4-Hydroxy-2-quinolones. 174.*Hydrochlorides of [(alkylamino)alkyl] amides of 1-allyl- 4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydro- quinoline-3-carboxylic acid - A new class of opioid receptor antagonists

Article abstract of DOI:10.1007/s10593-010-0529-7

Hydrochlorides salts of [(alkylamino)alkyl]amides of 1-allyl-4-hydroxy-6,7- dimethoxy-2-oxo-1,2-di-hydroquinoline-3-carboxylic acid were synthesized as potential biologically active compounds. Pharmacological testing showed promise for using these compounds to develop new highly efficient opioid receptor antagonists.

Full text of DOI:10.1007/s10593-010-0529-7

Chemistry of Heterocyclic Compounds, Vol. 46, No. 4, 2010
4-HYDROXY-2-QUINOLONES. 174.* HYDROCHLORIDES
OF [(ALKYLAMINO)ALKYL]AMIDES OF 1-ALLYL-
4-HYDROXY-6,7-DIMETHOXY-2-OXO-1,2-DIHYDRO-
QUINOLINE-3-CARBOXYLIC ACID – A NEW CLASS OF
OPIOID RECEPTOR ANTAGONISTS
I. V. Ukrainets1**, L. V. Sidorenko1, A. A. Davidenko2, and A. K. Yarosh3
Hydrochlorides salts of [(alkylamino)alkyl]amides of 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-di-
hydroquinoline-3-carboxylic acid were synthesized as potential biologically active compounds.
Pharmacological testing showed promise for using these compounds to develop new highly efficient
opioid receptor antagonists.
Keywords:, 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, opioid receptor antagonists
amidation.
Opioid receptor antagonists are a separate group of drugs, which have relatively recently appeared on
the pharmaceutical market [2]. The best-known members of this class, naloxone and naltrexone, are commonly
used in medicine for the elimination of acute intoxication by narcotic analgesics, cessation of the action of such
agents, restoration of breathing in neonates after the introduction of related opioid analgesics to women in
childbirth, for the diagnosis of addiction to narcotics, and the treatment of addiction to narcotics and alcoholism
[3-8]. In addition to their obvious positive properties, both naloxone and naltrexone have a common significant
drawback, namely, these compounds both have the chemical structure of semisynthetic morphines and, thus,
have many contraindications for use [8, 9]. Furthermore, similar to all morphinanes, these compounds are not
highly stable, which leads to difficulties in their preparation and the storage of drug formulations. The high cost
of these compounds is also a problem [10]. Improvement in some pharmaceutical and pharmacokinetic
properties of naloxone and naltrexone has been achieved by their chemical modification to create prodrugs [11-
15]. Nevertheless, in this approach, the biologically active basis is not altered in principle and, thus, many of the
problems indicated remain unresolved.
_______
*For Communication 173, see [1].
** To whom correspondence should be addressed, e-mail: uiv@kharkov.ua.
1National University of Pharmacy, Kharkiv 61002, Ukraine.
2N. I. Pirogov Vinnitsa National Medical University, 21018 Vinnitsa, Ukraine; e-mail: almusel@mail.ru.
3Institute of Pharmacology and Toxicology, Academy of Medical Sciences of Ukraine; Kiev 03680, Ukraine,
e-mail: yarosh44@mail.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 560-568, April, 2010. Original
article submitted May 13, 2009.
0009-3122/10/4604-0445©2010 Springer Science+Business Media, Inc.
445

Hence, the search for new, highly efficient opioid receptor antagonists among the more simple and
available compounds is an extremely important current concern. This work was initiated with computer
screening, which we first carried out for 4-hydroxy-2-quinolones using the program for the Prediction of
Activity Spectra for Substances (PASS) [16]. We found that the capacity to block opioid receptors falls in the
wide spectrum of biological properties of this class of compounds. While the probability for the manifestation of
this type of activity (pa) proved low, the calculated maximum for this index (0.433) was found for N-R-amides
of 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid. As noted by the developers
of the PASS program, a compound with pa < 0.5 will probably not display activity. However, if in subsequent
experiments the pharmacological property predicted with such a low probability nevertheless is found, this
implies that a new chemical class of biologically active compounds has been discovered with the given activity.
In other words, experimentally established high activity of N-R-amides of 1-allyl-4-hydroxy-2-oxo-1,2-
dihydroquinoline-3-carboxylic acid would indicate that opioid receptor antagonists with similar structure have
not been reported.
