A chiral spirocyclic monophosphine-oxazoline ligand and preparation method thereof

Abstract

The present invention provides a chiral spirocyclic monophosphine-oxazoline ligand, an intermediate thereof and a preparation method thereof. The structural compounds are respectively the following formula 1, formula 2 and formula 3, including racemates and optical isomers thereof, wherein m and n are integers of 0 to 3; X is CR 1’ R 2’ NR 1’ , O or S; R 1 and R 2 Each is independently hydrogen, alkyl, phenyl, 1-naphthyl, 2-naphthyl, alkoxy, or alkyl substituted with an ester group; R is hydrogen, alkyl, substituted phenyl, substituted alkyl, alkoxy, phenyl, 1-naphthyl, 2-naphthyl, halogen, cyano, carboxyl, or hydroxyl; R 2 is hydrogen, alkyl, phenyl, 1-naphthyl, 2-naphthyl, alkyl-substituted phenyl; M' is P(O)(R 3 )2 or P(R 3 )2; R 3 is alkyl, phenyl, 1-naphthyl, 2-naphthyl, substituted phenyl, furyl, thienyl; M is OTf, COOH or COOR 5 ; OTf represents trifluoromethanesulfonate, R 5 It is an alkyl group.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a chiral spirocyclic monophosphine-oxazoline ligand, an intermediate thereof and a preparation method thereof. Background Art

[0002] Asymmetric catalytic reaction is a research hotspot in the field of organic synthesis, and asymmetric catalytic hydrogenation is a research hotspot in the field of asymmetric catalytic synthesis. Asymmetric catalytic hydrogenation has the characteristics of perfect atom economy, cleanliness and high efficiency, and is one of the most popular asymmetric synthesis methods.

[0003] In the early 1960s, people did not know whether catalytic asymmetric hydrogenation was feasible. Whether an excess of a certain enantiomer could be produced by catalytic asymmetric reaction was confirmed by William S. Knowles. William S. Knowles' experiment was based on the compound with the structure shown in formula A published by Osborn and Wilkinson in 1966.

[0004]

[0005] The chiral phosphine synthesized with Horner and Mislow has the structure shown in formula B

[0006]

[0007] Based on. After analyzing and comparing the previous achievements, William S. Knowles proposed his own hypothesis. He speculated that if the triphenylphosphine in Osborn and Wilkinson's metal complex (Ph3P)3RhCl was replaced by an isomer of the chiral phosphide enantiomer, it might be possible to produce a chiral structure catalyst made of transition metals that can achieve asymmetric synthesis. At first, William S. Knowles replaced the triphenylphosphine in Wilkinson's catalyst with (-)-methyl n-propylphenylphosphine, and used it as a catalyst to catalyze the hydrogenation of α-phenylacrylic acid, obtaining a hydrogenation product with an enantiomeric excess of 15%. This important scientific breakthrough was reported in the journal Chem Commun, 1968: 1445 published by William S. Knowles et al. in 1968.

[0008] Although the enantiomeric excess is still low compared to the current level, it is a breakthrough in this direction. In the process of improving the catalytic efficiency of the catalyst, William S. Knowles and his collaborators finally prepared a suitable catalyst that can generate more ratios of beneficial isomers through repeated experiments on various phosphine enantiomers with different structures. They used [Rh((R,R)-DiPAMP)COD] + BF- 4 is a catalyst, starting from the achiral enamine, through a one-step catalytic asymmetric hydrogenation reaction and a one-step simple acid hydrolysis reaction, L-Dopa (an effective drug for the treatment of Parkinson's syndrome) with the following structural formula is obtained:

[0009]

[0010] Thus, the key step of industrial preparation of L-Dopa was solved. The route was reported in the journal Acc Chenm Res. 1983, 6: 106 published by William S. Knowles in 1983. The specific synthetic route is as follows:

[0011]

[0012] This synthetic route was put into production in 1974 and was the first commercial drug synthesized through catalytic asymmetric reaction.

[0013] In 1980, Ryoji Noyori, another pioneer in catalytic asymmetric hydrogenation, and his collaborators discovered a chiral bisphosphine ligand with the structural formula BINAP.

[0014]

[0015] The complexes of any of the enantiomers with rhodium have significantly stronger activity than other catalysts for catalyzing asymmetric hydrogenation reactions.

[0016] His greatest contribution was the introduction of BINAP-Ru complexes into catalytic asymmetric hydrogenation reactions. These chiral ruthenium complexes can be used to stereoselectively catalyze the hydrogenation of a series of unsaturated carboxylic acids. Its stereoselectivity is much higher than that of rhodium catalysts. In addition, the halogen-containing BINAP-Ru complex catalyst catalyzes the hydrogenation of β-ketoesters (enantiomeric excess reaches 100%), and the results are even better than many biocatalysts. This provides a powerful choice for organic chemists to design synthetic routes.

[0017] Due to the high efficiency of this series of catalysts, the ratio can reach 1:10 in some reactions. 6efficiency. It makes the reaction process more economical, and also greatly reduces the generation of hazardous waste, which is beneficial to environmental protection. In addition, the corresponding enantiomer of BINAP can be conveniently selected according to needs, and it is suitable for high-concentration (reactant concentration can reach 50%) organic solutions, which is of great significance to the production of medicines, pesticides and spices. Since the early 1980s, Japan's Takasago Company has used this series of catalysts to produce L-menthol. In addition, (R)-1,2-propylene glycol (a chiral intermediate for the synthesis of the antibacterial drug Levofloxacin) and azetidinone (a chiral intermediate for the synthesis of the antibiotic Carbapenem) can be put into industrial production, which is also a masterpiece of this series of catalysts.

