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CN-116655582-B - Synthesis method and application of sanguinarine intermediate compound bromo-compound

CN116655582BCN 116655582 BCN116655582 BCN 116655582BCN-116655582-B

Abstract

The invention relates to the field of medicine synthesis, and discloses a synthesis method and application of a sanguinarine intermediate compound bromo-compound. Firstly, compared with the existing method, the synthetic method of the sanguinarine intermediate compound bromo-compound can avoid the use of starting materials which are difficult to prepare, and has the advantages of short steps, mild reaction conditions, easy operation, low cost, environmental protection, high yield and high product purity. And secondly, the bromide is used as a raw material to synthesize the sanguinarine hemisulfate, compared with the prior method, the dosage of the noble metal palladium catalyst can be greatly reduced, the use of silver carbonate as a base (acid binding agent) is avoided, column chromatographic separation is not needed, and the high-purity sanguinarine hemisulfate can be obtained through post-treatment operations such as conventional extraction, pulping, concentration and the like.

Inventors

  • XU LINFENG
  • LOU KEXIA
  • ZHANG DA

Assignees

  • 宁波九胜创新医药科技有限公司

Dates

Publication Date
20260512
Application Date
20230504

Claims (11)

  1. 1. A method for synthesizing sanguinarine hemisulfate is characterized in that: The bromide III is subjected to intramolecular aromatic coupling reaction under the action of a palladium catalyst, a ligand, alkali and a phase transfer catalyst to prepare the sanguinarine oxide, and then is subjected to reduction reaction to prepare the sanguinarine hemisulfate, wherein the synthetic route is as follows: In the intramolecular aromatic coupling reaction: the palladium catalyst, ligand, base, phase transfer catalyst and solvent are selected from one of the following combinations: Palladium acetate, P (o-Tol) 3 , potassium phosphate, tetrabutylammonium bromide and NMP; palladium chloride, BINAP, potassium carbonate, tetrabutylammonium bromide and DMAC; palladium trifluoroacetate, DPPP, potassium phosphate, tetramethylammonium bromide and NMP; The equivalent ratio of the bromide III, the palladium catalyst, the ligand, the phase transfer catalyst and the alkali is 1:0.005-0.02:0.04-0.08:0.05-0.2:1.5-5.0, wherein the bromide III is synthesized by a condensation reaction of a compound I and a compound II, and the synthetic route is as follows:
  2. 2. The synthesis method of claim 1, wherein the compound II is first prepared into acyl chloride by chlorination reaction with thionyl chloride, and then the obtained acyl chloride is subjected to condensation reaction with the compound I under the alkaline catalysis condition to obtain the bromo-compound III.
  3. 3. The synthesis method according to claim 2, wherein: The basic catalytic conditions are provided by organic and/or inorganic bases; the organic base is selected from one or more of triethylamine, diisopropylamine and diisopropylethylamine; The inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate and sodium hydroxide; in the chlorination reaction, the equivalent ratio of the compound II to the thionyl chloride is 1:1-1.5, and in the condensation reaction, the equivalent ratio of the compound I to the compound II to the alkali is 1:1-1.3:1-2.0.
  4. 4. The method according to claim 1 or 2, wherein the reaction solvent is selected from the group consisting of methylene chloride, acetonitrile and toluene, and the reaction temperature is 40-50 ℃.
  5. 5. The method according to claim 1 or 2, wherein the reaction solvent is selected from the group consisting of methylene chloride, acetonitrile and toluene, and the reaction temperature is 0-20 ℃.
  6. 6. The synthesis method according to claim 1 or 2, wherein the compound I is prepared from piperonyl butoxide as a starting material, and the synthesis route is as follows:
  7. 7. the method according to claim 1 or 2, wherein the compound II is prepared from o-vanillin as a starting material, and the synthetic route is as follows:
  8. 8. the method of claim 1, wherein the reducing agent is selected from one or more of lithium aluminum hydride, red aluminum, DIBAL-H, borane, sodium borohydride, potassium borohydride, and lithium borohydride.
  9. 9. The method of claim 1, wherein the ratio of equivalents of the oxidized sanguinarine to the reducing agent is 1:1.0-3.0.
  10. 10. The method according to claim 1, wherein the reaction solvent for the reduction reaction is one or more selected from the group consisting of THF, dioxane, tert-butyl methyl ether and toluene.
  11. 11. The method of claim 1, wherein the reaction temperature of the reduction reaction is-30 to 110 ℃.

