CN102633777A - 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 ester, be specifically related to a kind of dabigatran ester 2-oxoglutaric acid salt.
Background technology
Dabigatran (Dabigatran) is a kind of anti-coagulant of innovation, i.e. the thin blood medicine of a new generation, on pharmacosystematics, belong to " directly thrombin inhibitors " (Direct Thrombin Inhibitors, DTI).At present medical circle has been studied the effect that confirmations " dabigatran " brought into play in multinomial clinical indication, and " warfarin " that it might replace the old-fashioned thin blood medicine of genus (warfarin) becomes and be used for anticoagulant choice drug in most of cases.
" dabigatran " gets into human body with the form oral administration of its premedicant " dabigatran ester " (dabigatran etexilate)." dabigatran ester " researched and developed by German Boehringer Ingelheim, and in the listing in Europe in 2008, commodity were called " Pradaxa ", and Canadian commodity are called " Pradax ".Hong Kong Chinese commodity of " Pradaxa " are " hundred reach life " by name then, and the Chinese trade name in China's Mainland and Taiwan is just in the application audit.At present, it is the trade(brand)name list marketing with " Pradaxa " to have 75 countries and regions approvals.Approval was used for non-valve property atrial fibrillation patient (AF) with dabigatran ester (a kind of oral direct thrombin inhibitors) on September 20th, 2010 in FDA (Food and Drug Adminstration) (FDA), to reduce the risk that palsy and general blood vessel embolism take place for it.
Dabigatran ester (DABIGATRAN ETEXILATE) is a kind of substituted benzimidazoles compound; 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 following:
Molecular formula: C
34H
41N
7O
5, molecular weight: 627.74.
The solubleness of dabigatran ester in water is less, and in the influence of pharmaceutical excipient with prevent down, it is not easy to stripping in pharmaceutical prepn, the preparation of pharmaceutical prepn is subject to many limitations.In addition; The dabigatran ester mesylate (seeing also Chinese patent CN1675193A) that has gone on the market has defectives such as less stable, bioavailability be low; Therefore need to seek the compound that is more suitable for medicinal dabigatran ester, to satisfy the demand of market and relative disease preventing and controlling.
Summary of the invention
Therefore; The objective of the invention is to overcome defective such as poor stability, the bioavailability of dabigatran ester and existing compound thereof be low; A kind of stability is better, water-soluble more greatly, bioavailability is higher dabigatran ester 2-oxoglutaric acid salt and hydrate and/or solvolyte are provided, and their preparation method and application.
Term as used herein " solvolyte " refers to the crystallized form that in the periodicity three-dimensional arrangement, comprises one or more organic solvent molecules.
The employed phrase of this paper " pharmaceutically acceptable " refers to and in the scope that rational medicine is judged, is applicable to and contacts compound, material, compsn and/or the formulation that does not have over-drastic toxicity, pungency, anaphylaxis or other problem or complication simultaneously and have rational benefit/risk ratio with the tissue of the mankind or animal.
The invention provides a kind of general formula following dabigatran ester 2-oxoglutaric acid salt, its hydrate and/or solvolyte:
Wherein, n is 1,2 or 3.
According to dabigatran ester 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvolyte, wherein, can contain the water of 0.5～10 molecule in the hydrate of the said dabigatran ester of per molecule 2-oxoglutaric acid salt, can be preferably the water that contains 0.5～2 molecule.The solvent of 0.5～10 molecule can be contained in the solvolyte of the said dabigatran ester of per molecule 2-oxoglutaric acid salt, the solvent that contains 0.5～2 molecule can be preferably.
