The diastereomeric ratio (dr) of the allylation products is determined by 1H and19F NMR spectroscopy,

Xiao-Yang Chen , Li-Sen Sun , Xiang Gao , andXing-Wen Sun *

Department of Chemistry, Fudan University, 220 Handan Road, Shanghai, Shanghai 200433, China

J. Chem. Educ., Article ASAP

DOI: 10.1021/ed500292q

Publication Date (Web): January 23, 2015

Copyright © 2015 The American Chemical Society and Division of Chemical Education, Inc.

*E-mail: sunxingwen@fudan.edu.cn.

Diastereoselective Allylation of N-tert-Butanesulfinyl Imines: An Asymmetric Synthesis Experiment for the Undergraduate Organic Laboratory

An asymmetric synthetic experiment that encompasses both diastereoselectivity and enantioselectivity is described. In this experiment, Zn-mediated allylation of an (R)-N-tert-butanesulfinyl imine is first performed to obtain either diastereomer using two different solvent systems, followed by oxidation of the homoallylic N-tert-butanesulfinyl amines, which gives either enantiomer of the corresponding products. Purification by flash column chromatography is required at the final step and the desired products are isolated in good overall yields. The diastereomeric ratio (dr) of the allylation products is determined by 1H and19F NMR spectroscopy, while the enantiomeric excess (ee) of the final products is measured by chiral HPLC. Overall, this experiment can be carried out with readily accessible reagents under mild conditions. Moreover, it enables students to learn the differences between enantiomers and diastereomers, the determination of ee and dr regarding optical compounds using HPLC and NMR spectroscopy, and how a reversal of stereochemical outcome is realized simply by tuning the reaction solvent.




NMR analyses of the homoallylic N-tert-butanesulfinyl amines obtained from the THF system (left) and the DMF system (right).

化学系

www.chemistry.fudan.edu.cn/

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EDIVOXETINE

EDIVOXETINE, LY 2216684

(1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol

UNII-3W9N3F4JOO, 1194508-25-2, Edivoxetine [USAN], Edivoxetine (USAN/INN), Edivoxetine [USAN:INN], 3W9N3F4JOO

Molecular Formula:C18H26FNO4

Molecular Weight:339.401743 g/mol

Edivoxetine (INN; LY-2216684) is a drug which acts as a selective norepinephrine reuptake inhibitor and is currently under development by Eli Lilly for attention-deficit hyperactivity disorder (ADHD) and as an antidepressant treatment.[1][2] It was in phase IIIclinical trials, in 2012, for major depressive disorder, but failed to get approval.[1][3]

Effectiveness

In a study published in 2010, edivoxetine failed to prove superiority over placebo, as measured by Hamilton Depression Rating Scale. However, effectiveness could be observed using the Self-Rated Quick Inventory of Depressive Symptomatology.[4]

In a study published in 2011, using the Montgomery-Åsberg Depression Rating Scale and the Sheehan Disability Scale, edivoxetine showed superiority over placebo, with higher response and remission rates.[5]

In December 2013, Eli Lilly announced that the clinical development of edivoxetine will be stopped due to lack of efficacy compared to SSRI alone in three separate clinical trials.[6]

Side effects

Side effects significantly associated with edivoxetine are headache, nausea, constipation, dry mouth and insomnia.[4]

The above mention studies report increases of the cardiac rhythm, and one also increases of diastolic and systolic blood pressures.[4][5]

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/op5003825

http://pubs.acs.org/doi/abs/10.1021/op5003825

There is a growing trend in Ireland toward greater collaboration between academia and the pharmaceutical industry. This is an activity encouraged at a national policy level as a means of providing researchers from academic institutions the opportunity to gain important first-hand experience in a commercial research environment, while also providing industry access to expertise and resources to develop new and improved processes for timely medicines. The participating company benefits in terms of its growth, the evolution of its strategic research and development, and the creation of new knowledge that it can use to generate commercial advantage. The research institute benefits in terms of developing skill sets, intellectual property, and publications, in addition to access to identified current industry challenges. A case study is provided describing the collaborative partnership between a synthetic chemistry research team at University College Cork (UCC) and Eli Lilly and Company.

Anita R. Maguire * ,

Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre,University College Cork, Cork, Ireland

E-mail: a.maguire@ucc.ie.

