Synthetic Approaches to Novel DPP-IV Inhibitors-A Literature Review

Abstract

Dipeptidyl peptidase IV (DPP-IV) is a serine protease whose inhibition has been an object of considerable interest in the context of developing novel treatments for type 2 diabetes mellitus. The development of novel DPP-IV inhibitors from natural or synthetic origin has seen a growing scientific interest in recent years, especially during the SARS-CoV-2 pandemic, when DPP-IV inhibitors were found to be of beneficial therapeutic value for COVID-19 patients. The present manuscript aims to summarize the most recent information on the synthesis of different DPP-IV inhibitors, emphasizing the various heterocyclic scaffolds that can be found in them. Special attention is devoted to DPP-IV inhibitors that are currently in clinical trials. Different synthetic approaches for the construction of DPP-IV inhibitors are discussed, as well as the most recent developments in the field.

Keywords: DPP-IV inhibitors; drug design; heterocyclic synthesis; medicinal chemistry; type 2 diabetes.

Figure 1

Cyanopyrrolidine-containing DPP-IV inhibitors.

Scheme 1

Reagents and conditions: (i) 2-Nitrobenzenesulfenyl chloride, 2 N NaOH; (ii) N-hydroxysuccinimide, carbodiimide; (iii) conc. NH₄OH, dioxane, 94% (over three steps); (iv) imidazole, POCl₃, pyridine, 95%; (v) 4 N HCl/dioxane, diethyl ether, 90%.

Scheme 2

Reagents and conditions: (i) DAST, dry CH₂Cl₂, -78 °C to rt; (ii) 2 equiv. LiOH, AcCN-H₂O (3-1), rt; (iii) EDC, HOBt, NH₃, DMF-AcCN; (iv) 4 M HCl, ethyl acetate; (v) cyanuric chloride, DMF, quantitative yield; (vi) 2 M HCl, H₂O-MeOH, quantitative yield.

Scheme 3

Reagents and conditions: (i) NaBH(OAc)₃, AcOH, 93%; (ii) H⁺, 78%.

Scheme 4

Reagents and conditions: (i) MeI, THF, potassium phthalimide, DMF, 150 °C, 5 h, 64%; (ii) THF, CHCl₃, pyridinium tribromide, −10 °C, 3 h, 56%; (iii) 2,4-dichlorophenylboronic acid, Pd(PPh₃)₄, LiCl, Na₂CO₃, toluene, EtOH, 105 °C, 4 h, 30%; (iv) R₁SO₂Cl or R₁COCl, NaH, DMF, 0 °C, 16 h 31–50%; (v) H₂N-NH₂, EtOH, rt for 1 h, 84–91%.

Scheme 5

Reagents and conditions: (i) NH₄OH, THF, thermal dehydration, 95–99%; (ii) borane, TFH; (iii) Et₃N, Boc₂O, CH₂Cl₂, 21–33% over two steps; (iv) TFA, CH₂Cl₂, 95–99%; (v) allo-Ile-Boc, TBTU, Et₃N, CH₂Cl₂, 38–80%; (vi) TFA, CH₂Cl₂, 95–99%.

Figure 2

Structure of Teneligliptin.

Scheme 6

Reagents and conditions: (i) NH₂NH₂·H₂O, ethanol, rt, 4 h; (ii) RC₆H₄CHO, ethanol, reflux, 8 h, 75–90%.

Scheme 7

Reagents and conditions: (i) Bi(NO₃)₂, ethanol, 60–70 °C, 3–5 h, 75–96%.

Scheme 8

Reagents and conditions: (i) CuI/DCM and DIPEA and Me₆TREN, 90–98%.

Scheme 9

Reagents and conditions: (i) Piperonal, 10% NaOH, absolute ethanol, rt 24 h; (ii) 4-substituted phenylhydrazine hydrochloride, AcOH, absolute ethanol, reflux 10 h, 85–87%.

Scheme 10

Reagents and conditions: (i) 3-chlorobenzaldehyde, NaOH, MeOH, reflux, 6 h; (ii) NH₂NH₂·H₂O, AcOH, 90 °C, 81%; (iii) 2-bromo-1-(p-tolyl)ethan-1-one, dry acetone, K₂CO₃, reflux, 8–10 h, 61–89%.

Scheme 11

Mechanism of the formation of pyrazole-derivative 23.

