CN105461706B - The related substance of razaxaban or its salt, wherein mesosome, preparation method and purposes - Google Patents
The related substance of razaxaban or its salt, wherein mesosome, preparation method and purposes Download PDFInfo
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- CN105461706B CN105461706B CN201410398162.5A CN201410398162A CN105461706B CN 105461706 B CN105461706 B CN 105461706B CN 201410398162 A CN201410398162 A CN 201410398162A CN 105461706 B CN105461706 B CN 105461706B
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Abstract
The invention discloses a kind of related substance of razaxaban or its salt, wherein mesosome, preparation method and purposes.The structural formula of razaxaban of the invention in relation to substance is as shown in formula I; preparation method includes the following steps: in organic solvent; in the presence of alkali; the related substance of razaxaban shown in formula I will be made such as formula III compound represented or its hydrochloride and such as formula IV compound represented progress acylation reaction；It is described if formula III compound represented and the molar ratio such as formula IV compound represented are 1:(1~1.5)；The temperature of the acylation reaction is -10 DEG C~30 DEG C.The related substance of razaxaban of the invention is the necessity of razaxaban quality control, the impurity generated in razaxaban synthesis can be effectively identified, to control the drug quality of razaxaban.
Description
Technical field
It is particularly related to a kind of related substance of razaxaban or its salt, wherein mesosome, preparation method and purposes.
Background technique
Razaxaban, the entitled chloro- N- of 5- of chemistry ((5S) -2- oxo -3- [4- (3- oxo -4- morpholinyl) phenyl] -1,
3- oxazoline -5- base } methyl) -2- thenoyl amine, molecular formula C19H18ClN3O5S, molecular weight 435.88, CAS registration number
366789-02-8 is developed by Beyer Co., Ltd (Bayer).It is listed for the first time in Canada within 2008, enters China within 2009
Market is obtained FDA approval in July, 2011 and is listed in the U.S..Razaxaban is clinically mainly used for carrying out select a time hip joint or knee
The adult patients of joint replacement surgery reduce non-valvular atrial fibrillation patient and stroke and whole body occur to prevent venous thronbosis
The risk of property embolism, structure are as follows:
The synthetic method of patent WO2013123893 report razaxaban are as follows: be with 4- (4- aminophenyl) -3- morpholone
Compound shown as a formula V is made in starting material under the action of solid phosgene, then with 2- [(2S) -2- Oxyranyle first
Base] the obtained such as Formula IV compound represented of -1H- iso-indoles -1,3 (2H)-diketone condensation, then remove amino protecting group and obtain such as formula
II compound represented finally reacts with such as formula IV compound represented and razaxaban is made, and specific synthetic route is as follows:
Summary of the invention
The technical problem to be solved by the present invention is to generate impurity, Bu Nengyou to overcome in existing razaxaban synthesis
The technical issues of effect identification and quality control, and provide a kind of related substance of razaxaban or its salt, wherein mesosome, preparation side
Method and purposes.The related substance of razaxaban of the invention is the necessity of razaxaban quality control, can effectively identify that benefit is cut down
The impurity generated in husky class's synthesis, to control the drug quality of razaxaban.
Inventor is during repeating the razaxaban of the process route synthesis in patent WO2013123893, discovery benefit
Cutting down can be containing the very small open loop impurity of a solubility in husky class, and the conventional purification methods such as recrystallization are difficult to be eliminated, and
And since the content of the impurity is too low, and poor solubility, determining structure can not be extracted, last inventor is by repeatedly examination
Collection razaxaban recrystallization mother liquor is checked and accepted, Structural Identification is carried out to it, and the presence of the impurity is to the quality shadow of razaxaban
Sound is very big, therefore efficiently controlling and remove the impurity is the key that the control of razaxaban quality.Inventor is through a large amount of experiment hair
Existing, the quality of razaxaban is controlled must use this open loop impurity reference substance to be positioned in the foundation of analysis method, thus
Open loop impurity is the necessity of razaxaban quality control.In addition, the presence of impurity is it is also possible to cause serious side reaction, because
And there is an urgent need in the art to effectively identify the impurity generated in razaxaban synthesis.
