CN108164461B - Total synthesis of natural product (+/-) -ylacrine and resolution method of enantiomer - Google Patents
Total synthesis of natural product (+/-) -ylacrine and resolution method of enantiomer Download PDFInfo
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Abstract
The invention discloses a total synthesis method of a natural product (+/-) -ylacrine and a chiral resolution method of an enantiomer thereof, belonging to the technical field of organic synthesis. The natural product (+/-) -ylacrine in the method is obtained by taking the natural product (+/-) -incarvillea base G as a substrate through tetrahydrofuran/methyllithium reaction, and the natural product (+/-) -ylacrine and an enantiomer thereof are obtained, and a chiral semi-preparative high performance liquid chromatograph is used for splitting the enantiomer, and the ylacrine and the enantiomer thereof are obtained, and the total yield is 17.9%.
Description
Technical Field
The invention relates to the technical field of organic synthesis and separation, in particular to a method for fully synthesizing a natural product (+/-) -ylacrine and splitting an enantiomer.
Background
Ylang (Cananga odorata) belongs to the Annonaceae family of evergreen tall trees, tropical woody flavor plants. Is widely distributed in tropical regions of the world, and cultivated in Guangdong, Guangxi, Fujian, Sichuan, Yunnan, Taiwan and other places in China. Ylang-ylang is mainly prepared by steaming oil with fresh petals, and is called ylang-ylang oil. The oil yield of the fresh flowers reaches 2-3%. The traditional Chinese medicine is mainly used for treating diseases such as skin tinea, malaria, influenza and the like. In 2001, ylang-base was first isolated from ylang-ylang in the Wu Yongchang subject group of Taiwan university of heroic medicine. Structurally, the compound of the type has a pyridine ring and a saturated seven-membered ring, has two chiral centers and is a typical epiguaiadine alkaloid. The guaiadine compounds contained in natural products generally have special physiological activity. This has therefore attracted a great deal of interest to synthetic chemists, biologists and pathologists. In 2008, the group of the Agziaki-Isa researchers at Xinjiang institute of science and technology, China, first isolated five guaiadine-type sesquiterpene alkaloids with novel structures from Artemisia rupestris. In 2012, eight compounds of this type were isolated from artemisia rupestris in this subject group, such as hayfei, etc. { (and name Compound 14 as alpine (Rupestine) }.
The typical epiguaiadine alkaloid, ylang-anin, is reported in the literature to have hepatotoxicity. In 2006, Gavin d.henry completed the total synthesis of the compound for the first time.
The Gavin topic group firstly uses citronellaene as a raw material to obtain an intermediate compound G-7, 2-methylene-1, 3-propylene glycol with a total yield of 20.52% in six steps to obtain another intermediate compound G-11 with a total yield of 36% in three steps, and then uses the intermediate G-7 to react with the intermediate G-11 to obtain the ylanthine with a total yield of 6% in eight steps. The method of Gavin topic group is not only complicated, but also low in yield, and the reagents such as KCN used in the reaction are extremely toxic; furthermore, they synthesized ylanthanine { [ alpha ]]D 21＝+17.9(c＝1.34,CHCl3) Separate compound { [ alpha ] from Wu Yongchang subject group]D 25＝–76.2(c＝0.06,CHCl3) The optical rotation values are opposite in sign. The explanation given for this Gavin topic group is that the higher the sample concentration the more reliable the measured optical rotation value is, and it is not convincing.
James Vyvyan also tried synthesis of ylanthanine and its isomers in 2017.
Although the Vyvyan subject composition resulted in the synthesis of isovanillin and isomers thereof, they not only gave poor reaction conditions and low yields, but also did not resolve the difference in optical rotation values of isovanillin obtained in the previous Gavin subject group and wu-mingchang subject group. Until now, no other individual or unit reports about the complete synthesis of the compound except the two groups of subjects, and in view of the divergence of the natural product chemist (Wu Yongchang) and the organic synthesis chemist (Gavin D.Henry) in the physical constant specific optical rotation of ylang-ylang base, the invention is further researched on the basis of 201710407508.7, the invention is named as the complete synthesis of the natural product (+/-) -achillea base G and the resolution method of the enantiomer thereof, thereby not only improving the previous reaction method, but also successfully obtaining ylang-ylang base and the corresponding isomer thereof, simplifying the synthesis method, improving the total yield of the complete synthesis, and providing a powerful guarantee for the further research of the compounds.
Reference to the literature
1.Tian-Jye Hsieh；Fang-Rong Chang；Yi-Chen Chia；Chung-Yi Chen；Hui-Fen Chiu；Wu,Y.-C.,Cytotoxic Constituents of the Fruits of Cananga odorata.J.Nat.Prod.2001,64,616-619.
2.Koyama,J.；Okatani,T.；Tagahara,K.；Suzuta,V.,Synthesis of guaipyridine,epiguaipyridine and related compounds.Heterocycles 1987,26(4),926-927.
3.Su,Z.；Wu,H.；Yang,Y.；Aisa,H.A.；Slukhan,U.；Aripova,S.,Preparative isolation of guaipyridine sesquiterpene alkaloid from Artemisia rupestris L.flowers using high-speed counter-current chromatography.J.Sep.Sci.2008,31(12),2161-6.4.Su,Z.；Wu,H.；Yang,Y.；Aisa,H.A.；Slukhan,U.；Aripova,S.,New Guaipyridine Sesquiterpene Alkaloids from Artemisia rupestris L.Helv.Chim.Acta 2010,93,33-38.5.He,F.；Nugroho,A.E.；Wong,C.P.；Hirasawa,Y.；Shirota,O.；Morita,H.；Aisa,H.A.,Rupestines F—M,New Guaipyridine Sesquiterpene Alkaloids from Artemisia rupestris.Chem.Pharm.Bull.2012,60(2),213-218.
6.Craig,D.；Henry,G.D.,Total Synthesis of the Cytotoxic Guaipyridine Sesquiterpene Alkaloid(+)-Cananodine.Eur.J.Org.Chem.2006,16,3558-3561.
7.Patrick Shelton,Toby J.Ligon,Jennifer M.Dell(née Meyer),Loagan Yarbrough,James R.Vyvyan,Synthesis of cananodine by intramolecular epoxide opening.Tetrahedron Letters,2017,58,3478-3481.
On the basis of comprehensive analysis of related patents and documents at home and abroad and a method for fully synthesizing a natural product (+/-) -alpine G and splitting an enantiomer thereof (patent application number: 201710407508.7) invented by the subject group, 2-methyl-5-bromopyridine is used as a raw material, and a series of organic synthesis methods before improvement successfully obtain the natural product (+/-) -ylacrine and simultaneously separate and split the natural product (+/-) -ylacrine to obtain the enantiomer thereof.
