Process for preparation of pyrrolizidine compounds

Abstract

Provided herein, in part, is a method of preparing a compound of Formula (II-1) or a salt thereof wherein the method comprises reacting a compound of Formula (III-1) with a first base in the presence of a first solvent, thereby producing a compound of Formula (II-1) or a salt thereof wherein R is an ester protecting group and X is a counter ion.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 488,356, filed March 3, 2023, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure provides compounds and synthetic methods for preparing the compounds, which can be used to prepare compounds that can be used to treat or inhibit cancer, and in particular, compounds that can be used to treat or inhibit cancer. Background Technology

[0004] KRAS is a molecular switch. Under normal physiological conditions, this protein binds to guanosine diphosphate (GDP) in the "off" state. In response to signaling via receptor tyrosine kinases (RTKs) such as EGFR, GDP is exchanged for guanosine triphosphate (GTP) in a process promoted by guanine nucleotide exchange factors (GEFs) such as SOS. The GTP-bound form of KRAS is in the "on" state and interacts with proteins such as RAF and PI3K to promote downstream signaling that leads to cell proliferation and survival. In a process promoted by GAPs (GTPase activators), KRAS can slowly hydrolyze GTP back to GDP, thus returning to the off state.

[0005] KRAS mutations are found in approximately 30% of all human cancers and are extremely common in the three deadliest forms of cancer: pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (35%). Meanwhile, in the United States alone, more than 200,000 patients are diagnosed with these cancers each year. One specific mutation, the substitution of glycine for cysteine ​​at position 12 (G12C), occurs in more than 40,000 patients annually. The KRAS G12C mutation weakens the hydrolysis of GTP to GDP, thus turning KRAS on and promoting cancer cell proliferation. Summary of the Invention

[0006] This article partially provides a preparative compound of formula (II-1):

[0007] (II-1),

[0008] A method using a salt thereof, wherein the method comprises making a compound of formula (III-1):

[0009] (III-1),

[0010] The compound reacts with a first base in the presence of a first solvent to produce a compound of formula (II-1) or a salt thereof, wherein R is an ester protecting group and X is a counterion.

[0011] In some embodiments, the compound of formula (II-1) is a compound of formula (IIa-1):

[0012] (IIa-1),

[0013] Or its salts, and the compound of formula (III-1) is a compound of formula (IIIa-1):

[0014] (IIIa-1).

[0015] In some implementations, the method further includes:

[0016] Compounds of formula (IV-1):

[0017] (IV-1),

[0018] Or its salt reacts with an alkylating agent in the presence of a second base and a second solvent to produce a compound of formula (III-1):

[0019] (III-1)

[0020] In some embodiments, the compound of formula (IV-1) is a compound of formula (IVa-1):

[0021] (IVa-1),

[0022] Or its salt.

[0023] In some embodiments, the method further includes using a compound of formula (V-1):

[0024] (V-1),

[0025] Or its salt reacts with an acid in the presence of a third solvent to produce a compound of formula (IV-1):

[0026] (IV-1),

[0027] Or its salt.

[0028] In some embodiments, the compound of formula (V-1) is a compound of formula (Va-1):

[0029] (Va-1),

[0030] Or its salt.

[0031] In some embodiments, the method further includes using a compound of formula (VI):

[0032] (VI),

[0033] Or its salt reacts with an agent introducing an R group in the presence of a third base and a fourth solvent to produce a compound of formula (V-1):

[0034] (V-1),

[0035] Or its salt.

[0036] In some embodiments, the compound of formula (VI) is a compound of formula (VIa):

[0037] (VIa),

[0038] Or its salt.

[0039] This article also provides a preparative compound of formula (I):

[0040] (I),

[0041] A method using a salt thereof, wherein the method comprises:

[0042] Compounds of formula (II-1):

[0043] (II-1),

[0044] The compound or its salt reacts with a reducing agent in the presence of a fifth solvent to produce a compound of formula (I) or a salt thereof, wherein the compound of formula (II-1) or its salt thereof is prepared according to the method described herein.

[0045] In some embodiments, the compound of formula (I) is a compound of formula (Ia):

[0046] (Ia),

[0047] Or its salt.

[0048] This disclosure also provides a compound of formula (I):

[0049] (I),

[0050] A method using its salt or a salt thereof, wherein the method comprises the following steps:

[0051] (1) Compounds of formula (VI):

[0052] (VI),

[0053] Or its salt reacts with an agent that introduces an R group to produce a compound of formula (V-1):

[0054] (V-1),

[0055] or its salt;

[0056] (2) Reacting a compound of formula (V-1) or its salt with an acid to produce a compound of formula (IV-1):

[0057] (IV-1),

[0058] or its salt;

[0059] (3) Reacting a compound of formula (IV-1) or a salt thereof with an alkylating agent to produce a compound of formula (III-1):

[0060] (III-1);

[0061] (4) React the compound of formula (III-1) with a base to produce the compound of formula (II-1):

[0062] (II-1),

[0063] or its salt; and

[0064] (5) React the compound of formula (II-1) or its salt with a reducing agent to produce the compound of formula (I) or its salt;

[0065] R is an ester protecting group and X is a counter ion.

[0066] On the other hand, this disclosure provides a compound of formula (III):

[0067] (III),

[0068] Where X - It is a counter ion.

[0069] In some embodiments, the compound is a compound of formula (IIIa):

[0070] (IIIa),

[0071] Where X - It is a counter ion.

[0072] On the other hand, this disclosure provides a compound of formula (II):

[0073] (II),

[0074] Or its salt.

[0075] In some embodiments, the compound is a compound of formula (IIa):

[0076] (IIa),

[0077] Or its salt.

[0078] On the other hand, this disclosure provides a compound of formula (II-1):

[0079] (II-1),

[0080] Or a salt thereof, wherein R is an ester protecting group, wherein the compound is prepared according to the methods described herein.

