CN102633777B - Dabigatran etexilate 2-ketoglutarate as well as preparation method and application thereof - Google Patents
Dabigatran etexilate 2-ketoglutarate as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention provides dabigatran etexilate 2-ketoglutarate shown in a general formula (I), hydrate and/or a solvate thereof. In the formula (I), n is 1, 2 or 3. The invention also provides a preparation method of dabigatran etexilate 2-ketoglutarate as well as hydrate and/or the solvate thereof and application in preparation of medicaments for treating or preventing cardiovascular diseases.
Description
Technical field
The present invention relates to a kind of acid salt of dabigatran etcxilate, be specifically related to a kind of dabigatran etcxilate 2-oxoglutaric acid salt and its preparation method and application.
Background technology
Dabigatran (Dabigatran) is a kind of anti-coagulant of innovation, and thin blood medicine of new generation, on pharmacosystematics, belongs to " direct thrombin inhibitor " (Direct Thrombin Inhibitors, DTI).At present medical circle studies confirm that the effect that " dabigatran " brought into play in multinomial clinical indication, it likely replace belong to old-fashioned thin blood medicine " warfarin " (warfarin), become in most of cases for anticoagulant choice drug.
" dabigatran " enters human body with the form oral administration of its premedicant " dabigatran etcxilate " (dabigatran etexilate)." dabigatran etcxilate " researched and developed by German Boehringer Ingelheim, and in 2008, in Europe listing, commodity were called " Pradaxa ", and Canadian commodity are called " Pradax ".The Hong Kong Chinese commodity of " Pradaxa " are " hundred reach life " by name, and the Chinese trade name in China's Mainland and Taiwan is just in application audit.At present, existing 75 countries and regions are ratified it and be take " Pradaxa " as trade(brand)name list marketing.FDA (Food and Drug Adminstration) (FDA) ratified dabigatran etcxilate (a kind of oral direct thrombin inhibitor) for non-valvular Patients With Atrial Fibrillation (AF), to reduce the risk of its generation palsy and general blood vessel embolism on September 20th, 2010.
Dabigatran etcxilate (DABIGATRAN ETEXILATE) is a kind of benzimidazoles compound of replacement, chemical name 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate, its molecular structural formula is as follows:
Molecular formula: C
34h
41n
7o
5, molecular weight: 627.74.
The solubleness of dabigatran etcxilate in water is less, and under the impact of pharmaceutical excipient and preventing, it is not easy to stripping in pharmaceutical preparation, and the preparation of pharmaceutical preparation is subject to many limitations.In addition, the dabigatran etcxilate mesylate having gone on the market (referring to Chinese patent CN1675193A) has the defects such as less stable, bioavailability be low, therefore need to find the compound that is more suitable for medicinal dabigatran etcxilate, to meet the demand of market and relative disease preventing and controlling.
Summary of the invention
Therefore, the object of the invention is to overcome the defect such as poor stability, the bioavailability of dabigatran etcxilate and existing compound thereof be low, a kind of stability is better, water-soluble more greatly, bioavailability is higher dabigatran etcxilate 2-oxoglutaric acid salt and hydrate and/or solvate are provided, and their preparation method and application.
Term as used herein " solvate ", refers to the crystallized form that comprises one or more organic solvent molecules in periodicity three-dimensional arrangement.
The phrase " pharmaceutically acceptable " using herein, refers in the scope of rational medicine judgement and is applicable to contact with the tissue of the mankind or animal compound, material, composition and/or the formulation that there is no excessive toxicity, pungency, anaphylaxis or other problem or complication simultaneously and have rational benefit/risk ratio.
The invention provides a kind of general formula following dabigatran etcxilate 2-oxoglutaric acid salt, its hydrate and/or solvate:
Wherein, n is 1,2 or 3.
According to dabigatran etcxilate 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvate, wherein, in the hydrate of dabigatran etcxilate 2-oxoglutaric acid salt, can contain the water of 0.5～10 molecule described in per molecule, can be preferably the water that contains 0.5～2 molecule.Described in per molecule, in the solvate of dabigatran etcxilate 2-oxoglutaric acid salt, can contain the solvent of 0.5～10 molecule, can be preferably the solvent that contains 0.5～2 molecule.
