CN107573291A - A kind of preparation method and purposes of Gadoxetic acid disodium part impurity - Google Patents
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Abstract
The present invention relates to a kind of preparation method and purposes of Gadoxetic acid disodium part impurity, Gadoxetic acid disodium part impurity of the present invention is as shown in Equation 1, and its preparation method is as follows：
Description
Technical field
The invention belongs to technical field of medicine synthesis, in particular to a kind of Gadoxetic acid disodium part impurity for preparing
Method, and the application in terms of Gadoxetic acid disodium part (EOB-DTPA) quality control.
Background technology
Gadoxetic acid disodium (Gadoxetic aciddisodium, Gd-EOB-DTPA), it is the tool of German Schering Corp's exploitation
There is the gadolinium chelating agent magnetic resonance contrast agent of liver specificity, for the early diagnosis of hepatic disease, in July, 2008, U.S. FDA was criticized
It is mutatis mutandis in clinic.It is by paramagnetism gadolinium ion with it is lipophilic to ethoxy benzyl diethylenetriamine pentaacetic acid part (EOB-
DTPA) chelating forms, the absorption Gd-EOB-DTPA molecules of normal cell selectivity, hence it is evident that improve the T1 relaxation efficiency of tissue, have
Help the detection of liver lesion, the recall rate of small liver neoplasm can be especially improved, so as to contribute to the early stage of hepatic disease to examine
Disconnected and treatment.
Part EOB-DTPA in Gadoxetic acid disodium molecular structure, chemical name (4S) -4- (4- ethoxyphenyls) -3,6,9-
Three (carboxymethyl) -3,6,9- tri- azepine heneicosanedioic acids, it is Gadoxetic acid disodium part, can be complexed to obtain gadolinium plug with gadolinium oxide
Acid disodium, its structural formula are as follows：
In the prior art, Gadoxetic acid disodium part EOB-DTPA preparation, using S-1- (4- ethoxy benzyls) -3- azepines
Pentane -1,5- diamines tri hydrochloride (compound of formula 2) obtains connecing five second on nitrogen with chloroacetic acid tert-butyl ester (compound of formula 3) reaction
The compound of tert-butyl acrylate, EOB-DTPA is then obtained by hydrolysis.Need to connect 5 tertiary fourths of acetic acid on nitrogen in its synthetic route
Ester, and chloroacetic acid tert-butyl ester steric hindrance is larger, there is steric hindrance, therefore easily reaction does not obtain intermediate impurities formula 4 and formula thoroughly
5。
The synthesis to Gadoxetic acid disodium part impurity and pharmacological activity are not reported in the prior art.Present invention hair
Existing, formula 4 and 5, which further hydrolyzes, can obtain the compound of formula 1, and the compound constitutes the impurity of Gadoxetic acid disodium part.
The present invention is studied the impurity, using its feature, in Gadoxetic acid disodium part and finished product this is miscellaneous
Matter is controlled, and can effectively solve the purity problem of Gadoxetic acid disodium part and finished product.The invention reside in prepare high-purity
The part impurity as reference substance, for controlling the drug quality of Gadoxetic acid disodium.
The content of the invention
The present invention provides a kind of Gadoxetic acid disodium part impurity and preparation method thereof, and its answering in medicine detection
With.
Gadoxetic acid disodium part Impurity Impurity of the present invention is the necessity of Gadoxetic acid disodium part quality control, can be effective
Caused part impurity in the synthesis of Gadoxetic acid disodium part is identified, so as to the drug quality of strict control Gadoxetic acid disodium.
Inventor has found there is a unknown impuritie, conventional purification process in end-product when synthesizing Gadoxetic acid disodium part
Such as recrystallization, column chromatography can not be such that it is removed completely in finished product, it is therefore desirable to customize synthetic route and the centre of the impurity
Body control program.The presence of the impurity is larger to Gadoxetic acid disodium medicine quality and safety effects.Effectively this can be controlled to match somebody with somebody
Body impurity content is the key of Gadoxetic acid disodium quality control.
The present invention successfully solves above-mentioned technical problem eventually through following technical scheme.
