CN114249681A - 7-fluoro-5-substituted tryptamine compound and preparation method and application thereof - Google Patents

7-fluoro-5-substituted tryptamine compound and preparation method and application thereof Download PDF

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CN114249681A
CN114249681A CN202111387707.9A CN202111387707A CN114249681A CN 114249681 A CN114249681 A CN 114249681A CN 202111387707 A CN202111387707 A CN 202111387707A CN 114249681 A CN114249681 A CN 114249681A
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金海晓
章彬
何山
方丽萍
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Ningbo University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • A61P25/06—Antimigraine agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a 7-fluoro-5-substituted tryptamine compound and a preparation method and application thereof, and is characterized in that the compound has a structural formula shown in formula I, namely 7-fluoro-5-substituted tryptamine or pharmaceutically acceptable salt, ester or solvate thereof, and the preparation method comprises the steps of 1) reacting the compound shown in formula II with iron and ammonium chloride to obtain a compound shown in formula III; 2) reacting a compound shown as a formula III with sodium nitrite to obtain a compound shown as a formula IV; 3) reacting a compound shown as a formula IV with stannous chloride to obtain a compound shown as a formula V; 4) reacting a compound shown as a formula V with a compound shown as a formula VI to obtain a compound shown as a formula VII; 5) reacting a compound of formula VII with a compound of formula VIII to obtain a compound of formula I, with the advantage that the compound is efficiently accessible via 5-HT coupled to G-proteins1BReceptor binding, in turn, inhibits adenylate cyclase activity.

Description

7-fluoro-5-substituted tryptamine compound and preparation method and application thereof
Technical Field
The invention relates to a tryptamine compound, in particular to a 7-fluoro-5-substituted tryptamine compound and a preparation method and application thereof.
Background
Migraine is a neurovascular disease, ranks third in the most common diseases, the incidence rate is 14.7%, moderate to severe headache and symptoms such as nausea, vomit, photophobia, phonophobia and the like are shown during the attack, the life quality of patients is seriously influenced, and great life burden is also caused to the patients and the society. At present, the pathological mechanism of migraine is not completely clear, and mainly includes the angiology, the neurology, the trigeminal neuro-angiology, etc. The Chinese patient has low diagnosis rate, insufficient preventive treatment and unsatisfactory treatment effect of nearly half of migraine patients caused by excessive use of analgesic drugs, so that the design and synthesis of the novel medicine for treating the migraine have important significance.
The current medicines for treating migraine are mainly divided into two types: specific drugs include ergotamines and triptans; non-specific drugs include analgesics and non-steroidal anti-inflammatory drugs. Ergotamines have long been widely used to treat migraine, but there are serious side effects and off-target effects associated with the drugs. Clinical practice proves that triptans are one of the most effective medicines for treating acute migraine. The efficacy and safety of triptans as specific treatment drugs for migraine attacks were confirmed by large sample randomized placebo-controlled clinical trials. Triptans are officially approved for migraine treatment, and new chapters are opened for acute migraine treatment.
Currently marketed triptan drugs are sumatriptan (sumatriptan), naratriptan (naratriptan), zolmitriptan (zolmitriptan), rizatriptan (rizatriptan), fluvastatin (frovatriptan), almotriptan (almotriptan) and eletriptan (eletriptan). The acting target of the medicine in vivo is 5-hydroxytryptamine receptor subtype 5-HT1BAnd 5-HT1DAre receptor agonists. The patent takes tryptamine as a parent nucleus structure and is based on target spot 5-HT1BThe receptor stimulant is combined with the structural characteristics of the pocket to carry out targeted design, synthesize a novel 7-fluoro-5-substituted tryptamine compound, and carry out activity evaluation and structure effect research, thereby having guiding significance for researching and developing novel anti-migraine micromolecular drugs.
Disclosure of Invention
The invention aims to solve the technical problem of providing a 7-fluoro-5-substituted tryptamine compound capable of effectively treating migraine and a preparation method and application thereof.
The technical scheme adopted by the invention for solving the technical problems is as follows: a7-fluoro-5-substituted tryptamine compound is a 7-fluoro-5-substituted tryptamine with a structural formula shown in a formula I or a pharmaceutically acceptable salt, ester or solvate of the 7-fluoro-5-substituted tryptamine compound with the structural formula shown in the formula I,
Figure 129056DEST_PATH_IMAGE001
the compound of the formula I is shown in the specification,
wherein R is fluorine, chlorine, bromine, iodine, benzene, toluene, ethylbenzene, propylbenzene, butylbenzene, pentylbenzene, hexylbenzene, fluorobenzene, chlorobenzene, bromobenzene, iodobenzene, phenol, anisole, vinylbenzene, 2-phenylacetonitrile, acetophenone, (trifluoromethyl) benzene, biphenyl, 4-methyl-1, 1'Biphenyl, methane, ethane, propane, butane, the above formula
Figure 673300DEST_PATH_IMAGE002
The compound is pharmaceutically acceptable salt, ester or solvate, wherein the salt is inorganic acid salt or organic acid salt, and the inorganic acid salt is formed by any one of inorganic acid of hydrochloric acid, sulfuric acid and phosphoric acid; the organic acid salt is formed by any one of acetic acid, trifluoroacetic acid, malonic acid, succinic acid, citric acid and p-toluenesulfonic acid.
The preparation method of the 7-fluoro-5-substituted tryptamine compound comprises the following steps:
(1) reacting the compound shown in the formula II with iron and ammonium chloride to obtain a compound shown in a formula III;
(2) reacting a compound shown as a formula III with sodium nitrite to obtain a compound shown as a formula IV;
(3) reacting a compound shown as a formula IV with stannous chloride to obtain a compound shown as a formula V;
(4) reacting a compound shown as a formula V with a compound shown as a formula VI to obtain a compound shown as a formula VII;
(5) reacting a compound shown as a formula VII with a compound shown as a formula VIII to obtain a compound shown as a formula I,
Figure 666664DEST_PATH_IMAGE003
wherein R is fluorine, chlorine, bromine, iodine, benzene, toluene, ethylbenzene, propylbenzene, butylbenzene, pentylbenzene, hexylbenzene, fluorobenzene, chlorobenzene, bromobenzene, iodobenzene, phenol, anisole, vinylbenzene, 2-phenylacetonitrile, acetophenone, (trifluoromethyl) benzene, biphenyl, 4-methyl-1,1'-biphenyl, methane, ethane, propane and butane.
