Post Tagged with: "Chemical Development"

More Development Adventures: The Nozaki-Hiyama-Kishi Reaction

The NHK reaction is nicely described in this Wiki article. Catalytic amounts of nickel were found to be beneficial in this system and Kishi used the reaction extensively during his synthesis of Halichondrin B, to great effect.

During a rather long synthesis we were trying to convert an aldehyde to a cis-diene using the NHK reaction as one of the steps. For various reasons we were locked into using the chromous chloride from one particular supplier and they kept us a larger quantity of that batch for our future use. As far as I remember the Ni content was not specified but here the quality of chromous chloride is obviously critical for the success of this reaction and it had not been adequately defined. Indeed this may be a reason for the extreme variability we observed during a scale-up campaign that was in direct contrast to the previous campaign, where all the batches went to completion, without problems, in 2 hours at room temperature.

Now each of the three batch reactions behaved differently, the first was not complete after 2 hours and required more (20%) CrCl2 to be added with stirring for 18 hours at RT before it was complete.

Because of this hiccup, prior to the second batch we made sure that the reaction started by taking a small sample and running it in the lab. It behaved as we expected it worked. However, the second batch reaction did not budge one inch. Having a keen eye for detail I observed that the samples taken from the reactor for reaction monitoring had all proceeded rapidly to completion by the time it took to get them to the analytical lab, about ten to fifteen minutes. It was rationalised by others and myself that this may have been an effect due to the contact of the sample with air (oxygen). So here was the answer, take 150,000 mL samples and let them react. However, the others did not like this idea and suggested that we could/should introduce air into the reaction vessel! Two things to note here; 1) air (oxygen) is normally deadly for this type of reaction and 2) the introduction of air into a reactor full of 150 L of THF is a procedure that is fraught with hazard and should not be attempted at home, never mind the pilot plant. But the batteries were obviously in the correct way and lo and behold the reaction went to completion after a further 18-hour period.

The third batch, however, when run under the conditions used for the second batch (extra chromous chloride and a catalytic amount of air) did not move at all. As a last resort it was warmed to 40°C and obliged us by going to completion within 2 hours! I might add at this point that all the reagents and starting materials were use-tested before starting the larger scale batches, no problems were observed, all reactions going to completion within the allotted 2-hour period. I should also point out that the aldehyde was not that stable, as these things tend to be, we did see decomposition and racemisation after stability experiments, and we were running out of chromous chloride so we could not afford to fool around indefinitely.

The reason for this extreme variability and discrepancy from the lab results remains a total mystery and will need to be examined before any further scale-up is planned. However, it is known that catalytic quantities of nickel (II) or palladium (II) may be required for an efficient coupling process. We did not examine the nickel (II) content of our chromous chloride but this is a point we filed for future reference.

Furthermore the chromium residues cannot be present in the wastewater from the process therefore they must be re-cycled for an ecologically sound process although at this stage of development we did not investigate this. Truthfully I would not have known how to start doing this re-cycling and the above sentence is there for effect only. I would guess that somewhere in the literature I would find a paper referencing the preparation of an insoluble chromium(III) salt. I did not look, because the project died and I moved on to better things.

So in the words of the Bard, it is “just like cooking”.

By October 25, 2012 0 comments synthetic chemistry

Life in Chemical Development, Part 3.

The last part of the trilogy: In the last two  I wrote about my first impressions as a chemist in chemical development blessed with a late stage project involving some azide chemistry. This project continued when I received a message that it was actually going into production. In the meantime all the use tests1 I had carried out bore fruit and we were able to define three suppliers for the benzyl alcohol and registered it as the starting material for the drug substance manufacture. So now I only had the synthesis of the benzyl chloride and its conversion to the azide to worry about.

Due to lack of capacity in chemical production it was decided to outsource these two steps to an external manufacturer and after a series of meetings with this particular company we went to their facilities to work with them in carrying out a pilot scale series so that they could get to grips with the chemistry. So off we trundled (the production chemist and I) to spend ten days or so to familiarise them with the chemistry.

