Org Prep Daily

November 14, 2006

2-Acetamido-5-chloropyridine-4-carboxylic acid

Filed under: procedures — milkshake @ 3:52 pm


A mixture of 2-amino-4-picoline 5.407g (50mmol), acetic acid 40mL and acetic anhydride 20mL (211mmol) was refluxed under Ar on oil bath (165-170C) for 90 min. The reaction mixture was cooled to 60C. A solution of tert-butyl hypochlorite 6.0mL(54.5 mmol) in acetic acid 40mL was added dropwise over 30 min (the addition funnel was washed with additional AcOH 10mL) and the mixture was then stirred at 60C for 8 hours. The mixture was quenched by adding water 3mL, stirred at 60C for 10 min, cooled and evaporated to dryness. The obtained semi-crystalline residue was suspended in ethanol 30mL, brought to reflux, diluted with hot water 70mL. The mixture was inoculated with a seed from crude material and allowed to crystallize at RT for 6 hours. The precipitated product was collected by filtration, washed with 3:7 ethanol-water mixture (50mL) , dried by suction and on highvac. Y=5.987g (65%) of large light-tan needles. 1H(d6-DMSO, 400MHz): 10.543(br s, 1H), 8.266(s, 1H), 8.071(br s, 1H), 2.332(s, 3H), 2.082(s, 3H)

Spatula-powdered 2-acetamido-5-chloro-4-picoline 2.908g (15.75mmol) was suspended in water 400mL and the mixture was heated to a gentle reflux on oil bath (140C). 40% aqueous NaMnO4 solution 26mL (35.25g, 99.4mmol; Aldrich) was added dropwise over 10 min into the refluxing mixture and the reflux was continued for 1 hour. The reaction mixture was removed from heating bath , charcoal 0.5g (as a slurry in some hot water) was added to absorb traces of unreacted starting material and the mixture was cooled to RT. Solid NaHSO3 3.5g was added and stirred for 10 min. The precipitated MnOx was removed by filtration and washed with 50mL of a 10:1 mixture of water+sat.NaCl. (Some salt is needed in washing to prevent MnOx colloid mud formation). The filtrates were acidified with conc. HCl 37.5%, 6.5g (=5.6mL). The mixture was placed into refrigerator overnight (+5C) . The collected product was washed with ice-cold 10:1 mix of water and sat.NaCl (2x15mL). The solids (containing some NaCl) were dried by suction and then dissolved in 99%+ EtOH 250mL under reflux, filtered while hot to remove NaCl, the filtrates were evaporated, the residue was suspended in acetonitrile 20ML, collected by filtration, washed with acetonitrile  and dried on highvac to provide 1.373g of a pure product. Evaporating the combined acetonitrile+aqueous supernatants to a small volume and adjusting pH to 2-3, a second crop precipitated in refrigerator over weekend. After dissolving the product in anh EtOH, evaporating the filtrate and washing the precipitate with acetonitrile, a second crop of product 1.272g was obtained. The combined yield was 2.645g (78%) of a white crystalline solid.

1H(d6-DMSO, 400MHz): 14.100(br s, 1H), 10.834(br s, 1H), 8.473(s, 1H), 8.395(s, 1H), 2.110(s, 3H)

November 13, 2006

Interviewing (how to get a job interview and live through it)

Filed under: industry life — milkshake @ 6:39 pm

Credit: Adolf Born 

I was laid off once – in bad times: several pharma companies just had job cuts or closed down entirely. There were only very few openings for medicinal chemists. I wanted to stay in San Francisco so I got a complete listing of companies in Bay Area from, about 30 of them, and I wrote to each one of them at least two letters – regardless whether they advertised job openings or not. One letter went to HR and one to the head of medicinal chemistry. (One cannot presume that the hiring process at every  company is well-organized and that the application letter and resume wouldn’t disappear in a pile on someone’s desk). So I was sending at least two copies and applying online, too. With the companies that I was particularly interested in, I found out the names of principal chemists and  people publishing articles in J Med Chem and Bioorg Med Chem Lett, and I wrote them also. 

Big pharma pays well and it is a worthwhile experience (pleasant or not, the companies differ). Another good alternative is an established medium-size biotech company. Startups are riskier and the salary is lower – but they can be generous on stock options. Generally, is better to start with a bigger company after school and later get hired away by a smaller company  as an experienced guy, with a corresponding promotion.

