Synthesis of Trelagliptin Succinate - Organic Process Research

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Synthesis of trelagliptin succinate Shenghui Xu, Qun Hao, Hongyan Li, Zhenren Liu, and weicheng zhou Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00013 • Publication Date (Web): 09 Mar 2017 Downloaded from http://pubs.acs.org on March 9, 2017

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Organic Process Research & Development

Synthesis of trelagliptin succinate Shenghui Xu, Qun Hao, Hongyan Li, Zhenren Liu and Weicheng Zhou* *Telephone: +86 21 20572198. E-mail: [email protected]. State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, State Institute of Pharmaceutical Industry, Shanghai 201203, China

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ABSTRACT An improved process for the synthesis of antidiabetic drug trelagliptin succinate through unprotected (R)-3-aminopiperidine was described. The impurity profile with different conditions of the key substitution was illustrated, and then the best reaction condition was identified. The optimizations also included the bromination of 4-fluoro-2-methylbenzonitrile so that the process became efficient and concise. KEYWORDS Trelagliptin; synthetic process; impurity; substitution. INTRODUCTION Trelagliptin succinate (1), a novel once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor, was approved for the Japanese market on March 26th 2015.1,2 Trelagliptin exhibited better potency against human DPP-4 than alogliptin and sitagliptin, along with its excellent selectivity and slow-binding property that may partially contribute to its sustained efficacy.3 In phase Ⅲ clinical studies, once-weekly oral trelagliptin provided long-term safety and efficacy in both monotherapy and combination with other antidiabetic medicines, and was proved to be non-inferior to its analogue alogliptin used once daily.4,5 For its unique therapeutic efficiency and promising market prospect, the synthesis has attracted much attention. The original company route (Scheme 1, in blue)6 was started from 4-fluoro-2-methylbenzonitrile (2), which was brominated to yield the desired compound 2-bromomethyl-4-fluorobenzonitrile (3) and the dibromide 3’, then the dibromide was converted to compound 3 in the presence of diethyl phosphite.7,8 The condensation of compound 3 with 3-methyl-6-chlorouracil (6) gave the key intermediate 4, then unprotected (R)-3-aminopiperidine (7) was introduced to compound 4 by nucleophilic substitution to form trelagliptin. Among the synthesis, the nucleophilic substitution is the key step in order to get the high regioselectivity. To avoid formation of the regio-isomer 8, Zhang et al. reported the substitution of compound 4 with (R)-3-N-protected-aminopiperidine in 2016,9,10 however, the following deprotection step may produce additional impurities resulting from the cyano-hydrolysis. In this paper, the improved synthesis of trelagliptin succinate based on the original company route was reported (Scheme 1, in red). Several conditions of the nucleophilic substitution were screened, and the impurity profile with reaction conditions was also elucidated. In addition, optimizations have been made in other steps to make the process efficient and concise.

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In Blue: the original route In Red: this paper’s route

Scheme 1.

Synthesis of trelagliptin succinate

RESULTS AND DISCUSSION In the reported literature on the bromination,6 compound 2 was reacted with one equivalent of 1,3-dibromo-5,5-dimethylhydantoin (DBH) in 1,2-dichloroethane (DCE) and the dibromide 3’ was obtained as the main product. Then 3’ was converted to the desired compound 3 in the presence of two equivalents of diethyl phosphite and one equivalent of diisopropylethylamine (DIPEA). In this paper, the ratio of N-bromosuccinimide (NBS) and compound 2 was set at 1.5, and the Class 1 solvent11 DCE was replaced by chloroform or dichloromethane. The outcome indicated that dichloromethane was a better solvent since less starting material remained. When a lower ratio of NBS was used, the result was unsatisfactory (Table 1). Then, since the dibromide contributed only ca. 50% in the product, 0.5 equivalents of diethyl phosphite and 0.2 equivalents of DIPEA was found to be adequate for complete conversion of 3’ into 3. Because the small amount of residual compound 2 did not affect the next reaction, compound 3, without further purification, was reacted with 3-methyl-6-chlorouracil (6) in the presence of DIPEA to obtain 4 (77.9% yield, based on 2).

