CN116730918A - Aporphine derivative, and preparation method and application thereof - Google Patents

Aporphine derivative, and preparation method and application thereof Download PDF

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CN116730918A
CN116730918A CN202310508659.7A CN202310508659A CN116730918A CN 116730918 A CN116730918 A CN 116730918A CN 202310508659 A CN202310508659 A CN 202310508659A CN 116730918 A CN116730918 A CN 116730918A
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synthesis
dmso
nmr
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叶娜
水雯箐
镇学初
秦望智
张冰洁
姜广仟
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Suzhou University
ShanghaiTech University
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ShanghaiTech University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • 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
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides an aporphine derivative, a preparation method and application thereof. The structural general formula of the aporphine derivative is shown as follows:wherein R is 1 Is C 1 ‑C 8 Alkoxy or hydrogen, R 2 Is hydroxyl or hydrogen; r is R 3 Selected from C 1 ‑C 8 Alkyl, C 1 ‑C 8 Alkoxy, C 2 ‑C 10 Alkynyl, C 2 ‑C 10 Alkenyl, halogen, C 1 ‑C 8 Haloalkyl, cyano, nitro or aryl. The invention relates to an application of a 5-hydroxytryptamine 2A receptor agonist and a 5-hydroxytryptamine 2C receptor agonist in preparing medicaments for preventing and/or treating obesity, urinary incontinence, depression, anxiety, obsessive compulsive disorder, epilepsy, schizophrenia, pain, diabetes and drug addiction.

Description

Aporphine derivative, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an aporphine derivative, a preparation method and application thereof.
Background
5-hydroxytryptamine (5-HT) receptor is wideIs widely distributed in the central and peripheral nervous systems and is involved in regulating a number of physiological responses such as cognition, memory processing, mood, circadian behaviors and appetite. Wherein 5-HT 2 The receptor comprises three subtypes of high homology, namely 5-HT 2A ，5-HT 2B And 5-HT 2C Receptors via G q / 11 The protein activates the corresponding downstream intracellular effector molecules, such as phospholipase C (PLC), whose activity depends on phosphomyo-inositol and/or intracellular calcium ion concentration, as well as Protein Kinase C (PKC). PLC catalyzes the hydrolysis of 4, 5-bisphosphate phosphatidylinositol to inositol triphosphate (IP) 3 ) And Diacylglycerol (DAG). IP (Internet protocol) 3 Can promote calcium ion release from intracellular calcium store, raise calcium ion concentration in cytoplasm, and combine with PKC in cytoplasm and aggregate to plasma membrane. DAG, phosphatidylserine and calcium ions together activate PKC, which in turn causes various corresponding biological effects.
In the central nervous system, 5-HT 2A The receptors are involved in the regulation of cognitive states, associative learning, mood and circadian rhythms, thus 5-HT 2A The efficacy of receptor agonists is being investigated for a variety of neurological disease indications, including the adjuvant psychotherapy of patients suffering from fear and anxiety associated with absolute or post-traumatic stress disorder (PTSD), major depressive disorder, refractory depressive disorder, addiction, obsessive-compulsive disorder, etc., and as potent tumor necrosis factor (TNF-a) -mediated inhibitors of inflammation, useful as novel treatments for inflammatory diseases. 5-hydroxytryptamine 2C (5-HT) 2C ) The risk of peripheral side effects of the receptor due to its mainly concentrated expression in the central nervous system is low, and thus 5-HT 2C The receptor becomes an ideal target for treating central nervous system diseases, such as children refractory epilepsy Dravet syndrome, obesity, anxiety, schizophrenia, addictive drugs and the like. While 5-HT 2B Receptors are predominantly distributed in heart valves and the like, when agonizing 5-HT 2B The occurrence of heart valve disease will likely be induced at the recipient. Thus, low 5-HT was developed 2B 5-HT of receptor Activity 2A/2C Or 5-HT 2C Receptor selective agonists are highly desirable for the treatment of central nervous system disorders.
At presentNot only does there yet be high agonistic activity of 5-HT 2A/2C Reports of receptor agonists and 5-HT which are marketed or in preclinical studies are disclosed 2C Receptor-highly selective agonists are also rare, as only lorcaserin and thiochromene have been marketed or entered into the clinic. Therefore, there is still a need to develop compounds with novel structures, high selectivity, high activity and good drug properties.
The aporphine derivatives can be separated from natural products, can be obtained through organic synthesis modification, and have wide biological activities such as anticancer activity, anti-inflammatory activity, antioxidant activity, platelet aggregation resistance, anti-parkinsonism, antiviral activity, adrenergic receptor action activity, antirheumatic activity, antimalarial activity, antibacterial activity and the like due to the changeable structure. Although the use of aporphine derivatives for the treatment of central nervous system disorders has been studied for many years, mainly as dopamine D 2 Receptors, 5-HT 1A Receptors, 5-HT 2A And 5-HT 2B Ligands for receptors, even compounds with unknown targets (e.g., CN112999225A and CN 113004201A), act on 5-HT 2C Receptors have not been explored until recently.
In the prior art, 5-HT was targeted 2C 5-HT is still present in aporphine agonists of the receptor 2C Weak receptor agonistic activity, such as 1857 (ACS CentSci,2020,6,213-25) and 18b (ACS Chem Neurosci,2020,11,549-59; ZL 201910594756.6); 5-HT 2C Defects such as poor receptor selectivity, e.g., 11b and 11f (Bioorganic Chemistry 123 (2022) 105795; zl 201910594756.6), ultimately limiting their further clinical development. And has 5-HT 2A And 5-HT 2C Dual agonists of the receptor have not been reported.
Disclosure of Invention
In order to solve the technical problems, the invention provides an aporphine derivative, and a preparation method and application thereof.
The first object of the invention is to provide an aporphine derivative, which has the following structural general formula:
wherein R is 1 Is C 1 -C 8 An alkoxy group or a hydrogen group,
R 2 is hydroxyl or hydrogen;
R 3 selected from C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 2 -C 10 Alkynyl, C 2 -C 10 Alkenyl, halogen, C 1 -C 8 Haloalkyl, cyano, nitro or aryl.
In one embodiment of the invention, R 2 When hydroxyl is present, R 1 Selected from C 1 -C 8 Alkoxy and hydrogen, R 3 Selected from halogen, C 1 -C 8 Alkoxy, C 1 -C 8 An alkyl group.
In one embodiment of the invention, R 2 When hydroxyl is present, R 1 Selected from hydrogen, R 3 Independently selected from halogen, C 1 -C 8 Alkoxy, C 1 -C 8 An alkyl group.
In one embodiment of the invention, R 2 When hydroxyl is present, R 1 Selected from C 1 -C 8 Alkoxy, R 3 Independently selected from halogen, C 1 -C 8 An alkoxy group.
In one embodiment of the invention, halogen is fluorine, chlorine, bromine or iodine.
Further, C 1 -C 8 Haloalkyl is a 1-8 carbon alkyl group containing halogen, the number and kind of which are not limited, such as trifluoromethyl, difluoromethyl, monofluoromethyl or trifluoroethyl;
C 2 -C 10 alkenyl is alkenyl of 2 to 10 carbons such as ethylene, propylene, butylene, styrene or styrene propylene;
C 2 -C 10 alkynyl is an alkynyl of 2 to 10 carbons such as acetylene, propyne, butyne, phenylacetylene or phenylpropyne;
C 1 -C 8 alkyl (R) and C 1 -C 8 Alkoxy (RO-), wherein alkyl (R) specifically includes aliphatic alkyl and aromatic alkyl; wherein the saidThe aliphatic alkyl group is preferably C 1 -C 8 Alkyl groups, which may be straight chain alkyl groups, branched chain alkyl groups, spirocycloalkyl groups, bridged cycloalkyl groups, alkenealkyl groups, alkynalkyl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxyalkyl groups, alkoxyacylalkyl groups, cycloalkylalkyl groups, more preferably aliphatic alkyl groups, include, without limitation: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, allyl, propargyl, cyclobutene, cyclohexenyl, 2-difluoroethyl, 2-fluoroethyl; the aromatic alkyl groups include, without limitation: aralkyl or heteroaralkyl groups, such as substituted aryloxy substituted or unsubstituted benzyl; substituted or unsubstituted phenethyl; substituted or unsubstituted phenylpropyl, and the like;
aryl refers to a substituted or unsubstituted aryl or heteroaryl group, including, without limitation: substituted or unsubstituted phenyl, naphthalene ring, benzene ring, etc.; the substituent is selected from one or more of halogen, amino, hydroxyl, oxime, alkoxy acyl, acyloxy, acyl, sulfonyl, sulfonylamino, urea, thiourea and carbamoyl.
Heteroaryl groups include, without limitation: substituted or unsubstituted aromatic heterocyclic groups and benzoheterocyclic substituents; including, without limitation, quinoline, isoquinoline, indole, benzofuran rings, furan rings, benzothiophene rings, thiophene rings, pyridine rings, pyrrole rings, and the like.
Further, isomers include the R-isomer and the S-isomer.
In one embodiment of the invention, R 3 Selected from halogen, C 1 -C 8 Alkoxy or C 1 -C 8 An alkyl group.
The second object of the present invention is to provide a preparation method of the aporphine derivative, comprising the following steps:
(1) The compound isAnd->Dehydration condensation to give an amide compound
Said->Introducing PG protecting group under the action of dehydrating agent and reducing agent to obtain the final product; />
(2) The step (1) is carried outCoupling and ring closing are carried out on the catalyst and the ligand, so that the catalyst is obtained;
(3) And (2) the step (2)Carrying out deprotection reaction to obtain the product
In one embodiment of the present invention, in step (1), theAnd->The molar ratio of (2) is: 1:1-1.5.
In one embodiment of the present invention, in step (1), the dehydrating agent is one or more of phosphorus pentoxide, phosphorus oxychloride, and phosphorus pentachloride.
In one embodiment of the present invention, in step (1), the reducing agent is selected from the group consisting of NaBH 4 (sodium borohydride), liAlH 4 (lithium aluminum tetrahydroide), BH 3 THF (tetrahydrofuran borane), KBH 4 (Potassium borohydride) and SnCl 2 (tin dichloride) one or more of the following.
In one embodiment of the present invention, in step (1), the protecting group is selected from one or more of Tfa (trifluoroacetyl), ts (p-toluenesulfonyl), and Boc (t-butoxycarbonyl).
In one embodiment of the invention, in step (2), the catalyst is selected from the group consisting of Pd (PPh) 3 ) 4 (Tetratriphenylphosphine palladium), pd (dppf) Cl 2 (1, 1' -bis-diphenylphosphino ferrocene palladium dichloride), pd (OAc) 2 (Palladium acetate) and Pd 2 (dba) 3 (dibenzylideneacetone dipalladium) one or more of the following.
In one embodiment of the invention, in step (2), the ligand is selected from the group consisting of PhDavephos (2-diphenylphosphine-2' - (N, N-dimethylamino) biphenyl), PCy 3 BHF 4 (Tricyclohexylphosphine tetrafluoroborate), (t-Bu) 2 PMeHBF 4 (Di-tert-butylmethylphosphonium tetrafluoroborate or Di-tert-butylmethylphosphonium tetrafluoroborate) and PPh 3 (triphenylphosphine) one or more of them.
