WO2023164889A1

WO2023164889A1 - Method for preparing codeine and derivative and intermediate thereof

Info

Publication number: WO2023164889A1
Application number: PCT/CN2022/079056
Authority: WO
Inventors: 怀特洛伦佐·瓦伦蒂诺; 班威尔马丁·格哈特; 蓝平; 何玉涛; 胡南
Original assignee: 暨南大学
Priority date: 2022-03-03
Filing date: 2022-03-03
Publication date: 2023-09-07

Abstract

Disclosed are a method for preparing codeine and a derivative and intermediate thereof. Simple, cheap and easily-available commercially available compounds are used as starting materials in the present invention, various intermediates that are required for the preparation of codeine and a derivative thereof, i.e., intermediates shown in formulas (I) - (VI), are synthesized sequentially by means of various reactions such as Suzuki-Miyaura cross-coupling reaction, Mitsunobu reaction and Heck reaction, and then, codeine, deoxycodeine, norcodeine and other derivatives are prepared using these intermediates, respectively. The method for preparing codeine and a derivative and intermediate thereof provided by the present invention has a short synthesis route and high yield, and various intermediate compounds involved in the synthesis process all can be prepared on a gram scale.

Description

Method for preparing codeine, its derivatives and intermediates

technical field

The invention belongs to the technical field of organic chemistry and relates to a preparation method of codeine, codeine derivatives and intermediates thereof.

Background technique

Codeine (codein) is one of the most commonly used plant-extracted prescription drugs extracted from poppy plants. It has significant effects in analgesia and cough relief, and it occupies a very important position in the field of medicine.

Codeine (-)-codein from natural sources has a five-ring condensed structure, including a five-membered dihydrofuran ring, five consecutive chiral centers, a benzylic quaternary carbon center, a nitrogen-containing bridge ring. Other codeine alkaloids such as morphine, thebaine, deoxycodeine, and codeinone (codeinone) have the same chemical structure and medicinal activity as codeine. At the same time, their It also plays an important role in the synthesis of codeine.

Codeine's unique chemical structure, pharmacophore and potential pharmaceutical components of codeine derivatives have attracted many scientists to study its chemical synthesis. However, these existing codeine total synthesis methods have long synthesis steps and low yields, are not suitable for industrial production or have high production costs. In the prior art, there is still a lack of a preparation method for synthesizing codeine and its derivatives with short synthesis steps and high yield.

Contents of the invention

The purpose of the present invention is mainly to provide a method for preparing codeine derivatives with short synthesis steps and high yield.

The present invention uses simple, cheap and easy-to-obtain commercially available compounds as starting materials, adopts a one-pot method (twice Heck cyclization) to construct the morphine ring structure, and synthesizes the piperidine ring structure through photocatalytic redox reaction, and then completes the Because of the total synthesis work of its derivatives. The method has short synthesis steps and high yield, and various intermediate compounds involved in the synthesis process can be prepared on a gram scale.

According to the first aspect of the present invention, there is provided intermediate I (i.e. compound 4) for the preparation of codeine and derivatives thereof whose structure is shown in formula (I):

According to the second aspect of this aspect, the preparation method of intermediate I shown in formula (I) is provided, comprising the following steps:

With tert-butyl vinyl carbamate and compound 1

Synthesis of compound 2 by Suzuki-Miyaura cross-coupling reaction

Compound 2 and Compound 3

Compound 4 was synthesized by Mitsunobu reaction.

In some embodiments, compound 1 can be obtained through commercial channels, and can also be synthesized by the following synthetic route:

In some embodiments, the preparation method of compound 2 may include the following steps:

Dissolve tert-butyl vinyl carbamate in the first solvent, add borane at room temperature to react until the solution becomes clear and transparent, and obtain solution I; wherein, the molar ratio of tert-butyl vinyl carbamate to borane is 1 :1–1:2;

Compound 1, palladium reagent and triphenylarsenic are dissolved in a second solvent, and then an alkali solution is added to obtain solution II; wherein, the amount of palladium reagent added is 5-25% of that of compound 1 in terms of the amount of the substance, The addition amount of triphenylarsenic is 9-50% of compound 1;

Add solution I to solution II, react for 0.5-1h under nitrogen protection, and obtain compound 2 after separation and purification.

In some embodiments, the first solvent may be at least one selected from tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide.

In some embodiments, the borane can be selected from 9-borabicyclo[3.3.1]nonane dimer, diisopinepinylchloroborane, diethylmethoxyborane, dimethylborane, At least one of common borohydride compounds such as catecholborane.

In some embodiments, the palladium reagent can be selected from 1,1-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex, palladium acetate, tetrakis(triphenylphosphine) At least one of common palladium reagents such as palladium, palladium dichloride, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium, and palladium trifluoroacetate.

In some embodiments, the second solvent may be at least one selected from tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide.

In some embodiments, the alkali can be selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; the concentration of the alkali solution can be 2-5mol/L, and the added volume can be 0.2% of the volume of solution II -0.5 times. Preferably, the alkaline solution can be a 3 mol/L sodium hydroxide solution, and the added volume is about 0.3 times that of the solution II.

In some embodiments, the preparation method of compound 3 comprises the following steps:

Dissolve potassium tert-butoxide in tetrahydrofuran, cool to -78°C~-60°C, then add (bromomethyl)triphenylphosphine bromide, mix and add dropwise 3-hydroxy-2-iodo-4- The tetrahydrofuran solution of methoxybenzaldehyde is reacted, and the reaction is continued for 0.5-1.5h after the dropwise addition is completed, and the reaction is quenched. After separation and purification, compound 3 is obtained; among them, potassium tert-butoxide and (bromomethyl)triphenyl The molar ratio of phosphine bromide is 1:1; the molar ratio of potassium tert-butoxide and 3-hydroxy-2-iodo-4-methoxybenzaldehyde is (3–5):1.

In some embodiments, the preparation method of compound 4 comprises the following steps:

Dissolve compound 2 and compound 3 in the third solvent, then add tributylphosphine and azo compound, or add triphenylphosphine and azo compound under the protection of nitrogen at 0°C for 0.5–1.5h, and the reaction is over Afterwards, the reaction mixture was warmed up to room temperature within 1 h, and compound 4 was obtained after purification.

Add tributylphosphine and azo compound or triphenylphosphine and azo compound in the third solvent under nitrogen protection at -20°C, and then add compound 2 and compound 3 at 0°C under nitrogen protection The reaction was carried out for 0.5-1.5 hours. After the reaction was completed, the reaction mixture was warmed up to normal temperature within 1 hour, and compound 4 was obtained after purification.

In some embodiments, the molar ratio of compound 2 and compound 3 can be 1:1-1.5:1; in terms of the amount of substance, the amount of tributylphosphine or triphenylphosphine added can be 1.5-2.5 of that of compound 2 times, the amount of azo compound added can be 1.5–2.5 times that of compound 2, and the material ratio of tributylphosphine or triphenylphosphine to azo compound is 1:1.

In some embodiments, the third solvent may be selected from tetrahydrofuran, toluene, or a mixture obtained by mixing tetrahydrofuran and toluene at a volume ratio of 1:1.

In some embodiments, the azo compound may be selected from at least one of ethyl azodicarboxylate, diisopropyl azodicarboxylate, and tetramethylazodicarbonamide.

According to a third aspect of the present invention, intermediate II (i.e. compound 5) for the preparation of codeine and its derivatives having a structure as shown in formula (II) is provided:

According to the fourth aspect of this aspect, a method for preparing intermediate II represented by formula (II) is provided, comprising the following steps: Compound 4 synthesizes intermediate II through Heck reaction.

