CN104725360A - Preparing method of dabigatran etexilate mesylate crystal form I - Google Patents
Preparing method of dabigatran etexilate mesylate crystal form I Download PDFInfo
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- CN104725360A CN104725360A CN201510165892.5A CN201510165892A CN104725360A CN 104725360 A CN104725360 A CN 104725360A CN 201510165892 A CN201510165892 A CN 201510165892A CN 104725360 A CN104725360 A CN 104725360A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
An embodiment of the invention discloses a preparing method of dabigatran etexilate mesylate crystal form I. The method includes the steps of adding dabigatran etexilate into acetone solution before heating for solution, and adding methylsulfonic acid to generate dabigatran etexilate mesylate; stirring the dabigatran etexilate mesylate in ester solvent or ether solvent under heating so that the dabigatran etexilate mesylate with low crystal form I (containing little crystal form II or part of semihydrate) is converted into the dabigatran etexilate mesylate with high content of the crystal form I. The dabigatran etexilate mesylate crystal form I prepared by the method is high in purity, lower in water content and more stable in quality.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to a kind of preparation method of methylsulfonic acid dabigatran etcxilate I crystal formation.
Background technology
Methylsulfonic acid dabigatran etcxilate is developed by Boehringer Ingelheim company the earliest, is applicable to palsy and the systemic embolism (SEE) of the adult's NVAF patient preventing to exist one or more Hazard Factor.This is the first new classification oral anticoagulant thing gone on the market over 50 years after warfarin.The listing of this product, is a major progress in anticoagulation therapy field and potential lethality thrombus prevention field, has milestone significance.
Methylsulfonic acid dabigatran etcxilate structural formula is as follows:
Boehringer Ingelheim company applied for patent CN1845917B in 2004, reported I crystal formation of methylsulfonic acid dabigatran etcxilate, II crystal formation and semihydrate.The powder x-ray diffraction 2 θ corner characteristics peak of I crystal formation: 4.4,8.94,9.23,9.55,10.55,12.73,13.46,14.26,15.17,15.93,16.46,17.66,18.07,18.60,19.89,20.28,20.54,21.12,22.06,22.85,24.12,25.10,25.9,26.52,26.83,27.16,27.64,28.09,29.08,29.26,29.94,31.88,34.37,36.21,38.26,39.47,39.98.The powder x-ray diffraction 2 θ corner characteristics peak of II crystal formation: 4.3,8.72,9.68,11.15,12.42,13.59,13.95,15.11,15.97,16.52,17.45,17.86,18.45,19.22,19.89,21.46,21.98,22.48,23.75,25.29,28.17,28.59.The powder x-ray diffraction 2 θ corner characteristics peak of semihydrate: 3.9, 4.4, 5.64, 7.7, 8.25, 8.77, 9.34, 10.69, 11.33, 11.66, 11.96, 13.04, 15.54, 15.16, 16.56, 17.27, 17.78, 18.75, 19.41, 19.95, 20.38, 20.84, 21.21, 22.22, 22.46, 23.05, 23.40, 23.85, 24.44, 25.30, 25.63, 2622, 26.52, 27.06, 27.45, 29.27, 30.78, 32.32, 32.59, 34.31, 34.91, 36.04, 37.00, 37.84, 38.13.Wherein, 13.5 ± 0.1 and 18.0 ± 0.1 is the distinctive characteristic peak of I crystal formation, and 12.4 ± 0.1 is the distinctive characteristic peak of II crystal formation, and 3.9 ± 0.1,7.6 ± 0.1,8.2 ± 0.1 is the distinctive characteristic peak of semihydrate.I crystal formation, II crystal formation and hemihydrated assessment fusing point are respectively 180 ± 3 DEG C, 190 ± 3 DEG C and 120 ± 5 DEG C.
CDER (CENTER FOR DRUG EVALUATION AND RESEARCH) reports about the assessment report of PRADAXA (dabigatran etcxilate) capsule, and the fusing point of the raw materials used medicine of current commercially available capsule is 180 ± 3 DEG C.As can be seen here, current streat drug bulk drug used is I crystal formation, and namely the active pharmaceutical ingredient of medicine is methylsulfonic acid dabigatran etcxilate I crystal formation crystal.
