Method for preparing mesaconine and related intermediaries thereof

Abstract

The present invention relates to a method for preparing mesaconine and related intermediaries. Specifically, in the method for preparing mesaconine of the present invention, aconitine extracted from the Aconitum soongaricum Stapf. of aconitum plant is used as a raw material and subjected to alkalization, acetylation, N-de-ethylation, N-methylation, and hydrolysis to obtain mesaconine. The method for preparing mesaconine in the present invention is simple in operation, high in yield, environmentally friendly and pollution-free, and suitable for industrial production.

Claims

1. A method for preparing mesaconine, comprising the following steps: 1) dissolving aconitine (I) in ethanol, adding sodium hydroxide thereto to hydrolyze, concentrating under reduced pressure, and diluting the residue with water, extracting with dichloromethane to remove impurity alkaloids, acidifying the alkaline aqueous solution with hydrochloric acid, adjusting to pH 11 to 12 by aqua ammonia or a solution of sodium hydroxide in ethanol, concentrating under reduced pressure to dryness, dissolving the residue with dichloromethane-ethanol, filtering, and concentrating the filtrate under reduced pressure to obtain aconine (II); ##STR00032## 2) dissolving aconine (II) in pyridine and reacting with acetic anhydride, concentrating under reduced pressure to obtain a residue, diluting the residue with water, alkalizing with aqua ammonia, extracting with dichloromethane, combining dichloromethane layers, and then drying, concentrating, and separating by silica-gel column chromatography in sequence to prepare 3,14,15-triacetyl aconine (III); ##STR00033## or reacting aconine (II) with acetic anhydride under the catalysis of p-toluene sulfonic acid, concentrating under reduced pressure to obtain a residue, diluting the residue with water, alkalizing with aqua ammonia, extracting with dichloromethane, combining dichloromethane layers, and then drying, concentrating, and separating by silica-gel column chromatography in sequence to prepare 3,8,13,14,15-pentaacetyl aconine (IV); ##STR00034## 3) dissolving 3,14,15-triacetyl aconine (III) in glacial acetic acid, adding N-bromosuccinimide thereto, stirring at room temperature, concentrating under reduced pressure to obtain a residue, adding aqua ammonia to the residue, extracting with dichloromethane, combining dichloromethane extracts, drying, and concentrating under reduced pressure to prepare N-desethyl-3,14,15-triacetyl aconine (V); ##STR00035## or dissolving 3,8,13,14,15-pentaacetyl aconine (IV) in glacial acetic acid, adding N-bromosuccinimide thereto, stirring at room temperature, concentrating under reduced pressure to obtain a residue, adding aqua ammonia to the residue, extracting with dichloromethane, combining dichloromethane extracts, drying, and concentrating under reduced pressure to prepare N-desethyl-3,8,13,14,15-pentaacetyl aconine (VI); ##STR00036## 4) dissolving N-desethyl-3,14,15-triacetyl aconine (V) in tetrahydrofuran, adding formaldehyde aqueous solution and glacial acetic acid thereto at room temperature, stirring at room temperature, adding NaBH(OAc).sub.3, continuing to stir, adding aqua ammonia, diluting with water, then extracting with dichloromethane, combining the dichloromethane extracts, and then washing with water, drying, and concentrating under reduced pressure in sequence to prepare 3,14,15-triacetylmesaconine (VII); ##STR00037## or dissolving N-desethyl-3,8,13,14,15-pentaacetyl aconine (VI) in tetrahydrofuran, adding formaldehyde aqueous solution and glacial acetic acid thereto at room temperature, stirring at room temperature, adding NaBH(OAc).sub.3, continuing to stir, adding aqua ammonia, diluting with water, extracting with dichloromethane, combining the dichloromethane extracts, and then washing with water, drying, and concentrating under reduced pressure in sequence to prepare 3,8,13,14,15-pentaacetylmesaconine (VIII); ##STR00038## 5) dissolving 3,14,15-triacetylmesaconine (VII) or 3,8,13,14,15-pentaacetylmesaconine (VIII) in ethanol solution, adding sodium hydroxide to react with the mesaconine derivative respectively, adjusting to pH 4 to 5 with hydrochloric acid, then adjusting to pH 9 to 12 with aqua ammonia or a solution of sodium hydroxide in ethanol, filtering off insoluble materials, concentrating under reduced pressure, dissolving the residue with dichloromethane-ethanol, filtering with suction, and concentrating the filtrate under reduced pressure to obtain mesaconine (IX) ##STR00039##

2. The method according to claim 1, wherein the aconitine (I) is prepared by the following method: after crushing the roots of the aconitum plant, adding sulfuric acid-ethanol aqueous solution to extract under reflux; concentrating the extract under reduced pressure to obtain a solid extract; diluting the solid extract with water, and after alkalization, extracting with ethyl acetate, and recovering the solvent to obtain an ethyl acetate extract; subjecting the ethyl acetate extract to acid dissolution, filtration, and alkalization and precipitation to obtain the aconitine (I).