In some embodiments, the step of compound 4 synthesizing the intermediate shown in formula (II) by Heck reaction comprises:

Add compound 4 into the fourth solvent, mix and add silver carbonate and palladium reagent, or add silver phosphate and palladium reagent to obtain a suspension;

The suspension was stirred and refluxed for 6-8h under nitrogen atmosphere, and the intermediate shown in formula (II) was obtained after purification;

Wherein, the molar ratio of compound 4, silver carbonate or silver phosphate, and palladium reagent is 1: (5-7): ( 0.15-0.25 );

In some embodiments, the fourth solvent may be selected from at least one of toluene, dimethylformamide, and dimethyl sulfoxide.

In some embodiments, the palladium reagent can be selected from 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex, palladium acetate, tetrakis(triphenylphosphine) ) palladium, palladium dichloride, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate.

According to a fifth aspect of the present invention, there is provided a method for preparing intermediate III (i.e. compound 6) with a structural formula such as formula (III), comprising the following steps:

Using 9-m-dimethyl-10-methylacridinium tetrafluoroborate as a catalyst, compound 5 was synthesized into compound 6 through a one-step photocatalytic redox reaction.

In some embodiments, the preparation method of compound 6 comprises the following steps:

Compound 5 was dissolved in 1,2-dichloroethane or acetonitrile, and then 9-m-dimethyl-10-methylacridinium tetrafluoroborate and thiophenol were added under nitrogen protection to obtain a mixture, The mixture was reacted at room temperature under blue light irradiation for 60-84h, and compound 6 was obtained after purification; wherein, the molar ratio of compound 5 and thiophenol was 1: (1.5–2.5); by mass percentage, 9-m-dimethyl -10-methylacridinium tetrafluoroborate is added in an amount of 4-6% of the mixture.

According to a sixth aspect of the present invention, there is provided a method for preparing intermediate IV (i.e. compound 7) with a structural formula such as formula (IV), comprising the following steps:

Compound 6 was synthesized into compound 7 by one-step tandem oxidation oxidation.

In some embodiments, the preparation method of compound 7 comprises the following steps:

Mix compound 6, dioxyiodobenzene, 1,2-bis(pyridin-2-yl)xylene and quartz sand, add solvent benzene under nitrogen protection, heat reaction at 75-85°C for 2-5h , after purification Obtain compound 7; Wherein, the mol ratio of compound 6 and dioxyiodobenzene is 1:(2-5), the mol ratio of

compound

6 and 1,2-bis(pyridin-2-yl)xylene is (8-12 ):1.

According to the seventh aspect of the present invention, there is provided a method for preparing codeine, comprising the following steps: compound 7 is reduced by LiAlH ₄ to obtain codeine.

In some embodiments, the preparation method of codeine comprises the following steps;

Compound 7 was dissolved in ethylene glycol dimethyl ether or tetrahydrofuran, and then added to the solution of ethylene glycol dimethyl ether or tetrahydrofuran dissolved in lithium aluminum hydride at 0°C under the protection of nitrogen to obtain a reaction solution. The reaction solution was prepared at 0.25 Rise to normal temperature within h, then react at 60-70°C for 2-5h, cool to room temperature after the reaction, and obtain codeine after separation and purification; wherein, the molar ratio of compound 7 to lithium aluminum hydride is 1 : (8–12).

According to the eighth aspect of the present invention, there is provided a method for preparing deoxycodeine, comprising the following steps: compound 6 is reduced by LiAlH ₄ to obtain deoxycodeine.

In some embodiments, the method for preparing deoxycodeine from compound 6 through LiAlH ₄ reduction comprises the steps of: dissolving compound 6 in at least one solvent selected from tetrahydrofuran, ethylene glycol dimethyl ether and acetonitrile, and then At room temperature and under the condition of nitrogen protection, add tetrahydrofuran or ethylene glycol dimethyl ether solution dissolved with lithium aluminum hydride, heat and reflux at 60-70°C for 2-5h, cool to room temperature after the reaction, after separation and purification, That is to obtain deoxycodeine; wherein, the molar ratio of compound 6 to lithium aluminum hydride is 1: (8–12).

According to a ninth aspect of the present invention, a method for preparing norcodeine is provided, comprising the steps of:

Under the protection of nitrogen, sequentially add compound 7, cerium trichloride heptahydrate and sodium borohydride to the fifth solvent, react for 0.5-1h, add water to quench the reaction, extract the reaction solution with dichloromethane or ethyl acetate, and then dry Combine the organic phases, concentrate, add dichloromethane and trifluoroacetic acid, or add ethyl acetate and trifluoroacetic acid to the concentrated solution, and react at room temperature for 2-4 hours. because;

Wherein, the molar ratio of compound 7, cerium trichloride heptahydrate and sodium borohydride is 1:1:1; the molar ratio of compound 7 and trifluoroacetic acid is 1:(10-15);

In some embodiments, the fifth solvent may be selected from at least one of methanol, ethanol, and ethyl acetate.

According to the tenth aspect of the present invention, there is provided a method for preparing intermediate V (i.e. compound 10) with a structural formula such as formula (V), comprising the following steps:

Under the protection of nitrogen, add compound 5, the first part of selenium dioxide and quartz sand to 1,4-dioxane, heat the reaction at 75°C for 1–1.5h, then add the second part of selenium dioxide, continue React at 75°C for 1-1.5h. After the reaction, compound 10 is obtained after separation and purification; wherein, the molar ratio of compound 5, the first part of selenium dioxide, and the second part of selenium dioxide is 1:1: 1–1:1.5:1.5.

According to an eleventh aspect of the present invention, there is provided a method for preparing intermediate VI (i.e. compound 11) with a structural formula such as formula (VI), comprising the following steps:

Mix compound 6, the first part of selenium dioxide and quartz sand, add 1,4-dioxane under nitrogen protection, react at 75°C for 1–1.5h, and then add the second part of selenium dioxide, Continue to react at 75°C for 1–1.5h. After the reaction is completed, compound 11 is obtained by separation and purification; wherein, the molar ratio of compound 6, the first part of selenium dioxide, and the second part of selenium dioxide is 1:1 :1–1:1.5:1.5.

According to the twelfth aspect of the present invention, another preparation method of Compound 11 is provided, comprising the following steps:

Under nitrogen protection, dissolve compound 10 in 1,2-dichloroethane or acetonitrile, then add 9-m-dimethyl-10-methylacridinium tetrafluoroborate and thiophenol, after sealing Under blue light irradiation, react at room temperature for 84-100h. After the reaction, purify to obtain compound 11; wherein, compound 10, 9-m-dimethyl-10-methylacridinium tetrafluoroborate and thiophenol The molar ratio is 15:1:3–20:1:5.

According to a thirteenth aspect of the present invention, a codeine derivative is provided, the structural formula of which is shown in formula (VII):

According to the fourteenth aspect of the present invention, there is provided a method for preparing codeine derivatives represented by formula (VII), comprising the following steps: dissolving compound 11 in ethylene glycol at 0°C under nitrogen protection conditions Dimethyl ether, and then dropwise added to the ethylene glycol dimethyl ether solution in which lithium aluminum hydride is dissolved. After the dropwise addition, heat the reaction at 65°C for 6.5-7h. After the reaction, separate and purify to obtain the formula ( The compound shown in VII); wherein, the molar ratio of compound 11 to lithium aluminum hydride is 1:2-1:4.

