CN104529898A - Heterocyclic nitrogen-dibenz-cyclooctyne class compound and preparation method thereof - Google Patents
Heterocyclic nitrogen-dibenz-cyclooctyne class compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a heterocyclic nitrogen-dibenz-cyclooctyne class compound and a preparation method of the heterocyclic nitrogen-dibenz-cyclooctyne class compound, and belongs to the field of organic chemical synthesis. The structural general formula of the compound is shown in the formula I. 5-dibenz cycloheptene ketene serves as a starting material, final end product heterocyclic nitrogen-dibenz-cyclooctyne hydrochloride is obtained through the reactions of oximation, Beckmann rearrangement, amid reduction, protection, addition, debromination, deprotection and the like, and the total yield is higher than 73.6%. The raw material is easy to obtain, after-treatment is convenient and easy to operate, and the total yield is high. The heterocyclic nitrogen-dibenz-cyclooctyne class compound without a substituent on nitrogen atoms is synthezied for the first time, a novel method can be provided for synthesizing a heterocyclic nitrogen-dibenz-cyclooctyne class compound with different substituents on the nitrogen atoms, especially for synthesizing multiple heterocyclic nitrogen-dibenz-cyclooctyne class compounds with the different substituents on the nitrogen atoms, wherein the heterocyclic nitrogen-dibenz-cyclooctyne class compounds are not easy to prepare through other methods, a product of the heterocyclic nitrogen-dibenz-cyclooctyne class compound can serve as the raw material, and H on nitrogen is replaced by the needed R base.
Description
Technical field
The present invention relates to organic chemical synthesis field, particularly relate to a kind of azepine dibenzo cyclooctyne compounds and preparation method thereof.
Background technology
1,3-Dipolar Cycloaddition of Cu (I) catalysis, because its selectivity is good, speed of response is fast and high yield is paid close attention to widely, is usually used in biomedical sector, such as, for the synthesis of polyoxyethylene glycol-protein bio conjugated body.But in the product of such reaction, usually can remain a small amount of Cu (I), and remaining Cu (I) can be attached to the avtive spot of enzyme, thus cause the activity of enzyme to reduce, even make enzyme deactivation, and then toxic action is produced to cell.Meanwhile, easily there is disproportionation reaction and speed of reaction declined in Cu (I) under aqueous environment.Therefore look for 1,3-Dipolar Cycloaddition that is new, that do not have Cu (I) to participate in receive much concern.
In recent years, azepine dibenzo cyclooctyne compounds is due to the chemical structure of its uniqueness and reactive behavior, be easy to occur 1 with nitrine or nitrone compound in a mild condition, 3-dipole-diople interaction, such reaction is not by metal superlattice catalyzed reaction, but the tension force possessed by self promotes the carrying out of reaction, " click " that can realize without metal is reacted.Meanwhile, it is fast that it still possesses reaction, good selective.Therefore, such reaction is widely used in biomedicine field, such as positron emission tomography (PET), glycan mark etc.And azepine dibenzo cyclooctyne is compared with cyclooctyne and dibenzo cyclooctyne, there is again the advantages such as strong, the favourable kinetics support of wetting ability.
At present, the synthesis of azepine dibenzo cyclooctyne compounds is very ripe, nitrogen-atoms has extensively been synthesized with substituent azepine dibenzo cyclooctyne compounds and has been carried out a series of research, as the polystep reaction that is raw material with 5-dibenzosuberenone (
synthesis, 2014,46,669), with the adjacent amino-benzene acetylene Sonogashira linked reaction that is raw material (
chem.Commun., 2010,46,97) and with the Heck that adjacent iodobenzene ammonia is raw material react (
chem.Eur.J. 2013,
19, 2150) etc.But, the synthesis azepine dibenzo cyclooctyne compounds of current report is all that nitrogen has substituent compound, and different substituting groups all needs to do from synthetic route raw material foremost, and the synthesis not with substituent azepine dibenzo cyclooctyne compounds on nitrogen-atoms have not been reported.
In addition, by observing its structure, we can find, by certain chemical means, we can nitrogen-atoms not to be with substituent azepine dibenzo cyclooctyne compounds for crucial general character intermediate, synthesize the azepine dibenzo cyclooctyne compounds with different substituents on a series of nitrogen-atoms as required, following conversion:
Especially for this compounds that some are not easily prepared by ordinary method.Therefore, providing on nitrogen-atoms is not with substituent azepine dibenzo cyclooctyne compounds to have very important realistic meaning.
