Process for the asymmetric catalytic hydrogenation of indolocyclopentenyl malonates and use thereof

Abstract

The application discloses an asymmetric catalytic hydrogenation method of indolocyclopentenyl malonate and application thereof. The method comprises the following steps: in the presence of hydrogen atmosphere, a chiral Ir-SpiroPAP catalyst, a base and a solvent, performing asymmetric catalytic hydrogenation on indolocyclopentenyl malonate to obtain indolocyclopentenyl malonate. The indolocyclopentenyl malonate containing one tertiary carbon chiral center prepared by the method can be used as a key chiral raw material for asymmetric synthesis of a chiral drug Velsipity (Etrasimod). The method has higher enantioselectivity, lower catalyst consumption and a wide substrate application range.

Description

Technical Field

[0001] This invention relates to the field of asymmetric synthesis technology, and in particular to an asymmetric catalytic hydrogenation method for indolecyclopentenyl malonate and its application. Background Technology

[0002] Asymmetric catalytic hydrogenation is one of the most atom-economical, green, and efficient methods for synthesizing chiral compounds, and it has been widely used in the industrial production of chiral drugs and pesticides. Asymmetric catalytic hydrogenation offers advantages such as simple operation, atom economy, and environmental friendliness. Generally, the activity and stability of the chiral catalyst determine the efficiency and selectivity of the hydrogenation reaction. Therefore, the development of highly efficient chiral ligands and their catalysts, as well as efficient and highly enantioselective asymmetric catalytic hydrogenation reactions, has attracted widespread attention from academia and industry.

[0003] Chiral indolocyclopentane structures are important chiral structural units in natural product molecules and chiral drugs. Asymmetric hydrogenation of indolocyclopentenyl compounds is a crucial method for obtaining chiral indolocyclopentanes. In 2006, Tellers et al., while studying the synthesis of laropiprant, a drug for treating allergic diseases, discovered that a ruthenium catalyst with the chiral bisphosphine ligand BINAP could catalyze the asymmetric hydrogenation of unsaturated carboxylic acids containing an indolocyclopentenyl skeleton. However, due to the ease with which the double bond isomerizes and the existence of Z / E-isomers when the double bond is outside the ring, controlling the stereoselectivity of the hydrogenation reaction is difficult. After optimizing the reaction conditions, at low pressure (2.2 atm), the chiral ruthenium catalyst favored the hydrogenation of intracyclic double bonds, yielding an enantioselectivity as high as 91% ee. Conversely, at relatively higher hydrogen pressures (34 atm), only 47% ee was given as enantioselectivity. Based on this asymmetric catalytic hydrogenation reaction, they completed the asymmetric synthesis of laropiprant. This method still suffers from a limited substrate range, requires a single (E)-isomer, and necessitates the formulation of the substrate as a guanidine salt to achieve good conversion. These limitations have hampered the synthetic application of the corresponding asymmetric hydrogenation reaction in chiral drug and natural product molecules (Tellers, DMe et al. J. Am. Chem. Soc. 2006, 128, 17063-17073.). Summary of the Invention

[0004] To address the problems existing in the prior art, one objective of this invention is to provide an asymmetric catalytic hydrogenation method for indolecyclopentenyl malonate with a broad substrate range, good enantioselectivity, and high yield.

[0005] Another object of the present invention is to provide an application of the above-described asymmetric catalytic hydrogenation method in the asymmetric synthesis of a key chiral intermediate of the commercially available chiral drug Velsipity (Etrasimod).

[0006] Therefore, the present invention adopts the following technical solution:

[0007] In a hydrogen atmosphere and in the presence of a chiral Ir-SpiroPAP catalyst, a base, and a solvent, indole-cyclopentenyl malonate is subjected to asymmetric catalytic hydrogenation to yield indole-cyclopentyl malonate, as shown in the following reaction formula:

[0008]

[0009] or:

[0010]

[0011] in:

[0012] R 1 It is a C1-C20 alkyl group; such as methyl, ethyl, etc.

[0013] R 2 The compounds are alkyl, benzyl, p-methoxybenzyl, p-chlorobenzyl, and (trimethylsilyl)ethoxymethyl.

[0014] X represents hydrogen, alkyl, alkoxy, or halogen.

[0015] The structural formula of the chiral Ir-SpiroPAP catalyst is:

[0016] Or its enantiomer (S)-1,

[0017] In the formula: Y is hydrogen, alkyl or halogen; Ar is 3,5-tBu2C6H3.

[0018] Preferably, the chiral Ir-SpiroPAP catalyst has the following structural formula:

[0019] Or its enantiomer (S)-1a.