For example, the hydrate of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention can be semihydrate, monohydrate, sesqui hydrate, dihydrate, two times of semihydrates, trihydrate, three times of semihydrates, tetrahydrate, four times of semihydrates, pentahydrate, five times of semihydrates, hexahydrate, six times of semihydrates, heptahydrate, seven times of semihydrates, eight hydrates, octuple semihydrate, nonahydrate, nine times of semihydrates or decahydrate.Again for example, the solvate of the dabigatran etcxilate 2-oxoglutaric acid salt of per molecule can contain the solvent of half molecule, 1 molecule, 1.5 molecules, 2 molecules, 2.5 molecules, 3 molecules, 3.5 molecules, 4 molecules, 4.5 molecules, 5 molecules, 5.5 molecules, 6 molecules, 6.5 molecules, 7 molecules, 7.5 molecules, 8 molecules, 8.5 molecules, 9 molecules, 9.5 molecules or 10 molecules.
Should illustrate, hydrate or the solvate of the above-mentioned dabigatran etcxilate 2-oxoglutaric acid salt of the present invention of enumerating, it is mainly a kind of existence form that dabigatran etcxilate 2-oxoglutaric acid salt of the present invention produces in crystallization or purge process, the crystal water that it is contained or crystallization organic solvent normally can be controlled or remove, such as can crystal water or crystallization organic solvent being removed by modes such as heating calcination or calcinings.Therefore, the hydrate of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention and solvate still belong to the content of technical scheme content of the present invention and scope of patent protection.
According to dabigatran etcxilate 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvate, wherein, described solvate can be one or more in alcohol solvent compound, methanol solvate compound, acetone solvate, acetonitrile solvate, ethyl acetate solvent compound, tetrahydrofuran solvate and ether solvent compound.
According to dabigatran etcxilate 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvate, wherein, in described hydrate, more than dabigatran etcxilate 2-oxoglutaric acid salt can account for 95wt%, more than can being preferably 98wt%, more preferably more than 99wt%.In described solvate, more than dabigatran etcxilate 2-oxoglutaric acid salt can account for 95wt%, more than can being preferably 98wt%, more preferably more than 99wt%.
The present invention also provides the method for preparing dabigatran etcxilate 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvate, the method can comprise: dabigatran etcxilate and 2-oxoglutaric acid are mixed to salify crystallization in water or the first organic solvent, after washing after filtration,, being dried, make water or the second organic solvent carry out recrystallization, make described dabigatran etcxilate 2-oxoglutaric acid salt, its hydrate or solvate.Those skilled in the art can be as required, by conventional means, as reduced Tc or steam except partial solvent etc., to accelerate the formation of crystallization.
The method according to this invention, wherein, the step of described mixing salify can be carried out at 0 ℃ to the reflux temperature of water or the first organic solvent, can be preferably at 0～30 ℃ and carry out.As preferably, the step of described crystallization can be carried out in room temperature or under lower than the condition of room temperature, can be preferably at 0～20 ℃ and carry out.Described the first organic solvent and the second organic solvent are identical or different, can be selected from ethanol, methyl alcohol, propyl alcohol, Virahol, butanols, ethyl formate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, glycol dimethyl ether, methyl tert-butyl ether, tetrahydrofuran (THF), sherwood oil, acetonitrile, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, toluene, N,N-DIMETHYLACETAMIDE or dimethylbenzene.
The method according to this invention, wherein, the mol ratio of described dabigatran etcxilate and described 2-oxoglutaric acid can be 10: 1～1: 10.This mol ratio can be preferably 3: 1～1: 3.
The present invention also provides a kind of pharmaceutical composition, this pharmaceutical composition comprises dabigatran etcxilate 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvate, or comprise dabigatran etcxilate 2-oxoglutaric acid salt, its hydrate and/or the solvate making according to method of the present invention, and pharmaceutically acceptable auxiliary material.
Described pharmaceutical composition can comprise dabigatran etcxilate 2-oxoglutaric acid salt of the present invention as active substance wherein, can also comprise the material that other has pharmaceutical active simultaneously, with the pharmaceutical composition that forms a kind of compound for combination therapy.
When dabigatran etcxilate 2-oxoglutaric acid salt of the present invention is used for the treatment of as activeconstituents, generally directly do not give patient simple chemical, the form that is all conventionally the pharmaceutical composition that contains pharmaceutically acceptable auxiliary material occurs.Dabigatran etcxilate 2-oxoglutaric acid salt of the present invention also can be by the administration of any appropriate, conventionally can be oral or parenteral route, so, the pharmaceutically acceptable auxiliary material that those skilled in the art also can select pharmaceutical composition to comprise according to required form of medication.
