**3.5. Multistep synthesis**

**3.3. Reductive amination**

274 New Advances in Hydrogenation Processes - Fundamentals and Applications

generated in a 91% yield (**Figure 6**) [27].

EtOH, Au/Al2O3 (70 mm), 125°C, 10 bar, 0.3 mL min−1.

**3.4. Protecting group manipulation**

process (**Figure 7**) [28].

materials [26].

Traditionally, borohydride reagents such as NaCNBH3, NaBH(OAc)3, or pyridine-BH3 have been used for reductive amination [25]. However, flow hydrogenation offers considerable advantages over transfer hydrogenation, such as improved atom economy, reduced environmental impact, simple reaction workups, and reduced exposure to toxic or reactive starting

Flow reductive aminations are generally conducted using 10% Pd/C or 20% Pd(OH)2/C, with the temperatures and pressures used substrate-dependent [1]. However, the use of an Au/ Al2O3 catalyst has facilitated a cascade nitro reduction and direct reductive amination to afford secondary amine **16** (**Figure 6**). Unlike many conventional Pd- and Ni-based catalysts, the Au/Al2O3 catalyst showed selective reduction in the nitrobenzene **14** over benzaldehyde **15**, aiding imine formation and subsequent reductive amination. Under optimised conditions (1:1.5 nitrobenzene **14**: benzaldehyde **15**, 80°C and 50 bar), the desired *N*-benzylaniline **16** was

**Figure 6.** Flow reductive amination to afford *N*-benzylaniline **16**. Reagents and conditions: H-cube® Pro, 0.05 M **15** in

Treatment of phenethylamine (**18**) and levulinic acid (**17**) in 2-methylfuran under the hydrogenation conditions of 85 bar H2 pressure, 150°C and carbon-supported Fe/Ni yielded pyrrolidine **19** with a 91% conversion via a sequential reductive amination and cyclisation

**Figure 7.** Flow reductive amination with carbon-supported Fe/Ni (C-Fe/Ni) to form pyrrolidine **19**. Reagents and con-

The synthesis of carbohydrate and nucleoside mimics has led to the development of Cnucleosides and C-glycosides as antibiotic, anticancer, and antiviral agents [29]. Using flow

ditions: H-cube® Pro, 0.025 M **18** in 2-methylfuran, C-Fe/Ni alloy (70 mm), 150°C, 85 bar, 0.3 mL min−1.

A number of integrated multistep flow syntheses, with hydrogenation a key step, have been reported and are typically characterised by the reduced need for purification between synthetic steps.

Previous batch syntheses of the kinase inhibitors CTx-0152960 and CTx-029488 required the use of Boc-piperidine in the key SNAr coupling with 1-fluoro-4-nitrobenzene to prevent formation of unwanted side products. Flow approaches removed this requirement facilitating rapid access to the Boc-free analogues in high yields (**Figure 9**) [33]. Of note, the flow hydrogenation of both the SNAr adducts of piperidine and morpholine (**27**) required no purification. Microwave coupling of 4-morphilinoaniline and 4-(piperazine-1-yl)aniline with 2-(2,5 dichloropyrimidine-4-ylamino)-*N*-methylbenzamide afforded access to the desired **31a** and **31b**. This hybrid approach reduced the number of synthetic steps, enhanced product yield, and increased atom economy through step reduction and minimal requirement for chromatographic purification, relative to the original batch approach [33].

**Table 3.** Flow reduction and removal of protecting groups.

The modular nature of flow chemistry instrumentation has allowed Ghislieri et al. by simple manipulation of the module order and selection of staring material to produce five active pharmaceutical ingredients (APIs) across three structural classes (γ-amino acids, γ-lactams, β-amino acids). From benzyl alcohol eight compounds of interest including the drugs Lyrica and Gabapentin were synthesised in good overall yields (49–75%) (**Figure 10**) [34].

Recent Developments in the Use of Flow Hydrogenation in the Field of Medicinal Chemistry http://dx.doi.org/10.5772/65518 277

**Starting material Product References**

276 New Advances in Hydrogenation Processes - Fundamentals and Applications

CBz protecting group 20% Pd(OH)2/C; 45°C, 10 bar, 1.0 mL min−1, 1 cycle; 67%

Benzyl protecting group 10% Pd/C; 65°C, full H2 mode, 1.0 mL min−1, 1 cycle; 60%

Phthalimide protecting group 10% Pd/C; 50°C, 1 bar, 50°C, 0.5 mL min-1; 56–81%

Cbz protecting group 10% Pd/C; RT, 1 bar, 50°C, 1.0 mL min−1; 99%; 97% ee

and Gabapentin were synthesised in good overall yields (49–75%) (**Figure 10**) [34].