According to a fifteenth aspect of the present invention, a codeine derivative is provided, the structural formula of which is shown in formula (VIII):

According to a sixteenth aspect of the present invention, there is provided a method for preparing codeine derivatives shown in formula (VIII), comprising the steps of:

Under the protection of nitrogen, dissolve codeine, 4-dimethylaminopyridine and N,N-diisopropylethylamine in dichloromethane, add 4-bromobenzoyl chloride at 0°C, and complete the addition Then warm up to room temperature and react for 2-3h. After the reaction, separate and purify to obtain the compound shown in formula (VIII); wherein, codeine, 4-dimethylaminopyridine and N,N-diisopropylethyl The molar ratio of base amine is 40:1:72–10:1:28; the molar ratio of codeine and 4-bromobenzoyl chloride is 1:2.5.

The compounds represented by the formula (VII) and the formula (VIII) are all codeine derivatives, and have anesthetic, analgesic and antitussive effects.

Description of drawings

Fig. 1 is a synthetic route diagram of codeine derivatives and intermediates thereof of the present invention.

Detailed ways

The present invention will be described in further detail below in conjunction with the embodiments. The examples are for illustration only and do not limit the invention in any way. Unless otherwise specified, the raw materials and reagents used in the examples are commercially available conventional products; the experimental methods not indicating specific conditions in the examples are conventional methods and conventional conditions well known in the art.

Embodiment 1: the synthesis of compound 2

Add tert-butyl vinyl carbamate (1917 mg, 13.39 mmol) to the first round bottom flask, dissolve it in 20 mL of degassed dry tetrahydrofuran, and add 9-borabicyclo[3.3 .1] Nonane dimer [recrystallized from hot solution of 1,2-dimethoxyethane] (1635 mg, 13.39 mmol). After reacting for 0.5h, the solution became clear and transparent.

In a second round bottom flask, compound 1 (2000 mg, 8.93 mmol), 1,1-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (367 mg, 0.45mmol), triphenylarsenic (273mg, 0.89mmol) was dissolved in 40mL of degassed dry tetrahydrofuran, and then degassed sodium hydroxide solution (3mol/L, 12mL) was added to the mixture.

Add the solution in the first round bottom flask to the second round bottom flask at room temperature, and then stir for 0.5 h under nitrogen protection. When thin-layer chromatography detects that compound 1 has been consumed, the light orange reaction mixture is diluted with ethyl acetate (20 mL), then added to saturated saline (60 mL), followed by aqueous hydrogen peroxide (9.8 mol/L , 1.2 mL). The aqueous solution was extracted three times with ethyl acetate (3×60 mL), the organic phases obtained after the extraction were combined, dried (anhydrous sodium sulfate) and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (gradient elution, ethyl acetate: Petroleum ether=1:5-1:3), 1980 mg of colorless oily compound 2 was obtained (R _f =0.25, petroleum ether:ethyl acetate=1:3), and the yield was 92%.

[α] _D = +41(c 1.0, CH ₂ Cl ₂ );

¹ H NMR (500MHz, CDCl ₃ ) δ5.55 (dd, J = 4.2, 3.1 Hz, 1H), 4.05 (dd, J = 5.2, 3.9 Hz, 1H), 3.49–3.39 (m, 1H), 3.10 ( ddd,J＝13.7,12.5,6.1Hz,1H),2.84–2.45(broad s,1H),2.30–2.23(m,1H),2.22–2.16(m,1H),2.03–1.97(m,1H) ,1.97–1.88(m,1H),1.75–1.70(m,2H),1.68–1.58(m,1H),1.57–1.48(m,1H),1.41(s,9H)signal due to Boc-NH group proton not observed;

¹³ C NMR (126MHz, CDCl ₃ ) δ156.6, 136.0, 127.9, 79.3, 67.5, 39.7, 36.6, 32.6, 28.4, 25.7, 17.9;

IR(KBr)v _max 3340, 2975, 2931, 1685, 1520, 1278, 1250, 1168, 1050, 985cm ^-1 ;

HRMS(ESI,+ve)[M+Na] ⁺ calculated for C ₁₃ H ₂₃ NO ₃ Na 264.1570,found 264.1569.

Embodiment 2: the synthesis of compound 3-(Z)

To 60 mL of dry tetrahydrofuran suspension dissolved in potassium tert-butoxide (3.23 g, 28.77 mmol) cooled to 78°C, (bromomethyl)triphenyl bromide recrystallized from hot isopropanol was added in one go Phosphine (12.55 g, 28.77 mmol). After 0.5h of stirring, the suspension was light yellow. A solution of 3-hydroxy-2-iodo-4-methoxybenzaldehyde (2.0 g, 7.19 mmol) dissolved in dry 20 mL tetrahydrofuran was then added dropwise through the dropping funnel for 1 h. Continue to stir for 1 h after the dropwise addition, add 100 mL of saturated ammonium chloride solution to quench the reaction, dilute the reaction solution with 20 mL of ethyl acetate, and then slowly warm up to normal temperature. It was extracted three times with 300 mL of ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid compound was dissolved in a small amount of hot toluene solution, purified by silica gel column chromatography (gradient elution, ethyl acetate:petroleum ether=1:10–1:1), and 2.26g of cis/trans configuration compound was obtained as a white solid ( The cis/trans configuration ratio=4:1), and the total yield was 88%. The separation of cis/trans configuration compounds was further purified by column chromatography by the above-mentioned gradient elution method.

Compound 3-(Z):

M.P.105–106°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.30(d, J=8.4Hz, 1H), 7.08(d, J=7.8Hz, 1H), 6.87(d, J=8.4Hz, 1H), 6.49(d ,J＝7.8Hz,1H),6.20(s,1H),3.93(s,3H);

¹³ C NMR (126MHz, CDCl ₃ ) δ145.7, 145.4, 136.1, 131.6, 121.6, 109.8, 108.2, 87.0, 56.3;

IR(KBr)v _max 3489,2922,2849,1584,1479,1438,1274,1236,1028,818cm ^-1 ;

HRMS(ESI,-ve)[M] ^─ calculated for C ₉ H ₇ BrIO ₂ 352.8680,found 352.8666.

Compound 3-(E):

M.P.137–138°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.30(d, J=13.7Hz, 1H), 6.93(d, J=8.4Hz, 1H), 6.80(d, J=8.4Hz, 1H), 6.56(d ,J＝13.7Hz,1H),6.21(s,1H),3.91(s,3H);

¹³ C NMR (126MHz, CDCl ₃ ) δ145.7, 145.6, 140.5, 133.1, 118.3, 110.5, 107.4, 86.3, 56.4;

IR(KBr)v _max 3470, 2921, 2843, 1594, 1478, 1438, 1271, 1239, 1021, ^776cm-1 ;

HRMS(ESI,-ve)[M] ^─ calculated for C ₉ H ₇ BrIO ₂ 352.8680,found 352.8663.

Dissolve compound 3-(E) (35 mg, 1.0 mmol), tris[2-phenylpyridine] iridium [Ⅲ] (1 mg, 0.001 mmol) in 2 mL of degassed methanol in a glove box, seal the reaction tube, and Take it out of the glove box. React for 12h under the irradiation of Kessil blue LED lamp (456nm, 40W). After the reaction was completed, it was concentrated under reduced pressure and purified by column chromatography to obtain 25 mg of white crystalline solid compound 3-(Z), with a yield of 70%.

Embodiment 3: the synthesis of compound 4

Tributylphosphine (3.68mL, 14.92mmol), ethyl azodicarboxylate (2.34mL, 14.92mmol) were sequentially added to dissolved compound 2 (1.8 g, 7.45mmol) and compound 3 at 0°C under a nitrogen atmosphere. - (Z) (1.8 g, 7.45 mmol) in a degassed tetrahydrofuran/toluene mixture (v/v=1:1; 36 mL). Then the reaction mixture was warmed to normal temperature within 1 h, and concentrated under reduced pressure to obtain a thick compound which was further purified by silica gel column chromatography (eluent, ethyl acetate:petroleum ether=1:10) to obtain 3.67 g of foamy compound 10 ( R _f =0.34, ethyl acetate:petroleum ether=1:5) yield 84%.

