CN112661765B - Tetrahydrodemethylthebaine derivative, preparation method and application - Google Patents
Tetrahydrodemethylthebaine derivative, preparation method and application Download PDFInfo
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Abstract
The invention relates to a preparation method of a compound with a general formula (I) or a pharmaceutically acceptable salt thereof, and relates to application of the derivatives in the field of opioid receptor treatment and application in preparing medicaments for treating pain, depression, opioid drug addiction and pruritus, wherein the pain comprises treatment or alleviation of pain, chronic pain, neuropathic pain and cancer pain during operation; the pruritus comprises intractable pruritus accompanied by severe diseases such as uremia, diabetic nephropathy, chronic liver diseases, malignant tumors and the like. Formula (I) is as follows:
Description
Technical Field
The present invention relates to a process for the preparation of compounds having the general formula (I) or a pharmaceutically acceptable salt thereof, and to the use of these derivatives in the field of opioid receptor therapy.
Background
Opioid receptors are mainly divided into three receptor subtypes, namely mu, delta, kappa and the like. Clinically used central analgesic drugs such as morphine and meperidine belong to the mu agonist type, and have side effects such as analgesia, sedation, respiratory depression and addiction. The delta receptor is widely distributed in the central nervous system, has a regulatory effect on the mu receptor and is involved in the development of tolerance dependence. The kappa receptor is widely expressed in brain, and the agonism of the kappa receptor has the effects of antagonizing mu receptor agonism, blocking drug addiction, anxiety, diuresis, hallucination and the like. Kappa ligands have been reported in the literature to have a variety of pharmacological activities, such as analgesia (see Dykstra LA et al, J.Pharmacol. Exp. Ther.1987,242, 413-420), antipruritic (see Husbands SM et al, J.Pharmacol. Exp. Ther.2009,328, 193-200), antidepressant (see Portoghese PS et al, life Sci,1987,40, 1287-92). Mu/kappa and other multi-action modulators have also found wide clinical application, such as analgesia, cocaine addiction withdrawal treatment (Neumeyer JL et al, J.Med.chem.2000,43, 114-122) and others, representing the drugs butorphanol, buprenorphine. Butorphanol is used for treating cancer pain and postoperative pain. 4,5-epoxymorphinans nalfuraphine (nalfurafine) is a kappa receptor agonist and is currently marketed in Japan and Korea for the treatment of intractable pruritus. The kappa receptor modulator buprenorphine (buprenorphine) is an oryzanol compound, and is clinically used for analgesia and withdrawal treatment of opioid addicted patients. The antidepressant drug ALKS 5461 (a compound of buprenorphine and ALKS 33) developed by Alkermes corporation has completed a clinical phase III test and proved to have an effect on refractory depression which is not effective in the existing antidepressant drug treatment. Therefore, the kappa regulator and the kappa/mu dual regulator have potential application prospects in the aspect of preparing medicines for treating pain, depression, opiate addiction, pruritus and the like.
Disclosure of Invention
The invention aims to provide a 7 alpha- (3' -substituted aminophenyl) -6 alpha, 14 alpha-ethylidene-tetrahydronorthebaine derivative with a formula (I) or a pharmaceutically acceptable salt thereof,
wherein R is 1 Is selected from H or CH 3 ；
R 2 Selected from H, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl radical, C 5 -C 7 Cycloalkenyl radical, C 3 -C 6 Cycloalkyl radical C 1 -C 6 Alkyl radical, C 5 -C 7 Cycloalkenyl radical C 1 -C 6 Alkyl, aryl, heteroaryl, aryl C 1 -C 6 Alkyl, or heteroaryl C 1 -C 6 An alkyl group;
R 3 is selected from H or CH 3 ；
R 4 Is selected from-CH = CH-or-CH 2 -CH 2 -；
R 5 Is selected from H, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl acyl radical, C 3 -C 6 Cycloalkyl radical, C 5 -C 7 Cycloalkenyl, aryl, substituted aralkanoyl, heteroaryl, substituted heteroarylalkylacyl, aryl C 1 -C 6 Alkyl, substituted aryl C 1 -C 6 Alkanoyl, heteroaryl C 1 -C 6 Alkyl, substituted heteroaryl C 1 -C 6 Alkanoyl wherein said substituted aryl or substituted heteroaryl substituent means independently selected from F, cl, br, I, CH 3 、CF 3 、OCH 3 、OCF 3 、OH、OCOCH 3 、
SO 2 CH 3 、NO 2 、NH 2 1 to 3 substituents of (a);
R 6 is selected from H or C 1 -C 3 An alkyl group.
As a preferable embodiment, wherein R 1 Is selected from H or CH 3 ；R 2 Is selected from H, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 3 -C 6 Cycloalkyl radical C 1 -C 6 Alkyl, aryl C 1 -C 6 An alkyl group; r 3 Is selected from CH 3 ；R 4 Is selected from-CH = CH-or-CH 2 -CH 2 -；R 5 Is selected from H, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl acyl, aryl, heteroaryl, aryl C 1 -C 6 Alkyl, substituted aralkanoyl, substituted aryl C 1 -C 6 Alkanoyl, substituted aralkanoyl, substituted heteroarylalkanoyl wherein said substituted aryl or substituted heteroaryl substituents are independently selected from F, cl, br, I, CH 3 、CF 3 、OCH 3 、OCF 3 、OH、OCOCH 3 、
SO 2 CH 3 、NO 2 、NH 2 1 substituent of (1); r is 6 Is selected from H or CH 3 。
As a preferred technical scheme, R in the invention 1 Is selected from CH 3 ，R 2 Is selected from C 3 -C 6 A cycloalkyl group; r 3 Is selected from CH 3 ；R 4 Is selected from-CH 2 -CH 2 -；R 6 Is selected from CH 3 ；R 5 Selected from the following formulas: H.
as a preferable technical scheme, in the invention, R2 is selected from cyclopropylmethyl, cyclobutylmethyl, phenethyl; r5 is selected from
R6 is selected from H.
As a preferred embodiment, the 7 α - (3' -substituted aminophenyl) -6 α,14 α -endo-ethenyl-tetrahydrothebaine derivative or a pharmaceutically acceptable salt thereof according to the present invention has the structural formula:
as a preferred technical scheme, the pharmaceutically acceptable salt is formed by inorganic acid or organic acid and is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate or biphosphate, acetate, benzoate, tartrate, succinate, maleate, fumarate, lactate, citrate, gluconate, methanesulfonate, benzenesulfonate and p-toluenesulfonate.
The second aspect of the invention provides a preparation method of the 7 alpha- (3' -substituted aminophenyl) -6 alpha, 14 alpha-ethylidene (ene) -tetrahydrodemethylthebaine derivative, wherein the substituted thebaine and the substituted styrene reagent are prepared by Diels-Alder reaction.
In a third aspect, the invention provides an application of the 7 alpha- (3' -substituted aminophenyl) -6 alpha, 14 alpha-ethylidene (ene) yl-tetrahydrodethiabaine derivative or the pharmaceutically acceptable salt thereof in preparing the medicament for treating the mediation of the opioid receptor.
The fourth aspect of the invention provides the application of the 7 alpha- (3' -substituted aminophenyl) -6 alpha, 14 alpha-ethylidene (ene) yl-tetrahydrodethiabaine derivative or the pharmaceutically acceptable salt thereof in preparing the medicines for treating pain, depression, opiate drug addiction and pruritus.
As a preferred embodiment, the pain includes treatment or alleviation of pain during surgery, chronic pain, neuropathic pain, cancer pain.
As a preferable technical scheme, the pruritus comprises intractable pruritus accompanied by severe diseases such as uremia, diabetic nephropathy, chronic liver diseases, malignant tumors and the like.
The described features, aspects, and advantages of the present invention will become better understood with regard to the following detailed description.
Drawings
FIG. 1: time course of analgesic Effect of Compound 12 in Hot plate assay Compound 12 was administered to mice by intraperitoneal injection (2 mg/kg). At different time nodes, pain perception was measured in mice in a hot plate test (8-10 mice/group).
FIG. 2 is a schematic diagram: the analgesic effect induced by compound 12 is mediated through kappa opioid receptors; mice were pretreated with the kappa-opioid receptor antagonist nor-BNI (10 mg/kg, i.p. -24 h). Compound 12 (1 mg/kg, i.p.) was then evaluated for antinociception 4 hours after administration in the writhing test. Data are expressed as mean ± s.e.m from 8 mice/data point. * P <0.001
FIG. 3: effects of u50,488h and compound 12 on spontaneous activity in mice; mice were treated with U50,488H (5 mg/kg) for 30 minutes or various doses of Compound 12 (0.1, 1.3, 3.4 mg/kg) for 4 hours, after which the total locomotor activity was monitored for 30 minutes. Data are expressed as mean ± s.e.m from 8 mice/data point. * p <0.05, compared to blank.
Detailed Description
The invention provides a 7 alpha- (3' -substituted aminophenyl) -6 alpha, 14 alpha-endo-ethenyl-tetrahydrodethiabaine derivative having the formula (I) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is as follows:
wherein, the first and the second end of the pipe are connected with each other,
R 1 is selected from H or CH 3 ；R 2 Is selected from H, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl radical, C 5 -C 7 Cycloalkenyl radical, C 3 -C 6 Cycloalkyl radical C 1 -C 6 Alkyl radical, C 5 -C 7 Cycloalkenyl radical C 1 -C 6 Alkyl, aryl, heteroaryl, aryl C 1 -C 6 Alkyl, or heteroaryl C 1 -C 6 An alkyl group; r is 3 Is selected from H or CH 3 ；R 4 Is selected from-CH = CH-or-CH 2 -CH 2 -；R 5 Is selected from H, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl acyl radical, C 3 -C 6 Cycloalkyl radical, C 5 -C 7 Cycloalkenyl, aryl, substituted aralkanoyl, heteroaryl, substituted heteroarylalkylacyl, arylC 1 -C 6 Alkyl, substituted aryl C 1 -C 6 Alkyl acyl, heteroaryl C 1 -C 6 Alkyl, substituted heteroaryl C 1 -C 6 Alkanoyl wherein said substituted aryl or substituted heteroaryl substituents are independently selected from F, cl, br, I, CH 3 、CF 3 、OCH 3 、OCF 3 、OH、OCOCH 3 、
SO 2 CH 3 、NO 2 、NH 2 1 to 3 substituents of (a); r 6 Is selected from H or C 1 -C 3 An alkyl group.
