Development of a Robust Process for the Preparation of High-Quality 4-Methylenepiperidine Hydrochloride

Article abstract of DOI:10.1021/acs.oprd.7b00350

An efficient route for the preparation of 4-methylenepiperidine hydrochloride 1 was designed, and then a process feasible for large-scale production was developed with a total yield of 83.5% at a purity of 99.9%.

Full text of DOI:10.1021/acs.oprd.7b00350

Subscriber access provided by READING UNIV
Full Paper
Development of a Robust Process for the Preparation
of High-Quality 4-Methylenepiperidine Hydrochloride
Fuqiang Zhu, Haji Akber Aisa, Jian Zhang, Tianwen Hu,
Changliang Sun, Yang He, Yuanchao Xie, and Jingshan Shen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00350 • Publication Date (Web): 19 Dec 2017
Downloaded from http://pubs.acs.org on December 19, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 18
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Development of a Robust Process for the Preparation of
HighꢀQuality 4ꢀMethylenepiperidine Hydrochloride
Fuqiang Zhu,†, ⊥ Haji A. Aisa, Jian Zhang, Tianwen Hu,
*,†
§
§
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
§
‡
‡
*,‡
Changliang Sun, Yang He, Yuanchao Xie, and Jingshan Shen
†
Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang
Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South
Beijing Road 40ꢀ1, Urumqi, Xinjiang 830011, P. R China.
⊥
University of Chinese Academy of Sciences，No.19A Yuquan Road, Beijing
1
‡
00049, 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.
Topharman Shanghai Co., Ltd., Building 1, No.388 Jialilue Road, Zhangjiang Hitech
§
Park, Shanghai 201209, P. R China.
ABSTRACT
An efficient route for the preparation of 4ꢀmethylenepiperidine hydrochloride 1 was
designed and then a process feasible for largeꢀscale production was developed with a
total yield of 83.5% at a purity of 99.9%.
Keywords: 4ꢀmethylenepiperidine hydrochloride, Efinaconazole, Nꢀbenzylpiperidinone
and ethyl chloroformate.
INTRODUCTION
Efinaconazole is a novel triazole antifungal administered as a 10% topical solution
1
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
for the treatment of mild to moderate onychomycosis (trade name Jublia (R),
1, 2
marketed in 2014) developed by Valeant Pharmaceuticals International.
It is
currently the most effective topical antiꢀfungal drug acting by inhibiting ergosterol
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
biosynthesis, and is predicted to have broad market prospects in the near future.
Retrosynthetic analysis shows that efinaconazole is constructed from
4ꢀmethylenepiperidine hydrochloride 1 and epoxytriazole 2 (Figure 1). Since the
4ꢀmethylenepiperidine moiety is introduced to the efinaconazole structure in the final
step, the impurity profile of 1 will impact significantly on the quality of the final API.
Thus, development of a reliable, robust and costꢀeffective process for the preparation
of 4ꢀmethylenepiperidine hydrochloride 1 is critical for the commercial production of
efinaconazole.
Figure 1. Structure of Efinaconazole and its Two Key Intermediates
Several approaches of the synthesis of 4ꢀmethylenepiperidine hydrochloride 1 have
4
ꢀ8
been reported. Started from Nꢀbenzyl piperidinone 3 or NꢀBoc piperidinone 6,
4, 5
Mimura and Cooper
reported the preparation of hydrochloride 1 involving
formation of the methylene unit by Wittig reaction (Scheme 1 and Scheme 2).
However, the use of nꢀBuLi and column chromatography are not desirable for
industrial production. More importantly, when we repeated these procedures, two
undesired impurities (1A and 1B) were detected and could not be completely removed
2
ACS Paragon Plus Environment

Page 3 of 18
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
by normal purification. This fact revealed that the terminal methylene structure was
unstable and prone to generate related impurities in an acidic environment. Naito et al.
reported another route for the synthesis of 1 starting from ethyl isonipecotate 8
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
ꢀ8
(Scheme 3). The terminal methylene unit was constructed by elimination reaction of
the chloromethyl piperidine 11 in the presence of tꢀBuOK. This route consisted of a
linear sequence of six steps and the overall yield was only 35%. Attolini et al. adopted
a similar route using Boc as protection group to prepare 4ꢀmethylenepiperidine
9
hydrochloride 1(Scheme 4).