[0018] In the field of asymmetric catalytic hydrogenation, although many chiral ligands and catalysts have been reported, overall, there are still few catalyst systems used in the asymmetric hydrogenation of unsaturated carboxylic acid compounds. In view of the choice of multiple process routes in industrial production, it is necessary to develop other, more, efficient and highly selective chiral ligands and catalysts that can be applied to the asymmetric hydrogenation of unsaturated carboxylic acid compounds for selection in industrial production. Summary of the invention

[0019] The present invention provides a chiral spirocyclic monophosphine-oxazoline ligand, an intermediate thereof and a preparation method thereof. Finally, the prepared chiral spirocyclic monophosphine-oxazoline ligand has a high yield and optical purity, and a new intermediate is obtained. This not only reflects the novelty of the preparation method of the present invention, but also the high-purity product proves that the present invention has a significant technical effect.

[0020] In order to achieve the technical purpose of the present invention, the present invention provides the following technical solutions:

[0021] The first aspect of the present invention provides a chiral spirocyclic monophosphine-oxazoline ligand having the structure of the following formula 1:

[0022]

[0023] Including its racemate and optical isomers, among which,

[0024] m, n are each independently an integer of 0, 1, 2 or 3;

[0025] X is CR 1’ R 2’ NR 1’ , O or S; R 1’ and R 2’Each is independently hydrogen, C1-C8 alkyl, phenyl, 1-naphthyl, 2-naphthyl, C1-C8 alkoxy, C1-C8 alkyl substituted with 1-3 C2-C9 ester groups; R is hydrogen, C1-C8 alkyl, C1-C8 alkoxy, phenyl, phenyl substituted with 1-5 C1-C8 alkyl, phenyl substituted with 1-5 C1-C8 alkoxy, phenyl substituted with 1-5 phenyl, 1-naphthyl, 2-naphthyl, fluoro , chloro, bromo, iodo, cyano, carboxyl, hydroxyl, C1-C8 alkyl substituted by 1-3 fluorine groups, C1-C8 alkyl substituted by 1-3 chlorine groups, C1-C8 alkyl substituted by 1-3 bromine groups, C1-C8 alkyl substituted by 1-3 iodine groups, C1-C8 alkyl substituted by 1-3 hydroxyl groups, C1-C8 alkyl substituted by 1-3 carboxyl groups, C1-C8 alkyl substituted by 1-3 C2-C9 ester groups; R 2 R is hydrogen, C1-C8 alkyl, phenyl, 1-naphthyl, 2-naphthyl, or phenyl substituted by 1 to 5 C1-C8 alkyl groups; 3 is C1-C8 alkyl, phenyl, 1-naphthyl, 2-naphthyl, phenyl substituted by 1-5 C1-C8 alkoxy groups, phenyl substituted by 1-5 halogen groups, phenyl substituted by 1-5 amino groups, phenyl substituted by (C1-C8 acyl)-amino, phenyl substituted by di(C1-C8 alkyl)amino, phenyl substituted by 1-5 hydroxyl groups, phenyl substituted by 1-5 sulfonic acid groups, phenyl substituted by 1-5 C1-C8 acyl groups, phenyl substituted by 1-5 C1-C8 alkyl groups, phenyl substituted by 1-5 C2-C9 ester groups, furyl, thienyl;

[0026] The C1-C8 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, n-heptyl, isoheptyl, neoheptyl, sec-heptyl, tert-heptyl, n-octyl, isooctyl, neooctyl, sec-octyl, tert-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane; preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, iso ... Preferably, the group is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane; more preferably, the group is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octyl, cyclopropane, cyclobutane, and cyclopentane; more preferably, the group is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and cyclopropane; particularly preferably, the group is methyl, isopropyl, and tert-butyl; most preferably, the group is methyl.

[0027] The C1-C8 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, n-pentoxy, isopentoxy, neopentoxy, sec-pentoxy, tert-pentoxy, cyclopentoxy, n-hexoxy, isohexoxy, neohexoxy, sec-hexoxy, tert-hexoxy, cyclohexoxy, n-heptoxy, isoheptoxy, neoheptoxy, sec-heptoxy, tert-heptoxy, cycloheptoxy, n-octoxy, isooctoxy, neo-octoxy, sec-octoxy, tert-octoxy, or cyclooctoxy; preferably methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, Preferably, the methoxy group is selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, tert-butoxy, cyclobutoxy, n-pentoxy, cyclopentoxy, n-hexoxy, tert-butoxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, tert-butoxy, cyclobutoxy, n-pentoxy, cyclopentoxy, n-hexoxy, cyclohexyloxy and n-heptoxy; more preferably, the methoxy group is selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy; particularly preferably, the methoxy group and ethoxy group are selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

[0028] The C2-C9 ester group is methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, cyclopropyloxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclobutyloxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, sec-pentyloxycarbonyl, tert-pentyloxycarbonyl, cyclopentyloxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl, neohexyloxycarbonyl, sec-hexyloxycarbonyl oxycarbonyl, tert-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, isoheptyloxycarbonyl, neoheptyloxycarbonyl, sec-heptyloxycarbonyl, tert-heptyloxycarbonyl, cycloheptyloxycarbonyl, n-octyloxycarbonyl, isooctyloxycarbonyl, neo-octyloxycarbonyl, sec-octyloxycarbonyl, tert-octyloxycarbonyl, cyclooctyloxycarbonyl; preferably methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, cyclopropyloxycarbonyl, n-butyloxycarbonyl , isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclobutoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, sec-pentyloxycarbonyl, tert-pentyloxycarbonyl, cyclopentyloxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl, neohexyloxycarbonyl, sec-hexyloxycarbonyl, tert-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, isohexyloxycarbonyl, neohexyloxycarbonyl, sec-heptyloxycarbonyl, tert-heptyloxycarbonyl; preferably methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, cyclopropyloxycarbonyl, isopropyloxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, cyclobutoxycarbonyl, n-pentyloxycarbonyl, cyclopentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl; more preferably methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, n-propyloxycarbonyl; most preferably methoxycarbonyl and ethoxycarbonyl.

