Removal of Azide Protection in the Identification and Development of a Manufacturing Process to Amlodipine

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1 Removal of Azide Protection in the Identification and Development of a Manufacturing Process to Amlodipine Alan Pettman Pfizer Global Research and Development 25th SI Process Development ambridge December

2 Amlodipine besylate Me 2 3 l 2 3.PhS 3 - alcium Antagonist for the Treatment of Ischemic eart Disease and ypertension Gradual onset of action, once-a-day dosing regimen and exceptional patient acceptance Known as ISTI TM in the U.K RVAS is the trademark in the rest of the world Marketed as the racemate 25th SI Process Development ambridge December

3 Some key data Discovered in the UK in 1982 Development started in 1982 Launched in the U.K. in 1989 Third biggest selling drug in 2004 with worldwide sales for the treatment of angina and hypertension of $4.6 billion ow ranked number 9 25th SI Process Development ambridge December

4 Discovery Synthesis single pot anztsch Br a3 3 2 l equiv. a, TF 70% Me 10% -15% l Reflux IMS Me 2 3 l 2 2 Pd/ 2 IMS 85% Me 2 3 l 2 3 Issues Safety Azido ethanol is a shock sensitive explosive* Efficiency Very poor antzsch reaction with the product isolated by chromatography Robustness Difficult to control de-chlorination in the azide reduction step Quality Unable to achieve regulatory quality by chromatography and multiple crystallisations * Appleby, I.. Process Res. Dev. Dep., Pfizer ent. Res., Sandwich/Kent, UK. hemistry & Industry (London, United Kingdom) (1986), (10), th SI Process Development ambridge December

5 Purification by derivative formation Me 2 l 2 2 Acetic Acid 90 Me 2 3 l 2 crude oil 1. ydrazine ydrate 2. Maleic acid/ IMS rystalline and pure product produced on filtering the cooled reaction mixture Me 2 l amlodipine maleate Prepared material for pre clinical toxicity studies 48gms! But introduced toxic hydrazine 25th SI Process Development ambridge December

6 Towards a commercial synthesis Fundamentally locked into a antzsch synthesis Main focus was selection of the -protecting group A number of different protecting groups were tried but the phthalimide was selected for our main focus given its crystallinity and ease of purification owever the ether preparation was capricious in discovery 2 l 2 equiv. a / TF 2 Quench water/ extract/ evaporate max 30% yield (variable) 25th SI Process Development ambridge December

7 Understanding the mass balance a _ 2 Quench water 2 rganic Soluble a _ a 2 Aqueous Soluble Product of the reaction is the sodium salt and quenching directly into water produces hydrolysis to a water soluble by-product Quenching into 1 l then extraction produced product in 70% assayed yield Later changed to tbuk/ toluene to avoid the use of a, with acetic acid neutralisation prior to aqueous workup Used as a crude oil directly in the antzsch reaction 25th SI Process Development ambridge December

8 antzsch reaction (single pot) Me l 2 Reflux IPA Me 2 3 l 2 Product was isolated from IPA without chromatography in a disappointing 20% yield Me 2 3 l 2 Me 3 Me 2 l 2 Main products were the symmetrical antzsch products 25th SI Process Development ambridge December

9 Two component antzch 2 l 2 piperidine / IPA l Me IPA reflux Me 2 3 l 2 Moved to a two stage antzsch reaction via the Knoevenagel product Product isolated in a modest 40% yield Symmetrical dihydropyridine products still formed suggesting some scrambling of the knoevenagel intermediate 25th SI Process Development ambridge December

10 Understanding the scrambling mechanism Me l 2 R l Me R Me 2 3 A l 2 R B Me 2 3 l 2 R 2 Me 2 3 l 2 R R l 2 R Me Me 2 3 l 2 Me 3 3 Me 2 R l 2 Me R Proposal that addition of acid would possibly decrease the equilibrium concentration of intermediate A by increasing the rate of the elimination step B Shown previously that acetic acid is a very good crystallisation solvent for the antzsch product What about acetic acid as the reaction solvent? 25th SI Process Development ambridge December

11 antzsch Reaction in acetic acid 2 l 2 piperidine / IPA l Me Acetic acid RT Me 2 3 l 2 Product was filtered from the acetic acid solution in 85-90% yield after reaction at RT 25th SI Process Development ambridge December

