Synthetic method of veratramine

Abstract

The present disclosure relates to the technical field of organic synthesis, and discloses a method for synthesizing veratrylamine. Using compound 1 as the starting material, a Grignard addition reaction is carried out with ethynylmagnesium bromide to obtain compound 2. Compound 2 undergoes a cyanation reaction to obtain compound 3. Compound 3 undergoes a rearrangement reaction to obtain compound 4. Compound 4 undergoes an epoxy ring-opening reaction to obtain compound 5. Compound 5 undergoes a reduction reaction and then further undergoes an elimination reaction to obtain compound 6. Compound 6 undergoes an oxidative aromatization reaction to obtain compound 7. Compound 7 undergoes a reduction reaction to obtain compound 8. Compound 8 undergoes a condensation reaction to obtain compound 9. Compound 9 and compound 10 undergo a reductive coupling reaction to obtain compound 11. Compound 11 undergoes a desulfinylation reaction and then further undergoes an intramolecular amidation reaction to obtain compound 12. Compound 12 undergoes a reduction amide reaction to obtain the natural product veratrylamine. This method can achieve the efficient chemical synthesis of veratrylamine.

Description

Technical Field

[0001] The present disclosure relates to the technical field of organic synthesis, and particularly relates to a method for synthesizing veratramine. Background Art

[0002] Isosteroidal alkaloids are characteristic chemical constituents of plants of the genera Veratrum and Fritillaria. These unique molecules have significant analgesic, anticancer, anti-inflammatory, antitussive, and insecticidal activities. Structurally, isosteroidal alkaloids have a common C-nor-D-homo steroid skeleton and can be divided into three different structural types according to their connection mode with the piperidine ring, namely, veratramine type, cevanine type, and germine type. Their structural formulas are as follows:

[0003]

[0004] Among these three types of isosteroidal alkaloids, veratramine-type alkaloids have a broken E-ring, and some of them contain an aromatized D-ring. The representative compound veratramine has various biological activities, such as blood pressure lowering and insecticidal effects. Veratramine can effectively control a variety of pests and has the characteristics of high efficiency, low toxicity, and broad spectrum. However, the extraction of veratramine from Veratrum plants is affected by unstable supply and price fluctuations. Therefore, chemists have been committed to exploring synthetic means to obtain veratramine.

[0005] Currently, the synthetic strategies for veratramine include: 1) The Johnson group obtained a high-level tetracyclic intermediate through 9 steps starting from Hageman's ester, and then completed the total synthesis of veratramine through 19 linear steps; 2) The Gao / Zhu group utilized the key photoinduced excited-state Nazarov reaction to achieve the convergent total synthesis of veratramine through the synthesis and coupling of two functionalized fragments.

[0006] 1) Synthesis of veratramine by the Johnson group

[0007]

[0008] 2) Synthesis of veratramine by the Gao / Zhu group

[0009]

[0010] However, although the above two synthetic strategies solve the problem of artificial synthesis of veratramine, they still have defects such as long reaction steps and low overall yield. To solve the problem of limited natural sources of veratramine, it is necessary to develop a more efficient and concise synthetic route. Summary of the Invention

[0011] The object of the present disclosure is to overcome the deficiencies of the prior art and provide a method for synthesizing veratrylamine, so as to at least shorten the reaction route and improve the reaction yield, thereby achieving the effect of efficient chemical synthesis of veratrylamine.

[0012] The object of the present disclosure is achieved by the following technical solutions:

[0013] On the one hand, a method for synthesizing veratrylamine is provided. The synthesis method includes the following steps:

[0014] S1.

[0015] Provide compound 1, and subject compound 1 to a Grignard addition reaction with ethynylmagnesium bromide to obtain compound 2;

[0016] S2.

[0017] Subject compound 2 to a cyanation reaction under the conditions of adding nickel acetylacetonate, zinc cyanide (Zn(CN)2), and manganese (Mn) to obtain compound 3;

[0018] S3.

[0019] Subject compound 3 to a rearrangement reaction under the conditions of adding trifluoromethanesulfonic anhydride and a base to obtain compound 4, and then continue to add an acid to carry out an epoxy ring-opening reaction to obtain compound 5;

[0020] S4.

[0021] Subject compound 5 to a reduction reaction under the conditions of adding a catalyst, and then further carry out an elimination reaction to obtain compound 6;

[0022] S5.

[0023] Subject compound 6 to an oxidative aromatization reaction under the conditions of adding an oxidant to obtain compound 7;

[0024] S6.

[0025] Subject compound 7 to a reduction reaction under the conditions of adding a reducing agent to obtain compound 8;

[0026] S7.

[0027] Subject compound 8 to a condensation reaction under the conditions of adding tert-butylsulfinamide and a catalyst to obtain compound 9;

[0028] S8.

[0029] Provide compound 10, and subject compound 9 to a reductive coupling reaction with compound 10 under the conditions of adding tert-butanol and samarium diiodide to obtain compound 11;

[0030] S9.

[0031] Subject compound 11 to a desulfinyl reaction under the condition of adding an acid, and then subject it to an intramolecular amidation reaction under the condition of adding a base to obtain compound 12;

[0032] S10.

