Process for the asymmetric catalytic hydrogenation of cyclohexene derivatives

Abstract

The application provides an asymmetric catalytic hydrogenation method of a compound shown in formula I, which comprises the following steps: under the atmosphere of hydrogen, in a solvent, asymmetric hydrogenation reduction of the compound shown in formula I is carried out in the presence of a catalyst formed by a ligand, an iridium salt and an inorganic salt, to form a compound shown in formula II, and the reaction formula is shown in the following. The asymmetric catalytic hydrogenation synthesis method provided by the application has low catalyst cost, complete conversion of raw materials, and the ee value of the obtained target product can reach 99%, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of hydrogenation of organic compounds, in particular, to a method for asymmetric catalytic hydrogenation of cyclohexene derivatives. BACKGROUND

[0002] Asymmetric hydrogenation to reduce double bond to obtain a compound with target configuration is a reaction step often encountered in the process of compound synthesis, especially in the process of synthesis of drug intermediates. The most commonly used method for asymmetric catalytic hydrogenation to reduce double bond is to use metal or metal complex catalyst to catalyze the reduction of double bond. The problem of using metal or metal complex catalyst to catalyze the reduction of double bond is that the reduction product obtained by using the catalyst to catalyze the reduction of substrate usually has poor selectivity, and the compound with target configuration needs to be obtained by subsequent separation, or the conversion efficiency of the substrate is low, especially when the substrate and the reduction product have small structural difference and are difficult to separate, this method is not good. Therefore, the selection of catalyst is particularly important for the reduction of substrate, and the catalyst which can make the conversion rate of the substrate to be reduced (for example, the conversion rate reaches 99% or more) and the reduction selectivity good (for example, the ee value reaches 99 or more) is the ideal catalyst.

[0003] Elacestrant is an anti-breast cancer drug developed by Italian Menarini and American Square Health, which was approved for marketing by FDA on January 27, 2023, and is the first selective estrogen receptor degrader that can be used for patients with advanced or metastatic breast cancer. The compound shown in the following formula II-1 is an important intermediate of Elacestrant.

[0004]

[0005] For the method for synthesizing the compound shown in formula II-1 from the compound shown in formula I-1, Square Health has disclosed the following reaction route in the prior art WO 2020 / 167855 Al:

[0006]

[0007] The synthesis process of the compound B5 is as follows: the compound B3 is used as a catalyst to obtain the compound B4, and the acyl group on the nitrogen is removed to obtain two enantiomers (A4), and then the enantiomers B5 are prepared by separation, which needs to use expensive chromatographic column to separate the enantiomers.

[0008] Although diastereoisomers can be separated by separation / resolution techniques based on solubility difference, or prepared as individual stereoisomers by enzymatic resolution, these methods are only applicable to compounds with special structures, and in addition, the corresponding isomers for enzymatic resolution often have relatively harsh requirements for reaction conditions, which restricts their subsequent application. Therefore, it is difficult to prepare high-purity enantiomers, which seriously restricts their industrial production. For example, there is currently no suitable method for preparing the above-mentioned intermediate B5 compound in the Ila group at low cost and high yield. SUMMARY

[0009] The present application provides an asymmetric catalytic hydrogenation method of a compound shown in formula I, which comprises the step of: under the atmosphere of hydrogen, in a solvent, the compound shown in formula I is subjected to asymmetric hydrogenation reduction in the presence of a catalyst formed by a ligand, an iridium salt and an inorganic salt, to form a compound shown in formula II, and the reaction formula is as shown below:

[0010]

[0011] wherein the A ring is selected from cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, acyl-containing group, sulfonyl-containing group, aryl or heteroaryl,

[0012] R' is selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, acyl-containing group, sulfonyl-containing group, aryl, heteroaryl,

[0013] the ligand is selected from a compound shown in the following formula:

[0014]

[0015] in formula III and V, R, R 1 and R 2 are each independently selected from H, alkyl, alkoxy, cycloalkyl or aryl, wherein the alkyl, alkoxy, cycloalkyl or aryl is optionally further substituted with one or more substituents selected from halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, acyl-containing group, sulfonyl-containing group or aryl,

[0016] in formula IV and VI, R and R 1 are each independently selected from H, alkyl, alkoxy, cycloalkyl or aryl, or R and R 1together with the carbon to which they are attached form a 5- to 6-membered ring, wherein the alkyl, alkoxy, cycloalkyl, aryl, 5- to 6-membered ring are optionally further substituted by one or more substituents selected from halogen, nitro, cyano, alkyl, alkoxy, acyl-containing group, sulfonyl-containing group, or aryl,

[0017] in formula VII, R 3 and R 4 are each independently selected from H, halogen, alkyl, alkoxy, cycloalkyl, or aryl, or R 3 and R 4 together with the carbon to which they are attached form a 5- to 6-membered ring, or R 4 together with the carbon to which they are attached form a 7- to 12-membered ring, wherein the alkyl, alkoxy, cycloalkyl, aryl, 5- to 6-membered ring, 7- to 12-membered ring are optionally further substituted by one or more substituents selected from halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, acyl-containing group, sulfonyl-containing group, or aryl,

[0018] Ar is aryl, wherein the aryl is optionally further substituted by one or more substituents selected from halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, acyl-containing group, sulfonyl-containing group, or aryl,

[0019] M is Fe or Ru,

[0020] the iridium salt is selected from 1,5-cyclooctadiene iridium chloride dimer, bis(1,5-cyclooctadiene)iridium tetrafluoroborate, bis(1,5-cyclooctadiene)iridium(I) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, methoxy(cyclooctadiene)iridium dimer, chloro bis(cyclooctene)iridium(I) dimer, bis(acetonitrile)(1,5-cyclooctadiene)iridium(I) tetrafluoroborate, 1,5-cyclooctadiene(acetylacetonate)iridium, 1,5-cyclooctadiene(hexafluoroacetylacetonate)iridium(I),

[0021] the inorganic salt is selected from fluoroborates, fluorophosphates.

