Synthesis method of beta-carboline compound

Abstract

The invention belongs to the technical field of chemical synthesis methods, and discloses a synthesis method of beta-carboline compounds. The method comprises the following steps: cyclizing alpha-aminoketone (A) and 3-substituted acrolein (B), reacting the obtained product with hydroxylamine hydrochloride without purification under the catalysis of acid to prepare a 3-aminopyridine derivative, and synthesizing a compound with a beta-carboline structure as shown in a general formula I or a general formula II in the presence of an alkaline reagent or a copper catalyst. According to the method provided by the invention, alpha-aminoketone is taken as a raw material, the beta-carboline compound can be synthesized under a metal-free condition, and the route is short. The synthesis method has a high-efficiency and high-yield synthesis route for natural products, namely harmine and harmine. The synthesis method disclosed by the invention can be used for synthesizing harmine and harmine. The method is simple to operate and high in yield, and provides a new idea for efficient synthesis of the compounds.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis methods, and specifically relates to a method for synthesizing a class of β-carboline compounds, particularly a method for preparing β-carboline compounds including the natural products harmane and harmine. Background Art

[0002] β-Carboline alkaloids are a large class of alkaloids derived from natural sources or chemical synthesis, with a broad spectrum of pharmacological activities, including highly effective antifungal activity, and have great potential for development into botanical fungicides. β-Carboline compounds are widely used in medicine, complexes, polymers, etc. There are two main chemical synthesis methods for β-carboline alkaloids: one is to construct a pyridine ring through an indole nucleus; the other is to construct an aza-five-membered ring. The methods for constructing a pyridine ring include: Pictet-Spengler method, Bischler-Napieralski method, electrocyclization method, Naichun insertion of CH bonds, vonBaeyer-Piccard reaction, intramolecular S N Ar reaction, Friedel-Crafts reaction, Larock method, metal rearrangement reaction, metal cycloisomerization and acid-catalyzed [3+3] cyclization reaction. The methods for constructing nitrogen five-membered rings are: S in the molecule N Ar reaction, insertion of C—H bonds by nitropropene, and nucleophilic substitution on the pyridine ring. The following describes the common synthesis methods of β-carboline compounds (Scheme 1):

[0003] The first method involves the Pictet-Spengler method, which involves oxidizing the compound produced by the Pictet-Spengler reaction of tryptophan and acetaldehyde under manganese catalysis to a β-carboline compound. This is then followed by NBS bromination and a Suzuki reaction to couple other substituents to the 6-position of the β-carboline. The 6-substituted β-carboline derivative is then subjected to a substitution reaction with a brominated or iodinated compound in the presence of NaH. (Eq. 1)

[0004] The second method is the Bischler-Napieralski method, which uses tryptamine and carboxylic acid as starting materials, introduces an acyl group at the 2-position of tryptamine through Friedel-Crafts acylation, and then closes the ring under alkaline conditions to obtain dihydro-β-carboline, which is further oxidized to obtain a β-carboline compound.

[0005] (eq.2)

[0006] The third method is the electrocyclization method, which uses 2-formaldehyde indole as the starting material and reacts with methyltriphenylphosphine iodide to produce 3-vinyl indole. 3-Formyl indole is then obtained through the Vilsmeier-Haack reaction in a series of electrocyclization reactions. 3-Formyl indole is then treated with hydroxylamine hydrochloride and sodium acetate and refluxed in o-dichlorobenzene for 8 hours to obtain the β-carboline alkaloid. (eq. 3)

[0007] Fourth: Method for constructing nitrogen five-membered ring: S in the molecule N Ar reaction, 3-pyridine carboxylate reacts with DPPA to generate acyl azide, which is then subjected to Curtius rearrangement to obtain Boc-protected amine, and finally undergoes intramolecular S N Ar reaction yields β-carboline compounds. (eq.4)

[0008] Fifth: Naichun inserted the C-H bond, converted the amino group of the raw material 3-aminopyridine compound into an azide, and then inserted the C-H bond into the molecule to synthesize the β-carboline compound. (eq.5)

[0009]

[0010] In summary, the current main method for synthesizing β-carboline is to obtain tetrahydroβ-carboline compounds by cyclizing tryptamine and its derivatives through the Pictet-Spengler method and then oxidizing them. This method has the following disadvantages: 1) The expansion of derivatives is limited. Substituted tryptophan and its derivatives are difficult to obtain, and the method of synthesizing β-carboline compounds from tryptamine and its derivatives with different substitutions is relatively difficult; 2) The use of metal catalysts increases the cost of raw materials and brings about problems with sewage treatment, which is not conducive to environmental protection and has the risk of metal residues; 3) There are few synthetic methods for natural products such as harmane and harmine with important biological activities. Summary of the Invention

[0011] To overcome the shortcomings of the prior art, the present invention provides a method for synthesizing β-carbolines. Using α-aminoketones as starting materials, the method allows for the synthesis of β-carbolines in a metal-free, streamlined manner. Furthermore, the method provides an efficient and high-yield synthetic route for the natural products harmane and harmine. The method is simple to operate and offers high yields, providing a new approach for the efficient synthesis of this class of compounds.

