CN109942593A - A kind of total synthesis method of racemization hanfangchin A - Google Patents
A kind of total synthesis method of racemization hanfangchin A Download PDFInfo
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Abstract
The invention discloses a kind of total synthesis methods of racemization hanfangchin A, belong to technical field of medicine synthesis, synthetic route of the invention is using convergence synthesis mode, it is respectively that starting material respectively obtains compound 4 and compound 6 with 5- bromine vanillic aldehyde, that is, compound 1 and 3- hydroxyl -4- methoxyphenylacetic acid, that is, compound 5, then compound 4 and compound 6 are that Material synthesis obtains compound 11 after, it is synthesized to obtain compound 19 by compound 11 again, finally reacted by compound 11 with compound 19, combined coefficient is higher, yield is higher, and cost is lower；Reaction condition is milder, easy to operate, more has the value of industry amplification, and the total synthesis method for optical voidness hanfangchin A provides reference.
Description
Technical field
The present invention relates to technical field of medicine synthesis more particularly to a kind of total synthesis methods of racemization hanfangchin A.
Background technique
Hanfangchin A, also known as tetrandrine or tetrandrine are the one kind being present in menispermaceous plants Stephania tetrandra root
Alkaloid has and resists myocardial ischemia, inhibits platelet aggregation, spasmolysis, analgesia, calmness, anti-inflammatory, antiulcer, liver protection, adjusting immune
The effects of power and resist oxygen lack.Hanfangchin A has been listed for treating the diseases such as hypertension, rheumatalgia, arthralgia, neuralgia
The drug of disease.It merges with low dose of radiological agent can be used for lung cancer therapy, also can be used for simple silicosis I, II, III phase and each phase
The treatment of quartz lung.
It is industrially that separation is extracted by the root to Stephania tetrandra to produce hanfangchin A.But in Stephania tetrandra root
Total alkaloid content is 1.5-2.3%, and the content of hanfangchin A is about 1%.Therefore, the side by being extracted from Stephania tetrandra root
Method has the disadvantages that 1, Stephania tetrandra plant resources are gradually rare to produce hanfangchin A, and supply falls short of demand.2, production efficiency compared with
Low, extraction process is complicated；3, quantity of three wastes is big in production process, and environmental protection pressure is big.
Although also there is the report using hanfangchin B as Material synthesis hanfangchin A at present, Stephania tetrandra second
Element is used as raw material, however it remains above-mentioned similar problem.
Chemical complete synthesizing process production drug has the advantage that 1, raw material is cheap and easy to get, unrestricted；2, related in production
Raw material, intermediate, solvent etc. can multiple recovery, quantity of three wastes is few；3, can continuous production, realize prepare with scale.So opening
Hair chemical synthesis production hanfangchin A has a very important significance, and the fully synthetic research of hanfangchin A is for exploitation
The chemical synthesis production technology of hanfangchin A has highly important directive function.
Currently, the fully synthetic side that only J. Chem. Soc. 1969,1547 ~ 1556 reports a kind of hanfangchin A
Method, this method using 4- methoxyl group -3- hydroxy acetophenone as Material synthesis 4- benzyloxy -3- methoxyphenylacetic acid, then with 3,4- bis-
Methoxyl group -5- Bretylium Tosylate carries out acid amide condensation, the synthesising racemation after Bischler-Napieralski reaction, reduction reaction
Tetrahydroisoquinoline intermediate obtains carrying out after S- tetrahydroisoquinoline methylation reaction by splitting, then with N- tertbutyloxycarbonyl -3-
O- methyldopamine carries out intermolecular Ullmann condensation, then occurs to divide again after hydrogenated de- benzyl and to bromo-acid methyl esters
Ullmann condensation reaction between son is condensed into ester with p-nitrophenol after hydrolysis of ester group under alkaline condition, after sloughing Boc protecting group
The transesterification of intramolecular amine occurs, Bischler-Napieralski reaction, reduction reaction, the methylation that intramolecular then occurs are anti-
It answers, finally and picric acid is at salt, isolated optical voidness hanfangchin A.
This method route is tediously long, cumbersome, and splits inefficiency, and total recovery is only 1% or so, it is difficult to realize industry
Metaplasia produces.Therefore, a fully synthetic route of hanfangchin A capable of being industrialized is developed to be of great significance.
Summary of the invention
The object of the invention is that a kind of total synthesis method of new racemization hanfangchin A is provided, to solve above-mentioned ask
Topic.
To achieve the goals above, the technical solution adopted by the present invention is that such: a kind of full conjunction that racemization hanfangchin A is new
At method, using vanillic aldehyde and 5- bromine vanillic aldehyde as starting material, racemization hanfangchin A is obtained by multistep reaction, synthesizes road
Line is as follows:
In conjunction with said synthesis route, specific steps are as follows:
(1) with 5- bromine vanillic aldehyde (compound 1) for starting material, synthesis compound is reacted with methylating reagent under alkaline condition
2；
(2) compound 2 and nitromethane under the action of catalyst, react synthesis compound 3 by Henry；
(3) compound 3 passes through reducing agent reduction synthesis compound 4；
(4) with 3- hydroxyl -4- methoxyphenylacetic acid (compound 5) for raw material, the synthesisization after hydroxyl protection under alkaline condition
Close object 6；
(5) compound 4 and compound 6 synthesize compound 7 by acid amide condensation reaction under condensing agent effect；
(6) compound 7 carries out intramolecular condensation in anhydrous inert solvent under dehydrating agent effect, and dehydration ring closure synthesizes chemical combination
Object 8；
(7) compound 8 passes through reducing agent reduction synthesis compound 9；
(8) compound 9 reacts synthesis compound 10 with methylating reagent；
(9) compound 10 synthesizes compound 11 after sloughing hydroxyl protection base in acid condition；
(10) with vanillic aldehyde (compound 12) for raw material, compound 13 is synthesized after hydroxyl protection under alkaline condition；
(11) compound 13 and nitromethane under the action of catalyst, react synthesis compound 14 by Henry；
(12) compound 14 passes through reducing agent reduction synthesis compound 15；
(13) compound 15 with to bromo-acid condensing agent effect under, by acid amide condensation reaction synthesize compound 16；
(14) compound 16 carries out intramolecular condensation, dehydration ring closure synthesisization under dehydrating agent effect in anhydrous inert solvent
Close object 17；
(15) compound 17 passes through reducing agent reduction synthesis compound 18；
(16) compound 18 reacts synthesis compound 19 with methylating reagent；
(17) compound 11 and compound 19 are under the action of catalyst, anti-by intermolecular Ullmann under alkalinity, hot conditions
Compound 20 should be synthesized；
(18) compound 20 synthesizes compound 21 after sloughing hydroxyl protection base in acid condition；
(19) compound 21 under the action of catalyst, synthesizes chemical combination by intramolecular Ullmann reaction under alkalinity, hot conditions
Object 22, i.e. racemization hanfangchin A.
As a preferred technical scheme: in the step (1), alkaline reagent is selected from potassium carbonate, sodium carbonate, cesium carbonate, hydrogen
One of sodium oxide molybdena, potassium hydroxide, triethylamine or pyridine, further preferably sodium hydroxide；Methylating reagent is selected from sulfuric acid
One of dimethyl ester, dimethyl carbonate, iodomethane, bromomethane or methyl tosylate, further preferably iodomethane；It is molten
Agent is selected from one of methylene chloride, chloroform, methanol, ethyl alcohol, acetonitrile, tetrahydrofuran, benzene, toluene or water or a variety of, further
Preferably methylene chloride.
As a preferred technical scheme: in the step (1), 5- bromine vanillic aldehyde (compound 1) and methylating reagent mole
Than for 1:1 ~ 1:4, reaction temperature is 20 ~ 100oC, reaction time are 2 ~ 20 hours.
As a preferred technical scheme: in the step (2), catalyst be selected from sodium hydroxide, potassium hydroxide, sodium carbonate,
One of potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine, preferably triethylamine；Solvent is selected from nitromethane, first
One of alcohol, ethyl alcohol, isopropanol, acetic acid, DMF or DMSO, further preferred ethyl alcohol.
As a preferred technical scheme: in the step (2), the molar ratio of compound 2 and nitromethane is 1:1 ~ 1:10,
Catalyst amount is the 10% ~ 80% of 2 weight of compound, reaction temperature 50oFor C to flowing back, the reaction time is 10 ~ 20 hours.
As a preferred technical scheme: in the step (3), reducing agent is selected from sodium borohydride, potassium borohydride, lithium aluminium hydride reduction
Or one or more of borine, further preferred lithium aluminium hydride reduction；Solvent is in methanol, ethyl alcohol, tetrahydrofuran, benzene or toluene
One kind, further preferred tetrahydrofuran.
