A process for the preparation of a phenylpiperidine derivative

Abstract

The application provides a preparation method of a phenylpiperidine derivative (formula (I)). The method has low cost, simple reaction route, simple operation, high intermediate yield in each step and is suitable for industrial production.

Description

A preparation method of phenylpiperidine derivatives Technical Field

[0001] The present invention relates to a preparation method of a pharmaceutical compound, in particular to a preparation method of a phenylpiperidine derivative, and belongs to the technical field of pharmaceutical chemistry. Background Art

[0002] Complement factor B is a component of the alternative complement pathway, involved in both specific and nonspecific immune responses. It contains a serine protease (SP) domain that, when activated, provides catalytic activity for the alternative pathway C3 and C5 convertases. Complement factor B circulates as an inactive proenzyme (i.e., zymogen) and becomes activated only after cleavage by the protein factor D. However, factor D can cleave complement factor B only when bound to the activated forms of C3: C3(H2O) and C3b. Complement factor B is produced as a single-chain protein and is cleaved by factor D to produce two peptide fragments (Ba and Bb). The Bb region (containing the SP domain) remains bound to C3(H2O) and C3b, forming the alternative pathway convertases (C3(H2O)Bb and C3bBb). As part of the C3 convertase, the SP domain of Bb has specific catalytic activity for the cleavage of C3 molecules. Another C3b molecule is added to the alternative pathway C3 convertase to produce C5 convertase (C3bBbC3b). As part of the alternative pathway C5 convertase, the SP domain of Bb cleaves the C5 molecule, enabling the assembly of C5-C9 and ultimately forming the membrane attack complex (MAC). This complex mediates various renal diseases through multiple pathways, including cell lysis, promotion of cytokine and inflammatory mediator release, synergistic cytokine action, and promotion of collagen IV synthesis. Therefore, complement factor B is a key enzyme in the activation of the alternative pathway of complement and could serve as a suitable target for inhibiting the complement activation pathway.

[0003] Patent WO2023020566 describes a compound of formula (A) that has good complement factor B (CFB) inhibitory activity. Compound of formula (I) is an intermediate in the synthesis of compound of formula (A):

[0004] The synthetic route of the compound of formula (I) described in the above patent is as follows:

[0005] In the above preparation method, the starting materials are expensive and difficult to obtain, and the products in each step need to be purified by silica gel column, which has low efficiency, low yield and high cost, and is not suitable for industrial scale-up production. Summary of the Invention

[0006] The present invention provides a method for preparing a compound of formula (I), which comprises the following reaction:

[0007] In some embodiments, the reaction is carried out in the presence of a catalyst selected from DPPF palladium dichloride, DPPP palladium acetate, allyl palladium chloride dimer, Pd2(dba)3, preferably DPPF palladium dichloride or DPPP palladium acetate.

[0008] In some embodiments, the reaction is carried out in the presence of a base, and the base is selected from triethylamine, N,N-diisopropylethylamine, triisopropylamine, preferably triethylamine or N,N-diisopropylethylamine.

[0009] In some embodiments, the CO pressure is 0.1-3.0 MPa, preferably 0.5-0.8 MPa.

[0010] In some embodiments, the reaction is carried out in the presence of a solvent, and the solvent is methanol.

[0011] In some embodiments, the reaction temperature is 40-120°C, preferably 60±5°C.

[0012] The present invention also provides a method for refining the compound of formula (I), comprising

[0013] 1) adding the crude compound of formula (I) into an organic solvent and dissolving it;

[0014] 2) adding an organic acid to form a salt and crystallize;

[0015] 3) Filter to obtain a refined product of the compound of formula (I).

[0016] In some embodiments, the organic solvent is selected from at least one of isopropyl acetate, ethyl acetate, and methyl tert-butyl ether, preferably isopropyl acetate or ethyl acetate; the organic acid is selected from at least one of naphthalene disulfonic acid, succinic acid, tartaric acid, and maleic acid, preferably naphthalene disulfonic acid.

[0017] The present invention also provides a method for preparing a compound of formula (II), which comprises the following reaction:

[0018] In some embodiments, the reaction is carried out in the presence of a reducing agent, wherein the reducing agent is selected from at least one of sodium borohydride, lithium borohydride, potassium borohydride, and borane, preferably sodium borohydride.

[0019] In some embodiments, the reaction is carried out in the presence of a catalyst, and the catalyst is selected from at least one of boron trifluoride tetrahydrofuran complex, boron trifluoride ethyl ether complex, calcium chloride, lithium chloride, and iodine, preferably boron trifluoride tetrahydrofuran complex or boron trifluoride ethyl ether complex.

[0020] In some embodiments, the reaction is carried out in the presence of a solvent, and the solvent is selected from at least one of tetrahydrofuran, diethyl ether, and methyltetrahydrofuran, preferably tetrahydrofuran.