The present invention solves above-mentioned technical problem eventually by following technical scheme.
The present invention provides a kind of related substances of razaxaban or its salt shown in formula I；
Salt of the razaxaban shown in formula I in relation to substance is the salt that compound and acid shown in formula I are formed.
The acid can be the acid of this field routine, preferably inorganic acid or organic acid.The inorganic acid is preferably hydrochloric acid, hydrogen
Bromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid.The organic acid is preferably formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, amber
Amber acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid or glutamic acid.
The present invention also provides a kind of above-mentioned preparation method of razaxaban shown in formula I in relation to substance or its salt:
When preparing the related substance of razaxaban shown in formula I comprising the following steps: in organic solvent, in alkali
Under effect, it will be made such as such as formula III compound represented or its hydrochloride and such as formula IV compound represented progress acylation reaction
The related substance of razaxaban shown in Formulas I；Described the rubbing such as formula III compound represented and such as formula IV compound represented
You are than being 1:(1~1.5)；The temperature of the acylation reaction is -10 DEG C~30 DEG C；
When preparing the salt of razaxaban shown in formula I in relation to substance comprising the following steps: in organic solvent,
It, will be such as formula III compound represented or its hydrochloride and such as formula IV compound represented progress acylation reaction, system under the action of alkali
Obtain the related substance of razaxaban shown in formula I；It is described as formula III compound represented or its hydrochloride with such as formula IV institute
The molar ratio of the compound shown is 1:(1~1.5)；The temperature of the acylation reaction is -10 DEG C~30 DEG C；Then in solvent
In, the related substance of razaxaban shown in formula I obtained and acid are subjected to salt-forming reaction, are made shown in formula I
Salt of the razaxaban in relation to substance；
When preparing the related substance of razaxaban shown in formula I, the following steps are preferably included: by organic solvent, alkali
It mixes, then mixed with the organic solution of such as formula IV compound represented, carries out with such as formula III compound represented or its hydrochloride
The related substance of razaxaban shown in formula I is made in acylation reaction；It is described as formula III compound represented with such as formula IV
The molar ratio of compound represented is 1:(1~1.5)；The temperature of the acylation reaction is -10 DEG C~30 DEG C.
When preparing the salt of razaxaban shown in formula I in relation to substance, the following steps are preferably included: will be organic molten
Agent, alkali and such as formula III compound represented or its hydrochloride mix, then mixed with the organic solution of such as formula IV compound represented
It closes, carries out acylation reaction, the related substance of razaxaban shown in formula I is made；It is described as formula III compound represented with
If the molar ratio of formula IV compound represented is 1:(1~1.5)；The temperature of the acylation reaction is -10 DEG C~30 DEG C；Then
In a solvent, the related substance of razaxaban shown in formula I obtained and acid are subjected to salt-forming reaction, such as Formulas I is made
Shown in salt of the razaxaban in relation to substance.
The acid can be the acid of this field routine, preferably inorganic acid or organic acid.The inorganic acid is preferably
For hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid.The organic acid be preferably formic acid, acetic acid, propionic acid, oxalic acid,
Malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid or paddy
Propylhomoserin.
The temperature of the acylation reaction is preferably -5~20 DEG C, more preferably 0~10 DEG C.
It is described as formula III compound represented or its hydrochloride and the molar ratio of such as formula IV compound represented are preferably
1:(1~1.4).
Organic solvent in the acylation reaction can be the organic solvent of the such reaction routine in this field, as long as not influencing
Reaction carries out, preferably one of halogenated hydrocarbon solvent, aromatic hydrocarbon solvent and esters solvent or a variety of.It is described
Halogenated hydrocarbon solvent be preferably methylene chloride.The aromatic hydrocarbon solvent is preferably toluene.The esters solvent
Preferably ethyl acetate and/or butyl acetate.
The alkali can be the alkali of the such reaction routine in this field, preferably triethylamine, n,N-diisopropylethylamine, carbon
One of sour hydrogen sodium, saleratus, sodium carbonate and potassium carbonate are a variety of, are more preferably triethylamine.
