Industrial production process of palmatine and analogues thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses an industrial production process of fibrauretine and analogues thereof, which comprises the following steps: carrying out a Strecker reaction on a compound (II) or an inorganic salt thereof to obtain a compound (III), carrying out hydrolysis and amino protection group removal on the compound (III) to obtain a compound (IV), carrying out a condensation reaction on the compound (IV) and a compound (V) or an inorganic salt thereof to obtain a compound (VI), and carrying out a condensation reaction on the compound (VI) and the compound (V) to obtain the fibrauretine and analogues thereof. The compound (VI) is subjected to a Friedel-Crafts acylation reaction to obtain a compound (VII), and the compound (VII) is subjected to a Pomeranz-Fritsch reaction to obtain the target compound (I). The invention overcomes the defects of difficult acquisition of initial raw materials, use of toxic auxiliary materials, high material cost, low product yield and the like in the existing total chemical synthesis technology of fibrauretine, and provides an industrialized fibrauretine production process.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to an industrial production process of flavonoids and analogs thereof. Background Art

[0002] The calendula (chemical formula shown in I) included in the 2020 edition of the Chinese Pharmacopoeia is an alkaloid extracted from the dry rattan stems of the Menispermaceae plant calendula, which has the effect of clearing away heat and detoxifying, and is widely used in gynecological inflammation, bacillary dysentery, enteritis, respiratory and urinary tract infections, surgical infections, conjunctivitis, etc. Because calendula has multiple pharmacological effects and is safe and reliable, the market demand is increasing. However, the growth cycle of calendula is long, and long-term large-scale felling has led to the depletion of natural resources. Therefore, artificial synthesis of calendula instead of natural plant extracts is the best solution.

[0003]

[0004] At present, there are two ways to artificially synthesize calendula:

[0005] Approach 1: Patents CN102285981B, CN102875545A, CN108586451B, CN100999522B, etc. use berberine (berberine hydrochloride) as raw material, demethylate with Lewis acid, and then methylate to obtain berberine. As shown in the following formula:

[0006]

[0007] Although berberine is cheap and easy to obtain, and the cost of preparing berberine is low, berberine also needs to be extracted from natural plants and also faces the problem of increasingly scarce resources and insufficient market supply.

[0008] Pathway 2: Full chemical synthesis of calendula

[0009] 1) CN101973991B uses 3-bromo-7,8-dimethoxyisoquinoline (1) and 2-(2-hydroxyethyl)-4,5-dimethoxyboronic acid (2) as starting materials, firstly condenses by palladium catalysis, then chlorinates under the action of triphenylphosphine, and then closes the ring to obtain calendula. The formula is as follows:

[0010]

[0011] Although the process route is simple, the starting materials 3-bromo-7,8-dimethoxyisoquinoline (1) and 2-(2-hydroxyethyl)-4,5-dimethoxyboric acid (2) are not easy to obtain. There are almost no manufacturers in China, and the starting materials are in short supply in the market. In addition, toxic auxiliary materials such as triphenylphosphine are used in the process, which seriously pollutes the environment. The use of palladium catalyst also increases the material cost, making it unsuitable for industrial production.

[0012] 2) CN1687064A and CN100526311C use 2-methoxyphenol 01 or catechol 02 as raw materials, and obtain 3,4-dimethoxyphenylethylamine 06 through etherification, chlorination, cyanation, and hydrogenation amination, and then condense with 2,3-dimethoxybenzaldehyde 07, and then obtain calendula by 7 steps of reduction, cyclization, etc. CN102532130A and CN103980271B have improved the process, using 3,4-dimethoxyphenylethylamine and 2,3-dimethoxybenzaldehyde as raw materials, and obtaining calendula by condensation, reduction, cyclization, etc. The reaction formula is as follows:

[0013]

[0014] The process route is long, and toxic and harmful auxiliary materials such as formaldehyde, sodium cyanide, and diacetaldehyde are used in the process, which is not conducive to labor protection. The last step of the cyclization reaction uses copper-containing compounds such as CuSO4 and CuCl2 as catalysts, and a cumbersome post-treatment process is required to remove the residual copper ions in the final product. Due to the long process route and cumbersome post-treatment, the yield is low (total yield is about 27%), so it is not suitable for industrial production. Summary of the invention

[0015] In view of the shortcomings of the prior art described above, the purpose of the present invention is to provide an industrial production process of calendula and its analogs, which is used to solve the problems of the prior art of fully chemical synthesis of calendula, such as the difficulty in obtaining starting raw materials, the use of toxic auxiliary materials in the process, high material costs, and low product yields.

[0016] To achieve the above-mentioned and other related purposes, the present invention provides an industrial production process of calendula and its analogs, comprising the following steps:

[0017] (1) subjecting the compound represented by formula (II) or its inorganic salt to a Strecker reaction to obtain a compound represented by formula (III);

[0018] (2) hydrolyzing the compound represented by formula (III) and removing the amino protecting group to obtain the compound represented by formula (IV);

[0019] (3) condensing the compound represented by formula (IV) with the compound represented by formula (V) or an inorganic salt thereof to obtain the compound represented by formula (VI);

[0020] (4) subjecting the compound represented by formula (VI) to a Friedel-Crafts acylation reaction to obtain a compound represented by formula (VII);

[0021] (5) subjecting the compound represented by formula (VII) to a Pomeranz-Fritsch reaction to obtain a compound represented by formula (I);

[0022]

[0023] Among them, in the above formulas, R1, R2, R3 and R4 are selected from C 1-6 Alkyl, or R1 and R2, R3 and R4 are connected to form -(CH2) n — and forms a 5-7 membered ring with the oxygen atom to which it is connected, wherein n=1, 2 or 3; R5 is an amino protecting group; X - Selected from organic acid radicals or inorganic acid radicals.

[0024] Further, R1, R2, R3 and R4 are each selected from methyl groups.

