AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

RG 6080

 phase 1, Uncategorized  Comments Off on RG 6080
Jul 152016
 

STR1

RG-6080

Sulfuric acid, mono[(1R,​2S,​5R)​-​2-​[[(2-​aminoethoxy)​amino]​carbonyl]​-​7-​oxo-​1,​6-​diazabicyclo[3.2.1]​oct-​6-​yl] ester

Phase I

A β-lactamase inhibitor potentially for the treatment of bacterial infections.

RG-6080; FPI-1459; OP-0595

CAS No. 1452458-86-4

Molecular Formula C9 H16 N4 O7 S
Formula Weight 324.31
  • Originator Fedora Pharmaceuticals
  • Developer Meiji Seika Pharma
  • Class Antibacterials; Azabicyclo compounds
  • Mechanism of Action Beta lactamase inhibitors
  • Phase IBacterial infections

Most Recent Events

  • 13 Jan 2015 OP 0595 licensed to Roche worldwide, except Japan ,
  • 30 Nov 2014 Meiji Seika Pharma completes a phase I trial in Healthy volunteers in Australia (NCT02134834)
  • 01 May 2014 Phase-I clinical trials in Bacterial infections (in volunteers) in Australia (IV)

 

 

SYNTHESIS

WO 2015046207,

STR1

 

CONTD…………………..

 

 

STR1

CONTD………………………………..

STR1

 

Patent

WO 2015053297

The novel heterocyclic compound in Japanese Patent 4515704 (Patent Document 1), preparation and shown for their pharmaceutical use, sodium trans-7-oxo-6- (sulfooxy) as a representative compound 1,6-diazabicyclo [3 .2.1] discloses an octane-2-carboxamide (NXL104). Preparation in regard to certain piperidine derivatives which are intermediates Patent 2010-138206 (Patent Document 2) and JP-T 2010-539147 (Patent Document 3) are shown at further WO2011 / 042560 (Patent Document 4) NXL104 to disclose a method for producing the crystals.
 In Patent 5038509 (Patent Document 5) (2S, 5R) -7- oxo -N- (piperidin-4-yl) -6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane – 2- carboxamide (MK7655) is shown, discloses the preparation of certain piperidine derivatives with MK7655 at Patent 2011-207900 (Patent Document 6) and WO2010 / 126820 (Patent Document 7).
 The present inventors also disclose the novel diazabicyclooctane derivative represented by the following formula (VII) in Japanese Patent Application 2012-122603 (Patent Document 8).
Patent Document 1: Japanese Patent No. 4515704 Pat
Patent Document 2: Japanese Patent Publication 2010-138206 Pat
Patent Document 3: Japanese patent publication 2010-539147 Pat
Patent Document 4: International Publication No. WO2011 / 042560 Patent
Patent Document 5: Japanese Patent No. 5038509 Pat
Patent Document 6: Japanese Patent Publication 2011-207900 Pat
Patent Document 7: International Publication No. WO2010 / 126820 Patent
Patent Document 8: Japanese Patent application 2012-122603 Pat.
[Chemical formula 1] (In the formula, R 3 are the same as those described below)