3. The method according to claim 2, wherein the content of sulfuric acid is 1-10% and the content of ethanol is 80-90%, based on the total mass of the sulfuric acid-ethanol aqueous solution.

4. The method according to claim 2, wherein the content of sulfuric acid is 5% and the content of ethanol is 85%, based on the total mass of the sulfuric acid-ethanol aqueous solution.

5. The method according to claim 2, wherein the aconitum plant is Aconitum soongaricum Stapf. or Aconitum karakolicum Rapaics.

6. N-desethyl-3,14,15-triacetyl aconine, its structural formula is shown as formula (V) ##STR00040## or N-desethyl-3,8,13,14,15-pentaacetyl aconine, its structural formula is shown as formula (VI) ##STR00041##

7. 3,14,15-triacetylmesaconine, its structural formula is shown as formula (VII) ##STR00042##

8. The method according to claim 3, wherein the content of sulfuric acid is 5% and the content of ethanol is 85%, based on the total mass of the sulfuric acid-ethanol aqueous solution.

Description

EMBODIMENTS

(1) The following examples will further explain the present invention, however, they do not constitute a restriction or limitation on the scope of the present invention.

EXAMPLE 1

Extraction of Total Alkaloids from Aconitum soongaricum Stapf. of Aconitum Plant

(2) (1) 10 kg of dried roots of Aconitum soongaricum Stapf. were taken, crushed and sifted through a 20-mesh sieve;

(3) (2) the powder of Aconitum soongaricum Stapf. of aconitum plant was extracted for 3 times in reflux with 80 L, 36 L and 24 L of an aqueous solution of 5% sulfuric acid and 85% ethanol, extracted for 2 hours each time, filtered and combined the filtrate;

(4) (3) the filtrate was concentrated under reduced pressure, ethanol was recovered until the relative density of the fluid extract was 1.05 to 1.10, and 0.46 kg fluid extract was collected;

(5) (4) the fluid extract was diluted by adding 1.4 L of water, alkalized with aqua ammonia, adjusted to pH 10, placed in an extractor and extracted with ethyl acetate (2 L×3 times), stirred for 5 to 10 minutes each time, and the extract was collected;

(6) (5) ethyl acetate was recovered by concentration under reduced pressure, and 129 g total alkaloids were obtained. The total alkaloids were sampled and the content of aconitine in total alkaloids was determined by HPLC method. The total amount of aconitine (I) in the total alkaloids was calculated to be about 42.5 g based on its content in the total alkaloids and wet weight of the total alkaloids, and the yield was about 0.42%.

EXAMPLE 2

Preparation of Mesaconine

(7) (1) Preparation of aconine (II)

(8) ##STR00023##

(9) 100 g total alkaloids (including 33 g of aconitine) were taken and dissolved with 500 mL of 95% ethanol, then 7.2 g (78 mmol) of sodium hydroxide was added thereto, the mixture was stirred for 2 hours at room temperature, and the solvent was recovered under reduced pressure to obtain 120 g of solid. The solid was diluted with 1000 mL of water, and extracted with dichloromethane (500 mL×2). The aqueous layer was adjusted to pH 5 with concentrated hydrochloric acid, and then adjusted to pH 11 to 12 with a diluted solution of sodium hydroxide in ethanol, and concentrated to dryness under reduced pressure to obtain 90 g of solid, which was dissolved by heating in 900 mL of dichloromethane-absolute ethanol (9:1, V/V),=, filtered, and the filtrate was concentrated under reduced pressure and a solid (22.5 g) was obtained as the desired compound.

(10) Yield: 86%, white amorphous powder, C.sub.25H.sub.41NO.sub.9.