Summary of the invention
An object of the present invention, is to provide on a kind of nitrogen-atoms and is not with substituent azepine dibenzo cyclooctyne compounds, to solve the problem.
To achieve these goals, the technical solution used in the present invention is such: a kind of azepine dibenzo cyclooctyne compounds, its structural formula general formula such as formula (
i) shown in:
Wherein:
Formula (
i) in R
1, R
2for H, alkyl, halogen, R
1and R
2can be the same or different;
And R
1, R
2the substituting group put is subrogated for desirable arbitrarily on phenyl ring.
As preferred technical scheme: R
1=R
2=H.
Object two of the present invention, is a kind of preparation method providing above-claimed cpd, and the technical scheme of employing is: comprise the steps:
(1) with 5-dibenzosuberenone for starting raw material, through condensation obtain formula (
iII) shown compound;
(2) through Beckmann rearrangement synthesis obtain formula (
iV) shown compound;
(3) through reduction synthesis obtain formula (
v) shown compound;
(4) again on nitrogen protecting group synthesis obtain formula (
vI) shown compound;
(5) by with bromine addition synthesize the formula that obtains (
vII) shown compound;
(6) then through debrominate obtain formula (
vIII) shown compound;
(7) eventually pass deprotection obtain formula (
i) shown compound, i.e. azepine dibenzo cyclooctyne.
Its synthetic route chart is as follows:
In above-mentioned step (7), after deprotection, the inorganic acids such as hydrochloric acid, sulfuric acid can also be added, generate salt compounds, such as add hydrochloric acid, form the compound of following structural formula:
As preferred technical scheme, formula in above-mentioned steps (1) (
iII) shown in compound can adopt document " Scalable Synthesis of Strained Cyclooctyne Derivatives " (
synthesis.2014,
46, 669-677.) in the method reported be prepared, reaction expression is as follows:
As preferred technical scheme, formula in above-mentioned steps (2) (
iV) shown in compound can adopt document " Scalable Synthesis of Strained Cyclooctyne Derivatives " (
synthesis. 2014,
46, 669-677.) in the method reported be prepared, reaction expression is as follows:
As preferred technical scheme, formula in above-mentioned steps (3) (
v) shown in compound can adopt document " Scalable Synthesis of Strained Cyclooctyne Derivatives " (
synthesis.
2014,
46, 669-677.) in the method reported be prepared, reaction expression is as follows:
As preferred technical scheme, above-mentioned step (4) comprises following sub-step: under the temperature condition of 0 ~ 25 DEG C, formula (
v) shown in compound be dissolved in tetrahydrofuran (THF), add alkali wherein in batches; Finish, after continuing to stir, then add wherein and adopt tetrahydrofuran (THF) as the Benzoyl chloride solution of solvent, continue stirring reaction completely after, cancellation is reacted, and extraction, washs organic phase, dry, obtain formula (
vI) shown compound.The tetrahydrofuran (THF) that described tetrahydrofuran (THF) preferably newly steams; The cancellation that preferably adds water is reacted; During extraction, ethyl acetate is preferably adopted to extract;
As further preferred technical scheme, 1 ~ 2 hour described reaction times; When washing described organic phase, employing concentration is the sodium hydroxide solution of 0.5 mol/L;
Add in 1mL tetrahydrofuran (THF) 0.05 ~ 0.1g formula (
v) shown compound;
Formula (
v) shown in compound be 1:1.2 with the ratio of the amount of substance of sodium hydride;
Formula (
v) shown in compound be 1:1.2 with the ratio of the amount of substance of Benzoyl chloride;
Described employing tetrahydrofuran (THF) is as in the Benzoyl chloride solution of solvent, and the weightmeasurement ratio of Benzoyl chloride and tetrahydrofuran (THF) is 1.0 ~ 2.0 g/mL;
Described alkali is NaH, formula (
v) shown in compound be 1:1.2 with the ratio of the amount of substance of NaH.