Reference Example
5 of 5 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)
Formula 43]
step 1 tert-butyl {2 – [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate  (IV-1)(2S, 5R)-6-(benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxylic acid (4 .30g, dehydrated ethyl acetate (47mL) solution of 15.56mmol) was cooled to -30 ℃, isobutyl chloroformate (2.17g, washing included dehydration ethyl acetate 1mL), triethylamine (1.61g, washing included dehydration ethyl acetate 1 mL), successively added dropwise, and the mixture was stirred 1 hour at -30 ° C.. To the reaction solution tert- butyl 2-dehydration of ethyl acetate (amino-oxy) ethyl carbamate (3.21g) (4mL) was added (washing included dehydration ethyl acetate 1mL), raising the temperature over a period of 1.5 hours to 0 ℃, It was further stirred overnight. The mixture of 8% aqueous citric acid (56 mL), saturated aqueous sodium bicarbonate solution (40 mL), sequentially washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, filtered, concentrated to 5 mL, up to 6mL further with ethanol (10 mL) It was replaced concentrated. Ethanol to the resulting solution (3mL), hexane the (8mL) in addition to ice-cooling, and the mixture was stirred inoculated for 15 minutes. The mixture was stirred overnight dropwise over 2 hours hexane (75 mL) to. Collected by filtration the precipitated crystals, washing with hexane to give the title compound 5.49g and dried in vacuo (net 4.98 g, 74% yield). HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 50/50, 1.0 mL / min, UV 210 nm, Retweeted 4.4 min; 1 H NMR (400 MHz, CDCl 3 ) [delta] 1.44 (s, 9H), 1.56-1.70 (m, 1H), 1.90-2.09 (m, 2H), 2.25-2.38 (m, 1H), 2.76 (d, J = 11.6 Hz, 1H), 3.03 (br.d., J = 11.6 Hz , 1H), 3.24-3.47 (m, 3H), 3.84-4.01 (m, 3H), 4.90 (d, J = 11.6 Hz, 1H), 5.05 (d, J = 11.6 Hz, 1H), 5.44 (br. . s, 1H), 7.34-7.48 (yd, 5H), 9.37 (Br.S., 1H); MS yd / z 435 [M + H] + .
Step 2
tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate
(V-1) tert-butyl {2 – [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl ] carbonyl} amino) oxy] ethyl} carbamate (3.91 g, to a methanol solution (80 mL) of 9.01mmol), 10% palladium on carbon catalyst (50% water, 803 mg) was added, under hydrogen atmosphere and stirred for 45 minutes . The reaction mixture was filtered through Celite, after concentrated under reduced pressure to give 3.11g of the title compound (quantitative).
HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 75/25, 1.0 mL / min, UV 210 nm, Retweeted 3.9 from min; 1 H NMR (400 MHz, CD 3 OD) [delta] 1.44 (s, 9H) , 1.73-1.83 (m, 1H), 1.86-1.99 (m, 1H), 2.01-2.12 (m, 1H), 2.22 (br.dd., J = 15.0, 7.0 Hz, 1H), 3.03 (d, J= 12.0 Hz, 1H), 3.12 (br.d., J = 12.0 Hz, 1H), 3.25-3.35 (m, 2H), 3.68-3.71 (m, 1H), 3.82-3.91 (m, 3H); MS M / Z 345 [M Tasu H] Tasu .
Step 3
Tetrabutylammonium tert- butyl {2 – [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate
(VI-1) tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct 2-yl] carbonyl} amino) oxy] ethyl} carbamate (3.09g, in dichloromethane (80mL) solution of 8.97mmol), 2,6- lutidine (3.20mL), sulfur trioxide – pyridine complex (3 .58g) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into half-saturated aqueous sodium bicarbonate solution, washed the aqueous layer with chloroform, tetrabutylammonium hydrogen sulfate to the aqueous layer and (3.47 g) chloroform (30 mL) was added and stirred for 10 minutes. The aqueous layer was extracted with chloroform, drying the obtained organic layer with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound 5.46g (91% yield).
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 80/20, 1.0ML / Min, UV210nm, RT 2.0 Min; 1 H NMR (400 MHz, CDCl 3 ) Deruta 1.01 (T, J = 7.4 Hz, 12H), 1.37-1.54 (m , 8H), 1.45 (s, 9H), 1.57-1.80 (m, 9H), 1.85-1.98 (m, 1H), 2.14-2.24 (m, 1H), 2.30- 2.39 (m, 1H), 2.83 (d, J = 11.6 Hz, 1H), 3.20-3.50 (m, 11H), 3.85-3.99 (m, 3H), 4.33-4.38 (m, 1H), 5.51 (br s , 1H), 9.44 (Br.S., 1H); MS yd / z 425 [M-Bu 4 N + 2H] + .
Step 4 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)
tetra butylammonium tert- butyl {2 – [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (5.20g, 7.82mmol) in dichloromethane (25mL) solution of ice-cold under trifluoroacetic acid (25mL), and the mixture was stirred for 1 hour at 0 ℃. The reaction mixture was concentrated under reduced pressure, washed the resulting residue with diethyl ether, adjusted to pH7 with aqueous sodium bicarbonate, subjected to an octadecyl silica gel column chromatography (water), after freeze drying, 1.44 g of the title compound obtained (57% yield).
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 99/1, 1.0ML / Min, UV210nm, RT 3.1 Min; 1 H NMR (400 MHz, D 2O) Deruta 1.66-1.76 (M, 1H), 1.76-1.88 (m, 1H ), 1.91-2.00 (m, 1H), 2.00-2.08 (m, 1H), 3.02 (d, J = 12.0 Hz, 1H), 3.15 (t, J = 5.0 Hz , 2H), 3.18 (br d , J = 12.0 Hz, 1H), 3.95 (dd, J = 7.8, 2.2 Hz, 1H), 4.04 (t, J = 5.0 Hz, 2H), 4.07 (dd, J = 6.4 3.2 Hz &, 1H); MS yd / z 325 [M + H] + .

