Efficient and Scalable Synthesis of Glucokinase Activator with a Chiral

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Efficient and Scalable Synthesis of Glucokinase Activator with a Chiral Thiophenyl-Pyrrolidine Scaffold Hiroki Fujieda, Koji Maeda, and Noriyasu Kato Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00354 • Publication Date (Web): 11 Dec 2018 Downloaded from http://pubs.acs.org on December 11, 2018

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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.

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Organic Process Research & Development

Efficient and Scalable Synthesis of Glucokinase Activator with a Chiral Thiophenyl-Pyrrolidine Scaffold Hiroki Fujieda,* Koji Maeda, and Noriyasu Kato

Sanwa Kagaku Kenkyusho Co., Ltd., 35 Higashisotobori-cho, Higashi-ku, Nagoya-shi, Aichi 461-8631, Japan

ACS Paragon Plus Environment

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Organic Process Research & Development 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

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TABLE OF CONTENTS GRAPHIC S

N N Boc

O

3 steps

O

O

S

N Boc

4 steps

HO

N

O HN

HCl HO

telescoped process 2

O including high-atom-economy process


1

S

O N

F

2

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ABSTRACT

Herein we describe the practical synthesis of a potent glucokinase activator (1) that has a chiral thiophenyl-pyrrolidine scaffold. The key to the successful synthesis was the application of a telescoped chiral-pool synthesis from a commercially available L-proline methyl ester derivative to introduce the chirality of the thiophenyl-pyrrolidine moiety. This second-generation synthesis of 1 provided several advantages over the previous method including an operational simplicity and avoidance of purification by column chromatography. The industrial relevance of this synthetic method in large-scale preparation was demonstrated by the production of 54.6 kg of 1 with an excellent chemical and optical purity.

KEYWORDS glucokinase activator; telescoped process; one-pot synthesis; thiophenyl-pyrrolidine scaffold


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INTRODUCTION Glucokinase (GK) is an enzyme that regulates the conversion of glucose to glucose 6phosphate and acts as a glucose sensor to maintain glucose homeostasis. The activation of GK in the pancreas enhances glucose-stimulated insulin release and in the liver, increases hepatic glucose utilization. Therefore the development of small-molecule glucokinase activators (GKAs) represents a promising approach to treat type 2 diabetes mellitus.1,2 As part of these efforts, compound 1, which possesses a chiral thiophenyl-pyrrolidine scaffold, has been identified as a potent GKA (Figure 1).3 Compound 1 shows a good GK activation potency with an appropriate distribution pattern in the liver and pancreas. Therefore, 1 has not only a good antihyperglycemic effect, but also low risk of the limitations that accompany other known GKAs.4,5 chiral thiophenylpyrrolidine scaffold N

S

O HO

N

O HN

HCl

S GKA 1

O N

N Boc

S

HO

O

key intermediate 2

F

Figure 1. Chemical structures of GKA 1 and key intermediate 2. Thiophenyl-pyrrolidine is a novel scaffold which has not been used previously as the basis of a drug candidate. As such, reports of its synthesis are limited. Our medicinal chemistry route to the synthesis of 1 had several problems: (1) a multi-step transformation (15 steps in total) that includes sequential protection/deprotection steps, (2) the need for multiple chromatographic purifications, and (3) a low overall yield (2%) mainly due to the difficulty of forming the chiral


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pyrrolidine ring.3 To evaluate 1 in a preclinical study, it is clear that the construction of a practical process appropriate for large-scale preparation is necessary. In this study we developed a new, concise second-generation synthetic method that reliably produced 1 on a kilogram scale. The practical preparation of GKA 1 hinges on the development of an effective synthetic method for key intermediate 2, which contains the chiral scaffold (Figure 1). The first-generation synthesis of 2 begins with the methylation of the thiophene ring of 3 under cryogenic conditions (−60 °C) (Scheme 1). Then, the methyl esterification of carboxylic acid 4 under acidic conditions, followed by bromination using NBS, gives bromide 6. The halogen-magnesium exchange reaction of 6 with iPrMgBr (iPr = isopropyl) and consecutive addition of N-Boc pyrrolidone (Boc = tert-butyloxycarbonyl) yields ketone 7. The Boc group of 7 is subsequently deprotected under acidic conditions, and the pyrrolidine ring is formed by intramolecular reductive amination. Racemate 8 is then optically resolved using the diastereomeric salt formation method with (−)dibenzoyl-L-tartaric acid. Boc-protection of pyrrolidine 10 and subsequent hydrolysis gives key intermediate 2. Because this route allows the preparation of a variety of derivatives such as those of ethyl thiophene and thiophenyl piperidine (both enantiomers), it is well suited for drug discovery. However, this route is far from practical in terms of large-scale preparation because it requires too many transformations to obtain 2, and the total yield is low mainly due to the optical resolution process. Optical resolution through diastereomeric salt formation has some drawbacks in practical synthetic processes. One of these is the generation of an undesired chiral isomer that must be discarded, resulting in a maximum yield of only 50%. Furthermore, after optical resolution the free base of the salt must be regenerated, and the secondary amino group must be protected for the installation of 2-amino-5-fluorothiazole in the next amidation step to accomplish the synthesis of GKA 1 (Figure 1).


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Scheme 1. Laboratory-scale synthesis of key intermediate 2 O S

HO

n-BuLi diisopropylamine

S THF

O

HO

3

Boc

O

Br

S

SOCl2

MeI

S

NBS

MeOH

O

O

DMF O

4

5

6

85%

96%

96%

THF

O

O

H N

S

O

O

TFA

NaBH3CN cHCl

CH2Cl2

iPrOH O

7 51%

sat.NaHCO3aq.