Scheme 1. Mimura’s Approach for the Synthesis of 4-Methylenepiperidine
Hydrochloride
Scheme 2. Cooper’s Approach for the Synthesis of 4-Methylenepiperidine
Hydrochloride
Scheme 3. Naito and Mimura’s Approach for the Synthesis of
4-Methylenepiperidine Hydrochloride 1
3
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
COOC H
CH2OH
CH Cl
2
COOC H
2
5
2
5
BzCl,Py
toluene
NaBH4
dioxane, MeOH
SOCl2
DCM
t-BuOK
DMF
N
N
N
N
N
H
Bz
Bz
Bz
Bz
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
9
10
12
11
KOH, ethylene glycol
6%, 5 steps
hydrochloric acid
6%
4
7
·HCl
N
N
H
H
13
1
Scheme 4. Attolini’s Approach for the Synthesis of 4-Methylenepiperidine
Hydrochloride 1
Herein we report the development of a reliable and robust process, which is suitable
to produce high quality 4ꢀmethylenepiperidine hydrochloride 1 in large quantities.
RESULTS AND DISCUSSION
Through literature search and market survey, the commercially available
Nꢀbenzylpiperidinone 3 was considered to be the ideal starting material for the
synthesis of 4ꢀmethylenepiperidine hydrochloride 1. The potential synthetic routes for
hydrochloride 1 from Nꢀbenzylpiperidinone 3 are shown in Scheme 5. It was
particularly noted that the free base of 4ꢀmethylenepiperidine 13 was prepared before
4
ACS Paragon Plus Environment

Page 5 of 18
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
the formation of hydrochloride in all routes considering its instability in an acid
environment. 4ꢀMethylenepiperidine 13 was produced from the common key amide
intermediate 20, which could be prepared by three synthetic routes. In route A, the
methylene unit was first constructed and then Nꢀbenzyl was removed by appropriate
chloroformate reagent to give key intermediate 20. In both route B and C, Nꢀbenzyl
was first removed, and the difference between them was the conditions of removing
benzyl group. It was considered that the oneꢀstep method of using chloroformate in
route C was far more easier than hydrogenation and followed acylation reactions in
route B. Preliminary experiments confirmed that the reactions in route A and C gave
similar results, but the workꢀup procedure of Wittig reaction step in route A was
greatly easier than that in route C by employing simple acidꢀbase switching. Thus,
route A was adopted for process development of 4ꢀmethylenepiperidine hydrochloride
1 and depicted in more detail in Scheme 6.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Possible Routes for the Synthesis of 4-Methylenepiperidine
Hydrochloride 1
Scheme 6. Established Route for the Synthesis of 4-Methylenepiperidine
5
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Hydrochloride 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
ꢀ
o
3 3 2 2 3
Reagents and conditions: (a) CH P(Ph) Br , tꢀBuONa, toluene, 20ꢀ30 C; (b) ClCO Et, Na CO ,
o
toluene, 55ꢀ60 C; (c) ethylene glycol, NaOH; (d) 20% HCl/EtOH, isopropyl acetate. 83.5% over
four steps.
For the Wittig reaction between Nꢀbenzylpiperidinone 3 and methyltriphenylꢀ
phosphonium bromide, hazardous nꢀBuLi was successfully replaced by tꢀBuONa.
This reaction proceeded well with tꢀBuONa in THF or toluene at 0ꢀ10 °C. After
workꢀup, the methylene intermediate 4 was obtained as a pale yellow liquid in 95%
yield. As a switch from tꢀBuONa to tꢀBuOK did not provide any advantage (Table 1,
entry 1ꢀ4), detail reaction parameters of toluene / tꢀBuONa system were further
o
optimized. Raising reaction temperature to 20ꢀ30 C did not decrease the yield and
selectivity. The optimal amounts of methyltriphenylphosphonium bromide and
tꢀBuONa were both 1.1 equiv (entry 5ꢀ7).
