CN103539779B - A kind of hydroxyl-substituted sulfonate of dabigatran etcxilate and its production and use - Google Patents
A kind of hydroxyl-substituted sulfonate of dabigatran etcxilate and its production and use Download PDFInfo
- Publication number
- CN103539779B CN103539779B CN201210242230.XA CN201210242230A CN103539779B CN 103539779 B CN103539779 B CN 103539779B CN 201210242230 A CN201210242230 A CN 201210242230A CN 103539779 B CN103539779 B CN 103539779B
- Authority
- CN
- China
- Prior art keywords
- dabigatran etcxilate
- amino
- hydroxyl
- sulfonic acid
- crystal formation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the hydroxyl-substituted sulfonate of a kind of dabigatran etcxilate, Preparation Method And The Use.In organic solvent, add dabigatran etcxilate, hydroxyl-substituted sulfonic acid, stirring respectively, dissolve, obtain settled solution.React at a certain temperature, concentrate, stand, separate out crystallization, filter the hydroxyl-substituted sulfonate i.e. obtaining dabigatran etcxilate.The hydroxyl-substituted sulfonate of the dabigatran etcxilate that the present invention provides, has good stability；The preparation method provided is simple and easy to do, reliable and stable, can obtain applicable medicinal crystal formation；Products obtained therefrom quality is good, and yield is high.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of dabigatran etcxilate (dabigatran with blood coagulation resisting function
Etexilate) hydroxyl-substituted sulfonate, its preparation method and the pharmaceutical composition with this compound as active component, with
And the purposes in they preventions of disease of causing for thrombosis or thromboembolism in preparation or medicine.
Background technology
In recent years, cardiovascular and cerebrovascular disease sickness rate is in rising trend, serious harm human health, wherein, and thrombosis or bolt
The relevant disease that plug causes is currently to cause disabled and dead primary factor.The preventing and treating of thrombosis and complication thereof has become the world
The important topic that medical circle faces.Anticoagulation medicine can be effectively improved the cardiovascular and cerebrovascular disease caused with pre-preventing thrombosis, reduces dead
Die rate, thus the research and development of related drugs have become the focus for the treatment of cardiovascular disease.
For more than half a century, anticoagulation medicine is mainly made up of vitamin K antagon and heparin class material.Wherein warfarin
(warfarin) it is the anticoagulant that the orally active vitamin K antagon of only one and only one are approved prolonged application clinically
Blood medicine.Although warfarin is effective, but also bring along the bleeding risk of serious even lethal.Meanwhile, because of the individuality of pharmacokinetics
Diversity is big, and drug interaction is complicated, and is vulnerable to the impact of diet, is difficult to clinically correctly, determines to medicament easily
Amount, must frequently carry out coagulation function monitoring, and compliance is poor.Its onset is relatively slow, treatment window is narrower.And heparin class material is because needing injection
It is administered, therefore is often limited the use of and prevent venous thromboembolism in inpatient or short-term.Need also exist for carrying out during the clinical practice of heparin
Coagulation function detects, and its side effect includes inducing thrombocytopenia and osteoporosis etc..Therefore, urgent clinical needs new, safer
, the oral anticoagulant drug that medication is easier.
Formula I, dabigatran etcxilate (dabigatran etexilate) formula II, dabigatran (Dabigatran)
Dabigatran etcxilate (dabigatran etexilate, formula I), chemical entitled 3-[[[2-[[[4-[[[(hexyloxy)
Carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl] (pyridine-2-base) ammonia
Base] ethyl propionate, it is by the novel anticoagulation medicine of Boehringer Ingelheim company of Germany exploitation, it lists the salt form used
For mesylate, trade name Pradaxa.Dabigatran etcxilate is that over 50 years, the anticoagulation of first listing is administered orally after warfarin
New drug, is described as anticoagulation therapy field and another milestone in potential lethal thrombus prevention field.Dabigatran etcxilate is
Bi precursor medicine, is converted into activated dabigatran (dabigatran, formula II) in vivo, and the latter passes through direct anticoagulant
Enzyme and play anticoagulation effect.Dabigatran etcxilate system oral administration, has potent, without special Medication monitor, medicine phase interaction
By the feature such as few.Potential applicability in clinical practice is optimistic, to prevention of deep vein thrombosis and prevent the aspects such as apoplexy from having obvious action.It becomes
Merit listing indicates the important breakthrough of anticoagulation medicine research field.But similar with anticoagulation medicines such as warfarins, reach
The untoward reaction being easily caused hemorrhage (particularly gastrointestinal hemorrhage) is there is also than adding group ester.