[0021] In some embodiments, the reaction temperature is 30-70°C, preferably 55±5°C.

[0022] The present invention also provides a method for preparing a compound of formula (III), which comprises the following reaction:

[0023] In some embodiments, the reaction is carried out in the presence of a base, and the base is selected from at least one of triethylamine, N,N-diisopropylethylamine, triisopropylamine, potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide, preferably triethylamine or N,N-diisopropylethylamine.

[0024] In some embodiments, the molar ratio of the compound of formula (IV) to the base is 1:2-6, preferably 1:2.5-4.0.

[0025] In some embodiments, the reaction temperature is 20-100°C, preferably 80±5°C.

[0026] The present invention also provides a method for preparing a compound of formula (IV), which comprises the following reaction:

[0027] The reaction is carried out in the presence of hydrogen chloride, which is added in the form of being dissolved in an organic solvent. The organic solvent is selected from at least one of methanol, ethanol, and isopropanol, preferably methanol or isopropanol.

[0028] In some embodiments, the reaction temperature is 0-80°C, preferably 45±5°C.

[0029] The present invention also provides a method for preparing a compound of formula (V), which comprises the following reaction:

[0030] In some embodiments, the reaction is carried out in the presence of a catalyst and a catalyst ligand, wherein the catalyst is selected from dichlorobis(4-methylisopropylphenyl)ruthenium(II) or dichlorotris(triphenylphosphine)ruthenium, and the catalyst ligand is selected from 2-amino-2-methyl-1-propanol or 2-amino-2-ethyl-1-propanol.

[0031] In some embodiments, the reaction is carried out in the presence of a solvent selected from isopropanol or 2-butanol.

[0032] In some embodiments, the reaction temperature is 30-80°C, preferably 45±5°C.

[0033] The present invention also provides a method for preparing a compound of formula (VI), which comprises the following reaction:

[0034] In some embodiments, the reaction is carried out in the presence of a catalyst, and the catalyst is selected from at least one of lithium diisopropylamide, lithium diethylamide, and n-butyllithium, preferably lithium diisopropylamide.

[0035] In some embodiments, the reaction is carried out in the presence of a solvent selected from methyltetrahydrofuran or tetrahydrofuran.

[0036] In some embodiments, the reaction temperature is -70 to 10°C, preferably -25±5°C.

[0037] The present invention also provides a method for preparing a compound of formula (VII), which comprises the following reaction:

[0038] In some embodiments, the reaction is carried out in the presence of a catalyst selected from tetraethyl titanate or tetraisopropyl titanate.

[0039] In some embodiments, the reaction temperature is 40-120°C, preferably 60±5°C.

[0040] In addition, the present invention also provides another method for preparing the compound of formula (I), which comprises the following reaction:

[0041] In some embodiments, formula (II) is reacted in the presence of a complex catalyst to obtain formula (II-2), wherein the complex catalyst is selected from allylpalladium (II) chloride dimer / 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl, bis(triphenylphosphine)palladium dichloride / 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl.

[0042] In some embodiments, the reaction of formula (II) is carried out in the presence of potassium hexacyanoferrate (II) or its hydrate, or zinc cyanide, cuprous cyanide, potassium cyanide, sodium cyanide to obtain formula (II-2), preferably in the presence of potassium hexacyanoferrate (II) trihydrate.

[0043] In some embodiments, formula (II) is reacted in the presence of a base to obtain formula (II-2), wherein the base is selected from at least one of N,N-diisopropylethylamine, triethylamine, tripropylamine, and triisopropylamine, preferably N,N-diisopropylethylamine and triethylamine.

[0044] In some embodiments, the reaction solvent of formula (II) → formula (II-2) is selected from at least one of a mixed solution of 2-methyl-2-butanol and water, a mixed solution of tert-butanol and water, and a mixed solution of tetrahydrofuran and water, preferably a mixed solution of 2-methyl-2-butanol and water, and a mixed solution of tert-butanol and water.

[0045] In some embodiments, the reaction temperature of formula (II) → formula (II-2) is 60-100°C, preferably 90±5°C.

[0046] In some embodiments, formula (II-2) is reacted in the presence of a base to obtain formula (II-1), wherein the base is selected from at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide, preferably sodium hydroxide and potassium hydroxide.

[0047] In some embodiments, the reaction solvent of formula (II-2) → formula (II-1) is selected from at least one of a mixed solution of methanol and water, a mixed solution of ethanol and water, and a mixed solution of tetrahydrofuran and water, preferably a mixed solution of methanol and water, and a mixed solution of ethanol and water.

[0048] In some embodiments, the reaction temperature of formula (II-2) → formula (II-1) is 50-80°C, preferably 75±5°C.