Be to be understood that, according to method well known in the art, pharmaceutically acceptable auxiliary material can be matrix or the auxiliary material that keeps pharmaceutical dosage form, conventionally according to different medicaments, select or be used in combination, optionally comprise vehicle, for example one or more in Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, propylene glycol, glycerine, cyclodextrin, cyclodextrin derivative etc.; Can also comprise tackiness agent, for example one or more in polyvidone (polyvinylpyrrolidone), methylcellulose gum, Walocel MT 20.000PV, HPMC, hydroxypropylcellulose, Natvosol, gelatin, guar gum, xanthan gum etc.; Also comprise lubricant, for example one or more in Magnesium Stearate, stearic acid, talcum powder, stearyl fumarate, Sodium Lauryl Sulphate BP/USP etc.; Can also comprise disintegrating agent, one or more in sodium starch glycolate, low-substituted hydroxypropyl cellulose, Xylo-Mucine, cross-linked polyvinylpyrrolidone, croscarmellose sodium, crosslinked carboxymethyl fecula sodium, pregelatinized Starch for example, etc.; Also comprise tensio-active agent, one or more of sodium lauryl sulphate, Tween-80 for example, etc.; Can also comprise pH value conditioning agent or buffer reagent, one or more of phosphate buffered saline buffer, citric acid, Trisodium Citrate, acetate buffer, dilute hydrochloric acid, sodium carbonate, sodium hydroxide for example, etc.; Can also comprise sanitas, one or more in Sodium Benzoate, potassium sorbate, methyl p-hydroxybenzoate, propylparaben for example, etc.; Can also comprise stablizer and oxidation inhibitor, one or more in Calcium Disodium Edetate, S-WAT, vitamins C for example, etc.; Can also comprise taste conditioning agent, one or more in maltose alcohol, fructose, sucrose, soluble saccharin, orange essence, strawberry flavour for example, etc.; Can also comprise in addition additive other routines, appropriate.
In addition,, when pharmaceutical dosage form is tablet or capsule, pharmaceutically acceptable auxiliary material can also comprise film dressing.For the material of film dressing, comprise applicable Drug coating, for example HPMC, Natvosol, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, etc.; Can also comprise softening agent, for example polyoxyethylene glycol, triethyl citrate, etc.; Also comprise suitable solubilizing agent, as Tween-80; Can also comprise suitable pigment, as titanium dioxide, various ferric oxide, pink pigment, etc.
According to pharmaceutical composition of the present invention, described pharmaceutical composition can be tablet, hard capsule, soft capsule, pill, granule, pellet or oral fluid agent.
Pharmaceutical composition of the present invention can be prepared as acceptable any pharmaceutical dosage form in pharmaceutics as required, as oral preparations, injection formulations, parenteral liquid preparation, etc.; As oral tablet, capsule, granule, oral solution, powder agent, pill, sublingual administration agent, etc.; And for example injection, comprises powder ampoule agent for injection and injection liquid, etc., the emulsion of parenteral eye drop, nasal drops, [Dan, Transdermal absorption for another example, etc.Also can be the formulation such as quick-release, slowly-releasing, controlled release of above various formulations, for example oral dispersible tablet, slow releasing tablet, chewable tablet, slow releasing capsule, enteric coated tablet, effervescent tablet, orally disintegrating tablet, Special-shaped sheet, effervescent granule, etc.Especially, by means known in the art preparation, be preferred for preparing tablet edible in pharmaceutics (comprising dispersible tablet, slow releasing tablet, chewable tablet, enteric coated tablet, orally disintegrating tablet, Special-shaped sheet), capsule (comprise that stomach is molten, enteric, slow releasing capsule), granule, oral solution, injection (comprising powder ampoule agent for injection and injection liquid) etc., to meet the various needs in clinical use.
According to pharmaceutical composition of the present invention, wherein, in described pharmaceutical composition, the weight ratio of described dabigatran etcxilate 2-oxoglutaric acid salt and described pharmaceutically acceptable auxiliary material can be 1: 1～5, can be preferably 1: 1～and 2.The content of dabigatran etcxilate 2-oxoglutaric acid salt in pharmaceutical composition can be 0.1～100mg, can be for example 0.1mg, 0.5mg, 1mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg or 150mg, etc.
The present invention also provides dabigatran etcxilate 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvate, or the dabigatran etcxilate 2-oxoglutaric acid salt, its hydrate and/or the solvate that according to method of the present invention, make, the application in the medicine for the preparation for the treatment of or preventing cardiovascular disease.Can be preferably the application in the medicine for the preparation for the treatment of or prevention phlebothrombosis or acute coronary syndrome.
Dabigatran etcxilate 2-oxoglutaric acid salt provided by the present invention, its hydrate and/or solvate have higher liberation degree, and its water-soluble acquisition is greatly improved.This can make dissolution process rapider on the one hand, also can reduce on the other hand the amount of required aqueous solvent.In addition, dabigatran etcxilate 2-oxoglutaric acid salt of the present invention and hydrate thereof and solvate also have higher stability and bioavailability.
