Development of an Efficient and Scalable Asymmetric Synthesis of

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Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via Ruthenium (II)-catalyzed Asymmetric Transfer Hydrogenation Guodong Sun, Weilin Jian, Zhonghua Luo, Tengfei Sun, Chao Li, Jiancun Zhang, and Zhongqing Wang Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 23 May 2019 Downloaded from http://pubs.acs.org on May 23, 2019

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Organic Process Research & Development

Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via Ruthenium (II)-Catalyzed Asymmetric Transfer Hydrogenation Guodong Sun†,‡, Weilin Jian‖, Zhonghua Luo‖, Tengfei Sun‖, Chao Li‖, Jiancun Zhang†,*, Zhongqing Wang‖, §,* †Guangzhou

Institutes of Biomedicine and Heath, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou,

510530, P. R. China ‡University

‖HEC

of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing, 100049, P. R. China

Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China

§Anti-infection

Innovation Department, New Drug Research Institute, HEC Pharma Group, Dong Guan 523871, P.

R. China *E-mail:[email protected] *E-mail:[email protected]

ACS Paragon Plus Environment

1

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 22

TOC Graphic: O O

OH O OH

DKR-ATH

O

O

Ph

Ph 5

telescoped processing

excellent stereoselectivity

mild conditions, easily operated

high overall yield

N

O

N

O 7

OH OEt

O

HN

O

eliglustat,1 >99.9% de, >99.9% ee 56.8% overall yield in 9 steps


2

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ABSTRACT

An efficient and scalable synthesis of eliglustat (1) is herein reported. This novel route features a three-step telescoped process to afford the α-dibenzylamino β-ketoester 6 in 85% overall yield from commercially available 1,4-benzodioxane-6-carboxylic acid 7. The key intermediate 5 was obtained via an efficient Ruthenium catalyzed DKR-ATH reaction, which afforded the desired product in 90% isolated yield with >99:1 dr, and 99.7% ee on 100gram scale. In addition, the amidation of sterically hindered carboxylic acid 14 was optimized and amenable to scale-up. This process not only gives desirable total yield, but also avoids hazardous conditions and chromatographic purification. The robustness of this synthesis was successfully performed on multigram scale to afford eliglustat (1) with >99.9% de, and >99.9% ee in 56.8% overall yield in nine steps. KEYWORDS eliglustat, asymmetric synthesis, Ruthenium catalyst, asymmetric transfer hydrogenation, dynamic kinetic resolution


3


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INTRODUCTION Eliglustat (1), an orphan drug developed by Genzyme, is a specific and potent inhibitor of glucosylceramide synthase.1 In 2014, eliglustat tartrate (Cerdelga®) was approved by the FDA for the treatment of adults with Gaucher disease type 1, a rare genetic disease caused by a deficiency of the lysosomal hydrolase acid βglucosidase.2 Due to the demonstrated efficacy in the long-term treatment with eliglustat (1), attention has been paid to find efficient methods for its synthesis. To date, several approaches have been developed for the asymmetric synthesis of eliglustat (1), and the reported analysis was summarized in Scheme 1.3 These methods showed a similar synthetic strategy using the key intermediate 2, the synthesis of which was however the major challenge in the development of a robust processes. Known methods of preparing this chiral aryl β-hydroxy α-amino acid derivative are poorly amenable to manufacturing scale. In 2003, Genzyme disclosed the medicinal chemistry route of eliglustat (1) utilizing a substrate-controlled chiral aldol reaction with 1,4-benzodioxan-6-carbaldehyde A and a chiral pool material B, which was derived from (s)-2-phenylglycinol.3a This route could efficiently establish the two contiguous stereogenic centers of 2. However, multiple chromatographic purifications were needed and the overall yield was very low (9.5%, for 6 steps). Other approaches utilized D-serine derivative C3b,3c as chiral pool or chiral source E3d have also been reported but were unlikely suitable for large scales as harsh conditions, such as microwave and cryogenic condition were needed. Recently, Xu et al.

3e

reported a concise synthesis of eliglustat involving an organocatalytic

asymmetric Henry reaction. This synthetic route was short and eliglustat (1) could be obtained in only three steps starting from A and nitro compound F. Last year, another concise synthesis based on Crimmins aldol reaction between A and Evans auxiliary G was reported by Liu and coworkers.3f Although these two methods seem interesting and could shorten the synthetic steps, neither is suitable for scale up, because both suffer from safety issues for the use of the potentially explosive reagents or toxic tin compound. Therefore, an efficient and readily scalable asymmetric synthesis of eliglustat (1) with improved yield, without using harsh conditions or hazardous reagents and chromatographic purification is highly desirable. Scheme 1. Reported Retrosynthetic Analysis of Eliglustat (1)


