CN115703767A

CN115703767A - Preparation method of 3-aryloxy-3-five-membered heteroaryl-propylamine compound

Info

Publication number: CN115703767A
Application number: CN202110924835.6A
Authority: CN
Inventors: 王友鑫; 张玲玲; 丁强
Original assignee: Shanghai Leado Pharmatech Co ltd
Current assignee: Shanghai Leado Pharmatech Co ltd
Priority date: 2021-08-12
Filing date: 2021-08-12
Publication date: 2023-02-17
Also published as: WO2023016249A1; CN117769547A

Abstract

The invention relates to a preparation method of a 3-aryloxy-3-five-membered heteroaryl-propylamine compound. Specifically, the present invention provides a process for the preparation of a compound of formula I, said process comprising the steps of: reacting a compound of formula a with a compound of formula b in a first solvent in the presence of a first catalyst and a first base reagent to provide a compound of formula I. The method has the advantages of simplicity, easy operation, high yield and the like, and is beneficial to industrial production.

Description

Preparation method of 3-aryloxy-3-five-membered heteroaryl-propylamine compound

Technical Field

The invention relates to the field of pharmaceutical chemistry and pharmacotherapeutics, in particular to a preparation method of a 3-aryloxy-3-five-membered heteroaryl-propylamine compound.

Background

Pain is known as the fifth vital sign and is a warning sign of damage to body tissues. Pain is one of the most common reasons for hospitalization, and is classified into acute pain (acute onset, short duration, and persistent state) and chronic pain (slow onset or conversion from acute pain, long duration, and intermittent onset, and many chronic pains have no obvious injury). Acute pain is often nociceptive pain caused by tissue trauma, and includes postoperative pain, trauma, pain after burn, labor pain, visceral pain such as angina pectoris, biliary colic, renal colic, fracture pain, toothache, cancer pain, etc. Surgical and post-traumatic pain are the most common and most acute pain to be treated clinically. Chronic pain mainly includes neuropathic pain, pain osteoarthritis, chronic low back pain, angiogenic pain and the like. Trigeminal neuralgia, diabetic pain, sciatica, or postherpetic neuralgia are the main types of neuropathic pain. Neuropathic pain has a global prevalence of about 10%, high morbidity, and a large population of patients. Between 10% and 30% of people in the united states suffer from chronic pain, resulting in a social expenditure of about $ 6350 million annually, exceeding the sum of cancer and heart disease. The etiology of chronic pain is complex, the chronic pain belongs to intractable diseases, and only less than 50% of patients can achieve effective analgesia through drug therapy. The total market scale of the Chinese neuralgia medicaments in 2026 is estimated to be close to 260 billion yuan, and the market scale of the ion channel type neuralgia medicaments is over 200 billion yuan.

Traditional analgesic drugs mainly include opioids and non-steroidal anti-inflammatory drugs. Opioid drugs have strong analgesic action, but are liable to cause tolerance, dependence and addiction after long-term use, and have adverse reactions such as respiratory depression and central sedation. The non-steroidal anti-inflammatory drug only exerts moderate analgesic effect and has reactions such as gastrointestinal hemorrhage and cardiotoxicity. The recent release of preventable death reports by the american national committee of safety shows that, for the first time in the united states, opiates overdose outweigh the percentage of deaths due to car accidents. According to the analysis of the 2017 unexpected death data by the committee, 1 out of 96 americans died from opioid overdose, while 1 out of 103 were the car accident deaths. Opioid abuse has created a serious social crisis now rolling across the united states, and the market therefore requires new mechanisms for analgesics.

TRPA1 is a member of TRP ion channel superfamily, the only member of TRPA subfamily, belongs to non-selective cation channel, and can penetrate Na ⁺ ，K ⁺ ，Ca ²⁺ And Mg ²⁺ . TRPA1 is distributed primarily on primary sensory neurons of the dorsal root nerve (DRG), trigeminal nerve (TG) and vagus nerve (VG). From the viewpoint of distributed human systems, TRPA1 is highly expressed in the peripheral nervous system, respiratory system, gastrointestinal system, and urinary system, and when these organ tissues are abnormally expressed, the expression and function of TRPA1 channels are also normally abnormally synchronized. TRPA1 can convert cold, chemical and mechanical stimuli into inward currents, trigger a range of physiological functions and participate in the development of multiple pain sensations. Inflammatory pain is a common affliction in some chronic diseases, and clinically, a very effective treatment means is not yet available. Animal experimental studies have shown that TRPA1 is involved in inflammatory responses and plays an important role in inflammatory pain, and by using TRPA 1-specific blockers, inflammatory pain responses in rats can be significantly reduced. From the current research, TRPA1 plays an important role in the occurrence of asthma and cough, and compounds inducing asthma and cough, whether endogenous factors of cells or exogenous factors, can activate TRPA1. Antagonists of TRPA1 can alleviate asthma symptoms and block airway hyperresponsiveness. Through different visceral hypersensitive animal models such as colitis, colorectal distension or stress, the fact that TRPA1 participates in the regulation of visceral hypersensitive diseases and plays an important role in visceral pain is proved. Neuropathic pain is a pain syndrome caused by injury or disease of the central or peripheral nervous system, and is mainly manifested by hyperalgesia, allodynia, spontaneous pain and the like. Recent years have seen an increasing number of studies that TRPA1 channels play an important role in different neuropathic pain states, such as diabetic neuropathy and chemotherapy induced neuropathy. Recent studies have also shown that TRPA1 also has a mediating effect in pain such as toothache, migraine, etc., and the generation of pain symptoms can be significantly alleviated by administration of an antagonist of TRPA1.

The prior art discloses a 3-aryloxy-3-pentanary heteroaryl-propylamine compound with effective treatment effect on pain, which has the following structure:

however, the compounds of formula a disclosed in the prior art are complicated to prepare and have low yields, thereby limiting the use of 3-aryloxy-3-pentanary heteroaryl-propylamines in the treatment of pain.

Therefore, the preparation method of the 3-aryloxy-3-pentanary heteroaryl-propylamine compound, which is simple, easy to operate and high in yield, needs to be developed in the field, so that the application value of the 3-aryloxy-3-pentanary heteroaryl-propylamine compound medicine is improved.