Disclosure of Invention
The invention aims to provide a method for fully synthesizing a natural product (+/-) -ylacrine and splitting an enantiomer, and determining the absolute configuration of the natural product (+/-) -ylacrine. The natural product (+/-) -ylacrine in the method is obtained by taking the natural product (+/-) -artemisia rupestris G as a substrate and carrying out tetrahydrofuran/methyllithium reaction to obtain (+/-) -ylacrine and an enantiomer thereof, and then using a chiral semi-preparative high performance liquid chromatograph to carry out resolution on the corresponding isomer, and successfully obtaining the ylacrine and the corresponding isomer thereof with a total yield of 17.9%.
The invention relates to a method for fully synthesizing a natural product (+/-) -ylacrine and splitting an enantiomer, wherein the natural product (+/-) -ylacrine in the method is obtained by taking a natural product (+/-) -alpine G as a substrate and carrying out tetrahydrofuran/methyllithium reaction to obtain the (+/-) -ylacrine and an enantiomer thereof, and then splitting the enantiomer by using a chiral semi-preparative high performance liquid chromatograph, wherein the structural formula is as follows:
wherein:
the compound 2 is N-oxygen-5-bromine 2-methylpyridine;
compound 4 is methyl 3- (3-bromo-6-methylpyridine) -3-carbonylpropionate;
compound 6 is methyl 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoate;
compound 7 is 2, 5-dimethyl-5-en-9-oxo-cyclohepta [ b ] pyridine-8-carboxylic acid methyl ester;
compound 8 is 2, 5-dimethyl-5-en-9-hydroxy-cyclohepta [ b ] pyridine-8-carboxylic acid methyl ester;
compound 9 is 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-carboxylic acid methyl ester;
the compound 10 is (5-methyl-8-methyl formate) -cycloheptane [ b ] pyridine-2-methyl/{ (+ -) -alpine G };
compound 11 is { (5-methyl-8- (2-methyl-1-propanol)) } -cyclohepta [ b ] pyridine-2-methyl/{ (±) -ylanthranine };
compound 12 is ylacrine;
compound 13 is (5S,8S) -ylanthranine;
the specific operation is carried out according to the following steps:
a. dissolving 2.0g of 5-bromo-2-methylpyridine 1 in a dichloromethane solution, adding 2.9g of m-chloroperoxybenzoic acid with the purity of 85% in batches into the system under an ice bath, naturally heating to room temperature, stirring for overnight reaction, pouring reaction liquid into a saturated sodium sulfite solution for quenching after the reaction is finished, extracting for 3 times by using dichloromethane after stirring for 1 hour, combining organic phases, drying by using anhydrous magnesium sulfate, and removing an organic solvent to obtain a nitrogen oxidation product compound 2, namely 5-bromo-2-methyl-N-oxypyridine;
b. under the protection of nitrogen, 1.0g of compound 2, 5-bromo-2-methyl-N-oxypyridine, is dissolved in acetonitrile solution, 2.1g of trimethylsilyl cyanide and 2.2ml of triethylamine are sequentially added, after refluxing for 12 hours, the organic solvent is removed, and purification is carried out, thus obtaining compound 3, 3-bromo-6-methyl-2-cyanopyridine;
c. heating 7.2-8.0 g of crystal water, namely zinc chloride, in a mass ratio of 40:60 to melt and remove water under a vacuum state, sequentially adding 1, 2-dichloroethane, 5.5g of 3-bromo-6-methyl-2-cyanopyridine as a compound 3, 11g-13g of monomethyl malonate potassium salt and 1.5g-1.8g of diisopropylethylamine under the protection of nitrogen, stirring and refluxing for 12-16 hours, adding 6N hydrochloric acid after the system is cooled to room temperature, refluxing for 1 hour again, separating out an organic phase, extracting an aqueous phase for 3 times by using dichloromethane, combining the organic phases, drying by using anhydrous magnesium sulfate, removing an organic solvent, and purifying to obtain a compound 4, namely 3- (3-bromo-6-methylpyridine) -3-carbonyl methyl propionate;
d. dissolving 1.0g of compound 4 methyl 3- (3-bromo-6-methylpyridine) -3-carbonyl propionate in absolute ethyl alcohol, adding 0.6g-1.0g of sodium ethoxide in an ice bath, adding 0.7ml-1.0ml of 3-bromopropylene while stirring, reacting at room temperature overnight, removing the organic solvent, and purifying by column chromatography to obtain compound 5 methyl 2- (3-bromo-6-methylpyridine-2-formyl) -4-enevalerate;
e. dissolving 1.0g of compound 5, namely 2- (3-bromo-6-methylpyridine-2-formyl) -4-pentenoic acid methyl ester, in a mixed solution of dioxane and water, adding 0.4g to 0.8g of palladium tetratriphenylphosphine catalyst, 1g to 1.5g of sodium carbonate and 0.71ml to 1.0ml of isopropenylboronic acid pinacol ester, stirring, heating and refluxing for 3 to 5 hours, removing the solvent after the system is cooled to room temperature, and purifying by column chromatography to obtain compound 6, namely 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoic acid methyl ester;
f. under the protection of nitrogen, dissolving 1.0g of compound 6, namely 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoic acid methyl ester, into a dichloromethane solution, adding 0.3g to 0.5g of Grubbs secondary catalyst, heating and refluxing for reaction for 12 to 16 hours, cooling the system to room temperature, removing the organic solvent, and carrying out column chromatography to obtain compound 7, namely 2, 5-dimethyl-5-ene-9-oxo-cyclohepta [ b ] pyridine-8-formic acid methyl ester;
g. dissolving 100mg of compound 7, namely 2, 5-dimethyl-5-alkene-9-oxo-cycloheptane [ b ] pyridine-8-methyl formate in absolute methanol under ice bath, adding 15mg-30mg of sodium borohydride, naturally heating to room temperature, adding water to quench the reaction after reacting for 3-5 hours, removing the solvent, performing column chromatography, and purifying to obtain compound 8, namely 2, 5-dimethyl-5-alkene-9-hydroxy-cycloheptane [ b ] pyridine-8-methyl formate;
h. dissolving 100mg of 2, 5-dimethyl-5-ene-9-hydroxy-cyclohepta [ b ] pyridine-8-methyl formate serving as the compound 8 in pyridine, heating to 60 ℃, adding 45mg-60mg of methylsulfonyl chloride, reacting for 3-5 hours, cooling to room temperature, adding water to quench the reaction, extracting with dichloromethane to separate an organic phase, drying the organic phase with anhydrous magnesium sulfate, and purifying by column chromatography to obtain 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-methyl formate serving as the compound 9;
i. dissolving 50mg of compound 9, namely 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-methyl formate in absolute methanol, adding 15mg-20mg of palladium carbon catalyst in ice bath, introducing hydrogen, stirring at room temperature overnight for reaction, removing the solvent, and separating and purifying by using a thin layer chromatography method to obtain compound 10, namely (5-methyl-8-methyl formate) -cyclohepta [ b ] pyridine-2-methyl;
j. dissolving 50mg of compound 10 (5-methyl-8-methyl formate) -cyclohepta [ b ] pyridine-2-methyl in dry tetrahydrofuran, placing the system at the temperature of-10 ℃, adding 3-5 times of methyllithium, adding water to quench the reaction after reacting for 1 hour, extracting 3 times by using dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, filtering solids, and removing the solvent from the filtrate to obtain compound 11 { (5-methyl-8- (2-methyl-1-propanol)) } -cyclohepta [ b ] pyridine-2-methyl;
k. resolving compound 11 as { (5-methyl-8- (2-methyl-1-propanol)) } -cyclohepta [ b ] pyridin-2-methyl by semi-preparative high performance liquid chromatography to give compound 12 as ylanthranine and compound 13 as (5S,8S) -ylanthranine.