[0022] In another more preferred embodiment, in formula I and II, the A ring is selected from a phenyl ring, wherein the phenyl ring is substituted by one or more substituents selected from halogen, alkyl, alkoxy.

[0023] In another more preferred embodiment, R' is selected from a phenyl ring, wherein the phenyl ring is substituted by one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy.

[0024] In another more preferred embodiment, in formula III and V, R, R 1 and R 2each independently selected from H, alkyl, cycloalkyl or phenyl, wherein said alkyl, cycloalkyl or phenyl are optionally further substituted with alkyl, alkoxy, cycloalkyl, phenyl.

[0025] In another more preferred embodiment, in formulae IV and VI, R and R 1 each independently selected from H, alkyl, cycloalkyl or phenyl, or R and R 1 form together with the carbon to which they are attached a 5- to 6-membered ring, wherein said alkyl, cycloalkyl or phenyl are optionally further substituted with alkyl, alkoxy, cycloalkyl, phenyl, said 5- to 6-membered ring is substituted with a phenyl ring and shares two carbon atoms with the substituted phenyl ring.

[0026] In another more preferred embodiment, in formula VII, R 3 and R 4 each independently selected from H, alkyl, alkoxy or halogen, or R 3 and R 4 form together with the carbon to which they are attached a 5- to 6-membered ring, or R 4 form together with the carbon to which they are attached a 7- to 12-membered ring, said 5- to 6-membered ring is cyclopentane, cyclohexane or a ketal containing two oxygen atoms, said 7- to 12-membered is a ketal containing at least two oxygen atoms.

[0027] In another more preferred embodiment, in formula VII, Ar is selected from phenyl.

[0028] In another more preferred embodiment, the iridium salt is selected from 1,5- cyclooctadiene iridium chloride dimer, bis(1,5-cyclooctadiene)iridium tetrafluoroborate, bis(1,5-cyclooctadiene)iridium(I) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, methoxy(cyclooctadiene)iridium dimer, chloro bis(cyclooctene)iridium(I) dimer, 1,5-cyclooctadiene(acetylacetonato)iridium, 1,5-cyclooctadiene(hexafluoroacetylacetonato)iridium(I).

[0029] In another preferred embodiment, the fluoroborate salt is selected from sodium tetrafluoroborate, silver tetrafluoroborate, sodium tetrakis(3,5-di(trifluoromethyl)phenyl)borate (NaBAr F ).

[0030] In another preferred embodiment, the inorganic salt is selected from sodium tetrakis(3,5-di(trifluoromethyl)phenyl)borate.

[0031] In another preferred embodiment, the fluorophosphate salt is selected from sodium hexafluorophosphate, potassium hexafluorophosphate.

[0032] In another preferred embodiment, the compound of formula I has the following structure according to formula I-1:

[0033]

[0034] wherein R 5 and R 6 each independently is selected from H, alkyl, acyl-containing group, said alkyl being optionally further substituted by one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, phenyl, acyl-containing substituents,

[0035] R 7 is H or a hydroxyl protecting group,

[0036] R 8 is selected from H or alkyl, cycloalkyl, said alkyl, cycloalkyl being optionally further substituted by one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy, phenyl.

[0037] In another preferred embodiment, said hydroxyl protecting group is selected from the group consisting of TMS (trimethylsilyl), TIPS (triisopropylsilyl), TBS (tert-butyldimethylsilyl), Me (methyl), Et (ethyl), Pr (propyl), or Bn (benzyl), CH3CO (acetyl), CH3CH2CO (propionyl), PhCO (benzoyl), CH3SO2 (methylsulfonyl), PhSO2 (phenylsulfonyl).

[0038] In another more preferred embodiment, formula I-1 is selected from the group consisting of compounds represented by the following structures:

[0039]

[0040] In another preferred embodiment, said catalyst is selected from the group consisting of compounds represented by the following structures:

[0041]

[0042]

[0043]

[0044] In another more preferred embodiment, said catalyst is selected from the group consisting of compounds represented by the following structures:

[0045]

[0046]

[0047] In another more preferred embodiment, said catalyst is selected from the group consisting of compounds represented by the following structures:

[0048]

[0049]

[0050] In another more preferred embodiment, the catalyst is selected from the group consisting of compounds represented by the following structures:

[0051]

[0052] In another preferred embodiment, the reaction temperature of the asymmetric catalytic hydrogenation is from -20 to 60 °C, more preferably from 4 to 40 °C, and most preferably from 10 to 30 °C.

[0053] In another preferred embodiment, the asymmetric catalytic hydrogenation is carried out under a hydrogen pressure of from 1 to 80 bar, more preferably from 40 to 60 bar.