Present invention aims at a kind of Gadoxetic acid disodium part impurity as shown in Equation 1 is provided, its structure is as follows,
It is another object of the present invention to provide the preparation method of the Gadoxetic acid disodium part impurity shown in formula 1, its is anti-
Answer process as follows：
Specifically, the preparation method of the shown Gadoxetic acid disodium part impurity shown in formula 1, including following step
Suddenly：
(a) by the compound of formula 2 with it is water-soluble it is clear after, be added to the compound of formula 3 in solvent, and add alkali, under heating condition
Reaction, obtains formula 4 and the compound of formula 5, wherein, the compound of formula 2 is according to document Inorg.Chem.1999,38,1134-1144 reports
The method in road is prepared；
Wherein, solvent is selected from：95% ethanol, absolute ethyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran, 2- methyl tetrahydrochysene furans
Mutter, the one or more in methyl tertiary butyl ether(MTBE)；Alkali is triethylamine, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, hydrogen-oxygen
Change the one or more in sodium, potassium hydroxide；Reaction temperature is 50 DEG C-backflow；
(b) formula 4 and the compound of formula 5 are dissolved in solvent, and add catalyst, the compound of formula 1 is obtained under heating condition, i.e.,
Gadoxetic acid disodium part impurity；
Wherein, solvent is selected from：Methanol, ethanol, isopropanol, the tert-butyl alcohol, ether, N,N-dimethylformamide, N, N- diformazans
One or more in yl acetamide, dimethyl sulfoxide；Catalyst be selected from sulfuric acid, hydrochloric acid, sodium hydroxide, sodium acid carbonate, sodium methoxide,
One or more in potassium hydroxide；
Reaction temperature is 40 DEG C-backflow.
In the preparation method of the present invention,
Preferably, in step a, the one kind of solvent in tetrahydrofuran, the tert-butyl alcohol, 2- methyltetrahydrofurans；Alkali is selected from
One kind in triethylamine, sodium acid carbonate, potassium carbonate；Reaction temperature is 50-60 DEG C；
Preferably, in step b, solvent is one kind in methanol, absolute ethyl alcohol, isopropanol, the tert-butyl alcohol；Catalyst selects
One kind from potassium hydroxide, sodium methoxide, sodium hydroxide；Temperature is 50-60 DEG C；
It is further preferred that the preparation method of the present invention, comprises the following steps：
(a) preparation of the compound of formula 4 and 5
The compound of 50-200g formulas 2 is added in 200-800g tetrahydrofuran, sequentially adds the compound 35- of formula 3
150g and acid binding agent potassium carbonate 30-100g, 50~60 DEG C are heated to, after reacting 24-120h, HPLC monitoring reaction process,
After completion of the reaction, 25-35 DEG C is cooled to, is filtered, 15% saline solution is added and stirs, extract, take upper organic phase, add nothing
Water magnesium sulfate, filtered after stirring 20min, 50 DEG C of filtrate, which is concentrated under reduced pressure into, dry obtains formula 4 and the crude compound of formula 5, crude product second
After acetoacetic ester dissolved clarification, silica gel mixed sample is added, silica gel dress post, eluant, eluent is ethyl acetate and n-hexane, through silica gel column chromatography gradient
Formula 4 and the compound of formula 5 are obtained after elution.
(b) preparation of the compound of formula 1
5-10g formulas 4 and the compound of formula 5 are dissolved in 50-100ml methanol, stirs to solution and clarifies, adds sodium hydroxide,
Be placed in oil bath pan and heat, 50-60 DEG C of temperature control reacts 24-48h, 50 DEG C be concentrated under reduced pressure into it is dry, with it is water-soluble it is clear after adjust pH to 2-3
Through macroporous absorbent resin (model：XAD-1600) purify, freeze, obtain off-white powder, the as compound of formula 1.
Still more preferably, preparation method of the invention, comprises the following steps：
(a) preparation of the compound of formula 4 and 5
By the compound of 100.0g formulas 2 250g drinking water dissolved clarifications, 800g tetrahydrofurans, the compound of 435g formulas 3 are sequentially added
With 320g potassium carbonate, 50~55 DEG C are heated to, after keeping thermotonus 24h, filters, adds the saline solutions of 260g 15%, stand
Liquid separation, upper organic phase is taken, add anhydrous magnesium sulfate and dry, 50 DEG C of crude compounds of formula 4 and 5 that are concentrated under reduced pressure to obtain, with 1.5W silicon
Glue mixes sample, silica gel upper prop, ethyl acetate and n-hexane system gradient elution, obtains the compound of formula 4 and the compound of formula 5.
(b) preparation of the compound of formula 1
5g formulas 4 and the compound of formula 5 are dissolved in 50mL methanol, lower dissolved clarification is stirred, adds 1.6g sodium hydroxides, be placed in oil bath
Heated in pot, after 50-55 DEG C of temperature control reaction 24h, 50 DEG C be concentrated under reduced pressure into it is dry, it is water-soluble clear with 30ml, add 25% sulfuric acid and adjust pH
To 2-3, through macroporous absorbent resin (model：XAD-1600) purify, freeze, obtain off-white powder, the as compound of formula 1.
