Method for preparing substituted phenylpropionic acid derivative using olefin reduction

Abstract

Provided in the present disclosure is a method for preparing a substituted phenylpropionic acid derivative using olefin reduction. Specifically, provided in the present disclosure is a method for preparing a compound represented by formula I or a pharmaceutically acceptable salt thereof.

Description

Method for preparing substituted phenylpropionic acid derivatives using olefin reduction Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a method for preparing substituted phenylpropionic acid derivatives using an olefin reduction method. Background Technology

[0002] Lipoprotein(a) [Lp(a)] is a type of low-density lipoprotein (LDL) lipid particle, mainly composed of a cholesterol-rich core and a unique apolipoprotein(a) [Apo(a)]. It exhibits genetic polymorphism and long-term stability, showing a skewed distribution in the population. Studies have found that elevated Lp(a) levels are associated with an increased risk of cardiovascular events and related revascularization.

[0003] Novel lipoprotein compound WO2023078333, namely (2S)-3-(3-{[(2-{3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenoxy}ethyl)({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl}methyl)amino]methyl}phenyl)-2-[(3R)-pyrrolidine-3-yl]propionic acid (compound AA)

[0004] Meanwhile, WO2023078333 discloses a method for preparing this compound, which includes the following reaction steps: Summary of the Invention

[0005] This disclosure provides a method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof.

[0006] The method includes the step of reducing the compound shown in formula D to form the compound shown in formula F.

[0007] Among them, R 1 R 2 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro or cyano;

[0008] R 3 R 4 Each is independently selected from hydrogen and halogens;

[0009] R 5 Each is independently selected from halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0010] R 6 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0011] R 7 Selected from hydrogen, C 1-6 Alkyl, benzyl, or p-methoxybenzyl;

[0012] R 8 Selected from amino protecting group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0013] L1 is a key or selected from

[0014] n is selected from 0, 1, 2, 3 or 4;

[0015] w can be selected from 1, 2, 3 or 4.

[0016] In some embodiments, the compound represented by Formula D undergoes a reduction reaction in the presence of a hydrogen source and a catalyst. In some embodiments, the hydrogen source is selected from hydrogen, formic acid, formic acid amine, borane, or silane (e.g., trimethylsilane).

[0017] In some embodiments, the catalyst is selected from palladium catalysts, copper catalysts, platinum catalysts, ruthenium catalysts, rhodium catalysts, iridium catalysts, or cobalt catalysts.

[0018] In addition, the reduction reaction also includes a ligand reagent selected from chiral phosphine ligands, including but not limited to phosphonopentane chiral ligands (such as BPE, DuPhos, Butiphane, UlluPhos, RoPhos, BasPhos, Duanphos, Tangphos, QuinoxP*, Miniphos) and chiral biarylphosphine ligands (such as BINAP, DM-BINAP, BIPHEP, MeO-BIPHEP, HexaPHEMP, Xyl-HexaPHEMP, MeO-xyl-BIMO, H8-BINAP). P, TunaPhos, SegPhos, SynPhos, MonoPhos, TetraMe-BITIANP, P-Phos, TetraMe-BITTIOP), spirocyclic chiral phosphine ligands (such as SpirOP, SDP, SiPhos, SpiroPAP, etc.), and ferrocene skeleton chiral phosphine ligands (such as bppfa, bppfoh, f-Binaphane, Trifer, ChenPhos, JosiPhos, TaniaPhos, Bophos, WalPhos, Trap, WudaPhos).

[0019] In some embodiments, the ruthenium catalyst is selected from, but not limited to, RuCl3·H2O, Ru(OAc)2, Ru(OAc)2·[(R)-BINAP], [Ru(COD)](Methallyl)2, [Ru(COD)]TMHD2, RuTMHD3, [Ru(PPh3)3]HCl, [Ru(PPh3)3]Cl2, [Ru(η 6 -C6H6)Cl2]2 or [Ru(p-CYMENE)]Cl2.

[0020] In some embodiments, the rhodium catalyst is selected from, but not limited to, [Rh(COD)2]BF4, [Rh(COD)2]ClO4, [Rh(COD)2]PF6, [Rh(NBD)2]BF4, [Rh(NBD)2]ClO4, [Rh(NBD)2]PF6 or [Rh(COD)Cl]2.