[0020] In the above reaction, the concentration of indolecyclopentenylmalonate is 0.01–2.0 mmol / mL, and the molar ratio of indolecyclopentenylmalonate to chiral Ir-SpiroPAP catalyst is (100–5000):1; the pressure of hydrogen is 1–100 atm; the concentration of base is 0.01–1.0 mmol / mL; the asymmetric catalytic hydrogenation time is 24–120 hours; and the reaction temperature is 0–50 °C.

[0021] Preferred reaction conditions are as follows: the hydrogen pressure is 50 atm; the reaction temperature is 30–35 °C; the molar ratio of indolecyclopentenyl malonate to chiral Ir-SpiroPAP catalyst is 400:1; and the concentration of the base is 0.05–0.5 mmol / mL.

[0022] The base is an alkali metal salt of an alcohol, an alkali metal hydroxide, or an alkali metal carbonate. Preferably, the alkali metal salt of the alcohol is lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium isopropoxide, or sodium isopropoxide; the alkali metal hydroxide is preferably potassium hydroxide or sodium hydroxide; and the alkali metal carbonate is preferably potassium carbonate, sodium carbonate, or cesium carbonate.

[0023] The solvent is one or a mixture of several of the following: alcohol solvents, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N,N-dimethylformamide, and dimethyl sulfoxide. The preferred alcohol solvents are methanol, ethanol, n-propanol, isopropanol, or butanol.

[0024] Preferably, the C1-C20 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, or isopentyl. Alkyl group R 2 The alkyl group is methyl, ethyl, or n-propyl; the alkyl group X is methyl or ethyl; the halogen is fluorine, chlorine, or bromine.

[0025] The reaction products of the asymmetric catalytic hydrogenation include:

[0026]

[0027] Note: PMB=p-methoxybenzyl; PCB=p-chlorobenzyl; SEM=2-(trimethylsilyl)ethoxymethyl.

[0028] This invention also protects the application of the above-described asymmetric catalytic hydrogenation method in the preparation of the chiral drug Velsipity. The reaction process is as follows:

[0029]

[0030] In the above asymmetric catalytic hydrogenation reaction, the molar ratio of indolecyclopentenyl malonate 2k to chiral spirocyclic pyridine aminophosphine iridium catalyst (R)-1a was (100-5000):1; the hydrogen pressure was 1–100 atm; the concentration of potassium tert-butoxide was 0.01–1.0 mmol / mL; the asymmetric catalytic hydrogenation time was 24–168 hours; and the reaction temperature was 0–50 °C.

[0031] The product (R)-3k obtained from the asymmetric catalytic hydrogenation reaction, a mixture of lithium chloride, water and dimethyl sulfoxide was heated under reflux in an oil bath for 12–24 hours, and post-processed to obtain the chiral product (R)-4, wherein the equivalence ratio of (R)-3k to lithium chloride was 1:(1.0–5.0); and the mixed solvent of water and dimethyl sulfoxide was in a volume ratio of 1:(5–10).

[0032] Etrasimod was prepared from the chiral product (R)-4.

[0033] This invention describes the asymmetric hydrogenation of indole-cyclopentenyl malonate in the presence of a chiral Ir-SpiroPAP catalyst, yielding a series of chiral indole-cyclopentenyl malonates containing a tertiary carbon stereocenter with high enantioselectivity and yield. The chiral products prepared by this method can be used for the asymmetric synthesis of the recently marketed chiral drug Velsipity (Etrasimod).

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] 1. This invention uses a chiral Ir-SpiroPAP catalyst to hydrogenate indole-cyclopentenyl malonate to obtain a series of chiral indole-cyclopentenyl malonates containing a tertiary carbon stereocenter in high yield and enantioselectivity, with an enantioselectivity of up to 96% ee. It has a low catalyst dosage (0.5 mol%) and a wide substrate applicability.

[0036] 2. The chiral indodocyclopentylmalonic acid ester 3k prepared by the method of this invention can be used for the asymmetric synthesis of the recently marketed chiral drug Velsipity (Etrasimod). This drug is a selective sphingosine 1-phosphate (S1P) receptor antagonist with therapeutic effects in immune and inflammatory mediated diseases such as ulcerative colitis, Crohn's disease, and atopic dermatitis (Sandborn, WJ; Peyrin-Biroulet, L.; Zhang, J.; et al. Gastroenterology 2020, 158, 550). Therefore, developing efficient and atom-economical asymmetric catalytic hydrogenation of such substrates has significant pharmaceutical value. Attached Figure Description

[0037] Figure 1 The image shows the X-ray single-crystal diffraction results of indolecyclopentylmalonic acid ester (R)-3h prepared in Example 8. Detailed Implementation

[0038] The asymmetric catalytic hydrogenation method of indolecyclopentenyl malonate of the present invention will be described in detail below with reference to embodiments.

