Method for preparing nervonic acid and analogues thereof
By employing a mild organic chemical reaction process and selecting a suitable catalyst, the problems of cumbersome preparation steps and low product purity in existing technologies have been solved, achieving high-yield and high-purity preparation of nervonic acid, which is suitable for industrial production.
Patent Information
- Application Number
- CN202511672442.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-14
- Publication Date
- 2026-02-24
AI Technical Summary
Existing technologies for preparing nervonic acid suffer from problems such as cumbersome reaction steps, harsh conditions, use of toxic reagents, and difficulty in isomer separation, which leads to reduced bioactivity of the product and limits its application in the food and pharmaceutical fields.
A mild organic chemical reaction process is employed, including the reduction, oxidation, and rearrangement of compounds. Safe catalysts such as nickel acetate and sodium borohydride are used for reduction, while oxidants such as iodobenzene acetate and TEMPO are used for oxidation. High-purity nervonic acid is prepared by controlling reaction conditions and selecting appropriate solvents.
A high-yield and high-purity preparation of nervonic acid was achieved. The reaction conditions were mild, the operation was safe and reliable, and it was suitable for industrial production, thus reducing production costs.
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Figure CN121554376A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic chemical synthesis, and in particular to a method for preparing nervonic acid and its analogues. Background Technology
[0002] Nervonic acid is a naturally occurring 24-carbon monounsaturated fatty acid, hailed as a "high-grade nutrient" for brain development and repair. Originally discovered in shark brains and human brain white matter, it is a core lipid component of nerve cell membranes (especially myelin sheaths), crucial for maintaining the structure and function of the nervous system. The core function of nervonic acid lies in its powerful "repairing" ability. It can effectively cross the blood-brain barrier, acting as a precursor in myelin sheath synthesis, promoting the repair of damaged nerve fibers and the regeneration of myelin sheaths. The myelin sheath acts like an "insulator" surrounding nerve fibers, and its integrity directly affects the speed and accuracy of nerve signal transmission. Therefore, supplementing with nervonic acid is beneficial for delaying brain aging, improving memory, enhancing cognitive function, and assisting in the repair of nerve damage caused by trauma or disease (such as stroke). Because the human body's own synthesis of nervonic acid is extremely inefficient, and its sources in daily diet are limited (mainly found in shark liver oil, certain nuts, and seeds), it has become a precious and highly sought-after dietary supplement. With increasing emphasis on healthy aging and the prevention of neurodegenerative diseases, nervonic acid, as a strategic nutrient for brain health, has a very broad application prospect.
[0003] The production sources of nervonic acid mainly include two pathways: natural extraction and artificial synthesis. Natural extraction is the earliest and most common method. Extraction from the liver or brain of deep-sea fish such as sharks and cod was once the main source. However, due to limitations such as species conservation, resource scarcity, high extraction costs, and the potential accumulation of heavy metals, it has gradually been restricted. Later, it was discovered that some woody plant oils (such as garlic fruit oil and Acer truncatum seed oil) are also rich in nervonic acid, making plant extraction a more sustainable, safe, and mainstream approach. However, this method is limited by the distribution of plant resources and the planting area, and it is difficult to improve the purity of the extraction. Nervonic acid is artificially synthesized through organic chemical reactions. This method does not rely on biological resources and can theoretically achieve large-scale production. However, its synthesis steps are cumbersome, the reaction conditions are harsh, toxic reagents may be used, and it is easy to generate isomers that are difficult to separate, leading to reduced bioactivity of the final product, thus limiting its application in the food and pharmaceutical fields. Biosynthesis utilizes genetically engineered yeast or microalgae (such as those overexpressing key enzymes like ELOVL1 / FADS2) for microbial fermentation. Although environmentally friendly, current yields are only at the mg / L level. Summary of the Invention
[0004] To address the aforementioned deficiencies in the prior art, the present invention provides a method for preparing the compound shown in Formula I, the method comprising the following steps:
[0005] in, R is selected from alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. R' is selected from H and THP; n is an integer from 1 to 20; When R' is selected from THP, step S4: compound c is reduced and then deprotected to obtain compound b; When R' is selected from H, step S4': compound c is reduced to obtain compound b; Step S5: Compound b is oxidized to obtain the compound shown in Formula I.
