Ind. Eng. Chem. Res. 2000, 39, 2761-2765
2761
New Salts of N-Substituted Piracetam Juliusz Pernak* Poznan´ University of Technology, 60-965 Poznan´ , Poland
Jerzy Drygas Institute of Biotechnology and Antibiotics, Warsaw, Poland
Methyl (2-oxo-1-pyrrolidinyl)acetate reacts with (aminomethyl)pyridines with the elimination of methanol to form (2-oxo-1-pyrrolidinyl)(N-pyridinylmethyl)acetamide, which, quaternized smoothly by ROCH2Cl, gives the new salts of N-substituted piracetam. Both steps occur in high yields. The obtained pyridinium chlorides showed antielectrostatic properties, which depend on a carbon chain in alkoxymethyl substituent and bactericidal and fungicidal activity. 1. Introduction
Chart 1
The discovery in 1971 of the nootropic properties of piracetam [(2-oxo-1-pyrrolidinyl)acetamide] was the reason for the synthesis of hundreds of analogues within the 2-oxo-1-pyrrolidinyl group. So far, a few of them have been marked as nootropic drugsspiracetam, oxiracetam, aniracetam, pramiracetam, and nefiracetam (Chart 1). Synthetic, analytical aspects of chemistry and the pharmacological activities of piracetam-type-substituted pyrrolidines have been summarized previously.1,2 We now reported the realization of the strategy of constructing new analogues of piracetam which include the pyridine ring. We used the aminolysis for the sidechain modification of piracetamsformation of the C-N bond and quaternization of the pyridine ring converted to pyridinium chloride. Methyl or ethyl (2-oxo-1-pyrrolidinyl)acetate have been employed in the aminolysis with primary amines (ethanolamine,3 benzylamine, propylamine, ethylamine, and their derivatives4-6 and pyrrolizidinylmethanamine7,8) to yield analogues of piracetam. The reaction of ester with primary amine followed by the coupling addition/elimination mechanism in which the C-N bond formation and C-O bond cleavage occur in separate steps.9 In many cases, the observed rate law for the aminolysis of ester includes the amine substrate in higher order, once as a substrate and once as a catalyst.10 Pyridinium salts deserve considerable attention for their use as acylating agents, phase-transfer catalysts and dyes, as well as photo- and solvatochromic materials,11 such as biocides with a wide range of antimicrobial spectra12 and catalysts of estrification in supercritical fluid.13 We have published the results on the synthesis and bactericidal properties of pyridinium chlorides with alkoxymethyl substituent.14-18 These chlorides have bacteriostatic properties and are active against cocci, rods, fungi, and bacilli. 2. Experimental Methods 1H NMR spectra were recorded with a Varian model XL 300 spectrometer at 300 MHz with tetramethylsilane as the standard and 13C NMR spectra on the same
* To whom correspondence should be addressed. E-mail:
[email protected].