[0054] In another preferred embodiment, the molar ratio of the compound of Formula I to the catalyst is from 10,000:1 to 100:1, more preferably from 3,000:1 to 200:1.

[0055] In another more preferred embodiment, the asymmetric catalytic hydrogenation reaction system further comprises Na3PO4, Na2HPO4, NaH2PO4, triethylamine, pyridine, 2,6-dimethylpyridine, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, benzoic acid, hydrochloric acid, sodium tetrafluoroborate, silver tetrafluoroborate, sodium hexafluorophosphate, potassium hexafluorophosphate, or a combination thereof.

[0056] In another preferred embodiment, the asymmetric catalytic hydrogenation method comprises the steps of:

[0057] treating the reaction solution containing the catalyst generated from the reaction of the ligand, the iridium salt, and the inorganic salt to obtain a purified catalyst, and adding the purified catalyst, the compound of Formula I, and a solvent into a reaction vessel to undergo asymmetric hydrogenation reduction under a hydrogen atmosphere.

[0058] In another preferred embodiment, the asymmetric catalytic hydrogenation method comprises the steps of:

[0059] treating the reaction solution containing the catalyst generated from the reaction of the ligand, the iridium salt, and the inorganic salt to obtain a purified catalyst, and adding the purified catalyst, the compound of Formula I, and a solvent into a reaction vessel to undergo asymmetric hydrogenation reduction under a hydrogen atmosphere.

[0060] In another preferred embodiment, the method for generating a catalyst from the reaction of the ligand, the iridium salt, and the inorganic salt comprises the steps of:

[0061] (1) reacting the chiral ligand and the iridium salt to form a complex;

[0062] (2) adding the inorganic salt to the reaction solution of step (1) so that the inorganic salt and the complex form the catalyst.

[0063] In another aspect, the present application provides a method for asymmetric catalytic hydrogenation of a compound of Formula I-1, characterized in that the method comprises the step of asymmetric hydrogenation reduction of a compound of Formula I-1 in the presence of a catalyst in a solvent under a hydrogen atmosphere to form a compound of Formula II-1, as shown in the following reaction scheme:

[0064]

[0065] wherein R 7 is selected from H, Bn, Cbz or Ac,

[0066] The catalyst is:

[0067] In another aspect, the present application provides a catalyst as shown in the following structure:

[0068]

[0069]

[0070]

[0071] In another more preferred embodiment, the catalyst is selected from the following:

[0072]

[0073] In another aspect, the present application provides the use of the above-mentioned compound in asymmetric catalytic reduction of a double bond. BRIEF DESCRIPTION OF DRAWINGS

[0074] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of (R)-2-{2-[6-benzyloxy-(1,2,3,4-tetrahydronaphthalene)]-yl}-5-methoxyaniline (a compound of Formula II-1-1) obtained in Example 1. 1 = R 2 = H.

[0075] Figure 2 is the nuclear magnetic resonance carbon spectrum of (R)-2-{2-[6-benzyloxy-(1,2,3,4-tetrahydronaphthalene)]-yl}-5-methoxyaniline (a compound of Formula II-1-1) obtained in Example 1.

[0076] Figure 3is the HPLC chromatogram of the crude (R)-2-{2-[6-benzyloxy-(l,2,3,4- tetrahydronaphthalen)]-yl}-5-methoxyaniline (compound shown in formula II- 1-1) obtained in Example 1, in which the target product of R configuration has 99% ee; HPLC [DAICEL CHIRALPAK OD, n-hexane / i-PrOH = 85 / 15, 254 nm, 0.8 mL / min, 30 °C]; the peak time of (R)-2-{2-[6-benzyloxy-(l,2,3,4- tetrahydronaphthalen)]-yl}-5-methoxyaniline is t R1 = 33.441 min, and the peak time of its enantiomer is t R2 = 38.236; the starting material was not checked, and the starting material was completely converted.

[0077] Figure 4 is the HPLC chromatogram of the crude (R)-2-{2-[6-hydroxy-(l,2,3,4- tetrahydronaphthalen)]-yl}-5-methoxyaniline (compound shown in formula II- 1-2) obtained in Example 2, in which the target product of R configuration has 99% ee; HPLC [DAICEL CHIRALPAK OD, n-hexane / i-PrOH = 85 / 15, 254 nm, 0.8 mL / min, 30 °C]; the peak time of (R)-2-{2-[6-hydroxy-(l,2,3,4- tetrahydronaphthalen)]-yl}-5-methoxyaniline is t R1 = 37.099 min, and the peak time of its enantiomer is t R2 = 44.422. The starting material was not checked, and the starting material was completely converted. DETAILED DESCRIPTION

[0078] For the asymmetric catalytic hydrogenation process of the compound shown in formula I in the prior art, the present inventors have developed a series of new catalysts formed by iridium and ligands through extensive and in-depth research, which are used for the asymmetric catalytic hydrogenation of the compound shown in formula I, so that the conversion rate of the compound shown in formula I is high, and the reduction selectivity is good.

[0079] Terminology

[0080] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0081] The term "room temperature (r.t.)" refers to 4-40 °C, for example, 10-30 °C, 15-28 °C, 20-25 °C.

[0082] "Alkyl" when used as a group or part of a group refers to a straight-chain or branched-chain alkyl radical, including C1-C 10Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C6 alkyl, more preferably C1-C4 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and the like. The alkyl group can be substituted or unsubstituted.

