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WO2023016249A1 - 3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法 - Google Patents

3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法 Download PDF

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WO2023016249A1
WO2023016249A1 PCT/CN2022/107947 CN2022107947W WO2023016249A1 WO 2023016249 A1 WO2023016249 A1 WO 2023016249A1 CN 2022107947 W CN2022107947 W CN 2022107947W WO 2023016249 A1 WO2023016249 A1 WO 2023016249A1
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王友鑫
张玲玲
丁强
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Shanghai Leado Pharmatech Co Ltd
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Shanghai Leado Pharmatech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a preparation method of 3-aryloxy-3-pentaaryl-propylamine compounds.
  • Pain known as the fifth vital sign, is a warning signal of damage to body tissues. Pain is one of the most common reasons for patients to seek medical treatment. According to the duration, it can be divided into acute pain (sharp onset, short duration, or continuous state) and chronic pain (slow onset or transformed from acute pain, long duration, It can also be intermittent, and many chronic pains cannot find obvious damage). Acute pain is mostly nociceptive pain caused by tissue trauma, including postoperative pain, trauma, burn pain, labor pain, angina, biliary colic, renal colic and other visceral pain, fracture pain, toothache, cancer pain, etc. Surgical and post-traumatic pain is the most common and most urgent acute pain in clinical practice.
  • Chronic pain mainly includes neuropathic pain, osteoarthritis, chronic low back pain and vascular pain.
  • Trigeminal neuralgia, diabetic pain, sciatica, or postherpetic neuralgia are the main types of neuropathic pain.
  • the global prevalence of neuropathic pain is about 10%, with a high incidence and a large number of patients.
  • Chronic pain affects 10%-30% of people in the United States and costs society about $635 billion a year, more than cancer and heart disease combined.
  • the etiology of chronic pain is complex, and it is a refractory disease. Only less than 50% of patients can achieve effective analgesia through drug treatment. It is estimated that the total market size of China's neuralgia drugs will be close to 26 billion yuan in 2026, and the market size of ion channel neuralgia drugs will exceed 20 billion yuan.
  • Opioids have strong analgesic effects, but long-term use can easily lead to tolerance, dependence and addiction, and have adverse reactions such as respiratory depression and central sedation.
  • Non-steroidal anti-inflammatory drugs only exert a moderate analgesic effect, and at the same time have reactions such as gastrointestinal bleeding and cardiotoxicity.
  • opioid overdoses accounted for more deaths than car accidents, according to a recent National Security Council report on preventable deaths.
  • Opioid overdoses accounted for 1 in 96 Americans, compared with 1 in 103 in car crashes, according to the committee's analysis of unintentional death data in 2017.
  • Opioid drug abuse has caused a serious social crisis that is sweeping across the United States today, so the market needs analgesics with new mechanisms.
  • TRPA1 is a member of the TRP ion channel superfamily and the only member of the TRPA subfamily. It is a non-selective cation channel and can permeate Na + , K + , Ca 2+ and Mg 2+ .
  • TRPA1 is mainly distributed in primary sensory neurons of dorsal root nerve (DRG), trigeminal nerve (TG) and vagus nerve (VG). From the point of view of the distribution of human systems, TRPA1 is highly expressed in the peripheral nervous system, respiratory system, gastrointestinal system and urinary system. When these organs and tissues are dysfunctional, the expression and function of TRPA1 channels are usually abnormal simultaneously.
  • TRPA1 can convert cold stimulation, chemical stimulation and mechanical stimulation into inward current, trigger a series of physiological functions, and participate in the formation of various pain sensations. Inflammatory pain is a common problem of some chronic diseases, and there is still a lack of effective treatment methods in clinical practice. Animal experiments have shown that TRPA1 is involved in inflammatory responses and plays an important role in inflammatory pain. By using TRPA1-specific blockers, the inflammatory pain response in rats can be significantly reduced. According to the current research, TRPA1 plays an important role in the occurrence of asthma and cough, and compounds that induce asthma and cough, whether they are endogenous factors or exogenous factors, can activate TRPA1. Antagonists of TRPA1 can reduce asthma symptoms and block airway hyperresponsiveness.
  • TRPA1 is involved in the regulation of visceral hypersensitivity and plays an important role in visceral pain.
  • Neuropathic pain is a pain syndrome caused by central or peripheral nervous system injury or disease, mainly manifested as hyperalgesia, allodynia, and spontaneous pain.
  • TRPA1 channels play an important role in different neuropathic pains, such as diabetic neuropathy and neuropathy induced by chemotherapy drugs.
  • TRPA1 also plays a mediating role in pain such as toothache and migraine, and the pain symptoms can be significantly relieved by administering TRPA1 antagonists.
  • this area needs to develop a kind of simple, easy to operate and the preparation method of the 3-aryloxyl-3-five yuan heteroaryl-propylamines compound with high yield, thereby improve 3-aryloxyl group-3-five yuan Pharmaceutical application value of heteroaryl-propylamine compounds.
  • the object of the present invention is to provide a simple, easy-to-operate and high-yield 3-aryloxy-3-pentaaryl-propylamine preparation method.
  • the first aspect of the present invention provides a method for preparing a compound of formula I, the method comprising the steps of:
  • Ring A is a substituted or unsubstituted 4-12 membered carbocyclic ring, a substituted or unsubstituted 4-12 membered heterocyclic ring, a substituted or unsubstituted 5-12 membered heteroaryl ring, a substituted or unsubstituted C 6 -C 12 Aromatic ring;
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, Substituted or unsubstituted C 6 -C 12 aryl;
  • X and Y are each independently a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom;
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted Substituted C 6 -C 12 aryl;
  • R 4 is halogen
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkane Base, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C 6 -C 12 aryl;
  • W is O or S
  • n 1, 2 or 3;
  • heterocycle, heteroaryl ring and heteroaryl each independently have 1-3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.
  • Ring A is a substituted or unsubstituted 5-10 membered carbocyclic ring, a substituted or unsubstituted 5-10 membered heterocyclic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted Substituted C 6 -C 12 aromatic rings.
  • ring A is a substituted or unsubstituted 5-10 membered carbocyclic ring, a substituted or unsubstituted 5-10 membered heterocyclic ring, or a substituted or unsubstituted 5-12 membered heteroaromatic ring.
  • ring A is not a benzene ring.
  • ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, or a substituted or unsubstituted 5-7 membered heteroaromatic ring.
  • ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring or 5-7 membered heteroaryl ring.
  • ring A is a substituted or unsubstituted 5-membered carbocycle, a substituted or unsubstituted 6-membered carbocycle or a substituted or unsubstituted furan ring.
  • ring A is a 5-membered carbocycle, a 6-membered carbocycle or a furan ring.
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • connection structure between ring A and adjacent benzene rings is:
  • X and Y are each independently a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom.
  • At least one of X and Y is a heteroatom.
  • Y is a carbon atom or a nitrogen atom.
  • X is S or O.
  • X is S.
  • Y is a carbon atom.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 5 - 10-membered heteroaryl, substituted or unsubstituted C 6 -C 12 aryl.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl.
  • R 1 and R 2 are each independently hydrogen or substituted or unsubstituted C 1 -C 3 alkyl.
  • R 1 and R 2 are each independently hydrogen, methyl or ethyl.
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted 5-12 membered Heteroaryl, substituted or unsubstituted C 6 -C 12 aryl.
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl.
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl.
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl.
  • R3 is a hydrogen atom, a chlorine atom or a methyl group.
  • the halogen is F, Cl, Br or I.
  • R 4 is F, Cl, Br or I.
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 6 -C 12 aryl.
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl.
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen.
  • W is O or S.
  • W is O.
  • n 1 or 2.
  • n 1
  • each R 3 is the same or different.
  • any "substituted” means that 1-4 (preferably 1, 2, 3 or 4) hydrogen atoms on the group are each independently selected from the substituents in the following group Substituted: C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, C 1 -C 4 carboxy, C 2 -C 4 Ester, C 2 -C 4 amido, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, benzyl, six-membered aryl, five- or six-membered heteroaryl (preferably C 5 heteroaryl).
  • the The structure is:
  • the compound of formula a has the structure of formula a-1:
  • the compound of formula b has the structure of formula b-1:
  • the compound of formula I has the structure of formula I-A:
  • the compound of formula I is selected from the following group:
  • the first solvent is selected from the group consisting of dimethyl sulfoxide, toluene, DMF, or combinations thereof.
  • the first solvent is selected from the group consisting of dimethyl sulfoxide.
  • the first catalyst is selected from the group consisting of halide salts, tetrabutylammonium bromide, 4-dimethylaminopyridine, dibenzo-18-crown-6, pyridine, or combination.
  • the halide salt is selected from the group consisting of potassium fluoride, potassium chloride, potassium bromide, potassium iodide, sodium fluoride, sodium chloride, sodium bromide, sodium iodide, or combinations thereof .
  • the first catalyst includes potassium iodide.
  • the first base reagent is selected from the group consisting of inorganic bases, organic bases, or combinations thereof.
  • the first alkaline reagent is selected from the group consisting of sodium hydrogen, hydroxide, or a combination thereof.
  • the hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, or a combination thereof.
  • the first alkaline reagent includes hydroxide.
  • the first alkaline reagent includes sodium hydroxide.
  • the feeding temperature is below 40°C, preferably below 30°C.
  • the reaction temperature is 30-90°C, preferably 40-80°C, more preferably 50-70°C, most preferably 55-65°C .
  • the mass ratio of the compound of formula a to the compound of formula b is 1:1-4, preferably 1:1-3, more preferably 1:1-2.
  • the mass ratio of the compound of formula a to the first alkaline reagent is 1:1-4, preferably 1:1-3, more preferably 1:1-2.
  • the mass ratio of the compound of formula b to the first alkaline reagent is 1-4:1, preferably 1-3:1, more preferably 1-2:1.
  • the mass ratio of the first catalyst to the first alkaline reagent is 1:5-30, more preferably 1:5-20, more preferably 1:5-10.
  • the mass ratio of the first catalyst to the compound of formula a is 1:1-50, preferably 1:2-40, more preferably 1:3-30, more preferably 1:5-25, better 1:5-20, best 1:5-10.
  • the reaction in the step (1), is carried out under normal pressure (such as 1 atm).
  • step (1) includes the steps of:
  • the first alkaline reagent is added at 25-35°C.
  • step (1) after the reaction, add water and ethyl acetate (at 0-10°C) to the reaction solution for extraction, collect the organic phase, and separate to obtain the formula I compound.
  • the salt of the compound of formula I is obtained by isolation.
  • the aqueous acid solution is an aqueous solution of oxalic acid.
  • the reaction solution obtained from the reaction is separated and purified to obtain the compound of formula I, and the described separation and purification includes the steps of:
  • Extract the organic extractant layer with oxalic acid solution combine the water phases, add sodium hydroxide (at 20°C) to the water phase, then add aqueous sodium bicarbonate solution to adjust the pH to 6-7, solids are formed, filter, filter cake Rinse with an organic extractant; let the filtrate stand still, separate the water phase, adjust the pH of the water phase to 6-7 again, add an organic extractant to extract, dry, filter, and distill and concentrate under reduced pressure to obtain the compound of formula I.
  • the organic extractant is selected from the group consisting of ethyl acetate, dichloromethane, petroleum ether, or combinations thereof.
