CN105503920B - A kind of preparation method of borate compound - Google Patents
A kind of preparation method of borate compound Download PDFInfo
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- CN105503920B CN105503920B CN201510964696.4A CN201510964696A CN105503920B CN 105503920 B CN105503920 B CN 105503920B CN 201510964696 A CN201510964696 A CN 201510964696A CN 105503920 B CN105503920 B CN 105503920B
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- 0 CCN(C(C(F)(F)F)=O)c(cc1)ccc1C([C@]1C(*C)=CC(S=*)=CC1)=C(C=C1C)C#CC1=[N+] Chemical compound CCN(C(C(F)(F)F)=O)c(cc1)ccc1C([C@]1C(*C)=CC(S=*)=CC1)=C(C=C1C)C#CC1=[N+] 0.000 description 3
- LMGIOBFPCKRTOB-UHFFFAOYSA-N Bc(cc1)ccc1C(NCC(C)CN)=O Chemical compound Bc(cc1)ccc1C(NCC(C)CN)=O LMGIOBFPCKRTOB-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to a kind of compound recognized for carbohydrate, especially a kind of preparation method of borate compound.Compound 1 is protected by BOC, is then condensed to yield with compound 3 in compound 4, reaction and is reacted very clean, the polarity of compound is not practically insoluble in water very much, and yield is very high, then drags BOC by hydrochloric acid methanol, and the purity and yield for obtaining compound 5 are all very high yet.This addresses the problem the issues of purification of chemical combination 5.Compound 6 is protected by trifluoro formoxyl, then does sulfonic acid chloride, and yield purity all improves a lot, and 90% the purity of compound 8 can be just brought up to by washing, and compound 8 is also very stable does not allow perishable be readily produced.Because the purifying of the very high such compound 9 of the purity of sulfonic acid chloride is also high with regard to very convenient yield in the reaction of synthesis compound 10, most rear dragging fluoroform acyl group need not purify and directly can obtain sterling compound 10.
Description
Technical field
The present invention relates to a kind of compound recognized for carbohydrate, especially a kind of preparation method of borate compound.
Background technology
Synthetic route is in United States Patent (USP) US5631364：
Have the shortcomings that in above-mentioned process route three it is fatal：
First, there are many accessory substance polarity very big in the reaction of the compound 5 of synthesis, and compound 5 is highly soluble in water,
Organic solvent extraction does not come out, and so causes the low purification difficult of yield.
2nd, reaction is very miscellaneous when the synthesis of compound 6 compound 11, it is impossible to purify, compound 11 is apt to deteriorate during purifying
So can only directly down single step reaction use.
3rd, cause compound 10 extremely difficult because compound 11 is impure when synthesizing compound 10, it is pure with normal-phase chromatography
Change it is convenient to both it is anti-phase purifying it is convenient to both just can be so that yield is very low less than 1%.
Therefore, find that simple to operate, safe, side reaction is few, high conversion rate, high income, environmental pollution is small, be produced into
Originally preparation method that is low, being suitable for industrialized production compound 10 is the current technical problem for being badly in need of solving.
The content of the invention
Because direct polycondensation can react this due to two amino in the reaction of synthesis 5 in United States Patent (USP) US5631364
Sample causes side reaction to increase, and product is soluble in water is not dissolved in organic solvent very much, can not thus wash, and directly crosses post product
Polarity is easily adsorbed greatly by pillar, and it is all difficult to improve to cause yield and purity.So by two amino of compound 1 in the present invention
In one protected with BOC, carry out the clean purifying yield that is easy to of condensation reaction reaction and also greatly improve.
Synthesized in United States Patent (USP) US5631364 due to there is the naked leakage of ammonia hydrogen to cause reaction very miscellaneous in compound 6 in compound 11,
And unstable can not wash of sulfonic acid chloride made can not cross post purifying, can only be directly used in synthesis compound 10, causing
The purification difficult yield of compound 10 is very low.Compound 6 is protected by trifluoro formoxyl in the present invention, sulfonic acid chloride is then done, received
Rate purity is all improved a lot, and 90% the purity of compound 8 can be just brought up to by washing, and compound 8 is also very steady
Surely perishable be readily produced is not allowed.In addition, the present invention synthesis compound 10 reaction in due to the purity of yellow acyl chlorides it is very high, this
The purifying of sample compound 9 is also high with regard to very convenient yield, and most rear dragging fluoroform acyl group need not purify and directly can obtain sterling compound
10。
A kind of preparation method of borate compound, comprises the following steps：
(1) compound 1 obtains compound 2 by BOC protections；
(2) compound 2 is condensed to yield compound 4 with compound 3；
(3) compound 4 drags BOC by hydrochloric acid methanol, obtains compound 5；
(4) compound 6 obtains compound 7 by the protection of trifluoro formoxyl；
(5) compound 7 obtains compound 8 by sulfonic acid chloride；
(6) compound 5 and the synthesis compound 9 of compound 8；
(7) compound 9 is by dragging trifluoro formoxyl to obtain compound 10.
