CN113880858A - Clopidogrel hydrogen sulfate impurity A and preparation method thereof - Google Patents
Clopidogrel hydrogen sulfate impurity A and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a clopidogrel hydrogen sulfate impurity A and a preparation method thereof, wherein the structural formula of the impurity A is shown as
The method comprises the following steps: 1) reacting the condensate hydrochloride with paraformaldehyde and formic acid in a DCM solvent; the generated product clopidogrel reacts under the acidic condition to continuously form hydroxymethyl clopidogrel impurities; 2) after the reaction is finished, respectively washing with water, adjusting with a sodium bicarbonate solution, separating liquid and retaining an organic phase, and carrying out vacuum concentration, separation and purification to obtain an impurity Z1; 3) reacting the obtained impurity Z1 with Z1-SM1, HATU and triethylamine in a DMF solvent in the step 2), then adding water and EA for extraction, and carrying out rotary evaporation of an organic phase for separation and purification to obtain an impurity A. The clopidogrel bisulfate impurity A provided by the invention is a brand new compound, the structure confirmation and synthesis of the impurity solve the structure problem of the clopidogrel small polar region impurity, and sufficient theoretical support and quality standard establishment can be provided for the research of raw material medicine impurities and the raw material medicineThe material basis of the study.
Description
Technical Field
The invention relates to the technical field of impurities in medicinal chemistry and preparation, in particular to clopidogrel hydrogen sulfate impurity A and a preparation method thereof.
Background
Clopidogrel is a common anti-platelet aggregation drug, and can inhibit the combination of adenosine diphosphate and platelet receptors and inhibit platelet aggregation. Platelet aggregation is an important part of atherosclerosis, and inhibition of platelet aggregation is effective in preventing thrombosis. Therefore, clopidogrel has wide market prospect and attracts wide attention of the medical field.
Clopidogrel in the chinese pharmacopoeia reports three impurities, impurity i:
C15H15Cl2NO2S 344.26
(+) -2- [ S- (2-chlorophenyl) ] -2- (4, 5, 6, 7-tetrahydrothieno [3, 2-c ] pyridin-5-yl) acetate hydrochloride
Impurity II:
C16H17Cl2NO2S 358.28
(±)2- [ (2-chlorophenyl) ] -2- (4, 5, 6, 7-tetrahydrothieno [2, 3-c ] pyridin-6-yl) acetic acid methyl ester hydrochloride
Impurity III:
C16H18ClNO6S2 419.9
(-) -R-2- [ (2-chlorophenyl) ] -2- (4, 5, 6, 7-tetrahydrothieno [3, 2-c ] pyridin-5-yl) acetic acid methyl ester sulfate
Impurities contained in the medicine are main factors influencing the purity of the medicine, for example, if the medicine contains more than limited impurities, the physicochemical constant can be changed, the appearance character is changed, the stability and the curative effect of the medicine are influenced, even the health of a human body is influenced, the content of the medicine is inevitably low or the activity is reduced due to the increase of the impurities, and the toxic and side effects are obviously increased. Therefore, the impurity inspection of the medicine is a very important link for controlling the medicine purity and improving the medicine quality, simultaneously, the safety and the effectiveness of the medicine use are ensured, and a basis is provided for the quality assurance of the production and circulation processes and the assessment of enterprise management, so that the harm of the medicine impurities is determined in the production process, whether the impurities have toxicity is determined, and the method is an important process for medicine research and development.
The impurities of the medicine are important indexes reflecting the quality of the medicine, and the research also goes through the whole process of medicine research, development, production and sale. The research on impurities is carried out to clarify the structures of the impurities and the minimum quantity of toxic and side reactions, theoretical basis can be provided for setting limit for single impurities, and the research technology and the research method of the impurities in the medicine are continuously updated along with the continuous development of the technology of analytical instruments. In order to meet the technical requirements of the declaration of bulk drugs and improve the yield, the impurity research is indispensable.
In view of this, the present application is specifically made.
Disclosure of Invention
The invention aims to provide a novel clopidogrel bisulfate impurity A, and the discovery of the impurity is beneficial to controlling the content of clopidogrel bisulfate impurity compounds, so that the structural problem of the clopidogrel small-polarity region impurity is solved, and sufficient theoretical support and a material basis for research can be provided for the research of raw material medicine impurities and the establishment of quality standards of the raw material medicines.
