Chemical method for preparing phenylpiperidinyl indole derivatives

Abstract

The present invention relates to a method for synthesizing a compound of formula (I), also known as 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid, or a pharmaceutically acceptable salt thereof and / or an intermediate thereof; their use as a medicament and a pharmaceutical composition and the use of the intermediate for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] The present invention relates to methods, method steps and intermediates that can be used to prepare phenylpiperidinyl indole derivatives. Specifically, the present invention is in the field of organic synthesis and relates to a method for synthesizing a compound of formula (I), also known as 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid, or a pharmaceutically acceptable salt thereof and / or an intermediate thereof; a method for further preparing a pharmaceutical composition of a compound of formula (I) or an intermediate thereof; the use of an intermediate for preparing a compound of formula (I) and the intermediate itself. Background Art

[0002] The present invention relates to a method for preparing phenylpiperidinyl indole derivatives. More particularly, the present invention relates to a method for preparing a compound of formula (I)

[0003]

[0004] Also known as 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid, or a pharmaceutically acceptable salt thereof, the compound of formula (I) or a pharmaceutically acceptable salt thereof is capable of inhibiting activation of the alternative pathway of the complement system. The complement system plays a major role in the innate and adaptive immune systems and comprises a group of proteins that are normally present in an inactive state. These proteins are organized into three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway (Holers, In Clinical Immunology: Principles and Practice, ed. R. R. Rich, Mosby Press; 1996, 363-391). Molecules, antibodies, or cellular components from microorganisms can activate these pathways, leading to the formation of protease complexes known as C3-convertase and C5-convertase. The classical pathway is a calcium / magnesium-dependent cascade that is normally activated by forming an antigen-antibody complex. It can also be activated in an antibody-independent manner by binding to a ligand-complexed C-reactive protein and many pathogens (including Gram-negative bacteria). The alternative pathway is a magnesium-dependent cascade that is activated by the deposition and activation of C3 on certain sensitive surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials). The alternative pathway (AP) utilizes C3 fragments (C3b) to opsonize pathogens, thus targeting them for phagocytosis without the need for antibodies. The complement system, and in particular its overactivity in the AP, plays a role in many complement-driven diseases, such as C3 glomerulopathy (C3G), paroxysmal nocturnal hemoglobinuria (PNH), and IgA nephropathy (IgAN). Phenylpiperidinyl indole derivatives, such as compounds of formula (I) or pharmaceutically acceptable salts thereof, play a role in inhibiting complement factor B, a known key enzyme for activating the alternative complement pathway (Lesavre et al. J. Exp. Med. [Journal of Experimental Medicine] 1978, 148, 1498-1510; Volanakis et al. New Eng. J. Med. [New England Journal of Medicine] 1985, 312, 395-401), which may also be a suitable target for inhibiting complement pathway amplification. Phenylpiperidinyl indole derivatives, such as compounds of formula (I), or pharmaceutically acceptable salts thereof, and methods for preparing such derivatives are described in WO 2015 / 009616. Specifically, compounds of formula (I) are described in Example 26 of WO 2015 / 009616.One of the disadvantages of the synthesis is the use of hazardous chemicals such as sodium hydride or dimethylacetamide, which represent a great safety hazard, and the poor enantio- and diastereoselectivity of the steps, leading to undesired stereoisomers.

[0005] Therefore, there is a need to provide alternative reaction pathways in processes for producing compounds of formula (I) or pharmaceutically acceptable salts thereof which produce fewer by-products and are easier to handle on a large scale. Summary of the invention

[0006] Chemical processes are often performed on a small scale during the research / early development phase and gradually scaled up in late development, ultimately reaching full-scale production scale. As processes are scaled up, topics related to process safety become increasingly important, such as health or environmental hazards when handling large quantities of hazardous and / or toxic chemicals.

[0007] Surprisingly, it was found that the compound of formula (I) or a pharmaceutically acceptable salt thereof, also known as 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid, or a pharmaceutically acceptable salt thereof and intermediates thereof, can be prepared by a shorter, cost-effective and safer process. Thus, the present invention relates to a novel synthetic process for compounds of formula (I) and intermediates thereof, which uses fewer hazardous chemicals and / or reaction conditions, produces fewer by-products and provides a reproducible process that is easily handled at a larger scale (a process involving fewer reaction steps (and therefore more efficient) and producing high quality compounds).

[0008] In one embodiment, the present invention provides a method for preparing a compound of formula (C15) or a salt thereof as disclosed herein, the method comprising the following steps: reacting a compound of formula (II) or a salt thereof as disclosed herein with a compound of formula (III) or a salt thereof as disclosed herein in the presence of an iridium catalyst, under hydrogen pressure, optionally in the presence of an additive, to provide a compound of formula (C15) or a salt thereof.

[0009] In another embodiment, the present invention provides a method for preparing a compound of formula (S)-(C4) as disclosed herein, the method comprising reacting a compound of formula (C6) as disclosed herein with an aromatic-boronyl compound of formula (C7) as disclosed herein in the presence of a catalyst and a ligand to obtain a compound of formula (S)-(C4).

[0010] In another embodiment, the present invention provides a method for preparing a compound of formula (S)-(C5) as disclosed herein, comprising the following steps:

[0011] (i) preparing compounds of formula (S)-(C4) as disclosed herein according to the methods described herein; and

[0012] (ii) treating the compound of formula (S)-(C4) obtained from step (i) under reductase conditions as disclosed herein;

[0013] To obtain the compound of formula (S)-(C5).

[0014] In another embodiment, the present invention provides a method for preparing a compound of formula (S)-(C9) as disclosed herein, comprising the following steps:

[0015] (i) reacting an alcohol of a compound of formula (S)-(C5) as defined herein with an oxygen protecting group P2 to obtain a compound of formula (S)-(C8) as disclosed herein,

[0016] (ii) reacting the protected alcohol of the compound of formula (S)-(C8) with an ethylating agent such as 2,4,6-trimethyl-1,3,5-trioxane;

[0017] to obtain a compound of formula (S)-(C9).

[0018] In another embodiment, the present invention provides a compound of formula (C13) as disclosed herein.

[0019] In another embodiment, the present invention provides a method for preparing a compound of formula (C13) as disclosed herein, comprising the following steps: reacting a compound of formula (C12) as disclosed herein with a Grignard reagent in the presence of an aldehyde source to obtain a compound of formula (C13).

[0020] In another embodiment, the present invention provides a method for preparing a compound of formula (III) or a salt thereof as disclosed herein, the method comprising reacting a compound of formula (C13) with an inorganic base in the presence of a methylating agent to obtain a compound of formula (III) or a salt thereof.

[0021] In another embodiment, the present invention provides a method for preparing a compound of formula (III) or a salt thereof as disclosed herein, the method comprising the following steps:

[0022] (i) preparing a compound of formula (C13) as disclosed herein; and

[0023] (ii) further reacting a compound of formula (C13) as disclosed herein;

[0024] To obtain the compound of formula (III) or its salt.

[0025] In another embodiment, the present invention relates to the use of a compound of formula (C13) as disclosed herein for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0026] In another embodiment, the present invention relates to a method for preparing a pharmaceutical composition, comprising the method as disclosed herein, and mixing the obtained compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Depicted is the X-ray powder diffraction pattern of the maleate salt of methyl 4-((2S,4S)-4-ethoxypiperidin-2-yl)benzoate (maleate salt of the compound of formula (II)). DETAILED DESCRIPTION

[0028] Increasing the amounts of reactants and solvents in order to scale up the process to full-scale commercial production may be associated with low yields or some safety issues when handling large amounts of hazardous and / or toxic chemicals.

[0029] Surprisingly, it is found that improving the method as described in WO 2015 / 009616 to synthesize the compound of formula (I) or its pharmaceutically acceptable salt and its synthetic intermediate in a manner as disclosed herein provides a scalable method, which can be safely processed on a large scale, with reproducible yields, using less dangerous / toxic chemicals. In addition, this method provides the desired compound with high enantioselectivity and diastereoselectivity, and produces the compound of formula (I) or its pharmaceutically acceptable salt with fewer synthesis steps. An overview of the entire method is shown in Scheme 1, see below.

[0030]

[0031] Solution 1

[0032] 1. Asymmetric synthesis of compounds of formula (II):

[0033] (C1)->(C6)->(S)-(C4)->(S)-(C5)->(II).

[0034] One aspect of the present invention relates to an asymmetric process for preparing compounds of formula (II) or salts thereof as outlined in Scheme 2 below, wherein stereocenters at positions 2 and 4 on the piperidine are obtained with high enantio- and diastereoselectivity.

[0035]

[0036] 1.1. Synthesis of compounds of formula (S)-(C4)

[0037] In one embodiment, the present invention provides a method for preparing a compound of formula (S)-(C4) as defined below, the method comprising the steps of: reacting a compound of formula (C6) with an aryl-boryl compound of formula (C7) in the presence of a catalyst and a ligand to obtain a compound of formula (S)-(C4) as defined in Scheme 3,

[0038]

[0039] Solution 3

[0040] in

[0041] P1 is a nitrogen protecting group, for example selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyl (Bz), benzyloxycarbonyl (Cbz) and allyloxycarbonyl (Alloc), preferably the nitrogen protecting group is benzyloxycarbonyl (Cbz); and

[0042] R is a C1-C6 alkyl group, preferably R is a methyl group.

[0043] Intermediate compounds of formula (C6) as described in Scheme 3 can be prepared according to any literature and textbooks available to those skilled in the art. For example, compounds of formula (C6) can be prepared from compounds of formula (C1) as disclosed in Scheme 1 (e.g., according to the first experimental procedure of Knapp et al. J. Org. Chem. 2005, 70(19), 7715, p. 7718).

[0044] The catalyst used for the enantioselective conjugate addition between the compound of formula (C6) and the aryl-boryl compound of formula (C7) as described in Scheme 3 can be selected, for example, from the group consisting of: Rh(acac)(C2H4)2, Rh(nbd)2BF4, Rh(COD)BF4, Rh(acac)(COD), [Rh(COD)Cl]2, [Rh(COD)OMe]2, [Rh(MeCN)2(COD)]BF4, [RhCl(S)-BINAP]2, [Rh(OH)((S)-BINAP)]2, (NHC-Pd(II)) and Pd(O2CCF3)2. The reaction as described in Scheme 3 is best carried out in the presence of a rhodium catalyst. Preferably, the catalyst is selected from the group consisting of: Rh(acac)(C2H4)2, Rh(nbd)2BF4 and Rh(COD)BF4. Most preferably, the catalyst is Rh(acac)(C2H4)2. Relative to the amount of the compound of formula (C6), the catalyst may be present in an amount less than 15mol%. Typically, the catalyst may be present in an amount less than 5mol%. Most preferably, the catalyst may be present in an amount from 0.01mol% to 2mol%.

[0045] The ligand used to carry out the reaction as depicted in Scheme 3 can be selected from the group consisting of: (S)-BINAP ((S)-(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)), (S)-Tol-BINAP ((R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl), (S)-SDP ((S)-(-)-7,7'-bis(diphenylphosphino)-2, 2',3,3'-tetrahydro-1,1'-spirobiindene), (R)-SegPhos((R)-(+)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole), (R)-(+)-MeO-BIPHEP((R)-(+)-(6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphine)), (S,S)-Me-Ferrocelane (1,1'-bis[(2S,5S)-2,5-dimethylphosphino]ferrocene), chiral Josiphos ligand, (S)-(-)XylBINAP(1,1'-binaphthyl-2,2'-diylbis[bis(3,5-dimethylphenyl)phosphine]), (S,S)-Me-DUPHOS((+)-1,2-bis[(2S,5S)-2,5-dimethylphosphino]benzene), (S,S)-E Preferably, the ligand is selected from the group consisting of: (S)-(-)XylBINAP, (S,S)-Me-DUPHOS, (S,S)-Et-DUPHOS, (R,R)-Ph-BPE or a mixture thereof. More preferably, the ligand is selected from the group consisting of: (S)-(-)XylBINAP, (R,R)-Ph-BPE or a mixture thereof. Relative to the amount of the compound of formula (C6), the ligand may be present in an amount from about 0.005mol% to about 5mol%. Most preferably, the ligand may be present in an amount from about 0.01mol% to about 3mol%. Typically, the ligand is present in an amount less than 2mol%.

[0046] The reaction as described in Scheme 3 can be carried out in a solvent selected from the following: for example, 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, toluene, dimethylformamide (DMF), dimethylacetamide (DMA), water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, tert-amyl alcohol, cyclopentyl methyl ether (CPME) or a mixture thereof. The preferred solvent for the reaction is one or more solvents selected from the following: dimethylformamide (DMF), tert-amyl alcohol, toluene, cyclopentyl methyl ether (CPME), tetrahydrofuran (THF), 2-methyltetrahydrofuran, water or a mixture thereof. Most preferably, the solvent is a mixture of tert-amyl alcohol and water. The ratio (volume to volume) of the mixture can be in the range of 20:1 to 1:20. Most preferably, the ratio is in the range of from 15:1 to 10:1. Typically, the ratio is about 10:1, so that tert-amyl alcohol is in excess relative to water.

[0047] The substituents X1 and X2 on the aryl-boryl compound of formula (C7) may be the same or different and may be halogen, hydroxyl, C1-C4 alkoxy, hydrogen or C1-C 12 Alkyl. The substituents X1 and X2 may also be bridged together in a cyclic manner, for example the combined X1, X2 is an alkylene group which together with the boron and oxygen atoms forms a 5 or 6 membered ring, for example to form a diol residue. For example, the boron group B(X1)(X2) on the compound of formula (C7) is selected from the group consisting of: B(OH)2, -B(OC(CH3)2C(CH3)2O) and 9-BBN. Preferably, B(X1)(X2) is B(OH)2. The aryl-boryl compound of formula (C7) may be commercially available or may be prepared from commercially available starting materials according to any literature and textbooks available to those skilled in the art.

[0048] Optionally, the reaction as described in Scheme 3 can be carried out in the presence of a base. The base can be, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, trisodium phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, triethylamine, N,N-diisopropylethylamine (DIPEA), sodium tert-butoxide, potassium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), potassium fluoride or cesium fluoride.

[0049] When the nitrogen protecting group P1 is benzyloxycarbonyl (Cbz), the aryl-boryl compound of formula (C7) is 4-(methoxycarbonyl)phenyl)boronic acid (B(OH)2), the catalyst is Rh(acac)(C2H4)2 and the ligand is (S)-(-)XylBINAP or (R,R)-Ph-BPE, the reaction as described in Scheme 3 is advantageously carried out. Preferably, the reaction is carried out at a temperature between about 25°C and about 85°C, more preferably between about 40°C and about 70°C. Most preferably, the reaction is carried out at a temperature between about 50°C and about 60°C. Carrying out the reaction under these conditions is particularly advantageous because the reaction is efficient, the enantioselectivity is improved, and thus the formation of by-products is reduced. The enantioselectivity is between 84% and greater than 99% ee. Therefore, the steps of the present invention are particularly suitable for large-scale production. Furthermore, it has been unexpectedly discovered that ligands used to catalyze arylations, as described herein, can significantly enhance both reactivity and selectivity, leading to highly enantioselective arylations.

[0050] In another embodiment, when the catalyst as disclosed herein and the ligand as disclosed herein are mixed together to form a new active reagent before being introduced into the reaction mixture, the reaction as depicted in Scheme 3 is advantageously performed. In one embodiment, the new active reagent is a catalyst-ligand complex. The catalyst-ligand complex can be, for example, but not limited to (R,R)-Ph-BPE-Rh(Acac) or (S)-XylBINAP-Rh(Acac). It was unexpectedly found that when reacting in the presence of an air-sensitive catalyst, it is advantageous to mix the catalyst and the ligand to form a complex. The advantages of the new catalyst-ligand complex are higher activity and lower sensitivity to air. Therefore, a smaller amount of catalyst is required to carry out the reaction as depicted in Scheme 3 with high yield.

[0051] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by a method comprising the following steps: preparing a compound of formula (S)-(C4) by reacting a compound of formula (C6) with an aryl-boryl compound of formula (C7) in the presence of a catalyst and a ligand to obtain a compound of formula (S)-(C4), as defined in Scheme 3.

[0052] 1.2. Synthesis of compounds of formula (S)-(C5)

[0053] In another embodiment, the present invention relates to a process for preparing a compound of formula (S)-(C5) as defined below, comprising the following steps:

[0054] (i) preparing a compound of formula (S)-(C4) according to the method of Section 1.1; and

[0055] (ii) treating the compound of formula (S)-(C4) obtained from step (i) under reductase conditions;

[0056] to obtain compounds of formula (S)-(C5), as defined in Scheme 4.

[0057]

[0058] Solution 4

[0059] wherein R is a C1-C6 alkyl group, preferably R is a methyl group; and

[0060] wherein P1 is a nitrogen protecting group as defined above in Section 1.1.

