CN116199615A - Preparation method of ramipril intermediate azabicyclo [3, 0] octane-3 (S) -carboxylic acid - Google Patents

Abstract

The present invention relates to ramipril as main intermediate of azabicyclo [3, 0] of formula I]A method for preparing octane-3 (S) -carboxylic acid. Taking N-acyl glycine derivatives as raw materials, and obtaining a 4- (alkoxymethylene) -2-alkyl oxazolone intermediate formula II through one step or multiple steps; reacting the intermediate formula II with various N- (1-cyclopentenyl) amine at room temperature to obtain an intermediate formula III; alcoholysis of the intermediate formula III under the condition of catalytic amount of alkyl alkoxide to generate an unsaturated amino acid intermediate formula IV; intermediate formula IV generates enantiomer enriched intermediate formula V (including formula Va and formula Vb) under the condition of transition metal rhodium-chiral phosphine ligand complex catalyst; intermediate type vb generates azabicyclo [3, 0] in the presence of hydrochloric acid and catalytic amount of palladium carbon]Octane-3 (S) -carboxylic acid. The process has the characteristics of higher yield, simple process, environmental friendliness and the like, and has good industrialized application prospect.

Description

Preparation method of ramipril intermediate azabicyclo [3, 0] octane-3 (S) -carboxylic acid

Technical Field

The invention relates to a method for preparing ramipril (formula IX) main intermediate azabicyclo [3, 0] octane-3 (S) -carboxylic acid (formula I). The process has the characteristics of higher yield, simple process, environmental friendliness and the like, and has good industrialized application prospect.

Background

Ramipril (Ramipril) is a second generation long-acting angiotensin converting enzyme inhibitor, developed by one of the German companies as the first choice for the treatment of mild and primary hypertension, renal hypertension and moderate and malignant congestive heart failure. The main intermediate is azabicyclo [3, 0] octane-3 (S) -carboxylic acid, and the method used for synthesizing the intermediate in the prior art is chemical resolution [ e.g. DE 3345355,EP 115345] or biological conversion [ e.g. US 2009/0017509], however, the method wastes nearly half of precursor raw materials, and the energy consumption and resource waste are serious.

Disclosure of Invention

The invention solves the problems of serious energy consumption and resource waste caused by the traditional chemical resolution. The invention provides a preparation method of ramipril main intermediate aza-bicyclo [3, 0] octane-3 (S) -carboxylic acid. The invention takes N-acyl glycine derivative as raw material, and obtains the intermediate formula II of 4- (alkoxymethylene) -2-alkyl oxazolone through one step or multiple steps; reacting the intermediate formula II with various N- (1-cyclopentenyl) amine at room temperature to obtain an intermediate formula III; alcoholysis of the intermediate formula III under the condition of catalytic amount of sodium methoxide or sodium ethoxide to generate unsaturated amino acid intermediate formula IV; intermediate formula IV generates enantiomer enriched intermediate formula V (including formula Va and formula Vb) under the condition of transition metal rhodium-chiral phosphine ligand complex catalyst; intermediate type vb under the condition of hydrochloric acid aqueous solution and catalytic amount of palladium carbon to generate the azabicyclo [3, 0] octane-3 (S) -carboxylic acid of formula I. The process has the characteristics of higher yield, simple process, environmental friendliness and the like, has better industrialized application prospect, and has the same advantages in raw material utilization.

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Firstly, the invention provides a method for preparing a 4- (alkoxymethylene) -2-alkyl oxazolone intermediate as shown in a formula II by taking an N-acyl glycine derivative as a raw material through one or more steps.

The method comprises the following steps: the N-acyl glycine and triethyl orthoformate or trimethyl orthoformate are reacted in acetic anhydride solvent at 100-130 ℃ to generate intermediate formula II;

the second method is as follows: n-acylglycine can be obtained in multiple steps as intermediate of formula II, first in POCl ₃ Reacting under DMF condition to obtain intermediate formula VI, hydrolyzing under NaOH aqueous solution/organic solvent condition at room temperature to obtain intermediate formula VII, and methylation reacting intermediate formula VII with dimethyl sulfate under alkali to obtain intermediate formula II.

