CN108059169B - A kind of synthesis technology of two boron of tetrahydroxy - Google Patents
A kind of synthesis technology of two boron of tetrahydroxy Download PDFInfo
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- CN108059169B CN108059169B CN201711357849.4A CN201711357849A CN108059169B CN 108059169 B CN108059169 B CN 108059169B CN 201711357849 A CN201711357849 A CN 201711357849A CN 108059169 B CN108059169 B CN 108059169B
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Abstract
The invention discloses a kind of synthesis technologies of two boron of tetrahydroxy.Using tetraalkyl amine connection boron as raw material, it is added into excessive aqueous acid, is filtered after reaction, two boron of tetrahydroxy is obtained after vacuum drying.This method is easy to operate, high income, and product purity and content reach 97% or more, is suitble to industrial amplification production.
Description
Technical field
The present invention relates to a kind of synthesis technologies of two boron of tetrahydroxy, belong to pharmaceutical intermediate synthesis field.
Background technique
Two boron of tetrahydroxy, also known as union II boric acid, hypoboric acid or connection boric acid, English name are as follows:
Tetrahydroxydiboron or Bis-boronic acid, CAS:13675-18-8, English abbreviation BBA are mainly used for
Medicine intermediate is synthesized in Suzuki coupling.
It is existing few about synthetic method at present it has been reported that but application example after 2010 year by year
Increase, compared with conventional connection boric acid pinacol ester, connection boric acid neopentyl glycol ester or catechol connection boron, by-product when coupling reaction
Object is inorganic boric acid, and there is no by-products, academia and the industry such as pinacol, neopentyl glycol or catechol to present and replace
For the trend of mentioned reagent.
From the point of view of only several documents, the earliest synthesis of two boron of tetrahydroxy can trace back to 1955, and Wartik is used
It is inserted into zinc electrode in liquid boron chloride and generates four chlorinations, two boron, then four chlorinations, two boron is reacted with water firstly generates tetrahydroxy
Two boron are then heated to 220 DEG C of dehydrations and generate (BO)X；Quantitative hydrochloric acid is added dropwise to four using at 0 DEG C by McCloskey in 1961
(dimethylamino), which joins, generates two boron of tetrahydroxy, yield 56% in boron and aqueous mixtures.In nearly 50 years hereafter just almost again
There is no document to carry out published method report, until Molander in 2012 synthesizes tetrahydroxy two referring again to using the latter's method
Boron.
In aforesaid operations, process optimization has been carried out to the synthetic method most possibly amplified, it has unexpectedly been found that, in reality
In operating process, the acid-base property of reaction system has a significant impact to reaction yield, becomes the key factor of reaction success or failure.Using text
Method is offered, the method that four (dimethylamino) connection boron is added dropwise to hydrochloric acid, in the verifying of the scale of amplification, yield fluctuation is very big, is added dropwise
There are obvious correlations for speed and temperature, while having gas generation when temperature raising, and by being verified as hydrogen, there are potential peaces
Full hidden danger.
Summary of the invention
In order to overcome drawbacks described above, using tetraalkyl amine connection boron as raw material, the mistake after reaction into excessive aqueous acid is added
Filter, obtains two boron of tetrahydroxy after vacuum drying.This method is easy to operate, high income, product purity and content reach 97% with
On, it is suitble to industrial amplification production.
A kind of synthetic method of two boron of tetrahydroxy, which comprises the following steps: by tetraalkyl amine connection boron be added to
Two boron of tetrahydroxy is obtained in excessive aqueous acid, after filtration drying.
In above-mentioned steps, tetraalkyl amine join boron in, alkylamine be selected from dimethylamine, diethylamine, diisopropylamine, dibutyl amine,
Diisobutyl amine, nafoxidine；It is preferred that: four (dimethylamino) join boron or four (nafoxidines) join boron.Corresponding specific structure is such as
Under:
In above-mentioned steps, temperature control is reacted at -40 DEG C to 40 DEG C, preferably reaction temperature control is at -20 DEG C to 20 DEG C.