[0049] In some embodiments, formula (II-1) is reacted in the presence of methanol and thionyl chloride or an acid to obtain formula (I), wherein the acid is selected from at least one of hydrogen chloride, hydrogen bromide, and sulfuric acid, preferably hydrogen chloride or sulfuric acid.

[0050] In some embodiments, the reaction solvent of formula (II-1) → formula (I) is methanol.

[0051] In some embodiments, the reaction temperature of formula (II-1) → formula (I) is 20-80°C, preferably 70±5°C.

[0052] The preparation methods of the above-mentioned compounds of the present invention are not limited to obtaining a certain compound by the above-mentioned single reaction steps, but also include the preparation steps of intermediates of the compound. For example, the preparation method of the compound of formula (VI) is not limited to the step of obtaining the compound of formula (VI) by reacting the compound of formula (VII) with the compound of formula (VIII), but may also include the step of preparing the compound of formula (VII) from the compound of formula (IX). The reaction conditions of each step are the same as the reaction conditions of the corresponding step described above.

[0053] For example:

[0054] The present invention also provides a method for preparing the compound of formula (VI), comprising the following steps:

[0055] The present invention also provides a method for preparing a compound of formula (V), comprising the following steps:

[0056] Furthermore, the preparation method of the compound of formula (V) of the present invention comprises the following steps:

[0057] Similarly, the method for preparing the compound of formula (IV) of the present invention comprises the steps (VI) → (V) → (IV), and may also comprise the steps (VII) → (VI) → (V) → (IV), or the steps (IX) → (VII) → (VI) → (V) → (IV);

[0058] Similarly, the method for preparing the compound of formula (III) of the present invention comprises the steps of (V) → (IV) → (III), and may also comprise the steps of (VI) → (V) → (IV) → (III), or (VII) → (VI) → (V) → (IV) → (III), or (IX) → (VII) → (VI) → (V) → (IV) → (III);

[0059] Similarly, the method for preparing the compound of formula (II) of the present invention comprises the steps of (IV) → (III) → (II), and may also comprise the steps of (V) → (IV) → (III) → (II), or (VI) → (V) → (IV) → (III) → (II), or (VII) → (VI) → (V) → (IV) → (III) → (II), or (IX) → (VII) → (VI) → (V) → (IV) → (III) → (II);

[0060] Similarly, the method for preparing the compound of formula (I) of the present invention comprises the steps of (III) → (II) → (I), and may also comprise the steps of (IV) → (III) → (II) → (I), or (V) → (IV) → (III) → (II) → (I), or (VI) → (V) → (IV) → (III) → (II) → (I), or (VII) → (VI) → (V) → (IV) → (III) → (II) → (I);

[0061] In particular, the present invention also provides a method for preparing a compound of formula (I), comprising the following steps:

[0062] In some embodiments, step 1 is performed in the presence of a catalyst selected from tetraethyl titanate or tetraisopropyl titanate;

[0063] In some embodiments, step 2 is performed in the presence of a catalyst, wherein the catalyst is selected from at least one of lithium diisopropylamide and lithium diethylamide, preferably lithium diisopropylamide;

[0064] In some embodiments, step 3.1 is performed in the presence of a catalyst and a catalyst ligand, wherein the catalyst is selected from dichlorobis(4-methylisopropylphenyl)ruthenium(II) or dichlorotris(triphenylphosphine)ruthenium, and the catalyst ligand is selected from 2-amino-2-methyl-1-propanol or 2-amino-2-ethyl-1-propanol;

[0065] In some embodiments, step 3.2 is performed in the presence of hydrogen chloride / organic solvent, wherein the organic solvent is selected from at least one of methanol, ethanol, and isopropanol, preferably methanol or isopropanol;

[0066] In some embodiments, step 3.3 is performed in the presence of a base, and the base is selected from at least one of triethylamine, N,N-diisopropylethylamine, triisopropylamine, potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide, preferably triethylamine or N,N-diisopropylethylamine;

[0067] In some embodiments, in step 3.3, the molar ratio of the compound of formula (IV) to the base is 1:2 to 6, preferably 1:2.5 to 4.0;

[0068] In some embodiments, step 4 is performed in the presence of a reducing agent, wherein the reducing agent is selected from at least one of sodium borohydride, lithium borohydride, potassium borohydride, and borane, preferably sodium borohydride;

[0069] In some embodiments, step 4 is carried out in the presence of a catalyst, and the catalyst is selected from at least one of boron trifluoride tetrahydrofuran complex, boron trifluoride ethyl ether complex, calcium chloride, lithium chloride, and iodine, preferably boron trifluoride tetrahydrofuran complex or boron trifluoride ethyl ether complex;

[0070] In some embodiments, step 5 is carried out in the presence of a catalyst, and the catalyst is selected from DPPF palladium dichloride, DPPP palladium acetate, allyl palladium chloride dimer, tris dibenzylideneacetone dipalladium, preferably DPPF palladium dichloride or DPPP palladium acetate;

[0071] In some embodiments, step 5 is performed in the presence of a base, and the base is selected from triethylamine, N,N-diisopropylethylamine, triisopropylamine, preferably triethylamine or N,N-diisopropylethylamine.

