Synthesis of Tamibarotene via Ullmann-Type Coupling - Organic

Subscriber access provided by UB + Fachbibliothek Chemie | (FU-Bibliothekssystem)

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

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 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Organic Process Research & Development

Synthesis of Tamibarotene via Ullmann-type Coupling Xuefei Bao, Xuejun Qiao, Changshun Bao, Yuting Liu, Xuan Zhao, Yi Lu, Guoliang Chen* Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China

1 Environment ACS Paragon Plus


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Table of Contents Graphic and Synopsis:


Page 2 of 20

Page 3 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ABSTRACT: An effective process was developed for the preparation of Tamibaroten via an Ullmann-type coupling in non-pressurized L-proline/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.

KEYWORDS: Tamibarotene, Synthesis, Ullmann-type coupling, retinoic acid receptor alpha agonists



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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 leukemia (APL) in 2005.1 Recently, the drug was in clinical development for the treatment of acute myeloid leukemia (AML), myelodysplasia, pediatric solid tumor and steroid-refractory chronic graft-versus-host disease.2 Besides anti-cancer, other bioactivities were reported, such as the treatment of Alzheimer’s Disease, preventing periodontitis and reducing the effects of aging.3

Figure 1. The chemical structure of tamibarotene(1). Several synthetic methods had been reported for the preparation of 1 (Scheme 1). Initially, Kagechika et al. disclosed Route A for its synthesis in the early stage of drug discovery.4 In this process, benzene was used as starting material to provide 1 via a five-step process with 17% total yield. Sun and Bian et al. also prepared 1 based on route A.5 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 Nphenyl-acetamide via three steps process with total yield of 39-23%.6 The method, producing gram scale 1 in a single batch, had two drawbacks, limiting the large-scale 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 Friedel-Crafts reaction.7 Recently, several palladium-catalyzed methods (Route D) were reported for the


Page 4 of 20

Page 5 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


preparation of 1, [11C] tamibarotene or [13C] tamibarotene, and sub-gram scale 1 could be obtained via these methods.8 But expensive palladium catalysts were employed and industrialscale starting material was not commercially available. In this report, we discuss our attempts to develop a safe scalable process for the synthesis of tamibarotene. Scheme 1. Reported Synthetic Route of Tamibarotene



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Page 6 of 20

Page 7 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


RESULTS AND DISCUSSION Initially, our study was focused on the optimization of Route B and Route C, however, the Friedel-Crafts reaction of N-phenyl-amide 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 copper-mediated coupling reactions have numerous industrial applications,9 we adopted Ullmann-type coupling to prepare the key intermediate 3. The alternative synthetic route of 1, from commercially available 6-bromo1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-

naphthalene

2,

involved

Ullmann-type

coupling,

condensation of 3 and terephthalic acid monomethyl ester and hydrolysis of ester. (Scheme 2). Scheme 2. Alternative Synthetic Route of Tamibarotene

According to previous report on Ullmann-type coupling,10 in a hydrothermal synthesis reactor, a mixture of 2 (7.5 mmol), cuprous chloride (0.7 mmol) and copper powder (1.5 mmol) in aqueous ammonia (sp. gr. 0.91, 20 mL) was stirred at 190 oC (about 700 psi) for 15 h, providing an acceptable yield (72%) of the desired product 3 (Table 1, entry 1). However, the coppermediated 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 2-3). Although the reaction with incremental amount of



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 20

cuprous chloride afforded a higher yield, high temperature was still indispensable for the amination reaction (entries 3-5). Among various copper sources investigated, cuprous iodide was the most efficient, but also proved to be inefficient at a slighter low temperature (entries 5-9). Table 1. Optimization of the Ullmann-type coupling a

a

entry

Cu (equiv)

Cu(I) (equiv)

temp.(oC)

Product (%, area)b

1

0.2

CuCl (0.1)

190

97

2

0.2

CuCl (0.1)

120

-

3

0.2

CuCl (0.1)

160

63

4

0.2

CuCl (0.2)

120

-

5

0.2

CuCl (0.2)

160

96

6

-

CuCl2 (0.2)

120

-

7

-

CuBr (0.2)

120

-

8

-

Cu2O (0.2)

120

-

9

-

CuI (0.2)

120

12

Reaction condition: 2 (7.5 mmol), aqueous ammonia (10 mL), stirred in a hydrothermal synthesis reactor. bPercentage 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 ammonia, and encouraged by Buchwald’s report11 on the Cu-catalyzed N-arylation of imidazoles using poly (ethylene glycol) (PEG) as a solid–liquid phase-transfer catalyst (PTC). We tested PTC in several experiments, such as PEG-400, tetra-n-butyl-ammonium bromide (TBAB) and 18-crown-6, 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