In light of these arguments, we obtained a series of [(alkylamino)alkyl]amides of 1-allyl-4-hydroxy-
6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 1a-j. The specific selection of N-R-amides of this
type is attributed only to the feasibility of their conversion into water-soluble hydrochloride salts 2a-j and not to
some fundamental reason.
COOMe
NH2
MeO
MeO
COOMe
MeO
MeO
AllBr, DMSO, К2СО3
N
H
3
4
ClOCCH2COOMe
OH
MeONa,
MeOH
COOMe
MeO
MeO
COOMe
MeO
MeO
NHCOCH2COOMe
O
N
5
6
H2NR
OH
OH
.
CONHR
O
MeO
MeO
HCl
CONHR
O
MeO
MeO
HCl
N
N
2a–j
1a–j
1, 2 a R = 2-(dimethylamino)ethyl, b R = 2-(ethylamino)ethyl, c R = 2-[(2-hydroxyethyl)amino]ethyl,
d R = 3-(diethylamino)ethyl, e R = 3-(dimethylamino)propyl, f R = 3-(diethylamino)propyl,
g R = (1-ethylpyrrolidin-2-yl)methyl, h R = 2-morpholin-4-ylethyl, i R = 3-morpholin- 4-ylpropyl,
j R = 3-piperidin-1-ylpropyl
446

The commercially available methyl ester of 2-amino-4,5-dimethoxybenzoic acid (3) was the most
rational choice as the starting compound. The N-alkylation of acid 3 by alkyl bromide in the DMSO/K2CO3
system proceeds with good yield. Then, N-allylanthranilate 4 was acylated with methyl malonyl chloride, and
the resultant anilide 5 undergoes Dieckmann heterocyclization to give the methyl ester of 1-allyl-4-hydroxy-
6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (6).
The amidation of ester 6 by alkylaminoalkylamines may be carried out by a standard procedure [17],
i.e., by heating equimolar amounts of the reagents in ethanol at reflux over several hours. We should also note a
method usually employed in the synthesis of arylamides and hetarylamides of 4-hydroxy-2-oxo-1,2-dihydro-
quinoline-3-carboxylic acids involving heating the corresponding esters with amines with the same equimolar
reagent ratio [17]. Such a modification permits a shortening of the reaction time to several minutes with
retention of high yields.
All the synthesized [(alkylamino)alkyl]amides of 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydro-
quinoline-3-carboxylic acid 1a-j and their hydrochlorides 2a-j are colorless crystalline compounds with sharp
melting points (Table 1), which are readily soluble in DMF and DMSO.
1H NMR spectroscopy was used to establish the structure of the final hydrochlorides 2a-j (Table 2).
The capacity of the alkylaminoalkylamide hydrochlorides 2a-j to block opioid receptors was studied in
white mice with mass 20-30 g by a method involving the elimination of the analgesic effect of narcotic
analgesics, in particular, tramadol, a well-known synthetic opioid [8]. The tested animals were separated into
groups of six for each dose and compound studied. The initial pain threshold was found for all the animals using
a hot plate [18] (Table 3).
Then, tramadol in dose 10 mg/kg was introduced into the animals intramuscularly in the thigh. The
predicted analgesic effect was induced after 60 min and confirmed by retesting of the pain threshold. Then,
60 min after tramadol introduction, the animals of the control group were treated with the reference compound
naloxone in dose 1 mg/kg in the same manner, while the animals of the other groups were treated with
TABLE 1. Characteristics of Alkylaminoalkylamide Hydrochlorides 2a-j
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C*
Yield, %
C
H
N
2a
2b
2c
2d
2e
2f
C19H25N3O5 · HCl
C19H25N3O5 · HCl
C19H25N3O6 · HCl
C21H29N3O5 · HCl
C20H27N3O5 · HCl
C22H31N3O5 · HCl
C22H29N3O5 · HCl
C21H27N3O6 · HCl
C22H29N3O6 · HCl
C23H31N3O5 · HCl
55.54
55.41
55.56
55.41
53.25
53.33
57.44
57.33
56.31
56.40
58.35
58.21
58.57
58.44
55.45
55.57
6.45
6.36
6.49
6.36
6.01
6.12
7.02
6.87
6.50
6.63
7.23
7.11
6.84
6.69
6.09
6.22
10.12
10.20
10.11
10.20
9.74
9.82
9.64
9.55
9.98
9.87
9.37
9.26
9.15
9.29
9.32
9.26
251-253
96
92
83
92
90
88
94
97
91
84
(155-157)
244-246
(160-162)
223-225
(151-153)
210-212
(116-118)
235-237
(122-124)
206-208
(109-111)
197-199
(134-136)
231-233
(149-151)
221-223
(137-139)
2g
2h
2i
56.36
56.45
59.39
59.28
6.60
6.46
7.05
6.92
9.13
8.98
9.14
9.02
2j
230-232
(108-110)
_______
* The melting points of the corresponding free bases 1a-j are given in
parentheses.
