CN110143941A - A kind of synthetic method of Barrow Sa Weimabo ester intermediate - Google Patents
A kind of synthetic method of Barrow Sa Weimabo ester intermediate Download PDFInfo
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- CN110143941A CN110143941A CN201910479296.2A CN201910479296A CN110143941A CN 110143941 A CN110143941 A CN 110143941A CN 201910479296 A CN201910479296 A CN 201910479296A CN 110143941 A CN110143941 A CN 110143941A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/89—Benzo [c] furans; Hydrogenated benzo [c] furans with two oxygen atoms directly attached in positions 1 and 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
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Abstract
The present invention provides a kind of synthetic methods of Barrow Sa Weimabo ester intermediate.Invention provides a kind of synthetic method of compound III, is prepared by the reaction of 3 steps, and yield improves, and production is easy to control；A kind of synthetic method of compounds Ⅳ is provided simultaneously, i.e. compound III and diphenyl disulfide generates compounds Ⅳ by " one pot of self-catalysis circulation " reaction；And the method that Barrow Sa Weimabo ester intermediate VIII prepared by above-mentioned reaction.The preparation method has found " one pot of self-catalysis circulation " reaction, solves the problems, such as benzenethiol severe toxicity, control, provides the synthetic method an of safety, suitable industrialized production for Barrow Sa Weimabo ester.
Description
Technical field
The present invention relates to a kind of synthetic method of medicine intermediate more particularly to newfound " one pot of self-catalysis circulation " are anti-
The method for answering and preparing Barrow Sa Weimabo ester intermediate.
Background technique
Influenza is that a kind of acute respiratory communicable disease, the World Health Organization as caused by influenza virus estimate annual stream
Susceptible example is about 3,000,000 to 5,000,000, causes about 250,000 to 500,000 people dead.Barrow Sa Weimabo ester is the research and development of Yan Yeyi company
Novel Tamiflu, on 2 23rd, 2018 in the granted listing of Japan, for treating the A type of adult and children and B-mode
Influenza.Barrow Sa Weimabo ester is the Tamiflu that first case has novel mechanism of action in the past 20 years, by inhibiting influenza
The cap- dependent form endonuclease of virus, to inhibit the transcription and replication of virus.The mechanism of action of existing Tamiflu is all
It is to prevent virus from propagating in vivo by targeting neuraminidase (Neuraminidase).Compared with these drugs, Barrow Sa
Wei Mabo ester targeting works faster in the earlier stage of virus replicative cycle.Barrow Sa Weimabo ester is anti-as a new generation
Flu pharmaceutical has very big research and development meaning and market prospects.
It is mainly at present two pieces up and down for passing through compound mother nucleus structure about the synthetic method of Barrow Sa Weimabo ester
Section is formed by connecting.
Patent CN109311911A, which is disclosed, a kind of prepares lower segment intermediate 8- difluorodiphenyl simultaneously seven ring of [b, e] thia-
The method of 11 (6H) -ol (descending the compound 19 in route).
In CN109311911A in step 1 operating process, diisopropylamine steam is big to respiratory tract, eyes, skin irritation；
In addition, diisopropylamine is inflammable, steam, which mixes with air, can form explosive mixture.2 low-temperature sensitives involved in this step
Reaction, the strict exclusion of moisture such as agents useful for same, solvent need to need to be steamed again diisopropylamine, therefore can expose a large amount of steam, deposit
In potential hazard.In addition this step further relates to the opportunity problem for adding methanol, otherwise will cause and generates by-product etc., not easily-controllable in production
System.Step reaction is not suitable for industrialized production.Step 2 uses reagent benzenethiol, the product stench, and sucking has high toxicity, has arranged
Enter control class chemicals-severe poisonous chemicals register, buy, using being restricted, factory is built and proposes requirements at the higher level,
Be not suitable for commercially producing.
CN109134428A discloses under a kind of synthesis segment intermediate 8- difluorodiphenyl simultaneously seven ring -11 of [b, e] thia
The method of (6H) -ol.
