The Synaptic Leap

 

 
Here we started another synthetic approach to PZQ. The Pictet-Spengler route, used for the industrial synthesis of (rac)-PZQ, offers a straightforward way to this anthelmetic drug in 5 steps.[1]
Starting from inexpensive 2-phenylethylamine and chloroacetyl chloride the amide 2 can be obtained in a short reaction time with high yield. 
 

 

 
This experiment was conducted in order to examine whether the cyclohexanoyl amid bond could be cleaved under mild acidic conditions by using a 50 vol% TFA solution in DCM. After 48 h under refluxing temperature 99% of the starting material could be recovered.
As a result, this procedure can be used for the scission of acid-labile protecting groups of prospective derivatives of PZQ without touching the cyclohexanoyl group.
 

 

 
After the first test reaction of an acidic hydrolysis of PZQ with 12 N HCl the conditions for the cleavage of the cyclohexanoyl group were varied. Lower concentrations of aq. HCl were used and the reaction times for the total consumption of the starting material needed to be extended.
 

 

 
rac-PZQ 1 (1.00 g, 3.20 mmol) was solved in EtOH (25 mL) and 12 N HCl (75 mL) and heated to reflux. After 4 h a reaction control by TLC of a worked-up sample showed a complete consumption of the starting material. The ice cooled solution was made basic to pH 12 by adding cooled 5 N NaOH and extracted with DCM. Then the combined layers were washed with basified brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product 2 was yielded as a light yellow solid (204 mg, 1.01 mmol, 32%). [1,2]
 

 
General procedure
 

 
The first large scale synthesis of rac-PZQ was developed by the Merck KG and Bayer AG (Merck process).[1,2]  Isoquinoline as a cheap starting material was transformed by the Reissert reaction with cyanide and cyclohexanoyl chloride 2 to the cyano amide 3.
 

 
In the literature to this reaction only a few patent procedures are known, which are not very detailed in description.[3]  To understand the Reissert reaction we start a screening approach under various conditions.

Dear TSL Members,

You are invited to the first annual QB3-UCSF-CDD developing world disease research community meeting scheduled for March 5^th 2007 at the UCSF Mission Bay Campus (details below and attached).  The collaborative community includes leading experts on developing world infectious disease research from Stanford, UCSF, UC Berkeley, UCLA, UW, SBRI, St. Jude CRH, U. Penn, Univ. of Sydney, and industry too.  

Collaborative Drug Discovery
First Annual Community Meeting

Monday, March 5^th 2007 1:00-6:00 pm; Auditorium: J. David Gladstone Institute (1^st Floor)

Hosted by Gladstone Institute and QB3 at the UCSF, Mission Bay Campus

Two major themes of this event are:

1)      Public-Private-Partnerships for Global Health Issues
2)      “Open” concepts for Collaborative Drug Discovery

Confirmed Speakers:
 

• Dr. Christopher Lipinski, Pfizer, retired. (Keynote presentation)
  
• Jim McKerrow, Professor, Dept. of Pathology, QB3 - UCSF
  
• Matt Bogyo, Professor, Dept. of Pathology, Stanford Medical School
  
• Andrej Sali, Professor, Dept of Biopharmaceutical Sciences, QB3 - UCSF
  
• Dr. Anang Shelat, St. Jude Children’s Research Hospital
  
• David Roos, Biology Professor, Univ. of Penn tentatively confirmed (Director, Penn Genomics Institute).

Symposium – Coffee/Snacks – Demos – Posters – Networking – Wine Reception

Registration is free. To register contact/RSVP to: kgregory@collaborativedrug.com.

In the U.S. we just celebrated Thanksgiving. It's a day we spend with family, eat too much (what's new?), and reflect on all the things we're thankful for. I have a lot to be thankful for. I have a wonderful family, we're generally healthy, and I've been relatively successful in my career in software.

A little more than a year ago, while feeling fortunate and thankful, I was reflecting on what I could do to give back to the world. I thought about it for quite a while, asking myself, with my experience with corporate portals (I was the R&D leader at PeopleSoft for their portal application), how could I best leverage my skills to give something back to the world. Founding The Synaptic Leap was and still is my answer.

It has become a calling for me. I believe passionately that this should be done; I know emphatically that it is technically possible. The question is simply a cultural one. Are biomedical scientists willing to do it? I think so. I believe in the human race. I believe that most of us will give a bit if we think it will make a difference. I hope, that providing The Synaptic Leap, we're giving you a place to connect with other scientists, a place to check your egos at the door and give your ideas freely, and a place to encourage and nurture the ideas of others. I hope we're giving you the perfect place to leverage your talents to give back to the world.

Sample ideas: 

• Volunteer. Help with an existing project.
• Take a project you're writing a grant for and make some of it open source. Granting agencies are increasingly favoring this.
  

It’s been a long, hot, fun summer for me. Due to budgetary constraints, I chose not to send my kids to weekly day camps. This was the first summer I didn’t officially work since I was 15 and it’s been great to spend it with my kids. I still managed to work mornings, a few evenings and Mondays when my mom took the kids. Did I say I wasn’t working?? See below for our accomplishments this summer.