ROSAPROSTOL

Uncategorized Comments Off

Jul 292015

Rosaprostol

CAS Registry Number: 56695-65-9

CAS Name: 2-Hexyl-5-hydroxycyclopentaneheptanoic acid

Additional Names: 9-hydroxy-19,20-bisnorprostanoic acid

Manufacturers’ Codes: C-83; IBI-C83

Trademarks: Rosal (IBI)

Molecular Formula: C18H34O3

Molecular Weight: 298.46

Percent Composition: C 72.44%, H 11.48%, O 16.08%

Derivative Type: Sodium salt

CAS Registry Number: 56695-66-0

Molecular Formula: C18H33NaO3

Molecular Weight: 320.44

Percent Composition: C 67.47%, H 10.38%, Na 7.17%, O 14.98%

Properties: White solid. LD50 orally in mice: ~3000 mg/kg (Valcavi, 1978); orally in rats: >5 g/kg (Valcavi, 1982).

Toxicity data: LD50 orally in mice: ~3000 mg/kg (Valcavi, 1978); orally in rats: >5 g/kg (Valcavi, 1982)

Therap-Cat: Antiulcerative.

J. Org. Chem. 1998, 63, 8894-8897

http://pubs.acs.org/doi/pdf/10.1021/jo981120g

A total synthesis of racemic rosaprostol, an untiulcer drug, has been achieved in seven synthetic steps and in 42% overall yield starting from dimethyl methanephosphonate. The key steps include intramolecular carbenoid cyclization of dimethyl 1-diazo-2-oxoundecanephosphonate 4 leading to 2-dimethoxyphosphoryl-3-hexylcyclopentanone 5 and the Horner−Wittig reaction of the latter with methyl 5-formylpentanecarboxylate 6 employed for the introduction of the methoxycarbonylhexyl moiety at C(2) of the cyclopentanone ring

1 (0.076 g, 95%) as a mixture of trans-trans and trans-cis isomers: Rf ) 0.18 and 0.23 (petroleum ether/Et2O/ AcOH 8:8:0.1);

1H NMR δ 4.19-4.10 (m, 1H), 3.92-3.80 (m, 1H), 2.18 (t, J ) 7.3, 4H), 2.10-1.96 (m, 1H), 1.82-0.85 (m, 51H), 0.93 (t, J ) 6.6, 6H);

13C NMR δ 180.13, 79.93, 75.13, 55.09, 52.71, 45.71, 43.02, 37.15, 36.33, 35.23, 34.95, 34.71, 34.61, 33.03, 30.86, 30.77, 30.69, 30.48, 30.12, 30.03, 29.53, 29.48, 29.21, 28.79, 28.67, 25.68, 23.81, 15.06;

HRMS (CI) (M + H – H2O)+ calcd for C18H33O2 281.2480, obsd 281.2476.

References: Prostaglandin analog. Prepn, hypolipemic, platelet aggregation inhibitory activity: U. Valcavi, DE 2535343,eidem, US 4073938 (1976, 1978 both to Ist. Biochim. Ital.).

Alternate process: V. Marotta, G. Zabban, EP 155392 (1985 to Ist. Biochim. Ital.).

Gastric antisecretory, cytoprotective activity: U. Valcavi et al., Arzneim.-Forsch. 32, 657 (1982).

Effect on mucus and gastrin secretion in duodenal ulcer: D. Foschi et al., Prostaglandins Leukotrienes Med. 15, 147 (1984). Comparison with cimetidine, q.v.: eidem, Drugs Exp. Clin. Res. 10, 427 (1984).

Clinical evaluation in treatment of ulcers: G. P. Tincani et al.,Minerva Med. 78, 847 (1987).

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Telescoping multistep reactions

PROCESS, SYNTHESIS Comments Off

Jul 292015

Telescoping multistep reactions

The synthesis of fine chemicals sometimes requires multiple reactions and tedious work-up between each step is often necessary. Purification may involve the addition of a quenching reagent, multiple aqueous and organic extractions, the addition of a drying agent, filtration, evaporation, and further purification by chromatography, distillation, or recrystallization. These operations all require significant input of energy and materials that ultimately end up as large amounts of waste. Methods and technologies that eliminate or simplify one or many of these steps can make a significant influence on the environmental impact of a multistep chemical synthesis. Continuous processing is particularly suitable for ‘telescoping’ reaction sequences, and many methods have been developed to facilitate this.¹

One strategy utilizes solid supported reagents packed into columns which allow starting materials to flow in and product to be collected at the outlet without requiring separation of the spent reagent. Different columns may be linked in series, allowing multistep processes to take place. Extra operations may also be necessary, such as solvent changes or the removal of unwanted side products. Methods for automating these processes have also been developed. An example from the Ley group illustrates many of these technologies in the design of a single apparatus to continuously prepareImatinib (Gleevec) from simple starting materials (Scheme 1).2Acid chloride 5 and aniline 6 in DCM were flowed through a cartridge containing immobilized DMAP as a nucleophilic catalyst, followed by a basic cartridge to scavenge any remaining 5. The formation of the amide 7 was monitored by an in-line UV spectrometer and subsequently added to a vial containing piperazine 8 in DMF at 50 °C, which facilitated evaporation of the DCM. Once a particular amount of 7 was obtained, as indicated by the UV spectrometer, a connected autosampler would collect this solution and pump it through an immobilized base to induce a substitution reaction, followed by an immobilized isonitrile to scavenge any remaining 8. An immobilized acid was used to ‘catch’ amine 9 through protonation, allowing unreacted 7 to go to waste. ‘Release’ of 9 through deprotonation followed by the addition of aniline 10 and a palladium catalyst facilitated a cross-coupling reaction, furnishing the crude Imatinib, which was then evaporated onto a silica gel column for automated chromatography. Pure product was isolated in 32% overall yield and >95% purity. While not explicitly demonstrated, the possibility of using this apparatus to form analogs by using modified starting materials is proposed. The ability to perform multi-step synthesis of pharmaceuticals without handling of the intermediates is particularly interesting, as exposure to these species can be hazardous.


	Scheme 1 Multistep synthesis of Imatinib (Gleevec).

The above example utilizes packed cartridges of scavengers to effect purification. An alternative method is to more closely emulate typical batch purification operations such as distillation andextraction, but on a small, continuous scale. Several different ‘chip’ purification devices have been developed for this purpose.^3-12 Some of these technologies were used together in a combined triflation/Heck reaction of phenols (Scheme2). After the initial triflation step in dichloromethane, the product is combined with a stream of aqueous HCl and passed on to a chip containing a membrane that allows the organic phase to pass through while the aqueous stream is passed to waste. The purified triflate then combines with a stream of DMF and the material enters a distillation device heated to 70 °C which allows the volatile dichloromethane to be carried out of the reactor with a stream of nitrogen gas. The product then enters a final reactor where it combines with a stream ofalkene and catalyst to form the Heck product. The whole reactor was operated continuously for 5.5 hours, generating approximately 32 mg of product per hour.


	Scheme 2 Triflation/Heck coupling facilitated by automated extraction and distillation.

Integration of multiple reaction steps, separations, and purifications into one continuous process has great potential for avoiding energy intensive and wasteful intermediate purification. While great progress has been made, the development of a truly general set of reagents, methods, and devices still requires more research. Immobilized reagents can be wasteful to scale up, and there are significant limitations to current microreactor extraction and distillation technologies. Crystallization is another very important technique in pharmaceutical synthesis, and while there are an increasing number of methods for continuous crystallization,14 15 , it is yet to be used as an intermediate purification step in an automated multi-step synthesis. Lastly, large scale applications of such complex, streamlined processes are required before a thorough assessment of their environmental impact in comparison with traditional batch routes can be made.

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Heterogeneous catalysis and catalyst recycling

MANUFACTURING, SYNTHESIS 1 Response »

Jul 282015

Heterogeneous catalysis and catalyst recycling

Heterogeneous catalysis is a type of catalysis in which the catalyst occupies a different phase from the reactants and products. This may refer to the physical phase — solid, liquid or gas — but also to immiscible fluids. Heterogeneous catalysts can be more easily recycled than homogeneous, but characterization of the catalyst and optimization of properties can be more difficult.