In some preferred embodiments, R 1 Is selected from H or CH 3 ；R 2 Is selected from H, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 3 -C 6 Cycloalkyl radical C 1 -C 6 Alkyl, aryl C 1 -C 6 An alkyl group; r 3 Is selected from CH 3 ；R 4 Is selected from-CH = CH-or-CH 2 -CH 2 -；R 5 Is selected from H, C 1 -C 6 Alkyl radical, C 1 -C 6 An alkyl acyl group, an aryl group,heteroaryl, aryl C 1 -C 6 Alkyl, substituted aralkanoyl, substituted aryl C 1 -C 6 Alkanoyl, substituted aralkanoyl, substituted heteroarylalkanoyl wherein said substituted aryl or substituted heteroaryl substituents are independently selected from F, cl, br, I, CH 3 、CF 3 、OCH 3 、OCF 3 、OH、OCOCH 3 、
SO 2 CH 3 、NO 2 、NH 2 1 substituent of (a); r 6 Is selected from H or CH 3 。
In some preferred embodiments, R 2 Selected from the group consisting of cyclopropylmethyl, cyclobutylmethyl, phenylethyl; r is 5 Is selected from
R 6 Is selected from H.
In some embodiments, the 7 α - (3' -substituted aminophenyl) -6 α,14 α -endo-ethenyl-tetrahydrodesmethylthebaine derivative, or a pharmaceutically acceptable salt thereof, has the formula:
in some embodiments, the pharmaceutically acceptable salt thereof is a salt of the 7 α - (3' -substituted aminophenyl) -6 α,14 α -ethylenyl-tetrahydrodethiabaine derivative with an inorganic or organic acid selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate or biphosphate, acetate, benzoate, tartrate, succinate, maleate, fumarate, lactate, citrate, gluconate, methanesulfonate, benzenesulfonate, p-toluenesulfonate.
In some embodiments, R in the formula 1 The derivative of = H may be represented by R in formula (I) 1 ＝CH 3 Under certain conditions. The transformation preparation condition refers to BBr 3 /CH 2 Cl 2 Of different concentrations of H 2 SO 4 HBr, methanesulfonic acid or KOH/diethylene glycol (DEG) in various concentrations, sodium propylmercaptide/HMPA, preferably BBr 3 /CH 2 Cl 2 。
In some embodiments, R in the formula 2 ＝H，C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl radical, C 5 -C 7 Cycloalkenyl radical, C 3 -C 6 Cycloalkyl, aryl, heterocycloaryl, aryl C 1 -C 6 Alkyl, or heterocyclic aryl C 1 -C 6 The alkyl derivatives can be represented by formula (I) wherein R 2 ＝CH 3 The derivatives of (1) are prepared by transformation under certain conditions. The transformation conditions are as follows: reacting with nitrile bromide, ethyl chloroformate, phenyl chloroformate, vinyl chloroformate, diisopropyl azodicarboxylate, ethyl azoformate (KauerJC, organic Synthesis,1963,4, 411) in a first inert solvent, and hydrolyzing with acid to obtain R in formula (I) 2 Derivatives of = H; the conversion conditions are preferably ethyl azoformate.
Preferably, the first inert solvent is selected from acetonitrile, tetrahydrofuran (THF), diethyl ether, chloroform, dichloromethane, benzene, toluene, N-Dimethylformamide (DMF) or mixtures of the above solvents, preferably acetonitrile;
preferably, the acidic conditions are selected from different concentrations of H 2 SO 4 HCl or HBr. Intermediate (II, R) 2 Reaction of = H) and monohalogenated hydrocarbon in a second inert solvent to obtain the compound of the formula (I) R 2 ＝C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical，C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl radical, C 5 -C 7 Cycloalkenyl radical, C 3 -C 6 Cycloalkyl, aryl, heterocyclic aryl, aryl C 1 -C 6 Alkyl, or heterocyclic aryl C 1 -C 6 Derivatives of alkyl groups. The monohalogenated hydrocarbon is selected from C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl radical, C 5 -C 7 Cycloalkenyl radical, C 3 -C 6 Cycloalkyl, aryl, heterocycloaryl, aryl C 1 -C 6 Chlorine, bromine, iodide of the alkyl group,
the second inert reagent is selected from THF, diethyl ether, chloroform, dichloromethane, benzene, toluene, N-Dimethylformamide (DMF) or mixtures of the above solvents.
R in formula (I) according to methods well known in the art 3 Derivatives of = H may be prepared by R in formula (I) 3 ＝CH 3 Under certain conditions, the certain conditions are H with different concentrations 2 SO 4 HBr, methane sulfonic acid or KOH/diethylene glycol (DEG) at various concentrations.
R in formula (I) according to methods well known in the art 4 is-CH 2 CH 2 The derivatives of (A) can be prepared by reacting R in formula (I) 4 Derivatives of-CH = CH-are prepared by conversion under certain reducing conditions. The reduction conditions are selected from Pd/C catalytic hydrogenation.
In some embodiments, R in formula (I) 5 ＝H，R 6 Derivatives of formula (ii) = H may be obtained by reaction of a derivative of formula (III) under conversion conditions: firstly, carrying out a Diels-Alder reaction on the derivative of the formula (III) and 3-nitrostyrene in a high-boiling inert solvent to obtain a derivative of an Intermediate (IV);
preferably, the high-boiling inert solvent is selected from benzene, toluene, xylene or a mixture of the above solvents; xylene is preferred.
In some embodiments, derivatives of Intermediate (IV)Under certain reduction conditions, R in the formula (I) can be obtained 5 Derivatives of H, said reducing conditions being selected from reduction under Pd/C catalytic hydrogenation.
In some embodiments, R in formula (I) 6 ＝H，R 5 ＝C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl radical, C 5 -C 7 Cycloalkenyl, aryl, heterocyclic aryl, aryl C 1 -C 6 Alkyl, heterocyclic aryl C 1 -C 6 The alkyl derivatives can be represented by formula (I) wherein R 5 ＝H，R 6 Reaction of derivatives of H with halogenated hydrocarbons in inert solvents.
Preferably, said halogenated hydrocarbon is selected from C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl radical, C 5 -C 7 Cycloalkenyl radical, C 3 -C 6 Cycloalkyl, aryl, heterocycloaryl, aryl C 1 -C 6 Chlorine, bromine, iodide of alkyl.
Preferably, the inert agent is selected from THF, diethyl ether, chloroform, dichloromethane, benzene, toluene, N-Dimethylformamide (DMF) or mixtures of the above solvents.
In some embodiments, R in formula (I) 6 ＝H，R 5 ＝C 1 -C 6 Alkyl-substituted acyl, aryl-substituted acyl, heterocyclic aryl C 1 -C 6 Alkyl-substituted acyl or aryl C 1 -C 6 The derivatives of alkyl-substituted acyl can be obtained by the reaction of R in formula (I) 6 ＝H，R 5 The derivative of = H, acyl chloride and alkali react in an inert solvent.
Preferably, the acid chloride is selected from C 1 -C 6 Alkyl substituted acyl chloride, aryl substituted acyl chloride, heterocyclic aryl C 1 -C 6 Alkyl-substituted acyl chlorides or aryl radicals C 1 -C 6 Alkyl substituted acyl chloride.
Preferably, the base is selected from pyridine, triethylamine, 4-Dimethylaminopyridine (DMAP), diisopropylethylamine, potassium or sodium carbonate, potassium or sodium hydroxide, and the like, preferably triethylamine.
Preferably, the inert solvent is selected from Tetrahydrofuran (THF), diethyl ether, chloroform, dichloromethane (DCM), benzene, toluene, N-Dimethylformamide (DMF) or mixtures of the above solvents, preferably DCM.
In some embodiments, R in formula (I) 6 ＝CH 3 ，R 5 ＝C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl radical, C 5 -C 7 Cycloalkenyl, aryl, heterocyclic aryl, aryl C 1 -C 6 Alkyl, heterocyclic aryl C 1 -C 6 The alkyl derivatives can be obtained by the following two-step reaction: (1) By R in formula (I) 5 ＝H,R 6 Reaction of derivative of = H, benzyl chloroformate and alkali in water and ethyl acetate two-phase solvent, reduction in tetrahydrofuran solvent with lithium aluminium hydride to obtain R 6 ＝CH 3 ,R 5 Derivatives of = H; (2) R 6 ＝CH 3 ,R 5 Reaction of the derivative of H with halogenated hydrocarbons in an inert solvent to give the desired derivative. The halogenated hydrocarbon is selected from C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl radical, C 5 -C 7 Cycloalkenyl radical, C 3 -C 6 Cycloalkyl, aryl, heterocycloaryl, aryl C 1 -C 6 Alkyl chlorides, bromides, iodides, said inert agent being selected from THF, diethyl ether, chloroform, dichloromethane, benzene, toluene, N-Dimethylformamide (DMF) or mixtures of the above solvents.
In a third aspect, the invention provides the use of the 7 alpha- (3' -substituted aminophenyl) -6 alpha, 14 alpha-endo (ethenyl) -tetrahydro-desmethylthebaine derivative or the pharmaceutically acceptable salt thereof in the preparation of an opioid receptor mediated therapeutic drug.
The fourth aspect of the invention provides an application of the 7 alpha- (3' -substituted aminophenyl) -6 alpha, 14 alpha-ethylidene (ene) yl-tetrahydrodethia derivative or the pharmaceutically acceptable salt thereof in preparing medicines for treating pain, depression, opiate drug addiction and pruritus.
As a preferred embodiment, the pain includes treatment or alleviation of pain during surgery, chronic pain, neuropathic pain, cancer pain.
As a preferable technical scheme, the pruritus comprises intractable pruritus accompanied by serious diseases such as uremia, diabetic nephropathy, chronic liver disease, malignant tumor and the like.
The invention relates to a 7 alpha- (3' -substituted aminophenyl) -6 alpha, 14 alpha-ethylene (ene) tetrahydro-northebaine derivative, the affinity and selectivity of which to three opiate receptors can be determined by the radioactive receptor ligand binding experiment, using 35 S]GTP γ The receptor agonistic activity of the compound can be measured by an S binding experiment, the analgesic action level of the compound can be measured by mouse hot plate and writhing analgesic experiments, whether the analgesic mechanism is generated by selectively stimulating kappa rather than mu opioid receptors in vivo or not can be verified by mouse spontaneous activity experiments, and whether the compound can cause sedation side effect under a certain dosage or not can be verified.
The present invention will be illustrated by the following examples, which are given to illustrate the present invention in more detail.
