CN109020912A - The synthesis technology of C-Fos/AP-1 inhibitor - Google Patents
The synthesis technology of C-Fos/AP-1 inhibitor Download PDFInfo
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- CN109020912A CN109020912A CN201810835780.XA CN201810835780A CN109020912A CN 109020912 A CN109020912 A CN 109020912A CN 201810835780 A CN201810835780 A CN 201810835780A CN 109020912 A CN109020912 A CN 109020912A
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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Abstract
The invention belongs to technical field of medicine synthesis, in particular to a kind of synthesis technology of C-Fos/AP-1 inhibitor, with relatively inexpensive raw material 2, 4- dimethoxybenzoic acid and 2- methoxybenzene propionic acid set out, acyl chlorides is prepared with thionyl chloride, Aluminium Trichloride as Catalyst carries out friedel-crafts acylation, obtain coupled product, then, using pyridine hydrobromide salt and 160 degree of sodium chloride reactions 30 minutes can a step complete demethylation and at the reaction of lactonic ring, products therefrom, which does not need purifying, can be directly used for reacting in next step, cyclopenta is introduced by nucleophilic displacement of fluorine, methyl esters is made after lactonic ring open loop, benzo isoxazolyl group is introduced by nucleophilic displacement of fluorine again after purification, sloughing protecting group can be prepared by final product T5224;Route of the present invention is shorter, and intermediate only friedel-crafts acylation, lactone open loop and introducing three step of benzo isoxazolyl need to purify, and the cost of raw material is lower, and the reaction time of process route is shorter, is suitble to industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, in particular to a kind of synthesis technology of C-Fos/AP-1 inhibitor.
Background technique
T5224 is a kind of selective c-Fos/AP-1 inhibitor, c-Fos/AP-1 adjust control inflammatory cytokine and
The expression of matrix metalloproteinase, then the two has vital effect in the pathogenesis of rheumatoid arthritis.
The structural formula of T5224 is as follows:
T5224 refers to 3- { [2- [3- oxygen-(1,2- benzo isoxazole -6- base) methoxyl group -5- (2- hydroxyl -4- cyclopentyloxy
Benzoyl)] phenyl } propionic acid;In the prior art, the synthetic route of T5224 mainly has four: 1) United States Patent (USP)
Using 6-Methylcoumarin as raw material described in US2009099369A1, Coumarin-6-carboxylic acid is generated through peroxidating, then be prepared into acyl
Chlorine and phenylene dimethyl ether are coupled by friedel-crafts acylation, slough the methyl protecting group on phenolic hydroxyl group, then bromo ring in nucleophilic displacement of fluorine
Amyl, the lactonic ring of cumarin is opened under alkaline condition, and hydro-reduction double bond will again will after carboxyl ester, with benzyl bromine reaction
Methyl esters hydrolyzes to obtain final product.2) using Coumarin-6-carboxylic acid as starting material described in Chinese patent CN106565529A, with
Between phenylene dimethyl ether be coupled by the acylation reaction of phosphorus pentoxide and methanesulfonic acid catalyzed, slough first using pyridine hydrochloride
Base protecting group, subsequent step and United States Patent (USP) US2009099369A1 are substantially similar.3) institute in Chinese patent CN103183647A
It states using the bromo- 4- fluobenzoic acid of 3- as starting material, passes through the acylation of phosphorus pentoxide and methanesulfonic acid catalyzed with phenylene dimethyl ether
Reaction is coupled, then demethylating protecting group, nucleophilic displacement of fluorine introduce bromo cyclopenta under 200 degree with pyridine hydrochloride, then
SnAr aromatic nucleophilic substitution reaction is carried out with 2- trityl -6- (methylol) -1,2- benzo isoxazole -3- (2H) -one, is led to
It crosses grignard reaction and Michael's addition occurs for methyl acrylate, finally slough protecting group and obtain final product.4)Nature
Biotechnology, 2008, volume 26, with 2,4- dimethoxybenzoic acid for starting material described in 817-823, with 2- first
Oxygroup base methyl phenylpropionate is coupled by friedel-crafts acylation, the demethylating that flowed back in ethyl acetate with alchlor protection
Base, light prolong reaction and introduce cyclopenta, and nucleophilic displacement of fluorine introduces benzo isoxazolyl group, finally sloughs protecting group and obtain T5224.