The step (1) is specifically as follows: and (3) reacting the compound shown in the formula II with iron and ammonium chloride in absolute ethyl alcohol for 1-12 hours at 0-100 ℃ by taking iron as a reducing agent according to the molar ratio of 1:5:3 to obtain the compound shown in the formula III.
The step (2) is specifically as follows: and reacting the compound shown in the formula III with sodium nitrite at the temperature of between 20 ℃ below zero and 20 ℃ for 0.5 to 5 hours to obtain a compound solution shown in the formula IV.
The step (3) is specifically as follows: and reacting the compound shown in the formula IV with stannous chloride at the temperature of-20-20 ℃ for 1-5 hours to obtain the compound shown in the formula V.
The step (4) is specifically as follows: reacting the compound shown in the formula V with the compound shown in the formula VI in a 4% sulfuric acid solution at 60-100 ℃ for 2-12 hours to obtain the compound shown in the formula VII.
The step (5) is specifically as follows: reacting a compound of the formula VII with a compound of the formula VIII in a solution of 1, 4-dioxane at 80-100 ℃, [ 2 ]1,1' -bis (diphenylphosphino) ferrocene]And (3) reacting the palladium dichloride and the potassium phosphate for 6-12 hours to obtain the compound shown in the formula I.
The application of the 7-fluoro-5-substituted tryptamine compound in preparing the medicine for treating the migraine.
Compared with the prior art, the invention has the advantages that: the invention relates to a 7-fluoro-5-substituted tryptamine compound, a preparation method and application thereof, wherein the compound can effectively pass through 5-HT coupled with G protein1BReceptor (5-HT)1BR) junctionAnd, in turn, inhibit adenylate cyclase activity. The compounds provided by the invention are subjected to 5-HT1BTesting the agonistic activity of R and a binding test. The compound provided by the invention has the advantages of easily obtained raw materials, simple preparation method and design and synthesis of a series of 5-HT1BThe receptor is a novel-structure small-molecule agonist, and experiments prove that the compound of the invention is used for treating 5-HT1BR has good in vitro activity and binding affinity, and has good application prospect in the field of design and research of anti-migraine drugs.
Drawings
FIG. 1 shows that compounds 6 and 11 are on 5-HT1BData for agonist Activity of R receptor, EC of Compound 650=10.77 nM, EC of compound 1150=8.57 nM；
FIG. 2 shows that compounds 6 and 11 are on 5-HT1BBinding Activity of R receptor test data, K of Compound 6i=36.95 nM, K of Compound 11i=16.56 nM。
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. Herein, a "compound of formula N" is also sometimes referred to herein as "compound N", where N is any integer from 1 to 17, e.g., "compound of formula 2" may also be referred to herein as "compound 2".
Detailed description of the preferred embodiment
A7-fluoro-5-substituted tryptamine compound is a compound with a structural formula shown in a formula I or a pharmaceutically acceptable salt, ester or solvate of the compound with the structural formula shown in the formula I,
Figure 420994DEST_PATH_IMAGE001
the compound of the formula I is shown in the specification,
the above formula
Figure 95689DEST_PATH_IMAGE002
Wherein R is bromine, benzene, benzyl, biphenyl, chlorobenzene, ethylbenzene, phenol, butane, anisole, styrene, propylbenzene, 2-phenyl acetonitrile, 4-methyl-1,1'-biphenyl, acetophenone, hexylbenzene or (trifluoromethyl) benzene; the above formula
Figure 619074DEST_PATH_IMAGE002
The compound is pharmaceutically acceptable salt, ester or solvate, wherein the salt is inorganic acid salt or organic acid salt, and the inorganic acid salt is formed by any one of inorganic acid of hydrochloric acid, sulfuric acid and phosphoric acid; the organic acid salt is formed by any one of acetic acid, trifluoroacetic acid, malonic acid, succinic acid, citric acid and p-toluenesulfonic acid.
The above formula
Figure 48918DEST_PATH_IMAGE002
The 7-fluoro-5-substituted tryptamine compound is preferably any one of the following compounds:
Figure 228227DEST_PATH_IMAGE004
the compound can effectively inhibit the activity of adenylate cyclase by coupling with G protein. The compounds provided by the invention are subjected to 5-HT1BAnd testing the agonistic activity and the binding force of R. The compound provided by the invention has the advantages of easily obtained raw materials, simple preparation method and design and synthesis of a series of 5-HT1BThe receptor is a novel-structure small-molecule agonist with the target, and experiments prove that the compound has potential anti-migraine effect.
Detailed description of the invention
The preparation method of the 7-fluoro-5-substituted tryptamine compound in the first embodiment of the present invention includes the following steps:
(1) reacting the compound shown in the formula II with iron and ammonium chloride to obtain a compound shown in a formula III; according to the embodiment of the present invention, the conditions for reacting the compound represented by formula II with the compound represented by iron and ammonium chloride are not particularly limited, but may be specifically: reacting the compound shown in the formula II with iron and ammonium chloride in absolute ethyl alcohol for 1-12 hours at 0-100 ℃ by taking iron as a reducing agent according to the molar ratio of 1:5:3 to obtain a compound shown in the formula III; therefore, the method is beneficial to improving the reaction efficiency, reducing side reactions and improving the yield;
(2) reacting a compound shown as a formula III with sodium nitrite to obtain a compound shown as a formula IV; the method can also specifically comprise the following steps: reacting the compound shown in the formula III with sodium nitrite at the temperature of-20-20 ℃ for 0.5-5 hours to obtain a compound solution shown in the formula IV; therefore, the reaction can be carried out under the most appropriate conditions, which is beneficial to improving the reaction efficiency, reducing side reactions and improving the yield;
(3) reacting a compound shown as a formula IV with stannous chloride to obtain a compound shown as a formula V; the method can also specifically comprise the following steps: reacting the compound shown in the formula IV with stannous chloride at the temperature of-20-20 ℃ for 1-5 hours to obtain a compound shown in the formula V; therefore, the method is beneficial to improving the reaction efficiency, reducing side reactions and improving the yield;
(4) reacting a compound shown as a formula V with a compound shown as a formula VI to obtain a compound shown as a formula VII; the method can also specifically comprise the following steps: reacting the compound shown in the formula V with the compound shown in the formula VI in a sulfuric acid solution with the mass concentration of 4% at the temperature of 60-100 ℃ for 2-12 hours to obtain a compound shown in the formula VII; therefore, the method is beneficial to improving the reaction efficiency, reducing side reactions and improving the yield;
(5) reacting a compound shown as a formula VII with a compound shown as a formula VIII to obtain a compound shown as a formula I; the method can also specifically comprise the following steps: reacting a compound of the formula VII with a compound of the formula VIII in a solution of 1, 4-dioxane at 80-100 ℃, [ 2 ]1,1' -bis (diphenylphosphino) ferrocene]Reacting palladium dichloride and potassium phosphate for 6-12 hours to obtain a compound shown in the formula I; therefore, the reaction can be carried out under the most appropriate conditions, which is beneficial to improving the reaction efficiency, reducing side reactions and improving the yield.