 

PATENT

WO 2015046207

Example
64 tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy ] ethyl} carbamate (V-1)
[of 124]

tert- butyl {2 – [({[(2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl } carbamate (example 63q, net 156.42g, 360mmol) in methanol solution (2.4L) of 10% palladium carbon catalyst (50% water, 15.64g) was added, under an atmosphere of hydrogen, stirred for 1.5 hours did. The catalyst was filtered through celite, filtrate was concentrated under reduced pressure until 450mL, concentrated to 450mL by adding acetonitrile (1.5 L), the mixture was stirred ice-cooled for 30 minutes, collected by filtration the precipitated crystals, washing with acetonitrile, and vacuum dried to obtain 118.26g of the title compound (net 117.90g, 95% yield). Equipment data of the crystals were the same as those of the step 2 of Reference Example 3.

Example
65 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VI-1)
[of 125]

 

 tert- butyl {2 – [({[(2S, 5R) -1,6- -6- hydroxy-7-oxo-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (example 64,537.61g, 1.561mol) in acetonitrile (7.8L) solution of 2,6-lutidine (512.08g), sulfur trioxide – pyridine complex (810.3g) was added, at room temperature in the mixture was stirred overnight. Remove insolubles and the mixture was filtered, the filtrate concentrated to 2.5 L, diluted with ethyl acetate (15.1L). The mixture was extracted with 20% phosphoric acid 2 hydrogencarbonate aqueous solution (7.8L), the resulting aqueous layer into ethyl acetate (15.1L), added tetrabutylammonium hydrogen sulfate (567.87g), was stirred for 20 min. The organic layer was separated layers, dried over anhydrous magnesium sulfate (425 g), after filtration, concentration under reduced pressure, substituted concentrated tetrabutylammonium tert- butyl with dichloromethane (3.1L) {2 – [({[(2S, 5R ) -7-oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate was obtained 758g (net 586.27g, Osamu rate 84%).

 

 The tetra-butyl ammonium salt 719g (net 437.1g, 0.656mol) in dichloromethane (874mL) solution was cooled to -20 ℃, dropping trifluoroacetic acid (874mL) at 15 minutes, 1 the temperature was raised to 0 ℃ It was stirred time. The reaction was cooled to -20 ° C. was added dropwise diisopropyl ether (3.25L), and the mixture was stirred for 1 hour the temperature was raised to 0 ° C.. The precipitate is filtered, washed with diisopropyl ether to give the title compound 335.36g of crude and vacuum dried (net 222.35g, 99% yield).