The invention is realized by the following technical scheme:
an impurity A of clopidogrel hydrogen sulfate, the structural formula of the impurity A is
The 1HNMR (MeOD-d6) spectrum parameters of impurity A are: 2.32ppm (m, 3H) (s, 3H), 2.72-2.79ppm (m, 4H), 2.81-2.89ppm (m, 2H), 2.91-2.96 ppm (m, 2H), 3.45-3.60ppm (m, 2H), 3.69ppm (s, 3H), 4.59ppm (s, 2H), 4.80ppm (s, 1H), 5.12-5.18ppm (m, 2H), 6.59ppm (s, 1H), 6.67-6.68ppm (d, 1H), 6.83-6.85ppm (m, 1H), 7.10-7.12ppm (m, 1H), 7.21-7.28ppm (m, 2H), 7.30-7.39ppm (m, 3H), 7.43-7.47ppm (m, 2H), 7.62-7.64ppm (m, 1H).
A preparation method of clopidogrel hydrogen sulfate impurity A comprises the following steps: 1) reacting condensate hydrochloride (SM1) with paraformaldehyde and formic acid in a DCM solvent, and reacting the generated product clopidogrel under an acidic condition to continuously form hydroxymethyl clopidogrel impurities; 2) after the reaction is finished, respectively washing with water, adjusting with a sodium bicarbonate solution, separating the solution and retaining an organic phase, and carrying out vacuum concentration, separation and purification to obtain a hydroxymethyl clopidogrel impurity Z1; 3) reacting the hydroxymethyl clopidogrel impurity Z1 obtained in the step 2) with (S) -2- (2-chlorophenyl) -2- (methyl (2- (thiophene-2-yl) ethyl) amino) acetic acid (Z1-SM1), HATU and triethylamine in a DMF solvent, then adding water and EA for extraction, and carrying out separation and purification on a rotary evaporation organic phase to obtain an impurity A; the reaction route is as follows:
the DCM solvent is a dichloromethane solution which absorbs hydrogen chloride gas to be saturated.
The molar weight ratio of the condensate hydrochloride, the paraformaldehyde and the formic acid is 1: 1-10: 0.2 to 1.0, preferably 1: 6: 0.31.
the molar weight ratio of (S) -2- (2-chlorphenyl) -2- (methyl (2- (thiophene-2-yl) ethyl) amino) acetic acid (Z1-SM1), hydroxymethyl clopidogrel impurity, HATU and triethylamine is 1: 0.8-2.0: 1.1-3.0: 1.1 to 3.0, preferably 1: 1.2: 1.5: 1.5.
the reaction conditions of the step 1) are that liquid is added on a condenser pipe for sealing reaction, the external bath is set to be 40-45 ℃, the reflux temperature and the internal temperature are 35-40 ℃, and the reflux reaction is carried out for 48 hours.
The reaction condition of the step 3) is that the mixture is stirred for 20 hours at room temperature of 12 ℃.
The present application analyzes the generation mechanism of impurity a as follows: the clopidogrel preparation process comprises the steps of taking condensate hydrochloride SM1 and paraformaldehyde as raw materials, carrying out a ring closing reaction to obtain a ring closing product clopidogrel hydrochloride SM2, wherein in the process of the ring closing reaction, excessive formic acid exists, so that the clopidogrel hydrochloride SM2 reacts with paraformaldehyde under the acidic condition containing formic acid to generate hydroxymethyl clopidogrel impurity Z1, meanwhile, the system reacts under the acidic condition of polyformaldehyde and the acidic condition to generate (S) -2- (2-chlorphenyl) -2- (methyl (2- (thiophene-2-yl) ethyl) amino) acetic acid (Z1-SM1), and the newly generated impurities Z1 and Z1-SM1 are continuously dehydrated and condensed into ester under the acidic condition to obtain the target impurity A.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the clopidogrel bisulfate impurity A provided by the embodiment of the invention is a brand new compound, the structural confirmation and synthesis of the impurity solve the structural problem of the clopidogrel small polar region impurity, and can provide sufficient theoretical support and a material basis for research for the impurity research of raw material medicines and the establishment of quality standards of the raw material medicines.
Drawings
In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the drawings that are required to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and that for those skilled in the art, other related drawings can be obtained from these drawings without inventive effort.
FIG. 1 is an HPLC plot of the hydroxymethyl clopidogrel impurity Z1 provided by an embodiment of the present invention;
FIG. 2 is a LC-MS diagram of impurity A provided by an embodiment of the present invention;
FIG. 3 is a TLC chart of elution separation
FIG. 4 shows 1HNMR of impurity A provided by an embodiment of the present invention.
