CN116178252A - Raw material impurity of dabigatran etexilate mesylate, and preparation method and application thereof - Google Patents

Raw material impurity of dabigatran etexilate mesylate, and preparation method and application thereof Download PDF

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CN116178252A
CN116178252A CN202210887192.7A CN202210887192A CN116178252A CN 116178252 A CN116178252 A CN 116178252A CN 202210887192 A CN202210887192 A CN 202210887192A CN 116178252 A CN116178252 A CN 116178252A
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raw material
reaction
dabigatran etexilate
etexilate mesylate
impurity
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何敏焕
石岳崚
黄光东
董玉龙
徐定洪
陶敏杰
赵富录
孙杨
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Shanghai Hisoar Pharmaceutical Technology & Development Co ltd
Zhejiang Hisoar Pharmaceutical Co Ltd
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Zhejiang Hisoar Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract

The invention provides a raw material impurity of dabigatran etexilate mesylate, which has a structure shown in a formula (1), and a preparation method and application of the raw material impurity of dabigatran etexilate mesylate. The invention provides the detailed information and the preparation method of the raw material impurity of the dabigatran etexilate mesylate, the technical process is simple, the prepared high-purity product which can be used as an impurity reference substance can be further used for establishing methods of qualitative and quantitative analysis, detection, purification and the like of the impurity, has very important significance in the aspects of quality control, production process optimization, safety research and the like of the dabigatran etexilate mesylate and the raw material thereof,

Description

Raw material impurity of dabigatran etexilate mesylate, and preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a raw material impurity of dabigatran etexilate mesylate, a preparation method and application thereof.
Background
Dabigatran etexilate mesylate (CAS number: 872728-81-9) has the following structural formula:
Figure BDA0003766155550000011
dabigatran etexilate mesylate is an anticoagulant drug developed by the company bologna, germany, and is marketed in germany and uk first in 4 months of 2008 under the trade name Pradaxa, and is a brand new oral direct anticoagulant drug marketed for 50 years after warfarin, for preventing deep venous thrombosis and pulmonary arterial embolism after artificial joint replacement. Dabigatran etexilate mesylate not only has effective, predictable and consistent anticoagulation and good stroke prevention effects, but also has the advantages of low bleeding risk, no need of conventional detection and the like, and is therefore considered as a milestone progress in the field of global anticoagulants.
The chemical name of the starting material DA of dabigatran etexilate mesylate is N- [ 3-amino-4- (methylamino) benzoyl ] -N-2-pyridine-beta-alanine ethyl ester, the CAS number is 212322-56-0, and the structural formula is as follows:
Figure BDA0003766155550000012
DA is a key raw material for synthesizing dabigatran etexilate mesylate, related impurities can be generated in the synthesis process of DA, and some impurities remained in DA can participate in the synthesis process of dabigatran etexilate mesylate in the later period to form new impurities, so that the quality of dabigatran etexilate mesylate is finally influenced, and therefore, the research and control of the impurities in the initial raw material DA is also an important ring for improving the quality of dabigatran etexilate mesylate products.
Disclosure of Invention
In order to further study the product quality and safety of dabigatran etexilate mesylate and raw materials thereof, an object of the invention is to provide raw material impurities of dabigatran etexilate mesylate.
Another object of the present invention is to provide a process for the preparation of the starting impurities of dabigatran etexilate mesylate.
It is a further object of the present invention to provide the use of the starting impurities of dabigatran etexilate mesylate.
The raw material impurity of dabigatran etexilate mesylate (hereinafter referred to as impurity R) provided by the invention has a structure shown in a formula (1),
Figure BDA0003766155550000021
synthetic routes to the starting material DA for dabigatran etexilate mesylate have been disclosed in the prior art (e.g. document J. Med. Chem.2002,45,1757-1766, which is incorporated herein by reference), specifically as follows:
Figure BDA0003766155550000022
the present inventors have studied the above synthetic route and have found that the synthesized DA contains a new impurity, namely, impurity R having the structure represented by formula (1). The mechanism analysis was performed in combination with the synthetic route of DA, and the possible mechanism of impurity R generation was as follows:
1) N-2-pyridyl-alanine ethyl ester as a main product may be produced as a by-product during the preparation;
Figure BDA0003766155550000031
2) The by-product can also participate in the derivatization reaction in the subsequent DA preparation process, and finally the impurity R is formed.