a
Table 1 Screening Results of Wittig Reaction Parameters of 3
+
ꢀ
o
b
entry
solvent
base (equiv)
MeP(Ph)
3
Br
temp ( C)
6 (area %)
（
equiv）
1.5
1
2
3
THF
THF
tꢀBuOK (1.5)
tꢀBuONa (1.5)
tꢀBuOK (1.5)
0ꢀ10
0ꢀ10
0ꢀ10
98.6
98.3
98.2
1.5
toluene
1.5
6
ACS Paragon Plus Environment

Page 7 of 18
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
4
5
6
7
toluene
toluene
toluene
toluene
tꢀBuONa (1.5)
tꢀBuONa (1.1)
tꢀBuONa (1.05)
tꢀBuONa (1.1)
1.5
1.1
0ꢀ10
0ꢀ10
98.4
98.6
96.5
98.7
1.05
1.1
0ꢀ10
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20ꢀ30
a
Conditions: 3 (500 mg scale), magnetic stirring. All reagents were charged followed
b
by a nitrogen purge. Determined by HPLC
The stability of intermediate 4 in an acidic environment was studied in order to take
appropriate workꢀup procedure. The results revealed that the impurities with
structures similar to 1A and 1B were obviously observed when pH was lower than 1.0
o
even at ꢀ10 C. The level of these impurities was reduced to less than 0.15%
o
(
calculated by area of chromatography) when pH was higher than 3.0 at 5ꢀ10 C and
the quality of the final product was unaffected.
Upon completion of the Wittig reaction monitored by HPLC, the reaction mixture
o
was quenched with water and 6N hydrochloric acid at 5ꢀ10 C. The separated organic
layer containing triphenylphosphine oxide was discarded, and the methylene
intermediate 4 was left in the aqueous phase as its hydrochloride form. Then the
aqueous phase was basified to pH = 9.5~10 by 20% NaOH solution and methylene
intermediate 4 was extracted back into the organic phase with toluene. This solution
of methylene intermediate 4 in toluene was directly used in the subsequent
Nꢀdebenzylation reaction.
NꢀDealkylation of tertiary amines via acylation using cloroformate has been well
7
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
0ꢀ13
reported and demonstrated many applications in organic synthesis,
as well as
14, 15
synthesis of Noromorphine and Loratadine.
The preferred reagent was ethyl
chloroformate, the most widely used reagent in this field. Fortunately, the methylene
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
intermediate 4 was smoothly transformed to amide 21 with ethyl chloroformate in the
16
presence of catalytic quantity sodium carbonate (entry 1, Table 2). Then, the
reaction temperature, time and the equivalent of ethyl chloroformate were fully
o
investigated. As shown in Table 2, the optimal temperature range was 55ꢀ60 C. Lower
temperature obviously decreased the yield (entry 4), while higher temperature caused
more impurities (entry 3). The optimal equivalent of ethyl chloroformate was found to
be 1.1 equiv as lower equivalent led to incomplete conversion of methylene
intermediate 4 (entry 2). This Nꢀdebenzylation reaction generated an equivalent of
benzyl chloride, which could be collected and purified as a raw material.
Table 2 Optimization Results of the N-Debenzylation Reaction
o
b,c
c,d
entry
ClCO
2
Et
Na
2
CO
3
temp ( C)
time (h) conversion
(%)
15
(
equiv)
2.5
(equiv)
0.1
(area %)
92.5
1
2
3
4
5
85ꢀ90
85ꢀ90
85ꢀ90
35ꢀ40
55ꢀ60
1.5
8
99.7
93
1.02
1.1
0.1
83.6
0.1
3
99.6
82.3
99.7
95.7
1.1
0.1
10
4
81.5
1.1
0.1
97.8
a
Conditions: 4 (10g scale), magnetic stirring. All reagents were charged followed by a
b
c
d
nitrogen purge. Conversion was calculated from the HPLC area. Detected by HPLC.
8
ACS Paragon Plus Environment

Page 9 of 18
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
The amount of benzyl chloride generated in this reaction mixture was not calculated.
