Continuous-Flow Chemistry and Photochemistry for Manufacturing of Active Pharmaceutical Ingredients

Abstract

An active pharmaceutical ingredient (API) is any substance in a pharmaceutical product that is biologically active. That means the specific molecular entity is capable of achieving a defined biological effect on the target. These ingredients need to meet very strict limits; chemical and optical purity are considered to be the most important ones. A continuous-flow synthetic methodology which utilizes a continuously flowing stream of reactive fluids can be easily combined with photochemistry, which works with the chemical effects of light. These methods can be useful tools to meet these strict limits. Both of these methods are unique and powerful tools for the preparation of natural products or active pharmaceutical ingredients and their precursors with high structural complexity under mild conditions. This review shows some main directions in the field of active pharmaceutical ingredients' preparation using continuous-flow chemistry and photochemistry with numerous examples of industry and laboratory-scale applications.

Keywords: active pharmaceutical ingredients; flow chemistry; photochemistry.

Scheme 1

Ibuprofen flow synthesis: 1—isobutylbenzene, 2—propionic acid, 3—triflic acid, 4—1-(4-isobutylphenyl)propan-1-one, 3—methyl 2-(4-isobutylphenyl)propanoate, 6—ibuprofen.

Scheme 2

Scheme of the three-minute ibuprofen synthesis from Jamison (2015) [16]: 1—isobutylbenzene, 4—1-(4-isobutylphenyl)propan-1-one, 5—methyl 2-(4-isobutylphenyl)propanoate, 6–ibuprofen (sodium salt), 7—propionyl chloride.

Scheme 3

Enantioselective continuous-flow synthesis of (S)-warfarin: 8—4-hydroxy-coumarin, 9—cinchona-derived primary amine catalyst, 10—benzalacetone, 11—warfarin.

Scheme 4

First flow formation of atropine: 12—tropine, 13—phenylacetyl chloride, 14—formaldehyde, 15—atropine.

Scheme 5

Atropine flow synthesis: 12—tropine, 13—phenylacetyl chloride, 14—formaldehyde, 15—atropine.

Scheme 6

Parke–Davis and Company’s 1956 synthesis of ketamine: 16—o-chlorobenzonitrile, 17—cyclopentylmagnesium bromide, 18—(2-chlorophenyl)(cyclopentyl)methanone, 19—(2-chlorophenyl)(methylimino)methylcyclopentan-1-ol, 20—ketamine.

Scheme 7

Flow synthesis of ketamine: 18—(2-chlorophenyl)(cyclopentyl)methanone, 19—(2-chlorophenyl)(methylimino)methylcyclopentan-1-ol, 20—ketamine, 21—2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.

Scheme 8

Flow synthesis of imatinib by Ley and co-workers: 22—4-(chloromethyl)benzoyl chloride, 23—3-bromo-4-methylaniline, 24—N-(3-bromo-4-methylphenyl)-4-(chloromethyl)benzamide, 25—1-methylpiperazine, 26—substituted benzamide 27—4-(pyridin-3-yl)pyrimidin-2-amine, 28—imatinib.

Scheme 9

Flow synthesis of imatinib: 29—(4-methylpiperazin-1-yl)methyl benzonitrile, 30—4-bromo-2-chloro toluene, 28—imatinib, 31—2-aminopyrimidine hydrochloride.

Scheme 10

Flow synthesis of rufinamide: 32—difluorobenzyl bromide, 33—2-(azidomethyl)-1,3-difluorobenzene, 34—methyl propiolate, 35—propiolamide, 36—rufinamide.

Scheme 11

Convergent-flow synthesis of rufinamide utilizing radial system: 32—difluorobenzyl bromide, 33—2-(azidomethyl)-1,3-difluorobenzene, 34—methyl propiolate, 35—propiolamide, 36—rufinamide.

Scheme 12

Linear Flow synthesis of rufinamide utilizing radial system: 32—difluorobenzyl bromide, 33—2-(azidomethyl)-1,3-difluorobenzene, 36—rufinamide, 37—methyl propiolate, 38—methyltriazole carboxylate.

Scheme 13

One-flow approach in (−)-oseltamivir synthesis: 39—N-(2-nitrovinyl)acetamide, 40—2-(pentan-3-yloxy)acetaldehyde, 41—thiourea, 42—diphenylmethyl pyrrolidine, 43—ethyl 2-(diethoxyphosphoryl)acrylate, 44—oseltamivir.

