Development of Asymmetric Transfer Hydrogenation with a

Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Development of Asymmetric Transfer Hydrogenation with a Bifunctional Oxo-Tethered Ruthenium Catalyst in Flow for the Synthesis of a Ceramide (D-erythro-CER[NDS]) Taichiro Touge,*,† Masahiro Kuwana,†,‡ Yasuhiro Komatsuki,† Shigeru Tanaka,† Hideki Nara,† Kazuhiko Matsumura,† Noboru Sayo,† Yoshinobu Kashibuchi,‡ and Takao Saito‡

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†

Corporate Research & Development Division, Takasago International Corporation, 1-4-11 Nishi-yawata, Hiratsuka City, Kanagawa 254-0073, Japan ‡ Process Development Division, Takasago Chemical Corporation, Kakegawa Factory, 2746 Kuniyasu, Kakegawa City, Shizuoka 437-1413, Japan S Supporting Information *

ABSTRACT: The development of an efficient synthetic route for an optically active ceramide compound (D-erythroCER[NDS]) is described. The route proceeds through asymmetric transfer hydrogenation in a pipes-in-series flow reactor with oxo-tethered ruthenium complex-catalyzed dynamic kinetic resolution. This synthesis was accomplished without any expensive reagents, and none of the intermediates required isolation. This resulted in a robust process that has been successfully run on a production scale. KEYWORDS: asymmetric transfer hydrogenation, oxo-tethered ruthenium catalyst, dynamic kinetic resolution, pipes-in-series flow reactor, ceramide, DENEB

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INTRODUCTION The optically active ceramide N-((2S,3R)-1,3-dihydroxyoctadecan-2-yl)stearamide (10, D-erythro-CER[NDS]) (Figure 1)

On the other hand, since a string of Ru catalysts with 1,2diamine scaffolds was established for asymmetric hydrogenation or transfer hydrogenation of a ketone or imine substrate in the mid-1990s, the utility of metal/NH cooperation has been highlighted via advances in redox transformations of carbonyl or alcoholic compounds.4 Using a systematic approach to structural tuning of the bifunctional catalyst derived from sulfonylated 1,2-diphenylethylenediamine (DPEN), we designed a new family of oxo-tethered Ru complexes (DENEB)(R,R)-12 and (R,R)-13that exhibit excellent catalytic performance for the asymmetric transfer hydrogenation of simple ketones (Figure 2).5,6 Asymmetric transfer hydrogenation of α-amido-β-keto ester 5 catalyzed by Ru−DPEN is erythro-selective and renders the (2R,3R) form of compound 7 directly via dynamic kinetic resolution (DKR).7 Thus, the synthesis route using Ru−DPEN catalyst will skip the hydroxyl inversion step of 6 to 7. This new route described in Scheme 2 is very attractive because hydroxyl inversion using SOCl2 in the conventional route not only is sometimes tortuous and troublesome but also implies additional cost. Therefore, we started to examine the asymmetric transfer hydrogenation of 5 catalyzed by Ru− DPEN catalysts.

Figure 1. Structure of the ceramide D-erythro-CER[NDS].

plays a critical role in the intercellular lipid model of the stratum corneum to form a lamellar structure that is essential for the barrier function of mammalian skin. Prominent skin diseases such as psoriasis and atopic dermatitis are associated with diminished ceramide levels and can be effectively improved by ceramide treatment.1 The conventional synthesis route for D-erythro-CER[NDS] is shown in Scheme 1.2 The key intermediate, methyl 2acetamido-3-oxooctadecanoate (5), is available on a hundreds of kilograms scale from β-keto ester 3. α-Oximation of 3 and subsequent Pd-catalyzed hydrogenation of 4 with acetic anhydride give 5 in satisfactory yield. Following syn-selective hydrogenation of α-amido-β-keto ester 5 catalyzed by the Ru− SEGPHOS3 complex, the syn/anti selectivity was 93/7 and the enantioselectivity was 99%. Continuous hydroxyl inversion using SOCl2, NaBH4 reduction, and deacetylation by NaOH gives D-erythro-dihydrosphingosine (9). Condensation of 9 with methyl stearate renders the target ceramide compound 10. © XXXX American Chemical Society

