Development of the method of novocain production

Full text of DOI:10.1023/A:1014762419378

Pharmaceutical Chemistry Journal
Vol. 35, No. 10, 2001
DEVELOPMENT OF THE METHOD
OF NOVOCAIN PRODUCTION
M. G. Abdullaev1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 10, pp. 30 – 33, October, 2001.
Original article submitted May 24, 2001.
There are several industrial methods for the synthesis of
novocain, representing p-aminobenzoic acid diethylamino-
ethyl ester hydrochloride (I × HCl) [1 – 3]. In all cases, the
first stage of the process is the esterification of p-nitroben-
zoic acid (II) with the formation of p-aminobenzoic acid
ethylate (III):
of simultaneously conducting hydrogenation of the nitro
group with transesterification of an ester group on a palla-
dium-containing polymer.
The process of simultaneous hydrogenation of ester III
and in situ transesterification of anesthesin IV was conducted
either on a carbon-supported platinum catalyst (Pd/C) or on
palladium-containing anion exchangers of the AV-17-8 and
AN-1 types (AV-17-8-Pd and AN-1-Pd, respectively). AN-1
(polytrimethylolmelamine) exhibits virtually no swelling in
organic solvents and is a weakly basic anion exchanger,
while AV-17-8 (aminated chloromethylated styrene – divi-
nylbenzene copolymer) exhibits limited swelling in organic
solvents and represents a strongly basic anion exchanger.
The results of preliminary investigations showed that the
simultaneous hydrogenation of ester III and in situ
transesterification of anesthesin IV proceed in the kinetic re-
gion, both processes representing reactions of the first order
C2H5OH
Î2NC6H4COOH
II
O2NC6H4COOC2H5
III
H2SO4
In the next stage, compound III is reduced with iron fil-
ings in the presence of acetic acid. This leads to the forma-
tion of anesthesin acetate, from which anesthesin is isolated
under the action of sodium carbonate:
Fe
H2NC6H4COOC2H5
IV
III
CH3COOH
Then the isolated compound IV is purified by
recrystallization from ethanol in the presence of activated
charcoal and sodium hydrosulfite (decolorizing the solution
by reducing colored impurities). Reaction of the purified
ethyl ester IV with diethylaminoethanol (V) in the presence
of a catalyst (sodium ethylate) yields novocain base I:
TABLE 1. Yield of Novocain Base I Depending on the Concentra-
tion of Diethylaminoethanol V and KOH
Yield, wt.%
Concentration,
mole/liter
Compound
Pd/C
AH-1-Pd
AB-17-8-Pd
C2H5ONa
IV +
HOCH2CH2N(C2H5)2
V
0.04
0.08
0.10
0.14
0.18
0.02
0.06
0.10
0.14
0.20
72
73
74
78
80
73
73
74
76
80
84
88
89
93
94
91
92
94
91
90
87
89
91
95
97
91
95
97
96
92
V
H2NC6H4COOC2H4N(C2H5)2 C H OH
+
2
5
I
Finally the base I is purified and converted into the hy-
drochloride form (novocain) by reacting with a calculated
amount of a hydrogen chloride solution in ethanol.
In order to develop the above technology, we have stud-
ied the possibility of combining the reactions of hydrogena-
tion of ester III and in situ transesterification of anesthesin
IV. Previously [4, 5], we demonstrated the basic possibility
KOH
Note. Reaction conditions: ethanol, 10 – 50 ml; T = 45°C; hydrogen
pressurfe, 1 atm; amount of catalyst, 0.1 – 0.5 g; Pd content, 4 wt.%;
granule size, 0.075 – 0.102 mm; concentration of III,
0.1 – 0.7 mole/liter; reaction duration, 4 – 6 h.
1
Derbent Branch, Dagestan State University, Derbent, Dagestan, Russia.
556
0091-150X/01/3510-0556$25.00 © 2001 Plenum Publishing Corporation