[0081] On the other hand, this disclosure provides a compound of formula (I):

[0082] (I),

[0083] Or a salt thereof, wherein the compound of formula (I) is prepared according to the methods described herein. Detailed Implementation

[0084] This document partially provides methods for preparing compounds (e.g., synthetic intermediates) that can be used to prepare compounds that can be used to treat cancer. The methods considered may result in higher stereoselectivity and / or yields of the target compound compared to known methods, and are therefore more suitable for large-scale manufacturing processes. This disclosure also provides novel compounds and compositions that can be used to prepare compounds that can be used to treat cancer. Cancer can be characterized, for example, by KRAS G12C.

[0085] In some embodiments, the compounds and synthetic methods described in this disclosure can be used to prepare the compounds described in PCT application number PCT / US2022 / 079324, the contents of which are hereby incorporated by reference.

[0086] Unless otherwise stated, the abbreviations used in this article have their conventional meanings in the fields of chemistry and biology.

[0087] It should be understood that the description of the compound structure, including possible substitutions, is limited to those that are chemically possible.

[0088] Unless otherwise stated, the absolute stereochemistry of all chiral atoms is shown in the figure. Those skilled in the art will be able to separate racemic compounds into their respective enantiomers using methods known in the art, such as chiral chromatography, chiral recrystallization, etc. References to compounds as racemic mixtures also mean including individual enantiomers contained in the mixture.

[0089] References to “about” a value or parameter in this document include (and descriptions) variations with respect to said value or parameter itself. For example, a description of “about X” includes a description of “X”. Specifically, the term “about” considers values ​​within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a specified value.

[0090] As used herein, and unless otherwise stated, the term “about” when used in conjunction with temperature means the temperature at which a person skilled in the art would consider to provide a chemical reaction result equivalent to that obtained from a particular temperature.

[0091] Unless the context clearly indicates otherwise, the terms “a” or “an” as used herein mean one or more.

[0092] While the compounds described herein may exist as neutral (non-salt) compounds and may be used as such compounds, this specification is intended to include all salts of the compounds described herein, as well as methods of using such salts. In some embodiments, the salts of the compounds include pharmaceutically acceptable salts.

[0093] The term "pharmaceutically acceptable salt" for a compound means a salt that is pharmaceutically acceptable to humans and / or animals and retains at least some of the desired pharmacological activity of the parent compound upon administration. Such salts include: (a) salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or salts formed from organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc. Salts formed from the following acid additions: (a) glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (b) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

[0094] When chemically relevant, this document includes all stereoisomers of the compound, including diastereomers and enantiomers. Mixtures of possible stereoisomers in any proportion are also included, including, but not limited to, racemic mixtures. Unless the stereochemistry is explicitly specified in the structure, the structure is intended to include all possible stereoisomers of the compound. If the stereochemistry is explicitly specified for one or more parts of the molecule, but not for another one or more parts, the structure is intended to include all possible stereoisomers for the parts for which the stereochemistry is not explicitly specified.

[0095] As used in this article, the term "alkylating agent" refers to a chemical agent that introduces an alkyl or alkylene group.

[0096] The term "alkyl" refers to a saturated monovalent hydrocarbon group that is straight-chain, branched, cyclic, or a combination thereof, having a specified number of carbon atoms. For example, alkyl groups can be C1-C6 alkyl groups, including, for example, methyl, ethyl, propyl, 2-propyl, butyl, cyclopropyl, cyclobutyl, pentyl, hexyl, etc.

[0097] The term "alkylene" refers to a saturated divalent hydrocarbon group that has a specified number of carbon atoms and is either straight-chain, branched, cyclic, or a combination thereof. For example, alkylenes can be C1-C6 alkylenes, including, for example, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, hexylene, etc.

[0098] As used herein, the term "metal alkoxide" refers to a compound obtained by replacing a hydroxyl hydrogen atom with a metal. In some embodiments, the metal alkoxide may be potassium tert-butoxide.

[0099] As used in this article, “metal hydride” refers to a compound containing a metal that is bonded to hydrogen.

[0100] As used in this article, the term "counter ion" refers to an ion that accompanies an ionic compound to maintain electronic neutrality.

[0101] As used herein, the term "ester protecting group" refers to a functional group that protects a carboxylic acid by substituting the acidic proton of the carboxylic acid to form an ester. For example, the ester protecting group can be alkyl or benzyl. Benzyl is a monovalent group -CH2-C6H5.

[0102] As used in this article, the term "polar aprotic solvent" refers to a polar solvent that does not have acidic protons.

[0103] A "diasteretropically pure" compound is substantially free of another diastereomer. In some embodiments, the compound may be >95%, >97%, >98%, or >99% pure, as measured by HPLC or NMR. In other embodiments, the diasteretropically pure compound is obtained in the form of a single diastereomer, and no other diastereomer is detected by HPLC or NMR.

[0104] The term "halogenated group" refers to fluorine, chlorine, bromine, or iodine.

[0105] The term "benzyl halide" refers to benzyl fluorine, benzyl chloride, benzyl bromide, or benzyl iodine.

[0106] As used in this article, the term "room temperature" refers to a temperature of approximately 20-25°C.

[0107] Selected implementation plan

[0108] Implementation Scheme 1. A compound of formula (II-1):

[0109] (II-1),

[0110] A method using a salt thereof, wherein the method comprises making a compound of formula (III-1):

[0111] (III-1),

[0112] The compound reacts with a first base in the presence of a first solvent to produce a compound of formula (II-1) or a salt thereof, wherein R is an ester protecting group and X is a counterion.

[0113] Implementation Scheme 2. The method as described in Implementation Scheme 1, wherein the reaction of the compound of formula (III-1) with the first base is carried out at about 0°C to about room temperature.

[0114] Implementation Scheme 3. The method as described in Implementation Scheme 1 or 2, wherein the first base is a metal alkoxide base.

[0115] Implementation Scheme 4. The method as described in Implementation Scheme 3, wherein the first base is KOtBu.

[0116] Implementation Scheme 5. The method of any one of Implementation Schemes 1 to 4, wherein the first solvent is a polar aprotic solvent.

[0117] Implementation Scheme 6. The method as described in Implementation Scheme 5, wherein the polar aprotic solvent is an ether solvent.