Solute in the organic solution such as formula IV compound represented is such as formula IV compound represented, described
As formula IV compound represented organic solution in the type of organic solvent be not especially limited, as long as do not influence reaction into
Row.Organic solvent in the organic solution such as formula IV compound represented is preferably aromatic hydrocarbon solvent, halogenated
One of hydrocarbon solvent and esters solvent are a variety of.The aromatic hydrocarbon solvent is preferably toluene.The halogenated hydrocarbon
It is preferred solvents methylene chloride.The esters solvent is preferably ethyl acetate.It is described such as formula IV compound represented
The mass percent of solute of organic solution be preferably 20%~35% (preferably 29%), the percentage refers to such as formula
The quality of IV compound represented accounts for the percentage of the gross mass of the described organic solution such as formula IV compound represented.
The alkali is preferably 1:1~2:1 with the molar ratio such as formula III compound represented or its hydrochloride.It is described
Acylation reaction in organic solvent be preferably with such as volume mass of formula III compound represented or its hydrochloride ratio
10mL/g~50mL/g.
The process of the acylation reaction can using the traditional test methods (such as TLC, HPLC or NMR) in this field into
Row monitoring, generally using such as formula III compound represented or the disappearance of its hydrochloride when as reaction end, the acylation reaction
Time is preferably 0.5~1 hour.
After the acylation reaction, preferably, also can further include the operation of post-processing.The post-processing
Method and condition can be the method and condition of the such post-reaction treatment routine in this field, preferably: after acylation reaction
Reaction solution, washed with the bicarbonate solution (sodium bicarbonate solution being preferably saturated) of saturation, organic layer is dry, filtering, filter
Through column chromatographic purifying (the preferred methylene chloride of mobile phase: methanol=20:1, volume ratio) after liquid concentration.
It wherein, is the preferred solvents of the salt-forming reaction water and/or organic solvent.It is used when in the salt-forming reaction
When to organic solvent, the organic solvent in the salt-forming reaction is preferably amide solvent, sulfoxide type solvents, C1~C4's
One of alcohols solvent and ketones solvent are a variety of.The amide solvent is preferably N,N-dimethylformamide
(DMF).The sulfoxide type solvents are preferably dimethyl sulfoxide (DMSO).The C1~C4Alcohols solvent be preferably
One of methanol, ethyl alcohol and isopropanol are a variety of.The ketones solvent is preferably acetone.In the salt-forming reaction
The volume mass of solvent and compound shown in formula I is more preferably 1.5mL/g~3mL/ than being preferably 1mL/g~4mL/g
g.The acid (HCl in such as hydrochloric acid, the H in sulfuric acid2SO4) with the molar ratio of the compound shown in formula I be preferably
1:1~4:1.The temperature of the salt-forming reaction is preferably 0~5 DEG C.The time of the salt-forming reaction is preferably 0.5~
1h.It is added, can not also dilute or straight in solid form after the sour adding manner can dilute or after being configured to aqueous solution
Connect addition.When the acid is configured to aqueous solution, the acid (HCl in such as hydrochloric acid, the H in sulfuric acid2SO4) configured
Aqueous solution in molar concentration be preferably 1mol/L~6mol/L, be more preferably 2mol/L~4mol/L, mole
Concentration refers to acid (HCl in such as hydrochloric acid, the H in sulfuric acid2SO4) substance amount and aqueous solution volume percentage.
After the salt-forming reaction, preferably, also can further include the operation of post-processing.The post-processing
Method and condition can be the method and condition of the such post-reaction treatment routine in this field, preferably: after salt-forming reaction
Reaction solution, mix with acetone, in 0~5 DEG C of (ice bath) crystallization, filter, it is dry.The time of the crystallization, which does not do, to be had
Body limits, and preferably 2 hours.
