Synthetic Strategies toward SGLT2 Inhibitors - Organic Process

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SYNTHETIC STRATEGIES TOWARD SGLT2 INHIBITORS Anderson R. Aguillon, Alessandra Mascarello, Natanael D. Segretti, Hatylas F. Z. de Azevedo, Cristiano R. W. Guimaraes, Leandro S. M. Miranda, and Rodrigo Octavio Mendonça Alves de Souza Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00017 • Publication Date (Web): 30 Mar 2018 Downloaded from http://pubs.acs.org on March 30, 2018

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Organic Process Research & Development

SYNTHETIC STRATEGIES TOWARD SGLT2 INHIBITORS Anderson R. Aguillón, 1 Alessandra Mascarello, 2 Natanael D. Segretti, 2 Hatylas F. Z de Azevedo, 2 Cristiano R. W. Guimaraes, 2 Leandro S. M. Miranda, 1 Rodrigo O. M. A. de Souza, *1 1

Biocatalysis and Organic Synthesis Group, Universidade Federal do Rio de Janeiro, RJ, Brazil 2

Aché Laboratórios Farmacêuticos, Guarulhos – SP, Brazil [email protected]

ABSTRACT Gliflozins are an important class of prescription drugs used to treat type II diabetes. It reduces blood sugar levels by targeting the sodium-glucose transport protein 2 (SGLT2) and consequently inhibit glucose reabsorption in the kidney. There are currently several FDA-approved gliflozins as well as others in the pipeline to be launched in the next few years. This review describes the synthetic strategies used for manufacturing SGLT2 inhibitors on both bench and industrial scales. Moreover, the drawbacks to the strategies and the improvements made to obtain select gliflozins and their glucose derivatives over the years are highlighted.

Keywords: gliflozins, SGLT2 inhibitors, diabetes, sodium-glucose transport, blood sugar

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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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INTRODUCTION Diabetes and its complications are prevalent public health problems that are reaching epidemic proportions worldwide.1,2 In 2012, 1.5 million deaths were attributed to diabetes, and 2.2 million deaths were directly connected to high blood glucose. Half of all deaths linked to high blood sugar occur before the age of 70 years. The World Health Organization (WHO) estimates that diabetes will be the 7th leading cause of death in 2030.3–5 More than 420 million people have diabetes worldwide, and according to a global prevalence projection, by 2040, that number is expected to increase to 642 million.6 Diabetes is a metabolic and chronic disease that occurs either when the pancreas does not produce enough insulin or when insulin does not work efficiently in the body due to resistance mechanisms.7 Insulin controls blood glucose levels, and the most common effect in uncontrolled diabetes, called hyperglycemia, can lead to several health problems over time.8 The consequences of these metabolic changes are manifested in diminished wound healing and tissue damage in retina, nerves, and kidney that increase the incidence of gangrene, retinopathy, neuropathy, and nephropathy. These effects result in amputations of extremities, blindness, renal failure, cardiovascular disease and stroke.9 Chronic hyperglycemia can also cause higher glycosylated hemoglobin levels (HbA1C), reduced insulin secretion, increased β-cell apoptosis, increased oxidative stress, and increased insulin resistance (IR).10,11 As reported by the American Diabetes Association (ADA)12 and the WHO,7 the types of diabetes can be classified into four main groups: type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes and other more specific types of diabetes. According to the WHO, impaired glucose tolerance (IGT) and



impaired fasting glycaemia (IFG) should also be considered clinically relevant.5 T1DM is characterized by an absolute insulin deficiency caused by T-cell–mediated autoimmune destruction of pancreatic β-cells.13 T1DM is one of the most common chronic childhood disease. According to the ADA, this is the form present in 5–10% of diabetic patients.14 The decreased insulin secretory capacity results in hyperglycemia with a susceptibility to developing ketoacidosis.15,16 Analogously, T2DM is characterized by the deregulation of carbohydrate, lipid, and protein metabolism due to impaired insulin secretion, IR, or a combination of both in the pancreatic β-cells.9,17,18 Of the three major types of diabetes, T2DM is the most prevalent type, and it accounts for more than 90% of cases.9,17,18 Although the main pathological mechanisms of T2DM remain elusive, genetic and environmental factors contribute to the disease phenotype.19 Moreover, etiologic factors such as obesity, hypertension, and elevated cholesterol might also contribute to IR to some degree.9,20 There is considerable heterogeneity in therapeutic responses to diabetes. Individuals may require multiple medications to control blood glucose levels and to reduce the risk of long-term cardiovascular, renal, and ocular complications.21 These pharmacological approaches work by several modes of action such as i) reducing glucose output by the liver; ii) decreasing glucose absorption by the small intestine; iii) increasing glucose cellular uptake by adipocytes or muscle; iv) promoting glucose metabolism; v) enhancing incretin action by serum proteases; and vi) increasing insulin release by the pancreas.19,22,23 Currently, the treatment paradigm for T2DM management aims at controlling glycemic levels through the administration of oral or injectable agents and avoiding the long-term complications of the disease.24 In addition to insulin, the therapies available


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for

treating

T2DM

include

biguanides

(e.g.,

metformin

and

buformin),

thiazolidinediones (e.g., pioglitazone, rosiglitazone, and rivoglitazone), dipeptidylpeptidase-IV or DDP-4 inhibitors (e.g., alogliptin, gemigliptin, and saxagliptin), sulfonylureas (e.g., carbutamide, chlorpropamide, metahexamide, and tolbutamide), alpha-glucosidase inhibitors (e.g., acarbose, miglitol, and voglibose), glinides (e.g., voglibose, mitiglinide, and nateglinide), and more recently, sodium-glucose transport protein 2 (SGLT2) inhibitors.25–27 Despite the variety of available therapies, the antidiabetic drugs used to treat T2DM are usually associated with several adverse effects and must be used in conjunction with insulin therapy. The global market for anti-diabetes drugs can be considered a large market segment, and in 2014, it generated combined sales of $28.6 billion.28 Merck & Co.'s DPP-4 inhibitor Januvia® (sitagliptin) is the highest selling oral drug for diabetes (US$ 3.9 billion), and in combination with Janumet®, their total revenue has reached US$ 6 billion. By 2020, it is estimated that the number of blockbuster diabetes medications will reach 17, and they will have combined sales of around US$ 40 billion.28 Interestingly, the number of oral blockbusters will increase by the end of the decade, and they will be led by Johnson & Johnson's first-in-class SGLT2 inhibitor canagliflozin (InvokanaTM, Janssen), which has experienced increasing sales since its launch in 2013 and is expected to reach almost US$ 3 billion in sales by 2022.29 Figure

1 depicts the chronology of the launches of the main T2DM drugs as well as their mechanisms of action.



Figure 1 Launch timeline for the main T2DM drugs.

