Ind. Eng. Chem. Res. 2006, 45, 1259-1265
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APPLIED CHEMISTRY Calcium Pantothenate. Part 1. (R,S)-Pantolactone Technology Improvement at the Tonnage Scale Tomasz Rowicki, Ludwik Synoradzki,* and Marek Włostowski Laboratory of Technological Processes, Faculty of Chemistry, Warsaw UniVersity of Technology, ul. Noakowskiego 3, 00-664 Warszawa, Poland
The synthesis of (R,S)-pantolactone at the laboratory and industrial scales has been investigated. Major side products were separated and identified, leading to a thorough understanding of the nature of the reactions occurring. The technology was thereby improved at many stages, resulting in an increased yield, a decrease of the process duration, and reductions of the raw-material and energy consumptions as well as the waste emission. Some of the elaborated solutions have already been implemented in production. Introduction
yield was ca. 72%. Our goal was to improve the yield as well as other coefficients of the process.
(R)-Pantolactone, i.e., (R)-4,5-dihydro-3-hydroxy-4,4-dimethylfuran-2(3H)-one [(R)-5], is a key compound in the synthesis of calcium (R)-pantothenate and (R)-panthenol, both precursors of vitamin B5.1 Both compounds are widely used as ingredients in pharmaceutical and cosmetic compositions, as well as food and feed supplements. The global production of pantothenates has grown continuously over the past >10 years, and in 2002, it exceeded 9000 tons, with the world market value reaching $200 million. Recently, the optically pure enantiomers of pantolactone have also found application in organic synthesis as chiral resolving agents and auxiliaries.2,3 Because the current methods of (R)-pantolactone manufacturing are based on the resolution of the racemate4,5 or asymmetric hydrogenation of ketopantolactone,6 there is still demand for the synthesis of (R,S)-pantolactone, which serves as a starting material for both racemate resolution and ketopantolactone synthesis. Racemic pantolactone (5) can be obtained from 2-methylpropionicaldehyde (1) in a three-step procedure involving the aldol reaction with formaldehyde (2), hydrocyanation of the 3-hydroxy-2,2-dimethylaldehyde (3) formed, followed by 2,4dihydroxy-3,3-dimethylbutanenitrile (4) hydrolysis (Scheme 1). Even though it has been over 100 years from the first pantolactone synthesis by Glaser,7 the essential steps of its production method remain the same. Naturally, the technology has been improved through the years, bringing the yield of final product up to 80-90%, when the process is carried out without isolation of the intermediates.8 The (R,S)-pantolactone technology development described herein was accomplished in cooperation with Grodziskie Zakłady Farmaceutyczne “Polfa” Ltd., a Polish pharmaceutical plant. Therefore, most of the experiments have been performed not only at the laboratory scale, but also at the technical scale, in reactors up to 3 m3, with a considerable synthesis scale-up factor of 9500. At the starting point, the annual production capacity was 300 tons of (R,S)-pantolactone, and the process * To whom correspondence should be addressed. E-mail:
[email protected]. Fax: +48(22)6255317.