As a preferred technical scheme: in the step (3), the molar ratio of compound 3 and reducing agent is 1:1 ~ 1:10, instead
Answering temperature is 30oFor C to flowing back, the reaction time is 6 ~ 20 hours.
As a preferred technical scheme: in the step (4), alkaline reagent is selected from sodium hydroxide, potassium hydroxide, carbonic acid
One of sodium, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine, further preferred sodium hydroxide；Hydroxyl protection
Base be selected from trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triisopropylsilyl, benzyl, to methoxyl group
One of benzyl, methoxy or 2- ethoxyethyl group, further preferred benzyl；Solvent is selected from methanol, ethyl alcohol, isopropyl
One of alcohol, methylene chloride, chloroform, pyridine or DMF, further preferred methanol.
As a preferred technical scheme: in the step (4), the molar ratio of compound 5 and hydroxy protecting agent be 1:1 ~
1:4, reaction temperature 30oFor C to flowing back, the reaction time is 3 ~ 10 hours.
As a preferred technical scheme: in the step (5), condensing agent in CDI, EDCI, HATU or HBTU one
Kind, preferably CDI；Solvent is selected from one of methylene chloride, chloroform or DMF, further preferred methylene chloride.
As a preferred technical scheme: in the step (5), the molar ratio of compound 4 and compound 6 is 1:1 ~ 1:1.5,
The molar ratio of compound 4 and condensing agent is 1:1 ~ 1:3, and reaction temperature is 0 ~ 60oC, reaction time are 1 ~ 5 hour.
As a preferred technical scheme: in the step (6), dehydrating agent is selected from phosphorus oxychloride, phosphorus pentoxide, poly phosphorus
One of acid or trifluoroacetic anhydride, preferably phosphorus oxychloride；Anhydrous inert solvent is selected from methylene chloride, chloroform, tetrahydro furan
It mutters, one of benzene, toluene or nitrobenzene, further preferred toluene.
As a preferred technical scheme: in the step (6), the molar ratio of compound 7 and dehydrating agent is 1:1 ~ 1:20, instead
Answering temperature is 30oFor C to flowing back, the reaction time is 2 ~ 8 hours.
As a preferred technical scheme: in the step (7), reducing agent in sodium borohydride or potassium borohydride one
Kind, further preferred potassium borohydride；Solvent is selected from one of methanol, ethyl alcohol, isopropanol or tetrahydrofuran, further preferred second
Alcohol.
As a preferred technical scheme: in the step (7), the molar ratio of compound 8 and reducing agent is 1:1 ~ 1:10, instead
Answering temperature is 0 ~ 50oC, reaction time are 1 ~ 5 hour.
As a preferred technical scheme: in the step (8), methylating reagent is selected from iodomethane, dimethyl suflfate, carbonic acid
One of dimethyl ester, methyl tosylate or formaldehyde/formic acid, further preferred methyl tosylate；Solvent is selected from four
One of hydrogen furans, acetonitrile, acetone or DMF, further preferred DMF.
As a preferred technical scheme: in the step (8), the molar ratio of compound 9 and methylating reagent is 1:1 ~ 1:
3, reaction temperature 30oFor C to flowing back, the reaction time is 2 ~ 6 hours.
As a preferred technical scheme: in the step (9), acid reagent is selected from acetic acid, trifluoracetic acid, hydrochloric acid or hydrogen bromine
One of acid, further preferred trifluoracetic acid；Solvent is selected from one of methanol, ethyl alcohol or isopropanol, further preferred first
Alcohol.
As a preferred technical scheme: in the step (9), the molar ratio of compound 10 and acid reagent is 1:20 ~ 1:
200, reaction temperature 40oFor C to flowing back, the reaction time is 4 ~ 10 hours.
As a preferred technical scheme: in the step (10), alkaline reagent is selected from sodium hydroxide, potassium hydroxide, carbonic acid
One of sodium, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine, further preferred sodium hydroxide；Hydroxyl protection
Base be selected from trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate, triisopropylsilyl, benzyl, to methoxyl group
One of benzyl, methoxy or 2- ethoxyethyl group, further preferred benzyl；Solvent is selected from methanol, ethyl alcohol, isopropyl
One of alcohol, methylene chloride, chloroform, pyridine or DMF, further preferred methylene chloride.
As a preferred technical scheme: in the step (10), vanillic aldehyde (compound 12) rubs with hydroxy protecting agent
You are than being 1:1 ~ 1:4, reaction temperature 30oFor C to flowing back, the reaction time is 3 ~ 10 hours.
As a preferred technical scheme: in the step (11), catalyst be selected from sodium hydroxide, potassium hydroxide, sodium carbonate,
One of potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine, further preferred triethylamine；Solvent is selected from nitro first
One of alkane, methanol, ethyl alcohol, isopropanol, acetic acid, DMF or DMSO, further preferred ethyl alcohol.
As a preferred technical scheme: in the step (11), the molar ratio of compound 13 and nitromethane is 1:1 ~ 1:
10, catalyst amount is the 10% ~ 80% of 13 weight of compound, reaction temperature 50oFor C to flowing back, the reaction time is 10 ~ 20 small
When.
As a preferred technical scheme: in the step (12), reducing agent is selected from sodium borohydride, potassium borohydride, aluminum hydride
One or more of lithium or borine, further preferred lithium aluminium hydride reduction；Solvent is selected from methanol, ethyl alcohol, tetrahydrofuran, benzene or toluene
One of, further preferred tetrahydrofuran.
As a preferred technical scheme: in the step (12), the molar ratio of compound 14 and reducing agent is 1:1 ~ 1:10,
Reaction temperature is 30oFor C to flowing back, the reaction time is 6 ~ 20 hours.
As a preferred technical scheme: in the step (13), condensing agent in CDI, EDCI, HATU or HBTU one
Kind, further preferred CDI；Solvent is selected from one of methylene chloride, chloroform or DMF, further preferred methylene chloride.
As a preferred technical scheme: in the step (13), compound 15 with to the molar ratio of bromo-acid be 1:1 ~
The molar ratio of 1:1.5, compound 15 and condensing agent is 1:1 ~ 1:3, and reaction temperature is 0 ~ 60oC, reaction time are 1 ~ 5 hour.
As a preferred technical scheme: in the step (14), dehydrating agent is selected from phosphorus oxychloride, phosphorus pentoxide, poly
One of phosphoric acid or trifluoroacetic anhydride, further preferred phosphorus oxychloride；Anhydrous inert solvent is selected from methylene chloride, three chloromethanes
One of alkane, tetrahydrofuran, benzene, toluene or nitrobenzene, further preferred toluene.
As a preferred technical scheme: in the step (14), the molar ratio of compound 16 and dehydrating agent is 1:1 ~ 1:20,
Reaction temperature is 30oFor C to flowing back, the reaction time is 2 ~ 10 hours.
As a preferred technical scheme: in the step (15), reducing agent in sodium borohydride or potassium borohydride one
Kind, further preferred potassium borohydride；Solvent is selected from one of methanol, ethyl alcohol, isopropanol or tetrahydrofuran, further preferred second
Alcohol.
As a preferred technical scheme: in the step (15), the molar ratio of compound 17 and reducing agent is 1:1 ~ 1:10,
Reaction temperature is 0 ~ 50oC, reaction time are 1 ~ 5 hour.
As a preferred technical scheme: in the step (16), methylating reagent is selected from iodomethane, dimethyl suflfate, carbon
One of dimethyl phthalate, methyl tosylate or formaldehyde/formic acid, further preferred methyl tosylate；Solvent is selected from
One of tetrahydrofuran, acetonitrile, acetone or DMF, further preferred DMF.
As a preferred technical scheme: in the step (16), the molar ratio of compound 18 and methylating reagent be 1:1 ~
1:3, reaction temperature 50oFor C to flowing back, the reaction time is 2 ~ 6 hours.
As a preferred technical scheme: in the step (17), catalyst is selected from copper powder, copper oxide, cuprous oxide, iodate
One of cuprous or cuprous bromide dimethyl sulphide mixture, further preferred cuprous iodide；Alkaline reagent be selected from sodium hydroxide,
One of potassium hydroxide, potassium carbonate, cesium carbonate or triethylamine, further preferred cesium carbonate；Solvent is selected from pyridine, acetonitrile, first
One of benzene, DMF or DMSO, further preferred DMF.
As a preferred technical scheme: in the step (17), the molar ratio of compound 11 and compound 19 be 1:0.5 ~
The molar ratio of 1:2, compound 11 and alkaline reagent is 1:1 ~ 1:5, and catalyst amount is the 5% ~ 50% of 11 weight of compound, reaction
Temperature is 70oFor C to flowing back, the reaction time is 24 ~ 72 hours.
