A sparteine ligand and its use in the preparation of chiral beta-lactones

Abstract

The application discloses synthesis of a sparteine derivative ligand and application of the sparteine derivative ligand in preparation of chiral beta-butyrolactone, and specifically, the sparteine derivative ligand is prepared from sparteine, a catalyst is prepared in situ from the sparteine derivative ligand and a metal iridium precursor, and the catalyst is used for catalyzing asymmetric hydrogenation of a double ethylene ketone to synthesize chiral beta-butyrolactone. The synthesis route of the ligand is simple, the catalyst has high activity and low cost, and the chemical selectivity and the stereoselectivity are very high, so that the production cost of the beta-butyrolactone is greatly reduced.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of fine chemical industry, and particularly relates to synthesis of a sparteine ligand and application thereof in preparation of chiral beta-butyrolactone. BACKGROUND

[0002] Sparteine, also known as wild indigo base and sparteine base, is a natural quinolizidine alkaloid isolated from various legume plants, such as Sophora alopecuroides Linnaeus and Thermopsis lanceolata R. Br., and is particularly rich in the seeds of Laburnum anagyroides Medic. (Wang et al. 2018a; Rouden et al. 2014; Perez et al. 2012), and can be used for producing emergency medicine, smoking cessation medicine and cough medicine. In addition, Dieter Hoppe and Peter Beak groups reported in the 1990s that this kind of diamine compound can be used as a chiral ligand in combination with organolithium reagents such as butyllithium to realize asymmetric deprotonation process, and sparteine and its structural analogues are commonly used chiral ligands in asymmetric catalytic reactions.

[0003] Beta-butyrolactone is a very important intermediate in the production of degradable plastics due to its large four-membered ring structure tension and easy ring-opening polymerization under mild conditions. The chiral methyl group of beta-butyrolactone is crucial to the performance of the material, and diketene is prepared by acetic acid cracking, and the industrialization conditions are mature. The asymmetric hydrogenation of diketene to prepare chiral beta-butyrolactone is the most studied and most feasible method. This method was reported by Takasago in the early stage, but due to the low activity and high price of the developed catalyst, it has not been applied in industrialization.

[0004] Chiral beta-butyrolactone is an important synthetic intermediate. In order to control the production cost of the intermediate, a new type of high-efficiency and low-cost catalyst system needs to be developed. SUMMARY

[0005] In order to develop a new asymmetric hydrogenation catalyst system for diketene, the present application provides a sparteine derivative ligand. The sparteine derivative ligand of the present application is used to prepare a catalyst in situ with an iridium metal precursor, and the catalyst is used to catalyze the asymmetric hydrogenation of diketene to synthesize chiral beta-butyrolactone. The synthesis route of the ligand of the present application is simple, the catalyst has high activity and low cost, and the chemical selectivity and stereoselectivity are very high, which can greatly reduce the production cost of chiral beta-butyrolactone.

[0006] The technical scheme provided by the present application is as follows:

[0007] A sparteine derivative ligand has the following general structure:

[0008]

[0009] wherein R is mainly selected from aryl and its derivatives, preferably C1-C10 alkyl-substituted phenyl, C1-C6 alkoxy-substituted phenyl and fluorine-substituted phenyl, more preferably selected from 2-butylphenyl, 4-butylphenyl, 2,4-dibutylphenyl, 2,6-dibutylphenyl, 2-isopropylphenyl, 4-isopropylphenyl, 2,4-diisopropylphenyl, 2,6-diisopropylphenyl, 2-ethylphenyl, 4-ethylphenyl, 2,4-diethylphenyl, 2,6-diethylphenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 4-methoxyphenyl, o-methoxyphenyl, 4-ethoxyphenyl, o-ethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl.

