Article pubs.acs.org/OPRD
Process Safety Evaluation and Scale-up of a Lactam Reduction with NaBH4 and TFA Takashi Naka,* Hiroki Ozawa, Ken-ichi Toyama, and Tadashi Shirasaka Process Development Laboratories, CMC Division, Mitsubishi Tanabe Pharma Corporation, 3-16-89 Kashima, Yodogawa-ku, Osaka-shi, Osaka 532-8505, Japan S Supporting Information *
ABSTRACT: The development of a practical and scalable method for the synthesis of morpholine derivative 2 via reduction of lactam 1 using NaBH4 and trifluoroacetic acid (TFA) is described. Through the mechanistic studies using 11B NMR spectroscopy, we observed that active species were generated during TFA addition, which avoids the deactivation of the active species involved in the reduction process. Process safety assessments were performed on the basis of the reaction mechanism using reaction calorimetry and gas evolution analyses. Furthermore, safety equipment was prepared to prevent the leakage of diborane gas during the reaction, and the process was successfully scaled up to the pilot plant at a 35 kg scale.
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INTRODUCTION Lactam reduction is employed in a wide range of syntheses by the pharmaceutical and chemical industries.1 Lactams are usually reduced using LiAlH4,2 borane complexes,3 or NaBH4.4 Generally, these reagents generate hydrogen and high reaction heat; therefore, safety evaluation of such reduction processes is essential for plant-scale manufacturing. Morpholine derivative 2 is a key intermediate in our tau protein kinase 1 inhibitor program. 2 can be obtained via the reduction of lactam derivative 1.5 In the medicinal chemistry route, lactam has been reduced using LiAlH4, which is difficult to handle in plant-scale manufacturing because it is flammable and explosive and causes undesirable side reactions.6 Several reducing agents having reactivities similar to LiAlH4 are available;1 however, some reagents cause difficulties when a reaction using them is scaled up. For example, BH3·THF is a high-cost reagent and presents a storage hazard due to the risk of explosion.7,8 Meanwhile, a combination of NaBH4 and additives is equivalent to LiAlH4 in terms of its reducing properties and is easy to handle in a manufacturing plant.6 Therefore, we focused on the reduction conditions during the conversion of 1 to 2 using NaBH4 and additives. However, the reduction process is highly exothermic, and evaluation of the safety of the process is difficult because the active species involved are not well understood.9,10 We focused on performing a safety assessment based on the reaction mechanism because a deeper understanding of the reaction mechanism can help us better control the active species involved in the reduction process. Here we show that lactam reduction can be achieved using NaBH4 and TFA, and we report the results of our safety evaluation and scale-up of the reduction process.
investigated in an attempt to avoid the disadvantages of using LiAlH4 (Table 1). Table 1. Screening of lactam-reducing agentsa
entry 1 2 3 4 5 a b
LiAlH4 (2.0 equiv) Vitride (2.0 equiv) BH3·THF (2.3 equiv) (1) KBH4 (5 equiv), LiCl (5 equiv); (2) TMSCl (10 equiv) NaBH4 (3.5 equiv), TFA (3.5 equiv)
temp. (°C)
yieldb (%)
2c (%)
3c (%)
66 30 15 25
79 86 95 80
97.6 93.5 97.6 99.4
0.6 0.2 n.d.d n.d.d
25
85
99.6
n.d.d
Screening were carried out in THF for the solubility of 1 and 2. Determined by HPLC. cDetected by HPLC. dNot detected.
