Synthesis method and use of a modified long-chain fatty acid type PET reagent precursor

Abstract

The present application discloses a method for synthesizing a modified long-chain fatty acid-type PET reagent precursor and its use. The reaction and post-treatment operations of this route are simple, the reactants are easily available, the reagents used are safe and environmentally friendly, and the overall yield can reach more than 15%.

Description

[0001] This application is a divisional application of the Chinese patent application with Chinese application number 2022108670415, invention name “A method for synthesizing a modified long-chain fatty acid type PET reagent precursor and its use” and application date July 22, 2022. Technical Field

[0002] The present application relates to the field of organic chemical synthesis, and in particular to a new process route for modifying fatty acid-type PET reagent precursors. Background Art

[0003] PET (positron emission tomography) is a relatively advanced clinical imaging technology in the field of nuclear medicine. Its general method is to label a substance, generally a substance necessary for biological metabolism, such as glucose, protein, nucleic acid, fatty acid, with a short-lived radionuclide (such as 18 F, 11 C, etc.), after being injected into the human body, the accumulation of the substance in metabolism is used to reflect the status of life metabolic activities, thereby achieving the purpose of diagnosis.

[0004] In the basic aerobic metabolism of the myocardium, 70% of ATP is produced by β-oxidation of fatty acids, so fatty acids or modified fatty acids are suitable cardiac positron emission tomography imaging agents. Because the metabolism rate of unmodified fatty acids is too fast and the radioactive atoms are more concentrated in the liver or lungs rather than in the parts required for diagnosis, modified fatty acids have greater diagnostic value.

[0005] [ 18 F]CardioPET is an innovative PET reagent, a modified long-chain fatty acid PET reagent, which is currently undergoing clinical research. Its characteristic is that a cyclopropane ring is introduced at the CH2CO2H group, making its absorption and enrichment behavior similar to that of fatty acids, but difficult to undergo β-oxidation, so it can be retained in cardiomyocytes, and then can be used for 18 The decay of F produces positrons, which form medically useful images to study cardiac metabolism and diagnose diseases, especially coronary heart disease.

[0006]

[0007] The compounds of formula (I), (Ia) and (Ib) are [ 18 F]CardioPET precursor can be used with K produced by isotope irradiation 18 After F undergoes substitution reaction and hydrolysis reaction, it is purified by semi-preparative chromatography for diagnostic purposes (references: US7790142, US2004253177).

[0008]

[0009] Chinese Patent CN108727229B also discloses a preparation method of the compounds of formula (I), (Ia) and (Ib). However, the yield of the 18 precursor of [18F]CardioPET prepared by the disclosed preparation method is relatively low, only about 5%, so it is necessary to explore ways to improve 18 the synthesis yield of the precursor of [18F]CardioPET. Summary of the Invention

[0010] Therefore, the present application has developed a new route for synthesizing a modified long-chain fatty acid PET reagent precursor. Specifically, the following technical methods are adopted in the present application:

[0011] 1. A method for using compound 7 to synthesize a compound of formula (I), wherein the compound of formula (I) is as follows:

[0012]

[0013] wherein R represents C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, cyclopropyl or cyclopentyl, etc.; more preferably, R is tert-butyl;

[0014] X is a sulfonyl group; preferably, X is selected from mesyl group, p-toluenesulfonyl group, trifluoromethanesulfonyl group, etc.; preferably, X is mesyl group;

[0015] Compound 7 is as follows:

[0016]

[0017] wherein Pg represents a protecting group; preferably, Pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; most preferably, Pg is benzyl.

[0018] 2. The method according to item 1, which includes the step of oxidizing compound 7 to compound 8:

[0019]

[0020] Preferably, the oxidation reaction is carried out using an oxidant selected from the following: sodium chlorite, potassium permanganate;

[0021] Preferably, the oxidation reaction temperature is 10 - 50 °C.

[0022] 3. The method according to item 1 or 2, further comprising the step of esterifying compound 8 to obtain compound 9:

[0023]

[0024] 4. The method according to any one of items 1 - 3, further comprising the step of removing the protecting group from compound 9 to obtain compound 10:

[0025]

[0026] 5. The method according to any one of items 1 - 4, further comprising the step of sulfonating compound 10 to obtain the compound of formula (I):

[0027]

[0028] 6. The method according to any one of items 1 - 5, further comprising the step of cyclizing compound 6 to convert it into compound 7:

[0029]

[0030] Preferably, the following cyclization reagents selected from are used for the cyclization reaction: zinc diiodomethylide, potassium (iodomethyl)trifluoroborate, chloroiodomethane and diiodomethane, preferably diiodomethane;

[0031] Preferably, the cyclization reaction is carried out in a reagent selected from the following: n - hexane, dichloromethane, tetrahydrofuran, dichloroethane, toluene, diethyl ether and 1,4 - dioxane, preferably tetrahydrofuran.

[0032] 7. The method according to any one of items 1 - 6, further comprising the step of deprotecting compound 5 to convert it into compound 6:

[0033]

[0034] Preferably, the following reagents selected from are used for the deprotection reaction: sulfonic acid, p - toluenesulfonic acid, hydrochloric acid, hydrobromic acid, boron trifluoride diethyl etherate, acetic acid, phosphoric acid or formic acid, more preferably p - toluenesulfonic acid.

[0035] 8. The method according to any one of items 1 - 7, further comprising the step of reducing compound 4 to convert it into compound 5:

[0036]

[0037] Preferably, the molar ratio of compound 4 to the reducing agent is 1:1.0 - 1:4.0;

[0038] Preferably, the reducing agent is lithium aluminum hydride.