When being prepared as pharmaceutically active substances or preparation, storage and application galenical, the improvement of above biochemical property is very important, this quality that can guarantee galenical is higher, and its high stability also makes the procedure of processing of post-processed simpler, has reduced production cost.And its high crystalline can be used such as analytical procedures such as X-ray diffractions the release of its hydrate or solvate is carried out to simple and clear analysis, to carry out appropriate selection.For the galenical of these factors during for the quality of active substance and for preparation, storage and administration, be all very important.In addition, because the activeconstituents in galenical is more stable, thereby can avoid complicated preparation work.
The operation of use physical-chemical, processes as galenics such as dry, screening, grinding and medicament figurations, comprises combination treatment, granulation, spray-drying, compressing tablet etc., can make active substance absorb or loss moisture.This is also subject to temperature in its environment of living in and the impact of relative humidity.Under the situation of some preparations of preparation, the relating operation that free-water can be introduced into in conjunction with water or process because of preparation together with vehicle adds water in handled material.Therefore,, under differing temps and relative humidity, pharmaceutically active substances can contact with free-water within quite long period.In the case, dabigatran etcxilate 2-oxoglutaric acid salt of the present invention does not show measurable moisture absorption or loss, therefore this stability is conducive to the final stage of its chemical preparation, also the treatment stage of being conducive to the galenic of different dosage form, and its stable lasting validity is of value to patient equally.
Meanwhile, dabigatran etcxilate 2-oxoglutaric acid salt of the present invention also has better solvability or compressibility, thereby is more suitable for being directly compressed into corresponding tablet formulation or capsule.
In addition, dabigatran etcxilate 2-oxoglutaric acid salt of the present invention also has better chemical stability, owing to containing aliphatic amide structure in dabigatran ester molecular structure, easily oxidized, can increase the stability of dabigatran etcxilate after salify.This salt also may have advantages of avoiding or reduce other activeconstituents degraded.
With Compound Phase ratio well known in the prior art, described salt also has more effectively, toxicity is lower, action time is longer, field of activity is wider, effect is higher, side effect still less, the advantage or other the useful pharmacological property that more easily absorb.
More specifically, dabigatran etcxilate 2-oxoglutaric acid salt of the present invention and hydrate thereof and/or solvate also have but are not limited to following beneficial effect:
1), with respect to dabigatran etcxilate mesylate, dabigatran etcxilate 2-oxoglutaric acid salt provided by the present invention has satisfactory stability.For example, dabigatran etcxilate mesylate was degraded to 50% left and right at 10 days under super-humid conditions, and dabigatran etcxilate 2-oxoglutaric acid salt is almost without content.
2) dabigatran etcxilate 2-oxoglutaric acid salt of the present invention has water-solublely preferably, through test, confirms, its solubleness in water can reach 2.3mg/ml H
2o (25 ℃ of temperature), and dabigatran etcxilate pH value be greater than 4 o'clock almost insoluble,, dabigatran etcxilate mesylate is 1.8mg/ml.Thereby dabigatran etcxilate 2-oxoglutaric acid salt of the present invention has the bioavailability better or at least suitable compared with dabigatran etcxilate mesylate.
3) the application's dabigatran etcxilate 2-oxoglutaric acid salt also has good mobility and compressibility.Contriver carries out mobility and compressibility mensuration to dabigatran etcxilate 2-oxoglutaric acid salt of the present invention and dabigatran etcxilate mesylate respectively, and it the results are shown in following table 1.
The mobility of table 1 dabigatran etcxilate 2-oxoglutaric acid salt and dabigatran etcxilate mesylate and compressibility are measured
Wherein, the mobility of powder is general main to be weighed with slope of repose, and slope of repose is less, and mobility is better.Conventional θ≤30 ° good fluidity, θ≤40 ° can meet need of production.Loose density refers to that powder quality is divided by the shared volume of a container of this powder, the density of trying to achieve.Its volume used comprises the cumulative volume in space between the hole of particle itself and particle.What loose density was large is heavy, and what loose density was little is lightweight, and the less pressure of the large use of loose density just can moulding, shows that compressibility is good.Gu density be after certain speed and time are knocked vibrations powder quality divided by the shared volume of a container of this powder, the density of trying to achieve.Gu density value shows greatly good fluidity.The less compressibility of compression ratio is better, is generally less than 0.2 and can meets need of production.Above data show, dabigatran etcxilate 2-oxoglutaric acid salt of the present invention all shows better mobility and compressibility on indices with respect to dabigatran etcxilate mesylate, thereby is more suitable for the scale operation of medicine.
