CN104788483A - A method of preparing phenylboronic acid ortho- meta- and para-substituted with hydroxy and mercapto - Google Patents
A method of preparing phenylboronic acid ortho- meta- and para-substituted with hydroxy and mercapto Download PDFInfo
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- CN104788483A CN104788483A CN201510032761.XA CN201510032761A CN104788483A CN 104788483 A CN104788483 A CN 104788483A CN 201510032761 A CN201510032761 A CN 201510032761A CN 104788483 A CN104788483 A CN 104788483A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
A method of preparing phenylboronic acid ortho- meta- and para-substituted with hydroxy and mercapto is disclosed. The method includes adding a compound of a formula I into an organic solvent, adding 1.2-2.0 eq of acetyl chloride, lowering the temperature of the solution to a temperature between -10 DEG C and 0 DEG C, adding 0.1-0.3 eq of anhydrous aluminium chloride, heating to 20-120 DEG C, stirring for 2-10 h to obtain a compound of a formula II, adding an alkali to adjust pH to be 11-12 after TLC detection proves that the reaction is finished, layering, removing the organic layer, adding hydrochloric acid into the water layer to adjust pH to be 2-3, extracting with ethyl acetate, subjecting the organic layer to rotary drying, and beating the obtained crude product with a mixture of acetone or dichloromethane and n-heptane to obtain a solid product of a formula III, wherein R in the formula I is methyl or tert-butyl, and M in the formula I, M in the formula II and M in the formula III are oxygen simultaneously or sulfur simultaneously. The product produced by the method is high in purity and high in yield.
Description
Technical field
The present invention relates to a kind of method preparing para-orientation hydroxyl, mercaptophenyl boronic acid between neighbour, belong to pharmaceutical intermediate synthesis field.
Technical background
Suzuki reaction is used in synthetic chemistry building various types of sp
2one of important method of the C-C singly-bound of type, the main raw material organic boronic of this reaction remains the more vigorous market requirement always, hydroxyl/sulfydryl boric acid because phenol/sulfhydryl structure unit can be introduced by Suzuki coupling in the molecule easily, so be also widely used in daily-use chemical industry and pharmaceutical synthesis.The biomolecules of boracic sulfydryl also starts to be applied to boron neutron capture therapy (BNCT) field simultaneously.
At present, the synthetic method of hydroxyl/mercaptophenyl boronic acid mainly contains: 1) adopt THP protection from hydroxyl bromobenzene, and then be prepared into Grignard reagent, be obtained by reacting the hydroxybenzene boric acid (reference: Org.Process.Res.Dev.2000 that THP protects subsequently with borane reagent, 4,153); 2) from hydroxyl/sulfydryl bromobenzene, after adopting silica reagent protection, after being prepared into Grignard reagent or the raw exchange of butyllithium occurs at low temperatures again, react with borane reagent again, last hydrolysis under strongly acidic conditions obtains hydroxyl or mercaptophenyl boronic acid (reference: Chin.J.Org.Chem.2006,26,1004 and J.Organomet.Chem.1999,581,82); 3) from o-bromophenol, the butyllithium adding 2.2 equivalents completes deprotonation and the exchange of bromine lithium simultaneously, is obtained by reacting o-hydroxy boric acid (reference: Tetrahedron Lett.2010,51,2335) subsequently with borane reagent.
In above synthetic method, there is part document to have to the phenylo boric acid protected, or the by product that boric acid is oxidized to hydroxyl occurs in protecting group subtractive process, cannot sterling be obtained.
Summary of the invention
When amplifying the above-mentioned hydroxyl of synthesis or mercaptophenyl boronic acid, find that de-boron product is very serious, such as, in o-hydroxy boric acid process, when yield is reduced to feather weight scale from 83% during lab scale 42%; In mercaptophenyl boronic acid process, due to serious de-boron product, the easily oxidizable of sulfydryl itself in addition, can not cannot purify by product when feather weight is amplified.
In order to overcome the above problems, we are through repeatedly attempting, and have found a new synthetic method, namely adopt corresponding bromo-derivative to set out, first/tertiary fourth oxygen or the first/tertiary fourth mercaptophenyl boronic acid of easily synthesis after adopting grignard and boronation set out, through the anhydrous AlCl with catalytic amount
3reaction, the intermediate obtained is caught by Acetyl Chloride 98Min. at once, and this intermediate stability is extremely strong, and the methyl taken off or the tertiary butyl are also at AlCl
3there is the second line of a couplet to receive on solvent molecule.After protection removes end, add alkali product can be hydrolyzed laggard enter water layer, water layer can obtain the product of purity more than 98% again after acidified conventional processing, and feather weight scale checking yield is at 63-78%.