Disclosure of Invention

The invention aims to provide a preparation method of a 3-aryloxy-3-pentabasic heteroaryl-propylamine compound, which is simple, easy to operate and high in yield.

In a first aspect of the invention, there is provided a process for the preparation of a compound of formula I, said process comprising the steps of:

(1) Reacting a compound of formula a with a compound of formula b in a first solvent in the presence of a first catalyst and a first base reagent to obtain a compound of formula I;

wherein:

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 heteroaromatic ring, a substituted or unsubstituted C ₆ -C ₁₂ An aromatic ring;

R ¹ and R ² 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 An aryl group;

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 C ₆ -C ₁₂ An aryl group;

R ⁴ is halogen;

R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ and R ¹¹ Each independently of the other being 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 An aryl group;

w is O or S;

n is 1,2 or 3;

wherein, any "substitution" means that 1 to 4 (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted with a substituent selected from the group consisting of: c ₁ -C ₆ Alkyl radical, C ₃ -C ₇ Cycloalkyl radical, C ₁ -C ₃ Haloalkyl, halogen, nitro, cyano, amino, hydroxy, = O, C ₁ -C ₄ Carboxyl group, C ₂ -C ₄ Ester group, C ₂ -C ₄ Amide group, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy, benzyl, C ₆ -C ₁₂ Aryl, 5-10 membered heteroaryl;

wherein the heterocycle, heteroaryl ring and heteroaryl each independently have 1 to 3 heteroatoms (preferably 1,2 or 3 heteroatoms) selected from N, O and S.

In another preferred embodiment, 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 C ₆ -C ₁₂ An aromatic ring.

In another preferred embodiment, 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.

In another preferred embodiment, ring a is not a benzene ring.

In another preferred embodiment, ring A is a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstituted 5-7 membered heteroaromatic ring.

In another preferred embodiment, ring A is a substituted or unsubstituted 5-7 membered carbocyclic or 5-7 membered heteroaromatic ring.

In another preferred embodiment, ring a is a substituted or unsubstituted 5-membered carbocyclic ring, a substituted or unsubstituted 6-membered carbocyclic ring, or a substituted or unsubstituted furan ring.

In another preferred embodiment, ring a is a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, or a furan ring.

In another preferred embodiment, ring A is

In another preferred embodiment, the connecting structure of ring a and the adjacent benzene ring is:

in another preferred embodiment, X and Y are each independently a carbon atom, an oxygen atom, a sulfur atom, or a nitrogen atom.

In another preferred embodiment, at least one of X and Y is a heteroatom.

In another preferred embodiment, Y is a carbon atom or a nitrogen atom.

In another preferred embodiment, X is S or O.

In another preferred embodiment, X is S.

In another preferred embodiment, Y is a carbon atom.

In another preferred embodiment, R ¹ And R ² 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 And (4) an aryl group.

In another preferred embodiment, R ¹ And R ² Each independently hydrogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₃ -C ₇ A cycloalkyl group.

In another preferred embodiment, R ¹ And R ² Each independently is hydrogen or substituted or unsubstituted C ₁ -C ₃ An alkyl group.

In another preferred embodiment, R ¹ And R ² Each independently hydrogen, methyl or ethyl.

In another preferred embodiment, 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 And (4) an aryl group.

In another preferred embodiment, R ³ Is hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₃ -C ₇ A cycloalkyl group.

In another preferred embodiment, R ³ Is hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ An alkyl group.

In another preferred embodiment, R ³ Is hydrogen, halogen, substituted or unsubstituted C ₁ -C ₄ An alkyl group.

In another preferred embodiment, R ³ Is a hydrogen atom, a chlorine atom or a methyl group.

In another preferred embodiment, the halogen is F, cl, br or I.

In another preferred embodiment, R ⁴ Is F, cl, br or I.

In another preferred embodiment, R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ And R ¹¹ 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 And (4) an aryl group.

In another preferred embodiment, R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ And R ¹¹ Each independently hydrogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₃ -C ₇ A cycloalkyl group.

In another preferred embodiment, R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ And R ¹¹ Each independently hydrogen.

In another preferred embodiment, W is O or S.

In another preferred embodiment, W is O.

In another preferred embodiment, n is 1 or 2.

In another preferred embodiment, n is 1.

In another preferred embodiment, when n.gtoreq.2, each R ³ The same or different.

In another preferred embodiment, any "substitution" means that 1 to 4 (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted with a substituent selected from the group consisting of: c ₁ -C ₆ Alkyl radical, C ₃ -C ₇ Cycloalkyl radical, C ₁ -C ₃ Haloalkyl, halogen, nitro, cyano, amino, hydroxy, = O, C ₁ -C ₄ Carboxy, C ₂ -C ₄ Ester group, C ₂ -C ₄ Amide group, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy, benzyl, six-membered aryl, five-or six-membered heteroaryl (preferably C) ₅ Heteroaryl) group.

In another preferred embodiment, any "substitution" means that 1 to 4 (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted with a substituent selected from the group consisting of: c ₁ -C ₄ Alkyl radical, C ₃ -C ₇ Cycloalkyl radical, C ₁ -C ₃ Haloalkyl, halogen, nitro, cyano, hydroxy, C ₁ -C ₄ Carboxy, C ₂ -C ₄ Ester group, C ₂ -C ₄ Amide group, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy, benzyl, six-membered aryl, five-or six-membered heteroaryl (preferably C) ₅ Heteroaryl).

In another preferred embodiment, the

The structure is as follows:

in another preferred embodiment, the compound of formula a is of formula a-1:

in another preferred embodiment, the compound of formula b has the structure of formula b-1:

in another preferred embodiment, the compound of formula I is of formula I-A:

in another preferred embodiment, the compound of formula I is selected from the group consisting of:

in another preferred embodiment, the first solvent is selected from the group consisting of: dimethyl sulfoxide, toluene, DMF, or a combination thereof.

In another preferred embodiment, the first solvent is selected from the group consisting of: dimethyl sulfoxide (DMSO).

In another preferred embodiment, the first catalyst is selected from the group consisting of: a halide salt, tetrabutylammonium bromide, 4-dimethylaminopyridine, dibenzo 18 crown 6, pyridine, or a combination thereof.

