Principles of Ksimedon production technology

Full text of DOI:10.1023/A:1015396630902

Pharmaceutical Chemistry Journal
Vol. 35, No. 12, 2001
DRUG SYNTHESIS METHODS
AND MANUFACTURING TECHNOLOGY
PRINCIPLES OF KSIMEDON PRODUCTION TECHNOLOGY
V. S. Reznik,1 A. A. Muslinkin,1 A. N. Shirshov,1 N. A. Spiridonova,1 N. G. Pashkurov ,1,2
V. D. Akamsin,1 and É. A. Gurylev1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 12, pp. 28 – 31, December, 2001.
Original article submitted July 9, 2001.
Ksimedon [1], representing 1-(2-oxyethyl)-4,6-dime-
thyl-1,2-dihydropyrimidin-2-one (I), was originally obtained
in 1965 within the framework of a systematic investigation
into the synthesis and biological activity of N-(w-oxoalkyl)-
oxodihydropyrimidines – nonglycoside analogs of pyrimi-
dine nucleosides [2, 3]. Among a number of synthesized sub-
stances, compound I showed the best combination of proper-
ties and was selected for clinical testing. Initially, ksimedon
was considered as comparable in activity with 6-methyluracil
(metacil). However, subsequent investigations showed that
these drugs are pharmacologically different: ksimedon has a
pronounced action upon the immune system, while metacil
shows no such activity.
In connection with the good prospects for the broad ap-
plication and increased commercial production of ksimedon,
we have conducted a chemico-technological investigation
of the process of synthesis, isolation, and purification of
the parent compound. The results of this study are presented
below.
We have developed a special three-stage technology for
the synthesis of ksimedon based on readily available re-
agents: acetylacetone (II) and carbamide (III). The first stage
is essentially the reaction of condensation of II and III in the
presence of HCl, which was originally described in [12].
This reaction leads to the formation of 2-oxy-4,6-dimethyl-
pyrimidine hydrochloride (V):
According to the results of clinical tests, ksimedon was
recommended for commercial production and application in
medicine as an antiburn agent with immunostimulant action
[4]. However, subsequent pharmacological and clinical in-
vestigations showed that the therapeutic spectrum of
ksimedon extends far beyond treating burns. The preparation
has proved to be effective in cases of various nosologic
forms of surgical disorders in adults and children [5]. This
drug was recommended for accelerating wound healing in
cases of large injury areas [6], for the prophylaxis of postop-
erative pyoinflammatory complications [7], and for the treat-
ment of trophic ulcers [8]. According to experimental and
clinical data, ksimedon produces positive effects in the treat-
ment of osteomyelitis [9], osteoporosis, gastric and duodenal
ulcers, chronic gastritis, hepatitis, and leukopenia induced by
chemo-, x-ray-, and radiotherapy of malignancies. It was also
reported that the drug was effective in the complex therapy
of patients with acute pneumonia [10] and tuberculosis [11].
CH3
HCl 35 %, 80 – 82 °C
NH
CH2(COCH3)2
II
+ CO(NH2)2
III
· HCl
i-C3H7OH
H3C
N
O
V
t < 80 °C
CH3COCH2CCH3
· HCl
NCONH2
IV
Although carrying out this reaction presents no difficul-
ties, deviation from the indicated temperature regime results
in the formation of a certain amount of the incomplete con-
densation product IV. Replacing ethanol (used in the original
process [12]) by isopropyl alcohol somewhat increases the
yield of product V.
In the second stage, compound V is converted into so-
dium salt VI. Previously [2], we described the two-step syn-
thesis of compound VI, whereby V is converted first into a
free base by treatment with NaOH and then into a Na salt by
interaction with sodium alcoholate. Now we have established
that compound VI is simply and conveniently synthesized in
1
Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific
Center, Russian Academy of Sciences, Kazan, Tatarstan, Russia.
Deceased.
2
672
0091-150X/01/3512-0672$25.00 © 2001 Plenum Publishing Corporation

Principles of Ksimedon Production Technology
673
one step by treating V with two moles of NaOH in a strictly
controlled amount of water, followed by separating and dry-
ing the target product:
by the side reactions leading to the formation of a consider-
able amount of oligomers (IX) appearing as viscous liquids:
VI
H2C CH2
ClCH2CH2OH
–
–NaCl
O
CH3
NH
CH3
VIII
2NaOH
H2O
N
Na+ + NaCl + 2H2O
CH3
· HCl
H3C
N
V
O
H3C
N
O
H2C CH2
n
NCH2CH2OH
O
+
VI
O
H3C
N
I
VIII
The results of this reaction depend to a certain extent on
the ratio of compound V and NaOH (as can be seen from Ta-
ble 1, the alkali should be taken in a small excess).
