CN104177337A - Novel intermediate of dabigatran etexilate and preparation method of novel intermediate - Google Patents

Novel intermediate of dabigatran etexilate and preparation method of novel intermediate Download PDF

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CN104177337A
CN104177337A CN201410202121.4A CN201410202121A CN104177337A CN 104177337 A CN104177337 A CN 104177337A CN 201410202121 A CN201410202121 A CN 201410202121A CN 104177337 A CN104177337 A CN 104177337A
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acid
ethyl ester
imidic
salt
acid ethyl
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CN104177337B (en
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陈洪
杜全胜
赵永龙
李芳群
徐同利
曾琴
向志祥
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Tibet Haisco Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention discloses a novel intermediate form of dabigatran etexilate, wherein the novel intermediate is a salt of 3-[[[2-[[[4-[[ethyoxyl] formimino]phenyl]amino]methyl]-1-methyl-1H-benzimidazole-5-yl]carbonyl](pyridine-2-yl)amino]ethyl propionate as shown in a formula V-A as shown in the specification, and the salt has good purity and stability, can be stored for a long time and can be taken as a process intermediate or a starting raw material for use; and moreover, in the preparation of the subsequent intermediate and the dabigatran etexilate, the reaction operation is simple and convenient, the product purity is high and the industrial application is facilitated.

Description

A kind of new intermediate of dabigatran etcxilate and preparation method thereof
Technical field
The present invention relates to pharmacy and organic chemistry filed, be specifically related to a kind of new intermediate of anticoagulant dabigatran etcxilate, the preparation method of this new intermediate with and for the preparation of the application of dabigatran etcxilate.
Background technology
In recent years, cardiovascular and cerebrovascular diseases sickness rate is in rising trend, serious harm human health, and wherein, the relative disease that thrombus or embolism cause is current cause disabled and dead primary factor.The control of thrombus and complication thereof has become the important topic that world medical circle faces.The cardiovascular and cerebrovascular diseases that anticoagulation medicine can effectively improve and pre-preventing thrombosis causes, reduce mortality ratio, thereby the research and development of related drugs has become the focus for the treatment of cardiovascular disease.
For more than half a century, anticoagulation medicine is mainly comprised of vitamin K antagon and heparin class material.Wherein warfarin (Warfarin) is a unique orally active vitamin K antagon and a unique anticoagulation medicine of getting permission prolonged application clinically.Although warfarin is effective, also can bring the serious even bleeding risk of lethality; Meanwhile, because the individual difference of pharmacokinetics is large, drug interaction is complicated, and is vulnerable to the impact of diet, is difficult to clinically correctly, determines easily and must frequently carry out coagulation function monitoring by dosage, and compliance is poor; In addition, its onset is slow, treatment window is narrower.And heparin class material is because needing drug administration by injection, therefore often limited the use of in inpatient or short-term prevention venous thromboembolism; During the clinical application of heparin, need to carry out coagulation function detection equally, its side effect comprises brings out thrombopenia and osteoporosis etc.Therefore the oral anticoagulant medicine that, urgent clinical needs are new, safer, medication is easier.
Dabigatran etcxilate (Dabigatran etexilate, formula I), chemistry 3-[[[2-[[[4-[[[(hexyloxy by name) carbonyl] amino] formimino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate, it is the novel anticoagulation medicine by the exploitation of German Boehringer Ingelheim company, on March 18th, 2008 is ratified by the listing of EMEA, and April is first in Germany and Britain's listing; On October 19th, 2010 is ratified by the listing of U.S. FDA.Dabigatran etcxilate is the oral new drug of the anticoagulation of first listing over 50 years after warfarin, is described as another milestone in anticoagulation therapy field and potential lethality thrombus prevention field.Dabigatran etcxilate is bi precursor medicine, is converted in vivo activated dabigatran (Dabigatran, formula II), and the latter brings into play anticoagulation effect by direct Trombin inhibiting.Dabigatran etcxilate is oral administration, have potent, without features such as special medication monitoring, drug interaction are few, to prevention of deep vein thrombosis and prevent that from there is significant effect the aspects such as palsy, it successfully goes on the market and indicates the important breakthrough of anticoagulation medicine research field.
Patent CN1248251A discloses dabigatran etcxilate and dabigatran and preparation method thereof first, and this preparation method is:
Above-mentioned preparation method reacts compound IV in saturated ethanol solution of hydrogen chloride, then steams hydrogenchloride ethanol; Resistates is dissolved in ethanol and reacts and spend the night with volatile salt, obtains the hydrochloride of amidine compound III through precipitation, column chromatography, and the hydrochloride of amidine compound III, under the existence of salt of wormwood, reacts with the just own ester of chloroformic acid, through aftertreatment and column chromatography purification, makes dabigatran etcxilate I.
Patent CN1861596A reacts compound IV in saturated ethanol solution of hydrogen chloride, then concentrated; Resistates reacts in saturated ammonia ethanol, and through hydrochloride concentrated, that column chromatography obtains amidine compound III, the hydrochloride of amidine compound III, under the existence of potassium hydroxide, reacts with the just own ester of chloroformic acid, through aftertreatment and column chromatography purification, obtains dabigatran etcxilate I.
Patent CN101600709A reacts the hydrobromate of intermediate compound IV and tosic acid in ethanol solution of hydrogen chloride, and alcohol dilution then adds ammoniacal liquor reaction, steams part ethanol, thin up, crystallization, the tosilate of dry amidine compound III.The purity of the tosilate of the amidine compound III of the method gained is not high.
Patent WO2010045900 reacts the oxalate of compound IV in ethanol solution of hydrogen chloride, then concentrated; Resistates is dissolved in ethanol, adds volatile salt reaction, removes by filter insolubles, the ethanol compound of concentrating filter liquor, ethyl acetate/alcohol crystal, dry amidine compound III hydrochloride, purity 89%; The ethanol compound of amidine compound III hydrochloride is dissolved in the mixing solutions of ethanol and ethyl acetate, adds equimolar hydrogenchloride ethanol, crystallization, filters, the dihydrochloride of dry amidine compound III, purity 96%; The dihydrochloride of amidine compound III, under triethylamine exists, reacts to obtain dabigatran etcxilate I with the just own ester of chloroformic acid.
Because there is column chromatography operation, steam corrosive gases hydrogenchloride in aforesaid method, intermediate purity is not high, produce the factor that a large amount of by-product ammonium chloride etc. are unfavorable for suitability for industrialized production.Patent CN102985416A improves aforesaid method, in the process of preparing amidine compound III by the hydrochloride of compound IV, under nitrogen protection, isolated Intermediates compound V-1 (HCl in this structural formula represents more than 1 or 1 HCl), be 3-[[[2-[[[4-[[oxyethyl group] formimino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate hydrochloride, hereinafter to be referred as " imidic acid carbethoxy hydrochloride ", the purity 94% of the intermediate state imidic acid carbethoxy hydrochloride that this is separated; And then this separated intermediate state imidic acid carbethoxy hydrochloride V-1 is spent the night and more than the time obtains the hydrochloride of amidine compound III with volatile salt or ammonia react, purity 93% under argon shield and anhydrous condition; The hydrochloride of amidine compound III reacts and obtains dabigatran etcxilate I, purity 97% with the just own ester of chloroformic acid again.The method has been avoided column chromatography for separation, but also has improved the purity of amidine compound III hydrochloride, is conducive to the raising of purifying and the yield of subsequent reactions.But the purity of imidic acid carbethoxy hydrochloride V-1 not high (<95%) in the method, and then affected the purity (<94%) of prepared amidine compound III hydrochloride; And imidic acid carbethoxy hydrochloride V-1 poor stability, need to protect separated with under anhydrous condition and carry out next step reaction at noble gas, be more not suitable for long-term storage.
Due to above-mentioned dabigatran etcxilate preparation technology's deficiency, be therefore necessary to continue to find the preparation technology who is more conducive to industrializing implementation.After deliberation, we find the imidic acid ethyl ester salt that the acid weak acid such as imidic acid ethyl ester V and oxalic acid, phosphoric acid, citric acid forms pleasantly surprisedly, not only purity and stability improve, can store for a long time and use as process intermediates or starting raw material, and when further reacting preparation intermediate III or its salt with ammonia reagent, operation is easier, and the intermediate III of gained or its purity salt are higher, are more conducive to industrial applications.
Summary of the invention
One of object of the present invention is to provide a kind of 3-[[[2-[[[4-[[oxyethyl group] formimino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] the new solid-state form of ethyl propionate (formula V), this new solid-state form purity is higher, more stable, be more conducive to preparation of industrialization dabigatran etcxilate.
Another object of the present invention is to provide above-mentioned 3-[[[2-[[[4-[[oxyethyl group] formimino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] preparation method of the new solid-state form of ethyl propionate (formula V).