(11) .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 0.99(3H, t, NCH.sub.2CH.sub.3), 1.86-1.97(6H, m), 2.23-2.28(2H, m), 2.33-2.38(4H, m), 2.48(2H, m), 2.70(2H, m), 2.76(1H, d, J=6.8 Hz), 2.88-2.98(2H, m), 3.06(1H, t, J=6.8 Hz), 3.10(1H, s), 3.15, 3.20, 3.25, 3.50(each 3H, s, 4×OCH.sub.3), 3.59(1H, dd, J=12.0, 4.0 Hz, H-3β), 3.71(1H, d, J=6.8 Hz, H-15β), 3.77(1H, d, J=8.0 Hz, H-16α), 4.09(1H, d, J=8.0 Hz, H-15β), 4.32(1H, d, J=4.0 Hz, H-14β);

(12) .sup.13C NMR (100 MHz, CD.sub.3OD) δ: 13.8(q), 35.5(t), 38.8(t), 43.1(d), 44.5(s), 47.5(d), 48.3(t), 49.5(d), 50.1(t), 50.3(d), 51.1(s), 56.2(q), 58.2(q), 59.1(q), 61.6(q), 62.1(d), 70.7(d), 75.3(t), 77.7(s), 79.5(s), 79.7(d), 82.3(d), 84.2(d), 85.0(d), 93.1(d);

(13) ESI-MS m/z (%): 500(100)[M+H].sup.+.

(14) (2) Preparation of 3,14,15-triacetyl aconine (III)

(15) ##STR00024##

(16) 10.0 g (20 mmol) of aconine (II) was taken and mixed with 7.1 g (70 mmol) of acetic anhydride and 100 mL of pyridine, and the mixture was reacted under reflux for 2.5 hours, concentrated under reduced pressure to obtain a residue. The residue was diluted with 170 mL of water, and the diluent was alkalized to pH 9 to 10 with aqua ammonia, extracted with dichloromethane (80 ml×3). The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a solid, then the solid was subjected to silica gel column chromatography and eluted by dichloromethane-anhydrous ethanol (200:1) to obtain 10.7 g of the desired compound.

(17) Yield: 85.6%, white amorphous powder, C.sub.31H.sub.47NO.sub.12.

(18) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.13 (3H, t, J=7.2 Hz, NCH.sub.2CH.sub.3), 1.86-1.97 (4H, m), 2.06, 2.07, 2.18 (each 3H, s, 3×OAc), 2.26, 2.54 (2H, ABq, J=6.0 Hz), 2.33-2.38 (4H, m), 2.54 (2H, m), 2.72 (2H, m), 2.88-2.94 (2H, m), 3.07 (1H, t, J=6.8 Hz), 3.20, 3.23, 3.27, 3.56 (each 3H, s, 4×OCH.sub.3), 3.54 (1H, d, J=6.4 Hz), 3.91 (1H, d, J=6.0 Hz, H-16α), 4.10 (1H, d, J=4.0 Hz), 4.65 (1H, d, J=5.2, H -14β), 4.88 (1H, t, J=8.8 Hz, H-3β), 5.25 (1H, d, J=6.0 Hz, H-15β);

(19) .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 13.4(q), 20.8(q), 21.1(q), 21.1(q), 31.9(t), 36.2(t), 40.6(d), 42.0(s), 44.5(d), 45.5(d), 47.4(t), 48.9(t), 49.5(d), 49.5(s), 56.1(q), 57.8(q), 58.7(q), 60.6(d), 61.3 (q), 71.4(d), 71.7(t), 74.3(s), 76.5(s), 78.6(d), 81.7(d), 82.8(d), 87.2(d), 88.3(d), 170.1(s), 170.9(s), 173.3(s);

(20) ESI-MS m/z (%): 626(100)[M+H].sup.+.

(21) (3) Preparation of 3,8,13,14,15-pentaacetyl aconine (IV)

(22) ##STR00025##

(23) 150 mg (0.31 mmol) of aconine (II) was taken and dissolved in 1 mL of acetic anhydride, and 176 mg (0.93 mmol) of p-toluenesulfonic acid was added thereto at room temperature under stirring. The reaction solution was heated to 120° C., reacted for 3 to 4 hours, concentrated under reduced pressure to evaporate most of the solvent, the resulting residue was diluted with 20 mL of water, adjusted to pH 9 to 10 with 5 mL of aqua ammonia, and extracted with dichloromethane (10 mL×2). The extracts were combined, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain a residue. The residue was separated by silica gel column chromatography and eluted by petroleum ether-acetone (10:1 to 2:1) to obtain 161 mg of the desired compound.