As preferred technical scheme, described step (5) comprises following sub-step :-25
oc ~ 15
oat C temperature, by formula (
vI) shown in compound be dissolved in methylene dichloride, drip wherein under stirring and adopt methylene dichloride as the bromine solution of solvent, drip and finish, continue to stir, after question response terminates, cancellation is reacted, and separates organic phase, described organic phase washing, dry, obtain formula (
vII) shown compound.Preferred employing S-WAT saturated solution cancellation reaction; During washing organic phase, preferably adopt S-WAT saturated solution to wash twice successively, washing once, then washes twice with saturated nacl aqueous solution.
As further preferred technical scheme, temperature is 0 DEG C; Reaction times is 2 ~ 3 hours;
1mL methylene dichloride add 0.05 ~ 0.1g formula (
vI) shown compound;
Formula (
vI) shown in compound be 1:1 with the ratio of the amount of substance of bromine;
Dripping wherein under described stirring adopts methylene dichloride as in the bromine solution of solvent, and the volume ratio of bromine and methylene dichloride is 0.2 ~ 0.4:1.
As preferred technical scheme, described step (6) comprises following sub-step: by formula (
vII) shown in the alcoholic solvent that is suspended in of compound, under stirring, add potassium tert.-butoxide wherein, finish, react at 25 ~ 90 DEG C of temperature, question response completely after, cancellation is reacted, and then extracts, and organic phase is washed, dry, obtain formula (
vIII) shown compound.The cancellation that preferably adds water is reacted; Preferred employing methylene dichloride extracts, and during washing organic phase, preferably adopts saturated common salt to wash three times.
As further preferred technical scheme, temperature is solvent reflux temperature; Described alcoholic solvent is the alcohol of C1-C4, is preferably the trimethyl carbinol; The described reaction times is 4 ~ 6 hours;
Add in the 1mL trimethyl carbinol 0.1 ~ 0.15g formula (
vII) shown compound;
Formula (
vII) shown in compound be 1:2.5 with the ratio of the amount of substance of potassium tert.-butoxide;
As preferred technical scheme, described step (7) comprises following sub-step: by formula (
vIII) shown in compound be suspended in ethanol, add in 1mL ethanol 0.1 ~ 0.15g formula (
vIII) shown compound, under stirring, the hydrochloric acid added wherein, the concentration of described hydrochloric acid is preferably 6 mol/L, and the volume ratio of hydrochloric acid and ethanol is 1 ~ 2:1, finishes, and reacts at 25 ~ 100 DEG C of temperature, is preferably 100
oc, the reaction times is 4 ~ 6 hours, and after question response is complete, cool to room temperature, then filters, and after solids wash, obtains azepine dibenzo cyclooctyne hydrochloride.Preferably adopt ethyl acetate to wash twice during washing solid successively, ethanol is washed once, and ether is washed once.
Compared with prior art; the invention has the advantages that: the present invention with 5-dibenzosuberenone for starting raw material; final product azepine dibenzo cyclooctyne hydrochloride has been obtained by reacting, total recovery more than 73.6% through oximate, Beckmann rearrangement, reduction of amide, protection, addition, debrominate, deprotection etc.Its raw material is simple and easy to get, and convenient post-treatment is easy to operate, and total recovery is higher.The present invention has synthesized the azepine dibenzo cyclooctyne compounds of unsubstituted on nitrogen-atoms first, new method can be provided for the azepine dibenzo cyclooctyne compounds with different substituents on synthetic nitrogen atom, especially the azepine dibenzo cyclooctyne compounds with different substituents on the nitrogen-atoms not easily prepared with additive method for some, with product of the present invention for raw material, the R base that the H above nitrogen needs can be replaced.
Accompanying drawing explanation
Fig. 1 is formula
vshown compound
1h NMR schemes;
Fig. 2 is compound shown in formula VII
1h NMR schemes;
Fig. 3 is embodiment 5 gained compound
1h NMR schemes;
Fig. 4 is embodiment 5 gained compound
13c NMR schemes;
Fig. 5 is the mass spectrum of embodiment 5 gained compound.
Embodiment
Below in conjunction with accompanying drawing, the invention will be further described.