O

S

N H

Optica l O resolu tion

Ph HO

S

CHCl3 O 10

(Boc)2O Et3N O

CH2Cl2

O

O O

O

OH Ph

O

9 O 48% (of 50% th)

S

N Boc

S

N H

O

8 70%

N H

N Boc

iPrMgBr

O

LiOH O

THF MeOH

11

S

N Boc

HO

O

2 3 steps 94% Key intermediate

Our strategy to improve the efficiency of this synthesis was the formation of the thiophene ring from a starting material that already possesses a chiral pyrrolidine ring, in order to circumvent the problematic construction of the latter. Since the chiral carbon center of 2 has the same absolute configuration as natural L-proline, we decided to apply substrate-controlled synthesis using chiral-pool material 12, which is readily available as a starting material. Our devised approach is shown in Scheme 2. Key intermediate 2 can be prepared by hydrolysis of 13, whose thiophene core can be generated from diketoester 14 via Paal-Knorr thiophene synthesis.6,7 The ketoester of 14 can be introduced by adding methylacetoacetate to N-Boc haloacetyl pyrrolidine


6

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15, which can be synthesized by halomethylation of 12. Herein, we describe the optimization of each step toward establishing our approach as a practical synthetic method. Scheme 2. Second-generation retrosynthetic analysis for 2 Step 3 Paal-Knorr thiophene synthesis

Step 4 hydrolysis

S

N Boc

HO

S

N Boc

O

2

13

O R1

N Boc

O

O

O

O R1

14

Step 2

Step 1

alkylation

halomethylation N Boc

O

X O 15

O

N Boc

R2

O 12

RESULTS AND DISCUSSION Chiral-pool synthesis of key intermediate 2 Chloromethylation and alkylation (Steps 1 and 2) Different methods for the conversion of a carboxylic acid or ester to halomethyl carbonyl, such as the chloromethylation of ester with CH2ClI or ClCH2CO2Na and the bromomethylation of carboxylic acid via an azide intermediate, are found in literature.8,9,10 Considering safety and operational simplicity, the conversion of ester using t-BuMgCl and ClCH2CO2Na (Scheme 3) was chosen in this study for the synthesis of halomethyl carbonyl compound. Treating commercially available 16 with t-BuMgCl and ClCH2CO2Na in THF afforded chloroacetyl pyrrolidine 17 via a simple manipulation. Optimization of this method achieved 96% yield and 99% ee. After complete conversion, the reaction was quenched with aqueous citric acid solution,


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and the resulting mixture was washed with aqueous NaHCO3 solution, yielding 17 in adequate purity. The subsequent alkylation of 17 with methylacetoacetate was most successfully achieved using the mixed solvent of THF and DMF in the presence of KI and K2CO3. Under these conditions, 19 was obtained in 78% yield, although the generation of dehalogenated byproduct 20 was observed. The production of 20 was not affected by changing the amount of DMF in the mixed solvent, but suppressed by decreasing the amount of KI from 1 to 0.1 equiv. This was attributed to the reduced generation of iodide 18, from which 20 is believed to be derived. These optimized conditions afforded 19 in adequate purity, such that further purification by column chromatography was no longer required. Scheme 3. Chloromethylation using Grignard reagent and alkylation with methylacetoacetate

N Boc

O

1) t-BuMgCl ClCH2CO2Na Et3N, THF 2) aqueous citric acid solution

O

N Boc

Cl

methylacetoacetate K2CO3 KI THF/DMF

O 17 96%

16

N Boc

I O 18

O N Boc

O

O

19 83%

O

N Boc

O 20

Paal-Knorr thiophene synthesis and hydrolysis (Steps 3 and 4) The Paal-Knorr thiophene synthesis is a valuable synthetic method for the production of substituted thiophenes, although its application to large-scale preparation is challenging. A


8

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furanyl by-product was reported to be generated along with the desired thiophene product in this reaction.11 Therefore, the reaction conditions were first optimized to suppress the formation of furanyl by-product 22. The results from the screening are shown in Table 1. The Paal-Knorr thiophene synthesis of 19 using Lawesson’s reagent (LR) in THF yielded both 21 and 22 in a 7.4:1 ratio (Table 1, entry 1), which agrees with the study of Minetto et al.11 Notably, changing LR to other sulfating reagents, i.e., Davy reagent or P4S10 (Table 1, entries 2 and 3, respectively), did not improve the ratio. In contrast, diluting the concentration of 19 in the reaction mixture and increasing the reaction temperature were effective (Table 1, entries 1, 4, and 5). Increasing the proportion of the poorly soluble LR in solution by increasing dilution and increasing temperature was postulated to increase the selectivity for the thiophene. The conditions indicated in entry 5, which provided a 11.6:1 ratio of compounds 21 and 22, were therefore selected. Table 1. Paal-Knorr thiophene synthesis from 19. O N Boc

O

O

Sulfating Reagent THF

O

1

sulfating reagent LR

+ O

19

entry

S

N Boc

O

21

concentration

O

N Boc

O

O

22

temperature

12% (g/mL)

21:22 (HPLC area ratio) 7.4:1

25 °C

2

Davy Reagent Methyl

12% (g/mL)

1.9:1

25 °C

3

P4S10

4% (g/mL)

2.5:1

25 °C

4

LR

4% (g/mL)

9.6:1

25 °C

5

LR

4% (g/mL)