[0025] Furthermore, R5 is an amino protecting group for protecting primary amino groups, which is selected from any one of an alkoxycarbonyl amino protecting group, an acyl amino protecting group, and an alkyl amino protecting group.

[0026] Further, X - Selected from hydrochloride.

[0027] Furthermore, in the step (1), the compound represented by formula (II) or its inorganic salt is reacted with a cyanide source and an ammonia source containing an amino protecting group by a Strecker reaction to prepare a compound represented by formula (III), wherein the cyanide source is selected from at least one of diethyl cyanophosphate (DEPC), acetone cyanohydrin, sodium cyanide, and potassium cyanide, and the ammonia source containing an amino protecting group is selected from at least one of benzylamine (BnNH2) and p-methoxybenzyl (PMB).

[0028] Furthermore, in the step (1), the Strecker reaction is carried out at room temperature.

[0029] Furthermore, in the step (1), the Strecker reaction time is not less than 3 hours.

[0030] Furthermore, in the step (2), the compound represented by formula (III) is hydrolyzed under alkaline or acidic conditions.

[0031] Furthermore, in the step (2), the hydrolysis reaction temperature is 55 to 105°C.

[0032] Furthermore, in the step (2), the hydrolysis reaction time is not less than 12 hours.

[0033] Furthermore, in the step (2), the reagent used for removing the amino protecting group is selected from 1-chloroethyl chloroformate or 2,2,2-trichloroethyl chloroformate.

[0034] Furthermore, in the step (2), the deamino protecting group reaction is carried out at room temperature.

[0035] Furthermore, in the step (2), the reaction time for deamino protecting group is not less than 3 hours.

[0036] Furthermore, in the step (3), the condensation reaction is carried out at room temperature.

[0037] Furthermore, in the step (3), the condensation reaction time is not less than 10 hours.

[0038] Furthermore, in the step (3), the condensation reaction is carried out under acidic conditions.

[0039] Furthermore, in step (3), an adsorbent is added to the condensation reaction, and the adsorbent is used to adsorb water. The adsorbent is selected from at least one of natural zeolite and molecular sieve (ie, artificially synthesized zeolite).

[0040] Furthermore, in the step (4), the compound represented by formula (VI) is reacted with an acylating agent through a Friedel-Crafts acylation reaction to obtain a compound represented by formula (VII).

[0041] Furthermore, in the step (4), a catalyst is added to catalyze the Friedel-Crafts acylation reaction, and the catalyst is selected from at least one of non-metallic halides, Lewis acids, and inorganic acids.

[0042] Furthermore, in the step (4), the Friedel-Crafts acylation reaction temperature is 0 to 80°C.

[0043] Furthermore, in the step (4), the Friedel-Crafts acylation reaction time is not less than 3 hours.

[0044] Furthermore, in step (4), after the Friedel-Crafts acylation reaction is completed, a base is added to the reaction solution, and the acylated product undergoes imide ring closure / oxidative aromatization under alkaline conditions to form a 3-aryl isoquinoline compound represented by formula (VII).

[0045] Furthermore, the step (5) of subjecting the compound represented by formula (VII) to a Pomeranz-Fritsch reaction to obtain the compound represented by formula (I) comprises the following steps:

[0046] (5-1) The compound represented by formula (VII) is reacted with the halogenated acetal diol represented by formula (VIII) to obtain the aminoacetal intermediate represented by formula (IX), which is then cyclized and reduced to obtain the tetracyclic isoquinoline alkaloid compound represented by formula (X);

[0047] (5-2) The tetracyclic isoquinoline alkaloid compound represented by formula (X) is subjected to neutralization reaction to obtain the compound represented by formula (I);

[0048]

[0049] Among them, in the above formulas, R6 and R7 are selected from C 1-6 Alkyl, or R6 and R7 are connected to form -(CH2) n — and forms a 5- to 9-membered ring with the oxygen atom to which it is connected, wherein n=1, 2 or 3; X is a halogen atom.

[0050] Furthermore, in step (5), R6 and R7 are respectively selected from any one of methyl and ethyl, and the halogenated acetaldehyde acetal is selected from at least one of bromoacetaldehyde dimethyl acetal, bromoacetaldehyde diethyl acetal (BADEA), chloroacetaldehyde dimethyl acetal, and 2-chloroacetaldehyde diethyl acetal.

[0051] Furthermore, in step (5), X is selected from a chlorine atom (Cl) or a bromine atom (Br).

[0052] Furthermore, in step (5), a reducing agent is added during the Pomeranz-Fritsch reaction, and the reducing agent is selected from at least one of sodium hydride, sodium ethoxide, and n-butyl lithium.

[0053] Furthermore, in the step (5), the Pomeranz-Fritsch reaction temperature is 80 to 160°C.

[0054] Furthermore, in the step (5), the Pomeranz-Fritsch reaction time is not less than 6 hours, preferably 6 to 10 hours.

[0055] Furthermore, in the step (5), the Pomeranz-Fritsch reaction product is reacted with hydrochloric acid through a neutralization reaction to obtain a compound represented by formula (I).

[0056] Furthermore, in the step (5), after the Pomeranz-Fritsch reaction is completed, extraction is performed with water, and the organic layer (containing the tetracyclic isoquinoline alkaloid compound represented by formula (X)) is obtained by standing and separation. Hydrochloric acid is added to the organic layer, and the compound represented by formula (I) is obtained by neutralization reaction.

[0057] Furthermore, in the step (5), the neutralization reaction temperature is 50-60°C.

[0058] Furthermore, in the step (5), the neutralization reaction time is not less than 4 hours.

[0059] Furthermore, in the step (5), after the neutralization reaction is completed, the reaction solution is separated to remove the water layer, the pH of the organic layer is adjusted to weak acidity, and purified to obtain the compound shown in (I).