1-3 route starting material price is relatively expensive in four routes, and route is longer, also uses in special No. 3 routes
Grignard reaction, anhydrous and oxygen-free operation are not easy.No. 4 routes are raw materials used cheap, and route is moderate, but are sloughing phenol methyl ether
On methyl protecting group step when the alchlor and ethyl acetate condition yield 53% that use, first three step gross production rate 17% is obvious
It is relatively low.And it needs to first pass through Catalyzed by p-Toluenesulfonic Acid before introducing cyclopenta and forms lactonic ring, reuse light and prolong reaction introducing
Cyclopenta increases step, and the cost of raw material improves.
Summary of the invention
The present invention solves the above-mentioned technical problems in the prior art, provides a kind of synthesis of C-Fos/AP-1 inhibitor
Technique.
To solve the above problems, technical scheme is as follows:
The synthesis technology of C-Fos/AP-1 inhibitor, the C-Fos/AP-1 inhibitor structure formula are as follows:
The C-Fos/AP-1 inhibitor synthetic route is as follows:
The synthesis technology of C-Fos/AP-1 inhibitor, comprising the following steps:
Step 1, compound 1 being dissolved in methanol, the concentrated sulfuric acid is added dropwise, reaction flask substantially remains in room temperature during dropwise addition,
It after being added dropwise, is heated to flowing back under the conditions of 90 DEG C, overnight, compound 2 is made in washing purifying for reaction;
Step 2, thionyl chloride will be added in compound 3, oil bath heating is reacted 2h, isolated and purified to flowing back, and chemical combination is made
Object 4;It is stood overnight under the conditions of nitrogen protection;
Step 3, compound 2 made from step 1 is dissolved in methylene chloride, under nitrogen atmosphere, ice-water bath and stirring condition
Under, anhydrous aluminum chloride is added, after continuing stirring to anhydrous aluminum chloride largely dissolution, the two of compound 4 made from a dropping step 2
Chloromethanes solution, after being added dropwise, ice-water bath becomes cold bath, after the reaction was continued with this condition 3h;Under ice-water bath, toward stirring
Dilute hydrochloric acid is added dropwise in reaction solution under state, separation, washing purify obtained compound 5;
Step 4, pyridine hydrogen bromide salt, sodium chloride are added into compound 5 made from step 3, in nitrogen atmosphere and stirring
Under the conditions of, it after heating reactant is molten into liquid, maintains heating voltage constant, continues after stirring 1.1h, stop heating and stirring,
The mixed solvent of ethyl acetate and water is added in cooled to room temperature, until the solid in reaction system all dissolves, purifying system
Obtain compound 6;
Step 5, under nitrogen atmosphere, potassium carbonate, n,N-Dimethylformamide is added into compound 6, bromine is added for the first time
For the n,N-Dimethylformamide solution of pentamethylene, under the conditions of 85 DEG C, oil bath heating stirring after reacting about 3h, stops heating, from
When being so cooled to interior temperature lower than 60 DEG C, it is added the n,N-Dimethylformamide solution of bromocyclopentane for second, under the conditions of 85 DEG C,
Oil bath heating stirring after reacting about 3h, stops heating, and when naturally cooling to interior temperature lower than 60 DEG C, bromo ring penta is added in third time
The n,N-Dimethylformamide solution of alkane, under the conditions of 85 DEG C, oil bath heating stirring after reacting about 4h, stops heating, then continues
It is stirred overnight, purifies and compound 7 is made;
Step 6, compound 7 made of step 5 is dissolved in ethanol solution, is stirred at room temperature, sodium hydroxide solution is added dropwise,
After dripping, 1.5h is reacted under the conditions of 60 DEG C, the reaction was continued after temperature rises to 70 DEG C 1.5h is purified and compound 8 is made;
Step 7, compound 8 made from step 6 is dissolved in methanol, is stirred under ice-water bath, thionyl chloride, 1.5h is added dropwise
Afterwards, thionyl chloride is added;After the reaction was continued 1h, thionyl chloride is added again;After reacting 1h again, stop reaction, purifies obtainedization
Close object 9;
Step 8, compound 9 made from step 7 is dissolved in acetone, sequentially adds compound 10, potassium carbonate thereto, stirs
After mixing, under nitrogen atmosphere, oil bath heating after the 5.5h that flows back, stops reaction, purifies and compound is made to flowing back under the conditions of 68 DEG C
11;
Step 9, ethanol solution is added made from the step 8 in compound 11, NaOH solution is added, is heated to outer temperature 60
DEG C, until reactant solid all dissolves, then after reacting 10min, purify and compound 12 is made;
Step 10, glacial acetic acid and water is added made from the step 8 in compound 12, is stirred at room temperature reaction, after 46h,
Stop reaction, purifies and final product is made.