[0010] The present application provides a preparation method of the ligand, comprising the following steps:

[0011] (1) In a glove box, add sparteine to PCl3 solution at low temperature, filter after the reaction is completed at this temperature, wash the solid with solvent for multiple times, and remove the solvent from the organic phase to obtain ligand intermediate A;

[0012]

[0013] (2) Slowly add aryl Grignard reagent or organolithium reagent to the solution of intermediate A obtained in step (1) at -60 to -80 ℃, slowly raise the reaction temperature from -60 to -80 ℃ to room temperature, continue to react for 4-12 h, and obtain sparteine derivative ligand after quenching and purification;

[0014]

[0015] In step (1) of the present application, the molar ratio of sparteine to PCl3 is 1.2:1 to 2:1, preferably 1.5:1; the preferred solvent is one or more of toluene, xylene, methyl tert-butyl ether, ethyl acetate, dichloromethane, diethyl ether, tetrahydrofuran, n-hexane, more preferably diethyl ether or n-hexane; the reaction temperature is preferably -40 to 0 ℃; and the reaction time is 0.5-10 h.

[0016] In step (2) of the present application, the general formula of aryl Grignard reagent or organolithium reagent can be RMgBr or RLi.

[0017] The molar ratio of ligand intermediate A to Grignard reagent or organolithium reagent is 1:2 to 1:2.5, preferably 1:2.2;

[0018] The solvent is one or more of diethyl ether, tetrahydrofuran, dioxane, dichloromethane, preferably diethyl ether or tetrahydrofuran.

[0019] The present application provides the use of the ligand, which is prepared in situ with metal iridium precursor into asymmetric hydrogenation catalyst, for preparing chiral β-butyrolactone from diacetylenic ketone. In a specific embodiment, the method comprises: adding diacetylenic ketone into a reaction kettle, then adding solvent, mixing, adding metal iridium precursor, derivative ligand, carrying out hydrogenation reaction, and preparing chiral β-butyrolactone.

[0020]

[0021] Preferably, the metal iridium precursor is acetylacetone iridium, acetylacetone dicarbonyl iridium, carbonyl di(triphenylphosphine) iridium chloride, acetylacetone bis(ethylene) iridium, fac-tris(2-phenylpyridine) iridium, carbonyl dihydrogen tris(triphenylphosphine) iridium, bis(1,5-cyclooctadiene) iridium tetrafluoroborate, dichloro(pentamethylcyclopentadienyl) iridium dimer, iridium acetate, dodecacarbonyl tetrairidium, iridium pentammine chloride, tris(chloro) tris(pyridine) iridium, dicarbonyl chloro bis(triphenylphosphine) iridium, trans-dichloro bis(ethylenediamine) iridium chloride, bis(cyclooctadiene) iridium hexafluoroantimonate, diacetate pentamethylcyclopentadienyl iridium, dicarbonyl(pentamethylcyclopentadienyl) iridium, (1,5-cyclooctadiene)-η5-indene iridium, bis(1,5-cyclooctadiene) iridium triflate, chloro(1,5-cyclooctadiene)(1,10-phenanthroline) iridium, tris(1-phenylisoquinoline) iridium, bis(2-phenylisoquinoline)(acetylacetone) iridium, (SP-4-2)-carbonyl chloro bis(triphenylphosphine) iridium, dichlorohydrogeno(triphenylphosphine) iridium.

[0022] The molar ratio of the sparteine derivative ligand to the metal iridium precursor is preferably 1:1-1.5:1.

[0023] Preferably, the molar ratio (S / C) of diacetylenic ketone to the metal iridium precursor is 10000-60000.

[0024] The hydrogenation reaction solvent is preferably one or more of dichloromethane, 1,2-dichloroethane, dioxane, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, toluene, xylene, n-hexane.

[0025] The hydrogenation reaction temperature is preferably 40-100℃, the reaction hydrogen pressure is preferably 0.8-10 MPa, and the reaction time is preferably 1-12 h.

[0026] Compared with the prior art, the present application has the following positive effects:

[0027] The application prepares catalytic double vinyl ketone asymmetric hydrogenation by two-step reaction, in-situ preparation of iridium catalyst, and reaction without other additives, the highest conversion rate is 98%, the highest ee value of product beta-butyl lactone is 96%, the highest ratio of substrate to catalyst (S / C) is 50000:1; the reaction condition is mild, the operation is simple and the cost is controllable. DETAILED DESCRIPTION

[0028] The following specific examples only illustrate the application, but these examples are only part of the application, and do not limit the application in other fields.