In the prior art, such as, patent CN1845917B is reacted in 30 ~ 35 DEG C and methylsulfonic acid in acetone by dabigatran etcxilate and prepares methylsulfonic acid dabigatran etcxilate I crystal formation, during temperature generation deviation, or stably can not prepare methylsulfonic acid dabigatran etcxilate I crystal formation containing during a certain amount of moisture in reaction system, products obtained therefrom contains small part II crystal formation or semihydrate.A kind of medicine can have multiple crystal habit to exist, the different crystal form of same medicine, the stability of its medicine may be different with physico-chemical property, also may there is obvious difference with absorption in the dissolving of its oral solid formulation in human body, the bioavailability of final medicine also may there are differences.
Summary of the invention
In order to overcome the above problems, the object of the present invention is to provide a kind of preparation method of methylsulfonic acid dabigatran etcxilate I crystal formation.
Another object of the present invention is to provide a kind of method reducing methylsulfonic acid dabigatran etcxilate moisture content of finished products content.
In addition, the 3rd object of the present invention is the stability improving methylsulfonic acid dabigatran etcxilate quality product.
The preparation method of a kind of methylsulfonic acid dabigatran etcxilate I crystal formation provided in the embodiment of the present invention, comprises the steps:
(1) under room temperature, joined by dabigatran etcxilate in acetone, wherein, acetone volumetric usage is 5 ~ 50 times of dabigatran etcxilate quality; Being warming up to 30 ~ 56 DEG C makes dabigatran etcxilate dissolve completely; Then be cooled to 25 ~ 40 DEG C, keep temperature 25 ~ 40 DEG C, add methylsulfonic acid acetone soln, mix;
(2) by step (1) gained mixture, 0 ~ 25 DEG C is cooled to, stirring and crystallizing 1 ~ 10 hour;
(3) filtration step (2) gained mixture, enters in esters solvent or ether solvent by filter cake, wherein, and 5 ~ 30 times that esters solvent or ether solvent volumetric usage are dabigatran etcxilate quality described in step (1); Be warming up to 45 ~ 78 DEG C, keep temperature 45 ~ 78 DEG C, stir 1 ~ 5 hour;
(4) by step (3) gained mixture, 0 ~ 30 DEG C is cooled to, stirring and crystallizing 1 ~ 5 hour;
(5) filtration step (4) gained mixture, is dried to constant weight by filter cake in 30 ~ 80 DEG C, obtained methylsulfonic acid dabigatran etcxilate I crystal formation product.
Preferably, in above-mentioned preparation method, step (3) described esters solvent be selected from ethyl formate, propyl formate, isopropyl formate, n-buty formate, tetryl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, n-butyl propionate and isobutyl propionate one or more.
Preferably, in above-mentioned preparation method, ether solvent described in step (3) be selected from dipropyl ether, diisopropyl ether, ethyl propyl ether, methyl tertiary butyl ether, methyl n-butyl ether, ethyl n-butyl ether, tetrahydrofuran (THF) and Isosorbide-5-Nitrae-dioxane one or more.
Preferably, in above-mentioned preparation method, 5 ~ 30 times that the esters solvent described in step (3) or ether solvent volumetric usage are dabigatran etcxilate quality described in step (1).
The preparation method above-mentioned according to any one, prepared methylsulfonic acid dabigatran etcxilate I crystal formation crystal powder X-ray diffraction 2 θ corner characteristics peak is as follows:
4.48、9.00、9.30、9.62、10.58、11.00、12.77、13.46、14.26、15.92、16.54、17.70、18.08、18.60、20.30、20.50、21.14、22.06、22.92、24.20、25.11、25.94、26.22、26.54、26.88、27.54、27.66、28.02、29.08、29.28。
Compared with prior art, the present invention has following beneficial effect:
1, the methylsulfonic acid dabigatran etcxilate I crystal formation crystal habit that prepared by the present invention has the advantage that crystal purity is higher and quality is more stable.