We spent the first morning just finding the place, the taxi driver got lost! Ending up back at the hotel I decided to rent a car and eventually found the site. After discussing the chemistry in depth they decided to run the first 1 kMol reaction. Off they went and we disappeared back to the hotel to get some decent food and wait for a phone call. Five hours reaction time came and went, no call, so off we went back to the plant. The place looked suspiciously quiet, I thought “Oh dear” (to put it politely) something has gone wrong. We eventually found the responsible chemist wandering around in front of the building, shaking his head and mumbling to himself, and tears were streaming down his face. Obviously he had been exposed to the physiochemical properties of the benzyl halide. Indeed he had! We followed him into the pilot plant, wearing gas masks and there it was, the source of his mumbling. They had used an “old” reactor. The enamel was cracked (history does repeat itself) but this time the crack was larger and the 37% hydrochloric acid had merrily eaten it way through the reactor and into the cooling coils. Of course they shut the whole thing down, upon which the whole mess solidified. Scratch one reactor. Well we went home leaving them to it. I do not know how they disposed of the mess, and I don’t really want to.

Some weeks later we were back. They were ready to have a second go at it. This time it worked. During the five-hour reaction time I took a wander outside and started crying again. The room beneath the reactor was open to the world. I went in and saw an open bottle of ammonia directly under the valve in the bottom of the reactor. Looking up I saw a steady drip of the benzyl halide emerging from the valve. Pointing this out to the operator he was not bothered at all and said that ammonia was good for the lungs and anyway not a lot was being lost. But the reaction worked as advertised, as did the azide step. So we returned home and gave them the outsourcing work.

Months later we returned to their state of the art production facility. A rather large building containing safety boxes, each with two floors the upper one with two 10 m3 reactors and beneath centrifuges and pressure filters etc. There were four such boxes on each side of the building that was only about three years old. The control room was at the entrance end and everything was computer controlled, apart from adding the reagents manually which needed a human being! So this was quite a scale-up, about 15 times but far as I remember I think we did 12 kMol batches.

Before we started we had a look at the safety box we were going to use. For some reason this had all the glass tubes for the exhaust gases ziz-zagging up the walls, presumably to save space. One of them was full of a liquid with a very light greenish tinge. After several enquiries I was told it was hydrochloric acid remnants from the cleaning process. Well as we were going to use hundreds of kilos of dusty sodium azide I insisted the liquid was removed. This put the schedule back and we actually began the next day with the chemistry.

Off we went with the synthesis of the benzyl chloride. All went well until the operator tried to transfer the product to the other reactor. The technician could not put more than 0.5 bar nitrogen pressure on the reactor to get the transfer going. He kept trying to increase the nitrogen pressure, no luck, so I suggested he should go and look. No response. So I ambled along and peered in the porthole. Wow, it looked like Old Faithful. The product was being pushed out of an inlet port of the reactor with the nitrogen pressure. The stream was about 2 meters high. So I sauntered  back to the control room and told them this. Off went the nitrogen pressure on went the gas masks and safety suits and we went along to the box. It turned out that the operator who removed the pH electrode had not replaced the cap properly hence causing the geyser effect. I went back to the hotel so they could clean up the entire mess. The next day we started again. This time all went well and we were able to produce both the halide and the azide and obtained the required yield. That was I thought.

It was all quiet on the western front when the phone rang again, yes the second time it rang. There was a nice voice on the other end and we were having a pleasant conversation until the word INSPECTION was uttered. A mock FDA inspection was planned for Monday next week and did I have time to attend? This was Wednesday. Did I have a choice? No, came back down the line. This was a three-day event run by our internal QA, who at some time and no doubt considerable expense had poached a FDA inspector. So I examined the SOP telling me what to do in the event and spent the rest of that week getting the house in order. The great day arrived at last and I packed all my folders and computer into the car and took off for the meeting site.

An enormous empty room greeted me. I was always early for meetings so I could drink all the coffee and eat the small sandwiches provided or snaffle all the ones I liked. People commenced arriving and the room started filling up with conversation, computers and grey A4 folders. The production chemist arrived accompanied by two mammoth shopping trolleys full of these folders, I don’t know where the trolleys came from but they were full to overflowing. In rolled the tame ex FDA inspector followed by his minions and got the meeting started.

As it turned out they were interested in everything except the chemistry. The production validation protocols were examined in minute detail, as were the analytical methods and their results. Cleaning practices, labelling procedures, Sop’s, calibration, you name it, it was examined, but not the chemistry. They probably even looked to see if the toilet paper conformed to cGMP, but still no chemistry. Finally on the last day chemistry reared its ugly head! “Did you examine your starting material for the existence of positional isomers and other elements (those related to the ones we had in the drug substance)?” Some kindly neighbour kicked the chair from under me where I had been happily dreaming about seaside holidays. “Yes and yes”, I said after picking myself up off the floor. “Good, good” said the fake inspector and turned back to giving the analytics guy round 15 of his version of the Spanish Inquisition. I went back to sleep. During a waking period I did observe that some of the questions they asked were silly to say the least, but I suppose he was only earning his big bucks. Still it was an interesting few days and I learnt what not to do.