The invention relates to a method for fully synthesizing a natural product (+/-) -ylacrine and splitting an enantiomer, which is a method for fully synthesizing a natural product (+/-) -alpine G and splitting an enantiomer thereof, which is applied in the early stage of the subject group, and has the following patent application numbers: 201710407508.7, 2-methyl-5-bromopyridine (1) is used as raw material, an oxynitride compound (2) is obtained by oxidation of m-chloroperoxybenzoic acid, and a compound (3) is obtained by cyano substitution of the compound (2) through Reissert-Henze reaction, wherein the two are different: the method comprises the steps of carrying out decarboxylation Blaise reaction on an obtained compound (3) and potassium monomethyl malonate to obtain beta-keto ester (4), alkylating the compound (4) under the condition of sodium ethoxide to obtain a compound (5), further carrying out Suzuki coupling reaction to obtain a compound (6), carrying out intramolecular olefin metathesis reaction on the compound (6) to obtain a key intermediate compound (7), reducing the compound (7) by using sodium borohydride to obtain a compound (8), eliminating the compound (8) under the condition of pyridine/methylsulfonyl chloride to obtain a compound (9), dissolving the compound (9) in methanol, carrying out palladium-carbon catalytic hydrogenation to obtain a compound (10), dissolving the compound (10) in tetrahydrofuran, dropwise adding methyllithium at the temperature of-10 ℃ to obtain a compound (11), and resolving the compound (11) by using a semi-preparative high-performance liquid phase of SHIMADZU LC20A to obtain CHIRALPAK ID (Lot No. ID00CE-QI), compound (12) ylanthranine and compound (13) (5S,8S) -ylanthranine are obtained respectively.
The invention relates to a method for fully synthesizing a natural product (+/-) -ylacrine and splitting an enantiomer, which comprises the following synthetic route:
drawings
FIG. 1 is a high-resolution mass spectrum of the compound (13) of the present invention;
FIG. 2 is a high resolution mass spectrum of the natural product of the present invention, canavanine;
FIG. 3 is a diagram showing the optical rotation values of the compound (13) of the present invention;
FIG. 4 is a diagram showing the optical rotation values of the natural product of ylacrine of the present invention;
FIG. 5 is an experimental ECD and calculated ECD spectra of compound (13) and vanillin of the present invention, wherein curve A is the experimental ECD curve of compound (13); curve B is the experimental ECD curve for ylacrine; curve C is the calculated ECD curve for ylacrine;
Detailed Description
In order to make the present invention clearer, the present invention is further described in detail below with reference to examples, and it should be understood that the examples are only for explaining the present invention and do not limit the present invention.
Example 1
a. Dissolving 2.0g (12mmol) of 5-bromo-2-methylpyridine 1 in 30ml of dichloromethane solution, adding 2.9g (13.9mmol) of m-chloroperoxybenzoic acid with the purity of 85% in batches under ice bath, naturally heating to room temperature, stirring for overnight reaction, pouring the reaction solution into a saturated sodium sulfite solution for quenching after the reaction is finished, extracting with 150ml of dichloromethane for 3 times after stirring for 1 hour, combining organic phases, drying with anhydrous magnesium sulfate, and removing an organic solvent to obtain a nitrogen oxidation product compound 2, namely 5-bromo-2-methyl-N-oxypyridine, wherein the yield is 93% and 2.0 g;
b. under the protection of nitrogen, 1.0g (5.4mmol) of compound 2, 5-bromo-2-methyl-N-oxopyridine, is dissolved in 20ml of acetonitrile solution, 2.1g (21.6mmol) of trimethylsilyl cyanide and 2.2ml (16.2mmol) of triethylamine are added in succession, after 12 hours of reflux, the organic solvent is removed and the resulting mixture is chromatographed using medium-pressure preparative chromatography to COMBIFLASH, mobile phase: purifying ethyl acetate and petroleum ether in a volume ratio of 1:10 to obtain 0.9g of compound 3 which is 3-bromo-6-methyl-2-cyanopyridine with a yield of 85%;
1H NMR(400MHz,Chloroform-d)δ7.98(d,J＝8.2Hz,1H),7.24(d,J＝3.0Hz,1H),2.57(s,3H)；
c. heating 7.2(32.5mmol) of zinc chloride containing crystal water and having a mass ratio of 40:60 to melt and remove water under vacuum, sequentially adding 75ml of 1, 2-dichloroethane, 5.5g (27.9mmol) of 3-bromo-6-methyl-2-cyanopyridine compound 3, 11g (65mmol) of monomethyl malonate potassium salt and 1.5ml (9.1mmol) of diisopropylethylamine under the protection of nitrogen, stirring and refluxing for 12 hours, cooling the system to room temperature, adding 20ml of 6N hydrochloric acid, refluxing for 1 hour again, separating out an organic phase, extracting an aqueous phase for 3 times by dichloromethane, combining the organic phases, drying by anhydrous magnesium sulfate, removing an organic solvent, and purifying to obtain a compound 4 of 3- (3-bromo-6-methylpyridine) -3-carbonyl methyl propionate with a yield of 75% and 6.0 g;
d. dissolving 1g (3.5mmol) of methyl 3- (3-bromo-6-methylpyridine) -3-carbonylpropionate 4 in 10ml of absolute ethanol, adding 0.6g (3.9mmol) of sodium ethoxide in an ice bath, adding 0.7ml (3.9mmol) of 3-bromopropylene while stirring, reacting at room temperature overnight, removing the organic solvent after the reaction is finished, and purifying by column chromatography (mobile phase: ethyl acetate in volume ratio of 1: 10: petroleum ether) to obtain methyl 2- (3-bromo-6-methylpyridine-2-formyl) -4-Entanoate as compound 5 with yield of 80% and 0.9 g;
e. dissolving 1g (3.1mmol) of methyl 2- (3-bromo-6-methylpyridine-2-formyl) -4-pentenoate as compound 5 in a mixed solution of dioxane and water in a volume ratio of 3:1, adding 0.4g (0.3mmol) of a palladium tetratriphenylphosphine catalyst, 1g (9.3mmol) of sodium carbonate and 0.71ml (3.3mmol) of pinacol isopropenylborate, stirring, heating and refluxing for 3 hours, removing the solvent after the system is cooled to room temperature, and purifying by column chromatography (mobile phase: ethyl acetate: petroleum ether in a volume ratio of 1: 10) to obtain methyl 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoate as compound 6 in 85% yield and 0.7 g;