[α] _D ＝-85(c 1.0, CH ₂ Cl ₂ ).

¹ H NMR (500MHz, CDCl ₃ ) δ7.41(d, J=8.5Hz, 1H), 7.09(d, J=7.8Hz, 1H), 6.91(d, J=8.5Hz, 1H), 6.45(d ,J=7.8Hz,1H),5.76(dd,J=4.5,2.9Hz,1H),5.00(dd,J=5.5,3.3Hz,1H),4.71(s,1H),3.87(s,3H) ,3.38–3.30(m,2H),2.65–2.56(m,1H),2.33–2.24(m,1H),2.22–2.13(m,1H),2.09–1.97(m,2H),1.95–1.86( m,1H),1.57–1.49(m,2H),1.42(s,9H);

¹³ C NMR (126MHz, CDCl ₃ ) δ156.1, 151.5, 146.7, 136.9, 134.4, 132.1, 129.5, 124.9, 111.6, 107.8, 99.7, 78.8, 76.4, 55.7, 39.4, 34.6, 28.4, 28.2, 25. 5,18.7;

IR(KBr)v _max 3359, 2925, 2851, 1701, 1469, 1247, 1168, 1050, 1026, 818cm ^-1 ;

HRMS(ESI,+ve)[M+Na] ⁺ calculated for C ₂₂ H ₂₉ BrINO ₄ Na 600.0217,found 600.0209.

In other embodiments, tributylphosphine and ethyl azodicarboxylate can also be added to a degassed tetrahydrofuran/toluene mixture (v/v=1:1; 36 mL) at -20°C under nitrogen protection, Then add compound 2 and compound 3-(Z) at 0°C under the protection of nitrogen for 0.5–1.5 hours of reaction. After the reaction, the reaction mixture was warmed up to room temperature within 1 hour, concentrated under reduced pressure to obtain a thick compound, and then passed through a silica gel column. Purified by column chromatography to obtain compound 4.

Embodiment 4: the synthesis of compound 5

Add silver carbonate (10.66g, 38.65mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.05g, 1.29mmol) into 100mL to dissolve Compound 4 (3.73g, 6.44mmol) in a mixed solution of toluene. The gas atmosphere inside the reaction vessel is circulated with a nitrogen balloon and a vacuum pump through a three-way valve, and the cycle is repeated three times, and the nitrogen atmosphere is ensured. The suspension was refluxed under nitrogen atmosphere with vigorous stirring for 6 h [Note: On larger scales, the rate of this reaction is highly sensitive to the efficiency of reactant mixing. For example, if a sufficiently large stir bar is not used and the solid residue is allowed to settle on the rim of the flask, the reaction will not be complete within 6 h]. After the reaction was completed, the cooled reaction mixture was concentrated under reduced pressure and subjected to silica gel column chromatography (eluent, ethyl acetate/petroleum ether=1:5 solvent) to obtain 1.55 g of compound 12 (R _f =0.33, ethyl acetate:petroleum ether Ether 1:5), yield 65%.

¹ H NMR (500MHz, CDCl ₃ ) δ6.66(d, J=8.0Hz, 1H), 6.61(d, J=8.0Hz, 1H), 6.40(d, J=9.4Hz, 1H), 5.85(dd ,J=9.4,5.8Hz,1H),5.63(ddd,J=11.0,7.1,3.8Hz,1H),5.44(dd,J=10.1,2.5Hz,1H),4.97(dd,J=7.8,5.0 Hz, 1H), 4.47(broad s, 1H), 3.86(s, 3H), 3.12(dd, J=13.7, 6.8Hz, 1H), 3.06–2.99(m, 2H), 2.51(dddd, J=17.6 ,7.3,4.6,2.2Hz,1H),2.11(d,J=17.6Hz,1H),1.88(app.t,J=7.6Hz,2H),1.40(s,9H).;

¹³ C NMR (126MHz, CDCl ₃ ) δ155.9, 145.2, 144.7, 128.6, 128.4, 125.8, 124.0, 123.9, 123.5, 117.7, 112.3, 88.0, 79.0, 56.2, 43.1, 39.1, 39.0, 36.7, 28 .7, 28.4;

IR(KBr)v _max 3392,3028,2926,2852,1701,1505,1452,1279,1165,806cm ^-1 ;

HRMS(ESI,+ve)[M+Na] ⁺ calculated for C ₂₂ H ₂₇ NO ₄ Na 392.1832,found 392.1835.

Embodiment 5: the synthesis of compound 6

9-m-Dimethyl-10-methylacridinium tetrafluoroborate (70 mg), freshly prepared thiophenol (78 mg, 0.71 mmol) were sequentially added to a dry degassed solution under nitrogen atmosphere. Compound 5 (1300 mg, 0.39 mmol) was dissolved in 7 mL of 1,2-dichloroethane, then stirred at room temperature under a blue light (456 nm, 10 watts) for 72 h. After the reaction was completed, it was purified by silica gel column (eluent, ethyl acetate:petroleum ether=1:10) to obtain 733 mg of compound 6 (R _f =0.45, ethyl acetate:petroleum ether=1:3) as a white foam. rate 56%.

When the same reaction was carried out using 30 mg of compound 5, the reaction was reacted for 10 h under the irradiation of two 40-watt lamps to obtain 37 mg of the product, and the yield was 82%.

[α] _D = –112 (c 1.0, CH ₂ Cl ₂ )

¹ H NMR (500MHz, CDCl ₃ ) δ6.68(d, J=8.2Hz, 1H), 6.54(d, J=8.2Hz, 1H), 5.81–5.70(m, 1H), 5.36(d, J= 9.9Hz, 1H), 4.89–4.83(m, 1.6H), 4.67(s, 0.4H), 4.04(d, J＝13.8Hz, 0.4H), 3.91(dd, J＝13.8, 5.1Hz, 0.6H ),3.85(s,3H),2.99–2.88(m,0.7H),2.88–2.77(m,1.3H),2.70(s,0.6H),2.66(s,0.4H),2.60(s,1H ),2.44–2.31(m,2H),1.93–1.76(m,2H),1.50(s,3.5H),1.48(s,5.5H);

¹³ C NMR (126MHz, CDCl ₃ ) δ154.9, 154.6, 146.4, 146.3, 142.5, 130.0, 128.9, 128.6, 126.5, 126.3, 126.0, 119.0, 118.9, 112.9, 112.9, 89.0, 79.8, 79. 7, 56.3, 51.3, 50.1 ,43.4,39.5,39.4,38.5,37.5,35.3,34.9,30.6,29.3,29.1,28.5,28.4;

IR(KBr)v _max 2926,1686,1503,1441,1412,1253,1167,1130,1027,952cm ^-1 ;

HRMS(ESI,+ve)[M+Na] ⁺ calculated for C ₂₂ H ₂₇ NO ₄ Na 392.1832,found 392.1826.

Embodiment 6: the synthesis of compound 7

Add compound 6 (100 mg, 0.27 mmol), freshly prepared dioxyiodobenzene (192 mg, 0.81 mmol), freshly prepared 1,2-di(pyridin-2-yl)xylene (8 mg, 0.03 mmol) and dried quartz sand (250mg). The gas atmosphere inside the reaction vessel was circulated through a three-way valve with a nitrogen balloon and a vacuum pump for three times, and the nitrogen atmosphere was ensured, and then 4 mL of dry benzene was added. The subsequent suspension was heated at reflux for 3 h with vigorous stirring. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and the obtained light brown mixture was further purified by silica gel column (eluent, ethyl acetate:petroleum ether 1:3-1:1 gradient elution) to obtain 55 mg of white foamy compound 7 ( R _f =0.15, ethyl acetate:petroleum ether 1:3), yield 52%.