Wherein R is bromine, benzeneMethyl, biphenyl, chlorobenzene, ethylbenzene, phenol, butane, anisole, styrene, propylbenzene, 2-phenylacetonitrile, 4-methyl-1,1'-biphenyl, acetophenone, hexylbenzene, (trifluoromethyl) benzene. The compound can be quickly and effectively prepared and obtained by the preparation method, and the method is simple to operate, convenient and quick, and suitable for large-scale production.
Example 1:
Figure 503350DEST_PATH_IMAGE005
preparation of (Compound 1)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoro-1-nitrobenzene (4.57 mmol) and reduced iron powder (22.85 mmol) were added to 10 mL of anhydrous ethanol, stirred at 60 ℃ for 20 minutes, then aqueous ammonium chloride (1.5 mmol) was added, and the reaction was terminated by TLC (developer: petroleum ether/ethyl acetate = 20/1). The resulting reaction mixture was then filtered with celite while it was hot, the resulting filtrate was added to 15 mL of water, basified with saturated sodium bicarbonate to 7-8, the mixture was extracted with ethyl acetate (3 × 20 mL), the organic phase was washed with brine and water, followed by drying over anhydrous magnesium sulfate, the solvent was removed by vacuum distillation, and a white solid powder, i.e., 4-bromo-2-fluoroaniline, was obtained by column chromatography (petroleum ether/ethyl acetate = 20/1) in 70% yield. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 7.22 (dd, J = 11.1, 2.2 Hz, 1H), 7.03 (ddd, J = 8.5, 2.1, 0.8 Hz, 1H), 6.71 (dd, J = 9.6, 8.6 Hz, 1H), 5.32 (s, 2H).
2. preparation of diazo liquid
4-bromo-2-fluoroaniline (7.30 mmol) obtained in step 1 was dissolved in acetic acid (5 mL), then 15 mL of concentrated hydrochloric acid was added, the mixture was kept at 0 ℃ or below, and an aqueous solution of sodium nitrite (10.95 mmol of sodium nitrite was added to 3 mL of water) was added dropwise over 20 minutes to give a clear yellow solution, which was directly subjected to the next reaction without purification.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine hydrochloride
Adding the diazo liquid in the step 2 into the chlorite chloride within half an hourTin hydrochloride solution (21.9 mmol stannous chloride added to 5 mL concentrated hydrochloric acid), stirring at 0 deg.C for 2 hours, washing the precipitate from the solution with brine (10 mL), and vacuum drying the resulting solid to obtain white solid powder, i.e. (4-bromo-2-fluorophenyl) hydrazine hydrochloride, in 64% overall yield over two steps. Compound structural data are characterized as:1H NMR (600 MHz, Deuterium Oxide) δ 7.44 (dd, J = 10.9, 2.2 Hz, 1H), 7.37 (dt, J = 8.6, 1.7 Hz, 1H), 7.05 (t, J = 8.8 Hz, 1H)。
4. preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Heating 4% sulfuric acid aqueous solution (10 mL) to 50 ℃ for 30-60 minutes under nitrogen, adding (4-bromo-2-fluorophenyl) hydrazine hydrochloride (7.35 mmol) obtained in step 3 to the solution, then 4-dimethylamino butyraldehyde dimethyl acetal (8.83 mmol) is added into the solution within half an hour, and the mixture was heated under reflux for 12 hours, TLC detection (developing solvent: petroleum ether/ethyl acetate = 5/1) ended, the reaction was cooled to room temperature, and 30% ammonium hydroxide solution (10 mL) was added over a half hour period, the product was extracted with ethyl acetate (3 × 10 mL), the solvent was removed by concentration in vacuo, and a white solid powder was obtained by chromatography (petroleum ether/ethyl acetate = 6/1-4/1).N,N-dimethyl-5-bromo-1H-indole-3-ethylamine in 50% yield, mp 124.3-124.8 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.55 (s, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.13 (dd, J = 10.8, 1.8 Hz, 1H), 2.80 – 2.77 (m, 2H), 2.50-2.47 (m, 2H), 2.20 (s, 6H).13C NMR (151 MHz, DMSO-d 6) δ 148.80 (d, J = 249.2 Hz) , 132.28 (d, J = 7.5 Hz), 125.35 , 122.83 (d, J = 13.59 Hz), 117.20 , 113.92 , 109.31 (d, J = 7.6 Hz) , 109.00 (d, J = 19.6 Hz) , 59.72 , 45.17 (2C) , 22.74。
5. preparation of Compound 1
Heating the mixture obtained in the step 4 at 80 DEG CN,N-dimethyl-5-bromo-1H-indole-3-ethylamine (0.7 mmol), phenylboronic acid (0.78 mmol),[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.03 mmol) and potassium phosphate (2.11 mmol) were heated in 4 mL of 1, 4-dioxane under reflux overnight TLC detection (developing solvent: petroleum ether/ethyl acetate = 1/1) and the reaction was terminated, the reaction solution was cooled to room temperature and filtered through celite, and extracted with ethyl acetate to obtain a solid powder of orange-red color by chromatography (petroleum ether/ethyl acetate = 2/1-1/1), i.e. compound 1, yield 70%, melting point 123.4-125.9 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.36 (s, 1H), 7.70-7.69 (m, 2H), 7.61 (s, 1H), 7.46-7.43 (m, 2H), 7.33-7.30 (m, 1H), 7.25 (d, J = 2.4, 1H), 7.24-7.21 (m, 1H), 2.88 – 2.85 (m, 2H), 2.55-2.52 (m,2H), 2.22 (s, 6H).13C NMR (151 MHz, DMSO-d6) δ 149.40 (d, J = 243.11 Hz) ,140.79 , 131.75(d, J = 7.55 Hz) , 131.55(d, J = 6.04 Hz) , 128.85(2C) , 126.82(2C) , 126.63 , 124.51 ,123.28(d, J = 13.59 Hz), 114.55 , 112.57 ,105.01 (d, J = 18.12 Hz) , 59.89 , 45.21(2C) , 22.97 .HR-MS(ESI): Calcd for [M+H]+: 283.1679; Found: 283.1611。
