein d'un mélangeur M à double enveloppe maintenu à basse température entre -9°C et -11°C. L'homogénéisation est assurée par entraînement magnétique.On leaving RI, the monochloramine solution obtained above (2 liters) is made alkaline by continuous introduction of a concentrated solution of sodium hydroxide (0.37 liter at 30% by weight) within a double jacket mixer M kept at low temperature between -9 ° C and -11 ° C. Homogenization is ensured by magnetic drive.

La synthèse de la N-aminopipéridine est effectuée en milieu monophasique dans un réacteur tubulaire (R2) agité, sous balayage d'argon ou d'azote. Le mélange NH2CI / NaOH obtenu (2,37 litres) et la solution de pipéridine (2,36 litres à 66% en poids) sont introduits simultanément (sous argon ou azote) en continu dans le réacteur R2 avec un débit adéquat pour avoir un rapport molaire pipéridine sur monochloramine environ égal à 8 et un titre en hydroxyde de sodium dans le milieu réactionnel en fin de réaction égal à 0,3 mol.L"1. La température de la réaction est maintenue à environ 55°C. Après 30 secondes de réaction, le mélange réactionnel subit ensuite une opération de dégazage pour éliminer l' ammoniac contenu dans la solution. La solution réactionnelle est tout d'abord débarrassée de l'ammoniac par stripping (colonne de distillation CD1, on récupère en tête de colonne environ 62 g d'ammoniac) puis environ 4,6 kg de la solution débarrassée de l'ammoniac sont distillés à 92,2°C sous pression atmosphérique (colonne de distillation CD2) pour éliminer l'aminé qui n'a pas réagi, la pipéridine. Ainsi, après cette étape de distillation, on obtient en tête de colonne la pipéridine sous la forme d'une solution aqueuse de composition d'environ 66% en poids en aminé (environ 2 kg). Cette solution est ensuite recyclée et ré-injectée immédiatement au sein de R2, sans traitement supplémentaire (figure 1 : flèche en pointillé).The synthesis of N-aminopiperidine is carried out in a single-phase medium in a stirred tubular reactor (R2), under scanning of argon or nitrogen. The NH 2 CI / NaOH mixture obtained (2.37 liters) and the piperidine solution (2.36 liters at 66% by weight) are introduced simultaneously (under argon or nitrogen) continuously into the reactor R2 with an adequate flow rate for have a piperidine to monochloramine molar ratio of approximately 8 and a titer of sodium hydroxide in the reaction medium at the end of the reaction equal to 0.3 mol.L "1. The reaction temperature is maintained at approximately 55 ° C. After 30 seconds of reaction, the reaction mixture then undergoes a degassing operation to remove the ammonia contained in the solution The reaction solution is first of all freed from the ammonia by stripping (distillation column CD1, recovery is obtained at the head about 62 g of ammonia) then about 4.6 kg of the ammonia-free solution are distilled at 92.2 ° C. at atmospheric pressure (CD2 distillation column) to remove the unreacted amine, piperidine. Thus, after this distillation step, the piperidine is obtained at the top of the column in the form of an aqueous solution of composition of approximately 66% by weight in amine (approximately 2 kg). This solution is then recycled and immediately re-injected into R2, without additional treatment (Figure 1: dotted arrow).

Après séparation de la pipéridine, la solution réactionnelle contenant l'hydrazine (récupérée en bas de colonne CD2, environ 2,7 kg) est traitée par addition d'hydroxyde de sodium solide sous refroidissement et sous balayage d'argon, pour séparer la N- aminopipéridine dans une phase organique titrant près de 70 à 80% en hydrazine à 80°C. Le titre massique de soude anhydre injectée se situe de préférence entre 15 et 30% en poids. On récupère ainsi ladite phase organique titrant près de 92% en hydrazine et une phase aqueuse comprenant l'eau et les sels (NaCl, NaOH). Suivant les spécifications d'emploi, la solution concentrée de l'hydrazine (phase organique) peut ensuite être utilisée directement ou distillée sous pression réduite (colonne de distillation CD3).After separation of the piperidine, the reaction solution containing the hydrazine (recovered at the bottom of the CD2 column, approximately 2.7 kg) is treated by addition of solid sodium hydroxide under cooling and under scanning of argon, to separate the N - aminopiperidine in an organic phase titrating nearly 70 to 80% hydrazine at 80 ° C. The mass titer of anhydrous soda injected is preferably between 15 and 30% by weight. This organic phase is thus recovered, titrating nearly 92% of hydrazine and an aqueous phase comprising water and the salts (NaCl, NaOH). According to the specifications for use, the concentrated solution of hydrazine (organic phase) can then be used directly or distilled under reduced pressure (CD3 distillation column).