f. under the protection of nitrogen, 1g (3.5mmol) of methyl 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoate as a compound 6 is dissolved in 30ml of a dry dichloromethane solution, 0.3g (0.3mmol) of Grubbs secondary catalyst is added, heating reflux reaction is carried out for 12 hours, after the reaction is finished, when a system is cooled to room temperature, organic solvent is removed, and column chromatography is carried out (mobile phase: ethyl acetate in a volume ratio of 1: 5: petroleum ether) to obtain methyl 2, 5-dimethyl-5-ene-9-oxo-cycloheptane [ b ] pyridine-8-carboxylate as a compound 7, wherein the yield is 42 percent and 0.4 g;
g. dissolving 100mg (0.4mmol) of methyl 2, 5-dimethyl-5-ene-9-oxo-cyclohepta [ b ] pyridine-8-carboxylate serving as a compound 7 in 5ml of absolute methanol under ice bath, adding 15mg (0.4mmol) of sodium borohydride, naturally heating the system to room temperature, reacting for 3 hours, adding water to quench the reaction, removing the solvent, and purifying by column chromatography (mobile phase: ethyl acetate in a volume ratio of 1: 3: petroleum ether) to obtain the methyl 2, 5-dimethyl-5-ene-9-hydroxy-cyclohepta [ b ] pyridine-8-carboxylate serving as a compound 8, wherein the yield is 71% and 72 mg;
h. dissolving 100mg (0.4mmol) of 2, 5-dimethyl-5-ene-9-hydroxy-cyclohepta [ b ] pyridine-8-methyl formate of the compound 8 in 10ml of pyridine, heating to 60 ℃, adding 45mg (0.4mmol) of methylsulfonyl chloride, reacting for 3 hours, cooling to room temperature, adding water to quench the reaction, extracting with 30ml of dichloromethane to separate an organic phase, drying the organic phase with anhydrous magnesium sulfate, and purifying by column chromatography (mobile phase: ethyl acetate: petroleum ether in a volume ratio of 1: 5) to obtain the compound 9 of 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-methyl formate, wherein the yield is 78% and 75 mg;
i. dissolving 50mg (0.2mmol) of 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-methyl formate of a compound 9 in 10ml of anhydrous methanol, adding 15mg of a palladium-carbon catalyst with the concentration of 0.5% under ice bath, introducing hydrogen, stirring at room temperature overnight for reaction, removing the solvent after the reaction is finished, and separating and purifying by a thin layer chromatography (a developing solvent, ethyl acetate and petroleum ether in a volume ratio of 1: 5) to respectively obtain the compound 10 of (5-methyl-8-methyl formate) -cycloheptane [ b ] pyridine-2-methyl, wherein the yield is 78% and 39 mg;
j. 50mg (0.2mmol) of compound 10 (methyl 5-methyl-8-carboxylate) -cyclohepta [ b ] pyridine-2-methyl is dissolved in anhydrous tetrahydrofuran, 3 times as much methyllithium (0.6mmol) is added, 1ml of water is added after completion of the reaction, after quenching the reaction, extraction is performed 3 ml. times.3 times, drying is performed over anhydrous magnesium sulfate, and column chromatography (mobile phase: ethyl acetate: petroleum ether in a volume ratio of 1: 1) is performed to purify to obtain compound 11 as { (5-methyl-8- (2-methyl 1-propanol)) } -cyclohepta [ b ] pyridine-2-methyl, yield 88%, 44mg.
k. Resolving compound 11 as { (5-methyl-8- (2-methyl 1-propanol)) } -cyclohepta [ b ] pyridine-2-methyl by semi-preparative high performance liquid chromatography (SHIMADZU LC-20A), chiral column CHIRALPAK ID (Lot No. ID00CE-QI011), enantiomers (mobile phase: n-hexane: ethanol in a volume ratio of 98: 2) to obtain compound 12 as ylanthranine; compound 13 is (5S,8S) -ylanthranine.
Example 2
a. Dissolving 2.0g (12mmol) of compound 15-bromo-2-methylpyridine in 30ml of dichloromethane solution, adding 2.9g (13.9mmol) of m-chloroperoxybenzoic acid with the purity of 85% in batches under ice bath, naturally heating to room temperature, stirring for overnight reaction, pouring the reaction solution into a saturated sodium sulfite solution for quenching after the reaction is finished, extracting for 3 times by using 150ml of dichloromethane after stirring for 1 hour, combining organic phases, drying by using anhydrous magnesium sulfate, and removing the organic solvent to obtain an oxynitride product compound 2, namely 5-bromo-2-methyl-N-oxypyridine, wherein the yield is 93%, 2.0 g;
b. under the protection of nitrogen, 1.0g (5.4mmol) of compound 2, 5-bromo-2-methyl-N-oxopyridine, is dissolved in 20ml of acetonitrile solution, 2.1g (21.6mmol) of trimethylsilyl cyanide and 2.2ml (16.2mmol) of triethylamine are added in succession, after 12 hours of reflux, the organic solvent is removed and the resulting mixture is chromatographed using medium-pressure preparative chromatography to COMBIFLASH, mobile phase: purifying ethyl acetate and petroleum ether in a volume ratio of 1:10 to obtain 0.9g of compound 3 which is 3-bromo-6-methyl-2-cyanopyridine with a yield of 85%;
1H NMR(400MHz,Chloroform-d)δ7.98(d,J＝8.2Hz,1H),7.24(d,J＝3.0Hz,1H),2.57(s,3H)；
c. heating 7.5(33.9mmol) zinc chloride containing crystal water and in a mass ratio of 40:60 under vacuum to melt and remove water, sequentially adding 75ml 1, 2-dichloroethane, 5.5g (27.9mmol) 3-bromo-6-methyl-2-cyanopyridine, 12g (70.9mmol) monomethyl malonate potassium salt and 1.6ml (9.8mmol) diisopropylethylamine under the protection of nitrogen, stirring and refluxing for 14 hours, cooling the system to room temperature, adding 20ml 6N hydrochloric acid, refluxing for 1 hour again, separating out an organic phase, extracting an aqueous phase for 3 times by dichloromethane, combining the organic phases, drying by anhydrous magnesium sulfate, removing an organic solvent, and purifying to obtain 4, namely 3- (3-bromo-6-methylpyridine) -3-carbonyl methyl propionate, wherein the yield is 78% and 6.3 g;
d. dissolving 1g (3.5mmol) of methyl 3- (3-bromo-6-methylpyridine) -3-carbonylpropionate 4 in 10ml of absolute ethanol, adding 0.8g (5.2mmol) of sodium ethoxide in an ice bath, adding 0.9ml (5.0mmol) of 3-bromopropylene while stirring, reacting at room temperature overnight, removing the organic solvent after the reaction is finished, and purifying by column chromatography (mobile phase: ethyl acetate in volume ratio of 1: 10: petroleum ether) to obtain methyl 2- (3-bromo-6-methylpyridine-2-formyl) -4-enevalerate 5 with yield of 91% and 1.0 g;