[0118] Implementation Scheme 7. The method as described in Implementation Scheme 5 or 6, wherein the polar aprotic solvent is THF or 2-MeTHF.

[0119] Implementation Scheme 8. The method of any one of Implementation Schemes 1 to 7, wherein the method produces a compound of formula (II-1) in diastereomeric pure form.

[0120] Implementation Scheme 9. The method of any one of Implementation Schemes 1 to 8, wherein the compound of formula (II-1) is a compound of formula (IIa-1):

[0121] (IIa-1),

[0122] Or its salts, and the compound of formula (III-1) is a compound of formula (IIIa-1):

[0123] (IIIa-1).

[0124] Implementation Scheme 10. The method of any one of Implementation Schemes 1 to 9, wherein the method further comprises: making the compound of formula (IV-1):

[0125] (IV-1),

[0126] Or its salt reacts with an alkylating agent in the presence of a second base and a second solvent to produce a compound of formula (III-1):

[0127] (III-1)

[0128] Implementation Scheme 11. The method as described in Implementation Scheme 10, wherein the reaction of the compound of formula (IV-1) with the alkylating agent is carried out at approximately room temperature.

[0129] Implementation Scheme 12. The method as described in any one of Implementation Schemes 1 to 11, wherein X - It is trifluoromethanesulfonate (TfO) - )ion.

[0130] Implementation Scheme 13. The method of any one of Implementation Schemes 10 to 12, wherein the alkylating agent is , where X is a trifluoromethanesulfonate or a halide.

[0131] Implementation Scheme 14. The method as described in Implementation Scheme 13, wherein the alkylating agent is:

[0132] .

[0133] Implementation Scheme 15. The method of any one of Implementation Schemes 10 to 14, wherein the second base is an amine.

[0134] Implementation Scheme 16. The method of any one of Implementation Schemes 10 to 14, wherein the second base is a weak base anion exchange resin.

[0135] Implementation Scheme 17. The method as described in Implementation Scheme 16, wherein the anion exchange resin is Amberlyst™ A-21.

[0136] Implementation Scheme 18. The method of any one of Implementation Schemes 15 to 17, wherein the amine is N,N-diisopropylethylamine.

[0137] Implementation Scheme 19. The method of any one of Implementation Schemes 10 to 18, wherein the second solvent is a nonpolar solvent.

[0138] Implementation Scheme 20. The method of any one of Implementation Schemes 10 to 19, wherein the second solvent is selected from the group consisting of toluene, THF, 2-MeTHF and acetonitrile.

[0139] Implementation Scheme 21. The method of Implementation Scheme 20, wherein the second solvent is acetonitrile.

[0140] Implementation Scheme 22. The method of any one of Implementation Schemes 10 to 21, wherein the compound of formula (IV-1) is a compound of formula (IVa-1):

[0141] (IVa-1),

[0142] Or its salt.

[0143] Implementation Scheme 23. The method of any one of embodiments 10 to 22, wherein the method further comprises making a compound of formula (V-1):

[0144] (V-1),

[0145] Or its salt reacts with an acid in the presence of a third solvent to produce a compound of formula (IV-1):

[0146] (IV-1),

[0147] Or its salt.

[0148] Implementation Scheme 24. The method as described in Implementation Scheme 23, wherein the acid is an organic acid or an inorganic acid.

[0149] Implementation Scheme 25. The method as described in Implementation Scheme 24, wherein the acid is trifluoroacetic acid.

[0150] Implementation Scheme 26. The method of any one of Implementation Schemes 23 to 25, wherein the third solvent is a polar aprotic solvent.

[0151] Implementation Scheme 27. The method of any one of Implementation Schemes 23 to 26, wherein the third solvent is dichloromethane.

[0152] Implementation Scheme 28. The method of any one of Implementation Schemes 23 to 27, wherein the compound of formula (V-1) is a compound of formula (Va-1):

[0153] (Va-1),

[0154] Or its salt.

[0155] Implementation Scheme 29. The method of any one of Implementation Schemes 23 to 28, wherein the method further comprises making a compound of formula (VI):

[0156] (VI),

[0157] Or its salt reacts with an agent introducing an R group in the presence of a third base and a fourth solvent to produce a compound of formula (V-1):

[0158] (V-1),

[0159] Or its salt.

[0160] Implementation Scheme 30. The method as described in Implementation Scheme 29, wherein the third base is an amine base.

[0161] Implementation Scheme 31. The method of Implementation Scheme 30, wherein the amine base is selected from the group consisting of N,N-diisopropylethylamine, triethylamine and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).

[0162] Implementation Scheme 32. The method of any one of Implementation Schemes 29 to 31, wherein the fourth solvent is a polar aprotic solvent.

[0163] Implementation Scheme 33. The method as described in Implementation Scheme 32, wherein the fourth solvent is acetonitrile.

[0164] Implementation Scheme 34. The method of any one of Implementation Schemes 29 to 33, wherein the compound of formula (VI) is a compound of formula (VIa):

[0165] (VIa),

[0166] Or its salt.

[0167] Implementation Scheme 35. The method of any one of Implementation Schemes 29 to 34, wherein the agent into which the R group is introduced is a benzyl halide.

[0168] Implementation Scheme 36. The method as described in Implementation Scheme 35, wherein the agent incorporating the R group is benzyl bromide.

[0169] Implementation Scheme 37. The method of any one of Implementation Schemes 1 to 36, wherein R is benzyl.

[0170] Implementation Scheme 38. A compound of formula (I):

[0171] (I),

[0172] A method using a salt thereof, wherein the method comprises:

[0173] Compounds of formula (II-1):

[0174] (II-1),

[0175] The compound or its salt reacts with a reducing agent in the presence of a fifth solvent to produce a compound of formula (I) or its salt, wherein the compound of formula (II-1) or its salt is prepared according to any one of embodiments 1 to 37.

[0176] Implementation Scheme 39. The method of Implementation Scheme 38, wherein the reducing agent is a metal hydride.

[0177] Implementation Scheme 40. The method of Implementation Scheme 39, wherein the metal hydride is selected from the group consisting of LiAlH4, LiBH4 and Red-Al®.