Some months later I learnt that we (the company) had sold it lock stock and barrel to someone else. They of course visited us and carried out an inspection, more or less as above. I did not attend the meetings but was available should chemistry expertise have been required, but I wasn’t needed. That was that for me. I went back to the lab and cleared out all the samples and archived all the folders. Where they are now I don’t know, buried under a foot thick pile of dust I suppose. A happy end to my first large project


1      A use test is employed in order to investigate material from potential starting material suppliers: The compound must meet the given specifications and perform in the series of reactions to deliver the desired product according to its specifications.


After all this I have come to the conclusion that cGMP does not stand for “current Good Manufacturing Practice but Grosse Mengen Papier (translated from the German it means large quantities of Paper).

Life in Chemical Development, Part 2.

In the first part of this little series I recounted my experience with two steps of a four-step sequence, now I would like to move on to the last two steps: The preparation of a benzyl chloride and it’s conversion to a benzyl azide.

If you remember I had to convert 7098 kg of the benzyl alcohol ultimately to the azide. According to the plan:

Now benzyl halides are well known for their lachrymatory properties and this one made me cry just thinking about it. All that was required was to walk past the building, where it was being produced, to burst into tears and I had to run 46 batches (1.02 kMol) to make this stuff plus 9 for use tests. In fact we made the chloride then almost immediately concerted it to the azide.

As part of the safety checks in the pre-reaction control of the equipment the conductance of the enamelled stainless steel reactor was checked to make sure there were no cracks in the enamelling, it was deemed to be ok so we carried on. The alcohol was placed in a 630 L reactor and 312.8 kg of 37% hydrochloric acid was pumped in. The solution was heated slowly to an internal temperature of 90-93°C ( to avoid loosing too much HCl) and held there for 5 hours. During the reaction a two-phase system formed and we all cried. The product was on the bottom and it was separated from the acid after cooling to 40°- 45°C because the compound solidified at 37°C. It was then filtered and the pH adjusted to 9-12 with 30% NaOH solution and stored at 40°C as a two-phase system with water with minimal stirring and constant pH adjustment maintaining the 9-12 range. In the meantime we got things going for the conversion to the benzyl azide, more about that later.

When we examined the filter from the very last reaction we observed bits of blue glass. I hear you say “not again”. I don’t seen to have much luck with enamelled reactors. Well this time we were really lucky, and I mean really. Have a look at these two pictures.

The hole was a hairline crack in the enamel. Now this did not show up in the conductivity tests as it was right up at the top of the reactor where the stirrer joined together with the motor and could not be reached with the equipment we had, a pathetic excuse really. Maybe we should have used, you know that beer that reaches places that other beers can’t.  Remember under the enamel is stainless steel and we were using almost boiling 37% hydrochloric acid. So the acid seeped through during the course of the 46 batches and started munching away at the steel. The metal was so thin that if you pinched it between thumb and forefinger you could move the bottom part back and forward. I would say that one more reaction and the stirrer would have broken off at 100 rpm making God only knows what kind of mess. Furthermore it is well known that the presence of iron (rust) benzyl halides decompose exothermically at quite low temperatures. I can’t remember the exact temperatures but it moves the decomposition point (where the exotherm begins in DSC measurements) down about 50 or so degrees and increases the size of the exotherm markedly. So I guess we were lucky on two points, we stopped just in time and we were using steel with a very low iron content. After I saw this and realised the implications I my knees started knocking together and I staggered across the road to a pub and had a few stiff drinks and went home where I continued the treatment.

Back to the chemistry: Working with azides is particularly dangerous because of potential explosion and health hazards. Sodium azide is a very nasty compound. It is a CNS depressant and breathing the dust causes almost immediate breathing problems amongst others, see this page for more information, azides. Furthermore it also contains traces of hydrogen azide, which has similar biological behaviour to sodium azide but has the pleasant habit of being shock sensitive and hence explosive. The stirrer episode was bad enough; and we were using 70 kg of sodium azide per batch, my poor knees (never mind the liver). Even at pH 9 or above one can still detect HN3 in the gas phase. For the reaction we had an extensive gas washing system with 4 washers filled with 30% sodium hydroxide solution through which the exhaust went. At the end of this chain we periodically monitored for the presence of HN3 using ferric chloride spot tests, which are very sensitive for this compound. I’m happy to say that at the end of the chain we never detected any HN3. The reactor was specially made out of high quality tantalum steel, where the heavy metal content was minimised so we hopefully avoided the formation of heavy metal azides, I do not know if tantalum azide exists (perhaps someone who reads this may know) and heated glass tubing was employed for the transfers.