4

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O N

+

NO2 F

O

O

O

O

A

asymmetric Henry reaction

O O

TBSO

ref 3e

ref 3d

N H

E chiral source

OH

OH

N

N chiral pool

O

O HN

O

O

NH2

ref 3a

2 chiral auxiliary

O B

O

N3

chiral pool ref 3b,c

ref 3f

N

O

BrMg

OMe +

NHR

O

+

X1

N

RO

O

X2

O A

O O

O

+

O

eliglustat, 1

O

H N

Ph

O

C

D

O X = O or S

A

G

Asymmetric reduction via dynamic kinetic resolution (DKR) is regarded as a powerful synthetic method to simultaneously set up two adjacent stereogenic centers in a single transformation from racemic substrates.4,5 Recently, we have developed an efficient asymmetric synthesis of enantiomeric pure syn-aryl β-hydroxy αdibenzylamino esters via a DKR asymmetric transfer hydrogenation (DKR-ATH) in high yields.6 Excellent diastereoselectivity and enantioselectivity were obtained by using oxo-tethered Ru (II) catalyst that could be applied to a wide range of substrates. Thus, we believed that this highly stereoselective reaction would be a promising candidate for a practical synthesis of eliglustat (1). The novel approach envisioned for the synthesis of eliglustat (1) based on the above-mentioned DKR-ATH reaction is displayed in the retrosynthetic strategy shown in Scheme 2. Scheme 2. Retrosynthetic Strategy of Eliglustat Based on Ru-catalyzed DKR-ATH N

OH HN

O

OH

OH

acylation

O

O

O

N

debenzylation

NH2

O

O O Ph

2

OH O O

N N Ph 4

Ph

3

1

O

reduction

N N

HN

OEt N

O Ph

Ph

O

O

OH O O

DKR-ATH

O

OEt N

O Ph

Ph

5

6

steps

O O

HO

O

Ph 7


5


Page 6 of 22

As shown in Scheme 2, we envisioned that eliglustat (1) could be obtained through acylation of intermediate 2, of which the free amino group could be released via debenzylation from 3. Compound 3 could in turn be generated from reduction of amide 4, which was readily derived from the key intermediate 5. The key transformation from αdibenzylamino β-ketoester 6 to 5 with the introduction of the two adjacent stereogenic centers could be achieved by the Ru-catalyzed DKR-ATH reaction. Compound 6 could be synthesized from the commercially available 1,4benzodioxane-6-carboxylic acid 7. Herein, we report our result of this efficient and readily scalable approach and describe its implementation on multigram scale preparation of eliglustat (1). RESULTS AND DISCUSSION Preparation of α-dibenzylamino β-ketoester 6 Our synthetic efforts started with the synthesis of the α-dibenzylamino β-ketoester 6 from commercially available 1,4-benzodioxane-6-carboxylic acid 7. Although this type of compounds could be easily obtained from the corresponding acyl chloride in high yields in one step, cryogenic condition (-60 °C) was often required.7 With the aim of developing a convenient and readily scalable process we need to explore an alternative approach avoiding such harsh conditions. Thus, a three-step telescoped process was identified (Scheme 3). Acid 7 was activated by CDI, and then underwent condensation reaction with potassium monoethylmalonate to afford β-ketoester 8. After aqueous HCl and aqueous NaHCO3 washes the DCM solution of 8 was telescoped directly into the bromination step. 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) was added portionwise to the DCM solution of 8 to suppress the dibromide impurity. Upon completion of the bromination, the mixture was washed with aqueous NaHCO3 and the organic phase was concentrated and the solvent was switched to MeCN. The amination of 9 was conducted with dibenzylamine at reflux (80 °C) and mild base NaHCO3 was used, as high levels of debromination of 9 were observed when stronger bases were used. The overall yield of 6 varied from 80% to 90% on small scales, and 85% overall yield was achieved when the process was operated on 100-gram scale, demonstrating a good reproducibility. With this robust scalable process, the remaining challenge remains on the downstream steps from 6 to the key intermediate 2 in the synthesis of eliglustat (1). Scheme 3. Preparation of α-dibenzylamino β-ketoester 6 from Acid 7


6

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O O

O OH

O 7

1, CDI, DCM, 25 C

O

2, EtO2CCH2CO2K, MgCl2, DMAP,Et3N, DCM, 0~25 C

O OEt

O

O

O DBDMH

O

DCM 25 C

O

OEt

O

MeCN, 80 C

O

Br

OEt N Ph 6

9

8

O

O Bn2NH/NaHCO3

three-step telescoped process

Ph

overall yield: 80-90%

Asymmetric Synthesis of 6 via a Ru-Catalyzed DKR-ATH. With substrate 6 in hand, the investigation of asymmetric transfer hydrogenation of 6 using Ru catalysts was undertaken. Based on our experience in the field of Ru-catalyzed DKR-ATH reactions, we deliberately focused on two class of Ru catalysts, oxo-tethered catalyst (R,R)-10 ((R,R)-Ts-DENEB) and catalyst (R,R)-11 (RuCl[(R,R)TfDPEN](p-Cymene)).4f,6 As expected, catalyst (R,R)-10 used in our previous work gave excellent stereoselectivity with full conversion (entry 1, table 1), and catalyst (R,R)-11 resulted in moderate conversion (entry 2, table 1) under the same condition. After fine-tuning of the reaction conditions, improved result (>33:1 dr and 99.7% ee, entry 3, table 1) was obtained with catalyst (R,R)-11 when applying a slow addition of HCO2H over 15 h. As previously reported, slow addition of HCO2H was shown to be favorable for achieving the high conversion and selectivity.8 Catalyst (R,R)-11 was therefore considered due to its excellent catalytic potency and cost-effective preparation at larger scale.9 Upon the completion of the reaction (6 remained 99:1 dr, and 99.7% ee. Table 1. Ru-Catalyzed DKR-ATH of Substrate 6a O