CH3
N(CH2CH2O) H
n
In order to purify the intermediate product VI from the
unavoidable NaCl admixture, the product was recrystallized
from an aqueous isopropyl alcohol (IPA) solution. In the case
of a 25 – 30% aqueous IPA solution, the filtration of the hot
solution is hindered by rapid crystallization. Increasing the
IPA concentration to 35 – 40% renders the process techno-
logically feasible and leads to a 4 – 5% increase in the con-
tent of the target compound in the mixture, although the yield
is still as low as 30 – 35%. For this reason, taking into ac-
count that the admixture of NaCl does not hinder the third
stage in the synthesis of ksimedon, we simplified the process
and carried out this stage using dry salt VI without additional
purification.
H3C
N
O
IX
n = 3 – 6
The formation of ethylene oxide (VIII) takes place in vir-
tually all cases, reaching a maximum when compound I is
synthesized in an aqueous medium using 2-oxy-4,6-dime-
thylpyrimidine potassium salt and minimum, when the reac-
tion is conducted in an anhydrous alcohol using a sodium salt
(VI). As for the interaction between VIII and I, this process
is most significant both in aqueous media and in DMF. Com-
pound VIII also reacts to a certain extent with salt VI to form
I, but the contribution of VIII to ksimedon is probably more
significant. In a special experiment, salt VI was reacted with
compound VIII in a molar ratio of 1 : 2 in DMF at 60 – 80°C,
which led to the formation of a mixture containing 10 – 25% of
initial salt VI, 25 – 35% of I, and 30 – 40% of oligomers IX.
An important factor complicating the process of crude
ksimedon purification until obtaining the required white
color is related to the formation of otherwise insignificant
(below 0.03%) impurities rendering the technical product I
cherry-red, cream, or yellow. The most intense coloration is
observed when ksimedon is synthesized in an aqueous me-
dium or DMF. The formation of these impurities is related to
the acid properties of methyl groups in compound IV and I:
these groups are capable of detaching protons in an alkaline
medium and entering various condensation reactions with
the formation of unidentified colored products.
In the final stage, the alkylating agent ethylene chloro-
hydrin (ECH) interacts with salt VI according to the scheme
CH3
NCH2CH2OH
–
CH3
H3C
N
O
I
N
Na+ + ClCH2CH2OH
H3C
N
O
CH3
VI
N
H3C
N
OCH2CH2OH
VII
This reaction yields only product I (the formation of an
O-alkylation product VII was never observed). The reaction
proceeds smoothly in an alcohol medium (methanol, IPA,
n-propanol), as well as in aqueous solutions and DMF. How-
ever, both isolation of I from the reaction medium containing
water or DMF and subsequent purification are complicated
The most difficult technological problem consists in pu-
rifying the technical product I so as to obtain a substance of
TABLE 2. Effect of Compound I Concentration in Solution on the
Results of Chromatographic Purification of Ksimedon
Purified product
Concentration
of I in CHCl3,
Parent substance
content, %
Yield, %
Color
kg/liter
TABLE 1. Effect of Reagent Ratio on the Yield and Purity of So-
dium Salt VI
1.0
0.9
61.0
58.9
99.7
99.8
Pink
Molar ratio
[V]/[NaOH]
Yield
of VI, %
Parent substance
content, %
White with pink
tint
1 : 1.96 (equimolar)
1 : 2.06 (+5 %)
85.0
87.5
84.0
91.7
94.9
87.7
0.8
0.7
58.8
60.0
99.5
99.3
White with slight
pink tint
–”–
1 : 1.86 (–5 %)

674
V. S. Reznik et al.
pharmacopoeial quality. In attempts to reach this goal by
recrystallization, we tried using various solvents such as
acetonitrile, methyl ethyl ketone, dichloromethane, and their
mixtures, as well as ethyl acetate – pure and in mixtures with
methanol, ethanol, and IPA. We have also attempted at using
various schemes for extracting VI or I from technical product
or its solutions in chloroform and other solvents. Neither of
these methods allowed us to obtain a product of the required
quality.
