Preparation method of 3-ethoxy-8-azabicyclo [3.2. 1] octane-1-yl benzoic acid and derivatives thereof

Abstract

The present disclosure relates to a process for the preparation of 3-ethoxy-8-azabicyclo [3.2. 1] octane-1-yl) benzoic acid and derivatives thereof. Specifically, the invention provides a preparation method for chiral synthesis of 4-((1S, 3S, 5R)-3-ethoxy-8-azabicyclo [3.2. 1] octane-1-yl benzoic acid and a derivative thereof, and an application of the intermediate in preparation of a Factor B inhibitor.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a method for preparing 3-ethoxy-8-azabicyclo[3.2.1]octane-1-ylbenzoic acid and its derivatives. Background Technology

[0002] The complement system is a crucial component of the body's innate immunity, responsible for resisting infections from exogenous pathogens, bacteria, and parasites. It also plays a vital role in the transition between innate and adaptive immunity. Complement is composed of plasma proteins, including soluble proteins, membrane-bound proteins, and complement receptors. It is primarily produced by membrane proteins expressed on the liver or cell surface and functions in plasma, tissues, or cells. The complement system is activated mainly through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).

[0003] Complement factor B acts on the AP pathway. Inhibiting Factor B activity can prevent API pathway activation without interfering with the CP and LP pathways, thus avoiding increased infection risk due to complement system inhibition.

[0004] Ipatecan, the first marketed Factor B inhibitor, is used to treat IgA nephropathy. Meanwhile, several other small-molecule Factor B inhibitors have been reported, such as:

[0005]

[0006] Methyl 4-((1S,3S,5R)-3-ethoxy-8-azabicyclo[3.2.1]octane-1-yl)benzoate is a key intermediate in the preparation of the aforementioned Factor B inhibitor.

[0007]

[0008] WO2022143845 discloses a process for preparing the target product from 4-(4-bromophenyl)-4-oxobutyraldehyde as a starting material through a 7-step reaction. The chiral intermediate is obtained by chiral column separation, but the yield is low, making it difficult to use industrially.

[0009]

[0010] WO2023237041 discloses a process for preparing the target product from 4-(4-oxobutyryl)benzonitrile via a 7-step reaction, in which chiral intermediates are obtained by resolution with chiral reagents. However, this process has low yields and high production costs.

[0011] Summary of the Invention

[0012] This disclosure provides a method for reacting a compound of formula D or a salt thereof, the method comprising the step of reacting a compound of formula C to form a compound of formula D.

[0013]

[0014] Z and Y are each independently selected from CH and N;

[0015] R 1 Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4 and -CONR 5 R 6 ;

[0016] R 2 Selected from C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0017] R 4 Selected from 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 5 R 6 Each is independently selected from hydrogen 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 groups;

[0018] P 1 P 2 Each is independently selected from C 1-3 Alkyl and C 1-3 Acyl group, the C 1-3 Alkyl or C 1-3 The acyl group may be optionally substituted with one or more halogens or phenyl groups, or P 1 P 2 Together with adjacent atoms, they form a 5-6 membered heterocyclic alkyl group, which is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl groups are substituted;

[0019] P 3 Selected from C 1-6 Alkyl, the C 1-6The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano.

[0020] In some embodiments, the compound shown in formula C reacts under acidic conditions to form the compound shown in formula D.

[0021] In some embodiments, the acid used in the reaction of the compound represented by Formula C is selected from, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, or p-toluenesulfonic acid.

[0022] In some embodiments, the amount of acid used in the reaction is 10 to 15 times the molar amount of the compound shown in Formula C, including 10, 11, 12, 13, 14, 15 times or any two of these values.

[0023] In some embodiments, the reaction temperature of the compound represented by Formula C is selected from 40 to 80°C, including 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, or any value between any two numbers.

[0024] In some embodiments, the reaction solvent for the compound represented by Formula C is selected from protic solvents, including but not limited to one or more of methanol, ethanol, isopropanol, or water.

[0025] In some embodiments, the compound shown in formula C reacts under hydrochloric acid conditions to form the compound shown in formula D or a salt thereof.

[0026] In some embodiments, the method for preparing the compound of formula D or a salt thereof further includes reacting the compound of formula A with a sulfinamide to form the compound of formula B, and reacting the compound of formula B with the compound of formula W to form the compound of formula C.

[0027] Where R 1 R 2 Z, Y, P 1 P 2 P 3 As defined above; R 1a Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4a and -CONR 5a R 6a R 4a Selected from 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 5a R 6a Each is independently selected from hydrogen 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.

[0028] In some embodiments, the compound represented by Formula A reacts with sulfinamide in the presence of a titanate, such as tetraethyl titanate or tetraisopropyl titanate.

[0029] When R 1a Selected from ester group - COOR 4a The compound shown in Formula A undergoes ester exchange in the presence of titanate, for example, methyl ester is converted to ethyl ester or isopropyl ester.

[0030] In some embodiments, the compound shown in Formula A reacts with sulfinamide in the presence of a titanate ester.

[0031] In some embodiments, the amount of titanate used is 2 to 5 times the molar amount of the compound shown in Formula A, including 2, 3, 4, 5 times or any two of these values.

[0032] In some embodiments, the compound shown in Formula B reacts with the compound shown in Formula W under alkaline conditions, wherein the base is selected from, but not limited to, butyllithium and diisopropylaminolithium.

[0033] In some embodiments, the reaction temperature of the compound represented by Formula B with the compound represented by Formula W is selected from -30 to 0°C, including -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, or any value between any two numbers.

[0034] In some embodiments, the solvent in which the compound of formula B reacts with the compound of formula W is selected from aprotic solvents, including but not limited to tetrahydrofuran or toluene.

[0035] In some embodiments, P in the compound represented by formula W 3 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl.

[0036] In some embodiments, the compound represented by formula W is tert-butyl acetoacetate.

[0037] In some embodiments, the compound represented by formula W is methyl acetoacetate.

[0038] In some embodiments, the compound represented by formula W is ethyl acetoacetate.

[0039] In some embodiments, Z is CH and Y is CH in the compound shown in Formula D; or Z is CH and Y is N.

[0040] In some embodiments, R in the compound shown in formula D 1 It is a halogen, such as bromine.

[0041] In some embodiments, R in the compound shown in formula D 1 It is a cyano group.

[0042] In some embodiments, R in the compound shown in formula D 1 -COOR 4 R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl.

[0043] In some embodiments, R in the compound shown in formula D 1 For -CONR 5 R 6 R 5 R 6 Each is independently selected from hydrogen.

[0044] In some embodiments, R in the compound shown in formula D 1 For -CONR 5 R 6 R 5 R 6 Each is independently selected from methyl groups.

[0045] In some embodiments, the compound represented by formula D is the compound represented by formula D-1. Where X is a halogen, such as bromine.

[0046] In some embodiments, the method for preparing the compound of formula D-1 or a salt thereof includes the step of reacting the compound of formula C-1 under acidic conditions to form the compound of formula D-1.

[0047] Where R 2 P 1 P 2 P 3 As defined above; X is a halogen, such as bromine.

[0048] In some embodiments, the method for preparing the compound of formula D-1 or a salt thereof further includes the steps of reacting the compound of formula A-1 with a sulfinamide to form the compound of formula B-1, and reacting the compound of formula B-1 with the compound of formula W to form the compound of formula C-1.

[0049]

[0050] Where R 2 P 1 P 2 P 3 As defined above; X is a halogen, such as bromine.

[0051] In some embodiments, the compound represented by formula D-1 is selected from...

[0052] In some embodiments, the compound represented by formula D is the compound represented by formula D-2.

[0053] In some embodiments, the method for preparing the compound of formula D-2 or a salt thereof includes the step of reacting the compound of formula C-2 to form the compound of formula D-2.

[0054] Where R 2 P 1 P 2 P 3 As defined above.

[0055] In some embodiments, the method for preparing the compound of formula D-2 or a salt thereof further includes reacting the compound of formula A-2 with a sulfinamide to form the compound of formula B-2, and reacting the compound of formula B-2 with the compound of formula W to form the compound of formula C-2.

[0056] Where R 2 P 1 P 2 P 3 As defined above.

[0057] On the other hand, in some embodiments, the compound shown in formula D is the compound shown in formula D-3. Where R 4 As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0058] In some embodiments, the method for preparing the compound of formula D-3 or a salt thereof includes the step of reacting the compound of formula C-3 to form the compound of formula D-3.

[0059] Where R 2 P 1 P 2 P 3 As defined above; R 4 As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0060] In some embodiments, the method for preparing the compound of formula D-3 or a salt thereof further includes reacting the compound of formula A-3 with a sulfonamide to form the compound of formula B-3, and reacting the compound of formula B-3 with the compound of formula W to form the compound of formula C-3.

[0061] Where R 2 P 1 P 2 P 3As defined above; R 4 R 4a As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0062] In some embodiments, the compound represented by formula D-3 is selected from...

[0063] On the other hand, in some implementation schemes, P in the compound shown in formula C 1 P 2 Each was independently selected from C 1-3 Alkyl groups, such as methyl groups.

[0064] In some implementation schemes, P is present in the compound shown in formula C. 1 P 2 Each was independently selected from C 1-3 Acyl groups, such as acetyl groups.

[0065] In other implementations, P is present in the compound of formula C. 1 P 2 Each was independently selected from P 1 P 2 Together with adjacent atoms, they form 5-6 membered heterocyclic alkyl groups.

[0066] In some implementation schemes, R in the compound of formula C 2 Selected from methyl or ethyl.

[0067] In some implementation schemes, R in the compound of formula C 2 Selected from phenyl or naphthyl.

[0068] In some implementation schemes, P is present in the compound of formula C. 3 It is selected from methyl, ethyl, isopropyl or tert-butyl.

[0069] In some embodiments, the compounds represented by formula C or C-1 are selected from... Where X is a halogen, such as bromine.

[0070] In some implementation schemes, the compounds represented by formula C or C-2 are selected from...

[0071] Some embodiments show compounds represented by formula C or C-3 selected from... R 4 As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0072] Some embodiments show compounds represented by formula C or C-3 selected from...

[0073] In some embodiments, the method for preparing the compound of formula D-1 or a salt thereof includes the step of reacting the compound of formula C-1a under acidic conditions to form the compound of formula D-1.

[0074] X is selected from halogens, such as bromine.

[0075] In some embodiments, the method for preparing the compound of formula D-1 or a salt thereof includes the step of reacting the compound of formula C-1b under acidic conditions to form the compound of formula D-1.

[0076] X is selected from halogens, such as bromine.

[0077] In some embodiments, the method for preparing the compound of formula D-1 or a salt thereof includes the steps of reacting the compound of formula A-1a with R-tert-butylsulfinamide to form the compound of formula B-1a, and reacting the compound of formula B-1a with tert-butyl acetoacetate to form the compound of formula C-1a.

[0078] Where X is a halogen, such as bromine.

[0079] In some embodiments, the method for preparing the compound of formula D-1 or a salt thereof includes the steps of reacting the compound of formula A-1b with R-tert-butylsulfinamide to form the compound of formula B-1b, and reacting the compound of formula B-1b with tert-butyl acetoacetate to form the compound of formula C-1b.

[0080] Where X is a halogen, such as bromine.

[0081] On the other hand, the method for preparing the compound shown in formula D-2 or a salt thereof includes the step of reacting the compound shown in formula C-2a under acidic conditions to form the compound shown in formula D-2.

[0082]

[0083] In some embodiments, the method for preparing the compound of formula D-2 or a salt thereof includes the step of reacting the compound of formula C-2b under acidic conditions to form the compound of formula D-2.