[0012] The above-mentioned object of the present invention is achieved through the following technical solutions:

[0013] A method for synthesizing β-carboline compounds comprises cyclizing an α-aminoketone (A) and a 3-substituted acrolein (B) in the presence of a secondary amine catalyst and an additive. The resulting product, without purification, reacts with hydroxylamine hydrochloride under acid catalysis to produce a 3-aminopyridine derivative. In the presence of an alkaline reagent or a copper catalyst, a compound having a β-carboline structure represented by general formula I or general formula II is synthesized.

[0014] The reaction formula for preparing the compound of β-carboline structure represented by general formula I or general formula II is as follows:

[0015]

[0016] in:

[0017] The secondary amine catalyst structural formula is:

[0018] or

[0019] R 1 is a hydrocarbon group having 1 to 20 carbon atoms and optionally containing heteroatoms.

[0020] R 2 C1-C 20 Alkanoyl, containing one or more C1-C 20 Alkyl, C1-C 20 any one of an alkoxy group, a halogen group, a nitro group, a nitrile group, a phenyl group, a trifluoromethyl-substituted benzoyl group, a phenylsulfonyl group, a naphthoyl group, a thenoyl group, a furoyl group and a picolinoyl group, and a benzoyl group, a p-toluenesulfonyl group and a trifluoroacetyl group.

[0021] R 3 is one or more hydrocarbon groups having 1 to 20 carbon atoms and optionally containing heteroatoms, one or more halogen groups, one or more nitro groups, one or more cyano groups, one or more C1-C 20 The alkoxy group, one or more trifluoromethyl groups or the above substituents are optionally disubstituted, trisubstituted or tetrasubstituted at different positions.

[0022] R 4 For trimethylsilyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenylsilyloxy, tri-n-propylsilyloxy, triisopropylsilyloxy, phenyldimethylsilyloxy, C 1- C 20 Any of alkoxyphenyl groups.

[0023] R 5 is a hydrocarbon group having 1 to 20 carbon atoms and optionally containing heteroatoms.

[0024] X is any one of fluorine, chlorine, bromine and iodine.

[0025] Furthermore, a method for synthesizing β-carboline compounds comprises the following steps: a first step: reacting an α-aminoketone compound (A) with a 3-substituted acrolein compound (B); removing the solvent after the reaction, and reacting the resulting mixture with hydroxylamine hydrochloride in a solvent to obtain a 3-aminopyridine derivative (C); and a second step: reacting the 3-aminopyridine derivative (C) in the presence of an alkaline reagent or a copper catalyst to obtain a β-carboline compound having the general formula I or II.

[0026] In the first step, the additives are not added or added with benzoic acid, p-toluic acid, p-nitrobenzoic acid, p-toluenesulfonic acid, acetic acid, triethylamine, and DBU, and the molar ratio of α-aminoketone to the additives is 1:0-5.

[0027] In the first step, the solvent is any one of dichloromethane, tetrahydrofuran, ethyl acetate, toluene, acetonitrile, methanol, ethanol, and acetic acid.

[0028] In the first step, the reaction temperature is 0-150°C.

[0029] In the second step, the alkaline reagent is any one of potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, n-butyl lithium, tert-butyl lithium, and lithium diisopropylamide.

[0030] In the second step, the copper catalyst is any one of copper, copper acetate, tris(triphenylphosphine)copper bromide, cuprous cyanide, cuprous bromide, cuprous chloride, cuprous iodide, and cuprous oxide.

[0031] In the second step, the temperature is 0-200°C.

[0032] Preferably, in the first step, the additive is p-nitrobenzoic acid.

[0033] Preferably, in the first step, the solvent is methanol.

[0034] Preferably, in the first step, the temperature is 60°C.