[0039] Unless otherwise specified, the structural formula of the iridium catalyst (Ir-SpiroPAPs)(R)-1a using the chiral spirocyclic pyridine aminophosphine ligand used in the following specific examples is as follows:

[0040]

[0041] Wherein, Ar is 3,5-(tBu)2C6H3).

[0042] In the following reaction formulas, Et represents ethyl; PMB = p-methoxybenzyl; PCB = p-chlorobenzyl; SEM = 2-(trimethylsilyl)ethoxymethyl.

[0043] Example 1

[0044]

[0045] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate 2a (0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 50 atm, and stirred at 30 °C for 40 hours. After the hydrogenation reaction was complete, hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3a, 74 mg, 90% yield, 92% ee. (c0.2,CHCl3). 1 H NMR (400MHz, CDCl3): δ = 7.42 (d, J = 7.8Hz, 1H), 7.23 (d, J = 8.6Hz, 1H), 7.14 (t, J = 7.5Hz, 1H), 7.05 (t, J = 7.4Hz, 1H), 4.16 (q, J = 7.1Hz, 2H), 4.06–3.94(m,3H),3.75(d,J=6.3Hz,1H),3.66(s,3H),2.92–2.69(m,3H),2.61–2.49(m,1H),1.20(t,J=7.1Hz,3H),0.99(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3): δ=168.5,168.3,144.2,142.1,123.9,120.7,119.8,119.0,118 .9,109.4,61.5,61.3,55.2,38.4,34.3,31.0,23.1,14.0,13.7.HRMS(ESI)m / z:[M+H] + calcd for C 19 H 24 NO4 330.1700; Found:330.1698.

[0046] The high-performance liquid chromatography (HPLC) column separation conditions were: Chiralpak AD-3 column, hexane / isopropanol = 98:2, flow rate = 1.0 mL / min, column temperature: 26℃, UV detection wavelength: 210 nm, 104 bar, t R =6.27min(minor),7.47min(major).

[0047] Example 2

[0048]

[0049] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate 2b (0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 50 atm, and stirred at 30 °C for 40 hours. After the hydrogenation reaction was complete, the hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3b. 75 mg, 88% yield, 96% ee. (c0.5,CHCl3). 1 H NMR (400MHz, CDCl3): δ = 7.41 (d, J = 7.8Hz, 1H), 7.26 (d, J = 8.2Hz, 1H), 7.13 (t, J = 7.6Hz, 1H), 7.04 (t, J = 7.4Hz, 1H), 4.25–4.04 (m, 4H), 4.02–3.9 4(m,3H),3.76(dd,J=5.6,1.6Hz,1H),2.91–2.69(m,3H),2.67–2.57(m, 1H), 1.37(t,J=7.2Hz,3H), 1.22(t,J=7.1Hz,3H), 0.94(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3): δ=168.6,168.2,143.3,140.9,124.2,120.6,120.1,119.0,118.9, 109.7,61.5,61.2,55.0,39.3,38.5,34.0,23.1,15.3,14.0,13.6.HRMS(ESI)m / z:[M+H] + calcd for C 20 H 26 NO4 344.1857; Found:344.1855.

[0050] The high-performance liquid chromatography (HPLC) column separation conditions were: Chiralpak AD-3 column, hexane / isopropanol = 98:2, flow rate = 1.0 mL / min, column temperature: 26℃, UV detection wavelength: 230 nm, 98 bar, t R =5.26min(minor),6.34min(major).

[0051] Example 3

[0052]

[0053] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate 2c (0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 50 atm, and stirred at 30 °C for 40 hours. After the hydrogenation reaction was complete, the hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3c. 90 mg, 89% yield, 91% ee. (c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ=7.48–7.40(m,1H),7.31–7.17(m,3H),7.15–6.96(m,5H),5.36(d,J=16.8Hz,1H),5.23(d,J=16.8Hz,1H),4.17–3 .92(m,4H),3.90–3.79(m,1H),3.66(d,J=5.7Hz,1H),2.97–2.72(m,3H),2.66–2.53(m,1H),1.17(t,J=7.1Hz,3H),0.98(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3): δ=168.5,168.1,144.2,141.9,137.8,128.6,127.2,126.2,124.2,121.0,120 .8,119.3,119.0,110.3,61.4,61.2,54.8,48.0,38.4,34.0,23.2,13.9,13.7.HRMS(ESI)m / z:[M+H] + calcd for C 25 H 28NO4 406.2013; Found:406.2013.