  • the present invention provides a method for preparing a compound of formula I-1, said method comprising the steps of:
  • Ring A is a substituted or unsubstituted 4-12 membered carbocyclic ring, a substituted or unsubstituted 4-12 membered heterocyclic ring, a substituted or unsubstituted 5-12 membered heteroaryl ring, a substituted or unsubstituted C 6 -C 12 Aromatic ring;
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, Substituted or unsubstituted C 6 -C 12 aryl;
  • X and Y are each independently a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom;
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted Substituted C 6 -C 12 aryl;
  • R 4 is halogen
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkane Base, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C 6 -C 12 aryl;
  • R 12 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 6 -C 16 aryl, substituted or unsubstituted 5- 16-membered heteroaryl, substituted or unsubstituted C 1 -C 6 alkyl-W-, substituted or unsubstituted C 3 -C 12 cycloalkyl-W-, substituted or unsubstituted C 6 -C 16 aryl Base-W-, substituted or unsubstituted 5-16 membered heteroaryl-W-;
  • R 13 is halogen
  • W is O or S
  • n 1, 2 or 3;
  • heterocycle, heteroaryl ring and heteroaryl each independently have 1-3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.
  • ring A, X, Y, W, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 Each independently as described in the first aspect of the present invention.
  • R 12 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, Substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C 1 -C 6 alkyl-W-, substituted or unsubstituted C 3 -C 8 cycloalkyl-W-, substituted or unsubstituted C 6 -C 12 aryl-W-, substituted or unsubstituted 5-12 membered heteroaryl-W-.
  • R 12 is substituted or unsubstituted phenyl-W-.
  • R 13 is halogen
  • halogen is fluorine, chlorine, bromine or iodine.
  • the first solvent, the first catalyst and the first alkali reagent are independently as described in the first aspect of the present invention.
  • the compound of formula a, the compound of formula b and the compound of formula I are each independently as described in the first aspect of the present invention.
  • step (1) is as described in the first aspect of the present invention.
  • the second solvent is selected from the group consisting of dichloromethane, dimethyl sulfoxide, toluene, or DMF, or a combination thereof.
  • the second solvent includes dichloromethane.
  • the second alkaline reagent is selected from the group consisting of triethanolamine, triethylamine (TEA), 1,8-diazabicycloundec-7-ene (DBU), N , N-diisopropylethylamine (DIEA), sodium carbonate, or a combination thereof.
  • the second alkaline reagent includes N,N-diisopropylethylamine (DIEA).
  • DIEA N,N-diisopropylethylamine
  • the reaction temperature is 20-80°C, preferably 20-70°C, more preferably 25-60°C, more preferably 30-55°C , more preferably 35-50°C, most preferably 40-45°C.
  • the N-dealkylation agent represented by formula c is an N-demethylation agent.
  • the N-demethylation reagent represented by formula c includes phenyl chloroformate.
  • the mass ratio of the compound of formula I to the second alkaline reagent is 1:0.1-5, preferably 1:0.2-3, more preferably 1:0.4-2, more preferably 1:0.5-1.
  • the mass ratio of the compound of formula I to the compound of formula c is 1:0.1-5, preferably 1:0.2-3, more preferably Better 1:0.4-2, better 1:0.5-1.
  • the mass ratio of the second alkaline reagent to the compound of formula c is 0.1-5:0.1-5, preferably 0.2-3: 0.2-3, more preferably 0.3-2: 0.3-2, most preferably 0.5-1: 0.5-1.
  • the reaction in the step (2), is carried out under normal pressure (such as 1 atm).
  • said step (2) includes the steps of:
  • the N-demethylation reagent represented by formula c is added at 25-35°C.
  • step (2) after the reaction is completed, water and dichloromethane are added to the reaction solution for extraction, and the organic phase is collected and concentrated to obtain the compound of formula I-a.
  • the compound of formula I-a has the structure of formula I-a-1:
  • the third solvent is selected from the group consisting of dimethyl sulfoxide, toluene, or DMF, or a combination thereof.
  • the third solvent is dimethyl sulfoxide.
  • the third base reagent is selected from the group consisting of inorganic bases, organic bases, or combinations thereof.
  • the third alkaline reagent is selected from the group consisting of potassium tert-butoxide, potassium carbonate, hydroxide, or a combination thereof.
  • the hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, or a combination thereof.
  • the third alkaline reagent includes hydroxide.
  • the third alkaline reagent includes sodium hydroxide.
  • the reaction temperature is 20-100°C, preferably 30-90°C, more preferably 50-70°C, more preferably 55-65°C .
  • the mass ratio of the compound of formula I-a to the third alkaline reagent is 1:0.1-20, preferably 1:0.1-15, more preferably 1 :0.1-10, more preferably 1:0.1 ⁇ 1, most preferably 1:0.58.
  • step (3) after the reaction, water and ethyl acetate are added to the reaction solution for extraction, the organic phase is collected, and the compound of formula I is obtained by isolation.
  • the salt of the compound of formula I is separated.
  • the aqueous acid solution is an aqueous solution of oxalic acid.
  • the compound of formula I-1 has the structure of formula I-1-1:
  • the method includes the steps of:
  • the compound of formula a is the compound of formula i.
  • the compound of formula b is a compound of formula ii.
  • the compound of formula I is a compound of formula iii.
  • the compound of formula I-a is a compound of formula iv.
  • the compound of formula I-1 is a compound of formula v.
  • the present invention provides a method for preparing a compound of formula I-a, said method comprising the steps of:
  • Ring A is a substituted or unsubstituted 4-12 membered carbocyclic ring, a substituted or unsubstituted 4-12 membered heterocyclic ring, a substituted or unsubstituted 5-12 membered heteroaryl ring, a substituted or unsubstituted C 6 -C 12 Aromatic ring;
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, Substituted or unsubstituted C 6 -C 12 aryl;
  • X and Y are each independently a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom;
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted Substituted C 6 -C 12 aryl;
  • R 4 is halogen
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkane Base, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C 6 -C 12 aryl;
  • R 12 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 6 -C 16 aryl, substituted or unsubstituted 5- 16-membered heteroaryl, substituted or unsubstituted C 1 -C 6 alkyl-W-, substituted or unsubstituted C 3 -C 12 cycloalkyl-W-, substituted or unsubstituted C 6 -C 16 aryl Base-W-, substituted or unsubstituted 5-16 membered heteroaryl-W-;
  • R 13 is halogen
  • W is O or S
  • n 1, 2 or 3;
  • heterocycle, heteroaryl ring and heteroaryl each independently have 1-3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.
  • ring A, X, Y, W, n, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently As described in the first aspect of the present invention.
  • R 12 and R 13 are independently as described in the second aspect of the present invention.
  • the second solvent, the second catalyst and the N-demethylation agent represented by formula c are independently as described in the second aspect of the present invention.
  • step (2) is as described in the second aspect of the present invention.
  • the compound of formula I, the compound of formula c and the compound of formula I-a are each independently as described in the second aspect of the present invention.
  • the present inventor unexpectedly developed a preparation method for 3-aryloxy-3-pentaaryl-propylamines for the first time.
  • the method is simple, easy to operate, and high in yield. Advantages are conducive to industrial production.
  • the inventors have completed the present invention.
  • the terms “comprising”, “including”, and “containing” are used interchangeably to include not only closed definitions, but also semi-closed, and open definitions. In other words, the terms include “consisting of”, “consisting essentially of”.
  • R 1 As used herein, “R 1 ", “R 1 ", and “R1” have the same meaning and can be replaced with each other, and other similar definitions have the same meaning.
  • alkyl refers to a straight chain (ie, unbranched) or branched chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight chain and branched chain groups.
  • alkyl group is limited by the number of carbon atoms (such as a C1-C6 alkyl group), it means that the said alkyl group contains 1-6 carbon atoms, for example, a C1-C4 alkyl group refers to an alkyl group containing 1-4 carbon atoms, Representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, or the like.
  • C2-C4 alkynyl refers to a straight-chain or branched chain alkynyl molecule of 2-4 carbon atoms having one or more triple bonds, minus one hydrogen atom connected to the triple bond. , such as ethynyl (CH ⁇ CH-), (H3C-C ⁇ CH-), or similar groups.
  • halogen refers to F, Cl, Br or I.
  • halo refers to substitution by halogen.
  • haloalkyl means that one or more (preferably 1, 2, 3 or 4) hydrogens of an alkyl group are replaced by a halogen, said alkyl and halogen being as defined above, when the alkyl
  • a limited number of carbon atoms such as C1-C8 haloalkyl refers to the alkyl group containing 1-8 carbon atoms, for example, C1-C6 haloalkyl refers to a haloalkyl group containing 1-6 carbon atoms
  • representative examples include But not limited to -CF3, -CHF2 , monofluoroisopropyl, difluorobutyl, or similar groups.
  • cycloalkyl refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system group having a saturated or partially saturated ring.
  • a certain cycloalkyl group is limited by the number of carbon atoms (such as C3-C12), it means that the cycloalkyl group has 3-12 ring carbon atoms.
  • C3-C8 cycloalkyl refers to a saturated or partially saturated monocyclic or bicyclic alkyl group with 3-8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl group, cycloheptyl group, or similar groups.
  • Spirocycloalkyl means a bicyclic or polycyclic group in which the single rings share a single carbon atom (called a spiro atom), these may contain one or more double bonds, but none of the rings has fully conjugated pi electrons system.
  • “Fused cycloalkyl” means an all-carbon bicyclic or polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more bicyclic bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system .
  • alkoxy refers to the R-O- group, wherein R is an alkyl group, and the alkyl group is as defined herein above, when the alkoxy group is preceded by a limited number of carbon atoms, such as C1-C8 alkoxy group refers to the described alkyl
  • the alkyl group in the oxy group has 1-8 carbon atoms.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, or the like.
  • alkylthio refers to an R-S- group, wherein R is an alkyl group, and the alkyl group is as defined herein above, with a limit on the number of carbon atoms before the alkylthio group, as indicated by the C1-C8 alkylthio group
  • the alkyl group in the above-mentioned alkylthio group has 1-8 carbon atoms.
  • Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, t-butylthio, or the like.
  • cycloalkoxy refers to the R-O- group, wherein R is cycloalkyl, and cycloalkyl is as defined herein above, when the cycloalkoxy is limited by the number of carbon atoms, such as C3-C8 cycloalkoxy It means that the cycloalkyl group in the cycloalkoxy group has 3-8 carbon atoms.
  • Representative examples of cycloalkoxy include, but are not limited to, cyclopropoxy, cyclobutoxy, or the like.
  • cycloalkylthio refers to an R-S-group, wherein R is a cycloalkyl group, and the cycloalkyl group is as defined herein above, when the cycloalkylthio group has a limit of carbon atoms, such as C3-C8 cycloalkylthio group It means that the cycloalkyl group in the cycloalkylthio group has 3-8 carbon atoms.
  • Representative examples of cycloalkylthio include, but are not limited to, cyclopropylthio, cyclobutylthio, or the like.
  • haloalkoxy refers to haloalkyl-O-, the haloalkyl is as defined above, for example, C1-C6 haloalkoxy refers to haloalkoxy containing 1-6 carbon atoms, representative examples Including, but not limited to, monofluoromethoxy, monofluoroethoxy, bisfluorobutoxy, or similar groups.