[0035] The β-carboline compound represented by the general formula I is prepared by the following steps: Step 1: 1 equivalent of α-aminoketone (A), 0.5-5 equivalents of 3-substituted acrolein (B), 0-5 equivalents of an additive, and 1-100 mmol% of a secondary amine catalyst are dissolved in a solvent and reacted at 0-100°C for 1-168 hours. After removing the solvent, 0.5-5 equivalents of hydroxylamine hydrochloride and an acid are added, and the mixture is stirred and reacted at 50-150°C for 0.5-24 hours. The mixture is neutralized to a pH > 7, extracted, dried, and purified to obtain a 3-aminopyridinium derivative (C). Step 2: The 3-aminopyridine derivative (C) is stirred with 0.1-10 equivalents of an alkaline reagent and a solvent at 0-150°C for 0.1-10 hours. After the reaction is completed, the reaction solution is cooled to room temperature, extracted, dried, and purified to obtain the product represented by the general formula I.

[0036] The β-carboline compound represented by general formula II is prepared by the following steps: Step 1: 1 equivalent of α-aminoketone (A), 0.5-5 equivalents of 3-substituted acrolein (B), 0-5 equivalents of an additive, and 1-100 mmol% of a secondary amine catalyst are dissolved in a solvent and reacted at 0-100°C for 1-168 hours. After removing the solvent, 0.5-5 equivalents of hydroxylamine hydrochloride and an acid are added, and the mixture is stirred and reacted at 50-150°C for 0.5-24 hours. The mixture is neutralized to a pH > 7, extracted, dried, and purified to obtain a 3-aminopyridyl derivative (C). Step 2: The 3-aminopyridine derivative (C) is stirred with 0.1-10 equivalents of a copper catalyst and a solvent at 0-150°C for 0.1-10 hours. After the reaction is completed, the reaction solution is cooled to room temperature, extracted, dried, and purified to obtain the product represented by general formula II.

[0037] Unless otherwise specified, the terms used herein have the following meanings.

[0038] As used herein, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. Reference to a single alkyl group, such as "methyl," specifically refers to the straight-chain alkyl group; reference to a single branched-chain alkyl group, such as "isopropyl," specifically refers to the branched-chain alkyl group. For example, "C4 or less alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl. Similar rules apply to other groups used in this specification.

[0039] As used herein, the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0040] Table 1 lists the substituents R of the α-amino ketone compound in the above reaction formula. 1 But it is not limited to these structures.

[0041] Table 1 R 1 The structure of the substituent

[0042]

[0043]

[0044] Table 2 lists the substituents R of the α-amino ketone compound in the above reaction formula. 2 But it is not limited to these structures.

[0045] Table 2 R 2 The structure of the substituent

[0046]

[0047]

[0048] Table 3 lists the 3-propenal substituents R in the above reaction formula. 3 But it is not limited to these structures.

[0049] Table 3 R 3 The structure of the substituent

[0050] 3-Me- 3-F-4-Br 3-F- 3-F-4-F 4-F- 3-F-4-Cl 4-Me- -COOMe 3-CI- -COOEt 4-CI- <![CDATA[-COO i Pr]]> 3-Et- <![CDATA[-COO n Pr]]> 3-Br- <![CDATA[-COO n This]]> 4-Br- <![CDATA[-COO t This]]> 4-Et- <![CDATA[-COO n Pentyl]]> 3-I- <![CDATA[-COO i Pentyl]]> 4-I- <![CDATA[-COO n Hexyl]]> 5-Et- <![CDATA[-COO n Heptyl]]> 3-NO2- <![CDATA[-COO n Octyl]]> 4-NO2- <![CDATA[-C6H5]]>

[0051] Table 4 lists the secondary amine catalyst substituents R in the above reaction formula. 4 But it is not limited to these structures.

[0052] Table 4 R 4 The structure of the substituent

[0053]

[0054]

[0055] Table 5 lists the secondary amine catalyst substituents R in the above reaction formula. 5 But it is not limited to these structures.

