M E T H O D S AND T E C H N O L O G Y IN T H E S Y N T H E S I S

A N D M A N U F A C T U R E O F DRUGS
NITRATION OF ~-METHOXY-8-CHLOROETHYLBENZENE

B. M. Pyatin, G. M. Sanzharova, UDC 615.332(Laevomycetinum)J

Yu. L. Kopaevich, T. S. Gorokhova, .012.1.002.62
M. R. Bagreeva, and T. A. Uglova

The nitration of a-methoxy-B-chloroethylbenzene (I) with a mixture of nitric and sul-

furic acids is one of the key steps in the industrial synthesis of the antibiotic levomy-
cetin [i]; side products, viz., m- and o-nitro-a-methoxy-~-chloroethylbenzene (lib and llc),
are formed in addition tothe desired p-nitro-a-methoxy-B-chloroethylbenzene (lla).
In the present research for the first time we studied the effect of the composition of
the nitrating mixture on the yields of lla-c. The nitration products were analyzed by gas-
liquid chromatography (GLC).
The yield of lla-c as a function of the ratio of the concentrations of nitric and sul-
furic acids, i.e., as a function of the nitrating capacity of the mixture of these acids,
which is characterized quantitatively by the nitrating activity factor (NAF) [2], are pre-
sented in Table i.
A 60% molar excess of HNOa with respect to I was used in all of the experiments. We
established that the use of a smaller molar excess of nitric acid leads to a decrease in the
yields of lla-c. The process was carried out at 20~ for 2 h. The yield of lla increases
slightly at lower temperatures (--5 to 0~ but the reaction time increases to 4-6 h. In ad-
dition, the nitration of I at temperature below 0~ is hindered because of the high viscosity
of the reaction mass. At temperature above 30~ the yield of lla decreases significantly
with a change in the lla:llb:llc ratio to favor an increase in the amounts of lib and llc.
In experiments Nos. 1-8 the nitric acid concentration was approximately the same (23-
25%), and the NAF changed due to an increase in the sulfuric acid concentration. Nitration
does not take place when NAF = 48.3 (experiment No. i), and starting I was isolated unchanged.
When the NAF was changed from 57.7 (experiment No. 2) to 66.3 (experiment No. 4), the amount
of I in the reaction mass decreased from 92% to 15.5%. An increase in the NAF to 71-74 (ex-
periments Nos. 15 and 16) leads to complete nitration of I, and the yield of lla reaches
62.38%. The yield of lla decreases as the NAF is further increased from 79 (experiments Nos.
TABLE I. Dependence of the Yields of lla-c on the Composition
of the Nitrating Mixture
Com,poskion of t h e n i ~ a t i n g m N t ~ e Amounts of I and IIa-c in the nkro mass, %
Ex~. " HNOa H 2~24'
NO. NAF I IIa tl.b IlC
g %
1 20,68 24,37 39,86 48,3 lO0
2 21,13 23,85 48,04 57,7 2,21 4,42 1.47 0,67
3 20,18 24,97 52,3l 63,3 4,60 34,81 13,56 5,09
4 20,49 24,60 54,65 66,3 5,49 51:38 21,22 7,84
5 20,87 24,16 58,93 71,22 61.18 23.58 10,50
6 20,24 24,90 60,83 73,98 62,38 23,ll 10,34
7 20,00 25,39 64,93 79,31 61.24 22.75 8.73
8 22.60 22,23 69.36 82,44 53100 20,84 7,69
9 13,70 36,92 43,57 59,18 5.49 34.30 9.90 6.15
I0 11,41 43,25 44,60 64,54 1,17 62,98 23,35 11,07
11 11,30 44,55 49,50 72,60 62121 27.14 10,05
12 13,50 37,50 52,38 71,54 ),37 68.53 19127 l 1,49
13 16,20 31,24 58,28 75,02 66.11 19,90 9.83
14 t4,60 34,60 59,19 78,62 58,5o 25,02 8.08
15 35,00 14,43 73,78 82,27 59.46 17,99 9,73
16 33,50 15,03 78,73 89,60 42.47 I 1,74 7,20

S. Ordzhonikidze All-Union Scientific-Research Institute of Pharmaceutical Chemistry,

Moscow. Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 16, No. i, pp. 84-86, Janu-
ary, 1982. Original article submitted July 6, 1981.

