Synthesis of 1-chloro-3-aminopyrazolylisoquinoline

In doing research on the latest patents on WIPO (28.06.2007), I found a patent from Hoffmann-La Roche describing the synthesis of different isoquinoline aminopyrazoles, this type of molecules are protein kinase inhibitors (Aurora A)(I don't find it on Kinasepro's blog, but maybe I am wrong, otherwise nobody's perfect...).

I present here, only the synthesis of the main nucleus.

Interestingly, this synthesis starts with 1-indanone, which upon the treatment of butylnitrite, furnishes the 2-oxime derivative in 2 hours and in 65% yield (19.5g scale). Then the 2-cyanomethylbenzoic acid is obtained with a Beckmann rearrangement of the oxime previously prepared using the para-toluenesulfonylchloride (Yield = 74%). The reaction of the 2-cyanomethylbenzoic acid and 3-amino-5-pyrazole by a microwave-assisted cyclization in acetic acid in sealed vessel provides the isoquinolone in 75% yield (2g scale). Finally, the chlorination is performed using POCl3 to deliver the 1-chloro-3-aminopyrazolylisoquinoline in 61% yield.

Of course the synthesis continues with either O or S nucleophilic substitution on the chlorine atom or by Suzuki cross-coupling, furthermore different substituents can be introduced on either the pyrazole ring or the phenyl ring of the isoquinoline.

WO/2007/071348

Synthesis of 7-Prenylindole

I have seen some days ago this publication from M. Pirrung concerning the synthesis of 7-Prenylindole starting from indoline. This molecule is key ring in many natural products. As depicted below, the synthesis starts with copper catalyzed N-alkylation of indoline with 2-chloro- 2-methylbut-3-yne in THF in 91% yield on 10 mmol scale. After the reduction of the CC triple bound in alkene, the dimethylallylindoline obtained is submitted to a micro-wave assisted aza-claisen rearrangement in 90% yield (this step has been performed in a monomode micro-wave oven in a sealed tube at 150°C). Finally, the indoline has been oxidized into indole with MnO2 in DCM in 88% Yield.



I like this synthesis first, of course because this is indole ring, but also because the author uses one of my favorite reaction, the aza-claisen rearrangement, and my favorite tool for organic synthesis, a micro-wave oven.

Practical Synthesis of 7-Prenylindole
Xin Xiong and Michael C. Pirrung
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/jo070734v

For the application of the 7-Prenylindole from the same author see:

Glyceraldehyde 3-Phosphate Dehydrogenase Is a Cellular Target of the Insulin Mimic Demethylasterriquinone B1
Hyunsoo Kim, Liu Deng, Xin Xiong, William D. Hunter, Melissa C. Long, and Michael C. Pirrung
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/jm070437i

Synthesis of benzothiazole

Yes, I am still alive, but lot of work, so not time to post something this last weeks...

Of course I have missed a lot of things, but I will start the most recent chemistry.

In looking the e-first of Synthesis, I discover the one-pot synthesis of benzothiazoles starting from o-haloanilide with a tandem thionation with the Lawesson's reagent and an intramolecular cyclization, the authors propose as mechanism an intramolecular nucleophilic substitution, for me that sounds weird because the best results are obtained with both fluoro and iodio thioanilide, I would propose the formation of radical anion on sulfur or something like this which could be consistent with the results, nonetheless, this is a very interesting transformation.

One-Pot Preparation of 2-(Alkyl)arylbenzothiazoles from the Corresponding o-Halobenzanilides, Dan Bernardi, Lalla Aïcha Ba, Gilbert Kirsch, Synthesis, 2007, e-first.

That reaction reminds me a 2006 JOC have read some months ago, talking about, of course, the synthesis of benzothiazoles starting from simple thioanilides and using Dess-Martin periodinane to promote the cyclization in only 15minutes in DCM. And in their case they propose a radical intramolecular cyclization!!!

Hypervalent Iodine Mediated Intramolecular Cyclization of Thioformanilides: Expeditious Approach to 2-Substituted Benzothiazoles, D. Subhas Bose, Mohd. Idrees,J. Org. Chem. 2006, 71, 8261-8263.

Synthesis of Isradipine

Isradipine is a drug used to lower blood pressure but recently it was found by a team from Nortwestern University, that this molecule can also slow the progression of Parkinson's disease, and restore the dopamine neurons (In animals tests). Isradipine is a calcium channel blocker of the 1,4-dihydropyridine class with a benzoxadiazole moiety in position 4.
The synthesis of the 1,4-dihydropyridine ring is quite classic, the first step consists in a Knoevenagel reaction of methyl acetoacetate on the benzoxadiazole 4-carboxaldehyde using piperidine and acetic acid as catalyst and diisopropylether as solvent in a 61% yield (this is the first time I see a Knoevenagel reaction in an ether!!!???? DCM, Toluene OK, but maybe I am wrong). The second step of this synthesis is the condensation of the acrylate obtained with the isopropyl aminocrotonate in ethanol to give the desire 1,4-dihydropyridine Isradipine in 67% yield after recrystallisation.


(WO/2005/005437) An improved Process for the Manufacture of Isradipine (Shasun Chemical & Drugs Limited)

Synthesis of Alprazolam

In reading about Synthesis of Essential Drugs, I have found in my lab (not a very good book, from a chemical point of view, a lot of mistakes), I have come upon a very strange way to synthesize benzodiazepines (actually triazolobenzodiazepines).
This synthesis starts by a nucleophilic substitution of hydrazine on a 2-chloroquinoline (2,6-dichloro-4-phenylquinoline), boiling this hydrazinoquinoline with orthoacetate in xylene affords triazoloquinoline intermediates.



This intermediate undergoes the key step of the synthesis, a oxidative ring opening of the quinoline with sodium periodate and ruthenium oxide, leading to the triazolobenzophenone.



The 1,3,4-triazole is treated with formaldehyde to provide hydroxymethyl intermediate, subsequent bromination using phosphorous tribromide gives bromomethyltriazole which after spontaneous cyclization with ammonia produces the Alprazolam.



Sorry for the lack of informations, I don't have the two patents concerning this molecule.

Solid-Phase Heterocyclic Synthesis

For those who are interested by heterocyclic synthesis on solid-phase and/or by cycloaddition, will be concerned by a recent review published in Journal of Combinatorial Chemistry by Alvarez and coll., you will find [2+2], [3+2] and [4+2] cycloadditions, and a very small chapter on tandem [4+2]/[3+2].


Advances in Solid-Phase Cycloadditions for Heterocyclic Synthesis
Lidia Feliu, Patricia Vera-Luque, Fernando Albericio, and Mercedes Alvarez
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/cc070019z

Depolymerization of nylon

The world's annual consumption of plastic materials has increased from around 5 million tonnes in the 1950s to nearly 100 million tonnes today.

For ecological but also for economical reasons, it becomes more and more important to recycle plastics. One way to accomplish this recycling is to develop depolymerization methodologies.

In this area, Kamimura and coll. has published in Organic Letters a very intriguing methodology to depolymerize nylon. They heated 6-nylon at 300°C in a ionic liquid (PP13 TFSI) in presence of DMAP as catalyst for 1h under nitrogen atmosphere until the mixture became homogeneous. After distillation with a Kugelrohr apparatus, the caprolactam was obtained in a 86% yield.

An Efficient Method To Depolymerize Polyamide Plastics: A New Use of Ionic Liquids
Akio Kamimura and Shigehiro Yamamoto
Org. Lett.; 2007; ASAP