Development of the Method of Novocain Production
557
Kef, mole/(liter × sec × kg-cat.)
with respect to the catalyst. Figure 1 shows a plot of the ef-
fective reaction rate constant (Kef ) versus amount of catalyst
for the transesterification of anesthesin IV. The Kef values
were calculated from the growth of the concentration of
product I (determined by gas chromatography) in the reac-
tion mixture. As can be seen from Fig. 1, the first-order ki-
netics with respect to the catalyst is retained in all three
cases; however, the most steep increase in Kef is observed for
the AV-17-8-Pd catalyst (line 1 ). With respect to the activity,
the catalysts can be arranged in the following order:
AV-17-8-Pd > AN-1-Pd > Pd/C (the same as the order of ba-
sicity). Apparently, the basic properties of metal – polymer
catalysts is the main factor accounting for the possibility of
effectively combining the hydrogenation and transesterifica-
tion reactions. When the initial amount of palladium (4%) is
immobilized, the functional groups of anion exchangers re-
main for the most part free [6] and can operate as active cen-
ters in the transesterification reaction.
The rate constant of the formation of compound I is inde-
pendent of the initial concentration of compound III
(Fig. 2a ), which indicates that the hydrogenation of III to IV
is a zero-order reaction (in agreement with our previous re-
sults [4, 5]). Therefore, the simultaneous hydrogenation and
transesterification reactions obey the laws of hydrogenation
of nitro compounds and allow the hydrogenation product to
be obtained with a high yield.
At the same time, the plot of Kef versus the initial con-
centration of compound V exhibits a rather ambiguous be-
havior (Fig. 2b ). For the metal – polymer catalysts (lines 1
and 2 ), the reaction is of the first order, whereas the process
on the heterogeneous catalyst (line 3 ) is close to a zero-order
reaction (albeit a small increase in the reaction rate with the
concentration of V still takes place). The growth in the initial
concentration of V leads to an increase both in the rate of for-
mation and in the yield of the final product I (see Table 1).
The further development of novocain production tech-
nology was related to studying the effect of acid and base re-
action components on the rate constant of formation of I
from III, since it was known [7] that the transesterification
reaction accelerates in the presence of acids or bases. When
hydrochloric acid was introduced into the reaction mixture
(Fig. 3a ), a more pronounced increase in the reaction rate
was observed on the Pd/C catalyst (line 3 ). At a hydrochlo-
ric acid concentration of 0.12 mole/liter, the rate of the reac-
tion on this catalyst became comparable to that on AN-1-Pd
(line 2 ), although still lower as compared to the case of
AV-17-8-Pd (line 1 ). The observed differences in behavior
for the heterogeneous and metal – polymer catalysts may in-
dicate that the catalysts not only participate in the hydroge-
nation of III, but in the transesterification of IV as well.
This hypothesis is confirmed by the data for bases
(Fig. 3b ), according to which an increase in the concentra-
tion of KOH did not influence the reactions on metal – poly-
mer catalysts (lines 1 and 2 ). At the same time, the effect of
KOH on the process on Pd/C was even more pronounced
0.05
0.03
0.01
1
2
3
200
300 400
Catalyst weight, mg
500
Fig. 1. Plots of the transesterification rate constant (for compound
IV) versus amount of catalyst: (1 ) AV-17-8-Pd; (2 ) AN-1-Pd; (3 )
Pd/C. The reaction conditions are indicated in Table 1.
than the effect of hydrochloric acid (Fig. 3a, line 3 ). The
zero-order reaction with respect to KOH is evidence that
AV-17-8-Pd and AN-1-Pd are directly involved in the
transesterification of IV. The active centers are the free func-
tional groups of both strongly- and weakly-basic anion
exchangers. This is confirmed by the first order of the
transesterification reaction with respect to the catalyst
(Fig. 1, lines 1 and 2 ).
According to the experimental data (Figs. 3a and 3b; Ta-
ble 1), the reaction catalyzed by a base should be preferred
because the processes on metal – polymer catalysts
AV-17-8-Pd and AN-1-Pd (Fig. 3b, lines 1 and 2 ) require
comparatively low base concentrations. As noted above, the
metal – polymer systems contain free functional groups re-
sponsible for the transesterification process. As can be seen
from Table 1, the yield of product I (by gas chromatography
data) as a function of the KOH concentration exhibits an
extremum (probably, related to the hydrolysis of I), while the
same yield monotonically increases with the nucleophilic
agent concentration.
Thus, the whole body of experimental data indicates that
the modified catalytic synthesis of I from III, involving com-
bined reactions of hydrogenation of III and in situ
transesterification of IV, is a promising technology for
novocain production.
EXPERIMENTAL PART
The experiments were performed with p-nitrobenzoic
acid ethyl ester (reagent grade, additionally purified by
recrystallization from ethanol) and diethylaminoethanol base
(reagent grade).