Preferably, in the step 1, the corresponding addition 5mL concentrated sulfuric acid of 1g compound 1 is added.
Preferably, in the step 2, the corresponding addition 1.5mL thionyl chloride of 1g compound 3 is added.
Preferably, in the step 3, the molar ratio of compound 2, anhydrous aluminum chloride are as follows: 1g compound 2 is added in 1:1.44
It is corresponding that 3.24mL compound 4 is added.
Preferably, in the step 4, the molar ratio of compound 5, pyridine hydrogen bromide salt, sodium chloride are as follows: 1:4.18:7.45.
Preferably, in the step 5, the molar ratio of compound 6, potassium carbonate, bromocyclopentane are as follows: 1:3:2.
Preferably, in the step 6, the molar ratio of compound 7, sodium hydroxide are as follows: 1:6.
Preferably, in the step 7, the corresponding addition 0.85mL thionyl chloride of 1g compound 8 is added.
Preferably, in the step 8, the molar ratio of compound 9, compound 10, potassium carbonate are as follows: 1:1.54:1.13.
Preferably, in the step 9, the molar ratio of compound 11, NaOH are as follows: 1:5.12.
Preferably, in the step 10, the corresponding addition 5.62mL glacial acetic acid of 1g compound 12 and 0.15mL water is added.
Compared with the existing technology, advantages of the present invention is as follows, 1, raw material 2,4- dimethoxybenzoic acid and 2- methoxybenzene
Propionic acid price is relatively more cheap;It 2,30 minutes can one step of high productivity using pyridine hydrobromide salt and 160 degree of sodium chloride reactions
Demethylation and the reaction at lactonic ring are completed, products therefrom, which does not need purifying, can be directly used for reacting in next step, increase substantially
Yield shortens reaction and finishing time simultaneously;3, general line is shorter, and centre only has friedel-crafts acylation, lactone open loop and draws
Enter three step of benzo isoxazolyl to need to purify, the cost of raw material is lower, and the reaction time of process route is shorter, is suitble to industry raw
It produces.
Detailed description of the invention
Fig. 1 is T5224 synthetic route chart provided by the invention.
8 crude product of T5224 intermediate that Fig. 2 is prepared by embodiment 61H-NMR figure.
9 crude product of T5224 intermediate that Fig. 3 is prepared by embodiment 71H-NMR figure.
The T5224's that Fig. 4 is prepared by embodiment 101H-NMR figure.
