A Facile Epoxide Aminolysis Promoted by (t-BuO)2Mg and Its Application to the Synthesis of Efinaconazole

Article abstract of DOI:10.1021/acs.oprd.8b00081

A novel and efficient method for the aminolysis of trizole epoxides is described. This method consists of a facile ring opening of the epoxides mediated by t-BuOMgCl generated in situ from amine hydrochlorides and (t-BuO)₂Mg. The desired β-amino alcohols were obtained in good yields without employing other heavy metals or precious catalysts. The optimized conditions were successfully applied to the synthesis of a number of potential triazole antifungal compounds as well as efinaconazole on up to a 700 g scale.

Full text of DOI:10.1021/acs.oprd.8b00081

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A Facile Epoxide Aminolysis Promoted by (t-BuO)2Mg
and Its Application to the Synthesis of Efinaconazole
Fuqiang Zhu, Yuanchao Xie, Jian Zhang, Guanghui Tian, Hongjian Qin,
Xiaojun Yang, Tianwen Hu, Yang He, Haji Akber Aisa, and Jingshan Shen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00081 • Publication Date (Web): 26 Apr 2018
Downloaded from http://pubs.acs.org on April 26, 2018
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A Facile Epoxide Aminolysis Promoted by (tꢀBuO)2Mgand Its
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Application to the Synthesis of Efinaconazole
Fuqiang Zhu,†, ⊥, ǁ Yuanchao Xie,‡, ǁ Jian Zhang,§ Guanghui Tian,§ Hongjian Qin,§
Xiaojun Yang,§ Tianwen Hu,§ Yang He,‡ Haji A. Aisa,*, † and Jingshan Shen*, ‡
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†Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang
Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South
Beijing Road 40–1, Urumqi, Xinjiang 830011, P. R. China.
⊥University of Chinese Academy of Sciences，No.19A Yuquan Road, Beijing
100049, P. R. China.
§Topharman Shanghai Co., Ltd., Building 1, No.388 Jialilue Road, Zhangjiang Hitech
Park, Shanghai 201209, P. R. China.
‡CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
ǁThe first two authors contribute equally to this paper.
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ABSTRACT
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A novel and efficient method for the aminolysis of trizole epoxide is described. This
method consists of a facile ring opening of epoxides mediated by tꢀBuOMgCl
generated in situ from hydrochloride of amines and (tꢀBuO)2Mg. The desired βꢀamino
alcohol molecules were obtained in good yields without employing other heavy
metals or precious catalysts. The optimized conditions were successfully applied to
the synthesis of a number of potential triazole antifungal compounds, as well as
efinaconazole up to 700 g scale.
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Keywords: Epoxide aminolysis, Triazole, Magnesium tertꢀbutoxide
INTRODUCTION
The βꢀamino alcohol moiety, is a popular structural component widely present in a
variety of biologically active natural products,1 active pharmaceutical ingredients
(APIs)2 and chiral auxiliaries or ligands used in asymmetric synthesis.3 Since its
versatile functionality and potential applications, a number of synthetic pathways
have been well established to provide βꢀamino alcohol group in the past decades.4
One of the best known and straightꢀforward method is the ringꢀopening reaction of
epoxides with various amines.5 However, in many cases, it would not proceed
smoothly or even fail in the preparation of hindered βꢀamino alcohols. Large excess of
materials and elevated temperature are frequently required, which likely resulted in
undesired side reactions such as rearrangement or polymerization.
To address these issues, a lot of methods have been developed to promote epoxide
aminolysis, such as the employment of Lewis acids,6 microwaveꢀassisted synthesis,7
and performing these reactions in continuousꢀflow microreactors.8 However, some of
these methods are still associated with shortcomings like the use of dangerous
perchlorate, toxic heavy metals and costly catalyst which greatly limited their
practical application in pharmaceutical manufacturing. Therefore, developing a safe,
efficient and inexpensive epoxide ammonolysis method is still highly desirable.
RESULTS AND DISCUSSION
Efinaconazole (trade name Jublia (R)), a new triazole antifungal drug, was
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approved by FDA in 2014 for the topical treatment of mild to moderate toenail
onychomycosis.9 It has shown significant antifungal activity against dermatophytes,
Candida spp. and nondermatophyte molds in a mechanism of inhibiting fungal
lanosterol 14αꢀdemethylase.10 There are several routes established for the synthesis of
efinaconazole,11 but from an application perspective, the ringꢀopening reaction of
epoxide 1 with piperidine hydrochloride 2 was believed to be the most efficient
method, and also a suitable case for studying the reaction conditions for epoxide
aminolysis (Scheme 1).
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Scheme 1. Synthetic Route of Efinaconazole
Reagents and conditions: a. Additives, solvent, heating.