[0083] "Alkoxy" refers to a group of the formula (alkyl-O-). Alkyl is as defined above. Preferably C1-C6 alkoxy. For example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, and the like.

[0084] "Cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic rings. Preferably C3-C 12 C8 cycloalkyl, and most preferably C5-C6 cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, preferably cyclopentyl, cyclohexyl. The cycloalkyl group can be optionally substituted or unsubstituted.

[0085] "Heterocyclyl" refers to non-aromatic heterocyclic groups in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, nitrogen, sulfur, and the like, including monocyclic, polycyclic, fused, bridged, and spiro rings. Preferably 4- to 11-membered heterocyclyl groups, which can contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heterocyclyl" groups include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl.

[0086] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings can be connected together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, for example, aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. The aryl group can be substituted or unsubstituted.

[0087] "Heteroaryl" means an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring which can contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. For example, furyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, thienyl, isoxazyl, oxazyl, imidazyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzothienyl, benzimidazyl, indolyl, isoindolyl, quinolyl, indazolyl and the like, the heteroaryl group can be substituted or unsubstituted.

[0088] Preparation of the catalyst

[0089] In some embodiments, the method for preparing the catalyst by reacting the ligand with the iridium salt comprises two steps:

[0090] (1) reacting the chiral ligand and the iridium salt to form a complex;

[0091] (2) adding an inorganic salt to the reaction solution of step (1) so that the inorganic salt forms the catalyst with the complex.

[0092] In some embodiments, the temperature for the reaction of the chiral ligand and the iridium salt in step (1) is preferably 40-120°C, and the reaction time is preferably 0.3-1 hour.

[0093] In some embodiments, the reaction temperature in step (2) is preferably room temperature, and the reaction time is 2-4 hours.

[0094] In some embodiments, the reaction solvent can be selected from methanol, ethanol, isopropanol, propanol, butanol, isobutanol, acetone, 1,4-dioxane, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, acetonitrile, toluene, xylene, ethyl acetate, methyl acetate. The amount of the reaction solvent is a conventional amount so that the reactants can be completely dissolved therein, preferably, the weight / volume ratio of the ligand to the solvent is 3-10 mg / mL.

[0095] In some embodiments, the molar ratio of the chiral ligand to the iridium salt in step (1) is 1:0.5-2. In step (2), the inorganic salt is used to form a salt with the complex, and the amount of the inorganic salt is related to the number of charges of the anions provided by the inorganic salt, and the number of anions provided by the inorganic salt is the same as the number of metal cations in the complex. When the inorganic salt provides a " " anion, the amount of the inorganic salt is 1-1.5 times the molar amount of the iridium salt; when the inorganic salt provides a "2 - " anion, the amount of the inorganic salt is 0.5-1 times the molar amount of the iridium salt.

[0096] In some embodiments, the reaction solution containing the catalyst can be used directly for the asymmetric catalytic hydrogenation of the compound of formula I without any treatment.

[0097] In some embodiments, the reaction solution comprising the catalyst is removed of solvent to obtain a crude catalyst, which is then separated by column chromatography to obtain a purified catalyst, which is used in the asymmetric catalytic hydrogenation of the compound of Formula I.

[0098] Asymmetric catalytic hydrogenation of compounds of formula I

[0099] The asymmetric catalytic hydrogenation synthesis method of the compound of Formula I in the present application comprises: under a hydrogen atmosphere, in a solvent, the compound of Formula I is subjected to asymmetric catalytic hydrogenation reduction in the presence of the catalyst provided by the present application to form a compound of Formula II, and the reaction formula is shown as follows:

[0100]

[0101] wherein A ring is selected from cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, acyl-containing group, sulfonyl-containing group, aryl or heteroaryl,

[0102] R' is selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, acyl-containing group, sulfonyl-containing group, aryl, heteroaryl,

[0103] The reaction temperature of the asymmetric catalytic hydrogenation is preferably -20-60°C, more preferably room temperature. The asymmetric catalytic hydrogenation is carried out under a hydrogen pressure of preferably 1-80 bar, more preferably 40-60 bar. The molar ratio of the compound of Formula I to the catalyst is preferably 10000:1-100:1, more preferably 3000:1-200:1.

[0104] The reaction solvent can be selected from methanol, ethanol, isopropanol, propanol, butanol, isobutanol, acetone, 1,4-dioxane, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, acetonitrile, toluene, xylene, ethyl acetate, methyl acetate. The amount of the reaction solvent is a conventional amount, so that the reactants can be completely dissolved therein, preferably, the weight / volume ratio of the compound of Formula I to the solvent is 10-30 mg / mL, more preferably 15-25 mg / mL.

[0105] Compared with the prior art, the present application has the following advantages:

[0106] 1. In the asymmetric catalytic synthesis method of the present application, the conversion rate of the cyclohexene derivative substrate is high, the selectivity is good, and the ee value of the reduced product is high, which is suitable for industrial scale-up production.

[0107] 2. The amount of metal catalyst is small, which greatly reduces the problem of heavy metal residues.

[0108] 3. The cost of using catalyst for asymmetric catalytic hydrogenation of cyclohexene derivatives is lower than that of chiral resolution commonly used in the prior art.

[0109] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application and not to limit the scope of the application. The experimental methods in the following examples are not specified, which are usually carried out according to the conventional conditions or the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

[0110] The reagents and raw materials used in the application are commercially available unless otherwise specified.