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Table 1. Condition for bromination of compound 2. Entry Solventa 1 2 3

chloroform dichloromethane dichloromethane

NBS(eq) Time (h)

Composition of the productb 2

3

3'

1.5 1.5

16 24

6.69% 3.47%

57.83% 47.76%

34.14% 48.77%

1.3

24

16.11%

59.70%

22.80%

a

All reactions were refluxed under the protection of nitrogen.

b

Determined by HPLC.

The following nucleophilic substitution is the key step in the whole scheme and the by-products from this reaction will make up most of the impurity profile of the drug. The possible by-products include the regio-isomer 8, the di-pyrimidine compound 9 and the di-piperidine compound 10. In addition, if the reaction is carried out in protic solvents (MeOH, EtOH, i-PrOH) or DMF, some by-products such as 11a-11d may be formed. So, before preparation of trelagliptin, these seven compounds were prepared as shown in Scheme 2. With these substances in hand, HPLC methods were established for monitoring the key nucleophilic substitution (Table 2).

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F

F HN O H3C

N

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H3C

n-BuOH

N

O

O

TBA

CN NH2 2 HCl

Cl

CN

N

N NH N H 8 yield: 26.3 %

O

F F O

HN O H3C

N

N

N

IPA

N

O

H3C

DIPEA

CN

Boc HN

O H3C O

N

N

HN

O

Boc

HCl

CN

N

O H3C

EtOH

N

H N

N

O

Cl

N

H2N

O H3C

DMSO

CH3 O yield: 21.5 %

N

N H

NaHCO3

CN

N N

9

F

F

H N

N

O

NH2 2 HCl

Cl

NC

CN

Boc

N

N

NH2

10 F

O N

N

O

12 F

H3C

CN

K2CO3

CN

MeOH

N

O

O H3C

Cl

O

N

CN N OCH3

F

11a

F EtONa

O H3C

N

CN N

O

H3C

iPrONa Cl

N

O

11b: R=OEt 11c: R=O-iPr

R F

O N

N

O

F

H3C

CN

O

or

CN

K2CO3

NHMe2 HCl

DMF

N Cl

O H3C

N

O

CN N NMe2

11d

Scheme 2 Synthesis of compound 8~11. Table 2. The Related retention time of the substances in HPLC. HPLC Method b

Method 1 c Method 2

4 2.06 1.69

5 1 1

Relative retention timea 8 9 10 11a 11b 0.83 2.48 0.45 / / 0.83 1.78 0.45 1.53 1.66

a

11c 2.32 1.78

11d / 1.57

relative to trelagliptin which appeared at ca. 15.2 min both in method 1 and in method 2. HPLC methods can be found in the experimental section. b HPLC method for monitoring the reaction in isopropanol. c HPLC method for monitoring the reaction in other solvents.

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Table 3. Conditions for the synthesis of trelagliptin. Entrya 1

a

Scaleb

T

Solven

(g)

(°C)

t

5

40

DMF

Base

Yieldc

Composition of the crude product by HPLC (%)

(%)

4

5

8

9

10

11

Unknown

NaHCO3

72.1

0.46

71.31

n.d

6.47

n.d

7.30

14.46

2

5

50

THF

NaHCO3

97.4

0.67

90.47

0.31

4.09

1.7

n.d

2.76

3

5

65

MeOH

NaHCO3

92.3

0.08

76.99

0.51

0.97

1.43

16.00

4.02

4

5

65

EtOH

NaHCO3

96.0

0.16

94.36

0.58

2.84

0.66

0.41

0.99

d

0.03

5

5

65

i-PrOH

NaHCO3

98.6

n.d

94.86

0.69

1.91

1.38

6

5

65

t-BuOH

NaHCO3

95.2

n.dd

94.86

0.56

2.03

1.55

1.13

7

5

65

i-PrOH

K2CO3

91.1

0.03

94.94

0.53

0.73

1.45

0.73

8

5

65

i-PrOH

DIPEA

90.6

0.24

90.39

0.11

7.40

0.09

0.06

1.71

9

80

65

i-PrOH

NaHCO3

99.1

0.06

94.71

0.38

2.70

0.53

n.d

1.62

1.00

All reactions were carried out in the presence of 1.1 equivalents of compound 7.