[0021] In some embodiments, the iridium catalyst is selected from, but not limited to, IrCl3, [Ir(COD)Cl]2, [Ir(COD)(OMe)]2, [Ir(COD)(OH)]2, Ir(OAc)3, Ir(PPy)2(tmd), [Ir(COD)(ACN)2]BF4, Ir(acac)3 or [Ir(PPY)2]BF4.

[0022] In some embodiments, the palladium catalyst is selected from, but not limited to, palladium on carbon or palladium hydroxide. In some embodiments, the platinum catalyst is selected from, but not limited to, platinum dichloride or platinum oxide.

[0023] In some embodiments, the compound shown in formula D reacts with Ru(OAc)2·[(R)-BINAP] in the presence of hydrogen to form the compound shown in formula F.

[0024] In some embodiments, the compound of formula D reacts in the presence of Pd / c and hydrogen to form the compound of formula F. In some embodiments, the compound of formula D reacts in the presence of Pd / c and formic acid to form the compound of formula F. In some embodiments, the compound of formula D reacts in the presence of Pd / c and formic acid amine to form the compound of formula F.

[0025] In some embodiments, the compound shown in formula D reacts in the presence of [Ru(PPh3)3]Cl2 and hydrogen to form the compound shown in formula F.

[0026] On the other hand, the olefin functional groups are reduced using a reducing agent (1). In some embodiments, the reducing agent (1) used in the reduction reaction of the compound shown in Formula D is selected from sodium borohydride, lithium borohydride, or lithium aluminum hydride. To ensure the smooth progress of the reduction reaction, an appropriate amount of Lewis acid, including but not limited to cobalt chloride, nickel chloride, and zinc chloride, may be added.

[0027] In some embodiments, the compound shown in Formula D reacts in the presence of sodium borohydride / nickel chloride to form the compound shown in Formula F. In some embodiments, the compound shown in Formula D reacts in the presence of lithium borohydride / nickel chloride to form the compound shown in Formula F. In some embodiments, the compound shown in Formula D reacts in the presence of lithium borohydride / zinc chloride to form the compound shown in Formula F.

[0028] In some embodiments, the catalyst is used in an amount of 0.1% to 5% of the molar amount of the compound shown in Formula D, for example 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, ... 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, or any value between two numbers.

[0029] On the other hand, the solvent used in the reduction reaction of the compound represented by Formula D is selected from protic solvents, including but not limited to methanol or ethanol. In some embodiments, the reduction reaction temperature of the compound represented by Formula D is selected from 30 to 80°C, for example 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, or any value between two of these numbers.

[0030] In some embodiments, R in the compound shown in Formula I 1 R 2 Each is independently selected from hydrogen.

[0031] In some embodiments, R in the compound shown in Formula I 1 R 2 Each is independently selected from halogens, C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro or cyano.

[0032] In some embodiments, R in the compound shown in Formula I 3 R 4 Each is independently selected from hydrogen.

[0033] In some embodiments, R in the compound shown in Formula I 3 R 4 Each is independently selected from halogens.

[0034] In some embodiments, R in the compound shown in Formula I 1 R 2 R 3 R 4 Each is independently selected from hydrogen.

[0035] In some embodiments, R in the compound shown in Formula I 6 Selected from hydrogen.

[0036] In some embodiments, R in the compound shown in Formula I 6 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0037] In some embodiments, R in the compound shown in Formula I 6 Selected from difluoromethyl or trifluoromethyl.

[0038] In some embodiments, R in the compound shown in Formula I7 Selected from hydrogen. In some embodiments, R in the compound shown in Formula I 7 Selected from hydrogen, benzyl, p-methoxybenzyl, methyl, ethyl, isopropyl, and tert-butyl.

[0039] In some embodiments, R in the compound shown in formula D 8 It is selected from amino protecting groups, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, or 9-fluorenylmethoxycarbonyl.

[0040] In some embodiments, R in the compound shown in Formula I 5 Selected from halogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0041] In some embodiments, R in the compound shown in Formula I 5 Selected from halogens, such as fluorine, chlorine, or bromine.

[0042] In some embodiments, R in the compound shown in Formula I 5 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, or tert-butyl.

[0043] In some embodiments, L1 in the compound represented by Formula I is selected from...