[0061] Reductase conditions as disclosed herein include treating a compound of formula (S)-(C4) with an enzyme, a cofactor, in an aqueous buffer solution, optionally in the presence of a surfactant, to provide a compound of formula (S)-(C5) as defined herein. In one embodiment, the reductase conditions are enzyme catalyzed conditions.

[0062] The enzyme used to carry out the reaction outlined in Scheme 4 is any enzyme suitable for carrying out the above transformation. Suitable enzymes for the reaction mixture of the present invention include, for example, ketoreductase (KRED), alcohol dehydrogenase, glucose dehydrogenase (GDH) or mixtures thereof. Preferably, the enzyme is ketoreductase (KRED). Optionally, the reaction may comprise a second enzyme, a so-called coenzyme, such as glucose dehydrogenase (GDH). Suitable ketoreductases (KRED) for use in the present invention are available from Codexis Inc. ( KRED screening kit), and described in, for example, WO 2005 / 017135, WO 2008 / 103248, WO 2009 / 029554, WO 2009 / 036404, WO 2016 / 130412, and WO 2018 / 013710. The KRED-EW124 enzyme was purchased from Enzyme Works Inc., China. Suitable ketoreductases can be selected from, for example, but not limited to, the group consisting of KRED-EW124, KRED-P3-G09, KRED-P1-B02, KRED-P1-C01, KRED-P2-B02, KRED-P2-C02, KRED-P3-B03, KRED-P2-D03, KRED-P2-D11, KRED-P2-D12, KRED-P2-H07, KRED-P3-H12, KRED-101, KRED-119 or a mixture thereof. Preferably, the ketoreductase (KRED) is selected from KRED-EW124, KRED-P3-G09 or a mixture thereof.

[0063] The enzyme is present in the reaction mixture at a concentration suitable for carrying out the reaction as outlined in Scheme 4 (e.g., in an amount of about 0.01% to about 100% relative to the amount of the compound of Formula (S)-(C4)). In particular, the enzyme may be present in an amount of about 0.1% to about 75%, about 0.5% to about 50%, about 1% to about 40%, about 2% to about 30%, about 4% to about 25%, or about 5% to about 20% relative to the amount of the compound of Formula (S)-(C4).

[0064] The reaction as outlined in Scheme 4 also comprises a cofactor. The presence and type of the cofactor depends on the enzyme reaction to be performed. The cofactor can be selected, for example, from the group consisting of nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADP), flavin adenine dinucleotide (FAD), pyridoxal monophosphate or a mixture thereof. The cofactor can be used to provide protons or electrons for the enzyme reaction. On the other hand, the cofactor can be present in the reaction mixture in ionic form (e.g., like NAD+, NADP+). On the other hand, the cofactor can be present in the reaction mixture in a protonated form (e.g., to NAD-H, NADP-H or NADP-Na). On the other hand, the reaction is an enzyme-catalyzed reaction. For example, the reaction mixture can comprise another enzyme, a so-called coenzyme, which regenerates the cofactor. For example, if NAD, NADP or FAD is used as a cofactor, the aqueous reaction mixture can further comprise a dehydrogenase, such as an alcohol dehydrogenase or a glucose dehydrogenase; and a corresponding substrate, such as an alcohol or glucose. The cofactor can be present in the aqueous reaction mixture in a stoichiometric amount. For example, the molar amount may be at least as high as the molar amount of the compound of formula (S)-(C4). In another aspect, the amount of the cofactor is lower than the amount of the compound of formula (S)-(C4), in particular in the range of from about 0.01% to about 20%, about 0.05% to about 15%, about 0.1% to about 10%, about 0.25% to about 7.5% or about 0.5% to about 5% relative to the amount of the compound of formula (S)-(C4).

[0065] The reaction as outlined in Scheme 4 is carried out in an aqueous buffer solution. The buffer solution should be suitable for maintaining the pH of the reaction mixture at or about neutral pH. The aqueous reaction mixture preferably has a pH at which the enzyme is active and stable and the pH is suitable for the enzyme reaction. In certain embodiments, the pH value is in the range of from about 6.0 to about 8.0. More preferably, the pH is from about 6.5 to about 7.5, such as about 7.0. The buffer can be selected from the group consisting of: 2-amino-2-(hydroxymethyl)propane-1,3-diol (TRIS), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 3-(N-morpholino)propanesulfonic acid (MOPS), piperazine-N, N'-bis(2-ethanesulfonic acid (PIPES), borate, glycine, triethanolamine, phosphate, citrate, acetate and ammonia. More particularly, the buffer solution is a phosphate buffered saline (PBS) solution.

[0066] The reaction as described in Scheme 4 can also be carried out in the presence of a surfactant. Suitable surfactants can be selected from, for example, vitamin E, tocopherol, α-tocopherol and tocopherol polyethylene glycol succinate (TPGS). Specifically, the surfactant is TPGS. Suitable tocopherol polyethylene glycol succinate (TPGS) surfactants can be selected from, for example, but not limited to, DL-α-tocopherol polyethylene glycol succinate, such as TPGS-750-M, TPGS-1000, TPGS-1500, TPGS-400, TPGS-1100-M, TPGS-2000, TPGS-860-oleate, TPGS-PEG-PPG-PEG-1100 and TPGS-PPG-PEG-70-butyl; and DL-α-tocopherol polypropylene glycol succinate, such as TPPG-1000 and TPPG-1000-butyl; and polyethylene glycol α-tocopherol diester (PTS) of sebacic acid, such as PTS-600. Preferably, the surfactant is selected from the group consisting of: TPGS-750-M, TPGS-1000 and PTS. Most preferably, the surfactant is TPGS-750-M.

[0067] The reaction as described in Scheme 4 is advantageously carried out when the enzyme is a ketoreductase (KRED) and the cofactor is nicotinamide adenine dinucleotide phosphate (NADP), preferably NADP-Na, in an aqueous buffer solution containing a surfactant. In particular, the reaction is particularly well carried out when the buffer solution is a mixture of a phosphate buffered saline (PBS) solution containing a TPGS-750-M surfactant. Preferably, the reaction is carried out at a temperature between about 30°C and about 90°C, more preferably between about 40°C and about 70°C. Most preferably, the reaction is carried out at a temperature of about 50°C. Carrying out the reaction under these conditions is particularly advantageous because the reaction provides an environmentally friendly and scalable method for reducing ketones to alcohols because the reaction is carried out in an aqueous medium. In addition, the reaction is diastereoselective, providing the desired alcohol in high yield, thereby avoiding a mixture of diastereomers as a by-product.

[0068] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by a method comprising the steps of reacting a compound of formula (S)-(C4) using an enzyme, a cofactor, and optionally a coenzyme in an aqueous buffer solution, optionally in the presence of a surfactant, to provide a compound of formula (S)-(C5), and further reacting the compound of formula (S)-(C5) to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0069] In another embodiment, the present invention provides a useful intermediate for synthesizing a compound of formula (II) or a salt thereof, a compound of formula (S)-(C5):

[0070]

[0071] wherein R is C1-C6 alkyl, preferably R is methyl; and P1 is a nitrogen protecting group as defined above in Section 1.1.

[0072] In another embodiment, the present invention provides the use of a compound of formula (S)-(C5) for preparing a compound of formula (II) or a salt thereof.

[0073] In another embodiment, the present invention provides the use of a compound of formula (S)-(C5) for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0074] 1.3. Synthesis of the compound of formula (II) or its salt

[0075] In another embodiment, the present invention provides a method for preparing a compound of formula (S)-(C9) as outlined in Scheme 5, comprising the following steps:

[0076] (i) reacting the alcohol of the compound of formula (S)-(C5) with an oxygen protecting group P2 to obtain a compound of formula (S)-(C8),

[0077] (ii) reacting the protected alcohol of the compound of formula (S)-(C8) with an ethylating agent such as 2,4,6-trimethyl-1,3,5-trioxane;

[0078] to obtain a compound of formula (S)-(C9).

[0079]

[0080] Solution 5

[0081] wherein R is a C1-C6 alkyl group, preferably a methyl group;

[0082] wherein P1 is a nitrogen protecting group as defined in Section 1.1 above; and

[0083] Wherein P2 is an oxygen protecting group. Preferably, the oxygen protecting group P2 is selected from the silyl group such as being composed of the following group: tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS) and tert-butyldiphenylsilyl (TBDPS). Most preferably, P2 is tert-butyldimethylsilyl (TBS).

[0084] As described above, the alcohol group of the compound of formula (S)-(C5) is protected with an oxygen protecting group P2 in the presence of a base in a solvent to obtain a first intermediate of formula (S)-(C8), as outlined in Scheme 6,

[0085]

[0086] Solution 6

[0087] Wherein P2 oxygen protecting group, such as silyl selected from the group consisting of, for example, tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS) and tert-butyldiphenylsilyl (TBDPS). The base can be, for example, an amine base. The base can be selected from the group consisting of, for example, triethylamine, pyridine, imidazole, 2,6-lutidine, dimethylaminopyridine or a mixture thereof.

[0088] Solvents generally known in the art can be used. The solvent is selected from the group consisting of, for example, isopropanol, ethanol, dimethylformamide, acetonitrile, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane (DCM), dichloroethane (DCE), toluene, heptane or a mixture thereof.

[0089] In another embodiment, the present invention provides a useful intermediate for synthesizing a compound of formula (II) or a salt thereof, a compound of formula (S)-(C8),

[0090] ((S)-(C8)),

[0091] wherein R is a C1-C6 alkyl group, preferably a methyl group;

[0092] wherein P1 is a nitrogen protecting group as defined in Section 1.1 above; and

[0093] Wherein P2 is an oxygen protecting group. Preferably, the oxygen protecting group P2 is selected from the silyl group such as being composed of the following group: tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS) and tert-butyldiphenylsilyl (TBDPS). Most preferably, P2 is tert-butyldimethylsilyl (TBS).

[0094] In another embodiment, the present invention provides the use of a compound of formula (S)-(C8) for preparing a compound of formula (II) or a salt thereof.

[0095] In another embodiment, the present invention provides the use of a compound of formula (S)-(C8) for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0096] In the next step, the oxygen protecting group P2 on the compound of formula (S)-(C8) is then cleaved. The resulting alcohol is reacted in situ with an ethylating agent to obtain an intermediate of formula (S)-(C9), as outlined in Scheme 7, see below.

[0097]

[0098] Solution 7

[0099] Typically, any ethylating agent known in the art is suitable. Examples of suitable ethylating agents are iodoethane, bromoethane, chloroethane, fluoroethane, diethyl sulfate, ethyl trifluoromethanesulfonate (EtOTf), 4-ethylsulfonyltoluene, 2,4,6-trimethyl-1,3,5-trioxane and mixtures thereof. Preferably, the ethylating agent is 2,4,6-trimethyl-1,3,5-trioxane.

[0100] The removal of oxygen protecting group P2 and the in-situ alkylation of free alcohol can be carried out with ethylating agent Et3SiH in the presence of solvent and Lewis acid. The Lewis acid can be selected from, for example, TESOTf, TMSBr, BiBr3, TMSOTf, TBSOTf or a mixture thereof. The reaction consisting of removing oxygen protecting group P2 can be carried out in a solvent that promotes the removal of oxygen protecting group and alkylation. As an example, the solvent can be selected from the group consisting of: dichloromethane, ethyl acetate, 1,4-dioxane, ether, tetrahydrofuran, methanol and acetonitrile. The reaction mixture is carried out at a temperature between about 0°C and about 10°C. Preferably, between about 3°C ​​and about 7°C. Most preferably, between about 4°C and about 5°C.

[0101] In another embodiment, the present invention relates to a process further comprising the step of reacting a compound of formula (S)-(C9) to remove the nitrogen protecting group P1 to obtain a compound of formula (II) or a salt thereof, as summarized in Scheme 8 below,

[0102]

[0103] Solution 8

[0104] wherein R is C1-C6 alkyl, preferably methyl; and

[0105] wherein P1 is a nitrogen protecting group as defined above in Section 1.1.

[0106] The removal of nitrogen protecting group P1 can be carried out under standard reaction conditions known in the art. Unless otherwise indicated, the nitrogen protecting group can be removed in the absence of acid or base or usually in the presence of acid or base, and the acid or base is preferably an acid or base that causes the removal of the nitrogen protecting group but does not cause the chemical degradation of the compound at the same time. Preferably, the nitrogen protecting group is removed with acid. For example, when P1 is tert-butyloxycarbonyl (Boc), deprotection reaction is carried out optimally under acidic conditions. The particularly suitable acid for removing the nitrogen protecting group P1 is HF pyridine, HF triethylamine ammonium fluoride, hexafluoroisopropanol, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or its combination. The nitrogen protecting group P1 can be removed under catalytic conditions in the presence of a hydrogen source. For example, when P1 is benzyl (Bz), benzyloxycarbonyl (Cbz) or allyloxycarbonyl (Alloc), deprotection reaction is carried out optimally under catalytic conditions in the presence of a hydrogen source. The particularly suitable catalyst for removing the nitrogen protecting group P1 can be, for example, palladium carbon (Pd / C) or palladium acetate (II) (Pd(OAc)2). The reaction consisting of removing the nitrogen protecting group can be carried out in a solvent that promotes the removal of the protecting group, and the solvent is any solvent that a person skilled in the art can select from a common textbook. As an example, the nitrogen protecting group can be removed in a solvent selected from the group consisting of: dichloromethane, ethyl acetate, 1,4-dioxane, ether, tetrahydrofuran, methanol, ethanol, isopropanol and acetonitrile. For example, the deprotection reaction of the tert-butyloxycarbonyl (Boc) nitrogen protecting group is carried out with trifluoroacetic acid, preferably in dichloromethane, optionally at ambient temperature. For example, the deprotection reaction of the benzyloxycarbonyl (Cbz) nitrogen protecting group is carried out with palladium carbon (Pd / C) at room temperature, in isopropanol, under hydrogen.

[0107] When the alcohol on the compound of formula (S)-(C5) is protected with an oxygen protecting group P2 (tert-butyldimethylsilyl (TBS)), the reaction as described in Scheme 5 is advantageously carried out in a mixture of acetonitrile and isopropanol in the presence of imidazole as a base to obtain the first intermediate of formula (S)-(C8). Then, the cleavage and substitution of the oxygen protecting group P2 on the compound of formula (S)-(C8) by the ethyl group is carried out in the presence of TESOTf, Et3SiH, 2,4,6-trimethyl-1,3,5-trioxane in acetonitrile at a temperature between 4°C and 5°C to obtain the intermediate of formula (S)-(C9). Then, the nitrogen protecting group P1 on the compound of formula (S)-(C9) is cleaved under catalytic conditions at room temperature in isopropanol in the presence of palladium on carbon (Pd / C), hydrogen to obtain the compound of formula (II) or its salt. Under these conditions, the protection of the alcohol group of the compound of formula (S)-(C5) in two steps (the first step is protected with P2, the second step removes P2 and adds ethyl) is particularly advantageous because it provides a scalable reaction that avoids any hazardous chemicals (such as the sodium hydride used in WO 2015 / 009616) without affecting the conversion yield. Therefore, the method safely produces a compound or a salt thereof of formula (II). In one embodiment, the compound of formula (II) is maleate.

[0108] In another embodiment, removal of the oxygen protecting group and alkylation are performed sequentially in one pot.

[0109] In one embodiment, the method comprises the following steps:

[0110] - protecting the alcohol of the compound of formula (S)-(C5) with an oxygen protecting group P2 to obtain a compound of formula (S)-(C8),

[0111] - alkylating the protected alcohol of the compound of formula (S)-(C8) with an ethyl group to obtain the compound of formula (S)-(C9),

[0112] - removing the nitrogen protecting group P1 to obtain a compound of formula (II) or a salt thereof, and

[0113] - reacting a further compound of formula (II) or a salt thereof to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0114] 2. Racemic synthesis of compounds of formula (II): (C1)->(C3)->(C4)->(C5)->(II).

[0115] In another embodiment, the compound of formula (II) or a salt thereof can be prepared using the method outlined in Scheme 9 below.

[0116]

[0117] Solution 9

[0118] wherein R is a C1-C6 alkyl group, preferably a methyl group;

[0119] Wherein P1 is a nitrogen protecting group selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyl (Bz), benzyloxycarbonyl (Cbz) and allyloxycarbonyl (Alloc), preferably, the nitrogen protecting group is benzyloxycarbonyl (Cbz).

[0120] Wherein P2 is an oxygen protecting group selected from, for example but not limited to, the group consisting of tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS) and tert-butyldiphenylsilyl (TBDPS). Most preferably, P2 is tert-butyldimethylsilyl (TBS).