In the route using 2- bromomethyl -3,4- difluorophenyl acetonitrile be used as raw material, one side cyano prepare be related to potassium cyanide,
The severe toxicity tubing products such as Cymag, on the other hand prepare that cyano route is longer, and cost of material is very high with amide.When industrialized production,
It is not easy to obtain there are raw material because of control and problem that price is high.
CN109504721A discloses a kind of method for preparing Barrow Sa Weimabo ester, has following steps in route
Carboxyl has difficulties when Friedel-Crafts reaction occurs with difluorobenzene on benzenethiol ring in this method, and yield is difficult to control.
CN109721585A discloses the preparation side of fluoro- 6,11- dihydro-dibenzo [b, the e] thiotropilium -11- ketone of 7,8- bis-
Method, this method have carried out the reaction of 4 steps.Firstly, starting material 2, the halogenated benzylalcohol nucleo philic substitution reaction of the fluoro- 6- of 3- bis- generates 2,3-
The two fluoro- halogenated benzyl halogen of 6-, then nucleo philic substitution reaction generates under sodium borohydride, sodium hydroxide existence condition with diphenyl disulfide
Then 2,3- bis- fluoro- 6- halogeno-benzyl diphenyl sulfides synthesize the fluoro- 2- of 3,4- bis- ((thiophenyl) methyl) benzoic acid through grignard reaction,
Most fluoro- 6,11- dihydro-dibenzo [b, the e] thiotropilium -11- ketone of 7,8- bis- is obtained through friedel-crafts acylation cyclization afterwards.In step
In 1, bromo-reaction is carried out using 40% hydrobromic acid in reaction, hydrobromic acid strong acid, strong corrosive are easy damage equipment, in addition also
It should be noted environmental issue；And bromo-reaction is carried out using phosphorus tribromide in step 3, yield is low, and Grignard Reagent is to anhydrous nothing
Oxygen requires height, is not suitable for industrialized production；In addition, with a large amount of CO in production2Need special equipment.In addition, respectively being walked according to embodiment
Reacting highest yield to calculate gained total recovery is only 35.7%, and production cost is substantially increased, and is not suitable for industrialized production.
To sum up, the synthetic route of segment intermediate is less under Barrow Sa Weimabo ester at present, and there are the above problems, need
Develop new synthetic method.
Summary of the invention
The present invention provides a kind of low in cost, the simple synthetic route that is controllable, being suitble to industrialized production of working condition
The synthetic method of Barrow Sa Weimabo ester intermediate.
Specific technical solution of the present invention is as follows:
Firstly, the present invention provides intermediate synthetic method shown in a kind of following compound III of structure, the method uses 3
Step reaction carries out, and reaction yield is high and simple controllable.
(1) synthesis of compound III, including following reaction step:
Wherein R1, R2It is independently selected from C1~C6Alkyl, or 3~6 circle heterocyclic rings can be connected to form through C-C, O, N.
Further, R1-N-R2It is selected from
Specifically, above-mentioned route is divided into the progress of 3 steps, wherein
(1) synthesis of chemical compounds I, including step 1a) and 1b)
Step 1a) 3,4- difluoro-benzoic acid and acyl chloride reaction generate 3,4- difluoro benzoyl chloride,
Step 1b) 3,4- difluoro benzoyl chloride is in organic solvent and water mixed solvent, with R1、R2Disubstituted amino exists
The lower reaction of inorganic base effect generates chemical compounds I, wherein R1, R2Such as (1) described definition.
