CN102617376A - Synthesis method of calcium ion selective chelating agents - Google Patents
Synthesis method of calcium ion selective chelating agents Download PDFInfo
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- CN102617376A CN102617376A CN2012100650373A CN201210065037A CN102617376A CN 102617376 A CN102617376 A CN 102617376A CN 2012100650373 A CN2012100650373 A CN 2012100650373A CN 201210065037 A CN201210065037 A CN 201210065037A CN 102617376 A CN102617376 A CN 102617376A
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Abstract
The invention provides a synthesis method of calcium ion selective chelating agents and relates to a synthesis method of biological medicaments. According to the synthesis method, 1, 2-bi(2-aminophenoxy) ethane is used as raw materials to take two steps of reaction: esterification reaction and acidification reaction, 2-bi(2-aminophenoxy) ethane-N, N, N', N'-quadrol(2a, BAPTA) is synthesized, and the structure of compounds 2a is shown by IR, 1HNMR. Through regulating the mixture ratio and the catalyst consumption, the mol ratio of 1, 2-bi(2-aminophenoxy) ethane to methyl bromoacetate to diisopropylethylamine is 1:5.2:5.2, the yield of the 2-bi(2-aminophenoxy) ethane-N, N, N', N'-quadrol methyl ester(1a, BAPTA methyl ester) is 86 percent, and the purity is 97.45 percent. A chemical purification method is adopted, the BAPTA purity can reach 99 percent, and the yield can reach 94 percent at the purity. The method has the advantages that the production cost is reduced, the process steps are optimized, and in addition, the quality and the yield are improved.
Description
Technical field
The present invention relates to a kind of compound method of biological agent, particularly relate to a kind of compound method of calcium ion selective sequestrant.
Background technology
Two (2-amino-benzene oxygen) ethane-N of 2-, N, N', N'-tetraacethyl 2a (O; O'-Bis (2-aminophenyl) ethyleneglycol-N, N, N'; N'-tetraacetic acid), being called for short BAPTA, is a kind of nontoxic calcium ion selective sequestrant and indicator.Its basic chelating unit and EDTA are similar, and just two fatty nitrogen are substituted by aromatic nitrogen.Therefore, BAPTA can be by not protonated under physiological pH.The pKa3 of BAPTA is 5.47, and pKa4 is 6.36.These characteristics have shown that the step of deprotonation is not comprised in the chelation step of Ca.Owing to do not receive the interference of proton, its chelation percent is high more a lot of than EGTA.
Tsien in 1980 etc. have proposed in EDTA, introducing fragrant chromophoric group (being BAPTA) on the basis of calcium ion best selective structure; The introducing of phenyl ring has kept the highly selective to calcium ion; Complete ionize under physiological condition; Thereby the influence that not changed by pH value with the calcium ion complexing, also improved greatly in conjunction with the speed of calcium ion.(Tsien R Y. Biochemistry, 1980,19 (11): 2396) yet, its verivate is hydrolysis at an easy rate in cytoplasm, thus it can form the variation that inner complex is effectively alleviated plasma concns with calcium ion.This inner complex contacts with endotheliocyte can increase the release rate of prostacyclin in arterial endothelial cell.And in aromatic ring, introduce greatly enhanced electronic prostaglandin(PG) and the effect of free calcium carboxylates ionic of halogen, this effect can make the prostacyclin of increase dissociate, so with the calcium ion chelating.Prostacyclin, it is that a kind of anticoagulant helps vasodilation, prevents that to increase active hematoblastic quantity the hemostatic tube breakage forms thrombus.Because reduced content of cholesterol among the artery myocyte, thereby reduce arteriosclerotic probability of occurrence.(Heilporn?S,?Broeders?F,?Daloze?D.?Bull.?Soc.?Chim.?Belg,?1994,?103(7):?309)
Two (2-amino-benzene oxygen) ethane-N of 2-, N, N', the N'-tetraacetate can permeate through cell membranes become research cell Ca
2+The favourable instrument of physiological function, Yang Liping etc. propose two (2-amino-benzene oxygen) ethane-N of 2-, N; N'; N'-tetraacethyl methyl esters 1a can be under the situation of damaging cells film not and get into cell, and hydrolysis goes out free BAPTA in cell, under the physiological pH condition and Cytoplasmic Ca
2+In conjunction with; The ability (YANG Li-Ping, TU Hui-Ping, the FU Hong-Yan. Journalof East China Normal University (Narural Science) that make red corpuscle skeletin conformation play stabilization and improve the red corpuscle high temperature resistance are seemingly arranged; 1996, (1): 45)
Following synthetic route is to have delivered and disclosed reaction scheme, two (2-amino-benzene oxygen) ethane-N of its product yield compound 2-, and N, N', N'-tetraacethyl methyl esters 1a is 71%, two (2-amino-benzene oxygen) ethane-N of 2-, N, N', N'-tetraacethyl 2a yield does not have report.
