Synthesis of a diphosphine ligand derivative and its catalytic applications

Abstract

The application provides synthesis of a chiral diphosphine ligand and catalytic application thereof. The synthesis method is as follows: 2,3-diphenylphosphineoxy-1,3-butadiene and a Grignard reagent are subjected to an addition reaction to obtain a racemic phosphine oxide intermediate, then a chiral phosphine oxide intermediate is obtained by using a chemical resolution method, and finally a chiral diphosphine ligand is obtained by silicon hydrogen reduction; the chiral diphosphine ligand is obtained by using the above method. The application can realize asymmetric hydrogenation of neral, geranial and the like, and obtain a chiral product with high stereoselectivity. The synthesis method is novel, the synthesis route is short, the chiral diphosphine ligand is obtained through three steps, the overall yield of the route is high, and the operation is convenient. The diphosphine ligand obtained by the method has a good chiral induction effect, and compared with known methods, the stereoselectivity of asymmetric hydrogenation of neral, geranial and the like is improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of fine chemical and essence and perfume, and particularly relates to synthesis of a bisphosphine ligand derivative and its application in catalytic asymmetric hydrogenation. BACKGROUND

[0002] Citronellal is an important component of natural citronella oil and lemon eucalyptus oil, and has a strong, fresh green citrus fragrance. Because of a chiral carbon in its molecular structure, citronellal has two optical isomers, (R)-citronellal and (S)-citronellal; because (R)-citronellal can be used for the synthesis of the cooling agent L-menthol, it has higher economic value, and (S)-citronellal has relatively low added value.

[0003] At present, in the existing literature reports, there are mainly the following three methods for the synthesis of (R)-citronellal, namely, asymmetric hydrogenation of neral or geranial, myrcene method, and chiral citronellol dehydrogenation. Neral or geranial is a pair of double bond isomers, which is obtained by rectification separation of citral. The chiral catalyst is used for hydrogenation of citral, so that chiral citronellal can be conveniently synthesized (J. Mol. Cat. 1982, 16, 51; Helv. Chim. Acta. 2001, 84, 230.). Using the catalysts of the same configuration, neral and geranial are hydrogenated to obtain (R)-citronellal and (S)-citronellal, respectively; therefore, in order to selectively obtain (R)-citronellal, pure neral or geranial must be first separated, and the boiling points of the two are very close, so that the separation is difficult (EP0000315, CN101039894A, CN101675020A, CN101932543A). At present, in the existing literature reports, the asymmetric hydrogenation of neral or geranial can only achieve an ee value of 91-92% at most. Due to the low ee value, the yield is low, and the product of the opposite configuration needs to be removed by recrystallization, which further reduces the yield and increases the cost.

[0004]

[0005] The myrcene method is invented by Takasago (J. Chem. Soc. Chem. Comm., 1982, 11, 600; Topics in Catalysis, 1997, 4, 271.), in which myrcene derived from turpentine oil is used as a raw material, reacts with diethylamine lithium to obtain allylamine, the allylamine isomerizes under the catalysis of chiral rhodium to obtain chiral enamine, and finally hydrolysis is carried out to obtain (R)-citronellal (US4605750A, CN101602651A, CN102935384A, CN103254047A). Although this route has realized kiloton-scale amplification, in the first step, amine lithium is used, which is expensive, sensitive to water and oxygen, and has a great safety risk in production.

[0006]

[0007] In summary, chiral citronellal has important economic value. Among the known synthesis methods of chiral citronellal, the asymmetric hydrogenation method of neral or geranial is the synthesis method of chiral citronellal with the lowest cost at present, but the ee value of the asymmetric hydrogenation method is low at present, and the highest ee value is only 91-92%, which affects the economy of the route. Therefore, it is urgent to develop a new type of biphosphine ligand at present, which can improve the enantioselectivity of the asymmetric hydrogenation method of neral or geranial and improve the reaction yield, so as to promote the scale production of chiral citronellal. SUMMARY

[0008] The purpose of the present application is to provide a synthesis method of biphosphine ligand derivative and its application in catalytic asymmetric hydrogenation: firstly, addition reaction of 2,3-diphenylphosphinyl-1,3-butadiene and Grignard reagent to obtain a racemic phosphine oxide intermediate, then chiral phosphine oxide intermediate is obtained by chemical resolution, and finally chiral biphosphine ligand is obtained by silicon hydrogen reduction; the chiral biphosphine ligand obtained by the above method realizes the asymmetric hydrogenation of equal substrate of neral and geranial, and the chiral product is obtained with high stereoselectivity.