[0056] Table 5 R 5 The structure of the substituent

[0057] <![CDATA[CH3-]]> <![CDATA[C6H5-]]> <![CDATA[CH3CH2-]]> <![CDATA[2-Me-C6H4-]]> <![CDATA[CH3(CH2)2-]]> <![CDATA[3-Me-C6H4-]]> <![CDATA[CH3(CH2)3-]]> <![CDATA[4-Me-C6H4-]]> <![CDATA[CH3(CH2)4-]]> <![CDATA[2-Et-C6H4-]]> <![CDATA[CH3(CH2)5-]]> <![CDATA[3-Et-C6H4-]]> <![CDATA[CH3(CH2)6-]]> <![CDATA[4-Et-C6H4-]]> <![CDATA[CH3(CH2)7-]]> <![CDATA[2- i Pr-C6H4-]]> <![CDATA[CH3(CH2)8-]]> <![CDATA[3- i Pr-C6H4-]]> <![CDATA[CH3(CH2)9-]]> <![CDATA[4- i Pr-C6H4-]]> <![CDATA[CH3(CH2) 10 -]]> <![CDATA[2- n This is-C6H4-]]> <![CDATA[(CH3)2CH(CH2)2-]]> <![CDATA[3- n This is-C6H4-]]> <![CDATA[(CH3)3C(CH2)2-]]> <![CDATA[4- n This is-C6H4-]]> <![CDATA[(CH3)3CCH2-]]> <![CDATA[4-NO2-C6H4-]]>

[0058] The beneficial effects of the present invention compared with the prior art are:

[0059] 1) The synthesis method provided by the present invention is simple and efficient, with simple synthesis steps and post-processing;

[0060] 2) The synthesis method provided by the present invention has mild reaction conditions, less by-products, and high atom utilization rate.

[0061] 3) Hydroxylamine hydrochloride is used as the nitrogen source for synthesizing pyridine, water is produced as a by-product, and the conversion rate is high, which is green and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 This is the NMR spectrum of the product prepared in Example 1.

[0063] Figure 2 This is the NMR spectrum of the product prepared in Example 23.

[0064] Figure 3 This is the NMR spectrum of the product prepared in Example 25. DETAILED DESCRIPTION

[0065] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is described in detail below with reference to the examples. It is necessary to point out that the following examples are only used to explain and illustrate the present invention and are not intended to limit the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above invention content still fall within the scope of protection of the present invention. The test methods described in the following examples, unless otherwise specified, are conventional methods; the reagents and materials, unless otherwise specified, can be obtained from commercial channels.

[0066] The synthetic route of embodiment 1-22 is

[0067]

[0068] The synthetic route of Example 23-24 is

[0069]

[0070] The synthetic route of Example 25-26 is

[0071]

[0072] The synthetic route of Example 27-28 is

[0073]

[0074] The synthetic routes of Examples 29-36 are

[0075]

[0076] Example 1

[0077] A method for synthesizing the β-carboline alkaloid harmine (Harmine), wherein the structural formula of the described harmine is as follows:

[0078]

[0079] The synthesis method is as follows:

[0080] (1) Weigh N-benzoyl-α-aminopropanone (177 mg, 1.0 mmol), 3(4-methoxy-2-fluoro-phenyl)-propenal (216 mg, 1.2 mmol), 4-nitrobenzoic acid (33 mg, 0.2 mmol), diphenylprolinol trimethylsilyl ether (33 mg 0.1 mmol) and 3 mL of methanol, place them in a 10 mL reaction bottle and stir at 60 °C for 24 h.

[0081] (2) After removing the solvent, hydroxylamine hydrochloride (140 mg, 2 mmol) and 3 mL of acetic acid were added. The mixture was stirred at 110°C for 3 h. After cooling to room temperature, 20 mL of dichloromethane was added, and the mixture was neutralized with sodium hydroxide (4 M) to pH>7, and extracted with DCM (2×20 mL). The combined organic layer was washed with brine (2×10 mL) and dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation and purified by column chromatography (PE / EA=1 / 1) to obtain 3-aminopyridine compound as a white solid with a yield of 80%.

[0082] (3) 3-Aminopyridine compound (336 mg, 1.0 mmol), t-BuONa (288 mg, 3.0 mmol) and 3 mL DMSO were weighed in a 10 mL reaction flask and stirred at 130°C for 2 h. TLC (P / E = 1 / 1) was used for monitoring. After the reaction was completed, the reaction solution was cooled to room temperature, 5 mL of water was added, and the mixture was extracted with ethyl acetate (2 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL) and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to obtain 201 mg of the product Harmine with a yield of 95%. The total yield of Harmine from N-benzoyl-α-aminopropanone was 76%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0083] Its H NMR spectrum is Figure 1 As shown; NMR data are as follows:

[0084] 1 H NMR (400MHz, DMSO-d6) δ11.43(s,1H),8.16(s,1H),8.04(d,J=8.1Hz,1H),7.79(s,1H),7.03(s,1H),6.85(d,J=7.7Hz,1H),3.87(s,3H),2.73(s,3H).

