CN104558070B - The chemical synthesis process and midbody compound of Neomangiferin - Google Patents

Abstract

The invention discloses a chemical semi-synthesis method of new mangiferin. This method takes mangiferin as the starting material, sequentially undergoes acylation, protective group conversion and selective removal of phenolic acyl group to obtain the intermediate compound shown in formula D, and then uses bromotetraacylglucose as the donor, through phase transfer catalysis Carry out the glycosylation reaction to obtain the intermediate compound shown in formula E, and finally remove the acyl protecting group by catalytic hydrogenation, or acidolysis, or reduction and alkaline conditions to obtain new mangiferin; wherein, the substitution in formulas D and E The definition of the base is detailed in the specification. The method of the invention has the characteristics of mild reaction conditions, high yield, simple operation, low cost, high universality, etc., is suitable for large-scale industrial production, and has good application prospects.

Description

Chemical synthesis method and intermediate compound of new mangiferin

technical field

The invention relates to the field of medicinal chemistry, more specifically, to a chemical semi-synthesis method and an intermediate compound of a natural product neomangiferin.

Background technique

Mangiferin (Mangiferin, 2-C-β-D-glucosyl-1,3,6,7-tetrahydroxyxanthone) is a natural polyphenolic carbon glycoside compound with a xanthone structure , mainly found in the fruits, leaves, and bark of Mango (Mangiferin indica L), rhizomes and aerial parts of Liliaceae (Anemarrhena asphodeloides Bge.), and Belamcanda chinensis (L.) DC .) in flowers, leaves and other plants [Li Haowen, Deng Jiagang, Deng Jing. Research progress of mangiferin abroad. Journal of Guangxi University of Traditional Chinese Medicine, 2003, 6(4): 62-66]. Neomangiferin (Neomangiferin, 2-C-β-D-glucosyl-7-O-β-D-glucosyl-1,3,6-trihydroxyxanthone) is the 7-O-glucose of mangiferin Glycoside derivatives, mostly present in the rhizome of Anemarrhena anemarrhena, and its natural content is far less than that of mangiferin [Hong Yongfu, Han Gongyu, Guo Xuemin. Separation and identification of new mangiferin from Xiling Anemarrhena. Acta Pharmaceutica Sinica, 1997, 32(7): 473 –475].

Studies have shown that mangiferin has a variety of biological activities and pharmacological effects, including antibacterial, antiviral, antitumor, antioxidative, anti-inflammatory, antithrombotic, monoamine oxidase inhibitory activity, etc. [Adam Matkowski, PiotrKus et al., Mangiferin–a Bioactive Xanthonoid , not only from Mango and not justAntioxidant. Mini-Reviews in Medicinal Chemistry, 2013, 13, 439-455; It is also found that it has a good effect on anti-diabetes, and it has a good medicinal prospect [Ichiki H, et al., New Antidiabetic Compounds, Mangiferin and Its Glucoside. Biol. Pharm. Bull, 1998, 21 (12): 1389-1390; Huang Fang, et al., Antidiabetic activity of compounds of extracting from Anemarrhena asphodeloides. Chinese Journal of Biochemical Pharmaceuticals. 2005, 26(6): 332-335].

At present, the research on the activity of new mangiferin is mostly limited to the total flavonoid extracts of corresponding medicinal plants, such as Anemarrhena water extract [Yang Jia. Antidiabetic effect of Anemarrhena water extract and active ingredients mangiferin and its glycosides. Medicine (Traditional Chinese Medicine Subvolume), 2002, 6:353-354], but the research on the activity of single neomangiferin is relatively scarce, the main reason is that the content of neomangiferin in plants is extremely low, only about a few ten thousandths, And it is difficult to extract and separate, and it is difficult to meet the needs of research. To solve this problem, it is meaningful to find a suitable method for preparing new mangiferin.

There are mainly two methods for the large-scale preparation of natural products: plant extraction and synthesis.

At present, the acquisition of new mangiferin is mainly plant extraction, that is, the total crude product of mangiferin is first extracted from the rhizome of Anemarrhena, and then the new mangiferin is further separated by column chromatography, recrystallization and other technologies. This method is not only cumbersome to operate, but also has low efficiency and high cost, and it is difficult to obtain high-purity samples.

For the synthesis of new mangiferin, whether it is based on enzyme-catalyzed biosynthesis or chemical synthesis based on small molecule fragments, there is no relevant literature report so far. Based on this, the development of a new synthetic method for mangiferin is of great significance for its medicinal research.

Contents of the invention

The present inventors use mangiferin with higher content in plants and easier to extract as raw material to carry out glycosylation reaction, which ensures a large supply of new mangiferin and can be produced on a large scale; on the other hand, through appropriate conditions and purification methods If selected, samples with high purity can be obtained for research, which is convenient for the exploration of mangiferin-related medicinal chemicals.

The first object of the present invention is to provide a synthetic method of natural product neomangiferin.

The second object of the present invention is to provide intermediate compounds for the synthesis of neomangiferin.