example 2:
Figure 84504DEST_PATH_IMAGE006
(preparation of Compound 2)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 2
Compound 2 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced by AThe phenyl boronic acid is reacted. The obtained compound is a white solid, and the yield is 90%; the melting point is 139.3-140.8 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.32 (s, 1H), 7.59-7.58 (m, 3H), 7.25-7.24 (m, 3H), 7.18 (dd, J = 12.6, 1.2 Hz, 1H), 2.87 – 2.84 (m, 2H), 2.54 – 2.52 (m, 2H), 2.34 (s, 3H), 2.21 (s, 6H). 13C NMR (151 MHz, DMSO-d6) δ149.37 (d, J = 243.11 Hz) , 137.91 , 135.78 , 131.73(d, J = 6.04 Hz) , 131.50 (d, J = 4.53 Hz), 129.44 (2C) , 126.62 (2C), 124.43 , 123.11(d, J = 13.59 Hz) , 114.45 , 112.18 , 104.85 (d, J = 16.61 Hz), 59.88 , 45.20 (2C) , 22.97 , 20.64. HR-MS(ESI): Calcd for [M+H]+: 297.1839; Found:297.1767。
example 3:
Figure 419671DEST_PATH_IMAGE007
preparation of (Compound 3)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 3
Compound 3 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with biphenylboronic acid and reacted. The obtained compound was a white solid with a yield of 69%; melting point 151.7-153.2 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.38 (s, 1H), 7.82 – 7.80 (m, 2H), 7.75 – 7.71 (m, 4H), 7.69 (s, 1H),7.50-7.47 (m, 2H), 7.39 – 7.36 (m, 1H), 7.31-7.28 (dd, J = 12.6, 1.2 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 2.90 – 2.87 (m, 2H), 2.57 – 2.54 (m, 2H), 2.23 (s, 6H).13C NMR (151 MHz, DMSO-d 6) δ 149.45 (d, J = 243.11 Hz), 139.81 , 139.76 , 138.33 , 131.79 (d, J = 6.04 Hz), 130.92 (d, J = 6.04 Hz), 129.00 (2C), 127.41 , 127.28 (2C), 127.09 (2C), 126.52 (2C), 124.57 , 123.37 (d, J = 15.10 Hz), 114.60 , 112.52 , 104.89 (d, J = 16.61 Hz), 59.88 , 45.20 (2C), 22.97. HR-MS(ESI): Calcd for [M+H]+359.1904；Found:359.1924。
example 4:
Figure 148592DEST_PATH_IMAGE008
preparation of (Compound 4)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 4
Compound 4 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with chlorobenzeneboronic acid and reacted. The obtained compound was a white solid with a yield of 81%; melting point 129.0-129.7 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.39 (s, 1H), 7.74-7.73 (m,2H), 7.64 (s, 1H), 7.49-7.48 (m,2H), 7.26 (d, J = 1.8 Hz, 1H), 7.24 (dd, J = 12.6, 1.2 Hz, 1H), 2.87 – 2.85 (m, 2H), 2.55 – 2.52 (m, 2H), 2.21 (s, 6H).13C NMR (151 MHz, DMSO-d 6) δ 149.40 (d, J = 243.11 Hz) , 139.60 , 131.79 , 131.41 , 130.11 , 128.74(2C) , 128.52 (2C), 124.66 ,123.47, 114.68 , 112.71 , 104.90 (d, J = 16.61 Hz), 59.84 , 45.20 (2C) , 22.92.HR-MS(ESI): Calcd for [M+H]+317.1267; Found:317.1221。
example 5:
Figure 165090DEST_PATH_IMAGE009
preparation of (Compound 5)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 5
Compound 5 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with (4-ethylphenyl) boronic acid and reacted. The compound obtained was a white solid with a yield of 76%; melting point 123.1-123.7 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.33 (s, 1H), 7.61-7.60 (m, 2H), 7.58 (s, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.20 (m, 1H), 2.88 – 2.85 (m, 2H), 2.63 (q, J = 7.6 Hz, 2H), 2.57 – 2.54 (m, 2H), 2.23 (s, 6H), 1.21 (t, J = 7.8 Hz, 3H).13C NMR (151 MHz, DMSO-d 6) δ 149.38 (d, J = 241.60 Hz), 142.18 , 138.23 , 131.72 (d, J = 6.04 Hz) , 131.59 (d, J = 6.04 Hz), 128.26(2C) , 126.74 (2C) , 124.47 , 123.14 (d, J = 13.59 Hz) ,114.34 , 112.27, 104.91 (d, J = 16.61 Hz) , 59.80 , 45.12 (2C) , 27.79 , 22.90 , 15.73 .HR-MS(ESI): Calcd for [M+H]+311.1982; Found:311.1924。
example 6:
Figure 663067DEST_PATH_IMAGE010
preparation of (Compound 6)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 6
Compound 6 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with (4-hydroxyphenyl) boronic acid. The obtained compound was a white solid with a yield of 69%; the melting point is 95.8-97.3 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.26 (s, 1H), 9.44 (s, 1H), 7.50-7.49 (m, 3H), 7.21 (d, J = 1.8 Hz, 1H), 7.12 (dd, J = 13.2, 1.2 Hz, 1H), 6.84-6.82 (m, 2H), 2.85 – 2.83 (m, 2H), 2.54 – 2.51 (m, 2H), 2.21 (s, 6H).13C NMR (151 MHz, DMSO-d 6) δ 156.48 , 149.34 (d, J = 243.11 Hz) , 131.82 , 131.76 (d, J = 6.04 Hz), 131.68 (d, J = 6.04 Hz), 127.82 (2C), 124.29 , 122.73 (d, J= 13.59 Hz), 115.63 (2C), 114.27 , 111.55 , 104.67 (d, J = 16.61 Hz) , 59.90 , 45.21 (2C) , 23.00 .HR-MS(ESI): Calcd for [M+H]+299.1616; Found:299.1560。
