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Sommaire du brevet 2461574 

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Disponibilité de l'Abrégé et des Revendications

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(12) Brevet: (11) CA 2461574
(54) Titre français: PROCEDE DE PREPARATION D'HYDROCHLORURE DE VANILLYLAMINE
(54) Titre anglais: PROCESS FOR PREPARING VANILLYLAMINE HYROCHLORIDE
Statut: Réputé périmé
Données bibliographiques
(51) Classification internationale des brevets (CIB):
  • C07C 217/58 (2006.01)
(72) Inventeurs :
  • MEYER, OLIVER (Allemagne)
  • HEDDESHEIMER, INGO (Allemagne)
(73) Titulaires :
  • BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG (Allemagne)
(71) Demandeurs :
  • BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG (Allemagne)
(74) Agent: FETHERSTONHAUGH & CO.
(74) Co-agent:
(45) Délivré: 2011-01-11
(86) Date de dépôt PCT: 2002-09-26
(87) Mise à la disponibilité du public: 2003-04-10
Requête d'examen: 2007-09-24
Licence disponible: S.O.
(25) Langue des documents déposés: Anglais

Traité de coopération en matière de brevets (PCT): Oui
(86) Numéro de la demande PCT: PCT/EP2002/010803
(87) Numéro de publication internationale PCT: WO2003/029208
(85) Entrée nationale: 2004-03-24

(30) Données de priorité de la demande:
Numéro de la demande Pays / territoire Date
101 47 958.1 Allemagne 2001-09-28

Abrégés

Abrégé français

L'invention concerne un procédé de production de vanillylamine ou d'un de ses sels par : a) mise en réaction de vanilline avec de l'hydroxylamine ou avec les sels de celle-ci, en présence d'un sel organique qui, éventuellement, peut être produit in situ ; et b) hydrogénation consécutive de la vanillyloxime produite avec de l'hydrogène, en présence d'un catalyseur approprié et d'un acide organique et/ou d'un acide inorganique. Ce procédé se caractérise en ce que l'étape a) est réalisée dans un acide inorganique ou dans un acide organique servant de diluant.


Abrégé anglais




Process for preparing vanillylamine or one of the salts thereof by
a) reacting vanillin with hydroxylamine or the salts thereof in the presence
of an
organic salt, which may optionally be produced in situ, and
b) subsequently hydrogenating the resulting vanillyloxime with hydrogen in the

presence of a suitable catalyst and an organic and/or inorganic acid,
characterised in that step a) is carried out in an inorganic or organic acid
as
diluent.

Revendications

Note : Les revendications sont présentées dans la langue officielle dans laquelle elles ont été soumises.




6

CLAIMS:


1. Process for preparing vanillylamine or a salt thereof by

a) reacting vanillin with hydroxylamine or a salt thereof in the
presence of an organic salt, which may optionally be produced in situ, to
produce
a vanillyloxime, and

b) subsequently hydrogenating the resulting vanillyloxime with
hydrogen in the presence of a suitable catalyst and an organic and/or
inorganic
acid,

wherein step a) is carried out in an inorganic or organic acid as a
diluent.

2. The process according to claim 1, wherein steps a) and b) are
carried out in a one-pot process.

3. The process according to claim 1 or 2, wherein in step a) sodium
acetate and glacial acetic acid are used.

4. The process according to any one of claims 1 to 3, wherein in step
a) vanillin is reacted with hydroxylamine hydrochloride.

5. The process according to any one of claims 1 to 4, wherein in step
b) Pd/C or Pt/C is used as the catalyst.

6. The process according to any one of claims 1 to 5, wherein the
hydrogenation step b) is carried out in the presence of glacial acetic acid
and
concentrated hydrochloric acid.

7. The process according to any one of claims 1 to 6, wherein the
reaction temperature in step a) is 15°C to 50°C.



7

8. The process according to any one of claims 1 to 6, wherein the
reaction temperature in step b) is 0°C to 70°C.

9. The process according to any one of claims 1 to 8, wherein vanillin is
used in a molar ratio to hydroxylamine or a salt thereof of 1:2 to 2:1.

