Preparation method for catalytic synthesis of tofacitinib intermediate by chiral quaternary ammonium salt ion pair

Abstract

The invention discloses a preparation method for catalytic synthesis of a tofacitinib intermediate through chiral quaternary ammonium salt ion pairs. The invention specifically provides a preparation method of a compound 4, which comprises the following step: in an aprotic solvent, in the presence of an alkaline reagent and a chiral catalyst I, carrying out a reaction as shown in the specification on a compound 2 and a compound 3 to generate the compound 4. According to the preparation method disclosed by the invention, the use of a highly toxic reagent is avoided, the pollution is small, the synthesis route is simplified, the safety is high, the process cost is reduced, and meanwhile, the yield and ee value of the preparation method are relatively high.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing an intermediate for the chiral quaternary ammonium salt ion-catalyzed synthesis of tofacitinib. Background Technology

[0002] Tofacitinib citrate is a tyrosine kinase (JAK) family inhibitor developed by Pfizer in recent years for the treatment of some patients with moderate to severe active rheumatoid arthritis (Mark E. Flanagan et al., J. Med. Chem. 2010, 53, 8468-8484). Its key intermediate, (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine (3R,4R-1), is used to prepare tofacitinib citrate, with the following chemical structure:

[0003]

[0004] This product was first approved for marketing in the United States on November 6, 2012, and has since been approved for marketing in more than 50 countries and regions worldwide, including the United States, Japan, Russia, Australia, and Canada. Tofacitinib is indicated for adult patients with moderate to severe active rheumatoid arthritis (RA) who have had insufficient response to or are intolerant of methotrexate, and can be used in combination with methotrexate or other non-biological disease-modifying antirheumatic drugs (DMARDs). Tofacitinib citrate was approved for marketing in my country on March 10, 2017. Global sales of tofacitinib citrate reached $1.3 billion in 2017 and are projected to reach $2.4 billion in 2022. The chiral piperidineamine (3R, 4R-1) with two chiral centers in its molecular structure is a key challenge in the synthesis of this drug, and it is currently mainly prepared through chemical chiral resolution, asymmetric hydrogenation, and chiral source synthesis methods.

[0005] In 2003, B. Ripin et al. of Pfizer (Org. Process Res. Dev. 2003, 7, 115-120) used readily available 4-methylpyridine, which was converted to a salt by benzyl chloride, followed by three-step reduction with sodium borohydride to obtain N-benzyl-4-methyltetrahydropyridine (5). The double bond was borohydride, hydrogen peroxide was used for oxidation, p-toluenesulfonic acid was used for salt formation and Swern oxidation, and the carbonyl group was reduced by methylamine to obtain cis racemic rac-3. The three-step yield was about 55%. Finally, it was resolved by L-dibenzoyl tartaric acid to obtain (3R,4R)-1 with a maximum total yield of 11.4%.

[0006]

[0007] In 2007, Pfizer researchers SG Ruggeri et al. (2007, WO2007012953-A2) used methyl (4-methylpyridin-3-yl)carbamate as a starting material. They achieved asymmetric hydrogenation via benzylation followed by a high-pressure reaction with rhodium as a catalyst. Alternatively, the benzylated pyridinium salt was reduced with sodium borohydride to generate an enamine intermediate. High-pressure rhodium-catalyzed asymmetric hydrogenation was also achieved, yielding 68% ee (84% cis) and 66% ee (97% cis) respectively.

[0008]

[0009] In 2018, L. Lefort et al. (Org. Process Res. Dev. 2018, 22, 1817-1822) developed a method for axially chiral bisphosphine ligand S-BipheP / iridium-catalyzed piperidinone 6 to yield the key intermediate chiral amine (3R,4R)-1 in 86% separate yield and 97% ee under 50 bar hydrogen atmosphere at a substrate / catalyst molar ratio of (1000:1) equivalent, with a 97% ee. [8] .

[0010]

[0011] In 2019, Tang Wenjun et al. (Angew. Chem. Int. Ed. 2019, 58, 13573-13583) used a sterically hindered bisphosphine ligand developed by our research group to form a complex with a rhodium salt to catalyze the high-pressure (500 psi) asymmetric hydrogenation of 1-trifluoromethanesulfonyl-3-acetamido-4-methyltetrahydropyridine with high enantioselectivity of 96% ee to obtain the corresponding hydrogenation product. After detrifluoromethanesulfonylation, 1-benzyl protection, hydrolysis of the acetyl group with hydrochloric acid, and formylation of the nitrogen atom at the 3-position, further reduction with DIBAL-H yielded the chiral amine (3R,4R)-1.

[0012]

[0013] In 2022, Zhu Dengming, Wu Qiaqing, and others (Adv. Synth. Catal. 2022, 364, 2380-2386) used imine reductase and the coenzyme NADPH to catalyze the dynamic kinetic amination reduction of N-benzylpiperidinone and methylamine. Eight of the reductases exhibited high stereoselectivity (99% ee, 99:1 dr), and the substrate N-benzylpiperidinone showed good conversion at a concentration of 100 μmol. Notably, using different reductases yielded (3R,4R)-1 (83% yield, 97% ee, >99:1 dr) or (3S,4S)-1 (91% yield, 99% ee, >99:1 dr). This research lays the foundation for further green synthesis of tofacitinib.

[0014]

[0015] The synthetic methods reported above suffer from problems such as low synthesis efficiency, expensive chiral catalysts, and the generation of large amounts of wastewater during the production process. Developing a practical asymmetric synthetic method to prepare the key tofacitinib intermediate (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine (3R,4R)-1 has practical application value. Summary of the Invention

[0016] The main objective of this invention is to provide a method for preparing tofacitinib intermediates via chiral quaternary ammonium salt ion-pair catalysis. This route utilizes a chiral amino acid-derived hydrogen-bonded quaternary ammonium salt organic catalyst to catalyze the Michael addition reaction of unsaturated acylpyrroles as a key step. This route avoids the use of highly toxic reagents, has low pollution, simplifies the synthetic route, ensures high safety, reduces process costs, and also achieves high yields and ee values.

