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The application of flow microreactors to the preparation of a family of casein kinase I inhibitors

December 31, 2014 6:43 am / 1 Comment on The application of flow microreactors to the preparation of a family of casein kinase I inhibitors

Graphical Abstract

The Application of Flow Microreactors to the Preparation of a Family of Casein Kinase I Inhibitors.
Venturoni, F.; Nikbin, N.; Ley S. V.; Baxendale, I. R.
Org. Biomol. Chem. 2010, 8, 1798-1806. Link: 10.1039/b925327k http://pubs.rsc.org/en/Content/ArticleLanding/2010/OB/b925327k#!divAbstract

In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle binding vectors.

Francesco Venturoni,^a Nikzad Nikbin,^a Steven V. Ley^a and Ian R. Baxendale^a

^aInnovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK

E-mail: TheITC@ch.cam.ac.uk

Org. Biomol. Chem., 2010,8, 1798-1806

DOI: 10.1039/B925327K

Meclinertant (SR48692)

December 31, 2014 6:32 am / 1 Comment on Meclinertant (SR48692)

2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)pyrazole-3-carbonyl]amino]adamantane-2-carboxylic acid

Meclinertant (SR-48692) is a drug which acts as a selective, non-peptide antagonist at the neurotensin receptor NTS₁, and was the first non-peptide antagonist developed for this receptor.^[1]^[2] It is used in scientific research to explore the interaction between neurotensin and other neurotransmitters in the brain,^[3]^[4]^[5]^[6]^[7]^[8] and produces anxiolytic, anti-addictive and memory-impairing effects in animal studies.^[9]^[10]^[11]^[12]

PatentSubmittedGranted1-(7-chloroquinolin-4-yl)pyrazole-3-carboxamide N-oxide derivatives, method of preparing them, and their pharmaceutical compositions [US5561234]1996-10-01

Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin [US5585497]1996-12-17

3-amidopyrazole derivatives, process for preparing these and pharmaceutical composites containing them [US5420141]1995-05-30

Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin, their preparation and pharmaceutical compositions containing them [US5523455]1996-06-04

3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5607958]1997-03-04

3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5616592]1997-04-01

3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5635526]1997-06-03

Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them [US5965579]1999-10-12

Systematic (IUPAC) name
2-([1-(7-Chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carbonyl]amino)admantane-2-carboxylic acid
Clinical data
Legal status	?
Identifiers
CAS number	146362-70-1
ATC code	?
PubChem	CID 119192
IUPHAR ligand	1582
UNII	5JBP4SI96H
Chemical data
Formula	C₃₂H₃₁Cl N₄O₅
Mol. mass	587.064

A Machine-Assisted Flow Synthesis of SR48692: A Probe for the Investigation of Neurotensin Receptor-1 (pages 7917–7930)

Dr. Claudio Battilocchio, Benjamin J. Deadman, Dr. Nikzad Nikbin, Dr. Matthew O. Kitching, Prof. Ian R. Baxendale and Prof. Steven V. Ley

Article first published online: 16 APR 2013 | DOI: 10.1002/chem.201300696

Flow and pharmaceuticals? An investigation into whether machine-assisted technologies can be of true help in the multistep synthesis of a potent neurotensin receptor-1 probe, Meclinertant (SR48692; see structure), is reported.

Meclinertant (SR 48692)
We developed an improved synthesis of the neurotensin antagonist biological probe SR 48692. The preparation includes an number of chemical conversions and strategies involving the use of flow chemistry platforms which helped overcome some of the limiting synthetic transformations in the original chemical route .

Meclinertant (SR 48692): The synthesis of neurotensin antagonist SR 48692 for prostate cancer research I.R. Baxendale, S. Cheung, M.O. Kitching, S.V. Ley, J.W. Shearman Bio. Org. Med. Chem. 2013, 21, 4378-4387.

A synthesis of the neurotensin 1 receptor probe Merclinertant (SR48692) has been reported using a range of continuous flow through synthesis, in-line reaction monioring and purification techniques. This strategy has been contrasted with a more conventional batch synthesis approach.

Notably the safe use of phosgene gas (generated in situ), the superheating of solvents to accelerate reaction rates, the processing of a reagent suspension under continuous flow-through conditions and the application of semi-permeable membrane technology to facilitate work-up and purification were all techniques that could be beneficially applied in the synthetic scheme.

C. Battilocchio, B. J. Deadman, N. Nikbin, M. O. Kitching, I. R. Baxendale, S. V. Ley, Eur. J. Chem., 2013, DOI: 10.1002/chem.201300696

…………………….

Abstract:

An improved synthesis of the molecule SR 48692 is presented and its use as a neurotensin antagonist biological probe for use in cancer research is described. The preparation includes an number of enhanced chemical conversions and strategies to overcome some of the limiting synthetic transformations in the original chemical route.

The Synthesis of Neurotensin Antagonist SR 48692 for Prostate Cancer Research.Bioorg. Med. Chem. 2013, 21, 4378-4387.

Link: 10.1016/j.bmc.2013.04.075Baxendale, I. R.; Cheung, S.; Kitching, M. O.; Ley, S. V. Shearman, J. W.

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Meclinertant, Reminertant, SR-48692
The condensation of 2′,6′-dimethoxyacetophenone (I) with diethyl oxalate (II) by means of sodium methoxide in refluxing methanol gives the dioxobutyrate (III), which is cyclized with 7-chloroquinoline-4-hydrazine (IV) in refluxing acetic acid yielding the pyrazole derivative (V). The hydrolysis of the ester group of (V) with KOH in refluxing methanol/water affords the corresponding carboxylic acid (VI), which is finally treated with SOCl2 in refluxing toluene and condensed with 2-aminoadamantane-2-carboxylic acid.

EP 0477049; FR 2665898; JP 1992244065; US 5420141; US 5607958; US 5616592; US 5635526; US 5744491; US 5744493

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Gully D, Canton M, Boigegrain R, Jeanjean F, Molimard JC, Poncelet M, Gueudet C, Heaulme M, Leyris R, Brouard A (January 1993).“Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor”. Proceedings of the National Academy of Sciences of the United States of America 90 (1): 65–9. doi:10.1073/pnas.90.1.65. PMC 45600. PMID 8380498.
Gully D, Jeanjean F, Poncelet M, Steinberg R, Soubrié P, Le Fur G, Maffrand JP (1995). “Neuropharmacological profile of non-peptide neurotensin antagonists”. Fundamental & Clinical Pharmacology 9 (6): 513–21. doi:10.1111/j.1472-8206.1995.tb00528.x.PMID 8808171.
Rostene W, Azzi M, Boudin H, Lepee I, Souaze F, Mendez-Ubach M, Betancur C, Gully D (April 1997). “Use of nonpeptide antagonists to explore the physiological roles of neurotensin. Focus on brain neurotensin/dopamine interactions”. Annals of the New York Academy of Sciences 814: 125–41. doi:10.1111/j.1749-6632.1997.tb46151.x. PMID 9160965.
Jump up^ Jolas T, Aghajanian GK (August 1997). “Neurotensin and the serotonergic system”. Progress in Neurobiology 52 (6): 455–68.doi:10.1016/S0301-0082(97)00025-7. PMID 9316156.
Jump up^ Dobner PR, Deutch AY, Fadel J (June 2003). “Neurotensin: dual roles in psychostimulant and antipsychotic drug responses”. Life Sciences73 (6): 801–11. doi:10.1016/S0024-3205(03)00411-9. PMID 12801600.
Jump up^ Chen L, Yung KK, Yung WH (September 2006). “Neurotensin selectively facilitates glutamatergic transmission in globus pallidus”.Neuroscience 141 (4): 1871–8. doi:10.1016/j.neuroscience.2006.05.049. PMID 16814931.
Petkova-Kirova P, Rakovska A, Della Corte L, Zaekova G, Radomirov R, Mayer A (September 2008). “Neurotensin modulation of acetylcholine, GABA, and aspartate release from rat prefrontal cortex studied in vivo with microdialysis”. Brain Research Bulletin 77 (2–3): 129–35. doi:10.1016/j.brainresbull.2008.04.003. PMID 18721670.
Petkova-Kirova P, Rakovska A, Zaekova G, Ballini C, Corte LD, Radomirov R, Vágvölgyi A (December 2008). “Stimulation by neurotensin of dopamine and 5-hydroxytryptamine (5-HT) release from rat prefrontal cortex: possible role of NTR1 receptors in neuropsychiatric disorders”.Neurochemistry International 53 (6–8): 355–61. doi:10.1016/j.neuint.2008.08.010. PMID 18835308.
Griebel G, Moindrot N, Aliaga C, Simiand J, Soubrié P (December 2001). “Characterization of the profile of neurokinin-2 and neurotensin receptor antagonists in the mouse defense test battery”. Neuroscience and Biobehavioral Reviews 25 (7–8): 619–26. doi:10.1016/S0149-7634(01)00045-8. PMID 11801287.
Tirado-Santiago G, Lázaro-Muñoz G, Rodríguez-González V, Maldonado-Vlaar CS (October 2006). “Microinfusions of neurotensin antagonist SR 48692 within the nucleus accumbens core impair spatial learning in rats”. Behavioral Neuroscience 120 (5): 1093–102. doi:10.1037/0735-7044.120.5.1093. PMID 17014260.
Felszeghy K, Espinosa JM, Scarna H, Bérod A, Rostène W, Pélaprat D (December 2007). “Neurotensin receptor antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference”. Neuropsychopharmacology 32 (12): 2601–10. doi:10.1038/sj.npp.1301382. PMC 2992550. PMID 17356568.
Lévesque K, Lamarche C, Rompré PP (October 2008). “Evidence for a role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine”.European Journal of Pharmacology 594 (1–3): 132–8. doi:10.1016/j.ejphar.2008.07.048. PMID 18706409.

Continuous Flow Synthesis of alpha-Halo Ketones: Building Blocks for Anti-retroviral Agents

December 31, 2014 4:01 am / 1 Comment on Continuous Flow Synthesis of alpha-Halo Ketones: Building Blocks for Anti-retroviral Agents

Chiral alpha-halo ketones derived from N-protected amino acids are key building blocks for the synthesis of HIV protease inhibitors such as atazanavir used in HAART combination therapy.

Kappe and De Souza have reported a continuous flow through route to these intermediates which utilises a tube-in-tube reactor to introduce diazomethane generated on demand into the reaction stream containing mixed anhydride derivatives of N-protected amino acids. The resulting alpha-diazo ketones are then decomposed with HCl or HBr to afford the corresponding alpha-halo ketones.

This process allows the safe generation, separation and use of diazomethane in a continuous integrated multi-step synthesis of important API intermediates.

Abstract Image

The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor.

The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber.

The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide.

This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ∼4.5 h (87% yield).

V. D. Pinho, B.Gutmann, L. S. M. Miranda, R. O. M. A. de Souza, C. O. Kappe, J. Org. Chem., 2014, 79, 4, 1555.

http://pubs.acs.org/doi/abs/10.1021/jo402849z

Arteflene

December 30, 2014 5:09 am / Leave a comment

Arteflene

CAS : 123407-36-3 (Z-form)

[1S-[1a,4b(Z),5a,8b]]-4-[2-[2,4-Bis(trifluoromethyl)phenyl]ethenyl]-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one

(1S,4R,5R,8S)-4-[(Z)-2,4-bis(trifluoromethyl)styryl]-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one

(1S,4R,5R,8S)-4-[(Z)-2,4-Bis(trifluoromethyl)styryl]-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one

Manufacturers’ Codes: Ro-42-1611

Properties: Crystalline stable material, mp 124°. Highly lipophilic, not sol in water. Stable in soln except in the presence of strong bases or strong reducing agents.

Melting point: mp 124°

Therap-Cat: Antimalarial

The oxidation of (5R)-(-)-carvone (I) with 3-chloroperbenzoic acid (3-CPB) in dichloromethane gives 5(R)-acetyl-2-methyl-2-cyclohexen-1-one (II), which is condensed with ethyltriphenylphosphonium bromide (III) by means of butyllithium in THF yielding 2-methyl-5(Z)-(1-methyl-1-propenyl)-2-cyclohexen-1-one (IV). The photochemical oxidation of (IV) in acetonitrile catalyzed by methylene blue affords (1R,4RS,5R,8S)-4,8-dimethyl-4-vinyl-2,3-dioxabicyclo[3.3.1]nonan-7-one (V), which is ozonolyzed with O3 in methanol to the corresponding aldehyde as a mixture of enantiomers, which is submitted to crystallization giving the (1S,4R,5R,8S)-isomer (VI). Finally, this compound is submitted to a Wittig condensation with 2,4-bis(trifluoromethyl)benzyltriphenylphosphonium bromide (VII) by means of sodium bis(trimethylsilyl)amide (NaBTSA) in dichloromethane.

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Literature References:

Synthetic sesquiterpene peroxide; structurally derived from the natural peroxides artemisinin, q.v. and yingzhaosu. Prepn: W. Hofheinz et al., EP 311955; eidem, US 4977184 (1989, 1990 both to Hoffmann-La Roche).

Series of articles on prepn, biological activities, pharmacokinetics and clinical evaluations: Trop. Med. Parasitol. 45, 261-291 (1994).

Safe Generation and Synthetic Utilization of Hydrazoic Acid in a Continuous Flow Reactor.

December 30, 2014 4:08 am / Leave a comment

tetrazole synthesis

Safe Generation and Synthetic Utilization of Hydrazoic Acid in a Continuous Flow Reactor.

B. Gutmann, J.-P. Roduit, D. Roberge, C. O. Kappe, J. Flow Chem. 2012, 2,8-19.

http://www.akademiai.com/content/l622j82k3171t080/?p=0213e26b691f494d8eb782308d34fe77&pi=2

Authors

Bernhard Gutmann¹, David Obermayer¹, Jean-Paul Roduit², Dominique M. Roberge² , C. Oliver Kappe²

¹Christian Doppler Laboratory for Microwave Chemistry and Institute of Chemistry, Karl-Franzens-University Graz A-8010 Heinrichstrasse 28 Graz Austria
²Microreactor Technology, Lonza AG CH-3930 Visp Switzerland

Abstract

Hydrazoic acid (HN₃) was used in a safe and reliable way for the synthesis of 5-substitued-1H-tetrazoles and for the preparation of N-(2-azidoethyl)acylamides in a continuous flow format. Hydrazoic acid was generated in situ either from an aqueous feed of sodium azide upon mixing with acetic acid, or from neat trimethylsilyl azide upon mixing with methanol.

For both processes, subsequent reaction of the in situ generated hydrazoic acid with either organic nitriles (tetrazole formation) or 2-oxazolines (ring opening to β-azido-carboxamides) was performed in a coil reactor in an elevated temperature/pressure regime. Despite the explosive properties of HN₃, the reactions could be performed safely at very high temperatures to yield the desired products in short reaction times and in excellent product yields.

The scalability of both protocols was demonstrated for selected examples. Employing a commercially available benchtop flow reactor, productivities of 18.9 g/h of 5-phenyltetrazole and 23.0 g/h of N-(1-azido-2-methylpropan- 2-yl)acetamide were achieved.

Keywords

flow chemistry, hydrazoic acid, microreactor, process intensification, tetrazoles

Ensuring Process Stability with Reactor Temperature Control Systems

December 28, 2014 5:58 am / 2 Comments on Ensuring Process Stability with Reactor Temperature Control Systems

Temperature control plays an important role in industrial processes, pilot plants, and chemical and pharmaceutical laboratories. When controlling reactors, both exothermic and endothermic reactions must be offset with high speed and reliability. Therefore, different conditions and effects must be taken into account when specifying an optimum and highly dynamic temperature control system.

Temperature Control of Reactors

Most temperature control systems are used with chemical reactors made of either steel or glass. The former is more rugged and long-lasting, while the latter enables chemists to observe processes inside the reactor.

However, in the case of glass reactors, extensive precautions have to be followed for safe usage. Reactors usually include an inner vessel to hold the samples, which need temperature control. This inner vessel is enclosed by a jacket containing heat-transfer liquid. This reactor jacket is linked to the temperature control system.

In order to control the reactor’s temperature, the temperature control system pumps the heat-transfer liquid through the reactor’s jacket. Rapid temperature change inside the reactor is balanced by instant cool-down or heat-up, and the liquid is either cooled or heated inside the temperature control system. Figure 1 shows a schematic of a simple temperature control system.

Figure 1. Functional view of reactor temperature control

Process Stability

Both materials and reactor design can affect the temperature control of highly dynamic reactor systems. However, the heat transferred by a glass-walled vessel will be different than that transferred by a steel-walled vessel. In addition, both wall thickness and surface area can also affect accuracy. Therefore, proper mixing of the initial materials inside the reactor is important to obtain good uniformity, which in turn will guarantee optimal heat exchange.

For each type of reactor, maximum pressure values have been provided as per the specifications established by reactor manufacturers and in the Pressure Equipment Directive 97/23/EG. Regardless of any temperature control application, these limit values may not be surpassed during operation under any situations. Prior to starting a temperature control application, the applicable limits must be programmed within the temperature control unit.

Another important criterion in reactors is the maximum permissible temperature difference, which is referred to as Delta-T limit. It defines the highest difference between the temperature of the contents of the reactor and the actual thermal fluid temperature.