Specific embodiment
Embodiment 1:
The synthesis technology of C-Fos/AP-1 inhibitor:
(1)
Compound 1 (50g, 0.28mol) is dissolved in 600mL methanol, is in faint yellow clear liquid, and reaction system is dry with calcium chloride
Pipe completely cuts off the moisture in air, the 30mL concentrated sulfuric acid is added dropwise in reaction flask, and reaction solution is made to substantially remain in room temperature;It drips
Bi Hou is heated to flowing back, and after reaction 8 hours, stops heating, and concentration removes solvent, and Liquid Residue is poured into appropriate ice water and is mixed
In object, with 200mL DCM extraction 2 times, merges organic phase, successively respectively washed with suitable water, saturated sodium bicarbonate solution, saline solution
Primary, the dry organic phase of anhydrous sodium sulfate is washed, 52g yellow liquid (HPLC purity: 95%, thick yield 96%) is obtained after concentration,
Purification is not needed to be directly used in next step.
(2)
Total 50mL thionyl chloride is added portionwise to compound 3 (55g, 0.3mol) under stiring, has bulk gas to generate (anti-
System is answered to need to connect acid gas absorption plant), reaction solution is initially yellow, and quickly becomes atropurpureus;Sulfoxide to be chlorinated
After addition, oil bath heating to reflux 2 hours passes through after cooling and most of thionyl chloride is commonly distilled off, is cooled to room
The residue in suitable DCM dissolution reaction flask is added in temperature, is concentrated to give the solidliquid mixture of atropurpureus, as compound 4 again,
It is directly used in next step without purifying.
(3)
The crude product 52g of compound 2 is dissolved in the methylene chloride that 400mL is impregnated through molecular sieve, N2Under protection, ice-water bath it is cold
But, anhydrous aluminum chloride (31g, 0.23mol) is added, reaction solution becomes peony from faint yellow;Continue stirring to anhydrous aluminum chloride
After most of dissolution, the dichloromethane solution (dichloro of 100mL compound 4 (being made by previous step) is slowly added dropwise in 90 minutes
Methane is impregnated through molecular sieve), reaction solution becomes dark brown from peony;After being added dropwise, room temperature is returned to the reaction was continued 3h.Ice water
Bath cooling, the dilute hydrochloric acid of 1mol/L is slowly added dropwise under stiring, has gas generation, and generate white precipitate, does not regenerate then
Gas, white precipitate disappear after slowly dissolving, and can stop that dilute hydrochloric acid is added dropwise;Isolate organic phase, 2 × 100mL methylene chloride
Aqueous phase extracted twice, merges organic phase, successively with 100mL water, 100mL saturated sodium bicarbonate solution, the washing of 100mL saturated common salt
It washs, anhydrous sodium sulfate is dry, concentration.Column chromatography: with petroleum ether-ethyl acetate system gradient elution, 93.7g white solid is obtained
Compound 5 (HPLC purity 98% calculates two step yields 93% with compound 1).
(4)
Under nitrogen protection and quick mechanical stirring, with 2000w electric jacket by compound 5 (40.76g,
0.11mol), the mixture of pyridine hydrogen bromide salt (73.5g, 0.46mol) and sodium chloride (48g, 0.82mol) is heated to molten
State, reaction solution stop heating after heating one hour at brown, continue stirring until being cooled to nearly room temperature, reaction system condensation
At solid-state.The mixed solvent of 20mL water is added to be added into reaction flask with 50mL ethyl acetate, ultrasound shakes to dissolve solid in bottle,
Solution is poured out after a few minutes, repeats this process until the solid in reaction flask is entirely molten.Merge each acquired solution, separatory funnel point
Organic layer is separated out, water layer is extracted with 2 × 150mL ethyl acetate, merges organic phase, and respectively with 3 × 200mL water, 1 × 200mL
Saturated common salt water washing, anhydrous sodium sulfate is dry, and after concentration, it is solid to obtain the foam-like slightly sticky as yellowish-brown of 31.2g compound 6
Body (HPLC purity 95%, thick yield 95%), this crude product are not required to purification and are used directly for reacting in next step.
