DE3323047A1 - METHOD FOR PRODUCING PHENAETHYLAMINES - Google Patents

Description

The invention relates to an improved method for electrochemical Reduction of nitrostyrenes to phenethylamines.

Although the electrochemical reduction of nitrostyrenes has already been described in the chemical literature (see, for example, JAPS 49-13 777), this technique has become practical Production of phenethylamines rarely used due to insufficient chemical efficiency.

It has now been found that a method for the preparation of phenethylamines in water solutions in high yields and can be obtained with excellent purity.

This new process is characterized in that nitrostyrene of the general formula

X-Ar-C

R ²

1O _n II

where Ar is an aromatic radical, X is one or more substituents on the aromatic radical from the group consisting of hydrogen, alkyl, alkoxy, hydroxy,
3

-N. (R and R are identical or different and mean ^ R

each hydrogen or alkyl), -N (CH-) (η = 4, 5 or 6),

-NCCH ₃ , -CN, -COOR ³ , -CF ₃ , -NO ₂ and halogen, R ¹ denotes a hydrogen atom or a methyl group and R ² denotes a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, in the presence of hydroxylamine or

a salt thereof and with a strong negative cathode potential Electrochemically reduced during the entire process and a phenethylamine of the general formula

R ² XH-NH,

Y-Ar-CH R ¹

or a pharmaceutically acceptable salt thereof, wherein Ar, R and R ² have the same meaning as above and Y has the same meaning as X with the exception that it is not

also means -NO ".

15 The phenethylamines have the general formula

R ² .CH-NH,

Y-Ar-CH ¹ I.

20 R

where Ar is an aromatic radical, Y is one or more substituents on the aromatic radical from the group Hydrogen, alkyl, alkoxy, hydroxy,

/ ^r3 4

-N. (R ³ or R are the same or different and each

^X R

a hydrogen atom or an alkyl group), -N (£ ** ") (n =

30 4, 5 or 6),

-NCCH ₃ , -CN, -COOR ³ , -CF ₃ and halogen, R ¹ denotes a hydrogen atom or a methyl group and R ² denotes a hydrogen atom or an alkyl group having 1 to 4 carbon atoms

35 means.

Aromatic groups here include, for example, phenyl radicals, Naphtnylreste or Indolylreste understood.

-ΑΙ Alky] is understood here to mean straight-chain or branched-chain Alkyl groups having 1 to 5 carbon atoms such as Methyl, ethyl, n-propyl and isopropyl.

Alkoxy is understood here to mean alkyl-O groups, in which the Alkyl radical is as defined above.

Halogen is understood here to mean chlorine, bromine or fluorine.

Pharmaceutically acceptable salts of the compounds of the formula I are also obtained by the process of the invention. Such Salts can, for example, hydrobromides, hydrochlorides, Be phosphates, sulfates, citrates, and tartrates.

The compounds of formula I can be used as pharmaceuticals.

The nitrostyrenes used as starting material in the process of the invention have the general formula
20th

X-Ar-C ^ II

R ¹ 25

wherein Ar, R and R ^{2 have} the above meaning and X has the same meaning as Y, with the exception that it can also mean -NO ₇ .

The catholyte can consist of a dilute aqueous solution of a strong acid alone or a mixture of a strong acid, water and an organic solvent. The strong acid is, for example, sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid or a sulfonic acid. The concentration of acid and organic solvent, if the latter has acid-base properties, should be such that the hydronium ion concentration is between 10 ^JM and 20M, preferably above 10M. the

relative amounts of water and organic solvent can vary over a wide range. The organic one Solvent can be an alcohol, a carboxylic acid, an ether, an amide or a nitrite. The relationship between

The tholyte volume and cathode area should be as small as possible be.

The anolyte consists of dilute aqueous mineral acids, preferably sulfuric acid or hydrochloric acid. The concentration is 2 to 10% by volume.

The anode is usually a DSA ^ (metal anode with a noble metal oxide layer), but can also consist of lead, lead dioxide, graphite or platinum group metals.