The modular nature of flow chemistry instrumentation has allowed Ghislieri et al. by simple manipulation of the module order and selection of staring material to produce five active pharmaceutical ingredients (APIs) across three structural classes (γ-amino acids, γ-lactams, β-amino acids). From benzyl alcohol eight compounds of interest including the drugs Lyrica

**Table 3.** Flow reduction and removal of protecting groups.

Benzoyl protecting group

[30]

[31]

[32]

[56]

[57]

**Figure 9.** Synthesis of broad kinase inhibitors **31a** and **31b** by multistep flow synthesis. Reagents and conditions: (i) Vapourtec R2+, 4M piperidine or morpholine in DMF, 2 M 1-fluoro-2-nitrobenzene in DMF, 8 bar, 5 mL min−1; (ii) H-CubePro, 0.05M in MeOH, 10% Pd/C CatCart® (70 mm), 50 bar, 50°C, 1.0 mL min−1; (iii) Syrris FRX-100, 40% w/w aq. MeNH2, 0.5 mL min−1, 0–19°C, 19 h; (iv) Vapourtec R2+, 2,3,5-tri-chloropyrimidine, *<sup>i</sup>* PrNEt, *<sup>i</sup>* PrOH, 4 bar 100°C; (v) *n*-BuOH, 4 M HCl in dioxane (cat), 150°C, μW, 20 min.

**Figure 10.** Divergent multistep flow synthesis of γ-amino acid derivatives. Reagents and conditions: (i) bleach (2.5 eq.), TEMPO (0.05 eq.), NaHCO3 (0.3 eq.), KBr (0.2 eq.), 0°C; (ii) triethylphosphonoacetate (1.1 eq.), *t*BuOK (1.1 eq.), 50°C; (iii) CH3NO2 (11 eq.), TBAF (1.3 eq.), 50°C; (iv) H-cube®, Pd/C (10%), 60°C, 60 bar; (v) LiOH (3 eq.), 50°C. LLS = liquidliquid separator. Yields for individual modules determined upon isolation.

The flow chemistry modules above have also been used for the efficient synthesis of a number of known APIs (**Figure 11**). Within this multistage process, module five employed the use of the H-cube for the preparation of β-amino acids from unsaturated α-nitrile ester (90 bar, 100°C, Raney Ni). For nitro reductions, Pd/C and Raney Ni catalysts were favoured and afforded the desired compounds in good-to-excellent yields.

**Figure 11.** APIs prepared via the convergent multistep synthesis exemplified in **Figure 10**. Yields are reported for full processes without immediate purification over the 3–5 steps.

Both (*R*)- and (*S*)-rolipram were generated by using flow approaches and required no isolation of intermediates or purification, a significant step towards the automated manufacture of APIs [35]. The overall process used is outlined in **Figure 12**. While commercially available Ni and Pd catalysts failed in the case of aliphatic nitro compounds, however, a newly developed dimethylpolysilane-supported palladium/carbon (Pd/DMPSi-C) catalyst afforded the desired δ-lactam in a 74% yield (94% ee).

**Figure 12.** (**A**) Multistep flow synthesis of (*S*)-rolipram. Reagents and conditions: (i) Si-NH2/CaCl2, toluene, 75°C, 50 μL min−1; (ii) PS-(*S*)-Pybox, CaCl2·2H2O, 0°C, 100 μL min−1 (total); (iii) Pd/(DMPSi-C) (1.6 mmol), 100°C, 100 μL min−1 (total); (iv) HOOC-silica gel, 120°C, 210 μL min−1 (total). The flow reaction was continued for a week and the yield and the enantioselectivity maintained. (**B**) Further details of the flow hydrogenation step.

The success of multistage flow synthesis in API production, especially the use of flow hydrogenation suggests that these approaches will continue to rapidly develop and potentially become a standard method of synthesis.