[0006] Furthermore, the method also includes the following steps:
[0007] When R' is selected from THP, in step S3: compound d first reacts with DHP, and then reacts with R-Br to obtain compound c; When R' is selected from H, step S3': compound d reacts with R-Br to give compound c.
[0008] Furthermore, the method also includes the following steps:
[0009] Step S2: Compound e undergoes a rearrangement reaction to give compound d; Furthermore, the method also includes the following steps:
[0010] Step S1: Compound f and The reaction yields compound e; Or step S1': Compound f first reacts with DHP, and then with... The reaction proceeds, and finally, deprotection is performed to yield compound e.
[0011] The effects of the invention The method of this invention features mild reaction conditions, easy operation and control, safety and reliability, and low cost, laying the foundation for subsequent industrial-scale production. Furthermore, the preparation method of this invention achieves high reaction yield and high product purity. Detailed Implementation
[0012] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.
[0013] This invention provides a method for preparing the compound shown in Formula I, the method comprising the following steps:
[0014] in, R is selected from alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. R' is selected from H and THP; n is an integer from 1 to 20; When R' is selected from THP, step S4: compound c is reduced and then deprotected to obtain compound b; When R' is selected from H, step S4': compound c is reduced to obtain compound b; Step S5: Compound b is oxidized to obtain the compound shown in Formula I.
[0015] In some embodiments, R is selected from alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from halogen, cyano, amino, nitro, hydroxy, and carboxyl.
[0016] In some embodiments, R is selected from alkyl and cycloalkyl.
[0017] In some embodiments, R is selected from alkyl groups.
[0018] In some embodiments, R is selected from C5-C. 10 alkyl.
[0019] In some embodiments, R is selected from C8 alkyl groups.
[0020] In some implementations, n is an integer between 7 and 15.
[0021] In some implementations, n is an integer from 9 to 12.
[0022] In some implementations, n is 11.
[0023] In some embodiments, the reduction reaction in step S4 is carried out in the presence of nickel acetate and sodium borohydride.
[0024] In some embodiments, the reduction reaction in step S4' is carried out in the presence of nickel acetate and sodium borohydride.
[0025] In some implementations, the deprotection step in step S4 is carried out in the presence of an acid.
[0026] In some embodiments, the acid is selected from one or more organic acids and inorganic acids.
[0027] In some embodiments, the acid is selected from inorganic acids.
[0028] In some embodiments, the acid is selected from one or more of hydrochloric acid and nitric acid.
[0029] In some embodiments, the acid is selected from hydrochloric acid.
[0030] In some embodiments, step S5 is performed in the presence of an oxidant.
[0031] In some embodiments, the oxidant is selected from one or more of iodobenzene acetate, TEMPO, and 1-HCPK.
[0032] In some embodiments, the oxidant is a mixture of iodobenzene acetate and TEMPO or 1-HCPK.
[0033] In some embodiments, the method further includes the following steps:
[0034] When R' is selected from THP, in step S3: compound d first reacts with DHP, and then reacts with R-Br to obtain compound c.
[0035] When R' is selected from H, step S3': compound d reacts with R-Br to give compound c.
[0036] In some embodiments, in step S3, compound d is reacted with DHP in the presence of PPTS.
[0037] In some embodiments, the product of the reaction of compound d with DHP in step S3 is reacted with R-Br in the presence of n-butyllithium to obtain compound c.
[0038] In some embodiments, in step S3', compound d reacts with R-Br in the presence of n-butyllithium to obtain compound c.
[0039] In some embodiments, the method further includes the following steps:
[0040] Step S2: Compound e undergoes a rearrangement reaction to obtain compound d.
[0041] In some embodiments, step S2 is performed in the presence of sodium hydride.