Example 1
Preparation of N-desmethyl thebaine hydrochloride (1):
10.0g of thebaine (32.12mmol, 1.0eq) was charged in a 250mL single-neck flask, and 100mL of acetonitrile and 7.6mL of diisopropyl azodicarboxylate (38.54mmol, 1.2eq) were added and reacted under reflux for 6 hours. The reaction was stopped, the solvent was removed by rotation under reduced pressure, 100mL of methanol was added to dissolve the solvent, 11.1g of pyridine hydrochloride (96.36mmol, 3.0 eq) was added to the solution, and the mixture was stirred at room temperature for 6 hours, whereupon a large amount of solid precipitated after the reaction was completed, filtered, the filter cake was washed with ethyl acetate, and dried to obtain intermediate 1 as a white solid (4.5 g), yield 46.6%, melting point: 260.3 ℃. ESI-MS (M + H) +:298.2.
Example 2
Preparation of N-cyclopropylmethyl-northebaine (2):
in a 50mL single-neck flask under nitrogen protection, 3.5g (10.5 mmol) of compound N-demethylthebaine hydrochloride, 30mL DMF and 3.3g (31.5 mmol) of sodium carbonate are added, then 1.3mL (13.6 mmol) of bromocyclopropanemethane is added, the temperature is raised to 110 ℃ for reaction for 2.5h, the reaction is stopped, the reaction solution is extracted three times with EA, washed with saturated saline, dried overnight, and silica gel column chromatography (PE: EA = 1) after spin drying obtains 2.6g of light yellow oil, yield: 70.0 percent. 1 H NMR(400MHz,CDCl 3 )δ6.68(d,J＝8.2Hz,1H),6.61(d,J＝8.1Hz,1H),5.60(d,J＝6.4Hz,1H),5.06(d,J＝6.4Hz,1H),3.98(d,J＝6.9Hz,1H),3.86(s,3H),3.61(s,3H),3.31(d,J＝17.7Hz,1H),3.01–2.80(m,2H),2.75(dd,J＝18.0,6.7Hz,1H),2.53(d,J＝6.1Hz,2H),2.22(td,J＝12.5,5.3Hz,1H),1.75(d,J＝11.9Hz,1H),0.96(s,1H),0.58(d,J＝6.9Hz,2H),0.19(d,J＝3.9Hz,2H)；ESI-MS(M+H) + :352.2。
Example 3
Preparation of N-cyclopropylmethyl-7 α - (3' -nitro) phenyl-6 α,14 α -endo-etheno-tetrahydrodetbaine (3):
n-cyclopropylmethyl northebaine (2.0 g, 5.69mmol), 2-nitrostyrene (1.5 mL,11.2 mmol) and anhydrous o-xylene (20 mL) are placed in a 50mL three-necked flask with magnetic stirring, reflux condenser and thermometer. Reflux reaction for 30h, vacuum concentrationTo dryness, silica gel column chromatography (PE: EA =10 1) gave a-1 as a pale yellow foamy solid 1.3g, yield 45.7%, melting point: 190.0-191.4 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.13–8.03(m,2H),7.56(d,J＝6.0Hz,1H),7.40(t,J＝7.8Hz,1H),7.28–7.24(m,1H),6.65(d,J＝7.9Hz,1H),6.56(d,J＝8.0Hz,1H),5.95(d,J＝8.4Hz,1H),5.77–5.67(m,1H),4.75(s,1H),3.84(d,J＝2.3Hz,3H),3.60(s,1H),3.46(t,J＝10.6Hz,1H),3.38(d,J＝2.5Hz,3H),3.15(d,J＝18.8Hz,2H),2.74(s,1H),2.43(dd,J＝33.4,21.1Hz,4H),2.19–2.06(m,1H),1.96(d,J＝12.5Hz,1H),1.36(d,J＝13.6Hz,1H),0.81(s,1H),0.52(d,J＝8.9Hz,2H),0.14(s,2H),0.01(dd,J＝4.5,1.9Hz,1H)；ESI-MS(M+H) + :501.5.
Example 4
Preparation of N-cyclopropylmethyl-7 α - (3' -amino) phenyl-6 α,14 α -endo-ethylene-tetrahydrodetibaine (4):
adding the intermediate A-1 (1.3 g,2.6 mmol), methanol (20 ml) and 10% palladium-carbon (0.26g, 2.4 mmol) into a pressure bottle, introducing hydrogen, heating at 65psi at 50 ℃ for 48h, stopping the reaction, filtering the reaction solution to remove the palladium-carbon, and spin-drying the filtrate to obtain 4 which is a white foamy solid 1.0g, wherein the yield is as follows: 92.3%, melting point: 116.5-117.2 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.10(t,J＝7.4Hz,1H),6.77(d,J＝7.6Hz,1H),6.72(d,J＝8.1Hz,1H),6.68(s,1H),6.58(t,J＝8.9Hz,2H),4.60(s,1H),3.88(s,3H),3.63(s,2H),3.20(d,J＝1.1Hz,3H),3.08(d,J＝4.9Hz,1H),3.05(s,1H),3.00(s,1H),2.64(s,1H),2.31(d,J＝21.3Hz,4H),2.15(s,1H),1.73(t,J＝11.3Hz,2H),1.64(dd,J＝13.3,6.4Hz,1H),1.52–1.41(m,1H),1.40–1.29(m,1H),0.76(s,1H),0.47(d,J＝7.5Hz,2H),0.09(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ147.05,146.11,143.63,141.83,132.94,128.92,128.74,120.02,118.93,116.60,113.64,113.43,93.26,59.77,58.53,56.64,53.41,51.05,45.99,43.87,36.45,36.11,35.68,29.69,22.79,18.79,9.46,4.12,3.28；HMRS:calc.for C 30 H 36 N 2 O 3 ([M+H] + )473.2799,found 473.2796；purity:95％,t R ＝2.2min.
Example 5
Preparation of N-cyclopropylmethyl 7 α - (3' -methylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydro-desmethylthebaine (5):
after 4 (50mg, 0.11mmol) and ethyl acetate (2 mL) were added to a 10mL round-bottomed flask, a saturated aqueous solution of sodium carbonate (0.8 mL) was added, benzyl chloroformate (34. Mu.L, 0.32 mmol) was added dropwise with gentle stirring in an ice bath, and the mixture was reacted at room temperature for 3 hours, after completion of the reaction, twice with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then directly charged into the next step. A solution of lithium aluminum hydride in tetrahydrofuran (1n, 3ml) was added to a 10mL three-necked flask under nitrogen, under ice bath, slowly added dropwise to the tetrahydrofuran solution of the product of the previous step, then overnight at room temperature, after completion of the reaction, quenched by addition of sodium sulfate decahydrate, followed by addition of 0.5ml of 2N sodium hydroxide solution, filtered off of a white solid, the filter cake was washed with DCM: CH3OH =10, concentrated under reduced pressure and separated by a high performance preparative plate (DCM: CH3OH = 50) to give 22.0mg of a light yellow oil, yield: 41.0 percent. 1 H NMR(400MHz,CDCl 3 )δ7.14(t,J＝7.7Hz,1H),6.73(d,J＝7.2Hz,2H),6.61(s,2H),6.50(d,J＝7.8Hz,1H),4.62(s,1H),3.88(s,3H),3.20(s,3H),3.03(d,J＝17.6Hz,3H),2.84(s,3H),2.67(s,1H),2.34(s,4H),2.17(s,1H),1.75(d,J＝12.1Hz,3H),1.44(d,J＝9.9Hz,2H),1.32(s,2H),0.74(d,J＝25.9Hz,1H),0.47(s,2H),0.10(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ149.14,147.08,128.87,118.94,118.55,114.33,113.65,110.50,93.12,59.76,58.53,56.64,50.98,45.92,43.92,36.50,36.14,35.65,30.83,29.74,22.83,18.92,9.45,4.11,3.28；HMRS:calc.for C 31 H 38 N 2 O 3 ([M+H] + )487.2955,found 487.2951；purity:95％,t R ＝2.6min.
Example 6
Preparation of N-cyclopropylmethyl 7 α - (3' -cyclopropylmethylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydro-northebaine (6):
after 4 (100mg, 0.21mmol) and DMF (2 mL) were added to a 10mL single-neck reaction flask, anhydrous sodium carbonate (67.0 mg, 0.63mmol) and bromomethylcyclopropane (31.0. Mu.L, 0.32 mmol) were added and reacted in an oil bath at 80 ℃ for 2 hours. TLC monitoring, reaction stopped, ethyl acetate (10 mL × 3) extraction, organic layers combined, organic phase washed successively with water and saturated solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by silica gel column chromatography (PE/EA = 10/1) to give 34.0mg of white solid, yield: 30.4%, melting point: 100-101.3 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.12(t,J＝7.2Hz,1H),6.71(d,J＝7.1Hz,2H),6.61(s,2H),6.49(d,J＝8.0Hz,1H),4.62(s,1H),3.88(d,J＝1.3Hz,3H),3.20(d,J＝1.6Hz,4H),3.03(d,J＝18.2Hz,3H),2.95(d,J＝6.9Hz,2H),2.64(s,1H),2.34(s,3H),2.16(s,1H),1.75(d,J＝11.8Hz,2H),1.69–1.59(m,1H),1.46(d,J＝4.7Hz,1H),1.38–1.23(m,2H),1.15–1.04(m,1H),0.88(s,1H),0.76(s,1H),0.54(t,J＝6.8Hz,2H),0.46(s,2H),0.24(d,J＝4.7Hz,2H),0.09(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ148.34,147.11,128.88,118.96,118.61,114.58,113.69,110.91,93.15,59.74,58.53,56.66,51.02,49.17,45.92,43.93,36.49,36.15,35.67,29.77,29.70,22.86,18.93,10.95,9.49,4.17,3.45,3.30；HMRS:calc.for C 34 H 42 N 2 O 3 ([M+H] + )527.3268,found 527.3263；purity:95％,t R ＝1.2min.