[0072] In addition, the present invention also provides a method for preparing the compound of formula (I), comprising the following steps:

[0073] In some embodiments, step 1 is performed in the presence of a catalyst selected from tetraethyl titanate or tetraisopropyl titanate;

[0074] In some embodiments, step 2 is performed in the presence of a catalyst, wherein the catalyst is selected from at least one of lithium diisopropylamide and lithium diethylamide, preferably lithium diisopropylamide;

[0075] In some embodiments, step 3.1 is performed in the presence of a catalyst and a catalyst ligand, wherein the catalyst is selected from dichlorobis(4-methylisopropylphenyl)ruthenium(II) or dichlorotris(triphenylphosphine)ruthenium, and the catalyst ligand is selected from 2-amino-2-methyl-1-propanol or 2-amino-2-ethyl-1-propanol;

[0076] In some embodiments, step 3.2 is performed in the presence of hydrogen chloride / organic solvent, wherein the organic solvent is selected from at least one of methanol, ethanol, and isopropanol, preferably methanol or isopropanol;

[0077] In some embodiments, step 3.3 is performed in the presence of a base, and the base is selected from at least one of triethylamine, N,N-diisopropylethylamine, triisopropylamine, potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide, preferably triethylamine or N,N-diisopropylethylamine;

[0078] In some embodiments, in step 3.3, the molar ratio of the compound of formula (IV) to the base is 1:2 to 6, preferably 1:2.5 to 4.0;

[0079] In some embodiments, step 4 is performed in the presence of a reducing agent, wherein the reducing agent is selected from at least one of sodium borohydride, lithium borohydride, potassium borohydride, and borane, preferably sodium borohydride;

[0080] In some embodiments, step 4 is carried out in the presence of a catalyst, and the catalyst is selected from at least one of boron trifluoride tetrahydrofuran complex, boron trifluoride ethyl ether complex, calcium chloride, lithium chloride, and iodine, preferably boron trifluoride tetrahydrofuran complex or boron trifluoride ethyl ether complex;

[0081] In some embodiments, step 5A.1 is performed in the presence of a complex catalyst, wherein the complex catalyst is selected from allylpalladium(II) chloride dimer / 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl or bis(triphenylphosphine)palladium dichloride / 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl;

[0082] In some embodiments, step 5A.1 is carried out in the presence of potassium hexacyanoferrate (II) or its hydrate, or zinc cyanide, cuprous cyanide, potassium cyanide, or sodium cyanide, preferably in the presence of potassium hexacyanoferrate (II) trihydrate;

[0083] In some embodiments, step 5A.1 is performed in the presence of a base, wherein the base is selected from at least one of N,N-diisopropylethylamine, triethylamine, tripropylamine, and triisopropylamine, preferably N,N-diisopropylethylamine, potassium hydroxide, and lithium hydroxide;

[0084] In some embodiments, step 5A.2 is performed in the presence of a base, wherein the base is selected from at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide, preferably sodium hydroxide or potassium hydroxide;

[0085] In some embodiments, step 5A.3 is performed in the presence of methanol and thionyl chloride or an acid, wherein the acid is selected from at least one of hydrogen chloride, hydrogen bromide, and sulfuric acid, preferably hydrogen chloride or sulfuric acid.

[0086] The present invention also provides a compound of formula (II), (II-1), (II-2), (III), (IV), (V), (VI) or a salt thereof:

[0087] Definitions of abbreviations and key terms in this invention:

[0088] Technical effects of the present invention:

[0089] 1. The process for synthesizing the compound of formula (I) of the present invention is novel, with mild reaction conditions in each step, simple operation, high yield, high product purity, convenient post-processing, and is suitable for industrial production.

[0090] 2. The process of the present invention has readily available raw materials and simple steps. The entire synthesis process does not use silica gel column chromatography or other preparative chromatography methods, has low cost, good intermediate stability, high purity, and high yield, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0091] The present invention is further described in detail below with reference to the embodiments, but the present invention is not limited thereto. Any equivalent replacements in the art made according to the disclosure of the present invention shall fall within the scope of protection of the present invention.