example 7:
Figure 434714DEST_PATH_IMAGE011
preparation of (Compound 7)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 7
Compound 7 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with propylboronic acid. The obtained compound was a white solid with a yield of 23%; melting point 119.9-121.3 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.11 (s, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.10 (s, 1H), 6.75-6.72 (m, 1H), 2.78 – 2.76 (m, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.49-2.48 (m, 2H), 2.20 (s, 6H), 1.60 (dt, J = 14.7, 7.4 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H).13C NMR (151 MHz, DMSO-d 6) δ148.93 (d, J = 243.11 Hz) , 132.83 (d, J = 6.04 Hz) , 131.22 (d, J = 6.04 Hz) , 123.73,122.27 (d, J = 12.08 Hz), 113.44,113.42, 106.43 (d, J = 15.10 Hz) , 59.85 , 45.17 (2C) , 37.36 , 24.69 , 23.04 , 13.67 .HR-MS(ESI): Calcd for [M+H]+ 249.1810; Found:249.1767。
example 8:
Figure 323036DEST_PATH_IMAGE012
preparation of (Compound 8)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 8
Compound 8 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with (4-methoxyphenyl) boronic acid. The compound obtained was a white solid with a yield of 63%; melting point 165.4-166.0 ℃. Compound structural data are characterized as:1H NMR (600 M-Hz, DMSO-d 6) δ 11.29 (s, 1H), 7.63-7.62 (m, 2H), 7.54 (s, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.18-7.15 (m, 1H), 7.01-7.00 (m, 2H), 3.79 (s, 3H), 2.87 – 2.84 (m, 2H), 2.55 – 2.52 (m, 2H), 2.22 (s, 6H).13C NMR (151 MHz, DMSO-d 6) δ 158.32 , 149.35 (d, J = 241.6 Hz) ,133.26 , 131.73 (d, J = 6.04 Hz) , 131.33 (d, J = 6.04 Hz), 127.82 (2C), 124.36 , 122.89 (d, J = 13.59 Hz) , 114.36 , 114.25 (2C), 111.87 , 104.76 (d, J = 16.61 Hz) , 59.88 , 55.15 , 44.19 (2C), 22.97 . HR-MS(ESI): Calcd for [M+H]+ 313.1732; Found:313.1716.HR-MS(ESI): Calcd for [M+H]+ 313.1732; Found:313.1716。
example 9:
Figure 205541DEST_PATH_IMAGE013
preparation of (Compound 9)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 9
Compound 9 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with (4-vinylphenyl) boronic acid and reacted. The obtained compound was a white solid with a yield of 83%; the melting point is 92.0-93.0 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.36 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H), 7.54 -7.53 (m, 2H), 7.26 – 7.24 (m, 2H), 6.77 (dd, J = 17.4, 10.8 Hz, 1H), 5.86 (d, J = 17.7 Hz, 1H), 5.27 (d, J = 11.4 Hz, 1H), 2.88 – 2.86 (m, 2H), 2.55 – 2.53 (m, 2H), 2.22 (s, 6H).13C NMR (151 MHz, DMSO-d 6) δ 149.54 (d, J = 243.11 Hz), 140.21 , 136.29 , 135.44 , 131.75 (d, J = 7.55 Hz) , 130.98 (d, J = 6.04 Hz) , 126.87 (2C) , 126.64 (2C) , 124.52 , 123.33 (d, J = 13.59 Hz), 114.60 , 113.92 , 112.42, 104.83 (d, J = 16.61 Hz) , 59.86 , 45.19 (2C) , 22.95 .HR-MS(ESI): Calcd for [M+H]+ 309.1815; Found: 309.4084。
example 10:
Figure 558025DEST_PATH_IMAGE014
preparation of (Compound 10)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indole-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 10
Compound 10 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with (4-propylphenyl) boronic acid. The compound obtained was a white solid with a yield of 87%; melting point 132.2-133.5 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.32 (s, 1H), 7.60 – 7.58 (m, 3H), 7.26 – 7.24 (m, 3H), 7.21-7.18 (m, 1H), 2.87 – 2.84 (m, 2H), 2.59 – 2.57 (m, 2H), 2.54 – 2.52 (m, 2H), 2.21 (s, 6H), 1.62 (dt, J = 15.0, 7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H).13C NMR (151 MHz, DMSO-d 6) δ 149.36 (d, J = 241.60 Hz),140.51 , 138.22 , 131.72 (d, J = 6.04 Hz) , 131.54 (d, J = 6.04 Hz) , 128.82 (2C), 126.63 (2C) , 124.41 , 123.12(d, J = 13.59 Hz) , 114.46 , 112.23 , 104.87 (d, J = 18.12 Hz),59.88, 45.19 (2C) , 36.84 , 24.12 , 22.97 , 13.68 .HR-MS(ESI): Calcd for [M+H]+ 325.2124; Found:325.2080。
example 11:
Figure 435327DEST_PATH_IMAGE015
preparation of (Compound 11)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 11
Compound 11 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with (4- (cyanomethyl) phenyl) boronic acid and reacted. The obtained compound was a white solid with a yield of 89%; melting point 148.0-148.7 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.37 (s, 1H), 7.74-7.73 (m, 2H), 7.63 (s, 1H), 7.42-7.41 (m, 2H), 7.25-7.23 (m, 2H), 4.07 (s, 2H), 2.88-2.85 (m, 2H), 2.55 – 2.52 (m, 2H), 2.22 (s, 6H).13C NMR (151 MHz, DMSO-d 6) δ 149.39 (d, J = 243.11 Hz), 140.09 , 131.74 (d, J =6.04 Hz) , 130.78 (d, J = 6.04 Hz) , 129.53 , 128.58 (2C) , 127.27 (2C) , 124.56 , 123.34 (d, J = 13.59 Hz), 119.33 , 114.59 , 112.57 , 104.92 (d, J = 18.12 Hz) , 59.85 , 45.19 (2C) , 22.94 , 21.99 .HR-MS(ESI): Calcd for [M+H]+ 322.1726; Found:322.1720。
example 12:
Figure 873261DEST_PATH_IMAGE016