Heterogeneous catalysis is widely used in the synthesis of bulk and fine chemicals. In a general, small scale batch reaction, the catalyst, reactants, and solvent are stirred together until completion of the reaction, after which the bulk liquid is separated by filtration. The catalyst can then be collected for either recycling or disposal. In a continuous process, the catalyst can be fixed in space and the reaction mixture allowed to flow over it. The reaction and separation are thus combined in a single step, and the catalyst remains in the reactor for easy recycling. Beyond facilitating separation, thecatalyst may have improved lifetime due to decreased exposure to the environment, and reaction rates and turnover numbers can be enhanced through the use of high concentrations of a catalyst with continuous recycling. The benefits of flow are seemingly obvious, yet it has only recently become a widely adopted method for bench-scale synthesis.¹

Hydrogenation of ethene on a solid surface

The most common application of continuous heterogeneous catalysis is in hydrogenation reactions,² where the handling and separation of solid precious metal catalysts is not only tedious but hazardous under batch conditions. Moreover, the mixing between the three phases in a hydrogenation is generally quite poor. The use of a flow reactor gives a higher interfacial area between phases and thus more efficient reactions. For example, Ley and co-workers found that the hydrogenation of alkene 1 to 2 was challenging in batch, requiring multiple days at 80 bar of H₂ (Scheme 1).³ Using a commercially available H-Cube® reactor, the reaction time was shortened to 4 hours, the pressure reduced to 60 bar, and manual separation and recycling of the catalyst from the reaction was unnecessary. The increased efficiency is due to a combination of improved mixing of the three phases, as well as the continuous recycling and high local concentration of the catalyst. The H-Cube offers a further safety advantage because it generates hydrogen gas on demand from water, obviating the need for a high pressure H₂ tank.


	Scheme 1 Hydrogenation with an immobilized heterogeneous catalyst.

Homogeneous catalysis has many advantages over heterogeneous catalysis, such as increased activity and selectivity, and mechanisms of action that are more easily understood. Unfortunately, the difficulty associated with separating homogeneous catalysts from the product is a significant hindrance to their large scale application. In an attempt to combine the high activity of homogeneous catalysis with the practical advantageous of heterogeneous catalysis, there has been much research into immobilizing homogeneous catalysts on solid supports.⁴ This is generally achieved by linking thecatalyst to the surface of an insoluble solid such as silica or polymer beads. As was the case in batch hydrogenation reactions, the process of separating and purifying the catalyst is inefficient, potentially dangerous, and may lead to degradation and loss of material. Performing these reactions in a flow system can help overcome these problems.⁵ A highly efficient example has been demonstrated by van Leeuwen and co-workers, who sought to immobilize a catalyst used in transfer hydrogenation reactions (Scheme 2).6Their test reaction was the asymmetric reduction of acetophenone; homogeneousreduction with ruthenium and ligand 3 provided 88% conversion and 95% enantioselectivity. The ligand was then covalently linked to silica gel through the benzyl group to form 4. Using this heterogenized system under batch conditions, conversion dropped to 38% on the same time scale, and a slight decrease in enantioselectivity occurred. A reduction in activity of a catalyst upon immobilization is common, so highly efficient recycling is required. Unfortunately, when attempting to re-use the catalyst after filtration, significant degradation and leaching occurred. The catalyst was then packed in a glass column for application in flow chemistry. After a short optimization of flow rate, 95% conversion and 90% ee were obtained. Importantly, the reaction could be run continuously for up to one week without significant degradation in conversion or enantioselectivity. The physical isolation of catalyst species on the solid support is suggested to contribute to the long catalystlifetime. Interestingly, the basic potassium tert-butoxide additive was only required initially to activate the catalyst, and the reaction could subsequently be run without additional base, allowing the product to be isolated completely free of additives. It is important to note, on top of the decreased activity due to modification, that leaching from cleavage off the solid support and the increased cost of the catalyst due to derivatization are all potential downsides of immobilization of catalysts. In some instances, a seemingly heterogeneous catalyst has been shown to leach active homogeneous species into solution.⁷ However, as can be seen above, robust systems can be developed which do combine the best features of both homogeneous and heterogeneous catalysis.


	Scheme 7 Immobilization of a homogeneous catalyst on a solid support.

Another important method for recycling expensive catalysts is through the use of liquid–liquid biphasic conditions where the catalyst and reactants can be separated by extraction upon completion of the reaction. Such processes have already been utilized on the medium and large scale in a continuous or semi-continuous fashion.^8,9 Recycling on a small scale is typically done through batch liquid–liquid extractions, but examples using continuous methods are increasing.^10-13 A recent automated small scale recycling of a biphasic catalyst system was demonstrated by the George group in the continuous oxidation of citronellol (Scheme 3).14A highly fluorinated porphyrin was used as the photocatalyst, and a combination of hydrofluoroether (HFE) and scCO₂ was used as the solvent. Under high pressure flow conditions, a single phase was observed. Depressurization occurred after the reactor, resulting in two phases – the organic product in one, and the catalyst and HFE in the other. The denser, catalyst-containing fluorous phase was continuously pumped back through the reactor. With this method, the catalyst was recycled 10 times while maintaining 75% of its catalytic activity, giving an increase in TON of approximately 27-fold compared to previous batch conditions. Some leaching of the fluorinated catalyst into the organic product was observed, accounting for the decreased activity over time.


	Scheme 3 Automated recycling of a biphasic catalyst system.

*Examples of heterogeneous catalysisThe hydrogenation of a carbon-carbon double bond*The simplest example of this is the reaction between ethene and hydrogen in the presence of a nickel catalyst.In practice, this is a pointless reaction, because you are converting the extremely useful ethene into the relatively useless ethane. However, the same reaction will happen with any compound containing a carbon-carbon double bond.One important industrial use is in the hydrogenation of vegetable oils to make margarine, which also involves reacting a carbon-carbon double bond in the vegetable oil with hydrogen in the presence of a nickel catalyst.Ethene molecules are adsorbed on the surface of the nickel. The double bond between the carbon atoms breaks and the electrons are used to bond it to the nickel surface. Hydrogen molecules are also adsorbed on to the surface of the nickel. When this happens, the hydrogen molecules are broken into atoms. These can move around on the surface of the nickel. If a hydrogen atom diffuses close to one of the bonded carbons, the bond between the carbon and the nickel is replaced by one between the carbon and hydrogen. That end of the original ethene now breaks free of the surface, and eventually the same thing will happen at the other end. As before, one of the hydrogen atoms forms a bond with the carbon, and that end also breaks free. There is now space on the surface of the nickel for new reactant molecules to go through the whole process again. Catalytic converters** Catalytic converters change poisonous molecules like carbon monoxide and various nitrogen oxides in car exhausts into more harmless molecules like carbon dioxide and nitrogen. They use expensive metals like platinum, palladium and rhodium as the heterogeneous catalyst. The metals are deposited as thin layers onto a ceramic honeycomb. This maximises the surface area and keeps the amount of metal used to a minimum. Taking the reaction between carbon monoxide and nitrogen monoxide as typical:

Catalytic converters can be affected by *catalyst poisoning. This happens when something which isn’t a part of the reaction gets very strongly adsorbed onto the surface of the catalyst, preventing the normal reactants from reaching it.Lead is a familiar catalyst poison for catalytic converters. It coats the honeycomb of expensive metals and stops it working.In the past, lead compounds were added to petrol (gasoline) to make it burn more smoothly in the engine. But you can’t use a catalytic converter if you are using leaded fuel. So catalytic converters have not only helped remove poisonous gases like carbon monoxide and nitrogen oxides, but have also forced the removal of poisonous lead compounds from petrol. The use of vanadium(V) oxide in the Contact Process* During the Contact Process for manufacturing sulphuric acid, sulphur dioxide has to be converted into sulphur trioxide. This is done by passing sulphur dioxide and oxygen over a solid vanadium(V) oxide catalyst.

This example is slightly different from the previous ones because the gases actually react with the surface of the catalyst, temporarily changing it. It is a good example of the ability of transition metals and their compounds to act as catalysts because of their ability to change their oxidation state.

The sulphur dioxide is oxidised to sulphur trioxide by the vanadium(V) oxide. In the process, the vanadium(V) oxide is reduced to vanadium(IV) oxide.The vanadium(IV) oxide is then re-oxidised by the oxygen.This is a good example of the way that a catalyst can be changed during the course of a reaction. At the end of the reaction, though, it will be chemically the same as it started.

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How flow chemistry can make processes greener…………Supercritical fluids

PROCESS, SYNTHESIS, Uncategorized Comments Off

Jul 232015

Safe, small scale access to supercritical fluids

The ability to safely access high temperatures and pressures in flow reactors has implications not only on the rate of chemical reactions, but also on the types of solvents one can use. Many greensolvents such as methanol and acetone have boiling points too low for certain batch applications, whereas performing reactions at high pressure in a flow reactor may allow for their safe use at elevated temperatures.

Supercritical fluids are particularly interesting, since these solvents are entirely inaccessible without high pressure conditions. The use of supercritical fluids in a flow system offers numerous advantages over batch reactors.

Reactions may be performed on a small scale, improving safety and reducing the amount of material required. Depending on the type of reactor, it may be possible to visualize the reaction to evaluate the phase behaviour. Moreover, the reaction can be analyzed and the temperature and pressure subsequently changed without stopping the reaction and cleaning the vessel, as is necessary in a simple autoclave.