2, the more existing preparation method of preparation method of the present invention more stably can prepare methylsulfonic acid dabigatran etcxilate I crystal formation product, and processing condition are more suitable for industrialization.
Accompanying drawing explanation
In order to be illustrated more clearly in the embodiment of the present invention or technical scheme of the prior art, be briefly described to the accompanying drawing used required in embodiment below, apparently, accompanying drawing in the following describes is only some embodiments of the present invention, for those of ordinary skill in the art, under the prerequisite not paying creative work, other accompanying drawing can also be obtained according to these accompanying drawings.
The methylsulfonic acid dabigatran etcxilate product powder x-ray diffraction figure of Fig. 1, the embodiment of the present invention 1 preparation;
The methylsulfonic acid dabigatran etcxilate product powder x-ray diffraction figure of Fig. 2, the embodiment of the present invention 2 preparation;
The methylsulfonic acid dabigatran etcxilate product powder x-ray diffraction figure of Fig. 3, the embodiment of the present invention 3 preparation;
The methylsulfonic acid dabigatran etcxilate product powder x-ray diffraction figure of Fig. 4, the embodiment of the present invention 4 preparation;
The methylsulfonic acid dabigatran etcxilate product powder x-ray diffraction figure of Fig. 5, the embodiment of the present invention 5 preparation;
The methylsulfonic acid dabigatran etcxilate product powder x-ray diffraction figure of Fig. 6, the embodiment of the present invention 6 preparation
The methylsulfonic acid dabigatran etcxilate product powder x-ray diffraction figure of Fig. 7, the embodiment of the present invention 7 preparation
The methylsulfonic acid dabigatran etcxilate product powder x-ray diffraction figure of Fig. 8, comparative example of the present invention 1 preparation;
The methylsulfonic acid dabigatran etcxilate product powder x-ray diffraction figure of Fig. 9, comparative example of the present invention 2 preparation;
The methylsulfonic acid dabigatran etcxilate product of Figure 10, the embodiment of the present invention 2 preparation accelerates powder x-ray diffraction figure after June;
Methylsulfonic acid dabigatran etcxilate product prepared by Figure 11, comparative example of the present invention 1 accelerates the powder x-ray diffraction figure after June;
The methylsulfonic acid dabigatran etcxilate product of Figure 12, comparative example of the present invention 2 preparation accelerates powder x-ray diffraction figure after June;
The methylsulfonic acid dabigatran etcxilate product DSC collection of illustrative plates of Figure 13, the embodiment of the present invention 2 preparation.
Embodiment
Below in conjunction with the accompanying drawing in the embodiment of the present invention, carry out clear, complete description to the technical scheme in the embodiment of the present invention, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
Embodiment
Preparation method of the present invention is used to prepare methylsulfonic acid dabigatran etcxilate I crystal formation crystal.
Raw material dabigatran etcxilate of the present invention prepares according to CN1088702C.
Embodiment 1
(1) under room temperature, joined by dabigatran etcxilate in acetone, wherein, acetone volumetric usage is 20 times of dabigatran etcxilate quality; Be warming up to 30 DEG C and make dabigatran etcxilate CL; Then be cooled to 25 DEG C, keep temperature 25 DEG C, add methylsulfonic acid acetone soln, wherein, the amount of substance of methylsulfonic acid is 0.98 times of dabigatran etcxilate amount of substance, and acetone volumetric usage is 15 times of methylsulfonic acid quality; Mix, obtained methylsulfonic acid dabigatran ester solution;
(2) by step (1) gained mixture, 10 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(3) filtration step (2) gained mixture, joins filter cake in ethyl acetate solvent, and wherein, ethyl acetate solvent volumetric usage is 30 times of dabigatran etcxilate quality described in step (1); Be warming up to 45 DEG C, keep temperature 45 C, stir 5 hours;
(4) by step (3) gained mixture, 0 DEG C is cooled to, stirring and crystallizing 1 hour;
(5) filtration step (4) gained mixture, is dried to constant weight by filter cake in 30 DEG C, obtained methylsulfonic acid dabigatran etcxilate I crystal formation product.