University College Cork

http://www.ucc.ie/en/support/senior-mgt/researchandinnovation/

http://chemweb.ucc.ie/people/amaguire.htm

SYSTEMATIC (IUPAC) NAME
(1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(tetrahydro-2H-pyran-4-yl)ethanol
CLINICAL DATA
LEGAL STATUS	?
IDENTIFIERS
CAS NUMBER	1194508-25-2 1194374-05-4 (hydrochloride)
ATC CODE	None
PUBCHEM	CID 11186829
CHEMSPIDER	9361913
CHEMICAL DATA
FORMULA	C18H26FNO4
MOLECULAR MASS	339.402 g/mol

References

1.  Jun Yan (March 2012). “Pipeline for new antidepressants flowing slowly”. Psychiatric News (American Psychiatric Association) 47 (5): 1b-29. Retrieved 2012-04-27.
2.  “Statement on a nonproprietary name adopted by the USAN council – Edivoxetine”(Press release). American Medical Association. 2012. Retrieved 2012-04-12.
3.  Chancellor D (November 2011). “The depression market”. Nature Reviews. Drug Discovery 10 (11): 809–10. doi:10.1038/nrd3585. PMID 22037032.
4.  Dubé S, Dellva MA, Jones M, Kielbasa W, Padich R, Saha A, Rao P (April 2010). “A study of the effects of LY2216684, a selective norepinephrine reuptake inhibitor, in the treatment of major depression”. Journal of Psychiatric Research 44 (6): 356–363.doi:10.1016/j.jpsychires.2009.09.013. PMID 19909980.
5.  Pangallo P, Dellva MA, D’Souza DN, Essink B, Russell J, Goldberger C (June 2011).“A randomized, double-blind study comparing LY2216684 and placebo in the treatment of major depressive disorder”. Journal of Psychiatric Research 45 (6): 748–755. doi:10.1016/j.jpsychires.2011.03.014. PMID 21511276.
6.  https://investor.lilly.com/releasedetail.cfm?ReleaseID=811751

H-NMR spectral analysis

CAS NO. 1194508-25-2, (1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol H-NMR spectral analysis

C-NMR spectral analysis

CAS NO. 1194508-25-2, (1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol C-NMR spectral analysis

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Vilsmeier-Haack Synthesis of 2,5-dimethyl-1H-(p-tolyl)-pyrrole-3-carboxaldehyde

Vilsmeier-Haack Synthesis of 2,5-dimethyl-1H-(p-tolyl)-pyrrole-3-carboxaldehyde



DMF (1.5 mL, 19.4 mmol, 6.5 equiv.) was stirred under a nitrogen atmosphere in an ice-bath. Phosphoryl chloride (0.308 mL, 3.3 mmol, 1.1 equiv.) was added and the reaction stirred for 30 minutes. Reaction mixture was a very pale yellow. A solution of 2,5-dimethyl-1H-(p-tolyl)-pyrrole (556 mg, 3 mmols, 1 equiv.) in DMF (2 mL) was added dropwise over 1 minute. After 5 minutes, flask removed from ice and reaction stirred for a further 55 mins. TLC at 1 hr showed reaction at completion. Reaction mixture was then poured onto ice (50 mL) and 1M NaOH added (pH 11), until adjusted to pH 6. Total volume approximately 50 mL after ice has melted and solution was pH 3 the next day. 20% NaOH was added to achieve pH 11 and flask bathed in a brine ice-bath for 20 minutes. Product filtered and washed with water to produce a wet brown paste. Product was dissolved in MeCN and concentrated under a nitrogen atmosphere. Brown solution with precipitation of fine crystals was observed overnight. Solution was cooled in an ice bath and filtered. Filter cake washed with water (3 x 10 mL). Filtered product was then dried under vacuum to produce a lumpy grey-brown powder (423 mg, 71%).