[0017] This invention provides a method for preparing compound 4, which includes the following steps:

[0018] In an aprotic solvent, in the presence of a basic reagent and chiral catalyst I, compounds 2 and 3 undergo the reaction shown below to produce compound 4;

[0019] ;

[0020] X is either N or CH;

[0021] R 1 For H, C6-C 10 aryl or aryl with one or more R 1-1 Replacement C6-C 10 Aryl;

[0022] R 2For C6-C 10 aryl, or with one or more R 2-1 Replacement C6-C 10 Aryl;

[0023] R 1-1 and R 2-1 Each is independently a C1-C6 alkyl, halogen, nitro, or a C1-C6 alkyl group substituted with one or more halogens;

[0024] R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C1-C6 alkyl or C6-C 10 Aryl;

[0025] R 3-1 For C6-C 10 Aryl;

[0026] Z is either O or S;

[0027] Y represents a halogen;

[0028] R 4 For C6-C 10 aryl, or with one or more R 4-1 Replacement C6-C 10 Aryl;

[0029] R 4-1 Independently -NO2, a C1-C6 alkyl group substituted with one or more halogens, a halogen, or a C1-C6 alkyl group;

[0030] R 5 For C1- 10 alkyl, by one or more R 5-1 Replacement C1- 10 Alkyl, C6-C 10 aryl, or with one or more R 5-2 Replacement C6-C 10 Aryl;

[0031] R 5-1 Independently for C6-C 10 Aryl, -OH, or 5-12-membered heteroaryl; wherein the heteroatoms in the 5-12-membered heteroaryl are independently selected from 1, 2, or 3 of N, O, and S, and the number of heteroatoms is independently 1-4;

[0032] R 5-2 It is a C1-C6 alkyl group;

[0033] R 6 For C6-C 10 aryl, or with one or more R 6-1 Replacement C6-C10 Aryl;

[0034] R 6-1 Independently halogenated, C1-C6 alkyl, and formed by one or more R a Substituted C1-C6 alkyl, C1-C6 alkoxy, or substituted with one or more R b Substituted C1-C6 alkoxy groups;

[0035] R a and R b Each is an independent halogen.

[0036] In one embodiment, certain groups in the compound may be defined as follows, and other groups may be defined as in any embodiment of the present invention (hereinafter referred to as "in one embodiment").

[0037] In one embodiment, the C6-C 10 The aryl group can be phenyl or naphthyl independently; for example, phenyl.

[0038] In one embodiment, the C1-C6 alkyl group is independently a C1-C4 alkyl group; preferably methyl, ethyl, propyl, isopropyl, or tert-butyl; for example, methyl or tert-butyl.

[0039] In one embodiment, the halogen is independently fluorine, chlorine, bromine, or iodine; for example, fluorine, chlorine, or bromine.

[0040] In one scheme, the C 1-10 The alkyl group is independently C 1-6 Alkyl; such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; such as methyl, isopropyl, sec-butyl or tert-butyl.

[0041] In one embodiment, the 5-12-membered heteroaryl group is a 5-6-membered heteroaryl group, the heteroatom is preferably N, and the number of heteroatoms is preferably 1 or 2.

[0042] In one embodiment, the C1-C6 alkoxy group is independently a C1-C4 alkoxy group; preferably methoxy, ethoxy, propoxy, isopropoxy, or tert-butoxy; for example, methoxy.

[0043] In one particular scheme, R 1 For C6-C 10 Aryl.

[0044] In one particular scheme, R 2 For C6-C 10 Aryl.

[0045] In one particular scheme, R 3 It is a C1-C6 alkyl group.

[0046] In one particular scheme, R 4 For one or more R 4-1 Replacement C6-C 10 Aryl.

[0047] In one particular scheme, R 4-1 Independently -NO2, or a C1-C6 alkyl group substituted with one or more halogens.

[0048] In one particular scheme, R 5 For one or more R 5-1 Replacement C1- 10 Alkyl groups.

[0049] In one particular scheme, R 5-1 For C6-C 10 Aryl.

[0050] In one particular scheme, R 6-1 Independently halogenated, C1-C6 alkyl, and formed by one or more R a Substituted C1-C6 alkyl or C1-C6 alkoxy.

[0051] In one particular scheme, R 4 for or .

[0052] In one particular scheme, R 5 It can be phenyl, benzyl, isobutyl, sec-butyl, tert-butyl, 2-hydroxy-ethyl, or 2-imidazolylmethyl.

[0053] In one particular scheme, R 6 For phenyl, , , or .

[0054] In one embodiment, compound 2 is... .

[0055] In one embodiment, compound 3 is... .

[0056] In one embodiment, compound 4 is... .

[0057] In one embodiment, the chiral catalyst is: , , , , , , , , , , , , , , or .

[0058] In one embodiment, the molar ratio of compound 2 to compound 3 is 1:(0.5~3), preferably 1:(0.8~1.5); for example, 1:1.

[0059] In one embodiment, the molar ratio of compound 2 to chiral catalyst I is 1:(0.005~0.2), preferably 1:(0.05~0.15); for example, 1:0.1.

[0060] In one embodiment, the alkaline reagent is a carbonate of an alkali metal (lithium, sodium, potassium, rubidium, cesium), an hydroxide of an alkali metal (lithium, sodium, potassium, rubidium, cesium), or an alkoxy anion, preferably cesium carbonate, cesium hydroxide, or potassium carbonate; for example, cesium carbonate.

[0061] In one embodiment, the amount of the alkaline reagent relative to compound 2 is 1-100 mol%, preferably 20-50 mol; for example, 30 mol.

[0062] In this invention, the aprotic solvent is a conventional aprotic solvent used in this type of reaction in the art.

[0063] In one embodiment, the aprotic solvent is an aromatic solvent, an ether solvent, a haloalkanes solvent, or a nitrile solvent;

[0064] The aromatic solvent is preferably toluene or benzene;

[0065] The preferred ether solvent is tetrahydrofuran, 1,4-dioxane, or diethyl ether.

[0066] The preferred halogenated hydrocarbon solvent is dichloromethane or carbon tetrachloride;

[0067] The preferred nitrile solvent is acetonitrile.

[0068] The aprotic solvent is diethyl ether.

[0069] The amount of solvent is not limited, as long as it does not affect the reaction. In one embodiment, the molar volume ratio of compound 2 to the aprotic solvent is (0.05~0.3) mol / L; for example, 0.15 mol / L.