As a preferred technical scheme: in the step (18), acid reagent is selected from acetic acid, trifluoracetic acid, hydrochloric acid or hydrogen
One of bromic acid, further preferred trifluoracetic acid；Solvent is selected from one of methanol, ethyl alcohol or isopropanol, further preferably
Methanol.
As a preferred technical scheme: in the step (18), the molar ratio of compound 20 and acid reagent is 1:20 ~ 1:
200, reaction temperature 40oFor C to flowing back, the reaction time is 4 ~ 10 hours.
As a preferred technical scheme: in the step (19), catalyst is selected from copper powder, copper oxide, cuprous oxide, iodate
One of cuprous or cuprous bromide dimethyl sulphide mixture, further preferred cuprous iodide；Alkaline reagent be selected from sodium hydroxide,
One of potassium hydroxide, potassium carbonate, cesium carbonate or triethylamine, further preferred cesium carbonate；Solvent is selected from pyridine, acetonitrile, first
One of benzene, DMF or DMSO, further preferred DMF.
As a preferred technical scheme: in the step (19), the molar ratio of compound 21 and alkaline reagent is 1:1 ~ 1:
5, catalyst amount is the 5% ~ 50% of 21 weight of compound, reaction temperature 70oFor C to flowing back, the reaction time is 24 ~ 72 hours.
Compared with the prior art, the advantages of the present invention are as follows: synthetic route of the invention is using convergence synthesis mode
To be respectively synthesized compound 4 and compound 6 simultaneously, compound 11 is obtained, then synthesized to obtain compound 19 by compound 11, finally
Reacted by compound 11 with compound 19, combined coefficient is higher, and yield is higher, this patent method yield up to 1.7 %-2.2 %,
Under conditions of not considering solvent recovery, the cost for having literature procedure is 15.6 ten thousand yuan/kilogram or so, the side of the application
The cost of method is 5.5 ten thousand yuan/kilogram or so, and the cost of the fully synthetic target product of this method is greatly lowered；This method is anti-
It answers condition milder, has in method reported in the literature, acid amide condensation step reaction temperature has reached 190 DEG C or so,
Ullmann setting-up point is about 145-150 DEG C, well beyond the boiling point of reaction dissolvent, there are greater risk, and it is our
In method, only Ullmann setting-up point is higher, is reacted under reaction dissolvent reflux temperature, safety greatly improves.
This method post-processing is all made of the modes such as extraction, washing, concentration or crystallization, easy to operate, more has the value of industry amplification,
Total synthesis method for optical voidness hanfangchin A provides reference.
Specific embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment 1
(1) preparation of compound 2
100 g 5- bromine vanillic aldehydes and 1000 g methylene chloride are added in 3 L there-necked flasks, dissolution clarification is stirred at room temperature.It is added 200
20% NaOH solution of g reacts at room temperature 1 hour.100 g iodomethane are added, are heated to back flow reaction 10 hours, raw material reaction
Completely.Reaction solution is down to room temperature, stands liquid separation, and water phase is extracted twice with 200 g methylene chloride.Merge methylene chloride phase, respectively
Primary with 500 g saturated salt solutions, 500 g water washings, anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain yellow
90.3 g of solid, as compound 2, yield 85.1%.
(2) preparation of compound 3
100 g compounds 2,62 g triethylamines, 125 g nitromethanes and 500 g dehydrated alcohols are added in 2 L there-necked flasks, heat
To back flow reaction 12 hours, raw material fully reacting.Reaction solution is down to room temperature, and 500 g water are added, a large amount of solids are precipitated.Filtering, filter
Cake is stirred with water to be washed twice, and isopropanol, which stirs, to be washed twice, and 60oC is dry, obtains 89.4 g of yellow solid, as compound 3, yield
76.1%。
(3) preparation of compound 4
570 g tetrahydrofurans and 22.8 g lithium aluminium hydride reductions are added in 2 L there-necked flasks, are cooled to -5oC or so；By 57 g compounds
3 are dissolved in 228 g tetrahydrofurans, are slowly added dropwise into above-mentioned there-necked flask, and drop finishes, and are heated to back flow reaction 8 hours, raw material reaction
Completely.It is cooled to 0o280 g ethyl acetate, 150 g water quenching reactions are successively added dropwise in C or so.It is small that sodium sulphate stirring half is added
When after filter, filtrate decompression is concentrated to dryness, and adjusts pH=2 or so with 10% dilute hydrochloric acid, 500 g ethyl acetate extracting impurities are twice.
Water phase uses 20% sodium hydroxide solution to adjust pH=10 or so again, and 500 g methylene chloride are extracted twice.Merging methylene chloride phase, 200
G is washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and are obtained 38.8 g of yellow oil, are solidified after cooling,
As compound 4, yield 75.4%.
(4) preparation of compound 6
45 g compounds 5,1.6 g potassium iodide, 38 g potassium hydroxide and 350 g methanol are added in 1 L there-necked flask, are added dropwise at room temperature
64 g cylites.Drop finishes, and is heated to back flow reaction 8 hours, raw material fully reacting.It is down to room temperature, 150 g water are added, it is dilute with 10%
A large amount of solids are precipitated in salt acid for adjusting pH=1 or so.Filtering, filter cake is stirred with water to be washed twice, and 60oC is dry, obtains yellow solid 61.8
G, as compound 6, yield 91.9%.
(5) preparation of compound 7
The 30 g methylene chloride of g compound 6 and 500 are added in 1 L there-necked flask, 21 g CDI are added portionwise after dissolution clarification.Add
Finish, 26 g compounds 4 are added after 2 hours in room temperature reaction, and the reaction was continued 2 hours, raw material fully reacting.260 g water quenchings are added to go out
Reaction, stands liquid separation, and water phase is extracted twice with 260 g methylene chloride.Merge methylene chloride phase, 400 g are washed twice, anhydrous sulphur
Sour sodium is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain light yellow oil, obtain faint yellow solid after the crystallization of 150 g isopropanols
37.1 g, as compound 7, yield 72.1%.
(6) preparation of compound 8
20 g compounds 7,46.8 g phosphorus oxychloride and 400 g toluene are added in 1 L there-necked flask, are heated to flowing back under nitrogen protection
Reaction 6 hours, raw material fully reacting.It is down to room temperature, 300 g water are slowly added dropwise into reaction solution, drop finishes, and continues stirring 1 hour.
Liquid separation is stood, toluene is mutually washed twice with 300 g again, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain yellow
13.5 g of grease, as compound 8, yield 69.9%.
(7) preparation of compound 9
The 10 g ethyl alcohol of g compound 8 and 200 are added in 500 mL there-necked flasks, 4 g potassium borohydrides are added portionwise after dissolution clarification.Add
Finish, is heated to 40oC reacts 3 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 150 g water is added, with 200 g bis-
Chloromethanes is extracted twice, and merges methylene chloride phase, and 200 g are washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression concentration
To doing, 9.8 g of yellow oil, as compound 9, yield 97.6% are obtained.
(8) preparation of compound 10
The 9 g DMF of g compound 9 and 45, dissolution clarification are added in 250 mL there-necked flasks.It is cooled to 15o1.5 g are added in C or so
Potassium hydroxide, insulation reaction 1 hour.4 g methyl tosylates are dissolved in 9 g DMF, are added drop-wise in above-mentioned there-necked flask.
Drop finishes, and is heated to 50oC or so reacts 4 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 45 g water is added, with 90
G ethyl acetate is extracted twice.Combined ethyl acetate phase, 90 g are washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are dense
Be reduced to dry, obtain grease, after the crystallization of 36 g dehydrated alcohols 4.8 g of off-white powder, as compound 10, yield 51.9%.
(9) preparation of compound 11
5 g compounds 10,33 g trifluoracetic acids and 50 g methanol are added in 250 mL there-necked flasks, are heated to flowing back under nitrogen protection
Reaction 6 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 50 g water are added, saturated sodium bicarbonate solution is slowly added dropwise
PH=8 or so are adjusted, are extracted twice with 100 g methylene chloride.Merge methylene chloride phase, 100 g are washed twice, anhydrous sodium sulfate
It is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain 3.9 g of white solid, as compound 11, yield 94.6%.
(10) preparation of compound 13
152 g vanillic aldehydes, 16.6 g potassium iodide, 48 g sodium hydroxides and 1200 g methylene chloride, room temperature are added in 2 L there-necked flasks
205 g cylites of lower dropwise addition.Drop finishes, and is heated to back flow reaction 8 hours, raw material fully reacting.It is down to room temperature, is filtered, filtrate is used
800 g, 5% sodium hydroxide solution is washed twice, and 400 g washing is primary, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated into
It is dry, yellow oil is obtained, obtains 168 g of white solid, as compound 13, yield 69.4% after the crystallization of 450 g petroleum ethers.
