NMR study on (±)-1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6- dimethylphenyl)aminocarbonylmethyl]piperazine dihydrochloride salt

Article abstract of DOI:10.1016/j.saa.2004.04.028

(±)-1-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl) aminocarbonylmethyl]piperazine dihydrochloride salt was studied spectroscopically. Complete NMR assignments for dihydrochloride salt were made using DEPT, H-H COSY, as well as HMQC and HMBC heteronuclear correlation techniques.

Full text of DOI:10.1016/j.saa.2004.04.028

Spectrochimica Acta Part A 61 (2005) 665–671
NMR study on ( )-1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-
[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine
dihydrochloride salt
Bingjie Qin, Jimao Lin∗, Zhenguang Lin, Yun Xue, Huixue Ren
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China
Received 13 January 2004; accepted 13 April 2004
Abstract
( )-1-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine dihydrochloride salt was stud-
ied spectroscopically. Complete NMR assignments for dihydrochloride salt were made using DEPT, H–H COSY, as well as HMQC and HMBC
heteronuclear correlation techniques.
© 2004 Elsevier B.V. All rights reserved.
Keywords:
( )-1-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine dihydrochloride salt; NMR assign-
ment; DEPT; H–H COSY; HMQC; HMBC
1. Introduction
ride salt was prepared by the as following method: to
the solution of 1-4[(2,6-dimethylphenyl)aminocarbonyl-
methyl]piperazine 15 g (0.06 mol) [7] in 80 ml ethanol,
1-(2-methoxyphenoxy)-2,3-epoxypropane 13 g (0.072 mol)
[7] was added, and the mixture was stood for two
days at −5 to 0 ◦C. Hydrochloric was led into the so-
lution to pH 2 and precipitated with ether. pure salt
was obtained by recrystallization with ethanol for two
times.
( )-1-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-
dimethylphenyl)aminoarbonylmethyl]piperazine (free base)
was prepared from its dichloride salt 1.5 g above suspended
in 60 ml benzene by neutralization with 20% sodium
hydroxide, and then by separation, washing, evaporation.
NMR spectra were recorded on a 400 MHz Bruker Avance
spectrometer in DMSO-d6 solvent. TMS was used as the in-
ternal standard.
( )-1-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-[(2,
6-dimethylphenyl)aminocarbonylmethyl]piperazine dichlo-
ride salt is the flagship member of a new potential antianginal
drugs called partial fatty acid oxidation (pFOX) inhibitors
[1-6].
Although different methods for the synthesis of this com-
pound have reported previously [7,8], the structure have not
been proved by spectrum.
The present paper is devoted to HMR characterization of
this compound (IR and MS characterization in next paper).
1
To assign H NMR and 13C NMR for the structure, DEPT,
H–H COSY, as well as HMQC and HMBC heteronuclear
correlation techniques were used.
2. Experimental
( )-1-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4-(2,
6-dimethylphenyl)aminocarbonylmethyl]piperazine dichlo-
3. Results and discussion
13C NMR spectrum (Fig. 1) shows 19 different carbon
atoms which is consistent with the structure of ( )-1-[3-
(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylp-
∗
Corresponding author. Fax: +86 0531 8564464.
E-mail address: linjm@sdu.edu.cn (J. Lin).
1386-1425/$ – see front matter © 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2004.04.028