Scheme 12

Reagents and conditions: (i) 50% NaOH, dibromopropane, Et₄NBr, toluene, reflux, 5 h, 87%; (ii) 4 M HCl, dioxane, 100%; (iii) Boc–isoleucine, EDCI, TEA, CH₂Cl₂, 78%; (iv) RNCO, CH₂Cl₂, rt, 12 h, 70–80%; (v) 4 M HCl, dioxane–EtOAc, rt, 12 h, 87%.

Scheme 13

Reagents and conditions: (i) (CH₃)₂SO₄, K₂CO₃, acetone; (ii) benzoyl chloride, pyridine, 1 h, rt, 82% over two steps; (iii) KOH, pyridine, 8 h, rt, 82%; (iv) NH₂OH·HCl, pyridine, 45%.

Scheme 14

Reagents and conditions: (i) Na metal, 70–80 °C, 1 h, 45%; (ii) NH₂OH.HCl, NaHCO₃, MeOH, 64–66 °C, 15 h, 40%; (iii) NR¹R².TFA/NR¹R², EDCl, HOBt, TEA, DCM, rt, 16 h, 32–71%.

Scheme 15

Reagents and conditions: (i) CH₃NH₂, THF, 82%; (ii) o-ClC₆H₄-B(OH)₂, Pd₂dba₃, DavePhos, K₃PO₄, DMA, 68 °C, 74%; (iii) Br₂, AcOH, 88 °C, 94%; (iv) Fe, AcOH; (v) formic acid, polyphosphoric acid, 73% over two steps; (vi) BH₃-THF, reflux then HCl, 33%; (vii) Boc₂O; (viii) Zn(CN)₂, Pd₂dba₃, DavePhos, K₃PO₄, DMA, 92 °C; (ix) TFA, DCM, 70% over three steps.

Scheme 16

Reagents and conditions: (i) BrCN, H₂O, 4 h, 70%; (ii) chloroacetyl chloride, dry benzene, 0–5 °C, then reflux for 6 h, 85%; (iii) aminoacetic acid, pyridine, EtOH, 6 h, 75%.

Scheme 17

Reagents and conditions: (i) KMnO₄, NaOH, H₂O, reflux, 52%; (ii) NH₄OH, 150 °C in welded ampoule, 77%; (iii) Tetrabutylammonium bromide, dry K₂CO₃, 2-chloro-1-phenylethan-1-one, 25 °C, acetonitrile, 82%.

Scheme 18

Reagents and conditions: (i) NaBH₄, I₂, THF, 88%; (ii) TsCl, TEA, DCM, 76%; (iii) NaN₃, DMSO, 80 °C, 85%; (iv) alkynes, Cu(OAc)₂, CH₃CN, (v) 10% Pd/C-H₂, MeOH, 65–85%.

Scheme 19

Reagents and conditions: (i) CAN/MeOH, rt, 5 h, 97%; (ii) DIBAL, −78 °C, 3 h, 86%; (iii) Bestmann–Ohira reagent, K₂CO₃, MeOH, rt, 14 h, 94%; (iv) arylazides, Cu(OAc)₂, CH₃CN, rt, 3 h, 98–82%; (v) HBr/AcOH, 80 °C, 14 h, 65–85%.

Scheme 20

Reagents and conditions: (i) NH₂OH.HCl, toluene; (ii) toluene, reflux, 1–2 h, 28–91%, (iii) DBU, MeOH, r.t., 6 h, >90%; (iv) 2-hydroxy-N-(2,4,5- trifluorophenyl)acetamide or 2-amino-N-(2,4,5-trifluorophenyl)acetamide, Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), NEt₃, CH₂Cl₂, 4 h, 71–92%.

Scheme 21

Reagents and conditions: (i) acetonitrile, rt, 10 min; (ii) Et₃N, CuI, rt, 5 h; (iii) NaN₃, methanol-water, rt, 8 h, 60–77% overall yield.

Scheme 22

Reagents and conditions: (i) EDC, HOBt, DIEA, pyrrolidine, DMF; (ii) KHMDS, MeI, −78 °C; (iii) LiOH, THF, H₂O; (iv) CDI, 4- methanesulfonylbenzamidoxime, rt, 1 h, then 110 °C, 12 h; (v) TFA/CH₂Cl₂, 1 h.