(11) preparation of compound 14
109 g compounds 13,68 g triethylamines, 110 g nitromethanes and 545 g dehydrated alcohols are added in 2 L there-necked flasks, heat
To back flow reaction 12 hours, raw material fully reacting.Reaction solution is down to room temperature, and 545 g water are added, a large amount of solids are precipitated.Filtering, filter
Cake is stirred with water to be washed twice, and isopropanol, which stirs, to be washed twice, and 60oC is dry, obtains 111 g of yellow solid, as compound 14, yield
86.5%。
(12) preparation of compound 15
572 g tetrahydrofurans and 22.8 g lithium aluminium hydride reductions are added in 2 L there-necked flasks, are cooled to -5oC or so；By 57.2 g chemical combination
Object 14 is dissolved in 229 g tetrahydrofurans, is slowly added dropwise into above-mentioned there-necked flask, and drop finishes, and is heated to back flow reaction 8 hours, raw material
Fully reacting.It is cooled to 0o280 g ethyl acetate, 150 g water quenching reactions are successively added dropwise in C or so.Sodium sulphate stirring is added
It is filtered after half an hour, filtrate decompression is concentrated to dryness, and adjusts pH=2 or so, 500 g ethyl acetate extracting impurities two with 10% dilute hydrochloric acid
It is secondary.Water phase uses 20% sodium hydroxide solution to adjust pH=10 or so again, and 500 g methylene chloride are extracted twice.Merge methylene chloride phase,
200 g are washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and 44.8 g of yellow oil are obtained, after cooling
Solidification, as compound 15, yield 86.8%.
(13) preparation of compound 16
27.9 g are added in 1 L there-necked flask to bromo-acid and 500 g methylene chloride, 32.4 g are added portionwise after dissolution clarification
CDI.It finishes, 25.7 g compounds 15 are added after 2 hours in room temperature reaction, and the reaction was continued 2 hours, raw material fully reacting.It is added 260
G water quenching reaction, stands liquid separation, and water phase is extracted twice with 260 g methylene chloride.Merge methylene chloride phase, 400 g washing two
Secondary, anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain light yellow oil, after the crystallization of 129 g isopropanols
34.4 g of faint yellow solid, as compound 16, yield 75.7%.
(14) preparation of compound 17
22.7 g compounds 16,61.3 g phosphorus oxychloride and 454 g toluene are added in 1 L there-necked flask, are heated under nitrogen protection
Back flow reaction 6 hours, raw material fully reacting.It is down to room temperature, 340 g water are slowly added dropwise into reaction solution, drop finishes, and continues stirring 1
Hour.Liquid separation is stood, toluene is mutually washed twice with 300 g again, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, obtain
17.8 g of yellow oil, as compound 17, yield 81.6%.
(15) preparation of compound 18
The 10.9 g ethyl alcohol of g compound 17 and 218 are added in 500 mL there-necked flasks, 5.4 g hydroborations are added portionwise after dissolution clarification
Potassium.It finishes, is heated to 40oC reacts 3 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 150 g water are added, and is used
200 g methylene chloride are extracted twice, and merge methylene chloride phase, and 200 g are washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate subtract
Pressure is concentrated to dryness, and obtains 10.6 g of yellow oil, as compound 18, yield 96.8%.
(16) preparation of compound 19
The 8.8 g DMF of g compound 18 and 44, dissolution clarification are added in 250 mL there-necked flasks.It is cooled to 15oC or so is added 1.5
G potassium hydroxide, insulation reaction 1 hour.4 g methyl tosylates are dissolved in 9 g DMF, above-mentioned there-necked flask is added drop-wise to
In.Drop finishes, and is heated to 50oC or so reacts 4 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 45 g water are added,
It is extracted twice with 90 g ethyl acetate.Combined ethyl acetate phase, 90 g are washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate subtract
Pressure is concentrated to dryness, and obtains grease, obtains 7.0 g of off-white powder, as compound 19, yield after the crystallization of 36 g dehydrated alcohols
77.1%。
(17) preparation of compound 20
2.1 g compounds 11,2.3 g compounds 19,0.21 g cuprous iodide, 4.9 g cesium carbonates are added in 250 mL there-necked flasks
With 42 g DMF, back flow reaction is heated to 48 hours under nitrogen protection, raw material fully reacting.Reaction solution is concentrated to dryness, and is added
Enter 21 g water, adjusts pH=3 or so with 10% dilute hydrochloric acid, then be extracted twice with 82 g methylene chloride.Merge methylene chloride phase, with 82
G is washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, obtain brown solid, by column chromatographic purifying, obtain light
2.3 g of yellow solid, as compound 20, yield 58.3%.
(18) preparation of compound 21
2 g compounds 20,28.7 g trifluoracetic acids and 40 g methanol are added in 100 mL there-necked flasks, are heated to back under nitrogen protection
Stream reaction 6 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 40 g water are added, it is molten that saturated sodium bicarbonate is slowly added dropwise
Liquid adjusts pH=8 or so, is extracted twice with 80 g methylene chloride.Merge methylene chloride phase, 80 g are washed twice, anhydrous sodium sulfate
It is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain 1.7 g of white solid, as compound 21, yield 95.9%.
(19) preparation of racemization hanfangchin A (compound 22)
1.5 g compounds 21,0.3 g cuprous iodide, 2.1 g cesium carbonates and 75 g DMF, nitrogen are added in 250 mL there-necked flasks
Back flow reaction is heated under protection 60 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 30 g water are added, dilute with 10%
Salt acid for adjusting pH=3 or so, then be extracted twice with 60 g methylene chloride.Merge methylene chloride phase, it is twice with 60 g washing, anhydrous
Sodium sulphate is dry.Filtering, filtrate decompression are concentrated to dryness, obtain brown solid, by column chromatographic purifying, obtain 0.6 g of off-white powder,
As racemization hanfangchin A, yield 45.2%.
Embodiment 2
(1) preparation of compound 2
115 g 5- bromine vanillic aldehydes and 1150 g chloroforms are added in 3 L there-necked flasks, dissolution clarification is stirred at room temperature.It is added 200
20% NaOH solution of g reacts at room temperature 1 hour.130 g iodomethane are added, are heated to back flow reaction 10 hours, raw material reaction
Completely.Reaction solution is down to room temperature, stands liquid separation, water phase with 200 g chloroform extractions twice.Merge chloroform phase, respectively
Primary with 500 g saturated salt solutions, 500 g water washings, anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain yellow
95.2 g of solid, as compound 2, yield 78.0%.
(2) preparation of compound 3
131 g compounds 2,62 g potassium carbonate, 98 g nitromethanes and 500 g acetic acid are added in 2 L there-necked flasks, are heated to flowing back
Reaction 15 hours, raw material fully reacting.Reaction solution is down to room temperature, and 500 g water are added, a large amount of solids are precipitated.Filtering, filter cake water
It stirring and washes twice, isopropanol, which stirs, to be washed twice, and 60oC is dry, obtains 109 g of yellow solid, as compound 3, yield 70.8%.
(3) preparation of compound 4
560 g tetrahydrofurans and 27.6 g lithium aluminium hydride reductions are added in 2 L there-necked flasks, are cooled to -5oC or so；By 70 g compounds
3 are dissolved in 280 g tetrahydrofurans, are slowly added dropwise into above-mentioned there-necked flask, and drop finishes, and are heated to back flow reaction 8 hours, raw material reaction
Completely.It is cooled to 0o280 g ethyl acetate, 150 g water quenching reactions are successively added dropwise in C or so.It is small that sodium sulphate stirring half is added
When after filter, filtrate decompression is concentrated to dryness, and adjusts pH=2 or so with 10% dilute hydrochloric acid, 500 g ethyl acetate extracting impurities are twice.
Water phase uses 20% sodium hydroxide solution to adjust pH=10 or so again, and 500 g methylene chloride are extracted twice.Merging methylene chloride phase, 200
G is washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and are obtained 43.5 g of yellow oil, are solidified after cooling,
As compound 4, yield 68.8%.
(4) preparation of compound 6
50 g compounds 5,2.5 g potassium iodide, 75.7 g potassium carbonate and 400 g ethyl alcohol are added in 1 L there-necked flask, are added dropwise at room temperature
61 g cylites.Drop finishes, and is heated to back flow reaction 8 hours, raw material fully reacting.It is down to room temperature, 150 g water are added, it is dilute with 10%
A large amount of solids are precipitated in salt acid for adjusting pH=1 or so.Filtering, filter cake is stirred with water to be washed twice, and 60oC is dry, obtains yellow solid 67.5
G, as compound 6, yield 90.3%.