[0029] The raw materials used in the examples are all conventional raw materials in the art, and the purity specifications used are analytical pure or chemical pure.

[0030] The raw material source information is as follows:

[0031] Double vinyl ketone: 98%, Deyi Chemical;

[0032] Bis(cyclooctadiene) iridium hexafluoroantimonate, dichloro bis(triphenylphosphine) iridium, tris(1-phenylisoquinoline) iridium, bis(2-phenylisoquinoline) (acetylacetone) iridium, from Shanghai Bide Pharmaceutical Co., Ltd.;

[0033] Phosphorus trichloride and Grignard reagent from Yanchuang Technology.

[0034] The catalyst activity of asymmetric hydrogenation reaction is analyzed by qualitative and quantitative analysis of each component in the reaction liquid, and the conditions of GC analysis instrument used are as follows:

[0035] Instrument model: Shimadzu GC2010

[0036] Chromatographic column: DB-5 (30m 0.25mm 0.25μm)

[0037] Column temperature program: first keep at 35℃ for 10min, then increase to 250℃ at the speed of 10℃ / min, keep at this temperature for 10min.

[0038] Detector temperature: 300℃

[0039] Carrier gas: 1bar

[0040] Air: 0.3bar

[0041] Fuel gas (H2): 0.3bar

[0042] Sample mass analysis is carried out by internal standard method. There should be:

[0043]

[0044] wherein ml is the mass of the product, m is the mass of the internal standard, al is the peak area of the product detected in gas chromatography, a is the peak area of the internal standard. k is a correction factor related to the measured substance and the detection conditions.

[0045] Example 1

[0046] Preparation of ligand intermediate A

[0047] In a glove box, PCl3(20.4 g, 0.15 mol) was dissolved in diethyl ether (450 mL), the system was cooled to -40 °C, and the skullcap alkaloid (42.77 g, 0.225 mol) was slowly added to the solution in several portions. After 2 h of reaction, the reaction solution was filtered while cold, and the solid precipitate was washed with diethyl ether (4 x 100 mL). The organic phase solution was combined, and the solvent was removed under reduced pressure to obtain ligand intermediate A (yield 85%).

[0048] 1 H NMR (400 MHz, CDC13) δ 7.30 (m, 1H), 6.45 (dd, J = 9.0, 1.5 Hz, 1H), 6.07 (m, J = 6.8, 1.6 Hz, 1H), 3.73 (dd, J = 10.5, 3.0 Hz, 1H), 3.59 (dd, J = 10.5, 5.8 Hz, 1H), 3.38 (m, 1H), 3.34 - 3.21 (m, 2H), 3.11 (m, 1H), 2.80 - 2.72 (m, 1H), 2.15 (m, 1H), 1.77 (m, 1H), 1.56 - 1.48 (m, 1H).

[0049] Example 2

[0050] Synthesis of the ligand B derived from the skullcap alkaloid

[0051] Ligand intermediate A (29 g, 0.1 mol) was dissolved in 100 mL of tetrahydrofuran, and the system was cooled to -78 °C. The p-isopropylbenzyl Grignard reagent (110 mL, 0.22 mol) was added dropwise to the reaction solution. After the reaction temperature was slowly increased from -78 °C to room temperature and the reaction was continued for 10 h, saturated aqueous ammonium chloride solution (100 mL) was slowly added to the reaction solution to quench the reaction. After separation, the aqueous phase was extracted with ethyl acetate (3 x 100 mL), and the combined organic phase was dried with anhydrous sodium sulfate. After filtration and concentration, ligand B derived from the skullcap alkaloid was obtained by purification (yield 85%).