Preferably, it is in step (1), compound 1 is molten in methyl alcohol, BOC2O dioxane solution is added dropwise, temperature is kept
Degree is less than 10 DEG C, is then stirred overnight at room temperature, reaction solution, which is concentrated to dryness, to add water, and is extracted at least 3 times with dichloromethane, merges organic
Phase, is concentrated to dryness and obtains compound 2.
Preferably, in step (2), compound 3 is dissolved in DMF, 0 DEG C of addition HOBT is cooled to, is then added dropwise DCC's
DMF solution, keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature, filtering reacting liquid, pyridine of the filtrate added drop-wise to compound 2
Keeping temperature is less than 10 DEG C in solution, is then stirred overnight at room temperature, reaction solution is concentrated to dryness, and crosses post and obtains compound 4.
Preferably, it is in step (3), compound 4 is molten in methyl alcohol, 0 DEG C of dropwise addition HCl methanol solution is cooled to, is kept
Temperature is less than 10 DEG C, is then stirred overnight at room temperature, reaction solution, which is concentrated into, obtains compound 5.
Preferably, in step (4), compound 6 is dissolved in TFAA, heating-up temperature is reacted 8 hours to 50 DEG C,
Reaction solution is concentrated to dryness, and obtains compound 7.
Preferably, in step (5), compound 7 is dissolved in dichloromethane and DMF, 0 DEG C of dropwise addition oxalyl chloride is cooled to,
Keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature, reaction solution is concentrated to dryness, and then adds dichloromethane and dissolves and use frozen water
Wash, organic phase is concentrated to give compound 8.
Preferably, in step (6), compound 5 is dissolved in methanol and DMF, and is cooled to 0 DEG C, addition sodium bicarbonate water
Solution；Then the acetonitrile solution of compound 8 is added dropwise, keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature；Reaction solution is concentrated
Post obtains the crude product of compound 8, then obtains compound 9 after reversed-phase column.
Preferably, in step (7), compound 9 is molten in methyl alcohol, adds potassium carbonate, is stirred overnight at room temperature, reaction solution mistake
Filter and then obtain compound 10 crossing reversed-phase column.
Compound technical term is explained and its Chinese：
Illustrated below for structural formula of compound and its Chinese：
The structural formula of compound 1：1,3- diaminourea -2- propyl alcohol
The structural formula of compound 2：Tert-butyl group 3- amino -2- hydroxypropanols
The structural formula of compound 3：4- Carboxybenzeneboronic acids
The structural formula of compound 4：4- ((tert-butyl group 3- amino-2-hydroxy-propyls) amino carbonyl)-phenyl boric acid (N-BOC-
CPBA-DAPOL)
The structural formula of compound 5：4- ((3- amino-2-hydroxy-propyls) amino carbonyl)-phenyl boric acid (CPBA-DAPOL)
The structural formula of compound 6：Xylene cyanol blue FF
The structural formula of compound 7：Borontrifluoride carbon-based-xylene cyanol blue FF
The structural formula of compound 8：Borontrifluoride carbon-based-xylene blue-SO2Cl
The structural formula of compound 9：Borontrifluoride carbon-based-xylene blue-phenyl boric acid (CF3-XC-CPBA-DAPOL)
The structural formula of compound 10：Xylene blue-phenyl boric acid (XC-CPBA--DAPOL)
Few with impurity by the compound 10 prepared by the present invention, the distinguishing feature such as purity height is mainly used in carbohydrate
Identification, the beneficial effect such as error small high with identification sensitivity.