For example, the hydrate of dabigatran ester 2-oxoglutaric acid salt of the present invention can be semihydrate, monohydrate, sesqui hydrate, duohydrate, two sesquialter hydrates, trihydrate, three sesquialter hydrates, tetrahydrate, four sesquialter hydrates, pentahydrate, five sesquialter hydrates, hexahydrate, six sesquialter hydrates, heptahydrate, seven sesquialter hydrates, eight hydrates, octuple semihydrate, nonahydrate, nine sesquialter hydrate or decahydrates.Again for example, the solvolyte of the dabigatran ester 2-oxoglutaric acid salt of per molecule can contain the solvent of half point, 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 explain; The hydrate or the solvolyte of the above-mentioned dabigatran ester 2-oxoglutaric acid salt of enumerating of the present invention; It mainly is a kind of existence form that dabigatran ester 2-oxoglutaric acid salt of the present invention produces in crystallization or purge process; Crystal water that it contained or crystallization organic solvent normally can be controlled or remove, and for example can crystal water or crystallization organic solvent removed through modes such as heating calcination or calcinings.Therefore, the hydrate of dabigatran ester 2-oxoglutaric acid salt of the present invention and solvolyte still belong to the content of technical scheme content of the present invention and scope of patent protection.
According to dabigatran ester 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvolyte; Wherein, said solvolyte can be in alcohol solvent compound, methanol solvate thing, acetone solvate, acetonitrile solvate, ethyl acetate solvent thing, tetrahydrofuran solvate and the ether solvent thing one or more.
According to dabigatran ester 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvolyte; Wherein, in said hydrate, dabigatran ester 2-oxoglutaric acid salt can account for more than the 95wt%; Can be preferably more than the 98wt%, more preferably more than the 99wt%.In said solvolyte, dabigatran ester 2-oxoglutaric acid salt can account for more than the 95wt%, can be preferably more than the 98wt%, more preferably more than the 99wt%.
The present invention also provides the method for preparing dabigatran ester 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvolyte; This method can comprise: dabigatran ester and 2-oxoglutaric acid are mixed salify and crystallization in the water or first organic solvent; After filtration, washing, drying; Make the water or second organic solvent carry out recrystallization, make said dabigatran ester 2-oxoglutaric acid salt, its hydrate or solvolyte.Those skilled in the art can through conventional means, remove partial solvent etc. like reduction Tc or steaming, with the formation of accelerate crystallisation as required.
According to the method for the invention, wherein, the salifiable step of said mixing can be carried out to the reflux temperature of the water or first organic solvent at 0 ℃, can be preferably under 0～30 ℃ and carry out.As preferably, the step of said crystallization can be carried out under room temperature or subambient condition, can be preferably under 0～20 ℃ and carry out.Said first organic solvent and second organic solvent are identical or different, can be selected from ethanol, methyl alcohol, propyl alcohol, Virahol, butanols, ethyl formate, ETHYLE ACETATE, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, glycol dimethyl ether, methyl tert-butyl ether, THF, sherwood oil, acetonitrile, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, toluene, N,N-DIMETHYLACETAMIDE or YLENE.
According to the method for the invention, wherein, the mol ratio of said dabigatran ester and said 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 ester 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvolyte; Or comprise dabigatran ester 2-oxoglutaric acid salt, its hydrate and/or the solvolyte that makes according to method of the present invention, and acceptable accessories.
Said pharmaceutical composition can comprise dabigatran ester 2-oxoglutaric acid salt conduct of the present invention active substance wherein, can also comprise the material that other has pharmaceutical active simultaneously, is used for combination therapy with the pharmaceutical composition that forms a kind of compound.
When dabigatran ester 2-oxoglutaric acid salt of the present invention is used to treat as activeconstituents, generally directly not giving the patient simple chemical, all is the form appearance with the pharmaceutical composition that contains acceptable accessories usually.Dabigatran ester 2-oxoglutaric acid salt of the present invention also can be through the administration of any appropriate; Usually can be oral or parenteral route; So those skilled in the art also can select the acceptable accessories that pharmaceutical composition comprised according to required form of medication.