[0039] 9. The method according to any one of items 1 - 8, further comprising the step of converting compound 3 into compound 4 through a substitution reaction:

[0040]

[0041] Preferably, compound 3 undergoes a substitution reaction with 2-(4-pentynyloxy)tetrahydro-2H-pyran.

[0042] More preferably, the molar ratio of compound 3 to 2-(4-pentynyloxy)tetrahydro-2H-pyran is 1:1.0 to 1:3.0;

[0043] Preferably, the deprotonating agent used is selected from the following strong basic reagents: NaH, KH, lithium amide or n-butyllithium, preferably n-butyllithium.

[0044] 10. The method according to any one of items 1 - 9, further comprising the step of converting compound 2 into compound 3 through an Appel reaction:

[0045]

[0046] Preferably, the following halogenating reagents are used for the Appel reaction: methyl iodide or iodine, preferably iodine;

[0047] Preferably, the molar ratio of compound 2 to the halogenating reagent is 1:1.0 to 1:2.0.

[0048] 11. The method according to any one of items 1 - 10, further comprising the step of converting compound 1 into compound 2 through a Brown hydroboration-oxidation reaction:

[0049]

[0050] Preferably, the following reagents are used for the reaction:

[0051] The solvent is selected from diglyme, tetrahydrofuran, diethyl ether or 1,4-dioxane, preferably tetrahydrofuran;

[0052] Preferably, the oxidizing agent is selected from m-chloroperoxybenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid or perbenzoic acid, preferably hydrogen peroxide;

[0053] Preferably, the molar ratio of compound 1 to the oxidizing agent is 1:3.0 to 1:8.0.

[0054] 12. A method for synthesizing a compound of formula (I) using compound 1, comprising the following steps:

[0055] The compound of formula (I) is as follows:

[0056]

[0057] Wherein, R represents C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, cyclopropyl or cyclopentyl, etc.; more preferably, R is tert-butyl;

[0058] X is a sulfonyl group; preferably, X is selected from mesyl, p-toluenesulfonyl, trifluoromethanesulfonyl, etc.; preferably, X is mesyl;

[0059]

[0060] 13. The method according to item 12, which comprises the following steps:

[0061]

[0062] 14. The method according to item 13, which comprises the following steps:

[0063]

[0064] 15. Compound 7:

[0065]

[0066] Wherein Pg represents a protecting group; preferably, Pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; most preferably, Pg is benzyl.

[0067] 16. A method for synthesizing compound 7 using compound 1, which comprises the following steps:

[0068] Compound 7 is as follows:

[0069]

[0070] Wherein Pg represents a protecting group; preferably, Pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl; most preferably, Pg is benzyl.

[0071]

[0072] 17. Compound 6:

[0073]

[0074] Wherein Pg represents a protecting group; preferably, Pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl; most preferably, Pg is benzyl.

[0075] 18. Compound 5:

[0076]

[0077] Wherein Pg represents a protecting group; preferably, Pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl; most preferably, Pg is benzyl.

[0078] 19. Compound 4:

[0079]

[0080] Wherein Pg represents a protecting group; preferably, Pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl; most preferably, Pg is benzyl.

[0081] 20. Compound 3:

[0082]

[0083] Wherein Pg represents a protecting group; preferably, Pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl; most preferably, Pg is benzyl.

[0084] 21. Compound 2:

[0085]

[0086] Wherein Pg represents a protecting group; preferably, Pg is a protecting group selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl; most preferably, Pg is benzyl.

[0087] Advantages of the Invention

[0088] Through a large number of experimental attempts, this application has developed a new route for synthesizing a modified long-chain fatty acid PET reagent precursor, which has the following advantages:

[0089] 1. The synthesis route reaction and post-treatment operation of this application are simple, the reactants are easily available, and the reagents used are environmentally friendly. In the existing methods for synthesizing modified long-chain fatty acid PET reagent precursors, such as those disclosed in Chinese Patent CN108727229B, NaH is used as a reactant multiple times. This substance releases hydrogen that can explode when exposed to water or moist air, posing a relatively high risk. In the new synthesis method provided by this application, NaH-like substances are no longer used, resulting in better safety. In the current existing processes, meta-chloroperoxybenzoic acid is mostly used during the oxidation process. This substance is prone to decomposition and explosion when heated, is corrosive, and is not environmentally friendly. After changing the reaction route in the new synthesis method provided by this application, the water-soluble oxidation reagent hydrogen peroxide is used for the reaction, which is more environmentally friendly. Moreover, most of the reaction types used in the new reaction route of this application are classical reactions, which have been verified for a long time, with stable processes and easy to complete.

[0090] 2. This application significantly improves the total yield of the modified long-chain fatty acid PET reagent precursor. Compared with the synthesis method disclosed in Chinese Patent CN108727229B in the prior art, whose total yield is about 5%, the total yield of the synthesis route provided by this application can reach more than 15%, with the yield increased by more than 2 times, showing an obvious cost advantage.

[0091] 3. The overall synthesis method of this application involves 10 reaction steps, with a more concise and easy-to-operate reaction process. Compared with the synthesis route with up to 20 steps in the prior art, it saves a large amount of labor and material costs and has better application prospects. Detailed Embodiments

[0092] The following describes exemplary embodiments of this application, including various details of the embodiments of this application to facilitate understanding. It should be considered merely exemplary. Therefore, those of ordinary skill in the art should recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of this application. Similarly, for the sake of clarity and conciseness, the description of well-known functions and structures is omitted below.

[0093] Definitions

[0094] All terms used in this application have the meanings commonly understood by those skilled in the art. Additionally, they can also have the following meanings.