[0084]

[0085] In some embodiments, the method for preparing the compound of formula D-2 or a salt thereof includes the steps of reacting the compound of formula A-2a with R-tert-butylsulfinamide to form the compound of formula B-2a, and reacting the compound of formula B-2a with tert-butyl acetoacetate to form the compound of formula C-2a.

[0086]

[0087] In some embodiments, the method for preparing the compound of formula D-2 or a salt thereof includes the steps of reacting the compound of formula A-2b with R-tert-butylsulfinamide to form the compound of formula B-2b, and reacting the compound of formula B-2b with tert-butyl acetoacetate to form the compound of formula C-2b.

[0088]

[0089] In other embodiments, the method for preparing the compound of formula D-3 or a salt thereof includes the step of reacting the compound of formula C-3a under acidic conditions to form the compound of formula D-3.

[0090] R 4 As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0091] In some embodiments, the method for preparing the compound of formula D-3 or a salt thereof includes the steps of reacting the compound of formula A-3a with R-tert-butylsulfinamide to form the compound of formula B-3a, and reacting the compound of formula B-3a with tert-butyl acetoacetate to form the compound of formula C-3a.

[0092] Where R 4 R 4a As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0093] Another aspect of this disclosure provides a method for preparing the compound of formula G or a salt thereof.

[0094] The method includes the steps described above for preparing the compound of formula D or its salt.

[0095] In some embodiments, the method for preparing the compound of formula G or a salt thereof further includes the step of converting the compound of formula D into the compound of formula G.

[0096] Where R 1 Z, Y are defined as shown in the compound of formula C; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0097] In some embodiments, a method for preparing the compound of formula G or a salt thereof includes the steps of reacting the compound of formula D in the presence of a reducing agent to form the compound of formula E, reacting the compound of formula E with an amino protecting agent to form the compound of formula F, and reacting the compound of formula F with an alkylating agent to form the compound of formula G.

[0098] Where R 1 Z, Y are defined as shown in the compound of formula C; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0099] In some embodiments, a compound of formula E or a salt thereof reacts with an amino protecting agent under basic conditions to form a compound of formula F or a salt thereof, wherein the base includes, but is not limited to, triethylamine, isopropylamine, imidazole, or pyridine. Specific procedures are described in Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th edition, 2006, and the relevant content is incorporated herein by reference.

[0100] In some implementations, the amino protecting agent is selected from, but not limited to, di-tert-butyl dicarbonate.

[0101] On the other hand, in some other embodiments, the method for preparing the compound of formula G or a salt thereof includes the steps of reacting the compound of formula D with an amino protecting agent to form the compound of formula EL, reacting the compound of formula EL in the presence of a reducing agent to form the compound of formula F, and reacting the compound of formula F with an alkylating agent to form the compound of formula G.

[0102] Where R 1 Z, Y are defined as shown in the compound of formula C; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0103] In some embodiments, a compound of formula D or a salt thereof reacts with an amino protecting agent under organic base conditions to form a compound of formula F or a salt thereof, wherein the organic base includes, but is not limited to, triethylamine, isopropylamine, imidazole, or pyridine. Specific operational procedures are described in Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th edition, 2006, and the relevant content is incorporated herein for illustrative purposes.

[0104] In some embodiments, the amount of organic base used is 1 to 3 times the molar amount of the compound shown in Formula D, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0105] In some embodiments, the reducing agent used in the reduction reaction of the compound shown in Formula D is selected from lithium trisec-butylborohydride or (-)diisopinepine chloroborane.

[0106] In some implementations, the amount of reducing agent used is 1 to 3 times the molar amount of the compound shown in Formula D, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0107] In some embodiments, Z is CH and Y is CH in the compound of formula G or its salt.

[0108] In some embodiments, the compound represented by formula G is the compound represented by formula G-1. Where X is selected from halogens, such as bromine; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0109] In some embodiments, the compound represented by formula G-1 is the compound represented by formula G-1a. X is a halogen, such as bromine.

[0110] In some embodiments, the method for preparing the compound of formula G-1 or a salt thereof includes the step of converting the compound of formula D-1 into the compound of formula G-1.

[0111] Where X is selected from halogens, such as bromine; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0112] In some embodiments, the method for preparing the compound of formula G-1 or a salt thereof includes the steps of reacting the compound of formula D-1 in the presence of a reducing agent to form the compound of formula E-1, reacting the compound of formula E-1 with an amino protecting agent to form the compound of formula F-1, and reacting the compound of formula F-1 with an ethylating agent to form the compound of formula G-1.

[0113]

[0114] Where X is selected from halogens, such as bromine; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0115] In some embodiments, the reducing agent used in the reduction reaction of the compound shown in Formula D-1 is selected from lithium trisec-butylborohydride or (-)diisopinepine chloroborane.

[0116] In some implementations, the amount of reducing agent used is 1 to 3 times the molar amount of the compound shown in Formula D-1, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0117] In some embodiments, the ethylating agent includes a haloethane (e.g., iodoethane) or diethyl sulfate. The ethylation reaction is carried out under basic conditions, wherein the base (1) is selected from, but not limited to, sodium tert-butoxide or sodium hydride. For specific procedures / dosages, see WO2023237041 and WO2022143845, the relevant contents of which are incorporated herein for illustrative purposes.

[0118] On the other hand, in some embodiments, the method for preparing the compound of formula G-1a or a salt thereof includes the steps of reacting the compound of formula D-1 in the presence of a reducing agent to form the compound of formula E-1, reacting the compound of formula E-1 with di-tert-butyl dicarbonate to form the compound of formula F-1a, and reacting the compound of formula F-1a with iodoethane or diethyl sulfate to form the compound of formula G-1.

[0119]

[0120] X is selected from halogens, such as bromine.

[0121] In some embodiments, the compound shown in Formula E-1 reacts with ditert-butyl dicarbonate in the presence of an organic base selected from, but not limited to, triethylamine and N,N-diisopropylethylamine.

[0122] In some embodiments, the amount of organic base used is 1 to 3 times the molar amount of the compound shown in Formula E-1, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0123] In some embodiments, the compound of formula F-1a is reacted with iodoethane under sodium tert-butyl or sodium hydride conditions to introduce an ethyl group. For specific procedures / dosages, see WO2022143845, the relevant content of which is incorporated herein for illustration.

[0124] In some embodiments, the method for preparing the compound of formula G-1 or a salt thereof includes the steps of reacting the compound of formula D-1 with an amino protecting agent to form the compound of formula E-1L, reacting the compound of formula E-1L with a reducing agent to form the compound of formula F-1, and reacting the compound of formula F-1 with an ethylating agent to form the compound of formula G-1.

[0125]

[0126] Where X is selected from halogens, such as bromine; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0127] In some embodiments, the method for preparing the compound of formula G-1a or a salt thereof includes the steps of reacting the compound of formula D-1 with di-tert-butyl dicarbonate to form the compound of formula E-1La, reacting the compound of formula E-1La in the presence of a reducing agent to form the compound of formula F-1a, and reacting the compound of formula F-1a with iodoethane or diethyl sulfate to form the compound of formula G-1a.

[0128]

[0129] X is selected from halogens, such as bromine.

[0130] In some embodiments, the compound shown in Formula D-1 reacts with ditert-butyl dicarbonate in the presence of an organic base selected from, but not limited to, triethylamine and N,N-diisopropylethylamine.

[0131] In some embodiments, the reducing agent used in the reduction reaction of the compound represented by formula E-1La is selected from lithium trisec-butylborohydride or (-)diisopinepine chloroborane.

[0132] In some embodiments, the compound represented by formula F-1a reacts with iodoethane under sodium tert-butyl or sodium hydride conditions. For specific procedures / dosages, please refer to WO2022143845, the relevant content of which is incorporated herein for illustrative purposes.

[0133] In other embodiments, the compound represented by formula G is the compound represented by formula G-2. Where P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0134] In some embodiments, the compound represented by formula G-2 is the compound represented by formula G-2a.

[0135] In some embodiments, the method for preparing the compound of formula G-2 or a salt thereof includes the step of converting the compound of formula D-2 into the compound of formula G-2.

[0136] Where P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0137] In some embodiments, the method for preparing the compound of formula G-2 or a salt thereof includes the steps of reacting the compound of formula D-2 in the presence of a reducing agent to form the compound of formula E-2, reacting the compound of formula E-2 with an amino protecting agent to form the compound of formula F-2, and reacting the compound of formula F-2 with an ethylating agent to form the compound of formula G-2.

[0138]

[0139] Where P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0140] In some embodiments, the method for preparing the compound of formula G-2a or a salt thereof includes the steps of reacting the compound of formula D-2 in the presence of a reducing agent to form the compound of formula E-2, reacting the compound of formula E-2 with di-tert-butyl dicarbonate to form the compound of formula F-2a, and reacting the compound of formula F-2a with iodoethane or diethyl sulfate to form the compound of formula G-2a.

[0141]

[0142] In some embodiments, the reducing agent used in the reduction reaction of the compound shown in Formula D-2 is selected from lithium trisec-butylborohydride or (-)diisopinepine chloroborane.

[0143] In some implementations, the amount of reducing agent used is 1 to 3 times the molar amount of the compound shown in Formula D-2, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0144] In some embodiments, the ethylating agent includes a haloethane (e.g., iodoethane) or diethyl sulfate. The ethylation reaction is carried out under basic conditions, wherein the base (1) is selected from, but not limited to, sodium tert-butoxide or sodium hydride. For specific procedures / dosages, see WO2023237041 and WO2022143845, the relevant contents of which are incorporated herein for illustrative purposes.

[0145] In some embodiments, the compound shown in Formula E-2 reacts with ditert-butyl dicarbonate in the presence of an organic base selected from, but not limited to, triethylamine and N,N-diisopropylethylamine.

[0146] In some embodiments, the amount of organic base used is 1 to 3 times the molar amount of the compound shown in Formula E-2, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0147] In some embodiments, the compound shown in formula F-2a is reacted with iodoethane under sodium tert-butyl or sodium hydride conditions. For specific procedures / dosages, please refer to WO2022143845, the relevant content of which is incorporated herein for illustrative purposes.

[0148] In some embodiments, the method for preparing the compound of formula G-2 or a salt thereof includes the steps of reacting the compound of formula D-2 with an amino protecting agent to form the compound of formula E-2L, reacting the compound of formula E-2L with a reducing agent to form the compound of formula F-2, and reacting the compound of formula F-2 with an ethylating agent to form the compound of formula G-2.

[0149]

[0150] Where P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0151] In some embodiments, the method for preparing the compound of formula G-2a or a salt thereof includes the steps of reacting the compound of formula D-2 with di-tert-butyl dicarbonate to form the compound of formula E-2La, reacting the compound of formula E-2La in the presence of a reducing agent to form the compound of formula F-2a, and reacting the compound of formula F-2a with iodoethane or diethyl sulfate to form the compound of formula G-2a.

[0152]

[0153] In some embodiments, the compound shown in formula D-2 reacts with ditert-butyl dicarbonate in the presence of an organic base selected from, but not limited to, triethylamine and N,N-diisopropylethylamine.

[0154] In other embodiments, the compound represented by formula G is the compound represented by formula H-1. Where R 4 As defined in compounds of formula C, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0155] In some embodiments, the compound represented by formula H-1 is of formula Ha.

[0156] In some embodiments, the compound represented by formula H-1 is selected from...

[0157] In some embodiments, the method for preparing the compound of formula H-1 or a salt thereof includes the step of converting the compound of formula D-3 into the compound of formula H-1.

[0158] Where P 4 Amino protecting groups, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl; R 4 As defined in compounds of formula C, such as methyl, ethyl, isopropyl, or tert-butyl.