[0044] In some embodiments, the method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof further includes the step of converting the compound of formula B into the compound of formula D.

[0045] Where R 1 ~R 5 R 7 R 8 w, n, and L1 are defined as described above.

[0046] In some embodiments, the method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof includes reacting the compound of formula B with the compound of formula M to form the compound of formula C, and subjecting the compound of formula C to an olefination reaction to form the compound of formula D.

[0047] Where R 1 ~R 5 R 8 w, n, and L1 are as defined above; X is a leaving group, such as chlorine, bromine, iodine, or -OTs.

[0048] In some embodiments, the compound shown in Formula B reacts with the compound shown in Formula M in the presence of zinc powder to form the compound shown in Formula C.

[0049] In some implementations, the amount of zinc powder used is 1 to 10 times the molar amount of the compound shown in Formula B, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or any two of these values.

[0050] In other embodiments, the reaction solvent for the compound of formula B with the compound of formula M is selected from aprotic solvents, such as tetrahydrofuran.

[0051] In some embodiments, the reaction temperature of the compound represented by formula B with the compound represented by formula M is selected from 30 to 80°C, for example 30°C, 40°C, 50°C, 60°C, 70°C, 80°C or any value between two numbers.

[0052] In some embodiments, the compound shown in formula C reacts with a base (1) and a sulfonyl chloride to form the compound shown in formula D. In some embodiments, the base (1) is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropylethylamine, triethylamine, pyridine, 2,4,6-trimethylpyridine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and lithium bis(trimethylsilylamine).

[0053] In some embodiments, the molar ratio of the compound shown in Formula C to the base (1) is 1:10 to 1:30, for example, 1:10, 1:15, 1:20, 1:25, 1:30 or any value between the two numbers.

[0054] In some embodiments, the sulfonyl chloride is selected from methanesulfonyl chloride or benzenesulfonyl chloride. In embodiments, the molar ratio of the compound represented by formula C to the sulfonyl chloride is 1:5 to 1:15, for example 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15 or any value between the two numbers.

[0055] In some embodiments, the compound represented by formula D is selected from the compound represented by formula D-1. Where R 7 As defined above; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0056] In other schemes, the compound shown in Formula I is the same as the compound shown in Formula II-1.

[0057] In some embodiments, the method for preparing the compound of formula II-1 includes the step of reacting the compound of formula D-1 in the presence of a hydrogen source and a catalyst to form the compound of formula F-1.

[0058] Where R 7 As defined above; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0059] Furthermore, the method for preparing the compound shown in Formula II-1 also includes the step of converting compound B-1 into the compound shown in Formula D-1.

[0060] Where R 7 As defined above; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0061] In some embodiments, the method for preparing the compound of formula II-1 includes reacting compound B-1 with the compound of formula M-1 to form the compound of formula C-1, and subjecting the compound of formula C-1 to an olefination reaction to form the compound of formula D-1.

[0062] Where R 7 As defined above; P 1 X is an amino protecting group, such as tert-butoxycarbonyl; X is a leaving group, such as chlorine, bromine, iodine or -OTs.

[0063] In some embodiments, the method for preparing the compound shown in Formula II-1 includes:

[0064] Step a: Compound B-1 reacts with compound M-1a in the presence of zinc powder to form compound C-1a.

[0065] Step b: The step in which compound C-1a reacts in the presence of DBU / methanesulfonyl chloride to form compound D-1a.

[0066] Step c: Compound D-1a reacts in the presence of a hydrogen source and a catalyst to form compound F-1a.

[0067] In some embodiments, the method for preparing the compound shown in Formula II-1 includes:

[0068] Step a: Compound B-1 reacts with compound M-1a in the presence of zinc powder to form compound C-1a.

[0069] Step b: The step in which compound C-1a reacts in the presence of DBU / methanesulfonyl chloride to form compound D-1a.

[0070] Step c-1: Compound D-1a hydrolyzes to form compound DE-1a.

[0071] Step c-2: Compound DE-1a reacts in the presence of a hydrogen source and a catalyst to form compound FE-1a.

[0072] In some embodiments, compound D-1a is hydrolyzed in the presence of a base (3) to form compound DE-1a, wherein the base (3) includes, but is not limited to, lithium hydroxide, sodium hydroxide, or potassium hydroxide.