(24) Yield: 75%, white amorphous powder, C.sub.35H.sub.51NO.sub.14.

(25) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.14 (3H, t, J=7.2 Hz, NCH.sub.2CH.sub.3), 1.94 (3H, s, OAc), 2.01 (1H, d, J=5.6 Hz), 2.04, 2.08 (each 3H, s, 2×OAc), 2.10, 2.13 (each 3H, s, 2×OAc), 2.25-2.54 (5H, m), 2.72-2.81(4H, m), 2.94 (1H, d, J=8.9 Hz), 3.08 (1H, dd, J=10.3, 6.9 Hz), 3.12 (1H, s), 3.19, 3.21, 3.25, 3.33 (each 3H, s, 4×OCH.sub.3), 3.36 (1H, s), 3.62 (1H, dd, J=15.4, 5.3 Hz), 3.74 (1H, d, J=3.4 Hz, H-16), 3.76 (1H, s), 4.05 (1H, d, J=6.0 Hz, H-6β), 4.84 (1H, d, J=5.2 Hz, H-14β), 4.88 (1H, dd, J=12.4, 6.8 Hz, H-3β), 5.84 (1H, d, J=6.0 Hz, H-15β);

(26) .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 13.5 (q), 21.1 (q), 21.1 (q), 21.2 (q), 21.3 (q), 22.0 (q), 31.9 (t), 36.0 (t), 41.1 (d), 42.1 (s), 43.7 (d), 45.0 (d), 45.5 (d), 47.0 (t), 48.8 (t), 49.8 (s), 56.1 (q), 58.7 (q), 58.8 (q), 60.3 (q), 61.0 (d), 71.2 (t), 71.3 (d), 76.3 (d), 78.2 (d), 80.7 (s), 81.4 (d), 83.7 (d), 88.2 (d), 88.8 (s), 168.4 (s), 169.6 (s), 170.2 (s), 170.3 (s), 170.7 (s);

(27) ESI-MS m/z (%): 710(100) [M+H].sup.+.

(28) (4) Preparation of N-desethyl-3,14,15-triacetyl aconine (V)

(29) ##STR00026##

(30) 10.0 g (17 mmol) of 3,14,15-triacetyl aconine (III) was taken and dissolved in 100 mL of glacial acetic acid, 9.9 g (66 mmol) of N-bromosuccinimide was added thereto. The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure to obtain a solid. The solid was dissolved with a small amount of dichloromethane, after 150 mL of water was added, the solution was alkalized to pH 10 with strong aqua ammonia, and extracted with dichloromethane (80 ml×2). The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10.5 g of solid. The solid was subjected to silica gel column chromatography and eluted by petroleum ether-acetone (2:1) to obtain 6.4 g of the desired compound.

(31) Yield: 67.0%, white amorphous powder, C.sub.29H.sub.43NO.sub.12.

(32) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.95-1.99 (4H, m), 2.05, 2.08, 2.27 (each 3H, s, 3×OAc), 2.19-2.28 (4H, m), 2.47 (2H, m), 2.74 (1H, d, J=6.8 Hz), 2.99 (2H, m), 3.10 (1H, d, J=8.6 Hz), 3.24, 3.25, 3.29, 3.57 (each 3H, s, 4×OCH.sub.3), 3.52 (1H, m), 3.68 (1H, m), 3.76 (1H, t, J=4.8 Hz), 4.10 (1H, d, J=4.0 Hz), 4.19 (1H, s), 4.68 (1H, d, J=4.8 Hz, H-14β), 5.09 (1H, t, J=6.4 Hz, H-3β), 5.25 (1H, d, J=6.4 Hz, H-15β);

(33) .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 21.0(q), 21.1(q), 21.2(q), 30.4(0, 35.1(t), 40.4(d), 41.4(t), 42.6(s), 43.3(d), 44.0(d), 49.3(t), 54.5(s), 55.2(q), 56.1(q), 57.8(q), 58.8(q), 61.4(d), 72.1(d), 74.2(t), 74.4(s), 76.7(s),78.5(d), 80.3(d), 82.6(d), 86.8(d), 87.9(d), 170.1(s), 170.7(s), 174.2(s);

(34) ESI-MS m/z (%): 598(100)[M+H].sup.+.