Embodiment
Below by specific embodiment, further illustrate the present invention, still, should be understood to, these embodiment are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.
General description is carried out to the material and the test method that use in the present invention's test in this part.Although be well known in the art for realizing many materials and the working method that the object of the invention used, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that in context, if not specified, material therefor of the present invention and working method are well known in the art.
If no special instructions, the mass spectrograph using in following examples is Agientl 100 type level Four bar LC-MS instrument, and the nuclear magnetic resonance analyser of using is Bruker ARX-400NMR type nuclear magnetic resonance analyser.
embodiment 1
The present embodiment is for illustrating the preparation of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention.
The 2-oxoglutaric acid of the dabigatran etcxilate of 1.6mmol and 1.6mmol is joined in the dehydrated alcohol of 20ml at 20 ℃, 6 hours salifies of mix and blend, then crystallization at 20 ℃, filter, the washing of use ethyl acetate, after drying, add ether to carry out recrystallization, obtain the ether solvent compound of the dabigatran etcxilate 2-oxoglutaric acid salt of 0.310g.Record ESI-MS (electron spray ionisation-mass spectrum) (m/z): 811[M+H]
+.
Above-mentioned ether solvent compound is dried, obtains the dabigatran etcxilate 2-oxoglutaric acid salt 0.296g of white solid, as calculated, in above-mentioned ether solvent compound, the content of dabigatran etcxilate 2-oxoglutaric acid salt is 95.4wt%.The ether that contains 0.5 molecule in this ether solvent compound of per molecule.
Above-mentioned dabigatran etcxilate 2-oxoglutaric acid salt is measured:
ESI-MS(m/z)：774[M+H]
+
1H?NMR(DMAO-d
6，400MHz)δ：0.84(t，J＝9.0Hz，3H，CH
3)，1.09(t，J＝8.4Hz，3H，CH
3)，1.28-1.32(m，6H，CH
2CH
2CH
2)，1.55-1.60(m，2H，CH
2)，2.41-2.48(m，2H，CH
2)，2.66(t，J＝14.4Hz，2H，CH
2)，2.88-2.92(m，2H，CH
2)，3.76(s，3H，CH
3)，3.94-4.04(m，4H，2CH
2)，4.20(t，J＝14.4Hz，2H，CH
2)，4.60(d，J＝5.6Hz，2H，CH
2)，6.76(d，J＝8.8Hz，2H，ArH)，6.87(d，J＝7.6Hz，1H，ArH)，7.01-7.16(m，3H，ArH)，7.38(d，J＝8.6Hz，1H，ArH)，7.46(s，1H，ArH)，7.51(dt，J＝10.4Hz，J＝1.6Hz，1H，ArH)，7.75(d，J＝8.6Hz，2H，ArH)，8.37(d，J＝4.0Hz，1H，ArH)，9.31(br，2H，NH
2)。
Fusing point: 142-143 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/nC
4H
6O
5
Discovery value: C 60.53 N12.67 H6.12 O20.68
Calculate: n=1
Therefore the molecular structural formula of prepared dabigatran etcxilate 2-oxoglutaric acid salt is:
embodiment 2
The present embodiment is for illustrating the preparation of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention.
The 2-oxoglutaric acid of the dabigatran etcxilate of 3.2mmol and 1.6mmol is joined in 20ml water at 30 ℃, 6 hours salifies of mix and blend, then crystallization at 30 ℃, filter, the washing of use ethyl acetate, after drying, add water to carry out recrystallization, obtain the hydrate of the dabigatran etcxilate 2-oxoglutaric acid salt of 0.450g.Record ESI-MS (m/z): 719[M+H]
+.
Above-mentioned hydrate is dried, obtains the dabigatran etcxilate 2-oxoglutaric acid salt 0.439g of white solid, as calculated, in above-mentioned hydrate, the content of dabigatran etcxilate 2-oxoglutaric acid salt is 97.5wt%.The water that contains 1 molecule in this hydrate of per molecule, i.e. monohydrate.