Wherein R is ₁ Is alkyl, R ₂ Is aryl or alkyl; r is R ₁ Preferably C ₁ ～C ₆ Alkyl, R ₂ Aryl or C of less than 12C ₁ ～C ₆ Alkyl, R ₁ Further preferred are methyl, ethyl, propyl or butyl, R ₂ Further preferred is phenyl or methyl. Wherein the aryl or phenyl group may have a substituent, and the substituent is C ₁ ～C ₆ Alkyl, C ₁ ～C ₆ Alkoxy, halogen, trifluoromethyl, hydroxy, nitro or cyano, preferably methyl, ethyl, methoxy, ethoxy, F, cl, br, trifluoromethyl, hydroxy, nitro or cyano.

Next, the present invention provides the reaction of 4- (alkoxymethylene) -2-alkyl oxazolone intermediate of formula II with N- (1-cyclopentenyl) amine at room temperature to produce intermediate of formula III.

Wherein R is ₂ As described above, R is independently selected from C ₁ ～C ₆ Alkyl, or R is linked with N and another R to form a five-membered or six-membered ring, which may contain O. Further, the five-membered ring may be piperidinyl, morpholinyl, cyclopentylamino or cyclohexylamino.

Furthermore, the invention provides an unsaturated amino acid intermediate formula IV which is obtained by ring opening of oxazolone parent nucleus under the condition of catalytic amount of alkyl alkoxide.

Wherein R, R ₂ As described above, R ₃ Is alkyl, preferably C ₁ ～C ₆ Alkyl, R ₃ Preferably methyl, ethyl, propyl or butyl.

Most importantly, the present invention provides for the formation of enantiomerically enriched intermediate formula V (including formulas Va and Vb) of intermediate formula IV in the presence of a transition metal rhodium-chiral phosphine ligand complex catalyst

Wherein R, R ₂ ，R ₃ As described above, the transition metal-chiral phosphine ligand complex catalyst has the structure: m (L) (P) X, wherein M is Rh, ru and Ir; l=1, 5-cyclooctadiene or 2, 5-norbornadiene; the reaction medium is dichloromethane, methanol, tetrahydrofuran, acetonitrile, ethyl acetate, toluene or a mixed solvent; the P is chiral monodentate or bidentate ligand, and X is tetrahalogenated borate. In this reaction according to the invention P is R-BINAP, S-BINAP, scRp-DuanPhos, rcSp-DuanPhos, SSRR-tangPhos, RRSS-TangPhos, duPhos, or BPE.

Preferably, in [ Rh (cod) (2R, 5R-Me-Duphos)]BF ₄ Or [ Rh (cod) (2S, 5S-Me-Duphos)]BF ₄ Or [ Rh (cod) (2R, 5R-Et-Duphos)]BF ₄ Or [ Rh (cod) (2R, 5R-Et-Duphos)]BF ₄ In the presence of an asymmetric hydrogenation reaction.

Finally, the invention provides an intermediate formula vb which is firstly subjected to N-acyl protecting group removal under the heating condition of a hydrochloric acid solution and enamine hydrolysis to generate an intermediate formula VIII, and then palladium hydro-carbon heating and pressurizing conditions are used to generate the azabicyclo [3, 0] octane-3 (S) -carboxylic acid of the formula I.

Wherein R, R ₂ ，R ₃ As described above.

Preferably, the intermediate formula V is subjected to a reaction for generating azabicyclo [3, 0] octane-3 (S) -carboxylic acid as shown in formula I, wherein the condition is selected that the intermediate formula V is subjected to reflux in a hydrochloric acid aqueous solution to generate an intermediate formula VIII, and a catalytic amount of palladium carbon is added into an acidic aqueous solution to perform hydrogenation, heating and pressurizing reaction to generate the [3, 0] octane-3 (S) -carboxylic acid as shown in formula I.

Preferably, the intermediate formula V is reacted to form the intermediate formula VIII under the condition of hydrochloric acid aqueous solution and the temperature is 60-100 ℃.

Preferably, this step can be carried out in a polar solvent, such as one or more of water, methanol, ethanol and acetic acid, under a hydrogen pressure of 5 to 15bar and a reaction temperature of 20 to 80 ℃. The reaction is preferably carried out in acetic acid at 40 ℃.

Detailed Description

The invention provides a preparation method of ramipril main intermediate aza-bicyclo [3, 0] octane-3 (S) -carboxylic acid, which is prepared according to the following synthetic route.