[α] _D ＝ - 200(c 0.5, CH ₂ Cl ₂ ).

¹ H NMR (500MHz, CDCl ₃ ) δ6.70(d, J=8.2Hz, 1H), 6.66–6.59(m, 2H), 6.12(d, J=10.3Hz, 1H), 5.00(s, 0.7H ),4.79(s,0.3H),4.69(s,1H),4.06(d,J=13.4Hz,0.3H),3.94(dd,J=13.4,5.1Hz,0.7H),3.85(s,3H ),3.09–3.01(m,1H),2.91–2.74(m,3H),1.98–1.85(m,2H),1.51(s,3H),1.48(s,6H);

¹³ C NMR (126MHz, CDCl ₃ ) δ194.1, 154.8, 154.4, 147.4, 147.1, 145.0, 142.8, 133.2, 133.1, 128.0, 124.9, 124.7, 120.5, 115.1, 87.8, 80.3, 56.8, 51.1 ,49.8,43.5,40.3 ,38.4,37.5,33.7,33.3,29.4,29.1,28.4;

IR(KBr)v _max 3360, 2919, 2850, 1677, 1502, 1409, 1273, 1165, 944, ^801cm-1 ;

HRMS(ESI,+ve)[M+Na] ⁺ calculated for C ₂₂ H ₂₅ NO ₅ Na 406.1625,found 406.1622.

Embodiment 7: the synthesis of compound 8 (codeine)

Add 1 mL of dry ethylene glycol dimethyl ether dissolved in compound 7 (40 mg, 0.10 mmol) to 2 mL of dry ethylene glycol dimethyl dissolved in lithium aluminum hydride (38 mg, 1 mmol) at 0 ° C under a nitrogen atmosphere. in ether solution. Then the reaction solution was raised to normal temperature within 0.25h, and then reacted at 65°C for 3h. Cool to normal temperature after the reaction, and then add 10 drops of water, 10 drops of 3mol/L sodium hydroxide solution and 20 drops of water, and dilute with 10 mL of ethyl acetate. Filter and wash the white solid in the reaction flask with 10 mL of ethyl acetate. Extracted three times with ethyl acetate, 10 mL each time, combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a silica gel column (eluent, saturated ammonia methanol solution: dichloromethane = 1:19, to obtain 25 mg of white Solid compound 8, yield 84%.

M.P.145-146℃.

[α] _D = - 139(c 0.7, EtOH).

¹ H NMR (500MHz, CDCl ₃ ) δ6.66 (d, J=8.1Hz, 1H), 6.56 (d, J=8.1Hz, 1H), 5.70 (ddd, J=9.9, 3.0, 1.2Hz, 1H) ,5.29(ddd,J=8.1,5.4,2.7Hz,1H),4.89(dd,J=6.5,1.3Hz,1H),4.17(ddd,J=8.1,5.1,2.8Hz,1H),3.84(s ,3H),3.35(dd,J＝6.3,3.3Hz,1H),3.04(d,J＝18.6Hz,1H),2.84(broad s,1H),2.70–2.64(m,1H),2.58(dd ,J=12.4,4.1Hz,1H),2.43(s,3H),2.39(td,J=12.3,3.6Hz,1H),2.29(dd,J=18.6,6.3Hz,1H),2.06(td, J=12.5,5.1Hz,1H),1.87(ddd,J=12.7,3.7,1.8Hz,1H).;

¹³ C NMR (126MHz, CDCl ₃ ) δ146.3, 142.2, 133.4, 131.0, 128.2, 127.2, 119.5, 112.8, 91.3, 66.4, 58.9, 56.3, 46.4, 43.1, 42.9, 40.8, 35.8, 20.4;

IR(KBr)v _max 3375, 2919, 2848, 1502, 1449, 1276, 1120, 1052, 786, 728cm-1;

HRMS(ESI,+ve)[M+H] ⁺ calculated for C ₁₈ H ₂₂ NO ₃ 300.1594,found 300.1582.

Embodiment 8: the synthesis of compound 9 (deoxycodeine)

Under the condition of room temperature and nitrogen protection, lithium aluminum hydride tetrahydrofuran solution (1mol/L, 1.35mL) was added into 2mL of dry tetrahydrofuran dissolved with compound 6 (50mg, 0.14mmol), and then the reaction mixture was heated to reflux for 3 h . After completion of the reaction, cool to room temperature, then add 10 drops of water, then add 10 drops of 3mol/L sodium hydroxide aqueous solution, and finally add 20 drops of water. The mixture was diluted with 10 mL of ethyl acetate and filtered. Wash the white solid in the reaction bottle with ethyl acetate, wash three times, 10 mL each time. The washings were combined, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent, saturated ammonia methanol solution: dichloromethane = 1:19) to obtain 34 mg of white solid compound 9 (R _f =0.33, saturated ammonia Gas methanol solution: dichloromethane = 1:19), the yield was 85%.

M.P.75–77°C.

[α] _D ＝-72(c 1.0, CH ₂ Cl ₂ ).

¹ H NMR (500MHz, CDCl ₃ ) δ6.65 (d, J=8.2Hz, 1H), 6.54 (d, J=8.1Hz, 1H), 5.71 (ddd, J=12.4, 6.9, 3.4Hz, 1H) ,5.36(dd,J=9.9,2.0Hz,1H),4.88(dd,J=5.2,2.9Hz,1H),3.84(s,3H),3.31(dd,J=5.9,3.3Hz,1H), 3.02(d,J=18.4Hz,1H),2.77–2.73(m,1H),2.58(dd,J=12.1,3.3Hz,1H),2.44(s,3H),2.40–2.35(m,3H) ,2.30(dd,J=18.4,6.0Hz,1H),2.02(td,J=12.4,5.0Hz,1H),1.81(ddd,J=12.6,3.6,1.8Hz,1H);

¹³ C NMR (126MHz, CDCl ₃ ) δ146.4, 142.2, 130.9, 127.9, 127.8, 127.3, 118.4, 112.5, 89.4, 59.3, 56.3, 47.1, 43.2, 43.1, 40.6, 35.6, 30.7, 20.2;

IR(KBr)v _max 3358, 2923, 2850, 1634, 1604, 1503, 1441, 1277, 1151, 1034cm ^-1 ;

HRMS(ESI,+ve)[M+H] ⁺ calculated for C ₁₈ H ₂₂ NO ₂ 284.1645, found 284.1639.

Embodiment 9: the synthesis of compound 10

Under nitrogen, compound 5 (250mg, 0.68mmol), finely ground selenium dioxide (75mg, 0.68mmol), oven-dried quartz sand (500mg) were sequentially added to 5mL of dry 1,4-dioxygen Hexacyclic solution. Then the reaction mixture was heated at 75°C for one hour, and finely ground selenium dioxide (75mg, 0.68mmol) was added. The yellow suspension was heated at 75°C for one hour, then cooled to room temperature, diluted with 20 mL of ethyl acetate, and the aqueous phase was washed with aqueous sodium hydroxide (1.5 mol/L, 20 mL). Extract the aqueous phase with ethyl acetate, wash three times, each 20mL, then dry the combined ethyl acetate phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent, ethyl acetate:petroleum ether= 1:3-1:1 gradient elution), to obtain 152 mg of compound 10 in the form of yellow foam, with a yield of 58%.

[α] _D ＝+41(c＝0.7, CH ₂ Cl ₂ ).