OH O

O

O

OEt NBn2

O

catalyst (5 mol %) HCO2H/Et2NH (5:2)

O

OEt NBn2

O

5

6

O Ts

Ru

N N

Ph

Tf

Cl

Cl

NH2

Ph

H

Ph

Ph

(R,R)-10 entry

Ru N

(R,R)-11

catalyst

conv.b (%)

drc (syn/anti)

eed (%)


7


aReaction

Page 8 of 22

1

(R,R)-10 e

99

>18:1

>99

2

(R,R)-11e

86

>29:1

>99

3

(R,R)-11f

96

>33:1

99.7

conditions: compound 6 (22.4 mmol), Ru catalysts (5 mol %, (R,R)-10 was used directly, (R,R)-11 was generated with

R,R-TfDPEN and [Ru(p-cymene)Cl2]2) and used in situ), HCO2H (88.1 mmol), and Et2NH (35.2 mmol), stirred at 50 °C in toluene (45 mL) for 40 h. bDetermined by HPLC. cDetermined by 1H NMR. dDetermined by chiral HPLC using a CHIRALPAK IA column. eHCO2H was added over 10 min. f HCO2H was added over 15 h.

Considering the variety of options within this strategy, we also synthesized an alternative substrate, racemic αdibenzylamino-β-ketoamide 13, which could be a more straightforward starting material for the synthesis of the key intermediate 2 (Scheme 4). But, surprisingly, no conversion was observed when substrate 13 was applied under the optimized DKR-ATH conditions. Based on these observations, we consequently focused our attention on using compound 5 for the subsequent studies. Scheme 4. Possible Routes toward Key Intermediate 2 via DKR-ATH O

O

O

OH O OEt DKR-ATH

O

N

O Ph

OEt N

O Ph

Ph

6

O

5

O

O

OH O N

O

DKR-ATH

N

O Ph

Ph

Ph

13

N

N

O Ph

OH O

N

NH2

O

Ph

2

4

Amide Synthesis. Scheme 5. Direct Amidation OH

O

O

OH O

R1

NR2

O

NH direct amidation

O

O O

N NR2

1

R=Bn or H, R =Me or Et

At this stage, amidation of 5 with pyrrolidine would be the most direct way to obtain amide 4.10 (Scheme 5) Unfortunately, this approach was unsuccessful in our case presumably due to the steric hindrance of the two bulky Bn protecting groups. Alternative attempts by displacing the ethyl ester with methyl ester or subsequently


8

Page 9 of 22

deprotecting Bn groups were envisaged to promote this transformation. Indeed, the reaction proceeded to give amide as the major product in pyrrolidine; however, decomposition via retro-aldol was then observed. In addition, the high loss of the product during isolation in Bn deprotection process made this method unamenable to scale-up. Therefore, we sought to explore the amide coupling through carboxylic acid 14 to prepare 4.( Scheme 6) We decided to start with the widely used EDCI/HOBt, but low conversion was found. Our initial screen with other coupling reagents (Table 2), such as CDI, EDCI/HOAt, and EDCI/HOSu, also gave poor results. It was rationalized that sterically hindered Bn groups at the nitrogen atom possibly decreased the coupling efficiency. Literature searching led us to examine the more active reagents, such as ethyl 2-cyano-2-(hydroxyimino) acetate (Oxyma),11 4(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methyl-morpholinium

chloride

(DMTMM),12

and

recently

reported

N,N,N’,N’-tetramethylchloroformamidinium hexafluorophosphate (TCFH),13 which are considered optimal reagents for the couplings of sterically hindered carboxylic acids.14 Scheme 6. Synthesis of Amide 4 from 5 through carboxylic acid 14 OH O

OH O

O NBn2

THF/EtOH

O

OH NBn2

O

5

OH O

NH

O

NaOH

OEt

O

coupling agents

N NBn2

O

14

4

Table 2. Screening of Coupling Agents for Amidation Process

Activated ester

a m

e

xy /O IC

.0

D

rro eq

py

rro py eq

+3

.0 Product

lid

in lid

/N FH D

M

TM

M

+2 M TM M D Starting material

in

e

I M

I D TC

xy I/O C

C

m

a

At O ED

I/H C ED

O I/H C ED

C

I/H

O

Su

Bt

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

ED

HPLC area %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Unknown impurities


