Industrial Scale-Up of Enantioselective Hydrogenation for the

The first route was easy to scale up in industry and provided the commercial intermediate (S)-3-(1-dimethylaminoethyl)phenol, 6, which is suitable for...
0 downloads 0 Views 242KB Size
Download PDF
Communication pubs.acs.org/OPRD

Industrial Scale-Up of Enantioselective Hydrogenation for the Asymmetric Synthesis of Rivastigmine Pu-Cha Yan,† Guo-Liang Zhu,† Jian-Hua Xie,‡ Xiang-Dong Zhang,† Qi-Lin Zhou,‡ Yuan-Qiang Li,† Wen-He Shen,† and Da-Qing Che*,† †

Zhejiang Jiuzhou Pharmaceutical Co., Ltd., 99 Waisha Road, Jiaojiang District, Taizhou City, Zhejiang Province 318000, P.R. China State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P.R. China

‡

racemic mixture of 3-(1-dimethylaminoethyl)phenol (6),6,12 that is time-consuming and labour intensive when run in standard batch reactors. Foulkes, M. et al.13 at Novartis recently reported an improved process by using a Ru-catalyzed enantioselective hydrogenation of m-hydroxyacetophenone (2) in degassed isopropanol to access optically pure alcohol intermediate 3 with 98% ee and 85% yield after crystallization at a ratio of substrate to catalyst (S/C) of 10,000. Further transformation of 3 afforded (S)-3-(1-dimethylaminoethyl)phenol (6). Finally, the treatment of 6 with N-ethyl-N-methyl carbamoyl chloride in the presence of base furnished the free base of 1. In this report, we present an efficient, economical, and suitable for scale-up process by applying a highly efficient and stable chiral spiro-iridium catalyst developed by Zhou et al.14 to produce of rivastigmine on kilogram scale.

ABSTRACT: Two efficient processes for the synthesis of rivastigmine, one of the most potent drugs for the treatment of mild-to-moderate dementia of the type presenting in Alzheimer’s disease, has been developed. Of particular note is the processes used for the asymmetric hydrogenation by applying the highly efficient chiral spiro catalyst, Ir-SpiroPAP. The first route was easy to scale up in industry and provided the commercial intermediate (S)3-(1-dimethylaminoethyl)phenol, 6, which is suitable for the manufacture of rivastigmine in active pharmaceutical ingredient (API) demand. The second route was convenient for operation and purification and completed the synthesis of rivastigmine (1) in four steps and 84% overall yield.

■

■

RESULTS AND DISCUSSION The new iridium catalysts with chiral tridentate spiro ligands, SpiroPAP, have proved to be extremely efficient for the asymmetric hydrogenation of ketones, especially for the acetophenone derivatives, TON up to 4,550,000.14 mHydroxyacetophenone (2) was chosen as the starting material, as it is commercially available and inexpensive. Rivastigmine (1) can be synthesized through two different routes starting from 2 by applying catalyst Ir-SpiroPAP in asymmetric hydrogenation as the key technology (Scheme 1, Route A, and Scheme 2, Route B). Route A is shown in Scheme 1. We initially carried out the hydrogenation of 2 under conditions previously optimized for the reaction of acetophenone (Ir-(S)-SpiroPAP-3-Me, S/C = 5000, S/B = 50, 10 atm H2, 25−30 °C).14 However, only 33% conversion was obtained within 48 h (Table 1, entry 1). We attributed the deactivation of catalyst to the acidity of the phenolic hydroxy group in the substrate. When more than one equivalent base (B/S = 1.06) was used, the hydrogenation reaction could be completed smoothly within 2 h, giving (R)-3 in 95% ee (Table 1, entry 2). The reaction rate could be accelerated by raising the reaction temperature to 50 °C, and full conversion was obtained within 1 h without loss of enantioselectivity (Table 1, entry 3). Screening of bases (Table 1, entries 4−7) revealed that both tBuOK and tBuONa (Table 1, entries 3 and 5) could provide 100% conversion and high ee. Although the solubility of tBuONa in ethanol was poor than t BuOK, we chose tBuONa in the further studies taking the price