[0178] Implementation Scheme 41. The method of any one of Implementation Schemes 38 to 40, wherein the fifth solvent is a polar aprotic solvent.

[0179] Implementation Scheme 42. The method of any one of Implementation Schemes 38 to 41, wherein the fifth solvent is an ether solvent.

[0180] Implementation Scheme 43. The method of any one of Implementation Schemes 38 to 42, wherein the fifth solvent is selected from the group consisting of THF, Me-THF, diethyl ether, dimethoxyethane and 1,4-dioxane.

[0181] Implementation Scheme 44. The method of any one of Implementation Schemes 38 to 43, wherein the method produces a compound of formula (I) in diastereomeric pure form.

[0182] Implementation Scheme 45. The method of any one of Implementation Schemes 38 to 44, wherein the compound of formula (I) is a compound of formula (Ia):

[0183] (Ia),

[0184] Or its salt.

[0185] Implementation Scheme 46. A compound of formula (I):

[0186] (I),

[0187] A method using its salt or a salt thereof, wherein the method comprises the following steps:

[0188] (1) Compounds of formula (VI):

[0189] (VI),

[0190] Or its salt reacts with an agent that introduces an R group to produce a compound of formula (V-1):

[0191] (V-1),

[0192] or its salt;

[0193] (2) Reacting a compound of formula (V-1) or its salt with an acid to produce a compound of formula (IV-1):

[0194] (IV-1),

[0195] or its salt;

[0196] (3) Reacting a compound of formula (IV-1) or a salt thereof with an alkylating agent to produce a compound of formula (III-1):

[0197] (III-1);

[0198] (4) React the compound of formula (III-1) with a base to produce the compound of formula (II-1):

[0199] (II-1),

[0200] or its salt; and

[0201] (5) React the compound of formula (II-1) or its salt with a reducing agent to produce the compound of formula (I) or its salt;

[0202] R is an ester protecting group and X is a counter ion.

[0203] Implementation Scheme 47. The method as described in Implementation Scheme 46, wherein step (4) produces a compound of formula (II-1) in diastereomeric pure form.

[0204] Implementation Scheme 48. The method as described in Implementation Scheme 46 or 47, wherein the compound of formula (II-1) is a compound of formula (IIa-1):

[0205] (IIa-1),

[0206] Or its salts, and the compound of formula (III-1) is a compound of formula (IIIa-1):

[0207] (IIIa-1).

[0208] Implementation Scheme 49. The method of any one of Implementation Schemes 46 to 48, wherein the compound of formula (I) is a compound of formula (Ia):

[0209] (Ia),

[0210] Or its salt.

[0211] Implementation Scheme 50. The method of any one of Implementation Schemes 46 to 49, wherein the compound of formula (IV-1) is a compound of formula (IVa-1):

[0212] (IVa-1),

[0213] Or its salt.

[0214] Implementation Scheme 51. The method of any one of Implementation Schemes 46 to 50, wherein the compound of formula (V-1) is a compound of formula (Va-1):

[0215] (Va-1),

[0216] Or its salt.

[0217] Implementation Scheme 52. The method of any one of Implementation Schemes 46 to 51, wherein the compound of formula (VI) is a compound of formula (VIa):

[0218] (VIa),

[0219] Or its salt.

[0220] Implementation Scheme 53. The method of any one of Implementation Schemes 46 to 52, wherein the reaction in step (4) is carried out at about 0°C to about room temperature.

[0221] Implementation Scheme 54. The method of any one of Implementation Schemes 46 to 53, wherein the reducing agent is a metal hydride.

[0222] Implementation Scheme 55. The method of Implementation Scheme 54, wherein the metal hydride is selected from the group consisting of LiAlH4, LiBH4, or Red-Al®.

[0223] Implementation Scheme 56. The method as described in Implementation Scheme 54, wherein the metal hydride is LiAlH4.

[0224] Implementation Scheme 57. The method of any one of Implementation Schemes 46 to 56, wherein the base is a metal alkoxide base.

[0225] Implementation Scheme 58. The method of any one of Implementation Schemes 46 to 57, wherein the alkali is KO t Bu.

[0226] Implementation Scheme 59. The method of any one of Implementation Schemes 46 to 58, wherein the reaction in step (3) is carried out at room temperature.

[0227] Implementation Scheme 60. The method as described in any one of Implementation Schemes 46 to 59, wherein X - It is trifluoromethanesulfonate (TfO) - )ion.

[0228] Implementation Scheme 61. The method of any one of Implementation Schemes 46 to 60, wherein the alkylating agent is , where X is a trifluoromethanesulfonate or a halogen.

[0229] Implementation Scheme 62. The method of Implementation Scheme 61, wherein the alkylating agent is:

[0230] .

[0231] Implementation Scheme 63. The method of any one of Implementation Schemes 46 to 62, wherein the acid is an organic acid or an inorganic acid.

[0232] Implementation Scheme 64. The method as described in Implementation Scheme 63, wherein the acid is trifluoroacetic acid.

[0233] Implementation Scheme 65. The method of any one of Implementation Schemes 46 to 64, wherein R is benzyl.

[0234] Implementation Scheme 66. The method of any one of Implementation Schemes 46 to 65, wherein the agent in which the R group is introduced is a benzyl halide.

[0235] Implementation Scheme 67. The method as described in Implementation Scheme 66, wherein the agent incorporating the R group is benzyl bromide.

[0236] Implementation Scheme 68. A compound of formula (III):

[0237] (III),

[0238] Where X - It is a counter ion.

[0239] Implementation Scheme 69. The compound as described in Implementation Scheme 68, wherein the compound is a compound of formula (IIIa):

[0240] (IIIa),

[0241] Where X - It is a counter ion.

[0242] Implementation Scheme 70. The compound as described in Implementation Scheme 68 or 69, wherein X - It is trifluoromethanesulfonate (TfO) - )ion.

[0243] Implementation Scheme 71. A compound of formula (II):

[0244] (II),

[0245] Or its salt.

[0246] Implementation Scheme 72. The compound as described in Implementation Scheme 71, wherein the compound is a compound of formula (IIa):

[0247] (IIa),

[0248] Or its salt.

