药物化学实验 MEDICINAL CHEMISTRY EXPERIMENTS LI SHAO-SHUN XU DE-FENG School of Pharmacy,Shanghai Jiaotong University January 2008 0
0 药 物 化 学 实 验 MEDICINAL CHEMISTRY EXPERIMENTS LI SHAO-SHUN XU DE-FENG School of Pharmacy, Shanghai Jiaotong University January 2008
PREFACE "Experimental teaching material of medicinal chemistry"is composed according to the outline of medicinal chemistry.The purpose of this book is,through experiment,to comprehend elementary theory and knowledge of medicinal chemistry better,to grasp fundamental methods of synthesis and structural modification of drugs,to be familiar with how to design the experiment plan and how to select the experiment condition,to understand application of principle of hybridization and modern new technology and method in medicinal chemistry experiment,to standard and consolidate manipulative technology and relevant theory knowledge of organic chemistry experiment,to train students'style of integrating theory with practice,scientific attitude of seeking truth from fact and being rigorous and serious,ability of analyzing and solving actual problems,and good custom of scientific research. The characteristic of this book is adding much designing experiments to guiding experiments. It requires students to complete as independently as possible that consulting literatures,designing route and experimental manipulate.Through the training of designed experiments,whole process of scientific research is simulated.Students'consciousness of scientific research,spirit of bringing new ideas,ability of working independently and solving actual problems by theory and relevant elementary and professional knowledge of medicinal chemistry are trained.It can be the foundation of being engaged in medicine synthesis,studying new drugs and carrying out clinical medicinal chemistry. This book is the collective summary of teaching experience in department of medicinal chemistry.If there is any mistake in this book,please produce precious opinions during using it, so that we will corret and elevate when second printing or edition. School of Pharmacy Shanghai Jiaotong University 2008.1
1 PREFACE “Experimental teaching material of medicinal chemistry” is composed according to the outline of medicinal chemistry. The purpose of this book is, through experiment, to comprehend elementary theory and knowledge of medicinal chemistry better, to grasp fundamental methods of synthesis and structural modification of drugs, to be familiar with how to design the experiment plan and how to select the experiment condition, to understand application of principle of hybridization and modern new technology and method in medicinal chemistry experiment, to standard and consolidate manipulative technology and relevant theory knowledge of organic chemistry experiment, to train students’ style of integrating theory with practice, scientific attitude of seeking truth from fact and being rigorous and serious, ability of analyzing and solving actual problems, and good custom of scientific research. The characteristic of this book is adding much designing experiments to guiding experiments. It requires students to complete as independently as possible that consulting literatures, designing route and experimental manipulate. Through the training of designed experiments, whole process of scientific research is simulated. Students’ consciousness of scientific research, spirit of bringing new ideas, ability of working independently and solving actual problems by theory and relevant elementary and professional knowledge of medicinal chemistry are trained. It can be the foundation of being engaged in medicine synthesis, studying new drugs and carrying out clinical medicinal chemistry. This book is the collective summary of teaching experience in department of medicinal chemistry. If there is any mistake in this book, please produce precious opinions during using it, so that we will corret and elevate when second printing or edition. School of Pharmacy Shanghai Jiaotong University 2008.1
CATALOGUE Preface …1 General Medicinal Chemistry Labortory Rules 3 Standard Operating Procedures in the Medicinal Chemistry Labortory …4 Experimental Report… …11 Experiment Experiment 1 Preparation of Aspirin 15 Experiment 2 Preparation of Paracetamol 17 Experiment 3 Preparation of Benorylate 19 Experiment 4 Preparation of Benzocaine 21 Experiment 5 Synthesis of mandelic acid 25 Experiment 6 Preparation of Leucoacetates Shikonin 28 2
2 CATALOGUE Preface ………………………………………………………………………………… 1 General Medicinal Chemistry Labortory Rules ………………………………………… 3 Standard Operating Procedures in the Medicinal Chemistry Labortory ………… 4 Experimental Report ………………………………………………………………… 11 Experiment Experiment 1 Preparation of Aspirin …………………………………………………… 15 Experiment 2 Preparation of Paracetamol …………………………………………… 17 Experiment 3 Preparation of Benorylate ……………………………………………… 19 Experiment 4 Preparation of Benzocaine …………………………………………… 21 Experiment 5 Synthesis of mandelic acid ………………………………………… 25 Experiment 6 Preparation of Leucoacetates Shikonin …………………………… 28
