THE CHEMISTRY OF PILLS ppt for msc chemistry level students

this ppt is related to the pills taken by womens which can be harmful

1. THE CHEMISTRY OF “PILLS” BY:- RAJPUROHIT SANDEEP PRATAPSINGH M.sc CHEMISTRY (ORGANIC) Sem :- 3 Enroll no:- 2212030101019 External Examination Bhagwan Mahavir College of Basic and Applied Sciences

2. Agenda INTRODUCTION 3 HISTORY OF PILLS 4 PILLS SYNTHESIS 9 USES 19 HARMFUL EFFECTS 20

3. Introduction Carl Djerassi , organic chemist, professor, author, playwright, and most notably, “ Father of the Pill ”. Lots of people these days – especially startups –   talk  about changing the world. Unlike, say,  Udacity , the invention which Djerassi had a major hand in  actually did change the world . It’s estimated that over a third of women in the USA have taken some type of birth control pill during their reproductive lifetime, for example, and over 100 million women worldwide are taking it now.  By giving women control over their own reproductive process, the technological advance laid the groundwork for the social change of the 1960s. Today we’re going to take a tour of the organic chemistry that went into the synthesis of the Pill’s original key ingredient and show that the 6 steps involved are entirely comprehensible to an involved student of organic chemistry who is about halfway through 2024/01/12 THE CHEMISTRY OF PILLS 3

4. HISTORY OF PILLS

5. HISTORY OF PILLS It had been known since the 1930s  that large doses of steroid hormones could inhibit ovulation in mammals.  B ut the basic idea is that high concentrations of sex hormones (such as progesterone, below) fool the body into thinking it is pregnant . So if this was known by the 1930’s, you might wonder why the 1940’s or 1950’s weren’t the decade of the sexual revolution, with women self-administering progesterone and throwing off the shackles of conventional sexual mores? 2024/01/12 THE CHEMISTRY OF PILLS 5

6. 2024/01/12 THE CHEMISTRY OF PILLS 6 First, in the 1930s progesterone was  extremely expensive  – at  over $80/gram,  far  more precious than  gold . This is because it had to be isolated from animal ovaries and the process was extremely inefficient (to say the least). Secondly, progesterone is rapidly metabolized in the liver, meaning it was not practical for use in a pill. In the late 1930s there was some  initial work  on developing chemical relatives of progesterone [“progestins”]  that mimicked the effects of progesterone but were more biologically active when taken orally, but the difficulty of obtaining large quantities of steroid starting materials was a huge limiting factor. Two problems :

7. Sex Hormones – The Mexican High Tech Industry Of The 1940s The progesterone supply problem –  which is well worth a blog post on its own –  was solved in the late 1930s by American chemist  Russell Marker , who developed a method to produce progesterone and other sex hormones from steroids present in the Mexican yam. Notably, in the first batch process, 10 tons of yams yielded over 3 kg of progesterone, with a value of over $3 million in today’s dollars. Marker moved to Mexico to be closer to the source – one presumes that shipping dozens of tons of Mexican yams across the border to the USA was problematic – and hired a team of chemists to join his new company,  Syntex .   As Syntex grew, competitors emerged, and these efforts drove the cost of progesterone down from $80/gram to about $2/gram by the end of the 1940s.

8. Djerassi joined Syntex shortly after the war. With a ready supply of sex hormones established, work focused on developing synthetic analogues of progesterone that would mimic the biological activity but not be as easily metabolized.  In 1951, Djerassi and coworkers Miramontes and Rozenkrantz developed the following route to a molecule called  norethindrone . This molecule would eventually be the key ingredient of the birth control pills well into the 1970’s. [The whole story of Syntex , the Mexican steroid industry, and how the Pill was eventually developed and marketed would be a great subject of a movie – I’ve only excerpted a few parts.

9. PILLS SYNTHESIS

10. 2024/01/12 THE CHEMISTRY OF PILLS 10 6 Steps To The Pill

11. BIRCH REDUCTION WILLIAMSON ETHER OXIDATION OF SECONDARY ALCOHOL  Migration of the Double Bond Hydrolysis of the Enol Ether Synthesis :-

12. 2024/01/12 THE CHEMISTRY OF PILLS 12 The first step is to make the 3-methyl ether of estradiol. The idea is to use a weak base such as K 2 CO 3  (potassium carbonate) in the presence of methyl iodide. Because the phenol OH is considerably more acidic than the secondary alcohol ( pK a  of 10 vs pK a  of 17)  it will be preferentially deprotonated by the weak base. Since the  conjugate base is always a better nucleophile , the deprotonated phenol will react with the alkyl iodide, forming the ether. WILLIAMSON ETHER

13. The second step employs a  Birch reduction  to convert the aromatic ring into a diene. Because the OCH 3  group is electron donating [through donation of the oxygen lone pairs], the reduction occurs in a way that maximizes the distance between the oxygen and the transient negative charge.  The resulting product has a double bond with an OCH3 group attached, a functional group we call an  enol ether . As we’ll see, this is a masked (or “protected”) form of a  ketone . 2024/01/12 THE CHEMISTRY OF PILLS 13   Birch Reduction

14.  Oxidation of Secondary Alcohol The next step is conversion of the secondary alcohol to a ketone. Djerassi’s route uses a reaction called the  Oppenauer oxidation , which involves adding a Lewis acid catalyst such as Al( OiPr )3 in the presence of a ketone (usually acetone, but cyclohexanone was used here).