b

Scale of compound 4. Yield for crude product after washing by water. d not detected To investigate the nucleophilic substitution, the feed ratio of (R)-3-aminopiperidine was set at 1.1 while different solvents and bases were screened. At the beginning, sodium bicarbonate was chosen as base. In general, an aprotic c

solvent was the recommended solvent for nucleophilic substitution, but when the reaction was run in DMF (Table 3, entry 1), the yield of the crude product was poor (72.1%) and the by-products included not only the dimethylamino compound 11d (7.3%) but also the di-pyrimidine compound 9 (6.5%), together with 14.5% of unknown impurities. When THF was used, the result was improved greatly although another impurity (compound 10) was found (1.7%). As far as the protic solvents are concerned, ethanol was the reported solvent for the reaction.1,9 In this paper, it was found that when the steric hindrance of the solvent increased, the amount of the by-product (11) from the solvents decreased (entries 3-5). Methanol was too active to be the solvent, whereas iso-propyl alcohol was found to be the best, giving the desired 5 with 94.9% purity in the crude product (98.6% of yield) and 11c was almost negligible. Although tert-butyl alcohol gave a similar result to iso-propyl alcohol (entry 6), it has the disadvantage of being solid at low temperature. For the screening of the base, potassium carbonate gave a higher content of 11c, and to our surprise, the organic base DIPEA resulted in compound 9 as the main impurity (7.4%, entry 8). Finally, the reaction was scaled up according to the condition in entry 5, and a similar outcome was obtained (entry 9). Since the crude product had a purity of > 94%, the purification was easier than the reported procedure. Trelagliptin was purified as the hydrochloride, converted to the free base and isolated as the succinate.6 In our process, trelagliptin succinate was 7


1.59


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formed by mixing crude 5 and succinic acid in iso-propyl alcohol, and then recrystallized with a mixture of iso-propyl alcohol and water (9:1) in a purity of 99.93%. CONCLUSION In summary, an efficient and concise synthetic process of trelagliptin succinate (in a purity of 99.93%) via unprotected (R)-3-aminopiperidine was described with a total yield of 61% from 2. The by-products formed in different conditions in the nucleophilic substitution were elucidated. In addition, only three kinds of organic solvents (CH2Cl2, THF, i-PrOH) were used in the whole process including reactions and recrystallization, avoiding the Class 1 solvent 1,2-dichloroethane. EXPERIMENTAL SECTION Melting points were determined on a capillary melting point apparatus and were uncorrected. Solvents and reagents were obtained from commercial sources and used without further purification. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance Ⅲ 400-MHz instrument with tetramethylsilane (TMS) as an internal standard. Mass spectra were recorded with a Q-TOF mass spectrometer by electrospray ionization (ESI). Both HPLC methods were conducted on a Waters ACQUITY Arc using an Agilent Eclipse plus C18 column (4.6 mm × 250 mm, 5 µm) with acetonitrile−ammonium acetate aqueous solution (10 mM) as the mobile phase, 1 mL/min at 40 °C with detection at 235 nm. Acetonitrile content for method 1: 15% (0 min); 18% (15 min); 30% (20 min); 40% (40 min); acetonitrile content for method 2: 15% (0 min); 18% (15 min); 40% (20 min); 55% (35 min). HPLC purity is reported in area %. 2-bromomethyl-4-fluorobenzonitrile (3). N-bromosuccinimide (98.78 g, 0.555 mol) and 2,2'-azobisisobutyronitrile (6.08 g, 0.037 mol) was added to a solution of 4-fluoro-2-methylbenzonitrile (50 g, 0.37 mol) in dichloromethane (250 mL). The slurry was refluxed for 24 h under an atmosphere of nitrogen, filtered and washed with dichloromethane (100 mL). The filtrate was cooled to 0 °C, then diethyl phosphite (25.55 g, 0.185 mol) and diisopropylethylamine (9.56 g, 0.074 mol) was added. The solution was stirred at 0 °C for 1 h and at room temperature for another hour. Potassium carbonate solution (125 mL, 0.2 g/mL) was added, and the organic phase was separated and washed with water (50 mL × 2). Then the solution was concentrated to dryness to give the raw product of 3 as a brown oil (109.5 g), which was used in the next reaction without any purification. 8


