Continuous Flow Multipoint Dosing Approach for Selectivity

Aug 23, 2013 - ABSTRACT: A continuous synthesis approach with multipoint dosing of ... Use of multipoint dosing of the oxidizing agent helped to minim...
3 downloads 0 Views 854KB Size
Download PDF
Article pubs.acs.org/OPRD

Continuous Flow Multipoint Dosing Approach for Selectivity Engineering in Sulfoxidation A. A. Kulkarni,*,† N. T. Nivangune,† R. R. Joshi,‡ and R. A. Joshi‡ †

Chemical Engineering Division and ‡Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411021, India S Supporting Information *

ABSTRACT: A continuous synthesis approach with multipoint dosing of one of the reagents is demonstrated for the synthesis of sulfoxide compounds such as proton pump inhibitors. Use of multipoint dosing of the oxidizing agent helped to minimize the possibility of over-oxidation leading to sulfone. Different oxidizing agents were used, and the effect of various parameters (viz. mole ratio of sulfide to oxidizing agent, temperature, residence time, concentration of oxidizing agent, etc.) on the yield of the desired sulfoxide compound was studied. Single-point and multipoint dosing approaches of the oxidizing agent were used for the most promising set of parameters. The performance was compared in terms of conversion of sulfide and the selectivity of the desired sulfoxide. Numbering up approach was used to produce the sulfoxide in a relatively large quantity at laboratory scale with complete conversion and over 99% selectivity for the sulfoxide.

1. INTRODUCTION Series parallel reactions are very common in the synthesis of active pharmaceutical ingredients (APIs) resulting in poor process economy due to complex downstream processing to remove the undesired byproducts formed during the reaction. Some of the examples of these include nitration, chlorination, oxidation (including ozonolysis), and reactions involving diazonium salts, etc. Such reactions are moderately or highly exothermic. Conventionally, by the use of slow addition of reagents and maintaining very low temperatures the rate of heat evolution is moderated. However, prolonged reagent addition times followed by extended reaction time actually causes byproduct formation and reduces the yield of the desired product.1 It is possible to overcome these limitations by the use of continuous flow synthesis. The continuous flow synthesis approach allows for excellent control of residence time distribution in the reactor, and the use of miniaturized devices can attain more rapid mixing and better heat- and mass-transfer rates than those of a batch approach. Over the last two decades, continuous flow synthesis for small-volume/high-value chemicals has evolved into a mature approach for synthesis with better ability to control the reactions leading to improved yields of the desired products in a sequence of reactions.2−6 Over the years, the single-step as well as multistep7 (catalytic as well as noncatalytic, homogeneous, or multiphase) reactions are shown to be feasible and better in flow synthesis than in the conventional batch approach. For reactions where one of the reactants is used in excess such as for nitration, halogenations, oxidation, polymerization, etc., the sequential reactions cannot be ruled out. Typically, even in the continuous flow synthesis, by virtue of good mixing and the residence time distribution with the use of a microreactor, the reactions continue to some extent even after the mono derivative is formed in the presence of excess reagent. The secondary derivatives can be avoided at the cost of incomplete conversion of the substrate. However, in such cases an additional separation step is required in the process for the © 2013 American Chemical Society