 

 The title compound of crude were obtained (212.99g, net 133.33g) and ice-cold 0.2M phosphate buffer solution of pH5.3 mix a little at a time, alternating between the (pH6.5,4.8L). The solution was concentrated under reduced pressure to 3.6L, it was adjusted to pH5.5 at again 0.2M phosphate buffer (pH6.5,910mL). The solution resin purification (Mitsubishi Kasei, SP207, water ~ 10% IPA solution) is subjected to, and concentrated to collect active fractions, after lyophilization, to give the title compound 128.3 g (96% yield). Equipment data of the crystals were the same as those of step 3 of Reference Example 3.

PATENT

US 20140288051

WO 2014091268

WO 2013180197

US 20130225554

///////////RG-6080, 1452458-86-4, FPI-1459,  OP-0595, Phase I ,  β-lactamase inhibitor, bacterial infections, Fedora parmaceuticals, Meiji Seika Pharma

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Chemistry in Water

 Uncategorized  Comments Off on Chemistry in Water
Jul 152016
 

Chemistry in Water


1
Isley et al. reported the use of the nonionic amphiphile TPGS-750-M (2 wt %) in water to facilitate nucleophilic aromatic substitution reactions (SNAr) with oxygen, nitrogen, and sulfur nucleophiles. The team eliminated the use of dipolar aprotic organic solvents traditionally required for SNAr reactions, such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and N-methyl-2-pyrrolidone (NMP).
Moderate to high yields at ambient or slightly elevated temperatures (up to 45 °C) were observed, and a diverse substrate scope with respect to thermal stability was established. The team additionally demonstrated the ability to recycle the water/micelle mixture by extracting the product with organic solvent. Recycling of the aqueous media resulted in improving the E-factor and reducing aqueous waste ( Org. Lett. 2015, 17,4734−4737).Supporting Info

Nucleophilic Aromatic Substitution Reactions in Water Enabled by Micellar Catalysis

Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
Chemical & Analytical Development, Novartis Pharma AG, 4056 Basel, Switzerland
Org. Lett., 2015, 17 (19), pp 4734–4737
DOI: 10.1021/acs.orglett.5b02240
STR1
2
Wang et al. described the development of a copper-catalyzed hydroxylation of aryl halides in water. The syntheses of phenols generally require the use of energy intensive and/or harsh reaction conditions which can impact the substrate scope. This methodology utilized a hydroxylated phenanthroline ligand to improve solubility in water. Optimization of this method through screening resulted in the selection of copper(I) oxide (Cu2O) as the copper source and tetrabutyl-ammonium hydroxide (TBAOH) at 110 °C. The TBAOH was proposed to function as both phase transfer catalyst and nucleophile, resulting in high yields and excellent selectivity toward phenol versus biphenyl ether.
The scope of this method with substituted aryl halides was demonstrated, affording excellent yields and high selectivity for para-substituted electron-rich and electron-deficient aryl bromides, as well as meta-substituted bromo-halides. Functional groups such as carboxyl and hydroxyl groups were also tolerated. The team additionally demonstrated a one-pot synthesis of either alkyl aryl ethers or benzofuran by trapping the in situ generated phenol with an alkyl bromide or through intramolecular cyclization ( Green Chem. 2015, 17, 3910−3915).
Graphical abstract: Copper-catalyzed hydroxylation of aryl halides: efficient synthesis of phenols, alkyl aryl ethers and benzofuran derivatives in neat water
Yangxin Wang,ab   Chunshan Zhoua and   Ruihu Wang*a  
*Corresponding authors
aState Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
E-mail: ruihu@fjirsm.ac.cn
bUniversity of Chinese Academy of Sciences, Beijing, China
Green Chem., 2015, 17, 3910-3915
DOI: 10.1039/C5GC00871A , supporting info,
 An efficient catalytic protocol for hydroxylation of aryl halides in water is proposed to prepare phenols, ethers and benzofuran derivatives.
A thorough study of environmentally friendly hydroxylation of aryl halides is presented. The best protocol consists of hydroxylation of different aryl bromides and electron-deficient aryl chlorides by water solution of tetrabutylammonium hydroxide catalyzed by Cu2O/4,7-dihydroxy-1,10-phenanthroline. Various phenol derivatives can be obtained in excellent selectivity and great functional group tolerance. This methodology also provides a direct pathway for the formation of alkyl aryl ethers and benzofuran derivatives in a one-pot tandem reaction.
3
Jung et al. reported the use of a continuous flow reactor to synthesize propargylamines in an atom economic fashion using stoichiometric quantities of reagents, water as solvent, and generating only CO2 and water as byproducts. The team exploited the use of a pressurized tube reactor to achieve temperatures above the boiling point of water, enabling excellent yields (≥88%) and reasonable residence time (2 h).
This procedure improved the atom economy of previously reported methods for this transformation by eliminating the use of transition metal catalysts and excess of reagents. The substrate scope was demonstrated for multiple alkynyl carboxylic acids and secondary amines ( Tetrahedron. Lett. 2015, 56, 4697−4700).
image

