The present application is a National Stage Application of PCT/CN2011/082432, filed Nov. 18,2011, which claims benefit of application No. 201010550836.0, filed on Nov. 19, 2010 in China, titled “Chiral spiro-pyridylamidophosphine ligand compound, synthesis method therefor and application thereof”, which applications are incorporated herein by reference. To the extent appropriate, a claim of priority is made to each of the above disclosed applications.

      The present invention relates to a chiral spiro-pyridylamidophosphine ligand compound, synthesis method therefor and application thereof. Said chiral spiro-amidophosphine compound can be used in an asymmetric organic reaction as a chiral ligand. The present invention further provides a method for preparing the novel spiro-pyridylamidophosphine ligand, which is used in the asymmetric hydrogenation reaction of carbonyl compounds to prepare compounds of optical activity.

      In organic synthesis reactions, the chiral phosphine-nitrogen ligand of the containing amido coordination group is one of the most important chiral ligands. Such chiral phosphine-nitrogen ligands can coordinate with many transition metals to form chiral catalysts that are of great use in the asymmetric catalytic reaction. At present, such transition metal catalysts of chiral phosphine-nitrogen ligand containing amido coordination group have shown excellent reaction activity and enantioselectivity in a large number of asymmetric catalytic reactions (Amoroso, D.; Graham, T. W.; Guo, R.; Tsang, C.-W.; Abdur-Rashid, K. Aldrich. Chimica Acta. 2008, 41, 15).

      More recently, due to the development of highly efficient chiral ruthenium-diphosphine/diamine catalysts by Noyori et al. ((a) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 2675; (b) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.; Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 13529), extremely high catalytic activity and enantioselectivity have been achieved in the asymmetric hydrogenation reaction of non-functionalized ketones which is quite difficult in the past, resulting in close attention to such chiral catalysts. Although quite high enantioselectivity (>99% ee) and reaction activity (S/C>100,000) have been realized in a series of asymmetric catalytic hydrogenations of aromatic ketones, heterocyclic aromatic ketones, α,β-unsaturated ketones by such chiral catalysts, excellent result can be obtained only if the chiral and stereoscopic effect of the chiral diphosphine ligand and diamine ligand are both precisely matched. Therefore, in recent years, research has been focused on the chiral amidophosphine ligand containing amido group, especially containing hydrogen atom on the nitrogen atom, with advantages such as simple synthesis, flexible coordination and having the features of chiral phosphine ligand and amido ligand.

      A series of amidophosphine ligands containing NH ₂ coordination group have been reported by Morris et al. From University of Toronto, Canada in around 2004, and better hydrogenation has been accomplished by the ruthenium complexes with these chiral ligands in the asymmetric catalytic hydrogenation of ketones, imides etc. ((a) Abdur-Rashid, K.; Guo, R.; Lough, A. J.; Morris, R. H.; Song, D. Adv. Synth. Catal. 2005, 347, 571; (b) Guo, R.; Lough, A. J.; Morris, R. H.; Song, D. Organometallics, 2004, 23, 5524; (c) Guo, R.; Morris, R. H.; Song, D. J. Am. Chem. Soc. 2005, 127, 516). It has been reported by Chen's group from University of Liverpool, UK that moderate enantioselectivity (<79% ee) has been achieved in the asymmetric catalytic hydrogenation reaction of aryl alkyl ketones catalyzed by the ruthenium complex with chiral amidophosphine ligand having ferrocene skeleton (Chen, W.; Mbafor, W.; Roberts, S. M.; Whittall, J. Tetrahedron: Asymmetry, 2006, 17, 1161). It has also been reported by Dahlenburg's group from University of Erlangen-Nuremberg, Germany that moderate ee value was obtained in the simple ketone hydrogenation reaction catalyzed by iridium, rhodium complex with chiral amidophosphine ligand derived from β-amido alcohols ((a) Dahlenburg, L.; Götz, R. Eur. J. Inorg. Chem. 2004, 888; (b) Dahlenburg, L.; Gotz, R. Inorg. Chem. Commun. 2003, 6, 443). However, the enantioselectivity of these reported chiral catalysts of the chiral amidophosphine ligands in the asymmetric catalytic hydrogenation of simple ketones is much inferior to those chiral ruthenium-diphosphine/diamine catalysts developed by Noyori et al.

      Recently, a series of bidentate chiral spiro-amidophosphine ligands containing aromatic amido group has been designed and synthesized by our group (Jian-Bo Xie, Jian-Hua Xie, Xiao-Yan Liu, Wei-Ling Kong, Shen Li, Qi-Lin Zhou, J. Am. Chem. Soc. 2010, 132, 4538; Qi-Lin Zhou, Jian-Hua Xie, Jian-Bo Xie, Li-Xin Wang, C N 101671365A). Better reaction activity and enantioselectivity have been achieved in the asymmetric catalytic hydrogenation of α,β-unsaturated ketones having exocyclic double bond by the iridium catalysts with such chiral amidophosphine ligands compared with the chiral ruthenium-diphosphine/diamine catalyst; excellent performance has also been observed in the asymmetric catalytic hydrogenation of simple aryl alkyl ketones. However, for this catalyst, the conversion number is still relatively low; although its conversion number (the ratio of substrate to catalyst) in the catalytic hydrogenation reaction of simple ketones and α,β-unsaturated ketones is much higher than that of other chiral catalysts, the maximum value is only 10,000, which is still needed to be further improved.