In an embodiment of the present invention, the present invention provides a kind of efficient new mangiferin synthetic method, described method comprises the steps:

(1) The compound of formula A (i.e. mangiferin) reacts with the acid anhydride R ₁ -OR ₁ in acetic acid in the presence of sodium acetate, and selectively acylates all the hydroxyl groups except the 1-position phenolic hydroxyl to obtain the compound of formula B; R ₁ -OR _{In 1} , R is aliphatic acyl, unsubstituted benzoyl or substituted benzoyl:

(2) In the presence of potassium iodide or sodium iodide, the compound of formula B reacts with alkyl halide R ₂ X in a polar organic solvent under alkaline conditions, selectively protects the 1-position hydroxyl group and converts the 3 and 6-position protecting groups to obtain formula C Compound, in R ₂ X, R ₂ is unsubstituted benzyl or substituted benzyl, or C1-C4 alkoxy-C1-C4 alkyl, or allyl; X is halogen (selected from fluorine, chlorine, bromine or iodine, preferably selected from chlorine, bromine or iodine):

(3) In the presence of ammonium acetate, the compound of formula C selectively removes the 7-position acyl protecting group in a mixed solvent to obtain the compound of formula D:

(4) The compound of formula D is glycosylated with α-D-bromotetraacyl (R ₁₁ ) glucose in the presence of a phase transfer catalyst under alkaline conditions to obtain the compound of formula E through phase transfer catalysis:

The compound of formula E is deprotected to obtain neomangiferin;

Preferably, (5) the compound of formula E undergoes catalytic hydrogenation or reduction or acidolysis to remove the 1, 3, and 6 protecting groups to obtain the compound of formula F:

(6) The compound of formula F removes the acyl protecting group under alkaline conditions to obtain the compound of formula G, i.e. neomangiferin:

Here, in the compound of formula C-formula E, R ₂ is selected from unsubstituted benzyl or substituted benzyl, C1-C4 alkoxy-C1-C4 alkyl, or allyl; Here, the substituted benzyl The group means that the benzene ring is substituted by one or two or more substituents selected from halogen (such as fluorine, chlorine, bromine or iodine), nitro, C1-C4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), C1-C4 haloalkyl (e.g. trifluoromethyl), C1-C4 alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy); and, optionally, the substituent is at any position of the benzene ring _; preferably, R is selected from Benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, methoxymethyl, allyl, more preferably selected from benzyl, methoxymethyl, allyl ;

_In the compound of formula B _- formula F, R and R are each independently selected from aliphatic acyl, unsubstituted benzoyl or substituted benzoyl; here, the aliphatic acyl refers to C2-C6 alkanoyl ( For example, acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, pivaloyl or n-hexanoyl); the substituted benzoyl refers to the benzene ring being substituted by one or more than two substituents, the The substituents are selected from halogen (such as fluorine, chlorine, bromine or iodine), nitro, C1-C4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert butyl), C1-C4 alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy); and, optionally Preferably, the substituent is at any position _of the benzene ring; preferably, R and R are each independently selected from acetyl, pivaloyl, benzoyl, ₄ -chlorobenzoyl, 4-nitrobenzene Formyl is more preferably selected from acetyl.

In the synthesis method of the new mangiferin provided by the present invention, in the step (1), preferably, the molar ratio of mangiferin to sodium acetate and acid anhydride is 1:7.0～10.0:7.0～10.0, and the reaction temperature is 120～ 140°C; in the acid anhydride R ₁ -OR ₁ , R ₁ is as defined above.

In the synthetic method of the new mangiferin provided by the present invention, in the step (2), under the alkaline condition means in the presence of the following bases: selected from hydrogen phosphate di-salt, phosphate, borate, ethyl salt, carbonate, NaOH or a mixture of two or more, preferably selected from potassium carbonate; the R ₂ X is haloalkane, wherein R ₂ is as defined above, and X is selected from chlorine, bromine or Iodine, preferably, X is bromine (while R ₂ is unsubstituted benzyl or substituted benzyl, methoxymethyl, allyl); the polar organic solvent is selected from acetone, DMF (N,N - dimethylformamide), preferably selected from acetone.

In the synthesis method of new mangiferin provided by the present invention, in the step (2), preferably, the molar ratio of the compound of formula B to potassium carbonate, potassium iodide and R2X is ₁ :9.0～15.0:0.5～1.5: 4.0-8.0, the reaction temperature is 50-70°C (when the solvent is acetone), or 110-130°C (when the solvent is DMF).

In the synthetic method of new mangiferin provided by the present invention, in the step (3), the mixed solvent is selected from the mixed solvent of alcohol water and low boiling point solvent, preferably, the alcohol is selected from C1-C4 alkanol, low boiling point solvent selected from acetone, dichloromethane, more preferably, the alcohol is selected from methanol, and the low boiling point solvent is selected from acetone.

In the synthesis method of new mangiferin provided by the present invention, in the step (3), preferably, the molar ratio of the compound of formula C to ammonium acetate is 1:6.0-10.0, and the reaction temperature is 50-70°C.

In the synthetic method of the new mangiferin provided by the invention, in the step (4), the phase transfer catalyst is selected from quaternary ammonium salts (such as benzyltriethylammonium chloride (TEBA), tetrabutyl bromide ammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bisulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride), preferably Ground, be selected from tetrabutylammonium bromide, tetrabutylammonium bisulfate; Under said alkaline condition, refer to in the presence of following alkali: be selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate One or more, preferably selected from sodium hydroxide; the reaction system is a two-phase system of organic solvent and water, preferably selected from chloroform water or dichloromethane water.