[0092] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0093] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0094] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph with a Zorbax SB-C18 column (100 × 4.6 mm, 3.5 μm);

[0095] Thin layer chromatography (TLC) analysis used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates with a size of 0.15 mm-0.20 mm, and thin layer chromatography separation and purification used a size of 0.4 mm-0.5 mm.

[0096] Example 1

[0097] (S,E)-N-(1-(4-bromophenyl)ethylidene)-2-methylpropane-2-sulfonamide (compound of formula (VII))

[0098] (S,E)-N-(1-(4-bromophenyl)ethylidene)-2-methylpropane-2-sulfinamide (compound of formula (VII))

[0099] Under nitrogen, 1.00 kg of the compound of formula (IX), 0.913 kg of the compound of formula (X), and 4.01 kg of tetraethyl titanate were added to a reactor and heated to 60°C for reaction. After the reaction, 8 kg of ethyl acetate and 15 kg of purified water were added, stirred, filtered, and the filtrate collected. The filter cake was washed with ethyl acetate. The filtrates were combined, separated, and the organic phase collected. The organic phase was washed with 20% sodium chloride solution, separated, and the organic phase collected. The organic phase was concentrated to dryness under reduced pressure at below 50°C, 4 kg of n-heptane was added, stirred to separate crystals, filtered, and dried under vacuum to obtain 1.20 kg of the intermediate compound of formula (VII). HPLC purity: 99.00%, yield: 80%.

[0100] Example 2

[0101] Methyl (S,Z)-5-(4-bromophenyl)-5-(((S)-tert-butylsulfinyl)imino)-3-cyclopropylpentanoate (compound of formula (VI))

[0102] methyl(S,Z)-5-(4-bromophenyl)-5-(((S)-tert-butylsulfinyl)imino)-3-cyclopropylpentanoate (compound of formula (VI))

[0103] The nitrogen atmosphere was replaced. Under nitrogen protection, 0.50 kg of the compound of formula (VII), 0.522 kg of the compound of formula (VIII), and 4.0 kg of 2-methyltetrahydrofuran were added to the reactor. After the addition was completed, the temperature was lowered to -25±5°C and the temperature was controlled at -25±5°C. 1.08 L of LDA solution was added dropwise. After the addition was completed, the reaction was kept warm for 2.5 hours.

[0104] After the reaction, the temperature was controlled below 0°C, and an acetic acid aqueous solution (0.130 kg acetic acid dissolved in 1 kg water) was added dropwise, stirred, and allowed to stand for separation, and the organic phase was collected and washed with a 20% sodium chloride aqueous solution.

[0105] The mixture was concentrated to dryness under reduced pressure at a temperature below 50°C, 1.2 kg of n-hexane was added, the temperature was lowered to -10±5°C, and the mixture was stirred for crystallization. After the crystallization was completed, the mixture was filtered, the filter cake was collected, dried, and collected to obtain 0.40 kg of the intermediate compound of formula (VI).

[0106] HPLC purity: 97.00%, yield: 55%.

[0107] Example 3

[0108] (4S,6S)-6-(4-bromophenyl)-4-cyclopropylpiperidin-2-one (compound of formula (III))

[0109] (4S,6S)-6-(4-bromophenol)-4-cyclopropylpiperidin-2-one (compound of formula (III))

[0110] Under nitrogen protection, 0.8 kg of isopropanol, 10.72 g of dichlorobis(4-methylisopropylphenyl)ruthenium(II), and 3.12 g of 2-amino-2-methyl-1-propanol (AMP) were heated under reflux for about 0.5 h and then cooled to 45±5° C. to obtain a prefabricated ligand solution for use.

[0111] Under nitrogen protection, 300 g of the compound of formula (VI) and 2.4 kg of isopropanol were heated to 45±5°C and stirred to dissolve. After nitrogen was bubbled in for 1 hour, the pre-prepared ligand solution and 15.72 g of potassium tert-butoxide were added. After the addition was complete, the mixture was kept at 45±5°C and reacted for about 1 hour. The TLC was controlled until the compound of formula (VI) disappeared to obtain the compound of formula (V).

[0112] After the reaction was completed, 0.7 L of hydrogen chloride / methanol solution (4 M) was added to the reaction solution, and the mixture was reacted at 45±5° C. for about 1 h. The reaction was controlled by TLC until completion to obtain the compound of formula (IV).

[0113] After the reaction was complete, 400 g of triethylamine was added and the mixture was kept at 80 ± 5 °C for about 2 h. The reaction was monitored by TLC until the reaction was complete.

[0114] After the reaction is complete, concentrate under reduced pressure at 50±5°C to remove most of the solvent. Add 1.8 kg of purified water, cool to 25±5°C, stir to crystallize, filter, rinse with water, and collect the filter cake; add the filter cake to methyl tert-butyl ether, heat to 50±5°C, and stir; add n-heptane, cool to 10±5°C, and stir to crystallize.