Theoretical Analysis of the Process When starting our research, we decided to focus on the side products present in the final product as well as in the intermediary streams. We intended to use them as key factors, allowing us to fully understand the process, thus helping in a quicker and more efficient improvement of the technology. The first step of pantolactone (5) synthesis is an aldol reaction of 2-methylpropionicaldehyde (1) and formaldehyde (2). Because it is a crossed-aldol reaction, there is also the possibility of the formation of an undesired products3-hydroxy-2,2,4trimethylvaleraldehyde (6)sas a result of 1 self-condensation (Scheme 2). The too-low conversion of 1, in addition to the obvious yield lowering, might also affect the process by leaving unreacted aldehydes 1 and 2. The second step of 5 synthesis is hydrocyanation of 3 with sodium cyanide. The hypothetical presence of aldehydes 1, 2, and 6 would follow in their reaction with NaCN to cyanohydrins 7-9, respectively (Scheme 2). The third step of the process is cyanohydrin 4 hydrolysis that, with subsequent lactonization, leads to the final product 5. The result of the presence of compounds formed at earlier steps seems to pose a possible hazard for the progress of this reaction. For example, the cyanohydrins 7 and 8 formed earlier might hydrolyze to the respective hydroxy acids 10 and 11. An even more undesirable reaction can occur in the case of 9, which, during hydrolysis, might also undergo lactonization, resulting in the formation of dihydro-3-hydroxy-5-isopropyl-4,4-dimethylfuran-2(3H)-one (12), an alkyl-substituted pantolactone (Scheme 2). Because of structural analogies between 5 and 12, the latter might be a difficult to remove as a contaminant of the former. Experimental Section Commercially available solvents and reagents were used without further purification. GC analysis was performed with a Hewlett-Packard 6890 chromatograph with a flame ionization detector (FID), equipped with an HP-1 capillary column. 1H
10.1021/ie050774u CCC: $33.50 © 2006 American Chemical Society Published on Web 01/21/2006
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Scheme 1. Synthesis of (R,S)-Pantolactone (5)
Scheme 2. Formation of Possible Side Products during 5 Synthesis
and 13C NMR spectra were obtained using a Varian Gemini 200 spectrometer. Infrared spectra were recorded on a Carl Zeiss Jena spectrophotometer (Specord M80). Laboratory-Scale Synthesis of Pantolactone (5). Optimized Procedure. To a 30% water/methanol solution of formaldehyde (12.25 g, 0.41 mol) was added 2-methylpropionicaldehyde (28.84 g, 0.40 mol), followed by sodium carbonate (1.26 g, 0.0112 mol). The temperature immediately increased, thus indicating the beginning of the reaction. The reaction mixture was maintained at 65 °C for 3 h and then allowed to cool to room temperature for 5 h. After further cooling to 2 °C, a 30% water solution of sodium cyanide (20.35 g, 0.41 mol) (Caution: toxic) was quickly dropped into the post-aldol reaction mixture. An intensive cooling was required to maintain the temperature below 10 °C. Next, a 50% sulfuric acid (41.16 g, 0.42 mol) solution was added at a temperature not exceeding 15 °C. The mixture was then warmed to about 100 °C for 3 h. Methanol was distilled off during heating, and the mixture was maintained for an additional 3 h under reflux. After the twophase mixture had cooled to approximately 30 °C, its pH was adjusted to ∼6.0 with sodium carbonate. 1,2-Dichloroethane (70 g) was then added, and the mixture stirred intensively for a few minutes and left to allow the layers to separate. The organic layer (127 g) containing 33.6% (GC) of 5 was collected (yield 82%). For analysis, a sample was recrystallized from benzene/ hexane. 1H NMR (CDCl3, 200 MHz): δ 1.04 (s, 3H, CH3), 1.18 (s, 3H, CH3), 3.94 and 3.97 (AB system, J ) 9.0 Hz, 2H, CH2), 4.17 (s, 1H, CH). 13C NMR (D2O, 50 MHz): δ 18.5 (CH3), 21.8 (CH3), 40.9 (C), 75.7 (CH2), 77.1 (CH), 180.0 (C). IR (KBr): 3430, 1780 cm-1. Mp: 82 °C. GC-MS (C6H10O3): 130 (0, M+), 71 (100), 43 (63), 41 (42), 57 (31), 29 (30), 39 (25), 27 (21), 55 (14), 72 (12), 53 (11). Technical-Scale Synthesis of Pantolactone (5). 