Figure BDA0003766155550000032
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The inventors have also found that if the content of impurity R is not controlled, this impurity would participate in the overall synthesis of dabigatran etexilate mesylate with the raw material DA (e.g., the crude drug synthesis disclosed in chinese patent CN 1972919a, pages 8/15 of the specification, which is incorporated herein by reference), the reaction proceeds as follows:
Figure BDA0003766155550000041
as can be seen, impurity R reacts with the corresponding reaction mass under the process conditions for the preparation of dabigatran etexilate, eventually forming aminopyridine impurity V (CAS number 1637238-96-0), which has been reported in the prior art (e.g., WO 2014178017A 1).
More complex, the aminopyridine impurity V is difficult to remove in the refining process of dabigatran etexilate, when the content of the impurity R in DA is high, the ratio of the aminopyridine impurity V in the dabigatran etexilate mesylate product is obviously increased, and then the impurity quality control threshold value is possibly exceeded, the quality of medicines is influenced and the medicine effect is reduced, so that the content of the impurity R needs to be strictly controlled. It can be seen from this that the study of impurity R is of great importance for improving the quality of dabigatran etexilate mesylate.
The invention also provides a preparation method of the raw material impurity of dabigatran etexilate mesylate, which comprises the following steps:
Figure BDA0003766155550000051
s1: taking a nitro compound with a structure shown in a formula (2) as a starting material, and obtaining a compound A through hydrolysis reaction;
s2: the compound A and 2-aminopyridine undergo a condensation reaction to obtain a compound B; and
s3: and (3) carrying out reduction reaction on the compound B to obtain the raw material impurity.
In some preferred embodiments of the preparation method according to the present invention, in the step S1, the hydrolysis reaction is performed in the presence of a base, wherein the base used may be a common kind for hydrolysis reactions. In some more preferred embodiments, the base may be selected from sodium hydroxide and/or potassium hydroxide, either in solid form or in solution form. In still more preferred embodiments, the molar ratio of the amount of base to the amount of nitro compound may be in the range of 1.1 to 1.5:1, including but not limited to a molar ratio of 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, or any combination of molar ratio intervals.
In some preferred embodiments of the preparation method according to the present invention, the reaction temperature of the hydrolysis reaction in the step S1 may be 25 to 60 ℃, including, but not limited to, a temperature value of 25 ℃, 30 ℃, 35 ℃, 40 ℃,45 ℃, 50 ℃, 55 ℃, 60 ℃, or a temperature value interval of any combination. In some more preferred embodiments, the reaction temperature of the hydrolysis reaction may be 25 to 35 ℃.
In some preferred embodiments of the preparation method according to the present invention, the reaction time of the hydrolysis reaction in the step S1 may be 2 to 4 hours.
In some preferred embodiments of the preparation method according to the present invention, in the step S1, the hydrolysis reaction uses an aqueous solution of methanol or ethanol as a reaction medium, wherein the volume ratio of the methanol or ethanol to water may be 1-5:1, including but not limited to volume ratio ranges of 1:1, 2:1, 3:1, 4:1, 5:1, or any combination thereof. In some more preferred embodiments, the volume ratio of methanol or ethanol to water may be 2:1.
In some preferred embodiments of the preparation method according to the present invention, in the step S2, the condensation reaction is performed in the presence of a condensing agent. In some more preferred embodiments, the condensing agent may be selected from N, N' -Carbonyldiimidazole (CDI), or may be selected from a mixture of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole. In still more preferred embodiments, the molar ratio of the amount of condensing agent to the amount of compound a may be in the range of 1.2 to 3:1, including but not limited to a molar ratio of 1.2:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 3:1, or any combination of molar ratio intervals.