The cathode material must be carefully selected. There must be an electrode surface with high hydrogen overpotential to have. This is achieved by making the cathode from a material with a high hydrogen overpotential, or by electroplating or galvanic deposition of a metal with a high hydrogen overpotential on the Cathode before or during the procedure. The cathode material can be zinc, lead, cadmium, mercury, tin or a conductive one Material (such as graphite, lead, nickel, copper, aluminum or titanium) on which a deposit, such as for example zinc, lead, cadmium, tin or mercury was applied.

The electrolytic cell should be a divided one with good mass transport properties. The diaphragm can be a be of the ion exchange type or a plastic fabric.

The temperature should be as low as possible. The process is usually carried out at a temperature below 20 ° C carried out.

Cathode potential, current density, nitrostyrene concentration

and mass transport properties to the cathode surface are a function of one another. According to the invention it has been found that a large negative potential is important in order to carry out the reduction successfully. Therefore, the reduction should be either as a controlled potential electrolysis at a large negative potential or as a constant current electrolysis in which the values for current density, nitrostyrene concentration and mass transport properties to the cathode surface are such that the potential has a large negative value , be performed. The potential should be more negative than
-1.0 V in relation to an SCE (saturated calomel electrode) as a reference electrode. The reference electrode is in contact with the cathode at an angle of approximately 45 ° to the

15 cathode surface.

In addition, it has been found according to the invention that a successful implementation of the reduction is the addition of a hydroxylamine or a salt thereof to the catholyte, preferably of hydroxylamine. Concentration can ranging from trace to a saturated solution.

The chemical efficiency increases with the increasing concentration of hydroxylamine. The upper limit of the hydroxylamine concentration is determined by the solubility in the catholyte. A concentration greater than 0.1 M is preferred.

Suitable hydroxylamine salts are hydroxylammonium hydrogen sulfate, Hydroxylammonium sulfate, Hydroxylammoniurochlorid and Hydroxylammonium phosphate.

The product is isolated according to known methods. The pH of the catholyte is set appropriately adjusted (pH 4 in most cases), and then extracted, for example with toluene or dichloromethane. Thereafter the pH of the water phase is increased to about pH 9 to 10 if the phenethylamine is a phenolic group contains, and in other cases · increased to about pH 12

and then extracted several times, for example with toluene or dichloromethane. The solvent is evaporated and that obtained free amine with high purity.

According to a preferred embodiment of the invention, a compound of the formula

V, "^) - CH = C
H ₃ C ^ ^ = ^

CH ₃

to a compound of formula 15

H ₃ C

reduced. The reduction is carried out with the addition of hydroxylamine to the catholyte and with a strong negative potential carried out during the entire process «-1.2 V).

example 1

The electrolytic equipment used was of the filter press type with DSA ^ anodes and lead cathodes. The exposed surface of both the anode and the cathode was 20 cm ² . The device had a reference electrode which was in contact with the cathode at an angle of 45 ° to the cathode surface. The anode and cathode chambers were separated from one another by a strong cation exchange diaphragm (Nation ^ 390). Both the anolyte and the catholyte were pumped through the cell with centrifugal pumps.

The substrate was placed in a plastic mesh container. The container was immersed in the catholyte solution.

The analyzes were carried out with HPLC. The applied Conditions and results are shown in Table I. . The conversion of the substrate was 100% in all examples.

The catholyte pH was through during the electrolysis Acid addition kept constant.

The anolyte consisted of 1 M H SO.,

Table I.

CH ,.

CH;

-CH = C
CHn

/ CH ₃ .