Be to be understood that; According to method well known in the art; Acceptable accessories can be matrix or the auxiliary material that keeps pharmaceutical dosage form; Usually select or make up use for use according to different medicaments; Optionally comprise vehicle, for example one or more in Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, Expex, N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, Ucar 35, glycerine, Schardinger dextrins, the cyclodextrin derivative or the like; Can also comprise tackiness agent, for example one or more in polyvidone (Vinylpyrrolidone polymer), methylcellulose gum, Walocel MT 20.000PV, HPMC, hydroxypropylcellulose, Natvosol, gelatin, X 5363, the XG 550 or the like; Also comprise lubricant, for example one or more in Magnesium Stearate, Triple Pressed Stearic Acid, talcum powder, stearyl fumarate, the Sodium Lauryl Sulphate BP/USP or the like; Can also comprise disintegrating agent; One or more in sodium starch glycolate, low-substituted hydroxypropyl cellulose, Xylo-Mucine, cross-linked polyvinylpyrrolidone, Sodium Croscarmellose, crosslinked carboxymethyl fecula sodium, the pregelatinized Starch for example, or the like; Also comprise tensio-active agent, one or more of sodium lauryl sulphate, Tween-80 for example, or the like; Can also comprise pH value regulator or buffer reagent, one or more of phosphate buffered saline buffer, Hydrocerol A, Trisodium Citrate, acetate buffer, Hydrogen chloride, yellow soda ash, sodium hydroxide for example, or the like; Can also comprise sanitas, one or more in Sodium Benzoate, POTASSIUM SORBATE GRANULAR WHITE, methyl paraben, the propylben for example, or the like; Can also comprise stablizer and oxidation inhibitor, one or more in Calcium Disodium Edetate, S-WAT, the vitamins C for example, or the like; Can also comprise the taste regulator, one or more in maltose alcohol, fructose, sucrose, soluble saccharin, orange essence, the strawberry flavour for example, or the like; Can also comprise other conventional, appropriate additives in addition.
In addition, when pharmaceutical dosage form was tablet or capsule, acceptable accessories can also comprise the film dressing.The material that is used for the film dressing comprises suitable seed dressing agent, for example HPMC, Natvosol, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, or the like; Can also comprise softening agent, for example polyoxyethylene glycol, triethyl citrate, or the like; Also comprise suitable solubilizing agent, like Tween-80; Can also comprise suitable pigment, like titanium oxide, various red stone, pink pigment, or the like.
According to pharmaceutical composition of the present invention, said 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 on the pharmaceutics as required, like oral prepns, injection formulations, non-oral liquid preparation, or the like; Like oral tablet, capsule, granule, oral solution, powder agent, pill, sublingual administration agent, or the like; And for example injection comprises powder ampoule agent for injection and injection liquid, or the like, the emulsion of non-for another example oral eye drop, nasal drops, [, Transdermal absorption, or the like.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, or the like.Especially; By the means known in the art preparation; Be preferred for preparing on the pharmaceutics edible tablet (comprising dispersible tablet, slow releasing tablet, chewable tablet, enteric coated tablet, orally disintegrating tablet, special-shaped sheet), capsule (comprise that stomach dissolves, enteric, slow releasing capsule), granule, oral solution, injection (comprising powder ampoule agent for injection and injection liquid) etc., to satisfy the various needs in the clinical use.
According to pharmaceutical composition of the present invention, wherein, in said pharmaceutical composition, the weight ratio of said dabigatran ester 2-oxoglutaric acid salt and said acceptable accessories can be 1: 1～5, can be preferably 1: 1～and 2.The content of dabigatran ester 2-oxoglutaric acid salt in pharmaceutical composition can be 0.1～100mg; For example can be 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, or the like.
The present invention also provides dabigatran ester 2-oxoglutaric acid salt of the present invention, its hydrate and/or solvolyte; Or the dabigatran ester 2-oxoglutaric acid salt, its hydrate and/or the solvolyte that make according to method of the present invention, be used for treating or the application of the medicine of preventing cardiovascular disease in preparation.Can be preferably the application that is used for treating or prevent the medicine of phlebothrombosis or acute coronary syndrome in preparation.