Fig. 5 is an enlarged view 1 of 1HNMR of impurity a provided in an embodiment of the present invention.
Fig. 6 is an enlarged view 2 of 1HNMR of impurity a provided in an embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples and accompanying drawings, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not meant to limit the present invention.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that: it is not necessary to employ these specific details to practice the present invention. In other instances, well-known structures, circuits, materials, or methods have not been described in detail so as not to obscure the present invention.
Throughout the specification, reference to "one embodiment," "an embodiment," "one example," or "an example" means: the particular features, structures, or characteristics described in connection with the embodiment or example are included in at least one embodiment of the invention. Thus, the appearances of the phrases "one embodiment," "an embodiment," "one example" or "an example" in various places throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features, structures, or characteristics may be combined in any suitable combination and/or sub-combination in one or more embodiments or examples. Further, those of ordinary skill in the art will appreciate that the illustrations provided herein are for illustrative purposes and are not necessarily drawn to scale. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the description of the present invention, the terms "front", "rear", "left", "right", "upper", "lower", "vertical", "horizontal", "upper", "lower", "inner", "outer", etc. indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience of description and simplicity of description, but do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed in a particular orientation, and be operated, and therefore, should not be construed as limiting the scope of the present invention.
Example 1
The preparation method of the clopidogrel bisulfate impurity A provided by the embodiment of the invention comprises the following steps:
1. preparation of hydroxymethyl clopidogrel impurity Z1:
1.1 taking a proper amount of hydrochloric acid and a 250ml three-neck flask, adding a proper amount of concentrated sulfuric acid into a constant pressure dropping funnel, slowly dropping into the hydrochloric acid, drying the generated hydrogen chloride gas by using a mixed solution of the concentrated sulfuric acid and urea, introducing into a three-neck flask filled with 520.01g of dichloromethane, absorbing until saturation, and sealing for later use;
1.2 taking another 500ml three-necked bottle, accurately weighing a condensate hydrochloride (38.72g, 1eq), paraformaldehyde (19.95g, 6.0eq), formic acid (1.61g, 0.31eq), configuring a thermometer, a magnetic stirring device and a reflux device, adding 1.1. absorbing hydrogen chloride gas to a saturated dichloromethane solution, sealing for reaction, refluxing at 40 ℃, refluxing at 37 ℃ for 48 hours, stopping the reaction, cooling to room temperature, washing with 80g of water for one time for liquid separation, retaining an organic phase, adjusting the pH of the organic phase to 7.5 by using an 8% sodium bicarbonate solution, retaining the organic phase in the liquid separation, concentrating under reduced pressure at 40 ℃ to obtain an impurity Z1 crude product, and detecting by HPLC, wherein the HPLC purity of the crude product is 49.12%;
1.3 preparing a sample solution reference standard solution, spotting, developing and inspecting on the same thin layer plate, wherein the position of a spot displayed in a sample chromatogram is consistent with that of a spot of a fluorescence response standard substance chromatogram, and determining that Rf of an impurity Z1 is approximately equal to 0.3; additionally, 40X 40cm thin layer chromatography was used, spotted in stripes using petroleum ether: developing with methyl acetate at a ratio of 2:1 as developing agent, irradiating with ultraviolet lamp, scraping silica gel plate with Rf about 0.3, dissolving with methyl acetate, magnetically stirring for 5min, vacuum filtering, and concentrating to obtain impurity Z1 sample 10.4mg, which is HPLC shown in FIG. 1 and has HPLC conditions shown in Table 1 (retention time 4.15min, purity 95%).
TABLE 1 HPLC conditions
2. Preparation of impurity A
Adding 50mg of N-methyl acid, 68.4mg of hydroxymethyl clopidogrel impurity Z1, 98.05mg of HATU, 24.45mg of triethylamine and 2.5ml of DMF into a 25ml single-mouth bottle, stirring at room temperature (12 ℃) for 20 hours to complete the reaction, adding 1.5ml of water into the system, extracting once by 3ml of EA, performing TLC to show that all water phases are HATU, performing rotary evaporation on an organic phase sample, preparing the organic phase sample by TLC, scraping a TLC plate with Rf being equal to 0.5, adding 5ml of EA, stirring at room temperature for 5 minutes, performing suction filtration, concentrating at room temperature (13 ℃) to obtain 14.7mg of sample, and monitoring by LC-MS (liquid chromatography-mass spectrometry), wherein the molecular weight of the target impurity A is shown in figure 2.