Another object of the present invention is to provide above-mentioned 3-[[[2-[[[4-[[oxyethyl group] formimino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] the new solid-state form of ethyl propionate (formula V) is for the preparation of the application of dabigatran etcxilate.
Object of the present invention realizes by following proposal:
On the one hand, the invention provides a kind of salt of formula V compound, i.e. compound shown in formula V-A,
Wherein, the value of n is 1 to 3; A is selected from pKa and is greater than-2 acid, comprises phosphoric acid, oxalic acid, citric acid, formic acid, acetic acid, oxyacetic acid, L-amygdalic acid, D-amygdalic acid, DL-amygdalic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, DL-LACTIC ACID, pyruvic acid, propanedioic acid, succsinic acid, fumaric acid, L MALIC ACID, D-malic acid, DL-oxysuccinic acid, L-TARTARIC ACID, D-tartrate, DL-tartrate, mesotartaric acid, toxilic acid, phenylformic acid, 4-HBA, toluylic acid, nicotinic acid, styracin, Whitfield's ointment, 2-phenoxy benzoic acid or acetylsalicylic acid etc.
In above formula V-A, n refers to mole ratio of components of contained acid in molecular structure, can pass through 1the modes such as H-NMR, ultimate analysis, HPLC are measured.N preferably 1,2 or 3.
In above formula V-A, pKa is to be the negative logarithm of acid ionization constant Ka, if selected acid is polyprotonic acid, pKa is this sour pKa1.The acid that the preferred pKa of A is greater than-1, the acid that more preferably pKa is greater than 0, the acid that most preferably pKa is greater than 1.The pKa of common acid is all on the books at various kinds of document, handbook or reference book, as recorded the pKa value of multiple acid in " Handbook of Pharmaceutical Salts Properties, Selection, the and Use " of WILEY-VCH publication.
In above formula V-A, imidic acid ethyl ester (formula V) is combined by the form of the non covalent bonds such as ionic linkage, hydrogen bond with acid.Be understandable that, although claim in the present invention that formula V-A compound is salt, it should comprise salt, eutectic or their mixed form of classical definition, and the form such as their polycrystalline, hydrate, solvate.
In one embodiment, the invention provides the imidic acid ethoxal salt shown in a kind of formula V-2,
In one embodiment, the invention provides the imidic acid ethyl ester dioxalic acid salt shown in a kind of formula V-3,
In one embodiment, the invention provides imidic acid ethyl ester three oxalate shown in a kind of formula V-4,
In one embodiment, the invention provides the imidic acid ethyl ester benzoate shown in a kind of formula V-5,
In one embodiment, the invention provides the imidic acid ethyl ester fumarate shown in a kind of formula V-6,
In one embodiment, the invention provides the imidic acid acetophos hydrochlorate shown in a kind of formula V-7,
In one embodiment, the invention provides the imidic acid ethyl ester Citrate trianion shown in a kind of formula V-8,
On the other hand, the invention provides the preparation method of imidic acid ethyl ester salt V-A, the method comprises:
(1), compound IV or its salt are mixed with ethanol, under the effect of hydrogenchloride, be converted into imidic acid carbethoxy hydrochloride V-1;
(2), with alkali, imidic acid carbethoxy hydrochloride V-1 is converted into imidic acid ethyl ester V;
(3), imidic acid ethyl ester V and corresponding sour A are dissolved in suitable solvent, separate out solid, minute isolated solid;
(4), optionally, separated solid is dried, or dry again after being further purified.
In above-mentioned steps (1), compound IV or its salt can be by disclosed method preparations in CN1248251A, CN1861596A, CN102985416A etc.
In above-mentioned steps (1), the salt of compound IV comprises hydrochloride, hydrobromate, hydriodate, vitriol, mesylate, benzene sulfonate, tosilate, phosphoric acid salt, formate, acetate, maleate etc.
In above-mentioned steps (1), the consumption of hydrogenchloride generally should make ethanolic soln saturated; Temperature of reaction is generally-30～60 ℃, preferably 0～40 ℃; Definite ordinary method that can adopt this area in reaction times, as determined the reaction times with TLC or HPLC monitoring reaction process.
In above-mentioned steps (2), described alkali comprises mineral alkali, as the aqueous solution of sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide etc.; Also comprise organic bases, as the aqueous solution of triethylamine etc.
In above-mentioned steps (2), by the method that alkali transforms, comprise: step (1) is direct alkaline cleaning after completion of the reaction; If or the imidic acid carbethoxy hydrochloride V-1 that step (1) forms separates out in reaction system, can be isolated, and then with alkaline purification; Or the combination of above-mentioned one or more methods.By the process of alkaline purification, be generally with alkali the system pH containing imidic acid ethyl ester V is adjusted to alkalescence, preferably pH is 9-11; Use again and the immiscible organic solvent extraction of water, comprise methylene dichloride, trichloromethane, butylacetate, ethyl acetate, methyl acetate, methyl tertiary butyl ether, toluene etc. with the immiscible organic solvent of water, preferred methylene dichloride wherein, butylacetate, ethyl acetate; Then concentrated organic phase obtains imidic acid ethyl ester V; Optionally, organic phase can be first through desiccant dryness such as anhydrous sodium sulphate, anhydrous magnesium sulfate, molecular sieves before concentrated.
In above-mentioned steps (3), A is selected from pKa and is greater than-2 acid, comprises phosphoric acid, oxalic acid, citric acid, formic acid, acetic acid, oxyacetic acid, L-amygdalic acid, D-amygdalic acid, DL-amygdalic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, DL-LACTIC ACID, pyruvic acid, propanedioic acid, succsinic acid, fumaric acid, L MALIC ACID, D-malic acid, DL-oxysuccinic acid, L-TARTARIC ACID, D-tartrate, DL-tartrate, mesotartaric acid, toxilic acid, phenylformic acid, 4-HBA, toluylic acid, nicotinic acid, styracin, Whitfield's ointment, 2-phenoxy benzoic acid or acetylsalicylic acid etc.
In above-mentioned steps (3), the molar ratio of sour A and imidic acid ethyl ester V is generally at 0.5:1 to 4:1.
In above-mentioned steps (3), " suitable solvent " comprises ethanol, methylene dichloride, acetone etc.Dissolution mechanism comprises imidic acid ethyl ester V and sour A is dissolved in to suitable solvent simultaneously; Or imidic acid ethyl ester V and sour A are dissolved in respectively to suitable solvent, remix etc.Solvent temperature is generally 0 ℃ to solvent boiling point, preferably 10～30 ℃.
In above-mentioned steps (3), the method of " separating out solid " is conventional in the art method, comprise reacting and separate out solid, the cooling solid of separating out, add poor solvent to separate out solid, separate out solid etc. after concentrating out partial solvent, these methods can be used separately also and can be used in combination, can under standing condition, carry out, also can under agitation condition, carry out.Described " solid is separated out in reaction " refers in the suitable solvent at a certain temperature, and imidic acid ethyl ester V and acid have formed the less imidic acid ethyl ester salt V-A of solubleness and separated out solid because mutually combining.Described " poor solvent " refers at normal temperatures to formed imidic acid ethyl ester salt V-A solvability solvent bad and can be miscible with the suitable solvent of dissolving imidic acid ethyl ester V and sour A, as ether, isopropyl ether, methyl tertiary butyl ether, normal hexane, normal heptane etc.
In above-mentioned steps (3), " separation " can adopt and filter the ordinary method waiting in the art.Optionally, can to collected solid, wash with suitable solvent.
In above-mentioned steps (4), " being dried " mode comprises constant pressure and dry, drying under reduced pressure or their applied in any combination.The method " being further purified " comprises the forms such as recrystallization, pulp, washing.
Exemplary, in one embodiment, the invention provides the preparation method of the imidic acid ethoxal salt shown in a kind of formula V-2.The method comprises:
(1), compound IV or its salt are mixed with ethanol, under the effect of hydrogenchloride, be converted into imidic acid carbethoxy hydrochloride V-1;
(2), with alkali, imidic acid carbethoxy hydrochloride V-1 is converted into imidic acid ethyl ester V;
(3) molar ratio, by imidic acid ethyl ester V and oxalic acid with 1:0.8 to 1:1.5 is dissolved in suitable solvent, separates out solid, minute isolated solid;
(4), optionally, separated solid is dried, or dry again after being further purified.
In above-mentioned steps (1), the salt of compound IV comprises hydrochloride, hydrobromate, hydriodate, vitriol, mesylate, benzene sulfonate, tosilate, phosphoric acid salt, formate, acetate, maleate etc.
