Org Prep Daily

October 25, 2007


Filed under: procedures — milkshake @ 2:25 pm


In a round flask with a large egg-shaped stirbar, a solution of diisopropyl amine 3.1 g (4.2 mL; 30 mmol) in anh. THF (approx 140mL) under Ar was cooled to 0C, 2.5M BuLi solution in hexane 11 mL (27.5 mmol) was added over 5 min and the mixture was stirred on ice for additional 5 min and then cooled to -78C. To this LDA solution, an ice-cooled solution of 2,5-dibromopyridine 5.925 g (25 mmol) in anh THF (approx 50 mL) was slowly added via thin canula (gauge 18) along the flask wall over 20 min with vigorous stirring (at near-maximum speed). The flask and the canula were washed with additional anh THF (2x5mL). [Note 1] After the complete addition the mixture was stirred at -78C for extra 20 min. Anhydrous DMF 2.4 mL was then added drop-by drop over 6 min period, the mixture was then stirred for additional 30 min at -78C. The reaction was quenched by dropwise water addition (10mL), the cooling bath was replaced with ambient water bath and when the mixture warmed above 0 C additional water 90mL was added. The mixture was stirred at RT for 30 min during which time the color turned from purplish to yellow-brown. The reaction mixture was combined with hexane 100mL and sat NaCl 100mL in a separatory funnel and separated. The organic phase was washed twice with sat. NaHCO3, 2x150mL. The aqueous phases were re-extracted with ether 100mL. The combined organic extracts were dried (MgSO4) and evaporated. The residue was re-evaporated from benzene 60mL and dried on highvac. The obtained semi-solid residue was dissolved in refluxing cyclohexane 60mL, the solution was decanted and the remaining dark gummy insoluble residue was re-extracted with some additional cyclohexane (2x10mL) at reflux. The combined cyclohexane solutions were allowed to cool down to RT, after 1 hour the cloudy solution was filtered through a medium-porosity Buchner funnel (to remove a small amount of insoluble sticky impurities; the filtration funnel was washed with additional cyclohexane) and the filtrates were evaporated.

The obtained solid residue was re-crystallized from cyclohexane 25mL (reflux to RT, overnight). The supernatants were decanted and the crystallized product was suspended in a mixture cyclohexane-hexane 1:1 (approx 10mL), filtered, washed with some additional 1:1 cyhex-hex mixture and dried on highvac to yield 3.398g of pure product. The supernatants were combined with the washings and placed in refrigerator (+2C) overnight. The supernatants were decanted from the crystals, the obtained second fraction was suspended in 1:1 cyhex-hexane mixture, filtered, covered with a small volume (4 mL) of cyclohexane on a Buchner funnel and crushed and stirred with spatula (to remove some sticky oil adhering to the crystals), then filtered and washed again with some 1:1 cyhex-hex mixture and then dried – to provide additional 633mg of pure product.
Combined Y = 4.031g (61% th) of a light orange-tan crystalline solid

1H(d6-DMSO, 400MHz): 10.080(s, 1H), 8.814(s, 1H), 7.899(s, 1H); 13C(d6-DMSO, 100MHz): 189.70, 154.09, 141.43, 140.71, 127.43, 120.68

Note 1: 5-halo-4-pyridyl lithium species are very sensitive, they decompose readily above -78C and they also tend to equilibrate to isomeric 3-pyridyl lithiums. It is important to avoid overheating when adding the pyridine to the LDA solution. Efficient stirring aids the heat transfer. The halopyridine substrate solution should be added slowly, pre-cooled. As 2,5-dibromopyridine is poorly soluble in THF at low temperatures, it was pre-cooled only to 0C. (Some dibromopyridine precipitation occurs on the flask wall during the canula addition but the material is washed down into the reaction mixture during the canula wash with additional THF.) 

Credit: Lithiation of 2,5-dibromopyridine in the 4 position is not described in the literature but the procedure is based on Schlosser work. I am grateful to my colleague, Par, whose advice and pyridines I took. 

October 11, 2007

When the red water comes out

Filed under: industry life — milkshake @ 2:36 am


A friend had an unforgettable experience from hiking in Madagascar: a horror called terrestrial leeches. These slug-like creeps wait patiently in trees, bushes and tall plants. They can feel you coming from some distance and they converge and drop onto you from foliage, then bite through the shirt (pants, socks) and sneak in, migrating over your skin towards the juicier body regions where they attach themselves. This is painless – in fact you are not likely to notice the leeches munching on you under the shirt as the leeches exude a potent anesthetic in their saliva. They also inject a thrombin inhibitor that suppresses the blood clotting in the wound – which unfortunately causes you to bleed profusely (though painlesly) from the bite long after the leech has got her fill + dropped off to the ground, happy and slumberous; (this is a leech version of the Thanksgiving dinner – they can live of one good fill for many months). My friend said he knew nothing about these tree leeches until he returned from the hike and found himself covered with his own blood and with some dozen of leechey hitchhikers, attached to various parts…