[0042] In some embodiments, the method further includes the following steps:
[0043] Step S1: Compound f and The reaction yields compound e; Or step S1': Compound f first reacts with DHP, and then with... The reaction proceeds, and finally, deprotection is performed to yield compound e.
[0044] In some embodiments, in step S1, compound f reacts with n-butyllithium. The reaction yields compound e.
[0045] In some embodiments, in step S1', compound f is first reacted with DHP in the presence of PPTS, and then with... The reaction proceeds, and finally, in the presence of acid, deprotection is carried out to give compound e.
[0046] In some embodiments, the acid in step S1' is selected from one or more organic and inorganic acids.
[0047] In some embodiments, the acid in step S1' is selected from inorganic acids.
[0048] In some embodiments, the acid in step S1' is selected from one or more of hydrochloric acid and nitric acid.
[0049] In some embodiments, the acid in step S1' is selected from hydrochloric acid.
[0050] Terminology Explanation Unless otherwise stated, the terms used in the specification and claims have the following meanings.
[0051] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. The substituents are preferably independently selected independently from one or more substituents chosen from the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
[0052] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.
[0053] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.
[0054] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.
[0055] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between its rings, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include: .
[0056] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include: .
[0057] The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
[0058] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... , , etc.; preferred and .
[0059] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.
[0060] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), where alkyl and cycloalkyl are defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, they are preferably one or more of the following groups, independently selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.
[0061] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but excluding the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it contains 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.
[0062] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include: .
[0063] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include: .
[0064] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include: .
[0065] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include: and wait.
[0066] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.
[0067] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include: and .
[0068] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable linker. The substituent is preferably independently selected independently from one or more substituents chosen from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include: and .
[0069] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.
[0070] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".
[0071] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.
[0072] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.
[0073] The term "hydroxyl group" refers to -OH.
[0074] The term "thiol" refers to -SH.
[0075] The term "amino" refers to -NH2.
[0076] The term "cyano" refers to -CN.
[0077] The term "nitro" refers to -NO2.
[0078] The term "carboxyl group" refers to -C(O)OH.
[0079] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
[0080] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).
[0081] The method of the present invention will be described below through specific embodiments. It should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.
[0082] Experimental methods in the embodiments of this invention that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.
[0083] The following describes the general test conditions in the embodiments of the present invention: First, the reactions in the examples are generally carried out under nitrogen protection.
[0084] Furthermore, the intermediates and final products were separated and purified using chromatographic columns, preparative chromatographic plates, and the ISCO rapid preparative chromatography system.
[0085] Example 1
[0086] (1) Synthesis of the compound shown in e: High propargyl alcohol (4.5 mL), 2.5% mol pyridine 4-methylbenzenesulfonic acid (PPTS) (377.0 mg), tetrahydrofuran (THF) (180.0 mL), and 3,4-dihydro-2H-pyran (DHP) (8.4 mL) were added to a round-bottom flask under nitrogen protection. After reacting at 60 °C for 2 h, hexamethylphosphoric triamine (HMPA) (45.0 mL) was added. The mixture was then cooled to -78 °C, and 2.5 M 15.0 mmol of n-butyllithium (2.5 M, 15.0 mmol) was added. After reacting for 1 h, 1-bromododecane (24.8 mL) was added, and the mixture was slowly heated to room temperature. After the reaction was complete as monitored by TLC, THF was removed by rotary evaporation. 6 M hydrochloric acid-methanol solution was added under ice bath conditions, and the mixture was stirred at 60 °C for 1 h to remove DHP. After the reaction was complete as monitored by TLC, the mixture was extracted with methyl tert-butyl ether, washed with water to remove HMPA, and finally washed with saturated brine. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound e in 82% yield.
[0087] (2) Synthesis of compound d: Sodium hydride (8.1 g) was added to ethylenediamine (48.0 mL) in an ice bath and reacted at room temperature for 1 h, then at 65 °C for 1 h. The temperature was lowered to 40 °C, compound e (8.0 g) was added, and the temperature was raised to 65 °C for 2 h. After the reaction was complete as monitored by TLC, water and 2 M dilute hydrochloric acid were added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, and the combined organic phases were purified by column chromatography to obtain compound d with a yield of 72%.