In some preferred embodiments of the preparation method according to the present invention, in the step S2, the molar ratio of the amount of the 2-aminopyridine to the amount of the compound a may be 1 to 2:1.
In some preferred embodiments of the preparation method according to the present invention, the reaction temperature of the condensation reaction in the step S2 may be 20 to 60 ℃, including, but not limited to, a temperature value of 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃,45 ℃, 50 ℃, 55 ℃, 60 ℃, or any combination of temperature value intervals. In some more preferred embodiments, the reaction temperature of the condensation reaction may be 45 to 60 ℃.
In some preferred embodiments of the preparation method according to the present invention, the reaction time of the condensation reaction in the step S2 may be 20 to 48 hours, including but not limited to time values of 20 hours, 25 hours, 30 hours, 35 hours, 40 hours, 45 hours, 48 hours or time value intervals of any combination. In some more preferred embodiments, the reaction time of the condensation reaction may be 22 to 24 hours.
In some preferred embodiments of the preparation method according to the present invention, in the step S2, the condensation reaction uses tetrahydrofuran or dichloromethane as a reaction medium.
In some preferred embodiments of the preparation method according to the present invention, in the step S3, the reduction reaction is performed in the presence of a catalyst using hydrogen as a reducing agent. In some more preferred embodiments, the catalyst may be selected from palladium on carbon (e.g., 10% palladium on carbon, 5% palladium on carbon) or Raney nickel, which may be used in an amount of 5 to 20% by weight of the compound B. In still other more preferred embodiments, the pressure of the hydrogen gas may be from 0.2 to 2.5MPa, and more preferably may be from 0.2 to 1.2MPa.
In some preferred embodiments of the preparation method according to the present invention, the reaction temperature of the reduction reaction in the step S3 may be 20 to 65 ℃, including, but not limited to, a temperature value of 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃,45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, or a temperature value interval of any combination. In some more preferred embodiments, the reaction temperature of the condensation reaction may be 30 to 55 ℃.
In some preferred embodiments of the preparation method according to the present invention, in the step S3, the reduction reaction uses methanol, ethanol or tetrahydrofuran as a reaction medium.
In some preferred embodiments of the preparation process according to the present invention, when the reaction medium is an alcohol such as methanol, ethanol, etc., the following post-treatment process may be included after the completion of the reduction reaction: filtering the reaction liquid of the reduction reaction, dissolving a filter cake by using an organic solvent (such as dichloromethane), filtering to remove the catalyst of the reduction reaction, and concentrating the obtained filtrate to obtain the target product. In other preferred embodiments of the preparation process according to the invention, when the reaction medium is tetrahydrofuran, the reduction reaction may comprise the following work-up procedure after completion: filtering the reaction liquid of the reduction reaction to remove the catalyst of the reduction reaction, and concentrating the obtained filtrate to obtain the target product. The purity of the target product obtained in the post-treatment process can reach more than 99 percent.
The impurity R provided by the invention has important effects on analysis and detection, quality control, safety research and other aspects of dabigatran etexilate mesylate and the raw material DA thereof.
Therefore, the invention also provides the application of the raw material impurity of dabigatran etexilate mesylate or the raw material impurity of dabigatran etexilate mesylate prepared by the preparation method according to any one of the technical schemes as an impurity reference substance of dabigatran etexilate mesylate raw material DA (with a structure shown in a formula (3)).
In addition, the invention also provides the application of the raw material impurity of dabigatran etexilate mesylate disclosed in any one of the technical schemes or the raw material impurity of dabigatran etexilate mesylate prepared by the preparation method disclosed in any one of the technical schemes in detecting and/or controlling the quality of dabigatran etexilate mesylate and/or the raw material DA (with a structure shown in a formula (3)) thereof.