Description

Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.



CA 02461574 2004-03-24
1/1257 Prio/ff 1

Process for preparing vanillylamine hydrochloride
78894tra.206

The invention relates to a process for preparing vanillylamine hydrochloride
which
can be used on an industrial scale.

Background to the invention
Vanillylamine hydrochloride is an intermediate product in the preparation of
1o pelargonic acid vanillylamide, which is used as a hyperemia inducing active
substance, e.g. in plasters.
German Patent DE 760 746 describes the preparation of vanillylamine
hydrochloride,
in which the isolated 4-hydroxy-3-methoxy-benzaldoxime used as starting
material is
reduced using hydrogen in the presence of activated charcoal and palladium
oxide in
an acetic acid solution and with the subsequent addition of hydrochloric acid
to obtain
the vanillylamine hydrochloride.
The preparation of 4-hydroxy-3-methoxy-benzaldoxime from vanillin and
hydroxylamine hydrochloride in a basic medium is described in the literature
(J. Org.
Chem. Vol. 53, No. 5, 1988). First, the oxime is isolated and then reduced to
the
amine in an ethanolic hydrochloric acid solution. The isolation of the oxime
represents a significant expenditure of cost and time, particularly in the
production of
vanillylamine hydrochloride on an industrial scale.

The problem of the present invention is therefore to prepare a cost effective
process
for preparing vanillylamine hydrochloride which can be used on an industrial
scale.
Detailed description of the invention

The present invention solves the problem described above by the following
method
of synthesis.

The invention thus relates to a process for preparing vanillylamine or one of
the salts
thereof by
a) reacting vanillin with hydroxylamine or the salts thereof in the presence
of an
organic salt, which may optionally be produced in situ, and


CA 02461574 2004-03-24
1/1257 Prio/ff 2

b) subsequently hydrogenating the resulting vanillyloxime with hydrogen in the
presence of a suitable catalyst and an organic and/or inorganic acid, wherein
step a) is carried out in an inorganic or organic acid as diluent.

In a preferred process steps a) and b) are carried out in a one-pot process.

Also preferred is a process wherein sodium acetate and glacial acetic acid are
used
in step a).

1o In a particularly preferred process vanillin is reacted with hydroxylamine
hydrochloride in step a).

Also particularly preferred is a process wherein Pd/C or Pt/C is used as
catalyst in
step b).
Of particular importance according to the invention is a process wherein the
hydrogenation step b) is carried out in the presence of glacial acetic acid
and
concentrated hydrochloric acid.

The invention preferably relates to a process wherein the reaction temperature
in
step a) is 15 C to 50 C.

The invention preferably relates to a process wherein the reaction temperature
in
step b) is 0 C to 70 C.

Particularly preferred is a process wherein vanillin is used in a molar ratio
to
hydroxylamine or the salt thereof of 1:2 to 2:1, preferably 1:1.

The invention also relates to the use of the vanillylamine or one of the salts
thereof
obtained by the process according to the invention for preparing
pharmaceutically
active compounds.

The invention further relates to the use of the vanillylamine or one of the
salts thereof
obtained by the process according to the invention for preparing pelargonic
acid
vanillylamide.


CA 02461574 2004-03-24
1/1257 Prio/ff 3

Acids suitable for forming salts of vanillylamine or vanillyloxime include for
example
hydrochloric acid, acetic acid, hydrobromic acid, sulphuric acid, phosphoric
acid,
nitric acid, succinic acid, oxalic acid, malonic acid, fumaric acid, maleic
acid, tartaric
acid, citric acid, ascorbic acid and methanesulphonic acid, particularly
hydrochloric
acid, sulphuric acid or acetic acid.

