Synthesis of Tamibarotene via Ullmann-Type Coupling

Article abstract of DOI:10.1021/acs.oprd.7b00089

An effective process was developed for the preparation of tamibarotene via an Ullmann-type coupling in a nonpressurized l-proline/DMSO system. Notable features were the telescoping of reactions, avoiding environmentally hazardous materials, and an accepta

Full text of DOI:10.1021/acs.oprd.7b00089

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Full Paper
Synthesis of Tamibarotene via Ullmann-type Coupling
Xuefei Bao, Xuejun Qiao, Changshun Bao, Yuting Liu, Xuan Zhao, Yi Lu, and Guoliang Chen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00089 • Publication Date (Web): 12 Apr 2017
Downloaded from http://pubs.acs.org on April 12, 2017
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Synthesis of Tamibarotene via Ullmannꢀtype
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Coupling
Xuefei Bao, Xuejun Qiao, Changshun Bao, Yuting Liu, Xuan Zhao, Yi Lu, Guoliang Chen*
Key Laboratory of StructureꢀBased Drug Design & Discovery, Ministry of Education, Shenyang
Pharmaceutical University, Shenyang 110016, China
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Table of Contents Graphic and Synopsis:
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ABSTRACT: An effective process was developed for the preparation of Tamibaroten via an
Ullmannꢀtype coupling in nonꢀpressurized Lꢀproline/DMSO system. Notable features were
telescoping of reactions, avoiding environmentally hazardous materials and acceptable overall
yield. The safe scalable process was validated on 1 kg scale.
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KEYWORDS: Tamibarotene, Synthesis, Ullmannꢀtype coupling, retinoic acid receptor alpha
agonists
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INTRODUCTION
Tamibarotene (1, Figure. 1), a small molecule retinoic acid receptor alpha (RARα) agonists
developed by Nippon Shinyaku, was approved in Japan for the treatment of acute promyelocytic
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leukemia (APL) in 2005. Recently, the drug was in clinical development for the treatment of
acute myeloid leukemia (AML), myelodysplasia, pediatric solid tumor and steroidꢀrefractory
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chronic graftꢀversusꢀhost disease. Besides antiꢀcancer, other bioactivities were reported, such as
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the treatment of Alzheimer’s Disease, preventing periodontitis and reducing the effects of aging.
Figure 1. The chemical structure of tamibarotene(1).
Several synthetic methods had been reported for the preparation of 1 (Scheme 1). Initially,
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Kagechika et al. disclosed Route A for its synthesis in the early stage of drug discovery. In this
process, benzene was used as starting material to provide 1 via a fiveꢀstep process with 17% total
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yield. Sun and Bian et al. also prepared 1 based on route A. The method suffered from long
synthetic procedure, low yield and laborious workups. Besides, toxic benzene and nitration
reaction were environmentally hazardous. Hamada et al. developed Route B to obtain 1 from Nꢀ
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phenylꢀacetamide via three steps process with total yield of 39ꢀ23%. The method, producing
gram scale 1 in a single batch, had two drawbacks, limiting the largeꢀscale synthesis of 1: (a)
complicated purification process, (b) the employment of excessive environmentally unfriendly
phosphorus pentachloride. Chen et al. reported Route C to prepare 1 based on route B and the
key improvement in this procedure was bringing condensation forward to FriedelꢀCrafts
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reaction. Recently, several palladiumꢀcatalyzed methods (Route D) were reported for the
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preparation of 1, [ C] tamibarotene or [ C] tamibarotene, and subꢀgram scale 1 could be
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obtained via these methods. But expensive palladium catalysts were employed and industrialꢀ
scale starting material was not commercially available. In this report, we discuss our attempts to
develop a safe scalable process for the synthesis of tamibarotene.
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Scheme 1. Reported Synthetic Route of Tamibarotene
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RESULTS AND DISCUSSION
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Initially, our study was focused on the optimization of Route B and Route C, however, the
FriedelꢀCrafts reaction of Nꢀphenylꢀamide always yielded a complex mixture of products which
had to be further purified by column chromatography to provide a small amount of target
compound. Encouraged by the fact that copper has been used as an effective catalyst for the
useful and practical formation of C(aryl)–N bond, and such copperꢀmediated coupling reactions
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have numerous industrial applications, we adopted Ullmannꢀtype coupling to prepare the key
intermediate 3. The alternative synthetic route of 1, from commercially available 6ꢀbromoꢀ
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,2,3,4ꢀtetrahydroꢀ1,1,4,4ꢀtetramethylꢀ naphthalene 2, involved Ullmannꢀtype coupling,
condensation of 3 and terephthalic acid monomethyl ester and hydrolysis of ester. (Scheme 2).
