CN105037408B - Method for preparing formyl phenylboronic acid - Google Patents
Method for preparing formyl phenylboronic acid Download PDFInfo
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- CN105037408B CN105037408B CN201510321210.5A CN201510321210A CN105037408B CN 105037408 B CN105037408 B CN 105037408B CN 201510321210 A CN201510321210 A CN 201510321210A CN 105037408 B CN105037408 B CN 105037408B
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- aldehyde radical
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- 238000000034 method Methods 0.000 title claims abstract description 19
- KFIFDKLIFPYSAZ-UHFFFAOYSA-N formyloxy(phenyl)borinic acid Chemical compound O=COB(O)C1=CC=CC=C1 KFIFDKLIFPYSAZ-UHFFFAOYSA-N 0.000 title abstract 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 33
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims abstract description 25
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 13
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract 5
- 239000013638 trimer Substances 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 abstract description 11
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000007796 conventional method Methods 0.000 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 238000013341 scale-up Methods 0.000 abstract 1
- 150000001299 aldehydes Chemical class 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- PLVCYMZAEQRYHJ-UHFFFAOYSA-N (2-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1Br PLVCYMZAEQRYHJ-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 5
- CQHNJWAZNZBMMO-UHFFFAOYSA-N B(O)(O)O.IC1=CC=CC=C1 Chemical compound B(O)(O)O.IC1=CC=CC=C1 CQHNJWAZNZBMMO-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- UQWQCMSYGMAGKF-UHFFFAOYSA-N hexane;lithium Chemical compound [Li].CCCCCC UQWQCMSYGMAGKF-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- OFGJZUBGZYMANZ-UHFFFAOYSA-N (2-bromophenoxy)boronic acid Chemical compound OB(O)OC1=CC=CC=C1Br OFGJZUBGZYMANZ-UHFFFAOYSA-N 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- -1 ethylene glycol Acetal Chemical class 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 2
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 2
- 229960003277 atazanavir Drugs 0.000 description 2
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- KYOIPUDHYRWSFO-UHFFFAOYSA-N [Br].[Li] Chemical compound [Br].[Li] KYOIPUDHYRWSFO-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- MLSKXPOBNQFGHW-UHFFFAOYSA-N methoxy(dioxido)borane Chemical compound COB([O-])[O-] MLSKXPOBNQFGHW-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
Classifications
-
- 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 Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing formyl phenylboronic acid, which comprises the following steps: heating halogenated phenylboronic acid in toluene or heptane under reflux for dewatering to form a tripolymer, mixing the tripolymer with dimethylformamide, dropwisely adding n-butyllithium at low temperature to react by a one-pot process, hydrolyzing with hydrochloric acid, and recrystallizing to obtain the formyl phenylboronic acid. The method is simple to operate, avoids the process of separating the intermediate after formyl protection in the conventional technique, has high universality, can obtain favorable yield for ortho-, meta- and para- formyl phenylboronic acids, and is beneficial to scale-up production.
Description
Technical field
The present invention relates to a kind of method for preparing aldehyde radical phenylboric acid, belongs to fine-chemical intermediate synthesis field.
Background technology
In recent years, the synthetic reaction for carrying out key intermediate of medicament using Suzuki coupling reactions is more and more universal.For example
In the potent protease inhibitor atazanavir synthesis of listing new drug, just use to aldehyde radical phenylboric acid.
Atazanavir
The method of synthesis aldehyde radical phenylboric acid is set out for bromo benzaldehyde at present, is first protected with trimethyl orthoformate or ethylene glycol
Acetal, after subsequently there is the exchange of bromine lithium with butyl lithium, then acidic hydrolysises obtain target product after reacting with methyl borate..The party
Need to protect aldehyde radical in advance in method synthesis, simultaneous reactions are also required to carry out under ultralow temperature, are amplified in the method
During synthesis, product impurity is more, purification difficult.
