A new method of dicaine synthesis from p-nitrobenzoic acid ethylate

Full text of DOI:10.1023/A:1015748808266

Pharmaceutical Chemistry Journal
Vol. 36, No. 1, 2002
A NEW METHOD OF DICAINE SYNTHESIS
FROM p-NITROBENZOIC ACID ETHYLATE
M. G. Abdullaev1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 36, No. 1, pp. 28 – 30, January, 2002.
Original article submitted June 18, 2001.
The commercial synthesis of dicaine, representing
p-butylaminobenzoic acid b-dimethylaminoethyl ester hy-
drochloride (I × HCl), proceeds from p-nitrobenzoic acid and
is analogous to the synthesis of novocain. The only differ-
ence is that the former process includes an additional stage of
alkylating the amino group appearing upon reduction of
p-nitrobenzoic acid (II) to p-aminobenzoic acid (III). The
subsequent processing of the resulting p-butylaminobenzoic
acid (IV) can be performed using different pathways accord-
ing to the following scheme [1, 2]:
The proposed synthesis of I based on the catalytic hydro-
genation process allows many of the above disadvantages to
be partly or completely eliminated. The hydrogenation pro-
cess was conducted either on a traditional carbon-supported
palladium catalyst (Pd/C) or on palladium-containing anion
exchangers of the AN-1 and AV-17-8 types (AN-1-Pd and
AV-17-8-Pd, respectively). Polytrimethylolmelamine AN-1
is a weakly basic highly crosslinked anion exchanger that ex-
hibits virtually no swelling in organic solvents, while
AV-17-8 (aminated chloromethylated styrene – divinylben-
zene copolymer) represents a slightly crosslinked strongly
basic anion exchanger and exhibits pronounced swelling in
organic solvents.
H C OOC
NHC H9
4
5
2
+
HCl
C H OH, H
2
5
V
H , OH–
C H Br
2
4
9
The initial compound was p-nitrobenzoic acid ethyl ester
VIII. Hydrogenation in the presence of butanal and amino
alcohol VII yields p-aminobenzoic acid ethyl ester IX
II
III
IV
POCl3
H C HN
HOCH CH N(CH ) I · HCl
2
2
3 2
–
2H O
–HBr
2
VII
(Fig. 1, curve 4 ). The in situ interaction of ethylate IX with
COCL
9
4
butanal present in the reaction mass (Fig. 1, curve 2 ) yields
azomethine X representing p-butylideneaminobenzoic acid
ethyl ester (Fig. 1, curve 5 ). Reduction of the latter interme-
diate yields ethylate V (Fig. 1, curve 6 ). Previously [4 – 9], it
was established that the course of condensation of aldehydes
with aromatic amines depends strongly on the catalyst. In
particular, the yield of azomethine in the presence of a cata-
lyst is significantly higher than in the case of noncatalyzed
condensation [6 – 9]. The mechanism of catalyst action shift-
ing the equilibrium toward the azomethine formation is still
incompletely clear, but it is known that palladium-containing
polymers are much more effective in this respect as com-
pared to conventional Pd/C. This circumstance probably ac-
counts for the relatively low yield of I from the process on
Pd/C (Table 1).
VI
Both pathways possess significant disadvantages [3]:
i) The synthesis of the key intermediate compound IV
involves the formation of a tertiary amine, so that acid IV is
(
obtained with an admixture of p-dibutylaminobenzoic acid.
(
ii) The intermediate product IV is converted, in one
case, into p-butylaminobenzoic acid ethylate (V) and in an-
other case, into p-butylaminobenzoyl chloride (VI). The for-
mer process has a disadvantage of reversibility, while the lat-
ter pathway encounters technological difficulties related to
the use of POCl3.
iii) The final stage of obtaining the target product I from
intermediates V or VI interacting with dimethylaminoethanol
VII) is also not free from disadvantages. The interaction of
(
(
V with VII is an equilibrium process, thus requiring an ex-
cess of VII, whereas the use of readily hydrolyzable com-
pound VI may lead to unadmissible contamination [3] of the
final product with acid IV.
Compound V is subjected to transesterification in situ
with the formation of the target product I (Fig. 1, curve 3 ).
The amination of butanal and the transesterification of V pro-
ceed simultaneously but with different rates, which leads to
the accumulation of intermediate products IX and X in the
reaction mass (Fig. 1, curves 4 and 5 ).
1
Derbent Branch, Dagestan State University, Derbent, Dagestan, Russia.
28
0
091-150X/02/3601-0028$27.00 © 2002 Plenum Publishing Corporation