1. SGLT2 INHIBITORS

Transporters play an important role in the regulation of glucose homeostasis because they are required for D-glucose to cross plasma membranes.30 Among the proteins that transport glucose in different tissues, sodium-dependent glucose transporters (SGLTs) are one of the most relevant proteins for glucose absorption- and reabsorption-independent insulin processes.31,32 SGLTs are integral membrane proteins that mediate the active transport of glucose and galactose (with much lower affinity) across the plasma membrane via a symport mechanism.32 SGLTs actively transport glucose against the concentration gradient with the concomitant transport of sodium (Figure 2).33–35 In the kidneys of healthy individuals, D-glucose is filtered in the glomerulus and completely reabsorbed by the proximal tubules since the glucose concentration in the ACS Paragon Plus Environment

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glomerular filtrate does not exceed the renal recovery capacity.36 Nearly all the filtered glucose is reabsorbed in the proximal tubules (S1/S2) through both SGLT2 and SGLT1 transport, although SGLT2 is responsible for approximately 90% of this reabsorption. SGLT2 expression and activity are higher in T2DM patients, and consequently, glucose reabsorption occurs in higher-than-normal levels, which contributes to the maintenance of hyperglycemia in the bloodstream.33,37-38

Figure 2 Glucose reabsorption by the kidney in proximal renal tubular cells (A) by SGLTs proteins (B).

SGLT2 has attracted much attention as a therapeutic target due to its important role in renal glucose reabsorption.39 Reducing hyperglycemia by inhibiting SGLT2 represents a non-insulin dependent strategy that minimizes blood sugar levels by preventing renal glucose reabsorption and consequently decreasing the renal glucose threshold.39 Progressive inhibition of the SGLT2 transporter is manifested in a dosedependent lowering of the maximal absorptive capacity of the proximal tubule, which results in increased urinary glucose excretion.40 The first SGLT inhibitor discovered was phlorizin (1), a natural phenolic Oglucoside containing a dihydrochalcone moiety (Figure 3A).10,41 However, phlorizin



acts as a nonspecific SGLT inhibitor by blocking both SGLT1 and SGLT2 activity, limiting its applicability as a drug. The poor selectivity of phlorizin is associated with adverse gastrointestinal effects since SGLT1 is highly expressed in the intestine,42 which dampened the initial enthusiasm for the clinical development of this agent.43 Phlorizin (1) exhibits high metabolic instability due to the hydrolysis of the Oglycosidic bond by intestinal disaccharidases.

Figure 3 Chemical structure of A) phlorizin and B) Markush structure of gliflozins.

Thus, efforts to identify new SGLT2 inhibitors suitable for oral administration that do not require the use of a prodrug led to the discovery of C-aryl glucoside-derived SGLT2 inhibitors.44 C-glucosides are glucoside analogs in which the oxygen atom of the exo-glycosidic bond is replaced by a carbon atom. These compounds present a new, non-hydrolyzable C-C bond (Figure 3B).45,46 Some C-glucosides have received much attention from the pharmaceutical industry due to their potent and selective inhibition of SGLT2. They constitute a novel class of glucose-lowering agents known as gliflozins.47 Six gliflozins have been approved as hypoglycemic agents for the treatment of type 2 diabetes (Figure 4).48 Four of these drugs (canagliflozin (Invokana®, Johnson & Johnson/Tanabe), dapagliflozin


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(Forxiga®, Farxiga®, AstraZeneca), empagliflozin (Jardiance®, Boehringer Ingelheim) and ertugliflozin (Steglatro®, Steglujan®, Merck/Pfizer) are currently approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA).49 Other gliflozins, such as ipragliflozin (Suglat®, Astellas), luseogliflozin (Lusefi®, Taisho) and tofogliflozin (Apleway®, Deberza®, Chugai), are currently approved in Japan.33 Other SGLT2 inhibitors, including sotagliflozin and bexagliflozin, are in late development (Figure 4).

Figure 4. Chemical structures of SGLT2 inhibitors approved by the FDA and EMA (dapagliflozin, ertugliflozin, canagliflozin, and empagliflozin), approved by Japan’s PMDA (tofogliflozin, ipragliflozin, and luseogliflozin), and currently in phase III clinical trials (sotagliflozin and bexagliflozin).

Gliflozins are β-D-glucoside derivatives with an aryl or heteroaryl aglycone attached to the anomeric carbon. In addition, the aglycones of β-C-glucosides are



characterized by the presence of a methylene bridge that connects different aryl or heteroaryl groups. Despite the small structural differences in the aglycone and the sugar moieties between the gliflozins, multiple synthetic approaches have been reported to date.50 Although many reviews that address certain aspects of the design and synthesis of SGLT2 inhibitors have been published,9,25,44,48,50–53 the present work is primarily focused on the synthetic strategies employed by both academic research groups and pharmaceutical companies at laboratory and industrial scales. More importantly, this review aims to illustrate the search for alternative synthetic routes and methods when transitioning from the bench to industrial scale syntheses that afford improvements in safety, efficiency, and yield.

2. General aspects of the synthesis of SGLT2 inhibitors

Typically, the syntheses of gliflozins face three main challenges: a) building the aryl substituent, b) forming the C-C bond between the aryl group and the glycon, and c) asymmetrically reducing the anomeric carbon and the subsequent removal of the protecting groups from the glycosidic group.44,48 For the first challenge, there are two classical approaches for forming the methylene bridge of the biarylmethane: 1) nucleophilic addition to the carbonyl group using an organometallic reagent (such as a Grignard or organolithium reagent) and 2) an electrophilic aromatic substitution by Friedel-Crafts acylation. In each case, the formation of the C-C bond to generate the diarylcarbinol and diarylketone intermediate is followed by a reduction to obtain the corresponding methylene group. Furthermore,


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addition to the carbonyl group using a phenylboronic acid derivative via a metalcatalyzed cross-coupling reaction has also been reported (Figure 5).44

Figure 5 Retrosynthetic analysis of aglycone scaffolds.

The glycosylation of the aglycone and the selective reduction of the ketal intermediates (when lactones are used as the substrate) represent two major challenges in terms of regio- and stereoselectivity. Usually, the chemical routes for the formation of the C-C bond between the anomeric carbon and the aglycone involve a nucleophilic attack (e.g., by an aryl metal reagent) on an electrophilic species derived from the sugar components. Common glycosyl donors such as glycosyl halides,54 gluconolactones55,56 and sugar-derived epoxides57,58 as well as open-chain hemiketal derivates59 have been used in multistep syntheses (Figure 6). Other reagents such as stannanes,60,61 boronium



glycals62,63 and derivates of 1,6-anhydroglucose64 have also been used in the synthesis of C-β-glucosides.

Figure 6 Retrosynthetic analysis of glycone scaffolds.