[0009] In order to achieve the above purpose and achieve the above technical effect, the technical scheme adopted by the present application is as follows:

[0010] A synthesis method of biphosphine ligand derivative, the method comprising the following steps:

[0011] S1: addition reaction of Grignard reagent RMgX and 2,3-diphenylphosphinyl-1,3-butadiene to obtain a racemic phosphine oxide intermediate A;

[0012] S2: racemic phosphine oxide intermediate A is resolved by chemical resolution to obtain chiral phosphine oxide intermediate B;

[0013] S3: chiral phosphine oxide intermediate B is reduced by silicon hydrogen to obtain target biphosphine ligand C.

[0014] Compared with ChiraPhos ligand, the substituent steric hindrance of the chiral carbon of the biphosphine ligand of the present application is larger, a larger chiral cavity can be formed around the phosphorus atom, so the chiral recognition effect is better, and a higher product ee value can be induced.

[0015] In an embodiment, the synthesis route is as follows:

[0016]

[0017] In the present application, R in the Grignard reagent RMgX described in S1 is one or more of saturated alkyl, unsaturated alkyl, aromatic ring, and substituted aromatic ring, heteroaromatic ring, and substituted heteroaromatic ring, preferably one or more of ethyl, isopropyl, isobutyl, and benzene ring; X is one or more of halogen elements, preferably one or more of chlorine, bromine, and iodine, more preferably chlorine and / or bromine; preferably, the amount of the Grignard reagent is 200.0-400.0 mol%, preferably 220.0-250.0 mol% of the molar amount of 2,3-diphenylphosphinyl-1,3-butadiene.

[0018] In the present application, the addition reaction in S1 is carried out in the presence of a catalyst and a ligand; preferably, the catalyst is a metal having catalytic activity for Michael addition reaction, preferably one or more of copper, nickel, iron, manganese, and palladium, more preferably the catalyst is one or more of, but not limited to, copper chloride, cuprous chloride, copper bromide, cuprous bromide, copper iodide, cuprous iodide, copper acetate, copper acetylacetonate, iron acetylacetonate, nickel acetate, palladium chloride, palladium acetate, most preferably cuprous iodide; preferably, the amount of the catalyst is 1.0-5.0 mol%, preferably 2.0-5.0 mol% of the molar amount of 2,3-diphenylphosphinyl-1,3-butadiene.

[0019] In the present application, the ligand in S1 is one or more of o-phenanthroline, bipyridine, and isoquinoline; preferably, the amount of the ligand is 2.0-10.0 mol% of the molar amount of 2,3-diphenylphosphinyl-1,3-butadiene.

[0020] In the present application, the addition reaction in S1 is carried out in a solvent; preferably, the solvent is an aprotic solvent, preferably one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, benzene, and xylene, more preferably tetrahydrofuran.

[0021] In the present application, the temperature of the reaction in S1 is 0-40℃, preferably 25-30℃, the reaction pressure is normal pressure, and the reaction time is 1-2 hours.

[0022] In the present application, the resolution reagent used in the chemical resolution method in S2 is a chiral organic acid, preferably one or more of sulfonic acid and / or carboxylic acid, more preferably one or more of camphorsulfonic acid, mandelic acid, tartaric acid, and tartaric acid derivatives, most preferably one or more of dibenzoyltartaric acid, di-p-toluoyltartaric acid, and di-p-methoxybenzoyltartaric acid; preferably, the amount of the resolution reagent is 90.0-120.0 mol%, preferably 100.0-110.0 mol% of the molar amount of the racemic phosphine oxide intermediate A.

[0023] In the present application, the resolving solvent used in the chemical resolution method of S2 is an aprotic solvent, preferably one or more of ethyl acetate, methyl acetate, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, and more preferably ethyl acetate.

[0024] In the present application, the temperature of the chemical resolution of S2 is 25-120℃.

[0025] In the present application, the reducing agent used in the hydrosilylation of S3 is a chlorosilane reagent, preferably trichlorosilane and / or dichlorosilane; preferably, the amount of the reducing agent is 3-6 times the molar amount of the chiral phosphine oxide intermediate B.