      In the field of asymmetric catalytic hydrogenation reaction, there are only a few chiral catalysts developed with truly high efficiency. The development of highly efficient chiral ligand with simple synthesis and flexible coordination as well as its catalyst remains difficult and challenge in the asymmetric catalysis area.

      The objective of the present invention is to provide a novel chiral spiro-pyridylamidophosphine ligand compound, synthesis method therefor and application thereof, and the chiral spiro-pyridylamidophosphine compound can be used as a chiral ligand in the iridium-catalyzed asymmetric catalytic hydrogenation reaction of carbonyl compounds, i.e., extremely high yield (>90%) and enantioselectivity (up to 99.9% ee) have been achieved in the iridium-catalyzed asymmetric hydrogenation reaction of carbonyl compounds including aryl alkyl ketones, ketenes and keto esters. The reaction has very high activity, in which the amount of catalyst used can be reduced to 0.0001% mol. The synthesis process in the present invention is simple, and has a high yield; and the resulting chiral spiro-pyridylamidophosphine compound is a very efficient chiral ligand.

      The chiral spiro-pyridylamidophosphine ligand provided herein is a compound having a structure of Formula (I),

      
(MOL) (CDX)
or a racemate or optical isomer thereof, or a catalytically acceptable salt thereof,

  wherein, R¹ is C₁-C₈ chain hydrocarbyl or saturated cyclic hydrocarbyl or cycloalkenyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, furyl or thienyl, and the substituent on said substituted phenyl is halogen, C₁-C₈ alkyl or alkoxy, with a substituent amount of 1-5, and said heteroaryl is pyridyl;

R², R³, R⁴ and R⁵ are H, C₁-C₈ alkyl or alkoxy, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, furyl or thienyl, and the substituent on said substituted phenyl is C₁-C₈ hydrocarbyl, alkoxy, with a substituent amount of 1-5, and said heteroaryl is pyridyl; or R²-R³, R⁴-R⁵ are incorporated into C₃-C₇ aliphatic ring, aromatic ring; R², R³, R⁴ and R⁵ can be the same or different;

R⁶, R⁷ are selected from the group consisting of H, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ aliphatic amido group, and n=0-3; or when n≧2, two adjacent R⁶ groups or two adjacent R⁷ groups can be incorporated into a C₃-C₇ aliphatic ring or aromatic ring, and R⁶, R⁷ can be the same or different;

R⁸, R⁹ are H, halogen, C₁-C₈ alkyl, C₁-C₈ alkoxy, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, furyl or thienyl, and the substituent on said substituted phenyl is halogen, C₁-C₈ alkyl, alkoxy, with a substituent amount of 1-5, and said heteroaryl is pyridyl, and m=0-3; or when m≧2, adjacent R⁹ or R⁸ and R⁹ groups can be incorporated into a C₃-C₇ aliphatic ring or aromatic ring, and R⁸, R⁹ can be the same or different;

R¹⁰ is H, C₁-C₈ alkyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, furyl or thienyl, and the substituent on said substituted phenyl is C₁-C₈ alkyl, alkoxy, with a substituent amount of 1-5, and said heteroaryl is pyridyl;

      Preferably, in the structural Formula (I) of the compound described herein, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸ and R ¹⁰ are H simultaneously, and R ¹ is phenyl or substituted phenyl, and the substituent on said substituted phenyl is halogen, C ₁-C ₈ hydrocarbyl and alkoxy, with a substituent amount of 1-5; R ⁹ is H, halogen, C ₁-C ₈ alkyl, C ₁-C ₈ alkoxy, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, furyl or thienyl, and the substituent on said substituted phenyl is halogen, C ₁-C ₈ alkyl or alkoxy, with a substituent amount of 1-5, and said heteroaryl is pyridyl, and m=0-3; or when m≧2, adjacent R ⁹ groups can be incorporated into C ₃-C ₇ aliphatic ring or aromatic ring.

      The present invention further specifically provides typical compounds of chiral spiro-pyridylamidophosphine ligand having the structures as follows, or racemate or optical isomer thereof, or catalytically acceptable salt thereof:

      
(MOL) (CDX)
(MOL) (CDX)

      The present invention further provides the synthesis methods for said chiral spiro-pyridylamidophosphine compound, which are characterized by preparation through the following reactions using racemically or optically active compound 7-diaryl/alkylphosphino-7′-amino-1,1′-spiro-dihydro-indene shown as Formula (II) having a chiral spiro-dihydro-indene skeleton as the starting material:

      
(MOL) (CDX)

wherein, R¹-R¹⁰ and the values of n and m are defined as claim 1,

wherein, the racemically or optically active compound 7-diaryl/alkylphosphino-7′-amino-1,1′-spiro-dihydro-indene of Formula (II) is synthesized by the method according to references (Jian-Bo Xie, Jian-Hua Xie, Xiao-Yan Liu, Wei-Ling Kong, Shen Li, Qi-Lin Zhou, J. Am. Chem. Soc. 2010, 132, 4538; Qi-Lin Zhou, Jian-Hua Xie, Jian-Bo Xie, Li-Xin Wang, C N 101671365A).

wherein, R¹-R¹⁰ and the values of n and m are defined as claim 1,

wherein, the racemically or optically active compound 7-diaryl/alkylphosphino-7′-amino-1,1′-spiro-dihydro-indene of Formula (II) is synthesized by the method according to references (Jian-Bo Xie, Jian-Hua Xie, Xiao-Yan Liu, Wei-Ling Kong, Shen Li, Qi-Lin Zhou, J. Am. Chem. Soc. 2010, 132, 4538; Qi-Lin Zhou, Jian-Hua Xie, Jian-Bo Xie, Li-Xin Wang, C N 101671365A).