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2-{[6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]methyl}-4-fluoro benzonitrile (4). A solution of 2-bromomethyl-4-fluorobenzonitrile (109.5 g, from the above step) in THF (250 mL) was stirred while 3-methyl-6-chlorouracil (59.41 g, 0.37 mol) and DIPEA (52.60 g, 0.407 mol) was added at room temperature. After addition, the solution was stirred at 40 °C for 6 h, and then cooled to room temperature. Water (100 mL) was added to the solution and the reaction was stirred for 2 h. The solids were filtered, washed with isopropanol (70 mL × 3), and dried at 60 °C to afford the product 4 as a white solid (84.7 g, 77.9 % yield based on 2). Mp: 193-195 °C. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.74-7.76(m, 1H), 7.14-7.17 (m, 1H), 6.95-6.97 (m, 1H), 6.05 (s, 1H), 5.51 (s, 2H), 3.40 (s, 3H). 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2 H)-yl}methyl)-4-fluorobenzonitrile (5). To a solution of compound 4 (80 g, 0.272 mol) in isopropanol (800 mL) was added (R)-3-aminopiperidine dihydrochloride (51.86 g, 0.300 mol) and sodium bicarbonate (84.67 g, 1.01 mol) at room temperature. The reaction mixture was warmed to 65 °C and heated for 22 h. The solid was removed by filtration, and the filtrate was concentrated to dryness. The product was dissolved in dichloromethane (800 mL) and washed with water (270 mL × 3). The organic solvent was removed and the residue was dried at 60 °C to furnish title compound 5 as a yellow solid (96.47 g, 99.1 % yield), HPLC purity (area %): 94.71%. 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2 H)-yl}methyl)-4-fluorobenzonitrile monosuccinate (1). The crude product of 5 (96.47 g, 0.27 mol) in isopropanol (900 mL) was heated to 60 °C to get a clear solution, then succinic acid (38.26 g, 0.324 mol) was added and kept warm for 6 h. The solid was isolated by filtration and washed with isopropanol (300 mL), and then dried at 60 °C for 12 h to give a crude product of 1 (116.3 g, 90.6 % yield), HPLC purity (area %): 98.79%. Crude 1 (106 g) was added to a mixture of isopropanol (954 mL) and water (106 mL). When the mixture was heated to reflux, it became a clear solution, then activated charcoal (5.3 g) was added. After stirring for 1 h, the hot solution was filtered by Buchner funnel. The light yellow filtrate was cooled to room temperature and then the solid was isolated by filtration and washed with a mixture of isopropanol (106 mL) and water (11 mL). After drying at 60 °C for 12 h, the desired product 1 was obtained as a white solid (92.7 g, 87.5 % yield). Mp: 186-188 °C (187.1 °C in literature12), [α] 12 1 20 D =16.4 (c 1, DMSO, 16.7 in literature ), HPLC purity (area %): 99.93%. H NMR (400 MHz, CD3OD) δ (ppm):7.79-7.82 (m, 1H), 7.15-7.25 (m, 2H), 5.46 (s, 1H), 5.20-5.32 (m, 2H), 3.35-3.37 (m, 2H), 3.22 (s, 3H), 3.03-3.06 (m, 1H), 2.74-2.81 (m, 2H), 2.49 (s, 4H), 2.07-2.11 (m, 1H), 1.82-1.89 (m, 1H), 1.65-1.76 (m, 1H), 1.55-1.59 9