Dabigatran ester 2-oxoglutaric acid salt provided by the present invention, its hydrate and/or solvolyte 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 the amount of required aqueous solvent on the other hand.In addition, dabigatran ester 2-oxoglutaric acid salt of the present invention and hydrate thereof and solvolyte 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 crucial; This quality that can guarantee galenical is higher, and its high stability makes that also the procedure of processing of post-processed is simpler, has reduced production cost.And its high crystalline can use such as analytical procedures such as X-ray diffractions simple and clear analysis is carried out in the release of its hydrate or solvolyte, so that carry out appropriate selection.For the galenical of these factors during, all be very important for the quality of active substance and for preparation, storage and administration.In addition, because the activeconstituents in the galenical is more stable, thereby can avoid complicated preparation work.
The operation of use physical-chemical is handled like galenics such as drying, screening, grinding and medicament figurations, comprises combination treatment, granulation, spraying-drying, compressing tablet etc., active substance is absorbed or loss moisture.This also receives temperature and the influence of relative humidity in its environment of living in.Under the situation of some preparations of preparation, free-water and combination water can add entry with the relating operation that vehicle is introduced into or handles because of preparation in handled material.Therefore, under differing temps and relative humidity, pharmaceutically active substances can contact in quite long period with free-water.In the case; Dabigatran ester 2-oxoglutaric acid salt of the present invention does not show measurable moisture absorption or loss; Therefore this stability helps the final stage of its chemical preparation; The treatment stage of also helping the galenic of different dosage form, and its stable lasting validity is of value to the patient equally.
Simultaneously, dabigatran ester 2-oxoglutaric acid salt of the present invention also has better solvability or compressibility, thereby is more suitable for directly being compressed into corresponding tablet formulation or capsule.
In addition, dabigatran ester 2-oxoglutaric acid salt of the present invention also has better chemicalstability, contains the aliphatic amide structure owing in the dabigatran ester molecular structure, and is oxidized easily, can increase the stability of dabigatran ester behind the salify.This salt also possibly have avoiding or reduce the advantage of other activeconstituents degraded.
Compare said salt also has more effectively, toxicity is lower, action time is longer, field of activity is wider, it is higher to render a service, spinoff still less, more is prone to absorption advantage or other useful pharmacological property with compound well known in the prior art.
More specifically, dabigatran ester 2-oxoglutaric acid salt of the present invention and hydrate thereof and/or solvolyte also have but are not limited to following beneficial effect:
1) with respect to dabigatran ester mesylate, dabigatran ester 2-oxoglutaric acid salt provided by the present invention has satisfactory stability property.For example, dabigatran ester mesylate was degraded to about 50% under the super-humid conditions at 10 days, and dabigatran ester 2-oxoglutaric acid salt does not almost have content.
2) dabigatran ester 2-oxoglutaric acid salt of the present invention has better water solubility, confirms that through test its solubleness in water can reach 2.3mg/ml H
2O (25 ℃ of temperature), and the dabigatran ester is almost insoluble greater than 4 o'clock in the pH value,, dabigatran ester mesylate is 1.8mg/ml.Thereby dabigatran ester 2-oxoglutaric acid salt of the present invention has than the better or suitable at least bioavailability of dabigatran ester mesylate.
3) the application's dabigatran ester 2-oxoglutaric acid salt also has good mobility and compressibility.The contriver carries out flowability and compressibility mensuration to dabigatran ester 2-oxoglutaric acid salt of the present invention and dabigatran ester mesylate respectively, and its result sees the following form 1.
The flowability of table 1 dabigatran ester 2-oxoglutaric acid salt and dabigatran ester mesylate and compressibility are measured
Wherein, the mobile general main of powder weighed with the slope of repose, and the slope of repose is more little, and is better mobile.Conventional θ≤30 ° of good fluidities, the production needs ° can be satisfied in θ≤40.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 used volume comprises the TV in space between hole and the particle of particle itself.What loose density was big is heavy, and what loose density was little is lightweight, and the less pressure of the big usefulness 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 good fluidity greatly.The more little compressibility of compression ratio is good more, is generally less than 0.2 and can satisfies the production needs.Above data show that dabigatran ester 2-oxoglutaric acid salt of the present invention all shows better flowability and compressibility with respect to dabigatran ester mesylate on each item index, thereby is more suitable for the scale operation of medicine.