Further,
Step 1a) in acyl chlorides be selected from phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride or phosphorus oxychloride, it is preferably careless
Acyl chlorides；Solvent be selected from N ' dinethylformamide, methylene chloride, dichloroethanes, chloroform, tetrahydrofuran, dioxane, toluene,
One of pyridine is a variety of, preferably N ' dinethylformamide, methylene chloride；Reaction temperature is 0~40 DEG C, preferably room
Temperature；
Step 1b) described in inorganic base be selected from one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide or a variety of,
Preferably potassium carbonate；The organic solvent is selected from methylene chloride, chloroform, tetrahydrofuran, dioxane, N ' N- dimethyl formyl
One of amine, acetonitrile are a variety of, preferably methylene chloride；Reaction temperature is 0~40 DEG C, preferably room temperature.
(2) synthesis of compound ii
In step 2, the Li reagent is selected from n-BuLi, tert-butyl lithium, lithium diisopropylamine, preferably normal-butyl
Lithium；The ligand is optional tetramethylethylenediamine, tetramethyl piperidine, preferably tetramethylethylenediamine；Solvent be selected from tetrahydrofuran,
One or more, the preferably tetrahydrofuran of n-hexane, hexamethylene；Temperature is -80 DEG C~room temperature.Preferably -80 DEG C~-75 DEG C
It heats up naturally after being added dropwise.
(3) synthesis of compound III
In step 3, acid is selected from any one of hydrochloric acid, dilute sulfuric acid, preferably hydrochloric acid；Solvent is optional water, dioxy six
One of ring, acetic acid, formic acid are a variety of, preferably water；Temperature is room temperature~reflux, is preferably flowed back.
The present invention is carried out using the reaction of 3 steps, and each yield that walks is respectively as follows: 90% or more, 100%, 90% or more, comprehensive yield
It is 85% or more, yield greatly improves, and greatly reduces production cost, has well solved 3,4- difluoro-benzoic acid, one step system
The problem of standby fluoro- 3- hydroxyl isobenzofuran -1 (3H) -one (compound III) industrialized production of 4,5- bis- is difficult to realize, keeps away simultaneously
Exempt from potential danger existing for a large amount of diisopropylamine steam of generation, is very suitable to industrialized production.
Further, the present invention provides the intermediate synthetic method as shown in structure following compounds Ⅳ.
(2) synthesis of compounds Ⅳ, including following synthetic route:
Further, it can be optionally added water in reaction, it is preferable that water can be catalyst dosage.
Further, the phosphonate reagent is selected from triphenylphosphine, tri-n-butyl phosphine, preferably triphenylphosphine.
Further, the catalyst is selected from D- camphorsulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, methanesulfonic acid, ethanesulfonic acid, preferably
For p-methyl benzenesulfonic acid.
Further, solvent for use is aprotic solvent, preferred fragrance hydrocarbon solvent.
Further, solvent for use is selected from one of toluene, benzene, dimethylbenzene or a variety of, preferably toluene.
Further, reaction temperature is 40~80 DEG C, preferably 60 DEG C.
CN109311911A uses benzenethiol severe toxicity tubing products, the diphenyl disulfide odorless that the present invention uses, safety
Height, not by national regulatory, transport is easy to use, is very suitable to industrialized production；2,3- is used relative to CN109721585A
The two fluoro- halogenated benzyl halogen of 6- react under sodium borohydride, sodium hydroxide existence condition with diphenyl disulfide, intermediate 4,5- of the present invention
Ketone of two fluoro- -1 (3H) -one of 3- hydroxyl isobenzofuran under the conditions of sodium borohydride, sodium hydroxide in facile hydrolysis and intermediate
It is reduced into alcohol, generates by-product, it is difficult to which realization is reacted with diphenyl disulfide, and mentality of designing is different.Further, to avoid two
Diphenyl disulfide ether, which generates, largely exposes benzenethiol and post-processing benzenethiol problem in the reaction of thiophenol, the present invention is using one kettle way
Reaction is not necessarily to specially treated, is very suitable to industrialization continuous operation.