INTRODUCTION Alzheimer’s disease (AD) is the most common form of dementia, a severe human health threat with more than 30 million sufferers worldwide. 1 Rivastigmine, (S)-3-[1(dimethylamino)ethyl]phenyl ethyl (methyl) carbamate (1), represents one of the most potent drugs for the treatment of mild-to-moderate dementia of the Alzheimer’s type.2 In addition, it is supposed to be effective in the treatment of mild-to-moderate dementia related to Parkinson’s disease3 and Lewy bodies.4 In 2006, it has been used in more than 6 million patients worldwide. Clinical trials proved that the (S)enantiomer exhibits the desired cholinesterase inhibition, which requires the drug in enantiomerically pure form.5 Its tartrate salt is marketed under brand name Exelon. To date, several methods for the synthesis of enantiomerically pure rivastigmine have been reported. Initial approaches have been developed via resolution of racemates using various chiral acids6 and copper-catalyzed addition of Me2Zn to aldimine.7 Recent approaches are based on lipase-catalyzed kinetic resolution,8 chemoenzymatic asymmetric synthesis,9 and diastereoselective reductive amination.10 Transition metalcatalyzed asymmetric transfer hydrogenation has also been applied to the synthesis of rivastigmine,11 but the catalyst loading was usually very high (10 mol % to 0.05 mol %). All of these methods have certain drawbacks, such as complex sequential operations, trace impurities of metals, or multiple crystallization steps involving diastereomeric salts. Currently, there is still no efficient large-scale production method through asymmetric synthesis of rivastigmine. The disclosed processes mostly rely on a kinetic resolution of a © XXXX American Chemical Society

Received: November 4, 2012

A

dx.doi.org/10.1021/op3003147 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

Scheme 1. Route A for the synthesis of rivastigminea

Reagents and conditions: (a) H2, Ir-(S)-SpiroPAP-3-Me, tBuONa, EtOH, 50 °C; (b) MsCl, Et3N, THF, 0 °C; (c) Me2NH, THF, 0−20 °C; (d) 30% aq NaOH, 90 °C; (e) K2CO3, N-ethyl-N-methyl carbamoyl chloride, ethyl acetate, reflux. a

Table 1. Laboratory studies of asymmetric hydrogenation of ketone 2a entry 1 2 3 4 5 6 7 8g 9g 10g

ketone 2 (g) 0.68 0.68 0.68 0.68 0.68 0.68 0.68 6.8 13.6 50

S/Cb 5000 5000 5000 5000 5000 5000 5000 50000 100000 100000

base (B/Sc)

temp. (°C)

time (h)

conv. (%)d

BuOK (0.02) BuOK (1.06) t BuOK (1.06) KOH (1.06) t BuONa (1.06) EtONa (1.06) MeONa (1.06) t BuONa (1.06) t BuONa (1.06) t BuONa (1.06)

25 25 50 50 50 50 50 50 50 50

48 2 1 10 1 3 5 8 24 24

33 100 100 100 100 100 100 100 100 100

t t

ee (%)e n.d.f 95 95 92 95 96 95 96 97 97

(R) (R) (R) (R) (R) (R) (R) (R) (R)

a

Conditions: catalyst Ir-(S)-SpiroPAP-3-Me prepared in EtOH, PH2 = 10 atm unless otherwise noted. bSubstrate to catalyst ratio. cBase to substrate ratio. dDeterminde by 1H NMR ananlysis. eDetermined by HPLC on a chiral OD-H column. fn.d. = not determined. gPH2 = 30 atm (initial).

entry 10), the process was carried out for the first pilot batch (Table 2, entry 1).15 Ultimately the premade catalyst was used in the remaining pilot batches (Table 2, entries 2−4) and provided a total of 51.7 kg of alcohol (R)-3 in 91−96% yield with 96−97% ee. The ee value of 3 could be upgraded to >99% by crystallization from ethyl acetate/heptanes.

of tBuOK into account which was about 4 times as expensive in comparison to that of tBuONa. When the catalyst loading was lowered to 0.002 mol % (S/C = 50000), the hydrogenation product (R)-3 was still obtained in 96% ee with 100% conversion within 8 h under an initial hydrogen pressure of 30 atm (Table 1, entry 8). Lowering the catalyst loading further to 0.001 mol % (S/C = 100000), the reaction was completed within 24 h, providing the product (R)-3 in 97% ee (Table 1, entries 9 and 10). Although the reaction of 2 with tBuONa was found to be almost not exothermic, dissolving tBuONa in EtOH was obviously exothermic. A procedure for the preparation of 3 was developed which allowed operation safely on large scale. By adding tBuONa slowly to an ethanol solution of 2 at 0−5 °C, while controlling the reaction temperature allowed for it to be performed safely on scale-up. When tBuONa was completely dissolved, this solution was transferred to autoclave followed by addition of the Ir-(S)-SpiroPAP-3-Me catalyst for hydrogenation. After a final demonstration in the lab (Table 1,