Description

Synthesis method and application of sanguinarine intermediate compound bromo-compound Technical Field The invention relates to the field of medicine synthesis, in particular to a synthesis method and application of a sanguinarine intermediate compound bromo-compound. Background Aromatic benzo [ c ] phenanthridine alkaloids include sanguinarine, chelerythrine, etc. The effective chemical components in the macleaya cordata mainly comprise sanguinarine and chelerythrine, and the content of the macleaya cordata in fruits is highest. The macleaya cordata extract is obtained by extracting and purifying macleaya cordata cheeks and can be used as a feed additive to replace antibiotics. As shown below, the molecular skeleton of benzo [ c ] phenanthridine comprises A, B, C rings and 1 benzene ring (D ring), and the chemical synthesis method can be divided according to the order of constructing the four rings A-D. In the prior art, it is most common to construct the B-or C-ring last. Traditional cyclization reactions using benzyne, free radical or enamide as intermediates and palladium-catalyzed intramolecular coupling reactions rapidly developed in recent years generally adopt the connection of C10a-C11a bonds to construct a benzo [ C ] phenanthridine skeleton in the last step. Bromo-III is a key intermediate compound for constructing sanguinarine and salts thereof, wherein the synthetic route of sanguinarine hemisulfate is as follows: the existing synthetic method of the bromo-compound III comprises the following steps: Calder et al (JOC 2014) prepared bromo III (JOC 2014,22d, r1+r2=och2o, r3=h) in a 4-step procedure starting from trichloroacetamide substituted 1, 4-dihydronaphthalene compounds (JOC 2014,16c CAS 1620902-92-2) in 72% (column chromatography separation), 98%,89%,98% yields, respectively. The synthetic route is as follows: Scheme 4.Synthesis of Amides 22a-d The synthesis method has obvious defects and limits the industrialized application of the method: (1) The step 1 is to oxidize manganese oxide, the product is to separate by column chromatography, the step 2 is to react for 60h, and the step 4 is to methylate by genotoxic reagent MeI and strong alkali NaH. Because of long reaction time, column chromatography purification, use of genotoxic reagents, and the like, hidden troubles of operation, product use safety and the like exist. (2) The initial trichloroacetamide substituted 1, 4-dihydronaphthalene compound (JOC 2014, 16C) needs to be prepared by self, bromopiperonal (JOC 2014, 5C) is used as a raw material, the preparation is carried out in 4 steps, the yields of the steps are 100%,100%,97% and 81%, the low temperature of-78 ℃ is used when the step 3 aryl ethyl acrylate is reduced into aryl allyl alcohol, column chromatography separation is needed, and the noble metal ruthenium Grubbs second generation catalyst is used when the step 4 ring closure metathesis is needed. The reaction conditions are ultralow temperature, the column chromatography is used for purifying, the noble metal ruthenium catalyst is complex in operation and high in raw material cost. Therefore, the development of a chemical synthesis method for preparing the sanguinarine intermediate bromide, which has the advantages of short steps, mild reaction conditions, easy operation, low production cost, environment-friendly process, high yield and high product purity, becomes a difficult problem to be solved urgently. In addition, with respect to the bromo coupling route for the preparation of sanguinarine and its analogues, the prior art has been reported as follows: The synthesis of benzophenanthridine alkaloids and derivatives thereof is reviewed in J. Organic chemistry of Hunan agricultural university, and palladium-catalyzed aryl coupling reaction route in the bonding ring formation of the B ring C10a-C11a of the benzophenanthridine basic skeleton is carried out by catalyzing a bromine or iodine substituted aromatic amide intermediate with palladium acetate as a catalyst to carry out intramolecular aromatic coupling reaction. The intramolecular coupling reaction is pointed out to have regioselectivity, and the selection of different phosphine ligand/base (acid binding agent) combinations can lead to the formation of C10a-C4 coupling products, which affects the yield of the coupling target products. Harayama et al (CHEM PHARM bull 1996,Synthesis 2001,Heterocycles 2005) using palladium acetate catalyst, screening out an optimal system of P (o-Tol) 3/silver carbonate (preparation of chelerythrine oxide as a sanguinarine analogue), bromide, palladium acetate catalyst, ligand and alkali equivalent ratio of 1:0.2:0.4:2, DMF solvent, reacting for 3h, and separating by column chromatography, wherein the yield and purity are unknown. Cadler et al (JOC 2014) prepared the sanguinarine oxide by using a Hermann-Beller ring palladium catalyst/silver carbonate system, and required column chromatography separation, wherein the stoichiometric ratio