9


Page 10 of 22

We subsequently found that the combination of Oxyma and other additives such as DIC and EDCI, displayed superior coupling efficiency to TCFH and DMTMM (Table 2). Notably, the use of DMTMM led to considerable amounts of recovered 14 and N-arylation impurity due to competitive addition of pyrrolidine. Considering the good coupling efficiency and the lower risk of explosion harzard, DIC/Oxyma was chosen for the further development. Preliminary research showed that the main impurities detected in this transformation were N-acylurea 15 and activated ester 16. Consequently, the equivalents of DIC and pyrrolidine and order of addition were screened with the aim of suppressing these impurities. We found that the formation N-acylurea 15 was significantly suppressed by addition of DIC to the mixture of 14 and Oxyma in CH2Cl2 followed by pyrrolidine (Table 3, entry 3). Further process optimization identified a telescoped sequence from hydrolysis step to amide 7, which obviated the need for isolation and further streamlining the process. After saponification was completed, the reaction mixture was concentrated to remove the solvent and acidified with aqueous HCl solution, then carboxylic acid 14 was telescoped into the amide formation as a CH2Cl2 solution. Under the optimized conditions, the desired amide 4 was readily crystallized from EtOH with excellent yield (94% over two steps) and no detectable amounts of the other diastereomers were found. Table 3. Optimization of Amidation Process Using DIC/Oxyma

N

OH O O OH O O

OH O

NH

O

OH NBn2

O

Oxyma, DIC, DCM

NBn2

O

14

O

N

O 15 OH O

O

4

O

NH

NBn2

N Bn2N

O

NH

16

DIC

pyrrolidine

entrya

Conv. c 15b

16b

equiv.

equiv.

(%)

1

1.0

1.0

NDd

9.6

99.4

2

1.0

2.0

NDd

0.4

93.2

3

1.8

2.0

NDd

NDd

100


10

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aOrder

4

1.8

2.0

6.8

0.2

99.3

5

1.8

2.0

0.2

NDd

99.9

of addition: entries 1-3, DIC was added to a mixture of 14 and Oxyma in CH2Cl2 followed by addition of pyrrolidine;

entry 4, Oxyma was added to a mixture of 14 and DIC in CH2Cl2 followed by addition of pyrrolidine; entry 5, DIC was added to a mixture of 14, Oxyma and pyrrolidine in CH2Cl2. bArea percent by HPLC analysis. cDetermined by HPLC analysis. dNot detected.

Amide Reduction With a reliable process in place to prepare 4, we next focused our efforts on amide reduction step. In the Genzyme route, amide reduction was conducted using LiAlH4, which also worked well with amide 4 in our case (Table 4, entry 1). However, considering the safety issue related to LiAlH4 for pilot-scale manufacturing,15 alternative reagents were investigated (Table 4, entries 2-8). Early work showed that NaBH4/TFA gave low conversion in amide reduction (Table 4, entry 2). The combination of NaBH4 and other additives also led to poor results (Table 4, entries 3-7). Gratifyingly, reduction of amide 4 using Red-Al gave 3 smoothly with a good impurity profile (Table 4, entry 8). As a result, Red-Al was identified for this amide reduction process and toluene was chosen as the solvent. The reaction using 2.8 equiv. of Red-Al in toluene at 60°C achieved complete conversion in 4 h. After basic quench and workup, 3 was afforded as an oil in >95 A% HPLC and used in the next step without any further purification. Table 4. Screening of Amide Reducing Agentsa OH O O

OH N

Reduction

NBn2

O

O

N NBn2

O

4

3

entry

reagent

additive

solvent

4 (area %)b

3 (area %)b

1

LiAlH4 (3.0 equiv)

none

THF

NDc

74

2

NaBH4 (6.5 equiv)

TFA (3.0 equiv)

THF

52

34

3

NaBH4 (10 equiv)

TiCl4 (5.0 equiv)

DME

82

NDc

4

NaBH4 (20 equiv)

AlCl3 (10 equiv)

THF

47

16

6

NaBH4 (20 equiv)

LiCl (20 equiv)

THF

4

NDc

7

NaBH4 (20 equiv)

I2 (10 equiv)

THF

78

11

8

Red-Al (5.0 equiv)

none

toluene

NDc

86


11


aReactions cNot

Page 12 of 22

were performed with 4 (0.3 mmol), reducing agents and additives in 10 mL solvents at 70°C. b Detected by HPLC.

detected.

The subsequent debenzylation of 3 was conducted with Pd/C as catalyst under hydrogen atmosphere. From a preliminary screen of reaction conditions, the use of 5.0 mol % of Pd/C under 1 atm of H2 at room temperature in ethanol, in the presence of 2.5 equiv. of aqueous HCl, was found to be optimal in debenzylation reaction. Initially, the desired product 2 was isolated by filtration after workup in 89% yield over two steps with >97 A% HPLC purity. However, a formylated impurity 17 (Figure 1) was observed (up to 1 A% HPLC). The formation of 17 might be attributed to the presence of residual isopropylurea, which was reduced by Red-Al and further coupled with 2 under the acidic condition. Although recrystallization of the isolated solid from a mixture of ethyl acetate and cyclohexane could upgrad the purity to >99 A% HPLC, reduction of the yield was also observed during recrystallization. Fortunately, we subsequently found that recrystallization was not necessary because of efficient purging in downstream processing.