Patent DE19706229A1, WO9837075, EP0966454B1 and CN1088702C make public for the first time Da Bijia
The preparation of group's ester and as thrombin inhibitor in the purposes of field of medicaments.Above-mentioned patent also protects dabigatran etcxilate physiology
Upper acceptable salt, but and not expressly provide related embodiment.
Patent WO2005028468 discloses three kinds of crystal formations of dabigatran etcxilate mesylate, including crystal formation I, crystal formation II and
Semihydrate crystal formation.Use X-ray powder diffraction (XRPD) and means of differential scanning calorimetry (DSC) method that above-mentioned crystal formation has been carried out table
Levy.
Patent WO2006114415 discloses the acid-addition salts of 6 kinds of new dabigatran etcxilates, including hydrochlorate, citric acid
Salt, tartrate, malonate, maleate, salicylate, these salt are also provided without X-ray powder diffraction methods and carry out table
Levy, characterized only with DSC method.
Patent WO2006131491 discloses the crystal formation of 3 kinds of dabigatran etcxilate free alkalis, and these polymorphic systems are with crystallization side
Formula obtains, and this patent have employed the methods such as X-ray powder diffraction, DSC and TG and characterized each crystal formation.
Patent WO2008043759 further discloses acid-addition salts and the polymorphic thereof of multiple dabigatran etcxilate, including two
Plant phosphatic crystal formation (crystal formation I, II), the crystal formation (crystal formation III, IV) of two kinds of fumarates, the crystal formation (crystal formation of three kinds of oxalates
I, II, V), the crystal formation (crystal formation II, V, VI) of three kinds of hydrochlorates, the crystal formation of four kinds of tosilate (crystal formation I, V, VI,
VII).This patent have employed X-ray powder diffraction and DSC method and characterized each crystal formation.
Patent WO2008059029 discloses two kinds of anhydrides and the crystal formation of three kinds of solvates of dabigatran etcxilate, including
Anhydride crystal formation (II, IV), monohydrate crystal formation (I, II) and Nitrobenzol solvate (crystal formation I).
Patent WO2011110876A1 discloses multiple new dabigatran etcxilate acid-addition salts and polymorphic thereof, including phosphoric acid
Salt (crystal formation III), fumarate (crystal formation V), sulfate (crystal formation I), sulfate dihydrate (crystal formation I), sulfate one are hydrated
Thing (crystal formation I), maleate (crystal formation II), oxalates (crystal formation VI), hydrochlorate (VII, VIII, Ⅸ, Ⅹ), tosilate are (brilliant
Type VIII, Ⅸ), mesylate (crystal formation IV).This patent have employed X-ray powder diffraction and DSC method and each crystal formation carried out table
Levy.
Patent CN102050815A discloses the multiple alkyl derivative of dabigatran and non-toxic pharmaceutically can connect
Salt (sulfate, hydrochlorate, hydrobromate, phosphate, acetate, oxalates, citrate, gluconate, the succinic acid being subject to
Salt, tartrate, tosilate, mesylate, benzoate, lactate, maleate etc.), wherein disclosed reach
Ratio adds group's multiple alkyl derivative hydrochlorate, and has carried out anticoagulating active evaluation.
In view of the acid-addition salts with Good Pharmacy character is the most important to the clinical practice of medicine, therefore continually look for new
The pharmaceutically acceptable dabigatran etcxilate acid-addition salts of type is the most necessary.
Summary of the invention
It is an object of the invention to improve the water solublity of dabigatran etcxilate and relevant pharmaceutical properties, it is provided that a kind of new reach ratio
Add the hydroxyl-substituted sulfonate of the acid-addition salts of group ester, i.e. dabigatran etcxilate.
Another object of the present invention is to provide the preparation side of the hydroxyl-substituted sulfonate of a kind of above-mentioned dabigatran etcxilate
Method.
A further object of the present invention is to provide more than one to state the hydroxyl-substituted sulfonate of dabigatran etcxilate for activity
The pharmaceutical composition of composition.
It is a further object of the present invention to provide the hydroxyl-substituted sulfonate of a kind of above-mentioned dabigatran etcxilate in preparation
Purposes in the prevention of the disease caused for thrombosis or thromboembolism or medicine.
The purpose of the present invention is realized by following proposal:
The hydroxyl-substituted sulfonate of a kind of dabigatran etcxilate that the present invention provides, has a following formula (III) structure:
Formula III
Wherein, R1、R2、R3、R4And R5Can be H or OH, and at least one be OH.
The hydroxyl-substituted sulfonate of described dabigatran, it is characterised in that described compound is 3-[[[2-[[[4-
[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl]
(pyridine-2-base) amino] ethyl propionate 2,5-dihydroxy benzenes sulfonic acid salt.