The invention provides detailed structural information and preparation methods of the impurity R, and also provides reasons for the generation of aminopyridine impurity V of dabigatran etexilate mesylate caused by the impurity R, so that a person skilled in the art can easily obtain high-purity impurity samples (for example, as external standard substances), establish qualitative and quantitative analysis and detection methods (for example, external standard methods and the like) of the impurity R according to conventional technology in the art, and establish corresponding purification methods, content control methods and the like of the impurity R and the impurity V, thereby realizing the application of the impurity R in quality detection and/or quality control of dabigatran etexilate mesylate and/or raw material DA thereof.
In summary, the invention provides the detailed information and the preparation method of the raw material impurity of the dabigatran etexilate mesylate, the technical process is simple, the prepared high-purity product (the purity is more than or equal to 99.0%) which can be used as an impurity reference substance can be further used for establishing methods of qualitative and quantitative analysis, detection, purification and the like of the impurity, and the method has very important significance in the aspects of quality control, production process optimization, safety research and the like of the dabigatran etexilate mesylate and the raw material DA thereof.
Detailed Description
The technical scheme of the invention is further described in detail below with reference to specific embodiments.
In the examples of the present invention, the raw materials and reagents used are shown in table 1:
TABLE 1
Figure BDA0003766155550000081
In the embodiment of the invention, the following detection instruments and detection conditions are adopted:
1. nuclear Magnetic Resonance (NMR)
Instrument model: bruker AVANCE III HD MHz NMR apparatus; test conditions: deuterated DMSO was used as solvent.
2. High resolution mass spectrometry
Instrument model: us Bruker micrOTOF QII; test conditions: ESI source, positive mode.
3. High performance liquid chromatography
Instrument: high performance liquid chromatograph equipped with ultraviolet detector (VWD) or diode array detector (PDA);
chromatographic column: xterra MS C18,3.5 μm, 150X 4.6mm; column temperature: 25 ℃; flow rate: 1.4mL/min; detection wavelength: 225nm; sample injection amount: 1 μl; mobile phase a: 1.0g of potassium dihydrogen phosphate is weighed and dissolved in 1000mL of water, and the pH value is adjusted to 2.4 by phosphoric acid; mobile phase B: acetonitrile; gradient elution was as follows:
time (min) Mobile phase A% Mobile phase B%
0 90 10
25 80 20
30 70 30
40 40 60
45 40 60
In the examples of the present invention, other materials and reagents were commercially available products unless otherwise specified.
The percentages used in the examples of the present invention are mass percentages unless otherwise indicated.
EXAMPLE 1 preparation of impurity R
(1) Preparation of Compound A
89.76g of the raw material nitro compound, 18.01g of potassium hydroxide (1.33 eq), 1800mL of ethanol and 900mL of water are added into a 5L reaction flask, the temperature is raised to 25-35 ℃, and the mixture is stirred for 4 hours under heat preservation. After incubation, ethanol was removed by concentrating under reduced pressure. After concentration, 1mol/L of dilute hydrochloric acid is slowly added dropwise at room temperature, the pH value is regulated to 2-3 while stirring, and a large amount of solids are separated out. Suction filtration and vacuum drying, the yellow solid 76.85g is obtained, the purity is 99.40%, and the yield is 92.59%.
The nuclear magnetism and mass spectrum data of the product are as follows: 1 H-NMR(600MHz，DMSO-d 6 )δ(ppm)：2.59～2.62(m，2H)，2.91(d，3H)，4.14(t，2H)，6.83(d，1H)，7.12(d，1H)，7.20～7.22(m，1H)，7.33(dd，1H)，7.69～7.72(m，1H)，7.94(d，1H)，8.35(q，1H)，8.42～8.43(m，1H)，12.26(brs，1H)。 13 C-NMR(150MHz，DMSO-d 6 )δ(ppm)：30.20，33.14，44.99，114.25，122.04，122.19，122.31，128.09，130.15，136.40，138.84，146.98，149.33，156.23，168.23，172.97.
MS(m/z)：345.1179[M+H] + .