[0052] 1H NMR (400 MHz, CDC13) δ 7.30 (dd, J = 9.0, 6.8 Hz, 1H), 7.21 (m, 4H), 7.08 - 7.02 (m, 4H), 6.45 (dd, J = 9.0, 1.5 Hz, 1H), 6.07 (m, 1H), 3.75 (dd, J = 10.5, 2.9 Hz, 1H), 3.63 (dd, J = 10.5, 5.5 Hz, 1H), 3.51 (m, 1H), 3.43 (m, 1H), 3.22 (m, 1H), 3.06 (m, 1H), 2.86 (m, 2H), 2.80 (m, 1H), 1.81 - 1.70 (m, 2H), 1.52 (m, 1H), 1.27 (d, J = 6.6 Hz, 12H).

[0053] Example 3

[0054] Synthesis of delphinidin derived ligand C

[0055] Ligand intermediate A (14.5 g, 0.05 mol) was dissolved in 50 mL of tetrahydrofuran, the system was cooled to -78 °C, and m-methoxyphenyl Grignard reagent (55 mL, 0.11 mol) was added dropwise to the reaction solution. After the reaction temperature was slowly increased from -78 °C to room temperature and the reaction was continued for 10 h, saturated aqueous ammonium chloride solution (50 mL) was slowly added to the reaction solution to quench the reaction. After separation, the aqueous phase was extracted with ethyl acetate (3 x 50 mL), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration and concentration, delphinidin derived ligand C was obtained by purification (yield 80%).

[0056] Example 4

[0057] Synthesis of delphinidin derived ligand D

[0058] Ligand intermediate A (8.7 g, 0.03 mol) was dissolved in 30 mL of tetrahydrofuran, the system was cooled to -78 °C, and o-fluorophenyl Grignard reagent (35 mL, 0.07 mol) was added dropwise to the reaction solution. After the reaction temperature was slowly increased from -78 °C to room temperature and the reaction was continued for 12 h, saturated aqueous ammonium chloride solution (30 mL) was slowly added to the reaction solution to quench the reaction. After separation, the aqueous phase was extracted with ethyl acetate (3 x 30 mL), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration and concentration, delphinidin derived ligand D was obtained by purification (75%).

[0059] Example 5

[0060] Synthesis of delphinidin derived ligand E

[0061] The ligand intermediate A (2.9 g, 0.01 mol) was dissolved in 10 mL of tetrahydrofuran, the system was cooled to -78 °C, 3,5-bis(trifluoromethyl)phenyl Grignard reagent (22 mL, 0.022 mol) was added dropwise to the reaction, the reaction temperature was slowly increased from -78 °C to room temperature, and the reaction was continued for 11 h. The reaction was quenched by slowly adding saturated aqueous ammonium chloride solution (10 mL) to the reaction, the liquid was separated, and the aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and then purified to obtain the orinidine derivative ligand E (82%).

[0062] Example 6

[0063] Chiral β-butyrolactone synthesis with ligand B

[0064] In the glove box, divinyl ketone (79 g, 0.94 mol) was added to the reaction kettle, followed by dichloromethane (80 g). After mixing, bis(cyclooctadiene)iridium hexafluoroantimonate (20 mg, 0.03 mmol) and ligand B derivative (0.03 mmol) were added in sequence. The reaction kettle was sealed and removed from the glove box for reaction preparation. After 5 times of hydrogen replacement, the hydrogen pressure was increased to 2 MPa. The heating was started at 40 °C, and the reaction was continued for 8 h. GC sampling detection showed that the raw material divinyl ketone was almost completely reacted, the yield of the product chiral β-butyrolactone was 96%, the ee value was 95%, and the TON was 28723.

[0065] Example 7

[0066] Chiral β-butyrolactone synthesis with ligand C

[0067] In the glove box, divinyl ketone (62.2 g, 0.74 mol) was added to the reaction kettle, followed by 1,2-dichloroethane (60 g). After mixing, dicarbonyl chloride bis(triphenylphosphine)iridium (15 mg, 0.018 mmol) and ligand C derivative (0.022 mmol) were added in sequence. The reaction kettle was sealed and removed from the glove box for reaction preparation. After 5 times of hydrogen replacement, the hydrogen pressure was increased to 4 MPa. The heating was started at 70 °C, and the reaction was continued for 6 h. GC sampling detection showed that the raw material divinyl ketone was almost completely reacted, the yield of the product chiral β-butyrolactone was 97%, the ee value was 94%, and the TON was 38800.