      The specific synthesis method for the chiral spiro-pyridylamidophosphine compound I is described as below:

      Step 1:

Synthesis method 1: racemically or optically active 7-diaryl/alkylphosphino-7′-amino-1,1′-spiro-dihydro-indene having the structure of Formula (II) is reacted with substituted pyridylaldehyde or pyridone in a reactor for 2-24 hours in the presence of organic solvent and reducing agent to obtain the spiro-pyridylamidophosphine compound I with one hydrogen atom on corresponding nitrogen atom (R¹⁰=H); the molar ratio among said racemically or optically active 7-diaryl/alkylphosphino-7′-amino-1,1′-spiro-dihydro-indene II of Formula (II), pyridylaldehyde and reducing agent is in the range of 1:1-5:1-10; and the reaction temperature is 0-120° C.

Synthesis method 2: racemically or optically active 7-diaryl/alkylphosphino-7′-amino-1,1′-spiro-dihydro-indene having the structure of Formula (II) is initially reacted with pyridine formyl chloride in a reactor in the presence of organic solvent and alkali, to obtain a corresponding acylated compound, followed by reduction with a reducing agent to obtain the spiro-pyridylamidophosphine compound I with one hydrogen atom on corresponding nitrogen atom (R¹⁰=H); in the acylation reaction, the molar ratio among said racemically or optically active 7-diaryl/alkylphosphino-7′-amino-1,1′-spiro-dihydro-indene II, pyridine formyl chloride and alkali is in the range of 1:1-5:1-10; and the reaction temperature is 0-100° C. During the reduction reaction, the molar ratio of the resulting acylated compound to the reducing agent is in the range of 1:1-10, and the reaction temperature is from −20 to 100° C.

Synthesis method 3: racemically or optically active 7-diaryl/alkylphosphino-7′-amino-1,1′-spiro-dihydro-indene having the structure of Formula (II) is initially reacted with pyridine formic acid in a reactor in the presence of organic solvent, alkali and carboxyl-activating reagent to obtain a corresponding acylated compound, followed by reduction with a reducing agent to obtain the spiro-pyridylamidophosphine compound I with one hydrogen atom on corresponding nitrogen atom (R¹⁰=H); in the acylation reaction, the molar ratio among said racemically or optically active 7-diaryl/alkylphosphino-7′-amino-1,1′-spiro-dihydro-indene II, pyridine formic acid and activating reagent is in the range of 1:1-5:1-10, and the reaction temperature is from −30 to 100° C.; in the reduction reaction, the molar ratio of the resulting acylated compound to the reducing agent is in the range of 1:1-10, and the reaction temperature is from −20 to 100° C.

      Step 2: according to the synthesis method or step mentioned above, using the resulting spiro-pyridylamidophosphine compound I with one hydrogen atom contained on the nitrogen atom (R ¹⁰=H) as the starting material, the spiro-pyridylamidophosphine compound I with no hydrogen atom on the nitrogen atom (R ¹⁰≠H) can be synthesized by replacing the pyridylaldehyde, pyridine formyl chloride, pyridine formic acid described above with fatty aldehyde or aromatic aldehyde, acyl chloride and carboxylic acid.

      In the above synthesis method, the molecular formula of said substituted pyridylaldehyde, pyridone, pyridine formyl chloride, pyridine formic acid and the fatty aldehyde or the aromatic aldehyde, acyl chloride, carboxylic acid are defined by the R ⁸-R ¹⁰ in the Formula (I) and the values of m. Said organic solvent can be any one of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, xylene, methyl tert-butyl ether, diethyl ether, dioxane, N,N-dimethyl formamide, dimethyl sulfoxide, or any mixture thereof; said reducing agent can be lithium aluminium hydride, sodium borohydride, sodium triacetyl borohydride or sodium cyanoborohydride; said alkali is an organic base or an inorganic base, in which said organic base can be pyridine, triethylamine, tributyl amine, N-methylmorpholine or N,N-diethyl isopropyl amine; said inorganic base can be sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; said carboxyl-activating reagent is ethyl chloroformate, isopropyl chloroformate, N,N′-dicyclohexylcarbodiimide or carbonyl diimidazole.

