Enantioselective phase-transfer catalyzed alkylation of 1-methyl-7-methoxy-2-tetralone: An effective route to dezocine

Article abstract of DOI:10.3762/bjoc.14.119

In order to prepare asymmetrically (R)-(+)-1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone (3a), a key intermediate of dezocine, 17 cinchona alkaloid-derived catalysts were prepared and screened for the enantioselective alkylation of 1-methyl-7- methoxy-2-tetralone with 1, 5-dibromopentane, and the best catalyst (C7) was identified. In addition, optimizations of the alkylation were carried out so that the process became practical and effective.

Full text of DOI:10.3762/bjoc.14.119

Enantioselective phase-transfer catalyzed alkylation of
1-methyl-7-methoxy-2-tetralone: an effective route to dezocine
Ruipeng Li, Zhenren Liu, Liang Chen, Jing Pan and Weicheng Zhou*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1421–1427.
State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key
Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry,
China State Institute of Pharmaceutical Industry, No. 285, Gebaini
Rd., Shanghai 201203, P. R. of China
doi:10.3762/bjoc.14.119
Received: 19 March 2018
Accepted: 21 May 2018
Published: 11 June 2018
Email:
Weicheng Zhou* - zhouweicheng58@163.com
Associate Editor: I. R. Baxendale
* Corresponding author
© 2018 Li et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alkylation; asymmetric catalysis; cinchonidine; dezocine
Abstract
In order to prepare asymmetrically (R)-(+)-1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone (3a), a key intermediate of
dezocine, 17 cinchona alkaloid-derived catalysts were prepared and screened for the enantioselective alkylation of 1-methyl-7-
methoxy-2-tetralone with 1,5-dibromopentane, and the best catalyst (C7) was identified. In addition, optimizations of the alkyl-
ation were carried out so that the process became practical and effective.
Introduction
The preparation of enantiomerically pure compounds has tional resolution [4,5]: alkylation of 1-methyl-7-methoxy-2-
become a stringent requirement for pharmaceutical synthesis tetralone (2) with 1,5-dibromopentane gave the designed (R)-
[1]. In this context, asymmetric catalysis is probably one of the (+)-1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone (3a)
most attractive procedures for the synthesis of active pharma- and an equal amount of the S-isomer 3b, both 3a and 3b under-
ceutical ingredients (APIs) due to environmental, operational, went the following cyclization, oximation and reduction, and
and economic benefits.
then, (5R,11S,13S)-3-methoxy-5-methyl-5,6,7,8,9,10,11,12-
octahydro-5,11-methanobenzocyclodecen-13-amine (6a) and
Dezocine, (5R,11S,13S)-13-amino-5-methyl-5,6,7,8,9,10,11,12- (5S,11R,13R)-3-methoxy-5-methyl-5,6,7,8,9,10,11,12-
octahydro-5-methyl-5,11-methanobenzocyclodecen-3-ol (1, octahydro-5,11-methanobenzocyclodecen-13-amine (6b) were
Scheme 1), a typical opioid analgesic developed by separated by two times of resolution with L-tartaric acid and
AstraZeneca, was extensively used in China recently. Because D-tartaric acid (Scheme 1).
of its effectiveness and safety [2,3], it would have a very good
marketing prospect. However, the cost of dezocine was very Phase-transfer asymmetric catalysis with cinchona alkaloid-
high since the commercial synthesis process involved the tradi- derived quaternary ammonium compounds has become one of
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Beilstein J. Org. Chem. 2018, 14, 1421–1427.
Scheme 1: Synthesis of dezocine by resolution.
the topics in stereoselective synthesis in both industry and acad- In the beginning, the alkylation of 2 in the catalysis of C1 in the
emia [6-9]. It was reported [10] that the alkylation of 2 in the two-phase system (toluene and 50% NaOH aqueous solution)
catalysis of N-(p-trifluoromethylbenzyl)cinchonidinium bro- was tested, although the yield was moderate (60.1%, entry 1 in
mide in a two-phase system gave the enantioselective product Table 1), the enantiomeric ratio (3a:3b) was only 55:45. When
3a, although the ee value of the product was 60%, determined the benzyl in C1 was replaced by the bulky groups, such as
by 1H NMR. And so far, no further report on the stereoselec- methylnaphthalene or methylanthracene, neither the enan-
tive alkylation of 2a was found. (Some reports on the non- tiomeric ratio was improved (Table 1, entry 2) nor the reaction
stereoselective alkylation of 2 were given in references [11,12]). took place (Table 1, entry 3). Subsequently, when the groups
In this paper, several cinchona-derived phase-transfer catalysts substituted at the para-position on the benzyl group were inves-
were screened for this reaction, and the structure–activity rela- tigated, the structure–activity relationship showed that catalyst
tionship for the catalysis was studied. In addition, optimiza- C4 (with methyl substituent) did not work for the reaction
tions had been made to make the process efficient.