In one embodiment of the invention, R 1 、R 2 、R 3 Wherein one or two of the compounds are hydrogen and the other group is a non-hydrogen substituent, and the preparation method of the compound shown in the formula M is as follows:
step 1: dissolving phenethylamine M1 containing substituent groups and substituted or unsubstituted o-bromophenylacetic acid M2 into anhydrous dichloromethane, adding HOBt and EDC under stirring, stirring the obtained reaction mixture at room temperature for reaction, and obtaining an amide compound of a formula M3 after the reaction is completed;
step 2: placing an amide compound of the formula M3 and a dehydrating agent in a solvent to perform a ring closure reaction, then performing a reduction reaction under the action of a reducing agent, and introducing a trifluoroacetyl protecting group after the reaction is completed to obtain a compound of the formula M4;
step 3: reacting a compound of the formula M4 under the action of alkali, a ligand and a catalyst at 130 ℃ to obtain a compound of the formula M5 after the reaction is completed;
step 4: removing the protecting group from the compound of the formula M5 under the action of a reducing agent and salifying to obtain the compound of the formula M.
A third object of the present invention is to provide a pharmaceutical composition comprising said aporphine derivative.
A fourth object of the present invention is to provide the use of the aporphine derivative and the pharmaceutical composition for preparing 5-hydroxytryptamine 2A receptor agonist and 5-hydroxytryptamine 2C receptor agonist, and the use of the 5-hydroxytryptamine 2A receptor agonist and 5-hydroxytryptamine 2C receptor agonist for preparing the medicine for preventing and/or treating obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes or drug addiction.
In one embodiment of the invention, the use of a 5-hydroxytryptamine 2A receptor agonist, a 5-hydroxytryptamine 2C receptor agonist, for the manufacture of a medicament for the prevention and/or treatment of depression, anxiety, obsessive-compulsive disorder or drug addiction.
In one embodiment of the invention, the medicament further comprises a pharmaceutically or pharmacologically acceptable carrier.
In one embodiment of the invention, the carrier is selected from one or more of a disintegrant, a diluent, a lubricant, a binder, a wetting agent, a flavoring agent, a suspending agent, a surfactant, and a preservative.
In one embodiment of the invention, the dosage form of the pharmaceutical composition is a tablet, a capsule, a soft capsule, a granule, a pill, an oral liquid, an emulsion, a dry suspension, a dry extract or an injection.
In one embodiment of the invention, the medicament further includes pharmaceutically or pharmacologically acceptable salts, esters, hydrates, solvates, crystalline forms, enantiomers, stereoisomers, ethers, metabolites and prodrugs.
In one embodiment of the invention, the salt is selected from one or more of mineral acid salts, organic acid salts, alkyl sulfonates, and aryl sulfonates.
In one embodiment of the present invention, the inorganic acid salts include, but are not limited to, at least one of hydrochloride, hydrobromide, nitrate, sulfate, and phosphate; preferably, the organic acid salt includes, but is not limited to, at least one of formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, and citrate; preferably, the alkyl sulfonates include, but are not limited to, at least one of methyl sulfonate and ethyl sulfonate; the arylsulfonate includes, but is not limited to, at least one of benzenesulfonate and p-toluenesulfonate.
Compared with the prior art, the technical scheme of the invention has the following advantages:
the design of the invention has the general formulaAporphine compounds of the structure and discovery of pairs of 5-HT with compounds of such structure 2C Or 5-HT 2A / 2C The receptors all exhibit excellent activation, but against 5-HT 2B The receptor has no agonism. The invention reveals and clarifies the relationship between the aporphine structure and the activity efficiency in a larger range, and has important application value. The aporphine compound of the invention is used as 5-HT 2C Receptor agonists are useful in the prevention or treatment of obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes and drug addiction; and is used as 5-HT 2A / 2C The receptor agonist can be used for preventing or treating depression, anxiety, obsessive-compulsive disorder and addiction.
Drawings
In order that the invention may be more readily understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings, in which,
FIG. 1 shows the measurement result of in vivo anti-schizophrenia activity in example 68 of the present invention.
Detailed Description
The present invention will be further described with reference to specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the present invention and practice it.
In the following examples of the present invention, the structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was performed using Agilent 400MHz or 600MHz instrument with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS), and GCT Premier is used for MS TM (CI) Mass Spectrometry measurements were performed with the exception of CI source (70 ev).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.2mm, and the column chromatography generally uses smoke table yellow sea silica gel with 100-200 meshes or 200-300 meshes as a carrier.
The reaction conditions were purged with nitrogen by connecting the reaction flask to a nitrogen balloon of about 1L volume. The reaction conditions are filled with hydrogen gas, which means that the reaction flask is connected with a hydrogen balloon with a volume of about 1L. The reaction conditions were room temperature (rt) and the temperature range was 20-30 ℃.
In the following examples of the invention, all solvents were redistilled before use and the anhydrous solvents used were all obtained by drying according to standard methods.
The synthetic routes for compounds S1-S9 are shown below:
synthesis of intermediate 3 a-i: in an ice water bath, phenylacetic acid derivatives 2a to i (1.0 eq) were dissolved in an anhydrous dichloro solution (0.2M), and 1-hydroxybenzotriazole (1.2 eq), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.2 eq) and p-methoxyphenylethylamine 1-1 (1.2 eq) were added sequentially with stirring. Gradually warm to room temperature and stir overnight, TLC detects the reaction until it is complete. The mixture was separated by extraction with dichloromethane and water, and the organic phase was washed successively with 1N diluted hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. A small amount of dichloromethane was dissolved, cooled in ice bath, stirred for crystallization, and white solid 3a-i was obtained in 78-92% yield.
Synthesis of intermediate 4 a-i: amide 3a-i (1.0 eq) and phosphorus pentoxide (5.0 eq) were refluxed in toluene for 3h, and after cooling the reaction system, toluene was concentrated. The mixture was neutralized with saturated aqueous sodium bicarbonate, the resulting mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated, then redissolved in methanol (0.2M). Sodium borohydride (3.0 eq) was added in portions to the mixture under ice-water bath and the resulting mixture was stirred at room temperature for 3h. The methanol was concentrated, diluted with 50mL of water, and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography gives yellow oil in 55-65% yield in two steps.
Triethylamine (2.5 eq) was added to a solution of yellow oil (1.0 eq) in dichloromethane (0.2M) at room temperature. The mixture was cooled to 0 ℃ and trifluoroacetic anhydride (1.2 eq) was added dropwise to the mixture, gradually warmed to room temperature and stirred for 1h. The mixture was diluted with dichloromethane (50 mL) and the mixture was then washed with 1N HCl (hydrochloric acid), saturated aqueous sodium bicarbonate and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography gave white solids 4a-i in 80-85% yield.
Synthesis of intermediate 5 a-i: potassium carbonate (2.5 eq), 2-diphenylphosphine-2' - (N, N-dimethylamino) biphenyl (0.2 eq), palladium acetate (0.1 eq) and 4a-i (1.0 eq) were placed in a round bottom flask under nitrogen. Solvent N, N-dimethylacetamide (0.2M) was then added and the resulting mixture was heated at 130 ℃ for 4h. N, N-dimethylacetamide was concentrated, diluted with water, the mixture was separated by extraction with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography gave white solids 5a-i in 40-45% yield.
Synthesis of Compounds S1-S9: to a round bottom flask was added intermediate 5a-i (1.0 eq) and ethanol (0.2M). Sodium borohydride (20 eq) was then added successively under ice bath, the round bottom flask was charged with nitrogen and the reaction mixture was stirred at room temperature for 60 minutes. Then, the solvent was evaporated under reduced pressure, and a saturated sodium chloride solution was added to the residue to extract with methylene chloride. The organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, column chromatography was performed using ethyl acetate solution of hydrogen chloride to form a salt, the solvent was dried by spin-drying, and the procedure was repeated three times to obtain white solids S1 to S9 in 40 to 56% yield.
Example 1: synthesis of Compound S1 (8-chloro-1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-6-chloroacetic acid 2a is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),9.81(s,1H),δ8.28(d,J＝7.7Hz,1H),7.41–7.27(m,3H),7.19(d,J＝8.6Hz,1H),4.39(dd,J＝14.1,3.4Hz,1H),3.91(s,3H),3.77(dd,J＝12.0,5.7Hz,1H),3.70(dd,J＝14.2,4.4Hz,1H),3.45–3.37(m,1H),3.25(d,J＝6.1Hz,1H),3.08(dd,J＝16.9,4.1Hz,1H),2.75(t,J＝14.3Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ155.94,133.56,132.17,130.00,129.81,129.56,127.99,127.63(d,J＝15.7Hz),121.83,120.69,112.81,54.96,52.82,41.22,29.21,24.14.MS(CI)calcd for C 17 H 17 Cl 2 NO[M+H] + :322.23.
Example 2: synthesis of Compound S2 (9-chloro-1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-5-chloroacetic acid 2b is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ9.91(s,2H),8.22(d,J＝8.5Hz,1H),7.51(s,1H),7.42–7.14(m,3H),4.33(d,J＝13.3Hz,1H),3.86(s,3H),3.59(d,J＝6.4Hz,1H),3.22–2.89(m,5H). 13 C NMR(101MHz,DMSO-d 6 )δ155.5,136.0,131.9,130.9,130.6,130.1,128.1,127.4,123.4,120.1,113.2,56.4,52.2,32.7,24.7.MS(CI)calcd for C 17 H 17 Cl 2 NO[M+H] + :322.23.
Example 3: synthesis of Compound S3 (10-chloro-1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-4-chloroacetic acid 2c is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),9.81(s,1H),8.22(s,1H),7.41(d,J＝7.8Hz,1H),7.33(d,J＝7.6Hz,1H),7.26(d,J＝8.4Hz,1H),7.18(d,J＝8.5Hz,1H),4.31(d,J＝12.4Hz,1H),3.88(s,3H),3.57(d,J＝5.6Hz,1H),3.25–3.10(m,3H),2.94(t,J＝14.3Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ155.62,133.51,132.52,131.90,131.21,130.55,130.17,128.38,127.56,123.51,119.82,113.12,56.50,52.23,32.29,24.63.MS(CI)calcd for C 17 H 17 Cl 2 NO[M+H] + :322.23.
Example 4: synthesis of Compound S4 (11-chloro-1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-3-chloroacetic acid 2d is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.35(s,1H),9.65(s,1H),7.41(dd,J＝20.2,7.0Hz,2H),7.30(s,2H),7.16(d,J＝8.2Hz,1H),4.18(d,J＝12.0Hz,1H),3.84(s,3H),3.57(s,1H),3.26–3.09(m,3H),2.98–2.78(m,2H). 13 C NMR(151MHz,DMSO-d 6 )δ154.99,137.37,133.18,132.75,130.68,130.44,129.77,128.82,126.66,122.52,119.05,112.51,55.50,52.43,40.54,24.14.MS(CI)calcd for C 17 H 17 Cl 2 NO[M+H] + :322.23.
