Method for synthesizing substituted phenylpropionic acid derivative

Abstract

The present disclosure relates to a method for synthesizing a substituted phenylpropionic acid derivative. Specifically, the present disclosure relates to a method for preparing a compound as represented by formula I or a pharmaceutically acceptable salt thereof, which method exhibits a good yield.

Description

A method for synthesizing substituted phenylpropionic acid derivatives Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a method for preparing a synthetically substituted phenylpropionic acid derivative. 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 reacting the compound shown in Formula A with the compound shown in Formula B to form the compound shown in Formula C.

[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 or C 1-6 alkyl;

[0012] Y is E and F are each independently selected from O or S;

[0013] R 8 Selected from hydrogen, C 1-6 Alkyl or -(CH2) m R A R A Selected from phenyl, the C 1-6 Alkyl or phenyl groups may optionally be selected from one or more halogens, C 1-6 Alkyl, C 1-6 Alkoxy, trifluoromethyl, amino, C 1-6 Alkylamino, di-C 1-6 alkylamino or tri-C 1-6 Alkylamino substituents;

[0014] R 9 R 10 Each is independently selected from hydrogen and C. 1-6 Alkyl, phenyl, the C 1-6 Alkyl or phenyl groups may optionally be selected from one or more halogens, C 1-6 Alkyl, trifluoromethyl, amino, C 1-6 Alkylamino or di-C 1-6 Alkylamino substituents;

[0015] R 11 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, C3-6 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;

[0016] L1 is selected from

[0017] X is selected from leaving groups, such as halogens;

[0018] n is selected from 0, 1, 2, 3 or 4;

[0019] m is selected from 0, 1, or 2;

[0020] w can be selected from 2, 3, or 4.

[0021] In some embodiments, the compound of formula A reacts with the compound of formula B in the presence of a basic reagent, said basic reagent being potassium tert-butoxide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, lithium hexamethyldisilamide, butyllithium, or lithium diisopropylamide.

[0022] In some embodiments, the compound shown in Formula A reacts with the compound shown in Formula B in the presence of hexamethyldisilamide lithium.

[0023] In some embodiments, the molar ratio of the compound of formula A to the basic reagent 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 two of these numbers. In some embodiments, the reaction solvent for the compound of formula A and the compound of formula B is selected from polar aprotic solvents, such as tetrahydrofuran.

[0024] In some embodiments, the reaction temperature of the compound shown in Formula A with the compound shown in Formula B is -40 to -10°C, for example -40°C, -35°C, -30°C, -25°C, -20°C, -15°C, -10°C or any value between two of these numbers.

[0025] In some embodiments, R in the compound shown in Formula I 1 R 2 Each is independently selected from hydrogen.

[0026] 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.

[0027] In some embodiments, R in the compound shown in Formula I3 R 4 Each is independently selected from hydrogen.

[0028] In some embodiments, R in the compound shown in Formula I 3 R 4 Each is independently selected from halogens.

[0029] In some embodiments, R in the compound shown in Formula I 1 R 2 R 3 R 4 Each is independently selected from hydrogen.

[0030] In some embodiments, R in the compound shown in Formula I 6 Selected from hydrogen.

[0031] 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;

[0032] In some embodiments, R in the compound shown in Formula I 6 Selected from difluoromethyl or trifluoromethyl.

[0033] In some implementation schemes, R 8 Selected from C 1-6 Alkyl groups, such as methyl or tert-butyl.

[0034] In some implementation schemes, R 8 Selected from phenyl, wherein the phenyl is optionally mixed with one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, trifluoromethyl, amino, C 1-6 Alkylamino or di-C 1-6 alkylamino or tri-C 1-6 Alkylamino groups are substituted.

[0035] In some implementation schemes, R 8 Selected from benzyl, wherein the benzyl group is optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, trifluoromethyl, amino, C 1-6 Alkylamino or di-C 1-6 alkylamino or tri-C 1-6 Alkylamino groups are substituted.

[0036] In some implementation schemes, R 8 Selected from -(CH2) m R A R A Selected from phenyl, m is 2, wherein the phenyl is optionally coated with one or more compounds selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, trifluoromethyl, amino, C 1-6 Alkylamino or di-C 1-6 alkylamino or tri-C 1-6 Alkylamino groups are substituted.