[0068] Example 8

[0069] Chiral β-butyrolactone synthesis with ligand D

[0070] In the glove box, the divinyl ketone (153 g, 1.82 mol) was added to the reactor, then THF (150 g) was added, after mixing, the bis(2-phenylisoquinoline)(acetylacetone) iridium (25 mg, 0.035 mmol) and the ligand E (0.043 mmol) were added in turn, the reactor was sealed and removed from the glove box for reaction; after 5 times of hydrogen replacement, the hydrogen was pumped to 6 MPa, the heating was started at 50°C, the reaction was carried out for 8 h, the GC sampling detection showed that the raw material divinyl ketone was basically completely reacted, the yield of the product chiral β-butyrolactone was 98%, the ee value was 96%, and the TON was 50039.

[0071] Example 9

[0072] Chiral β-butyrolactone synthesis involving ligand E

[0073] In the glove box, the divinyl ketone (153 g, 1.82 mol) was added to the reactor, then THF (150 g) was added, after mixing, the bis(2-phenylisoquinoline)(acetylacetone) iridium (25 mg, 0.035 mmol) and the ligand E (0.043 mmol) were added in turn, the reactor was sealed and removed from the glove box for reaction; after 5 times of hydrogen replacement, the hydrogen was pumped to 6 MPa, the heating was started at 50°C, the reaction was carried out for 8 h, the GC sampling detection showed that the raw material divinyl ketone was basically completely reacted, the yield of the product chiral β-butyrolactone was 98%, the ee value was 96%, and the TON was 50039.

[0074] Comparative Example 1

[0075] In the glove box, the divinyl ketone (153 g, 1.82 mol) was added to the reactor, then THF (150 g) was added, after mixing, the bis(2-phenylisoquinoline)(acetylacetone) iridium (25 mg, 0.035 mmol) and the ligand E (0.043 mmol) were added in turn, the reactor was sealed and removed from the glove box for reaction; after 5 times of hydrogen replacement, the hydrogen was pumped to 6 MPa, the heating was started at 50°C, the reaction was carried out for 8 h, the GC sampling detection showed that the raw material divinyl ketone was basically completely reacted, the yield of the product chiral β-butyrolactone was 98%, the ee value was 96%, and the TON was 50039.

[0076] Comparative Example 2

[0077] In the glove box, the divinyl ketone (153 g, 1.82 mol) was added to the reactor, then THF (150 g) was added, after mixing, the bis(2-phenylisoquinoline)(acetylacetone) iridium (25 mg, 0.035 mmol) and the ligand E (0.043 mmol) were added in turn, the reactor was sealed and removed from the glove box for reaction; after 5 times of hydrogen replacement, the hydrogen was pumped to 6 MPa, the heating was started at 50°C, the reaction was carried out for 8 h, the GC sampling detection showed that the raw material divinyl ketone was basically completely reacted, the yield of the product chiral β-butyrolactone was 98%, the ee value was 96%, and the TON was 50039. 1.5((S)-T-BINAP)]2(OTf)(45 mg, 0.042 mmol), the reaction kettle was charged with divinylketone (21 g, 0.25 mol), THF (80 mL) and water (0.45 mL), the reaction kettle was sealed and removed from the glove box; after 5 times of hydrogen replacement, the hydrogen pressure was 5 MPa, the heating was started at 50 °C, and the reaction was carried out for 15 h. GC sampling detection showed that the raw material divinylketone was substantially completely reacted, the yield of the product chiral β-butyrolactone was 81%, the ee value was 93%, and the TON was 4807.