Example 5: synthesis of Compound S5 (8-fluoro-1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-6-fluorophenylacetic acid 2e is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.09(s,2H),8.09(d,J＝8.0Hz,1H),7.37(dd,J＝14.8,7.7Hz,1H),7.27(d,J＝8.6Hz,1H),7.18(dt,J＝8.5,4.4Hz,2H),4.34(dd,J＝14.2,4.4Hz,1H),3.87(s,3H),3.59(t,J＝9.5Hz,1H),3.43(dd,J＝14.3,4.6Hz,1H),3.21(d,J＝7.1Hz,2H),2.94(t,J＝11.8Hz,1H),2.72(t,J＝14.3Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ159.1(d,J＝241.6Hz),155.7,133.8,130.9,130.4,128.4(d,J＝7.6Hz),125.1,123.4,120.3(d,J＝18.1Hz),120.2,114.5(d,J＝22.7Hz),113.2,56.4,51.9,40.6,24.6,24.4.MS(CI)calcd for C 17 H 17 ClFNO[M+H] + :305.78.
Example 6: synthesis of Compound S6 (9-fluoro-1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-5-fluorophenylacetic acid 2f is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ9.88(s,2H),8.25(dd,J＝8.3,6.3Hz,1H),7.29(d,J＝8.1Hz,1H),7.19(dd,J＝25.2,8.4Hz,3H),4.33(d,J＝11.1Hz,1H),3.86(s,3H),3.58(d,J＝6.9Hz,1H),3.23–3.10(m,3H),2.95(dd,J＝26.0,13.2Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ161.96,160.33,155.24,136.49(d,J＝8.5Hz),131.04(d,J＝8.1Hz),130.70,129.62,128.12,123.33,120.37,115.24,115.09,114.15,114.02,113.10,40.67,24.67.MS(CI)calcd for C 17 H 17 ClFNO[M+H] + :305.78.
Example 7: synthesis of Compound S7 (10-fluoro-1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2g of 2-bromo-4-fluorophenylacetic acid is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.39(s,1H),9.75(s,1H),7.99(d,J＝10.1Hz,1H),7.41(t,J＝7.1Hz,1H),7.26(d,J＝8.5Hz,1H),7.17(d,J＝8.6Hz,1H),7.12(t,J＝7.3Hz,1H),4.31(s,1H),3.88(s,3H),3.57(s,1H),3.27–3.07(m,3H),2.92(dd,J＝17.3,10.2Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ162.21,160.62,155.65,133.42(d,J＝9.1Hz),131.08,130.44,129.93(d,J＝8.3Hz),129.57,123.39,120.08,115.55,115.39,114.51,114.37,113.08,56.42,52.45,40.56,32.12,24.62.MS(CI)calcd for C 17 H 17 ClFNO[M+H] + :305.78.
Example 8: synthesis of Compound S8 (11-fluoro-1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-3-fluorophenylacetic acid is taken as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.41(s,1H),9.67(s,1H),7.39–7.27(m,2H),7.25(d,J＝6.5Hz,1H),7.17(d,J＝7.3Hz,2H),4.22(d,J＝11.8Hz,1H),3.83(s,3H),3.58(s,1H),3.26–2.84(m,5H). 13 C NMR(151MHz,DMSO-d 6 )δ159.4(d,J＝253.7Hz),155.3,136.7,132.1,130.3,129.5(d,J＝9.1Hz),123.9,122.9,119.4(d,J＝15.1Hz),117.4,115.7(d,J＝24.2Hz),112.9,56.3,52.4,40.6,33.3,24.3.MS(CI)calcd for C 17 H 17 ClFNO[M+H] + :305.78.
Example 9: synthesis of Compound S9 (1, 9-dimethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-5-methoxyphenylacetic acid 2i is used as a raw material, and is synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.33(s,1H),9.67(s,1H),8.16(d,J＝8.8Hz,1H),7.13(q,J＝8.5Hz,2H),6.95(s,1H),6.90(d,J＝8.8Hz,1H),4.27(d,J＝11.2Hz,1H),3.84(s,3H),3.79(s,3H),3.55(s,1H),3.19(d,J＝10.1Hz,2H),3.11–3.03(m,1H),2.94(dd,J＝30.5,13.9Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ158.72,155.07,135.40,130.44,130.28,128.66,124.29,123.31,121.34,113.73,113.04,112.91,56.34,55.64,52.50,33.36,24.71.MS(CI)calcd for C 18 H 20 ClNO 2 [M+H] + :317.81.
The synthetic routes for compounds S10-S23 are shown below:
synthesis of intermediate 6a-n, as well as synthesis of intermediate 3a-i.
Synthesis of intermediates 7 a-n: to an acetonitrile (0.2M) solution of amide 6a-c (1.0 eq) was added phosphorus oxychloride (3.0 eq) and refluxed for 2h. After the reaction system was cooled, acetonitrile was concentrated, and neutralized with a saturated aqueous sodium hydrogencarbonate solution. The resulting mixture was extracted with dichloromethane, concentrated, and then redissolved in methanol (0.2M). Subsequent steps are identical to the synthesis of intermediates 4a-i. Column chromatography gave white solids 7a-c.
Synthesis of intermediates 8a-n, as well as synthesis of intermediates 5 a-c.
Synthesis of intermediates 9 a-n: intermediate 8a-C (1.0 eq) was dissolved in an appropriate amount of methanol and dichloromethane, 10% Pd/C (0.2 eq) was added, hydrogen was added, the reaction was allowed to proceed for 4h at ambient temperature, and TLC was monitored until the reaction was complete. Filtration, DCM extraction, salt washing, drying and crude silica gel column chromatography separation to obtain white solid 9a-c.
Synthesis of Compounds S10-S23, synthesis of Compounds S1-S9.
Example 10: synthesis of Compound S10 (1-methoxy-9-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
2-bromo-5-chloroacetic acid 2b and 3-benzyloxy-4-methoxyphenylethylamine 1a are used as raw materials, and synthesized according to the above steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.05(s,1H),9.70(s,1H),9.44(s,1H),8.25(d,J＝8.6Hz,1H),7.52(s,1H),7.43(d,J＝8.5Hz,1H),6.76(s,1H),4.24(s,1H),3.58(d,J＝15.3Hz,4H),3.23–3.06(m,3H),2.97–2.81(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ151.24,144.78,136.38,132.41,130.72,129.91,128.48,127.91,127.17,125.29,120.75,116.53,60.09,51.82,33.06,24.98.MS(CI)calcd for C 17 H 17 Cl 2 NO 2 [M+H] + :338.23.
Example 11: synthesis of Compound S11 (1-methoxy-11-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
2-bromo-3-chloroacetic acid 2d and 3-benzyloxy-4-methoxyphenylethylamine 1a are used as raw materials, and synthesized according to the above steps. 1 H NMR(300MHz,DMSO-d 6 )δ10.15(s,1H),9.63(s,1H),9.28(s,1H),7.53-7.25(m,3H),6.81(s,1H),4.08(s,1H),3.56(s,1H),3.42(s,3H),3.25(s,1H),3.09(d,J＝10.5Hz,2H),2.82(dd,J＝24.4,11.6Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ150.71,145.18,137.71,132.94,130.77,129.90,129.27,126.85,125.97,124.03,122.71,116.51,60.89,52.22,34.90,24.58.MS(CI)calcd for C 17 H 17 Cl 2 NO 2 [M+H] + :338.23.
Example 12: synthesis of Compound S12 (1, 9-dimethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
2-bromo-5-methoxyphenylacetic acid 2i and 3-benzyloxy-4-methoxyphenylethylamine 1a are used as raw materials, and synthesized according to the above steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.20(s,1H),9.55(s,1H),8.21(d,J＝8.7Hz,1H),7.51(d,J＝7.3Hz,2H),7.43(t,J＝7.3Hz,2H),7.35(t,J＝7.0Hz,1H),6.96(dd,J＝14.7,7.2Hz,3H),5.17(s,2H),4.23(s,1H),3.80(s,3H),3.63(s,3H),3.56(d,J＝6.6Hz,1H),3.24–3.04(m,3H),2.92(dd,J＝29.4,14.5Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ159.13,152.26,145.23,137.35,135.82,129.84,128.95,128.36,128.06,127.02,126.39,123.97,121.99,113.99,113.46,112.95,70.34,60.16,55.62,51.99,40.58,33.60,25.32.MS(CI)calcd for C 18 H 20 ClNO 3 [M+H] + :333.81.
Example 13: synthesis of Compound S13 (1-methyl-11-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-3-chloroacetic acid 2d and 3-benzyloxy-4-methylphenylethylamine 1b are used as raw materials, and synthesized according to the above steps. 1 H NMR(400MHz,DMSO-d6)δ7.45(dd,J＝7.9,1.3Hz,1H),7.37(t,J＝8.1Hz,1H),7.32(dq,J＝8.2,1.1Hz,1H),6.75(s,1H),6.49(t,J＝1.0Hz,1H),3.89(dt,J＝6.2,4.9Hz,1H),3.45–3.35(m,1H),3.11–3.05(m,1H),3.05(dddd,J＝7.2,5.3,2.9,1.2Hz,4H),2.95–2.85(m,1H). 13 C NMR(101MHz,DMSO-d6)δ155.14,135.27,133.31,131.21,131.16,130.71,129.73,127.83,127.13,124.81,120.83,114.46,54.58,43.21,36.85,28.81,12.48.MS(CI)calcd for C 17 H 17 Cl 2 NO[M+H] + :333.23.
Example 14: the compound S14 (1-ethyl-11-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline.
-2-ol hydrochloride) synthesis
2-bromo-3-chloroacetic acid 2d and 3-benzyloxy-4-ethyl phenethylamine 1c are used as raw materials, and are synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ7.46(dd,J＝7.9,1.3Hz,1H),7.38(t,J＝8.0Hz,1H),7.33(dq,J＝8.1,1.1Hz,1H),6.91(s,1H),6.48(t,J＝1.0Hz,1H),3.90(dt,J＝6.0,5.0Hz,1H),3.45–3.35(m,1H),3.11–3.01(m,5H),2.93–2.84(m,1H),2.87–2.72(m,2H),1.30(s,1H),1.30(d,J＝14.5Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ152.49,135.13,134.45,131.74,130.75,130.41,129.75,127.65,127.03,124.68,123.64,115.60,54.40,43.21,37.00,28.81,20.85,14.56.MS(CI)calcd for C 18 H 19 Cl 2 NO[M+H] + :336.26.
Example 15: synthesis of Compound S15 (1, 11-dichloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-3-chloroacetic acid 2d and 3-benzyloxy-4-chlorophenylethylamine 1a are used as raw materials, and are synthesized according to the steps. 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),10.33(s,1H),9.63(s,1H),7.44–7.22(m,3H),6.88(d,J＝2.6Hz,1H),3.98(d,J＝12.8Hz,1H),3.47(s,1H),3.19–2.96(m,3H),2.78(q,J＝13.6,13.1Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ152.60,135.13,134.81,132.02,131.19,130.54,129.78,129.01,127.95,125.43,117.76,115.40,54.36,43.21,37.00,28.84.MS(CI)calcd for C 16 H 14 Cl 3 NO 2 [M+H] + :341.64.