      The chiral spiro-pyridylamidophosphine compound according to the present invention can be used in the asymmetric catalytic reaction as a chiral ligand, in which corresponding transition metal complexes can be formed by the compound as the chiral ligand together with the metal precursor of transition metals such as rhodium, ruthenium, iridium, palladium, copper, iron, nickel etc., and the chiral catalyst is formed and used in the asymmetric reaction, especially in the iridium-catalyzed asymmetric catalytic hydrogenation reaction of carbonyl compounds including aryl alkyl ketone, ketene and keto ester, which allows for the production of chiral alcohol compounds, that are of important use in the chiral pharmaceutical synthesis, the important chiral organic compound synthesis and the biologically active natural product synthesis, in an almost quantitative yield, and with excellent reaction activity and enantioselectivity. The preparation reaction of said chiral catalyst is described below:

hydrogenated chiral catalyst is obtained by the initial 0.5-4 hours of complexation reaction of the chiral spiro-pyridylamidophosphine compound and iridium catalyst precursor in an organic solvent at 25-120° C., followed by 0.1-3 hours of reaction stirred under the hydrogen atmosphere at the pressure of 0.1-10 Mpa; or

complexation reaction between chiral spiro-pyridylamidophosphine compound and iridium catalyst precursor is performed in an organic solvent for 0.5-4 hours, then desolventization is performed to obtain the corresponding complex, which is then subjected to reaction under stirring in the organic solvent under the hydrogen atmosphere at the pressure of 0.1-10 Mpa for 0.1-3 hours, to obtain the chiral catalyst.

      The molar ratio of said iridium catalyst precursor to the chiral spiro-amidophosphine ligand is in the range from 1:1.2 to 1:1.5 (Ir/L); said iridium catalyst precursor is [Ir(cod)]Cl ₂ (cod=Cyclooctadiene), [Ir(cod) ₂]BF ₄, [Ir(cod) ₂]PF ₆, [Ir(cod) ₂]SbF ₆ or [Ir(cod) ₂] OTf.

      The chiral catalyst prepared can be used for the asymmetric catalytic hydrogenation reaction of carbonyl compound, and the reaction is described below:

      In an organic solvent, the resulting reaction solution or solid mentioned above is reacted as the catalyst with the carbonyl compound and the alkali added by stirring under the hydrogen atmosphere at the pressure of 0.1-10 Mpa for 0.1-24 hours, to obtain the chiral alcohol compounds.

      The amount of said catalyst used is 0.0001-5 mol %. The concentration of the substrate is 0.001-10.0 M. Said alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, triethyl amine, tributyl amine or N-methyl morpholine. The concentration of the alkali is 0.005 M-1.0 M, and the reaction temperature is 0-80° C.

      The above organic solvent is any one of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, DMF, DMSO, or any mixture thereof.

      The chiral spiro-pyridylamidophosphine compound provided herein is a compound having the structure of Formula (I), or a racemate or optical isomer thereof, or a catalytically acceptable salt thereof, and the main structural characteristic thereof is the chiral spiro-dihydro-indene skeleton. It can be used as the chiral ligand in the iridium-catalyzed asymmetric catalytic hydrogenation reaction of carbonyl compounds, and an extremely high yield (>90%) and enantioselectivity (up to 99.9% ee) have been achieved in the iridium-catalyzed asymmetric hydrogenation reaction of carbonyl compounds including aryl alkyl ketones, ketenes and keto esters. The reaction has very high activity, in which the amount of catalyst used can be reduced to 0.0001% mol. The synthesis process in the present invention is simple, with a high yield; and the resulting chiral spiro-pyridylamidophosphine compound is a very efficient chiral ligand.

      In order to further understand the present invention, preferable embodiments of the present invention will be described by reference to the examples, but it should be appreciated that these descriptions are merely intended to further illustrate the features and advantages of the present invention, rather than limiting the claims of the invention.

      The results of the present invention are illustrated by the specific examples below, but the scope of the present invention is not limited by the following Examples.

      
(MOL) (CDX)

      Under nitrogen atmosphere, (R)-7-di-(3,5-di-tert-butylphenyl)phosphino-T-amino-1,1′-spiro-dihydro-indene (966 mg, 1.5 mmol), sodium triacetoxyborohydride (509 mg, 2.4 mmol) and 6 ml 1,2-dichloroethane were weighed into a 50 ml dry two-neck bottle. After the solid was dissolved by stirring at room temperature, pyridylaldehyde was added (161 mg, 1.5 mmol). After the reaction was stirred for 6 h at room temperature, the starting material was almost consumed (monitored by TLC, petroleum ether:ethyl acetate=7:1). The reaction was quenched by saturated aqueous solution of sodium bicarbonate, extracted by ethyl acetate, and dried by anhydrous magnesium sulfate. After desolventization, 1.01 g white solid was obtained by purification of the resulting solid through silica gel column chromatography (petroleum ether:ethyl acetate=10:1, 2% triethylamine), with a yield of 92%.