2-Methylpropionicaldehyde (175 dm3, 1899 mol) and 190 dm3 of a water/ methanol formaldehyde solution containing 2017 mol of HCHO were placed in each of the two parallel reactors. Then, 6 kg of sodium carbonate was added to each reactor, thus starting the aldol reaction. The reaction mixtures were maintained at 65 °C for 3 h and then allowed to cool to room temperature for 5 h. Next, the reaction mixtures were transferred to two other parallel reactors and cooled to 2 °C. The addition of a 30% sodium cyanide water solution (Caution: toxic) was immediately started [100 kg (2035 mol) of NaCN per reactor]. While the reactors were being cooled, the rate of cyanide solution addition was regulated to maintain the temperature below 10 °C. Immediately after the sodium cyanide addition was finished, the reaction
mixtures were transferred to the other two parallel reactors, and 463 kg of concentrated hydrochloric acid was added to each of the reactors. The rate of HCl addition was regulated to maintain the temperature below 15 °C. The acidified mixtures were combined in one reactor, and heating was started to perform hydrolysis. In approximately 3 h, the temperature reached 100 °C, and methanol distilled off. The mixture was maintained for 4 h under reflux and then cooled to ca. 40 °C. After the mixture had been transferred to the other reactor, the pH was adjusted to ∼6.0 with sodium hydroxide and sodium carbonate. The precipitate of sodium and ammonium chlorides was filtered off, and the resulting water solution of 5 (ca. 2400 kg) and 1,2dichloroethane (ca. 4600 kg) was pumped into continuous extractors for ca. 10 h. DCE was evaporated from the resulting 5 solution (ca. 5000 kg). The crude 5 was distilled under reduced pressure to afford 384 kg of 5 as white pellets (yield 77.7%). Isolation and Identification of Dihydro-3-hydroxy-5-isopropyl-4,4-dimethylfuran-2(3H)-one (12). Dihydro-3-hydroxy5-isopropyl-4,4-dimethyl-2(3H)-furanone as white needles was isolated from the samples taken at the plant. 1H NMR (CDCl3, 200 MHz): δ 0.93 (s, 3H, CH3), 0.96 (d, J ) 6.6 Hz, 3H, CH3), 1.06 (d, J ) 6.6 Hz, 3H, CH3), 1.25 (s, 3H, CH3), 1.91 (m, J ) 6.6, 9.8 Hz, 1H, CH), 3.62 (d, J ) 9.8 Hz, 1H, CH), 3.66 (d, J ) 3.4 Hz, 1H, OH), 4.11 (d, J ) 3.4 Hz, 1H, CH). IR (KBr): 3396, 1752 cm-1. Mp: 89-91 °C. GC-MS (C9H16O3): 172 (0, M+), 85 (100), 72 (33), 57 (23), 43 (22), 55 (19), 41 (16), 73 (14), 101 (10), 39 (8), 29 (8). Synthesis of 2,2-Dimethyl-1,3-propanediol (14). 3-Hydroxy2,2-dimethylpropionicaldehyde (4.0 g, 0.04 mol) and sodium hydroxide (1.6 g, 0.04 mol) in 90 mL of water were stirred at room temperature. When TLC analysis (hexane/ethyl acetate 1:2) showed no substrate, the water solution was extracted with diethyl ether (15 × 40 mL), and the combined extracts were dried over magnesium sulfate. MgSO4 was filtered off, and the filtrates were concentrated. 2,2-Dimethyl-1,3-propanediol crystallized from concentrated filtrates as white needles (yield 34%). 1H NMR (CDCl , 200 MHz): δ 0.89 (s, 6H, 2CH ), 2.83 (s, 3 3 2H, 2OH), 3.48 (s, 4H, 2CH2). IR (KBr): 3390 cm-1. Mp: 118-121 °C. GC-MS (C5H12O2): 104 (0, M+), 56 (100), 55 (84), 73 (53), 43 (37), 41 (36), 31 (32), 29 (28), 45 (24), 57 (21), 39 (21). Isolation and Identification of 2-Isopropyl-5,5-dimethyl1,3-dioxane (16). 2-Isopropyl-5,5-dimethyl-1,3-dioxane was isolated by distillation under reduced pressure (59 °C, 2.0 kPa) from samples taken at the plant. 1H NMR (CDCl3, 200 MHz):
Ind. Eng. Chem. Res., Vol. 45, No. 4, 2006 1261 Scheme 3. Formation of 2,2-Dimethyl-1,3-propanediol (14)
Table 1. Pantolactone and Side-Product Distribution in Selected Streams after Decreasing the Hydrocyanation Duration Time yielda (%) stream
1
5
12
14
16
total
mixture after hydrolysis final product
1.4 -
85.8 77.7
1.9 0.7
9.1 4.2
0.9
98.2 83.5
a
Scheme 4. Formation of 2-Isopropyl-5,5-dimethyl-1,3-dioxane (16)