Embodiment
Further specify the present invention through concrete embodiment below, still, be to be understood that into, these embodiment are only used for the usefulness of explanation more in detail particularly, are used for limiting in any form the present invention and should not be construed as.
General description is carried out to the material and the TP that are used in the present invention's test in this part.Though for realizing that employed many materials of the object of the invention and working method are well known in the art, 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 do not specify that material therefor of the present invention and working method are well known in the art.
If no special instructions, the employed mass spectrograph in following examples is Agientl 100 type level Four bar LC-MS appearance, and employed NMR is a Bruker ARX-400NMR type NMR.
Embodiment 1
Present embodiment is used to explain the preparation of dabigatran ester 2-oxoglutaric acid salt of the present invention.
Under 20 ℃, join the dabigatran ester of 1.6mmol and the 2-oxoglutaric acid of 1.6mmol in the absolute ethyl alcohol of 20ml; Mix and stir 6 hours salifies,, filter then at 20 ℃ of following crystallizatioies; The washing of use ETHYLE ACETATE; After drying, add ether and carry out recrystallization, obtain the ether solvent thing of the dabigatran ester 2-oxoglutaric acid salt of 0.310g.Record ESI-MS (electron spray ionisation-mass spectrum) (m/z): 811 [M+H]
+
Above-mentioned ether solvent thing is carried out drying, obtain the dabigatran ester 2-oxoglutaric acid salt 0.296g of white solid, through calculating, in above-mentioned ether solvent thing, the content of dabigatran ester 2-oxoglutaric acid salt is 95.4wt%.The ether that contains 0.5 molecule in this ether solvent thing of per molecule.
Above-mentioned dabigatran ester 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 ester 2-oxoglutaric acid salt is:
Embodiment 2
Present embodiment is used to explain the preparation of dabigatran ester 2-oxoglutaric acid salt of the present invention.
Under 30 ℃, join the dabigatran ester of 3.2mmol and the 2-oxoglutaric acid of 1.6mmol in the 20ml water; Mix and stir 6 hours salifies,, filter then at 30 ℃ of following crystallizatioies; The washing of use ETHYLE ACETATE; After drying, add entry and carry out recrystallization, obtain the hydrate of the dabigatran ester 2-oxoglutaric acid salt of 0.450g.Record ESI-MS (m/z): 719 [M+H]
+
Above-mentioned hydrate is carried out drying, obtain the dabigatran ester 2-oxoglutaric acid salt 0.439g of white solid, through calculating, in the above-mentioned hydrate, the content of dabigatran ester 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 ester 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 ester 2-oxoglutaric acid salt is:
Embodiment 3
Present embodiment is used to explain the preparation of dabigatran ester 2-oxoglutaric acid salt of the present invention.
Under 0 ℃, join the dabigatran ester of 4.8mmol and the 2-oxoglutaric acid of 1.6mmol in the 20ml absolute ethyl alcohol; Mix and stir 6 hours salifies,, filter then at 0 ℃ of following crystallization; The washing of use ETHYLE ACETATE; After drying, add glycol dimethyl ether and carry out recrystallization, obtain the dabigatran ester 2-oxoglutaric acid salt 0.420g of white solid.
Above-mentioned dabigatran ester 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 ester 2-oxoglutaric acid salt is:
Embodiment 4
Present embodiment is used to explain the preparation of dabigatran ester 2-oxoglutaric acid salt of the present invention.