Après distillation sous pression réduite, on obtient la N-aminopipéridine avec un degré de pureté supérieur à 99,5%. Le rendement en hydrazine par rapport à la pipéridine consommée est supérieur à 92%.After distillation under reduced pressure, N-aminopiperidine is obtained with a degree of purity greater than 99.5%. The hydrazine yield relative to the piperidine consumed is greater than 92%.

EXEMPLE 2 : Préparation de la N-amino pipéridine en batchEXAMPLE 2 Preparation of N-amino piperidine in batch

Toutes les quantités indiquées correspondent à une unité en régime et sont rapportées à un litre d'hypochlorite injecté. Le procédé est caractérisé en ce que l'on fait réagir une solution d'hydroxyde d'ammonium et de chlorure d'ammonium ([NH3] = 3,60 mol.L'1 ; [NH4C1] = 2,38 mol.L"1 ; 5 mL/min) avec une solution aqueuse d'hypochlorite de sodium (débit de 5 mL/min) à une température comprise entre -15°C et -7°C en milieu alcalin dans un réacteur agité continu RI. Le fluide réactionnel issu de RI (2 litres) de titre supérieur à 1 mol.L"1 en monochloramine est introduit dans un mélangeur M alimenté en continu par une solution d'hydroxyde de sodium à 30% (débit de 1,75 mL/min). Un enveloppe fhermostatique permet de fixer la température, au sein du mélangeur, à -10°C. La synthèse de la N-aminopipéridine est effectuée au moyen d'un agitateur tubulaire R2 agité et sous balayage d'argon. La monochloramine alcalinisée (2,35 litres), issue de l'enceinte du mélange M, et le réactif aminé sont introduits simultanément à la base du réacteur au moyen de pompes doseuses. On ajoute 1,69 litres, soit 1,455 kg car la densité est de 0,861, de pipéridine anhydre. Le débit de la pipéridine anhydre est de 8,47 mL/min et une partie de la réaction est effectuée en milieu hétérogène à 55°C. La concentration finale en NaOH au sortir de R2 est de 0,3 mol.L"1. La présente variante est caractérisée en ce que l'on ajoute, à la liqueur réactionnelle homogène (4,04 litres), une quantité en hydroxyde de sodium comprise entre 13 et 30% sous refroidissement de manière que la température ne dépasse pas 60°C. Dans ces conditions, on obtient deux phases dont l'une, légère (1,8 kg), contient la totalité des organiques, c'est-à-dire la N-aminopipéridine et la pipéridine en excès qui titre environ entre 15 et 20% en poids. Ce traitement permet ainsi d'éliminer entre 80 et 85% de l'eau présente dans les solutions de synthèse. L'obtention de la N-aminopipéridine nécessite ensuite deux étapes successives : - récupération de la pipéridine qui n'a pas réagi par distillation de la phase organique à la pression atmosphérique sous argon. On récupère, dans un premier temps, environ 1 kg d'une solution concentrée d'aminé à 66% en poids (1") à une température de 92,2°C jusqu'à épuisement de l'eau puis, environ 600 g de pipéridine anhydre (1 ') à une température de 105°C (colonne de distillation CD1 '). - Rectification