Example 7
Preparation of N-cyclopropylmethyl-7 α - (3' -cyclobutylmethylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydro-northebaine (7):
a10 mL single-neck reaction flask was charged with 4 (50mg, 0.11mmol) and DMF(2 mL), cesium carbonate (104.0 mg, 0.32mmol), bromomethylcyclobutane (15.0. Mu.L, 0.16 mmol) and the mixture were added and reacted in an oil bath at 95 ℃ for 24 hours. TLC monitoring, reaction was stopped, ethyl acetate (10 mL × 3) was extracted, organic layers were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by silica gel column chromatography (DCM/MeOH = 50/1) to give 10.0mg of light yellow oil, yield: 16.8 percent. 1 H NMR(400MHz,CDCl 3 )δ7.11(t,J＝7.7Hz,1H),6.69(d,J＝6.7Hz,2H),6.57(s,2H),6.48(d,J＝7.8Hz,1H),4.63(s,1H),3.89(s,3H),3.20(s,3H),3.12(d,J＝7.2Hz,3H),3.06(s,2H),2.60(td,J＝15.0,7.5Hz,2H),2.32(s,2H),2.19–2.05(m,3H),1.99–1.83(m,3H),1.74(dt,J＝16.9,8.4Hz,5H),1.46(dd,J＝13.7,8.6Hz,3H),1.28(s,1H),1.00–0.93(m,1H),0.77(s,1H),0.46(s,2H),0.07(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ154.74,149.63,146.91,130.92,128.85,128.21,126.98,119.01,117.11,113.99,111.35,109.03,97.98,79.53,65.58,59.76,58.93,56.84,52.67,49.90,39.62,38.82,38.63,35.96,34.83,30.90,30.87,29.70,29.29,28.45,25.51,25.38,19.19,15.78,3.45；HMRS:calc.for C 35 H 44 N 2 O 3 ([M+H] + )541.3425,found 541.3437；purity:92％,t R ＝2.5min.
Example 8
Preparation of N-cyclopropylmethyl-7 α - (3' -benzylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydrodethiabaine (8):
4 (100mg, 0.21mmol) and DMF (2 mL) were added to a 10mL single-neck reaction flask, followed by addition of anhydrous sodium carbonate (67.0 mg, 0.63mmol) and benzyl chloride (37.0. Mu.L, 0.32 mmol), and reaction was carried out in an oil bath at 80 ℃ for 3 hours. TLC, stopped the reaction, extracted with ethyl acetate (10 mL × 3), combined organic layers, washed the organic phase with water and saturated sodium chloride solution in order, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by silica gel column chromatography (PE/EA = 5/1) to give 93.0mg of a white solid, yield: 78.4%, melting point: 196.1-198.1 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.31(s,1H),7.29(s,1H),7.28(s,1H),7.22(t,J＝6.9Hz,2H),7.11(t,J＝7.9Hz,1H),6.69(s,2H),6.63(d,J＝7.5Hz,2H),6.56(d,J＝7.7Hz,1H),4.67(s,2H),4.54(s,1H),3.86(s,3H),3.14(s,1H),3.05(s,3H),2.96(s,2H),2.60(s,1H),2.28(d,J＝11.6Hz,3H),2.10(s,1H),1.68(d,J＝12.2Hz,1H),1.60(s,1H),1.54–1.39(m,2H),1.29(d,J＝7.4Hz,1H),1.00(s,1H),0.73(d,J＝10.1Hz,1H),0.46(s,2H),0.08(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ148.86,146.99,143.16,141.74,138.86,132.97,128.76,128.70,128.59,126.80,126.61,118.81,118.26,114.34,113.58,110.84,92.62,59.75,58.58,56.62,54.65,50.65,45.79,43.88,43.68,36.47,35.98,35.64,29.52,22.76,18.99,9.49,4.07,3.31；HMRS:calc.for C 37 H 42 N 2 O 3 ([M+H] + )563.3268,found 563.3272；purity:97％,t R ＝2.9min.
Example 9
Preparation of N-cyclopropylmethyl-7 α - (3' -p-fluorobenzylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydro-northebaine (9):
a10 mL single-neck reaction flask was charged with 4 (50mg, 0.11mmol) and DMF (2 mL), followed by addition of sodium carbonate (104.0mg, 0.32mmol) and 4-fluorobenzyl bromide (19.0. Mu.L, 0.16 mmol), and reaction in an oil bath at 95 ℃ for 24 hours. Monitored by TLC, the reaction was stopped, extracted with ethyl acetate (10 mL × 3), and the organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM/MeOH = 50/1) to give 18.0mg of a colorless transparent oil, yield: 28.2 percent. 1 H NMR(400MHz,CDCl 3 )δ7.34(dd,J＝5.4,2.4Hz,2H),7.12(dd,J＝13.0,7.6Hz,1H),7.02(dd,J＝13.7,8.4Hz,2H),6.74(d,J＝5.4Hz,2H),6.59(s,2H),6.53(d,J＝5.4Hz,1H),4.60(s,1H),4.31(d,J＝4.5Hz,2H),3.88(d,J＝5.1Hz,3H),3.16(d,J＝5.1Hz,3H),3.03(d,J＝17.5Hz,3H),2.65(s,1H),2.33(s,4H),2.15(s,1H),1.72(s,2H),1.65(d,J＝12.0Hz,2H),1.50–1.35(m,2H),0.77(s,1H),0.47(s,2H),0.10(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ162.80,161.18,147.73,147.03,143.50,141.80,135.25,132.92,128.97,128.91,128.71,119.19,118.92,115.45,115.31,114.44,113.62,111.20,93.02,59.76,58.54,56.63,50.91,47.75,45.93,43.82,36.49,36.08,35.67,29.68,22.79,18.90,9.46,4.09,3.27；HMRS:calc.for C 37 H 41 N 2 O 3 ([M+H] + )581.3174,found 581.3188；purity:97％,t R ＝3.9min.
Example 10
Preparation of N-cyclopropylmethyl-7 α - (3' -p-methylbenzylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydrodetibamide (10):
after 4 (100mg, 0.21mmol) and DMF (2 mL) were added to a 10mL single-neck reaction flask, anhydrous sodium carbonate (67.0 mg, 0.63mmol) and 4-methylbenzyl bromide (40.0. Mu.L, 0.25 mmol) were added and reacted in an oil bath at 80 ℃ for 6 hours. TLC monitoring, the reaction was stopped, ethyl acetate (10 mL × 3) was extracted, organic layers were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE/EA = 10/1) to give 34.0mg of a colorless transparent oil, yield: 41.7 percent. 1 H NMR(400MHz,CDCl 3 )δ7.27(s,1H),7.25(s,1H),7.14(d,J＝7.6Hz,2H),7.10(d,J＝7.9Hz,1H),6.72(s,2H),6.59(s,2H),6.52(d,J＝7.9Hz,1H),4.60(s,1H),4.29(s,2H),3.88(s,3H),3.14(s,3H),3.02(d,J＝16.3Hz,3H),2.64(s,1H),2.33(s,2H),2.33(s,3H),2.29(s,2H),2.17(s,1H),1.69(s,3H),1.49–1.34(m,2H),1.28(s,1H),0.88(s,1H),0.81–0.66(m,1H),0.47(s,2H),0.09(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ148.02,147.08,136.77,136.47,129.26,128.88,127.50,118.91,114.51,113.61,111.14,93.00,59.77,58.55,56.65,50.88,48.21,45.87,43.86,36.47,36.12,35.67,29.69,22.80,21.06,18.90,9.46,4.09,3.28；HMRS:calc.for C 38 H 44 N 2 O 3 ([M+H] + )577.3425,found 577.3402；purity:97％,t R ＝3.3min.
Example 11
Preparation of N-cyclopropylmethyl-7 α - (3' -m-methylbenzylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydronorthebaine (11):
after 4 (100mg, 0.21mmol) and DMF (2 mL) were added to a 10mL single-neck reaction flask, anhydrous sodium carbonate (67.0mg, 0.63mmol) and 3-methylbenzyl bromide (44.8. Mu.L, 0.32 mmol) were added and reacted in an oil bath at 80 ℃ for 5 hours. Monitored by TLC, the reaction was stopped, extracted with ethyl acetate (10 mL × 3), and the organic layers were combined, washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE/EA = 10/1) to give 60.0mg of a colorless transparent oil, yield: 47.3 percent. 1 H NMR(400MHz,CDCl 3 )δ7.24–7.15(m,3H),7.12(t,J＝7.8Hz,1H),7.07(d,J＝6.9Hz,1H),6.72(d,J＝7.3Hz,2H),6.59(d,J＝7.7Hz,2H),6.54(d,J＝7.9Hz,1H),4.59(s,1H),4.30(s,2H),3.88(s,3H),3.17(s,1H),3.15(s,3H),3.02(d,J＝18.0Hz,3H),2.65(s,1H),2.34(s,3H),2.33(s,3H),2.31–2.24(m,1H),2.17(s,1H),1.73(d,J＝15.9Hz,2H),1.67(s,1H),1.48–1.29(m,2H),1.02–0.90(m,1H),0.81(s,1H),0.47(s,2H),0.10(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ148.03,147.05,143.42,141.79,139.50,138.24,132.96,128.85,128.51,128.23,127.89,124.55,119.00,114.39,113.61,111.19,93.06,59.77,58.56,56.64,50.90,48.51,45.92,43.87,36.48,36.10,35.68,29.66,22.80,21.40,18.89,9.48,4.11,3.28；HMRS:calc.for C 38 H 44 N 2 O 3 ([M+H] + )577.3425,found 577.3441；purity:97％,t R ＝3.1min.
Example 12
Preparation of N-cyclopropylmethyl-7 α - (3' -p-methoxybenzylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydro-northebaine (12):
after 4 (100mg, 0.21mmol) and DMF (2 mL) were added to a 10mL single-neck reaction flask, anhydrous sodium carbonate (67.0mg, 0.63mmol) and 4- (methoxy) benzyl chloride (28.0. Mu.L, 0.32 mmol) were added and reacted in an oil bath at 80 ℃ for 4 hours. TLC, stopped the reaction, extracted with ethyl acetate (10 mL × 3), combined organic layers, washed the organic phase sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by silica gel column chromatography (PE/EA = 5/1) to give 34.0mg of a white solid, yield: 27.3%, melting point: 122.1-123.0 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.29(d,J＝7.3Hz,2H),7.12(t,J＝7.6Hz,1H),6.87(d,J＝7.2Hz,2H),6.72(d,J＝7.9Hz,2H),6.59(d,J＝13.2Hz,2H),6.53(d,J＝8.0Hz,1H),4.59(s,1H),4.26(s,2H),3.87(s,3H),3.79(s,3H),3.16(s,3H),3.01(d,J＝18.7Hz,3H),2.63(s,1H),2.37–2.20(m,4H),2.14(s,1H),1.77–1.66(m,2H),1.66–1.56(m,2H),1.41(s,1H),1.31(s,1H),0.84(s,1H),0.75(s,1H),0.45(t,J＝7.9Hz,2H),0.08(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ158.81,148.00,147.04,143.44,141.79,132.96,131.53,128.85,128.78,118.96,118.88,114.45,113.99,113.60,111.09,93.06,59.78,58.58,56.62,55.29,50.93,47.94,45.93,43.91,43.85,36.51,36.09,35.69,29.68,22.80,18.94,9.48,4.09,3.30；HMRS:calc.for C 38 H 44 N 2 O 4 ([M+H] + )593.3374,found 593.3370；purity:98％,t R ＝2.6min.