separation of unreacted reactant, its recycle, and its reuse. It is possible to avoid such a situation by adapting to a multipoint dosing concept where the reagent in excess is dosed spatially at discrete locations. In this article we demonstrate the use of this concept for the sulfoxidation reaction where the secondary oxidation of sulfoxide to sulfone needs to be avoided. Sulfoxidation is an important route for the synthesis of sulfoxide compounds.8,9 Selective oxidation of sulfides to sulfoxides has been studied in the past, and several methods exist that use a variety of oxidizing agents. The most common oxidizing agents include sodium hypochlorite, aqueous hydrogen peroxide,10,11 m-chloroperbenzoic acid (m-CPBA),12 peracetic acid, and the halogens13 such as bromine and chlorine. In a typical sulfoxidation reaction, the presence of excess oxidizing agent gives sulfoxide and also undesired sulfone, if the reaction is not stopped at the sulfoxide stage. The resulting sulfoxide compounds predominantly find use as proton pump inhibitors12 such as pantoprazole, rabeprazole, lansoprazole, omeprazole, tenatoprazole, and modafinil (a drug for the treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea). The prazole types of molecules inhibit gastric acid by blocking specific adenosine triphosphatase enzyme, which acts as a proton pump in gastric parietal cells.14 Typically, in the synthesis of the tenatoprazole, 2, the imidazo[4,5-b]pyridine compound 1, shown in Scheme 1, is mixed with an oxidizing agent (usually dissolved in solvents in large quantities). For this exothermic reaction poor heat transfer and competing reaction rates for the formation of overoxidized product give poor selectivity to the sulfoxide. A batch process for the synthesis of compound 2 is known and has been reported. For example, U.S. Patent 4,808,596 discloses a Special Issue: Engineering Contributions to Chemical Process Development Received: May 30, 2013 Published: August 23, 2013 1293

dx.doi.org/10.1021/op400138v | Org. Process Res. Dev. 2013, 17, 1293−1299

Organic Process Research & Development

Article

Scheme 1. Synthesis of tenatoprazole

Figure 1. Schematic of the experimental setup. (A) Setup with single tubular reactor. (B) Arrangement of numbering-up with single-point dosing of oxidizing agent. (C) Setup with multipoint injection. (D) Configurations of the tubular reactor used for multipoint injection with numbering-up (blue line = sulfide inlet; black line = product outlet; lines 1, 2, 3, and 4 correspond to different inlets for the oxidizing agent along the reactor length).

is also known.15 For example, Sripathi et al.16 have reported an improved method for the synthesis of tenatoprazole. The sulfide, when treated with 0.9 equiv of m-CPBA at −10 to −15 °C in a batch process is reported to yield about 72% of crude

process for the synthesis of sulfinyl compounds by reacting compound 1 in chloroform with m-CPBA at 0 to −5 °C. A batch process in the presence of a catalyst wherein the oxidizing agent is aqueous alkali or alkali earth metal hypohalite solution 1294

dx.doi.org/10.1021/op400138v | Org. Process Res. Dev. 2013, 17, 1293−1299

Organic Process Research & Development

Article

Analysis and quantification were done using HPLC (Agilent), and characterization was done by NMR (Bruker). For HPLC, buffer was prepared by dissolving 0.1 M potassium dihydrogen phosphate solution in water and adjusting the pH to 7.4 by 0.1 M NaOH solution. The final clear sample was analysed by HPLC (Agilent model 1100 II, equipped with a UV−vis detector, and a Lichrosphere 100 RP-18 5 μm HPLC column). The mobile phase used for analysis was acetonitrile− KH2PO4 (pH 7.4) buffer, 30:70 v/v at 25 °C; flow rate was set at 1 mL/min, and analysis was carried out at 306 nm wavelength. The same procedure for isolation and quantification was also followed for the samples obtained from the continuous flow experiments. 2.1.3. Continuous Flow Experiments. The flow experiments were carried out in two modes. In the first method we used a single-point dosing of the oxidizing agent, while in the second method we divided the oxidizing agent into different amounts, and dosing was carried out at different locations along the reactor length. 2.1.3.1. Single-Point Dosing. The typical experimental setup consisted of two syringe pumps (Longer Pumps, China), a constant temperature bath (Julabo, Germany), at least one micromixer (IMM’s caterpillar micromixer or an internally structured Tee-micromixer), and a tubular reactor (1.3 mm i.d., 1.58 mm o.d., and 1 m long). The inlet compositions for the two streams were (i) 80 mg of m-CPBA (55−70% concentration) in 5 mL of solvent (methanol) and (ii) 100 mg of sulfide in 10 mL of methanol, the two solutions were mixed using a Tee-micromixer followed by a 1 m long retention time tube. Numbering approach was followed for the scale-up and the schematic of the setup is shown in Figure 1B. 2.1.3.2. Multipoint Dosing. Experiments were also carried out by injecting the oxidizing agent at multiple locations (using more pumps) along the reactor length. In these experiments with multipoint injection, the tube length was 5 m. The necessary residence time was achieved by choosing a combination of flow rates. For example, at constant flow rate of oxidizing agent, the pointwise flow was distributed in different proportions in four different ways, viz. (0.25, 0.25, 0.25, 0.25), (0.5, 0, 0.5, 0), (0.1, 0.2, 0.3, 0.4), and (0.4, 0.3, 0.2, 0.1). The connection at the inlet of each tube went through a 40-mm long union having a bore diameter (0.8 mm) smaller than the tube diameter. This along with the helical coil helped create a relatively large upstream pressure drop which helped to achieve uniform flow distribution in the numbering-up approach.