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B. Qin et al. / Spectrochimica Acta Part A 61 (2005) 665–671
Fig. 1. 13C NMR spectrum.
Fig. 7) using delay values which corresponded to 1J (C, H),
henyl)aminocarbonylmethyl]piperazine dichloride salt (C24
H35Cl2N3O4) on the basis of molecular symmetry. The
DEPT 135 spectrum (Fig. 2) gives the CH2 peaks at δ
48.074, δ 48. 898, δ 56.147, δ 58.360 and δ 71.389, and
the CH, CH3 peaks at δ 17.882, δ 55.644, δ 64.029, δ
112.795, δ 115.056, δ 120.632, δ 121.652, δ 126.492, δ
127.44 (Table 1). The other peaks of 13C NMR except for
the peaks in DEPT spectrum are non-protonated carbons
(Table 1).
HMBC (Fig. 8) using delay values which corresponded to
3
4
2J (C, H) or J (C, H) even J (C, H) between the carbons
and protons., and H–H correlation spectroscopy which cor-
responded to 2J (H, H) of CH2 group and 3J (H, H) between
the proton–carbon–protons.
δ 2.072 (1 H, s), which can not been found any
proton–proton correlative signal in H–H COSY spectrum and
any proton–carbon signal in HMQC spectrum, is assigned to
the proton of hydroxyl group.
δ 2.184 (6 H, s) is assigned to the both same methyl groups
on the basis of molecular symmetry. HMBC spectrum shows
that this proton exhibits long range coupling 4J with δ 7.076
proton, and so the δ 7.076 (3H, m) proton is assigned to
neighbor H-Ben (H16, H17). HMQC Spectrum shows the δ
2.184protoncorrespondstoδ17.882carbon(C1), andδ7.076
proton corresponds to δ 127.441 (C17) and δ 126.492 (C13)
carbons.
Table 2 list 1H NMR, J and H–H COSY spectral data of
this salt.
1
The H NMR spectrum shows that the protons of two
HCl joining at nitrogen atom of piperazine exhibit two broad
single peaks at 4013.8 Hz (10.037 ppm, 1 H) and 4134.7 Hz
(10.337ppm, 1 H), respectively, which have not correlation
with carbon in HMQC spectrum and have not H–H correla-
tion in H–H COSY spectrum (Fig. 6).
Other protons (free base part) exhibit peaks in 828.8 Hz
(2.072 ppm)–2830.3 Hz (7.076 ppm) (Figs. 3–5).
Assignments of the protons and carbons were made by two
dimensional heteronuclear-correlated experiments (HMQC,
The δ 3.297 (1 H, q) and δ 3.441 (1 H, q) are the protons at
a same carbon atom exhibited in HMQC spectrum and corre-
spond to δ 58.36 carbon (C6). DEPT spectrum shows δ 58.36
Fig. 2. The DEPT spectrum.

B. Qin et al. / Spectrochimica Acta Part A 61 (2005) 665–671
667
Table 1
13C NMR, DEPT135, HMQC, and HMBC spectral data and assignments
Chemical shift
DEPT
HMQC
HMBC
Assignments
17.882
48.074
48.898
55.644
56.147
58.360
64.029
71.389
112.795
115.056
120.632
121.652
126.497
127.441
133.782
134.850
147.822
149.427
163.043
CH3
CH2
CH2
CH3
CH2
CH2
CH
CH2
CH
CH
CH
CH
CH
CH
C
2.184
3.673
3.708, 3.363
3.781
4.171
3.297, 3.441
4.447
3.949, 4.019
6.973
7.027
6.876
7.076
4.171
3
4
1
2
5
3.949, 4.019
3.949, 4.019
3.297, 3.297
3.441
6.876
6.876
6
7
8
9
10
11
12
13
14
15
16
17
18
19
6.934
7.076
7.076
6.973
2.184, 7.706
2.184, 7.706
2.184, 7.706
3.949, 4.019, 7.027, 6.875
3.781, 6.973, 7.027
4.171
C
C
C
C=0
Table 2
1H NMR, J, H–H COSY spectral data and assignments
Chemical shift
Hz
Multiplet
J (Hz)
Number of H
H–H COSY (ppm)
Assignments
ppm
2.072
828.8
873.5
S
s
q
q
s, br.
d
s
s
q
1
6
1
1
6
2
3
1
1
1
2
1
1
1
1
1
3
1∗
1∗
–
–
1
2
3
4
5
5ꢀ
6
7
2.184
3.297
3.441
3.673
3.708
3.781
3.781
3.949
4.019
4.171
4.447
6.876
6.934
6.973
7.027
7.076
10.04
10.34
1318.6
1376.3
1469.1
1483.0
1512.5
1512.5
1579.8
1607.6
1668.3
1778.9
2750.3
2773.7
2789.1
2810.9
2830.3
4013.8
4134.7
9.2, 13.4
2.1, 13.4
4.447
4.447
–
–
–
–
4.447
4.447
–
0.6
5.5, 10.2
5, 10.3
8
9
q
s, br.
M
m
q
m
q
m
s
br.
10
11
12
13
14
15
16, 17
18
18
–
3.297, 3.441, 3.949, 4.019
6.973, 7.027, 6.294
6.876, 6.973
6.876, 6.934, 7.027
6.876, 6.973
1.8, 7.6
1.6, 7.8
1.8, 7.9
1.6, 7.8