The content of the invention
In order to overcome drawbacks described above, the present invention to adopt from halo phenylboric acid, shape after dehydration is heated to reflux in toluene
Into trimer, subsequently the trimer is mixed with dimethylformamide, is hydrolyzed after being added dropwise to n-BuLi one pot reaction under low temperature
Obtain aldehyde radical phenylboric acid.A kind of method for preparing aldehyde radical phenylboric acid, including step in detail below：
The first step：Halo phenylboric acid I obtains trimer II after adding solvent refluxing point water；
Second step：Trimer II is mixed with dimethylformamide, and -60 DEG C to -80 DEG C add n-BuLi reaction, then exist
In hydrochloric acid, hydrolysis obtains aldehyde radical phenylboric acid.
Further, in above-mentioned technical proposal, in formula I, formula II, X is bromine or iodine, and the position of substitution is o-, m- or p- position.
Further, in above-mentioned technical proposal, in the first step, solvent is toluene or heptane.
Further, in above-mentioned technical proposal, in the second step, trimer II and n-BuLi, dimethyl formyl
Amine mol ratio is 1:3-3.6:3-5.
Further, in above-mentioned technical proposal, in the second step, it is 1-2 that PH is adjusted in salt adding acid.
Further, in above-mentioned technical proposal, in the second step, recrystallization solvent is acetonitrile or toluene.
Invention beneficial effect
The present invention is set out using halo phenylboric acid, is easy to dehydration and is formed trimer by toluene or heptane backflow, utilizes
Trimer in the basic conditions stablize the characteristics of, add dimethylformamide after with butyl lithium one pot reaction after, followed by will
Boric acid trimer is hydrolyzed into boric acid in acid condition.
The method is by elder generation into after boric acid by way of upper aldehyde radical, it is to avoid the operation of aldehyde radical protection, synthesis in previous methods
Step is short, easy to operate, and o-, m- and p- position aldehyde radical phenylboric acid can obtain good yield, is conducive to amplifying production.While the
One step makees solvent using toluene or heptane so that reaction can be carried out continuously, and not affect aldehyde radical on butyl lithium/dimethylformamide
Reaction.
Specific embodiment
Embodiment 1
Synthesis to bromobenzeneboronic acid trimer (formula II, X=p-Br)：
In the there-necked flask equipped with reflux water-dividing device of 1L, add to bromobenzeneboronic acid (201 grams, 1.0 moles) and 700 millis
Normal heptane is risen, reflux water-dividing is heated to, when system separates about 17.5-18.5 gram water, and system is when there is no longer water and continuing to separate,
Stopped reaction.After cooling, heptane is distilled to not flow liquid, obtained to bromobenzeneboronic acid trimer crude product, now containing about 2-5% heptan
Alkane.Can be directly entered in the next step.
Synthesis to aldehyde radical phenylboric acid：
Under nitrogen protection, add 600 milliliters of dissolvings of anhydrous tetrahydro furan equal to bromobenzeneboronic acid trimer by obtained above
After even, it is transferred in the there-necked flask of 2L, adds dimethylformamide (80.4 grams, 1.1 moles).Subsequently system is cooled to-
Less than 70 DEG C, start to be slowly added dropwise 750 milliliters of 1.6M lithium hexane solutions (1.2 moles), in adition process, control temperature
Not more than -60 DEG C, addition finishes maintenance and continues stirring reaction 1-3 hour at this temperature, is subsequently warmed to room temperature naturally stirring
3-5 hours.TLC detects after completion of the reaction, system is cooled to 0 DEG C, adds 10% aqueous hydrochloric acid solution to be quenched reaction, regulation PH to
2-3 continues 2-3 hours are stirred at room temperature, it is ensured that trimer hydrolysis is complete.Distillation reaction liquid, after organic solvent is distilled, has solid
Separate out, filter, light yellow solid is obtained after recrystallized from acetonitrile to 112.5 grams of aldehyde radical phenylboric acid, HPLC：99.2%, two step total recoverys
75%。
Embodiment 2
Between bromobenzeneboronic acid trimer (formula II, X=m-Br) synthesis：
In the there-necked flask equipped with reflux water-dividing device of 1L, bromobenzeneboronic acid (201 grams, 1.0 moles) and 600 millis between addition
Toluene is risen, reflux water-dividing is heated to, when system separates about 17.5-18.5 gram water, and system is when there is no longer water and continuing to separate, and stops
Only react.After cooling, heptane is distilled to not flow liquid, obtain a bromobenzeneboronic acid trimer crude product, now containing about 5-10% first
Benzene.Can be directly entered in the next step.