Continuous methods for utilizing supercritical fluids for extraction,¹ chromatography,² and as a reaction medium³ have all been commercialized, particularly for supercritical carbon dioxide (scCO₂).⁴ Academic examples using scMeOH, scH₂O, and scCO₂ for continuous reactions such as hydrogenations, esterifications, oxidations, and Friedel–Crafts reactions have been reported.⁵

A recent example that illustrates many of the green advantages of performing supercritical fluid chemistry in flow is in the ring opening of phthalic anhydride with methanol by Verboom and co-workers (Scheme 1).⁶ They designed a microreactor with a volume of just 0.32 μL that can withstand very high pressures.

The exceptionally small channel causes a large build-up of pressure, and supercritical conditions with pressures of up to 110 bar and temperatures up to 100 °C can occur inside the reactor, giving an ‘on-chip’ phase transition. The channel size increases near the outlet, allowing the fluid to expand to atmospheric conditions.

Thus, the total volume of scCO₂ under high pressure is exceptionally small, alleviating the major hazards of operating under supercritical conditions. The reaction was thoroughly studied on this small scale, allowing the authors to determine rate constants at several different temperatures and pressures.


	Scheme 1 Small scale continuous use of supercritical fluids.

Near- and supercritical water (scH₂O) can be an interesting green solvent only obtainable at very high temperature (T_c = 374 °C) and pressure (P_c = 221 bar). It is commonly used for completeoxidation of organic waste materials to CO₂; however, it has also been shown to be an effective solvent for selective oxidations.⁷ Given the harshness of the reaction conditions, it is not surprising that side product formation is common and highly dependent on the reaction time. For fast reactions in a batch reactor, precise control of reaction time is challenging, as the vessel takes time to heat and cool. In contrast, rapid heating, cooling, and quenching can be accomplished in a continuous process, allowing for well defined reaction times.

Fine tuning of the temperature, pressure, and time is also easier in a continuous process, as these variables can be changed without stopping and starting the reaction between samples. Thus, more data points can be obtained with less material and fewer heating and cooling cycles.

The Poliakoff group used these advantageous to perform a detailed study on the oxidation of p-xylene to terephthalic acid in scH₂O, a reaction carried out on industrial scale in acetic acid (Scheme 2).⁸ By using a flow reactor, reaction times as low as 9 seconds could be used. The equivalents of oxygen could also be finely varied on a small scale through the controlled thermal decomposition of H₂O₂.

Studying this aerobic oxidation with such precision in a batch process would prove highly challenging. Under optimal conditions, excellent selectivity for the desired product could be obtained. Further research by the same group identified improved conditions for this transformation.⁹


	Scheme 2 Selective oxidation in supercritical water.

Schematic Diagram of sample Supercritical CO2 system

Table 1. Critical properties of various solvents (Reid et al., 1987)
Solvent	Molecular weight	Critical temperature	Critical pressure	Critical density
Solvent	g/mol	K	MPa (atm)	g/cm³
Carbon dioxide (CO₂)	44.01	304.1	7.38 (72.8)	0.469
Water (H₂O) (acc. IAPWS)	18.015	647.096	22.064 (217.755)	0.322
Methane (CH₄)	16.04	190.4	4.60 (45.4)	0.162
Ethane (C₂H₆)	30.07	305.3	4.87 (48.1)	0.203
Propane (C₃H₈)	44.09	369.8	4.25 (41.9)	0.217
Ethylene (C₂H₄)	28.05	282.4	5.04 (49.7)	0.215
Propylene (C₃H₆)	42.08	364.9	4.60 (45.4)	0.232
Methanol (CH₃OH)	32.04	512.6	8.09 (79.8)	0.272
Ethanol (C₂H₅OH)	46.07	513.9	6.14 (60.6)	0.276
Acetone (C₃H₆O)	58.08	508.1	4.70 (46.4)	0.278
Nitrous oxide (N₂O)	44.013	306.57	7.35 (72.5)	0.452

Table 2 shows density, diffusivity and viscosity for typical liquids, gases and supercritical fluids.

Comparison of Gases, Supercritical Fluids and Liquids
	Density (kg/m³)	Viscosity (µPa∙s)	Diffusivity (mm²/s)
Gases	1	10	1–10
Supercritical Fluids	100–1000	50–100	0.01–0.1
Liquids	1000	500–1000	0.001

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Cyclopentene-1,3-dione derivative

PROCESS, spectroscopy, SYNTHESIS Comments Off

Jul 202015

the isolated cyclopentenedione derivative may have structure 1a or 1b or even exist as an equilibrium mixture between these two enol forms showing average ¹H and ¹³C NMR spectra due to a proposed rapid interconversion between 1a and 1b.

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532005000300024

Synthetic results

Our approach to cyclopentenedione derivative (1) started with the preparation of furylmethylcarbinol (3) by the reduction of commercially available 2-acetylfuran (2) with NaBH₄ (Scheme 2).⁵ Compound 3 was isolated in 98% yield and transformed into 4-hydroxy-5-methylcyclopenten-2-one (4) in 90% yield after treatment with ZnCl₂-HCl (pH 6.0) under reflux in dioxane-H₂O for 48 h.⁶ Upon treatment of 4-hydroxy-5-methylcyclopenten-2-one (4) with phosphate buffer (pH 8.0) in refluxing dioxane for 24 h, 4-hydroxy-2-methylcyclopenten-2-one (5) was obtained in 65% yield.⁷By using this strategy we were able to prepare up to gram quantities of hydroxyketone 5.

Diketone 6 was obtained in almost quantitative yield by the smooth oxidation of hydroxyketone 5 with MnO₂(Scheme 3).^8,9 At this point, all that remained was to carry out the necessary acylation coupling. It was with some gratification that we observed that the reaction between lithium enolate of diketone 6 and cinnamic anhydride 7 gave a 57:43 mixture of cyclopentenediones 1a/1b in 22% yield, after purification by flash column chromatography, together with starting material and by-products arising from O-acylation (Scheme 3).

In order to try to improve the yields for formation of 1a/1b, we tested a new synthetic route (Scheme 4). Protection of the OH-functionality in 5 with TESCl and imidazole at room temperature gave ketone 8 in 85% yield. Treatment of 8 with LDA in THF at –78 ºC, followed by slow addition of cinnamaldehyde, gave aldol adduct 9 as a mixture of diastereoisomers. Oxidation of the OH-function at C9 in allylic alcohol 9 under standard Swern¹¹ conditions followed by removal of the TES protecting group with TBAF in THF led to diol 10 in 60% overall yield. The last step involved treatment of diol 10 under standard Swern oxidation conditions, to give a 59:41 mixture of 1a/1b in 79% yield.¹¹

The correct structure for the natural product was confirmed as being 1a by the heteronuclear long-range coupling (ⁿJ_CH; n = 2,3,4) obtained by HMBC experiments in CDCl₃ as solvent. Heteronuclear long-range coupling of C11 (d_C 201.3) with H13 (d_H6.70,³J_CH) and H15 (d_H2.12, ³J_CH), as well as between C14 (d_C 191.8) with H13 (d_H6.70,²J_CH) and H15 (d_H2.12, ⁴J_CH) for 1a, together with the long-range coupling of C11 (d_C 200.7) with H12 (d_H6.61,²J_CH) and H15 (d_H2.11, ⁴J_CH), as well as between C14 (d_C 192.3) with H12 (d_H6.61,³J_CH) and H15 (d_H2.11 ppm, ³J_CH) for 1b, unambiguously established the correct structure as being 1a (Figure 10).

cyclopentenedione derivative (1) as a yellow solid. Rf 0.37 (30% EtOAc/Hexane); IR (film) n_max/cm^-1: 3428, 2965, 1632, 1589, 1266, 1103, 1023, 803, 742, 699; (HRMS) Exact mass calc. for C₁₅H₁₂O₃: 240.0786. Found: 240.0787.

Journal of the Brazilian Chemical Society

On-line version ISSN 1678-4790

J. Braz. Chem. Soc. vol.16 no.3a São Paulo May/June 2005

http://dx.doi.org/10.1590/S0103-50532005000300024

Short synthesis of a new cyclopentene-1,3-dione derivative isolated from Piper carniconnectivum

Luiz C. Dias^*; Simone B. Shimokomaki; Robson T. Shiota

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532005000300024

Instituto de Química, Universidade Estadual de Campinas, CP 6154, 13083-970 Campinas – SP, Brazil

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Flow chemistry can make processes greener….Swern oxidation

MANUFACTURING, PROCESS, SYNTHESIS Comments Off

Jul 202015

The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride,dimethyl sulfoxide (DMSO) and an organic base, such as triethylamine.The reaction is known for its mild character and wide tolerance of functional groups.