In another preferred embodiment, 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 a combination thereof.

In another preferred embodiment, the first catalyst comprises potassium iodide.

In another preferred embodiment, the first alkaline agent is selected from the group consisting of: an inorganic base, an organic base, or a combination thereof.

In another preferred embodiment, the first alkaline agent is selected from the group consisting of: sodium hydrogen, hydroxide, or a combination thereof.

In another preferred embodiment, the hydroxide is selected from the group consisting of: sodium hydroxide, potassium hydroxide, or a combination thereof.

In another preferred embodiment, the first alkaline agent comprises a hydroxide.

In another preferred embodiment, the first alkaline agent comprises sodium hydroxide.

In another preferred embodiment, in the step (1), the reaction temperature is 30-90 ℃, preferably 40-80 ℃, more preferably 50-70 ℃, and most preferably 55-65 ℃.

In another preferred embodiment, 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.

In another preferred embodiment, the mass ratio of the compound of formula a to the first basic agent is 1:1-4, preferably 1:1-3, more preferably 1:1-2.

In another preferred embodiment, the mass ratio of the compound of formula b to the first basic agent is 1 to 4:1, preferably 1-3:1, more preferably 1-2:1.

In another preferred embodiment, the mass ratio of the first catalyst to the first alkali agent is 1:5-30, preferably 1:5-20, more preferably 1:5-10.

In another preferred embodiment, 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, more preferably 1:5-20, most preferably 1:5-10.

In another preferred embodiment, in the step (1), the reaction is performed under normal pressure (e.g., 1 atm).

In another preferred example, the step (1) comprises the steps of:

dissolving the compound shown in the formula a in a first solvent, adding the compound shown in the formula b and a first catalyst, and adding a first alkali reagent to react to obtain the compound shown in the formula I.

In another preferred embodiment, the first alkaline agent is added at 25-35 ℃.

In another preferred embodiment, in the step (1), after the reaction is finished, water and ethyl acetate are added into the reaction solution for extraction, and the organic phase is collected and separated to obtain the compound of formula I.

In another preferred embodiment, the organic phase is extracted with aqueous acid and isolated to give the salt of the compound of formula I.

In another preferred example, the acid aqueous solution is oxalic acid aqueous solution.

In another preferred embodiment, in the step (1), the reaction solution obtained from the reaction is separated and purified to obtain the compound of formula I, and the separation and purification comprises the steps of:

cooling the reaction liquid obtained by the reaction to 0-10 ℃, adding water and an organic extractant for extraction, and separating to obtain an organic extractant layer;

extracting the organic extractant layer with oxalic acid solution, mixing the water phases, adding sodium hydroxide into the water phase, adding sodium bicarbonate water solution to adjust the pH to 6-7, generating solid, filtering, and leaching the filter cake with organic extractant; standing the filtrate, separating out water phase, adjusting pH of the water phase to 6-7, adding organic extractant, extracting, drying, filtering, and concentrating under reduced pressure to obtain compound of formula I.

In another preferred embodiment, the organic extractant is selected from the group consisting of: ethyl acetate, dichloromethane, petroleum ether, or combinations thereof.

In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I-1, said process comprising the steps of:

(2) Reacting the compound of formula I with an N-demethylating reagent of formula c in a second solvent in the presence of a second base reagent to obtain a compound of formula I-a;

(3) In a third solvent, in the presence of a third alkali reagent, carrying out hydrolysis reaction on the compound shown in the formula I-a to obtain a compound shown in the formula I-1;

wherein,

R ⁴ is halogen;

R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ and R ¹¹ 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 An aryl group;

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-W-, substituted or unsubstituted 5-16 membered heteroaryl-W-;

R ¹³ is halogen;

w is O or S;

n is 1,2 or 3;

wherein, any "substitution" means that 1 to 4 (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted with a substituent selected from the group consisting of: c ₁ -C ₆ Alkyl radical, C ₃ -C ₇ Cycloalkyl radical, C ₁ -C ₃ Haloalkyl, halogen, nitro, cyano, amino, hydroxy, = O, C ₁ -C ₄ Carboxy, C ₂ -C ₄ Ester group, C ₂ -C ₄ Amide group, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy, benzyl, C ₆ -C ₁₂ Aryl, 5-10 membered heteroaryl;

wherein the heterocycle, heteroaryl ring and heteroaryl each independently have 1 to 3 (preferably 1,2 or 3) heteroatoms selected from N, O and S.

In another preferred embodiment, rings 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 of the other asAccording to the first aspect of the invention.

In another preferred embodiment, 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-.

In another preferred embodiment, R ¹² Is substituted or unsubstituted phenyl-W-.

In another preferred embodiment, R ¹³ Is halogen.

In another preferred embodiment, halogen is fluorine, chlorine, bromine or iodine.

In another preferred embodiment, the first solvent, the first catalyst and the first base reagent are each independently as described in the first aspect of the invention.

In another preferred embodiment, 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 invention.

In another preferred embodiment, the step (1) is as described in the first aspect of the present invention.

In another preferred embodiment, the second solvent is selected from the group consisting of: dichloromethane, dimethylsulfoxide, toluene, or DMF, or a combination thereof.

In another preferred embodiment, the second solvent comprises dichloromethane.

In another preferred embodiment, the second alkaline agent is selected from the group consisting of: triethanolamine (TEA), 1,8-diazabicycloundc-7-ene (DBU), N-Diisopropylethylamine (DIEA), sodium carbonate, or combinations thereof.

In another preferred embodiment, the second basic agent comprises N, N-Diisopropylethylamine (DIEA).

In another preferred embodiment, in the step (2), the reaction temperature is 20 to 80 ℃, preferably 20 to 70 ℃, more preferably 25 to 60 ℃, more preferably 30 to 55 ℃, more preferably 35 to 50 ℃, and most preferably 40 to 45 ℃.

In another preferred embodiment, the N-demethylating reagent of formula c comprises phenyl chloroformate.

In another preferred embodiment, in the step (2), the mass ratio of the compound of formula I to the second basic agent is 1.

In another preferred embodiment, in said step (2), the mass ratio of said compound of formula I to said compound of formula c is 1.