Scheme 23

Reagents and conditions: (i) NH₂OH, K₂CO₃, MeOH; (ii) DIC, DCM; (iii) pyridine, reflux.

Scheme 24

Reagents and conditions: (i) t-BuOK, AcCN, rt, 16 h, 81%.

Scheme 25

Reagents and conditions: (i) NH₄OAc; 10 mol% p-toluenesulfonic acid, MeOH, reflux, 75–93%.

Scheme 26

Reagents and conditions: (i) KOH, MeOH, rt, 10–15 h; (ii) CH₃COCl, EtOH, 70 °C, 6–8 h, 85–93% over two steps; (iii) p-toluenesulfonic acid, MeOH, rt, 78–92%; (iv) NH₄OAc, EtOH, reflux, 88–95%; (v) NaOH, MeOH, 80–97%.

Scheme 27

Reagents and conditions: (i) 4-hydroxybenzaldehyde, DMF, K₂CO₃, 100 °C 6 h; (ii) 4-methoxyacetophenone, ethanol, 10% aq. NaOH, stirring for 2 h, 64% over two steps; (iii) hydrazine hydrate, ethanol, reflux 4 h, 80%; (iv) phenylhydrazine ethanol, reflux for 6 h, 75%; (v) 4-hydroxyacetophenone, DMF, K₂CO₃, reflux for 12 h; (vi) aldehydes (2-chlorobenzaldehyde or 4-methoxybenzaldehyde), ethanol, 10% aq. NaOH, stirring for 2 h, 57–65% over two steps.

Scheme 28

Reagents and conditions: (i) ethyl acetoacetate, piperidine, 0 °C to rt, overnight; (ii) KSF montmorillonite, 160 °C, 46%; (iii) substituted amine, anhydrous K₂CO₃, KI, DMF, 70–80 °C, 12–18 h, 43–91%.

Scheme 29

Reagents and conditions: (i) N-acetyl glycine, Ac₂O, NaOAc, reflux, 7 h, 47%; (ii) EtOH, conc. HCl, reflux, 1 h, 61%; (iii) 2-bromoacetyl bromide, TEA, DCM, rt, 2 h, 89%; (iv) substituted amine, Et₃N, DMF, rt, 16 h, 49–85%.

Scheme 30

Reagents and conditions: (i) ethyl chloroformate, EtOAc, rt, 2 h, 48%; (ii) ethyl acetoacetate, 70% EtOH in H₂SO₄, rt, 16 h, 85%; (iii) AcOH, H₂SO₄, 106–108 °C, 1 h, 71% (iv) bromo acetyl bromide, Et₃N, DCM, rt, 2 h, 93%; (v) substituted amine derivatives, TEA, DMF, rt, 16 h, 47–72%.

Scheme 31

Reagents and conditions: (i) NaNO₂, MeOH, AcOH, 6 h, rt, 43%; (ii) 3-oxoglutaric acid, conc. H₂SO₄, sonication, 1.5 h, 30 °C, 88%; or 3-oxoglutaric acid, conc. H₂SO₄, 20 h, rt, 80%; (iii) substituted phenol derivative, SOCl₂, 63–76%.

Scheme 32

Reagents and conditions: (i) (R)-ArCH₂CH(NHBoc)CH₂CO₂H, EDC, HOBt, DIEA, DMF; (ii) H₂, Pd(OH)₂, MeOH.

Scheme 33

Reagents and conditions: (i) chloroacetyl chloride, TEA, DCM, −15 °C to 0 °C, 2 h, 80–93%; (ii) chloroacetic acid, DCC, DCM, 0 °C, 4 h; (iii) TEA, TFH, rt, 6–8 h, 64–87%.

Scheme 34

Reagents and conditions: (i) NaOH, acetone, reflux, 1.5 h, 1–76%.

Scheme 35

Reagents and conditions: (i) benzil, K₂CO₃, MeOH, reflux, 90–95%; (ii) ethyl 2-chloroacetate, K₂CO₃, anhydrous DMF, 2 h, good to excellent yield.

Figure 3

Structure of Linagliptin.