With the trisubstituted epoxide 1 and hindered piperdine 2, it was estimated that
the reaction would not go well if only classical procedure was utilized. This
assumption was proved in our lab by performing the ringꢀopening reaction in the
presence of stoichiometric amounts of bases. As shown in Table 1, the reactions
generally proceeded sluggishly in most of entries, and satisfactory results did not arise
with varying types of bases and equivalents of piperidine 2. A 44% isolated yield of
this reaction was reported using similar conditions in a literature, in which microwave
irradiation was employed to solve this problem, affording 90% yield.11b The adjacent
trizole group, a electronꢀwithdrawing group, facilitated the arrangement of epoxide 1
under basic conditions, leading to the formation of the main side product 3.12 The
initial reaction results confirmed that this transformation was troublesome due to the
low activity of the two substrates.
Table 1 Initial Screening Results of the Aminolysis of Epoxide 1a
Entry
Equiv of 2
Base (equiv)
Conversion b (%)
Yield c (%)
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1.5
1.5
1.5
3.0
3.0
2.0
LiOH (2.0)
NaOH (2.0)
KOH (2.0)
76.5
46.8
54.2
26.1
66.2
< 10
63.8
30.5
32.9
18.7
40.8
< 10
K2CO3 (3.0)
tꢀBuONa (3.5)
TEA (2.5)
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aConditions: Epoxide 1 at 5 g scale. All reactions were performed by refluxing for
16 h in acetonitrile under a nitrogen atmosphere. b Conversion was calculated from
c
the HPLC area. The yield of efinaconazole was determined by HPLC area in
reaction mixture.
Scheme 2. Formation of Impurity 3
Many studies have showed that the ring opening reaction of epoxides could be
promoted by various lithium salts, such as LiOH,13a, b LiBr,11f, 13c Li2CO3 and
11d
LiClO4.13d In Table 1, we also noted that moderate conversion and yield was achieved
in the presence of lithium hydroxide (entry 1), which was the present perfect
conditions. This improvement may be rationalized by coordination of the epoxy
oxygen with the metal center, and thereby greatly facilitating the epoxide aminolysis
with 4ꢀmethylenepiperidine. Accordingly, we considered other metal salts would also
promote this reaction by the way of coordination.
For the purpose of seeking better catalysts, a broad screen of possible alternatives
was initiated from economical and readily available metal salts, including series of Li,
Fe, Cu, Mg, Co, Mn, Zn, most of which have been well documented in the literature
to promote ringꢀopening reactions.6 The screening results were illustrated in Table 2,
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showing the conversion rate of triazole epoxide 1 and the yield of efinaconazol.
Notably, all the reactions proceeded in favor of forming Cꢀ3ꢀregioisomer of the epoxy
triazole, rather than Cꢀ2ꢀregioisomer.
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A survey of 11 catalysts revealed that the reactions were significantly influenced by
the nature of Lewis acidic metal salt. As shown in Table 2, except Li and Mg salts
(Entries 1ꢀ4), most of the others gave poor conversion or significantly resulted in the
byproduct of allylic alcohol 3. For FeCl3 (Entry 6), ZnCl2 (Entry 9) and MnCl2 (Entry
10), only trace product was observed. The use of Al(OTf)3 (Entry 5), Cu(OTf)2 (Entry
7), CoCl2 (Entry 8) and Ti(OꢀiꢀPr)4 (Entry 11) gave low conversion. Moderate
conversion and yields were obtained with Liꢀseries (Entry 1 and 2). To our delight, the
combination of MgCl2 and DIPEA gave better results with 85.3% conversion and
78.8% yield (Entry 3 and 4).14 Indeed, some magnesium salts, such as Mg(ClO4)2,
EtMgBr, and MgBr2 have also been reported to catalyze the epoxide aminolysis. 15 As
a readily available inorganic salt, MgCl2 remarkably improve the reaction, so we were
encouraged to search for more effective and selective magnesium salts.
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Table 2. Lewis Acids Promoted Ring Opening of Epoxide
4-Methylenepiperidine Hydrochloride 2a
1 with
Entry
Base (equiv)
TEA (2.5)
Lewis acid (equiv)
LiCl (2.0)
Conversion b (%) Yield c (%)
1
2
68.5
75.4
77.5
85.3
20.3
< 10
45.6
38.1
< 10
< 10
56.9
62.7
63.5
72.2
78.8
15.5
–
tꢀBuONa (2.0)
Py (2.5)
LiBr (1.5)
3
MgCl2 (2.0)
MgCl2 (1.5)
Al(OTf)3 (0.2)
FeCl3 (1.0)
4
DIPEA (2.0)
TEA (2.5)
5
6
TEA (2.0)
7
NaHCO3 (1.5)
TEA (2.0)
Cu(OTf)2 (0.2)
CoCl2 (1.5)
30.6
32.7
–
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TEA (2.0)
ZnCl2 (1.5)
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11
NaHCO3 (1.5)
TEA (2.0)
MnCl2 (0.5)
Ti(OꢀiꢀPr)4 (0.2)
–
38.3
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a Conditions: All reactions were performed as a molar ratios of 1 and 2 with 1:1.5 at
b
5 g scale by refluxing for 16 h in acetonitrile under a nitrogen atmosphere.
c
Conversion was calculated from the HPLC area. The yield of efinaconazole was
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determined by HPLC area in reaction mixture.