Example 13
Preparation of N-cyclopropylmethyl-7 α - (3' -m-methoxybenzylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydro-northebaine (13):
after 4 (100mg, 0.21mmol) and DMF (2 mL) were added to a 10mL single-neck reaction flask, anhydrous sodium carbonate (67.0 mg, 0.63mmol) and 3-methoxybenzyl chloride (46.0. Mu.L, 0.32 mmol) were added and reacted in an oil bath at 80 ℃ for 12 hours. TLC monitoring, stopping reaction, extracting with ethyl acetate (10 mL. Times.3),the organic layers were combined, and the organic phase was washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE/EA = 10/1) to obtain 20.0mg of a colorless transparent oil, yield: 15.3 percent. 1 H NMR(400MHz,CDCl 3 )δ7.23(d,J＝7.8Hz,1H),7.12(t,J＝7.5Hz,1H),6.96(d,J＝7.6Hz,1H),6.93(s,1H),6.79(d,J＝8.2Hz,1H),6.73(s,2H),6.59(s,2H),6.53(d,J＝7.8Hz,1H),4.59(s,1H),4.31(s,2H),3.88(s,3H),3.78(s,3H),3.14(s,3H),3.02(d,J＝16.7Hz,4H),2.64(s,1H),2.32(s,4H),2.14(s,1H),1.70(s,2H),1.41(d,J＝12.0Hz,2H),1.33(s,1H),0.96(s,1H),0.80–0.67(m,1H),0.46(s,2H),0.09(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ159.89,147.92,147.04,143.43,141.78,141.30,129.62,128.85,119.69,119.07,118.89,114.43,113.61,112.92,112.64,111.20,93.07,59.77,58.57,56.64,55.19,50.90,48.48,45.92,43.88,36.49,36.09,35.68,29.69,22.80,18.88,9.48,4.10,3.29；HMRS:calc.for C 38 H 44 N 2 O 4 ([M+H] + )593.3374,found 593.3336；purity:97％,t R ＝2.3min.
Example 14
Preparation of N-cyclopropylmethyl-7 α - (3' -p-trifluoromethoxybenzylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydrodethiabaine (14):
after 4 (100mg, 0.21mmol) and DMF (2 mL) were added to a 10mL single-neck reaction flask, anhydrous sodium carbonate (67.0 mg, 0.63mmol) and 4-trifluoromethoxybenzyl bromide (53.0. Mu.L, 0.25 mmol) were added and reacted in an oil bath at 80 ℃ for 22 hours. Monitored by TLC, the reaction was stopped, extracted with ethyl acetate (10 mL × 3), and the organic layers were combined, washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE/EA = 5/1) to give 56.0mg of a colorless transparent oil, yield: 41.7 percent. 1 H NMR(400MHz,CDCl 3 )δ7.40(d,J＝7.6Hz,2H),7.17(d,J＝7.8Hz,2H),7.12(s,1H),6.73(d,J＝4.8Hz,2H),6.58(d,J＝14.1Hz,2H),6.51(d,J＝7.5Hz,1H),4.59(s,1H),4.35(s,2H),4.08(d,J＝6.4Hz,1H),3.87(s,3H),3.14(s,3H),3.01(d,J＝16.8Hz,3H),2.64(s,1H),2.32(s,4H),2.13(s,1H),1.73(d,J＝10.1Hz,1H),1.43(s,2H),1.19(s,1H),0.78(d,J＝15.6Hz,1H),0.46(s,2H),0.09(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ148.23,147.60,147.02,143.56,141.79,138.44,128.91,128.59,121.15,119.27,118.94,114.39,113.62,111.26,92.92,59.76,58.56,56.62,50.85,47.71,45.91,43.88,43.77,36.50,36.08,35.68,29.67,22.79,18.94,9.45,4.06,3.30；HMRS:calc.for C 38 H 41 F 3 N 2 O 4 ([M+H] + )647.3091,found 647.3074；purity:92％,t R ＝2.0min.
Example 15
Preparation of N-cyclopropylmethyl-7 α - (3' -p-trifluoromethylbenzylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydrodetibane (15):
after 4 (100mg, 0.21mmol) and DMF (2 mL) were added to a 10mL single-neck reaction flask, anhydrous sodium carbonate (67.0 mg, 0.63mmol) and 4- (trifluoromethyl) benzyl bromide (37.0. Mu.L, 0.32 mmol) were added and reacted in an oil bath at 80 ℃ for 4 hours. Monitored by TLC, the reaction was stopped, extracted with ethyl acetate (10 mL × 3), the organic layers were combined, washed with water and saturated sodium chloride solution in order, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by silica gel column chromatography (PE/EA = 5/1) to give 43.0mg of a clear oil, yield: 32.7 percent. 1 H NMR(400MHz,CDCl 3 )δ7.58(d,J＝7.8Hz,2H),7.49(d,J＝7.9Hz,2H),7.12(t,J＝7.7Hz,1H),6.78–6.67(m,2H),6.64–6.52(m,2H),6.50(d,J＝7.8Hz,1H),4.58(s,1H),4.42(s,2H),3.87(s,3H),3.13(s,3H),3.01(dd,J＝12.4,5.7Hz,3H),2.64(dd,J＝11.5,4.8Hz,1H),2.29(dd,J＝15.9,6.3Hz,4H),2.18–2.07(m,1H),1.72(d,J＝12.7Hz,1H),1.67–1.49(m,3H),1.33(s,1H),1.19–1.07(m,2H),0.75(s,1H),0.51–0.40(m,2H),0.08(d,J＝4.7Hz,2H)； 13 C NMR(151MHz,CDCl 3 )δ147.47,147.00,143.96,143.61,141.79,132.89,128.92,128.70,127.42,125.53,125.51,119.36,118.91,114.47,113.62,111.26,92.96,59.78,58.61,56.61,50.87,48.01,45.93,43.86,43.79,36.52,36.05,35.69,29.68,29.63,22.78,18.96,9.46,4.03,3.32；HMRS:calc.for C 38 H 41 F 3 N 2 O 3 ([M+H] + )631.3142,found 631.3137；purity:96％,t R ＝4.1min.
Example 16
Preparation of N-cyclopropylmethyl-7 α - (3' -p-nitrobenzylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydro-northebaine (16):
after 4 (100mg, 0.21mmol) and DMF (2 mL) were added to a 10mL single-neck reaction flask, anhydrous sodium carbonate (67.0mg, 0.63mmol) and 4-nitrobenzyl bromide (53.0. Mu.L, 0.25 mmol) were added and reacted in an oil bath at 80 ℃ for 2 hours. TLC monitoring and stopping of the reaction, ethyl acetate (10 mL × 3) extraction, combining the organic layers, washing the organic phase with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure and separating by silica gel column chromatography (DCM/MeOH = 30/1) to give 34.0mg of yellow foamy solid, yield: 26.6 percent. Melting point: 160.8-162.7 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.20(d,J＝8.5Hz,2H),7.56(d,J＝7.4Hz,2H),7.11(s,1H),6.74(s,2H),6.62(s,1H),6.52(s,1H),6.46(d,J＝7.1Hz,1H),4.60(s,1H),4.49(s,2H),3.89(s,3H),3.14(s,3H),2.63(s,5H),2.32(s,2H),1.77(s,1H),1.65(s,5H),1.42(s,2H),1.27(s,1H),0.78–0.61(m,1H),0.47(s,1H),0.07(d,J＝3.6Hz,1H)； 13 C NMR(151MHz,CDCl 3 )δ148.31,147.69,147.16,143.72,132.84,129.04,128.65,127.75,123.88,119.60,119.00,114.63,113.68,111.19,93.04,59.79,58.62,56.65,50.96,47.86,45.97,43.87,36.50,36.09,35.70,31.93,29.71,22.83,22.70,18.90,14.13,9.47,4.07,3.34,1.02；HMRS:calc.for C 37 H 41 N 3 O 5 ([M+H] + )608.3119,found 608.3099；purity:95％,t R ＝3.4min.
Example 17
Preparation of N-cyclopropylmethyl-7 α - (3' -p-aminobenzylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydrodethiabaine (17):
compound 16 (30mg, 0.049mmol), methanol (2 mL) and 10% palladium on charcoal (5.0 mg, 0.046mmol) were added to the reaction flask, replaced with hydrogen, and the reaction was heated at 50 ℃ for 10 hours. TLC monitoring stopped the reaction, filtered the reaction solution to remove palladium on carbon, concentrated the filtrate under reduced pressure and separated by silica gel column chromatography (PE/EA = 3/1) to give 17.0mg of a light yellow oil, yield: 60.0 percent. 1 H NMR(400MHz,CDCl 3 )δ7.16(s,1H),7.12(d,J＝6.0Hz,1H),6.74(d,J＝11.0Hz,3H),6.67(d,J＝8.2Hz,2H),6.61(s,2H),6.53(d,J＝6.1Hz,1H),4.62(s,1H),4.20(s,1H),3.89(s,3H),3.20(d,J＝4.2Hz,3H),3.18–3.15(m,2H),3.04(d,J＝12.6Hz,4H),2.66(s,1H),2.33(s,4H),2.17(s,1H),1.45(d,J＝10.2Hz,4H),1.30(s,1H),0.78(s,1H),0.47(s,2H),0.10(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ148.16,147.13,146.12,145.54,141.85,132.99,129.33,128.95,128.83,119.94,118.95,116.64,115.23,114.49,113.48,111.08,93.93,65.56,59.77,58.47,56.66,51.05,50.92,48.09,45.97,43.86,36.15,35.69,29.68,29.35,22.68,18.75,14.11,9.46,4.12,3.27；HMRS:calc.for C 37 H 43 N 3 O 3 ([M+H] + )578.3377,found 578.3382；purity:97％,t R ＝2.8min.
