CN111440169A - Alkaloid nitrogen nitride derivative and preparation method thereof - Google Patents

Alkaloid nitrogen nitride derivative and preparation method thereof Download PDF

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CN111440169A
CN111440169A CN202010260240.0A CN202010260240A CN111440169A CN 111440169 A CN111440169 A CN 111440169A CN 202010260240 A CN202010260240 A CN 202010260240A CN 111440169 A CN111440169 A CN 111440169A
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membered
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刘运根
支志明
张世龙
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Southwest University of Science and Technology
Southern University of Science and Technology
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Abstract

The invention relates to alkaloid nitrogen nitride and salts thereof and a preparation method, and the alkaloid nitrogen nitride and the salts thereof have potential pharmaceutical application prospects. The method takes alkaloid natural products as raw materials, takes phenyl hydroxylamine compounds as nitrogen sources, and reacts in a reaction medium under the catalysis of a metal-organic catalyst and at normal temperature in a container for 2-24 hours to realize the amination reaction of tertiary amine so as to obtain the alkaloid nitrogen nitride, and the salt formation can be realized through acidification. The method of the invention can obtain target products with low cost and high yield, the used amination reagent and metal-organic catalyst are cheap and easy to obtain, and the reagent and reaction conditions used in the reaction have good tolerance to functional groups of reaction raw materials, thus having wide universality and hopefully endowing medical research value to biological alkali nitrogen nitride.

Description

Alkaloid nitrogen nitride derivative and preparation method thereof
Background
The existing mode of nitrogen element in organic compound is various, but in alkaloid in natural product, nitrogen element mainly exists in the form of alkylamine (primary amine, secondary amine, tertiary amine) or arylamine (indole, quinoline, isoquinoline) and amide. Alkaloids, a class of natural products, generally possess significant biological activity and are present in the natural products in free, salt and nitroxide forms. Alkaloid nitroxides are structurally similar to the parent alkaloids and therefore both exhibit similar biological activity. And because the oxidized alkaloid has electronegative oxygen atoms, the alkaloid nitrogen oxide has larger polarity compared with the parent compound, and the distribution, metabolism, toxicity and targeting in vivo have larger changes, so the alkaloid nitrogen oxide also has great progress in clinical application. For example, Matrine-N-oxide (Matrine-N-oxide) which is a natural product from sophora flavescens is clinically applied to the auxiliary treatment of tumors, and large-tail-shaken alkali nitrogen oxide (indigo-N-oxide) separated from green bristlegrass can be clinically used for the treatment of gastrointestinal cancer, leukemia and melanoma. Meanwhile, due to the fact that electronegativity of oxygen element is large, some nitrogen oxides synthesized based on tertiary amine alkaloid have poor thermal stability and light stability, so that all alkaloids have nitrogen oxides corresponding to the nitrogen oxides.
The nitrogen element is a neighboring element of the oxygen element and has a smaller electronegativity, and the chemical properties of parts of the nitrogen element are similar. Thus if a tertiary amine alkaloid nitrogen nitride (R) could be prepared3N+-NH-) Its stability, membrane permeability in cells, is theoretically better than its corresponding nitroxide. At present, only one document (nat. chem,5,510-517) reports nitrogen nitrides as tertiary amine alkaloids3N+-NH-) The preparation of (1) but the procedure is somewhat cumbersome: 1. and (3) the sulfamide reacts with tertiary amine under the rhodium catalyst to generate nitrogen sulfamide. 2. Palladium/carbon catalyzed hydrogenation of nitrogen sulfonamide compound to nitrogen sulfonamide compound to obtain nitrogen nitride (R) as tertiary amine alkaloid3N+-NH-). This study coincidentally produced alkaloid nitrogen nitride (R) for the first time3N+-NH-) However, the reaction steps are complicated, the yield is very low, the substrate universality is low, the reaction conditions are harsh, and the rhodium catalyst is too expensive. The content density of natural products in plants is low, and the medical research value of the natural products can be improved only by inventing an efficient and economic nitrogen nitride preparation method.
Disclosure of Invention
The invention aims to provide a series of nitrogen nitrides of tertiary amine alkaloid, and the invention aims to overcome the problems of the prior art (such as low nitrogen nitride yield, low substrate universality, harsh reaction conditions and excessively expensive rhodium catalyst).