Prepare a method for para-orientation hydroxyl, mercaptophenyl boronic acid between neighbour, comprise the following steps:
Formula I is dissolved in organic solvent, adds the Acetyl Chloride 98Min. of 1.2 ~ 2.0eq, solution temperature is dropped to-10 ~ 0 DEG C, add Aluminum chloride anhydrous 0.1 ~ 0.3eq, be warmed up to 20 ~ 120 DEG C subsequently and stir 2 ~ 10h, obtain formula II.After TLC detection reaction is complete, adds alkali and regulate pH to 11 ~ 12, after layering, water intaking layer salt adding acid for adjusting pH to 2 ~ 3, extraction into ethyl acetate, after layering, organic layer is spin-dried for, and pulls an oar, obtain formula III solid phase prod with acetone or methylene dichloride mixing normal heptane;
In its Chinese style I, R is methyl or the tertiary butyl, and in formula I, formula II and formula III, M is simultaneously for oxygen or simultaneously for sulphur.
Further, in technique scheme, described organic solvent is selected from the one in toluene, dimethylbenzene, methyl-phenoxide, phenyl ether.
Further, in technique scheme, described alkali is selected from sodium hydroxide or potassium hydroxide.
Further, in technique scheme, the consumption of described organic solvent is 8-20 times of substituted benzene boric acid weight.
Invention beneficial effect
The method raw material that this invention adopts easily adopts conventional form/boronation reaction preparation; make use of Lewis acid catalysis deprotection rear center body in deprotection process dexterously to be caught by ethanoyl immediately; avoid unstable intermediate due to the long-time by product stirring generation in amplification process; have selected the solvent that friedel-crafts reaction easily occurs simultaneously and receive the methyl or number butyl taken off; both are combined when making reaction can be amplified to the above scale of feather weight smoothly; product purity is high, also maintains higher yields.
Embodiment
Following non-limiting example can make the present invention of those of ordinary skill in the art's comprehend, but does not limit the present invention in any way.
Test method described in following embodiment, if no special instructions, is ordinary method; Described reagent and material, if no special instructions, all can obtain from commercial channels, or can prepare in conventional manner.
Embodiment 1
The synthesis of o-hydroxy boric acid:
Under nitrogen protection, in 30L glass reaction still, add 1.5 kilograms of 2-methoxyphenylboronic acids, 18 liters of methyl-phenoxides and 1.56 kilograms of Acetyl Chloride 98Min.s, after adding, reaction solution is cooled to-10 ~ 0 DEG C, stir 1 hour.Start to add 133 grams of aluminum trichloride (anhydrous)s in batches, add complete naturally rise to room temperature after, insulated and stirred reaction until TLC show raw material reaction completely till, this process about needs 8 ~ 10 hours.In this process, reaction mixture solid dissolves gradually, has again solid to separate out subsequently gradually.
Add the cancellation of 5M potassium hydroxide aqueous solution, till adjusting PH=11 ~ 12.Now separate organic layer, discard.Water layer adds 6M aqueous hydrochloric acid and adjusts PH=2 ~ 3,12 liters of extraction into ethyl acetate twice, merges organic layer, saturated common salt is washed, and organic layer is spin-dried for, and obtains pale solid o-hydroxy boric acid 1.06 kilograms after adding acetone/normal heptane making beating, yield 77%, HPLC content: 98.6%.
Embodiment 2
The synthesis of para hydroxybenzene boric acid:
Under nitrogen protection, in 30L glass reaction still, add 1.5 kilograms of 4-methoxyphenylboronic acids, 20 liters of toluene and 1.17 kilograms of Acetyl Chloride 98Min.s, after adding, reaction solution is cooled to-10 ~ 0 DEG C, stir 1 hour.Start to add 267 grams of aluminum trichloride (anhydrous)s in batches, rise to 80 DEG C after adding, insulated and stirred reaction is till TLC display raw material reaction completely, and this process about needs 3 ~ 5 hours.In this process, reaction mixture solid dissolves gradually, has again solid to separate out subsequently gradually.