¹ H NMR (500MHz, CDCl ₃ ) δ6.67(d, J=7.9Hz, 1H), 6.63(d, J=8.0Hz, 1H), 6.41(d, J=9.5Hz, 1H), 5.82(dd ,J=9.6,5.6Hz,1H),5.70(d,J=10.4Hz,1H),5.59(d,J=10.3Hz,1H),4.71(d,J=4.7Hz,1H),4.51(s ,1H),4.10(s,1H),3.92–3.83(m,4H),3.17(s,2H),3.03–2.95(m,1H),1.94(ddd,J＝14.6,9.4,6.3Hz,1H ),1.84(ddd,J=14.1,9.1,6.0Hz,1H),1.40(s,9H);

¹³ C NMR (126MHz, CDCl ₃ ) δ155.9, 145.4, 144.2, 128.8, 128.2, 127.7, 127.4, 123.8, 123.4, 118.1, 112.6, 95.6, 79.2, 68.7, 56.2, 43.1, 39.6, 39.5, 36 .5, 28.4;

IR(KBr)v _max 3366, 2924, 2851, 1687, 1506, 1453, 1278, 1167, 1054, 808cm ^-1 ;

HRMS(ESI,+ve)[M+Na] ⁺ calculated for C ₂₂ H ₂₇ NO ₅ Na 408.1781,found 408.1783.

Embodiment 10: the synthesis of compound 11

In the glove box, 0.7 mL of dry degassed 1,2-dichloroethane was sequentially added to compound 10 (116 mg, 0.30 mmol), followed by 9-m-dimethyl-10-methylacridinium tetra Fluoborate (6 mg, 0.02 mmol), freshly prepared thiophenol (7 mg, 0.06 mmol), and the vial was sealed. Place the reaction bottle under a Kessil blue LED lamp (456 nm, 10 watts) and stir at room temperature for 84 hours. After the reaction is complete, purify by silica gel column chromatography (eluent, 1:2.5–1:1.5 gradient elution) to obtain 81 mg of white foam Compound 11 was obtained with a yield of 71%.

[α] _D ＝–181(c＝0.2, CH ₂ Cl ₂ ).

¹ H NMR (500MHz, CDCl ₃ ) δ6.69(d, J=8.2Hz, 1H), 6.55(d, J=8.2Hz, 1H), 6.05–5.97(m, 1H), 5.63(d, J= 8.6Hz,1H),5.04–4.81(m,0.6H),4.78(s,0.4H),4.76(s,0.6H),4.73–4.67(m,0.2H),4.29–4.19(m,1H) ,4.09–3.98(m,0.4H),3.98–3.87(m,0.6H),3.84(s,2H),3.83(s,1H),2.98–2.73(m,3H),2.73–2.64(m, 1H), 2.00–1.79(m, 3H), 1.47(s, 9H).;

¹³ C NMR (126MHz, CDCl ₃ ) δ154.7, 145.7, 142.3, 132.1, 131.6, 129.5, 126.0, 119.2, 113.3, 94.1, 79.9, 67.8, 56.3, 49.6, 44.3, 39.0, 38.3, 35.5, 29.1 ,28.4;

IR(KBr)v _max 3419,2924,2853,1686,1664,1414,1273,1165,1028,947cm ^-1 ;

HRMS(ESI,+ve)[M+Na] ⁺ calculated for C ₂₂ H ₂₇ NO ₅ Na 408.1781,found 408.1772

The second method for synthesizing compound 11:

Under nitrogen, 5 mL of dry 1,4 - dioxane solution. The reaction mixture was reacted at 75° C. for 1 h, and then finely ground selenium dioxide (15 mg, 0.13 mmol) was added to the reaction liquid, and the obtained yellow suspension was further reacted at this temperature for 1 h, then stopped heating and cooled to room temperature. Add 20 mL of ethyl acetate to dilute the reaction solution, and then wash the mixture with 1.5 mol/L aqueous sodium hydroxide solution. The reaction mixture was extracted with ethyl acetate, 15 mL each time, and washed three times. The reaction solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 36 mg of compound 11 in the form of foam, with a yield of 73%.

Embodiment 11: the synthesis of compound 12

Under nitrogen protection conditions and zero temperature conditions, compound 11 (70mg, 0.18mmol) was dissolved in dry 2mL ethylene glycol dimethyl ether, and slowly added dropwise to dry 2mL dissolved lithium aluminum hydride (14mg, 0.36mmol) in a solution of ethylene glycol dimethyl ether. After the dropwise addition, the reaction was heated at 65°C for 6.5h. After the reaction was completed, the mixed solution was cooled to room temperature, and 15 drops of water, 15 drops of 3M sodium hydroxide solution, and then 20 drops of water were added to the reaction mixture in turn. Dilute with 10 mL of ethyl acetate, then filter the mixture, and wash the reaction bottle with 10 mL of ethyl acetate three times. The obtained organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (eluent, saturated ammonia methanol solution:dichloromethane=1:19) to obtain 25 mg of compound 12 with a yield of 46%.

[α] _D ＝ - 50(c 0.5, CH ₂ Cl ₂ ).

¹ H NMR (500MHz, CDCl ₃ ) δ6.66(d, J=8.2Hz, 1H), 6.55(d, J=8.3Hz, 1H), 6.07(s, broad, 1H), 5.61(app.d, J=9.9Hz,1H),5.51(app.d,J=9.9Hz,1H),4.19(ddd,J=10.8,3.7,1.8Hz,1H),3.84(s,3H),3.61(ddd,J =12.2,5.6,1.3Hz,1H),3.09–3.03(m,1H),2.91(d,J=18.0Hz,1H),2.68(dd,J=17.9,5.0Hz,1H),2.65–2.62( m,1H),2.55(ddd,J=11.9,4.4,1.9Hz,1H),2.40(s,3H),2.07(app.td,J=12.0,4.1Hz,1H),1.89–1.82(m, 1H), 1.83–1.77(m, 1H), 1.48(dd, J=12.0, 10.5Hz, 1H);

¹³ C NMR (126MHz, CDCl ₃ ) δ144.4, 144.3, 132.4, 131.2, 129.9, 124.5, 118.2, 108.5, 67.0, 56.7, 56.1, 47.8, 46.3, 42.6, 42.5, 38.0, 36.2, 24.2;

IR(KBr)v _max 3356, 2920, 2851, 2361, 1633, 1484, 1277, 1053, 1021, ^796cm-1 ;

HRMS(ESI,+ve)[M+H] ⁺ calculated for C ₁₈ H ₂₄ NO ₃ 302.1751,found 302.1739.

Embodiment 12: the synthesis of compound 13 (Norcodeine, norcodeine)

Under nitrogen protection conditions, compound 7 (50mg, 0.13mmol), cerium trichloride heptahydrate (49mg, 0.13mmol), sodium borohydride (5mg, 0.13mmol) were added to a flask containing 2.5mL methanol successively, and the reaction was stirred. After 0.5 h, 10 mL of water was added to the reaction solution to quench the reaction. Then the reaction solution was extracted with 15 mL of dichloromethane three times. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then 2.5 mL of dichloromethane and trifluoroacetic acid (0.25 mL, 1.47 mmol) were added to the concentrated solution, and reacted at room temperature for two hours. After the reaction was completed, 10 mL of saturated sodium carbonate solution was added, and then the reaction solution was extracted with dichloromethane, 15 mL each time, for a total of three extractions. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent, saturated ammonia methanol solution: dichloromethane = 1:10) to obtain 37 mg of white solid compound 13 with a yield of 100% .

M.P.188–190°C.

[α] _D ＝ - 96(c 0.6, CH ₂ Cl ₂ ).