Among the glycone scaffolds described in Figure 6, some of the most widely used glycosyl donors for the formation of SGLT2 inhibitors are lactones 11-13. The use of lactones as sugar donors in the preparation of C-glucoside derivatives was initially reported by Kishi and co-workers65 and was extended by other authors such as Kraus et al.66 and Czernecki et al.67 for the preparation of β-C-aryl glucosides. The method involves a two-step reaction sequence. In the first step, gluconolactone reacts with an organometallic reagent such as Grignard or organolithium reagent to give a hemiacetal intermediate. The following step involves the reduction of the resulting hemiacetal under Lewis acidic conditions to produce the β-C-glucosides as the major product


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(Figure 7).65 The sequential reactions are performed in low-polarity solvents (toluene, THF or MeCN) and/or at low temperatures in the presence of a Lewis acid such as BF3⋅OEt2. 48

Figure 7 Formation of C-glucosides via nucleophilic addition and reductive removal of the resulting lactol.

The stereoselectivity of the reduction step can be explained by anomeric effects.65,68 According to the literature, substituents can stabilize the transition state during anomeric bond-forming (or bond-cleavage) processes.68 Experimentally, the hydride attack on the oxonium intermediate seems to occur predominantly from the αaxial direction. Therefore, the 4C1-chair conformation stabilizes the oxocarbenium transition state through the kinetic anomeric effect (Figure 8).

Figure 8 Stereoselectivity during the reduction step.

Overall, the diastereoselectivity of Lewis acid-mediated silane reductions of tetra-O-protected glycopyranosides to β-C-glucosides varies from moderate to high.65,69 Studies have shown that the stereoselectivity of the reduction step might be affected by the use of bulky reducing agents such as TIPS-H (i-Pr3SiH) or (TMS)3SiH,70,71



conformationally restricted substrates68 or other factors such as the nature of the Lewis acid1,72,73 and the aglycone.74

3. Synthesis of gliflozins

To explore the recent advances in the synthesis and development of gliflozins, the following section describes the different approaches to the production of five gliflozins (ipragliflozin, tofogliflozin, luseogliflozin, ertugliflozin, and sotagliflozin) explored by pharmaceutical and fine chemical companies. Although patent publications do not offer the same insights and experimental details as journal articles, the patent literature offers useful synthetic details that frequently are not disclosed in any public forum.75

3.1 Ipragliflozin (ASP1941), Astellas Pharma, Katobuki and MSD

Figure 9 Chemical structure of ipragliflozin 4.

Suglat® (ipragliflozin, 4), was launched in Japan in 2014 as the first SGLT2 inhibitor approved in that country for the treatment of T2DM (Figure 9).76 Ipragliflozin was manufactured and sold by Astellas Pharma Inc. under the brand name Suglat® and is co-promoted by Kotobuki and Merck Sharp & Dohme (MSD). Currently, it is


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approved for use as monotherapy or in combination with other antihyperglycemic agents.76

3.1.1 Synthetic routes

In 2004, Imamura and co-workers published the first synthesis of 4 and several others C-glucosides derivatives.77 Registered in the US under application number US 20070161787,78 the authors described a 6-step process with an overall yield of 7% (Scheme 1).

F S

1) n-BuLi-hexane, 21, THF, -78 °C, 0.5 h

21 +

F

22

TBDMSCl

S

Br

S

Br

OTBDMS

DMAP, DMF, r.t.

OH

2) THF, 22, -78 °C to r.t. 87 %

H

Br

F

78 %

23

24

O

OBn 1) n-BuLi-hexane THF, -78 °C, 0.5 h,

O

O BnO

2) 11, THF, -78 to 0 °C, 0.5 h 50 %

OBn OBn 11

F F

S Et3SiH, BF3OEt2 BnO

MeCN, -20 °C, 5 h 30 %

O OBn BnO 27

BnO

S OH

HO O

74 %

OBn

OBn BnO

F

TBAF, THF, r.t., 1 h

OBn

BnO

S

HO O OBn

BnO

OTBDMS 25

OBn

26 BCl3-heptane pentametilbenzene CH2Cl2, -78 °C 87 % F

OH O HO

S OH

HO

4

Scheme 1 Synthetic route to 4 reported by Imamura and co-workers.

The first step in the synthetic route was the construction of the tertbutyldimethylsilyl ether (24). Using benzothiophene (21) as the starting material, an



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electrophilic aromatic substitution was conducted using n-butyllithium to form the lithiated heterocycle, which could them add to aldehyde 22. Subsequently, the secondary hydroxyl group of 23 was silyl protected with tert-butyldimethylsilyl chloride (TBDMSCl) to afford silyl ether 24. Then, 24 was subjected to lithium– halogen exchange, and then it was added to 11 at -78 °C to afford intermediate 25. The deprotection

of

the

TBDMS

group

was

accomplished

employing

tetra-n-

butylammonium fluoride (TBAF) in THF at room temperature, allowing the formation of advanced intermediate 26. Compound 26 was then reduced with triethylsilane as the reducing agent and boron trifluoride diethyl etherate (BF3·OEt2) as the Lewis acid to give 27. ipragliflozin (4) was formed by removal of the benzyl groups with BCl3. This chemical process offers some advantages such as the use of commercially available substrates to generate 4 and its intermediates. However, this synthetic route faces several challenges. First, three of the five steps of this strategy require cryogenic conditions, which makes its scale-up difficult. This problem is present in almost all synthetic approaches, especially in the formation of the glycosidic bond and its stereoselective reduction, which in the case of 4, are also the steps with the lowest yields, 50% and 30%, respectively. In the reports by Masakazu et al.,77,79 no data on the α/β ratio or any information related to the stereoselectivity obtained in the synthesis of 4 or its advanced intermediates were presented. Furthermore, the use of Et3SiH on scale is always a concern. Unreacted silane can generate reaction streams that contain hydrogen gas, which makes the waste streams more hazardous and complicates storage and transport.80 Another publication from the same group reported a second approach for the synthesis of advanced intermediate 27 (Scheme 2).79 In a shorter methodology, the authors avoided the protection of diaryl alcohol 23 by directly reducing it with Et3SiH.


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The formation of the C-glucoside was carried out by a lithium–halogen exchange on aryl derivative 28 employing BuLi, and subsequent addition of the lithiate to 11 using low temperatures to minimize lactone enolization. This step was followed by reduction of lactol intermediate 29 using Et3SiH in the presence of a Lewis acid, BF3·OEt2, to afford 27. Finally, gliflozin (4) was isolated after global deprotection of 27 with BCl3. Under the optimal conditions, the alternative strategy not only reduced the number of steps but also increased the overall yield of the process, affording 4 in an overall yield of 24%. The patent did not report any data on the α/β ratio.

Scheme 2 Alternative route to intermediate 27 reported by Imamura and coworkers, 2012.

In a patent application in 2007, Kumenoi and co-workers claimed the multikilogram scale synthesis of the free base of ipragliflozin and its co-crystal with Lproline through the sequence of steps described in Scheme 3.81



Scheme 3 Synthesis of 4 and 34 reported by Kumenoi and co-workers in 2007.