[0029] The C1-C8 acyl group is formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, secondary valeryl, pivaloyl, n-hexanoyl, isohexanoyl, neohexanoyl, secondary hexanoyl, n-heptanoyl, isoheptanoyl, neoheptanoyl, secondary heptanoyl, n-octanoyl, isooctanoyl, neooctanoyl, secondary octanoyl, 1-cyclopropylformyl, 1-cyclobutylformyl, 1-cyclopentylformyl, 1-cyclohexylformyl, 1-cycloheptylformyl; preferably formyl, acetyl, propionyl, , n-butyryl, isobutyryl, n-valeryl, n-hexanoyl, n-heptanoyl, n-octanoyl, 1-cyclopropylformyl, 1-cyclobutylformyl, 1-cyclopentylformyl, 1-cyclohexylformyl, 1-cycloheptylformyl; preferably formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, 1-cyclopropylformyl, 1-cyclobutylformyl, 1-cyclopentylformyl; more preferably formyl, acetyl, propionyl, 1-cyclopropylformyl, 1-cyclobutylformyl, 1-cyclopentylformyl; more preferably formyl, acetyl, propionyl, 1-cyclopropylformyl; most preferably formyl and acetyl.

[0030] Preferably, the chiral spirocyclic monophosphine-oxazoline ligand of the above formula 1 can be a compound of the following formula 1':

[0031]

[0032] Among them, m, n, X, R, R 3 , R 2 The definition is the same as above, connect R 2 With oxazoline ring Key is key or key.

[0033] Preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand of the above formula 1 can be:

[0034]

[0035] Among them, R 3 , R 2 The definition is the same as above, connect R 2 With oxazoline ring Key is key or key.

[0036] More preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand of the above formula 1 is:

[0037]

[0038] Among them, R 3 , R 2 The definition is the same as above, connect R 2 With oxazoline ring Key is key or key.

[0039] Particularly preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand of the above formula 1 is:

[0040]

[0041] Among them, R 3 , R 2 Same definition as above.

[0042] Particularly preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand of the above formula 1 is:

[0043]

[0044]

[0045]

[0046]

[0047] Most preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand of the above formula 1 is:

[0048]

[0049]

[0050] The second aspect of the present invention provides a chiral spirocyclic monophosphine-oxazoline ligand intermediate having the structure of Formula 2,

[0051]

[0052] Including its racemate and optical isomers, among which,

[0053] Among them, m, n, X, R, R 3 , R 2 Same definition as above.

[0054] Preferably, the chiral spirocyclic monophosphine-oxazoline ligand intermediate of the above formula 2 can be a compound of the following formula 2':

[0055]

[0056] Among them, m, n, X, R, R 3 , R 2 The definition is the same as above, connect R 2 With amide alcohol Key is key or key.

[0057] Preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand intermediate of the above formula 2 can be:

[0058]

[0059] Among them, R 3 , R 2 The definition is the same as above, connect R 2 With amide alcohol Key is key or key.

[0060] More preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand intermediate of the above formula 2 is:

[0061]

[0062] Among them, R 3 , R 2 The definition is the same as above, connect R 2 With amide alcohol Key is key or key.

[0063] Particularly preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand intermediate of the above formula 2 is:

[0064]

[0065] Among them, R 3 , R 2 Same definition as above.

[0066] Particularly preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand intermediate of the above formula 2 is:

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074] Most preferably, the specific structure of the chiral spirocyclic monophosphine-oxazoline ligand intermediate of the above formula 2 is:

[0075]

[0076] The third aspect of the present invention provides an intermediate of the following formula 3:

[0077]

[0078] Including its racemate and optical isomer, wherein m, n, R, X are as defined above, M is OTf, COOH or COOR 5 ,M' is P(O)(R 3 )2 or P(R 3 )2; R 5 is a C1-C8 alkyl group, R 3 The definition of is the same as above, OTf represents trifluoromethanesulfonyl group; the definition of the C1-C8 alkyl group is the same as above.

[0079] Preferably, the intermediate of the above formula 3 can be a compound of the following formula 3-1, formula 3-2, formula 3-3, formula 3-4:

[0080]

[0081] Including its racemate and optical isomers, wherein m, n, R, X, OTf, R 3 , R 5 Same definition as above.

[0082] Preferably, the intermediate of the above formula 3 can be a compound of the following formula 3'-1, formula 3'-2, formula 3'-3, formula 3'-4:

[0083]

[0084] Among them, m, n, R, X, OTf, R 3 , R 5 Same definition as above.

[0085] More preferably, the intermediate of the above-mentioned formula 3'-1 structure can be:

[0086]

[0087] Among them, OTf, R 3 is as defined above;

[0088] The intermediate of the above formula 3'-2 structure can be:

[0089]

[0090] Among them, OTf, R 3 is as defined above;

[0091] The intermediate of the above formula 3'-3 structure can be:

[0092]

[0093] Among them, R 3 is as defined above;

[0094] The intermediate of the above formula 3'-4 structure can be:

[0095]

[0096] Among them, R 3 is as defined above;

[0097] Particularly preferably, the intermediate of the above-mentioned formula 3'-1 structure can be:

[0098]

[0099]

[0100] Wherein, the definition of OTf is the same as above;

[0101] The intermediate of the above formula 3'-2 structure can be:

[0102]

[0103] Wherein, the definition of OTf is the same as above;

[0104] The intermediate of the above formula 3'-3 structure can be:

[0105]

[0106]

[0107] The intermediate of the above formula 3'-4 structure can be:

[0108]

[0109] Most preferably, the intermediate of the above formula 3'-1 structure can be:

[0110]

[0111]

[0112] Wherein, the definition of OTf is the same as above;

[0113] The intermediate of the above formula 3'-2 structure can be:

[0114]

[0115] Wherein, the definition of OTf is the same as above;

[0116] The intermediate of the above formula 3'-3 structure can be:

[0117]

[0118] The intermediate of the above formula 3'-4 structure can be:

[0119]

[0120]

[0121] The fourth aspect of the present invention provides a method for preparing the chiral spirocyclic monophosphine-oxazoline ligand of the above-mentioned formula 1.

