CN104090000A - Method for determining content of important bortezomib intermediate, and applications of method - Google Patents
Method for determining content of important bortezomib intermediate, and applications of method Download PDFInfo
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- CN104090000A CN104090000A CN201410288715.1A CN201410288715A CN104090000A CN 104090000 A CN104090000 A CN 104090000A CN 201410288715 A CN201410288715 A CN 201410288715A CN 104090000 A CN104090000 A CN 104090000A
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- boric acid
- isobutyl boric
- isobutyl
- acid content
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Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a method for determining the content of an important bortezomib intermediate, and applications of the method. Under the existence condition of polyatomic alcohol, a C-B bond is easily quantitatively oxidized and hydrolyzed to generate boric acid through adopting isobutylboronic acid, the boric acid can be titrated by a strong-basicity solution in the presence of polyatomic alcohol, and the problem that the content of isobutylboronic acid cannot be determined by adopting a high-performance liquid chromatography method can be solved, so that the synthesis yield and quality requirement of bortezomib can be guaranteed, and the high-quality bortezomib can be obtained.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to a kind of assay method and application thereof of bortezomib intermediate.
Background technology
Isobutyl boric acid, suc as formula (I), CAS 84110-40-7, molecular formula: C4H11BO2, molecular weight: 101.94, fusing point is 108-111 DEG C, and it is one of synthetic important source material of novel tumor medicine bortezomib (Bortezomib), and in synthesis technique, use for twice front and back.Its quality directly has influence on the synthetic yield of bortezomib and quality.Chinese Journal of Pharmaceuticals Chinese Journal of Pharmaceuticals2012, 43 (5), isobutyl boric acid and (1S are disclosed in 393-395 page, 2S, 3R, 5S)-(+)-2, the reaction of 3-pinane diol, generate the preparation method of important intermediate BT-2104, BT-2104 intermediate less stable, easily become grease, and place for a long time, impurity content increases sharply, if while feeding intake, BT-2104 is grease, and impurity content is high, finally in the time of crystallization, the easy retrogradation of crystallizing system and occur situation about cannot stir, even possibly cannot separate out solid, cause the failure of an experiment.In addition at BT-2108 in the time that deprotection obtains bortezomib (BT-2109), use for the second time isobutyl boric acid.BT-2104, BT-2108 and BT-2109 structural formula are as follows:
Formula (I) is isobutyl boric acid
The content of isobutyl boric acid is difficult to control at present.Known according to the structure of isobutyl boric acid, acomia color group, is difficult to uv absorption and realizes its high performance liquid chromatography detection.The character that isobutyl boric acid has a distillation is difficult to again realize the control of its loss on drying, during because of its determination of moisture, can react with Ka Shi liquid, is difficult to measure moisture.Two boric acid hydroxyl acidity extremely a little less than, cannot realize chemistry titration, even if sodium methoxide can not titration.Its character has determined the difficulty of its quality testing.
If carrying out HPLC detection after isobutyl boric acid derivatization, be difficult to find suitable quantitative chemical reaction for measuring, and derivatization reagent interference liquid phase mensuration, the process of derivative reaction is difficult to determine, causes detecting inaccurate; The laggard promoting the circulation of qi phase method of derivatization detects and is difficult to equally quantitative measurement content.
If adopt the content of gas phase process control isobutyl boric acid, cost is high, and complicated operation does not still have its ripe gas phase content control method at present.
Summary of the invention
Object of the present invention is exactly in order to overcome the deficiencies in the prior art, and a kind of content assaying method of bortezomib important intermediate isobutyl boric acid is provided, and has solved the unmanageable problem of current content.
The inventor has done a large amount of experiments to the quality research of isobutyl boric acid; find out the effective content assaying method of a kind of isobutyl boric acid; first isobutyl boric acid is oxidized to boric acid; adopt again specific titration method to control the content of isobutyl boric acid; detect by the present invention the important intermediate BT-2104 purity that the isobutyl boric acid after qualified prepares higher; more stable; be convenient to store; taking BT-2104 as raw material reaction; add deprotection work smoothly; for follow-up crystallization work has reduced difficulty, also improve overall yield simultaneously.