[0111] The catalyst used in the following examples, and the ligand and iridium salt used to form the catalyst are shown in Table 1, and the inorganic salt used is sodium tetra(3,5-di(trifluoromethyl)phenyl)borate, sodium tetrafluoroborate, silver tetrafluoroborate, sodium hexafluorophosphate.

[0112] Table 1

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] Example 1

[0122] 1.1 Preparation of the catalyst

[0123] The ligand 1 (170 mg) and iridium chloride dimer of 1,5-cyclooctadiene (220 mg) were dissolved in dichloromethane (25 mL) and heated and stirred at 45°C for 2h. After cooling to (25°C), sodium tetra(3,5-di(trifluoromethyl)phenyl)borate (NaBAr F)(660 mg) and 20 mL of distilled water, at room temperature for 3 h. The solvent was removed under reduced pressure, and column chromatography was performed [eluent: V(dichloromethane):V(ethyl acetate) = 1:1] to obtain a red solid (580 mg, 95%), which was catalyst 1, and the 1H NMR, 13C NMR and 31P NMR data were as follows, respectively:

[0124] (aS)-Ir / InBiphPHOX., Orange-red solid. 1 H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.2 Hz, 1H), 7.72 (s, 8H), 7.59 - 7.46 (m, 6H), 7.46 - 7.29 (m, 7H), 7.24 - 6.94 (m, 8H), 6.75 - 6.69 (m, 3H), 5.95 (d, J = 7.6 Hz, 1H), 5.71 (d, J = 8.4 Hz, 1H), 5.54 (td, J = 8.4, 4.0 Hz, 1H), 5.39 (s, 1H), 4.51 - 4.38 (m, 1H), 3.14 (dd, J = 18.0, 8.4 Hz, 1H), 3.06 - 3.02 (m, 1H), 3.00 - 2.92 (m, 1H), 2.38 - 2.17 (m, 3H), 2.06 - 1.87 (m, 3H), 1.72 (dd, J = 18.0, 3.6 Hz, 1H), 1.49 - 1.36 (m, 1H).

[0125] 13 C NMR (100 MHz, CDCl3) δ 169.5, 162.4, 162.0, 161.5, 161.0, 142.1, 142.0, 140.6, 139.1, 136.4, 135.9, 135.7, 134.8, 134.7, 133.6, 133.5, 132.0, 131.5, 131.4, 131.3, 131.2, 130.7, 130.6, 129.9, 129.5, 129.0, 128.9, 128.7, 128.6, 128.55, 128.4, 128.0, 127.9, 127.6, 127.3, 126.8, 126.2, 126.1, 125.9, 125.6, 123.2, 120.5, 117.4, 91.6, 91.5, 85.2, 80.0, 79.8, 76.4, 76.3, 62.2, 39.4, 35.4, 35.3, 33.6, 28.5, 26.6.

[0126] 31 P NMR (162 MHz, CDCl3) δ 18.2.

[0127] 1.2 Preparation of (R)-2-{2-[6-hydroxy-(l,2,3,4-tetrahydronaphthalenyl)]- methyl}-5-methoxyaniline

[0128]

[0129] The compound of formula I-1-1 (1000.0 mg, 2.798 mmol), catalyst 1 (22.4 mg, 0.014 mmol, 0.5 mol%) were added into a 50 mL dry round bottom flask with magnetic stirrer in sequence. After vacuum replacement of nitrogen, degassed dichloromethane (10 mL) was added, and the round bottom flask was placed in a hydrogenation reactor after stirring uniformly (until the solution was blood red). After replacing the gas in the reactor with hydrogen three times, hydrogen was added to a pressure of 50 bar. After stirring at room temperature for 72 hours, the hydrogen was slowly released, the solvent was evaporated under reduced pressure, water (10 mL) was added for dilution, and extraction was performed with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain a crude product of (R)-2-{2-[6-benzyloxy-(1,2,3,4-tetrahydronaphthalene)]-yl}-5-methoxyaniline (a compound of formula II-1-1) (>1.0 g, ee value 99%), and its HPLC spectrum is shown in Figure 3 .

[0130] The crude product was purified by recrystallization to obtain a pure product of 935.7 mg, with a yield of about 93% (molar yield). The proton nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum of the pure product are shown in Figure 1 and Figure 2 , respectively, as follows:

[0131] 1 H NMR (500 MHz, CDCl3) δ 7.49-7.33 (m, 5H), 7.07 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.84-6.79 (m, 2H), 6.40 (dd, J = 8.5, 2.5 Hz, 1H), 6.33 (d, J = 2.5 Hz, 1H), 5.08 (s, 2H), 3.80 (s, 3H), 3.09-2.69 (m, 5H), 2.17-2.09 (m, 1H), 2.02-1.90 (m, 1H).

[0132] 13 C NMR (500 MHz, CDCl3) δ 158.7, 156.9, 144.5, 137.39, 137.30, 129.8, 129.2, 128.5, 127.8, 127.4, 126.8, 123.3, 114.6, 112.8, 104.3, 101.7, 70.0, 55.1, 35.5, 34.4, 30.2, 29.0.