tenatoprazole. Usually, the low temperature is required to prevent the formation of side products and thus improves the specificity of the reaction. For example, a similar process15 claims about 85% yield of the desired product if the addition is carried over from 1 to 4 h. Thus in general, (i) the reaction temperature is maintained below 0 °C to avoid the formation of sulfone, (ii) the addition of oxidizing agent is done slowly over a longer time,17 and (iii) formation of noticeable amounts of undesired sulfone is common. Therefore, it is necessary to develop a more efficient and selective process for the synthesis of sulfoxide compounds. In this report we focus on the continuous flow synthesis of tenatoprazole and its scale-up. The approach developed in this work can also be extended for the synthesis of other prazole derivatives.18

2. EXPERIMENTAL SECTION The experiments were performed in batch as well as in continuous mode for the synthesis of different sulfoxide compounds in order to compare the two approaches. The reaction mixture was quenched to monitor the completion of the reaction. The details of the experimental setup, procedure, and the analysis are given in this section. 2.1. Experimental Setup and Experimental Procedure. 2.1.1. Preparation of Solutions. The solutions of sulfide 1 were prepared in chloroform or in methanol or in a mixture of both solvents (50% v/v). Three different oxidizing agents H2O2 (28% solution), sodium hypochlorite, and m-CPBA (available as a solid with 55−70% content), all from Thomas Baker, were used for the batch experiments. It was observed that, depending upon the solvent used for dissolving the sulfide, the reaction can be single phase or two phase as the oxidizing agent was always kept in aqueous solution. Using solvents such as acetonitrile for both sulfide and the oxidizing agent can help achieve a single-phase reaction. However, isolation of highboiling solvent requires additional energy in the process of salt formation followed by filtration. On the other hand, the use of IMM caterpillar micromixer or a Tee-mixer (0.5 mm i.d.) followed by a tubular reactor (1.38 mm i.d.) helps overcome the mass-transfer limitations due to narrow-channel dimensions that help enhance mixing and mass transfer rates. In most of the cases the solvents used for both substrates were maintained the same to facilitate an easy isolation of the product. In almost all of the experiments, 100−300 mg of oxidizing agent was taken in 5−20 mL of the solvent, and 50−200 mg of sulfide was taken in 5−20 mL solvent to achieve different concentrations. The oxidizing agent was used in the concentration range of 0.5−20 mol equiv when compared with the sulfide, and the concentration of sulfide was varied in the range from 0.01 to 0.1 w/v. 2.1.2. Batch Experiments. In a typical batch experiment, the oxidizing agent (0.46 mmol in 10 mL of chloroform19) was added dropwise to the sulfide 1 solution (100 mg, i.e. 0.3 mmol in 10 mL of chloroform). The batch experiment was performed in a jacketed, stirred glass reactor, and a constant temperature bath (Julabo, Germany) was used for maintaining the temperature. During the experiments, the temperature was varied in the range of −20 to 5 °C. The addition rate was adjusted to ensure that the temperature in the reactor was within ±1 °C of the experimental temperature. After complete addition the solution was stirred for over 60 min, and samples were withdrawn to monitor the reaction progress. The reaction mass was quenched using aqueous sodium thiosulfate. The product was subjected to analysis after further dilution.