e. dissolving 1g (3.1mmol) of methyl 2- (3-bromo-6-methylpyridine-2-formyl) -4-pentenoate as compound 5 in a mixed solution of dioxane and water in a volume ratio of 3:1, adding 0.6g (0.45mmol) of a palladium tetratriphenylphosphine catalyst, 1.3g (12mmol) of sodium carbonate and 0.85ml (3.9mmol) of pinacol isopropenylborate, stirring, heating and refluxing for 4 hours, removing the solvent after the system is cooled to room temperature, and purifying by column chromatography (mobile phase: ethyl acetate: petroleum ether in a volume ratio of 1: 10) to obtain methyl 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoate as compound 6 in 87% yield of 0.76 g;
f. under the protection of nitrogen, 1g (3.5mmol) of methyl 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoate as a compound 6 is dissolved in 30ml of a dry dichloromethane solution, 0.4g (0.4mmol) of Grubbs secondary catalyst is added, heating reflux reaction is carried out for 14 hours, after the reaction is finished, when a system is cooled to room temperature, organic solvent is removed, and column chromatography is carried out (mobile phase: ethyl acetate in a volume ratio of 1: 5: petroleum ether) to obtain the compound 7, namely methyl 2, 5-dimethyl-5-ene-9-oxo-cyclohepta [ b ] pyridine-8-carboxylate, wherein the yield is 44 percent and 0.42 g;
g. dissolving 100mg (0.4mmol) of methyl 2, 5-dimethyl-5-ene-9-oxo-cyclohepta [ b ] pyridine-8-carboxylate serving as a compound 7 in 5ml of absolute methanol under ice bath, adding 20mg (0.53mmol) of sodium borohydride, naturally heating the system to room temperature, reacting for 4 hours, adding water to quench the reaction, removing the solvent, and purifying by column chromatography (mobile phase: ethyl acetate in a volume ratio of 1: 3: petroleum ether) to obtain methyl 2, 5-dimethyl-5-ene-9-hydroxy-cyclohepta [ b ] pyridine-8-carboxylate serving as a compound 8, wherein the yield is 73% and 74 mg;
h. dissolving 100mg (0.4mmol) of methyl 2, 5-dimethyl-5-ene-9-hydroxy-cyclohepta [ b ] pyridine-8-carboxylate serving as a compound 8 in 10ml of pyridine, heating to 60 ℃, adding 50mg (0.45mmol) of methylsulfonyl chloride, reacting for 3.5 hours, cooling to room temperature, adding water to quench the reaction, extracting with 30ml of dichloromethane to separate an organic phase, drying the organic phase with anhydrous magnesium sulfate, and purifying by column chromatography (mobile phase: ethyl acetate: petroleum ether in a volume ratio of 1: 5) to obtain methyl 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-carboxylate serving as a compound 9, wherein the yield is 80% and 77 mg;
i. dissolving 50mg (0.2mmol) of 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-methyl formate of a compound 9 in 10ml of anhydrous methanol, adding 18mg of palladium-carbon catalyst with the concentration of 0.5% under ice bath, introducing hydrogen, stirring at room temperature overnight for reaction, removing the solvent after the reaction is finished, and separating and purifying by a thin layer chromatography (developing solvent: ethyl acetate: petroleum ether with the volume ratio of 1: 5) to respectively obtain a compound 10 of (5-methyl-8-methyl formate) -cycloheptane [ b ] pyridine-2-methyl, wherein the yield is 84% and 42 mg;
j. 50mg (0.2mmol) of compound 10 (methyl 5-methyl-8-carboxylate) -cyclohepta [ b ] pyridine-2-methyl is dissolved in anhydrous tetrahydrofuran, 4 times of methyllithium (0.8mmol) is added, 1ml of water is added after completion of the reaction, after quenching the reaction, extraction is performed 3 ml. times.3 times, drying is performed over anhydrous magnesium sulfate, and column chromatography (mobile phase: ethyl acetate: petroleum ether in a volume ratio of 1: 1) is performed to purify to obtain compound 11 as { (5-methyl-8- (2-methyl 1-propanol)) } -cyclohepta [ b ] pyridine-2-methyl in 90% yield, 45mg.
k. Resolving compound 11 as { (5-methyl-8- (2-methyl 1-propanol)) } -cyclohepta [ b ] pyridine-2-methyl by semi-preparative high performance liquid chromatography (SHIMADZU LC-20A), chiral column CHIRALPAK ID (Lot No. ID00CE-QI011), and separating enantiomers (mobile phase: n-hexane: ethanol in a volume ratio of 98: 2) to obtain compound 212 as ylanthranine; compound 13 is (5S,8S) -ylanthranine.
Example 3
a. Dissolving 2.0g (12mmol) of compound 15-bromo-2-methylpyridine in 30ml of dichloromethane solution, adding 2.9g (13.9mmol) of m-chloroperoxybenzoic acid with the purity of 85% in batches under ice bath, naturally heating to room temperature, stirring for overnight reaction, pouring the reaction solution into a saturated sodium sulfite solution for quenching after the reaction is finished, extracting for 3 times by using 150ml of dichloromethane after stirring for 1 hour, combining organic phases, drying by using anhydrous magnesium sulfate, and removing the organic solvent to obtain an oxynitride product compound 2, namely 5-bromo-2-methyl-N-oxypyridine, wherein the yield is 93%, 2.0 g;
b. under the protection of nitrogen, 1.0g (5.4mmol) of compound 2, 5-bromo-2-methyl-N-oxopyridine, is dissolved in 20ml of acetonitrile solution, 2.1g (21.6mmol) of trimethylsilyl cyanide and 2.2ml (16.2mmol) of triethylamine are added in succession, after 12 hours of reflux, the organic solvent is removed and the resulting mixture is chromatographed using medium-pressure preparative chromatography to COMBIFLASH, mobile phase: purifying ethyl acetate and petroleum ether in a volume ratio of 1:10 to obtain 0.9g of compound 3 which is 3-bromo-6-methyl-2-cyanopyridine with a yield of 85%;
1H NMR(400MHz,Chloroform-d)δ7.98(d,J＝8.2Hz,1H),7.24(d,J＝3.0Hz,1H),2.57(s,3H)；
c. under the vacuum state, the mixture of crystal water with the mass ratio of 40: 60: heating 8g (36.1mmol) of zinc chloride to melt and remove water, sequentially adding 75ml of 1, 2-dichloroethane, 5.5g (27.9mmol) of 3-bromo-6-methyl-2-cyanopyridine as a compound 3, 13g (77mmol) of monomethyl malonate potassium salt and 1.8ml (11.0mmol) of diisopropylethylamine under the protection of nitrogen, stirring and refluxing for 16 hours, cooling the system to room temperature, adding 20ml of 6N hydrochloric acid, refluxing for 1 hour again, separating an organic phase, extracting an aqueous phase with dichloromethane for 3 times, combining the organic phases, drying with anhydrous magnesium sulfate, removing an organic solvent, and purifying to obtain the compound 4 of methyl 3- (3-bromo-6-methylpyridine) -3-carbonyl propionate with the yield of 82% and 6.6 g;
1H NMR(400MHz,Chloroform-d)δ7.87(d,J＝8.2Hz,1H),7.14(d,J＝8.2Hz,1H),4.13(s,2H),3.71(s,3H),2.52(s,3H)；13C NMR(100MHz,Chloroform-d)δ193.16,168.26,156.38,148.83,142.88,127.11,115.38,52.02,46.13,23.52.