Under 30 ℃, join the dabigatran ester of 1.6mmol and the 2-oxoglutaric acid of 4.8mmol in the 20ml anhydrous methanol; Mix and stir 6 hours salifies,, filter then at 10 ℃ of following crystallizatioies; The washing of use ether; After drying, add THF and carry out recrystallization, obtain the tetrahydrofuran solvate of the dabigatran ester 2-oxoglutaric acid salt of 0.350g.Record its ESI-MS (m/z): 810 [M+H]
+
Above-mentioned tetrahydrofuran solvate is carried out drying, obtain the dabigatran ester 2-oxoglutaric acid salt 0.334g of white solid, through calculating, the content of dabigatran ester 2-oxoglutaric acid salt is 95.6wt% in the above-mentioned solvolyte.The THF that contains 0.5 molecule in this tetrahydrofuran solvate of per molecule.
Above-mentioned dabigatran ester 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 ester 2-oxoglutaric acid salt is:
Embodiment 5
Present embodiment is used to explain the preparation of dabigatran ester 2-oxoglutaric acid salt of the present invention.
The dabigatran ester of 1.6mmol and the 2-oxoglutaric acid of 3.2mmol are joined 20ml acetone under 10 ℃; Mix and stir 6 hours salifies,, filter then at 10 ℃ of following crystallizatioies; The washing of use ether; After drying, add acetone and carry out recrystallization, obtain the acetone solvate of the dabigatran ester 2-oxoglutaric acid salt of 0.460g.Record its ESI-MS (m/z): 803 [M+H]
+
Above-mentioned acetone solvate is carried out drying, obtain the dabigatran ester 2-oxoglutaric acid salt 0.450g of white solid, through calculating, in the above-mentioned solvolyte, the content of dabigatran ester 2-oxoglutaric acid salt is 96.0wt%.The acetone that contains 0.5 molecule in this methanol solvate thing of per molecule.
Above-mentioned dabigatran ester 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 ester 2-oxoglutaric acid salt is:
Embodiment 6
Present embodiment is used to explain the preparation of dabigatran ester 2-oxoglutaric acid salt of the present invention.
Under 30 ℃, join the dabigatran ester of 1.6mmol and the 2-oxoglutaric acid of 8mmol in the 20ml trichloromethane; Mix and stir 6 hours salifies,, filter then at 20 ℃ of following crystallizatioies; The washing of use ether; After drying, add entry and carry out recrystallization, obtain the hydrate of the dabigatran ester 2-oxoglutaric acid salt of 0.440g.Record its ESI-MS (m/z): 784 [M+H]
+
Above-mentioned hydrate is carried out drying, obtain the dabigatran ester 2-oxoglutaric acid salt 0.435g of white solid, through calculating, the content of dabigatran ester 2-oxoglutaric acid salt is 99wt% in the above-mentioned hydrate.The water that contains 0.5 molecule in this hydrate of per molecule, i.e. semihydrate.
Above-mentioned dabigatran ester 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 ester 2-oxoglutaric acid salt is:
Stability test:
The contriver observes and does assay to dabigatran ester 2-oxoglutaric acid salt and the dabigatran ester mesylate of embodiment 1 under differing temps, humidity and illumination condition, data are seen 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
-1Detect wavelength: 250nm; Column temperature: 25 ℃; Sample size: 20 μ l
The content of table 2 dabigatran ester 2-oxoglutaric acid salt and dabigatran ester mesylate
Table 2 is the contrast of the content of dabigatran ester 2-oxoglutaric acid salt and mesylate through the influence factor test-results.Data show, (high temperature, high humidity, illumination) under the same conditions, and the former content changes very little in time; Belong to the error at measurment scope; And the latter is very unstable under super-humid conditions, especially can be degraded under the super-humid conditions about 50% at 10 days, shows tangible unstable.
The cosmetic variation of table 3 dabigatran ester 2-oxoglutaric acid salt and dabigatran ester mesylate
Can know that from table 3 under the hot conditions, dabigatran ester 2-oxoglutaric acid salt is no change almost, and dabigatran ester mesylate can be observed color and produces considerable change in time.Under the super-humid conditions, the former outward appearance is almost constant, shows more stable character, and the latter then moisture absorption is serious.