[0085] Example 2

[0086] According to the synthesis method of Example 1, methanol in step (1) was replaced by ethyl acetate. The total yield of N-benzoyl-α-aminopropanone to Harmine was 68%. HRMS (ESI) m / z [M+H] + calcd.forC 13 H 13 N2O213.1022; found 213.1025.

[0087] Example 3

[0088] According to the synthesis method of Example 1, methanol in step (1) was replaced with acetonitrile. The total yield of N-benzoyl-α-aminopropanone to Harmine was 60%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0089] Example 4

[0090] According to the synthesis method of Example 1, methanol in step (1) was replaced by toluene. The total yield of N-benzoyl-α-aminopropanone to Harmine was 54%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0091] Example 5

[0092] According to the synthesis method of Example 1, methanol in step (1) was replaced by tetrahydrofuran. The total yield of N-benzoyl-α-aminopropanone to Harmine was 24%. HRMS (ESI) m / z [M+H] + calcd.forC 13 H 13 N2O213.1022; found 213.1025.

[0093] Example 6

[0094] According to the synthesis method of Example 1, the temperature in step (1) was changed from 60°C to 40°C. The total yield of N-benzoyl-α-aminopropanone to Harmine was 69%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H13 N2O 213.1022; found 213.1025.

[0095] Example 7

[0096] According to the synthesis method of Example 1, the temperature in step (1) was changed from 60°C to 20°C. The total yield of N-benzoyl-α-aminopropanone to Harmine was 40%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0097] Example 8

[0098] According to the synthesis method of Example 1, the temperature in step (1) was replaced by 0°C at 60°C. The total yield of N-benzoyl-α-aminopropanone to Harmine was 23%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0099] Example 9

[0100] According to the synthesis method of Example 1, the p-nitrobenzoic acid in step (1) was replaced by benzoic acid. The total yield of N-benzoyl-α-aminopropionone to Harmine was 70%. HRMS (ESI) m / z [M+H] + calcd.forC 13 H 13 N2O213.1022; found 213.1025.

[0101] Example 10

[0102] According to the synthesis method of Example 1, the p-nitrobenzoic acid in step (1) was replaced by p-toluic acid. The total yield of N-benzoyl-α-aminopropionone to Harmine was 62%. HRMS (ESI) m / z [M+H] + calcd.forC 13 H 13 N2O 213.1022; found 213.1025.

[0103] Example 11

[0104] According to the synthesis method of Example 1, p-nitrobenzoic acid in step (1) was replaced with p-toluenesulfonic acid. The total yield of N-benzoyl-α-aminopropionone to Harmine was 2%. HRMS (ESI) m / z [M+H] + calcd.forC 13 H 13 N2O 213.1022; found 213.1025.

[0105] Example 12

[0106] According to the synthesis method of Example 1, the p-nitrobenzoic acid in step (1) was replaced by acetic acid. The total yield of N-benzoyl-α-aminopropanone to Harmine was 29%. HRMS (ESI) m / z [M+H] + calcd.forC 13 H 13 N2O213.1022; found 213.1025.

[0107] Example 13

[0108] According to the synthesis method of Example 1, 0.2 mmol of p-nitrobenzoic acid in step (1) was replaced with 0.1 mmol of p-nitrobenzoic acid. The total yield of N-benzoyl-α-aminopropionone to Harmine was 67%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0109] Example 14

[0110] According to the synthesis method of Example 1, 0.2 mmol of p-nitrobenzoic acid in step (1) was replaced with 0.5 mmol of p-nitrobenzoic acid. The total yield of N-benzoyl-α-aminopropanone to Harmine was 69%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0111] Example 15

[0112] According to the synthesis method of Example 1, 0.2 mmol of p-nitrobenzoic acid in step (1) was replaced with 1.0 mmol of p-nitrobenzoic acid. The total yield of N-benzoyl-α-aminopropionone to Harmine was 66%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0113] Example 16

[0114] According to the synthesis method of Example 1, 0.2 mmol of p-nitrobenzoic acid in step (1) was replaced by no additive. The total yield of N-benzoyl-α-aminopropanone to Harmine was 76%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0115] Example 17

[0116] According to the synthesis method of Example 1, 2 mmol of hydroxylamine hydrochloride in step (2) was replaced with 5 mmol of hydroxylamine hydrochloride. The total yield of N-benzoyl-α-aminopropanone to Harmine was 76%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0117] Example 18

[0118] According to the synthesis method of Example 1, the temperature in step (2) was replaced by 100°C at 110°C. The total yield of N-benzoyl-α-aminopropanone to Harmine was 76%. HRMS (ESI) m / z [M+H] + calcd.forC 13 H 13 N2O213.1022; found 213.1025.