Example 18
Preparation of N-cyclopropylmethyl-7 α - (3' -p-hydroxybenzylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydro-northebaine (18):
a10 mL single-neck reaction flask was charged with intermediate 4 (50mg, 0.11mmol) and 1, 2-dichlorethane (2 mL), followed by acetic acid (50. Mu.L), 4-hydroxybenzaldehyde (14.2mg, 0.12mmol), and reacted at room temperature for 2 hours.TLC detection, stop reaction, spin-dry reaction solution, add ethyl acetate (10 mL. Times.3) extract, combine organic layers, wash organic phase with saturated aqueous solution of sodium bicarbonate (10 mL), saturated aqueous solution of sodium chloride (10 mL) in order, dry over anhydrous sodium sulfate, concentrate under reduced pressure. The concentrate was dissolved in methanol (2 mL) and NaBH was added 4 (5.4mg, 0.14mmol) and reacted at room temperature for 3 hours. TLC monitoring, reaction completion, addition of acetone (2 mL) for quenching, and concentration under reduced pressure. The residue was isolated with a thick prep plate (DCM/MeOH = 50/1) to give 43.0mg of a light yellow oil, yield: 71.3 percent. 1 H NMR(400MHz,CDCl 3 )δ7.17(d,J＝8.1Hz,2H),7.12(t,J＝7.8Hz,1H),6.78(d,J＝8.0Hz,1H),6.71(d,J＝7.3Hz,3H),6.59(d,J＝9.0Hz,2H),6.53(d,J＝7.9Hz,1H),4.59(d,J＝9.0Hz,2H),4.20(s,2H),3.87(s,3H),3.16(s,3H),3.06–2.95(m,3H),2.70(s,1H),2.35(d,J＝12.5Hz,4H),2.19(s,1H),1.79–1.67(m,2H),1.63(dd,J＝13.9,6.7Hz,2H),1.49–1.33(m,2H),1.28(s,1H),0.81(s,1H),0.48(s,2H),0.12(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ155.09,148.02,147.03,143.14,141.88,132.88,131.17,128.91,119.02,118.85,115.46,115.42,114.51,113.79,111.24,92.71,65.06,59.68,58.51,56.65,50.85,47.93,45.83,43.97,43.66,36.40,36.11,29.67,22.91,18.93,9.33,4.21,3.30；HMRS:calc.for C 37 H 42 N 2 O 4 ([M+H] + )579.3217,found 579.3185；purity:97％,t R ＝2.5min.
Example 19
Preparation of N-cyclopropylmethyl-7 α - (3' - (4 "-acetoxybenzyl) amino) phenyl-6 α,14 α -endo-ethylene-tetrahydrodethiba-ine (19):
18 (40mg, 0.069mmol) and DCM (2 mL) were added to a 10mL single-neck reaction flask, triethylamine (35.0. Mu.L, 0.27 mmol) was added, acetyl chloride (12.5. Mu.L, 0.21 mmol) was added under ice-bath, and the reaction was carried out at room temperature for 5 hours. TLC monitoring, stopping reaction, extracting with ethyl acetate (10 mL. Times.3), combining organic layers, washing the organic phase with water and saturated solution of sodium chloride in turn,dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by silica gel column chromatography (DCM/MeOH = 15/1) to give 12.0mg of a white oil, yield: 28.0 percent. 1 H NMR(400MHz,CDCl 3 )δ7.39(d,J＝8.2Hz,2H),7.11(t,J＝7.6Hz,1H),7.04(d,J＝8.2Hz,2H),6.73(s,2H),6.57(s,2H),6.52(d,J＝7.9Hz,1H),4.61(s,1H),4.33(s,2H),4.06(s,1H),3.88(s,4H),3.22(s,1H),3.15(s,4H),3.10–2.94(m,3H),2.65(s,1H),2.30(s,2H),2.29(s,3H),2.27–2.22(m,1H),2.16(s,1H),1.67(s,3H),1.47–1.36(m,1H),1.25(s,1H),0.81–0.69(m,1H),0.48(s,2H),0.10(s,1H)； 13 C NMR(151MHz,CDCl 3 )δ169.54,149.70,147.82,147.06,143.48,137.20,132.96,128.91,128.42,121.68,119.05,114.42,113.61,111.09,92.99,59.76,58.53,56.66,50.89,47.92,45.94,43.90,36.47,36.13,35.65,29.71,22.76,21.10,18.91,9.48,7.89,4.07,3.28；HMRS:calc.for C 39 H 44 N 2 O 5 ([M+H] + )621.3250,found 621.3256；purity:95％,t R ＝3.6min.
Example 20
Preparation of N-cyclopropylmethyl-7 α - (3' - (4 "-cyclopropylmethoxybenzyl) amino) phenyl-6 α,14 α -endo-ethylene-tetrahydrothebaine (20):
to a 10mL single-neck reaction flask were added compound 18 (40mg, 0.069mmol) and DMF (2 mL), followed by addition of anhydrous sodium carbonate (22.0mg, 0.21mmol), bromomethylcyclopropane (8.0. Mu.L, 0.091 mmol), and reaction in an oil bath at 50 ℃ for 3 hours. TLC monitoring, reaction stopped, ethyl acetate (10 mL × 3) extraction, organic layers combined, organic phase washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by silica gel column chromatography (PE/EA = 5/1) to give 20.0mg of white oil, yield: 45.9 percent. 1 H NMR(400MHz,CDCl 3 )δ7.28(s,1H),7.12(t,J＝7.7Hz,1H),6.90(s,1H),6.86(d,J＝8.1Hz,2H),6.72(d,J＝7.0Hz,2H),6.59(s,2H),6.52(d,J＝7.8Hz,1H),4.60(d,J＝9.4Hz,1H),4.25(s,2H),3.87(s,3H),3.77(d,J＝6.9Hz,2H),3.15(s,3H),3.01(d,J＝16.2Hz,3H),2.63(s,1H),2.32(s,4H),2.14(s,1H),1.70(d,J＝13.0Hz,3H),1.40(dd,J＝15.7,9.9Hz,2H),1.27(s,1H),0.76(s,1H),0.64(d,J＝7.8Hz,2H),0.46(s,2H),0.34(t,J＝4.8Hz,2H),0.08(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ158.25,148.01,147.04,143.41,141.79,133.03,131.46,128.85,128.73,128.62,118.93,114.69,114.65,114.42,113.59,111.13,93.04,72.84,65.09,59.78,58.58,56.62,50.91,47.94,45.93,43.84,36.50,36.10,35.68,29.69,22.80,18.92,10.26,9.48,4.08,3.30,3.16；HMRS:calc.for C 41 H 48 N 2 O 4 ([M+H] + )633.3687,found 633.3665；purity:95％,t R ＝3.8min.
Example 21
Preparation of N-cyclopropylmethyl-7 α - (3' - (4 "-cyclobutylmethoxybenzyl) amino) phenyl-6 α,14 α -endo-ethylene-tetrahydrothebaine (21):
compound 18 (40mg, 0.069mmol) and DMF (2 mL) were added to a 10mL single-neck reaction flask, followed by addition of cesium carbonate (50.0mg, 0.21mmol), bromomethylcyclobutane (10.0. Mu.L, 0.091 mmol), and reaction in an oil bath at 95 ℃ for 3 hours. Monitored by TLC, the reaction was stopped, extracted with ethyl acetate (10 mL × 3), and the organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE/EA = 5/1) to give 28mg of a white oil, yield: and (4) percent. 1 H NMR(400MHz,CDCl 3 )δ7.29(s,2H),7.12(t,J＝7.5Hz,1H),6.86(d,J＝7.7Hz,2H),6.71(d,J＝7.3Hz,2H),6.59(s,2H),6.53(d,J＝7.6Hz,1H),4.62(s,1H),4.25(s,2H),3.90(d,J＝6.9Hz,2H),3.88(s,3H),3.15(s,3H),3.04(d,J＝15.8Hz,3H),2.76(dd,J＝14.3,7.2Hz,2H),2.69–2.52(m,1H),2.31(s,3H),2.13(s,3H),2.01–1.90(m,2H),1.86(dd,J＝16.1,7.5Hz,4H),1.70(s,2H),1.40(s,2H),0.94(d,J＝19.3Hz,1H),0.81–0.66(m,1H),0.47(s,2H),0.10(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ158.52,148.03,147.04,143.41,141.79,132.92,131.32,128.84,128.71,128.60,118.91,114.66,114.62,114.42,113.58,111.13,93.03,72.21,65.10,59.76,58.57,56.61,53.41,50.91,47.96,45.91,43.82,36.48,36.09,35.68,34.60,29.68,24.86,22.79,18.92,18.57,9.47,4.08,3.30；HMRS:calc.for C 42 H 50 N 2 O 4 ([M+H] + )647.3771,found 647.3771；purity:97％,t R ＝3.9min.
Example 22
Preparation of N-cyclopropylmethyl-7 α - (3' -1- (4 "-chloro-3" -pyridine) -methylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydrodethiabaine (22):
after adding intermediate 4 (20mg, 0.042mmol) and 1,2-dichloroethane (2 mL) to a 10mL single-neck reaction flask, acetic acid (20. Mu.L, 0.63 mmol) and 2-chloropyridine-5-carbaldehyde (6.6mg, 0.047mmol) were added and reacted at room temperature for 2 hours. TLC monitoring, stop reaction, spin-dry reaction solution, extract with ethyl acetate (10 mL. Times.3), combine organic layers, wash organic phase with saturated aqueous solution of sodium bicarbonate (10 mL), saturated aqueous solution of sodium chloride (10 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate was dissolved in methanol (2 mL) and NaBH was added 4 (2.1mg, 0.055mmol), and reacted at room temperature for 3 hours. TLC monitoring, reaction completion, addition of acetone (2 mL) for quenching, and concentration under reduced pressure. The residue was isolated with a thick prep plate (DCM/MeOH = 50/1) to give 18.0mg of a light yellow oil, yield: 71.0 percent. 1 H NMR(400MHz,CDCl 3 )δ8.40(s,1H),7.70(d,J＝8.0Hz,1H),7.29(d,J＝9.1Hz,1H),7.11(t,J＝7.6Hz,1H),6.75(t,J＝9.4Hz,2H),6.64(d,J＝7.6Hz,1H),6.53(s,1H),6.48(d,J＝7.7Hz,1H),4.63(s,1H),4.36(s,2H),3.88(s,3H),3.14(s,3H),3.07(d,J＝17.7Hz,2H),2.59(s,3H),2.32(s,1H),2.25–2.11(m,1H),2.01(s,1H),1.83(d,J＝12.1Hz,1H),1.67(t,J＝12.5Hz,2H),1.43(s,1H),1.28(s,2H),0.85–0.77(m,1H),0.59(s,2H),0.28(s,1H)； 13 C NMR(151MHz,CDCl 3 )δ150.18,148.70,147.12,138.02,134.32,129.04,124.25,119.37,114.71,111.46,59.22,58.26,56.66,50.91,45.17,36.17,31.89,29.78,29.67,29.49,29.33,29.29,22.66,18.73,14.09,3.28,0.98；HMRS:calc.for C 36 H 40 ClN 3 O 3 ([M+H] + )598.2831,found 598.2831；purity:97％,t R ＝2.9min.