11.6:1

50 °C


9


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Unfortunately, the complete suppression of furan 22 was not accomplished in the condition screening. Furthermore, this step generated colored, malodorous substances (including those derived from LR), thereby necessitating chromatographic purification to obtain 21 in adequate purity. Our strategy to solve these problems was to conduct the formation of the thiophene ring and its subsequent hydrolysis in a one-pot process without isolating 21. Since the hydrolysis of 21 would lead to solid 2, the former could be purified by recrystallization without using column chromatography. Furthermore, the odor would be minimized since this one-pot procedure does not involve the removal of substances from the reactor after the thiophene synthesis. In addition to these benefits, by-passing the isolation of 21 would save time and costs. After the Paal-Knorr thiophene synthesis, the reaction mixture was washed with aqueous NaOH, diluted with MeOH, and hydrolyzed with aqueous NaOH. The resulting product, 2, was purified by extraction and solvent washing. This procedure enabled the removal of most of the LR-derived substances and avoided handling of malodorous intermediates. However, 2 still contained furanyl by-product 23, derived from 22. Since 2 was obtained as a solid, the recrystallization conditions for the purification of 2 were investigated. Solvent screening with MeOH, EtOH, iPrOH, and MeCN revealed that the purity of 2 was improved regardless of the solvent used. Considering the yield of 2, MeCN was chosen as the solvent for recrystallization. As a result, compound 2 was obtained in 52% yield with 99% purity without purification by column chromatography. In order to further improve the efficiency of the synthesis, a telescoped sequence from 16 to 2 was developed (Scheme 4). As described above, since the by-products generated in Steps 1 and 2 were minimal, the telescoped synthesis from 16 afforded 19 in adequate purity. We then focused our attention on the residual DMF and H2O in 19 that was prepared via this process because the


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presence of these solvents in the reaction mixture was found to affect the Paal-Knorr thiophene synthesis of 19. In the condition screening for Step 3, the use of DMF as a solvent caused a significant decrease in the reaction yield, while a water content of more than 0.3% was found to inhibit the progress of the reaction. To reduce the amount of residual DMF and H2O in 19, toluene was used as an extraction solvent. This allowed the use of 19 in the Paal-Knorr thiophene synthesis without additional manipulation to remove DMF and H2O. The one-pot procedure including this step and the subsequent hydrolysis of 21 provided compound 2 in adequate purity. Scheme 4. Telescoped synthesis from 16 to 2.

N Boc

Cl O

Methylacetoacetate K2CO3 KI THF/DMF

17

O N Boc

O

O 19

O

Lawesson's reagent THF

One-pot reaction

O NaO

Cl

t-BuMgCl Et3N

N Boc

5 N aq.NaOH

THF

O O 16

MeOH

Overall yield 45% 3-step telescoped reaction

N Boc

S

HO 2

N Boc O

O

HO

O

23 by-product (removed by recrystalization)

Consequently, the synthesis of 2 was optimized to a three-step telescoped process from readily available 16. This new route has multiple advantages over our initial one (Scheme 1), specifically the significantly reduced number of steps and simplified manipulation. Furthermore,


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this procedure increased the overall yield dramatically (13% versus 45%) and reduced the time required for the synthesis (Scheme 4).12 Practical synthesis of 1 from 2 Scheme 5. Medicinal Chemistry synthesis of 1 from 2 OH H 2N S

S

N Boc

S

N F Boc N,N-diethylaniline

(COCl)2 DMF toluene

HO

O

Boc N

N

CH2Cl2

HN

N

S

S

F

24

2

TFA

O

HN

O

S

N H

25

O

S

N

EDCI HOBt DIPEA

O

Boc N

DMF

HN

N

S

F

26 83%

58% 2 steps

TFA CH2Cl2

HN

O

S

N

O DIPEA

O HN

27 87%

S F

O

DMF

N

Cl

S

O

N

O HN

N

S 28 60%

O

4 N HCl in AcOEt

N

F

S

N

O

O

O HO

N

O HN

HCl N

F

S 1 99%

O N

F

With a new, efficient synthesis of 2 in place, all that remained to complete the synthesis of 1 was the introduction of 2-amino-5-fluorothiazole and N-ethyl-iminodiacetic acid. The medicinal chemistry synthesis of 1 is depicted in Scheme 5. Compound 1 was obtained from key intermediate 2 through a linear sequence of 6 steps. Coupling of 2 with 2-amino-5-fluorothiazole, followed by deprotection of the Boc group under acidic conditions, afforded pyrrolidine derivative 25. Condensation of 25 with N-Boc-N-ethyl glycine using 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (EDCI) as a condensation reagent gave 26. The Boc group in the terminal amino moiety of 26 was then removed via a treatment with TFA. The resulting amine, 27, was alkylated with t-butoxycarbonylmethyl chloride to afford ester 28. Deprotection


12

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of the t-butyl ester of 28 and formation of the HCl salt through treatment with 4 N HCl in AcOEt resulted in 1. Notably, this route is suitable for drug discovery because it allows the variation of both the moiety connecting thiophene carboxylic acid and the pyrrolidine of 2. However, the practical application of this route has several drawbacks that require improvement. N-Boc-Nethyl glycine is an expensive raw material and difficult to source on a large scale. In addition, using EDCI as a condensing reagent for large-scale synthesis is very costly. Furthermore, this route is a linear process that includes 6 steps and involves 2 chromatographic purifications. Our strategy to solve these problems was to apply convergent synthesis, as depicted in Scheme 6. Scheme 6. Second-generation retrosynthetic analysis for 1 from 2

N

S

HO

N

O HN

HCl

S 1

S

N H

O O

HN

N

S

F

S

N Boc O

HN

N

S

F

O HO

2

N

O

+

F

25

S

N Boc

H 2N

24 S

+

N

F

O

N O

N

COOH

HN

COOH

COOH

COOH

30

31

O 29

In this approach, the N-ethyl-iminodiacetic acid unit can be introduced through the coupling reaction of 25 with cyclic anhydride 29. Compound 25 can be prepared from Boc-protected pyrrolidine 24. Compound 24 can be prepared from the coupling reaction of 2 and 2-amino-5fluorothiazole. Anhydride 29 can be formed from N-ethyl-iminodiacetic acid 30, which will be derived from the inexpensive, easily available iminodiacetic acid, 31.