558
M. G. Abdullaev
Kef, mole/(liter × sec × kg-cat.)
à
Kef, mole/(liter × sec × kg-cat.)
à
1
0.0150
1
0.03
3
2
0.01
2
3
0.0075
0.1
0.2
Concentration of HCl, mole/liter
Kef, mole/(liter × sec × kg-cat.)
0.1
Concentration of III, mole/liter
Kef, mole/(liter × sec × kg-cat.)
0.2
b
1
3
b
0.015
1
0.03
2
2
0.075
0.01
3
0.1 0.2
Concentration of KOH, mole/liter
Fig. 3. Plots of the rate constant of the formation of compound I
versus the initial concentration of (a) HCl and (b ) KOH: (1 )
AV-17-8-Pd; (2 ) AN-1-Pd; (3 ) Pd/C. The reaction conditions are
indicated in Table 1.
0.1 0.2
Concentration of V, mole/liter
Fig. 2. Plots of the rate constant of the formation of compound I
versus the initial concentration of (a) compound III and (b) com-
pound V: (1 ) AV-17-8-Pd; (2 ) AN-1-Pd; (3 ) Pd/C. The amount of
catalyst, 100 mg.
exchanger fraction of a certain size can be obtained by crush-
ing in a mortar and sieving.
2. Synthesis of Potassium tetrachloropalladate (II).
The compound K2[PdCl4] was synthesized as described
in [4].
3. Synthesis of palladium-containing anion exchan-
ger. The samples of AV-17-8-Pd and AN-1-Pd were obtained
as described in [4].
Synthesis of Catalysts
The samples of heterogeneous Pd/C catalysts were pre-
pared by a conventional method [8]. The synthesis of palla-
dium-containing anion exchangers AN-1 and AV-17-8 in-
cluded several stages.
4. Activation of the catalysts. A weighed amount (10 g)
of a catalyst was charged into a glass reactor-thermostat
equipped with a stirrer. The system is heated to 45°C, after
which 50 ml of ethanol was poured in and 0.5 g of sodium
borohydride was added. The reactor was purged with hydro-
gen and the catalyst was activated for 60-min with intensive
stirring. Then the catalyst was filtered and washed with water
and 50 ml of acetone. Prior to the work, the catalysts were
stored under a layer of acetone.
1. Anion exchanger converted into the OH form. A
mixture of 10 g of AV-17-8 anion exchanger and 20 ml of
1 N hydrochloric acid in a 100-ml cone-shaped flask was al-
lowed to stand for 3 h, after which the anion exchanger was
filtered and washed with distilled water (to a neutral reaction
of the washing water). The washed anion exchanger was
placed into a new 100-ml flask, 60 ml of 1 N sodium hydrox-
ide was poured in, and the mixture was kept for 3 h with pe-
riodic stirring. Then the anion exchanger was again filtered,
washed sequentially with distilled water (to a neutral reac-
tion of the washing water), acetone (50 ml), and diethyl ether
or ethanol (50 ml), and dried in air.
Analytical methods
Palladium content in a catalyst. The content of Pd was
evaluated by the loss of [PdCl4]2– ions in solution in the
course of immobilization on the carrier. The [PdCl4]2– con-
An analogous procedure was used for the obtaining of
AN-1 anion exchanger in the OH form. If necessary, an anion

Development of the Method of Novocain Production
559
centration in the matrix solution was spectrophotometrically
determined for samples measured in 1-cm-thick cells on a
Specord-UV instrument (Hungary). The optical density of
solutions measured at l = 280 nm was converted into con-
centrations with the aid of a calibration plot.
hydrogen flowing, a weighed amount (0.1 – 0.7 mole/liter)
of the substrate III was introduced into the reactor. The reac-
tion mixtures were stirred at
a
constant rate of
900 – 1100 rpm at a hydrogen pressure of 98 – 103 kPa. Af-
ter termination of the reaction, alkali was added to form
novocain base I representing an oily liquid isolated with
chloroform. Finally, the base was converted into hydrochlo-
ride under the action of a calculated amount of a hydrogen
chloride solution in ethanol. The reaction rates were deter-
mined by volumetrically measuring the hydrogen uptake and
by analyzing the reaction mixtures with the aid of gas chro-
matography.
Gas chromatography. The hydrogenation products
were analyzed on a Model 3700 gas chromatograph (Russia)
equipped with a plasma ionization detector and a glass col-
umn (2000 ´ 3 mm) filled with Lucopren G-1000 (5%) on
Chromaton (carrier gas, helium; evaporator temperature,
250°C; column temperature, 200°C; carrier flow rate, 1.6 li-
ter/h; sample volume, 0.1 – 0.5 ml; analysis duration,
40 – 80 min; internal standard, tridecane). The quantitative
analysis was performed using calibration coefficients deter-
mined for artificial mixtures. The percentage content of each
component was determined with respect to an internal stan-
dard and normalized using the corresponding calibration co-
efficients.
Thin-layer chromatography. The products of the hy-
drogenation and transesterification reactions were qualita-
tively analyzed by TLC on Silufol plates. The plates were
eluted with an acetone – toluene – ammonia (1 : 1 : 1) mix-
ture; the spots were visualized by exposure to a UV radia-
tion.
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3. A. G. Melent’eva, Pharmaceutical Chemistry [in Russian],
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4. M. G. Abdullaev, Khim.-Farm. Zh., 35(1), 42 – 45 (2001).
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Khim. Khim. Tekhnol., 42(5), 3 – 13 (1999).
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Khim., 64(3), 724 – 728 (1990).
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Boston (1970).
8. New Pathways for Organic Synthesis: Practical Applications of
Transition Metals, H. M. Colquhoun et al. (eds.), New York
(1984).
Hydrogenation and transesterification procedures. A
weighed amount (100 – 500 mg) of a catalyst was charged
under a solvent layer (10 – 50 ml of ethanol) in a water-jack-
eted glass reactor-thermostat equipped with a magnetic stir-
rer and activated for 20 – 30 min in a flow of hydrogen. With