With a view to the prospect of using an injection form of
ksimedon, it was of interest to develop a method for addi-
tionally purifying I so as to obtain a substance forming abso-
lutely colorless transparent aqueous solutions. This was
achieved by recrystallization of I from acetonitrile in the
presence of activated charcoal. Table 3 presents the results of
a series of experiments, all of which yielded transparent
aqueous solutions. However, an absolutely colorless prepara-
tion was obtained only if the initial weight of I did not ex-
ceed 40 – 50 g and the amount of activated charcoal was
about 1.7 – 2.6% of the total charge. If the weight of I was
50 – 100 g or higher, the recrystallized product (albeit still
forming transparent solutions) acquired a yellowish tint and
needed additional recrystallization (unavoidably reducing the
pure product yield).
In the final stage of our investigation, we have tried (on a
laboratory scale) a more convenient method of synthesis,
which excludes isolation and drying of the intermediate so-
dium salt VI – the “bottleneck” of the technological scheme
described above. According to the modified scheme, hydro-
chloride V treated with an alkali in a methanol solution con-
verts into sodium salt VI, which (without isolation) is reacted
in methanol with ECH so as to form I. It was found that, if
the alkali is taken in equimolar amount, the content of salt VI
in technical product I is rather high (up to 20% and above). A
more satisfactory result was obtained using the alkali in a
20% excess, whereby the content f sodium salt VI in techni-
cal I was about 12%. Dissolution in chloroform and purifica-
tion by filtration through aluminum oxide completely re-
moved salt VI and increased the yield of pharmacopoeial
ksimedon to 40 – 45% (calculated for the initial carbamide).
Based on the results of these investigations, a technologi-
cal process has been developed by which the parent sub-
stance of ksimedon (according to Pharmacopoeial Clause FS
42-3754–99) is now synthesized at the Arbuzov Institute of
Organic and Physical Chemistry (Kazan). Using this parent
Finally, we succeeded in obtaining ksimedon of
pharmacopoeial purity by chromatographic filtration of tech-
nical I through a column with neutral aluminum oxide, fol-
lowed by precipitating the target product with acetone and
drying. The chromatographic procedure simultaneously re-
moved both residual salt VI and colored viscous impurities
and yields a product containing not less than 99% of the tar-
get parent compound with a yield of 30% and above (calcu-
lated for the initial compound III). However, ksimedon ob-
tained by this method exhibited coloration (from yellow to
pink) on storage even in the dark. This color could be elimi-
nated by repeated purification of I using the same chromato-
graphic filtration through Al2O3 (with unavoidable loss of
the product). As can be seen from Table 2, the lower the con-
centration of the initial colored chloroform solution of I, the
closer the final product color approaches the desired white.
In order to solve the problem of product I coloration, we
tried to precipitate ksimedon in the presence of various
discolorating additives (H2O2, activated charcoal, zinc pow-
der, 25% aqueous NH3, etc.). These agents were introduced
both in the initial chloroform solution or in acetone used to
precipitate the product. The most successful variant of “whit-
ening” was offered by treating the initial solution of I with a
mixture of aqueous H2O2 and NH3 solutions. This treatment
eliminates the pink color; the yellow tint (if present) can be
eliminated by additional treatment with an aqueous
chloramine B solution.
TABLE 3. Effect of Recrystallization Conditions on the Yield and Purity of Ksimedon
Amount (g) and fraction (%) in charge
Experi-
ment
Yield
of pure I,
%
Parent substance content
ksimedon
activated charcoal
acetonitrile
g
%
g
%
g
%
initial, %
final, %
1
2
3
4
5
6
7
8
9
20
20
17.4
17.2
17.1
-“-
1.0
2.0
3.0
6.0
12.0
40
0.9
1.7
2.6
-“-
94
-“-
81.7
81.1
80.3
-“-
95.05
-“-
99.2
99.1
99.4
99.5
99.7
99.2
99.9
99.2
98.0
98.7
99.1
83.4
82.2
72.0
72.6
81.6
80.3
83.3
81.0
84.1
77.0
91.3
20
-“-
-“-
40
188
376
1880
-“-
99.3
“
80
-“-
-“-
-“-
400
-“-
-“-
-“-
-“-
320
17.2
17.1
17.0
16.9
16.5
24.2
1.7
2.6
3.0
3.4
6.2
81.1
80.3
80.0
79.7
77.3
75.8
95.05
98.9
96.3
-“-
60
70
-“-
80
-“-
10
11
150
-“-
-“-
Repeated without activated
charcoal
1020
98.0

Principles of Ksimedon Production Technology
675
substance, “TatKhimFarmPreparaty” Company produces
ksimedon tablets (according to Pharmacopoeial Clause FS
42-3774–99). Both products are registered at the State
Pharmacopoeial Committee (reg. Nos. 93/287/7 and
94/34/11).