The reported chemical route was an eight-step linear strategy with an overall yield of 33%. Due to the use of less expensive reagents and milder conditions, the process incorporated improvements such as the use of higher temperatures to generate aryl compound 23, the substitution of a common organosilane reducing agent and Lewis acid catalyst with less expensive reducing agents such as NaBH4 for the formation of 30, the use of trimethylsilane (TMS) as the protecting group on glycosyl donor 12 in the one-pot glycosylation and acidic quench with methanol. Advanced intermediate 31 was


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further acetylated to obtain stable crystalline compound 33. Finally, the removal of the acetyl groups under basic conditions afforded 4, which was further recrystallized using L-proline to produce 34. Furthermore, the co-crystal of 4 with L-proline (34) was more stable and less hygroscopic compared to the free compound. Another patent application described a solid dispersion formulation of ipragliflozin L-proline in combination with crystalline cellulose.82 Again, no data on the α/β ratio was reported in this patent. A similar approach was developed by Guoliang and co-workers in 2014 using D-glucono1,4-lactone (35) as the starting material (Scheme 4).83 The synthesis of 4 was a four-step chemical process that took advantage of previously prepared 28 as the aryl fragment. This alternative process involved the use of different silyl protecting groups. Silyl-protected D-aldolactones 16/17 were subjected to sequential aryllithium addition by treatment with n-BuLi and silyl deprotection under acidic conditions. Then, 4 was formed by the reduction of ketals 38/39 in the presence of Et3SiH and BCl3. According to the information provide in the patent application, the process afforded 4 with an overall yield of 54%. However, the glycosyl donor (35) employed during this synthesis is not commercially available.



OH O

OH

O

HO

OH 35

a)

b)

OR1

TMSCl, DIEA,THF, 45 °C, 99 %.

O

or TBDMSCl, Et3N, THF, toluene, 98 %.

R1O

1) n-BuLi-hexane, THF, -78 °C, 2 h

OR1

O

S

F

F

OR1

16: R1 = TMS 17: R1 = TBDMS

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S

Br

HO O

28

OR1

R1O

OR1 OR1

36: R1 = TMS 37: R1 = TBDMS a) n-PrOH, HCl, r.t., 77 % b) n-BuOH, TBAF, HCl, 78%

F

OH O HO

S OH

OH

4

Et3SiH, BCl3 CH2Cl2/MeCN, -5 to 0 °C, 70 %

OH R2O O HO

F S

OH OH 38: R2= Pr 39: R2= Bu

Scheme 4 Synthesis of ipragliflozin reported by Guoliang and co-workers in 2014.

Recently, two interesting routes were published by Lek and Kotobuki Pharmaceuticals.84,85 In the first method, reported in 2015, Zupancic and co-workers presented a synthesis of 4 and its intermediate through the condensation of benzylprotected D-glucoepoxide 14 and aglycone 28 (Scheme 5). During the synthesis, the halogen exchange of 28 was carried out using tri-n-butylmagnesate followed by transmetalation with CuCN in THF at room temperature to afford advanced intermediate 40 after 2 h. Although Zupancic’s approach claimed a different route to prepare the glycoside without cryogenic conditions, their report did not describe the yields or stereoselectivity achieved. Similar approaches for the formation of Cglucoside using Ph2CuLi as the nucleophile that selectively give the β-C-glucoside have been reported in the literature.86


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F

F

OBn 28

O

1) 28, THF, 0 °C

S

Br

2) (n-Bu)3MgLi-hexane, 0 °C, 0.33 h

OBn

BnO

OH OBn

3) CuCN2LiCl,THF

O

S

40

O

NaI/TMSCl, MeCN, r.t., 2 h yield not reported

BnO OBn 14

F

OH O HO

S OH

OH

4

Scheme 5 Asymmetric synthesis of 4 via biaryl cuprate coupling of benzylprotected glycal epoxide 14.

A similar approach for the preparation of the alpha anomer of canagliflozin using an aryl zinc bromide complex was explored by Lemaire and co-workers.57 This experiment shows the influence of the catalyst on the selectivity for the C-glycosylation as both the syn- and anti-products can be obtained by selecting the appropriate catalyst57,87 (Figure 10).

Figure 10 Diastereodivergent substitution of 1,2-anhydro glycals.



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85

In the second alternative, Shuai and co-workers

reported a highly

stereoselective synthesis of 34 through the C-glycosylation of arylzinc reagents with αglucosyl bromide (Scheme 6). 1) n-BuLi-hexane, 28, toluene and n-butylether, -20 °C, 0.5 h

F S

Br

2) ZnBr2, LiBr, n-butylether -25 °C, 4 h

28

F

F

S

S

Zn

OPiv O PivO

Br

CH3SO3H/MeOH 120 °C, 4 h 63 - 80 %

OPiv OPiv 15

O

O

. HO

OH OH

34

2) L-proline, EtOH reflux, 1 h 90 %

F

OPiv O

S

OH NH

1) NaOH, NaOMe, 50 °C, 10 h 94 %

F

OH

PivO

S OH

OPiv 41

Scheme 6 Arylation attempts with glycosyl bromides 14 and arylzinc reagents.

In this approach, the authors report using halogenated aglycone 28 (using both the bromide and the iodide) and α-bromide glycosyl donor 15 for the nucleophilic substitution reaction with various zinc salts. The diarylzinc species was generated by halogen-lithium exchange and subjected to transmetalation with the ZnBr2–LiBr complex and the lithiated derivative of 28. Finally, the pivaloyl groups of 41 were successfully removed in the presence of sodium methoxide in refluxing methanol, and recrystallization using L-proline for co-crystal formation afforded 34 in a 53% overall yield. Notably, this methodology afforded the target compound using advanced intermediates such as 15 and 28, which increased the overall yield. Although the report of Shuai and Weicheng does not offer any information regarding the α/β ratios, a recent work by the same group of authors reported diastereomeric excesses between 85 and


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97%.88 The use of zinc as catalyst in the stereoselective C-glycosylation reactions was also explored for the synthesis of other gliflozins such as 9, 2 and 3.54,57,58 Lemaire described a stereoselective arylzinc substitution based on the reports of Gagné

89–91

et al. and Tomoo et al.,

92

the reaction proceeded through a nucleophilic

substitution with formation of an intermediate oxocarbenium via vicinal group participation by the pivaloyl ester at the 2-position (Figure 11).54

Figure 11 Diastereoselective C-glycosylation of pivaloyl-protected glycosides via arylzinc substitution.

This type of method could serve as an alternative to the methods that require cryogenic temperatures that are commonly used for the arylation of the glycosyl derivate.

3.2 Tofogliflozin (CSG452), Kowa and Sanofi

Figure 12 Chemical structure of 7.

Tofogliflozin, 7, is an orally active SGLT2 inhibitor that was launched in Japan in 2014 by Sanofi (Deberza®) and Kowa (Apleway®) for the treatment of T2DM. 7



was discovered by Chugai Pharmaceuticals; however, in 2012, Chugai entered into a co-development license agreement for 7 in Japan with Sanofi K.K. and Kowa for marketing purposes.93 In 2015, the license between Kowa and Chugai was expanded for the development and marketing of this agent in the USA and the European Union (EU).