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The amidation of 2 with 2-amino-5-fluorothiazole was first optimized. Compound 2 was first transformed to the acid chloride by oxalyl chloride in the presence of DMF before the reaction with 2-amino-5-fluorothiazole. In this step, the main by-products were amide 32 and acidanhydride 33 (Figure 2). From the optimization study, by-product 33 was found to be purged in the work-up process. Therefore, condition screening was conducted to suppress the production of 32. The amount of 32 decreased dramatically by using cyclopentylmethylether (CPME) as the solvent for the preparation of acid chloride. The resulting acid chloride and 2-amino-5fluorothiazole were amidated in CPME/MeCN in the presence of pyridine. Figure 2. Chemical structures of main amidation by-products.

O F

S

NH

N

S

O HN

N

S 32

N Boc O

S

O

O

S

O

N 33

F

Boc

N

An effective means to introduce the N-ethyl-iminodiacetic acid unit was then investigated. Anhydride 29 was selected as an excellent precursor because its use would not require a protection-deprotection sequence. Furthermore, this represents an ideal method to introduce the N-ethyl-iminodiacetic acid unit from the viewpoint of atom economy.13–15 In practice, the reductive amino alkylation of 31 in the presence of a Pd catalyst under H2 atmosphere gave 30. In situ formation of cyclic anhydride 29 was conducted by adding trifluoroacetic anhydride (TFAA) to a solution of 30 in AcOEt. The resulting mixture was added to the AcOiPr solution of 25 derived from 24 to afford 34 (Scheme 7).


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Scheme 7. New convergent synthesis of 34 H 2N N

S S

N Boc

2

HO

(COCl)2 DMF CPME

O

F pyridine

S

N Boc

HN

CPME/MeCN

S 24 86%

HN

COOH

CH3CHO Pd/C

COOH 31

H 2O

N

COOH COOH

30 92%

O

N

S

O

conc. HCl HN

AcOiPr/H2O N

S 25 98%

F TFAA

S

N H

O

AcOiPr

HO

N

O

N

F

O

HN

N

S 34 71%

F

O

N O

AcOEt O 29

telescope

We have succeeded in optimizing our previous linear route from intermediate 2 to 1 to a convergent one. The new route has several advantages over the previous one, including operational simplicity, cheaper raw materials, and avoidance of purification by column chromatography. After constructing a synthetic process from 2 to 1, we developed a new practical route from 16 to 1. On the basis of the result of an optimization study, the large-scale synthesis of 1 was conducted according to Scheme 8. The main by-product of this process was the furan by-product derived from 23. Recrystallization of 2 was effective for purifying 2, which could reduce the amount of 23. Furthermore, slurry purification of 34 with MeOH was also effective for purifying 34. These treatments allowed strict control over the purity of 1. Starting with 150 kg of ester 16, the route gave 54.6 kg of 1 in 20% overall yield with an excellent optical purity.16


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Scheme 8. Large-scale synthesis of 1 1) t-BuMgCl ClCH2CO2Na Et3N, THF 2) aqueous citric acid solution

O

N Boc

N Boc

O

Cl

N Boc

THF/DMF

O

16

O

methylacetoacetate K2CO3, KI

17 97%

O

O

L.R. THF

O

S

N Boc

5 N aq. NaOH MeOH

2 O

19 73%

O

N Boc OH

OH

23 O

57%

H 2N S (COCl)2 DMF CPME

N

F pyridine

S

N Boc

S

24 82%

HN

COOH COOH

CH3CHO Pd/C H 2O

31

O

HN

CPME/MeCN

conc. HCl HN

AcOiPr/H2O N

S

25

F

N

COOH COOH

30 93%

F

S

O N

AcOiPr

HO

N

S

N

O

O

O HN

S 34 2 steps 65% F

O N

conc. HCl EtOH

O

N TFAA AcOEt

N

S

N H

HO

N

O

O

HN

HCl 1 94%

S

N

F

Overall yield 20% 7 steps

O O 29

CONCLUSIONS In this study, we developed an efficient and practical synthetic route to achieve the large-scale synthesis of a potent GKA, namely 1. The chirality of the thiophenyl-pyrrolidine scaffold was successfully introduced by a chiral-pool method using a cheap and readily available L-proline derivative. The N-ethyl-N-iminodiacetic acid unit was introduced via a cyclic acid anhydride intermediate, thus achieving high atom economy. Our work significantly simplified the manipulation of the original route, decreased the number of synthetic steps from 15 to 7, increased the reaction yield from approximately 2% to 20%, and removed all chromatographic purifications. Furthermore, in this method, the purity of 1 can be strictly controlled by recrystallization of intermediate 2 and slurry purification of 34. This synthesis was successfully scaled up to 54.6 kg, demonstrating the industrial relevance of this process.


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EXPERIMENTAL SECTION General. All reagents and solvents were commercially available and used without further purification. The 1H and 13C NMR spectra were recorded using a 400 MR spectrometer (Agilent Technologies, CA, USA) in the solvents indicated. Data are reported as follows: chemical shift in ppm () relative to tetramethylsilane, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, dd = doublet of doublets, td = triplet of doublets, br = broad, m = multiplet), coupling constant (Hz), and integration. Infrared spectra were recorded on a FT/IR4200 spectrometer (Jasco, Tokyo, Japan) with a single-reflection diamond ATR unit. Liquid chromatography-mass spectrometry was conducted on a SQ detector equipped with the Acquity ultra-performance liquid chromatography system (Waters, MA, USA). High-performance liquid chromatography (HPLC) analysis was performed using the Prominence (Shimadzu, Kyoto, Japan) or Alliance (Waters, MA, USA) systems. High-resolution mass spectral (HRMS) data were obtained using the LTQ Orbitrap mass spectrometer (Thermo Fisher Scientific, MA, USA). The water content was determined by Karl Fischer titration using the KF-004 Karl Fischer moisture meter (Mitsubishi Chemical Analytech, Kanagawa, Japan). Melting points were determined using the MP-J micro-melting point apparatus (Yanaco, Kyoto, Japan) and given as uncorrected values. The specific rotation was measured on the Autopol IV polarimeter (Rudolph Research Analytical, NJ, USA). The following HPLC conditions were employed: (a) Column: CAPCELLPACK C18 MGII, 3 m, 2.0 × 20.0 mm (Osaka Soda); eluent: (A) 0.2% HCOOH in H2O and (B) MeOH; gradient: A:B 95:5 (0 min), 1:99 (28 min); flow rate: 0.4