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Based on above reaction result, magnesium cation was thought to be favorable to
promote the reaction by coordinating with the epoxide oxgen, and thereafter, various
magnesium compounds were attempted for studying the reaction (Table 3). The use of
Mg(OH)2 or MgCO3 gave disappointing results due to their poor solubility (Entry 1
and 2). Combination of MgCl2 with various alkaline metals did not display beneficial
effect too (Entry 3–8), compared with the above mentioned condition, DIPEA/MgCl2
(Entry 4, Table 2). The addition of tꢀBuOK provided high conversion, but a large
amount of allylic alcohol 3 was formed. A slight increase in yield was observed in the
presence of (MeO)2Mg and (EtO)2Mg (Entry 9 and 10). To our delight, the use of
(tꢀBuO)2Mg afforded a 99.4% conversion and 96.1% yield, with no formation of
byproduct 3 (Entry 11). However, when in conjunction with LiCl, the yield was
reduced to 76.8% (Entry 12). In a recent example, (tꢀBuO)2Mg was utilized as a weak
Lewis acid to participate intramolecular ringꢀopening reaction of 2,3ꢀepoxy alcohols
with high regioselectivity.16 .
Table 3. Mg-salts Promoted Aminolysis of Epoxide 1 with 4-Methylenepiperidine
Hydrochloride 2a
Entry
Base (equiv)
Mg(OH)2 (2.0)
MgCO3 (2.0)
NaOH (1.5)
Additives (equiv) Conversion b (%) Yield c (%)
1
2
3
4
5
6
7
/
< 10
< 10
59.3
49.7
32.7
96.4
82.3
–
/
–
MgCl2 (1.0)
MgCl2 (1.0)
MgCl2(1.0)
MgCl2 (1.5)
MgCl2 (1.5)
33.5
38.9
26.8
22.7
59.1
K2CO3 (1.0)
Na2CO3 (1.0)
tꢀBuOK (1.5)
tꢀBuONa (1.5)
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tꢀBuOLi (1.5)
MgCl2 (1.5)
79.6
25.3
59.3
62.5
96.1
76.8
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(MeO)2Mg (2.0)
(EtO)2Mg (2.0)
(tꢀBuO)2Mg (2.0)
(tꢀBuO)2Mg (2.0)
/
68.2
72.1
99.7
86.6
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LiCl (1.0)
a Conditions: All reactions were performed as a molar ratio of 1 and 2 with 1:1.5 at 5
b
g scale by refluxing for 16 h in acetonitrile under a nitrogen atmosphere.
c
Conversion was calculated from the HPLC area. The yield of efinaconazole was
determined by HPLC area in reaction mixture.
The high yield of the reaction using (tꢀBuO)2Mg led us to investigate the other
reaction parameters. A solvent survey (MeCN, THF, tꢀBuOH and toluene) indicated
that MeCN was optimal in aspects of the yield and impurities (Table 4). With THF in
place of MeCN, the reaction gave poor conversion. For tꢀBuOH, the triazole epoxide
1 disappeared almost completely, but, about 10% of byproduct 3 was formed. The
sluggish reaction in toluene might be explained by the low solubility of (tꢀBuO)2Mg.
Table 4. The Results of Solvents Screeninga
Entry
Solvents
MeCN
THF
Conversion b (%)
Byꢀproduct 3 b (%) Yield c (%)
1
2
3
4
99.5
35.2
99.2
< 10
< 0.1
3.6
96.2
30.8
86.2
–
tꢀBuOH
10.3
Toluene
–
a Conditions: All reactions were performed as a molar ratio of 1, 2 and (tꢀBuO)2Mg
with 1:1.5:1.5 at 5 g scale by refluxing for 16 h in acetonitrile under a nitrogen
b
c
atmosphere. Conversion was calculated from the HPLC area. The yield of
efinaconazole was determined by HPLC area in reaction mixture.
While the equivalent of (tꢀBuO)2Mg was decreased to 1.5 equiv from 2.0 equiv, a
99.5% conversion was still achieved without the need of extending reaction time. A
further reduction to 1.2 equiv led to incomplete reaction, even though the aging time
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was extended 24 h. Therefore, 1.5 equiv was thought to be the optimal equivalent.