3.2.1 Synthetic routes

The first reported synthesis of 7 was an 8-step sequence (Scheme 7).94–96 The strategy consisted of the formation of spiroketal intermediate 47 using 2bromoterephthalic acid 42 as the starting material and 11 as the glycosyl donor. In the early steps, 42 is reduced by BH3 in THF to give 43, which upon treatment with triphenyl methyl chloride (TrCl) in the presence of triethylamine (Et3N) and 4dimethylaminopyridine (DMAP) in CH2Cl2-DMF, afforded intermediate 44. Then, lithium–halogen exchange of 44 was accomplished with sec-butyllithium (sec-BuLi), and subsequent nucleophilic addition of the lithiate to 11 afford 45, which after a reductive cyclization with Et3SiH and BF3·Et2O in CH3CN, afforded intermediate 46. The aryl coupling was achieved by treating 47 with Grignard reagent 48. Finally, the synthesis of 7 was completed by the reduction of intermediate 49 with Et3SiH and BF3·Et2O and deprotection of 50 by palladium-catalyzed hydrogenolysis producing an overall yield of 6.5%.


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O OH

BH3, THF

OH

HO

HO O

0 to 40 °C 2.5 h 90 %

Br 42

OTr

TrCl, Et3N

OTr 44

DMAP, CH2Cl2-DMF 50 °C, 5.5 h 68 %

Br 43

Br O O

BnO

OBn

H

BnO

OH Dess-Martin periodinane

OBn

O

CH2Cl2, r.t.

OBn

33 %

OBn 47

O O BnO

OTr

OBn

BF3OEt2 Et3SiH, MeCN

OBn

-40 to 0 °C, 1 h 56 %.

OTr OH OBn

O BnO

OBn

OBn OBn 45

46

-Br+Mg

1. sec-BuLi toluene -78 °C to r.t. 0.5 h , 80 %

11 OBn

O

O

OBn

or n-BuLi, THF 87 %

48 Et2O, -78 °C, 80 % HO BF3OEt2 Et3SiH, CH2Cl2

O

OBn

O

O

OBn

O BnO

-40 °C, 1 h 83 %

OBn

MeOH/AcOEt, r.t. 99 %

OBn

OBn OBn

BnO

49

O

H2 Pd-C, HCl (2N)

OH

O HO

OH OH

50

7

Scheme 7 Synthetic route to 7 described by Kobayashi and co-workers.

One of the drawbacks of the abovementioned methodology is the lack of crystalline intermediates. Ether 11 and its benzyl-protected intermediates (46, 47, 49 and 50) were isolated as non-crystalline hygroscopic syrups. This prevents purification by methods such as filtration and crystallization and as a consequence, forces the use of cost- and time-inefficient column chromatography procedures for purification.97 Murakata and co-workers reported an alternative synthetic route using dibromobenzyl alcohol 51 as the starting material, and this route gave the desired product with a 47% overall yield (Scheme 8).98,99 Under a nitrogen atmosphere, the hydroxyl group of 51 was protected with 2-methoxypropene. n-BuLi was employed for the halogen-metal exchange and subsequent glycosylation to generate intermediate 54.



According to the authors, when the reaction was carried out in a mixture of toluene and MTBE (7.3:0.7), a homogeneous solution was obtained, which allowed the formation of 54.100 The authors also emphasized the importance of the slow addition of n-BuLi to preferentially obtain the ortho-lithiated intermediate. The regioselectivity of the bromide-lithium exchange was explained by the coordination between the oxygen atom of the methoxy group and a lithium atom. Thus, intermediate 54 was preferentially formed as a result of the proximity to the ortho-position; the regioselectivity of the reaction was 53:1 (ortho:para), and 98% conversion was observed.101 Then, a second lithiation was carried out using n-BuLi followed by the addition of the lithiate to 4ethylbenzaldehyde to afford 56, which undergoes a deprotection and intramolecular cyclization in the presence of HCl in THF/H2O to produce spiroketal derivative 57. Finally, hydrogenolysis of intermediate 57 over Pd/C in dimethoxyethane gives 7. Notably, the authors did not specify α/β ratio during spiro ring formation. To avoid chromatographic purification of the amorphous API as a final step, the authors reported the preparation of tetracarbonate 58 to allow the desired product to be purified by crystallization.101 58 was obtained as a stable crystalline solid, allowing the purification of 7 by filtration.


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Scheme 8 Synthetic route to 7 described by Murakata and co-workers.

Despite the improvements in the purification steps, the route has some challenges to consider. In terms of process safety, some of the reagents such as borane (BH3) and 2-methoxypropene are toxic or highly volatile, which necessitates greater control of handling and waste. Furthermore, the use of palladium as a catalyst for benzyl deprotection might lead to an excess of residual heavy metal in the final API (Scheme 8). For industrial purposes, two different routes are described in the literature for the large-scale synthesis of tofogliflozin hydrate.



Ohtake and co-workers reported a 12-step procedure for the synthesis of 7 in 39% overall yield (Scheme 9).97 The first challenge was the synthesis of crystalline intermediate 62. To prepare that compound, the hydroxyl groups of 42 were protected using 2-methoxy-1-propene in the presence of a catalytic amount of p-toluenesulfonic acid pyridine salt (PPTS) in THF to yield diether 59. Then, the crude intermediate was condensed with 12 (the glycosyl donor) and BuLi (or the Grignard reagent MgBr2·Et2O) in THF under cryogenic conditions to afford lactol 60. The last step in the construction of spiroketal 62 was the cyclization of 60 using p-TsOH in MeOH-THF, which upon treatment with chloroformate, DMAP and dichloromethane, gives corresponding carbonate 62. Although the author did not reported the α/β ratio, the protocol suggested that combining the reaction mixture (60, MeOH and THF) with MTBE in a 3:1 ratio led to the precipitation of the beta aglycone, which had been enriched during the spirocyclization procedure. Additionally, the authors determined the stereochemistry of tofogliflozin using X-ray crystallography and compared the observed structure with previous reports.96 The second challenge was the construction of the methylene bridge utilizing a Suzuki coupling reaction. In this case, 62 was reacted with the corresponding boronic acid in the presence of Pd(OAc)2 and 1,1’-bis(diphenylphosphanyl)ferrocene (ddpf) as the ligand. During this step, intermediate 58 was generated in 88% yield with less than 1 ppm residual Pd. The residue was recrystallized from EtOH-H2O (ratio 10:1) and acetylcysteine to afford the O-protected tofogliflozin. Finally, hydrolysis of the tetracarbonate (58) with NaOH in DME provided the target tofogliflozin.