12 Phthalimide deprotection steps Me 2 3 l 2 hanolic methylamine oncentrate Quench into water Extract oncentrate to an oil (salt formation) Me 2 3 l 2 2 Me Me "by-product" Main objective was to find an alternative to hydrazine 33% ethanolic methylamine selected hemistry worked well on small scale but yields and quality plummeted on scaleup with the formation of starting material Workup by concentration, quench with water, extraction and evaporation 25th SI Process Development ambridge December

13 Reversibility in the deprotection Me Me 2 Me Me Me 2 l Me 2 Me 2 3 l 2 Me 2 3 l 2 Me Reaction is reversible and needs excess methyl amine to be present Suggestion that on scale-up the methylamine distils off faster than small scale therefore effecting the equilibrium 25th SI Process Development ambridge December

14 De-protection in aqueous methylamine Me Me _ Me 3 Me Literature MR study showed that the by-product of the deprotection, rapidly and irreversibly hydrolyses in water (neighbouring group participation) Simply stirring the phthalimide in 40% aqueous methylamine at room temperature overnight then filtering, produced amlodipine free base in 92-95% yield First time amlodipine free base had been seen as solid after several years of development 25th SI Process Development ambridge December

15 Salt form 2 Me 2 3 l RT/ IMS Me 2 3 l Maleate salt form was used for early development but produced formulation problems, both stability and processing Also scaleup issues during the preparation and maleate salt recrystallisation resulting from aspartic acid formation (michael addition) Also a formulation degradant Me 2 l th SI Process Development ambridge December

16 Amlodipine besylate and benzene sulphonic acid issues After a detailed alternative salt screening program, the besylate salt was selected for further development on the basis of a number of unexpected performance characteristics Initially prepared by the addition of benzenesulphonic acid to amlodipine free base in IMS owever, benzene sulphonic acid is a waxy impure solid which would be difficult to handle on large scale ommercial sources of benzene sulphonic acid were also impure containing benzene, sulphuric acid, and the sulphone During the salt formation, significant levels of the oxidised pyridine product were formed along with some of the diethyl ester derivate of amlodipine by transesterification 2 3 l 2 2 Me 2 3 l 2 3 There were also concerns about ethyl besylate formation Proposed than effectively buffering the salt formation would prevent impurity formation which were all thought to be acid catalysed So we decided to prepare and use the ammonium salt of benzene sulphonic acid which also helped purify the crude benzene sulphonic acid 25th SI Process Development ambridge December

17 Use of ammonium besylate Me 2 3 l S 3 4 eat in refluxing IMS to displace ammonia Me 2 3 l 2 3 S 3-3 eating amlodipine free base in IMS with ammonium besylate then cooling and filtering produced product with minimal oxidation and transesterification in 90-95% yield o detectable ethyl besylate formation owever, just before the DA filing it was decided that we needed to rapidly identify and alternative process to prepare the besylate salt which did not have the potential to form ethyl besylate The process was rapidly changed to an ammonium besylate/ DMA/ Toluene/ water system 25th SI Process Development ambridge December

18 Process Summary 2 l KBu t (2 equiv.), Toluene, 65% yield 2 piperidine / IPA l 2 l Me Ac 73 % yield, 2 steps 2. Recrystallisation 80% Me 2 3 l 2 amlodipine besylate 3.PhS 3-1. Aqueous methylamine (90%) 2. Ammonium benzene sulphonate/ Toluene/ DMA/ Water (90%) Me 2 3 l 2 25th SI Process Development ambridge December

19 Acknowledgements Process RD Arthur Bentley (Retired) Mark Glanfield (Retired) Ian Sinclair (Retired) Paul igginson Alan Pettman Analytical Peter Brewer (Retired) Anne Berry (Retired) Pilot Plant Derrick Morgan (Retired) Dave Sims (Retired) 25th SI Process Development ambridge December

How to make pyridines: the Hantzsch pyridine synthesis

How to make pyridines: the Hantzsch pyridine synthesis ow to make pyridines: the antzsch pyridine synthesis 1191 Zinc in acetic acid (Chapter 24) reduces the oxime to the amine and we can start the synthesis by doing the conjugate addition and then reducing