In above-mentioned steps, the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or acetic acid.It is still acid after reaction
Property system, PH < 7, this is the key parameter of the Product Process process.Specifically, when acid is hydrochloric acid or hydrobromic acid, acid and four alkane
It is 4-10:1 that base amine, which joins boron equivalent,；When acid is sulfuric acid, acid is 2-5:1 with tetraalkyl amine connection boron equivalent；Acid be nitric acid, phosphoric acid or
When acetic acid, acid is 4-15:1 with tetraalkyl amine connection boron equivalent.
In the present invention program, reaction yield is not influenced whether reacting nitrogen, average yield can reach 90-
95%；
Comparative test discovery: (acid is added dropwise in four (dimethylamino) connection boron) when being added dropwise using literature method, reaction temperature
Degree and inert gas shielding are affected to reaction, when using same operation, at -30 DEG C hereinafter, can achieve 75-84% points
From yield, reaction yield is down to 56% and 44% when temperature is increased to 0 DEG C and 20 DEG C, thus it is speculated that may be first with system when being added dropwise
Alkaline system is undergone, subsequently becomes acidic environment, product is easy to degenerate related under alkaline condition.
Two boron of tetrahydroxy poor solubility in common solvent, when using the high solvent of degree miscible with water, such as tetrahydro furan
Mutter, acetone, acetonitrile when, to yield without substantially changeing.In order to reduce the use of solvent, this experimental implementation can use solvent-free item
It is carried out under part.
The acid concentration being added in reaction has a significant effect to number of processes, when acid concentration increases, obtained product needs
It is primary using 0.1-2.0% Diluted Acid Washing again, secondary amine (such as the dimethylamine or nafoxidine) salt of product surface remnants is cleaned
Completely.From number of processes and waste water yield, comprehensively consider, acid concentration is most preferably with 5-20%.
Advantageous effect of the invention
The present invention passes through the discovery of reaction process internal factor, and after simply adjusting charging sequence, yield is promoted obviously,
Process safety is controllable, to inert environments and temperature-insensitive, can obtain high purity product in wider temperature range.
Specific embodiment
Embodiment 1
In reaction flask, be added 10% hydrochloric acid (4.5eq) after, be cooled to 0 DEG C, by four (dimethylamino) join boron (39.6g,
0.2mol, 1.0eq) it is slowly added dropwise in above-mentioned hydrochloric acid solution, during dropwise addition, gradually there is solid precipitation, be added dropwise, gradually
It is warmed to room temperature insulated and stirred 3 hours, filters, obtain 16.9g, yield after obtaining 40-60 DEG C of white solid product vacuum drying
94.2%；Derivative (it is derivative that pinacol in methyl alcohol by product dissolution, the is added) detection level 97.9% of GC, HPLC:99.5%；
HNMR (DMSO-d6+H2O): 8.84 (0.02), 8.61 (1.00), 7.59 (5.28), { note: being peak in bracket for 6.50 (0.02)
Area value }；0.05% dilute hydrochloric acid 60mL is added in the said goods, at 5-10 DEG C of temperature control, stirs 30 minutes, filtering, obtained solid
40-60 DEG C of drying obtains white products 16.5g.GC derives detection level 99.6%, HPLC:99.9%； HNMR(DMSO-d6+
H2O):8.84(0.03),8.61(1.00),7.59(5.35).
Embodiment 2
In reaction flask, be added 10% hydrochloric acid (5.5eq) after, be cooled to 10 DEG C, by four (dimethylamino) join boron (39.6g,
0.2mol, 1.0eq) it is slowly added dropwise in above-mentioned hydrochloric acid solution, during dropwise addition, temperature control gradually has solid analysis within 30 DEG C
Out, it is added dropwise, incubation at room temperature stirs 3 hours, filtering, obtains after obtaining 40-60 DEG C of white solid product vacuum drying
16.2g, yield 90.4%；Derivative (it is derivative that pinacol in methyl alcohol by product dissolution, the is added) detection level 97.3% of GC,
HPLC:99.6%；HNMR(DMSO-d6+H2O):8.84,8.61, 7.59.