GENERAL MEDICINAL CHEMISTRY LABORATORY RULES Students should come to the lab on time. Wear safety goggles.You may only remove your goggles if no one in the lab room is using chemicals or washing glassware Contact lenses must not be worn. Wear protective clothing:You should be covered from the top of your shoulder to below your knees.A laboratory coat is suitable,especially if you are not well-protected by the clothes you have chosen to wear to lab.Wear closed-toed shoes.Gloves are highly recommended at all times. Food and drink are not allowed in the lab room. You may not use personal music players(mp3,CD,tape,etc.)during your laboratory session ●No smoking Prevent chemical spills by clamping flasks containing chemicals whenever possible. Work in your hood at all times.Cover containers of compounds during transport through the lab. Prevent breakage by handling glassware with care at all times.Securely clamp reaction and vacuum flasks. Place broken glassware in the proper receptacle. Use a Bunsen burner only when directed by your TA. Place hazardous waste in the proper container. o When the fire alarm sounds,leave the building immediately. Keep a clear pathway to the exits:Do not bring your bike to lab and keep all personal items off the floor or close to the wall by the coatrack. Never conduct experiments in the laboratory alone. 3
3 GENERAL MEDICINAL CHEMISTRY LABORATORY RULES ● Students should come to the lab on time. ● Wear safety goggles. You may only remove your goggles if no one in the lab room is using chemicals or washing glassware. ● Contact lenses must not be worn. ● Wear protective clothing: You should be covered from the top of your shoulder to below your knees. A laboratory coat is suitable, especially if you are not well-protected by the clothes you have chosen to wear to lab. Wear closed-toed shoes. Gloves are highly recommended at all times. ● Food and drink are not allowed in the lab room. ● You may not use personal music players (mp3, CD, tape, etc.) during your laboratory session. ● No smoking. ● Prevent chemical spills by clamping flasks containing chemicals whenever possible. ● Work in your hood at all times. Cover containers of compounds during transport through the lab. ● Prevent breakage by handling glassware with care at all times. Securely clamp reaction and vacuum flasks. ● Place broken glassware in the proper receptacle. ● Use a Bunsen burner only when directed by your TA. ● Place hazardous waste in the proper container. ● When the fire alarm sounds, leave the building immediately. ● Keep a clear pathway to the exits: Do not bring your bike to lab and keep all personal items off the floor or close to the wall by the coatrack.. ● Never conduct experiments in the laboratory alone
STANDARD OPERATING PROCEDURES IN THE MEDICINAL CHEMISTRY LABORATORY Any student working in an unsafe manner may be dismissed from the laboratory by an instructor. 1.Attitudes and Preparation a.Come to laboratory periods on time and mentally prepared by studying the experiment and planning your activities. b.Be prepared physically;for example,don't try to do lab work on an empty stomach, or without sleep. c.Write everything you do and see in your notebook so that you can trace your actions and make corrections if necessary d.Wear sensible clothing,including shoes that are comfortable and permit rapid movement in case of emergency,and hair or hat that does not obstruct your view or dangle into the experiment. e.If you wear contact lenses,try to avoid wearing them in the lab.If you must wear contact lenses,your goggles must seal particularly well to your face. f.If you injure yourself,even slightly,report it to your instructor,who will direct you to first aid.If you experience eye irritation,flush your eyes at the nearest emergency eyewash station for 15 minutes (remove contacts)and seek medical attention immediately. g.If you have any existing physical conditions that might affect your performance,your health,or other peoples'health in the lab,please inform your instructor.This information will be kept confidential;examples might include pregnancy, medications,allergies,epilepsy,AIDS.Special arrangements may be possible. 2.Your Working Environment a.GOGGLES for chemical splash protection are required at all times in labs or instrument rooms,i.e.all parts of the lab,even when your are not handling chemicals. 4