Example 23
Preparation of N-cyclopropylmethyl-7 α - (3 ' - (N ' -methyl-N ' -benzyl) amino) phenyl-6 α,14 α -endo-ethylene-tetrahydrothebaine (23):
a10 mL single-neck reaction flask was charged with Compound 5 (30mg, 0.062mmol) and DMF (2 mL), followed by addition of anhydrous sodium carbonate (19.2mg, 0.18mmol), benzyl bromide (9. Mu.l, 0.074 mmol), and oil bath reaction at 80 ℃ for 22 hours. TLC monitoring, the reaction was stopped, ethyl acetate (10 mL × 3) was extracted, organic layers were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE/EA = 10/1) to give 20.0mg of colorless transparent oil, yield: and 56.2 percent. 1 H NMR(400MHz,CDCl 3 )δ7.28(d,J＝7.5Hz,2H),7.26–7.20(m,3H),7.17(t,J＝7.7Hz,1H),6.72(d,J＝5.6Hz,2H),6.69–6.62(m,2H),6.58(d,J＝7.5Hz,1H),4.59(s,1H),4.54(s,2H),3.87(s,3H),3.18(s,1H),3.12(s,3H),3.04(s,3H),2.99(s,3H),2.63(s,1H),2.32(s,4H),2.14(s,1H),1.77–1.66(m,1H),1.39(d,J＝27.5Hz,2H),1.22(d,J＝26.5Hz,2H),0.87–0.71(m,2H),0.46(s,2H),0.09(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ149.51,147.03,143.13,141.77,139.24,132.96,128.77,128.52,126.77,126.67,118.90,117.77,114.40,113.60,110.65,92.78,59.76,58.57,56.96,56.62,50.76,45.85,43.89,38.82,36.50,36.08,35.66,29.67,22.79,19.05,9.47,4.09,3.30；HMRS:calc.for C 38 H 44 N 2 O 3 ([M+H] + )577.3425,found 577.3424；purity:95％,t R ＝3.7min.
Example 24
Preparation of N-cyclopropylmethyl-7 α - (3 '- (3 "- (carbazol-4"' -oxy) -2 "-propanolyl) amino) phenyl-6 α,14 α -endo-ethylene-tetrahydrodetibamide (24):
4 (30mg, 0.063mmol) and isopropanol (2 mL) were added to a 10mL single-neck reaction flask under nitrogen protection, followed by 4-epoxypropyleneoxycarbazole (15mg, 0.063mmol), and reacted in an oil bath at 85 ℃ for 16 hours. TLC, stopped the reaction, removed the solvent under reduced pressure, and chromatographed on silica gel (PE/EA = 2/1) to give 18mg of a white solid, yield: 40.1%, melting point: 145.5-146.8 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.26(d,J＝7.7Hz,1H),7.40(d,J＝8.9Hz,2H),7.32(t,J＝8.0Hz,1H),7.28(d,J＝4.5Hz,1H),7.14(t,J＝7.6Hz,1H),7.07(d,J＝8.0Hz,1H),6.80–6.64(m,4H),6.59(t,J＝6.0Hz,2H),4.55(s,1H),4.46(s,1H),4.35(s,2H),3.88(d,J＝8.4Hz,3H),3.61(s,1H),3.49(d,J＝6.6Hz,1H),3.16(d,J＝2.3Hz,3H),3.03(s,1H),2.98(s,2H),2.72(s,1H),2.65(s,1H),2.31(s,4H),2.11(s,1H),1.72(s,2H),1.43(s,1H),1.28(s,1H),1.24(s,1H),0.82(d,J＝8.6Hz,2H),0.46(s,2H),0.09(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ154.87,147.94,147.09,140.98,138.75,129.02,126.70,125.11,122.75,122.38,119.79,119.04,115.05,114.97,112.63,111.50,110.19,104.15,101.26,70.10,70.04,69.01,58.44,56.64,50.91,47.11,47.06,36.12,29.68,22.68,18.95,14.10,3.29；HMRS:calc.for C 45 H 49 N 3 O 5 ([M+H] + )712.3745,found 712.3730；purity:97％,t R ＝4.5min.
Example 25
Preparation of N-cyclopropylmethyl-7 α - (3' -cyclopropylcarboxamido) phenyl-6 α,14 α -endo-ethylene-tetrahydro-northebaine (25):
a10 mL single-neck reaction flask was charged with 4 (100mg, 0.21mmol) and DCM (2 mL), followed by HATU (121.6mg, 0.32mmol), diisopropylethylamine (70. Mu.L, 0.42 mmol), and cyclopropanecarboxylic acid(20. Mu.L, 0.25 mmol), the reaction was stirred at room temperature for 4 hours. TLC monitoring, stopping the reaction, removing the solvent under reduced pressure, extracting with ethyl acetate (10 mL × 3), combining the organic layers, washing the organic phase with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and separating by silica gel column chromatography (PE/EA = 5/1) to give 26.0mg of light yellow oil, yield: 23.7 percent. 1 H NMR(400MHz,CDCl 3 )δ7.70(s,1H),7.54(s,1H),7.24(s,1H),7.08(s,1H),6.73(d,J＝8.1Hz,1H),6.59(d,J＝8.1Hz,1H),4.60(s,1H),3.88(s,3H),3.19(s,3H),3.15–3.05(m,2H),3.01(d,J＝18.4Hz,1H),2.71(s,1H),2.36(dd,J＝25.9,7.7Hz,5H),2.19(d,J＝8.2Hz,2H),1.82–1.63(m,4H),1.49(d,J＝7.4Hz,2H),1.07(s,2H),0.82(d,J＝6.7Hz,2H),0.78(s,1H),0.55–0.39(m,2H),0.11(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ171.80,146.98,143.37,141.82,138.11,132.81,128.52,125.30,120.66,119.00,117.46,113.64,93.09,59.84,58.52,56.62,51.06,46.02,43.91,43.80,36.40,36.11,35.65,29.66,22.81,18.86,15.84,9.43,7.87,4.14,3.38；HMRS:calc.for C 34 H 40 N 2 O 4 ([M+H] + )541.3061,found 541.3062；purity:99％,t R ＝3.0min.
Example 26
Preparation of N-cyclopropylmethyl-7 α - (3' -benzoylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydrodethiabaine (26):
to a 10mL single-neck reaction flask were added 4 (50mg, 0.11mmol) and DCM (2 mL), followed by triethylamine (45.0. Mu.L, 0.34 mmol), benzoyl chloride (15. Mu.L, 0.13 mmol) under ice-bath, and the reaction was carried out at room temperature for 6 hours. TLC, stopped the reaction, extracted with ethyl acetate (10 mL × 3), combined organic layers, washed the organic phase with water and saturated sodium chloride solution in order, dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on silica gel column (PE/EB = 20/1) to give 32.0mg of white solid, yield: 55.2%, melting point: 125.2-126.2 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.87(d,J＝8.2Hz,3H),7.57–7.51(m,1H),7.48(t,J＝7.4Hz,2H),7.41(d,J＝7.8Hz,1H),7.31(t,J＝7.8Hz,1H),7.15(d,J＝7.5Hz,1H),6.73(d,J＝8.1Hz,1H),6.59(d,J＝8.1Hz,1H),4.63(s,1H),3.88(s,3H),3.23(s,3H),3.12(dd,J＝14.7,6.2Hz,2H),3.02(d,J＝18.4Hz,1H),2.67(dd,J＝11.6,4.9Hz,1H),2.40–2.30(m,3H),2.30–2.22(m,2H),2.16(td,J＝12.5,5.3Hz,1H),1.75(d,J＝14.0Hz,2H),1.69(d,J＝6.9Hz,1H),1.51(dd,J＝21.6,9.2Hz,1H),1.41(dd,J＝13.0,5.6Hz,1H),1.37(s,1H),0.76(d,J＝6.0Hz,1H),0.46(t,J＝7.9Hz,2H),0.09(d,J＝4.5Hz,2H)； 13 C NMR(151MHz,CDCl 3 )δ165.75,146.98,143.59,141.79,137.81,135.13,132.85,131.77,128.77,128.60,126.97,125.95,121.20,118.98,118.07,113.68,93.33,59.85,58.54,56.63,51.16,46.08,43.97,43.86,36.39,36.11,35.68,29.67,29.64,22.77,18.75,14.10,9.46,4.09,3.36；HMRS:calc.for C 37 H 40 N 2 O 4 ([M+H] + )577.3061,found 577.3058；purity:96％,t R ＝3.4min.
Example 27
Preparation of N-cyclopropylmethyl-7 α - (3' -p-methoxybenzoylamino) phenyl-6 α,14 α -endo-ethylene-tetrahydrodetibaine (27):
after 4 (100mg, 0.21mmol) and DCM (2 mL) were added to a 10mL single-neck reaction flask, triethylamine (90.0. Mu.L, 0.63 mmol) was added, and 4-methoxybenzoyl chloride (56.0. Mu.L, 0.42 mmol) was added under ice-bath and reacted at room temperature for 4 hours. Monitored by TLC, the reaction was stopped, extracted with ethyl acetate (10 mL × 3), the organic layers were combined, washed successively with water and saturated solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by silica gel column chromatography (DCM/MeOH = 15/1) to give 44.0mg of white oil, yield: 32.9 percent. 1 H NMR(400MHz,CDCl 3 )δ7.84(d,J＝7.7Hz,3H),7.39(d,J＝7.5Hz,1H),7.31(d,J＝7.5Hz,1H),7.13(d,J＝7.2Hz,1H),6.97(d,J＝8.2Hz,2H),6.73(d,J＝8.0Hz,1H),6.60(d,J＝7.9Hz,1H),4.62(s,1H),3.87(s,6H),3.27(d,J＝11.0Hz,1H),3.22(s,3H),3.13(s,2H),3.03(d,J＝18.3Hz,1H),2.69(s,1H),2.34(d,J＝21.3Hz,4H),2.19(s,1H),1.77(s,1H),1.74(s,1H),1.55–1.33(m,3H),0.91(t,J＝11.7Hz,1H),0.78(s,1H),0.49(d,J＝7.6Hz,2H),0.11(s,2H)； 13 C NMR(151MHz,CDCl 3 )δ165.28,162.42,147.01,141.89,138.01,128.87,128.57,127.27,125.74,121.14,119.03,118.05,113.95,113.80,93.19,59.76,58.48,56.64,55.45,51.15,45.96,44.02,43.85,36.32,36.13,29.67,22.92,18.73,14.18,9.25,4.25,3.35；HMRS:calc.for C 38 H 42 N 2 O 5 ([M+H] + )607.3166,found 607.3137；purity:98％,t R ＝3.7min.