δ 0.67 (s, 3H, CH3), 0.91 (d, J ) 6.8 Hz, 6H, 2CH3), 1.13 (s, 3H, CH3), 1.78 (m, J ) 6.8, 4.6 Hz, 1H, CH), 3.36 and 3.56 (AB system, J ) 10.4 Hz, 4H, 2CH2), 4.11 (d, J ) 4.6 Hz, 1H, CH). 13C NMR (CDCl3, 50 MHz): δ 16.9 (2CH3), 21.7 (CH3), 22.8 (CH3), 30.1 (C), 32.5 (CH), 77.1 (2CH2), 105.6 (CH). GCMS (C9H18O2): 158 (1, M+), 115 (100), 69 (61), 56 (58), 41 (32), 43 (19), 71 (17), 45 (17), 57 (16), 157 (13), 55 (12). Results and Discussion Side Product Identification. To verify our hypotheses concerning the nature of the side reactions taking place in the synthesis process, we isolated and identified the main side products present in the pantolactone. We found three compounds permanently present in the final product. One of them was lactone 12, an anticipated analogue of 5; however, the remaining two, hydroxy acids 10 and 11, were not detected. Instead, two other compounds that had not been predicted by the theoretical analysis were found as side products. These were 2,2-dimethyl1,3-propanediol (14) and 2-isopropyl-5,5-dimethyl-1,3-dioxane (16). A few other compounds also could be found in the final product, but they appeared irregularly and in negligible amounts. The question is: What reactions were responsible for the formation of compounds 14 and 16? Considering the compounds present in the reaction mixture, the only possible means of diol 14 formation was the Cannizzaro reaction of aldehyde 3 or aldehydes 3 and 2 (Scheme 3). Because the Cannizzaro reaction requires a stoichiometric amount of a base, it could take place solely during hydrocyanation, where an equivalent amount of NaOH was formed for each mole of product. By a short analysis of the reactions proceeding during hydrocyanation, we could conceive how dangerous the Cannizzaro reaction is for the whole technology. Actually, that reaction is secondary to hydrocyanation, which is the main reaction, but in contrast to hydrocyanation, the Cannizzaro reaction is irreversible, which bears important consequences. Therefore, the consumption of aldehyde 3 in the Cannizzaro reaction shifts the reversible hydrocyanation back toward reactants, which obviously decreases the yield of 5 and, in the most unfavorable case, might even reduce the yield to one-third of the theoretical value. The third, identified side product, dioxane 16, could be formed in the reaction of diol 14 with starting aldehyde 1 (Scheme 4). Because acetal formation requires acid catalysis and water removal, this reaction could take place only during solvent distillation after extraction of 5, if neutralization of excess acid after hydrolysis was incomplete.
Yields measured by GC analysis based on calibration curves.
Improvement of the Pantolactone Technology. Among the identified side products, diol 14 constituted the largest amount, so we first investigated the step responsible for its formation, i.e., hydrocyanation of aldehyde 3. Because the Cannizzaro reaction is secondary to the main reaction (Scheme 3), an overly long reaction time would favor the formation of diol 14. On the other hand, the reaction time should be long enough to ensure the completion of aldehyde 3 hydrocyanation. Fortunately, the latter is a much faster process and proceeds smoothly with a significant thermal effect, so very intensive cooling is necessary to maintain the temperature within the range assigned. We decided, therefore, to curtail the hydrocyanation time to the minimum. Thus, the reaction mixture was acidified immediately after the addition of sodium cyanide solution, with an approximately 15-min delay time necessary to transfer the mixture to the next reactor. Considering safety (possible emission of hydrogen cyanide), we did not measure the cyanohydrin 4 yield, but we took into account only the overall yield of 5. The yield of 5 increased by at least 5%, and the amounts of impurities in the final product decreased similarly. Because the production method remained unchanged except for the shorter hydrocyanation time, the innovation was easily implemented in production, and the average data from about 90 batches are summarized in Table 1. The yield of 5 in the mixture after hydrolysis exceeded 85%, but it was only 77.7% in the final product. Small amounts of 5 were also found in the forerunnings and the residue after distillation. The rest of 5 (over 8%) was certainly lost during isolation, probably at the stage of extraction from aqueous solution, which points at the isolation process as a second very important