447

aminoalkylamide hydrochlorides 2a-j in doses 1 and 10 mg/kg. As expected, naloxone eliminated the analgesic
effect of tramadol as indicated by the return of the pain threshold virtually to the initial level following its
injection after only 30 min (Table 3).
TABLE 2. 1H NMR Spectra of Compounds 2a-j
Com-
pound
Chemical shifts, , ppm (J, Hz)
2a
2b
16.86 (1Н, s, 4-ОН); 10.43 (1Н, t, J = 5.8, CONH); 10.12 (1Н, br. s, NH+);
7.39 (1Н, s, Н-5); 6.93 (1Н, s, Н-8); 5.92 (1Н, m, CH=СН2);
5.16 (1H, d, J = 10.5, NСН2СН=СН-cis); 5.05 (1H, d, J = 17.6, NСН2СН=СН-trans);
4.96 (2H, s, NСН2); 3.90 (3H, s, OCH3); 3.83 (3H, s, OCH3);
3.74 (2Н, q, J = 6.2, CONHCH2); 3.29 (2Н, t, J = 6.3, NHCH2СН2); 2.79 (6Н, s, 2СН3)
+
16.94 (1Н, s, 4-ОН); 10.40 (1Н, t, J = 5.8, CONH); 8.89 (2Н, br. s, NH2 );
7.38 (1Н, s, Н-5); 6.92 (1Н, s, Н-8); 5.92 (1Н, m, CH=СН2);
5.16 (1H, d, J = 10.6, NСН2СН=СН-cis); 5.05 (1H, d, J = 17.8, NСН2СН=СН-trans);
4.96 (2H, s, NСН2); 3.90 (3H, s, OCH3); 3.83 (3H, s, OCH3);
3.67 (2Н, q, J = 6.9, CONHCH2); 3.11 (2Н, quint, J = 6.3, NHCH2СН3);
2.95 (2Н, q, J = 7.3, CONHCH2СН2); 1.18 (3Н, t, J = 7.2, NCH2СН3)
+
2c
2d
2e
2f
17.02 (1Н, s, 4-ОН); 10.45 (1Н, t, J = 5.1, CONH); 9.23 (2Н, br. s, NH2 );
7.41 (1Н, s, Н-5); 6.94 (1Н, s, Н-8); 5.91 (1Н, m, CH=СН2);
5.15 (1H, d, J = 10.5, NСН2СН=СН-cis); 5.06 (1H, d, J = 17.6, NСН2СН=СН-trans);
4.95 (2H, s, NСН2); 3.89 (3H, s, OCH3); 3.82 (3H, s, OCH3); 5.20 (1Н, br. s, ОН);
3.70 (4Н, m, CONHCH2 + NCH2CH2OH); 3.17 (2Н, t, J = 6.2, СОNHCH2СН2);
3.02 (2Н, t, J = 5.3, NCH2СН2ОН)
16.88 (1Н, s, 4-ОН); 10.41 (1Н, t, J = 5.8, CONH); 10.24 (1Н, br. s, NH+);
7.37 (1Н, s, Н-5); 6.91 (1Н, s, Н-8); 5.92 (1Н, m, CH=СН2);
5.16 (1H, d, J = 10.6, NСН2СН=СН-cis); 5.04 (1H, d, J = 17.8, NСН2СН=СН-trans);
4.95 (2H, s, NСН2); 3.90 (3H, s, OCH3); 3.82 (3H, s, OCH3);
3.73 (2Н, q, J = 6.4, CONHCH2); 3.25 (2Н, t, J = 6.5, NHCH2СН2);
3.15 (4Н, q, J = 7.2, N(СН2CH3)2); 1.22 (6Н, t, J = 7.2, N(СН2CH3)2)
17.20 (1Н, s, 4-ОН); 10.39 (1Н, t, J = 6.1, CONH); 9.98 (1Н, br. s, NH+);
7.39 (1Н, s, Н-5); 6.93 (1Н, s, Н-8); 5.93 (1Н, m, CH=СН2);
5.16 (1H, d, J = 10.2, NСН2СН=СН-cis); 5.04 (1H, d, J = 17.7, NСН2СН=СН-trans);
4.96 (2H, s, NСН2); 3.89 (3H, s, OCH3); 3.83 (3H, s, OCH3);
3.43 (2Н, q, J = 6.2, CONHCH2); 3.06 (2Н, t, J = 7.3, NHСН2CH2СН2);
2.73 (6Н, s, 2CH3); 1.94 (2Н, quint, J = 7.1, NHСН2CH2СН2)
17.19 (1Н, s, 4-ОН); 10.40 (1Н, t, J = 5.8, CONH); 10.07 (1Н, br. s, NH+);