OH

N

O HN

O 17

O H

Figure 1. Structure of formylated impurity 17 Synthesis of Eliglustat (1) The final step involves condensation of 2 with 2,5-dioxopyrrolidin-1-yl octanoate to afford eliglustat (1). Originally, the amidation reaction was performed under the previously reported condition in absence of a base.3a Further process development revealed a beneficial effect when base was introduced. The reaction using 2.0 equiv. of Et3N showed better impurity profiles in this transformation. Upon reaction completion, the reaction mixture was subjected to an aqueous workup to remove N-hydroxysuccinimide. The crude product was recrystallized from nhexane/MTBE to afford eliglustat (1) in 90% yield and >99 A% HPLC with >99.9% de, and >99.9% ee. The overall synthetic route of eliglustat (1) was summarized in Scheme 7. Scheme 7. The Overall Synthetic Route of Eliglustat(1)


12

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O O

O OH

O 7

1, CDI, DCM, 25 C

O

2, EtO2CCH2CO2K, MgCl2, DMAP,Et3N, DCM, 0~25 C

O

O

O OEt

O

DBDMH

O

DCM 25 C

O

8

O

O OEt

Bn2NH/NaHCO3 MeCN, 80 C

Br

O

OEt NBn2

O

9

6 85% yield over 3 steps 105 g scale

OH O

OH O

(R,R)-11 HCO2H, Et2NH toluene, 50C

O

OEt NBn2

O

NaOH aq EtOH/THF, 25C

O

Red-Al toluene, 60C

O

N NBn2

O 3

NBn2

O

5 90% yield >99:1 dr, 99.7% ee 100 g scale OH

OH

pyrrolidine DIC, Oxyma DCM, 28C

14

OH O O O

N NBn2

4 94% yield over 2 steps O

Pd/C H2 (1atm) 3N HCl MeOH, 28C

N OH O

OH O

N NH2

O

O

O 2,5-dioxopyrrolidin-1-yl octanoate Et3N, DCM, 28C

N

O O

HN

O

2

Eliglustat (1)

89% yield over 2 steps

90% yield >99.9% de, >99.9% ee

CONCLUSION In conclusion, we have successfully developed an efficient and readily scalable asymmetric synthesis of eliglustat. This process features a three-step telescoped process to afford the α-dibenzylamino β-ketoester 6 in 85% overall yield on 100-gram scale. The key intermediate 5 was obtained via an efficient Ruthenium catalyzed DKR-ATH reaction, which afforded the desired product in 90% isolated yield with >99:1 dr, and 99.7% ee. The Ru-catalyst was successfully switched to a cheaper catalyst (R,R)-11, due to its excellent catalytic performance and cost-effective preparation at large scale. In addition, the amidation of sterically hindered carboxylic acid 14 was optimized to allow for scale-up. Our process not only gives desirable total yield, but also avoids hazardous conditions and chromatographic purification, which could be amenable to large scale manufacture. The robustness of this synthesis was successfully performed on multigram scale to afford eliglustat (1) with >99.9% de, and >99.9% ee in 56.8% overall yield in nine steps. EXPERIMENTAL SECTION General. Commercially available materials purchased from Alfa Aesar or Kelong (China) were used as received. Catalyst (R,R)-10 ((R,R)-Ts-DENEB) was purchased from Sino compound Catalysts Co., Ltd. (China) and (R,R)TfDPEN] for the preparation of (R,R)-11 was synthesized in house. If no special treatments are indicated, all reagents and solvents were used without further purification. NMR spectra were measured on a Bruker Avance 400


13


Page 14 of 22

spectrometer or 600 spectrometer in solvents indicated; chemical shifts are reported in units (ppm) by assigning TMS resonance in the 1H spectrum as 0.00 ppm, CDCl3 resonance in the

13C

spectrum as 77.0 ppm. Coupling

constants are reported in Hz with multiplicities denoted as singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets); m (multiplets), and etc. HRMS were performed on Fourier Transform Ion Cyclotron Resonance Mass Spectrometer. Analytical HPLC for liquid phase was carried out on an Agilent HPLC workstation, equipped with a Chiral MX (2) column (purchased from FLM Inc. Guangzhou, China). Optical rotations were measured using a 1 20