[0088] (3) Synthesis of compound c: Compound d (4.20 g), 2.5% mol PPTS (97.5 mg), tetrahydrofuran (50.0 mL), and 3,4-dihydro-2H-pyran (1.6 mL) were added to a round-bottom flask under nitrogen protection. After reacting at 60 °C for 2 h, HMPA (15 mL) was added. The temperature was lowered to -78 °C and n-butyllithium (10.1 mL) was added. After reacting for 1 h, 1-bromooctane was added and the temperature was slowly raised to room temperature. After the reaction was complete by TLC, THF was removed by rotary evaporation, quenched with saturated ammonium chloride solution, extracted with methyl tert-butyl ether, washed with water to remove HMPA, and finally washed with saturated brine. The product was dried with anhydrous sodium sulfate and the solvent was removed by rotary evaporation to obtain the crude product of compound c. It can be used directly in the next step without separation and purification.
[0089] (4) Synthesis of compound b: Nickel acetate (1.37 g) was dissolved in methanol (50.0 mL) solution. Sodium borohydride (220.0 mg) was added under ice bath conditions. After 5 min, ethylenediamine (0.7 mL) was added and stirred until the nickel acetate was dissolved. Compound c was added to a new reaction flask and placed under a hydrogen atmosphere. Then, the nickel acetate solution was added. The reaction was monitored by TLC. After the reaction was completed, 2 M dilute hydrochloric acid (8 mL) was added directly. After stirring at 60 °C for 1 h, the DHP protecting group was removed. After the reaction was completed by TLC, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound b. The total yield of the two steps was 80%.
[0090] (5) Synthesis of the compound shown in Formula I: Compound b (151.0 mg), iodobenzene acetate (274.0 mg), and 2,2,6,6-tetramethylpiperidine oxide (TEMPO) (13.2 mg) were added sequentially to a system containing THF (2.1 mL) and H2O (0.7 mL). After stirring at room temperature for 2 h, iodobenzene acetate (68.0 mg) was added. The reaction was monitored by TLC. After completion, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain nervonic acid with a purity >95% and a yield of 95%.
[0091] Example 2
[0092] (1) Synthesis of compound e: Using high propargyl alcohol (4.5 mL, 60 mmol) as raw material, tetrahydrofuran (240.0 mL) and HMPA (60.0 mL) as solvents, n-butyllithium (2.5 M, 150.0 mmol, 60.0 mL) was added at -78 °C. After one hour, 1-bromododecane (48 mL, 180 mmol) was added, and the temperature was slowly raised to room temperature. After the reaction was completed by TLC spotting, THF was evaporated, and the mixture was extracted with methyl tert-butyl ether and ethyl acetate. After drying, the mixture was separated and purified by vacuum distillation to obtain compound e with a yield of 65%.
[0093] (2) Synthesis of the compound shown in d: Same as in Example 1.
[0094] (3) Synthesis of compound c': Using compound d (3.15 g) from the previous step as raw material, tetrahydrofuran (40.0 mL) and HMPA (10.0 mL) were added to n-butyllithium (12.6 mL) at -78 °C. After dehydrogenation for one hour, 1-bromooctane was added, and the temperature was slowly raised to room temperature. After the reaction was completed by TLC spotting, the reaction was quenched with saturated ammonium chloride solution, extracted, dried, and distilled under reduced pressure to obtain compound c'. It was used directly in the next step without being separated and purified by column chromatography.
[0095] (4) Synthesis of compound b: Nickel acetate (1.37 g) was dissolved in methanol (50.0 mL) solution. Sodium borohydride (220.0 mg) was added under ice bath conditions. After 5 min, ethylenediamine (0.7 mL) was added and stirred until the nickel acetate dissolved. Compound c' was added to a new reaction flask, and hydrogen was purged three times. Then, the nickel acetate solution was added. After hydrogenation by TLC spotting, the mixture was extracted, dried, and distilled under reduced pressure to obtain compound b. The overall yield of the two steps was 81%.