Page 9 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


different co-solvents, such as isopropanol, dimethylformamide (DMF), dimethylsulfoxide (DMSO) and dioxane, with aqueous ammonia, the coupling process was still ineffective. Recent progress in Ullmann-type coupling has led to the emergence of several protocols utilizing ligands to achieve efficiency at moderate reaction temperatures.12 We first screened two reported ligands,13 ethylene glycol and L-proline, 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 cosolvent, the conversion of our coupling reaction was still low (entries 1-3). Ma’s L-proline turned out to be an acceptable ligand, and in different solvents other than DMSO, efficiency of the coupling was decreased significantly (entries 4-8). The slighter high temperature and appropriate base were essential (entries 9-11). Besides, several reports demonstrated that PEG could facilitate the Ullmann-type coupling without ligand,14 so we tested PEG-400 in several experiments. Unfortunately, the reaction did not take place in PEG-400 when performed without ligand, and the efficiency of this method was still unsatisfactory when it was used in combination with L-proline (entries 12-14). Merck Research Laboratories discovered that ethylene glycol was the best solvent for amination reaction with moderate pressure.15 When ethylene glycol was employed as solvent, the Ullmann-type coupling gave a moderate conversion (entry 15). Table 2. Effects of Ligands on Ullmann-type Coupling a

entry

ligand(equiv)

base (equiv)

solvent

temp.(oC)

Product (%, area)b

1

ethylene glycol (2)

Na3PO4 (2)

isopropanol

120

-

2

ethylene glycol (2)

Na3PO4 (2)

n-butanol

120

-



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 20

3c

ethylene glycol

Na3PO4 (2)

-

120

35

4

L-proline (0.4)

K2CO3 (3)

DMSO

120

92

5

L-proline (0.2)

K2CO3 (3)

DMSO

120

57

6

L-proline (0.4)

K3CO3 (3)

1,4-dioxane

120

-

7

L-proline (0.4)

K2CO3 (3)

DMF

120

31

8

L-proline (0.4)

K2CO3 (3)

-

120

22

9

L-proline (0.4)

K2CO3 (3)

DMSO

100

43

10

L-proline (0.4)

Na3PO4 (3)

DMSO

100

24

11

L-proline (0.4)

CsCO3(3)

DMSO

100

29

12

-

-

PEG-400

120

26

13

-

Na3PO4 (3)

PEG-400

120

33

14

L-proline (0.4)

K3CO3 (3)

PEG-400

120

61

15

L-proline (0.4)

K3CO3 (3)

ethylene glycol

120

59

a

Reaction condition: 2 (7.5 mmol), cuprous iodide (1.5 mmol), aqueous ammonia (10 mL), solvent (10 mL), stirred in a hydrothermal synthesis reactor. b Percentage of 3 in the reaction mixture, determined by HPLC analysis. c Ethylene glycol (10 mL) was employed as co-solvent. Though cuprous iodide was effective in DMSO when it was used in combination with Lproline, the reaction temperature was still beyond desired safety range. In general, water was unfavorable to Ullmann-type 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 non-pressure 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 2-7).


Page 11 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 3. Optimization of the Ullmann reaction a

entry

base (equiv)

solvent

temp.(oC)

Product (%, area)b

1

K2CO3 (3)

DMSO

100

91

2

K2CO3 (3)

ethylene glycol

100

25

3

K2CO3 (3)

DMSO

80

67

4

Na3PO4 (3)

DMSO

80

36

5

Na3PO4 (3)

ethylene glycol

80

13

6

Na3PO4 (3)

DMF

80

41

7

K2CO3 (3)

DMF

80

48

a

Reaction condition: 2 (7.5 mmol), ammonia chloride (4 mmol), cuprous iodide (1.5 mmol), solvent(15 mL), stirred in a non-pressure 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 two-stage procedure was the condensation of 3 and terephthalic acid monomethyl ester, and a hydrolysis reaction. Several issues needed to be addressed with the condensation-hydrolysis step in order to develop a route suitable for further scale-up. 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 chloride intermediate.16 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



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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). Scheme 3. Synthesis of Tamibarotene from 3


Page 12 of 20

Page 13 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


clean, dry reactor distillation (30 oC) TAME ethyl acetate DMF oxalyl chloride

distillat e distillat e

EtOH 20% aq NaOH

hydrolysis (60 oC) chlorination (60 oC)