Example 28
Preparation of N-cyclopropylmethyl-7 α - (3' - (3 ",4" -dimethylbenzoylamino)) phenyl-6 α,14 α -endo-ethylene-tetrahydrothebaine (28):
to a 10mL single-neck reaction flask were added 4 (100mg, 0.21mmol) and DCM (2 mL), followed by HATU (121.6 mg, 0.32mmol), diisopropylethylamine (70. Mu.L, 0.42 mmol), and 3, 4-dimethylbenzoic acid (37.5mg, 0.25mmol), and the reaction was stirred at room temperature for 4 hours. TLC, stops the reaction, removes the solvent under reduced pressure, extracts with ethyl acetate (10 mL × 3), combines the organic layers, washes the organic phase with saturated sodium chloride solution, dries over anhydrous sodium sulfate, concentrates under reduced pressure and separates by silica gel column chromatography (PE/EA = 5/1) to give 50.0mg of white solid, yield: 39.4%, melting point: 202.6-204.5 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.85(d,J＝9.3Hz,1H),7.66(s,1H),7.58(d,J＝7.6Hz,1H),7.39(d,J＝7.9Hz,1H),7.34–7.19(m,2H),7.12(d,J＝7.1Hz,1H),6.73(d,J＝8.2Hz,1H),6.60(d,J＝7.7Hz,1H),4.63(s,1H),3.87(s,3H),3.22(s,3H),3.13(s,2H),3.02(d,J＝18.3Hz,1H),2.68(s,1H),2.34(s,2H),2.32(s,6H),2.30–2.24(m,1H),2.19(s,1H),1.76(d,J＝12.0Hz,4H),1.58–1.29(m,4H),0.78(s,1H),0.47(s,1H),0.11(s,1H)； 13 C NMR(151MHz,CDCl 3 )δ165.82,146.98,143.51,141.78,140.95,137.98,137.19,132.86,132.56,129.89,128.73,128.54,128.29,125.75,124.26,121.09,118.96,117.96,113.68,93.34,59.84,58.52,56.63,51.15,46.06,43.97,43.87,36.38,36.10,35.66,29.63,22.77,19.82,19.77,18.73,9.45,4.09,3.35；HMRS:calc.for C 39 H 44 N 2 O 4 ([M+H] + )605.3374,found 605.3365；purity:99％,t R ＝4.0min.
Performance test 1:radioligand binding assay (Ki value determination)
The compounds used in pharmacological binding force screening are all in free base form. The experiment is divided into a binding tube and a non-specific binding tube, and a plurality of groups of sample tubes are additionally arranged for adding the compound to be screened. 80uL of cell suspension for expressing kappa, mu and delta receptors of opium is added into the total binding tube, and the [ 2 ], [ mu ] and [ delta ] receptors are respectively added into the three tubes 3 H]U69593、[ 3 H]DAMGO、[ 3 H]DPDPDPE, (final concentration 0.35 nM) 10uL; u50488, DAMGO and DPDPDPE are respectively added into the corresponding non-specific tube to enable the final concentration to be 1uM; the sample tube was filled with the same concentration of drug 10uL (final concentration of 1 uM) and adjusted to a final volume of 100uL with 50mM Tris.HCl (pH 7.4). The reaction was incubated at 37 ℃ for 30min and then quenched in an ice bath. The samples were suction filtered through GF/C (Whatman) glass fiber filter at negative pressure on a Millipore sample collector. After washing three times with ice-cold 50mM Tris.HCl (pH 7.4), 3mL each time, and drying the filter paper, the filter paper is placed in a 0.5mL Eppendorf tube, 0.5mL lipophilic scintillation fluid is added, and the radioactivity is measured by a Beckman LS-6500 multifunctional liquid scintillation counter. Each concentration is two-fold. Inhibition = (total binding rate dpm-sample tube dpm)/(total binding tube dpm-non-specific binding tube dpm) × 100%. IC calculation Using Prism 5.0 software 50 . Calculating K by the following formula i Value, K i ＝IC 50 /(1+[L]/K d )，[L]As concentration of the labeled ligand added, K d Is the equilibrium dissociation parameter of the labeled ligand. The results of the experiment are shown in table 1.
TABLE 1 binding Activity of Compounds to receptors
Performance test 2[ 35 S]GTP γ S binding experiments
Protein concentration was measured with Bradford protein concentration assay kit: respectively adding standard protein BSA with the concentrations of 0, 50, 100, 200 and 250 mu g/ml and a sample to be detected into a 96-well plate, and adding 20 mu l of the sample into each well; adding 200 μ l of G250 staining solution into each well, standing at room temperature for 3-5min, and measuring absorbance at A595 wavelength with microplate reader. Protein concentration was calculated from the standard curve.
Table 2 [ 2 ] 35 S]GTP γ Non-specific binding tubes, base tubes, volumes of each component in sample tubes in S-binding assays
The prepared membrane receptor was diluted to the desired concentration with reaction buffer (R.B) and loaded (unit: μ l) as shown in Table 2. The reaction tubes were incubated in a water bath at 27 ℃ for 1 hour, filtered under reduced pressure with a glass fiber membrane and counted by liquid scintillation. The following formula is used for calculation:
[ 35 S]GTP γ s binding Rate =100 × (cpm) Sample(s) –cpm Non-specific binding )/(cpm Substrate -cpm Non-specific binding )
The results of the experiment are shown in table 3.
Table 3 functional activity assay data.
a Under the stimulation of a compound 35 S]Efficacy of GTP γ S binding to CHO cell membranes stably expressing opioid receptors. Each value represents the mean ± SEM of at least three independent experiments; b was not determined. c Compounds were tested at 1. Mu.M and 10. Mu.M concentrations for [35S ]]The activation degree of GTP gamma S is low.
The male Kunming mice (18-22 g) used in the experimental animal experiments were from the Experimental animal center of the Chinese academy of sciences (Shanghai, china). All mice were randomly divided into groups (5 mice per group) and kept for a 12 hour light/dark cycle (8 am, 00 light) in a temperature controlled environment, with free access to food and water. All animal tests were conducted under the guidelines of the care and use of laboratory animals of the national institutes of health, usa, with reference to standard animal protocols (2019-01-LJG-41).
Hot Plate model (Hot Plate Test) analgesia Test mice were placed on a heated smooth surface (55 ℃) and the pain latency (latency) between their placement and the licking of the hindpaw was measured. Before dosing, the time to pain response was measured twice for each mouse, and the average was taken as the basal pain latency (basal latency). Mice that did not respond within 30 seconds were no longer used as subjects for subsequent trials. The mice were removed within 60s of analgesia, avoiding tissue damage. The analgesic effect results were calculated as follows: % antinociception =100 × (test latency-pre-basal latency)/(cut-off time-basal latency), analgesic ED 50 Values are compound doses at which 50% analgesia is produced. The results are shown in FIG. 1.
Writhing model (Abdominal constraint Test) analgesia Test mice writhing method indicates that Abdominal cavity injection of injury substances causes Abdominal pain of mice, and writhing reaction (namely, abdominal indent, trunk and hind limb stretch, and hip rising) is shown. After intraperitoneal injection of different doses of the test compound, 0.6% acetic acid (10 ml/kg body weight) was intraperitoneally injected into each mouse, and the number of writhing that occurred within 20min was recorded for each mouse. Calculated by the following formula: % analgesia =100 × (control group average)Number of average writhing-number of writhing in experimental group)/number of average writhing in control group. Analgesic ED 50 Values are compound doses at which 50% analgesia is produced.
The results are shown in Table 4 and FIG. 2.
Table 4 hot plate and writhing assay to evaluate analgesic ED of intraperitoneal injections of compounds 8 and 12 50
a Analgesic ED of Compound 12 50 Calculated from the data 4 hours after dosing (8-10 mice/group). In parentheses are 95% confidence intervals.
Spontaneous activity (lococotoractivity) test: the mouse spontaneous activity behavior detection assay is a classical behavioral assay for evaluating spontaneous activity and anxiety states in mice. Mice were first pretreated with u50,488h (5 mg/kg) or test compounds by intraperitoneal injection, placed in a test chamber (30 × 30 × 40 cm) after injection or 2h after injection, and the spontaneous locomotor activity of the mice was monitored within 30min using a video tracking system (JLBehv-LAG, shanghai, china). The results are shown in FIG. 3.
Claims (6)
1. A 7 α - (3' -substituted aminophenyl) -6 α,14 α -endo-ethylene-tetrahydrodesmethylthebaine derivative having the formula (i) or a pharmaceutically acceptable salt thereof, wherein the structural formula is:
2. the 7 α - (3' -substituted aminophenyl) -6 α,14 α -endo-ethylene-tetrahydrodesmethyl-thebaine derivative according to claim 1 or a pharmaceutically acceptable salt thereof, which is a salt with an inorganic or organic acid selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate or biphosphate, acetate, benzoate, tartrate, succinate, maleate, fumarate, lactate, citrate, gluconate, methanesulfonate, benzenesulfonate, p-toluenesulfonate.
3. Use of a 7 α - (3' -substituted aminophenyl) -6 α,14 α -endo-ethylene-tetrahydrodethiabaine derivative according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of an opioid receptor-mediated therapeutic agent.
4. The use of a 7 α - (3' -substituted aminophenyl) -6 α,14 α -endo-ethylene-tetrahydrodethiabaine derivative according to claim 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pain, depression, opiate addiction, pruritus.
5. The use according to claim 4, wherein the pain is pain during treatment or relief of surgery, chronic pain, neuropathic pain, cancer pain.
6. The use according to claim 4, wherein the pruritus is intractable pruritus accompanied by uremia, diabetic nephropathy, chronic liver disease, malignant tumor and serious disease.
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