The purity of methylsulfonic acid dabigatran etcxilate I crystal formation prepared by the present embodiment is 99.75%, moisture content is 0.25% (massfraction).
The obtained methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction of the present embodiment is as shown in Figure 1: this collection of illustrative plates contains the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction, that is, 2 θ angles are 13.5 ± 0.1 and 18.0 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate II crystal formation powder x-ray diffraction, that is, 2 θ angles are 12.4 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate semihydrate powder x-ray diffraction, that is, 2 θ angles are 3.9 ± 0.1,7.6 ± 0.1,8.2 ± 0.1.
Embodiment 2
(1) under room temperature, joined by dabigatran etcxilate in acetone, wherein, acetone volumetric usage is 20 times of dabigatran etcxilate quality; Being warming up to 56 DEG C makes dabigatran etcxilate dissolve completely; Then be cooled to 40 DEG C, keep temperature 40 DEG C, add methylsulfonic acid acetone soln, wherein, the amount of substance of methylsulfonic acid is 0.98 times of dabigatran etcxilate amount of substance, and acetone volumetric usage is 15 times of methylsulfonic acid quality; Mix, obtained methylsulfonic acid dabigatran ester solution;
(2) by step (1) gained mixture, 15 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(3) filtration step (2) gained mixture, joins filter cake in ethyl acetate solvent, and wherein, ethyl acetate solvent volumetric usage is 15 times of dabigatran etcxilate quality described in step (1); Be warming up to 55 DEG C, keep temperature 55 DEG C, stir 1 hour;
(4) by step (3) gained mixture, 10 DEG C are cooled to, stirring and crystallizing 3 hours;
(5) filtration step (4) gained mixture, is dried to constant weight by filter cake in 45 DEG C, obtained methylsulfonic acid dabigatran etcxilate I crystal formation product.
The purity of methylsulfonic acid dabigatran etcxilate I crystal formation prepared by the present embodiment is 99.72%, moisture content is 0.24% (massfraction).
The obtained methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction of the present embodiment is as shown in Figure 2: this collection of illustrative plates contains the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction, that is, 2 θ angles are 13.5 ± 0.1 and 18.0 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate II crystal formation powder x-ray diffraction, that is, 2 θ angles are 12.4 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate semihydrate powder x-ray diffraction, that is, 2 θ angles are 3.9 ± 0.1,7.6 ± 0.1,8.2 ± 0.1.
The DSC collection of illustrative plates of methylsulfonic acid dabigatran etcxilate I crystal formation that the present embodiment obtains, as shown in figure 13: DSC result shows that the fusing point of methylsulfonic acid dabigatran etcxilate I crystal formation prepared by the present embodiment is 178 DEG C, meet methylsulfonic acid dabigatran etcxilate I crystal formation DSC and assess melting range.
Embodiment 3
(1) under room temperature, joined by dabigatran etcxilate in acetone, wherein, acetone volumetric usage is 20 times of dabigatran etcxilate quality; Being warming up to 40 DEG C makes dabigatran etcxilate dissolve completely; Then be cooled to 30 DEG C, keep temperature 30 DEG C, add methylsulfonic acid acetone soln, wherein, the amount of substance of methylsulfonic acid is 0.98 times of dabigatran etcxilate amount of substance, and acetone volumetric usage is 15 times of methylsulfonic acid quality; Mix, obtained methylsulfonic acid dabigatran ester solution;
(2) by step (1) gained mixture, 12 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(3) filtration step (2) gained mixture, joins in methyl propionate solvent by filter cake, wherein, methyl propionate solvent volume consumption is 5 times of dabigatran etcxilate solid masses described in step (1); Be warming up to 78 DEG C, keep temperature 78 DEG C, stir 2 hours;
(4) by step (3) gained mixture, 30 DEG C are cooled to, stirring and crystallizing 5 hours;
(5) filtration step (4) gained mixture, is dried to constant weight by filter cake in 80 DEG C, obtained methylsulfonic acid dabigatran etcxilate I crystal formation product.