Using the optimized conditions, efinaconazol was synthesized from epoxide 1 and
piperidine 2 in 88.5% isolated yield, 99.5% HPLC purity, and > 99.9% ee at a 700 g
scale. Compared with the existing epoxide ring–opening regents, such as LiOH,13a, b
MgCl2/DIPEA14 and LiClO4, 13d the choice of (tꢀBuO)2Mg gave a higher yield and
dispelled safety concern.
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Remarkably, the using of (tꢀBuO)2Mg for epoxide aminolysis has not been
previously reported to our knowledge. To understand the detailed process, several
control experiments were performed and the results were summarized in Table 5.
When the free base of 4ꢀmethylenepiperidine was used in place of the hydrochloride
(entries 1ꢀ4), incomplete conversion and low yield were observed in the presence of
(tꢀBuO)2Mg, MgCl2, MgBr2 or (tꢀBuO)2Mg/MgCl2,. These results indicated that the
actually optimal activator was not likely the (tꢀBuO)2Mg or MgCl2. It was also notable
that reduction of (tꢀBuO)2Mg equivalent from 1.5 equiv to 0.75 equiv resulted in
significant lower conversion. This visible difference related to the quantity of
(tꢀBuO)2Mg was probably attributed to the different components of magnesium salts
existing in the reaction system. With the same equivalent of compound 2 and
(tꢀBuO)2Mg (Entry 4), tꢀBuOMgCl was mainly formed; however, the main product
was changed to MgCl2 while a 2:1 molar ratio of 2 and (tꢀBuO)2Mg was employed
(Scheme 3). Therefore, we concluded that tꢀBuOMgCl generated in situ was the real
mediator that contributed to the efficient aminolysis.
Table 5. Control Epoxide Aminolysis of 1 Promoted by Mg-salts
Entry
1
Form of 2
Additive (equiv)
Conversion b (%) Yield c (%)
base
(tꢀBuO)2Mg (1.5)
52.2
89.2
83.5
45.2
61.4
58.7
2
3
base
base
MgCl2 (1.5)
MgBr2 (1.5)
(tꢀBuO)2Mg (1.0)
and MgCl2 (0.5)
(tꢀBuO)2Mg (1.5)
4
5
base
79.4
99.5
76.8
96.3
hydrochloride
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hydrochloride
(tꢀBuO)2Mg (0.75)
81.8
76.4
a Conditions: All reactions were performed as a molar ratio of 1 and 2 with 1:1.5
b
at 5 g scale by refluxing for 16 h in acetonitrile under a nitrogen atmosphere.
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Conversion was calculated from the HPLC area. The yield of efinaconazole was
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determined by HPLC area in reaction mixture.
Scheme 3. Different Magnesium Salts Generated by (t-BuO)2Mg
To the best of our knowledge, this is the first report on the chemistry of tꢀBuOMgCl,
which greatly facilitated the epoxide aminolysis. Despite the deficiency of
physicochemical data of tꢀBuOMgCl, it would be defined as a weaker Lewis acid than
MgCl2, yet stronger than (tꢀBuO)2Mg through the judgment of electronegativity of
oxygen and chlorine. The overall catalytic activity of these three magnesium reagents
were found to be in the order tꢀBuOMgCl > MgCl2 > (tꢀBuO)2Mg (Entry 1, 2 and 5,
Table 4) that was not parallel with their acidity.
It was generally thought that the coordination of a Lewis acid with the oxirane
oxygen would induce polarization of the oxirane C−C bond and increase the
electrophilicity of these two carbon atoms. As a result, the epoxide ring was more
accessible to be attacked by a nucleophile.17 In the present study, the Mg cation
coordinated with the epoxide oxygen and the trizole nitrogen in a rigid, bidentate
manner, which facilitated the ring opening with 4ꢀmethylenepiperidine. The suggested
role of magnesium tꢀbutoxide chloride in the process was depicted in Schemes 4.
Scheme 4. Plausible Mechanism of the Epoxide 1 Aminolysis
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Further, we examined the scope of this method by reacting epoxide 1 with different
aliphatic amines. As was showed in Table 6, Nꢀaryl substituted piperazines afforded
the 2ꢀamino alcohols in good yields (entry 1−4), as well as the piperidine fused
thiophene (entry 5). Similar results were observed for the pyrrole 2f (entry 6),
diethylamine 2h (entry 8) or azepine 2i (entry 9), but 2g (entry 7) resulted in a relative
lower yield.