When compared to steel reactors, glass reactors are more susceptible to thermal stress. For that matter, any temperature control system should enable users to program reactor-specific values for the Delta-T limit per time unit. Within the temperature control equipment itself, three components considerably affect the stability of the process and these include heat exchanger, pump, and control electronics.

Heat Exchanger

It is important to ensure that a temperature control system has sufficient heating and cooling capacity, as this can significantly affect the speed to reach the preferred temperatures. In order to determine the preferred heating and cooling capacities, users must consider the essential differences in temperature, the volume of the samples, the preferred heat-up and cool-down times, and the specific heat capacity of the temperature control medium.

Highly dynamic temperature control solutions are commercially available in the market with water or air cooling. Air-cooled systems do not utilize water and may be deployed where there is sufficient air flow.

The heat thus removed from the reactor is eventually transferred to ambient air. Water-cooled systems need to be joined to a cooling water supply, but they operate more quietly and do not add surplus heat in small labs. These units could be completely enclosed by the application, if required.

Pump

The integrated pump of the temperature control unit equipment must be sufficiently strong to obtain the preferred flow rates at stable pressure. To ensure that pressure limit values mentioned above are not exceeded, the pump should provide the preferred pressure quickly and with maximum control.

Operating conditions and pressure specifications of the reactor must always be taken into account, and regulation of pump capacity must be done by presetting a limit value. Sophisticated temperature control solutions include pumps that balance the variations of the viscosity of the heat transfer liquid to make sure that energy efficiency is maintained continuously.

This is because viscosity influences flow and hence the heat transfer. An additional advantage provided by magnetically coupled pumps is that they guarantee a hydraulically-sealed thermal circuit. Also, self-lubricated pumps are beneficial as they require only minimum maintenance.

The closed loop circuit prevents contact between the ambient air and the heat transfer liquid. This not only prevents permeation of oxidation and moisture, bit also prevents oil vapors from entering into the work environment.

Additionally, an internal expansion vessel must permanently absorb temperature-induced volume variations inside the heat exchanger. Individual cooling of the expansion vessel will help in ensuring that the temperature control unit does not overheat and ultimately ensures operator safety.

A temperature control equipment should operate consistently even at high ambient temperatures. In majority of cases, the real work environment will diverge from the ideal temperature of 20°C. During hot summer months, temperature control solutions are exposed to adverse conditions. In laboratories, ambient temperatures are usually higher because of energy saving measures. These instances demonstrate the benefits of temperature control solutions that work consistently at temperatures as high as 35°C.

Control Electronics

Temperature control equipment includes advanced control electronics that monitor and control the process inside the reactor and also the internal processes of the system. When a control variable changes, the system is capable of readjusting the variable to the setpoint sans overshooting.

Accurate control electronics are needed to maintain the stability of a temperature control application. One option to assess control electronics is to look at the effort needed to set parameters. In a temperature control unit, users can enter a setpoint. Control electronics must be self-optimizing throughout the temperature control process to ensure optimum results.

Conclusion

To sum up, the process safety and stability during reactor temperature control relies on the effectiveness of heat transfer, the type of reactor, and the efficiency of the components within the temperature control unit. Therefore, different conditions and effects must be considered when specifying a highly dynamic temperature control system.

CMI 977, LDP 977

December 28, 2014 5:45 am / 1 Comment on CMI 977, LDP 977

CMI 977

C16-H19-F-N2-O4

322.3341

Millennium (Originator), Taisho (Licensee)

(2S,5S)-1-[4-[5-(4-Fluorophenoxymethyl)tetrahydrofuran-2-yl]-3-butynyl]-1-hydroxyurea 175212-04-1 CMI-977 is a potent 5-lipoxygenase inhibitor that intervenes in the production of leukotrienes and is presently being developed for the treatment of chronic asthma. It is a single enantiomer with an all–trans (2S,5S) configuration. Of the four isomers of CMI-977, the S,Sisomer was found to have the best biological activity and was selected for further development. The enantiomerically pure product was synthesized on a 2-kg scale from (S)-(+)-hydroxymethyl-γ-butyrolactone.

CytoMed, Inc. announced y the initiation of Phase I clinical trials for CMI-977, its orally active therapeutic product for the treatment of asthma. CMI-977 inhibits the 5-lipoxygenase (5-LO) cellular inflammation pathway to block the generation of leukotrienes, which play a key role in triggering bronchial asthma. The Company also announced that it has received a U.S. patent covering a number of 5-LO inhibitor compounds, including CMI-977, and their use in treating inflammatory and other disorders.
"Asthma is a chronic, persistent inflammatory disease of the airways characterized by coughing and wheezing. These symptoms are induced by the release of inflammatory mediators, including leukotrienes, from inflammatory cells in the lining of the airways," said Colin Scott, Vice President, Clinical and Regulatory Affairs of CytoMed. "CMI-977 inhibits the production of all classes of leukotrienes by inhibiting the 5-LO pathway. Preclinical studies of CMI-977 have shown similar efficacy to steroid treatment in reducing inflammation, without any evidence of the significant toxicity that has been associated with long-term use of steroids."
"CytoMed's product development strategy focuses on leveraging its expertise in molecular biology, medicinal chemistry and pharmacology to develop a broad range of product candidates," commented Thomas R. Beck, M.D., Chairman and CEO of CytoMed. "Moving our second product into the clinic is a significant step towards the Company's goal of developing a portfolio of safe and efficacious anti-inflammatory compounds." The Company's lead product, CMI-392, is currently in Phase II studies in collaboration with Stiefel Laboratories as a topical treatment for inflammation-related skin disorders.
The Phase I trial of CMI-977, which involves 56 healthy human volunteers, is being conducted at a single site. The double blind, randomized, escalating single dose study is designed to assess CMI-977's safety and tolerability.
The Company plans to complete the study in mid-1998. Over 14.6 million Americans suffer from chronic asthma. The disease is characterized by a widespread narrowing of the airways due to a contraction (spasm) of smooth muscle and overproduction of mucous, which blocks the air passages. These changes are caused by the release of spasmogens and vasoactive substances, including leukotrienes. Current long-term therapies include corticosteroids, which function by non-selectively suppressing a variety of cellular pathways that initiate inflammation. Steroids, while often effective, are associated with significant adverse side effects. CMI- 977 is a leukotriene modulator, part of a new class of drugs designed to
provide patients with a viable alternative to steroids.
CytoMed, Inc. is a growing biopharmaceutical company committed to the discovery and development of novel proprietary products for the treatment of inflammatory disease. The Company has three products in clinical or preclinical stage of development: CMI-392 in Phase II studies for the treatment of inflammatory skin disorders in collaboration with Stiefel
Laboratories; CMI-977, an orally active product in Phase I clinical trials for the treatment of asthma; and CMI-CAB-2, in late-stage preclinical development for the treatment of acute pulmonary and cardiovascular inflammation. To date, the Company has been funded primarily by investments from institutional and venture investors including Schroder Ventures, Oracle Strategic Partners, Atlas Venture, CIP Capital, BioAsia Investors, WPG Farber, Gateway Ventures, HealthCare Ventures and New York Life Insurance.

Org. Proc. Res. Dev., 1999, 3 (1), pp 73–76

DOI: 10.1021/op980209l

http://pubs.acs.org/doi/abs/10.1021/op980209l

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PAPER

A practical gram scale asymmetric synthesis of CMI-977 is described. A tandem double elimination of an α-chlorooxirane and concomitant intramolecular nucleophilic substitution was used as the key step. Jacobsen hydrolytic kinetic resolution and Sharpless asymmetric epoxidation protocols were applied for the execution of the synthesis of the key chiral building block.

Enantioselective gram scale synthesis of CMI-977 has been described using the tandem sequence of α-chloroepoxide fragmentation and intramolecular nucleophilic substituion as the key step. Combinations of Jacobsen’s hydrolytic kinetic resolution and Sharpless asymmetric epoxidation were explored on the way to achieve the key intermediate.

http://www.sciencedirect.com/science/article/pii/S0957416603001575 ………………………………. The reaction of oxirane (I) with vinylmagnesium bromide in THF gives 1-(4-fluorophenoxy)-4-penten-2(S)-ol (II), which is treated with ethyl vinyl ether and mercuric trifluoroacetate to yield the vinyl ether (III). The cyclization of (III) by means of Grubb’s catalyst in refluxing benzene affords the dihydrofuran (IV), which is treated with benzenesulfinic acid in dichloromethane to give the sulfone (V). The reaction of (V) with the acetylenic tetrahydropyranyl ether (VI) by means of isopropylmagnesium bromide in THF yields the expected addition product (VII), which is treated with TsOH to eliminate the tetrahydropyranyl group and provide the alcohol (VIII). The condensation of (VIII) with N,O-bis (phenoxycarbonyl)hydroxylamine (IX) by means of PPh3 and DEAD in THF affords the protected carbamate derivative (X), which is finally treated with ammonia in methanol.http://www.chemdrug.com/databases/8_0_sluqxnnnfcuabcvj.html

Synthesis 2000, 4, 557

””””””””””””””””””””

J. Braz. Chem. Soc. vol.24 no.2 São Paulo Feb. 2013

http://dx.doi.org/10.5935/0103-5053.20130024

http://www.scielo.br/scielo.php?pid=S0103-50532013000200003&script=sci_arttext Asthma is a chronic inflammatory disease of the respiratory system that results in the reduction or even the obstruction of air flow into the lungs.¹ Over the last 40 years, there have been sharp increases in the global prevalence of asthma and the mortality due to this condition. In 2006, approximately 300 million people worldwide developed asthma, and there are approximately 180,000 deaths annually.² In Brazil, asthma is the third most common cause of hospitalization in the Brazilian Unified Health System (SUS).³ The underdiagnosis and undertreatment of this disease have motivated the scientific community to search for new target-specific drugs to treat asthma and related respiratory diseases.⁴The compound CMI-977 (LDP-977) (1) was discovered by Cyto-Med Inc., USA,⁵ and has been demonstrated to be a prominent candidate for the treatment of chronic asthma (Figure 1). This compound inhibits the 5-lipoxygenase pathway, thus blocking the production of leukotrienes.⁶ LDP-977 (1), containing a THF-2,5-trans-substituted ring with a (2S,5S) configuration, is orally active, and exhibits a good safety profile, a high degree of potency and excellent oral bioavailability relative to the three other stereoisomers.⁵

(2S,5S)-trans-5-[(4-Fluorophenoxy)methyl]-2-(4-N-hydroxyureidyl-1-butynyl)tetrahydrofuran, CMI-977 Over the years, several synthetic routes have been proposed for the stereoselective synthesis of the THF moiety present in CMI-977 (1) (Scheme 1).^5,7,8 Intermediate 4 was prepared by Cyto-Med Inc., USA, using the first synthetic route developed,⁵ which involved a chiral pool approach for the creation of the C9 stereogenic center (Scheme 1). A nucleophilic attack involving an oxonium electrophile intermediate, obtained from 3, produced C6, but a disappointing low degree of selectivity was observed. In a similar oxonium strategy, Ley and co-workers⁷ employed an anomeric oxygen to promote the carbon rearrangement of an alkynyltributylstannane to access the THF unit, but their reaction also exhibited low selectivity (Scheme 1). Other similar strategies have led to similar results.⁸ Gurjar et al.⁹ reported a new stereoselective approach that installs the stereocenters at C6 and C9 in 6 using both Jacobsen hydrolytic kinetic resolution (HKR) and a Sharpless asymmetric epoxidation step (Scheme 1). The formation of a tandem propargyl alkoxide followed by intramolecular substitution resulted in the creation of the key tetrahydrofuran ring intermediate 7. Ley and co-workers¹⁰ also explored a similar tandem strategy providing the Retrosynthetic analysis of CMI-977 (LDP-977) (1) suitable intermediate 11, which in turn afforded the key fragment 7. These two new approaches were clearly Our disconnection approach began with a superior for the construction of the 2,5-anti THF unit as higher levels of diastereoselectivity were achieved. However, numerous steps are involved in these synthetic epoxide routes. In this paper, it is described our approach for the total synthesis of CMI-977 (LDP-977) (1). The biological importance of the target molecule and its structural features inspired us to devise a more concise and diastereoselective route to achieve the THF-2,5-trans ring of intermediate 7. Results and Discussion Retrosynthetic analysis of CMI-977 (LDP-977) (1) Our disconnection approach began with a long-established strategy for the insertion of the N-hydroxy urea moiety by alkylation involving acetylene 7 and epoxide 13, followed by a Mitsunobu-like reaction involving alcohol 4 and hydroxycarbamate 12 (Scheme 2).^9,10 The terminal acetylene 7 can be assembled via Seyferth-Gilbert homologation (using the Ohira-Bestmann protocol)¹¹ involving the aldehyde prepared from alcohol 14. It was intended to create the trans-THF configuration in our key fragment 14 using a Mukaiyama oxidative cyclization protocol with homoallylic alcohol 15.¹² The functional groups in fragment 15 could be installed starting from commercially available and inexpensive 4-fluorophenol 16, rac-epichlorohydrin 17 and allylbromomagnesium 18, in a strategy similar to that applied by Gurjar et al.⁹ Preparation of the key fragment 14 Our approach to the total synthesis of CMI-977 (LDP-977) (1) began with the reaction of p-fluorophenol 16 with rac-epichlorohydrin 17 in the presence of KOH, providing rac-5 in 97% yield (Scheme 3).¹³ The epoxide rac-5was resolved by hydrolytic kinetic resolution under Jacobsen conditions,¹⁴ using the catalyst (R, R)-(salen)Co^III(OAc) (19, 0.5 mol%) and H₂O (0.57 equiv) in tert-butyl methyl ether, providing (S)-5 in a 48% yield.⁹ The next step involved the epoxide ring-opening of (S)-5 with allylmagnesium bromide (18), providing homoallylic alcohol 15 in a quantitative yield (Scheme 4). The subsequent oxidative cyclization of 15 according to the Mukaiyama protocol,¹² mediated by the Co(modp)₂ (20) (30 mol%) catalyst,¹⁵ provided trans-THF 14 as the only observed diastereoisomer in an 84% yield.⁸ This approach has proven to be a powerful strategy for accessing the 2,5-trans-THF unit in a highly diastereoselective fashion. Preparation of the key fragment 4 and conclusion of the synthesis The alcohol 14 was then oxidized to aldehyde 21 under Parikh-Doering conditions, followed by Seyferth-Gilbert homologation¹⁶ using the Ohira-Bestmann reagent 22,¹¹ assembling the terminal acetylene 7 in a 75% yield over two steps (Scheme 5). The ¹H NMR and ¹³C NMR spectra and the optical rotation of trans-THF 7 matched the reported values for this compound.⁹ Next, the treatment of 7 with n-BuLi and ethylene oxide 13 led to alcohol 4 in a 70% yield. As shown in Scheme 5, the preparation of hydroxycarbamate 26 (53% yield), followed by its acetylation using acetyl chloride 27, provided 12 in a quantitative yield. A Mitsunobu-like reaction between alcohol 4 and N-hydroxycarbamate 12 provided 23 in a 93% yield. Finally, 23 was ammonolysed with NH₃·MeOH, yielding CMI-977 as a white solid in a 38% yield. The spectral and physical data of the synthetic sample were in complete agreement with those reported in the literature.^5,7-9

SPECTRAL DATA (2S,5S)-trans-5-[(4-Fluorophenoxy)methyl]-2-(4-N-hydroxyureidyl-1-butynyl)tetrahydrofuran, CMI-977 (1) To a round-bottomed flask, it was added 15 (85 mg, 0.19 mmol) at 0 ºC. Then, NH₃ (2 mL, 14 mmol, 7 mol L^-1in MeOH) was added, and the mixture was stirred at 0 ºC for 36 h. The reaction was concentrated under reduced pressure and purified by flash column chromatography using a mixture of CHCl₃/MeOH (20:1) as the eluent, providing the compound CMI-977 (1) (24 mg, 0.074 mmol) as a colorless solid in a 38% yield; mp 106-107 ºC, 106-107 ºC;⁹

[α]_D²⁰ -40 (c 1.1, MeOH), [α]_D -46.0 (c 1.1, MeOH);⁹

¹H NMR (CDCl₃, 250 MHz) δ 1.19 (s, 1H), 1.67-1.81 (m, 1H), 1.86-1.98 (m, 1H), 2.08-2.21 (m, 2H), 2.46 (t, 2H, J 6.5 Hz), 3.60 (t, 2H, J 6.8 Hz), 3.77-3.89 (m, 2H), 4.34-4.43 (m, 1H), 4.63-4.67 (m, 1H), 5.48 (s, 2H), 6.74-6.92 (m, 4H), 8.60 (br, 1H);

¹³C NMR (CDCl₃, 150.9 MHz) δ 17.2 (CH₂), 27.7 (CH₂), 33.3 (CH₂), 48.7 (CH₂), 69.1 (CH), 70.7 (CH₂), 76.9 (CH), 80.7 (C₀), 82.9 (C₀), 115.5 (CH), 115.7 (CH), 115.9 (CH), 154.8 (C₀), 156.6 (C₀), 158.2 (C₀), 161.7 (C₀);

IR (film) ν_max/cm^-1 3445, 3331, 3178, 2918, 2878, 1639, 1583, 1512, 1454, 1362, 1302, 1229, 1097, 1078, 1038, 937, 827, 762;

HRMS (ESI-TOF) m/z [M + H]⁺ for C₁₆H₂₀FN₂O₄ calcd. 323.1407, observed 323.1438.