mL cell with a 1 dm path length on a Jasco P-1030 polarimeter and are reported as follows: [α] D (c in g per 100 mL solvent). Ethyl 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopropanoate (8). To an agitated DCM (1.5 L) slurry of potassium monoethyl malonate (118.1 g, 693.8 mmol) and magnesium chloride (79.3 g, 832.6 mmol) in Reactor A was added DMAP (1.9 g, 13.9 mmol), followed by addition of Et3N (56.2g, 555.1 mmol). The mixture was maintained at 25°C for 3-4 h. Reactor B was charged with 7 (50 g, 277.5 mmol) in DCM (400 mL) to afford a clear solution. CDI (74.3 g, 457.9 mmol) was added portionwise at 25°C over a period of 20 min (CAUTION! CO2 evolution!). The reaction mixture was stirred at 25°C for 2 h. Then the mixture of Reactor B was transferred to Reactor A using an addition funnel under nitrogen atmosphere at 0°C over a period of 30 min. After stirred for additional 3 h, the mixture was cooled to 10-15°C at which point 2 M HCl solution (500 mL) was slowly added over a period of 35 min and the mixture was stirred at 25°C for about 45 min. The organic layer was separated, washed with 5 wt% NaHCO3 (450 mL) and saturated NaCl solution (600 mL). The resulting biphasic mixture was allowed to settle for 20 min, and the organic layer was collected and used for the next step directly. Ethyl 2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopropanoate (9). To the above obtained solution of 8 in DCM was added DBDMH (40.5 g, 141.5 mmol) at 25°C over a period of 1 h. The reaction mixture was stirred at 25°C for additional 30-60 min. Then 10 wt% solution of Na2S2O3 (300 mL) was added and the mixture stirred at 25°C for 30 min. The organic layer was separated and washed with H2O (320 mL) followed by complete distillation under vacuum to afford the crude compound 9, which was used for the next step directly. 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 12.1, 9.9 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 5.61 (s, 1H), 4.32 (ddd, J = 14.2, 8.2, 4.8 Hz, 6H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 186.59, 165.27, 149.16, 143.62, 126.97, 123.46, 118.71, 117.55, 64.80, 64.06, 63.20, 46.17, 13.89.


14

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Ethyl 2-(dibenzylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopropanoate (6). MeCN (600 mL) was added to the above obtained 9, followed by addition of NaHCO3 (37.3g, 444.1 mmol) and dibenzylamine (76.7g, 388.5 mmol). The reaction mixture was heated to 80°C for about 4 h and then cooled to room temperature. The mixture was diluted with toluene (500 mL) and H2O (750 mL), and stirred for 20 min. The aqueous layer was separated and extracted with 200 mL of toluene. The combined organic phase was washed with water (2 × 400 mL), and concentrated to afford crude compound. MeOH (250 mL) was added and the mixture was stirred at 40-45°C for 1h. The mixture was then cooled to 10-20°C, the obtained solid was filtered and washed with MeOH (100 mL) followed by vacuum drying to afford the title compound 6 (105.2 g, 85.1% yield). Mp 124-126°C. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 2.0 Hz, 1H), 7.31 (dt, J = 7.9, 4.0 Hz, 5H), 7.26 (dd, J = 7.6, 6.2 Hz, 6H), 6.83 (d, J = 8.5 Hz, 1H), 4.89 (s, 1H), 4.41 – 4.25 (m, 6H), 3.94 (q, J = 13.7 Hz, 4H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 194.14, 169.66, 148.42, 143.27, 138.92, 129.35, 129.28, 128.33, 127.32, 123.61, 118.74, 116.86, 67.32, 64.77, 64.06, 60.77, 55.38, 14.32. (2S,3R)-Ethyl 2-(dibenzylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxypropanoate (5). To a solution of (R,R)-11 (6.9 g, 11.2 mmol) and 6 (100 g, 224.5 mmol) in toluene (400 mL), was added Et2NH (26.3 g, 359.2 mmol) at 20-30°C. HCO2H (47.1 g, 901.6 mmol) was then added slowly over 15 h. The reaction mixture was stirred at 50°C until >95% conversion was obtained. Upon reaction completion (6 remained 99:1 dr and 99.7% ee. The enantiomeric excess was determined by chiral HPLC method: Chiral MX (2) column, 4.6 x 250 mm x 5μm; flow rate 0.8 mL/min; temperature: 20°C; detection wavelength: 210 nm; eluent: Hexane/Ethanol/Isopropanol = 40/30/20; retention time: 8.70 min (syn-5) and 13.14 min (ent-syn-5). Mp 91-93°C. [α]

20 D

-54.1, (c = 0.28, MeCN). 1H NMR (400 MHz,

CDCl3) δ 7.43 – 7.29 (m, 10H), 6.69 (ddd, J = 13.6, 10.1, 5.1 Hz, 3H), 4.86 (d, J = 10.0 Hz, 1H), 4.28 – 4.06 (m, 9H), 3.49 (d, J = 13.3 Hz, 2H), 3.38 (d, J = 10.0 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 169.36, 143.26, 143.19, 138.00, 133.55, 129.26, 128.65, 127.61, 120.57, 116.86, 116.27, 69.09, 67.58, 64.32, 64.24, 60.37, 54.82, 14.42. HRMS (ESI) calcd for C27H30NO5 [M+H]+: 448.2108, found 448.2115. Analysis by ICP-MS showed 144 ppm Ru.