[0159] In some embodiments, the method for preparing the compound of formula H-1 or a salt thereof includes the steps of reacting the compound of formula D-3 in the presence of a reducing agent to form the compound of formula E-3, reacting the compound of formula E-3 with an amino protecting agent to form the compound of formula F-3, and reacting the compound of formula F-3 with an ethylating agent to form the compound of formula H-1.

[0160] Where R 4 As defined in the compound shown in formula C; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0161] In some embodiments, the ethylating agent includes a haloethane (e.g., iodoethane) or diethyl sulfate. The ethylation reaction is carried out under basic conditions, wherein the base (1) is selected from, but not limited to, sodium tert-butoxide or sodium hydride. For specific procedures / dosages, see WO2023237041 and WO2022143845, the relevant contents of which are incorporated herein for illustrative purposes.

[0162] In some embodiments, the method for preparing the compound of formula H-1 or a salt thereof includes the steps of reacting the compound of formula D-3 in the presence of a reducing agent to form the compound of formula E-3, reacting the compound of formula E-3 with di-tert-butyl dicarbonate to form the compound of formula F-3a, and reacting the compound of formula F-3a with iodoethane or diethyl sulfate to form the compound of formula H-1a.

[0163] Where R 4 Defined in the compound shown in Formula C.

[0164] In some embodiments, the compound shown in Formula E-3 reacts with ditert-butyl dicarbonate in the presence of an organic base selected from, but not limited to, triethylamine and N,N-diisopropylethylamine.

[0165] In some embodiments, the amount of organic base used is 1 to 3 times the molar amount of the compound shown in Formula E-3, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0166] In some embodiments, the compound shown in formula F-3a reacts with iodoethane under sodium tert-butyl or sodium hydride conditions. For specific procedures / dosages, please refer to WO2022143845, the relevant content of which is incorporated herein for illustrative purposes.

[0167] In some embodiments, the method for preparing the compound of formula H-1 or a salt thereof includes the steps of reacting the compound of formula D-3 with an amino protecting agent to form the compound of formula E-3L, reacting the compound of formula E-3L with a reducing agent to form the compound of formula F-3, and reacting the compound of formula F-3 with an ethylating agent to form the compound of formula H-1.

[0168]

[0169] Where R 4 As defined in the compound shown in formula C; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0170] In some embodiments, the method for preparing the compound shown in G or a salt thereof includes the following steps:

[0171] a) The compound shown in formula C reacts under acidic conditions to form the compound shown in formula D.

[0172] b) The compound shown in formula D reacts in the presence of a reducing agent to form the compound shown in formula E.

[0173] c) The compound shown in formula E reacts with an amino protecting agent to form the compound shown in formula F, and,

[0174] d) The compound shown in formula F reacts with an alkylating agent to form the compound shown in formula G.

[0175]

[0176] In some embodiments, the method for preparing the compound shown in G-1a or a salt thereof includes the following steps:

[0177] a) The compound shown in formula C-1a reacts under acidic conditions to form the compound shown in formula D-1.

[0178] b) The compound shown in formula D-1 reacts with the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-1.

[0179] c) The compound shown in formula E-1 reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-1a, and,

[0180] d) The compound shown in formula F-1a reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-1a.

[0181] Where X is a halogen, such as bromine or chlorine.

[0182] In some embodiments, the method for preparing the compound shown in G-2a or a salt thereof includes the following steps:

[0183] a) The compound shown in formula C-2a reacts under acidic conditions to form the compound shown in formula D-2.

[0184] b) The compound shown in formula D-2 reacts with the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-2.

[0185] c) The compound shown in formula E-2 reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-2a, and,

[0186] d) The compound shown in formula F-2a reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-1a.

[0187]

[0188] In some embodiments, the method for preparing the compound shown in H-1a or a salt thereof includes the following steps:

[0189] a) The compound shown in formula C-3a reacts under acidic conditions to form the compound shown in formula D-3.

[0190] b) The compound shown in formula D-3 reacts in the presence of the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-3.

[0191] c) The compound shown in formula E-3 reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-3a, and,

[0192] d) The compound shown in formula F-3a reacts with iodoethane or diethyl sulfate to form the compound shown in formula H-1a.

[0193] Where R 4 C 1-6Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl.

[0194] This disclosure also provides a method for preparing the compound of formula I or a salt thereof.

[0195] Z and Y are each independently selected from CH and N; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; R 7 Selected from hydrogen, 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 groups.

[0196] The method includes the steps of the aforementioned method for preparing the compound of formula D or its salt, and / or the steps of the aforementioned method for preparing the compound of formula G or its salt.

[0197] In some embodiments, Z is CH and Y is CH in the compound of Formula I or its salt.

[0198] In some embodiments, the method for preparing the compound of formula I or a salt thereof further includes the step of converting the compound of formula G into the compound of formula I.

[0199] Z and Y are each independently selected from CH and N; R 1 Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4 and -CONR 5 R 6 ;R 4 Selected from 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 5 R 6 Each is independently selected from hydrogen 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 groups;

[0200] R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 alkyl;

[0201] P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0202] In some embodiments, Z is CH and Y is CH in the compound of Formula I or its salt.

[0203] In some embodiments, the compound represented by Formula I is the same as the compound represented by Formula II-1. Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl.

[0204] In some embodiments, the compound represented by Formula II-1 is selected from...

[0205] In some embodiments, the compound represented by Formula I is compound II-2.

[0206] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the step of removing the amino protecting group from the compound of formula H-1 to form the compound of formula I.

[0207] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0208] The conditions for removing the amino protecting group disclosed herein are selected according to the type of protecting group. See the corresponding conditions for removing the protecting group 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 of formula H-1 or its salt is deamino protecting the -Boc under acid (1) conditions, wherein the acid (1) is selected from trifluoroacetic acid, acetic acid or hydrochloric acid.

[0209] In some embodiments, the compound of formula H-1 or its salt is deprotected under metal reducing conditions such as hydrogen / Pd / c by removing the amino protecting group -Bn or -Cbz.

[0210] On the one hand, in some embodiments, the method for preparing the compound of formula II-1 or a salt thereof further includes the step of converting the compound of formula G-1 into the compound of formula H-1.

[0211] Where X is a halogen, such as bromine; R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0212] In some embodiments, the compound shown in formula G-1 reacts with carbon monoxide in the presence of divalent palladium to form the compound shown in formula H-1, wherein the divalent palladium is selected from, but is not limited to, palladium acetate, palladium chloride, or Pd(dppf)Cl2.

[0213] In some embodiments, the compound shown in formula G-1 reacts with carbon monoxide in the presence of palladium acetate or Pd(dppf)Cl2 to form the compound shown in formula H-1. For specific procedures, see WO2022218429A (Example 5) and WO2022143845A (Example 3), the relevant contents of which are incorporated herein by reference. The solvent used in the aforementioned reactions is selected from fatty alcohols, such as methanol or ethanol.

[0214] In some embodiments, the compound represented by formula H-1 is selected from...

[0215] In some embodiments, the compound represented by Formula II-1 is selected from...

[0216] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the steps of converting the compound of formula G-1 into the compound of formula H-1, and removing the amino protecting group from the compound of formula H-1 to form the compound of formula II-1.

[0217] Where X is a halogen, such as bromine; R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0218] In other embodiments, the compound shown in formula G-1 reacts with carbon dioxide in the presence of a Grignard reagent and / or an organolithium reagent to form the compound shown in formula II-2. Or its salt.

[0219] In some embodiments, the Grignard reagent is selected from, but not limited to, isopropyl magnesium chloride, cyclohexyl magnesium chloride, methyl magnesium chloride, ethyl magnesium chloride, isopropyl magnesium bromide, cyclohexyl magnesium bromide, methyl magnesium bromide, and ethyl magnesium bromide.

[0220] In other embodiments, the organolithium reagent is selected from, but not limited to, n-butyllithium, tert-butyllithium, isobutyllithium, phenyllithium, methyllithium, diisopropylaminolithium, and bis(trimethylsilyl)aminolithium.

[0221] In some embodiments, the compound shown in Formula G-1 reacts with carbon dioxide in the presence of isopropyl magnesium chloride (i-PrMgCl) / n-butyllithium (n-BuLi) to form the compound shown in Formula II-2. Or its salt.

[0222] Furthermore, the compound shown in Formula II-2 or its salt reacts with C 1-6 Fatty alcohols react to form compounds with the corresponding formula H-1.

[0223] In some embodiments, the compound shown in Formula II-2 or its salt reacts with methanol in the presence of thionyl chloride to form the corresponding methyl ester compound.

[0224] In some embodiments, the compound shown in Formula II-2 or its salt reacts with ethanol in the presence of thionyl chloride to form the corresponding ethyl ester compound.

[0225] In some embodiments, the compound shown in Formula II-2 or its salt reacts with tert-butanol in the presence of thionyl chloride to form the corresponding tert-butyl ester compound.

[0226] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the steps of converting the compound of formula G-1 to the compound of formula HZ, subjecting the compound of formula HZ to esterification to form the compound of formula H-1, and removing the amino protecting group from the compound of formula H-1 to form the compound of formula II-1.

[0227] Where X is a halogen, such as bromine; R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0228] On the other hand, some methods for preparing the compound shown in Formula II-1 or its salts also include the step of converting the compound shown in Formula G-2 into the compound shown in Formula H-1.

[0229] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0230] In some embodiments, the compound shown in formula G-2 undergoes a hydrolysis reaction to form the compound shown in formula H-Z1, and the compound shown in formula H-Z1 is converted into the compound shown in formula H-1.

[0231] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0232] In some embodiments, the compound shown in formula H-Z1 is in sulfone chloride / C 1-6 The reaction in the presence of fatty alcohols forms the compound shown in formula H-1.

[0233] In some embodiments, the compounds shown in formula H-Z1 react in the presence of sulfone chloride / methanol to form methyl ester compounds.

[0234] In some embodiments, the compounds shown in formula H-Z1 react in the presence of sulfone chloride / ethanol to form ethyl ester compounds.

[0235] In some embodiments, the compounds shown in formula H-Z1 react in the presence of dimethylformamide dimethyl acetal (DMFDMA) / methanol to form methyl ester compounds.

[0236] In some embodiments, the compound shown in formula G-2 reacts in the presence of hydrogen peroxide / potassium carbonate to form the compound shown in formula H-Z1.

[0237] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the steps of converting the compound of formula G-2 into the compound of formula H-1, and removing the amino protecting group from the compound of formula H-1 to form the compound of formula II-c.

[0238] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0239] In other embodiments, the compound of formula G-2 undergoes hydrolysis to form the compound of formula HZ, and formula HZ undergoes esterification to form the compound of formula H-1.

[0240] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0241] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the following steps:

[0242] a) The compound shown in formula C-1 reacts under acidic conditions to form the compound shown in formula D-1.

[0243] b) The compound shown in formula D-1 is reduced in the presence of a reducing agent to form the compound shown in formula E-1.

[0244] c) The compound shown in formula E-1 reacts with an amino protecting agent to form the compound shown in formula F-1.

[0245] d) The compound shown in formula F-1 reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-1.

[0246] e) The compound shown in formula G-1 is converted into the compound shown in formula H-1.

[0247] f) The compound shown in formula H-1 is deamino protected to form the compound shown in formula II-1.

[0248]

[0249] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the following steps:

[0250] a) The compound shown in formula C-1 reacts under acidic conditions to form the compound shown in formula D-1.

[0251] b) The compound shown in formula D-1 is reduced in the presence of a reducing agent to form the compound shown in formula E-1.

[0252] c) The compound shown in formula E-1 reacts with an amino protecting agent to form the compound shown in formula F-1.

[0253] d) The compound shown in formula F-1 reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-1.

[0254] e) The compound shown in formula G-1 is converted into the compound shown in formula HZ.