Table 6. (t-BuO)2Mg-Promoted Epoxide Ring-Opening Reaction of 1 with
Various Aliphatic Amine Hydrochloride a
Entry
1
Amine
Productb
Yield c (%)
N
N
N
HO
N
S
N
86
CH3
F
F
6a
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N
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2f
CH3
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6h
N
N
N
HO
HN
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CH3
F
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a
Conditions: All reactions were performed as a molar ratio of 1 and amines
hydrochloride with 1:1.5 at 200 mg scale by refluxing for 16 h in acetonitrile
under a nitrogen atmosphere. b The products were characterized by 1H, 13C NMR,
and ESIꢀMS. c Isolated yield of the corresponding epoxide aminolysis.
CONCLUSION
The development of a novel and efficient method of triazole epoxide ring opening
with amines to form βꢀamino alcohols has been described, and (tꢀBuO)2Mg was found
to be a highly efficient reagent with the advantage of high yields, readily
commercially available and low toxicit.18 This method was demonstrated by applying
it to the ring opening with a number of amines, including the synthesis of
efinaconazole. Moreover, the method will be contributed to synthesize new triazole
compounds with potential antifungal activity. Meanwhile, the expanding to other
types of epoxides will also be studied.
EXPERIMENTAL SECTION
General Method. All reactions were performed under a nitrogen atmosphere using
anhydrous techniques unless otherwise noted. All commercially available material
and solvents were used directly without further purification. Yields reported are for
isolated, spectroscopically pure compounds. H NMR (400 MHz), 13C NMR (100
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MHz) were recorded with a Bruker spectrometer using TMS as internal standard. The
ESI mass spectra were determined on a THERMO LTQ spectrometer. HPLC
conditions for efinaconazole: column: C18 (3.5 ꢁm, 100 mm × 4.6 mm); flow rate:
1.0 mL/min; and detection at 210 nm; injection vol: 20 ꢁL; gradient elution from
83:17 A/B to 30:70 A/B over 50 min. Mobile phase A: 0.01 mol/L KH2PO4ꢀ
K3PO4/MeOH, 92:8. Mobile phase B: acetonitrile. Run time: 55 min. Temperature:
30 °C.
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Representative Experimental Procedure for (t-BuO)2Mg-Promoted Epoxide
Aminolysis To a 25 mL roundꢀbottom flask with a magnetic stir bar were charged
epoxide 1 (500 mg), acetonitrile (10 mL), amine hydrochloride and (tꢀBuO)2Mg (1.5
mol equiv to epoxide 1) under nitrogen. The reaction mixture was heated and stirred
under reflux for 16 h. Then the mixture was concentrated under vacuum and the
residual was poured into water and extracted with dichloromethane. The organic
phase was washed with brine, dried over sodium sulfate, and evaporated under
reduced pressure to give the crude material. The amino alcohols 6a to 6k were isolated
by column chromatography on silica gel using nꢀheptane/acetone (5:1–10:1, v/v) or
dichloromethane/methanol (50:1–20:1, v/v) as eluents.
6a. White solid, 256 mg, 86% yield. Mp: 74.9−75.0 °C; 1H NMR (400 MHz, CDCl3)
δ (ppm): 8.01 (s, 1 H), 7.81 (s, 1 H), 7.59–7.49 (m, 2 H), 7.40 (s, 2 H), 7.32–7.30 (m,
1 H), 6.92 (d, J = 7.6 Hz, 1 H), 6.81–6.74 (m, 2 H), 5.38 (brs, 1 H), 5.00 (d, J = 14.4
Hz, 1 H), 4.90 (d, J = 14.4 Hz, 1 H), 3.19 (brs, 4H), 3.07–3.04 (m, 3 H), 2.71–2.65 (m,
2 H), 1.08 (d, J = 6.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm): 163.66, 161.67
(dd, J = 199.2, 9.8 Hz), 159.49, 157.46 (dd, J = 194.7, 8.8 Hz), 151.55, 148.31,
144.35, 141.16, 134.05, 130.86–130.74 (m), 125.06, 125.01, 124.79–124.68 (m),
121.82, 117.13, 112.18, 111.66–111.47 (m), 104.37–103.94 (m), 78.46 (d, J = 4.4 Hz),
64.17, 55.96 (d, J = 6.6 Hz), 52.66 (d, J = 12.8 Hz), 30.95, 7.44; MS (ESI): m/z =
470.4 [M + H] +; HRMS (ESI): Calcd for C24H25F2N5OS [M + H]+ 470.1826, Found
470.1830.