preparation of (Compound 12)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 12
Compound 12 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with 4-methylbiphenylboronic acid and reacted. The obtained compound is a white solid, and the yield is 90%; melting Point166.1-167.5 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.37 (s, 1H), 7.79-7.78 (m, 2H), 7.72-7.71 (m, 2H), 7.67 (s, 1H), 7.62-7.61 (m, 2H), 7.29 – 7.26 (m, 4H), 2.89 – 2.87 (m, 2H), 2.56 – 2.54 (m, 2H), 2.35 (s, 3H), 2.22 (s, 6H).13C NMR (151 MHz, DMSO-d 6) δ 149.43 (d, J = 243.11 Hz),139.49 , 138.23 , 136.84 , 136.69 , 131.78 (d, J = 6.04 Hz) , 130.98 (d, J = 6.04 Hz), 129.58 (2C) , 127.21 (2C), 126.80 (2C), 126.31 (2C), 124.53 , 123.32 (d, J = 12.08 Hz) ,114.59, 112.44 , 104.85 (d, J = 16.61 Hz), 59.88 , 45.20 (2C) , 22.97 , 20.69 .HR-MS(ESI): Calcd for [M+H]+ 373.2088; Found: 373.2080。
example 13:
Figure 293878DEST_PATH_IMAGE017
preparation of (Compound 13)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 13
Compound 13 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with (4-acetylphenyl) boronic acid and reacted. The obtained compound was a white solid with a yield of 69%; melting point 140.9-141.4 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.45 (s, 1H), 8.02-8.01 (m, 2H), 7.88-7.87 (m, 2H), 7.75 (s, 1H), 7.34 (d, J = 11.9 Hz, 1H), 7.28 (s, 1H), 2.89 – 2.87 (m, 2H), 2.61 (s, 3H), 2.56 – 2.53 (m, 2H), 2.22 (s, 6H). 13C NMR (151 MHz, DMSO-d 6) δ 197.41 , 149.44 (d, J = 243.11 Hz) ,145.19, 134.89 ,131.78(d, J = 6.04 Hz) ,130.05(d, J = 6.04 Hz) , 128.86(2C) , 126.79 (2C), 124.76 , 123.79(d, J = 13.59 Hz),114.90,113.29 , 105.05(d, J = 16.61 Hz) , 59.83 , 45.20 (2C) , 26.73 , 22.90. HR-MS(ESI): Calcd for [M+H]+ 325.1749；Found: 325.1716。
example 14:
Figure 766448DEST_PATH_IMAGE018
preparation of (Compound 14)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 14
Compound 14 was prepared according to example 1, step 5, except that: the phenyl boronic acid in step 5 of example 1 was replaced with (4-heptylphenyl) boronic acid and reacted. The obtained compound is a white solid, and the yield is 85%; melting point 100.5-100.6 deg.C. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.32 (s, 1H), 7.60 – 7.58 (m, 3H), 7.25-7.24 (m, 3H), 7.19 (dd, J = 12.8, 1.1 Hz, 1H), 2.87 – 2.84 (m, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.55 – 2.52 (m, 2H), 2.21 (s, 6H), 1.61 – 1.56 (m, 2H), 1.29 (s, 6H), 0.87 – 0.85 (m, 3H).13C NMR (151 MHz, DMSO-d 6) δ 149.37(d, J = 243.11 Hz), 140.74 , 138.16 , 131.72 (d, J = 6.04 Hz), 131.54 (d, J = 6.04 Hz) , 128.76 (2C) , 126.63 (2C) , 124.41, 123.12(d, J = 13.59 Hz) , 114.44 , 112.22 , 104.87 (d, J = 16.61 Hz), 59.88 , 45.19 (2C) , 34.73 , 31.15 , 30.98 , 28.37 , 22.97 , 22.10 , 13.98 .HR-MS(ESI): Calcd for [M+H]+367.2599; Found: 367.2550。
example 15:
Figure 817581DEST_PATH_IMAGE019
preparation of (Compound 15)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 15
Compound 15 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with (4- (trifluoromethyl) phenyl) boronic acid and reacted. The compound obtained was a white solid with a yield of 49%; melting point 182.1-183.5 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.46 (s, 1H), 7.95-7.93 (m, 2H), 7.78-7.77 (m, 2H), 7.73 (s, 1H), 7.32 (dd, J = 12.7, 1.2 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 2.89 – 2.87 (m, 2H), 2.56 – 2.53 (m, 2H), 2.22 (s, 6H).13C NMR (151 MHz, DMSO-d 6) δ 149.44 (d, J = 243.11 Hz) ,144.76, 131.78 (d, J = 6.04 Hz) , 129.72 (d, J = 6.04 Hz), 127.44 (2C), 126.95 (d, J = 31.71 Hz), 125.64, 125.62, 124.81 , 123.83 , 123.74 , 114.87 , 113.35 , 105.08 (d, J = 18.12 Hz), 59.82 , 45.18 (2C), 22.90 .HR-MS(ESI): Calcd for [M+H]+351.1551; Found:351.1484。
example 16:
Figure 742811DEST_PATH_IMAGE020
preparation of (Compound 16)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 16
Compound 16 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with m-tolylboronic acid and reacted. The compound obtained was a white solid with a yield of 78%; melting point 123.8-124.1 deg.C. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.33 (s, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 13.2, 1.2 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 2.88 – 2.85 (m, 2H), 2.55 – 2.53 (m, 2H), 2.39 (s, 3H), 2.22 (s, 6H).13C NMR (151 MHz, DMSO-d 6) δ 149.34(d, J = 243.11 Hz), 140.73 , 137.90 ,131.72, 131.65(d, J = 6.04 Hz), 128.70 , 127.46 , 127.26 , 124.43 , 123.93 , 123.22(d, J = 13.59 Hz), 114.51 , 112.46 , 104.99 (d, J = 18.12 Hz) , 59.84 , 45.20 (2C) , 22.96 , 21.16 .HR-MS(ESI): Calcd for [M+H]+ 297.1830; Found:297.1767。
example 17:
Figure 967119DEST_PATH_IMAGE021
preparation of (Compound 17)
1. Preparation of 4-bromo-2-fluoroaniline
4-bromo-2-fluoroaniline was prepared according to example 1, step 1.