Scheme 2. Alternative Synthetic Route of Tamibarotene
1
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According to previous report on Ullmannꢀtype coupling, in a hydrothermal synthesis reactor,
a mixture of 2 (7.5 mmol), cuprous chloride (0.7 mmol) and copper powder (1.5 mmol) in
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aqueous ammonia (sp. gr. 0.91, 20 mL) was stirred at 190 C (about 700 psi) for 15 h, providing
an acceptable yield (72%) of the desired product 3 (Table 1, entry 1). However, the copperꢀ
mediated Ullmann reaction suffered from its required harsh reaction conditions: high
temperature and high pressure. Unfortunately, when lowering the temperature, a remarkable
decrease of yield was observed (entries 2ꢀ3). Although the reaction with incremental amount of
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cuprous chloride afforded a higher yield, high temperature was still indispensable for the
amination reaction (entries 3ꢀ5). Among various copper sources investigated, cuprous iodide was
the most efficient, but also proved to be inefficient at a slighter low temperature (entries 5ꢀ9).
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entry
Cu (equiv)
Cu(I) (equiv)
temp.( C)
Product (%, area)
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0.2
0.2
0.2
0.2
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ꢀ
CuCl (0.1)
CuCl (0.1)
CuCl (0.1)
CuCl (0.2)
CuCl (0.2)
190
120
160
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160
120
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120
120
97
ꢀ
63
ꢀ
96
ꢀ
CuCl (0.2)
2
ꢀ
CuBr (0.2)
ꢀ
ꢀ
Cu O (0.2)
ꢀ
2
ꢀ
CuI (0.2)
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a
Reaction condition: 2 (7.5 mmol), aqueous ammonia (10 mL), stirred in a hydrothermal synthesis
b
reactor. Percentage of 3 in the reaction mixture, determined by HPLC analysis.
We postulated that the poor results might be due to the poor solubility of 2 in aqueous
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ammonia, and encouraged by Buchwald’s report on the Cuꢀcatalyzed Nꢀarylation of imidazoles
using poly (ethylene glycol) (PEG) as a solid–liquid phaseꢀtransfer catalyst (PTC). We tested
PTC in several experiments, such as PEGꢀ400, tetraꢀnꢀbutylꢀammonium bromide (TBAB) and
18ꢀcrownꢀ6, but the addition of 0.2 equiv PTC did not provide an acceptable result. On the other
hand, when the reactions were carried out under the same conditions with the exception of
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different coꢀsolvents, such as isopropanol, dimethylformamide (DMF), dimethylsulfoxide
(DMSO) and dioxane, with aqueous ammonia, the coupling process was still ineffective.
Recent progress in Ullmannꢀtype coupling has led to the emergence of several protocols
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utilizing ligands to achieve efficiency at moderate reaction temperatures. We first screened two
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reported ligands, ethylene glycol and Lꢀproline, as they were commercially available in large
quantities and inexpensive. As shown in Table 2, ethylene glycol was an ineffective ligand for
the amination reaction, and even though a large amount of ethylene glycol was employed as coꢀ
solvent, the conversion of our coupling reaction was still low (entries 1ꢀ3). Ma’s Lꢀproline
turned out to be an acceptable ligand, and in different solvents other than DMSO, efficiency of
the coupling was decreased significantly (entries 4ꢀ8). The slighter high temperature and
appropriate base were essential (entries 9ꢀ11). Besides, several reports demonstrated that PEG
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could facilitate the Ullmannꢀtype coupling without ligand, so we tested PEGꢀ400 in several
experiments. Unfortunately, the reaction did not take place in PEGꢀ400 when performed without
ligand, and the efficiency of this method was still unsatisfactory when it was used in combination
with Lꢀproline (entries 12ꢀ14). Merck Research Laboratories discovered that ethylene glycol was
1
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the best solvent for amination reaction with moderate pressure. When ethylene glycol was
employed as solvent, the Ullmannꢀtype coupling gave a moderate conversion (entry 15).