The synthesis method of the azabicyclo [3, 0] octane-3 (S) -carboxylic acid shown in the formula I comprises the following steps:

(1) In a specific example, the process of formula II is carried out in one or more steps starting from N-acylglycine derivatives to give 4- (alkoxymethylene) -2-alkyl oxazolone intermediates.

The method comprises the following steps: the N-acyl glycine derivative and triethyl orthoformate or trimethyl orthoformate are reacted in acetic anhydride solvent at 100-130 deg.c to produce intermediate II;

wherein the N-acyl glycine derivative is preferably N-acetyl glycine or N-benzoyl glycine, and the molar ratio of the N-acyl glycine derivative, triethyl orthoformate or trimethyl orthoformate to acetic anhydride is 1.0:1.0 to 2.0:1.0 to 3.0.

The second method is as follows: the N-acylglycine derivatives can be obtained in a plurality of steps as intermediates of formula II, first in POCl ₃ Reacting under DMF condition to obtain intermediate formula VI, hydrolyzing under NaOH aqueous solution/organic solvent condition at room temperature to obtain intermediate formula VII, and methylation reacting intermediate formula VII with dimethyl sulfate under alkali to obtain intermediate formula II.

Wherein the N-acyl glycine derivative and POCl ₃ DMF molar ratio of 1.0:2.0 to 3.0:2.0 to 3.0; the molar ratio of the intermediate formula VI to NaOH is 1.0:1.0 to 1.5; intermediate formula VII, dimethyl sulfate and alkali mole ratio of 1.0:1.0 to 3.0:1.0 to 3.0, wherein the alkali can be sodium hydroxide, potassium hydroxide, triethylamine, potassium carbonate and sodium carbonate.

(2) The 4- (alkoxymethylene) -2-alkyl oxazolone intermediate of formula II reacts with N- (1-cyclopentenyl) amine at room temperature to produce intermediate of formula III.

In particular embodiments, the N- (1-cyclopentenyl) amine is N- (1-cyclopentenyl) morpholine, N- (1-cyclopentenyl) cyclopentylamine, N- (1-cyclopentenyl) cyclohexylamine, and the molar ratio of intermediate II to enamine is 1.0:1.0 to 1.5, and the solvent can be selected from dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, methanol and ethanol.

(3) Under the condition of catalytic amount of alkyl alkoxide, the oxazolone mother nucleus is ring-opened to generate unsaturated amino acid intermediate as shown in the formula IV.

In a specific embodiment the alkyl alkoxide is sodium methoxide, sodium ethoxide, under conditions selected to be 5 to 20 mole% sodium methoxide or sodium ethoxide, methanol or ethanol reflux, preferably 10 mole% sodium methoxide or sodium ethoxide, methanol or ethanol reflux.

(4) In the presence of hydrogen, the intermediate formula IV is prepared into an enantiomerically enriched intermediate formula V by using a transition metal rhodium-chiral phosphine ligand complex catalyst.

Intermediate formula V includes formulas Va and Vb

The preferred chiral phosphine-transition metal catalyst has the general formula [ M (L) (P ]]X, wherein M is Rh, ru or Ir; l is 1, 5-cyclooctadiene or 2, 5-norbornadiene; p (P) ^* Is a chiral phosphine compound, such as ScRp-DuanPhos, rcSp-DuanPhos, SSRR-TangPhos, RRSS-TangPhos, (R) -BINAP, (S) -BINAP, duPhos, BPE; x is BF ₄ ,ClO ₄ ,SbF ₆ ,PF ₆ ,CF ₃ SO ₃ RCOO or mixtures thereof, B (Ar) ₄ Wherein Ar is fluorophenyl or 3, 5-di-trifluoromethyl-1-phenyl.

In a preferred embodiment, M is Rh, ru or Ir; l is 1, 5-cyclooctadiene or 2, 5-norbornadiene; p is (2R, 5R) -Me-Duphos, (2S, 5S) -Me-Duphos, (2R, 5R) -Et-Duphos, (2S, 5S) -Et-Duphos, X is BF ₄ 。

In at least one embodiment of this step, the hydrogen pressure may be between 10 and 50bar,

the converted reaction medium is selected from one or more of dichloromethane, methanol, tetrahydrofuran, toluene and ethyl acetate; preferably dichloromethane, methanol or tetrahydrofuran; further preferred is dichloromethane. Suitable reaction temperatures for intermediate IV to intermediate V are from 10 to 50℃and preferably from 20 to 30 ℃.