Scheme 14

Fast-flow synthesis of Linezolid: 45—(+)-epichlorhydrin, 46—3,4-difluoronitrobenzene, 47—morfoline, 48—linezolid.

Scheme 15

Lomustine flow synthesis: 49—cyclohexylamine, 50—1-chloro-2-isocyanatoethane, 51—tert-butyl nitrite, 52—lomustine.

Scheme 16

Continuous-flow synthesis of rolipram: 53—3-(cyclopentyloxy)-4-methoxybenzaldehyde, 54—dimethyl malonate, 55—rolipram.

Scheme 17

Continuous-flow synthesis of norephedrine: 56—benzaldehyde, 57—nitroethane, 58—norephedrine.

Scheme 18

Photochemical synthesis of ibuprofen: 1—isobutylbenzene, 59—2-chloropropanoyl chloride, 60—chloropropiophenone, 61—transition state, 6—ibuprofen.

Scheme 19

Synthesis of hypericin by utilization of LED light source: 62—emodin, 63—photohypericin, 64—hypericin.

Scheme 20

Photocycloaddition synthesis of neostenine: 65—difuran intermediate, 66—pyrrole intermediate, 67—furoindole intermediate, 68—neostenine.

Scheme 21

Total synthesis of (+)-goniofufurone: 69—D-isosorbide, 70—tetrahydrofuro[3,2-b]furan-3-yl acetate, 71—2-phenylhexahydro-2H-furo[3,2-b]oxeto[3,2-d]furan-5-yl acetate, 72—2-phenylhexahydro-2H-furo[3,2-b]oxeto[3,2-d]furan-5-yl acetate isomer, 73—goniofufurone.

Scheme 22

Synthesis of ascaridol: 74—L-terpinene, 75—ascaridol.

Scheme 23

Fulvestrant side chain preparation via continuous-flow photochemistry: 76—allyl alcohol, 77—pentafluoro-2-iodopentan-1-ol, 78—pentafluoro-1-ol, 79—fulvestrant.

Scheme 24

(+)-Epigalcatin photocatalytic preparation: 80—1,2-bis benzylidene succinate amide ester, 81—cyclization product—(3,4-dimethoxyphenyl-hexahydro-1H-[1,3]dioxolo[4′,5′:6,7]naphtho[2,3-f]pyrrolo[2,1-c][1,4]oxazocine-6,14-dione), 82—isolated product—(methyl (5R,6R)-5-(3,4-dimethoxyphenyl)-7-((S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl)-5,6-dihydronaphtho[2,3-d][1,3]dioxole-6-carboxylate), 83—epigalcatin.

Scheme 25

Synthesis of myriceric acid A intermediate: 84—heptamethyl-3,16-dioxooctadecahydro-(epoxymethano)picen-13-yl nitrite, 85—myriceric acid A intermediate.

Scheme 26

Continuous-flow synthesis of artemisinin: 86—dihydroartemisinic acid, 87—hydroperoxy-4,7-dimethyl-octahydronaphthalen-1-yl propanoic acid, 88—artemisinin.

Scheme 27

Continuous-flow synthesis of vitamin D3: 89—provitamin D3, 90—previtamin D3, 91—vitamin D3.

Scheme 28

Flow photobromination of an intermediate for the production of rosuvastatin: 92—5-methyl substituted pyrimidine, 93—5-methyl brominated pyrimidine, 94—rosuvastatin.

Scheme 29

Two-step continuous-flow hydantoin synthesis: 95—amine, 96—aminonitrile, 97—hydantoin.

Scheme 30

Synthesis of oxazolidinone in batch: 98—L-phenylalanine methyl ester hydrochloride, 99—methyl bis(tert-butoxycarbonyl)-L-phenylalaninate, 100—bromo-phenylpropanoate, 101—oxazolidinone.

Scheme 31

Synthesis of oxazolidinone under the flow conditions: 99—methyl bis(tert-butoxycarbonyl)-L-phenylalaninate, 100—bromo-phenylpropanoate, 101—Oxazolidinone.

Scheme 32

Continuous-flow synthesis of CDK9 inhibitor: 102—pyridin-4-ylmethanol, 103—propionaldehyde, 104—(R)-2-methyl-3-(pyridin-4-yl)propanal, 105—4-(4-fluoro-2-methoxyphenyl)pyridin-2-amine, 106—CDK9 inhibitor.