[0070] In one embodiment, the reaction is carried out under the protection of an inert gas; the inert gas is preferably nitrogen, helium, or argon; for example, nitrogen.

[0071] In one embodiment, the reaction temperature is 0~50℃, preferably 20~30℃.

[0072] In one embodiment, the reaction time is 1 to 24 hours, preferably 2 to 6 hours.

[0073] In one embodiment, the preparation method of compound 4 further includes the following post-processing steps: after the reaction is completed, the reaction solution is separated (using water), the aqueous phase is extracted (using ethyl acetate), the obtained organic phase is dried, concentrated, and purified by column chromatography to obtain compound 4.

[0074] This invention provides a method for preparing compound 1, which includes the following steps:

[0075] ;

[0076] S1: Compound 4 was prepared by the method described in the preceding item;

[0077] S2: In an aprotic solvent and in the presence of a basic reagent, compound 4 reacts with benzylamine to give compound 5;

[0078] S3: In an aprotic solvent and in the presence of a basic reagent, compound 5 undergoes intramolecular cyclization to give compound 6;

[0079] S4: In an aprotic solvent and in the presence of a basic reagent, compound 6 reacts with di-tert-butyl dicarbonate to give compound 7;

[0080] S5: In an aprotic solvent, compound 7 reacts with a reducing agent to give compound 1.

[0081] In one embodiment, in S2, the aprotic solvent is an aromatic solvent, an ether solvent, a haloalkanes solvent, or a nitrile solvent;

[0082] The aromatic solvent is preferably toluene or benzene;

[0083] The preferred ether solvent is tetrahydrofuran, 1,4-dioxane, or diethyl ether.

[0084] The preferred halogenated hydrocarbon solvent is dichloromethane, dichloroethane, or carbon tetrachloride.

[0085] The preferred nitrile solvent is acetonitrile.

[0086] The aprotic solvent is tetrahydrofuran.

[0087] The amount of solvent is not limited, as long as it does not affect the reaction. In one embodiment, in S2, the molar volume ratio of compound 4 to the aprotic solvent is (0.1-0.4) mol / L; for example, 0.22 mol / L.

[0088] In one embodiment, in S2, the alkaline reagent is a nitrogen-containing organic base, an alkali metal carbonate, an alkali metal phosphate, or an alkali metal hydroxide.

[0089] The nitrogen-containing organic base is preferably triethylamine, N,N-diisopropylethylamine, triethylenediamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0090] The alkali metal in the alkali metal carbonate, alkali metal phosphate, and alkali metal hydroxide is preferably lithium, sodium, potassium, rubidium, or cesium.

[0091] The alkaline reagent is preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0092] In one embodiment, in S2, the amount of the alkaline reagent relative to compound 4 is 10-200 mol%, preferably 120-180 mol% or 30-50 mol%; for example, 41 mol.

[0093] In one embodiment, in S2, the molar ratio of compound 4 to benzylamine is 1:(1~3), preferably 1:(1.2~2); for example, 1:1.5.

[0094] In one embodiment, in S2, the reaction is carried out under the protection of an inert gas; the inert gas is preferably nitrogen, helium, or argon; for example, nitrogen.

[0095] In one embodiment, in step S2, the reaction temperature is 20~60℃, preferably 40~60℃; for example, 50℃.

[0096] In one embodiment, in S2, the reaction time is 1 to 24 hours, preferably 10 to 16 hours.

[0097] In one particular scheme, S2 also includes the following post-processing steps: after the reaction is completed, the reaction solution is separated (using water), the aqueous phase is extracted (using ethyl acetate), the obtained organic phase is dried, concentrated, and purified by column chromatography to obtain compound 5.

[0098] In one embodiment, in S3, the aprotic solvent is an aromatic solvent, an ether solvent, a haloalkanes solvent, or a nitrile solvent;

[0099] The aromatic solvent is preferably toluene or benzene;

[0100] The preferred ether solvent is tetrahydrofuran, 1,4-dioxane, or diethyl ether.

[0101] The preferred halogenated hydrocarbon solvent is dichloromethane, dichloroethane, or carbon tetrachloride.

[0102] The preferred nitrile solvent is acetonitrile.

[0103] The aprotic solvent is tetrahydrofuran.

[0104] The amount of solvent is not limited, as long as it does not affect the reaction. In one embodiment, in S3, the molar volume ratio of compound 5 to the aprotic solvent is (0.1-0.4) mol / L; for example, 0.21 mol / L.

[0105] In one embodiment, compound 5 is... .

[0106] In one embodiment, in S3, the alkaline reagent is a nitrogen-containing organic base, an alkali metal carbonate, an alkali metal hydroxide, or an amino-lithium compound.

[0107] The nitrogen-containing organic base is preferably triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0108] The preferred alkali metal carbonate is cesium carbonate.

[0109] The alkali metal hydroxide is preferably lithium hydroxide, sodium hydroxide, or potassium hydroxide.

[0110] The preferred amino-lithium compound is diisopropylaminolithium (LDA), bis(trimethylsilylaminolithium) (LiHMDS), bis(trimethylsilylaminosodium) (NaHMDS), or bis(trimethylsilylaminopotassium) (KHMDS).

[0111] The preferred base used is lithium bistrimethylsilylaminolithium (LiHMDS), sodium bistrimethylsilylaminolithium (NaHMDS), potassium bistrimethylsilylaminolithium (KHMDS), lithium diisopropylaminolithium (LDA), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0112] In one embodiment, in S3, the amount of the alkaline reagent relative to compound 5 is 20-150 mol%, preferably 90-110 mol; for example, 100 mol.

[0113] In one embodiment, in step S3, the reaction is carried out under the protection of an inert gas; the inert gas is preferably nitrogen, helium, or argon; for example, nitrogen.

[0114] In one embodiment, in step S3, the reaction temperature is -80~60℃, preferably -70~30℃; for example, -70℃.

[0115] In one embodiment, in step S3, the reaction time is 1 to 24 hours, preferably 2 to 10 hours.