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MeO OH

OMe

OMe

1) n-BuLi-hexane, 59, toluene, -70°C, 1 h

O

O

HO Br 42

OMe Br crude (yellow oil) 59

PPTS (cat), THF r.t. to 10 °C, 2 h

2) 12, toluene, -60°C, 2 h

O OMe OH OTMS

O TMSO

OTMS OTMS crude (orange oil) 60

1) 60 in THF-MeOH, TsOH, r.t., 2 h 2) the mixture, MTBE, 0 °C, 1 h 60 % (over 3 steps)

HO

OCO2Me

OH B

OH O

O

OCO2Me

O MeO2CO Pd(OAc)2, ddpf, K2CO3, DME. 85 °C, 3.5 h 88 %

O OCO2Me

O MeO2CO

OCO2Me OCO2Me 58

Cl

O

O

OCO2Me OCO2Me

DMAP, CH2Cl2 , -10 °C, 2 h 98 %

62

2N NaOH DME/MeOH, 1 h, r.t. 75 %

OH

O HO

OH OH 61

O OH

O HO

OH OH

7

Scheme 9 Scalable synthetic route to 7 reported by Ohtake and co-workers.

A third route was published by Yang and co-workers.102 Their method consists of a 9-step procedure that includes the purification and crystallization of tofogliflozin hydrate (Scheme 10). Unlike the methods previously discussed, the diaryl aglycone was formed by a regioselective Friedel-Crafts acylation of iodine intermediate 65 followed by the reduction of 67 with tetramethyldisiloxane and hydrolysis of the acetyl group under basic conditions. The protecting group on the benzyl intermediate was changed because the original protecting group was not compatible with a Grignard reagent and was therefore not suitable for the organometallic reagents used in the arylation step to generate 7. This alternative methodology offers some advantages. First, the formation of the aglycone moiety avoids non-crystalline intermediates, which simplifies the work-up



steps during the synthesis. Second, the methodology employs less expensive reagents and catalysts for the synthesis of 7 and thus reduces the manufacturing costs. Finally, the methodology allows the formation of the API in 23% overall yield after 9 steps without column chromatography.102

Scheme 10 Scalable synthetic route to tofogliflozin hydrate reported by Yang and co-workers.

3.3 Luseogliflozin (TS 071), Taisho Pharmaceutical

Figure 13 Chemical structure of luseogliflozin (6). ACS Paragon Plus Environment

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Luseogliflozin (6) was developed by Taisho Pharmaceutical and is marketed under the brand name Lusefi®. The drug received its first global-approval on the 24th of March, 2014, in Japan for use both as a monotherapy and in combination with other antihyperglycemic agents.103 Taisho Pharmaceutical collaborated with Novartis on the production of 6 starting in November 2013. Under this agreement, 6 is manufactured by Taisho Pharmaceutical and marketed by both Taisho and Novartis.33

3.3.1 Synthetic route

One synthetic strategy for the preparation of 6 was described and claimed by the pharmaceutical company Taisho (Scheme 11).104,105 The chemical process followed a similar approach to what was used for other SGLT2 inhibitors, which includes the synthesis of compound 73 and its condensation with 13 through the addition-reduction reactions of organometallic aromatic species. Furthermore, the protecting groups were removed in good yields (Scheme 11).



OH

Br2, Fe, CHCl3 5 °C to r.t. 34 %

O

Br

OH

Br

2) 72, AlCl3, CHCl3, -4 to 5 °C 82 % OEt

O 71

70

O

1) (COCl)2, DMF, CHCl3

O

O

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O

O

Et

73

72

Et3SiH, BF3OEt2 MeCN, 4 °C to r.t. , 5 h, 99 % (2 steps)

O

O O

OBn

1) Mg, C2H4Br2 THF, 74, reflux to r.t.

Et3SiH, BF3OEt2

S

MeCN, -15 °C . 77 %

BnO

OBn OBn 76

BnO

O HO S

OBn

BnO H2, 20% Pd(OH)2/C EtOAc, EtOH, r.t. 81%

OBn

75

O

2) THF, 13, 0 °C to r.t. Br 75 % BnO

S

BnO

O

Et

74

O OBn

OBn 13

O OH

O S

HO

OH

6

OH

Scheme 11 Synthesis of luseogliflozin reported by Hiroyuki and co-workers.

The first step in the synthesis of luseogliflozin is the bromination of 70 with Br2 in the presence of Fe in CHCl3. Bromide intermediate 71 was then treated with oxalyl chloride and then subjected to a Friedel-Crafts reaction with ethoxybenzene and AlCl3 as the Lewis catalyst to give benzophenone derivative 73. The synthesis of 74 was completed by the reduction of diaryl ketone 73 in the presence of Et3SiH and BF3·Et2O. Compound 76 was obtained by the activation of diaryl bromide 74 with Mg and condensation of the activated species with thiolactone 13. The condensate was further reduced to thioglucitol 76 using Et3SiH. Then, compound 6 was generate by hydrogenolysis of the benzyl groups by treatment with hydrogen (H2) over palladium.

A 6-step, regioselective synthesis of advanced intermediate 13 was reported previously (Scheme 12).104 In this route, the first step was the removal of the anomeric


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acetate using a base such as methylhydrazine in the presence of AcOH in DMF. Polyacetate 76 can be prepared in 8 steps using D-glucurono-3,6-lactone as the starting material with an overall yield of 35%.106–108 Then, the hydroxyl group of 77 was protected using 3,4-dihydropyran (DHP) in the presence of p-TsOH in CHCl3. After completion, the removal of acetate groups of 78 was accomplished with sodium methoxide in methanol. Later, benzyl bromide (PhCH2Br) with NaH in DMF was used to protect the free hydroxyl groups of 79, which generated tetrabenzyl ether 80. The tetrahydropyranyl group (THP) was removed by treatment with PPTS in EtOH at 80 °C, and this afforded tetrabenzyl-5-thio-D-glucopyranose 81. In the last step, 81 was oxidized by acetic anhydride in DMSO.

Scheme 12 Synthesis of thiolactone intermediate 13 by Kakinuma and co-workers



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The main drawback of this chemical route is the high number of steps to prepare the intermediate, reducing the overall yield of the final API to 7% based on the formation of 13 from 76.

3.4 Ertugliflozin (MK8835), Pfizer and Merck

Figure 14 Chemical structure of ertugliflozin (9)

Ertugliflozin (9) is an SGLT2 inhibitor developed by Pfizer and Merck for the treatment of T2DM.109 The product, which contains a novel bridged bicyclic ketal motif, was approved by the FDA in 2017.110,111


Initially, the synthesis of 9 was attempted via the nucleophilic addition of 84 to 83 using n-BuLi at low temperatures. However, according to their report, the reaction did not afford desired C-aryl glucoside 85. Instead, the high steric hindrance of the tetrasubstituted carbon (C5) affords only unsaturated lactone 86 instead of the desired lactol (Scheme 13).52,112 Cl Br

PMBO PMBO

O

O

BnO

O OBn

OBn 83

84 1) nBu-Li, toluene, THF, -84 °C, toluene-THF, 2) 83, THF, -78 °C,

Cl

PMBO PMBO BnO

O

PMBO

O

O

PMBO OH OBn

OBn not formed 85


+

BnO

O OBn

only product identified 86

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Scheme 13 Byproducts afforded by arylation of 85 at low temperatures reported by Bowles and co-workers.