[0115] After crystallization, the product was filtered and the filter cake was washed with n-heptane. The filter cake was dried under reduced pressure and collected to obtain 120 g of the intermediate compound of formula (III).

[0116] HPLC purity: 98.00%, yield: 65%.

[0117] Example 4

[0118] (2S,4R)-2-(4-bromophenyl)-4-cyclopropylpiperidine (compound of formula (II))

[0119] (2S,4R)-2-(4-bromophenyl)-4-cyclopropylpiperidine (compound of formula (II))

[0120] 0.30 kg of the compound of formula (III) and 2.7 kg of tetrahydrofuran were stirred and dissolved, 0.097 kg of sodium borohydride was added, and 0.428 kg of boron trifluoride tetrahydrofuran complex was added dropwise. The temperature was raised to 55±5° C. and the reaction was kept warm until completion.

[0121] In another reactor, add 4.5 kg of purified water and slowly add the above reduction reaction solution while stirring. After the addition is complete, stir. Add hydrochloric acid to adjust the pH to 1-2. Raise the temperature to 55±5℃ and keep the reaction warm.

[0122] After the reaction is complete, cool to below 30°C, add solid sodium hydroxide, adjust the pH to 8-9, and stir. Add 0.45 kg of isopropyl acetate, extract, separate, and collect the organic phase; extract the aqueous phase with isopropyl acetate, separate, and collect the organic phase.

[0123] The organic phase was washed with a 20% sodium chloride aqueous solution, separated, and the organic phase was concentrated to dryness under reduced pressure at 50±5°C to obtain 0.275 kg of the intermediate compound of formula (II).

[0124] HPLC purity: 96.00%, yield 90%.

[0125] Example 5

[0126] Methyl 4-((2S,4R)-4-cyclopropylpiperidin-2-yl)benzoate (compound of formula (I))

[0127] methyl 4-((2S,4R)-4-cyclopropylpiperidin-2-yl)benzoate (compound of formula (I))

[0128] 0.15 kg of the compound of formula (II), 1.2 kg of methanol, 108.3 g of triethylamine, and 11.8 g of DPPF palladium dichloride were added to displace CO, and CO was introduced to a pressure of 0.5-0.8 MPa. The temperature was raised to 60±5° C. and the reaction was completed.

[0129] After the reaction is complete, pad with celite and filter; rinse with methanol; combine the filtrates, concentrate under reduced pressure at 50±5°C to dryness, add 1.5 kg of isopropyl acetate, heat to 60±5°C, dissolve completely, add 0.3 kg of cysteine / potassium phosphate aqueous solution and wash twice (0.05 kg of cysteine, 0.05 kg of potassium phosphate, 0.2 kg of purified water, stir and dissolve for later use); separate the liquids; collect the organic phase, wash the organic phase with 20% sodium chloride aqueous solution, collect the organic phase, and concentrate under reduced pressure at 50±5°C to dryness to obtain 0.132 kg of the crude compound of formula (I).

[0130] 0.132 kg of the crude compound of formula (I) was added to 1.0 kg of isopropyl acetate and heated to 50±5° C. to dissolve. A solution of 150 g of naphthalene disulfonic acid in 0.5 kg of isopropanol was added, stirred for 2 h, and then cooled to room temperature for crystallization. The mixture was filtered, and the filter cake was added to 1 L of sodium hydroxide solution (1 mol / L), stirred and dissolved. The mixture was extracted twice with isopropyl acetate, the organic phase was collected, and washed with 20% aqueous sodium chloride solution. The organic phase was collected and concentrated under reduced pressure at 50±5° C. to dryness to obtain 0.118 kg of the compound of formula (I).

[0131] HPLC purity: 98.49%, chiral purity: 98.5%, yield: 85.0%.

[0132] Example 6

[0133] 4-((2S,4R)-4-cyclopropylpiperidin-2-yl)benzonitrile (compound of formula (II-2))

[0134] 4-((2S,4R)-4-cyclopropylpiperidin-2-yl)benzonitrile (compound of formula (II-2))

[0135] 1.00 kg of the compound of formula (II), 0.61 kg of N,N-diisopropylethylamine, 0.40 kg of potassium hexacyanoferrate (II) trihydrate, 4.85 kg of 2-methyl-2-butanol, and 8 kg of purified water were added to a reaction kettle and passed through N2 for more than 1 hour;

[0136] In another reaction vessel, 4.3 g of allylpalladium (II) chloride dimer and 22 g of 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (Ruphos) were added to 100 g of 2-methyl-2-butanol and 100 g of purified water, and N2 was passed through the mixture for more than 1 hour.

[0137] Add the complexed catalyst into the reactor, heat it to 90±5°C, and react for about 18 hours.