The preparation method of the hydroxyl-substituted sulfonate of dabigatran etcxilate of the present invention, comprises the steps:
1) in organic agent, add dabigatran etcxilate, hydroxyl-substituted sulfonic acid, stirring respectively, dissolve, at a certain temperature
Reaction, obtains settled solution；
2) being concentrated by above-mentioned reactant liquor, cooling, stand, separate out crystallization, sucking filtration, the hydroxyl obtaining dabigatran etcxilate replaces
The course of reaction of the present invention is as follows:
In step 1, described reaction temperature is 0-100 DEG C, preferably 30 DEG C.
In step 1, as long as described organic solvent can dissolve reactant and not hinder reaction to carry out, can be chlorine
Imitative, dichloromethane, ethyl acetate, acetone, oxolane, methyltetrahydrofuran, dioxane, acetonitrile, propionitrile, propanol, positive fourth
Alcohol, the tert-butyl alcohol, ethanol, methanol one or more, preferably ethyl acetate.
In step 1, described dabigatran etcxilate is 1:1-2, preferably 1:1.2 with the mol ratio of hydroxyl-substituted sulfonic acid.
Described 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-first
Base-1H-benzimidazole-5-base] carbonyl] (pyridine-2-base) amino] ethyl propionate 2, the crystal formation of 5-dihydroxy benzenes sulfonic acid salt, its
Be characterised by, angle of reflection 2 θ of its powder X-ray diffraction figure 5.47 ± 0.2,10.85 ± 0.2,13.54 ± 0.2,18.13 ±
0.2, there is characteristic absorption peak at 22.32 ± 0.2,24.85 ± 0.2,27.05 ± 0.2 °.
Described 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-first
Base-1H-benzimidazole-5-base] carbonyl] (pyridine-2-base) amino] the crystal formation A of ethyl propionate p-hydroxybenzenyl sulfonate salt, its feature
Be, angle of reflection 2 θ of its powder X-ray diffraction figure 7.02 ± 0.2,11.73 ± 0.2,15.46 ± 0.2,17.62 ± 0.2,
Characteristic absorption peak is had at 19.92 ± 0.2,20.97 ± 0.2,23.64 ± 0.2,25.26 ± 0.2 °.
The formula (III) compound of the present invention can per os or not oral administration.During oral administration, the preparation of routine can be used
Technology, is mixed and made into the solid preparation of routine, such as granule, capsule by these chemicals and conventional pharmaceutically acceptable carrier
Agent, tablet, powder or syrup etc.；During non-oral administration, the preparation technique of routine can be used to be made into preparation capable of permeating skin, note
Penetrate liquid, infusion solution or suppository etc..Described pharmaceutically acceptable carrier refers to the pharmaceutical carrier that pharmaceutical field is conventional, such as figuration
Agent, disintegrating agent, binding agent, lubricant, antioxidant, coating materials, coloring agent, aromatic, surfactant.
The pharmaceutical composition of the present invention contains the active component above-mentioned formula (III) compound of therapeutically effective amount, and contains
One or more pharmaceutically acceptable carriers.The various dosage forms of this pharmaceutical composition can be according to the conventional production of pharmaceutical field
Prepared by method, such as, make active component mix with one or more carriers, be then made into required dosage form.
These preparations can be manufactured by known method following additives: excipient is (such as: lactose, white sugar, Fructus Vitis viniferae
The sugar derivativess such as sugar, mannitol, sorbitol；The starch derivatives such as corn starch, potato starch, alphalise starch, dextrin；Crystallization fibre
Dimension element derivant；Radix Acaciae senegalis；Dextran；The organic excipients such as Pullulan；And light silicon anhydride, synthetic aluminium silicate,
The silicate derivative such as calcium silicates, Magnesiumaluminumsilicate；The phosphate such as calcium hydrogen phosphate；The carbonate such as calcium carbonate；The sulfate such as calcium sulfate
Deng inorganic excipients), lubricant (such as: the Metallic stearates such as stearic acid, calcium stearate, magnesium stearate；Ethylene glycol；Anti-fourth
Enedioic acid；Sodium benzoate；DL-LEUCINE；The lauryl sulfate such as sodium lauryl sulphate, Stepanol MG；Silicic acid
The silicic acid class such as acid anhydride, hydrate of silicic acid；And above-mentioned starch derivatives), binding agent (such as: hydroxypropyl cellulose, hydroxypropyl methylcellulose
Element, polyvinylpyrrolidone, Polyethylene Glycol and the compound as opening agent with above-mentioned tax), disintegrating agent (such as: low-substituted hydroxypropyl
Base cellulose derivative；The chemically modified starch such as carboxymethyl starch, carboxymethyl starch sodium, crospolyvinylpyrrolidone or
Cellulose family；Above-mentioned starch derivatives), emulsifying agent (such as: the colloidal clays such as bentonite, V word glue；Magnesium hydroxide, aluminium hydroxide
Deng metal hydroxides；The anion surfactant such as sodium lauryl sulphate, calcium stearate；The cationic surfaces such as benzalkonium chloride
Activating agent；And the non-ionic surface such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sucrose-fatty lives
Property agent), stabilizer is (such as: the parabens such as methyl butex, propyl p-hydroxybenzoate；Chlorobutanol, benzene
The alcohols such as methanol, phenethanol；The phenols such as benzalkonium chloride, phenol, cresol；Thimerosal；Dehydroactic acid；And sorbic acid), correctives
(such as: normally used sweetening material, acid flavoring, spice), diluent etc..