Collected data: 2,5-dimethyl-1H-(p-tolyl)-pyrrole-3-carboxaldehyde

mpt: 109-111^oC
¹H-NMR (300 MHz, CDCl₃): δ 9.86 (s, 1H), 7.30, 7.33 (d, 2H), 7.06, 7.09 (d, 2H), 6.37 (s, 1H), 2.44 (s, 3H), 2.27 (s, 3H), 1.98 (s, 3H)
¹³C-NMR (75 MHz, CDCl₃): δ 185.18, 138.98, 138.94, 134.30, 131.08, 130.18, 127.65, 121.82, 105.63, 21.19, 12.64, 11.19 
m/z (ESI+/-): 214 [M+H]⁺, 100% 
IR: 810.51, 1421.53, 1514.85, 1651.24, ~3934.95


References:
doi: 10.1002/cmdc.200600026

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Ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

Ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate 


HAS A TRIFLUORO GP


Synthesis of ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate from condensation of p-(trifluoromethyl)aniline with ethyl 2-acetyl-4-oxopentanoate.



Ethyl acetoacetate (6 mL,47 mmol, 1 equiv.) and K₂CO₃ (8.45 g, 61.1 mmol, 1.3 equiv.) were mixed in MeCN (55 mL). NaI (7.05 g, 47 mmol, 1 equiv.) and Chloroacetone (4.8 mL, 51.7 mmol, 1.1 equiv.) were added and mixture heated to 80^oC in an oil bath. TLC at 2 hours showed reaction at completion. Reaction was allowed to cool to room temperature. Mixture washed with EtOAc (2 x 20 mL), water (2 x 20 mL), 1:1 water:brine (2 x 20 mL) and brine (2 x 20 mL) and dried with MgSO4 and concentrated under reduced pressure to form a yellow oil.

Ethyl 2-acetyl-4-oxopentanoate intermediate  (2 mL, 10.7 mmol, 1 equiv.) was added to p-(trifluoromethyl)aniline (1.62 mL, 12.9 mmol, 1.2 equiv.) and heated at 80^oC in an oil bath for 1.25 hrs. TLC at 1 hour showed reaction at completion and reaction was allowed to cool to room temperature. Product was washed with EtOAc (2 x 20 mL), 10% citric acid (3 x 20 mL), water (20 mL) and brine (2 x 20 mL) and then concentrated under reduced pressure to form a dark brown oil. Brown oil was dissolved in 20 mL EtOH and heated before filtering under heat to remove residual salts and washing with hot EtOH. Filtrate was concentrated under reduced pressure and purified by chromatography on silica (2-15% EtOAc in petrol). Pure fractions were taken and concentrated under reduced pressure to produce a light yellow oil. Product was cooled in a refrigerator overnight forming a pale yellow crystalline solid (1.85 g, 55%).


data: ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate 

mpt: 66-68^oC

m/z (APCI+): 312[M+H]⁺, 100%


¹H-NMR (300 MHz, CDCl₃): 
δ 7.77, 7.80 (d, 1H), 7.32, 7.35 (d, 1H),6.41 (s, 1H), 4.25-4.32 (qr, 2H), 

2.30 (s, 3H), Methyls on pyrrole ring
1.99 (s, 3H), Methyls on pyrrole ring
1.33-1.37 (t, 3H)  CH2CH3


¹³C-NMR (75 MHz, CDCl₃): δ 165.5 140.98, 135.85, 131.00, 128.76, 128.47, 126.64, 126.59, 125.50, 121.89, 112.24, 108.24, 59.38, 14.52, 12.65, 12.35


¹⁹F-NMR (280 MHz, CDCl₃): δ -62.65


IR: 770.27, 840.98, 1065.03, 119.55, 1215.36, 1322.48, 1413.83, 1613.74, 1681.96, 2928.23


NMR Spectra:

1H NMR.........http://malaria.ourexperiment.org/data/704.html

13C NMR..........http://malaria.ourexperiment.org/data/706.html

19F NMR........http://malaria.ourexperiment.org/data/708.html

WITHOUT THE FLUORO GP

Synthesis of ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate from condensation of aniline with ethyl 2-acetyl-4-oxopentanoate 