[0255] f) The compound shown in formula HZ undergoes an esterification reaction to form the compound shown in formula H-1, and the compound shown in formula H-1 undergoes the removal of an amino protecting group to form the compound shown in formula II-1.

[0256]

[0257] In some embodiments, the method for preparing the compound of formula II-1a or a salt thereof includes the following steps:

[0258] a) The compound shown in formula C-1a reacts under acidic conditions to form the compound shown in formula D-1.

[0259] b) The compound shown in formula D-1 reacts with the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-1.

[0260] c) The compound shown in formula E-1 reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-1a.

[0261] d) The compound shown in formula F-1a reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-1a.

[0262] e) The compound shown in formula G-1a reacts with carbon dioxide in the presence of isopropyl magnesium chloride (i-PrMgCl) / n-butyllithium (n-BuLi) to form the compound shown in formula H-Za.

[0263] f) The compound shown in formula H-Za undergoes esterification in the presence of sulfone chloride / methanol to form the compound shown in formula H-1a, and the compound shown in formula H-1a is deamino-protected to form the compound shown in formula II-1.

[0264]

[0265] In other embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the following steps:

[0266] a) The compound shown in formula C-2 or its salt reacts under acidic conditions to form the compound shown in formula D-2 or its salt.

[0267] b) The compound shown in formula D-2 is reduced in the presence of a reducing agent to form the compound shown in formula E-2.

[0268] c) The compound shown in formula E-2 reacts with an amino protecting agent to form the compound shown in formula F-2.

[0269] d) The compound shown in formula F-2 reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-2.

[0270] e) The hydrolysis reaction of the compound shown in G-2 forms the compound shown in H-Z1.

[0271] f) The compound shown in formula H-Z1 is converted into the compound shown in formula H-1.

[0272] g) The compound shown in formula H-1 is deamino protected to form the compound shown in formula II-1.

[0273]

[0274] In other embodiments, the method for preparing the compound of formula II-1a or a salt thereof includes the following steps:

[0275] a) The compound shown in formula C-2a reacts under acidic conditions to form the compound shown in formula D-2.

[0276] b) The compound shown in formula D-2 is reduced in the presence of the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-2.

[0277] c) The compound shown in formula E-2 reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-2a.

[0278] d) The compound shown in formula F-2a reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-2a.

[0279] e) The compound shown in G-2a undergoes a hydrolysis reaction in the presence of hydrogen peroxide / potassium carbonate to form the compound shown in H-Z1a.

[0280] f) The compound of formula H-Z1a in the presence of dimethylformamide dimethyl acetal (DMFDMA) / methanol is the compound of formula H-1a.

[0281] g) The compound shown in formula H-1 is deamino protected to form the compound shown in formula II-1a.

[0282]

[0283] In other embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the following steps:

[0284] a) The compound shown in formula C-3 reacts under acidic conditions to form the compound shown in formula D-3.

[0285] b) The compound shown in formula D-3 is reduced in the presence of a reducing agent to form the compound shown in formula E-3.

[0286] c) The compound shown in formula E-3 reacts with an amino protecting agent to form the compound shown in formula F-3.

[0287] d) The compound shown in formula F-3 reacts with iodoethane or diethyl sulfate to form the compound shown in formula H-1.

[0288] e) The compound shown in formula H-1 is deamino protected to form the compound shown in formula II-1.

[0289]

[0290] In other embodiments, the method for preparing the compound of formula II-1a or a salt thereof includes the following steps:

[0291] a) The compound shown in formula C-3a-a reacts under acidic conditions to form the compound shown in formula D-3a.

[0292] b) The compound shown in formula D-3a is reduced in the presence of the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-3.

[0293] c) The compound shown in formula E-3 reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-3a.

[0294] d) The compound shown in formula F-3a reacts with iodoethane or diethyl sulfate to form the compound shown in formula H-1a.

[0295] e) The compound shown in formula H-1a is deamino protecting to form the compound shown in formula II-1a.

[0296]

[0297] In other embodiments, the method for preparing the compound of formula II-1a or a salt thereof includes the following steps:

[0298] a) The compound shown in formula C-3a-b reacts under acidic conditions to form the compound shown in formula D-3b.

[0299] b) The compound shown in formula D-3b is reduced in the presence of the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-3b.

[0300] c) The compound shown in formula E-3b reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-3b.

[0301] d) The compound shown in formula F-3b reacts with iodoethane or diethyl sulfate to form the compound shown in formula H-1b.

[0302] e) The compound of formula H-1b hydrolyzes in the presence of a base (2) to form the compound of formula H-Za, wherein the base (2) is selected from, but is not limited to, lithium hydroxide or sodium hydroxide.

[0303] f) The compound shown in formula H-Za undergoes esterification in the presence of sulfone chloride / methanol to form the compound shown in formula H-1a, and the compound shown in formula H-1a is deamino-protected to form the compound shown in formula II-1a.

[0304]

[0305] In other embodiments, the method for preparing the compound of formula II-1a or a salt thereof includes the following steps:

[0306] a) The compounds shown in formula C-3a-c react under acidic conditions to form the compound shown in formula D-3c.

[0307] b) The compound shown in formula D-3c is reduced in the presence of the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-3c.

[0308] c) The compound shown in formula E-3c reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-3c.

[0309] d) The compound shown in formula F-3c reacts with iodoethane or diethyl sulfate to form the compound shown in formula H-1c.

[0310] e) The compound of formula H-1c hydrolyzes in the presence of a base (2) to form the compound of formula H-Za, wherein the base (2) is selected from, but is not limited to, lithium hydroxide, potassium hydroxide, or sodium hydroxide.

[0311] f) The compound shown in formula H-Za undergoes esterification in the presence of sulfone chloride / methanol to form the compound shown in formula H-1a, and the compound shown in formula H-1a is deamino-protected to form the compound shown in formula II-1a.

[0312]

[0313] In other embodiments, the method for preparing the compound of formula II-1a or a salt thereof includes the following steps:

[0314] a) The compound shown in formula C-3a-d reacts under acidic conditions to form the compound shown in formula D-3d.

[0315] b) The compound shown in formula D-3d is reduced in the presence of the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-3d.

[0316] c) The compound shown in formula E-3d reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-3d.

[0317] d) The compound shown in formula F-3d reacts with iodoethane or diethyl sulfate to form the compound shown in formula H-1d.

[0318] e) The compound shown in formula H-1d hydrolyzes in the presence of a base (2) to form the compound shown in formula H-Za, wherein the base (2) is selected from, but is not limited to, lithium hydroxide or sodium hydroxide.

[0319] f) The compound shown in formula H-Za undergoes esterification in the presence of sulfone chloride / methanol to form the compound shown in formula H-1a, and the compound shown in formula H-1a is deamino-protected to form the compound shown in formula II-1a.

[0320]

[0321] The esterification and deprotection steps of the compounds represented by formula H-Za are not sequential. For example, esterification followed by deprotection of the compound represented by formula H-Za, or deprotection followed by esterification of the compound represented by formula H-Za, can yield the target product, such as compound II-1a. In some embodiments, deprotection and esterification can be performed in a one-pot process without separation steps.

[0322] On the other hand, this disclosure also provides the following compounds or salts thereof, said compounds being selected from:

[0323] Z and Y are each independently selected from CH and N;

[0324] R 1 Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4 and -CONR 5 R 6 ;

[0325] R 2 Selected from C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0326] R 4 Selected from 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 5 R 6 Each is independently selected from hydrogen 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 groups;

[0327] P 1 P 2 Each is independently selected from C 1-3 Alkyl and C 1-3 Acyl group, the C 1-3 Alkyl or C 1-3 The acyl group may be optionally substituted with one or more halogens or phenyl groups, or P 1 P 2Together with adjacent atoms, they form a 5-6 membered heterocyclic alkyl group, which is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl groups are substituted;

[0328] P 3 Selected from 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.

[0329] In some embodiments, the compound represented by Formula A is selected from... Where X is selected from halogens, such as bromine; P 1 P 2 Each is independently selected from C 1-3 Alkyl and C 1-3 Acyl group, the C 1-3 Alkyl or C 1-3 The acyl group may be optionally substituted with one or more halogens or phenyl groups, or P 1 P 2 Together with adjacent atoms, they form a 5-6 membered heterocyclic alkyl group, which is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl groups are substituted;

[0330] R 4a Selected from 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.

[0331] In some embodiments, the compound represented by formula A is selected from... X is selected from halogens, such as bromine.

[0332] In some embodiments, the compound represented by formula B is selected from... Where X is selected from halogens, such as bromine; P 1 P 2 Each is independently selected from C 1-3 Alkyl and C 1-3 Acyl group, the C 1-3 Alkyl or C 1-3 The acyl group may be optionally substituted with one or more halogens or phenyl groups, or P 1 P 2 Together with adjacent atoms, they form a 5-6 membered heterocyclic alkyl group, which is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl groups are substituted;

[0333] R 2 Selected from C 1-6 Alkyl, C6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0334] R 4 Selected from 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.

[0335] In some embodiments, the compound represented by formula B is selected from... X is selected from halogens, such as bromine.

[0336] In some embodiments, the compound represented by formula C is selected from... Where X is selected from halogens, such as bromine; P 1 P 2 Each was independently selected from C 1-3 Alkyl and C 1-3 Acyl group, the C 1-3 Alkyl or C 1-3 The acyl group may be optionally substituted with one or more halogens or phenyl groups, or P 1 P 2 Together with adjacent atoms, they form a 5-6 membered heterocyclic alkyl group, which is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl groups are substituted;

[0337] P 3 Selected from 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 groups;

[0338] R 2 Selected from C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0339] R 4 Selected from 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.

[0340] In some embodiments, the compound represented by formula D is selected from... Where X is selected from halogens, such as bromine; R 4 Selected from 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.

[0341] In some embodiments, the compound represented by formula E is selected from... Where X is selected from halogens, such as bromine; R 4 Selected from 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.

[0342] This disclosure also provides, in another aspect, steps of the method for preparing the compound of formula D or its salt, or / and the method for preparing the compound of formula G or its salt, or / and the method for preparing the compound of formula I or its salt, or the use of the aforementioned compound or its salt in the preparation of Factor B inhibitors.

[0343] In this disclosure, the Factor B inhibitors are selected from, but are not limited to:

[0344]

[0345] This disclosure also provides a method for preparing compound AA or a salt thereof, the method comprising the steps of the aforementioned methods for preparing the compound of formula D or a salt thereof, the compound of formula G or a salt thereof, and the compound of formula I or a salt thereof.

[0346]

[0347] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting the compound of formula II-1 with the compound of formula DD-1 to form the compound of formula EE.

[0348] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 5 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0349] In some embodiments, the method for preparing compound AA or a salt thereof includes reacting compound II-1a with compound DD-1a in the presence of trimethylchlorosilane, phenylsilane, and pyridine to form compound EE-1a.

[0350] For specific reaction procedures, please refer to WO2023 / 237041 (Example 2), and the relevant content is incorporated herein for illustration.

[0351] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting the compound of formula II-1 with the compound of formula DD-2 to form the compound of formula EE.

[0352] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 5 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0353] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting compound II-1a with compound DD-2a in the presence of triphenylphosphine and carbon tetrachloride to form a compound shown in formula EE-b.

[0354] For specific reaction procedures, please refer to WO2022143845A (Example 3), and the relevant content is incorporated herein for illustration.

[0355] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting the compound of formula II-1 with the compound of formula DD-3 to form the compound of formula EE.

[0356] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 5 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl; X1 is selected from halogens, such as bromine.

[0357] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting compound II-1a with compound DD-3a in the presence of a base (4) to form compound EE-c, wherein the base (4) is selected from, but is not limited to, cesium carbonate or potassium carbonate.