[0037] In some implementation schemes, R 8 Selected from phenylethyl.

[0038] In some implementation schemes, R 9 R 10 Each is independently selected from hydrogen or C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally surrounded by one or more elements selected from halogens, C 1-6 Alkoxy, trifluoromethyl, amino, C 1-6 Alkylamino or di-C 1-6 alkylamino or tri-C 1-6 Alkylamino groups are substituted.

[0039] In some implementation schemes, R 9 R 10 Each is independently selected from phenyl, and the phenyl is optionally selected from one or more halogens, C 1-6 Alkyl, trifluoromethyl, amino, C 1-6 Alkylamino or di-C 1-6 alkylamino or tri-C 1-6 Alkylamino groups are substituted.

[0040] In some implementations, F is O and E is O.

[0041] In some embodiments, Y in the compound represented by formula B is selected from...

[0042] In some embodiments, Y in the compound represented by formula B is selected from...

[0043] In some embodiments, Y in the compound represented by formula B is selected from...

[0044] In some embodiments, R in the compound shown in formula B 11It is selected from amino protecting groups, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, or 9-fluorenylmethoxycarbonyl.

[0045] In some embodiments, the compound represented by formula B is selected from the compound represented by formula B-1. Where P 1 It is an amino protecting group, such as tert-butoxycarbonyl; Y is as defined above.

[0046] In some embodiments, the compound represented by formula B is selected from... Where P 1 It is an amino protecting group, such as tert-butoxycarbonyl; Y is as defined above.

[0047] In some embodiments, the compound represented by formula B is selected from...

[0048] In some embodiments, L1 in the compound represented by formula C is selected from...

[0049] In some embodiments, the compound represented by formula C is selected from... Where P 1 It is an amino protecting group, such as tert-butoxycarbonyl; Y is as defined above.

[0050] In some embodiments, the compound represented by formula C is selected from... Where P 1 It is an amino protecting group, such as tert-butoxycarbonyl; Y is as defined above.

[0051] In some embodiments, Y in the compound represented by formula C-1 or C-1a is

[0052] In some embodiments, Y in the compound represented by formula C-1 or C-1a is

[0053] In some embodiments, the compound represented by formula C is selected from... Where P 1 It is an amino protecting group, such as tert-butoxycarbonyl; Y is as defined above.

[0054] In some embodiments, the compound represented by formula C is selected from... Where P 1 It is an amino protecting group, such as tert-butoxycarbonyl; Y is as defined above.

[0055] In some embodiments, Y in the compound represented by formula C-2 or C-2a is

[0056] In some embodiments, Y in the compound represented by formula C-2 or C-2a is On the other hand, the method described in this disclosure also includes the step of hydrolyzing the compound of formula C to form the compound of formula D.

[0057] Where R 1 ~R 5 R 11 w, Y and L1 are defined in the compound shown in Formula I.

[0058] In some embodiments, the compound of formula C is hydrolyzed in the presence of a base (1) / peroxide to form the compound of formula D. In some embodiments, the base (1) is selected from lithium hydroxide, sodium hydroxide, potassium carbonate, and tetrabutylammonium hydroxide. In some embodiments, the peroxide is selected from hydrogen peroxide.

[0059] In some embodiments, the compound shown in Formula C is hydrolyzed in the presence of lithium hydroxide / hydrogen peroxide, potassium hydroxide / hydrogen peroxide, sodium hydroxide / hydrogen peroxide, potassium carbonate / hydrogen peroxide, or tetrabutylammonium hydroxide / hydrogen peroxide to form the compound shown in Formula D.

[0060] In some implementations, the molar ratio of the base (1) to the peroxide is 1:1 to 2:1, for example 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1 or any value between the two.

[0061] In some embodiments, the solvent used for the hydrolysis reaction of the compound shown in Formula C is selected from polar aprotic solvents, such as tetrahydrofuran.

[0062] In other embodiments, the compound shown in Formula I is compound II-1.