[0119] Example 19

[0120] According to the synthesis method of Example 1, the temperature in step (3) was replaced by 100°C at 130°C. The total yield of N-benzoyl-α-aminopropanone to Harmine was 76%. HRMS (ESI) m / z [M+H] +calcd.forC 13 H 13 N2O213.1022; found 213.1025.

[0121] Example 20

[0122] According to the synthesis method of Example 1, 3.0 mmol of potassium tert-butoxide in step (3) was replaced with 4.0 mmol of potassium tert-butoxide. The total yield of N-benzoyl-α-aminopropanone to Harmine was 76%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0123] Example 21

[0124] According to the synthesis method of Example 1, 3(4-methoxy-2-fluoro-phenyl)-propenal in step (1) was replaced with compound 3(4-methoxy-2-chloro-phenyl)-propenal. Column chromatography purification was added to the purification step in step (3). The total yield of N-benzoyl-α-aminopropanone to harmine was 47%. HRMS (ESI) m / z [M+H] + calcd.forC 13 H 13 N2O213.1022; found 213.1025.

[0125] The NMR data are as follows:

[0126] 1 H NMR (400MHz, DMSO-d6) δ11.43(s,1H),8.16(s,1H),8.04(d,J=8.1Hz,1H),7.79(s,1H),7.03(s,1H),6.85(d,J=7.7Hz,1H),3.87(s,3H),2.73(s,3H).

[0127] Example 22

[0128] According to the synthesis method of Example 1, the diphenylprolinol trimethylsilyl ether in step (1) was replaced with 4-(tert-butyl)-1-(diphenyl(pyrrolidin-2-yl)methyl)-1H-1,2,3-triazole. The final total yield of Harmine was 35%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13N2O 213.1022; found 213.1025.

[0129] Example 23

[0130] A method for synthesizing a β-carboline alkaloid N-benzoyl-dehydroharmine, wherein the structural formula of the N-benzoyl-dehydroharmine is as follows:

[0131]

[0132] The synthesis method is as follows:

[0133] According to the synthesis method of Example 1, 3(4-methoxy-2-fluoro-phenyl)-propenal in step (1) was replaced with 3(4-methoxy-2-bromo-phenyl)-propenal. Step (3) was modified as follows: 3-aminopyridine compound (C) (352 mg, 1.0 mmol), cuprous iodide (76 mg, 0.4 mmol), potassium carbonate (276 mg, 2 mmol), and 3 mL of DMF were weighed in a 10 mL reaction flask and stirred at 100°C for 3 h. TLC (P / E = 1 / 1) was used for monitoring. After completion of the reaction, the reaction solution was cooled to room temperature, 5 mL of water was added, and the mixture was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to obtain the product N-benzoyl-dehydroharmaline. Yield Y = 95%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0134] Its H NMR spectrum is Figure 2 As shown; NMR data are as follows:

[0135] 1 H NMR (400MHz, DMSO-d6) δ11.43(s,1H),8.16(s,1H),8.04(d,J=8.1Hz,1H),7.79(s,1H),7.03(s,1H),6.85(d,J=7.7Hz,1H),3.87(s,3H),2.73(s,3H).

[0136] Example 24

[0137] According to the synthesis method of Example 23, 0.4 mmol of cuprous iodide in step (3) was replaced with 0.1 mmol of cuprous iodide. The total yield of N-benzoyl-α-aminopropanone to N-benzoyl-dehydroharmaline was 76%. HRMS (ESI) m / z [M+H]+ calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0138] Example 25

[0139] A method for synthesizing a β-carboline alkaloid, Harmane, wherein the structural formula of the Harmane is as follows:

[0140]

[0141] The synthesis method is as follows:

[0142] According to the synthesis method of Example 1, the compound 3(4-methoxy-2-fluoro-phenyl)-propenal in step (1) was replaced with the compound 3(2-fluoro-phenyl)-propenal. The purification step in step (3) was supplemented with a column chromatography purification step. The total yield of Harmane from N-benzoyl-α-aminopropanone was 60%. HRMS (ESI) m / z [M+H] + calcd.forC 12 H 11 N2183.0916; found 183.0914

[0143] Its H NMR spectrum is Figure 3 As shown; NMR data are as follows:

[0144] 1 H NMR(400MHz,Chloroform-d)δ9.08(s, 1 H),8.38(d,J=5.3Hz,1H),8.13(d,J=7.9Hz,1H),7.84(d,J=5.3Hz,1H),7.55–7.51(m,2H),7.29(ddd,J=8.2,5.9,2.3Hz,1H),2.84(s,3H).