The formula (III) compound of the present invention and aforementioned pharmaceutical compositions can be used for preparing the medicine with enzyme effect anticoagulant
Thing, prevents or treats thrombosis or disease that thromboembolism causes.
The amount of application of formula (III) compound of the present invention can be according to route of administration, the age of patient, body weight, the disease treated
Sick and the order of severity etc. changes and takes different consumptions.
Sometimes, the hydroxyl-substituted sulfonate of dabigatran etcxilate of the present invention is placed in atmosphere or by recrystallization,
Will absorb moisture and produce absorption water formation hydrate, the acid-addition salts therefore containing moisture is also contained in the present invention.
Sometimes, the hydroxyl-substituted sulfonate of dabigatran etcxilate of the present invention crystallizes or in organic solvent organic molten
In agent in placement process, it will forming solvate, therefore corresponding solvate is also contained in the present invention.
The invention have the advantages that and effect:
1) the hydroxyl-substituted sulfonate of the dabigatran etcxilate that the present invention provides, has good stability；
2) preparation method of the present invention is simple and easy to do, reliable and stable, and products obtained therefrom quality is good, and yield is high.
Accompanying drawing explanation
The X-ray powder diffraction pattern of Fig. 1 dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt (X ' Pert PRO MPD X penetrates
Line diffractometer；Co/K-alpha1 radiation source,)
The X-ray powder diffraction data report (page 1) of Fig. 2 dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt
The X-ray powder diffraction data report (page 2) of Fig. 3 dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt
The DSC collection of illustrative plates of Fig. 4 dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt
The TGA collection of illustrative plates of Fig. 5 dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt
The powder diffraction spectrum of Fig. 6 dabigatran etcxilate p-hydroxybenzenyl sulfonate salt (X ' Pert PRO MPD X-ray diffractometer；
Cu/K-alpha1 radiation source,)
The X-ray powder diffraction data report (page 1) of Fig. 7 dabigatran etcxilate p-hydroxybenzenyl sulfonate salt
The X-ray powder diffraction data report (page 2) of Fig. 8 dabigatran etcxilate p-hydroxybenzenyl sulfonate salt
Detailed description of the invention
Below in conjunction with embodiment, the present invention done further detailed description, but embodiments of the present invention are not limited to this.
Embodiment 1: the synthesis of dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (10.3g,
0.054mol) being equipped with in the reaction bulb of ethyl acetate (300ml), temperature control is at 30 DEG C, and stirring makes it dissolve, and obtains clarifying molten
Liquid.Concentration of reaction solution, to 1/2 volume, stands, and cooling separates out crystallization, for the 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.Will
This crystal is suspended in water (300ml), and temperature control, at 30 DEG C, stirs 4 hours.Filter, filter cake 40 DEG C vacuum drying.Weight:
33.8g, yield: 92%.Crystal formation named crystal formation A corresponding to this product.
It is below the structural characterization data of dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt:
m.p.163.5-164.5℃.
IR(KBr)v:3280(N-H),3174(O-H),2980(-CH3),2933(-CH2-),2856(-CH3),1759,
1734,(-CO2-),1647(-CON-),1608(-O-CO-NH-),1207,1072(SO3 -).
ESI-MS (positive): m/z=628, [M+H]+;m/z=650,[M+Na]+.
ESI-MS (negtive): m/z=189, [M-H]-.