[0249] Implementation Scheme 73. A compound of formula (II-1):

[0250] (II-1),

[0251] Or a salt thereof, wherein R is an ester protecting group, wherein the compound is prepared according to any one of embodiments 1 to 37.

[0252] Implementation Scheme 74. A compound of formula (I):

[0253] (I),

[0254] Or a salt thereof, wherein the compound of formula (I) is prepared according to any one of embodiments 38 to 67.

[0255] Synthesis method

[0256] The compounds disclosed herein can be prepared according to the disclosure in the examples shown below.

[0257] The starting materials and reagents used to prepare these compounds can be purchased from commercial suppliers such as MilliporeSigma, Bachem, etc., or prepared by methods known to those skilled in the art, following the procedures described in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (John Wiley and Sons, 4th edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of methods by which the compounds disclosed herein can be synthesized, and various modifications can be made to these schemes, which will be suggested to those skilled in the art upon reading this disclosure. If necessary, conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography, can be used to separate and purify the starting materials, intermediates, and final products of the reaction. These materials can be characterized using conventional methods, including obtaining physical constants and spectroscopic data.

[0258] Unless otherwise specified, the reactions described herein are carried out at atmospheric pressure in a temperature range of about -78°C to about 150°C (such as about 0°C to about 125°C), and further such as at about room temperature (or ambient temperature) of about 20°C.

[0259] Example

[0260] The following methods for preparing the compounds of formulas (I)-(VI) and their salts are given to enable those skilled in the art to more clearly understand and implement this disclosure. They should not be considered as limiting the scope of this disclosure, but are merely illustrative and representative.

[0261] The following abbreviations are used in this section:

[0262] ABq AB Quartet Boc tert-butoxycarbonyl br Broad Peak <![CDATA[CDCl3]]> deuterated chloroform d Double peak ddd Double peaks dt Double Triple Peak dq Double Quadruple Peak DCM dichloromethane EtOAc Ethyl acetate h Hour hex hexane HPLC High performance liquid chromatography <![CDATA[iPr2Net]]> N,N,-Diisopropylethylamine (Hunig's base) KOtBu Potassium tert-butoxide LCAP Percentage of area in liquid chromatography LCMS Liquid chromatography-mass spectrometry <![CDATA[LiAlH4]]> Lithium aluminum hydride MeCN Acetonitrile MeOH methanol m / z mass-to-charge ratio MHz megahertz mL milliliters min minute MTBE tert-butyl methyl ether <![CDATA[Na2CO3]]> Sodium carbonate NaOH Sodium hydroxide <![CDATA[Na2SO4]]> Sodium sulfate NMR Nuclear magnetic resonance OTf Trifluoromethanesulfonate Ph Phenyl q Four Peaks RT room temperature Rt Retention time s Single peak t Triple Peak tBu tert-butyl TFA Trifluoroacetic acid <![CDATA[Tf2O]]> Trifluoromethanesulfonic anhydride THF Tetrahydrofuran

[0263] Unless otherwise stated, all reagents are available from commercial suppliers and can be used without further purification.

[0264] Synthesis of trans-1-Boc-4-fluoro-L-proline benzyl ester

[0265]

[0266] Trans-1-Boc-4-fluoro-L-proline (1,100 g; 428 mmol) was suspended in anhydrous MeCN (450 ml) and stirred with a stir bar in a 1 L flask under nitrogen at room temperature. N,N-diisopropylethylamine (57.08 g / 77 ml; 441.6 mmol) was added from the feed funnel over 30 min. The solid was dissolved at room temperature to form a pale yellow solution, which was then cooled to 0–5 °C in an ice-water bath and stirred for 15 min. Benzyl bromide (75.53 g / 52.5 ml) was added to the yellow solution from the feed funnel over 1 hour. The reaction mixture was stirred overnight, and the temperature was raised from 0 °C to room temperature. LCMS data indicated that ester formation was complete after approximately 24 hours of stirring (< 2% remaining). The mixture was concentrated under reduced pressure using a rotary evaporator connected to a Teflon pump (approximately 30 mm vacuum), and the residue was partitioned with 2-methyltetrahydrofuran (2-MeTHF) (400 ml) and an aqueous solution of citric acid (50 g dissolved in 250 ml water). The phases were separated, and the aqueous layer was re-extracted with 2-MeTHF (2 x 100 ml). The 2-MeTHF layers were combined, washed with water (150 ml), and concentrated under vacuum. The crude product, a grayish-white solid, was purified by crystallization from MTBE-hexane (approximately 1:4 v / v), yielding 113.1 g of product 2. The mother liquor was concentrated and crystallized to give product 2 (yield 15.2 g). The total yield of benzyl ester 2 was 128.3 g (92.5%, 98.2 LCAP purity).

[0267] 1 ¹H-NMR (CDCl₃, 400 MHz): δ 1.36 (s) and 1.48 (s) (9H, tBu); 2.10 (1H, complex peak, -CH-); 2.60 (1H, complex peak, -CH-); 3.61 (1H, complex peak -CH-N); 3.87 (ddd, 1H, -CH-N); 4.45 (t) and 4.54 (t) (1H, -CH-CO-); 5.09 (complex peak) and 5.28 (complex peak) (3H, -CH₂-O and -CH-F); 7.36 ppm (5H, complex peak, Ph).

[0268] 19F-NMR (CDCl3; 282 MHz): δ -177.56 (multiplet), -176.90 (multiplet).

[0269] LCMS: 346.1 (M+Na) + .