We threw the following into a 630 L reactor; 200 kg water, 2.6 mL of 30%NaOH solution, 700g tetra-n-butylammonium bromide, 70 kg sodium azide and a pH electrode. After heating this mixture to 90-95°C internal temperature and added the alkaline mixture of the benzyl chloride to it within 60 minutes. The pH drifted during this reaction and it was constantly monitored and kept between 9 and 12. The reaction is exothermic and the temperature control was also monitored closely during the 2 hour stirring at 90-95°C.

We then cooled to room temperature and filtered the lower organic phase (this time no glass was observed!) and removed the aqueous layer. This time everything went ok and from 55 batches we obtained a total of 9284.64 kg with an average purity of 94% and an average yield of 97.9%. All of the batches were released for the next step by QA. At last I was almost finished, I still had to dispose of all the azide containing waste from all the gas washers and all the water layers and reactor cleaning! This was really funny. We disposed of it by treatment of the waste with 37% hydrochloric acid and sodium nitrite, generating nitrogen, laughing gas and various other oxides or nitrogen that were washed out by the exhaust treatment. This was another foaming reaction, but by this time I was immune to foaming, didn’t worry me anymore. The aqueous phases went down to the water treatment plant.

There it was finished at last, with enough material for my colleague to play with. There is still more to tell about this chemistry but that will be part 3.

I hope you enjoyed my ramblings and look forward to many comments!

Life in Chemical Development Part 1.

After spending some years in medicinal chemistry (CNS) I moved to chemical development. Now this change I can recommend to everyone. In med. chem. you are just another tool for the biologists churning out compounds (methyl, ethyl, futile). I think this says it all, one of my biological colleagues asked me for more of a particular compound and added “make it more soluble the next time.”

You don’t get a real chance to use your chemical knowledge and training, you know all that stuff you learnt at university, some of which may have gone into a thesis. Now, in chemical development that is completely different. There you can actually apply your knowledge to scores of problems, even using physical organic chemistry! For me it was like a breath of fresh air and it re-vitalised my organic chemistry tick. At that time we were responsible for everything, reservation of the pilot plant equipment, ordering the starting materials, carrying out use tests of material from new suppliers1, organisation of all the analytics, all the lab work to produce a lab procedure, all the pilot plant supervision including writing a pilot plant procedure, all the safety studies, proposing and carrying out alternative routes, when required, in fact, everything one can think of we were responsible for. It all boiled down to quality, quantity and delivery (on time).

In a previous post here I recalled some of my experiences my first project, now I recount the second. This compound could loosely be called a dinosaur, it had been in development for more than a decade or so and the chemistry, as we will see, had some bite to it. It was a 9-step synthesis of which I had the first 4 steps. The steps under my supervision were; 1) an acid catalysed esterification of a benzoic acid to its methyl ester, 2) reduction with sodium borohydride, 3) conversion of the benzyl alcohol to the benzyl chloride, 4) conversion of the benzyl chloride to the benzyl azide.

A good friend and colleague, not to mention an excellent chemist, had largely completed the chemical development; there were just a few more things to look at in the lab. My role was to produce quantities in the pilot plant to maintain the clinical supply and for the formulation validation. This, of course, meant lots of material had to be produced. We had to obtain around 7000 kg’s of drug substance by a date given by the start of the clinical trials (I don’t remember which ones it was, Phase II Z perhaps?). Calculated was 1 month for release of the drug product by QA, which meant for me I had to start in January and deliver my last step by the end of September. Here is the plan I generated at that time.


The esterification was easy: it was done in a 2-phase system, hexane/methanol and catalysed by conc. sulphuric acid (extractive esterification). We did 16 batches of 528 kg of the benzoic acid using 238 kg 98% conc. sulphuric acid per batch. After a bicarbonate neutralisation, phase separation and distillation of solvent I got 614 kg of the ester. I did it 16 times, the average yield was 95.75%, and 9145 kg was prepared and used in the next step. It had some residual hexane in it,, about 10% per batch, but this was not a problem for the reduction. The hexane distillate was re-used each batch, just being replenished with fresh material to make up the losses.