Lactam reduction proceeded when several reducing agents were employed. The amount of byproduct 3 could not be maintained within the desired range when Vitride (NaAlH2(OCH2CH2OCH3)2)8 was used (entry 2). Using BH3·THF caused the lactam moiety to be reduced without forming byproduct 3 (entry 3). However, BH3·THF is difficult to handle as a storage hazard due to the risk of explosion. KBH4 and LiCl in the presence of TMSCl11 also reduced 1 without producing byproduct 3 (entry 4). Furthermore, 1 was selectively reduced using a combination of NaBH4 and TFA12 (entry 5), which is easier to handle than either LiAlH4 or BH3·
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RESULTS AND DISCUSSION Screening of Reducing Agents. In the medicinal chemistry route, lactam reduction has been conducted using LiAlH4.5 Several other methods for reducing lactams were © XXXX American Chemical Society
conditions
Special Issue: Safety of Chemical Processes 15 Received: September 3, 2014
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DOI: 10.1021/op500284e Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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trifluoroacetoxy species and the borane species were observed (Figure 1c and d). We speculated that the reactivity of the trifluoroacetoxy species depends on the number of trifluoroacetoxy groups. The lactam reduction reaction was not completed when NaBH4 and TFA were mixed before 1 was added. From this result, we speculated that the species containing more TFA moieties had a lower ability to reduce 1. Next, the actual reaction system using 1 was investigated. 11B NMR spectra of borate derivative 4 are shown in Figure 2a. When 1.75 equiv for 1 and 3.5 equiv of TFA for 1 was added to 1 and NaBH4 in THF, trifluoroacetoxy species and borane species were both observed (Figure 2d and e). This indicates that there are two active species involved in the reduction process, trifluoroacetoxy and borane species. From the 11B NMR results, the following reaction mechanism is speculated (Scheme 1): NaBH4 is converted into sodium monotrifluoroacetoxyborohydride 5, along with hydrogen generation. 5 is then converted into sodium bistrifluoroacetoxyborohydride 6, which is a reducing agent exhibiting less reactivity with 1 than 5. Finally, tetrakis trifluoroacetoxy borate 7 is generated. However, the reaction is not completed when NaBH4 and TFA are mixed before the addition of 1, indicating that only 5 can react with 1 and generate borane, which can further react with 1. Therefore, we conclude that adding TFA is a reasonable sequence that would result in an appropriate reaction condition. The active species are generated and 1 is reduced simultaneously when TFA is added. Adding TFA avoids the deactivation of active species involved in the reduction process (Scheme 1). We tried to evaluate the safety of this reduction process involving TFA addition. Reaction Calorimetry and Gas Evolution Analyses. As already discussed, adding TFA is important for controlling the active species involved in the reduction process. Evaluating the safety during addition of TFA therefore means evaluating the safety of the reduction process. Recently Veedhi reported reaction calorimetry and thermal behavior of the reaction of NaBH4 and TFA.14 Controlled addition of TFA leads the increasing the thermal stability of the reaction mixture. The reaction calorimetry of this reduction reaction was conducted based on this knowledgement using RC1e reaction calorimeter. The heat released during the reaction was determined to be 521 kJ/mol of 1 (Figure 3). The specific heat capacity was determined experimentally, and an adiabatic temperature rise of
THF. Therefore, NaBH4 combined with TFA was used in the subsequent investigations. The actual reducing agent in the NaBH4 and TFA mixture is known to be sodium trifluoroacetoxyborohydride (NaBH4−n(OCOCF3)n (n = 1, 2, or 3)). The effects of using different additives were also investigated. The reducing mixture was more reactive with TFA than with acetic acid.12 However, the detailed reaction mechanism and safety assessment of the reduction process using NaBH4 and TFA have not been reported. Therefore, we investigated the reaction mechanism using 11B NMR spectroscopy and performed a safety assessment for the reaction process on the basis of the reaction mechanism using reaction calorimetry and gas evolution analyses.9,10 Reaction Mechanism. The detailed reaction mechanism was investigated so that the safety of the reaction using the reducing agents could be evaluated. We focused on semibatch approach by the addition of TFA. Another procedure was not appropriate for the following reasons: (1) The lactam reduction reaction was not completed when NaBH4 and TFA were mixed before 1 was added. (2) Solid NaBH4 addition was an unsafe operation.
Figure 1. 11B NMR spectra of NaBH4 combined with TFA. (a) NaBH4, (b) BH3·THF, (c) NaBH4 and TFA (0.5 equiv for NaBH4), and (d) NaBH4 and TFA (1 equiv for NaBH4).