In a preferred embodiment of the process according to the invention for
preparing the
vanillylamine, as a rule one equivalent of vanillin is suspended in 3 to 20
parts (based
to on the weight of vanillin used), preferably about 5 parts, of an acid
diluent, preferably
glacial acetic acid, hydrochloric acid or sulphuric acid, most preferably
glacial acetic
acid, and combined with 1 to 2 equivalents, preferably one equivalent of an
organic
salt, for example sodium hydroxide or sodium acetate, preferably sodium
acetate,
most preferably anhydrous sodium acetate.
1s The suspension is combined with 1 to 2 equivalents, preferably one
equivalent, of
hydroxylamine or a hydroxylamine salt, preferably hydroxylamine hydrochloride
or
hydroxylamine sulphate, preferably hydroxylamine hydrochloride, with stirring.
The
reaction mixture is heated to 25 C to 50 C, preferably 28 C to 40 C, more
preferably about 30 C to 35 C, and stirred for 0.5 to 8 hours, preferably
about 3
20 hours.
The vanillyloxime produced remains in suspension and is hydrogenated by the
addition of 0.1 to 10 parts (based on the weight of vanillin used), preferably
about 0.7
parts, of acid, preferably hydrochloric acid or sulphuric acid, preferably
hydrochloric
acid, and 1 to 20 % by weight (based on the vanillin used), preferably 10 % by
25 weight, of a catalyst, preferably a transition metal catalyst, preferably a
Pd/C, Pt or
Ra-Ni catalyst, most preferably a Pd/C catalyst, while hydrogen is piped into
the
reaction mixture, under a hydrogen pressure of 1 to 7 bar, but preferably from
3 to 5
bar, most preferably 4 bar, at a temperature of 0 C to 70 C, preferably 10
C to
35 C, preferably about 10 C.
3o Then the vanillylamine produced or the salt thereof is completely dissolved
by the
addition of water and optionally heating to 40 C to 70 C, preferably about 60
C. The
catalyst is filtered off. The filtrate is heated to 50 C to 70 C, preferably
about 60 C,
optionally after the diluent used, preferably acetic acid, has been distilled
off, in order
to dissolve the salts and the vanillylamine or the salt thereof, and water is
added


CA 02461574 2004-03-24
1/1257 Prio/ff 4

thereto. In order to precipitate the vanillylamine salt the reaction mixture
is combined
with an inorganic or organic acid, preferably hydrochloric acid. The
suspension
formed is cooled and the salt of the vanillylamine is filtered, optionally
washed with a
solvent, preferably acetone, and dried.
The procedure according to the invention results in a cost effective process
with a
high space/time yield with regard to the vanillylamine or the salts thereof.

The Examples that follow serve to illustrate some processes for preparing
to vanillylamine or the salts thereof which are carried out by way of example.
They
should be understood as being only possible procedures described purely by way
of
example without restricting the invention to their content.

Example 1
a) Synthesis of vanillyloxime

56.58 g of vanillin are suspended in 283 ml of glacial acetic acid and
combined with
32.02 g of anhydrous sodium acetate. Then 28.29 g of hydroxylamine
hydrochloride
are added, the reaction mixture is heated to 30 C to 35 C with stirring and
stirred for
hours.

b) Synthesis of vanillylamine

25 The reaction mixture obtained in a) is combined with 38 ml of hydrochloric
acid and
6.2 g of Pd/C. Hydrogen is piped into the reaction mixture, with stirring, at
10 C over
a period of 4 hours under a pressure of 4 bar. After the addition of 71 ml of
water the
mixture is heated to 60 C and stirred for 1 hour. The catalyst is filtered
off and the
acetic acid is eliminated from the filtrate by distillation at 60 C. Then the
reaction
30 mixture is combined with 141 ml of water in order to dissolve the
vanillylamine
hydrochloride and the salts and stirred at 60 C for 0.5 hours. After the
addition of 99
ml of hydrochloric acid and 1 hour's stirring, the suspension formed is cooled
to 3 C
and after 3 hours the vanillylamine hydrochloride is filtered off, washed with
acetone
and dried at 50 C.
Yield: 57.66 g (82 % of theory).