[0116] In one embodiment, S3 further includes the following post-processing steps: after the reaction is completed, a saturated ammonium chloride solution is added to the reaction solution for separation and extraction of the aqueous phase (using ethyl acetate). The obtained organic phase is washed with water, dried, and concentrated. The crude product is dissolved in THF, an acidic reagent is added, the pH value is adjusted (using a saturated sodium bicarbonate solution to a value greater than 7), extraction is performed, and the obtained organic phase is dried and concentrated. After purification by column chromatography, compound 6 is obtained.

[0117] In one embodiment, the acidic reagent is an inorganic or organic acid. The inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, hypochlorous acid, hypobromic acid, hypophosphorous acid, and hyposulfuric acid. The organic acid includes formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, citric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, or camphorsulfonic acid. Hydrochloric acid is preferably the acidic reagent.

[0118] In one embodiment, the amount of the acidic reagent relative to compound 5 is 20-300 mol%, preferably 90-150 mol.

[0119] In one embodiment, in S4, the aprotic solvent is an aromatic solvent, an ether solvent, a haloalkanes solvent, or a nitrile solvent;

[0120] The aromatic solvent is preferably toluene or benzene;

[0121] The preferred ether solvent is tetrahydrofuran, 1,4-dioxane, or diethyl ether.

[0122] The preferred halogenated hydrocarbon solvent is dichloromethane, dichloroethane, or carbon tetrachloride.

[0123] The preferred nitrile solvent is acetonitrile.

[0124] The aprotic solvent is dichloromethane.

[0125] The amount of solvent is not limited, as long as it does not affect the reaction. In one embodiment, in S4, the molar volume ratio of compound 6 to the aprotic solvent is (0.2-0.5) mol / L; for example, 0.3 mol / L.

[0126] In one embodiment, in S4, the molar ratio of compound 6 to ditert-butyl dicarbonate is 1:(1~4), preferably 1:(1~2); for example, 1:1.38.

[0127] In one embodiment, in S4, the alkaline reagent is a nitrogen-containing organic base, an alkali metal carbonate, or an alkali metal hydroxide.

[0128] The nitrogen-containing organic base is preferably triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0129] The alkali metal carbonate is preferably cesium carbonate, potassium carbonate, or sodium carbonate.

[0130] The alkali metal hydroxide is preferably lithium hydroxide, sodium hydroxide, or potassium hydroxide.

[0131] The alkaline reagent is preferably triethylamine.

[0132] In one embodiment, in S4, the amount of the alkaline reagent relative to compound 6 is 20-500 mol%, preferably 100-300 mol; for example, 200 mol.

[0133] In one embodiment, in step S4, the reaction temperature is 10~60℃, preferably 20~30℃.

[0134] In one embodiment, in step S4, the reaction time is 1 to 24 hours, preferably 1 to 5 hours.

[0135] In one particular scheme, S4 also includes the following post-processing steps: after the reaction is completed, the reaction solution is separated, the aqueous phase is extracted (using ethyl acetate), the resulting organic phase is dried, concentrated, and purified by column chromatography to obtain compound 4.

[0136] In one embodiment, in S5, the aprotic solvent is an aromatic solvent, an ether solvent, a haloalkanes solvent, or a nitrile solvent;

[0137] The aromatic solvent is preferably toluene or benzene;

[0138] The preferred ether solvent is tetrahydrofuran, 1,4-dioxane, or diethyl ether.

[0139] The preferred halogenated hydrocarbon solvent is dichloromethane, dichloroethane, or carbon tetrachloride.

[0140] The preferred nitrile solvent is acetonitrile.

[0141] The aprotic solvent is preferably tetrahydrofuran.

[0142] The amount of solvent is not limited, as long as it does not affect the reaction. In one embodiment, in step S5, the molar volume ratio of compound 7 to the aprotic solvent is (0.05-0.3) mol / L; for example, 0.12 mol / L.

[0143] In one embodiment, in step S5, the reducing agent is lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium triethylborohydride, borane, lithium aluminum hydride, or red aluminum, preferably red aluminum or lithium aluminum hydride.

[0144] In one embodiment, in step S5, the molar ratio of compound 7 to the reducing agent is 1:(2-10); preferably 1:(4-8); for example, 1:6.

[0145] In one embodiment, in step S5, the reaction is carried out under the protection of an inert gas; the inert gas is preferably nitrogen, helium, or argon; for example, nitrogen.

[0146] In one embodiment, in step S5, the reaction temperature is 10~120℃, preferably 50~80℃.

[0147] In one embodiment, in step S5, the reaction time is 1 to 24 hours, preferably 2 to 8 hours.

[0148] In one scheme, S5 also includes the following post-processing steps: after the reaction is completed, the reaction solution is quenched (using sodium sulfate decahydrate), filtered, and the resulting organic phase is concentrated to obtain compound 7.

[0149] This invention provides a catalyst with the following structure:

[0150] .

[0151] The present invention also provides the application of the catalyst described above in the Michael addition reaction of unsaturated acyl aryl groups.

[0152] In one embodiment, the reaction conditions and operations in the application are as described in any embodiment of the preparation method of the preceding compound 4.

[0153] This invention provides a compound or a salt thereof.

[0154] or ;

[0155] R 2 R 3 The definition of X is as stated in the previous item.

[0156] The present invention provides a method for preparing compound 5, which includes the following steps: in an aprotic solvent, in the presence of a basic reagent, compound 4 reacts with benzylamine to obtain compound 5;

[0157] ;

[0158] The preparation conditions of compound 5 are as described in any embodiment of the present invention.

[0159] Preferably, the method for preparing compound 4 further includes the preparation of compound 4; the preparation conditions of compound 4 are as described in any embodiment of the present invention.

[0160] The present invention provides a method for preparing compound 6, which includes the following steps: in an aprotic solvent, in the presence of a basic reagent, compound 5 undergoes intramolecular cyclization to obtain compound 6;

[0161] ;

[0162] The preparation conditions of compound 6 are as described in any embodiment of the present invention.

[0163] Preferably, the preparation method of compound 6 further includes the preparation of compound 5; the preparation conditions of compound 5 are as described in any embodiment of the present invention.

[0164] The present invention provides a method for preparing compound 7, which includes the following steps: reacting compound 6 with ditert-butyl dicarbonate in an aprotic solvent in the presence of a basic reagent to obtain compound 7;

[0165] ;

[0166] The preparation conditions of compound 7 are as described in any embodiment of the present invention.