In the semi-synthetic method of new mangiferin provided by the present invention, in the step (4), preferably, the molar ratio of the compound of formula D to bromosugar and alkali is 1:2.0～4.0:5.0～10.0, and the reaction temperature 30 to 40°C (when the reaction solvent is dichloromethane water), or 50 to 70°C (when the reaction solvent is chloroform water).

In the semi-synthetic method of new mangiferin provided by the invention, the removal of the protective group of the compound of formula E includes catalytic hydrogenation removal or reduction removal or acidolysis removal of the R2 protecting group and removal of the acyl group under alkaline conditions _; The catalyst in the catalytic hydrogenation is selected from palladium carbon, palladium hydroxide carbon; the reducing system in the described reduction removal is selected from palladium chloride/sodium borohydride, tetrakis (triphenylphosphine) palladium/sodium borohydride, preferably, Selected from tetrakis(triphenylphosphine) palladium/sodium borohydride; the acidolysis system in the acidolysis removal is selected from catalytic amount p-toluenesulfonic acid/methanol; deacylation under the alkaline condition refers to the reaction in sodium hydroxide , potassium hydroxide or sodium C1-C4 alkoxide, preferably selected from sodium C1-C4 alkoxide, more preferably selected from sodium methoxide or sodium tert-butoxide.

In the synthetic method of new mangiferin provided by the present invention, in the step (5), the catalyst for catalytic hydrogenation is selected from palladium carbon or palladium hydroxide carbon.

In the synthetic method of new mangiferin provided by the present invention, in the step (6), the alkaline condition refers to the presence of sodium hydroxide, potassium hydroxide or C1-C4 sodium alkoxide, preferably, It is selected from sodium C1-C4 alkoxide, more preferably from sodium methoxide or sodium tert-butoxide.

In the second aspect, the present invention provides intermediate compounds for the preparation of neomangiferin, that is, compounds of formula B to formula F:

Wherein, in the compounds of formula B to formula F, R ₁ and R ₁₁ are each independently selected from aliphatic acyl, unsubstituted benzoyl or substituted benzoyl; here, the aliphatic acyl refers to C2-C6 alkane Acyl (such as acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, pivaloyl or n-hexanoyl); the substituted benzoyl refers to the benzene ring being substituted by one or more than two substituents , the substituent is selected from halogen (such as fluorine, chlorine, bromine or iodine), nitro, C1-C4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), C1-C4 alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy); and, Optionally, the substituent is at any position of the benzene ring; preferably, R is selected from acetyl, pivaloyl, benzoyl, ₄ -chlorobenzoyl, 4-nitrobenzoyl, more is preferably selected from acetyl;

In the compound of formula C～formula E, R ₂ is selected from unsubstituted benzyl or substituted benzyl, C1-C4 alkoxy-C1-C4 alkyl, or allyl; Here, the substituted benzyl is Refers to the benzene ring being substituted by one or more substituents selected from halogen (such as fluorine, chlorine, bromine or iodine), nitro, C1-C4 alkyl (such as methyl, ethyl, n-propyl group, isopropyl, n-butyl, isobutyl or tert-butyl), C1-C4 haloalkyl (such as trifluoromethyl), C1-C4 alkoxy (such as methoxy, ethoxy, n-propyl Oxygen, isopropoxy, n-butoxy, isobutoxy or tert-butoxy); And, optionally, the substituent is at any position of the benzene ring _; Preferably, R is selected from benzyl , 4-nitrobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, methoxymethyl, allyl, more preferably selected from benzyl, methoxymethyl, allyl.

In a preferred embodiment of the invention, the invention provides an intermediate compound for the preparation of neomangiferin, selected from:

2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-1-hydroxy-3,6,7-triacetoxyxanthone;

2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-1,3,6-tribenzyloxy-7-acetoxyxanthone;

2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-hydroxy-1,3,6-tribenzyloxyxanthone;

2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-1,3,6-triallyloxy-7-acetoxyxanthone;

2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-1,3,6-tri-p-methoxybenzyloxy-7-acetoxyxanthene ketone;

2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-hydroxy-1,3,6-triallyloxyxanthone;

2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-hydroxy-1,3,6-tri-p-methoxybenzyloxyxanthone;

2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-O-(2,3,4,6-O-tetraacetyl-β-D- Glucosyl)-1,3,6-tribenzyloxyxanthone;

2-C-β-D-glucosyl-7-O-β-D-glucosyl-1,3,6-tribenzyloxyxanthone; or

2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-O-(2,3,4,6-O-tetraacetyl-β-D- Glucosyl)-1,3,6-trihydroxyxanthone.

Compared with the existing plant extraction method, the synthetic route of the new mangiferin provided by the present invention overcomes the problem of low efficiency on the one hand, and the raw material used is mangiferin with higher natural content and easier extraction, which can be prepared in large quantities. It has the possibility of industrialization; on the other hand, the obtained new mangiferin has high purity, which is convenient for the research of biological activity and pharmacological effect. In general, the method of the present invention has the characteristics of mild reaction conditions, high yield, simple operation, low cost, high universality, etc., and is suitable for industrial production.

detailed description

The practicability of the present invention is further illustrated by the following examples, which are not intended to limit the protection scope of the present invention.