While the methylene intermediate 4 was consumed to less than 0.5% (monitored
by HPLC), water was charged to quench reaction and wash off the inorganic salts.
Then the separated organic phase was concentrated in vacuum to remove most of
toluene and a mixture of benzyl chloride and amide 21 was obtained. Because the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
boiling point of benzyl chloride is 35 C lower than amide 21 under reduced pressure
(2.6 kPa), the two could be separated by fractional distillation in vacuum. The benzyl
chloride was successfully distilled off and collected under reduced pressure (2.7 kPa)
at 95ꢀ110 °C while the amide 21 remained in the vessel. Experimental result
confirmed that the remaining amide 21 could be directly used in the following
hydrolysis reaction without extra purification procedure.
Normal hydrolysis conditions, such as NaOH/EtOHꢀH O, KOH/EtOH and
2
KOH/2ꢀpropanol only gave poor to moderate conversion of the amide 21 (table 3,
entry 1ꢀ4). But this reaction proceeded completely in ethylene glycol at 115 °C (entry
6), which indicated the reaction temperature was the key parameter. Increasing the
reaction temperature not only achieved higher conversion, but also shortened the
reaction time (entry 5 and 6). The quantity of NaOH could not be less than 3.0 equiv,
otherwise it led to incomplete conversion even if the reaction time was extended to 18
hours (entry 7). After the completion of hydrolysis reaction, the mixture of free base
of 4ꢀmethylenepiperidine 13 and byꢀproduct ethanol were distilled and collected from
the reaction mixture under reduced pressure (20 kPa). Based on the GC analysis result,
the collected mixture consisted of 71% 4ꢀmethylenepiperidine, 25% ethanol, 2%
9
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ethylene glycol as well as several unknown impurities.
a
Table 3. Screening Results of Hydrolysis Reaction of 21
o
b,c
entry
base (equiv.)
NaOH (3.0)
NaOH (6.0)
KOH (3.0)
KOH (3.0)
NaOH (3.0)
NaOH (3.0)
NaOH (2.5)
solvent
70% EtOHꢀH
70% EtOHꢀH
EtOH
temp ( C)
time (h)
20
conversion (%)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
2
O
O
80
26.3
81.6
83.5
86.7
94.8
100
2
80
20
80
20
2ꢀpropanol
85
20
Ethylene glycol
Ethylene glycol
Ethylene glycol
95
15
115
115
6
18
96.3
a
Conditions: 21 (500mg scale), magnetic stirring. All reagents were charged followed by nitrogen
b
purge. Conversion was determined from the HPLC area
Treatment of the above obtained crude 4ꢀmethylenepiperidine 13 with 20%
HCl/EtOH only afforded a small amount of precipitated solid but two liquid phases
were formed. Then water content of the different batches of material was determined
to be 5ꢀ7 % by Karl Fischer method. It was thought that this water was derived from
the reaction of ethylene glycol with NaOH. Therefore, water in the distillate needs to
be removed before proceeding with the hydrochloride salt formation.
Calcium oxide, as one of the most popular dehydrating reagents applied in alkaline
environments, was carefully tested. But water content was only decreased to 2ꢀ3%
from 5ꢀ7% even when increasing the amount of calcium oxide and raising
10
ACS Paragon Plus Environment

Page 11 of 18
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
dehydration temperature. Then azeotropic distillation was ready to be used to remove
water. Due to the low boiling point of 4ꢀMethylenepiperidine 13 (bp: 130−135 °C,
measured value), its hydrochloride had to be formed prior to azeotropic distillation.
The pH was adjusted to 6.0 ~ 6.2 using 20% HCl/EtOH monitored by a pH meter. In
order to prevent the formation of related impurities 1A and 1B shown in Scheme 1, it
must be ensured that no excess acid was charged. The water content was successfully
reduced to 0.35% using ethanol as coꢀzeotropic solvent and no other impurity was
formed.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
After the required water content was met (< 0.5%), isopropyl acetate was charged
with stirring and crystals of 4ꢀmethylenepiperidine hydrochloride 1 gradually
precipitated. The precipitated solid was filtered, rinsed by a solution of isopropyl
acetate and ethanol (10/1, v/v) and dried in vacuum to give the final product
4ꢀmethylenepiperidine hydrochloride 1 in a total yield of 83.5% with a purity of
99.9%.