[0073] In some embodiments, compound DE-1a reacts with Ru(OAc)2·[(R)-BINAP] and hydrogen to form compound FE-1a.

[0074] In other embodiments, the compound represented by Formula I is compound AA.

[0075] In some embodiments, compound AA can be obtained by chiral resolution of the compound shown in formula F-1 or formula II-1, or by chiral reduction of the compound shown in formula D-1.

[0076] In other embodiments, the method for preparing compound AA includes the step of reacting the compound of formula D-1 in the presence of a hydrogen source and a catalyst to form the compound of formula F-1.

[0077] Where R 7 As defined above; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0078] On the other hand, the compound shown in Formula I of this disclosure is the same as the compound shown in Formula II-2.

[0079] In some embodiments, the method for preparing the compound of formula II-2 includes reacting the compound of formula D-2 in the presence of a hydrogen source and a catalyst to form the compound of formula F-2.

[0080] Where R 7 As defined above; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0081] In some other embodiments, the method for preparing the compound shown in formula II-2 further includes the step of converting compound B-2 into the compound shown in formula D-2.

[0082] Where R 7 As defined above; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0083] Furthermore, the method for preparing the compound shown in formula II-2 includes the steps of reacting compound B-2 with the compound shown in formula M-1 to form the compound shown in formula C-2, and subjecting the compound shown in formula C-2 to an olefination reaction to form the compound shown in formula D-2.

[0084] Where R 7 As defined above; P 1 X is an amino protecting group, such as tert-butoxycarbonyl; X is a leaving group, such as chlorine, bromine, iodine or -OTs.

[0085] In some embodiments, the method for preparing the compound shown in Formula II-2 includes:

[0086] Step a: Compound B-2 reacts with compound M-1a in the presence of zinc powder to form compound C-2a.

[0087] Step b: The step in which compound C-2a reacts with DBU and methanesulfonyl chloride to form compound D-2a.

[0088] Step c: Compound D-2a reacts in the presence of a hydrogen source and a catalyst to form compound F-2a.

[0089] In some embodiments, the method for preparing the compound shown in Formula II-2 includes:

[0090] Step a: Compound B-2 reacts with compound M-1a in the presence of zinc powder to form compound C-2a.

[0091] Step b: The step in which compound C-2a reacts with DBU and methanesulfonyl chloride to form compound D-2a.

[0092] Step c-1: Compound D-2a hydrolyzes to form compound DE-2a.

[0093] Step c-2: Compound DE-2a reacts in the presence of a hydrogen source and a catalyst to form compound FE-2a.

[0094] In some embodiments, compound D-2a is hydrolyzed in the presence of a base (3) to form compound DE-2a, wherein the base (3) includes, but is not limited to, lithium hydroxide, sodium hydroxide, or potassium hydroxide.

[0095] In some embodiments, compound DE-2a reacts in the presence of Ru(OAc)2·[(R)-BINAP] and hydrogen to form compound FE-2a.

[0096] In other embodiments, the compound shown in Formula II-2 is compound BB.

[0097] In some embodiments, compound BB can be obtained by chiral resolution of the compound shown in formula F-2 or formula II-2, or by chiral reduction of the compound shown in formula D-2.

[0098] In some embodiments, the method for preparing compound BB includes reacting the compound shown in formula D-2 in the presence of a reducing agent (1) to form the compound shown in formula F-2.

[0099] Where R 7 As defined above; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0100] This disclosure also provides compounds of formula B or salts thereof.

[0101] Where R 5 Each is independently selected from halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; n is selected from 0, 1, 2, 3 or 4;

[0102] L1 is a key or selected from

[0103] w can be selected from 1, 2, 3 or 4.

[0104] In some embodiments, the compound represented by formula B is selected from:

[0105] On the other hand, this disclosure also provides a method for preparing compound B-1 or a salt thereof.

[0106] The method involves reacting the compound represented by formula Ba with the compound represented by formula Bb in the presence of a reducing agent (2) to form the compound represented by formula Bc.

[0107] Where R a R b Each selected from C 1-6 Alkyl, or R a Rb It can form 5-6 membered heterocyclic alkyl groups with adjacent atoms through optional substitution; TG is a leaving group, such as chlorine or -OTs.