Embodiment 1
The synthesis of following compound
Add in the round-bottomed flask of 1L formula (
iI) shown compound 5-dibenzosuberenone 40 g, oxammonium hydrochloride 67.4 g, then add dehydrated alcohol 480 mL wherein, pyridine 104 mL, reflux 15 h; After TLC monitoring reacts completely, be cooled to room temperature, system 100 mL diluted ethyl acetate, then add 1 M hydrochloric acid 500 mL, stir half an hour; With ethyl acetate (3 × 200 mL) extraction, merge organic phase, organic phase saturated aqueous common salt (2 × 150 mL) washing, organic phase anhydrous sodium sulfate drying, filters, and concentrate to obtain above-claimed cpd 41.3 g white solid, yield is 96%.
Embodiment 2
The synthesis of following compound
In the round-bottomed flask of 1L, add fluoro-5-dibenzosuberenone 48 g of compound 3,7-bis-, oxammonium hydrochloride 68 g, then adds dehydrated alcohol 500 mL wherein, pyridine 104 mL, reflux 15 h; After TLC monitoring reacts completely, be cooled to room temperature, system 100 mL diluted ethyl acetate, then add 1 M hydrochloric acid 500 mL, stir half an hour; With ethyl acetate (3 × 200 mL) extraction, merge organic phase, organic phase saturated aqueous common salt (2 × 150 mL) washing, organic phase anhydrous sodium sulfate drying, filters, and concentrate to obtain above-claimed cpd 49.1 g white solid, yield is 95%.
Embodiment 3
The synthesis of following compound
Preparation Eaton reagent: 25 g Vanadium Pentoxide in FLAKESs are dissolved in 200 mL methanesulfonics.
Add in 500 mL round-bottomed flasks 41.3 g formulas (
iIIa) shown compound, under argon shield, once add above-mentioned joined Eaton reagent.Now, system becomes garnet at once, then stirring reaction half an hour at being placed on 100 DEG C.Directly poured into by reaction solution in 1L mixture of ice and water, separate out white solid, filter, filter cake washes 2 ~ 3 times with water, and under infrared lamp dry white powdery solids 41.2 g, i.e. above-claimed cpd, yield 99.8%.
Embodiment 4
The synthesis of following compound
Preparation Eaton reagent: 25 g Vanadium Pentoxide in FLAKESs are dissolved in 200 mL methanesulfonics.
Add in 500 mL round-bottomed flasks 49.1 g formulas (
iIIb) shown compound, under argon shield, once add above-mentioned joined Eaton reagent.Now, system becomes garnet at once, then stirring reaction half an hour at being placed on 100 DEG C.Directly poured into by reaction solution in 1L mixture of ice and water, separate out white solid, filter, filter cake washes 2 ~ 3 times with water, and under infrared lamp dry white powdery solids 48.6g, i.e. above-claimed cpd, yield 99%.
Embodiment 5
The synthesis of following compound
Add in 500 mL tri-neck round-bottomed flasks formula (
iVa) shown compound 20.2 g, lithium aluminum hydride 57.0 g; Mechanical stirring to two material mixes, and under argon shield, slowly drip anhydrous diethyl ether 300 mL wherein, system produces a large amount of gas simultaneously, and reaction solution becomes glassy yellow.Drip and finish, by reaction mixture heating reflux reaction 15 h; TLC detection reaction completely after, be cooled to 0 DEG C, under stirring under being placed on ice-water bath, slowly drip that to add water to the whole cancellation of lithium aluminum hydride in system complete wherein.Filter, filter residue ethyl acetate is washed (3 × 200 mL).From filtrate, separate organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains above-claimed cpd yellow solid 18.3 g, yield 97%.
1h NMR (CDCl
3, 300 MHz) and d:4.30 (bs, 1H), 4.60 (s, 2H), 6.39 (d, 1H), 6.48 (d, 1H), 6.57 (d, 1H), 6.66 (t, 1H), 6.89 (t, 1H), 7.00 (d, 1H), (7.18-7.28 m, 4H), as shown in Figure 1.
Embodiment 6
The synthesis of following compound
Add in 500 mL tri-neck round-bottomed flasks formula (
iVb) shown compound 23.5g, lithium aluminum hydride 57.0 g; Mechanical stirring to two material mixes, and under argon shield, slowly drip anhydrous diethyl ether 310 mL wherein, system produces a large amount of gas simultaneously, and reaction solution becomes glassy yellow.Drip and finish, by reaction mixture heating reflux reaction 15 h; TLC detection reaction completely after, be cooled to 0 DEG C, under stirring under being placed on ice-water bath, slowly drip that to add water to the whole cancellation of lithium aluminum hydride in system complete wherein.Filter, filter residue ethyl acetate is washed (3 × 200 mL).From filtrate, separate organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains above-claimed cpd yellow solid 21.2 g, yield 96%.