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention provides a nitrogen nitride of tertiary amine alkaloid shown in formula (2) or formula (4),
Figure BDA0002439012430000021
wherein R in formula (2) or formula (4)1、R2、R3、R4、R5Five-membered rings, six-membered rings, seven-membered rings, spiro rings or fused rings can be formed between two of them, and n is 1,2 or 3.
In some embodiments, the five-, six-, or seven-membered ring may be a saturated or unsaturated ring, which may carry more than one olefinic bond; in some embodiments, the five-membered, six-membered, seven-membered, spiro, or fused ring may be substituted on the ring with a fused or spiro ring group; in some embodiments, each ring of the five-membered, six-membered, seven-membered, spiro, or fused rings can be carbocyclic or heterocyclic, and each ring is optionally substituted with one or more substituents described herein. The substituents described herein may be hydroxyl, methoxy, carbomethoxy, vinyl, carbonyl, heterocyclyl or carbocyclyl, and the like.
In some embodiments, the compound of formula (2) or formula (4) has the following structural formula:
Figure BDA0002439012430000022
Figure BDA0002439012430000031
in some embodiments, the biobase (2) or formula (4) of the present invention is a compound,
Figure BDA0002439012430000032
Figure BDA0002439012430000041
Figure BDA0002439012430000051
in still other embodiments, the biobase (2) or formula (4) of the present invention is a compound,
Figure BDA0002439012430000052
the invention also provides application of the nitrogen nitride of the tertiary amine alkaloid shown in the formula (2) or the formula (4) in preparation of antitumor drugs.
In another aspect, the present invention provides a method for preparing a nitrogen nitride compound as a tertiary amine alkaloid represented by formula (2) or formula (4), comprising: biological alkali type (1) or formula (3) is taken as a raw material, phenyl hydroxylamine compound is taken as a nitrogen source, the raw material is stirred in a reaction medium at normal temperature for 2 to 24 hours in an open way under the catalytic action of a metal-organic catalyst, and the compounds shown in formula (2) and formula (4) are obtained after purification,
Figure BDA0002439012430000061
wherein R in the formula (1), the formula (2), the formula (3) and the formula (4)1、R2、R3、R4、R5Five-membered rings, six-membered rings, seven-membered rings, spiro rings or fused rings can be formed between two of them, and n is 1,2 or 3.
In some embodiments, the five-, six-, or seven-membered ring may be a saturated or unsaturated ring, which may have more than one ethylenic bond thereon, which may be substituted with a substituent as described herein.
The terms "fused bicyclic ring," "fused bicyclic group," and "fused ring group" are used interchangeably herein and all refer to a monovalent or multivalent saturated or partially unsaturated bridged ring system, which refers to a non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturated systems, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic groups may be substituted thereon).
The terms "spirocyclic", "spiro", "spirobicyclic" or "spirobicyclic" are used interchangeably herein to refer to a monovalent or multivalent saturated or partially unsaturated ring system in which one ring is derived from a specific ring carbon atom on another ring. For example, as described below, one saturated bridged ring system (rings B and B') is referred to as "fused bicyclic ring", while ring a and ring B share one carbon atom in two saturated ring systems, referred to as "spiro" or "spirobicyclic ring". Each ring in the fused bicyclic and spirobicyclic groups may be a carbocyclic or heterocyclic group, and each ring is optionally substituted with one or more substituents described herein.
Figure BDA0002439012430000062
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2The radicals may optionally be substituted-C (O) -substitution. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, thiazepinyl, thiazepanyl, homopiperazinyl, homopiperidinyl, oxazepanyl, and the like
Figure BDA0002439012430000071
Radical, diaza
Figure BDA0002439012430000072
Radical, S-N-aza
Figure BDA0002439012430000073
Radicals, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
In one embodiment, heterocyclyl is a 4-7 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 4 to 7 atoms may be carbon-based or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may beOptionally oxidized to S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 to 7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxacycloheptanyl, oxazepanyl, thiazepanyl, thiazepan
Figure BDA0002439012430000074
Radical, diaza
Figure BDA0002439012430000075
Radical, S-N-aza
Figure BDA0002439012430000076
And (4) a base. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. Said heterocyclyl group of 4 to 7 atoms may be optionally substituted by one or more substituents as described herein.