The by-products are dimethyl sulfide (Me₂S), carbon monoxide (CO), carbon dioxide (CO₂) and — when triethylamine is used as base — triethylammonium chloride (Et₃NHCl). Two of the by-products, dimethyl sulfide and carbon monoxide, are very toxic volatile compounds, so the reaction and the work-up needs to be performed in a fume hood.Dimethyl sulfide is a volatile liquid (B.P. 37 °C) with an extremely unpleasant odour.

The first step of the Swern oxidation is the low-temperature reaction of dimethyl sulfoxide (DMSO), 1a, formally as resonance contributor 1b, with oxalyl chloride, 2. The first intermediate, 3, quickly decomposes giving off CO₂ and CO and producing chloro(dimethyl)sulfonium chloride, 4.

After addition of the alcohol 5, the chloro(dimethyl)sulfonium chloride 4 reacts with the alcohol to give the key alkoxysulfonium ion intermediate, 6. The addition of at least 2 equivalents of base — typically triethylamine — will deprotonate the alkoxysulfonium ion to give the sulfur ylide 7. In a five-membered ring transition state, the sulfur ylide 7decomposes to give dimethyl sulfide and the desired ketone (or aldehyde) 8.

Dimethyl sulfide, a byproduct of the Swern oxidation, is one of the most foul odors known in organic chemistry. Human olfactory glands can detect this compound in concentrations as low as 0.02 to 0.1 parts per million. A simple remedy for this problem is to rinse used glassware with bleach (usually containing sodium hypochlorite), which will oxidize the dimethyl sulfide, eliminating the smell.

The reaction conditions allow oxidation of acid-sensitive compounds, which might decompose under the acidic conditions of a traditional method such as Jones oxidation. For example, in Thompson & Heathcock’s synthesis of the sesquiterpene isovelleral,the final step uses the Swern protocol, avoiding rearrangement of the acid-sensitive cyclopropanemethanol moiety.

Rapid, exothermic reactions are challenging to do in batch reactors. Reagents such as organometallics, strong bases, and highly active electrophiles are often added slowly to a reaction mixture under energy-intensive cryogenic conditions to prevent an uncontrollable exotherm. Quenching of these high-energy reagents may again require low temperature. This issue is scale dependent,1 and without proper precautions, both the likelihood and hazard of a runaway reaction increase with the size of a reactor.

The high surface area to volume ratio found in flow reactors makes heat transfer more efficient than in batch, allowing rapid removal of thermal energy given off. These features serve to give the chemist or engineer more control over reaction temperature and reduces the risk of thermal runaway.

Many instances have been reported of reactions being performed safely at 0 °C or room temperature in flow that would require cryogenic conditions in batch.^2,3,4 This has a further benefit on the overall processing time, as the reaction will occur faster at the elevated temperature and inefficient cooling and warming steps are avoided. A remarkable example demonstrating these principles is the room temperature Swern oxidation reaction by Yoshida and co-workers .⁵

The Swern reaction is a reliable procedure for converting alcohols to ketones and aldehydes using DMSOactivated by an electrophile (typically COCl₂ or TFAA) as the oxidant. In batch, the reaction takes place over three exothermic steps, each of which requires dropwise addition of reagents at cryogenic temperatures.^{6, 7}

PROCESS TO FLOW

When converting the process to flow, the Yoshida group found that the Swern oxidation could be done at room temperature with good yields and purity. Moreover, instead of having reaction times on the order of minutes or hours, the whole process was completed in seconds. They attributed the success of their process to the precise temperature control that can be obtained in flow systems, as well as the ability to quickly transfer unstable intermediates to subsequent steps. Using only a series of syringe pumps, stainless steel tubing, and commercial micromixers, they could prepare over 10 grams of material per hour. Being able to perform reactions on species with very short lifetimes is another general advantage of performing reactions in flow.⁸


	Scheme Room temperature Swern oxidation.

……………

MORE……..

http://thalesnano.com/products/IceCube

…………………

The Swern oxidation. The center column (green background) shows the desired chemical path, with added reagents shown in black boxes. The outer columns (red background) show the potential chemical pathways for side-product formation (8 and 9).

http://www.mdpi.com/2227-9717/2/1/24/htm

REF

R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew. Chem., Int. Ed., 2011, 50, 7502–7519
V. Hessel, C. Hofmann, H. Löwe, A. Meudt, S. Scherer, F. Schönfeld and B. Werner, Org. Process Res. Dev., 2004, 8, 511–523 Search PubMed.
A. Nagaki, Y. Tomida, H. Usutani, H. Kim, N. Takabayashi, T. Nokami, H. Okamoto and J.-i. Yoshida, Chem.–Asian J., 2007, 2, 1513–1523
T. Gustafsson, H. Sörensen and F. Pontén, Org. Process Res. Dev., 2012, 16, 925–929 Search PubMed.
T. Kawaguchi, H. Miyata, K. Ataka, K. Mae and J.-I. Yoshida, Angew. Chem., Int. Ed., 2005, 44, 2413–2416
A. K. Sharma and D. Swern, Tetrahedron Lett., 1974, 15, 1503–1506 Search PubMed.
A. K. Sharma, T. Ku, A. D. Dawson and D. Swern, J. Org. Chem., 1975, 40, 2758–2764
J.-i. Yoshida, Chem. Rec., 2010, 10, 332–341

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ETC-159

Uncategorized Comments Off

Jul 172015

ETC-159

Duke-NUS Graduate Medical School; Experimental Therapeutics Centre of Singapore

Cysteine palmitoyltransferase porcupine inhibitor

Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer

By Proffitt Kyle David; Madan Babita; Ke Zhiyuan; Pendharkar Vishal; Ding Lijun; Lee May Ann; Hannoush Rami N; Virshup David M

Cancer research (2013), 73(2), 502-7…..http://cancerres.aacrjournals.org/content/73/2/502.abstract

Ke, Z.; Madan, B.; Lim, S.Q.Y.; et al.

A novel porcupine inhibitor is effective in the treatment of cancers with RNF43 mutations
106th Annu Meet Am Assoc Cancer Res (AACR) (April 18-22, Philadelphia) 2015, Abst 4449

Madan, B.; Ke, Z.; Lim, S.Q.Y.; et al.
Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers
25th EORTC-NCI-AACR Symp Mol Targets Cancer Ther (October 19-23, Boston) 2013, Abst C248

2013 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics

C248: Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers
Tuesday, Oct 22, 2013, 12:30 PM – 3:00 PM
Babita Madan¹, Zhiyuan Ke², Shermaine Q.y. Lim², Jenefer Alam², Soo Yei Ho², Duraiswamy A. Jeyaraj², Kakaly Ghosh¹, Yun Shan Chew², Jamal Aliyev¹, Li Jun Ding², Vishal Pendharkar², Sifang Wang², Kanda Sangthongpitag², Thomas Keller², May Ann Lee², David M. Virshup¹. ¹Duke-NUS Graduate Medical School, Singapore, Singapore; ²Experimental Therapeutics Center, A*STAR, Singapore, Singapore

Abstract Number:	C248
Presentation Title:	Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers
Presentation Time:	Tuesday, Oct 22, 2013, 12:30 PM – 3:00 PM
Location:	Exhibit Hall C-D
Author Block:	Babita Madan¹, Zhiyuan Ke², Shermaine Q.y. Lim², Jenefer Alam², Soo Yei Ho², Duraiswamy A. Jeyaraj², Kakaly Ghosh¹, Yun Shan Chew², Jamal Aliyev¹, Li Jun Ding², Vishal Pendharkar², Sifang Wang², Kanda Sangthongpitag², Thomas Keller², May Ann Lee², David M. Virshup¹. ¹Duke-NUS Graduate Medical School, Singapore, Singapore; ²Experimental Therapeutics Center, A*STAR, Singapore, Singapore
Abstract Body:	Dysregulation of the Wnt signaling cascades is implicated in multiple disorders. There are 19 human Wnts that mediate signaling through diverse downstream pathways. To achieve maximum benefit from inhibition of Wnt signaling, targeting all of these pathways may be useful. The secretion and biological activity of all human Wnts requires palmitoylation mediated by Porcupine (PORCN), an endoplasmic reticulum-localized membrane bound O-acyltransferase. Several small molecule inhibitors of PORCN have been developed. Here we report a novel pharmacophore with derivatives that are nanomolar inhibitors of Wnt signaling. By a number of criteria, these compounds potently inhibit PORCN catalytic activity and hence suppress downstream Wnt-activated signaling pathways. The compounds effectively reduce autocrine Wnt signaling activity in selected cancer cell lines. The inhibitory activity is stereospecific, as an (R) enantiomer is inactive. Compounds with good oral bioavailability were tested for their in vivo activity and found to be highly efficacious in reversing tumor growth in both MMTV-WNT1 mice and of tumor xenografts. Treated tumors showed marked nuclear exclusion and decreased cytoplasmic staining of beta-catenin compared to vehicle controls. Importantly the treatment modulated downstream markers of Wnt signaling. No signs of toxicity were observed in mice at therapeutically effective doses. These results and our published results on C59 demonstrate that inhibiting the Wnt/beta-catenin pathway by targeting PORCN with small-molecule inhibitors is a feasible and nontoxic strategy. Use of porcupine inhibitors overcomes the problem of redundancy of Wnts, thereby, providing new options for therapy in diseases with high Wnt activity

Abstract C248: Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers.