Volume 52, Issue 36, 7 September 2011, Pages 4697–4700

Basic alumina supported tandem synthesis of bridged polycyclic quinolino/isoquinolinooxazocines under microwave irradiation

  • Department of Chemistry, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700 032, India
4
Wang et al. reported the synthesis of an easily accessible diammonium functionalized Ru-alkylidene complex capable of ring-closing metathesis (RCM) and cross metathesis (CM) reactions in water. The NHBoc penultimate intermediate was isolated as an air-stable, nonhygroscopic Ru-alkylidene complex. Acidic cleavage of the Boc groups with trifluoroacetic acid (TFA) in dichloromethane generated the diammonium catalyst as a green solid after removal of volatiles under reduced pressure. The diammonium catalyst (5 mol %) achieved modest to high conversion to cyclic RCM products in D2O at ambient to elevated temperatures (up to 80 °C). Lowering the catalyst loading to 0.1 mol % established a turnover number (TON) of >900.
Homocoupling of allyl alcohol and long chain alkenylammonium salts provided the desired diammonium cross products in high yield/conversion. Short chain alkenyl-ammonium salts were poor substrates for the CM reaction.
Catalyst deactivation was attributed to the ammonium:free amine equilibration in water followed by Lewis basic nitrogen coordination to the Ru-center (Green Chem. 2015, 17, 3407−3414).
Graphical abstract: A simple and practical preparation of an efficient water soluble olefin metathesis catalyst

A simple and practical preparation of an efficient water soluble olefin metathesis catalyst

*Corresponding authors
aSchool of Chemistry, Monash University, Clayton 3800, Australia
E-mail: andrea.robinson@monash.edu
Green Chem., 2015,17, 3407-3414

DOI: 10.1039/C5GC00252D, supp info

5
The same research group additionally reported the divergent functionalization of L-tyrosine to generate a family of tyrosine-derived Ru-alkylidene RCM catalysts. This common ligand precursor approach was utilized to successfully create not only a hydrophilic/water-soluble PEG Ru-alkylidene, but a hydrophobic alkane Ru-alkylidene for solvent-free catalysis and a solid-phase supported Ru-alkylidene to access a potentially recyclable precatalyst system.
The PEG Ru-alkylidene complex displayed poor solubility in water at 40 °C under ultrasonication, providing the desired model RCM product in only 25% conversion. >95% conversion was achieved by utilizing a 1:1 water–MeOH solvent system at 40 °C with 2.5 mol % catalyst loading. It was rationalized in the Green Chemistry report (vide supra) that functionalization of the benzylidene ligand to increase aqueous solubility may be problematic due to the dissociation of the labile ligand during the catalytic cycle, whereas functionalization of nondissociating NHC ligand could sustain the desired solubility throughout the reaction.
The hydrophobic alkane Ru-alkylidene provided solvent-free RCM and CM products in high conversion. The solid-phase Ru-alkylidene also provided the desired RCM products in high conversion and demonstrated stable performance after multiple catalyst recovery/reuse operations. Sustained leaching of Ru metal into the reaction media was monitored and observed for the recycled solid-phase catalyst method. However, this iterative loss of metal did not negatively impact conversion ( J. Org. Chem. 2015, 80, 7205−7211).