[0063] In some embodiments, the method for preparing compound II-1 includes the step of reacting the compound of formula A-1 with the compound of formula B-1 in the presence of a basic reagent to form the compound of formula C-1.

[0064] Where X and Y are defined as in the compound shown in Formula I; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0065] The method for preparing compound II-1 further includes the steps of hydrolyzing the compound of formula C-1 to form the compound of formula D-1, and deprotecting formula D-1 to form compound II-1.

[0066] Where Y is defined in the compound shown in Formula I; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0067] In some embodiments, the conditions / methods for removing the amino protecting group are described in the corresponding deprotection conditions in "Protective Groups in Organic Synthesis," 5th Ed. TW Greene & P. ​​GMWuts, and the relevant content is incorporated herein for illustration. For example, the compound is deprotected from the amino protecting group -Boc under acidic conditions, wherein the acid is selected from trifluoroacetic acid, acetic acid, or hydrochloric acid.

[0068] Furthermore, the method for preparing compound II-1 also includes the step of reacting the compound shown in formula A-1c with the compound shown in formula A-1d to form the compound shown in formula A-1e.

[0069] Peg is selected from leaving groups or -OP. 2 P 2 It is a hydroxyl protecting group, such as tert-butyldimethylsilyl.

[0070] In some embodiments, the compound shown in formula A-1c reacts with the compound shown in formula A-1d in the presence of a reducing agent to form the compound shown in formula A-1e. In some embodiments, the reducing agent is selected from sodium borohydride, sodium triacetoxyborohydride, sodium tripropionyloxyborohydride, and sodium cyanoborohydride.

[0071] In some embodiments, the molar ratio of the compound represented by formula A-1c to the reducing agent is 1:2 to 1:5, for example, 1:2, 1:3, 1:4, 1:5, or any value between two of these numbers. In some embodiments, the solvent used for the reaction of the compound represented by formula A-1c is selected from polar aprotic solvents, such as tetrahydrofuran.

[0072] In some embodiments, the method for preparing compound II-1 includes: reacting the compound of formula A-1c with the compound of formula A-1d to form the compound of formula A-1e, converting the compound of formula A-1e into the compound of formula A-1, and reacting the compound of formula A-1 with the compound of formula B-1 in the presence of a basic reagent to form the compound of formula C-1.

[0073] Peg is selected from leaving groups or -OP. 2 P 2 X is a hydroxyl protecting group; X is selected from leaving groups; P 1 It is an amino protecting group.

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

[0075] In some embodiments, the method for preparing compound AA includes the step of reacting the compound of formula A-1 with the compound of formula B-1a in the presence of a basic reagent to form the compound of formula C-1a.

[0076] Where X and Y are defined in the compound shown in Formula I; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0077] In some embodiments, the method for preparing compound AA further includes the step of hydrolyzing the compound shown in formula C-1a to form the compound shown in formula D-1a.

[0078] Where X and Y are defined in the compound shown in Formula I; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0079] In some embodiments, the method for preparing compound AA includes the following reaction steps:

[0080] Step a) The compound shown in formula A-1c reacts with the compound shown in formula A-1d to form the compound shown in formula A-1e.

[0081] Step a-1) The compound shown in formula A-1e is converted into the compound shown in formula A-1.

[0082] Step b) The compound shown in formula A-1 reacts with the compound shown in formula B-1a in the presence of a basic reagent to form the compound shown in formula C-1a.

[0083] Step c) The compound shown in formula C-1a is hydrolyzed to form the compound shown in formula D-1a.

[0084] Step d) The compound shown in formula D-1a undergoes deamination to form compound AA.

[0085] Where X and Y are defined as in the compound shown in Formula I; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl; Peg is selected from leaving groups or -OP. 2 P 2 It is a hydroxyl protecting group.

[0086] In some embodiments, the method for preparing compound AA includes the following reaction steps:

[0087] Step a) Compound a-1c reacts with compound a-1d in the presence of the reducing agent sodium triacetoxyborohydride to form compound a-1e.

[0088] In step a-1), compound a-1e reacts in the presence of hydrobromic acid to form compound A-1a.

[0089] Step b) Compound A-1a reacts with the compound shown in formula B-1ab in the presence of a basic reagent to form the compound shown in formula C-1ab.