References 1. Barnes P. J.; Br. J. Clin. Pharm. 1996,42, 3.

2. Braman, S. S.; Chest. 2006,130,4S. [ Links ]

3. Cabral, A. L. B.; Martins, M. A.; Carvalho, W. A. F.; Chinen,M.; Barbirotto, R. M.; Boueri, F. M. V.; Eur. Resp. J. 1998,12,35.

4. Jacobsen, J. R.; Choi, S. K.; Combs, J.; Fournier, E. J. L.; Klein, U.; Pfeiffer, J. W.; Thomas, G. R.; Yu, C.; Moran, E. J.; Bioorg. Med. Chem. Lett. 2012,22, 1213; [ Links ]

Millan, D. S.; Ballard, S. A.; Chunn, S.; Dybowski, J. A.; Fulton, C. K.; Glossop, P. A.; Guillabert, E.; Hewson, C. A.; Jones, R. M.; Lamb, D. J.; Napier, C. M.; Payne-Cook, T. A.; Renery, E. R.; Selby, M. D.; Tutt, M. F.; Yeadon, M.; Bioorg. Med. Chem. Lett.2011,21, 5826; [ Links ]

Sun, X. S.; Wasley, J. W. F.; Qiu, J; Blonder, J. P.; Stout, A. M.; Green, L. S.; Strong, S. A.; Colagiovanni, D. B.; Richards, J. P.; Mutka, S. C.; Chun, L.; Rosenthal, G. J.; ACS Med. Chem. Lett. 2011,2, 402; [ Links ]

Semko, C. M.; Chen, L.; Dressen, D. B.; Dreyer, M. L.; Dunn, W.; Farouz, F. S.; Freedman, S. B.; Holsztynska, E. J.; Jefferies, M.; Konradi, A. K.; Liao, A.; Lugar, J.; Mutter, L.; Pleiss, M. A.; Quinn, K. P.; Thompson, T.; Thorsett, E. D.; Vandevert, C.; Xu, Y.-Z.; Yednock, T. A.; Bioorg. Med. Chem. Lett .2011,21,1741. [ Links ]

5. Cai, X.; Hwang, S.; Killan, D.; Shen, T. Y.; US pat. 5,648,486 1997; [ Links ] Cai, X.; Grewal, G.; Hussion, S.; Fura, A.; Biftu, T.; US pat. 5,681,966 1997; [ Links ]

Cai, X.; Cheah, S.; Eckman, J.; Ellis, J.; Fisher, R.; Fura, A.; Grewal, G.; Hussion, S.; Ip, S.; Killian, D. B.; Garahan, L. L.; Lounsbury, H.; Qian, C.; Scannell, R. T.; Yaeger, D.; Wypij, D. M.; Yeh, C. G.; Young, M. A.; Yu, S.; Abs. Pap. Am. Chem. Soc.,1997,214,214-MEDI. [ Links ]

6. Cai, X.; Chorghade, M. S.; Fura, A.; Grewal, G. S.; Juaregui, K. A.; Lounsbury, H. A.; Scannell, R. T.; Yeh, C. G.; Young, M. A.; Yu, S.; Org. Process Res. Dev. 1999,3,73.

7. Dixon, D. J.; Ley, S. V.; Reynolds, D. J.; Chorghade, M. S.; Synth. Commun. 2000,30, 1955; [ Links ]Dixon, D. J.; Ley, S. V.; Reynolds, D. J.; Chorghade, M. S.; Indian J. Chem., Sect B 2001,40,1043.

8. Chorgade, M. S.; Gurjar, M. K.; Adikari, S. S.; Sadalapure, K.; Lalitha, S. V. S.; Murugaiah, A. M. S.; Radhakrishna, P.; Pure Appl. Chem. 1999,71, 1071; [ Links ] Gurjar, M. K.; Murali Krishna, L.; Sridhar Reddy, B.; Chorghade, M. S.; Synthesis 2000, 557; [ Links ] Chattopadhyay, A.; Vichare, P.; Dhotare, B.;Tetrahedron Lett. 2007,48,2871.

9. Gurjar, M. K.; Murugaiah, A. M. S.; Radhakrishna, P.; Ramana, C. V.; Chorghade, M. S.; Tetrahedron: Asymmetry 2003,14,1363.

10. Sharma, G. V. M.; Punna, S.; Prasad, T. R.; Krishna, P. R.; Chorghade, M. S.; Ley, S. V.; Tetrahedron: Asymmetry 2005,16,1113.

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read

Pure Appl. Chem., Vol. 71, No. 6, pp. 1071-1074, 1999.

http://pac.iupac.org/publications/pac/pdf/1999/pdf/7106×1071.pdf

Full text – pdf 322 kB – IUPAC

………………………………………………… US 5703093; US 5792776; WO 9600212 Ether (III) was prepared by condensation of (S)-4-(hydroxymethyl)butyrolactone (I) and 4-fluorophenol (II) in the presence of diisopropylazodicarboxylate (DIAD) and triphenylphosphine under Mitsunobu conditions. Then, reduction of lactone (III) with DIBAL-H in toluene at -78 C gave lactol (IV), which was converted to silyl ether (V) by treatment with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole. Subsequent reaction of (V) with TBDMS-Br in CH2Cl2 at -78 C, followed by condensation with the lithium acetylide derived from acetylene (VI), yielded compound (VII) as a mixture of isomers. Chromatographic separation of the mixture provided the desired trans isomer, which was deprotected by treatment with tetra-n-butylammonium fluoride to give alcohol (VIII). This was then condensed with N,O-bis(phenoxycarbonyl)hydroxylamine (IX) in the presence of DIAD and Ph3P to furnish the hydroxamic acid derivative (X). Finally, concomitant deprotection of the O-phenoxycarbonyl group and substitution of the remaining phenoxy group for an amino group by treatment with methanolic ammonia in a pressure tube, provided the title compound.http://www.chemdrug.com/databases/8_0_sluqxnnnfcuabcvj.html…………………………………………………. PAPER

Title:	A short and efficient stereoselective synthesis of the potent 5-lipoxygenase inhibitor, CMI-977^†
Authors:	Dixon, Darren J Ley, Steven V Reynolds, Dominic J Chorghade, Mukund S
Issue Date:	Nov-2001
Publisher:	NISCAIR-CSIR, India
Abstract:	A short and efficient synthesis of the potent 5-lipoxygenase inhibitor CMI-977 has been accomplished, utilising an oxygen to carbon rearrangement of an anomerically linked alkynyl stannane tetrahydrofuranyl ether derivative as the key step.
Page(s):	1043-1053
CC License:	CC Attribution-Noncommercial-No Derivative Works 2.5 India

Source:	IJC-B Vol.40B(11) [November 2001]

Files in This Item:

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http://nopr.niscair.res.in/bitstream/123456789/22437/1/IJCB%2040B%2811%29%201043-1053.pdf……………………………………………….

http://www.google.com.ar/patents/US20080081835 Specific inhibitors of 5-LO that may be mentioned include the following.

- (1) Zileuton (synonyms: A-64077, ABT 077, Zyflo®), described in, for example, EP 0 279 263, U.S. Pat. No. 4,873,259, Int. J. Immunopharmacol. 14, 505 (1992), Br. J. Cancer 74, 683 (1996) and Am. J. Resp. Critical Care Med. 157, Part 2, 1187 (1998).

- (2) A-63162, described in, for example, Anticancer Res. 14, 1951(1994).

- (3) A-72694.

- (4) A-78773, described in, for example, Curr. Opin. Invest. Drugs 2, 69 (1993).

- (5) A-79175 (the R-enantiomer of A 78773), described in, for example, Carcinogenesis 19, 1393 (1998) and J. Med. Chem. 40, 1955 (1997).

- (6) A-80263.

- (7) A-81834.

- (8) A-93178

- (9) A-121798, described in, for example, 211th Am. Chem. Soc. Meeting. 211: abstr. 246, 24 Mar. 1996.
- (10) Atreleuton (synonyms ABT-761 and A-85761), described in, for example, Exp. Opin. Therap. Patents 5 127 (1995).

- (11) MLN-977 (synonyms LPD-977 and CMI-977), described in, for example, Curr. Opin. Anti–Inflamm. &Immunomod. Invest. Drugs 1, 468 (1999). This, as well as similar compounds are described in U.S. Pat. No. 5,703,093.

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WO 0001381 The reaction of 4-fluorophenol (I) with epichlorohydrin (II) by means of K2CO3 in refluxing acetone gives 2-(4-fluorophenoxymethyl)oxirane (III), which is submitted to an enantioselective ring opening with the Jacobsen (R,R)-catalyst yielding a mixture of the (R)-diol (IV) and unaltered epoxide (V), easily separated by column chromatography. The reaction of (IV) with tosyl chloride and pyridine in dichloromethane affords the primary monotosylate (VI), which is converted into the chiral epoxide (VII) by reaction with NaH in THF/DMF. The reaction of (VII) with allylmagnesium bromide (VIII) in ethyl ether gives the 2-hexenol derivative (IX), which is treated with benzenesulfonyl chloride and DMAP yielding the sulfonate (X). The ozonolysis of (X) with ozone in dichloromethane affords the aldehyde (XI), which is condensed with ethoxycarbonylmethylene(triphenyl)phosphorane (XII) yielding the 2-heptenoic ester (XIII). The reduction of (XIII) with diisobutylaluminum hydride (DIBAL) in toluene/dichloromethane provides the 2-hepten-1-ol (XIV), which is epoxidized with cumene hydroperoxide in the presence of diisopropyl (+)-tartrate and Ti(Oi-Pr)4 in dichloromethane to give the chiral epoxyalcohol (XV). The reaction of (XV) with triphenylphosphine/CCl4 in chloroform affords the corresponding chloride (XVI). …………………………………….

WO 0001381 Intermediate (XVI) is treated with BuLi and diisopropylamine in THF giving the chiral acetylenic tetrahydrofuran (XVII). The addition of ethylene oxide (XVIII) to the terminal acetylene of (XVII) by means of BF3/Et2O in THF gives the 3-butyl-1-ol derivative (XIX), which is condensed with N,O-bis(phenoxy- carbonyl)hydroxylamine (XX) by means of PPh3 and diisopropylazodicarboxylate (DIAD) in THF yielding the final intermediate (XXI). Finally, this compound is treated with ammonia in methanol to obtain the target urea derivative.

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poster

http://www.prp.rei.unicamp.br/pibic/congressos/xxcongresso/paineis/092085.pdf

SÍNTESE TOTAL DO CMI-977 (LDP-977), UM PODEROSO AGENTE ANTIASMÁTICO
Lui Strambi Farina (IC), Marco Antonio Barbosa Ferreira (PG) e Luiz Carlos Dias (PQ)*
INSTITUTO DE QUÍMICA, UNIVERSIDADE ESTADUAL DE CAMPINAS, C.P. 6154, 13084-971, CAMPINAS, SP, BRASIL
*ldias@iqm.unicamp.br
Agência Financiadora: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ).
Palavras-Chave: Síntese orgânica, Tetrahidrofuranos, CMI-977 (LDP-977)

……………………………

Synthesis of (+)-Muricatacin and a Formal Synthesis of CMI-977 from l-Malic Acid

https://www.thieme-connect.de/DOI/DOI?10.1055/s-0033-1338934

A total synthesis of (+)-muricatacin and a formal synthesis of CMI-977 have been achieved using commercially available l-malic acid based on our furan approach to oxacyclic systems, the proven scope of which is thus broadened.

KAE 609, NITD 609, Cipargamin for Malaria

December 27, 2014 3:30 am / Leave a comment

Cipargamin, NITD 609

IUPAC Name: (3R,3’S)-5,7′-dichloro-6′-fluoro-3′-methylspiro[1H-indole-3,1′-2,3,4,9-tetrahydropyrido[3,4-b]indole]-2-one |

CAS Registry Number: 1193314-23-6
Synonyms: NITD609, NITD 609, NITD-609, GNF-609
KAE-609
NITD-609

390.238, C19 H14 Cl2 F N3 O

(1’R,3’S)-5,7′-Dichloro-6′-fluoro-3′-methyl-1,2,2′,3′,4′,9′-hexahydrospiro[indole-3,1′-pyrido[3,4-b]indole]-2-one

(1R,3S)-5′,7-Dichloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one

Novartis Ag innovator

CURRENTLY IN -PHASE2

NITD609 is an experimental synthetic antimalarial molecule belonging to the spiroindolone class.^[1]^[2] The compound was developed at the Novartis Institute for Tropical Diseases in Singapore, through a collaboration with the Genomics Institute of the Novartis Research Foundation (GNF), the Biomedical Primate Research Centre and the Swiss Tropical Institute. NITD609 is a novel, synthetic antimalarial molecule belonging to the spiroindolone class, awarded MMV Project of the Year 2009.

It is structurally related to GNF 493, a compound first identified as a potent inhibitor of Plasmodium falciparum growth in a high throughput phenotypic screen of natural products conducted at the Genomics Institute of the Novartis Research Foundation in San Diego, California in 2006. NITD609 was discovered by screening the Novartis library of 12,000 natural products and synthetic compounds to find compounds active against Plasmodium falciparum. The first screen turned up 275 compounds and the list was narrowed to 17 potential candidates.

KAE609 (cipargamin; formerly NITD609, Novartis Institute for Tropical Diseases) is a new synthetic antimalarial spiroindolone analogue with potent, dose-dependent antimalarial activity against asexual and sexual stages of Plasmodium falciparum.http://www.nejm.org/doi/full/10.1056/NEJMoa1315860

ChemSpider 2D Image | cipargamin | C19H14Cl2FN3O

KAE609 shows promise as next generation treatment for malaria

http://www.novartis.com/newsroom/media-releases/en/2014/1843976.shtml

KAE609 is the first antimalarial drug candidate with a novel mechanism of action to achieve positive clinical proof-of-concept in over 20 years
KAE609 was tested in adult patients with uncomplicated malaria and showed a median parasite clearance time of 12 hours, including in patients with resistant infections[1]
For more than a decade, Novartis has been a leader in the fight against malaria, setting the current gold standard for treatment and building one of the strongest malaria pipelines in the industry

KAE609 shows promise as next generation treatment for malaria

KAE609 is the first antimalarial drug candidate with a novel mechanism of action to achieve positive clinical proof-of-concept in over 20 years
KAE609 was tested in adult patients with uncomplicated malaria and showed a median parasite clearance time of 12 hours, including in patients with resistant infections[1]
For more than a decade, Novartis has been a leader in the fight against malaria, setting the current gold standard for treatment and building one of the strongest malaria pipelines in the industry

The digital press release with multimedia content can be accessed here:

Basel, Switzerland, July 30, 2014 – Today, Novartis published clinical trial results in the New England Journal of Medicine showing that KAE609 (cipargamin), a novel and potent antimalarial drug candidate, cleared the parasite rapidly in Plasmodium falciparum (P. falciparum) and Plasmodium vivax (P. vivax) uncomplicated malaria patients[1]. Novartis currently has two drug candidates in development. Both KAE609 and KAF156 are new classes of anti-malarial compounds that treat malaria in different ways from current therapies, important to combat emerging drug resistance. Novartis has also identified PI4K as a new drug target with potential to prevent, block and treat malaria.

“Novartis is in the fight against malaria for the long term and we are committed to the continued research and development of new therapies to eventually eliminate the disease,” said Joseph Jimenez, CEO of Novartis. “With two compounds and a new drug target currently under investigation, Novartis has one of the strongest malaria pipelines in the industry.”

Malaria is a life-threatening disease primarily caused by parasites (P. falciparum and P. vivax) transmitted to people through the bites of infected Anopheles mosquitoes. Each year it kills more than 600,000 people, most of them African children[2].

“KAE609 is a potential game-changing therapy in the fight against malaria,” said Thierry Diagana, Head of the Novartis Institute for Tropical Diseases (NITD), which aims to discover novel treatments and prevention methods for major tropical diseases. “Novartis has given KAE609 priority project status because of its unique potential of administering it as a single-dose combination therapy.”

In June 2012, 21 patients infected by one of the two main malaria-causing parasite types took part in a proof-of-concept clinical study conducted in Bangkok and Mae Sot near the Thailand/Burma border where resistance to current therapies had been reported. Researchers saw rapid parasite clearance in adult patients (median of 12 hours)[2] with uncomplicated P. vivax or P. falciparum malaria infection including those with resistant parasites. No safety concerns were identified, however the study was too small for any safety conclusions.

“The growing menace of artemisinin resistance threatens our current antimalarial treatments, and therefore our attempts to control and eliminate falciparum malaria,” said Nick White, Professor of Tropical Medicine at Mahidol University in Thailand and lead author of the NEJM article. “This is why we are so enthusiastic about KAE609; it is the first new antimalarial drug candidate with a completely novel mechanism of action to reach Phase 2 clinical development in over 20 years.”

KAE609, the first compound in the spiroindolone class of treatment, works through a novel mechanism of action that involves inhibition of a P-type cation-transporter ATPase4 (PfATP4), which regulates sodium concentration in the parasite. Because KAE609 also appears to be effective against the sexual forms of the parasite, it could potentially help prevent disease transmission. The clinical trial was done in collaboration with the Wellcome Trust-Mahidol University – Oxford Tropical Medicine Research Programme. Research was supported by the Wellcome Trust, Singapore Economic Development Board, and Medicines for Malaria Venture.