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(m, 1H). MS (ESI+): m/z, 358.24 ([M + H]+). Anal. (C22H26FN5O6) Calc: C, 55.57; H, 5.51; N, 14.73; found: C, 55.32; H, 5.46; N, 14.62. 2-({3-methyl-6-[(3R)-3-piperidinylamino]-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl}methyl)-4-fluorobenzonitrile (8) To a solution of compound 4 (5 g, 17 mmol) in n-butanol (200 mL) was added (R)-3-aminopiperidine dihydrochloride (3.24 g, 19 mmol) and tributylamine (11.68 g, 63 mmol) at room temperature, and the reaction mixture was refluxed for 10 h and then cooled to room temperature. Water was added to form azeotrope and the solvent was concentrated under reduced pressure to dryness. The residue was dissolved in dichloromethane (50 mL) and washed with water (20 mL × 3). The organic solvent was removed, and the residue was further purified by silica gel column chromatography (dichloromethane/ methanol = 5:1, Rf = 0.3) to give compound 8 (1.60 g, 26.3% yield). Mp: 90 °C decomposed. 1H NMR (400 MHz, CD3OD) δ (ppm):7.85-7.89 (m, 1H), 7.25-7.28 (m, 1H), 6.96-6.99 (m, 1H), 5.37-5.51 (m, 2H), 4.84 (s, 1H), 3.42-3.49 (m, 1H), 3.28 (s, 3H), 3.11-3.15 (m, 1H), 2.89-2.93 (m, 1H), 2.46-2.58 (m, 2H), 1.92-1.95 (m, 1H), 1.48-1.70 (m, 3H). MS (ESI+): m/z, 358.06 ([M + H]+). N1,N3-bis[1-(2-cyano-4-fluorobenzyl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin6(2H)-yl]-3-aminopiperidine (9). To a solution of compound 4 (2.5 g, 8.5 mmol) in isopropanol (30 mL) was added (R)-3-aminopiperidine dihydrochloride (1.03 g, 6 mmol) and DIPEA (2.5 g, 25 mmol) at room temperature. The reaction mixture was stirred at reflux for 24 h. Then the solution was cooled to room temperature, hydrochloric acid (0.5 M, 17 mL) was added and the solvent was removed by evaporation. The residue was dissolved in dichloromethane (30 mL), washed with water (30 mL × 3), and then the organic solvent was removed. The crude product was purified by column chromatography (dichloromethane/ methanol = 50:1) to obtain compound 9 as a yellow solid (0.56 g, 21.5% yield). Mp: 155-158 °C. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92-8.00 (m, 2H), 7.33-7.35 (m, 2H), 6.91-6.94 (m, 1H), 6.33-6.35 (d, 1H), 5.34 (s, 1H), 5.05-5.33 (m, 4H), 4.82 (s, 1H), 3.47-3.49 (m, 1H), 2.99-3.13 (m, 8H), 2.55-2.61 (m, 2H), 1.84-1.87 (m, 1H), 1.56-1.72 (m, 2H), 1.34-1.40 (m, 1H). (ESI+): m/z, 615.32 ([M + H]+). 1-{2-cyano-4-[(3R)-3-aminopiperidin-1-yl]benzyl}-3-methyl-6-[(3R)-3-aminopipe ridin-1-yl]-2,4-dioxo-3,4-dihydropyrimidine (10). Compound 4 (5 g, 17 mmol), (R)-3-Boc-aminopiperidine (8.86 g, 44 mmol), sodium bicarbonate (4.43 g, 53 mmol) and DMSO (25 mL) were charged into the reactor and stirred at 75 °C for 22 h. After cooling to room temperature, dichloromethane (90 mL) was added and the mixture was washed with water (40 mL × 6). The organic layer was concentrated to dryness. Toluene (40 mL) was added to the residue and refluxed until becoming a solution and then cooled to room temperature. The solid was isolated by filtration, washed with toluene, and dried at 80 °C to provide 12 as a yellow solid (7.65 g, 70.6 % yield). 10