Here is couple of hints for getting an interview: The cover letter should be short, and to the point. “I am writing to apply for a position in Medicinal Chemistry at…” The things you want them to take notice in your CV should be mentioned in the cover letter. (“As you can see from my resume…”) The resume should name all school/career achievements and professional experience (including teaching). The nature of the research you participated in, list of publications (patents,presented posters, lectures). Awards, scholarships, membership. List of personal references, (= advisors and non-student collaborators). You can name areas of synthetic chemistry you especialy like (asymmetric synthesis, transition-metal-catalyzed reactions, etc) under professional interests but be prepared that you may get asked about it. The tone of your cover letter and resume should be confident but not self-indulgent. If you got a good award/important result, you should place it in a proper perspective so that it is visible on cursory reading. But you shouldn’t dwell on it – mentioning it once is enough. Make sure that the people you ask for reference will give you an excellent one – a mediocre reference is much worse than no reference at all. 

When preparing the job interview presentation, it is best to avoid the temptation of Powerpoint (cheesy clipart-diluted blather) – so keep the presentation uncluttered, like old-fashioned projector slides at the conference, black and white if possible, without too many different fonts/sizes, and with a neutral background. Put plenty of structures (reagents, mechanisms) into your slides but minimum text. Don’t recite the full text from your slides – people can read faster than you speak (and nothing is more dull for the audience than slow repetition of what they just saw on a slide).  Avoid bullets, catchy phrases and management-speak – you will be hired by chemists, not by business people. Don’t make the slides all too entry-level didactic – you want to impress chemists rather then bore them and if someone from biology or administration doesn’t understand fine points of your talk, it’s OK.

Try to make the presentation into a coherent story (“this is what we wanted because it would be very valuable etc and we made this and we had these complications so we had to go back and re-design and eventually we got these impressive results and we also found out these other interesting things, etc.”) If you worked on several different projects, pick only two, maximum three of them – present only your best stuff and put the rest into one summary slide before concluding remarks (“I also participated in these projects and could expand more on this work if there is interest” Switching topics  can be confusing so don’t do it unless you must.) Don’t get too long – you will get usualy 45 min, but you should reserve some of this time for the discussion and have spare time for some unexpected  problem (like trouble with laptop). It is better to go faster over things rather than too slowly. Prepare few extra slides going into more detail about things that you may get asked about, and put them at the end (after the credits) and show them only when asked about it. Practice the job presentation first in front of some jaded chemistry audience (=your current colleagues can be suitable).

Bring couple of printouts of your presentation on a nice paper to the job interview – some people may want to get a copy, some will ask questions in the office during one-on-one talk and you will not have the projector there. You can get into minute details of your research in these one-on-one meetings. The guys that will interview you can have just as little experience as you do with interviewing so things can get awkward. When the embarassing silence happens,  ask the interviewer guys about their chemistry – what kind of molecules they do, what kind of protein, if they have something close to clinical candidate, about their NMRs, etc. Don’t ask technical types about recreation opportunities, vacation time or dental benefits – you can sort this out later with HR, you are there to do a lot of chemistry first. If they ask you about negative stuff – about yourself, your school, etc – don’t take the bait. Stay positive: if you were unhappy in your school/had abusive adviser or colleagues, such remark always reflects badly on you (regardless of how you try to explain it away) so don’t talk about it at all. Don’t make any excuses. Don’t gossip. Also, don’t discuss your interviewing progress so far – how many interviews or offers you got. If they ask you, you can say that you have something already but are still looking. (Even if you are desperate and ready to grab any job, you must pretend during the interview that your job situation is excellent. Nobody is interested in hiring a desperate loser.)

Get lots of sleep the night before, the interview day will be long. Stay away from greasy foods and strong coffee. Wear formal but a comfortable suit: it is better to overdress than under-dress. Invest into some expensive bright-white shirts – they do make a difference. Get a good haircut. It is OK to be nervous and scared, nearly everybody is – much better than overconfident. But definitely get enough sleep before.