The low overall yields and the problems with byproducts in this initial phase motivated the development of a new strategy that would provide efficient access to a variety of compounds. The first synthesis of 9 was published by Mascitti and coworkers from the Pfizer Process Research Group. The authors described a process with 13 linear steps using D-glucose as the starting material, and they obtained the desired product in 0.3% overall yield after HPLC separation of its C-4 epimer. (Scheme 14).113,114 This general strategy involves the preparation of Weinreb amide 19, which is synthesized in 10 steps from D-glucose (Scheme 14).59,114,115 In their synthesis, allyl protected intermediate 88 was prepared through a four-step process.114 These steps included the condensations of D-glucose with allyl alcohol followed by the protection of the remaining free hydroxy groups using trityl and benzyl chloride and the subsequent removal of the O-trityl group in an acidic medium.116–118 Other strategies based on allylation of the poly acetylated D-glucose catalyst with ZnCl2 followed by protection and deprotection were also employed.115,119 Thus, Swern oxidation of primary alcohol 88 generated the aldehyde precursor, which simultaneously undergoes an aldol condensation and Canizzaro reduction with formaldehyde to give tetrasubstituted intermediate 89.120,121 Lactol 92 was then prepared by the protection of 89 with p-methoxybenzyl bromide (PMBBr) in the presence of NaH in DMF followed by removal of the allyl moiety by PdCl2. The oxidation of hemiacetal 92 with DMSO and its subsequent activation with 93 provided corresponding Weinreb amide intermediate 19.



The next step consisted of the formation of the glycosidic bond to aryl moiety 84. A nucleophilic addition of aglycone 84 to open-chain gluconamide 19 was performed with partial epimerization at C4 and afforded corresponding cyclic lactol 95. Dioxabicyclo derivative 96 was formed through a one-pot process, which included the removal of the p-methoxybenzyl (PMB) ethers under acidic conditions followed by stereoselective intramolecular cyclization of the corresponding oxonium ion intermediate. Finally, 9 was obtained by hydrogenolysis of the benzyl protecting groups under transfer hydrogenation conditions followed purification of the desired product using preparative HPLC.114

Scheme 14 Synthetic route to 9 reported by Mascitti and co-workers.


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The synthesis of aglycone 84 was previously reported by Ellsworth Bruce and co-workers in their synthesis of 2.122,123 Their scheme was a linear 2-step process with an overall yield of 40% (Scheme 15). In this route, the authors carried out the chlorination of 97 using oxalyl chloride (COCl)2 in the presence of DMF in CH2Cl2 and generated the corresponding acyl chloride derivate. That intermediate was then converted to 98 via a Friedel-Crafts reaction with ethoxybenzene (72) in the presence of AlCl3 in CH2Cl2. The next step, the reduction of diaryl ketone 98, was accomplished using Et3SiH and BF3·Et2O in acetonitrile. This approach afforded 9 with an overall yield of approximately 13% (Scheme 15). Cl OH

Br 97 O +

O 72

1) 100 in CH2Cl2 (COCl)2 in DMF, r.t., overnight 2) 101, 4 °C, AlCl3, 1.5 h 3) recrystallization (x2) EtOH 64%

O O

Br Cl 98

Et3SiH, 98, CH2Cl2/MeCN (1:2), BF3OEt2, 20-50 °C, overnight 62 %

Br

O Cl 84

Scheme 15 Preparation of aglycone 84 cited by Ellsworth and co-workers.

An alternative approach was developed by the Pfizer Process Research Group (Scheme 16).

124

The key step of their improved stereoselective synthesis was the

addition of aryl dithiane 102 to aldehyde 101 using BuLi in THF at low temperatures (Scheme 16).124 Compound 102 was obtained in a 7-step process.125,126



Scheme 16 Selective synthesis of ertugliflozin from 9 developed by Mascitti.

Initially, diacetone-α-D-mannofuranose 99 was protected by silylation with TBDMSCl in the presence of imidazole. Compound 99 was prepared ketalization from mannose by.127 Carbonyl intermediate 101 was obtained in two consecutive steps by selective hydrolysis of 18 followed by oxidative cleavage of 100 with NaIO4 in EtOH. Then, the C-4 chiral center was generated by diastereoselective addition of aryl dithiane 102 to 101 employing n-BuLi and THF at low temperature. The high diastereoselectivity was explained by chelation effects in which a Cram chelate-type pretransition state promoted the preferential nucleophilic attack of the Si face, and this was confirmed by X-ray crystallography.124 The next step consisted of the removal of the silyl protecting group followed by the condensation of cyclic hemiacetal 104 with formaldehyde. This reaction allowed the formation of the tetrasubstituted derivative 105, which was subsequently treated with sodium borohydride (NaBH4) in MeOH at 23 °C to yield 106. Then, compound 9 was obtained following acidic hydrolysis of the acyclic advanced intermediate with TFA/H2O followed by an intramolecular one-pot


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cyclization. According to the authors, in contrast to the original discovery route, 9 was obtained without epimerization of C-4.114 The diastereoselective synthesis provided 9 in an overall yield of 26%, and the stereoselectivity was confirmed by X-ray crystallography. The advanced aromatic intermediates and aryl moiety 102126 were prepared in 7 linear steps in an overall yield of 6% (Scheme 17).

Scheme 17 Synthesis of advance intermediate 102 reported by Samas and co-workers.

In the first step, intermediate 107 was converted to the corresponding acyl chloride, which then undergoes Friedel-Crafts acylation in the presence of AlCl3 in CH2Cl2 to afford diaryl ketone 108. Then, radical bromination with NBS in the presence of AIBN in refluxing CCl4 provided 5-bromo-methanone 109, which after reduction with Et3SiH and BF3·Et2O in CH3CN/CH2Cl2, yielded 110. Then, a nucleophilic substitution reaction was carried out using sodium acetate in DMF at 100 °C to obtain 111. The next step involved a deacetylation reaction to give alcohol 112. The last intermediate was oxidized using DMSO and py·SO3 in the presence of Nethyldiisopropylamine (DIEA) to obtain aldehyde 113, which in turn was reacted with propane-1,3-dithiol and BF3·Et2O to produce desired dithiane 102.



Derivatives of 1,3-dithianes as masked nucleophilic acylating agents have been widely used as a strategy for C–C bond formation since these compounds change the normal reactivity of a carbonyl compound.128,129 Although the reported strategy solves the epimerization problems seen in other synthetic routes, increases the overall yields and does not require preparative chromatography for purification, this methodology was not implemented on the kilogram scale. Aglycone 102 not being commercially available and the high number of steps make this route unsuitable for industrial implementation based on cost, time, and manufacturing efficiency.130 To overcome this problem, the same group of authors developed an alternative approach for the synthesis of 9 and its co-crystalline complex, 118 (Scheme 18).113–115


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Scheme18 Multi-kilogram route to 9 and its crystalline form, 118.