      Mp 172-174° C.; [α]D ²⁰+172 (c 0.5, CH ₂Cl ₂); ¹H NMR (400 mhz, cdcl ₃) δ 8.30 (d, J=4.8 Hz, 1H, Ar—H), 7.44-7.39 (m, 1H, Ar—H), 7.31 (d, J=7.2 Hz, 1H, Ar—H), 7.26-7.19 (m, 3H, Ar—H), 7.12-7.06 (m, 2H, Ar—H), 7.02-6.99 (m, 1H, Ar—H), 6.88-6.84 (m, 3H, Ar—H), 6.77-6.75 (dd, J=1.6, 7.6 Hz, 2H, Ar—H), 6.68 (d, J=9.2 Hz, 1H, Ar—H), 6.10 (d, J=8.0 Hz, 1H, Ar—H), 4.20 (t, J=5.2 Hz, 1H), 3.97 (dd, J=6, 16.4 Hz, 1H), 3.73 (dd, J=4.4, 16.4 Hz, 1H), 3.13-2.76 (m, 4H), 2.49-2.40 (m, 1H), 2.19-2.09 (m, 3H), 1.09 (s, 18H), 1.16 (s, 18H); ³¹P NMR (162 mhz, cdcl ₃) δ −18.17 (s); ¹³C NMR (100 mhz, cdcl ₃) δ 155.8, 152.5 (d, J=24.3 Hz), 149.9 (d, J=6.3 Hz), 148.9, 144.3, 144.2, 144.1, 138.2 (d, J=11.7 Hz), 136.1, 135.2, 134.9, 133.8, 132.6 (d, J=3.4 Hz), 128.4, 128.1, 128.0, 127.9, 126. 9, 125.7, 122.2, 121.5, 121.5, 120.7, 113.9, 108.6, 61.7 (d, J=3.3 Hz), 48.5, 38.6 (d, J=3.4 Hz), 36.1, 34.7 (d, J=3.8 Hz), 31.4 (d, J=2.4 Hz), 30.92, 31.36. HRMS (ESI) calcd for C ₅₁H ₆₃N ₂P [M+H] ⁺: 735.4802. Found: 735.4804.

      (In the following Examples, Compounds Ib-Ij were prepared via the same process as Example 1 except for the reactants changed).

      
(MOL) (CDX)

      Specific process can be found in Example 1, and white solid was obtained with a yield of 85%.

      Mp 172-174° C.; [α]D ²⁰+265 (c 0.5, CH ₂Cl ₂), ¹HNMR (400 mhz, cdcl ₃) δ 8.23 (d, J=3.6 Hz, 1H), 7.38 (t, J=6.8 Hz, 1H), 7.26-7.24 (m, 1H), 7.16-7.07 (m, 5H), 7.03-6.83 (m, 10H), 6.61 (d, J=7.2 Hz, 1H), 5.88 (d, J=8.0 Hz, 1H), 3.98 (brs, 1H), 3.82-3.77 (m, 1H), 3.56-3.51 (m, 1H), 3.02-2.92 (m, 4H), 2.42-2.30 (m, 2H), 2.25-2.22 (m, 1H), 2.12-2.08 (m, 1H); ³¹P NMR (162 mhz, cdcl ₃) δ −22.47 (s); ¹³C NMR (100 mhz, cdcl ₃) δ 157.6, 152.2, 151.9, 147.6, 143.4, 143.3, 142.3, 138.5, 138.4, 135.4, 135.3, 135.2, 133.4 (d, J=2.6 Hz), 133.0, 132.8, 132.2, 132.0, 131.9, 127.2 (d, J=4 Hz), 127.0 (d, J=5.7 Hz), 126.9, 126.8, 126.6, 126.3, 125.0. 120.4, 119.6, 112.7, 107.3, 64.8, 60.6 (d, J=3.2 Hz), 47.1, 38.5 (d, J=5.1 Hz), 35.0, 30.3, 29.9. HRMS (ESI) calcd for C ₃₅H ₃₁N ₂P[M+H] ⁺: 511.2298. Found: 511.2296.

      
(MOL) (CDX)

      Specific process can be found in Example 1, and white solid was obtained with a yield of 82%.

      Mp 172-174° C.; [α] _D ²⁰ +262 (c 0.5, CH ₂Cl ₂), ¹H NMR (400 mhz, cdcl ₃) δ 8.29 (d, J=4.4 Hz, 1H), 7.44-7.40 (m, 1H), 7.32-7.30 (m, 1H), 7.22 (t, J=7.2 Hz, 1H), 7.12-7.00 (m, 3H), 6.82-6.76 (m, 3H), 6.70 (d, J=7.6 Hz, 1H), 6.60 (d, J=7.6 Hz, 4H), 5.96 (d, J=7.6 Hz, 1H), 4.00-3.97 (m, 1H), 3.91-3.85 (m, 1H), 3.47 (dd, J=4, 16.4 Hz, 1H), 3.13-2.99 (m, 4H), 2.53-2.39 (m, 2H), 2.33-2.28 (m, 1H), 2.17 (s, 6H), 2.01 (s, 6H); ³¹P NMR (162 mhz, cdcl ₃) δ −22.32 (s); ¹³C NMR (100 mhz, cdcl ₃) δ 158.6, 153.1, 152.9, 148.7, 144.4, 144.3, 144.2, 143.6, 137.2 (d, J=6.0 Hz), 137.0 (d, J=7.8 Hz), 136.2, 134.4, 133.4, 132.2, 132.0, 131.0, 130.8, 130.1, 129.5, 128.0, 127.2, 125.7, 121.4, 120.5, 113.7, 108.4, 61.7, 48.0, 39.4 (d, J=5.4 Hz), 36.1., 31.4, 31.0, 21.4, 21.1. HRMS (ESI) calcd for C ₃₉H ₃₉N ₂P[M+H] ⁺: 567.2924. Found: 567.2916.

      
(MOL) (CDX)

      Specific process can be found in Example 1, and white solid was obtained with a yield of 95%.