Further, it is " one pot of self-catalysis circulation " reaction that above-mentioned route is practical, i.e. first step diphenyl disulfide is in triphenyl
The benzenethiol generated in the presence of phosphine, water is in second step and compound III reaction generates compounds Ⅳ and water；What second step generated
Water is further catalyzed first step reaction and generates benzenethiol and then be used for second step reaction progress, while the water that second step generates is continuous
It is consumed and reaction forward is promoted to carry out；It circuits sequentially down.Water is optionally added into reaction, the dosage of water can be catalyst
Amount.
Further, the present invention provides the intermediate synthetic method as shown in structure following compound VII.
(3) synthesis of compound VII
Wherein, synthesized by compound III using the prior art or above-mentioned route (one), then with benzene sulphur reagent or route
(2) reaction generates compounds Ⅳ, and then open loop obtains the fluoro- 2- Ophenylthiomethyl benzoic acid of 3,4- bis-, then in polyphosphoric acids
In the presence of heating cyclization generate compound 7, fluoro- 6,11- dihydro-dibenzo [b, the e] thiotropilium -11- ketone of 8- bis-, most afterwards through restoring
Obtain fluoro- 6,11- dihydro-dibenzo [b, the e] thiotropilium -11- alcohol of object 7,8- bis-.
Further, specific experiment condition is as follows:
Step 1a) in, acyl chlorides is oxalyl chloride, and solvent is methylene chloride, N ' dinethylformamide, and reaction temperature is room
Temperature；
Step 1b) in, the inorganic base is potassium carbonate, and the organic solvent is methylene chloride, and reaction temperature is room temperature；
In step 2, the Li reagent is n-BuLi, and ligand is tetramethylethylenediamine, and solvent is tetrahydrofuran, temperature
For -80 DEG C~room temperature；
In step 3, acid is hydrochloric acid, and temperature is room temperature~reflux；
In step 4, phosphonate reagent is triphenylphosphine, and the catalyst is p-methyl benzenesulfonic acid, and solvent for use is toluene, reaction temperature
Degree is 60 DEG C.
The invention has the following advantages:
First, a kind of preparation method of compound III is provided, avoids generating potential existing for a large amount of diisopropylamine steam
Danger, while solving the problems, such as that 1 footwork is industrially difficult to realize in the prior art.
Second, benzenethiol has insufferable off-odor, will affect the normal of a wide range of interior personnel in use process
Work；And benzenethiol severe toxicity, there is serious irritation, The book of Changes sucking, percutaneous absorbtion encroach on human body, be put into control catalogue.This
Invention replaces benzenethiol with diphenyl disulfide, avoids special odor in benzenethiol use and toxicity to the wound of staff
Evil solves the problems, such as to be conducive to industrialized production using control.
Third, the present invention provides a kind of " one pot of self-catalysis circulation " reaction, since the limitation of water is kept away in reaction process
Exempt from benzenethiol excessively to expose, reduced the harm to experimenter and the pollution to environment in production process, solves toxicity problem；
It simultaneously because the water that reaction generates constantly consumes, can further promote the progress of reaction, form circular response, be suitable for industry metaplasia
It produces.
Specific embodiment mode
Illustrate specific process step of the invention by the following examples, but be not limited by the example, not with any side
Formula limits the scope of the invention.
Term as used in the present invention generally there are those of ordinary skill in the art usually to manage unless otherwise indicated
The meaning of solution.