The active species involved in the reduction reaction were analyzed using 11B NMR spectroscopy. The 11B NMR chemical shift values allowed us to estimate the structure of the boron species.13 In Figure 1a and b, 11B NMR spectra of NaBH4 and BH3·THF each are shown. And when 0.5 and 1.0 equiv of TFA for NaBH4 was added to NaBH4 in THF without 1, both the
Figure 2. 11B NMR spectra of the lactam reduction mixtures. (a) 4, (b) NaBH4, (c) BH3·THF, (d) 1, NaBH4 (3.5 equiv for 1) and TFA (1.75 equiv for 1), and (e) 1, NaBH4 (3.5 equiv for 1) and TFA (3.5 equiv for 1). B
DOI: 10.1021/op500284e Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Organic Process Research & Development Scheme 1. Proposed reaction mechanism for lactam reduction of 1
The specific heat capacity was determined experimentally, and an adiabatic temperature rise of 51 K was estimated to occur during the reaction. Comparing the data with 1 and without 1, about half of heat reaction of this reduction reaction is caused by the reaction of NaBH4 and TFA. This heat output ratio was also in good agreement with the TFA addition ratio. These data are similar to the results of Veedhi. These results indicate that TFA addition could control the heat output during the reaction. Gas evolved when TFA was added; therefore, gas evolution analysis was conducted. The gas evolution ratio was in good agreement with the TFA addition ratio (Figure 5). The total
Figure 3. Reaction calorimetry of lactam reduction by NaBH4 and TFA. Conditions: TFA (3.5 equiv for 1) was added to a mixture of 1 (0.35 M) and NaBH4 (3.5 equiv for 1) in THF (10 v/w) at 15 °C (time for dropwise addition of TFA was 60 min). The conversions measured by reaction calorimetry and HPLC are compared.
93 K was estimated to occur during the reaction. The heat output ratio was in good agreement with the TFA addition ratio, and the reaction and heat conversions were almost the same (78.8% and 73.8%, respectively) at the end of the TFA addition process. The maximum temperature of synthesis reaction (MTSR) of this reaction was 34 °C. The heat released during the reaction between NaBH4 and TFA without 1 was found to be 263 kJ/mol of 1 (Figure 4).
Figure 5. Gas evolution during the lactam reduction by NaBH4 and TFA. Conditions: TFA (3.5 equiv) was added to a mixture of 1 (0.34 M) and NaBH4 (3.5 equiv) in THF (10 v/w) at 15 °C (time for dropwise addition of TFA was 60 min). TFA addition ratio and gas generation ratio for total amount of off-gas are also compared.
amount of evolved gas corresponded to 3.5 equiv of hydrogen, which is equivalent to the amount of added TFA. This result shows that TFA addition could control the amount of gas evolved. Pilot Manufacturing. The generation of diborane in the reaction mixture is described in the reaction mechanism section. Results of the elemental analysis of the evolved gas showed that diborane gas was released along with hydrogen. Diborane gas has to be decomposed to boric acid before it can be purged into the atmosphere because of its toxicity. A maximum concentration of diborane gas of 10 ppb is stipulated in the appropriate guidelines.15 To determine the most appropriate scrubber system, the abilities of different scrubber solutions were investigated using the laboratory equipment (Figure 6). When the TFA addition time was set as 1 h and a 1
Figure 4. Reaction calorimetry of the reaction between NaBH4 and TFA without 1. Conditions: TFA (1.0 equiv for NaBH4) was added to NaBH4 in THF at 15 °C (time for dropwise addition of TFA was 60 min). C
DOI: 10.1021/op500284e Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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to prevent the release of diborane gas allowed the process to be successfully scaled up to a 35 kg pilot plant scale.
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EXPERIMENTAL SECTION General. All reactions were performed under a nitrogen atmosphere. Solvents and reagents were used without any purification or drying. 