1
6b. Isolated as an oil, 280 mg, 73% yield. H NMR (400 MHz, CDCl3) δ (ppm):7.98
(s, 1 H), 7.80 (s, 1 H), 7.50–7.48 (m, 1 H), 7.17–7.15 (m, 2 H), 6.97–6.95 (m, 1 H),
6.80–6.73 (m, 2 H), 5.22 (s, 1 H), 4.97 (d, J = 14.8 Hz, 1 H), 4.88 (d, J = 14.8 Hz, 1
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H), 3.06–2.98 (m, 7 H), 2.64–2.61 (m, 2 H), 1.03–1.01 (m, 3 H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 163.64, 161.65 (dd, J = 198.7, 10.7 Hz), 159.37, 157.42 (dd, J =
195.2, 9.0 Hz), 151.59, 151.15, 144.30, 134.06, 130.83–130.70 (m), 127.50, 127.45,
124.81–124.70 (m), 124.65, 111.64–111.45 (m), 104.35–103.93 (m), 78.53 (d, J = 4.5
Hz), 64.13, 55.97 (d, J = 5.9 Hz), 51.88, 30.94, 7.43; MS (ESI): m/z = 482.3 [M + H] +;
HRMS (ESI): Calcd for C22H23Cl2F2N5O [M + H]+ 482.1326, Found 482.1332.
6c: Isolated as an oil, 268 mg, 79% yield. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.08
(s, 1 H), 7.85 (s, 1 H), 7.54–7.50 (m, 1 H), 7.20–7.17 (m, 2 H), 7.05–6.98 (m, 2 H),
6.82–6.73 (m, 2 H), 5.37 (s, 1 H), 4.98 (d, J = 14.4 Hz, 1 H), 4.88 (d, J = 14.8 Hz, 1
H), 3.01–2.94 (m, 7 H), 2.59–2.56 (m, 2 H), 2.30 (s, 3 H), 1.06–1.04 (m, 3 H); 13C
NMR (100 MHz, CDCl3) δ (ppm): 163.63, 161.65 (dd, J = 198.3, 9.2 Hz), 159.49,
157.53 (dd, J = 196.4, 9.6 Hz), 151.49, 151.36, 144.39, 132.56, 131.10,
130.90–130.78 (m), 126.59, 124.84–124.70 (m), 123.20, 118.94, 111.61–111.43 (m),
104.35–103.92 (m), 78.25 (d, J = 4.4 Hz), 64.18, 55.97 (d, J = 5.9 Hz), 52.28, 30.94,
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+
17.90, 7.52; MS (ESI): m/z = 428.4 [M + H] ; HRMS (ESI): Calcd for
C23H27F2N5O [M + H]+ 428.2262, Found 428.2264.
6d. Isolated as an oil, 318 mg, 81% yield. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.00
(s, 1H), 7.81 (s, 1H), 7.52–7.46 (m, 1H), 7.02 (t, J = 8.3 Hz, 1H), 6.83–6.75 (m, 2H),
6.69 (d, J = 7.2 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 5.20 (s, 1H), 4.95–6.86 (m, 2H),
3.11–3.14 (m, 4H), 3.03–2.98 (m, 3H), 2.65–2.63 (m, 2H), 1.27 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm): 163.68, 161.69 (dd, J = 198.5, 9.4 Hz), 159.37, 157.36
(dd, J = 195.1, 8.5 Hz), 151.55, 144.54, 144.35, 135.79, 133.66, 131.14,
130.79–130.66 (m), 124.69 (d, J = 12.6 Hz), 124.06, 111.70–111.52 (m),
104.39–103.96 (m), 102.00, 78.62 (d, J = 4.4 Hz), 64.22, 56.01 (d, J = 4.9 Hz), 49.44,
29.28, 7.22; MS (ESI): m/z = 494.4 [M + H] +; HRMS (ESI): Calcd for C23H23F4N5O3
[M + H]+ 494.1815, Found 494.1820.
6e. Isolated as an oil, 287 mg, 93% yield. 1H NMR (400 MHz, CDCl3) δ (ppm):7.98
(s, 1 H), 7.79 (s, 1 H), 7.55–7.49 (m, 1 H), 7.11 (d, J = 5.1 Hz, 1 H), 6.83–6.74 (m, 3
H), 5.29 (brs, 1 H), 4.96 (d, J = 14.4 Hz, 1 H), 4.87 (d, J = 14.8 Hz, 1 H), 3.89 (d, J =
14.4 Hz, 1 H), 3.64 (d, J = 14.0 Hz, 1 H), 3.20–3.13 (m, 2 H), 2.90–2.83 (m, 2 H),
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2.61 (br. s., 1 H), 1.05 (m, 3 H); 13C NMR (100 MHz, DMSOꢀd6) δ (ppm): 163.13,
161.17 (dd, J = 195.6, 9.8 Hz), 159.91, 157.96 (dd, J = 195.0, 9.2 Hz), 150.93, 145.16,
135.28, 133.62, 130.74–130.61 (m), 126.27, 126.25–126.01 (m), 123.11,
111.30–111.13 (m), 104.54–104.10 (m), 79.25 (d, J = 5.6 Hz), 63.11 (d, J = 2.7 Hz),
56.23 (d, J = 4.3 Hz), 51.46, 47.80 (d, J = 9.9 Hz), 26.13, 7.71; MS (ESI): m/z = 391.3
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+
[M + H] ; HRMS (ESI): Calcd for C19H20F2N4OS [M + H]+ 391.1404, Found
391.1397.
