Synthesis and Low Temperature Spectroscopic Observation of 1,3,5-Trioxane-2,4,6-Trione: The Cyclic Trimer of Carbon Dioxide

spectroscopy, SYNTHESIS Comments Off

Jun 172016

1,3,5-Trioxane-2,4,6-trione (cyclic trimer of CO₂) is the product of a four-step synthesis: chlorination of isobutyraldehyde; cyclotrimerization of 2-chloro-2-methylpropanal; dehydochlorination of 2,4,6-tris(2-chloropropan)-2-yl-1,3,5-trioxane; ozonolysis at −80 °C of 2,4,6-tri(propan-2-ylidene)-1,3,5-trioxane. This trioxane-trione is detected in solution at temperatures between −80 to −40 °C, and its conversion to CO₂ is monitored by ¹³C NMR and FTIR. The CO₂ trimer has a half-life of approximately 40 min at −40 °C.

As a product of combustion and respiration whose accumulation in the atmosphere has become a cause for significant concern, carbon dioxide has been the subject of much research directed at its reutilization. Various approaches toward this CO₂ reutilization goal have been described in excellent reviews over the past two decades.Important processes involve reduction with hydrogen,coupling with other small molecules, incorporation into polymers and artificial photosynthesis. The main products include fuels, solvents, chemical intermediates and polymers.

The efficiency of these commercial processes in terms of reagent usage is relatively low with respect to the fraction of CO₂ incorporated into the product; the highest being for urea (57%), and decreasing for salicylic acid (36%) and methanol (10%). This could be raised to 100% if a CO₂ self-fixation chemistry could be developed. Ideally with a sufficient input of energy, CO₂ would react with itself to yield a liquid or solid product from which this energy could be extracted when needed for useful work. Such chemistry has been the subject of theoretical calculation for structures representing the linear polymer and cyclic oligomers of CO₂.

With respect to thermodynamic stability, the cyclic trimer has been described as “feasible” although energetically less stable than three CO₂ molecules by 27 kJ/mol per CO₂ unit.(10)Regarding kinetic stability of the cyclic trimer toward fragmentation to CO₂, calculated barriers for this decomposition have ranged from activation energies of 61 to 172 kJ/mol depending on the computational method with calculated half-lives ranging from days to milliseconds at ambient conditions and substantially longer at lower temperatures.

The cyclic trimer of CO₂has also been proposed as a low-energy intermediate in the transformation of CO₂ to an extended solid.

The formation of an orthocarbonate extended covalent structure of interconnected six-membered rings was predicted by model calculation with the finding of a stabilization energy that increased with molecular size. Later experimental work found under extreme pressure/temperature (40 GPa/1800 K), CO₂ will transform to a metastable extended solid which has been characterized as a Phase V form of CO₂ with a sigma bonded quartz-like structure.

It has also been proposed that sorption of CO₂ into the isolated nanoscale confined spaces of sulfur- or nitrogen-treated porous carbon at 30 bar pressure can produce a polymeric structure of carbon dioxide as has been reported for other molecules in nanoconfined spaces.

The 1,3,5-trioxane-2,4,6-trione structure of the CO₂ cyclic trimer, 1, may represent an important intermediate or product in the self-fixation of gaseous CO₂. Theoretical studies on this molecule have indicated a possibility of kinetic stability at room temperature and as well as a possibility for it to be thermodynamically feasible.To date, no experimental evidence has been reported for its existence. The objective of this work is to synthesize compound 1 and to make an assessment of its stability. The approach is that of a model compound synthesis where the trioxane ring is first generated from substituted aldehydes and then the peripheral carbonyl structures are incorporated at low temperature in the final step. As will be shown, compound 1does not possess the stability for facile isolation and storage

Synthesis and Low Temperature Spectroscopic Observation of 1,3,5-Trioxane-2,4,6-Trione: The Cyclic Trimer of Carbon Dioxide