Embodiment 3
In reaction flask, after 10% nitric acid (4.8eq) is added, -10 DEG C are cooled to, four (dimethylamino) are joined into boron
(39.6g, 0.2mol, 1.0eq) is slowly added dropwise in above-mentioned nitric acid solution, during dropwise addition, gradually there is solid precipitation, temperature control exists
It within 0 DEG C, is added dropwise, is gradually increased to incubation at room temperature and stirs 3 hours, it is dry to obtain 40-60 DEG C of vacuum of white solid product for filtering
16.7g, yield 93.3% are obtained after dry；Derivative (it is derivative that pinacol in methyl alcohol by product dissolution, the is added) detection level of GC
97.3%, HPLC:99.6%；HNMR(DMSO-d6+H2O):8.84, 8.61,7.59.
Embodiment 4
In reaction flask, after 10% hydrochloric acid (4.8eq) is added, -10 DEG C are cooled to, four (nafoxidines) are joined into boron
(60.4g, 0.2mol, 1.0eq) is slowly added dropwise in above-mentioned hydrochloric acid solution, during dropwise addition, gradually there is solid precipitation, temperature control exists
0 DEG C hereinafter, be added dropwise, be gradually increased to incubation at room temperature and stir 3 hours, and it is dry to obtain 40-60 DEG C of vacuum of white solid product for filtering
16.9g, yield 94.4% are obtained after dry；Derivative (it is derivative that pinacol in methyl alcohol by product dissolution, the is added) detection level of GC
98.8%, HPLC:99.7%；HNMR(DMSO-d6+H2O):8.84, 8.61,7.59.
Embodiment 5
In reaction flask, be added 10% hydrochloric acid (6.0eq) after, be cooled to 0 DEG C, by four (nafoxidines) join boron (60.4g,
0.2mol, 1.0eq) it is slowly added dropwise in above-mentioned hydrochloric acid solution, during dropwise addition, gradually there is solid precipitation, be added dropwise, gradually
It is warmed to room temperature insulated and stirred 3 hours, filters, obtain 16.4g, yield after obtaining 40-60 DEG C of white solid product vacuum drying
91.5%；Derivative (it is derivative that pinacol in methyl alcohol by product dissolution, the is added) detection level 98.1% of GC, HPLC:99.6%；
HNMR(DMSO-d6+H2O):8.84,8.61,7.59.
Embodiment 6
In reaction flask, after 10% acetic acid (10.0eq) aqueous solution is added, it is cooled to 0 DEG C, four (dimethylamino) are joined into boron
(39.6g, 0.2mol, 1.0eq) is slowly added dropwise in above-mentioned acetum, during dropwise addition, gradually has solid precipitation, drips
To finish, is gradually increased to incubation at room temperature and stirs 3 hours, filtering obtains 16.4g after obtaining 40-60 DEG C of white solid product vacuum drying,
Yield 91.5%；Derivative (it is derivative that pinacol in methyl alcohol by product dissolution, the is added) detection level 98.1% of GC, HPLC:
99.6%；HNMR(DMSO-d6+H2O):8.84,8.61, 7.59.
Embodiment 7
In reaction flask, be added 15% hydrochloric acid (4.5eq) after, at room temperature by four (dimethylamino) join boron (39.6g,
0.2mol, 1.0eq) it is slowly added dropwise in above-mentioned hydrochloric acid solution, during dropwise addition, gradually there is solid precipitation, be added dropwise, gradually
It is warmed to room temperature insulated and stirred 3 hours, filters, obtain 16.9g, yield after obtaining 40-60 DEG C of white solid product vacuum drying
94.2%；Derivative (it is derivative that pinacol in methyl alcohol by product dissolution, the is added) detection level 98.2% of GC, HPLC:99.1%；
HNMR(DMSO-d6+H2O):8.84,8.61,7.59.
Embodiment 8
In reaction flask, be added 15% hydrochloric acid (4.5eq) after, be cooled to -10 DEG C, by four (dimethylamino) join boron (396g,
2mol, 1.0eq) it is slowly added dropwise in above-mentioned hydrochloric acid solution, during dropwise addition, gradually there are solid precipitation, temperature control during dropwise addition
No more than 0 DEG C.It is added dropwise, is gradually increased to incubation at room temperature and stirs 5 hours, filtering obtains 40-60 DEG C of vacuum of white solid product
169g, yield 94.2% are obtained after drying；Derivative (it is derivative that pinacol in methyl alcohol by product dissolution, the is added) detection level of GC
97.7%, HPLC:99.4%；HNMR (DMSO-d6+H2O): 8.84 (0.02), 8.61 (1.00), 7.59 (5.50), 6.50
(0.03)；0.08% dilute hydrochloric acid 500mL is added in the said goods, at 5-10 DEG C of temperature control, stirs 30 minutes, filtering, obtained solid
40-60 DEG C of drying obtains white products 162g.GC derives detection level 99.2%, HPLC:99.9%；HNMR(DMSO-d6+
H2O):8.84,8.61,7.59.