Wherein, preparation method of the razaxaban shown in formula I in relation to substance or its hydrochloride, can also be into one
Step comprise the steps of solvent or it is solvent-free in, under conditions of 50 DEG C~120 DEG C, by hydrazine hydrate with such as Formula II shown in change
It closes object and carries out reaction as follows, be made described such as formula III compound represented；Alternatively, solvent or it is solvent-free in, 50
DEG C~120 DEG C under conditions of, by hydrazine hydrate and such as Formula II compound represented carry out it is as follows react, be made it is described as
Formula III compound represented；Then in organic solvent, by it is obtained it is described as formula III compound represented and hydrochloric acid into
The described hydrochloride such as formula III compound represented is made in row salt-forming reaction；
When preparation it is described such as formula III compound represented when, the temperature of the reaction is preferably 80 DEG C~100
℃.It is the preferred solvents water and/or organic solvent in the preparation reaction such as formula III compound represented.
When using organic solvent in the preparation reaction such as formula III compound represented, the preparation is as shown in formula III
Organic solvent in the reaction of compound can be the organic solvent of the such reaction routine in this field, carry out as long as not influencing reaction,
, preferably C1~C4One of alcohols solvent, ether solvent and heteroaryl hydrocarbon solvent or a variety of.The C1~
C4Alcohols solvent be preferably one of methanol, ethyl alcohol and isopropanol or a variety of.The ether solvent is preferably two
Six ring of oxygen.The heteroaryl hydrocarbon solvent is preferably pyridine.Mole of the hydrazine hydrate and such as Formula II compound represented
It is more preferably 5:1~15:1 than being preferably 2:1~25:1.When preparation it is described such as formula III compound represented when, it is described
The process of reaction can be monitored using the traditional test methods (such as TLC, HPLC or NMR) in this field, generally with such as
As reaction end when Formula II compound represented disappears, the time of the reaction is preferably 8~12 hours.
It is described after reaction, also can further include the operation of post-processing.The method and item of the post-processing
Part can be the method and condition of the such post-reaction treatment routine in this field, preferably: by above-mentioned reaction solution after reaction,
Concentration (is preferably concentrated under reduced pressure), column chromatographic purifying (preferably methylene chloride/methanol/ammonium hydroxide=10/1/0.05, volume ratio).
When the preparation such as hydrochloride of formula III compound represented, the method and condition of the salt-forming reaction can be this
The conventional method and condition of the such reaction in field.It is described anti-at salt when the preparation such as hydrochloride of formula III compound represented
Organic solvent in answering is preferably one of alcohol solvent, ketone solvent and nitrile solvents or a variety of.The alcohols is molten
Agent is preferably isopropanol.The ketones solvent is preferably acetone.The nitrile solvents are preferably acetonitrile.Work as preparation
As formula III compound represented hydrochloride when, the hydrochloric acid adding manner can be concentrated hydrochloric acid after diluting or be configured to
It is added after aqueous solution, can not also dilute and be directly added into the form of concentrated hydrochloric acid.The concentration of HCl can be in the concentrated hydrochloric acid
The various normal concentrations in this field, preferably 36%~37%, the percentage refers to that the quality of hydrogen chloride accounts for the total matter of hydrochloric acid
The percentage of amount.When the concentrated hydrochloric acid is configured to aqueous solution, molar concentration of the HCl in the aqueous solution configured is preferable
Ground is 1mol/L~6mol/L, is more preferably 2mol/L~4mol/L, the molar concentration refers to the amount and water of the substance of HCl
The percentage of the volume of solution.It is described in the salt-forming reaction when the preparation such as hydrochloride of formula III compound represented
Hydrochloric acid in HCl, be preferably 1:1~6:1, more preferably 2:1~4:1 with the molar ratio of such as formula III compound represented.
The organic solvent and such as formula III when the preparation such as hydrochloride of formula III compound represented, in the salt-forming reaction
The volume mass of compound represented is more preferably 1.5mL/g~3mL/g than being preferably 1mL/g~5mL/g.When preparation such as
When the hydrochloride of formula III compound represented, the temperature of the salt-forming reaction is preferably 0~5 DEG C.When preparation such as formula III
When the hydrochloride of compound represented, it (is more preferably 5h) that the time of the salt-forming reaction, which is preferably 4~6h,.