Michael J. Rodig^†, Arthur W. Snow^*^†, Paul Scholl^§, and Simon Rea^§

^† Chemistry Division, Naval Research Laboratory, Washington, D. C. 20375, United States

^§Mettler-Toledo AutoChem, Inc., Columbia, Maryland 21046, United States

J. Org. Chem., Article ASAP

DOI: 10.1021/acs.joc.6b00647

*E-mail: arthur.snow@nrl.navy.mil.

http://pubs.acs.org/doi/full/10.1021/acs.joc.6b00647

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

2,4,6-Tri(propan-2-ylidene)-1,3,5-trioxane (2a)

crude product was purified by vacuum distillation (10 mmHg at 185 °C) to yield the title compound as a colorless liquid (2.32 g, 71%). ¹H NMR (CDCl₃, 300 MHz) δ = 1.63 (s, 18 H,) ppm; ¹³C NMR (CDCl₃, 75 MHz) δ = 15.0, 86.9, 144.7 ppm; IR ν_max (liquid) 2991, 2919, 2863, 1726, 1284, 1212 cm^–1; UV (CH₃CN) λ_max = 210 nm (ε = 1.57 × 10⁴ L/mol·cm); HRMS (ESI) m/z calcd for C₁₂H₁₈O₃ [M + H]⁺ 211.1334, found 211.1342. Anal. Calcd for C₁₂H₁₈O₃: C, 68.54; H, 8.68; O, 22.83. Found: C, 68.48; H; 8.76.

/////////Synthesis, Low Temperature, Spectroscopic Observation, of 1,3,5-Trioxane-2,4,6-Trione, The Cyclic Trimer, Carbon Dioxide

Supporting Info
http://pubs.acs.org/doi/suppl/10.1021/acs.joc.6b00647

EXTRAS

1,3,5-Trioxane

1,3,5-Trioxane, sometimes also calledtrioxane or trioxin, is a chemical compound with molecular formula CHO. It is a white solid with a chloroform-like odor. It is a stable cyclictrimer of formaldehyde, and one of the three trioxaneisomers; its molecular backbone consists of a six-membered ring with three carbon atoms alternating with three oxygen atoms. Thus, cyclotrimerization of formaldehyde affords 1,3,5-trioxane:

The mechanism can be explained in an acidic catalyzed reaction:

Uses

In chemistry, 1,3,5-trioxane is used as a stable, easily handled source of anhydrousformaldehyde. In acidic solutions, it decomposes to generate three molecules of formaldehyde. It may also be used in polymerization to form acetal resins, such aspolyoxymethylene plastic. It is a feedstock for certain types of plastic, is an ingredient in some solid fuel tablet formulas, and is used in chemical laboratories as a stable source of formaldehyde.

Trioxane is combined with hexamine and compressed into solid bars to makehexamine fuel tablets, used by the military and outdoorsmen as a cooking fuel.

1,3,5-Trioxane is a mortician‘s restorative chemical that maintains the corpse’s contours after postmortem tissue constriction.

Amneal Pharma’s, 4,5-Dihydro-1H-pyrazolo[3,4-d]pyrimidine containing phenothiazines as antitubercular agents

Uncategorized Comments Off

Jun 152016

Cas 1580464-40-9

MW458.97, C₂₄ H₁₉ Cl N₆ S,

1H-Pyrazolo[3,4-d]pyrimidin-6-amine, 4-(4-chlorophenyl)-4,7-dihydro-3-methyl-1-(10H-phenothiazin-2-yl)-

4-(4-chlorophenyl)-3-methyl-1-(10H-phenothiazin-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-amine

4-(4-chlorophenyl)-3-methyl-1-(10H-Phenothiazin-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d] pyrimidin-6-amine

Yield 79%, m.p.: 186-188 ^ºC.