KAE609 represents one of two new classes of antimalarial compounds that Novartis has discovered and published in the last four years.[3],[4] This drug candidate has shown potent in vitro activity against a broad range of parasites that have developed drug resistance against current therapies. KAE609 is currently being planned for Phase 2b trials.

References
[1] http://www.nejm.org/doi/full/10.1056/NEJMoa1315860
[2] World Health Organization, http://www.who.int/mediacentre/factsheets/fs094/en/
[3] Spiroindolones, a Potent Compound Class for the Treatment of Malaria, KAE609, Science, Sept. 2010
[4] Imaging of Plasmodium liver stages to drive next generation antimalarial drug discovery. Science Express, Nov. 17, 2011

http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=6368

The current spiroindolone was optimized to address its metabolic liabilities leading to improved stability and exposure levels in animals. As a result, NITD609 is one of only a handful of molecules capable of completely curing mice infected withPlasmodium berghei (a model of blood-stage malaria).

Given its good physicochemical properties, promising pharmacokinetic and efficacy profile, the molecule was recently approved as a preclinical candidate and is now entering GLP toxicology studies with the aim of entering Phase I studies in humans in late 2010. If its safety and tolerability are acceptable, NITD609 would be the first antimalarial not belonging to either the artemisinin or peroxide class to go into a proof-of-concept study in malaria.

If NITD609 behaves similarly in people to the way it works in mice, it may be possible to develop it into a drug that could be taken just once – far easier than current standard treatments in which malaria drugs are taken between one and four times a day for up to seven days. NITD609 also has properties which could enable it to be manufactured in pill form and in large quantities. Further animal studies have been performed and researchers have begun human-stage trials.

NITD609

IUPAC name [hide] (1R,3S)-5’,7-Dichloro-6-fluoro-3-methyl-spiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,3’-indoline]-2’-one
Identifiers
ChemSpider	24662493
Jmol-3D images	Image 1
Properties
Molecular formula	C₁₉H₁₄Cl₂FN₃O
Molar mass	390.24 g mol⁻¹

Malaria is an old infectious disease caused by four protozoan parasites, Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. These four parasites are typically transmitted by the bite of an infected female Anopheles mosquito. Malaria is a problem in many parts of the world, and over the last few decades the malaria burden has steadily increased. An estimated 1 to 3 million people die every year from malaria – mostly children under the age of 5. This increase in malaria mortality is due in part to the fact that Plasmodium falciparum, the deadliest malaria parasite, has acquired resistance against nearly all available antimalarial drugs, with the exception of the artemisinin derivatives.

Leishmaniasis is caused by one of more than twenty (20) varieties of parasitic protozoa that belong to the genus Leishmania, and is transmitted by the bite of female sandflies. Leishmaniasis is endemic in some 90 countries, including many tropical and sub-tropical areas.

There are four main forms of leishmaniasis. Visceral leishmaniasis, also called kala-azar, is the most serious form and is caused by the parasite Leishmania donovani. Patients who develop visceral leishmaniasis can die within months unless they receive treatment. The two main therapies for visceral leishmaniasis are the antimony derivatives sodium stibogluconate (Pentostam®) and meglumine antimoniate (Glucantim®). Sodium stibogluconate has been used for about 70 years and resistance to this drug is a growing problem. In addition, the treatment is relatively long and painful, and can cause undesirable side effects. Human African Trypanosomiasis, also known as sleeping sickness, is a vector-bome parasitic disease. The parasites concerned are protozoa belonging to the Trypanosoma Genus. They are transmitted to humans by tsetse fly {Glossina Genus) bites which have acquired their infection from human beings or from animals harbouring the human pathogenic parasites.

Chagas disease (also called American trypanosomiasis) is another human parasitic disease that is endemic amongst poor populations on the American continent. The disease is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to humans by blood-sucking insects. The human disease occurs in two stages: the acute stage, which occurs shortly after the infection, and the chronic stage, which can develop over many years. Chronic infections result in various neurological disorders, including dementia, damage to the heart muscle and sometimes dilation of the digestive tract, as well as weight loss. Untreated, the chronic disease is often fatal.

The drugs currently available for treating Chagas disease are nifurtimox and benznidazole. However, problems with these current therapies include their adverse side effects, the length of treatment, and the requirement for medical supervision during treatment. Furthermore, treatment is really only effective when given during the acute stage of the disease. Resistance to the two frontline drugs has already arisen. The antifungal agent amphotericin b has been proposed as a second-line drug, but this drug is costly and relatively toxic.

PAPER

Stereoselective Total Synthesis of KAE609 via Direct Catalytic Asymmetric Alkynylation to Ketimine

Hisashi Takada^†, Naoya Kumagai^*^†, and Masakatsu Shibasaki^*^†^‡

^† Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan

^‡ JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan

Org. Lett., 2015, 17 (19), pp 4762–4765

DOI: 10.1021/acs.orglett.5b02300

Publication Date (Web): September 14, 2015

*E-mail: nkumagai@bikaken.or.jp., *E-mail: mshibasa@bikaken.or.jp.

Abstract

A direct catalytic asymmetric alkynylation protocol is applied to provide the requisite enantioenriched propargylic α-tertiary amine, allowing for the stereoselective total synthesis of KAE609 (formerly NITD609 or cipargamin).

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http://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b02300?journalCode=orlef7

http://pubs.acs.org/doi/suppl/10.1021/acs.orglett.5b02300/suppl_file/ol5b02300_si_001.pdf

PATENT

WO 2009/132921

In this process, the chiral amine is installed via an enzymatic resolution via deacylation of the acetamide 2. In addition to the wasteful resolution, other inefficiencies of this route include protection/deprotection (Ac/Boc, 2 to 4, and 5 to 6) and a three-step sequence to reduce the carboxylic acid to a methyl group (3 to 6).

Patent

US 2015/0045562

Improved Route to Cipargamin Employing Transaminase Reaction

For the transamination step, the enzyme ATA-256 was engineered by Codexis to accommodate the non-natural indole substrate 12. Since the substrate is not water-soluble, PEG 200 (approximately 20 vol %) is used as a cosolvent, an interesting selection given that DMSO or methanol are the most common cosolvents for enzymatic reactions. Isopropylamine is employed as the amine donor, a strategy that was adopted from the work of Merck and Codexis for the transamination of sitagliptin ketone.(2) During the transamination, which is a reversible reaction,i-PrNH₂ is converted to acetone, which can be readily removed by evaporation to drive the reaction to completion. The workup involves filtration to remove enzyme residues followed by pH swings in which the product is extracted into the aqueous layer under acidic conditions, then basified for extraction into the organic layer. Addition of (+)-camphorsulfonic acid (CSA) provides the amine 14 as the crystalline CSA salt. No details are provided on enantioselectivity for the transamination, and it is not clear if the (+)-CSA is required to upgrade the ee or whether this salt was selected based on physical properties and the ability to develop a scalable crystallization process.

The final step to generate the spiroindole involves a diastereoselective condensation of the chiral amine with 5-chloroisatin (7) under acidic conditions. The diastereoselectivity of this reaction is not provided, nor any ee or de data for the final product. The spiroindole is also isolated as a (+)-CSA salt, which is then converted to the crystalline free base hemihydrate as the final form of cipargamin.

Example 12: Process for Preparing a Compound of formula (IVA) ¹/z Hydrate

622.54 399.25

In a 750ml reactor with impeller stirrer 50g of compound (IVB) salt were dissolved in 300ml Ethanol (ALABD) and 100 ml deionised Water (WEM). The clear, yellowish sollution was heated to 58°C internal temperature. To the solution 85 g of a 10% aqueous sodium carbonate solution was added within 10 minutes. The clear solution was particle filtered into a second reaction vessel. Vessel and particle filter were each rinsed with 25 ml of a mixture of ethanohwater (3:1 v/v) in the second reaction vessel. The combined particle filtered solution is heated to 58°C internal temperature and 200ml water (WEM) were added dropwise within 15 minutes. Towards the end of the addition the solution gets turbid. The mixture is stirred for 10 minutes at 58°C internal temperature and is then cooled slowely to room temperature within 4hours 30 minutes forming a thick, well stirable white suspension. To the suspension 200 ml water are added and the mixture is stirred for additional 15hours 20 minutes at room temperature. The suspension is filtered and the filter cake is washed twice with 25 ml portions of a mixture of ethanohwater 9: 1 (v/v). The colourless crystals are dried at 60°C in vacuum yielding 26.23g (=91.2% yield). H NMR (400 MHz, DMSO-d₆)

0.70 (s, 1H), 10.52 (s, 1H), 7.44 (d, J = 10.0 Hz, 1H), 7.33 (dd, J = 8.4, 2.1 Hz, 1H),.26 (d, J = 6.5 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 3.83 – 4.00 (m,H), 3.13 (d, J = 6.0 Hz, 1H), 2.77 (dd, J = 15.1, 3.8 Hz, 1H), 2.38 (dd, J = 15.1, 10.5 Hz,H), 1.17 (d, J = 6.3 Hz, 3H).

Patent

http://www.google.com/patents/WO2009132921A1?cl=en

SCHEME G: Preparation of (lR,3S)-5′,7-dichloro-6-fluoro-3-methyl-2,3,4,9- tetrahydrospiro[β-carboline-l,3′-indol-2′(l’iϊ)-one (35) and (lR,3S)-5′-chloro-6-fluoro-3- methyl-2,3,4,9-tetrahydrospiro[β-carboline-l,3′-indoI-2′(l’H0-one (36)

Step 1 : POCl₃ (2.43 mL, 26.53 mmol) was added dropwise to N, N-dimethylformamide (15.0 mL) at -20 °C and stirred below -5 ⁰C for one hour. A solution of 6-chloro-5-fluoroindole (3.0 g, 17.69 mmol) in dimethylformamide (5.0 mL) was added dropwise to the above reaction mixture at -20 °C. The salt-ice bath was removed and the reaction mixture was warmed to 35 ⁰C, After one hour, the reaction was poured onto ice and basified by solid sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was washed with water and then concentrated to give 6-chloro-5-fluoro-1H-indole-3-carbaldehyde (3.4 g, 97 %) as a light brown solid. ¹H ΝMR (500 MHz, CDCl₃): δ 10.02 (s, 1 H), 8.10 (d, IH, J = 9.5 Hz), 7.87 (s, 1 H), 7.49 (d, IH, J= 5.5 Hz).

Step 2: The solution (0.2 M) of 6-chloro-5-fluoro-1H-indole-3-carbaldehyde (4.0 g, 20.24 mmol) in nitroethane (100 mL) was refluxed with ammonium acetate (1.32 g, 0.85 mmol) for 4 hours. The reaction mixture was concentrated under vacuum to remove nitroethane, diluted with ethylacetate and washed with brine. The organic layer was concentrated to give 6-chloro-5- fluoro-3-(2-nitro-propenyl)-1H-indole (5.0 g, 97 %) as a reddish orange solid. ¹H ΝMR (500 MHz, CDCl₃): δ 8.77 (s, IH), 8.32 (s, IH), 7.58 (d, IH, J= 2.5 Hz), 7.54 (d, IH, J = 9 Hz), 7.50 (d, IH, J= 5.9 Hz), 2.52 (s, 3H). Step 3: A solution of 6-chloro-5-fluoro-3-(2-nitro-propenyl)-1H-indole (5.0 g, 19.63 mmol) in tetrahydrofuran (10 mL) was added to the suspension of lithium aluminium hydride (2.92 g, 78.54 mmol) in tetrahydrofuran (20 mL) at 0 ⁰C and then refluxed for 3 hours. The reaction mixture was cooled to 0 °C, and quenched according to the Fischer method. The reaction mixture was filtered through celite and the filtrate concentrated to give 2-(6-chloro-5-fluoro-1H-indol-3- yl-1-methyl-ethylamine (4.7 g crude) as a viscous brown liquid. The residue was used without further purification. ¹H NMR (500 MHz, CDCl₃): δ 8.13 (s, IH), 7.37 (d, IH, 6.Hz), 7.32 (d, IH, J = 10 Hz), 7.08 (s, IH), 3.23-3.26 (m, IH), 2.77-2.81 (m, IH), 2.58-2.63 (m, IH), 1.15 (d, 3H, J= 6.5 Hz).

Step 4: A mixture of 2-(6-chloro-5-fluoro-1H-indol-3-yl-l-methyl-ethylamine (4.7 g, 20.73 mmol), 5-chloroisatin (3.76 g, 20.73 mmol) and p-toluenesulphonic acid (394 mg, 2.07 mmol) in ethanol (75 mL) was refluxed overnight. The reaction mixture was concentrated to remove ethanol, diluted with ethyl acetate and washed with saturated aqueous NaHCO₃. The organic layer was concentrated to give a brown residue, which was purified by silica gel chromatography (20 % ethyl acetate in hexane) to provide the corresponding racemate (4.5 g, 56 %) as a light yellow solid. The racemate was separated into its enantiomers by chiral chromatography to provide 35.

Compound 36 can be obtained in a similar fashion from 5-fluoroindole.

Alternatively 35 and 36 were be prepared in enantiomerically pure form by the following scheme.

SCHEME H: Alternative preparation of (lR,3S)-5′,7-dichloro-6-fluoro-3-methyl-2,3,4,9- tetrahydrospiro[β-carboline-l,3′-indol-2′(1’H)-one (35)

Step 1 : To a solution of 6-chloro-5-fluoroindole (1.8 g, 10.8 mmol) and Ac₂O (10 niL) in AcOH (3OmL) was added L-serine (2.2 g, 20.9 mmol), the mixture was heated to 80 °C. After TLC indicated the reaction was complete, the mixture was cooled to 0 °C, neutralized to pH 11 , and washed with MTBE. The aqueous phase was acidified to pH 2 and extracted with EtOAc. The combined organic layers were washed with water and bπne, dπed with Na₂SO₄, filtered, and concentrated. The residue was purified with chromatography (Petroleum ether /EtOAc 1:1) to give 2-acetylamino-3-(6-chloro-5-fluoro-1H-mdol-3-yl)-propπonic acid as a light yellow solid (1.2 g, 37% yield).

Step 2: 2-Acetylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionic acid (2.5g, 8.4mmol) was dissolved in aqueous NaOH (IN, 10 niL) and water added (70 mL). The mixture was heated to 37-38⁰C and neutralized with HCl (IN) to pΗ 7.3-7.8. L-Aminoacylase (0.5 g) was added to the mixture and allowed to stir for 2 days, maintaining 37-38⁰C and pΗ 7.3-7.8. The mixture was heated to 60 °C for another hour, concentrated to remove part of water, cooled and filtered. The filtrate was adjusted to pΗ 5.89 and filtered again. The filtrate was adjusted to pΗ 2.0 and extracted with EtOAc. The combined organic layer was dried over Na₂SO₄, filtered, concentrated and the residue was purified with chromatography (petroleum ether /EtOAc 1 : IEtOAc) to give R- 2-acetylamino-3-(6-chloro-5-fluoro-1H-mdol-3-yl)-propπonic acid as a light yellow solid (1.2 g, 48% yield). Step 3: R-2-acetylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-proprionic acid (1.2 g, 4.0 mmol) was dissolved in HCl (6N, 10 mL) and the mixture heated to reflux for 4 hours, and then concentrated to dryness. Toluene (50 mL) was added to the residue and concentrated to dryness to remove water and HCl. The residue was dried under vacuum and then dissolved in MeOH (20 mL). To the solution was added dropwise SOCl₂ (0.5 mL, 6.8 mmol) at 0 °C, and the mixture was stirred overnight. After removal of solvent, the residue was dissolved in THF/water (40/10 mL) and NaHCO₃ (1.0 g, 11.9 mmol) was added portionwise. Upon basifϊcation, BoC₂O (1.2 g, 5.5 mmol) added at 0 °C and allowed to stir at room temperature. After TLC indicated the reaction was finished, EtOAc was added and separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried with Na₂SO₄, filtered, concentrated and the residue was purified with chromatography (petroleum ether /EtOAc: 5/1) to give R-2-tert-butoxycarbonylamino-3-(6-chloro-5-fluoro-l/-/-indol-3-yl)-proprionic acid methyl ester 460 g, 31% yield for 3 steps).

Step 4: To a solution of R-2-tert-butoxycarbonylamino-3-(6-chloro-5-fluoro-l//-indol-3-yl)- proprionic acid methyl ester (460mg, 1.2mmol) in dry ether (20 mL) was added portionwise LiAlH₄ (92 mg, 2.4 mmol) at 0 °C. The mixture was heated to reflux for 2 hours. After TLC indicated the reaction was finished, the mixture was cooled and carefully quenched with Na₂SO₄. The mixture was filtered and the filtrate was washed with saturated aqueous NH₄Cl and water, dried with Na₂SO₄, filtered, concentrated to give a crude product (400 mg), which was used without further purification.