CA 02461574 2004-03-24
1/1257 Prio/ff 5
Example 2
a) Synthesis of vanillyloxime

20.0 g of vanillin are suspended in 150 ml of glacial acetic acid and combined
with
8.6 ml of NaOH (50%). Then 10.96 g of hydroxylamine hydrochloride are added.
The
reaction mixture is stirred for 2 hours at 20 C.

b) Synthesis of vanillylamine hydrochloride
The reaction mixture obtained in a) is combined with 27 ml of hydrochloric
acid and 2
g of Pd/C. Hydrogen is piped into the reaction mixture, with stirring, at 0 C
over a
period of 2.5 hours under a pressure of 4 bar. After working up, 13.12 g (53 %
of
theory) of vanillylamine hydrochloride are obtained.


Dessin représentatif

Désolé, le dessin représentatatif concernant le document de brevet no 2461574 est introuvable.

États administratifs

Pour une meilleure compréhension de l'état de la demande ou brevet qui figure sur cette page, la rubrique Mise en garde , et les descriptions de Brevet , États administratifs , Taxes périodiques et Historique des paiements devraient être consultées.

États administratifs

Titre Date
Date de délivrance prévu 2011-01-11
(86) Date de dépôt PCT 2002-09-26
(87) Date de publication PCT 2003-04-10
(85) Entrée nationale 2004-03-24
Requête d'examen 2007-09-24
(45) Délivré 2011-01-11
Réputé périmé 2013-09-26

Historique d'abandonnement

Il n'y a pas d'historique d'abandonnement

Historique des paiements

Type de taxes Anniversaire Échéance Montant payé Date payée
Enregistrement de documents 100,00 $ 2004-03-24
Le dépôt d'une demande de brevet 400,00 $ 2004-03-24
Taxe de maintien en état - Demande - nouvelle loi 2 2004-09-27 100,00 $ 2004-03-24
Taxe de maintien en état - Demande - nouvelle loi 3 2005-09-26 100,00 $ 2005-08-23
Taxe de maintien en état - Demande - nouvelle loi 4 2006-09-26 100,00 $ 2006-08-22
Taxe de maintien en état - Demande - nouvelle loi 5 2007-09-26 200,00 $ 2007-08-22
Requête d'examen 800,00 $ 2007-09-24
Taxe de maintien en état - Demande - nouvelle loi 6 2008-09-26 200,00 $ 2008-08-21
Taxe de maintien en état - Demande - nouvelle loi 7 2009-09-28 200,00 $ 2009-08-24
Taxe de maintien en état - Demande - nouvelle loi 8 2010-09-27 200,00 $ 2010-08-20
Taxe finale 300,00 $ 2010-10-27
Taxe de maintien en état - brevet - nouvelle loi 9 2011-09-26 200,00 $ 2011-09-16
Titulaires au dossier

Les titulaires actuels et antérieures au dossier sont affichés en ordre alphabétique.

Titulaires actuels au dossier
BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG
Titulaires antérieures au dossier
HEDDESHEIMER, INGO
MEYER, OLIVER
Les propriétaires antérieurs qui ne figurent pas dans la liste des « Propriétaires au dossier » apparaîtront dans d'autres documents au dossier.
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Description du
Document 
Date
(yyyy-mm-dd) 
Nombre de pages   Taille de l'image (Ko) 
Page couverture 2010-12-22 1 30
Abrégé 2004-03-24 1 13
Revendications 2004-03-24 2 49
Description 2004-03-24 5 214
Page couverture 2004-05-21 1 30
Revendications 2010-01-22 2 38
Abrégé 2010-12-16 1 13
PCT 2004-03-24 9 381
Cession 2004-03-24 4 131
PCT 2004-03-25 3 154
Poursuite-Amendment 2007-09-24 1 44
Poursuite-Amendment 2009-07-22 2 55
Poursuite-Amendment 2010-01-22 4 109
Correspondance 2010-10-27 2 62