(35) (5) Preparation of N-desethyl-3,8,13,14,15-pentaacetyl aconine (VI)

(36) ##STR00027##

(37) 10.0 g (14 mmol) of 3,8,13,14,15-pentaacetyl aconine (IV) was taken and dissolved in 100 mL of glacial acetic acid, 9.9 g (66 mmol) of N-bromosuccinimide was added thereto. The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure to obtain a solid. The solid was dissolved with a small amount of dichloromethane, after 150 mL of water was added, the solution was alkalized to pH 10 with strong aqua ammonia, and extracted with dichloromethane (80 ml×2). The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8.5 g of solid. The solid was subjected to silica gel column chromatography and eluted by petroleum ether-acetone (2:1) to obtain 6.5 g of the desired compound.

(38) Yield: 67.7%, white amorphous powder, C.sub.33H.sub.47NO.sub.14.

(39) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.88-1.93 (2H, m), 1.94 (3H, s, OAc), 2.01-2.04 (4H, m), 2.03, 2.07 (each 3H, s, 2×OAc), 2.14, 2.16 (each 3H, s, 2×OAc), 2.27 (1H, q, J=6.4 Hz), 2.34 (1H, d, J=6.8 Hz), 2.71 (1H, dd, J=7.5, 5.4 Hz), 2.78 (1H, d, J=12.9 Hz), 2.95 (1H, d, J=8.8 Hz), 3.08 (1H, d, J=12.9 Hz), 3.15 (1H, t, J=7.1 Hz), 3.22 (3H, s, OMe), 3.26 (6H, s, 2×OMe), 3.32 (3H, s, OMe), 3.37 (1H, d, J=11.6 Hz), 3.72 (1H, d, J=8.8 Hz), 3.77 (1H, d, J=6.1 Hz), 4.06 (1H, dd, J=6.8, 1.8 Hz), 4.86 (1H, d, J=5.2 Hz, H-14β), 5.02 (1H, dd, J=9.6, 5.6 Hz, H-3β), 5.84 (1H, d, J=6.0 Hz, H-15β);

(40) .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 21.0 (.sub.q), 21.1 (q), 21.3 (q), 21.3 (q), 22.1 (q), 31.6 (t), 34.7 (t), 41.1 (t), 41.2 (d), 42.7 (s), 42.8 (d), 44.5 (d), 49.3 (s), 51.4 (d), 55.7 (q), 55.8 (q), 58.7 (q), 58.8 (q), 61.1 (d), 71.8 (d), 73.0 (t), 76.3 (d), 78.2 (d), 80.5 (s), 80.6 (d), 83.8 (d), 87.8 (d), 88.4 (s), 168.3 (s), 169.7 (s), 170.3 (s), 170.4 (s), 170.6 (s);

(41) ESI-MS m/z (%): 682 (100) [M+H].sup.+.

(42) (6) Preparation of 3,14,15-triacetylmesaconine (VII)

(43) ##STR00028##

(44) 10 g (17 mmol) of N-desethyl-3,14,15-triacetyl aconine (V) was taken and dissolved in 25 mL of tetrahydrofuran, and 2 ml of 40% formaldehyde aqueous solution and 1 mL of glacial acetic acid were added at room temperature, kept stirring at this temperature for 30 minutes. Then 7.1 g (33.5 mmol) of NaBH(OAc).sub.3 was added, and continued stirring for 30 minutes. The solution was adjusted to pH 9 with strong aqua ammonia, diluted with 15 mL of water, extracted with 20 mL of dichloromethane twice. The extracts was combined, and then washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure in sequence to obtain 5.5 g of solid. The solid was subjected to silica gel column chromatography and eluted by chloroform-methanol (9:1) to obtain 5.41 g of the desired compound.

(45) Yield: 53.1%, white amorphous powder, C.sub.30H.sub.45NO.sub.12.