[0033] Subject compound 12 to a reductive amide reaction under the condition of adding a reducing agent to obtain the veratrylamine.

[0034] In some embodiments, in S1, the solvents used in the format addition reaction include at least one of tetrahydrofuran, toluene, dichloromethane, diethyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether.

[0035] In some embodiments, in S2, the molar ratio of compound 2, nickel acetylacetonate, zinc cyanide (Zn(CN)2), and manganese (Mn) is 1:0.015-1.5:0.018-1.8:0.12-6.

[0036] In some embodiments, in S2, the solvents used in the cyanation reaction include acetonitrile and water; wherein, the volume ratio of acetonitrile to water is 1-10:1-5.

[0037] In some embodiments, in S3, the base includes at least one of diphenylamine, HMPA, TMEDA, imidazole, pyrrolidine, piperidine, N,N-dimethylaniline, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 2,6-di-tert-butyl-4-methylpyridine, 2-fluoropyridine, DIPEA, 2-iodopyridine, 2-bromopyridine, and dichloropyridine.

[0038] In some embodiments, in S3, the acid includes at least one of triphenylphosphine + trifluoromethanesulfonic anhydride + triethylamine, lithium bromide, sulfuric acid, bis(dimethylamino)phosphoryl chloride, hydrochloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, phosphorus oxychloride + pyridine, p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride diethyl etherate, and diisopropoxytitanium dichloride.

[0039] In some embodiments, in S3, the molar ratio of compound 3, trifluoromethanesulfonic anhydride, the base, and the acid is 1:1-9:2.5-15:5-30.

[0040] In some embodiments, in S3, the solvent used in the rearrangement reaction includes at least one of dichloromethane, tetrahydrofuran, toluene, diethyl ether, ethylene glycol dimethyl ether, DMF, and methanol.

[0041] In some embodiments, in S4, the catalyst includes at least one of rhodium(III) chloride triphenylphosphine complex, palladium on carbon, Raney nickel, platinum(IV) oxide, platinum on carbon, and Crabtree's catalyst.

[0042] In some embodiments, in S4, the reagents used in the elimination reaction include thionyl chloride and triethylamine; wherein, the molar ratio of the compound 5, the catalyst, thionyl chloride to triethylamine is 1:0.01 to 1:0.5 to 10:0.25 to 5.

[0043] In some embodiments, in S4, the solvent used in the reduction reaction includes at least one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, methanol, ethyl acetate, acetone, MTBE, DMF, and NMP.

[0044] In some embodiments, in S5, the solvent used in the oxidative aromatization reaction includes at least one of dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, benzene, methanol, ethyl acetate, acetone, MTBE, DMF, and NMP.

[0045] In some embodiments, in S5, the oxidant used in the oxidative aromatization reaction includes at least one of DDQ, IBX, Oxone, NBS, K2S2O8, CAN, and O2.

[0046] In some embodiments, in S5, the molar ratio of the compound 6 to the oxidant is 1:1 to 10.

[0047] In some embodiments, in S6, the reducing agent includes at least one of diisobutylaluminum hydride, lithium aluminum hydride, Red-Al, sodium borohydride + aluminum chloride, Li(EtO)3AlH, and Raney nickel.

[0048] In some embodiments, in S6, the molar ratio of the compound 7 to the reducing agent is 1:1 to 8.

[0049] In some embodiments, in S6, the solvent used in the reduction reaction includes at least one of dichloromethane, dichloroethane, tetrahydrofuran, toluene, benzene, ethyl acetate, MTBE, diethyl ether, and NMP.

[0050] In some embodiments, in S7, the catalyst includes at least one of tetraethyl titanate, tetraisopropyl titanate, potassium bisulfate, copper sulfate, magnesium sulfate, PPTS, cesium carbonate, sodium hydroxide, potassium tert-butoxide, and ytterbium(III) trifluoromethanesulfonate.

[0051] In some embodiments, in S7, the molar ratio of the compound 8, the tert-butanesulfinamide to the catalyst is 1:0.5 to 6:2 to 8.

[0052] In some embodiments, in S7, the solvent used in the condensation reaction includes at least one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, benzene, ethyl acetate, acetone, MTBE, ether, 2-methyltetrahydrofuran, and NMP.

[0053] In some embodiments, in S8, the molar ratio of the compound 9, the compound 10, tert-butanol to samarium diiodide is 1:0.5 to 6:1 to 8:1 to 8.

[0054] In some embodiments, in S8, the solvent used in the reductive coupling reaction includes at least one of dichloromethane, tetrahydrofuran, toluene, ether, 2-methyltetrahydrofuran, and NMP.

[0055] In some embodiments, in S9, the acid includes at least one of hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.

[0056] In some embodiments, in S9, the base includes at least one of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, and sodium methoxide.

[0057] In some embodiments, in S9, the molar ratio of the compound 11, the acid to the base is 1:2 to 20:1 to 10.

[0058] In some embodiments, in S9, the solvent used in the desulfinylation reaction includes at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, water, ether, dioxane, and ethyl acetate.