CH

³ >

CH _n -C

/ ^CH 3

'NO,

CH ₃

i / he isub- IH ₂ O K a t h ο 105 · ml ¹ y ml t - B e d i η g u r -Salt igen. mg pH Temp ν Il cathode current Potential ⁶ ^ ¹ Amp. Chemical rf UC
No. t strat,
mole ml ^C £ dMl ¥ ^ng Acid ⁰ ' 6th Hydroxyl oil Metal salt 100 0.2 ° c density
7th V / SCE -1.60 - »-1.80 hour Efficiency Uli. amine. 23 Pb A / dm -1.60-> '-1.90 % H ₂ SO ₄ Il ZnCO ₃ Il Il 16 It -1 55 -> -1.90 I. 0.05 Il '_ - 0.018 It Il 15th -1.55 -> -2.00 -1.40-> -1.46 45.8 66 Ii It (NH ₂ -
OHJ ₂ Il Il Il 16 -1.72 - »-1.90 2 ' ί " i
Il _ It H ₂ SO ₄ Il It It 23 Il Il It -1.65 - »-1.53 Il 80 Il _
j Il Il ti 0.09 Il dd Il 16 Il -1.40-9- -1.47 3 It It _
T Il Il It Il ti Il M. 52 It 35 -1.25 - »-1.42 Il. 80 it ti "I. Il 12th Il 0.018 Il 200 Il 16 Il Il -1.28- * -1.42 49 86 0.14 j
210 j - It 6th Ii 0.036 dd 100 Il Il Il It 79 79 0.0045 105 ^: - It ti Il 0.018 ti Il Il graphite 10.8 42 81 7th 0.05 Il _ Il 15th Il Il H Il - Pb 35 45.5 74 j 0.0045 95 Il 30th Il Il Il ti Il 10.8 4.2 74 VU dd 80 Il Il Il Il Il 27.5 It 72 LO
I. It Il ohJ ₂ Il 10.8 Il 79 Ll j It Il 4.2 76

(cont'd).

Table I (continued)

'Zinc was electroplated on the cathode surface before the nitrostyrene reduction.

^b ) Conditions according to JA-PS 49-13 777.

^c > The acid volume before electrolysis, d) electrolysis with constant potential.

The ^arrows show the changes during electrolysis.

iVer isub- H _? 0 Co-rLp
.. mitt K a t h ο 1 ν t - 'B e things - -Salt ί η mg pH Temp, s 1
cathode Current- ¹ e) "
Potential ' 15-H2.5 ^e) r d /
- 1 . D. Amp. Cheinis SViC
No. I "strat,
. mole ml sunga acid e; • hydroxyl (NH ₂ OH) ₂
H ₂ SO ₄ hoi & - Metal salt 100 0.A ⁰ C . / 2 V / SCE 5 hours Efficient -,. ml " amine Il Il It 16 A / dm 15th - % 12- 0.00A5 100 MeOH HCl ml Il 0.008 ZnCO ₃ ti Il Il Pb M. - A.2 13th 0.01A 17th EtOH 89 H ₂ SO ₄ 5 - Il Il M. Il It It 13.5 -1.20- »-1.70 11.1 78 IA M. A5 i-PrOH 60 Il A.I Il Il . _ Il Il Il 86 Ib Il M. MeOH Il M. 6th It It M. Il 83 , 6 ^b) 0.032 27 87 40% HBr Il a) M. 20. A. Bl 20th . 61-

CO CO NJ CO CD

Example 2

NH,

The same equipment was used and the experiments were carried out in the same manner as in Example 1.

i sub H ₀ O K a t h ml ο 1 ι ml Table II mole Metal salt rag Temp. Cathode current Kathode-.
potential ^; Amp. Chemical i strat
mole ml Co-solution
middle - 87
It 22nd
ti 0.012 100
Il ° C Pb
Il density V / SCE hours Efficiency Ver 1 ^t - ^ Conditions ZnO
ti 16
ti A / dm -ltf.50- »-1.54
-l.A9-> -1.55 t sucb 0.0106
Il 27
Il MeOH
Il Acid ⁰ ' Hydroxyl 13.5
Il 15.8
It 60
81 INr. atnm * salt 1
2
I. HCl
It (NH "Ol £ L
H ₂ SO ₄

a) The acid volume before electrolysis.

b) The arrows show the changes during the electrolysis.

CO CO K) CO CD

Miixample 3

The same equipment was used, and the experiments were carried out in the same manner as in Example 1.

