化学药实用工艺研究PracticalProcessResearchandDevelopment—冯鑫

1、Practical Process Research and DevelopmentContent： 1：Route Selection 2: Reagent Selection 3: Solvent Selection 4: Running Reaction 5: Optimizing the reaction by minimizing impurities 6: Tools for Purifying the product 1 Route SlectionA Health, SAFETY, and Environmental assessment is a critical crite

2、rion in our process development.Its got to be dealt with, and its not taken lightly. If problems are insurmountable, or If there is danger to the environment, a synthesis will be replaced.”1-1: Analyzing Waste Streams (First Principle) It is far better to prevent waste, not just reducing waste. Rout

3、es with fewer steps require smaller quantities of starting materials, solvents, and reagents, and require less labor.1-2: Atom EconomyAtom economy is not the primary consideration for manufacturing in the pharmaceutical industry1-3: Less Hazardous Chemical syntheses1-4: Reduce use of Protecting grou

4、psThe route with the fewest steps may be the greenest and cheapest and the fewest opportunities for errors.-difficult!1-5: CatalysisWith catalytic reactions involving expensive catalysts cost-efficient route will recycle the catalysts.1-6: Direct IsolationsDirect isolation minimize consumption of RM

5、, energy, time and labor. And it is very convenient both for plant and Kilo-lab.Filtration/ crystallization/recrystallization/slurry is the favorite.Example Biotransformations Biotransformations provide exciting opportunities for changing synthetic routes. Previously fermentations were considered fo

6、r complex molecules such as antibiotics. Biocatalysts have been developed for synthetic purposes and it was usually associated with enzymes: transaminasesExampleExample:Guidelines for developing biocatalytic processsQuickest to effectChange Example 1Screen mediumDissolve substrate in DMF, DMSO, or a

7、cetone2Modify starting materialChange Boc for benzyl3Screen biocatalystsHigh-throughputCost estimates Cost = raw material + manufacturing + waste disposal2 Reagent SelectionSome ideal characteristics of reagentscharacteristicComments or examplesSpecific for the desired synthetic transformationIsolat

8、ion is easier from high-yielding reactionSafe: posed no chemical reaction hazardLiability increases with scaleNo shipping restrictionsCH3Li in Et2ONo purchasing restrictionsTime is required to obtain licenses, the chemical could be used to make illegal drugsNon-toxicPPE is time-consuming, cumbersome

9、, inconvenientIf highly toxic, non-volatileDimethyl sulfate may be preferred over CH3IReadily available from multiple vendorsOne vendor may hold up supply or raise costInexpensive, with consistent quality batch to batchInexpensive, high-quality reagents lower the cost of goodsStable, good shelf-life

10、Greater flexibility in scheduling manufacturingReadily generated and used if short shelf-lifeGreater flexibility in scheduling operationsFacilitates work-up and isolation of pure product, or has no effect on work-up of the productIncreased productivityProduces non-toxic byproductLower disposal costC

11、atalytic, and readily recovered and reusedLower the cost of goodsRequires no specialized equipment or facilitiesHydrogenation facility2-1 Strong basesKot-Bu is a moderately strong base, and its use on scale can be hampered by its low solubility in organic solvent. Characteristics of some amines usef

12、ul for scale-upCompound pKaComments 3-dimethylaminopropylamine11Used to remove excess RCOClTEA10.75HCl salt insoluble in MeCNDIPEA10.4HCl salt insoluble in MeCN4-methylmorpholine10.08Peptide couplingImidazole 7.0Peptide coupling/silylation2,6-lutidine6.65sulfationDMAP9.7Acylation/ catalyst2-4 Oxidat

13、ions Oxidations are often troublesome for scale-up The highly reactivity reagents can lead to hazardous operations Waste disposal costs can be high if toxic byproducts and a large amount waste are produced.So .The preferred approach is to design catalyzed oxidations with bulk oxidants that are inexp

14、ensive, readily available, less hazardous and non-toxic.Such as : H2O2 in concentrations no greater than 30%, NaClO2, NaClO, NMO, Oxone.Example 2-5 Reductions Caution !.H2 generated. BH3.THF/ NaBH4/BF3.Et2O with NaBH4/Red Al/H2 with Pd3 Solvent Selection Solvents can have huge impacts on processing