[0121] 2.1. Synthesis of compounds of formula (C4)

[0122] In another embodiment, the present invention relates to a method for preparing a compound of formula (C4), comprising the following steps:

[0123] - reacting a compound of formula (C1) with a compound of formula (C2) in the presence of a ligand, a Grignard reagent and a protecting group precursor in a solvent to form a compound of formula (C3); and

[0124] - further reducing the double bond of the compound of formula (C3) to form a compound of formula (C4), as outlined in Scheme 10,

[0125]

[0126] Solution 10

[0127] wherein Y is halogen, wherein R is C1-C6 alkyl, preferably methyl; and

[0128] wherein P1 is a nitrogen protecting group as described herein. According to the present invention, preferred nitrogen protecting groups P1 are selected as described in Section 2 above.

[0129] The protecting group precursor used to carry out the coupling reaction between the compound of formula (C1) and the compound of formula (C2) as outlined in Scheme 10 is selected according to the nitrogen protecting group P1 used to carry out the transformation. For example, when P1 is benzyloxycarbonyl (Cbz), the precursor is benzyl chloroformate (Cbz-Cl); when P1 is benzyl (Bz), the precursor is benzoyl chloride (Bz-Cl); when P1 is allyloxycarbonyl (Alloc), the precursor is allyl chloroformate (Alloc-Cl); or when P1 is tert-butyloxycarbonyl (Boc), the precursor is di-tert-butyl dicarbonate (Boc2O).

[0130] The ligand used to carry out the reaction as depicted in Scheme 10 can be selected from, for example, but not limited to, the group consisting of: N,N,N',N',N"-pentamethylethylenetriamine, N,N,N',N'-tetraethylethylenediamine, bis[2-(dimethylamino)ethyl]ether, tetramethylethylenediamine, or methoxypoly(ethylene glycol) or a mixture thereof. Preferably, the ligand is bis[2-(dimethylamino)ethyl]ether.

[0131] The Grignard reagent is selected from, for example, the group consisting of MeMgBr, MeMgCl, EtMgBr, EtMgCl, iPrMgCl, iPrMgBr or mixtures thereof. Most preferably, the Grignard reagent is iPrMgCl or iPrMgBr.

[0132] The first reaction described in Scheme 10 can be carried out in a solvent selected from, for example, 1,4-dioxane, 4-methyl-1,3-dioxane, diglyme, tetrahydrothiophene, 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), diethoxymethane (DEM), toluene, tetrahydrofuran (THF), diethyl ether or a mixture thereof. Preferably, the solvent is an anhydrous solvent selected from 1,4-dioxane, tetrahydrofuran (THF), diethyl ether or a mixture thereof. Typically, the solvent is THF.

[0133] According to the method disclosed in WO 2015 / 009616 (page 97, Intermediate 2-12-B), the double bond of the intermediate compound of formula (C3) can be reduced to obtain the compound of formula (C4).

[0134] When the reaction as described in Scheme 10 is carried out in the presence of benzyloxycarbonyl (Cbz) chloride as a protecting group precursor, iPrMgCl or iPrMgBr as a Grignard reagent and bis[2-(dimethylamino)ethyl]ether as a ligand, a compound of formula (C3) is advantageously provided. Preferably, the reaction is carried out at a temperature between 10°C and 40°C, more preferably between 15°C and 35°C. Typically, the reaction is best carried out at a temperature of from 20°C to 30°C. Carrying out the reaction under these conditions is particularly advantageous because the reaction is carried out in high yield, thus making the reaction of the present invention suitable for large-scale manufacturing.

[0135] In one embodiment, the method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises the following steps: preparing a compound of formula (C4) by reacting a compound of formula (C1) with a compound of formula (C2) in the presence of a ligand, a metal reagent and a protecting group precursor in a solvent to form a compound of formula (C3), and further reducing the compound of formula (C3) to form a compound of formula (C4), as outlined in Scheme 10.

[0136] 2.2. Synthesis of compounds of formula (C5)

[0137] In one embodiment, the method for preparing a compound of formula (I) as defined in Scheme 1 or a pharmaceutically acceptable salt thereof comprises reacting a compound of formula (C4) using an enzyme, a cofactor, in an aqueous buffer solution, optionally in the presence of a surfactant, to provide a compound of formula (C5) or a salt thereof, as outlined in Scheme 11 below.

[0138] In another embodiment, the present invention relates to a method for preparing a compound of formula (C5), comprising the following steps:

[0139] (i) preparing a compound of formula (C4) as disclosed in the method of Section 2.1; and

[0140] (ii) treating the compound of formula (C4) obtained from step (i) under reductase conditions;

[0141] To obtain a compound of formula (C5), as outlined in Scheme 11 below,

[0142]

[0143] Solution 11

[0144] wherein R is C1-C6 alkyl, preferably methyl; and

[0145] wherein P1 is a nitrogen protecting group as described above in Section 2, preferably benzyloxycarbonyl (Cbz).

[0146] Reductase conditions as disclosed herein include treating a compound of formula (C4) with an enzyme, a cofactor, in an aqueous buffer solution, optionally in the presence of a surfactant, to provide a compound of formula (C5).

[0147] Suitable enzymes, cofactors, aqueous buffer solutions and surfactants are those for carrying out the reaction as described in Section 1.2. When the enzyme is a ketoreductase (KRED), when the cofactor is nicotinamide adenine dinucleotide phosphate (NADP), the reaction as described in Scheme 11 is advantageously carried out in an aqueous buffer solution that does not contain a surfactant and optionally contains a second enzyme, a so-called coenzyme (as defined in Section 1.2). In particular, the reaction is particularly well carried out when the coenzyme is glucose dehydrogenase (GDH) and the cofactor is D-glucose. Preferably, the reaction is carried out at a temperature between 30°C and 90°C, more preferably between 40°C and 70°C. Most preferably, the reaction is carried out at a temperature of about 50°C.

[0148] Carrying out the reaction under these conditions is particularly advantageous because the enantioselectivity of the reduction is enhanced. In addition, the reaction is carried out under mild conditions, thereby producing fewer by-products. The reaction provides an environmentally friendly and scalable method for reducing ketones to alcohols because the reaction is carried out in an aqueous medium.

[0149] 2.3. Synthesis of compounds of formula (II)

[0150] In one embodiment, the method comprises the following steps:

[0151] - protecting the alcohol of the compound of formula (C5) by reaction with an oxygen protecting group P2 to form a compound of formula (C8),

[0152] - alkylating the protected alcohol on the compound of formula (C8) with an ethyl group to obtain a compound of formula (C9),

[0153] - removing the nitrogen protecting group P1 to obtain a compound of formula (II) or a salt thereof, and

[0154] - reacting a further compound of formula (II) or a salt thereof to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0155] In another embodiment, the present invention provides a method for preparing a compound of formula (C9) as summarized in Scheme 12 below, comprising the following steps:

[0156] (i) reacting the alcohol of the compound of formula (C5) with an oxygen protecting group P2 to obtain a compound of formula (C8),

[0157] (ii) reacting the protected alcohol of the compound of formula (C8) with an ethylating agent;

[0158] To obtain a compound of formula (C9),

[0159]

[0160] Solution 12

[0161] wherein R is a C1-C6 alkyl group, preferably a methyl group;

[0162] wherein P1 is a nitrogen protecting group. Preferably, the nitrogen protecting group P1 is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyl (Bz), benzyloxycarbonyl (Cbz) and allyloxycarbonyl (Alloc). Most preferably, the nitrogen protecting group is benzyloxycarbonyl (Cbz);

[0163] Wherein P2 is an oxygen protecting group. Preferably, the oxygen protecting group P2 is a silyl selected from, for example, but not limited to, the group consisting of tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS) and tert-butyldiphenylsilyl (TBDPS). Most preferably, P2 is tert-butyldimethylsilyl (TBS).

[0164] Using the same conditions as described above for the conversion of (S)-(C5) to (S)-(C8) (see Section 1.3), in a solvent, in the presence of a base, the alcohol group of the compound of formula (C5) is protected with an oxygen protecting group P2 to obtain a first intermediate of formula (C8). In particular, when the oxygen protecting group P2 is tert-butyldimethylsilyl (TBS) and the base is imidazole, the protection of the compound of formula (C5) to obtain the first intermediate of formula (C8) is particularly well performed in a mixture of toluene and heptane.

[0165] The oxygen protecting group P2 on the compound of formula (C8) is then cleaved, and the resulting alcohol is reacted with an ethylating agent using the same conditions as described above for obtaining the intermediate of formula (S)-(C9) (see Section 1.3) to obtain the intermediate of formula (C9). In particular, in acetonitrile, in situ cleavage and substitution of the oxygen protecting group P2 by ethyl is advantageously performed with TESOTf, Et3SiH and 2,4,6-trimethyl-1,3,5-trioxane at a temperature between 4°C and 5°C to obtain the intermediate of formula (C9). Ethylation of the alcohol group under these conditions is particularly advantageous because it provides a scalable method that avoids any hazardous chemicals (such as sodium hydride (NaH) used in WO 2015 / 009616) without affecting the conversion yield.

[0166] In another embodiment, the nitrogen protecting group P1 on the compound of formula (C9) is cleaved off, and then chiral separation is performed to obtain a compound of formula (II) or a salt thereof. The removal of the oxygen protecting group P1 can be carried out under standard reaction conditions, as described in Section 1.3 ((S)-C9 to (II) above). Chiral separation can be performed, for example, according to WO 2015 / 009616 (e.g., intermediates 2-13, pages 96-97). The compound of formula (II) can exist in the form of a salt as described above (e.g., maleate).

[0167] 3. Synthesis of compounds of formula (III): (C12)->(C13)->(III).

[0168] 3.1. Synthesis of compounds of formula (C13)

[0169] In another embodiment, the present invention provides a method for preparing a compound of formula (C13), comprising the steps of reacting a compound of formula (C12) with a Grignard reagent or with a Lewis acid in the presence of an aldehyde source to obtain a compound of formula (C13), as outlined in Scheme 13.

[0170] In another embodiment, the present invention provides a method for preparing a compound of formula (C13), comprising the steps of reacting a compound of formula (C12) with a Grignard reagent in the presence of an aldehyde source to obtain a compound of formula (C13), as summarized in Scheme 13, see below.

[0171]

[0172] Solution 13

[0173] Wherein P3 is a nitrogen protecting group selected from the group consisting of tert-butyloxycarbonyl (Boc), toluenesulfonyl (Tosyl) and trifluoromethanesulfonyl. Preferably, the nitrogen protecting group P3 is tert-butyloxycarbonyl (Boc).

[0174] The intermediate compound of formula (C12) as described in Scheme 13 above can be prepared according to the method disclosed in WO 2014 / 143638 (Example 2).

[0175] The reaction as outlined in Scheme 13 can be carried out in the presence of a Grignard reagent or with a Lewis acid. The Grignard reagent used to carry out the reaction as outlined in Scheme 13 can be selected from the group consisting of MeMgBr, MeMgCl, MeMgl, EtMgBr, EtMgCl, EtMgl, iPrMgCl, iPrMgBr, iPrMgl or a mixture thereof. Preferably, the Grignard reagent is selected from MeMgBr and MeMgCl. The Lewis acid that can be used to carry out the reaction as outlined in Scheme 13 can be selected from the group consisting of MgCl2, MgBr2, MgI2 or a mixture thereof.

[0176] Optionally, the reaction as described in Scheme 13 can be carried out in the presence of a base. The base can be any suitable base that the skilled person will select based on a general textbook. The base can be, for example, but not limited to, selected from triethylamine, N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] undecane-7-ene (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO) or a mixture thereof. Preferably, the base is triethylamine, DBU or a mixture thereof.

[0177] The aldehyde source used to carry out the reaction may be selected from the group consisting of formaldehyde, paraformaldehyde, hexamethylenetetramine and 2,4,6-trimethyl-1,3,5-trioxane. Preferably, the aldehyde source is paraformaldehyde.

[0178] Suitable solvents that can be used for the reaction are, for example, but not limited to, 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether or a mixture thereof.

[0179] When the Grignard reagent is MeMgBr, the aldehyde source is paraformaldehyde and the oxygen protecting group P2 is tert-butyloxycarbonyl, the synthesis of the compound of formula (C13) is advantageously carried out. In another embodiment, when Lewis acid is MgCl2, the aldehyde source is paraformaldehyde, and the oxygen protecting group P2 is tert-butyloxycarbonyl, the synthesis of the compound of formula (C13) is also advantageously carried out. The reaction is best carried out at a temperature between room temperature and reflux. In order to obtain a good yield, the temperature may need to be higher than room temperature. In particular, when using a reactive Grignard reagent, the temperature may need to be between -30°C and reflux. The reflux temperature is preferably between about 60°C and about 80°C, most preferably between about 65°C and about 75°C. It is particularly advantageous to react under these conditions because the reaction provides 100% regioselectivity, making the steps of the present invention particularly suitable for large-scale manufacturing.

[0180] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by a method comprising the steps of reacting a compound of formula (C12) with a Grignard reagent in the presence of an aldehyde source to obtain a compound of formula (C13), as outlined in Scheme 13, and further reacting the compound of formula (C13) to obtain a compound of formula (I) or a salt thereof.

[0181] 3.2. Compound of formula (C13)

[0182] In another embodiment, the present invention provides a useful intermediate for synthesizing a compound of formula (III) or a salt thereof, a compound of formula (C13),

[0183] (C13),

[0184] wherein P3 is a nitrogen protecting group as defined above in Section 3.1.

[0185] In another embodiment, the present invention provides use of a compound of formula (C13) for preparing a compound of formula (III) or a salt thereof.

[0186] In another embodiment, the present invention provides use of a compound of formula (C13) for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0187] 3.3. Synthesis of the compound of formula (III) or its salt

[0188] In another embodiment, the present invention provides a method for preparing a compound of formula (III) or a salt thereof, comprising reacting a compound of formula (C13) with an inorganic base in the presence of a methylating agent to obtain a compound of formula (III) or a salt thereof, as summarized in Scheme 14.

[0189]

[0190] Solution 14

[0191] wherein P3 is a nitrogen protecting group as defined above in Section 3.1.

[0192] The inorganic base used to carry out the reaction is an inorganic base from which a salt can be derived, including, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts. Preferably, the inorganic base is an alkali metal base. Examples of suitable bases are, for example, Na2CO3, K2CO3, Cs2CO3 or mixtures thereof. Preferably, the base is potassium carbonate (K2CO3).

[0193] The methylating agent that can be used to convert the alcohol into a methoxy group can be any methylating agent that the technician will select based on general textbooks. Examples of suitable methylating agents are methyl iodide, methyl bromide, methyl chloride, dimethyl sulfate, methyl trifluoromethanesulfonate (MeOTf), 4-methylsulfonyltoluene, methyl benzenesulfonate and mixtures thereof. Preferably, methyl iodide, methyl benzenesulfonate and dimethyl sulfate. Preferably, the methylating agent is dimethyl sulfate.

[0194] Suitable solvents that can be used for the reaction are, for example, dimethylformamide (DMF), dimethoxyethane (DME), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), toluene, acetonitrile or mixtures thereof. Preferably, the solvent is dimethylformamide (DMF).

[0195] When the methylating agent is dimethyl sulfate and the base is a base such as potassium carbonate, the synthesis of the compound of formula (III) or a salt thereof as described in Scheme 14 is advantageously performed. In particular, the reaction proceeds well at a temperature of about 15° C. to about 35° C. Preferably, from about 20° C. to about 25° C.

[0196] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by a process comprising the steps of reacting a compound of formula (C13) with a base in the presence of an alkylating agent to prepare a compound of formula (III) or a salt thereof, as outlined in Scheme 14.

[0197] In another embodiment, the present invention provides a method for preparing a compound of formula (III) or a salt thereof disclosed herein, the method comprising the following steps:

[0198] (i) preparing a compound of formula (C13) as described in Section 3.1; and

[0199] (ii) further reacting the compound of formula (C13) as described in Section 3.3;

[0200] To obtain the compound of formula (III) or its salt.

[0201] 4. Synthesis of compounds of formula (I) = (II) + (III):

[0202] 4.1. Synthesis of compounds of formula (C15)

[0203] In one embodiment, the method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises: reacting a compound of formula (II) or a salt thereof with a compound of formula (III) or a salt thereof, optionally in the presence of an additive, under hydrogen pressure, in the presence of an iridium catalyst in a solvent to obtain a compound of formula (C15) or a salt thereof, as described in Scheme 15 below,

[0204] In another embodiment, the present invention provides a method for preparing a compound of formula (C15) or a salt thereof, comprising the following steps: reacting a compound of formula (II) or a salt thereof with a compound of formula (III) or a salt thereof, optionally in the presence of an additive, under hydrogen pressure, in the presence of an iridium catalyst to provide a compound of formula (C15) or a salt thereof, as outlined in Scheme 15 below.