Example 16: synthesis of Compound S16 (1-methoxy-11-propoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-3-propoxyphenylacetic acid 2j and 3-benzyloxy-4-methoxyphenylethylamine 1a are used as raw materials, and synthesized according to the above steps. 1 H NMR(400MHz,DMSO-d6)δ7.25–7.14(m,1H),6.86(dd,J＝7.9,1.5Hz,1H),6.50(t,J＝1.0Hz,1H),4.02(t,J＝5.4Hz,2H),3.86(dt,J＝6.2,4.9Hz,1H),3.84(s,2H),3.45–3.36(m,1H),3.13–3.02(m,4H),2.98(ddd,J＝12.5,5.0,0.9Hz,1H),2.93–2.84(m,1H),1.82(qt,J＝7.8,5.3Hz,2H),1.08(t,J＝7.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ154.88,147.79,144.76,135.49,130.06,129.94,127.37,124.10,121.21,120.55,115.74,111.24,71.37,60.28,54.39,43.21,37.36,28.85,22.69,10.64.MS(CI)calcd for C 20 H 24 Cl 2 NO 3 [M+H] + :361.14.
Example 17: synthesis of Compound S17 (1-chloro-11-propoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-3-propoxyphenylacetic acid 2j and 3-benzyloxy-4-chlorophenylethylamine 1d are used asThe raw materials are synthesized according to the steps. 1 H NMR(400MHz,DMSO-d6)δ7.24(t,J＝8.1Hz,1H),7.19(dq,J＝8.0,1.0Hz,1H),6.86(dd,J＝8.0,1.4Hz,1H),6.73(s,1H),6.50(t,J＝1.0Hz,1H),4.02(t,J＝5.4Hz,2H),3.90(dt,J＝6.2,5.1Hz,1H),3.45–3.35(m,1H),3.11–3.02(m,4H),2.98(ddd,J＝12.5,5.0,0.9Hz,1H),2.93–2.85(m,1H),1.82(qt,J＝7.8,5.3Hz,2H),1.08(t,J＝7.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ154.76,152.16,135.89,134.21,132.39,129.84,128.88,121.59,121.43,116.79,115.73,111.41,71.37,54.63,43.21,37.37,28.84,22.70,10.64.MS(CI)calcd for C 19 H 21 Cl 2 NO 2 [M+H] + :366.28.
Example 18: synthesis of Compound S18 (1-methyl-11-propoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-3-propoxyphenylacetic acid 2j and 3-benzyloxy-4-methylphenylethylamine 1b are used as raw materials, and synthesized according to the above steps. 1 H NMR(400MHz,DMSO-d6)δ7.22(t,J＝8.0Hz,1H),7.17(dq,J＝8.1,1.1Hz,1H),6.86(dd,J＝8.0,1.4Hz,1H),6.74(s,1H),6.46(t,J＝1.0Hz,1H),4.02(t,J＝5.4Hz,2H),3.89(dt,J＝6.2,5.0Hz,1H),3.45–3.35(m,1H),3.11–3.02(m,4H),2.97(ddd,J＝12.3,4.9,1.0Hz,1H),2.94–2.85(m,1H),1.82(qt,J＝7.8,5.3Hz,2H),1.08(t,J＝7.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ154.87,154.28,136.72,133.48,132.63,130.08,127.53,122.07,120.80,119.74,114.48,110.41,71.37,54.83,43.21,37.21,28.81,22.70,12.51,10.64.MS(CI)calcd for C 20 H 24 ClNO 2 [M+H] + :345.87.
Example 19: synthesis of Compound S19 (1-ethyl-11-propoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-3-propoxyphenylacetic acid 2j and 3-benzyloxy-4-ethylphenylethylamine 1c were used as raw materials, and synthesized according to the above steps. 1 H NMR(400MHz,DMSO-d6)δ7.25(t,J＝8.1Hz,1H),7.18(dq,J＝8.1,1.1Hz,1H),6.91(s,1H),6.87(dd,J＝8.1,1.3Hz,1H),6.45(t,J＝0.9Hz,1H),4.02(t,J＝5.4Hz,2H),3.90(dt,J＝6.2,5.1Hz,1H),3.45–3.35(m,1H),3.11–3.02(m,4H),2.97(ddd,J＝12.3,4.9,1.0Hz,1H),2.93–2.84(m,1H),2.86–2.71(m,2H),1.82(qt,J＝7.8,5.3Hz,2H),1.30(t,J＝7.2Hz,3H),1.08(t,J＝7.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ155.03,152.25,136.22,133.71,132.86,130.04,127.81,123.47,121.36,120.72,115.90,110.34,71.37,54.66,43.21,37.36,28.81,22.70,20.81,14.56,10.64.MS(CI)calcd for C 21 H 26 ClNO 2 [M+H] + :359.89.
Example 20: synthesis of Compound S20 (1-methoxy-11-cyclopropylmethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-3-cyclopropylmethoxy phenylacetic acid 2k and 3-benzyloxy-4-methoxyphenylethylamine 1a are used as raw materials, and synthesized according to the above steps. 1 H NMR(400MHz,DMSO-d6)δ7.25–7.14(m,1H),6.82(dd,J＝7.9,1.5Hz,1H),6.50(t,J＝1.0Hz,1H),4.03(d,J＝4.6Hz,2H),3.86(dt,J＝6.2,4.9Hz,1H),3.84(s,2H),3.45–3.36(m,1H),3.13–3.02(m,4H),2.98(ddd,J＝12.5,5.0,0.9Hz,1H),2.93–2.84(m,1H),1.36(dddd,J＝12.4,6.1,4.5,1.7Hz,1H),0.63–0.46(m,4H). 13 C NMR(125MHz,Common NMR Solvents)δ155.33,147.79,144.76,135.68,130.07,129.94,127.37,124.10,121.22,120.38,115.74,111.44,74.01,60.28,54.39,43.21,37.36,28.85,11.84,4.02.MS(CI)calcd for C 21 H 24 ClNO 3 [M+H] + :373.14.
Example 21: synthesis of Compound S21 (1-methoxy-11-cyclobutylmethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2l of 2-bromo-3-cyclobutanemethoxy phenylacetic acid and 3-benzyloxy-4-methoxyphenylethylamine 1a are used as raw materials, and the synthesis is carried out according to the steps. 1 H NMR(400MHz,DMSO-d6)δ7.25–7.14(m,1H),6.82(dd,J＝7.9,1.5Hz,1H),6.50(t,J＝1.0Hz,1H),4.04(d,J＝4.5Hz,2H),3.86(dt,J＝6.2,4.9Hz,1H),3.84(s,2H),3.45–3.36(m,1H),3.13–3.02(m,4H),2.98(ddd,J＝12.5,5.0,0.9Hz,1H),2.93–2.84(m,1H),2.09–1.99(m,1H),1.84–1.78(m,1H),1.81–1.63(m,4H). 13 C NMR(101MHz,DMSO-d6)δ155.47,147.79,144.76,135.68,130.07,129.94,127.37,124.10,121.22,120.38,115.74,111.44,71.88,60.28,54.39,43.21,37.36,35.12,28.85,27.51,19.88.MS(CI)calcd for C 22 H 26 ClNO 3 [M+H] + :387.90.
Example 22: synthesis of Compound S22 (1, 11-dimethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
2-bromo-3-methoxyphenylacetic acid 2m and 3-benzyloxy-4-methoxyphenylethylamine 1a are used as raw materials, and synthesized according to the above steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.22(s,1H),9.48(s,1H),9.30(s,1H),7.28(t,J＝7.8Hz,1H),7.04(d,J＝8.3Hz,1H),6.96(d,J＝7.3Hz,1H),6.71(s,1H),4.00(s,1H),3.80(s,3H),3.59(s,3H),3.51(s,1H),3.20(s,1H),3.11(d,J＝12.7Hz,1H),3.00(d,J＝13.8Hz,1H),2.83(s,1H),2.78–2.65(m,1H). 13 C NMR(101MHz,DMSO-d 6 )δ155.28,147.79,144.76,136.45,129.94,128.90,127.37,124.26,121.39,121.04,115.74,109.10,60.28,56.11,54.39,43.21,37.36,28.85.MS(CI)calcd for C 18 H 20 ClNO 3 [M+H] + :333.81.
Example 23: synthesis of Compound S23 (1-chloro-11-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
2m of 2-bromo-3-methoxy phenylacetic acid and 3-benzyloxy-4-chlorophenyl ethylamine 1d are used as raw materials, and the synthesis is carried out according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ7.23(t,J＝8.0Hz,1H),7.19(ddt,J＝8.1,1.7,0.9Hz,1H),6.89(dd,J＝7.9,1.5Hz,1H),6.73(s,1H),6.50(t,J＝0.9Hz,1H),3.90(s,3H),3.93–3.87(m,1H),3.45–3.35(m,1H),3.11–3.02(m,4H),2.98(ddd,J＝12.5,5.0,0.9Hz,1H),2.94–2.85(m,1H). 13 C NMR(101MHz,DMSO-d6s)δ155.06,152.16,135.98,134.21,132.40,128.91,128.88,121.39,121.03,116.79,115.73,109.20,56.11,54.63,43.21,37.37,28.84.MS(CI)calcd for C 17 H 17 Cl 2 NO 2 [M+H] + :338.23.
The synthesis of compounds S24-S34 is shown below:
synthesis of intermediates 10a-g, as well as synthesis of intermediates 3a-i.
Synthesis of intermediates 11a-g, as well as synthesis of intermediates 7a-c.
Synthesis of intermediates 12a-g, as well as synthesis of intermediates 5a-i.
Synthesis of intermediates 13 a-g: intermediate 12a-f (1 eq) was dissolved in DCM, placed at-78℃under nitrogen protection, and after dropwise addition of boron tribromide in dichloromethane (3 eq), the reaction was carried out at-78℃for 0.5h and then at normal temperature for 1h. After quenching with water, extraction with ethyl acetate, washing with salt, drying, filtering and crystallizing. Intermediate 13a-f was obtained.
Synthesis of intermediates 14 a-g: to a solution of 13a-d (1.0 eq) in dichloromethane (0.2M) at 0℃was added trifluoromethanesulfonic anhydride (1.2 eq) and triethylamine (2.5 eq). The reaction mixture was stirred for 30 minutes and then quenched with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography to obtain the product. Triethylamine (8.0 eq) and anhydrous N, N-dimethylformamide (0.2M) were added to a round bottom flask, and 98% formic acid (8.0 eq) was added dropwise. The above product (1.0 eq) was then added followed by palladium acetate (0.04 eq) and 1,1' -bis (diphenylphosphine) ferrocene (0.08 eq) in sequence, and the mixture was heated to 60 ℃. After 15 minutes, the mixture was cooled to room temperature, diluted with water and extracted with dichloromethane). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography gave white products 14a-d.
Example 24: synthesis of Compound S24 (8-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-6-chloroacetic acid 2a is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ9.84(s,1H),9.68(d,J＝7.0Hz,1H),9.25(s,1H),7.77(s,1H),7.46(d,J＝21.6Hz,2H),7.16(s,1H),6.69(s,1H),4.48(s,1H),3.65(s,2H),3.29(s,1H),3.13(s,1H),2.97(s,1H),2.77(d,J＝9.6Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ158.01,135.72,133.65,133.07,130.81,129.40(d,J＝42.8Hz),129.17,123.53,119.07,115.61,110.70,51.38,40.95,29.18,25.27.MS(CI)calcd for C 16 H 15 Cl 2 NO[M+H] + :308.20.