In order to solve the problems of the technologies described above, the present invention is solved by following technical proposals:
An assay method for isobutyl boric acid content, comprises the steps:
(1) preparation of solution and processing:
Get isobutyl boric acid 0.10-0.20g in container bottle, add polyvalent alcohol 1-7g and 0.05-0.15mol oxygenant, after heating water bath, be transferred in potentiometric titration cup, shift in the lump with the chilled water washing of newly boiling, making solution is totally 30-50ml;
(2) be titrated to terminal with strong basicity vs;
(3) do blank test and proofread and correct, calculate the content of isobutyl boric acid, wherein content described in step (3) is that 97%-103% is specification product, can be used as the intermediate of preparing bortezomib; Content is less than 97% or be greater than 103% for substandard product, can not be as the intermediate of preparing bortezomib.
As preferably, described in step (1), polyvalent alcohol is sorbierite, sweet mellow wine, glycerine, cis-1, any one in 2-ring pentanediol, fructose, xylitol or d-galactose, preferably PEARLITOL 25C; Described oxygenant is any one in hydrogen peroxide, potassium dichromate or potassium permanganate; Described heating water bath is heating water bath 15-25 minute at 60-80 DEG C; Described overall solution volume is 40ml.
As preferably, the isobutyl boric acid described in step (1) is 0.15g, and described sweet mellow wine is PEARLITOL 25C 4g, adds 10ml30% hydrogen peroxide, 70 DEG C of water-baths 20 minutes.
As preferably, strong basicity vs described in step (2) is any one vs in NaOH or potassium hydroxide.
As preferably, described strong basicity vs is sodium hydroxide solution.
As preferably, the concentration of described strong basicity vs is 0.01 to 0.5mol/L.
As preferably, the concentration of described strong basicity vs is 0.1mol/L, and after blank test described in step (3) is proofreaied and correct, every 1.0ml strong basicity vs is equivalent to the isobutyl boric acid of 10.19mg.
The assay method that the invention also discloses a kind of isobutyl boric acid content is the application in 97.0-103.0% detecting isobutyl boric acid content.
Assay method principle of the present invention is as follows:
Isobutyl boric acid is under polyvalent alcohol existence condition, and C-B key easily oxidized dose of quantitative oxydrolysis generates boric acid, and boric acid can be by strong alkali solution titration under polyvalent alcohol existence condition.
As preferably, described polyvalent alcohol is sorbierite, sweet mellow wine, glycerine, cis-1, in 2-ring pentanediol, fructose, xylitol or d-galactose any one, preferably sweet mellow wine, more preferably PEARLITOL 25C; In reaction, polyvalent alcohol is reaction mass in addition, again as reaction dissolvent.
As preferably, described oxygenant can be in hydrogen peroxide, potassium dichromate or potassium permanganate any one, preferably hydrogen peroxide;
As preferably, described strong alkali solution is potassium hydroxide or sodium hydroxide solution, preferably sodium hydroxide solution; Isobutyl boric acid oxidation reaction as shown in the formula:
Preferred reaction is as follows:
Compared with prior art, the useful technique effect that the present invention brings is as follows:
(1) pass through isobutyl boric acid under polyvalent alcohol existence condition, C-B key easily oxidized dose of quantitative oxydrolysis generates boric acid, and boric acid can be by strong alkali solution titration under polyvalent alcohol existence condition, by the method for simple to operation, environmental protection, applicable industrial production control, solve and passed through at present the insurmountable problem of efficient liquid-phase chromatography method, found out the effective content assaying method of a kind of isobutyl boric acid;
(2) by controlling the content of isobutyl boric acid; the important intermediate BT-2104 purity obtaining is higher; more stable; be convenient to store; taking BT-2104 as raw material reaction; add deprotection work smoothly, for follow-up crystallization work has reduced difficulty, also improved the yield of bortezomib entirety simultaneously.
(3) in large production, if because of the defective situation that occurs a collection of the failure of an experiment of isobutyl boric acid content, economic loss is serious, so it is most important to control the content of isobutyl boric acid well.
Embodiment
The raw materials used lot number of following examples is LE90L03/LE90L04 (manufacturer: J & k Scientific Ltd), and the isobutyl boric acid of other lot numbers is also applicable to the present invention.