[0095] The compound of formula (I) is shown as follows:

[0096] The compound (I) refers to the modified long-chain fatty acid type PET reagent precursor mentioned in this application, that is 18 F] CardioPET reagent precursor.

[0097] “C 1-6"Alkyl" refers to a straight-chain or branched-chain saturated monovalent alkyl (hydrocarbon) group containing 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl is preferred. Typical C 1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), isopentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6), etc. The term "C 1-6 alkyl" also includes heteroalkyl groups in which 1 to 3 atoms selected from O, S, N, or substituted nitrogen atoms may replace carbon atoms.

[0098] "C 2-6 Alkenyl" denotes a straight-chain or branched-chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond, including but not limited to vinyl, 3-buten-1-yl, 2-vinylbutyl, 3-hexen-1-yl, etc. In some embodiments, C 2-4 alkenyl is preferred. The term "C 2-6 alkenyl" also includes heteroalkenyl groups in which 1 to 3 atoms selected from O, S, N, or substituted nitrogen atoms may replace carbon atoms.

[0099] "C 2-6 Alkynyl" refers to a straight-chain or branched-chain hydrocarbon group having 2 to 6 carbon atoms, which contains at least one carbon-carbon triple bond and optionally one or more unsaturated carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Typical alkynyl groups include ethynyl, propynyl, isopropylnyl, butynyl, isobutynyl, pentynyl, and hexynyl. The term "C 2-6 alkynyl" also includes heteroalkynyl groups in which 1 to 3 atoms selected from O, S, N, or substituted nitrogen atoms may replace carbon atoms.

[0100] The term "halogen" as used in this application refers to F, Cl, Br, and I. Preferably, the halogen in this application is selected from Cl, Br, and I; more preferably, the halogen in this application is selected from Cl or Br.

[0101] "C 1-6 Halogenated alkyl" refers to the above-mentioned "C 1-6 alkyl" which is substituted by one or more halogens. In some embodiments, C 1-4 halogenated alkyl is preferred, and more preferably C 1-2Haloalkyl. Exemplary haloalkyls include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethylethyl, and the like.

[0102] "C 3-7 Cycloalkyl" means a non-aromatic cycloaliphatic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-6 Cycloalkyl is particularly preferred, and more preferably C 5-6 Cycloalkyl. Cycloalkyl also includes ring systems in which the above cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like.

[0103] "3- to 7-membered heterocyclic group" means a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably a 3- to 6-membered heterocyclic group, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4- to 6-membered heterocyclic group, which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclic group, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. The heterocyclic group also includes a ring system in which the above-mentioned heterocyclic group ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or a ring system in which the above-mentioned heterocyclic group ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic group ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclic group ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolidine-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxasulfuranyl, disulfuranyl and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridyl and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepanyl and thiepanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, iso-dihydroindolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0104] "C 6-10"Aryl" refers to a group having from 6 to 10 ring carbon atoms and zero heteroatoms, which is a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement). In some embodiments, the aryl has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl has ten ring carbon atoms ("C 10 10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system.

[0105] "5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6 or 10 π electrons shared in a cyclic arrangement), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In a heteroaryl containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence allows. The bicyclic heteroaryl system can include one or more heteroatoms in one or two rings. Heteroaryl also includes a ring system in which the above heteroaryl ring is fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5 membered heteroaryls containing one heteroatom include, but are not limited to: pyrrolyl, furyl, and thienyl. Exemplary 5 membered heteroaryls containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5 membered heteroaryls containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5 membered heteroaryls containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6 membered heteroaryls containing one heteroatom include, but are not limited to: pyridyl. Exemplary 6 membered heteroaryls containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6 membered heteroaryls containing three or four heteroatoms include, but are not limited to: triazinyl and tetrazinyl, respectively. Exemplary 7 membered heteroaryls containing one heteroatom include, but are not limited to: azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, isobenzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0106] "Sulfonyl" means the group R-SO2-, where R represents C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0107] "Methanesulfonyl" means the group Me-SO2-.

[0108] "p-Toluenesulfonyl" means the group p-CH3-C6H4-SO2-.

[0109] "Trifluoromethanesulfonyl" means the group CF3-SO2-.

[0110] As used herein, the term "aldehyde group" refers to the group -C(O)H.

[0111] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined herein are optionally substituted groups.

[0112] Exemplary substituents on a carbon atom include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb ) 3+ X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(Rbb ) 2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa )3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;

[0113] or two geminal hydrogens on a carbon atom are substituted by a group =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc ;

[0114] Each R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, or two R aa groups combine to form a heterocyclic group or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;

[0115] Each R bb is independently selected from: hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, or two R bb groups combine to form a heterocyclic group or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 Rdd Group substitution;

[0116] R cc Each of the is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, or two R cc groups combine to form a heterocyclic group or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;

[0117] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff ) 3+ X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee , -OC(=NRff)R ee , -OC(=NRff)OR ee , -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)Ree , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may combine to form =O or =S;

[0118] Each of R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;

[0119] Each of R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, or two R ff groups combine to form a heterocyclic group or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;

[0120] Each of R gg is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl) 3+ X - , -NH(C 1-6 alkyl) 2+ X - , -NH2(C 1-6 alkyl) + X - , -NH 3+ X- ,-N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 alkyl, -SO2OC 1-6 alkyl, -OSO2C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6(alkyl), C(=S)NH2, -C(=O)S(C 1-6 (alkyl), -C(=S)SC 1-6 (alkyl), -SC(=S)SC 1-6 (alkyl), -P(=O)2(C 1-6 (alkyl), -P(=O)(C 1-6 (alkyl)2, -OP(=O)(C 1-6 (alkyl)2, -OP(=O)(OC 1-6 (alkyl)2, C 1-6 (alkyl), C 1-6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 aryl, C3-C7 heterocyclic group, C5-C 10 heteroaryl; or two geminal R gg substituents may combine to form =O or =S; wherein, X - is a counterion.