Claims

1. A cytisine-derived ligand, the general structural formula of which is as follows: in, R is selected from C1-C10 alkyl-substituted phenyl, C1-C6 alkoxy-substituted phenyl, and fluorine-substituted phenyl.

2. The ligand according to claim 1, wherein, R is selected from 2-butylphenyl, 4-butylphenyl, 2,4-dibutylphenyl, 2,6-dibutylphenyl, 2-isopropylphenyl, 4-isopropylphenyl, 2,4-diisopropylphenyl, 2,6-diisopropylphenyl, 2-ethylphenyl, 4-ethylphenyl, 2,4-diethylphenyl, 2,6-diethylphenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 4-methoxyphenyl, o-methoxyphenyl, 4-ethoxyphenyl, o-ethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl.

3. A cytisine-derived ligand, the general structural formula of which is as follows: in, R is selected from 4-trifluoromethylphenyl and 3,5-bis(trifluoromethyl)phenyl.

4. A method for preparing the ligand according to any one of claims 1-3, comprising the following steps: (1) Add cytisine to PCl3 solution at low temperature, filter after reaction, wash the solid with solvent multiple times, remove solvent from organic phase to obtain ligand intermediate A; (2) The aryl Grignard reagent or organolithium reagent is slowly added to the solution of intermediate A obtained in step (1) at low temperature. The reaction temperature is slowly raised to room temperature and the reaction continues. After the reaction is quenched and purified, the cytisine-derived ligand is obtained.

5. The preparation method according to claim 4, wherein, In step (1), the molar ratio of cytisine to PCl3 is 1.2:1 to 2:

1.

6. The preparation method according to claim 4, wherein, In step (1), the molar ratio of cytisine to PCl3 is 1.5:

1.

7. The preparation method according to claim 4 or 5, wherein, In step (1), the reaction temperature is -40℃ to 0℃ and the reaction time is 0.5-10h.

8. The preparation method according to claim 4, wherein, In step (2), the molar ratio of intermediate A to Grignard reagent or organolithium reagent is 1:2 to 1:2.

5.

9. The preparation method according to claim 4, wherein, In step (2), the molar ratio of intermediate A to Grignard reagent or organolithium reagent is 1:2.

2.

10. The preparation method according to claim 4 or 8, wherein, In step (2), the low temperature is -60 to -80°C.

11. A method for preparing chiral β-butyrolactone by hydrogenation of diketene, comprising: Diketene is added to a reaction vessel, followed by a solvent. After mixing, an iridium precursor and the ligand described in any one of claims 1-3 are added, and a hydrogenation reaction is carried out to prepare chiral β-butyrolactone.

12. The method according to claim 11, wherein, The metallic iridium precursors are selected from: iridium acetylacetonate, iridium acetylacetonate dicarbonyl, iridium acetylacetonate bis(ethylene) iridium, fac-tris(2-phenylpyridine) iridium, carbonyl dihydrotris(triphenylphosphine) iridium, iridium bis(1,5-cyclooctadiene)tetrafluoroborate, iridium dichloro(pentamethylcyclopentadienyl) iridium dimer, iridium acetate, trichlorotris(pyridine) iridium, dicarbonyl chloride bis(triphenylphosphine) iridium, bis(cyclooctadiene) iridium hexafluoroantimonate, pentamethylcyclopentadienyl diacetate, dicarbonyl(pentamethylcyclopentadienyl) iridium, (1,5-cyclooctadiene)-η5-indiridium, bis(1,5-cyclooctadiene) iridium trifluoromethanesulfonate, chloro(1,5-cyclooctadiene)(1,10-phenanthroline) iridium, tris(1-phenylisoquinoline) iridium, and bis(2-phenylisoquinoline)(acetylacetonate) iridium. The molar ratio of the ligand to the metallic iridium precursor is 1:1 to 1.5:1; The molar ratio of diketene to iridium precursor is 10,000-60,000.

13. The method according to claim 11 or 12, wherein, The hydrogenation reaction temperature is 40-100℃; the hydrogen pressure is 0.8-10MPa; and the reaction time is 1-12h.

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