[0205]

[0206] Solution 15

[0207] wherein P3 is a nitrogen protecting group as defined in Section 3.1 above; and

[0208] Wherein R is C1-C6 alkyl, preferably R is methyl.

[0209] The catalyst used to carry out the reaction can be, for example, selected from the group consisting of [Ru(Triphos)(CO)H2], [Ru(S)-BINAP(p-cymene)Cl]Cl, [Ru(CO)ClH(PPh3)3], [Ru(R)-BINAP(benzene)Cl]Cl, Ir(CO)2acac, Ir(COD)Cl, Ir(CO)3 and IrCl3,xH2O. Preferably, the catalyst is an iridium catalyst selected from the group consisting of Ir(CO)2acac, Ir(COD)Cl, Ir(CO)3 and IrCl3,xH2O. The catalyst can be present in a range from about 0.05 mol% to about 10.0 mol%. Preferably, the catalyst is present in a range from 0.1 mol% to about 5.0 mol%. Suitable solvents for the reaction are, for example, methanol, ethanol, isopropanol, ethylene glycol, diethyl carbonate, DMSO, acetonitrile, tetrahydrofuran or a mixture thereof.

[0210] The additive may be a ligand, a base, an acid or a mixture thereof. The additive may be selected from, for example, but not limited to, the group consisting of tetrabutylammonium iodide (TBAI), ((oxydi-2,1-phenylene)bis(diphenylphosphine)) (DPEPhos), triethylamine (Et3N), sodium trifluoromethanesulfonate (NaOTf), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 1,4-diazabicyclo[2.2.2]octane (DABCO), tri(4-fluorophenyl)phosphine ((4-F-C6H4)3P), acetic acid, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS) or a mixture thereof.

[0211] When there is 0.1mol% of Ir(CO)2acac catalyst in ethanol as solvent under hydrogen pressure, the reaction as described in Scheme 15 is particularly well performed. In particular, the reaction is well performed at a temperature ranging from about room temperature to reflux. Preferably, the temperature is in the range of from about 60°C to about 100°C. Typically, the temperature is about 80°C. The reaction is best performed in the presence of hydrogen. The pressure of hydrogen in the reaction can be in the range of from about 1 bar to about 30 bar, preferably between about 2.5 bar to about 20 bar. It is particularly advantageous to react under these conditions because the reaction is efficient and the amount of by-product formation is reduced compared to the preparation of the compound of formula (C15) described in WO2015 / 009616 (Intermediate 4-3, pages 127-128).

[0212] In another embodiment, the present invention provides a method for preparing a compound of formula (C15) or a salt thereof, the method comprising the following steps: reacting a compound of formula (II) or a salt thereof with a compound of formula (III) or a salt thereof, as described in Scheme 15, to prepare a compound of formula (C15) or a salt thereof, wherein the aldehyde group on the compound of formula (III) is first reduced to the corresponding alcohol to obtain an intermediate compound of formula (IIIa) or a salt thereof,

[0213]

[0214] Scheme 16

[0215] wherein P3 is a nitrogen protecting group as defined in Section 3.1 above; and

[0216] Wherein R is C1-C6 alkyl, preferably R is methyl.

[0217] The compound of formula (IIIa) or a salt thereof is then reacted with a compound of formula (II) or a salt thereof, optionally in the presence of an additive, in a hydrogen atmosphere in the presence of an iridium catalyst in a solvent, as described above in Section 4.1.

[0218] In another embodiment, the present invention provides an aldehyde group on a compound of formula (III) or a salt thereof is reduced in situ to a corresponding alcohol to obtain a compound of formula (IIIa) or a salt thereof. The compound of formula (IIIa) or a salt thereof is then reacted with a compound of formula (II) or a salt thereof, optionally in the presence of an additive, under hydrogen pressure, in the presence of an iridium catalyst in a solvent, as described in Section 4.1 above.

[0219] 4.2. The compound of formula (I) or a pharmaceutically acceptable salt thereof

[0220] In another embodiment, the present invention provides a method as defined in Section 4.1, wherein the compound of formula (C15) or a salt thereof is further reacted under hydrolysis conditions to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0221] The term "hydrolysis conditions" refers to the hydrolysis of an ester group of the formula -CO2R, wherein R is a C1-C6 alkyl group, such as a methyl group, to form a carboxylic acid of the formula -CO2H. The ester group can be hydrolyzed, for example, under basic conditions (e.g., using an alkali metal base such as NaOH, LiOH or KOH) or under acidic conditions (e.g., using a mineral acid such as HCl, H2SO4, HBr, H3PO4) to provide a carboxylic acid.

[0222] In one embodiment, the compound of formula (C15) or a salt thereof is reacted under hydrolysis conditions to obtain the corresponding carboxylic acid, as outlined in Scheme 1. For example, hydrolysis conditions as described in WO 2015 / 009616 (Example 26, page 174) are used.

[0223] Certain variants or alternative methods for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof are described below. For example, the method comprises the following steps:

[0224] (i) preparing a compound of formula (S)-(C4) as disclosed in Section 1.1;

[0225] (ii) preparing a compound of formula (S)-(C5) by reacting a compound of formula (S)-(C4) under reductase conditions as disclosed in Section 1.2;

[0226] (iii) preparing a compound of formula (C13) as disclosed in Section 3.2;

[0227] (iv) preparing a compound of formula (III) or a salt thereof as disclosed in Section 3.3;

[0228] (v) reacting a compound of formula (II) or a salt thereof with a compound of formula (III) or a salt thereof as disclosed in Section 4.1 to obtain a compound of formula (C15) or a salt thereof; and

[0229] (vi) reacting a compound of formula (C15) or a salt thereof under hydrolysis conditions to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0230] In another embodiment, the present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described below. For example, the method comprises the following steps:

[0231] (i) preparing a compound of formula (S)-(C5) by reacting a compound of formula (S)-(C4) under reductase conditions as disclosed in Section 1.2;

[0232] (ii) preparing a compound of formula (C13) as disclosed in Section 3.2; and

[0233] (iii) reacting a compound of formula (II) or a salt thereof with a compound of formula (III) or a salt thereof as disclosed in Section 4.1.

[0234] In another embodiment, the present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0235] (i) preparing a compound of formula (C5) by reacting a compound of formula (C4) using an enzyme-catalyzed step as disclosed in Section 2.2;

[0236] (ii) preparing a compound of formula (C13) as disclosed in Section 3.2;

[0237] (iii) preparing a compound of formula (III) or a salt thereof as disclosed in Section 3.3;

[0238] (iv) reacting a compound of formula (II) or a salt thereof with a compound of formula (III) or a salt thereof as disclosed in Section 4.1 to obtain a compound of formula (C15) or a salt thereof; and

[0239] (v) reacting a compound of formula (C15) or a salt thereof under hydrolysis conditions to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0240] In another embodiment, the present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0241] (i) preparing a compound of formula (C5) by reacting a compound of formula (C4) under reductase conditions as disclosed in Section 2.2;

[0242] (ii) preparing a compound of formula (C13) as disclosed in Section 3.2; and

[0243] (iii) reacting a compound of formula (II) or a salt thereof with a compound of formula (III) or a salt thereof as disclosed in Section 4.1.

[0244] In yet another embodiment, the present invention relates to a method for preparing a pharmaceutical composition, comprising the method according to Section 4.2, and mixing the obtained compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient.

[0245] The compound of formula (I) or a pharmaceutically acceptable salt thereof prepared as described above may optionally be further purified by recrystallization from a suitable solvent, and may optionally be ground or sieved to obtain the final pharmaceutically active ingredient.

[0246] Once the pharmaceutically active ingredient compound of formula (I) or a pharmaceutically acceptable salt thereof (as described above) is obtained, it can be mixed with a pharmaceutically acceptable excipient. This can be achieved by mixing, granulating, compressing, etc. In this way, a pharmaceutical composition can be prepared and can be used to prepare a final dosage form, such as a tablet or capsule, or any other suitable pharmaceutical composition.

[0247] definition

[0248] The term "catalyst" as used herein refers to a catalytic amount of a chemical agent that increases the rate of a chemical reaction by reducing the activation energy of the chemical reaction. The catalyst can be a heterogeneous catalyst or a homogeneous catalyst. The term "heterogeneous catalyst" refers to a catalyst supported on a carrier, typically but not necessarily a substrate consisting of an inorganic material (e.g., a porous material such as carbon, silicon and / or aluminum oxide). The term "homogeneous catalyst" refers to a catalyst that is not supported on a carrier.

[0249] The term "one pot" or "one pot process" refers to a series of (e.g., continuous) reactions, such as two or more continuous reactions, in which each reaction product is provided to the next reaction without separation and purification. The one pot process defined herein not only encompasses a series of (i.e., continuous) reactions carried out in a single reaction vessel, but also includes a series of (i.e., continuous) reactions carried out in multiple reaction vessels without separation and purification (e.g., by transferring the reaction mixture from one vessel to another). Preferably, the one pot process is carried out in a single reaction vessel.

[0250] The term "ligand" means any compound (achiral or chiral) that can form a complex with a transition metal. The term "chiral" refers to a molecule that has the property of non-superimposability on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0251] The term "amount" herein refers to the weight of a compound or the molar amount of a compound.

[0252] The term "protecting group" may be present, and the functional group of interest should be protected from unwanted secondary reactions, such as acylation, etherification, esterification, oxidation, solvolysis and similar reactions. Protecting groups are characterized in that they are themselves easily (i.e., without or with very limited unwanted secondary reactions) typically removed by solvolysis, reduction, photolysis or also by enzyme activity (e.g., under conditions similar to physiological conditions), and they are not present in the final product. The professional knows or can easily determine which protecting group is suitable for the reactions mentioned above and below. Preferably, if two or more protecting groups are present in a mentioned intermediate, their selection is such that if one protecting group needs to be removed, this can be done selectively, for example using two or more different protecting groups that are cleavable under different conditions (e.g., one by mild hydrolysis, another by hydrolysis under more difficult conditions; one by hydrolysis in the presence of an acid, another by hydrolysis in the presence of a base; or one by reduction cleavage (e.g., by catalytic hydrogenation), another by hydrolysis, etc.). Suitable nitrogen protecting groups are routinely used in peptide chemistry and are described, for example, in the relevant chapters of standard reference works such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TW Greene and PGM Wuts, "Greene's Protective Groups in Organic Synthesis", 4th edition, Silicon Valley, New York 2007; "Peptides", Vol. 3, Academic Press, London and New York 1981 and "Methoden der organischen Chemie", Houben Weyl, 4th edition, Vol. 15 / 1, Georg Thieme Verlag, Stuttgart 1974.

[0253] The term "oxygen protecting group" generally comprises any group capable of reversibly protecting oxygen functionality. Hydroxyl protecting groups may, for example, be selected from the group comprising (especially consisting of) silyl protecting groups, especially diarylalkyl-silyl groups, such as diphenyl-tert-butylsilyl or more preferably trialkylsilyl groups, such as tert-butyldimethylsilyl or trimethylsilyl; acyl groups, for example alkanoyl groups, such as acetyl; benzoyl; alkoxycarbonyl groups, such as tetrabutoxycarbonyl (Boc), or arylalkoxycarbonyl groups, such as benzyloxycarbonyl; tetrahydropyranyl; unsubstituted or substituted arylalkyl groups, such as benzyl or p-methoxybenzyl and methoxymethyl. Exemplary hydroxy protecting groups are acetyl, propionyl, butyryl, pivaloyl, 2-chloroacetyl, benzoyl; formate derivatives such as phenoxycarbonyl, tert-butoxycarbonylethoxycarbonyl, vinyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and benzyloxycarbonyl; alkyl ether forming groups such as methyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl alkyl, ...

[0254] The term "nitrogen protecting group" generally comprises: C1-C6-alkyl, preferably C1-C4-alkyl, more preferably C1-C2-alkyl, (e.g. acetyl, allyl, tert-butyl) most preferably C1-alkyl, which is mono-, di- or tri-substituted by trialkylsilyl-C1-C7-alkoxy (e.g. trimethylsilylethoxy); aryl, preferably phenyl; or a heterocyclic group (e.g. benzyl, cumyl, diphenylmethyl, pyrrolidinyl, triphenylmethyl, pyrrolidinylmethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl ) methylbenzene), wherein the aryl ring or heterocyclic group is unsubstituted or substituted by one or more (e.g. two or three) residues, for example, selected from the group consisting of: C1-C7-alkyl, hydroxy, C1-C7-alkoxy, C2-C8-alkanoyl-oxy, halogen, nitro, cyano, and CF3; aryl-C1-C2-alkoxycarbonyl (preferably, phenyl-C1-C2-alkoxycarbonyl (e.g. benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl (POM); C1-C 10 -alkenyloxycarbonyl; C1-C6 alkylcarbonyl (e.g., acetyl or pivaloyl); C6-C 10 -arylcarbonyl; C1-C6-alkoxycarbonyl (e.g. tert-butoxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl); C6-C 10 - aryl C1-C6-alkoxycarbonyl (for example 9-fluorenylmethyloxycarbonyl (Fmoc)); allyl or cinnamyl; sulfonyl or sulfenyl; succinimidyl, silyl (for example triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl or tert-butyldimethylsilyl).

[0255] As used herein, the term "C1-C 12 "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 12 carbon atoms, and attached to the remainder of the molecule by a single bond. The term "C1-C6 alkyl" should be interpreted accordingly. C1-C 12 Examples of alkyl groups include, but are not limited to, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl).

[0256] As used herein, the term "halogen" or "halo" refers to bromine, chlorine, fluorine, or iodine.

[0257] As used herein, the term "about" is intended to provide flexibility for numerical range endpoints, provided that a given value can be "slightly above" or "slightly below" the endpoint to account for differences seen in measurements made between different instruments, samples, and sample preparations. The term generally means within 10%, preferably within 5%, and more preferably within 1% of a given value or range.

[0258] Unless otherwise stated, the term "room temperature" or "ambient temperature" as used herein means a temperature from 15°C to 30°C, such as from 20°C to 30°C, particularly such as from 20°C to 25°C. Unless otherwise stated, the term "internal temperature" as used herein means the temperature measured inside the reactor vessel in which the reaction is carried out. Such temperatures are expressed in degrees Celsius. Unless otherwise stated, the term "jacket temperature" as used herein means the temperature measured inside the jacket of the reactor vessel in which the reaction is carried out.

[0259] The term "stereoisomer" means one of the absolute configurations of a single organic molecule with at least one asymmetric carbon. In addition, as used herein, the term refers to any of the various stereoisomer configurations that can exist for a given compound of the present invention and includes geometric isomers. It should be understood that substituents can be attached to the chiral center of a carbon atom. Therefore, the present invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomer" is a pair of stereoisomers that cannot overlap each other. A 1:1 mixture of an enantiomer pair is a "racemic" mixture. The term is used to specify a racemic mixture when appropriate. "Diastereomer" is a stereoisomer with at least two asymmetric atoms, but it is not a mirror image of each other. Absolute stereochemistry is specified according to the Cahn-lngold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be illustrated by R or S. Resolved compounds of unknown absolute configuration can be assigned (+) or (-) depending on the direction (right-handed or left-handed) in which they rotate plane polarized light of the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and can therefore generate enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- based on absolute stereochemistry. The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures.

[0260] In the formula of the present application, in C-sp 3 Terminology Absolute stereochemistry is indicated, (R) or (S).

[0261] In the formula of the present application, in C-sp 3 Terminology Absolute stereochemistry is indicated, (R) or (S).

[0262] The term "resolution" refers to the separation or enrichment or depletion of one stereoisomer of a molecule.

[0263] The term "seed" can be used as a noun to describe one or more crystals of a crystalline compound of the same formula as the final compound of the reaction of interest. The term "seed" can also be used as a verb to describe the act of introducing the one or more crystals of the crystalline compound into an environment (including but not limited to, for example, a solution, mixture, suspension, or dispersion) to result in the formation of more crystals of the final compound.

[0264] The term "pharmaceutically acceptable salt" or "salt thereof" refers to a salt that can be formed, for example, as an acid addition salt, preferably with an organic acid or an inorganic acid. For the purpose of isolation or purification, pharmaceutically unacceptable salts, such as picrates or perchlorates, may also be used. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred. Salts of the compounds and intermediates of formula (I) as described in the present invention are preferably pharmaceutically acceptable salts; suitable counterions for forming pharmaceutically acceptable salts are known in the art. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for contact with human and animal tissues without producing excessive toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0265] The term "additive" as used herein refers to a base, acid, ligand, or any other chemical substance that can enhance the reactivity of a reaction.

[0266] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0267] Similarly, "comprise," "comprises," "comprising," "include," "includes," and "including" are used interchangeably and are not intended to be limiting.