(2) Preparation of Compound B
To a 1L four-necked flask, 30.64g of CDI (1.5 eq) and 500mL of tetrahydrofuran were charged, and the temperature was raised to 45-50 ℃. 43.38g of Compound A (1.0 eq) were added, stirred for 30min with heat preservation, then 12.60g of 2-aminopyridine (1.06 eq) were added and reacted for 24h with heat preservation. After incubation, the solvent was removed by concentrating under reduced pressure, 600mL of methylene chloride was added and the mixture was washed with 90mL of water, and the organic layer was concentrated to dryness after washing to give a yellow oil. Purifying the crude product by column chromatography (column chromatography silica gel 200-300 meshes), collecting eluent with higher purity by using ethyl acetate, concentrating to dryness to obtain yellow solid 21.20g, wherein the purity is 99.80%, and the yield is 40.02%.
The nuclear magnetism and mass spectrum data of the product are as follows: 1 H-NMR(600MHz，DMSO-d 6 )δ(ppm)：2.80(t，2H)，2.91(d，3H)，4.24(t，2H)，6.83(d，1H)，7.05～7.08(m，1H)，7.15(d，1H)，7.17～7.19(m，1H)，7.33(dd，1H)，7.66～7.69(m，1H)，7.72～7.75(m，1H)，7.97(brs，1H)，7.95(d，1H)，8.27～8.28(m，1H)，8.34(q，1H)，8.37～8.38(m，1H)，10.49(brs，1H)； 13 C-NMR(150MHz，DMSO-d 6 )δ(ppm)：30.20，35.43，45.40，114.02，114.24，119.72，122.09，122.18，122.24，128.05，130.16，136.38，138.45，138.76，146.95，148.31，149.23，152.35，156.31，168.25，170.56.
MS(m/z)：421.1616[M+H] + .
(3) Preparation of impurity R
A500 mL hydrogenation reactor was charged with 12.61g of Compound B, 150mL of methanol, and 1.0g of 10% Pd-C, and the air was replaced with nitrogen, followed by replacement of the nitrogen with hydrogen. Then heating to 30-40 ℃, controlling the hydrogen pressure to be 0.2-0.4MPa, and keeping the temperature for reaction until the hydrogenation is complete. Cooling to room temperature, opening the kettle, precipitating a large amount of solid in the kettle, filtering the reaction solution, discarding brown filtrate, dissolving filter cake with 200mL of dichloromethane, and filtering to remove palladium carbon. The filtrate was concentrated to dryness to give 10.66g of the product with a purity of 99.80% and a yield of 91.03%.
The nuclear magnetism and mass spectrum data of the product are as follows: 1 H-NMR(600MHz，DMSO-d 6 )δ(ppm)：2.66(d，3H)，2.76(t，2H)，4.21(t，2H)，4.53(brs，2H)，5.76(brs，1H)，6.10(d，1H)，6.35(d，1H)，6.69(s，1H)，6.83(d，1H)，7.06～7.09(m，2H)，7.53～7.56(m，1H)，7.72～7.74(m，1H)，7.98(d，1H)，8.27～8.28(m，1H)，8.37～8.38(m，1H)，10.47(brs，1H)； 13 C-NMR(150MHz，DMSO-d 6 )δ(ppm)：29.7，35.1，44.3，106.8，113.5，114.1，119.2，119.8，120.4，121.7，122.9，134.0，137.3，137.9，139.3，147.8，148.3，151.9，156.7，170.2，170.6.
MS(m/z)：413.1691[M+Na] + .
EXAMPLE 2 preparation of impurity R
(1) Preparation of Compound A
89.76g of the raw material nitro compound, 20.29g of potassium hydroxide (1.5 eq), 1600mL of ethanol and 800mL of water are added into a 5L reaction bottle, the temperature is raised to 55-60 ℃, and the mixture is stirred for 2 hours under heat preservation. After incubation, ethanol was removed by concentrating under reduced pressure. After concentration, 1mol/L of dilute hydrochloric acid is slowly added dropwise at room temperature, the pH value is regulated to 2-3 while stirring, and a large amount of solids are separated out. Suction filtration and vacuum drying, thus obtaining 75.58g of yellow solid with purity of 99.32% and yield of 91.06%. The nuclear magnetic resonance and mass spectrometry data for compound a are consistent with example 1.