A New Method of Dicaine Synthesis from p-Nitrobenzoic Acid Ethylate
29
Relative content, %
Kef ´ 10–3, mole / (liter · kg-càt)
8
6
4
2
0
0
0
0
5
.0
1
1
3
2
2
5
3
4
3
.0
6
1
00
200
300 400
Catalyst weight, mg
3
0
90
150
Time, min
Fig. 2. Plots of the effective rate constant of the formation of com-
pound I versus amount of catalyst: (1 ) AV-17-8-Pd; (2 ) AN-1-Pd;
Fig. 1. Time variation of the reaction mixture composition (gas chro-
matography data) during the synthesis of I from I (not taking into ac-
count the amount of compound VII, ethanol, and water): (1 ) com-
pound VIII; (2 ) butanal; (3 ) compound I; (4 ) compound IX; (5 )
compound X; (6 ) compound V (for reaction conditions, see Table 1).
(
3 ) Pd/C. The reaction conditions are indicated in Table 1.
H , Cat, VII, butanal
2
VIII ¾ ¾ ¾ ¾ ¾ ¾¾ ® I + 3H O + C H OH.
2
2
5
H , Càt
The resulting dicaine base I requires no additional purifi-
2
O N
COOC H
2
2
5
cation because both water and ethanol enter into the compo-
sition of the alcohol solution of HCl used to convert I into a
hydrochloride.
–
2H O
2
VIII
IX
CH CH CH CHO
3
2
2
H N
COOC H
The results of our preliminary investigation showed that,
under the conditions selected (process temperature T = 45°C;
hydrogen pressure 1 atm; solvent ethanol), the simultaneous
reactions of hydrogenation, hydroamination, and transesteri-
fication proceed in the kinetic domain. The mild reaction
conditions allow resinification of the products to be avoided,
thus providing for a high yield of the target product I (Ta-
ble 1). With respect to the activity and selectivity, the cata-
2
2
5
H O
2
H , Càt
2
H C OOC
N
CHCH CH CH
2 2 3
5
2
X
VII
H C OOC
NHC H
4 9
5
2
V
(
CH ) NCH CH OOC
NHC H
4 9
3
2
2
2
TABLE 1. Yield of Dicaine Base I Depending on the Concentration
of Dimethylaminoethanol VII
I
Concentration
of VII,
mole/liter
Yield of I, wt.%
AN-1-Pd
Previously, it was demonstrated that the hydroamination
of aliphatic aldehydes (by aromatic amines [4, 5]) or
heterocyclic aldehydes (by cyclohexyl amine [6] or aromatic
amines [7]) on Pd/C and palladium-containing polymers
Compound
Pd/C
AM-17-8-Pd
1
2
3
4
5
0.1
0.3
0.5
0.7
1.0
68
70
71
73
77
73
76
78
84
85
82
86
87
91
94
[
8, 9] leads to the target products (secondary amines) with a
yield of 84 – 100%. Moreover, it was found that the use of
palladium catalysts allows the processes of hydrogenation of
nitro groups, hydroamination of aldehydes, and
transesterification of ester groups to be conducted simulta-
neously [6 – 10]. Based on our experimental results and the
published data, the overall scheme of obtaining ester I from
acid VIII can be presented as follows:
Reaction conditions: ethanol, 30 – 70 ml; T = 45°C; hydrogen pres-
sure, 1 atm; amount of catalyst, 0.2 g; Pd content, 4 wt.%; granule
size, 0.075 – 0.102 mm; concentration of substrate VIII and butanal,
0
.1 – 0.5 mole/liter; reaction duration, 4 – 6 h.