In another preferred embodiment, in the step (2), the mass ratio of the second alkali agent to the compound of formula c is 0.1-5:0.1-5, preferably 0.2-3:0.2 to 3, more preferably 0.3 to 2:0.3 to 2, preferably 0.5 to 1:0.5 to 1.

In another preferred embodiment, in the step (2), the reaction is performed under normal pressure (e.g. 1 atm).

In another preferred example, the step (2) includes the steps of:

dissolving the compound shown in the formula I and a second alkali reagent in the second solution, adding an N-demethylation reagent shown in the formula c, and reacting to obtain the compound shown in the formula I-a.

In another preferred embodiment, the N-demethylating agent of formula c is added at 25-35 ℃.

In another preferred embodiment, in the step (2), after the reaction is finished, water and dichloromethane are added into the reaction liquid for extraction, and the organic phase is collected and concentrated to obtain the compound of the formula I-a.

In another preferred embodiment, the compound of formula I-a has the structure of formula I-a-1:

in another preferred embodiment, the third solvent is selected from the group consisting of: dimethyl sulfoxide, toluene, or DMF, or a combination thereof.

In another preferred embodiment, the third solvent is dimethyl sulfoxide.

In another preferred embodiment, the third alkaline agent is selected from the group consisting of: an inorganic base, an organic base, or a combination thereof.

In another preferred embodiment, the third alkaline agent is selected from the group consisting of: potassium tert-butoxide, potassium carbonate, hydroxides, or combinations thereof.

In another preferred embodiment, the third alkaline agent comprises a hydroxide.

In another preferred embodiment, the third alkaline agent comprises sodium hydroxide.

In another preferred embodiment, in the step (3), the reaction temperature is 20 to 100 ℃, preferably 30 to 90 ℃, more preferably 50 to 70 ℃, and still more preferably 55 to 65 ℃.

In another preferred embodiment, in the step (3), the mass ratio of the compound of formula I-a to the third basic agent is 1:0.1 to 1, optimally 1.

In another preferred embodiment, in the step (3), after the reaction is finished, water and ethyl acetate are added into the reaction solution for extraction, and the organic phase is collected and separated to obtain the compound of formula I.

In another preferred embodiment, the organic phase is washed with an aqueous acid solution and isolated to provide the salt of the compound of formula I.

In another preferred embodiment, the compound of formula I-1 has the structure of formula I-1-1:

in another preferred embodiment, the method comprises the steps of:

(1) Reacting a compound of formula i with a compound of formula ii in a first solvent in the presence of a first catalyst and a first base reagent to provide a compound of formula iii;

(2) Reacting the compound of formula iii with phenyl chloroformate in a second solvent in the presence of a second base reagent to obtain a compound of formula iv;

(3) In a third solvent, in the presence of a third alkali reagent, carrying out hydrolysis reaction on the compound shown in the formula iv to obtain a compound shown in the formula v;

in a third aspect of the invention, there is provided a process for the preparation of a compound of formula I-a, said process comprising the steps of:

wherein,

R ¹ and R ² Each independently of the other being 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 An aryl group;

R ⁴ is halogen;

R ¹³ is halogen;

w is O or S;

n is 1,2 or 3;

wherein, any "substitution" means that 1 to 4 (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted with a substituent selected from the group consisting of: c ₁ -C ₆ Alkyl radical, C ₃ -C ₇ Cycloalkyl, C ₁ -C ₃ Haloalkyl, halogen, nitro, cyano, amino, hydroxy, = O, C ₁ -C ₄ Carboxy, C ₂ -C ₄ Ester group, C ₂ -C ₄ Amide group, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy, benzyl, C ₆ -C ₁₂ Aryl radical5-10 membered heteroaryl;

In another preferred embodiment, rings 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 Each independently as described in the first aspect of the invention.

In another preferred embodiment, R ¹² And R ¹³ Each independently as described in the second aspect of the invention.

In another preferred embodiment, the second catalyst and the N-demethylating agent of formula c in the second solvent are each independently as described in the second aspect of the present invention.

In another preferred embodiment, the step (2) is as described in the second aspect of the present invention.

In another preferred embodiment, 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 invention.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be repeated herein, depending on the space.

Detailed Description

The inventor of the invention unexpectedly develops a preparation method of 3-aryloxy-3-pentabasic heteroaryl-propylamine compound for the first time through extensive and intensive research, and the method has the advantages of simplicity, easy operation, high yield and the like and is beneficial to industrial production. On this basis, the inventors have completed the present invention.

Term(s) for

As used herein, the terms "comprising," "including," "containing," and "containing" are used interchangeably and include not only closed-form definitions, but also semi-closed and open-form definitions. In other words, the term includes "consisting of … …" and "consisting essentially of … …".

As used herein, "R" refers to a group of atoms ₁ ”、“R ¹ "and" R1 "have the same meaning and may be substituted for each other, and other meanings similarly defined are the same.

As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched-chain groups. When an alkyl group is preceded by a carbon atom number limitation (e.g., C1-C6 alkyl) means that the alkyl group contains 1-6 carbon atoms, for example, C1-C4 alkyl means an alkyl group containing 1-4 carbon atoms, representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

As used herein, the term "C2-C4 alkenyl" refers to a straight or branched chain alkene molecule of 2-4 carbon atoms with 1 or more double bonds with one less hydrogen atom attached to the double bond forming a hydrocarbon group, such as vinyl (CH 2= CH-), (C (CH 3) ₂ = CH-), or the like

As used herein, the term "C2-C4 alkynyl" refers to a straight or branched chain alkynyl molecule of 2-4 carbon atoms having 1 or more triple bonds with less than one hydrocarbon group formed by a hydrogen atom attached to the triple bond, such as ethynyl (CH-), (H3C-C.ident.CH-), or similar groups.

In the present invention, the term "halogen" means F, cl, br or I.

In the present invention, the term "halo" means substituted by halogen.

As used herein, the term "haloalkyl" means an alkyl group wherein one or more (preferably 1,2,3 or 4) hydrogens are replaced with a halogen, said alkyl and halogen being as defined above, when the alkyl group previously has a carbon atom number limitation (e.g., C1-C8 haloalkyl) means that said alkyl group contains 1-8 carbon atoms, e.g., C1-C6 haloalkyl means a haloalkyl group containing 1-6 carbon atoms, representative examples include, but are not limited to, -CF3, -CHF ₂ Monofluoroisopropyl, difluorobutyl, or the like.