      Mp 153-155° C., [α] _D ²⁰ +191 (c 1.0, CH ₂Cl ₂), ¹H NMR (400 mhz, cdcl ₃) δ 7.32-7.28 (m, 2H), 7.24-7.17 (m, 3H), 7.14-7.08 (m, 2H), 6.87-6.83 (m, 3H), 6.77-6.75 (m, 2H), 6.68 (d, J=7.2 Hz, 1H), 6.59 (d, J=7.6 Hz, 1H), 6.17 (d, J=8 Hz, 1H), 4.27 (brs, 1H), 4.03 (dd, J=6.4, 16 Hz, 1H), 3.67-3.63 (m, 1H), 3.09-2.89 (m, 3H), 2.80-2.74 (m, 1H), 2.51-2.43 (m, 1H), 2.34 (s, 3H), 2.18-2.03 (m, 3H), 1.15 (s, 3H), 1.06 (s, 3H); ³¹P NMR (162 mhz, cdcl ₃) δ −18.20 (s); ¹³C NMR (100 mhz, cdcl ₃) δ 157.7, 157.5, 152.8, 152.6, 144.4, 144.3 (d, J=3.4 Hz), 144.0, (d, J=7.3 Hz), 138.2, 138.1, 136.4, 136.3, 136.1, 135.1, 134.8, 133.7, 132.3 (d, J=3.5 Hz), 128.4, 128.2, 128.1, 127.9, 127.8, 126.9, 125.8, 122.0, 121.5, 121.0, 117.6, 113.7, 108.6, 61.7 (d, J=3.3 Hz), 48.4, 38.6 (d, J=3.2 Hz), 35.8, 34.7, 34.6, 31.4, 31.3, 30.8, 24.5. HRMS (ESI) calcd for C ₅₂H ₆₅N ₂P[M+H] ⁺: 749.4958. Found: 749.4952

      
(MOL) (CDX)

      Specific process can be found in Example 1, and white solid was obtained with a yield of 81%.

      Mp 84-85° C., [α] _D ²⁰ +216 (c 1.0, CH ₂Cl ₂), ¹H NMR (400 mhz, cdcl ₃) δ 7.33-7.31 (m, 1H), 7.28-7.20 (m, 5H), 7.13-7.05 (m, 2H), 6.88 (d, J=7.6 Hz, 2H), 6.82 (d, J=7.2 Hz, 1H), 6.75-6.70 (m, 3H), 6.04 (d, J=8 Hz, 1H), 3.92-3.82 (m, 2H), 3.71-3.66 (dd, J=4.4, 16.4 Hz, 1H), 3.10-2.92 (m, 3H), 2.83-2.77 (m, 1H), 2.42 (m, 1H), 2.20-2.11 (m, 3H), 1.15 (s, 18H), 1.13 (s, 18H); ³¹P NMR (162 mhz, cdcl ₃) δ −18.52 (s); ¹³C NMR (100 mhz, cdcl ₃) δ 160.1, 151.4 (d, J=24.5 Hz), 149.0, 148.9, 148.8, 148.7, 143.4, 142.9 (d, J=7.4 Hz), 142.5 (d, J=2.9 Hz), 140.2, 137.7, 137.1, 137.0, 135.0, 134.8, 133.9, 133.7, 132.7, 131.7 (d, J=3.2 Hz), 127.2, 127.0, 126.8, 126.1, 125.0, 124.8, 121.3, 120.4, 128.3, 113.3, 107.7, 60.6 (d, J=3.0 Hz), 47.2, 37.6, 34.9, 33.7 (d, J=2.9 Hz), 30.3, 30.1, 29.8. HRMS (ESI) calcd for c ₅₁h ₆₂brn ₂p[M+H] ⁺: 813.3907. Found: 813.3906

      
(MOL) (CDX)

      Specific process can be found in Example 1, and white solid was obtained with a yield of 92%.

      Mp 79-80° C., [α] _D ²⁰ +224 (c 1.0, CH ₂Cl ₂), ¹H NMR (400 mhz, cdcl ₃) δ 7.35-7.30 (m, 2H), 7.22-7.17 (m, 3H), 7.13-7.07 (m, 2H), 6.88-6.83 (m, 3H), 6.74 (d, J=7.6 Hz, 2H), 6.68 (d, J=7.2 Hz, 1H), 6.59 (d, J=8 Hz, 1H), 6.16 (d, J=7.6 Hz, 1H), 4.30-4.28 (m, 1H), 3.99 (dd, J=6.4, 16 Hz, 1H), 3.65-3.61 (m, 1H), 3.10-2.92 (m, 3H), 2.82-2.80 (m, 1H), 2.59 (q, J=7.6 Hz, 2H), 2.51-2.43 (m, 1H), 2.16-2.09 (m, 3H), 1.21-1.16 (m, 3H), 1.11 (s, 18H), 1.06 (s, 18H); ³¹P NMR (162 mhz, cdcl ₃) δ −18.34 (s); ¹³C NMR (100 mhz, cdcl ₃) δ 162.7, 157.5, 152.9, 152.6, 149.8 (d, J=6.2 Hz), 144.3 (d, J=2.8 Hz), 144.2 (d, J=3.2 Hz), 143.9, 143.8, 138.3, 138.1, 136.4, 136.2, 136.0, 134.9, 134.7, 133.7, 132.2 (d, J=3.5 Hz), 128.3, 128.1, 128.0, 127.9, 127.8, 126.9, 125.7, 122.0, 121.3, 119.5, 117.7, 113.6, 108.5, 61.6 (d, J=3.3 Hz), 48.3, 38.6 (d, J=3.1 Hz), 35.6, 34.7, 34.6, 31.3, 31.2, 31.1, 30.8, 14.4. HRMS (ESI) calcd for C ₅₃H ₆₇N ₂P[M+H] ⁺: 763.5115. Found: 763.5116.