The 1HNMR of the impurity A is shown in figures 4-6, and the test results are as follows:
1HNMR(MeOD-d6)：2.32ppm(m，3H)(s，3H)，2.72-2.79ppm(m，4H)，2.81-2.89ppm(m，2H)，2.91-2.96pm(m，2H)，3.45-3.60ppm(m，2H)，3.69ppm(s，3H)，4.59ppm(s，2H)，4.80ppm(s，1H)，5.12-5.18ppm(m，2H)，6.59ppm(s，1H)，6.67-6.68ppm(d，1H)，6.83-6.85ppm(m，1H)，7.10-7.12ppm(m，1H)，7.21-7.28ppm(m，2H)，7.30-7.39ppm(m，3H)，7.43-7.47ppm(m，2H)，7.62-7.64ppm(m，1H)。
example 2
The preparation method of the clopidogrel bisulfate impurity A provided by the embodiment of the invention comprises the following steps:
1. preparation of hydroxymethyl clopidogrel impurity Z1:
1.1 taking a proper amount of hydrochloric acid and a 250ml three-neck flask, adding a proper amount of concentrated sulfuric acid into a constant pressure dropping funnel, slowly dropping into the hydrochloric acid, drying the generated hydrogen chloride gas by using a mixed solution of the concentrated sulfuric acid and urea, introducing into a three-neck flask filled with 520.01g of dichloromethane, absorbing until saturation, and sealing for later use;
1.2 taking another 500ml three-necked bottle, accurately weighing a condensate hydrochloride (38.72g, 1eq), paraformaldehyde (19.95g, 6.0eq), formic acid (1.61g, 0.31eq), configuring a thermometer, a magnetic stirring device and a reflux device, adding 1.1. absorbing hydrogen chloride gas to a saturated dichloromethane solution, sealing for reaction, refluxing at 40 ℃, refluxing at 37 ℃ for 48 hours, stopping the reaction, cooling to room temperature, washing with 80g of water for one time for liquid separation, retaining an organic phase, adjusting the pH of the organic phase to 7.5 by using an 8% sodium bicarbonate solution, retaining the organic phase in the liquid separation, concentrating under reduced pressure at 40 ℃ to obtain an impurity Z1 crude product, and detecting by HPLC, wherein the HPLC purity of the crude product is 49.12%;
1.3 weigh 200g of 200-mesh 300-mesh silica gel; loading into a chromatographic column with diameter of 4cm, vacuum-pumping, beating with rubber tube while packing, and washing with 500ml petroleum ether to make the column packed uniformly, with adsorbent height of about 20 cm. Weighing 5g of crude product in a single-mouth bottle, adding a proper amount of methyl acetate to dissolve the crude product, adding 5g of 100-mesh 200-mesh silica gel, vacuum concentrating at 40 ℃, spin-drying until no obvious solid particles exist, reserving a section of solvent on a packed column, slowly pouring the silica gel adsorbing the sample, adding some solvent, washing the silica gel adhered to the column wall, and adding a small amount of quartz sand particles in the upper layer. And (3) elution: the purity of the crude impurity only accounts for 47%, HPLC (high performance liquid chromatography) maps show that other impurities exist before and after the preparation of the impurity, according to the principle that the impurity is eluted firstly with large polarity, Rf & lt 0.3 & gt on TLC is collected and received as shown in figure 3, a single impurity point of a TLC picture is collected, vacuum reduced pressure concentration is carried out at 40 ℃, and an impurity Z1 sample 432.69mg is obtained, wherein the yield is 8.65%, and the purity is 90.01%.
2. Preparation of impurity A
50mg of (S) -2- (2-chlorophenyl) -2- (methyl (2- (thiophen-2-yl) ethyl) amino) acetic acid (Z1-SM1), 68.4mg of hydroxymethyl clopidogrel impurity Z1, 98.05mg of HATU, 24.45mg of triethylamine and 2.5ml of DMF were added to a 25ml single-neck flask, and the mixture was stirred at room temperature (12 ℃) for 20 hours to complete the reaction, 1.5ml of water was added to the system, 3ml of EA was extracted once, TLC showed that the aqueous phase was HATU all, the organic phase was evaporated, the sample of the organic phase was prepared by TLC, a TLC plate with Rf of 0.5 was scraped, 5ml of EA was added, and the mixture was stirred at room temperature for 5 minutes, filtered under suction, concentrated at room temperature (13 ℃) to obtain 14.7mg of a sample, which was monitored by LC-MS to show the molecular weight of the target impurity A.