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RESULTS AND DISCUSSION We initially examined the asymmetric transfer hydrogenation of 5 using a 0.2 mol % loading of DPEN-derived Ru complexes Special Issue: Japanese Society for Process Chemistry Received: October 11, 2018 Published: November 22, 2018 A

DOI: 10.1021/acs.oprd.8b00338 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Scheme 1. Conventional Synthesis Route for the Ceramide Compound D-erythro-CER[NDS] (10)

Optimization of Asymmetric Transfer Hydrogenation and Subsequent NaBH4 Ester Reduction. In the reaction using 0.1 mol % (R,R)-Ts-DENEB catalyst, the asymmetric transfer hydrogenation of 5 was complete with a reaction time of 20 h (Table 2, entry 1, reaction A). To reduce the operating cost, we planned to use the hydroxy amide ester product 7 without isolation in the next ester reduction step. However, treatment of the resulting solution of 7 with 3.0 equiv of NaBH4 gave almost no conversion to the reduced product 8 (entry 1, reaction B). To investigate ester reduction using NaBH4, we screened the amounts of formic acid and triethylamine in the asymmetric transfer hydrogenation (Table 2, reaction A) as well as the effect of HCO2H as an additive to control the pH of the solution in the subsequent ester reduction (Table 2, reaction B). The conditions in which formic acid was reduced to 2.0 equiv and triethylamine was reduced to 1.0, 0.6, or 0.3 equiv also consumed 5 completely and gave the same diastereoselectivity (entries 2−6). However, for the subsequent ester reduction using NaBH4 from the solution using 1 equiv of triethylamine, the conversion to 8 was moderate and the de decreased (entry 2), perhaps because of the basicity of the reaction mixture. Fortunately, ester reductions for solutions of

Figure 2. Structures of nontethered and tethered Ru−DPEN catalysts.

with 3 equiv of formic acid and 3 equiv of triethylamine in THF solvent at 60 °C. As shown in Table 1, the corresponding erythro-alcohol 7 was obtained via DKR with 62−77% de and 88−97% ee after 8 h. Compared with the prototype catalyst (R,R)-11 (entry 1), the Ts-derivative oxo-tethered Ru(II) complex (R,R)-12 ((R,R)-Ts-DENEB) exhibited superior activity (entry 2) and optimal catalytic performance in terms of the yield and enantioselectivity. When the reaction time was increased to 20 h, the reaction completed without loss of diastereoselectivity or enantioselectivity (entry 4).

Scheme 2. New Synthesis Route for Intermediate 7 Leading to Ceramide Compound 10

B



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Table 1. Asymmetric Transfer Hydrogenation of Methyl 2-Acetamido-3-oxooctadecanoate (5) Catalyzed by Ru−DPEN Complexes

entry

catalyst

conv. (%)a

de (%)b

ee (%)c

1 2 3 4d

(R,R)-11 (R,R)-12 (R,R)-13 (R,R)-12

81.3 98.1 73.8 >99.9

77 74 62 74

93 97 88 97

a

Determined by HPLC analysis (ODS-3). bDetermined by 1H NMR analysis (the major product is 7). cDetermined by HPLC analysis (AD-H). The reaction time was 20 h.

d

Table 2. Optimization of Asymmetric Transfer Hydrogenation and Subsequent Ester Reduction Using NaBH4a

reaction A entry c

1 2 3 4 5 6

reaction B

a

b

conv. to 7 (%)b

de of 7 (%)b

c

conv. to 8 (%)b

de of 8 (%)b

3.0 2.0 2.0 2.0 2.0 2.0

3.0 1.0 0.6 0.3 0.3 0.3

98.9 100 100 100 100 100

73 73 73 73 73 73

0 0 0 0 0.2 0.4

1.2 62.5 80.2 98.3 99.5 99.5

n.d. 50 69 69 73 73

a

In all cases, the enantioselectivity was 96−97% ee. bDetermined by HPLC analysis (ODS-3). cThe catalyst loading in reaction A was 0.1 mol %.