Step 5: To a solution of the crude product (400 mg, 1.2mmol) and Et₃N (0.3 mL, 2.2 mmol) in CH₂Cl₂ (5 mL) was added MsCl (160 mg, 1.4 mmol) dropwise at 0 °C. The mixture was stirred for 2 hours at room temperature. After TLC indicated the reaction was completed, the mixture was washed with water and brine, dried with Na₂SO₄, filtered, concentrated and the residue was purified with chromatography (petroleum ether/EtOAc 5:1) to give methansulfonic acid (R)-2- ?ert-butoxycarbonylamino-3-(6-chloro-5-fluoro-1H-indol-3-yl)-propyl ester as a light yellow solid (300 mg, 57% yield, 2 steps)

Step 6: To a solution of mesylate (300 mg, 0.7mmol) in dry ether (20 mL) was added portionwise LiAlH₄ (55 mg, 1.4 mmol) at 0 °C. The mixture was stirred at room temperature overnight. After TLC indicated the reaction was finished, the mixture was cooled and carefully quenched with Na₂SO₄. The mixture was filtered and the filtrate was washed with saturated aqueous NH₄Cl and water, dried with Na₂SO₄, filtered, concentrated and the residue was purified with chromatography (petroleum ether/EtOAc 10: 1) to give [(5)-2-(6-chloro-5-fluoro-1H-indol-3-yl)- 1 -methyl-ethyl] -carbamic acid tert-butyl ester as a light yellow solid (200 mg, 87% yield).

Step 7: A solution of [(S)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-l-methyl-ethyl]-carbamic acid tert-butyl ester (200 mg, 0.6 mmol) in HCl/MeOH (10 mL) was stirred at room temperature. After TLC indicated the reaction was finished, the mixture was concentrated to remove the solvent. To the residue was added EtOAc (5OmL), and the mixture was neutralized with saturated NaHCO₃ to pH 8~9, and then extracted with EtOAc. The combined organic phases were dried with Na₂SO₄, filtered, concentrated to give a crude (S)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-l- methyl-ethylamine which was used without further purification.

Step 8: To a solution of (5)-2-(6-chloro-5-fluoro-1H-indol-3-yl)-l-methyl-ethylamine (120 mg, 0.5 mmol) in EtOH (1OmL) was added 5-chloroisatin (90 mg, 0.5 mmol) and p-TsOΗ (8 mg, 0.04 mmol). The mixture was heated in a sealed tube at 110⁰C for 16 hours. After TLC indicated the reaction was finished, the mixture was cooled and concentrated. The residue was dissolved in EtOAc (2OmL) and washed with NaOH (IN) and brine, dried with Na₂SO₄, filtered, concentrated and the residue was purified with chromatography (petroleum ether/EtOAc 5:1) to give 36 (150mg, 64% yield over two steps).

Example 48 (15,3R)-5′-Chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-l,3′-indol]-2′(l’_JH)-one

(35)

Compound 35 may be prepared according to Scheme F using the same or analogous synthetic techniques and/or substituting with alternative reagents.

(lS^RVS’-Chloro-S-methyl-l^^^-tetrahydrospirotβ-carboline-l.S’-indoll-l^l’ZO-one: ¹H NMR (300 MHz, DMSO-^₆): δ 10.45 (s, IH), 10.42 (s, IH), 7.43 (d, J= 7.5 Hz, IH), 7.31 (dd, J = 2.1, 8.4 Hz, IH), 7.16 (d, J = 7.2 Hz, IH), 7.05-7.02 (m, 2H), 7.00-6.96 (m, IH), 6.92 (d, J = 8.1 Hz, IH), 3.98-3.86 (m, IH), 2.78 (dd, J= 3.6, 14.9 Hz, IH), 2.41 (dd, J= 4.5, 25.5 Hz, IH), 1.18 (d, J= 6.3 Hz, 3H); MS (ESI) m/z 338.0 (M+H)⁺.

Chiral compounds such as 36 and 37 can be prepared according to Scheme G or H using the same or analogous synthetic techniques and/or substituting with alternative reagents. Example 49

(IR^^-S’.T-Dichloro-ό-fluoro-S-methyl-l^^^-tetrahydrospiroIβ-carboline-l^’-indol]- 2\VH)-one (36)

35: ¹H NMR (500 MHz, DMSO-Jd) δ 10.69 (s, IH), 10.51 (s, IH), 7.43 (d, J = 10.0 Hz, IH), 7.33 (dd, J= 8.4, 2.2 Hz, IH), 7.27 (d, J= 6.5 Hz, IH), 7.05 (d, J= 2.3, IH), 6.93 (d, J= 8.5 Hz, IH), 3.91 (m, IH), 3.13 (bd, J= 6.2 Hz, IH), 2.74 (dd, J= 15.0 , 3.0 Hz, IH), 2.35 (dd, J= 15.0, 10.3, IH), 1.15 (d, J= 6.0, 3H);

MS (ESI) m/z 392.0 (M+2H)⁺;

[α]²⁵ _D = + 255.4°

Example 50

(lS,3R)-5′,7-Dichloro-6-fluoro-3-methyI-2,3,4,9-tetrahydrospiro[β-carboline-l,3′-indol]- 2′(l’H)-one (37)

(lS^^-S’^-Dichloro-o-fluoro-S-methyl^jS^^-tetrahydrospirojP-carboline-l-S’-indol]- 2′(l’H)-one: ¹H NMR (500 MHz, CDCl₃) δ 8.49 (s, IH), 7.54 (s, IH), 7.24 (d, J= 9.7 Hz, IH), 7.21 (dd, J = 8.6, 2.0 Hz, IH), 7.14 (d, J= 6.0 Hz, IH), 7.11 (d, J= 1.8, IH), 6.77 (d, J= 8.3 Hz, IH), 4.14 (m, IH), 2.89 (dd, J = 15.4, 3.7 Hz, IH), 2.49 (dd, J = 15.3, 10.5, IH), 1.68 (bs, IH), 1.29 (d, J= 6.4 Hz, 3H); MS (ESI) m/z 392.0 (M+2H)⁺; [α]²⁵_D -223.3°

PATENT

US 2011275613

http://www.google.com/patents/WO2013139987A1?cl=en

Prior art:

(1 ‘R, 3’S)-5, 7′-dichloro-6′-fIuoro-3′-methyl-2′, 3′,4′, 9’-tetrahydrospiro[indoline-3, 1 – pyrido[3,4-b]indol]-2-one (eg. a compound of formula (IV), which comprises a spiroindolone moiety) and a 6-steps synthetic method for preparing, including known chiral amine intermediate compound (MA) are known (WO 2009/132921 ):

he present invention relates to processes for the preparation of spiroindolone compounds, such as (1’R,3’S)-5, 7′-dichloro-6′-fIuoro-3′-methyl-2′,3′,4′,9′- tetrahydrospiro[indoline-3, 1 ‘-pyhdo[3.4-b]indol]-2-one.

(1 ‘R, 3’S)-5, 7′-dichloro-6′-fluoro-3′-methyl-2′, 3′,4 9’-tetrahydrospiro[indoline-3, 1 ‘- pyrido[3, 4-b]indol]-2-one is useful in the treatment and/or prevention of infections such as those caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Trypanosoma cruzi and parasites of the Leishmania genus such as, for example, Leishmania donovani., and it has the following structure:

(IVA)

(1 ‘R, 3’S)-5, 7′-dichloro-6′-fluoro-3′-methyl-2 3′, 4′, 9’-tetrahydrospiro[indoline-3, 1 – pyhdo[3, 4-b]indol]-2-one and a synthesis thereof are described in WO 2009/132921 Al in particular in Example 49 therein.

Example 10: Process for Conversion of Compound (IA) to Compound (IIA) in 30g Scale

458.97

152.48g /so-propylamine hydrochloride and 0.204g pyridoxalphosphate monohydrate were dissolved in 495ml water while stirring. To this yellow clear solution a solution of 30. Og ketone in 85ml poly ethylene glycol (average mol weight 200) within 15 minutes. Upon addition the ketone precipitates as fine particles which are evenly distributed in the reaction media. To the suspension 180ml triethanolamine buffer (0.1 mol/l, pH 7) were added and the pH was adjusted to 7 by additon of aqueous sodium hydroxide solution (1 mol/l). The reaction mixture is heated to 50°C and a solution of 1.62g transaminase SEQ ID NO: 134 dissolved in 162ml triethanolamine buffer (0 1 mol/l, pH 7) is added. The reaction mixture is continiously kept at pH 7 by addition of 1 mol/l aqueous sodium hydroxide solution. The reaction mixture is stirred 24h at 50°C and a stream of Nitrogen is blown over the surface of the reaction mixture to strip off formed acetone. The reaction mixture is then cooled to 25°C and filtered over a bed of cellulose flock. The pH of the filtrate is adjusted to «1 by addition of concentrated sulfuric acid. The acidified filtrated is extracted with 250 ml /so-Propyl acetate. The layers are separated and the pH of the aqueous phase is adjusted to ¾10 by additon of concentrated aqueous sodium hydroxide solution. The basified aqueous phase is extracted with /^‘so-propyl acetate. The layers are seperated and the organic phase is washed with 100 ml water. The organic phase is concentrated by distillation to 2/3 of its origin volume. In a second reactor 33.98g (+)- camphor sulfonic acid is dissolved in 225 ml /^‘so-propyl acetate upon refluxing and the concentrated organic phase is added within 10 minutes. After complete addition the formed thin suspension is cooled to 0°C within 2 hours and kept at 0°C for 15 hours. The precipitated amine-(+)-camphor sulfonate salt is filtered, washed with 70 ml /so-propyl acetate and dried at 40°C in vaccuum yielding 51.57g of colourless crystals (84.5% yield t.q.)

Analytical Data

IR:

v (crn ¹)=3296, 3061 , 2962, 2635, 2531 , 2078, 1741 , 1625, 1577, 1518, 1461 , 1415, 1392, 1375, 1324, 1302, 1280, 1256, 1226, 1 170, 1 126, 1096, 1041 , 988, 966, 937, 868, 834, 814, 790, 766, 746, 719, 669, 615.

LC-MS (ESI +):

Ammonium ion: m/z =227 ([M+H]), 268 ([M+H+CH₃CN]), 453 ([2M+H]).

Camphorsulfonate ion: m/z =250 ([M+NH₄]), 482 ([2M+NH4]).

LC-MS (ESI -):

Camphorsulfonate ion: m/z=231 ([M-H]), 463 ([2M-H]).

1H-NMR (DMSO-d6, 400 MHz):

1 1.22 (br. s., 1 H), 7.75 (br. s., 3H), 7.59 (d, J = 10.3 Hz, 1 H), 7.54 (d, J = 6.5 Hz, 1 H), 7.36 (d, J = 2.3 Hz, 1 H), 3.37 – 3.50 (m, 1 H), 2.98 (dd, J = 14.3, 5.8 Hz, 1 H), 2.91 (d, J = 14.8 Hz, 1 H), 2,81 (dd, J = 14.3, 8.0 Hz, 1 H), 2.63 – 2.74 (m, 1 H), 2.41 (d, J = 14.6 Hz, 1 H), 2.24 (dt, J = 18.3, 3.8 Hz, 1 H), 1 .94 (t, J = 4.4 Hz, 1 H), 1.86 (dt, J = 7.4, 3 6 Hz, 1 H), 1.80 (d, J = 18.1 Hz, H), 1.23 – 1 .35 (m, 2H), 1.15 (d, J = 6.3 Hz, 3H), 1.05 (s, 3H), 0.74 (s, 3H)

Free Amine (obtained by evaporatig the iso-Propylacetate layer after extraction of the basified aqueous layer):

¹H NMR (400MHz, DMSO-d₆): 11 .04 (br. s., 1 H), 7.50 (d, J = 10.5 Hz, 1 H), 7.48 (d, J = 6.5 Hz, 1 H), 7.25 (s, 1 H), 3.03 (sxt, J = 6.3 Hz, 1 H), 2.61 (dd, J – 14.3, 6.5 Hz, 1 H), 2.57 (dd, J = 14.1 , 6.5 Hz, 1 H), 1.36 (br. s., 2H), 0.96 (d, J = 6.3 Hz, 3H)

Example 11: Process for Conversion of Compound (HA) to Compound (IVB)

3. solvent exchange to TP

13.62 g 5-chloroisatin is suspended in 35 ml /so-propanol and 2.3 g triethyl amine is added. The suspension is heated to reflux and a solution of 34.42g amine-(+)-camphor sulfonate salt dissolved in 300 ml /^‘so-propanol is added within 50 minutes. The reaction mixture is stirred at reflux for 17 hours. The reaction mixture is cooled to 75°C and 17.4g (+)-camphorsulfonic acid are added to the reaction mixture. Approximately 300 ml /so- propanol are removed by vacuum distillation. Distilled off /so-propanol is replaced by iso- propyl acetate and vacuum distillation is continued. This is distillation is repeated a second time. To the distillation residue 19 ml ethanol and 265 ml ethyl acetate is added and the mixture is heated to reflux. The mixture is cooled in ramps to 0°C and kept at 0°C for 24 hours. The beige to off white crystals are filtered off, washed with 3 portions (each 25 ml) precooled (0°C) ethylacetate and dried in vacuum yielding 40.3 g beige to off white crystals. (86.3% yield t.q.)

IR:

v (crrr)= 3229, 3115, 3078, 3052, 2971 , 2890, 2841. 2772. 2722, 2675, 2605, 2434. 1741 , 1718, 1621 , 1606, 1483, 1460, 1408, 1391 , 1372, 1336, 1307, 1277, 1267, 1238, 1202, 1 184, 1 162, 1 149, 1 128, 1067, 1036, 987, 973, 939, 919, 896, 871 , 857, 843, 785, 771 , 756, 717, 690, 678, 613.

LC-MS (ESI +):

Ammonium ion: m/z =390 ([M+H]), 431 ([M+H+CH₃CN]) Camphorsulfonate ion: m/z =250 ([M+NH₄]), 482 ([2M+NH4])

LC-MS (ESI -):

Camphorsulfonate ion: m/z=231 ([M-H]), 463 ([2M-H])

1H NMR (DMSO-d₆, 600 MHz):

11.49 (s, 1 H), 1 1.23 (s, 1 H), 10.29 – 10.83 (m, 1 H), 9.78 – 10.31 (m, 1 H), 7.55 – 7.60 (m, 2H), 7.52 (s, 1 H), 7.40 (d, J = 6.2 Hz, H), 7.16 (d, J = 8.8 Hz, 1 H), 4.52 – 4.63 (m, 1 H). 3.20 (dd, J = 16.3, 4.2 Hz, 1 H), 2.96 (dd, J = 16.1 , 11.3 Hz, 1 H), 2.90 (d, J = 15.0 Hz, 1 H), 2.56 – 2.63 (m, 1 H), 2.39 (d, J = 14.6 Hz, 1 H), 2.21 (dt, J = 18.0, 3.8 Hz, 1 H), 1.89 – 1.93 (m, 1 H), 1.81 (ddd, J = 15.3, 7.8, 3.7 Hz, 1 H), 1.76 (d, J = 18.3 Hz, 1 H), 1 .53 (d, J = 6.6 Hz, 3H), 1.20 – 1.33 (m, 2H), 0.98 (s, 3H), 0.70 (s, 3H)

Example 12: Process for Preparing a Compound of formula (IVA) ¹/z Hydrate

mw622.54 …………………………………………………………………..mw399.25

The mixture is stirred for 10 minutes at 58°C internal temperature and is then cooled slowely to room temperature within 4hours 30 minutes forming a thick, well stirable white suspension. To the suspension 200 ml water are added and the mixture is stirred for additional 15hours 20 minutes at room temperature. The suspension is filtered and the filter cake is washed twice with 25 ml portions of a mixture of ethanohwater 9: 1 (v/v). The colourless crystals are dried at 60°C in vacuum yielding 26.23g (=91.2% yield). H NMR (400 MHz, DMSO-d₆)

PAPER

Journal of Medicinal Chemistry, 2010 , vol. 53, 14 p. 5155 – 5164

http://pubs.acs.org/toc/jmcmar/53/14

(1R,3S)-5′,7-Dichloro-6-fluoro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one (19a)

¹H NMR (500 MHz, DMSO-d₆): δ 10.69 (s, 1H), 10.51 (s, 1H), 7.43 (d, J = 10.0 Hz, 1H), 7.33 (dd, J = 8.0, 2.2 Hz, 1H), 7.27 (d, J = 6.5 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 3.91 (m, 1H), 3.13 (bd, J = 6.2 Hz, 1H), 2.74 (dd, J = 15.0, 3.0 Hz, 1H), 2.35 (dd, J = 15.0, 10.3 Hz, 1H), 1.15 (d, J = 6.0 Hz, 3H). MS (ESI) m/z 392.0 (M + 2H)⁺; [α]_D²⁵ = +255.4° (c = 0.102 g/L, methanol).

CLIPS

http://www.google.com/patents/CN102432526A?cl=en&dq=%22cipargamin%22+OR+%22cipargamina%22+OR+%22cipargamine%22+OR+%22cipargaminum%22+OR+%22NITD609%22&source=uds

Z.Zhang, WO 2007 / 104714,2007).