6f. White solid as a mixture of diastereoisomer at cyclopropyl position, 262 mg, 91%
yield. Mp: 72.5−73.4 °C; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.03 (s, 1 H), 7.78 (s,
1 H), 7.51–7.47 (m, 1 H), 6.82–6.72 (m, 2 H), 5.51 (s, 1 H), 4.86–4.77 (m, 2 H),
3.14–3.12 (m, 1 H), 2.74–2.70 (m, 1 H), 2.57–2.42 (m, 3 H), 2.32–2.26 (m, 2 H),
1.80–1.62 (m, 3 H), 1.49–1.32 (m, 3 H), 0.93–0.87 (m, 3 H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 163.57, 161.59, (dd, J = 198.4, 9.9Hz), 159.69, 157.73 (dd, J =
195.7, 9.5 Hz), 151.24, 144.37, 131.05–130.93 (m), 124.51–124.38 (m),
111.46–111.28 (m), 104.18–103.75 (m), 77.84 (d, J = 4.5 Hz), 59.01, 58.48, 55.99 (d,
J = 6.0 Hz), 55.75, 41.91, 41.33, 33.85, 33.62, 26.84, 7.18 (d, J = 2.7 Hz); MS (ESI):
m/z = 363.3 [M + H] +; HRMS (ESI): Calcd for C19H24F2N4O [M + H]+ 363.1996,
Found 363.1997.
6g. White solid, 266 mg, 77% yield. Mp: 49.6−54.3 °C; 1H NMR (400 MHz, CDCl3) δ
(ppm): 1H NMR (400 MHz, CDCl3) δ (ppm): 7.94 (s, 1 H), 7.79 (s, 1 H), 7.47–7.44
(m, 1 H), 7.13–7.05 (m, 4 H), 6.80–6.71 (m, 2 H), 4.95 (brs, 1 H), 4.85 (m, 2 H),
3.32–3.20 (m, 2 H), 3.12–2.93 (m, 3 H), 2.34 (s, 3 H), 1.71–1.70 (m, 1 H), 1.37–1.35
(m, 1 H), 0.91–0.90 (m, 3 H), 0.86–0.83 (m, 3 H); 13C NMR (100 MHz, CDCl3) δ
(ppm): 163.56–161.49 (m), 159.32–157.24 (m), 151.64 (d, J = 3.2 Hz), 144.13, (d, J
= 2.6 Hz), 139.81, 139.57, 135.44, 130.78 (d, J = 5.3 Hz), 129.02 (d, J = 3.5 Hz),
126.43 (d, J = 7.3 Hz), 124.84–124.73 (m), 111.57 (d, J = 15.9 Hz), 104.20–103.77
(m), 79.25 (d, J = 4.3 Hz), 79.11 (d, J = 4.3 Hz), 58.83–58.34 (m), 56.07–55.15 (m),
51.18, 47.33, 31.02, 29.03, 24.99, 24.38–23.07 (m), 20.98, 17.03, 16.96, 7.27 (d, J =
3.2 Hz); MS (ESI): m/z = 425.4 [M + H] +. HRMS (ESI): Calcd for C24H26F2N4O [M
+ H]+ 425.2153, Found 425.2154.
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6h. White solid, 227 mg, 88% yield. Mp: 61.0−62.8 °C; 1H NMR (400 MHz, CDCl3)
δ (ppm): 8.12 (s, 1H), 7.82 (s, 1H), 7.61–7.55 (m, 1H), 6.85–6.74 (m, 2H), 5.87 (brs,
1H), 4.93 (d, J = 14.4 Hz, 1H), 4.67 (d, J = 14.4 Hz, 1H), 2.94–2.89 (m, 1H),
2.28–2.22 (m, 4H), 1.03–0.87 (m, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm): 163.63,
161.65 (dd, J = 197.4, 8.9 Hz), 161.55,157.86 (dd, J = 195.9, 9.3 Hz), 151.17, 144.86,
130.93–130.80 (m), 124.90 (dd, J = 8.1 Hz), 111.44–111.26 (m), 104.33–103.90 (m),
76.26 (d, J = 4.2 Hz), 59.28, 55.61 (d, J = 6.1 Hz), 44.41 (d, J = 8.4 Hz), 13.81, 7.98
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(d, J = 4.5 Hz); MS (ESI): m/z = 325.3 [M + H] ; HRMS (ESI): Calcd for
C16H22F2N4O [M + H]+ 325.1840, Found 325.1827.