Above-mentioned dabigatran etcxilate 2-oxoglutaric acid salt is measured:
ESI-MS(m/z)：701[M+H]
+
1H?NMR(DMAO-d
6，400MHz)δ：0.84(t，J＝9.0Hz，3H，CH
3)，1.09(t，J＝8.4Hz，3H，CH
3)，1.28-1.32(m，6H，CH
2CH
2CH
2)，1.55-1.60(m，2H，CH
2)，2.41-2.48(m，1H，CH
2)，2.66(t，J＝14.4Hz，1H，CH
2)，2.88-2.92(m，2H，CH
2)，3.76(s，3H，CH
3)，3.94-4.04(m，4H，2CH
2)，4.20(t，J＝14.4Hz，2H，CH
2)，4.60(d，J＝5.6Hz，2H，CH
2)，6.76(d，J＝8.8Hz，2H，ArH)，6.87(d，J＝7.6Hz，1H，ArH)，7.01-7.16(m，3H，ArH)，7.38(d，J＝8.6Hz，1H，ArH)，7.46(s，1H，ArH)，7.51(dt，J＝10.4Hz，J＝1.6Hz，1H，ArH)，7.75(d，J＝8.6Hz，2H，ArH)，8.37(d，J＝4.0Hz，1H，ArH)，9.31(br，2H，NH
2)。
Fusing point: 135-136 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/nC
4H
6O
5
Discovery value: C 62.56 N13.99 H6.33 O17.12
Calculate: n=2
Therefore the molecular structural formula of prepared dabigatran etcxilate 2-oxoglutaric acid salt is:
embodiment 3
The present embodiment is for illustrating the preparation of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention.
The 2-oxoglutaric acid of the dabigatran etcxilate of 4.8mmol and 1.6mmol is joined in 20ml dehydrated alcohol at 0 ℃, 6 hours salifies of mix and blend, then crystallization at 0 ℃, filter, the washing of use ethyl acetate, after drying, add glycol dimethyl ether to carry out recrystallization, obtain the dabigatran etcxilate 2-oxoglutaric acid salt 0.420g of white solid.
Above-mentioned dabigatran etcxilate 2-oxoglutaric acid salt is measured:
ESI-MS(m/z)：677[M+H]
+
1H?NMR(DMAO-d
6，400MHz)δ：0.84(t，J＝9.0Hz，3H，CH
3)，1.09(t，J＝8.4Hz，3H，CH
3)，1.28-1.32(m，6H，CH
2CH
2CH
2)，1.55-1.60(m，2H，CH
2)，2.41-2.48(m，0.7H，CH
2)，2.66(t，J＝14.4Hz，0.7H，CH
2)，2.88-2.92(m，2H，CH
2)，3.76(s，3H，CH
3)，3.94-4.04(m，4H，2CH
2)，4.20(t，J＝14.4Hz，2H，CH
2)，4.60(d，J＝5.6Hz，2H，CH
2)，6.76(d，J＝8.8Hz，2H，ArH)，6.87(d，J＝7.6Hz，1H，ArH)，7.01-7.16(m，3H，ArH)，7.38(d，J＝8.6Hz，1H，ArH)，7.46(s，1H，ArH)，7.51(dt，J＝10.4Hz，J＝1.6Hz，1H，ArH)，7.75(d，J＝8.6Hz，2H，ArH)，8.37(d，J＝4.0Hz，1H，ArH)，9.31(br，2H，NH
2)。
Fusing point: 130-131 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/nC
4H
6O
5
Discovery value: C 63.33 N14.49 H6.41 O15.77
Calculate: n=3
Therefore the molecular structural formula of prepared dabigatran etcxilate 2-oxoglutaric acid salt is:
embodiment 4
The present embodiment is for illustrating the preparation of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention.
The 2-oxoglutaric acid of the dabigatran etcxilate of 1.6mmol and 4.8mmol is joined in 20ml anhydrous methanol at 30 ℃, 6 hours salifies of mix and blend, then crystallization at 10 ℃, filter, the washing of use ether, after drying, add tetrahydrofuran (THF) to carry out recrystallization, obtain the tetrahydrofuran solvate of the dabigatran etcxilate 2-oxoglutaric acid salt of 0.350g.Record its ESI-MS (m/z): 810[M+H]
+.
Above-mentioned tetrahydrofuran solvate is dried, obtains the dabigatran etcxilate 2-oxoglutaric acid salt 0.334g of white solid, as calculated, in above-mentioned solvate, the content of dabigatran etcxilate 2-oxoglutaric acid salt is 95.6wt%.The tetrahydrofuran (THF) that contains 0.5 molecule in this tetrahydrofuran solvate of per molecule.
Above-mentioned dabigatran etcxilate 2-oxoglutaric acid salt is measured:
ESI-MS(m/z)：774[M+H]
+。
Fusing point: 141-142 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/nC
4H
6O
5
Discovery value: C 60.53 N12.67 H6.12 O20.68
Calculate: n=1
Therefore the molecular structural formula of prepared dabigatran etcxilate 2-oxoglutaric acid salt is:
embodiment 5
The present embodiment is for illustrating the preparation of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention.