7.38 (1Н, s, Н-5); 6.91 (1Н, s, Н-8); 5.92 (1Н, m, CH=СН2);
5.15 (1H, d, J = 10.4, NСН2СН=СН-cis); 5.03 (1H, d, J = 17.6, NСН2СН=СН-trans);
4.95 (2H, s, NСН2); 3.90 (3H, s, OCH3); 3.82 (3H, s, OCH3);
3.42 (2Н, q, J = 6.1, CONHCH2); 3.08 (6Н, m, N(СН2)3);
1.95 (2Н, quint, J = 6.6, NHСН2CH2СН2); 1.18 (6Н, t, J = 7.3, N(СН2CH3)2)
2g
2h
2i
16.79 (1Н, s, 4-ОН); 10.53 (2Н, m, CONH + NH+); 7.35 (1Н, s, Н-5); 6.89 (1Н, s, Н-8);
5.93 (1Н, m, CH=СН2); 5.15 (1H, d, J = 10.5, NСН2СН=СН-cis);
5.04 (1H, d, J = 18.0, NСН2СН=СН-trans); 4.95 (2H, s, NСН2); 3.89 (3H, s, OCH3);
3.81 (3H, s, OCH3); 3.71-2.94 (7Н, m, NHCН2СНN(CH2)2);
2.23-1.69 (4H, m, 3'-CH2 + 4'-CH2); 1.24 (3Н, t, J = 6.7, NCH2СН3)
16.96 (1Н, s, 4-ОН); 10.97 (1Н, br. s, NH+); 10.42 (1Н, t, J = 5.6, CONH);
7.36 (1Н, s, Н-5); 6.90 (1Н, s, Н-8); 5.92 (1Н, m, CH=СН2);
5.16 (1H, d, J = 10.6, NСН2СН=СН-cis); 5.04 (1H, d, J = 17.3, NСН2СН=СН-trans);
4.94 (2H, s, NСН2); 3.89 (3H, s, OCH3); 3.82 (3H, s, OCH3);
3.76 (6Н, m, CONHCH2 + О(СН2)2); 3.07 (6Н, m, N(CH2)3)
17.20 (1Н, s, 4-ОН); 10.87 (1Н, br. s, NH+); 10.38 (1Н, t, J = 5.8, CONH);
7.38 (1Н, s, Н-5); 6.91 (1Н, s, Н-8); 5.92 (1Н, m, CH=СН2);
5.16 (1H, d, J = 10.6, NСН2СН=СН-cis); 5.04 (1H, d, J = 17.4, NСН2СН=СН-trans);
4.95 (2H, s, NСН2); 3.90 (3H, s, OCH3); 3.82 (3H, s, OCH3);
4.00-3.67 (4Н, m, CН2OCH2); 3.43 (2Н, q, J = 6.0, NHCH2);
3.35-2.91 (6Н, m, CН2N(CH2)2); 2.01 (2Н, quint, J = 7.6, NНCH2СН2СН2N)
2j
17.19 (1Н, s, 4-ОН); 10.37 (1Н, t, J = 5.8, CONH); 10.14 (1Н, br. s, NH+);
7.37 (1Н, s, Н-5); 6.91 (1Н, s, Н-8); 5.92 (1Н, m, CH=СН2);
5.16 (1H, d, J = 10.5, NСН2СН=СН-cis); 5.04 (1H, d, J = 17.3, NСН2СН=СН-trans);
4.95 (2H, s, NСН2); 3.89 (3H, s, OCH3); 3.82 (3H, s, OCH3);
3.41 (4Н, m, CONHCH2СН2СН2); 3.03 (2Н, m, 2-СН2 piperidine);
2.82 (2Н, m, 6-СН2 piperidine); 2.00 (2Н, quint, J = 7.8, NHСН2CH2СН2);
1.72 (6Н, m, 3,4,5-СН2 piperidine)
448

TABLE 3. Biological Characteristics of Compounds 2a-j
Pain threshold level, sec
Com-
pound
Dose,
mg/kg
60 min after tramadol
introduction
30 min after introduction
of test compound*
Initial
2a
2b
2c
2d
2e
2f
1
10
1
14.0 ± 1.05
9.2 ± 0.77
8.8 ± 0.63
14.3 ± 1.10
19.0 ± 1.22
8.6 ± 0.58
14.0 ± 0.94
9.4 ± 0.60
13.8 ± 0.91
9.2 ± 0.61
8.5 ± 0.53
10.8 ± 0.92
19.6 ± 1.37
12.4 ± 0.88
8.4 ± 0.49
7.6 ± 0.35
15.5 ± 1.22
17.3 ± 1.38
11.5 ± 0.96
17.6 ± 1.43
18.9 ± 1.40
34.4 ± 4.06
22.6 ± 2.34