As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic (fused, bridged, or spiro) ring system radical having a saturated or partially saturated unit ring. When a cycloalkyl group is preceded by a carbon atom number limitation (e.g., C3-C12), it is intended that the cycloalkyl group has 3-12 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3 to 8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like. "spirocycloalkyl" refers to a bicyclic or polycyclic group having a single ring with a common carbon atom (called the spiro atom) between them, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. "fused cyclic alkyl" refers to an all-carbon bicyclic or polycyclic 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 of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Representative examples of cycloalkyl groups include, but are not limited to:

the term "alkoxy" refers to the group R-O-, wherein R is alkyl, alkyl is as defined herein, when alkoxy is previously defined by the number of carbon atoms, e.g., C1-C8 alkoxy means that the alkyl in the alkoxy group has from 1 to 8 carbon atoms. Representative examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or the like.

As used herein, the term "alkylthio" refers to the group R-S-wherein R is alkyl and alkyl is as defined herein above, when an alkylthio group has a carbon atom number limitation at the outset, e.g., C1-C8 alkylthio means that the alkyl group in the alkylthio group in question has from 1 to 8 carbon atoms. Representative examples of alkylthio groups include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, or the like.

The term "cycloalkoxy" refers to the group R-O-, wherein R is cycloalkyl, cycloalkyl is as defined herein above, when cycloalkoxy is defined as having a carbon number before, e.g., C3-C8 cycloalkoxy means that the cycloalkyl in said cycloalkoxy has 3-8 carbon atoms. Representative examples of cycloalkoxy groups include, but are not limited to: cyclopropoxy, cyclobutoxy, or the like.

The term "cycloalkylthio" refers to the group R-S-, wherein R is cycloalkyl, cycloalkyl is as defined herein above, when cycloalkylthio is preceded by a carbon atom number limitation, e.g., C3-C8 cycloalkylthio means that the cycloalkyl in said cycloalkylthio has 3-8 carbon atoms. Representative examples of cycloalkylthio groups include, but are not limited to: cyclopropylthio, cyclobutylthio, or the like.

As used herein, the term "haloalkoxy" refers to haloalkyl-O-, said haloalkyl being as defined above, e.g., C1-C6 haloalkoxy refers to haloalkoxy having 1 to 6 carbon atoms, representative examples include, but are not limited to, monofluoromethoxy, monofluoroethoxy, difluorobutoxy, or the like.

As used herein, the term "haloalkylthio" refers to haloalkyl-S-, wherein haloalkyl is as defined above, e.g., C1-C6 haloalkylthio refers to haloalkylthio having 1-4 carbon atoms, representative examples include, but are not limited to, monofluoromethylthio, monofluoroethylthio, difluorobutylthio, or the like.

As used herein, 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 12 membered monocyclic, bicyclic or polycyclic ring, a carbocycle may be a saturated, partially unsaturated, unsaturated ring, but not an aromatic ring. Examples of such carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentene, cyclohexane, or mixtures thereof cyclohexene ring, cycloheptane ring, cycloheptene ring, adamantane ring, cyclooctane ring, cyclooctene ring, cyclooctadiene ring, bicyclo ring

The term "heterocycle" refers to a fully saturated or partially unsaturated ring (including but not limited to, e.g., a 3-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered tricyclic ring system) in which at least one heteroatom is present in the ring having at least one carbon atom. When a heterocycle is preceded by a defined number of members, this refers to the number of ring atoms of the heterocycle, for example, a 3-16 membered heterocycle refers to a heterocycle having 3-16 ring atoms. Each heteroatom-containing heterocyclic ring may carry one or more heteroatoms (e.g., 1,2,3 or 4) each independently selected from nitrogen, oxygen or sulfur atoms, wherein the nitrogen or sulfur atoms may be oxidized or the nitrogen atoms may be quaternized. The heterocyclic ring may be attached to any heteroatom or residue of a carbon atom of the ring or ring system molecule. Typical monocyclic heterocycloalkyl rings include, but are not limited to, azetidine, oxetane, imidazoline, imidazolidine, tetrahydrofuran, piperidine, piperazine, 2-oxopiperazine, 2-oxopiperidine, 4-piperidone, tetrahydropyran, morpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, 1,3-dioxane, and tetrahydro-1,1-dioxythiophene rings, and the like. Polycyclic heterocycloalkyl rings include spiro, fused and bridged heterocyclic rings; wherein the heterocyclic rings of the spiro, fused and bridged rings are optionally linked to other rings by single bonds, or further linked to other cycloalkane rings, heterocycles by any two or more atoms on the rings.

The term "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic ring (i.e., rings which share adjacent pairs of carbon atoms) having a conjugated pi-electron system, and is an aromatic cyclic hydrocarbon compound, when the aromatic ring has a carbon number limitation as in the preceding, e.g., a C6-C12 aromatic ring, meaning that the aromatic ring has 6 to 12 ring carbon atoms, such as a benzene ring and a naphthalene ring. The aromatic ring may be fused to other carbocyclic rings (including saturated or unsaturated rings), but may not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be at a carbon atom in the ring having a conjugated pi-electron system. Representative aromatic rings are benzene and naphthalene rings, or the like.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, and is an aromatic cyclic hydrocarbon group, when an aryl group has a carbon atom number limitation as in C6-C12, it means that the aryl group has 6-12 ring carbon atoms, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated or unsaturated rings) but must not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with the conjugated pi-electron system. Representative examples of aryl groups include, but are not limited to:

the term "heteroaromatic ring" refers to an aromatic heterocyclic ring having one to more (preferably 1,2,3 or 4) heteroatoms, which may be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic or polycyclic) fused together or covalently linked, and which may have one or more (e.g., 1,2,3, 4) heteroatoms per heteroatom-containing heterocyclic ring independently selected from the group consisting of: oxygen, sulfur and nitrogen. When a heteroaryl ring is preceded by a number of members, this refers to the number of ring atoms of the heteroaryl ring, for example a 5-12 membered heteroaryl ring refers to a heteroaryl ring having 5-12 ring atoms, representative examples include, but are not limited to: a pyrrole ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, a thiadiazole ring, an isothiazole ring, a furan ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a triazine ring, a tetranitrogen ring and the like.