a
Table 2. Effects of Ligands on Ullmannꢀtype Coupling
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b
entry
ligand(equiv)
base (equiv)
Na PO (2)
solvent
temp.( C) Product (%, area)
1
2
ethylene glycol (2)
ethylene glycol (2)
isopropanol
nꢀbutanol
120
120
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ꢀ
3
4
Na PO (2)
3
4
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c
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ethylene glycol
Lꢀproline (0.4)
Lꢀproline (0.2)
Lꢀproline (0.4)
Lꢀproline (0.4)
Lꢀproline (0.4)
Lꢀproline (0.4)
Lꢀproline (0.4)
Lꢀproline (0.4)
ꢀ
Na PO (2)
ꢀ
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ꢀ
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K CO (3)
DMSO
DMSO
1,4ꢀdioxane
DMF
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K CO (3)
2 3
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K CO (3)
3
3
K CO (3)
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3
K CO (3)
ꢀ
2
3
K CO (3)
DMSO
DMSO
DMSO
PEGꢀ400
PEGꢀ400
PEGꢀ400
2
3
1
0
1
2
Na PO (3)
3 4
1
1
CsCO (3)
3
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Na PO (3)
3
4
Lꢀproline (0.4)
Lꢀproline (0.4)
K CO (3)
3 3
1
5
K CO (3) ethylene glycol
3 3
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Reaction condition: 2 (7.5 mmol), cuprous iodide (1.5 mmol), aqueous ammonia (10 mL),
solvent (10 mL), stirred in a hydrothermal synthesis reactor.
Percentage of 3 in the reaction mixture, determined by HPLC analysis.
b
c
Ethylene glycol (10 mL) was employed as coꢀsolvent.
Though cuprous iodide was effective in DMSO when it was used in combination with Lꢀ
proline, the reaction temperature was still beyond desired safety range. In general, water was
unfavorable to Ullmannꢀtype coupling, and when aqueous ammonia as starting material reacted
under high temperature, pressure vessel was indispensable which could increase the equipment
cost and safety risk. So we focused on ammonium chloride, an ammonia source without water
reacting in a nonꢀpressure vessel (Table 3). We observed that the reaction proceeded at 100 °C
to give naphthalenamine 3 in 91% conversion (entry 1). Further lowering the reaction
temperature to 80 °C, no satisfactory result was obtained, indicating that reaction temperature
was critical factor of this transformation (entries 2ꢀ7).
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a
Table 3. Optimization of the Ullmann reaction
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entry
base (equiv)
K CO (3)
solvent
temp.( C)
Product (%, area)
1
2
3
4
5
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7
DMSO
ethylene glycol
DMSO
100
100
80
91
25
67
36
13
41
48
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3
K CO (3)
2
3
K CO (3)
2
3
Na PO (3)
DMSO
80
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4
Na PO (3)
ethylene glycol
DMF
80
3
4
Na PO (3)
80
3
4
K CO (3)
DMF
80
2
3
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Reaction condition: 2 (7.5 mmol), ammonia chloride (4 mmol), cuprous iodide (1.5 mmol),
solvent(15 mL), stirred in a nonꢀpressure vessel.
b
Percentage of 3 in the reaction mixture, determined by HPLC analysis.
With an acceptable route to key intermediate 3 in hand, the remainder of the twoꢀstage
procedure was the condensation of 3 and terephthalic acid monomethyl ester, and a hydrolysis
reaction. Several issues needed to be addressed with the condensationꢀhydrolysis step in order to
develop a route suitable for further scaleꢀup.
Considering the cost of coupling agents, the condensation of 3 and terephthalic acid
monomethyl ester (TAME) had initially been performed using dicyclohexylcarbodiimide (DCC),
but filtration of the voluminous N,N’ꢀdicyclohexylurea (DCU) byproduct was unattractive on
scale. We sought further alternatives and were interested in the precedented process via an acyl
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chloride intermediate. Though thionyl chloride and oxalyl chloride are common chloride
reagent, the latter is generally preferred because of the facile removal and mild reaction
conditions. And the minor increase in cost was traded off for a process that would be less
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environmental pollution. After solvent screen, dichloromethane, methyltetrahydrofuran and ethyl
acetate proved to be efficient, but we focused on ethyl acetate as moving away from a
chlorinated solvent reduced the cost of waste stream disposal and working with an organic upper
phase made the aqueous wash sequence quicker to operate in plant. Crude amide 4 was obtained
as a solution in ethyl acetate with acceptable purity. When the solution was carried forward
directly, it would require a biphasic hydrolysis, and the process was carried out by adding TBAB
as a phase transfer catalyst. Unfortunately, amide hydrolysis occurred in ethyl acetate/ sodium
hydroxide (aq) biphasic system. The undesired hydrolysis of 4 was presumably due to the
increased solubility of carboxylate in strong basic sodium hydroxide (aq). A variety of bases
were investigated, but to no avail. Finally, tamibarotene was obtained via the hydrolysis in
ethanol/ sodium hydroxide (aq) system. (Scheme 3).