  • haloalkylthio refers to haloalkyl-S-, the haloalkyl is as defined above, for example, C1-C6 haloalkylthio refers to haloalkylthio containing 1-4 carbon atoms, representative examples Including, but not limited to, monofluoromethylthio, monofluoroethylthio, difluorobutylthio, or similar groups.
  • the term "4-12 membered carbocycle”, “5-10 membered carbocycle” or “5-7 membered carbocycle” is any stable 4, 5, 6, 7, 8, 9, 10, 11 Or a 12-membered monocyclic, bicyclic or polycyclic ring.
  • the carbocycle can be saturated, partially unsaturated or unsaturated, but not aromatic.
  • carbocycles include, but are not limited to, cyclopropane, cyclobutyl, cyclobutene, cyclopentyl, cyclopentene, cyclohexyl, cyclohexene, cycloheptene, cycloheptene, Adamantane ring, cyclooctane ring, cyclooctene ring, cyclooctadiene ring, bicyclic ring
  • heterocycle refers to a fully saturated or partially unsaturated ring (including but not limited to such as 3-7 membered monocyclic ring, 7-11 membered bicyclic ring, or 8-16 membered tricyclic ring system), in which at least one Heteroatoms are present in rings with at least one carbon atom.
  • the heterocyclic ring is defined by the number of ring atoms, it refers to the number of ring atoms in the heterocyclic ring, for example, a 3-16 membered heterocyclic ring refers to a heterocyclic ring with 3-16 ring atoms.
  • Each heteroatom-containing heterocyclic ring can have one or more (such as 1, 2, 3 or 4) heteroatoms, and these heteroatoms are each independently selected from a nitrogen atom, an oxygen atom or a sulfur atom, wherein the nitrogen atom Or sulfur atoms can be oxidized and nitrogen atoms can also be quaternized.
  • a heterocyclic ring can be attached to any heteroatom or carbon atom residue of the ring or ring system molecule.
  • Typical monocyclic heterocycloalkane rings include, but are not limited to, azetidine ring, oxetane ring, imidazoline ring, imidazolidine ring, tetrahydrofuran ring, piperidine ring, piperazine ring, 2-oxopiperazine ring ring, 2-oxopiperidine ring, 4-piperidone ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, thiomorpholine sulfoxide ring, thiomorpholine sulfone ring, 1, 3-dioxane ring and tetrahydro-1,1-dioxythiophene ring, etc.
  • Polycyclic heterocycloalkane rings include spiro rings, fused rings and bridged heterocyclic rings; the spiro rings, fused rings and bridged heterocycles involved are optionally connected to other rings through single bonds, or through rings Any two or more atoms in the ring are further connected to other cycloalkane rings and heterocycles.
  • aromatic ring refers to a full-carbon monocyclic or fused polycyclic ring (that is, a ring sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system. It is an aromatic ring hydrocarbon compound. When the aromatic ring is preceded by The limited number of carbon atoms, such as C6-C12 aromatic ring, means that the aromatic ring has 6-12 ring carbon atoms, such as benzene ring and naphthalene ring.
  • the aromatic ring can be fused to other carbocyclic rings (including saturated or unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on the ring with a conjugated ⁇ -electron system on the carbon atom.
  • Representative aromatic rings are benzene and naphthalene rings, or similar rings.
  • aryl refers to a full-carbon monocyclic or condensed polycyclic (that is, a ring sharing adjacent pairs of carbon atoms) group with a conjugated ⁇ -electron system, and is an aromatic ring hydrocarbon compound group, when The number of carbon atoms in front of the aryl group is limited, such as C6-C12 aryl group, which means that the aryl group has 6-12 ring carbon atoms, such as phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated or unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated ⁇ -electron system on the carbon atoms in the ring.
  • aryl groups including but not limited to:
  • heterocyclic ring refers to an aromatic heterocyclic ring having one to more (preferably 1, 2, 3 or 4) heteroatoms, which may be monocyclic (monocyclic) or fused together or covalently Ground-connected polycyclic rings (bicyclic, tricyclic or polycyclic), each heteroatom-containing heterocyclic ring can have one or more (such as 1, 2, 3, 4) each independently selected from the following Group of heteroatoms: oxygen, sulfur and nitrogen.
  • the heteroaryl ring is limited by the number of members, it refers to the number of ring atoms in the heteroaryl ring.
  • a 5-12 membered heteroaryl ring refers to a heteroaryl ring with 5-12 ring atoms.
  • pyrrole ring pyrazole ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, thiadiazole ring, isothiazole ring, furan ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridyl Oxyzine ring, triazoxide ring, triazole ring and tetrazole ring, etc.
  • heteroaryl refers to an aromatic heterocyclic ring system group having one to more (preferably 1, 2, 3 or 4) heteroatoms, which may be monocyclic (monocyclic) or fused together Or covalently linked polycyclic rings (bicyclic, tricyclic or polycyclic), each heterocycle containing heteroatoms can have one or more (such as 1, 2, 3, 4) independently Heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.
  • heteroaryl group is limited by the number of ring atoms, it refers to the number of ring atoms of the heteroaryl group.
  • a 5-12 membered heteroaryl group refers to a heteroaryl group with 5-12 ring atoms.
  • pyrrolyl pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridyl Azinesyl, triazazinyl, triazolyl and tetrazolyl, etc.
  • carboxy refers to a -COOH group or -alkyl-COOH group
  • alkyl is as defined herein above, for example "C 2 -C 4 carboxy” refers to -C 1 -C 3 alkyl
  • carboxyl include (but not limited to): -COOH, -CH 2 COOH, -C 2 H 4 COOH, or similar groups.
  • ester group refers to a group with R-CO-O- group or -CO-OR group, wherein R is an alkyl group, and the alkyl group is as defined herein above, such as "C 2 -C 4 ester group "Refers to a group with a C 1 -C 3 alkyl-CO-O- structure or a group with a -CO-OC 1 -C 3 alkyl structure.
  • ester groups include but are not limited to: CH 3 COO- , C 2 H 5 COO-, C 3 H 8 COO-, (CH 3 ) 2 CHCOO-, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 8 , or similar groups.
  • amido refers to a group having R-CO-N- or -CO-NR, wherein R is an alkyl group as defined herein, such as "C 2 -C 4 amido "Refers to a group with a C 1 -C 3 alkyl-CO-N- structure or a group with a -CO-NC 1 -C 3 alkyl structure.
  • Representative examples of amido groups include but are not limited to: CH 3 CO- N-, C 2 H 5 CO-N-, C 3 H 8 CO-N-, (CH 3 ) 2 CHCO-N-, -CO-N-CH 3 , -CO-NC 2 H 5 , -CO- NC 3 H 8 , or similar groups.
  • amino alone or as part of another substituent means -NH2 .
  • nitro alone or as part of another substituent means -NO2 .
  • hydroxyl alone or as part of another substituent, means -OH.
  • mercapto alone or as part of another substituent means -SH.
  • substitution means that the hydrogen atom on the group is replaced by a non-hydrogen atom group, but it needs to meet its valence requirements and produce a chemically stable compound from the substitution.
  • substituents should be construed as being unsubstituted unless explicitly described as “substituted” herein.
  • connection point As used herein, for the connection point.
  • a substituent may be attached to the parent group or substrate at any atom, unless its attachment violates valence requirements; the hydrogen atoms of the parent group or substrate may be on the same atom, Can also be on different atoms.
  • room temperature refers to 25 ⁇ 5°C.
  • the range includes not only the endpoints P1 and P2, but also includes any numerical points between the endpoints P1 and P2.
  • the numerical range includes any integer numerical points between the endpoints P1 and P2.
  • the value range when its value range is 1-10, it includes 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the value range 3-7 includes 3, 4, 5 , 6, 7.
  • C3-C7 includes C3, C4, C5, C6, and C7.
  • the present invention provides a compound of formula I structure, or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising the steps of:
  • step (1) is as described above in the first aspect of the present invention.
  • the present invention also provides a preparation method of a compound of formula I-1, said method comprising the steps of:
  • the present invention also provides a preparation method of a compound of formula I-a, said method comprising the steps of:
  • step (2) is as described in the third aspect of the present invention above.
  • the preparation method of the present invention has the advantages of simplicity, easy operation, high yield, etc., and is beneficial to industrial production, and specifically includes the following aspects:
  • the preparation method is economical, and the raw materials and related materials are easy to obtain and low in cost;
  • the preparation method does not involve highly toxic chemicals and harsh reaction conditions
  • the core advantage of the preparation method is that the configuration of the chiral center is well controlled, and the chiral purity of key intermediates and final products is very high.
  • the inhibitory activity of the compound of formula V of the present invention on the transient receptor potential channel protein TRPA1 was tested.
  • the positive control compound adopts the compound of formula B (WO2010075353):
  • IWB IonWorks Barracuda
  • Extracellular solution in mM: 140NaCl, 5KCl, 1MgCl 2 , 10HEPES, 0.5EGTA, 10Glucose (pH 7.4);
  • Intracellular solution in mM: 140CsCl, 10HEPES, 5EGTA, 0.1CaCl 2 , 1MgCl 2 (pH 7.2).
  • amphotericin B was freshly prepared with DMSO to 28 mg/mL, and then prepared with intracellular solution to a final concentration of 0.1 mg/mL.
  • the IWB experiment uses a population patch clamp (PPC) plate, and the entire detection process is automatically completed by the instrument, that is, adding extracellular fluid to the 384 wells of the PPC plate, adding intracellular fluid to the plenum under the PPC plate, and then adding 6L of cells
  • PPC population patch clamp
  • the sealing test was carried out with liquid, and finally the intracellular solution in the plenum was replaced with the intracellular solution containing amphotericin B, so that the sealed cells were perforated to form a whole-cell recording mode.
  • the sampling frequency of recording the TPRA1 current is 10kHz
  • the cell is clamped at 0mV
  • the voltage stimulation command (channel protocol) is a ramp (ramp) voltage from -100mV to +100mV for 300ms, and this voltage stimulation is given every 10s
  • the mTRPA1 current is induced by 300M AITC .
  • the compound of formula V prepared in the embodiment of the present invention was tested for IC50 inhibitory activity by the test method of IonWorks Barracuda (IWB) automated patch clamp detection, and the activity data are shown in Table 2.