[0108] In some embodiments, the reducing agent (2) is selected from sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride.

[0109] In some embodiments, the molar ratio of the compound represented by formula Bb to the reducing agent (2) is 1:2 to 1:5, for example 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5 or any value between the two numbers.

[0110] In some embodiments, the solvent used for the reaction of the compound of formula Ba with the compound of formula Bb is selected from aprotic solvents, including but not limited to dichloromethane. In some embodiments, the reaction temperature of the compound of formula Ba with the compound of formula Bb is -15 to 30°C, for example -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, or any value between any two of these values.

[0111] In other embodiments, the method for preparing the compound shown in formula B-1 further includes reacting the compound shown in formula Bc with compound Bd in the presence of a base (2) to form the compound shown in formula B-1.

[0112] Wherein TG is a leaving group, such as chlorine or -OTs. In some embodiments, the base (2) is selected from potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). In some embodiments, the compound represented by formula Bc reacts with compound Bd in the presence of cesium carbonate to form compound B-1.

[0113] In some embodiments, the molar ratio of the compound represented by formula Bc to the base (2) is 1:1 to 1:4, for example 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4 or any value between the two numbers.

[0114] In some embodiments, the solvent for the reaction of the compound of formula Bc with compound Bd is selected from N,N-dimethylacetamide. In some embodiments, the reaction temperature of the compound of formula Bc with compound Bd is 60–100°C, for example, 60°C, 70°C, 80°C, 90°C, 100°C, or any value between two of these values.

[0115] In some embodiments, the compound represented by formula Bc is compound B-c1.

[0116] In some embodiments, the compound represented by formula Ba is compound B-a1.

[0117] In some embodiments, the method for preparing compound B-1 or a salt thereof includes reacting compound B-a1 with compound B-b1 in the presence of a reducing agent (2) to form compound B-c1.

[0118] This disclosure also provides compounds of formula M or salts thereof. Where R 1 R 2 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted by one or more groups selected from halogen, nitro, or cyano groups; R 3 R 4 Each is independently selected from hydrogen and halogens;

[0119] R 7 Selected from hydrogen, C 1-6 Alkyl, benzyl, or p-methoxybenzyl;

[0120] R 8 Selected from amino protecting group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0121] X is a leaving group, such as chlorine, bromine, iodine, or -OTs.

[0122] In some embodiments, the compound represented by formula M is selected from the compound represented by formula M-1. Where R 7 As defined above; P 1 X is an amino protecting group, such as tert-butoxycarbonyl; X is a leaving group, such as chlorine, bromine, iodine or -OTs.

[0123] In some embodiments, the compound represented by formula M is selected from:

[0124] This disclosure also provides compounds of formula C or salts thereof. Where R 1 R 2 Each is independently selected from hydrogen, halogen, and C. 1-6Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro or cyano;

[0125] R 3 R 4 Each is independently selected from hydrogen and halogens;

[0126] R 5 Each is independently selected from halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0127] R 7 Selected from hydrogen, C 1-6 Alkyl, benzyl, or p-methoxybenzyl;

[0128] R 8 Selected from amino protecting group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0129] L1 is a key or selected from

[0130] n is selected from 0, 1, 2, 3 or 4;

[0131] w can be selected from 1, 2, 3 or 4.

[0132] In some embodiments, the compound represented by formula C is selected from... Where R 7 As defined above; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0133] In other embodiments, the compound shown in Formula C is selected from...

[0134] This disclosure also provides compounds of formula D or salts thereof. Where R 1 R 2 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro or cyano;

[0135] R 3 R 4 Each is independently selected from hydrogen and halogens;

[0136] R 5 Each is independently selected from halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0137] R 8 Selected from amino protecting group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0138] R 7 Selected from hydrogen, C 1-6 Alkyl, benzyl, or p-methoxybenzyl;

[0139] L1 is a key or selected from

[0140] n is selected from 0, 1, 2, 3 or 4;

[0141] w can be selected from 1, 2, 3 or 4.

[0142] In some embodiments, the compound represented by formula D is selected from... Where R 7 As defined above; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0143] In some embodiments, the compound represented by formula D is selected from...