2. Preparation of diazo liquid
Diazo liquid was prepared according to step 2 of example 1.
3. Preparation of (4-bromo-2-fluorophenyl) hydrazine
(4-bromo-2-fluorophenyl) hydrazine was prepared according to step 3 of example 1.
4. Preparation ofN,N-dimethyl-5-bromo-1H-indol-3-ethylamine
Preparation according to step 4 of example 1N,N-dimethyl-5-bromo-1H-indole-3-ethylamine.
5. Preparation of Compound 17
Compound 17 was prepared according to example 1, step 5, except that: the phenylboronic acid in step 5 of example 1 was replaced with o-tolylboronic acid and reacted. The obtained compound is a white solid, and the yield is 85%; melting point 114.6-114.9 ℃. Compound structural data are characterized as:1H NMR (600 MHz, DMSO-d 6) δ 11.34 (s, 1H),7.30- 7.24 (m, 6H), 6.88 (dd, J = 12.0 Hz ,1.2 Hz ,1H), 2.83 – 2.81 (m, 2H), 2.53-2.51 (m, 2H), 2.26 (s, 3H), 2.19 (s, 6H).13C NMR (151 MHz, DMSO-d 6) δ148.55 (d, J = 243.11 Hz) , 141.74 , 134.95 , 132.08 (d, J = 6.04 Hz) , 131.15 (d, J = 6.04 Hz) , 130.25 , 129.98 , 126.87 , 125.81 , 124.33 ,122.80 (d, J = 13.59 Hz), 114.84, 114.22 , 107.17 (d, J = 16.61 Hz), 59.92 , 45.16 (2C), 22.96 , 20.37 .HR-MS(ESI): Calcd for [M+H]+ 297.1816; Found:297.1767。
detailed description of the preferred embodiment
Use of a compound prepared according to the above embodiment one or embodiment two in the manufacture of a medicament. The drug is a latent 5-HT1BReceptor agonists, capable of efficiently passingG protein-coupled 5-HT1BReceptor binding, which in turn inhibits adenylate cyclase activity, may prevent and or treat migraine.
It is to be noted that the above-mentioned drug of the present invention can be introduced into the body, such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue, by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or can be mixed or coated with other materials and introduced into body. If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field. In addition, the medicine of the invention can be prepared into various forms such as injection, tablets, powder, granules, capsules, oral liquid, ointment, cream and the like. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
Example 1
In vitro functional Activity assay
Recombinant 5HT in humans1BcAMP agonist function was performed on an R stable cell line (CHO-K1). Cells were incubated at 37 ℃ and 5% CO2Next, the cells were cultured in a medium (90% F12K + 10% FBS + 800. mu.g/mL G418). The positive compound 5-hydroxytryptamine (5-HT) was diluted 3-fold starting with 1 uM. The positive compound sumatriptan (sumatriptan) and all synthesized compounds were diluted 5-fold starting at a concentration of 200 uM. Then, 50 nL of the compound was transferred through an Echo machine. After collecting cells with buffer (1 × HBSS containing 5 mM HEPES +0.5 mM IBMX +0.1% BSA) and plating the cells at an appropriate density, centrifuging at 600 rpm for 3 minutes, and then incubating with the compound at room temperature for 60 minutes, 5uL 4X Eu-cAMP tracer solution and 5uL 4X ULight-anti-cAMP solution were added to the cells, centrifuged at 600 rpm for 3 minutes, and incubated for 60 minutes. cAMP signal was detected using Envision. GraphPad Prism (version 6.0) was used for data analysis. The results are shown in Table 1.
Figure 966299DEST_PATH_IMAGE022
In the form of
Figure 250650DEST_PATH_IMAGE002
。
TABLE 1 results of in vitro functional Activity assays for Compounds 1-17
Figure 663177DEST_PATH_IMAGE023
Figure 628859DEST_PATH_IMAGE024
Note: EC (EC)50Represents the half maximal effect concentration.
Table 1 shows cAMP method 5-HT of 7-fluoro-5-substituted tryptamine compounds1BResults of the R agonist Activity screening, it can be seen from the results that when the R substituent is a phenyl group, the compound is p-5-HT1BThe agonistic activity of R is obviously improved compared with biphenyl, wherein the agonistic activity of compound 6 and compound 11 is the highest (shown in figure 1), and the compound has the highest effect on 5-HT1BEC of R50The activity of the compound is 10.77 nM and 8.57 nM respectively, which are improved by more than 3 times and 4 times than the positive control sumatriptan (sumatriptan). The addition of methyl groups at different positions of the phenyl group of the R group shows that the activity of the compound is not greatly changed, and the activity values are all around 100 nM.