Embodiment 7
The synthesis of following compound
Add in 500 mL round-bottomed flasks formula (
va) shown compound 17 g, anhydrous tetrahydro furan 250 mL; Stir under being placed on ice-water bath after being cooled to 0 DEG C, in solution, add sodium hydride 4.0 g in batches, finish, stir 20 minutes; Benzoyl chloride (13.8 tetrahydrofuran (THF) (10 mL) solution g) are dripped in system.Drip and finish, shift out ice-water bath, after continuing to stir half an hour, TLC monitoring reacts completely.Be poured in appropriate frozen water, with ethyl acetate (3 × 100 mL) extraction, organic phase with 0.5 mol/L sodium hydroxide solution (2 × 100 mL) washing, organic phase anhydrous sodium sulfate drying, reduce pressure steam solvent obtain gray solid formula (
vI, R 1 =R 2 =H) shown compound.This gray solid is all placed in 500 mL round bottom beakers, adds 250 mL methylene dichloride, after ice-water bath is cooled to 0 DEG C, drip methylene dichloride (12 mL) solution of bromine (4.2 mL) wherein.Drip and finish, after continuing stirring 2 h, TLC detection reaction is complete.Add appropriate saturated sodium bisulfite solution wherein, and q. s. methylene chloride, separate organic phase, organic phase is washed by saturated sodium bisulfite solution successively, washing, saturated common salt is washed, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain above-claimed cpd white solid 34.7 g, two step total recoverys 90%.
1h NMR (DMSO-
d 6, 300 MHz) and d:4.57 (d, 0.41H), 4.98 (d, 0.53H), 5.54 (d, 0.50H), 5.62-5.80 (m, 0.80H), 5.88 (d, 0.51H), 6.15 (d, 0.50H), 6.41-6.45 (m, 1.00H), 6.75-6.85 (t, 0.57H), 6.97-7.45 (m, 9.86H), 7.52-7.57 (m, 1.50H), (7.67 d, 0.67H), as shown in Figure 2.
Embodiment 8
The synthesis of following compound
Add in 500 mL round-bottomed flasks formula (
vb) shown compound 20 g, anhydrous tetrahydro furan 260 mL; Stir under being placed on ice-water bath after being cooled to 0 DEG C, in solution, add sodium hydride 4.0 g in batches, finish, stir 20 minutes; Benzoyl chloride (13.8 tetrahydrofuran (THF) (10 mL) solution g) are dripped in system.Drip and finish, shift out ice-water bath, after continuing to stir half an hour, TLC monitoring reacts completely.Be poured in appropriate frozen water, with ethyl acetate (3 × 100 mL) extraction, organic phase with 0.5 mol/L sodium hydroxide solution (2 × 100 mL) washing, organic phase anhydrous sodium sulfate drying, reduce pressure steam solvent obtain solid type (
vI, R 1 =R 2 =F) shown compound.This solid is all placed in 500 mL round bottom beakers, adds 250 mL methylene dichloride, after ice-water bath is cooled to 0 DEG C, drip methylene dichloride (12 mL) solution of bromine (4.2 mL) wherein.Drip and finish, after continuing stirring 2 h, TLC detection reaction is complete.Add appropriate saturated sodium bisulfite solution wherein, and q. s. methylene chloride, separate organic phase, organic phase is washed by saturated sodium bisulfite solution successively, washing, saturated common salt is washed, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain above-claimed cpd white solid 37.8 g, two step total recoverys 89%.