(46) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.98-2.01 (4H, m), 2.05, 2.07, 2.21 (each 3H, s, 3×OAc), 2.22-2.30 (2H, m), 2.32 (3H, s, NCH.sub.3), 2.42 (2H, m), 2.58 (1H, m), 2.63 (1H, m), 2.82 (1H, s), 2.92 (1H, m), 2.97 (1H, d, J=4.0 Hz), 3.10 (1H, dd, J=4.8 Hz), 3.20, 3.25, 3.27, 3.54 (each 3H, s, 4×OCH.sub.3), 3.26 (1H, d, J=4.0 Hz), 3.95 (1H, d, J=8.0 Hz), 4.00 (1H, s), 4.13 (1H, d, J=6.0 Hz), 4.65 (1H, d, J=4.0 Hz, H-14β), 4.85 (1H, t, J=4.8 Hz, H-3β), 5.24 (1H, d, J=6.0 Hz, H-15β);

(47) .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 20.9(q), 21.0(q), 21.1(q), 31.9(t), 36.0(t), 40.7(d), 42.3(s), 42.5(q), 44.4(d), 44.8(d), 48.4(d), 49.5(s), 49.9(t), 56.5(q), 57.8(q), 58.7(q), 61.2(q), 62.0 (d), 72.1(d), 71.5(t), 74.3(s), 76.3(s),78.5(d), 81.8(d), 82.6(d), 87.2(d), 88.3(d), 170.1(s), 170.9(s), 173.4(s);

(48) ESI-MS m/z (%): 612(100) [M+H].sup.+.

(49) (7) Preparation of 3,8,13,14,15-pentaacetylmesaconine (VIII)

(50) ##STR00029##

(51) 10 g (14.6 mmol) of N-desethyl-3,8,13,14,15-pentaacetyl aconine (VI) was taken and dissolved in 25 mL of tetrahydrofuran, and 2 mL of 40% formaldehyde aqueous solution and 1 mL of glacial acetic acid were added at room temperature, stirred for 30 minutes. Then 7.1 g (33.5 mmol) of NaBH(OAc).sub.3 was added, and continued stirring for 30 minutes. The solution was adjusted to pH 9 with strong aqua ammonia, diluted with 15 mL of water, extracted with 20 mL of dichloromethane twice. The extracts were combined, and then washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure in sequence to obtain 6.5 g of solid. The solid was subjected to silica gel column chromatography and eluted by chloroform-methanol (9:1) to obtain 6.1 g of the desired compound.

(52) Yield: 59.8%, white amorphous powder, C.sub.34H.sub.49NO.sub.14.

(53) .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 1.18 (1H, s), 1.95 (3H, s, OAc), 2.04, 2.08 (each 3H, s, 2×OAc), 2.14 (6H, s, 2×OAc), 2.28 (1H, d, J=6.8 Hz), 2.33-2.42 (4H, m), 2.43 (3H, s, NMe), 2.66 (1H, d, J=11.5 Hz), 2.78 (1H, dd, J=7.3, 5.4 Hz), 2.95 (1H, d, J=8.9 Hz), 3.05 (1H, s), 3.09 (1H, dd, J=10.6, 6.9 Hz), 3.19, 3.23, 3.26, 3.33 (each 3H, s, 4×OMe), 3.40 (1H, d, J=1.7 Hz), 3.62 (1H, dd, J=15.4, 5.4 Hz), 3.75 (1H, d, J=5.8 Hz), 3.77 (1H, d, J=2.9 Hz), 4.06 (1H, d, J=6.4 Hz, H-6β), 4.86 (1H, d, J=5.2 Hz, H-14β), 4.90 (1H, dd, J=12.4, 6.0 Hz, H-3β), 5.83 (1H, d, J=6.0 Hz, H-15β);

(54) .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 21.1 (q), 21.3 (q), 21.3 (q), 22.0 (q), 26.9 (q), 31.9 (t), 35.8 (t), 41.2 (q), 42.4 (s), 42.7(d), 43.8 (d), 44.1 (d), 44.8 (d), 49.6 (t), 49.9 (s), 56.4 (q), 58.7 (q), 58.8 (q), 60.9 (q), 61.9 (d), 71.1 (t), 71.2 (d), 76.3 (d), 78.3 (d), 80.7 (s), 81.5 (d), 83.6 (d), 88.2 (d), 88.7 (s), 168.4 (s), 169.5 (s), 170.1 (s), 170.2 (s), 170.7 (s);

(55) ESI-MS m/z (%): 696(100)[M+H].sup.+.