[0054] The high-performance liquid chromatography (HPLC) column separation conditions were: Chiralpak AD-3 column, hexane / isopropanol = 98:2, column temperature: 26℃, flow rate = 1.0 mL / min, UV detection wavelength: 210 nm, 106 bar, t R =6.44min(minor),9.08min(major).

[0055] Example 4

[0056]

[0057] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate 2d (0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 50 atm, and stirred at 30 °C for 40 hours. After the hydrogenation reaction was complete, hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3d. 96 mg, 88% yield, 92% ee. (c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ=7 7.48–7.40(m,1H),7.16–7.12(m,1H),7.09–7.04(m,2H),6.99(d,J=8.5Hz,2H),6. 79(d,J=8.6Hz,2H),5.29(d,J=16.4Hz,1H),5.15(d,J=16.4Hz,1H),4.17–4.05(m, 2H),3.98(q,J=7.1Hz,2H),3.86–3.80(m,1H),3.74(s,3H),3.66(d,J=5.6Hz,1H), 2.91–2.72(m,3H),2.65–2.53(m,1H),1.18(t,J=7.1Hz,3H),0.97(t,J=7.1Hz,3H). 13C NMR (101MHz, CDCl3): δ=168.5,168.1,158.8,144.1,141.8,129.8,127.5,124.2,120.9,120.7,119.2, 119.0,114.0,110.3,61.4,61.2,55.2,54.8,47.6,38.5,33.9,23.2,13.9,13.7.HRMS(ESI)m / z:[M+H] + calcd for C 26 H 30 NO5 436.2119; Found:436.2115.

[0058] The high-performance liquid chromatography (HPLC) column separation conditions were: Chiralpak AD-3 column, hexane / isopropanol = 98:2, flow rate = 1.0 mL / min, column temperature: 26℃, UV detection wavelength: 210 nm, 106 bar, t R =9.29min(minor),13.69min(major).

[0059] Example 5

[0060]

[0061] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate 2e (0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 50 atm, and stirred at 30 °C for 40 hours. After the hydrogenation reaction was complete, hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3e. 104 mg, 90% yield, 91% ee. (c1.0,CHCl3). 1H NMR (400MHz, CDCl3): δ=7.49–7.42(m,1H),7.23(d,J=8.2Hz,2H),7.14–7.03(m,3H),6.97(d,J=8.2Hz,2H),5.32(d,J=16.9Hz,1H),5.21(d,J=16.9H z,1H),4.15–3.95(m,4H),3.90–3.80(m,1H),3.69–3.57(m,1H),2.96–2.7 3(m,3H),2.65–2.50(m,1H),1.17(t,J=7.1Hz,3H),1.02(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3): δ=168.5,168.1,144.1,141.7,136.4,133.0,128.8,127.6,124.3,121.13,121 .11,119.5,119.1,110.2,61.5,61.3,55.0,47.5,38.4,34.2,23.2,13.9,13.7.HRMS(ESI)m / z:[M+H] + calcdfor C 25 H 27 ClNO4440.1623; Found:440.1620.

[0062] High performance liquid chromatography (HPLC) column separation conditions: Chiralpak AD-3 column, hexane / isopropanol = 98:2, flow rate = 1.0 mL / min, column temperature: 26℃, UV detection wavelength: 210 nm, 104 bar, t R =7.16min(minor),9.40min(major).

[0063] Example 6

[0064]

[0065] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate 2f (0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 50 atm, and stirred at 30 °C for 40 hours. After the hydrogenation reaction was complete, hydrogen was slowly released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3f. 100 mg, 90% yield, 89% ee. (c 0.5, CHCl3). 1 H NMR (400MHz, CDCl3): δ = 7.42 (d, J = 7.6Hz, 1H), 7.38 (d, J = 8.2Hz, 1H), 7.21–7. 12(m,1H),7.12–7.06(m,1H),5.49(d,J=11.3Hz,1H),5.38(d,J=11.3Hz,1H), 4.26–4.14(m,2H),4.05–3.90(m,4H),3.49(t,J=8.3Hz,2H),2.90–2.72(m,3H ),2.72–2.62(m,1H),1.25(t,J=7.1Hz,3H),0.98–0.82(m,5H),–0.04(s,9H). 13 C NMR (101MHz, CDCl3): δ=168.8,168.4,143.9,142.1,124.4,121.8,121.3,119.7,119.0,109.9 ,73.3,65.6,61.4,61.1,54.4,38.6,33.4,23.3,17.7,14.0,13.7,–1.5.HRMS(ESI)m / z:[M+H] + calcd for C 24 H 36 NO5Si 446.2357;Found:446.2365.