Embodiment 9
The synthesis of following structural formula compound
Add in 500 mL round-bottomed flasks formula (
vIIa) shown compound 31.2 g, the trimethyl carbinol 250 mL; Under stirring, add potassium tert.-butoxide 18.6 g wherein.Finish, by reaction mixture heating reflux reaction 6 h, TLC detection reaction is complete.Add suitable quantity of water cancellation reaction, methylene dichloride (3 × 100 mL) extract, organic phase saturated common salt washes 2 times, anhydrous sodium sulfate drying, filter, filtrate decompression steam solvent obtain buff white solid formula (
vIII, R 1 =R 2 =H) shown compound.This buff white solid is all placed in 500 mL round-bottomed flasks, adds 120 mL ethanol, under stirring at room temperature, add 6 M hydrochloric acid 130 mL, reflux 7 h.After TLC detection reaction is complete, shift out oil bath, question response liquid cool to room temperature, suction filtration, filter cake washes 2 times by ethyl acetate successively, and ethanol washes 1 time, and ether washes 1 time, drains to obtain light yellow powder solid compound 14.0g as implied above, two step total recoverys 88%.
1h NMR (DMSO-
d 6, 300 MHz) and d:5.19 (s, 2H), 6.67 (s, 1H), 7.03 (t, 1H), 7.14 (t, 1H), 7.36 (t, 1H), 7.44 (t, 2H), 7.60 (d, 2H), 7.80 (d, 1H), as shown in Figure 3;
13c NMR (DMSO-
d 6, 75 MHz) and d:48.3,90.9,109.8,119.3,120.6,121.1,124.0,127.0,128.0,132.1,133.5,142.1, as shown in Figure 4;
HRMS (ESI) Calcd for C
15h
12n [M]
+: 206.0964; Found:206.0955, as shown in Figure 5.
Embodiment 10
The synthesis of following structural formula compound
Add in 500 mL round-bottomed flasks formula (
vIIb) shown compound 36.6 g, the trimethyl carbinol 280 mL; Under stirring, add potassium tert.-butoxide 18.6 g wherein.Finish, by reaction mixture heating reflux reaction 6 h, TLC detection reaction is complete.Add suitable quantity of water cancellation reaction, methylene dichloride (3 × 100 mL) extract, organic phase saturated common salt washes 2 times, anhydrous sodium sulfate drying, filter, filtrate decompression steam solvent obtain solid type (
vIII, R 1 =R 2 =F) shown compound.This solid is all placed in 500 mL round-bottomed flasks, adds 120 mL ethanol, under stirring at room temperature, add 6 M hydrochloric acid 130 mL, reflux 7 h.After TLC detection reaction is complete, shift out oil bath, question response liquid cool to room temperature, suction filtration, filter cake washes 2 times by ethyl acetate successively, and ethanol washes 1 time, and ether washes 1 time, drains to obtain light yellow powder solid compound 19.5g as implied above, two step total recoverys 86%.
Embodiment 11
The synthesis of following structural formula compound
R is added in 500 mL flasks
1=R
2the formula of=H (
i) shown compound azepine dibenzo cyclooctyne 20.5g, pyridine 25 mL, nitrogen protection, adds methylene dichloride 150 mL, is cooled to 0
oc, dropping palmityl chloride 79 mL. dropwises and rises to room temperature, continues reaction 5 hours, adds 50 mL dchloromethane, wash (3 × 100 mL), then wash, saturated common salt water washing with 1M HCl.Organic phase anhydrous sodium sulfate drying, filters, and vacuum concentration removing methylene dichloride, obtains yellow oil, obtain above-mentioned off-white color solid 50g, yield 80% after this oily matter is purified.
As can be seen from embodiment 11, the main advantage of the present invention is: be general character intermediate with formula (I) compound, can according to the azepine dibenzo cyclooctyne compounds needed to synthesize with different substituents on a series of nitrogen-atoms of click chemistry.
Claims (10)
1. an azepine dibenzo cyclooctyne compounds, is characterized in that, its structural formula general formula such as formula (
i) shown in:
Wherein:
Formula (
i) in R
1, R
2for H, alkyl, halogen;
And R
1, R
2the substituting group put is subrogated for desirable arbitrarily on phenyl ring.
2. azepine dibenzo cyclooctyne compounds according to claim 1, is characterized in that, R
1=R
2=H.
3. the preparation method of azepine dibenzo cyclooctyne compounds according to claim 1, is characterized in that, comprise the steps:
(1) with 5-dibenzosuberenone for starting raw material, through condensation obtain formula (
iII) shown compound;
(2) through Beckmann rearrangement synthesis obtain formula (
iV) shown compound;
(3) through reduction synthesis obtain formula (
v) shown compound;
(4) again on nitrogen protecting group synthesis obtain formula (
vI) shown compound;
(5) by with bromine addition synthesize the formula that obtains (
vII) shown compound;
(6) then through debrominate obtain formula (
vIII) shown compound;
(7) eventually pass deprotection obtain formula (
i) shown compound, i.e. azepine dibenzo cyclooctyne.