  • IWB IonWorks Barracuda

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Abstract

本发明涉及3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法。具体地，本发明提供一种式I化合物的制备方法，所述的方法包括步骤：在第一溶剂中，在第一催化剂和第一碱试剂的存在下，式a化合物与式b化合物反应，得到式I化合物。本发明所述的方法具有简单、易操作、收率高等优势，有利于工业化生产。

Description

3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法 技术领域
本发明涉及药物化学和药物治疗学领域，具体地涉及一种3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法。
背景技术
疼痛被称为第五大生命体征，是机体组织受到损害的警戒信号。疼痛是患者就医的最常见原因之一，根据持续时间分为急性疼痛(急剧发病，持续时间短，也可呈持续状态)和慢性疼痛(发病缓慢或由急性疼痛转化而来，持续时间长，亦可呈间断发作，很多慢性疼痛查不出明显的损伤)。急性疼痛多是由组织创伤引起的伤害性疼痛，包括手术后疼痛，创伤、烧伤后疼痛，分娩痛，心绞痛、胆绞痛、肾绞痛等内脏痛，骨折痛，牙痛，癌性疼痛等。手术和创伤后疼痛是临床最常见和最急需处理的急性疼痛。慢性疼痛主要包括神经病理性疼痛、痛骨关节炎、慢性腰背痛和血管源性痛等。三叉神经痛、糖尿病性疼痛、坐骨神经痛或带状孢疹后神经痛为神经病理性疼痛的主要类型。神经病理性疼痛全球患病率大约是10％，发病率高，患者群体数量多。在美国有10％-30％的人患有慢性疼痛，造成每年约6350亿美元的社会支出，超过癌症和心脏病的总和。慢性疼痛病因复杂，属难治性疾病，只有不足50％的患者能够通过药物治疗达到有效的镇痛。预计2026年中国神经痛药物总市场规模接近260亿元，离子通道类神经痛药物市场规模超200亿元以上。
传统镇痛药物主要包括阿片类药物和非甾体抗炎药。阿片类药物镇痛作用强，但长期使用易导致耐受性、依赖性和成瘾性，并且有呼吸抑制、中枢镇静等不良反应。非甾体抗炎药仅发挥中等程度镇痛作用，同时具有消化道出血和心脏毒性等反应。近日美国国家安委会发布关于可预防死亡报告显示，美国历史上第一次，阿片类药物过量致死超过了车祸所致死亡人口比例。根据委员会对2017年意外死亡数据的分析，每96名美国人中，就有1名死于阿片类药物过量，而车祸致死的数据为每103名美国人中有1名。阿片类药物滥用已经造成了如今席卷全美国的严重社会危机，因此市场需要新机制的镇痛药物。
TRPA1是TRP离子通道超家族中的一员，TRPA亚家族的唯一成员，属于非选择性阳离子通道，可通透Na +，K +，Ca 2+和Mg 2+。TRPA1主要分布在背根神经(DRG)、三叉神经(TG)和迷走神经(VG)的初级感觉神经元上。从分布的人体系统来看，TRPA1高表达在外周神经系统、呼吸系统、胃肠系统和泌尿系统，当这些器官组织出现功能异常时，TRPA1通道的表达和功能通常也同步发生异常。TRPA1可以将冷刺激、化学刺激以及机械刺激转化为内向电流，引发一系列生理功能，并参与多种痛觉的形成。炎性痛是某些慢性疾病的共同困扰，临床上尚缺乏很有效的治疗手段。动物实验研究显示，TRPA1参与炎性反应，并在炎性疼痛中发挥重要作用，通过使用TRPA1特异性阻断剂，可以明显减轻大鼠炎性疼痛反应。从目前的研究来看，TRPA1在哮喘和咳嗽的发生中扮演重要的作用，诱导哮喘与咳嗽的化合物，无论是细胞内源因子，还是外源因子，都能激活TRPA1。TRPA1的拮抗剂能够减轻哮喘症状，能阻断气道高反应性。通过不同的内脏高敏感动物模型如结肠炎、直结肠扩张或应激，证实TRPA1参与内脏高敏感的调控，在内脏痛中发挥重要作用。神经源性疼痛是由中枢或外周神经系统损伤或者疾病引起的疼痛综合征，主要表现为痛觉过敏、异常痛敏和自发性疼痛等。近年来越来越多的研究显示，TRPA1通道在不同的神经源性疼痛中起到重要作用，例如糖尿病性神经病变和化疗药引起的神经病变等。最近研究还表明，TRPA1在牙痛、偏头痛等疼痛中也有介导作用，通过给予TRPA1的拮抗剂能明显缓解疼痛 症状的产生。
现有技术中公开了一种对疼痛具有有效治疗效果的3-芳氧基-3-五元杂芳基-丙胺类化合物，结构如下：
Figure PCTCN2022107947-appb-000001
然而，现有技术中公开的式A化合物的制备方法复杂、收率低，从而限制了3-芳氧基-3-五元杂芳基-丙胺类化合物在治疗疼痛方面中的应用。
因此，本领域需要开发一种简单、易操作和收率高的3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法，从而提高3-芳氧基-3-五元杂芳基-丙胺类化合物药物应用价值。
发明内容
本发明的目的在于提供一种简单、易操作和收率高的3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法。
本发明第一方面，提供一种式I化合物的制备方法，所述的方法包括步骤：
(1)在第一溶剂中，在第一催化剂和第一碱试剂的存在下，式a化合物与式b化合物反应，得到式I化合物；
Figure PCTCN2022107947-appb-000002
其中：
环A为取代或未取代的4-12元碳环、取代或未取代的4-12元杂环、取代或未取代的5-12元杂芳环、取代或未取代的C 6-C 12芳环；
R 1和R 2各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
X和Y各自独立地为碳原子、氧原子、硫原子或氮原子；
R 3为氢、卤素、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
R 4为卤素；
R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基，取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
W为O或S；
n为1、2或3；
其中，所述的任一“取代”是指基团上的1-4个(优选为1、2、3或4个)氢原子各自独立地被选自下组的取代基所取代：C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、氨基、羟基、＝O、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、C 6-C 12芳基、5-10元杂芳基；
其中，所述的杂环、杂芳环和杂芳基各自独立地具有1-3个(优选为1、2或3个)选自N、O和S杂原子。
在另一优选例中，环A为取代或未取代的5-10元碳环、取代或未取代的5-10元杂环、取代或未取代的5-12元杂芳环、取代或未取代的C 6-C 12芳环。
在另一优选例中，环A为取代或未取代的5-10元碳环、取代或未取代的5-10元杂环、取代或未取代的5-12元杂芳环。
在另一优选例中，环A不为苯环。
在另一优选例中，环A为取代或未取代的5-7元碳环、取代或未取代的5-7元杂环、取代或未取代的5-7元杂芳环。
在另一优选例中，环A为取代或未取代的5-7元碳环或5-7元杂芳环。
在另一优选例中，环A为取代或未取代的5元碳环、取代或未取代的6元碳环或取代或未取代的呋喃环。
在另一优选例中，环A为5元碳环、6元碳环或呋喃环。
在另一优选例中，环A为
Figure PCTCN2022107947-appb-000003
在另一优选例中，环A与相邻苯环的连接结构为：
Figure PCTCN2022107947-appb-000004
在另一优选例中，X和Y各自独立地为碳原子、氧原子、硫原子或氮原子。
在另一优选例中，X和Y中至少一个是为杂原子。
在另一优选例中，Y为碳原子或氮原子。
在另一优选例中，X为S或O。
在另一优选例中，X为S。
在另一优选例中，Y为碳原子。
在另一优选例中，R 1和R 2各自独立为氢、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的5-10元杂芳基、取代或未取代的C 6-C 12芳基。
在另一优选例中，R 1和R 2各自独立为氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基。
在另一优选例中，R 1和R 2各自独立为氢或取代或未取代C 1-C 3烷基。
在另一优选例中，R 1和R 2各自独立为氢、甲基或乙基。
在另一优选例中，R 3为氢、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基。
在另一优选例中，R 3为氢、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基。
在另一优选例中，R 3为氢、卤素、取代或未取代的C 1-C 6烷基。
在另一优选例中，R 3为氢、卤素、取代或未取代的C 1-C 4烷基。
在另一优选例中，R 3为氢原子、氯原子或甲基。
在另一优选例中，所述的卤素为F、Cl、Br或I。
在另一优选例中，R 4为F、Cl、Br或I。
在另一优选例中，R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立为氢、取代或未取代的C 1-C 10烷基、取代或未取代的C 3-C 8环烷基，取代或未取代的5-10元杂芳基、取代或未取代的C 6-C 12芳基。
在另一优选例中，R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立为氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基。
在另一优选例中，R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立为氢。
在另一优选例中，W为O或S。
在另一优选例中，W为O。
在另一优选例中，n为1或2。
在另一优选例中，n为1。
在另一优选例中，n≥2时，各个R 3相同或不同。
在另一优选例中，所述的任一“取代”是指基团上的1-4个(优选为1、2、3或4个)氢原子各自独立地被选自下组的取代基所取代：C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、氨基、羟基、＝O、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、六元的芳基、五元或六元的杂芳基(优选C 5杂芳基)。
在另一优选例中，所述的任一“取代”是指基团上的1-4个(优选为1、2、3或4个)氢原子各自独立地被选自下组的取代基所取代：C 1-C 4烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、羟基、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、苄基、六元的芳基、五元或六元的杂芳基(优选C 5杂芳基)。
在另一优选例中，所述的
Figure PCTCN2022107947-appb-000005
结构为：
Figure PCTCN2022107947-appb-000006
在另一优选例中，所述的式a化合物为具有式a-1结构：
Figure PCTCN2022107947-appb-000007
在另一优选例中，所述的式b化合物为具有式b-1结构：
Figure PCTCN2022107947-appb-000008
在另一优选例中，所述的式I化合物为具有式I-A结构：
Figure PCTCN2022107947-appb-000009
在另一优选例中，所述的式I化合物选自下组：
Figure PCTCN2022107947-appb-000010
在另一优选例中，所述的第一溶剂选自下组：二甲基亚砜、甲苯、DMF，或其组合。
在另一优选例中，所述的第一溶剂选自下组：二甲基亚砜。
在另一优选例中，所述的第一催化剂选自下组：卤化盐、四丁基溴化铵、4-二甲氨基吡啶、二苯并-18-冠醚-6、吡啶，或其组合。
在另一优选例中，所述的卤化盐选自下组：氟化钾、氯化钾、溴化钾、碘化钾、氟化钠、氯化钠、溴化钠、碘化钠，或其组合。
在另一优选例中，所述的第一催化剂包括碘化钾。
在另一优选例中，所述的第一碱试剂选自下组：无机碱、有机碱，或其组合。