[0066] High performance liquid chromatography (HPLC) column separation conditions: Chiralpak OJ-3 column, hexane / isopropanol = 99:1, flow rate = 1.0 mL / min, column temperature: 26℃, UV detection wavelength: 210 nm, 122 bar, t R =6.11min(minor),7.95min(major).

[0067] Example 7

[0068]

[0069] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate (2 g, 0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 50 atm, and stirred at 30 °C for 40 hours. After the hydrogenation reaction was complete, hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3g. 106 mg, 90% yield, 93% ee. (c1.0,CDCl3). 1 H NMR (400MHz, CDCl3): δ=7.27–7.18(m,2H),7.03–6.85(m,4H),6.72(dd,J=8.8,2.5Hz,1H),5.27(d,J=16.9Hz,1H),5.17(d,J=16.9Hz,1H),4. 14–3.97(m,4H),3.89–3.77(m,4H),3.61(d,J=5.9Hz,1H),2.91–2.70( m,3H),2.62–2.50(m,1H),1.17(t,J=7.1Hz,3H),1.03(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3): δ=168.5,168.1,154.0,144.8,136.9,136.5,133.0,128.8,127.5,120.6,110 .9,110.8,101.3,61.5,61.3,55.8,55.1,47.6,38.4,34.2,23.1,13.9,13.8.HRMS(ESI)m / z:[M+H] + calcd for C 26 H 29 ClNO5470.1729; Found:470.1725.

[0070] High performance liquid chromatography (HPLC) column separation conditions: Chiralpak AD-3 column, hexane / isopropanol = 90:10, column temperature: 26℃, flow rate = 1.0 mL / min, UV detection wavelength: 210 nm, 112 bar, t R =6.77min(minor),8.90min(major).

[0071] Example 8

[0072]

[0073] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate 2h (0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 50 atm, and stirred at 30 °C for 40 hours. After the hydrogenation reaction was complete, hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3h. 104 mg, 92% yield, 92% ee. (c1.0,CHCl3). 1 H NMR (400MHz, CDCl3): δ=7.30–7.15(m,3H),7.08–6.80(m,4H),5.28(d,J=16.9Hz,1H),5.18(d,J=16.9Hz,1H),4.20–3.92(m,4H),3.88 -3.75(m,1H),3.61(d,J=5.3Hz,1H),2.93–2.69(m,3H),2.61–2.50(m,1H),2.41(s,3H),1.17(t,J=7.0Hz,3H),1.04(t,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3): δ=168.5,168.1,144.2,140.1,136.6,132.9,128.8,127.6,124.5,122.6,120 .6,119.0,109.9,61.5,61.3,55.1,47.5,38.4,34.2,23.1,21.4,13.9,13.8.HRMS(ESI)m / z:[M+H] + calcd for C 26 H 29 ClNO4 454.1780; Found:454.1775.

[0074] High performance liquid chromatography (HPLC) column separation conditions: Chiralpak AD-3 column, hexane / isopropanol = 90:10, column temperature: 26℃, flow rate = 1.0 mL / min, UV detection wavelength: 210 nm, 94 bar, t R =7.12min(minor),11.18min(major).

[0075] Absolute configuration determination:

[0076] 20 mg of (+)-2-(7-methyl-4-p-chlorobenzyl-indolanocyclopentyl)malonate (3 h) was dissolved in 0.5 mL of dichloromethane, and 0.5 mL of n-hexane was slowly added. The mixture was then allowed to stand at room temperature to allow the solvent to slowly evaporate and crystals to precipitate. X-ray single-crystal diffraction analysis was performed on the obtained compound crystals, and their structure is shown below. Figure 1 As shown, its single-crystal data are shown in the table below:

[0077] XRD single-crystal data of compound (+)-3h (CCDC 2336188)

[0078]

[0079] Test results show that the hydrogenated product 3h obtained in this embodiment has the (R)- configuration.

[0080] Example 9

[0081]

[0082] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate 2i (0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reaction vessel was sealed, purged with hydrogen to 90 atm, and stirred at 45 °C for 40 hours. After the hydrogenation reaction was complete, hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3i. 102 mg, 92% yield, 85% ee. (c 1.0, CHCl3). 1 H NMR (400MHz, CDCl3): δ = 7.24 (d, J = 8.4Hz, 2H), 7.09 (dd, J = 9.5, 2.5Hz, 1H), 7 .03–6.88(m,3H),6.86-6.72(m,1H),5.29(d,J=16.9Hz,1H),5.20(d,J=16.9 Hz,1H),4.16–3.96(m,4H),3.88–3.78(m,1H),3.62(d,J=5.7Hz,1H),2.89–2 .68(m,3H),2.63–2.50(m,1H),1.17(t,J=7.1Hz,3H),1.02(t,J=7.1Hz,3H). 13C NMR (101MHz, CDCl3): δ = 168.4, 168.0, 157.9 (d, 1 J C-F =234.7Hz),146.0,138.2,136.1,133.2,128.9,127.5,124.5(d, 3 J C-F =10.0Hz), 121.0(d, 4 J C-F =4.7Hz), 110.8(d, 3 J C-F =9.7Hz), 109.2(d, 2 J C-F =26.2Hz), 104.2(d, 2 J C-F =23.4Hz),61.6,61.4,55.0,47.7,38.4,34.1,23.1,13.9,13.7.HRMS(ESI)m / z:[M+H] + calcd for C 25 H 26 ClFNO4 458.1529; Found:458.1525.