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mL/min; and detection: 244 nm. The retention times for 23 and 2 were 20.9 and 21.9 min, respectively. (b) column XBridge C18, 5 m, 4.6 × 150 mm (Waters); eluent: 4.08 g/L aqueous KH2PO4 solution/MeOH = 60/40 (The pH was adjusted to 2.5 by H3PO4); flow rate: 0.8 mL/min; and detection: 290 nm. The retention time for 1 was 24.7 min. The following chiral HPLC conditions were employed: (a) column CHIRALPAK IC, 3 m, 0.46 × 25 cm (Daicel); eluent: n-hexane/iPrOH/TFA = 90/10/0.1; flow rate: 1.0 mL/min; and detection: 244 nm. The retention times for ent-2 and 2 were 10.1 and 12.6 min, respectively. (b) column Chiral MB-S, 5 m, 4.6 × 250 mm (TCI); eluent: 9% MeCN in 50 mM aqueous KH2PO4; flow rate: 1.8 mL/min; and detection: 280 nm. The retention time for 1 was 15.0 min. tert-Butyl (S)-2-(2-chloroacetyl)pyrrolidine-1-carboxylate (17) To a mixture of 16 (75.0 kg, 327 mol), sodium chloroacetate (95.3 kg, 818 mol), and triethylamine (66.2 kg, 654 mol) in THF (750 L) was added tert-butylmagnesium chloride (818 mol, THF solution) at −5 to −2 °C, and the mixture was stirred at 0–1 °C for 1 h. The reaction mixture was then added to aqueous citric acid (143 kg citric acid in 420 L H2O) while maintaining the temperature between 0–7 °C. The organic layer was washed twice with aqueous NaHCO3 solution (18.8 kg NaHCO3 and 67.5 kg NaCl in 413 L H2O) and once with brine (75.0 kg NaCl in 300 L H2O), and concentrated to about 158 L under reduced pressure. After AcOEt (225 L) was added to the residue, the organic layer was separated, washed with aqueous NaHCO3 solution (3.8 kg NaHCO3 and 13.5 kg NaCl in 75 L H2O), and concentrated to about 68 L under reduced pressure. The residue was diluted with THF (38 L) and taken directly into the next step as a THF solution. Quantitative analysis of the organic phase by HPLC revealed the


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formation of 17 (78.5 kg, 97% yield). This process was operated in 2 batches, generating a total of 156 kg of crude product 17 in an average yield of 97%. tert-Butyl (2S)-2-(3-(methoxycarbonyl)-4-oxopentanoyl)pyrrolidine-1-carboxylate (19) To a stirred mixture of KI (10.5 kg, 63.1 mol) and K2CO3 (105 kg, 757 mol) in DMF/THF (78/391 L) were added THF solution of 17 (156 kg, 631 mol) and methylacetoacetate (95.3 kg, 820 mol) at 20–26 °C. After stirring at 26–33 °C for 6 h, additional methylacetoacetate (8.1 kg, 69.4 mol) and K2CO3 (8.7 kg, 63.1 mol) were added, and the mixture was stirred at 29 °C for additional 2 h. To the resulting mixture were added toluene (782 L) and water (156 L), and the pH was adjusted to 3.0 by adding 2 M aqueous HCl solution (625 L) while maintaining the temperature under 10 °C. NaCl (78.2 kg) was then added and the layers were separated. The organic layer was washed with aqueous NaHCO3 solution (20.3 kg NaHCO3 and 39.1 kg NaCl in 547 L H2O) and brine (39.1 kg NaCl in 313 L H2O), and concentrated to about 219 L under reduced pressure. The organic layer was added to THF (156 L) and used directly in the next step. Quantitative analysis of the organic phase by HPLC revealed the formation of 19 (151 kg, 73% yield). Water content: 0.09%. (S)-5-(1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-2-methylthiophene-3-carboxylic acid (2) To LR (117 kg, 288 mol) in THF (980 L) was added 19 (75.4 kg, 230 mol) in THF (75 L) at 45– 50 °C, and the mixture was stirred at 50–58 °C for 1.5 h. To this mixture was added 48% aqueous NaOH solution (226.1 kg NaOH in 392 L H2O) while maintaining the temperature at 6– 7 °C. The organic layer was separated, diluted with MeOH (377 L), and mixed with aqueous NaOH solution (46.0 kg NaOH in 234 L H2O). The resulting mixture was stirred at 45–63 °C for 3 h. After cooling, the pH was adjusted to 7.0 by adding 2 M aqueous HCl solution (450 L) at 5– 8 °C, and the mixture was concentrated to 904 L under reduced pressure. After diluting the