3
0
M. G. Abdullaev
à
b
Kef ´ 10–3, mole / (liter · kg-càt)
Kef ´ 10–3, mole / (liter · kg-càt)
1
4
.0
8.0
1
2
6
.0
2
3
2
.0
4.0
3
0.1
0.3
0.5
0.2
0.6 1.0
Concentration of VII, mole/liter
Concentration of VIII, mole/liter
Fig. 3. Plots of the effective rate constant of the formation of compound I versus the initial concentration of (a) substrate VIII
and (b) dimethylaminoethanol VII for the processes on various catalysts: (1 ) AV-17-8-Pd; (2 ) AN-1-Pd; (3 ) Pd/C.
lysts studied can be arranged in the following order:
EXPERIMENTAL PART
AV-17-8-Pd > AN-1-Pd > Pd/C.
Synthesis of catalysts. The samples of heterogeneous
Pd/C catalysts were prepared by a conventional method [12].
The synthesis of palladium-containing anion exchangers
AN-1 and AV-17-8 included several stages [10]: (i) conver-
sion of the anion exchanger into the OH-form; (ii) synthesis
of potassium tetrachloropalladate(II); and (iii) preparation of
palladium-containing anion exchanger.
Activation of the catalysts. A weighed amount (10 g) of
a catalyst was charged into a temperature-controlled glass re-
actor equipped with a stirrer. The reactor was heated to 45°C,
charged with 50 ml of ethanol and 0.5 g of sodium
borohydride, and purged with hydrogen for 60-min with in-
tensive stirring to activate the catalyst. Then the catalyst was
filtered and washed with water and 50 ml of acetone. Prior to
the work, the activated catalysts are stored under a layer of
acetone.
According to the data obtained, the process is character-
ized by first-order kinetics with respect to the catalyst
(
Fig. 2) and by the zero-order kinetics with respect to sub-
strate (Fig. 3a ). The effective reaction rate constants (Kef )
were calculated from the kinetics (Fig. 1) of increase in the
concentration of I (determined by gas chromatography) in
the reaction mixture. The data presented in Fig. 2 (cures 1
and 2 ) indicate that both the active centers of palladium cata-
lysts and the free functional groups of anion exchangers,
which remain free after immobilization of palladium
(
4 wt.%), are involved in the process. The free functional
groups of anion exchangers act as catalytically active centers
in the transesterification of V.
As can be seen from Fig. 3b, dependence of the effective
Analytical methods. The content of Pd in a catalyst was
rate constant on the concentration of VII is rather ambiguous,
showing evidence of the first-order reaction for palla-
dium-containing polymers (lines 1 and 2 ) and of zero-order
reaction for Pd/C (line 3 ). Therefore, dimethylaminoethanol
VII can be used as a solvent in order to increase the reaction
rate and the yield of I from the process on AV-17-8-Pd and
2
–
evaluated by the loss of [PdCl4] ions in solution in the
course of Pd immobilization on the carrier. The [PdCl4]2–
concentration in the matrix solution was spectrophotometri-
cally determined in 1-cm-thick cells on a Spekord-UV
spectrophotometer (Hungary). The optical density of solu-
tions measured at l = 280 nm was converted into concentra-
tions with the aid of a calibration plot.
AN-1-Pd.
Thus, using the proposed method, it is possible to per-
The chromatographic measurements were performed as
described elsewhere [10].
form the catalytic synthesis of dicaine base I in a single stage
Hydrogenation, hydroamination, and transesterifica-
tion procedures. A weighed amount (100 – 500 mg) of the
catalyst was charged under a solvent layer (30 – 70 ml of
ethanol) into a water-jacketed glass reactor-thermostat
equipped with a magnetic stirrer and activated for
20 – 30 min in a flow of hydrogen. With hydrogen flowing,
(
proceeding from acid VIII) with a high yield (up to 94%)
under mild conditions. The process combines the reactions of
hydrogenation, hydroamination, and transesterification,
which significantly increases the efficiency of the given tech-
nology of dicaine synthesis.

A New Method of Dicaine Synthesis from p-Nitrobenzoic Acid Ethylate
31
2
3
4
. A.G. Melent’eva, Pharmaceutical Chemistry [in Russian],
Meditsina, Moscow (1968), pp. 320 – 322.
weighed amounts (0.1 – 0.5 mole/liter) of reagents VIII, VII,
and butanal were charged into the reactor. Then the reaction
mixtures were stirred at a constant rate of 900 – 1100 rpm at
a hydrogen pressure of 98 – 103 kPa. After termination of
the reaction, alkali was added to obtain novocain base I in the
form of an oily liquid (isolated with chloroform). Finally,
the product was converted from base to hydrochloride form
under the action of a calculated amount of a hydrochloric
acid solution in ethanol. The effective reaction rate constants
were determined using the data of gas chromatography.
The experiments were performed with p-nitrobenzoic
acid ethyl ester (reagent grade, additionally purified by
recrystallization from ethanol) and diethylaminoethanol base
. P. L.Senov, Pharmaceutical Chemistry [in Russian], Meditsina,
Moscow (1971), p. 367.
. M.V. Klyuev, A.A. Nasibulin, and M.G. Abdullaev, RF Patent
No. 2.039,599 (Submitted 12.10.92, published 20.07.95); Byull.
Izobret., No. 20 (1995).
5
. M.V. Voronin, A.A. Nasibulin, and M.V. Klyuev, Neftekhimiya,
37(6), 516 – 522 (1997).
6
. M.V. Klyuev, M.G. Abdullaev, and A.A. Nasibulin, Zh. Org.
Khim., 31(3), 416 – 418 (1995).
7. M.G. Abdullaev, A.A. Nasibulin, and M.V. Klyuev, Izv. Vyssh.
Uchebn. Zaved., Khim. Khim. Tekhnol., 37(7 – 9), 55 – 58
(
1994).
8. M.G. Abdullaev, A.A. Nasibulin, and M.V. Klyuev, Izv. Vyssh.
Uchebn. Zaved., Khim. Khim. Tekhnol., 37(7 – 9), 58 – 62
(
reagent grade). The purity of dicaine base was not worse
(
1994).
than 97% as determined by thin-layer and gas chromatogra-
phy techniques.
9. M.V. Klyuev, A.A. Nasibulin, and M.G. Abdullaev,
Neftekhimiya, 34(5), 413 – 420 (1994).
10. M.G. Abdullaev, Khim.-Farm. Zh., 35(1), 42 – 45 (2001).
11. V. D. Kopylova, T.V. Pogodina, and M.V. Klyuev, Zh. Fiz.
Khim., 64(3), 724 – 728 (1990).
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2. New Pathways for Organic Synthesis: Practical Applications of
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1
. USSR State Pharmacopoeia (XIth Ed.) [in Russian], Meditsina,
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