Between aldehyde radical phenylboric acid synthesis：
Under nitrogen protection, add 600 milliliters of dissolvings of anhydrous tetrahydro furan equal obtained above bromobenzeneboronic acid trimer
After even, it is transferred in the there-necked flask of 2L, adds dimethylformamide (80.4 grams, 1.1 moles).Subsequently system is cooled to-
Less than 70 DEG C, start to be slowly added dropwise 440 milliliters of 2.5M lithium hexane solutions (1.1 moles), in adition process, control temperature
Not more than -60 DEG C, addition finishes maintenance and continues stirring reaction 1-3 hour at this temperature, is subsequently warmed to room temperature naturally stirring
3-5 hours.TLC detects after completion of the reaction, system is cooled to 0 DEG C, adds 10% aqueous hydrochloric acid solution to be quenched reaction, regulation PH to
1-2 continues 2-3 hours are stirred at room temperature, it is ensured that trimer hydrolysis is complete.Distillation reaction liquid, after organic solvent is distilled, has solid
Separate out, filter, after re crystallization from toluene, obtain 106.5 grams of aldehyde radical phenylboric acid, HPLC between light yellow solid：99.5%, two step total recoverys
71%。
Embodiment 3
The synthesis of bromophenyl boric acid trimer (formula II, X=o-Br)：
In the there-necked flask equipped with reflux water-dividing device of 1L, bromophenyl boric acid (201 grams, 1.0 moles) and 600 millis are added
Toluene is risen, reflux water-dividing is heated to, when system separates about 17.5-18.0 gram water, and system is when there is no longer water and continuing to separate, and stops
Only react.After cooling, heptane is distilled to not flow liquid, obtain a bromobenzeneboronic acid trimer crude product, now containing about 5-10% first
Benzene.Can be directly entered in the next step.
The synthesis of adjacent aldehyde radical phenylboric acid：
Under nitrogen protection, add 600 milliliters of dissolvings of anhydrous tetrahydro furan equal bromophenyl boric acid trimer obtained above
After even, it is transferred in the there-necked flask of 2L, adds dimethylformamide (87.7 grams, 1.2 moles).Subsequently system is cooled to-
70 DEG C to -80 DEG C, start to be slowly added dropwise 520 milliliters of 2.5M lithium hexane solutions (1.3 moles), in adition process, control temperature
Not more than -70 DEG C of degree, addition finish maintenance and continue stirring reaction 1-3 hour at this temperature, are subsequently warmed to room temperature naturally and stir
Mix 3-5 hours.TLC is detected after completion of the reaction, system is cooled to 0 DEG C, is added 15% aqueous hydrochloric acid solution that reaction is quenched, is adjusted PH
Continue 3-5 hours are stirred at room temperature to 1-2, it is ensured that trimer hydrolysis is complete.Distillation reaction liquid, after organic solvent is distilled, has solid
Body is separated out, and is filtered, and obtains 93.0 grams of light gray solid neighbour's aldehyde radical phenylboric acid, HPLC after re crystallization from toluene：99.0%, two steps are always received
Rate 62%.
Embodiment 4
Between iodobenzene boric acid trimer (II, X=m-I) synthesis：
In the there-necked flask equipped with reflux water-dividing device of 1L, iodobenzene boric acid (186 grams, 0.75 mole) and 700 between addition
Milliliter toluene, is heated to reflux water-dividing, and when system separates about 17.5-14.0 gram water, and system is when there is no longer water and continuing to separate,
Stopped reaction.After cooling, heptane is distilled to not flow liquid, obtain an iodobenzene boric acid trimer crude product, now containing about 5-8% first
Benzene.Can be directly entered in the next step.