[0268] abbreviation

[0269] δ Chemical shift

[0270] (4-F-C6H4)3P tri(4-fluorophenyl)phosphine

[0271] (Boc)2O Di-tert-butyl carbonate

[0272] (R)-(+)-MeO-BIPHEP) (R)-(+)-(6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphine)

[0273] (R)-segphos (R)-(+)-5,5'-bis(diphenylphosphino)-4,4'-di-1,3-benzodioxole

[0274] (R,R)-Ph-BPE (+)-1,2-Bis((2R,5R)-2,5-diphenylphosphino)ethane

[0275] (S)-BINAP (S)-(2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl)

[0276] (S)-SDP (S)-(-)-7,7'-bis(diphenylphosphino)-2,2',3,3'-tetrahydro-1,1'-spirobiindene

[0277] (S)-Tol-BINAP (R)-(+)-2,2'-Bis(di-p-tolylphosphino)-1,1'-binaphthyl

[0278] (S)-XylBINAP 1,1'-binaphthyl-2,2'-diylbis[bis(3,5-dimethylphenyl)phosphine]

[0279] (S,S)-Et-DUPHOS (+)-1,2-Bis[(2S,5S)-2,5-diethylphosphino]benzene

[0280] (S,S)-iPr-DUPHOS (+)-1,2-Bis[(2S,5S)-2,5-diisopropylphosphino]benzene

[0281] (S,S)-Me-DUPHOS (+)-1,2-Bis[(2S,5S)-2,5-dimethylphosphino]benzene

[0282] (S,S)-Me-Ferrocelane 1,1'-Bis[(2S,5S)-2,5-dimethylphosphino]ferrocene

[0283] [Rh(COD)Cl]2 Chloro(1,5-cyclooctadiene)rhodium(I) dimer

[0284] [Rh(COD)OMe]2 Methoxy(cyclooctadiene)rhodium(I) dimer

[0285] [Rh(MeCN)2(COD)]BF4 Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate

[0286] [Rh(OH)((S)-BINAP)]2 Hydroxy[-(S)-BINAP]-Rhodium(I) dimer

[0287] [RhCl(S)-BINAP]2 Chloro[-(S)-BINAP]-rhodium(I) dimer

[0288] 1 H-NMR Proton Nuclear Magnetic Resonance

[0289] 9-BBN 9-Borabicyclo(3.3.1)nonyl

[0290] acac Acetylacetone

[0291] alloc allyloxycarbonyl

[0292] Boc / Boc2O tert-Butyloxycarbonyl / di-tert-butyl dicarbonate

[0293] Br / d / m / t / s / q Broad / Double / Multiplet / Triplet / Singlet / Quadruplet

[0294] Bz / Cbz Benzyl / Benzyl Chloroformate

[0295] CDCl3 Deuterated chloroform

[0296] COD Cyclooctadiene

[0297] CPME Cyclopentyl Methyl Ether

[0298] DABCO 1,4-diazabicyclo[2.2.2]octane

[0299] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0300] DEM Diethoxymethane

[0301] DIPEA N,N-Diisopropylethylamine

[0302] DMA Dimethylacetamide

[0303] DMAP 4-dimethylaminopyridine

[0304] DMF Dimethylformamide

[0305] DMSO / DMSO-d6 Dimethyl sulfoxide / deuterated dimethyl sulfoxide

[0306] DPEPhos Oxydi-2,1-phenylene)bis(diphenylphosphine)

[0307] EDTA-4Na·2H2O Tetrasodium dihydrate

[0308] ee enantiomeric excess

[0309] eq equivalent

[0310] Et3N Triethylamine

[0311] Et3SiH Triethylsilane

[0312] FAD Flavin adenine dinucleotide

[0313] g / mg gram / milligram

[0314] GC Gas chromatography

[0315] GDH Glucose dehydrogenase

[0316] H2 Dihydrogen

[0317] HCl / HF Hydrogen chloride / hydrogen fluoride

[0318] HEPES 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

[0319] HPLC High Performance Liquid Chromatography

[0320] HRMS High Resolution Mass Spectrometry

[0321] Hz / MHz Hertz / Megahertz

[0322] IT / JT Internal temperature (degrees Celsius) / Jacket temperature (degrees Celsius)

[0323] J coupling constant

[0324] K2CO3 Potassium carbonate

[0325] KRED Ketoreductase

[0326] LCMS liquid chromatography-mass spectrometry

[0327] M Moore

[0328] MCC Microcrystalline Cellulose

[0329] mL / L milliliters / liter

[0330] Mol / mmol mole / millimole

[0331] MOPS 3-(N-morpholino)propanesulfonic acid

[0332] MTBE Methyl tert-butyl ether

[0333] N Positive

[0334] Na2HPO4 Disodium hydrogen phosphate

[0335] NAD Nicotinamide adenine dinucleotide

[0336] NADP Nicotinamide adenine dinucleotide phosphate

[0337] NaHCO3 Sodium bicarbonate

[0338] NaOTf Sodium trifluoromethanesulfonate

[0339] nbd norbornadiene

[0340] NBS / NCS N-bromosuccinimide / N-chlorosuccinimide

[0341] NH4Cl / NaCl Ammonium chloride / Sodium chloride

[0342] NHC-Pd(II) N-Heterocyclic Carbene-Palladium(II)

[0343] PBS Phosphate buffered saline

[0344] Pd(O2CCF3)2 Palladium(II) trifluoroacetate

[0345] Pd(OAc)2 Palladium(II) acetate

[0346] Pd / C Palladium Carbon

[0347] PIPES Piperazine-N,N'-bis(2-ethanesulfonic acid

[0348] ppm parts per million

[0349] PTS Tocopheryl polyethylene glycol succinate

[0350] Rh(acac)(C2H4)2 Bis(ethylene)rhodium(I)acetylacetonate

[0351] Rh(acac)(COD) (acetylacetonato)(1,5-cyclooctadiene)rhodium(I)

[0352] Rh(COD)BF4 Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate

[0353] Rh(nbd)2BF4 Bis(norbornadiene)rhodium(I) tetrafluoroborate

[0354] RPM revolutions per minute

[0355] TBAI Tetrabutylammonium iodide

[0356] TBDPS tert-Butyldiphenylsilyl

[0357] TBS tert-Butyldimethylsilyl

[0358] TES / TESOTf Triethylsilyl trifluoromethanesulfonate / triethylsilyl

[0359] TFA Trifluoroacetic acid

[0360] THF Tetrahydrofuran

[0361] TIPS Triisopropylsilyl

[0362] TMS Trimethylsilyl

[0363] Tosyl

[0364] TPGS Tocopheryl polyethylene glycol succinate

[0365] TRIS 2-Amino-2-(hydroxymethyl)propane-1,3-diol

[0366] v / v volume to volume

[0367] Wt% Weight percentage

[0368] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0369] XRPD X-ray diffraction pattern

[0370] Examples

[0371] The following examples are merely illustrative of the present invention, and they should not be construed as limiting the scope of the present invention in any way, as these examples and other equivalents thereof will become apparent to those skilled in the art in light of the present invention and the appended claims.

[0372] synthesis

[0373] The skilled person will appreciate that the general synthetic routes detailed above show common reactions for converting starting materials as desired. Where specific reactions are not provided, the skilled person will appreciate that such reactions are well known to those skilled in the art, and that appropriate conditions are considered to be within the common knowledge of those skilled in the art. Starting materials are commercially available compounds or known compounds and can be prepared by procedures described in the field of organic chemistry.

[0374] In a conventional manner understood by those skilled in the art, the compounds as described herein in free form can be converted into salt forms, and vice versa. The compounds in free form or salt form can be obtained in the form of hydrates or solvates containing solvents for crystallization. The compounds described herein can be recovered from the reaction mixture and purified in a conventional manner. Isomers (such as stereoisomers) can be obtained in a conventional manner, for example, by fractional crystallization or asymmetric synthesis from corresponding asymmetric substitutions such as optically active starting materials. When appropriate, conventional techniques (such as precipitation, filtration, crystallization, evaporation, distillation and chromatography) can be used to separate and purify various starting materials, intermediates and compounds of preferred embodiments. Unless otherwise indicated. Salts can be prepared by known salt-forming procedures from compounds.

[0375] The compounds described herein can be prepared, for example, using the reactions and techniques described below and in the examples. The reactions can be carried out in a solvent suitable for the reagents and materials used and suitable for the transformations to be carried out. It will be appreciated by those skilled in the art of organic synthesis that the functional groups present on the molecule should be consistent with the proposed transformations. Sometimes this will require judgment to modify the order of the synthetic steps or to select a particular process scheme rather than another in order to obtain the desired compounds of the present invention.

[0376] It will be appreciated by those skilled in the art that the reactions are first conducted on a small scale in order to assess whether the starting materials can react in high yield and purity before they can be scaled up. The desired compound obtained during such a small scale reaction of spontaneous crystallization is used to enhance the latest reaction using the "seeding" technique. Hereinafter, if desired, seeding crystals of about 1% or less by weight are added to the reaction mixture to more rapidly produce spontaneous crystallization of the desired product.

[0377] Measurement method

[0378] - Proton-NMR: measurements were performed on a Bruker 400Mhz spectrophotometer. Chemical shifts (δ values) were reported in low field ppm and the spectral splitting patterns were designated as single signals (s), double signals (d), triple signals (t), quartet signals (q), quintet signals (quint), multiple signals, unresolved or overlapping signals (m), broad signals (br). Deuterated solvents are given in brackets.

[0379] -HPLC: measured on Agilent 1200HPLC (column: Waters XBridge BEH C18) and Agilent 1290UHPLC (column: Water Acquity BEH C18) with high pressure mixing

[0380] 1. C4 CPD Method:Agilent 1200HPLC with high pressure mixing

[0381] Solvent: Mobile phase A: 10 mM ammonium acetate in water, and mobile phase B: acetonitrile.

[0382] This method is only applicable to compounds of formula (C4).

[0383] 2. 1601 Method: Agilent 1290UHPLC

[0384] Solvent: Mobile phase A: 0.05% TFA in water / acetonitrile 95 / 5 (v / v), and mobile phase B: 0.05% TFA in water / ACN 5 / 95 (v / v)

[0385] -HRMS: Waters ACQUITY UPLC / SYNAPT HDMS QTOF system.

[0386] -LCMS: Waters ACQUITY UPLC / SYNAPT HDMS QTOF system or Agilent 1290 Infinity / MSD LC / MS system.

[0387] -XRPD: at Bruker The measurements are performed on. It will be appreciated by those of ordinary skill in the art that an X-ray diffraction pattern may be obtained which has a measurement error depending on the measurement conditions employed. In particular, it is generally known that the intensity in an X-ray diffraction pattern may fluctuate depending on the measurement conditions employed. It will be further appreciated that the relative intensity may also vary depending on the experimental conditions, and therefore, the exact order of the intensity should not be considered. In addition, the measurement error of the diffraction angle of a conventional X-ray diffraction pattern is typically about 5% or less, and the degree of such measurement error associated with the above-mentioned diffraction angle should be considered. Therefore, it will be appreciated that the crystalline form of the present invention is not limited to providing an X-ray diffraction pattern that is exactly the same as the X-ray diffraction pattern depicted in the accompanying drawings disclosed herein. Any crystalline form that provides an X-ray diffraction pattern that is substantially the same as the X-ray diffraction pattern disclosed in the accompanying drawings falls within the scope of the present invention. The ability to determine the essential features of an X-ray diffraction pattern is within the capabilities of those of ordinary skill in the art.

[0388] Example 1: Benzyl 2-[4-(methoxycarbonyl)phenyl]-4-oxopiperidine-1-carboxylate (C4) was synthesized according to the following sequence:

[0389]

[0390] Step 1: Synthesis of benzyl 2-[4-(methoxycarbonyl)phenyl]-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (C3, wherein P1 = Cbz and R = methyl)

[0391] iPrMgCl (2N THF, 109.96 g, 54.98 mL, 2.0 equiv) was charged into a reactor. A solution of bis[2-(N,N-dimethylaminoethyl)]ether (2.5 equiv, 22.03 g, 137.46 mmol) in THF (24 mL) was added at 15°C-25°C. The mixture was stirred for 1 hour. A solution of C1 (20.17 g, 76.98 mmol, 1.4 equiv) in THF (102 mL) was slowly added at 15°C-25°C. The mixture was heated to 25°C-30°C, stirred for more than 1 hour, and checked by HPLC. The mixture was cooled to -30°C. A solution of C2 (methyl 4-iodobenzoate, 6.0 g, 54.98 mmol, 1.0 eq.) in THF (20 mL) was added, followed by a solution of benzyl chloroformate (1.15 eq., 10.79 g, 63.23 mmol) in THF (36 mL). The mixture was stirred for 2 hours and quenched with AcOH (6.60 g, 109.96 mmol, 2 eq.). Isopropyl acetate (60 mL) was added. Hydrogen chloride (15%, 90 g) was added to adjust pH=1-2. The organic layer was separated and washed with brine (15%, 100 g), and concentrated. Isopropyl acetate (160 mL) was added and concentrated to remove THF. The crude product was recrystallized in isopropyl acetate (114 mL) and n-heptane (120 mL). The product was dried at 60 °C to afford C3 (16.0 g, 79.65% yield) as a light yellow solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm) = 8.11 (dd, J = 8.39, 1.01Hz, 1H), 7.91 (d, J = 8.39Hz, 2H), 7.33-7.37 (m, 6H), 5.82 (d, J = 7. 20Hz,1H),5.20-5.35(m,3H),3.83(s,3H),3.41(br.s,1H),3.31(dd,J=16.64,7.52Hz,1H),2.66(br.d,J=16.55Hz,1H).

[0392] Step 2: Synthesis of benzyl 2-[4-(methoxycarbonyl)phenyl]-4-oxopiperidine-1-carboxylate (C4, wherein P1 = Cbz and R = methyl)

[0393] A solution of C3 (25 g, 68.42 mmol, 1.0 eq.) in AcOH (200 mL) was heated to 50-60 ° C to form a clear solution. The solution was then cooled to 35 ° C. Zinc powder (13.42 g, 205.26 mmol, 3.0 eq.) was added in batches while the internal temperature was maintained at 35-40 ° C. After addition, the mixture was stirred for more than 8 hours and checked by HPLC. THF (250 mL) was added. The mixture was cooled to 25 ° C, filtered, and the filter cake was washed with THF (125 volumes). The filtrate was concentrated to dryness. Isopropanol (375 mL) was added. The solution was cooled to 0-5 ° C. EDTA-4Na·2H2O (40 g) in water (200 mL) was added. The mixture was neutralized to pH=9-10 with 30% sodium hydroxide solution and stirred for 2 hours. The organic layer is collected and washed with brine (15%, 250 g) and concentrated to about 50 mL. MTBE (100 mL) is added and concentrated to about 50 mL. MTBE (80 mL) is added and then n-heptane (20 mL) is added dropwise. The mixture is then gradually cooled to 0 ° C. The mixture is filtered and the filter cake is dried to obtain C4 (20.11 g, 80.0% yield) as a light yellow solid. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.99 (d, J = 8.31Hz, 2H), 7.27-7.39 (m, 7H), 5.83 (br.s, 1H), 5.14-5.28 (m, 2H), 4.20-4.42(m,1H),3.92(s,3H),3.12-3.33(m,1H),2.84-3.04(m,2H),2.46-2.65(m,1H),2.23-2.45(m,1H).