[0090] Step c) The compound shown in formula C-1ab hydrolyzes in the presence of potassium hydroxide / hydrogen peroxide to form the compound shown in formula D-1ab.

[0091] Step d) The compound shown in formula D-1ab undergoes deamination under acidic conditions to form compound AA.

[0092] Where Y P 1 It is a tert-butoxycarbonyl group.

[0093] In some embodiments, the method for preparing compound AA includes the following reaction steps:

[0094] Step a) Compound a-1c reacts with compound a-1d in the presence of the reducing agent sodium triacetoxyborohydride to form compound a-1e.

[0095] In step a-1), compound a-1e reacts in the presence of hydrobromic acid to form compound A-1a.

[0096] Step b) Compound A-1a reacts with the compound shown in formula B-1ac in the presence of a basic reagent to form the compound shown in formula C-1ac.

[0097] Step c) The compound shown in formula C-1ac hydrolyzes in the presence of potassium hydroxide / hydrogen peroxide to form the compound shown in formula D-1ac.

[0098] Step d) The compound shown in formula D-1ac undergoes deamination under acidic conditions to form compound AA.

[0099] Where Y is P 1 It is a tert-butoxycarbonyl group.

[0100] On the other hand, in some embodiments, the compound shown in Formula I is compound II-2.

[0101] In some embodiments, the method for preparing compound II-2 includes the step of reacting the compound of formula A-2 with the compound of formula B-2 in the presence of a basic reagent to form the compound of formula C-2.

[0102] Where X and Y are defined as in the compound shown in Formula I; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0103] In some embodiments, the method for preparing compound II-2 further includes the steps of hydrolyzing the compound of formula C-2 to form the compound of formula D-2, and deprotecting formula D-2 to form compound II-2.

[0104] Where Y is defined in the compound shown in Formula I; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0105] Furthermore, the method for preparing compound II-2 also includes the step of reacting the compound shown in formula A-2c with the compound shown in formula A-1d to form the compound shown in formula A-2e.

[0106] Peg is selected from leaving groups or -OP. 2 P 2 It is a hydroxyl protecting group, such as tert-butyldimethylsilyl.

[0107] In some embodiments, the method for preparing compound II-2 includes the steps of: reacting the compound shown in formula A-2c with the compound shown in formula A-1d to form the compound shown in formula A-2e, converting the compound shown in formula A-2e to formula A-2, and reacting the compound shown in formula A-2 with the compound shown in formula B-1 in the presence of a basic reagent to form the compound shown in formula C-2.

[0108] Peg is selected from leaving groups or -OP. 2 P 2 It is a hydroxyl protecting group; X is selected from leaving groups, P 1 It is an amino protecting group.

[0109] In other embodiments, the compound shown in Formula I is compound BB.

[0110] In some embodiments, the method for preparing compound BB includes the step of reacting the compound shown in formula A-2 with the compound shown in formula B-2a in the presence of a basic reagent to form the compound shown in formula C-2a.

[0111] Where X and Y are defined as in the compound shown in Formula I; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0112] In some embodiments, the method for preparing compound BB further includes the step of hydrolyzing the compound shown in formula C-2a to form the compound shown in formula D-2a.

[0113] Where X and Y are defined as in the compound shown in Formula I; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl.

[0114] In some embodiments, the method for preparing compound BB includes the following reaction steps:

[0115] Step a) The compound shown in formula A-2c reacts with the compound shown in formula A-1d in the presence of the reducing agent sodium triacetoxyborohydride to form the compound shown in formula A-2e.

[0116] Step a-1) The compound shown in formula A-2e is converted into the compound shown in formula A-2.

[0117] Step b) The compound shown in formula A-2 reacts with the compound shown in formula B-1a in the presence of a basic reagent to form the compound shown in formula C-2a.

[0118] Step c) The compound shown in formula C-2a hydrolyzes in the presence of potassium hydroxide / hydrogen peroxide to form the compound shown in formula D-2a.

[0119] Step d) The compound shown in formula D-2a undergoes deamination under acidic conditions to form compound BB.