15


Page 16 of 22

(2S,3R)-2-(dibenzylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxypropanoic acid (14). To a reaction vessel was charged 5 (90.4 g, 204.2 mmol), THF (140 mL), and EtOH (280 mL). A solution of NaOH (16.2 g, 405.0 mmol) in 140 mL of water was added, and the mixture was stirred at 24-28 °C for 15 h. After that the reaction mixture was adjusted to pH=5~6 with 4M HCl solution, the solvent was removed by distillation under reduced pressure. Dichloromethane (400 mL) and water (100 mL) were added into the residue. The organic phase was washed with brine (200 mL), and used for the next step directly. An analytical sample of 14 was obtained by crystallization from ethanol: white solid. Mp 76-78°C. [α]

20 D

-110.6, (c = 0.26, MeOH). 1H NMR (400 MHz, CDCl3)

δ 7.49 – 7.30 (m, 10H), 6.76 (d, J = 8.5 Hz, 2H), 6.69 (dd, J = 8.3, 1.7 Hz, 1H), 5.00 (d, J = 9.0 Hz, 1H), 4.20 (s, 4H), 4.09 (d, J = 13.2 Hz, 2H), 3.70 (d, J = 13.2 Hz, 2H), 3.52 (d, J = 9.0 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 172.66, 143.34, 143.31, 136.98, 133.32, 129.40, 128.82, 127.98, 120.40, 117.10, 116.25, 68.93, 67.04, 64.30, 64.24, 54.91. HRMS (ESI) calcd for C25H26NO5 [M+H]+: 420.1793, found 420.1804. (2S,3R)-2-(dibenzylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxy-1-(pyrrolidin-1-yl)propan1-one (4). Oxyma (28.7 g) was added to the DCM solution of acid 14, followed by the addition of DIC (45.9 g). The mixture was stirred and cooled to 5-10 °C. Pyrrolidine (28.7 g) was added dropwise over 20 min while maintaining the temperature below 15°C. After the completion of addition, the mixture was warmed to room temperature, and stirring was continued for 5 h. The solvent was removed by distillation under reduced pressure. 95% Ethanol (330 mL) was added, and the mixture was heated to 60-70°C for 45 min, then the mixture was cooled to 10-15°C and stirred for another 1 h. The product was collected by filtration and washed with EtOH/H2O (1:1, 2 × 110 mL), then dried at 60°C under vacuum for 10 h to afford 4 as a white solid (89.4 g, 94% yield, >99.9 % ee, >99:1 dr). The enantiomeric excess was determined by chiral HPLC method: Chiral MX (2) column, 4.6 x 250 mm x 5μm; flow rate: 0.6 mL/min; temperature: 20°C; detection wavelength: 210 nm; eluent: Hexane/Ethanol = 35/65; retention time: 8.57 min (anti-4), 9.27 min (syn-4), 10.12 min (ent-anti-4) and 13.24 min (ent-syn-4). Mp 132-134°C. [α]

20 D

-36.4, (c = 3.5, MeCN). 1H NMR (400 MHz, CDCl3) δ 7.31 (m, 9H), 6.88 (d, J = 1.4 Hz, 1H), 6.76

(dt, J = 16.3, 5.0 Hz, 2H), 5.30 (s, 1H), 5.01 (d, J = 9.7 Hz, 1H), 4.38 (d, J = 14.4 Hz, 2H), 4.28 (s, 1H), 4.19 (s, 4H), 3.66 (d, J = 14.4 Hz, 2H), 3.46 (d, J = 9.7 Hz, 1H), 3.36 (m, 2H), 2.57 (m, 1H), 1.88 (m, 1H), 1.69 (m, 1H), 1.54 (m, 2H), 1.33 (td, J = 12.5, 6.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 168.64, 143.18, 143.08, 139.21, 133.67, 128.59, 128.55, 127.29, 119.69, 116.75, 115.33, 70.40, 66.83, 64.31, 54.83, 53.40, 45.85, 45.27, 25.88, 23.97. HRMS (ESI) calcd for C29H33N2O4 [M+H]+: 473.2428, found 473.2433.


16

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(1R,2R)-2-(dibenzylamino)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol

(3).

Toluene (400 mL) and 4 (89 g) were charged to a reaction vessel. Red-Al (168 g, 70% solution in toluene) was added to the solution over a 60-min period using an addition funnel under nitrogen atmosphere. The reaction mixture was stirred at 60°C for 4 h. The mixture was cooled to 5°C and quenched with 20% sodium hydroxide (660 mL), while keeping the temperature below 15°C. The aqueous layer was separated and extracted with 200 mL of toluene. The combined organic phase was washed with water (3 × 300 mL), and concentrated to afford 3 as an oil (>95 A% HPLC), which was directly used in the next step without further purification. Mp 102-104°C. [α]

20 D

-35.5,

(c = 3.0, MeCN). 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 8.6, 5.3 Hz, 8H), 7.28 (dd, J = 7.8, 4.1 Hz, 2H), 6.67 (ddd, J = 17.5, 10.0, 5.0 Hz, 3H), 5.53 (s, 1H), 4.27 (d, J = 8.4 Hz, 1H), 4.22 (s, 4H), 3.90 (d, J = 13.2 Hz, 2H), 3.80 (d, J = 13.2 Hz, 2H), 3.18 – 2.95 (m, 2H), 2.51 – 2.27 (m, 4H), 2.24 (d, J = 8.9 Hz, 1H), 1.74 (s, 4H). 13C NMR (101 MHz, CDCl3) δ 143.09, 142.90, 139.59, 135.96, 129.05, 128.43, 127.13, 120.66, 116.77, 116.39, 72.68, 64.32, 64.28, 61.55, 54.35, 54.30, 53.00, 23.65. HRMS (ESI) calcd for C29H35N2O3 [M+H]+: 459.2637, found 459.2644. (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (2).