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Scheme 3. Synthesis of Tamibarotene from 3
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clean, dry reactor
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distillation (30 C)
distillat
distillat
TAME
ethyl acetate
EtOH
DMF
oxalyl chloride
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20% aq NaOH
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hydrolysis (60 C)
EtOH
M aq H SO4
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chlorination (60 C)
5
2
acidify to pH 2
o
distillation (30 C)
water
water
distillat
distillat
ethyl acetate
filtration
filtrate
o
cooled to 10 C
aqueous wash
2
ꢀnaphthalenamine 3
dry
triethylamine
ethyl acetate
nꢀhexane
condensation (ambient temperature)
1
M aq HCl
aqueous wash
aqueous wash
aqueous wash
recrystallization
water
1
0% aq Na CO
2 3
Tamibarotene
To validate the largeꢀscale applicability of this method, all two synthetic steps were performed
in triplicate on 1.0 kg scale. The reaction progresses were monitored by TLC. The results of
scaleꢀup batches are presented in Table 4.
Table 4. Results of scaleꢀup batches
a
b
entry
batch size (Kg)
output (Kg)
0.569
yield(%)
HPLC purity (%, area)
Step 1: Ullmannꢀtype coupling
1.0
1
75
99.5
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0.556
0.578
73
76
99.7
99.5
Step 2: Condensation ꢀ hydrolysis
0
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0
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1.07
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99.7
99.7
99.6
a
b
Isolated yield. % area by HPLC.
CONCLUSION
In conclusion, we provided an alternative scalable method for the production of tamibarotene,
validated on 1 kg scale. The key step in this twoꢀstage process was the conversion of 6ꢀbromoꢀ
naphthalene 2 to 2ꢀnaphthalenamine 3 via a safe nonꢀpressurized Ullmannꢀtype coupling, and the
advantages of the method were telescoped process and acceptable total yield.
EXPERIMENTAL SECTION
General. All of the starting materials, reagents and solvents are commercially available and
used without further purification. Melting points were determined with a Xꢀ4 apparatus and were
uncorrected. The nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Ascend
4
00 (Billerica, MA, USA) using tetramethylsilane (TMS) as an internal standard. Electrospray
ionization mass spectrometry (ESIꢀMS) analyses was recorded in an Agilent 1100 Series MSD
Trap SL (Santa Clara, CA, USA). The reactions were monitored by thinꢀlayer chromatography
(
TLC; HG/T2354ꢀ92, GF254). The purity of tamibarotene and key intermediate 3 was
determined by HPLC using a Shimadzu LCꢀ20A series instrument. The HPLC analysis data was
reported in relative area % and was not adjusted to weight %.
Preparation of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenamine (3).
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Anhydrous potassium carbonate powder (1.55 Kg, 11.2 mol, 3 eq) was added to a solution of
bromide 2 (1 Kg, 3.7 mol, 1 eq) and Lꢀprodine (172 g, 1.5 mol, 0.4 eq) in DMSO (7.5 L), and the
mixture were sparged with N (g) for 30 min. After the addition of cuprous iodide (142 g, 0.7
2
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mol, 0.2 eq) and ammonium chloride (0.5 Kg 15.0 mol, 4 eq), the reaction mixture was heated to
100 °C and stirred for 37 h until the reaction was deemed complete by TLC analysis. The
reaction mixture was cooled to below 30 °C and treated with toluene (12 L) and aqueous
ammonia (sp. gr. 0.91, 12 L). The layers were separated, and the lower aqueous phase was
extracted with toluene (6 L). The organic phases were combined, washed with aqueous ammonia
(sp. gr. 0.91, 6 L), and then extracted with 2 M HCl (aq) (6 L, ×3). The aqueous phase was
combined, basified to pH 10 with 20% sodium hydroxide, and steam distilled. When the
distillate was cooled, the amine crystallized and collected by filtration. The solid amine was
dissolved in ethyl acetate (2 L), dried over anhydrous calcium chloride, filtered, and concentrated
under vacuum (30 °C) to a volume of 1 L. The mixture was heated to 55 °C, and nꢀhexane (4.5
L) was added at 50−55 °C over 2 h. The slurry was cooled to 20 °C and stirred overnight. After
filtration, filter cake was washed with nꢀhexane (500 mL, ×3) and dried in vacuum to give offꢀ
4
1
white solid naphthalenamine 3 (569 g, 75%). Mp 68ꢀ70 °C (lit. Mp 73 °C); HꢀNMR (600 MHz,
Chloroformꢀd) δ 7.12 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 2.5 Hz, 1H), 6.58 (dd, J = 8.3, 2.5 Hz,
+
1
H), 4.25 (s, 2H), 1.65 (s, 4H), 1.25 (s, 6H), 1.23 (s, 6H); MS (ESI) m/z: 204.3 [M + H] .