According to one of embodiment, preparation method of the invention, comprise the following steps：
(a) preparation of formula 4 and the compound of formula 5
By the compound of formula 2 (100.0g, 0.29mol) drinking water (250g) dissolved clarification, tetrahydrofuran (800g) is sequentially added,
The compound of formula 3 (435g, 2.89mol) and potassium carbonate (320g, 2.31mol), are heated to 50~55 DEG C, keep the thermotonus
After 24h, room temperature is cooled to, is filtered, adds 15% saline solution (260g), liquid separation is stood, takes upper organic phase, anhydrous magnesium sulfate is done
It is dry, 50 DEG C of crude compounds of formula 4 and 5 that are concentrated under reduced pressure to obtain, sample is mixed with silica gel (200-300 mesh, 350g), silica gel (200-300 mesh,
1050g) fill post, ethyl acetate and n-hexane system gradient elution (20:1~1：1), obtain the compound of formula 4 about 25g and formula 5 is changed
Compound 8g.
(b) preparation of the compound of formula 1
Formula 4 (5g, 7mmol) and the compound of formula 5 (5g, 8mmol) are dissolved in methanol (50ml) respectively, stir lower dissolved clarification,
Sodium hydroxide (1.6g, 0.04mol) is added, is placed in oil bath pan and heats, after 50-55 DEG C of reaction 24h of temperature control, 50 DEG C are concentrated under reduced pressure
To doing, with water (30ml) dissolved clarification, add 25% sulfuric acid and adjust pH to 2-3, through macroporous absorbent resin (model：XAD-1600) purify,
It is lyophilized, obtain off-white powder 1.8g, the as compound of formula 1.
The present invention still further comprises following formula 4 or the compound of formula 5, and formula 4 and the compound of formula 5 in the chemical combination of formula 1
Application in thing as intermediate.
It is another object of the present invention to provide the impurity shown in formula 1 in detection Gadoxetic acid disodium and its with weight
Application.
The purposes of above-mentioned impurity is for relevant material reference substance, Huo Zheyong in Gadoxetic acid disodium and its part quality control
Identified in the impurity of Gadoxetic acid disodium and its part.
The present invention in terms of existing technologies, obtains the effect of highly significant, is mainly manifested in the following aspects：
(1) present invention successfully prepares Gadoxetic acid disodium part impurity as obtained by synthesis.The synthetic route step is short, behaviour
Make simply, reagent is easy to get, and Gadoxetic acid disodium part impurity HPLC purity prepared by the present invention is more than 96%, can be used as reference substance
Use.
(2) preparation technology of the invention is simple, and the used time is short, substantially reduces cost.
Embodiment
Embodiment is only that the present invention is further explained and described, and is not necessarily to be construed as any limit to the present invention
System, is described in further detail with reference to embodiment to the present invention.
Agents useful for same and material of the present invention are commercially available.
The preparation of embodiment 1, formula 4 and the compound of formula 5
By the compound of formula 2 (100.0g, 0.29mol) drinking water (250g) dissolved clarification, tetrahydrofuran (800g) is sequentially added,
The compound of formula 3 (435g, 2.89mol) and potassium carbonate (320g, 2.31mol), are heated to 50~55 DEG C, keep the thermotonus
After 24h, room temperature is cooled to, is filtered, adds 15% saline solution (260g), liquid separation is stood, takes upper organic phase, anhydrous magnesium sulfate is done
It is dry, 50 DEG C of crude compounds of formula 4 and 5 that are concentrated under reduced pressure to obtain, sample is mixed with silica gel (200-300 mesh, 350g), silica gel (200-300 mesh,
1050g) fill post, ethyl acetate and n-hexane system gradient elution (10:1~1:1) compound of formula 4 about 25g, is obtained, it is faint yellow
Glutinous material, HPLC 96.4% and the compound 8g of formula 5, faint yellow glutinous material, HPLC 92.0%.