[0144] This disclosure also provides the use of the compound shown in Formula B, Formula M, Formula C, or Formula D in the preparation of Lpa inhibitors, wherein the Lpa inhibitors are selected from...

[0145] On the other hand, the preparation method described in this disclosure also includes one or more steps such as filtration, concentration, column chromatography purification and drying.

[0146] "Formation" and "conversion" do not specifically refer to a single-step conversion reaction between two substrates; they can be single-step or multi-step reactions between two substrates. If the intermediate contains a protecting group, the intermediate undergoes a step to remove the protecting agent, and then reacts with the corresponding substrate to obtain the corresponding target product.

[0147] The values ​​in this disclosure are instrument measurements and are subject to a certain degree of error. Generally, ±10% is within the reasonable error range. Of course, the context in which the value is used must be considered. For example, in the case of particle size of the active ingredient, where the measurement error variation does not exceed ±10%, the value can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0148] The compounds described in this disclosure may be pharmaceutical salts or salts thereof, which may be selected from inorganic or organic salts. These include acid addition salts and base addition salts. For example, salts formed by an acid-base reaction with a basic group (amino group), wherein the acid includes organic or inorganic acids.

[0149] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0150] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, and tert-butyl. Alkyl groups can be substituted or unsubstituted.

[0151] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted.

[0152] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 6 carbon atoms, such as 4 or 5 carbons. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted.

[0153] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 6 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, excluding the ring moiety of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Heterocyclic alkyl groups can be substituted or unsubstituted.

[0154] Term "C" 1-6 Alkylamino, di-C 1-6 alkylamino or tri-C 1-6 "alkylamino", where alkyl is defined as described above.

[0155] "Hydroxy" refers to the -OH group.

[0156] “Cyano” refers to the -CN group.

[0157] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0158] "Amino" refers to -NH2.

[0159] The "amino or hydroxyl protecting group" disclosed herein refers to a group known in the art that can be used to protect an amino or hydroxyl group, see the amino protecting group in the literature (Protective Groups in Organic Synthesis, 5th Ed. TW Greene & P. ​​GMWuts). As examples, it includes, but is not limited to, tert-butoxycarbonyl (Boc).

[0160] When the functional group of this disclosure is substituted, the substituent is preferably one or more of the following groups: halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl group. Detailed Implementation

[0161] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0162] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0163] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm).

[0164] The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (d6-DMSO) as the solvent.

[0165] MS measurements were performed using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer, in positive / negative ion mode, with a mass scan range of 120–1300.

[0166] HPLC column: YMC-Pack ODS-A (3μm, 4.6mm x 150mm)

[0167] The silica gel plates used for thin-layer chromatography are Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.2mm ± 0.03mm, and the size used for thin-layer chromatography separation and purification of products is 0.4mm-0.5mm.

[0168] Example 1:

[0169] Step 1: Add m-bromobenzaldehyde (27 g, 1.0 eq.), trimethyl orthoformate (77.43 g, 5.0 eq.), p-toluenesulfonic acid (2.51 g, 0.1 eq.), and methanol (270 ml, 10 V) sequentially to a three-necked flask and react at room temperature for 3 h. Add sodium bicarbonate (2.45 g, 0.2 eq.) to the system, stir at room temperature for 0.5 h, concentrate the system, add n-heptane (270 ml, 10 V), filter, concentrate again, and obtain 32.26 g of colorless oil with a purity of 95.8% and a yield of 95.7%.

[0170] Step 2: Compound 1b (32 g, 1.0 eq.), magnesium strip (4.04 g, 1.2 eq.), and tetrahydrofuran (340 mL, 10V) were added sequentially to a three-necked flask. The temperature was raised to 45°C, and 3 drops of 1,2-dibromoethane were added. The system temperature was lowered to -10°C, and DMF was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed to room temperature for 2 hours. A 10% ammonium chloride aqueous solution was added to the system, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with a 10% sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to give 26.47 g of pale yellow oil with a purity of 82.8% and a yield of 106.1%.