Ethyl acetoacetate (6 mL,47 mmol, 1 equiv.) and K₂CO₃ (8.45 g, 61.1 mmol, 1.3 equiv.) were mixed in MeCN (55 mL). NaI (7.05 g, 47 mmol, 1 equiv.) and Chloroacetone (4.8 mL, 51.7 mmol, 1.1 equiv.) were added and mixture heated to 80^oC in an oil bath. TLC at 2 hours showed reaction at completion. Reaction was allowed to cool to room temperature. Mixture washed with EtOAc (2 x 20 mL), water (2 x 20 mL), 1:1 water:brine (2 x 20 mL) and brine (2 x 20 mL) and dried with MgSO4 and concentrated under reduced pressure to form a yellow oil. Ethyl 2-acetyl-4-oxopentanoate intermediate (2 mL, 10.7 mmol, 1 equiv.) was added to Aniline (1.17 mL, 12.89 mmol, 1.2 equiv.) and heated at 80^oC in an oil bath for 1.25 hrs. TLC at 1 hour showed reaction at completion and reaction was allowed to cool to room temperature. Product was washed with EtOAc (2 x 20 mL), 10% citric acid (3 x 20 mL), water (20 mL) and brine (2 x 20 mL) and then concentrated under reduced pressure to form a dark brown oil. Product was purified by chromatography on silica (2-15% EtOAc in petrol – suggest a lower % EtOAc). Product containing fractions concentrated under reduce pressure to produce a yellow oil (952 mg, approximate yield 37%). Product did not crystallise.

data: ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate

mpt: n/a
m/z (APCI+): 244 [M+H]⁺, 100%
¹H-NMR (300 MHz, CDCl₃): δ 7.41-7.50 (qn, 2H), 7.15, 7.18 (m, 2H), 6.38 (s, 1H), 4.20-4.32 (sx, 2H), 2.29 (s, 3H), 1.97 (s, 3H), 1.27-1.36 (qn, 3H)
¹³C-NMR (75 MHz, CDCl₃): δ 165.72, 137.76, 136.16, 129.39, 129.19, 128.93, 128.68, 128.53, 128.18, 111.49, 107.55, 59.21, 14.59, 12.64, 12.37
IR: 696.57, 770.6, 1072.8, 121.34, 1411.26, 1693.25, 2978.29

NOW WITH A METHYL

ethyl 2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxylate from condensation of p-toluidine with ethyl 2-acetyl-4-oxopentanoate.


Ethyl acetoacetate (2 mL, 15.7mmol, 1 equiv.) and K₂CO₃ (2.82 g, 20.4 mmol, 1.3 equiv.) in MeCN (30 mL) were mixed. Chloroacetone (1.6 mL, 17.2 mmol, 1.1 equiv.) and NaI (2.7 g, 18 mmol, 1.15 equiv.) were added and heated in an oil bath at 80°C. TLC showed reaction at completion after 2.5 hrs. After 3 hrs reflux, solution was allowed to cool to room temperature and then filtered and washed with EtOAc (30 mL). Mixture was concentrated under reduced pressure, dissolved in EtOAc (40 mL) and washed with water (20 mL), 1:1 water:brine (20 mL) and brine (20 mL). Crude product was then concentrated under reduced pressure. p-toluidine (2.02 g, 18.8 mmol, 1.2 equiv.) was added to crude intermediate and heated in an oil bath at 90°C. At 1.5 hrs, reaction was complete by TLC and reaction was allowed to cool to room temperature. Dark brown product was washed with EtOAc (2 x 20 mL), 10% citric acid (3 x 20 mL), water (2 x 20 mL) and brine (20 mL) and then concentrated under reduced pressure to form a black oil. Product was dissolved in EtOH and activated charcoal added to remove coloured impurities. Product was stirred for 1 hr then filtered and washed with EtOH. Filtrate was concentrated under reduced pressure to form a black oil. Oil was purified by chromatography on silica (2-10% EtOAc in petrol). Pure and impure fractions were taken separately and concentrated under reduced pressure to produce yellow and dark yellow oils respectively. Pure fraction crystallised overnight to a bright yellow crystalline solid (1.8 g, 45.6%).

Collected data: ethyl 2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxylate

mpt: 60-63^oC
m/z (APCI+): 258 [M+H]⁺, 100%
¹H-NMR (300 MHz, CDCl₃): δ 7.29, 7.26 (d, 2H), 7.03, 7.06 (d, 2H), 6.36 (s, 1H), 4.24-4.31 (qr, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 1.96 (s, 3H), 1.32-1.36 (t, 3H) 
¹³C-NMR (75 MHz, CDCl₃): δ 165.75, 138.46, 136.28, 135.12, 129.99, 128.78, 127.88, 111.31, 107.36, 59.17, 21.15, 14.59, 12.63, 12.36 
IR: 767.43, 1080.99, 1218.07, 1411.09, 1515.22, 1693.11, 2982.09