[0121] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, or two R's attached to the nitrogen atom ccGroups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rs dd groups, and wherein R aa , R bb , R cc and R dd are as described above.

[0122] The term "oxidation reaction" as used in this application refers to a reaction that introduces oxygen or removes hydrogen in the compounds of this application. More specifically, it refers to the reaction of converting an aldehyde group into a carboxylic acid group. The oxidation reaction can be achieved using a variety of oxidants well-known in the art, including but not limited to sodium chlorite, potassium permanganate, PCC (pyridinium chlorochromate), and manganese dioxide.

[0123] Preferably, the temperature of the oxidation reaction in this application is 10 - 50 °C, for example, it can be 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C.

[0124] The term "protecting group" as used in this application refers to a group that can covalently bind to a functional group to protect it from chemical reactions and can be removed after the reaction is completed to restore the functional group. More specifically, the protecting group in this application refers to an oxygen protecting group (also known as a hydroxyl protecting group). Oxygen protecting groups are well-known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, Third Edition, John Wiley & Sons, 1999, which is hereby incorporated by reference.

[0125] Exemplary oxygen protecting groups include, but are not limited to, methyl, tert-butoxycarbonyl (BOC or Boc), methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyl oxymethyl (POM), silyloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothienyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylseleno)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridylmethyl, 4-pyridylmethyl, 3-methyl-2-pyridylmethyl N-oxide, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, bis(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4'-bromobenzoyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(acetylpropionyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiol-2-yl, benzisothiazolyl S,S - dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert - butyldimethylsilyl (TBDMS), tert - butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri - p - xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert - butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p - chlorophenoxyacetate, 3 - phenylpropionate, 4 - oxopentanoate (levulinate), 4,4 - (ethylenedithio)pentanoate (levulinoyl dithioacetal), pivalate, adamantoate, crotonate, 4 - methoxycrotonate, benzoate, p - phenylbenzoate, 2,4,6 - trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9 - fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2 - trichloroethyl carbonate (Troc), 2 - (trimethylsilyl)ethyl carbonate (TMSEC), 2 - (phenylsulfonyl)ethyl carbonate (Psec), 2 - (triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p - nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p - methoxybenzyl carbonate, alkyl 3,4 - dimethoxybenzyl carbonate, alkyl o - nitobenzyl carbonate, alkyl p - nitobenzyl carbonate, alkyl S - benzylthiocarbonate, 4 - ethoxy - 1 - naphthyl carbonate, methyl dithiocarbonate, 2 - iodobenzoate, 4 - azidobutyrate, 4 - nitro - 4 - methylpentanoate, o - (dibromomethyl)benzoate, 2 - formylbenzenesulfonate, 2 - (methylthiomethoxy)ethyl, 4 - (methylthiomethoxy)butyrate, 2 - (methylthiomethoxymethyl)benzoate, 2,6 - dichloro - 4 - methylphenoxyacetate, 2,6 - dichloro - 4 - (1,1,3,3 - tetramethylbutyl)phenoxyacetate, 2,4 - bis(1,1 - dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E) - 2 - methyl - 2 - butenoate, o - (methoxycarbonyl)benzoate, α - naphthoate, nitrate, alkyl N,N,N’,N’ - tetramethylphosphorodiamidate, alkyl N - phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4 - dinitrophenylsulfinate, sulfate, methanesulfonate (mesylate), benzylsulfonate and toluenesulfonate (Ts).

[0126] "Hydroxy protection" and "deprotection" respectively refer to the reaction of introducing a protecting group to the hydroxyl functional group and removing the protecting group to restore the hydroxyl functional group. The reaction conditions for introducing and removing the protecting group are well-known to those skilled in the art. The preferred reaction reagents in this application are sulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, boron trifluoride etherate, acetic acid, phosphoric acid or formic acid, and the more preferred reagent is p-toluenesulfonic acid.

[0127] The term "esterification reaction" used in this application refers to the reaction of converting a carboxyl group into an ester group. The esterification reaction can be achieved using a variety of reagents well-known in the art, including but not limited to halogenated hydrocarbons, alcohols, etc.

[0128] The term "sulfonylation" used in this application refers to the reaction of converting a hydroxyl group into a sulfonyloxy group. For example, methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc. can achieve the said reaction.

[0129] The term "cyclization reaction" used in this application refers to the reaction of forming a new carbon ring or heterocyclic ring in an organic compound molecule, also known as ring closure or ring-forming condensation. When forming a carbon ring, the ring closure reaction is completed by forming a carbon-carbon bond; when forming a cyclic structure containing heteroatoms, it can be completed by forming a carbon-carbon bond, or by forming a carbon-heteroatom bond (C-N, C-O, C-S bonds, etc.), and sometimes it can also be completed by forming a bond between two heteroatoms (N-N, N-S bonds, etc.). The cyclization reaction can be achieved using a variety of reagents well-known in the art, including but not limited to iodomethylzinc, potassium (iodomethyl)trifluoroborate, chloroiodomethane and diiodomethane. The further preferred reagent in this application is diiodomethane; the cyclization reaction in this application is further preferably carried out in a selected one of the following reagents: n-hexane, dichloromethane, tetrahydrofuran, dichloroethane, toluene, ether and 1,4-dioxane, preferably tetrahydrofuran.

