Retrosynthesis in the Manufacture of Generic Drugs: Selected Case Studies

ISBN-13: 9781119155539 / Angielski / Twarda / 2020 / 432 str.

Pedro P. Santos;William Heggie

Spis treści

Preface xvA note about the book and its use xviiAbbreviations xix1 Introduction 12 Gabapentin 52.1 Worldwide sales and patent status 62.2 Gabapentin structure and general retrosynthetic strategy 72.2.1 Using the primary amine for retrosynthesis 72.2.2 Rearrangement as a key synthetic step: taking advantage of symmetrical intermediates 82.2.3 Avoiding the rearrangement and obtaining the amine by a reduction step 102.2.4 Disconnecting only one carbon chain from the cyclohexane ring 102.2.5 Using an aromatic ring to produce the saturated cyclohexane ring 112.3 The first reported synthesis of gabapentin 132.4 The evolution of the chemical synthesis of gabapentin 142.4.1 Initial development of synthetic routes to Gabapentin using a rearrangement step 142.4.2 Routes to the spiro-anhydride or spiro-imide intermediates 162.4.3 Synthetic routes of Gabapentin using a one carbon atom nucleophile 182.4.4 The 1,4-dicarbonyl intermediate routes 232.4.5 Synthetic processes based on a Birch reduction 252.4.6 Re-visiting the rearrangement as a key step 262.4.7 Other synthetic routes 262.4.8 Purifying the product 272.5 Strategy comparison and conclusions 282.6 Lessons from the gabapentin case 292.7 Reaction conditions for schemes A to D 312.8 References 343 Clopidogrel 393.1 Worldwide sales and patent status 403.2 Clopidogrel structure and general retrosynthetic strategy 413.2.1 Chirality and Clopidogrel 413.2.2 Retrosynthetic analysis 443.3 The first reported synthesis of Clopidogrel 493.4 The evolution of chemical synthesis of Clopidogrel 503.4.1 Synthetic routes using a resolution step 503.4.2 Asymmetric synthesis in Clopidogrel production 663.4.3 Other synthetic processes 673.4.4 Synthesis of the Thiophene building block 693.5 Strategy comparison and conclusions 713.6 Lessons from the Clopidogrel case 733.7 Reaction conditions for schemes C to J 733.8 References 784 Citalopram And Escitalopram 854.1 Worldwide sales and patent status 864.2 Escitalopram/Citalopram structure 874.3 Retrosynthetic analysis of Citalopram 884.3.1 Disconnection of the propylamine side chain 884.3.2 The aromatic nitrile group 894.3.3 Retrosynthesis of the trisubstituted aromatic intermediate 894.4 Escitalopram retrosynthesis 934.5 The first reported synthesis of Citalopram 954.6 The evolution of chemical synthesis of Citalopram 964.7 A quick glimpse of Escitalopram 974.8 The two Grignard phase in Citalopram synthesis 984.8.1 Two Grignard route using 5-bromophthalide as starting material 984.8.2 Two Grignard route using 5-cyanophthalide as starting material 1024.8.3 Coupling the hydrofuran ring formation with the second Grignard reaction 1034.8.4 A two Grignard route not using 3-dimethylamino propyl Grignard 1034.8.5 Phthalide synthesis 1044.8.6 The non-Grignard C3 nucleophilic route 1054.9 The phthalane route - alkylation of a phthalane with an electrophilic side chain 1074.10 Other synthetic routes to Citalopram 1124.11 Strategy comparison and conclusions for the synthesis of Citalopram 1134.12 The evolution of Escitalopram synthesis 1134.12.1 The chiral switch 1134.12.2 The first process for Escitalopram 1134.12.3 Diol as a key intermediate in Escitalopram synthesis 1154.12.4 Resolution of Citalopram and desmethyl analogues 1194.12.5 Recovery of DPTTA 1204.12.6 Recycling of unwanted R-isomers 1214.12.7 Key Diels-Alder cycloaddition in the synthesis of Escitalopram 1224.12.8 Escitalopram by asymmetric synthesis 1234.13 Best processes for Escitalopram 1264.14 Lessons from the Citalopram/Escitalopram case 1274.15 Reaction conditions for schemes A to H 1284.16 References 1355 Sitagliptin 1415.1 Worldwide sales and patent status 1425.2 Sitagliptin structure and general retrosynthetic analysis 1435.2.1 Disconnecting the heterocycle first 1435.2.2 Retrosynthetic analysis starting by transformation of the chiral amine 1465.2.3 Retrosynthetic analysis starting from haloaromatic ring 1475.2.4 Retrosynthesis analysis summary and most efficient routes 1475.3 The first reported Sitagliptin synthesis 1495.4 The search for an industrial synthesis for Sitagliptin 1495.4.1 Coupling the triazolopyrazine heterocycle at the end of the synthesis: producing a key chiral ß-amino acid intermediate 1515.4.2 Producing the chiral amine during the final stages of the synthesis 1685.4.3 Synthesis of Sitagliptin by attaching the 2,4,5-trifluorophenyl ring at the end of the synthesis 1795.4.4 Triazolopyrazine synthesis 1815.5 Strategy comparison and conclusions 1845.5.1 Main strategies for asymmetric synthesis 1845.5.2 The relative positions of the asymmetric step and the amide forming coupling reaction in route selection 1865.5.3 Preferred routes for the synthesis of Sitagliptin 1875.6 Lessons from the Sitagliptin case 1895.7 Reaction conditions for schemes A to J 1915.8 References 2006 Ezetimibe 2076.1 Worldwide sales and patent status 2086.2 Ezetimibe structure and general retrosynthetic analysis 2096.2.1 The azetidin-2-one ring formation 2106.2.2 Key structural features for