[0060] Furthermore, the industrial production process of the palmatine and its analogs comprises the following steps:

[0061] (1) 3,4-dimethoxybenzaldehyde (II), diethyl cyanophosphate (DEPC), and benzylamine (BnNH2) are reacted by Strecker reaction to prepare compound (III);

[0062] (2) Compound (III) is hydrolyzed and debenzyl protected to obtain compound (IV);

[0063] (3) Compound (IV) is reacted with 2,3-dimethoxybenzaldehyde (V) to obtain compound (VI);

[0064] (4) Compound (VI) is subjected to Friedel-Crafts acylation reaction to obtain compound (VII);

[0065] (5) Compound (VII) is subjected to Pomeranz-Fritsch reaction to obtain the target compound (I);

[0066]

[0067] Among them, X - Selected from organic acid radicals or inorganic acid radicals.

[0068] Furthermore, in the steps (1) to (5), the solvent used is selected from at least one of methanol, ethanol, dichloromethane, toluene, water, tetrahydrofuran, acetonitrile, dioxane, N,N-dimethylformamide, n-heptane, petroleum ether, and methyl tert-butyl ether. As described above, the industrial production process of calendula and its analogs of the present invention has the following beneficial effects:

[0069] 1) The raw and auxiliary materials used in the process provided by the present invention are all synthetic compounds, which are in sufficient supply in the domestic market, solving the problem of raw material supply shortage caused by the depletion of natural resources, and the process avoids the use of toxic auxiliary materials (such as sodium cyanide);

[0070] 2) The process provided by the present invention is a total synthesis approach, and its technical breakthrough is mainly reflected in the last step of the cyclization reaction. The prior art uses copper-containing compounds as catalysts, and copper ions need to be removed after the reaction is completed; while the cyclization step of the present process is to prepare the target compound (I) by the Pomeranz-Fritsch reaction of compound (VII), the post-reaction treatment is simpler, and the product is easier to purify.

[0071] 3) The process provided by the present invention has mild reaction conditions, high yield in each step, low material cost, and the quality of the obtained product meets the current drug application requirements, and is very suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1Shown is a synthetic route diagram of the industrial production process of calendula and its analogs in one embodiment of the present invention.

[0073] Figure 2 Shown is a synthetic route for obtaining the target compound (I) from compound (VII) in some embodiments of the present invention via Pomeranz-Fritsch reaction.

[0074] Figure 3 Shown is a synthetic route for the industrial production process of calendula and its analogs in some embodiments of the present invention.

[0075] Figure 4 Shown is the synthesis route of the industrial production process of flavonoids in Example 17 of the present invention. DETAILED DESCRIPTION

[0076] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0077] like Figure 1 As shown, one embodiment of the present invention provides an industrial production process of calendula and its analogs, comprising the following steps:

[0078] (1) subjecting the compound represented by formula (II) or its inorganic salt to a Strecker reaction to obtain a compound represented by formula (III);

[0079] (2) hydrolyzing the compound represented by formula (III) and removing the amino protecting group to obtain the compound represented by formula (IV);

[0080] (3) condensing the compound represented by formula (IV) with the compound represented by formula (V) or an inorganic salt thereof to obtain the compound represented by formula (VI);

[0081] (4) subjecting the compound represented by formula (VI) to a Friedel-Crafts acylation reaction to obtain a compound represented by formula (VII);

[0082] (5) subjecting the compound represented by formula (VII) to a Pomeranz-Fritsch reaction to obtain a compound represented by formula (I);

[0083] Among them, in the above formulas, R1, R2, R3 and R4 are selected from C 1-6 Alkyl, or R1 and R2, R3 and R4 are connected to form -(CH2) n— and forms a 5-7 membered ring with the oxygen atom to which it is connected, wherein n=1, 2 or 3; R5 is an amino protecting group; X - Selected from organic acid radicals or inorganic acid radicals.

[0084] In some embodiments, R1, R2, R3 and R4 are independently selected from methyl.

[0085] In some embodiments, R5 is an amino protecting group for protecting primary amino groups, including but not limited to alkoxycarbonyl amino protecting groups, acyl amino protecting groups, alkyl amino protecting groups, etc., wherein the alkoxycarbonyl amino protecting groups include but are not limited to benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), 2,2,2-trichloroethoxycarbonyl (Troc), methoxycarbonyl, ethoxycarbonyl, etc., the acyl amino protecting groups include but are not limited to phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, etc., the alkyl amino protecting groups include but are not limited to trityl (Trt), 2,4-dimethoxybenzyl (DMB), benzyl (Bn), p-methoxybenzyl (PMB), (trimethylsilyl)ethoxymethyl (SEM), etc.

[0086] In some embodiments, X - The compound selected from hydrochloride is represented by formula (I) is flavonoids.

[0087] In some embodiments, in step (1), the compound represented by formula (II) or its inorganic salt is reacted with a cyanide source and an ammonia source containing an amino protecting group by Strecker reaction to obtain a compound represented by formula (III), wherein the cyanide source includes but is not limited to diethyl cyanophosphate (DEPC), acetone cyanohydrin, sodium cyanide, potassium cyanide, etc., and the ammonia source containing an amino protecting group includes but is not limited to benzylamine (BnNH2), p-methoxybenzylamine (MeOC6H4CH2NH2), etc.

[0088] In some embodiments, in step (1), the Strecker reaction is carried out at room temperature.

[0089] In some embodiments, in step (1), the Strecker reaction time is not less than 3 hours, preferably 3 to 6 hours.

[0090] In some embodiments, in step (2), the compound represented by formula (III) is hydrolyzed under alkaline or acidic conditions, preferably under alkaline conditions. The alkaline reagent used in the hydrolysis includes but is not limited to sodium hydroxide, potassium hydroxide, etc.

[0091] In some embodiments, in step (2), the hydrolysis reaction temperature is 55-105°C.

[0092] In some embodiments, in step (2), the hydrolysis reaction time is not less than 12 hours, preferably 12 to 36 hours.