[0270] Synthesis of trans-4-fluoro-L-proline benzyl ester

[0271]

[0272] Trifluoroacetic acid (TFA) (25 ml) was mixed with anhydrous dichloromethane (25 ml) and stirred with a stir bar in a 500 ml flask at 0 °C under nitrogen. Trans-1-Boc-4-fluoro-L-proline benzyl ester (2, 20 g, 61.9 mmol) was added in fractions of approximately 2 g over 10 min. A pale yellow solution was formed. The cooling bath was removed, and the solution was allowed to reach room temperature. After 8 hours, a small aliquot was taken and examined by LCMS and HPLC, which showed that the reaction was complete (2 was not detected by HPLC). The mixture was concentrated under reduced pressure, and the yellow liquid residue was partitioned in a 500 ml separatory funnel with tert-butyl methyl ether (MTBE) (200 ml), washed with saturated Na₂CO₃ aqueous solution (100 ml), and then 1 M NaOH (approximately 200 ml) was added to adjust the pH of the aqueous layer to 12. The phases were separated, and the lower aqueous layer was re-extracted with MTBE (2 x 100 ml). The MTBE extracts were combined and washed with brine (150 ml). The combined MTBE extracts were filtered and concentrated under reduced pressure. The crude product was purified by elution through a silica stopper (approximately 100 g; under slight vacuum of approximately 500 mm Hg) with 15% EtOAc-hexane (150 ml), 50% EtOAc-hexane (150 ml), and 75% EtOAc-hexane (300 ml). The filtrates from the 50% and 75% EtOAc-hexane eluates were combined and concentrated under reduced pressure to a pale yellow liquid. The yield of trans-4-fluoro-L-proline benzyl ester 3 was 11.5 g (83.5%).

[0273] 11H-NMR (CDCl3, 400 MHz): δ 2.00 (1H, multiplet, -CH); 2.13 (1H, multiplet, -CH); 2.45 (1H, ddd, NH); 3.17 (1H, dq, -CH-N); 3.22 (1H, q, -CH-N); 4.08 (1H,t, -CH-CO); 5.23 (1H, dt, -CHF), 5.17 (2H, s, -CH2O-); 7.35 (5H, complex peak, Ph).

[0274] 19 F-NMR (CDCl3; 282 MHz): δ -174.60 ppm.

[0275] LCMS: 224.1 (M+H) + .

[0276] Synthesis of (5S,7R)-5-((benzyloxy)carbonyl)-7-fluoro-4-azaspiro[3.4]octyl-4-onium trifluoromethanesulfonate

[0277]

[0278] Trans-4-fluoro-L-proline benzyl ester (4, 2.0 g; 8.96 mmol) and N,N-diisopropylethylamine (3.12 ml; 17.92 mmol) were dissolved in anhydrous toluene (65 ml) in a 100 ml flask equipped with a stir bar under nitrogen atmosphere. The toluene solution was heated and stirred in a heating bath to an internal temperature of approximately 45 °C. A solution of 1,3-propanediol ditrifluoromethanesulfonate (5, 3.04 g; 8.96 mmol) in toluene (10 ml) was added over 30 min, and heating was continued for 4 h. Heating was stopped, and the mixture was allowed to cool to room temperature to obtain a two-phase mixture. The pale yellow upper toluene layer was decanted and stored, and the remaining lower gel in the flask, consisting of product trifluoromethanesulfonate 6, was slowly dried overnight under a nitrogen atmosphere. After drying overnight, the amount of solid containing the product and reagent-related salts was 7.5 g.

[0279] LCMS: 264.1 (M) for amine salt cations. + .

[0280] Synthesis of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-benzyl formate

[0281]

[0282] Crude (5S,7R)-5-((benzyloxy)carbonyl)-7-fluoro-4-azaspiro[3.4]octyl-4-onium trifluoromethanesulfonate (6, 7.36 g, assuming a quantitative conversion from 4 to approximately 8.96 mmol) was dissolved in anhydrous THF and stirred at 0 °C (external ice / water bath temperature) under a nitrogen atmosphere. A potassium tert-butoxide solution (12.9 ml; 1 M THF solution, 12.9 mmol) was added to the solution of ammonium salt 6 via syringe over 15 minutes. The cold water bath was removed, and the mixture was stirred at room temperature for 2 hours. The reactants were filtered through a diatomaceous earth pad, which was then rinsed with THF (5 ml). The combined THF filtrate was concentrated under reduced pressure to give a beige gel powder. The sample was dissolved in DCM and chromatographically separated on a Biotage SP4 system using a silica gel column (25 g) with a gradient of 0-100% EtOAc-hexane: approximately 1 g crude; 25 g silica gel column (Sfar-silica gel column); eluent = 100% hexane (3 column volumes (CV); equivalent), 15% to 100% EtOAc-hexane (15 CV), 100% EtOAc (4 CV); detection at 210 nm and 254 nm (collect all); threshold 35 mAU, 16 x 150 mm tubes; collection of 30 x 21 mL fractions; the enriched fractions #9-14 were combined and concentrated to an oil (322 mg, 13.6%, from 4) containing (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-benzyl formate (7).

[0283] 1 ¹H-NMR: (CDCl₃; 400 MHz): δ 1.80–1.97 (3H, complex peak, 3 x -CH-); 2.25 (1H, dd, -CH-); 2.37–2.54 (2H, complex peak, -CH₂-); 2.93 ppm (1H, complex peak, -CH-N); 3.23–3.86 (3H, complex peak, 3 x -CH-N); 5.13 (2H, s, CH₂O); 5.21 (1H, broad d, -CH-F) and 7.34 (5H, complex peak, Ph).

[0284] 19 F-NMR (CDCl3; 282 MHz): δ -173.34 ppm (complex peak).

[0285] LCMS: 264.1 (M+H) + .

[0286] Synthesis of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol

[0287]

[0288] (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-carboxylic acid benzyl ester (7,263 mg; 1 mmol) was dissolved in anhydrous THF (5 mL) and stirred with a stir bar at 0 °C (external ice-water bath temperature) under a nitrogen atmosphere. Lithium aluminum hydride solution (2 M THF solution, 1.5 mL) was added over 5 min at 0 °C using a syringe. After the addition was complete, the cold bath was removed, and the reaction mixture was stirred at room temperature for 30 min. The reaction progress was assessed by LCMS, and no starting material was detected. The reaction mixture was quenched by adding saturated aqueous Na₂SO₄, resulting in the release of hydrogen gas and the formation of a white gel-like solid. The quenched mixture was filtered through a diatomaceous earth stopper and the stopper was washed with about 30 mL of CH2Cl2. All the filtrate was collected and concentrated under vacuum to give a colorless oil (85 mg) containing a small amount of benzyl alcohol ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol 8.