stage of the overall technology. Additionally, we can see that the sum of the compounds in the mixture after hydrolysis accounts for over 98% of starting aldehyde 1, which corresponds with our earlier findings about the negligible amount of other side products in the process. Also, the absence of dioxane 16 in the mixture after hydrolysis and its further appearance together with the disappearance of starting aldehyde 1 confirms our conclusion relating to the origin of the 16. Next, we turned to the aldol reaction that seemed to be an essential stage for successful synthesis of 5. The aim was to improve the 1 conversion and minimize the side reactions (Schemes 2-4). Unfortunately, the mixture after the aldol reaction was a two-phase mixture, which prevented us from making an immediate estimation of the reaction progress, so as in the case of hydrocyanation, we had to use data obtained after complete 5 synthesis. We investigated the influence of the decrease in formaldehyde excess (from 5% to 2%) and the increase in catalyst amount (from 1.4% to 2.8%) on the synthesis of 5. Two series of 37 and 33 experiments, respectively, were performed at the industrial scale. In the two series, the yield of 5 remained almost unchanged. The observed differences, i.e., 1.3% yield decrease for the lower formaldehyde excess and 0.1% yield increase for the greater catalyst amount, were well within the experimental error. However, we noticed a positive change in the final product composition. In almost all cases, the amount of side products decreased when compared to the previously monitored batches (Table 2). Aside from this optimistic sign,
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Table 2. Side-Product Distribution in the Experiments Concerning the Aldol Reaction side-product amounta (%) experiment
12
14
16
total
monitored batches under standard conditions after HCHO excess reduction after catalyst amount increase
0.9
5.4
1.2
7.5
0.7 0.1
5.1 4.7
1.1 1.8
6.9 6.6
a
Molar ratio to 5 in the final product after distillation.
the experimental error for the results obtained here was generally too large, and more experiments are needed to determine the definite implementation of the proposed changes in the production process. The third developed stage of the technology is cyanonydrin 4 hydrolysis and lactonization leading to 5 with its excessively long time of 10 h. For comparison, the hydrolysis of Nsubstituted 2,4-dihydroxy-3,3-dimethylbutyric acid amides at elevated temperature studied earlier in our laboratory proceeded quantitatively in less than 3 h.9 Because of safety regulations, we were not able to take samples from the production reactor, so we performed the experiments at the laboratory scale, with
precise simulation of the technology conditions (especially important was the temperature profile). Because the mixture after hydrocyanation might contain sodium cyanide, there was also a possible hazard of hydrogen cyanide emission after acidification. Hydrolysis was then carried out under slightly reduced pressure, with evolving hydrogen cyanide and hydrogen chloride absorbed in alkali. The reaction time should thus have been long enough to allow all of the HCN to leave the reactor. To ensure the proper safety level, we measured not only the 5 concentration in the reaction mixture but also the hydrogen cyanide emission during the reaction (Figure 1). As expected, the 5 concentration reached a constant level after less than 3 h, thus showing completion of the cyanohydrin 4 hydrolysis reaction. The hydrogen cyanide emission ceased in a similar time. Considering these results, there is no doubt that the hydrolysis time of 10 h employed to date can be reduced to about 4 h. In addition to obvious process time shortening, this also allows for a reduction of the energy consumption, which is wasted by overly long heating. Another problem during the hydrolysis was a quite large emission of hydrogen chloride. It was absorbed together with
Figure 1. Concentration of 5 and HCN emission during cyanohydrin 4 hydrolysis with HCl.
Figure 2. Concentration of 5 and HCN emission during cyanohydrin 4 hydrolysis with sulfuric acid (laboratory scale).