在另一优选例中，所述的第一碱试剂选自下组：钠氢、氢氧化物，或其组合。
在另一优选例中，所述的氢氧化物选自下组：氢氧化钠、氢氧化钾，或其组合。
在另一优选例中，所述的第一碱试剂包括氢氧化物。
在另一优选例中，所述的第一碱试剂包括氢氧化钠。
在另一优选例中，所述的步骤(1)中，投料温度为40℃以下，优选30℃以下。
在另一优选例中，所述的步骤(1)中，所述反应的温度为30-90℃，较佳地40-80℃，更佳地50-70℃，最佳地55-65℃。
在另一优选例中，式a化合物与式b化合物的质量比为1:1-4，较佳地1:1-3，更佳地1:1-2。
在另一优选例中，式a化合物与第一碱试剂的质量比为1：1-4，较佳地1:1-3，更佳地1:1-2。
在另一优选例中，式b化合物与第一碱试剂的质量比为1～4：1，较佳地1-3:1，更佳地1-2:1。
在另一优选例中，所述的第一催化剂与所述的第一碱试剂的质量比为1:5-30，更佳地1:5-20，更佳地1:5-10。
在另一优选例中，所述的第一催化剂与所述的式a化合物的质量比为1:1-50，较佳地1:2-40，更佳地1:3-30，更佳地1:5-25，更佳地1:5-20，最佳地1:5-10。
在另一优选例中，所述的步骤(1)中，所述的反应在常压下(如1atm)下进行。
在另一优选例中，所述的步骤(1)包括步骤：
将式a化合物溶于第一溶剂中，加入式b化合物和第一催化剂，加入第一碱试剂，反应得到式I化合物。
在另一优选例中，在25-35℃下加入第一碱试剂。
在另一优选例中，所述的步骤(1)中，反应结束后，向反应液中加入水和乙酸乙酯(在0-10℃下进行)进行萃取，收集有机相，分离得到式I化合物。
在另一优选例中，所述的有机相用酸水溶液萃取后，分离得到式I化合物的盐。
在另一优选例中，所述的酸水溶液为草酸水溶液。
在另一优选例中，所述的步骤(1)中，反应得到的反应液经分离纯化得到式I化合物，所述的分离纯化包括步骤：
将反应得到的反应液降温至0～10℃，加水和有机萃取剂进行萃取，分离得到的有机萃取剂层；
将有机萃取剂层用草酸溶液萃取，合并水相，向水相加入氢氧化钠(在20℃下进行)，再加入碳酸氢钠水溶液调pH至6-7，有固体生成，过滤，滤饼用有机萃取剂淋洗；将滤液静置，分出水相，将水相再次调pH至6-7，加有机萃取剂萃取干燥、过滤，减压蒸馏浓缩得到式I化合物。
在另一优选例中，所述的有机萃取剂选自下组：乙酸乙酯、二氯甲烷、石油醚，或其组合。
本发明第二方面，提供一种式I-1化合物的制备方法，所述的方法包括步骤：
(1)在第一溶剂中，在第一催化剂和第一碱试剂的存在下，式a化合物与式b化合物反应，得到式I化合物；
Figure PCTCN2022107947-appb-000011
(2)在第二溶剂中，在第二碱试剂的存在下，式I化合物与式c所示的N-去甲基化试剂反应，得到式I-a化合物；
Figure PCTCN2022107947-appb-000012
(3)在第三溶剂中，在第三碱试剂的存在下，式I-a化合物发生水解反应，得到式I-1化合物；
Figure PCTCN2022107947-appb-000013
其中，
环A为取代或未取代的4-12元碳环、取代或未取代的4-12元杂环、取代或未取代的5-12元杂芳环、取代或未取代的C 6-C 12芳环；
R 1和R 2各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
X和Y各自独立地为碳原子、氧原子、硫原子或氮原子；
R 3为氢、卤素、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
R 4为卤素；
R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基，取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
R 12为取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 12环烷基、取代或未取代 的C 6-C 16芳基、取代或未取代的5-16元杂芳基、取代或未取代的C 1-C 6烷基-W-、取代或未取代的C 3-C 12环烷基-W-、取代或未取代的C 6-C 16芳基-W-、取代或未取代的5-16元杂芳基-W-；
R 13为卤素；
W为O或S；
n为1、2或3；
其中，所述的任一“取代”是指基团上的1-4个(优选为1、2、3或4个)氢原子各自独立地被选自下组的取代基所取代：C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、氨基、羟基、＝O、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、C 6-C 12芳基、5-10元杂芳基；
其中，所述的杂环、杂芳环和杂芳基各自独立地具有1-3个(优选为1、2或3个)选自N、O和S杂原子。
在另一优选例中，环A、X、Y、W、n、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立地如本发明第一方面所述。
在另一优选例中，R 12为取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的C 6-C 12芳基、取代或未取代的5-12元杂芳基、取代或未取代的C 1-C 6烷基-W-、取代或未取代的C 3-C 8环烷基-W-、取代或未取代的C 6-C 12芳基-W-、取代或未取代的5-12元杂芳基-W-。
在另一优选例中，R 12为取代或未取代的苯基-W-。
在另一优选例中，R 13为卤素。
在另一优选例中，卤素为氟、氯、溴或碘。
在另一优选例中，所述的第一溶剂中、在第一催化剂和第一碱试剂各自独立地如本发明第一方面所述。
在另一优选例中，式a化合物、式b化合物和式I化合物各自独立地如本发明第一方面所述。
在另一优选例中，所述的步骤(1)如本发明第一方面所述。
在另一优选例中，所述的第二溶剂选自下组：二氯甲烷、二甲基亚砜、甲苯，或DMF，或其组合。
在另一优选例中，所述的第二溶剂包括二氯甲烷。
在另一优选例中，所述的第二碱试剂选自下组：三乙醇胺、三乙胺(TEA)、1，8-二氮杂二环十一碳-7-烯(DBU)、N,N-二异丙基乙胺(DIEA)、碳酸钠，或其组合。
在另一优选例中，所述的第二碱试剂包括N,N-二异丙基乙胺(DIEA)。
在另一优选例中，所述的步骤(2)中，所述反应的温度为20-80℃，较佳地20-70℃，更佳地25-60℃，更佳地30-55℃，更佳地35-50℃，最佳地40-45℃。
在另一优选例中，当R1、R2的其中之一为甲基时，所述式c所示的N-去烷基化试剂为N-去甲基化试剂。
在另一优选例中，所述的式c所示的N-去甲基化试剂包括氯甲酸苯酯。
在另一优选例中，在所述的步骤(2)中，所述的式I化合物与第二碱试剂的质量比为1:0.1-5，较佳地1:0.2-3，更佳地1:0.4-2，更佳地1:0.5-1。
在另一优选例中，在所述的步骤(2)中，所述的式I化合物与所述的式c化合物的质量比为1:0.1-5，较佳地1:0.2-3，更佳地1:0.4-2，更佳地1:0.5-1。
在另一优选例中，在所述的步骤(2)中，所述的第二碱试剂与所述的式c化合物的质量比为0.1-5：0.1-5，较佳地0.2-3：0.2-3，更佳地0.3～2：0.3～2，最佳地0.5～1：0.5～1。
在另一优选例中，所述的步骤(2)中，所述的反应在常压下(如1atm)下进行。
在另一优选例中，所述的步骤(2)包括步骤：
将式I化合物和第二碱试剂溶于第二溶液中，加入式c所示的N-去甲基化试剂，反应得到式I-a化合物。
在另一优选例中，在25-35℃加入式c所示的N-去甲基化试剂。
在另一优选例中，所述的步骤(2)中，反应结束后，向反应液中加入水和二氯甲烷萃取，收集有机相，浓缩得到式I-a化合物。
在另一优选例中，所述的式I-a化合物具有式I-a-1的结构：
Figure PCTCN2022107947-appb-000014
在另一优选例中，所述的第三溶剂选自下组：二甲基亚砜、甲苯，或DMF，或其组合。
在另一优选例中，所述的第三溶剂为二甲基亚砜。
在另一优选例中，所述的第三碱试剂选自下组：无机碱、有机碱，或其组合。
在另一优选例中，所述的第三碱试剂选自下组：叔丁醇钾、碳酸钾、氢氧化物，或其组合。
在另一优选例中，所述的氢氧化物选自下组：氢氧化钠、氢氧化钾，或其组合。
在另一优选例中，所述的第三碱试剂包括氢氧化物。
在另一优选例中，所述的第三碱试剂包括氢氧化钠。
在另一优选例中，所述的步骤(3)中，所述反应的温度为20-100℃，较佳地30-90℃，更佳地50-70℃，更佳地55-65℃。
在另一优选例中，所述的步骤(3)中，所述的式I-a化合物与第三碱试剂的质量比为1:0.1-20，较佳地1:0.1-15，更佳地1:0.1-10，更佳地1：0.1～1，最佳地1:0.58。
在另一优选例中，所述的步骤(3)中，反应结束后，向反应液中加入水和乙酸乙酯进行萃取，收集有机相，分离得到式I化合物。
在另一优选例中，所述的有机相将酸水溶液洗涤后，分离得到式I化合物的盐。
在另一优选例中，所述的酸水溶液为草酸水溶液。
在另一优选例中，所述的式I-1化合物具有式I-1-1的结构：
Figure PCTCN2022107947-appb-000015
在另一优选例中，所述的方法包括步骤：
(1)在第一溶剂中，在第一催化剂和第一碱试剂的存在下，式i化合物与式ii化合物反应，得到式iii化合物；
Figure PCTCN2022107947-appb-000016
(2)在第二溶剂中，在第二碱试剂的存在下，式iii化合物与氯甲酸苯酯反应，得到式iv化合物；
Figure PCTCN2022107947-appb-000017
(3)在第三溶剂中，在第三碱试剂的存在下，式iv化合物发生水解反应，得到式v化合物；
Figure PCTCN2022107947-appb-000018
在另一优选例中，所述式a化合物为式i化合物。所述式b化合物为式ii化合物。所述式I化合物为式iii化合物。式I-a化合物为式iv化合物。所述式I-1化合物为式v化合物。
本发明第三方面，提供一种式I-a化合物的制备方法，所述的方法包括步骤：
(2)在第二溶剂中，在第二碱试剂的存在下，式I化合物与式c所示的N-去甲基化试剂反应，得到式I-a化合物；
Figure PCTCN2022107947-appb-000019
其中，
环A为取代或未取代的4-12元碳环、取代或未取代的4-12元杂环、取代或未取代的5-12元杂芳环、取代或未取代的C 6-C 12芳环；
R 1和R 2各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
X和Y各自独立地为碳原子、氧原子、硫原子或氮原子；
R 3为氢、卤素、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
R 4为卤素；
R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基，取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
R 12为取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的C 6-C 16芳基、取代或未取代的5-16元杂芳基、取代或未取代的C 1-C 6烷基-W-、取代或未取代的C 3-C 12环烷基-W-、取代或未取代的C 6-C 16芳基-W-、取代或未取代的5-16元杂芳基-W-；
R 13为卤素；
W为O或S；
n为1、2或3；
其中，所述的任一“取代”是指基团上的1-4个(优选为1、2、3或4个)氢原子各自独立地被选自下组的取代基所取代：C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、氨基、羟基、＝O、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、C 6-C 12芳基、5-10元杂芳基；
其中，所述的杂环、杂芳环和杂芳基各自独立地具有1-3个(优选为1、2或3个)选自N、O和S杂原子。
在另一优选例中，环A、X、Y、W、n、R 1、R 2、R 3、R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立地如本发明第一方面所述。
在另一优选例中，R 12和R 13各自独立地如本发明第二方面所述。