In addition, although synthetic route of the invention is compared with US5631364 to be added four-step reaction but have following several
Advantage：
Compound 1 is protected by BOC, is then condensed to yield with compound 3 in compound 4, reaction and is reacted very clean, chemical combination
The polarity of thing is not practically insoluble in water very much yet, and yield is very high, then drags BOC by hydrochloric acid methanol, obtain compound 5 purity and
Yield is all very high.This addresses the problem the issues of purification of chemical combination 5.
Compound 6 is protected by trifluoro formoxyl, then does sulfonic acid chloride, and yield purity all improves a lot, and passes through water
Can just the purity of compound 8 be brought up to 90% by washing, and compound 8 is also very stable does not allow perishable be readily produced.
Purifying due to the very high such compound 9 of the purity of sulfonic acid chloride in the reaction of synthesis compound 10 is just easily received
Rate is also high, and most rear dragging fluoroform acyl group need not purify and directly can obtain sterling compound 10.
Brief description of the drawings
The structural representation of borate compound 10 that Fig. 1 present invention is recognized for carbohydrate
Embodiment
The present invention is further illustrated with reference to the accompanying drawings and examples.
Embodiment 1
Compound 1 (178g) is dissolved in 500mL methanol, BOC2O (86.3) dioxane solution (400mL) is added dropwise,
Keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature, reaction solution, which is concentrated to dryness, to add water, is extracted with dichloromethane (5 times), merges
Organic phase, is concentrated to dryness and obtains compound 2 (150g, yield：50%).
Compound 3 (26.2g) is dissolved in 200mL DMF, 0 DEG C is cooled to and adds HOBT (31.2g), DCC is then added dropwise
The DMF (150mL) of (65g), keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature, then filters, filtrate added drop-wise to compound
Keeping temperature is less than 10 DEG C in 2 (30g) pyridine (200mL) solution and then is stirred overnight at room temperature, and reaction solution was concentrated to dryness post
Obtain compound 4 (30g, yield：57%).
Compound 4 (30g) is dissolved in 100mL methanol, 0 DEG C is cooled to and HCl methanol solutions (6M, 100mL) is added dropwise, keep
Temperature is less than 10 DEG C, is then stirred overnight at room temperature, reaction solution, which is concentrated into, obtains compound 5 (25g, yield：100%).
Compound 6 (5.4g) is dissolved in TFAA 30mL, heating-up temperature is reacted 8 hours to 50 DEG C, reaction solution concentration
To dry, compound 7 (6.0g, yield are obtained：95%).
Compound 7 (3.2g) is dissolved in 60mL dichloromethane and 0.1mL DMF, 0 DEG C of dropwise addition oxalyl chloride is cooled to
2.5mL, keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature；Reaction solution is concentrated to dryness, and then adds dichloromethane dissolving simultaneously
Washed with frozen water, organic phase is concentrated to give compound 8 (1.6g, yield：52%).
Compound 5 (1.0g) is dissolved in 1mL methanol and 5mL DMF and is cooled to 0 DEG C, addition sodium bicarbonate aqueous solution
(0.1M, 60mL)；Then acetonitrile (25mL) solution of compound 8 (1.0g) is added dropwise, keeping temperature is less than 10 DEG C, and then room temperature is stirred
Mix overnight；The concentrated post of reaction solution obtains the crude product (900mg) of compound 8, then obtains compound 9 after reversed-phase column
(400mg, 30%, purity 98%).
Compound 9 (100mg) is dissolved in 10mL methanol, adds potassium carbonate (100mg), is stirred overnight at room temperature, reacting liquid filtering
Then compound 10 (80mg, 85%, purity 98%) is obtained in reversed-phase column excessively.
Comparative example 1
Compound 3 (26.2g) is dissolved in 200mL DMF, 0 DEG C is cooled to and adds HOBT (31.2g), DCC is then added dropwise
The DMF (150mL) of (65g), keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature, then filters, filtrate added drop-wise to compound
Keeping temperature is less than 10 DEG C in 1 (15g) pyridine (200mL) solution and then is stirred overnight at room temperature, and reaction solution is concentrated to dryness, and crosses post
Obtain compound 5 (5g, yield：10%).
Compound 6 (3.2g) is dissolved in 60mL dichloromethane and 0.1mLDMF, 0 DEG C of dropwise addition oxalyl chloride 2.5mL is cooled to,
Keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature；Reaction solution is concentrated to dryness, obtain compound 11 (3.5g, purity 10%,
The method for not finding purifying at present, can only be directly used in next step reaction).