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The solid in above step (3 g, 4.7 mmol) was dissolved in ethanol (30 mL), the solution was heated to 60 °C, then 12 M HCl (5 mL) was added and the mixture was stirred for 0.5 h. After adding 4 M NaOH (20 mL), the ethanol was distilled under vacuum. The residue in water was extracted with dichlromethane (20 mL × 3). The combined organic phases were washed with water (20 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to dryness to give a crude product of compound 10 as a yellow solid (1.32 g, 64.3 % yield). Compound 10 (1 g, 2.3 mmol) was dissolved in dichloromethane (10 mL), and succinic acid (0.30 g, 2.5 mmol) was added. After stirring for 12 h, the solid was isolated by filtration and washed with dichloromethane (5 mL) at room temperature, then dried at 60 °C to give a succinate of compound 10 (0.83 g, 65.0 % yield). Mp: 135-139 °C. 1H NMR (400 MHz, CD3OD) δ (ppm): 7.49-7.51 (d, 1H), 6.92-6.94 (m, 1H), 6.70-6.71 (d, 1H), 5.41 (s, 1H), 5.17-5.26 (m, 2H), 3.77-3.81 (m, 1H), 3.65-3.71 (m, 1H), 3.28 (s, 3H), 3.20-3.23 (m, 1H), 3.05-3.08 (m, 1H), 2.65-2.95 (m, 5H), 2.44-2.49 (m, 1H), 1.94-2.02 (m, 2H), 1.75-1.83 (m, 2H), 1.55-1.64 (m, 2H), 1.25-1.41 (m, 2H). MS (ESI+):m/z, 438.27 ([M + H]+). 2-{[6-methoxy-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]methyl}-4-fluo robenzonitrile (11a). Compound 4 (2 g, 6.8 mmol), potassium carbonate (3.54 g, 20.4 mmol) and methanol (25 mL) were charged into the reactor and stirred at 60 °C for 2 h. The solvent was then removed by evaporation, and the residue was dissolved in dichloromethane (20 mL) and washed with water (20 mL × 3). The organic solvent was removed and the product was dried at 50 °C to give compound 11a (1.76 g, 89.4 % yield). Mp: 157-159 °C. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.66-7.70 (m, 1H), 7.08-7.12 (m, 2H), 5.29 (s, 2H), 5.16 (s, 1H), 3.87 (s, 3H), 3.36 (s, 3H). MS (ESI+): m/z, 290.94 ([M + H]+). 2-{[6-ethoxy-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]methyl}-4-fluoro benzonitrile (11b). Sodium (0.31 g, 13.6 mmol) was added to ethanol (40 mL) at room temperature, and the mixture was stirred for 1 h until the sodium disappeared. Then compound 4 (2 g, 6.8 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The solution was concentrated to dryness, and then the residue was dissolved in dichloromethane (20 mL) and washed with water (20 mL × 3). The organic solvent was removed, and the residue was further purified by silica gel column chromatography to give compound 11b (1.56 g, 75.7 % yield). Mp: 166-168 °C. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.69-7.72 (m, 1H), 7.05-7.15 (m, 2H), 5.33 (s, 2H), 5.16 (s, 1H), 4.07-4.12 (q, 2H), 3.39 (s, 3H), 1.38-1.42 (t, 3H). MS (ESI+): m/z, 304.10 ([M + H]+). 2-{[6-isopropoxy-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]methyl}-4-fl uorobenzonitrile (11c). Sodium (0.2 g, 8.7 mmol) was added to isopropanol (10 mL) at room temperature, then heated to 35 °C until all of the sodium disappeared. 11