+Author Affiliations

¹Duke-NUS Graduate Medical School, Singapore, Singapore
²Experimental Therapeutics Center, A*STAR, Singapore, Singapore

Abstract

Dysregulation of the Wnt signaling cascades is implicated in multiple disorders. There are 19 human Wnts that mediate signaling through diverse downstream pathways. To achieve maximum benefit from inhibition of Wnt signaling, targeting all of these pathways may be useful. The secretion and biological activity of all human Wnts requires palmitoylation mediated by Porcupine (PORCN), an endoplasmic reticulum-localized membrane bound O-acyltransferase. Several small molecule inhibitors of PORCN have been developed. Here we report a novel pharmacophore with derivatives that are nanomolar inhibitors of Wnt signaling. By a number of criteria, these compounds potently inhibit PORCN catalytic activity and hence suppress downstream Wnt-activated signaling pathways. The compounds effectively reduce autocrine Wnt signaling activity in selected cancer cell lines. The inhibitory activity is stereospecific, as an (R) enantiomer is inactive. Compounds with good oral bioavailability were tested for their in vivo activity and found to be highly efficacious in reversing tumor growth in both MMTV-WNT1 mice and of tumor xenografts. Treated tumors showed marked nuclear exclusion and decreased cytoplasmic staining of beta-catenin compared to vehicle controls. Importantly the treatment modulated downstream markers of Wnt signaling. No signs of toxicity were observed in mice at therapeutically effective doses. These results and our published results on C59 demonstrate that inhibiting the Wnt/beta-catenin pathway by targeting PORCN with small-molecule inhibitors is a feasible and nontoxic strategy. Use of porcupine inhibitors overcomes the problem of redundancy of Wnts, thereby, providing new options for therapy in diseases with high Wnt activity.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C248.

Citation Format: Babita Madan, Zhiyuan Ke, Shermaine Q.y. Lim, Jenefer Alam, Soo Yei Ho, Duraiswamy A. Jeyaraj, Kakaly Ghosh, Yun Shan Chew, Jamal Aliyev, Li Jun Ding, Vishal Pendharkar, Sifang Wang, Kanda Sangthongpitag, Thomas Keller, May Ann Lee, David M. Virshup. Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C248.

Made-in-Singapore cancer drug advances to clinical trials on humans

The drug, ETC-159, was developed in a collaboration between A*STAR and Duke-NUS, and is expected to target a range of cancers, including colorectal, ovarian and pancreatic cancers.

POSTED: 16 Jul 2015 10:13

Prof David Virshup (centre, in blazer) and the rest of the research teams. (Photo: A*STAR, Duke-NUS)

SINGAPORE: A made-in-Singapore cancer drug is touted to be the first publicly-funded drug candidate discovered and developed in Singapore to make it to trials on humans.

In a statement on Thursday (Jul 16), The Agency for Science, Technology and Research (A*STAR) and Duke-National University of Singapore Graduate Medical School (Duke-NUS), announced the start of the Phase I clinical trial of novel cancer drug candidate, ETC-159.

The Phase I clinical trial is meant to evaluate the safety and tolerability of ETC-159 in advanced solid tumours of up to 58 patients, and the first patient was dosed on Jun 18. The first two sites for the trial are the National Cancer Centre Singapore and the National University Hospital, and sites in the US will be added as the trial progresses.

The drug is expected to target a range of cancers, including colorectal, ovarian and pancreatic cancers. These cancers are linked to a group of cell signalling pathways known as Wnt signalling, which have been identified to promote cancer growth and spread, said the agencies. ETC-159 acts as an inhibitor of these pathways.

“This drug candidate therefore offers a promising novel and targeted cancer therapy that could shape future cancer therapeutic strategies,” said A*STAR and Duke-NUS.

ETC-159 was discovered and developed through a collaboration between A*STAR’s Experimental Therapeutics Centre (ETC), Drug Discovery and Development (D3) unit and Duke-NUS since 2009. It was based on the discovery work of Prof David Virshup from Duke-NUS.

Prof David Virshup, inaugural Director of the Programme in Cancer and Stem Cell Biology at Duke-NUS, said: “As the drug candidate provides a targeted cancer therapy, it could potentially minimise side effects and make cancer treatments more bearable for cancer patients.”

He added: “It is fitting that Singaporeans might be the first to benefit from this Singapore-developed drug.”

http://www.channelnewsasia.com/news/singapore/made-in-singapore-cancer/1988090.html?cid=FBSG

Duke-NUS Graduate Medical School, Singapore, Singapore

Map of duke nus

Babita MADAN

Assistant Professor

babita.madan@duke-nus.edu.sg

Kakaly GHOSH

Research Assistant

kakaly.ghosh@duke-nus.edu.sg

David VIRSHUP

Professor & Program Director

Cancer & Stem Cell Biology Program

Office no.:

+65 6516 6954

Lab no.:

+65 6516 1790

Email:

david.virshup@duke-nus.edu.sg

Administrative Support’s Email:

jamie.liew@duke-nus.edu.sg

Experimental Therapeutics Center, A*STAR, Singapore, Singapore

Map of Experimental Therapeutic Centre (ETC)

A*STAR Scientist Alex Matter Awarded Prestigious Szent-Gyorgyi Prize For Progress In Cancer

… of the Programme in Cancer and Stem Cell Biology at Duke-NUS, and Professor Alex Matter, chief executive of A*Star’s Experimental Therapeutics Centre

Kanda Sangthongpitag, Ph.D.

Group Leader, Preclinical Pharmacology

Kanda Sangthongpitag obtained a Bachelor of Science (nursing and midwifery) from Mahidol University and worked as the registered nurse in the EENT theatre at the Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand. She continued her studies and obtained a Master of Applied Science (Biotechnology) at the University of New South Wales, Sydney, Australia.

May Ann Lee, Ph.D.

Group Leader, Cell Based Assay Development

May Ann Lee completed her PhD in Molecular Biology in Epstein Barr Virus research from State University in New York at Buffalo. Molecular and Cell Biology Department, Roswell Park Cancer Institute in 1993. She did her postdoctoral training in HIV research in the Picower Institute of Medical Research in Manhasset, New York

Experimental Therapeutics Centre (ETC)

31 Biopolis Way
Nanos Level 3
Singapore 138669

Main: +65 6478 8767
Fax: +65 6478 8768
Enquiries: info@etc.a-star.edu.sg

////

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Application in Febuxostat synthesis

PROCESS, SYNTHESIS, Uncategorized Comments Off

Jul 172015

………..

Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions

Abstract

Electron-rich arenes bearing methyl or methoxy groups on the aromatic ring were treated with dichloromethyl methyl ether and ZnBr₂, and then with molecular iodine and aq. ammonia to give the corresponding aromatic nitriles in good yields. Using this method, febuxostat was efficiently prepared from 4-bromophenol in four steps. The method can be used for the preparation of aromatic nitriles from arenes in one pot under metal-cyanide-free conditions.

The nitrile moiety is an important group that is found in pharmaceuticals and agrochemicals. In addition the nitrile can serve as a stable intermediate for amides, carboxylic acids, ketones, aldehydes, etc. As a result, many methods to make nitriles have been reported. In a new publication Togo et al. report their development of a one-pot metal-cyanide-free protocol to make electron-rich aromatic nitriles ( Eur. J. Org. Chem. 2015, 2023). The reaction first reacts arenes with zinc bromide (ZnBr₂) and dichloromethyl methyl ether to make in situ the (dichloromethyl)arene, that then reacts with aq. ammonia and iodine to make the nitrile. The electron-rich aromatic nitriles are formed in moderate-to-high yields (59–94%). They demonstrate usefulness of this reaction by synthesizing febuxostat.

Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions

Toshiyuki Tamura,
Katsuhiko Moriyama and
Hideo Togo^*

Article first published online: 9 FEB 2015

Tamura, T., Moriyama, K. and Togo, H. (2015), Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions. Eur. J. Org. Chem., 2015: 2023–2029. doi: 10.1002/ejoc.201403672

Author Information

Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan, http://reaction-2.chem.chiba-u.jp/index.html

Email: Hideo Togo (togo@faculty.chiba-u.jp)

^*Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan

Issue

European Journal of Organic Chemistry

Volume 2015, Issue 9, pages 2023–2029, March 2015

http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201403672/abstract

What is SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem

diabetes, Uncategorized Comments Off

Jul 152015

A new “flozin” seems to me appearing on the horizon in form of SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem, picked up a list from WO 2012160218, from TFChem…….see link , Sirona Biochem Announces SGLT2 Inhibitor and Skin Lightening Patent Granted, 29 Jun 2015, Patent entitled “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars”

This led me to search, “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars”
WO 2012160218 A1, IN 2013-DN10635, CN 103649033Tf化学公司

Applicant

Tfchem

Figure imgf000110_0001

List above as in http://www.google.com/patents/WO2012160218A1?cl=en

FROM THE ABOVE LIST, SBM-TFC-039 MAY BE PREDICTED/OR AS SHOWN BELOW

COMPD 16 as in/WO2012160218

COMPD 16, PREDICTED/LIKELY SBM-TFC-039 has CAS 1413373-30-4, name D-myo-Inositol, 1-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1,2,3-trideoxy-2,2-difluoro-3-(hydroxymethyl)-

Just scrolling through the patent gave me more insight

MORE EVIDENCE….http://www.google.com/patents/WO2012160218A1?cl=en, this patent descibes compd 16 as follows

Compound 16 according to the invention has been compared to Dapaglifozin to underline the improvement of the duration of action, i.e. the longer duration of glucosuria, of the compound when the intracyclic oxygen atom of the glucose moiety is replaced by a CF₂ moiety.

This assay has been carried out at a dose of 3 mg/ kg.

The results obtained are presented on Figure 5. It appears thus that 16 (3 mg/kg) triggered glucosuria that lasted beyond 24 hours compared to Dapagliflozin.

• Compound 16 according to the invention has been compared to the compound 9 of WO 2009/1076550 to underline the improvement of the duration of action of the compound when a mimic of glucose bearing a CH-OH moiety instead of the intracyclic oxygen atom is replaced by a mimic of glucose bearing a CF₂ in place of the CH-OH moiet .

NOTE=COMPD 9 OF WO 2009/1076550 has CAS 1161430-16-5, D-scyllo– Inositol, 1-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1,3-dideoxy-3- (hydroxymethyl)- and is very similar to the compd under discussion

Company	Sirona Biochem Corp.
Description	Sodium-glucose cotransporter 2 (SGLT2) inhibitor
Molecular Target	Sodium-glucose cotransporter 2 (SGLT2)
Mechanism of Action	Sodium-glucose cotransporter 2 (SGLT2) inhibitor
Therapeutic Modality	Small molecule

Latest Stage of Development	Preclinical
Standard Indication	Diabetes
Indication Details	Treat Type II diabetes
Regulatory Designation
Partner	Shanghai Fosun Pharmaceutical Group Co. Ltd.

SBM-TFC-039

PATENT

WO 2012160218

http://www.google.com/patents/WO2012160218A1?cl=en

Examples within this first subclass include but are not limited to:

Synthesis of compound 8

C35H34O5 M = 534.64 g.mol^“

Mass: (ESI ): 535.00 (M + H); 552.00 (M + H₂0); 785.87; 1086.67 (2M + H₂0)

Procedure A:

To a solution of 4 (10.5g, 15.89mmol, leq) in toluene (400mL) were added 18-crown-6 (168mg, 0.64mmol, 0.04eq) and potassium carbonate (6.69g, 48.5mmol, 3.05eq.). The mixture was stirred overnight at room temperature, and then the remising insoluble material was filtered off and washed with toluene. The filtrate and the washings were combined, washed with 2N hydrochloric acid aqueous solution followed by saturated sodium hydrogencarbonate aqueous solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford cyclohexenone 8 (4.07g; 48% yield) as yellowish oil.

Procedure B:

A solution of 7 (3.27g, 5.92mmol, leq) in pyridine (14mL) was cooled to 0°C before POCl₃ (2.75mL, 29.6mmol, 5eq) was added dropwise. The mixture was stirred at this temperature for 10 min before the cooling bath was removed. The reaction mixture was stirred overnight at room temperature before being re-cooled to 0°C. POCI3 (2.75mL, 29.6mmol, 5eq) was added once again trying to complete the reaction. The mixture was stirred for an additional 20h at room temperature before being diluted with Et₂0 (20mL) and poured onto crushed ice. 1M HC1 aqueous solution (lOOmL) was added, and the mixture was extracted with Et₂0 (200mL & l OOmL). The combined organic extracts were washed with brine (lOOmL), dried over sodium sulphate, filtered and concentrated before being purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 80:20) to afford compound 8 (1.46g, 46% yield) as an orange oil. Synthesis of compound 9

C₁₅H₁₂BrC10₂ M = 339.61 g.moF¹

Mass: (GC-MS): 338-340

The synthesis of this product is described in J. Med. Chem. 2008, 51, 1 145—1149.Synthesis of compound 10

C15H14B1CIO M = 325.63 g.mof¹

10 The synthesis of this product is described in J. Med. Chem. 2008, 51, 1145-1 149.

Synthesis of compound 11

C50H49CIO6 M = 781.37 g.moF¹

Mass: ESI⁺): 798.20 (M + H₂0)

Under inert atmosphere, Mg powder (265mg, 10.9mmol, 2.4eq) was charged into a three necked flask, followed by addition of a portion of 1/3 of a solution of the 4- bromo-l-chloro-2-(4-ethylbenzyl)benzene (2.95g, 9.1mmol; 2eq) in dry THF (25mL) and 1 ,2-dibromoethane (10 mol % of Mg; 85mg; 0.45mmol). The mixture was heated to reflux. After the reaction was initiated (exothermic and consuming of Mg), the remaining solution of 2-(4-ethylbenzyl)-4-bromo-l-chlorobenzene in dry TFIF was added dropwise. The mixture was then allowed to react for another one hour under gentle reflux until most of the Mg was consumed.

The above Grignard reagent was added dropwise into the solution of cyclohexenone 8 (2.42g, 4.53mmol, leq) in dry THF (25mL) under inert atmosphere at room temperature (about 25°C), then allowed to react for 3h. A saturated aqueous solution of ammonium chloride was added into the mixture to quench the reaction. The mixture was extracted with Et₂0, washed with brine, dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 100:0 to 80:20) to afford the target compound 11 as a yellow oil (3.01g, 86%).

Synthesis of compound 12

C₅oH49C10₅ M = 765.37 g.mol^“1

+): 782.13 (M + H₂0)

Triethylsilane (0.210mL, 1.30mmol, 3eq) and boron-trifluoride etherate (48% BF₃, O. l lOmL, 0.866mmol, 2eq) were successively added into a solution of alcohol 1 1 (338mg, 0.433mmol, leq) in dichloromethane (5mL) under inert atmosphere at -20°C. After stirring for 2.5h, a saturated aqueous solution of sodium chloride was added to quench the reaction. The mixture was extracted with CH₂C1₂ (10mLx3) and the organic layer was washed with brine, dried over Na₂S0₄, filtrated and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 9.8:0.2 to 8:2) to afford the target compound 12 as a white powder (278 mg, 0.363mmol, 84%).

Synthesis of compound 13

C₅oH_5tC10₆ M = 783.39g.moF¹

Mass: (ESI⁺): 800 (M + H₂0); 1581 (2M + H₂0)

Under inert atmosphere, borane-dimethyl sulfide complex (2M in THF, 16.7mL, 33mmol, 10.5eq) was added to a solution of 12 (2.41g; 3.15mmol, leq) in dry THF (lOOmL) cooled to 0°C. The reaction mixture was then refluxed for lh,cooled to 0°C and treated carefully with sodium hydroxide (3M in H₂0, 10.5mL, 31.5mmol, lOeq), followed by hydrogen peroxide (30% in H₂0, 3.2mL, 31.5mmol, l Oeq) at room temperature (above 30°C). The mixture was allowed to react overnight at room temperature (~25°C) before a saturated aqueous solution of ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate 97:3 to 73:27) to afford the desired compound 13 (1.05g; 43%) as a yellowish oil.

Synthesis of compound 14

C50H49CIO6 M = 781.37g.mol^“1

Mass: (ESI⁺): 798 (M + H₂0); 1471; 1579 (2M + H₂0)

13 14

Dess-Martin periodinane (81mg; 1.91mmol; 1.5eq) was added portion wise to a solution of alcohol 13 (l .Og; 1.28mmol, leq) in anhydrous dichloromethane (20mL) at 0°C. The reaction was then stirred overnight at room temperature before being quenched with IN aqueous solution of sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 82: 18), to afford the target ketone 14 (783mg, 79% yield) as a colorless oil. Synthesis of compound 15

C₅oH49ClF₂0₆ M = 803.37g.moF¹

¹⁹ F NMR (CDCU, 282.5MHz): -100.3 (d, J=254Hz, IF, CFF); -1 13.3 (td, Jl=254Hz, J2=29Hz, IF, CFF).