Testing equipment:

Nuclear magnetic resonance: Bruker AV-400 nuclear magnetic resonance instrument, solvents are CDCl ₃ , DMSO-d ₆ , TMS is the internal standard unless otherwise noted.

Mass spectrometer: Bruker APEX IV mass spectrometer.

Optical rotation: Optical Activity AA-10R type polarimeter, the solvent is CHCl ₃ .

Melting point: X-5 microscopic melting point apparatus

Abbreviations:

PTP1B indicates protein tyrosine phosphatase 1B

SGLT-2 represents sodium-glucose symporter-2

DMF stands for N,N-Dimethylformamide

NMR stands for nuclear magnetic resonance scan

HRMS stands for High Resolution Mass Spectrometry

MS stands for Mass Spectrum

ESI stands for Electrospray Ion Source

Example 1: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-1-hydroxyl-3,6,7-triacetoxyxanthone synthesis

Take 5g (11.84mmol) of mangiferin and 8.16g (99.46mmol, 8.4eq) of sodium acetate and add it to 20ml of acetic acid, heat it to 120°C while stirring, add dropwise 10ml of acetic anhydride (105.79mmol, 8.9eq) to it, and reflux the reaction After 3h, 2ml of acetic anhydride (21.16mmol, 1.8eq) was added, and the reaction was continued for 0.5h. After the reaction, the reaction solution was poured into 200ml of ice water, stirred to separate out the solid, suction filtered, the filter cake was dissolved in dichloromethane, washed 3 times with saturated aqueous sodium bicarbonate solution, washed 3 times with water, washed 3 times with saturated aqueous sodium chloride solution. Dry over sodium sulfate, concentrate, and suck to dryness to obtain 7.94 g of a yellow solid, with a yield of 93.6%. Melting point 123.9-124.8°C, [α] _D = -12.0° (c 1.00, CHCl ₃ ).

¹ H NMR (400MHz, CDCl ₃ ) δ13.23(s,1H),8.06(s,1H),7.42(s,1H),6.77(s,1H),5.65(t,1H),5.49–4.94( m,3H),4.56–4.28(m,1H),4.08–3.90(m,1H),3.89–3.71(m,1H),2.45(s,3H),2.36(s,3H),2.35(s, 3H),2.07(s,3H),2.06(s,3H),2.03(s,3H),1.79(s,3H). ¹³ CNMR(100MHz,CDCl ₃ )δ180.00,170.15,169.82,169.36,169.11,167.72 ,166.85,160.93,156.40,156.19,153.46,148.12,139.13,119.74,117.92,112.67,110.34,105.58,103.36,76.13,74.14,70.85,70.06,68.01,61.78,21.02,20.46,20.39,20.35,20.16,20.10 .HRMS(ESI): Calculated for (C ₃₃ H ₃₃ O ₁₈ )[M+H] ⁺ 717.1661 Found 717.1655.

Example 2: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-1,3,6-tribenzyloxy-7-acetoxyxanthene Ketone synthesis

Take 5g (6.98mmol ) was dissolved in 100ml of acetone, potassium carbonate 11.57g (83.73mmol, 12eq), potassium iodide 1.16g (6.98mmol, 1eq), benzyl bromide 4.97ml (41.86mmol, 6eq) were added thereto, stirred at room temperature for 0.5h and then moved to Reflux reaction at 60°C for 13h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated. Petroleum ether: ethyl acetate = 1:1 column chromatography separation to obtain 5.35 g of white solid with a yield of 84.9%. Melting point 218.0-219.6°C, [α] _D = -67.4° (c 0.95, CHCl ₃ ).

¹ H NMR (400MHz, CDCl ₃ )δ7.93(s,1H),7.68–7.52(m,4H),7.50–7.07(m,11H),6.83(s,1H),6.74(s,1H), 6.09(t, J=9.7Hz, 1H), 5.34–4.80(m, 9H), 4.20(dd, J=12.4, 4.0Hz, 1H), 3.96(d, J=11.2Hz, 1H), 3.39(dt ,1H),2.26(s,3H),2.01(s,3H),1.96(s,3H),1.89(s,3H),1.77(s,3H). ¹³ CNMR(100MHz,CDCl ₃ )δ173.04,170.25 ,169.87,169.12,169.07,168.56,162.74,159.33,159.18,155.12,153.70,137.30,136.55,135.44,135.13,128.89,128.42,128.16,128.01,127.96,126.95,126.78,119.61,115.88,114.68,109.35,100.86 , 97.36, 78.06, 75.48, 74.44, 72.33, 70.77, 70.72, 68.91, 68.07, 61.85, 20.32, 20.27, 20.10. HRMS (ESI): Calculated (C ₅₀ H ₄₇ O ₁₆ )[M+H] ⁺ 903.2858, The measured value is 903.2851.

Example 3: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-hydroxyl-1,3,6-tribenzyloxyxanthone synthesis

Take 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-1,3,6-tribenzyloxy-7-acetoxyxanthone 5g ( 5.54mmol) was added to 100ml mixed solvent (methanol: acetone: water = 4:2:1), 3.41g (44.30mmol, 8eq) of ammonium acetate was added thereto, and refluxed at 60°C for 12h. After the reaction was completed, the reaction solution was concentrated and evaporated to dryness. The residue was dissolved in dichloromethane, washed three times with water and three times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Dichloromethane: acetone = 30:1 column chromatography to obtain 4.02 g of yellow solid with a yield of 84.4%. Melting point 111.7-112.9°C, [α] _D = -60.0° (c 1.00, CHCl ₃ ).