Embodiment 1: the preparation of chemical compounds I N, N- diethyl -3,4- difluorobenzamide
Put into 31.62g3 in reaction flask, 4- difluoro-benzoic acid, 500ml methylene chloride, 5ml N ' dinethylformamide,
It is stirred at room temperature, instills 48.22g oxalyl chloride, drip off and be stirred at room temperature 1 hour, it is molten that 200ml methylene chloride is added in evaporated under reduced pressure solvent
Solution residual grease directly instills diethylamine aqueous solution and (dissolves 60.81g potassium carbonate, 26.26g hydrochloric acid diethyl in 200ml water
Amine), it is stirred at room temperature after dripping off, separates organic layer, water phase is extracted with dichloromethane, and merges organic layer, saturated common salt water washing, nothing
Aqueous sodium persulfate dries, filters evaporated under reduced pressure and obtains grease 39.23g.Yield 92.1%,1H NMR(400MHz,CDCl3) δ 7.13~
7.25(m,3H),3.52 (br m,2H),3.27(br m,2H),1.21(br m,3H),1.16(br m,3H)；MS(ESI)m/
z(M+H)+: 214.2
Embodiment 2: the preparation of compound ii N, N- diethyl -2- aldehyde radical -3,4- difluorobenzamide
26.00g N, N- diethyl -3,4- difluorobenzamide, 250ml tetrahydrofuran, 18.42g are put into reaction flask
Tetramethylethylenediamine is cooled to -80 DEG C, instills 84ml 1.6M n-BuLi, drips off stirring 1h, instills 22.30g N ' N- diformazan
Base formamide is dripped off and is moved back except refrigerating fluid reacts half an hour, and dilute hydrochloric acid quenching reaction separates organic layer, water phase ethyl acetate
Extraction, merges organic layer, and evaporated under reduced pressure obtains grease 29.50g, yield 100%.1H NMR(400MHz,CDCl3)δ10.33(s,
1H), 7.41~7.46 (m, 1H), 7.03~7.07 (m, 1H), 3.56 (q, J=7.2Hz, 2H), 3.06 (q, J=7.2Hz,
2H), 1.30 (t, J=7.2Hz, 2H), 1.02 (t, J=7.2Hz, 2H)；MS(ESI)m/z(M+H)+:242.1
Embodiment 3: the preparation of fluoro- 3- hydroxyl isobenzofuran -1 (3H) -one of compound III 4,5- bis-
29.50g N, N- diethyl -2- aldehyde radical -3,4- difluorobenzamide, 200ml 6M hydrochloric acid liter are put into reaction flask
Temperature stirs 2.5h to 100 DEG C, is extracted with the methylene chloride of 100ml X4, separates organic layer, is washed with purified water, saturated common salt
It washs, anhydrous sodium sulfate dries, filters evaporated under reduced pressure and obtains brown solid 20.98g, yield 92.4%.1H NMR(400MHz,
CDCl3) δ 7.66~7.70 (m, 1H), 7.40~7.50 (m, 1H), 6.78 (s, 1H), 4.54 (br s, 1H)；(MS-ESI)m/
z(M-H)-:185.0
Embodiment 4: the preparation of fluoro- 3- thiophenyl isobenzofuran -1 (3H) -one of compounds Ⅳ 4,5- bis-
In reaction flask put into fluoro- 3- hydroxyl isobenzofuran -1 (3H) -one of 20.00g 4,5- bis-, 200ml toluene,
14.08g diphenyl disulfide, 16.92g triphenylphosphine, 2.04g p-methyl benzenesulfonic acid, 60 DEG C of stirrings for 24 hours, are cooled to room temperature and use 100ml
The washing of 4 1M sodium hydroxide of X, purifies water washing, saturated common salt water washing, and anhydrous sodium sulfate dries, filters evaporated under reduced pressure for institute
It obtains and normal heptane is added in solid, room temperature mashing is filtered, and normal heptane elution, evaporated under reduced pressure dissolves to obtain white solid 27.1g, yield