[0358] For specific reaction procedures, please refer to WO2022218429A (Example 5), and the relevant content is incorporated herein for illustration.

[0359] In some embodiments, the method for preparing compound AA or its salts further includes a deprotection of the compound represented by formula EE and an ester hydrolysis step. The deprotection step and the ester hydrolysis step may be performed in any order. In some embodiments, the deprotection and ester hydrolysis can be performed in a one-pot process without any separation steps. Example operations are described in WO2022218429A, WO2022143845A, and WO2023 / 237041, the contents of which are incorporated herein by reference.

[0360] This disclosure also provides a method for preparing compound BB or a salt thereof, the method comprising the steps of the aforementioned methods for preparing the compound of formula D or a salt thereof, the compound of formula G or a salt thereof, and the compound of formula I or a salt thereof.

[0361]

[0362] 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.

[0363] "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.

[0364] 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%.

[0365] 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.

[0366] In the chemical structure of the compounds described in this disclosure, the bond " "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " "can be " "or" , or both contain " "and" "Two configurations."

[0367] "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.

[0368] "Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic 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.

[0369] "Aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl. Aryl groups can be substituted or unsubstituted.

[0370] "Heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 6 to 10-membered, such as naphthyl. More preferably, it is 5- or 6-membered. The heteroaryl group can be substituted or unsubstituted.

[0371] "Acyl" refers to -C(O)R a R a Selected from hydrogen or C 1-2 alkyl.

[0372] "Hydroxy" refers to the -OH group.

[0373] “Cyano” refers to the -CN group.

[0374] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0375] "Amino" refers to -NH2.

[0376] The "amino protecting group" disclosed herein is a group known in the art that can be used to protect amino groups, see the amino protecting groups 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).

[0377] 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

[0378] 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.

[0379] 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.

[0380] 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).

[0381] The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (d6-DMSO) as the solvent.

[0382] MS measurements were performed using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer, scanning in positive / negative ion mode, with a mass scan range of 120–1300.

[0383] HPLC column: YMC-Pack ODS-A (3μm, 4.6mm x 150mm)

[0384] 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.

[0385] Example 1: Preparation of Compound 1

[0386]

[0387]

[0388] Step 1:

[0389] Compound 1a (100.16 g, 0.50 mol, purchased from Energie), thionyl chloride (118.97 g, 1.0 mol, purchased from General), and DMF (2 mL, 25.83 mmol) were dissolved in toluene (1000 mL). The mixture was heated and stirred for 4 hours. After the system became clear, it was concentrated to dryness to obtain 112.60 g of pale yellow oily compound 1b.

[0390] Compound 1b (112.60 g, 0.50 mol) was dissolved in 1000 mL of dichloromethane, and N,O-dimethylhydroxylamine hydrochloride (52.52 g, 0.525 mol, purchased from Shaoyuan) and triethylamine (151.88 g, 1.50 mol, purchased from Cologne) were added. The mixture was reacted for 13 hours, and 200 mL of water was added to separate the layers. The organic layer was washed with 200 mL of saturated sodium bicarbonate and then separated again. The organic layer was washed with 200 mL of hydrochloric acid water and then separated again. The organic layer was evaporated to dryness to give 112.70 g of compound 1c (yield 93.11%).

[0391] MS(ESI): m / z 243.9 [M+1] + .

[0392] 1 H NMR (500MHz, DMSO-d6): δ7.67~7.65(d,2H), 7.57~7.56(d,2H), 3.54(s,3H), 3.27(s,3H).

[0393] Step 2:

[0394] Magnesium strip (19.32 g, 0.795 mol, purchased from Sinopharm) was added to a three-necked flask, along with two iodine grains, and protected with nitrogen. 2-(2-bromoethyl)-1,3-dioxane (120.31 g, 0.662 mol, purchased from Leyan) was dissolved in tetrahydrofuran (720 mL). One-tenth of the solution was added to the three-necked flask to initiate the reaction, and then the remaining solution was added dropwise at 20–35 °C. After the addition was complete, the mixture was stirred for 1–2 hours to obtain (1,3-dioxane-2-ethyl)magnesium bromide, which was then set aside.

[0395] Compound 1c (64.69 g, 0.265 mol) was dissolved in 130 mL of tetrahydrofuran and stirred. The Grignard reagent prepared above was added dropwise at 0–10 °C and reacted at this temperature for 1–2 hours. A saturated ammonium chloride aqueous solution was added to separate the layers. The organic layer was evaporated to dryness to obtain a solid. A mixed solvent of ethyl acetate and petroleum ether was added and the mixture was stirred at 25–35 °C for 0.5–1 hour. The mixture was filtered, and the filter cake was dried to obtain 67.93 g of compound 1d (yield 89.89%).

[0396] MS(ESI): m / z 285.1 [M+1] + .

[0397] 1 H NMR (500MHz, DMSO-d6): δ7.90~7.87(d,2H), 7.75~7.72(d,2H), 4.90~4.88(m,1H), 3.89~3.74(m,4H), 3.09~3.06(m,2H), 1.95~1.91(m,2H).

[0398] Step 3:

[0399] Tetraethyl titanate (189.68 g, 0.831 mol, purchased from Adamas), R-tert-butylsulfinamide (43.65 g, 0.360 mol, purchased from Bide), and compound 1d (79.0 g, 0.277 mol) were mixed and stirred at 75 °C for 7–20 hours. Ethyl acetate was added to dilute the reaction mixture, which was then poured into a saturated sodium bicarbonate aqueous solution. The mixture was filtered, and the layers were separated. The organic layer was washed with water and evaporated under reduced pressure to obtain 111.01 g of compound 1e (100% yield), which was used directly in the next step.

[0400] MS(ESI): m / z 389.9 [M+1] + .

[0401] 1 H NMR (500MHz, DMSO-d6): δ7.78~7.68(dd,4H), 4.89~4.87(m,1H), 3.88~3.77(m,4H), 3.33(m,2H), 1.88~1.80(m,2H), 1.21~1.15(m,9H).

[0402] Step 4:

[0403] 74.97 g (0.469 mol) of tert-butyl acetoacetate (purchased from Adamas) was diluted in 150 mL of tetrahydrofuran in a 2000 mL three-necked flask, and the mixture was purged with nitrogen three times. A solution of lithium diisopropylaminoacetate (100.60 g (0.939 mol) was added dropwise to the reaction flask at -10 to 0 °C, and the mixture was stirred for 0.5 to 1 hour. Then, compound 1e (91.17 g (0.234 mol)) was diluted in 450 mL of tetrahydrofuran and added dropwise to the reaction flask at -10 to 0 °C, and the reaction was allowed to proceed for 1 to 2 hours. A saturated ammonium chloride aqueous solution was added to quench the reaction, and the mixture was allowed to separate into layers. The organic layer was washed once with water and then separated again. The organic layer was evaporated under reduced pressure to obtain 179.98 g of compound 1f (yield 140%), which was used directly in the next step.

[0404] MS(ESI): m / z 546.1 [M-1] + .

[0405] Step 5:

[0406] Compound 1f (168.0 g, 0.307 mol) was dissolved in 800 mL of ethanol and added to a 2000 mL three-necked flask. 300 mL of concentrated hydrochloric acid solution (336 g, 3.36 mol, purchased from Cologne) was added to the reaction flask. The mixture was stirred at 50 °C for 8–28 hours. The reaction solution was then evaporated to dryness under reduced pressure. 800 mL of dichloromethane was added to dissolve the solution. The pH was adjusted to 9–10 with sodium hydroxide aqueous solution, and the mixture was allowed to separate into layers. The dichloromethane was evaporated to dryness, and the solution was dissolved in ethyl acetate. Ethyl hydrochloride solution was added and stirred to form a salt. The mixture was filtered, and the filter cake was dried to obtain 52.36 g of 1 g of compound hydrochloride (yield 54.34%).

[0407] MS(ESI): m / z 281.7 [M+1] + .

[0408] 1 H NMR (500MHz, DMSO-d6): δ11.49(s,1H),10.34(s,1H),7.70~7.60(dd,4H),4.39(m,1H),3.29~3.25(m ,1H),3.13~3.09(m,1H),2.76~2.72(m,1H),2.56~2.50(m,2H),2.30~2.22(m,2H),1.91~1.86(m,1H).

[0409] Step 6:

[0410] 1 g of the compound hydrochloride (27.0 g, 85 mmol) was suspended in 250 mL of dichloromethane in a 500 mL three-necked flask. The pH of the aqueous phase was adjusted to 9-10 with 2N sodium hydroxide aqueous solution. The layers were then separated, and the dichloromethane layer was evaporated under reduced pressure to obtain 24.22 g of the compound.

[0411] 1 g (20.12 g, 71.4 mmol) of the above-mentioned free compound was dissolved in 200 mL of tetrahydrofuran, and (-)diisopinepine chloroborane (85 mL, 142.8 mmol, purchased from Adamas) was added dropwise. After the addition was complete, the mixture was stirred at room temperature until the reactants had reacted completely. Water was added, and the mixture was separated into layers. The pH of the aqueous layer was adjusted to 9-10 with 2N sodium hydroxide. Ethyl acetate was added for extraction, and the ethyl acetate layer was evaporated to dryness under reduced pressure. The mixture was then stirred with n-heptane and filtered to obtain 19.42 g of the compound for 1 h (yield 96.32%).

[0412] MS(ESI): m / z 283.7 [M+1] + .

[0413] 1H NMR (500MHz, DMSO-d6): δ7.49~7.47(d,2H),7.34~7.32(d,2H),4.49(m,1H),3.97~3.96(m,1H),3.51~3.4 9(m,1H),2.64~2.60(m,1H),2.19~2.14(m,1H),1.93~1.90(m,1H),1.82~1.75(m,4H),1.70~1.51(m,1H).

[0414] Step 7:

[0415] Compound 1h (21.90 g, 77.6 mmol) was dissolved in 220 mL of tetrahydrofuran, and 13.83 g (13.04 g, 100.9 mmol, purchased from Kolomb) of N,N-diisopropylethylamine was added, along with 20.33 g (93.1 mmol, purchased from Leyen). The mixture was stirred at room temperature for 18 hours. 100 mL of dilute hydrochloric acid was added to the reaction solution, and the mixture was allowed to separate into layers. The organic layer was washed once with 100 mL of sodium bicarbonate. The organic layer was concentrated under reduced pressure to obtain a pale yellow oily substance. The oily substance was then stirred with n-heptane, filtered, and 25.67 g of compound 1i was obtained (yield 86.52%).

[0416] MS(ESI): m / z 383.9 [M+1] + .

[0417] 1 H NMR (500MHz, DMSO-d6): δ7.47~7.46(d,2H), 7.26~7.24(d,2H), 4.79~4.79(m,1H), 4.27~4.26(m,1H), 4.14(m,1H), 2.65~2.64(m,1H), 2.51~2.49(m,2H), 2.27~2.26(m,3H), 2.06~2.04(m,1H), 1.66~1.64(m,1H), 1.11~1.07(m,9H).

[0418] Step 8:

[0419] Compound 1i (20.42 g, 53.4 mmol) was dissolved in 200 mL of tetrahydrofuran. 200 mL of N,N-dimethylformamide was added, followed by sodium tert-butoxide (30.80 g, 320.48 mmol, purchased from Adamas). Iodoethane (41.65 g, 267.07 mmol, purchased from Adamas) was added dropwise in five portions at -10 to 0 °C, with an interval of 1 hour between additions. After the iodoethane addition was complete, the reaction was carried out at -10 to 0 °C for 27 hours. 200 mL of water was added to the reaction solution, and the layers separated. The organic layer was washed once with 100 mL of water. The organic layer was concentrated under reduced pressure to obtain 22.16 g of a pale yellow oily substance, compound 1j (100% yield).