sous 115 mm de Hg de la solution obtenue en pied de colonne (colonne de distillation CD2'). Après distillation sous pression réduite, on obtient la N-aminopipéridine avec un degré de pureté supérieur à 99,5%. Le rendement en hydrazine par rapport à la pipéridine consommée est supérieur à 90%. All the quantities indicated correspond to a unit in regime and are related to a liter of hypochlorite injected. The process is characterized in that a solution of ammonium hydroxide and ammonium chloride is reacted ([NH 3 ] = 3.60 mol.L '1 ; [NH 4 C1] = 2.38 mol.L "1 ; 5 mL / min) with an aqueous solution of sodium hypochlorite (flow rate of 5 mL / min) at a temperature between -15 ° C and -7 ° C in alkaline medium in a continuous stirred reactor RI. The reaction fluid from RI (2 liters) with a titer greater than 1 mol.L "1 in monochloramine is introduced into a mixer M fed continuously by a 30% sodium hydroxide solution (flow rate of 1.75 mL / min). A thermostatic jacket allows the temperature in the mixer to be set at -10 ° C. The synthesis of N-aminopiperidine is carried out by means of an agitated tubular agitator R2 and under scanning of argon. The alkalized monochloramine (2.35 liters), coming from the enclosure of the mixture M, and the amino reagent are introduced simultaneously at the base of the reactor by means of metering pumps. 1.69 liters, or 1.455 kg are added since the density is 0.861 of anhydrous piperidine. The flow rate of anhydrous piperidine is 8.47 ml / min and part of the reaction is carried out in a heterogeneous medium at 55 ° C. The final NaOH concentration at the end of R2 is 0.3 mol.L "1. The present variant is characterized in that an amount of hydroxide of hydroxide is added to the homogeneous reaction liquor (4.04 liters). sodium between 13 and 30% under cooling so that the temperature does not exceed 60 ° C. Under these conditions, two phases are obtained, one of which, light (1.8 kg), contains all of the organic, ie that is to say the excess N-aminopiperidine and piperidine which titer approximately between 15 and 20% by weight. This treatment thus makes it possible to remove between 80 and 85% of the water present in the synthesis solutions. Obtaining N-aminopiperidine then requires two successive stages: recovery of the piperidine which has not reacted by distillation of the organic phase at atmospheric pressure under argon. concentrated amine solution at 66% by weight (1 ") at a temperature from 92.2 ° C until the water is used up, then about 600 g of anhydrous piperidine (1 ') at a temperature of 105 ° C (distillation column CD1'). - Rectification under 115 mm Hg of the solution obtained at the bottom of the column (CD2 'distillation column). After distillation under reduced pressure, N-aminopiperidine is obtained with a degree of purity greater than 99.5%. The hydrazine yield relative to the piperidine consumed is greater than 90%.