[0026] In the present application, the temperature of the hydrosilylation of S3 is 120-150℃.

[0027] In the present application, a solvent is used in S3, preferably an alkane solvent, and more preferably toluene and / or xylene.

[0028] In the present application, an aqueous solution of alkali metal hydroxide is used to quench the excess hydrosilane reagent after the reaction of S3.

[0029] Another object of the present application is to provide a ChiraPhos-type diphosphine ligand.

[0030] A ChiraPhos-type diphosphine ligand is prepared by the above synthesis method, and the diphosphine ligand has geminal chiral centers, and the size of the chiral carbon atom substituent can be adjusted.

[0031] Still another object of the present application is to provide a method for asymmetric hydrogenation.

[0032] A method for asymmetric hydrogenation, which uses the ChiraPhos-type diphosphine ligand prepared by the above synthesis method, or uses the ChiraPhos-type diphosphine ligand described above; in the asymmetric hydrogenation reaction, the metal catalyst is rhodium; preferably, the amount of the metal catalyst is 0.05-0.5 mol% of the substrate; preferably, the amount of the ligand is 0.06-0.6 mol% of the substrate.

[0033] In the present application, the substrate of the asymmetric hydrogenation reaction is an aldehyde or a ketone, preferably one or more of neral, geranil, 3-methyl-2-butenal, isophorone, E,E-farnesal, more preferably neral and / or geranil.

[0034] In the present application, in the asymmetric hydrogenation reaction, the hydrogen pressure is 4.0-6.0 MPaG, the reaction temperature is 60-80℃, and the reaction time is 4-12 hours.

[0035] In the present application, the reaction of asymmetric hydrogenation is carried out in an aprotic solvent; preferably, the aprotic solvent is selected from one or more of methyl tert-butyl ether, tetrahydrofuran, toluene, benzene, xylene, ethyl acetate, propyl acetate, dichloromethane, dichloroethane.

[0036] The present application adopts the above technical solution, and has the following positive effects:

[0037] 1. The raw material for preparing the diphosphine ligand is easy to obtain and low in price, the synthetic route is novel, the yield is high, and the synthesis and preparation are easy to scale up.

[0038] 2. The Michael addition reaction catalyzed by the catalyst in the preparation process can efficiently obtain the addition product.

[0039] 3. The diphosphine ligand can have a higher ee value in asymmetric hydrogenation. DETAILED DESCRIPTION

[0040] The present application is described in detail below through examples, but the present application is not limited to the following examples.

[0041] The main raw material information is as follows:

[0042] 2,3-diphenylphosphinyl-1,3-butadiene, self-made, 98% (HPLC); ethylmagnesium bromide (tetrahydrofuran solution, 1M), isopropylmagnesium bromide (tetrahydrofuran solution, 1M), phenylmagnesium bromide (tetrahydrofuran solution, 2M), Aladdin reagent, 99%; iodine, acetylacetone copper, Aladdin reagent, 99%; nickel acetate, Inokem, 98%.

[0043] Anhydrous tetrahydrofuran, ethyl acetate, butyl acetate, toluene, xylene, National Pharmaceutical Reagent, AR; trichlorosilane, TCI, 98%; (+)-dibenzoyl tartaric acid, (+)-di-p-toluoyl tartaric acid, (+)-di-p-methoxybenzoyl tartaric acid, Sigma-Aldrich, 99%; [Rh(COD)(acac)], [Rh(CO)2(acac)], Sigma-Aldrich, 98%; (R,R)-ChiraPhos, Aladdin, purity 99%, ee 99%.

[0044] Nerolidal (99%), geraniol (99%), isophorone (99%), 3-methyl-2-butenal (98%), E,E-farnesal (97%), Wanhua Chemical.

[0045] The gas chromatography test conditions of the present application are as follows:

[0046] Instrument model: Agilent GC; column: Agilent cyclodex-B (30 m x 0.25 mm x 0.25 μm); column temperature: initial temperature 40 °C, increased to 70 °C at 3 °C / min, then increased to 100 °C at 10 °C / min, finally increased to 200 °C at 15 °C / min, and maintained for 6 min; injection port temperature: 270 °C; FID detector temperature: 290 °C; split injection, split ratio 60:1; injection volume: 2.0 μL; H2flow rate: 20 mL / min; air flow rate: 300 mL / min.