[0133] Example 2

[0134] 2.1 Preparation of the catalyst

[0135] Ligand 1 (340 mg) and 1,5-cyclooctadiene iridium dichloride dimer (440 mg) were dissolved in dichloromethane (35 mL) and stirred at 45 °C for 2 h. Tetra(3,5-di(trifluoromethyl)phenyl)borate sodium (NaBAr F )(1320 mg) and 10 mL distilled water were added and the reaction was allowed to proceed at room temperature for 3 h. The solvent was removed under reduced pressure and the product was isolated by column chromatography [eluent: V(dichloromethane) : V(ethyl acetate) = 1 : 1] to give a blood red solid (900 mg, 73%), which was catalyst 1.

[0136] 1.2 Preparation of (R)-2-{2-[6-hydroxy-(l,2,3,4-tetrahydronaphthalenyl)]- methyl}-5-methoxyaniline

[0137]

[0138] A compound represented by Formula I-1-2 (R 1 = R 2 = H) (800.0 mg, 2.993 mmol), catalyst 1 (22.2 mg, 0.014 mmol, 0.5 mol%) were sequentially added to a 50 mL dry round-bottom flask equipped with a magnetic stirrer. After vacuum replacement with nitrogen, degassed dichloromethane (10 mL) was added, and the round-bottom flask was placed in a hydrogenation reactor after stirring until the solution was blood red. After replacing the reactor gas with hydrogen three times, hydrogen was added to a pressure of 50 bar. After stirring at room temperature for 72 h, the hydrogen was slowly released, the solvent was evaporated under reduced pressure, and water (10 mL) was added to dilute the solution, which was then extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give a crude 2(R)-2-{2-[6-hydroxy-(1,2,3,4-tetrahydronaphthalene)]-yl}-5-methoxyaniline (a compound represented by Formula II-1-2) (>1.0 g, ee value 99%), the HPLC spectrum of which is shown in Figure 4 .

[0139] The crude product was purified by recrystallization to give a pure product 774.1 mg, yield about 96% (molar yield). The nuclear magnetic resonance hydrogen spectrum and carbon spectrum of the pure product are as follows:

[0140] 1H NMR (500 MHz, CDC13) δ 7.05 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 2H), 6.39 (dd, J = 8.0, 2.5 Hz, 1H), 6.31 (d, J = 3.0 Hz, 1H), 3.79 (s, 3H), 3.01 (ddd, J = 6.0, 5.0, 2.0 Hz, 1H), 2.95 - 2.84 (m, 3H), 2.75 (dd, J = 16.0, 11.5 Hz, 1H), 2.15 - 2.05 (m, 1H), 2.00 - 1.88 (m, 1H).

[0141] 13 C NMR (500 MHz, CDC13) δ 158.7, 153.5, 144.5, 137.6, 130.0, 128.8, 126.8, 123.3, 115.1, 113.0, 104.3, 101.7, 55.1, 35.5, 34.3, 30.0, 29.0.

[0142] Examples 3-49

[0143] The preparation method of catalysts 1-47 (the structures of these catalysts are shown in Table 1) formed by the ligands used in the following Examples 3-49 and iridium salts is similar to the preparation method of catalyst 1 of Example 1, and the conditions and results of using these catalysts to catalyze the asymmetric hydrogenation of compounds shown in Formula I-1-1 are shown in Table 2 below.

[0144] Table 2

[0145]

[0146]

[0147]

[0148] Note, conversion, refers to the conversion of compounds shown in Formula I-1-1.

[0149] From the above Examples 3-49, it can be seen that catalysts 1, 2, 3, 7, 8, 9, 12, 13, 14, 24-28, 30, 31 have relatively good selectivity catalytic effects.

[0150] Examples 50-112

[0151] The preferred catalysts in Table 2 were selected to catalyze the asymmetric hydrogenation of compounds shown in Formula I-1-1, and the solvent for catalytic reduction, reaction temperature, reaction time, hydrogen pressure, etc. were screened.

[0152] The following Examples 50-112 use catalysts 1, 2, 3, 7, 8, 9, 12, 13, 14, 24-28, 30, 31 to asymmetrically catalyze the hydrogenation of compounds of Formula I-1-1 to produce compounds of Formula II-1-1 (R 1 = R 2 = H) using the solvents, additives, reaction system temperatures (solvent temperatures), hydrogen pressures, reaction times, and reaction results (substrate conversion, ee values) shown in Table 3 below (the ee values in Table 3 are the ee values obtained after separation on silica gel plates).

[0153] Table 3

[0154]

[0155]

[0156]

[0157] As can be seen from the above Examples 50-112, these catalysts can asymmetrically catalyze the reduction of compounds of Formula I-1-1 under the following conditions (which are not limiting conditions): in an aprotic solvent, at a temperature of 4-40°C, under a hydrogen pressure of 40-60 bar, for 72 hours (which is not a limiting time period). The selective catalytic effect is better at a temperature of 4-25°C, and the addition of a salt has a certain effect on the asymmetric catalytic reduction reaction.

[0158] Examples 113-117

[0159] Examples 113-117 use catalyst 1 to asymmetrically catalyze the reduction of compounds of Formula I-1-1 under conditions that are substantially the same as those of Example 1, except that the molar ratio of the substrate (a compound of Formula I-1-1) to the catalyst (catalyst 1) is different. The specific molar ratio of the substrate to the catalyst and the reaction results are shown in Table 4 below.