The structural identification of the compound of formula 4
Mass spectrum：ESI-MS(m/z)：620.39[M+H]+
Hydrogen nuclear magnetic resonance spectrogram：1HNMR (400MHz, DMSO-d6) δ 7.05-7.03 (d, J=8.4Hz, 2H), 6.82-
6.80 (d, J=8.4Hz, 2H), 4.01-3.96 (m, 3H), 3.56-3.47 (m, 7H), 2.96-2.84 (m, 5H), 2.60-2.58
(m, 1H), 2.57-2.43 (m, 3H), 1.49-1.34 (m, 30H)
Carbon-13 nmr spectra figure：13CNMR(100MHz,DMSO-d6)δ170.58,168.13,167.90,157.85,
130.26,130.11,129.80,115.11,114.83,82.04,81.19,63.48,59.33,57.36,56.22,52.67,
50.97,47.68,37.45,28.24,28.14,28.10,27.92,14.92。
The structural identification of the compound of formula 5
Mass spectrum：ESI-MS(m/z)：694.46[M+H]+
Hydrogen nuclear magnetic resonance spectrogram：1HNMR (400MHz, DMSO-d6) δ 7.05-7.03 (d, J=8.4Hz, 2H), 6.89-
6.88 (d, J=8.4Hz, 2H), 4.00-3.99 (q, 2H), 3.95 (s, 4H), 3.41-3.24 (m, 4H), 2.80-2.65 (m,
7H),2.64-2.32(m,4H),1.43-1.36(m,39H).
Carbon-13 nmr spectra figure：13CNMR(100MHz,DMSO-d6)δ171.62,171.05,170.81,157.44,
131.18,130.23,114.53,80.91,80.80,63.47,58.91,56.98,56.25,56.21,52.91,52.84,
49.83,38.65,29.79,28.29,14.99。
The preparation of embodiment 2, the compound of formula 1
Formula 4 (5g, 7mmol) and the compound of formula 5 (5g, 8mmol) are dissolved in methanol (50ml), lower dissolved clarification is stirred, adds
Sodium hydroxide (1.6g, 0.04mol), it is placed in oil bath pan and heats, after 50-55 DEG C of reaction 24h of temperature control, 50 DEG C is concentrated under reduced pressure into
It is dry, with water (30ml) dissolved clarification, add 25% sulfuric acid and adjust pH to 2-3, through macroporous absorbent resin (model：XAD-1600) purify, freeze
It is dry, obtain off-white powder 1.8g, the as compound of formula 1, HPLC purity 96.7%.
The structural identification of the compound of formula 1
Mass spectrum：ESI-MS(m/z)：452.1[M+H]+
Hydrogen nuclear magnetic resonance spectrogram：1HNMR (400MHz, DMSO-d6) δ 7.22-7.20 (d, J=7.6Hz, 2H), 6.89-
6.88 (d, J=7.6Hz, 2H), 4.26-3.86 (m, 4H), 3.53-3.46 (m, 6H), 2.98-2.33 (m, 8H), 3.62 (m,
3H).
Carbon-13 nmr spectra figure：13CNMR(100MHz,DMSO-d6)δ172.50,170.45,166.70,157.13,
130.39,130.01,114.34,62.89,58.70,56.74,55.11,54.97,51.64,50.62,46.66,36.64,
14.73.
The application of embodiment 3, the compound of formula 1 in Gadoxetic acid disodium part is detected：
Chromatographic condition is as follows：
With octadecylsilane base bonded silica gel；Using 0.1%HClO4 as mobile phase A；Using acetonitrile as Mobile phase B, according to the form below
1 carries out gradient elution；Detection wavelength is 225nm；Column temperature is 30 DEG C, flow velocity 1.0ml/min.
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 5 | 80 | 20 |
| 30 | 70 | 30 |
Detection method is as follows：
The preparation of reference substance solution：
The compound control product of modus ponens 1 and Gadoxetic acid disodium part reference substance are appropriate, put in same measuring bottle, add acetonitrile-water (1:
1) dissolve and quantify dilution and the solution containing 0.01mg in every 1ml is made.
The preparation of need testing solution：
Take Gadoxetic acid disodium part appropriate, add acetonitrile-water (1:1) dissolve and dilute and be made in every 1ml containing the molten of 1.0mg
Liquid.
Detection method：
Need testing solution and each 10ul of reference substance solution are taken, injects liquid chromatograph, records chromatogram.By external standard method with peak
Areal calculation.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not limited to the substantial technological content of the present invention,
The substantial technological content of the present invention is that the right for being broadly defined in application collects, and any technology that other people complete is real
Body or method, or with the right of application defined in it is identical, also or a kind of equivalent change, will be by
It is considered as and is covered by among present claims scope.
