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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Enzymatic resolution of antidepressant drug precursors in an undergraduate laboratory

 drugs, spectroscopy, SYNTHESIS  Comments Off on Enzymatic resolution of antidepressant drug precursors in an undergraduate laboratory
Apr 012015
 

Enzymatic resolution of antidepressant drug precursors in an undergraduate laboratory

EducaçãoQuim. Nova 2015, 38(2), 285-287

Enzymatic resolution of antidepressant drug precursors in an undergraduate laboratory

Luís M. R. SolanoI; Nuno M. T. LourençoII,*
This paper describes a multi-step chemo-enzymatic synthesis of antidepressant drug precursors.

http://dx.doi.org/10.5935/0100-4042.20140306

Publicado online: novembro 13, 2014
Quim. Nova, Vol. 38, No. 2, 285-287, 2015
Educação http://dx.doi.org/10.5935/0100-4042.20140306
*e-mail: nmtl@tecnico.ulisboa.pt
ENZYMATIC RESOLUTION OF ANTIDEPRESSANT DRUG PRECURSORS IN AN UNDERGRADUATE LABORATORY
Luís M. R. Solanoa and Nuno M. T. Lourençob,* a Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal b Departamento de Bioengenharia, Instituto de Biotecnologia e Bioengenharia, Instituto Superior Técnico, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal
Recebido em 07/07/2014; aceito em 17/09/2014; publicado na web em 13/11/2014
The use of biocatalysts in synthetic chemistry is a conventional methodology for preparing enantiomerically enriched compounds. Despite this fact, the number of experiments in chemical teaching laboratories that demonstrate the potential of enzymes in synthetic organic chemistry is limited. We describe a laboratory experiment in which students synthesized a chiral secondary alcohol that can be used in the preparation of antidepressant drugs. This experiment was conducted by individual students as part of a Drug Synthesis course held at the Pharmacy Faculty, Lisbon University. This laboratory experiment requires six laboratory periods, each lasting four hours. During the first four laboratory periods, students synthesized and characterized a racemic ester using nuclear magnetic resonance spectroscopy and gas chromatography. During the last two laboratory periods, they performed enzymatic hydrolysis resolution of the racemic ester using Candida antarctica lipase B to yield enantiomerically enriched secondary alcohol. Students successfully prepared the racemic ester with a 70%-81% overall yield in three steps. The enzymatic hydrolysis afforded (R)- secondary alcohol with good enantioselectivity (90%–95%) and reasonable yields (10%–19%). In these experiments, students were exposed to theoretical and practical concepts of aromatic acylation, ketone reduction, esterification, and enzymatic hydrolysis. Keywords: sec-alcohols; esters; lípase; enantiomers; resolution.
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Ensuring Process Stability with Reactor Temperature Control Systems

 PROCESS, spectroscopy, SYNTHESIS  Comments Off on Ensuring Process Stability with Reactor Temperature Control Systems
Dec 272014
 

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

Temperature Control of Reactors

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

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

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

Figure 1. Functional view of reactor temperature control

Process Stability

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

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

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

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

 

Heat Exchanger

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

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

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

 

 

 

Pump

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

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

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

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

 

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

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

 

 

Control Electronics

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

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

 

 

Conclusion

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

 

 

 

 

 

 

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(S)-(+)-3-HYDROXY-2,2-DIMETHYLCYCLOHEXANONE

 spectroscopy, SYNTHESIS, Uncategorized  Comments Off on (S)-(+)-3-HYDROXY-2,2-DIMETHYLCYCLOHEXANONE
Dec 192014
 

 

 

 

(S)-(+)-3-hydroxy-2,2-dimethylcyclohexanone

bp 85–87°C at 3.7 mm, [α]21D + 23.0° (CHCl3, c 2.0)

The spectral properties of (S)-(+)-3-hydroxy-2,2-dimethylcyclohexanone are as follows:

 