(2) Preparation of Compound B
40.86g of CDI (2.0 eq) and 500mL of tetrahydrofuran were added to a 1L four-necked flask, and the temperature was raised to 55-60 ℃. 43.38g of Compound A (1.0 eq) were added, stirred for 30min with heat preservation, then 23.71g of 2-aminopyridine (2.0 eq) were added and reacted for 22h with heat preservation. After incubation, the solvent was removed by concentrating under reduced pressure, 600mL of methylene chloride was added and the mixture was washed with 90mL of water, and the organic layer was concentrated to dryness after washing to give a yellow oil. Purifying the crude product by column chromatography (column chromatography silica gel 100-200 meshes), collecting eluent with higher purity by using ethyl acetate, concentrating to dryness to obtain 22.78g of yellow solid with purity of 99.78% and yield of 43.00%. The nuclear magnetic resonance and mass spectrometry data for compound B are consistent with example 1.
(3) Preparation of impurity R
A500 mL hydrogenation reactor was charged with 12.61g of Compound B, 200mL of ethanol, and 1.8g of 5% Pd-C, and the air was replaced with nitrogen, followed by replacement of the nitrogen with hydrogen. Then heating to 35-45 ℃, controlling the hydrogen pressure to be 1.0-1.2MPa, and keeping the temperature for reaction until the hydrogenation is complete. Cooling to room temperature, opening the kettle, precipitating a large amount of solid in the kettle, filtering the reaction solution, discarding brown filtrate, dissolving filter cake with 250mL of dichloromethane, and filtering to remove palladium carbon. The filtrate was concentrated to dryness to give 10.31g of the product with a purity of 99.65% and a yield of 88.04%. The nuclear magnetic and mass spectral data of impurity R are consistent with example 1.
EXAMPLE 3 preparation of impurity R
(1) Preparation of Compound A
Into a 5L reaction flask, 89.76g of the raw material nitro compound, 10.60g of sodium hydroxide (1.1 eq), 1200mL of methanol and 600mL of water were added, the temperature was raised to 35-40℃and the mixture was stirred at a constant temperature for 3h. After incubation, methanol was removed by concentration under reduced pressure. After concentration, 1mol/L of dilute hydrochloric acid is slowly added dropwise at room temperature, the pH value is regulated to 2-3 while stirring, and a large amount of solids are separated out. Suction filtration and vacuum drying gave 72.88g of yellow solid with a purity of 99.20% and a yield of 87.81%. The nuclear magnetic resonance and mass spectrometry data for compound a are consistent with example 1.
(2) Preparation of Compound B
Into a 500mL four-necked flask were charged 10.30g of Compound A (1.0 eq), 180mL of methylene chloride and 2.90g of 2-aminopyridine (1.03 eq), and 4.86g of 1-hydroxybenzotriazole (1.2 eq) and 6.90g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.2 eq). The reaction is carried out for 48h at 20-30 ℃. After the reaction, the organic phase was washed with 40mL of water. After washing the organic layer was concentrated to dryness to give a yellow oil. Purifying the crude product by column chromatography (column chromatography silica gel 200-300 meshes), collecting eluent with higher purity by using ethyl acetate, concentrating to dryness to obtain yellow solid 4.86g, wherein the purity is 99.40%, and the yield is 38.63%. The nuclear magnetic resonance and mass spectrometry data for compound B are consistent with example 1.
(3) Preparation of impurity R
A500 mL hydrogenation reactor was charged with 12.61g of Compound B, 200mL of tetrahydrofuran, and 2.50g of Raney Nickel, and the air was replaced with nitrogen, followed by replacement of the nitrogen with hydrogen. Then heating to 45-55 ℃, controlling the hydrogen pressure to be 1.5-2.5MPa, and keeping the temperature for reaction until the hydrogenation is complete. Cooling to room temperature, opening the kettle, and filtering the reaction solution to remove Raney nickel. The filtrate was concentrated to dryness to give 9.96g of the product with a purity of 99.30% and a yield of 85.05%. The nuclear magnetic and mass spectral data of impurity R are consistent with example 1.