3. RESULTS AND DISCUSSION 3.1. Batch Experiments. A limited number of batch experiments was carried out to identify the conditions that can be extended for a continuous flow system. Also, it was thought desirable to observe a batch reaction first so that the possibilities viz. phase change, rapid heat generation, and issues related to nonhomogeneities specific to individual solvents, etc. can be known. In each experiment, 100 mg of sulfide 1 was dissolved in 10 mL of chloroform and mixed with 80 mg of the respective oxidizing agent dissolved in 10 mL of chloroform. At very low temperatures, viz. −15, −5, and 5 °C, the conversion of 1 was 33, 46, and 86%, respectively, in 20 min. However, the selectivity of the sulfoxide 2 was 100, 98, and 78%, respectively. Additional experiments at 5 °C showed that the quantity of undesired sulfone continues to increase gradually with time and 1295

dx.doi.org/10.1021/op400138v | Org. Process Res. Dev. 2013, 17, 1293−1299

Organic Process Research & Development

Article

cannot be avoided due to inherent back-mixing in the batch mode formation of sulfone. 3.2. Continuous Flow Synthesis. Continuous flow experiments were carried out using the experimental setup discussed in section 2.1.3. The basic setup included a single micromixer followed by tubular reactor. Experiments were carried out at different flow rates, substrate concentrations, and temperatures. In order to identify the right oxidizing agent for these studies, we initially carried out the sulfoxidation in continuous mode with three different oxidizing agents, viz. H2O2, sodium hypochlorite, and m-chloroperbenzoic acid. A stock solution of 300 mg of sulfide 1 in 30 mL of chloroform was prepared. For each experiment, an equimolar concentration of the respective oxidizing agent was dissolved in 10 mL of chloroform. The two reacting solutions were mixed using a Tee-micromixer followed by a 1-m long residence time tube. The reaction was carried out at 5 °C, and the residence time in the tube was maintained at 60 s. With the separate use of hydrogen peroxide, sodium hypochlorite, or m-CPBA as the oxidizing agent dissolved in chloroform, the conversions of sulfide 1 were 3%, 2%, and 84%, respectively. It is interesting to note that with m-CPBA as the oxidizing agent the selectivity towards the sulfoxide compound 2 was 97−99%. The variation corresponds to the different experiments repeated at the same condition. As per the literature data, in general H2O2 is used to a large extent,10 or a transition metal catalyst needs to be used to expedite the reaction at lower concentrations of the oxidizing agent. Both of these options are not economical and viable for the process. We preferred to use m-CPBA as oxidizing agent as it can be used in equimolar quantity and also because of its stability. In view of this, all further experiments were carried out with the same concentrations of substrate and m-CPBA as the oxidizing agent. In order to study the effect of residence time, the experiments were carried out by changing the flow rates to achieve the residence time over a range of 10−300 s. The observations are shown in Table 1. It is evident that, with an

Table 2. Effects of mass equivalents of oxidizing agent and temperature on the performance of continuous flow sulfoxidation at a constant residence time of 60 s

residence time (s)

% conversion of 1

1 2 3 4 5

10 30 60 120 300

51 76 99 (±1) 88.5 (±1.2) 78.7 (±1)

temp °C

1 2 3 4 5 6 7b 8 9 10c 11c 12d 13e

0.8 0.9 1 1.1 1.25 1.5 1 0.8 1.1 1 1.5 1 1.5

5 5 5 5 5 5 5 0 0 5 5 5 5

% conversion of 1 83 88 99 99 100 100 98 77 92 98 98 98 3

(±1) (±2) (±1)

(±2) (±1) (±1)

% selectivity of 2 98 (±1) 94 (±1) 96 (±2) 94 (±1) 94 (±2) 92 (±2) 99 (±1) 97 (±1) 97 (±1) 96 (±1) 95−97 95 100

Mole equivalents in the same solvent volume. bIncrease in the concentration of both the sulfide and oxidizing agent by 100%. c Mixture of methanol and chloroform (50% v/v) as the solvent. d Methanol as the solvent. eH2O2 in methanol as the oxidizing agent.