Figure 3. Vertical pipes-in-series reactor.

low-cost method for achieving a high pressure rating, especially compared with the cost of a high-pressure batch autoclave. For example, a study by Eli Lilly and Company found that a 32 L pipes-in-series reactor cost only $3000 to fabricate (not counting the pumps and control system), while a 100 L batch autoclave capable of the same weekly throughput would cost an order of magnitude more.10 Continuous processing has made great strides in pharmaceutical development, manufacturing, and academic research over the past decade.11 The steady-state operation of continuous processing offers qualitycontrol advantages that have been recognized and supported by the FDA.12 While there are several reports on the use of

7 that used 0.3 equiv of triethylamine in the asymmetric transfer hydrogenation (reaction A) proceeded smoothly and gave the corresponding diol 8 in satisfactory yield (entry 4). Moreover, the addition of a slight amount of formic acid was effective in suppressing the decrease in diastereoselectivity (entries 5 and 6). Asymmetric Transfer Hydrogenation in a 400 mL Vertical Pipes-in-Series Continuous Reactor. Continuous reactors8 are advantageous for high-pressure gas/liquid reactions in the pharmaceutical industry because of their safety, low cost, and quality compared with batch processes.9 Continuous reactors made of pipes and tubing offer a relatively C



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Table 3. Asymmetric Transfer Hydrogenation of 5 Using a Vertical Pipes-in-Series Reactora

entry

T (°C)

τ (h)

conv. (%)b

de (%)b

1-1 1-2 1-3 2-1 2-2 2-3 3-1 3-2 3-3 4-1

70

2 4 6 2 4 6 2 4 6 2

46.3 77.6 91.8 67.8 91.9 96.5 67.4 82.6 79.1 30.4

70 71 71 68 67 69 66 67 67 61

85

100

115

a

In all cases, the enantioselectivity was 96−97% ee. bDetermined by HPLC analysis (ODS-3) (the major product was 7).

continuous reactors for asymmetric hydrogenation on a production scale,8b,c,10 there have been no reports on their use for asymmetric transfer hydrogenation. Therefore, we decided to start our examination of the asymmetric transfer hydrogenation of 5 using a continuous-flow reactor. The 400 mL vertical pipes-in-series reactor10,13 (Figure 3) was fabricated from 15 stainless steel pipes (each 9.55 mm o.d., 8.00 mm i.d., and 540 mm long) connected by 14 smallerdiameter jumper tubes (each 1.59 mm o.d., 1.00 mm i.d., and 650 mm long). The reaction was conducted at 70, 85, 100, and 115 °C under 0.8 MPa N2 with 0.1 mol % catalyst and a substrate 5 concentration of 0.4 M in combined reagent solutions. The continuous reactor was run for residence times (τ) of 2, 4, and 6 h. Six samples were taken at 1 h intervals to demonstrate a steady state. The results are shown in Table 3. At τ = 2 h, the area % of the products (7 and 6) was maximized at 85−90 °C. The reaction achieved over 95% conversion to the desired product with 69% de at τ = 6 h and 85 °C (Figure 4). To compare the reactions in a vertical pipes-in-series reactor and batch autoclave, we examined the same reaction using a general autoclave in batch (Table 4, entries 2 and 3). The results showed that the reaction using a pipes-in-series reactor gave slightly better conversion under the same reaction conditions (i.e., reagents, reaction temperature, and residence or reaction time). However, in these reactions, while the volume of N2 in the vertical pipes-in-series reactor was about 13%, the headspace of the autoclave in batch in entry 2 was about 30%. Generally, as a reaction proceeds, CO2 accumulates in the reactor, and this CO2 inhibits asymmetric transfer hydrogenation. Thus, if the headspace of the autoclave in batch was close to that in the vertical pipes-in-series reactor, the conversion of 5 would decrease. In reality, when the headspace of the autoclave was set at 13%, which is the same gas volume as in the vertical pipes-in-series reactor, the conversion of 5 dropped to 82.0% (entry 3). Furthermore, a flow reactor such as a vertical pipes-in-series reactor has the advantage of having better throughput compared with a batch autoclave. Next, we decided to adopt this flow system to synthesize the material on a production scale.

Figure 4. Results obtained at various reaction temperatures (top) and residence times (bottom).