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B. Qin et al. / Spectrochimica Acta Part A 61 (2005) 665–671
Fig. 3. 1H NMR spectrum in δ 0.0–␦ 8.5 ppm.
Fig. 4. The 1H NMR spectrum (partly enlarged in δ 3.2–4.5).
carbon is CH2 group. H–H COSY spectrum shows both pro-
tons are interrelated each other and interrelated with δ 3.279.
Because only the asymmetry carbon C7 in this compound
leads to different chemical shifts of neighbor CH2–protons,
δ 3.297 and δ 3.441 protons are assigned to H3 and H4. Three
coupling constants are J3,4 13.4 Hz, J3,11 9.2 Hz, and J4,11
2.1 Hz, respectively.
Similar chemical environment as above, δ 3.949 (1H, q)
and δ 4.019 (1H, q) are assigned to H8 and H9. HMQC shows
the corresponding carbon chemical shift of H8 and H9 is δ
71.389 and belongs to C8.
The δ 3.708 (2 H, d) protons correspond to δ 48.898 carbon
in HMQC spectrum. The DEPT spectrum exhibits δ 48.898
carbon is CH2 group. J 0.6 Hz is long range coupling 4J. On

B. Qin et al. / Spectrochimica Acta Part A 61 (2005) 665–671
669
Fig. 5. The 1H NMR spectrum (partly enlarged in δ 6.8–δ 7.2).
Fig. 6. The H–H COSY spectrum.

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B. Qin et al. / Spectrochimica Acta Part A 61 (2005) 665–671
Fig. 7. The HMQC spectrum.
Fig. 8. The HMBC spectrum.

B. Qin et al. / Spectrochimica Acta Part A 61 (2005) 665–671
671
the basis of characteristic of the asymmetry carbon which
can made chemical shifts different beyond three bonds, the δ
HMBC, being H14. The δ 6.876 proton is H12.The H8, H9 pro-
tons are correlative in HMBC with δ 147.822 carbon (C17).
Further, the δ 6.934 protons is correlative with δ 147.822 car-
bon in HMBC, being H13.The 7.027 proton is H15. HMQC
give corresponding carbons: δ 6.876 (H12)–δ 120.632 (C11),
δ 6.934 (H13)–δ 121.652 (C12), δ 6.973(H12)–δ 112.975 (C9),
and δ 7.027 (H15)–δ 115.056 (C10).
δ 7.076 (3H, m) protons, correlating in HMBC with δ
17.882 carbon (CH3, C1), assigned to H16, H17. The cor-
responding carbons are δ 126.497 (C14) and δ 127.441 (C13).
DEPT spectrum shows δ 149.427 is a non-protonated car-
bon. Long range coupling of δ 149.427 was observed in
HMBC spectrum with H6 and H15. This peak is belong to
C18 certainly.
ꢀ
3.708 (2 H, br.) protons are assigned to H5 , and the δ 48.898
carbon is assigned to C3.
The δ 3.673 (6 H, br.) protons, corresponding to δ 48.074
carbon and δ 48.898 carbon in HMQC spectrum and corre-
sponding to CH2 group in DEPT spectrum, are assigned to
H5. The δ 48.074 carbon is assigned to C2.
δ 3.781 (4 H, s), corresponding only to δ 55.644 carbon
in HMQC spectrum and showing non correlation with any
proton, is assigned to H6 and H7. The δ 55.644 carbon is
belong to C4.
δ 4.171 (2 H, br.), corresponding only to δ 56.147 carbon in
HMQC spectrum and corresponding to CH2 group in DEPT
spectrum, is assigned to H10. The δ 56.147 carbon is belong
to C5.
δ 4.447 (1 H, m.), coupling with H3, H4, H8 and H9, is
assigned to H11. Corresponding δ 64.029 carbon in HMQC is
belong to C7. DEPT spectrum confirms this tertiary carbon.
δ 6.876 (1H, six), δ 6.934 (1H, six), δ 6.973 (1H, q), and
δ 7.027 (1H, q) are parts of protons of aromatic ring. H–H
COSY spectrum shows that δ 6.934 and δ 7.027 protons are
not interrelated each other but interrelated with δ 6.876 and δ
6.934 protons, however, δ 6.876 and δ 6.973 protons are not
only interrelated each other but also interrelated with δ 6.934
and δ 7.027 protons. The δ 6.934 and δ 7.027 protons belong
to H13 and H15, and δ 6.876 and δ 6.973 protons belong to H12
and H 14. By HMBC spectrum, specific assignments of pro-
tonsandcarbonsaremadeasfollowing. The δ149.427carbon
is correlative with δ 3.781 (H6) proton and is assigned to C18.
The δ 6.973 protons is correlative with δ 149.427 carbon in
The last δ 163.043 carbon is C O (C19). Correlative sig-
nal in HMBC spectrum with H10 confirms the correlation
structure.
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