Upon cooling, the reaction mass was filtered and the deposit
on filter was washed with 4.0 liters of methanol. The filtrate
was poured into a 25-liter enameled jacketed reactor
equipped with a stirrer, descending-flow cooler, and a bot-
tom outlet valve, after which methanol was distilled off in
vacuum (20 – 30 Torr). The process is continued (with stir-
ring) until complete removal of methanol, with the rate of
distillation controlled by the rate of the heating agent flow in
the jacket. Then 18.0 liters of acetone was added to the reac-
tor (at a temperature not exceeding 40°C) and the mixture
was stirred about 0.5 h at 20 – 25°C. The reaction mass was
filtered and the deposit on the filter was washed with 5 – 6 li-
ters of acetone.
The obtained technical product was dried in air for
7 – 8 h to obtain 3.4 kg of a dry substance; 1.0 kg of this
product was dissolved in 10.0 liters of chloroform. The solu-
tion was filtered and passed through a Simax glass column
filled with aluminum oxide (~2.5 kg). Then the column was
washed with 5 liters of chloroform and the obtained solution
was combined with the first eluate. The entire solution was
evaporated until the first signs of crystallization were visible
(at a volume of about 3 – 4 liters), poured with stirring into a
reactor containing 20 liters of acetone, and allowed to stand
for 10 – 15 min. The obtained suspension was filtered, and
the deposit on the filter was washed with acetone (1.0 liter)
and dried in air to constant weight to obtain 0.66 kg of
pharmacopoeial ksimedon; m.p., 139 – 141°C (reported
m.p., 134.5 – 135.5°C [3]); total yield in this stage, 2.26 kg
(43.2%).
EXPERIMENTAL PART
2-Oxy-4,6-dimethylpyrimidine hydrochloride (V). A
63-liter enameled jacketed reactor equipped with a stirrer
and a bottom outlet valve was charged (with stirring) with
21.1 liters (16.6 kg) of IPA, 4.23 kg (70.4 mole) of
carbamide and 7.2 liters (7.0 kg, 70.0 mole) acetylacetone.
To this mixture heated to 80 – 82°C was gradually (over
1.5 – 2 h) added from a measuring tank 9.5 liters (11.2 kg,
107.4 mole) of 35% hydrochloric acid. The temperature of
the reaction mixture was initially controlled by the rate of
dosing; in the later stage, by switching on the heater. Then
the reaction mass was stirred on weak boiling for 2.5 – 3 h
and allowed to stand overnight. Finally, the mass was filtered
and the deposit on filter was washed with 2.0 – 2.5 liters IPA
and dried in air to constant weight (15 – 20 h); yield, 8.5 kg
(77%); m.p., 255 – 256°C (analytical sample recrystallized
from aqueous IPA). The data of elemental analyses agree
with the results of calculation according to the empirical for-
mula C6H8N2O × HCl.
2-Oxy-4,6-dimethylpyrimidine sodium salt (VI). A so-
lution of 2.24 kg NaOH in 8.3 liters of distilled water was
charged into a 20-liter Simax glass reactor equipped with a
paddle stirrer, immersed heating coil, and bottom outlet
valve. Then the heater was switched on and 4.4 kg of V was
added by portions with stirring such that the temperature
would not rise above 95°C. When V was fully added, the
mixing was continued with heating to 98 – 105°C until com-
plete dissolution of the solid phase, after which the hot solu-
tion was immediately discharged into a stainless steel (or
porcelain) crystallization vessel and allowed to stand over-
night. The crystallized mass was transferred onto a suction
(Nutsch) filter and thoroughly squeezed. Then the product
was dried in air for 15 – 20 h and then in vacuum
(20 – 30 Torr) at 100 – 110°C; yield, 3.5 kg (85%); m.p.,
255 – 256°C; content of the parent compound (by data of
potentiometric titration with 0.1 M aqueous HCl), 91.7%.
The data of elemental analyses agree with the results of cal-
culation according to the empirical formula C6H7N2ONa (an-
alytical sample recrystallized from aqueous IPA).
