Org Prep Daily

February 24, 2008

Such, such were the joys

Filed under: industry life — milkshake @ 8:07 pm

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When I was laid off 2003 by a giant pharma company, we were told that – because we were getting a better severance payment than the absolute minimum required by law – we must sign a gag agreement. The agreement was that we won’t say anything negative about being fired and about the company that fired us. In this gag agreement we also promised that we would not disclose the severance amount and the existence of the gag agreement.

Since our closed site was quite large, they did not fire us all at once but they divided us into “waves” . I was lucky to get out early so I still got what was promised – but the colleagues fired few weeks afer me were screwed. Someone at the headquarters figured out that they were giving away too generous severance so they cut it. Many of my colleagues ended up suing the company: their class-action dragged on for years but eventually the company coughed up the rest of the promised money to settle.

I soon found a job at a medium-sized company in South San Francisco. The place was crazy – they drove us extremely hard there because the company was in trouble and we needed to save it or we would lose our jobs. So we were working like nuts “to have a clinical candidate by the end of the year”and the biggest problem was our management: they were very nervous, they made all kinds of unrealistic promises to appease their superiors but wouldn’t spend money on equipment we needed for the candidate scale-ups. The management was setting us for failure – we were short of people but they would always come up with ridiculous new ideas what else we should do for somebody, ontop of our work. So our medicinal chemistry group ended up doing the scale up, the bulk purifications, the process optimisation, and the formulation work also – while trying to find the best candidate. After 10 months I got tired of this baloney (and our boss) and since I got a job offer I prepared to quit. There was plenty of good chemists there and I talked to some friends discreetly – to see if they would like to go with me – but not discreetly enough and our management found out. And so they decided to fire me preventively. The problem was that they did not have an official reason for firing me – and they would have to pay a severance if they fired me.

The way it happened was rather entertaining: our evil boss came and asked me if the rumor was true – that I would be leaving. I said yes but I would want to stay for another 6 weeks or so, before my new job starts. She said they needed to find a replacement for me and they couldn’t advertise my job because they did not have an open position. So as a favour, please would I write an informal note about the timing so that they could start the hiring process? I wrote the e-mail and the next morning I found myself fired on moment notice. I was called into HR office in administrative building and told I cannot go back because my “written resignation was accelerated” by the HR, and my poor boss could do nothing about it “because it was a standard industry practice”. They would box and mail my stuff.

I asked HR whose idea it was – they told me our boss wanted me out. So I explained the HR that this was a manifest scam: the real reason why they fired me was the argument between me and my group leader. I told the HR the boss was going after me for some time because I criticised her management style and the decisions she made which delayed our project and hurt our company. In these difficult circumstances I did what I could to save our company and was working 14 hours a day including the weekends and I was punished for it – while my boss was trying to fabricate any reasons to fire me in order to cover up her mistakes. Now she did it in a sleazy way and she also manipulated the HR in the process. It was a textbook wrongful dismissal.

The HR immediately called my boss and overruled the firing and I went back to work. The victory lived short: the same evening the boss called an emergency management meeting – all the senior staf, with site director, etc – and she went about the terrible danger that I would steal the company’s intellectual property and lure other employees away. I found myself fired the next Monday.

It took several letters to the company director with “wrongful dismissal” prominently in them – and suddenly I got a check in the mail – over $7000 – and it was much more than they owed me for my unused vacation; it was the money that I would make if I stayed for another 2 months.  Incidentally, two months is the minimum severance required by law to be paid to dismissed employees (in California). After the check cleared I got a phone call from the headquarters: their HR boss explained that someone has made a clerical error and they overpaid me by mistake but they did not want me to return their money. You see – they could not call it severance “because I resigned voluntarily and they accelerated it” but they decided to pay my lost income to shut me up.

Some time after I left, my colleagues in South San Francisco were told that there were going to be “some limited job cuts in the future” and they needn’t to worry as the downsizing would affect only few people in some groups but the company was required by law to give a notice of possible job cuts to everybody. What the top management did not tell the employees was that the headquarters already decided to axe the company site no matter what. The top company decision was to quit the pharma business altogether – the only problem was that their research projects were unfinished. To get the best value for their research, the management needed its employees to take the projects to some reasonable stage before they could sell it to other companies. So the harder the people in the labs worked the sooner they would find themselves out of job…

And the notice was a ploy also: the legal minimum severance counts from the moment of the written notification. The employees believed the management promises that their jobs were not in danger (despite the notice) and that they were protected by the company written policies. They were told that those few people who would lose their jobs would get much better severance than the legal minimum. In fact, they did not. One day the employees were invited for all hands meeting in the administrative building and there they were told there that they can’t go back to lab again. Suddenly guards and boxes appeared at the chemistry building and the chemists were given only few minutes to pack their office belonging. They were constantly watched as to not to sabotage anything.  Despite the assurances, they all got just the minimum, which turned out to be less than 1 month salary because the notice was already in effect. (The group bosses were employed few weeks or months longer, in the empty building, in order to wrap up the projects and put the documentation together. I suppose they got a better deal.)

So as you can see, the industry has various ways of maximising the shareholders’ value. There is probably someone at your company who will get a bonus for firing you and then screwing you out of your severance.