Large-Scale Production Using a 100 L Vertical Pipesin-Series Continuous Reactor. With the reaction conditions in hand, we decided to carry out the reaction on a large scale. A schematic diagram of the 100 L vertical pipes-in-series reactor is shown in Scheme 3, and photographs are presented in Figure 5. The reactor was fabricated from 19 stainless steel pipes (100 L) (each 60.5 mm o.d., 53.5 mm i.d., and 2.25 m long) connected by 18 smaller-diameter jumper tubes (each 6.35 mm o.d., 4.35 mm i.d., and 2.75 m long). The reaction was D



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Table 4. Comparison of the Reactivities of a Vertical Pipes-in-Series Reactor and a Batch Autoclave

entry

reactor

conv. (%)a

de (%)a

ee (%)b

1 2c 3d

pipes-in-series reactor autoclave in batch autoclave in batch

96.5 95.0 82.0

69 69 69

97 97 97

a

Determined by HPLC analysis (ODS-3). bDetermined by HPLC analysis (AD-H). cThe headspace of the autoclave was ca. 30%. dThe headspace of the autoclave was ca. 13%.

Scheme 3. Asymmetric Transfer Hydrogenation of 5 Using a 100 L Vertical Pipes-in-Series Reactor

conducted at 85 °C under 0.95 MPa N2 with 0.1 mol % catalyst and a substrate 5 concentration of 0.4 M in combined reagent solutions. THF was flowed through the 100 L pipes-inseries reactor, which was heated to 85 °C, followed by the solutions in vessels 1 and 2. The substrate pump flow rate was set at 14.6 kg/h (0.4 M solution), and the catalyst pump flow rate was set at 0.359 kg/h (0.016 M solution). During the reaction, sampling was conducted every 3 h. The product solution was collected and maintained at about 40 °C. The trends of reaction temperature, flow rates of the substrate and catalyst solutions, and pressures at the inlet and outlet are described in the Supporting Information. Figure 6 shows the area % of the target material 7 (with 6) and its diastereoselectivity over time.

In Figure 6, point A is the time at the start of feeding of the substrate and reagent solution from vessel 1 in to the pipes-inseries reactor. Point B is the time at which the substrate and reagent solution reached the inlet of the pipes-in-series reactor. Point C is the time at which the reaction mixture started to flow out of the pipes-in-series reactor. Point D is the time at which the feeding of the substrate and reagent solution from vessel 1 to the pipes-in-series reactor was finished. Point E is the time at which the reaction ended. The results were very consistent across 36 h: the conversion to the target material 7 (and 6) reached 98.9% on average. In total, 77.4 kg of 7 (and 6) was obtained in this way in a total yield of 96.2% (by quantitative analysis) with 69.4% de. E



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Figure 5. Photographs of the 100 L pipes-in-series reactor.

After asymmetric transfer hydrogenation in flow, NaBH4 reduction proceeded smoothly without isolation of 7, and the solvent was replaced by n-BuOH. Deacetylation by NaOH in n-BuOH gave 9 quantitatively, and the solvent was replaced by heptane. Condensation of 9 with methyl stearate along with a small amount of NaOMe in heptane also rendered the target ceramide compound 10 quantitatively as a mixture of diastereomers and enantiomers, which were purified by crystallization in MeOH/heptane and subsequent reslurry in EtOH to give 58 kg of the target compound D-erythroCER[NDS] with perfect diastereoselectivity and enantioselectivity (>99% de, >99% ee) (Scheme 4).

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the ceramide compound D-erythro-CER[NDS] with high quality (>99% de, >99% ee)

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EXPERIMENTAL SECTION Synthesis of Methyl (2R,3R)-2-Acetamido-3-hydroxyoctadecanoate (7).

Construction of the 100 L Pipes-in-Series Reactor. The reactor was fabricated from 19 stainless steel pipes (100 L) (each 60.5 mm o.d., 53.5 mm i.d., and 2.25 m long) connected by 18 smaller-diameter jumper tubes (each 6.35 mm o.d., 4.35 mm i.d., and 2.75 m long). Solution in Vessel 1. Methyl 2-acetamido-3-oxooctadecanoate (5) (80.0 kg, 0.216 kmol, 1.0 equiv), HCO2H (19.9 kg, 0.432 kmol, 2 equiv), Et3N (6.6 kg, 0.065 kmol, 0.3 equiv), and THF (379.2 kg) were added to a 3.0 m3 glass-lined reactor

CONCLUSION

We have developed the first example of asymmetric transfer hydrogenation in a pipes-in-series flow reactor with oxotethered ruthenium complex-catalyzed dynamic kinetic resolution on a production scale. This process was accomplished with no expensive reagents and no isolation of intermediates. The process has been successfully run at a >50 kg scale to give F



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Figure 6. Trends of the conversion to 7 (and 6) and its diastereoselectivity.