Claims

REVENDICATIONS 1. Procédé de synthèse de dérivés de cycloalkyl-hydrazines et d'hétérocycloalkyl- hydrazines exocycliques caractérisé en ce qu'il comprend les étapes successives suivantes : a) synthétiser le dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl- hydrazine exocyclique dans un réacteur approprié en faisant réagir en milieu alcalin et à une température comprise entre 30 et 60°C une monochloramine avec une aminé hétérocyclique ; puis b) démixter la solution obtenue suite à l'étape a) en une phase organique et une phase aqueuse par l'ajout d'hydroxyde de sodium anhydre sous refroidissement afin que la température ne dépasse pas la température d'ébullition des composés ; et c) le cas échéant, isoler, par distillation de la phase organique ainsi obtenue, le dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique.1. Process for the synthesis of exo-cyclic cycloalkyl-hydrazine derivatives and heterocycloalkyl-hydrazines, characterized in that it comprises the following successive steps: a) synthesizing the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine in a suitable reactor by reacting in an alkaline medium and at a temperature between 30 and 60 ° C a monochloramine with a heterocyclic amine; then b) demixing the solution obtained following step a) into an organic phase and an aqueous phase by adding anhydrous sodium hydroxide under cooling so that the temperature does not exceed the boiling point of the compounds; and c) if necessary, isolating, by distillation of the organic phase thus obtained, the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine. 2. Procédé selon la revendication 1, caractérisé en ce que le dérivé de cycloalkyl- hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique est de formule (I)2. Method according to claim 1, characterized in that the exocyclic cycloalkylhydrazine or heterocycloalkylhydrazine derivative is of formula (I) dans laquelle un des atomes de carbone du cycle est éventuellement remplacé par un hétéroatome choisi parmi un atome d'azote ou d'oxygène, RI et R2, identiques ou différents, représentent un atome d'hydrogène ou un radical alkyle en Cj-C6 ou RI et R2 forment ensemble un radical cycloalkyle en C3-C8et n vaut 1 à 3. in which one of the ring carbon atoms is optionally replaced by a heteroatom chosen from a nitrogen or oxygen atom, RI and R2, identical or different, represent a hydrogen atom or a Cj-C 6 alkyl radical or RI and R2 together form a C 3 -C 8 cycloalkyl radical and n is 1 to 3. 3. Procédé selon la revendication 1 ou 2, caractérisé en ce que, à l'étape a), le rapport molaire aminé hétérocyclique /monochloramine est compris entre 4 et 10. 3. Method according to claim 1 or 2, characterized in that, in step a), the heterocyclic amine / monochloramine molar ratio is between 4 and 10. 4. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que le réacteur de l'étape a) est placé sous atmosphère inerte.4. Method according to any one of the preceding claims, characterized in that the reactor of step a) is placed under an inert atmosphere. 5. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que préalablement à l'étape a) la monochloramine est alcalinisée dans un mélangeur par ajout d'une solution d'hydroxyde de sodium de telle sorte que le titre massique en hydroxyde de sodium soit compris entre 2 et 6%.5. Method according to any one of the preceding claims, characterized in that prior to step a) the monochloramine is made alkaline in a mixer by adding a solution of sodium hydroxide so that the mass content of hydroxide sodium is between 2 and 6%. 6. Procédé selon la revendication 5, caractérisé en ce que le mélangeur est maintenu à une température comprise entre -10 et 5°C.6. Method according to claim 5, characterized in that the mixer is maintained at a temperature between -10 and 5 ° C. 7. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que la quantité d'hydroxyde de sodium anhydre ajoutée lors de l'étape b) est telle que le titre massique en hydroxyde de sodium soit compris entre 10 et 35 %.7. Method according to any one of the preceding claims, characterized in that the quantity of anhydrous sodium hydroxide added during step b) is such that the mass content of sodium hydroxide is between 10 and 35%. 8. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que l'aminé hétérocyclique est introduite, à l'étape a), sous forme d'aminé hétérocyclique anhydre.8. Method according to any one of the preceding claims, characterized in that the heterocyclic amine is introduced, in step a), in the form of anhydrous heterocyclic amine. 9. Procédé selon la revendication 8, caractérisé en ce que l'étape c) comprend les étapes successives suivantes : i) isoler l'aminé hétérocyclique qui n'a pas réagi et une solution concentrée du dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique par distillation de la phase organique obtenue suite à l'étape b) ; puis ii) le cas échéant, rectifier par distillation sous pression réduite ladite solution concentrée du dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique.9. Method according to claim 8, characterized in that step c) comprises the following successive steps: i) isolating the heterocyclic amine which has not reacted and a concentrated solution of the cycloalkyl-hydrazine derivative or heterocycloalkyl exocyclic hydrazine by distillation of the organic phase obtained following step b); then ii) if necessary, rectify by distillation under reduced pressure said concentrated solution of the exocyclic cycloalkyl-hydrazine derivative or heterocycloalkyl-hydrazine. 