Divergent Approach to a Family of Tyrosine-Derived Ru−Alkylidene Olefin Metathesis Catalysts

divergent

Authors

Ellen C. Gleeson, Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson

Published Journal of Organic Chemistry
Graphical abstract divergent
Abstract

A simple and generic approach to access a new family of Ru−alkylidene olefin metathesis catalysts with specialized properties is reported. This strategy utilizes a late stage, utilitarian Hoveyda-type ligand derived from tyrosine, which can be accessed via a multigram-scale synthesis. Further functionalization allows the catalyst properties to be tuned, giving access to modified second-generation Hoveyda−Grubbs-type catalysts. This divergent synthetic approach can be used to access solid-supported catalysts and catalysts that function under solvent-free and aqueous conditions.

Citation

Ellen C. Gleeson, Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson, J. Org. Chem., 201580(14), 7205–7211

Pdf Article
Doi 10.1021/acs.joc.5b01091
6
Bhowmick et al. published a review “Water: the most versatile and nature’s friendly media in asymmetric organocatalyzed direct aldol reactions”. This review addressed the various types of organocatalysts based on (1) l-proline, (2) 4-hydroxy-l-proline, (3) amino acid derivatives, (4) enzymes, and (5) other miscellaneous catalysts applied to the aldol reaction in aqueous media. In general, the intermolecular asymmetric aldol reaction has been shown to perform poorly in pure aqueous media and is typically performed in organic solvents such as DMF, DMSO, etc.
However, structural modifications to l-proline and 4-hydroxy-l-proline have generated catalysts capable of asymmetric aldol reactions in aqueous media.
Examples provided in this review highlight (a) instances of enhanced reactivity using water as a solvent, cosolvent, or additive, (b) formation of enzyme mimics that use hydrophobic forces to reinforce substrate/catalyst binding, (c) the use of aqueous media to interrogate proposed transition state geometries, and (d) the pH dependence of organocatalyzed aldol reactions. Limitations presented in the review include (a) substrate specific catalyst activities, (b) multistep/low-yielding synthesis of the organocatalysts, (c) slow catalysis rate in pure aqueous media, (d) high catalyst loading, and (e) poor to moderate selectivity (Tetrahedron: Asymmetry 2015, 26, 1215−1244).
Image for unlabelled figure

Volume 26, Issues 21–22, 1 December 2015, Pages 1215–1244

Tetrahedron: Asymmetry Report Number 159

Water: the most versatile and nature’s friendly media in asymmetric organocatalyzed direct aldol reactions

  • Division of Organic Synthesis, Department of Chemistry, Visva-Bharati (A Central University), Bolpur, West Bengal 731 235, India
7
Hot water’s ability to promote unexpected reactions without any other reagents or catalysts.

Chinese and Japanese chemists have highlighted hot water’s ability to promote unexpected reactions without any other reagents or catalysts. The work should expand our understanding of how to harness the physicochemical properties of water to potentially replace more complex reagents and catalysts.

Above its critical point at 374°C and 218atm the properties of water change quite dramatically, explains Hiizu Iwamura from Nihon University in Tokyo. But even below that point, as water is heated, hydrogen bonding and hydrophobic interactions are disrupted. ‘This means that organic compounds get more soluble and salts become insoluble in hot pressurised water,’ Iwamura says. Dissociation of water into hydroxide (OH) and hydronium (H3O+) ions also increases, he adds, so there are higher concentrations of these ions available to act as catalysts for reactions.