In another embodiment, heterocyclyl is a 4-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4 ring atoms in which at least one ring atom is substituted by a member selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group consisting of 4 atoms may be carbon-based or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Hetero having 4 atomsExamples of cyclic groups include, but are not limited to: azetidinyl, oxetanyl, thietanyl. The 4-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In another embodiment, heterocyclyl is a5 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a 5-atom heterocyclic group may be carbon-based or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl. In heterocyclic radicals of-CH2Examples of the-group substituted by-C (O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In another embodiment, heterocyclyl is a 6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 6 atoms may be carbon-based or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 6 atoms include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. In heterocyclic radicals of-CH2-groupExamples of substitution by-C (O) -include, but are not limited to, 2-piperidinonyl, 3, 5-dioxopiperidinyl, and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In yet another embodiment, heterocyclyl is a 7-12 atom heterocyclyl and refers to a saturated or partially unsaturated spiro-or fused-bicyclic ring containing 7-12 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group of 7 to 12 atoms may be carbon-based or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 7 to 12 atoms include, but are not limited to: indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. Said heterocyclyl group of 7 to 12 atoms may be optionally substituted by one or more substituents as described herein.
The substituents described in the present invention may be hydroxyl, methoxy, carbomethoxy, vinyl, carbonyl or the like.
In some embodiments, the biobase (1) or formula (3) of the present invention is a compound of:
Figure BDA0002439012430000091
Figure BDA0002439012430000101
in still other embodiments, the biobase (1) or formula (3) of the present invention is a compound of:
Figure BDA0002439012430000102
Figure BDA0002439012430000111
Figure BDA0002439012430000121
as a preferred embodiment of the present invention, the alkaloid, nitrogen source and metal-organic catalyst are comprised of the following proportions: alkaloid: nitrogen source: the metal-organic catalyst is 1: 1-2: 0.025-0.05.
In a preferred aspect, the starting alkaloid contains at least one free alkaloid of aliphatic, saturated tertiary amine structure, a hydrochloride salt, or a hydrobromide salt.
In a preferred aspect, the feedstock nitrogen source consists of a nitrogen source selected from the group consisting of: one of O- (2, 4-dinitrophenyl) hydroxylamine, O- (2-trifluoromethyl-4-nitrophenyl) hydroxylamine and O- (2, 4, 6-trinitrophenyl) hydroxylamine.
In a preferred aspect, the metal-organic catalyst is selected from one of the following metals and one or more selected from the following ligands, and the metal or metal ion thereof is selected from iron, manganese, cobalt, nickel, copper, rhodium, ruthenium; the ligand is selected from polypyridine, substituted polypyridine, porphyrin and phthalocyanine.
In a preferred aspect, the reaction medium is one of dichloromethane, dichloroethane, acetonitrile, chloroform, N-dimethylformamide, tetrahydrofuran, or a combination thereof.
In one embodiment, the purification method is to use 200 mesh alumina column chromatography to obtain the alkaloid nitrogenates represented by the formulas (2) and (4), add the obtained alkaloid nitrogenate compound into a reaction medium, add the corresponding acid, and evaporate the solvent to obtain the corresponding salt.
In a preferred aspect, the salts may be inorganic acid salts such as their hydrochloride, hydrobromide, nitrate, sulphate, phosphate and organic salts such as their methanesulfonate, ethanesulfonate, propanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, p-nitrobenzenesulfonate and the like.
In a preferred aspect, the 200 mesh alumina can be acidic, neutral, and basic alumina.
The invention has the advantages that:
the invention provides a series of nitrogen nitrides of tertiary amine alkaloids shown in formulas (2) and (4), and the nitrogen nitrides are found to have antitumor activity.
The invention also provides a preparation method of the tertiary amine alkaloid nitrogen nitride shown in the formula (2) and the formula (4) by taking the biological alkali type (1) or the formula (3) as a raw material, taking a phenyl hydroxylamine compound as a nitrogen source, stirring the mixture in a reaction medium at normal temperature for 2 to 24 hours in an open manner under the catalytic action of a metal-organic catalyst, and purifying the mixture. The preparation method has the advantages of high yield, wide substrate universality, mild reaction conditions, cheap catalyst and one-step synthesis.
Detailed Description
The present invention will be further described below by way of specific embodiments, but the present invention is not limited to only the following examples. It will be apparent to those skilled in the art that the preparation method of the present invention may be appropriately modified and substituted for the components having the same effects without departing from the spirit, scope and spirit of the present invention, and they are all considered to be included in the scope of the present invention.
In the present invention, the term alkaloid refers to a class of nitrogen-containing basic organic compounds existing in nature (mainly plants, but also in animals), preferably, the raw material alkaloid has at least one tertiary amine structure, and further the tertiary amine is preferably saturated fatty amine.