EtOH 5M aq H2SO4 acidify to pH 2

distillation (30 oC)

water

distillat ethyl acetate e distillat e cooled to 10 oC

filtration filtrate water aqueous wash

2-naphthalenamine 3 triethylamine

dry ethyl acetate

condensation (ambient temperature)

n-hexane

1M aq HCl

aqueous wash

recrystallization

water aqueous wash 10% aq Na2CO3

aqueous wash

Tamibarotene

To validate the large-scale 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 scale-up batches are presented in Table 4. Table 4. Results of scale-up batches entry

batch size (Kg)

output (Kg)

yield(%)a

HPLC purity (%, area)b

0.569

75

99.5

Step 1: Ullmann-type coupling 1

1.0



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 20

2

1.0

0.556

73

99.7

3

1.0

0.578

76

99.5

Step 2: Condensation - hydrolysis

a

1

1.0

1.12

65

99.7

2

1.0

1.10

64

99.7

3

1.0

1.07

62

99.6

Isolated yield. b % 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 two-stage process was the conversion of 6-bromonaphthalene 2 to 2-naphthalenamine 3 via a safe non-pressurized Ullmann-type 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 X-4 apparatus and were uncorrected. The nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Ascend 400 (Billerica, MA, USA) using tetramethylsilane (TMS) as an internal standard. Electrospray ionization mass spectrometry (ESI-MS) analyses was recorded in an Agilent 1100 Series MSD Trap SL (Santa Clara, CA, USA). The reactions were monitored by thin-layer chromatography (TLC; HG/T2354-92, GF254). The purity of tamibarotene and key intermediate 3 was determined by HPLC using a Shimadzu LC-20A 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).


Page 15 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 L-prodine (172 g, 1.5 mol, 0.4 eq) in DMSO (7.5 L), and the mixture were sparged with N2(g) for 30 min. After the addition of cuprous iodide (142 g, 0.7 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 n-hexane (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 n-hexane (500 mL, ×3) and dried in vacuum to give offwhite solid naphthalenamine 3 (569 g, 75%). Mp 68-70 °C (lit.4 Mp 73 °C); 1H-NMR (600 MHz, Chloroform-d) 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, 1H), 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



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 20

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. The remnant (about 3 L) was cooled to 10 °C followed by the addition of 5,6,7,8-tetrahydro5,5,8,8-tetramethyl-2-naphthalenamine (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 diluted with water (2.2 L) at 45-50 oC, 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. (1.37 Kg, 79%). Mp 223-225 °C (lit.4 Mp 231-232 °C); 1H NMR (400 MHz, Chloroform-d) 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] -.


Page 17 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The crude 1 (1.37 Kg ) was dissolved in ethyl acetate (4.1 L) at 50 °C, and n-hexane (2.7 L) was then added over 2 h while keeping the temperature at 45-50 °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 n-hexane (680 mL×2) and dried in vacuum to afford a 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. HPLC information with chromatogram and1H NMR spectra (PDF) AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] Present Addresses Shenyang Pharmaceutical University, NO.103, Wenhua Road, Shenyang, P. R. CHINA. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 20

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). REFERENCES (1) Thomson reuters, integrity [EB/OL] https://integrity.thomson-pharma.com/integrity/xmlxsl/ pk_prod_list.exec_form_pro_pr?p_par_pro=PRO_DRUG_NAME&p_val_pro=Tamibarotene&p _origen=PROD&p_oper_pro=AND&p_par_tar=&p_val_tar=&p_oper_tar=AND&p_par_ref=& p_val_ref=&p_oper_ref=AND&p_par_pat=&p_val_pat=&p_oper_pat=AND#1, 2017-1-18. (2) (a) National Institutes of Health [EB/OL] https://clinicaltrials.gov/ct2/results?term= Tamibarotene&Search=Search, 2017-1-18. (b) Maeda, Y.; Nishimori, H.; Inamoto, Y.; Nakamae, H.; Sawa, M.; Mori, Y.; Ohashi, K.; Fujiwara S.; Tanimoto M. Acta Med. Okayama, 2016, 70, 409. (c) Sanford,D.; Lo-Coco, F.; Sanz, M. A.; Di Bona, E.; Coutre, S.; Altman, J. K.; Wetzler, M.; Allen, S. L.; Ravandi, F.; Kantarjian, H.; Cortes, J. E. Brit. J. Haematol., 2015, 171, 471. (3) (a) Kawahara, K.; Suenobu, M.; Ohtsuka, H.; Kuniyasu, A.; Sugimoto, Y.; Nakagomi, M.; Fukasawac, H.; Shudoc, K.; Nakayama, H. J. Alzheimers Dis., 2014, 42, 587. (b) Habchi, J.; Chia, S.; Limbocker, R.; Mannini, B.; Ahn, M.; Perni, M.; Hansson, O.; Arosio, P.; Kumita, J. R.; Kumar Challa, P.; Cohen, S. I. A.; Linse, S.; Dobson, C. M.; Knowles, T. P. J.; Vendruscolo, M. Proc Natl Acad Sci USA., 2017, 114, E200. (c) Jin, Y.; Wang, L.; Liu, D.; Lin, X. Int Immunopharmacol., 2014, 23, 537. (d) Durrani, M. J. Topical compositions for reducing the effects of aging. US Patent 2016000674 A1, 7, Jan, 2016.