[0138] After the reaction is complete, cool the mixture and separate the layers. Extract the aqueous phase with isopropyl acetate. Combine the organic phases and wash them with 20% sodium chloride solution. Collect the organic phases and concentrate under reduced pressure at 60±5°C to remove 2-methyl-2-butanol. Add 2 kg of anhydrous ethanol and evaporate until a large amount of solid precipitates. Add 10 kg of purified water and stir for 1 hour. Filter and dry the filter cake under reduced pressure at 55±5°C. Collect 804 g of the intermediate compound of formula (II-2).

[0139] HPLC purity: 98.10%, yield: 92%.

[0140] Example 7

[0141] 4-((2S,4R)-4-cyclopropylpiperidin-2-yl)benzoic acid (compound of formula (II-1))

[0142] 4-((2S,4R)-4-cyclopropylpiperidin-2-yl)benzoic acid (compound of formula (II-1))

[0143] 1 kg of the compound of formula (II-2) and 5 kg of methanol were stirred, and 0.94 kg of sodium hydroxide and 5 kg of purified water were added. The temperature was raised to 80±5°C and the reaction was carried out for more than 18 hours.

[0144] After the reaction, the temperature was controlled at 60±5°C and most of the methanol was concentrated under reduced pressure. After concentration, the temperature was lowered to below 20°C and the pH was adjusted to 5-6 with hydrochloric acid to precipitate a large amount of solid. The mixture was kept at 20±5°C with stirring. Filtered, the filter cake was washed with isopropanol, and dried under reduced pressure at 60±5°C to obtain 965 g of the intermediate compound of formula (II-1).

[0145] HPLC purity: 98.10%, yield: 90.4%.

[0146] Example 8

[0147] Methyl 4-((2S,4R)-4-cyclopropylpiperidin-2-yl)benzoate (compound of formula (I))

[0148] methyl 4-((2S,4R)-4-cyclopropylpiperidin-2-yl)benzoate (compound of formula (I))

[0149] Example 1:

[0150] 1 kg of the compound of formula (II-1), 8 kg of methanol, and 0.61 L of 4 mol / L methanolic hydrogen chloride were heated to 70±5°C and reacted for approximately 8 hours. After completion of the reaction, the mixture was concentrated at 60±5°C to remove most of the methanol. 5 kg of purified water was added, and the pH was adjusted to 7-8 with 6 M sodium hydroxide solution. 3 kg of isopropyl acetate was added for extraction, and the layers were separated. The aqueous phase was extracted again with isopropyl acetate, and the organic phase was separated and collected.

[0151] 5.9 kg of cysteine / potassium phosphate aqueous solution (0.2 kg of cysteine, 0.7 kg of potassium phosphate, and 5 kg of purified water, stirred and dissolved for later use) was added to the organic phase, heated to 60±5°C, stirred for 30 minutes, and separated. The organic phase was collected and washed with 20% sodium chloride aqueous solution. The organic phase was concentrated to dryness under reduced pressure at 50±5°C to obtain 986 g of the compound of formula (I).

[0152] HPLC purity: 99.10%, yield: 92.9%.

[0153] Example 2:

[0154] 4.00 kg of methanol and 1.00 kg of the compound of formula (II-1) were added to the reactor, and 0.73 kg of dichlorothionyl was added dropwise; after the addition was completed, the temperature was raised to reflux (about 63±5°C) for reaction; after the reaction was completed, the temperature was lowered to 0±5°C, 3.00 kg of water was added at a temperature control of 0±5°C, and stirred for 0.5 hours; the temperature was controlled at 5±5°C, and the pH was adjusted to 10-11 with a 50% aqueous potassium carbonate solution; 10.00 mL of water was added, the temperature was controlled at 5±5°C, the crystallization was stirred, the mixture was filtered, and the mixture was dried to obtain the compound of formula (I) with a yield of 95%.

Claims

1. A method for preparing a compound of formula (I), which comprises the following reaction:

2. The preparation method according to claim 1, wherein the reaction is carried out in the presence of a catalyst, and the catalyst is selected from dichlorobis(triphenylphosphine)palladium(II), bis(triphenylphosphine)palladium(II) acetate, allylpalladium chloride dimer, bis(tri-tert-butylphosphine)palladium(0), preferably dichlorobis(triphenylphosphine)palladium(II) or bis(triphenylphosphine)palladium(II) acetate; The reaction is carried out in the presence of a base, and the base is selected from triethylamine, N,N-diisopropylethylamine, triisopropylamine, preferably triethylamine or N,N-diisopropylethylamine.