4. preparation method according to claim 3, is characterized in that, described step (4) comprises following sub-step: under the temperature condition of 0 ~ 25 DEG C, formula (
v) shown in compound be dissolved in tetrahydrofuran (THF), add alkali wherein in batches; Finish, after continuing to stir, then add wherein and adopt tetrahydrofuran (THF) as the Benzoyl chloride solution of solvent, continue stirring reaction completely after, cancellation is reacted, and extraction, washs organic phase, dry, obtain formula (
vI) shown compound.
5. preparation method according to claim 4, is characterized in that, 1 ~ 2 hour described reaction times; When washing described organic phase, employing concentration is the sodium hydroxide solution of 0.5 mol/L;
Add in 1mL tetrahydrofuran (THF) 0.05 ~ 0.1g formula (
v) shown compound;
Formula (
v) shown in compound be 1:1.2 with the ratio of the amount of substance of sodium hydride;
Formula (
v) shown in compound be 1:1.2 with the ratio of the amount of substance of Benzoyl chloride;
Described employing tetrahydrofuran (THF) is as in the Benzoyl chloride solution of solvent, and the weightmeasurement ratio of Benzoyl chloride and tetrahydrofuran (THF) is 1.0 ~ 2.0 g/mL;
Described alkali is NaH, formula (
v) shown in compound be 1:1.2 with the ratio of the amount of substance of NaH.
6. preparation method according to claim 3, is characterized in that, described step (5) comprises following sub-step :-25
oc ~ 15
oat C temperature, by formula (
vI) shown in compound be dissolved in methylene dichloride, drip wherein under stirring and adopt methylene dichloride as the bromine solution of solvent, drip and finish, continue to stir, after question response terminates, cancellation is reacted, and separates organic phase, described organic phase washing, dry, obtain formula (
vII) shown compound.
7. preparation method according to claim 6, is characterized in that, temperature is 0 DEG C; Reaction times is 2 ~ 3 hours;
1mL methylene dichloride add 0.05 ~ 0.1g formula (
vI) shown compound;
Formula (
vI) shown in compound be 1:1 with the ratio of the amount of substance of bromine;
Described employing methylene dichloride is as in the bromine solution of solvent, and the volume ratio of bromine and methylene dichloride is 0.2 ~ 0.4:1.
8. preparation method according to claim 3, is characterized in that, described step (6) comprises following sub-step: by formula (
vII) shown in the alcoholic solvent that is suspended in of compound, under stirring, add potassium tert.-butoxide wherein, finish, react at 25 ~ 90 DEG C of temperature, question response completely after, cancellation is reacted, and then extracts, and organic phase is washed, dry, obtain formula (
vIII) shown compound.
9. preparation method according to claim 8, is characterized in that, temperature is solvent reflux temperature; Described alcoholic solvent is the alcohol of C1-C4, is preferably the trimethyl carbinol; The described reaction times is 4 ~ 6 hours;
Add in the 1mL trimethyl carbinol 0.1 ~ 0.15g formula (
vII) shown compound;
Formula (
vII) shown in compound be 1:2.5 with the ratio of the amount of substance of potassium tert.-butoxide.
10. preparation method according to claim 3, is characterized in that, described step (7) comprises following sub-step: by formula (
vIII) shown in compound be suspended in ethanol, add in 1mL ethanol 0.1 ~ 0.15g formula (
vIII) shown compound, under stirring, the hydrochloric acid added wherein, the concentration of described hydrochloric acid is preferably 6 mol/L, and the volume ratio of hydrochloric acid and ethanol is 1 ~ 2:1, finishes, and reacts at 25 ~ 100 DEG C of temperature, is preferably 100
oc, the reaction times is 4 ~ 6 hours, and after question response is complete, cool to room temperature, then filters, and after solids wash, obtains azepine dibenzo cyclooctyne hydrochloride.
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| CN114394933A (en) * | 2022-01-07 | 2022-04-26 | 厦门沃克沃德医药科技有限公司 | Method for synthesizing 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid |
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