[0083] High performance liquid chromatography (HPLC) column separation conditions: Chiralpak AD-3 column, hexane / isopropanol = 90:10, flow rate = 1.0 mL / min, column temperature: 26℃, UV detection wavelength: 210 nm, 106 bar, t R =7.83min(minor),10.56min(major).

[0084] Example 10

[0085]

[0086] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate 2j (0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 80 atm, and stirred at 30 °C for 48 hours. After the hydrogenation reaction was complete, the hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3j. 85 mg, 63% yield, 82% ee. (c1.0,CHCl3).1 H NMR (400MHz, CDCl3): δ=7.21(d,J=8.5Hz,2H),7.10–6.98(m,2H),6.79(d,J=8.5Hz,2H),5.88(d,J=17.4Hz,1H),5.43(d,J=17.4Hz,1H),4.19–4.08(m ,2H),4.06–3.96(m,2H),3.84–3.75(m,1H),3.57(d,J=5.6Hz,1H),2.89–2. 68(m,2H),2.61–2.49(m,1H),1.20(t,J=7.1Hz,3H),1.04(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3): δ = 168.4, 167.8, 157.0 (d, 1 J C-F =239.4Hz),148.6,137.6,134.6,132.9,128.8,127.2(d, 3 J C-F =10.1Hz), 126.9, 121.8 (d, 4 J C-F =4.8Hz), 114.8(d, 2 J C-F =28.6Hz), 103.7(d, 2 J C-F =22.5Hz), 103.4(d, 3 J C-F =11.6Hz),61.7,61.4,54.5,48.7,38.5,33.9,23.1,13.9,13.7.HRMS(ESI)m / z:[M+H] + calcd for C 25 H 25 BrClFNO4 536.0634,538.0614; Found:536.0635,538.0635.

[0087] High-performance liquid chromatography (HPLC) column separation conditions: Chiralpak AD-3 column, hexane / isopropanol = 99:1, column temperature: 26℃, flow rate = 1.0 mL / min, UV detection wavelength: 210 nm, 106 bar, t R =8.99min(minor),9.64min(major).

[0088] Example 11

[0089]

[0090] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate 2k (0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 80 atm, and stirred at 30 °C for 40 hours. After the hydrogenation reaction was complete, hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3k. 107 mg, 90% yield, 95% ee. (c0.5,CHCl3). 1 H NMR (400MHz, CDCl3): δ=7.25 (d, J=8.9Hz, 1H), 6.88 (s, 1H), 6.80 (dd, J=8.9 ,2.5Hz,1H),5.44(d,J=11.3Hz,1H),5.33(d,J=11.3Hz,1H),4.25–4.13(m,2 H),4.05–3.93(m,4H),3.83(s,3H),3.50–3.43(m,2H),2.86–2.59(m,4H),1. 24(t,J=7.1Hz,3H),0.94(t,J=7.1Hz,3H),0.93–0.82(m,2H),–0.05(s,9H). 13 C NMR (101MHz, CDCl3): δ=168.7,168.3,154.2,144.6,137.2,124.7,121.31,110.8,110.6,101.3,7 3.4,65.5,61.4,61.1,55.8,54.4,38.6,33.4,23.2,17.7,14.0,13.7,–1.5.HRMS(ESI)m / z:[M+H] + calcdfor C 25 H 38 NO6Si 476.2463; Found:476.2458.

[0091] High-performance liquid chromatography (HPLC) column separation conditions: Chiralpak IC-3 column, hexane / isopropanol = 95:5, flow rate = 1.0 mL / min, column temperature: 26℃, UV detection wavelength: 210 nm, 100 bar, t R =8.93min(minor),10.04min(major).