1H NMR(DMSO-d6, δ/ppm): 0.8654-0.8789 (d, 3H ,-CH3);1.0797-1.1385(m,3H,-
CH3);1.3056-1.3753(m,4H,-CH2-);1.6390-1.6906(m,2H,-CH2-);2.6668-2.7013(t,2H,-
CH2-);3.7742(s,3H,-CH3);3.9467-3.9997(m,2H,-CH2-);4.2078-4.2634(m,4H,-CH2-);
4.6945(s,2H,-CH2-);6.5511-6.6255(m,2H,-ArH);6.8569-6.9105(m,4H,-ArH);7.1047-
7.1759(m,2H,-ArH);7.4093-7.4303(d,2H,-ArH);7.4748,(s,1H,-NH-);7.5326-7.5914
(m,2H,-ArH);7.6425-7.6641(d,2H,-ArH);8.3835-8.3908(d,1H,-ArH);8.8095(s,1H,-
NH-);9.8412(s,1H, -NH-);9.9997(s,1H,-OH);10.5749(br.,1H,-OH);11.8550-11.8644
(br.,1H,-SO3H).
Data above confirms that products therefrom is dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt.
Embodiment 2: the synthesis of dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (10.3g,
0.054mol) being equipped with in the reaction bulb of ethyl acetate (500ml), temperature control is at 10 DEG C, and stirring makes it dissolve, and obtains clarifying molten
Liquid.Concentration of reaction solution, to 1/2 volume, stands, and cooling separates out crystallization, for the 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.Will
This crystal is suspended in water (300ml), and temperature control, at 30 DEG C, stirs 4 hours.Filter, filter cake 40 DEG C vacuum drying.Weight:
30.1g, yield: 82%.
The characterization result of product is with embodiment 1.
Embodiment 3: the synthesis of dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (10.3g,
0.054mol) being equipped with in the reaction bulb of EtOAc (200ml), be heated to 60 DEG C, stirring makes it dissolve, and obtains clarifying molten
Liquid.Concentration of reaction solution, to 1/2 volume, stands, and cooling separates out crystallization, for the 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.Will
This crystal is suspended in water (300ml), and temperature control, at 30 DEG C, stirs 4 hours.Filter, filter cake 40 DEG C vacuum drying.Weight:
31.3g, yield: 85%.
The characterization result of product is with embodiment 1.
Embodiment 4: the synthesis of dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (17.1g,
0.09mol) being equipped with in the reaction bulb of ethyl acetate (300ml), temperature control is at 30 DEG C, and stirring makes it dissolve, and obtains clarifying molten
Liquid.Concentration of reaction solution, to 1/2 volume, stands, and cooling separates out crystallization, for the 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.Will
This crystal is suspended in water (300ml), and temperature control, at 30 DEG C, stirs 4 hours.Filter, filter cake 40 DEG C vacuum drying.Weight:
29.8g, yield: 81%.
The characterization result of product is with embodiment 1.
Embodiment 5: the synthesis of dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (10.3g,
0.054mol) being equipped with in the reaction bulb of acetone (200ml), temperature control is at 30 DEG C, and stirring makes it dissolve, and obtains settled solution.
Concentration of reaction solution, to 1/2 volume, stands, and cooling separates out crystallization, for the 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.By this
Crystal is suspended in water (300ml), and temperature control, at 30 DEG C, stirs 4 hours.Filter, filter cake 40 DEG C vacuum drying.Weight: 33.1g,
Yield: 90%.
The characterization result of product is with embodiment 1.
Embodiment 6: the synthesis of dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), 2,5-dihydroxy benzenes sulfonic acid (10.3g,
0.054mol) being equipped with in the reaction bulb of dichloromethane (400ml), temperature control is at 30 DEG C, and stirring makes it dissolve, and obtains clarifying molten
Liquid.Concentration of reaction solution, to 1/2 volume, stands, and cooling separates out crystallization, for the 2 of dabigatran etcxilate, 5-dihydroxy benzenes sulfonic acid salt.Will
This crystal is suspended in water (300ml), and temperature control, at 30 DEG C, stirs 4 hours.Filter, filter cake 40 DEG C vacuum drying.Weight:
29.4g, yield: 80%.
The characterization result of product is with embodiment 1.
Embodiment 7: the synthesis of dabigatran etcxilate p-hydroxybenzenyl sulfonate salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (9.4g,
0.054mol) being equipped with in the reaction bulb of ethyl acetate (300ml), temperature control is at 30 DEG C, and stirring makes it dissolve, and obtains clarifying molten
Liquid.Concentration of reaction solution to 1/2 volume, stands, and cooling separates out crystallization, for the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, and weight:
33.9g, yield: 94%.
It is below the structural characterization data of dabigatran etcxilate p-hydroxybenzenyl sulfonate salt:
m.p.:174.0-176.0℃.
IR(KBr)v:3300(N-H),3200(O-H),2956(-CH3),2933(-CH2-),2860(-CH3),1731,(-
CO2-),1654(-CON-),1608(-O-CO-NH-),1197,1031(SO3 -).
ESI-MS (positive): m/z=628, [M+H]+;m/z=650,[M+Na]+.
ESI-MS (negtive): m/z=173, [M-H]-.