Embodiment 7
Present embodiment is used to explain the preparation of drug combination of dabigatran ester 2-oxoglutaric acid salt of the present invention.
Dabigatran ester 2-oxoglutaric acid salt is crossed 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.It is even to take by weighing dabigatran ester 2-oxoglutaric acid, Microcrystalline Cellulose and lactose thorough mixing by recipe quantity, adds 1% (weight/volume) hypromellose aqueous solution, and the system softwood sieves, and the system wet granular is in 55 ℃ of dryings.PVPP and Magnesium Stearate are added in the above-mentioned particle, measure midbody content, compressing tablet, packing.
Embodiment 8
Present embodiment is used to explain the preparation of drug combination of dabigatran ester 2-oxoglutaric acid salt of the present invention.
Dabigatran ester 2-oxoglutaric acid salt is crossed 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.It is even to take by weighing dabigatran ester 2-oxoglutaric acid, Microcrystalline Cellulose, pregelatinized Starch and lactose thorough mixing by recipe quantity, adds 1% (weight/volume) hypromellose aqueous solution, and the system softwood sieves, and the system wet granular is in 55 ℃ of dryings.Magnesium Stearate is added in the above-mentioned particle, measures midbody content, encapsulated, packing.
Embodiment 9
Present embodiment is used to explain the preparation of drug combination of dabigatran ester 2-oxoglutaric acid salt of the present invention.
Dabigatran ester 2-oxoglutaric acid salt is crossed 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.Take by weighing dabigatran ester 2-oxoglutaric acid salt, lactose, N.F,USP MANNITOL, aspartame, essence thorough mixing by recipe quantity; Add 2% (weight/volume) hypromellose aqueous solution system softwood again, 16 mesh sieves are granulated, 55 ℃ of dryings; The whole grain of 14 mesh sieves; Measure midbody content and moisture, packing makes 100 bags of granules altogether.
Embodiment 10
Present embodiment is used to explain the preparation of drug combination of dabigatran ester 2-oxoglutaric acid salt of the present invention.
Dabigatran ester 2-oxoglutaric acid salt is crossed 80 mesh sieves, and auxiliary material is crossed 60 mesh sieves.Taking by weighing dabigatran ester 2-oxoglutaric acid, polyvidone, aspartame and essence by recipe quantity mixes earlier; Even with N.F,USP MANNITOL, Microcrystalline Cellulose and lactose thorough mixing successively again, add Magnesium Stearate at last and mix, measure midbody content; Compressing tablet, packing.
Although the present invention has carried out description to a certain degree, significantly, under the condition that does not break away from the spirit and scope of the present invention, can the suitable variation of each condition of carrying out.Be appreciated that to the invention is not restricted to said embodiment, and belong to the scope of claim, it comprises the replacement that is equal to of said each factor.
Claims (12)
1. dabigatran ester 2-oxoglutaric acid salt, its hydrate and/or solvolyte with general formula (I) structure:
Wherein, n is 1,2 or 3.
2. dabigatran ester 2-oxoglutaric acid salt according to claim 1, its hydrate and/or solvolyte; It is characterized in that; Contain the water of 0.5～10 molecule in the per molecule hydrate of said dabigatran ester 2-oxoglutaric acid salt, be preferably the water that contains 0.5～2 molecule; Contain the solvent of 0.5～10 molecule in the per molecule solvolyte of said dabigatran ester 2-oxoglutaric acid salt, be preferably the solvent that contains 0.5～2 molecule.
3. dabigatran ester 2-oxoglutaric acid salt according to claim 1 and 2, its hydrate and/or solvolyte; It is characterized in that said solvolyte is one or more in alcohol solvent compound, methanol solvate thing, acetone solvate, acetonitrile solvate, ethyl acetate solvent thing, tetrahydrofuran solvate and the ether solvent thing.