[0093] In some embodiments, in step (2), the reagent used to remove the amino protecting group includes but is not limited to 1-chloroethyl chloroformate, 2,2,2-trichloroethyl chloroformate, etc.

[0094] In some embodiments, in step (2), the deamino protecting group reaction is carried out at room temperature.

[0095] In some embodiments, in step (2), the reaction time for deamino protecting group is not less than 3 hours, preferably 4 to 6 hours.

[0096] In some embodiments, in step (3), the condensation reaction is carried out at room temperature.

[0097] In some embodiments, in step (3), the condensation reaction time is not less than 10 hours, preferably 10 to 24 hours.

[0098] In some embodiments, in step (3), the condensation reaction is carried out under acidic conditions; preferably, an acidic solution is also added in step (3), and the acidic solution includes but is not limited to glacial acetic acid, hydrochloric acid, sulfuric acid, etc.

[0099] In some embodiments, in step (3), an adsorbent is also added to the condensation reaction, and the adsorbent is used to adsorb water. The adsorbent includes but is not limited to natural zeolite, molecular sieve (i.e., artificially synthesized zeolite), etc. The molecular sieve includes but is not limited to type A molecular sieve, and the type A molecular sieve includes but is not limited to 3A molecular sieve, 4A molecular sieve, 5A molecular sieve, etc.

[0100] In some embodiments, in step (4), the compound represented by formula (VI) is reacted with an acylating agent through a Friedel-Crafts acylation reaction to obtain a compound represented by formula (VII), wherein the acylating agent includes but is not limited to acyl halides, acid anhydrides, carboxylic acids, enones, etc., and the acid anhydrides include but are not limited to trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, trifluoroacetyltrifluoromethanesulfonic anhydride, etc.

[0101] In some embodiments, in step (4), a catalyst is further added to catalyze the Friedel-Crafts acylation reaction, and the catalyst includes but is not limited to non-metallic halides, Lewis acids, inorganic acids, etc., the non-metallic halides include but are not limited to boron trifluoride, the Lewis acids include but are not limited to AlCl3, FeCl3, etc., the inorganic acids include but are not limited to sulfuric acid, etc. In a specific embodiment, the catalyst includes but is not limited to boron trifluoride, and the Friedel-Crafts acylation reaction catalyzed by boron trifluoride has high positional selectivity, fewer reaction steps, and simple operation.

[0102] In some embodiments, in step (4), the Friedel-Crafts acylation reaction temperature is 0 to 80°C.

[0103] In some embodiments, in step (4), the Friedel-Crafts acylation reaction time is not less than 3 hours, preferably 3 to 6 hours.

[0104] In some embodiments, in step (4), after the Friedel-Crafts acylation reaction is completed, a base is added to the reaction solution, and the acylated product undergoes imine ring closure / oxidative aromatization under alkaline conditions to form a 3-aryl isoquinoline compound represented by formula (VII).

[0105] In some embodiments, the base includes but is not limited to potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and the like.

[0106] In some embodiments, the imine ring-closure / oxidative aromatization reaction is carried out at room temperature.

[0107] In some embodiments, the imine ring-closure / oxidative aromatization reaction time is not less than 0.5 hours, preferably 0.5 to 2 hours.

[0108] In some embodiments, after the imine ring-closure / oxidative aromatization reaction is completed, the liquid is allowed to stand for separation, and the organic phase is collected to obtain a 3-aryl isoquinoline compound represented by formula (VII).

[0109] In some embodiments, the method of collecting the organic phase includes: standing the liquid to separate the organic phase, extracting the aqueous phase with an organic solvent, and then separating the extract phase (i.e., the organic phase); repeating the extraction multiple times, combining the organic phases, and evaporating the organic solvent to obtain the 3-aryl isoquinoline compound represented by formula (VII); preferably, the organic solvent used as the extractant includes but is not limited to dichloromethane, n-heptane, petroleum ether, methyl tert-butyl ether, etc.

[0110] like Figure 2As shown, in some embodiments, the step (5) of subjecting the compound represented by formula (VII) to a Pomeranz-Fritsch reaction to obtain the compound represented by formula (I) comprises the following steps:

[0111] (5-1) The compound represented by formula (VII) is reacted with the halogenated acetal diol represented by formula (VIII) to obtain the aminoacetal intermediate represented by formula (IX), which is then cyclized and reduced to obtain the tetracyclic isoquinoline alkaloid compound represented by formula (X);

[0112] (5-2) The tetracyclic isoquinoline alkaloid compound represented by formula (X) is subjected to neutralization reaction to obtain the compound represented by formula (I);

[0113] Among them, in the above formulas, R6 and R7 are selected from C 1-6 Alkyl, or R6 and R7 are connected to form -(CH2) n — and forms a 5- to 9-membered ring with the oxygen atom to which it is connected, wherein n=1, 2 or 3; X is a halogen atom.

[0114] The Pomeranz-Fritsch reaction used in the embodiment of the present invention is a Bobbitt improved method, namely, the Pomeranz-FritschPomeranz-Fritsch-Bobbitt reaction, which is beneficial to reduce the formation of by-products.

[0115] In some embodiments, R6 and R7 include but are not limited to methyl, ethyl, etc., respectively, and the halogenated acetaldehyde acetal includes but is not limited to bromoacetaldehyde dimethyl acetal, bromoacetaldehyde diethyl acetal (BADEA), chloroacetaldehyde dimethyl acetal, 2-chloroacetaldehyde diethyl acetal, etc.

[0116] In some embodiments, X includes, but is not limited to, a chlorine atom (Cl) or a bromine atom (Br).

[0117] In some embodiments, in step (5), a reducing agent is added during the Pomeranz-Fritsch reaction, and the reducing agent includes but is not limited to sodium hydride, sodium ethoxide, n-butyl lithium, and the like.

[0118] In some embodiments, in step (5), the Pomeranz-Fritsch reaction temperature is 80-160°C.