(5)
Compound 6 (15.13g, 0.053mol), potassium carbonate (22.12g, 0.16mol) are placed in three-necked bottle, by 100mL
Reaction system is added in DMF and bromocyclopentane (7.88g, 0.053mol), and oil bath heating stirring makes to keep internal temperature at 82 DEG C, instead
Answer liquid in bronzing.After reacting about 3h, stop heating, when naturally cooling to interior temperature and being lower than 60 DEG C, then by bromocyclopentane
(3.94g, 0.026mol) is dissolved in 5mL DMF, and reaction system is added, is then reheated to 82 DEG C, reacts at this temperature
After about 3h, stop heating, when naturally cooling to interior temperature lower than 60 DEG C, then bromocyclopentane (4.00g, 0.027mol) is dissolved in
In 5mL DMF, reaction system is added, is then reheated to 82 DEG C, stops heating after reacting 4h, then continues to be stirred at room temperature
Night.Reaction solution is poured onto beaker, the solid precipitating for staying in reaction flask bottom is taken out with ethyl acetate rinse into suction funnel
Filter;Into reaction solution plus 300mL water and use 3mol/L salt acid for adjusting pH to about 3, filter gained precipitating with 100mL water dissolution
Afterwards, with 3mol/L salt acid for adjusting pH to about 3, merge water phase, and merge with gained filtrate is filtered, be transferred in separatory funnel,
It is extracted with ethyl acetate three times, merges organic phase, successively with 3 × 150mL water, 1 × 200mL saturated common salt water washing, anhydrous sulphur
Sour sodium is dry, and concentration obtains the crude product (HPLC purity 95%, thick yield 70%) of crude product 13.7g compound 7, can be straight without purification
It connects for reacting in next step.
(6)
Compound 7 (crude product obtained by previous step) is dissolved in 95% ethyl alcohol of 70mL, is stirred at room temperature;Sodium hydroxide
(14.88g, 0.37mol) is dissolved in 20mL water, after it is cooled to room temperature, is slowly instilled to reaction system, after dripping,
10mL water washing container is simultaneously transferred to reaction solution, and 95% ethyl alcohol of 10mL rinses reaction bottle wall, and 3h is reacted after 70 DEG C, and hydrolysis is completed,
Stop reaction.Ethyl alcohol is concentrated, about 150mL water is added into reaction flask, with 3mol/L salt acid for adjusting pH to about 3, about 200mL,
150mL, 100mL ethyl acetate extract three times, merge organic phase, and with about 2 × 100mL water, 100mL saturated common salt water washing,
Anhydrous sodium sulfate is dry, after concentration the crude product of 14.8g compound 8 (HPLC purity 88%, yield 95%, 1H-NMR is shown in figure
2), character: brown-red oil is directly used in and reacts in next step.
(7)
The crude product 14.8g of compound 8 is dissolved in 120mL methanol, is stirred under ice-water bath, is slowly added dropwise by dropping funel
14mL thionyl chloride, it is bronzing clear liquid that front and back reaction solution, which is added dropwise,;Continuation is stirred to react 90 minutes under ice-water bath, then slowly
Slowly 5mL thionyl chloride is added;The reaction was continued after sixty minutes, adds 2.5mL thionyl chloride again, is concentrated under reduced pressure and removes after one hour
Most of solvent is removed, about 200mL methylene chloride is added into residue, it is successively molten with 150mL water, 100mL saturated sodium bicarbonate
Liquid washed once, and merges the water phase isolated and is extracted with 2 × 100mL methylene chloride, merges all organic phases and use saline solution
It washes once, anhydrous sodium sulfate is dry, is concentrated to give dark brown liquid crude product, isolates and purifies to obtain 12.1g compound 9 through rapid column chromatography
(yield 90%), character: orange.
(8)
Compound 9 (9.44g, 0.024mol) is dissolved in 100mL acetone, under nitrogen protection, sequentially adds compound
10 (17.39g, 0.037mol), potassium carbonate (3.76g, 0.027mol), obtain yellow turbid, are heated to flowing back, outside under stirring
About 68 DEG C of temperature.As reaction carries out, reaction solution fades to bronzing turbid.After reflux 5.5 hours, 100mL is added into reaction solution
Water simultaneously adjusts pH=6 with 1mol/L hydrochloric acid, three times with the extraction of about 150mL ethyl acetate, merges organic phase, successively uses 100mL
Water, 100mL saturated common salt water washing are stood overnight so that two phase stratification is thorough, and anhydrous sodium sulfate dry organic phase is fast after concentration
Fast column chromatography for separation: with ethyl acetate-light petrol gradient elution, 14.99g compound 11 (yield 80%) is obtained as yellow green wax
Shape solid.