¹ H NMR (400MHz, CDCl ₃ )δ7.68–7.55(m,5H),7.49–7.22(m,11H),6.72(s,1H),6.67(s,1H),6.43(s,1H), 6.08(t, J=9.7Hz, 1H), 5.44–4.78(m, 9H), 4.15(dd, J=12.4, 4.1Hz, 1H), 3.93(d, J=11.0Hz, 1H), 3.28(dt ,1H),2.02(s,3H),1.97(s,3H),1.89(s,3H),1.81(s,3H). ¹³ C NMR(100MHz,CDCl ₃ )δ173.70,170.55,170.12,169.53,169.26 ,162.46,159.43,159.24,151.52,149.75,143.24,136.77,135.67,135.05,129.04,128.61,128.51,128.41,128.21,128.02,127.55,127.06,116.28,114.26,109.50,109.40,99.73,97.34,78.09,75.42 , 74.57, 72.48, 71.14, 70.80, 69.15, 68.12, 61.93, 20.51, 20.49, 20.45, 20.42. HRMS (ESI): Calculated (C ₄₈ H ₄₅ O ₁₅ )[M+H] ⁺ 861.2753, found 861.2741.

Example 4: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-1,3,6-triallyloxy-7-acetoxyoxa Synthesis of Anthrone

Take 2.0g (2.79 mmol) was dissolved in 30ml of acetone, 4.62g of potassium carbonate (33.48mmol, 12eq), 0.53g of potassium iodide, 1.93ml of allyl bromide (22.32mmol, 8eq) were added thereto, stirred at room temperature for 0.5h, and then moved to reflux at 60°C Reaction 13h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated. Separation by column chromatography gave 1.80 g of light yellow solid with a yield of 85.6%.

¹ H NMR (400MHz, CDCl ₃ )δ7.92(s,1H),6.86(s,1H),6.68(s,1H),6.35–5.89(m,4H),5.67–5.11(m,8H), 4.77(dd,J=12.8,4.9Hz,1H),4.72–4.40(m,5H),4.25(dd,J=12.4,4.9Hz,1H),4.16–4.05(m,2H),3.81(ddd, J＝9.9,4.7,1.9Hz,1H),2.34(s,3H),2.07(s,3H),2.05(s,3H),2.02(s,3H),1.75(s,3H).MS(ESI ): 753[M+H] ⁺ , 775[M+Na] ⁺ .

Example 5: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-1,3,6-tri-p-methoxybenzyloxy-7-acetoxy Synthesis of Xanthones

Take 2.67g (3.73 mmol) was dissolved in 35ml of acetone, 6.18g (44.76mmol, 12eq) of potassium carbonate was added thereto, appropriate amount of potassium iodide, 4.2ml (29.84mmol, 8eq) of p-methoxybenzyl chloride, stirred at room temperature for 0.5h and then moved to 60°C Reflux reaction for 13h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated. After separation by column chromatography, 2.65 g of light yellow solid was obtained, and the yield was 86.2%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.98(s, 1H), 7.74–6.88(m, 13H), 6.76(s, 1H), 6.01(t, J=9.7Hz, 1H), 5.26–4.75( m,8H), 4.16(dd,J=12.4,4.4Hz,1H),3.93(dd,J=12.4,1.9Hz,1H),3.85(s,7H),3.83(s,3H),3.43–3.37 (m,1H),2.29(s,3H),2.02(s,3H),1.98(s,3H),1.93(s,3H),1.76(s,3H).MS(ESI):993[M+ H] ⁺ .

Example 6: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-hydroxy-1,3,6-triallyloxyxanthone Synthesis

Take 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-1,3,6-triallyloxy-7-acetoxyxanthone 960mg (1.28mmol) was added to 30ml mixed solvent (methanol: acetone: water = 4:2:1), 786mg (10.20mmol, 8eq) of ammonium acetate was added thereto, and the reaction was refluxed at 60°C for 12h. After the reaction was completed, the reaction solution was concentrated and evaporated to dryness. The residue was dissolved in dichloromethane, washed three times with water and three times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Separated by column chromatography, 769 mg of yellow solid was obtained, with a yield of 84.9%.

¹ H NMR (400MHz, CDCl ₃ )δ7.63(s,1H),6.72(s,1H),6.62(s,1H),6.38–5.94(m,4H),5.72–5.12(m,9H), 4.87–4.43(m,6H),4.41–4.22(m,1H),4.15(d,J=11.4Hz,1H),3.85(d,J=6.3Hz,1H),2.75(s,1H),2.09 (s, 3H), 2.06(s, 3H), 2.04(s, 3H), 1.80(s, 3H). MS(ESI): 711[M+H] ⁺ .