Dimethyl ether formation was not a problem. It maximised at a production rate of 500 mg/minute after 1 hour then dropped away to <50 mg/minute after the regular reaction time was over. Not bad for a 528 kg batch and certainly not a hazard.

In contrast to med. chem. at least you can see what you get from your reaction, 16×1 cubic meter containers were used to store the stuff until we started the next step. Remember the plan, it was overlapping so we started step 2 about halfway through the step 1 campaign so thing were getting more complicated.

The borohydride reduction was a bit trickier. I did 42 batches of 200kg of the ester as a 90% solution in hexane corresponding to around 1 kMol of starting material plus 8 more batches as “use tests”. Everything was tossed into a 1000 L reactor, warmed to 55-57°C and methanol added via a membrane pump over an 8 hour period.

There is still not a good system for the introduction of such solids as sodium borohydride to a reactor. Borohydride is very hydroscopic and it blocks up the machine. We tried pellets, and these bags that dissolve and release the reagent, but then you just get mushy plastic bag in your product. Neither was as good as the powdered stuff. So in the end we just quickly shovelled it in through the manhole. The hydrogen liberated was vented with a nitrogen flow via a cold (-30°C condenser to trap THF) to the roof via a specially designed pipe with a non-return valve built in so no flames could return and cause a nasty experience.

We set up the first reaction and got it going, then the operator turned to me and said “I’m off for my coffee break now, if anything happens press the red button.” And with that left me standing there praying nothing would happen. Of course he was joking, I hoped, sure enough another operator arrived laughing at my obvious relief. Just as well he came. I looked in the reactor to see a wall of foam coming up to meet me, alarms started to go off as we had about 0.5 Bar overpressure in the reactor which was rapidly increasing. The hydrogen-venting pipe was blocked. So everything was shut down (except the stirrer) and fortunately the foam was contained. Now, it turned out that this pipe had not been used for some months. We went up on the roof and blew a terrific pressure of nitrogen through it from below, and saw several dead birds and various other bits of detritus shooting out of it. Thank God for the non-return valve. The blockage problem solved they placed a steel net over the top to prevent this happening again although why this had not been done before I don’t know. Anyway I went off to change my underclothes and when I got back we started the thing up again and it seemed to be ok this time.

The safety department recommended that, if the reaction got out of control, we should dilute the reaction rapidly mixture by pumping in THF, so a 500 L container under 1 Bar pressure was connected at all times during the reaction, fortunately we never had to use it. This was a safety measure because during DSC experiments we observed a long flat exothermic decomposition between 75°C – 500°C. Our requirements said the reaction must be carried out 20°C below the start of the decomposition temperature which is why we did it at 55-56°C. In any case it would not have been critical, as the maximum temperature of the synthetic reaction (132°C) would not have been reached even if all the THF had evaporated in the case of a condenser problem, the evaporation of the THF would cool the system down. The total energy under that curve from 75° – 500°C was around 700 kJ/kg. Note here the time to maximum rate of the decomposition reaction was estimated at >24 hours, which was fine and meant we would just about survive and the blast proof windows would live another day.

The work-up was interesting; it involved a solvent change to toluene followed by aqueous extraction. So off we went and distilled off the THF/MeOH down to a predetermined volume in the reactor. Note if you applied the vacuum too hard you obtained another foamy mixture advancing its way up and out of the reactor. This was fascinating to watch but I was used to foam by now I knew it would stop which it did, just in time before it reached the condensers. Toluene went in, toluene/THF/MeOH came out and more toluene went in and toluene/THF/MeOH came out, more toluene went in this time followed by water. Now if you did not stir for long enough (2 hours) the aqueous layer was on the top! But I didn’t fall for this one, after the required time the phases swapped over and I obtained a normal water/toluene/product mixture. Off came the water, which was re-extracted and the combined toluene layers evaporated to dryness. All the toluene from the extractions was re-cycled, and used in the next operation for the extraction after checking to make sure there was no accumulation of any side products (which, of course, there was not). Filtration of the distillation residue to remove floating white solids provided the product.

So, after nearly 5 months we ended up with the benzyl alcohol. The mean yield was 96.88% corrected for the concentration of the product (as about 3% toluene remained) and we produced 7098 kg. With this we were ready for the two most critical steps in the sequence, the formation of the benzyl chloride and finally the benzyl azide. That will be the topic of the next missive in this small series.


  1. A use test is employed in order to investigate material from potential starting material suppliers: The compound must meet the given specifications and perform in the series of reactions to deliver the desired product according to its specifications.
By September 12, 2012 9 comments general chemistry, synthetic chemistry