Mass: (ESI⁺): 820.00 (M+H₂0)

14 15

A solution of ketone 14 (421mg, 0.539mmol, leq) in DAST (2mL, 16.3mmol, 30eq.) was stirred under inert atmosphere at 70°C for 12h. The mixture was then cooled to room temperature and dichloromethane was added. The solution was poured on a mixture of water, ice and solid NaHC0₃. Agitation was maintained for 30min while reaching room temperature. The aqueous layer was extracted with dichloromethane and the organic phase was dried over Na₂S0₄, filtered and concentrated. The crude product was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford the desired compound 15 as a yellowish oil ( 182mg, 42% yield).

Synthesis of compound 16

C22H25CIF2O5 M = 442.88g.mor¹

¹⁹ F NMR (MeOD, 282.5MHz): -96.7 (d, J=254Hz, IF, CFF); 12.2 (td,

Jl=254Hz, J2=28Hz, IF, CFF).

Mass: (ESI⁺): 465.3 (M+Na)

o-Dichlorobenzene (0.320mL, 2.82mol, lOeq) followed by Pd/C 10% (0.342g, 0.32mol, l .leq) were added to a solution of 15 (228mg, 0.28mmol, leq) in a mixture of THF and MeOH (2: 1, v/v, 160mL). The reaction was placed under hydrogen atmosphere and stirred at room temperature for 2h. The reaction mixture was filtered and concentrated before being purified on silica gel chromatography (dichloromethane/methanol 100: 1 to 90: 10) to afford compound 16 (105mg, 83% yield).

…………………….

CN 103649033

http://www.google.com/patents/CN103649033A?cl=en

Sirona Biochem’s SGLT Inhibitor Performs Better Than Johnson and Johnson’s SGLT Inhibitor, According to Study

Vancouver, British Columbia – December 7, 2012 – Sirona Biochem Corp. (TSX-V: SBM), announced its sodium glucose transporter (SGLT) inhibitor for Type 2 diabetes reduced blood glucose more effectively than Johnson and Johnson’s canagliflozin, an advanced SGLT inhibitor being considered for market approval in Europe and the U.S. Studies compared Sirona Biochem’s SGLT Inhibitor, SBM-TFC-039, with canagliflozin and were conducted on Zucker Diabetic Fatty (ZDF) rats.

In the study, SBM-TFC-039 significantly and rapidly reduced blood glucose levels at a dose of 1.0 mg/kg. Six (6) hours after administration, SBM-TFC-039 reduced blood glucose by 44% compared to canagliflozin at 26%. SBM-TFC-039 also had a longer duration of effect than canagliflozin. At 36 and 48 hours after treatment, SBM-TFC-039, at a dose of 1.0 mg/kg, was still effective at reducing blood glucose, whereas canagliflozin lost its effect after 36 hours. Studies were conducted at the Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ) by Principal Investigator Dr. Denis Richard, Research Chair on Obesity and Professor, Faculty of Medicine, Department of Anatomy & Physiology at Laval University.

“SGLT Inhibitors are a ground-breaking new treatment for Type 2 diabetes and these results demonstrate that SBM-TFC-039 will be a significant competitor for other SGLT Inhibitors,” said Neil Belenkie, Chief Executive Officer of Sirona Biochem. “The first SGLT Inhibitor,Forxiga™, was approved last month by the European Commission. We believe there is tremendous market potential worldwide for SGLT Inhibitors in the treatment of diabetes.”

SBM-TFC-039 is a sodium glucose transporter (SGLT) inhibitor. SGLT inhibitors are a new class of drug candidates for the treatment of diabetes. In the kidneys, SGLT inhibitors reduce the reabsorption of glucose into the bloodstream by eliminating excess glucose into the urine.

About Sirona Biochem Corp.
Sirona Biochem is a biotechnology company developing diabetes therapeutics, skin depigmenting and anti-aging agents for cosmetic use, biological ingredients and cancer vaccine antigens. The company utilizes a proprietary chemistry technique to improve pharmaceutical properties of carbohydrate-based molecules. For more information visit www.sironabiochem.com.

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Fispemifene for hypogonadism

phase 2, Uncategorized Comments Off

Jul 142015

Fispemifene, HM 101

Fispemifene; UNII-3VZ2833V08;

cas 341524-89-8

Molecular Formula:	C₂₆H₂₇ClO₃
Molecular Weight:	422.94378 g/mol

2-[2-[4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]ethoxy]ethanol

Treatment of Hypogonadism

Androgen Decline in the Aging Male (Andropause) in phase 2

Fispemifene is the Z-isomer of the compound of formula (I)

WO 01/36360 describes a group of SERMs, which are tissue-specific estrogens and which can be used in women in the treatment of climacteric symptoms, osteoporosis, Alzheimer’s disease and/or cardiovascular diseases without the carcinogenic risk. Certain compounds can be given to men to protect them against osteoporosis, cardiovascular diseases and Alzheimer’s disease without estrogenic adverse events (gynecomastia, decreased libido etc.). Of the compounds described in said patent publication, the compound (Z)-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol (also known under the generic name fispemifene) has shown a very interesting hormonal profile suggesting that it will be especially valuable for treating disorders in men. WO 2004/108645 and WO 2006/024689 suggest the use of fispemifene for treatment or prevention of age-related symptoms in men, such as lower urinary tract symptoms and diseases or disorders related to androgen deficiency in men.

Quatrx had been conducting phase II clinical development for the treatment of androgen decline in the aging male. Unlike testosterone replacement therapies that are typically topical or injection therapies, fispemifene is an oral treatment and is not a formulation of testosterone. Fispemifene utilizes the body’s normal feedback mechanism to increase testosterone levels. Originally developed at Hormos, QuatRx gained rights to the drug candidate following a merger of the companies pursuant to which Hormos became a wholly-owned subsidiary of QuatRx.

Known methods for the syntheses of compounds like ospemifene and fispemifene include rather many steps. WO 02/090305 describes a method for the preparation of fispemifene, where, in a first step, a triphenylbutane compound with a dihydroxysubstituted butane chain is obtained. This compound is in a second step converted to a triphenylbutene where the chain is 4-chlorosubstituted. Then the desired Z-isomer is crystallized. Finally, the protecting group is removed to release the ethanol-ethoxy chain of the molecule.

Fispemifene is a selective estrogen receptor modulator (SERM) studied in phase II clinical trials at Forendo Pharma for the treatment low testosterone in men. The compound is also in phase II clinical studies at Apricus for the treatment of men with secondary hypogonadism.

In 2013, Forendo Pharma acquired the drug from Hormos Medical for the treatment of male low testosterone.

In 2014, Apricus Biosciences acquired U.S. rights for development and commercialization

PATENT

https://www.google.com/patents/US7504530

EXAMPLE 2 2-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-ethanol (Compound I)

{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-acetic acid ethyl ester was dissolved in tetrahydrofuran at room temperature under nitrogen atmosphere. Lithium aluminium hydride was added to the solution in small portions until the reduction reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution. The product was extracted into toluene, which was dried and evaporated in vacuo. The residue was purified with flash chromatography with toluene/triethyl amine (9.5:0.5) as eluent. Yield 68%.

¹H NMR (200 MHz, CDCl₃):

2.92 (t, 2H, ═CH ₂CH₂Cl),

3.42 (t, 2H, ═CH₂ CH₂ Cl),

3.59-3.64 (m, 2H, OCH₂CH₂O CH₂CH ₂OH),

3.69-3.80 (m, 4H, OCH₂ CH ₂OCH ₂CH₂OH),

3.97-4.02 (m, 2H, OCH₂CH₂OCH₂CH₂OH),

6.57 (d, 2H, aromatic proton ortho to oxygen),

6.78 (d, 2H, aromatic proton meta to oxygen),

7.1-7.43 (m, 10H, aromatic protons).

………….

PATENT

WO 2001036360

https://www.google.com/patents/WO2001036360A1?cl=en

……………

PATENT

WO 2002090305

http://www.google.co.in/patents/WO2002090305A1?cl=en

EXAMPLE

a) [2-(2-chloroethoxy)ethoxymethyl]benzene

is prepared from benzyl bromide and 2-(2-chloroethoxy)ethanol by the method described in literature (Bessodes, 1996).

b) {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}phenylmethanone

The mixture of 4-hydroxybenzophenone (16.7 g, 84.7 mmol) and 48 % aqueous sodium hydroxide solution (170 ml) is heated to 80 °C. Tetrabutylammonium bromide (TBABr) (1.6 g, 5.1 mmol) is added and the mixture is heated to 90 °C. [2-(2-Chloroethoxy)ethoxymethyl]benzene (18. g, 84.7 mmol) is added to the mixture during 15 min and the stirring is continued for additional 3.5 h at 115-120 °C. Then the mixture is cooled to 70 °C and 170 ml of water and 170 ml of toluene are added to the reaction mixture and stirring is continued for 5 min. The layers are separated and the aqueous phase is extracted twice with 50 ml of toluene. The organic phases are combined and washed with water, dried with sodium sulphate and evaporated to dryness. Yield 31.2 g.