[0394] Example 2: (4S)-4-hydroxy-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (C5, wherein P1 = Cbz and R = methyl)

[0395]

[0396] 0.1M pH=7.0 PBS was prepared with disodium hydrogen phosphate dodecahydrate (22.2 g), sodium dihydrogen phosphate dihydrate (6.2 g) and purified water (999 g). 0.1M pH=7.0 PBS (499 g), D-glucose (40.2 g, 233.14 mmol, 2.0 equiv), NADP (Enzyme Works, 0.72 g), GDH (Enzyme Works, 0.41 g) and KRED-EW124 (Enzyme Works, 2.05 g) were added to a reactor equipped with a pH meter, followed by an emulsion of C4 (41 g, 111.60 mmol, 1.0 equiv) in DMSO (102.5 mL). The mixture was heated to JT≤45°C, IT 41±3°C and stirred at IT 41±3°C for ≥16 h while controlling pH 6.9-7.2 by adding 1M sodium hydroxide solution. A mixture of NADP (0.29 g), GDH (0.16 g) and KRED-EW124 (0.82 g, #China Enzyme Engineering Company) in 0.1M pH=7.0 PBS (11 g) was charged and stirred for ≥20 hours at IT41°C±3°C. The reaction was detected by HPLC. The reaction was filtered to obtain a white wet cake. A 1.0L Radleys reactor equipped with an anchor stirrer was charged with a crude C5 wet cake (80 g) and acetonitrile (500 mL). The mixture was stirred to form a light yellow suspension (700 RPM). The suspension was heated to IT=70°C±5°C, stirred for 4 hours, and then cooled to IT=25°C±5°C. The suspension was filtered and the cake was washed with acetonitrile (75 mL). The resulting mother liquor was charged into a clean 500mL Radleys reactor equipped with an anchor stirrer. The mother liquor is concentrated to about 95 g and solvent exchanged with three portions of toluene (105 g) to 95 g residue. Toluene (170 g) is charged and the reaction is checked by GC (acetonitrile / (toluene+acetonitrile)≤1.2%). The suspension is heated to IT=80°C±5°C, maintained for 1 hour, cooled to IT=45°C±3°C, and the stirring speed is adjusted to low mode. The sequence of inoculation and aging for 2 hours, charging n-heptane (10.2 g) within 0.5 hours and aging for 1 hour, charging n-heptane (34 g) over 1.5 hours and aging for 0.5 hours is performed. The mixture is cooled to 10°C±3°C over 7 hours and maintained at 10°C±3°C for 2 hours. The mixture is filtered and the filter cake is washed with a cold mixed solvent of toluene (50 mL) and n-heptane (10 mL) to obtain a light yellow solution of C5 (330 g, trans / cis=90 / 10, assay 6.8%, yield 52%). The mother liquor was used simply in the next step. 1H-NMR (400 MHz, CDCl3, mixture of two isomers, data of the minor isomer are shown in brackets): δ (ppm) = 7.99 (d, J = 8.44 Hz, 2H) [7.92 (d, J = 8.44 Hz, 0.04H)], 7.23-7.39 (m, 7H) [7.10-7.18 (m, 0.21H)], 5.69 (br.s, 1H) [5.40-5.42 (m, 0.11H)], 5.19 (s, 2H) [5.14 (s, 0.23H)], 4.26 (br.d, J = 13.33 Hz, 1H) [4. 18-4.20(m,0.13H)],3.91(s,3H)[3.90(s,0.4H)],3.67-3.79(m,1H)[3.38-3.45(m,0.11H)],2.83(td,J=13.51,2.81Hz,1H),2.6 4(br.d,J=13.33Hz,1H)[2.41-2.47(m,0.12H)],1.81-1.91(m,2H)[2.17-2.22(m,0.12H)],1.72-1.77(m,1H),1.45-1.56(m,1H). HRMS: for C 21 H 24 Calculated value of NO5 (M+H): 370.1654m, found value 370.1662.

[0397] Example 3: Methyl 4-[(2S,4S)-4-ethoxypiperidin-2-yl]benzoate (Formula (II)) was synthesized according to the following sequence: Compounds):

[0398]

[0399] Step 1: Synthesis of benzyl (4S)-4-((tert-butyldimethylsilyl)oxy)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (C8, wherein P1 = Cbz, P2 = TBS and R = methyl).

[0400] A 500 mL Radleys reactor was charged with C5 (1.0 eq., 145.67 g from the previous step, assay 6.07%, 23.94 mmol) in toluene / heptane solution. The solution was concentrated to about 25 g. Dichloromethane (117.1 g) was then charged and the solution was cooled to 23°C ± 4°C. Imidazole (3.42 g, 50.26 mmol, 2.1 eq.) and TBS-Cl (6.13 g, 40.69 mmol, 1.7 eq.) were introduced into the clear solution. The yellow suspension was stirred at 23°C ± 4°C for 10 hours. The reaction was monitored by HPLC. 10% Na2CO3 (70.7 g) was then charged and the mixture was stirred for 1 hour. The organic phase was washed with 5% brine (53 g) and concentrated to about 30 g. The solvent was then exchanged with toluene (45 g) to about 25 g. The residue is diluted with dichloromethane (66 g), and the mixture is filtered through a 200-300 mesh silica gel (1.66 g) pad. The silica gel is eluted with another portion of dichloromethane (17.5 g). The eluent is concentrated and the residue is subjected to an exchange of the solvent with acetonitrile (71.1 g + 98.2 g) to 90 g (yield 100%). The C8 in the acetonitrile solution is used for the next step. 1 H-NMR (400 MHz, CDCl3, mixture of two isomers, data of the minor isomer are shown in brackets): δ (ppm) = 8.01 (d, J = 8.44 Hz, 2H) [7.94 (d, J = 8.44 Hz, 0.17H)], 7.26-7.34 (m, 7H) [7.09-7.18 (m, 0.13H)], 5.65 (br.d, J = 2.04 Hz, 1H) [5.41 (br.d, J = 2.04 Hz, 0.08H)], 5.19 (s, 2H) [5.13 (s, 0.16H)], 4.22 (br.d, J = 13.69 Hz, 1H) [4.10-4.14 (m, 0.19H)], 3.92(s,3H)[3.90(s,0.3H)],3.62-3.69(m,1H)[3.43-3.50(m,0.08H)],2. 81(td,J=13.54,2.87Hz,1H),2.49(br.d,J=13.57Hz,1H)[2.31-2.35(m,0. 10H)],1.84-1.92(m,1H)[2.08-2.14(m,0.07H)],1.74-1.75(m,1H),1.48- 1.59(m,1H),0.86(s,9H)[0.56(s,0.65H)],0.03(s,3H)[0.09(s,0.27H)].

[0401] Step 2: Synthesis of benzyl (4S)-4-ethoxy-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (C9, wherein P1 = Cbz, R = methyl)

[0402] A 250mL Radleys reactor equipped with an impeller stirrer was charged with C8 (135.5 g, assay 12.53%, 35.10 mmol) in acetonitrile solution and rinsed with acetonitrile (8.5 g). Et3SiH (12.25 g, 105.31 mmol, 3.0 equiv) was charged. The reactor was cooled to IT = 4 °C ± 5 °C. TESOTf (1.392 g, 5.265 mmol, 0.15 equiv) was charged. At IT = 4 °C ± 5 °C, within 60 min, a solution of 2,4,6-trimethyl-1,3,5-trioxane (4.64 g, 35.10 mmol, 1.0 equiv) in acetonitrile (7.9 g) was added to the mixture. After addition, the mixture was stirred for 15 min and then tracked by HPLC. 5% Na2CO3 aqueous solution (21.22g) and water (30g) were loaded into the reaction mixture. Then n-heptane (20.4g) was loaded, and the mixture was stirred at 25°C ± 5°C for 30min. The phase was cut and the bottom acetonitrile phase was collected. The acetonitrile phase was concentrated to about 65g. MTBE (100.6g) and 5% Na2CO3 aqueous solution (43.44g) were loaded into the residual acetonitrile solution. The mixture was stirred for 30min. The upper MTBE phase was collected and filtered through a carbon membrane. The carbon membrane was washed with MTBE (7.4g). The mother liquor was concentrated to about 35g. Methanol (79.2g) was loaded into the residue and the solution was concentrated to 70g. The solution was used concisely in the next step. 1H NMR (400 MHz, CDCl3, mixture of two isomers, data for the minor isomer are shown in brackets) δ (ppm) = 8.01 (d, J = 8.31 Hz, 2H) [7.96 (d, J = 8.31 Hz, 0.21 H)], 7.29-7.32 (m, 7H) [7.07-7.22 (m, 0.40 H)], 5.68 (br. s, 1H) [5.32-5.34 (m, 0.10 H)], 5.19 (s, 2H) [5.11 (s, 0.19 H)], 4.27 (br. d, J = 13.08 Hz, 1H) [4.0 5-4.14(m,0.15H)],3.91(s,3H)[3.89(s,0.15H)],3.41-3.54(m,2H)[3.14-3.25(m,0.21)],3.30-3.40(m,1H)[3.86-3.75(m,0. 13H)], 2.84 (td, J = 13.51, 2.81Hz, 1H), 2.66 (br.d, J = 13.20Hz, 1H), 1.62-1.95 (m, 2H), 1.40-1.53 ​​(m, 1H), 1.18 (t, J = 6.97Hz, 3H).

[0403] Step 3: Synthesis of methyl 4-((4S)-4-ethoxypiperidin-2-yl)benzoate (removal of protecting group P1 = Cbz-R = methyl)

[0404] 10% Pd / C (50% wet, 3.83 g), C9 solution in methanol (measured 19.97%, 192 g, 96.46 mmol) and methanol (28 g) were loaded into a 500 mL autoclave. The reactor was purged three times with vacuum / H2. The mixture was hydrogenated for 4 hours at 3 bar and at a temperature of 25°C ± 4°C. The mixture was filtered and the Pd / C filter cake was washed with methanol (20 g). The mother liquor was concentrated to 48 g, solvent exchanged twice with 142 g isopropyl acetate to 106 g, cooled to 8°C ± 5°C, and 3% hydrogen chloride solution (90.2 g) was added. After phase separation, the aqueous phase was collected and washed with isopropyl acetate (86.4 g). MTBE (72 g) and 10% Na2CO3 (99.2 g) were added to the aqueous phase. After phase separation, the aqueous phase was extracted with MTBE (72 g). The combined MTBE phase was washed with water (40 g). The MTBE solution was carried into the next step. 1H NMR (400 MHz, CDCl3, mixture of two isomers, data for the minor isomer are shown in brackets) δ (ppm) = 7.96 (m, J = 8.31 Hz, 2H), 7.40-7.46 (m, 2H), 4.06 (dd, J = 11.62, 2.45 Hz, 1H), 3.88 (s, 3H), 3.70-3.79 (m, 1H) [3.64-3.69 (m, 0.12H)], 3.48-3.56 (m, 2H) [3.38-3.45 (m, 0.11H)], 3.11-3.18 (m, 1H) [3.21-3.26 (m, 0.11H)], 2 .88-2.97(m,1H)[2.73-2.80(m,0.12H)],1.94-2.00(m,1H)[2.14-2. 19(m,0.10H)],1.84-1.89(m,1H)[2.02-2.07(m,0.12H)],1.75(S,1H ),1.65-1.70(m,1H)[1.45-1.49(m,0.10H)],1.59-1.64(m,1H)[1.36 -1.42(m,0.11H)],1.22-1.25(t,3H)[1.17-1.20(t,J=6.97,0.24H)].

[0405] Step 4: Synthesis of methyl 4-[(2S,4S)-4-ethoxypiperidin-2-yl]benzoate (compound of formula (II) - R = methyl).

[0406] To a 500 mL single-necked flask was added the crude solution of step 3 (above) in MTBE (110 g, assay 10.52%, light yellow solution, 43.95 mmol, used from the previous step). The solution was concentrated to 18.4 g, and the solvent was exchanged with 55 g of n-heptane (JT = 60°C) to give 35 g of yellow solution. The solution was transferred to a 100 mL Easy Max equipped with an impeller stirrer. The solution was heated to 50°C at 300 RPM, aged for 30 min, cooled to 41°C ± 2°C and seeds were added. Agitation was adjusted to low speed. The mixture was aged at 41°C ± 2°C for 2 hours, cooled to 35°C ± 2°C over 8-10 hours, and then aged at 35°C ± 2°C for 1-2 hours. n-heptane (7.9 g) was added dropwise. Agitation was adjusted to medium speed. The mixture was cooled to IT = 25 ° C ± 2 ° C within 1 hour and aged at 25 ° C ± 2 ° C for 10-20 minutes. The mixture was filtered. The filtrate was recharged into the reactor to rinse the solids on the reactor wall. The mixture was filtered and the filter cake was washed with pre-cooled (-5 ° C) n-heptane (7.9 g). The filter cake was dried at 40 ° C for ≥ 10 hours to obtain 6.4 g of a white solid (50% yield). 1HNMR (400MHz, CDCl3) δ (ppm) = 7.99 (m, J = 8.31Hz, 2H), 7.45 (m, J = 8.19Hz, 2H), 4.09 (dd, J=11.62,2.20Hz,1H),3.90(s,3H),3.75(t,J=2.81Hz,1H),3.53(q,J=6.97Hz,2H),3.1 7(td,J=12.13,2.63Hz,1H),2.91-2.99(m,1H),1.99(dd,J=13.57,2.69Hz,1H),1.88(d t,J=13.79,2.58Hz,1H),1.69-1.79(m,1H),1.57-1.68(m,2H),1.25(t,J=7.03Hz,3H).

[0407] Example 4: Enantioselectivity of the synthesis of compound (S)-(C4) according to the following sequence:

[0408]

[0409] Step 1: Synthesis of benzyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (C6, wherein P1 = Cbz and R = methyl)

[0410] 4-Methoxypyridine (C1, 45.0 g, 412.39 mmol, 1.0 equiv) and methanol (900 mL) were added to a 2.0 L reactor. The mixture was cooled to -75 ° C with a dry ice / acetone bath. A solution of benzyl chloroformate (73.86 g, 432.99 mmol, 1.05 equiv) in THF (90 mL) was added dropwise while keeping IT≤-70 ° C. The reaction was stirred for 1 hour to obtain a white suspension at -70 ° C. Sodium borohydride (16.38 g, 432.99 mmol, 1.05 equiv) was added in batches while keeping IT≤-70 ° C. The reaction was stirred at -70 ° C for 2 hours. Water (200 g) was added and the cooling bath was removed. At 0°C-5°C, a solution of 36% hydrogen chloride (16.72 g, 164.95 mmol, 0.4 equivalent) in water (50 mL) was added within 10 min and stirred for 1 hour. Then 20% Na2CO3 (85.5 g) was added to adjust pH=7 while maintaining IT≤5°C. The organic solvent was removed under vacuum. The resulting residue was extracted with dichloromethane (450 mL). The dichloromethane phase was washed with 3wt% hydrogen chloride (151 mL) and 3wt% Na2CO3 (151 mL). After solvent exchange with MTBE, about 4 volumes (180 ml) of MTBE mixture were obtained. The mixture was heated to 50°C to obtain a solution, and then cooled to 45°C. Seeds of C6 were loaded, and the mixture was aged for 7 hours at 40°C-45°C. Within 3 hours, the mixture was cooled to 10°C-15°C. The white suspension was filtered and the wet cake was rinsed with cold MTBE (45 mL).The filter cake was dried under vacuum at 40-50°C for 2 h to give C6 (91.56 g, 60% yield) as a white powder. 1 H NMR (400MHz, CDCl3): δ (ppm) = 7.85 (br.s, 1H), 7.37-7.43 (m, 5H), 5.43 (br.s, 1H), 5.26 (s, 2H), 4.05 (t, J = 7.34Hz, 2H), 2.54-2.58 (m, 2H).

[0411] Step 2: Synthesis of (S)-benzyl 2-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate ((S)-C4, wherein P1 = Cbz and R = methyl)

[0412] Method 1:500ml Radleys reactor is purged 3 times with vacuum / N2.Add C6 (8g, 34.60mmol, 1.0 equivalent), C7 (9.34g, 51.89mmol, 1.5 equivalent), tert-amyl alcohol (160mL) and deionized water (16mL).The mixture is stirred ≥40 minutes to provide a clear colorless solution.The solution is purged 4 times with vacuum / N2, and bubbled 1 hour with N2 via a syringe needle.Into the colorless solution, a mixed solid of (S)-XylBINAP (0.381g, 0.519mmol, 0.015 equivalent) and Rh(Acac)(C2H4)2 (0.134g, 0.519mmol, 0.015 equivalent) is loaded.The mixture is continued to be bubbled 15 minutes with N2, and purged 4 times with vacuum / N2.The suspension is stirred for another 2 hours to dissolve (S)-XylBINAP. The reaction mixture was stirred at 55°C ± 4°C for 15 hours. The reaction was then followed by HPLC. The mixture was cooled and treated with 7.7% sodium hypochlorite (1 g, 1.04 mmol, 0.03 equiv) at 40°C ± 4°C for 1.5 hours. Tert-amyl alcohol was distilled off. The residue was extracted with isopropyl acetate (64 mL) and ethyl acetate (8 mL) and filtered. At 50°C ± 5°C, the organic phase was washed with 5% NaHCO3 (50 g) and then with 15% brine (40 g). Some solvent was removed and ethyl acetate (21.6 g) was added. The solution was treated with Smopex-234 (1.2 g) for 2 hours at IT = 55°C ± 5°C and then filtered through 200-300 mesh silica gel (1.6 g). After solvent exchange with n-heptane, MTBE (44.4 g) was added. The mixture was cooled to IT = 42°C ± 3°C. (S)-C4 seeds (10 mg) were added. The mixture was aged for 2 hours and cooled to IT = 31 ° C ± 3 ° C within 3 hours. Then n-heptane (23.2 g) was charged within 1-2 hours. The mixture was aged for 2 hours and cooled to IT = 20 ° C ± 3 ° C within 2 hours. The mixture was filtered and the filter cake was washed with a mixed solvent of MTBE (4.4 g) and n-heptane (4.1 g). The wet cake was dried at 60 ° C for ≥ 5 hours to obtain (S)-C4 (7.63 g, 60% yield) as a yellow powder. 1 H NMR (400MHz, CDCl3): δ (ppm) = 7.99 (d, J = 8.44Hz, 2H), 7.28-7.37 (m, 7H), 5.82 (br.s, 1H), 5.14-5.28 (m, 2H), 4.30 (b r.s,1H),3.91(s,3H),3.22(br.d,J=8.31Hz,1H),2.84-3.03(m,2H),2.46-2.64(m,1H),2.38(br.d,J=16.26Hz,1H).