The new strategy was based on the stereoselective arylation of 12 described for other SGLT2 inhibitors.73,131 The 5-step process affords the final product in 26% overall yield. As a first step, intermediate 114 was prepared through the arylation of 84 and 12 followed by the removal of the silyl ether protecting group using methanesulfonic acid (MsOH), which afforded 114 in 71% and >98% chemical purity. Then, persilylated intermediate 115 was obtained from the treatment of 114 with TMSCl in the presence of imidazole, producing the tetrasilyl ether intermediate, which upon selective monodesilylation with aqueous pyridinium p-toluenesulfonate (PPTS), provides the free primary alcohol. Then, intermediate 115 was treated with SO3-pyridine in DMSO and produce corresponding aldehyde 116. Compound 116 was subsequently reacted with formaldehyde under basic conditions to promote two sequential reactions (the formation of an aldol intermediate and a crossed-Cannizzaro reduction) that formed corresponding tetrasubstituted intermediate 117. Considering the described conditions, the authors were able to reduce the degradation of the DMSO-SO3 adduct at room temperature during the scale-up process and generated desired intermediate 116 after 3 h at 10 °C.115 Furthermore, the formation of byproducts during the aldol/Crossed-Cannizzaro step was reduced by using anhydrous reaction conditions and NaOEt as the base.115 After work-up, 9 was formed in the presence of p-toluenesulfonic acid immobilized on silica132 (Si-TsOH) as the acid promotor and dichloromethane (DCM) as the solvent. The use of a solid acid promotor allows the formation of the bicyclic ketal with high stereoselectivity, and it can be easily removed by filtration.113,115 An amorphous foam inappropriate for clinical development was generated during the



manufacture of 9.112 Meanwhile, the crystalline form, 118, was obtained by the treatment of 9 with L-pyroglutamic acid (L-PGA) using a solution of propanol:water heated to 55 °C.133 A new twelve-step process based on the addition of the aryl moiety to an openchain amide was reported by Pfizer (Scheme 19).133 The synthesis started with the oxidation of tetra-O-benzyl-D-glucose 119 under Swern conditions, which was followed by condensation with N-methylpiperazine and affording crystalline intermediate 120. To introduce the hydroxymethyl group, intermediate 121 was formed through oxidation of C-5 by adapting a method reported by Parikh-Doering.134 After that, ketoamide 121 was used to perform the stereoselective addition to the carbonyl with iodomethyl pivalate under Grignard conditions to produce subsequent product 122.

The removal of the pivaloyl group using NaOMe followed by ketalization gave protected diol 123. The introduction of aglycone moiety 125 was carried out via the arylation of methylpiperazine amide 124 to afford intermediate 126, which after a reduction using TFA and Et3SiH, provided bicylic 127. Then, a metal-catalyzed hydrogenolysis was performed under acidic conditions to afford a diastereomeric mixture of the desired API as the only detectable product. The final product was obtained through the acetylation and hydrolysis of the hydroxyl groups, which upon crystallization in a biphasic system with L- pyroglutamic acid (L-PGA), provided the API as a solid product. Although the authors did not report the diastereoselectivity, Xray crystallography was carried out to establish the structure of the desired diastereomer.


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Scheme 19 Synthetic route to 123 developed by Brenek and co-workers.

Nevertheless, the described methodology provided the target compound in a relatively lengthy linear process, and most of the intermediates had to be prepared inhouse. This increased the production cost and hindered implementation on a large scale. Furthermore, the use of cryogenic reaction temperatures during the protection steps, the preparation of the aryl moiety, and subsequent arylation of the aryl moiety make this process quite expensive.

3.5 Sotagliflozin (LX4211), Lexicon Pharmaceuticals



Figure 15 Chemical structure of 8.

Sotagliflozin or LX4211 is an orally administered small molecule (i.e., Lxyloside) developed by Lexicon Pharmaceuticals, Inc. (Princeton, NJ, USA) that acts as a dual SGLT1/SGLT2 inhibitor.135 Unlike most gliflozins, which are highly selective inhibitors of SGLT2, compound 8 was developed as a part of an alternative strategy that suggest that combining SGLT-1 and SGLT2 inhibition in a single molecule would provide complementary insulin-independent mechanisms for treating diabetes.136 Currently, sotagliflozin is in phase III clinical trials for the oral treatment of T1DM.137


The dual SGLT-1/SGLT2 inhibitor was prepared according to Scheme 20.138 The synthesis starts with the ketalization of commercially available L-xylose 129, which after subsequent hydrolysis, affords diol 130. Oxidation of the ketal intermediate using TEMPO and trichloroisocyanuric acid (TCCA) followed by treatment with morpholine provides key intermediates 131 and 132, respectively. Further, lithium– halogen exchange of 133 and addition of the resulting aryllithium to 132 (via a Grignard addition) produces ketone 134. Stereoselective reduction of 134 was performed using a combination of NaBH4 and cerium (III) chloride (CeCl3). Then, deprotection and rearrangement of the resulting crude alcohol under acidic conditions provided C-aryl glucoside 135. The thiol was introduced at the anomeric center in two steps. Initially,


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the free hydroxyl groups were acetylated by the treatment of 135 with pyridine and DMAP. Then, the nucleophilic thiol was generated in situ by the treatment of tetraacetate

136

with

thiourea

in

the

presence

of

trimethylsilyl

trifluoromethanesulfonate (TMSOTf), which provided methyl thioglucoside 137 after alkylation with methyl iodine (MeI) and DIEA. Finally, the desired methyl thioglucoside was obtained by the removal of the acetate groups via hydrolysis under basic conditions.

Scheme 20 Synthetic route to 8 reported by Cathleen and co-workers.

The use of amide derivatives (analogs of Weinreb amides) as electrophiles has been previously documented for the synthesis of other gliflozins.139,140 Those intermediates have been reported to be excellent acylating agents in organolithium or organomagnesium reactions.

CONCLUSIONS



Page 46 of 64

The increasing use of gliflozins for the treatment of diabetes has motivated the design of new synthetic approaches to overcome scale-up challenges, such as the poor crystallinity of advanced intermediates and cryogenic temperatures during the formation of carbon−carbon bonds to the anomeric center, as well as strategies focused on stereo and regioselective reactions. The review of the reported syntheses of gliflozins illustrates the recent efforts toward designing simpler, more efficient, less expensive and lower energy-cost processes. Although there are a variety of strategies available for the synthesis of these C-glycosyl compounds, most of the process chemistry improvements were focused on the C-glycosylation step; the strategies evolved from the use of classical strategies for the addition of gluconolactone derivatives to more sophisticated catalytic reactions using glycosyl cationic/anionic/radical species and transition-metal complexes.

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