CA2461574C - Process for preparing vanillylamine hyrochloride - Google Patents
Process for preparing vanillylamine hyrochloride Download PDFInfo
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- CA2461574C CA2461574C CA2461574A CA2461574A CA2461574C CA 2461574 C CA2461574 C CA 2461574C CA 2461574 A CA2461574 A CA 2461574A CA 2461574 A CA2461574 A CA 2461574A CA 2461574 C CA2461574 C CA 2461574C
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- acid
- vanillylamine
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- salt
- vanillin
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- WRPWWVNUCXQDQV-UHFFFAOYSA-N vanillylamine Chemical compound COC1=CC(CN)=CC=C1O WRPWWVNUCXQDQV-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 229940053939 vanillylamine Drugs 0.000 title claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 claims abstract description 14
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 235000012141 vanillin Nutrition 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 7
- 150000007524 organic acids Chemical class 0.000 claims abstract description 7
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003085 diluting agent Substances 0.000 claims abstract description 5
- 238000011065 in-situ storage Methods 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 24
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 14
- 229960000583 acetic acid Drugs 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 claims description 2
- PUDMGOSXPCMUJZ-UHFFFAOYSA-N (4-hydroxy-3-methoxyphenyl)methylazanium;chloride Chemical compound Cl.COC1=CC(CN)=CC=C1O PUDMGOSXPCMUJZ-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000001117 sulphuric acid Substances 0.000 description 4
- 235000011149 sulphuric acid Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- RJJVVYVLHWMYAA-UHFFFAOYSA-N 4-(hydroxyiminomethyl)-2-methoxyphenol Chemical compound COC1=CC(C=NO)=CC=C1O RJJVVYVLHWMYAA-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- RGOVYLWUIBMPGK-UHFFFAOYSA-N nonivamide Chemical compound CCCCCCCCC(=O)NCC1=CC=C(O)C(OC)=C1 RGOVYLWUIBMPGK-UHFFFAOYSA-N 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- NXPHCVPFHOVZBC-UHFFFAOYSA-N hydroxylamine;sulfuric acid Chemical compound ON.OS(O)(=O)=O NXPHCVPFHOVZBC-UHFFFAOYSA-N 0.000 description 1
- 150000002443 hydroxylamines Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
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.
Description
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 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.
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 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).
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.
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 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.
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 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).
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.
Claims (9)
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.
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.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10147958A DE10147958A1 (en) | 2001-09-28 | 2001-09-28 | Process for the preparation of yanillylamine hydrochloride |
| DE10147958.1 | 2001-09-28 | ||
| PCT/EP2002/010803 WO2003029208A2 (en) | 2001-09-28 | 2002-09-26 | Method for producing vanillylamine hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2461574A1 CA2461574A1 (en) | 2003-04-10 |
| CA2461574C true CA2461574C (en) | 2011-01-11 |
Family
ID=7700689
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2461574A Expired - Fee Related CA2461574C (en) | 2001-09-28 | 2002-09-26 | Process for preparing vanillylamine hyrochloride |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1432675B1 (en) |
| JP (1) | JP4272521B2 (en) |
| AT (1) | ATE312071T1 (en) |
| AU (1) | AU2002333879A1 (en) |
| CA (1) | CA2461574C (en) |
| DE (2) | DE10147958A1 (en) |
| ES (1) | ES2253581T3 (en) |
| WO (1) | WO2003029208A2 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE760746C (en) * | 1941-02-21 | 1953-05-18 | Boehringer & Soehne Gmbh | Process for the preparation of primary amines |
| FR2397387A1 (en) * | 1976-04-27 | 1979-02-09 | Serobiologiques Lab Sa | 4,4'-BIS-FORMYL-POLYHALO-DIPHENOXYALCANES, PROCESS FOR PREPARATION AND APPLICATION TO THE SYNTHESIS OF 4,4'-DICYANO-POLYHALO-DIPHENOXYALCANES |
-
2001
- 2001-09-28 DE DE10147958A patent/DE10147958A1/en not_active Ceased
-
2002
- 2002-09-26 CA CA2461574A patent/CA2461574C/en not_active Expired - Fee Related
- 2002-09-26 EP EP02800124A patent/EP1432675B1/en not_active Expired - Lifetime
- 2002-09-26 AT AT02800124T patent/ATE312071T1/en active
- 2002-09-26 DE DE50205226T patent/DE50205226D1/en not_active Expired - Lifetime
- 2002-09-26 JP JP2003532458A patent/JP4272521B2/en not_active Expired - Lifetime
- 2002-09-26 WO PCT/EP2002/010803 patent/WO2003029208A2/en active IP Right Grant
- 2002-09-26 AU AU2002333879A patent/AU2002333879A1/en not_active Abandoned
- 2002-09-26 ES ES02800124T patent/ES2253581T3/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003029208A2 (en) | 2003-04-10 |
| ATE312071T1 (en) | 2005-12-15 |
| EP1432675A2 (en) | 2004-06-30 |
| CA2461574A1 (en) | 2003-04-10 |
| DE50205226D1 (en) | 2006-01-12 |
| JP2005527478A (en) | 2005-09-15 |
| EP1432675B1 (en) | 2005-12-07 |
| DE10147958A1 (en) | 2003-04-30 |
| ES2253581T3 (en) | 2006-06-01 |
| WO2003029208A3 (en) | 2003-09-12 |
| AU2002333879A1 (en) | 2003-04-14 |
| JP4272521B2 (en) | 2009-06-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20130926 |