The present invention provides two enantiomers of intermediate formula V (including formulas Va and Vb) by use of different chiral catalysts. In a specific embodiment of this aspect, [ Rh (COD) (2S, 5S-Me-DuPhos)]BF ₄ Or [ Rh (COD) (2S, 5S-Et-DuPhos)]BF ₄ As a catalyst, R-configuration intermediate formula Va was obtained using [ Rh (COD) (2R, 5R-Me-DuPhos)]BF ₄ Or [ Rh (COD) (2R, 5R-Et-DuPhos)]BF ₄ And (3) preparing an S-configuration intermediate formula Vb by using the catalyst.

(5) The intermediate formula vb is firstly subjected to N-acyl protecting group removal and enamine hydrolysis under the heating condition of a hydrochloric acid solution to generate an intermediate formula VIII, and then palladium hydro-carbon is subjected to heating and pressurizing conditions to generate the azabicyclo [3, 0] octane-3 (S) -carboxylic acid of the formula I.

In a specific embodiment the hydrochloric acid solution is a 6N hydrochloric acid solution, and this step may be carried out in a polar solvent, such as one or more of water, methanol, ethanol and acetic acid, at a hydrogen pressure of 5 to 15bar and a reaction temperature of 20 to 80 ℃. The reaction is preferably carried out in acetic acid at 40 ℃.

Example 1: preparation of 4- (alkoxymethylene) -2-alkyl oxazolone intermediate formula II

The method comprises the following steps: preparation of 4- (ethoxymethylene) -2-phenyloxazolone

To a 100mL three-necked flask equipped with a stirrer, a thermometer and a reflux tube were added 25g of hippuric acid under argon atmosphere, 24mL of triethyl orthoformate and 26mL of acetic anhydride were added at room temperature, and the mixture was refluxed at 130℃for 30 minutes. After the reaction was completed, the reaction solution was cooled to room temperature. Under ice bath condition, saturated NaHCO is added ₃ Until no bubbles are generated. The reaction solution was extracted three times with 50mL of diethyl ether (50 mL. Times.3), the organic phases were combined, washed with saturated brine once, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to give a thick solid, which was recrystallized from 100mL of isopropyl alcohol to give 15g of pale red solid in 49% yield.

¹ HNMR(500 MHz,CDCl ₃ )：δ8.12–8.04(m,1H),7.60–7.52(m,1H),7.51–7.45(m,1H),7.35(s,1H),4.44(q,J＝7.1 Hz,1H),1.50(t,J＝7.1 Hz,2H)。

The second method is as follows: preparation of 4- (methoxymethylene) -2-phenyloxazolone

9g of hippuric acid is added into a two-port bottle with 100mL of stirrer, 10mL of LDMF and argon are added for protection, 12mL of phosphine oxide trichloride (more than 1 h) is slowly added through a syringe under the ice bath condition, the reaction is continued for 30min after the dripping is finished, and the reaction is carried out at room temperature for 2h. After the reaction is finished, saturated NaHCO is added under the ice bath condition ₃ The solution was left until no bubbles were generated. The reaction mixture was extracted three times with 50mL of methylene chloride (50 mL. Times.3), washed with saturated brine once, and the solvent was removed under reduced pressure to give 10.6g of yellow product VI, which was used in the next step without purification in 90% yield. The product of the above step was added to 50mL of acetonitrile and 35mL of 2N NaOH and reacted overnight at room temperature. After the reaction was completed, the solvent was removed under reduced pressure, filtered, and rinsed with a small amount of acetonitrile to obtain 9.8g of a white solid product VII, which was used in the next step without purification. 50 mM MF is added to the product VII of the previous step 9.8, 9.8g of potassium carbonate is added,under the protection of argon, 8.5mL of dimethyl sulfate is added and reacted for 5 hours at the temperature of 60 ℃. After completion of the reaction, water was added thereto, and the reaction mixture was extracted three times with 50mL of methylene chloride (50 mL. Times.3), washed once with saturated brine, and the solvent was removed under reduced pressure to obtain 7.8g of a product. The total yield was 76%.