The first step reaction
The reaction of second step
There is the low problem of complex steps, product purity and yield in aforesaid method.In order to reduce cost, improve purity and yield, need to improve process step.And above-claimed cpd is used for the biological medicine aspect, and its purity must reach certain standard could guarantee using character.
Summary of the invention
The object of the present invention is to provide a kind of compound method of calcium ion selective sequestrant; This method proposes a kind of improvement of process method; Save with phosphoric acid washing to neutral this step; And the method for employing chemical purification, compound 2a purity can reach 99%, and the yield under this purity can reach 94%.
The present invention realizes through following technical scheme:
A kind of compound method of calcium ion selective sequestrant, promptly 2-two, be 2-amido benzene oxygen, ethane-N; N, N', is 1a at N'-tetraacethyl methyl esters; The methyl esters of BAPTA; Compound method, this method comprises at first sloughs moisture wherein with liquid raw material methyl bromoacetate and diisopropylethylamine and second cyanogen drying, secondly the entire reaction device is removed moisture; Proportioning raw materials is 1, and 2-is two, be 2-amido benzene oxidative ethane, and the molar ratio of methyl bromoacetate and diisopropylethylamine is 1:5.2:5.2, and the reaction end system is a neutrality; Concrete steps are: the first step: the activated molecular sieve of solvent second cyanogen and raw material methyl bromoacetate and diisopropylethylamine soaked more than 24 hours, and molecular sieve was dried 4 hours with luxuriant good fortune stove down at 400 ℃ before use; Experimental installation is dry, feeds high pure nitrogen and removes its air and moisture; With 1,2-is two, be 2-amido benzene oxygen, and ethane and METHYL BROMOACETATE are that 1.5 equivalents, catalyzer anhydrous sodium iodide and diisopropylethylamine are mixed into 1.2 equivalents, and mixing is dissolved in them in the second cyanogen; Mixture reflux under protection of nitrogen gas stirs 20h; After reaction finished, dilution with toluene was used in cooling, filtered, and with a large amount of toluene wash filter cakes, at last toluene was combined; Earlier mixed phase is used washing; Use dried over mgso then, pressure reducing and steaming toluene carries out recrystallization to the solid that obtains with ethanol again and gets white crystal and be accredited as compound 1a through infrared, nucleus magnetic hydrogen spectrum; The crystal that recrystallization is twice reaches 97.45 % through HPLC checking purity; Second step: compound 1a is dissolved in the ethanol of low-grade fever, adds the strong solution of 4 normal KOH, be saponified into the sylvite of compound 2a; Be reflected at carry out one hour under the low-grade fever condition after, steam ethanol, inwards adds zero(ppm) water then; With hydrochloric acid the pH value is transferred to 2, suction filtration, can obtain the white solid compound, be accredited as compound 2a, and product reaches 99 % through HPLC checking purity repeatedly after purifying and the washing through infrared, hydrogen spectrum with water washing, drying.
The compound method of described a kind of calcium ion selective sequestrant; Its described method for use the chemical purification method to thick product separate, the method for purification processes; This method purification elder generation dissolves with 15% potassium hydroxide solution; Hydrochloric acid soln with 0.33M makes it deposition again, washs with ultrapure water at last.
Description of drawings
Fig. 1 is the ir spectra of The compounds of this invention 1a;
Fig. 2 is The compounds of this invention 1a's
1The H-NMR spectrogram;
Fig. 3 is the ir spectra of The compounds of this invention 2a;
Fig. 4 is The compounds of this invention 2a's
1The H-NMR spectrogram.
Annotate: Fig. 1-Fig. 4 of the present invention is the analysis synoptic diagram of product state, figure Chinese words or the unintelligible understanding that does not influence technical scheme of the present invention of image.
Embodiment
The compound method of compound 1a comprises the steps:
1. compound 1a synthetic reactions step:
The first step: in the 500ml four-hole bottle, add the good 19.52g of weighing (80mmol) 1 behind the logical nitrogen, the second cyanogen of two (the 2-amido benzene oxygen) ethane of 2-, 3.344g (62.4mmol) anhydrous sodium iodide, 72ml (416mmol) diisopropylethylamine and 120ml.