Table 1. Quaternary Pyridinium Chlorides (2-20 and 22-40) 1-(alkoxymethyl)-3-[2-(2-oxo1-pyrrolidinyl)acetamideN-methyl]pyridinium
1-(alkoxymethyl)-4-[2-(2-oxo1-pyrrolidinyl)acetamideN-methyl]pyridinium
product
OR
yield [%]
product
OR
yield [%]
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
OCH2CH3 O(CH2)2CH3 O(CH2)3CH3 O(CH2)4CH3 O(CH2)5CH3 O(CH2)6CH3 O(CH2)7CH3 O(CH2)8CH3 O(CH2)9CH3 O(CH2)10CH3 O(CH2)11CH3 OC5H9 OC6H11 OC7H13 OC8H15 OC12H23 OCH2C6H11 O(CH2)2C6H11 O(CH2)3C6H11
80 82 78 80 79 82 78 83 82 81 85 83 79 81 80 86 82 83 82
22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
OCH2CH3 O(CH2)2CH3 O(CH2)3CH3 O(CH2)4CH3 O(CH2)5CH3 O(CH2)6CH3 O(CH2)7CH3 O(CH2)8CH3 O(CH2)9CH3 O(CH2)10CH3 O(CH2)11CH3 OC5H9 OC6H11 OC7H13 OC8H15 OC12H23 OCH2C6H11 O(CH2)2C6H11 O(CH2)3C6H11
92 89 89 85 83 90 83 88 88 84 94 94 94 90 94 93 98 95 91
instrument at 75 MHz. Elemental analyses were performed at the University of Poznan´. Satisfactory elemental analyses of CHN for all synthesized compounds were acquired with 0.38% tolerance between the calculated and experimental values. Chloromethyl alkyl ether was prepared by (chloromethyl)alkylation of the appropriate alcohol.19 2.1. Aminolysis. A mixture of methyl (2-oxo-1pyrrolidinyl)acetate (37.8 g, 0.35 mol) and 3-(amino-
10.1021/ie990849s CCC: $19.00 © 2000 American Chemical Society Published on Web 07/12/2000
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methyl)pyridine or 4-(aminomethyl)pyridine (55 g, 0.35 mole) was heated at 90 °C for 12 h. Methanol formed during the reaction was removed. Then the mixture was heated at 130 °C for 30 min. The oily product was diluted with H2O (60 mL) and 1 N HCl (35 mL). Then it was extracted several times with CHCl3. The chloroform extract was dried over Na2SO4, and the solvent was evaporated under reduced pressure. The isolated oil was (2-oxo-1-pyrrolidinyl)[N(3-pyridinylmethyl)]acetamide (1). (2-Oxo-1-pyrrolidinyl)[N-(4-pyridinylmethyl)]acetamide (21) was obtained by the crystallization of the resulting precipitate from anhydrous acetone (mp 154156 °C). 2.2. General Procedure for the Preparation of 1-(Alkoxymethyl)pyridinium Chlorides. (2-Oxo-1pyrrolidinyl)[N-(3-pyridinylmethyl)]acetamide or (2-oxo1-pyrrolidinyl)[N-(4-pyridinylmethyl)]acetamide (3.5 g, 0.015 mol) were dissolved in warm anhydrous dimethylformamide (20 mL) and anhydrous tetrahydrofuran (100 mL), and ROCH2Cl (0.0165 mol) was added. The mixture was stirred and heated for 1 h. The product was crystallized from the reaction mixture after cooling. The order numbers of chlorides and yield of reaction are given in Table 1. Table 2.
1H