In above-mentioned steps (1), the consumption of hydrogenchloride generally should make ethanolic soln saturated; Temperature of reaction is generally-30～60 ℃, preferably 0～40 ℃; Definite ordinary method that can adopt this area in reaction times, as determined the reaction times with TLC or HPLC monitoring reaction process.
In above-mentioned steps (2), described alkali comprises mineral alkali, as the aqueous solution of sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide etc.; Also comprise organic bases, as the aqueous solution of triethylamine etc., preferred aqueous sodium carbonate, the aqueous solution of wet chemical or triethylamine.
In above-mentioned steps (2), treat that step (1) adds after completion of the reaction alkali and adjusts system pH to alkalescence, preferably pH is 9-11; Use again and the immiscible organic solvent of water, as extractions such as methylene dichloride, trichloromethane, butylacetate, ethyl acetate, methyl acetate, methyl tertiary butyl ether, toluene, preferred methylene dichloride wherein, butylacetate, ethyl acetate; Then concentrated organic phase obtains imidic acid ethyl ester V; Optionally, organic phase can be first through desiccant dryness such as anhydrous sodium sulphate, anhydrous magnesium sulfate, molecular sieves before concentrated.
In above-mentioned steps (3), the preferred acetone of suitable solvent.Dissolution mechanism comprises imidic acid ethyl ester V and oxalic acid is dissolved in to suitable solvent simultaneously; Or imidic acid ethyl ester V and oxalic acid are dissolved in respectively to suitable solvent, remix etc.Solvent temperature is generally 0 ℃ to solvent boiling point, preferably 10～30 ℃.
In above-mentioned steps (3), the method of " separating out solid " is conventional in the art method, comprise reacting and separate out solid, the cooling solid of separating out, add poor solvent to separate out solid, separate out solid etc. after concentrating out partial solvent, these methods can be used separately also and can be used in combination, can under standing condition, carry out, also can under agitation condition, carry out.Poor solvent comprises ether, isopropyl ether, methyl tertiary butyl ether, normal hexane, normal heptane etc.
In above-mentioned steps (3), " separation " can adopt and filter the ordinary method waiting in the art.Optionally, can to collected solid, wash with suitable solvent.
In above-mentioned steps (4), " being dried " mode comprises constant pressure and dry, drying under reduced pressure or their applied in any combination.The method " being further purified " comprises the forms such as recrystallization, pulp, washing.
Imidic acid ethoxal salt shown in the prepared formula V-2 of this embodiment is a kind of crystal.
Therefore, the invention provides the crystal of a kind of imidic acid ethoxal salt V-2.Being characterized as of the powder x-ray diffraction collection of illustrative plates of this crystal (using CuK α source): be that 7.0 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.3 ° ± 0.2 °, 19.2 ° ± 0.2 °, 22.5 ° ± 0.2 °, 23.8 ° ± 0.2 ° equipotential is equipped with characteristic of correspondence diffraction peak in 2 θ values.In order to express easily, this crystal formation is called to " imidic acid ethoxal salt crystal form A ".
In one embodiment, in the powder x-ray diffraction collection of illustrative plates of imidic acid ethoxal salt crystal form A provided by the invention (using CuK α source), in 2 θ values, be that 7.0 ° ± 0.2 °, 14.1 ° ± 0.2 °, 14.5 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.3 ° ± 0.2 °, 16.8 ° ± 0.2 °, 19.2 ° ± 0.2 °, 22.0 ± 0.2 °, 22.5 ° ± 0.2 °, 23.8 ° ± 0.2 °, 28.8 ° ± 0.2 ° equipotential is equipped with characteristic of correspondence diffraction peak.
In one embodiment, imidic acid ethoxal salt crystal form A provided by the invention has the feature of powder x-ray diffraction collection of illustrative plates representative as shown in Figure 1.
In one embodiment, the crystal formation purity of imidic acid ethoxal salt crystal form A provided by the invention (being to contain the quality percentage composition of crystal form A in imidic acid ethoxal salt) is generally greater than 10%, is preferably greater than 40%, is most preferably greater than 70%.
Aforesaid method does not need the protection of the rare gas elementes such as nitrogen, and operation is easy; The imidic acid ethoxal salt V-2 making generally more than 96%, and has satisfactory stability, suitable long-term storage without the purity being further purified.
Exemplary, in another embodiment, the invention provides the preparation method of the imidic acid ethyl ester dioxalic acid salt shown in a kind of formula V-3.The method comprises:
(1), compound IV or its salt are mixed with ethanol, under the effect of hydrogenchloride, be converted into imidic acid carbethoxy hydrochloride V-1;
(2), with alkali, imidic acid carbethoxy hydrochloride V-1 is converted into imidic acid ethyl ester V;
(3) molar ratio, by imidic acid ethyl ester V and oxalic acid with 1:1.8 to 1:2.5 is dissolved in suitable solvent, separates out solid, minute isolated solid;
(4), optionally, separated solid is dried, or dry again after being further purified.
In above-mentioned steps (1), the salt of compound IV comprises hydrochloride, hydrobromate, hydriodate, vitriol, mesylate, benzene sulfonate, tosilate, phosphoric acid salt, formate, acetate, maleate etc.
In above-mentioned steps (1), the consumption of hydrogenchloride generally should make ethanolic soln saturated; Temperature of reaction is generally-30～60 ℃, preferably 0～40 ℃; Definite ordinary method that can adopt this area in reaction times, as determined the reaction times with TLC or HPLC monitoring reaction process.
In above-mentioned steps (2), described alkali comprises mineral alkali, as the aqueous solution of sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide etc.; Also comprise organic bases, as the aqueous solution of triethylamine etc., preferred aqueous sodium carbonate, the aqueous solution of wet chemical or triethylamine.
In above-mentioned steps (2), treat that step (1) adds after completion of the reaction alkali and adjusts system pH to alkalescence, preferably pH is 9-11; Use again and the immiscible organic solvent of water, as extractions such as methylene dichloride, trichloromethane, butylacetate, ethyl acetate, methyl acetate, methyl tertiary butyl ether, toluene, preferred methylene dichloride wherein, butylacetate, ethyl acetate; Then concentrated organic phase obtains imidic acid ethyl ester V; Optionally, organic phase can be first through desiccant dryness such as anhydrous sodium sulphate, anhydrous magnesium sulfate, molecular sieves before concentrated.
In above-mentioned steps (3), the preferred acetone of suitable solvent.Dissolution mechanism comprises imidic acid ethyl ester V and oxalic acid is dissolved in to suitable solvent simultaneously; Or imidic acid ethyl ester V and oxalic acid are dissolved in respectively to suitable solvent, remix etc.Solvent temperature is generally 0 ℃ to solvent boiling point, preferably 10～30 ℃.
In above-mentioned steps (3), the method of " separating out solid " is conventional in the art method, comprise reacting and separate out solid, the cooling solid of separating out, add poor solvent to separate out solid, separate out solid etc. after concentrating out partial solvent, these methods can be used separately also and can be used in combination, can under standing condition, carry out, also can under agitation condition, carry out.Poor solvent comprises ether, isopropyl ether, methyl tertiary butyl ether, normal hexane, normal heptane etc.
In above-mentioned steps (3), " separation " can adopt and filter the ordinary method waiting in the art.Optionally, can to collected solid, wash with suitable solvent.
In above-mentioned steps (4), " being dried " mode comprises constant pressure and dry, drying under reduced pressure or their applied in any combination.The method " being further purified " comprises the forms such as recrystallization, pulp, washing.
Imidic acid ethyl ester dioxalic acid salt shown in the prepared formula V-3 of this embodiment is a kind of crystal.
Therefore, the invention provides the crystal of a kind of imidic acid ethyl ester dioxalic acid salt V-3.Being characterized as of the powder x-ray diffraction collection of illustrative plates of this crystal (using CuK α source): be that 4.7 ° ± 0.2 °, 5.0 ° ± 0.2 °, 5.8 ° ± 0.2 °, 9.3 ° ± 0.2 °, 19.5 ° ± 0.2 °, 25.3 ° ± 0.2 ° equipotential is equipped with characteristic of correspondence diffraction peak in 2 θ values.In order to express easily, this crystal formation is called to " imidic acid ethyl ester dioxalic acid salt crystal form A ".
In one embodiment, in the powder x-ray diffraction collection of illustrative plates of imidic acid ethyl ester dioxalic acid salt crystal form A provided by the invention (using CuK α source), in 2 θ values, be that 4.7 ° ± 0.2 °, 5.0 ° ± 0.2 °, 5.8 ° ± 0.2 °, 9.3 ° ± 0.2 °, 11.6 ° ± 0.2 °, 13.5 ° ± 0.2 °, 14.8 ° ± 0.2 °, 19.5 ° ± 0.2 °, 20.5 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.9 ° ± 0.2 °, 25.3 ° ± 0.2 °, 27.0 ° ± 0.2 ° equipotential is equipped with characteristic of correspondence diffraction peak.