4. according to each described dabigatran ester 2-oxoglutaric acid salt, its hydrate and/or solvolyte in the claim 1 to 3; It is characterized in that in said hydrate, dabigatran ester 2-oxoglutaric acid salt accounts for more than the 95wt%; Be preferably more than the 98wt%, more preferably more than the 99wt%; In said solvolyte, dabigatran ester 2-oxoglutaric acid salt accounts for more than the 95wt%, is preferably more than the 98wt%, more preferably more than the 99wt%.
5. the preparation method of each described dabigatran ester 2-oxoglutaric acid salt, its hydrate and/or solvolyte in the claim 1 to 4; It is characterized in that; This method comprises: dabigatran ester and 2-oxoglutaric acid are mixed salify and crystallization in the water or first organic solvent; After filtration, washing, drying, make the water or second organic solvent carry out recrystallization, make said dabigatran ester 2-oxoglutaric acid salt, its hydrate or solvolyte.
6. preparation method according to claim 5 is characterized in that, said mixing salify carries out to the reflux temperature of the water or first organic solvent at 0 ℃, is preferably under 0～30 ℃ and carries out; Preferably, said crystallization carries out under room temperature or subambient condition, is preferably under 0～20 ℃ and carries out; Said first organic solvent and second organic solvent are identical or different, are selected from ethanol, methyl alcohol, propyl alcohol, Virahol, butanols, ethyl formate, ETHYLE ACETATE, isopropyl acetate, butylacetate, ether, isopropyl ether, n-butyl ether, glycol dimethyl ether, methyl tert-butyl ether, THF, sherwood oil, acetonitrile, methylene dichloride, trichloromethane, normal hexane, hexanaphthene, acetone, butanone, pentanone, toluene, N,N-DIMETHYLACETAMIDE or YLENE.
7. according to claim 5 or 6 described preparing methods, it is characterized in that the mol ratio of said dabigatran ester and said 2-oxoglutaric acid is 10: 1～1: 10, be preferably 3: 1～1: 3.
8. a pharmaceutical composition is characterized in that, this pharmaceutical composition comprises each described dabigatran ester 2-oxoglutaric acid salt, its hydrate and/or solvolyte and acceptable accessories in the claim 1 to 4.
9. pharmaceutical composition according to claim 8 is characterized in that, said pharmaceutical composition is tablet, hard capsule, soft capsule, pill, granule, pellet or oral fluid agent.
10. according to Claim 8 or the pharmaceutical composition described in 9, it is characterized in that the weight ratio of said dabigatran ester 2-oxoglutaric acid salt and said acceptable accessories is 1: 1～5, be preferably 1: 1～2.
11. each described dabigatran ester 2-oxoglutaric acid salt, its hydrate and/or solvolyte in the claim 1 to 4 are used for treating or the application of the medicine of preventing cardiovascular disease in preparation.
12. each described dabigatran ester 2-oxoglutaric acid salt, its hydrate and/or solvolyte in the claim 1 to 4 are used for treating or prevent the application of the medicine of phlebothrombosis or acute coronary syndrome in preparation.
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| CN103788063A (en) * | 2012-10-29 | 2014-05-14 | 天津药物研究院 | Dabigatran etexilate tetrahydrate crystal, and preparation method and medicinal use thereof |
| CN105348259A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate oxaloacetate, 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 |
| CN105348261A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate pyruvate, 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 |
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| 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 |
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| CN103788063A (en) * | 2012-10-29 | 2014-05-14 | 天津药物研究院 | Dabigatran etexilate tetrahydrate crystal, and preparation method and medicinal use thereof |
| CN103788063B (en) * | 2012-10-29 | 2016-01-20 | 天津药物研究院 | Four hydration dabigatran crystalline esters and preparation method thereof and pharmaceutical use |
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| CN105348259A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate oxaloacetate, 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 |
| CN105348261A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate pyruvate, 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 |
| CN105646531A (en) * | 2016-03-28 | 2016-06-08 | 沈阳工业大学 | Dabigatran cyclic derivatives and 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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