[0008] (2) year 2008 Roche pharmaceutical company disclosed a spiro [oxindole – cyclohexenone] skeleton biomedicine, PCT International Application No. W02008 / 055812. It also announced the preparation of anti-cancer agents and antagonists of the application of the compound is used as the interaction with MDM2 (reference:. Liu, J.-J; Zhang, Z; (Hoffmann-LaRoche AG), PCT Int App 1. . W02008 / 055812, 2008), its structural formula is as follows:

[0009]

(3) Melchiorre research group abroad chiral amines and o-fluoro-3-benzyl benzoate as catalyst methylene-indole-2-one (3-benzylideneindolin-2-one, CAS Number: 3359-49- 7) with α, β – unsaturated ketone synthesis of chiral spiro [cyclohexane _1,3′- indole] _2,4 ‘- dione [s pir0 [cycl0hexane-l, 3’ -indoline] – 2 ‘, 4-diones] compounds (see:.. Bencivenni, G; ffu, LY; Mazzanti, A .; Giannichi, B.; Pesciaioli, F; Song, Μ P.; Bartoli, G.; Melchiorre, P …. .Angew Chem Int Ed 2009,48,7200), the structure of the total formula is as follows:

(4) Gong Flow column team found to cyclohexanediamine derived Bronsted acid – a bifunctional catalyst Lewis base catalysis of 3-benzyl-methylene-indole-2-one and α, β- unsaturated 1,3 tandem reaction dicarbonyl compound (Nazarov reagent) can be obtained with high stereoselectivity chiral spiro [cyclohexane _1,3′- indol] -2 ‘, 4-dione [spiro [cyclohexane-l, 3 ‘-indoline] -2’, 4-diones] compounds; and by this method successfully synthesized 7 Roche pharmaceutical companies to develop chiral anti-tumor agents (see: Q Wei, L -Z Gong, Org Lett 2010….. , 12, 1008.).

(5) Wang Lixin research group recently reported that primary amines derived from cinchona alkaloids and Bronsted acid as catalyst N- protected indolone compounds and double Michael addition reaction of diketene generate hand spiro [cyclohexane-1, 3′-indol] -2 ‘, 4-dione [spiro [cyclohexane-l, 3’ -indoline] -2 ‘, 4-diones] type of tx ^ (: L. -L. Wang, L. Peng, J. -F. Bai, L. -N. Jia, X. -Y. Luo, QC Huang, L. -X. Wang, Chem. Commum. 2011,47, 5593.).

WO2009132921A1 *	Apr 1, 2009	Nov 5, 2009	Novartis Ag	Spiro-indole derivatives for the treatment of parasitic diseases
WO2010081053A2 *	Jan 8, 2010	Jul 15, 2010	Codexis, Inc.	Transaminase polypeptides
WO2012007548A1 *	Jul 14, 2011	Jan 19, 2012	Dsm Ip Assets B.V.	(r)-selective amination
AT507050A1 *	Title not available
EP0036741A2 *	Mar 17, 1981	Sep 30, 1981	THE PROCTER & GAMBLE COMPANY	Phosphine compounds, transition metal complexes thereof and use thereof as chiral hydrogenation catalysts
EP0120208A2 *	Jan 24, 1984	Oct 3, 1984	Degussa Aktiengesellschaft	Microbiologically produced L-phenylalanin-dehydrogenase, process for obtaining it and its use
EP0135846A2 *	Aug 31, 1984	Apr 3, 1985	Genetics Institute, Inc.	Production of L-amino acids by transamination
GB974895A *	Title not available
US3282959 *	Mar 21, 1962	Nov 1, 1966	Parke Davis & Co	7-chloro-alpha-methyltryptamine derivatives
US4073795 *	Jun 22, 1976	Feb 14, 1978	Hoffmann-La Roche Inc.	Synthesis of tryptophans

WO2005009370A2 *	Jul 22, 2004	Feb 3, 2005	Pharmacia Corp	Beta-carboline compounds and analogues thereof and their use as mitogen-activated protein kinase-activated protein kinase-2 inhibitors
EP0466548A1 *	Jun 27, 1991	Jan 15, 1992	Adir Et Compagnie	1,2,3,4,5,6-Hexahydroazepino[4,5-b]indole and 1,2,3,4-tetrahydro-beta-carbolines, processes for their preparation, and pharmaceutical compositions containing them

Рисунок из Science 2010, 329, 1175

Исследовательская группа Элизабет Винцелер (Elizabeth A. Winzeler) разработала новый препарат, первоначально проведя скрининг библиотеки, состоящей из 12000 соединений, а затем получив производные наиболее перспективных кандидатов. В результате долгой работы исследователи отобрали единственное соединение спироиндолоновой структуры, получившее регистрационный номер NITD609. В случае успешного прохождения экспертизы фармакологических и токсикологических свойств нового соединения исследователи надеются приступить к первой фазе его клинических испытаний уже в конце этого года.

Было обнаружено, что NITD609 быстро останавливает белковый синтез в организме возбудителя малярии, ингибируя ген аденозинтрифосфатазы, ответственной за транспорт катионов через мембрану клетки возбудителя. То, что механизм действия нового соединения отличается от механизма, характерного для других средств лечения малярии, объясняет причины успешного действия нового препарата в том числе и против штаммов малярии, выработавших резистентность.

HPLC

Analyte quantization was performed byLC/MS/MS. Liquid chromatography was performed using an Agilent

1100 HPLC system(Santa Clara, CA), with the Agilent Zorbax XDB Phenyl (3.5μ, 4.6 x75 mm) column at

an oven temperature of 35 °C, coupled with a QTRAP4000 triple quadruple mass

spectrometer (Applied Biosystems, Foster City, CA). Instrumentcontrol and dataacquisition were performed using Applied Biosystems software Analyst 1.4.2. Themobile phases used were A: water:acetic acid (99.8:0.2, v/v) and B: acetonitrile:aceticacid (99.8:0.2, v/v), using a gradient, with flow rate of 1.0 mL/min, and run time of 5minutes. Under these conditions the retention time of9a

was 3.2 minutes. Compounddetection on the mass spectrometer was performed in electrospraypositive ionizationmode and utilized multiple reaction monitoring (MRM) for specificity (9atransitions338.3/295.1, 338.3/259.2) together with their optimized MS parameters. The lower limitof quantification for9awas 70 ng/mL.

Extraction and LCMS analysis of 20a.Plasma samples were extracted withacetonitrile:methanol-acetic acid (90:9.8:0.2 v/v) for the analyte and internal standard(17a) using a 3.6 to 1 extractant to plasma ratio. Analyte quantitation was performed by

LC/MS/MS. Liquid chromatography was performed using an Agilent1100 HPLC systemS7(Santa Clara, CA), with the Agilent Zorbax XDB-Phenyl (3.5μ, 4.6x75mm) column atan oven temperature of 45 °C coupled with a QTRAP 4000 triple quadruple massSpectrometer (Applied Biosystems, Foster City, CA). Instrumentcontrol and dataacquisition were performed using Applied Biosystems software Analyst 1.4.2. Themobile phases used were A: water:acetic acid (99.8:0.2, v/v) and B: methanol:acetic acid

(99.8:0.2, v/v), using gradient elution conditions with a flow rate of 1.0 mL/min and a runtime of 6 minutes

++++++++++++++++++++++==

Acs presentation march 2011 from fnesbitt

+++++++++++++++++++++++++++=

References

“NITD 609”. Medicines for Malaria Venture.
Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT (2010). “Spiroindolones, a potent compound class for the treatment of malaria”. Science329 (5996): 1175–80. doi:10.1126/science.1193225. PMC 3050001. PMID 20813948.

Ang, S. H., Krastel, P., Leong, S. Y., Tan, L. J., Wong, W. L. J., Yeung, B. K., and Zou, B. Spiro-indole derivatives for the treatment of parasitic diseases. WO2009132921 A1, November 5, 2009.

Cipargamin
Names

IUPAC name (1R,3S)-5’,7-Dichloro-6-fluoro-3-methyl-spiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,3’-indoline]-2’-one
Identifiers
CAS Number	1193314-23-6
ChemSpider	24662493
Jmol interactive 3D	Image
PubChem	44469321
InChI [show]
SMILES [show]
Properties
Chemical formula	C₁₉H₁₄Cl₂FN₃O
Molar mass	390.24 g·mol⁻¹

SEE……….http://apisynthesisint.blogspot.in/2016/02/kae-609-nitd-609-cipargamin-for-malaria.html

////

C[C@H]1Cc2c3cc(c(cc3[nH]c2[C@]4(N1)c5cc(ccc5NC4=O)Cl)Cl)F

PDE4 Inhibitor, SB-207499, Cilomilast……….REVISTED

December 26, 2014 6:19 am / Leave a comment

Cilomilast (Ariflo, SB-207,499)

cas 153259-65-5

cis-{-4-cyano-4-[3- (trans-3-hydroxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-l -carboxylic acid}

cis-4-Cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-r-1-cyclohexanecarboxylic acid

C20-H25-N-O4, 343.4205

GSK….INNOVATOR

Ariflo
Cilomilast
SB 207499
SB207499
UNII-8ATB1C1R6X

A selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease.

CLINICAL https://clinicaltrials.gov/search/intervention=Cilomilast

Cilomilast (Ariflo, SB-207,499) is a drug which was developed for the treatment of respiratory disorders such as asthma and Chronic Obstructive Pulmonary Disease (COPD). It is orally active and acts as a selective Phosphodiesterase-4 inhibitor.^[1]

SB-207499 is a potent second-generation inhibitor of PDE4 (phosphodiesterase-4) with decreased side effects versus those of the well-known first-generation inhibitor, (R)-rolipram. SB-207499 is in clinical development both for asthma and chronic obstructive pulmonary disease (COPD)……..J. Med. Chem. 1998, 41, 821

Cilomilast (Ariflo™, SB 207499) is an orally active, second-generation phosphodiesterase (PDE) 4 inhibitor that is being developed by GlaxoSmithkline for the treatment of chronic obstructive pulmonary disease (COPD). The results of Phase I and Phase II studies have demonstrated that cilomilast significantly improves lung function and quality of life to a clinically meaningful extent, which has led to a comprehensive Phase III programme of research evaluating efficacy, safety and mechanism of action. However, the results of those Phase III studies are unremarkable and disappointing, raising doubt over the future of cilomilast as a novel therapy for COPD. This review summarizes data obtained from the Phase III clinical development programme, highlights some of the potential concerns both specific to cilomilast and to PDE4 inhibitors in general and assesses the likelihood that cilomilast will reach the market.

Cilomilast is GlaxoSmithKline’s selective phosphodiesterase type 4 (PDE4) inhibitor. The drug candidate had been preregistered in the U.S. for the maintenance of lung function in patients with chronic obstructive pulmonary disease (COPD) who are poorly responsive to albuterol. GlaxoSmithKline received an approval letter from the FDA in October 2003, however, in 2007, the company discontinued development of the compound. In 2008, the product was licensed to Alcon by GlaxoSmithKline for the treatment of eye disorders.

Chemical structure for Cilomilast

Phosphodiesterase (PDE) inhibitors, such as theophylline, have been used to treat Chronic Obstructive Pulmonary Disease (COPD) for centuries; however, the clinical benefits of these agents have never been shown to out-weigh the risks of their numerous adverse effects. Four clinical trials were identified evaluating the efficacy of cilomilast, the usual randomized, double-blind, and placebo-controlled protocols were used. It showed reasonable efficacy for treating COPD, but side effects were problematic and it is unclear whether cilomalast will be marketed, or merely used in the development of newer drugs.^[2]^[3]

Cilomilast is a second-generation PDE4 inhibitor with antiinflammatory effects that target bronchoconstriction, mucus hypersecretion, and airway remodeling associated with COPD.

Clinical data
4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid
Legal status	?
Identifiers
CAS number	153259-65-5
ATC code	None
PubChem	CID 151170
ChemSpider	18826005
UNII	8ATB1C1R6X

Chemical data
Formula	C₂₀H₂₅N O₄
Mol. mass	343.417 g/mol

Synthesis

Christensen, Siegfried B.; Guider, Aimee; Forster, Cornelia J.; Gleason, John G.; Bender, Paul E.; Karpinski, Joseph M.; Dewolf,, Walter E.; Barnette, Mary S. et al. (1998). “1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma”. Journal of Medicinal Chemistry 41 (6): 821–35. doi:10.1021/jm970090r. PMID 9526558.

The reaction of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with LiBr, trimethylsilyl chloride (TMS-Cl) and 1,1,3,3-tetramethyldisiloxane in acetonitrile gives the corresponding benzyl bromide (II), which by reaction with NaCN in DMF affords 2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (III).

The condensation of (III) with methyl acrylate (IV) by means of Triton B in refluxing acetonitrile yields the 4-cyanopimelate (V), which is cyclized by means of NaH in refluxing DME, giving the 2-oxocyclohexanecarboxylic ester (VI). The decarboxylation of (VI) by means of NaCl in DMSO/water at 150 C yields the cyclohexanone (VII), which is condensed with 2-(trimethylsilyl)-1,3-dithiane (VIII) by means of BuLi in THF, affording the cyclohexylidene-dithiane (IX).

The methanolysis of (IX) catalyzed by HgCl2 and HClO4 in refluxing methanol gives a mixture of the cis- and trans-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanecarboxylic acid methyl ester which is submitted to flash chromatography to obtain the cis-isomer (XII). Finally, this compound is hydrolyzed with KOH in methanol/THF/water.

Org. Proc. Res. Dev., 2003, 7 (1), pp 101–108

DOI: 10.1021/op025584z

http://pubs.acs.org/doi/full/10.1021/op025584z

The synthesis of SB-207499 is described. Investigation and development of new strategies for the homologation of ketone, 4-cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-cyclohexan-1-one 2 are described which produce SB-207499. Our ultimate route of synthesis to SB-207499 is robust and operationally simple and produces the final drug substance in good yield and purity.

cis-4-Cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-r-1-cyclohexanecarboxylic acid (1a):

mp 148−150 °C; IR (KBr pellet) cm^–¹ 3300−2400, 2231, 1707, 1694;

¹H (400 MHz, CDCl₃) δ 11.75 (1Η, br s), 7.02 (1H, d, J = 2.3 Hz), 6.98 (1H, dd, J = 2.3, 8.4 Hz), 6.87 (1H, d, J = 8.4 Hz), 4.82 (1H, m), 3.86 (3H, s), 2.43 (1H, tt, J = 3.7, 12.2 Hz), 2.29 (2H, br d, J = 15.6 Hz), 2.25 (2H, br d, J = 16.4 Hz), 2.05 (2H, m), 1.94 (4H, m), 1.86 (2H, m), 1.82 (2H, m), 1.64 (2H, m); ¹³C (100 MHz, CDCl₃) δ 180.5, 149.8, 147.8, 132.8, 122.2, 117.3, 112.9, 111.9, 80.7, 56.1, 43.0, 41.7, 36.4, 32.8, 25.9, 24.0.

………………………………………..

http://www.google.com/patents/WO1995024381A1?cl=en

cis-{-4-cyano-4-[3- (trans-3-hydroxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-l -carboxylic acid} or the corresponding compounds as defined by Formula I. The preparation of any remaining compounds of the Formula (I) not described therein may be prepared by the analogous processes disclosed herein which comprise:

Example 1

Preparation of cis-r4-cvano-4-⁽3-cyclopentyloxy-4-methoxyphenyl)cvclohexane- 1 – carboxylic acid]

1 fa (3-Cyclopentyloxy-4-methoxyphenv acetonitrile

To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8 mmol) in acetonitrile (100 mL) was added lithium bromide (15 g, 173 mmol) followed by the dropwise addition of trimethylsilylchloride (17.4 mL, 137 mmol). After 15 min, the reaction mixture was cooled to 0° C, 1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise and the resulting mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was separated into two layers. The lower layer was removed, diluted with methylene chloride and filtered through Celite®. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacuo to provide a light tan oil. To a solution of this crude a- bromo-3-cyclopentyloxy-4-methoxy toluene in dimethylformamide (160 mL) under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol) and the resulting mixture was stirred at room temperature for 18 h, then poured into cold water (600 mL) and extracted three times with ether. The organic extract was washed three times with water, once with brine and was dried (K2CO3). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 10% ethyl acetate/hexanes) to provide an off-white solid ( m.p. 32-34^g C); an additional quantity of slightly impure material also was isolated. Kb Dimethyl 4-cvano-4-(‘3-cvclopentyloxy-4-methoxyphenv pimelate

To a solution of (3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (7 g, 30.3 mmol) in acetonitrile (200 mL) under an argon atmosphere was added a 40% solution of Triton-B in methanol (1.4 mL, 3.03 mmol) and the mixture was heated to reflux. Methyl acrylate (27 mL, 303 mmol) was added carefully, the reaction mixture was maintained at reflux for 5 h and then cooled. The mixture was diluted with ether, was washed once with IN hydrochloric acid and once with brine, was dried (MgSO4) and the solvent was removed in vacuo. The solid residue was triturated with 5% ethanol/hexane to provide a white solid (m.p. 81-82° C); an additional quantity was also obtained from the filtrate. Anal. (C22H29NO6) calcd: C 65.49, H 7.25, N 3.47. found: C 65.47, H 7.11, N 3.49. 1. c) 2-Caf bomethoxy-4-cvano-4-⁽3-cyclopentyloxy-4-methoxyphen vDcvclohexan- 1 -one To a suspension of sodium methoxide (350 mL, 1.55 mol, 25% w/w in methanol) in toluene (2.45 L) heated to 80° C under a nitrogen atmosphere was added a solution of dimethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate (350.0 g, 0.87 mol) in toluene (1.05 L) over 10 min. The reaction was heated to 85° C by distilling away 250 mL of solvent and was vigorously stirred under nitrogen for 2 hours. The reaction was cooled to 50° C and was quenched with 3N (aq) HC1 (700 mL, 2.1 mol). The organic layer was isolated, was washed once with deionized water (700 mL) and once with brine (700 mL). The organic layer was concentrated via low vacuum distillation to afford crude 2- carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -one in toluene. This was dissolved in 4.2 L of dimethyl sulfoxide and used in the next step. 1 (d) 4-Cvano-4-f3-cyclopentyloxy-4-methoxyphenyl cvclohexan- 1-one