Example 25: synthesis of Compound S25 (9-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-5-chloroacetic acid 2b is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ9.81(s,1H),9.44(d,J＝30.2Hz,1H),7.75(s,1H),7.52(s,1H),7.43(s,1H),7.13(s,1H),6.65(s,1H),4.41(d,J＝13.2Hz,1H),3.59(s,1H),3.28(s,1H),3.15(d,J＝14.2Hz,2H),2.93(t,J＝15.0Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ157.99,135.42,133.44,133.21,132.89,132.36,128.81,128.32,126.21,119.23,115.31,110.22,51.53,40.93,32.33,25.33.MS(CI)calcd for C 16 H 15 Cl 2 NO[M+H] + :308.20.
Example 26: synthesis of Compound S26 (10-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-4-chloroacetic acid 2c is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),9.77(d,J＝20.2Hz,1H),9.44(s,1H),7.77(s,1H),7.39(dd,J＝23.3,7.9Hz,2H),7.18(s,1H),6.68(s,1H),4.39(d,J＝12.1Hz,1H),3.68–3.48(m,1H),3.25(d,J＝12.0Hz,1H),3.16(d,J＝13.5Hz,2H),2.92(t,J＝13.9Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ158.02,135.43,133.22,133.01,132.02,130.94,128.29,124.08,119.43,115.66,110.53,51.58,40.85,32.04,25.31.MS(CI)calcd for C 16 H 15 Cl 2 NO[M+H] + :308.20.
Example 27: synthesis of Compound S27 (11-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-3-chloroacetic acid 2d is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.22(s,1H),9.78(s,1H),9.50(d,J＝7.0Hz,1H),7.63(s,1H),7.50(d,J＝7.8Hz,1H),7.40(d,J＝7.1Hz,1H),7.30(t,J＝7.6Hz,1H),6.69(s,1H),4.25(s,1H),3.56(s,1H),3.25–3.10(m,3H),2.89(t,J＝13.8Hz,2H). 13 CNMR(151MHz,DMSO-d 6 )δ156.72,137.27,132.34,131.82,131.33,131.11,130.65,129.40,128.10,121.38-121.28(m),115.19,114.82,51.45,40.45,34.21,25.27.MS(CI)calcd for C 16 H 15 Cl 2 NO[M+H] + :308.20.
Example 28: synthesis of Compound S28 (11-fluoro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-3-fluorophenylacetic acid 2j is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.18(s,1H),9.76(s,1H),9.52(s,1H),7.34(s,2H),7.29–7.18(m,2H),6.67(s,1H),4.35(d,J＝12.1Hz,1H),3.58(d,J＝7.2Hz,1H),3.22(t,J＝18.6Hz,3H),2.94(dd,J＝26.2,13.8Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ160.66,159.01,157.38,136.39,132.79,130.16,129.88(d,J＝9.4Hz),125.17,121.24(d,J＝10.0Hz),120.12,116.22,116.06,115.23,114.06(d,J＝15.2Hz),51.56,40.66,33.10,25.43.MS(CI)calcd for C 16 H 15 ClFNO[M+H] + :291.75.
Example 29: synthesis of Compound S29 (11-methyl-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-3-methylphenylacetic acid 2k is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ9.99(s,1H),9.67(s,1H),9.27(d,J＝9.6Hz,1H),7.25(d,J＝6.8Hz,1H),7.21(q,J＝7.0Hz,2H),7.11(d,J＝1.9Hz,1H),6.63(d,J＝1.6Hz,1H),4.19(s,1H),3.57(d,J＝9.7Hz,1H),3.27–3.20(m,1H),3.14(dd,J＝12.5,5.4Hz,1H),3.05(dd,J＝13.8,4.1Hz,1H),2.86(dd,J＝30.0,15.9Hz,2H),2.54(s,3H).MS(CI)calcd for C 17 H 18 ClNO[M+H] + :287.79.
Example 30: synthesis of Compound S30 (11-ethyl-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2l of 2-bromo-3-ethyl phenylacetic acid is used as a raw material, and the synthesis is carried out according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ7.33(dq,J＝8.1,1.0Hz,1H),7.23(d,J＝15.9Hz,0H),7.16(dq,J＝7.8,1.0Hz,1H),7.08(s,1H),7.02(d,J＝2.2Hz,1H),6.51(dt,J＝2.1,1.0Hz,1H),3.91(dt,J＝6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–2.97(m,4H),2.93–2.85(m,1H),2.81(dt,J＝6.2,3.8Hz,1H),2.76(qd,J＝7.3,1.0Hz,2H),1.22(t,J＝7.3Hz,3H). 13 C NMR(151MHz,DMSO-d 6 )δ155.86,140.14,134.97,134.90,134.70,132.28,128.26,128.25,127.81,125.10,115.69,110.96,55.07,43.17,37.37,29.09,27.66,15.45.MS(CI)calcd for C1 8 H 20 ClNO[M+H] + :301.1233.
Example 31: synthesis of Compound S31 (8-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-6-chloroacetic acid 2a is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ9.91(s,2H),7.90(d,J＝7.2Hz,1H),7.80(d,J＝7.3Hz,1H),7.49(d,J＝7.6Hz,1H),7.44(d,J＝6.7Hz,2H),7.29(d,J＝7.2Hz,1H),4.57(d,J＝11.6Hz,1H),3.63(d,J＝16.4Hz,2H),3.27(d,J＝12.7Hz,2H),3.08–2.82(m,2H). 13 C NMR(151MHz,DMSO-d 6 )δ135.66,133.04,132.39,131.82,130.59,129.57,129.34,129.02,128.39,123.75,123.65(d,J＝29.4Hz),51.49,40.80,28.78,25.13.MS(CI)calcd for C 16 H 15 Cl 2 NO[M+H] + :292.20.
Example 32: synthesis of Compound S32 (9-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-5-chloroacetic acid 2b is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.22(s,1H),9.74(s,1H),7.89(s,1H),7.77(s,1H),7.54(s,1H),7.43(s,2H),7.26(s,1H),4.53(s,1H),3.62(s,2H),3.25–3.12(m,2H),3.03(d,J＝14.1Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ135.20,133.06,132.23,131.98,128.93(d,J＝28.8Hz),128.33,126.47,123.03,51.61,40.78,31.89,25.20.MS(CI)calcd for C 16 H 15 Cl 2 NO[M+H] + :292.20.
Example 33: synthesis of Compound S33 (10-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-4-chloroacetic acid 2c is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.22(s,1H),9.69(s,1H),7.94(s,1H),7.84(d,J＝7.6Hz,1H),7.48–7.34(m,3H),7.28(d,J＝7.5Hz,1H),4.52(s,1H),3.63(s,1H),3.28(s,1H),3.22(d,J＝14.8Hz,2H),3.00(dd,J＝18.7,9.1Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ135.35,133.14,131.94,131.72,130.91,129.45,128.99,128.75,128.40,124.34,123.42,51.70,40.70,31.59,25.17.MS(CI)calcd for C 16 H 15 Cl 2 NO[M+H] + :292.20.
Example 34: synthesis of Compound S34 (11-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline hydrochloride)
2-bromo-3-chloroacetic acid 2d is used as a raw material and synthesized according to the steps. 1 H NMR(400MHz,DMSO-d 6 )δ10.25(s,1H),9.58(s,1H),8.13(d,J＝7.7Hz,1H),7.52(d,J＝7.8Hz,1H),7.43(d,J＝6.3Hz,2H),7.32(dd,J＝12.6,7.5Hz,2H),4.40(d,J＝10.8Hz,1H),3.62(s,1H),3.28(s,2H),3.19(d,J＝16.7Hz,1H),2.96(dd,J＝31.0,16.3Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ137.02,131.29,131.13,130.91,130.72,129.57,129.19,128.06,127.68,127.00,51.67,40.37,33.73,25.12.MS(CI)calcd for C 16 H 15 Cl 2 NO[M+H] + :292.20.
The synthetic routes for compounds S35-S49 are shown below:
synthesis of intermediate 14, and synthesis of intermediates 3a-i.
Synthesis of intermediate 15, as well as synthesis of intermediates 7a-c.
Synthesis of intermediate 16, as well as synthesis of intermediates 5a-i.
Synthesis of intermediate 17, as well as synthesis of intermediates 9a-c.
Synthesis of intermediate 18: triethylamine (1.5 eq) was added to a solution of debenzylated intermediate 17 (1 eq) in DCM (0.2M) at room temperature. The mixture was cooled to 0 ℃, and 4-dimethylaminopyridine (0.2 eq) and 4-tosyl chloride (1.2 eq) were added dropwise to the mixture, gradually warmed to room temperature and stirred for 1h. The mixture was diluted with dichloromethane, and then the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated by evaporation. Column chromatography gave white solid 18.
Synthesis of intermediate 19 is identical to synthesis of intermediates 13a-f.
Synthesis of intermediates 20 a-n: intermediate 19 (1.0 eq) and the corresponding haloalkane were placed in acetone, potassium carbonate (2.0 eq) and potassium iodide (2.0 eq) were added, the mixture was refluxed and the reaction monitored by TLC. The solvent was concentrated and column chromatographed to give white solids 20a-n.
Example 35: synthesis of Compound S35 (11-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Synthesis of the same compounds S1-S9, 1 H NMR(300MHz,DMSO-d 6 )δ9.96(s,1H),9.51(s,1H),9.26(s,1H),7.67(s,1H),7.27(t,J＝7.8Hz,1H),7.08(d,J＝8.4Hz,1H),6.97(d,J＝7.5Hz,1H),6.57(s,1H),4.25(s,1H),3.87(s,3H),3.56(s,1H),3.18(s,1H),3.15-2.99(m,2H),2.85(t,J＝14.3Hz,2H).MS(CI)calcd for C 17 H 18 ClNO 2 [M+H] + :303.79.
example 36: synthesis of Compound S36 (11-propoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
With 10mL of potassium hydroxide (0.5M MeOH/H) 2 O) solution was added to intermediate 20a (1 eq), refluxed at 80℃for 5h and cooled to room temperature. The solvent was concentrated, a saturated sodium chloride solution was added to the mixture, and extraction was performed with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The product eluted by column chromatography was unstable at room temperature and was salted three times with ethyl acetate solution of hydrogen chloride to give S36 as a white solid. 1 HNMR(300MHz,DMSO-d 6 )δ10.24(s,1H),9.50(s,2H),7.73(s,1H),7.24(t,J＝7.8Hz,1H),7.05(d,J＝8.2Hz,1H),6.94(d,J＝7.2Hz,1H),6.59(s,1H),4.20(d,J＝16.2Hz,1H),4.16-4.07(m,1H),3.88(dd,J＝15.1,6.7Hz,1H),3.53(s,1H),3.19(d,J＝9.9Hz,2H),3.08(dd,J＝14.1,3.7Hz,1H),2.88(t,J＝13.3Hz,2H),1.82(dd,J＝11.8,5.7Hz,2H),1.01(t,J＝7.2Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ156.91,156.47,135.57,132.66,131.61,129.29,122.09,121.21,120.29,115.31,113.95,112.79,70.33,51.86,33.99,25.50,22.59,11.23.MS(CI)calcd for C 19 H 22 ClNO 2 [M+H] + :331.84.