The present invention also provides a kind of razaxaban as shown in formula III is in relation to the intermediate of substance or its acid salt；
The acid salt of the intermediate of the razaxaban as shown in formula III in relation to substance is preferably such as formula III institute
The hydrochloride of intermediate of the razaxaban shown in relation to substance.
System of the razaxaban as shown in formula III in relation to the intermediate of substance or its hydrochloride that the present invention also provides a kind of
Preparation Method:
When preparation is such as formula III compound represented comprising the following steps: solvent or it is solvent-free in, 50 DEG C~120
Under conditions of DEG C, by hydrazine hydrate and such as Formula II compound represented carry out it is as follows react, be made described such as formula III institute
The compound shown；
When preparation as formula III compound represented hydrochloride when comprising the following steps: solvent or it is solvent-free in,
Under conditions of 50 DEG C~120 DEG C, by hydrazine hydrate and such as Formula II compound represented carry out it is as follows react, be made described
Such as formula III compound represented；In organic solvent, by it is obtained it is described as formula III compound represented and hydrochloric acid carry out at
The described hydrochloride such as formula III compound represented is made in reactant salt；
Item of the condition of the method for the reaction with the method for the reaction above-mentioned for preparing compound as shown in Equation 3
Part.Side of the condition of the method for the salt-forming reaction with the salt-forming reaction of the salt above-mentioned for preparing compound as shown in Equation 3
The condition of method.
In the present invention, the related substance of razaxaban shown in formula I, preferably, its synthetic route is as follows:
The present invention also provides a kind of foregoing purposes of the razaxaban in relation to substance shown in formula I, wherein institute
The compound shown in formula I stated is used as the related substance reference substance of razaxaban quality control, or for the miscellaneous of razaxaban
Matter identification.
In the present invention, the preparation method and condition of the salt of razaxaban shown in formula I in relation to substance can also be pressed
Conventional method and condition preparation according to this field salt-forming reaction.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that:
The related substance of razaxaban of the invention is the necessity of razaxaban quality control, can effectively identify that benefit cuts down sand
The impurity generated in class's synthesis, and quantitative control is carried out to related substance.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
In the following example,1H-NMR spectrum uses Bruker-400 Nuclear Magnetic Resonance, and internal standard is tetramethylsilane,1H NMR
Chemical shift (δ) is with PPM record (10-6).Mass spectrum 6210 sewage sludge combined instrument of Agilent.
Liquid chromatogram inspection in the following example and in effect example in each HPLC detection and liquid chromatograph mass spectrography
The instrument of survey is 6210 liquid chromatogram of Agilent, and liquid chromatographic detection condition is all the same, is normal in the measurement of razaxaban
The condition of the liquid chromatogram of rule.
Razaxaban product in the following example refers to the razaxaban product obtained after recrystallization purifying.
Embodiment 1 (S) -2- (2- { [4- (5- methylamino -2- oxazoline -3- base) phenyl] amino } ethyoxyl) acethydrazide
It prepares (such as formula III compound represented)
It will be added in reaction flask such as Formula II compound represented (10g, 34mmol), and sequentially add 50mL methanol and hydrazine hydrate
(25mL, 424mmol) is warming up to 80 DEG C of reaction 12h.Yellow oil, column chromatographic purifying (mobile phase: DCM/ is concentrated under reduced pressure to obtain
MeOH/NH3H2O=10/1/0.05 off-white powder (5.5g, yield 49.5%, HPLC purity: 99.1%)) are obtained.
ESI-MS(m/z):324[M+H]+,346[M+Na]+。
1H NMR (400 MHz, DMSO-d6) δ: 1.55 (s, 2H), 2.75~2.85 (m, 2H), 3.18~3.22 (t,
2H), 3.56~3.59 (t, 2H), 3.73~3.77 (m, 1H), 3.91 (s, 2H), 3.93~3.98 (t, 1H), 4.23 (s, 2H),
4.50~4.56 (m, 1H), 5.56~5.59 (t, 1H), 6.61~6.64 (d, 2H), 7.24~7.26 (d, 2H), 9.00 (s,
1H)。
Embodiment 2 (S) -2- (2- { [4- (5- methylamino -2- oxazoline -3- base) phenyl] amino } ethyoxyl) acetyl hydrazonium salt
The preparation (such as hydrochloride of formula III compound represented) of hydrochlorate
It will be added in reaction flask such as formula III compound represented (2g, 6.2mmol), acetonitrile 10ml dissolution is added, is added dropwise
1.1mL (12.4mmol) concentrated hydrochloric acid (36%~37%), crystallization 5h under ice bath, filters to obtain white solid (1.98g, yield
80.6%, HPLC purity: 99.5%).