[0122] The chiral spirocyclic monophosphine-oxazoline ligand of the above formula 1 is prepared from the intermediate of the formula 2 by a cyclization reaction. The specific reaction formula is as follows:

[0123]

[0124] Including its racemates and optical isomers, wherein m, n, X, R, R 3 , R 2 is as defined above;

[0125] Preferably, the above reaction can be:

[0126]

[0127] Among them, m, n, X, R, R 3 , R 2 The definition is the same as above, connect R 2 With amide alcohol or connected R 2 With oxazoline ring Key is key or key.

[0128] Preferably, the above reaction can be:

[0129]

[0130]

[0131] Among them, R 3 , R 2 The definition is the same as above, connect R 2 With amide alcohol or connected R 2 With oxazoline ring Key is key or key.

[0132] More preferably, the above reaction can be:

[0133]

[0134] Among them, R 3 , R 2 The definition is the same as above, connect R 2 With amide alcohol or connected R 2 With oxazoline ring Key is key or key.

[0135] Particularly preferably, the above reaction can be:

[0136]

[0137] Among them, R 3 , R 2 Same definition as above.

[0138] Particularly preferably, the above reaction can be:

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145] Most preferably, the above reaction can be:

[0146]

[0147]

[0148] Furthermore, the amide alcohol of the above formula 2 can be prepared by the acid-amine condensation reaction of the intermediate of the formula 3-4 and the 2-substituted aminoethanol of the formula 4:

[0149]

[0150] Including its racemate and optical isomers, wherein m, n, R, X, R 2 , R 3 is as defined above;

[0151] Preferably, the above reaction can be:

[0152]

[0153] Among them, m, n, R, X, R 2 , R 3 Same definition as above for connection R 2 With amide alcohol or connected R 2 With oxazoline ring Key is key or key.

[0154] Preferably, the above reaction can be:

[0155]

[0156] Among them, R 2 , R 3 The definition is the same as above, connect R 2 With amide alcohol Key is key or key.

[0157] More preferably, the above reaction can be:

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165] Most preferably, the above reaction can be:

[0166]

[0167]

[0168] Furthermore, the intermediate of the above-mentioned formula 3-4 can be prepared by hydrolyzing the intermediate of the formula 3-3 under alkaline conditions:

[0169]

[0170] Including its racemate and optical isomers, wherein m, n, R, X, R 5 , R 3 is as defined above;

[0171] Preferably, the above reaction can be:

[0172]

[0173] Among them, m, n, R, X, R 5 , R 3 is as defined above;

[0174] Preferably, the above reaction can be:

[0175]

[0176] Among them, R 3 is as defined above;

[0177] More preferably, the above reaction can be:

[0178]

[0179]

[0180] Most preferably, the above reaction can be:

[0181]

[0182] Furthermore, the intermediate of the above-mentioned formula 3-3 can be prepared by esterification reaction of the intermediate of the formula 3-2 under the catalysis of a palladium reagent:

[0183]

[0184] Including its racemate and optical isomers, wherein m, n, R, X, OTf, R 3 , R 5 is as defined above;

[0185] Preferably, the above reaction can be:

[0186]

[0187] Among them, m, n, R, X, OTf, R 3 , R 5 is as defined above;

[0188] Preferably, the above reaction can be:

[0189]

[0190] Among them, OTf, R 3 is as defined above;

[0191] More preferably, the above reaction can be:

[0192]

[0193]

[0194] Most preferably, the above reaction can be:

[0195]

[0196] Furthermore, the intermediate of the above-mentioned formula 3-2 can be prepared by reducing the intermediate of the formula 3-1 under the action of trichlorosilane:

[0197]

[0198] Including its racemate and optical isomers, wherein m, n, R, X, OTf, R 3 is as defined above;

[0199] Preferably, the above reaction can be:

[0200]

[0201] Among them, m, n, R, X, OTf, R 3 is as defined above;

[0202] Preferably, the above reaction can be:

[0203]

[0204] Among them, R 3 is as defined above;

[0205] More preferably, the above reaction can be:

[0206]

[0207]

[0208] Most preferably, the above reaction can be:

[0209]

[0210]

[0211] The present invention also provides a method for preparing a chiral spirocyclic monophosphine-oxazoline ligand of the following formula 1, wherein a chiral spirocyclic diphenol of the formula 6 is used as a starting material, and after undergoing an esterification reaction with trifluoromethanesulfonic anhydride, a coupling reaction under the catalysis of a palladium reagent, a reduction reaction under the action of trichlorosilane, an esterification reaction under the catalysis of a palladium reagent, and a hydrolysis reaction under alkaline conditions, the ligand is further subjected to an acid-amine condensation reaction with aminoethanol of the formula 4 substituted at the 2 position to obtain an amide alcohol of the formula 2, and finally a ring-forming reaction is performed to obtain the amide alcohol, and the reaction formula is:

[0212]

[0213] Wherein, OTf is trifluoromethanesulfonate; R 3 Selected from

[0214]

[0215] or Preferably R 2 Selected from Preferably Connect R 2 With amide alcohol or connected R 2 With oxazoline ring Key is key or key.