Example 3
The preparation method of the clopidogrel bisulfate impurity A provided by the embodiment of the invention comprises the following steps:
1. preparation of hydroxymethyl clopidogrel impurity Z1:
1.1 taking a proper amount of hydrochloric acid and a 250ml three-neck flask, adding a proper amount of concentrated sulfuric acid into a constant pressure dropping funnel, slowly dropping into the hydrochloric acid, drying the generated hydrogen chloride gas by using a mixed solution of the concentrated sulfuric acid and urea, introducing into a three-neck flask filled with 520.01g of dichloromethane, absorbing until saturation, and sealing for later use;
1.2 taking another 500ml three-necked bottle, accurately weighing a condensate hydrochloride (38.72g, 1eq), paraformaldehyde (19.95g, 6.0eq), formic acid (1.61g, 0.31eq), configuring a thermometer, a magnetic stirring device and a reflux device, adding 1.1. absorbing hydrogen chloride gas to a saturated dichloromethane solution, sealing for reaction, refluxing at 40 ℃, refluxing at 37 ℃ for 48 hours, stopping the reaction, cooling to room temperature, washing with 80g of water for one time for liquid separation, retaining an organic phase, adjusting the pH of the organic phase to 7.5 by using an 8% sodium bicarbonate solution, retaining the organic phase in the liquid separation, concentrating under reduced pressure at 40 ℃ to obtain an impurity Z1 crude product, and detecting by HPLC, wherein the HPLC purity of the crude product is 49.12%;
1.3 weigh 200g of 200-mesh 300-mesh silica gel; loading into a chromatographic column with diameter of 4cm, vacuum-pumping, beating with rubber tube while packing, and washing with 500ml petroleum ether to make the column packed uniformly, with adsorbent height of about 20 cm. Weighing 5g of crude product in a single-mouth bottle, adding a proper amount of methyl acetate to dissolve the crude product, adding 5g of 100-mesh 200-mesh silica gel, vacuum concentrating at 40 ℃, spin-drying until no obvious solid particles exist, reserving a section of solvent on a packed column, slowly pouring the silica gel adsorbing the sample, adding some solvent, washing the silica gel adhered to the column wall, and adding a small amount of quartz sand particles in the upper layer. And (3) elution: the purity of the crude impurity only accounts for 47%, HPLC (high performance liquid chromatography) maps show that other impurities exist before and after the preparation of the impurity, according to the principle that the impurity is eluted firstly with large polarity, Rf & lt 0.3 & gt on TLC is collected and is connected with liquid as shown in figure 3, a single impurity point of a TLC diagram is collected, vacuum reduced pressure concentration is carried out at 40 ℃, and an impurity Z1 sample 538.31mg is obtained, wherein the yield is 10.77% and the purity is 96.21%.
2. Preparation of impurity A
50mg of (S) -2- (2-chlorophenyl) -2- (methyl (2- (thiophen-2-yl) ethyl) amino) acetic acid (Z1-SM1), 68.4mg of hydroxymethyl clopidogrel impurity Z1, 98.05mg of HATU, 24.45mg of triethylamine and 2.5ml of DMF were added to a 25ml single-neck flask, and the mixture was stirred at room temperature (12 ℃) for 20 hours to complete the reaction, 1.5ml of water was added to the system, 3ml of EA was extracted once, TLC showed that the aqueous phase was HATU all, the organic phase was evaporated, the sample of the organic phase was prepared by TLC, a TLC plate with Rf of 0.5 was scraped, 5ml of EA was added, and the mixture was stirred at room temperature for 5 minutes, filtered under suction, concentrated at room temperature (13 ℃) to obtain 14.7mg of a sample, which was monitored by LC-MS to show the molecular weight of the target impurity A.