In one embodiment, imidic acid ethyl ester dioxalic acid salt crystal form A provided by the invention has the feature of powder x-ray diffraction collection of illustrative plates representative as shown in Figure 2.
In one embodiment, the crystal formation purity of imidic acid ethyl ester dioxalic acid salt crystal form A provided by the invention (being to contain the quality percentage composition of crystal form A in imidic acid ethyl ester dioxalic acid salt) is generally greater than 10%, is preferably greater than 40%, is most preferably greater than 70%.
Aforesaid method does not need the protection of the rare gas elementes such as nitrogen, and operation is easy; The imidic acid ethyl ester dioxalic acid salt V-3 making generally more than 96%, and has satisfactory stability, suitable long-term storage without the purity being further purified.
In another embodiment, the present invention has substituted the oxalic acid in above-mentioned specific embodiments step (3) with phenylformic acid, and imidic acid ethyl ester V and benzoic molar ratio be 1:1 to 1:3.5, obtains the imidic acid ethyl ester benzoate shown in formula V-5.
In another embodiment, the present invention has substituted the oxalic acid in above-mentioned specific embodiments step (3) with fumaric acid, and the molar ratio of imidic acid ethyl ester V and fumaric acid is 1:1 to 1:3.5, obtains the imidic acid ethyl ester fumarate shown in formula V-6.
In another embodiment, the present invention has substituted the oxalic acid in above-mentioned specific embodiments step (3) with phosphoric acid, and the molar ratio of imidic acid ethyl ester V and phosphoric acid is 1:1 to 1:3.5, obtains the imidic acid acetophos hydrochlorate shown in formula V-7.
In another embodiment, the present invention has substituted the oxalic acid in above-mentioned specific embodiments step (3) with citric acid, and the molar ratio of imidic acid ethyl ester V and citric acid is 1:1 to 1:3.5, obtains the imidic acid ethyl ester Citrate trianion shown in formula V-8.
On the one hand, the invention provides the method for preparing amidine compound III or its salt with imidic acid ethyl ester salt V-A again, the method comprises: imidic acid ethyl ester salt V-A is reacted with ammonia reagent.
In aforesaid method, described " ammonia reagent " refers to comprise maybe and can discharge ammonia (NH 3) reagent, comprise ethanol, volatile salt, ammonium chloride, ammonium acetate of ammoniacal liquor, ammonia etc.
In aforesaid method, can directly imino acid ester ethyl ester salt V-A be reacted with ammonia reagent; Also can first imino acid ester ethyl ester salt V-A be dissociated into imidic acid ethyl ester V with alkali, then imidic acid ethyl ester V reacts with ammonia reagent again, wherein " free with alkali " available the art routine techniques carries out, as imino acid ester ethyl ester salt V-A joined in the two-phase system being formed by immiscible organic solvents of water such as the aqueous solution of sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide etc. and methylene dichloride, trichloromethane, ethyl acetate, methyl acetate, methyl tertiary butyl ether, toluene, then isolate organic phase, concentrated; Optionally, organic phase can be first through desiccant dryness such as anhydrous sodium sulphate, anhydrous magnesium sulfate, molecular sieves before concentrated.
In aforesaid method, when imino acid ester ethyl ester salt V-A directly reacts with ammonia reagent, can obtain the salt that amidine compound III and sour A form; Also can be in body, to add another kind of acid in reaction, as sulfuric acid, tosic acid, Phenylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid etc.
In aforesaid method, reaction solvent comprises the mixing solutions of ethanol or ethanol and other solvents (as water, methylene dichloride, acetone etc.).
In aforesaid method, the molar ratio of imidic acid ethyl ester salt V-A and ammonia reagent is generally 1:1 to 1:20, preferably 1:3 to 1:10.
In aforesaid method, temperature of reaction is generally 0 ℃ to solvent boiling point, preferably 10～30 ℃; Definite ordinary method that can adopt this area in reaction times, as determined the reaction times with TLC or HPLC monitoring reaction process.
In aforesaid method, after completion of the reaction, can adopt to filter and wait conventional in the art method to take separating obtained amidine compound III or its salt.Optionally, separated solid can be further purified, purifying method comprise the forms such as recrystallization, pulp, washing; Optionally, can separated solid be dried; Drying mode comprises constant pressure and dry, drying under reduced pressure or their applied in any combination.
In aforesaid method, can further comprise the amidine compound III of gained or its salt are reacted and obtain dabigatran etcxilate I with the just own ester of chloroformic acid.This operation can be by CN1248251A, and in CN1861596A, WO2010045900, CN102985416A etc., disclosed method is carried out.
In aforesaid method, can further comprise the amidine compound III of gained or its salt hydrolysis are obtained to dabigatran II or its salt.Because dabigatran II is amphoteric substance, thus it both can with alkali salify, also can with sour salify.As dabigatran II can become with sodium hydroxide, potassium hydroxide etc. relative sodium salt or sylvite, also can with the salifies such as hydrochloric acid, Hydrogen bromide, methylsulfonic acid, tosic acid, sulfuric acid, phosphoric acid.
Exemplary, the present invention in one embodiment, provides a kind of method of being prepared amidine compound III or its salt by imidic acid ethoxal salt V-2, and the method comprises: imidic acid ethoxal salt V-2 is reacted with ammonia reagent.
In aforesaid method, ammonia reagent comprises the ethanol, volatile salt, ammonium chloride, ammonium acetate of ammoniacal liquor, ammonia etc., preferably ammoniacal liquor.
In aforesaid method, can directly imidic acid ethoxal salt V-2 be reacted with ammonia reagent; Also can first imino acid ester ethoxal salt V-2 be dissociated into imidic acid ethyl ester V with alkali, then imidic acid ethyl ester V reacts with ammonia reagent again, wherein the process of " free with alkali " can be imino acid ester ethoxal salt V-2 and joins in the two-phase system being comprised of immiscible organic solvents of water such as the aqueous solution of sodium carbonate, salt of wormwood etc. and methylene dichloride, ethyl acetate, then isolate organic phase, concentrated; Optionally, organic phase can be first through desiccant dryness such as anhydrous sodium sulphate, anhydrous magnesium sulfate, molecular sieves before concentrated.
In aforesaid method, can be in body, to add another kind of acid in reaction, as tosic acid, Phenylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid etc.
In aforesaid method, reaction solvent comprises ethanol or ethanol and other solvents, as the mixing solutions of water, methylene dichloride, acetone etc.
In aforesaid method, the molar ratio of imidic acid ethoxal salt V-2 and ammonia reagent is generally 1:1 to 1:20, preferably 1:3 to 1:10.
In aforesaid method, temperature of reaction is generally 0 ℃ to solvent boiling point, preferably 10～30 ℃; Definite ordinary method that can adopt this area in reaction times, as determined the reaction times with TLC or HPLC monitoring reaction process.
In aforesaid method, after completion of the reaction, can adopt to filter and wait conventional in the art method to take separating obtained amidine compound intermediate III or its salt.Optionally, separated solid can be further purified, purifying method comprise the forms such as recrystallization, pulp, washing; Optionally, can separated solid be dried; Drying mode comprises constant pressure and dry, drying under reduced pressure or their applied in any combination.
Exemplary, the present invention in another embodiment, provides a kind of method of being prepared amidine compound III or its salt by imidic acid ethyl ester dioxalic acid salt V-3, and the method comprises: imidic acid ethyl ester dioxalic acid salt V-3 is reacted with ammonia reagent.
In aforesaid method, ammonia reagent comprises the ethanol, volatile salt, ammonium chloride, ammonium acetate of ammoniacal liquor, ammonia etc., preferably ammoniacal liquor.
In aforesaid method, can directly imidic acid ethyl ester dioxalic acid salt V-3 be reacted with ammonia reagent; Also can first imino acid ester ethyl ester dioxalic acid salt V-3 be dissociated into imidic acid ethyl ester V with alkali, then imidic acid ethyl ester V reacts with ammonia reagent again, wherein the process of " free with alkali " can be imino acid ester ethyl ester dioxalic acid salt V-3 and joins in the two-phase system being comprised of immiscible organic solvents of water such as the aqueous solution of sodium carbonate, salt of wormwood etc. and methylene dichloride, ethyl acetate, then isolate organic phase, concentrated; Optionally, organic phase can be first through desiccant dryness such as anhydrous sodium sulphate, anhydrous magnesium sulfate, molecular sieves before concentrated.
In aforesaid method, can be in body, to add another kind of acid in reaction, as tosic acid, Phenylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid etc.