IR vmax (film) cm−1: 3470 (s), 1705 (s), 1120 (m), 1055 (s), 985 (s), 965 (m);

 

1H NMR (250 MHz, CDCl3) δ: 1.11 (s, 3 H), 1.15 (s, 3 H), 1.60–1.71 (m, 1 H), 1.76–1.86 (m, 1 H), 1.96–2.05 (m, 2 H), 2.16 (br s, 1 H), 2.35–2.45 (m, 2 H), 3.69 (dd, 1 H, J = 7.6, 2.9);

 

13C NMR (76 MHz, CDCl3) δ: 19.7, 20.7, 22.9, 29.0, 37.3, 51.3, 77.8, 215.3.

The optical purity of (S)-(+)-3-hydroxy-2,2-dimethylcyclohexanone can be determined by HPLC analysis.
The (S)-α-methoxy-α-trifluoromethylphenylacetate (MTPA ester) is prepared according to the reported procedure:3 HPLC analysis (Column, Nucleosil® 50-5, 25 cm × 4.6 mm; eluant, hexane : THF = 30 : 1, 1.03 mL/min; detected at UV 256 nm) retention time 35.6 min (98.0–99.4%) and 29.6 min (0.6–(2.0%). Therefore, the optical purity is determined to be 96.0–98.8% ee.
Analysis of the MTPA ester of this product by 250 MHz 1H NMR and capillary GLC (12.5 m, 5% methyl silicone column) failed to detect any more of the minor diastereomer than would have been expected from the purity (98% ee) of the MTPA-Cl employed.

 

NOTE….Intermediate is

2,2-dimethylcyclohexane-1,3-dione bp 92–97°C (4 mm)

37–38°C.

The spectra are as follows: 1H NMR (250 MHz, CDCl3) δ: 1.29 (s, 6 H), 1.93 (5 lines, 2 H, J = 6.5), 2.67 (t, 4 H, J = 6.9); 13C NMR (76 MHz, CDCl3) δ: 18.1, 22.3, 37.4, 61.8, 210.6.

 

Natural products synthesized from (S)-3-hydroxy-2,2-dimethylcyclohexanone
Figure 1. Natural products synthesized from (S)-3-hydroxy-2,2-dimethylcyclohexanone

 


References and Notes
  1. Department of Agricultural Chemistry, The University of Tokyo, Yayoi 1-1-1, Bunkyo-Ku, Tokyo 113, Japan.
  2. Mekler, A. B.; Ramachandran, S.; Swaminathan, S.; Newman, M. S. Org. Synth., Coll. Vol. V 1973, 743, 3.
  3. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
  4. Kieslich, K. “Microbial Transformations of Non-Steroid Cyclic Compounds;” Georg Thieme; Stuttgart, 1976, pp. 28–31.
  5. Lu, Y.; Barth, G.; Kieslich, K.; Strong, P. D.; Duax, W. L.; Djerassi, C. J. Org. Chem. 1983, 48, 4549.
  6. Mori, K.; Mori, H. Tetrahedron 1985, 41, 5487.
  7. Yanai, M.; Sugai, T.; Mori, K. Agric. Biol. Chem. 1985, 49, 2373.
  8. Mori, K.; Watanabe, H. Tetrahedron 1986, 42, 273.
  9. Mori, K.; Nakazono, Y. Tetrahedron 1986, 42, 283.
  10. Mori, K.; Mori, H.; Yanai, M. Tetrahedron 1986, 42, 291.
  11. Mori, K.; Tamura, H. Tetrahedron 1986, 42, 2643.
  12. Sugai, T.; Tojo, H.; Mori, K. Agric. Biol. Chem. 1986, 50, 3127.
  13. Mori, K.; Mori, H. Tetrahedron 1986, 42, 5531.
  14. Mori, K.; Mori, H. Tetrahedron 1987, 43, 4097.
  15. Mori, K.; Komatsu, M. Liebigs Ann. Chem. 1988, 107.

 

 

 

 

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