Note: Descriptions are shown in the official language in which they were submitted.
' 0050/44176
216740~
A process for the preparation of N,N'-dibenzylbispidine
The present invention relates to a process for the preparation of
5 N,N'-dibenzylbispidine.
N,N'-Dibenzylbispidine is an intermediate for the preparation of
ambasilide (= N-(4-aminobenzoyl)-N'-benzylbispidine,
EP-A 62 119). According to DE-A 24 28 792, N,N'-dibenzylbispidine
10 can be prepared from N,N'-dibenzylbispidone by reduction with hy-
drazine hydrate in triethylene glycol in the presence of potas-
sium hydroxide. N,N'-Dibenzylbispidone was obtained by reacting
N-benzyl-4-piperidone with benzylamine. Although in this process
the intermediate and the final product were purified by distilla-
15 tion, the latter has only inadequate purity, which is a disadvan-
tage for further reaction to give ambasilide.
A process which provides N,N'-dibenzylbispidine in high purity
has now been found.
The invention relates to a process for the preparation of N,N'-
dibenzylbispidine, which comprises reacting N-benzylpiperidone
with formalin and benzylamine in the presence of acetic acid in a
solvent at 50 - 100 C, with the benzylamine, the acetic acid, the
25 solvent and part of the benzylpiperidone being initially
introduced at 50 - 100 C, subsequently the remaining benzylpiperi-
done and part of the formalin being added, and then, after addi-
tion of the r~;n;ng formalin, the reaction mixture being heated
to reflux, and the acetate of N,N'-dibenzylbispidone obtained in
30 this way being, after removal of the methanol by distillation,
purified from byproducts by extraction and subsequently the N,N'-
dibenzylbispidone being liberated and isolated, and then reacting
the N,N'-dibenzylbispidone with hydrazine at 80 - 200 C in a
solvent, and extracting the N,N'-dibenzylbispidine, after treat-
35 ment with acid and alkali, with toluene.
For the first reaction step, the benzylamine, the acetic acid andthe solvent are introduced first with part of the benzylpiperi-
done. 2 - 8 mol of acetic acid, preferably as pure substance, are
40 used per mol of benzylpiperidone. Examples of suitable solvents
are methanol, ethanol, tetrahydrofuran, toluene and chlorinated
hydrocarbons such as methylene chloride and chloroform. The ben-
zylpiperidone is used in the reaction in a total amount of from
0.8 to 1.3 mol per mole of benzylamine, with the amount of ben-
45 zylpiperidone introduced first being between 0 and 75%, prefer-
ably 20 - 30%. The reaction is carried out at 50 - 100 C and,
0050/44176 ~ I B~ g ~ 6
after all the reactants have been combined, the mixture is boiled
under reflux for some time.
After the reaction is complete, the solvent is stripped off in
5 vacuo, and the residue is taken up in water. After the aqueous
solution has been purified by extraction with a solvent such as
toluene, ethers or chlorinated hydrocarbons, preferably methylene
chloride, the N,N'-dibenzylbispidone is liberated from the salt
therefrom and extracted with one of said solvents. After the sol-
10 vent has been changed, preferably to n-propanol, the N,N'-diben-
zylbispidone crystallizes out and is washed with a solvent such
as n-propanol.
The product obtained in this way, which is more than 99% pure, is
15 reduced to N,N-dibenzylbispidine [sic] with hydrazine. The reac-
tion is carried out in an ethylene glycol such as diethylene gly-
col or triethylene glycol. 2 - 3 mol of alkali metal hydroxide
solution should be present per mole of bispidone. The bispi-
done:hydrazine molar ratio is from 1:1 to 1:5. The reaction tem-
20 perature should be at the start of the reaction 50 - 100 C and ïs
then slowly increased to 170 - 200 C, with a hydrazine/water mix-
ture dist;ll;ng out. The reaction is complete after 20 -
24 hours. The product obtained in this way is then treated with
hydrochloric acid and subsequently with sodium hydroxide solu-
25 tion, and is extracted with toluene, an ether such as methyltert-butyl ether or a chlorinated hydrocarbon such as methylene
chloride or chlorotoluene. Removal of the solvent results in very
pure N,N'-dibenzylbispidine.
30 The novel process for the preparation of N,N'-dibenzylbispidine
has the following advantages by comparison with the process dis-
closed in DE-A 24 28 792:
The reaction volume can be reduced by one half compared with the
35 process disclosed in DE-A 24 28 792. Furthermore, by use of a
mild extraction process, the temperature-sensitive crude product
can be freed of byproducts to such an extent that a pure N,N'-di-
benzylbispidone is obtained. Even on scale-up, the process makes
it possible for yields to be comparable with those in laboratory
40 tests, and the two high vacuum/high temperature distillations
which are costly in industrial and energy terms are saved. The
crystals obtained in this way are stable on storage.
The purity of the N,N'-dibenzylbispidone is a precondition for
45 its further processing to a high-purity N,N'-dibenzylbispidine
which can immediately be reacted further without isolation and
0050/44176 21674~6
without the high vacuum distillation or other purification pro-
cesses hitherto necessary.
Example
First stage: N,N'-Dibenzylbispidone
78.5 g (0.73 mol) of benzylamine, 30 g of N-benzylpiperidone and
120 ml (2.1 mol) of 99% pure acetic acid were dissolved in metha-
10 nol and heated to about 70 C. To this were added, separately andslowly, 87 g of N-benzylpiperidone and 95 g of formalin (37%
strength). After the introduction of piperidone was complete, a
further 30 g of formalin solution were added over the course of
15 min, and the temperature was increased to reflux for about
15 1 h. After complete conversion of the starting material, the con-
tents of the flask were cooled and the methanol was removed by
distillation in vacuo. Water was added to the mixture, and the
phases were separated. The product-containing aqueous phase was
purified several times with methylene chloride, and subsequently
20 N,N'-dibenzylbispidone was liberated with sodium hydroxide solu-
tion and extracted with methylene chloride. The solvent was re-
moved by distillation with vacuum assistance. The crude product
was taken up in hot n-propanol and slowly cooled to 0 C. The crys-
tallized material was filtered off with suction, washed and
25 dried. The yield was 109 g of N,N~-dibenzylbispidone. This corre-
sponds to a yield of 55% based on N-benzylpiperidone used. The
purity was 99.8%.
Second stage: N,N'-Dibenzylbispidine
50 ml of triethylene glycol and 24 g (0.075 mol) of N,N'-diben-
zylbispidone were initially introduced. A mixture of 40 ml of
triethylene glycol and 15 ml (0.18 mol) of 50% strength potassium
hydroxide solution was added. The mixture was heated to 85 C.
35 Then, 10 ml (0.21 mol) of 100% pure hydrazine hydrate were slowly
metered into the mixture in such a way that the internal tempera-
ture did not rise above 80 - 90 C.
The reaction mixture was slowly heated to reflux ~125 C). The tem-
40 perature was increased to 190 - 200 C, and the hydrazine/water
mixture was removed by distillation. The reaction was continued
at this temperature until conversion was complete. It was then
cooled to 70 C and diluted with 90 ml of water. In each case while
cooling, initially 30 ml of concentrated hydrochloric acid were
45 added and, after stirring for 2 h, sufficient sodium hydroxide
solution was added for the solution to have a distinct alkaline
reaction. After a further 2 h, the product was extracted with
0050/44176
4 ~1~7~0~
toluene. The solution contained 22.1 g of N,N'-dibenzylbispidine,
corresponding to a yield of 96.2%. The purity after removal of
the toluene was 99.9%.