[0420] MS(ESI): m / z 409.9 [M-1] +

[0421] 1 H NMR (500MHz, DMSO-d6): δ7.47~7.45(d,2H),7.29~7.27(d,2H),4.27~4.25(m,1H),3.79(m,1H), 3.48~3.47(m,2H), 2.51~2.50(m,1H), 2.22~2.19(m,1H), 1.93~1.78(m,6H), 1.14~1.07(m,12H).

[0422] Step 9:

[0423] Compound 1j (8.60 g, 20.96 mmol) was dissolved in 77 mL of tetrahydrofuran, purged three times with argon gas, and 2M isopropyl magnesium chloride (7.34 mL, 14.67 mmol, purchased from Anage) was added dropwise while maintaining an internal temperature ≤ -50 °C. The mixture was stirred for 15 minutes, then the temperature was lowered to -60 °C, and 1.6M n-butyllithium (18.34 mL, 29.34 mmol, purchased from Anage) was added dropwise. The mixture was stirred for 1 hour, and carbon dioxide (from a gas cylinder) was introduced while maintaining an internal temperature not exceeding -45 °C. The mixture was stirred for 1 hour. The solution was quenched with 30 mL of purified water, saturated ammonium chloride aqueous solution was added, followed by ethyl acetate. The mixture was separated, and the aqueous phase was extracted again with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness at 30 °C to give 8.17 g of compound 1k (100% yield).

[0424] MS(ESI): m / z 376.0 [M+1] + .

[0425] 1H NMR (500MHz, DMSO-d6): δ12.7(s,1H),7.88~7.86(d,2H),7.46~7.44(d,2H),4.29~4.27(m,1H),3.81~3.80(m,1H) ), 3.50~3.48(m,2H), 2.21~2.18(m,1H), 1.96~1.93(m,5H), 1.15~1.12(m,1H), 1.04(m,11H), 0.98~0.96(m,1H).

[0426] Step 10:

[0427] Compound 1k (14.96 g, 39.8 mmol) was dissolved in 150 mL of methanol, purged three times with argon, and thionyl chloride (6.22 g, 52.2 mmol, purchased from General) was added dropwise while maintaining an internal temperature ≤10 °C. The reaction was carried out at room temperature for 16 hours. A 10% sodium bicarbonate aqueous solution was added, and the mixture was distilled under reduced pressure at 30 °C until no liquid was dripped out (to remove methanol). The remaining aqueous phase was extracted once with dichloromethane, and the organic phase was washed once with saturated brine. The organic phase was concentrated to dryness to give 10.7 g of compound 1 (yield 92.87%).

[0428] MS(ESI): m / z 290.4 [M+1] + .

[0429] 1H NMR (500MHz, DMSO-d6): δ7.91~7.89(d,2H),7.55~7.53(d,2H),3.84(S,3H),3.61~3.49(m,1H),3.43~3.41(m,1H),3.33( S,2H),2.55~2.50(m,1H),2.08~2.01(m,2H),1.79~1.75(m,3H),1.66~1.63(m,1H),1.55~1.52(m,1H),1.19~1.15(m,3H).

[0430] Example 2 Preparation of Compound 1

[0431]

[0432] Step 1:

[0433] Potassium hydroxide (21.66 g, 386 mmol, purchased from Cologne) was added to toluene (825 mL) and methanol (750 mL) in a 2000 mL three-necked flask. The system became clear. Compound 2a (75.00 g, 386 mmol, purchased from Leybold Research Institute), a white suspension, was weighed out. After the addition was complete, the mixture was heated to 40–50 °C and stirred for 21 hours. The mixture was filtered, and the filter cake was washed with methanol and toluene. The filter cake was then suspended in 200 mL of water, and the pH was adjusted to 5–6 with 1 N hydrochloric acid aqueous solution, resulting in the precipitation of a large amount of solid. This solid was filtered, and the filter cake was dried at 45 °C with forced air to obtain 64.42 g of compound 2b (yield 92.58%).

[0434] Step 2:

[0435] 2b (20.50 g, 111 mmol) was added to toluene (100 mL) in a 250 mL three-necked flask; it was insoluble, forming a white suspension. DMF (3 mL, 38.8 mmol, purchased from Krohne Chemicals) was added dropwise to displace the argon gas. Then, thionyl chloride (12.08 mL, 166 mmol, purchased from Shanghai Experimental Chemicals) was added dropwise, causing exothermic reaction. After the addition was complete, the mixture was heated to 50–55 °C and stirred for 3 hours. The reaction solution dissolved completely, and the reaction was quenched with diethylamine. TLC confirmed the reaction was complete. The reaction solution was then directly evaporated to dryness, yielding 18.51 g of a white solid, compound 2c (yield 83.91%). This was used directly in the next step.

[0436] Step 3:

[0437] Add 2c (25.05g, 126mmol) to dichloromethane (250mL) in a three-necked flask, then add methoxymethylamine hydrochloride (14.73g, 151mmol, purchased from Shaoyuan) to displace the argon gas. Stirring was performed, and triethylamine (52.6 mL, 377 mmol, purchased from Anegy) was added dropwise. The mixture was then allowed to rise naturally to room temperature for 2 hours, after which TLC analysis showed the reaction was essentially complete. After adding 1 M HCl, the mixture was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate and then saturated sodium chloride, and concentrated to dryness. The solution was then slurried in 50 mL of EA / PE = 10% to give 27.2 g of a white solid, compound 2d (yield 80.63%).

[0438] MS(ESI): m / z 223.9 [M+1] + .

[0439] 1 H NMR (400MHz, DMSO-d6): δ8.02-8.00(m,2H),7.70-7.68(m,2H),3.87(s,3H),3.52(s,3H),3.26(s,3H).

[0440] Step 4:

[0441] Preparation of Grignard reagent: First, place magnesium strip (6.03g, 248mmol, purchased from Shanghai Test) at the bottom of the bottle, add iodine granules (35mg, 0.12mmol, purchased from Cologne Chemicals), replace the argon gas, and begin to dropwise add 2-(2-bromoethyl)-1,3-dioxane (41.56g, 229mmol, purchased from Adamas) dissolved in 250mL of dry tetrahydrofuran. After the reaction is initiated, control the internal temperature in a cold water bath to not exceed 30℃. After the dropwise addition is complete, react at room temperature for 3 hours and set aside.

[0442] Compound 2d (20.37 g, 91.8 mmol) was dissolved in tetrahydrofuran (100 mL), cooled in a dry ice-ethanol bath, and the prepared Grignard reagent was added dropwise when the temperature was below -60 °C, while maintaining the internal temperature below -50 °C. After the addition was complete, the reaction continued for 3 hours, and TLC showed that the starting material had basically reacted. The reaction solution was poured into a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate, and the organic phases were combined. The mixture was concentrated to dryness, and ethyl acetate (10 mL) and n-hexane (90 mL) were added. The mixture was stirred, filtered, and the filter cake was washed with n-hexane (10 mL). The filter cake was dried to give 16.2 g of compound 2e (yield 83.91%).

[0443] MS(ESI): m / z 265.9 [M+1] + .

[0444] 1 H NMR (400MHz, DMSO-d6): δ8.07(s,4H),4.91-4.88(t,1H),3.89(s,3H),3.88-3.87(m,2H),3.78-3.76(m,2H),3.15-3.12(t,2H),1.97-1.94(m,2H).

[0445] Step 5:

[0446] Compound 2e (15.03 g, 39.44 mmol) was added to tert-butylsulfinamide (8.96 g, 73.93 mmol, purchased from Bide), followed by tetraisopropyl titanate (25.95 g, 113.75 mmol, purchased from Bide). The resulting white, slurry-like reaction solution was purged with argon gas and heated to 66°C. The reaction solution dissolved completely, and the reaction continued at 66°C for 5 hours. HPLC analysis showed that the reaction was essentially complete, and that methyl ester had been almost entirely transesterified to isopropyl ester. After cooling the reaction solution to 27°C, 100 mL of saturated sodium bicarbonate was added while stirring to quench the reaction. Then, 100 mL of ethyl acetate was added, and the mixture was filtered through a diatomaceous earth filter. The filtrate was separated, the organic phase was washed with saturated sodium bicarbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography (PE:EA = 100:0-70:30) to give 15.6 g of compound 2f (yield 90.03%).

[0447] MS(ESI): m / z 396.1 [M+1] + .

[0448] 1 H NMR (400MHz, DMSO-d6): δ8.05-8.01(m,2H),7.96-7.95(m,2H),4.89-4.88(t,1H),4.36-4.33(m,1H),3.8 7-3.86(m,2H),3.78-3.76(m,2H),3.76-3.32(m,2H),1.98-1.88(m,2H),1.34-1.31(m,6H),1.23(s,9H).

[0449] Step 6:

[0450] tert-butyl acetoacetate (599 mg, 3.79 mmol, purchased from Adamas) was dissolved in dry tetrahydrofuran (10 mL), purged with argon, and cooled to -10 °C in an ice-salt bath. 2 M lithium diisopropylamino (3.79 mL, 7.59 mmol, purchased from Adamas) was then added dropwise, and the mixture was stirred at this temperature for 30 min. The reaction solution was transferred to a dry ice-ethanol bath and cooled to -60 °C. Compound 2f (15.03 g, 39.44 mmol) dissolved in dry tetrahydrofuran (10 mL) was then added dropwise, and the reaction continued for 3 hours in a dry ice-ethanol bath. TLC analysis showed that the starting material had largely reacted. The reaction solution was poured into a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate, and the organic phases were combined. The mixture was concentrated to dryness and purified by column chromatography (PE:EA = 100:0-60:40) to give 880 mg of compound 2 g (yield 60.11%).

[0451] MS(ESI): m / z 554.6 [M+1] + .

[0452] Step 7:

[0453] At room temperature, 2 g (1.41 g, 2.60 mmol) was dissolved in dichloromethane (15 mL) in a three-necked flask, purged with argon gas, and trifluoroacetic acid (3 mL, 40.24 mol, purchased from Anegy) was added dropwise. The mixture was stirred and mixed thoroughly, and then heated to 40 °C for 16 hours. Mass spectrometry showed that the starting material had basically reacted completely. The reaction solution was directly evaporated to dryness, and ethyl acetate (30 mL) and saturated sodium chloride solution (20 mL) were added. The mixture was separated, and the organic phase was washed with saturated sodium bicarbonate (20 mL). The absence of obvious bubbles indicated that the trifluoroacetic acid had been washed away. The solution was passed through a silica gel column (MeOH / DCM = 0-15%) to give 820 mg of a yellowish-brown oily compound for 2 hours (yield 48.52%).

[0454] MS(ESI): m / z 288.4 [M+1] + .

[0455] 1 H NMR (400MHz, DMSO-d6): δ7.92-7.90(d,2H),7.61-7.59(d,2H),5.16-5.10(m,1H),3.86-3.88(m,1H),3.17(s,1H),2.63- 2.55(m,2H),2.46-2.42(m,1H),2.24-2.17(m,1H),2.10-1.99(m,2H),1.69-1.68(m,1H),1.55-1.53(m,1H),1.31(d,6H).

[0456] Step 8:

[0457] At room temperature, 2h (1.68 g, 5.85 mmol) was dissolved in tetrahydrofuran (15 mL), argon gas was purged, and the mixture was cooled to -15 °C in an ice-salt bath. (-)-diisopinepine chloroborane (1.7 M, 6.19 mL, 10.52 mol, purchased from Adamas) was added dropwise, with the internal temperature controlled to not exceed -10 °C during addition. After the addition was complete, the reaction continued at this temperature for 4 hours. Liquid chromatography showed complete reaction of the starting material. Saturated sodium bicarbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by silica gel column chromatography (MeOH / DCM = 0-15%) to give 530 mg of a yellowish-brown oily compound 2i (yield 56.01%).