The 2-oxoglutaric acid of the dabigatran etcxilate of 1.6mmol and 3.2mmol is joined at 10 ℃ to 20ml acetone, 6 hours salifies of mix and blend, then crystallization at 10 ℃, filter, the washing of use ether, after drying, add acetone to carry out recrystallization, obtain the acetone solvate of the dabigatran etcxilate 2-oxoglutaric acid salt of 0.460g.Record its ESI-MS (m/z): 803[M+H]
+.
Above-mentioned acetone solvate is dried, obtains the dabigatran etcxilate 2-oxoglutaric acid salt 0.450g of white solid, as calculated, in above-mentioned solvate, the content of dabigatran etcxilate 2-oxoglutaric acid salt is 96.0wt%.The acetone that contains 0.5 molecule in this methanol solvate compound of per molecule.
Above-mentioned dabigatran etcxilate 2-oxoglutaric acid salt is measured:
ESI-MS(m/z)：774[M+H]
+。
Fusing point: 142-143 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/nC
4H
6O
5
Discovery value: C 60.53 N12.67 H6.12 O20.68
Calculate: n=1
Therefore the molecular structural formula of prepared dabigatran etcxilate 2-oxoglutaric acid salt is:
embodiment 6
The present embodiment is for illustrating the preparation of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention.
The 2-oxoglutaric acid of the dabigatran etcxilate of 1.6mmol and 8mmol is joined in 20ml trichloromethane at 30 ℃, 6 hours salifies of mix and blend, then crystallization at 20 ℃, filter, the washing of use ether, after drying, add water to carry out recrystallization, obtain the hydrate of the dabigatran etcxilate 2-oxoglutaric acid salt of 0.440g.Record its ESI-MS (m/z): 784[M+H]
+.
Above-mentioned hydrate is dried, obtains the dabigatran etcxilate 2-oxoglutaric acid salt 0.435g of white solid, as calculated, in above-mentioned hydrate, the content of dabigatran etcxilate 2-oxoglutaric acid salt is 99wt%.The water that contains 0.5 molecule in this hydrate of per molecule, i.e. semihydrate.
Above-mentioned dabigatran etcxilate 2-oxoglutaric acid salt is measured:
ESI-MS(m/z)：774[M+H]
+。
Fusing point: 140-141 ℃
Ultimate analysis:
C
34H
41N
7O
5(627.74)·1/nC
4H
6O
5
Discovery value: C 60.53 N12.67 H6.12 O20.68
Calculate: n=1
Therefore the molecular structural formula of prepared dabigatran etcxilate 2-oxoglutaric acid salt is:
Stability test:
Contriver observes and does assay to the dabigatran etcxilate 2-oxoglutaric acid salt of embodiment 1 and dabigatran etcxilate mesylate under differing temps, humidity and illumination condition, and data are in Table 2 and table 3.
Liquid-phase condition:
Chromatographic column: Agela Venusil MP C18 post (4.6mm * 250mm, 5 μ m) NO:VA952505-0
Moving phase: 0.01molL
-1secondary ammonium phosphate damping fluid-methyl alcohol (40: 60);
Flow velocity: 1mlmin
-1; Detect wavelength: 250nm; Column temperature: 25 ℃; Sample size: 20 μ l
The content of table 2 dabigatran etcxilate 2-oxoglutaric acid salt and dabigatran etcxilate mesylate
Table 2 is that the content of dabigatran etcxilate 2-oxoglutaric acid salt and mesylate is through the contrast of influence factor test-results.Data show, (high temperature, high humidity, illumination) under the same conditions, and the former content temporal evolution is very little, belong to error at measurment scope, and the latter is very unstable under super-humid conditions, especially at 10 days, under super-humid conditions, can be degraded to 50% left and right, show obvious unstable.
The appearance change of table 3 dabigatran etcxilate 2-oxoglutaric acid salt and dabigatran etcxilate mesylate
As known from Table 3, under hot conditions, dabigatran etcxilate 2-oxoglutaric acid salt is almost unchanged, and dabigatran etcxilate mesylate can be observed color and produces in time considerable change.Under super-humid conditions, the former outward appearance is almost constant, shows more stable character, and the latter moisture absorption is serious.
embodiment 7
The present embodiment is for illustrating the preparation of the pharmaceutical composition of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention.
Dabigatran etcxilate 2-oxoglutaric acid salt is crossed to 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.By recipe quantity, take dabigatran etcxilate 2-oxoglutaric acid, Microcrystalline Cellulose and lactose and fully mix, add 1% (weight/volume) hypromellose aqueous solution, softwood processed, sieves, and wet granular processed is dry in 55 ℃.Polyvinylpolypyrrolidone and Magnesium Stearate are added in above-mentioned particle, measure intermediate content, compressing tablet, packing.
embodiment 8
The present embodiment is for illustrating the preparation of the pharmaceutical composition of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention.