Another method to prepare {4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}phenyl- methanone is the reaction of 2-(2-benzyloxyethoxy)ethyl mesylate with 4- hydroxybenzophenone in PTC-conditions.

Η NMR (CDCI3): 3.64-3.69 (m, 2H), 3.74-3.79 (m, 2H), 3.90 (dist.t, 2H), 4.22 (dist.t, 2H), 4.58 (s, 2H), 6.98 (d, 2H), 7.28-7.62 (m, 8H), 7.75 (td, 2H), 7.81 (d, 2H).

c) 1- {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol

Figure imgf000013_0002 R = BENZYL

Lithium aluminum hydride (1.08 g, 28.6 mmol) is added into dry tetrahydrofuran (60 ml) under nitrogen atmosphere. Cinnamaldehyde (6.65 g, 50 mmol) in dry tetrahydrofuran (16 ml) is added at 24-28 °C. The reaction mixture is stirred at ambient temperature for 1 h. {4-[2-(2- Benzyloxyethoxy)ethoxy]phenyl}-phenyl-methanone (14.0 g, 37 mmol) in dry tetrahydrofuran (16 ml) is added at 50-55 °C. The reaction mixture is stirred at 60 °C for 3 h. Most of tetrahydrofuran is evaporated. Toluene (70 ml) and 2 M aqueous hydrogen chloride (50 ml) are added. The mixture is stirred for 5 min and the aqueous layer is separated and extracted with toluene (30 ml). The toluene layers are combined and washed with 2M HC1 and water, dried and evaporated. The product is crystallized from isopropanol as a mixture of stereoisomers (8.8 g, 50 %).

Η NMR (CDCI3 ): 1.75-2.10 (m, 2H), 3.20-4.16 (m, 1 OH), 4.52 and 4.55 (2s, together 2H), 6.61 and 6.88 (2d, together 2H), 6.95-7.39 (m, 15H), 7.49 and 7.57 (2d, together 2H).

d) Z- 1 – {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl-but- 1-ene

Figure imgf000013_0003 R = BENZYL

1 – {4- [2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol (10.0 g, 19.5 mmol) is dissolved in toluene (50 ml). Triethylamine (2.17 g, 21.4 mmol) is added to the solution and the mixture is cooled to -10 °C. Thionyl chloride (6.9 g, 58.5 mmol) is added to the mixture at -10 – ±0 °C. The mixture is stirred for 1 hour at 0-5 °C, warmed up to 70 °C and stirred at this temperature for 4 hours. Solvent is evaporated, the residue is dissolved to toluene, washed three times with 1M HC1 solution and twice with water. The Z-isomer of the product is crystallized from isopropanol-ethyl acetate. Yield 3.0 g. The filtrate is purified by flash chromatography to give E-isomer.

Z-isomer: Η NMR (CDCI3): 2.91 (t, 2H), 3.41 (t, 2H), 3.55-3.85 (m, 6H), 3.99 (dist.t, 2H), 4.54 (s, 2H), 6.40 (s, 1H), 6.56 (d, 2H), 6.77 (d, 2H), 7.10- 7.50 (m, 15H)

E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.82 (m, 4H), 3.88 (dist.t, 2H), 4.15 (dist.t, 2H), 4.58 (s, 2H), 6.86 -7.45 (m, 19H)

FINAL STEP

e) 2- {2-[4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy } ethanol:

Z- 1 – {4-[2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl -but- 1-ene (3.8 g, 7.4 mmol) is dissolved in ethyl acetate under nitrogen atmosphere , Zn powder (0.12 g, 1.85 mmol) and acetyl chloride (1.27 g, 16.3 mmol) are added and the mixture is stirred at 50 °C for 3 h (Bhar, 1995). The reaction mixture is cooled to room temperature, water (10 ml) is added and stirring is continued for additional 10 min. The aqueous layer is separated and the organic phase is washed with 1 M aqueous hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in methanol (16 ml) and water (4 ml). The acetate ester of the product is hydrolysed by making the mixture alkaline with sodium hydroxide (1 g) and stirring the mixture at room temperature for 1 h. Methanol is evaporated, water is added and the residue is extracted in ethyl acetate and washed with 1 M hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in toluene (25 ml), silica gel (0.25 g) is added and mixture is stirred for 15 min. Toluene is filtered and evaporated to dryness. The residue is crystallised from heptane-ethyl acetate (2:1). The yield is 71 %.

Z-isomer: 1H NMR (CDCI3): 2.92 (t, 2H), 3.41 (t, 2H), 3.58-3.63 (m, 2H), 3.69-3.80 (m, 4H), 3.96-4.01 (m, 2H), 6.56 (d, 2H), 6.78 (d, 2H), 7.10-7.40 (m, 10H).

Z ISOMER IE FISPEMIFENE

E-2- {2- [4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy} ethanol is prepared analogously starting from E-l-{4-[2-(2-benzyloxy- ethoxy)ethoxy]phenyl} -4-chloro- 1,2-diphenyl-but-l-ene. The product is purified by flash chromatography with toluene-methanol (10:0.5) as eluent.

E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.79 (m, 4H), 3.85-3.90 (m, 2H), 4.13-4.17 (m, 2H), 6.85-7.25 (m, 2H).

Debenzylation of 1 – {4-[2-(2-benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2- diphenyl-but- 1-ene is also carried out by hydrogenation with Pd on carbon as a catalyst in ethyl acetate-ethanol solution at room temperature.

………….

PATENT

http://www.google.com/patents/US5491173

Patent	Submitted	Granted
Method for the preparation of 2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol and its isomers [US6891070]	2004-06-17	2005-05-10
Formulations of fispemifene [US2007104743]	2007-05-10
METHODS FOR THE PREPARATION OF FISPEMIFENE FROM OSPEMIFENE [US7504530]	2008-09-04	2009-03-17
METHOD FOR THE PREPARATION OF THERAPEUTICALLY VALUABLE TRIPHENYLBUTENE DERIVATIVES [US2011015448]	2011-01-20
METHOD FOR THE PREPARATION OF THERAPEUTICALLY VALUABLE TRIPHENYLBUTENE DERIVATIVES [US7812197]	2008-08-28	2010-10-12

WO2001036360A1	1 Nov 2000	25 May 2001	Pirkko Haerkoenen	Triphenylalkene derivatives and their use as selective estrogen receptor modulators
EP0095875A2	20 May 1983	7 Dec 1983	Farmos Group Ltd.	Novel tri-phenyl alkane and alkene derivatives and their preparation and use

Citing Patent	Filing date	Publication date	Applicant	Title
WO2008099059A1 *	13 Feb 2008	21 Aug 2008	Hormos Medical Ltd	Method for the preparation of therapeutically valuable triphenylbutene derivatives
WO2008099060A2 *	13 Feb 2008	21 Aug 2008	Hormos Medical Ltd	Methods for the preparation of fispemifene from ospemifene
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EP1636159A1 *	5 May 2004	22 Mar 2006	Hormos Medical Ltd.	Method for the treatment or prevention of lower urinary tract symptoms
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US7504530	13 Feb 2008	17 Mar 2009	Hormos Medical Ltd.	Methods for the preparation of fispemifene from ospemifene
US7812197	13 Feb 2008	12 Oct 2010	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
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US8962693	19 Aug 2013	24 Feb 2015	Hormos Medical Ltd.	Method for the treatment or prevention of lower urinary tract symptoms

WO2002090305A1	Mar 21, 2002	Nov 14, 2002	Hormos Medical Corp	A new method for the preparation of 2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol and its isomers
WO2004108645A1	May 5, 2004	Dec 16, 2004	Hormos Medical Corp	Method for the treatment or prevention of lower urinary tract symptoms
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EP2518039A1	Feb 13, 2008	Oct 31, 2012	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
EP2821385A2	Feb 13, 2008	Jan 7, 2015	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
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US7504530	Feb 13, 2008	Mar 17, 2009	Hormos Medical Ltd.	Methods for the preparation of fispemifene from ospemifene
US7560589	Jul 27, 2004	Jul 14, 2009	Smithkline Beecham Corporation	Cycloalkylidene compounds as modulators of estrogen receptor
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