在另一优选例中，所述的第二溶剂中、在第二催化剂和式c所示的N-去甲基化试剂各自独立地如本发明第二方面所述。
在另一优选例中，所述的步骤(2)如本发明第二方面所述。
在另一优选例中，式I化合物、式c化合物和式I-a化合物各自独立地如本发明第二方面所述。
应理解，在本发明范围内，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人通过广泛而深入的研究，首次意外地开发了一种3-芳氧基-3-五元杂芳基-丙胺类化合物制备方法，所述的方法具有简单、易操作、收率高等优势，有利于工业化生产。在此基础上，发明人完成了本发明。
术语
如本文所用，术语“包含”、“包括”、“含有”可互换使用，不仅包括封闭式定义，还包括半封闭、和开放式的定义。换言之，所述术语包括了“由……构成”、“基本上由……构成”。
如本文所用，“R 1”、“R 1”和“R1”的含义相同，可相互替换，其它类似定义的含义相同。
如本文所用，术语“烷基”指只含碳原子的直链(即，无支链)或支链饱和烃基，或直链和支链组合的基团。当烷基前具有碳原子数限定(如C1-C6烷基)指所述的烷基含有1-6个碳原子，例如，C1-C4烷基指含有1-4个碳原子的烷基，代表性实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用，术语“C2-C4烯基”指具有1个或多个双键的2-4个碳原子的直链或支链烯烃分子少掉一个和双键连接的氢原子形成的烃基，例如乙烯基(CH2＝CH-)、(C(CH3) 2＝CH-)，或类似基团
如本文所用，术语“C2-C4炔基”指具有1个或多个三键的2-4个碳原子的直链或支链炔基分子少掉一个和三键连接的氢原子形成的烃基，例如乙炔基(CH≡CH-)、(H3C-C≡CH-)，或类似基团。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，术语“卤代”是指被卤素取代。
如本文所用，术语“卤代烷基”是指烷基的一个或多个(优选为1、2、3或4个)氢被卤素取代，所述的烷基和卤素如上所定义，当烷基前具有碳原子数限定(如C1-C8卤代烷基)指所述的烷基含有1-8个碳原子，例如，C1-C6卤代烷基指含有1-6个碳原子的卤代烷基，代表性实例包括但不限于-CF3、-CHF 2、单氟代异丙基、双氟代丁基、或类似基团。
如本文所用，术语“环烷基”指具有饱和的或部分饱和的单元环，二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C3-C12)时，指所述的环烷基具有3-12个环碳原子。在一些优选实施例中，术语“C3-C8环烷基”指具有3-8个环碳原子的饱和或部分饱和的单环或二环烷基，包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。如下是环烷基的代表性实例，包括但不限于：
Figure PCTCN2022107947-appb-000020
术语“烷氧基”指R-O-基团，其中R为烷基，烷基为如上本文所定义，当烷氧基前具有碳原子数限定，如C1-C8烷氧基基指所述的烷氧基中的烷基具有1-8个碳原子。烷氧基的代表性示例包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基，或类似基团。
如本文所用，术语“烷硫基”指R-S-基团，其中R为烷基，烷基为如上本文所定义， 当烷硫基前具有碳原子数限定，如C1-C8烷硫基指所述的烷硫基中的烷基具有1-8个碳原子。烷硫基的代表性示例包括但不限于：甲硫基、乙硫基、正丙硫基、异丙硫基、叔丁硫基，或类似基团。
术语“环烷氧基”指R-O-基团，其中R为环烷基，环烷基为如上本文所定义，当环烷氧基前具有碳原子数限定，如C3-C8环烷氧基基指所述的环烷氧基中的环烷基具有3-8个碳原子。环烷氧基的代表性示例包括但不限于：环丙氧基、环丁氧基，或类似基团。
术语“环烷硫基”指R-S-基团，其中R为环烷基，环烷基为如上本文所定义，当环烷硫基前具有碳原子数限定，如C3-C8环烷硫基基指所述的环烷硫基中的环烷基具有3-8个碳原子。环烷硫基的代表性示例包括但不限于：环丙硫基、环丁硫基，或类似基团。
如本文所用，术语“卤代烷氧基”是指卤代烷基-O-，所述的卤代烷基如上所定，例如，C1-C6卤代烷氧基指含有1-6个碳原子的卤代烷氧基，代表性实例包括但不限于、单氟代甲氧基、单氟代乙氧基、双氟代丁氧基、或类似基团。
如本文所用，术语“卤代烷硫基”是指卤代烷基-S-，所述的卤代烷基如上所定，例如，C1-C6卤代烷硫基指含有1-4个碳原子的卤代烷硫基，代表性实例包括但不限于、单氟代甲硫基、单氟代乙硫基、双氟代丁硫基、或类似基团。
如本文所用，术语“4-12元碳环”、“5-10元碳环”或“5-7元碳环”为任何稳定的4、5、6、7、8、9、10、11或12元单环、二环或多环，碳环可以是饱和的、部分不饱和的、不饱和的环，但不能为芳族的环。所述碳环的实例包括但不限于环丙环、环丁环、环丁烯环、环戊环、环戊烯环、环己环、环己烯环、环庚环、环庚烯环、金刚烷环、环辛环、环辛烯环、环辛二烯环、二环
术语“杂环”是指完全饱和的或部分不饱和的的环(包含但不限于如3-7元单环，7-11元双环，或8-16元三环系统)，其中至少有一个杂原子存在于至少有一个碳原子的环中。当杂环前有元数限定时，指的是杂环的环原子个数，例如3-16元杂环指的是具有3-16个环原子的杂环。每个含有杂原子的杂环上可以带有一个或多个(如1，2，3或4个)杂原子，这些杂原子各自独立地选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环烷环包括但不限于氮杂环丁烷环、氧杂环丁烷、咪唑啉环、咪唑烷环、四氢呋喃环、哌啶环、哌嗪环、2-氧代哌嗪环、2-氧代哌啶环、4-哌啶酮环、四氢吡喃环、吗啡啉环、硫代吗啡啉环、硫代吗啡啉亚砜环、硫代吗啡啉砜环、1,3-二噁烷环和四氢-1,1-二氧噻吩环等。多环杂环烷环包括螺环、稠环和桥环的杂环环；其中涉及到的螺环、稠环和桥环的杂环任选与其他环通过单键相连接，或者通过环上的任意两个或两个以上的原子与其它环烷环、杂环进一步并环连接。
术语“芳环”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)，是一种芳香环状烃类化合物，当芳环前面具有碳原子数限定，如C6-C12芳环，则指所述的芳环具有6-12个环碳原子，例如苯环和萘环。所述芳环可以稠合于其它碳环(包括饱和或不饱和环)，但不能含有杂原子如氮、氧、或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。代表性地芳环为苯环和萘环，或类似环。
术语“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，是一种芳香环状烃类化合物基团，当芳基前面具有碳原子数限定，如C6-C12芳基，则指所述的芳基具有6-12个环碳原子，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和或不饱和环)，但不能含有杂原子如氮、氧、或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。如下是芳基代表性实例，包括但不限于：
Figure PCTCN2022107947-appb-000021
术语“杂芳环”指具有一个到多个(优选为1、2、3或4个)杂原子的芳族杂环，其可以是单环(单环的)或者稠合在一起或共价地连接的多环(二环的、三环的或多环的)，每个含有杂原子的杂环上可以具有一个或多个(如1、2、3、4个)各自独立选自下组的杂原子：氧、硫和氮。当杂芳环前有元数限定时，指的是杂芳环的环原子个数，例如5-12元杂芳环指的是具有5-12个环原子的杂芳环，代表性的例子包括但不限于：吡咯环、吡唑环、咪唑环、噁唑环、异噁唑环、噻唑环、噻二唑环、异噻唑环、呋喃环、吡啶环、吡嗪环、嘧啶环、哒嗪环、三氮嗪环、三氮唑环及四氮唑环等。
术语“杂芳基”指具有一个到多个(优选为1、2、3或4个)杂原子的芳族杂环系基团，其可以是单环(单环的)或者稠合在一起或共价地连接的多环(二环的、三环的或多环的)，每个含有杂原子的杂环上可以带有一个多个(如1、2、3、4个)各自独立选自下组的杂原子：氧、硫和氮。当杂芳基前有元数限定时，指的是杂芳基的环原子个数，例如5-12元杂芳基指的是具有5-12个环原子的杂芳基，代表性的例子包括但不限于：吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。
如本文所用，术语“羧基”指具-COOH基团或-烷基-COOH基团，烷基为如上本文所定义，例如“C 2-C 4羧基”是指-C 1-C 3烷基-COOH结构的基团，羧基的代表性示例包括(但不限于)：-COOH、-CH 2COOH、-C 2H 4COOH，或类似基团。
如本文所用，术语“酯基”指具R-CO-O-基团或-CO-O-R基团，其中R为烷基，烷基为如上本文所定义，例如“C 2-C 4酯基”是指C 1-C 3烷基-CO-O-结构的基团或者-CO-O-C 1-C 3烷基结构的基团，酯基的代表性示例包括但不限于：CH 3COO-、C 2H 5COO-、C 3H 8COO-、(CH 3) 2CHCOO-、-COOCH 3、-COOC 2H 5、-COOC 3H 8，或类似基团。
如本文所用，术语“酰胺基”指具R-CO-N-基团或-CO-N-R基团，其中R为烷基，烷基为如上本文所定义，例如“C 2-C 4酰胺基”是指C 1-C 3烷基-CO-N-结构的基团或者-CO-N-C 1-C 3烷基结构的基团，酰胺基的代表性示例包括但不限于：CH 3CO-N-、C 2H 5CO-N-、C 3H 8CO-N-、(CH 3) 2CHCO-N-、-CO-N-CH 3、-CO-N-C 2H 5、-CO-N-C 3H 8，或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语"氨基"表示-NH 2。
如本文所用，在单独或作为其他取代基一部分时，术语"硝基"表示-NO 2。
如本文所用，在单独或作为其他取代基一部分时，术语"氰基"表示-CN。
如本文所用，在单独或作为其他取代基一部分时，术语"羟基"表示-OH。
如本文所用，在单独或作为其他取代基一部分时，术语"巯基"表示-SH。
如本文所用，术语“取代”是基团上的氢原子被非氢原子基团取代，但需要满足其化合价要求并且由取代生成化学稳定的化合物。在本说明书中，应解释为所有取代基为未取代的，除非在本文中明确描述为“取代的”。
如本文所用，
Figure PCTCN2022107947-appb-000022
与
Figure PCTCN2022107947-appb-000023
含义相同，均表示具有未取代的或具有1-5个(优选1-3个)R 3取代基的杂芳基。
如本文所用，
Figure PCTCN2022107947-appb-000024
为连接位点。
同样，应当理解的是，在本发明中，取代基可以在任何原子上与母体基团或底物连接，除非其连接违反化合价要求；母体基团或底物的氢原子可以在同一原子上，也可以在不同的原子上。
如本文所用，室温指的是25±5℃。
如本文所用，对于一个数值范围P1至P2,则该范围不仅包括端点P1和P2，还包括介于端点P1和P2的任何数值点。此外，对于P1和P2均为正数时，则对于一个整数n，该数值范围包括介于端点P1和P2的任何整数数值点。例如，对于一个整数n，当其数值范围为1-10时，包括1、2、3、4、5、6、7、8、9、和10；数值范围3-7包括3、4、5、6、7。代表性地，对于基团而言，C3-C7包括C3、C4、C5、C6、和C7。
制备方法
本发明提供一种式I结构的化合物，或其药学上可接受的盐的制备方法，所述的方法包括步骤：
(1)在第一溶剂中，在第一催化剂和第一碱试剂的存在下，式a化合物与式b化合物反应，得到式I化合物；`
Figure PCTCN2022107947-appb-000025
其中，所述步骤(1)如上述本发明第一方面所述。
本发明还提供一种式I-1化合物的制备方法，所述的方法包括步骤：
(1)在第一溶剂中，在第一催化剂和第一碱试剂的存在下，式a化合物与式b化合物反应，得到式I化合物；
Figure PCTCN2022107947-appb-000026
(2)在第二溶剂中，在第二碱试剂的存在下，式I化合物与式c所示的N-去甲基化试剂反应，得到式I-a化合物；