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Isopropanol was removed via rotary evaporation and acetonitrile (40 mL) was added to the residue. Compound 4 (2 g, 6.8 mmol) was added into the reactor at room temperature and the reaction was stirred for 10 min. The solution was concentrated to dryness, and the residue was dissolved in dichloromethane (20 mL) and washed with water (10 mL × 3). The organic solvent was removed via rotary evaporation. The residue was purified by column chromatography (dichloromethane/ methanol = 40:1) to obtain compound 10c as white solid (1.70 g, 78.9% yield). Mp: 108-110 °C. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.69-7.72 (m, 1H), 7.09-7.14 (m, 1H), 6.99-7.02 (m, 1H), 5.32 (s, 2H), 5.15 (s, 1H), 4.48-4.58 (sept, 1H), 3.39 (s, 3H), 1.30-1.32 (d, 6H). MS (ESI+): m/z, 318.08 ([M + H]+). 2-{[3-methyl-6-dimethylamino-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]methyl} -4-fluorobenzonitrile (11d). Compound 4 (2 g, 6.8 mmol), dimethylamine hydrochloride (0.61 g, 7.5mmol), potassium carbonate (2.82 g, 20.4 mmol) and DMF (20 mL) were charged into the reactor and stirred at room temperature for 10 h. Dichloromethane (90 mL) and water (40 ml) were added and the organic layer was washed with water (40 mL × 5). The organic layer was concentrated to dryness to give the title product as white solid (1.95 g, 94.7% yield). Mp: 141-143 °C. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.69-7.72 (m, 1H), 7.08-7.13 (m, 1H), 6.95-6.98 (m, 1H), 5.37 (s, 1H), 5.30 (s, 2H), 3.35 (s, 3H), 2.69 (s, 6H). MS (ESI+): m/z, 303.14 ([M + H]+). ASSOCIATED CONTENT Supporting Information. Spectral data for compounds 1, 4, 8, 9, 10, 11a, 11b, 11c and 11d, HPLC chromatograms REFERENCES (1) Zhang, Z.; Wallace, M. B.; Feng, J.; Stafford, J. A.; Skene, R. J.; Shi, L.; Lee, B.; Aertgeerts, K.; Jennings, A.; Xu, R.; Kassel, D. B.; Kaldor, S. W.; Navre, M.; Webb, D. R.; Gwaltney, S. L. J. Med. Chem. 2011, 54, 510-524. (2) Feng, J.; Gwaltney, S. L.; et al. Dipeptidyl Peptidase Inhibitors. PCT Int. Appl. WO 2005095381, October 13, 2005. (3) Grimshaw, C. E.; Jennings, A.; Kamran, R.; Ueno, H.; Nishigaki, N.; Kosaka, T.; Tani, A.; Sano, H.; Kinugawa, Y.; Koumura, E.; Shi, L.; Takeuchi, K. PLoS. One. 2016, 11, e0157509. (4) Inagaki, N.; Onouchi, H.; Maezawa, H.; Kuroda, S.; Kaku, K. Lancet. Diabetes. Endocrinol. 2015, 3, 191-197. (5) Inagaki, N.; Sano, H.; Seki, Y.; Kuroda, S.; Kaku, K. J. Diabetes. Investig. 2016, 7, 718-726. (6) Feng, J.; Gwaltney, S. L.; et al. Dipeptidyl Peptidase Inhibitors. PCT Int. Appl. WO 2007035629, March 29, 2007. 12


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(7) Liu, P.; Chen, Y.; Deng, J.; Tu, Y. Synthesis. 2001, 14, 2078-2080. (8) Le Corre, S. S.; Berchel, M.; Couthon-Gourvès, H.; Haelters, J.; Jaffrès, P. Beilstein J. Org. Chem. 2014, 10, 1166-1196. (9) Zhang, H.; Sun, L.; Zou. L.; Hui, W.; Liu, L.; Zou, Q.; Ouyang, P. J. Pharm. Biomed. Anal. 2016, 128, 18-27. (10) Zhang, X.; Zhang, K.; et al. Compound for Preparing Pyrimidinedione DPP-IV Inhibitors. China Patent. CN 103030631, April 10, 2013. (11) International Conference on Harmonisation (ICH). Q3C (R5), Impurities: guideline for residual solvents. February 2011. (12) https://www.takedamed.com/mcm/medicine/download.jsp?id=165&type=INTE RVIEW_FORM

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Synthesis of Trelagliptin Succinate - Organic Process Research

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