90.1%.1H NMR(400MHz,CDCl3) δ 7.44~7.53 (m, 4H), 7.22~7.36 (m, 3H), 6.76 (s, 1H)
Embodiment 5: the preparation of the fluoro- 2- Ophenylthiomethyl benzoic acid of V 3,4- of compound bis-
12.46g alchlor is put into reaction flask, 100ml toluene cools to the lower instillation 1,1,3,3- tetramethyl of 0 DEG C of stirring
The toluene solution (12.55g is dissolved in 50ml toluene) of base disiloxane, drips off to be warming up to 30min is stirred at room temperature, by 20.00g 4,
Fluoro- 3- thiophenyl isobenzofuran -1 (3H) -one of 5- bis- is slowly dropped into reaction system after being dissolved in 50ml toluene, is stirred at room temperature
3 hours, aqueous sulfuric acid is instilled, separates organic layer, saturated common salt water washing, anhydrous sodium sulfate dries, filters evaporated under reduced pressure will
Normal heptane is added in obtained solid, is beaten in ice-water bath, filters, normal heptane elution, dry white solid 18.21g, yield
91.7%.1H NMR(400MHz, CDCl3) δ 7.84~7.88 (m, 1H), 7.34~7.37 (m, 2H), 7.27 (m, 1H), 7.25
(m,2H),7.13(m, 1H),4.60(ds,2H)；MS(ESI)m/z(M-H)-:279.0
Embodiment 6: the preparation of fluoro- 6,11- dihydro-dibenzo [b, the e] thiotropilium -11- ketone of VI 7,8- of compound bis-
In 100ml reaction flask put into the fluoro- 2- Ophenylthiomethyl benzoic acid of 20g 3,4- bis-, 120 DEG C of 100g polyphosphoric acids stir
4h is mixed, ice water is instilled after cooling, is extracted with ethyl acetate, sodium bicarbonate aqueous solution washing, saturated common salt water washing, anhydrous slufuric acid
Sodium dries, filters, and evaporated under reduced pressure is dry with normal heptane band, and normal heptane mashing, cooled and filtered obtains solid 17.2g, yield 92%.1H NMR(400MHz,CDCl3) δ 8.18~8.22 (m, 1H), 7.35~7.45 (m, 3H), 7.27~7.32 (m, 1H), 7.17
~7.12 (m, 1H), 4.14 (ds, 2H)；MS(ESI) m/z(M+H)+:263.1
Embodiment 7: the preparation of fluoro- 6,11- dihydro-dibenzo [b, the e] thiotropilium -11- alcohol of VII 7,8- of compound bis-
In reaction flask put into fluoro- 6,11- dihydro-dibenzo [b, the e] thiotropilium -11- ketone of 15g 7,8- bis-, 50ml ethyl alcohol,
5ml water cools down in ice-water bath, sodium borohydride is added several times, acetone is slowly dropped into after fully reacting, evaporated under reduced pressure solvent adds
Enter purified water mashing, filtering, dry solid 14.8g, yield 97%.1H NMR(400 MHz,CDCl3) δ 7.44~7.50 (m,
1H), 7.11~7.22 (m, 4H), 6.99~7.06 (m, 1H), 6.10 (d, J=3.2Hz, 1H), 4.70 (dd, J=14.4；
1.2Hz 1H), 4.20 (dd, J=14.4；1.2Hz, 1H), 2.68 (d, J=3.6Hz, 1H)；MS(ESI)m/z(M+H-H2O)+:
247.1。
Claims (10)
1. a kind of synthetic method of compound III, which is characterized in that including following reaction step:
Wherein R1, R2Independently selected from C1~C6Alkyl can be connected to form 3~6 circle heterocyclic rings through C-C, O, N.
2. synthetic method according to claim 1, which is characterized in that the chemical compounds I is obtained by following steps:
1a) 3,4- difluoro-benzoic acid and acyl chloride reaction generate 3,4- difluoro benzoyl chloride,
1b) 3,4- difluoro benzoyl chloride is in organic solvent and water mixed solvent, with R1、R2Disubstituted amino is made in inorganic base
Chemical compounds I is generated with lower reaction, wherein R1, R2Definition as described in claim 1；
Preferably, R1, R2It is ethyl.