Example 37: synthesis of Compound S37 (11-cyclopropylmethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Synthesis of assimilation compound S36 from intermediate 20 b. 1 H NMR(300MHz,DMSO-d 6 )δ10.57(s,1H),9.90-9.49(m,2H),7.78(s,1H),7.21(t,J＝7.7Hz,1H),7.01(d,J＝8.2Hz,1H),6.92(d,J＝7.2Hz,1H),6.60(s,1H),4.17(s,1H),4.06-3.95(m,1H),3.84–3.75(m,1H),3.48-3.37(m,1H),3.12(dd,J＝18.2,14.2Hz,3H),2.88(dd,J＝28.3,13.9Hz,2H),1.31(s,1H),0.56(d,J＝7.6Hz,2H),0.35(d,J＝4.0Hz,2H).MS(CI)calcd for C 20 H 22 ClNO 2 [M+H] + :343.85.
Example 38: synthesis of Compound S38 (11-allyl-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Synthesis of assimilation compound S36 from intermediate 20 c. 1 H NMR(300MHz,DMSO-d 6 )δ10.25(s,1H),9.58(d,J＝23.2Hz,2H),7.71(s,1H),7.24(t,J＝7.8Hz,1H),7.06(d,J＝8.3Hz,1H),6.96(d,J＝7.2Hz,1H),6.59(s,1H),6.19–6.03(m,1H),5.43(d,J＝17.4Hz,1H),5.27(d,J＝10.6Hz,1H),4.75(d,J＝9.6Hz,1H),4.65–4.51(m,1H),4.22(d,J＝11.1Hz,1H),3.54(d,J＝5.2Hz,1H),3.14(dd,J＝30.2,11.0Hz,3H),2.87(t,J＝13.1Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ156.90,155.93,135.69,134.05,132.53,131.70,129.24,122.31,121.51,120.37,117.61,115.34,114.04,113.26,69.50,51.83,33.98,25.49.MS(CI)calcd for C 19 H 20 ClNO 2 [M+H] + :329.82.
Example 39: synthesis of Compound S39 (11-propargyl-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol)
Synthesis of assimilation compound S36 starting from intermediate 20 d. 1 H NMR(300MHz,DMSO-d 6 )δ10.03(s,1H),9.54(s,1H),9.34(s,1H),7.65(s,1H),7.28(t,J＝7.9Hz,1H),7.15(d,J＝8.1Hz,1H),7.01(d,J＝7.1Hz,1H),6.59(s,1H),4.91(s,2H),4.25(d,J＝11.5Hz,1H),3.58(d,J＝18.2Hz,2H),3.12(dd,J＝26.1,12.8Hz,3H),2.86(t,J＝13.3Hz,2H).MS(CI)calcd for C 19 H 18 ClNO 2 [M+H] + :327.81.
Example 40: synthesis of Compound S40 (11- (2-fluoroethoxy) -5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
Synthesis of assimilation compound S36 from intermediate 20 e. 1 H NMR(400MHz,DMSO-d 6 )δ10.32(d,J＝8.4Hz,1H),9.55(s,2H),7.73(t,J＝8.6Hz,1H),7.29-7.22(m,1H),7.07(d,J＝8.3Hz,1H),6.99(d,J＝7.4Hz,1H),6.60(t,J＝4.5Hz,1H),4.99-4.68(m,2H),4.47-4.33(m,1H),4.27(dd,J＝16.8,8.4,Hz,1H),4.21(dd,J＝8.0,4.2Hz,1H),3.54(d,J＝6.2Hz,1H),3.25-3.15(m,2H),3.14-3.05(m,1H),2.89(dd,J＝16.2,12.5Hz,2H).MS(CI)calcd for C 18 H 19 ClNO 2 [M+H] + :335.80.
Example 41: synthesis of Compound S41 (11- (2, 2-difluoroethoxy) -5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Synthesis of assimilation compound S36 from intermediate 20 f. 1 H NMR(300MHz,DMSO-d 6 )δ10.32(s,1H),9.56(s,2H),7.66(s,1H),7.27(t,J＝7.7Hz,1H),7.11(d,J＝8.2Hz,1H),7.03(d,J＝7.2Hz,1H),6.71(s,1H),6.60(s,1H),6.52(s,1H),6.34(s,1H),4.48(dd,J＝26.4,12.7Hz,1H),4.29(dd,J＝26.8,12.7Hz,2H),3.47–3.35(m,1H),3.14(dd,J＝22.4,10.0Hz,3H),2.89(t,J＝13.9Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ157.05,155.21,132.13,131.77,129.31,122.41,120.35,115.31,114.23,113.16,67.52,51.75,33.87,25.47.MS(CI)calcd for C 18 H 18 ClNO 2 [M+H] + :353.79.
Example 42: synthesis of Compound S42 (11- ((2-methallyloxy) -5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Synthesis of Compound S36 from intermediate 20 g. 1 H NMR(300MHz,DMSO-d 6 )δ9.79(s,1H),9.50(s,1H),9.17(s,1H),7.69(s,1H),7.29–7.21(m,1H),7.06(d,J＝8.2Hz,1H),6.98(d,J＝7.3Hz,1H),6.59(s,1H),5.04(d,J＝34.9Hz,2H),4.66(d,J＝13.2Hz,1H),4.47(d,J＝13.0Hz,1H),4.25(s,1H),3.57(s,1H),3.19(s,1H),3.17–2.99(m,2H),2.88(d,J＝21.1Hz,2H),1.80(s,3H).MS(CI)calcd for C 20 H 22 ClNO 2 [M+H] + :343.85.
Example 43: synthesis of Compound S43 (11-Cyclobutylmethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
The intermediate 20h is used as a raw material for synthesizing an assimilation compound S36. 1 H NMR(300MHz,DMSO-d 6 )δ7.24(t,J＝8.0Hz,1H),7.21–7.16(m,1H),7.02–6.96(m,2H),6.86(dd,J＝8.0,1.4Hz,1H),6.46(dt,J＝2.1,1.0Hz,1H),4.04(d,J＝4.6Hz,2H),3.90(dt,J＝6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–3.01(m,3H),2.97–2.84(m,2H),2.81(dt,J＝6.4,3.8Hz,1H),2.09–1.99(m,1H),1.85–1.64(m,6H).MS(CI)calcd for C 21 H 24 ClNO 2 [M+H] + :357.14.
Example 44: synthesis of Compound S44 (11- (2-chloroethyl) oxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Synthesis of assimilation compound S36 from intermediate 20 i. 1 H NMR(300MHz,DMSO-d 6 )δ7.24(t,J＝8.0Hz,1H),7.21–7.16(m,1H),7.02–6.96(m,2H),6.89(dd,J＝8.0,1.4Hz,1H),6.46(dt,J＝2.1,1.0Hz,1H),4.32(q,J＝2.2Hz,2H),3.90(dt,J＝6.2,5.0Hz,1H),3.82(t,J＝2.3Hz,2H),3.44–3.35(m,1H),3.10–3.01(m,3H),2.97–2.85(m,2H),2.81(dt,J＝6.4,3.8Hz,1H).MS(CI)calcd for C 18 H 19 Cl 2 NO 2 [M+H] + :351.07.
Example 45: synthesis of Compound S45 (11-trifluoroethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
Synthesis of assimilation compound S36 from intermediate 20 j. 1 H NMR(300MHz,DMSO-d 6 )δ7.24(t,J＝8.1Hz,1H),7.21–7.16(m,1H),7.02–6.96(m,2H),6.94(dd,J＝8.0,1.4Hz,1H),6.46(dt,J＝2.1,1.0Hz,1H),4.68(qd,J＝9.0,3.1Hz,2H),3.90(dt,J＝6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–3.01(m,3H),2.97–2.84(m,2H),2.81(dt,J＝6.4,3.8Hz,1H).MS(CI)calcd for C 18 H 17 ClF 3 NO 2 [M+H] + :371.09.
Example 46: synthesis of Compound S46 (11-benzyloxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline-2-ol hydrochloride)
Using intermediate 20k as raw material, assimilating compound S36. 1 H NMR(300MHz,DMSO-d 6 )δ7.42(dq,J＝7.1,1.1Hz,2H),7.39–7.32(m,2H),7.35–7.26(m,1H),7.24(t,J＝8.0Hz,1H),7.21–7.16(m,1H),7.02–6.96(m,2H),6.92(dd,J＝8.0,1.4Hz,1H),6.46(dt,J＝2.1,1.0Hz,1H),5.19(t,J＝1.2Hz,2H),3.90(dt,J＝6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–3.01(m,3H),2.97–2.85(m,2H),2.81(dt,J＝6.4,3.8Hz,1H).MS(CI)calcd for C 23 H 22 ClNO 2 [M+H] + :379.13.
Example 47: synthesis of Compound S47 (11-p-methylbenzyloxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinoline-2-ol hydrochloride)
Synthesis of Compound S36 from intermediate 20 l. 1 H NMR(300MHz,DMSO-d 6 )δ7.30(dt,J＝7.9,1.1Hz,2H),7.24(t,J＝8.0Hz,1H),7.21–7.16(m,1H),7.19–7.13(m,2H),7.02–6.96(m,2H),6.92(dd,J＝8.0,1.4Hz,1H),6.46(dt,J＝2.1,1.0Hz,1H),5.15(q,J＝1.1Hz,2H),3.90(dt,J＝6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–3.01(m,3H),2.97–2.85(m,2H),2.81(dt,J＝6.4,3.8Hz,1H).MS(CI)calcd for C 24 H 24 ClNO 2 [M+H] + :393.1.
Example 48: synthesis of Compound S48 (11-cyclohexylmethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
Synthesis of assimilation Compound S36 Using intermediate 20m as a starting material. 1 H NMR(300MHz,DMSO-d 6 )δ7.24(t,J＝8.0Hz,1H),7.21–7.16(m,1H),7.02–6.96(m,2H),6.86(dd,J＝8.0,1.4Hz,1H),6.46(dt,J＝2.1,1.0Hz,1H),4.06(dd,J＝11.4,4.9Hz,1H),4.00(dd,J＝11.4,5.1Hz,1H),3.90(dt,J＝6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–3.01(m,3H),2.97–2.84(m,2H),2.81(dt,J＝6.4,3.8Hz,1H),1.92(tt,J＝6.4,5.1Hz,1H),1.69–1.36(m,11H).MS(CI)calcd for C 23 H 28 ClNO 2 [M+H] + :385.18.
Example 49: synthesis of Compound S49 (11- (4' -chlorobenzyl) oxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Synthesis of assimilation compound S36 from intermediate 20 n. 1 H NMR(300MHz,DMSO-d 6 )δ7.48–7.38(m,4H),7.25–7.16(m,2H),7.02–6.96(m,2H),6.92(dd,J＝8.0,1.4Hz,1H),6.46(dt,J＝2.1,1.0Hz,1H),5.15(q,J＝0.9Hz,2H),3.90(dt,J＝6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–3.01(m,3H),2.97–2.85(m,2H),2.81(dt,J＝6.4,3.8Hz,1H).MS(CI)calcd for C 23 H 21 Cl 2 NO 2 [M+H] + :413.09.