0091-150X/82/1601-0061507.50 9 1982 Plenum Publishing Corporation 61

7 and 8) to 82.5 (experiments Nos. 14-16); this is explained by the formation of polymeric
side products, which are not determined by GLC. In the case of analysis of the reaction prod-
ucts (experiments Nos. 7 and 8 and 14-16) by thin-layer chromatography (TLC) we detected
only traces of p-, m-, and o-nitrobenzoic acids. This fact constitutes evidence that the
decrease in the yields of lla-c as the NAF is increased is not associated with oxidation pro-
cesses.
In experiments Nos. 9-16 we used nitrating mixtures with various concentrations of nitric
acid; the dependence of the yield of lla on the NAF was the same as in experiments Nos. 1-8
in this case. The best result (experiment No. 12) was obtained in the nitration of I with
a nitrating mixture containing 37.5% nitric acid and 52.38% sulfuric acid (NAF = 71.5).
The use of a nitrating mixture with a higher percentage of nitric acid is optimal from
the point of view of reducing both the total amount of nitrating mixture and the amount of
acidic wastes in the realization of the nitration of I under industrial conditions.
On the basis of the experimental data presented above it may be concluded that the ni-
tration of I should be carried out with a 60% molar excess of nitric acid with a nitrating
mixture containing 37.5% HN03 and 52.38% H2SO~ (NAF = 71.5). A comparison of the results
that we obtained with the data on the nitration of I under industrial conditions shows that
the industrial parameters of this process are close to optimal.

EXPERIMENTAL
The analysis of the reaction masses by GLC was accomplished with an LKhM-8MD chromato-
graph with a catharometer as the detector and a 300 cm • 3 mm steel column. The support
was Chromaton NAW-DMCS, and the liquid phase was 5% polyethylene glycol succinate. The col-
umn temperature (programmed) ranged from 140 to 200~ the heating rate was 12~ and
the helium flow rate was 40 ml/min. The internal standards were o-nitrochlorobenzene for I
and 2,4-dinitrotoluene for lla-c. The development of the method for the determination of
lla-c and the synthesis of lla-c were described in [3].
Silufol-254 and benzene-acetic acid--acetone (100:5:2) were used for TLC with develop-
ment in UV light
140
The NAF were calculated from the formula NAF = A x 14n--B, were A is the sulfuric acid
concentration in the nitrating mixture (in mass percent), and B is the nitric acid concentra-
tion in the nitrating mixture (in mass percent).
Experiment No. I (See Table i). An 8.53 g (0.05 mole) sample of I was added in the course
of 20 min at 20~ to a mixture of 5.25 g (0.08 mole) of 96.5% nitric acid, 8.8 g (0.09 mole)
of 93.5% sulfuric acid, and 6.63 g of water, and the mixture was stirred at the same tempera-
ture for 2 h. It was then poured into I00 ml of cold water, and the aqueous mixture was ex-
tracted with three 50-ml portions of methylene chloride. The extract was washed three times
with 50-ml portions of water and dried with sodium sulfate, and the solvent was removed by
distillation to give 8.05 g of organic residue, which was analyzed by GLC.
All of the remaining experiments presented in Table i were carried out under similar con-
ditions with the same amount of I.

LITERATURE CITED
1. M. V. Rubtsov and A. G. Baichikov, Synthetic Pharmaceutical-Chemical Preparations [in
Russian], Moscow (1971), p. 56.
2. B. E. Berkman, Industrial Synthesis of Aromatic Nitro Compounds [in Russian], Moscow
(1964), p. 55.
3. B. M. Pyatin, M. R. Bagreeva, G. M. Sanzharova, et al., Khim.-farm. Zh., No. 12, 88
(1981).

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