To a suspension of sodium chloride (315 g, 5.39 mol) and deionized water ( 315 mL) was added the dimethyl sulfoxide (4.2 L) solution of 2-carbomethoxy-4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexane-l-one ( 323 g, 0.87 mol) and the resulting suspension was heated to 155° C for 1.75 h. The reaction was cooled to 40° C, was quenched into 8 L of iced water (2² C) and was extracted with ethyl acetate (3.5 L). The aqueous layer was isolated and re-extracted with 2.5 L of ethyl acetate. The combined organic extract (6 L) was washed two times with deionized water (2 x 1 L) and once with brine (1 L). The organic layer was isolated and concentrated in vacuo to afford a residue. This residue was dissolved in refluxing isopropanol (500 mL), was cooled to 0° C and held at this temperature for 1 hour. The crystals were isolated by filtration, were washed with 250 mL of isopropanol (0° C), and were dried in a vacuum oven (45° C at 20 inches) to produce 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l -one . m.p. 111-112° C; Anal. (C₁₉H₂3NO ) calcd: C 72.82, H 7.40, N 4.47; found: C 72.72, H 7.39, N 4.48. 1 (e) 2-r4-Cyano-4-G-cyclopentyloxy-4-methoxyphenyl)cvclohexylidenel- 1.3-dithiane To a solution of 2-trimethylsilyl-l,3-dithiane (9.25 mL, 48.7 mmol) in dry tetrahydrofuran (80 mL) at 0° C under an argon atmosphere was added rapidly n- butyllithium (2.5M in hexanes, 19.2 mL, 48 mmol). After 10 min, the mixture was cooled to -78° C and a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l- one (7.53 g, 23 mmol) in tetrahydrofuran (40 mL) was added. After 10 min, aqueous sodium chloride was added, the mixture was allowed to warm to room temperature and was diluted with water. This mixture was combined with the product of three substantially similar reactions conducted on ketone (3.04, 6.01 and 6.1 g, 48.3 mmol total), the combined mixture was extracted three times with methylene chloride, the extract was dried (MgSO4) and evaporated. Purification by flash chromatography (silica gel, 10% ethyl acetate/hexanes) provided a white solid, m.p. 115-116° C. \⁽f) cis-r4-Cyano-4-⁽3-cyclopentyloxy-4-methoxyphenyl^‘)cyclohexane- 1 -carboxylic acidl

To a suspension of 2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclo- hexylidene]-l,3-dithiane ( 140.0 g, 0.34 mol) in acetonitrile (500 mL) and deioinized water (140 mL) under nitrogen was added trifluoroacetic acid (136 g, 1.19 mol). The suspension was heated to 65² C for 1.25 h followed by the addition of 20% sodium hydroxide (420 g, 2.1 mol). The solution was heated at 70 to 75° C for an additional 1.25 h, was cooled to 45° C, deionized water (420 mL)was added followed by 3N (aq) HC1 (392 mL, 1.18 mol). The suspension was cooled to 5° C and held for 1 h. The suspension was filtered, was washed with cold (5^e C) deionized water ( 200 mL), and was dried in a vacuum oven (40°C at 20 inches) to obtain crude cis-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane-l -carboxylic acid]. This material was assayed at 98.5% and was found to a 98.8:1.2 mixture of cis-to-trans isomers, which was contaminated with 0.1% of residual 1,3-propanedithiol. This material was purified via an oxidative workup as follows.

To a hot solution (65° C) of crude cis-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane-l -carboxylic acid] (85 g, 0.247 mol) in acetonitrile (425 mL) was added 1M sodium hydroxide ( 425 mL, 0.425 mol). To the solution (60° C) was added 4.25 g of calcium hypochlorite and the suspension was vigorously stirred for 2 h. The reaction was concentrated by distilling out 320 mL of solvent, followed by the addition of ethyl acetate ( 425 mL). The reaction was again concentrated by distilling out 445 mL of solvent, was cooled to 55° C followed by the addition of ethyl acetate (1.0 L) and 6N (aq.) HC1 (100 mL). The organic layer was isolated, was washed three times with deionized water (3 x 300 mL), was filtered and was concentrated by distilling out 530 mL of solvent. To the solution was added ethyl acetate (635 mL) with continued distillation to remove 750 mL of solvent. The solution was cooled to 65° C followed by the addition of hexane ( 340 mL). The suspension was cooled to 5° C, held at this temperature for 1 hour, was filtered and was washed with cold (5° C) 10% ethyl acetate/ hexane ( 200 mL). The solid was collected and was dried in a vacuum oven (40° C at 20 inches) to obtain cis- [4- cyano-4- (3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -carboxylic acid] . This material was found to contain no trans isomer. Anal.(C2θH25-Nθ4) calcd: C 69.95, H 7.34, N 4.08; found: C 69.90, H 7.35, N 4.02. Example 2

Preparation of cis-f 4-cvano-4-r3-(trans-3-hydroxycyclopentyloxy)-4-methoxyphenyll- cyclohexane-1 -carboxylic acid)

2(a’) cis-F4-Cyano-4-(3-hvdroxy-4-methoxyphenvDcyclohexane- 1 -carboxylic acid]

To a solution of boron tribromide in dichlorormethane (0.1M, 335 mL, 33.5 mmol) under an argon atmosphere at -78° C was slowly added a solution of cis-[4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexane-l -carboxylic acid] (4.03 g, 11.7 mmol) in dichloromethane (180 mL). The mixture was stirred for 5 min, 15% sodium methoxide in methanol was added to pH 8-9 and the reaction was warmed to RT. Water (lOOmL) was added and the mixture was acidified with 3N aqueous hydrochloric acid to pH 1-2. The organic layer was separated, was dried (MgSO4/Na2SO4), was filtered and was evaporated. The residue was twice dissolved in chloroform and the solution was evaporated to yield a white solid. -1H NMR(400 MHz, CDCI3) δ 7.01 (d, J=2.4 Hz, 1H), 6.96 (d of d, J=2.4, 8.5 Hz, 1H), 3.89 (s, 3H), 2.31 (m, 1H), 2.21 (br t, J=13.6 Hz, 4H), 1.98 (m,2H), 1.77 (m, 2H); mp 190-193° C. Kb) Methyl cis- r-4-cvano-4-⁽3-hvdroxy-4-methoxyphenyl^‘)cvclohexane-l-carboxylatel -Toluenesulfonic acid monohydrate (0.015 g, 0.08 mmol) was added to a solution of the compound of Example 2(a) (0.70 g, 2.54 mmol) in dry methanol (20 mL) under an argon atmosphere and the reaction was stirred for 6 h at 45-50⁹ C. The reaction was cooled to RT and was stirred for an additional 16 h. The solution was evaporated and the residue was purified by flash chromatography (silica gel, 50% hexane/ethyl acetate) to yield the tide compound as a white solid. -1H NMR(400 MHz, CDC1₃) δ 7.01 (m, 2H), 6.85 (d, J=9.1 Hz, IH), 3.90 (s, 3H), 3.72 (s, 3H), 2.35 (t of t, J=3.6, 12.2 Hz, IH), 2.14-2.25 (m, 4H), 2.00 (app q, J=13.4 Hz, IH), 1.99 (app q, J=13.4 Hz, IH), 1.77 (app t, J=13.4 Hz, IH), 1.76 (app t, J=13.4 Hz, IH); mp 106-107° C.

2(c) Methyl cis- f -4-cvano-4-r3-(trans-3-hydroxycvclopentyloxy )-4-methoxyphenyl – cvclohexane- 1 -carboxylate 1

The compound of Example 2(b) (0.69 g, 2.37 mmol) was dissolved in tetrahydrofuran (20 mL) under an argon atmosphere and was treated with triphenylphosphine (1.24 g, 4.74 mmol) and cis-l,3-cyclopentanediol (0.49 g, 4.74 mmol). Diethyl azodicarboxylate (0.83 g, 4.74 mmol) was added and the mixture was stirred at RT for 16 h. The solution was evaporated, the residue was diluted with ether and the white solid was removed by filtration. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 50% hexane/ethyl acetate) to yield a mixture of the title compound and triphenylphosphine oxide. The mixture was diluted with ether and the white solid triphenylphosphine oxide was removed by filtration. Evaporation of the filtrate yielded the title compound as a sticky, colorless semi-solid. 1H NMR(400 MHz, CDCI3) δ 7.07 (d, J=2.4 Hz, IH), 7.02 (d of d, J=2.4, 8.8 Hz, IH), 6.87 (d, J=8.8 Hz, IH), 4.99 (m, IH), 4.37 (m, IH), 3.85 (s, 3H), 3.74 (s, 3H), 3.16 (d, J=9.1 Hz, IH), 2.39 (m, IH), 1.88-2.25 (m, 12H), 1.80 (br t, J=13.5 Hz, 2H).

2(d) cis-f-4-cyano-4-r3-(trans-3-hydroxycyclopentyloxy )-4- methoxyphenyllcyclohexane-1 -carboxylic acid )

The compound of Example 2(c) (0.10 g, 0.27 mmol) was dissolved in 5:5:2 tetrahydrofuran methanol/water (5 mL), sodium hydroxide (0.035 g, 0.88 mmol) was added and the mixture was stirred at RT for 3 h. The solvent was evaporated, the residue was partitioned between 5% aqueous NaOH and dichloromethane and the layers were separated. The aqueous layer was acidified to pH 3 with 3N aqueous hydrochloric acid and was extracted three times with 5% methanol in chloroform. The organic extracts were combined, were dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 90:10:1 chloroform/methanol water) to yield a solid which was slurried in ether, was collected by filtration and was dried in vacuo to afford the title compound. MS(d/NH₃) m e 377 [M + NH ]+; 1H NMR(400 MHz, CDCI3) δ 7.08 (br s, IH), 7.03 (br d, J=8.5Hz, IH), 6.88 (d, J=8.5 Hz, IH), 4.98 (m, IH), 4.38 (m, IH), 3.84 (s, IH), 2.41 (m, IH), 1.77-2.29 (m, 16H); Anal. (C₂oH₂5NO₅-»0.9 H₂O) calcd: C, 63.95; H,7.19; N,3.73. found: C, 64.06; H, 6.88; N, 3.77; mp 161-163° C.

Example 3 Preparation of cis- f 4-cvano-4-r3-(cis-3-hvdroxycvclopentyloxy)-4-methoxyphenyll- cyclohexane-1 -carboxylic acid) 3(a) Methyl cis-(-4-cvano-4-r3-⁽cis-3-formyloxycvclopentyloxy)-4-methoxyphenyll- cvclohexane- 1 -carboxylate ) The compound of Example 2(c) (0.68 g, 1.83 mmol) was dissolved in tetrahyrofuran (20 mL) under an argon atmosphere and was treated with triphenylphosphine ( 0.96 g, 3.66 mmol) and formic acid (0.17 g, 3.66 mmol). Diethyl azodicarboxylate (0.64 g, 3.66 mmol) was added and d e mixture was stirred at RT for 16 h. The solution was evaporated, ether was added and the white solid was removed by filtration. The filtrate was concentrated and die residue was purified by flash chromatography (silica gel, 65% hexane/ethyl acetate) to yield the title compound as a clear colorless oil. ^**-H NMR(400 MHz, CDC1₃) δ 8.02 (s,lH), 7.0 (d of d, J=2.4, 8.2 Hz, IH), 6.99 (d, J=2.4 Hz, 1 H), 6.87 (d, J=8.2 Hz, IH), 5.48 (m, IH), 4.95 (m, IH), 3.84 (s, 3H), 3.72 (s, 3H), 2.31-2.40 (m, 2H), 2.13-2.28 (m, 7H), 1.96-2.06 (m, 3H), 1.74-1.87 (m, 3H).

3⁽h⁾ cis- ⁽ -4-cvano-4-r3-⁽cis-3-hvdroxvcvclθDentvloxy⁾-4-methoχyphenyllcvclohexane- 1 -carboxylic acid)

The compound of Example 3(a) (0.52 g, 1.31 mmol) was dissolved in 5:5:2 tetrahydrofuran/methanol/water (20mL), sodium hydroxide (0.32 g, 8.0 mmol) was added and die mixture was stirred at RT for 2.5 h. The solvent was evaporated and the aqueous residue was acidified to pH 1-2 with 3N aqueous hydrochloric acid. The white solid product was collected, was washed with water and was dried in vacuo to afford the title compound as a white solid. MS(CI/NH3) m/e 377 [M + NH3]+;

IH NMR(250 MHz, CDCI3) δ 6.98 (m, 2H), 6.86 (d, J=8.2 Hz, IH), 4.97 (m, IH), 4.59 (m, IH), 3.85 (s, 3H), 1.64-2.47 (m, 17H);

mp 143-145° C.

References

http://www.medscape.com/viewarticle/549357
Torphy TJ, Barnette MS, Underwood DC, Griswold DE, Christensen SB, Murdoch RD, Nieman RB, Compton CH. Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulmonary Pharmacology and Therapeutics. 1999;12(2):131-5. PMID 10373396
Ochiai H, Ohtani T, Ishida A, Kusumi K, Kato M, Kohno H, Kishikawa K, Obata T, Nakai H, Toda M. Highly potent PDE4 inhibitors with therapeutic potential. Bioorganic and Medicinal Chemistry Letters. 2004 Jan 5;14(1):207-10. PMID 14684329

WO1993019747A1 *	Mar 5, 1993	Oct 14, 1993	Siegfried B Christensen Iv	Compounds useful for treating allergic and inflammatory diseases
WO1993019748A1 *	Mar 5, 1993	Oct 14, 1993	Paul Elliot Bender	Compounds useful for treating inflammatory diseases and for inhibiting production of tumor necrosis factor
WO1993019750A1 *	Mar 12, 1993	Oct 14, 1993	Paul Elliot Bender	Compounds useful for treating allergic or inflammatory diseases

US4795757 *	Nov 20, 1986	Jan 3, 1989	Rorer Pharmaceutical Corporation	Bisarylamines
US5096906 *	Dec 5, 1990	Mar 17, 1992	University Of Virginia Alumni Patents Foundation	Method of inhibiting the activity of leukocyte derived cytokines
WO1993019720A2 *	Mar 12, 1993	Oct 14, 1993	Paul Elliot Bender	Compounds

MSA 100 a serotonin receptor antagonist.

December 26, 2014 5:34 am / Leave a comment

(2E)-N-[2-[2-[(2S)-1-Methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2-propenamide (1)

(S)-2′[2-1-(methyl-2-piperidyl) ethyl] cinnamanilide

(2E)-Λ/-[2-[2-[(2S)-1-Methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2- propenamide

CAS 951155-17-2

C₂₃H₂₈ N₂O, 348.48

It was reported that the (S)-enantiomer of 2′-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide (MSA100, 1) is an active 5-HT (5-hydroxytryptamine or serotonin) receptor antagonist; however, its (R)-isomer is totally or substantially devoid of the same activity.(1)

1.

(a) Amer, M. S., U.S. Patent 5,780, 487, 1998.

(b) Prashad, M.; Liu, Y.; Hu, B.; Girgis, M. J.; Schaefer, F., WO2007/111705, 2007.

(c) Prashad, M.; Liu, Y.; Hu, B.; Girgis, M. J.; Schaefer, F., WO2007/111706, 2007.

…………………………………………………………………..

http://www.google.com/patents/WO2007111706A2?cl=en

Figure imgf000003_0001

Example 4:

Synthesis of (2E)-/V-[2-[2-[(2S)~1 -Methyl-2-piperidinyl]ethyI]phenyl]-3-phenyl-2- propenamide

(a) Free Base Generation:

A 250-mL, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, heating cooling bath, and addition funnel, is charged with 6.28 g (S)-2-[2-(1-methyl-2-piperidinyl)ethyl]-benzenamine (1R,3S)-(+)-camphoric acid salt (1 :1) and 60 mL of isopropyl acetate. Stir the mixture at 20-25 ⁰C under nitrogen and add a solution of 1.60 g of sodium hydroxide in 20 mL of water over a period of 5 min while maintaining an internal temperature at 20-25 ⁰C. Stir the suspension efficiently until all the solid dissolves (5 min). Separate the organic layer and save. Extract the aqueous layer with 20 mL of isopropyl acetate. Combine the organic layers and wash it with 20 mL of water. Separate the organic layer and concentrate it under vacuum (20-100 mbar) at an internal temperature at 20-40 ⁰C (external temperature 30-60 ⁰C) to obtain ~65 mL of a solution of (S)-2-[2-(1-methyl-2-piperidinyl)ethyl]-benzenamine (containing 3.28 g of free base) in isopropyl acetate. Save this solution for the next step and store it under nitrogen.