[0458] MS(ESI): m / z 290.4 [M+1]+ .

[0459] 1 H NMR (400MHz, DMSO-d6): δ7.96-7.94(d,2H),7.64-7.62(d,2H),5.20-5.14(m,1H),3.91(m,1H),3.38-3.31(d,2 H),2.67-2.46(m,4H),2.28-2.24(m,1H),2.13-2.01(m,2H),1.73-1.71(m,1H),1.58-1.56(m,1H),1.34(d,6H).

[0460] Step 9:

[0461] At room temperature, 2i (1.01 g, 3.39 mmol) was dissolved in dioxane (15 mL) in a three-necked flask, and diisopropylethylamine (0.91 mL, 5.24 mol, purchased from Kolomb) was added dropwise, followed by stirring. Argon gas was introduced to replace the solution, and di-tert-butyl dicarbonate (914 mg, 4.19 mol, purchased from Leyan) was added dropwise. After the addition was complete, the mixture was stirred at 20–25 °C for 20 hours, and TLC was used to determine the completeness of the reaction. Most of the solvent was removed by concentration. 10 mL of saturated brine and 10 mL of 1N dilute hydrochloric acid were added to the reaction mixture, and the solution was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was then passed through a silica gel column (EA / PE = 0–30%) to give 610 mg of a yellow oily compound 2j (yield 44.87%).

[0462] MS(ESI): m / z 390.1 [M+1] + .

[0463] 1 H NMR (400MHz, DMSO-d6): δ7.88-7.86(d,2H),7.44-7.42(d,2H),5.16-5.10(m,1H),4.82-4.81(d,1H),4.29(s,1H),4.16(s,1H), 2.67-2.65(m,1H),2.34-2.31(m,2H),2.10-1.99(m,3H),1.96-1.83(m,1H),1.69-1.65(m,1H),1.32-1.31(d,6H),1.05(s,9H).

[0464] Step 10:

[0465] At room temperature, sodium tert-butoxide (449 mg, 4.68 mmol, purchased from ADMAS) was added to 10 ml of DMAc, and the mixture was stirred until homogeneous and argon gas was displaced. The mixture was placed in a -10°C cold trap and stirred. At -5°C, 2j (607 mg, 1.56 mol) of the raw material dissolved in 2 ml of DMAc was added dropwise, with the internal temperature controlled below -3°C. After stirring for 20 minutes, iodoethane (729 mg, 4.68 mol, purchased from Haichuan) was added dropwise. Stirring was continued at -10°C for 1 hour, followed by the addition of sodium tert-butoxide (449 mg, 4.68 mmol, purchased from Admas). After stirring for 20 minutes, iodoethane (729 mg, 4.68 mol, purchased from Haichuan) was added dropwise. Stirring was continued at -10°C for 2 hours, followed by the addition of sodium tert-butoxide (225 mg, 2.34 mmol, purchased from Admas). After stirring for 20 minutes, iodoethane (729 mg, 4.68 mol, purchased from Haichuan) was added. TLC was used to confirm the complete reaction of the reactants. 20 ml of 1N dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 623 mg of a yellowish-brown oily compound, 2k, as crude product. Further purification was performed after hydrolysis.

[0466] MS(ESI): m / z 418.1 [M+1] + .

[0467] Step 11:

[0468] At room temperature, a mixture of 2kJ (623 mg, 1.49 mmol) dissolved in 2 ml of methanol and 2 ml of THF was placed in a 10 ml single-necked flask. The mixture was stirred and mixed thoroughly, purged with argon, and cooled in an ice bath (0–5 °C). Lithium hydroxide (107 mg, 4.48 mmol, purchased from Merck) dissolved in 1 ml of water was added dropwise. After the addition was complete, the temperature was slowly raised to 20–25 °C and the mixture was stirred for 20 hours. The reaction mixture was monitored by TLC until the reactants were completely reacted. The reaction mixture was evaporated to dryness, and 10 ml of 1N dilute hydrochloric acid was added. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 603 mg of a pale yellow solid compound. The compound was passed through a silica gel column (EA / PE = 30%–60%) to give 460 mg of a pale yellow oil, 1n (yield 82.11%).

[0469] MS(ESI): m / z 374.1 [M-1] - .

[0470] Step 12:

[0471] At room temperature, 2 kJ (460 mg, 1.23 mmol) was dissolved in 3 mL of methanol in a 10 mL single-necked flask, purged with argon gas, stirred until homogeneous, and cooled to -5 to 0 °C in an ice-salt bath. Thionyl chloride (0.27 mL, 3.68 mmol, purchased from Shanghai Experimental Plant) was added dropwise. After the addition was complete, the temperature was slowly raised to 20–25 °C and the reaction was stirred for 20 hours. The reaction was monitored by TLC until complete. The reaction mixture was evaporated to dryness, and 10 mL of saturated sodium bicarbonate was added. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 320 mg of compound 1 (yield 90.26%).

[0472] MS(ESI): m / z 290.4 [M+1] + .

[0473] 1 H NMR (400MHz, DMSO-d6): δ7.91-7.89(d,2H),7.55-7.53(d,2H),3.84(s,3H),3.61-3.49(t,1H),3.43-3.42(m,1H),3.42-3.4 1(m,2H),2.55-2.52(m,1H),2.08-2.05(m,2H),1.81-1.76(m,3H),1.67-1.65(m,1H),1.64-1.62(m,1H),1.15-1.14(t,3H).

[0474] Example 3 Preparation of Compound 3

[0475]

[0476] Step 1:

[0477] 2b (36.20 g, 201 mmol) was added to tetrahydrofuran (250 mL), followed by DMAP (2.69 g, 11 mmol, purchased from Aladdin) and di-tert-butyl dicarbonate (74.15 g, 341 mmol, purchased from Adamas). The mixture was heated to 35–45 °C and stirred for 17 hours. The reaction solution was washed with 400 mL of water, and the organic layer was evaporated to dryness to obtain a solid. The solid was then slurried with petroleum ether, filtered, and the filter cake was dried in a forced-air oven at 45 °C to obtain 42.21 g of compound 3a (yield 88.91%).

[0478] 1H NMR (400MHz, DMSO-d6): δ8.06-7.99 (m, 4H), 3.88 (s, 3H), 1.55 (s, 9H).

[0479] Step 2:

[0480] 3a (42.21 g, 179 mmol) was added to tetrahydrofuran (420 mL). Lithium hydroxide monohydrate (7.42 g, 179 mmol, purchased from Maclean's) was weighed and dissolved in 75 mL of water. The aqueous solution of lithium hydroxide was added to the reaction mixture and stirred overnight at 25–35 °C. The pH was adjusted to 1–2 with 1 N hydrochloric acid aqueous solution, and the mixture was allowed to separate into layers. The organic layer was evaporated under reduced pressure to obtain a solid. The solid was mixed with water and petroleum ether to form a slurry. After filtration, the filter cake was dried in a forced-air oven at 45 °C to obtain 29.33 g of compound 3b (yield 73.87%).

[0481] 1H NMR (400MHz, DMSO-d6): δ13.31(s,1H),8.05-8.00(m,2H),7.99-7.92(m,2H),1.55(s,9H).

[0482] Step 3:

[0483] 3b (28.98 g, 130 mmol) was added to dichloromethane (290 mL), followed by triethylamine (15.50 g, 153 mmol, purchased from Kolomb), and carbonyl diimidazole (27.10 g, 181 mmol, purchased from Anegy). The reaction was carried out at room temperature for 4 h. N,O-dimethylhydroxy hydrochloride (14.98 g, 153 mmol, purchased from Shaoyuan) was then added, and the mixture was stirred for 1 h. TLC analysis showed that the reaction was essentially complete. After adding 1 M HCl, the mixture was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate and saturated sodium chloride, and concentrated to dryness to give 31.34 g of a pale yellow viscous oil, compound 3c (yield 84.81%).

[0484] MS(ESI): m / z 266.3[M+1]+.

[0485] 1H NMR (400MHz, DMSO-d6): δ8.00-7.95(m,2H),7.68-7.64(m,2H),3.52(s,3H),3.27(s,3H),1.56(s,9H).

[0486] Step 4:

[0487] Preparation of Grignard reagent: First, place magnesium strip (6.03g, 248mmol, purchased from Shanghai Test) at the bottom of the bottle, add iodine granules (35mg, 0.12mmol, purchased from Cologne Chemicals) to replace the argon gas, and start adding 2-(2-bromoethyl)-1,3-dioxane (41.56g, 229mmol, purchased from Adamas) dissolved in 250mL of dry tetrahydrofuran. After the reaction is initiated, control the internal temperature in a cold water bath to not exceed 30℃. After the addition is complete, react at room temperature for 3 hours and set aside.

[0488] Compound 3c (20.37 g, 91.8 mmol) was dissolved in tetrahydrofuran (100 mL), cooled in a dry ice-ethanol bath, and the prepared Grignard reagent was added dropwise when the temperature was below -60 °C, while maintaining the internal temperature below -50 °C. After the addition was complete, the reaction continued for 3 hours, and TLC showed that the starting material had basically reacted. The reaction solution was poured into a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate, and the organic phases were combined. The mixture was concentrated to dryness, and ethyl acetate (10 mL) and n-hexane (90 mL) were added. The mixture was stirred, filtered, and the filter cake was washed with n-hexane. The filter cake was dried to give 16.2 g of compound 3d (yield 83.91%).

[0489] MS(ESI): m / z 265.9 [M+1] + .

[0490] Step 5:

[0491] Compound 3d (2.52 g, 8.16 mmol) was dissolved in tetrahydrofuran (20 mL), and tert-butylsulfonamide (1.98 g, 16.3 mmol, purchased from Bide) and tetraethyl titanate (5.58 g, 24.48 mmol, purchased from Anage) were added. Argon gas was purged, and the mixture was heated to 66 °C. The reaction solution was dissolved completely, and the reaction was continued at 66 °C for 5 hours. HPLC showed that the reaction was basically complete. After the reaction solution was cooled to 27 °C, 100 mL of saturated sodium bicarbonate was added to quench the reaction while stirring. Ethyl acetate (100 mL) was added to the reaction solution, and the mixture was stirred thoroughly and filtered through a diatomaceous earth filter. The filtrate was separated, and the organic phase was washed with saturated sodium bicarbonate solution, then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography (PE:EA = 100:0-70:30) to give 1.60 g of compound 3e (yield 96.18%).

[0492] MS(ESI): m / z 410.2 [M+1] + .

[0493] 1 H NMR (400MHz, DMSO-d6): δ7.42(d,2H),7.19(d,2H),4.69(t,1H),4.03(dd,1H),3.88-3.85( m,2H),3.75-3.79(m,2H),3.66-3.46(m,2H),3.40-3.17(m,2H),1.44(s,9H),1.29(s,9H).

[0494] Step 6:

[0495] tert-butyl acetoacetate (695 mg, 4.40 mmol, purchased from Bide) was dissolved in dry tetrahydrofuran (10 mL), purged with argon, and cooled to -10 °C in an ice-salt bath. 2 M diisopropylaminolithium (4.40 mL, 8.79 mmol, purchased from Adamas) was added dropwise, and the mixture was stirred at this temperature for 30 minutes after the addition was complete. The reaction mixture was then transferred to a dry ice-ethanol bath and cooled to -60 °C. Compound 3e (1.21 g, 2.93 mmol, self-made) dissolved in dry tetrahydrofuran (10 mL) was added dropwise, and the reaction was continued at this temperature for 3 hours after the addition was complete. TLC analysis showed that the starting material had largely reacted. The reaction mixture was poured into a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate, and the organic phases were combined. The mixture was concentrated to dryness and purified by column chromatography (PE:EA = 100:0-60:40) to give 1.60 g of compound 3f (yield 96.18%).