[0413] Method 2: C6 (8 g, 34.60 mmol, 1.0 eq.), C7 (9.34 g, 51.89 mmol, 1.5 eq.), tert-amyl alcohol (160 mL) and deionized water (16 mL) were added to a 500 ml Radleys reactor purged 3 times with vacuum / N2. The mixture was stirred for approximately 40 minutes to give a clear colorless solution. The solution was purged 4 times with vacuum / N2 and bubbled with N2 via a syringe needle for 1 hour. A mixed solid of (R,R)-Ph-BPE-Rh(Acac) (0.005 eq., 0.122 g, 0.173 mmol) was charged into the colorless solution. The mixture was bubbled with N2 for 15 minutes and purged with vacuum / N2. The reaction mixture was stirred at 55°C ± 4°C for 15 hours. The reaction was then followed by HPLC. Tert-amyl alcohol was distilled off. The residue was extracted with isopropyl acetate (64 mL) and ethyl acetate (8 mL) and then filtered. At 50°C ± 5°C, the organic phase was washed with 5% NaHCO3 (50 g) and then with 15% brine (40 g). Some solvent was removed and ethyl acetate (21.6 g) was added. The solution was treated with Smopex-234 (1.2 g) for 2 hours at IT = 55°C ± 5°C and then filtered through 200-300 mesh silica gel (1.6 g). After solvent exchange with n-heptane, MTBE (44.4 g) was added. The mixture was cooled to IT = 42°C ± 3°C. (S)-C4 seeds (10 mg) were added. The mixture was aged for 2 hours and cooled to IT = 31°C ± 3°C within 3 hours. Then n-heptane (23.2 g) was charged within 1-2 hours. The mixture was aged for 2 hours and cooled to IT = 20°C ± 3°C within 2 hours. The mixture was filtered and the filter cake was washed with a mixed solvent of MTBE (4.4 g) and n-heptane (4.1 g). The wet cake was dried at 60 °C for approximately 5 h to give (S)-C4 (10.17 g, 80% yield) as a yellow powder. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.99 (d, J = 8.44Hz, 2H), 7.28-7.37 (m, 7H), 5.82 (br.s, 1H), 5.14-5.28 (m, 2H), 4.30 (br .s,1H),3.91(s,3H),3.22(br.d,J=8.31Hz,1H),2.84-3.03(m,2H),2.46-2.64(m,1H),2.38(br.d,J=16.26Hz,1H).

[0414] Method 3:To a 500ml Radleys reactor purged 3 times with vacuum / N2. Add C6 (8g, 34.60mmol, 1.0 equivalent), C7 (9.34g, 51.89mmol, 1.5 equivalent), tert-amyl alcohol (160mL) and deionized water (16mL). The mixture was stirred for approximately 40 minutes to give a clear colorless solution. The solution was purged 4 times with vacuum / N2, and bubbled with N2 for 1 hour via a syringe needle. A mixed solid of (S)-XylBINAP-Rh(Acac) (0.01 equivalent, 0.324g, 0.346mmol) was loaded into the colorless solution. The mixture was continued to be bubbled with N2 for 15 minutes, and purged with vacuum / N2. The reaction mixture was stirred at 55°C ± 4°C for 15 hours. The reaction was then tracked by HPLC. Tert-amyl alcohol was distilled out. The residue was extracted with isopropyl acetate (64mL) and ethyl acetate (8mL) and then filtered. At 50°C ± 5°C, the organic phase was washed with 5% NaHCO3 (50 g) and then with 15% brine (40 g). Some solvent was removed and ethyl acetate (21.6 g) was added. The solution was treated with Smopex-234 (1.2 g) for 2 hours at IT = 55°C ± 5°C and then filtered through 200-300 mesh silica gel (1.6 g). After solvent exchange with n-heptane, MTBE (44.4 g) was added. The mixture was cooled to IT = 42°C ± 3°C. (S)-C4 seeds (10 mg) were added. The mixture was aged for 2 hours and cooled to IT = 31°C ± 3°C within 3 hours. Then n-heptane (23.2 g) was charged within 1-2 hours. The mixture was aged for 2 hours and cooled to IT = 20°C ± 3°C within 2 hours. The mixture was filtered and the filter cake was washed with a mixed solvent of MTBE (4.4 g) and n-heptane (4.1 g). The wet cake was dried at 60 °C for approximately 5 h to give (S)-C4 (10.30 g, 81% yield) as a yellow powder. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.99 (d, J = 8.44Hz, 2H), 7.28-7.37 (m, 7H), 5.82 (br.s, 1H), 5.14-5.28 (m, 2H), 4.30 (br .s,1H),3.91(s,3H),3.22(br.d,J=8.31Hz,1H),2.84-3.03(m,2H),2.46-2.64(m,1H),2.38(br.d,J=16.26Hz,1H).

[0415] Example 5: (2S,4S)-4-hydroxy-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester ((S)-C5, wherein Synthesis of P1 = Cbz and R = methyl)

[0416]

[0417] Preparation of 0.1M PBS, pH 7.0 with 0.1% TPGS buffer solution: A 500 mL Radleys reactor equipped with an impeller stirrer was charged with Na2HPO4.12H2O (8.63 g), NaH2PO4.2H2O (2.41 g), tap water (388.6 g) and TPGS-750-M.001 (0.388 g). The mixture was stirred for ≥3 hours at IT = 60°C ± 5°C and then cooled to IT = 51°C ± 3°C. 80 g of the buffer solution was taken out from the reactor into a flask and cooled to ≤ 35°C. The pH of the buffer solution was checked (7.0 ± 0.5). To the above Radleys reactor was added (S)-C4 (20.0 g, 54.4 mmol, 1.0 eq), isopropanol (16.36 g, 272.2 mmol, 5.0 eq) and 0.1% TPGS buffer solution (60 g). A 25 mL flask was charged with KRED-P3-G09 (0.4 g, #Codexis), NADP+ (0.1 g) and 0.1% TPGS buffer solution (60 g) from the above flask. All solids were dissolved. The enzyme solution was charged into a 500 mL reactor at IT = 50°C ± 5°C. The 25 mL flask was rinsed with 0.1% TPGS buffer (10 g) and the solution was transferred to a 500 mL reactor at IT = 50°C ± 5°C. The mixture was stirred at 51°C ± 3°C for ≥ 8 hours at a stirring speed ≥ 500 RPM. The reaction was then followed by HPLC. 2-MeTHF (200 mL) was added to the reactor, and the mixture was stirred for ≥60 minutes at 50°C ± 5°C. The mixture was kept without agitation for ≥50 minutes, and the bottom aqueous phase was separated. The organic phase was washed with an additional 200 g of water at 50°C ± 5°C. The organic phase was concentrated to about 70 g. Two solvent exchanges with 158 g of acetonitrile gave about 80 g of solution, which was cooled to <30°C and then filtered through MCC. The MCC filter cake was washed with isopropyl acetate (40 mL / 35.5 g) to give (S)-C5 (114.3 g, assayed 16.95%, 96.34% yield) in a light-colored solution. The acetonitrile / isopropyl acetate solution was used directly and simply in the next step. 1HNMR (400MHz, CDCl3): δ (ppm) = 7.98 (d, J = 8.44Hz, 2H), 7.23-7.38 (m, 7H), 5.61-5.72 (m, 1H), 5.18 (s, 2H), 4.23 (br.d, J = 13.33Hz, 1H), 3.90 ( s,3H),3.62-3.75(m,1H),2.81(td,J=13.51,2.81Hz,1H),2.62(br.d,J=13.33Hz,1H),2.45(br.s,1H),1.79-1.91(m,2H),1.41-1.56(m,1H).

[0418] Example 6: Methyl 4-[(2S,4S)-4-ethoxypiperidin-2-yl]benzoate (Formula (II)) was prepared according to the following sequence: Asymmetric synthesis of a compound or a salt thereof, -R = methyl):

[0419]

[0420] Step 1: Synthesis of benzyl (2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methoxycarbonyl)phenyl]piperidine-1-carboxylate ((S)-(C8), wherein P1 = Cbz, P2 = TBS and R = methyl).

[0421] A 500 ml Radleys reactor was charged with the (S)-C5 solution from the previous step (271.8 g, assay 14.72%, containing 40.0 g of (S)-C5, 108.31 mmol, 1.0 eq. in acetonitrile / isopropyl acetate). After solvent exchange with isopropyl acetate (159.8 g / 180 mL), 100 g of a clear solution was obtained. Isopropyl acetate (176 g / 198 mL), imidazole (26.54 g, 389.90 mmol, 3.6 eq.) and TBS-Cl (27.75 g, 184.12 mmol, 1.7 eq.) were added. The yellow suspension was stirred at 55°C ± 4°C for 7 hours. The reaction was then followed by HPLC. The reaction mixture was cooled to 23°C ± 4°C and filtered through MCC (2 g). The filter cake was washed with isopropyl acetate (88.8 g / 100 mL). Add 6%NaHCO (240g) and the mixture was stirred for 20 minutes.Organic phase is washed with 5% saline (2x 240g) and is concentrated to about 105g.After carrying out solvent exchange with toluene (120g / 135.4mL), obtain 105g solution.Add methylene chloride (298g / 224.5mL) and solution is filtered through 200-300 mesh silica gel (4.4g).Silica gel is eluted with the methylene chloride (44g / 33mL) of another part.Mother liquor is concentrated, and carries out solvent exchange to 100g with acetonitrile (2x280mL, 442.4g in total).Resistates is washed with acetonitrile (105g / 132.9mL) to obtain light yellow solution (205g, measures 25.55%, 100% productive rate), it is directly used in next step. 1 H NMR (400MHz, CDCl3) δ (ppm) = 8.01 (d, J = 8.44Hz, 2H), 7.23-7.37 (m, 7H), 5.60-5. 70(m,1H),5.18(s,2H),4.22(br.d,J=13.45Hz,1H),3.90(s,3H),3.62-3.71(m,1 H),2.82(td,J=13.51,2.81Hz,1H),2.49(br.d,J=13.45Hz,1H),1.83-1.96(m,1 H),1.75-1.80(m,1H),1.47-1.60(m,1H),0.86(s,9H),0.03(s,3H),0.00(s,3H).

[0422] Step 2: Synthesis of benzyl (2S,4S)-4-ethoxy-2-[4-(methoxycarbonyl)phenyl]piperidine-1-benzoate ((S)-C9, wherein P1 = Cbz and R = methyl)

[0423] A 500 mL Radleys reactor equipped with an impeller stirrer was charged with (S)-C8 (170.8 g, assay 29.28%, 103.38 mmol, 1.0 equiv) in acetonitrile solution and fresh acetonitrile (220 g), followed by Et3SiH (36.06 g, 310.13 mmol, 3.0 equiv). The mixture was cooled to IT = 4 ° C ± 5 ° C, and TESOTf (5.47 g, 20.68 mmol, 0.2 equiv) was charged. At IT = 4 ° C ± 5 ° C, over 60 minutes, a solution of 2,4,6-trimethyl-1,3,5-trioxane (13.66 g, 103.38 mmol, 1.0 equiv) in acetonitrile (23 g) was charged into the mixture. After addition, the mixture was stirred for 15 minutes. The reaction was then tracked by HPLC. 5% aqueous sodium hydroxide solution (16.54g, 20.68mmol, 0.2 equivalent) and 20g water were loaded into the reaction mixture, and then n-heptane (60g) was loaded. At 20°C ± 5°C, the mixture was stirred for 30 minutes. The bottom acetonitrile phase was collected. MTBE (111g) and 10% brine (300g) were loaded into the acetonitrile phase. The mixture was stirred for 30 minutes. The upper MTBE phase was washed with 10% brine (2x300g) and concentrated to 90g. MTBE (185g) and water (150g) were loaded. After phase separation and solvent exchange of the organic layer with isopropyl acetate (2x266.4g) at 38°C ± 4°C, 205g solution was obtained, which was slowly filtered through a carbon membrane. The carbon membrane was washed with isopropyl acetate (22.2g) to obtain a light yellow solution (223g, 100% yield). The solution was used directly and minimally in the next step. 1 H NMR (400MHz, CDCl3) δ (ppm) = 8.01 (d, J = 8.44Hz, 2H), 7.25-7.38 (m, 7H), 5.68 (br.s, 1H), 5.19(s,2H),4.27(br.d,J=13.33Hz,1H),3.92(s,3H),3.42-3.54(m,2H),3.34(ddd,J=1 0.88,6.91,4.22Hz,1H),2.84(td,J=13.51,2.81Hz,1H),2.66(br.d,J=13.20Hz,1H),1. 96(br.d,J=10.51Hz,1H),1.75-1.90(m,1H),1.33-1.53(m,1H),1.18(t,J=6.97Hz,3H).

[0424] Step 3: Synthesis of benzyl 4-((2S,4S)-4-ethoxypiperidin-2-yl)benzoate (compound of formula (II) or its salt - R = methyl)

[0425] A 500 mL autoclave purged with vacuum / N2 was charged with (S)-C9 (278.4 g, assay 17.96%, 50 g of (S)-C9, 125.80 mmol) and 10% Pd / C (5.0 g, 50% wet) in isopropyl acetate solution. The reactor was purged with vacuum / H2 and stirred for ≥7 hours at 25°C ± 5°C. The reaction was then followed by HPLC analysis. The reaction mixture was filtered through MCC (7.7 g) pre-washed with isopropyl acetate. The reactor and MCC were rinsed with isopropyl acetate (39 g). The mother liquors were combined to give a compound of formula (II) (315 g, assay 10.0%, 95.1% yield) as a light yellow solution. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.99 (m, J = 8.31Hz, 2H), 7.45 (m, J = 8.19Hz, 2H), 4.09 (dd, J=11.62,2.20Hz,1H),3.90(s,3H),3.75(t,J=2.81Hz,1H),3.53(q,J=6.97Hz,2H),3.1 7(td,J=12.13,2.63Hz,1H),2.91-2.99(m,1H),1.99(dd,J=13.57,2.69Hz,1H),1.88(d t,J=13.79,2.58Hz,1H),1.69-1.79(m,1H),1.57-1.68(m,2H),1.25(t,J=7.03Hz,3H).

[0426] Step 4: Synthesis of the maleate salt of the compound of formula (II) (R = methyl)

[0427] A 500 mL Radleys reactor equipped with an impeller stirrer was charged with a solution of methyl 4-((2S,4S)-4-ethoxypiperidin-2-yl)benzoate (381 g, assay 10.03%, 145.12 mmol, 1.0 eq) from the previous step. The solution was concentrated to 281 g and fresh isopropyl acetate (28.6 g) was added. A solution of maleic acid (8.45 g, 72.56 mmol, 0.5 eq) in acetone (30.5 mL) was then added at 51°C ± 3°C over 30 minutes. After stirring for 15 minutes, seeds of the maleate salt of the compound of formula (II) were added and the mixture was aged for 2 hours. A solution of maleic acid (8.45 g, 72.56 mmol, 0.5 eq) in acetone (30.5 mL) was charged at 51°C ± 3°C over 60 minutes and the mixture was aged for 2 hours. The mixture was cooled to IT = 10 ° C ± 3 ° C in 6 hours and stirred for ≥ 120 minutes. The mixture was filtered and the filter cake was washed with pre-cooled isopropyl acetate (44.4 g). The filter cake was dried at 55 ° C under high vacuum for 5-12 hours to obtain the maleate of the compound of formula (II) as a white solid (49.8 g, yield 90.4%). 1 H NMR (400MHz, CDCl3) δ (ppm) 9.35-9.78 (m, 2H), 8.02 (m, J = 8.31Hz, 2H), 7.58 (m, J = 8.31Hz, 2H), 6.17 (s, 2H), 4.56 (br.d, J = 11.13Hz, 1H), 3.90(s,3H),3.86(s,1H),3.48-3.57(m,2H),3.38-3.44(m,2H),2.42(br.t,J=13.57Hz,1H),1.98-2.20(m,3H),1.24(t,J=6.97Hz,3H).

[0428] The maleate salt of the compound of formula (II) can be prepared by heating at a temperature of about 22°C and The X-ray powder diffraction pattern (XRPD) measured at an X-ray wavelength λ of , wherein the X-ray powder diffraction pattern comprises four or more 2θ values ​​(CuKαλ= ): 5.893, 6.209, 11.704, 13.014, 16.403, 17.295, 17.592, 18.629, 18.942, 21.044, 21.733, 21.737, 22.380, 23.528, 24.195, 26.013, 26.825, 29.017, 29.515, 32.250, 35.069, 35.590 and 37.932.