Second step: slowly heat up, stir.Interior bath temperature rises to 55 ℃, dropwise at the uniform velocity adds methyl bromoacetate 38.4ml (416mmol).
The 3rd step: make after drip finishing to be full of the nitrogen rear enclosed in the system, be warming up in the system 80 ℃ of temperature once more after, refluxed 20 hours.
2. compound 1a synthetic post-processing step
The 4th step: after the end that refluxes, in four-hole bottle, add 140ml toluene, stirred 30 minutes, left standstill then 30 minutes.After leaving standstill end the upper strata stillness of night is poured in the beaker of a 500ml, in four-hole bottle, add the toluene of 50ml, stirred 30 minutes, left standstill then 30 minutes.
The 5th step: after putting end only the upper strata stillness of night is poured in original beaker, in four-hole bottle, add the toluene of 50ml again, stirred 30 minutes, left standstill then 30 minutes, repeat 2 times
The 6th step: after stirring end the solidliquid mixture in the four-hole bottle is carried out suction filtration, the filtrating behind the suction filtration is poured in original beaker.Filtrating in the beaker is divided into three parts, and every part of zero(ppm) water with 30ml washs in separating funnel five times, has used the zero(ppm) water of 450ml altogether.Filtrating after washing is put into the beaker of 500ml, in beaker, add the 40g anhydrous magnesium sulfate, stirred 30 minutes, suction filtration then, the filtrating that obtains behind the suction filtration is transferred in the pyriform bottle of 500ml.
3. compound 1a synthetic product separation step
The 7th step: revolve and steam second cyanogen and toluene fraction obtains brown solid.In the pyriform bottle, add the 35ml absolute ethyl alcohol, earlier bottle is put into water bath with thermostatic control, regulate outer bath temperature and rise to 78 ℃; Stir, become brown transparent liquid in the bottle, the normal temperature cooling is after 2 hours; Put into frozen water again and cool off, suction filtration after 3 hours, obtaining filter cake is little citrine body; With filter cake washing twice, use 20ml ethanol then at every turn, obtain white crystal at last.
The 8th step: the white crystal that will go up a step is put into a clean pyriform bottle, and inwards adds the absolute ethyl alcohol of 30ml, and bottle is put into water bath with thermostatic control; Regulate outer bath temperature and rise to 78 ℃, stir, become yellow transparent liquid in the bottle; The normal temperature cooling is after 2 hours; Put into frozen water again and cool off, suction filtration after 3 hours, obtaining filter cake is white crystal.Repeat 2 times, obtaining the 1a quality is 36.7g, and productive rate is 86%, and fusing point is 93-96 ℃.
IR(KBr)，R/cm
-1:υ(═C─H)?3004(m);?υ(C─H)?2955?(m)；υ（C=O）1744(s)；υ(C─N)?1259(s)?；υ(C─O─C)?1197(s)；δ(C─H)?1420(m)；δ(═C─H)?745(s)；?
1H?NMR(500MHz,CDCl
3),δ：3.55（s,12H）；4.15（s,8H）；4.27（s,4H）；6.84（m,4H）；7.26（m，4H）。
The compound method of compound 2a comprises the steps:
1. the reactions step of compound 2a:
The first step: claim to such an extent that the 1a36.7g solid product joins 250ml there-necked flask and 110ml absolute ethyl alcohol, slowly heat up that bath temperature is raised to 63 ℃ in treating, this moment, white solid all was dissolved in the ethanol, dropwise added the NaOH solution of 102ml 15%.
Second step: drip and stir under back and this temperature after 1 hour, the solution in the there-necked flask is transferred to carried out simple distillation in the single port flask, outer bath temperature is adjusted to 105 ℃, and residuum is a clear solution.
The 3rd step: the residuum in the single port flask is changed in the 500ml beaker, and with merging in the beaker behind the 30ml water washing flask, the pH value that record liquid in the beaker this moment is 12 again.Open magnetic agitation, drip the hydrochloric acid of 0.33mol/L while stirring with constant voltage, transparent liquid begins muddiness in the beaker when the pH value is 3.5-4; Gradually separate out white precipitate, when being titrated to the pH value and being 2 to 2.5, existing a large amount of solids are separated out; Stop to drip and stirring the 900ml hydrochloric acid soln of using up altogether.