(9)
To 200mL95% ethyl alcohol is added in compound 11 (14.99g, 0.019mol), under stirring slowly into reaction system
It is added 20mL NaOH aq. (3.3g, 0.08mol), reaction solution turns yellow;60 DEG C are warming up to, TLC (PE:EA=3:1) monitors raw material
After disappearance, stop reaction.Concentration removes solvent, the addition 300mL water into residue, 3mol/L salt acid for adjusting pH to less than 3, at
Emulsion is extracted with ethyl acetate three times, merges organic phase and is respectively washed once with suitable quantity of water, saline solution, 14g chemical combination is obtained after concentration
Object 12 is used as light yellow solid (yield 97%).
(10)
Toward 100mL glacial acetic acid and 4mL water are added in compound 12 (14g, 0.018mol), it is stirred at room temperature 46 hours
Afterwards, stop reaction, a large amount of Precipitations.It filters, filter cake successively with appropriate acetic acid and distillation water washing, is dried in vacuo at 45 DEG C
The micro- yellow solid of 8.3g, use dehydrated alcohol recrystallize 7.9g compound 13 (yield 84%) has the fluffy of slight yellowish as class is white
Solid.
Embodiment 2:
10 synthetic method of compound
(1)
Experimental procedure
Under nitrogen protection, reaction flask is added in 2- hydroxy-4-methyl benzoic acid (100g, 0.657mol) by 1L four-hole boiling flask
In, it adds methanol 800mL, after stirring and dissolving material, the concentrated sulfuric acid is slowly added dropwise into reaction flask, about 20min is dripped off.It is added dropwise
Oil bath heating is used after the completion, makes methanol start to flow back, oil bath is gone in recession in 24 hours, is cooled to room temperature, solution is transferred to 2L
In single port bottle, flask is rinsed with a small amount of methanol, is incorporated in single port bottle together.It is concentrated under reduced pressure after removing 400-500ml methanol, to bottle
Middle addition water and ethyl acetate, extraction, organic phase washed with water, saturated sodium bicarbonate, saturated common salt water washing, anhydrous sodium sulfate
It is dry, it is dried in vacuo 2h with oil pump after concentration removing solvent, obtains 90g yellow liquid.Yield 82%
(2)
Experimental procedure
(105.75g, 2.64mol) sodium hydroxide is dissolved in 800mL ice water, be added with stirring hydroxylamine hydrochloride (71.1g,
1.02mol).Compound 2 ' (90g, 0.54mol) is dissolved in 450mL1, in 4- dioxane, is slowly added dropwise in reaction flask,
There is insoluble matter generation, is completely dissolved after reacting a period of time.It is stirred overnight at room temperature, solution is in yellow, and about 600mL solution is concentrated
Afterwards, pH=1 is adjusted with 1N hydrochloric acid, there are a large amount of solids to be precipitated.Filtering, after being washed with distilled water 4 times, vacuum drying obtains light powder
Color solid 87g, yield 96%.
(3)
Experimental procedure
Compound 3 ' (87g, 0.52mol) is added under stiring in 700mL tetrahydrofuran, tetrahydrofuran is heated to and returns
Stream, has a small amount of solid insoluble.It is slightly cooling, wait tetrahydrofuran not after reboiling, be added several times CDI (127.7g,
0.78mol), it acutely deflates, speed is added and is subject to that ensure will not slug.Continue back flow reaction 4 hours after adding.It is cooled to room
After concentration removes tetrahydrofuran, ethyl acetate is added, with salt acid elution 2 times of 1mol/L, aqueous layer with ethyl acetate extracts again in temperature
3 times, merge organic phase, with saturated common salt water washing, anhydrous sodium sulfate is dry, and rapid column chromatography separates after concentration.It is light to obtain 4 '
Yellow solid 40.6g, yield 52%.