IR (KBr): 3328 (NH), 1648 (C-N), 640 (C-S-C). ¹H NMR (300 MHz, CDCl₃): d 2.32 (s, 3H, CH₃), 4.95 (s, 1H, CH), 7.36-7.38 (dd, 2H, J=8.10 Hz), 7.84-7.87 (dd, 2H, J=7.80 Hz), 7.90-8.05 (m, 7H, Ar-H), 8.46 (s, 1H, NH), 8.56 (s, 2H, NH₂), 9.11 (s, 1H, NH):

¹³C NMR (75 MHz, CDCl₃): d 26.1, 41.2, 52.5, 59.8, 103.6, 104.2, 105.3, 114.2, 116.6, 122.7, 127.1, 127.9, 128.2, 128.6, 129.2, 132.5, 134.6, 142.4, 143.7, 155.3, 162.5. Mass (m/z): 459. Anal. (%) for C₂₄H₁₉ClN₆S, Calcd. C, 62.81; H, 4.17; N, 18.31. Found: C, 62.75; H, 4.15; N, 18.26.

Mass spectrum of 4g

¹H NMR spectrum of 4g

Tuberculosis (TB) is a highly infectious airborne disease caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb). ¹According to the latest World Health Organization (WHO) report, an estimated 8.6 million people developed TB and 1.3 million died from the disease (including 320,000 deaths among HIV-positive people) in 2012. The majority of cases worldwide in 2012 were in the South-East Asia (29%), African (27%) and western Pacific (19%) regions. India and China alone accounted for 26% and 12% of total cases, respectively.² The standard antitubercular treatment regimen, termed DOTS (Directly Observed Therapy, Short-course), is based on the co-administration of age-old drugs like isoniazid (INH), rifampin (RMP), ethambutol (EMB), and pyrazinamide (PZA) for the first two months, followed by a prolonged treatment with INH and RMP for additional 4–7 months with no guarantee of complete sterilization from the infection. ^4 and 5 Furthermore, emergence of new virulent forms of TB such as multi drug resistant (MDR-TB) and extremely drug resistant (XDR-TB), and its synergy with human immunodeficiency virus (HIV) has fuelled its epidemic nature. These reasons make a compelling case for an urgent need for new and effective antitubercular agents with improved properties such as enhanced activity against MDR strains, reduced toxicity, rapid mycobactericidal mechanism of action and the ability to penetrate host cells and exert antimycobacterial effects in the intracellular environment.

Phenothiazines are important classes of compounds which have increasingly attracted attention, owing to their remarkable biological and pharmacological properties, such as antibacterial, antifungal, anticancer, antiviral, anti-inflammatory, antimalarial, antifilarial, trypanocidal, anticonvulsant, analgesic, immunosuppressive and multidrug resistance reversal. These activities are the results of the actions exerted by phenothiazines on biological systems via the interaction of the pharmacophoric substituent (in some cases of strict length), via the interaction multicyclic ring system (π–π interaction, intercalation in DNA) and via the lipophilic character permitting the penetration through the biological membranes to reach its site of action. Further, Phenothiazines have been shown to exhibit in vitro and in vivo activity against Mtb and multidrug-resistant Mtb. Some of the phenothiazine derived antipsychotic agents such as chlorpromazine, trifluoperazine (TPZ) and thioridazine are found to be effective inhibitors of Mtb.Phenothiazines are predicted to target the genetically validated respiratory chain component type II NADH:quinone oxidoreductase (Ndh)

Chintu Patel, RPh

Co-Chief Executive Officer and
Co-Chairman, Co-Founder

Chirag Patel

Co-Chief Executive Officer and
Co-Chairman, Co-Founder

Paper

Bioorganic & Medicinal Chemistry Letters

Volume 24, Issue 6, 15 March 2014, Pages 1493–1495

4,5-Dihydro-1H-pyrazolo[3,4-d]pyrimidine containing phenothiazines as antitubercular agents