[0171] Step 3: Add compound 1c (1.71 g, 2.2 eq.), 2-chloroethylamine hydrochloride (0.50 g, 1.0 eq.), and dichloromethane (5 mL, 10°C) to the reaction flask. Cool to 0°C and add sodium triacetoxyborohydride (3.20 g, 3.5 eq.) in portions. After the addition is complete, stir the reaction at room temperature for 2 h. Add hydrochloric acid and 25 mL of water, separate the layers, extract the aqueous phase with dichloromethane, wash the dichloromethane phase with saturated brine, and evaporate to dryness to obtain 1.13 g of oily substance 1d, with a purity of 68.0% and a yield of 83.1%.

[0172] Step 4: Compound 1d (0.2 g, 1.0 eq.), m-hydroxybenzaldehyde (0.078 g, 1.0 eq.), cesium carbonate (0.414 g, 2.0 eq.), and DMF (2 ml, 10V) were added sequentially to the reaction flask. The system was heated to 80°C and reacted overnight. Water and ethyl acetate were added to the reaction system, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 0.23 g of product 1e, with a purity of 71.5% and a yield of 90.5%.

[0173] 1 H NMR (400MHz, CDCl3): δ10.01 (s, 2H), 9.96 (s, 1H), 7.90 (d, J = 1.7Hz, 2H), 7.76 (d, J = 7.6Hz, 2H), 7.69 (d, J = 7.7Hz, 2H),7.55-7.37(m,4H),7.37-7.31(m,1H),7.15(m,1H),4.13(t,J=5.6Hz,2H),3.82(s,4H),2.97(t,J=5.6Hz,2H).

[0174] Ms(ESI): m / z 402.1[M+1] + .

[0175] Example 2

[0176] Step 1: Under nitrogen protection, zinc powder (8.12 g, 124.15 mmol, 8.0 eq.), 300 mL THF, and 0.1 mL 1,2-dibromoethane were added to the reaction flask. Compound 1e (6.23 g, 15.52 mmol, 1.0 eq.) diluted with 50 mL THF was added dropwise, followed by compound 1f (20.0 g, 62.07 mmol, 4.0 eq.) diluted with 50 mL THF. The reaction was carried out at 60 °C for 3 h. The reaction was quenched with 2 M dilute hydrochloric acid, followed by extraction with ethyl acetate and washing with saturated brine. After concentration, MTBE was slurryed to obtain 17.1 g of white solid 2a.

[0177] Step 2: Under nitrogen protection, compound 2a (17.1 g, 15.11 mmol, 1.0 eq.), DBU (57.53 g, 377.87 mmol, 25.0 eq.), and THF (280 mL) were added to the reaction flask. MsCl (15.58 g, 136.03 mmol, 9.0 eq.) was added dropwise to the system at low temperature. After reacting at 60 °C for 3 h, ethyl acetate was added to the system, followed by washing with saturated brine, drying over anhydrous sodium sulfate, concentration, and purification by column chromatography to obtain 13.4 g of a pale yellow oily substance 2b with a purity of 93.9%.

[0178] Step 3:

[0179] Under nitrogen protection, a 100 mL single-necked round-bottom flask was filled with 2b (2.8 g, 2.60 mmol, 1.0 eq.), LiOH (747 mg, 31.19 mmol, 12.0 eq.), ethanol (28 mL, 10 V), and water (14 mL, 5 V). The mixture was refluxed overnight. The reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate, dried, and concentrated to give 2.6 g of a white solid 2c, in 96.6% yield.

[0180] Step 4:

[0181] Under nitrogen protection, 2c (1.00 g, 965.97 μmol, 1.0 eq.), Ru(OAc)2[(R)-BINAP] (10 mg, 11.88 μmol, 0.01 eq.), triethylamine (147 mg, 1.45 mmol, 1.5 eq.), and methanol (5 mL) were added to the reaction flask. After purging with hydrogen (below 1.0 MPa), the reaction was carried out overnight at 60 °C. The reaction solution was concentrated and purified by column chromatography to give compound 2d 0.75 g, yield 73.8%, purity 95.6%.

[0182] Step 5: Add 2d (10g, 1.0eq), dioxane (50mL, 5V), and water (5mL, 0.5V) to the reaction vessel and stir. Under an ice-water bath, slowly add dioxane hydrochloride (40mL, 4V) and react overnight. After concentrating the reaction solution, add water and adjust the pH to 7-8 with saturated ammonium bicarbonate solution. Add isopropanol dropwise, stir, filter, and dry to obtain compound AA, 4.98g, yield 70%, purity 97%.