Table III

Sub
strat,
mole H ₂ O 0.0106 27 ■ ^'1:! -
Catholyte conditions ml Acid*' ml Hydroxyl amm. -
salt mole Metal salt mg Temp
⁰ C cathode Electricity- _{> t} Cathode, s Amp.
hours Chemical Ver ml Il "" Il vO solution
middle 87 22nd 0.012 100 16 Pb density
A / dm ² potential '
V / SCE 27.8 Efficiency search
In the- Il Il Il HCl • Il (NH ₂ OH) ₂
H ₂ SO ₄ Il ZnO M. Il Il 13.5 ·. w-1.52 H % MeOH Il Il Il Il - Il Il Il Il 5 -1.0 - * - 1 · 1 Il Il Il - ■ Il
¹ 13.5 w-1.5 80 Il 57 111. 7C 1 2 3

Example 4

The gle ¹ "" he Einrichtlang was used, and the experiments were carried out in the same manner as in Example. 1

H ₉ O K a t h ο 1 y, t ml Tabel ] mole η g e η mg Temp. cathode current ■ Cathode • Amp, Chem see 9.1 ^L.
ml Co-Lc
• mid jsungs
: el ■ · - CJ
acid 22nd 0.004 Metal salt. 100 ^U C Pb density
A / J- ' potential
'• V / SCE hours Efficiency !
Who- 'Sub- mi ml -Conditional 16 A / dm -1.32 -1.38 H Sf ?! ^strat ' 27 MeOH 87 .. HCl Hydroxyl
Ά mm - ^ & I * * ZnO 13.5
ι 27.8 fir.
mole <
I.
¹ 0.0024 - '
j (NH ₂ OH) ₂
H ₂ SO ₄

Example 5

ν
f

The experiment was carried out as in Example 1, with the exception that the anolyte consists of 90% ethanol and 10% concentr

Sulfuric acid existed.

Sub ΗλΟ Ka t h ml ο 1 y t ml Table V mole η g e η mg Temp, 23 cathode I.
Current-, cathode Amp, Cr.em-fc strat, ml Corl solution
• middle ·; 175 acid 10 0.02 Metalisak 300 C. density ' ^v .'
A / dm ² potential
'• V / SCE hours Efficient ι U .'Il
J mole 15th -Bed in g u 12.5
ι -1.8 -4.0 0.25 MeOH HCl · 'Hydroxyl
. λ mm -S ^a I ^ ZnSO ₄
• j
Pb 45 85 (NH ₂ OH) ₂
H ₂ SO ₄

Example 6

NO,

ι ¹

The experiment was carried out as in Example 5,

Table VI

Ver
: iUCh
No..* ■ · Sub
strat,
mole H ₂ O
ml Ka t h 0 1 yt conditions ml Acid' ml 'Hydroxyl
a mm - £ 5 ^a I * mole Metal salt, ZnSO ₄ 300 Temp,
⁰ C cathode Strait,
diqhte
A / dm ² cathode
potential
'■ V / SCE Amp,
hours 'Chemical' 0.25 15th Cor solutions
• middle -\ 175 10 0.02 I _m .24 Pb 12, δ '" -1.8 -4.5 45 Efficiency HCl (NH ₂ OH) ₂
H ₂ SO ₄ • MeOH 85

Example 7

The same equipment as in Example 1 was used and the experiment was carried out in the same manner

as in example 1
Table VII.

Ver Sub H ₂ O Ka t h ml ο 1 ml -Bedi'ngu mole η g e α mg Temp, cathode Current-,, Cathode ^;! Amp, ChenTt n uch
for ' strat, ml Co-rsolutions
• middle ·: 90 25th 'Hydroxyl
, λ mm --S £ I ^ 0.01 Metal salt :, 100 ^Ü C diqhte '
A / dm ² potential
■ • V / SCE ί hours of effxzie HI . mole 111 I. Ci.
acid 30th 12.5
I. -2.0 -3.0 0.1 35
η MeOK (NH ₂ OH) ₂
H ₂ SO ₄ ZnSO ₄ Pb ίο; 6o HCl

KJ CaJ CD -P-

Example 8

The experiment was carried out as in Example 1, with the exception / that the anolyte from 60%

Tetrahydrofuran and 1% H ₂ SO.