the conversion was seen to increase, while the selectivity of sulfoxide 2 continued to decrease as the excess oxidizing agent led to the formation of sulfone. Increasing the concentration of both the substrates while having equal mole ratio (entry 7, Table 2) actually helped to obtain a better yield of the desired product even at a shorter residence time (50 s). The use of different solvents (methanol, chloroform, and a mixture of both (50% v/v) actually did not show any effect on the conversion of 1 or on the selectivity towards 2. This observation was verified at −5, 0, and 5 °C. In order to increase the synthesis scale, the experiments were performed by splitting the mixed reactants into four parallel reaction tubes (in coil form) immersed in the same constant temperature bath (Figure 1B). The outlets of the four tubes were connected to a five-way connector to collect the product. The experiment corresponding to entry 3 was performed, and the product was subjected to analysis. The analysis shows that the results were close to those observed in single-tube experiments with over 99% conversion and 95.4% selectivity for the sulfoxide 2. The consistency in the observations from different sets was within ±2.4%. Since the undesired sulfone formed in these experiments could not be overlooked, it was necessary to use a novel way to reduce the formation of the product resulting from the sequential reaction. 3.3. Flow Synthesis with Multipoint Dosing Approach. The schematic of the experimental setup with multipoint dosing of the oxidizing agent is shown in Figure 1C. The total reactor length was 5 m, and four inlets for the oxidizing agent were spaced at every 1 m starting from the reactor inlet. Different syringe pumps were used for dosing m-CPBA at different inlets so that the flow rates could be varied independently. The solution of the sulfide was injected continuously in the tubular reactor at the first inlet, while the solution of m-CPBA was injected continuously in either similar or different proportions through the five inlets located discretely along the reactor length. At every inlet of the oxidizing agent, a Tee-mixer was used for inline mixing. One gram of compound 1 and 800 mg of m-CPBA were dissolved separately in 100 mL of chloroform. Ten different experiments

% selectivity of 2 99 98 96 87 73

mass equiv of m-CPBAa

a

Table 1. Effect of residence time on the performance of continuous flow sulfoxidation no.

no.

(±1) (±1) (±2) (±1) (±2)

increase in the residence time, the conversion of 1 and the selectivity of 2 go through a maximum. Since the increase in residence time was achieved by reducing the flow rates, the heat transfer rates also decreased, which also encourages the oxidation of sulfoxide 2 to sulfone. For an equimolar quantity of oxidizing agent with an increase in the residence time, sulfoxide is also available for oxidation (more due to its increasing concentration along the reactor length), thereby making sulfide 1 a limiting reactant. This reduces the conversion of sulfide 1 and also the selectivity of sulfoxide 2. In view of the above observations, further experiments were conducted with 60 s as residence time, and the effects of concentration of m-CPBA, temperature, and the solvent were studied (Table 2). With an increase in the mole ratio of mCPBA to compound 1 from 0.8 to 1.5 at identical conditions 1296

dx.doi.org/10.1021/op400138v | Org. Process Res. Dev. 2013, 17, 1293−1299

Organic Process Research & Development

Article

decrease (as the flow rate increased to some extent beyond every inlet) along the reactor length, unless the dosing profile was properly adjusted.21−26 The observations from our experiments on spatial dosing of oxidizing agent are shown in Figure 3. The conversion of 1 was found to be higher for the cases where the overall residence time was high and also at the higher temperature. The selectivity towards the desired sulfoxide 2 was higher at the lower temperature. However, at lower residence time the selectivity of sulfoxide 2 was higher at the higher temperature. The plot of the yield of the desired product (conversion of 1 × selectivity of 2) as a function of the residence time (which depends upon the flow rate variation at different injection points) showed that the yield of 2 goes through a maximum for both of the temperatures. Thus, for every reaction temperature the yield can be maximum only at a specific flow rate distribution (i.e., residence time). Thus, for a given flow rate distribution in a multipoint dosing system the temperature can be chosen such that the yield of the desired product is maximized at complete conversion. This approach will always give a much better yield of the desired product than the conventional single-point injection. In our experiments we found that the % flow rate distribution of 41:27:19:13 gave the best performance in terms of yield of the desired product with over 99% conversion.27 Hence, the experiments were carried out at 15 °C by bringing the residence time to 60 s while maintaining the flow rate distribution as above, which helped achieve 99% selectivity towards sulfoxide compound 2. In order to achieve a higher production scale, the numberingup approach was used at 15 °C. The schematic of the arrangement of tubes and the dosing network is shown in Figure 1D. The tube diameter was maintained the same as before, while the tube length was increased by 4 times. This helped us increase the capacity by 16 times using a simple setup. For a given dosing position in all tubes, a single pump was used for a specific flow rate, and the correctness in the flow rate was verified at each dosing point. Since the reaction is exothermic, higher mass flow rates actually helped enhance the conversion even at shorter residence time. The experiments were carried out for over 30 min, and the composition at the outlet was checked from time to time. The analysis of the product showed that, with 100% conversion of the substrate sulfide, the yield of sulfoxide was over 99%. This experiment was repeated thrice, and the variation in the observations was less than 0.3%.