Scheme 36

Reagents and conditions: (i) anhydrous pyridine, 2–8 °C, sodium bicarbonate, 1 h, 72–76%; (ii) H₂NN₂H.H₂O, ethanol, 6 h, 68–74%; (iii) aldehydes, ethanol, glacial acetic acid, reflux, 8 h, 66–76%; (iv) anhydrous toluene, DIPEA, POCl₃, reflux, 4–6 h, 64–82%; (v) phenol, reflux, 4 h, 70–78%.

Scheme 37

Reagents and conditions: (i) oxalic acid, 4 N HCl, reflux, 4 h; (ii) anhydrous K₂CO₃, DMF, methyl iodide, heating, 6 h, 99%; (iii) ClSO₃H, heating, 90 °C, 3 h; (iv) heterocycles or primary amines, EtOH, reflux, 3 h, 72–75%; (v) sulfa drugs, Et₃N, EtOH, 6 h, 81–85%.

Figure 4

Structure of alogliptin.

Scheme 38

Reagents and conditions: (i) POCl₃, dimethylaniline, reflux; (ii) NaOH, 47–76%; (iii) NaH, LiBr, 2-cyanobenzyl bromide, 20–52%; (iv) 3-(R)-aminopiperidine, NaHCO₃, 60 °C, 49–74%.

Scheme 39

Reagents and conditions: (i) R¹Br, DIPEA, DMF, rt; (ii) R²Br, K₂CO₃, KI, DMF, rt; (iii) (R)-3-(Boc-Amino)piperidine, K₂CO₃, DMF, 90 °C, N₂ atmosphere; (iv) CH₂Cl₂, TFA, rt, 65–84%.

Scheme 40

Reagents and conditions: (i) NaOH, dil. EtOH, rt; (ii) NaOH, abs. EtOH, 66–76%; (iii) abs. dichloromethane, TEA, rt, 65–75%.

Scheme 41

Reagents and conditions: (i) SOCl₂, DCM, reflux; (ii) N,O-dimethylhydroxylamine, DCM, rt, 47% over two steps; (iii) LiAlH₄, THF, −20 °C, quantitative yield; (iv) Zn, TBDMSiCl, ethyl bromoacetate, THF, reflux, 89%; (v) LiAlH₄, THF, −10 °C, 48%; (vi) TrtCl, TEA, DCM, rt, 96%; (vii) PPh₃, diethyl azodicarboxylate (DEAD), diphenylphosphorylazide (DPPA), THF, rt, 32%; (viii) Amberlist 15, DCM/MeOH, reflux, 41%; (ix) MsCl, TEA, DCM, rt, 92%; (x) K₂CO₃, N,N-dimethylformamide (DMF), 90 °C, 74%; (xi) NH₂NH₂·H₂O, MeOH; (xii) NH₂NH₂·H₂O, PdO, MeOH, reflux, 83%.

Scheme 42

Reagents and conditions: (i) RNH₂, NaOH, 40–45 °C, 64–87%; (ii) K₂CO₃, reflux, 120–135 °C; (iii) conc. H₂SO₄, H₂O, reflux, 80%.

Figure 5

Structure of Omarigliptin.

Scheme 43

Reagents and conditions: (i) SOCl₂, MeOH, 0 °C, 2 h, 89%; (ii) PhCHO, TEA, MgSO₄, CH₂Cl₂, rt, 18 h, 97%; (iii) t-BuOK, CH₂CHCH₂Br, THF, rt, 18 h; (iv) 6 N HCl, EtOAc, 1 h; (v) Boc₂O, THF, reflux, 18 h, 87%; (vi) O₃, PPh₃, CH₂Cl₂, −78 °C, 36%; (vii) LiOH, THF, 1 h, 95%; (viii) L-Cys-OMe·HCl, NaHCO₃, EtOH, 16 h, 51%; (ix) p-TsOH, toluene, reflux, 1 h, 23%; (x) NH₃, MeOH, rt, 2 h, 97%; (xi) TFAA, TEA, CH₂Cl₂, rt, 1 h, 84%; (xii) TFA, CH₂Cl₂, rt, 1 h, 14% after preparing HPLC; (xiii) HCl (g), CH₂Cl₂/Et₂O, 2 h, 53%.