The purity of methylsulfonic acid dabigatran etcxilate I crystal formation prepared by the present embodiment is 99.71%, moisture content is 0.21% (massfraction).
The obtained methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction of the present embodiment is as shown in Figure 3: this collection of illustrative plates contains the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction, that is, 2 θ angles are 13.5 ± 0.1 and 18.0 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate II crystal formation powder x-ray diffraction, that is, 2 θ angles are 12.4 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate semihydrate powder x-ray diffraction, that is, 2 θ angles are 3.9 ± 0.1,7.6 ± 0.1,8.2 ± 0.1.
Embodiment 4
(1) under room temperature, joined by dabigatran etcxilate in acetone, wherein, acetone volumetric usage is 20 times of dabigatran etcxilate quality; Being warming up to 45 DEG C makes dabigatran etcxilate dissolve completely; Then be cooled to 35 DEG C, keep temperature 35 DEG C, add methylsulfonic acid acetone soln, wherein, the amount of substance of methylsulfonic acid is 0.98 times of dabigatran etcxilate amount of substance, and acetone volumetric usage is 15 times of methylsulfonic acid quality; Mix, obtained methylsulfonic acid dabigatran ester solution;
(2) by step (1) gained mixture, 15 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(3) filtration step (2) gained mixture, joins in ethyl formate solvent by filter cake, wherein, ethyl formate solvent volume consumption is 10 times of dabigatran etcxilate quality described in step (1); Be warming up to 65 DEG C, keep temperature 65 DEG C, stir 2 hours;
(4) by step (3) gained mixture, 15 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(5) filtration step (4) gained mixture, is dried to constant weight by filter cake in 55 DEG C, obtained methylsulfonic acid dabigatran etcxilate I crystal formation product.
The purity of methylsulfonic acid dabigatran etcxilate I crystal formation prepared by the present embodiment is 99.70%, moisture content is 0.21% (massfraction).
The obtained methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction of the present embodiment is as shown in Figure 4: this collection of illustrative plates contains the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction, that is, 2 θ angles are 13.5 ± 0.1 and 18.0 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate II crystal formation powder x-ray diffraction, that is, 2 θ angles are 12.4 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate semihydrate powder x-ray diffraction, that is, 2 θ angles are 3.9 ± 0.1,7.6 ± 0.1,8.2 ± 0.1.
Embodiment 5
(1) under room temperature, joined by dabigatran etcxilate in acetone, wherein, acetone volumetric usage is 20 times of dabigatran etcxilate quality; Being warming up to 50 DEG C makes dabigatran etcxilate dissolve completely; Then be cooled to 40 DEG C, keep temperature 40 DEG C, add methylsulfonic acid acetone soln, wherein, the amount of substance of methylsulfonic acid is 0.98 times of dabigatran etcxilate amount of substance, and acetone volumetric usage is 15 times of methylsulfonic acid quality; Mix, obtained methylsulfonic acid dabigatran ester solution;
(2) by step (1) gained mixture, 10 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(3) filtration step (2) gained mixture, joins filter cake in methyl tert-butyl ether solvent, and wherein, methyl tert-butyl ether solvent volumetric usage is 13 times of dabigatran etcxilate solid masses described in step (1); Be warming up to 60 DEG C, keep temperature 60 C, stir 3 hours;
(4) by step (3) gained mixture, 12 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(5) filtration step (4) gained mixture, is dried to constant weight by filter cake in 50 DEG C, obtained methylsulfonic acid dabigatran etcxilate I crystal formation product.
The purity of methylsulfonic acid dabigatran etcxilate I crystal formation prepared by the present embodiment is 99.73%, moisture content is 0.21% (massfraction).