[0496] MS(ESI): m / z 568.2 [M+1] + .

[0497] 1 H NMR (400MHz, DMSO-d6): δ7.94(d,2H),7.38(d,2H),5.15(s,1H),4.68(t,1H),3.80-3.76(m,4H),3.86-3.70(dd,2 H),3.20-3.16(m,2H),2.35-2.31(m,1H),2.05(s,2H),2.04-1.94(m,1H),1.57(s,9H),1.44(s,9H),1.33(s,9H).

[0498] Step 7:

[0499] At room temperature, 200 mg (0.362 mmol) of compound 3 was dissolved in 3 mL of dichloromethane in a three-necked flask, purged with argon gas, and 1 mL (12.24 mol, purchased from Anegig) was added dropwise. The mixture was stirred and mixed thoroughly, and then the temperature was raised to 40 °C for 25 hours. Mass spectrometry showed that the starting material had basically reacted completely. The reaction solution was directly evaporated to dryness, purified by C18 reverse-phase column chromatography (mobile phase water / acetonitrile = 100-85%), and lyophilized to give 52 mg of compound 3 (yield 57.77%).

[0500] MS(ESI): m / z 245.9 [M+1] + .

[0501] 1H NMR (400MHz, DMSO-d6): δ10.46(s,1H),8.04-8.02(d,2H),7.65-7.63(d,2H),4.47( s,1H),3.02-2.98(m,2H),2.85-2.55(m,4H),2.28-2.26(m,2H),1.95-1.91(m,1H).

[0502] Example 4: Preparation of Compound 4

[0503]

[0504] Step 1:

[0505] 2a (7.12 g, 38.85 mmol, purchased from Shaoyuan) was added to toluene (50 mL) in a 100 mL three-necked flask; it was insoluble, forming a white suspension. DMF (1 mL, 1.99 mmol, purchased from Krohne Chemicals) was added dropwise to displace the argon gas. Then, thionyl chloride (4.08 mL, 48.57 mmol, purchased from Shanghai Chemical Industry) was added dropwise, causing exothermic reaction. After the addition was complete, the mixture was heated to 50–55 °C and stirred for 3 h. The reaction solution was dissolved completely, and the reaction was quenched with diethylamine and detected by TLC. After the reactants had completely reacted, the reaction solution was directly evaporated to dryness, yielding 7.70 g of a white solid, compound 2c (100% yield). This was used directly in the next step.

[0506] Step 2:

[0507] Preparation of Grignard reagent: First, place magnesium strip (1.36g, 57.45mmol, purchased from Shanghai Test) at the bottom of the bottle, add iodine granules (35mg, 0.12mmol, purchased from Cologne Chemicals) to replace the argon gas, and start adding 2-(2-bromoethyl)-1,3-dioxane (8.06g, 44.19mmol, purchased from Adamas) dissolved in 50mL of ultra-dry tetrahydrofuran. After the reaction is initiated, control the internal temperature in a cold water bath to not exceed 30℃. After the addition is complete, react at room temperature for 3 hours and set aside.

[0508] Compound 2c (7.90 g, 39.77 mmol, self-made) was dissolved in tetrahydrofuran (50 mL), cooled in a dry ice-ethanol bath, and the prepared Grignard reagent was added dropwise when the temperature was below -65 °C, while controlling the internal temperature not to exceed -60 °C. After the addition was complete, the reaction continued for 3 hours, and TLC showed that the starting material had basically reacted. The reaction solution was poured into a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium bicarbonate and saturated sodium chloride, concentrated to dryness, and purified by column chromatography (PE:EA:DCM = 70:10:20) to give 4.50 g of compound 2e (yield 38.53%).

[0509] MS(ESI): m / z 265.1 [M+1] + .

[0510] Step 3:

[0511] Compound 2e (3.92 g, 14.83 mmol, self-made) was dissolved in tetrahydrofuran (30 mL), followed by the addition of tert-butylsulfonamide (3.60 g, 29.67 mmol, purchased from Bidet), and tetraethyl titanate (10.15 g, 44.50 mmol, purchased from Bidet). The solution was dissolved completely, and argon gas was added to dissolve the precipitate. Heating was initiated at 66 °C. The reaction solution dissolved completely and turned yellow-green. The reaction was continued at 66 °C for 5 h, and HPLC showed that the reaction was essentially complete. After cooling the reaction solution to 27 °C, saturated sodium bicarbonate (50 mL) was added to quench the reaction while stirring. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was filtered through a diatomaceous earth filter. The filtrate was separated, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography (PE:EA = 100:0-70:30) to give 4.10 g of compound 4d (yield 72.46%).

[0512] MS(ESI): m / z 382.2 [M+1] + .

[0513] 1 H NMR (400MHz, DMSO-d6): δ8.05-8.03(m,2H),7.96-7.95(m,2H),4.89-4.88(m,1H),4.36-4.33(m ,2H),3.89-3.76(m,4H),3.32-3.30(m,2H),1.34-1.31(m,2H),1.25-1.23(m,3H),1.22(s,9H).

[0514] Step 4:

[0515] 168 mg, 1.05 mmol, of tert-butyl acetoacetate (from Adamas) was dissolved in 10 mL of dry tetrahydrofuran. Argon gas was purged, and the mixture was cooled to -10 °C in an ice-salt bath. 2 M LDA (0.52 mL, 1.05 mmol, from Adamas) was added dropwise, and the mixture was stirred at this temperature for 30 min. The reaction mixture was then transferred to a dry ice-ethanol bath and cooled to -60 °C. Compound 4d (200 mg, 0.524 mmol, homemade) dissolved in 10 mL of dry tetrahydrofuran was added dropwise, and the reaction was continued for 3 h in a dry ice-ethanol bath. TLC analysis showed that the starting material had largely reacted. The reaction mixture was poured into a saturated ammonium chloride solution (30 mL), extracted with ethyl acetate, and concentrated to dryness to give 280 mg of compound 4e (100% yield). The mixture was then directly introduced to the next step.

[0516] MS(ESI): m / z 540.3 [M+1]+ .

[0517] Step 5:

[0518] At room temperature, 4d (202 mg, 0.342 mmol, self-made) was dissolved in ethanol (3 mL) in a thumb flask, concentrated hydrochloric acid (1 mL, 10.31 mol, purchased from Anaiji) was added dropwise to replace the argon gas, and the mixture was heated to 45 °C for 20 h. The reaction solution was directly evaporated to dryness and purified by column chromatography (MeOH:DCM = 100:0-100:10) to obtain compound 4.

[0519] MS(ESI): m / z 274.0 [M+1] + .

[0520] 1 H NMR (400MHz, DMSO-d6): δ8.05-8.03(m,2H),7.96-7.95(m,2H),4.41-4.38(m,2 H),4.36-4.33(m,1H),2.71-2.42(m,4H),2.55-1.92(m,4H),1.40-1.38(t,3H).

Claims

1. A method for preparing compound D or its salt, The method includes the step of reacting the compound of formula C to form the compound of formula D. in, Z and Y are each independently selected from CH and N; R 1 Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4 and -CONR 5 R 6 ; R 2 Selected from C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; R 4 Selected from 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 groups; R 5 R 6 Each is independently selected from hydrogen 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 groups; P 1 P 2 Each was independently selected from C 1-3 Alkyl and C 1-3 Acyl group, the C 1-3 Alkyl or C 1-3 The acyl group may be optionally substituted with one or more halogens or phenyl groups, or P 1 P 2 Together with adjacent atoms, they form a 5-6 membered heterocyclic alkyl group, which is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl groups are substituted; P 3 Selected from 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.

2. The method according to claim 1, wherein the compound of formula C reacts under acidic conditions to form the compound of formula D, wherein the acid is preferably hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, hydrobromic acid or p-toluenesulfonic acid, more preferably hydrochloric acid.

3. The method according to claim 1 or 2, wherein in the compound represented by formula D, Z is CH and Y is CH; or Z is CH and Y is N.

4. The method according to any one of claims 1-3, wherein R in the compound represented by formula D 1 The halogen is, for example, bromine; furthermore, the compound shown in formula D is preferably the compound shown in formula D-1. A method for preparing the compound of formula D-1 or a salt thereof includes the step of reacting the compound of formula C-1 under acidic conditions to form the compound of formula D-1. Where R 2 P 1 P 2 P 3 As defined in claim 1, X is a halogen, such as bromine.

5. The method according to any one of claims 1-3, wherein R in the compound represented by formula D 1 It is cyano; further, the compound shown in formula D is preferably the compound shown in formula D-2. The method for preparing the compound shown in formula D-2 or a salt thereof includes the step of reacting the compound shown in formula C-2 to form the compound shown in formula D-2. Where R 2 P 1 P 2 P 3 As defined in claim 1.

6. The method according to any one of claims 1-3, wherein R in the compound represented by formula D 1 -COOR 4 R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; further, the compound shown in formula D is preferably the compound shown in formula D-3. The method for preparing the compound shown in formula D-3 or a salt thereof includes the step of reacting the compound shown in formula C-3 to form the compound shown in formula D-3. Where R 2 P 1 P 2 P 3 R 4 As defined in claim 1.

7. The method according to any one of claims 1-3, further comprising reacting the compound of formula A with a sulfinamide to form the compound of formula B, and reacting the compound of formula B with the compound of formula W to form the compound of formula C. Where R 1 R 2 Z, Y, P 1 P 2 P 3 As defined in claim 1; R 1a Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4a and -CONR 5a R 6a R 4a Selected from 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 5a R 6a Each is independently selected from hydrogen 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.

8. The method according to any one of claims 1-4, wherein the compound represented by formula C is selected from... Where X is a halogen, such as bromine; preferably 9. A method for preparing the compound of formula G or a salt thereof. The method comprises the steps of the method for preparing the compound of formula D or a salt thereof as described in any one of claims 1-8, wherein R 1 Z, Y are defined as shown in compound C; R is defined as shown in compound C. 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

10. The method of claim 9, further comprising the step of converting the compound of formula D into the compound of formula G. Where R 1 Z, Y are defined as shown in the compound of formula C; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

11. The method according to claim 10 or 11, further comprising the steps of reacting the compound of formula D in the presence of a reducing agent to form the compound of formula E, reacting the compound of formula E with an amino protecting agent to form the compound of formula F, and reacting the compound of formula F with an alkylating agent to form the compound of formula G. Where R 1 Z, Y are defined as shown in the compound of formula C; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

12. A method for preparing the compound of formula I or a salt thereof, Z and Y are each independently selected from CH and N; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; R 7 Selected from hydrogen, 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 groups. The method includes the steps of the method for preparing the compound of formula D or a salt thereof as described in any one of claims 1-8, or / and the steps of the method for preparing the compound of formula G or a salt thereof as described in any one of claims 9-11.

13. A compound or a salt thereof, said compound being selected from: Where R 1 R 2 P 1 P 2 P 3 Z and Y are as defined in claim 1; further, the compound is preferably: Where X is a halogen, such as bromine; R 2 R 4 P 1 P 2 P 3 As defined in claim 1; R 1a Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4a and -CONR 5a R 6a R 4a Selected from 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 5a R 6a Each is independently selected from hydrogen 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.

14. The method for preparing the compound of formula D or a salt thereof according to any one of claims 1-8; the method for preparing the compound of formula G or a salt thereof according to any one of claims 9-11; the method for preparing the compound of formula I or a salt thereof according to claim 12; the use of the compound of claim 13 or a pharmaceutically acceptable salt thereof in the preparation of a Factor B inhibitor, wherein the Factor B inhibitor is preferably...

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