Scheme 4. New Synthesis Route for Ceramide Compound 10

back pressure of nitrogen was 0.95 MPa. During the reaction, sampling was conducted every 3 h. The product solution was collected and maintained at about 40 °C. In total, 77.4 kg of 7 was obtained in a total yield of 96.2% (by quantitative analysis) with 69.4% de. The obtained solution was used for the following reaction without further purification. Synthesis of N-((2S,3R)-1,3-Dihydroxyoctadecan-2yl)acetamide (8).

(vessel 1). The solution was purged with nitrogen and stirred at 40 °C. Dissolution of all reagents was confirmed, and the solution was maintained at a temperature of 40 °C. Solution in Vessel 2. Under an atmosphere of N2, (R,R)-TsDENEB (0.180 kg, 0.277 mol) and THF (13.6 kg) were added to a 20 L four-neck flask, and the mixture was stirred at 20 °C for 1 h. Next, the solution was transferred to a 0.3 m3 glasslined reactor (vessel 2), and THF (1.51 kg) was used to wash the lines. Reaction in the 100 L Pipes-in-Series Reactor. THF was flowed through the 100 L pipes-in-series reactor, which was heated to 85 °C, followed by the solutions in vessels 1 and 2. The flow rates were set in such a way that there was a residence time of 6 h (i.e., 14.6 kg/h from vessel 1 (substrate and reagents) and 0.359 kg/h from vessel 2 (catalyst)), and the

Compound 7 (461.6 kg, 0.208 kmol, 1 equiv), MeOH (31 kg), and formic acid (3.9 kg, 0.084 kmol, 0.40 equiv) were added to G



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a 3.0 m3 glass-lined reactor. The solution was purged with nitrogen and maintained at around 30 °C. NaBH4 (23.9 kg, 0.631 kmol, 3.0 equiv) was added to the solution periodically over 3 h, and the temperature was kept below 40 °C. Next, the solution was stirred for 3 h at 30 °C and sampling was conducted (>99% conv.). The solution was concentrated at 32 kPa, and 344 kg of solvent was recovered. The solution was then heated to 60 °C, and n-BuOH (283 kg) was added. The resulting solution was stirred for 1 h at 80 °C and then used for the following reaction without further purification. Synthesis of (2S,3R)-2-Aminooctadecane-1,3-diol (9).

was then charged with ethanol (301 kg). The slurry was stirred at 20 °C for 1 h, collected via centrifugation, and washed with ethanol (120 kg). The wet cake was then dried at 50 °C at 2.2 kPa to obtain the desired product 10 as a white powder (58 kg, 0.102 kmol, 47% yield from 5). 1 H NMR (500 MHz, pyridine-d5): δ 8.73 (d, J = 8.5 Hz, 1H), 6.40 (br, 1H), 6.29 (d, J = 6.0 Hz, 1H), 4.67 (m, 1H), 4.47 (m, 1H), 4.36−4.26 (m, 2H), 2.49 (m, 2H), 2.02−1.79 (m, 5H), 1.64−1.57 (m, 1H), 1.45−1.20 (m, 52H), 0.90−0.80 (m, 6H). 13C NMR (125 MHz, pyridine-d5): δ 173.5, 70.0, 63.0, 55.6, 36.9, 35.3, 32.1, 30.2−29.6 (23C), 26.6, 26.5, 22.9 (2C), 14.3 (2C). HRMS (ESI): calcd for C36H74NO3 [M + H]+ 568.566322, found 568.566154 (error 0.3 ppm). The enantiomeric excess was determined by HPLC analysis (SUMICHIRAL OA-4600 column, 250 mm × 4.6 mm column, 98:2 hexane/EtOH as the eluent, 0.5 mL/min, 205 nm, 35 °C): t1 = 20.7 min ((2S,3S) diastereomer), t2 = 27.0 min ((2R,3R) diastereomer), t3 = 31.0 min ((2S,3R)-Derythro-CER[NDS]; >99% de, >99% ee), t4 = 37.0 min ((2R,3S) enantiomer). [α]20 D +149.0 (c 0.42 in THF). ICP analysis: remaining Ru < 20 ppm. Mp: 111.26 °C. IR (neat): 3349.6, 2955.4, 2914.9, 2849.1, 1630.4, 1568.0, 1471.2, 1133.0, 1073.7, 1047.9, 716.8 cm−1.