(b) Reaction:

A 250-mL, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, nitrogen inlet-outlet, heating mantle, condenser, and addition funnel is charged with -65 mL of a solution of (S)-2-[2-(1-methyl-2-piperidinyl)ethyl]-benzenamine (containing 3.28 g of free base) in isopropyl acetate and 6.22 g of potassium carbonate. Stir the reaction mixture under nitrogen at an internal temperature at 23 ± 3 ⁰C to afford a suspension. Add 3.75 g of cinnamoyl chloride over a period of 5 min while maintaining an internal temperature at 23 ± 3 ⁰C to obtain a slurry. Heat the reaction mixture to an internal temperature at 85 ± 5 ⁰C (external temperature 90-100 ⁰C) over a period of 30-60 min. Stir the reaction mixture at this temperature for an additional 2 h. Cool the reaction mixture to 23 ± 3 ⁰C over a period of 1 h. Add 50 mL of water. Stir the reaction mixture at 23 ± 3 ⁰C for 30-60 min to obtain a bi-phasic solution. Separate the organic layer. Add 80 mL of 0.5 N HCI solution over a period of 10 min while maintaining an internal temperature at 23 ± 3 ⁰C to afford a bi-phasic solution. Separate the aqueous layer. Add 60 mL of isopropyl acetate. Stir the reaction mixture and add a solution of 2.00 g of sodium hydroxide in 25 mL of water over a period of 10 min while maintaining an internal temperature at 23 ± 3 ⁰C to afford a bi- phasic solution. Separate the organic layer and save. Extract the aqueous layer with 60 mL of isopropyl acetate. Combine the organic layers and wash it with 40 mL of water. Separate the organic layer and concentrate it under vacuum (20-100 mbar) at an internal temperature at 20-40 ⁰C (external temperature 30-60 ⁰C) to obtain 22mL (19.3 g) of a solution of (iii) in isopropyl acetate. Stir and heat the reaction mixture to an internal temperature at 85 ± 5 ⁰C (external temperature 90-100 ⁰C) over a period of 30-60 min. Add 96 mL of hepatane over a period of 10 min while maintaining an internal temperature at 85 ± 5 ⁰C. Stir and Cool the reaction mixture to 23 ± 3 ⁰C over a period of 1 h. Stir the resulting slurry at 23 ± 3 ⁰C for an additional 2 h. Collect the solid by filtration over a polypropylene filter paper in a Buchner funnel with suction. Wash the solid with a total of 28 mL of a mixture of isopropyl acetate and heptane (1/6) in two equal portions of 14 mL each. Dry the solid at 45-50 ⁰C under vacuum (13-40 mbar) with nitrogen bleeding to obtain a constant weight (LOD < 1%, 4 h) of 4.06 g of (2£)-A/-[2-[2-[(2S)-1-methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2-propenamide as an off white solid.

Theoretical Yield: 5.23 g

Yield: 77.6%

Purity: 99.8% (HPLC area %).

Enantiomeric purity: (R)-(iii) was not detected by Chiral HPLC. Example 5:

Alternative synthesis of (2£)-/V-[2-[2-[(2S)-1-MethyI-2-piperidinyl]ethyl]phenyI]-3- phenyl-2-propenamide

(a) Free base generation:

In a 500 ml round bottomed flask equipped with a mechanical stirrer the resolved camphoric acid salt (IV) (20 g) in isopropyl acetate (120 g) is added at an internal temperature of 20 to 25 ⁰C (external temperature 20 ⁰C). Then, at an internal temperature of 25 to 30 ⁰C (external temperature 20 ⁰C) a solution of sodium hydroxide (38.24 g) in water (60 g) is added to the reaction mixture over a period of 5 minutes. The reaction mixture (suspension) is then stirred for a further 30 minutes. The resulting orange emulsion is then allowed to separate into a two-phase mixture and the water phase is removed. The organic phase is then subjected to a rotary evaporator and the isopropyl acetate is distilled at an internal temperature of 60 ⁰C and under reduced pressure (250 mbar). Approximately 90 g of isopropyl acetate is distilled. Prior to distilling, the organic phase is a clear, bright orange colour and of a volume of approximately 160 ml ( 13Og),

(b) Reaction:

In a 1.5 I flask equipped with a mechanical stirrer and at an internal temperature of 35 ⁰C (external temperature 38 ⁰C) and under inert conditions (nitrogen) 2-butanone (160 g) and isopropyl acetate (20 g) is added to the reaction mixture of part (a). Then, at an internal temperature of 35 ⁰C (external temperature of 38 ⁰C) a solution of cinnamoyl chloride (8.9 g) in 2-butanone (20 g) is added drop wise. Then, the reaction mixture is treated with more 2- butanone (2 x 5 g). The resulting suspension is then stirred for 20 minutes at an internal temperature of 35⁰C. The pH of the mixture is between 6 and 8.

The suspension of step (b) is then cooled to an internal temperature of 25 ⁰C (external temperature 20 ⁰C) and at the same time a mixture of water (200 g) and isopropyl acetate (60 g) is added. The reaction mixture is then stirred for a further 15 minutes at an internal temperature of 25 ⁰C (external temperature 20 ⁰C). The resulting two-phase reaction mixture is then separated and the water phase removed. The resulting yellow upper layer is then treated with 2.5 mol/l hydrochloric acid (200 g). The resulting two-phase mixture is then separated and the water phase is transferred into a 750 ml flask equipped with a mechanical stirrer. The organic phase is then washed with 2.5 mol/l hydrochloric acid (200 g) and the resulting two-phase mixture is separated and the water phase is added to the first water phase. The combined water phases are then treated with acetic acid (300 g) and sodium hydroxide (150 g) is added. The reaction mixture is then stirred at an internal temperature of 25 to 30 ⁰C (external temperature 20 ⁰C) for 15 minutes. The resulting two-phase reaction mixture is then separated.

(d) Crystallization

The organic phase from the above reaction step (c) is reduced in volume on a rorary evaporator at an external temperature of 60 ⁰C and at 250 mbar. Then, the reduced-volume reaction mixture is treated with isopropanol (60 g) and the resulting reaction mixture is reduced in volume on a rotary evaporator at an external temperature of 60 ⁰C and under a vacuum of 150 mbar. Then, at an internal temperature of 50 to 55 ⁰C (external temperature 60 ⁰C) the reaction mixture is treated with water (20 g) and the resulting suspension is further treated with the product (iv) (10 mg) in isopropanol (0.01 g). The reaction mixture is then stirred for a further 15 minutes at an internal temperature of 50 to 55 ⁰C (external temperature 60 ⁰C). Then, further water is added over a period of 15 to 30 minutes and the reaction mixture is maintained at an internal temperature of 50 to 55 ⁰C (external temperature 60 ⁰C). Then, the resulting suspension is cooled to an internal temperature of 22 to 22 ⁰C (external temperature 20 ⁰C. Then, the suspension is stirred for a further 30 minutes at an internal temperature of 22 to 22 ⁰C (external temperature 20 ⁰C) and the resulting solid is collected by filtration and washed with a mixture of water and isopropyl acetate (2 x 20 g), where the water: isopropyl acetate ratio is of 5:1 g/g. The resulting solid may then be dried under a vacuum at a temperature of 55 ⁰C.

Yield: 14.8 g (89.3% of theory). mp: 127.3 to 130.2 ⁰C

Example 6: Recrystallisation of (2E)-Λ/-[2-[2-[(2S)-1-Methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2- propenamide

(a) In a 200 ml round bottomed flask equipped with a magnetic stirrer, containing the product (iv) (15 g) is added isopropanol (25 g) and heptane (heptane fraction from petroleum having a boiling point of 65 to 100 ⁰C) (25 g) is added. Then, the reaction mixture is heated to an internal temperature of 75 ⁰C (external temperature 95 ⁰C) and refluxed for approximately 30 minutes, whilst stirring. Then, the reaction mixture is filtered over a glass fibre filter at an internal temperature of 70 to 75 ⁰C (external temperature 85 ⁰C) in to a 350 ml flask equipped with a magnetic stirrer. Then, a mixture of isopropanol (5 g) and heptane (5 g) is added and the reaction mixture is heated to an internal temperature of 70 ⁰C (external temperature 95 ⁰C). Then, further heptane is added drop wise to the reaction mixture at an internal temperature of 65 to 75 ⁰C (external temperature 75 ⁰C).

(b) Crystallization

The solution from step (a) is then cooled to an internal temperature of 40 ⁰C (external temperature 40 ⁰C) over a period of 15 minutes. The, at an internal temperature of 40 ⁰C, the solution is treated with a suspension of the recrystallized product (v) (11 mg) in heptane is added and the reaction mixture is stirred for 30 minutes at an internal temperature of 40 ⁰C (external temperature 40 to 45 ⁰C). Then, the reaction mixture is treated with some further heptane (15 g) at an internal temperature of 40 ⁰C. The resulting suspension is then cooled to an internal temperature of -10 ⁰C (external temperature -10 to -15 ⁰C) over a period of 30 minutes and then further stirred for a further hour. The reaction mixture is then filtered at an internal temperature of -10 ⁰C (external temperature -10 to -15 ⁰C) and the resulting solid may be washed in a mixture of isopropanol and heptane, where the isopropanohheptane ratio is 1 :1.5. The solid may be washed twice (2 x 11.25 g). The solid may then be dried in a vacuum at a temperature of 60 ⁰C.

Yield: 17.8 g (89% of theory) mp: 127.4 to 132.0 ⁰C.

………………………………………………………………..

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/op5003402

http://pubs.acs.org/doi/full/10.1021/op5003402

An efficient process was developed for the manufacture of MSA100, a serotonin receptor antagonist, via a five-step synthetic route furnishing a high quality of active pharmaceutical ingredient. Highlights of this synthesis include: (1) replacing carcinogenic methyl iodide with methyl p-toluenesulfonate as the methylating reagent; (2) a hydrogenation protocol with optimized temperature, pressure, and mass-transfer conditions that avoided one side product and reduced the other one effectively; (3) chemical resolution employing D-camphoric acid in a mixed-solvent system; (4) amidation under anhydrous conditions for controlling a Michael adduct impurity; and (5) plausible mechanisms for the formation of side products.

(2E)-N-[2-[2-[(2S)-1-Methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2-propenamide (1)

To a mixture of 14 (6.28 g, 15 mmol) ……………………………………………………to obtain 1 (4.06 g, 78% yield) as an off-white solid: mp 125–127 °C (lit. ref 1a, mp 128 °C);

Chiral HPLC for (S)-1 (t_R = 19.3 min), >99.9% ee; (R)-1 (t_R = 18.5 min): Chiralcel AD-H, 250 × 4.6 mm, flow rate = 1.0 mL/min, 25 °C, 900:100:1 A:B:C isocratic; A = hexanes; B = ethanol; C = diethylamine; UV λ = 230 nm. HPLC for 1 (t_R = 11.2 min) 99.8% purity; 8 (t_R = 5.4 min); 9 (t_R = 12.3 min): Waters Symmetry-C18 150 × 4.6 mm, flow rate = 1 mL/min, 25 °C, gradient elution from 93:7 A–B to 85:15 A–B over 5 min, to 10:90 A–B over 10 min and held for 2 min, to 93:7 A–B over 1 min; A = 0.1% TFA in water; B = acetonitrile; UV λ = 230 nm.

…………………

http://www.google.com/patents/EP0973741A1

Example I PREPARATION AND CONFIRMATION OF S-MPEC

racemic-APEMEP-HI -5/1-

– 6 –

1. 2 – nitrobenzaldehyde

2. 2 – picoline

3. 2 – (o-nitrostyryl) pyridine (NSP)

4. 2 – ^“(o-nitrostyryl)- 1 -methylpyridinium iodide 5. RS-2- (o-aminophenethyl)-l-methylpiperidine. HI

6. S-[2-(o-aminophenethyl)- 1 -methylpiperidine-dibenzoyl-L-tartrate] (S-APEMP. DBLT OR .L-DBT)

7. S-2′- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide (S-MPEC) 7a. Cinnamoyl chloride S-MPEC CHEMICAL PROCESS

(A) 2-(O-Nitrostyryl) – 1 -Methylpyridinium Iodide fNSMP-P

To a 50 L round bottomed flask was added 2-nitrobenzaldehyde (3,500 g. 23.2 moles), 2-picoline (3.2L., 32.8 moles) and acetic anhydride. The mixture was stirred efficiently under an inert atmosphere (nitrogen or another inert gas) and heated to reflux for 27 hrs. The mixture was cooled to under 100 C, for safe handling, and quenched in a suitable vessel equipped with external cooling and efficient stirring on 10.5 Kg. of ice. The pH was adjusted to 11 with 45% aqueous sodium hydroxide at a rate to keep the temperature below 50°C. After cooling to 20-30°C, the granular solid was collected by filtration, washed well with water. Yield 6572 g. of crude 2-(o-nitrostyryl) pyridine (NSP).

This solid was transferred to a 50L, round bottomed flask, dissolved in acetone (14L.) and iodomethane (2.94L., 47.7 moles) (quaternizing methylating agent) was added. (Other such (alkylating) agents may be used, generally having the formula CH₃X, X being an anion such as sulfate, methyl sulfate, halide (Cl, Br, I), etc.). The mixture was heated to reflux under an inert atmosphere (nitrogen or another inert gas) for 18 hrs. After cooling to 20°C. the precipitate was collected by filtration and washed with acetone or a 1 :1 mixture of acetone:ethyl acetate (3×3.5L.). Drying to constant weight at 50-60°C. yielded 6,839 g. (80%) of NSMP.I. (B) RS- 2-(o-Aminophenethyl)-l-Methylpiperidine. Hvdroiodide

ΓRS-APEMP.HΠ

In a 5 gallon reactor, a solution of NSNP.I (935 g., 2.5 moles) in – 7 – methanol (14L.) was reduced in a hydrogen atmosphere (Psi. 55) in the presence of Pt/C (5 or 10%, 98g.). After removal of the catalyst and evaporation of the filtrate in the usual manner, the residue was dissolved in hot methanol (2.8L.). Ethyl acetate (2.8L) was added to the hot mixture to induce crystallization, yield 516.3 g. (59%) of RS-APEMP.HI.

A solution of RS-APEMP.HI (516g., 1.5 mole) ethyl acetate (5.5g.) (or other low boiling water immiscible solvent such as benzene, toluene etc.) was extracted with 5% aqueous sodium hydroxide to liberate the free base (organic phase), washing the organic phase with water, drying over a suitable drying agent (such as anhydr. sodium sulfate, magnesium sulfate, potassium carbonate etc.) After separating the solvent from the drying agent the solution was evaporated in vacuo and the residual RS-APEMP free base was dissolved in methanol (l .O.L.) and a solution of dibenzoyl-L-tartaric acid (540 g., 1.5 moles) in methanol (2.3 L.) was added. The mixture was held overnight at room temperature. The crystalline precipitate was collected and recrystallized from methanol (3.4 L.), yield 246g. of S-APEMP.DBLT. (28.6%, wt; 57.2% of the S-APEMP). (O) S-2′-r2-π-Methyl-2-Piperidvnethyll Cinnamanilide f S-MPEC) A solution of S-APEMP.DBLT (287 g, 0.5 mole) in ethyl acetate

(3.2 L.) (or other low boiling water immiscible solvent) was extracted with 7.5% aqueous sodium bicarbonate (3.2 L.) to liberate the S-APEMP. After a water wash and drying over a suitable drying agent the solvent was removed in vacuo. The oily residue, S-APEMP, was dissolved in ethyl acetate (1.0 L.) and anhydrous potassium carbonate (412 g, 3.0 moles) (or other suitable acid acceptor such as triethyl amine, pyridine etc.) was added. Cinnamoyl chloride (143 g., 0.7 mole) in 700 ml. of ethyl acetate was added slowly. After the initial reaction, the mixture was refluxed for 14 hrs. After cooling to room temperature the mixture was extracted with water (1.7 L.) and dried over a suitable drying agent. After removing the drying agent the solvent was removed in vacuo and the residue was dissolved in hot ethyl acetate (280 ml.) and allowed to slowly cool to room temperature; filtration yielded S-MPEC, (136 g., 79% yield). Analysis: Calcd. For C, H, N : C, 79.27; H, 8.10;N, 8.04. Found: C, 79.27; H, 8.06; N, 8.07. HPLC(chiral)purity: 99.5%, [oc ]_D25, -46° (c=0.01,EtOH); Melting point: 128°C.
TABLE 2 CERTIFICATE OF ANALYSIS Compound Name: (-)-2′-[2-(l-Methyl-2 piperidyl)ethyl]cinnamanilide(/-MPEC,S- MPEC

……………………………….

http://www.google.com/patents/US20080300410?cl=en

synthesis of 2′[2-1-(methyl -2-piperidyl) ethyl] cinnamanilide (Y1), which is a compound of formula (Y) where R^ais hydrogen and R¹is methyl:

Processes for the preparation of compounds of formula (Y) are described in U.S. Pat. No. 3,931,195 which comprises the step of alkylating compounds of formula (i) (below) with an alkyl halide, such as methyl iodide for methylation. The same methylation step is described in EP0973741 for the synthesis of compound (Y1).

Thus, the processes described in the prior art involve the use of a highly toxic reagent (e.g. methyl iodide) and provides a yield of about 50%

US4064254 *	Oct 21, 1976	Dec 20, 1977	Mead Johnson & Company	Substituted piperidines therapeutic process and compositions
US5780487 *	Feb 28, 1997	Jul 14, 1998	Amer Moh Samir	S-2′- 2-(1-methyl-2-piperidyl) ethyl! cinnamanilide

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