[0130] The term "reduction reaction" used in this application refers to the reaction of introducing hydrogen or removing oxygen in the compounds of this application. More specifically, it refers to the reaction of converting an ester group into an aldehyde group. The reduction reaction can be achieved using a variety of reducing agents well-known in the art, including but not limited to the one-step conversion of DIBAL-H, and first using NaBH4, borane-tetrahydrofuran complex, lithium aluminum hydride, DIBAL-H, red aluminum, etc. The preferred reagent in this application is lithium aluminum hydride. In a further preferred embodiment, in the process of converting compound 4 into compound 5 by the reduction reaction, the molar ratio of compound 4 to the reducing agent is 1:1.0 to 1:4.0, for example, it can be 1:1.0, 1:1.5, 1:2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0.

[0131] The term "substitution reaction" used in this application refers to a reaction in which any atom or atomic group in a compound or organic molecule is replaced by another atom or atomic group of the same type in a reagent. The substitution reaction can be achieved using a variety of reagents well-known in the art. In a preferred embodiment of this application, compound 3 undergoes a substitution reaction with 2-(4-pentynyloxy)tetrahydro-2H-pyran. Further preferably, the molar ratio of compound 3 to 2-(4-pentynyloxy)tetrahydro-2H-pyran is 1:1.0 to 1:3.0; for example, it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0. In a preferred embodiment of this application, during the substitution reaction, the deprotonating reagent used is selected from the following reagents: alkali metal hydrides such as NaH and KH, lithium amide, or n-butyllithium, preferably n-butyllithium.

[0132] The term "Appel reaction" used in this application refers to the conversion of primary and secondary alcohols to alkyl halides using carbon tetrahalide and triphenylphosphine. Alkyl bromides and alkyl iodides can also be prepared by replacing carbon tetrachloride with carbon tetrabromide or bromine, carbon tetraiodide, iodomethane, or iodine, respectively. This reaction is a relatively mild method for introducing halogen atoms. The Appel reaction can be achieved using a variety of reagents well-known in the art, including but not limited to carbon tetrabromide, bromine, iodomethane, or iodine. The preferred halogenating reagent in this application is iodine. During the process of converting compound 2 to compound 3 by the Appel reaction, in a preferred embodiment, the molar ratio of compound 2 to the halogenating reagent is 1:1.0 to 1:2.0, for example, it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0.

[0133] The term "Brown hydroboration-oxidation reaction" used in this application refers to the reaction in which borane undergoes a concerted cis-addition to an alkene to obtain an organoboron addition product, and then undergoes oxidation under alkaline conditions to obtain an alcohol. The Brown hydroboration-oxidation reaction can be achieved using a variety of reagents well-known in the art. In a preferred embodiment, the solvent is selected from diglyme, tetrahydrofuran, diethyl ether, or 1,4-dioxane, and more preferably tetrahydrofuran. In another preferred embodiment, the oxidizing agent is selected from m-chloroperoxybenzoic acid, peracetic acid, hydrogen peroxide, trifluoroperacetic acid, or perbenzoic acid, and more preferably hydrogen peroxide. In the process of converting compound 1 into compound 2 through the hydroboration-oxidation reaction, the molar ratio of compound 1 to the oxidizing agent is 1:3.0 to 1:8.0, for example, it can be 1:3.0, 1:3.5, 1:4.0, 1:4.5, 1:5.0, 1:5.5, 1:6.0, 1:6.5, 1:7.0, 1:7.5, 1:8.0.

[0134] Examples

[0135] 1. Synthesis of compound 2a from compound 1a

[0136] The synthesis route is as follows:

[0137]

[0138] The specific synthesis steps are as follows: Add compound 1a (25.0 g, 86.73 mmol) to a 500 mL three-necked flask. Under a nitrogen atmosphere, add 100 mL of anhydrous tetrahydrofuran (THF). At 0-5 °C, dropwise add borane dimethyl sulfide complex (13.4 g, 173.46 mmol, 1 M THF solution). After the addition is complete, warm the reaction system to room temperature and then reflux for 4 hours. Cool the reaction system to 0 °C, and successively add 30 mL of ethanol, 4 M NaOH solution (30 mL), and 30% hydrogen peroxide (H2O2) (35 mL). Stir the solution of compound 1a at room temperature for 2 hours for the oxidation reaction. Add 100 mL of water and 100 mL of methyl tert-butyl ether to the system, extract and separate the layers; wash the organic phase with 200 mL of saturated ammonium chloride solution, separate the layers; wash the organic phase with 200 mL of saturated sodium chloride solution, separate the layers; dry the organic phase with anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, and purify the crude product by flash column chromatography on silica gel (eluent: cyclohexane / EtOAc 100 / 0 to 10 / 90) to obtain 20.0 g of the product. Yield: 75.3%.

[0139] 1H-NMR (400 MHz, CDCl3) δ: 0.86 (t, 3H), 1.24 - 1.58 (m, 20H), 2.98 (m, 2H), 3.38 (m, 1H), 4.62 (s, 2H), 4.76 (m, 1H), 7.28 - 7.32 (m, 5H)

[0140] 2. Synthesis of Compound 3a from Compound 2a

[0141] The synthesis route is as follows:

[0142]

[0143] The specific synthesis steps are as follows: Add Compound 2a (18.0 g, 58.75 mmol), imidazole (8.0 g, 0.1175 mol), triphenylphosphine (PPh3) (32.6 g, 0.1243 mol), and anhydrous tetrahydrofuran (THF) (250 mL) into a 500 - mL three - necked flask. Add iodine (I2) (31.5 g, 0.1242 mol) to Compound 2a under a nitrogen atmosphere at 0 °C. After addition, raise the temperature to room temperature and stir overnight. Quench the reaction with saturated sodium sulfite solution. Wash the combined organic solution with water and brine using ethyl acetate (2 × 100 mL). Dry over anhydrous sodium sulfate, filter, and concentrate to obtain a viscous oil. Purify it by silica gel column chromatography (eluent: cyclohexane / EtOAc 100 / 10 to 5 / 95) to obtain 14.8 g of Compound 3a. Yield: 81.1%.