[0119] In some embodiments, in step (5), the Pomeranz-Fritsch reaction time is not less than 6 hours, preferably 6 to 10 hours.

[0120] In some embodiments, in step (5), the Pomeranz-Fritsch reaction product is reacted with hydrochloric acid through neutralization to obtain a compound of formula (I).

[0121] In some embodiments, in step (5), after the Pomeranz-Fritsch reaction is completed, extraction is performed with water, and the organic layer (containing the tetracyclic isoquinoline alkaloid compound represented by formula (X)) is obtained by standing and separation. Hydrochloric acid is added to the organic layer, and the compound represented by formula (I) is obtained by neutralization reaction.

[0122] In some embodiments, in step (5), the neutralization reaction temperature is 50-60°C.

[0123] In some embodiments, in step (5), the neutralization reaction time is not less than 4 hours, preferably 4 to 6 hours.

[0124] In some embodiments, in step (5), after the neutralization reaction is completed, the reaction solution is separated to remove the water layer, the pH of the organic layer is adjusted to weak acidity, and purified to obtain the compound shown in (I); preferably, the pH of the organic layer is adjusted to 5-6.

[0125] like Figure 3 As shown, in some embodiments, the industrial production process of calendula and its analogs comprises the following steps:

[0126] (1) 3,4-dimethoxybenzaldehyde (II), diethyl cyanophosphate (DEPC), and benzylamine (BnNH2) are reacted by Strecker reaction to prepare compound (III);

[0127] (2) Compound (III) is hydrolyzed and debenzyl protected to obtain compound (IV);

[0128] (3) Compound (IV) is reacted with 2,3-dimethoxybenzaldehyde (V) to obtain compound (VI);

[0129] (4) Compound (VI) is subjected to Friedel-Crafts acylation reaction to obtain compound (VII);

[0130] (5) Compound (VII) is subjected to Pomeranz-Fritsch reaction to obtain the target compound (I);

[0131] Among them, X - Selected from organic acid radicals or inorganic acid radicals, preferably Cl - .

[0132] In some embodiments, in steps (1) to (5), the solvent used includes but is not limited to methanol, ethanol, dichloromethane, toluene, water, tetrahydrofuran, acetonitrile, dioxane, N,N-dimethylformamide, n-heptane, petroleum ether, methyl tert-butyl ether, etc.

[0133] In some embodiments, steps (1) to (5) also include a purification operation of the product. The specific purification operation method can be selected and designed according to the requirements of the reaction solution composition, product characteristics, etc. according to conventional or existing technical means in the field of organic synthesis, including but not limited to distillation, reduced pressure concentration, crystallization, recrystallization, extraction, washing, drying, etc.

[0134] The following specific examples are given to illustrate the present invention in detail. It should also be understood that the following examples are only used to specifically illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention belong to the scope of protection of the present invention. The specific process parameters and the like in the following examples are also only examples within a suitable range, that is, those skilled in the art can make a selection within a suitable range according to the description herein, and are not limited to the specific values ​​​​exemplified below.

[0135] Example 1

[0136] This embodiment provides a method for preparing compound (III), specifically:

[0137] Dissolve 3,4-dimethoxybenzaldehyde (II) (16.7 g, 0.1 mol) and DEPC (19.6 g, 0.12 mol) in 150 ml of methanol and stir for 30-45 min. Add 120 ml of methanol solution of benzylamine (23.6 g, 0.22 mol) and react at room temperature for 4 h. Concentrate under reduced pressure, wash the residue with 50 ml of methanol × 2, and dry to obtain 26.08 g of compound (III) (y = 92.4%).

[0138] Example 2

[0139] Referring to the method of Example 1, this example provides a method for preparing multiple compounds (III), as shown in Table 1:

[0140] Table 1. Preparation conditions, yield and yield of compound (III)

[0141]

[0142] Example 3

[0143] This embodiment provides a method for preparing compound (IV), specifically:

[0144] Compound (III) (25.0 g, 0.09 mol) was added to 250 ml of methanol, and 30 ml of 30% sodium hydroxide solution was added. The mixture was refluxed at 55-65°C for 24 h, and then cooled and filtered. The filter cake was dissolved in 150 ml of dichloromethane, cooled to below 20°C, and 9 ml of 1-chloroethyl chloroformate was added dropwise. The mixture was reacted at room temperature for 4-6 h, and the dichloromethane was evaporated under reduced pressure to obtain 17.1 g of compound (IV) (y=85.7%).

[0145] Example 4

[0146] This embodiment provides a method for preparing compound (IV), specifically:

[0147] Compound (III) (12.5 g, 0.045 mol) was added to 125 ml of methanol, and 15 ml of 30% potassium hydroxide solution was added. The mixture was refluxed at 65-75°C for 24 h, cooled and filtered. The filter cake was dissolved in 75 ml of dichloromethane, cooled to below 10°C, and 5 ml of 1-chloroethyl chloroformate was added dropwise. The mixture was reacted at room temperature for 4-6 h, and the dichloromethane was evaporated under reduced pressure to obtain 8.25 g of compound (IV) (y=82.69%).

[0148] Example 5

[0149] This embodiment provides a method for preparing compound (IV), specifically:

[0150] Compound (III) (12.5 g, 0.045 mol) was added to 125 ml of methanol, and 15 ml of 30% sodium hydroxide solution was added. The mixture was refluxed at 95-105°C for 24 h, and then cooled and filtered. The filter cake was dissolved in 75 ml of n-heptane, cooled to below 10°C, and 5.2 ml of 1-chloroethyl chloroformate was added dropwise. The mixture was reacted at room temperature for 4-6 h, and n-heptane was evaporated under reduced pressure to obtain 7.95 g of compound (IV) (y=79.68%).