[0092] Example 12

[0093]

[0094] Under argon protection, iridium catalyst (R)-1a (2.6 mg, 0.0025 mmol), potassium tert-butoxide (22.4 mg, 0.2 mmol), and an ethanol solution (1.0 mL) of indolecyclopentenyl malonate 2l (0.25 mmol) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 50 atm, and stirred at 30 °C for 48 hours. After the hydrogenation reaction was complete, hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 30:1, v / v) to give (R)-3l. 111 mg, 82% yield, 65% ee. (c0.5,CHCl3). 1 H NMR (400MHz, CDCl3): δ = 7.11 (dd, J = 8.9, 2.4Hz, 1H), 7.02 (dd, J = 8.5, 2.5Hz, 1H), 6.05 (d, J =11.0Hz,1H),5.52(d,J=11.0Hz,1H),4.2(q,J=7.1Hz,2H),4.00–3.95(m,1H),3.90(d,J=5. 6Hz,1H),3.57–3.49(m,1H),3.48–3.39(m,1H),2.86–2.75(m,2H),2.74–2.65(m,1H),2.64– 2.55(m,1H),1.23(t,J=7.1Hz,3H),1.00(t,J=7.1Hz,3H),0.91–0.82(m,2H),–0.07(s,9H). 13 C NMR (101MHz, CDCl3): δ = 168.6, 168.1, 157.0 (d, 1 J C-F =239.4Hz),148.8,135.0,127.7(d, 3 J C-F =10.0Hz), 122.2(d, 4 J C-F =4.4Hz), 114.9(d, 2 J C-F =28.3Hz).103.7(d, 2 J C-F =22.7Hz).103.6(d, 3 J C-F=11.7Hz),73.9,65.1,61.6,61.2,54.3,38.9,33.5,23.0,17.8,14.0,13.7,–1.5.HRMS(ESI)m / z:[M+H] + calcd forC 24 H 34 BrFNO5Si 542.1368,544.1348; Found:542.1368,544.1361.

[0095] High-performance liquid chromatography (HPLC) column separation conditions: Chiralpak IC-3 column, hexane / isopropanol = 98:2, flow rate = 1.0 mL / min, column temperature: 26℃, UV detection wavelength: 210 nm, 73 bar, t R =5.50min(minor),5.93min(major).

[0096] Example 13

[0097]

[0098] In a glove box, chiral spirocyclic pyridinium aminophosphine iridium catalyst (R)-1a (8.7 mg, 0.0083 mmol) and potassium tert-butoxide (224 mg, 2.00 mol) were added to a 60 mL hydrogenation inner tube. After sealing with a sealing film, the tube was removed and placed into an autoclave. After purging with argon, 2kJ of diethyl 2-(7-methoxy-4-(trimethylsilyl)ethoxymethyl-indolocyclopentenyl)malonate (1.18 g, 2.49 mmol) was dissolved in ethanol (10.0 mL) and transferred to the autoclave. The autoclave was then purged with hydrogen at 50 atm and released to purge it. This process was repeated three times. Hydrogen was then purged again to 60 atm, and the autoclave was placed in a 35°C oil bath for 5 days. After releasing the hydrogen pressure, 2.0 mL of saturated ammonium chloride solution was added to quench the reaction. The mixture was then filtered through a short silica gel column (eluent: ethyl acetate), and the solvent was removed under reduced pressure to obtain the residue. The hydrogenated product (R)-3k was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50:1) to give 1.06 g of hydrogenated product (R)-3k, 90% yield, 95% ee.

[0099] A mixture of (R)-3k (238 mg, 0.50 mmol), lithium chloride (105 mg, 2.50 mmol), water (2 mL), and dimethyl sulfoxide (20 mL) was heated under reflux in an oil bath for 20 hours. After the reaction was complete, the mixture was cooled to room temperature and diluted with water (20 mL) and diethyl ether (20 mL). The organic phase was separated, and the aqueous phase was extracted with diethyl ether (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oil. The product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give a yellow oil (R)-4, 95 mg, 70% yield. (c 0.2, CHCl3). 1 HNMR (400MHz, CDCl3): δ = 8.49 (s, 1H), 7.24 (d, J = 8.8Hz, 1H), 6.97 (s, 1H), 6.82 (d, J = 8.8Hz, 1H), 4.31–4.21 (m, 2H), 3.9 0(s,3H),3.64–3.54(m,1H),2.94–2.73(m,4H),2.55(dd,J=16.9,11.1Hz,1H),2.20–2.10(m,1H),1.35(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3): δ=173.8,153.9,146.5,135.5,124.5,118.7,112.1,11 0.5,101.0,60.7,55.9,39.8,35.7,35.0,23.4,14.2.HRMS(ESI)m / z:[M+Na] + calcd for C 16 H 19 NO3Na 296.1257; Found296.1255.