(5) preparation of compound 7
26 g compounds 4,30 g compounds 6,52 g HATU and 500 g methylene chloride are added in 1 L there-necked flask, are slowly added dropwise
26 g DIPEA, drop finish, and react at room temperature 3 hours, raw material fully reacting.Filtering, filtrate use respectively 200 g, 10% dilute hydrochloric acid,
200g saturated sodium bicarbonate is washed once, and 400 g are washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, obtain
Yellow solid obtains 34.1 g of faint yellow solid, as compound 7, yield 66.3% after the crystallization of 150 g isopropanols.
(6) preparation of compound 8
30 g compounds 7,75 g phosphorus oxychloride and 600 g toluene are added in 2 L there-necked flasks, it is anti-that reflux is heated under nitrogen protection
It answers 7 hours, raw material fully reacting.It is down to room temperature, 400 g water are slowly added dropwise into reaction solution, drop finishes, and continues stirring 1 hour.It is quiet
Liquid separation is set, toluene is mutually washed twice with 400 g again, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain yellow oil
19.8 g of shape object, as compound 8, yield 68.4%.
(7) preparation of compound 9
The 15 g methanol of g compound 8 and 300 are added in 500 mL there-necked flasks, 7 g sodium borohydrides are added portionwise after dissolution clarification.Add
Finish, is heated to 40oC reacts 3 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 150 g water is added, with 200 g bis-
Chloromethanes is extracted twice, and merges methylene chloride phase, and 200 g are washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression concentration
To doing, 14.2 g of yellow oil, as compound 9, yield 94.3% are obtained.
(8) preparation of compound 10
The 15 g methylene chloride of g compound 9 and 150 are added in 500 mL there-necked flasks, dissolution clarification is stirred at room temperature.20 g are added
20% NaOH solution reacts at room temperature 1 hour.6.4 g iodomethane are added, are heated to back flow reaction 5 hours, raw material has reacted
Entirely.Reaction solution is down to room temperature, stands liquid separation, water phase with 100 g chloroform extractions twice.Merge chloroform phase, uses respectively
100 g saturated salt solutions, 100 g water washings are primary, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and it is solid to obtain yellow
Body obtains 8.9 g of off-white powder, as compound 10, yield 57.7% after isopropanol crystallizes.
(9) preparation of compound 11
10 g compounds 10,150 g hydrochloric acid and 150 g ethyl alcohol are added in 500 mL there-necked flasks, are heated to flowing back under nitrogen protection
Reaction 8 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 50 g water are added, saturated sodium bicarbonate solution is slowly added dropwise
PH=8 or so are adjusted, are extracted twice with 100 g methylene chloride.Merge methylene chloride phase, 100 g are washed twice, anhydrous sodium sulfate
It is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain 7.6 g of white solid, as compound 11, yield 92.2%.
(10) preparation of compound 13
90 g vanillic aldehydes, 9 g potassium iodide, 90 g potassium carbonate and 450 g methylene chloride are added in 1 L there-necked flask, are added dropwise at room temperature
112 g cylites.Drop finishes, and is heated to back flow reaction 8 hours, raw material fully reacting.It is down to room temperature, is filtered, filtrate is with 400 g
5% sodium hydroxide solution is washed twice, and 200 g washing is primary, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, obtain yellow
Color grease obtains 102 g of white solid, as compound 13, yield 71.2% after the crystallization of 180 g petroleum ethers.
(11) preparation of compound 14
121 g compounds 13,138 g potassium carbonate, 83 g nitromethanes and 600 g acetic acid are added in 2 L there-necked flasks, are heated to back
Stream reaction 13 hours, raw material fully reacting.Reaction solution is down to room temperature, and 800 g water are added, a large amount of solids are precipitated.Filtering, filter cake are used
Water, which stirs, to be washed twice, and isopropanol, which stirs, to be washed twice, and 60oC is dry, obtains 119 g of yellow solid, as compound 14, yield 83.5%.
(12) preparation of compound 15
500 g tetrahydrofurans and 30 g lithium aluminium hydride reductions are added in 2 L there-necked flasks, are cooled to -5oC or so；By 50 g compounds 14
It is dissolved in 250 g tetrahydrofurans, is slowly added dropwise into above-mentioned there-necked flask, drop finishes, and is heated to back flow reaction 8 hours, raw material reaction
Completely.It is cooled to 0o250 g ethyl acetate, 150 g water quenching reactions are successively added dropwise in C or so.It is small that sodium sulphate stirring half is added
When after filter, filtrate decompression is concentrated to dryness, and adjusts pH=2 or so with 10% dilute hydrochloric acid, 400 g ethyl acetate extracting impurities are twice.
Water phase uses 20% sodium hydroxide solution to adjust pH=10 or so again, and 400 g methylene chloride are extracted twice.Merging methylene chloride phase, 200
G is washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and are obtained 38.1 g of yellow oil, are solidified after cooling,
As compound 15, yield 84.5%.
(13) preparation of compound 16
20 g compounds 15,20 g are added in 1 L there-necked flask to bromo-acid, 40 g HATU and 400 g methylene chloride, slowly
16 g DIPEA are added dropwise, drop finishes, and reacts at room temperature 3 hours, raw material fully reacting.Filtering, filtrate use the dilute salt of 200 g 10% respectively
Acid, 200g saturated sodium bicarbonate are washed once, and 400 g are washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness,
Yellow solid is obtained, obtains 26.1 g of faint yellow solid, as compound 7, yield 73.9% after the crystallization of 120 g isopropanols.
(14) preparation of compound 17
25 g compounds 16,75 g phosphorus oxychloride and 500 g toluene are added in 1 L there-necked flask, are heated to flowing back under nitrogen protection
Reaction 8 hours, raw material fully reacting.It is down to room temperature, 350 g water are slowly added dropwise into reaction solution, drop finishes, and continues stirring 1 hour.
Liquid separation is stood, toluene is mutually washed twice with 300 g again, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain yellow
20 g of grease, as compound 17, yield 83.3%.
(15) preparation of compound 18
The 15 g methanol of g compound 17 and 300 are added in 500 mL there-necked flasks, 9 g sodium borohydrides are added portionwise after dissolution clarification.
It finishes, is heated to 40oC reacts 3 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 150 g water is added, with 200 g
Methylene chloride is extracted twice, and merges methylene chloride phase, and 200 g are washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are dense
It is reduced to dry, obtains 14.5 g of yellow oil, as compound 18, yield 96.2%.
(16) preparation of compound 19
The 15 g methylene chloride of g compound 18 and 150 are added in 500 mL there-necked flasks, dissolution clarification is stirred at room temperature.20 g are added
20% NaOH solution reacts at room temperature 1 hour.6.8 g iodomethane are added, are heated to back flow reaction 6 hours, raw material has reacted
Entirely.Reaction solution is down to room temperature, stands liquid separation, water phase with 100 g chloroform extractions twice.Merge chloroform phase, uses respectively
100 g saturated salt solutions, 100 g water washings are primary, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and it is solid to obtain yellow
Body obtains 11.4 g of off-white powder, as compound 19, yield 73.6% after isopropanol crystallizes.
(17) preparation of compound 20
2.4 g compounds 11,2.0 g compounds 19, the mixing of 0.9 g cuprous bromide dimethyl sulphide are added in 250 mL there-necked flasks
Object, 4.2 g cesium carbonates and 40 g pyridines are heated to back flow reaction 48 hours under nitrogen protection, raw material fully reacting.Reaction solution
It is concentrated to dryness, 20g water is added, adjust pH=3 or so with 10% dilute hydrochloric acid, then be extracted twice with 80 g methylene chloride.Merge
Methylene chloride phase, twice with 80 g washing, anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain brown solid, are led to
Column chromatographic purifying is crossed, 1.9 g of faint yellow solid, as compound 20, yield 54.1% are obtained.
(18) preparation of compound 21
1.5 g compounds 20,30 g hydrochloric acid and 30 g methanol are added in 100 mL there-necked flasks, it is anti-that reflux is heated under nitrogen protection
It answers 6 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 30 g water are added, saturated sodium bicarbonate solution tune is slowly added dropwise
PH=8 or so are saved, are extracted twice with 60 g methylene chloride.Merge methylene chloride phase, 60 g are washed twice, and anhydrous sodium sulfate is dry.
Filtering, filtrate decompression are concentrated to dryness, and obtain 1.3 g of white solid, as compound 21, yield 97.8%.