Ind. Eng. Chem. Res., Vol. 45, No. 4, 2006 1263 Table 3. Pantolactone Concentration in Particular Layers after Hydrolysis and Extraction after hydrolysis and pH adjustment (%)a experiment average values with HCl selected experiments with H2SO4
organic layer 58.9 61.5 43.6
Scheme 5. Formation of Sodium 2,4-Dihydroxy-3,3-dimethylbutyrate (17)
after 1,2-dichloroethane addition to the mixture (%)a
water layer
organic layer
water layer
2.5b
0.75c
18 0.5 0.9 1.7
33.6 22.4 27.4
0.3 0.7 0.1
a Differences in 5 concentration between particular experiments are the result of different H2SO4 concentrations and DCE amounts used. b Typical value obtained with HCl and continuous extraction. c Maximum allowable level according to the technology.
Table 4. Selected Properties of the Two-Phase Mixture after Hydrolysis with 50% Sulfuric Acid density at 25 °C (g/cm3) layer
after hydrolysis and pH adjustment
after 1,2-dichloroethane addition to the mixturea
water content (%)
organic water
1.096 1.335
1.153 1.336
3.0 -
a Extraction was carried out with 14% of 1,2-dichloroethane calculated on the mass of water layer.
hydrogen cyanide in sodium hydroxide solution, necessitating the frequent exchange of the latter. A 15% excess of HCl was necessary to ensure acidic conditions during hydrolysis. We studied the application of sulfuric acid in the place of hydrochloric acid. As in earlier experiments, we precisely simulated the technology conditions at the laboratory scale, monitoring the 5 concentration in the reaction mixture and the hydrogen cyanide emission (Figure 2). The pantolactone concentration and hydrogen cyanide emission profiles obtained were very similar to the previous ones, thus validating the possibility of an easy exchange of HCl by sulfuric acid in the hydrolysis of cyanohydrin 4. Moreover, the reaction mixture after hydrolysis was somewhat unexpectedly a two-phase mixture. Because the concentration was similar to that with hydrochloric acid, there certainly was another reason for the different mixture properties. Pantolactone (5) has an extremely good solubility in water and can form solutions with a concentration even above 90%; therefore, in the case of hydrochloric acid, the chlorides precipitated from the posthydrolysis mixture because of their lower solubility in the water/
pantolactone mixture than in water. In the case of sulfuric acid, the much better solubility of sulfates than the corresponding chlorides, especially that of ammonium sulfate, prevented salt precipitation. As a consequence, a much larger salt effect caused the formation of a separate organic layer. An enormous change in the mixture’s physical properties created an opportunity to simplify the lactone 5 isolation process. We found that the 5 concentration in the water layer was comparable to that in the effluents after continuous extraction with 1,2-dichloroethane (DCE) used at the technical scale. The single extraction of the entire two-phase mixture with DCE allowed us to attain even lower values of 5 concentration in the exhausted liquid (Table 3). The possible elimination of inefficient and energy-consuming continuous extraction offers a significant shortening of the process, reduction of the 1,2-dichloroethane required, and minimization of the losses of 5. Therefore, we studied a few other parameters, important for the technology, employing 50% H2SO4, for which the best properties of the mixture after hydrolysis were observed. We decreased the amount of acid to 1.05 mol calculated for aldehyde 1, from 2.3 mol used in the case of hydrochloric acid. We investigated the density of both layers before and after single extraction with DCE and the water concentration in the organic phase (Table 4). The most important value, the density difference between layers after DCE extraction, was 0.18 g/cm3 compared to about 0.10 g/cm3 for the continuous extraction. This was the reason for the smooth and effective batch layer separation. The low water concentration in the organic layer was also advantageous, because it enabled the direct transfer of the organic phase to distillation. (DCE and water form an azeotrope containing 21% of the latter, so it should be easily removed in the forerunnings.) Thus, our studies clearly showed advantages of exchanging hydrochloric acid with sulfuric acid to the hitherto existing technology. The reaction was completed in less than 3 h, and a similar cessation of the hydrogen cyanide emission, the critical factor for process safety, occurred. Also, other parameters such as the density difference between layers and the water concen-
Figure 3. Gantt chart comparing batches with and without the proposed improvements.