In the present invention, the term "nitrogen nitride" refers to a compound in which a nitrogen atom of a tertiary amine forms an N-N bond with another nitrogen atom.
In the present invention, the term "metal-organic catalyst" refers to a catalyst formed from a metal atom or ion and a nitrogen-containing heterocyclic compound ligand.
In the present invention, preferably, the molar ratio of the nitrogen source to the alkaloid as the raw material for the reaction is 1: 1-2: 1. such nitrogen sources may be purchased directly from the market or synthesized.
In the present invention, a common reaction vessel, a reaction detection means, a product purification process, etc. are used, which are well known to those skilled in the art.
EXAMPLE 1 preparation of organic ligands in Metal-organic catalysts
In the present invention, the organic ligand in the metal-organic catalyst is prepared by the following steps: the benzaldehyde derivative and pyrrole are dissolved in dry dichloromethane (23mM) in one equivalent, boron trifluoride ethyl ether which is 0.3 times of the amount of the pyrrole is added under the protection of nitrogen, the mixture is stirred for 5 minutes, DDQ (2, 3-dichloro-5, 6-dicyan p-benzoquinone) which is 0.7 times of the amount of the pyrrole is added, the mixture is stirred for 3 hours at the temperature of 45 ℃, the solvent is evaporated, the mixture is washed three times by methanol which is one third of the volume of the dichloromethane solvent in the reaction, filter residue is dissolved in dichloromethane, and silica gel column chromatography separation is carried out by taking dichloromethane as eluent to obtain a dark purple product which has the yield of 15% and shows strong red fluorescence under a 365nm ultraviolet lamp, wherein the product is porphyrin ligand.
EXAMPLE 2 preparation of Metal-organic catalyst
In the present invention, the metal-organic catalyst is prepared with reference to the following steps: the porphyrin ligand was dissolved in DMF (N, N-dimethylformamide), and a metal salt was added thereto in an amount of 20 times the amount of the porphyrin ligand, followed by stirring at 130 ℃ for 12 hours under a nitrogen atmosphere. Then, the reaction system was allowed to cool, and deionized water was added in an amount of 2 times the volume of the reaction solvent. The precipitate produced in the above step was collected, dissolved in dichloromethane, dried over anhydrous magnesium sulfate and then purified with methanol: 1-dichloromethane: the 10 volume ratio of the eluate was separated and purified in a silica gel column to obtain a metal-organic catalyst (chem. Comm,46, 3776-253778; organic Chemistry,58,2576-2587) with a yield of 88%.
EXAMPLE 3 preparation of Nitrogen nitride of Tertiary amine alkaloid
The biological alkali type (1) or the biological alkali type (3) is taken as a raw material, 2, 4-Dinitrophenylhydroxylamine (DPH) is taken as a nitrogen source, and the raw material is stirred in a reaction medium at normal temperature for 2 to 24 hours in an open way under the catalytic action of manganese porphyrin Mn [ TDCPP ] Cl. After the reaction is finished, methanol is adopted: 1-dichloromethane: 10 of the eluent is separated by 200-mesh alumina column chromatography to obtain the alkaloid azotizer shown in the formula (2) and the formula (4), and the specific reaction conditions and the yield are shown in the following table 1:
table 1:
Figure BDA0002439012430000141
Figure BDA0002439012430000151
Figure BDA0002439012430000161
Figure BDA0002439012430000171
the nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the partial compounds are shown in the table 2:
table 2:
Figure BDA0002439012430000172
Figure BDA0002439012430000181
Figure BDA0002439012430000191
Figure BDA0002439012430000201
the high resolution mass spectral data for a portion of the compounds are shown in table 3:
table 3:
Figure BDA0002439012430000202
Figure BDA0002439012430000211
example 4 in vitro anti-cancer cell assay
Cytotoxicity test
Cytotoxicity assays take 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) as indicator cancer cells He L a (4000 cells/well), NCI-H460(3000 cells/well) and a549(4000 cells/well) were seeded in 96-well flat-bottomed microplates containing 100 μ Ι of medium and incubated for 24 hours the culture broth was removed, new culture broth dissolved with nitrogen compounds was added to the 96-well plates at different concentrations, the cells were contacted with the compounds for 72 hours, 10 μ Ι (3- (4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyltetrazolium bromide (MTT, 5mg/M L) was added to each well, incubated for 4 hours at 37 degrees, solubilized solution (10% SDS with 0.01M HCl) was added to each well, measured with a Thermo Scientific vasoska tm L ux multimode microplate reader, wavelength 580nm, the value of the compound 50 (IC cell growth inhibitory concentration) was determined to be as a better percentage of the biological activity of the compound when compared to the concentration of its parent nitrogen oxide when treated with a control base, as determined by comparison to the same biological activity of the control.