4 STANDARD OPERATING PROCEDURES IN THE MEDICINAL CHEMISTRY LABORATORY ● Any student working in an unsafe manner may be dismissed from the laboratory by an instructor. 1. Attitudes and Preparation a. Come to laboratory periods on time and mentally prepared by studying the experiment and planning your activities. b. Be prepared physically; for example, don't try to do lab work on an empty stomach, or without sleep. c. Write everything you do and see in your notebook so that you can trace your actions and make corrections if necessary. d. Wear sensible clothing, including shoes that are comfortable and permit rapid movement in case of emergency, and hair or hat that does not obstruct your view or dangle into the experiment. e. If you wear contact lenses, try to avoid wearing them in the lab. If you must wear contact lenses, your goggles must seal particularly well to your face. f. If you injure yourself, even slightly, report it to your instructor, who will direct you to first aid. If you experience eye irritation, flush your eyes at the nearest emergency eyewash station for 15 minutes (remove contacts) and seek medical attention immediately. g. If you have any existing physical conditions that might affect your performance, your health, or other peoples' health in the lab, please inform your instructor. This information will be kept confidential; examples might include pregnancy, medications, allergies, epilepsy, AIDS. Special arrangements may be possible. 2. Your Working Environment a. GOGGLES for chemical splash protection are required at all times in labs or instrument rooms, i.e. all parts of the lab, even when your are not handling chemicals
The goggles will protect your eyes from most splashes and impacts.The goggles do not meet the standard if the air baffles are removed.Some people have trouble with their goggles fogging up.The best solution is to take a short break outside the lab to clean them. b.Rubber gloves are strongly recommended to protect you from absorption of chemicals through the skin.We also recommend a lab coat to protect your clothes and skin from your and your neighbor's spills. c. Keeping your bench space tidy will minimize breakage and spills of your valuable products d.You are expected to clean up your own mess in community areas such as the IR room. e.Keep your glassware and other equipment cleaned up as you work.Having clean,dry glassware available at all times will save you much time in the long run. f.Be careful not to contaminate reagents with your spatulas or droppers.If you take too much of a reagent,give it to a needy neighbor-do no return it to the bottle. g.Do not wander off with the only bottle of a reagent that everyone needs;keep it in its assigned location h.Be sure the aisles are passable. 3.Glassware a.The most common laboratory injury is a cut occurring upon breakage of glass or porcelain.Most cuts can be prevented by careful work which prevents breakage. b.The safe procedure for inserting a glass tube or thermometer into a stopper with a hole is as follows: i.Be sure the tip of the tube is fire-polished. ii.Lubricate the glass with glycerol or water. iii. Be sure the hole in the stopper is large enough. iV. Grasp the glass about 1"(no farther)from the end and push and twist to insert it into the stopper. v.Be sure that the hand holding the stopper is not in line with the entering glass. 5
5 The goggles will protect your eyes from most splashes and impacts. The goggles do not meet the standard if the air baffles are removed. Some people have trouble with their goggles fogging up. The best solution is to take a short break outside the lab to clean them. b. Rubber gloves are strongly recommended to protect you from absorption of chemicals through the skin. We also recommend a lab coat to protect your clothes and skin from your and your neighbor's spills. c. Keeping your bench space tidy will minimize breakage and spills of your valuable products. d. You are expected to clean up your own mess in community areas such as the IR room. e. Keep your glassware and other equipment cleaned up as you work. Having clean, dry glassware available at all times will save you much time in the long run. f. Be careful not to contaminate reagents with your spatulas or droppers. If you take too much of a reagent, give it to a needy neighbor - do no return it to the bottle. g. Do not wander off with the only bottle of a reagent that everyone needs; keep it in its assigned location. h. Be sure the aisles are passable. 3. Glassware a. The most common laboratory injury is a cut occurring upon breakage of glass or porcelain. Most cuts can be prevented by careful work which prevents breakage. b. The safe procedure for inserting a glass tube or thermometer into a stopper with a hole is as follows: i. Be sure the tip of the tube is fire-polished. ii. Lubricate the glass with glycerol or water. iii. Be sure the hole in the stopper is large enough. iv. Grasp the glass about 1" (no farther) from the end and push and twist to insert it into the stopper. v. Be sure that the hand holding the stopper is not in line with the entering glass