[0144] 1H-NMR (400 MHz, CDCl3) δ: 0.88 (t, 3H), 1.24 - 1.85 (m, 18H), 2.92 (m, 2H), 3.40 (m, 1H), 3.64 (m, 2H), 4.52 (s, 2H), 7.30 - 7.35 (m, 5H)

[0145] 3. Synthesis of Compound 4a from Compound 3a

[0146] The synthesis route is as follows:

[0147]

[0148] The specific synthesis steps are as follows:

[0149] 2-(Pent-4-yn-1-yloxy)tetrahydro-2H-pyran (15.4 g, 91.38 mmol) and anhydrous tetrahydrofuran (THF) (200 mL) were added to a 500 mL three-necked flask. Under a nitrogen atmosphere and at a low temperature of -30 °C, n-butyllithium (n-BuLi) (57.1 mL of a 1.6 M hexane solution, 91.38 mmol) and compound 3a (19.0 g, 45.66 mmol) were added. After addition, the solution was warmed to room temperature and reacted for 6 hours. After the reaction was completed, saturated NH4Cl was added. The resulting mixture was extracted with hexane / EtOAc (1:1) (3 × 100 mL). The combined extracts were washed with water, dried over magnesium sulfate and concentrated to leave a residue, which was purified by silica gel column chromatography (n-heptane:ethyl acetate = 100:1 to 50:1) to obtain 17.8 g of a colorless oily liquid. Yield: 88.1%.

[0150] 1H NMR (400 MHz, CDCl3)) δ 0.88 (m, 3H), 1.26 - 1.79 (m, 26H), 2.15 (m, 2H), 2.40 (m, 2H) 3.11 (p, 1H), 3.52 (m, 2H), 3.72 (m, 2H) 4.56 (m, H) 4.63 (d, 2H), 7.30 - 7.32 (m, 5H)

[0151] 4. Synthesis of compound 5a from compound 4a

[0152] The synthetic route is as follows:

[0153]

[0154] Specific synthesis steps are as follows: Under argon, at 0 °C, lithium aluminum hydride (LAH / LiAlH4) (1.88 g, 49.54 mmol) was suspended in 200 mL of anhydrous tetrahydrofuran (THF). Ethanol (4.2 g, 91.16 mmol) was added dropwise to the suspension, and then compound 4a (20.0 g, 45.21 mmol) in 50 mL of anhydrous tetrahydrofuran (THF) was added dropwise. After the addition was completed, the two solutions were mixed, and the reaction mixture was warmed to room temperature and then heated to reflux for 1 hour. The mixture was carefully quenched with water and 2 M NaOH, and the resulting white aluminum salt was vacuum filtered through a sintered glass funnel. The salt was washed repeatedly with 100 mL of hot tetrahydrofuran, and the combined filtrates were dried over anhydrous sodium sulfate and concentrated under reduced pressure at 30 - 40 °C. Purification by silica gel column chromatography (n-heptane:ethyl acetate = 100:1 to 50:1) gave 16.5 g of compound 5a. Yield: 82.1%.

[0155] 1H NMR (400 MHz, CDCl3)) δ 0.88 (m, 3H), 1.24 - 1.78 (m, 26H), 2.15 (m, 2H), 2.20 (m, 2H) 3.21 (p, 1H), 3.43 (m, 2H), 3.72 (m, 2H) 4.58 (m, H) 4.62 (d, 2H), 5.42 - 5.46 (m, 2H), 7.26 - 7.32 (m, 5H)

[0156] Synthesis of Compound 6a from Compound 5a

[0157] The synthesis route is as follows:

[0158]

[0159] The specific synthesis steps are as follows: Under nitrogen protection, methanol (MeOH) (150 ml) and 5 ml of water were added to a 500 - milliliter three - necked flask. p - Toluenesulfonic acid (PTSA) (0.6 g, 4.0% wt.) and Compound 5a (15.0 g, 33.76 mmol) were added. The reaction mixture was heated to 60 °C and stirred for 2 hours. Then it was cooled to room temperature, diluted with water and adjusted to pH = 8 - 10 with saturated sodium bicarbonate solution. Then it was extracted with ethyl acetate (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 30 - 40 °C to obtain the crude product. It was purified by silica gel column chromatography (n - heptane:ethyl acetate = 100:1 - 50:1) to obtain 9.8 g. Yield: 80.6%.