[0216] Most preferably, the preparation method of the compound of formula 1 is:

[0217]

[0218] The present invention provides a chiral spirocyclic monophosphine-oxazoline ligand, an intermediate thereof and a preparation method thereof. The chiral spirocyclic monophosphine-oxazoline ligand finally prepared by the preparation method provided by the present invention has a high yield and purity, and a new intermediate is obtained. These indicate that the preparation method of the chiral spirocyclic monophosphine-oxazoline ligand of the present invention is a route with industrial advantages. DETAILED DESCRIPTION

[0219] In order to further understand the present invention, the preparation method of the chiral spirocyclic monophosphine-oxazoline ligand provided by the present invention is described in detail below in conjunction with the examples. It should be understood that these examples are only for further describing the features of the present invention in detail, rather than limiting the scope of the present invention or the scope of the claims of the present invention.

[0220] General Notes:

[0221] The following abbreviations are used in the examples and their meanings are as follows:

[0222] Tf2O is trifluoromethanesulfonic anhydride, Py is pyridine, OTf is trifluoromethanesulfonate, dppb is 4-diphenylphosphinobutane, DIPEA is diisopropylethylamine, Xyl is 3,5-dimethylphenyl, DTB is 3,5-di-tert-butylphenyl, dppp is 1,3-diphenylphosphinopropane, DMSO is dimethyl sulfoxide, TLC is thin layer chromatography, HOBt is 1-hydroxybenzotriazole, DCC is N,N'-dicyclohexylcarbodiimide, Ph is phenyl, Bn is benzyl, DMAP is 4-lutidine, MsCl is methanesulfonyl chloride, NMR is nuclear magnetic resonance, ee is enantiomeric excess, and HPLC is high performance liquid chromatography.

[0223] The solvents used were purified and dried by standard operations before use; the reagents used were commercially available or synthesized according to existing literature methods and purified before use.

[0224] Example 1: Preparation of Compound 5

[0225]

[0226] Add (S,S,S)-6 (17.5 g, 60 mmol), pyridine (14.1 mL, 175.0 mmol) and 200 mL of freshly distilled CH2Cl2 to a 500 mL reaction bottle, add trifluoromethanesulfonic anhydride (25.5 mL, 150 mmol) dropwise at 0°C, stir overnight at room temperature after the addition is complete. Add dilute hydrochloric acid to quench the reaction, adjust the pH of the aqueous phase to 6-7, and extract with CH2Cl2. The organic phase is washed with saturated NaHCO3 solution and saturated brine in turn, and dried over anhydrous sodium sulfate. After the filtrate is concentrated, 32.0 g of light yellow solid is obtained by chromatography on a silica gel column (eluent: n-hexane / ethyl acetate = 10 / 1), with a yield of 96%.

[0227] Example 2: Compound 3-1 (R 3 Preparation of

[0228]

[0229] Add the bistrifluoromethanesulfonate 5 (15.0 g, 27.0 mmol), diphenylphosphine oxide (7.0 g, 35.0 mmol), palladium acetate (303 mg, 1.35 mmol), 1,4-diphenylphosphinobutane (dppb, 576 mg, 1.35 mmol) and 70 mL of anhydrous DMSO to a 250 mL reaction bottle. Add diisopropylethylamine (19 mL, 108.0 mmol) under stirring, heat to 100 ° C and react for 6 hours. Cool to room temperature, add EtOAc / water to dilute, filter, remove the solvent from the filtrate and chromatograph on a silica gel column (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 15.0 g, yield 91%; light yellow solid.

[0230] Example 3: Compound 3-1 (R 3 Preparation of

[0231]

[0232] Add the bistrifluoromethanesulfonate 5 (15.0 g, 27.0 mmol) of the spirocyclic compound, di(3,5-dimethylphenyl)phosphine oxide (9.0 g, 35.0 mmol), palladium acetate (303 mg, 1.35 mmol), 1,4-diphenylphosphinobutane (dppb, 576 mg, 1.35 mmol) and 70 mL of anhydrous DMSO to a 250 mL reaction bottle. Add diisopropylethylamine (19 mL, 108.0 mmol) under stirring, heat to 100 ° C and react for 6 hours. Cool to room temperature, add EtOAc / water to dilute, filter, remove the solvent from the filtrate and chromatograph on a silica gel column (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 15.4 g, yield 86%; light yellow solid.

[0233] Example 4: Compound 3-1 (R 3 = Preparation of DTB

[0234]

[0235] Add the bistrifluoromethanesulfonate 5 (15.0 g, 27.0 mmol) of the spirocyclic compound, di(3,5-tert-butylphenyl)phosphine oxide (14.9 g, 35.0 mmol), palladium acetate (303 mg, 1.35 mmol), 1,4-diphenylphosphinobutane (dppb, 576 mg, 1.35 mmol) and 70 mL of anhydrous DMSO to a 250 mL reaction bottle. Add diisopropylethylamine (19 mL, 108.0 mmol) under stirring, heat to 100 ° C and react for 6 hours. Cool to room temperature, add EtOAc / water to dilute, filter, remove the solvent from the filtrate and chromatograph on a silica gel column (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 26.8 g, yield 92%; light yellow solid.

[0236] Example 5: Compound 3-2 (R 3 Preparation of

[0237]

[0238]

[0239] In a 250 mL reaction flask, add the monophosphine oxide 3-1 (R 3 =Ph) (15.0g, 25.0mmol) and 80mL of anhydrous toluene. Under the protection of inert gas, add diisopropylethylamine (19mL, 108.0mmol) and trichlorosilane (7.8mL, 75mmol) with stirring, heat to 100℃ in an oil bath and react for 6 hours. Cool to room temperature, add EtOAc to dilute, add 12M sodium hydroxide solution (5mL) dropwise, filter, remove the solvent from the filtrate and chromatograph on a silica gel column (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 11.9g, yield: 80%; white solid.