¹ H NMR (500MHz, CDCl ₃ ) δ6.67 (d, J=8.2Hz, 1H), 6.57 (d, J=8.2Hz, 1H), 5.71 (dd, J=9.9, 1.6Hz, 1H), 5.25 (dd,J=9.8,2.7Hz,1H),4.86(dd,J=6.5,1.3Hz,1H),4.17(ddd,J=6.2,4.9,2.8Hz,1H),3.84(s,3H), 3.66–3.60(m,1H),2.94(ddd,J＝13.1,10.9,4.9Hz,1H),2.89–2.82(m,2H),2.80(d,J＝18.4Hz,1H),2.61–2.55( m,1H),1.96–1.84(m,2H);

1 ¹³ C NMR (126MHz, CDCl ₃ ) δ146.4, 142.1, 133.6, 131.1, 128.1, 127.4, 119.5, 112.9, 92.0, 66.3, 56.3, 51.9, 43.8, 41.2, 38.5, 36.6, 31.3;

IR(KBr)v _max 3305,3029,2921,2849,1502,1450,1260,1058,784,731cm ^-1 ;

HRMS(ESI,+ve)[M+H] ⁺ calculated for C ₁₇ H ₂₀ NO ₃ 286.1438, found 286.1424.

Embodiment 13: the synthesis of compound 14

Under nitrogen atmosphere, compound 8, ie codeine (25mg, 0.08mmol), 4-dimethylaminopyridine (one crystal), N,N-diisopropylethylamine (28.43mg, 0.22mmol) Dissolve in 2 mL of dichloromethane and place at 0 °C. 4-Bromobenzoyl chloride (44mg, 0.2mmol) was added to the above reaction mixture at one time. After the addition, the reaction solution was warmed up to room temperature and stirred for 2h. After the reaction was completed, the reaction solution was diluted with 10 mL of dichloromethane, and then 10 mL of saturated sodium bicarbonate solution was added. The mixture was washed three times with dichloromethane, 10 mL each time, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under pressure, and purified by column chromatography (silica gel column, eluent=1:10 saturated ammonia methanol solution /dichloromethane) to obtain 16 mg of a white crystalline solid, namely the target compound 14 (R _f =0.3, 1:10 saturated ammonia methanol solution/dichloromethane), with a yield of 41%.

M.P.179–180°C.

[α] _D ＝ - 157(c 0.7, CH ₂ Cl ₂ ).

¹ H NMR (500MHz, CDCl ₃ ) δ7.95(d, J=8.5Hz, 2H), 7.58(d, J=8.5Hz, 2H), 6.69–6.63(m, 1H), 6.56(d, J= 8.2Hz, 1H), 5.75(dd, J=10.1, 2.8Hz, 1H), 5.51(dd, J=10.0, 2.6Hz, 1H), 5.42(dd, J=7.1, 2.6Hz, 1H), 5.18( d,J=6.8Hz,1H),3.72(s,3H),3.39(dd,J=6.0,3.3Hz,1H),3.06(d,J=18.5Hz,1H),2.83–2.78(m,1H ),2.60(dd,J=12.0,4.5Hz,1H),2.45(s,3H),2.39(app.td,J=12.2,3.6Hz,1H),2.33(dd,J=18.5,6.1Hz, 1H), 2.08(app.td, J=12.4, 5.0Hz, 1H), 1.89(d, J=12.7Hz, 1H);

¹³ C NMR (126MHz, CDCl ₃ ) δ165.3, 146.7, 142.1, 131.6, 131.5, 130.7, 129.8, 128.9, 128.3, 128.1, 127.0, 119.3, 114.3, 87.9, 68.7, 59.1, 56.7, 46.7, 43.1, 42.6, 40.7 ,35.4,20.3;

IR(KBr)v _max 2922,2849,1717,1589,1144,1258,1101,1012,799,731cm ^-1 ;

HRMS(ESI,+ve)[M+H] ⁺ calculated for C ₂₆ H ₂₄ BrNO ₄ 482.0961,found 482.0970.

What have been described above are only some embodiments of the present invention. For those of ordinary skill in the art, under the premise of not departing from the inventive concept of the present invention, several modifications and improvements can also be made, and these all belong to the protection scope of the present invention.

Claims

Intermediate I for the preparation of codeine and derivatives thereof, characterized in that the structure is as shown in formula (I):
The preparation method of intermediate I according to claim 1, is characterized in that, comprises the steps:

With tert-butyl vinyl carbamate and compound 1
Synthesis of compound 2 by Suzuki-Miyaura cross-coupling reaction

Compound 2 and Compound 3
Intermediate I was synthesized by Mitsunobu reaction.
The preparation method according to claim 2, wherein the preparation method of the compound 2 comprises the steps of:

Dissolve tert-butyl vinyl carbamate in the first solvent, add borane at room temperature to react until the solution becomes clear and transparent, and obtain solution I; wherein, the molar ratio of tert-butyl vinyl carbamate to borane is 1 : 1-1: 2; Preferably, the first solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide Preferably, the borane is selected from 9-borane bicyclo [3.3.1] nonane dimer, diisopine pinocampyl chloride borane, diethyl methoxy borane, dimethyl borane, children At least one of the teaphenol boranes;

Compound 1, palladium reagent and triphenylarsenic are dissolved in a second solvent, and then an alkali solution is added to obtain solution II; wherein, the amount of palladium reagent added is 5-25% of that of compound 1 in terms of the amount of the substance, The amount of triphenylarsenic added is 9-50% of compound 1; preferably, the palladium reagent is selected from 1,1-bis(diphenylphosphine)ferrocene-palladium dichloride(II) dichloromethane Complex, palladium acetate, tetrakis (triphenylphosphine) palladium, dichloride palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, trifluoroacetate palladium at least One; Preferably, the second solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide; preferably, The alkali is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; preferably, the concentration of the alkali solution is 2-5mol/L, and the added volume is 0.2-0.5 of the volume of solution II times.

Add solution I to solution II, react for 0.5-1h under nitrogen protection, and obtain compound 2 after separation and purification.
The preparation method according to claim 2, wherein the preparation method of the compound 3 comprises the steps of:

Dissolve potassium tert-butoxide in tetrahydrofuran, cool to -78°C~-60°C, then add (bromomethyl)triphenylphosphine bromide, mix and add dropwise 3-hydroxy-2-iodo-4- The tetrahydrofuran solution of methoxybenzaldehyde is reacted, and the reaction is continued for 0.5-1.5h after the dropwise addition is completed, and the reaction is quenched. After separation and purification, compound 3 is obtained; among them, potassium tert-butoxide and (bromomethyl)triphenyl The molar ratio of phosphine bromide is 1:1; the molar ratio of potassium tert-butoxide and 3-hydroxy-2-iodo-4-methoxybenzaldehyde is 3:1–5:1.
According to the preparation method described in any one of claims 2-4, it is characterized in that, the step of compound 2 and compound 3 through Mitsunobu reaction synthesis intermediate I comprises:

Dissolve compound 2 and compound 3 in the third solvent, then add tributylphosphine and azo compound, or add triphenylphosphine and azo compound under the protection of nitrogen at 0°C for 0.5–1.5h, and the reaction is over Afterwards, the reaction mixture was warmed up to room temperature within 1 h, and intermediate I was obtained after purification;

Alternatively, add tributylphosphine and an azo compound, or add triphenylphosphine and an azo compound, in a third solvent at -20°C under nitrogen protection, and then add compound 2 and compound 2 at 0°C under nitrogen protection 3. Carry out the reaction for 0.5-1.5 hours. After the reaction, the reaction mixture is warmed up to normal temperature within 1 hour, and intermediate I is obtained after purification;