[0167] Preferably, the preparation method of compound 7 further includes the preparation of compound 6; the preparation conditions of compound 6 are as described in any embodiment of the present invention.

[0168] The present invention solves the above-mentioned technical problems through the following technical solution:

[0169] The positive and progressive effects of this invention are as follows: the synthetic route of the tofacitinib intermediate (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine (3R,4R)-1 has a high yield and ee value. At the same time, the synthesis avoids the use of highly toxic reagents, has low pollution, is simple to operate, has high safety, and reduces process costs. Detailed Implementation

[0170] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0171] Example 1

[0172] Preparation of compound 4-1:

[0173]

[0174] Experimental procedure: 300 mg (2.22 mmol) of compound 2-1 (1 equiv.) and 655 mg (2.22 mmol) of compound 3-1 (1 equiv.) were added to a three-necked flask, followed by 15 mL of diethyl ether and stirring to dissolve. Then, a chiral catalyst (0.22 mmol, 0.1 equiv.) and 217 mg of cesium carbonate (0.67 mmol, 0.3 equiv.) were added. The mixture was purged with nitrogen and kept under nitrogen protection. The mixture was stirred at room temperature for 6 h.

[0175] Reaction monitoring: TLC (PE : EA = 5 : 1) showed that the reactants reacted completely, and LC-MS monitoring also confirmed that the reaction was complete.

[0176] Post-processing: The reaction solution was poured into 20 mL of water, stirred and separated. The aqueous phase was extracted with EA (3 x 15 mL), the organic phases were combined, backwashed with saturated brine (2 x 15 mL), dried with anhydrous sodium sulfate and then evaporated to dryness. The product 4-1 was purified by column chromatography. The yield and ee value of the reaction under different catalysts are shown in the table below.

[0177] 1 H-NMR (400 MHz, CDCl3) δ 7.71 - 7.61 (m, 2H), 7.50 - 7.30 (m, 8H), 7.16 (dd, J = 6.5, 3.1 Hz, 2H), 6.32 - 6.23 (m, 2H), 3.92 (d, J = 4.0 Hz,1H), 3.21 (m, 1H), 3.00 - 2.83 (m, 2H), 1.43 (s, 9H), 0.97 (dd, J = 6.5, 4.1Hz, 3H).

[0178]

[0179]

[0180] Example 2

[0181] Preparation of compound 5-1:

[0182]

[0183] Experimental procedure: 9.6 g (22.29 mmol) of compound 4-1 was added to a three-necked flask and 100 mL of THF was added and stirred to dissolve. Then, 3.58 g (33.41 mmol, 1.4 equiv.) of benzylamine and 1.5 g (9.85 mmol, 0.41 equiv.) of DBU were added separately. The mixture was purged with nitrogen and protected. The temperature was raised to 50 °C and the reaction was carried out for 16 h.

[0184] Reaction monitoring: TLC (PE : EA = 5 : 1) showed that the reaction was complete.

[0185] Post-processing: The reaction solution was poured into 200 mL of water, stirred, and separated. The aqueous phase was extracted with EA (3 x 50 mL). The organic phases were combined, backwashed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness. After purification by column chromatography, 7.2 g of white solid product 5-1 was obtained, with a yield of 68%.

[0186] 1 H-NMR (400 MHz, CDCl3) δ 7.68 - 7.58 (m, 2H), 7.50 - 7.35 (m, 4H), 7.34 - 7.21 (m, 8H), 7.13 (dd, J = 6.5, 3.1 Hz, 2H), 6.35 (s, 1H), 4.46 (dd,J = 14.7, 6.0 Hz, 1H), 4.34 (dd,J = 14.7, 5.4 Hz, 1H), 3.86 (d,J = 4.4 Hz,1H), 2.72 (m, 1H), 2.59 (m, 1H), 2.28 (m, 1H), 1.42 (s, 9H), 0.96 (d, J = 6.9Hz, 2H).

[0187] Example 3

[0188] Preparation of compound 6:

[0189]

[0190] Experimental procedure: Dissolve 6.0 g (12.75 mmol) of compound 5-1 in 60 mL THF, purge with nitrogen for protection, cool to -70 °C, slowly add LiHMDS (12.75 mmol, 1 equiv.) to the system, maintain the low temperature of -70 °C for 1 h, and then continue stirring for 8 h, allowing the system to return to room temperature naturally during the process.

[0191] Reaction monitoring: TLC showed that the reaction was complete.

[0192] Post-processing: The reaction solution was poured into 100 mL of saturated ammonium chloride solution, stirred, and separated. The aqueous phase was extracted with EA (3 x 30 mL), the organic phases were combined, backwashed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain 5.3 g of dark green crude product. The crude product was dissolved in 40 mL of THF, and 10 mL of water and 10 mL of dilute hydrochloric acid (2 M) were added respectively. The mixture was stirred at room temperature for 4 h. The reaction solution was then poured into saturated sodium bicarbonate solution and stirred, ensuring that the pH of the solution was greater than 7. After separation, the aqueous phase was extracted with DCM (3 x 30 mL), the organic phases were combined, backwashed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness. After purification by column chromatography, 2.7 g of dark green liquid was obtained, with a yield of 90%.

[0193] 1 H-NMR (400 MHz, CDCl3) δ 7.38 - 7.18 (m, 5H), 4.94 (s, 2H), 3.67 (d,J = 4.5 Hz, 1H), 2.89 - 2.67 (m, 2H), 2.44 - 2.30 (m, 1H), 1.92 (s, 2H), 0.93(d, J = 6.9 Hz, 3H).

[0194] Example 4

[0195] Preparation of compound 7:

[0196]

[0197] Experimental procedure: Dissolve 2.7 g (11.62 mmol) of substrate 6 in 40 mL of DCM, then add 2.35 g (23.22 mmol, 2.0 equiv.) of triethylamine and 2.79 g (16.01 mmol, 1.38 equiv.) of di-tert-butyl dicarbonate, and react at room temperature for 4 h.

[0198] Reaction monitoring: TLC showed that the reaction was complete.

[0199] Post-processing: The reaction solution was poured into 50 mL of water, stirred, and separated. The aqueous phase was extracted with EA (3 x 20 mL). The organic phases were combined, backwashed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness. After purification by column chromatography, 2.65 g of a pale yellow solid product was obtained, with a yield of 68%.