Figure PCTCN2022107947-appb-000027
(3)在第三溶剂中，在第三碱试剂的存在下，式I-a化合物发生水解反应，得到式I-1化合物；
Figure PCTCN2022107947-appb-000028
其中，所述步骤(1)、(2)和(3)如上述本发明第二方面所述。
本发明还提供一种式I-a化合物的制备方法，所述的方法包括步骤：
(2)在第二溶剂中，在第二碱试剂的存在下，式I化合物与式c所示的N-去甲基化试剂反应，得到式I-a化合物；
Figure PCTCN2022107947-appb-000029
其中，所述步骤(2)如上述本发明第三方面所述。
本发明的主要优点包括：
本发明的制备方法具有简单、易操作、收率高等优势，有利于工业化生产，具体包括以下方面：
1、制备方法的经济性好，原料和相关物料易于获取、成本低；
2、制备方法的不涉及到剧毒化学品，不涉及到苛刻的反应条件；
3、制备方法的路线的收率较高；
4、制备方法的核心优势在于，对手性中心的构型控制的很好，关键中间体和终产品的手性纯度很高。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发 明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1
式V化合物的制备
步骤(1)：(R)-3-(苯并呋喃-7-基氧基)-N,N-二甲基-3-(噻吩-2-基)丙-1-胺III)的制备
Figure PCTCN2022107947-appb-000030
控温30℃以下，向反应釜依次加入88kg DMSO(8.80w/w),10kg 7-氟苯并呋喃(式I化合物)(1.00w/w),16.3kg(R)-3-(二甲基氨基)-1-(噻吩-2-基)丙-1-醇(式II化合物)(1.63w/w),1.8kg碘化钾(0.18w/w),14.8kg氢氧化钠(1.48w/w)；体系于60℃～65℃保温反应20h，每隔2h取样一次，至HPLC转化率≥80.0％；反应完毕后降温，控温0℃～10℃，加入100kg饮用水(10.00w/w)；依次加入乙酸乙酯，萃取3次(8.1w/w,4.5w/w,4.5w/w)；合并有机相，用3.27w/w的工业盐及9.09w/w的水配置的盐水洗。用8kg草酸(0.80w/w)和100kg饮用水(10.00w/w)，配置成草酸溶液1；用草酸4kg草酸(0.40w/w)和50kg饮用水(5.00w/w)，配置成草酸溶液2。将乙酸乙酯相用草酸溶液1，草酸溶液2分别萃取。合并水相，加入40.5kg乙酸乙酯(4.05w/w)洗；控温20℃以下，向水相加入4kg氢氧化钠(0.40w/w)，再加入碳酸氢钠水溶液调pH＝6.4～6.6。有固体生成，过滤。滤饼用适量乙酸乙酯淋洗；将滤液搅拌10～30分钟，静置10～30分钟，分出水相，将水相再次调pH＝6.4～6.6，加81kg乙酸乙酯(8.10w/w)萃取；向有机相中加入10kg无水硫酸钠(1.00w/w)，搅拌干燥0.5～1h；过滤，减压蒸馏浓缩得到式III化合物，称重，检测，收率为51.13％。
式III化合物的 1H NMR(500MHz,CDCl 3)δ7.62(d,J＝2.1Hz,1H),7.21(dt,J＝12.8,6.4Hz,1H),7.16(dd,J＝7.8,0.9Hz,1H),7.05–7.01(m,2H),6.91(dd,J＝5.0,3.5Hz,1H),6.83(dd,J＝6.8,6.1Hz,1H),6.73(t,J＝4.2Hz,1H),5.85–5.77(m,1H),2.53–2.48(m,2H),2.48–2.40(m,1H),2.26(s,6H),2.16(tt,J＝10.1,4.9Hz,1H).MS(ESI,m/z):301.89(M+H) +，手性纯度为98.88％。
步骤(2)：(R)-苯基(3-(苯并呋喃-7-氧基)-3-(噻吩-2-基)丙基)(甲基)氨基甲酸酯(IV)的制备
Figure PCTCN2022107947-appb-000031
控温30℃以下，向反应釜加入65kg DCM(6.50w/w)，开启搅拌，依次加入10kg式III化合物(1.00w/w)，6.4kg DIEA(0.64w/w)。控温30℃以下，向反应釜滴加7.7kg氯甲酸苯酯(0.77w/w)。体系于40℃～45℃(回流)保温反应3h，每隔1h取样一次，至HPLC转化率≥90.0％；向桶中加入草酸4.3kg(0.43w/w)和53.2kg饮用水(5.32w/w)，配置成草酸溶液，待用。反应体系降温，控温10℃～20℃，加入草酸溶液，搅拌20～ 40分钟；反应体系静置10～20分钟，分出有机相。水相加入35kg DCM萃取(3.50w/w)。合并有机相，适量饱和盐水洗一次。向有机相中加入10kg无水硫酸钠(1.00w/w)，搅拌干燥0.5～1h，过滤，滤饼用DCM(1.00w/w)淋洗，淋洗后抽干。过滤得到的滤液减压蒸馏浓缩得到式IV化合物，称重，检测，收率为103.04％。
式IV化合物的 1H NMR(400MHz,CDCl 3)δ7.60(d,J＝13.6Hz,1H),7.31(dt,J＝15.7,7.7Hz,2H),7.23(t,J＝5.4Hz,1H),7.16(t,J＝9.6Hz,2H),7.02(dd,J＝21.0,7.3Hz,3H),6.96(d,J＝7.8Hz,1H),6.91(d,J＝3.2Hz,1H),6.84–6.78(m,1H),6.73(d,J＝9.0Hz,1H),5.81(dd,J＝7.8,5.1Hz,1H),3.83–3.51(m,2H),3.08(d,J＝31.9Hz,3H),2.62–2.53(m,1H),2.46–2.39(m,1H).MS(ESI,m/z):407.99(M+H) +。
步骤(3)：(R)-3-(苯并呋喃-7-基氧基)-N-甲基-3-(噻吩-2-基)丙-1-胺(V)的制备
Figure PCTCN2022107947-appb-000032
向反应釜加入25kg水(2.50w/w)，开启搅拌，依次加入5.8kg氢氧化钠(0.58w/w)，10kg式IV化合物(1.00w/w)，44kg DMSO(4.40w/w)。体系于60℃～65℃保温反应2小时，反应2小时后取样检测，每隔1～2小时取样检测至转化率≥95.0％。降温至5℃～15℃，向反应体系中加入24kg水(2.40w/w)，向反应体系中加入26kg乙酸乙酯(2.60w/w)，并搅拌5～10分钟，将反应体系静置10分钟，收集有机相，将水相转移至反应釜中；水相用乙酸乙酯萃取2次(每次2.60w/w)。合并有机相，用饱和盐水洗；将反应釜打开搅拌，加入草酸至pH＜5，搅拌30分钟；将反应体系离心，滤饼分别用乙酸乙酯(1.00w/w)淋洗2次，得草酸盐；向反应釜中加入水(3.00w/w)，打开搅拌；加入3kg氢氧化钠(0.30w/w)，搅拌至溶解；向反应釜中加入乙酸乙酯(2.60w/w)，搅拌5～10分钟，后静置分层，收集有机相，将水相转移至反应釜中；将反应釜打开搅拌，加入乙酸乙酯(2.60w/w)，搅拌5～10分钟后，静置分层，合并有机相，并转移至反应釜中，用盐水洗，分出水相，向有机相加入无水硫酸钠(1.00w/w)；将干燥后的有机相过滤，滤饼用乙酸乙酯(0.50w/w)洗一次，将滤液在40～50℃下减压浓缩，向浓缩完成的游离态加入甲醇(2.80w/w)，搅拌至溶解，加入活性炭(0.07w/w)脱色。将脱色的混合物过滤，减压浓缩得到式V化合物，称重，检测，收率为61.73％。
式V化合物的 1H NMR(400MHz,CDCl 3)δ7.63(d,J＝2.0Hz,1H),7.20(t,J＝6.6Hz,2H),7.08–6.99(m,2H),6.88(dd,J＝4.9,3.6Hz,1H),6.80(d,J＝7.9Hz,1H),6.75(d,J＝2.0Hz,1H),5.93(dd,J＝8.2,4.4Hz,1H),3.30(t,J＝7.0Hz,2H),2.82–2.69(m,3H),2.65–2.54(m,1H).MS(ESI,m/z):287.91(M+H) +，手性纯度为99.90％。
实施例2
(R)-3-(苯并呋喃-7-基氧基)-N-甲基-3-(噻吩-2-基)丙-1-胺盐酸盐的制备
Figure PCTCN2022107947-appb-000033
将0.7kg(R)-3-(苯并呋喃-7-基氧基)-N-甲基-3-(噻吩-2-基)丙-1-胺(V)加入20L的乙酸乙酯溶液中，缓慢滴加浓盐酸，调节pH至5～6后，继续搅拌10分钟， 有固体析出，抽滤，滤饼用乙酸乙酯洗涤一次，将滤饼放入烘箱中，升温至40～50℃，干燥至恒重，得到0.63kg白色固体式V化合物的盐，收率为79.50％。
1H NMR(500MHz,DMSO)δ8.77(s,2H),7.98(d,J＝2.1Hz,1H),7.50(dd,J＝5.0,1.1Hz,1H),7.25–7.17(m,2H),7.08(t,J＝7.9Hz,1H),6.99(dd,J＝5.0,3.5Hz,1H),6.97–6.93(m,2H),6.04(dd,J＝8.0,5.2Hz,1H),3.08(dtd,J＝22.2,12.3,5.6Hz,2H),2.59(s,3H),2.48–2.41(m,1H),2.29(ddd,J＝15.3,10.4,5.4Hz,1H).MS(ESI,m/z):287.91(M+H) +，手性纯度为99.90％。
实施例3
TRPA1的抑制活性测试
在本实施例中，测试本发明式V化合物对瞬时受体电位通道蛋白TRPA1的抑制活性。其中，阳性对照化合物采用式B化合物(WO2010075353)：
Figure PCTCN2022107947-appb-000034
方法如下：
通过IonWorks Barracuda(IWB)自动化膜片钳检测的测试方法：稳定表达TRPA1的HEK293细胞，用含有15μg/mL Blasticidin S HCl、200μg/mL Hygromycin B和10％FBS血清的DMEM培养基，置于T175的培养瓶中，放入37℃，5％CO 2的培养箱中培养，待细胞密度生长到～80％时，移走培养液，用无钙镁的磷酸缓冲液(PBS)冲洗一遍，加入3mL的Trypsin消化2分钟，加入7mL培养液终止消化。将细胞收集到15mL的离心管中以800转/每分钟离心3分钟，去除上清液后将细胞加入适当体积的细胞外液重悬，使细胞密度控制在2-3×10 6/mL并用于IWB实验。细胞外液配方(in mM)：140NaCl,5KCl,1MgCl 2,10HEPES,0.5EGTA,10Glucose(pH 7.4)；细胞内液配方(in mM)：140CsCl,10HEPES,5EGTA,0.1CaCl 2,1MgCl 2(pH 7.2)。两性霉素B与实验当天用DMSO新鲜配制成28mg/mL，再用细胞内液配制成0.1mg/mL的终浓度。
IWB实验使用population patch clamp(PPC)板，全部检测过程由仪器自动完成，即在PPC板的384孔中加入细胞外液，并在PPC板下即plenum内加入细胞内液后，加入6L的细胞液进行封接测试，最后将plenum中的细胞内液换成含两性霉素B的细胞内液，使封接的细胞穿孔后形成全细胞记录模式。记录TPRA1电流的采样频率为10kHz，细胞钳制在0mV，电压刺激命令(channel protocol)为一个300ms从-100mV到+100mV的斜坡(ramp)电压，每10s给予此电压刺激，mTRPA1电流由300M AITC诱发。
数据记录和电流幅度测量导出由IWB软件完成(version 2.5.3，Molecular Devices Corporation，Union City，CA)。封接阻抗低于20MΩ的孔将不记录数据统计。原始电流数据由软件进行漏减矫正，TRPA1电流幅度在+100mV时测得。实验的每块PPC板都将有一个HC030031的剂量效应数据作为阳性对照，如HC030031的IC 50值超过以往每块板上得到的IC 50平均值的3倍时，将进行复测。化合物剂量效应曲线和IC 50由GraphPad Prism 5.02(GraphPad Software,San Diego,CA)进行拟合计算。
实验结果
对本发明实施例制备的式V化合物通过IonWorks Barracuda(IWB)自动化膜片钳检测的测试方法，进行IC 50抑制活性测试，活性数据如表2所示。
表2.本发明的式V化合物在自动化膜片钳检测测试中对TRPA1的抑制活性数据(IC 50,μM)
编号 IC 50(μM)
式V化合物 +++++
式B化合物 +
其中活性：IC 50(μM)：