Example 2
And 5-HT1BBinding affinity of receptor
5-HT obtained from commercial sources1BCell membranes were subjected to radioactive ligand binding experiments. The specific operation is as follows: test compounds were diluted 5-fold in 8 concentration gradients in DMSO, starting at 20 uM. The positive reference compound 5-HT was diluted 4-fold in DMSO at 8 concentration gradients starting at 10 uM, and the positive compounds Sumatriptan Succinate (Sumatriptan Succinate) and Rizatriptan Benzoate (Rizatriptan Benzoate) were diluted 5-fold in DMSO at 8 concentration gradients starting at 20 uM. Transferring 1uL of diluted positive compound and test compound to a designated position in an assay plate, and transferring 1uL of non-specific compoundSpecifically bound compounds were applied to the assay plates as non-specific binding wells (LC) and 1uL of DMSO was transferred to the assay plates as total binding wells (HC). Add 100 uL of the prepared cell membrane and isotope to the plate, seal the plate, and incubate the plate on a shaker at 300 rpm for 2 hours at room temperature. 50uL of 0.3% PEI in each hole of the GF/C plate is soaked for at least more than half an hour, after the incubation is finished, the GF/C plate is washed by Harvest with plate washing buffer solution for 1 time, cell membranes in a 96-hole plate are collected on the GF/C plate by Harvest, the GF/C plate is washed by the plate washing buffer solution for four times, each time is about 250 uL, the GF/C plate is placed in an oven at 50 ℃ and baked for 1 hour, the bottom of the GF/C plate is sealed by a bottom sealing film, 50uL of Microscint-20 scintillation fluid is added in each hole, the plate is sealed by a transparent plate sealing film, the Microbeta2 is used for reading the plate, and GraphPad Prism 5.0 is used for data analysis, and the experimental results are shown in Table 2.
Figure 810441DEST_PATH_IMAGE022
Formula (II)
Figure 114DEST_PATH_IMAGE002
。
TABLE 2 binding affinity Activity results for Compounds 1-17
Figure 837620DEST_PATH_IMAGE025
Figure 403731DEST_PATH_IMAGE026
Table 2 shows 7-fluoro-5-substituted tryptamines and 5-HT1BAnd (4) screening the binding affinity activity of the receptor. From the results, it can be seen that when the R substituent is a linear alkane, the binding is weaker than that of the phenyl group, while the biphenyl substituent is weaker than that of the phenyl group as a whole, and in combination, the R substituent of the compound is a phenyl group and 5-HT1BThe receptor binding was best, most compounds were stronger than the positive controls Sumatriptan Succinate and Rizatriptan BenzoateWherein compounds 6 and 11 are reacted with 5-HT1BBinding activity of R as shown in figure 2, compound 11 bound better (Ki =16.56 nM) than the positive compound 5-hydroxytryptamine (serotonin) (Ki = 21.00) and compound 6 bound stronger (Ki =36.95 nM) than the positive controls Sumatriptan Succinate and Rizatriptan Benzoate (Rizatriptan Benzoate).
The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Those skilled in the art should also realize that changes, modifications, additions and substitutions can be made without departing from the true spirit and scope of the invention.

Claims (7)

1. A7-fluoro-5-substituted tryptamine compound is characterized in that: the compound is 7-fluoro-5-substituted tryptamine with a structural formula shown in a formula I or pharmaceutically acceptable salt, ester or solvate of the 7-fluoro-5-substituted tryptamine compound with the structural formula shown in the formula I,
Figure 405381DEST_PATH_IMAGE001
the compound of the formula I is shown in the specification,
wherein R is bromine, benzene, benzyl, biphenyl, chlorobenzene, ethylbenzene, phenol, butane, anisole, styrene, propylbenzene, 2-phenyl acetonitrile, 4-methyl-1, 1' -biphenyl, acetophenone, hexylbenzene or (trifluoromethyl) benzene; formula (II)
Figure 765955DEST_PATH_IMAGE002
The compound is pharmaceutically acceptable salt, ester or solvate, wherein the salt is inorganic acid salt or organic acid salt, and the inorganic acid salt is formed by any one of inorganic acid of hydrochloric acid, sulfuric acid and phosphoric acid; the organic acid salt is formed by any one of acetic acid, trifluoroacetic acid, malonic acid, succinic acid, citric acid and p-toluenesulfonic acid.
2. A method for preparing a 7-fluoro-5-substituted tryptamine compound according to claim 1, comprising the steps of:
(1) reacting the compound shown in the formula II with iron and ammonium chloride to obtain a compound shown in a formula III;
(2) reacting a compound shown as a formula III with sodium nitrite to obtain a compound shown as a formula IV;
(3) reacting a compound shown as a formula IV with stannous chloride to obtain a compound shown as a formula V;
(4) reacting a compound shown as a formula V with a compound shown as a formula VI to obtain a compound shown as a formula VII;
(5) reacting a compound shown as a formula VII with a compound shown as a formula VIII to obtain a compound shown as a formula I,
Figure 90757DEST_PATH_IMAGE003
，
wherein R is bromine, benzene, benzyl, biphenyl, chlorobenzene, ethylbenzene, phenol, butane, anisole, styrene, propylbenzene, 2-phenyl acetonitrile, 4-methyl-1, 1' -biphenyl, acetophenone, hexylbenzene or (trifluoromethyl) benzene.
3. The method for preparing a 7-fluoro-5-substituted tryptamine compound according to claim 2, wherein the step (1) is specifically: and (2) reacting the compound shown in the formula II with iron and ammonium chloride in absolute ethanol at a molar ratio of 1:5:3 for 2 hours at 40-60 ℃ by taking iron as a reducing agent to obtain the compound shown in the formula III.
4. The method for preparing a 7-fluoro-5-substituted tryptamine compound according to claim 2, wherein the step (2) is specifically: and reacting the compound shown in the formula III with sodium nitrite at 0 ℃ for half an hour to obtain a compound solution shown in the formula IV.
5. The method for preparing a 7-fluoro-5-substituted tryptamine compound according to claim 2, wherein the step (3) is specifically: and (3) reacting the compound shown as the formula IV with stannous chloride at 0 ℃ for 2 hours to obtain the compound shown as the formula V.
6. The method for preparing a 7-fluoro-5-substituted tryptamine compound according to claim 2, wherein the step (4) is specifically: and (2) reacting the compound shown in the formula V with the compound shown in the formula VI in a sulfuric acid solution with the mass concentration of 4% at 60-100 ℃ for 2-12 hours to obtain the compound shown in the formula VII.
7. The method for preparing a 7-fluoro-5-substituted tryptamine compound according to claim 2, wherein the step (5) is specifically: reacting a compound of the formula VII with a compound of the formula VIII in a solution of 1, 4-dioxane at 80-100 ℃, [ 2 ]1,1'-bis (diphenylphosphino) ferrocene]And (3) reacting the palladium dichloride and the potassium phosphate for 6-12 hours to obtain the compound shown in the formula I.
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