SYNTHESIS OF NEW HETEROCYCLES IN A NOVEL THREE-MODE FLOW PYROLYSIS REACTOR

Technical details

In this poster for the first time we introduce an in-house built multipurpose pyrolysis instrument. Our team

has particular interest in extending both the temperature and pressure ranges that can be applied to synthesis.

For the former, pyrolysis (such as flash vacuum pyrolysis, (FVP)) is an effective tool, while for the latter,

flow reactors can be the answer. Flash vacuum pyrolysis conditions are particularly suitable for thermal

cyclizations and the technique could be the method of choice due to its green nature or ability to affect

transformations at high temperature in a very short reaction time (1s or less) that reduces or eliminates

decompositions.

a. b. c.

Figure 1. Illustration of the three-function pyrolysis and flow reactor instrument. a.: FVP (Flash Vacuum

Pyrolysis) b.: PSP (Pneumatic Spray Pyrolysis) c.: HPP. (High Pressure Pyrolysis).

Results and Discussion:

The Gould-Jacobs and Conrad-Limpach type reactions are widely used pericyclic annulations leading to

quinolines, pyridopyrimidones and naphthols. The original approaches involved the condensation of an arylamine

with diethyl ethoxymethylenemalonate or acetoacetate followed by a heat induced cyclization into quinolones. In

alternative methods, the ring closure can be affected on heteroaromatic amines as well to yield condensed

pyrimidone bicyclic systems.

References: 1. a) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887. (b) Bemis, G. W.; Murcko, M. A. J. Med. Chem.

1999, 42, 5095. (c) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451. (d) Lipkus, A. H.; Yuan, Q.;

Lucas, K. A.; Funk, S. A.; Bartelt, W. F. 3rd; Schenck, R. J.; Trippe, A. J. J. Org. Chem. 2008, 73, 4443.

László Csaba Lengyel,1,2 Gellért Sipos,3 Tamás Sipőcz,3 Teréz Vágó,1 János Gerencsér,2 Gergely Makara,2 Ferenc Darvas3 1ComCix. Inc., 2ComInnex Inc., 3ThalesNano Inc., Záhony u. 7. H-1031 Budapest, Hungary lengyel.laszlo@cominnex.com

Introduction

The synthesis of novel heterocyclic frameworks is of particularly high interest, especially in the pharmaceutical industry’s pipeline drought observed throughout the last decade. While a

number of avenues is available to organic and medicinal chemists for the synthesis of these structures it has also been shown that chemists employ a relatively small chemical technology

toolbox1. Moreover, an analysis by Pitt et al. revealed that only a minor part of the synthetically tractable small aromatic systems can be found in the literature or in compound databases.

Previously unexplored chemical classes not only represent intellectual property opportunity but also expand the chemical matter available to interrogate challenging protein targets. Hence, new

technologies that enable the rapid and efficient synthesis of novel core structures are valuable for the chemical community.

Table 1. Parameter range of the three-function system

Scheme 3. Ten novel 7H-[1,2,5]oxadiazolo[2,3-a]pyrimidin-7-

one derivatives were synthesized using the established FVP

conditions (450 C, 30 cm tube length, 10-1 mbar)

Conclusion We demonstrated the capabilities of the pyrolysis instruments by applying the Gould-Jacobs and Conrad-Limpach

reaction for the synthesis of sixteen different fused pyrimidone heterocyclic systems, where the rapid energy transfer

and very low contact time significantly improved the yields of the intramolecular condensation reactions.

Furthermore, we have shown the different derivatization of the new heterocyclic compounds, by forming a 18-

membered library of molecules. In our opinion, pyrolysis in general and especially by using our 3-mode flow system

(Figure 1.) can be considered an advanced and effective tool for accessing an expanded parameter space (up to

thousand Celsius or up to 400 bar pressure) for organic reactions that can be exploited for the synthesis of novel

heterocyclic systems benefiting the chemical and pharmaceutical community.

The VEHICle database was searched for novel synthetically tractable compounds containing a pyrimidone motif, or

more generally an “alfa, beta unsaturated carbonyl” in an aromatic bicycle. Finally, 1,2,5-oxadiazoles was selected as

the corresponding precursor amines (4a-b) were synthetically accessible or commercially available.

Acknowledgement This work was supported by the Hungarian Government and

it was financed by the Research and Technology Innovation

Fund (grant No KMR_12-1-2012-0218).

Scheme 2. Synthesized molecular frameworks 2b-g with their synthetic precursors 1b-g and the isolated yields

for the prepared analogs.

Scheme 4. General synthesis of brominated derivatives and the Suzuki-Miyaura cross coupling reaction

Gould-Jacobs

Conrad-Limpach

We investigated the diversification possibility of produced heterocycles and we selected the Suzuki-Miyaura cross

coupling reaction, following a halogenation step with N-bromosuccinimide (Scheme 4). The bromination reaction of 7ad

and 7af was unsuccessful, presumably due to the steric inhibition of the R2 group.

Scheme 5. Succesfull library synthesis via Suzuki-Miyaura cross coupling reaction

Scheme 1. Synthesis of the 5H-thiazolo[3,2-a]pyrimidin-5-one core

Entry Technique Parameters Conversion

(%)

Product

2aa

By-

product 3 a

1 Batch1 Trichlorobenzene, 150 °C, 4 h N/A 76% -

2 MW DMF, 150 °C ,

30 min >99 60% -

3 Flow

reactorb

MeCN, 450 °C, 28 mL/min, 80

bar, 4 mL loop >99 85% -

4 Flow

reactorb

MeCN 150 °C, 0.5 mL/min, 80

bar, 4 mL loop >99 - 83%

5 FVP 450 °C, 2.5×10-1

mbar >99 88% -

6 Spray

pyrolysis

MeCN, 450 °C, 3.7 L/min carrier

gas flow (N2) 70 55% -

Table 2. Summarizes the results of the comparison reactions revealing that FVP produced the best results

(99% conversion, 88% a isolated yield), b Optimized Flow conditions by Simplex optimization method based

on the Nelder–Mead algorithm .

In our validation experiments after the successful generation of the key intermediate precursors 1a for the thermal

ring closure we initiated pilot experiments to compare the performance of the FVP device with liquid-phase flow

(mesoreactor) techniques as well as with batch processes using either conventional or MW heating. This reaction

is particularly difficult to realize since it often suffers from decarboxylation side reaction leading to 3.

FVP PSP HPP

Temperature range RT-+1000°C RT-+1000°C RT-+600°C

Reactor size 300-430×20mm 545×26mm 300×55mm

Pressure range vacuum (max 10-3

mbar) 2-3bar atm.-400bar

Flow rate - 0.1-10mL/min 0.1-50mL/min

Tube reactor volume - - 4.6mL

Heat exchanger

volume

- - 685mL

Column - - 8mm O.D., 4mm I.D.;

Long: 400mm