[0047] Examples 1-3

[0048] Grignard reagent addition to 2,3-diphenylphosphinyl-1,3-butadiene.

[0049] A 250 mL three-necked flask equipped with a magnetic stirrer was placed in an ice-water bath under nitrogen. After three times of nitrogen replacement, solvent tetrahydrofuran (30 mL), catalyst and ligand were added successively. After the two were stirred and dissolved, the reaction substrate 2,3-diphenylphosphinyl-1,3-butadiene (3.64 g, 8.0 mmol) was introduced to obtain a clear reaction solution. Finally, Grignard reagent was slowly added dropwise to the reaction solution. The addition was completed in 1 hour. After the ice-water bath was removed, the reaction was stirred at room temperature for 2 hours. After TLC detection, the reaction substrate 2,3-diphenylphosphinyl-1,3-butadiene completely disappeared, saturated ammonium chloride aqueous solution (10 mL) was slowly added dropwise to the reaction solution to quench the reaction. After treatment, the reaction solution was poured into a separatory funnel. After phase separation, the organic phase was washed successively with saturated ammonium chloride aqueous solution (10 mL) and saturated sodium chloride aqueous solution (20 mL). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated to remove the solvent tetrahydrofuran to obtain a crude product. Finally, the product was separated and purified by flash silica gel column chromatography to obtain racemic phosphine oxide intermediate A. The types and amounts of Grignard reagents used and the yield of phosphine oxide intermediate A are shown in the following table.

[0050] Reaction conditions and results of Examples 1-3

[0051]

[0052]

[0053] Examples 4-6

[0054] Chiral phosphine oxide intermediate B was obtained by chemical resolution of racemic phosphine oxide intermediate A.

[0055] The phosphine oxide compound A was dissolved in ethyl acetate under nitrogen and heated to a slight reflux (80°C). A 10 wt% ethyl acetate solution of the chiral resolving agent was slowly added to the solution. After the addition was complete, the reflux was continued for 5 minutes and then the solution was slowly allowed to cool to room temperature while stirring. White solids precipitated. The white solids were recrystallized once from ethyl acetate to further enhance the ee of the phosphine oxide intermediate. Finally, the white solids were dissolved in dichloroethane and a 10 wt% aqueous sodium hydroxide solution was added. The mixture was stirred rapidly for 30 minutes to dissociate the chiral phosphine oxide B from the complex. The reaction mixture was separated using a separatory funnel. The organic phase was washed with a 10 wt% aqueous sodium hydroxide solution, deionized water, and saturated brine. The organic phase was dried over sodium sulfate and purified by flash chromatography on silica gel to give the chiral phosphine oxide intermediate B. The type and amount of resolving agent and the resolution yield are shown in the following table.

[0056] Reaction conditions and results of Examples 4-6

[0057]

[0058]

[0059] Examples 7-9

[0060] The chiral phosphine oxide intermediate B was reduced to give the diphosphine ligand.

[0061] The chiral phosphine oxide intermediate B obtained from the resolution above was placed in a 200 mL three-necked flask equipped with a magnetic stirrer under nitrogen. The solvent p-xylene was added and the flask was placed in an ice-water bath. The mixture was stirred until the temperature of the reaction solution was reduced to 0°C. Then, trichlorosilane (60 mL) was slowly added. After the addition was complete, the reaction was stirred for 10 minutes and then the ice-water bath was removed. The flask was placed in an oil bath and the temperature was slowly increased to the reflux temperature of the solvent (145°C). The reaction was maintained at reflux for 4 hours. After the starting chiral phosphine oxide intermediate was completely consumed, as determined by TLC, the heating oil bath was removed and the reaction solution was allowed to cool to room temperature. The reaction solution was treated by slowly adding a 30% aqueous sodium hydroxide solution (10 mL). The reaction solution became cloudy and was heated to 60°C. The reaction was stirred until the solution became clear again. The reaction solution was allowed to cool to room temperature and was separated under nitrogen. The oil phase was washed with deionized water, dried over anhydrous sodium sulfate, filtered under nitrogen, and the solvent was removed by rotary evaporation. The crude product was purified by flash chromatography on silica gel to give the chiral diphosphine ligand. The yield of the diphosphine ligand is shown in the following table.

[0062] Reaction conditions and results of Examples 7-9

[0063]

[0064] Example 10

[0065] Asymmetric hydrogenation of neral to synthesize R-citronellal.