[0059] In some embodiments, in S9, the solvent used in the lactamization reaction includes at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, water, ether, dioxane, and ethyl acetate.

[0060] In some embodiments, in S10, the reducing agent includes at least one of lithium aluminum hydride, Red-Al, diisobutylaluminum hydride, and sodium borohydride / aluminum trichloride.

[0061] In some embodiments, in S10, the molar ratio of the compound 12 to the reducing agent is 1:1 to 10.

[0062] In some embodiments, in S10, the solvent used in the reduction amide reaction includes at least one of tetrahydrofuran, toluene, benzene, 2-methyltetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether.

[0063] The beneficial effects of the present disclosure are as follows:

[0064] A method for synthesizing veratrylamine provided by the present disclosure uses compound 1 (i.e., a ketone compound) as a starting material, undergoes a Grignard addition reaction with ethynylmagnesium bromide to obtain compound 2, compound 2 undergoes a cyanation reaction to obtain compound 3, compound 3 undergoes a rearrangement reaction to obtain compound 4, compound 4 undergoes an epoxy ring-opening reaction to obtain compound 5, compound 5 undergoes a reduction reaction and then further undergoes an elimination reaction to obtain compound 6, compound 6 undergoes an oxidative aromatization reaction to obtain compound 7, compound 7 undergoes a reduction reaction to obtain compound 8, compound 8 undergoes a condensation reaction to obtain compound 9, compound 9 and compound 10 (i.e., an aldehyde compound) undergo a reductive coupling reaction to obtain compound 11, compound 11 undergoes a desulfinyl reaction under the condition of adding an acid, and then undergoes an intramolecular amidation reaction under the condition of adding a base to obtain compound 12, and compound 12 undergoes a reduction amide reaction to obtain the natural product veratrylamine. The total number of steps in the reaction route of this synthesis method is only 10 steps, and the total yield is 12.4% - 18.6%, enabling the efficient chemical synthesis of veratrylamine. Detailed Embodiments

[0065] The technical solutions in some embodiments of the present disclosure will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present disclosure, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments provided by the present disclosure belong to the scope of protection of the present disclosure.

[0066] When describing some embodiments, the expression "A and / or B" may be used. It is easy to understand that "A and / or B" includes the following three combinations: only A, only B, and the combination of A and B.

[0067] When describing some embodiments, the expressions "at least one of A, B, and C" and "at least one of A, B, or C" may be used, and both have the same meaning, and both include the following combinations of A, B, and C: only A, only B, only C, the combination of A and B, the combination of A and C, the combination of B and C, and the combination of A, B, and C.

[0068] Example 1

[0069]

[0070] Under argon protection, compound 1 (20.0 g, 57.8 mmol) was dissolved in dry tetrahydrofuran (300 mL), and ethynylmagnesium bromide (0.5 M in THF, 576 mL, 289 mmol) was slowly added to the reaction solution at -78 °C. After the reaction solution was stirred at -78 °C for 30 min, it was transferred to 0 °C and stirred for 12 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (800 mL), and the mixture was extracted with ethyl acetate (3 × 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 - 1:1) to obtain compound 2 (18.1 g, yield 84%, white solid).

[0071] TLC (petroleum ether / ethyl acetate, 1:1 v / v): R f = 0.50;

[0072] 1 1H NMR (400 MHz, CDCl3): δ 5.36–5.34 (m, 1H), 4.60–4.52 (m, 1H), 4.14 (dd, J = 11.2, 4.8 Hz, 1H), 2.92 (s, 1H), 2.61 (s, 1H), 2.41–2.19 (m, 4H), 2.03–1.95 (m, 5H), 1.89–1.79 (m, 2H), 1.77–1.68 (m, 2H), 1.62–1.33 (m, 6H), 1.16–1.04 (m, 2H), 1.02 (s, 3H), 0.89 (s, 3H).

[0073] 13 13C NMR (100 MHz, CDCl3): δ 170.6, 139.5, 122.1, 86.9, 79.7, 74.5, 74.2, 73.7, 50.5, 49.4, 49.0, 38.5, 37.9, 36.9, 36.6, 31.5, 31.0, 29.8, 27.6, 22.9, 21.4, 19.2, 7.2.

[0074] IR (neat): ν max = 3425, 3303, 2948, 1724, 1438, 1365, 1248, 1025, 803, 751 cm -1 ;

[0075] HRMS (ESI): m / z calcd. for C 23 H 33 O4 [M + H] + 373.2373, found 373.2374.

[0076] Example 2

[0077]

[0078] Under argon protection, Ni(acac)2 (1.24 g, 4.84 mmol), neocuproine (1.21 g, 5.81 mmol), zinc cyanide (4.55 g, 38.7 mmol) and manganese powder (1.33 g, 24.2 mmol) were dissolved in degassed acetonitrile (193 mL). After the reaction was placed at 25 °C for 20 min, compound 2 (18.0 g, 48.4 mmol) and degassed water (39 mL) were added. The reaction mixture was heated to 50 °C and stirred for 16 h. Water (200 mL) and MTBE (100 mL) were added to the reaction solution. After filtration through diatomaceous earth, extraction was carried out with MTBE (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 - 2:1) to obtain compound 3 (17.6 g, yield 91%, white solid).