Example 50: synthesis of Compound S50 (1, 11-dimethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
Referring to the synthesis method of S11, compound S50 is synthesized. 1 H NMR(300MHz,DMSO-d 6 )δ9.79(s,1H),9.50(s,1H),9.17(s,1H),7.27(s,1H),6.97(s,1H),6.90(s,1H),6.82(s,1H),4.64(s,1H),4.05(s,1H),3.89(s,3H),3.76(s,3H),3.33(s,1H),3.22(d,J＝4.0Hz,2H),2.91(s,1H),2.75(d,J＝19.9Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ156.27,151.22,146.82,137.07,132.08,130.97,129.51,127.67,120.48,119.09,115.33,112.20,60.70,56.83,54.17,43.55,35.58,29.18.MS(CI)calcd for C 18 H 19 ClNO 3 [M+H] + :297.35.
Example 51: synthesis of Compound S51 (1-methoxy-11-propoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Referring to the synthesis method of S11, compound S51 is synthesized. 1 H NMR(300MHz,DMSO-d 6 )δ10.39(s,1H),9.49(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),4.58(s,1H),4.03(s,1H),3.99(s,2H),3.92(s,3H),3.35(s,1H),3.25(d,J＝1.8Hz,2H),2.96(s,1H),2.77(d,J＝20.0Hz,2H),1.74(s,2H),0.99(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ156.46,151.22,146.83,135.73,132.08,130.97,128.98,127.66,122.15,121.14,115.33,114.04,72.25,60.70,54.17,43.55,35.58,29.18,21.58,10.60.MS(CI)calcd for C 20 H 24 ClNO 3 [M+H] + :361.87.
Example 52: synthesis of Compound S52 (11- (cyclopropylmethoxy) -1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Reference to the synthesis method of S11, synthesisCompound S52. 1 H NMR(300MHz,DMSO-d 6 )δ10.39(s,1H),9.49(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),5.99(s,1H),4.05(s,1H),3.94–3.90(m,5H),3.35(s,1H),3.25(s,1H),3.24(s,1H),2.96(s,1H),2.79(s,1H),2.75(s,1H),1.11(t,J＝9.9Hz,1H),0.51(dd,J＝3.7,2.7Hz,1H),0.49(d,J＝1.3Hz,1H),0.26–0.20(m,1H),0.20–0.15(m,1H). 13 C NMR(101MHz,DMSO-d 6 )δ155.99,151.22,146.82,136.57,132.08,130.97,129.09,127.67,122.43,121.00,115.33,114.20,74.00,60.70,54.17,43.55,35.58,29.18,10.70,7.85.MS(CI)calcd for C 21 H 24 ClNO 3 [M+H] + :373.88.
Example 53: synthesis of Compound S53 (11- (allyloxy) -1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Referring to the synthesis method of S11, compound S53 is synthesized. 1 H NMR(300MHz,DMSO-d 6 )δ10.39(s,1H),9.49(s,1H),9.17(s,1H),7.19(s,1H),6.95(s,1H),6.87(s,1H),6.84(s,1H),6.07(d,J＝7.0Hz,2H),5.43(s,1H),5.31(s,1H),4.69(t,J＝1.9Hz,1H),4.67(t,J＝1.9Hz,1H),4.04(s,1H),3.92(s,3H),3.35(s,1H),3.27(s,1H),3.25(s,1H),2.98(s,1H),2.79(s,1H),2.75(s,1H). 13 C NMR(101MHz,DMSO-d 6 )δ155.99,151.22,146.83,136.57,132.93,132.08,130.97,129.08,127.66,122.42,121.00,117.23,115.33,114.20,70.87,60.70,54.17,43.55,35.58,29.18.MS(CI)calcd for C 20 H 22 ClNO 3 [M+H] + :359.85.
Example 54: synthesis of Compound S54 (11- (2-fluoroethoxy) -1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Referring to the synthesis method of S11, compound S54 is synthesized. 1 H NMR(300MHz,DMSO-d 6 )δ10.40(s,1H),9.22(s,1H),9.10(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),6.03(s,1H),5.10(t,J＝5.1Hz,1H),4.91(t,J＝5.2Hz,1H),4.20(t,J＝5.1Hz,1H),4.10(t,J＝5.2Hz,1H),4.04(s,1H),3.92(s,3H),3.35(s,1H),3.26(s,1H),3.25(s,1H),2.97(s,1H),2.79(s,1H),2.75(s,1H). 13 C NMR(101MHz,DMSO-d 6 )δ156.46,151.22,146.83,135.73,132.08,130.97,128.98,127.66,122.15,121.14,115.33,114.04,85.83,69.46,60.70,54.17,43.55,35.58,29.18.MS(CI)calcd for C 19 H 21 ClNO 3 [M+H] + :365.83.
Example 55: synthesis of Compound S55 (11- (2, 2-difluoroethoxy) -1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
Referring to the synthesis method of S11, compound S55 is synthesized. 1 H NMR(300MHz,DMSO-d 6 )δ10.47(s,1H),9.47(s,1H),9.21(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),6.14(s,1H),5.96(s,1H),4.40(s,2H),4.03(s,1H),3.92(s,3H),3.35(s,1H),3.25(s,1H),3.23(s,1H),2.95(s,1H),2.79(s,1H),2.75(s,1H). 13 CNMR(101MHz,DMSO-d 6 )δ155.99,151.22,146.83,136.57,132.08,130.97,129.08,127.66,122.42,121.00,115.33,114.20,68.23,60.70,54.17,43.55,35.58,29.18.MS(CI)calcd for C 19 H 20 ClF 2 NO 3 [M+H] + :383.82.
Example 56: synthesis of Compound S56 (1-methoxy-11- ((2-methallyl) oxy) -5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride
Referring to the synthesis method of S11, compound S56 is synthesized. 1 H NMR(300MHz,DMSO-d 6 )δ10.50(s,1H),9.44(s,1H),9.31(s,1H),7.19(s,1H),6.95(s,1H),6.87(s,1H),6.84(s,1H),6.00(s,1H),4.98(s,1H),4.82(s,1H),4.45(s,2H),4.05(s,1H),3.92(s,3H),3.35(s,1H),3.27(s,1H),3.25(s,1H),2.98(s,1H),2.79(s,1H),2.75(s,1H),1.66(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ155.54,151.22,146.83,140.25,137.40,132.08,130.97,129.14,127.66,122.76,120.96,115.33,114.39,113.66,72.94,60.70,54.17,43.55,35.58,29.18,19.21.MS(CI)calcd for C 21 H 24 ClNO 3 [M+H] + :373.88.
Example 57: synthesis of Compound S57 ((S) -11-chloro-1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride
Referring to the synthesis method of S11, compound S57 is synthesized. 1 H NMR(300MHz,DMSO-d 6 )δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.48(s,1H),7.42(s,1H),7.15(s,1H),6.87(s,1H),4.48(s,1H),4.04(s,1H),3.92(s,3H),3.35(s,1H),3.25(s,1H),3.11(s,1H),3.03(s,1H),2.79(s,1H),2.75(s,1H). 13 C NMR(101MHz,DMSO-d 6 )δ150.54,142.01,139.03,130.57,129.64,129.41,128.19,127.88,125.87,125.57,124.93,115.98,60.70,54.76,43.49,36.31,30.35.MS(CI)calcd for C 17 H 17 Cl 2 NO 2 [M+H] + :338.23.
Example 58: synthesis of Compound S58 ((R) -11-chloro-1-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride
Referring to the synthesis method of S11, compound S58 is synthesized. 1 H NMR(300MHz,DMSO-d 6 )δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.48(s,1H),7.42(s,1H),7.15(s,1H),6.87(s,1H),4.48(s,1H),4.04(s,1H),3.92(s,3H),3.35(s,1H),3.25(s,1H),3.11(s,1H),3.03(s,1H),2.79(s,1H),2.75(s,1H). 13 C NMR(101MHz,DMSO-d 6 )δ150.54,142.01,139.03,130.57,129.64,129.41,128.19,127.88,125.87,125.57,124.93,115.98,60.70,54.76,43.49,36.31,30.35.MS(CI)calcd for C 17 H 17 Cl 2 NO 2 [M+H] + :338.23.
Example 59: synthesis of Compound S59 ((S) -1, 11-dimethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride
Referring to the synthesis method of S11, compound S59 is synthesized. 1 H NMR(300MHz,DMSO-d 6 )δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),6.00(s,1H),4.04(s,1H),3.92(s,3H),3.79(s,3H),3.35(s,1H),3.25(s,1H),3.15(s,1H),3.07(s,1H),2.79(s,1H),2.75(s,1H). 13 C NMR(101MHz,DMSO-d 6 )δ156.50,151.51,146.82,137.13,131.39,130.11,129.62,127.39,120.55,119.38,115.30,112.27,60.70,56.83,54.76,43.49,37.44,30.35.MS(CI)calcd for C 18 H 20 ClNO 3 [M+H] + :333.81.
Example 60: synthesis of Compound S60 ((R) -1, 11-dimethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride
Referring to the synthesis method of S11, a compound is synthesizedS60. 1 H NMR(300MHz,DMSO-d 6 )δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),6.00(s,1H),4.04(s,1H),3.92(s,3H),3.79(s,3H),3.35(s,1H),3.25(s,1H),3.15(s,1H),3.07(s,1H),2.79(s,1H),2.75(s,1H). 13 C NMR(101MHz,DMSO-d 6 )δ156.50,151.51,146.82,137.13,131.39,130.11,129.62,127.39,120.55,119.38,115.30,112.27,60.70,56.83,54.76,43.49,37.44,30.35.MS(CI)calcd for C 18 H 20 ClNO 3 [M+H] + :333.81.
The synthetic routes for compounds S61-S66 are shown below:
example 61: synthesis of Compound S61 (1, 11-dichloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-5-chloroacetic acid and 3-benzyloxy-4-phenethylamine 1-5 are used as raw materials, and are synthesized according to the steps. 1 H NMR(300MHz,DMSO-d 6 )δ7.46(dd,J＝7.9,1.5Hz,1H),7.37(t,J＝8.0Hz,1H),7.33(dq,J＝8.2,1.1Hz,1H),6.76(s,1H),6.56–6.52(m,1H),3.91(dt,J＝6.2,5.0Hz,1H),3.45–3.36(m,1H),3.11–3.02(m,5H),2.93–2.85(m,1H).MS(CI)calcd for C 16 H 14 Cl 3 NO[M+H] + :342.64.