[0066] In a glove box, [Rh(CO)2(acac)] (26 mg, 0.1 mmol), bisphosphine ligand (R,R)-C1 (58 mg, 0.12 mmol) and toluene (10.0 g) were sequentially added into a single neck flask equipped with a magnetic stir bar. The flask was sealed and the stirring was turned on. After 15 min of dissolution and complexation of the metal precursor and the ligand, a yellowish clear catalyst solution was obtained. The flask was taken out of the glove box and the catalyst solution was pumped into a high pressure reactor using a laminar flow pump under strict nitrogen protection. The reactor was previously purged with nitrogen (2 bar G). In the glove box, the hydrogenation substrate neral (3.05 g, 20.0 mmol) and the reaction solvent toluene (10 mL) were mixed well and pumped into the reactor containing the catalyst under strict nitrogen protection. After all the reactants were added, the reactor was purged with high purity hydrogen three times (1.0 MPa G each time) and charged with 4.0 MPa G of hydrogen. Finally, carbon monoxide was charged through another inlet of the reactor to make the concentration of carbon monoxide in the hydrogen 1000 ppm. The reactor was turned on for stirring and heating. When the temperature in the reactor reached 80 °C, the reaction was started. The temperature and the hydrogen pressure were kept constant and the reaction was continued for 4 h. The sample was analyzed by GC and the conversion of the substrate neral was >99.5% with 94.0% ee of the product R-citronellal.

[0067] Example 11

[0068] Asymmetric hydrogenation of neral to synthesize R-citronellal.

[0069] In a glove box, [Rh(CO)2(acac)] (10 mg, 0.04 mmol), bisphosphine ligand (R,R)-C2 (41 mg, 0.08 mmol) and toluene (10.0 g) were added into a single neck flask equipped with a magnetic stirrer. The flask was sealed and the stirring was turned on. After 15 min of dissolution and complexation of the metal precursor and the ligand, a yellowish clear catalyst solution was obtained. The flask was taken out of the glove box and the catalyst solution was pumped into an autoclave using a laminar flow pump under strict nitrogen protection. The autoclave had been previously purged with nitrogen (2 bar G). In the glove box, the hydrogenation substrate, neral (6.09 g, 40.0 mmol), and the reaction solvent, toluene (10 mL), were mixed well and pumped into the autoclave containing the catalyst under strict nitrogen protection. After all the reactants were added, the autoclave was purged with high purity hydrogen three times at 1.0 MPa G. Hydrogen was charged to 6.0 MPa G and finally carbon monoxide was charged through another inlet of the reactor to give a hydrogen atmosphere with 500 ppm of carbon monoxide. The stirring and heating of the reactor were turned on and the temperature was increased to 80 °C. The reaction was started and the temperature and hydrogen pressure were kept constant. The reaction was continued for 6 h. The sample was analyzed by GC and the conversion of the substrate, neral, was >99.7% with 99.2% ee of the product, R-methonal.

[0070] Example 12

[0071] Asymmetric hydrogenation of neral to synthesize R-methonal.

[0072] In a glove box, [Rh(CO)2(acac)] (8 mg, 0.03 mmol), bisphosphine ligand (R,R)-C3 (21 mg, 0.04 mmol) and toluene (10.0 g) were added into a single neck flask equipped with a magnetic stir bar. The flask was sealed and the stirring was turned on. After 15 min of dissolution and complexation of the metal precursor and the ligand, a yellowish clear catalyst solution was obtained. The flask was taken out of the glove box and the catalyst solution was pumped into an autoclave using a laminar flow pump under strict nitrogen protection. The autoclave was previously purged with nitrogen (2 bar G). In the glove box, the hydrogenation substrate, neral (9.13 g, 60.0 mmol), and the reaction solvent, toluene (10 mL), were mixed well and pumped into the autoclave containing the catalyst under strict nitrogen protection. After all the reactants were added, the autoclave was purged with high purity hydrogen three times at 1.0 MPa G. Hydrogen was charged to 6.0 MPa G and finally carbon monoxide was charged through another inlet of the reactor to give a hydrogen stream containing 1000 ppm of carbon monoxide. The stirring and heating of the reactor were turned on and the temperature was increased to 80 °C. The reaction was started and the temperature and hydrogen pressure were kept constant. The reaction was continued for 12 h. The sample was analyzed by GC and the conversion of the substrate, neral, was >99.5% with 93.2% ee of the product, R-neral.