d. dissolving 1g (3.5mmol) of methyl 3- (3-bromo-6-methylpyridine) -3-carbonylpropionate serving as compound 4 in 10ml of absolute ethanol, adding 1.0g (6.5mmol) of sodium ethoxide into an ice bath, adding 1.0ml (5.6mmol) of 3-bromopropylene while stirring, reacting at room temperature overnight, removing an organic solvent after the reaction is finished, and purifying by column chromatography (mobile phase: ethyl acetate in a volume ratio of 1: 10: petroleum ether) to obtain the methyl 2- (3-bromo-6-methylpyridine-2-formyl) -4-enevalerate serving as compound 5, wherein the yield is 97% and 1.1 g;
1H NMR(400MHz,Chloroform-d)δ7.86(d,J＝8.2Hz,1H),7.13(d,J＝8.2Hz,1H),5.92–5.78(m,1H),5.11(dd,J＝17.1,1.6Hz,1H),5.03(dd,J＝10.1,1.5Hz,1H),4.64(t,J＝7.2Hz,1H),3.66(s,3H),2.76–2.69(m,2H),2.52(s,3H)；13C NMR(100MHz,Chloroform-d)δ195.39,170.86,156.84,149.94,143.37,135.10,127.48,119.46,117.62,54.80,52.62,32.76,24.11.
e. dissolving 1g (3.1mmol) of 2- (3-bromo-6-methylpyridine-2-formyl) -4-pentenoic acid methyl ester serving as compound 5 in a mixed solution of dioxane and water in a volume ratio of 3:1, adding 0.8g (0.6mmol) of palladium tetratriphenylphosphine catalyst, 1.5g (14.0mmol) of sodium carbonate and 1.0ml (4.6mmol) of isopropenylboronic acid pinacol ester, stirring, heating and refluxing for 5 hours, removing the solvent after the system is cooled to room temperature, and purifying by column chromatography (mobile phase: ethyl acetate and petroleum ether in a volume ratio of 1: 10) to obtain the compound 6, namely 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoic acid methyl ester, wherein the yield is 92% and the weight is 0.8 g;
1H NMR(400MHz,Chloroform-d)δ7.45(d,J＝7.9Hz,1H),7.23(d,J＝7.8Hz,1H),5.85(ddt,J＝17.0,10.2,6.8Hz,1H),5.12(d,J＝1.6Hz,1H),5.00(dd,J＝10.0,1.7Hz,1H),4.81(d,J＝0.9Hz,1H),4.74(t,J＝7.2Hz,1H),3.65(s,3H),2.76–2.68(m,2H),2.54(s,3H),2.03(d,J＝1.2Hz,3H)；13C NMR(100MHz,Chloroform-d)δ196.66,170.96,156.04,148.76,138.58,135.00,132.71,125.94,118.54,116.82,114.23,54.04,51.93,36.94,32.44,23.53.；
f. under the protection of nitrogen, 1g (3.5mmol) of methyl 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoate as a compound 6 is dissolved in 30ml of a dry dichloromethane solution, 0.5g (0.5mmol) of Grubbs secondary catalyst is added, heating reflux reaction is carried out for 16 hours, after the reaction is finished, when a system is cooled to room temperature, organic solvent is removed, and column chromatography is carried out (mobile phase: ethyl acetate in a volume ratio of 1: 5: petroleum ether) to obtain methyl 2, 5-dimethyl-5-ene-9-oxo-cycloheptane [ b ] pyridine-8-carboxylate as a compound 7, wherein the yield is 53 percent and 0.5 g;
1H NMR(400MHz,Chloroform-d)δ12.35(s,1H),7.76(d,J＝8.2Hz,1H),7.26(d,J＝8.2Hz,1H),6.08(t,J＝7.4Hz,1H),3.85(s,3H),2.69(s,3H),2.52(d,J＝7.0Hz,2H),2.09(s,3H)；13C NMR(100MHz,Chloroform-d)δ171.92,165.08,157.15,149.75,135.61,134.96,134.75,132.44,130.65,124.26,106.05,52.54,31.38,24.93,21.88.
g. dissolving 100mg (0.4mmol) of methyl 2, 5-dimethyl-5-ene-9-oxo-cyclohepta [ b ] pyridine-8-carboxylate serving as a compound 7 in 5ml of absolute methanol under ice bath, adding 30mg (0.8mmol) of sodium borohydride, naturally heating the system to room temperature, reacting for 5 hours, adding water to quench the reaction, removing the solvent, and purifying by column chromatography (mobile phase: ethyl acetate in a volume ratio of 1: 3: petroleum ether) to obtain the methyl 2, 5-dimethyl-5-ene-9-hydroxy-cyclohepta [ b ] pyridine-8-carboxylate serving as a compound 8, wherein the yield is 78% and 80 mg;
1H NMR(400MHz,DMSO-d6)δ7.71(d,J＝7.9Hz,1H),7.28(d,J＝7.9Hz,1H),6.03–5.96(m,1H),5.40(d,J＝5.4Hz,1H),4.81(t,J＝5.9Hz,1H),3.66(s,3H),3.49(dt,J＝10.8,6.6Hz,1H),2.52(s,3H),2.27–2.07(m,2H),2.04(s,3H)；
h. dissolving 100mg (0.4mmol) of 2, 5-dimethyl-5-ene-9-hydroxy-cyclohepta [ b ] pyridine-8-methyl formate of the compound 8 in 10ml of pyridine, heating to 60 ℃, adding 60mg (0.5mmol) of methylsulfonyl chloride, reacting for 5 hours, cooling to room temperature, adding water to quench the reaction, extracting with 30ml of dichloromethane to separate an organic phase, drying the organic phase with anhydrous magnesium sulfate, and purifying by column chromatography (mobile phase: ethyl acetate: petroleum ether in a volume ratio of 1: 5) to obtain 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-methyl formate of the compound 9, wherein the yield is 87% and 84 mg;
1H NMR(400MHz,Chloroform-d)δ1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.2Hz,1H),7.74(s,1H),7.15(d,J＝8.2Hz,1H),5.85(t,J＝7.3Hz,1H),3.82(s,3H),2.67(d,J＝7.2Hz,2H),2.62(s,3H),2.11(s,3H)；13C NMR(100MHz,Chloroform-d)δ167.15,156.77,152.60,138.30,135.85,135.17,134.96,133.33,126.87,122.27,52.60,24.95,24.77,22.29.