In aforesaid method, reaction solvent comprises ethanol or ethanol and other solvents, as the mixing solutions of water, methylene dichloride, acetone etc.
In aforesaid method, the molar ratio of imidic acid ethyl ester dioxalic acid salt V-3 and ammonia reagent is generally 1:1 to 1:20, preferably 1:3 to 1:10.
In aforesaid method, temperature of reaction is generally 0 ℃ to solvent boiling point, preferably 10～30 ℃; Definite ordinary method that can adopt this area in reaction times, as determined the reaction times with TLC or HPLC monitoring reaction process.
In aforesaid method, after completion of the reaction, can adopt to filter and wait conventional in the art method to take separating obtained amidine compound intermediate III or its salt.Optionally, separated solid can be further purified, purifying method comprise the forms such as recrystallization, pulp, washing; Optionally, can separated solid be dried; Drying mode comprises constant pressure and dry, drying under reduced pressure or their applied in any combination.
As stated above, also can make amidine compound III or its salt by imidic acid ethyl ester benzoate V-5, imidic acid ethyl ester fumarate V-6, imidic acid acetophos hydrochlorate V-7, imidic acid ethyl ester Citrate trianion V-8 etc.
In aforesaid method, can further comprise the amidine compound III of gained or its salt are reacted and obtain dabigatran etcxilate I with the just own ester of chloroformic acid.
In aforesaid method, can further comprise the amidine compound III of gained or its salt hydrolysis are obtained to dabigatran II or its salt.
In one embodiment, amidine compound or its salt, in the mixing solutions of ethanol and water, through basic hydrolysiss such as sodium hydroxide, potassium hydroxide, are separated out to solid, minute isolated solid, optional, the solid of gained is dried, obtain dabigatran (II).It is a kind of dabigatran hydrate that this scheme makes dabigatran; It is further dabigatran monohydrate; Further, this dabigatran monohydrate is a kind of crystal, being characterized as of the powder x-ray diffraction collection of illustrative plates of this crystal (use CuK α source): in 2 θ values, be that 10.7 ° ± 0.2 °, 12.9 ° ± 0.2 °, 15.8 ° ± 0.2 °, 18.9 ° ± 0.2 °, 22.5 ° ± 0.2 °, 25.9 ° ± 0.2 ° equipotential is equipped with characteristic of correspondence diffraction peak.In order to express easily, this crystal formation is called to " dabigatran crystal form A ".In one embodiment, in the powder x-ray diffraction collection of illustrative plates of dabigatran crystal form A provided by the invention (using CuK α source), in 2 θ values, be that 9.6 ° ± 0.2 °, 10.7 ° ± 0.2 °, 12.1 ° ± 0.2 °, 12.9 ° ± 0.2 °, 15.8 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.4 ° ± 0.2 °, 22.5 ° ± 0.2 °, 25.9 ° ± 0.2 °, 26.7 ° ± 0.2 ° equipotential is equipped with characteristic of correspondence diffraction peak.In one embodiment, dabigatran crystal form A provided by the invention has the feature of powder x-ray diffraction collection of illustrative plates representative as shown in Figure 3.In one embodiment, being characterized as of the means of differential scanning calorimetry of dabigatran crystal form A provided by the invention (DSC) collection of illustrative plates (temperature rise rate: 10 ℃/minute): have endotherm(ic)peak within the scope of to 190 ℃ at approximately 75 ℃.In one embodiment, dabigatran crystal form A provided by the invention has the feature of means of differential scanning calorimetry collection of illustrative plates representative as shown in Figure 4.In one embodiment, being characterized as of the thermogravimetric analysis of dabigatran crystal form A provided by the invention (TGA) collection of illustrative plates (temperature rise rate: 10 ℃/minute): have 3～4% weightlessness within the scope of to 125 ℃ at approximately 75 ℃.In one embodiment, dabigatran crystal form A provided by the invention has the feature of thermogravimetric analysis collection of illustrative plates representative as shown in Figure 5.In one embodiment, the crystal formation purity of dabigatran crystal form A provided by the invention (being to contain the quality percentage composition of crystal form A in dabigatran) is generally greater than 10%, is preferably greater than 40%, is most preferably greater than 70%.
In one embodiment, dabigatran is dispersed in the mixing solutions of alcohol and water, then add the acid such as hydrochloric acid to carry out acid adjustment, make system molten clear, use again sodium bicarbonate, the alkali such as saleratus are adjusted alkali, separate out solid, divide isolated solid, optionally, the solid of gained can be dried, obtain the another kind of crystal formation of dabigatran (II), being characterized as of the powder x-ray diffraction collection of illustrative plates of this crystal (using CuK α source): be 11.8 ° ± 0.2 ° in 2 θ values, 15.3 ° ± 0.2 °, 16.9 ° ± 0.2 °, 17.5 ° ± 0.2 °, 22.0 ° ± 0.2 °, 24.3 ° ± 0.2 ° equipotential is equipped with characteristic of correspondence diffraction peak.In order to express easily, this crystal formation is called to " dabigatran crystal form B ".In one embodiment, in the powder x-ray diffraction collection of illustrative plates of dabigatran crystal form B provided by the invention (using CuK α source), in 2 θ values, be that 8.4 ° ± 0.2 °, 11.8 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.4 ° ± 0.2 °, 16.9 ° ± 0.2 °, 17.5 ° ± 0.2 °, 19.3 ° ± 0.2 °, 21.3 ° ± 0.2 °, 22.0 ° ± 0.2 °, 22.8 ° ± 0.2 °, 23.6 ± 0.2 °, 24.3 ° ± 0.2 °, 25.4 ± 0.2 °, 27.1 ± 0.2 °, 28.1 ± 0.2 ° equipotentials are equipped with characteristic of correspondence diffraction peak.In one embodiment, dabigatran crystal form B provided by the invention has the feature of powder x-ray diffraction collection of illustrative plates representative as shown in Figure 6.In one embodiment, the crystal formation purity of dabigatran crystal form B provided by the invention (being to contain the quality percentage composition of crystal form B in dabigatran) is generally greater than 10%, is preferably greater than 40%, is most preferably greater than 70%.
Above-mentioned dabigatran crystal form A and crystal form B good stability, be easy to preparation, be applicable to store.
The preparation method of above-mentioned amidine compound III or its salt is without carrying out under noble gas protection, anhydrous condition, and operation is easy; By imidic acid ethoxal salt V-2, the amidine compound intermediate III of the preparations such as imidic acid ethyl ester dioxalic acid salt V-3 or its salt generally more than 98.5%, are more conducive to industrial applications without the purity being further purified.
Powder x-ray diffraction analysis of the present invention is the CuK α source through Dutch PANalytical X`Pert PRO type powder x-ray diffraction instrument mensuration completes.Be understandable that in test process, owing to being subject to the impact of many factors (as the treatment process of the granularity of test sample, when test sample, instrument, test parameter, test operation etc.), the X-ray powder diffraction that same crystal formation is measured go out peak position or peak intensity has certain difference.Generally, in X-ray powder diffraction the experimental error of diffraction peak 2 θ values can be ± 0.2 °.Differential scanning calorimetric analysis Shi Jing U.S. TA DSC Q200 type differential scanning calorimeter of the present invention has been measured.Thermogravimetric analysis Shi Jing U.S. TA TGA Q500 type thermogravimetric analyzer of the present invention has been measured.
In sum, the present invention has following improvement and effect:
(1), imidic acid ethyl ester salt V-A provided by the invention is (as imidic acid ethoxal salt V-2, imidic acid ethyl ester dioxalic acid salt V-3 etc.) compared with prior art, purity is better, and stability is better, suitablely as process intermediates or starting raw material, stores and uses.
(2), imidic acid ethyl ester salt V-A provided by the invention is (as imidic acid ethoxal salt V-2, imidic acid ethyl ester dioxalic acid salt V-3 etc.) when the follow-up product amidine compound III of preparation or its salt compared with prior art, operation is easier, amidine compound III or its purity salt of gained are higher, be conducive to it and simplify purification process in the process of further preparing dabigatran etcxilate I or dabigatran II, improve and prepare yield, reduce production costs, be more suitable for industrial applications.
Accompanying drawing explanation
Fig. 1 is imidic acid ethoxal salt crystal form A powder x-ray diffraction collection of illustrative plates
Fig. 2 is imidic acid ethyl ester dioxalic acid salt crystal form A powder x-ray diffraction collection of illustrative plates
Fig. 3 is dabigatran crystal form A powder x-ray diffraction collection of illustrative plates
Fig. 4 is dabigatran crystal form A means of differential scanning calorimetry collection of illustrative plates
Fig. 5 is dabigatran crystal form A thermogravimetric analysis collection of illustrative plates
Fig. 6 is dabigatran crystal form B powder x-ray diffraction collection of illustrative plates
Fig. 7 is amidine compound mesylate crystal form A powder x-ray diffraction collection of illustrative plates
Embodiment
Below in conjunction with embodiment, the present invention is done to further detailed description, can make professional and technical personnel in the field more fully understand the present invention, but embodiments of the present invention are not limited to this.