2.3. Antimicrobial Activity. Microorganisms used are as follows: Pseudomonas aeruginosa NCTC 6749, Escherichia coli ACTT 25922, Klebsiella pneumoniae ATCC 33495, Proteus vulgaris NCTC 4635, Staphylococcus aureus NCTC 4163, Moraxella catarrhalis ATCC 25238, Micrococcus luteus D. H. N., Enterococcus faecalis ATCC 29212, Candida albicans ATCC 10231, and Bacillus subtilis ATCC 6633. Standard strains were supplied by National Collection of Type Cultures, London (NCTC), and American Type Culture Collection (ATCC). The minimum inhibitory concentration (MIC) was determined by the tube dilution method with inoculum to give from 104 to 105 microorganisms/mL. A series of dilutions of the studied chlorides were prepared on the Μu¨ller-Hinton broth medium (bacteria) or on the Sabouraud broth medium (fungi). The growth of microorganisms was determined visually, and the lowest concentration of the chloride which inhibited the multiplication of cells after 24 h was taken as MIC. 2.4. Antielectrostatic Properties. The antielectrostatic effect was measured on polyethylene film Wigofil of a density of 150 g/m2. Thin films of studied chlorides were deposited on polyethylene disks. A disk of 0.125 m diameter was immersed in a 0.5% chloroform solution of pyridinium chloride for 30 s. Then the disk was hung up so that the solvent could evaporate spontaneously
NMR Spectral Dataa
product
NH
pyridine
CH2
CH2 acetyl
pyrrolidine
1
7.33 (d)
8.13 (m, 3H), 6.94 (m, 1H)
4.07 (d)
3.64 (s)
8
9.41 (t)
4.56 (d)
3.96 (s)
12
9.29 (t)
4.55 (d)
3.95 (s)
17
9.42 (t)
4.55 (d)
3.96 (s)
18
9.27 (t)
4.54 (d)
3.94 (s)
19
9.43 (t)
4.55 (d)
3.96 (s)
20
9.35 (t)
4.55 (d)
21
7.58 (t)
9.25 (s, 1H), 9.23 (d, 1H), 8.67 (d, 1H), 8.27 (dd, 1H) 9.18 (s, 1H), 9.16 (d, 1H), 8.64 (d, 1H), 8.25 (dd, 1H) 9.28 (m, 2H), 8.68 (t, 1H), 8.27 (m, 1H) 9,16 (m, 2H), 8.63 (d, 1H), 8.24 (dd, 1H) 9.26 (s, 1H), 9.24 (d, 1H), 8.67 (d, 1H), 8.27 (dd, 1H) 9.22 (s, 1H), 9.19 (d, 1H), 8.65 (d, 1H), 8.25 (dd, 1H) 8.52 (dd, 2H), 7.17 (d, 2H)
3.18 (t, 2H), 1.99 (t, 2H), 1.71 (m, 2H) 3.44 (t, 2H), 2.29 (t, 2H), 2.01 (m, 2H)
32
9.50 (t)
37
CH2 ether
OR
6.07 (s)
3.62 (t, 2H), 1.53 (m, 2H), 1.23 (s, 10H), 0.87 (t, 3H)
3.43 (t, 2H), 2.29 (t, 2H), 2.01 (m, 2H)
6.01 (s)
3.60 (t, 2H), 1.54 (m, 2H), 1.28 (m, 18H), 0.89 (t, 3H)
3.43 (t, 2H), 2.29 (t, 2H), 2.02 (m, 2H) 3.47 (m, 2H), 2.29 (t, 2H), 1.99 (m, 2H) 3.41 (t, 2H), 2.29 (t, 2H), 1.99 (m, 2H)
6.09 (s)
3.74 (t, 1H), 1.65 (m, 2H), 1.44 (m, 2H), 1.27 (m, 18H)
6.00 (s)
3.39 (m, 2H), 1.66 (m, 6H), 1.25 (m, 3H), 0.93 (m, 2H)
6.06 (s)
3.95 (s)
3.43 (t, 2H), 2.29 (t, 2H), 2.09 (m, 2H)
6.03 (s)
3.66 (t, 2H), 1.61 (m, 5H), 1.46 (m, 2H), 1.38 (m, 1H), 1.23 (m, 1H), 1.18 (m, 2H), 0.89 (m, 2H) 3.60 (t, 2H), 1.66 (m, 5H), 1.53 (m, 2H), 1.23 (m, 6H), 0.87 (m, 2H)
4.41 (d)
3.98 (s)
9.25 (d, 2H), 8.13 (d, 2H)
4.64 (d)
4.01 (s)
9.48 (t)
9.30 (d, 2H), 8.13 (d, 2H)
4.63 (d)
4.00 (s)
38
9.47 (t)
9.23 (d, 2H), 8.12 (d, 2H)
4.63 (d)
4.00 (s)
39
9.47 (t)
9.25 (d, 2H), 8.12 (d, 2H)
4.63 (d)
4.00 (s)