The 4th step: the turbid solution in the beaker is poured into suction filtration in the B that installs filter paper.Filter cake and rotor are poured in the beaker that fills 250ml zero(ppm) water, stirred 15 minutes with glass stick, suction filtration is got filter cake and is dried under 26 ℃ of conditions with vacuum drying oven then.Weighing then obtains white powder 29.7g, and yield 90.4%, fusing point are 151 ℃-156 ℃, and purity can reach 93 % through the HPLC checking.
2. the purifying of compound 2a:
The 5th step: the 2a that takes by weighing 20.3g with electronic balance puts into the clean beaker of 100ml, and the potassium hydroxide solution 60ml (10.56gKOH, 60ml zero(ppm) water) of preparation 15% is for use.
The 6th step: the potassium hydroxide solution of dropping 15% in the beaker that 2a is housed, solid begins dissolving, after treating to dissolve basically, stops to drip, and has used the KOH solution of 50ml altogether, and the PH of the solution in the beaker that use PH test paper is surveyed is 13.Solution in the beaker with cloth formula funnel suction filtration, is poured into filtrating in the clean beaker of one 500ml, rinsed with the zero(ppm) water of 20ml again and wash filter flask, will rinse washing lotion at last and pour in the lump in the beaker, drip the hydrochloric acid of 0.33mol/L then while stirring to the beaker the inside.
The 7th step: when pH value is 4, begin to occur muddy,, stop dripping hydrochloric acid at this moment, used the hydrochloric acid of 540ml altogether, obtain white solid with cloth formula funnel suction filtration when pH has a large amount of white solids to separate out during for 2-2.5.The solid that obtains behind the suction filtration is put into the beaker of a 500ml, and inwards adds the zero(ppm) water of 250ml, stirs suction filtration behind the 15min with glass stick.
The 8th step: the white solid behind the suction filtration is put into the clean beaker of 100ml, in beaker, drip 15% potassium hydroxide solution, solid begins dissolving.Treat whole dissolvings, stop to drip, used the KOH solution of 47ml altogether; The PH of the solution in the beaker that use PH test paper is surveyed is 13; Solution in the beaker with cloth formula funnel suction filtration, is poured into filtrating in the clean beaker of one 500ml, rinsed with the zero(ppm) water of 20ml again and wash filter flask; To rinse washing lotion at last and pour in the lump in the beaker, drip the hydrochloric acid of 0.33mol/L then while stirring to the beaker the inside.When the pH value is 4, begin to occur muddy, when pH has a large amount of white solids to separate out during for 2-2.5, stop dripping hydrochloric acid this moment, used the hydrochloric acid of 480ml altogether, obtains white solid with cloth formula funnel suction filtration.
The 9th step: the solid that obtains behind the suction filtration is put into the beaker of a 500ml, and inwards adds the zero(ppm) water of 250ml, stirs suction filtration behind the 15min with glass stick.Repeat 2 times, last suction filtration obtains white solid, and dry back is a white powder, and quality is 19.1g, and yield 94%, fusing point are 150-155 ℃, and purity can reach 99 % through the HPLC checking.