The preparation of 3 compound of formula I of embodiment
Such as formula III compound represented (1.62g, 5mmol), triethylamine (0.5g, 5mmol), two are added in reaction flask
29% toluene solution such as formula IV compound represented is added dropwise (wherein containing such as under -10 DEG C of stirrings in chloromethanes (60mL)
Formula IV compound represented 5mmol, toluene solution gross mass 3.1g, percentage are that the quality of formula IV compound represented such as accounts for first
The percentage of benzole soln gross mass), about 30min is finished, and is warming up to 0 DEG C the reaction was continued 0.5h.20ml saturated sodium bicarbonate is added
Solution, layering, organic layer dries, filters by anhydrous Na SO4, filtrate decompression concentration, residue through column chromatographic purifying (mobile phase:
DCM/MeOH=20/1) white solid (1.7g, yield 72%, HPLC purity 95.18%) is obtained.
ESI-MS(m/z):468[M+H]+,490[M+Na]+。
1H NMR(400 MHz,DMSO-d6) δ: 3.18~3.22 (dd, 2H), 3.56~3.59 (t, 4H), 3.72~3.75
(dd, 1H), 3.91 (s, 2H), 4.03~4.09 (m, 1H), 4.23 (s, 2H), 4.72~4.79 (m, 1H), 5.59~5.62 (t,
1H), 6.61~6.63 (d, 2H), 7.18~7.20 (t, 1H), 7.22 (s, 2H), 7.68~7.69 (d, 1H), 8.88~8.91
(t,1H),8.99(s,1H)。
The preparation of 4 compound of formula I of embodiment
Such as formula III compound represented (1.62g, 5mmol), n,N-diisopropylethylamine are added in reaction flask
29% toluene such as formula IV compound represented is added dropwise under 0 DEG C of stirring in (0.645g, 5mmol), methylene chloride (80mL)
(wherein containing such as formula IV compound represented 5mmol, toluene solution gross mass 3.1g, percentage is as shown in formula IV to solution
The quality of compound accounts for the percentage of toluene solution gross mass), it finishes, is warming up to 10 DEG C the reaction was continued 1h.20ml saturation is added
Sodium bicarbonate solution, layering, organic layer are dried, filtered by anhydrous Na SO4, and filtrate decompression concentration, residue is through column chromatographic purifying
(mobile phase: DCM/MeOH=20/1) obtains white solid (1.4g, yield 59%, HPLC purity: 96.5%)
The preparation of 5 compound of formula I of embodiment
Such as formula III compound represented (1.62g, 5mmol), triethylamine (0.5g, 5mmol), second are added in reaction flask
29% toluene solution such as formula IV compound represented is added dropwise (wherein containing as shown in formula IV in acetoacetic ester (60mL) at room temperature
Compound 7mmol, toluene solution gross mass 4.34g, percentage is as the quality of formula IV compound represented accounts for toluene solution
The percentage of gross mass), it finishes, is warming up to 30 DEG C the reaction was continued 0.5h.It is concentrated under reduced pressure, 10ml saturated sodium bicarbonate solution is added
Mashing, filtering, filter cake through column chromatographic purifying (mobile phase: DCM/MeOH=20/1) white solid (0.6g, yield 26%,
HPLC purity: 95.7%)
The preparation of 6 compound of formula I of embodiment
Be added in reaction flask as the hydrochloride (1.8g, 5mmol) of formula III compound represented, triethylamine (1g,
10mmol), 29% toluene solution (its such as formula IV compound represented is added dropwise under 0 DEG C of stirring in methylene chloride (60mL)
In containing such as formula IV compound represented 7mmol, toluene solution gross mass 4.34g, percentage is such as formula IV compound represented
Quality account for the percentage of toluene solution gross mass), finish, kept for 0 DEG C the reaction was continued 0.5h.20ml saturated sodium bicarbonate is added
Solution, layering, organic layer dries, filters by anhydrous Na SO4, filtrate decompression concentration, residue through column chromatographic purifying (mobile phase:
DCM/MeOH=20/1 white solid (1.3g, yield 56%, HPLC purity: 94.3%)) are obtained
Comparative example 7