6i. Isolated as an oil, 249 mg, 90% yield. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.10
(s, 1H), 7.80 (s, 1H), 7.59–7.53 (m, 1H), 6.84–6.74 (m, 2H), 5.79 (brs, 2H),
4.98–4.80(m, 2H), 2.95–2.92 (m, 2H), 2.68–2.65 (m, 1H), 2.36–2.20 (m, 4H),
1.77–1.63 (m, 2H), 1.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 163.61,
161.63 (dd, J = 198.3, 9.8 Hz), 159.59, 157.63 (dd, J = 195.2, 9.1 Hz), 151.09 (d, J =
6.3 Hz), 144.55, 132.51, 131.20–130.86 (m), 129.03, 124.59 (d, J = 2.7 Hz),
111.48–111.20 (m), 104.24–103.89 (m), 77.27 (d, J = 4.2 Hz), 67.38, 56.03–55.76
(m), 30.56, 27.19, 8.56 (d, J = 3.2 Hz); MS (ESI): m/z = 349.4 [M + H] +; HRMS
(ESI): Calcd for C18H22F2N4O [M + H]+ 349.1840, Found 349.1838.
Procedure for the Scalable Synthesis of Efinaconazole: (tꢀBuO)2Mg (712.8 g, 4.18
mol) was added to a mixture of epoxide 1 (700 g, 2.79 mol), piperidine 2 (558.4 g,
4.18 mol), and CH3CN (5.6 L) in three portions while maintaining the temperature
below 35 °C. The resulting mixture was heated to 82
HPLC. Upon completion (residual lactate: 1.0 HPLC area %), the reaction mixture
was cooled to 35 45 °C. Most of solvent was distilled off by concentration under
ꢀ86 °C for 16 h and monitored by
–
reduced pressure to give a semisolid mass. After the addition of EtOH (4 L) was
charged, followed by the addition of 20% NaOH solution (850 g) was added at <
20 °C. The precipitated solid (magnesium salt) was filtered and washed with EtOH (1
L). Water (4 L) and charcoal (25 g) were added to the combined filtrate and the
resulting mixture was then heated to 75–80 °C for 30 min. The charcoal was removed
by filtration at this temperature and was rinsed with a solution of EtOH (200 mL) and
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H2O (200 mL). The solution was cooled to 0
–
10 °C within 3 h and held for 2 h to
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make efinaconazole crystallized completely. The solid was filtered and dried in
vacuum to give efinaconazole as offꢀwhite powder (860 g) in 88.5% isolated yield,
99.5% HPLC purity, and > 99.9% ee. 1H NMR (400 MHz, DMSOꢀd6) δ (ppm): 8.31
(s, 1H), 7.68 (s, 1H), 7.37–7.30 (m, 1H), 7.14–7.08 (m, 1H), 6.93–6.88 (m, 1H), 5.50
(s, 1H), 4.89 (d, J = 14.4 Hz, 1 H), 4.83 (d, J = 15.2 Hz, 1 H), 4.63 (s, 2H), 3.15–3.11
(m, 1H), 2.86–2.82 (m, 2H), 2.43–2.40 (m, 2H), 2.25–2.22 (m, 4H), 0.75 (d, J = 6.8
Hz, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ (ppm): 163.36,160.91, (dd, J = 244.7,
12.7Hz), 160.15,157.71 (dd, J = 244.4, 11.3 Hz), 150.94, 147.10, 145.15,
130.80–130.65 (m), 126.28–126.14 (m), 111.27 (d, J = 18.5 Hz), 108.10,
104.56–104.02 (m), 79.02 (d, J = 6.6 Hz), 63.82 (d, J = 3.1 Hz), 56.19 (d, J = 5.5 Hz),
52.72, 35.37, 7.63; MS (ESI): m/z = 349.2 [M + H] +.
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ASSOCIATED CONTENT
Supporting Information
Experimental details and spectroscopic data for the compounds described in this paper.
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Address:
Tel:
+86–0991–3835679.
Fax:
+86–0991–3835679.
E–mail:
haji@ms.xjb.ac.cn.
*Address: Tel: +86–21–20231000–2407. Fax: +86–21–20231000–2407. E–mail:
shenjingshan@simm.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors acknowledge the support from National Science Foundation for Young
Scientists of China (Grant No. 21502209), and wish to thank Topharman Shandong
Ltd. for their helpful support. We thank Professor Weiliang Zhu for helpful
discussions.
REFERENCES
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/Q3D/Q3D_Step_4.pdf
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