Example 7: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-hydroxy-1,3,6-tri-p-methoxybenzyloxy Synthesis of Xanthones

Take 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-1,3,6-tri-p-methoxybenzyloxy-7-acetoxyoxa Anthrone 300mg (0.30mmol) was added to 25ml mixed solvent (methanol: acetone: water = 4:2:1), ammonium acetate 200mg (2.40mmol, 8eq) was added thereto, and refluxed at 60°C for 12h. After the reaction was completed, the reaction solution was concentrated and evaporated to dryness. The residue was dissolved in dichloromethane, washed three times with water and three times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Separation by column chromatography yielded 251 mg of a yellow solid with a yield of 87.5%. MS (ESI): 953 [M+H] ⁺ .

Example 8: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-O-(2,3,4,6-O-tetraacetyl- Synthesis of β-D-glucosyl)-1,3,6-tribenzyloxyxanthone

Take 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-hydroxyl 1,3,6-tribenzyloxyxanthone 3g (3.48mmol) , α-D-Tetraacetylbromoglucose 4.30g (10.44mmol, 3eq), tetrabutylammonium bromide TBAB1.69g (5.22mmol, 1.5eq) is dissolved in 30ml chloroform, adds 5% sodium hydroxide solution wherein 20ml, react at 60°C for 5h. After the reaction was completed, the reaction liquid was diluted with 50 ml of dichloromethane, washed 3 times with 1N dilute hydrochloric acid, washed 3 times with water, washed 3 times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Petroleum ether: ethyl acetate = 1:1 column chromatography to obtain 3.22 g of white solid with a yield of 77.6%. Melting point 115.1-115.9°C, [α] _D = -48.0° (c 1.00, CHCl ₃ ).

¹ H NMR (400MHz, CDCl ₃ )δ7.98(s,1H),7.63–7.57(m,4H),7.51–7.33(m,11H),6.88(s,1H),6.77(s,1H), 6.04(t,J＝9.7Hz,1H),5.39–4.90(m,13H),4.30–4.14(m,3H),3.98–3.90(m,2H),3.37–3.31(m,1H),2.10( s,3H),2.06(s,3H),2.02(s,3H),2.02(s,3H),1.97(s,3H),1.91(s,3H),1.82(s,3H),1.77(s ,3H). ¹³ C NMR(100MHz,CDCl ₃ )δ173.08,170.49,170.19,169.81,169.70,169.08,169.01,168.99,168.80,162.55,159.27,159.04,154.41,151.95,143.67,136.59,135.42,135.20,128.56 ,128.43,128.36,128.05,127.94,126.90,126.84,126.77,126.73,115.65,114.56,113.44,109.38,100.90,99.67,97.34,77.70,77.32,77.00,76.68,75.39,74.34,72.32,72.28,71.91,70.69 , 70.64, 70.55, 68.84, 68.02, 67.96, 61.73, 61.69, 20.24, 20.21, 20.19, 20.16, 19.90. HRMS (ESI): calculated value (C ₆₂ H ₆₃ O ₂₄ )[M+H] ⁺ 1191.3704, measured value 1191.3704.

Example 9: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-O-(2,3,4,6-O-tetraacetyl- Synthesis of β-D-glucosyl)-1,3,6-tribenzyloxyxanthone

Take 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-hydroxyl 1,3,6-tribenzyloxyxanthone 3g (3.48mmol) , α-D-Tetraacetylbromoglucose 2.87g (6.96mmol, 2eq), tetrabutylammonium bromide TBAB1.50g (4.63mmol, 1.33eq) was dissolved in 30ml of methylene chloride, 5% hydroxide was added thereto 20ml of sodium solution was reacted at 38°C for 12h. After the reaction was completed, the reaction liquid was diluted with 50 ml of dichloromethane, washed 3 times with 1N dilute hydrochloric acid, washed 3 times with water, washed 3 times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Petroleum ether: ethyl acetate = 1:1 column chromatography to obtain 2.43 g of white solid with a yield of 58.5%.

Example 10: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-O-(2,3,4,6-O-tetraacetyl- Synthesis of β-D-glucosyl)-1,3,6-triallyloxyxanthone

Take 1g (1.41 mmol), α-D-tetraacetylbromoglucose 1.74g (4.23mmol, 3eq), tetrabutylammonium bromide TBAB 0.68g (2.12mmol, 1.5eq) was dissolved in 15ml of chloroform, and 5% hydroxide was added thereto Sodium solution 10ml, react at 60°C for 5h. After the reaction was completed, the reaction liquid was diluted with 30 ml of dichloromethane, washed 3 times with 1N dilute hydrochloric acid, washed 3 times with water, washed 3 times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Petroleum ether: ethyl acetate = 1:1 column chromatography to obtain 1.05 g of white solid with a yield of 71.7%. MS (ESI): 1041 [M+H] ⁺ .

Example 11: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-O-(2,3,4,6-O-tetraacetyl- Synthesis of β-D-glucosyl)-1,3,6-tri-p-methoxybenzyloxyxanthone

Take 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-hydroxy-1,3,6-tri-p-methoxybenzyloxyxanthone 1g (1.05mmol), α-D-tetraacetylbromoglucose 1.30g (3.15mmol, 3eq), tetrabutylammonium bromide TBAB0.51g (1.58mmol, 1.5eq) was dissolved in 15ml of chloroform, and 5 % sodium hydroxide solution 10ml, react at 60°C for 5h. After the reaction was completed, the reaction liquid was diluted with 30 ml of dichloromethane, washed 3 times with 1N dilute hydrochloric acid, washed 3 times with water, washed 3 times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Petroleum ether: ethyl acetate = 1:1 column chromatography to obtain 0.98 g of white solid with a yield of 72.7%. MS (ESI): 1281 [M+H] ⁺ .