      
(MOL) (CDX)

      Specific process can be found in Example 1, and white solid was obtained with a yield of 100%.

      Mp 97-99° C., [α] _D ²⁰ +216 (c 1.0, CH ₂Cl ₂), ¹H NMR (400 mhz, cdcl ₃) δ 7.92 (d, J=8.4 Hz, 1H), 7.76-7.69 (m, 2H), 7.64-7.60 (m, 1H), 7.46-7.42 (m, 2H), 7.28-7.25 (m, 1H), 7.24-7.22 (m, 1H), 7.17-7.07 (m, 4H), 6.81-6.76 (m, 4H), 6.69 (d, J=6 Hz, 1H), 6.24 (d, J=7.6 Hz, 1H), 4.84-4.82 (m, 1H), 4.26 (dd, J=6.0, 16.4 Hz, 1H), 3.92 (dd, J=3.2, 16.8 Hz, 1H), 3.13-3.04 (m, 2H), 2.97-2.89 (m, 1H), 2.78-2.72 (m, 1H), 2.18-2.02 (m, 3H), 1.16 (s, 18H), 0.96 (s, 18H); ³¹P NMR (162 mhz, cdcl ₃) δ −17.74 (s); ¹³C NMR (100 mhz, cdcl ₃) δ 157.1, 151.8, 151.5, 148.8, 148.7, 148.6, 146.4, 143.4 (d, J=2.6 Hz), 143.2 (d, J=3.6 Hz), 143.1, 143.0, 137.0, 136.9, 135.4, 135.3, 134.9, 134.1, 133.8, 132.6, 131.0 (d, J=3.4 Hz), 128.3, 127.9, 127.3 (d, J=3.1 Hz), 127.1, 126.9, 126.7, 126.2, 126.1, 126.0, 124.7 (d, J=3.8 Hz), 120.7, 120.4, 118.4, 112.6, 107.3, 60.7 (d, J=3.2 Hz), 47.8, 37.5 (d, J=2.8 Hz), 34.7, 33.7, 33.5, 30.3, 30.1, 29.8. HRMS (ESI) calcd for C ₅₅H ₆₅N ₂P[M+H] ⁺: 785.4958. Found: 785.4955.

      
(MOL) (CDX)

      Specific process can be found in Example 1, and white solid was obtained with a yield of 96%.

      Mp 96-98° C., [α] _D ²⁰ +204 (c 1.0, CH ₂Cl ₂), ¹H NMR (400 mhz, cdcl ₃) δ 7.84 (d, J=8.0 Hz, 2H), 7.51-7.40 (m, 4H), 7.32 (brs, 1H), 7.26-7.24 (m, 2H), 7.21 (brs, 1H), 7.16-7.06 (m, 3H), 6.93 (d, J=8.0 Hz, 2H), 6.84 (d, J=7.6 Hz, 1H), 6.73-6.70 (m, 3H), 6.09 (d, J=8.0 Hz, 1H), 3.92-3.89 (m, 1H), 3.84-3.71 (m, 2H), 3.14-2.92 (m, 3H), 2.86-2.81 (m, 1H), 2.54-2.43 (m, 1H), 2.24-2.13 (m, 3H), 1.15 (s, 36H); ³¹P

      NMR (162 mhz, cdcl ₃) δ −19.06 (s); ¹³C NMR (100 mhz, cdcl ₃) δ 158.5, 154.0, 151.7, 151.5, 149.0 (d, J=6.7 Hz), 148.7 (d, J=5.8 Hz), 143.3 (d, J=2.7 Hz), 143.0 (d, J=3.2 Hz), 142.8 (d, J=7.4 Hz), 137.3, 137.2, 136.7, 136.1, 134.8, 134.7, 133.9, 133.7, 133.6, 132.9, 131.4 (d, J=3.5 Hz), 127.6, 127.2, 127.1, 127.0, 126.9 (d, J=7.6 Hz), 126.7, 125.9, 124.8, 121.4, 120.3, 118.2, 116.8, 113.0, 107.8, 60.6 (d, J=3.2 Hz), 48.1, 37.7 (d, J=3.7 Hz), 34.7, 33.7, 33.6, 30.3 (d, J=6.0 Hz), 30.1, 29.8. HRMS (ESI) calcd for c ₅₇h ₆₆cln ₂p[M+H] ⁺: 845.4725. Found: 845.4729.

      
(MOL) (CDX)

      Specific process can be found in Example 1, and white solid was obtained with a yield of 96%.