[0096] (5) Synthesis of the compound shown in Formula I: Add b (178 mg, 0.5 mmol), NaOH (44 mg, 1.1 mmol), 1-HCPK (225 mg, 1.1 mmol), and DME (0.75 ml) to a round-bottom flask, heat to 80 °C and react for 24 h, add H2O, extract with diethyl ether, acidify the aqueous phase with 3N concentrated hydrochloric acid, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, distill under reduced pressure, and purify by rapid column chromatography to obtain the product nervonic acid with a purity >95% and a yield of 80%.
[0097] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.
Claims
1. A method for preparing the compound shown in Formula I, characterized in that, The method includes the following steps: ； in, R is selected from alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. R' is selected from H and THP; n is an integer from 1 to 20; When R' is selected from THP, step S4: compound c is reduced and then deprotected to obtain compound b; When R' is selected from H, step S4': compound c is reduced to obtain compound b; Step S5: Compound b is oxidized to obtain the compound shown in Formula I.
2. The method according to claim 1, characterized in that, The R is selected from alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from halogen, cyano, amino, nitro, hydroxy, and carboxyl groups; preferably from alkyl and cycloalkyl groups; more preferably from alkyl groups; particularly preferably from C5-C6. 10 Alkyl; preferably selected from C8 alkyl groups.
3. The method according to any one of claims 1-2, characterized in that, The n is an integer from 7 to 15; preferably an integer from 9 to 12; more preferably 11.
4. The method according to any one of claims 1-3, characterized in that, The reduction reactions in steps S4 and S4' are carried out in the presence of nickel acetate and sodium borohydride; Preferably, the deprotection step in step S4 is carried out in the presence of acid; Preferably, the acid is selected from one or more organic acids and inorganic acids, preferably inorganic acids, and more preferably one or more hydrochloric acid and nitric acid, preferably hydrochloric acid.
5. The method according to any one of claims 1-4, characterized in that, Step S5 is performed in the presence of an oxidant; Preferably, the oxidant is selected from one or more of iodobenzene acetate, TEMPO and 1-HCPK, and more preferably a mixture of iodobenzene acetate and TEMPO or 1-HCPK.
6. The method according to any one of claims 1-5, characterized in that, The method further includes the following steps: ； When R' is selected from THP, in step S3: compound d first reacts with DHP, and then reacts with R-Br to obtain compound c; When R' is selected from H, step S3': compound d reacts with R-Br to give compound c.
7. The method according to claim 6, characterized in that, In step S3, compound d reacts with DHP in the presence of PPTS; Preferably, in step S3, the product of the reaction between compound d and DHP is reacted with R-Br in the presence of n-butyllithium to obtain compound c; Preferably, in step S3', compound d reacts with R-Br in the presence of n-butyllithium to obtain compound c.
8. The method according to any one of claims 6-7, characterized in that, The method further includes the following steps: ； Step S2: Compound e undergoes a rearrangement reaction to give compound d; Preferably, step S2 is performed in the presence of sodium hydride.
9. The method according to claim 8, characterized in that, The method further includes the following steps: ； Step S1: Compound f and The reaction yields compound e; Or step S1': Compound f first reacts with DHP, and then with... The reaction proceeds, and finally, deprotection is performed to yield compound e.
10. The method according to claim 9, characterized in that, In step S1, compound f reacts with n-butyllithium in the presence of... The reaction yields compound e; Preferably, in step S1', compound f first reacts with DHP in the presence of PPTS, and then reacts with... The reaction proceeds, and finally, in the presence of acid, deprotection is carried out to give compound e. Preferably, the acid is selected from one or more organic acids and inorganic acids, preferably inorganic acids, and more preferably one or more hydrochloric acid and nitric acid, preferably hydrochloric acid.