[0151] Example 6

[0152] This embodiment provides a method for preparing compound (VI), specifically:

[0153] Compound (IV) (22.5 g, 0.1 mol), 2,3-dimethoxybenzaldehyde (V) (18.3 g, 0.11 mol), glacial acetic acid (5-10 ml) and 3A molecular sieves (30 g) were added to 400 ml of dichloromethane, stirred at room temperature for 12 h, and the dichloromethane was concentrated by distillation to obtain 32.2 g of compound (VI) (y=86.4%).

[0154] Example 7

[0155] This embodiment provides a method for preparing compound (VI), specifically:

[0156] Compound (IV) (11.3 g, 0.05 mol), 2,3-dimethoxybenzaldehyde (V) (9.2 g, 0.13 mol) and 3 ml of glacial acetic acid were added to 200 ml of dichloromethane, stirred at room temperature for 12 h, and the dichloromethane was concentrated by distillation to obtain 13.5 g of compound (VI) (y = 72.45%).

[0157] Example 8

[0158] This embodiment provides a method for preparing compound (VI), specifically:

[0159] Compound (IV) (11.3 g, 0.05 mol), 2,3-dimethoxybenzaldehyde (V) (9.2 g, 0.11 mol), 10 ml of acid anhydride and 3A molecular sieves (15 g) were added to 200 ml of dichloromethane and stirred at room temperature for 12 h. The dichloromethane was concentrated by distillation to obtain 15.32 g of compound (VI) (y = 82.21%).

[0160] Example 9

[0161] This embodiment provides a method for preparing compound (VII), specifically:

[0162] Compound (VI) (30.0 g, 0.08 mol) and trifluoroacetic anhydride (33.6 g, 0.16 mol) were added to 300 mL of dichloromethane, refluxed at 40-45°C for 30 min, and then boron trifluoride (3.4 g, 0.05 mol) was added, and refluxed for 4 h. 300 ml of 10% K2CO3 solution was added to the reaction solution, stirred for 1 h, and then allowed to stand for separation. The aqueous phase was extracted with 100 ml of dichloromethane × 2, and the organic phases were combined and the solvent was evaporated to obtain 21.9 g of compound (VII) (y = 83.8%), mp: 113-116°C.

[0163] Example 10

[0164] This embodiment provides a method for preparing compound (VII), specifically:

[0165] Compound (VI) (15.0 g, 0.04 mol) and trifluoroacetic anhydride (12.6 g, 0.06 mol) were added to 150 mL of dichloromethane, refluxed at 45-55°C for 30 min, and then boron trifluoride (1.7 g, 0.025 mol) was added, and refluxed for 4 h. 150 ml of 10% K2CO3 solution was added to the reaction solution, stirred for 1 h, and then allowed to stand for separation. The aqueous phase was extracted with 50 ml of dichloromethane × 2, and the organic phases were combined and the solvent was evaporated to obtain 10.64 g of compound (VII) (y = 81.42%).

[0166] Embodiment 11

[0167] This embodiment provides a method for preparing compound (VII), specifically:

[0168] Compound (VI) (15.0 g, 0.04 mol) and trifluoroacetic anhydride (10.08 g, 0.048 mol) were added to 120 mL of dichloromethane, refluxed at 70-80°C for 30 min, and then boron trifluoride (1.7 g, 0.025 mol) was added, and refluxed for 4 h. 10% K2CO3 solution (150 ml) was added to the reaction solution, stirred for 1 h, and then allowed to stand for separation. The aqueous phase was extracted with 50 ml of dichloromethane × 2, and the organic phases were combined and the solvent was evaporated to obtain 10.48 g of compound (VII) (y = 80.2%).

[0169] Example 12

[0170] This embodiment provides a method for preparing compound (I), specifically:

[0171] Compound (VII) (13.0 g, 0.40 mol), bromoacetaldehyde diethyl acetal (9.5 g, 0.48 mol) and NaH (10.5 g, 0.44 mol) were added to toluene (250 ml) and refluxed at 105-115°C for 8 h. 100 ml of water was added and stirred for 0.5 h, and the mixture was allowed to stand for 4-6 h. The organic layer was added with 30 ml of concentrated hydrochloric acid and stirred at 50-60°C for 4-6 h. The organic layer was separated and washed with water until pH was 5-6. The mixture was concentrated under reduced pressure and recrystallized from methanol to obtain 15.5 g of compound (I) (y=85.2%), mp: 198-200°C (decomposition).

[0172] Embodiment 13

[0173] This embodiment provides a method for preparing compound (I), specifically:

[0174] Compound (VII) (6.5 g, 0.20 mol), bromoacetaldehyde diethyl acetal (5.94 g, 0.30 mol) and NaH (5.3 g, 0.22 mol) were added to DMF (120 ml) and refluxed at 150-155°C for 8 h. 50 ml of water was added and stirred for 0.5 h, and the mixture was allowed to stand for 4-6 h. The water layer was separated and washed with water until the pH value was 5-6. The mixture was concentrated under reduced pressure and recrystallized from methanol to obtain 7.81 g of compound (I) (y=85.86%).

[0175] Embodiment 14

[0176] This embodiment provides a method for preparing compound (I), specifically:

[0177] Compound (VII) (6.5 g, 0.20 mol), bromoacetaldehyde diethyl acetal (4.75 g, 0.24 mol) and n-butyl lithium (14.1 g, 0.22 mol) were added to toluene (120 ml) in sequence, and refluxed at 105-115°C for 8 h. Add 50 ml of water and stir for 0.5 h, let stand, and separate the water layer. Add 15 ml of concentrated hydrochloric acid to the organic layer, keep warm at 50-60°C and stir for 4-6 h. Separate the water layer, wash the organic layer with water until pH 5-6. Concentrate under reduced pressure, and recrystallize with methanol to obtain 7.32 g of compound (I) (y=80.45%).