i. 50mg (0.2mmol) of compound 9, 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-methyl formate is dissolved in 10ml of anhydrous methanol, 20mg of 0.5% palladium carbon catalyst is added under ice bath, hydrogen is introduced, the reaction is stirred overnight at room temperature, the solvent is removed after the reaction is finished, and the compound 10, namely (5-methyl-8-methyl formate) -cyclohepta [ b ] pyridine-2-methyl, is respectively obtained by separation and purification by a thin layer chromatography (developing solvent: ethyl acetate: petroleum ether with the volume ratio of 1: 5).
1H NMR(400MHz,Chloroform-d)δ6.93(d,J＝7.7Hz,1H),7.31(d,J＝7.7Hz,1H),3.04–2.95(m,1H),1.86–1.74(m,2H),2.01–1.93(m,1H),2.17–2.07(m,1H),2.70–2.61(m,1H),3.31(d,J＝14.6,2.7Hz,1H),3.36(dd,J＝14.6,9.7Hz,1H),1.32(d,J＝7.3Hz,3H),3.64(s,3H),2.49(s,3H)；13C NMR(100MHz,Chloroform-d)δ157.19,121.16,136.05,37.41,32.05,28.96,41.80,40.26,154.46,137.68,175.49,51.43,18.66,23.60.
j. 50mg (0.2mmol) of compound 10 (methyl 5-methyl-8-carboxylate) -cyclohepta [ b ] pyridine-2-methyl is dissolved in anhydrous tetrahydrofuran, 5 times as much methyllithium (1.0mmol) is added, 1ml of water is added after completion of the reaction, after quenching the reaction, extraction is performed 3 ml. times.3 times, drying is performed over anhydrous magnesium sulfate, and column chromatography (mobile phase: ethyl acetate: petroleum ether in a volume ratio of 1: 1) is performed to purify to obtain compound 11 as { (5-methyl-8- (2-methyl 1-propanol)) } -cyclohepta [ b ] pyridine-2-methyl in 95% yield, 44.2mg.
1H NMR(600MHz,Chloroform-d)δ7.31(d,J＝7.7Hz,1H),6.93(d,J＝7.7Hz,1H),3.27–3.23(m,1H),3.05–3.00(m,2H),2.49(s,3H),1.89–1.84(m,1H),1.82–1.75(m,1H),1.73–1.67(m,1H),1.64–1.59(m,1H),1.49–1.41(m,1H),1.31(d,J＝7.2Hz,3H),1.27(s,3H),1.24(s,3H).13C NMR(150MHz,Chloroform-d)δ159.59,154.86,137.37,135.92,121.38,74.07,47.59,39.52,34.06,30.06,27.81,27.14,26.46,24.10,18.96.
k. Resolving compound 11 as { (5-methyl-8- (2-methyl 1-propanol)) } -cyclohepta [ b ] pyridine-2-methyl by semi-preparative high performance liquid chromatography (SHIMADZU LC-20A), chiral column CHIRALPAK ID (Lot No. ID00CE-QI011), enantiomers (mobile phase: n-hexane: ethanol in a volume ratio of 98: 2) to obtain compound 12 as ylanthranine; compound 13 is (5S,8S) -ylanthranine.
Compound 12 is ylanthine:1H NMR(400MHz,Chloroform-d)δ7.33(d,J＝7.7Hz,1H),6.94(d,J＝7.7Hz,1H),3.30–3.22(m,1H),3.09–3.01(m,2H),2.50(s,3H),1.91–1.82(m,1H),1.81–1.74(m,1H),1.74–1.66(m,1H),1.66–1.58(m,1H),1.50–1.38(m,1H),1.31(d,J＝7.2Hz,3H),1.27(s,3H),1.24(s,3H).13C NMR(101MHz,Chloroform-d)δ159.10,154.36,135.76,121.11,109.99,73.70,47.11,38.91,36.26,33.66,27.40,26.89,26.00,23.60,18.60.
compound 13 is (5S,8S) -ylanthranine:1H NMR(400MHz,Chloroform-d)δ7.33(d,J＝7.7Hz,1H),6.94(d,J＝7.7Hz,1H),3.30–3.22(m,1H),3.09–3.01(m,2H),2.50(s,3H),1.91–1.82(m,1H),1.81–1.74(m,1H),1.74–1.66(m,1H),1.66–1.58(m,1H),1.50–1.38(m,1H),1.31(d,J＝7.2Hz,3H),1.27(s,3H),1.24(s,3H).13C NMR(101MHz,Chloroform-d)δ159.10,154.36,135.76,121.11,109.99,73.70,47.11,38.91,36.26,33.66,27.40,26.89,26.00,23.60,18.60。
example 4
Any one of the compounds 12 obtained in examples 1-3 is ylacrine and its enantiomer 13 is (5S,8S) -ylacrine, the accurate molecular weight of which is measured by AB SCIEX Qstar Elite quadrupole-time-of-flight hybrid high-resolution mass spectrometer, the optical rotation value is measured by Rudolph RS Autopol VI automatic polar analyzer, the absolute configuration is determined by measuring EDC by Chirascan circular dichrograph experiment and calculating ECD spectrum comparison by COSMOlogic GmbH & Co.KG TmoleX 3.4 software, and the high-resolution mass spectrum of ylacrine (Cananodine) and its enantiomer is shown in FIGS. 1-2.