Unless otherwise defined, all terms used herein are intended to have the meanings commonly understood by those skilled in the art.
The described embodiments of the present invention are intended to be illustrative only and not to limit the scope of the invention, and various other alternatives, modifications, and improvements may be made by those skilled in the art within the scope of the invention, and therefore the invention is not limited to the above embodiments but only by the claims.

Claims (10)

1. The raw material impurity of dabigatran etexilate mesylate is characterized by having a structure shown in a formula (1),
Figure FDA0003766155540000011
2. the method for preparing the raw material impurity of dabigatran etexilate mesylate according to claim 1, which is characterized by comprising the following steps:
Figure FDA0003766155540000012
s1: taking a nitro compound with a structure shown in a formula (2) as a starting material, and obtaining a compound A through hydrolysis reaction;
s2: the compound A and 2-aminopyridine undergo a condensation reaction to obtain a compound B; and
s3: and (3) carrying out reduction reaction on the compound B to obtain the raw material impurity.
3. The method according to claim 2, wherein in the step S1, the hydrolysis reaction is performed in the presence of a base; preferably, the base is selected from sodium hydroxide and/or potassium hydroxide; more preferably, the molar ratio of the amount of base to the amount of nitro compound is 1.1 to 1.5:1.
4. A method according to claim 3, wherein in step S1, the reaction temperature of the hydrolysis reaction is 25 to 60 ℃, preferably 25 to 35 ℃; and/or
The reaction time of the hydrolysis reaction is 2-4 hours; and/or
The hydrolysis reaction takes aqueous solution of methanol or ethanol as a reaction medium, wherein the volume ratio of the methanol or ethanol to water is 1-5:1.
5. The method according to any one of claims 2 to 4, wherein in step S2, the condensation reaction is performed in the presence of a condensing agent; preferably, the condensing agent is selected from the group consisting of N, N' -carbonyldiimidazole or a mixture of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole; more preferably, the molar ratio of the amount of condensing agent to the amount of compound a is 1.2-3:1.
6. The method according to claim 5, wherein in the step S2, the molar ratio of the amount of the 2-aminopyridine to the amount of the compound a is 1 to 2:1; and/or
The reaction temperature of the condensation reaction is 20-60 ℃, preferably 45-60 ℃; and/or
The reaction time of the condensation reaction is 20-48 h, preferably 22-24 h; and/or
The condensation reaction takes tetrahydrofuran or methylene dichloride as a reaction medium.
7. The method according to any one of claims 2 to 6, wherein in step S3, the reduction reaction is performed in the presence of a catalyst using hydrogen as a reducing agent; preferably, the catalyst is selected from palladium carbon or Raney nickel, and the pressure of the hydrogen is 0.2-2.5 MPa, preferably 0.2-1.2 MPa.
8. The method according to claim 7, wherein in step S3, the reaction temperature of the reduction reaction is 20 to 65 ℃, preferably 30 to 55 ℃; and/or
The reduction reaction takes methanol, ethanol or tetrahydrofuran as a reaction medium.
9. The use of a dabigatran etexilate mesylate raw material impurity of claim 1 or a dabigatran etexilate mesylate raw material impurity prepared by the preparation method of any one of claims 2 to 8 as an impurity reference substance of dabigatran etexilate mesylate raw material, the dabigatran etexilate mesylate raw material having a structure represented by formula (3),
Figure FDA0003766155540000031
10. the use of a dabigatran etexilate mesylate raw material impurity according to claim 1 or a dabigatran etexilate mesylate raw material impurity obtained by the production method according to any one of claims 2 to 8 for detecting and/or controlling the quality of dabigatran etexilate mesylate and/or raw material thereof, the dabigatran etexilate mesylate raw material having a structure represented by formula (3),
Figure FDA0003766155540000032
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CN202210887192.7A 2022-07-26 2022-07-26 Raw material impurity of dabigatran etexilate mesylate, and preparation method and application thereof Pending CN116178252A (en)

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