[0289] 1 ¹H-NMR: (CDCl₃; 400 MHz): δ 0.6–1.13 (6H, complex peak, 3 x -CH₂-); 2.7 (1H, br, -OH); 2.77–3.2 (4H, complex peak, 2 x -CH₂N-CH₂-)); 3.24 and 3.37 ppm (2H, ABq, -CH₂O); 5.11 and 5.30 ppm (1H, complex peak, CHF).

[0290] 19 F-NMR (CDCl3; 282 MHz): δ -172.91 ppm (complex peak).

[0291] LCMS: 160.1 (M+H) + .

[0292] Synthesis of 1,3-propanediol ditrifluoromethanesulfonate

[0293]

[0294] Before starting the experiment, 1,3-propanediol was stored on a molecular sieve at 4 Å for one week to remove trace amounts of water.

[0295] Under nitrogen atmosphere, 1,3-propanediol (8.75 g; 115 mmol) was dissolved in DCM (50 ml) in a dry 1 L flask equipped with a stir bar, followed by the addition of pyridine (18.7 g / 20.7 ml; 236 mmol), and the mixture was cooled to 0 °C. In a dry 250 ml flask, trifluoromethanesulfonic anhydride (68.3 g / 40 ml; 242 mmol) was added to DCM (125 ml) and stirred at -20 °C until a homogeneous solution was obtained. The propylene glycol and pyridine solution was transferred to a 125 mL feeding funnel and added to the trifluoromethanesulfonic acid ester solution over 10 min. The reaction mixture was stirred at -20 °C for 15 min, then the flask was removed and shaken for 10 seconds. The reaction flask was returned to the -20 °C cold bath and stirred for 0.5 h, then for 1 h. The mixture was then warmed to room temperature, resulting in a pink solution with a white precipitate. The reactants were poured into water (250 ml), and the layers were separated. The organic layer was washed with water (2 x 150 ml). The light pink solution was dried over anhydrous Na₂SO₄ for about 10 min, then filtered through a silica gel stopper (80 g), and the filtrate was collected. The silica gel stopper was washed with fresh DCM (150 ml), filtered, and the filtrates were combined. Volatile substances were removed by rotary evaporation under vacuum to obtain a light pink liquid. The yield of 1,3-propanediol ditrifluoromethanesulfonate was 35.5 g (90.5%). The ditrifluoromethanesulfonate was stored at about 0°C.

[0296] 1 H-NMR (CDCl3; 400MHz): d 2.37 (2H, quin, -CH2-); 4.80 ppm (4H, t, -CH2OTf).

[0297] 19 F-NMR (CDCl3; 282.2MHz): d -74.51 ppm.

Claims

1. A compound of formula (II-1): (II-1), A method using a salt thereof, wherein the method comprises making a compound of formula (III-1): (III-1), The compound reacts with a first base in the presence of a first solvent to produce a compound of formula (II-1) or a salt thereof, wherein R is an ester protecting group and X is a counterion.

2. The method of claim 1, wherein the reaction of the compound of formula (III-1) with the first base is carried out at about 0°C to about room temperature.

3. The method of claim 1 or 2, wherein the first base is a metal alkoxide base.

4. The method of claim 3, wherein the first base is KOtBu.

5. The method of any one of claims 1 to 4, wherein the first solvent is a polar aprotic solvent.

6. The method of claim 5, wherein the polar aprotic solvent is an ether solvent.

7. The method of claim 5 or 6, wherein the polar aprotic solvent is THF or 2-MeTHF.

8. The method according to any one of claims 1 to 7, wherein the method produces a compound of formula (II-1) in diastereomeric pure form.

9. The method according to any one of claims 1 to 8, wherein the compound of formula (II-1) is a compound of formula (IIa-1): (IIa-1), Or its salts, and the compound of formula (III-1) is a compound of formula (IIIa-1): (IIIa-1)。 10. The method of any one of claims 1 to 9, wherein the method further comprises: Compounds of formula (IV-1): (IV-1), Or its salt reacts with an alkylating agent in the presence of a second base and a second solvent to produce a compound of formula (III-1): (III-1)。 11. The method of claim 10, wherein the reaction of the compound of formula (IV-1) with the alkylating agent is carried out at approximately room temperature.

12. The method according to any one of claims 1 to 11, wherein X - It is trifluoromethanesulfonate (TfO) - )ion.

13. The method of any one of claims 10 to 12, wherein the alkylating agent is , where X is a trifluoromethanesulfonate or a halide.

14. The method of claim 13, wherein the alkylating agent is: 。 15. The method of any one of claims 10 to 14, wherein the second base is an amine.

16. The method according to any one of claims 10 to 14, wherein the second base is a weak base anion exchange resin.

17. The method of claim 16, wherein the anion exchange resin is Amberlyst™ A-21.

18. The method of any one of claims 15 to 17, wherein the amine is N,N-diisopropylethylamine.

19. The method of any one of claims 10 to 18, wherein the second solvent is a nonpolar solvent.

20. The method of any one of claims 10 to 19, wherein the second solvent is selected from the group consisting of toluene, THF, 2-MeTHF and acetonitrile.

21. The method of claim 20, wherein the second solvent is acetonitrile.

22. The method according to any one of claims 10 to 21, wherein the compound of formula (IV-1) is a compound of formula (IVa-1): (IVa-1), Or its salt.

23. The method of any one of claims 10 to 22, wherein the method further comprises a compound of formula (V-1): (V-1)， Or its salt reacts with an acid in the presence of a third solvent to produce a compound of formula (IV-1): (IV-1), Or its salt.

24. The method of claim 23, wherein the acid is an organic acid or an inorganic acid.

25. The method of claim 24, wherein the acid is trifluoroacetic acid.

26. The method of any one of claims 23 to 25, wherein the third solvent is a polar aprotic solvent.

27. The method of any one of claims 23 to 26, wherein the third solvent is dichloromethane.

28. The method according to any one of claims 23 to 27, wherein the compound of formula (V-1) is a compound of formula (Va-1): (And-1), Or its salt.