Example 2: preparation of intermediate III

To a 50mL two-necked flask equipped with a stirrer was added 4.2g of 4- (ethoxymethylene) -2-phenyloxazolone under argon protection, 30mL of anhydrous methylene chloride was added, and 3g N- (1-cyclopentenyl) morpholine (80% purity) was added at room temperature to react at room temperature for three hours. After the reaction was completed, the organic solvent was removed under reduced pressure to give a yellow solid product, which was used directly in the next step without purification.

¹ H NMR(500MHz,CDCl ₃ )：δ8.04–7.99(m,2H),7.54–7.39(m,3H),7.36(s,1H),3.86–3.74(m,4H),3.74–3.60(m,4H),3.17(t,J＝7.4Hz,2H),2.62(t,J＝7.7Hz,1H),2.09–1.84(m,2H)。

Example 3: preparation of intermediate formula IV

The intermediate II obtained in example 2 was put into a 50mL two-necked flask equipped with a stirrer, and was purged with argon, and 30mL of an anhydrous methanol solution and 2mL of a sodium methoxide methanol solution (1 mol/L) were added at room temperature, followed by refluxing for 1 hour. The reaction solution was cooled to room temperature and filtered to give 4.1g of the product as a yellow solid in a yield of 60% in two steps. ¹ H NMR(500MHz,CDCl ₃ )：δ7.92–7.81(m,3H),7.53(t,J＝7.4Hz,1H),7.46(t,J＝7.5Hz,2H),7.34(s,1H),3.78(s,3H),3.76–3.71(m,4H),3.31–3.20(m,4H),2.53-2.47(m，1H),1.85–1.71(m,2H)。

Example 4: preparation of intermediate Va

To the autoclave, 360mg (1 mmol) of intermediate IV, 15mL of methylene chloride and 1mol% [ Rh (COD) (2R, 5R-Me-DuPhos) were charged]BF ₄ The autoclave was hydrogenated to lObar and stirred at room temperature for 6h. After the reaction, the organic solvent is directly removed under reduced pressure to obtain 360mg of oily product Va, and the yield is more than 99%. In order to facilitate the stability of chiral analysis of the product, 2mL of 1N hydrochloric acid is added for hydrolysis for 30min after the reaction is finished, the water phase is discarded, the organic phase is dried over anhydrous sodium sulfate, and the organic solvent is removed under reduced pressure to obtain the oily ketone product. By HPLC analysis against racemate, via chiral AD-H column, E1 column, ee=98.3%.

Example 5: preparation of azabicyclo [3, 0] octane-3 (S) -carboxylic acid

To 360mg of the oil obtained in example 4 was added 2mL of 6N HC1, and the mixture was refluxed overnight. Cooled to room temperature, and the reaction was extracted twice with MTBE (2X 5 mL). The aqueous phase was concentrated to dryness under reduced pressure to give a solid which was used directly in the next step without further purification. The reaction mixture was introduced into a autoclave by adjusting p H to 1 to 2 with hydrochloric acid, 5mg of 0% palladium on carbon was then added thereto, and the mixture was pressurized to l0bar with hydrogen and reacted at 80C overnight. The reaction system was cooled and then hydrogen was slowly released. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Concentrating, drying, and recrystallizing with acetone to obtain the hydrochloride of the target product.

The invention describes a preparation method of ramipril main intermediate aza bicyclo [3, 0] octane-3 (S) -carboxylic acid in detail, and the preparation method has the characteristics of easily available raw materials, simple process, convenient operation, higher yield, low cost and the like, has potential industrialization value, and accords with the development direction of green chemistry.

Although the invention has been described with respect to preferred embodiments and methods of use, it should be understood that alternatives, modifications, and variations are possible without departing from the spirit of the invention. Accordingly, all such alternatives, modifications and variations as may be contemplated by those skilled in the art are within the scope of the present invention.

Claims (10)

1. Synthesis method of enantiomerically enriched azabicyclo [3, 0] octane-3 (S) -carboxylic acid shown in formula I

The method is characterized by comprising the following steps of:

(1) The N-acyl glycine derivative is reacted in one step or multiple steps to obtain a 4- (alkoxymethylene) -2-alkyl oxazolone intermediate formula II;

wherein R is ₁ Is methyl or ethyl, R ₂ Is phenyl or methyl;

(2) Reacting the intermediate formula II with various N- (1-cyclopentenyl) amines to generate an intermediate formula III;

wherein R is ₂ As described above, R is independently selected from C ₁ ～C ₆ Alkyl, or R is linked with N and another R to form a five-membered or six-membered ring, which may contain O.