[0079] TLC (petroleum ether / ethyl acetate, 1:1 v / v): R f = 0.43;

[0080] 1 1H NMR (400 MHz, CDCl3): δ 6.15 (s, 1H), 5.93 (s, 1H), 5.40–5.27 (m, 1H), 4.65–4.42 (m, 1H), 3.62 (dd, J = 11.2, 5.2 Hz, 1H), 2.60 (s, 2H), 2.35–2.22 (m, 2H), 2.09–1.93 (m, 6H), 1.87–1.77 (m, 2H), 1.75–1.65 (m, 2H), 1.61–1.41 (m, 5H), 1.33–1.21 (m, 1H), 1.14–1.03 (m, 2H), 1.02 (s, 3H), 0.99 (s, 3H).

[0081] 13 13C NMR (100 MHz, CDCl3): δ 170.5, 139.4, 131.6, 129.5, 121.9, 118.6, 85.5, 73.6, 73.3, 51.2, 48.7, 48.4, 37.8, 36.8, 36.5, 35.9, 31.4, 31.0, 29.9, 27.5, 23.5, 21.3, 19.1, 9.0.

[0082] IR (neat): ν max= 3455, 2947, 1719, 1375, 1365, 1250, 1066, 1027, 955, 746, 666 cm -1 ;

[0083] HRMS(ESI): m / z calcd. for C 24 H 34 NO4[M + H] + 400.2482, found 400.2485.

[0084] Example 3

[0085]

[0086] Under argon protection, compound 3 (12.0 g, 30.0 mmol) was dissolved in dry dichloromethane (300 mL). At -78 °C, 2-chloropyridine (21.1 mL, 225 mmol) was added to the reaction solution. After stirring for 10 min, trifluoromethanesulfonic anhydride (15.2 mL, 90.0 mmol) was slowly added dropwise, and the reaction was continued at -78 °C for 2 h. TLC monitoring showed that the raw materials completely disappeared. Methanesulfonic acid (29.4 mL, 450 mmol) was added dropwise to the reaction solution. After the reaction was stirred at -20 °C for 1 h, saturated aqueous NaHCO3 solution (250 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (3 × 250 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1 - 5:1) to obtain compound 5 (8.14 g, yield 71%, white foam).

[0087] TLC (petroleum ether / ethyl acetate, 2:1 v / v): R f = 0.53;

[0088] 11H NMR (400 MHz, CDCl3): δ 6.21 (d, J = 0.8 Hz, 1H), 6.06 (d, J = 0.4 Hz, 1H), 5.45–5.35 (m, 1H), 4.64–4.61 (m, 1H), 2.73 (d, J = 5.6 Hz, 1H), 2.46 (t, J = 8.4 Hz, 1H), 2.42–2.39 (m, 1H), 2.32–2.27 (m, 1H), 2.21–2.14 (m, 1H), 2.12–2.05 (m, 4H), 2.04 (s, 3H), 1.90–1.85 (m, 1H), 1.81–1.78 (m, 1H), 1.73 (t, J = 2.0 Hz, 1H), 1.68–1.58 (m, 2H), 1.57 (s, 2H), 1.29–1.22 (m, 1H), 1.06 (s, 3H), 0.92 (d, J = 4.8 Hz, 3H).

[0089] 13 13C NMR (100 MHz, CDCl3): δ 170.5, 141.8, 136.0, 135.2, 129.9, 129.4, 123.0, 117.7, 74.6, 74.0, 56.1, 42.9, 37.9, 37.8, 37.6, 36.9, 33.9, 31.6, 30.2, 27.4, 21.4, 19.8, 19.3, 11.2.

[0090] IR (neat): ν max = 3483, 2906, 2846, 2222, 1716, 1438, 1355, 1240, 1028, 962, 752 cm -1 ;

[0091] HRMS (ESI): m / z calcd. for C 24 H 32 NO3 [M + H] + 382.2377, found 382.2380.

[0092] Example 4

[0093]

[0094] Compound 5 (10.0 g, 26.2 mmol) and Rh(PPh3)3Cl (2.43 g, 2.62 mmol) were dissolved in dry dichloromethane (500 mL). The mixture was evacuated and backfilled with hydrogen, and then reacted at 25 °C for 24 h. TLC analysis showed that the starting materials had completely disappeared. The reaction solution was transferred to -78 °C, and Et3N (18.0 mL, 131 mmol) was added thereto. SOCl2 (4.76 mL, 66.1 mmol) was slowly added dropwise, and the reaction was continued at -78 °C for 30 min. The reaction was quenched with saturated aqueous NaHCO3 at -78 °C. The mixture was extracted with dichloromethane (3 × 300 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 - 10:1) to obtain compound 6 (7.76 g, yield 81%, white foam).

[0095] TLC (petroleum ether / ethyl acetate, 6:1 v / v): R f = 0.48;

[0096] HRMS (ESI): m / z calcd. for C 24 H 32 NO3 [M+H] + 366.2428, found 366.2430.