Page 19 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(4) Kagechika, H.; Kawachi, E.; Hashimoto, Y.; Himi, T.; Shudo, K. J. Med. Chem., 1988, 31, 2182. (5) (a) Sun, Y.; Xu, L.; Xu, P.; Yuan, H.; Shen, R. Tamibarotene-cinnamic hydroxamic acid derivative as histone deacetylase inhibitor and its preparation, pharmaceutical compositions and use in the treatment of cancer. Faming Zhuanli Shenqing, 103073451,01 May 2013. (b) Bian, H.; Xu, W. Zhongguo Yiyao Gongye Zazhi, 2009, 40, 9. (6) (a)Hamada, Y.; Yamada, I.; Uenaka, M.; Sakata, T. Preparation of 4-[(5,6,7,8-tetrahydro5,6,8,8-terramethyl-2-naphthalenyl)carbamoyl]benzoic acid

derivatives.

PCT

Int.

Appl.,

9114673, 03 Oct 1991. (b) Xiao, J.; Luo, L.; He, S. Zhongguo Yaowu Huaxue Zazhi, 2009, 19, 268. (c) Zhao, M.; Zang, C.; Cai, S.; Jiang, Z.; Huang, J.; Zhang, D. Yaoxue Shijian Zazhi, 2012, 30, 287. (7) (a) Chen, G.; Wang, H. New process for preparation of Tamibarotene. Faming Zhuanli Shenqing, 101121675, 13 Feb 2008. (b) Guo, X. Method for synthesizing tamibarotene. Faming Zhuanli Shenqing, 102633673, 15 Aug 2012. (8) (a) Takashima-Hirano, M.; Ishii, H.; Suzuki M. ACS Med. Chem. Lett., 2012, 3, 804. (b) Fang, W.; Deng, Q.; Xu, M.; Tu, T. Org. Lett., 2013, 15, 3678. (c) Friis, S. D.; Andersen, T. L.; Skrydstrup, T. Org. Lett., 2013, 15, 1378. (9) (a) Evano, G.; Blanchard, N. Copper-Mediated Cross-Coupling Reactions, Wiley-VCH, 2013. (b) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev., 2008, 108, 3054. (c) Graham, J. P.; Langlade, N.; Northall, J. M.; Roberts, A. J.; Whitehead, A. J. Org. Process Res. Dev., 2011, 15, 44. (d) Duan, S.; Venkatraman, S.; Hong, X.; Huang, K.; Ulysse, L.; Mobele, B. I.; Smith, A.; Lawless, L.; Locke, A.; Garigipati, R. Org. Process Res. Dev., 2012, 16, 1787. (10) Wisansky, W. A.; Ansbacher, S. Organic Syntheses, 1955, 3, 307.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 20

(11) Altman, R. A.; Buchwald, S. L. Org. Lett., 2006, 8, 2779. (12) (a)Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed., 2009, 48, 6954. (b) Wang, Y.; Zeng, J.; Cui, X. Chinese J. Org. Chem., 2010, 30, 181. (c) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc., 2006, 128, 8742. (d) Yang, B.; Mao, Z. X.; Zhu, X. H.; Wan, Y.Q. Catal. Commun., 2015, 60, 92. (e) Tang, J.; Xu, B.; Mao, X.; Yang, H.; Wang X.; Lv, X. J. Org. Chem., 2015, 80, 11108. (f) Zhou, W.; Fan, M.; Yin, J.; Jiang Y.; Ma, D.; J. Am. Chem. Soc., 2015, 137, 11942. (13) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett., 2002, 4, 581. (b) Jiang,L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74, 4542. (c) Kim, J.; Chang, S. Chem. Commun., 2008, 44, 3052. (14) (a) Jung, H. S.; Yun, T.; Cho, Y.; Jeon, H. B. Tetrahedron, 2016, 72, 5988. (b) Chen, J.; Yuan, T.; Hao, W.; Cai, M. Tetrahedron Lett., 2011, 52, 3710. (15) Lang, F.; Zewge, D.; Houpis, I. N.; Volante, R. P. Tetrahedron Lett., 2001, 42, 3251. (16) (a) Eisenbeis,A. S.; Chen, R.; Kang, M.; Barrila, M.; Buzon, R. Org. Process Res. Dev., 2015, 19, 244. (b) Kuroda, K.; Tsuyumine, S.; Kodama, T. Org. Process Res. Dev., 2016, 20, 1053.


Synthesis of Tamibarotene via Ullmann-Type Coupling - Organic

Recommend Documents