The instrument that the present invention uses is as follows:
Analytical balance (model: METTLER TOLEDO ABS135-S)
Potentiometric titrimeter (model: METTLER TOLEDO T50)
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiment do not form any restriction to the present invention.
Embodiment 1
Get this product 0.15g, precision weighing, in tool plug bottle, adds the PEARLITOL 25C of 4g, adds 0.1mol hydrogen peroxide, i.e. 30% hydrogen peroxide 10ml,, after 20 minutes, be transferred in potentiometric titration cup at 70 DEG C of heating water baths, with newly boiling, chilled water washing is shifted in the lump, making overall solution volume is 40ml, be titrated to terminal with 0.1mol/L NaOH vs, do blank test simultaneously and proofread and correct, every 1.0ml NaOH vs is equivalent to the isobutyl boric acid (C of 10.19mg
4h
11bO
2).
Measurement result is as following table 1:
| Lot number | 1# sample (%) | 2# sample (%) | Content (%) |
| LE90L03 (purchase reagent) | 100.29 | 100.49 | 100.39 |
Embodiment 2
Get this product 0.10g, precision weighing, in tool plug bottle, adds 1g sorbierite, 0.05mol potassium permanganate (7.9g, molecular weight 158.03),, after 15 minutes, be transferred in potentiometric titration cup at 60 DEG C of heating water baths, with newly boiling, chilled water washing is shifted in the lump, making overall solution volume is 30ml, be titrated to terminal with 0.5mol/L potassium hydroxide vs, do blank test simultaneously and proofread and correct, every 1.0ml potassium hydroxide vs is equivalent to the isobutyl boric acid (C of 50.97mg
4h
11bO
2)
Measurement result is as following table 2:
| Lot number | 1# sample | 2# sample | Content (%) |
| LE90L04 (purchase reagent) | 97.01 | 97.12 | 97.07 |
Embodiment 3
Get this product 0.20g, precision weighing, in tool plug bottle, adds 7g glycerine, 0.15mol potassium dichromate (44.13g, molecular weight: 294.18),, after 25 minutes, be transferred in potentiometric titration cup at 80 DEG C of heating water baths, with newly boiling, chilled water washing is shifted in the lump, making overall solution volume is 50ml, be titrated to terminal with 0.01mol/L NaOH vs, do blank test simultaneously and proofread and correct, every 1.0ml NaOH vs is equivalent to the isobutyl boric acid (C of 1.019mg
4h
11bO
2).
Measurement result is as following table 3:
| Lot number | 1# sample | 2# sample | Content (%) |
| LE90L03 (purchase reagent) | 102.25 | 102.11 | 102.18 |
Cis-1 in addition, 2-ring pentanediol, fructose, xylitol, d-galactose, with reference to embodiment 1, can be measured the content of isobutyl boric acid equally, and content is in the critical field of 97.0-103.0%.
Embodiment 4: contrast test
Prepare at present isobutyl boric acid method more, as disclosed the synthetic preparation of employing ultrasonic radiation in CN103242356A.Chinese Journal of Pharmaceuticals Chinese Journal of Pharmaceuticals2012,43 (5), in 393-395 page, disclose taking isobutyryl chloride as raw material, generate isobutyl boric acid through reduction, bromo, replacement, hydrolysis.By controlling the content of isobutyl boric acid, the important intermediate BT-2104 purity of acquisition is higher, more stable; be convenient to store, taking BT-2104 as raw material reaction, add deprotection work smoothly; for follow-up crystallization work has reduced difficulty, also improve overall yield simultaneously.
Know from following table 4: the quality control of isobutyl boric acid, affect very large on follow-up crystallization work and overall yield, if control bad, even can cause test failure, in large production, if there is the situation of a collection of the failure of an experiment, economic loss is serious, so it is most important to control the content of isobutyl boric acid well.
The preparation method of the refining rear total recovery of bortezomib of mentioning in following table 4: the preparation method of BT-2104 is with reference to Chinese Journal of Pharmaceuticals2012,43 (5), the preparation of 393-395 document is to prepare with reference to CN200580017645.5 by BT-2104 to the preparation of bortezomib (BT-2109).Crude product refining is ethyl acetate: acetone=3:1, temperature, 18-22 DEG C of crystallization, finally obtains finished product bortezomib.