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tration in the organic phase were all well within acceptable levels. The application of sulfuric acid enables the raw material consumption to be reduced significantly (for example, by 86% in the case of DCE) and diminishes the pantolactone losses. Moreover, eliminating the inconveniently long continuous extraction and curtailing solvent evaporation might radically shorten the process. The latter, together with reaction shortening, also offers a considerable energy saving. Next, we studied the isolation process with special attention on the extraction. We found that the average 5 concentration in the exhausted liquid was 0.4%, which corresponds to a 2% loss of 5 calculated with respect to starting aldehyde 1. However, after acidifying the samples to pH 1 and maintaining them for 4 h at 80 °C, the average concentration increased to 1.1%, which corresponds to 5% loss of 5. We ascertained that the reason for this difference was the route of mixture after hydrolysis neutralization. Because it was carried out at approximately 40 °C with concentrated sodium hydroxide, there were local areas with increased pH causing hydrolysis of 5 to sodium 2,4dihydroxy-3,3-dimethylbutyrate (17) (Scheme 5). The application of a weaker base for neutralization, such as sodium carbonate, could prevent this undesired reaction. This should effect an up to 3% pantolactone yield increase. On the contrary, a too-low pH might cause the formation of dioxane 16 as we showed before (Scheme 4). In addition to the overly acidic conditions, the elevated temperature and water removal during DCE evaporation resulted in 16 synthesis. It is worth mentioning that we observed a significant variation of 16 concentration in the batch distillation forerunnings in the range from 0 to 31%. The origin was a recycling of most forerunnings back to distillation because they contained 2-11% of 5, resulting in an accumulation of dioxane 16 in the forerunnings as a side effect. Despite the reasons for the formation of 16, its removal from the distillation forerunnings was a good way to improve the quality of the final product Conclusions As a result of the work presented herein, an existing (R,S)pantolactone technology has been significantly improved at the tonnage scale, with most of the steps being carefully studied and changed. Elaborated solutions enable the (R,S)-pantolactone yield to be increased by 10%, the process time to be cut by 40%, and the raw-material and energy consumption as well as waste emission to be significantly decreased. Most of the improvements were determined at large scale (up to 3 m3), and some have already been implemented into production. The actual scale of the developments elaborated is more easily visualized in a Gantt chart comparing batches with and without the proposed enhancements (Figure 3). Despite the considerable effects achieved, we want to emphasize the methodology of the process improvement used. For ultimate success, knowledge concerning side products and side reactions taking place in the process is an important tool, allowing the main product yield to be maximized and the other technology indexes to be improved with a relatively low number of experiments. Where possible, such an approach to technology development enables precise and efficient actions to be undertaken, leading to an objective achievement. Acknowledgment Financial support from the State Committee for Scientific Research (Grant T09B 627 99 C/4388) and from Warsaw University of Technology, Faculty of Chemistry, is gratefully
acknowledged. The authors kindly thank Grodziskie Zakłady Farmaceutyczne “Polfa” Ltd. for fruitful cooperation and for permission to publish the data concerning (R,S)-pantolactone technology. Literature Cited (1) Kaiser, K.; De Potzolli, B. Pantothenic acid. In Ullmann’s Encyclopedia of Industrial Chemistry, 5th ed.; Elvers, B., Hawkins, S., Eds.; VCH Verlagsgesellschaft: Weinheim, Germany, 1996; Vol. A27, pp 559566. (2) (a) Kitagawa, O.; Momose, S. I.; Fushimi, Y.; Taguchi, T. Efficient synthesis of various atropisomeric amides in optically pure forms and their application to asymmetric reactions. Tetrahedron Lett. 1999, 40, 8827. (b) Bolognesi, M. L.; Budriesi, R.; Cavalli, A.; Chiarini, A.; Gotti, R.; Leonardi, A.; Minarini, A.; Poggesi, E.; Recanatini, M.; Rosini, M.; Tumiatti, V.; Melchiorre, C. WB 4101-Related Compounds 2. Role of the Ethylene Chain Separating Amine and Phenoxy Units on the Affinity for R1-Adrenoreceptor Subtypes and 5-HT1A Receptors. J. Med. 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ReceiVed for reView June 30, 2005 ReVised manuscript receiVed November 10, 2005 Accepted November 10, 2005 IE050774U