10. Procédé selon l'une quelconque des revendications 1 à 7, caractérisé en ce que l'aminé hétérocyclique est introduite, à l'étape a), sous forme d'une solution aqueuse concentrée d'aminé hétérocyclique, le cas échéant sous la forme d'un azéotrope eau- amine hétérocyclique. 10. Method according to any one of claims 1 to 7, characterized in that the heterocyclic amine is introduced, in step a), in the form of a concentrated aqueous solution of heterocyclic amine, if necessary under the form of a heterocyclic water-amine azeotrope. 11. Procédé selon la revendication 10, caractérisé en ce que suite à l'étape a) et préalablement à l'étape b) le procédé comprend les étapes suivantes : i') éliminer l'ammoniac présent dans la solution obtenue suite à l'étape a) par stripping ; puis ii') isoler une solution comprenant le dérivé de cycloalkyl-hydrazine ou d'hétérocycloalkyl-hydrazine exocyclique formé et une solution aqueuse, le cas échéant azéotropique, d'aminé hétérocyclique qui n'a pas réagi par distillation de la solution obtenue suite à l'étape i') à une température comprise entre 50 et 180°C ; et iii') réinjecter dans le réacteur de l'étape a) ladite solution aqueuse, le cas échéant azéotropique, d'aminé hétérocyclique obtenue suite à l'étape ii').11. Method according to claim 10, characterized in that following step a) and prior to step b) the method comprises the following steps: i ') eliminating the ammonia present in the solution obtained following the step a) by stripping; then ii ′) isolating a solution comprising the exocyclic cycloalkyl-hydrazine or heterocycloalkyl-hydrazine derivative formed and an aqueous solution, if appropriate azeotropic, of heterocyclic amine which has not reacted by distillation of the solution obtained following step i ') at a temperature between 50 and 180 ° C; and iii ') reinjecting into the reactor of step a) said aqueous solution, if appropriate azeotropic, of heterocyclic amine obtained following step ii'). 12. Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que la monochloramine est préparée selon un procédé comprenant les étapes successives suivantes : α) préparer une solution aqueuse d'hypochlorite de sodium ayant un degré chlorométrique compris entre 36 et 100° éventuellement par dilution d'une solution d'hypochlorite ayant un degré chlorométrique compris entre 100 et 120° ; puis β), faire réagir une solution d'hydroxyde d'ammonium et de chlorure d'ammonium avec la solution aqueuse d'hypochlorite de sodium obtenue suite à l'étape α), en milieu faiblement alcalin, à une température comprise entre -15 et -7°C, pour former ladite monochloramine12. Method according to any one of the preceding claims, characterized in that the monochloramine is prepared according to a method comprising the following successive stages: α) preparing an aqueous solution of sodium hypochlorite having a chlorometric degree of between 36 and 100 ° optionally by dilution of a hypochlorite solution having a chlorometric degree of between 100 and 120 °; then β), reacting a solution of ammonium hydroxide and ammonium chloride with the aqueous solution of sodium hypochlorite obtained following step α), in a weakly alkaline medium, at a temperature between -15 and -7 ° C, to form said monochloramine 13. Procédé selon la revendication 12, caractérisé en ce que le rapport molaire solution d'hydroxyde d'ammonium et de chlorure d' ammonium/solution aqueuse d'hypochlorite de sodium est compris entre 2,5 et 3.13. The method of claim 12, characterized in that the molar ratio of ammonium hydroxide solution and ammonium chloride / aqueous solution of sodium hypochlorite is between 2.5 and 3. 14. Procédé selon la revendication 12 ou 13, caractérisé en ce que le rapport molaire chlorure d'ammonium/hydroxyde d'ammonium est compris entre 0,1 et 1,75, avantageusement il est d'environ 0,65. 1/214. Method according to claim 12 or 13, characterized in that the molar ratio of ammonium chloride / ammonium hydroxide is between 0.1 and 1.75, advantageously it is about 0.65. 1/2 Figure 1 Figure 1
EP04816423A 2003-12-17 2004-12-17 Method for the synthesis of exocyclic derivatives of cycloalkyl-hydrazines and exocyclic derivatives of heterocycloalkyl-hydrazines Withdrawn EP1699770A1 (en)

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FR0314795A FR2864081B1 (en) 2003-12-17 2003-12-17 PROCESS FOR THE SYNTHESIS OF EXOCYCLIC CYCLOALKYL HYDRAZINE DERIVATIVES AND EXOCYCLIC HETEROCYCLOALKYL HYDRAZINE DERIVATIVES
PCT/FR2004/003288 WO2005058852A1 (en) 2003-12-17 2004-12-17 Method for the synthesis of exocyclic derivatives of cycloalkyl-hydrazines and exocyclic derivatives of heterocycloalkyl-hydrazines

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