(3) Under the condition of catalytic amount of alkyl alkoxide, the oxazolone mother nucleus is ring-opened to generate unsaturated amino acid intermediate formula IV;

wherein R, R ₂ As described above, R ₃ Methyl or ethyl;

(4) Generating an enantiomerically enriched intermediate formula V (comprising formula Va and formula Vb) in the presence of a transition metal rhodium-chiral phosphine ligand complex catalyst;

wherein R, R ₂ ，R ₃ As described above, formula Va is in the R configuration and Vb is in the S configuration;

(5) The intermediate type vb is firstly subjected to N-acyl protecting group removal and enamine hydrolysis under the heating condition of hydrochloric acid solution, and then palladium hydrocarbon is subjected to heating and pressurizing conditions to generate the azabicyclo [3, 0] octane-3 (S) -carboxylic acid of the formula I.

2. The synthesis method according to claim 1, wherein: the synthesis method of the 4- (alkoxymethylene) -2-alkyl oxazolone intermediate in the formula II can be a method I or a method II: the method comprises the following steps: the N-acyl glycine and triethyl orthoformate or trimethyl orthoformate are reacted in acetic anhydride solvent at 100-130 ℃ to generate intermediate formula II; the second method is as follows: n-acylglycine can be obtained in multiple steps as intermediate of formula II, first in POCl ₃ Reacting under DMF condition to obtain intermediate formula VI, hydrolyzing under NaOH aqueous solution/organic solvent condition to obtain intermediate formula VII, and methylation reacting intermediate formula VII with dimethyl sulfate under alkali to obtain intermediate formula II.

3. The synthesis method according to claim 2, wherein: in the first method, the molar ratio of the N-acyl glycine derivative to the triethyl orthoformate or the trimethyl orthoformate to the acetic anhydride is 1.0:1.0-2.0:1.0-3.0; the N-acylglycine derivative is preferably N-methylglycine or N-phenylglycine.

4. The synthesis method according to claim 2, wherein: in method two, N-acyl glycine derivative and POCl ₃ DMF molar ratio of 1.0:2.0 to 3.0:2.0 to 3.0; the molar ratio of the intermediate formula VI to NaOH is 1:1.0 to 1.5; intermediate formula VII, dimethyl sulfate and alkali mole ratio of 1.0:1.0 to 3.0:1.0 to 3.0, wherein the alkali can be one or more of sodium hydroxide, potassium hydroxide, triethylamine, potassium carbonate and sodium carbonate.

5. The synthesis method according to claim 1, wherein: reacting the intermediate II with various enamines to obtain an intermediate III, wherein the selected condition is that the molar ratio of the intermediate II to the enamine is 1.0:1.0 to 1.5, and the solvent can be one or more selected from dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, methanol and ethanol.

6. The synthesis method according to claim 1, wherein: the intermediate formula III generates an intermediate formula IV reaction, and the selected conditions of sodium methoxide or sodium ethoxide and methanol or ethanol reflux.

7. The synthesis method according to claim 1, wherein: intermediate formula IV generates intermediate formula V reaction, transition metal-chiral phosphine ligand complex catalyst structure is: m (L) (P) X, wherein M is Rh; l=1, 5-cyclooctadiene; the reaction medium can be dichloromethane, methanol, tetrahydrofuran, acetonitrile, ethyl acetate, toluene or a mixed solvent; the P is BINAP series, scRp-DuanPhos, rcSp-DuanPhos, SSRR-TangPhos, RRSS-TangPhos, duPhos series such as Me-DuPhos, or BPE; the temperature is 10-100 ℃.

8. The method according to claim 7, wherein the synthetic method,the method is characterized in that: the catalyst is [ Rh (cod) (2R, 5R-Me-Duphos)]BF ₄ 、[Rh(cod)(2S,5S-Me-Duphos)]BF ₄ 、[Rh(cod)(2R,5R-Et-Duphos)]BF ₄ 、[Rh(cod)(2R,5R-Et-Duphos)]BF ₄ 。

9. The method of synthesis according to claim 7, wherein: the reaction temperature is 20-30 ℃.

10. The method of synthesis according to claim 7, wherein: the hydrogen pressure is 10-50 bar.