Claims (1)
1. A total synthesis and enantiomer resolution method of natural product (+/-) -ylacrine is characterized in that the natural product (+/-) -ylacrine in the method is obtained by taking a natural product (+/-) -achillea base G as a substrate and carrying out tetrahydrofuran/methyllithium reaction to obtain (+/-) -ylacrine and an enantiomer thereof, and then carrying out enantiomer resolution by using a chiral semi-preparative high performance liquid chromatograph, wherein the structural formula is as follows:
wherein:
compound 1 is 5-bromo-2-methylpyridine;
the compound 2 is N-oxy-5-bromo-2-methylpyridine;
compound 3 is 6-cyano-5-bromo-2-methylpyridine;
compound 4 is methyl 3- (3-bromo-6-methylpyridine) -3-carbonylpropionate;
compound 5 is 2- (3-bromo-6-methylpyridin-2-formyl) -4-enepentanoic acid methyl ester;
compound 6 is methyl 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoate;
compound 7 is 2, 5-dimethyl-5-en-9-oxo-cyclohepta [ b ] pyridine-8-carboxylic acid methyl ester;
compound 8 is 2, 5-dimethyl-5-en-9-hydroxy-cyclohepta [ b ] pyridine-8-carboxylic acid methyl ester;
compound 9 is 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-carboxylic acid methyl ester;
the compound 10 is (5-methyl-8-methyl formate) -cycloheptane [ b ] pyridine-2-methyl/{ (+ -) -alpine G };
compound 11 is { (5-methyl-8- (2-methyl-1-propanol)) } -cyclohepta [ b ] pyridine-2-methyl/{ (±) -ylanthranine };
compound 12 is ylacrine;
compound 13 is (5S,8S) -ylanthranine;
the specific operation is carried out according to the following steps:
a. dissolving 2.0g of 5-bromo-2-methylpyridine 1 in a dichloromethane solution, adding 2.9g of m-chloroperoxybenzoic acid with the purity of 85% in batches into the system under an ice bath, naturally heating to room temperature, stirring for overnight reaction, pouring reaction liquid into a saturated sodium sulfite solution for quenching after the reaction is finished, extracting for 3 times by using dichloromethane after stirring for 1 hour, combining organic phases, drying by using anhydrous magnesium sulfate, and removing an organic solvent to obtain a nitrogen oxidation product compound 2, namely 5-bromo-2-methyl-N-oxypyridine;
b. under the protection of nitrogen, 1.0g of compound 2, 5-bromo-2-methyl-N-oxypyridine, is dissolved in acetonitrile solution, 2.1g of trimethylsilyl cyanide and 2.2ml of triethylamine are sequentially added, after refluxing for 12 hours, the organic solvent is removed, and purification is carried out, thus obtaining compound 3, 3-bromo-6-methyl-2-cyanopyridine;
c. heating 7.2-8.0 g of crystal water, namely zinc chloride, in a mass ratio of 40:60 to melt and remove water under a vacuum state, sequentially adding 1, 2-dichloroethane, 5.5g of 3-bromo-6-methyl-2-cyanopyridine as a compound 3, 11g-13g of monomethyl malonate potassium salt and 1.5g-1.8g of diisopropylethylamine under the protection of nitrogen, stirring and refluxing for 12-16 hours, adding 6N hydrochloric acid after the system is cooled to room temperature, refluxing for 1 hour again, separating out an organic phase, extracting an aqueous phase for 3 times by using dichloromethane, combining the organic phases, drying by using anhydrous magnesium sulfate, removing an organic solvent, and purifying to obtain a compound 4, namely 3- (3-bromo-6-methylpyridine) -3-carbonyl methyl propionate;
d. dissolving 1.0g of compound 4 methyl 3- (3-bromo-6-methylpyridine) -3-carbonyl propionate in absolute ethyl alcohol, adding 0.6g-1.0g of sodium ethoxide in an ice bath, adding 0.7ml-1.0ml of 3-bromopropylene while stirring, reacting at room temperature overnight, removing the organic solvent, and purifying by column chromatography to obtain compound 5 methyl 2- (3-bromo-6-methylpyridine-2-formyl) -4-enevalerate;
e. dissolving 1.0g of compound 5, namely 2- (3-bromo-6-methylpyridine-2-formyl) -4-pentenoic acid methyl ester, in a mixed solution of dioxane and water, adding 0.4g to 0.8g of palladium tetratriphenylphosphine catalyst, 1g to 1.5g of sodium carbonate and 0.71ml to 1.0ml of isopropenylboronic acid pinacol ester, stirring, heating and refluxing for 3 to 5 hours, removing the solvent after the system is cooled to room temperature, and purifying by column chromatography to obtain compound 6, namely 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoic acid methyl ester;
f. under the protection of nitrogen, dissolving 1.0g of compound 6, namely 2- (3-isopropenyl-6-methylpyridine-2-formyl) -4-pentenoic acid methyl ester, into a dichloromethane solution, adding 0.3g to 0.5g of Grubbs secondary catalyst, heating and refluxing for reaction for 12 to 16 hours, cooling the system to room temperature, removing the organic solvent, and carrying out column chromatography to obtain compound 7, namely 2, 5-dimethyl-5-ene-9-oxo-cyclohepta [ b ] pyridine-8-formic acid methyl ester;
g. dissolving 100mg of compound 7, namely 2, 5-dimethyl-5-alkene-9-oxo-cycloheptane [ b ] pyridine-8-methyl formate in absolute methanol under ice bath, adding 15mg-30mg of sodium borohydride, naturally heating to room temperature, adding water to quench the reaction after reacting for 3-5 hours, removing the solvent, performing column chromatography, and purifying to obtain compound 8, namely 2, 5-dimethyl-5-alkene-9-hydroxy-cycloheptane [ b ] pyridine-8-methyl formate;
h. dissolving 100mg of 2, 5-dimethyl-5-ene-9-hydroxy-cyclohepta [ b ] pyridine-8-methyl formate serving as the compound 8 in pyridine, heating to 60 ℃, adding 45mg-60mg of methylsulfonyl chloride, reacting for 3-5 hours, cooling to room temperature, adding water to quench the reaction, extracting with dichloromethane to separate an organic phase, drying the organic phase with anhydrous magnesium sulfate, and purifying by column chromatography to obtain 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-methyl formate serving as the compound 9;
i. dissolving 50mg of compound 9, namely 2, 5-dimethyl-5, 8-diene-cyclohepta [ b ] pyridine-8-methyl formate in absolute methanol, adding 15mg-20mg of palladium carbon catalyst in ice bath, introducing hydrogen, stirring at room temperature overnight for reaction, removing the solvent, and separating and purifying by using a thin layer chromatography method to obtain compound 10, namely (5-methyl-8-methyl formate) -cyclohepta [ b ] pyridine-2-methyl;
j. dissolving 50mg of compound 10 (5-methyl-8-methyl formate) -cyclohepta [ b ] pyridine-2-methyl in dry tetrahydrofuran, placing the system at the temperature of-10 ℃, adding 3-5 times of methyllithium, adding water to quench the reaction after reacting for 1 hour, extracting 3 times by using dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, filtering solids, and removing the solvent from the filtrate to obtain compound 11 { (5-methyl-8- (2-methyl-1-propanol)) } -cyclohepta [ b ] pyridine-2-methyl;
k. resolving compound 11 as { (5-methyl-8- (2-methyl-1-propanol)) } -cyclohepta [ b ] pyridin-2-methyl by semi-preparative high performance liquid chromatography to give compound 12 as ylanthranine and compound 13 as (5S,8S) -ylanthranine.
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