3. synthetic method according to claim 2, which is characterized in that
Step 1a) in, the acyl chlorides is selected from phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride or phosphorus oxychloride, solvent choosing
From one of N ' dinethylformamide, methylene chloride, dichloroethanes, chloroform, tetrahydrofuran, dioxane, toluene, pyridine
Or it is a variety of, reaction temperature is 0~40 DEG C；Preferably, acyl chlorides is oxalyl chloride, solvent N ' dinethylformamide, methylene chloride,
Reaction temperature is room temperature；
Step 1b) in, the inorganic base is selected from potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide, and the organic solvent is selected from
One of methylene chloride, chloroform, tetrahydrofuran, dioxane, N ' dinethylformamide, acetonitrile or a variety of, reaction temperature
It is 0~40 DEG C；Preferably, inorganic base is potassium carbonate, and organic solvent is methylene chloride, and reaction temperature is room temperature；
In step 2, the Li reagent is selected from n-BuLi, tert-butyl lithium, lithium diisopropylamine, and the ligand is four optionally
Methyl ethylenediamine, tetramethyl piperidine, solvent be selected from tetrahydrofuran, n-hexane, hexamethylene, ether one or more, temperature be-
80 DEG C~room temperature；Preferably, Li reagent is n-BuLi, and ligand is tetramethylethylenediamine, and solvent is tetrahydrofuran, temperature is-
80 DEG C~-75 DEG C are added dropwise rear heating naturally；
In step 3, acid is selected from any one of hydrochloric acid, dilute sulfuric acid, and solvent is optional water, dioxane, acetic acid, formic acid, second
One of nitrile is a variety of, and temperature is room temperature~reflux；Preferably, acid is hydrochloric acid, and solvent is water, and temperature is reflux.
4. a kind of synthetic method of compounds Ⅳ, which is characterized in that its synthetic route is as follows:
5. synthetic method according to claim 4, which is characterized in that be optionally added into water in the reaction.
6. synthetic method according to claim 5, which is characterized in that the water is preferably the moisture of trace, further excellent
It is selected as by the moisture in air or solvent.
7. according to the described in any item synthetic methods of claim 4-6, which is characterized in that the phosphonate reagent be selected from triphenylphosphine,
Tri-n-butyl phosphine, the catalyst are selected from D- camphorsulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, methanesulfonic acid, ethanesulfonic acid, solvent for use
Selected from one of toluene, benzene, dimethylbenzene or a variety of, reaction temperature is 40~80 DEG C；Preferably, phosphonate reagent is triphenylphosphine,
Catalyst is p-methyl benzenesulfonic acid, and solvent is toluene, and reaction temperature is 60 DEG C.
8. according to the described in any item synthetic methods of claim 4-7, which is characterized in that compound III is by claim 1-3
Prepared by any legal manner.
9. a kind of synthetic method of intermediate VII,
Characterized by the following steps: by any synthetic method of claim 1-3 or prior art preparation compound III,
Then it is reacted with such as any synthesis side claim 4-6 or benzene sulphur reagent and generates compounds Ⅳ, then open loop obtains compound V
Then 3,4- bis- fluoro- 2- Ophenylthiomethyl benzoic acid heat cyclization in the presence of polyphosphoric acids and generate compound VI 7,8- bis-
Fluoro- 6,11- dihydro-dibenzo [b, e] thiotropilium -11- ketone most obtains object VII 7, fluoro- 6, the 11- dihydro of 8- bis- through reduction afterwards
Dibenzo [b, e] thiotropilium -11- alcohol.
10. synthetic method according to claim 9, which is characterized in that its specific experiment condition is as follows:
Step 1a) in, acyl chlorides is oxalyl chloride, and solvent is methylene chloride, N ' dinethylformamide, and reaction temperature is room temperature；
Step 1b) in, the inorganic base is potassium carbonate, and the organic solvent is methylene chloride, and reaction temperature is room temperature；
In step 2, the Li reagent is n-BuLi, and ligand is tetramethylethylenediamine, and solvent is tetrahydrofuran, and temperature is -80
DEG C~room temperature；
In step 3, acid is hydrochloric acid, and temperature is room temperature~reflux；
In step 4, phosphonate reagent is triphenylphosphine, and the catalyst is p-methyl benzenesulfonic acid, and solvent for use is toluene, and reaction temperature is
60℃。
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