[0097] Example 5

[0098]

[0099] Compound 6 (6.00 g, 16.4 mmol) was dissolved in a mixed solvent (330 mL, MeCN:THF = 4:1). Ammonium cerium(IV) nitrate (26.1 g, 49.2 mmol) was added, and the mixture was heated to 25 °C and reacted for 1 h. The reaction was quenched with water at 0 °C. The mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40:1 - 10:1) to obtain compound 7 (4.83 g, yield 80%, light yellow foam).

[0100] TLC (petroleum ether / ethyl acetate, 6:1 v / v): R f = 0.46;

[0101] 11H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 5.54–5.51 (m, 1H), 4.72–4.60 (m, 1H), 4.06 (q, J = 7.2 Hz, 1H), 2.98 (td, J = 12.0, 5.6 Hz, 1H), 2.80 (dd, J = 14.8, 7.2 Hz, 1H), 2.65–2.57 (m, 2H), 2.49–2.43 (m, 1H), 2.41–2.31 (m, 1H), 2.28 (s, 3H), 2.08–1.99 (m, 4H), 1.97–1.80 (m, 3H), 1.76–1.65 (m, 1H), 1.60 (d, J = 7.2 Hz, 3H), 1.39–1.26 (m, 1H), 1.16 (s, 3H).

[0102] 13 13C NMR (100 MHz, CDCl3): δ 170.4, 146.1, 143.6, 141.3, 133.2, 130.7, 125.0, 122.7, 122.1, 120.8, 73.7, 56.9, 41.1, 37.7 (×2), 36.9, 30.2, 30.1, 28.1, 27.4, 21.4, 20.3, 19.1, 15.3.

[0103] IR (neat): ν max = 2936, 2241, 1728, 1438, 1375, 1364, 1240, 1028, 961, 812, 752, 666 cm -1 ;

[0104] HRMS (ESI): m / z calcd. for C 24 H 30 NO2 [M + H] + 364.2271, found 364.2273.

[0105] Example 6

[0106]

[0107] Under argon protection, compound 7 (5.00 g, 13.8 mmol) was dissolved in dry dichloromethane (275 mL), and DIBAL-H (1 M in THF, 55.0 mL, 55.0 mmol) was slowly added dropwise at -78 °C. After the addition, the reaction was carried out at -78 °C for 4 h. The reaction was quenched by dropwise addition of EtOAc (10 mL), and sodium potassium tartrate solution (130 mL), water (130 mL) and 2.0 M aqueous hydrochloric acid solution (10 mL) were added. The mixture was stirred at 25 °C until obvious stratification occurred. The aqueous phase was extracted with dichloromethane (3 × 200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1 - 1:1, v / v) to obtain compound 8 (3.66 g, yield 82%, white foam).

[0108] TLC (petroleum ether / ethyl acetate 2:1 v / v): R f = 0.39;

[0109] 1 1H NMR (400 MHz, CD3CN): δ 9.61 (s, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 5.49–5.46 (m, 1H), 3.90 (q, J = 6.8 Hz, 1H), 3.42–3.35 (m, 1H), 2.96 (td, J = 12.0, 5.6 Hz, 1H), 2.88–2.79 (m, 2H), 2.67–2.54 (m, 2H), 2.35–2.30 (m, 1H), 2.24 (s, 3H), 1.99–1.88 (m, 2H), 1.87–1.73 (m, 3H), 1.59–1.47 (m, 1H), 1.31 (d, J = 7.2 Hz, 3H), 1.26–1.22 (m, 1H), 1.14 (s, 3H).

[0110] 13 13C NMR (100 MHz, CD3CN): δ 202.3, 146.2, 144.5, 144.1, 135.6, 133.4, 126.6, 121.8, 121.1, 71.8, 58.0, 49.4, 42.4, 41.8, 38.6, 37.5, 31.8, 30.8, 30.7, 19.4, 15.6, 14.7.

[0111] IR (neat): ν max = 3411, 2931, 1721, 1460, 1437, 1350, 1196, 1052, 1015, 810 cm -1 ;

[0112] HRMS(ESI): m / z calcd. for C 22 H 29 O2[M + H] + 325.2162, found 325.2160.

[0113] Example 7

[0114]

[0115] Dissolve compound 8 (3.00 g, 9.25 mmol) and (R)-(+)-tert-butylsulfinamide (1.34 g, 11.1 mmol) in a mixed solvent (185 mL, MeCN:THF = 1:4). Slowly add Ti(OEt)4 (9.70 mL, 46.2 mmol) dropwise at 0 °C. React at 35 °C for 10 h until compound 8 is completely consumed. Quench the reaction by adding saturated NaCl aqueous solution (200 mL) at -78 °C. Stir the mixture at 25 °C for 30 min. Filter the formed white suspension through diatomaceous earth. Separate the organic layer. Extract the aqueous phase with ethyl acetate (3 × 150 mL). Wash the combined organic phases with brine (80 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify the crude product by silica gel column chromatography (dichloromethane / ethyl acetate / ether = 80:1:1 - 10:1:1) to obtain compound 9 (3.55 g, yield 90%, white foam).