Such as formula III compound represented (1.62g, 5mmol), triethylamine (1g, 10mmol), dichloro are added in reaction flask
29% toluene solution such as formula IV compound represented is added dropwise (wherein containing such as formula IV under 0 DEG C of stirring in methane (80mL)
Compound represented 10mmol, toluene solution gross mass 6.2g, percentage are that the quality of formula IV compound represented such as accounts for toluene
The percentage of solution gross mass), it finishes, the reaction was continued 0.5h.It is concentrated under reduced pressure, the mashing of 10ml saturated sodium bicarbonate solution is added,
Yellow solid is filtered to obtain, wherein principal product is disubstituted product as shown in Equation 5 for HPLC detection, and the HPLC of compound of formula I is pure
Degree is 12%.Obtaining white solid through column chromatographic purifying (mobile phase: DCM/MeOH=20/1), (0.21g, yield 9%, HPLC is pure
Degree: 92.9%)
The mass spectrometric data of disubstituted product as shown in Equation 5:
ESI-MS(m/z):612[M+H]+,634[M+Na]+。
The NMR data of disubstituted product as shown in Equation 5:
1H NMR(400 MHz,DMSO-d6) δ: 3.23~3.27 (m, 2H), 3.55~3.59 (t, 2H), 3.65~3.68
(t, 2H), 3.72~3.76 (m, 2H), 4.07 (s, 2H), 4.04~4.08 (t, 1H), 4.73~4.79 (m, 1H), 5.57~
5.60 (t, 1H), 6.52~6.54 (d, 2H), 7.17~7.23 (m, 4H), 7.68~7.72 (dd, 2H), 8.88~8.91 (t,
1H),9.90(s,1H),10.44(s,1H)。
The preparation of 8 compound of formula I hydrochloride of embodiment
The compound (0.93g, 2mmol) and 1.5mlDMF such as Formulas I are added in reaction flask, stirs dissolved clarification, 1mL2N is added
Hydrochloric acid stirs 30min, 20mL acetone is added, ice bath crystallization 2h is filtered, 60 DEG C of dry 2h obtain white solid (0.58g, yield
57%, HPLC purity: 97.1%)
The preparation of 9 compound of formula I sulfate of embodiment
The compound (0.93g, 2mmol) and 2.5mlDMF such as Formulas I are added in reaction flask, stirs dissolved clarification, 0.1g is added
The concentrated sulfuric acid that mass percent is 98% stirs 30min, 20mL acetone is added, ice bath crystallization 2h is filtered, 60 DEG C of dry 2h are obtained
White solid (0.51g, yield 45%, HPLC purity: 95.8%)
The preparation of 10 compound of formula I formates of embodiment
The compound (0.93g, 2mmol) and 2.5mlDMF such as Formulas I are added in reaction flask, stirs dissolved clarification, 0.15g is added
Formic acid stirs 30min, 20mL acetone is added, ice bath crystallization 2h is filtered, 60 DEG C of dry 2h obtain white solid (0.58g, yield
57%, HPLC purity: 96.5%)
The preparation of 11 compound of formula I mesylate of embodiment
The compound (1.22g, 2mmol) and 3.5mlDMF such as Formulas I are added in reaction flask, stirs dissolved clarification, 0.2g is added
Methanesulfonic acid stirs 30min, 20mL acetone is added, ice bath crystallization 2h is filtered, 60 DEG C of dry 2h obtain white solid (0.58g, yield
49%, HPLC purity: 94.9%)
The chloro- N- of 12 5- of embodiment ({ (5S) -2- oxo -3- [4- (3- oxo -4- morpholinyl) phenyl] -1,3- oxazoline -
5- yl } methyl) -2- thenoyl amine (razaxaban) preparation
In 250ml reaction flask be added as Formula II compound represented (10.56g, 36.25mmol), triethylamine (4.04g,
39.88mmol), methylene chloride (100mL) stirs dissolved clarification at 0 DEG C.29% toluene such as formula IV compound represented is added dropwise
(wherein containing such as formula IV compound represented 38mmol, toluene solution gross mass 23.6g, percentage is as shown in formula IV to solution
The quality of compound account for the percentage of toluene solution gross mass), react at room temperature 0.5h.Saturated sodium bicarbonate aqueous solution is added
(90mL) and normal heptane (200mL), filtering drying obtain faint yellow razaxaban crude product, obtain razaxaban product through DMF- water crystallization
(12.59g, yield 81.0%, HPLC purity 99.91%).