29. The method of any one of claims 23 to 28, wherein the method further comprises a compound of formula (VI): (WE), Or its salt reacts with an agent introducing an R group in the presence of a third base and a fourth solvent to produce a compound of formula (V-1): (V-1)， Or its salt.

30. The method of claim 29, wherein the third base is an amine base.

31. The method of claim 30, wherein the amine base is selected from the group consisting of N,N-diisopropylethylamine, triethylamine, and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).

32. The method of any one of claims 29 to 31, wherein the fourth solvent is a polar aprotic solvent.

33. The method of claim 32, wherein the fourth solvent is acetonitrile.

34. The method according to any one of claims 29 to 33, wherein the compound of formula (VI) is a compound of formula (VIa): (VIa), Or its salt.

35. The method of any one of claims 29 to 34, wherein the agent incorporating the R group is a benzyl halide.

36. The method of claim 35, wherein the agent incorporating the R group is benzyl bromide.

37. The method of any one of claims 1 to 36, wherein R is benzyl.

38. A compound of formula (I): (I)， A method using a salt thereof, wherein the method comprises: Compounds of formula (II-1): (II-1), The compound or its salt reacts with a reducing agent in the presence of a fifth solvent to produce a compound of formula (I) or its salt, wherein the compound of formula (II-1) or its salt is prepared by the method according to any one of claims 1 to 37.

39. The method of claim 38, wherein the reducing agent is a metal hydride.

40. The method of claim 39, wherein the metal hydride is selected from the group consisting of LiAlH4, LiBH4, and Red-Al®.

41. The method of any one of claims 38 to 40, wherein the fifth solvent is a polar aprotic solvent.

42. The method of any one of claims 38 to 41, wherein the fifth solvent is an ether solvent.

43. The method of any one of claims 38 to 42, wherein the fifth solvent is selected from the group consisting of THF, Me-THF, diethyl ether, dimethoxyethane and 1,4-dioxane.

44. The method of any one of claims 38 to 43, wherein the method produces a compound of formula (I) in diastereomeric pure form.

45. The method according to any one of claims 38 to 44, wherein the compound of formula (I) is a compound of formula (Ia): (I), Or its salt.

46. ​​A compound of formula (I): (I)， A method using its salt or a salt thereof, wherein the method comprises the following steps: (1) Compounds of formula (VI): (WE), Or its salt reacts with an agent that introduces an R group to produce a compound of formula (V-1): (V-1)， or its salt; (2) Reacting a compound of formula (V-1) or its salt with an acid to produce a compound of formula (IV-1): (IV-1), or its salt; (3) Reacting a compound of formula (IV-1) or a salt thereof with an alkylating agent to produce a compound of formula (III-1): (III-1); (4) React the compound of formula (III-1) with a base to produce the compound of formula (II-1): (II-1), or its salt; as well as (5) React the compound of formula (II-1) or its salt with a reducing agent to produce the compound of formula (I) or its salt; R is an ester protecting group and X is a counter ion.

47. The method of claim 46, wherein step (4) produces a compound of formula (II-1) in diastereomeric pure form.

48. The method of claim 46 or 47, wherein the compound of formula (II-1) is a compound of formula (IIa-1): (IIa-1), Or its salts, and the compound of formula (III-1) is a compound of formula (IIIa-1): (IIIa-1)。 49. The method according to any one of claims 46 to 48, wherein the compound of formula (I) is a compound of formula (Ia): (I), Or its salt.

50. The method according to any one of claims 46 to 49, wherein the compound of formula (IV-1) is a compound of formula (IVa-1): (IVa-1), Or its salt.

51. The method according to any one of claims 46 to 50, wherein the compound of formula (V-1) is a compound of formula (Va-1): (And-1), Or its salt.

52. The method according to any one of claims 46 to 51, wherein the compound of formula (VI) is a compound of formula (VIa): (VIa), Or its salt.

53. The method according to any one of claims 46 to 52, wherein the reaction in step (4) is carried out at about 0°C to about room temperature.

54. The method of any one of claims 46 to 53, wherein the reducing agent is a metal hydride.

55. The method of claim 54, wherein the metal hydride is selected from the group consisting of LiAlH4, LiBH4, and Red-Al®.

56. The method of claim 54, wherein the metal hydride is LiAlH4.

57. The method according to any one of claims 46 to 56, wherein the base is a metal alkoxide base.

58. The method of any one of claims 46 to 57, wherein the base is KOtBu.

59. The method of any one of claims 46 to 58, wherein the reaction in step (3) is carried out at room temperature.

60. The method of any one of claims 46 to 59, wherein X - It is trifluoromethanesulfonate (TfO) - )ion.

61. The method of any one of claims 46 to 60, wherein the alkylating agent is , where X is a trifluoromethanesulfonate or a halogen.

62. The method of claim 61, wherein the alkylating agent is: 。 63. The method of any one of claims 46 to 62, wherein the acid is an organic acid or an inorganic acid.

64. The method of claim 63, wherein the acid is trifluoroacetic acid.

65. The method of any one of claims 46 to 64, wherein R is benzyl.

66. The method of any one of claims 46 to 65, wherein the agent incorporating the R group is a benzyl halide.

67. The method of claim 66, wherein the agent incorporating the R group is benzyl bromide.

68. A compound of formula (III): (III), Where X - It is a counter ion.

69. The compound of claim 68, wherein the compound is a compound of formula (IIIa): (IIIa), Where X - It is a counter ion.

70. The compound of claim 68 or 69, wherein X - It is trifluoromethanesulfonate (TfO) - )ion.

71. A compound of formula (II): (II), Or its salt.

72. The compound of claim 71, wherein the compound is a compound of formula (IIa): (IIa), Or its salt.

73. A compound of formula (II-1): (II-1), Or a salt thereof, wherein R is an ester protecting group, wherein the compound is prepared by the method according to any one of claims 1 to 37.

74. A compound of formula (I): (I)， Or a salt thereof, wherein the compound of formula (I) is prepared by the method according to any one of claims 38 to 67.

Images