(Table 1, entry 4) and those with Cl or F (C5 and C6) worked
well with an improvement in enantiocontrol (Table 1, entries 5
and 6). Fortunately, the p-CF3 derivative (C7) promoted the
Results and Discussion
A series of the quaternary ammonium bromides from cinchoni- reaction to give a enantiomeric ratio of 83:17 (Table 1, entry 7).
dine or quinine as phase-transfer catalysts was prepared These findings suggested that the presence of electron-with-
(Scheme 2). Cinchonidine was reacted with the benzyl bro- drawing groups on the benzyl group was favourable for the en-
mides (R1Br) in THF to obtain catalysts C1–C11 [13]. And antioselective reaction except the case of a nitro group (Table 1,
then C7 reacted with allyl or propargyl bromide to obtain C12 entry 8). And then, the catalysts with a di-substituted benzyl
and C13. In another way, cinchonidine was reduced by H2/Pd/C group were examined. C9 with 3.4-dichlorobenzyl resulted in a
to yield dihydrocinchonidine, and then reacted with 4-trifluo- slightly higher enantiomeric ratio (68:32) than C5 (Table 1,
romethylbenzyl bromide to obtained C14. C15 was prepared entry 9). But, neither C10 nor C11 (Table 1, entries 10 and 11)
from cinchonidine via bromination, debromination and conden- were as good as the mono-substituted counterparts (C6 and C7).
sation with 4-trifluoromethylbenzyl bromide [14]. Quinine was The derivatives (C12–C15) of C7, the best one so far, were
reacted with 4-trifluoromethylbenzyl bromide or 3,5-bis(tri- further studied. When the hydroxy group in C7 was protected
fluoromethyl)benzyl bromide to obtain C16 or C17.
by an allyl or a propargyl group, racemic product was obtained
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Beilstein J. Org. Chem. 2018, 14, 1421–1427.
Scheme 2: Synthesis of catalysts C1–C17.
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Table 1: Screening of phase-transfer catalysts for the asymmetry alkylation of 2a.
entry
catalyst
yieldb
3a:3bc
1
C1
60.1%
55:45
52:48
–
2
C2
58.3%
3
C3
no reaction
no reaction
47.5%
4
C4
–
5
C5
60:40
63:37
83:17
–
6
C6
65.3%
7
C7
62.0%
8
C8
no reaction
58.7%
9
C9
68:32
55:45
74:26
50:50
50:50
80:20
78:22
51:49
64:36
10
11
12
13
14
15
16
17
C10
C11
C12
C13
C14
C15
C16
C17
43.4%
52.2%
65.0%
65.0%
63.5%
61.1%
50.3%
53.2%
aThe reaction was performed with 0.045 mol/L of 2 in toluene (24 mL), 3.0 equiv of 1.5-dibromopentane and 50% aq NaOH (2.4 mL) in the presence
of 10 mol % of catalyst at 15–25 °C for 48 h under N2. bIsolated yield including 3a and 3b. cThe enantiomeric ratio was determined by HPLC using a
chiral column (Daicel chiral AY-H) with hexane/isopropyl alcohol 90:10 as the eluent, detected at 280 nm.
(Table 1, entries 12 and 13). This suggested that the free further increasing the substrate concentration (Table 2, entry 9)
hydroxy group in C7 was crucial to guarantee the stereoselec- decreased the stereoselectivity. For the screening of the base,
tivity. Meanwhile, the good catalysis was maintained with both the reduction of volume or concentration of 50% aq NaOH
dihydrocinchonidine-derived C14 and dehydro compound C15. resulted in a decreased yield (Table 2, entries 11 and 12). If
Finally, the quaternary ammonium group from quinine was ex- NaOH was replaced by K2CO3, no reaction took place (Table 2,
amined (Table 1, entries 16 and 17), and C16 and C17 gave the entry 13). As far as the reaction temperature was concerned
result inferior to the cinchonidine derivatives (C7 and C11).
(Table 2, entry 7, 14 and 15), it was found that the reaction at
15–25 °C gave the best result. Finally, the reaction was scaled
After a suitable catalyst (C7) was identified, further reaction op- up (90 g of 2) according to the conditions in entry 7, a similar
timization was performed (Table 2). In general, dichloro- outcome was obtained (Table 2, entry 16).
methane (DCM) was the common solvent for the two-phase
reaction, but to our surprise, when the reaction was run in DCM On the base of the above experimental results, a catalytic mech-
(entry 2 in Table 2), it resulted in the racemic product. When anism was proposed (Scheme 3). Compound 2 is deprotonated
other solvents, such as benzene, bromobenzene and fluoroben- by sodium hydroxide into an anion in the organic layer. The
zene, were used, neither the enantiomeric ratio nor the yield was anion goes to the interface between chlorobenzene and water,
improved, compared with toluene as the solvent (Table 2, where it interacts with the quaternary ammonium group of cata-
entries 1, 3–5). But, the reaction in chlorobenzene gave a lyst C7. The distance between two molecules is getting close by
slightly improved yield at a substrate concentration of the attraction between charges, then two additional interaction
0.045 mol/L (Table 2, entry 1 and 6). Surprisingly, when the forces in the complex are produced on the same plane, includ-
concentration increased to 0.07 mol/L, the improvement be- ing: 1) the carbonyl of 2 makes a hydrogen bond with the
came more significant (Table 2, entries 7 and 8). However, hydroxy group of C7; 2) the phenyl group of 2 forms a face-to-
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Beilstein J. Org. Chem. 2018, 14, 1421–1427.