The term "heteroaryl" refers to an aromatic heterocyclic group having one to more (preferably 1,2,3 or 4) heteroatoms, which may be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic or polycyclic) fused together or covalently linked, and each heteroatom-containing heterocycle may carry one more (e.g., 1,2,3, 4) heteroatoms each independently selected from the group consisting of: oxygen, sulfur and nitrogen. When a heteroaryl group is preceded by a number of members, this refers to the number of ring atoms of the heteroaryl group, for example 5-12 membered heteroaryl refers to heteroaryl groups having 5-12 ring atoms, representative examples include, but are not limited to: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, and the like.

As used herein, the term "carboxy" refers to a group having a-COOH group or an-alkyl-COOH group, alkyl being as defined herein, e.g., "C ₂ -C ₄ Carboxy "means a group of formula ₁ -C ₃ Representative examples of alkyl-COOH structural groups, carboxyl groups include (but are not limited to): -COOH, -CH ₂ COOH、-C ₂ H ₄ COOH, or the like.

<xnotran> , "" R-CO-O- -CO-O-R , R , , "C </xnotran> ₂ -C ₄ The "ester group" means C ₁ -C ₃ Radicals of alkyl-CO-O-structure or-CO-O-C ₁ -C ₃ Representative examples of alkyl structure, ester groups include, but are not limited to: CH (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 the like.

<xnotran> , "" R-CO-N- -CO-N-R , R , , "C </xnotran> ₂ -C ₄ Amido "means C ₁ -C ₃ alkyl-CO-N-structural groups or-CO-N-C ₁ -C ₃ Representative examples of alkyl and amido groups include, but are not limited to: CH (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-N-C ₂ H ₅ 、-CO-N-C ₃ H ₈ Or the like.

As used herein, the term "amino", alone or as part of another substituent, denotes-NH ₂ 。

As used herein, the term "nitro", alone or as part of another substituent, denotes-NO ₂ 。

As used herein, the term "cyano," alone or as part of another substituent, denotes — CN.

As used herein, the term "hydroxy", alone or as part of another substituent, denotes — OH.

As used herein, the term "mercapto", alone or as part of another substituent, denotes — SH.

As used herein, the term "substituted" is the replacement of a hydrogen atom on a group by a non-hydrogen atom group, but is required to satisfy its valence requirements and to produce a chemically stable compound from the substitution. In this specification, it is to be construed that all substituents are unsubstituted, unless explicitly described as "substituted" herein.

As used herein, the term "a" or "an" refers to,

and with

Are identical and each represents an unsubstituted or substituted radical or a radical having from 1 to 5, preferably from 1 to 3, R ³ Heteroaryl of a substituent.

As used herein, the term "a" or "an" refers to,

is a linking site.

Also, it is to be understood that in the present invention, a substituent may be attached to a parent group or substrate at any atom, unless the attachment violates valence requirements; the hydrogen atoms of the parent group or substrate may be on the same atom or on different atoms.

As used herein, room temperature refers to 25 ± 5 ℃.

As used herein, for a range of values P1 to P2, the range includes not only the endpoints P1 and P2, but also any point of value between the endpoints P1 and P2. Further, for both P1 and P2 being positive, then for an integer n, the numerical range includes any integer numerical point between the endpoints P1 and P2. For example, for an integer n, when ranging from 1 to 10, includes 1,2,3, 4, 5, 6, 7, 8, 9, and 10; the numerical range 3-7 includes 3, 4, 5, 6, 7. Representatively, for groups, C3-C7 includes C3, C4, C5, C6, and C7.

Preparation method

The present invention provides a process for preparing a compound of the structure of formula I, or a pharmaceutically acceptable salt thereof, said process comprising the steps of:

(1) Reacting a compound of formula a with a compound of formula b in a first solvent in the presence of a first catalyst and a first base reagent to obtain a compound of formula I; ' Qiyi

Wherein the step (1) is as described above in the first aspect of the present invention.

The present invention also provides a process for the preparation of a compound of formula I-1, said process comprising the steps of:

wherein the steps (1), (2) and (3) are as described above for the second aspect of the present invention.

The present invention also provides a process for the preparation of a compound of formula I-a, said process comprising the steps of:

wherein the step (2) is as described in the third aspect of the present invention.

The main advantages of the invention include:

the invention also provides a preparation method of the 3-aryloxy-3-pentabasic heteroaryl-propylamine compound, which has the advantages of simplicity, easy operation, high yield and the like and is beneficial to industrial production.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight.

Example 1

Preparation of Compounds of formula V

Step (1): preparation of (R) -3- (benzofuran-7-yloxy) -N, N-dimethyl-3- (thien-2-yl) propan-1-amine III)

Controlling the temperature below 30 ℃, adding 88kg DMSO (8.80 w/w), 10kg 7-fluorobenzofuran (compound shown in formula I) (1.00 w/w), 16.3kg (R) -3- (dimethylamino) -1- (thiophene-2-yl) propan-1-ol (compound shown in formula II) (1.63 w/w), 1.8kg potassium iodide (0.18 w/w) and 14.8kg sodium hydroxide (1.48 w/w) into the reaction kettle in sequence; the system is subjected to heat preservation reaction at 60-65 ℃ for 20h, and sampling is carried out once every 2h until the HPLC conversion rate is more than or equal to 80.0%; after the reaction is finished, cooling, controlling the temperature to be 0-10 ℃, and adding 100kg of drinking water (10.00 w/w); ethyl acetate was added in sequence and extracted 3 times (8.1 w/w,4.5w/w,4.5 w/w); the organic phases were combined and washed with brine in a 3.27w/w portion of technical salt and 9.09w/w portion of water. Preparing oxalic acid solution 1 by using 8kg of oxalic acid (0.80 w/w) and 100kg of drinking water (10.00 w/w); oxalic acid solution 2 was prepared from 4kg of oxalic acid (0.40 w/w) and 50kg of drinking water (5.00 w/w). The ethyl acetate phase is extracted with oxalic acid solution 1 and oxalic acid solution 2 respectively. The aqueous phases were combined and washed with 40.5kg ethyl acetate (4.05 w/w); the temperature was controlled to 20 ℃ or lower, 4kg of sodium hydroxide (0.40 w/w) was added to the aqueous phase, and an aqueous solution of sodium hydrogencarbonate was added thereto to adjust the pH =6.4 to 6.6. Solid is generated and filtered. Leaching the filter cake with a proper amount of ethyl acetate; stirring the filtrate for 10-30 minutes, standing for 10-30 minutes, separating out a water phase, adjusting the pH of the water phase to be 6.4-6.6 again, and adding 81kg of ethyl acetate (8.10 w/w) for extraction; adding 10kg of anhydrous sodium sulfate (1.00 w/w) into the organic phase, and stirring and drying for 0.5-1 h; filtering, distilling under reduced pressure and concentrating to obtain the compound shown in the formula III, weighing and detecting, wherein the yield is 51.13%.