Iwamura was synthesising triaroylbenzene molecules for a previous project on molecular magnets, using base-catalysed Michael addition reactions, when he first became interested in whether the reactions might work in water. He teamed up with a chemical engineer colleague, Toshihiko Hiaki, who is more familiar with working at the required temperatures and pressures. Together, they found that 4-methoxy-3-buten-2-one could be transformed into 1,3,5-triacetylbenzene in pressurised water at 150°C, with no other additives (see reaction scheme).1

Meanwhile, Jin Qu and her team at Nankai University in Tianjin have been investigating water-promoted reactions at lower temperatures, without the need for pressurised vessels, which Qu says is more accessible for many researchers and makes monitoring reactions easier. ‘In 2008, one of my students found he could hydrolyse epoxides in pure water at 60°C, in 90% yields,’ she explains. ‘At first I thought it was not very interesting, just a hydrogen-bonding effect, but as we found more examples I got more interested.’

More than a thermal effect

When Qu’s team hydrolysed an epoxide made from (-)-α-pinene, they found that at room temperature they got (-)-sobrerol, the product they expected. But at 60°C or higher, the sobrerol began to racemise, giving a mixture of the (+)- and (-)-forms (see reaction scheme). ‘We couldn’t understand why this was happening at first,’ says Qu, but eventually it became clear that the allylic alcohol group in the sobrerol, which is much less reactive than the epoxide in pinene, was also being hydrolysed. The same reactions happen at room temperature if acid is added, Qu says, but don’t happen in propanol or other alcoholic and hydrogen-bonding solvents heated to the same temperatures, so it is not simply a thermal effect.

Qu points out that these observations, along with those of Iwamura’s team, show that molecules that might usually be considered unreactive in water can undergo useful transformations. And these reactions can take place without other reagents or solvents, which would create extra waste streams. Also, owing to the decreased solubility of the organic product molecules when the solutions are cooled back to room temperature, they are often easy to purify as well.

Iwamura suggests that there are many other simple acid- and base-catalysed reactions that might be suitable for reacting in hot water. However, reactions with thermally unstable molecules, or those requiring delicate selectivity, are unlikely to be so effective at higher temperatures, he adds. He also makes a distinction between Qu’s work – in which the water molecules are directly involved in the reaction – and his own group’s, in which the water acts as the reaction medium and provides the catalyst. ‘Our reaction did not take place in water heated at reflux,’ Iwamura adds.

However, Hiaki points out that the potential environmental benefits of reduced waste streams will have little impact on industrial chemistry if the reactions remain confined to batch processes. ‘High temperature and pressure is detrimental for the scale up to commercial chemical plants,’ he says. For that reason, the team is developing a flow microreactor system that should be more industry compatible.REFERENCES, 1 T Iwado et al, J. Org. Chem., 2012, DOI: 10.1021/jo301979pZ-B Xu and J Qu, Chem. Eur. J., 2012 DOI: 10.1002/chem.201202886

 8
Hydration: A process which adds water.

In this hydration reaction, 1-methylcyclohexene (an alkene) is reacted with aqueous H3O+ (formed from water and a strong acid such as H2SO4), resulting in Markovnikov addition of water across the pi bond. The product is an alcohol.


Syn, anti-Markovnikov addition of water to an alkene can be achieved via a hydroboration-oxidation reaction.

–to be added– –to be added–
CuSO4 (anhydrous) CuSO4 . 5 H2O

Anhydrous CuSO4 (colorless) absorbs water vapor from the air, hydrating it to CuSO4 . 5 H2O (copper sulfate pentahydrate; blue).

///////////Chemistry in Water
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Photochemical Rearrangement of Chiral Oxaziridines in Continuous Flow: Application Toward the Scale-Up of a Chiral Bicyclic Lactam

 flow synthesis, SYNTHESIS  Comments Off on Photochemical Rearrangement of Chiral Oxaziridines in Continuous Flow: Application Toward the Scale-Up of a Chiral Bicyclic Lactam
Jul 152016
 
Abstract Image

A method for synthesizing chiral lactams from chiral oxaziridines in continuous flow is described. The oxaziridines are readily available from cyclic ketones. Photolysis of the oxaziridines using the Booker-Milburn flow system provides conversion to the chiral lactams in good yield and short residence times. Application of this chemistry toward the synthesis of a chiral bicyclic lactam is described.