(19) preparation of racemization hanfangchin A (compound 22)
Be added in 250 mL there-necked flasks 1.4 g compounds 21,0.6 g cuprous bromide dimethyl sulphide mixture, 1.8 g cesium carbonates and
70 g DMF are heated to back flow reaction 60 hours under nitrogen protection, raw material fully reacting.Reaction solution is concentrated to dryness, and is added
30 g water adjust pH=3 or so with 10% dilute hydrochloric acid, then are extracted twice with 60 g methylene chloride.Merge methylene chloride phase, with 60 g
Twice, anhydrous sodium sulfate is dry for washing.Filtering, filtrate decompression are concentrated to dryness, obtain brown solid, by column chromatographic purifying, obtain class
0.5 g of white solid, as racemization hanfangchin A, yield 40.4%.
Embodiment 3
(1) preparation of compound 2
50 g 5- bromine vanillic aldehydes and 500 g toluene are added in 1 L there-necked flask, dissolution clarification is stirred at room temperature.59 g carbonic acid are added
Potassium is cooled to 0 ~ 5 oC.41 g dimethyl suflfates are slowly added to, are finished, 40 oC is heated to and reacts 14 hours, raw material has reacted
Entirely.Reaction solution is concentrated to dryness, and 200 g of water is added, is extracted twice with 500 g methylene chloride.Merge methylene chloride phase, respectively
Primary with 200 g saturated salt solutions, 200 g water washings, anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain yellow
43.1 g of solid, as compound 2, yield 81.2%.
(2) preparation of compound 3
24.5 g compounds 2,8.2 g ammonium acetates, 20 g nitromethanes and 125 g isopropanols are added in 1 L there-necked flask, are heated to
75 oC react 17 hours, raw material fully reacting.Reaction solution is down to room temperature, and 200 g water are added, a large amount of solids are precipitated.Filtering, filter
Cake is stirred with water to be washed twice, and isopropanol, which stirs, to be washed twice, and 60 oC are dry, obtains 21.2 g of yellow solid, as compound 3, yield
73.7%。
(3) preparation of compound 4
200 g tetrahydrofurans and 12.2 g sodium borohydrides are added in 1 L there-necked flask, are cooled to 15 oC or so, 52 g are slowly added dropwise
Boron trifluoride ether solution；14.4 g compounds 3 are dissolved in 100 g tetrahydrofurans, are slowly added dropwise into above-mentioned there-necked flask, are dripped
Finish, is heated to back flow reaction 9 hours, raw material fully reacting.It is cooled to 0 oC or so, 150 g water quenching reactions are added dropwise.With 20%
Sodium hydroxide solution adjusts pH=10 or so, and 300 g methylene chloride are extracted twice.Merging methylene chloride phase, 200 g are washed twice,
Anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and are obtained 9.7 g of yellow oil, are solidified after cooling, as compound
4, yield 74.6%.
(4) preparation of compound 6
18.2 g compounds 5,0.5 g potassium iodide, 13.2 g sodium hydroxides and 180 g isopropanols are added in 500 mL there-necked flasks,
21.6 g benzyl chlorides are added dropwise at room temperature.Drop finishes, and is heated to 70 oC and reacts 6 hours, raw material fully reacting.It is down to room temperature, is added
150 g water adjust pH=2 or so with 10% dilute hydrochloric acid, a large amount of solids are precipitated.Filtering, filter cake is stirred with water to be washed twice, and 60 oC are dry,
Obtain 23.7 g of yellow solid, as compound 6, yield 86.9%.
(5) preparation of compound 7
13.6 g compounds 6, the 13 g DMF of g compound 4 and 80 are added in 250 mL there-necked flasks, are added portionwise after dissolution clarification
12.5 g EDCI.It finishes, 9 g DIPEA is slowly added dropwise, be heated to 50 oC and react 7 hours, raw material fully reacting.Reaction solution subtracts
Pressure is concentrated to dryness, and 80 g water are added, are extracted twice with 150 g methylene chloride.Merge methylene chloride phase, 100 g are washed twice, nothing
Aqueous sodium persulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain light yellow oil, are obtained after the crystallization of 70 g isopropanols faint yellow
17.2 g of solid, as compound 7, yield 67.1%.
(6) preparation of compound 8
17.1 g compounds 7,33.8 g polyphosphoric acids and 340 g benzene are added in 1 L there-necked flask, are heated to flowing back under nitrogen protection
Reaction 5 hours, raw material fully reacting.It is down to room temperature, 100 g water are slowly added dropwise into reaction solution, drop finishes, and uses saturated sodium bicarbonate
Solution adjusts pH=7 or so, continues stirring 1 hour.Liquid separation is stood, benzene is mutually washed twice with 300 g again, and anhydrous sodium sulfate is dry.
Filtering, filtrate decompression are concentrated to dryness, and obtain 10.7 g of yellow oil, as compound 8, yield 64.5%.
(7) preparation of compound 9
The 10 g isopropanols of g compound 8 and 200 are added in 500 mL there-necked flasks, 4.2 g hydroborations are added portionwise after dissolution clarification
Sodium.It finishes, is heated to 40 oC and reacts 3 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 150 g water are added, and is used
200 g methylene chloride are extracted twice, and merge methylene chloride phase, and 200 g are washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate subtract
Pressure is concentrated to dryness, and obtains 9.1 g of yellow oil, as compound 9, yield 90.7%.
(8) preparation of compound 10
The 10 g toluene of g compound 9 and 50, dissolution clarification are added in 250 mL there-necked flasks.5.1 g potassium carbonate are added, are cooled to 5
OC or so is slowly added to 3.8 g dimethyl suflfates.It finishes, is heated to 40 oC or so and reacts 5 hours, raw material fully reacting.Instead
It answers liquid to be concentrated to dryness, 45 g water is added, are extracted twice with 90 g ethyl acetate.Combined ethyl acetate phase, 90 g washing two
Secondary, anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain grease, obtain off-white color after the crystallization of 40g dehydrated alcohol
5.1 g of solid, as compound 10, yield 49.2%.
(9) preparation of compound 11
4g compound 10,30 g trifluoracetic acids and 40 g isopropanols are added in 250 mL there-necked flasks, are heated to back under nitrogen protection
Stream reaction 6 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 50 g water are added, it is molten that saturated sodium bicarbonate is slowly added dropwise
Liquid adjusts pH=8 or so, is extracted twice with 80 g methylene chloride.Merge methylene chloride phase, 80 g are washed twice, anhydrous sodium sulfate
It is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain 3.1 g of white solid, as compound 11, yield 95.1%.
(10) preparation of compound 13
76 g vanillic aldehydes, 7.6 g potassium iodide, 48 g sodium hydroxides and 600 g isopropanols are added in 2 L there-necked flasks, drip at room temperature
Add 100 g benzyl chlorides.Drop finishes, and is heated to 70 oC and reacts 8 hours, raw material fully reacting.It is down to room temperature, 150 g water are added, is used
10% dilute hydrochloric acid adjusts pH=2 or so, and a large amount of solids are precipitated.Filtering, filter cake cake is stirred with water to be washed twice, and 60 oC are dry, is obtained white solid
81.4 g of body, as compound 13, yield 67.3%.
(11) preparation of compound 14
80.7 g compounds 13,40 g ammonium acetates, 82 g nitromethanes and 400 g isopropanols are added in 1 L there-necked flask, are heated to
Back flow reaction 13 hours, raw material fully reacting.Reaction solution is down to room temperature, and 400 g water are added, a large amount of solids are precipitated.Filtering, filter cake
It is stirred and is washed twice with water, isopropanol, which stirs, to be washed twice, and 60 oC are dry, obtains 75.4 g of yellow solid, as compound 14, yield
79.4%。
(12) preparation of compound 15
200 g tetrahydrofurans and 12.2 g sodium borohydrides are added in 1 L there-necked flask, are cooled to 15 oC or so, 52 g are slowly added dropwise
Boron trifluoride ether solution；14.3 g compounds 3 are dissolved in 100 g tetrahydrofurans, are slowly added dropwise into above-mentioned there-necked flask, are dripped
Finish, is heated to back flow reaction 9 hours, raw material fully reacting.It is cooled to 0 oC or so, 150 g water quenching reactions are added dropwise.With 20%
Sodium hydroxide solution adjusts pH=10 or so, and 300 g methylene chloride are extracted twice.Merging methylene chloride phase, 200 g are washed twice,
Anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and are obtained 11.1 g of yellow oil, are solidified after cooling, as compound
15, yield 86.1%.
(13) preparation of compound 16
10.3 g are added in 250 mL there-necked flasks to bromo-acid, the 11.2 g DMF of g compound 15 and 100, divide after dissolution clarification
It criticizes and 12.1 g EDCI is added.It finishes, 8.6 g DIPEA is slowly added dropwise, be heated to 50 oC and react 7 hours, raw material fully reacting.