1H and 13C NMR spectra were acquired on a Bruker or JEOL spectrometer at frequencies of 400 and 100 MHz, respectively. Mass spectra were recorded on Waters ZQ-2000. HPLC chromatograms were recorded on Shimadzu LC-20. Reaction calorimetry was performed using Mettler Toledo MidTemp RC1e vessel. Gas evolution study was performed using SHINAGAWA wet gas meter WS type. (2S)-2-(4-Fluorophenyl)-4-benzylmorpholine (2). (6S)6-(4-fluorophenyl)-4-benzylmorpholine-3-one (1) (30.0 g, 105.2 mmol) in THF (180 mL) solution was added to a stirred suspension of NaBH4 (13.9 g, 368.2 mmol) in THF (120 mL) at 0 °C. Then TFA (42.0 g, 368.2 mmol) in THF (120 mL) was added over 2 h maintaining the internal temperature below 10 °C, followed by stirring for 5 h at 20 °C. Acetone (42.8 g, 736.4 mmol) and 17% HCl aqueous solution (186.12 g, 841.2 mmol) were added to the reaction mixture, followed by stirring for 3 h at 60 °C. The reaction mixture was cooled to room temperature and 25% NaOH aqueous solution (135.0 g, 841.2 mmol) was added, followed by stirring for 30 min. Once settled the upper organic layer was separated and the aqueous layer was extracted with THF (60 mL). The combined organic phases were washed with 10% NaCl aqueous solution (150 mL). The organic layer was evaporated to 90 mL total volume. Ethanol (600 mL) was added, and the organic layer was again evaporated to a 90 mL total volume. Ethanol (150 mL) and water (270 mL) were added at 30 °C, and the resulting slurry was cooled to 10 °C, aged for 1 h. The slurry was filtered and washed with the mixture of ethanol (15 mL) and water (75 mL) and dried under reduced pressure to yield 24.3 g of 2 (89.4 mmol, isolated yield: 85%). 1H NMR (DMSO-d6, 400 MHz) δ 7.34−7.24 (m, 7H), 7.03−6.97 (m, 2H), 4.54 (dd, J = 10.4, 2.2 Hz, 1 H), 4.00 (ddd, J = 11.5, 3.5, 1.5 Hz, 1H), 3.82 (td, J = 11.5, 2.4 Hz, 1 H), 3.53 (s, 2 H), 2.87 (dt, J = 11.5, 2.2 Hz, 1 H), 2.73−2.76 (m, 1 H), 2.27 (td, J = 11.5, 3.5 Hz, 1 H), 2.07 (dd, J = 11.5, 10.4 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) δ 163.5, 161.0, 137.5, 136.3, 136.3, 129.2, 128.3, 127.9, 127.9, 127.2, 115.2, 115.0, 77.5, 67.1, 63.2, 60.4, 52.8; ESI MS: Calcd for C17H18FNO [M + H]+ 272, Found 272; Anal. Calcd for C17H18FNO: C, 75.25; H, 6.69; F, 7.00; N, 5.16. Found: C, 75.05; H, 6.68; F, 6.92; N, 5.18.
Figure 6. Testing of scrubber systems for diborane gas removal.
N aqueous NaOH solution scrubber system was used, the concentration of the released diborane gas was observed to be ca. 500 ppb (entry 1). When the TFA addition time was set as 2 h and a 15% aqueous NaOH solution scrubber system was used, the concentration of the released diborane gas decreased to ca. 70 ppb (entry 2). Diborane gas was not detected when a 15% aqueous NaOH solution double scrubber system was used to quench diborane gas (entry 3). We conclude that a double scrubber system similar to that employed in the laboratory experiment would be necessary in the pilot plant. The addition of TFA was controlled in the pilot plant using a reducer pipe. A double scrubber system using 15% aqueous NaOH solution was used. Furthermore, the evolved gas was diluted with steam before releasing it in order to avoid static ignition (Figure 7). The scaled up pilot plant allowed 35 kg of 1 to be successfully reduced without releasing diborane gas. The yield of 2 corresponded with that achieved in the laboratoryscale experiments. The plant temperature profile data revealed that the conditions employed were successful in maintaining the process temperature within the desired range.
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CONCLUSIONS We have reported the approach for the safety evaluation based on mechanistic insight into lactam reduction using NaBH4 and TFA. The mechanistic study showed that active species were generated during the addition of TFA, which avoided deactivation of the active species involved in the reduction process. Based on this reaction mechanism, the safety assessments for the process were performed using reaction calorimetry and gas evolution analyses. Use of safety equipment
Figure 7. Schematic of the pilot plant, including the scrubber system. (a) TFA addition tank, (b) reducer pipe to control the TFA addition rate, (c) reactor tank used for the reduction process, (d) scrubber system using 15% aqueous NaOH solution, and (e) dilution of the evolved gas with steam. D
DOI: 10.1021/op500284e Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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ASSOCIATED CONTENT
* Supporting Information S
Copies of 1H NMR and 13C NMR of 1, 2, and 3. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Dr. Hajime Hiramatsu for support with the analyses, Dr. Masanori Hatsuda and Dr. Masayuki Utsugi for helpful discussions, Dr. Hiroshi Iwamura, Mr. Yasunari Takayasu, Mr. Keita Kawabata, Dr. Kazutoshi Watanabe, Dr. Fumiaki Uehara, Dr. Toshiyuki Kohara, and Mr. Kenji Fukunaga for supports of process development, and Mr. Takeshi Tamagawa and Mr. Akihiro Tsukamoto for the pilot manufacturing.
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