[0160] 1H NMR (400 MHz, CDCl3)) δ 0.86 (m, 3H), 1.16 - 1.45 (m, 20H), 2.15 (m, 2H), 2.20 (m, 2H) 3.21 (p, 1H), 3.58 (m, 2H), 4.24 (m, H) 4.62 (d, 2H), 5.43 - 5.46 (m, 2H), 7.28 - 7.32 (m, 5H)

[0161] Synthesis of Compound 7a from Compound 6a

[0162] The synthesis route is as follows:

[0163]

[0164] The specific synthesis steps are as follows: Using anhydrous tetrahydrofuran (THF) (250 mL) as the solvent, add it to a 500 mL three-necked flask, cool down to -30 °C, and sequentially dropwise add diethylzinc (DEZ) solution (15.4 g, 124.9 mmol), dimethyl ether (DME) (5.8 g, 124.9 mmol), and diiodomethane (CH2I2) (33.5 g, 124.9 mmol) into the anhydrous tetrahydrofuran while maintaining the reaction temperature between -25 °C and -10 °C. Then add compound 6a (9.0 g, 24.98 mmol). After the addition is complete, raise the temperature to room temperature. Quench the reaction with saturated ammonium chloride, extract with ethyl acetate (2×100 mL), wash with 100 mL of water, separate the layers, dry, filter, concentrate under reduced pressure at 30 - 40 °C, and purify by silica gel column chromatography (n-heptane:ethyl acetate = 100:1 - 40:1) to obtain 8.2 g of the product. Yield: 88.0%.

[0165] 1 1H-NMR (400 MHz, CDCl3) δ: 0.23 - 0.31 (m, 2H), 0.43 - 0.46 (m, 1H), 0.59 - 0.62 (m, 1H), 0.88 (m, 3H), 1.18 - 1.52 (m, 22H), 2.19 (m, 2H), 3.27 (m, 1H), 3.80 (m, 2H), 4.62 (m, 2H), 7.31 - 7.33 (m, 5H), 9.71 (d, 1H)

[0166] 7. Synthesis of compound 8a from compound 7a

[0167] The synthesis route is as follows:

[0168]

[0169] The specific synthesis steps are as follows: Add compound 7a (8.0 g, 21.37 mmol) to a 500 mL three-necked flask, add 100 mL of acetonitrile (MeCN), add 0.22 g of tetramethylpiperidine (TEMPO) to the reaction flask, then add 150 mL (0.67 M, pH = 6.7) of sodium dihydrogen phosphate / disodium hydrogen phosphate buffer solution, heat up to 30 °C, and at 30 °C, add sodium chlorite (4.38 g, 48.43 mmol, dissolved in 20 ml of water), and add 1 ml of 2.52% sodium hypochlorite. After stirring for 2 hours, cool down to 0 °C, quench with saturated sodium sulfite solution, add 200 ml of methyl tert-butyl ether to the system for extraction, separate the layers, adjust the pH of the organic phase to 2 - 4 with 2.0 N hydrochloric acid, wash the organic phase with water, separate the layers, filter, dry, and concentrate the organic phase under reduced pressure at 30 - 40 °C to obtain 7.3 g of compound 8a with a yield of 84.9%.

[0170] 1H-NMR (400 MHz, CDCl3) δ: 0.26 (m, 2H), 0.48 (m, 1H), 0.70 (d, 1H), 0.82 (t, 3H), 1.19 - 1.46 (m, 22H), 2.21 (d, 2H), 3.29 (m, 1H), 4.63 (s, 2H), 7.26 - 7.33 (m, 5H), 11.02 (s, 1H)

[0171] 8. Synthesis of Compound 9b from Compound 8a

[0172] The synthesis route is as follows:

[0173]

[0174] The specific synthesis steps are as follows: Add Compound 8a (7 g, 18.02 mmol) to a 250 - milliliter three - necked flask, add dichloromethane (35 ml) to the reaction flask, add 4 - dimethylaminopyridine (DMAP) (4.4 g) and tert - butyl alcohol (tBuOH) (6.7 g, 90.40 mmol). Cool the reaction system to about 10 °C, and add dicyclohexylcarbodiimide (DCC) (a solution of 4.5 g in 40 ml of dichloromethane) dropwise. After the addition, raise the temperature to room temperature and stir at room temperature for 4 h. Add 35 ml of dichloromethane and 2 ml of water to the system, stir for 3 h, filter, concentrate the filtrate at 30 - 40 °C, and purify by silica gel column chromatography (n - heptane:ethyl acetate = 100:1 - 40:1) to obtain 6.5 g of Compound 9b, yield: 84.0%.

[0175] 1 H-NMR (400 MHz, CDCl3) δ: 0.21 (m, 2H), 0.45 (m, 1H), 0.64 (m, 1H), 0.88 (t, 3H), 1.19 - 1.44 (m, 31H), 2.03 (m, 2H), 3.28 (m, 1H), 4.62 (s, 2H), 7.28 - 7.32 (m, 5H).

[0176] 9. Synthesis of Compound 10b from Compound 9b

[0177] The synthesis route is as follows:

[0178]

[0179] The specific synthesis steps are as follows: Add Compound 9b (4.0 g, 9.0 mmol) to a 200 - milliliter high - pressure reactor, add methanol (100 ml) and 1.0 g of 10% palladium on carbon (Pd / C) catalyst. Replace the system with hydrogen 3 times, control the temperature at 40 - 50 °C and react with hydrogen for 4 h. After cooling to room temperature, filter, and concentrate the filtrate under reduced pressure at 30 - 40 °C to obtain 2.9 g of Compound 10b, with a yield of 90.9%.

[0180] 1 H-NMR (400 MHz, CDCl3) δ: 0.22 (m, 2H), 0.48 (m, 1H), 0.69 (m, 1H), 0.86 (t, 3H), 1.21 - 1.47 (m, 31H), 1.92 - 2.14 (m, 2H), 3.42 (m, 1H), 4.82 (m, H)

[0181] Synthesis of the compound of formula (Ib)

[0182] The synthetic route is as follows:

[0183]

[0184] The specific synthesis steps are as follows: Add compound 10b (2.0 g, 6.644 mmol) into a 100 - milliliter three - necked flask, add dichloromethane (30 ml), add pyridine (4.46 g), dropwise add methanesulfonyl chloride (MsCl) (0.97 g, 8.468 mmol), and stir at room temperature for 16 hours. Concentrate the reaction solution under reduced pressure, and purify it by silica gel column chromatography (n - heptane:ethyl acetate = 100:1 - 20:1) to obtain 1.8 g of the product, with a yield of 77.8%.