[0429] Example 7: Synthesis of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate according to the following sequence (Compound of formula (III) or its salt):

[0430]

[0431] Step 1: Synthesis of 7-methyl-1H-indol-5-ol (C11)

[0432] Into a 250mL flask equipped with a thermometer, 3.4% Na2HPO4 (100g, pH=8.91) was charged, and then Fremy salt (4.84g, 2.4 equivalents) was added. The mixture was stirred at 20°C ± 5°C until a clear solution was formed. A solution of 7-methylindoline in acetone (9.1g, 11%) was added once. The mixture was stirred at 20°C ± 5°C for 1.5 hours. Sodium sulfite (0.38g) was then added. The mixture was extracted with ethyl acetate (100mL x 2), and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. 20mL acetonitrile was added to the residue. The solution was used directly in the next step.

[0433] Step 2: Synthesis of tert-butyl 5-hydroxy-7-methyl-1H-indole-1-carboxylate (C12, where P3 = Boc)

[0434] The solution prepared as above is cooled to 0 ℃ ± 5 ℃. DMAP (0.34 g, 0.4 eq.) is loaded, and then (Boc) 2 O (4.9 g, 3.0 eq.) is added. The mixture is warmed to 20 ℃ ± 5 ℃, stirred for 30 minutes and concentrated at 20 ℃ ± 5 ℃. Methanol (40 mL) is added to the residue. The mixture is cooled to 0 ℃ ± 5 ℃. Potassium carbonate (5.1 g, 5.0 eq.) is added. The mixture is stirred for 4 hours at 0 ℃ ± 5 ℃, warmed to 20 ℃ ± 5 ℃, and stirred for another 2 hours. The mixture is cooled to 0 ℃ ± 5 ℃. Acetic acid (2 g) is added. The pH is 7-8. The mixture is filtered, and the filter cake is washed with methanol (10 mL x 2). The filtrate is concentrated and ethyl acetate (30 mL) is added. The mixture is washed with water (20 mL) and 5% brine (20 mL). The organic layer was concentrated to give a dark oil which was slurried with (3:2) n-heptane:ethyl acetate (5 g) to give a yellow solid. The solid was collected by filtration and dried to give C12 as a yellow solid. The isolated yield from C10 was 27.4%. 1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 9.13 (s, 1H), 7.52 (d, J = 3.67 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 6.56 (m, 1H), 6.50 (d, J = 3.67 Hz, 1H), 2.45 (s, 3H), 1.57 (s, 9H). LCMS (m / z): positive ion mode 248.1 [M] +, LCMS (m / z): negative ion mode 246.1 [M-1] -.

[0435] Step 3: Synthesis of tert-butyl 4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (C13, where P3 = Boc)

[0436] To a solution of tert-butyl 5-hydroxy-7-methyl-1H-indole-1-carboxylate (C12) (53.8% assay, 1.0 g, 2.2 mmol) in THF (20 mL) was added dropwise a solution of CH3MgBr in THF (1 N, 2.2 mL, 2.2 mmol). The resulting mixture was stirred at 20°C-25°C for 10 minutes. n To the mixture was added 4-(4-(4-(4-piperidin-2-yl)-1-yl)-2-nitropropene (0.2 g, 6.53 mmol). The reaction mixture was heated to 65 ° C -70 ° C and stirred for 1 hour. The reaction mixture was cooled to 20 ° C -25 ° C. Saturated NH4Cl (20 mL) and MTBE (20 mL) were added. The mixture was separated and the aqueous layer was extracted with MTBE (20 mL). The organic layers were combined and concentrated to give compound C13 (0.7 g, 79% assay, 92% yield) as a yellow solid. 1 H-NMR (400 MHz, DMSO-d6) δ (ppm) = 10.74 (s, 1H), 10.54 (s, 1H), 7.82 (d, J = 4.0 Hz, 1H), 7.34 (d, J = 4.0 Hz, 1H), 6.81 (s, 1H), 2.59 (s, 3H), 1.65 (s, 9H). LCMS (m / z): positive ion mode 290.1 ​​[M] +.

[0437] Step 4: Synthesis of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (compound of formula (III)).

[0438] To a solution of compound C13 (50 mg, 0.182 mmol) in dry DMF (3 mL), KCO (50.2 mg, 0.363 mmol) is added. The mixture is stirred for 10 minutes, and then dimethyl sulfate (25.2 mg, 0.20 mmol) is added. The reaction mixture is stirred for 1 hour, and poured into ice water (12 mL). The mixture is filtered, and the filter cake is washed with water. The filter cake is dried under vacuum to give 4-formyl-5-methoxy-7-methyl-1H-indole-1-tert-butyl formate (compound of formula (III)) (48 mg, 91% yield) as a light solid. 1 H-NMR (400 MHz, DMSO-d6) δ (ppm) = 10.51 (s, 1H), 7.80 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 4.0 Hz, 1H), 6.81 (s, 1H), 3.95 (s, 3H), 2.61 (s, 3H), 1.59 (s, 9H). LCMS (m / z): negative ion mode 274.1 [M-1] -.

[0439] Example 8: Synthesis of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate according to the following sequence (Compound of formula (III) or its salt):

[0440]

[0441] Step 1: Synthesis of 5-(Benzyloxy)-1,3-dimethyl-2-nitrobenzene

[0442] Cs2CO3(230.8g, 708.5mmol) was added to a solution of commercially available 3,5-dimethyl-4-nitrophenol (100.0g, 590.4mmol) in DMF (500mL), and the resulting mixture was stirred for 10 minutes. Then, within 30 minutes, (bromomethyl)benzene (104.1g, 590.4mmol) was added dropwise to the mixture. At 20°C-25°C, the reaction mixture was stirred for 1 hour, and then ice water (1800mL) was poured into it. The isolated solid was collected by filtration and washed with water (500mL). The filter cake was dissolved in ethyl acetate (500mL), and the solution was washed with a saturated solution of NaCl (50mL), separated, and the solution was concentrated to give 5-(benzyloxy)-1,3-dimethyl-2-nitrobenzene 2 (147g, 97.8% yield) as a brown solid. HPLC purity 99.7%. 1 H-NMR (400 MHz, DMSO-d6) δ (ppm) = 7.42 (m, 5H), 6.94 (s, 2H), 5.16 (s, 2H), 2.25 (s, 6H); LCMS (m / z): negative ion mode 256.2 [M-1] -

[0443] Step 2: Synthesis of tert-butyl 5-hydroxy-7-methyl-1H-indole-1-carboxylate (C12, where P3 = Boc)

[0444] DMF-DMA (87.8 g, 699.6 mmol) and pyrrolidine (50.3 g, 699.6 mmol) are added to a solution of 5-(benzyloxy)-1,3-dimethyl-2-nitrobenzene (60.0 g, 233.2 mmol, from step 1) in DMF (300 mL). The solution is heated to 85°C-90°C and stirred for 19 hours under nitrogen, and then the mixture is cooled to 20°C-25°C. On a rotary evaporator, volatile components (DMF-DMA, pyrrolidine and DMF) are removed at 65°C-70°C. The crude mixture is dissolved in ethyl acetate (300 mL), and Raney nickel (6.0 g) is added. The reaction mixture is subjected to catalytic hydrogenation overnight at atmospheric pressure. Then, the reaction mixture is placed under nitrogen. The reaction mixture is filtered and the filtrate is concentrated to provide 5-(benzyloxy)-7-methyl-1H-indole as a black oil. 5-(Benzyloxy)-7-methyl-1H-indole was used in the next step without further purification.

[0445] 5-(Benzyloxy)-7-methyl-1H-indole is dissolved in acetonitrile (300mL), (Boc)2O (53.6g, 233.2mmol) and DMAP (5.7g, 46.6mmol) are added. The reaction mixture is stirred at 20°C-25°C for 1 hour. Acetonitrile is removed on a rotary evaporator, and the residual mixture is dissolved in ethyl acetate (300mL). The solution is washed with a saturated aqueous solution of NaHCO3, and then concentrated to give a crude oil, which is purified by column chromatography (SiO2, 500g) using a mixture of heptane / MTBE (1:10) to provide an intermediate 5-(benzyloxy)-7-methyl-1H-indole-1-tert-butyl formate (42.1g, 49.2% yield) in a brown oil. HPLC purity 93.5%. 1 H-NMR (400MHz, DMSO-d6) δ (ppm) = 7.59 (d, J = 3.67 Hz, 1H), 7.40 (m, 5H), 7.04 (d, J = 2.45 Hz, 1H), 6.81 (d, J = 2.2 Hz, 1H), 6.57 (d, J = 3.67 Hz, 1H), 5.11 (s, 2H), 2.51 (s, 3H), 1.58 (s, 9H). LCMS (m / z): negative ion mode 336.2 [M-1] -

[0446] Under nitrogen, 10% Pd / C (10.6 g, 10 mmol) and ammonium formate (6.8 g, 105 mmol) were added to a solution of intermediate 5-(benzyloxy)-7-methyl-1H-indole-1-tert-butyl formate (36.7 g, 100 mmol) in ethanol (250 mL). The solution was heated to 45°C-50°C and stirred for 5 hours under nitrogen. The mixture was then cooled to room temperature, filtered and the filtrate was concentrated to give a residual oil. The residual oil was dissolved in ethyl acetate (250 mL), the solution was washed with a saturated aqueous solution (100 mL) of NaCl, and each phase was separated. The organic layer was collected and concentrated. The crude mixture obtained was slurried with a mixture (160 mL) of MTBE / heptane (1:15) for 2 hours. The precipitate was filtered and washed with heptane (50 mL). The filter cake was dried under vacuum to give tert-butyl 5-hydroxy-7-methyl-1H-indole-1-carboxylate (C12) (21.8 g, 87.2% yield) as a tan solid. HPLC purity 97.7%. 1 H-NMR (400MHz, DMSO-d6) δ (ppm) = 9.13 (s, 1H), 7.52 (d, J = 3.67 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 6.56 (m, 1H), 6.50 (d, J = 3.67 Hz, 1H), 2.45 (s, 3H), 1.57 (s, 9H). LCMS (m / z): negative ion mode 246.2 [M-1] -

[0447] Step 3: Synthesis of tert-butyl 4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (C13, where P3 = Boc)

[0448] Under nitrogen, to MgCl2(11.6g, 119.7mmol) and (CHO)n(5.0g, 159.6mmol) in THF(150ml) mixture, triethylamine(17.8mL, 127.7mmol) was added dropwise, and the resulting mixture was stirred at 20 ℃-25 ℃ for 10 minutes. Then, 5-hydroxy-7-methyl-1H-indole-1-tert-butyl carboxylate(C12)(10.0g, 39.9mmol) was added to the mixture. The reaction mixture was heated to 65 ℃-70 ℃, and stirred for 3 hours. The reaction mixture was cooled to 20 ℃-25 ℃, then 2N HCl(70ml) and isopropyl acetate(150ml) were added. The mixture was separated, and the organic layer was washed with 5%NaCl solution. Then, the solution was concentrated to give a crude solid. The solid was slurried with ethanol(100mL) for 1 hour. The solid precipitate is filtered and washed with ethanol (20mL).The filter cake is dried under vacuum to give 4-formyl-5-hydroxy-7-methyl-1H-indole-1-tert-butyl formate (C13) (7.2g, 63.9% yield) as a tan solid.HPLC purity 96.5%.The filtrate solution is concentrated to 20mL, then stirred for 1 hour.The solid is filtered and washed with ethanol (5mL).The filter cake is dried under vacuum to give 4-formyl-5-hydroxy-7-methyl-1H-indole-1-tert-butyl formate (C13) (1.1g, 95.3% determination, 9.5% yield) as a tan solid.HPLC purity 90.5%. 1 H-NMR (400 MHz, DMSO-d6) δ (ppm) = 10.69 (s, 1H), 10.47 (s, 1H), 7.75 (d, J = 3.35 Hz, 1H), 7.27 (d, J = 3.55 Hz, 1H), 6.74 (s, 1H), 2.51 (s, 3H), 1.59 (s, 9H); LCMS (m / z): negative ion mode 274.2 [M-1] -.

[0449] Step 4: Synthesis of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (compound of formula (III)).

[0450] To a suspension of tert-butyl 4-formyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (C13) (6.0 g, 21.3 mmol) in MeCN (60 mL) was added 50% K2CO3 solution (20 mL) and dimethyl sulfate (2.26 mL, 23.4 mmol). The resulting mixture was stirred at 35°C-40°C for 3 hours. The reaction mixture was cooled to 20°C-25°C, and isopropyl acetate (30 mL) was added. The mixture was then extracted; the aqueous layer was extracted with isopropyl acetate (15 mL), and the organic layers were combined and concentrated to give a crude residue. The crude residue was dissolved in isopropyl acetate (60 mL), the solution was washed with saturated NH4Cl solution, and then concentrated to give a crude product (6.6 g). The crude product was slurried with ethyl acetate / heptane (100 mL, 1 / 50) for 3 hours. The solid was filtered and washed with heptane (20 mL). The filter cake was dried under vacuum to give tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (compound of formula (III)) (5.5 g, 87.8% yield) as a pink solid. HPLC purity 99.3%. 1 H-NMR (400 MHz, DMSO-d6) δ (ppm) = 10.52 (s, 1H), 7.79 (d, J = 3.67 Hz, 1H), 7.31 (d, J = 3.67 Hz, 1H), 7.02 (s, 1H), 3.95 (s, 3H), 2.61 (s, 3H), 1.60 (s, 9H); LCMS (m / z): positive ion mode 290 [M] +.

[0451] Example 9: Synthesis of the compound of formula (C15) or its salt (R = methyl).

[0452]

[0453] Method 1 (P3 = Boc and R = methyl): In the container, add Ir (CO) acac (1mg, 0.1mol%), the compound of formula (II) (maleate, 3mmol, 1.137g), the compound of formula (III) (3mmol, 0.867g). Under stirring (250RPM), the autoclave is purged with nitrogen 3 times and purged 3 times with H2. Under 700RPM, under 20 bar of H2, at 75 ℃, the reaction is run for 24 hours. The aliquots of the reaction are diluted in methanol and analyzed by HPLC. After 24 hours, the compound of formula (C15) is obtained, 88% conversion.

[0454] Method 2 (P3 = Boc and R = methyl):In the container, add IrCl in the degassed ethanol of 12mL, xH2O (0.05mol%, 0.9mg, anhydrous), the compound of formula (II) (maleate, 6mmol, 2.274g), the compound of formula (III) (6mmol, 1.735g). The autoclave is purged with nitrogen 3 times and purged with carbon monoxide (CO) 3 times (250RPM). The autoclave is pressurized with 1 bar CO and 19 bar H2, and operated at 75 ℃ for 24 hours under 20 bar H2 / CO with 700RPM. The aliquots of the reaction are diluted in methanol and analyzed by HPLC. After 24 hours, the compound of formula (C15) is obtained, 62% conversion.

[0455] 1 H NMR(400MHz,DMSO-d6)δppm 8.13(d,J=8.16Hz,2H),7.77(br.d,J=7.84Hz,2H),7.62-7.68(m,1H),6.8 5(s,1H),6.80(d,J=3.76Hz,1H),4.01(s,3H),3.92(s,3H),3.73(br.s,1H ),3.55-3.67(m,4H),3.39-3.42(m,1H),2.60-2.70(m,5H),1.99-2.02(br .d,1H),1.82-1.90(m,2H),1.74(s,9H),1.64-1.70(m,1H),1.35(t,J=6.97 Hz,3H).

Claims

1. A method for preparing a compound of formula (C15) or a salt thereof, wherein R is a C1-C6 alkyl group; The method comprises the following steps: In the presence of an iridium catalyst, under hydrogen pressure, a compound of formula (II) or a salt thereof, wherein R is a C1-C6 alkyl group; and a compound of formula (III), or its salt reaction, Wherein P3 is a nitrogen protecting group; The iridium catalyst is selected from the group consisting of: Ir(CO)2acac, Ir(COD)Cl, Ir(CO)3 and IrCl3,xH2O; The hydrogen pressure is from 1 to 30 bar; To provide the compound of formula (C15) or a salt thereof.

2. The method according to claim 1, wherein R is methyl.

3. The method according to claim 1, wherein P3 is tert-butyloxycarbonyl.

4. The method according to claim 1, wherein the compound of formula (C15) or a salt thereof is further reacted under hydrolysis conditions to obtain a compound of formula (I), or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1, wherein the compound of formula (II) is a maleate salt.

6. A method for preparing a pharmaceutical composition, comprising the method according to any one of claims 1 to 5, and mixing the obtained compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient.

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