[0116] TLC (dichloromethane / ethyl acetate / ether, 20:1:1 v / v / v): R f = 0.40;

[0117] 1 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 4.0 Hz, 1H), 7.00 - 6.95 (m, 2H), 5.49 - 5.47 (m, 1H), 4.13 - 4.08 (m, 1H), 3.61 - 3.54 (m, 1H), 2.98 (td, J = 11.6, 5.2 Hz, 1H), 2.79 (dd, J = 14.8, 7.2 Hz, 1H), 2.68 - 2.53 (m, 2H), 2.45 - 2.40 (m, 1H), 2.30 - 2.22 (m, 4H), 2.07 - 1.96 (m, 1H), 1.90 - 1.80 (m, 2H), 1.75 (s, 2H), 1.67 - 1.55 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.31 - 1.23 (m, 1H), 1.19 (s, 9H), 1.14 (s, 3H).

[0118] 1313C NMR (100 MHz, CDCl3): δ 171.0, 145.1, 143.4, 142.4, 136.9, 131.8, 125.4, 121.9, 120.5, 71.7, 57.0, 56.9, 41.9 (×2), 41.2, 38.0, 36.9, 31.3, 30.3 (×2), 22.4 (×3), 19.2, 17.7, 15.6.

[0119] IR (neat): ν max = 3392, 2930, 1616, 1456, 1363, 1240, 1186, 1057, 1015, 810, 751, 665 cm -1 ;

[0120] HRMS (ESI): m / z calcd. for C 26 H 38 NO2S [M + H] + 428.2618, found 428.2616.

[0121] Example 8

[0122]

[0123] Under argon protection, freshly prepared samarium diiodide (0.1 M in THF, 281 mL, 28.1 mmol) was added to the reaction flask and kept at -78 °C for later use. Under argon protection, Compound 9 (3.00 g, 7.01 mmol), Compound 10 (2.74 g, 21.1 mmol), and tert-butanol (2.68 mL, 28.1 mmol) were dissolved in dry and degassed tetrahydrofuran (200 mL). The mixed solution was slowly added dropwise to the samarium diiodide tetrahydrofuran solution at -78 °C. After addition, the mixture was stirred at -78 °C overnight. At -78 °C, the reaction was quenched by adding saturated aqueous sodium thiosulfate solution (200 mL). The mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:1 - 20:1) to obtain Compound 11 (2.95 g, yield 75%, white foam).

[0124] TLC (dichloromethane / methanol, 20:1 v / v): R f = 0.42;

[0125] 11H NMR (400 MHz, CDCl3): δ 7.11 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 5.51–5.45 (m, 1H), 3.75–3.70 (m, 1H), 3.69 (s, 3H), 3.62–3.48 (m, 3H), 3.48–3.43 (m, 1H), 2.99–2.89 (m, 1H), 2.88–2.74 (m, 3H), 2.62–2.52 (m, 2H), 2.46–2.38 (m, 1H), 2.32–2.25 (m, 4H), 2.06–1.93 (m, 2H), 1.92–1.82 (m, 3H), 1.75 (d, J = 16.7 Hz, 2H), 1.68–1.58 (m, 2H), 1.36 (d, J = 6.4 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.14 (s, 3H), 1.01 (s, 9H).

[0126] 13 13C NMR (100 MHz, CDCl3): δ 177.6, 144.5, 143.3, 142.4, 139.1, 132.4, 125.7, 122.1, 120.5, 71.8, 70.5, 65.2, 57.0, 56.5, 51.9, 41.9, 41.3, 38.1, 36.9, 36.3, 36.0, 35.3, 31.4, 30.6, 30.4, 22.7 (×3), 19.6, 19.3, 18.4, 16.0.

[0127] IR (neat): ν max = 3313, 2931, 1732, 1460, 1364, 1260, 1219, 1171, 1043, 771 cm -1 ;

[0128] HRMS (ESI): m / z calcd. for C 32 H 50 NO5S [M + H] + 560.3404, found 560.3405.

[0129] Example 9

[0130]

[0131] Compound 11 (2.80 g, 5.01 mmol) was dissolved in methanol (100 mL). At 0 °C, ethereal hydrochloric acid solution (2.0 M, 37.5 mL, 75.0 mmol) was added. After the addition, the mixture was warmed to 25 °C and reacted for 5 h. After monitoring by LC-MS that the raw material reaction was complete, the organic solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was dissolved in methanol (100 mL), potassium carbonate (3.45 g, 25.0 mmol) was added, and the reaction was carried out overnight at 25 °C. The organic solvent was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 80:1 - 20:1) to obtain Compound 12 (2.11 g, yield 84%, white solid).

[0132] TLC (dichloromethane / methanol, 20:1 v / v): R f = 0.40;

[0133] 1 1H NMR (400 MHz, CD3OD): δ 7.08 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 5.52–5.45 (m, 1H), 3.70–3.62 (m, 1H), 3.50–3.38 (m, 3H), 2.92 (td, J = 11.2, 5.6 Hz, 1H), 2.80 (dd, J = 14.8, 7.6 Hz, 1H), 2.66–2.54 (m, 2H), 2.42–2.33 (m, 1H), 2.30–2.20 (m, 4H), 2.17–2.07 (m, 1H), 2.05–1.71 (m, 5H), 1.68–1.54 (m, 2H), 1.34 (d, J = 6.4 Hz, 3H), 1.29–1.22 (m, 1H), 1.18–1.11 (m, 6H).