Table 2. Pilot batches of asymmetric hydrogenation of ketone 2a entry

ketone 2 (kg)

time (h)

yield (%)b

alcohol (R)-3 (kg)

ee (%)c

purity (area %)c

1 2 3 4

5.0 12.5 12.5 25.0

30 24 24 20

96 92 95 91

4.9 11.7 12.0 23.1

96 97 97 96

97.8 98.1 98.6 98.3

a

Conditions: catalyst Ir-(S)-SpiroPAP-3-Me prepared in EtOH, PH2 = 30 atm, 50 °C, 1.06 equiv tBuONa, 12 vol EtOH. bIsolated yield. c Determined by HPLC on a chiral OD-H column. B

dx.doi.org/10.1021/op3003147 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

purification of 1 was achieved by simple extraction and washing operations under different pH values. By route B, rivastigmine (1) was obtained in 84% yield without loss in optical purity from the intermediate 8.

With the alcohol (R)-3 in hand, the synthesis of 6 was completed in a three-step process (Scheme 1). Both hydroxyl groups on alcohol (R)-3 was mesylated by adding methanesulfonyl chloride dropwise in the presence of Et3N in THF at 0 °C. After addition, a slurry was formed and the stirring was continued for one hour at 15−20 °C to ensure that the mesylation was completed. The resulting compound 4 was used directly in the subsequent reaction. Compound 4 was treated with dimethylamine at 0−20 °C to afford 5 in >90% yield. Upon complete consumption of 4, the previously formed amine salt and other byproducts were removed by aqueous workup, and the organic extracts were distilled in vacuo resulting a yellow oil which was subjected to hydrolysis with 30% aqueous NaOH solution. The hydrolysis was performed at 90 °C with rapid stirring for 2−5 h, the initially biphasic solution became a clear, yellow monophasic solution. The pH of the resulting solution was adjusted to 7.5 with 6 M aqueous HCl at 0 °C and extracted with ethyl acetate. Ethyl acetate was distilled off and the product (S)-3-(1-dimethylaminoethyl)phenol (6) was isolated in 86% yield and >99% ee by crystallization from ethyl acetate/heptane (Table 3, entry 1). Pilot-plant operation was performed in three batches to provide 35 kg of (S)-3-(1dimethylaminoethyl)phenol (6) (Table 3, entries 2−4).

■

■

EXPERIMENTAL SECTION General. 1H and 13C NMR spectra were recorded on a Bruker Ultrashield 400 Plus spectrometer at 400 and 100.6 MHz, respectively. Melting points were determined on an open capillary apparatus and uncorrected. Chiral separations for ee determinations were conducted on Chiracel OD-H, 4.6 mm × 250 mm × 5 μm column on an Agilent 1200 series instrument. Optical rotations were determined using a SG WZZ-2S automatic polarimeter. Mass spectra were recorded on Agilent 6530 Accurate-Mass Q-TOF LC/MS spectrometer with ESI resource. The purity of intermediate 6 was analysed by reverse phase HPLC on a Waters e2695 instrument according to the following conditions: column XDB-C18, 4.6 mm × 250 mm × 3.5 μm; eluent A, 0.1% v/v trifluoroacetic acid in purified water; eluent B, 0.1% v/v trifluoroacetic acid in acetonitrile; flow rate, 1.0 mL/min.; wavelength, 225 nm; column temperature, 30 °C; injection volume, 20 uL; at t = 0 min, 5% eluent B; at t = 20 min, 65% eluent B; at t = 20.1 min, 5% eluent B; at t = 25 min, 5% eluent B. The catalyst Ir-(S)-SpiroPAP-3-Me was prepared per the reported method.14 Anhydrous EtOH was freshly distilled from calcium hydride. All reagents and solvents were used as received without further purification unless otherwise noted. Route A. (R)-3-(1-Hydroxyethyl)phenol (3). To a solution of m-hydroxyacetophenone (2) (12.5 kg, 91.8 mol) in anhydrous ethanol (147 L), was added tBuONa (9.4 kg, 97.3 mol) in portions at 0−5 °C over 15 min, maintaining a temperature less than 15 °C. The reaction mixture was then warmed to 20 °C and agitated for 1 h until all of the tBuONa dissolved into solution. The resulting solution was charged to a 300-L autoclave via cannula, and an ethanol (10 L) wash was used to rinse the charging lines into the autoclave. Nitrogen purging was done twice, and the solution was stirred with N2 bubbling through for a total of 15 min. Then the catalyst Ir-(S)SpiroPAP-3-Me (920 mg, 0.92 mmol) was transferred by Schlenk techniques as a solution in anhydrous ethanol (100 mL) into the autoclave. The autoclave was then purged with hydrogen (0.3 MPa, six times), and then pressurized with hydrogen to 3.0−3.2 MPa. The reaction was agitated at 50−55 °C until the hydrogen uptake ceased, signifying the reaction was complete (about 24 h). After the reaction mixture cooled to 20 °C, hydrogen pressure was released, and the mixture was purged with N2. The reaction mixture was distilled under reduced pressure. To the resulting residue was added 3 M HCl (33 L, 99 mol) and ethyl acetate (90 L) at 0−5 °C, followed by