Table 4:
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for the person of ordinary skill of the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (8)
1. an assay method for isobutyl boric acid content, comprises the steps:
(1) preparation of solution and processing:
Get isobutyl boric acid 0.10-0.20g in container bottle, add polyvalent alcohol 1-7g and 0.05-0.15mol oxygenant, after heating water bath, be transferred in potentiometric titration cup, shift in the lump with the chilled water washing of newly boiling, making overall solution volume is 30-50ml;
(2) be titrated to terminal with strong basicity vs;
(3) do blank test and proofread and correct, calculate the content of isobutyl boric acid.
2. the assay method of isobutyl boric acid content according to claim 1, it is characterized in that, described in step (1), polyvalent alcohol is sorbierite, sweet mellow wine, glycerine, cis-1, any one in 2-ring pentanediol, fructose, xylitol or d-galactose; Described oxygenant is any one in hydrogen peroxide, potassium dichromate or potassium permanganate; Described heating water bath is heating water bath 15-25 minute at 60-80 DEG C; Described overall solution volume is 40ml.
3. the assay method of isobutyl boric acid content according to claim 2, it is characterized in that, the isobutyl boric acid described in step (1) is 0.15g, and described sweet mellow wine is PEARLITOL 25C 4g, described hydrogen peroxide is 10ml30% hydrogen peroxide, 70 DEG C of water-baths 20 minutes.
4. according to the assay method of isobutyl boric acid content described in arbitrary claim in claims 1 to 3, it is characterized in that, strong basicity vs described in step (2) is any one vs in NaOH or potassium hydroxide.
5. the assay method of isobutyl boric acid content according to claim 4, is characterized in that, described strong basicity vs is sodium hydroxide solution.
6. the assay method of isobutyl boric acid content according to claim 4, is characterized in that, the concentration of described strong basicity vs is 0.01 to 0.5mol/L.
7. the assay method of isobutyl boric acid content according to claim 4, is characterized in that, the concentration of described strong basicity vs is 0.1mol/L.
8. be the application in 97.0-103.0% according to the assay method of any one isobutyl boric acid content in claim 1-7 detecting isobutyl boric acid content.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104111279A (en) * | 2014-08-08 | 2014-10-22 | 广东东阳光药业有限公司 | Method for measuring content of 2-pyrazinecarboxylic acid |
| CN108459136A (en) * | 2018-05-29 | 2018-08-28 | 上海福乐医药科技有限公司 | A kind of method of three boroxane content of titration measuring front three basic ring |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183695A (en) * | 2012-11-30 | 2013-07-03 | 大连联化化学有限公司 | Method for preparing fatty boric acid by utilizing isopropoxyboric acid pinacol ester |
| CN103242356A (en) * | 2013-05-24 | 2013-08-14 | 苏州卫生职业技术学院 | Preparation method of bortezomib intermediate isobutaneboronic acid |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183695A (en) * | 2012-11-30 | 2013-07-03 | 大连联化化学有限公司 | Method for preparing fatty boric acid by utilizing isopropoxyboric acid pinacol ester |
| CN103242356A (en) * | 2013-05-24 | 2013-08-14 | 苏州卫生职业技术学院 | Preparation method of bortezomib intermediate isobutaneboronic acid |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104111279A (en) * | 2014-08-08 | 2014-10-22 | 广东东阳光药业有限公司 | Method for measuring content of 2-pyrazinecarboxylic acid |
| CN108459136A (en) * | 2018-05-29 | 2018-08-28 | 上海福乐医药科技有限公司 | A kind of method of three boroxane content of titration measuring front three basic ring |
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Application publication date: 20141008 Assignee: Hangzhou Huadi Pharmaceutical Technology Co.,Ltd. Assignor: Hangzhou Huadong Medicine Group Biopharmaceutical Co.,Ltd. Contract record no.: X2021330000100 Denomination of invention: A content determination method of important intermediate of bortezomib and its application Granted publication date: 20160608 License type: Common License Record date: 20210820 |