[0073] Example 13

[0074] Asymmetric hydrogenation of geranial to synthesize S-citronellal.

[0075] In a glove box, [Rh(CO)2(acac)] (13 mg, 0.05 mmol), bisphosphine ligand (R,R)-C2 (31 mg, 0.06 mmol) and toluene (10.0 g) were added into a single neck flask equipped with a magnetic stir bar. The flask was sealed and the stirring was turned on. After 15 min of dissolution and complexation of the metal precursor and the ligand, a yellowish clear catalyst solution was obtained. The flask was taken out of the glove box and the catalyst solution was pumped into an autoclave using a laminar flow pump under strict nitrogen protection. The autoclave was previously purged with nitrogen (2 bar G). In the glove box, the hydrogenation substrate, geranial (7.61 g, 50.0 mmol), and the reaction solvent, toluene (10 mL), were mixed well and pumped into the autoclave containing the catalyst under strict nitrogen protection. After all the reactants were added, the autoclave was purged with high purity hydrogen three times at 1.0 MPa G. Hydrogen was charged to 6.0 MPa G and finally carbon monoxide was charged through another inlet of the reactor to give a hydrogen stream containing 600 ppm of carbon monoxide. The stirring and heating of the reactor were turned on. When the temperature of the reactor reached 80 °C, the reaction was started. The temperature and the hydrogen pressure were kept constant and the reaction was continued for 6 h. The sample was analyzed by GC and the conversion of the substrate, geranial, was >99.5% with 98.6% ee of the product, S-geraniol.

[0076] Example 14

[0077] Asymmetric hydrogenation of isophorone to synthesize dihydroisophorone.

[0078] In a glove box, [Rh(CO)2(acac)] (13 mg, 0.05 mmol), bisphosphine ligand (R,R)-C2 (31 mg, 0.06 mmol) and toluene (10.0 g) were added into a single neck flask equipped with a magnetic stir bar. The flask was sealed and the stirring was turned on. After 15 min of dissolution and complexation of the metal precursor and the ligand, a yellowish clear catalyst solution was obtained. The flask was taken out of the glove box and the catalyst solution was pumped into an autoclave using a laminar flow pump under strict nitrogen protection. The autoclave was previously purged with nitrogen (2 bar G). In the glove box, the hydrogenation substrate, 3-methyl-2-butenal (6.91 g, 50.0 mmol), and the reaction solvent, toluene (10 mL), were mixed well and pumped into the autoclave containing the catalyst under strict nitrogen protection. After all the reactants were added, the autoclave was purged with high purity hydrogen three times at 1.0 MPa G. The hydrogen pressure was charged to 6.0 MPa G and finally carbon monoxide was charged through another inlet of the reactor to make the concentration of carbon monoxide in hydrogen 400 ppm. The stirring and heating of the reactor were turned on and the temperature was increased to 80 °C. The reaction was started and the temperature and hydrogen pressure were kept constant. The reaction was continued for 12 h. The sample was analyzed by GC and the conversion of the substrate was >99.5% with 98.4% ee of the product.

[0079] Example 15

[0080] Asymmetric hydrogenation of 3-methyl-2-butenal to synthesize chiral 3-methyl butanal.

[0081] In a glove box, [Rh(COD)(acac)] (16 mg, 0.05 mmol), bisphosphine ligand (R,R)-C2 (31 mg, 0.06 mmol) and toluene (10.0 g) were added into a single neck flask equipped with a magnetic stir bar. The flask was sealed and the stirring was turned on. After 15 min of dissolution and complexation of the metal precursor and the ligand, a yellowish clear catalyst solution was obtained. The flask was taken out of the glove box and the catalyst solution was pumped into an autoclave using a laminar flow pump under strict nitrogen protection. The autoclave was previously purged with nitrogen (2 bar G). In the glove box, the hydrogenation substrate, isophorone (4.21 g, 50.0 mmol), and the reaction solvent, toluene (10 mL), were mixed well and pumped into the autoclave containing the catalyst under strict nitrogen protection. After all the reactants were added, the autoclave was purged with high purity hydrogen three times (1.0 MPa G each time), and then charged with 4.0 MPa G of hydrogen. Finally, carbon monoxide was charged through another inlet of the reactor to give a hydrogen stream containing 400 ppm of carbon monoxide. The stirring and heating of the reactor were turned on. When the temperature of the reactor reached 80 °C, the reaction was started. The temperature and the hydrogen pressure were kept constant during the reaction. After 6 h, the reaction was stopped and the sample was analyzed. The conversion of the substrate, 3-methyl-2-butenal, was >99.5% and the enantioselectivity of the product, 3-methylbutanal, was 99.0% ee.