[0178] Embodiment 15

[0179] This embodiment provides a method for preparing compound (I), specifically:

[0180] Compound (VII) (6.5 g, 0.20 mol), bromoacetaldehyde diethyl acetal (4.75 g, 0.24 mol) and n-butyl lithium (14.1 g, 0.22 mol) were added to toluene (120 ml) and refluxed at 150-160°C for 4 h. After cooling slightly, n-butyl lithium (5.12 g, 0.08 mol) was added and refluxed for 4 h. 50 ml of water was added and stirred for 0.5 h, and the mixture was allowed to stand and the water layer was separated. 20 ml of concentrated hydrochloric acid was added to the organic layer and the mixture was stirred at 50-60°C for 4-6 h. The water layer was separated and the organic layer was washed with water until the pH value was 5-6. Concentrated under reduced pressure and recrystallized from methanol to obtain 7.68 g of compound (I) (y=84.6%).

[0181] Example 16

[0182] This embodiment provides a method for preparing compound (I), specifically:

[0183] Compound (VII) (6.5 g, 0.20 mol), bromoacetaldehyde diethyl acetal (4.75 g, 0.24 mol) and sodium ethoxide (20.4 g, 0.3 mol) were added to toluene (120 ml) and refluxed at 80-90°C for 9 h. 50 ml of water was added and stirred for 0.5 h, and the mixture was allowed to stand for 4-6 h. The water layer was separated and washed with water until the pH value was 5-6. The mixture was concentrated under reduced pressure and recrystallized from methanol to obtain 6.75 g of compound (I) (y=74.18%).

[0184] Embodiment 17

[0185] like Figure 4 As shown, this embodiment provides a method for preparing compound (I), specifically:

[0186] 1. Preparation of compound (III)

[0187] Dissolve 3,4-dimethoxybenzaldehyde (II) (16.7 g, 0.1 mol) and DEPC (19.6 g, 0.12 mol) in 150 ml of methanol and stir for 30-45 min. Add 120 ml of methanol solution of benzylamine (23.6 g, 0.22 mol) and react at room temperature for 4 h. Concentrate under reduced pressure, wash the residue with 50 ml of methanol × 2, and dry to obtain 26.08 g of compound (III) (y = 92.4%).

[0188] 2. Preparation of compound (IV)

[0189] Compound (III) (25.0 g, 0.09 mol) was added to 250 ml of methanol, and 30 ml of 30% sodium hydroxide solution was added. The mixture was refluxed at 55-65°C for 24 h, and then cooled and filtered. The filter cake was dissolved in 150 ml of dichloromethane, cooled to below 20°C, and 9 ml of 1-chloroethyl chloroformate was added dropwise. The mixture was reacted at room temperature for 4-6 h, and the dichloromethane was evaporated under reduced pressure to obtain 17.1 g of compound (IV) (y=85.7%).

[0190] 3. Preparation of compound (VI)

[0191] Compound (IV) (22.5 g, 0.1 mol), 2,3-dimethoxybenzaldehyde (V) (18.3 g, 0.11 mol), glacial acetic acid (5-10 ml) and 3A molecular sieves (30 g) were added to 400 ml of dichloromethane, stirred at room temperature for 12 h, and the dichloromethane was concentrated by distillation to obtain 32.2 g of compound (VI) (y=86.4%).

[0192] 4. Preparation of compound (VII)

[0193] Compound (VI) (30.0 g, 0.08 mol) and trifluoroacetic anhydride (33.6 g, 0.16 mol) were added to 300 mL of dichloromethane, refluxed at 40-45°C for 30 min, and then boron trifluoride (3.4 g, 0.05 mol) was added, and refluxed for 4 h. 300 ml of 10% K2CO3 solution was added to the reaction solution, stirred for 1 h, and then allowed to stand for separation. The aqueous phase was extracted with 100 ml of dichloromethane × 2, and the organic phases were combined and the solvent was evaporated to obtain 21.9 g of compound (VII) (y = 83.8%), mp: 113-116°C.

[0194] 5. Preparation of compound (I)

[0195] Compound (VII) (13.0 g, 0.40 mol), bromoacetaldehyde diethyl acetal (9.5 g, 0.48 mol) and NaH (10.5 g, 0.44 mol) were added to toluene (250 ml) and refluxed at 105-115°C for 8 h. 100 ml of water was added and stirred for 0.5 h, and the mixture was allowed to stand for 4-6 h. The organic layer was added with 30 ml of concentrated hydrochloric acid and stirred at 50-60°C for 4-6 h. The organic layer was separated and washed with water until pH was 5-6. The mixture was concentrated under reduced pressure and recrystallized from methanol to obtain 15.5 g of compound (I) (y=85.2%), mp: 198-200°C (decomposition).

[0196] The yield of each step in this embodiment is higher than 83%, and the total yield is about 50%.

[0197] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. An industrial production process of calendula and its analogs, characterized in that: The steps include: (1) subjecting the compound represented by formula (II) or its inorganic salt to a Strecker reaction to obtain a compound represented by formula (III); (2) hydrolyzing the compound represented by formula (III) and removing the amino protecting group to obtain the compound represented by formula (IV); (3) condensing the compound represented by formula (IV) with the compound represented by formula (V) or an inorganic salt thereof to obtain the compound represented by formula (VI); (4) subjecting the compound represented by formula (VI) to a Friedel-Crafts acylation reaction to obtain a compound represented by formula (VII); (5) subjecting the compound represented by formula (VII) to a Pomeranz-Fritsch reaction to obtain a compound represented by formula (I); Among them, in the above formulas, R1, R2, R3 and R4 are selected from C 1-6 Alkyl, or R1 and R2, R3 and R4 are connected to form -(CH2) n — and form a 5-7 membered ring with the oxygen atom to which it is connected, wherein n=1, 2 or 3; R5 is an amino protecting group; X - Selected from organic acid radicals or inorganic acid radicals.