[0160] Table 4

[0161] Examples Molar ratio of substrate to catalyst Conversion (%) ee (%) 113 100:1 >99 99 114 1000:1 >99 99 115 2000:1 >99 99 116 3000:1 >96 99 117 10000:1 87 99

[0162] As can be seen from the above Examples 113-117, the catalyst can achieve a conversion rate of 87% when the molar ratio of the substrate to the catalyst is 10000:1 under the following conditions: dichloromethane as the reaction solvent, a temperature of 25°C, and a hydrogen pressure of 50 bar for 72 hours. When the molar ratio of the substrate to the catalyst is between 1000:1 and 3000:1, the conversion rate does not change significantly. In addition, it was found during actual experiments that a complete conversion and excellent ee value can be achieved when the molar ratio of the substrate to the catalyst is 10000:1, and this ratio can be further increased. However, from an economic perspective, the molar ratio of the substrate to the catalyst is preferably 3000-200:1.

[0163] All documents referred to in the present application are incorporated herein by reference as if each individual document were incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that each disclosed embodiment can be implemented with or without the corresponding use of the other embodiments. Other embodiments will occur to readers of the application from the teaching- presented herein.

Claims

1. Process for the asymmetric catalytic hydrogenation of a compound of formula 1-1 characterized in that, The hydrogenation method comprises the following steps: The asymmetric hydrogenation reduction of the compound of formula I-1 in a solvent in the presence of the catalyst forms a compound of formula II-1, and the reaction formula is as follows: wherein R 7 is selected from H, Bn, Cbz or Ac, The catalyst is 2. The asymmetric catalytic hydrogenation method according to claim 1, wherein the reaction temperature of the asymmetric catalytic hydrogenation is -20-60 ℃, and / or The asymmetric catalytic hydrogenation is carried out under the hydrogen pressure of 1-80 bar, and / or The molar ratio of the compound of formula I to the catalyst is 10,000:1-100:

1.

3. The asymmetric catalytic hydrogenation method according to claim 1, wherein the reaction temperature of the asymmetric catalytic hydrogenation is 4-40 ℃, and / or The asymmetric catalytic hydrogenation is carried out under the hydrogen pressure of 40-60 bar, and / or The molar ratio of the compound of formula I to the catalyst is 3,000:1-200:

1. The asymmetric catalytic hydrogenation method comprises the following steps: the asymmetric hydrogenation reduction of the compound of formula I in a solvent in the presence of the catalyst formed by the ligand, the iridium salt and the inorganic salt forms a compound of formula II, and the reaction formula is as follows: wherein the A ring is selected from a benzene ring, wherein the benzene ring is optionally further substituted with one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, acyl-containing group, sulfonyl-containing group, aryl or heteroaryl, 4. An asymmetric catalytic hydrogenation process of a compound of formula I ###0002### characterized in that, R' is selected from a benzene ring, wherein the benzene ring is optionally further substituted with one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, acyl-containing group, sulfonyl-containing group, aryl, heteroaryl, the ligand is selected from a compound of the following formula: Ar is aryl, wherein the aryl is optionally further substituted with one or more substituents selected from halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, acyl-containing group, sulfonyl-containing group or aryl, M is Fe or Ru, In formulae III and V, R, R 1 and R 2 each independently is selected from H, alkyl, alkoxy, cycloalkyl or aryl, wherein the alkyl, alkoxy, cycloalkyl or aryl is optionally further substituted by one or more substituents selected from halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, acyl- containing group, sulfonyl-containing group or aryl, R and R in formulae IV and VI are each independently selected from H, alkyl, alkoxy, cycloalkyl or aryl, or R and R together with the carbon to which they are attached form a 5- to 6-membered ring, wherein said alkyl, alkoxy, cycloalkyl, aryl, 5- to 6-membered ring are optionally further substituted by one or more substituents selected from halogen, nitro, cyano, alkyl, alkoxy, acyl-containing group, sulfonyl-containing group or aryl, 1 R and R in formulae IV and VI are each independently selected from H, alkyl, alkoxy, cycloalkyl or aryl, or R and R together with the carbon to which they are attached form a 5- to 6-membered ring, wherein said alkyl, alkoxy, cycloalkyl, aryl, 5- to 6-membered ring are optionally further substituted by one or more substituents selected from halogen, nitro, cyano, alkyl, alkoxy, acyl-containing group, sulfonyl-containing group or aryl, 1 R and R in formulae IV and VI are each independently selected from H, alkyl, alkoxy, cycloalkyl or aryl, or R and R together with the In equation VII, R 3 and R 4 Each is independently selected from H, halogen, alkyl, alkoxy, cycloalkyl, or aryl, or R on each benzene ring. 3 and R 4 Together with the carbon atoms attached to it, it forms a 5- or 6-membered ring, or R on the two benzene rings. 4 Together with the carbon atom it is attached to, it forms a 7- to 12-membered ring, wherein the alkyl, alkoxy, cycloalkyl, aryl, 5- to 6-membered ring, and 7- to 12-membered ring are optionally further substituted by one or more substituents selected from halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, acyl-containing group, sulfonyl-containing group, or aryl. the iridium salt is selected from 1,5-cyclooctadiene iridium chloride dimer, bis(1,5-cyclooctadiene)iridium tetrafluoroborate, bis(1,5-cyclooctadiene)iridium(I) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, methoxy(cyclooctadiene)iridium dimer, chloro bis(cyclooctene)iridium(I) dimer, bis(acetonitrile)(1,5-cyclooctadiene)iridium(I) tetrafluoroborate, 1,5-cyclooctadiene(acetylacetate)iridium, 1,5-cyclooctadiene(hexafluoroacetylacetone)(I) iridium, the inorganic salt is selected from fluoroborate, fluorophosphate.