MeOH (450

mL) and 4N HCl (145 mL) was added to the above obtained crude 3. Activated Pd/C (0.77 mmol) was charged and the mixture was stirred under H2 atomosphere (1 atm) at 25-30°C. Upon reaction completion, the mixture was filtrated to remove Pd/C and washed with MeOH (50 mL) and water (50 mL). Then the filtrate was subjected to distillation under vacuum. After completion of distillation, water (50 mL) was added followed by addition of 2N aqueous HCl (10 mL). The resulting mixture was washed with ethyl acetate (2 × 100 mL). The organic layer was discarded. The aqueous layer was cooled to 5-10°C, 15% aqueous NaOH (160 mL) was added over 30 min below 10°C to adjust pH 12-13. The reaction mixture was stirred for an additional 1 h. Then solid was collected by filtration, and washed with water and dried under reduced pressure at 25-28°C to give the desired product 2 (46.5 g, 89% yield). Mp 87-89°C. [α]

20 D

+22.2, (c = 1.50, MeCN). 1H NMR (400 MHz, CDCl3) δ 6.83 (ddd, J = 9.7, 6.3, 1.3

Hz, 3H), 4.55 (d, J = 2.9 Hz, 1H), 4.26 (s, 4H), 3.12 (dd, J = 8.6, 6.6 Hz, 1H), 2.57 (m, 9H), 1.78 (s, 4H). 13C NMR (151 MHz, CDCl3) δ 143.36, 142.69, 135.84, 119.25, 116.95, 115.22, 75.75, 64.39, 64.36, 60.11, 54.72, 54.43, 23.59. HRMS (ESI) calcd for C15H23N2O3 [M+H]+: 279.1694, found 279.1702. Analysis by ICP-MS showed 4.7 ppm Al, 310 ppm Pd.


17


Page 18 of 22

N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (Eliglustat, 1). 2 (45 g) was dissolved in anhydrous dichloromethane (360 mL) and the solution was cooled to 10°C. Triethylamine (24.5 g) was added to the mixture. A solution of 2,5-dioxopyrrolidin-1-yl octanoate (39.4 g) in anhydrous dichloromethane (200 mL) was added over 30 minutes. Then the mixture was stirred at room temperature for 14-16 hours. After completion of reaction, the reaction mixture was cooled to 5-10°C. 1M NaOH solution (230 mL) was added slowly to maintain the internal temperature below 15°C. After stirring for 30 min, the organic layer was separated and washed with 5 wt% NaCl solution (2 × 250 mL). The organic layer was dried with anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was again dissolved in MTBE (90 mL) and n-hexane (460 mL). After stirring for 30 min, the slurry was filtered. The product was washed with n-hexane (2 × 200 mL) and dried under reduced pressure to afford Eliglustat (1) free base as a white solid (58.7 g, 90% yield, >99.9 % ee, >99:1 dr). The enantiomeric excess was determined by chiral HPLC method: chiral MX (2) column, 4.6 x 250 mm x 5μm; flow rate: 0.8 mL/min; temperature: 25°C; detection wavelength: 210 nm; eluent: Hexane/Ethanol (0.1% diethylamine) = 80/20; retention time: 11.08 min (syn-1), 13.05 min (anti-1), 14.18 min (ent-syn-1) and 16.03 min (ent-anti-1). Mp 85-87°C. [α]

20 D

+7.3, (c = 3.00, MeCN). 1H NMR (400 MHz,

CDCl3) δ 6.95 – 6.67 (m, 3H), 5.87 (d, J = 7.2 Hz, 1H), 4.92 (d, J = 3.0 Hz, 1H), 4.26 (s, 4H), 4.20 (dt, J = 8.2, 4.0 Hz, 1H), 2.88 – 2.75 (m, 2H), 2.73 – 2.58 (m, 4H), 2.12 (t, J = 7.5 Hz, 2H), 1.80 (s, 4H), 1.61 – 1.44 (m, 2H), 1.39 – 1.15 (m, 9H), 0.89 (t, J = 6.8 Hz, 3H).

13C

NMR (151 MHz, CDCl3) δ 173.47, 143.41, 142.80, 134.53, 118.92,

116.98, 115.06, 75.31, 64.33, 57.79, 55.14, 52.34, 36.81, 31.63, 29.08, 28.98, 25.65, 23.65, 22.60, 14.05. HRMS (ESI) calcd for C23H37N2O4 [M+H]+: 405.2733, found 405.2746. Analysis by ICP-MS16 showed

Development of an Efficient and Scalable Asymmetric Synthesis of

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