[0120] Where X and Y are defined as in the compound shown in Formula I; P 1 It is an amino protecting group, for example, tert-butoxycarbonyl; Peg is selected from leaving groups or -OP. 2 P 2 It is a hydroxyl protecting group.

[0121] This disclosure also provides the following compounds or salts thereof:

[0122] Peg is selected from leaving groups or -OP. 2 P 2 is a hydroxyl protecting group; X is selected from leaving groups; n is selected from 0, 1, 2, 3 or 4; w is selected from 2, 3 or 4;

[0123] 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;

[0124] L1 is selected from

[0125] In some embodiments, the compound represented by formula Aa is Peg is selected from leaving groups or -OP. 2 P 2 It is a hydroxyl protecting group.

[0126] In some embodiments, the compound represented by formula A is X is selected from leaving groups, such as bromine.

[0127] This disclosure also provides the use of the compounds represented by Formula Aa, Formula A, Formula A-1c, or Formula A-1e in the preparation of Lpa inhibitors.

[0128] 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.

[0129] "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.

[0130] 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%.

[0131] 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.

[0132] 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 and Two configurations.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] Term "C" 1-6 Alkylamino, di-C 1-6 alkylamino or tri-C 1-6 "alkylamino", where alkyl is defined as described above.

[0138] "Hydroxy" refers to the -OH group.

[0139] “Cyano” refers to the -CN group.

[0140] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0141] "Amino" refers to -NH2.

[0142] 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).

[0143] When the functional group of this disclosure is substituted, the substituent is preferably one or more of the following groups: halogen, nitro, cyano, C1-6 Alkyl or C 1-6 Alkyl group. Detailed Implementation

[0144] 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.

[0145] 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.

[0146] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given.

[0147] The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (d6-DMSO), deuterated chloroform (CDCl3), and deuterated water (D2O) as the solvents.

[0148] 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.

[0149] HPLC column: YMC-Pack ODS-A (3μm, 4.6mm x 150mm)

[0150] 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.

[0151] Example 1:

[0152] Step 1: Add m-hydroxybenzyl alcohol (15 g, 1.0 eq.), N-Boc ethyl bromide (54.15 g, 2.0 eq.), cesium carbonate (78.7 g, 2.0 eq.), and acetonitrile (225 ml, 15 V) to the reaction flask. Reflux the reaction until the reactants are detected to be completely reacted. Cool to room temperature, wash with water, separate the liquids, dry and concentrate the organic phase to obtain an oily compound 1c 40.9 g, yield 126.6%, HPLC: 94.6%.

[0153] Step 2: Add compound 1c (40.9 g, 1.0 eq.) and dioxane (80 mL, 2V) to the reaction flask and start stirring. Slowly add dioxane hydrochloride solution (153 mL, 4.0 eq.) and stir for 18 h. Filter and dry the filter cake under vacuum to obtain 27.78 g of compound 1d, yield 89.1%, HPLC: 96.8%.

[0154] Step 3: Compound 1d (27 g, 1.0 eq.), imidazole (18.5 g, 2.0 eq.), and dichloromethane (270 ml, 10 V) were added to the reaction flask, and stirring was started. TBSCl (30 g, 1.5 eq.) was dissolved in 25 ml of dichloromethane and slowly added dropwise to the reaction solution. After the addition was complete, the reaction was stirred for 2 h, quenched with water, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried, concentrated, and purified by column chromatography to obtain 29.25 g of compound 1e, yield 78.4%, HPLC: 96.8%.

[0155] Step 4: At 0°C, compound 1e (29 g, 1.0 eq.), compound 1f (51.5 g, 2.0 eq.), and tetrahydrofuran (435 ml, 15 V) were added to a reaction flask, and stirring was started. Sodium triacetoxyborohydride (76.43 g, 3.5 eq.) was slowly added in portions, and the reaction was stirred for 2 h. The reaction was quenched with saturated sodium bicarbonate, separated, and the organic phase was concentrated to give 74.13 g of compound 1, yield 95.9%, HPLC: 92.1%.