3.57 (t, 2H), 2.38 (t, 2H), 2.11 (m, 2H) 3.46 (t, 2H), 2.30 (t, 2H), 2.03 (m, 2H) 3.45 (t, 2H), 2.30 (t, 2H), 2.03 (m, 2H) 3.45 (t, 2H), 2.30 (t, 2H), 2.03 (m, 2H) 3.46 (t, 2H), 2.30 (t, 2H), 2.03 (m, 2H)
40
9.50 (t)
9.26 (d, 2H), 8.13 (d, 2H)
4.63 (d)
4.01 (s)
3.46 (t, 2H), 2.30 (t, 2H), 2.03 (m, 2H) a Solvent: CDCl for 1 and 21; DMSO-d for 8, 12, 17-20, 32, and 37-40. 3 6
6.04 (s)
3.59 (t, 2H), 1.52 (m, 2H), 1.30 (m, 18H), 0.88 (t, 3H)
6.07 (s)
3.72 (m, 1H), 1.64 (m, 2H), 1.42 (m, 2H), 1.39 (m, 18H)
6.02 (s)
3.40 (d, 2H), 1.66 (m, 6H), 1.20 (m, 3H), 0.92 (m, 2H)
6.03 (s)
3.63 (t, 2H), 1.68 (m, 5H), 1.48 (m, 2H), 1.32 (m, 1H), 1.29 (m, 1H), 1.18 (m, 2H), 0.89 (m, 2H) 3.58 (t, 2H), 1.78 (m, 5H), 1.55 (m, 2H), 1.23 (m, 6H), 0.87 (m, 2H)
6.04 (s)
Ind. Eng. Chem. Res., Vol. 39, No. 8, 2000 2763 Scheme 1
and was then stored for 24 h in an air-conditioned room at 20 ( 2 °C and relative humidity of 55 ( 5%. For each studied chloride, three disks were prepared. Finally, the surface resistance and half charge decay time was examined. The relative error in the determination of these two parameters did not exceed 7%. The measuring apparatus and the measurement conditions were previously described by Pernak et al.20 3. Results Scheme 1 shows the reactions of the synthesis of developed quaternary pyridinium chlorides. In the first step, we prepared N-substituted piracetam by aminolysis of methyl (2-oxo-1-pyrrolidinyl)acetate with (aminomethyl)pyridines with 74 and 86% yields. In this coupling addition/elimination reaction, the primary Table 3.
13C
NMR Spectral Dataa pyridine
CH2
CH2 acetyl
pyrrolidine
148.2, 147.6, 135.0, 133.7, 123.0 145.5, 142.0, 141.9, 140.4, 127.6 145.5, 142.0, 141.8, 140.4, 127.6
47.6
45.4
40.0, 29.7, 17.1
47.5
45.3
39.2, 30.0, 17.4
88.5
47.5
45.3
39.2, 30.0, 17.4
88.5
47.4
45.2
39.2, 30.0, 17.4
86.6
47.5
45.3
39.2, 30.0, 17.4
88.7
47.4
45.3
39.2, 30.0, 17.4
88.5
47.4
45.2
39.2, 30.0, 17.4
88.5
48.6 47.5
46.8 45.2
42.0, 30.3, 17.8 41.7, 30.0, 17.4
87.7
161.4, 143.1, 125.5
47.4
45.2
41.7, 30.0, 17.4
85.9
168.7
161.4, 143.1, 125.5
47.5
45.2
41.7, 30.0, 17.5
87.9
174.7
168.6
161.4, 143.2, 125.4
47.5
45.2
41.6, 30.0, 17.4
87.9
174.7
168.7
161.4, 143.1, 125.5
47.5
45.2
41.6, 30.0, 17.4
87.7
product
CdO pyrrolidinyl
CdO acetyl
1
175.4
167.7
8
174.7
168.5
12
174.6
168.5
17
174.6
168.5
18
174.6
168.6
19
174.5
168.5
20
174.5
168.5
21 32
176.1 174.7
168.5 168.7
145.6, 142.0, 141.8, 140.4, 127.5 145.6, 142.0, 141.8, 140.4, 127.6 145.5, 142.1, 142.0, 140.4, 127.6 145.5, 142.0, 141.9, 140.4, 127.6 149.8, 147.2, 122.1 161.4, 143.1, 125.5
37
174.6
168.6
38
174.7
39 40 a