Example 12: 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-O-(2,3,4,6-O-tetraacetyl- Synthesis of β-D-glucosyl)-1,3,6-trihydroxyxanthone

Take 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-O-(2,3,4,6-O-tetraacetyl-β-D -Glucosyl)-1,3,6-tribenzyloxyxanthone 3g (2.52mmol) was dissolved in 50ml of mixed solvent (dichloromethane:methanol=4:1), and 10% palladium hydroxide was added thereto Carbon 600mg, stirred reaction 6～12h under 1atmH ₂ environment. After the reaction was completed, the catalyst was filtered off, the filter cake was washed with ethyl acetate, the filtrates were combined, concentrated, and drained to obtain 2.19 g of a light yellow solid, with a yield of 94.3%. Melting point 140.5-141.7°C, [α] _D =+64.0° (c 1.00, CHCl ₃ ).

¹ H NMR (400MHz, CDCl ₃ )δ13.52(s,1H),8.28(s,1H),7.74(s,1H),6.94(s,1H),6.76(s,1H),6.43(s, 1H),5.50–5.04(m,8H),4.40–4.15(m,4H),4.04–3.88(m,2H),2.16(s,3H),2.14(s,6H),2.08(s,3H) ,2.08(s,3H),2.07(s,3H),2.02(s,3H),1.81(s,3H). ¹³ C NMR(100MHz,CDCl ₃ )δ179.50,170.70,170.54,170.46,170.02,169.94, 169.40,169.12,163.45,160.45,157.58,153.93,153.82,141.87,113.14,111.11,103.78,103.34,101.94,100.75,95.94,76.30,73.29,73.14,72.43,71.91,71.42,70.36,68.05,67.80,61.74, 61.40, 20.77, 20.56, 20.48, 20.13.HRMS(ESI): Calculated (C ₄₁ H ₄₅ O ₂₄ )[M+H] ⁺ 921.2295, Found 921.2263.

Embodiment 13: the synthesis of new mangiferin

Add metallic sodium to 50ml of methanol, adjust the pH to 13-14, and filter out impurities. Add 2-C-(2,3,4,6-O-tetraacetyl-β-D-glucosyl)-7-O-(2,3,4,6-O-tetra Acetyl-β-D-glucosyl)-1,3,6-trihydroxyxanthone 3g (3.26mmol), stirred at room temperature for 2h. After the reaction was completed, 732 cation exchange resin was added to neutralize to pH = 7. Filtered, concentrated, and sucked dry to obtain the compound of formula G, namely neomangiferin 1.83g, yellow solid, yield 96.1%. The melting point is 226.4-227.3°C.

¹ H NMR (400MHz, DMSO-d ₆ )δ13.66(s,1H),7.71(s,1H),6.96(s,1H),6.40(s,1H),4.91(d,J＝7.2Hz, 1H), 4.59 (d, J=9.6Hz, 1H). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ179.23, 164.19, 161.72, 156.52, 154.95, 152.75, 143.73, 112.02, 110.45, 107.91, 103.43, 102.08 101.51, 93.77, 81.68, 78.97, 77.27, 75.90, 73.36, 73.25, 70.68, 70.35, 69.65, 61.58, 60.67. HRMS (ESI): calculated value C ₂₅ H ₂₉ O ₁₆ [M+H] ⁺ 585.1450, found value 5785.14 .

Claims (15)

1. a kind of Neomangiferin synthetic method, methods described comprises the following steps：

(1) formula A compounds are in the presence of sodium acetate, with acid anhydrides R₁-O-R₁Reacted in acetic acid, selectively acylating is except 1 phenolic hydroxyl group Outer whole hydroxyls obtain formula B compounds：

(2) formula B compounds are in the presence of KI or sodium iodide, in the basic conditions, with alkyl halide R₂X is in polar organic solvent Middle reaction, 1 hydroxyl of selective protection and conversion 3,6 protection groups obtain formula C compounds, wherein in R₂In X, R₂To be unsubstituted Benzyl or substituted benzyl, here, the substituted benzyl refers to that phenyl ring is replaced by one or more substituent, institute State substituent and be selected from halogen, nitro, C1-C4 alkyl or C1-C4 alkoxies；Also, the substituent is in any position of phenyl ring Put；X is selected from fluorine, chlorine, bromine or iodine；The polar organic solvent is selected from acetone or DMF：

(3) formula C compounds obtain formula Dization in the presence of ammonium acetate in 7 acyl protecting groups of in the mixed solvent selectively removing Compound：

(4) formula D compounds and the R of α-D- bromos four₁₁Acyl glucose in the presence of a phase transfer catalyst, in alkalescence condition, is passed through Phase transfer catalysis process is crossed glycosylate obtaining formula E compounds：

(5) formula E compounds obtain formula F compounds by catalytic hydrogenation removing 1,3,6 protection groups：

(6) formula F compounds remove acyl protecting groups and obtain formula G compounds, i.e. Neomangiferin in the basic conditions：

Here, in formula B- formulas F compounds, R₁And R₁₁It is each independently selected from aliphatic acyl radical, unsubstituted benzoyl or takes The benzoyl in generation；Here, the aliphatic acyl radical refers to C2-C6 alkanoyls；The substituted benzoyl refers to phenyl ring quilt One or more substituent is replaced, and the substituent is selected from halogen, nitro, C1-C4 alkyl or C1-C4 alkoxies；And And, the substituent is in the optional position of phenyl ring；

In formula C- formula E compounds, R₂Selected from unsubstituted benzyl or substituted benzyl；Here, the substituted benzyl refers to phenyl ring Replaced by one or more substituent, the substituent is selected from halogen, nitro, C1-C4 alkyl or C1-C4 alkoxies； Also, the substituent is in the optional position of phenyl ring.