[0156] Step 5: Add 1 g (74 g, 1.0 eq.) of compound, hydrobromic acid (166 g, 10.0 eq.), and toluene (370 ml, 5V) to the reaction flask, reflux for 18 h, cool to room temperature, add water, separate the layers, and discard the toluene phase. Extract the aqueous phase with dichloromethane and separate the layers. Wash the organic phase with saturated sodium bicarbonate solution, dry and concentrate, and purify the crude product by column chromatography to give 35.25 g of compound 1 h, yield 60%, HPLC: 99%.

[0157] 1 H NMR (400MHz, CDCl3): δ7.43(d,J=1.8Hz,1H),7.35-7.17(m,7H),6.95(m,1H),6.86(t,J=2.1Hz,1H),6. 77(m,0.9Hz,1H),4.49(s,4H),4.43(s,2H),4.03(t,J=5.9Hz,2H),3.70(s,4H),2.91(t,J=5.9Hz,2H).

[0158] Ms(ESI): m / z 597.9 [M+1] + .

[0159] Example 2

[0160] Step 1: Add L-homophenylalanine (20.0 g, 1.0 eq.) and methanol (200 mL, 10 V) to a reaction flask, cool to 0 °C, add thionyl chloride (39.82 g, 3.0 eq.) dropwise, reflux for 3 h after the addition is complete, evaporate to dryness, add water, adjust the alkali to 8-9 with saturated sodium bicarbonate, extract with dichloromethane, dry and evaporate to dryness to obtain 21.35 g of the compound, yield 99%, HPLC: 99%.

[0161] Step 2: The obtained L-polyphenylalanine methyl ester (21.35 g) was transferred to a reaction flask, methanol (214 mL, 10 V) was added, the temperature was lowered to 0 °C, sodium borohydride (20.89 g, 5.0 eq.) was added in portions, and the mixture was then heated to room temperature and reacted overnight. After quenching, the mixture was concentrated, water and n-butanol were added, the mixture was separated, the aqueous phase was extracted with n-butanol, dried and evaporated to dryness, and the salt was removed by slurrying with ethyl acetate to obtain 18.46 g of the compound, with a yield of 100% and HPLC 94%.

[0162] Step 3: Transfer the obtained L-phenylalanine (18.46 g) to a reaction flask, add toluene (148 mL, 8°C), cool to 0°C, add potassium carbonate (23.15 g, 1.5 eq.), and dropwise add a toluene (37 mL, 2°C) solution of triphosgene (16.57 g, 0.5 eq.). Then raise the temperature to room temperature and react overnight. After quenching, concentrate the solution, add water and ethyl acetate, separate the layers, extract the aqueous phase with ethyl acetate, wash the organic phase with saturated sodium chloride, dry and evaporate to dryness to obtain 21.46 g of the phenylethyl Evans cofactor, with a yield of 100% and a purity of 98%.

[0163] 1 H NMR (400M, DMSO-d6) δ7.90 (s, 1H), 7.32-7.26 (m, 2H), 7.25-7.14 (m, 3H), 4.36 (t, J = 8.4Hz, 1H), 3.94 (dd, J=8.5, 6.0Hz, 1H), 3.74 (m, 1H), 2.66 (m, 1H), 2.60-2.53 (m, 1H), 1.74 (m, 2H).

[0164] MS(ESI): m / z 192[M+1] + .

[0165] Step 4: In a reaction flask, add N-Boc tetrahydropyrrolidone (5.99 g, 1.0 eq.) and dichloromethane (25 mL, 5V), EDCI (7.52 g, 1.5 eq.), and DMAP (1.59 g, 0.5 eq.). Cool to 0°C and stir for 0.5 h. Add dropwise a mixture of phenethyl Evans cofactor (5.00 g, 1.0 eq.) and dichloromethane (25 mL, 5V). Then, raise the temperature to room temperature and react overnight. Dry by rotary evaporation, wash with 10% citric acid solution, wash with 5% sodium bicarbonate solution, wash with saturated sodium chloride solution, and purify by column chromatography to obtain compound 1i 6.44 g, yield 61%, purity 98%.