Of compounds of formula III ¹ H 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) ⁺ .

Step (2): preparation of (R) -phenyl (3- (benzofuran-7-yloxy) -3- (thiophen-2-yl) propyl) (methyl) carbamate (IV)

After controlling the temperature below 30 ℃, 65kg of DCM (6.50 w/w) was added to the reaction vessel, and 10kg of the compound of formula III (1.00 w/w) and 6.4kg of DIEA (0.64 w/w) were added in sequence with stirring. 7.7kg (0.77 w/w) of phenyl chloroformate was dropped into the reaction vessel while controlling the temperature at 30 ℃ or lower. The system is subjected to heat preservation reaction for 3 hours at the temperature of 40-45 ℃ (reflux), and sampling is carried out once every 1 hour until the HPLC conversion rate is more than or equal to 90.0%; 4.3kg (0.43 w/w) of oxalic acid and 53.2kg (5.32 w/w) of drinking water were added to the barrel to prepare an oxalic acid solution for use. Cooling the reaction system, controlling the temperature to be 10-20 ℃, adding an oxalic acid solution, and stirring for 20-40 minutes; the reaction system is kept stand for 10 to 20 minutes, and an organic phase is separated. The aqueous phase was extracted with 35kg DCM (3.50 w/w). The organic phases were combined and washed once with an appropriate amount of saturated brine. And adding 10kg of anhydrous sodium sulfate (1.00 w/w) into the organic phase, stirring and drying for 0.5-1 h, filtering, rinsing the filter cake with DCM (1.00 w/w), and draining after rinsing. And (3) distilling and concentrating the filtrate under reduced pressure to obtain the compound shown in the formula IV, weighing, and detecting to obtain the compound shown in the formula IV with the yield of 103.04%.

Of compounds of formula IV ¹ H 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) ⁺ 。

And (3): preparation of (R) -3- (benzofuran-7-yloxy) -N-methyl-3- (thien-2-yl) propan-1-amine (V)

25kg of water (2.50 w/w) were added to the reaction vessel, and 5.8kg of sodium hydroxide (0.58 w/w), 10kg of the compound of formula IV (1.00 w/w), and 44kg of DMSO (4.40 w/w) were added in succession with stirring. The system is reacted for 2 hours at the temperature of 60-65 ℃, sampling detection is carried out after the reaction is carried out for 2 hours, and sampling detection is carried out every 1-2 hours until the conversion rate is more than or equal to 95.0 percent. Cooling to 5-15 ℃, adding 24kg of water (2.40 w/w) into the reaction system, adding 26kg of ethyl acetate (2.60 w/w) into the reaction system, stirring for 5-10 minutes, standing the reaction system for 10 minutes, collecting an organic phase, and transferring a water phase into a reaction kettle; the aqueous phase was extracted 2 times with ethyl acetate (2.60 w/w each time). The organic phases were combined and washed with saturated brine; opening the reaction kettle and stirring, adding oxalic acid until the pH value is less than 5, and stirring for 30 minutes; centrifuging the reaction system, and leaching the filter cake for 2 times by using ethyl acetate (1.00 w/w) respectively to obtain oxalate; adding water (3.00 w/w) into the reaction kettle, and opening the stirring; adding 3kg of sodium hydroxide (0.30 w/w), and stirring until the sodium hydroxide is dissolved; adding ethyl acetate (2.60 w/w) into the reaction kettle, stirring for 5-10 minutes, standing for layering, collecting an organic phase, and transferring a water phase into the reaction kettle; opening the reaction kettle, stirring, adding ethyl acetate (2.60 w/w), stirring for 5-10 minutes, standing for layering, combining organic phases, transferring to the reaction kettle, washing with brine, separating out a water phase, and adding anhydrous sodium sulfate (1.00 w/w) into the organic phase; filtering the dried organic phase, washing the filter cake once with ethyl acetate (0.50 w/w), concentrating the filtrate at 40-50 deg.C under reduced pressure, adding methanol (2.80 w/w) into the concentrated free state, stirring to dissolve, and decolorizing with activated carbon (0.07 w/w). The decolorized mixture was filtered, concentrated under reduced pressure to give the compound of formula V, which was weighed and tested in 61.73% yield.

Of compounds of formula V ¹ H 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) ⁺ 。

Example 2

Preparation of (R) -3- (benzofuran-7-yloxy) -N-methyl-3- (thien-2-yl) propan-1-amine hydrochloride

Adding 0.7kg of (R) -3- (benzofuran-7-yloxy) -N-methyl-3- (thiophene-2-yl) propane-1-amine (V) into 20L of ethyl acetate solution, slowly dropwise adding concentrated hydrochloric acid, adjusting the pH to 5-6, continuing stirring for 10 minutes, separating out a solid, performing suction filtration, washing a filter cake once with ethyl acetate, putting the filter cake into an oven, heating to 40-50 ℃, and drying to constant weight to obtain 0.63kg of white solid salt of the compound V, wherein the yield is 79.50%.