[0134] 13 13C NMR (100 MHz, CD3OD): δ 177.5, 145.5, 144.0, 144.0, 139.9, 133.6, 126., 122.80, 121.2, 72.5, 68.5, 65.6, 58.7, 42.6, 42.4, 39.2, 38.7, 38.5, 38.0, 34.4, 32.0, 31.5, 31.4, 19.6, 19.4, 17.3, 16.0.

[0135] IR (neat): ν max = 3353, 2931, 1631, 1455, 1255, 1047, 1034, 801, 748, 664 cm -1 ;

[0136] HRMS: m / z calcd. for C 27H 38 NO3[M+H] + 424.2846, found 424.2847.

[0137] Example 10

[0138]

[0139] Under argon protection, compound 12 (2.00 g, 4.73 mmol) was dissolved in dry tetrahydrofuran (95 mL). At 0 °C, LiAlH4 (2.5 M in THF, 9.45 mL, 23.6 mmol) was added, and the mixture was stirred for 5 min. Then it was heated to 75 °C and refluxed for 4 h. After the reaction was cooled to room temperature, the reaction was quenched with saturated aqueous sodium potassium tartrate, the pH was adjusted to alkaline with potassium carbonate, and the resulting mixture was extracted with ethyl acetate (5 × 100 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 80:1 - 10:1) to obtain veratrylamine (1.79 g, yield 93%, white solid).

[0140] TLC (dichloromethane / methanol, 10:1 v / v): R f = 0.46;

[0141] 1 1H NMR (400 MHz, C5D5N): δ 7.69 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 5.52–5.43 (m, 1H), 4.13–4.02 (m, 1H), 3.90–3.80 (m, 1H), 3.60–3.47 (m, 1H), 3.02–2.88 (m, 2H), 2.83 (dd, J = 8.8, 4.0 Hz, 1H), 2.81–2.74 (m, 1H), 2.74–2.68 (m, 1H), 2.66–2.59 (m, 1H), 2.58 (s, 3H), 2.56–2.52 (m, 1H), 2.52–2.42 (m, 1H), 2.29–2.22 (m, 1H), 2.22–2.15 (m, 1H), 2.15–1.99 (m, 2H), 1.94–1.85 (m, 1H), 1.85–1.80 (m, 1H), 1.80–1.75 (m, 1H), 1.63 (d, J = 7.2 Hz, 3H), 1.53–1.41 (m, 1H), 1.41–1.26 (m, 3H), 1.10 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H).

[0142] 1313C NMR(100 MHz, C5D5N): δ 143.7, 143.6, 142.7, 141.2, 133.1, 126.7, 121.5, 119.9, 71.3, 70.7, 68.4, 57.5, 54.7, 45.3, 43.0, 41.5, 38.5, 37.2, 35.6, 32.6, 32.2, 30.8, 30.7, 21.1, 19.3, 19.1, 16.2.

[0143] IR(neat): ν max = 3314, 2929, 2904, 2843, 1646, 1456, 1266, 1032, 813, 629 cm -1 ;

[0144] HRMS: m / z calcd. for C 27 H 40 NO2[M + H] + 410.3054, found 410.3052.

[0145] The above are only the preferred embodiments of the present disclosure. It should be understood that the present disclosure is not limited to the forms disclosed herein, should not be regarded as excluding other embodiments, but can be used in various other combinations, modifications, and environments, and can be changed within the scope of the concept described herein through the above teachings or the techniques or knowledge in the relevant field. And the changes and alterations made by those skilled in the art that do not depart from the spirit and scope of the present disclosure shall fall within the protection scope of the appended claims of the present disclosure.