[0185] 1 H-NMR (400 MHz, CDCl3) δ: 0.26 (m, 2H), 0.55 (m, 1H), 0.74 (m, 1H), 0.88 (t, 3H), 1.22 - 1.46 (m, 27H), 1.62 - 1.72 (m, 4H), 2.17 (m, 2H), 3.12 (s, 3H), 4.65 (m, 1H).

[0186] MS: [M + H] + = 433.66, [M + Na] + = 455.3

[0187] To sum up, the overall yield of this route is the product of the yields of each step:

[0188] 75.3% * 81.1% * 88.1 * 82.1% * 80.6% * 88.0% * 84.9% * 84.0% * 90.9% * 77.8% = 15.8%.

[0189] Although the embodiments of the present application have been described in combination with the above, the present application is not limited to the above specific embodiments and application fields. The above specific embodiments are merely illustrative and guiding, rather than restrictive. Those of ordinary skill in the art can also make many forms under the inspiration of this specification and without departing from the scope protected by the claims of the present application, and all of these fall within the scope of protection of the present application.

Claims

1. Compound 4: wherein Pg represents a protecting group.

2. The compound 4 according to claim 1, wherein Pg is a protecting group selected from benzyl, 4 - methylbenzyl, 4 - methoxybenzyl, tert - butyldimethylsilyl, triisopropylsilyl, and triethylsilyl.

3. The compound 4 according to claim 2, wherein Pg is benzyl.

4. Use of compound 4 in the preparation of a compound of formula (I), the compound of formula (I) is as follows: Among them, R represents C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; X is a sulfonyl group; Compound 4 is as follows: wherein Pg represents a protecting group; The step of converting compound 4 into compound 5 by a reduction reaction: The step of deprotecting compound 5 to convert it into compound 6: The step of cyclizing compound 6 to convert it into compound 7: The step of oxidizing compound 7 to compound 8: The step of esterifying compound 8 to obtain compound 9: The step of removing the protecting group from compound 9 to obtain compound 10: The step of sulfonating compound 10 to obtain the compound of formula (I):

5. The use according to claim 4, wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec - butyl, tert - butyl, pentyl, isopentyl, cyclopropyl or cyclopentyl.

6. The use according to claim 5, wherein R is tert - butyl.

7. The use according to claim 4, wherein X is selected from mesyl, tosyl, trifluoromethanesulfonyl.

8. The use according to claim 7, wherein X is mesyl.

9. The use according to claim 4, wherein Pg is a protecting group selected from benzyl, 4 - methylbenzyl, 4 - methoxybenzyl, tert - butyldimethylsilyl, triisopropylsilyl, and triethylsilyl protecting groups.

10. The use according to claim 9, wherein Pg is benzyl.

11. Use of compound 3 in the preparation of a compound of formula (I), the compound of formula (I) is as follows: Among them, R represents C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; X is a sulfonyl group; Compound 3 is as follows: wherein Pg represents a protecting group; The step of converting compound 3 into compound 4 by a substitution reaction: The step of converting compound 4 into compound 5 by a reduction reaction: The step of deprotecting compound 5 to convert it into compound 6: The step of cyclizing compound 6 to convert it into compound 7: The step of oxidizing compound 7 to compound 8: The step of esterifying compound 8 to obtain compound 9: The step of removing the protecting group from compound 9 to obtain compound 10: The step of sulfonating compound 10 to obtain the compound of formula (I):

12. The use according to claim 11, wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec - butyl, tert - butyl, pentyl, isopentyl, cyclopropyl or cyclopentyl.

13. The use according to claim 12, wherein R is tert - butyl.

14. The use according to claim 11, wherein X is selected from mesyl, tosyl, trifluoromethanesulfonyl.

15. The use according to claim 14, wherein X is mesyl.

16. The use according to claim 11, wherein Pg is selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl protecting groups.

17. The use according to claim 16, wherein Pg is benzyl.

18. The use of compound 2 in the preparation of a compound of formula (I), the compound of formula (I) being as follows: Among them, R represents C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; X is a sulfonyl group; Compound 2 is as follows: wherein Pg represents a protecting group; The step of converting compound 2 to compound 3 by the Appel reaction: The step of converting compound 3 to compound 4 by a substitution reaction: The step of converting compound 4 to compound 5 by a reduction reaction: The step of deprotecting compound 5 to give compound 6: The step of cyclizing compound 6 to give compound 7: The step of oxidizing compound 7 to compound 8: The step of esterifying compound 8 to give compound 9: The step of removing the protecting group from compound 9 to give compound 10: The step of sulfonylating compound 10 to give the compound of formula (I):

19. The use according to claim 18, wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, cyclopropyl, or cyclopentyl.

20. The use according to claim 19, wherein R is tert-butyl.

21. The use according to claim 18, wherein X is selected from mesyl, tosyl, trifluoromethanesulfonyl.

22. The use according to claim 21, wherein X is mesyl.

23. The use according to claim 18, wherein Pg is selected from benzyl, 4-methylbenzyl, 4-methoxybenzyl, tert-butyldimethylsilyl, triisopropylsilyl, and triethylsilyl protecting groups.

24. The use according to claim 23, wherein Pg is benzyl.

Images