^a Amneal Pharmaceuticals India Pvt Ltd, 882/1-871, Village Rajoda, Tal.: Bavla Dist.: Ahmedabad 382220, Gujarat, India
^b Division of Medicinal Chemistry, Department of Chemistry (DST-FIST Sponsored), Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar 364002, Gujarat, India
^c Department of Chemistry, Saurashtra University, Kalawad Road, Rajkot 360005, Gujarat, India

doi:10.1016/j.bmcl.2014.02.012

A series of novel dihydropyrazolo[3,4-d]pyrimidine derivatives bearing a phenothiazine nucleus were synthesized in excellent yields via a modified Biginelli multicomponent reaction. The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, Mass spectra and elemental analysis followed by antimycobacterial screening. Among all the screened compounds, compound 4g showed most pronounced activity against Mycobacterium tuberculosis (Mtb) with minimum inhibitory concentration (MIC) of 0.02 μg/mL, making it more potent than first line antitubercular drug isoniazid.

Scheme 1.

Synthetic protocol of title compounds 4a–k. Reagents and conditions: (a) NH₂NH₂, reflux; (b) ethyl acetoacetate, sodium ethoxide, reflux; (c) guanidine hydrochloride, aldehyde (R-CHO), P₂O₅, EtOH, reflux.

Amneal Pharmaceuticals’ co-CEO Chirag Patel

Chirag Patel and Chintu Patel

Chintu Patel, owner of Amneal Pharmaceuticals,

///////Dihydropyrazolo[3,4-d]pyrimidine, Phenothiazines, Biginelli multicomponent reaction, Cytotoxicity, Antitubercular activity, 4,5-Dihydro-1H-pyrazolo[3,4-d]pyrimidine, phenothiazines, antitubercular agents, amneal, 1580464-40-9

Clc1ccc(cc1)C2N=C(N)Nc3c2c(C)nn3c4cc5Nc6ccccc6Sc5cc4

Benzyl 3-deoxy-3-(3,4,5-trimethoxybenzylamino)-β-L-xylopyranoside

Uncategorized Comments Off

Aug 202015

The title compound was synthesized by opening the epoxide of benzyl 2,3-anhydro-β-L-ribopyranoside with 3,4,5-trimethoxybenzylamine (Scheme 1). The three broad peaks in the 1 H-NMR due to one –NH at δ 2.20 ppm, and two –OH at δ 5.00 ppm and 5.26 ppm, disappeared upon D2O exchange. The chemical shifts of the sugar hydrogens, along with COSY and HMBC were used to assign C7, C1″, C2″, C3″, C4″, C5″ and C7′ atoms. The coupling constant between H-1″ and H-2″ on the sugar ring was found to be 7.98 Hz, indicating that the protons at the 1- and 2-positions were in axial positions and that the molecule exists in solution in 1 C4 conformation (Scheme 1). The coupling constant was similar to related analogs [14,15]. The coupling constant between H-2” and H-3” was found to be 9.12 Hz. The coupling constant between the pro-R and pro-S hydrogens on C7 was found to be 12.24 Hz. The 13C had five pairs of atoms with the same chemical shift. There were three pairs of carbon atoms on the 3,4,5-trimethoxybenzyl ring ( two ortho- and two meta-, and two equivalent methoxy groups) that had similar chemical shifts. On the benzyl group, chemical shifts of two pairs of carbon atoms (two ortho- and two meta-) were observed.

PREPN

Benzyl 2,3-anhydro-β-L-ribopyranoside (1) was obtained from L-arabinose in five steps using a previously reported synthetic route [14]. To a mixture of benzyl 2,3-anhydro-β-L-ribopyranoside 1 (0.15 g, 0.68 mmol) and 3,4,5-trimethoxybenzylamine 2 (180 mL, 0.91 mmol) was added ethyl alcohol (3 mL). After refluxing the mixture for 16 h and cooling at room temperature for 12 h, white crystals (needles) formed. Recrystallization from hexane/ethyl acetate mixture (3:2, v/v) produced a pure compound (0.206 g, 72%,

m.p. 158–160 °C);

[α]D 26 +50° (c 1, CHCl3).