Example 62: synthesis of Compound S62 (1-methoxy-11-chloro-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
2-bromo-5-chloroacetic acid and 3-benzyloxy-4-methoxyphenylethylamine 1a are used as raw materials, and synthesized according to the above steps. 1H NMR (300 MHz, DMSO-d) 6 )δ7.44(d,J＝1.7Hz,1H),7.35(d,J＝7.6Hz,1H),7.21(s,1H),6.54(t,J＝1.0Hz,1H),3.83(s,3H),3.10–3.04(m,3H).MS(CI)calcd for C 17 H 17 Cl 2 NO 2 [M+H] + :337.06.MS(CI)calcd for C 17 H 17 Cl 2 NO 2 [M+H]+:338.23。
Example 63: synthesis of Compound S63 (1-methoxy-11-propoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-5-propoxyphenylacetic acid and 3-benzyloxy-4-methoxyphenylethylamine 1a are used as raw materials, and synthesized according to the above steps. 1 H NMR(300MHz,DMSO-d 6 )δ7.25–7.14(m,1H),6.86(dd,J＝7.9,1.5Hz,1H),6.50(t,J＝1.0Hz,1H),4.02(t,J＝5.4Hz,2H),3.86(dt,J＝6.2,4.9Hz,1H),3.84(s,2H),3.43–3.37(m,1H),3.13–3.02(m,4H),2.98(ddd,J＝12.5,5.0,0.9Hz,1H),2.93–2.86(m,1H),1.86–1.78(m,2H),1.08(t,J＝7.8Hz,3H)..MS(CI)calcd for C 20 H 24 ClNO 3 [M+H] + :361.87。
Example 64: synthesis of Compound S64 (1, 11-dimethoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
2-bromo-5-methoxyphenylacetic acid and 3-benzyloxy-4-methoxyphenylethylamine 1a are used as raw materials, and synthesized according to the above steps. 1 H NMR(300MHz,DMSO-d 6 )δ7.23–7.15(m,3H),6.88(dd,J＝7.8,1.6Hz,1H),6.50(t,J＝1.0Hz,1H),3.92–3.82(m,6H),3.12–3.02(m,4H),2.99(dd,J＝4.9,0.9Hz,1H)..MS(CI)calcd for C 18 H 20 ClNO 3 [M+H] + :333.81。
Example 65: synthesis of Compound S65 (1-chloro-11-methoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-yl hydrochloride)
2-bromo-5-methoxyphenylacetic acid and 3-benzyloxy-4-chlorophenylethylamine 1-5 are used as raw materials, and the synthesis is carried out according to the steps. 1H NMR (300 MHz, DMSO-d) 6 ).δ7.23(t,J＝8.0Hz,1H),7.22–7.16(m,1H),6.89(dd,J＝7.9,1.5Hz,1H),6.73(s,1H),6.50(t,J＝0.9Hz,1H),3.90(s,3H),3.93–3.87(m,1H),3.44–3.36(m,1H),3.10–3.02(m,4H),2.98(ddd,J＝12.5,5.0,0.9Hz,1H),2.93–2.86(m,1H).MS(CI)calcd for C 17 H 17 Cl 2 NO 2 [M+H] + :333.06。
Example 66: synthesis of Compound S66 (1-chloro-11-propoxy-5, 6a, 7-tetrahydro-4H-dibenzo [ de, g ] quinolin-2-ol hydrochloride)
2-bromo-5-propoxyphenylacetic acid and 3-benzyloxy-4-chlorophenylethylamine 1-5 are used as raw materials, and synthesized according to the steps. 1 H NMR(300MHz,DMSO-d 6 ).δ7.24(t,J＝8.1Hz,2H),7.21–7.16(m,2H),6.86(dd,J＝8.0,1.4Hz,2H),6.73(s,2H),6.50(t,J＝1.0Hz,2H),4.02(t,J＝5.4Hz,4H),3.90(dt,J＝6.2,5.1Hz,2H),3.43–3.37(m,1H),3.10–3.02(m,8H),2.98(ddd,J＝12.5,5.0,0.9Hz,2H),2.93–2.87(m,1H),1.86–1.78(m,4H),1.08(t,J＝7.8Hz,6H)..MS(CI)calcd for C 19 H 21 Cl 2 NO 2 [M+H] + :366.28。
Example 67: determination of calcium ion flow
Some of the compounds in the above examples were selected as well as some of the compounds as controls as subjects to test their activity on the 5HT receptor calcium ion stream. Stably transfected 5-HT was subjected to a calcium flux assay 8 hours prior to 2A/2B/2C Recipient HEK 293T cells were seeded at a density of 15,000 cells/well in 384 well plates containing DMEM with 1% dialyzed FBS. After removal of the medium, the cells (20. Mu.L/well) were then incubated with reconstituted Fluo-4 direct dye (Invitrogen) in FLIPR buffer (19 HBSS,2.5mmol/L probenecid and 20mmol/L HEPES, pH 7.4) for 1 hour at 37 ℃. After loading the dye, the cells were placed in a FLIPRTETRA fluorescence imaging plate reader (Molecular Devices); drug dilutions were prepared at 3-fold concentration in FLIPR buffer and aliquoted into 384-well plates, which were also added to FLIPR. The fluid module and plate reader of FLIPRTETRA were programmed to read baseline fluorescence for 10 seconds (1 read/second), then 10 μl of drug/well was added and read for 6 minutes (1 read/second). Fluorescence in each well was normalized to the average of the first 10 degrees of initiation (i.e., baseline fluorescence). The maximal fold increase that occurs within 60s after drug addition is then measured over the baseline fluorescence caused by the vehicle or drug.
Table 1: partial Compound pair 5HT 2 Results of receptor calcium ion flux Activity assay
Wherein NA represents inactive and "-" represents that no activity assay was performed
As can be seen from table 1:
1. compared with the aporphine 5-HT reported at present 2C Receptor agonist, most of the compounds have an activity ratio 1857[ EC 50 (E max )＝308nM(86.1％),ACS Cent Sci,2020,6,213-25]And 18b [ EC 50 (E max )＝103nM(95.9％),ACS Chem Neurosci,2020,11,549-59；ZL201910594756.6]At least 2-6 times stronger, as compound S11; representative Compound S11 its 5-HT 2C Receptor selectivity significantly better than 11b [5-HT 2C :EC 50 (E max )＝51nM(93.6％)；5-HT 2B :EC 50 (E max )＝794.3nM(25.4％)；5-HT 2A :EC 50 (E max )＝317.7nM(55.2％)]And 11f [5-HT2C:EC 50 (E max )＝23.6nM(101.8％)；5-HT 2B :EC 50 (E max )＝278.4nM(63.5％)；5-HT 2A :EC 50 (E max )＝596.4nM(44.9％)](Bioorganic Chemistry 123 (2022) 105795; ZL 201910594756.6) with little 5-HT 2B Receptor agonistic activity other similar trisubstituted compounds S50-S64 have the same properties. Therefore, the compound of the invention has better safety.
2. The invention reports a class of 5-HT for the first time 2A And 5-HT 2C Dual agonists of the receptor and their use for 5-HT 2B The receptor is almost inactive. As compounds S35-S42 have 5-HT 2C Receptor agonistic activity and 5-HT 2A Equivalent receptors, EC 50 Up to even 4.85nM and almost no 5-HT 2B Receptor activity.
3、R 1 And R is 2 Regardless of the substituent, R is generally 3 The activity at the 11-position is better than that at the 8-,9-, 10-position, such as the compounds S4, S11, S27-29, S35-S42.
4. When R is 2 When H is the same, R 1 Whether small or large groups H or OMe, R 3 Regardless of the position of the substituent, the compoundsAlmost no activity of the compounds, such as compounds S1-S3, S5-S9, S19-S21; and when R is 2 When OH is present, R 1 Whether small or large groups H or OMe, R 3 Regardless of the substituents, the compounds are useful for 5-HT 2C The receptors have better agonistic activity, such as compounds S11-S12, S24, S26-S29 and S35-S42.
Example 68: in vivo anti-schizophrenia Activity test
Further selection of the 5-HT with better 2C Receptor activity S36 and S62 activity tests were carried out in a classical Phencyclidine (PCP) -induced in vivo model of anti-schizophrenia. As shown in fig. 1, both compounds S36 and S62 significantly improved PCP-induced spontaneous locomotion, suggesting that compounds S36 and S62 have potential anti-schizophrenia positive symptoms.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations and modifications of the present invention will be apparent to those of ordinary skill in the art in light of the foregoing description. It is not necessary here nor is it exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present invention.

Claims (10)

1. The aporphine derivative is characterized by having a structural general formula shown as follows:
wherein R is 1 Is C 1 -C 8 An alkoxy group or a hydrogen group,
R 2 is hydroxyl or hydrogen;
R 3 selected from C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 2 -C 10 Alkynyl, C 2 -C 10 Alkenyl, halogen, C 1 -C 8 Haloalkyl, cyano, nitro or aryl.
2. Aporphine derivative according to claim 1, characterized in that R 3 Selected from halogen, C 1 -C 8 Alkoxy or C 1 -C 8 An alkyl group.
3. A process for the preparation of an aporphine derivative according to claim 1 or 2, comprising the steps of:
(1) The compound isAnd->Dehydration condensation to give an amide compoundSaid->Introducing PG protecting group under the action of dehydrating agent and reducing agent to obtain +.>
(2) The step (1) is carried outCoupling and ring closing are carried out on the catalyst and the ligand, so that the catalyst is obtained;
(3) And (2) the step (2)Carrying out deprotection reaction to obtain the product>
4. A process according to claim 3, wherein in step (1) the reducing agent is selected from NaBH 4 、LiAlH 4 、BH 3 ·THF、KBH 4 And SnCl 2 One or more of the following.
5. A production method according to claim 3, wherein in the step (1), the PG protecting group is selected from one or more of trifluoroacetyl group, p-toluenesulfonyl group and t-butoxycarbonyl group.
6. A method of preparation according to claim 3 wherein in step (2) the catalyst is selected from one or more of tetra triphenylphosphine palladium, 1' -bis diphenylphosphine ferrocene palladium dichloride, palladium acetate and tris dibenzylideneacetone dipalladium.
7. A method of preparation according to claim 3 wherein in step (2) the ligand is selected from one or more of 2-diphenylphosphine-2' - (N, N-dimethylamino) biphenyl, tricyclohexylphosphine tetrafluoroborate, di-tert-butylmethylphosphine tetrafluoroborate or di-tert-butylmethylphosphine tetrafluoroborate and triphenylphosphine.
8. A pharmaceutical composition comprising an aporphine derivative according to claim 1 or 2.
9. Use of an aporphine derivative according to claim 1 or 2, a pharmaceutical composition according to claim 9 for the preparation of a 5-hydroxytryptamine 2A receptor agonist, a 5-hydroxytryptamine 2C receptor agonist, a 5-hydroxytryptamine 2A receptor agonist, and a 5-hydroxytryptamine 2C receptor agonist for the preparation of a medicament for the prevention and/or treatment of obesity, urinary incontinence, depression, anxiety, obsessive compulsive disorder, epilepsy, schizophrenia, pain, diabetes and drug addiction.
10. The use according to claim 9, wherein the 5-hydroxytryptamine 2A receptor agonist, 5-hydroxytryptamine 2C receptor agonist is used for the preparation of a medicament for the prevention and/or treatment of depression, anxiety, obsessive-compulsive disorder and drug addiction.
CN202310508659.7A 2022-06-14 2023-05-08 Aporphine derivative, and preparation method and application thereof Pending CN116730918A (en)

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