#### **3.6. Scaffold formation**

Raney Ni). For nitro reductions, Pd/C and Raney Ni catalysts were favoured and afforded the

**Figure 11.** APIs prepared via the convergent multistep synthesis exemplified in **Figure 10**. Yields are reported for full

Both (*R*)- and (*S*)-rolipram were generated by using flow approaches and required no isolation of intermediates or purification, a significant step towards the automated manufacture of APIs [35]. The overall process used is outlined in **Figure 12**. While commercially available Ni and Pd catalysts failed in the case of aliphatic nitro compounds, however, a newly developed dimethylpolysilane-supported palladium/carbon (Pd/DMPSi-C) catalyst afforded the desired

**Figure 12.** (**A**) Multistep flow synthesis of (*S*)-rolipram. Reagents and conditions: (i) Si-NH2/CaCl2, toluene, 75°C, 50 μL min−1; (ii) PS-(*S*)-Pybox, CaCl2·2H2O, 0°C, 100 μL min−1 (total); (iii) Pd/(DMPSi-C) (1.6 mmol), 100°C, 100 μL min−1 (total); (iv) HOOC-silica gel, 120°C, 210 μL min−1 (total). The flow reaction was continued for a week and the yield and the

The success of multistage flow synthesis in API production, especially the use of flow hydrogenation suggests that these approaches will continue to rapidly develop and potentially

enantioselectivity maintained. (**B**) Further details of the flow hydrogenation step.

become a standard method of synthesis.

desired compounds in good-to-excellent yields.

278 New Advances in Hydrogenation Processes - Fundamentals and Applications

processes without immediate purification over the 3–5 steps.

δ-lactam in a 74% yield (94% ee).

Flow hydrogenation has provided access to scaffolds that were inaccessible via batch hydrogenation pathways such as the 1,4-benzodiazepin-5-ones (**Figure 13**). This scaffold has been targeted in treatments for tuberculosis [36] and control of the melanocortin receptors implicated in appetite control [37] and was readily accessed under flow conditions (THF, 0.3 mL min−1, 50 bar and 80°C). Isolated yields of up to 94% (**45**) requiring no purifications were noted [38].

**Figure 13.** Synthesis of the desired 1,4-benzodiazepin-5-ones **43** via batch and flow hydrogenation. Reagents and conditions: (i) H2, Pd/C (10%, 0.1 eq.), EtOAc:EtOH, 2:1 (0.03 M), 20°C, 1 atm; (ii) 1,4-cyclohexadiene (6 eq.), microwave mode, Pd/C (10%, 0.05 eq.), MeOH (0.1 M), 120°C; (iii) H2, Ru/C (5%, 0.02 eq.), THF (0.03 M), 20°C, 1 atm; (iv) H2, Ru/C (5%, 0.02 eq.), THF (0.03 M), reflux, 1 atm; (v)) H2, Ru/C (5%, 0.04 eq.), THF (0.03 M), 20°C, 1 atm; (vi) FeSO4·7H2O (10 eq.), NH4OH, EtOH, reflux; (vii) Fe (20 eq.), AcOH (0.1 M), 70°C; (viii) H-cube Pro®, Ru/C (5%), THF, 80°C, 50 bar, 0.3 mL min−1.

The chiral ester (**45**) is a key intermediate in the synthesis of the angiotensin II receptor blocker sacubitril. Enantioselective flow hydrogenation using a tube-in-tube system, through two loops, provided access to the required diastereomer at 0.45 g h−1. The introduction of the second loop was critical increasing the yield from 78 to 99% (**Figure 14**) [39].

**Figure 14.** Enantioselective hydrogenation flow preparation of chiral ester **45**. Reagents and conditions: H2, cat. DIPEA in EtOH (1 mol%), 20°C, 25 bar, 0.2 mL min−1.

In a similar manner, H-cube mediated nitro reduction and lactam cyclisation of γ-nitro-αamino esters with in situ cyclisation afforded, quantitatively, the corresponding γ-lactams (**47**) (**Figure 15**). Raney Ni hydrogenation (10 bar, 65°C) of the *syn*- diastereomer affords exclusively the *trans*- configuration with the *anti*-γ-nitro-α-amino esters gave the *cis* diastereomer [40].

**Figure 15.** Formation of γ-lactams via flow hydrogenation. Reagents and conditions: (i) H-cube®, Raney Ni, MeOH (0.01 M), 65°C, 10 bar, 1.0 mL min−1.

#### **3.7. Other reactions**

A variety of other reductions that are pertinent to medicinal chemistry can also be performed via flow hydrogenation as shown in **Table 4**.


**Table 4.** Selected other common flow reduction reactions.

In the synthesis of the antimalarial drug, OZ439 **49**, Lau et al. optimised the hydrogenation step successfully reducing only one of the aromatic rings using 20% Pd/C (**Figure 16**) [44]. The concentration of the undesired minor by-products **50** and **51** was minimised by control of the temperature and the amount of hydrogen entering the system. This flow approach to **49** also avoided the use of genotoxic 4-(2-chloroethyl)morpholine.