Ksimedon synthesis without isolation and purifica-
tion of sodium salt (VI). A 1-liter flask equipped with me-
chanical stirrer, thermometer, and reflux cooler was charged
with 0.5 liter of methanol. Then 100.0 g (2.5 mole) of NaOH
was dissolved with stirring, 160.5 g (12.9 mole) of hydro-
chloride V was added by portions, and the mixture was
boiled with stirring for 12 h. Then 110 ml (132 g, 1.6 mole)
of ECH was added and boiling was continued for 19 – 20 h,
after which the reaction mass was cooled and filtered. The
deposit on the filter was washed with 50 ml of methanol and
the filtrate was evaporated at
a reduced pressure
(20 – 30 Torr) on a water bath. The residue was treated with
400 ml of acetone. The precipitated technical product was
separated by filtration, washed on filter with acetone, and
dried to constant weight in air to obtain 110 g (65.5 %) of
technical ksimedon. Purification on an aluminum oxide col-
umn as described above yields 72.0 g (42.9%) of a
pharmacopoeial product; m.p., 138.5 – 139.5°C. The data of
elemental analyses agree with the results of calculation ac-
cording to the empirical formula C8H12N2O2.
Ksimedon purification by recrystallization from
acetonitrile with activated charcoal. A suspension of 400 g
of I, 70 g activated charcoal, and 2.4 liters of acetonitrile was
heated to boiling, filtered hot, and allowed to stand for 4 h.
The precipitated product was separated by filtration, washed
with acetone, and dried to constant weight in air to obtain a
(2-Hydroxyethyl)–4,6-dimethyl-1,2-dihydropyrimidin
-2-one (I). A 20-liter Simax glass reactor equipped with a
paddle stirrer, immersed heating coil, and bottom outlet
valve was charged (with stirring) with 11.0 liters (8.7 kg) of
methanol and 3.8 liters (4.56 kg, 56.6 mole) of ECH. To this
mixture heated to 40 – 50°C was gradually (over 7 – 8 h)
added, by portions with stirring, 6.0 kg (34 mole) of sodium
salt VI. Then the temperature was increased to 68 – 70°C
(weak boiling) and the mixture was stirred for 18 – 20 h.

676
V. S. Reznik et al.
3. V. S. Reznik and N. G. Pashkurov, Izv. Akad. Nauk SSSR, Ser.
Khim., No. 6, 1323 – 1329 (1968).
4. USSR Inventor’s Certificate No. 1,685,454; Byull. Izobret.,
No. 39 (1991).
5. S. M. Gorbunov, Anabolic Preparations. Autoallodermoplastics
in Clinical Practice [in Russian], Poligrafizdat, Kazan (1980),
pp. 26 – 30.
6. G. A. Izmailov, S. G. Izmailov, V. Yu. Tereshchenko, et al., in:
Pharmacology and Toxicology of Organofluoric and Bio-
logically Active Substances [in Russian], Mari Poligrafizdat,
Ioshkar-Ola (1966), pp. 72 – 73.
yellowish coarse-crystalline product; yield, 320 g (80.0%);
m.p., 140 – 141°C (see Table 3, experiment no. 8).
Ksimedon purification by repeated crystallization
from acetonitrile. Ksimedon purified as described above
(320 g) was dissolved in acetone (1.3 liter). Immediately
upon complete dissolution of the product, the flask is placed
into a bath with ice-cold water. After keeping under these
conditions for 3 h, the precipitate was separated by filtration,
washed with acetone, and dried to constant weight in air to
obtain a slightly yellowish fine-crystalline product; yield,
292 g (91.0%); m.p., 142 – 143°C (see Table 3, experiment
no. 11).
7. S. G. Izmailov and I. F. Sharafislamov, Prophylaxis of
Postoperation Pyoinflammatory Wound Complications in Ab-
dominal Surgery [in Russian], State Technical University,
Kazan (1996), p. 192.
8. RF Patent, No. 2019176; Byull. Izobret., No. 17 (1994).
9. RF Patent, No. 2073514; Byull. Izobret., No. 5 (1997).
10. RF Patent, No. 2054937; Byull. Izobret., No. 6 (1996).
11. RF Patent, No. 2088231; Byull. Izobret., No. 24 (1997).
12. G. M. Kosolapoff and C. H. Roy, J. Org. Chem., 26, 1895
(1961).
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