(56) (8): Preparation of Mesaconine (IX)

(57) ##STR00030##

(58) Method 1: Preparation of mesaconine (IX) from 3,14,15-triacetylmesaconine (VII) 10 g (16.3 mmol) of 3,14,15-triacetylmesaconine (VII) was taken and dissolved in 75 mL of 95% ethanol solution. Then 2.29 g (57 2 mmol) of sodium hydroxide was added, and the mixture was refluxed for 30 minutes. The reaction solution was cooled to room temperature, adjusted to pH 5 with concentrated hydrochloric acid, and then adjusted to pH 11 to 12 with a diluted solution of sodium hydroxide in ethanol. The insoluble matter was filtered off and the filtrate was concentrated under reduced pressure to obtain a solid. The solid was dissolved in 110 mL of dichloromethane-anhydrous ethanol (9:1, V/V), filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain 7.22 g of mesaconine, with a yield of 91.1%.

(59) Method 2: Preparation of mesaconine (IX) from 3,8,13,14,15-pentaacetylmesaconine (VIII)

(60) 10 g (14.4 mmol) of 3,8,13,14,15-pentaacetylmesaconine (VIII) was taken and dissolved in 75 ml of 95% ethanol solution. Then 2.29 g (50.4 mmol) of sodium hydroxide was added, and the mixture was refluxed for 30 minutes. The reaction solution was cooled to room temperature, adjusted to pH 5 with concentrated hydrochloric acid, and then adjusted to pH 9 with strong aqua ammonia. The insoluble matter was filtered off and the filtrate was concentrated under reduced pressure to obtain 9.5 g of solid. The solid was dissolved in 95 mL of dichloromethane-anhydrous ethanol (9:1, V/V), filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain 6.2 g of mesaconine, with a yield of 90.0%.

(61) The above mesaconine has the following physicochemical properties:

(62) mesaconine: white solid, the specific rotation is [α].sub.D.sup.°+21.5(c, 0.5,H.sub.2O); the molecular formula is C.sub.24H.sub.39NO.sub.9; easily soluble in water and methanol, soluble in ethanol, slightly soluble in isopropanol, very slightly soluble in acetone, chloroform. By sufficient two-dimensional NMR and other spectral analysis, the structural formula is determined as formula (IX)

(63) ##STR00031##

(64) The spectral data of mesaconine is as follows:

(65) IR(KBr): 3424 cm.sup.−1, 2932 cm.sup.−1, 2892 cm.sup.−1, 2821 cm.sup.−1, 1639 cm.sup.−1, 1453 cm.sup.−1, 1106 cm.sup.−1;

(66) .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 4.47(1H, d, J=6.0 Hz, H-15β), 4.24(1H, d, J=6.8 Hz, H-6β), 3.94, 3.51(2H, 2×ABq, J=8.4 Hz, H.sub.2-18), 3.85(1H, d, J=5.2 Hz, H-14β), 3.71(1H, dd, J=11.2, 5.2 Hz, H-3β), 3.64(3H, s, OCH.sub.3-16), 3.40(3H, s, OCH.sub.3-6), 3.35(3H, s, OCH.sub.3-18), 3.31(3H, s, OCH.sub.3-1), 3.15(1H, dd, J=11.2, 6.8 Hz, H-1β), 3.08(1H, d, J=6.0 Hz, H-16), 2.96(1H, s, H-17), 2.71, 1.97(2H, 2×ABq, J=8.8 Hz, H.sub.2-12), 2.65, 2.42(2H, 2×ABq, J=11.2 Hz, H.sub.2-19), 2.38(1H, s, H-7), 2.35(3H, s, CH.sub.3N-21), 2.31, 2.24(2H, m, H.sub.2-2), 2.27(1H, m, H-9β), 2.11(1H, d, J=6.8 Hz, H-5β), 1.98(1H, m, H-10β);

(67) .sup.13C NMR (100 MHz, CD.sub.3OD) δ: 82.6(C-1), 33.8(C-2), 71.5(C-3), 43.4(C-4), 46.5(C-5), 83.2(C-6), 46.4(C-7), 78.8(C-8), 48.8(C-9), 41.6(C-10), 50.1(C-11), 36.9(C-12), 76.3(C-13), 78.7(C-14), 81.5(C-15), 90.7(C-16), 62.5(C-17), 76.8(C-18), 49.8(C-19), 42.5(NCH.sub.3), 56.3(OCH.sub.3-1), 57.9(OCH.sub.3-6), 61.3(OCH.sub.3-16), 59.1(OCH.sub.3-18);

(68) ESI-MS m/z (%): 486(100)[M+H].sup.+;

(69) HR-ESI-MS: The measured value of quasi-molecular weight is 486.2699, and the calculated value is 486.2644.