[0166] 1 H NMR (400M, DMSO-) d6 ): δ7.28(t,J=7.5Hz,2H),7.24-7.15(m,3H),4.48-4.38(m,2H),4.33-4.26(m,1H),3.47(dd,J=10.5,7.3Hz,1H),3.29(m,1H),3.22-3 .10(m,1H),2.93-2.77(m,3H),2.59(t,J=8.1Hz,2H),2.48-2.38(m,1H),2.05-1.86(m,3H),1.57-1.44(m,1H),1.39(d,J=2.7Hz,9H).

[0167] MS(ESI): m / z 303[M-Boc+1] + .

[0168] Example 3

[0169] Step 1: Compound 1i (1.01 g, 3 eq.), compound 1h (0.50 g, 1 eq.), and tetrahydrofuran (5 mL, 5 V) were mixed and cooled with liquid nitrogen (below -30 °C). Li-HMDS (0.56 g, 4 eq.) was added dropwise, and the mixture was stirred for 1 h after the addition was complete. The reaction was stirred for 15 h, and water and ethyl acetate were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed twice with saturated brine, concentrated, and purified by column chromatography to obtain compound 1j 0.53 g, with a yield of 40% and a purity of 94.7%.

[0170] 1H NMR (400MHz, DMSO-d6): δ7.25-6.93(m,24H),6.72(d,J=8.6Hz,2H),6.54(d,J=8.3Hz ,1H),4.35(q,J=8.8,8.2Hz,8H),4.09(dt,J=22.3,6.9Hz,3H),3.78(d,J=8.1Hz,2H), 3.42(m,5H),3.18-2.99(m,3H),2.87(m,9H),2.43-2.13(m,9H),1.86(m,3H),1.57(m ,7H),1.29(s,18H),1.27(s,9H),1.25(dd,J=11.8,3.9Hz,7H),0.85(t,J=6.8Hz,3H).

[0171] Step 2: Compound 1j (2.0 g, 1 eq.) was mixed with tetrahydrofuran (20 mL, 10 V), water (6 mL, 3 V), and hydrogen peroxide (2.2 g, 15 eq.). The mixture was cooled to 0 °C, and potassium hydroxide solution (0.32 g, 4.5 eq., 1 V) was added. After the addition was complete, the reaction was allowed to proceed for 16 h. Water and ethyl acetate were added, and the mixture was separated. Sodium sulfite solution was added dropwise to the aqueous phase, and the mixture was stirred for 1 h. Then, 2 M hydrochloric acid was added dropwise to adjust the concentration to 2-3, and the mixture was stirred for 0.5 h. Ethyl acetate was then added for extraction. The organic phase was dried and concentrated under reduced pressure to give 1.3 g of white solid compound 1K.

[0172] The obtained white solid (1.3 g, 1.0 eq) was transferred to a reaction flask, and 1,4-dioxane (13 mL, 10 V) and concentrated hydrochloric acid (13 mL, 10 V) were added. The mixture was refluxed for 1 hour, and then concentrated under reduced pressure. Water was added to the concentrate, and the pH was adjusted to neutral with saturated ammonium bicarbonate solution. Isopropanol was added dropwise, and the mixture was stirred, filtered, and dried to give compound AA, 0.6 g. The overall yield of the two steps was 60%, and the purity was 97%.

[0173] 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).

[0174] 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 reacting the compound shown in Formula A with the compound shown in Formula B to form the compound shown in Formula C. 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 or C 1-6 alkyl; Y is E and F are each independently selected from O or S; R 8 Selected from hydrogen, C 1-6 Alkyl or -(CH2) m R A R A Selected from phenyl, the C 1-6 Alkyl or phenyl groups may optionally be selected from one or more halogens, C 1-6 Alkyl, C 1-6 Alkoxy, trifluoromethyl, amino, C 1-6 Alkylamino, di-C 1-6 alkylamino or tri-C 1-6 Alkylamino substituents; R 9 R 10 Each is independently selected from hydrogen and C. 1-6 Alkyl, phenyl, the C 1-6 Alkyl or phenyl groups may optionally be selected from one or more halogens, C 1-6 Alkyl, trifluoromethyl, amino, C 1-6 Alkylamino or di-C 1-6 Alkylamino substituents; R 11 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 selected from X is selected from leaving groups, such as halogens; n is selected from 0, 1, 2, 3 or 4; m is selected from 0, 1, or 2; w can be selected from 2, 3, or 4.