¹ H 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) ⁺ 。

Example 3

Assay for inhibitory Activity of TRPA1

In this example, the compounds of formula V of the present invention were tested for their inhibitory activity against the transient receptor potential channel protein TRPA1. Wherein, the positive control compound adopts a compound of formula B (WO 2010075353):

the method comprises the following steps:

test method by IonWorks Barracuda (IWB) automated patch clamp detection: HEK293 cells stably expressing TRPA1 were placed in T175 flasks in DMEM medium containing 15. Mu.g/mL of blast S HCl, 200. Mu.g/mL of Hygromycin B and 10% FBS serum, charged at 37 ℃ and 5% CO ₂ Culturing in the incubator, removing the culture solution when the cell density reaches 80%, washing with Phosphate Buffer Solution (PBS) without calcium and magnesium, adding 3mL of Trypsin for digestion for 2 minutes, and adding 7mL of culture solution to stop digestion. Collecting cells in a 15mL centrifuge tube, centrifuging at 800 rpm for 3 min, removing supernatant, adding cells into appropriate volume of extracellular fluid, and resuspending to control cell density at 2-3 × 10 ⁶ /mL and used for IWB experiments. Extracellular fluid formulation (in mM): 140NaCl,5KCl,1MgCl ₂ 10HEPES,0.5EGTA,10Glucose (pH 7.4); intracellular fluid formulation (in mM): 140CsCl,10HEPES,5EGTA,0.1CaCl ₂ ,1MgCl ₂ (pH 7.2). Amphotericin B was freshly prepared with DMSO at 28mg/mL the day of the experiment and then with intracellular fluid at a final concentration of 0.1 mg/mL.

The IWB experiment uses a ligation batch clamp (PPC) plate, and the whole detection process is automatically completed by an instrument, namely extracellular fluid is added into 384 holes of the PPC plate, intracellular fluid is added into the PPC plate, namely plenum, and then 6L of the intracellular fluid is added for carrying out sealing test, and finally the intracellular fluid in the plenum is changed into the intracellular fluid containing amphotericin B, so that the sealed cells are perforated to form a whole cell recording mode. TPRA1 current was recorded at a sampling frequency of 10kHz, cell clamping at 0mV, and a voltage stimulation command (channel protocol) of a ramp voltage of 300ms from-100 mV to +100mV, with the voltage stimulation being given every 10s and mTRPA1 current induced by 300M AITC.

Data recording and current magnitude measurement derivation was done by IWB software (version 2.5.3, molecular Devices corporation, union City, CA). Holes with a seal impedance below 20M omega will not record data statistics. The raw current data was corrected for leakage by software, and the TRPA1 current amplitude was measured at +100 mV. Each PPC plate of the experiment will have one HC030031 dose effect data as a positive control, e.g., IC of HC030031 ₅₀ Value exceeding that of the IC obtained on each board ₅₀ At 3 times the average value, retesting will be performed. Compound dose response curves and IC ₅₀ Fitting calculations were performed by GraphPad Prism 5.02 (GraphPad Software, san Diego, CA).

Results of the experiment

IC testing of the compound of formula V prepared in the examples of the invention by IonWorks Barracuda (IWB) automated patch-clamp detection ₅₀ Inhibitory activity assay, activity data are shown in table 2.

TABLE 2 inhibitory Activity data (IC) of the inventive compounds of formula V on TRPA1 in an automated Patch Clamp assay ₅₀ ,μM)

Number of	IC ₅₀ (μM)
		A compound of formula V	+++++
A compound of formula B	+

Wherein the activity is as follows: IC (integrated circuit) ₅₀ (μM)：

51-100：+

1-5：+++++

The results indicate that the compounds of formula V of the present invention exhibit potent inhibitory activity against TRPA1.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined in the appended claims.

Claims

1. A process for the preparation of a compound of formula I, said process comprising the steps of:

wherein:

R ⁴ is halogen;

w is O or S;

n is 1,2 or 3;

2. A process for preparing a compound of formula I-1, said process comprising the steps of:

(3) In a third solvent, in the presence of a third alkaline reagent, carrying out hydrolysis reaction on the compound shown in the formula I-a to obtain a compound shown in the formula I-1;

wherein,

R ⁴ is halogen;

R ¹³ is halogen;

w is O or S;

n is 1,2 or 3;

3. The method of claim 2, wherein said method comprises the steps of:

(2) Reacting the compound of formula iii with phenyl chloroformate in a second solvent in the presence of a second base reagent to provide a compound of formula iv;

(3) In a third solvent, in the presence of a third alkali reagent, the compound shown in the formula iv undergoes a hydrolysis reaction to obtain a compound shown in the formula v;

4. a process for the preparation of a compound of formula I-a, said process comprising the steps of:

wherein,

R ⁴ is halogen;

R ¹³ is halogen;

w is O or S;

n is 1,2 or 3;

5. The method of claim 1 or 2, wherein the compound of formula I is selected from the group consisting of:

6. the method of claim 1,2 or 3, wherein the first solvent is selected from the group consisting of: dimethyl sulfoxide, toluene, DMF, or a combination thereof;

the first catalyst is selected from the group consisting of: a halide salt, tetrabutylammonium bromide, 4-dimethylaminopyridine, dibenzo 18 crown 6, pyridine, or a combination thereof; and/or

The first base reagent is selected from the group consisting of: an inorganic base, an organic base, or a combination thereof.

7. The process of claim 1,2 or 3, wherein in step (1), the reaction temperature is from 30 to 90 ℃, preferably from 40 to 80 ℃, more preferably from 50 to 70 ℃, and most preferably from 55 to 65 ℃.

8. The method of claim 2,3 or 4, wherein the second solvent is selected from the group consisting of: dichloromethane, dimethyl sulfoxide, toluene, or DMF, or a combination thereof; and/or

The second base reagent is selected from the group consisting of: triethanolamine (TEA), 1,8-diazabicycloundc-7-ene (DBU), N-Diisopropylethylamine (DIEA), sodium carbonate, or combinations thereof.

9. The process of claim 2,3 or 4, wherein in step (2), the temperature of the reaction is 20 to 80 ℃, preferably 20 to 70 ℃, more preferably 25 to 60 ℃, more preferably 30 to 55 ℃, more preferably 35 to 50 ℃, most preferably 40 to 45 ℃.

10. The method of claim 2 or 3, wherein the third solvent is selected from the group consisting of: dimethyl sulfoxide, toluene, or DMF, or a combination thereof; and/or

The third base reagent is selected from the group consisting of: potassium tert-butoxide, potassium carbonate, hydroxide, or combinations thereof.