Embodiment 1
The preparation of imidic acid ethyl ester (V)
At 10～15 ℃, by compound IV 48.2g (100mmol) stirring reaction 18 hours in saturated ethanol solution of hydrogen chloride 600mL, add wet chemical to regulate pH to be about 10, then with methylene dichloride 2000mL, divide three extractions, merge organic phase, successively water, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, concentrated, obtain imidic acid ethyl ester V.
(+)ESI-MS：(M+1) +＝529.2
Embodiment 2
The preparation of imidic acid ethoxal salt (V-2)
Under stirring at room, the solution that oxalic acid dihydrate 5.0g (40mmol) and acetone 100mL are made into drops in the solution that imidic acid ethyl ester V26.4g (50mmol) and acetone 200mL be made into, after dropwising, continue to stir 2 hours, separate out solid, filter, filter cake washing with acetone, drying under reduced pressure at 40-50 ℃, obtains imidic acid ethoxal salt V-2, white solid.
HPLC purity: 98.1%; Oxalic acid content: 14.3% (by HPLC external standard method).
1H-NMR(400MHz,d 6-DMSO,δ/ppm)：8.38-8.39(m,1H)，7.83-7.80(d,2H)，7.56-7.51(m,2H)，7.48(s，1H),7.41-7.38(d,1H)，7.17-7.09(m,2H)，6.90-6.84(m,3H)，4.67(s,2H)，4.47-4.40(q,2H)，4.25-4.21(t,2H)，4.00-3.93(q,2H)，3.76(s,3H)，2.71-2.66(t,2H)，1.41-1.36(t,3H)，1.13-1.09(t,3H)。
Through powder x-ray diffraction, measure, Fig. 1 is shown in by its powder x-ray diffraction collection of illustrative plates, and its observed value is as following table (get observed value corresponding to diffraction peak that relative intensity is greater than 3%, two-decimal is got in observed value round off):
By above-mentioned crystal formation called after " imidic acid ethoxal salt crystal form A ".
Embodiment 3
The preparation of imidic acid ethoxal salt (V-2)
Under stirring at room, the solution that oxalic acid dihydrate 9.5g (75mmol) and acetone 100mL are made into drops in the solution that imidic acid ethyl ester V26.4g (50mmol) and acetone 200mL be made into, after dropwising, continue to stir 2 hours, separate out solid, filter, filter cake washing with acetone, drying under reduced pressure at 40-50 ℃, obtains imidic acid ethoxal salt V-2, white solid.
HPLC purity: 98.4%; Oxalic acid content: 14.7% (by HPLC external standard method).
Embodiment 4
The preparation of imidic acid ethyl ester dioxalic acid salt (V-3)
Under stirring at room, the solution that oxalic acid dihydrate 12.6g (100mmol) and acetone 200mL are made into drops in the solution that imidic acid ethyl ester V26.4g (50mmol) and acetone 400mL be made into, after dropwising, continue to stir 2 hours, separate out solid, filter, filter cake washing with acetone, drying under reduced pressure at 40-50 ℃, obtains imidic acid ethyl ester dioxalic acid salt V-3, white solid.
HPLC purity: 97.3%; Oxalic acid content: 26.8% (by HPLC external standard method).
1H-NMR(400MHz,d 6-DMSO,δ/ppm)：8.39-8.37(m,1H)，7.81-7.79(d,2H)，7.59-7.46(m,3H)，7.42-7.40(d,1H)，7.17-7.11(m,2H)，6.88-6.85(m,3H)，4.67-4.66(d,2H)，4.49-4.44(m,2H)，4.24-4.20(m,2H)，4.00-3.95(m,2H)，3.76(s,3H)，2.70-2.66(m,2H)，1.44-1.41(t,3H)，1.14-1.10(t,3H)。
Through powder x-ray diffraction, measure, Fig. 2 is shown in by its powder x-ray diffraction collection of illustrative plates, and its observed value is as following table (get observed value corresponding to diffraction peak that relative intensity is greater than 3%, two-decimal is got in observed value round off):
By above-mentioned crystal formation called after " imidic acid ethyl ester dioxalic acid salt crystal form A ".
Embodiment 5
The preparation of imidic acid ethyl ester benzoate (V-5)
Under stirring at room, the solution that phenylformic acid 3.66g (30mmol) and acetone 20mL are made into drops to the solution that imidic acid ethyl ester V5.28g (10mmol) and acetone 40mL are made into, after dropwising, continue to stir 6 hours, filter, filter cake washing with acetone, at 40～50 ℃, vacuum-drying obtains imidic acid ethyl ester benzoate V-5, white solid.
HPLC purity: 96.2%.
1H-NMR(400MHz,d 6-DMSO,δ/ppm)：8.39(s,1H),7.95-7.93(m,2H),7.64-7.46(m,7H),7.40-7.38(d,1H),7.16-7.10(m,2H),6.89-6.87(d,1H),6.74-6.72(m,3H),4.55-4.54(d,2H),4.24-4.20(m,2H),4.18-4.12(m,2H),4.00-3.94(m,2H),3.76(s,3H),2.70-2.66(m,2H),1.29-1.26(t,3H),1.14-1.10(t,3H)。
Above-mentioned 1in H-NMR result, δ 8.39-6.72 (m, 17H) is attributed to H and the reactive hydrogen on phenyl ring, heterocycle, from its H number, can judge this title product that imidic acid ethyl ester and benzoic mole of ratio of components are 1:1.
Embodiment 6
The preparation of imidic acid ethyl ester fumarate (V-6)
Under stirring at room, the solution that fumaric acid 3.48g (30mmol) and ethanol 20mL are made into drop to imidic acid ethyl ester V5.28g (10mmol) and acetone 40mL solution in, after dropwising, continue to stir 6 hours, filter, filter cake washing with acetone, at 40～50 ℃, vacuum-drying obtains imidic acid ethyl ester fumarate V-6, white solid.
HPLC purity: 96.5%.
1H-NMR(400MHz,d 6-DMSO,δ/ppm)：8.39(s,1H)，7.60-7.38(m,5H)，7.16-7.10(m,2H)，6.89-6.87(d,1H)，6.78-6.82(m,1H)，6.75-6.73(d,2H)，6.61(s,2H)，4.55-4.54(d,2H)，4.24-4.20(m,2H)，4.19-4.15(m,2H)，4.00-3.94(m,2H)，3.76(s,3H)，2.70-2.66(m,2H)，1.32-1.27(t,3H)，1.14-1.10(t,3H)。
Above-mentioned 1in H-NMR result, δ 6.61 (s, 2H) is attributed to the H of two keys of fumaric acid, from its H number, can judge that this title product, mole ratio of components of imidic acid ethyl ester and fumaric acid is 1:1.
Embodiment 7
The preparation of imidic acid acetophos hydrochlorate (V-7)
Under stirring at room, the solution that phosphatase 11 .96g (20mmol) and ethanol 20mL are made into drop to imidic acid ethyl ester V5.28g (10mmol) and acetone 40mL solution in, after dropwising, continue to stir 6 hours, filter, filter cake washing with acetone, at 40～50 ℃, vacuum-drying obtains imidic acid acetophos hydrochlorate V-7, white solid.
HPLC purity: 97.5%, phosphoric analysis: 4.80%.
1H-NMR(400MHz,d 6-DMSO,δ/ppm)：8.39-8.38(d,1H)，7.71-7.68(d,2H)，7.56-7.52(t，1H),7.46(s，1H)，7.41-7.39(d，1H)，7.21-7.09(m,3H)，6.89-6.87(d,1H)，6.84-6.78(m,2H)，4.61(s,2H)，4.34-4.19(m,4H)，4.00-3.94(m,2H)，3.76(s,3H)，2.70-2.65(m,2H)，1.37-1.32(t,3H)，1.14-1.03(m,3H)。
From ultimate analysis, can judge that in this title product, mole ratio of components of imidic acid ethyl ester and phosphoric acid is 1:1 (its phosphorus content theoretical value is 4.94%).
Embodiment 8
The preparation of imidic acid ethyl ester Citrate trianion (V-8)
Under stirring at room, the mixing solutions that citric acid 3.84g (20mmol) and ethanol 20mL are made into drop to imidic acid ethyl ester V5.28g (10mmol) and acetone 40mL solution in, after dropwising, continue to stir 6 hours, filter, filter cake washing with acetone, at 40～50 ℃, vacuum-drying obtains imidic acid ethyl ester Citrate trianion V-8, white solid.