2. according to the method described in claim 1, wherein, in R₂In X, X is selected from chlorine, bromine or iodine；

In formula B- formula F compounds, R₁Selected from acetyl group, valeryl, benzoyl, 4- chlorobenzoyls base or 4- nitrobenzoyls Acyl group；

R₁₁Selected from acetyl group, valeryl, benzoyl, 4- chlorobenzoyls base or 4- nitro benzoyls；

Formula R₂In X and formula C- formula E compounds, R₂Selected from benzyl, 4- nitrobenzyls, 4- chlorobenzyls or 4- methoxy-benzyls.

3. method according to claim 2, wherein, in formula B- formula F compounds, R₁Selected from acetyl group；

R₁₁For acetyl group；

Formula R₂In X and formula C- formula E compounds, R₂Selected from benzyl.

4. according to the method described in claim 1, wherein, the polar organic solvent be selected from be selected from acetone.

5. according to the method described in claim 1, wherein, in the step (1), mole of A compounds and sodium acetate and acid anhydrides Than for 1：7.0~10.0：7.0~10.0, reaction temperature is 120~140 DEG C.

6. according to the method described in claim 1, wherein, in the step (2), refer under the alkalescence condition selected from following One or more alkali in the presence of：Phosphoric acid hydrogen disalt, phosphate, borate, acetate, carbonate, NaOH or KOH.

7. according to the method described in claim 1, wherein, in the step (2), refer under the alkalescence condition in potassium carbonate In the presence of.

8. method according to claim 7, wherein, in the step (2), formula B compounds, potassium carbonate, KI and R₂X Mol ratio be 1：9.0~15.0：0.5~1.5：4.0~8.0.

9. according to the method described in claim 1, wherein, in the step (3), the mixed solvent be selected from alcohol water and low boiling The mixed solvent of solvent；The alcohol is selected from C1-C4 alkanols；The low boiling point solvent is selected from acetone or dichloromethane.

10. method according to claim 9, wherein, in the step (3), the alcohol is selected from methanol；The low boiling is molten Agent is selected from acetone.

11. according to the method described in claim 1, wherein, in the step (3), the mol ratio of formula C compounds and ammonium acetate is 1：6.0~10.0.

12. according to the method described in claim 1, wherein, in the step (4), the phase transfer catalyst be selected from the tetrabutyl Ammonium bromide or 4-butyl ammonium hydrogen sulfate；Refer under the alkalescence condition in the presence of following one or more alkali：Hydrogen Sodium oxide molybdena, potassium hydroxide, sodium carbonate or potassium carbonate；Reaction system is the two-phase system of organic solvent and water, selected from chloroform, water, Or dichloromethane, water.

13. according to the method described in claim 1, wherein, in the step (4), formula D compounds, the R of α-D- bromos four₁₁Acyl group The mol ratio of glucose and alkali is 1：2.0~4.0：5.0~10.0.

14. it is used as the midbody compound for preparing Neomangiferin, the intermediate compound in the method as described in claim 1 Thing is the compound such as following formula B~formula F：

Wherein, R₁、R₂And R₁₁Definition is as claimed in claim 1.

15. midbody compound as claimed in claim 14, selected from one of following compounds：

2-C- (tetra-acetylated-β of 2,3,4,6-O--D-Glucose base) -1- hydroxyl -3,6,7- triacetoxyl group xanthones；

Benzyloxy -7- acetoxyl group the xanthones of 2-C- (tetra-acetylated-β of 2,3,4,6-O--D-Glucose base) -1,3,6- three；

The benzyloxy xanthones of 2-C- (tetra-acetylated-β of 2,3,4,6-O--D-Glucose base) -7- hydroxyls -1,3,6- three；

2-C- (tetra-acetylated-β of 2,3,4,6-O--D-Glucose base) -1,3,6- three are to methoxybenzyl epoxide -7- acetoxyl group oxygen Miscellaneous anthrone；

2-C- (tetra-acetylated-β of 2,3,4,6-O--D-Glucose base) -7- hydroxyls -1,3,6- three is to methoxybenzyl epoxide xanthene Ketone；

2-C- (tetra-acetylated-β of the 2,3,4,6-O--D-Glucose base) -7-O- (tetra-acetylated-β of 2,3,4,6-O--D-Glucose Base) three benzyloxy xanthones of -1,3,6-；

Or

2-C- (tetra-acetylated-β of the 2,3,4,6-O--D-Glucose base) -7-O- (tetra-acetylated-β of 2,3,4,6-O--D-Glucose Base) -1,3,6- trihydroxy xanthones.