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residue with AcOEt (754 L), 2 M aqueous HCl solution (300 L) was added at 9–10 °C to adjust the pH to 2.9. The organic layer was separated and washed with brine (52.7 kg NaCl in 301 L H2O), and the solvent was reduced to 136 L under reduced pressure. EtOH (377 L) was added to dissolve the precipitate at 60 °C, and the mixture was concentrated under reduced pressure to 226 L. The residue was dissolved by adding H2O (30 L) and heating to 65 °C. After cooling to 0– 10 °C and stirring for 5 h, the precipitate was collected by centrifugation, washed with MeCN (113 L) cooled to 7 °C, and dried under reduced pressure at 43–45 °C to give 44.5 kg of crude product 2. This process was operated in 2 batches, generating a total of 88.3 kg of crude product 2. After that, crude 2 (88.3 kg) was added to MeCN (1325 L), dissolved at 80 °C, and concentrated to 442 L at 50 °C. The residue was then heated to 75–85 °C, cooled down to 10 °C, and stirred at 10 °C for 18 h. The resulting precipitate was collected by centrifugation and washed with MeCN (132 L) cooled to 10 °C to give 81.5 kg of 2 (57% yield) as a white solid. HPLC purity: 99.2 area% (23: 0.8 area%, HPLC condition a). Optical purity: 99.4% ee (chiral HPLC condition a). 1H

NMR (400 MHz, CD3OD): δ 7.14–7.09 (m, 1H), 5.09–4.93 (m, 1H), 3.57–3.38 (m, 2H), 2.67

(s, 3H), 2.39–2.16 (m, 1H), 2.09–1.86 (m, 3H), 1.62–1.21 (m, 9H); 13C NMR (101 MHz, CD3OD): δ 166.8, 156.2, 148.9, 145.0, 129.4, 126.6, 81.3, 58.2, 47.4, 36.2, 28.7 (3C), 24.2, 15.5; MS (ESI) m/z: 312 (M+H)+, 310 (M−H)−; [α]D25 −91.0 (c 1.00, MeOH); HRMS (ESI) calcd for C15H22NO4S (M+H)+, 312.1264; found, 312.1266. tert-Butyl (S)-2-(4-((5-fluorothiazol-2-yl)carbamoyl)-5-methylthiophen-2-yl)pyrrolidine-1carboxylate (24) To a mixture of 2 (71.0 kg, 228 mol) and DMF (0.8 kg, 11.4 mol) in CPME (710 L) was added dropwise oxalyl chloride (34.6 kg, 274 mol) at 16–19 °C. After stirring at 20–27 °C for 2 h, the


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resulting mixture was concentrated to 300 L under reduced pressure. The residue was azeotroped with CPME (355 L), mixed with MeCN (355 L), and cooled to −5 to 5 °C. To the mixture were added slowly 2-amino-5-fluorothiazole (35.2 kg, 228 mol), pyridine (36.1 kg, 456 mol), and MeCN (355 L) at −5 to 2 °C. After stirring at 1–2 °C for 1 h and at 20–28 °C for additional 5 h, water (1562 L) was added, and the mixture was stirred at 23–28 °C for 30 min. The pH was adjusted to 7.1 using 1 M aqueous NaOH solution (460 L) at 23–25 °C, and the mixture was concentrated to 1910 L under reduced pressure. The residue was suspended in MeCN (689 L) and stirred at 55–66 °C for 1 h and at 22–30 °C for 1 h. The solids were allowed to settle and then, the supernatant was removed. The resulting solids were suspended in aqueous MeCN solution (369 L MeCN in 185 L H2O), and stirred at 19–20 °C for 1 h. After collection by filtration, the solids were washed with an aqueous MeCN solution (114 L MeCN in 57 L H2O) and dried under reduced pressure at 50 °C to give 24 (76.5 kg, 82%) as a white solid, which was utilized in the next step without any purification. 1H NMR (400 MHz, CD3OD):  7.24 (br s, 1H), 7.12 (d, J = 2.5 Hz, 1H), 5.15–4.96 (m, 1H), 3.59–3.38 (m, 2H), 2.69 (s, 3H), 2.40–2.21 (m, 1H), 2.13–1.89 (m, 3H), 1.59–1.23 (m, 9H); 13C NMR (101 MHz, CD3OD):  163.7, 160.1 (d, J = 291 Hz), 156.3, 149.4, 147.9, 145.9, 130.0, 123.7, 118.9 (d, J = 13 Hz), 81.5, 58.2, 47.5, 36.3, 28.8 (3C), 24.1, 15.2; MS (ESI) m/z: 412 (M+H)+, 410 (M−H)−; [α]D24 −75.0 (c 1.00, MeOH); HRMS (ESI) C18H23FN3O3S2 (M+H)+, 412.1159; found, 412.1160. (S)-N-(5-Fluorothiazol-2-yl)-2-methyl-5-(pyrrolidin-2-yl)thiophene-3-carboxamide (25) To 24 (75.0 kg, 182 mol) in AcOiPr (375 L) were added concentrated HCl (64.5 kg) and H2O (125 L). After stirring at 55–59 °C for 4 h, 5 M aqueous NaOH solution (583 L) was added at 9– 15 °C, and the pH of the mixture was adjusted to 9.9. The resulting mixture was combined with AcOiPr (450 L) and stirred at 35–45 °C, and the layers were separated. After the organic layer