      Mp 160-161° C., [α] _D ²⁰ +213 (c 0.5, CH ₂Cl ₂), ¹H NMR (400 mhz, cdcl ₃) δ 7.85 (d, J=4.4 Hz, 1H), 7.37 (d, J=7.2 Hz, 1H), 7.28-7.26 (m, 1H), 7.23-7.12 (m, 4H), 7.06-7.03 (m, 1H), 6.92-6.89 (m, 1H), 6.77 (d, J=7.6 Hz, 2H), 6.69-6.66 (m, 3H), 6.27 (d, J=8 Hz, 1H), 5.48 (d, J=5.6 Hz, 1H), 4.07 (dd, J=6, 16 Hz, 1H), 3.47 (d, J=16 Hz, 1H), 3.08-2.93 (m, 3H), 2.81-2.75 (m, 1H), 2.49-2.41 (m, 1H), 2.19-2.06 (m, 6H), 1.15 (s, 18H), 0.95 (s, 18H); ³¹P NMR (162 mhz, cdcl ₃) δ −17.55 (s); ¹³C NMR (100 mhz, cdcl ₃) δ 153.5, 151.4, 151.2, 148.7 (d, J=6 Hz), 148.4 (d, J=6.3 Hz), 144.5, 143.3, 143.2, 143.1, 137.4, 137.3, 135.7, 135.5, 133.7, 133.5, 132.5, 131.5 (d, J=3.5 Hz), 128.7, 127.2, 127.0 (d, J=5.5 Hz), 126.7, 125.5, 124.3, 120.4, 120.3, 120.1, 111.9, 106.7, 60.6 (d, J=3.2 Hz), 44.0, 37.7 (d, J=3.3 Hz), 34.9, 33.6, 33.4, 30.3, 30.1, 29.9, 16.2. HRMS (ESI) calcd for C ₅₂H ₆₅N ₂P[M+H] ⁺: 749.4958. Found: 749.4959.

      
(MOL) (CDX)

      Specific process can be found in Example 1, and white solid was obtained with a yield of 95%.

      Mp 86-88° C., [α] _D ²⁰ +204 (c 1.0, CH ₂Cl ₂), ¹H NMR (400 mhz, cdcl ₃) δ 8.14 (d, J=5.2 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.22-7.18 (m, 3H), 7.12-7.08 (m, 2H), 6.99 (d, J=5.2 Hz, 1H), 6.93 (brs, 1H), 6.82 (d, J=8 Hz, 2H), 6.73 (d, J=7.6 Hz, 2H), 6.69 (d, J=7.2 Hz, 1H), 6.15 (d, J=7.6 Hz, 1H), 4.40-4.39 (m, 1H), 4.03-3.97 (m, 1H), 3.54-3.58 (m, 1H), 3.14-2.91 (m, 3H), 2.86-2.80 (m, 1H), 2.52-2.44 (m, 1H), 2.20-2.09 (m, 3H), 1.19 (s, 9H), 1.15 (s, 18H), 1.05 (s, 18H); ³¹P NMR (162 mhz, cdcl ₃) δ −18.55 (s); ¹³C NMR (100 mhz, cdcl ₃) δ 158.8, 156.9, 151.7, 151.4, 148.7 (d, J=6.2 Hz), 147.5, 143.1, 143.0, 142.9 (d, J=11.8 Hz), 134.0 (d, J=12.4 Hz), 133.7, 133.5, 132.8, 131.8 (d, J=3.5 Hz), 127.2, 127.0 (d, J=5.4 Hz), 126.8 (d, J=4.4 Hz), 125.8, 124.7, 121.0, 120.2, 117.6, 116.6, 127.7, 107.6, 60.6 (d, J=3.3 Hz), 47.1, 37.7 (d, J=3.6 Hz), 34.7, 33.7, 33.6, 33.5, 30.3, 30.2, 29.8, 29.4. HRMS (ESI) calcd for C ₅₅H ₇₁N ₂P[M+H] ⁺: 791.5428. Found: 791.5430.

      
(MOL) (CDX)

      Under the protection of nitrogen atmosphere, 0.5 mg (0.74 gmol) [Ir(COD)]Cl ₂, 1.2 mg (1.6 μmol) (R)-Ii were added to the inner hydrogenation tube. Subsequently, 1 ml absolute ethyl alcohol was added and stirred for 1 h at room temperature. The inner reaction tube was placed into the hydrogenation reactor. After substitution by hydrogen, the reaction was stirred for 1 h at a hydrogen pressure of 1 atmosphere. The reactor was opened, and 7.5-150 mmol substrate (solid substrate, added after dissolved by ethanol) was added, followed by 0.05-25 mmol potassium tert-butoxide solution in ethanol (0.5 ml (0.1 mmol/mL)-25 ml (1 mmol/mL)) added with a syringe. The reactor was sealed, and hydrogen was filled to a pressure of 8-10 atm, and the reaction was stirred under the hydrogen pressure at room temperature for a while ranging from 10 minutes to 24 hours. After the hydrogenation was finished, the reaction solution was filtered through a short silica gel column to remove the catalyst, and the conversion rate and yield of the reaction were analyzed by gas chromatography or nuclear magnetic resonance (NMR); and the optical purity of the product was analyzed by gas chromatography or high performance liquid chromatography. The results of the hydrogenation experiments were listed in Table 1.

      

      The chiral spiro-pyridylamidophosphine ligand compound provided herein, the synthesis method and its application have been described by examples, and it is apparent that modification, or appropriate change and combination can be made to the chiral spiro-pyridylamidophosphine ligand compounds described herein, the synthesis method and its application by those skilled in the art, without departing from the contents, spirit and scope of the present invention, in order to achieve the present invention. In particular, it should be pointed out that all similar replacements and modifications become apparent to those skilled in the art, and they are deemed to be within the spirit, scope and contents of the present invention.