HPLC purity: 97.0%.
1H-NMR(400MHz,d 6-DMSO,δ/ppm)：8.39-8.38(d,1H)，7.69-7.66(d,2H)，7.56-7.52(t，1H),7.46(s，1H)，7.42-7.39(d，1H)，7.18-7.09(m,3H)，6.90-6.87(d,1H)，6.81-6.78(m,2H)，4.62-4.60(d,2H)，4.33-4.19(m,4H)，4.00-3.86(m,2H)，3.76(s,3H)，2.70-2.55(m,6H)，1.37-1.32(t,3H)，1.14-1.03(m,3H)。
Above-mentioned 1in H-NMR result, four hydrogen in δ 2.70-2.55 (m, 6H) are attributed to the H of citric acid methylene radical, from its H number, can judge that this title product, mole ratio of components of imidic acid ethyl ester and citric acid is 1:1.
Embodiment 9
The preparation of amidine compound oxalate (III-1)
At 15～20 ℃, imidic acid ethyl ester dioxalic acid salt V-37.08g (10mmol) is added in ethanol 100mL, and then add strong aqua 6mL (about 80mmol), stirring reaction, question response finishes rear suction filtration, filter cake is used ethanol, water washing successively, and at 50～55 ℃, vacuum-drying obtains amidine compound oxalate (III-1), white solid.
HPLC purity: 99.0%.
1H-NMR(400MHz,d-DMSO,δ/ppm)：8.39-8.37(d,1H)，7.63-7.39(m,6H)，7.16-7.13(d2H)，6.91-6.84(m,3H)，4.63(s,2H)，4.24-4.20(m,2H)，4.00-3.96(m,2H)，3.76(s,3H)，2.70-2.66(m,2H)，1.14-1.09(t,3H)。
Ultimate analysis: C59.2%, H5.02%, N16.5%.
Embodiment 10
The preparation of amidine compound oxalate (III-1)
At 15～20 ℃, imidic acid ethoxal salt V-26.18g (10mmol) is added in ethanol 100mL, and then add strong aqua 7mL (about 100mmol), stirring reaction, question response finishes rear suction filtration, filter cake is used ethanol, water washing successively, and at 50～55 ℃, vacuum-drying obtains amidine compound oxalate (III-1), white solid.
HPLC purity: 99.4%.
Embodiment 11
The preparation of amidine compound mesylate (III-2)
At 20～25 ℃, under stirring, wet chemical is joined in imidic acid ethyl ester dioxalic acid salt V-37.08g (10mmol), regulate pH value to be about 10, with methylene dichloride 150mL, divide three extractions, merge organic phase, with saturated sodium-chloride water solution, wash, anhydrous sodium sulfate drying, concentrated; To in enriched material, be dissolved in ethanol 60mL, then add methylsulfonic acid 1.92g (20mmol), then drip strong aqua 3.0mL (about 40mmol), stirring reaction 8 hours; Suction filtration, filter cake is used ethanol, water washing successively, and at 40～45 ℃, vacuum-drying obtains amidine compound mesylate (III-2), white solid.
HPLC purity: 99.2%.
1H-NMR(400MHz,d 6-DMSO,δ/ppm)：8.39-8.38(d,1H)，7.63-7.16(m,6H)，7.13-7.10(m,2H)，6.90-6.85(m,3H)，4.65-4.64(d,2H)，4.23-4.20(m,2H)，3.99-3.94(m,2H)，3.76(s,3H)，2.69-2.66(m,2H)，2.31(s,3H)，1.14-1.10(t,3H)。
Above-mentioned 1in H-NMR result, δ 2.31 (s, 3H) is attributed to the H of the methyl of methylsulfonic acid, from its H number, can judge that this title product, mole ratio of components of amidine compound and methylsulfonic acid is 1:1.
Through powder x-ray diffraction, measure, its powder x-ray diffraction figure is shown in Fig. 7, and its observed value is as following table (get observed value corresponding to diffraction peak that relative intensity is greater than 5%, two-decimal is got in observed value round off):
By above-mentioned crystal formation called after " amidine compound mesylate crystal form A ".
Embodiment 12
The preparation of dabigatran etcxilate (I)
Amidine compound oxalate (III-1) 5.0g (8.5mmol), acetone 40mL and water 40mL are mixed, add triethylamine 4.24g (42mmol), control temperature at 20～25 ℃, stir the lower just own ester 2.10g of chloroformic acid (12.8mmol) of dropping, dropwise rear continuation stirring reaction, in reaction process, separate out solid, reaction finishes rear suction filtration, and vacuum-drying obtains dabigatran etcxilate (I) at 45～55 ℃.
HPLC purity: 98.6%.
Embodiment 13
The preparation of dabigatran etcxilate (I)
Amidine compound mesylate (III-2) 5.0g (8.4mmol) and acetone 100mL are mixed, add triethylamine 4.24g (42mmol), control temperature at 20～25 ℃, stir the lower just own ester 2.10g of chloroformic acid (12.8mmol) of dropping, dropwise rear continuation and stir, reaction finishes rear suction filtration, concentrate filtrate to about 15mL, be cooled to 0～10 ℃ of stirring, filter the solid separate out, vacuum-drying obtains dabigatran etcxilate (I) at 45～55 ℃.
Embodiment 14
The preparation of dabigatran (II) and crystal form A
Amidine compound mesylate (III-2) 4.5g (7.5mmol) is joined in ethanol 60mL, stir the aqueous solution 150mL of the lower sodium hydroxide 1.2g of dropping (30mmol), dropwising rear continuation stirs 6 hours, filter, filter cake washes with water, and vacuum-drying obtains dabigatran (II) crystal form A at 40～50 ℃.
HPLC purity: 99.0%
(+)ESI-MS：(M+H) +＝472.2
1H-NMR(400MHz,d 6-DMSO+H 2SO 4,δ/ppm)：8.92(s,2H)，8.60(s,2H)，8.36-8.35(d,1H)，7.86-7.84(d,1H)，7.76-7.62(m,4H)，7.43-7.40(d,1H)，7.26-7.22(m,2H)，6.90-6.87(d,2H)，5.00(d,2H)，4.17-4.12(t,2H)，3.95(s,3H),，2.64-2.59(t,2H)。
Ultimate analysis (C 25h 25n 7o 3h 2o): C61.28%, H5.65%, N19.83%.
Through powder x-ray diffraction, measure, its powder x-ray diffraction figure is shown in Fig. 3, and its observed value is as following table (get observed value corresponding to diffraction peak that relative intensity is greater than 5%, two-decimal is got in observed value round off):
By above-mentioned crystal formation called after " dabigatran crystal form A ".
Through differential scanning calorimetric analysis, its means of differential scanning calorimetry (DSC) figure is shown in Fig. 4.
Through thermogravimetric analysis, its thermogravimetric analysis (TGA) figure is shown in Fig. 5.
Embodiment 15
The preparation of dabigatran crystal form B
Get dabigatran (II) 2.0g, join in the mixed solvent of water 30mL and methyl alcohol 30mL, drip dilute hydrochloric acid to completely molten clear, drip saturated aqueous solution of sodium bicarbonate to adularescent solid and separate out, continue stir about 1 hour, filter, filter cake washes with water, and drying under reduced pressure obtains dabigatran crystal form B.
Through powder x-ray diffraction, measure, its powder x-ray diffraction figure is shown in Fig. 6, and its observed value is as following table (get observed value corresponding to diffraction peak that relative intensity is greater than 10%, two-decimal is got in observed value round off):
By above-mentioned crystal formation called after " dabigatran crystal form B ".
Embodiment 16
The stability study of imines ester salt
Get respectively imidic acid carbethoxy hydrochloride V-1 (by the disclosed method preparation of embodiment 2a in patent CN102985416A), imidic acid ethoxal salt V-2 (pressing embodiment 2 method preparations), imidic acid ethyl ester dioxalic acid salt V-3 (pressing embodiment 4 method preparations), imidic acid ethyl ester fumarate V-6 (pressing embodiment 6 method preparations), imidic acid acetophos hydrochlorate V-7 (pressing embodiment 7 method preparations), imidic acid ethyl ester Citrate trianion V-8 (pressing embodiment 8 method preparations), be placed at 60 ℃ and test, after 10 days, with HPLC, detect related substance, result is as follows:
* the oxalic acid of listing in table, fumaric acid, phosphoric acid, the pKa that citric acid is corresponding is the value of its pKa1.
Above-mentioned research shows: the stability of imidic acid ethoxal salt provided by the invention, imidic acid ethyl ester dioxalic acid salt, imidic acid ethyl ester fumarate, imidic acid acetophos hydrochlorate, imidic acid ethyl ester Citrate trianion is obviously better than imidic acid carbethoxy hydrochloride.