Preparation
of
4-(((5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino)
carbonyl)benzoic acid, Tamibarotene (1).
To a slurry of terephthalic acid monomethyl ester (931 g, 5.2 mol, 1.05 eq) in ethyl acetate (5
L) was added DMF (75 mL, 0.2 equiv) followed by initiating stirring. After 30 min of stirring at
ambient temperature, oxalyl chloride (500 mL, 5.9 mol, 1.10 equiv) was charged while
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maintaining the temperature below 30 °C, then the mixture was stirred at 60 °C for 8 h. After the
completion of the reaction monitored by TLC, excess oxalyl chloride was purged by
distillation/replacement of ethyl acetate (2.5 L ×2) until the amount of distillate was about 7 L.
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The remnant (about 3 L) was cooled to 10 °C followed by the addition of 5,6,7,8ꢀtetrahydroꢀ
5,5,8,8ꢀtetramethylꢀ2ꢀnaphthalenamine (3) (1 kg, 4.9 mol, 1.0 equiv) in ethyl acetate (2 L) over
40 min while maintaining the temperature below 20 °C, and then triethylamine (1 L, 7.4 mol,
1.5 equiv) was charged such that the internal temperature remains below 20 °C. Upon complete
addition, the mixture stirred at ambient temperature for 3.5 h. When the reaction was deemed to
be complete with no 3 detected by TLC, 1 M Hydrochloric acid (2.4 L) was charged to the slurry
followed by 30 min of agitation. The heavy aqueous phase was disposed of followed by washing
the organic layer with water (2.5 L), and 10% sodium bicarbonate (aq) (2.5 L ×2). Once
washing was complete, the organic phase was concentrated to a volume of 500 mL, then ethanol
(6 L) was added and the mixture was concentrated again until the amount of remnant was about
4
L. The solution was cooled to ambient temperature and 40% sodium hydroxide (aq) (2 L) was
added. The reaction mixture was stirred at 60 °C for 3 h until hydrolysis of the ester was
complete by TLC analysis. The mixture was diluted with ethanol (2 L) and the pH was
cautiously adjusted to 2 by addition of 5 M sulfuric acid (about 1.53 L). Then the mixture was
o
diluted with water (2.2 L) at 45ꢀ50 C, slowly cooled down to ambient temperature and stirred
for an additional 4 h. The formed precipitate was isolated by filtration, and washed with water
(300 mL × 3). The product was dried in vacuum to give the product as a white crystalline solid.
4
1
(
1.37 Kg, 79%). Mp 223ꢀ225 °C (lit. Mp 231ꢀ232 °C); H NMR (400 MHz, Chloroformꢀd) δ 8.22
(
d, J = 7.7 Hz, 2H), 7.97 (d, J = 7.7 Hz, 2H), 7.80 (s, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.33 (d, J
ꢀ
= 8.3 Hz, 1H), 1.70 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H); MS (ESI) m/z: 350.0 [M ꢀ H] .
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The crude 1 (1.37 Kg ) was dissolved in ethyl acetate (4.1 L) at 50 °C, and nꢀhexane (2.7 L)
was then added over 2 h while keeping the temperature at 45ꢀ50 °C. After the addition, the
reaction mixture was then cooled to ambient temperature and stirred overnight. The crystals were
filtered and the cake was washed with nꢀhexane (680 mL×2) and dried in vacuum to afford a
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white solid (1.12 Kg, 82%) with a purity of 99.7% (relative area) by HPLC.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the ACS Publications website at
DOI: XXXXXXXXXX.
1
HPLC information with chromatogram and H NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: guoliang222@gmail.com
Present Addresses
Shenyang Pharmaceutical University, NO.103, Wenhua Road, Shenyang, P. R. CHINA.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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This work was financially supported by Liaoning Provincial Natural Science Foundation of
China (No. 201602707) and Discipline Construction Program of Shenyang Pharmaceutical
University (No. 52134606).
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