the retrosynthesis 2126.2.3 Retrosynthesis using the Staudinger cycloaddition for the azetidin-2-one synthesis 2126.2.4 Retrosynthesis using the Kinugasa reaction to produce the azetidin-2-one 2136.2.5 Retrosynthesis using a N to C2 ring closure to produce the azetidin-2-one 2146.2.6 The (S)-hydroxyl benzylic group of Ezetimibe 2176.2.7 Summary of the retrosynthesis analysis 2186.3 The first Ezetimibe syntheses 2196.4 The search for an industrial synthesis of Ezetimibe 2216.4.1 The synthesis of the C5 chain intermediates and the imines 2216.4.2 Using the Staudinger reaction in the azetedin-2-one ring formation 2246.4.3 The Wacker oxidation route 2246.4.4 The search for a selective ß-lactam formation 2276.4.5 Using Kinugasa cycloaddition 2276.4.6 N-C2 ring closing strategy and the build-up sequence 2306.4.7 N-C2 ring closure strategy: late attachment of the p-fluoroaromatic ring 2316.4.8 N-C2 ring closure strategy: attaching the p-fluoroaromatic ring at the beginning of the synthesis 2366.4.9 N-C2 ring closing strategy: implementing the reduction at the beginning of the route 2436.4.10 Ezetimibe by alkylation of a C3 unsubstituted ß-lactam 2526.4.11 Other ß-lactam ring formations by N-C4 cyclization 2546.5 Comparison of strategies and conclusions 2556.6 The best syntheses 2596.7 Lessons from the Ezetimibe case 2616.8 Reaction conditions for schemes A to M 2626.9 References 2697 Montelukast 2757.1 Worldwide sales and patent status 2757.2 Montelukast structure and general retrosynthetic analysis 2777.2.1 Chirality issues 2777.2.2 The thiol side chain and the enantioselectivity of the synthetic process 2787.2.3 Retrosynthetic analysis of the thiol side chain 2797.3 Retrosynthetic outline 2797.4 The first reported Montelukast synthesis 2827.5 The evolution of industrial chemical syntheses of Montelukast 2837.5.1 Processes to produce keto-ester intermediate 2867.5.2 Processes to convert the keto-ester intermediate to Montelukast 2867.5.3 Montelukast synthesis using an incomplete thiol for the SN2 displacement 2907.5.4 Montelukast synthesis using a Heck reaction as a key step 2927.5.5 Montelukast synthesis using a carbonyl olefination reaction as a key step 2947.5.6 Montelukast synthesis using a Michael addition as a key step 2977.6 Synthesis of the thiol side chain 2977.6.1 Electrophilic side chain reactants 3017.7 Strategy comparison and conclusions 3017.8 Lessons from the Montelukast case 3057.9 Reaction conditions for schemes A to F 3077.10 References 3128 Oseltamivir 3198.1 Worldwide sales and patents status 3208.2 Oseltamivir structure and general retrosynthetic analysis 3218.2.1 Starting material targeted retrosynthesis 3228.2.2 Retrosynthetic strategies of the Oseltamivir cyclohexene ring 3248.2.3 Retrosynthetic analysis summary 3308.3 The first reported Oseltamivir synthesis 3318.4 Routes from shikimic acid or quinic acid 3328.4.1 First developments from shikimic acid or quinic acid 3338.4.2 Azide free routes 3368.4.3 Other routes from (-)-shikimic acid 3388.5 The supply problem 3428.5.1 Quinic and shikimic acid supply 3428.6 First non-shikimic or quinic acid synthetic routes 3438.6.1 The Diels-Alder furan approach 3438.6.2 Oseltamivir by total hydrogenation of an aromatic ring 3438.7 Synthesis of Oseltamivir from cyclohexadiene derivatives 3448.7.1 Meso aziridines desymmetrization routes 3448.7.2 Using iron diene carbonyl complexes 3458.7.3 From cyclohexa-3,5-diene-1,2-diol derivatives 3478.8 Building the carboxylic ring of Oseltamivir by a Diels-Alder reaction 3508.8.1 Using a [4+2] cycloaddition to produce a trisubstituted six-membered ring adduct 3508.8.2 Using a [4+2] cycloaddition to produce a monosubstituted six-membered ring adduct 3568.8.3 Alternative syntheses for the Corey intermediate 3568.9 Oseltamivir ring by a [3,3] sigmatropic rearrangement 3608.10 Oseltamivir synthesis by a Michael addition-Horner-Wadsworth-Emmons cascade sequence 3608.11 Aldol type condensations as key ring-forming step 3658.12 Metathesis as key-ring forming step 3658.13 Strategy comparison and conclusions 3748.14 Lessons from the Oseltamivir case 3788.15 Reaction conditions for schemes B to R 3788.16 References 3909 A Final Word 395

O autorze

Pedro Paulo Santos, PhD, is Professor in Organic Chemistry at Universidade de Lisboa. He collaborates with Portuguese pharmaceutical companies-supporting the development and launching of new generic drugs and in auditing of plants, synthetic processes, and DMFs. As a patent expert and witness, he has been involved in more than 50 court litigation processes referring to more than 30 different APIs. Dr Santos also published two textbooks and one exercise book covering the basic organic chemistry.William Heggie, PhD, was the Chief Scientist at Hovione before his retirement. He is author of more than 25 patents dealing with various aspects of process chemistry for the production of drug substance together with several other scientific publications. He has more than 30 years' experience designing, developing, and overseeing chemical processes from laboratory through pilot to industrial scale and developed more than 20 processes for drug substances, both Generics and NCEs.