2. The industrial production process of flavonoids and analogs thereof according to claim 1, characterized in that: R1, R2, R3 and R4 are each selected from methyl; and / or, R5 is an amino protecting group for protecting primary amine; and / or, X - Selected from hydrochloride.

3. The industrial production process of flavonoids and analogs thereof according to claim 1, characterized in that: The process conditions of step (1) are selected from any one of the following conditions A1 to A3: A1. The compound represented by formula (II) or an inorganic salt thereof is reacted with a cyanide source and an ammonia source containing an amino protecting group by a Strecker reaction to obtain a compound represented by formula (III); A2. Strecker reaction is carried out at room temperature; A3.Strecker reaction time is not less than 3 hours.

4. The industrial production process of calendula officinalis and its analogs according to claim 1, characterized in that: The process conditions of step (2) are selected from any one of the following conditions B1 to B6: B1. The compound represented by formula (III) is hydrolyzed under alkaline or acidic conditions; B2. The hydrolysis reaction temperature is 55 to 105°C; B3. The hydrolysis reaction time is not less than 12 hours; B4. A reagent for deamino protecting group selected from 1-chloroethyl chloroformate or 2,2,2-trichloroethyl chloroformate; B5. Deamination of the protecting group reaction is carried out at room temperature; B6. The reaction time for deamino protecting group is not less than 3 hours.

5. The industrial production process of calendula officinalis and its analogs according to claim 1, characterized in that: The process conditions of step (3) are selected from any one of the following conditions C1 to C4: C1. The condensation reaction is carried out at room temperature; C2. The condensation reaction time is not less than 10 hours; C3. The condensation reaction is carried out under acidic conditions; C4. Condensation reaction An adsorbent is also added to adsorb water.

6. The industrial production process of calendula officinalis and its analogs according to claim 1, characterized in that: The process conditions of step (4) are selected from any one of the following conditions D1 to D5: D1. The compound represented by formula (VI) is reacted with an acylating agent by Friedel-Crafts acylation to obtain a compound represented by formula (VII); D2. A catalyst was also added to catalyze the Friedel-Crafts acylation reaction; D3. Friedel-Crafts acylation reaction temperature is 0-80°C; D4. Friedel-Crafts acylation reaction time is not less than 3 hours; D5. After the Friedel-Crafts acylation reaction is completed, a base is added to the reaction solution, and the acylated product undergoes imine ring closure / oxidative aromatization under alkaline conditions to form a 3-aryl isoquinoline compound represented by formula (VII).

7. The industrial production process of flavonoids and analogs thereof according to claim 1, characterized in that: The step (5) of subjecting the compound represented by formula (VII) to a Pomeranz-Fritsch reaction to obtain the compound represented by formula (I) comprises the following steps: (5-1) The compound represented by formula (VII) is reacted with the halogenated acetal diol represented by formula (VIII) to obtain the aminoacetal intermediate represented by formula (IX), which is then cyclized and reduced to obtain the tetracyclic isoquinoline alkaloid compound represented by formula (X); (5-2) The tetracyclic isoquinoline alkaloid compound represented by formula (X) is subjected to neutralization reaction to obtain the compound represented by formula (I); Among them, in the above formulas, R6 and R7 are selected from C 1-6 Alkyl, or R6 and R7 are connected to form -(CH2) n — and forms a 5- to 9-membered ring with the oxygen atom to which it is connected, wherein n=1, 2 or 3; X is a halogen atom.

8. The industrial production process of calendula officinalis and its analogs according to claim 7, characterized in that: The process conditions of step (5) are selected from any one of the following conditions E1 to E10: E1. The halogenated acetaldehyde diol is selected from at least one of bromoacetaldehyde dimethyl acetal, bromoacetaldehyde diethyl acetal, chloroacetaldehyde dimethyl acetal and 2-chloroacetaldehyde diethyl acetal; E2.X is selected from a chlorine atom or a bromine atom; E3. A reducing agent is added during the Pomeranz-Fritsch reaction, wherein the reducing agent is selected from at least one of sodium hydride, sodium ethoxide, and n-butyl lithium; E4.Pomeranz-Fritsch reaction temperature is 80~160℃; E5.Pomeranz-Fritsch reaction time is not less than 6 hours; E6. The product of the Pomeranz-Fritsch reaction is reacted with hydrochloric acid to obtain a compound represented by formula (I); E7. After the Pomeranz-Fritsch reaction is completed, extraction is carried out with water, and the organic layer is separated by standing. Hydrochloric acid is added to the organic layer, and the compound represented by formula (I) is obtained by neutralization reaction; E8. The neutralization reaction temperature is 50-60°C; E9. Neutralization reaction time is not less than 4 hours; E10. After the neutralization reaction is completed, the reaction solution is separated into a water layer, and the pH of the organic layer is adjusted to a weakly acidic state, and purified to obtain the compound shown in (I).

9. The industrial production process of calendula officinalis and its analogs according to any one of claims 1 to 8, characterized in that: The steps include: (1) 3,4-dimethoxybenzaldehyde (II), diethyl cyanophosphate (DEPC), and benzylamine (BnNH2) are reacted by Strecker reaction to prepare compound (III); (2) Compound (III) is hydrolyzed and debenzyl protected to obtain compound (IV); (3) Compound (IV) is reacted with 2,3-dimethoxybenzaldehyde (V) to obtain compound (VI); (4) Compound (VI) is subjected to Friedel-Crafts acylation reaction to obtain compound (VII); (5) Compound (VII) is subjected to Pomeranz-Fritsch reaction to obtain the target compound (I); Among them, X - Selected from organic acid radicals or inorganic acid radicals.

10. The industrial production process of palmatine and its analogs according to any one of claims 1 to 9, characterized in that: In the steps (1) to (5), the solvent used is selected from at least one of methanol, ethanol, dichloromethane, toluene, water, tetrahydrofuran, acetonitrile, dioxane, N,N-dimethylformamide, n-heptane, petroleum ether, and methyl tert-butyl ether.

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