12.2 ± 1.10
18.5 ± 1.52
36.0 ± 4.13
12.7 ±1.05
22.6 ± 2.77
20.4 ± 2.08
25.6 ± 3.03
18.4 ± 1.75
16.6 ± 1.50
20.8 ± 1.82
34.2 ± 3.30
23.6 ± 2.54
17.2 ± 1.21
35.1 ± 3.75
33.6 ± 3.44
24.9 ± 2.46
13.4 ± 1.03
15.7 ± 1.27
38.5 ± 3.93
21.4 ± 2.15 (+ 52.9 %)
17.9 ± 1.37 (+ 94.6 %)
11.3 ± 0.88 (+ 28.4 %)
10.2 ± 0.81 (– 28.7 %)
34.0 ± 3.56 (+ 78.9 %)
23.8 ± 2.48 (+ 176.7 %)
34.8 ± 3.70 (+ 148.6 %)
35.9 ± 3.82 (+ 281.9 %)
17.5 ± 1.33 (+ 26.8 %)
12.0 ± 0.95 (+ 30.4 %)
23.6 ± 2.02 (+ 177.6 %)
19.2 ± 2.10 (+ 77.7 %)
16.4 ± 1.27 (– 16.3 %)
10.3 ± 0.75 (– 16.9 %)
15.5 ± 1.22 (+ 84.5 %)
60.0 ± 8.50 (+ 689.5 %)
12.7 ± 0.91 (– 18.1 %)
11.2 ± 0.84 (– 35.3 %)
18.1 ± 1.53 (+ 57.4 %)
30.5 ± 3.44 (+ 73.3 %)
19.5 ± 1.52 (+ 3.2 %)
10
1
10
1
10
1
10
1
10
1
2g
2h
2i
10
1
10
1
10
1
2j
10
1
Naloxone
_______
*The changes of the pain threshold level in % relative to the initial data are
given in parentheses.
Considering that the pain threshold in animals receiving only tramadol rises by 104% after 90 min
following introduction in comparison with the initial data, naloxone-like action could be established reliably
only for a few of our compounds, namely, amides 2b,e,g,i,j. In this case, 2-(ethylamino)ethyl derivative 2b in
dose 10 mg/kg while (1-ethylpyrrolidin-2-yl)methyl derivative 2g and 3-morpholin-4-ylpropyl derivative 2i in
dose 1 mg/kg exceed the level of specific action of the naloxone reference. We should note that under the action
of these compounds, the pain sensitivity of the tested animals is even somewhat higher than the initial level. The
reason for this effect may be blocking of the opioid receptors not only for their classical agonist tramadol but
also for their own endorphins and encephalins, which act as internal natural analgesics.
Some of the alkylaminoalkylamide hydrochlorides tested such as 2a have almost no effect on the pain
sensitivity threshold while the remaining compounds, especially (2-morpholin-4-ylethyl)amide 2h in dose
10 mg/kg, markedly raise the threshold and thereby significantly strengthen the analgesic effect of tramadol. We
should note the strong similarity of the structures of (2-morpholin-4-ylethyl)amide 2h and (3-morpholin-
4-ylpropyl)amide 2i, which differ fundamentally in their biologic activity. Minimal structural differences
between agonists and antagonists of opioid receptors have long been the subject of scientific discussion [19].