Dabigatran etcxilate 2-oxoglutaric acid salt is crossed to 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.By recipe quantity, take dabigatran etcxilate 2-oxoglutaric acid, Microcrystalline Cellulose, pregelatinized Starch and lactose and fully mix, add 1% (weight/volume) hypromellose aqueous solution, softwood processed, sieves, and wet granular processed is dry in 55 ℃.Magnesium Stearate is added in above-mentioned particle, measures intermediate content, encapsulated, packing.
embodiment 9
The present embodiment is for illustrating the preparation of the pharmaceutical composition of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention.
Dabigatran etcxilate 2-oxoglutaric acid salt is crossed to 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.By recipe quantity, taking dabigatran etcxilate 2-oxoglutaric acid salt, lactose, N.F,USP MANNITOL, aspartame, essence fully mixes, add again 2% (weight/volume) hypromellose aqueous solution softwood processed, 16 mesh sieves are granulated, 55 ℃ dry, the whole grain of 14 mesh sieves, measure intermediate content and moisture, packing, makes 100 bags of granules altogether.
embodiment 10
The present embodiment is for illustrating the preparation of the pharmaceutical composition of dabigatran etcxilate 2-oxoglutaric acid salt of the present invention.
Dabigatran etcxilate 2-oxoglutaric acid salt is crossed to 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.By recipe quantity, taking dabigatran etcxilate 2-oxoglutaric acid, polyvidone, aspartame and essence first mixes, fully mix with N.F,USP MANNITOL, Microcrystalline Cellulose and lactose successively again, finally add Magnesium Stearate to mix, measure intermediate content, compressing tablet, packing.
Although the present invention has carried out description to a certain degree, significantly, do not departing under the condition of the spirit and scope of the present invention, can carry out the suitable variation of each condition.Be appreciated that and the invention is not restricted to described embodiment, and be attributed to the scope of claim, it comprises the replacement that is equal to of described each factor.
Claims (7)
1. a preparation method with dabigatran etcxilate 2-oxoglutaric acid salt, its hydrate and/or the solvate of general formula (I) structure: it is characterized in that, the method comprises: dabigatran etcxilate and 2-oxoglutaric acid are mixed to salify crystallization in water or the first organic solvent, after washing after filtration,, being dried, make water or the second organic solvent carry out recrystallization, make described dabigatran etcxilate 2-oxoglutaric acid salt, its hydrate or solvate;
Wherein, n is 1,2 or 3.
2. preparation method according to claim 1, it is characterized in that, described mixing salify carries out to the reflux temperature of water or the first organic solvent at 0 ℃, described the first organic solvent and the second organic solvent are identical or different, be selected from ethanol, methyl alcohol, propyl alcohol, Virahol, butanols, ethyl formate, ethyl acetate, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, glycol dimethyl ether, methyl tert-butyl ether, tetrahydrofuran (THF), sherwood oil, acetonitrile, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, toluene, N,N-DIMETHYLACETAMIDE or dimethylbenzene.
3. preparation method according to claim 2, wherein mixing salify temperature is 0～30 ℃.
4. preparation method according to claim 1, wherein recrystallization temperature is room temperature or lower than room temperature.
5. preparation method according to claim 1, wherein recrystallization temperature is 0～20 ℃.
6. according to the preparation method described in claim 1-5 any one, it is characterized in that, the mol ratio of described dabigatran etcxilate and described 2-oxoglutaric acid is 10:1～1:10.
7. preparation method according to claim 6, wherein the mol ratio of dabigatran etcxilate and described 2-oxoglutaric acid is 3:1～1:3.
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| CN103536535B (en) * | 2013-10-31 | 2015-04-08 | 江苏阿尔法药业有限公司 | Dabigatran etexilate liposome |
| CN105348259A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate oxaloacetate, preparation method and applications thereof |
| CN105348261A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate pyruvate, preparation method and applications thereof |
| CN105348260A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate hydrobromide, preparation method and applications thereof |
| CN105367551A (en) * | 2014-08-19 | 2016-03-02 | 天津药物研究院 | Dabigatran etexilate glycolate, preparation method and applications thereof |
| CN105732584A (en) * | 2014-12-12 | 2016-07-06 | 天津药物研究院有限公司 | Dabigatran etexilate 2-ketoglutarate crystal form I, preparation method and application thereof |
| CN105646531B (en) * | 2016-03-28 | 2017-11-21 | 沈阳工业大学 | Dabigatran cyclic derivatives and its production and use |
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