In addition to the above discussed route, another route, starting from
Nꢀmethylpiperidinone 22, was also investigated (Scheme 7). NꢀMethylpiperidinone 22
15
is a readily available starting material of Loratadine and has better atom economy
than Nꢀbenzylpiperidinone 3. The first step Wittig reaction proceeded well using
similar condition with preparation of compound 4. After acidꢀbase switching workꢀup,
Nꢀmethylꢀ4ꢀmethylenepiperidine 23 was obtained as a solution in toluene. However,
in the subsequent Nꢀdemethylation step, 20ꢀ30% compound 23 remained even if 3
equiv of ethyl chloroformate were employed.
11
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 7. Route of Amide 21 from N-Methylpiperidinone 22.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Owing to the incomplete Nꢀdemethylation of compound 23, then demethylation of
NꢀMethylpiperidinone 22 was attempted (Scheme 8). Using 2.5 equiv of ethyl
chloroformate realized complete Nꢀdemethylation, but unfortunately a ring opened
impurity 25 with a level of 15ꢀ20% was detected. It is likely that this was formed via
elimination of the resulting quaternary ammonium chloride. A previous research
reported that the yield of a similar ring opened product reached 40ꢀ50% in the
17
presence of Hünig’s base. Although the current results (Scheme 7 and 8) were
unsatisfactory, the protocol was still regarded to be of great potential and will
continue to be studied.
Scheme 8. Alternative Route of amide 21 from N-Methylpiperidinone 22.
CONCLUSION
In summary, we have developed a robust process to prepare 4ꢀmethylenepiperidine
hydrochloride 1, starting from Nꢀbenzylpiperidinone 3 in four steps and an overall
yield of 83.5%. This process was successfully transferred to the pilot plant and was
utilized to manufacture more than 100 kg of 1 with >99.9 % purity (as determined by
12
ACS Paragon Plus Environment

Page 13 of 18
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
HPLC).
EXPERIMENTAL SECTION
General Procedures. All reactions were performed under a nitrogen atmosphere
using anhydrous techniques unless otherwise noted. All commercially available
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
material and solvents were used directly without further purification. H NMR (400
1
3
MHz) and C NMR (100 MHz) were recorded on a Bruker spectrometer with TMS
as internal standard. The mass spectra were determined on a THERMO LTQ (ESI) or
Agilent 5973 MSD (EI) spectrometer. HPLC method of 4ꢀmethylenepiperidine
hydrochloride 1: YMC Pack Pro C18 (3
mL/min; 30 °C; gradient elution from 95:5 A/B to 20:80 A/B over 30 min, where A =
O/acetonitrile/HClO = 95:5:0.2 and B = acetonitrile/H O = 85:15; UV detection at
ꢀm，4.6 mm × 250 mm); flowing rate = 1.0
H
2
4
2
210 nm.
N-Benzyl-4-methylenepiperidine (6)
To a 10 L fourꢀnecked flask was charged toluene (3.2 L), sodium tꢀbutoxide (448 g,
4.66 mol) and methyltriphenylphosphonium bromide (1736 g, 4.86 mol). After
stirring for 2h, Nꢀbenzylpiperidinone 3 (802g, 4.24 mol) was added at 20ꢀ30 °C
within 3h. The resulting mixture was stirred at the same temperature for 1h and
monitored by HPLC. Upon completion, the mixture was quenched with water (2.4 L)
and stirred for 0.5 h. The resulting phases were separated and aqueous phase was
discarded. To the organic layer was added 0.8kg water, then the pH was adjusted to
o
3ꢀ4 using 6N hydrochloric acid leaving product 4 into the aqueous phase at 0ꢀ5 C.