amine is substrate and catalyst. Then quaternization was run with an electrophile like chloromethyl alkyl ether, which represents a specialized type of N-alkylation. ROCH2Cl is an excellent reagent in this reaction but very easily hydrolyzed. Quaternization should be conducted under strictly anhydrous conditions. The reactions proceed smoothly under simple conditions and give product soluble in water in high yield. The 1H and 13C NMR chemical shifts are summarized in Tables 2 and 3. Generally the CH2(acetyl) group was observed in a range from 4.01 to 3.94 ppm and the CH2(ether) group displayed from 6.09 to 6.00 ppm. These protons appeared as a singlet. Examination of the 13C NMR spectra shows the absorption peak for CH2(acetyl) in the region of 45.4-45.2 ppm and that for CH2(ether) in the region of 88.7-85.9 ppm. All of the obtained developed quaternary pyridinium chlorides are hygroscopic (Table 1). The alkoxymethyl group includes a lineal alkyl chain (2-12 and 21-32) or cycloalkyl (1317 and 33-37) or aromatic (18-20 and 38-40) substituent. The antimicrobial activity and their antielectrostatic properties were determined for all of the synthesized pyridinium chlorides. The minimal inhibitory concentration (MIC) of the most active compounds examined against various microorganisms in 37 °C of incubation is shown in Table 4. Results indicate that studied pyridinium chlorides of N-substituted piracetam show bactericidal and fungicidal activity. In comparison with commercially available didecyldimethylammonium chloride (Table 4, compound 41), the tested chlorides are only slightly effective. The mode of action of quaternary ammonium compounds against bacteria depends on the chemical structure. The pyrrolidine ring is not flat. The chemical structure of 1-[(octyloxy)methyl]-3-[2-(2-oxo-1-pyrrolidinyl)acetamide-N-methyl]pyridinium chloride (8) is shown in Figure 1, which was calculated by method MMX. The adsorption on a cell wall is possible by diffusion, but
Solvent: CDCl3 for 1 and 21; DMSO-d6 for 8, 12, 17-20, 32, and 37-40.
CH2 ether
OR
70.2, 31.2, 28.6, 28.5, 25.2, 22.0, 13.9 70.3, 31.3, 29.0, 28.98, 28.93, 28.7, 28.6, 25.2, 22.1, 13.9 78.1, 28.2, 24.1, 23.9, 22.5, 22.4, 19.8 75.4, 37.0, 28.9, 25.9, 25.1 68.2, 36.0, 33.6, 32.5, 26.0, 25.6 70.5, 36.7, 32.8, 32.7, 26.1, 26.0, 25.7 70.0, 31.3, 29.0, 28.9, 28.7, 25.2, 22.1, 13.9 77.9, 28.3, 24.1, 23.8, 22.6, 22.5, 19.9 75.2, 37.0, 28.9, 25.9, 25.1 68.0, 36.0, 33.6, 32.5, 25.9, 25.6 70.4, 36.7, 32.9, 32.7, 26.1, 26.0, 25.7
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Table 4. MICa of Examined Chlorides chlorides strains
10
11
12
16
Pseudomonas aeriginosa 0.57 0.55 0.53 0.61 Escherichia coli 0.57 0.28 0.27 0.61 Klebsiella pneumoniae 0.57 0.55 0.27 0.61 Proteus vulgaris 0.57 0.55 0.53 0.61 Staphylococcus aureus 0.57 0.28 0.27 0.61 Moraxella catarrhalis 0.57 0.28 0.13 0.61 Micrococcus luteus 0.57 0.28 0.13 0.61 Enterococcus faecalis 0.57 0.28 0.27 0.61 Candida albicans 0.57 0.28 0.27 0.61 Bacillus subtilis 0.28 0.28 0.27 0.61 a MIC in M/L. b Didecyldimethylammonium chloride in mM/L.