The leech thrombin inhibitor hirudin is medicinally useful as an anticoagulant. There has been enormous amount of medicinal chemistry and biology done on the blood coagulation cascade. At the previous company we were working on factor VIIa inhibitors (that were supposed to be safer than the anti-thrombin or anti-Xa agents), for treatment of deep vein thrombosis. The thrombosis project got shelved eventually  – one reason was the difficulty with developing good orally-active compounds – but we made some pretty potent i.v. compounds. I have inadvertently found out how potent these compounds actually were: One night working in the lab, I noticed my jeans felt little heavy and sticky so I looked down and saw that the front of one trouser was completely soaked with blood, from the knee down to the sock and I could not find out where all this blood was oozing from! Eventually I noticed a tiny splinter of glass, barely 2 mm across, embedded in the knee and I realized that few hours before I was purifying some final compounds on prep-HPLC and I dropped an empty test tube (after active fraction) and I kneeled down to the floor in order to pick up the splinters – a tiny piece must have stuck to my knee then.   

Here is an example of the VIIa chemical monstrosity we were making  – a true embodiment of the god-awful drug design. But they sure had some long-lasting potency: 



In US, the TV is now inundated with ads for Plavix. This inhibitor of platelet- aggregation is slightly more effective than aspirin in preventing heart attack (31% vs 23% risk reduction) and therefore widely prescribed as prophylactic over long periods of time. Plavix has more serious complications than aspirin – it causes prolonged bleeding. That makes the ER doctors quite unhappy as there is no available antidote for reversing the effect (like you get with the coumarine-based anticoagulants) and every mid-age weekend biker now seems to be on the drug whether they need it or not. With intracranial bleeding from head trauma, Plavix can provide a heroic and futile excersize for the entire surgery team.

Thanks to Abel Pharmboy for pointing out the story.

October 1, 2007

Don’t panic – We will serve you!

Filed under: Uncategorized — milkshake @ 6:24 pm

mantis2.jpg credit:Zooillogix

There is an interview-exam that one takes when applying for US citizenship and one of the questions that came up was to name the benefits of becoming a US citizen. (One can vote, work for government, etc). The most obvious answer to this question was: “As a US citizen I cannot be harassed or deported for some arbitrary reason by government officials and I won’t have to deal with your bloody retarded immigration administration ever again.”  I kept that extended answer to myself.

Even as the citizenship application process was an unpleasant experience and took almost a year to complete (the immigration officials “could not locate” my file – but only for 3 months), getting my green card ten years ago was far more nerve-wrecking business. I had a legal help since my employer sponsored me but I felt like naked and pushing through a scrub whenever I had to see the immigration officials: It was clear from their demeanor that I had no legal rights to get my visa/residency approved, that I could be removed from the country should they decide to do so – with or without a reason – and there are always some government regulations to provide such a reason in ways that even Franz Kafka could not have imagined.  I figured out that the actual role of the immigration officials is to keep out as many applicants as possible, and that it does not trouble them if few applicants are left hanging in limbo or pushed into the “out” group as a matter of a routine error of the immigration administration…

Getting up before the sunrise to stand in a line in front of the imigration office at 5:30 am (they opened at 9 am) to make it to the window already at 10:30am and turn the paperwork in – and then being told (incorrectly) that I needed to come back again with additional forms and documents – was just the initial experience. Being called for a hearing that was  canceled on the day of the appointment was another good one (my wife was doing internship in New York and she had to fly to this appointment to Arizona – twice because the nice people in Tucson office found it more convenient to re-schedule our hearing without sharing the news). Having friends who were removed from US did not attenuate my immigration-related paranoia either. (Husband and wife, both physicians, with 3 kids. He was a tenure-track assistant prof at university, she was a staff physician at a hospital. Their employers were sponsoring their H visa but the necessary J-to-H-visa waiver was denied by the immigration). Then another friend lost her job at Reuters in Boston and was doing an unpaid intern for 5 months because she had to re-new her J-visa-related work permit at the end of her first year in US. (But the immigration office did not care to process her renewal papers – which she turned in 3 months in advance). Also, practically every immigration official that I met came across as surly and tense, underpaid and overworked, and behaving like a postal worker about to turn serial.

My theory is that the original immigration rules were based perhaps on some common-sense reasoning but over the years the system got subverted by the changing agendas and got loaded with generous heaps bureacracy. It is now chaotic, inefficient and extremely slow and probably there is some political calculation in keeping it so. It works now like an obstacle course: the luckiest, the most persistant and informed applicants make it trough but others will not – and any idiotic reason is good for the purpose of keeping some immigrants out.

If you are US-born and if you had no personal experience with US immigration officials and if you think that I am exaggerating, please consider the experience that some people get at a DMV office or a courthouse. They could write about it in newspaper and complain to their senator,  go to another DMV office, and the worst misfortune that could befall them is a licence driving exam delayed for weeks. The US immigration is rarely held responsible for its mistakes, it gets away with screwing up lives, ruining careers and splitting families. It is certainly the most awful institution that I got to know since the end of communism.

I just learned that I have been approved and will have the oath-taking ceremony this Wednesday. It has been a huge relief for all the described reasons and also for being able to travel outside the US again.  And now that I won’t be deported I think I may try out some herbal remedies to celebrate.


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