2. The method according to claim 1, wherein the compound of formula A reacts with the compound of formula B in the presence of a basic reagent, wherein the basic reagent is selected from potassium tert-butoxide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, lithium hexamethyldisilamide, butyllithium, lithium diisopropylamide, etc., preferably lithium hexamethyldisilamide.

3. The method according to claim 1 or 2, wherein R 11 It is selected from amino protecting groups, preferably tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, trifluoroacetyl or 9-fluorenylmethoxycarbonyl.

4. The method according to any one of claims 1-3, wherein R 8 Selected from C 1-6 Alkyl groups, such as methyl or tert-butyl; or R 8 Selected from phenyl, wherein the phenyl is optionally mixed with one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, trifluoromethyl, amino, C 1-6 Alkylamino or di-C 1-6 Alkylamino substituents; or R 8 Selected from benzyl, wherein the benzyl group is optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, trifluoromethyl, amino, C 1-6 Alkylamino or di-C 1-6 alkylamino or tri-C 1-6 Alkylamino groups are substituted.

5. The method according to any one of claims 1-4, wherein R 9 R 10 Each is independently selected from hydrogen or C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally surrounded by one or more elements selected from halogens, C 1-6 Alkoxy, trifluoromethyl, amino, C 1-6 Alkylamino or di-C 1-6 Alkylamino substituents; or, R 9 R 10 Each is independently selected from phenyl, and the phenyl is optionally selected from one or more halogens, C 1-6 Alkyl, trifluoromethyl, amino, C 1-6 Alkylamino or di-C 1-6 alkylamino or tri-C 1-6 Alkylamino groups are substituted.

6. The method according to any one of claims 1-5, wherein E is 0 and F is 0.

7. The method according to any one of claims 1-6, wherein Y is selected from...

8. The method according to any one of claims 1-7, wherein the compound of formula B is selected from the compound of formula B-1. Where P 1 It is an amino protecting group, such as tert-butoxycarbonyl; Y is as defined in claim 1.

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

10. The method according to any one of claims 1-9, further comprising the step of hydrolyzing the compound of formula C to form the compound of formula D, wherein the hydrolysis conditions are lithium hydroxide / hydrogen peroxide, potassium hydroxide / hydrogen peroxide, sodium hydroxide / hydrogen peroxide, potassium carbonate / hydrogen peroxide, tetrabutylammonium hydroxide / hydrogen peroxide, preferably lithium hydroxide / hydrogen peroxide. Water or potassium hydroxide / hydrogen peroxide, Where R 1 ~R 5 R 11 w, Y and L1 are as defined in claim 1.

11. The method according to any one of claims 1-10, wherein the compound of formula I is the compound of formula II-1. The method includes the step of reacting the compound shown in formula A-1 with the compound shown in formula B-1 in the presence of a basic reagent to form the compound shown in formula C-1. Wherein X and Y are defined as in claim 1; P1 is an amino protecting group, for example, tert-butoxycarbonyl.

12. The method of claim 11, further comprising the step of reacting the compound of formula A-1c with the compound of formula A-1d to form the compound of formula A-1e. Peg is selected from leaving groups or -OP. 2 P 2 It is a hydroxyl protecting group, such as tert-butyldimethylsilyl.

13. The method according to claim 11 or 12, comprising: The steps include the reaction of the compound shown in formula A-1c with the compound shown in formula A-1d to form the compound shown in formula A-1e, the conversion of the compound shown in formula A-1e to the compound shown in formula A-1, and the reaction of the compound shown in formula A-1 with the compound shown in formula B-1 in the presence of a basic reagent to form the compound shown in formula C-1. Peg is selected from leaving groups or -OP. 2 P 2 It is a hydroxyl protecting group; X is selected from leaving groups, P 1 It is an amino protecting group.

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... Peg is selected from leaving groups or -OP. 2 P 2 The hydroxyl protecting group; X is selected from leaving groups; w, n, R 5 And L1 as defined in claim 1.

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...

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