[0082] Example 16

[0083] Asymmetric hydrogenation of E,E-farnesal to synthesize chiral dihydrofarnesal.

[0084] In a glove box, [Rh(CO)2(acac)] (13 mg, 0.05 mmol), bisphosphine ligand (R,R)-C2 (31 mg, 0.06 mmol) and toluene (10.0 g) were added into a single neck flask equipped with a magnetic stir bar. The flask was sealed and the stirring was turned on. After 15 min of dissolution and complexation of the metal precursor and the ligand, a yellowish clear catalyst solution was obtained. The flask was taken out of the glove box and the catalyst solution was pumped into an autoclave using a laminar flow pump under strict nitrogen protection. The autoclave was previously purged with nitrogen (2 bar G). In the glove box, the hydrogenation substrate E,E-farnesal (11.02 g, 50.0 mmol) and the reaction solvent toluene (10 mL) were mixed well and pumped into the autoclave containing the catalyst under strict nitrogen protection. After all the reactants were added, the autoclave was purged with high purity hydrogen three times (1.0 MPa G each time) and charged with 4.0 MPa G of hydrogen. Finally, carbon monoxide was charged through another inlet of the reactor to give a hydrogen stream containing 400 ppm of carbon monoxide. The stirring and heating of the reactor were turned on and the temperature was increased to 80 °C. The reaction was started and the temperature and hydrogen pressure were kept constant. The reaction was continued for 8 h. The sample was analyzed by GC and the conversion of the substrate E,E-farnesal was >99.5% with 99.6% ee of the product dihydrofarnesal.

[0085] Comparative Example 1

[0086] Asymmetric hydrogenation of citronellal to synthesize R-citronellal.

[0087] In a glove box, [Rh(CO)2(acac)] (26 mg, 0.1 mmol), bisphosphine ligand (R,R)-ChiraPhos (51 mg, 0.12 mmol) and toluene (10.0 g) were added into a single neck flask equipped with a magnetic stir bar. The flask was sealed and the stirring was turned on. After 15 minutes of dissolution and complexation of the metal precursor and the ligand, a yellowish clear catalyst solution was obtained. The flask was removed from the glove box and the catalyst solution was pumped into an autoclave using a laminar flow pump under strict nitrogen protection. The autoclave had been previously purged with nitrogen (2 bar G). In the glove box, the hydrogenation substrate, neral (3.05 g, 20.0 mmol), and the reaction solvent, toluene (10 mL), were mixed well and pumped into the autoclave containing the catalyst under strict nitrogen protection. After all the reactants were added, the autoclave was purged with high purity hydrogen three times (1.0 MPa G each time), charged with 4.0 MPa G of hydrogen and finally charged with carbon monoxide to give a hydrogen stream containing 1000 ppm of carbon monoxide. The stirring and heating of the autoclave were turned on and the temperature was increased to 80 °C. The reaction was started and the temperature and hydrogen pressure were kept constant. The reaction was continued for 8 hours. The conversion of the substrate, neral, was >99.5% and the enantioselectivity of the product, R-citronellal, was 88.0% ee as determined by GC.

Claims

1. A method for synthesizing a derivative of a bisphosphine ligand, characterized by, The method comprises the following steps: S1: Grignard reagent RMgX and 2,3-diphenylphosphinyl-1,3-butadiene undergo addition reaction to obtain racemic phosphine oxide intermediate A; S2: racemic phosphine oxide intermediate A is resolved by chemical resolution method to obtain chiral phosphine oxide intermediate B; S3: chiral phosphine oxide intermediate B is reduced by silicon hydrogen to obtain target diphosphine ligand C; In the Grignard reagent RMgX of S1, R is one or more of saturated alkyl, unsaturated alkyl, aromatic ring, heteroaromatic ring, and X is halogen element; The intermediate A, the intermediate B and the diphosphine ligand C are respectively: The S1 reaction is carried out in the presence of a catalyst and a ligand, the ligand in S1 is one or more of o-phenanthroline, bipyridine and isoquinoline, and the catalyst in S1 is one or more of copper chloride, cuprous chloride, copper bromide, cuprous bromide, copper iodide, cuprous iodide, copper acetate, copper acetylacetonate, iron acetylacetonate, nickel acetate, palladium chloride and palladium acetate.