were carried out by varying the flow rates, overall residence times, and the temperatures (5 and 15 °C). The proportion of flow rates in different inlets for the oxidizing agent is shown in Figure 2. Depending upon the

Figure 2. Fractional variation in the inlet flow rates at different locations in the multipoint injection experiment.

dosing configuration, the residence times for all of these experiments were found to vary in the range of 15−180 s.20 The observations from different experiments are shown in Figure 3. For the case of equal flow rates in all of the inlets for

4. CONCLUSIONS A continuous synthesis approach with multipoint dosing of an oxidizing reagent is demonstrated for the synthesis of tenatoprazole 2. Use of multipoint dosing of the oxidizing agent helped to minimize the possibility of over-oxidation leading to sulfone. Different oxidizing agents were tested, and the effects of various parameters, viz. the mole ratio of sulfide to oxidizing agent, the temperature, the residence time, the concentration of oxidizing agent, etc., on the yield of the desired sulfoxide compound were studied. A residence time of 60 s at 5 °C for an equimolar composition of the reactants was found to yield almost complete conversion of the sulfide 1 and 98% selectivity towards the sulfoxide 2. A numbering-up approach with single-point dosing and multipoint dosing was successfully tested to validate the feasibility for increasing the production capacity. The multipoint dosing system at 15 °C and cumulative residence time of 60 s with specific flow rate ratios helped achieve 99% selectivity towards the sulfoxide

Figure 3. Effect of temperature on the variation in the % yield of sulfoxide as a function of total residence time in the tubular reactor.

oxidizing agent and 60 s residence time, at 5 °C the analysis showed 85% conversion, 99% selectivity of sulfoxide, and 0.5% of sulfone. With 50 s residence time and identical temperature, conversion was 97%, while selectivity towards sulfoxide compound was 98.5%, and 1% sulfone was formed. At a given reactor temperature, spatial dosing of one of the reactants along the reactor length usually helped to avoid the secondary reaction. However, it also decreased the conversion of the main substrate as the residence time continued to 1297