The aqueous phase was extracted with 1.5L toluene again and the combined organic
layer containing triphenylphosphine oxide was separated and discarded. The aqueous
phase was basified until pH = 9 ~ 10 using 20% sodium hydroxide solution. Then
1
3
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
olefin 4 was extracted with 2 L toluene and this extract was used directly in the next
step. For characterization, an aliquot of an equivalent solution obtained in the
laboratory was evaporated and purified by flash chromatography on silicaꢀgel
(nꢀheptane / EtOAc = 12:1) to give intermediate 4 as colorless oil after evaporation of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
solvents. H NMR (400 MHz, d ꢀDMSO) δ 7.21ꢀ7.32 (m, 5H), 4.64 (s, 2H), 3.46 (s,
6
1
3
2
6
H), 2.49 (t, J = 4.0 Hz, 4H), 2.29 (t, J = 4.0 Hz, 4H); C NMR (100 MHz, d ꢀDMSO)
δ 146.13, 138.50, 128.65, 128.08, 126.80, 107.87, 61.84, 54.26, 34.08. ESIꢀMS (m/z):
+
188.26 [M + H] .
Ethyl 4-methylenepiperidine-1-carboxylate (21)
To a 10 L fourꢀnecked flask was charged 4 as a solution in toluene from the
previous step and sodium carbonate (44.5 g, 0.42 mol). Ethyl chloroformate (504 g,
4
6
0
.64 mol) was dropped under stirring while maintaining the internal temp below
0 °C. The mixture was then stirred for another 6 h at 50~60 °C. Upon completion,
.5 kg water was charged and resulting aqueous phase was discarded. The separated
organic layer was concentrated to remove most of toluene under reduced pressure
(25ꢀ30 kPa) at 55ꢀ60 °C. Then benzyl chloride was distilled and collected under
reduced pressure (2.7 kPa) at 95ꢀ110 °C. The crude amide 21 remained in the vessel
as yellow oil (Caution: Benzyl chloride should be handled under good protection as it
is hazardous as well as irritating to eyes and skin).
. For characterization, an aliquot of an equivalent solution obtained in the
laboratory was evaporated and purified by flash chromatography on silicaꢀgel
1
(
nꢀheptane / EtOAc 12:1) to give 21 as colorless oil after evaporation of solvents. H
NMR (400 MHz, d ꢀDMSO) δ 4.76 (s, 2H), 4.03 (q, J = 8.0 Hz, 2H), 3.37 (t, J = 8.0
6
13
Hz, 4H), 2.12 (t, J = 8.0 Hz, 4H), 1.18 (t, J = 8.0 Hz, 3H); C NMR (100 MHz,
14
ACS Paragon Plus Environment

Page 15 of 18
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
d
6
ꢀDMSO) δ 154.47, 144.83, 109.37, 60.69, 44.81, 33.85, 14.54. ESIꢀMS (m/z):
+
170.15 [M + H] .
4-methylenepiperidine hydrochloride (1)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
To a 5 L threeꢀnecked flask was charged ethylene glycol (1.2 kg) and NaOH (504 g,
12.6 mol). The reaction mixture was then heated to 90ꢀ100 °C. Crude amide 21 from
the previous step was added during 1 hour with stirring at 90ꢀ100 °C. Then the
resulting mixture was stirred at 110ꢀ120 °C for 6ꢀ8 h until complete conversion
monitored by HPLC. The mixture was cooled 30ꢀ40 °C and the distillation was started
at this temperature range under reduced pressure (20 kPa). The distillation was
stopped until the temperature reached 95ꢀ100 °C. The collected crude
4ꢀmethylenepiperidine 13(608 g) was used directly in the next step.
To a 3 L threeꢀnecked flask was charged ethanol (500 g) and the above crude
ꢀmethylenepiperidine 13. Then 20% HCl/EtOH (768 g) was added below 20 °C to
4
make pH = 6.0ꢀ6.2. Then coꢀazeotropic distillation with ethanol was conducted until
water content was below 0.5%. Then isopropyl acetate (1.5 kg) was added and the
resulting slurry was held for 2 h at 0~5 °C. The precipitated solid was filtered and
rinsed with a solution of isopropyl acetate and ethanol (10/1, v/v, 300 g). The wet
cake was dried in vacuum at 35~40 °C for 10 hours to yield 472.8 g
1
4ꢀmethylenepiperidine hydrochloride 1 (83.5% total yield, 99.9% HPLC purity). H
NMR (400 MHz, DMSOꢀd ) δ 9.44 (s, 2H), 4.83 (s, 2H), 3.02 (q, J = 8.0 Hz, 4H),
6
13
2.58 (t, J = 8.0 Hz, 4H); C NMR (100 MHz, DMSOꢀd
6
) δ 141.07, 111.03, 44.13,
30.22. EIꢀMS (m/z): 97.
15
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Associated Content
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.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Corresponding Author
*
Address:
Tel:
+86ꢀ0991ꢀ3835679.