Among them, the molar ratio of compound 2 and compound 3 is 1:1-1.5:1; in terms of the amount of substances, the amount of tributylphosphine or triphenylphosphine added is 1.5-2.5 times that of compound 2, tributylphosphine Or the substance ratio of triphenylphosphine and azo compound is 1:1; preferably, the third solvent is selected from tetrahydrofuran, toluene or a mixed solution obtained by mixing tetrahydrofuran and toluene in a volume ratio of 1:1; preferably , the azo compound is selected from at least one of ethyl azodicarboxylate, diisopropyl azodicarboxylate, and tetramethylazodicarbonamide.
Intermediate II for the preparation of codeine and derivatives thereof, characterized in that the structure is as shown in formula (II):
The preparation method of intermediate II according to claim 6, is characterized in that, comprises the steps:

Intermediate I was synthesized from intermediate II by Heck reaction.
The preparation method of intermediate II according to claim 7, is characterized in that, the step of intermediate I synthesizes intermediate II by Heck reaction comprises:

Add the intermediate I to the fourth solvent, add silver carbonate and palladium reagent after mixing, or add silver phosphate and palladium reagent to obtain a suspension;

The suspension was stirred and refluxed for 6-8h under nitrogen protection, and the intermediate shown in formula (II) was obtained after purification;

Wherein, the molar ratio of intermediate I, silver carbonate or silver phosphate, and palladium reagent is 1: (5-7): (0.15-0.25);

Preferably, the fourth solvent is selected from at least one of toluene, dimethylformamide, and dimethyl sulfoxide; the palladium reagent is selected from 1,1'-bis(diphenylphosphino)ferrocene - Palladium(II) dichloromethane complex, palladium acetate, tetrakis(triphenylphosphine)palladium, palladium dichloride, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylene) At least one of phosphine) palladium and palladium trifluoroacetate.
The preparation method of the intermediate III whose structural formula is shown in the formula (III), is characterized in that it comprises the following steps:

Dissolve intermediate II in 1,2-dichloroethane or acetonitrile, then add 9-m-dimethyl-10-methylacridinium tetrafluoroborate and thiophenol under nitrogen protection to obtain a mixture , the mixture was reacted at room temperature under blue light irradiation for 60-84h, and intermediate III was obtained after purification; wherein, the molar ratio of intermediate II to thiophenol was 1: (1.5-2.5); by mass percentage, 9-m Dimethyl-10-methylacridinium tetrafluoroborate was added in an amount of 4–6% of the mixture.
The preparation method of intermediate IV whose structural formula is shown in formula (IV), is characterized in that, comprises the following steps:

Mix intermediate III, dioxyiodobenzene, 1,2-bis(pyridin-2-yl)xylene and quartz sand, add benzene under nitrogen protection, reflux reaction for 2-5h, and obtain compound 7 after purification; among them, The molar ratio of Intermediate III to dioxyiodobenzene is 1:(2–5), and the molar ratio of Intermediate III to 1,2-bis(pyridin-2-yl)xylene is (8–12):1.
The preparation method of codeine is characterized in that, comprising the following steps;

Dissolve the intermediate IV in ethylene glycol dimethyl ether or tetrahydrofuran, and then add it to the ethylene glycol dimethyl ether or tetrahydrofuran solution dissolved in lithium aluminum hydride at 0°C under the protection of nitrogen, and the reaction solution rises within 0.25h to normal temperature, then react at 60-70°C for 2-5h, cool to room temperature after the reaction, and obtain codeine after separation and purification; wherein, the molar ratio of intermediate IV to lithium aluminum hydride is 1:( 8–12).
The preparation method of deoxycodeine is characterized in that it comprises the following steps: dissolving intermediate III in at least one solvent selected from tetrahydrofuran, ethylene glycol dimethyl ether and acetonitrile, and then at room temperature and under nitrogen protection conditions , add tetrahydrofuran or ethylene glycol dimethyl ether solution dissolved with lithium aluminum hydride, react at 60-70°C for 2-5h, cool to room temperature after the reaction, and obtain deoxycodeine after separation and purification; , the molar ratio of intermediate III to lithium aluminum hydride is 1:(8–12).
The preparation method of norcodeine is characterized in that, comprises the steps:

Under the protection of nitrogen, add intermediate IV, cerium trichloride heptahydrate and sodium borohydride to the fifth solvent successively, add water to quench the reaction after reacting for 0.5-1h, extract the reaction solution with dichloromethane or ethyl acetate, and then Dry and combine the organic phases, concentrate, add dichloromethane and trifluoroacetic acid, or add ethyl acetate and trifluoroacetic acid to the concentrated solution, and react at room temperature for 2-4 hours. waiting for;

Wherein, the molar ratio of intermediate IV, cerium trichloride heptahydrate and sodium borohydride is 1:1:1; the molar ratio of compound 7 and trifluoroacetic acid is 1:(10-15);

Preferably, the fifth solvent is at least one selected from methanol, ethanol, and ethyl acetate.
The preparation method of the intermediate V whose structural formula is shown in formula (V), is characterized in that, comprises the following steps:

Under the protection of nitrogen, add intermediate II, the first part of selenium dioxide and quartz sand to 1,4-dioxane, heat the reaction at 75°C for 1–1.5h, and then add the second part of selenium dioxide, Continue to react at 75°C for 1-1.5h. After the reaction is completed, intermediate V is obtained by separation and purification; wherein, the molar ratio of intermediate II, the first selenium dioxide, and the second selenium dioxide is 1 :1:1–1:1.5:1.5.
The preparation method of the intermediate VI shown in the formula (VI) is characterized in that it comprises the following steps:

Mix intermediate III, the first part of selenium dioxide and quartz sand, under the protection of nitrogen, add 1,4-dioxane, react at 75°C for 1–1.5h, and then add the second part of selenium dioxide , continue to react at 75°C for 1–1.5h, and after the reaction is completed, intermediate VI is obtained through separation and purification; wherein, the molar ratio of intermediate III, the first selenium dioxide, and the second selenium dioxide is 1:1:1–1:1.5:1.5.
The preparation method of the intermediate VI shown in the formula (VI) is characterized in that it comprises the following steps:

Under nitrogen protection, dissolve intermediate V in 1,2-dichloroethane or acetonitrile, then add 9-m-dimethyl-10-methylacridinium tetrafluoroborate and thiophenol, seal Then react at room temperature under blue light irradiation for 84-100h, and after the reaction, purify to obtain intermediate VI; among them, intermediate V, 9-m-dimethyl-10-methylacridinium tetrafluoroborate and benzene The molar ratio of thiophenols is 15:1:3–20:1:5.
Codeine derivatives are characterized in that their structural formula is as shown in formula (VII):
The preparation method of codeine derivatives according to claim 17, characterized in that it comprises the following steps;

Dissolve the intermediate VI in ethylene glycol dimethyl ether at 0°C under nitrogen protection, and then add dropwise to the ethylene glycol dimethyl ether solution in which lithium aluminum hydride is dissolved. After the dropwise addition, heat at 65°C Reaction for 6.5-7h, after the reaction, after separation and purification, the codeine derivative shown in formula (VII) can be obtained; wherein, the molar ratio of intermediate VI to lithium aluminum hydride is 1:2-1:4.
Codeine derivatives are characterized in that their structural formula is as shown in formula (VII):
The preparation method of codeine derivatives according to claim 19, is characterized in that, comprises the steps:

Under the protection of nitrogen, dissolve codeine, 4-dimethylaminopyridine and N,N-diisopropylethylamine in dichloromethane, add 4-bromobenzoyl chloride at 0°C, and complete the addition Then warm up to room temperature and react for 2-3h. After the reaction, after separation and purification, the codeine derivative shown in formula (VIII) can be obtained; wherein, codeine, 4-dimethylaminopyridine and N,N-di The molar ratio of isopropylethylamine is 40:1:72–10:1:28; the molar ratio of codeine and 4-bromobenzoyl chloride is 1:2.5.