vi.As the glass begins to slide into the rubber,move the hand holding the glass back a little,always keeping it no more than 1"from the rubber. vii. Most accidents occur because the glass snaps above the stopper from a force sideways(torque).Keeping your hand close to the stopper will help prevent your exerting a force sideways on the glass viii. The above considerations apply also to attaching rubber hoses to condensers. The condenser should be in your hand(not clamped to an apparatus)and gripped close to the lubricated connector being inserted into the hose c.Never use a thermometer as a stirrer!Always support a thermometer in a beaker or flask with a clamp.If a mercury thermometer breaks,immediately contact the laboratory instructor and restrict access to the area of contamination until cleanup can be arranged. d.Round-bottomed flasks will not stand upright by themselves and if rested on the counter will roll.They must be supported on a cork ring,in (not on)a beaker,or in a clamp. e.When glassware is assembled,care should be taken to use the minimum number of clamps needed for support,making sure: i.The clamp is attached to a vertical support bar. ii.No torque is applied by the clamp. iii. Top-heavy apparatus is prevented from rotating and tipping. iv. Hanging pieces are clamped-grease will not hold them against the force of gravity! f Do not use a glass stopper to seal a hot container or you may never get it out again. Cork is recommended for organic solvents since rubber dissolves in organic solvents and vice-versa g.Graduated cylinders are metastable and tip easily with the touch of a sleeve. h.Report breakage of glassware to your instructor for disposal instructions. i.Think before cleaning equipment-it makes little sense to scrub a graduated cylinder that contained ether or a water-insoluble material with soap and water. 4.Safety Equipment 6
6 vi. As the glass begins to slide into the rubber, move the hand holding the glass back a little, always keeping it no more than 1" from the rubber. vii. Most accidents occur because the glass snaps above the stopper from a force sideways (torque). Keeping your hand close to the stopper will help prevent your exerting a force sideways on the glass. viii. The above considerations apply also to attaching rubber hoses to condensers. The condenser should be in your hand (not clamped to an apparatus) and gripped close to the lubricated connector being inserted into the hose. c. Never use a thermometer as a stirrer! Always support a thermometer in a beaker or flask with a clamp. If a mercury thermometer breaks, immediately contact the laboratory instructor and restrict access to the area of contamination until cleanup can be arranged. d. Round-bottomed flasks will not stand upright by themselves and if rested on the counter will roll. They must be supported on a cork ring, in (not on) a beaker, or in a clamp. e. When glassware is assembled, care should be taken to use the minimum number of clamps needed for support, making sure: i. The clamp is attached to a vertical support bar. ii. No torque is applied by the clamp. iii. Top-heavy apparatus is prevented from rotating and tipping. iv. Hanging pieces are clamped - grease will not hold them against the force of gravity! f. Do not use a glass stopper to seal a hot container or you may never get it out again. Cork is recommended for organic solvents since rubber dissolves in organic solvents and vice-versa. g. Graduated cylinders are metastable and tip easily with the touch of a sleeve. h. Report breakage of glassware to your instructor for disposal instructions. i. Think before cleaning equipment - it makes little sense to scrub a graduated cylinder that contained ether or a water-insoluble material with soap and water. 4. Safety Equipment
Your instructor will show you where it is;remind yourself from time to time during the semester. a.Fire Extinguishers for smothering fires.SJTU policy regarding response to fires restricts the use of fire extinguishers to persons who are properly trained.Small fires may be extinguished by covering with a book or larger container. b.Fire Blanket for smothering fires c.Safety Shower for rinsing chemicals off the body. d.Eye Wash Fountain for rinsing chemicals from the eyes. e.First Aid Kit-Note:even minor injuries must be reported to your instructor. f.At least two exits. g.Dustpan and broom for removing broken glass. 5.Toxic Hazards a.The materials used in the organic lab are the safest we can find consistent with your need to develop skills in working with hazardous materials in your career in science. b.Since you are wearing eye protection,the opportunity for liquids or solids to enter the eye is small.Chemicals in the eye should be immediately flushed with copious amounts of water using the eyewash fountain. c.To prevent inhalation of organic and inorganic vapors,do your experiments in the fume hood or under the minihoods on the bench. d.If your need to determine the odor of any material,waft it gently toward your nose with your hand-don't stick your nose in the container and inhale e.Organic compounds can be absorbed through the skin,so be careful about spilling things.Wear rubber gloves to prevent contact with your skin,but treat the gloves as if they were bare skin,keeping them scrupulously clean.You might set aside a pen for laboratory work to minimize the possibility of contamination from your gloves via your pen to your hands and face.Obviously,chewing a pen or pencil that has been used in the lab would unwise. f.Organic vapors also can be absorbed into food or tobacco which you may ingest later. Moreover,any drinks brought into the lab could have things spilled into them.No