Reaction solution is concentrated to dryness, and 80 g water are added, are extracted twice with 150 g methylene chloride.Merge methylene chloride phase, 100 g water
It washes twice, anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain light yellow oil, after the crystallization of 70 g isopropanols
Obtain 13.8 g of faint yellow solid, as compound 16, yield 69.6%.
(14) preparation of compound 17
15.1 g compounds 16,30.2 g polyphosphoric acids and 300 g benzene are added in 1 L there-necked flask, are heated to back under nitrogen protection
Stream reaction 5 hours, raw material fully reacting.It is down to room temperature, 100 g water are slowly added dropwise into reaction solution, drop finishes, with unsaturated carbonate hydrogen
Sodium solution adjusts pH=7 or so, continues stirring 1 hour.Liquid separation is stood, benzene is mutually washed twice with 300 g again, and anhydrous sodium sulfate is dry
It is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain 11.4 g of yellow oil, as compound 17, yield 78.4%.
(15) preparation of compound 18
The 8.7 g isopropanols of g compound 17 and 130 are added in 500 mL there-necked flasks, 6.4 g boron hydrogen are added portionwise after dissolution clarification
Change sodium.It finishes, is heated to 35 oC and reacts 3 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 100 g water are added, and is used
200 g methylene chloride are extracted twice, and merge methylene chloride phase, and 200 g are washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate subtract
Pressure is concentrated to dryness, and obtains 8.1 g of yellow oil, as compound 18, yield 93.1%.
(16) preparation of compound 19
The 10 g toluene of g compound 18 and 50, dissolution clarification are added in 250 mL there-necked flasks.5.1 g potassium carbonate are added, are cooled to
5 oC or so are slowly added to 3.8 g dimethyl suflfates.It finishes, is heated to 40 oC or so and reacts 5 hours, raw material fully reacting.
Reaction solution is concentrated to dryness, and 45 g water are added, are extracted twice with 90 g ethyl acetate.Combined ethyl acetate phase, 90 g washing
Twice, anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain grease, and it is white to obtain class after the crystallization of 40g dehydrated alcohol
7.2 g of color solid, as compound 19, yield 70.0%.
(17) preparation of compound 20
Be added in 100 mL there-necked flasks 1.4 g compounds 11,1.4 g compounds 19,0.2 g cuprous oxide, 3.0 g potassium carbonate and
28 g DMSO are heated to 140 oC under nitrogen protection and react 48 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and is added
Enter 14 g water, adjusts pH=3 or so with 10% dilute hydrochloric acid, then be extracted twice with 56 g methylene chloride.Merge methylene chloride phase, with 56
G is washed twice, and anhydrous sodium sulfate is dry.Filtering, filtrate decompression are concentrated to dryness, obtain brown solid, by column chromatographic purifying, obtain light
1.3 g of yellow solid, as compound 20, yield 52.9%.
(18) preparation of compound 21
1.3 g compounds 20,9.3 g trifluoracetic acids and 26 g isopropanols are added in 100 mL there-necked flasks, are heated under nitrogen protection
To back flow reaction 8 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 26 g water are added, unsaturated carbonate hydrogen is slowly added dropwise
Sodium solution adjusts pH=8 or so, is extracted twice with 60 g methylene chloride.Merge methylene chloride phase, 60 g are washed twice, anhydrous sulphur
Sour sodium is dry.Filtering, filtrate decompression are concentrated to dryness, and obtain 1.0 g of white solid, as compound 21, yield 86.8%.
(19) preparation of racemization hanfangchin A (compound 22)
1.0 g compounds 21,0.2 g cuprous oxide, 1.5 g potassium carbonate and 50 g DMSO, nitrogen are added in 250 mL there-necked flasks
It is heated to 140 oC under protection to react 70 hours, raw material fully reacting.Reaction solution is concentrated to dryness, and 20 g water is added, with 10%
Dilute hydrochloric acid adjusts pH=3 or so, then is extracted twice with 40 g methylene chloride.Merge methylene chloride phase, twice with 40 g washing, nothing
Aqueous sodium persulfate is dry.Filtering, filtrate decompression are concentrated to dryness, obtain brown solid, by column chromatographic purifying, obtain off-white powder 0.37
G, as racemization hanfangchin A, yield 41.8%.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (10)
1. a kind of total synthesis method of racemization hanfangchin A, which comprises the following steps:
(1) it is starting material with 5- bromine vanillic aldehyde, that is, compound 1, reacts synthesis compound with methylating reagent under alkaline condition
2；
(2) compound 2 and nitromethane under the action of catalyst, react synthesis compound 3 by Henry；
(3) compound 3 passes through reducing agent reduction synthesis compound 4；
It (4) is raw material with 3- hydroxyl -4- methoxyphenylacetic acid, that is, compound 5, the synthesisization after hydroxyl protection under alkaline condition
Close object 6；
(5) compound 4 and compound 6 synthesize compound 7 by acid amide condensation reaction under condensing agent effect；
(6) compound 7 carries out intramolecular condensation in anhydrous inert solvent under dehydrating agent effect, and dehydration ring closure synthesizes chemical combination
Object 8；
(7) compound 8 passes through reducing agent reduction synthesis compound 9；
(8) compound 9 reacts synthesis compound 10 with methylating reagent；
(9) compound 10 synthesizes compound 11 after sloughing hydroxyl protection base in acid condition；
(10) it is raw material with vanillic aldehyde, that is, compound 12, synthesizes compound 13 after hydroxyl protection under alkaline condition；
(11) compound 13 and nitromethane under the action of catalyst, react synthesis compound 14 by Henry；
(12) compound 14 passes through reducing agent reduction synthesis compound 15；
(13) compound 15 with to bromo-acid condensing agent effect under, by acid amide condensation reaction synthesize compound 16；
(14) compound 16 carries out intramolecular condensation, dehydration ring closure synthesisization under dehydrating agent effect in anhydrous inert solvent
Close object 17；
(15) compound 17 passes through reducing agent reduction synthesis compound 18；
(16) compound 18 reacts synthesis compound 19 with methylating reagent；
(17) compound 11 and compound 19 are under the action of catalyst, anti-by intermolecular Ullmann under alkalinity, hot conditions
Compound 20 should be synthesized；
(18) compound 20 synthesizes compound 21 after sloughing hydroxyl protection base in acid condition；
(19) compound 21 under the action of catalyst, synthesizes chemical combination by intramolecular Ullmann reaction under alkalinity, hot conditions
Object 22, i.e. racemization hanfangchin A.
2. the total synthesis method of racemization hanfangchin A according to claim 1, it is characterised in that: in the step (1),
Alkaline reagent is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or pyridine, preferably
For sodium hydroxide；Methylating reagent is selected from dimethyl suflfate, dimethyl carbonate, iodomethane, bromomethane or methyl tosylate
One of, preferably iodomethane；Solvent be selected from methylene chloride, chloroform, methanol, ethyl alcohol, acetonitrile, tetrahydrofuran, benzene, toluene or
One of water is a variety of, preferably methylene chloride；
In the step (1), 5- bromine vanillic aldehyde (compound 1) and methylating reagent molar ratio are 1:1 ~ 1:4, reaction temperature 20
~100 oC, reaction time are 2 ~ 20 hours.
3. the total synthesis method of racemization hanfangchin A according to claim 1, it is characterised in that: in the step (2),
Catalyst is in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine
One kind, preferably triethylamine；Solvent is selected from one of nitromethane, methanol, ethyl alcohol, isopropanol, acetic acid, DMF or DMSO, preferably
Ethyl alcohol；
In the step (2), the molar ratio of compound 2 and nitromethane is 1:1 ~ 1:10, and catalyst amount is 2 weight of compound
10% ~ 80%, reaction temperature 50oFor C to flowing back, the reaction time is 10 ~ 20 hours.
4. the total synthesis method of racemization hanfangchin A according to claim 1, it is characterised in that: in the step (3),
Reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium aluminium hydride reduction or borine, preferably lithium aluminium hydride reduction；Solvent choosing
From one of methanol, ethyl alcohol, tetrahydrofuran, benzene or toluene, preferably tetrahydrofuran；
In the step (3), the molar ratio of compound 3 and reducing agent is 1:1 ~ 1:10, reaction temperature 30oC is reacted to flowing back
Time is 6 ~ 20 hours.
