课件 Medchem(2012)-13b(process development,medchemists,green chemistry, pollution and resources)

1⏹Regulatory affairs⏹Patents⏹Chemical process research anddevelopment Process Research and Development Process Research and DevelopmentSynthetic chemists working in the pharmaceutical industry◆Synthetic chemists working for pharmaceutical companies generally belong toone of two different tribes. Either you make new compounds (medicinal chemists), or you find new ways to make them (process chemists).◆Medicinal chemists.The new-compound people inside a company are themedicinal chemists, whose mandate is to make as many different analogs as possible while optimising their biological activities. While this can certainly require interesting chemistry, it certainly doesn't have to. Reactions straight from an introductory textbook will do nicely (very nicely, since those reactions tend to work). In fact, the shorter, easier, and less exciting the synthetic route, the better.◆Process chemists.The second tribe is the process chemists, who are chargedwith improving the medicinal chemist's synthetic routes when a compound goes into clinical trials. 'Improve‘is often synonymous with 'wad up and throw away'.The med-chem labs are biased towards reaction schemes that have the most flexibility for making analogues, but these aren't necessarily the cheapest, most scalable, and most reproducible paths for one particular compound. All of these qualities are vital in process work, though, and they have to be dealt with under some of the strictest deadlines in the whole industry.3做新药研发是一个很特殊的职业，一个人可能一生都发明不了一个新药，这种现象是被看作是正常的。

这个职业是容易让人得抑郁症的，特别是在现在这个制药企业时代，企业不断合并和裁员。

Medicinal chemist Megh Singh contributes to R&D at the Center for World Health & Medicine. Credit: Saint Louis University. Chemical & Engineering News, Volume 90 Issue 40 pp. 15-255"I once read that the best way to describe a medicinal chemist is a compulsive gambler. Every medicinal chemist thinks that the next compound is going to be the one that hits the jackpot”.Nick Hodge, founder and vice president of chemistry and technologyof a small chemical genomics firm, Amphora Discovery.(From: Louisa Wray Dalton, Medicinal chemistry, working in the fieldof drug discovery requires a broad mix of interests and skills, CEN (23 June 2003)81p53).7Chemical development:To devise a synthetic route that is straightforward, safe, cheap, efficient, and high yielding, has the minimum number of synthetic steps, and will provide a consistently high-quality product which meets predetermined specifications of purity.Process development:To ensure that the number of reactions in the synthetic route is as small as possible, and all the individual stages in the process are integrated with each other such that the full synthesis runs smoothly and efficiently on a production scale.9Impurity profiling :The regulatory authoritiesrequire that every batch of adrug product is analysed toensure that it meets the requiredspecifications, and that allimpurities are characterised,identified, and quantified. Thisnormally involves their isolationby preparative HPLC, followedby NMR spectroscopy or massspectrometry to identify theirstructure.Process Research and DevelopmentThe antihistamine drug （抗组胺药物）Terfenadine (特非那丁)is actually inactive in vitro , but in vivo it is metabolised by cytochrome P450 (CYP3A4) to an active form called Fexofenadine (非索非那丁).Terfenadine (特非那丁)had been withdrawn from the market.Terfenadine (Seldane)Fexofenadine (Allegra)NOHHO CO 2HN OH HO11The synthesis of Terfenadine (特非那丁)NOHO Cl Cl O+ClO Azacyclonol K 2CO 3, tolueneN OHHO NaBH 4, MeOH The key steps in the manufacturing of Terfenadineand Fexofenadine on commercial scalesFexofenadine process para:meta as 1:2ClOCl Cl O+Terfenadine processCl Cl O+CO 2Et CO 2Et ClO CO 2EtCl O+13KOHH 2O, MeOH, 76%C HO N CO 2HHO HgO, aq H 2SO 4MeOH, 75%C HO N CO 2CH 3OHO CH 3SO 2Cl pyridine, CH 2Cl 2, 100%MsO Azacyclonol K 2CO 3, CH 3CN 75%C HO N CO 2CH 3CO 2CH 3CO 2CH 3Br CO 2CH 3OH Pd(PPh 3)4, CuBr,Et 3N, 97%C HO N CO 2CH 3HO NaBH 4MeOH, 95%Fexofenadine (非索非那丁）An industrial process for Fexofenadine151719212325几张国内小试和中试设备的相片CPhI Shanghai 201227 The Synthesis of Sildenafil(Viagra)⏹VIAGRA®⏹Sildenafil citrate⏹1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate29The Synthesis of Sildenafil (Viagra)SOCl 2, reflux SOCl 2, toluene, 50 CNN O 2N NH 3(aq), acetoneNH 3(aq)NN O 2N SnCl 2, EtOH, reflux H 2, Pd-C, EtOAcCl OH 2N ONN H 2N H 2NOEt 3N, DMAP(cat), CH 2Cl 2Pyridine, EtOAcOEtCO 2H(COCl)2, CH 2Cl 2SOCl 2, DMF(cat), EtOAcOEtClO NaOH, EtOH, H 2O 2KOBu-t , t -BuOHClSO 3HN-methylpiperazine, EtOH N-methylpiperazine, tolueneOEt NHNNN OO 2S citric acid, acetoneSildenafil.HO 2CCO 2HHOCO 2HSildenafil citrateOEt NHNNN OSO 2ClOEt NHNNN ONH N HO O O 2NOEtN HO NN H 2N O NN OEt NHNNN OO 2SNNBlack colour is for the Medicinal Chemistry Process(1990), 9.8% overall yield from the nitro pyrazole acid to the final sildenafil citrate.Blue colour is for the Optimised Medicinal ChemistryProcess (1994), 35.9% overall yield from the nitro pyrazole acid to the final sildenafil citrate.Synthesis of 1-Methyl-4-nitro-3-propyl-1H -pyrazole-5-carboxylic AcidO(CO 2Et)2, NaOEtCO 2EtOO N 2H 4, H 2OMe 2SO 4NaOH, H 2OHNO 3, H 2SO 4NH N OONN OONN HOONH N HOOO 2N31The commercial route to Pfizer’s ViagraSOCl 2, DMF(cat)toluene, refluxNH 3(aq)H 2, Pd-C, EtOAcCDI (N,N'-carbonyldiimidazole)2-ethoxy-5-(4-methyl-1-piperazinesulphonyl)benzoic acidKOBu-t , t -BuOHcitric acid 2-butanoneNN O 2N ClONN O 2NHOO NN H 2NH 2NON HONN H 2N OOEt NHNNN OO 2SSildenafilNN OEtCO 2HClSO 3, SOCl 2OEtCO 2HSO 2ClN-methylpiperazineH 2OOEtCO 2HO 2SNNNN O 2N H 2NOOEt O 2SNN.HO 2CCO 2HHOCO 2HSildenafil citrateOEt NHNNN OO 2SNNEtOAC75% overall yield from the nitro pyrazole acid to the final sildenafil citrate.直接使用天然产物作为药物上临床和上市33Over 60 g of (+)-discodermolide was prepared in 39 steps. Required 17 chromatographic purifications.The entire process took some 20 months to complete.A total of over 43 chemists participated in the concept of the synthesis, experimental design, and execution.加上Tenofovir 的生产成本例子●在这里，讲一下仿制药的价格低的好处。