Table VIII

Ver Sub
strat,
mole H ₂ O
ml Ka t h 0 1 yt conditions ml "Acid' 5
I. 'Hydroxyl
. λ mm - * ■ »λ I ^ mole Metal salt. I. mg Temp
⁰ C cathode Current-.
density ¹ ;
A / dm ² Cathode
potential
• ■ V / SCE. Amp,
hours 'Chemical
Efficiency
(V
/ 9 search
hl »- ' 0.005 35
η Corlx5sung £
• medium ■ · 60 0.006 ZnCO ₃ 36 Pb 10
I. 6.7 en No. (NH ₂ OHJj
H ₂ SO ₄ THF ml

Example 9

The experiment was carried out as in Example 8.

Table IX

Ver Sub
strat,
mole H ₂ O
ml Ka t h 0 1 yt conditions _{i ¥} n _g . _G "Acid * ^ ml Hydroxyl mole Metal salt. mg Temp,
⁰ C cathode Current-,
diQhte
A / dm ² cathode
potential
'• V / SCE. Amp. I Chem
hours of efficiency
^% 90 search
Sir. ' 0.005 35
η Corlic
• mid ml 5 0.006 36 31 Pb 10 - 4th 60
# ■ ■ i ₂ so, (NH ₂ OH) ₂
H ₂ SO ₄ ZnCO ₃ THF

GJ CO NJ CO CD

Claims (1)

Dr. Dieter Weber Klaus Seiffert Patent attorneys Dipl.-Chom. Dr. Dieter Weber. Dlpl.-Phye. Klaus SelHert PoBt compartment 614B. 6200 Wiesbaden German Patent Office
Zweibrückenstrasse 12th 8000 Munich 2 D-6200 Wiesbaden 1 Gustav-Freytaß - Straße 25 Telephone O ^{6121/37 27 SO TelegrammadreBee: 1} WiIlPaIeHi Telex: 4-186247 Poetsciiecki Frankfurt / Main 676S-602 Bank: Dresdner Bank AG, Wiesbaden, account no. 27Θ8Ο7ΟΟ (BLZ B1O8006O) SX 7 01-1 DE June 23, 1983 We / Wh Stiftelsen Industriell Organisk Elektrokemi, c / o Prokoril, S-221 04 Lund Process for the preparation of phenethyamines Priority: Swedish patent application 10 No. 8 204 015-5 dated June 29, 1982 "-JL ' Claims . ' Process for the preparation of phenethylamines of the general formula R ² ^ CH-NH. Y-Ar-CH R ¹ 25 or pharmaceutically acceptable salts thereof, in which Ar is an aiomatic radical, Y is one or more Substituents on the aromatic radical from the group Hydrogen, alkyl, alkoxy, hydroxy, ^ 3 4 -N. (R and R are the same or different and each ^X R 5 each a hydrogen atom or an alkyl group), -if ("CH ₂ ) (n = 4, 5 or 6), -NCCH ₃ , -CN, -COOR ³ , -CF ₃ and halogen is R ¹ Is a hydrogen atom or a methyl group and R ^{2 is} a hydrogen atom or an alkyl group with 1 to 4 - means carbon atoms, characterized in that one is a nitrostyrene of the general formula 15 R ² Jl-UO ₂ II X-Ar-C R ¹ wherein Ar, R and R ^{2 have} the above meaning and X has the same meaning as Y and can also mean -NO ₃ , electrochemically reduced in the presence of hydroxylamine or a salt thereof and with a strong negative cathode potential during the entire process. 2. The method according to claim 1, characterized in that there is a nitrostyrene of the formula 30 J> N-C y-CH = C CH ₃ ^ CH ₃ to a phenethylamine of the formula. 35 reduced, -y- CH CH. CH.