[0183] 1 H NMR (400MHz, D2O): δ7.41-7.23(m,9H),6.92-6.90(d,1H),6.76-6.75(m,2H),4.37(s,4H),4.16-4.15(m,2H),3.54-3.48(m,5H),3. 43-3.37(m,3H),3.27-3.20(m,3H),2.99-2.94(m,3H),2.81-2.75(m,6H),2.54-2.40(m,6H),2.13-2.11(m,3H),1.80-1.68(m,3H).

[0184] MS(ESI): m / z 741.3 [M+1] + .

Claims

1. A method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof, The method includes the step of reducing the compound shown in formula D to form the compound shown in formula F. in, R 1 R 2 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro or cyano; R 3 R 4 Each is independently selected from hydrogen and halogens; R 5 Each is independently selected from halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; R 6 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; R 7 Selected from hydrogen, C 1-6 Alkyl, benzyl, or p-methoxybenzyl; R 8 Selected from amino protecting group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, nitro groups, cyano groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; L1 is a key or selected from n is selected from 0, 1, 2, 3 or 4; w can be selected from 1, 2, 3 or 4.

2. The method according to claim 1, wherein the reduction reaction is carried out in the presence of a hydrogen source and a catalyst, wherein the catalyst is preferably a palladium catalyst, platinum catalyst, copper catalyst, ruthenium catalyst, rhodium catalyst, iridium catalyst or cobalt catalyst.

3. The method according to claim 2, wherein the hydrogen source is selected from hydrogen, formic acid, formic acid amine, borane or silane.

4. The method according to claim 1, wherein the reducing agent (1) used in the reduction reaction is selected from sodium borohydride, lithium borohydride or lithium aluminum hydride.

5. The method according to any one of claims 1-4, wherein R 8 It is selected from amino protecting groups, preferably tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, trifluoroacetyl or 9-fluorenylmethoxycarbonyl.

6. The method according to any one of claims 1-5, wherein R 1 R 2 Each is independently selected from hydrogen or C. 1- 6-alkyl, the C 1-6 The alkyl group may optionally be substituted by one or more groups selected from halogen, nitro, or cyano groups; further, R 1 R 2 Hydrogen is preferred.

7. The method according to any one of claims 1-6, wherein R 5 Selected from halogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

8. The method according to any one of claims 1-7, wherein L1 is selected from...

9. The method according to any one of claims 1-8, wherein R 7 Selected from hydrogen, benzyl, p-methoxybenzyl, methyl, ethyl, isopropyl, and tert-butyl.

10. The method according to any one of claims 1-9, further comprising the step of converting the compound of formula B into the compound of formula D. Where R 1 ~R 5 R 8 w, n, and L1 are as defined in claim 1.

11. The method of claim 10, comprising reacting the compound of formula B with the compound of formula M to form the compound of formula C, and subjecting the compound of formula C to an olefination reaction to form the compound of formula D. Where R 1 ~R 5 R 8 w, n and L1 are as defined in claim 1; X is a leaving group, such as chlorine, bromine, iodine or -OTs.

12. The method according to any one of claims 1-11, wherein the compound of formula I is the compound of formula II-1. The method includes the step of reducing the compound shown in formula D-1 to form the compound shown in formula F-1. Where R 7 As defined in claim 1; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

13. The method of claim 12, further comprising the step of converting compound B-1 into the compound shown in formula D-1. Further, the method preferably includes the steps of reacting compound B-1 with the compound shown in formula M-1 to form the compound shown in formula C-1, and then subjecting the compound shown in formula C-1 to an olefination reaction to form the compound shown in formula D-1. Where R 7 As defined in claim 1; P 1 X is an amino protecting group, such as tert-butoxycarbonyl; X is a leaving group, such as chlorine, bromine, iodine or -OTs.

14. The method according to claim 1, wherein the compound represented by formula I is compound AA.

15. A compound or a salt thereof, said compound being selected from... Where R 1 ~R 5 R 7 R 8 w, n and L1 are as defined in claim 1; X is a leaving group, such as chlorine, bromine, iodine or -OTs.

16. Use of the compound of claim 15 or a salt thereof in the preparation of an Lpa inhibitor, wherein the Lpa inhibitor is preferably...

Images