[0240] Example 6: Compound 3-2 (R 3 Preparation of

[0241] In a 250 mL reaction flask, add the monophosphine oxide 3-1 (R 3 =Xyl) (16.6 g, 25.0 mmol) and 100 mL of anhydrous toluene. Under the protection of inert gas, diisopropylethylamine (19 mL, 108.0 mmol) and trichlorosilane (7.8 mL, 75 mmol) were added with stirring, and the oil bath was heated to 100°C for 6 hours. Cooled to room temperature, EtOAc was added to dilute, 12 M sodium hydroxide solution (5 mL) was added dropwise, filtered, and the filtrate was stripped of solvent and chromatographed on a silica gel column (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 14.3 g, yield: 88%; white solid.

[0242] Example 7: Compound 3-2 (R 3 = Preparation of DTB

[0243]

[0244] In a 250 mL reaction flask, add the monophosphine oxide 3-1 (R 3=DTB) (16.6 g, 25.0 mmol) and 100 mL of anhydrous toluene. Under the protection of inert gas, add diisopropylethylamine (19 mL, 108.0 mmol) and trichlorosilane (7.8 mL, 75 mmol) with stirring, heat to 100 ° C in an oil bath and react for 6 hours. Cool to room temperature, add EtOAc to dilute, add 12M sodium hydroxide solution (5 mL) dropwise, filter, remove the solvent from the filtrate, and chromatograph on a silica gel column (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 18.8 g, yield: 92%; white solid.

[0245] Example 8: Compound 3-3 (R 3 Preparation of

[0246]

[0247] Add compound 3-3 (R) into a 500 mL two-necked bottle. 3 =Ph)(10.0g, 16.9mmol), palladium acetate (584mg, 2.6mmol) and 1,3-diphenylphosphinopropane (dppp, 1073mg, 2.6mmol), equipped with a reflux condenser, a suction head and a reverse stopper, and the system was replaced with a CO atmosphere. Methanol (60mL), DMSO (150mL) and triethylamine (50mL) were added and stirred to mix evenly. The oil bath was heated to 80°C for 24 hours, and TLC tracking was performed until the reaction was complete. The system was replaced with a nitrogen atmosphere and the solvent was removed by concentration under reduced pressure. Dichloromethane was added to the residual reaction solution to dilute it, and silica gel was added to mix the sample and concentrate it, and then dry-type column chromatography (eluent: n-hexane / ethyl acetate = 20 / 1) was performed to obtain 7.3g of a yellow solid with a yield of 86%.

[0248] Example 9: Compound 3-3 (R 3 Preparation of

[0249]

[0250] Add compound 3-2 (R) into a 500 mL two-necked bottle. 3=Xyl)(11.0g, 16.9mmol), palladium acetate (584mg, 2.6mmol) and 1,3-diphenylphosphinopropane (dppp, 1073mg, 2.6mmol), equipped with a reflux condenser, a suction head and a reverse stopper, and the system was replaced with a CO atmosphere. Methanol (60mL), DMSO (150mL) and triethylamine (50mL) were added and stirred to mix evenly. The oil bath was heated to 80°C for 24 hours, and TLC tracking was performed until the reaction was complete. The system was replaced with a nitrogen atmosphere and the solvent was removed by concentration under reduced pressure. Dichloromethane was added to the residual reaction solution to dilute it, and silica gel was added to mix the sample and concentrate it, and then dry-type column chromatography (eluent: n-hexane / ethyl acetate = 20 / 1) was performed to obtain 8.3g of a yellow solid with a yield of 88%.

[0251] Example 10: Compound 3-3 (R 3 = Preparation of DTB

[0252]

[0253] Add compound 3-2 (R) into a 500 mL two-necked bottle. 3 =DTB) (13.8g, 16.9mmol), palladium acetate (584mg, 2.6mmol) and 1,3-diphenylphosphinopropane (dppp, 1073mg, 2.6mmol), equipped with a reflux condenser, a suction head and a reverse stopper, and the system was replaced with a CO atmosphere. Methanol (60mL), DMSO (150mL) and triethylamine (50mL) were added and stirred to mix evenly. The oil bath was heated to 80°C for 24 hours, and TLC tracking was performed until the reaction was complete. The system was replaced with a nitrogen atmosphere and the solvent was removed by concentration under reduced pressure. Dichloromethane was added to the residual reaction solution to dilute it, and silica gel was added to mix the sample and concentrate it, and then dry-type column chromatography (eluent: n-hexane / ethyl acetate = 20 / 1) was performed to obtain 11.0g of a yellow solid with a yield of 90%.

[0254] Example 11: Compound 3-4 (R 3 Preparation of

[0255]

[0256] Add compound 3-3 (R) into a 500 mL two-necked bottle. 3=Ph)(7.3g, 14.5mmol) and methanol (150mL), cool with ice water bath, add 60% KOH aqueous solution (30mL), install reflux condenser, and replace the system with nitrogen atmosphere. After stirring and mixing evenly, heat the oil bath to 100℃ for 24 hours, and follow the TLC detection until the reaction is complete. Stop the reaction, cool the system with ice water bath, add concentrated hydrochloric acid dropwise to pH=3-4, and a large amount of white solid precipitates in the system. Add dichloromethane to the residual reaction solution to dilute, stir to dissolve the solid and then separate the layers, extract the aqueous phase twice with dichloromethane, combine the organic phases, wash once with saturated brine, and dry over anhydrous sodium sulfate. Filter by suction, concentrate the filtrate and column chromatograph (eluent: n-hexane / ethyl acetate=10 / 1) to obtain 6.7g of white solid, yield: 95%.