dx.doi.org/10.1021/op400138v | Org. Process Res. Dev. 2013, 17, 1293−1299

Organic Process Research & Development

Article

(13) Kowalski, P.; Mitka, K.; Ossowska, K.; Kolarska, Z. Oxidation of sulfides to sulfoxides. Part 1: Oxidation using halogen derivatives. Tetrahedron 2005, 61, 1933−1953. (14) Ritter, J. M. L.; Lewis, L. D.; Mant, T. G. K. A Textbook of Clinical Pharmacology, 4th ed.; Hodder Arnold: London, U.K., 1999 (15) Kankan, R. N., Rao, D. R.; Srinivas, P. L. Pharmaceutical process and compounds prepared thereby. U.S. Patent 7,439,367, 2008. (16) Sripathi, S.; Bojja, R. R.; Karnati, V. R.; Raju, V. V. N. K. V. P.; Khunt, M. D. An improved synthesis of antiulcerative drug: Tenatoprazole. Org. Process Res. Dev. 2009, 13, 804−806. (17) Kotagiri, V., Kumar, K. V.; Jayantilal, V. P.; Kumar, N. U.; Reddy, B. S.; Chandrashekar, E. R. R.; Kumar, K. N.; Lilakar, D. J.; Reddy, P. R.; Gangula, S.; Reddy, J. V.; Thakur, P. Anitha, N.; Rambabu, K. V. A process for the preparation of benzimidazole derivatives and their salts. WO/2008/045777, 2008. (18) Kulkarni, A. A.; Joshi, R. A.; Joshi, R. R.; Nivangune, N. T.; Jagtap, M. A. Continuous flow process for the preparation of sulphoxide compounds. WO/2012/004802, 2012 (19) The substrates and the product used for the experiments had poor solubility in other water immiscible solvents viz. dichloromethane. Hence, methanol and chloroform were tried as solvents. In most of the cases methanol was used as solvent, and in some cases a mixture of methanol and chloroform were used as solvents. Chloroform was used as a solvent in very few experiments. (20) The flow rate of the sulfide solution was maintained constant at the first inlet, while the oxidizing agent was distributed at different locations. The flow rate of the stock solution was maintained such that the mole ratio of the reactants used for the reaction remained the same as discussed earlier. From the values of the flow rates at individual locations, the local velocity in individual segments was estimated. Since the volume of individual segments between two inlet points was fixed, the residence time entirely depended upon the velocity of fluid in that segment. The sum of residence time for every segments yielded the mean residence time for a given flow distribution combination. Thus, if [QS,1] is the flow rate of the sulfide at the first inlet, and [QO,1], [QO,2], [QO,3], and [QO,4], are the flow rates of the oxidizing agent at inlets 1− 4, and V1, V2, V3, and V4 are the volumes of the individual segments of the reactor between two inlets for the oxidizing agent, then

compound and minimized formation of the undesired sulfone. This approach can also be extended to the production of other prazole compounds.

■

ASSOCIATED CONTENT

S Supporting Information *

(i) Conversion of sulfide and selectivity of sulfoxide at different residence times for the case of the multipoint dosing approach. (ii) Method for the estimation of residence time for the multipoint dosing approach. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] Notes

The authors declare the following competing financial interest(s): CSIR’s Internal Disclosure Number: 78NF2009 an d Patent Applications US20120203003A1 and EP2451810A1.

■

ACKNOWLEDGMENTS We thank the Industrial Consortium for Microreaction Technology (NCL, Pune) and the Centre of Excellence for Microreactor Engineering (NCL, Pune) for the financial support for this work. We are grateful to Dr. Srinivas Hotha (IISER, Pune) for his valuable suggestions on restructuring the discussion in the manuscript.

■

REFERENCES

(1) am Ende, D. J. Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing; John Wiley & Sons: New York, 2011. (2) Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Deciding whether to go with the flow: Evaluating the merits of flow reactors for synthesis. Angew. Chem., Int. Ed. 2011, 50 (33), 7502−7519. (3) Ley, S. V. On being green: Can flow chemistry help? Chem. Rec. 2012, 12, 378−390. (4) Malet-Sanz, L.; Susanne, F. Continuous flow synthesis. A pharma perspective. J. Med. Chem. 2012, 55, 4062−4098. (5) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Greener approaches to organic synthesis using microreactor technology. Chem. Rev. 2007, 107, 2300−2318. (6) Illg, T.; Lob, P.; Hessel, V. Flow chemistry using milli- and microstructured reactors: From conventional to novel process windows. Bioorg. Med. Chem. 2010, 18, 3707−3719. (7) Webb, D.; Jamison, T. F. Continuous flow multistep organic synthesis. Chem. Sci. 2010, 1, 675−680. (8) Block, E.; Cai, X. J.; Uden, P. C.; Zhang, X.; Quimby, B. D.; Sullivan, J. J. Allium chemistry: Natural abundance of organoselenium compounds from garlic, onion and related plants and in human garlic breath. Pure Appl. Chem. 1996, 68, 937−944. (9) Block, E. The organosulfur chemistry of the genus Allium: Implications for the organic chemistry of sulfur. Angew. Chem., Int. Ed. Engl. 1992, 31, 1135−1178. (10) Noguchi, T.; Hirai, Y.; Kirihara, M. Highly selective 30% hydrogen peroxide oxidation of sulfides to sulfoxides using micromixing. Chem. Commun. 2008, 26, 3040−3042. (11) Kaczorowska, K.; Kolarska, Z.; Mitka, K.; Kowalski, P. Oxidation of sulfides to sulfoxides. Part 2: Oxidation by hydrogen peroxide. Tetrahedron 2005, 61, 8315−8327. (12) Kato M.; Toyoshima Y.; Iwano N. Production of 2-(2pyridylmethylsulfinyl) benzimidazole compounds by selective oxidation in the presence of a vanadium catalyst. U.S. Patent 5,578,732, 1996.