Table 3. Conversion of alcohol (R)-3 to (S)-3-(1dimethylaminoethyl)phenol (6)a entry

alcohol (R)-3 (kg)

ee of (R)-3 (%)

yield (%)b

(S)-6 (kg)

ee of (S)-6 (%)c

purity (area %)d

1 2 3 4

0.0075 10 10 15

99.4 99.6 99.8 99.9

86 82 84 85

0.0077 9.8 10.0 15.2

99.9 99.9 99.9 99.9

99.5 99.7 99.8 99.8

CONCLUSION

In conclusion, we have developed two efficient processes for the preparation of rivastigmine via asymmetric hydrogenation using the highly efficient chiral spiro catalyst Ir-SpiroPAP. The first route was easy to scale-up in industry and provided (S)-3(1-dimethylaminoethyl)phenol (6), which is a suitable intermediate for the manufacture of rivastigmine in API demand.16 The second route was convenient for operation and purification, giving rivastigmine in four steps in 84% overall yield. The presented method towards rivastigmine represents the shortest route published to date.

a

Conditions: see Experimental Section. bIsolated yield. cDetermined by HPLC on a chiral OD-H column. dDetermined by HPLC on a XDB-C18 column.

The final step in the sequence was the amidoesterification of 6 with 1.1 equiv N-ethyl-N-methyl carbamoyl chloride in the presence of K2CO3 under reflux in ethyl acetate to afford rivastigmine (1) in 90−95% isolated yield with >99% ee (Scheme 1). Route B. In order to avoid the use of a stoichiometric amount of tBuONa in the asymmetric hydrogenation step, we tried to perform the synthetic route B as shown in Scheme 2, which is the process for the synthesis 1 in four steps via the intermediate 8. The route B involved the condensation of m-hydroxyacetophenone (2) with 1.1 equiv N-ethyl-N-methyl carbamoyl chloride in ethyl acetate in the presence of K2CO3 as base to give 7. After simple aqueous workup and extraction, the crude 7 was subjected to hydrogenation with the catalyst Ir-(S)SpiroPAP-3-Me. With 0.04 equiv tBuONa and 0.001 mol % catalyst, the hydrogenation of 7 proceeded smoothly at 50 °C under 30 atm of H2 pressure and completed in 18 h, providing the product 8 in 96% yield and >98% ee. Following distillation of the solvent EtOH and with an aqueous workup, the organic extracts were distilled into THF, and the solution was subjected to mesylation with methanesulfonyl chloride in the presence of Et3N. The resulting suspension was used directly in the subsequent nucleophilic substitution with dimethylamine in portions at 0−20 °C to afford 1. It is noteworthy that C

dx.doi.org/10.1021/op3003147 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

Scheme 2. Route B for the synthesis of rivastigminea

a Reagents and conditions: (a) K2CO3, N-ethyl-N-methyl carbamoyl chloride, ethyl acetate, reflux; (b) H2, Ir-(S)-SpiroPAP-3-Me, tBuONa, EtOH, 50 °C; (c) MsCl, Et3N, THF, 0 °C; (d) Me2NH, THF, 0−20 °C.

Table 4. Asymmetric hydrogenation of ketone 7a entry

ketone 7 (g)

time (h)

yield (%)

1 2 3 4

15.5 22.1 22.1 36.5

18 20 16 20

96 97 96 98

b

alcohol (R)-8 (g)

ee (%)

15.0 21.6 21.4 36.1

98.2 98.7 98.4 98.4

solution was cooled to 0 °C, and methanesulfonyl chloride (19.9 kg, 173.8 mol) was added over 3 h, maintaining the temperature