When you are scheduling your job interview, you can politely ask if you can meet with a guy who does the computer modeling there (or X-ray crystallography, or cell-based screening of compounds), this will show that you are motivated and independent. You want to come across as someone who is very bright, motivated, independent, modest, calm, considerate, with good sense of humor – but not annoying or pushy. If they bring the dumb HR question “where do you want to be in 5 years”, the best answer is “I would like to have my compound in the clinic. “ – and, now the modesty part –  “I know that only few people get lucky like this but it would be very good to work on a project where I could actually make a difference, for example starting from a weak potency screening hit and learn from my colleagues how to optimize the compound all the way to a clinical candidate”. 

At one-on-one talks, ask all people that are interviewing you for a business card or e-mail. In the evening right after the interview (or at latest the next morning)  write an e-mail to all of them. This thank you note should be pretty flattering stuff (a love letter of sorts) but it should not be outright servile – you want to drive home the point that you are an exceptional candidate, that you are excited about the company and eager to join their chemistry group and if they hire you would certainly fit into their wonderfull team and get lots of work done right from the first day.

Once you get an offer: Beware of companies that are pressuring you to accept immediately – they should give you more than one week, at minimum, so that you could compare the offers and decide. It is up to you to decide if and when to negotiate. But wait until after you got your offer in writing, before trying to negotiate.  It does not hurt to ask politely (if the number was really the best offer they can give you – the people doing the hiring often have authority to improve the offer a bit, even if they insist they don’t.)  It is up to you to sense how much they really want you and would risk losing you to a competing offer.  If you got multiple offers, don’t overplay one company against another – just mentioning the other company once should be enough.

When you have accepted the offer, don’t forget to take a good vacation: it won’t help to start a new job tired – the first impressions matter. And all beginnings are a bit frustrating, especially when you have to set up your new place in the lab. 

 A note: I should hardly advise anybody about career – since mine took hit when I left the grad school without finishing the thesis. With a MS from there, I got fairly decent pharma industry jobs, at Aventis, Pharmacia/Pfizer and Celera. (It would be better money if I finished, though).

Chad Orzel has a good writeup on how to give a non-sucking presentation in Powerpoint:  Chad is a professor in experimental physicis (and is talking about a lecture, not a job interview) so some of his suggestions are not quite applicable for a synthetic chemistry talk. But the piece – and blog – is worth the time spent reading it. 

Derek Lowe has an entire category of posts on interviewing. It is very good and informative –  please check it out:

N-TBS-propiolactam and N-TBS-pyrrolidone

Filed under: procedures — milkshake @ 2:40 pm


DBU 11.7mL (78mmol) was added to a slurry of propiolactam 4.902g (68.9mmol, Aldrich) and TBS-Cl 11.43g (75.9mmol) in anh DMF (30mL) with cooling on ambient water bath. The reaction was stirred at RT for 3 hours at ambient bath and the obtained heterogennous mixture was quenched by addition of saturated aqueous ammonium chloride 200mL. The mixture was extracted with ether twice (2x250mL). The organic extracts were washed with water (250mL), combined, dried (MgSO4) and evaporated. The residue was distilled on highvac (0.5Torr). After a small front fraction (1.5g), the pure product distilled at 58-61C/0.5Torr. Y=10.823g (84.5%) of a clear liquid.

1H(CDCl3, 400MHz): 3.154(br t, 4.3Hz, 2H), 3.028(br t, 4.4Hz, 2H), 0.914(s, 9H), 0.191(s, 6H); 13C(CDCl3,100MHz):172.70, 39.18, 36.87, 26.23(3C), 18.75, -5.88 (2C)


Analogous procedure: DBU 16.5mL (110mmol) was added to a slurry of 2-pyrrolidone 8.511g (100mmol, Aldrich) and TBS-Cl 15.073g (100mmol) in anh DMF (40mL) with cooling on ambient water bath and the mixture was then stirred for 1 hour at RT. Y=17.641g (88.5%) of a colorless liquid, b.p. 69-71C/0.5Torr

1H(CDCl3, 400MHz): 3.354(t, 6.6Hz, 2H), 2.292(t, 8.2Hz, 2H), 1.990(m, 2H), 0.911(s, 9H), 0.228(s, 6H); 13C(CDCl3, 100MHz): 183.14, 48.16, 33.10, 26.85(3C), 22.14, 19.63,-4.88(2C)

November 10, 2006

Call for authors # 2

Filed under: Uncategorized — milkshake @ 6:28 pm

born3.jpg Credit: Adolf Born 

I will run out of procedures to post in about a week or two.  Since the chemistry cannot keep up with posting one decent procedure a day, I will have to revert into a more convenient one-post-per-month frequency. (I think I will also rename Org Prep Daily as The Reactionary Organiker and will proceed to expound my entire world-wiew here.) Only you can prevent it – by submitting a good reproducible scalable procedure to appear here.