Embodiment 9
In reaction flask, after 15% aqueous sulfuric acid (2.2eq) is added, it is cooled to 0 DEG C, four (dimethylamino) are joined into boron
(39.6g, 0.2mol, 1.0eq) is slowly added dropwise in above-mentioned aqueous sulfuric acid, during dropwise addition, gradually there is solid precipitation, is added dropwise
It finishes, is gradually increased to incubation at room temperature and stirs 1 hour, filtering obtains after obtaining 40-60 DEG C of white solid product vacuum drying
16.0g, yield 89.2%；GC derives detection level 98.5%, HPLC:99.7%；HNMR (DMSO-d6+H2O):8.84,
8.61,7.59。
Claims (6)
1. a kind of synthesis technology of two boron of tetrahydroxy, which comprises the following steps: being added tetraalkyl amine connection boron to mistake
It measures in aqueous acid, is still acid system after reaction, pH < 7 obtains two boron of tetrahydroxy after filtration drying.
2. the synthesis technology of two boron of a kind of tetrahydroxy according to claim 1, it is characterised in that: tetraalkyl amine joins in boron,
Alkylamine is selected from dimethylamine, diethylamine, diisopropylamine, dibutyl amine, diisobutyl amine or nafoxidine.
3. the synthesis technology of two boron of a kind of tetrahydroxy according to claim 1, it is characterised in that: reaction temperature control is at -40 DEG C
To 40 DEG C, tetraalkyl amine connection boron is added into excessive aqueous acid.
4. a kind of synthesis technology of two boron of tetrahydroxy according to claim 3, it is characterised in that: the reaction temperature control is -20
DEG C to 40 DEG C.
5. the synthesis technology of two boron of a kind of tetrahydroxy according to claim 1, it is characterised in that: it is described acid selected from hydrochloric acid,
Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or acetic acid.
6. the synthesis technology of two boron of a kind of tetrahydroxy according to claim 1, it is characterised in that: the acid is hydrochloric acid or hydrogen
When bromic acid, acid is 4-10: 1 with tetraalkyl amine connection boron equivalent；When acid is sulfuric acid, acid is 2-5 with tetraalkyl amine connection boron equivalent:
1；When acid is nitric acid, phosphoric acid or acetic acid, acid is 4-15: 1 with tetraalkyl amine connection boron equivalent.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3130009A (en) * | 1959-09-21 | 1964-04-21 | United States Borax Chem | Method for preparing tetrahydroxydiboron |
| CN102718787A (en) * | 2011-12-29 | 2012-10-10 | 大连联化医药技术有限公司 | Preparation method of combined borate |
| CN104530107A (en) * | 2014-12-31 | 2015-04-22 | 大连联化化学有限公司 | Synthetic method for 3-amino-4-fluorophenylboronic acid |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AUPO903897A0 (en) * | 1997-09-08 | 1997-10-02 | Commonwealth Scientific And Industrial Research Organisation | Organic boronic acid derivatives |
| AU7432400A (en) * | 1999-09-16 | 2001-04-17 | Cambridge Display Technology Limited | Preparation of benzenediboronic acid via a disilylated aryl-intermediate |
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2017
- 2017-12-17 CN CN201711357849.4A patent/CN108059169B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3130009A (en) * | 1959-09-21 | 1964-04-21 | United States Borax Chem | Method for preparing tetrahydroxydiboron |
| CN102718787A (en) * | 2011-12-29 | 2012-10-10 | 大连联化医药技术有限公司 | Preparation method of combined borate |
| CN104530107A (en) * | 2014-12-31 | 2015-04-22 | 大连联化化学有限公司 | Synthetic method for 3-amino-4-fluorophenylboronic acid |
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