5. the total synthesis method of racemization hanfangchin A according to claim 1, it is characterised in that: in the step (4),
Alkaline reagent is in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine
One kind, preferred sodium hydroxide；Hydroxyl protection base is selected from trimethyl silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon
Base, triisopropylsilyl, benzyl, to one of methoxy-benzyl, methoxy or 2- ethoxyethyl group, preferably benzyl；
Solvent is selected from one of methanol, ethyl alcohol, isopropanol, methylene chloride, chloroform, pyridine or DMF, preferably methanol；
In the step (4), the molar ratio of compound 5 and hydroxy protecting agent is 1:1 ~ 1:4, reaction temperature 30oC is extremely returned
Stream, reaction time are 3 ~ 10 hours.
6. the total synthesis method of racemization hanfangchin A according to claim 1, it is characterised in that: in the step (5),
Condensing agent is selected from one of CDI, EDCI, HATU or HBTU, preferably CDI；Solvent is selected from methylene chloride, chloroform or DMF
One of, preferred methylene chloride；
In the step (5), the molar ratio of compound 4 and compound 6 is 1:1 ~ 1:1.5, the molar ratio of compound 4 and condensing agent
For 1:1 ~ 1:3, reaction temperature is 0 ~ 60oC, reaction time are 1 ~ 5 hour.
7. the total synthesis method of racemization hanfangchin A according to claim 1, it is characterised in that: in the step (6),
Dehydrating agent is selected from one of phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acids or trifluoroacetic anhydride, preferably phosphorus oxychloride；It is anhydrous
Atent solvent is selected from one of methylene chloride, chloroform, tetrahydrofuran, benzene, toluene or nitrobenzene, preferably toluene；
In the step (6), the molar ratio of compound 7 and dehydrating agent is 1:1 ~ 1:20, reaction temperature 30oC is reacted to flowing back
Time is 2 ~ 8 hours.
8. the total synthesis method of racemization hanfangchin A according to claim 1, it is characterised in that: in the step (7),
Reducing agent is selected from one of sodium borohydride or potassium borohydride, preferably potassium borohydride；Solvent be selected from methanol, ethyl alcohol, isopropanol or
One of tetrahydrofuran, preferred alcohol；
In the step (7), the molar ratio of compound 8 and reducing agent is 1:1 ~ 1:10, and reaction temperature is 0 ~ 50oC, reaction time
It is 1 ~ 5 hour.
9. the total synthesis method of racemization hanfangchin A according to claim 1, it is characterised in that: in the step (8),
Methylating reagent is selected from one of iodomethane, dimethyl suflfate, dimethyl carbonate, methyl tosylate or formaldehyde/formic acid,
It is preferred that methyl tosylate；Solvent is selected from one of tetrahydrofuran, acetonitrile, acetone or DMF, preferably DMF；
In the step (8), the molar ratio of compound 9 and methylating reagent is 1:1 ~ 1:3, reaction temperature 30oC extremely flows back,
Reaction time is 2 ~ 6 hours.
10. the total synthesis method of racemization hanfangchin A according to claim 1, it is characterised in that: the step (9)
In, acid reagent is selected from one of acetic acid, trifluoracetic acid, hydrochloric acid or hydrobromic acid, preferably trifluoracetic acid；Solvent be selected from methanol,
One of ethyl alcohol or isopropanol, preferably methanol；
In the step (9), the molar ratio of compound 10 and acid reagent is 1:20 ~ 1:200, reaction temperature 40oC is extremely returned
Stream, reaction time are 4 ~ 10 hours；
In the step (10), alkaline reagent be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide,
One of potassium tert-butoxide or triethylamine, preferably sodium hydroxide；Hydroxyl protection base is selected from trimethyl silicon substrate, tert-butyldimethyl silyl
Base, tert-butyl diphenyl silicon substrate, triisopropylsilyl, benzyl, in methoxy-benzyl, methoxy or 2- ethoxyethyl group
One kind, preferred benzyl；Solvent is selected from one of methanol, ethyl alcohol, isopropanol, methylene chloride, chloroform, pyridine or DMF,
It is preferred that methylene chloride；
In the step (10), the molar ratio of vanillic aldehyde (compound 12) and hydroxy protecting agent is 1:1 ~ 1:4, and reaction temperature is
30 oFor C to flowing back, the reaction time is 3 ~ 10 hours；
In the step (11), catalyst is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide, uncle
One of butanol potassium or triethylamine, preferably triethylamine；Solvent is selected from nitromethane, methanol, ethyl alcohol, isopropanol, acetic acid, DMF
Or one of DMSO, preferred alcohol；
In the step (11), the molar ratio of compound 13 and nitromethane is 1:1 ~ 1:10, and catalyst amount is compound 13
The 10% ~ 80% of weight, reaction temperature 50oFor C to flowing back, the reaction time is 10 ~ 20 hours；
In the step (12), reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium aluminium hydride reduction or borine,
It is preferred that lithium aluminium hydride reduction；Solvent is selected from one of methanol, ethyl alcohol, tetrahydrofuran, benzene or toluene, preferably tetrahydrofuran；
In the step (12), the molar ratio of compound 14 and reducing agent is 1:1 ~ 1:10, reaction temperature 30oC is to flowing back, instead
It is 6 ~ 20 hours between seasonable；
In the step (13), condensing agent is selected from one of CDI, EDCI, HATU or HBTU, preferably CDI；Solvent is selected from dichloro
One of methane, chloroform or DMF, preferably methylene chloride；
In the step (13), compound 15 is 1:1 ~ 1:1.5, compound 15 and condensing agent with the molar ratio to bromo-acid
Molar ratio is 1:1 ~ 1:3, and reaction temperature is 0 ~ 60oC, reaction time are 1 ~ 5 hour；
In the step (14), dehydrating agent in phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acids or trifluoroacetic anhydride one
Kind, preferably phosphorus oxychloride；Anhydrous inert solvent is in methylene chloride, chloroform, tetrahydrofuran, benzene, toluene or nitrobenzene
One kind, preferred toluene；
In the step (14), the molar ratio of compound 16 and dehydrating agent is 1:1 ~ 1:20, reaction temperature 30oC is to flowing back, instead
It is 2 ~ 10 hours between seasonable；
In the step (15), reducing agent is selected from one of sodium borohydride or potassium borohydride, preferably potassium borohydride；Solvent is selected from
One of methanol, ethyl alcohol, isopropanol or tetrahydrofuran, preferred alcohol；
In the step (15), the molar ratio of compound 17 and reducing agent is 1:1 ~ 1:10, and reaction temperature is 0 ~ 50oC, when reaction
Between be 1 ~ 5 hour；
In the step (16), methylating reagent is selected from iodomethane, dimethyl suflfate, dimethyl carbonate, methyl tosylate
Or one of formaldehyde/formic acid, preferred methyl tosylate；Solvent in tetrahydrofuran, acetonitrile, acetone or DMF one
Kind, preferably DMF；
In the step (16), the molar ratio of compound 18 and methylating reagent is 1:1 ~ 1:3, reaction temperature 50oC is extremely returned
Stream, reaction time are 2 ~ 6 hours；
In the step (17), catalyst is selected from copper powder, copper oxide, cuprous oxide, cuprous iodide or cuprous bromide dimethyl sulphide
One of mixture, preferably cuprous iodide；Alkaline reagent is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate or three second
One of amine, preferably cesium carbonate；Solvent is selected from one of pyridine, acetonitrile, toluene, DMF or DMSO, preferably DMF；
In the step (17), the molar ratio of compound 11 and compound 19 is 1:0.5 ~ 1:2, compound 11 and alkaline reagent
Molar ratio is 1:1 ~ 1:5, and catalyst amount is the 5% ~ 50% of 11 weight of compound, reaction temperature 70oC is to flowing back, when reaction
Between be 24 ~ 72 hours；
In the step (18), acid reagent is selected from one of acetic acid, trifluoracetic acid, hydrochloric acid or hydrobromic acid, preferably trifluoro vinegar
Acid；Solvent is selected from one of methanol, ethyl alcohol or isopropanol, preferably methanol；
In the step (18), the molar ratio of compound 20 and acid reagent is 1:20 ~ 1:200, reaction temperature 40oC is extremely returned
Stream, reaction time are 4 ~ 10 hours；
In the step (19), catalyst is selected from copper powder, copper oxide, cuprous oxide, cuprous iodide or cuprous bromide dimethyl sulphide
One of mixture, preferably cuprous iodide；Alkaline reagent is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate or three second
One of amine, preferably cesium carbonate；Solvent is selected from one of pyridine, acetonitrile, toluene, DMF or DMSO, preferably DMF；
In the step (19), the molar ratio of compound 21 and alkaline reagent is 1:1 ~ 1:5, and catalyst amount is 21 weight of compound
The 5% ~ 50% of amount, reaction temperature 70oFor C to flowing back, the reaction time is 24 ~ 72 hours.
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