15. 20XX presentation title 15 Ketones undergo a variety of addition reactions, notably from nucleophiles such as Grignard and organolithium reagents. In this step, lithium acetylide  [the conjugate base of acetylene]  is added to the ketone to form a tertiary alcohol (after quenching the resulting alkoxide with a weak acid). A subtlety of this particular reaction is that the  acetylide approaches the ketone predominantly from the  bottom  face, resulting in the diastereomer shown . It’s the methyl group! That CH 3  group serves to shield the ketone from attack from the top face, resulting in nearly exclusive approach of the nucleophile from the bottom.   Addition of R-Li To A Ketone

16.  Hydrolysis of the Enol Ether We’ve discussed resonance and pi donation in previous posts. In the enol ether there is significant electron density on the end of the double bond (it is  nucleophilic  – try drawing a resonance form!). That means that it will react on the  carbon  with electrophiles such as acids. Protonation, addition of water, deprotonation of water, protonation of oxygen, elimination (of methanol), deprotonation. If that sounds vaguely familiar, you might recall that it’s yet another example of the PADPED pattern in action

17. In the last step [in practice,  this is just a continuation of the previous step] the double bond moves over one position so that it is in conjugation with the ketone. What’s going on here? First of all, recall  the ketone is in equilibrium with its tautomer , which is shown in the drawing below. Note that formation of the tautomer so that the double bond lies acoss C3-C4 results in an enol that is part of a  conjugated diene . The protonation step is a classic example of “1,4”  vs.  “1,2” addition to a diene. When the proton is added to the end (the “4” position of the diene) and then revert back from the enol to the ketone, we end up with a situation where  the ketone pi bond is in conjugation with the alkene pi bond . That situation is significantly  more stable  (about 2-3 kcal/mol) than that where the double bond lies out of conjugation. The result is that the double bond has “migrated” into conjugation with the ketone. 2024/01/12 THE CHEMISTRY OF PILLS 17   Migration of the Double Bond

18. One of the key elements in designing a good synthesis is ensuring that your reagent only reacts with the desired functional group, and this process is a perfect example of that. Note how important the  order of steps  is. For example, it’s very important that the Birch reduction comes  before  the acetylide addition, because if it was done afterward, Li/NH 3  might reduce the alkyne [recall Na/NH 3  for instance]. It’s likewise important that the acetylide addition come  before  the unmasking of the enol ether, because otherwise the acetylide would end up adding to  both  ketones rather than just the one desired. That would lead to less of the desired product, and since Djerassi’s team was making a very precious compound, it would have had bad  financial consequences as well. In that sense the enol ether acts as a  protecting group  for the leftmost ketone, which is only revealed after the key acetylide addition step. So that’s the conversion of estradiol to norhindrone – state of the art for 1951, but all comprehensible to the dedicated student of organic chemistry who has gone about halfway through Org 2! 2024/01/12 THE CHEMISTRY OF PILLS 18 Final note

19. Uses of Norethisterone Norethisterone Tablets has many uses. You can take Norethisterone Tablets to treat or manage: Heavy periods Painful periods Irregular periods or periods that are more frequent than normal Premenstrual tension (PMT) Endometriosis (where tissue from your womb is found outside your womb) Breast cancer. 2024/01/12 THE CHEMISTRY OF PILLS 19

20. Harmful Effects of Norethisterone Norethisterone may have side effects, some of which can be  Heavy and irregular menstrual bleeding. Spotting between menstrual cycles. Tender or swollen breasts. Headache & dizziness. Allergic reactions like itchy skin. Difficulty in breathing. Swollen lips/tongue/eyes/face. Swelling of the hands/feet. If you see any above signs, you should consult your doctor immediately. Some severe rare side effects can be seen after taking Norethisterone tablets, such as: Blood clot in lungs (coughing up blood, sharp pain in the chest, heart beating rapidly). Blood clot in brains (unusual severe headaches, difficulty speaking, faint feeling, severe eyesight issues)

21. Thank You A presentation by:- RAJPUROHIT SANDEEP PRATAPSINGH [email protected] (R.S.P)