The obtained methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction of the present embodiment is as shown in Figure 5: this collection of illustrative plates contains the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction, that is, 2 θ angles are 13.5 ± 0.1 and 18.0 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate II crystal formation powder x-ray diffraction, that is, 2 θ angles are 12.4 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate semihydrate powder x-ray diffraction, that is, 2 θ angles are 3.9 ± 0.1,7.6 ± 0.1,8.2 ± 0.1.
Embodiment 6
(1) under room temperature, joined by dabigatran etcxilate in acetone, wherein, acetone volumetric usage is 20 times of dabigatran etcxilate quality; Being warming up to 50 DEG C makes dabigatran etcxilate dissolve completely; Then be cooled to 35 DEG C, keep temperature 35 DEG C, add methylsulfonic acid acetone soln, wherein, the amount of substance of methylsulfonic acid is 0.98 times of dabigatran etcxilate amount of substance, and acetone volumetric usage is 15 times of methylsulfonic acid quality; Mix, obtained methylsulfonic acid dabigatran ester solution;
(2) by step (1) gained mixture, 10 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(3) filtration step (2) gained mixture, joins filter cake in tetrahydrofuran solvent, and wherein, tetrahydrofuran solvent volumetric usage is 13 times of dabigatran etcxilate solid masses described in step (1); Be warming up to 63 DEG C, keep temperature 63 DEG C, stir 2 hours;
(4) by step (3) gained mixture, 12 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(5) filtration step (4) gained mixture, is dried to constant weight by filter cake in 50 DEG C, obtained methylsulfonic acid dabigatran etcxilate I crystal formation product.
The purity of methylsulfonic acid dabigatran etcxilate I crystal formation prepared by the present embodiment is 99.68%, moisture content is 0.19% (massfraction).
The obtained methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction of the present embodiment is as shown in Figure 6: this collection of illustrative plates contains the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction, that is, 2 θ angles are 13.5 ± 0.1 and 18.0 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate II crystal formation powder x-ray diffraction, that is, 2 θ angles are 12.4 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate semihydrate powder x-ray diffraction, that is, 2 θ angles are 3.9 ± 0.1,7.6 ± 0.1,8.2 ± 0.1.
Embodiment 7
(1) under room temperature, joined by dabigatran etcxilate in acetone, wherein, acetone volumetric usage is 20 times of dabigatran etcxilate quality; Being warming up to 56 DEG C makes dabigatran etcxilate dissolve completely; Then be cooled to 30 DEG C, keep temperature 30 DEG C, add methylsulfonic acid acetone soln, wherein, the amount of substance of methylsulfonic acid is 0.98 times of dabigatran etcxilate amount of substance, and acetone volumetric usage is 15 times of methylsulfonic acid quality; Mix, obtained methylsulfonic acid dabigatran ester solution;
(2) by step (1) gained mixture, 13 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(3) filtration step (2) gained mixture, joins in diisopropyl ether solvent by filter cake, wherein, diisopropyl ether solvent volume consumption is 14 times of dabigatran etcxilate solid masses described in step (1); Be warming up to 65 DEG C, keep temperature 65 DEG C, stir 2 hours;
(4) by step (3) gained mixture, 12 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(5) filtration step (4) gained mixture, is dried to constant weight by filter cake in 50 DEG C, obtained methylsulfonic acid dabigatran etcxilate I crystal formation product.
The purity of methylsulfonic acid dabigatran etcxilate I crystal formation prepared by the present embodiment is 99.69%, moisture content is 0.20% (massfraction).
The obtained methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction of the present embodiment is as shown in Figure 7: this collection of illustrative plates contains the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction, that is, 2 θ angles are 13.5 ± 0.1 and 18.0 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate II crystal formation powder x-ray diffraction, that is, 2 θ angles are 12.4 ± 0.1; This collection of illustrative plates is not containing the distinctive 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate semihydrate powder x-ray diffraction, that is, 2 θ angles are 3.9 ± 0.1,7.6 ± 0.1,8.2 ± 0.1.