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was evaporated to 150 L under reduced pressure, the residue was diluted with AcOiPr (225 L). This mixture, containing compound 25, was evaporated to 150 L under reduced pressure and used in the next step without any purification. 2,2'-(Ethylazanediyl)diacetic acid (30) To 31 (70.0 kg, 526 mol) in H2O (1050 L) was added acetaldehyde (15 L, 263 mol), and the reactor was charged with N2. To this mixture was added 10% Pd/C (8.4 kg, 58 % wet), and N2 was replaced by hydrogen to conduct the reaction at a hydrogen pressure of 0.3 MPa at 45–46 °C for 1 h. The mixture was cooled down to under 20 °C, combined with acetaldehyde (15 L, 263 mol), and stirred at 45 °C at a pressure of 0.3 MPa for 1 h. The mixture was once again cooled down to under 20 °C, combined with acetaldehyde (29 L, 526 mol), and stirred at 45 °C at a pressure of 0.3 MPa for 1 h. The mixture was cooled down to under 20 °C, filtered through Celite, washed with water (126 L), and evaporated to 136 L under reduced pressure. The resulting mixture was combined with EtOH (364 L) and stirred at 25–27 °C for 6 h. After filtration, the reaction mixture was washed with EtOH (105 L) and dried under reduced pressure at 50 °C to give 30 (78.9 kg, 93%). Compound 30 was used in the next step without any purification. 1H NMR (400 MHz, CD3OD): δ 3.92 (s, 4H), 3.35 (q, J = 7.3 Hz, 2H), 1.32 (t, J = 7.3 Hz, 3H); 13C NMR (101MHz, CD3OD): δ169.6 (2C), 56.2 (2C), 52.4, 10.0; MS (ESI) m/z: 162 (M+H)+, 160 (M−H)−; HRMS (ESI) calcd for C6H12NO4 (M+H)+, 162.0761; found, 162.0758. (S)-N-Ethyl-N-(2-(2-(4-((5-fluorothiazol-2-yl)carbamoyl)-5-methylthiophen-2yl)pyrrolidin-1-yl)-2-oxoethyl)glycine (34) To 30 (91.1 kg, 565 mol) in AcOEt (568 L) was added dropwise TFAA (114 kg, 542 mol) at 3– 9 °C and stirred at 20–27 °C for 2.5 h. The resulting mixture was added to 25 (56.8 kg, 182 mol)


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in AcOiPr (150 L) at 12–21 °C and stirred at 65–68 °C for 2 h. The mixture was combined with water (1136 L) and 5 M aqueous NaOH solution (280 L) at 20–21 °C, adjusted to pH 7.5, and concentrated to 1460 L under reduced pressure. To the residue was added 5 M aqueous NaOH solution (100 L) at 26 °C, and the mixture was adjusted to pH 10.8 and filtered. The filtrate was washed with H2O (85 L), added to 6 M aqueous HCl (130 L), and adjusted to pH 6.0. The mixture was combined with 1 M aqueous HCl (20 L), adjusted to pH 5.5, and stirred at 30–40 °C for 14 h. The precipitate was collected by centrifugation, washed with H2O (398 L), suspended in AcOEt (1136 L), and stirred at 22–30 °C for 1 h. The precipitate was collected by centrifugation and washed with AcOEt (85 L). The solids were suspended in MeOH (426 L), stirred at 60– 62 °C for 2 h and at 27–30 °C for 1 h. The resulting solids were collected by centrifugation, washed with AcOEt (107 L), and suspended in AcOEt (710 L). After stirring at 28–30 °C for 1 h, the solids were collected by centrifugation, washed with AcOEt (107 L), and dried under reduced pressure at 35 °C to give 34 (57.9 kg, 65%). 1H NMR (400 MHz, CD3OD): δ 7.32 (s, 1H), 7.12 (d, J = 2.5 Hz, 1H), 5.41–5.33 (m, 1H), 4.34–4.20 (m, 2H), 3.92–3.53 (m, 4H), 3.40–3.22 (m, 2H), 2.66 (s, 3H), 2.48–1.95 (m, 4H), 1.32 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CD3OD): δ170.2, 165.8, 165.6, 163.5, 160.1 (d, J = 291 Hz), 148.6, 143.3, 129.9, 125.0, 118.9 (d, J = 13 Hz), 58.4, 57.8, 56.3, 52.8, 47.2, 34.4, 25.1, 15.3, 10.1; MS (ESI) m/z: 455 (M+H)+, 453 (M−H)−; HRMS (ESI) calcd for C19H24FN4O4S2 (M+H)+, 455.1217; found, 455.1213; [α]24D −109.8 (c 1.00, DMSO). (S)-N-Ethyl-N-(2-(2-(4-((5-fluorothiazol-2-yl)carbamoyl)-5-methylthiophen-2yl)pyrrolidin-1-yl)-2-oxoethyl)glycine hydrochloride (1) To 34 (57.9 kg, 118 mol) in EtOH (434 L) was added concentrated HCl (14.1 kg, 141 mol), and the mixture was stirred at 26–27 °C for 4 h. AcOiPr (648 L) was added, and the mixture was


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stirred at 45–50 °C for 19 h and cooled down to 30 °C. The precipitate was collected by centrifugation, washed with AcOiPr (87 L), suspended in AcOiPr (290 L), and stirred at 24 °C for 1 h. The resulting solids were collected by centrifugation, washed with AcOiPr (87 L), and suspended in AcOiPr (290 L). After stirring at 25 °C for 1 h, the resulting solids were collected by centrifugation, washed with AcOiPr (87 L), and dried under reduced pressure at 36–40 °C to give 1 (54.6 kg, 94%) as a white solid. HPLC purity: 98.8 area% (HPLC condition b). Optical purity: 99.4% ee (chiral HPLC condition b); mp: 229 °C; 1H NMR (400 MHz, CD3OD): δ 7.31 (br s, 1H), 7.16 (d, J = 2.4 Hz, 1H), 5.40 (d, J = 7.3 Hz, 1H), 4.55–4.07 (m, 4H), 3.96–3.54 (m, 2H), 3.50–3.28 (m, 2H), 2.69 (s, 3H), 2.56–2.25 (m, 1H), 2.22–1.97 (m, 3H), 1.37 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CD3OD): δ168.5, 165.0, 163.3, 163.1, 159.8 (d, J = 291 Hz), 149.7, 143.0, 130.5, 125.0, 118.9 (d, J = 13 Hz), 58.6, 56.9, 54.8, 54.2, 47.0, 34.4, 24.8, 15.2, 9.6; IR (ATR, cm-1): 1706, 1644, 1554; MS (ESI) m/z: 455 (M+H)+, 453 (M−H)−; HRMS (ESI) calcd for C19H24FN4O4S2 (M+H)+, 455.1217; found, 455.1220; [α]22D −105.1 (c 1.00, MeOH).