Example 4
The preparation method of the clopidogrel bisulfate impurity A provided by the embodiment of the invention comprises the following steps:
1. preparation of hydroxymethyl clopidogrel impurity Z1:
1.1 taking a proper amount of hydrochloric acid and a 250ml three-neck flask, adding a proper amount of concentrated sulfuric acid into a constant pressure dropping funnel, slowly dropping into the hydrochloric acid, drying the generated hydrogen chloride gas by using a mixed solution of the concentrated sulfuric acid and urea, introducing into a three-neck flask filled with 520.01g of dichloromethane, absorbing until saturation, and sealing for later use;
1.2 taking another 500ml three-necked bottle, accurately weighing a condensate hydrochloride (38.72g, 1eq), paraformaldehyde (19.95g, 6.0eq), formic acid (1.61g, 0.31eq), configuring a thermometer, a magnetic stirring device and a reflux device, adding 1.1. absorbing hydrogen chloride gas to a saturated dichloromethane solution, sealing for reaction, refluxing at 40 ℃, refluxing at 37 ℃ for 48 hours, stopping the reaction, cooling to room temperature, washing with 80g of water for one time for liquid separation, retaining an organic phase, adjusting the pH of the organic phase to 7.5 by using an 8% sodium bicarbonate solution, retaining the organic phase in the liquid separation, concentrating under reduced pressure at 40 ℃ to obtain an impurity Z1 crude product, and detecting by HPLC, wherein the HPLC purity of the crude product is 49.12%;
1.3 weigh 200g of 200-mesh 300-mesh silica gel; loading into a chromatographic column with diameter of 4cm, vacuum-pumping, beating with rubber tube while packing, and washing with 500ml petroleum ether to make the column packed uniformly, with adsorbent height of about 20 cm. Weighing 5g of crude product in a single-mouth bottle, adding a proper amount of methyl acetate to dissolve the crude product, adding 5g of 100-mesh 200-mesh silica gel, vacuum concentrating at 40 ℃, spin-drying until no obvious solid particles exist, reserving a section of solvent on a packed column, slowly pouring the silica gel adsorbing the sample, adding some solvent, washing the silica gel adhered to the column wall, and adding a small amount of quartz sand particles in the upper layer. And (3) elution: the purity of the crude impurity only accounts for 47 percent, an HPLC (high performance liquid chromatography) map shows that other impurities exist before and after the preparation of the impurity, according to the principle that the impurity is eluted firstly with large polarity, Rf & lt 0.3 & gt on TLC is collected and received as shown in figure 3, a single impurity point of a TLC diagram is collected, and vacuum reduced pressure concentration is carried out at 40 ℃ to obtain 2.425g of an impurity Z1 sample, wherein the yield is 48.5 percent, and the purity is 98.18 percent.
2. Preparation of impurity A
Adding 0.396g of (S) -2- (2-chlorophenyl) -2- (methyl (2- (thiophene-2-yl) ethyl) amino) acetic acid (Z1-SM1), 0.54g of hydroxymethyl clopidogrel impurity Z1, 0.72g of HATU, 0.19g of triethylamine and 8.0ml of DMF into a 50ml single-neck bottle, stirring at room temperature (12 ℃) for 20 hours, finishing the reaction, adding 8.0ml of water into the system, extracting by 20ml of EA once, indicating that the water phase is HATU completely by TLC, evaporating the organic phase by rotary evaporation at 30 ℃ to obtain 0.829g of organic phase, purifying by column chromatography on the organic phase, adding 53.0g of 100-200 mesh silica gel by chromatography, adding 0.82g of sample into 1.6g of silica gel, concentrating to be dry, and eluting: PE and EA are 10:1 and 5:1 respectively, an eluent PE and EA is 5:1, the eluent PE and EA is 300ml, and the mixture is concentrated under reduced pressure at 20 ℃ to obtain 403.8mg of a target impurity A with HPLC purity of 90.1%.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. An impurity A of clopidogrel hydrogen sulfate is characterized in that the structural formula of the impurity A is shown in the specification
2. Clopidogrel bisulfate impurity a according to claim 1, characterized in that of impurity a1HNMR (MeOD-d6) map parameters were: 2.32ppm (m,3H)(s，3H)，2.72-2.79ppm(m，4H)，2.81-2.89ppm(m，2H)，2.91-2.96pm(m，2H)，3.45-3.60ppm(m，2H)，3.69ppm(s，3H)，4.59ppm(s，2H)，4.80ppm(s，1H)，5.12-5.18ppm(m，2H)，6.59ppm(s，1H)，6.67-6.68ppm(d，1H)，6.83-6.85ppm(m，1H)，7.10-7.12ppm(m，1H)，7.21-7.28ppm(m，2H)，7.30-7.39ppm(m，3H)，7.43-7.47ppm(m，2H)，7.62-7.64ppm(m，1H)。
3. a process for the preparation of clopidogrel bisulfate impurity a as set forth in claim 1 or 2, which comprises the steps of: 1) reacting condensate hydrochloride (SM1) with paraformaldehyde and formic acid in a DCM solvent, and reacting the generated product clopidogrel under an acidic condition to continuously form hydroxymethyl clopidogrel impurities; 2) after the reaction is finished, respectively washing with water, adjusting with a sodium bicarbonate solution, separating the solution and retaining an organic phase, and carrying out vacuum concentration, separation and purification to obtain a hydroxymethyl clopidogrel impurity Z1; 3) reacting hydroxymethyl clopidogrel impurity Z1 prepared in the step 2) with (S) -2- (2-chlorophenyl) -2- (methyl (2- (thiophene-2-yl) ethyl) amino) acetic acid (Z1-SM1), HATU and triethylamine in a DMF solvent, then adding water and EA for extraction, and carrying out separation and purification on a rotary evaporation organic phase to prepare impurity A; the reaction route is as follows:
4. the method of claim 3, wherein the DCM solvent is a dichloromethane solution that absorbs hydrogen chloride gas to saturation.