15、cost, environment. Many green chemistry principles are reflected in using solvents, such as minimizing waste/ minimizing energy to recycle solvents. Solvents may be classified in to several groups as bellow:1: Protic, or hydrogen bond-donating solvents, such as H2O,EtOH,AcOH2: Hydrogen bond-acceptin

16、g solvents, such as H2O, TEA, EA, Acetone, DMF3: Polar aprotic solvents, such as DMSO,DMF,DMAC4: Chlorocarbon solvents, such as DCM, CHCl35: Fluorocarbon solvents, such as hexafluoroisopropanol6: Hydrocarbon solvents, such as heptanes, toluene3-1 Using azeotropes to select solvents Many organic solv

17、ents form azeotropes with water, and azeotroping out water can promote the reaction, sometimes it was used for drying. Azeotropic removal of volatile components can drive rections3-2 Solvent substitutions A number of chemicals have been used as inexpensive, green solvents, such as 2-methyl-tetrahydr

18、ofuran, DME, 1,3-propanediol. Used for kinds of reaction, such as organometallic reaction, extraction, PTC reaction. These solvents were demonstrated as commercial availability.3-3 Solvent free reaction In solvent-free(neat) reaction, a small excess of liquid reagent may function as solvent. The pro

19、duct are often non-crystalline. Quenching such reactions may produce high temperatures. Always increased the reaction rate but decreased the work-up process. Example: Perspective AspectComment Safety Avoid solvents that are toxic or highly flammablePromote high-yielding reactionsCompatible with desi

20、red chemistryCan isolate product in good yieldConvenient Isolate product from reaction solventH2O-miscibilityAzeotroping ability, control amount of H2O present during reactionsCost and recoverability Lower the costEnvironmental Easy for recycle , friendly Long-term availabilityMany vendorsWater as s

21、olvent Green, but waste water treatment may be highNeat reaction Selected application, but limited heat capacity can make temperature control difficult.4 Running ReactionA synthesis is not the same as a process. Process chemistry is not merely synthetic chemistryDetails of the operations can be very

22、 important.4-1 Safety Safety is always the first priority. Accidents incur great cost!Each reaction should be considered for possible hazards, including reaction exotherms, gas evolution, and the safety of handling reagents, solvents, and products.CHA, HAZOP Analysis. Safety issues should not be tak

23、en for granted. Review safety regularly.4-2 Selecting the reaction scale It was determined by : the amount of chemicals available how expensive the components are The size of available equipment How robust of the process4-3 Process Description Nonspecific descripsion found in chemistry experimental

24、proceduresStep by step procedure for setting up and running reaction4-5 In-process controlsIPCs include: Simple physical guidelines, such as reaching a color endpoint/ reaching and maintaining critical temperature/ PH values./ HPLC or UPLC or GC analysis.In-process assay considerations include: 1: o

25、btaining a representative sample 2: prepare the sample for accurate analysis 3: conducting the assay 4: analyzing the data for reproducibility and accuracy 4-6 Work up-Queching Safety is the foremost consideration in quenching a reaction4-6 Work up-Extraction Emulsions formed can delay processing an

26、d lead to product losses.Break Emulsions: Raise the temperature slightly Increase the ionic strength of aqueous phase by adding brine Adjust the PH values slightly Filter off small particles Increased the amount of solvent Adding small amount of a more polar solvent, e.g. 2-10% MeOH. Gentler agitati

27、on5 Optimizing the reaction by minimizing impurities Safety is also the first priority Improve the yield Improve the quality Improve the productivity on scale Reduce the cost Reduce the waste5-1 Benefits of heterogeneous processing Heterogeneous process can be beneficial if byproducts precipitate as

28、 they form or if the product crystallizes as it forms.5-2 Decrease side products by Decreasing degradation of starting materials5-3 Addition sequence, Duration of addition and the time between addition90% decreased to 57% due to the cecomposition of meldrum acid at high temperature.Addition sequence

29、5-4 Temperature control small temperature changes can greatly affect byproduct formation5-5 Minimizing impurities formed during workup At the end of the reaction, generating a stable reaction mixture is necessary to prevent formation of significant amounts of impurities during subsequent processing, especially on scale6 Tools for Purifying the product Purificat