Table 4:
Figure BDA0002439012430000212
Figure BDA0002439012430000221

Claims (10)

1. a tertiary amine alkaloid nitrogen nitride shown in a formula (2) or a formula (4),
Figure FDA0002439012420000011
wherein R in the formula (2)1、R2、R3、R4、R5Five-membered rings, six-membered rings, seven-membered rings, spiro rings or fused rings can be formed between every two; r in the formula (4)2、R3、R4、R5Five-membered rings, six-membered rings, seven-membered rings, spiro rings or fused rings can be formed between every two; in the formula (2) or the formula (4), n is 1,2 or 3.
2. The nitrogen nitride of a tertiary amine alkaloid according to claim 1, wherein the five-, six-or seven-membered ring is a saturated or unsaturated ring, or the unsaturated ring carries more than one olefinic bond; or the five-membered ring, the six-membered ring, the seven-membered ring, the spiro ring or the fused ring is substituted by the fused ring group or the spiro ring group.
3. The tertiary amine alkaloid nitrogenate of claim 1, wherein each of the five-membered, six-membered, seven-membered, spiro, or fused rings is a carbocyclyl or heterocyclyl and each ring is optionally substituted with one or more substituents.
4. The tertiary amine alkaloid nitrogenate of claim 3, wherein said substituent is a hydroxyl, methoxy, carbomethoxy, vinyl, carbonyl, heterocyclyl, or carbocyclyl group.
5. The nitrogen nitride tertiary amine alkaloid according to any of the claims 1-4, characterized in that the compound of formula (2) or (4) has the following structural formula:
Figure FDA0002439012420000012
Figure FDA0002439012420000021
6. a preparation method of tertiary amine alkaloid nitrogen nitride shown in formula (2) or formula (4) comprises the steps of taking biological alkali (1) or formula (3) as a raw material, taking a phenyl hydroxylamine compound as a nitrogen source, stirring in a reaction medium at normal temperature for 2-24 hours in an open manner under the catalytic action of a metal-organic catalyst, and purifying to obtain the compounds shown in formula (2) and formula (4),
Figure FDA0002439012420000022
wherein R in the formula (1) and the formula (2)1、R2、R3、R4、R5Five-membered rings, six-membered rings, seven-membered rings, spiro rings or fused rings are formed between every two of the two; r in formula (3) or formula (4)2、R3、R4、R5Five-membered rings, six-membered rings, seven-membered rings, spiro rings or condensed rings are formed between every two, and n in formula (1), formula (2), formula (3) or formula (4) is 1,2 or 3.
7. The process according to claim 6, wherein the five-membered, six-membered or seven-membered ring is a saturated or unsaturated ring, and the unsaturated ring is a ring having one or more ethylenic bonds; the five-membered ring, the six-membered ring, the seven-membered ring, the spiro ring or the fused ring is substituted by the fused ring group or the spiro ring group; each ring of the five-membered, six-membered, seven-membered, spiro or fused ring is carbocyclyl or heterocyclyl and each ring is optionally substituted with one or more substituents.
8. The method according to claim 6, wherein the alkaloid, the nitrogen source and the metal-organic catalyst are comprised of the following proportions: alkaloid: nitrogen source: the metal-organic catalyst is 1: 1-2: 0.025-0.05.
9. The method according to claim 6, wherein the metal-organic catalyst is selected from one of the following metals and one or more ligands selected from the following ligands, and the metal or metal ion thereof is selected from iron, manganese, cobalt, nickel, copper, rhodium, ruthenium; the ligand is selected from polypyridine, substituted polypyridine, porphyrin and phthalocyanine; the reaction medium is one or the combination of dichloromethane, dichloroethane, acetonitrile, chloroform, N-dimethylformamide and tetrahydrofuran.
10. Use of the tertiary amine alkaloid nitrogenate of formula (2) or formula (4) prepared according to the process of any one of claims 1 to 5 or of claims 6 to 9 in the preparation of an anti-tumor medicament.
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