Arnold Salt

Filed under: procedures — milkshake @ 5:33 pm

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Anhydrous DMF 160mL in a 0.5L round flask was cooled on ice bath and neat POCl3 40 mL (436mmol) was added greadually over 10 min period (exothermic). The mixture was warmed up to RT, bromoacetic acid solid 19.00g (136.7 mmol, Aldrich 99%+) was added quickly in one portion (hygroscopic, wear gloves – bromoacetic acid and POCl3 are nasty). The flask was equipped with a reflux condenser and the mixture was stirred under Ar on oil bath at 90C for 9 hours. The mixture turned orange, with a slow CO2 evolution. The mixture was cooled to RT, DMF was distilled out on highvac (RT to 90C at 0.5 Torr) and the obtained thick residue was treated with ice-cold water 100mL on a sonicator bath. An exothermic hydrolysis commenced. When all residue dissolved and the mixture cooled to RT, solid sodium hexafluorophosphate 46.2g (275 mmol) was added in one portion followed by some additional water (50 mL). The mixture was shaken vigorously for 10 min, the precipitated product was collected using a large Buchner funnel. The solid cake was compressed on the frit, washed with ice-cold water (5x20mL), dried by suction and then on highvac.
Y=61.05g (94%) of a yellowish-white solid

1H(d6-DMSO, 400MHz): 8.439(s, 3H), 3.535(s, 9H), 3.376(s, 9H)

Note 1: The formylation is complete in 6 hours at 90C. KPF6 is probably a better source of hexafluorophosphate because unlike the sodium salt it does not hydrolyse readily, does not etch glass and is non-hygroscopic. Aqueous HPF6 can be also used. It is important to remove most DMF from the reaction mixture, this takes some time (I used a rotovap hooked to oil pump).

Note 2:  The product can be re-crystallised to analytical purity from MeCN + some antisolvent (THF) but the crude material is suitable for most purposes. 

Note 3: Bromoacetic acid can be replaced with bromoacetyl chloride or bromide – in such case the POCl3 amount can be reduced by one equivalent

February 21, 2008

5-(N-pyrazolyl)-3-nitrobenzoic acid

Filed under: procedures — milkshake @ 7:14 pm

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3-hydrazinobenzoic acid 13.95g (91.68 mmol) suspension in water 100mL was diluted with acetic acid 100mL and 1,1,3,3-tetramethoxypropane 15.5mL (15.11g; 92mmol) was added to the mixture, followed by conc. HCl 10mL. The mixture was stirred under reflux on a 100C oil bath for 45 min. (The condensation was complete in less than 30 min). The dark reaction mixture was poured into a large beaker and the stirred mixture was diluted with gradual water addition up to 1L total volume. After 30 min stirring the obtained slurry was allowed to crystallize in a fridge (+1C) overnight. The precipitated m-(N-pyrazolyl)-benzoic acid was collected by filtration, washed with ice-cold water (100mL), dried by suction and on highvac.
Y=15.38g of a light tan powder (89% th.) 1H(d6-DMSO, 400MHz): 13.217(br s, 1H),  8.609(dd, 2.5Hz, 0.4Hz, 1H), 8.377(t, 1.9Hz, 1H), 8.095(ddd, 8.1Hz, 2.4Hz, 1.0Hz, 1H), 7.861(ddd, 7.7Hz, 1.4Hz, 1.0Hz, 1H), 7.784(dd, 1.7Hz, 0.4Hz, 1H), 7.627(t, 7.9Hz, 1H), 6.572(dd, 2.5Hz, 1.8Hz, 1H)

15.11g of m-(N-pyrazolyl)-benzoic acid from the previous step (80.29mmol) was gradually added to conc. sulfuric acid (96%) 55mL with cooling on ambient water bath. After 20 min stirring, when the starting material mostly dissolved in sulfuric acid, 8.0 mL of 70% nitric acid was added dropwise and the mixture was stirred on ambient water bath for 75min, then poured on ice (200g). The total volume of the slurry was adjusted to 0.5L with water and the mixture was stirred for 15 min, the precipitated crude product was collected by filtration, washed thoroughly with water and dried by suction. The crude product was dissolved in a mixture of ethanol 500mL and water 100mL at reflux, the hot solution was  diluted with hot water 400mL and the mixture was allowed to crystallise at RT overnight. The precipitated product was collected by filtration, washed with 1:1 ethanol+water mixture (300mL), dried by suction and on highvac. Y=13.85g of a pale yellow fluffy crystalline solid (73.5% th), containing 4.5% of a nitropyrazole impurity.

1H(d6-DMSO, 400MHz): 14.076(br s, 1H), 8.775(dd, 2.5Hz, 0.3Hz, 1H), 8.251(t, 1.4Hz, 1H), 8.200(d, 0.4Hz, 2H), 7.891(d, 1.5Hz, 1H), 6.661(dd, 2.6Hz, 1.7Hz, 1H)

Note: Even though pyrazole is a fairly electron-rich ring, in conc. sulfuric acid it becomes fully protonated so the bezoic acid portion of the molecule nitrates faster; the nitration is rather messy but the desired 1,3,5-substituted product crystallizes well.

To obtain the isomeric meta-(4-nitropyrazol-1-yl)-benzoic acid, one can nitrate by very slow addition of 2.5 equivs of 90% white fuming nitric acid dissolved in Ac2O 4 equivs, into AcOH slurry of the substrate at 60C  – a very dangerous system.

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