3. A method for preparing a compound of formula (II), which comprises the following reaction:

4. The preparation method according to claim 3, wherein the reaction is carried out in the presence of a reducing agent, and the reducing agent is selected from at least one of sodium borohydride, lithium borohydride, potassium borohydride, borane, preferably sodium borohydride; The reaction is carried out in the presence of a catalyst, and the catalyst is selected from at least one of boron trifluoride tetrahydrofuran complex, boron trifluoride diethyl ether complex, calcium chloride, lithium chloride, iodine, preferably boron trifluoride tetrahydrofuran complex or boron trifluoride diethyl ether complex.

5. A method for preparing a compound of formula (III), which comprises the following reaction:

6. The preparation method according to claim 5, wherein the reaction is carried out in the presence of a base, and the base is selected from at least one of triethylamine, N,N-diisopropylethylamine, triisopropylamine, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, preferably triethylamine or N,N-diisopropylethylamine.

7. A method for preparing a compound of formula (V), which comprises the following reaction:

8. The preparation method according to claim 7, wherein the reaction is carried out in the presence of a catalyst and a catalyst ligand, and the catalyst is selected from dichloro-bis(4-methylcumylphenyl)ruthenium(II) or RuCl2(PPh3)3; The catalyst ligand is selected from 2-amino-2-methyl-1-propanol or 2-amino-2-ethyl-1-propanol.

9. A method for preparing a compound of formula (VI), which comprises the following reaction:

10. The preparation method according to claim 9, wherein the reaction is carried out in the presence of a catalyst, and the catalyst is selected from at least one of lithium diisopropylamide, lithium diethylamide, n-butyllithium, preferably lithium diisopropylamide.

11. A method for preparing a compound of formula (I), which comprises the following reaction:

12. The preparation method according to claim 11, wherein formula (II) is reacted in the presence of a complex catalyst to obtain formula (II-2), and the complex catalyst is selected from allylpalladium(II) chloride dimer / 2-dicyclohexylphosphino-2,6-diisopropoxybiphenyl, bis(triphenylphosphine)palladium(II) chloride / 2-dicyclohexylphosphino-2,6-diisopropoxybiphenyl; Formula (II) is reacted in the presence of potassium ferrocyanide(II) or its hydrate, or zinc cyanide, cuprous cyanide, potassium cyanide, sodium cyanide to obtain formula (II-2), preferably in the presence of potassium ferrocyanide(II) trihydrate; Formula (II) is reacted in the presence of a base to obtain formula (II-2), and the base is selected from at least one of N,N-diisopropylethylamine, triethylamine, tripropylamine, triisopropylamine, preferably N,N-diisopropylethylamine, triethylamine; Formula (II-2) is reacted in the presence of a base to obtain formula (II-1), and the base is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, preferably sodium hydroxide, potassium hydroxide; The reaction of formula (II-1) is carried out in the presence of methanol and thionyl chloride or an acid to obtain formula (I), and the acid is selected from at least one of hydrogen chloride, hydrogen bromide, and sulfuric acid, preferably hydrogen chloride and sulfuric acid.

13. The preparation method of the compound of formula (I) according to any one of claims 1, 2, 11, and 12 further comprises the following steps:

14. The preparation method according to claim 13, wherein step 1 is carried out in the presence of a catalyst, and the catalyst is selected from tetraethyl titanate or tetraisopropyl titanate; Step 2 is carried out in the presence of a catalyst, and the catalyst is selected from at least one of lithium diisopropylamide and lithium diethylamide, preferably lithium diisopropylamide; Step 3.1 is carried out in the presence of a catalyst, and the catalyst is selected from dichloro bis(4-methylcumyl)ruthenium(II) or dichloro tris(triphenylphosphine)ruthenium; Step 3.1 is carried out in the presence of a catalyst ligand, and the catalyst ligand is selected from 2-amino-2-methyl-1-propanol or 2-amino-2-ethyl-1-propanol; Step 3.2 is carried out in the presence of hydrogen chloride / organic solvent, and the organic solvent is selected from at least one of methanol, ethanol, and isopropanol, preferably methanol or isopropanol; Step 3.3 is carried out in the presence of a base, and the base is selected from at least one of triethylamine, N,N-diisopropylethylamine, triisopropylamine, potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide, preferably triethylamine or N,N-diisopropylethylamine; Step 4 is carried out in the presence of a reducing agent, and the reducing agent is selected from at least one of sodium borohydride, lithium borohydride, potassium borohydride, and borane, preferably sodium borohydride; Step 4 is carried out in the presence of a catalyst, and the catalyst is selected from at least one of boron trifluoride tetrahydrofuran complex, boron trifluoride diethyl ether complex, calcium chloride, lithium chloride, and iodine, preferably boron trifluoride tetrahydrofuran complex or boron trifluoride diethyl ether complex.

15. A compound of formula (II), (II-1), (II-2), (III), (IV), (V), (VI) or a salt thereof:

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