[0200] 1H-NMR (400 MHz, CDCl3) δ 7.36 - 7.22 (m, 5H), 5.50 (s, 1H), 5.01 -4.88 (m, 2H), 4.48 (s, 1H), 2.91 (m, 1H), 2.72 (m, 2H), 1.45 (s, 9H), 0.87(d, J = 7.0 Hz, 3H).

[0201] Example 5

[0202] Preparation of compound (3R,4R)-1:

[0203]

[0204] Experimental procedure: Dissolve 2.0 g (6.01 mmol) of substrate 7 in 50 mL of ultradry THF, add 1.37 g (36.10 mmol, 6 equiv.) of lithium aluminum hydride, and heat under reflux for 5 h.

[0205] Reaction monitoring: TLC showed that the reaction was complete.

[0206] Post-processing: Sodium sulfate decahydrate was added in batches to quench the reaction in an ice bath. After filtration, THF was evaporated to obtain 1.2 g of the target compound, with a yield of 91% and an ee value of 97%.

[0207] 1 H-NMR (400 MHz, CDCl3) δ 7.39 - 7.10 (m, 5H), 3.64 - 3.32 (m, 2H), 2.80 - 2.56 (m, 2H), 2.42 (s, 1H), 2.30 (s, 3H), 2.18 - 1.98 (m, 2H), 1.64(m, 2H), 1.52 - 1.39 (m, 2H), 0.93 (d, J = 6.9 Hz, 3H).

[0208] Example 6: Preparation of compound I-13

[0209]

[0210] Catalyst I-13 was prepared via the synthetic route shown above. Boc-protected tertiary leucine II was condensed with diethylamine, deprotected by TFA, and then reduced with lithium aluminum hydride to give compound V, which reacted with isocyanate to give VI-1, and then formed a salt with 3,5-di-tert-butylbenzyl bromide to give catalyst I-13.

[0211]

[0212] Boc-protected tertiary leucine was dissolved in dichloromethane. HATU was added, followed by dropwise addition of TEA. After the addition was complete, stirring continued for 1 hour, then dimethylamine-THF solution was added dropwise. The mixture was stirred at room temperature for 1 hour after the addition was finished. The reaction solution was poured into water and stirred. After separation, the layers were extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The product was purified by DCM / MeOH column chromatography in 82.0% yield.

[0213]

[0214] Compound III was dissolved in 150 mL of dichloromethane, and dioxane hydrochloride solution (4 M, 5 eq) was added. The mixture was stirred at room temperature for 3 h. After the reaction was complete as monitored by TLC, saturated sodium bicarbonate solution was added dropwise to the reaction mixture and stirred until no more bubbles were generated. After separation, the aqueous phase was extracted three times with dichloromethane. The organic phases were combined and dried directly with anhydrous sodium sulfate to obtain compound IV, which could be used directly in the next reaction without purification. Crude yield: 100%.

[0215]

[0216] Take 11g of compound IV into a three-necked flask, add 250 mL of diethyl ether, purge with nitrogen for protection, and add 6.8g of lithium aluminum hydride in portions under ice bath conditions. After the addition is complete, continue purging with nitrogen to purge hydrogen from the flask until the liquid surface is almost completely bubbling. Remove the ice bath and react at room temperature for 6 hours. Add sodium sulfate decahydrate in portions under ice bath conditions, controlling the internal temperature to not exceed 30°C. Filter, dry the diethyl ether solution with anhydrous sodium sulfate, filter again, and concentrate the reaction solution to approximately 150 mL, which can be used directly for the next reaction step.

[0217]

[0218] 17.3 g of isocyanate (1.2 eq) was added to the prepared V ether solution and reacted at room temperature for 10 min. TLC showed that the starting material was basically completely reacted. Silica gel powder was added and the sample was directly mixed for column chromatography purification to obtain 14 g of white solid.

[0219]

[0220] 2 g of compound VI-1 was dissolved in 20 mL of acetonitrile, and 1.7 g of di-tert-butylbenzyl bromide was added. The reaction was carried out at room temperature for 1 h. The reaction was monitored by TLC until the starting material was completely reacted. Silica gel powder was added and the sample was directly mixed for column chromatography purification. 3.2 g of a white solid was obtained, which was catalyst I-13. 1HNMR (400 MHz, Chloroform-d) δ 9.58 (s, 1H), δ 8.03 (s, 2H), 7.88 (s, 1H), 7.55 (s, 1H), 7.39 (s, 1H), 7.32 (d, J = 1.5 Hz, 2H), 4.86 (d, J = 12.5 Hz,1H), 4.64 (d, J = 12.7 Hz, 1H), 4.23 (t, J = 9.5 Hz, 1H), 4.11 – 3.70 (m,2H), 3.23 (s, 3H), 3.11 (s, 3H), 1.29 (s, 18H), 1.09 (s, 9H).MS:ESI:602.25[M] + .

[0221] Comparative Example 1:

[0222]

[0223] Referring to the preparation of compound 4-1, benzylamide 2-X was reacted with Mannich base 3-1 under the condition of catalyst I-9, with the expectation of directly obtaining product 5-1. However, this reaction could not proceed, and the raw materials were recovered.