1H NMR(DMSO-d6, δ/ppm): 1.1009-1.1364 (t, 3H ,-CH3);1.2905-1.3743(m,4H,-
CH2-);1.6384-1.7062(m,2H,-CH2-);2.6628-2.6976(m,2H,-CH2-);3.7747(s,1H,-CH3);
3.9424-3.9957(m,2H,-CH2-);4.2026-4.2665(m,4H,-CH2O-);4.6971(s,1H,-ArH);6.6419-
6.6627(d,2H,-ArH);6.8536-6.9091(m,3H,-ArH);7.1047-7.1705(m,2H,-CH2);7.3807-
7.4366(m,3H,-ArH);7.4694(s,1H,-NH-);7.5305-7.5694(m,1H,-ArH);7.6329-7.6540(m,
3H,-ArH);8.3815-8.3909(d,1H,-ArH);9.5051(s,1H,-NH-);10.0226(s, 1H,-NH-);
10.6241(s,1H,-OH),11.8763(s,1H,-SO3H).
Data above confirms that products therefrom is dabigatran etcxilate p-hydroxybenzenyl sulfonate salt.
Embodiment 8: the synthesis of dabigatran etcxilate p-hydroxybenzenyl sulfonate salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (9.4g,
0.054mol) being equipped with in the reaction bulb of ethyl acetate (500ml), temperature control is at 10 DEG C, and stirring makes it dissolve, and obtains clarifying molten
Liquid.Concentration of reaction solution to 1/2 volume, stands, and cooling separates out crystallization, for the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, and weight:
30.3g, yield: 84%.
The characterization result of product is with embodiment 7.
Embodiment 9: the synthesis of dabigatran etcxilate p-hydroxybenzenyl sulfonate salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (9.4g,
0.054mol) being equipped with in the reaction bulb of ethyl acetate (200ml), be heated to 60 DEG C, stirring makes it dissolve, and obtains clarifying molten
Liquid.Concentration of reaction solution to 1/2 volume, stands, and cooling separates out crystallization, for the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, and weight:
31.4g, yield: 87%.
The characterization result of product is with embodiment 7.
Embodiment 10: the synthesis of dabigatran etcxilate p-hydroxybenzenyl sulfonate salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (15.7g,
0.09mol) being equipped with in the reaction bulb of ethyl acetate (300ml), temperature control is at 30 DEG C, and stirring makes it dissolve, and obtains clarifying molten
Liquid.Concentration of reaction solution to 1/2 volume, stands, and cooling separates out crystallization, for the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, and weight:
29.6g, yield: 82%.
The characterization result of product is with embodiment 7.
Embodiment 11: the synthesis of dabigatran etcxilate p-hydroxybenzenyl sulfonate salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (9.4g,
0.054mol) being equipped with in the reaction bulb of acetone (200ml), temperature control is at 30 DEG C, and stirring makes it dissolve, and obtains settled solution.
Concentration of reaction solution to 1/2 volume, stands, and cooling separates out crystallization, for the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, and weight:
32.8g, yield: 91%.
The characterization result of product is with embodiment 7.
Embodiment 12: the synthesis of dabigatran etcxilate p-hydroxybenzenyl sulfonate salt
Respectively by dabigatran etcxilate (tetrahydrate) (28.5g, 0.045mol), p-hydroxybenzenyl sulfonate (9.4g,
0.054mol) being equipped with in the reaction bulb of dichloromethane (500ml), temperature control is at 30 DEG C, and stirring makes it dissolve, and obtains clarifying molten
Liquid.Concentration of reaction solution to 1/2 volume, stands, and cooling separates out crystallization, for the p-hydroxybenzenyl sulfonate salt of dabigatran etcxilate, and weight:
29.9g, yield: 83%.
The characterization result of product is with embodiment 7.
Embodiment 13: containing the tablet of 60 milligrams of active substances
Composition:
Preparation: by (1), (2) and (3) mix, make granule with (4) aqueous solution.(5) are added to the particulate matter being dried
In.By this mixture tabletted, two-sided, all carve characters in two faces, and one side has separated time.
Tablet diameters: 9 millimeters
Embodiment 14: containing the tablet of 350 milligrams of active substances
Composition:
Preparation: by (1), (2) and (3) mix, make granule with (4) aqueous solution.(5) are added to the particulate matter being dried
In.By this mixture tabletted, two-sided, all carve characters in two faces, and one side has separated time.
Tablet diameters: 12 millimeters
Embodiment 15: containing the capsule of 350 milligrams of active substances
Composition:
Preparation: (1) is ground with (3).Abrasive material is joined under vigorous stirring in the mixture of (2) and (4).Should
Mixture of powders loads in No. 3 hard gelatin capsules with capsule loader.