[0145] Example 26

[0146] According to the synthesis method of Example 1, the compound 3(4-methoxy-2-fluoro-phenyl)-propenal in step (1) was replaced with the compound 3(2-bromo-phenyl)-propenal. The purification step in step (3) was supplemented with a column chromatography purification step. The total yield of Harmane from N-benzoyl-α-aminopropanone was 59%. HRMS (ESI) m / z [M+H] + calcd.forC 12 H 11N2183.0916; found 183.0914

[0147] Example 27

[0148] The synthesis method is as follows:

[0149] A mixture of N-benzoyl-dehydroharmaline (316 mg 1.0 mmol), 3 mL of HCl (conc.), and 3 mL of MeOH was placed in a 10 mL reaction vial and stirred at 60°C for 8 h. TLC (P / E = 1 / 1) was used to monitor the reaction. After completion, saturated sodium bicarbonate (10 mL) was added and the mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation to afford Harmine as a white solid in a 98% yield. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0150] The NMR data are as follows:

[0151] 1 H NMR (400MHz, DMSO-d6) δ11.43(s,1H),8.16(s,1H),8.04(d,J=8.1Hz,1H),7.79(s,1H),7.03(s,1H),6.85(d,J=7.7Hz,1H),3.87(s,3H),2.73(s,3H).

[0152] Example 28

[0153] Following the synthesis method of Example 26, the temperature in the step was changed from 60°C to 80°C, and the total yield of the final Harmine was 95%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2O 213.1022; found 213.1025.

[0154] Example 29

[0155] The structural formula is as follows

[0156]

[0157] According to the synthesis method of Example 1, 3(4-methoxy-2-fluoro-phenyl)-propenal in step (1) was replaced with compound 3(4-fluoro-2-fluoro-phenyl)-propenal, and the total yield was 64%. HRMS (ESI) m / z [M+H] + calcd.forC 12 H 10 FN2201.0822; found 201.0825.

[0158] Example 30

[0159] The structural formula is as follows

[0160]

[0161] According to the synthesis method of Example 1, 3(4-methoxy-2-fluoro-phenyl)-propenal in step (1) was replaced with compound 3(4-chloro-2-fluoro-phenyl)-propenal, and the total yield was 81%. HRMS (ESI) m / z [M+H] + calcd.forC 12 H 10 ClN2217.0527; found 217.0530.

[0162] Example 31

[0163] The structural formula is as follows

[0164]

[0165] According to the synthesis method of Example 1, 3(4-methoxy-2-fluoro-phenyl)-propenal in step (1) was replaced with compound 3(4-bromo-2-fluoro-phenyl)-propenal, and the total yield was 70%. HRMS (ESI) m / z [M+H] + calcd.forC 12 H 10 BrN2261.0021; found 261.0022.

[0166] Example 32

[0167] The structural formula is as follows

[0168]

[0169] According to the synthesis method of Example 1, 3(4-methoxy-2-fluoro-phenyl)-propenal in step (1) was replaced with compound 3(4-cyano-2-fluoro-phenyl)-propenal, and the total yield was 65%. HRMS (ESI) m / z [M+H] + calcd.forC 13H 10 N3208.0869; found 208.0870.

[0170] Example 33

[0171] The structural formula is as follows

[0172]

[0173] According to the synthesis method of Example 1, 3(4-methoxy-2-fluoro-phenyl)-propenal in step (1) was replaced with compound 3(5-chloro-2-fluoro-phenyl)-propenal, and the total yield was 76%. HRMS (ESI) m / z [M+H] + calcd.forC 13 H 13 N2197.1073; found 197.1075.

[0174] Example 34

[0175] The structural formula is as follows

[0176]

[0177] According to the synthesis method of Example 1, 3(4-methoxy-2-fluoro-phenyl)-propenal in step (1) was replaced with compound 3(5-methoxy-2-fluoro-phenyl)-propenal, and the total yield was 65%. HRMS (ESI) m / z [M+H] + calcd.forC 13 H 13 N2O213.1022; found 213.1025.

[0178] Example 35

[0179] The structural formula is as follows

[0180]

[0181] According to the synthesis method of Example 1, N-benzoyl-α-aminopropanone in step (1) was replaced with N-benzoyl-α-aminobutanone, and 3(4-methoxy-2-fluoro-phenyl)-propenal was replaced with compound 3(2-fluoro-phenyl)-propenal. The total yield was 74%. HRMS (ESI) m / z [M+H] + calcd.for C 13 H 13 N2197.1073; found 197.1074.