Comparative example 1
According to patent CN1845917B preparation containing a small amount of II crystal formation methylsulfonic acid dabigatran etcxilate.
(1) under room temperature, joined by dabigatran etcxilate in acetone, wherein, acetone volumetric usage is 20 times of dabigatran etcxilate quality, moisture content≤0.2% (massfraction) of acetone; Being warming up to 45 DEG C makes dabigatran etcxilate dissolve completely; Then be cooled to 25 DEG C, keep temperature 25 DEG C, add methylsulfonic acid acetone soln, wherein, the amount of substance of methylsulfonic acid is 0.98 times of dabigatran etcxilate amount of substance, and acetone volumetric usage is 15 times of methylsulfonic acid quality; Mix, obtained methylsulfonic acid dabigatran ester solution;
(2) by step (1) gained mixture, 10 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(3) by step (2) gained mixture, filter, filter cake is dried to constant weight in 45 ~ 50 DEG C, the obtained methylsulfonic acid dabigatran etcxilate I crystal formation product containing a small amount of II crystal formation.
The purity of methylsulfonic acid dabigatran etcxilate I crystal formation prepared by this comparative example is 99.70%, moisture content is 0.45% (massfraction).
The obtained methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction of this comparative example is as shown in Figure 8: this collection of illustrative plates contains 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate I crystal formation and methylsulfonic acid dabigatran etcxilate II crystal formation powder x-ray diffraction.
Comparative example 2
According to patent CN1845917B preparation containing part semihydrate methylsulfonic acid dabigatran etcxilate.
(1) under room temperature, joined by dabigatran etcxilate in acetone, wherein, acetone volumetric usage is 20 times of dabigatran etcxilate quality, and the moisture content (massfraction) of acetone is 0.2% ~ 0.6%; Being warming up to 45 DEG C makes dabigatran etcxilate dissolve completely; Then be cooled to 40 DEG C, keep temperature 40 DEG C, add methylsulfonic acid acetone soln, wherein, the amount of substance of methylsulfonic acid is 0.98 times of dabigatran etcxilate amount of substance, and acetone volumetric usage is 15 times of methylsulfonic acid quality; Mix, obtained methylsulfonic acid dabigatran ester solution;
(2) by step (1) gained mixture, 15 DEG C are cooled to, stirring and crystallizing 1.5 hours;
(3) by step (2) gained mixture, filter, filter cake is dried to constant weight in 45 ~ 50 DEG C, the obtained methylsulfonic acid dabigatran etcxilate I crystal formation product containing part semihydrate.
The purity of methylsulfonic acid dabigatran etcxilate I crystal formation prepared by this comparative example is 99.67%, moisture content is 2.53% (massfraction).
The obtained methylsulfonic acid dabigatran etcxilate I crystal formation powder x-ray diffraction of this comparative example is as shown in Figure 9: this collection of illustrative plates contains 2 θ corner characteristics peaks of methylsulfonic acid dabigatran etcxilate I crystal formation and methylsulfonic acid dabigatran etcxilate semihydrate powder x-ray diffraction.
Embodiment 1 to embodiment 7 shows with comparative example 1, comparative example 2 comparative result, and methylsulfonic acid dabigatran etcxilate I crystal form purity prepared by preparation method of the present invention is higher.
In order to prove the stability of methylsulfonic acid dabigatran etcxilate quality prepared by the present invention and crystal formation, acceleration June (temperature: 40 DEG C ± 2 DEG C, humidity: 75% ± 5%) test are carried out to the product of embodiment 2, comparative example 1 and comparative example 2.
The product of embodiment 2, comparative example 1 and comparative example 2 carries out accelerating powder x-ray diffraction collection of illustrative plates after June respectively as shown in Figure 10,11,12, result shows, the product of embodiment 2, comparative example 1 and comparative example 2 is after accelerating June, and compare with before acceleration, product crystal formation remains unchanged substantially.