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: 1H

and 13C NMR spectra of final compound 1 (docx)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]


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ACKNOWLEDGMENTS We are grateful to Dr. Masao Sakairi for his advice on the manuscript. We also thank Hamari Chemicals, Ltd. and Yonezawa Hamari Chemicals, Ltd. for their efforts in the large-scale production of 1.

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(4) Meininger, G. E.; Scott, R.; Alba, M.; Shentu, Y.; Luo, E.; Amin, H.; Davies, M. J.; Kaufman, K. D.; Goldstein, B. J. Effects of MK-0941, a Novel Glucokinase Activator, on Glycemic Control in Insulin–Treated Patients with Type 2 Diabetes. Diabetes Care 2011, 34, 2560–2566. (5) Bonadonna, R. C.; Heise, T.; Arbet-Engels, C.; Kapitza, C.; Avogaro, A.; Grimsby, J.; Zhi, J.; Grippo, J. F.; Balena, R. Piragliatin (RO4389620), a Novel Glucokinase Activator, Lowers Plasma Glucose both in the Postabsorptive State and after a Glucose Challenge in Patients with Type 2 Diabetes Mellitus: A Mechanistic Study. J. Clin. Endocrinol. Metab. 2010, 95, 5028– 5036. (6) (a) Knorr, L. Synthese von Pyrrolderivaten. Ber. Dtsch. Chem. Ges. 1884, 17, 1635–1642. (b) Paal, C. Synthese von Thiophen-und Pyrrolderivaten. Ber. Dtsch. Chem. Ges. 1885, 18, 367–371. (7) Khaghaninejad S.; Heravi M. M.; Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds. Adv. Heterocycl. Chem. 2014, 111, 95–146. (8) Bureš, F.; Kulhánek, J. Chiral Imidazole Derivatives Synthesis from Enantiopure N-Protected -Amino Acids. Tetrahedron: Asymmetry 2005, 16, 1347–1354. (9) Chen, P.; Cheng, P. T. W.; Spergel, S. H.; Zahler, R.; Xuebao, W.; Thottathil, J.; Barrish, J. C.; Polniaszek, R. P. A Practical Method for the Preparation of -Chloroketones of N-Carbamate Protected--Aminoacids. Tetrahedron Lett. 1997, 38, 3175–3178. (10) Nishiyama, A.; Sugawa, T.; Manabe, H.; Inoue, K.; Yoshida, N. Processes for Producing Halo Ketones, -Halohydrins and Epoxides. PCT Int. Appl. WO/1996023756, Oct 8, 1996. (11) (a) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Microwave-Assisted Paal-Knorr Reaction-Three-Step Regiocontrolled Synthesis of Polysubstituted Furans, Pyrroles and Thiophenes. Eur. J. Org. Chem. 2005, 28, 5277–5288. (b) Chawrai. S. R.; Williamson. N. R.; Mahendiran. T.; Salmond. G. P. C. ; Leeper. F. J. Characterisation of PigC and HapC, the


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Prodigiosin Synthetases from Serratia sp. and Hahella chejuensis with Potential for Biocatalytic Production of Anticancer Agents. Chem. Sci. 2012, 3, 447–454. (c) Martínez L. R.; Avila Zarraga J. G.; Duran M. E.; Ramírez Apam M. T.; Cañas R. Synthesis of Novel Furo, Thieno, and Benzazetoazepines and Evaluation of Their Cytotoxicity. Bioorg. Med. Chem. Lett. 2002, 12, 1675–1677. (d) Kawabata, S.; Oishi, A.; Nishino, H. Reaction of Electron-Deficient 3-Acetyl-1arylpent-2-ene-1,4-diones as a Building Block of Heterocycles. Heterocycles 2017, 94, 1479– 1505. (12) Aside from THF/DMF, we tested various solvents, including THF, DMF, MeCN, THF/H2O, DMF/H2O, DMA, EtOH, Acetone, DMSO, NMP, t-BuOH. However, none of them yielded a better result than THF/DMF. Therefore, THF/DMF was chosen as the solvent in step 2. (13) (a) Trost, B. M. The Atom Economy — A Search for Synthetic Efficiency. Science 1991, 254, 1471–1477. (b) Trost, B. M. Atom Economy—A Challenge for Organic Synthesis: Homogeneous Catalysis Leads the Way. Angew. Chem., Int. Ed. 1995, 34, 259–281. (14) Yoshida, K.; Nakayama, K.; Kuru, N.; Kobayashi, S.; Ohtsuka, M.; Takemura, M.; Hoshino, K.; Kanda, H.; Zhang, J. Z.; Lee, V. J.; Watkins, W. J. MexAB-OprM Specific Efflux Pump Inhibitors in Pseudomonas aeruginosa. Part 5: Carbon-Substituted Analogues at the C-2 Position. Bioorg. Med. Chem. 2006, 14, 1993–2004. (15) Santos, M. A.; Marques, S. M.; Tuccinardi, T.; Carelli, P.; Panelli, L.; Rossello, A. Design, Synthesis and Molecular Modeling Study of Iminodiacetyl Monohydroxamic Acid Derivatives as MMP Inhibitors. Bioorg. Med. Chem. 2006, 14, 7539–7550. (16) Compounds 1 and 2, produced in this synthesis, had excellent optical purities (99% and 100%, respectively).


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Efficient and Scalable Synthesis of Glucokinase Activator with a Chiral

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