17
30
31
32
36
41b
0.54 0.54 0.54 0.54 0.27 0.27 0.54 0.54 0.54 0.54
0.57 0.57 0.57 0.57 0.57 0.28 0.57 0.57 0.57 0.28
0.55 0.28 0.55 0.28 0.28 0.14 0.14 0.28 0.28 0.28
0.27 0.27 0.27 0.27 0.13 0.03 0.07 0.27 0.27 0.07
0.61 0.61 0.61 0.61 0.61 0.61 0.61 0.61 0.61 0.61
0.276 0.003 0.014 0.014 0.028 0.001 0.014 0.0003
Table 5. Criteria for the Estimation of the Antielectrostatic Effect Based on the Surface Resistance and Half Charge Decay Time surface resistance log R
half charge decay time [s]
13
100
antielectrostatic effect excellent very good good sufficient insufficient lack of antielectrostatic properties
Table 6. Surface Resistance, Half Charge Decay Time, and Antielectrostatic Effect product log R 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Figure 1. Most stable conformation of 1-[(octyloxy)methyl]-3-[2(2-oxo-1-pyrrolidinyl)acetamide-N-methyl]pyridinium chloride (8).
15.35 14.85 10.44 10.37 9.86 9.06 8.62 8.56 8.46 9.58 11.56 12.62 10.16 10.36 11.14 12.70 11.32 11.22 10.28
τ [s]
antistatic effect product
log R
τ [s]
antistatic effect
>600 >600 1.24 0.41 0.37 0.35 0.39 0.35 0.37 1.43 9.56 9.64 1.32 0.99 7.45 5.72 2.13 1.02 0.47
lack lack good good very good very good excellent excellent excellent good sufficient sufficient good good sufficient sufficient sufficient good good
14.56 12.49 12.10 10.90 10.94 10.45 9.98 9.03 8.69 8.52 8.79 10.30 11.18 11.10 12.52 15.30 14.22 11.64. 10.92
>100 5.07 2.85 0.64 0.53 0.42 0.36 0.36 0.29 0.37 0.37 0.45 2.25 1.11 7.07 >600 84.80 1.57 0.90
lack sufficient sufficient good good good very good very good excellent excellent excellent good good sufficient sufficient lack lack sufficient good
22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
antielectrostatic effect was shown by short alkyl chains like ethyl and propyl. 4. Conclusions
adsorption through the wall is difficult. This is the reason for weak antimicrobial activities. The result obtained suggests that compounds with a pyrrolidine ring, despite good solubility in water, are not very active against bacteria. The antielectrostatic properties are the result of two quantities: the surface resistance and the half charge decay time. The antielectrostatic effect was determined following the criteria listed in Table 5 and was presented in Table 6. Six studied chlorides showed an excellent effect, and four showed very good. The antielectrostatic properties were dependent on a long alkyl chain in an alkoxymethyl substituent. The best results were given for chlorides with the following substituent: (octyloxy)methyl (8), (nonyloxy)methyl (9) (decyloxy)methyl (10) (decyloxy)methyl (30), (undecyloxy)methyl (31), and (dodecyloxy)methyl (32). The worst
A new synthetic route has been developed for quaternary pyridinium chlorides. The reaction conditions are mild, the workup procedure is simple, and the yield is high. This work shows that 1-(alkoxymethyl)-3- and 1-(alkoxymethyl)-4-[2-(2-oxo-1-pyrrolidinyl)acetamide-Nmethyl]pyridinium chlorides have antielectrostatic properties. The antielectrostatic effect depends on the carbon chain in the alkoxymethyl substituent. Six new pyridinium chlorides showed excellent antielectrostatic effects; they are potentially antielectrostatic agents. For the first time salts of N-substituted piracetam which are bactericidal and fungicidal were obtained. Acknowledgment We are grateful for the financial support received from The Polish Committee of Scientific Research DS 32/281/ 99.
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Received for review November 24, 1999 Revised manuscript received May 24, 2000 Accepted June 4, 2000 IE990849S