Scheme 44

Reagents and conditions: (i) morpholine, toluene, reflux, Dean–Stark apparatus; (ii) Umemoto’s reagent (S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate), DMAP, DMAc, 57% over two steps; (iii) toluene, reflux, then NaBH(OAc)₃, CH₃COOH, 1,2-dichloroethane, 72%; (iv) CHCl₃, reflux, Dean-Stark apparatus, then NaBH(OAc)₃, CH₃COOH, 1,2-dichloroethane, 72–75%; (v) TFA, DCM, 77–90%; (vi) t-BuOK, THF, 60%.

Figure 6

Structure of Sitagliptin and alogliptin.

Scheme 45

Reagents and conditions: (i) CuBr₂, ethyl acetate, CHCl₃, reflux, 16 h, 90%; (ii) 2-aminopyridine, NaHCO₃, EtOH, rt, 80–84%; (iii) POCl₃, DMF, 0–60 °C, 2 h, 65–68%; (iv) NH₂OH. HCl, pyridine, EtOH, reflux, 83–90%; (v) Zn, NaOAc, AcOH, rt, 10 h, then Boc₂O, NaOH, EtOH, rt, 3 h, then HCl(gas), ethyl acetate/ether, 0 °C, 36–71%.

Scheme 46

Reagents and conditions: (i) diethyl malonate, EtONa EtOH, reflux, 71%; (ii) POCl₃, N,N-dimethyl-aniline, 100 °C, 80%; (iii) 1 N NaOH, 90 °C; (iv) Cs₂CO₃ or K₂CO₃ or DIPEA, DMF, 90 °C, 46–69%; (v) DIPEA, DMF, 90 °C, 20–33%.

Scheme 47

Reagents and conditions: (i) H₂O, KHCO₃, Br₂ in aqueous solution of KBr, stirring, 30–40 min, 80 °C, 71%; (ii) K₂CO₃, stirring, 4–6 h, rt, 68–85%; (iii) NH₂NH₂·H₂O 80%, MeOH, reflux, 8–9 h, 62–76%.

Scheme 48

Reagents and conditions: (i) Br₂/KSCN, DMF, 83%; (ii) DMF, 80–120 °C, 89%; (iii) R¹Cl, anhydrous K₂CO₃, DMF, 70 °C, 74–78% (iv) N-substituted chloracetamides, anhydrous K₂CO₃, DMF, 70–80 °C, 64–68%.

Scheme 49

Reagents and conditions: (i) malonodinitrile, ethanol, 10% aq KOH, 95%; (ii) propanol, 120 °C, 43%; (iii) BH₃-THF, THF, 65 °C, 46%.

Scheme 50

Reagents and conditions: (i) formamide, NaOEt, EtOH, reflux; (ii) POCl₃, reflux; (iii) 4-amino-3-fluorobenzonitrile, NaH, THF, reflux, overnight, 35% or 2-fluoro-4-(methylsulfonyl)aniline, X-Phos, Pd₂(dba)₃, Cs₂CO₃, dioxane, reflux, overnight, 83%; (iv) 2-chloroethyl chloroformate, 1,2-dichloroethane, reflux, overnight, then MeOH, reflux, 3 h, 76%; (v) R²Cl, K₂CO₃, DMF, 70 °C, overnight, 64–94%.

Scheme 51

Reagents and conditions: (i) 4,4′-dimethoxybenzhydrol, H₂SO₄, HOAc, 47%; (ii) LiOH(aq), THF, 80%; (iii) DPPA, TEA, toluene, BnOH, reflux, 65%; (iv) Pd(OH)₂, H₂, MeOH, Boc₂O, 73%; (v) ceric ammonium nitrate, CH₃CN, H₂O, 0 °C, 75%; (vi) CuI, MeNHCH₂CH₂NHMe, K₂CO₃, toluene, reflux; (vii) TFA, CH₂Cl₂, 33–80% over two steps.

Scheme 52

Reagents and conditions: (i) water bath, 1 h, then 5% Na₂CO₃; (ii) Pd(OAc)₂, PtBu₃, t-BuONa, THF, 21–51%; (iii) NH₂OH.HCl, NaOAc, EtOH, 83–99%; (iv) H₂, Raney Ni, aq NH₃, MeOH, THF, 34–85%.

Scheme 53

Reagents and conditions: (i) NaOH, 90%; (ii) BrCH₂CN, N,N-Diisopropylethylamine, DMF, 55%; (iii) MeNH₂ or EtNH₂, 1,4-dioxane, rt; (iv) 6 N HCl, reflux, 65%.