Claims

1. A method for synthesizing veratramine, characterized in that, Comprising the following steps: S1. Providing compound 1, subjecting the compound 1 to a Grignard addition reaction with ethynylmagnesium bromide to obtain compound 2; S2. Subjecting the compound 2 to a cyanation reaction under the conditions of adding nickel acetylacetonate, zinc cyanide, and manganese to obtain compound 3; S3. Subjecting the compound 3 to a rearrangement reaction under the conditions of adding trifluoromethanesulfonic anhydride and a base to obtain compound 4, and then continuing to add an acid for an epoxy ring-opening reaction to obtain compound 5; S4. Subjecting the compound 5 to a reduction reaction under the conditions of adding a catalyst, and then further subjecting it to an elimination reaction to obtain compound 6; S5. Subjecting the compound 6 to an oxidative aromatization reaction under the conditions of adding an oxidant to obtain compound 7; S6. Subjecting the compound 7 to a reduction reaction under the conditions of adding a reducing agent to obtain compound 8; S7. Subjecting the compound 8 to a condensation reaction under the conditions of adding tert-butylsulfinamide and a catalyst to obtain compound 9; S8. Providing compound 10, subjecting the compound 9 and the compound 10 to a reductive coupling reaction under the conditions of adding tert-butanol and samarium diiodide to obtain compound 11; S9. Subjecting the compound 11 to a desulfinyl reaction under the conditions of adding an acid, and then subjecting it to an intramolecular amidation reaction under the conditions of adding a base to obtain compound 12; S10. Subjecting the compound 12 to a reductive amide reaction under the conditions of adding a reducing agent to obtain the veratrylamine; Wherein, in S2, the molar ratio of the compound 2, the nickel acetylacetonate, the zinc cyanide, and the manganese is 1:0.015 - 1.5:0.018 - 1.8:0.12 - 6; In S3, the base is at least one of 2-fluoropyridine, 2-iodopyridine, 2-bromopyridine, and 2-chloropyridine; In S3, the acid is at least one of methanesulfonic acid and trifluoromethanesulfonic acid; In S3, the molar ratio of the compound 3, the trifluoromethanesulfonic anhydride, the base, and the acid is 1:1 - 9:2.5 - 15:5 - 30; In S4, the reagent used for the elimination reaction is thionyl dichloride and triethylamine, wherein the molar ratio of the compound 5, the catalyst, the thionyl dichloride, and the triethylamine is 1:0.01 - 1:0.5 - 10:0.25 - 5; In S5, the molar ratio of the compound 6 and the oxidant is 1:1 - 10; In S6, the reducing agent is diisobutylaluminum hydride; In S6, the molar ratio of the compound 7 and the reducing agent is 1:1 - 8; In S7, the molar ratio of the compound 8, the tert-butylsulfinamide, and the catalyst is 1:0.5 - 6:2 - 8; In S8, the molar ratio of the compound 9, the compound 10, the tert-butanol, and the samarium diiodide is 1:0.5 - 6:1 - 8:1 - 8; In S9, the acid is at least one of hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid; In S9, the base is at least one of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, and sodium methoxide; In S9, the molar ratio of the compound 11, the acid, and the base is 1:2 - 20:1 - 10; In S10, the molar ratio of the compound 12 to the reducing agent is 1:1 to 10.

2. The synthesis method according to claim 1, characterized in that, In S1, the solvent used in the Grignard addition reaction is at least one of tetrahydrofuran, toluene, dichloromethane, diethyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether; In S2, the solvent used in the cyanation reaction is acetonitrile and water; wherein, the volume ratio of the acetonitrile to the water is 1 to 10:1 to 5.

3. The synthesis method according to claim 1, characterized in that, In S3, the solvent used in the rearrangement reaction is at least one of dichloromethane, tetrahydrofuran, toluene, diethyl ether, ethylene glycol dimethyl ether, DMF, and methanol.

4. The synthesis method according to claim 1, characterized in that, In S4, the catalyst is at least one of rhodium(III) chloride triphenylphosphine, palladium on carbon, Raney nickel, platinum dioxide, platinum on carbon, and iridium(III) hexafluorophosphate (tricyclohexylphosphine)(1,5-cyclooctadiene)(pyridine). In S4, the solvent used in the reduction reaction is at least one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, methanol, ethyl acetate, acetone, MTBE, DMF, and NMP.

5. The synthesis method according to claim 1, wherein In S5, the solvent used in the oxidative aromatization reaction is at least one of dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, benzene, methanol, ethyl acetate, acetone, MTBE, DMF, and NMP; In S5, the oxidizing agent used in the oxidative aromatization reaction is at least one of DDQ, IBX, potassium peroxymonosulfate, NBS, K2S2O8, CAN, and O2.

6. The synthesis method according to claim 1, wherein In S6, the solvent used in the reduction reaction is at least one of dichloromethane, dichloroethane, tetrahydrofuran, toluene, benzene, ethyl acetate, MTBE, diethyl ether, and NMP.

7. The synthesis method according to claim 1, characterized in that In S7, the catalyst is at least one of tetraethyl titanate, tetraisopropyl titanate, potassium bisulfate, copper sulfate, magnesium sulfate, PPTS, cesium carbonate, sodium hydroxide, potassium tert-butoxide, and ytterbium(III) trifluoromethanesulfonate. In S7, the solvent used in the condensation reaction is at least one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, benzene, ethyl acetate, acetone, MTBE, diethyl ether, 2-methyltetrahydrofuran, and NMP.

8. The synthesis method according to claim 1, wherein In S8, the solvent used in the reductive coupling reaction is at least one of dichloromethane, tetrahydrofuran, toluene, diethyl ether, 2-methyltetrahydrofuran, and NMP.

9. The synthesis method according to claim 1, characterized in that, In S9, the solvent used in the desulfinylation reaction is at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, water, diethyl ether, dioxane, and ethyl acetate. In S9, the solvent used in the lactamization reaction is at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, water, diethyl ether, dioxane, and ethyl acetate.

10. The synthesis method according to claim 1, characterized in that, In S10, the reducing agent is at least one of lithium aluminum hydride, Red-Al, diisobutylaluminum hydride, and sodium borohydride + aluminum chloride. In S10, the solvent used in the reduction of amide reaction is at least one of tetrahydrofuran, toluene, benzene, 2-methyltetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether.

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