C22H29NO7 Calculated: C 62.99; H, 6.97; N, 3.34; O, 26.70 Found: C 62.89; H, 7.01; N, 3.29; O, 26.65

1 H-NMR (400 MHz, Me2SO-d6)

δ 2.20 (bs, 1H, –NH),

2.41 (t, J = 9.12, 7.98 Hz, 1H, H-3),

3.21 (m, 2H),

3.45 (bs, 1H),

3.65 (s, 3H, –OCH3),

3.75 (b, 1H),

3.80 (s, 6H, 2-OCH3),

3.97 (m, 2H),

4.31 (d, J = 7.98 Hz, 1H, H-1),

4.61 (d, J = 12.24 Hz, 1H, –OCH2Ar),

4.80 (d, J = 12.24 Hz, 1H, –OCH2Ar),

5.00 (bs, 1H, –OH), 5.26 (bs, 1H, –OH).

13C-NMR (100 MHz, Me2SO-d6),

δ 53.22 (C-7′),

56.61 (–OCH3),

60.81 (–OCH3),

65.11 (C-3″),

67.37 (C-5″),

70.14 (C-4″),

70.41 (C-7),

73.00 (C-2″),

103.90 (C-1″),

105.80, 128.23, 128.40, 129.00, 136.80, 138.23, 138.93, 153.52.

Nmr predict

Molbank 2013, 2013(1), M793; doi:10.3390/M793

Benzyl 3-deoxy-3-(3,4,5-trimethoxybenzylamino)-β-L-xylopyranoside

Fulgentius Nelson Lugemwa

Department of Chemistry, Pennsylvania State University-York, 1031 Edgecomb Avenue, York, PA 17403, USA

http://www.mdpi.com/1422-8599/2013/1/M793

//////epoxide ring-opening, 3,4,5-trimethoxybenzylamine, benzyl 2,3-anhydro-β-L-ribopyranoside

Polymorphism of felodipine co-crystals with 4,4′-bipyridine

polymorph Comments Off

Jul 032014

Graphical abstract: Polymorphism of felodipine co-crystals with 4,4′-bipyridine

http://pubs.rsc.org/en/Content/ArticleLanding/2014/CE/C4CE00756E?utm_medium=email&utm_campaign=pub-CE-vol-16-issue-29&utm_source=toc-alert#!divAbstract

The calcium-channel blocking agent felodipine (Fel) forms co-crystals with 4,4′-bipyridine (BP) with 1:1 and 2:1 molar ratios. The [Fel + BP] (1:1) co-crystal exists in two polymorphic forms. Differential scanning calorimetry and solution calorimetry show that form I of the [Fel + BP] (1:1) co-crystal is the most thermodynamically stable phase. The difference in the crystal lattice energies between different polymorphs of the co-crystal is found to be comparable with that between the polymorphic forms of pure felodipine. The enthalpies of formation of the co-crystals are small, which indicates that the packing energy gain originates from only weak van der Waals interactions. Analysis of Hirshfeld surfaces of the felodipine molecule shows a similar distribution of intermolecular contacts in the co-crystals and pure felodipine.

Polymorphism of felodipine co-crystals with 4,4′-bipyridine

Artem O. Surov,^a Katarzyna A. Solanko,^b Andrew D. Bond,^b Annette Bauer-Brandl^b and German L. Perlovich*^a

*Corresponding authors

^aInstitution of Russian Academy of Sciences, G.A. Krestov Institute of Solution Chemistry RAS, 153045 Ivanovo, Russia
E-mail: glp@isc-ras.ru;
Fax: +7 4932 336237 ;
Tel: +7 4932 533784

^bDepartment of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark

CrystEngComm, 2014,16, 6603-6611

DOI: 10.1039/C4CE00756E