Photochemical Rearrangement of Chiral Oxaziridines in Continuous Flow: Application Toward the Scale-Up of a Chiral Bicyclic Lactam

Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00213

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00213

John Cochran

Manager, Custom Synthesis Group at Vertex Pharmaceuticals

https://www.linkedin.com/in/john-cochran-00a86299

Experience

Research Fellow II (Manager, Custom Synthesis Group)

Vertex Pharmaceuticals

– Present (16 years 7 months)Boston, MA

– Supervised 10 chemists (6 Ph.D., 2 M.S., 2 B.S)

– Synthesized starting materials, intermediates, and preclinical tox lots for medicinal chemistry on
multigram to kilogram scale.

– Synthesized standards for various assays

– Performed kilo-scale enzymatic reactions

– Used flow chemistry on kilo scale

– Worked with several outsourcing firms in Europe and Asia

– Designed and updated an internal group website used to communicate with stakeholders

– Experienced with DOE and reaction optimization

Medicinal Chemist

Vertex Pharmaceuticals

(3 years 11 months)Cambridge, MA

– Supervised 4 chemists (2 M.S., 2 B.S.)

– Managed a lead generation team that synthesized hundreds of very potent and selective heterocyclic leads on several kinase programs including JNK3, GSK3, LCK, SYK, and JAK3.

– Chemistry Head of the p38 2nd-generation program.

– Designed and synthesized very potent and selective inhibitors of p38

– Designed synthetic routes for previously unknown substitution patterns on pyridine

– Made presentations to external collaborators on the program.

– Produced two clinical candidates that were substantially more potent and had much better physical
properties than the 1st-generation inhibitors.

– Filed several patents concerning the 1st-generation compounds and related scaffolds

Postdoctoral Research Associate

Emory University

(2 years 2 months)Atlanta, GA

– Designed and researched a proposal to use Pummerer chemistry to synthesize furans and to apply
the methodology to lignin synthesis

– Authored and investigated a proposal to synthesize 2-aminofurans using Pummerer or diazo
chemistry and to use them to make highly substituted anilines, phenols, indoles, and the general
framework found in the Amaryllidaceae, Erythrina, Lycopodium, and Aspidospermina classes of
alkaloids.

– Designed the synthetic strategy for indole synthesis using a vinylogous Pummerer rearrangement.

– Authored and supervised the research on a proposal to use Pummerer chemistry to synthesize
aromatic glides that can be used to make complex polycyclic systems.

– Supervised two graduate students working on the 2-aminofuran project and one graduate student on the vinylogous Pummerer project.

Industrial Chemist

Tennessee Valley Authority

(6 years)Muscle Shoals, AL

– Synthesized potential urease inhibitors in gram to several hundred gram quantities using high
temperature and high pressure equipment

– Performed gas-phase reactions in fluidized bed reactors containing transition-metal catalysts to find
an efficient industrial process for making dicyandiamide

– Characterized compounds and analyzed their decomposition kinetics using 1H and 31P NMR, HPLC,
and GC.

– Authored and researched a proposal to modify urea crystal morphology in fluid fertilizers

– Developed software for receiving and analyzing data from various instrumentation.

Education

University of Wisconsin-Madison

Doctor of Philosophy (Ph.D.), Organic Chemistry

Synthesized heterocyclophanes and studied their binding interactions with small neutral molecules in nonaqueous media. Complexation studies were performed with 1H , 13C, variable temperature, and 2D NMR, UV spectroscopy, and X-ray diffraction.

University of North Alabama

Bachelor of Science (B.S.), Industrial Chemistry

///////John E. Cochran, vertex, Chiral Bicyclic Lactam

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