Fax:
+86ꢀ0991ꢀ3835679.
Eꢀmail:
haji@ms.xjb.ac.cn.
*
Address: Tel: +86ꢀ21ꢀ2023100ꢀ2407. Fax: +86ꢀ21ꢀ20231000ꢀ2407. Eꢀmail:
shenjingshan@simm.ac.cn
NOTES
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors wish to thank Topharman Shandong Ltd. for their helpful scaleꢀup
support.
REFERENCES
(
1) Patel, T.; Dhillon, S. Efinaconazole: First Global Approval. Drugs. 2013, 73,
1977–1983.
(
2) http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203567s000lbl.pdf
(3) Tatsumi, Y.; Nagashima, M.; Shibanushi, T.; Iwata, A.; Kangawa, Y.; Inui, F.; Jo
Siu, W. J.; Pillai, R.; Nishiyama, Y. Antimicrob. Agents Chemother. 2013, 57,
2
405ꢀ2409.
(
4) Mimura, M.; Hayashida, M.; Nomiyama, K.; Ikegami, S.; Iida, Y.; Tamura, M.;
Hiyama, Y.; Qhishi, Y. Chem. Pharm. Bull. 1993, 41, 1971ꢀ1986.
16
ACS Paragon Plus Environment

Page 17 of 18
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(
(
5) Cooper, J.; Duan, M.; Grimes, R.; Kazmierski, W.; Tallant, Matthew. U.S. Patent.
20100196321, 2010.
6) Ogura, H.; Kobayashi, H.; Nagai, K.; Nishida, T.; Naito, T.; Tatsumi, Y.; Yokoo,
M.; Arika, T. Chem. Pharm. Bull. 1999, 47, 1417ꢀ1425.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
(
7) Naito, T. WO Patent. 9711939, 1997.
8) Mimura, M.; Watanabe, M.; Ishiyama, N.; Yamada, T. U.S. Patent. 20130150586,
2
013.
(
(
(
9) Emanuele, A.; Elisabeth, R.; Davide, R. E.P. Patent. 3091007, 2016.
10) Cooley, J. H.; Evain, E. J. Synthesis. 1989. 1ꢀ7. And references cited therein.
11) Časar, Z.; Mesar, T. Org. Process Res. Dev. 2015, 19, 378−385
(12)Fan, X.; Zhang, H. S.; Chen, Li.; Long, Y. Q. Eur. J. Med. Chem. 2010, 45,
827–2840.
2
(13)Truong, P. M.; Hassan, S. A.; Lee, YꢀS.; Kopajtic, T. A.; Katz, J. L.; Chadderdon,
A. M.; Traynor, J. R.; Deschamps, J. R.; Jacobson, A. E.; Rice, K. C. Bioorganic
&
Medicinal Chemistry. 2017, 25, 2406–2422.
14)Montzka, T. A.; Matiskella, J. D.; Partyka, R. A. Tetrahedron Lett. 1974, 14,
325ꢀ1327.
(
1
(
(
15)Villani, F. J.; Wong, J. K. U.S. Patent 4659716, 1987.
16)He, P.; Sun, H.; Jian, XꢀX.; Chen, Q. H.; Chen, D. L.; Liu, G. T.; Wang, F. P. J
Asian Nat Prod Res, 2012 , 14, 6, 564 ꢀ 576.
(
17)Lévy, J.; Laronze, J. Y.; Sapi, J. Tetrahedron Lett. 1988, 29, 3303ꢀ3306.
17
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Organic Process Research & Development
Msc: op-2017-00350s
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The following graphic will be used for the TOC:
ACS Paragon Plus Environment