Table 2: Screening of catalytic conditions.
entry
solvent
concentration
(mol/L)a
temperature (°C)
baseb
yieldc
3a:3bd
1
PhMe
CH2Cl2
PhH
0.045
0.045
0.045
0.045
0.045
0.045
0.070
0.070
0.175
0.070
0.070
0.070
0.070
0.070
0.070
15–25
15–25
15–25
15–25
15–25
15–25
15–25
15–25
15–25
15–25
15–25
15–25
0–5
50% aq NaOH
50% aq NaOH
50% aq NaOH
50% aq NaOH
50% aq NaOH
50% aq NaOH
50% aq NaOH
50% aq NaOH
50% aq NaOH
50% aq NaOH
25% aq NaOH
50% aq K2CO3
50% aq NaOH
50% aq NaOH
50% aq NaOH
62.0%
58.1%
60.0%
58.9%
60.4%
67.1%
76.2%
61.2%
70.8%
48.1%
42.8%
no reaction
incomplete
68.0%
77.8%
83:17
50:50
81:19
76:24
72:28
81:19
79:21
77:23
69:31
75:25
72:28
–
2
3
4
PhBr
PhF
5
6
PhCl
PhCl
PhMe
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
7
8
9
11e
12
13
14
15
16f
–
35–40
15–25
75:25
79:21
aConcentration of compound 2 (5 g). bThe volume ratio of aqueous solution and organic solvent was 1:10. cIsolated yield including 3a and 3b. dThe
enantiomeric ratio was determined by HPLC using a chiral column (Daicel chiral AY-H) with hexane/isopropyl alcohol 90:10 as the eluent, detected at
280 nm. eThe volume of 50% aq NaOH was decreased to 5% of the volume of PhCl. f90 g of 2 was added.
Scheme 3: The proposed catalytic mechanism of stereoselective alkylation.
face π-stacking interaction with the benzyl moiety of C7. The Conclusion
complex of 2 with C7 goes to the organic phase. Due to the In summary, an enantioselective synthesis of (R)-(+)-1-(5-
sterical hindrance from the benzyl group, the alkylation by 1,5- bromopentyl)-1-methyl-7-methoxy-2-tetralone (3a), a key inter-
dibromopentane takes place at the opposite side of the benzyl mediate of dezocine, in the catalysis of the quaternary ammoni-
group of C7 to afford 3a.
um benzyl bromides from cinchonidine was investigated and
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Beilstein J. Org. Chem. 2018, 14, 1421–1427.
the best catalyst (C7) was identified. In addition, the prepara- formed to dezocine with 23.0% overall yield and 100% purity.
tion of 3a with the optimized conditions was performed and the The mp, optical rotation value, MS and 1H NMR of the product
product was isolated in 77.8% yield with an enantiomeric ratio were consistent with those in the literature [4,10].
of 79:21. This method can be easily performed in large scale. In
addition, the structure–activity relationships for the cinchona
Supporting Information
alkaloids catalysts were elucidated.
Supporting Information File 1
Synthesis of catalysts C1–C17, synthesis of dezocine,
Experimental
All solvents and reagents were of commercial sources and used
without further purification. Melting points were determined on
a Büchi Melting Point M-565 apparatus and are uncorrected. 1H
and 13C NMR spectra were recorded using a Bruker 400 MHz
spectrometer with TMS as an internal standard. Mass spectra
were recorded with a Q-TOF mass spectrometer using electro-
spray positive ionization (ESI+). The enantiomeric ratio was de-
termined by HPLC using a chiral column (Daicel chiral AY-H)
with (hexane/isopropyl alcohol 90:10) as eluents, detected at
280 nm. Specific rotations were determined on a Rudolph
Research Analytical automatic polarimeter IV. All reactions
were monitored by TLC, which were carried out on silica gel
GF254. Column chromatography was carried out on silica gel
(200–300 mesh) purchased from Qindao Ocean Chemical
Company of China.
1H NMR and MS spectra of catalysts C1–C17 and chiral
HPLC diagrams of 3. 1H NMR, 13C NMR, MS spectra of
3. 1H NMR, MS spectra HPLC diagrams of dezocine.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-119-S1.pdf]
ORCID® iDs
Ruipeng Li - https://orcid.org/0000-0001-9520-0635
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Beilstein J. Org. Chem. 2018, 14, 1421–1427.
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