Compound 8 (459.0 kg, 0.208 kmol, 1 equiv), NaOH (26.9 kg, 0.673 kmol, 3.24 equiv), and water (93 kg) were added to a 1.5 m3 stainless-steel reactor. The solution was purged with nitrogen and stirred under reflux for 4 h. Sampling was then conducted (>99% conv.). The solution was charged with water (311 kg). The biphasic mixture was agitated with stirring for 30 min and allowed to settle for 30 min, and the aqueous layer was removed. Aqueous NaCl (made by dissolving 7.8 kg of NaCl in 155.5 kg of H2O) was added to the organic solution. The biphasic mixture was agitated with stirring for 20 min and allowed to settle for 30 min, and then the aqueous layer was removed. This wash operation using aqueous NaCl solution was repeated three times. The organic solution was then filtered using a Sparkler filter with Celite (1.0 kg), and nBuOH (41 kg) was used to wash the lines. The obtained solution was used for the following reaction without further purification. Synthesis of N-((2S,3R)-1,3-Dihydroxyoctadecan-2yl)stearamide (10, D-erythro-CER[NDS]).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.8b00338. Experimental section and characterization data (NMR, HPLC, HRMS, IR, [α]D) for the product and its diastereomers and enantiomer (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Taichiro Touge: 0000-0002-8783-0335 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to Yoshihiro Yaguchi, Satoru Moriya, Akihiro Kawaraya, Kyoko Zaizen, Noriko Yamamoto, Kazuhiko Sakaguchi, Jun Kurabe, Yumi Kusano, Hiroaki Izumi, and Eri Hiraki at Takasago International Corporation for the measurement of NMR, mass and IR spectra and experimental assistance. We also thank Hideharu Okamoto, Kenji Morita, Takeshi Shimizu, Masahiro Asai, Junpei Ishikawa, and Naoki Yamashita at Takasago Chemical Corporation for manufacturing the material.

The n-BuOH solution of 9 (428.0 kg, 0.208 kmol, 1 equiv) was added to a 3 m3 glass-lined reactor. The solution was concentrated at 3.5 kPa, and 322 kg of n-BuOH was recovered. Then heptane (53 kg) was added to the reactor. The solution was concentrated at 3.5 kPa, and 55 kg of solvent was recovered. Once more, heptane (53 kg) was added. The solution was concentrated at 3.5 kPa, and 55 kg of solvent was recovered. Methyl stearate (62.8 kg, 0.210 kmol, 1.01 equiv), 28% sodium methoxide methanol solution (2.0 kg, 0.011 kmol, 0.053 equiv), and heptane (638.1 kg) were then added to the solution. The solution was heated to 92 °C (reflux) and then stirred for 3 h. During the reaction, MeOH (3.8 kg) was recovered using a separator, and sampling was conducted (>99% conv.). The solution was cooled to 60 °C, and then MeOH (161 kg) was added. The solution was cooled to 35 °C at a rate of 4 °C/h. The cooled slurry was stirred for 7 h and then filtered through a continuous pressure filtering machine to collect the product (ca. 13% yield of product 10 remained in the filtering machine as a carryover to the next batch). The collected solid was washed with ethanol (122.7 kg). The wet cake (106.1 kg) was added to a 3 m3 glass-lined reactor, which

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REFERENCES

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NOTE ADDED AFTER ASAP PUBLICATION This Article was published ASAP on December 13, 2018. The graphics of Scheme 4 and Table 4 have been updated and the corrected version was reposted on December 17, 2018.

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Development of Asymmetric Transfer Hydrogenation with a

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