residence time for segment 1: t1 = V1/ Q S,1 + Q O,1⎤⎦

(

residence time for segment 2: t 2 = V2/ Q S,1 + Q O,1 + Q O,2 ⎤⎦

(

residence time for segment 3: t3 = V3/ Q S,1 + Q O,1 + Q O,2 + Q O,3⎤⎦

(

residence time for segment 4: t4 = V4 / Q S,1 + Q O,1 + Q O,2 + Q O,3 + Q O,4 ⎤⎦

(

total residence time in the reactor: T = t1 + t 2 + t3 + t4 (21) Lu, Y.; Dixon, A. G.; Moser, W. R.; Ma, Y. H. Analysis and optimization of cross-flow reactors with staged feed policies Isothermal operation with parallel-series, irreversible reaction systems. Chem. Eng. Sci. 1997, 52, 1349−1363. (22) Seidel-Morgenstern, A., Ed. Membrane Reactors: Distributing Reactants to Improve Selectivity and Yield; Wiley-VCH: Weinheim, 2010. (23) Sheintuch, M.; Lev, O.; Mendelbaum, S.; David, B. Optimal Feed Distribution in Reactions with Maximal Rate. Ind. Eng. Chem. Fund. 1986, 25, 228−233. (24) Delsman, E. R.; de Croon, M. H. J. M.; Kramer, G. J.; Cobden, P. D.; Hofmann, C.; Cominos, V.; Schouten, J. C. Experiments and modelling of an integrated preferential oxidation-heat exchanger microdevice. Chem. Eng. J. 2004, 101, 123−131. 1298

dx.doi.org/10.1021/op400138v | Org. Process Res. Dev. 2013, 17, 1293−1299

Organic Process Research & Development

Article

(25) Lu, Y. P.; Dixon, A. G.; Moser, W. R.; Ma, Y. H. Analysis and optimization of cross-flow reactors with distributed reactant feed and product removal. Catal. Today 1997, 35, 443−450. (26) Thomas, S.; Pushpavanam, S.; Seidel-Morgenstern, A. Performance improvements of parallel-series reactions in tubular reactors using reactant dosing concepts. Ind. Eng. Chem. Res. 2004, 43, 969−979. (27) The multipoint injection experiments were carried out at several conditions viz. equal flow rates at all locations, linearly increasing flow rates, linearly decreasing flow rates, exponentially increasing flow rates, exponentially decreasing flow rates, etc. The number of additional side feeds was chosen to be four as when we had used only two side feeds we had not obtained the expected results, and hence, the four was decided on the basis of the availability of resources. Distance between the side feeds was kept constant. We do understand that the parameters viz. number of side feed locations, actual distance between the side feed locations, nature of distribution of side feed locations on the reactor, nature of distribution of feed along the reactor, temperature in each segment of the reactor, etc. affect the reactor performance. The details given in this manuscript are specific for this synthesis. The reaction rates and the relative ratio of rate constants actually govern the selection of above parameters. While a few rules of thumb exist (see refs 20 and 21), it is necessary to explore the exact conditions experimentally for individual reaction systems.

1299

dx.doi.org/10.1021/op400138v | Org. Process Res. Dev. 2013, 17, 1293−1299