Scheme 1
The aspirin saga and the “first” synthetic drug.
Scheme 2
The penicillin antibiotics.
Scheme 3
From the Mexican yam to steroidal drugs and the birth-control pill.
Figure 1
Drug origins: TS, totally synthetic; S-NP inspired, synthetics inspired by NPs; S-NP derived, synthetics derived from NPs; Biologicals + vaccines; NP, isolated NPs.
Scheme 4
The building block approach for the synthesis of sildenafil (18).
Scheme 5
The totally synthetics sildenafil (18), vardenafil (19), tadalafil (20) and avanafil (21); a second social revolution?
Figure 2
Atorvastatin (22), imatinib (23), paclitaxel (24), azathioprine (25), efavirenz (26), diazepam (27) and artemisinin (28).
Scheme 6
General scheme for a continuous flow set-up.
Figure 3
Surface to volume ratio, Flow vs Batch reactors.
Figure 4
An overview on Novel Process Windows (NPWs).
Scheme 7
Rufinamide (32) synthesis: (a) Solvent- and catalyst-free Huisgen cycloaddition between 29 and 30. (b) Schematic representation of the microcapillary assembly.
Scheme 8
a) Comparison of the most common tetraphenylporphyrin (35a) syntheses in batch and flow conditions. b) Set-up for the one-pot 35a synthesis under continuous flow conditions.
Scheme 9
Adipic acid (37) synthesis - Set-up of the packed-bed reactor.
Scheme 10
Metal catalyzed molecular oxygen oxidation of 2-benzylpyridines, and some important intermediates for API synthesis.
Scheme 11
Set-up of the gas-liquid continuous flow reactor used by Pieber and Kappe.
Scheme 12
Pharmaceutically relevant compounds having β-amino alcohol moieties.
Scheme 13
a) Metoprolol (55) synthesis - comparison between microwave (MW) and flow conditions. b) Flow chemistry set-up.
Scheme 14
Set-up for the 1H-4-substituted imidazoles synthesis in continuous flow conditions and highT⁄p.
Scheme 15
Bisimidazole 61 synthesis - symmetrical core unit of daclatasvir (62).
Scheme 16
Set-up for the copper-catalyzed continuous flow couplings of aniline derivatives.
Scheme 17
Synthesis of 4-aryl-2-butanones - Nabumetone (67).
Scheme 18
Flow-plant system for aldol condensations.
Figure 5
The two main flow-photoreactor types.
Scheme 19
Continuous flow synthesis of Irinotecan® (69) by Heraeus Noblelight (Germany).
Scheme 20
Batch and continuous flow syntheses of vitamin D3 (74).
Scheme 21
Synthesis of artemisinin (28) under continuous photo-flow conditions, and transformation into derivatives 77-79.
Scheme 22
The brominated rosuvastatin intermediate (82) synthesis.
Scheme 23
Leucine fluorination under continuous flow conditions; Odanacatib® synthesis.
Scheme 24
Naphthol photooxidations followed by rearrangement; vitamin K3.
Scheme 25
Elbasvir (91) synthesis.
Scheme 26
Ibuprofen (93) synthesis by the photo-Favorskii rearrangement.
Scheme 27
General strategy for the multi-step continuous flow synthesis of NPs.
Scheme
28
Simplified set-up for the synthesis of neolignan natural product grossamide (95) in flow.
Scheme 29
Continuous flow synthesis of (±)-oxomaritidine (104).
Figure 6
NPs prepared using combined batch and continuous flow processes up to 2013.
Scheme 30
Continuous flow synthesis of the homoallylic alcohol 122.
Scheme 31
Integrated batch and flow synthesis of the key aldehyde 135.
Scheme 32
Continuous flow synthesis of the bis-alkyne 144.
Scheme 33
Final steps of the spirodienal A (147) synthesis.
Figure 7
NPs prepared using batch and flow integrated approaches, since 2014.
Scheme 34
An example of end-to-end continuous flow synthesis with integrated analysis and separation for diphenyldramine hydrochloride (161).
Scheme 35
Continuous flow three-step synthesis of prexasertib monolactate monohydrate (166) under GMP conditions.
Scheme 36
Semi-continuous isocyanate formation followed by Curtis rearrangement.
Scheme 37
Homogeneous continuous flow reductive amination of an intermediate of evacetrapib synthesis.
Scheme 38
DSM continuous-flow nitration process.
Scheme 39
Nitroethanol continuous flow synthesis developed for aliskiren production.
Scheme 40
The formylation process developed by Merck, in order to avoid batch scale-up problems.
Figure 8
Selected examples of bioactive heterocyclic molecules prepared in continuous flow regime.
Scheme 41
Continuous flow synthesis of highly substituted pyrazoles and pyrazolines.
Scheme 42
Synthesis of AS-136A using a unified continuous flow platform.
Scheme 43
Sequence in flow to prepare imidazo[1,2-a]pyridine scaffolds.