Add the cancellation of 2M aqueous sodium hydroxide solution, till adjusting PH=11 ~ 12.Now separate organic layer, discard.Water layer adds 6M aqueous hydrochloric acid and adjusts PH=2,15 liters of extraction into ethyl acetate twice, merges organic layer, saturated common salt is washed, and organic layer is spin-dried for, and obtains white crystalline solid para hydroxybenzene boric acid 1.01 kilograms after adding acetone/normal heptane making beating, yield 73%, HPLC content: 99.1%.
Embodiment 3
Synthesis to mercaptophenyl boronic acid:
Under nitrogen protection, in 50L glass reaction still, add 4.2 kilograms of tertiary fourth mercaptophenyl boronic acid of 4-, 25 liters of phenyl ether and 2.3 kilograms of Acetyl Chloride 98Min.s, after adding, reaction solution is cooled to-10 ~ 0 DEG C, stir 1 hour.Start to add 267 grams of aluminum trichloride (anhydrous)s in batches, add complete.Reaction solution is risen to 80 DEG C, insulated and stirred reaction is till TLC display raw material reaction completely, and this process about needs 2 ~ 3 hours.In this process, reaction mixture solid dissolves gradually, has again solid to separate out subsequently gradually.
Add the cancellation of 2M aqueous sodium hydroxide solution, till adjusting PH=11 ~ 12.Now separate organic layer, discard.Water layer adds 6M aqueous hydrochloric acid and adjusts PH=2 ~ 3,15 liters of extraction into ethyl acetate twice, merges organic layer, saturated common salt is washed, and organic layer is spin-dried for, and obtains pale solid to mercaptophenyl boronic acid 1.93 kilograms after adding methylene dichloride/normal heptane making beating, yield 63%, HPLC content: 98.2%.
Claims (4)
1. prepare a method for para-orientation hydroxyl, mercaptophenyl boronic acid between neighbour, it is characterized in that comprising the following steps:
Formula I is dissolved in organic solvent, adds the Acetyl Chloride 98Min. of 1.2 ~ 2.0eq, solution temperature is dropped to-10 ~ 0 DEG C, add Aluminum chloride anhydrous 0.1 ~ 0.3eq, be warmed up to 20 ~ 120 DEG C subsequently and stir 2 ~ 10h, obtain formula II.After TLC detection reaction is complete, adds alkali and regulate pH to 11 ~ 12, after layering, water intaking layer salt adding acid for adjusting pH to 2 ~ 3, extraction into ethyl acetate, after layering, organic layer is spin-dried for, and gained crude product acetone or methylene dichloride mixing normal heptane are pulled an oar, and obtain formula III solid phase prod;
In its Chinese style I, R is methyl or the tertiary butyl, and in formula I, formula II and formula III, M is simultaneously for oxygen or simultaneously for sulphur.
2. a kind of method preparing para-orientation hydroxyl, mercaptophenyl boronic acid between neighbour according to claim 1, is characterized in that: described organic solvent is selected from the one in toluene, dimethylbenzene, methyl-phenoxide, phenyl ether.
3. a kind of method preparing para-orientation hydroxyl, mercaptophenyl boronic acid between neighbour according to claim 1, is characterized in that: described alkali is selected from sodium hydroxide or potassium hydroxide.
4. a kind of method preparing para-orientation hydroxyl, mercaptophenyl boronic acid between neighbour according to claim 1, is characterized in that: the consumption of described organic solvent is 8 ~ 20 times of substituted benzene boric acid weight.
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Cited By (3)
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| CN111943971A (en) * | 2020-09-17 | 2020-11-17 | 商河知济新材料技术中心 | Preparation method of boric acid derivative |
| CN112047970A (en) * | 2020-09-17 | 2020-12-08 | 商河知济新材料技术中心 | Method for preparing boric acid derivative |
| CN114057782B (en) * | 2021-12-13 | 2024-02-27 | 大连双硼医药化工有限公司 | Process method for synthesizing 4-mercaptophenylboronic acid |
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Cited By (3)
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| CN111943971A (en) * | 2020-09-17 | 2020-11-17 | 商河知济新材料技术中心 | Preparation method of boric acid derivative |
| CN112047970A (en) * | 2020-09-17 | 2020-12-08 | 商河知济新材料技术中心 | Method for preparing boric acid derivative |
| CN114057782B (en) * | 2021-12-13 | 2024-02-27 | 大连双硼医药化工有限公司 | Process method for synthesizing 4-mercaptophenylboronic acid |
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