7 Your instructor will show you where it is; remind yourself from time to time during the semester. a. Fire Extinguishers for smothering fires. SJTU policy regarding response to fires restricts the use of fire extinguishers to persons who are properly trained. Small fires may be extinguished by covering with a book or larger container. b. Fire Blanket for smothering fires. c. Safety Shower for rinsing chemicals off the body. d. Eye Wash Fountain for rinsing chemicals from the eyes. e. First Aid Kit - Note: even minor injuries must be reported to your instructor. f. At least two exits. g. Dustpan and broom for removing broken glass. 5. Toxic Hazards a. The materials used in the organic lab are the safest we can find consistent with your need to develop skills in working with hazardous materials in your career in science. b. Since you are wearing eye protection, the opportunity for liquids or solids to enter the eye is small. Chemicals in the eye should be immediately flushed with copious amounts of water using the eyewash fountain. c. To prevent inhalation of organic and inorganic vapors, do your experiments in the fume hood or under the minihoods on the bench. d. If your need to determine the odor of any material, waft it gently toward your nose with your hand - don't stick your nose in the container and inhale. e. Organic compounds can be absorbed through the skin, so be careful about spilling things. Wear rubber gloves to prevent contact with your skin, but treat the gloves as if they were bare skin, keeping them scrupulously clean. You might set aside a pen for laboratory work to minimize the possibility of contamination from your gloves via your pen to your hands and face. Obviously, chewing a pen or pencil that has been used in the lab would unwise. f. Organic vapors also can be absorbed into food or tobacco which you may ingest later. Moreover, any drinks brought into the lab could have things spilled into them. No
food or drinks in the laboratory,not even stuffed in your backpack.If you do not have a locker to keep food in,please remove the food,drink and cigarettes to the hallway, or ask your instructor for a safe place to keep it.Smoking is not allowed in State buildings,as the nicotine and other contents of the smoke are well-known health hazards(look up the LDso of nicotine if you are skeptical) g.If you spill a liquid on the bench,immediately soak it up with paper towels and,if it is volatile,transfer the towels to the hood.Inform your instructor as to the nature of the spill in case further action is warranted. h.If concentrated acid is spilled,add sodium carbonate or bicarbonate,solution or solid. If concentrated base is spilled,add dilute and/or weak acid(e.g.acetic).Indicator solution or paper will be available in the lab.If your skin (or clothing)comes in contact with the spill,immediately flush the skin or clothing with water for 15 minutes. 1. Should you spill bromine solution anywhere,treat the spill immediately with sodium thiosulfate solution. j.Bottles of the reagents mentioned in g)and h)are available on the small counter above your bench. 6.Heat Hazards a.Most organic compounds are flammable and may catch fire even in the absence of flame at high temperatures. b.Flames are rarely allowed in the organic laboratory.If flames are permitted by your instructor,plan your experiments so that you never leave your flame unattended. c.If you light a flame,you are responsible for the consequences,so check with your instructor for a safe location. d.If you use a bunsen burner.be sure to tie back your hair and be careful that hair or clothing are kept clear of the flame. e.If there is a flame in the neighborhood,do not pour flammables;organic vapors are usually denser than air and will flow along the bench without alerting you by their odors. f.Make sure you know the location of the nearest fire extinguisher and the nearest exit. 8