Compound 5 (1.0g) is dissolved in 1mL methanol and 5mL DMF and is cooled to 0 DEG C, addition sodium bicarbonate aqueous solution
(0.1M, 60mL), is then added dropwise acetonitrile (25mL) solution of compound 11 (10.0g, purity 10%)；Keeping temperature is less than 10
DEG C, then it is stirred overnight at room temperature；The concentrated post of reaction solution obtains the crude product (300mg) of compound 10, then anti-phase after twice
Post obtains compound 10 (20mg, 0.7%, content 90%).
The foregoing is merely illustrative of the preferred embodiments of the present invention, is to combine specific preferred embodiment to institute of the present invention
The further description of work, it is impossible to assert that the specific implementation of the present invention is confined to these explanations.All spirit in the present invention
With any modifications, equivalent substitutions and improvements made within principle etc., it should be included in the scope of the protection.
Claims (8)
1. a kind of preparation method of borate compound, comprises the following steps：
(1) compound 1Compound 2 is obtained by BOC protections
(2) compound 2With compound 3It is condensed to yield compound 4
(3) compound 4BOC is taken off by hydrochloric acid methanol, compound 5 is obtained
(4) compound 6Compound 7 is obtained by trifluoroacetyl group protection
(5) compound 7Compound 8 is obtained by sulfonic acid chloride
(6) compound 5 and the synthesis compound 9 of compound 8
(7) compound 9 obtains compound 10 by de- trifluoroacetyl group
2. preparation method according to claim 1, it is characterised in that in the step (1), compound 1 is molten in methyl alcohol,
The dioxane solution of di-tert-butyl dicarbonate is added dropwise, keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature, reaction solution concentration
Add water, extracted at least 3 times with dichloromethane to dry, merge organic phase, be concentrated to dryness and obtain compound 2.
3. preparation method according to claim 1, it is characterised in that in the step (2), compound 3 is dissolved in N, N- bis-
In NMF, 0 DEG C of addition I-hydroxybenzotriazole is cooled to, the N of dicyclohexylcarbodiimide, N- dimethyl is then added dropwise
Formamide solution, keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature, filtering reacting liquid, pyrrole of the filtrate added drop-wise to compound 2
Keeping temperature is less than 10 DEG C in pyridine solution, is then stirred overnight at room temperature, reaction solution is concentrated to dryness, and crosses post and obtains compound 4.
4. preparation method according to claim 1, it is characterised in that in the step (3), compound 4 is molten in methyl alcohol,
0 DEG C of dropwise addition HCl methanol solution is cooled to, keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature, being concentrated into of reaction solution
Compound 5.
5. preparation method according to claim 1, it is characterised in that in the step (4), compound 6 is dissolved in trifluoro second
In acid anhydrides, heating-up temperature is reacted 8 hours to 50 DEG C, and reaction solution is concentrated to dryness, and obtains compound 7.
6. preparation method according to claim 1, it is characterised in that in the step (5), compound 7 is dissolved in dichloromethane
In alkane and DMF, 0 DEG C of dropwise addition oxalyl chloride is cooled to, keeping temperature is less than 10 DEG C, is then stirred overnight at room temperature, reaction solution is concentrated into
It is dry, then add dichloromethane and dissolve and washed with frozen water, organic phase is concentrated to give compound 8.
7. preparation method according to claim 1, it is characterised in that in the step (6), compound 5 is dissolved in methanol and DMF
In, and it is cooled to 0 DEG C, addition sodium bicarbonate aqueous solution；Then the acetonitrile solution of compound 8 is added dropwise, keeping temperature is less than 10 DEG C,
Then it is stirred overnight at room temperature；The concentrated post of reaction solution obtains the crude product of compound 8, then obtains compound 9 after reversed-phase column.
8. preparation method according to claim 1, it is characterised in that in the step (7), compound 9 is molten in methyl alcohol, plus
Enter potassium carbonate, be stirred overnight at room temperature, then reacting liquid filtering obtains compound 10 in reversed-phase column excessively.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5631364A (en) * | 1994-03-31 | 1997-05-20 | Axis Biochemicals Asa | Labelled boronic acid derivatives |
| DE19843094A1 (en) * | 1998-09-21 | 2000-03-23 | Roche Diagnostics Gmbh | Method for the determination of glycated hemoglobin |
| GB201215571D0 (en) * | 2012-08-31 | 2012-10-17 | Axis Shield Asa | Assay method |
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