The experimental result that the product of embodiment 2, comparative example 1 and comparative example 2 carries out accelerating after June is as shown in table 1:
Table 1
Table 1 result shows, the methylsulfonic acid dabigatran etcxilate quality that methylsulfonic acid dabigatran etcxilate quality prepared by the embodiment of the present invention 2 is comparatively prepared according to comparative example 1 and comparative example 2 is more stable.
Claims (5)
1. a preparation method for methylsulfonic acid dabigatran etcxilate I crystal formation, is characterized in that, comprise the steps:
(1) under room temperature, joined by dabigatran etcxilate in acetone, wherein, acetone volumetric usage is 5 ~ 50 times of dabigatran etcxilate quality; Being warming up to 30 ~ 56 DEG C makes dabigatran etcxilate dissolve completely; Then be cooled to 25 ~ 40 DEG C, keep temperature 25 ~ 40 DEG C, add methylsulfonic acid acetone soln, mix;
(2) by step (1) gained mixture, 0 ~ 25 DEG C is cooled to, stirring and crystallizing 1 ~ 10 hour;
(3) filtration step (2) gained mixture, joins filter cake in esters solvent or ether solvent, is warming up to 45 ~ 78 DEG C, keeps temperature 45 ~ 78 DEG C, stirs 1 ~ 5 hour;
(4) by step (3) gained mixture, 0 ~ 30 DEG C is cooled to, stirring and crystallizing 1 ~ 5 hour;
(5) filtration step (4) gained mixture, is dried to constant weight by filter cake in 30 ~ 80 DEG C, obtained methylsulfonic acid dabigatran etcxilate I crystal formation product.
2. preparation method according to claim 1, it is characterized in that, step (3) described esters solvent be selected from ethyl formate, propyl formate, isopropyl formate, n-buty formate, tetryl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, n-butyl propionate and isobutyl propionate one or more.
3. preparation method according to claim 1, it is characterized in that, ether solvent described in step (3) be selected from dipropyl ether, diisopropyl ether, ethyl propyl ether, methyl tertiary butyl ether, methyl n-butyl ether, ethyl n-butyl ether, tetrahydrofuran (THF) and Isosorbide-5-Nitrae-dioxane one or more.
4. preparation method according to claim 1, is characterized in that, 5 ~ 30 times that the esters solvent described in step (3) or ether solvent volumetric usage are dabigatran etcxilate quality described in step (1).
5. the preparation method according to any one of claim 1-4, is characterized in that, prepared methylsulfonic acid dabigatran etcxilate I crystal formation crystal, and its powder x-ray diffraction 2 θ corner characteristics peak is as follows:
4.48、9.00、9.30、9.62、10.58、11.00、12.77、13.46、14.26、15.92、16.54、17.70、18.08、18.60、20.30、20.50、21.14、22.06、22.92、24.20、25.11、25.94、26.22、26.54、26.88、27.54、27.66、28.02、29.08、29.28。
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| CN108570035A (en) * | 2018-07-01 | 2018-09-25 | 李万强 | A kind of method of purification of dabigatran etexilate methanesulfonate |
| JP2020193184A (en) * | 2019-05-30 | 2020-12-03 | ダイト株式会社 | Method for preparing form i of dabigatran etexilate methanesulphonate |
| CN114380793A (en) * | 2020-10-20 | 2022-04-22 | 北京澳合药物研究院有限公司 | Preparation method and application of dabigatran etexilate mesylate crystal form I |
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| EP2835370A1 (en) * | 2013-08-08 | 2015-02-11 | Medichem, S.A. | New crystals of dabigatran etexilate mesylate |
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| JP2020193184A (en) * | 2019-05-30 | 2020-12-03 | ダイト株式会社 | Method for preparing form i of dabigatran etexilate methanesulphonate |
| CN114380793A (en) * | 2020-10-20 | 2022-04-22 | 北京澳合药物研究院有限公司 | Preparation method and application of dabigatran etexilate mesylate crystal form I |
| CN114380793B (en) * | 2020-10-20 | 2024-02-23 | 北京澳合药物研究院有限公司 | Preparation method and application of dabigatran etexilate mesylate crystal form I |
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