(4)
Experimental procedure
By Ph3CCl (58.8g, 0.212mol) is dissolved in 550mL methylene chloride, and 16.8mL pyridine is added, is quickly stirring
20% is added into reaction flask after being heated to 40 DEG C, reaction about 1.5 hours for lower addition compound 4 ' (40g, 0.268mol)
(wt%) sodium hydrate aqueous solution is transferred in separatory funnel after stirring, and water phase DCM is extracted once, dense after merging organic phase
Contracting removes solvent to stopping when having the precipitation of a large amount of solids, and the isopropyl alcohol and water (isopropanol: water=1:2) of 4-5 times of total volume is added
Washing.Vacuum drying obtains white solid 72.5g (yield 69%) after filtering.
(5)
Experimental procedure
By compound 5 ' (72.5g, 0.186mol), N- bromo-succinimide (59.8g, 0.336mol) and 150mL chlorine
After benzene mixing, side stirring, while being heated to 80 DEG C.0.4mL azobisisoheptonitrile is dissolved in 20mL methylene chloride, divides 5 times and delays
Slowly it is added dropwise in flask, after being added dropwise to complete every time, stirs 1h.TLC monitoring reaction stops in time when there is the generation of two bromo objects
Reaction.Decompression boils off chlorobenzene, and residue is dissolved with methylene chloride, is saturated Na2SO3Washing 2 times, DCM aqueous phase extracted 2 times, is associated with
Machine phase, anhydrous sodium sulfate is dry, after concentration removes DCM, with petroleum ether-ethyl acetate system rapid column chromatography.Obtain brown color
Solid 87.5g (comprising reacting incomplete compound 5 ' on a small quantity, does not influence subsequent reactions).
It should be noted that above-described embodiment is only presently preferred embodiments of the present invention, there is no for the purpose of limiting the invention
Protection scope, the equivalent substitution or substitution made on the basis of the above all belong to the scope of protection of the present invention.
Claims (10)
1.C-Fos/AP-1 the synthesis technology of inhibitor, which is characterized in that the C-Fos/AP-1 inhibitor structure formula is as follows:
The C-Fos/AP-1 inhibitor synthetic route is as follows:
2. the synthesis technology of C-Fos/AP-1 inhibitor as described in claim 1, which comprises the following steps:
Step 1, compound 1 is dissolved in methanol, the concentrated sulfuric acid is added dropwise, reaction flask substantially remains in room temperature during dropwise addition, is added dropwise
After, it is heated to flowing back under the conditions of 90 DEG C, overnight, compound 2 is made in washing purifying for reaction;
Step 2, thionyl chloride will be added in compound 3, oil bath heating is reacted 2h, isolated and purified to flowing back, and compound 4 is made;
It is stood overnight under the conditions of nitrogen protection;
Step 3, compound 2 made from step 1 is dissolved in methylene chloride, under nitrogen atmosphere, under ice-water bath and stirring condition, is added
Enter anhydrous aluminum chloride, after continuing stirring to anhydrous aluminum chloride largely dissolution, the dichloromethane of compound 4 made from a dropping step 2
Alkane solution, after being added dropwise, ice-water bath becomes cold bath, after the reaction was continued with this condition 3h;Under ice-water bath, toward stirring
Under reaction solution in be added dropwise dilute hydrochloric acid, separation, washing purify compound 5 are made;
Step 4, pyridine hydrogen bromide salt, sodium chloride are added into compound 5 made from step 3, in nitrogen atmosphere and stirring condition
Under, it after heating reactant is molten into liquid, maintains heating voltage constant, continues after stirring 1.1h, stop heating and stirring, it is natural
It is cooled to room temperature, the mixed solvent of ethyl acetate and water is added, until the solid in reaction system all dissolves, purify obtainedization
Close object 6;
Step 5, under nitrogen atmosphere, potassium carbonate, n,N-Dimethylformamide is added into compound 6, bromo ring is added for the first time