[0224] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for preparing compound 4, characterized in that, It includes the following steps: In an aprotic solvent, in the presence of a basic reagent and chiral catalyst I, compounds 2 and 3 undergo the reaction shown below to produce compound 4; ； X is either N or CH; R 1 For H, C6-C 10 aryl or aryl with one or more R 1-1 Replacement C6-C 10 Aryl; R 2 For C6-C 10 aryl, or with one or more R 2-1 Replacement C6-C 10 Aryl; R 1-1 and R 2-1 Each is independently a C1-C6 alkyl, halogen, nitro, or a C1-C6 alkyl group substituted with one or more halogens; R 3 It is a C1-C6 alkyl group, with one or more R 3-1 Substituted C1-C6 alkyl or C6-C 10 Aryl; R 3-1 For C6-C 10 Aryl; Z is either O or S; Y represents a halogen; R 4 For C6-C 10 aryl, or with one or more R 4-1 Replacement C6-C 10 Aryl; R 4-1 Independently -NO2, a C1-C6 alkyl group substituted with one or more halogens, a halogen, or a C1-C6 alkyl group; R 5 For C1- 10 alkyl, by one or more R 5-1 Replacement C1- 10 Alkyl, C6-C 10 aryl, or with one or more R 5-2 Replacement C6-C 10 Aryl; R 5-1 Independently for C6-C 10 Aryl, -OH, or 5-12-membered heteroaryl; wherein the heteroatoms in the 5-12-membered heteroaryl are independently selected from 1, 2, or 3 of N, O, and S, and the number of heteroatoms is independently 1-4; R 5-2 It is a C1-C6 alkyl group; R 6 For C6-C 10 aryl, or with one or more R 6-1 Replacement C6-C 10 Aryl; R 6-1 Independently halogenated, C1-C6 alkyl, and formed by one or more R a Substituted C1-C6 alkyl, C1-C6 alkoxy, or substituted with one or more R b Substituted C1-C6 alkoxy groups; R a and R b Each is an independent halogen.

2. The method for preparing compound 4 according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The C6-C 10 The aryl group can be phenyl or naphthyl independently; for example, phenyl. (2) The C1-C6 alkyl group is independently a C1-C4 alkyl group; preferably methyl, ethyl, propyl, isopropyl or tert-butyl; for example methyl or tert-butyl; (3) The halogen is independently fluorine, chlorine, bromine or iodine; for example, fluorine, chlorine or bromine; (4) The C 1-10 The alkyl group is independently C 1-6 Alkyl; such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; such as methyl, isopropyl, sec-butyl, or tert-butyl. (5) The 5-12-membered heteroaryl group is a 5-6-membered heteroaryl group, the heteroatom is preferably N, and the number of heteroatoms is preferably 1 or 2; (6) The C1-C6 alkoxy group is independently a C1-C4 alkoxy group; preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or a tert-butoxy group; for example, a methoxy group.

3. The method for preparing compound 4 as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) Compound 2 is ; (2) Compound 3 is ; (3) Compound 4 is ; (4) The chiral catalyst is , , , , , , , , , , , , , , or .

4. The method for preparing compound 4 according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The molar ratio of compound 2 to compound 3 is 1:(0.5~3), preferably 1:(0.8~1.5); for example, 1:1; (2) The molar ratio of compound 2 to chiral catalyst I is 1:(0.005~0.2), preferably 1:(0.05~0.15); for example, 1:0.1; (3) The alkaline reagent is an alkali metal carbonate, alkali metal hydroxide, or alkoxy anion, preferably cesium carbonate, cesium hydroxide, or potassium carbonate; for example, cesium carbonate; (4) The amount of the alkaline reagent relative to compound 2 is 1-100 mol%, preferably 20-50 mol%; for example, 30 mol% (5) The aprotic solvent is an aromatic solvent, an ether solvent, a haloalkanes solvent, or a nitrile solvent; The aromatic solvent is preferably toluene or benzene; The preferred ether solvent is tetrahydrofuran, 1,4-dioxane, or diethyl ether. The preferred halogenated hydrocarbon solvent is dichloromethane or carbon tetrachloride; The preferred nitrile solvent is acetonitrile; The preferred aprotic solvent is diethyl ether; (6) The molar volume ratio of compound 2 to the aprotic solvent is (0.05~0.3) mol / L; for example, 0.15 mol / L; (7) The reaction is carried out under the protection of an inert gas; the inert gas is preferably nitrogen, helium or argon; for example, nitrogen; (8) The reaction temperature is 0~50℃, preferably 20~30℃; (9) The preparation method of compound 4 further includes the following post-processing steps: after the reaction is completed, the reaction solution is separated, the aqueous phase is extracted, the obtained organic phase is dried, concentrated, and purified by column chromatography to obtain compound 4.

5. A method for preparing compound 1, characterized in that, It includes the following steps: ； S1: Compound 4 is prepared by the method described in any one of claims 1 to 4. S2: In an aprotic solvent and in the presence of a basic reagent, compound 4 reacts with benzylamine to give compound 5; S3: In an aprotic solvent and in the presence of a basic reagent, compound 5 undergoes intramolecular cyclization to give compound 6; S4: In an aprotic solvent and in the presence of a basic reagent, compound 6 reacts with di-tert-butyl dicarbonate to give compound 7; S5: In an aprotic solvent, compound 7 reacts with a reducing agent to give compound 1.