Claims (10)
- A kind of 1. Gadoxetic acid disodium part impurity as shown in Equation 1：
- 2. the preparation method of impurity described in claim 1, its course of reaction is as follows：
- 3. the preparation method described in claim 2, comprises the following steps：(a) by the compound of formula 2 with it is water-soluble it is clear after, be added in solvent with the compound of formula 3, and add alkali, reacted under heating condition, Obtain formula 4 and the compound of formula 5；Wherein, solvent is selected from：95% ethanol, absolute ethyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran, 2- methyltetrahydrofurans, first One or more in base tertbutyl ether；Alkali be triethylamine, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, sodium hydroxide, One or more in potassium hydroxide；Reaction temperature is 50 DEG C-backflow；(b) formula 4 and the compound of formula 5 are dissolved in solvent, and add catalyst, the compound of formula 1 is obtained under heating condition；Wherein, solvent is selected from：Methanol, ethanol, isopropanol, the tert-butyl alcohol, ether, N,N-dimethylformamide, N, N- dimethyl second One or more in acid amides, dimethyl sulfoxide；Catalyst is selected from sulfuric acid, hydrochloric acid, sodium hydroxide, sodium acid carbonate, sodium methoxide, hydrogen-oxygen Change the one or more in potassium；Reaction temperature is 40 DEG C-backflow.
- 4. the preparation method described in claim 3, it is characterised in thatIn step a, the one kind of solvent in tetrahydrofuran, the tert-butyl alcohol, 2- methyltetrahydrofurans；Alkali is selected from triethylamine, carbonic acid One kind in hydrogen sodium, potassium carbonate；Reaction temperature is 50-60 DEG C；In step b, solvent is one kind in methanol, absolute ethyl alcohol, isopropanol, the tert-butyl alcohol；Catalyst be selected from potassium hydroxide, One kind in sodium methoxide, sodium hydroxide；Temperature is 50-60 DEG C.
- 5. the preparation method described in claim 3, it is characterised in that comprise the following steps：(a) preparation of the compound of formula 4 and 5The compound of 50-200g formulas 2 is added in 200-800g tetrahydrofuran, sequentially add the compound 35-150g of formula 3 and Acid binding agent potassium carbonate 30-100g, 50~60 DEG C are heated to, after reacting 24-120h, HPLC monitoring reaction process, reacted Bi Hou, 25-35 DEG C is cooled to, filtered, added 15% saline solution and stir, extract, take upper organic phase, add anhydrous slufuric acid Magnesium, filtered after stirring 20min, 50 DEG C of filtrate, which is concentrated under reduced pressure into, dry obtains formula 4 and the crude compound of formula 5, crude product ethyl acetate After dissolved clarification, silica gel mixed sample is added, silica gel dress post, eluant, eluent is ethyl acetate and n-hexane, after silica gel column chromatography gradient elution Obtain formula 4 and the compound of formula 5；(b) preparation of the compound of formula 15-10g formulas 4 and the compound of formula 5 are dissolved in 50-100ml methanol, stirs to solution and clarifies, sodium hydroxide is added, is placed in Heat in oil bath pan, 50-60 DEG C of temperature control, react 24-48h, 50 DEG C be concentrated under reduced pressure into it is dry, with it is water-soluble it is clear after adjust pH to 2-3 through big Macroporous adsorbent resin purifies, and freezes, obtains off-white powder, the as compound of formula 1.
- 6. the impurity described in claim 1 is in detection Gadoxetic acid disodium and its with the application in weight.
- 7. compound shown in formula 4,
- 8. compound shown in formula 5,
- 9. application of the compound of formula 4 in the compound of formula 1 as intermediate.
- 10. application of the compound of formula 5 in the compound of formula 1 as intermediate.
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| CN109030668A (en) * | 2018-10-24 | 2018-12-18 | 上海司太立制药有限公司 | The high efficient liquid phase analysis method of Primovist intermediate |
| CN109232279A (en) * | 2018-10-24 | 2019-01-18 | 上海司太立制药有限公司 | A kind of purification process of Primovist intermediate |
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| CN109030668A (en) * | 2018-10-24 | 2018-12-18 | 上海司太立制药有限公司 | The high efficient liquid phase analysis method of Primovist intermediate |
| CN109232279A (en) * | 2018-10-24 | 2019-01-18 | 上海司太立制药有限公司 | A kind of purification process of Primovist intermediate |
| CN109030668B (en) * | 2018-10-24 | 2021-03-09 | 上海司太立制药有限公司 | High performance liquid phase analysis method of gadoxetic acid disodium intermediate |
| CN109232279B (en) * | 2018-10-24 | 2021-03-30 | 上海司太立制药有限公司 | Purification method of gadoxetic acid disodium intermediate |
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Application publication date: 20180112 |