Between aldehyde radical phenylboric acid synthesis：
Under nitrogen protection, add 500 milliliters of dissolvings of anhydrous tetrahydro furan equal obtained above iodobenzene boric acid trimer
After even, it is transferred in the there-necked flask of 2L, adds dimethylformamide (65.7 grams, 0.90 mole).Subsequently system is cooled to-
75 DEG C to -80 DEG C, start to be slowly added dropwise 609 milliliters of 1.6M lithium hexane solutions (0.98 mole), control in adition process
Not more than -70 DEG C of temperature, addition finish maintenance and continue stirring reaction 1-3 hour at this temperature, are subsequently warmed to room temperature naturally
Stirring 3-5 hours.TLC is detected after completion of the reaction, system is cooled to 0 DEG C, is added 15% aqueous hydrochloric acid solution that reaction is quenched, is adjusted
PH to 1-2 continues 3-5 hours are stirred at room temperature, it is ensured that trimer hydrolysis is complete.Distillation reaction liquid, after organic solvent is distilled, has
Solid is separated out, and cooling is filtered, and obtains 86.6 grams of aldehyde radical phenylboric acid, HPLC between light yellow solid after recrystallized from acetonitrile：99.8%, two
Step total recovery 77%.
Claims (3)
1. a kind of method for preparing aldehyde radical phenylboric acid, it is characterised in that comprise the following steps：
Ⅰ Ⅱ Ⅲ
The first step：After halo phenylboric acid I adds toluene or heptane, backflow to separate 1 equivalent water, reaction system is distilled to not flow liquid
When, trimer II is obtained, next step reaction is directly used in；
Second step：Trimer II is mixed with dimethylformamide, and -60 DEG C to -80 DEG C add n-BuLi reaction, then in hydrochloric acid
Middle hydrolysis, acetonitrile or re crystallization from toluene obtain aldehyde radical phenylboric acid III；
In the second step, trimer II is 1 with n-BuLi, dimethylformamide mol ratio:3-3.6:3-5.
2. the method for preparing aldehyde radical phenylboric acid according to claim 1, it is characterised in that：In formula I, formula II, X is bromine or iodine,
The position of substitution is o-, m- or p- position.
3. the method for preparing aldehyde radical phenylboric acid according to claim 1, it is characterised in that：In second step, adjust after salt adding acid
PH is 1-2.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510321210.5A CN105037408B (en) | 2015-06-12 | 2015-06-12 | Method for preparing formyl phenylboronic acid |
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| CN201510321210.5A CN105037408B (en) | 2015-06-12 | 2015-06-12 | Method for preparing formyl phenylboronic acid |
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| CN105669730B (en) * | 2016-01-10 | 2018-01-16 | 沧州普瑞东方科技有限公司 | A kind of purification process of organic boron acid compounds |
| CN105541887B (en) * | 2016-01-12 | 2017-08-15 | 沧州普瑞东方科技有限公司 | A kind of method for preparing the aldehyde radical phenyl boric acid of 3 fluorine 2 |
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| DE10032017A1 (en) * | 2000-07-01 | 2002-01-10 | Clariant Gmbh | Process for the production of high-purity formylphenylboronic acids |
| JP4118682B2 (en) * | 2000-12-14 | 2008-07-16 | アルキミカ、ゲゼルシャフト、ミット、ベシュレンクテル、ハフツング | Process for producing formylphenylboronic acid |
| WO2015066371A1 (en) * | 2013-10-31 | 2015-05-07 | Forum Pharmaceuticals, Inc. | SPIRO-OXADIAZOLINE COMPOUNDS AS AGONISTS OF α-7-NICOTINIC ACETYLCHOLINE RECEPTORS |
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