Filed under: procedures — milkshake @ 6:03 pm


A mixture of 2-methyl-4,6-dichloropyrimidine 25.41g (0.1559 mol) and 7M NH3 in anhydrous methanol 260mL was heated in a pressure flask at 110 C for one day. The cooled reaction mixture was evaporated and the obtained solid residue was re-crystallized from water (100mL, at +5C, overnight). The crystallized product (14.587g) was collected by filtration, rinsed with ice-cold water and dried on highvac. A second pure fraction (2.536g) was obtained by concentrating the supernatants to a small volume. Y=17.123g (76.5%) of a white crystalline solid. 1H(d6-DMSO, 400MHz): 7.101(br s, 2H), 6.258(s, 1H), 2.284(s, 3H) 

A mixture of 2-methyl-4-chloro-6-aminopyrimidine 2.532g (17.63 mmol) and N-(2-hydroxyethyl)-piperazine 6.0mL (48.9 mmol) was heated without solvent under Ar at 165 C for 75min. The amine excess was removed on highvac (with heating on oil bath), the solid residue was re-evaporated from a mixture of chloroform-methanol (1:1, 60mL), the oily residue was diluted with chloroform 10mL and allowed to crystallize overnight. The product was collected by quick filtration under Ar blanket, washed with chloroform (2x10mL) and dried on highvac. Y=2.774g (66%) of a white hygroscopic crystalline solid. 1H(d6-DMSO, 400MHz): 6.081(br s, 2H), 5.417(s, 1H), 4.434(br s, 1H), 3.515(app t, 6.0Hz, 2H), 3.380(app br t, 4.8Hz, 4H), 2.413(m, 6H), 2.149(s, 3H)

November 9, 2006

Who ordered a phenol?

Filed under: mechanisms, procedures — milkshake @ 3:41 pm

Some time ago I was making very dull series of isatin-hydrazones by a simple condensation reaction and everything worked as expected until I run into a curious problem:

Apparently the 4-chloro on the isatin got displaced with water. But there was no water in the reaction mixture (except for the one equivalent generated during the condensation) and there was no trace of the expected trichloro derivative nor any ethoxy-containing product in the reaction mixture:

4,6,7-trichloro-5-methoxyindolin-2-one (0.5 mol MeOH adduct) 296.5mg (1.00mmol) and p-hydroxyphenacetyl hydrazide 166.5mg (1.00mmol) in anhydrous ethanol 10 mL was heated in a pressure glass flask to 130-140C for 1 day (26 hours) . The reaction mixture was allowed to cool to RT and crystallize overnight. The precipitated product was collected by filtration, washed with EtOH and dried on highvac. Y=337mg (82%) of a pale-yellow crystalline solid, in 95% purity by HPLC.

1H(d6-DMSO, 400MHz): 12.517(br s, 1H), 11.629(br s, 1H), 10.862(s, 1H), 9.276(br s, 1H), 7.128(app d, 8.6Hz, 2H), 6.693(br d, 7.8Hz, 2H), 3.958(br s, 2H), 3.742(s, 3H) There is also 15% of a minor rotamer signals in the 1H(d6-DMSO) spectra: 12.983(br s, 1H), 11.550(br s, 1H); LC/MS (+cAPCI): 410(412, 408; M+1), 276(278, loss of acyl); LC/MS(-cAPCI): 410(408, M-1)

I believe the only conceivable explanation of what happened is that somehow the water molecule got delivered by intramolecular participation of the acyl group. Here is a hairy mechanistic proposal that I came up with:


I think the best way to confirm it would be by using 18-O carbonyl labeled starting materials to see where the oxygen label ends up. But this is not a piece-of-cake study. The only other corroboration I found was in a reaction with the corresponding diaminotriazole (please see the post on tetracyclic compounds from Oct 10), which also gave an irregular product:


This does not prove anything except that the 4-chlorine on the isatine is reactive in displacement with a nucleophile, which should not be a surprise. So I am still not certain on how the phenol got there. Please, let me know what you think.

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