IR(KBr),R/cm
-1:?υ(O─H)?3427(m)；υ(═C─H)?3160(m);?υ(C─H)?2953?(m)；υ(C=O)?1698(s)；υ(C─N)?1242(s)；υ(C─O─C)?1210(s)；δ(C─H)?1399(m)；δ(═C─H)?751(s)；
1H?NMR(500MHz,CDCl
3),δ：4.00(s,8H)；4.23（s,4H）；6.73（m,2H）；6.82(m,4H)；6.94(m,2H)。
Claims (2)
1. the compound method of a calcium ion selective sequestrant, promptly 2-two, be 2-amido benzene oxygen, ethane-N; N, N', is 1a at N'-tetraacethyl methyl esters; The methyl esters of BAPTA, compound method, it is characterized in that; This method comprises at first sloughs moisture wherein with liquid raw material methyl bromoacetate and diisopropylethylamine and second cyanogen drying, secondly the entire reaction device is removed moisture; Proportioning raw materials is 1, and 2-is two, be 2-amido benzene oxidative ethane, and the molar ratio of methyl bromoacetate and diisopropylethylamine is 1:5.2:5.2, and the reaction end system is a neutrality; Concrete steps are: the first step: the activated molecular sieve of solvent second cyanogen and raw material methyl bromoacetate and diisopropylethylamine soaked more than 24 hours, and molecular sieve was dried 4 hours with luxuriant good fortune stove down at 400 ℃ before use; Experimental installation is dry, feeds high pure nitrogen and removes its air and moisture; With 1,2-is two, be 2-amido benzene oxygen, and ethane and METHYL BROMOACETATE are that 1.5 equivalents, catalyzer anhydrous sodium iodide and diisopropylethylamine are mixed into 1.2 equivalents, and mixing is dissolved in them in the second cyanogen; Mixture reflux under protection of nitrogen gas stirs 20h; After reaction finished, dilution with toluene was used in cooling, filtered, and with a large amount of toluene wash filter cakes, at last toluene was combined; Earlier mixed phase is used washing; Use dried over mgso then, pressure reducing and steaming toluene carries out recrystallization to the solid that obtains with ethanol again and gets white crystal and be accredited as compound 1a through infrared, nucleus magnetic hydrogen spectrum; The crystal that recrystallization is twice reaches 97.45 % through HPLC checking purity; Second step: compound 1a is dissolved in the ethanol of low-grade fever, adds the strong solution of 4 normal KOH, be saponified into the sylvite of compound 2a; Be reflected at carry out one hour under the low-grade fever condition after, steam ethanol, inwards adds zero(ppm) water then; With hydrochloric acid the pH value is transferred to 2, suction filtration, can obtain the white solid compound, be accredited as compound 2a, and product reaches 99 % through HPLC checking purity repeatedly after purifying and the washing through infrared, hydrogen spectrum with water washing, drying.
2. the compound method of a kind of calcium ion selective sequestrant according to claim 1; It is characterized in that; Described method for use the chemical purification method to thick product separate, the method for purification processes; This method purification elder generation dissolves with 15% potassium hydroxide solution, and the hydrochloric acid soln with 0.33M makes it deposition again, washs with ultrapure water at last.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288664A (en) * | 2013-04-23 | 2013-09-11 | 合肥恒星药物研究所 | Novel BAPTA derivative, preparation method thereof and medicinal use thereof |
| CN105001180A (en) * | 2015-06-11 | 2015-10-28 | 陈嫣 | Novel calcium-ion selective chelating agent and preparation method and application thereof |
| CN112724030A (en) * | 2020-12-24 | 2021-04-30 | 福建福缘生物科技有限公司 | Kit for measuring calcium ions and use method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102030670A (en) * | 2010-11-29 | 2011-04-27 | 江苏万邦生化医药股份有限公司 | Method for synthesizing DP-b99 |
| CN102093885A (en) * | 2011-03-04 | 2011-06-15 | 西北大学 | Indole calcium ion fluorescent probes and preparation method and use thereof |
-
2012
- 2012-03-13 CN CN2012100650373A patent/CN102617376A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030670A (en) * | 2010-11-29 | 2011-04-27 | 江苏万邦生化医药股份有限公司 | Method for synthesizing DP-b99 |
| CN102093885A (en) * | 2011-03-04 | 2011-06-15 | 西北大学 | Indole calcium ion fluorescent probes and preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| ROGER Y. TSIEN: "New Calcium Indicators and Buffers with High Selectivity against Magnesium and Protons: Design, Synthesis, and Properties of Prototype Structures", 《BIOCHEMISTRY》, vol. 19, no. 11, 31 December 1980 (1980-12-31) * |
| 成昭等: "一种新型荧光素类Ca2+荧光探针的合成", 《化学试剂》, vol. 33, no. 12, 31 December 2011 (2011-12-31) * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288664A (en) * | 2013-04-23 | 2013-09-11 | 合肥恒星药物研究所 | Novel BAPTA derivative, preparation method thereof and medicinal use thereof |
| CN105001180A (en) * | 2015-06-11 | 2015-10-28 | 陈嫣 | Novel calcium-ion selective chelating agent and preparation method and application thereof |
| CN105001180B (en) * | 2015-06-11 | 2017-06-13 | 安徽恒星制药有限公司 | A kind of calcium ion selective chelating agent and its production and use |
| CN112724030A (en) * | 2020-12-24 | 2021-04-30 | 福建福缘生物科技有限公司 | Kit for measuring calcium ions and use method thereof |
| CN112724030B (en) * | 2020-12-24 | 2022-09-06 | 福建福缘生物科技有限公司 | Kit for measuring calcium ions and use method thereof |
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Application publication date: 20120801 |