2. The method of synthesis of claim 1, wherein, In the Grignard reagent RMgX of S1, R is one or more of ethyl, isopropyl, isobutyl and benzene ring, and X is one or more of chlorine, bromine and iodine; And / or, the addition reaction in S1 is carried out in a solvent; And / or, the temperature of the reaction in S1 is 0-40℃, the reaction pressure is normal pressure, and the reaction time is 1-2 hours.

3. The method of synthesis of claim 2, wherein, In the Grignard reagent RMgX of S1, X is chlorine and / or bromine; The amount of the Grignard reagent in S1 is 200.0-400.0 mol% of the molar amount of 2,3-diphenylphosphinyl-1,3-butadiene; The amount of the catalyst in S1 is 1.0-5.0 mol% of the molar amount of 2,3-diphenylphosphinyl-1,3-butadiene; The amount of the ligand in S1 is 2.0-10.0 mol% of the molar amount of 2,3-diphenylphosphinyl-1,3-butadiene; The solvent in S1 is an aprotic solvent; And / or, the temperature of the reaction in S1 is 25-30℃.

4. The method of synthesis of claim 3, wherein, The amount of the Grignard reagent in S1 is 220.0-250.0 mol% of the molar amount of 2,3-diphenylphosphinyl-1,3-butadiene; The amount of the catalyst in S1 is 2.0-5.0 mol% of the molar amount of 2,3-diphenylphosphinyl-1,3-butadiene; The solvent in S1 is one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, benzene and xylene.

5. The method of synthesis of claim 4, wherein, The solvent in S1 is tetrahydrofuran.

6. The method of synthesis of claim 1, wherein, The catalyst in S1 is cuprous iodide.

7. The method of synthesis of claim 1 or 2, wherein, The resolving reagent used in the chemical resolution method of S2 is a chiral organic acid; And / or, the resolving solvent used in the chemical resolution method of S2 is an aprotic solvent; And / or, the temperature of the chemical resolution of S2 is 25-120℃.

8. The method of synthesis of claim 7, wherein, The resolving reagent used in the chemical resolution method of S2 is sulfonic acid and / or carboxylic acid; The amount of the resolving reagent used in the chemical resolution method of S2 is 90.0-120.0 mol% of the molar amount of racemic phosphine oxide intermediate A; And / or, the resolving solvent used in the chemical resolution method of S2 is one or more of ethyl acetate, methyl acetate, dichloromethane, dichloroethane, chloroform and tetrahydrofuran.

9. The method of synthesis of claim 8, wherein, The resolution reagent used in the chemical resolution method of S2 is one or more of camphorsulfonic acid, mandelic acid, tartaric acid, and tartaric acid derivatives; The amount of the resolution reagent used in S2 is 100.0-110.0 mol% of the molar amount of the racemic phosphine oxide intermediate A; And / or, the resolution solvent used in the chemical resolution method of S2 is ethyl acetate.

10. The method of synthesis of claim 9, wherein, The resolution reagent used in the chemical resolution method of S2 is one or more of dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, and di-p-methoxybenzoyl tartaric acid.

11. The method of synthesis of claim 1, wherein, The reducing reagent used in the silicon hydride reduction of S3 is a chlorosilane reagent; And / or, the temperature of the silicon hydride reduction of S3 is 120-150°C; And / or, a solvent is used in S3; And / or, after the reaction is completed, an aqueous solution of sodium hydroxide is used to quench the excess silicon hydride reagent.

12. The method of synthesis of claim 11, wherein, The reducing reagent used in the silicon hydride reduction of S3 is trichlorosilane and / or dichlorosilane; The amount of the reducing reagent used in S3 is 3-6 times the molar amount of the chiral phosphine oxide intermediate B; And / or, the solvent used in S3 is an alkane solvent.

13. The method of synthesis of claim 12, wherein, The solvent used in S3 is toluene and / or xylene.

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