5. The method for preparing clopidogrel bisulfate impurity a according to claim 3, characterized in that the molar weight ratio of the condensate hydrochloride, paraformaldehyde and formic acid is 1: 1-10: 0.2 to 1.0.
6. The method for preparing clopidogrel bisulfate impurity a according to claim 5, characterized in that the molar weight ratio of the condensate hydrochloride, paraformaldehyde and formic acid is 1: 6: 0.31.
7. the method for preparing clopidogrel bisulfate impurity a according to claim 3, characterized in that the molar weight ratio of (S) -2- (2-chlorophenyl) -2- (methyl (2- (thiophen-2-yl) ethyl) amino) acetic acid (Z1-SM1), the hydroxymethylclopidogrel impurity, HATU, triethylamine is 1: 0.8-2.0: 1.1-3.0: 1.1 to 3.0.
8. The method for preparing clopidogrel bisulfate impurity a according to claim 7, characterized in that the molar weight ratio of (S) -2- (2-chlorophenyl) -2- (methyl (2- (thiophen-2-yl) ethyl) amino) acetic acid (Z1-SM1), the hydroxymethylclopidogrel impurity, HATU, triethylamine is 1: 1.2: 1.5: 1.5.
9. the preparation method of the clopidogrel bisulfate impurity A according to claim 3, wherein the reaction conditions in the step 1) are that a liquid seal is added on a condensation pipe, the reaction is sealed, an external bath is set at 40-45 ℃, the internal reflux temperature is 35-40 ℃, and the reflux reaction is carried out for 48 hours.
10. The method for preparing clopidogrel bisulfate impurity a according to claim 3, characterized in that the reaction condition of the step 3) is stirring at room temperature (12 ℃) for 20 hours.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101585842A (en) * | 2009-07-13 | 2009-11-25 | 北京赛科药业有限责任公司 | Research and control method of impurity B control method in clopidogrel |
| CN101766573A (en) * | 2010-02-05 | 2010-07-07 | 上海安必生制药技术有限公司 | Preparation process of clopidogrel bisulfate solid preparation |
| CN103435631A (en) * | 2013-08-29 | 2013-12-11 | 成都蓉药集团四川长威制药有限公司 | Preparation method of type I clopidogrel hydrogen sulfate |
| CN110590805A (en) * | 2019-09-11 | 2019-12-20 | 天方药业有限公司 | Preparation method of high-purity II crystal form clopidogrel hydrogen sulfate |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585842A (en) * | 2009-07-13 | 2009-11-25 | 北京赛科药业有限责任公司 | Research and control method of impurity B control method in clopidogrel |
| CN101766573A (en) * | 2010-02-05 | 2010-07-07 | 上海安必生制药技术有限公司 | Preparation process of clopidogrel bisulfate solid preparation |
| CN103435631A (en) * | 2013-08-29 | 2013-12-11 | 成都蓉药集团四川长威制药有限公司 | Preparation method of type I clopidogrel hydrogen sulfate |
| CN110590805A (en) * | 2019-09-11 | 2019-12-20 | 天方药业有限公司 | Preparation method of high-purity II crystal form clopidogrel hydrogen sulfate |
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