Embodiment 16: containing the capsule of 60 milligrams of active substances
Composition:
Preparation: (1) is ground with (3).Abrasive material is joined under vigorous stirring in the mixture of (2) and (4).Should
Mixture of powders loads in No. 3 hard gelatin capsules with capsule loader.
Test case 1: dabigatran etcxilate and the stability study of dabigatran etcxilate salt
Take and reach ratio and add ester group four hydrated free base, dabigatran etcxilate mesylate (commercially available product) and dabigatran etcxilate 2,5-bis-
Phenolsulfonate (embodiment 1 gained) is accelerated failure test respectively under high temperature, high humidity, intense light conditions, and 10 days laggard
Row Liquid Detection, result is as follows:
The stability study (0 day content is set as 100%) of table 1. dabigatran etcxilate and dabigatran etcxilate salt
From table 1, under conditions of high humidity 2,5-dihydroxy benzenes sulfonic acid salt and four hydrated free base stability differences are less,
And apparently higher than mesylate, under high temperature and intense light conditions, 2,5-dihydroxy benzenes sulfonic acid salt-stables are substantially better than methanesulfonic acid
Salt and free alkali hydrate, therefore data above shows that dabigatran etcxilate 2,5-dihydroxy benzenes sulfonic acid salt have more preferable stablizing
Property.Test case 2: activated partial thromboplastin time (APTT) measures
By the kunming mice random packet of quality 18-20 gram, often group 10, overnight fasting.By dabigatran etcxilate, Da Bijia
Group's ester 2,5-dihydroxy benzenes sulfonic acid salt (embodiment 1 gained), dabigatran etcxilate p-hydroxybenzenyl sulfonate salt (embodiment 7 gained) and sky
Compare in vain in the aqueous solution of the sodium carboxymethyl cellulose being suspended or dissolved in 1%, be made into the concentration of 1mg/ml, by the agent of 10mg/kg
Amount (being converted into dabigatran etcxilate) gastric infusion, through heart puncturing extracting blood after 30min, plasma sample after certain time heats,
Adding partial thromboplastin reagent, the light using wavelength to be 660nm irradiates sample, and in coagulation process, the turbidity of blood dissipates by measuring
The change penetrating light intensity measures, and tries to achieve clotting time by Percentage Detection method, is APTT value.Instrument
Model: Sysmex CA-1500 automatic blood blood coagulation analyzer.The results are shown in Table 2.
Table 2. dabigatran etcxilate and dabigatran etcxilate salt activated partial thromboplastin time (APTT) measure (n=10)
。
Claims (3)
1. a 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl-
1H-benzimidazole-5-base] carbonyl] (pyridine-2-base) amino] ethyl propionate 2, the crystal formation of 5-dihydroxy benzenes sulfonic acid salt, its feature
Be, angle of reflection 2 θ of its powder X-ray diffraction figure 5.47 ± 0.2,10.85 ± 0.2,13.54 ± 0.2,18.13 ± 0.2,
Characteristic absorption peak is had at 22.32 ± 0.2,24.85 ± 0.2,27.05 ± 0.2 °.
2. a pharmaceutical composition, it is characterised in that the 3-[[[2-[[[4-described in the claim 1 containing effective therapeutic dose
[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl]
(pyridine-2-base) amino] crystal formation of ethyl propionate 2,5-dihydroxy benzenes sulfonic acid salt.