Claims (17)

1. the compound shown in formula V-A,
Wherein, the value of n is 1 to 3; A is selected from pKa and is greater than-2 acid.
2. compound claimed in claim 1, wherein A comprises phosphoric acid, oxalic acid, citric acid, formic acid, acetic acid, oxyacetic acid, L-amygdalic acid, D-amygdalic acid, DL-amygdalic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, DL-LACTIC ACID, pyruvic acid, propanedioic acid, succsinic acid, fumaric acid, L MALIC ACID, D-malic acid, DL-oxysuccinic acid, L-TARTARIC ACID, D-tartrate, DL-tartrate, mesotartaric acid, toxilic acid, phenylformic acid, 4-HBA, toluylic acid, nicotinic acid, styracin, Whitfield's ointment, 2-phenoxy benzoic acid or acetylsalicylic acid; Preferred oxalic acid, phenylformic acid, fumaric acid, phosphoric acid or citric acid.
3. a preparation method for compound described in claim 1, the method comprises:
(1), compound IV or its salt are mixed with ethanol, under the effect of hydrogenchloride, be converted into imidic acid carbethoxy hydrochloride V-1;
(2), with alkali, imidic acid carbethoxy hydrochloride V-1 is converted into imidic acid ethyl ester V;
(3), imidic acid ethyl ester V and corresponding sour A are dissolved in suitable solvent, separate out solid, minute isolated solid;
(4), optionally, separated solid is dried, or dry again after being further purified;
?。
4. method claimed in claim 3, wherein, in step (2), alkali comprises the aqueous solution of sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, triethylamine; In step (3), A is selected from pKa and is greater than-2 acid.
5. method claimed in claim 4, in step (3), A comprises phosphoric acid, oxalic acid, citric acid, formic acid, acetic acid, oxyacetic acid, L-amygdalic acid, D-amygdalic acid, DL-amygdalic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, DL-LACTIC ACID, pyruvic acid, propanedioic acid, succsinic acid, fumaric acid, L MALIC ACID, D-malic acid, DL-oxysuccinic acid, L-TARTARIC ACID, D-tartrate, DL-tartrate, mesotartaric acid, toxilic acid, phenylformic acid, 4-HBA, toluylic acid, nicotinic acid, styracin, Whitfield's ointment, 2-phenoxy benzoic acid or acetylsalicylic acid; Preferred oxalic acid, phenylformic acid, fumaric acid, phosphoric acid or citric acid.
6. compound claimed in claim 1 is prepared a method for amidine compound III or its salt, and the method comprises: imidic acid ethyl ester salt V-A is reacted with ammonia reagent.
7. method claimed in claim 6, wherein ammonia reagent comprises ethanol, volatile salt, ammonium chloride, the ammonium acetate of ammoniacal liquor, ammonia.
8. an imidic acid ethyl ester salt, is selected from, the imidic acid ethoxal salt shown in a kind of formula V-2,
；
An imidic acid ethyl ester dioxalic acid salt shown in formula V-3,
；
An imidic acid ethyl ester benzoate shown in formula V-5,
；
An imidic acid ethyl ester fumarate shown in formula V-6,
；
An imidic acid acetophos hydrochlorate shown in formula V-7,
；
An imidic acid ethyl ester Citrate trianion shown in formula V-8,
。
9. salt claimed in claim 8, wherein,
Imidic acid ethoxal salt shown in described formula V-2 is specially imidic acid ethoxal salt crystal form A, uses CuK α source, and its powder x-ray diffraction collection of illustrative plates has characteristic diffraction peak in following 2 θ positions: 7.0 o± 0.2 o, 15.7 o± 0.2 o, 16.3 o± 0.2 o, 19.2 o± 0.2 o, 22.5 o± 0.2 o, 23.8 o± 0.2 o;
Imidic acid ethyl ester dioxalic acid salt shown in described formula V-3 is specially imidic acid ethyl ester dioxalic acid salt crystal form A, uses CuK α source, and its powder x-ray diffraction collection of illustrative plates has characteristic diffraction peak in following 2 θ positions: 4.7 o± 0.2 o, 5.0 o± 0.2 o, 5.8 o± 0.2 o, 9.3 o± 0.2 o, 19.5 o± 0.2 o, 25.3 o± 0.2 o.
10. the preparation method of imidic acid ethyl ester salt described in claim 8 or 9, the method comprises:
(1), compound IV or its salt are mixed with ethanol, under the effect of hydrogenchloride, be converted into imidic acid carbethoxy hydrochloride V-1;
(2), with alkali, imidic acid carbethoxy hydrochloride V-1 is converted into imidic acid ethyl ester V;
(3), imidic acid ethyl ester V and corresponding acid are dissolved in suitable solvent, separate out solid, minute isolated solid,
When described imidic acid ethyl ester salt is imidic acid ethoxal salt V-2, the molar ratio of imidic acid ethyl ester V and oxalic acid is 1:0.8 to 1:1.5,
When described imidic acid ethyl ester salt is imidic acid ethyl ester dioxalic acid salt V-3, the molar ratio of imidic acid ethyl ester V and oxalic acid is 1:1.8 to 1:2.5,
When described imidic acid ethyl ester salt is imidic acid ethyl ester benzoate V-5, imidic acid ethyl ester V and benzoic molar ratio are 1:1 to 1:3.5,
When described imidic acid ethyl ester salt is imidic acid ethyl ester fumarate V-6, the molar ratio of imidic acid ethyl ester V and fumaric acid is 1:1 to 1:3.5,
When described imidic acid ethyl ester salt is imidic acid acetophos hydrochlorate V-7, the molar ratio of imidic acid ethyl ester V and phosphoric acid is 1:1 to 1:3.5,
When described imidic acid ethyl ester salt is imidic acid ethyl ester Citrate trianion V-8, the molar ratio of imidic acid ethyl ester V and citric acid is 1:1 to 1:3.5;
(4), optionally, separated solid is dried, or dry again after being further purified.
11. methods claimed in claim 10, wherein,
In step (2), alkali comprises the aqueous solution of sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, triethylamine, preferred aqueous sodium carbonate, wet chemical or triethylamine aqueous solution;
In step (3), suitable solvent comprises ethanol, methylene dichloride, acetone.
Described in 12. 1 kinds of claims 8 or 9, imidic acid ethyl ester salt is prepared the method for amidine compound III or its salt, and the method comprises: imidic acid ethyl ester salt described in claim 8 or 9 is reacted with ammonia reagent.
Method described in 13. claims 12, wherein ammonia reagent comprises ethanol, volatile salt, ammonium chloride, the ammonium acetate of ammoniacal liquor, ammonia, preferably ammoniacal liquor.
Method described in 14. claims 12 adds another kind of acid in reaction system, comprises tosic acid, Phenylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid.
Method described in 15. claims 12, further comprises the amidine compound III of gained or its salt is reacted and obtain dabigatran etcxilate I with the just own ester of chloroformic acid.
Compound shown in 16. 1 kinds of formula V,
。
The preparation method of compound V described in 17. 1 kinds of claims 16, the method comprises:
(1), compound IV or its salt are mixed with ethanol, under the effect of hydrogenchloride, be converted into imidic acid carbethoxy hydrochloride V-1;
(2), with alkali, imidic acid carbethoxy hydrochloride V-1 is converted into imidic acid ethyl ester V.
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CN115322172A (en) * 2022-09-22 2022-11-11 安徽美诺华药物化学有限公司 High-yield synthesis process of dabigatran etexilate intermediate

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Publication number Priority date Publication date Assignee Title
CN102633713A (en) * 2012-03-22 2012-08-15 南京工业大学 Dabigatran etexilate intermediate, preparation method thereof and method for preparing dabigatran etexilate
CN102985416A (en) * 2010-07-09 2013-03-20 埃斯特维化学股份有限公司 Process of preparing a thrombin specific inhibitor
WO2013144903A1 (en) * 2012-03-28 2013-10-03 Dr. Reddy's Laboratories Limited Processes for the preparation of dabigatran etexilate

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CN102985416A (en) * 2010-07-09 2013-03-20 埃斯特维化学股份有限公司 Process of preparing a thrombin specific inhibitor
CN102633713A (en) * 2012-03-22 2012-08-15 南京工业大学 Dabigatran etexilate intermediate, preparation method thereof and method for preparing dabigatran etexilate
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* Cited by examiner, † Cited by third party
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CN115322172A (en) * 2022-09-22 2022-11-11 安徽美诺华药物化学有限公司 High-yield synthesis process of dabigatran etexilate intermediate
CN115322172B (en) * 2022-09-22 2024-01-26 安徽美诺华药物化学有限公司 High-yield synthesis process of dabigatran etexilate intermediate

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