51-100：+
1-5：+++++
结果表明，本发明的式V化合物对TRPA1表现出强效抑制活性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范上围。

Claims (18)

  1. 一种式I化合物的制备方法，其特征在于，所述的方法包括步骤：
    (1)在第一溶剂中，在第一催化剂和第一碱试剂的存在下，式a化合物与式b化合物反应，得到式I化合物；
    Figure PCTCN2022107947-appb-100001
    其中：
    环A为取代或未取代的4-12元碳环、取代或未取代的4-12元杂环、取代或未取代的5-12元杂芳环、取代或未取代的C 6-C 12芳环；
    R 1和R 2各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
    X和Y各自独立地为碳原子、氧原子、硫原子或氮原子；
    R 3为氢、卤素、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
    R 4为卤素；
    R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基，取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
    W为O或S；
    n为1、2或3；
    其中，所述的任一“取代”是指基团上的1-4个(优选为1、2、3或4个)氢原子各自独立地被选自下组的取代基所取代：C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、氨基、羟基、＝O、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、C 6-C 12芳基、5-10元杂芳基；
    其中，所述的杂环、杂芳环和杂芳基各自独立地具有1-3个(优选为1、2或3个)选自N、O和S杂原子。
  2. 一种式I-1化合物的制备方法，其特征在于，所述的方法包括步骤：
    (1)在第一溶剂中，在第一催化剂和第一碱试剂的存在下，式a化合物与式b化合物反应，得到式I化合物；
    Figure PCTCN2022107947-appb-100002
    (2)在第二溶剂中，在第二碱试剂的存在下，式I化合物与式c所示的N-去烷基化试剂反应，得到式I-a化合物；
    Figure PCTCN2022107947-appb-100003
    (3)在第三溶剂中，在第三碱试剂的存在下，式I-a化合物发生水解反应，得到式I-1化合物；
    Figure PCTCN2022107947-appb-100004
    其中，
    环A为取代或未取代的4-12元碳环、取代或未取代的4-12元杂环、取代或未取代的5-12元杂芳环、取代或未取代的C 6-C 12芳环；
    R 1和R 2各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
    X和Y各自独立地为碳原子、氧原子、硫原子或氮原子；
    R 3为氢、卤素、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
    R 4为卤素；
    R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基，取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
    R 12为取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 12环烷基、取代或未取代 的C 6-C 16芳基、取代或未取代的5-16元杂芳基、取代或未取代的C 1-C 6烷基-W-、取代或未取代的C 3-C 12环烷基-W-、取代或未取代的C 6-C 16芳基-W-、取代或未取代的5-16元杂芳基-W-；
    R 13为卤素；
    W为O或S；
    n为1、2或3；
    其中，所述的任一“取代”是指基团上的1-4个(优选为1、2、3或4个)氢原子各自独立地被选自下组的取代基所取代：C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、氨基、羟基、＝O、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、C 6-C 12芳基、5-10元杂芳基；
    其中，所述的杂环、杂芳环和杂芳基各自独立地具有1-3个(优选为1、2或3个)选自N、O和S杂原子。
  3. 如权利要求2所述的方法，其特征在于，所述的方法包括步骤：
    (1)在第一溶剂中，在第一催化剂和第一碱试剂的存在下，式i化合物与式ii化合物反应，得到式iii化合物；
    Figure PCTCN2022107947-appb-100005
    (2)在第二溶剂中，在第二碱试剂的存在下，式iii化合物与氯甲酸苯酯反应，得到式iv化合物；
    Figure PCTCN2022107947-appb-100006
    (3)在第三溶剂中，在第三碱试剂的存在下，式iv化合物发生水解反应，得到式v化合物；
    Figure PCTCN2022107947-appb-100007
  4. 一种式I-a化合物的制备方法，其特征在于，所述的方法包括步骤：
    (2)在第二溶剂中，在第二碱试剂的存在下，式I化合物与式c所示的N-去甲基化试剂反应，得到式I-a化合物；
    Figure PCTCN2022107947-appb-100008
    其中，
    环A为取代或未取代的4-12元碳环、取代或未取代的4-12元杂环、取代或未取代的5-12元杂芳环、取代或未取代的C 6-C 12芳环；
    R 1和R 2各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
    X和Y各自独立地为碳原子、氧原子、硫原子或氮原子；
    R 3为氢、卤素、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
    R 4为卤素；
    R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立为氢、取代或未取代的C 1-C 12烷基、取代或未取代的C 3-C 12环烷基，取代或未取代的5-12元杂芳基、取代或未取代的C 6-C 12芳基；
    R 12为取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 12环烷基、取代或未取代的C 6-C 16芳基、取代或未取代的5-16元杂芳基、取代或未取代的C 1-C 6烷基-W-、取代或未取代的C 3-C 12环烷基-W-、取代或未取代的C 6-C 16芳基-W-、取代或未取代的5-16元杂芳基-W-；
    R 13为卤素；
    W为O或S；
    n为1、2或3；
    其中，所述的任一“取代”是指基团上的1-4个(优选为1、2、3或4个)氢原子各自独立地被选自下组的取代基所取代：C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、氨基、羟基、＝O、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、C 6-C 12芳基、5-10元杂芳基；
    其中，所述的杂环、杂芳环和杂芳基各自独立地具有1-3个(优选为1、2或3个)选自N、O和S杂原子。
  5. 如权利要求1、2、4中任一项所述的方法，其特征在于，环A为取代或未取代的5-7元碳环、取代或未取代的5-7元杂环、取代或未取代的5-7元杂芳环；
    R 1和R 2各自独立为氢或取代或未取代C 1-C 3烷基；
    R 3为氢、卤素、取代或未取代的C 1-C 6烷基；
    R 5、R 6、R 7、R 8、R 9、R 10和R 11各自独立为氢。
  6. 如权利要求1、2、4中任一项所述的方法，其特征在于，所述的式I化合物选自下组：
    Figure PCTCN2022107947-appb-100009
    Figure PCTCN2022107947-appb-100010
  7. 如权利要求1、2或3所述的方法，其特征在于，所述的第一溶剂选自下组：二甲基亚砜、甲苯、DMF，或其组合；
    所述的第一催化剂选自下组：卤化盐、四丁基溴化铵、4-二甲氨基吡啶、二苯并-18-冠醚-6、吡啶，或其组合；和/或
    所述的第一碱试剂选自下组：无机碱、有机碱，或其组合。
  8. 如权利要求7所述的方法，其特征在于，所述的第一溶剂为二甲基亚砜；
    所述的卤化盐选自下组：氟化钾、氯化钾、溴化钾、碘化钾、氟化钠、氯化钠、溴化钠、碘化钠，或其组合，优选所述的第一催化剂包括碘化钾；和/或
    所述的第一碱试剂选自下组：钠氢、氢氧化物，或其组合；其中，所述的氢氧化物选自下组：氢氧化钠、氢氧化钾，或其组合。
  9. 如权利要求1、2或3所述的方法，其特征在于，所述的步骤(1)中，所述反应的温度为30-90℃，较佳地40-80℃，更佳地50-70℃，最佳地55-65℃。
  10. 如权利要求1或2所述的方法，其特征在于，式a化合物与式b化合物的质量比为1:1-4，较佳地1:1-3，更佳地1:1-2；
    式a化合物与第一碱试剂的质量比为1:1-4，较佳地1:1-3，更佳地1:1-2；
    式b化合物与第一碱试剂的质量比为1～4:1，较佳地1-3:1，更佳地1-2:1；
    所述的第一催化剂与所述的第一碱试剂的质量比为1:5-30，更佳地1:5-20，更佳地1:5-10；和/或
    所述的第一催化剂与所述的式a化合物的质量比为1:1-50，较佳地1:2-40，更佳地1:3-30，更佳地1:5-25，更佳地1:5-20，最佳地1:5-10。
  11. 如权利要求2或4所述的方法，其特征在于，R 12为取代或未取代的苯基-W-。
  12. 如权利要求2、3或4所述的方法，其特征在于，所述的第二溶剂选自下组：二氯甲烷、二甲基亚砜、甲苯，或DMF，或其组合，优选二氯甲烷；和/或
    所述的第二碱试剂选自下组：三乙醇胺、三乙胺(TEA)、1，8-二氮杂二环十一碳-7-烯(DBU)、N,N-二异丙基乙胺(DIEA)、碳酸钠，优选N,N-二异丙基乙胺(DIEA)，或其组合。
  13. 如权利要求2、3或4所述的方法，其特征在于，所述的步骤(2)中，所述反应的温度为20-80℃，较佳地20-70℃，更佳地25-60℃，更佳地30-55℃，更佳地35-50℃，最佳地40-45℃。
  14. 如权利要求2或4所述的方法，其特征在于，在所述的步骤(2)中，所述的式I化合物与第二碱试剂的质量比为1:0.1-5，较佳地1:0.2-3，更佳地1:0.4-2，更佳 地1:0.5-1；
    所述的式I化合物与所述的式c化合物的质量比为1:0.1-5，较佳地1:0.2-3，更佳地1:0.4-2，更佳地1:0.5-1；和/或
    所述的第二碱试剂与所述的式c化合物的质量比为0.1-5:0.1-5，较佳地0.2-3:0.2-3，更佳地0.3～2:0.3～2，最佳地0.5～1:0.5～1。
  15. 如权利要求2或3所述的方法，其特征在于，所述的第三溶剂选自下组：二甲基亚砜、甲苯，或DMF，或其组合；和/或
    所述的第三碱试剂选自下组：叔丁醇钾、碳酸钾、氢氧化物，或其组合。
  16. 如权利要求15所述的方法，其特征在于，所述的第三溶剂为二甲基亚砜；和/或
    所述的第三碱试剂选自下组：叔丁醇钾、碳酸钾、氢氧化物，或其组合；其中，所述的氢氧化物选自下组：氢氧化钠、氢氧化钾，或其组合。
  17. 如权利要求2或3所述的方法，其特征在于，所述的步骤(3)中，所述的式I-a化合物与第三碱试剂的质量比为1:0.1-20，较佳地1:0.1-15，更佳地1:0.1-10，更佳地1：0.1～1。
  18. 如权利要求2或3所述的方法，其特征在于，所述的步骤(3)中，所述反应的温度为30-90℃，较佳地40-80℃，更佳地50-70℃，最佳地55-65℃。
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