The n,N-Dimethylformamide solution of pentane, under the conditions of 85 DEG C, oil bath heating stirring after reacting about 3h, stops heating, naturally cold
When being but lower than 60 DEG C to interior temperature, the n,N-Dimethylformamide solution of second addition bromocyclopentane, under the conditions of 85 DEG C, oil bath
Heating stirring after reacting about 3h, stops heating, and when naturally cooling to interior temperature lower than 60 DEG C, bromocyclopentane is added in third time
N,N-Dimethylformamide solution, under the conditions of 85 DEG C, oil bath heating stirring after reacting about 4h, stops heating, then continues to stir
Overnight, it purifies and compound 7 is made;
Step 6, compound 7 made of step 5 is dissolved in ethanol solution, is stirred at room temperature, sodium hydroxide solution is added dropwise, be added dropwise
After complete, 1.5h is reacted under the conditions of 60 DEG C, the reaction was continued after temperature rises to 70 DEG C 1.5h is purified and compound 8 is made;
Step 7, compound 8 made from step 6 is dissolved in methanol, is stirred under ice-water bath, thionyl chloride is added dropwise, after 1.5h, mended
Add thionyl chloride;After the reaction was continued 1h, thionyl chloride is added again;After reacting 1h again, stop reaction, purifies and compound 9 is made;
Step 8, compound 9 made from step 7 is dissolved in acetone, sequentially adds compound 10, potassium carbonate thereto, stirred
Afterwards, under nitrogen atmosphere, oil bath heating after the 5.5h that flows back, stops reaction, purifies and compound is made to flowing back under the conditions of 68 DEG C
11;
Step 9, ethanol solution is added made from the step 8 in compound 11, NaOH solution is added, is heated to 60 DEG C of outer temperature, directly
It is all dissolved to reactant solid, then after reacting 10min, purify and compound 12 is made;
Step 10, glacial acetic acid and water is added made from the step 8 in compound 12, is stirred at room temperature reaction, after 46h, stopping
Reaction purifies and final product is made.
3. the synthesis technology of C-Fos/AP-1 inhibitor as claimed in claim 2, which is characterized in that in the step 3, chemical combination
The molar ratio of object 2, anhydrous aluminum chloride are as follows: the corresponding addition 3.24mL compound 4 of 1g compound 2 is added in 1:1.44.
4. the synthesis technology of C-Fos/AP-1 inhibitor as claimed in claim 2, which is characterized in that in the step 4, chemical combination
The molar ratio of object 5, pyridine hydrogen bromide salt, sodium chloride are as follows: 1:4.18:7.45.
5. the synthesis technology of C-Fos/AP-1 inhibitor as claimed in claim 2, which is characterized in that in the step 5, chemical combination
The molar ratio of object 6, potassium carbonate, bromocyclopentane are as follows: 1:3:2.
6. the synthesis technology of C-Fos/AP-1 inhibitor as claimed in claim 2, which is characterized in that in the step 6, chemical combination
The molar ratio of object 7, sodium hydroxide are as follows: 1:6.
7. the synthesis technology of C-Fos/AP-1 inhibitor as claimed in claim 2, which is characterized in that in the step 7, be added
1g compound 8 is corresponding to be added 0.85mL thionyl chloride.
8. the synthesis technology of C-Fos/AP-1 inhibitor as claimed in claim 2, which is characterized in that in the step 8, chemical combination
The molar ratio of object 9, compound 10, potassium carbonate are as follows: 1:1.54:1.13.
9. the synthesis technology of C-Fos/AP-1 inhibitor as claimed in claim 2, which is characterized in that in the step 9, chemical combination
The molar ratio of object 11, NaOH are as follows: 1:5.12.
10. the synthesis technology of C-Fos/AP-1 inhibitor as claimed in claim 2, which is characterized in that in the step 10, add
Enter the corresponding addition 5.62mL glacial acetic acid of 1g compound 12 and 0.15mL water.
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