[0182] Example 36 The structural formula is as follows

[0183]

[0184] According to the synthesis method of Example 1, N-benzoyl-α-aminopropanone in step (1) was replaced with N-benzoyl-α-aminoacetophenone, and 3(4-methoxy-2-fluoro-phenyl)-propenal was replaced with compound 3(2-fluoro-phenyl)-propenal. The total yield was 70%. HRMS (ESI) m / z [M+H] + calcd.for C 17 H 13 ClN2245.1073; found 245.1073.

[0185] The above-described embodiments are only preferred embodiments of the present invention, and are not intended to be all feasible embodiments of the present invention. Any obvious modifications made by a person skilled in the art without departing from the principles and spirit of the present invention should be considered to be included within the scope of protection of the claims of the present invention.

Claims

1. A method for synthesizing a class of β-carboline compounds, characterized in that: In the presence of a secondary amine catalyst and an additive, an α-aminoketone (A) and a 3-substituted acrolein (B) undergo cyclization. The resulting product, without purification, reacts with hydroxylamine hydrochloride under acid catalysis to produce a 3-aminopyridine derivative. In the presence of an alkaline reagent or a copper catalyst, a compound having a β-carboline structure represented by Formula I or Formula II is synthesized. The reaction formula is as follows: in: The secondary amine catalyst structural formula is: R 1 is a hydrocarbon group having 1 to 20 carbon atoms and optionally containing heteroatoms; R 2 C1-C 20 Alkanoyl, containing one or more C1-C 20 Alkyl, C1-C 20 substituted alkoxy, halogen, nitro, nitrile, phenyl, trifluoromethyl-substituted benzoyl, phenylsulfonyl, naphthoyl, thenoyl, furoyl and picolinoyl, as well as any one of benzoyl, p-toluenesulfonyl and trifluoroacetyl; R 3 is one or more hydrocarbon groups having 1 to 20 carbon atoms and optionally containing heteroatoms, one or more halogen groups, one or more nitro groups, one or more cyano groups, one or more C1-C 20 alkoxy, one or more trifluoromethyl groups, or optionally disubstituted, trisubstituted or tetrasubstituted by the above substituents at different positions; R 4 For trimethylsilyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenylsilyloxy, tri-n-propylsilyloxy, triisopropylsilyloxy, phenyldimethylsilyloxy, C 1- C 20 Any of alkoxyphenyl; R 5 is a hydrocarbon group having 1 to 20 carbon atoms and optionally containing heteroatoms; X is any one of fluorine, chlorine, bromine and iodine.

2. The method for synthesizing a β-carboline compound according to claim 1, wherein: The specific steps are as follows: Step 1: In the presence of a secondary amine catalyst and an additive, an α-aminoketone compound is reacted with a 3-substituted acrolein compound; after the reaction is completed, the solvent is removed and the mixture is reacted with hydroxylamine hydrochloride in a solvent to obtain a 3-aminopyridine derivative; Step 2: The 3-aminopyridine derivative is reacted in the presence of an alkaline reagent or a copper catalyst to obtain a β-carboline compound having a general formula I or a general formula II.

3. The method for synthesizing β-carboline compounds according to claim 2, wherein in the first step, the additives are not added or are added with benzoic acid, p-toluic acid, p-nitrobenzoic acid, p-toluenesulfonic acid, acetic acid, triethylamine, or DBU, and the ratio of α-aminoketone to additive is 1:0-5.

4. The method for synthesizing a β-carboline compound according to claim 2, wherein in the first step, the solvent is any one of dichloromethane, tetrahydrofuran, ethyl acetate, toluene, acetonitrile, methanol, ethanol, and acetic acid.

5. The method for synthesizing a class of β-carboline compounds according to claim 2, characterized in that: In the first step, the reaction temperature is 0 to 150°C.

6. The method for synthesizing a β-carboline compound according to claim 2, wherein in the second step, the alkaline reagent is any one of potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, n-butyl lithium, tert-butyl lithium, and lithium diisopropylamide.

7. The method for synthesizing a β-carboline compound according to claim 2, wherein in the second step, the copper catalyst is any one of copper, copper acetate, tris(triphenylphosphine)copper bromide, cuprous cyanide, cuprous bromide, cuprous chloride, cuprous iodide, and cuprous oxide.

8. The method for synthesizing a class of β-carboline compounds according to claim 2, characterized in that: In the second step, the temperature is 0-200°C.

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