6. The method for preparing compound 1 as described in claim 5, characterized in that, It satisfies one or more of the following conditions: (1) In S2, the aprotic solvent is an aromatic solvent, an ether solvent, a haloalkanes solvent, or a nitrile solvent; The aromatic solvent is preferably toluene or benzene; The preferred ether solvent is tetrahydrofuran, 1,4-dioxane, or diethyl ether. The preferred halogenated hydrocarbon solvent is dichloromethane, dichloroethane, or carbon tetrachloride. The preferred nitrile solvent is acetonitrile; The aprotic solvent is preferably tetrahydrofuran; (2) In S2, the molar volume ratio of compound 4 to the aprotic solvent is (0.1-0.4) mol / L; for example, 0.22 mol / L; (3) In S2, the alkaline reagent is a nitrogen-containing organic base, an alkali metal carbonate, an alkali metal phosphate, or an alkali metal hydroxide; The nitrogen-containing organic base is preferably triethylamine, N,N-diisopropylethylamine, triethylenediamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene; The alkali metal in the alkali metal carbonate, alkali metal phosphate, and alkali metal hydroxide is preferably lithium, sodium, potassium, rubidium, or cesium. The alkaline reagent is preferably 1,8-diazabicyclo[5.4.0]undec-7-ene; (4) In S2, the amount of the basic reagent relative to compound 4 is 10-200 mol%, preferably 120-180 mol% or 30-50 mol%; for example, 41 mol%; (5) In S2, the molar ratio of compound 4 to benzylamine is 1:(1~3), preferably 1:(1.2~2); for example, 1:1.5; (6) In S2, the reaction is carried out under the protection of an inert gas; the inert gas is preferably nitrogen, helium or argon; for example, nitrogen; (7) In S2, the reaction temperature is 20~60℃, preferably 40~60℃; for example, 50℃; (8) S2 also includes the following post-processing steps: after the reaction is completed, the reaction solution is separated, the aqueous phase is extracted, the obtained organic phase is dried, concentrated, and purified by column chromatography to obtain compound 5; (9) In S3, the aprotic solvent is an aromatic solvent, an ether solvent, a haloalkanes solvent, or a nitrile solvent; The aromatic solvent is preferably toluene or benzene; The preferred ether solvent is tetrahydrofuran, 1,4-dioxane, or diethyl ether. The preferred halogenated hydrocarbon solvent is dichloromethane, dichloroethane, or carbon tetrachloride. The preferred nitrile solvent is acetonitrile; The aprotic solvent is preferably tetrahydrofuran; (10) In S3, the molar volume ratio of compound 5 to the aprotic solvent is (0.1-0.4) mol / L; for example, 0.21 mol / L; (11) Compound 5 is ; (12) In S3, the alkaline reagent is a nitrogen-containing organic base, an alkali metal carbonate, an alkali metal hydroxide, or an amino lithium compound; The nitrogen-containing organic base is preferably triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene; The preferred alkali metal carbonate is cesium carbonate; The alkali metal hydroxide is preferably lithium hydroxide, sodium hydroxide, or potassium hydroxide; The preferred amino-lithium compound is diisopropylaminolithium, bis(trimethylsilylaminolithium), bis(trimethylsilylaminosodium), or bis(trimethylsilylaminopotassium); The preferred base used is lithium bis(trimethylsilylamino), sodium bis(trimethylsilylamino), potassium bis(trimethylsilylamino), lithium diisopropylamino, or 1,8-diazabicyclo[5.4.0]undec-7-ene; (13) In S3, the amount of the basic reagent relative to compound 5 is 20-150 mol%, preferably 90-110 mol%; for example, 100 mol%. (14) In S3, the reaction is carried out under the protection of an inert gas; the inert gas is preferably nitrogen, helium or argon; for example, nitrogen; (15) In S3, the reaction temperature is -80~60℃, preferably -70~30℃; for example -70℃; (16) The S3 further includes the following post-processing steps: after the reaction is completed, saturated ammonium chloride solution is added to the reaction solution for separation and extraction of the aqueous phase. The obtained organic phase is washed with water, dried and concentrated. The crude product is dissolved in THF, acidic reagent is added, pH value is adjusted and extracted, the obtained organic phase is dried and concentrated, and compound 6 is obtained after purification by column chromatography. Preferably, the acidic reagent is an inorganic acid or an organic acid; the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, hypochlorous acid, hypobromic acid, hypophosphorous acid, and hyposulfuric acid; the organic acid includes formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, citric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, or camphorsulfonic acid; the acidic reagent is preferably hydrochloric acid. Preferably, the amount of the acidic reagent relative to compound 5 is 20-300 mol%, more preferably 90-150 mol%.

7. The method for preparing compound 1 as described in claim 5, characterized in that, It satisfies one or more of the following conditions: (1) In S4, the aprotic solvent is an aromatic solvent, an ether solvent, a haloalkanes solvent, or a nitrile solvent; The aromatic solvent is preferably toluene or benzene; The preferred ether solvent is tetrahydrofuran, 1,4-dioxane, or diethyl ether. The preferred halogenated hydrocarbon solvent is dichloromethane, dichloroethane, or carbon tetrachloride. The preferred nitrile solvent is acetonitrile; The aprotic solvent is preferably dichloromethane; (2) In S4, the molar volume ratio of compound 6 to the aprotic solvent is (0.2-0.5) mol / L; for example, 0.3 mol / L; (3) In S4, the molar ratio of compound 6 to ditert-butyl dicarbonate is 1:(1~4), preferably 1:(1~2); for example, 1:1.38; (4) In S4, the alkaline reagent is a nitrogen-containing organic base, an alkali metal carbonate, or an alkali metal hydroxide; The nitrogen-containing organic base is preferably triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene; The alkali metal carbonate is preferably cesium carbonate, potassium carbonate, or sodium carbonate. The alkali metal hydroxide is preferably lithium hydroxide, sodium hydroxide, or potassium hydroxide; The alkaline reagent is preferably triethylamine; (5) In S4, the amount of the basic reagent relative to compound 6 is 20-500 mol%, preferably 100-300 mol%; for example, 200 mol%. (6) In S4, the reaction temperature is 10~60℃, preferably 20~30℃; (7) S4 also includes the following post-processing steps: after the reaction is completed, the reaction solution is separated, the aqueous phase is extracted, the obtained organic phase is dried, concentrated, and purified by column chromatography to obtain compound 4; (8) In S5, the aprotic solvent is an aromatic solvent, an ether solvent, a haloalkanes solvent, or a nitrile solvent; The aromatic solvent is preferably toluene or benzene; The preferred ether solvent is tetrahydrofuran, 1,4-dioxane, or diethyl ether. The preferred halogenated hydrocarbon solvent is dichloromethane, dichloroethane, or carbon tetrachloride. The preferred nitrile solvent is acetonitrile; The aprotic solvent is preferably tetrahydrofuran; (9) In S5, the molar volume ratio of compound 7 to the aprotic solvent is (0.05-0.3) mol / L; for example, 0.12 mol / L; (10) In S5, the reducing agent is lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium triethylborohydride, borane, lithium aluminum hydride or red aluminum, preferably red aluminum or lithium aluminum hydride; (11) In S5, the molar ratio of compound 7 to the reducing agent is 1:(2-10); preferably 1:(4-8); for example 1:6; (12) In S5, the reaction is carried out under the protection of an inert gas; the inert gas is preferably nitrogen, helium or argon; for example, nitrogen; (13) In S5, the reaction temperature is 10~120℃, preferably 50~80℃; (14) S5 also includes the following post-processing steps: after the reaction is completed, the reaction solution is quenched, filtered, and the resulting organic phase is concentrated to obtain compound 7.

8. A catalyst having the structure shown below: 。 9. The application of the catalyst as described in claim 8 in the Michael addition reaction of unsaturated acylaryl groups; Preferably, the reaction conditions and operations in the application are as described in the preparation method of compound 4 according to any one of claims 1 to 4.

10. A compound or a salt thereof: or .

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