[0257] Example 12: Compound 3-4 (R 3 Preparation of

[0258]

[0259] Add compound 3-3 (R) into a 500 mL two-necked bottle. 3 =Xyl)(8.3g, 14.9mmol) and methanol (150mL), cooled with ice water bath, added 60% KOH aqueous solution (30mL), installed with reflux condenser, replaced the system with nitrogen atmosphere. After stirring and mixing evenly, heated to 100℃ in oil bath for 24 hours, followed by TLC detection until the reaction is complete. Stop the reaction, cool the system with ice water bath, add concentrated hydrochloric acid dropwise to pH=3-4, and a large amount of white solid precipitates in the system. Add dichloromethane to the residual reaction solution to dilute, stir to dissolve the solid and separate the layers, extract the aqueous phase twice with dichloromethane, combine the organic phases, wash once with saturated brine, and dry over anhydrous sodium sulfate. Filter by suction, concentrate the filtrate and column chromatograph (eluent: n-hexane / ethyl acetate=10 / 1) to obtain 7.8g of white solid, yield: 96%.

[0260] Example 13: Compound 3-4 (R 3 = Preparation of DTB

[0261]

[0262] Add compound 3-3 (R) into a 500 mL two-necked bottle. 3=DTB) (11.0g, 15.2mmol) and methanol (150mL), cool with ice water bath, add 60% KOH aqueous solution (30mL), install reflux condenser, and replace the system with nitrogen atmosphere. After stirring and mixing evenly, heat the oil bath to 100℃ for 24 hours, and follow the TLC detection until the reaction is complete. Stop the reaction, cool the system with ice water bath, add concentrated hydrochloric acid dropwise to pH=3-4, and a large amount of white solid precipitates in the system. Add dichloromethane to the residual reaction solution to dilute, stir to dissolve the solid and then separate the layers, extract the aqueous phase twice with dichloromethane, combine the organic phases, wash once with saturated brine, and dry over anhydrous sodium sulfate. Filter by suction, concentrate the filtrate and column chromatograph (eluent: n-hexane / ethyl acetate=10 / 1) to obtain 10.8g of white solid, yield: 99%.

[0263] Example 14: Compound 2 (R 3 =Ph,R 2 =H) Preparation

[0264]

[0265] Add compound 2 (R) into a 500 mL two-necked bottle. 3 =Ph,R 2 =H) (6.7g, 13.7mmol), HOBt (4.6g, 30.3mmol) and DCC (8.1g, 39.4mmol), replace with nitrogen atmosphere. Add redistilled tetrahydrofuran (180mL) under ice-water bath cooling, stir and mix evenly, then add ethanolamine (1.9g, 31.1mmol). After the addition, naturally warm to room temperature and stir to react, a large amount of white solid is generated in the system. TLC tracking detection until the reaction is complete. Stop the reaction, concentrate to remove part of the solvent, add silica gel, concentrate and column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 7.3g of yellow foam solid, yield: 100%.

[0266] Example 15: Compound 2 (R 3 =Xyl,R 2 =H) Preparation

[0267]

[0268] Add compound 3-4 (R) into a 500 mL two-necked bottle. 3=Xyl)(7.8g, 14.3mmol), HOBt(4.6g, 30.3mmol) and DCC(8.1g, 39.4mmol), replace with nitrogen atmosphere. Add redistilled tetrahydrofuran (180mL) under ice-water bath cooling, stir and mix evenly, then add ethanolamine (1.9g, 31.1mmol). After adding, naturally warm to room temperature and stir to react, a large amount of white solid is generated in the system. TLC tracking detection until the reaction is complete. Stop the reaction, concentrate to remove part of the solvent, add silica gel, concentrate and column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 8.4g of yellow foam solid, yield: 100%.

[0269] Example 16: Compound 2 (R 3 =DTB,R 2 =H) Preparation

[0270]

[0271] Add compound 3-4 (R) into a 500 mL two-necked bottle. 3 =DTB) (10.8g, 15.0mmol), HOBt (5.0g, 33.2mmol) and DCC (8.9g, 43.2mmol), replace with nitrogen atmosphere. Add redistilled tetrahydrofuran (180mL) under ice-water bath cooling, stir and mix evenly, then add ethanolamine (1.9g, 31.1mmol). After the addition, naturally warm to room temperature and stir to react, a large amount of white solid is generated in the system. TLC tracking detection until the reaction is complete. Stop the reaction, concentrate to remove part of the solvent, add silica gel, concentrate and column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 11.4g of yellow foam solid, yield: 100%.

[0272] Example 17: Compound 2 (R 3 =DTB,R 2 Preparation of

[0273]

[0274] Add compound 2 (R) into a 500 mL two-necked bottle. 3 =DTB,R 2=Ph)(10.8g, 15.0mmol), HOBt(5.0g, 33.2mmol), DCC(8.9g, 43.2mmol) and L-phenylglycinol(4.3g, 31.1mmol), replaced with nitrogen atmosphere. Add redistilled tetrahydrofuran (180mL) under ice-water bath cooling, and naturally warm to room temperature after addition to stir and react. A large amount of white solid is generated in the system. TLC tracking detection until the reaction is complete. Stop the reaction, concentrate to remove part of the solvent, add silica gel, concentrate and column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 12.5g of white solid, yield: 100%.

[0275] Example 18: Compound 2 (R 3 =DTB,R 2 =Bn) preparation

[0276]

[0277] Add compound 2 (R) into a 500 mL two-necked bottle. 3 =DTB,R 2 =Bn) (10.8g, 15.0mmol), HOBt (5.0g, 33.2mmol), DCC (8.9g, 43.2mmol) and L-phenylpropanol (4.7g, 31.1mmol), replaced with nitrogen atmosphere. Add redistilled tetrahydrofuran (180mL) under ice-water bath cooling, and naturally warm to room temperature after addition to stir and react. A large amount of white solid is generated in the system. TLC tracking detection until the reaction is complete. Stop the reaction, concentrate to remove part of the solvent, add silica gel, concentrate and column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 12.8g of yellow foam solid, yield: 100%.