8 food or drinks in the laboratory, not even stuffed in your backpack. If you do not have a locker to keep food in, please remove the food, drink and cigarettes to the hallway, or ask your instructor for a safe place to keep it. Smoking is not allowed in State buildings, as the nicotine and other contents of the smoke are well-known health hazards (look up the LD50 of nicotine if you are skeptical). g. If you spill a liquid on the bench, immediately soak it up with paper towels and, if it is volatile, transfer the towels to the hood. Inform your instructor as to the nature of the spill in case further action is warranted. h. If concentrated acid is spilled, add sodium carbonate or bicarbonate, solution or solid. If concentrated base is spilled, add dilute and/or weak acid (e.g. acetic). Indicator solution or paper will be available in the lab. If your skin (or clothing) comes in contact with the spill, immediately flush the skin or clothing with water for 15 minutes. i. Should you spill bromine solution anywhere, treat the spill immediately with sodium thiosulfate solution. j. Bottles of the reagents mentioned in g) and h) are available on the small counter above your bench. 6. Heat Hazards a. Most organic compounds are flammable and may catch fire even in the absence of flame at high temperatures. b. Flames are rarely allowed in the organic laboratory. If flames are permitted by your instructor, plan your experiments so that you never leave your flame unattended. c. If you light a flame, you are responsible for the consequences, so check with your instructor for a safe location. d. If you use a bunsen burner, be sure to tie back your hair and be careful that hair or clothing are kept clear of the flame. e. If there is a flame in the neighborhood, do not pour flammables; organic vapors are usually denser than air and will flow along the bench without alerting you by their odors. f. Make sure you know the location of the nearest fire extinguisher and the nearest exit
g.Reactions that are exothermic or are being heated must be monitored;do not leave them without having someone watch. h.Never,never,never heat a closed system!Pressure will build up and cause the glass to fail,sending projectiles of glass in all directions.Do not depend on small leaks-a substantial air exit must be provided. 7.If There is a Fire a.In the lab where you are working i.Shout "fire"to alert your neighbors and instructor if you discover it ii.A small fire in a test tube or other container can usually be extinguished by covering the container with a watch glass or book.If the fire cannot be extinguished by one extinguisher or by sand or water,you will be instructed to evacuate,following the procedure in b). iii. One terrible possibility is that someone's clothing is set on fire.If the person runs,the flame will be increased by increasing the supply of oxygen.It must be smothered.Wrap the person in a lab coat,fire blanket,or whatever is handy to exclude oxygen. b.Elsewhere in the building(fire alarm sounds): i.Extinguish any flames and turn off electrical equipment. ii.Close any open windows and internal doors near you. Walk quickly through the nearest exit to the hallway and leave the building by the nearest stairwell. iv. The last person leaving the room,usually your instructor,will close the hall door. 8.Laboratory Electrical Equipment a.During the semester you will use a variety of instruments to analyze your samples.As with all electrical equipment,a certain amount of care is needed to prevent fire,shock and damage to the equipment.Be careful not to bring water,especially on your hands, into contact with connected electrical equipment. b.The hot plates you are provided are powerful and seldom need to be set higher than 3. 9
9 g. Reactions that are exothermic or are being heated must be monitored; do not leave them without having someone watch. h. Never, never, never heat a closed system! Pressure will build up and cause the glass to fail, sending projectiles of glass in all directions. Do not depend on small leaks - a substantial air exit must be provided. 7. If There is a Fire a. In the lab where you are working. i. Shout "fire" to alert your neighbors and instructor if you discover it. ii. A small fire in a test tube or other container can usually be extinguished by covering the container with a watch glass or book. If the fire cannot be extinguished by one extinguisher or by sand or water, you will be instructed to evacuate, following the procedure in b). iii. One terrible possibility is that someone's clothing is set on fire. If the person runs, the flame will be increased by increasing the supply of oxygen. It must be smothered. Wrap the person in a lab coat, fire blanket, or whatever is handy to exclude oxygen. b. Elsewhere in the building (fire alarm sounds): i. Extinguish any flames and turn off electrical equipment. ii. Close any open windows and internal doors near you. iii. Walk quickly through the nearest exit to the hallway and leave the building by the nearest stairwell. iv. The last person leaving the room, usually your instructor, will close the hall door. 8. Laboratory Electrical Equipment a. During the semester you will use a variety of instruments to analyze your samples. As with all electrical equipment, a certain amount of care is needed to prevent fire, shock and damage to the equipment. Be careful not to bring water, especially on your hands, into contact with connected electrical equipment. b. The hot plates you are provided are powerful and seldom need to be set higher than 3