EXPERIMENTAL
The 1H NMR spectra of the products were taken on a Varian Mercury-VX-200 spectrometer at 200 MHz
in DMSO-d6 with TMS as the internal standard.
449

Commercial samples of the methyl ester of 2-amino-4,5-dimethoxybenzoic acid (3) and methyl malonyl
chloride obtained from Fluka were used in these experiments.
Methyl Ester of 1-Allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic Acid
(6). Anhydrous potassium carbonate (20.7 g, 0.15 mol) and alkyl bromide (9.3 ml, 0.011 mol) were added to a
solution of methyl ester of 2-amino-4,5-dimethoxybenzoic acid (3) (21.12 g, 0.1 mol) in DMSO (70 ml) and
stirred for 5 h at 90°C. After cooling, the reaction mixture was diluted by adding cold water. The N-allyl-
substituted ester formed 4 was extracted with four 100-ml portions of dichloromethane. The organic extracts
were combined and ~100 ml solvent was then distilled off. Triethylamine (15.4 ml, 0.11 mol) was added to the
solution of ester 4 in CH2Cl2. Then, methyl malonyl chloride (11.8 ml, 0.11 mol) was added dropwise with
cooling and stirring. The solution was left to stand at room temperature for 5 h and then diluted by adding water.
The organic layer was separated and dried over anhydrous calcium chloride. The solvent was distilled off,
initially at atmospheric pressure and then under reduced pressure. A solution of sodium methylate obtained by
adding metallic sodium (3.45 g, 0.15 mol) to absolute methanol (80 ml) was added to residue, the mixture was
heated to reflux, and left for 10-12 h at room temperature. The reaction mixture was diluted by adding cold
water and acidified by adding a 1:1 solution of concentrated hydrochloric acid and water to pH 4.5-5.0. The
precipitate of ester 6 was filtered off, washed with water, and dried to give 24.27 g (76%) 6; mp 174-176°C
1
(methanol). H NMR spectrum, , ppm (J, Hz): 13.46 (1H, s, OH); 7.31 (1H, s, H-5); 6.78 (1H, s, H-8); 5.86
(1H, m, CH=CH2); 5.13 (1H, d, J = 10.6, NCH2CH=CH-cis); 5.04 (1H, d, J = 17.9, NCH2CH=CH-trans); 4.82
(2H, d, J = 4.4, NCH2); 3.87 (3H, s, OCH3); 3.83 (3H, s, OCH3); 3.79 (3H, s, CO2CH3). Found, %: C 60.32;
H 5.46; N 4.28. C16H17NO6. Calculated, %: C 60.18; H 5.37; N 4.39.
2-[(Dimethylamino)ethyl]amide of 1-Allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-
3-carboxylic Acid (1a). A. 2-(Dimethylamino)ethylamine (1.1 ml, 0.01 mol) was added to a solution of ester 6
(3.19 g, 0.01 mol) in ethanol (15 ml) and heated at reflux for 3 h. The solution was purified with activated
charcoal and then maintained for 7-8 h at 0°C. The crystalline precipitate of [(dimethylamino)ethyl]amide 1a
was filtered off, washed with cold ethanol, and dried to give 3.26 g (87%) 1a.
B. A mixture of ester 6 (3.19 g, 0.01 mol) and 2-(dimethylamino)ethylamine (1.1 ml, 0.1 mol) was
maintained in a metal bath at 140°C for 3-5 min, permitting the methanol formed to distill off. The residue was
cooled, dissolved in ethanol, and then treated as in procedure A to give 3.41 g (91%) 1a.
Mixed melting points of samples of [(dimethylamino)ethyl]amide 1a synthesized by the different
methods as well as the derived hydrochlorides proved undepressed.
Hydrochloride of 2-[(Dimethylamino)ethyl]amide of 1-Allyl-4-hydroxy-6,7-dimethoxy-2-oxo-
1,2-dihydroquinoline-3-carboxylic Acid (2a). 2-Propanol saturated with gaseous HCl was added to a solution
compound 1a (3.75 g, 0.01 mol) in 2-propanol (15 ml) to pH 3. Then, dry diethyl ether (10 ml) was added and
maintained for 5 h at 0°C. The precipitate of hydrochloride 2a was filtered off, washed with dry diethyl ether,
and dried.
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