3. 3-[[[2-[[[4-[[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] first described in claim 1
Base]-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl] (pyridine-2-base) amino] ethyl propionate 2,5-dihydroxy benzenes sulfonic acid salt
Crystal formation application in preparing anticoagulation medicine and the prevention of disease caused for thrombosis or thromboembolism or medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210242230.XA CN103539779B (en) | 2012-07-13 | 2012-07-13 | A kind of hydroxyl-substituted sulfonate of dabigatran etcxilate and its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210242230.XA CN103539779B (en) | 2012-07-13 | 2012-07-13 | A kind of hydroxyl-substituted sulfonate of dabigatran etcxilate and its production and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103539779A CN103539779A (en) | 2014-01-29 |
| CN103539779B true CN103539779B (en) | 2016-12-21 |
Family
ID=49963683
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210242230.XA Expired - Fee Related CN103539779B (en) | 2012-07-13 | 2012-07-13 | A kind of hydroxyl-substituted sulfonate of dabigatran etcxilate and its production and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103539779B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016009405A1 (en) * | 2014-07-18 | 2016-01-21 | Sifavitor S.R.L. | Crystalline compounds of dabigatran etexilate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102123707A (en) * | 2008-08-19 | 2011-07-13 | 贝林格尔.英格海姆国际有限公司 | Dabigatran for percutaneous interventional cardiac catheterisation |
| WO2011110876A1 (en) * | 2010-02-02 | 2011-09-15 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Novel salts for the manufacture of pharmaceutical compositions |
| CN102391250A (en) * | 2011-08-29 | 2012-03-28 | 石药集团欧意药业有限公司 | Dabigatran compound and preparation method and medicinal composition thereof |
| WO2012077136A2 (en) * | 2010-12-06 | 2012-06-14 | Msn Laboratories Limited | Process for the preparation of benzimidazole derivatives and its salts |
| CN102558153A (en) * | 2012-02-08 | 2012-07-11 | 北京阜康仁生物制药科技有限公司 | Novel pharmaceutical salt of dabigatran etexilate and preparation method thereof |
-
2012
- 2012-07-13 CN CN201210242230.XA patent/CN103539779B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102123707A (en) * | 2008-08-19 | 2011-07-13 | 贝林格尔.英格海姆国际有限公司 | Dabigatran for percutaneous interventional cardiac catheterisation |
| WO2011110876A1 (en) * | 2010-02-02 | 2011-09-15 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Novel salts for the manufacture of pharmaceutical compositions |
| WO2012077136A2 (en) * | 2010-12-06 | 2012-06-14 | Msn Laboratories Limited | Process for the preparation of benzimidazole derivatives and its salts |
| CN102391250A (en) * | 2011-08-29 | 2012-03-28 | 石药集团欧意药业有限公司 | Dabigatran compound and preparation method and medicinal composition thereof |
| CN102558153A (en) * | 2012-02-08 | 2012-07-11 | 北京阜康仁生物制药科技有限公司 | Novel pharmaceutical salt of dabigatran etexilate and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103539779A (en) | 2014-01-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2013333953B2 (en) | Multicomponent crystalline system comprising nilotinib and selected co-crystal formers | |
| TWI804933B (en) | Compounds and uses thereof as CDK7 kinase inhibitors | |
| CN104262330B (en) | A kind of urea substituted biphenyl compounds and combinations thereof thing and purposes | |
| CN105131003B (en) | Crystal of 6,7 unsaturated 7 carbamoyl morphinan derivatives and preparation method thereof | |
| CN104736526A (en) | Vortioxetine salt and crystal thereof, their preparation method, pharmaceutical compositions and usage | |
| TWI718104B (en) | POLYMORPHIC FREE ACID, HEMI-CALCIUM SALT AND α-PHENETHYLAMINE SALT OF AHU-377 AND PREPARATION METHOD AND USE THEREOF | |
| CN110612292A (en) | Crystal form of addition salt of ozapimod, preparation method, pharmaceutical composition and application | |
| WO2011140816A1 (en) | Thienopyridine ester derivative containing nitrile, preparation method, use and composition thereof | |
| PH26545A (en) | Anhydrous crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide | |
| KR20210000719A (en) | Solid forms and formulations comprising glucocorticoid receptor antagonists and uses thereof | |
| TWI784276B (en) | New uses of complexes of metabolites of angiotensin II receptor antagonists and NEP inhibitors | |
| EP3023416A1 (en) | Preparation of (-)-huperzine a | |
| RU2468015C2 (en) | Polymorphic forms of deferasirox (icl670a) | |
| CN103864760A (en) | Hydroxyfasudil compound | |
| CN103539779B (en) | A kind of hydroxyl-substituted sulfonate of dabigatran etcxilate and its production and use | |
| CN111454229B (en) | Dihydronaphthoisoxazole derivative and application thereof in antitumor drugs | |
| WO2018103119A1 (en) | Hydrobromate of benzodiazepine derivative, preparation method and use thereof | |
| CN101851209B (en) | Imidazole ethyl vanillic acid ether, preparation method and medicinal application thereof | |
| CN104059030A (en) | Derivative of [(thiophenyl alkyl)-phenyl] piperazine as well as pharmaceutical composition and application thereof | |
| CN103864756B (en) | Fourth disulfonic acid dabigatran etcxilate and its preparation method and application | |
| CN102746325B (en) | Compound 1,10-N-decylene lycorine dibromo salt, pharmaceutical composition and application thereof in medicine | |
| WO2021235392A1 (en) | Anti-sars-cov-2 durg | |
| CN102746227A (en) | Dimemorfan phosphate crystal form II and preparation method thereof, and pharmaceutical composition | |
| EP1927591A1 (en) | Polymorphic Forms of Deferasirox (ICL670) | |
| CN108658843B (en) | Acetylbenzylamine piperidine amide derivative and application thereof as cerebral nerve protective agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20161221 Termination date: 20190713 |