[0100] This chiral compound is a key chiral intermediate in the asymmetric synthesis of Etrasimod (APD334) (Buzard, DJ; Kim, SH; Lopez, L.; et al. ACS Med. Chem. Lett., 2014, 5, 1313; Sengupta, D.; Gharbaoui, T.; Krishnan, A.; et al. Org. Process Res. Dev. 2015, 19, 618-623).

Claims

1. An asymmetric catalytic hydrogenation method for indolecyclopentenyl malonate, characterized in that... Includes the following steps: In a hydrogen atmosphere and in the presence of a chiral Ir-SpiroPAP catalyst, a base, and a solvent, indole-cyclopentenyl malonate is subjected to asymmetric catalytic hydrogenation to yield indole-cyclopentyl malonate, as shown in the following reaction formula: in: R 1 It is an alkyl group of C1-C20; R 2 The alkyl group is alkyl, benzyl, p-methoxybenzyl, p-chlorobenzyl, or (trimethylsilyl)ethoxymethyl, wherein the alkyl group is methyl, ethyl, or n-propyl. X is hydrogen, alkyl, alkoxy, or halogen, wherein the alkyl group is methyl or ethyl; The structural formula of the chiral Ir-SpiroPAP catalyst is: Or its enantiomer (S)-1, In the formula: Y is hydrogen, alkyl or halogen; Ar is 3,5-tBu2C6H3; The concentration of the substrate indolecyclopentenyl malonate was 0.01–2.0 mmol / mL; the molar ratio of indolecyclopentenyl malonate to the chiral Ir-SpiroPAP catalyst was (50–500):1; the pressure of the hydrogen gas was 30–100 atm; the concentration of the base was 0.01–1.0 mmol / mL; the reaction temperature was 0–50 °C; and the reaction time was 24–120 hours.

2. The asymmetric catalytic hydrogenation method for indolecyclopentenyl malonate according to claim 1, characterized in that, The concentration of the substrate indolecyclopentenyl malonate was 0.05–1.0 mmol / mL; the molar ratio of indolecyclopentenyl malonate to the chiral Ir-SpiroPAP catalyst was 100:1; the pressure of the hydrogen gas was 50 atm; the concentration of the base was 0.05–0.5 mmol / mL; and the reaction temperature was 30–50 °C.

3. The asymmetric catalytic hydrogenation method for indolecyclopentenyl malonate according to claim 1, characterized in that: The alkali includes alkali metal salts of alcohols, alkali metal hydroxides, or alkali metal carbonates, wherein: The alkali metal salt of the alcohol is lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium isopropoxide, or sodium isopropoxide. The hydroxide of the alkali metal is potassium hydroxide or sodium hydroxide; The alkali metal carbonate is potassium carbonate, sodium carbonate, or cesium carbonate.

4. The asymmetric catalytic hydrogenation method for indolecyclopentenyl malonate according to claim 1, characterized in that: The solvent is one or a mixture of several of the following: alcohol solvents, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N,N-dimethylformamide, and dimethyl sulfoxide.

5. The asymmetric catalytic hydrogenation method for indolecyclopentenyl malonate according to claim 1, characterized in that: The alcohol solvent is methanol, ethanol, n-propanol, isopropanol, or butanol.

6. The asymmetric catalytic hydrogenation method for indolecyclopentenyl malonate according to claim 1, characterized in that: The alkyl groups of C1-C20 are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, or isopentyl.

7. The asymmetric catalytic hydrogenation method for indolecyclopentenyl malonate according to claim 1, characterized in that: The halogen is fluorine, chlorine, or bromine.

8. An asymmetric catalytic hydrogenation method for indole-cyclopentenyl malonate to prepare the chiral drug Etrasimod is characterized by the following reaction process: In the above asymmetric catalytic hydrogenation reaction, the molar ratio of indole-cyclopentenyl malonate 2k to chiral Ir-SpiroPAP catalyst (R)-1a was (100-500):1; the hydrogen pressure was 30–100 atm; the concentration of potassium tert-butoxide was 0.05–1.0 mmol / mL; the asymmetric catalytic hydrogenation time was 24–120 hours; and the reaction temperature was 0–50 °C. A mixture of the product (R)-3k obtained from the asymmetric catalytic hydrogenation reaction, lithium chloride, water, and dimethyl sulfoxide was heated under reflux in an oil bath for 12–24 hours. Following post-treatment, the chiral product (R)-4 was obtained. (R)-3k is used in an equivalent ratio of lithium chloride of 1:(1.0–10.0); and a mixed solvent of water and dimethyl sulfoxide is used in a volume ratio of 1:(5–10). The chiral drug Velsipity was prepared from the chiral product (R)-4. The structural formula of the chiral Ir-SpiroPAP catalyst (R)-1a is as follows: In the formula, Ar is 3,5-tBu2C6H3.

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