[0278] Example 19: Compound 1 (R 3 =Ph,R 2 =H) Preparation

[0279]

[0280] Add compound 2 (R) into a 500 mL two-necked bottle. 3 =Ph,R 2=H)(7.3g, 13.7mmol) and DMAP (61mg, 0.5mmol), replace with nitrogen atmosphere. Add redistilled dichloromethane (240mL), stir and mix evenly, then add triethylamine (4.1mL, 29.6mmol) and MsCl (2.1mL, 27.1mmol) in turn under ice-water bath cooling. Keep stirring and react at this temperature for 30 minutes, and add 17.6mL of triethylamine. After the addition is completed, naturally warm to room temperature and stir to react, and follow up with TLC detection until the reaction is complete. Stop the reaction, concentrate to remove part of the solvent, add silica gel, concentrate and column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 5.1g of white foam solid, yield: 72%.

[0281] Example 20: Compound 1 (R 3 =Xyl,R 2 =H) Preparation

[0282]

[0283] Add compound 1 (R) into a 500 mL two-necked bottle. 3 =Xyl,R 2 =H) and DMAP (64mg, 0.5mmol), replace with nitrogen atmosphere. Add redistilled dichloromethane (240mL), stir and mix evenly, then add triethylamine (4.1mL, 29.6mmol) and MsCl (2.1mL, 27.1mmol) in turn under ice-water bath cooling. Keep stirring and react at this temperature for 30 minutes, and add 17.6mL triethylamine. After adding, naturally warm to room temperature and stir to react, and TLC tracking detection until the reaction is complete. Stop the reaction, concentrate to remove part of the solvent, add silica gel, concentrate and column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 6.3g of white foam solid, yield: 77%.

[0284] Example 21: Compound 1 (R 3 =DTB,R 2 =H) Preparation

[0285]

[0286] Add compound 2 (R) into a 500 mL two-necked bottle. 3 =DTB,R 2=H)(11.4g, 15.0mmol) and DMAP (74mg, 0.6mmol), replace with nitrogen atmosphere. Add redistilled dichloromethane (240mL), stir and mix evenly, then add triethylamine (4.1mL, 29.6mmol) and MsCl (2.1mL, 27.1mmol) in turn under ice-water bath cooling. Keep stirring and react at this temperature for 30 minutes, and add 17.6mL of triethylamine. After the addition is complete, naturally warm to room temperature and stir to react, and follow up with TLC detection until the reaction is complete. Stop the reaction, concentrate to remove part of the solvent, add silica gel, concentrate and column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 8.9g of white foam solid, yield: 80%.

[0287] Example 22: Compound 1 (R 3 =DTB,R 2 Preparation of

[0288]

[0289] Add compound 2 (R) into a 500 mL two-necked bottle. 3 =DTB,R 2 =Ph)(12.5g, 15.0mmol) and DMAP(74mg, 0.6mmol), replace with nitrogen atmosphere. Add redistilled dichloromethane (240mL), stir and mix evenly, then add triethylamine (4.1mL, 29.6mmol) and MsCl(2.1mL, 27.1mmol) in turn under ice-water bath cooling. Keep stirring and react at this temperature for 30 minutes, then add 17.6mL triethylamine. After adding, naturally warm to room temperature and stir to react, and follow up with TLC until the reaction is complete. Stop the reaction, concentrate to remove part of the solvent, add silica gel, concentrate and column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 10.4g of white foam solid, yield: 85%.

[0290] Example 23: Compound 1 (R 3 =DTB,R 2 =Bn) preparation

[0291]

[0292] Add compound 2 (R) into a 500 mL two-necked bottle. 3 =DTB,R 2=Bn)(12.8g, 15.0mmol) and DMAP(74mg, 0.6mmol), replace with nitrogen atmosphere. Add redistilled dichloromethane (240mL), stir and mix evenly, then add triethylamine (4.1mL, 29.6mmol) and MsCl(2.1mL, 27.1mmol) in turn under ice-water bath cooling. Keep stirring and react at this temperature for 30 minutes, then add 17.6mL triethylamine. After adding, naturally warm to room temperature and stir to react, and follow up with TLC until the reaction is complete. Stop the reaction, concentrate to remove part of the solvent, add silica gel, concentrate and column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 9.2g of white foam solid, yield: 74%.

[0293] Example 24: Chiral spirocyclic monophosphine-oxazoline ligand 1 (R 3 =DTB,R 2 =H) Application

[0294]

[0295] In a glove box, weigh the compound of formula 7 (32.3 g, 75 mmol) and the catalyst (the molar amount is 1 / 6000 of the substrate compound of formula 7) into a reaction inner tube equipped with a stirrer, and seal it for later use. After taking it out, add triethylamine (22.8 g, 225 mmol) and anhydrous methanol (150 mL), place the inner tube in a hydrogenation reactor, replace the system with a hydrogen atmosphere through three hydrogenation-degassing operations, and finally pressurize it to 12 atm and stir at 70°C until the hydrogen pressure no longer decreases. Then stop the reaction, release the hydrogen, concentrate the reaction system by rotary evaporation, add 100 mL of ether to dilute, adjust the system to acidity with 3N hydrochloric acid, separate the liquids, extract the aqueous phase twice with ether (100 mL), combine the organic phases, wash once with saturated brine, and dry over anhydrous sodium sulfate. Filter out the desiccant, and remove the solvent by rotary evaporation to obtain a crude product. 1 The conversion rate was greater than 99% by H NMR analysis, the ee value was 97% by chiral HPLC analysis, and the product yield was 95% by column chromatography.

Claims

1. A chiral spirocyclic monophosphine-oxazoline ligand 1, whose structural formula is as follows: in, DTB is 3,5-di-tert-butylphenyl.

2. An intermediate 2 for preparing the chiral spirocyclic monophosphine-oxazoline ligand 1 according to claim 1, whose structural formula is as follows: in, DTB is 3,5-di-tert-butylphenyl.

3. A method for preparing a chiral spirocyclic monophosphine-oxazoline ligand 1, characterized in that: The reaction route is as follows: in,

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