#### **3.8. Deuteration**

The incorporation of a deuterium label has been used widely to probe reaction mechanisms, to probe a compound's pharmacokinetic properties, and as an internal standard in NMR and mass spectrometry [46]. The increase in bond strength (C-H versus C-D) can modify a drug's pharmacokinetic profile, and this has led to the development of deuterium containing drugs. Deutetrabenazine (SD-809) is expected to be the first deuterated drug approved by the FDA.

**Figure 15.** Formation of γ-lactams via flow hydrogenation. Reagents and conditions: (i) H-cube®, Raney Ni, MeOH

A variety of other reductions that are pertinent to medicinal chemistry can also be performed

**Type of reaction Starting material Product Conditions References** Azide reduction 10% Pd/C, RT, 1 bar, 1.0 mL min−1, 94% [41]

94%

In the synthesis of the antimalarial drug, OZ439 **49**, Lau et al. optimised the hydrogenation step successfully reducing only one of the aromatic rings using 20% Pd/C (**Figure 16**) [44]. The concentration of the undesired minor by-products **50** and **51** was minimised by control of the temperature and the amount of hydrogen entering the system. This flow approach to **49** also

The incorporation of a deuterium label has been used widely to probe reaction mechanisms, to probe a compound's pharmacokinetic properties, and as an internal standard in NMR and mass spectrometry [46]. The increase in bond strength (C-H versus C-D) can modify a drug's

mL min−1, 100%

De-aromatisation 10% Ru/C or 10% Rh/C, 75–100°C, 50 bar, 1.0

11 examples

Selective reduction 20% Pd/C, 100°C, 5 bar, 1.0 mL min−1, 58% [44]

10% Pd/C, 80°C, 60 bar, 2.0 mL min−1, 90% [42]

Rh(CO)2(acac), 65°C, 25 bar, 0.6 mL min−1, 69–

[43]

[45]

(0.01 M), 65°C, 10 bar, 1.0 mL min−1.

via flow hydrogenation as shown in **Table 4**.

280 New Advances in Hydrogenation Processes - Fundamentals and Applications

**Table 4.** Selected other common flow reduction reactions.

avoided the use of genotoxic 4-(2-chloroethyl)morpholine.

**3.7. Other reactions**

Olefin reduction

Hydroformylation

**3.8. Deuteration**

**Figure 16.** Selective continuous flow hydrogenation of 4-4′-biphenol **48**. Reagents and conditions: (i) H2 (0.1 L min−1), Pd/C (20%), EtOH/H2O (1:1 v/v, 0.05 M), 100°C, 5 bar, 1.0 mL min−1.

The synthesis of SD-809 is not flow mediated, but its success does suggest that the incorporation of deuterium will become a more common feature in future drugs [47]. Deuterium incorporation can be accomplished from D2 gas and catalytic H-D exchange reactions between H2 and D2O. There are disadvantages to using deuterium gas on a laboratory scale, such as the handling of the gas itself, and the catalytic approaches are time consuming and do not always produce high purity D2. However, electrolysis of D2O by the Thales Nano H-cube® offers direct and rapid access to high purity D2 gas and is applicable across the suite of reduction chemistries discussed above affording highly flexible incorporation of deuterium. Hsieh et al. have demonstrated this in the deuteration of a series of *trans*-chalcones (**52**) of interest for their antidiabetic activity (**Figure 17**) [48].

**Figure 17.** Deuteration of *trans*-chalcone and various derivatives. Reagents and conditions: (i) H-cube®, D2O, 5% Pt/ Al2O3, 100°C, 100 bar, 1 mL min−1. Insert: chemical structure of SD-809.

Access to the required D2-gas uses two separate inlet streams where the sample is introduced in an aprotic solvent and with D2O electrolysis providing the required gas at which point the streams were combined and passaged over the deuteration catalyst (**Figure 18**).

**Figure 18.** Schematic outline of the continuous flow reactor used to prepare deuterated compounds by Hsieh et al [48].

The C2-halogen played a significant role in determining the ratio of di- to tri-deuterated species. With all analogues except the 2-F, conversions of ≥90% and exclusive formation of the di-deuterated species (**53**) were observed with 5% Pt/Al2O3. However with (*E*)-1-(2-fluorophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one this catalyst afforded a 5:95 ratio of **53**:**54** with 97% conversion. Switching to the less active Pd/BaSO4 catalyst afforded 100% conversion of the 2-F analogue, with a best ratio of 89:11 (**53**:**54**). The presence of the fluorine had a significant effect on the deuteration of this family of chalcones.