5. The asymmetric catalytic hydrogenation synthesis method according to claim 4, wherein the benzene ring of the A ring in formula I and formula II is substituted with one or more substituents selected from halogen, alkyl, alkoxy, and / or the benzene ring of R' in formula I and formula II is substituted with one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy, and / or Ar in formula VII is selected from phenyl, and / or ​ ​ In formulae III and V, R, R 1 and R 2 are each independently selected from H, alkyl, cycloalkyl or phenyl, wherein the alkyl, cycloalkyl or phenyl are optionally further substituted by alkyl, alkoxy, cycloalkyl, phenyl, and / or R and R in formulae IV and VI are each independently selected from H, alkyl, cycloalkyl or phenyl, or R and R form together with the carbon to which they are attached a 5- to 6-membered ring, wherein the alkyl, cycloalkyl or phenyl are optionally further substituted by alkyl, alkoxy, cycloalkyl, phenyl, the 5- to 6-membered ring is optionally further substituted by a phenyl ring and shares two carbon atoms with the substituted phenyl ring, and / or 1 R and R in formulae IV and VI are each independently selected from H, alkyl, cycloalkyl or phenyl, or R and R form together with the carbon to which they are attached a 5- to 6-membered ring, wherein the alkyl, cycloalkyl or phenyl are optionally further substituted by alkyl, alkoxy, cycloalkyl, phenyl, the 5- to 6-membered ring is optionally further substituted by a phenyl ring and shares two carbon atoms with the substituted phenyl ring, and / or 1 R and R in formulae IV and VI are each independently selected from H, alkyl, cycloalkyl or phenyl, or In formula VII, R 3 and R 4 are each independently selected from H, alkyl, alkoxy or halogen, or R 3 and R 4 together with the carbon to which they are attached form a 5- to 6-membered ring, or R 4 and R 4 together with the carbon to which they are attached form a 7- to 12-membered ring, the 5- to 6-membered ring being cyclopentane, cyclohexane or a ketal containing two oxygen atoms, the 7- to 12-membered being a ketal containing at least two oxygen atoms, and / or ​ the iridium salt is selected from the group consisting of chloro(1,5-cyclooctadiene)iridium dimer, bis(1,5-cyclooctadiene)iridium tetrafluoroborate, bis(1,5-cyclooctadiene)iridium(I) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, methoxy(cyclooctadiene)iridium dimer, chloro bis(cyclooctene)iridium(I) dimer, 1,5-cyclooctadiene(acetylacetonato)iridium, 1,5-cyclooctadiene(hexafluoroacetylacetonato)iridium(I), and / or the fluoroborate salt is selected from the group consisting of sodium tetrafluoroborate, silver tetrafluoroborate, sodium tetrakis(3,5-di(trifluoromethyl)phenyl)borate, or a combination thereof, and / or the fluorophosphate salt is selected from the group consisting of sodium hexafluorophosphate, potassium hexafluorophosphate, or a combination thereof.

6. The asymmetric catalytic hydrogenation synthesis method according to claim 4 or 5, wherein, the compound of formula I has the following structure of formula I-1: wherein R 5 and R 6 each independently is selected from H, an alkyl group, an acyl-containing group, said alkyl group being optionally further substituted by one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, phenyl, acyl-containing substituents, R 7 is H or a hydroxyl protecting group, R 8 is selected from H or alkyl, cycloalkyl, said alkyl, cycloalkyl being optionally further substituted by one or more substituents selected from halogen, nitro, cyano, amino, alkyl, alkoxy, phenyl.

7. The asymmetric catalytic hydrogenation synthesis process of claim 3, wherein, formula I-1 is selected from the group consisting of the following structures:

8. The asymmetric catalytic hydrogenation synthesis method according to claim 4 or 5, characterized in that, the catalyst is selected from the group consisting of the following structures:

9. The asymmetric catalytic hydrogenation synthesis process of claim 7, wherein, the catalyst is selected from the group consisting of the following structures:

10. The asymmetric catalytic hydrogenation synthesis process of claim 9, wherein, the catalyst is selected from the group consisting of the following structures:

11. The asymmetric catalytic hydrogenation method according to claim 4 or 5, wherein, the reaction temperature of the asymmetric catalytic hydrogenation is -20-60°C, and / or the asymmetric catalytic hydrogenation is carried out under a hydrogen pressure of 1-80 bar, and / or the molar ratio of the compound of formula I to the catalyst is 10000:1-100:

1.

12. The asymmetric catalytic hydrogenation method according to claim 4 or 5, wherein, the reaction temperature of the asymmetric catalytic hydrogenation is 4-40°C, and / or the asymmetric catalytic hydrogenation is carried out under a hydrogen pressure of 40-60 bar, and / or the molar ratio of the compound of formula I to the catalyst is 3000:1-200:

1.

13. The asymmetric catalytic hydrogenation synthesis process of claim 4 or 5, wherein, the method for preparing the catalyst by reacting the ligand, the iridium salt, and the inorganic salt comprises the steps of: (1) reacting the ligand and the iridium salt to form a complex; (2) adding the inorganic salt to the reaction solution of step (1) so that the inorganic salt and the complex form the catalyst.

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