ESI-MS(m/z):436[M+H]+,438[M+H]+；
1H NMR(400MHz,CDCl3)δ:3.62(m,2H),3.72(m,2H),3.86(m,1H),3.98(m,2H),4.19
(m,3H),4.84(m,1H),7.17(m,1H),7.40(m,2H),7.56(m,2H),7.68(m,1H),8.89(s,1H)。
Effect example 1
Razaxaban crude product obtained in embodiment 12 is subjected to liquid chromatographic detection, testing result is shown in Table 1.
The retention time at each peak in the HPLC spectrogram of razaxaban crude product made from table 1, embodiment 12, peak height, peak area,
The information of relative area
In table 1, the peak number of the chromatographic peak of razaxaban is 7, as the peak number of the chromatographic peak of I compound represented of formula is
1。
Compound shown in formula I obtained in embodiment 3 is subjected to liquid chromatographic detection, testing result is shown in Table 2.
The retention time at each peak, peak height, peak in the HPLC spectrogram of compound shown in formula I made from table 2, embodiment 3
The information of area, relative area
In table 2, the peak number of the chromatographic peak of razaxaban is 3, as the peak number of the chromatographic peak of I compound represented of formula is
1。
Razaxaban product obtained in embodiment 12 is subjected to liquid chromatographic detection, testing result is shown in Table 3.Table 3 is implemented
The retention time at each peak, the information of peak height, peak area, relative area in the HPLC spectrogram of razaxaban product made from example 12
In table 3, the peak number of the chromatographic peak of razaxaban is 1.
Peak number is 7 in table 1 compound, the compound that peak number is 3 in table 2, the compound that peak number is 1 in table 3
Their chromatographic peak retention time is consistent, is all the chromatographic peak of razaxaban.
Peak number is 1 in table 1 compound, the compound that peak number is 1 in table 2, their chromatographic peak retention time one
It causes, is all the chromatographic peak of compound shown in formula I.
In summary the result of each example is as it can be seen that the related substance of razaxaban of the invention can effectively identify that razaxaban closes
At the impurity of middle generation, and its content in razaxaban product is calculated, to control the drug quality of razaxaban.And
And razaxaban product HPLC purity obtained is greater than 99.9% in embodiment 12, the impurity content of I compound represented of formula is small
In 0.01% (percentage is HPLC purity).
The identification of impurity in 13 razaxaban of embodiment
Be added in 250ml reaction flask compound as shown in Equation 2 (10.56g, 36.25mmol), triethylamine (4.04g,
39.88mmol), methylene chloride (100ml) stirs dissolved clarification at 0 DEG C.29% toluene that compound as shown in Equation 4 is added dropwise is molten
Liquid, percentage are mass percent of the quality of compound as shown in Equation 4 relative to solution gross mass, solution gross mass
23.6g reacts at room temperature 0.5h wherein the molal quantity of compound as shown in Equation 4 is 38mmol.It is molten that saturated sodium bicarbonate water is added
Liquid (90ml) and normal heptane (200ml), filtering drying obtain faint yellow razaxaban crude product (13.6g, yield 87%, HPLC purity:
97.3%), obtain razaxaban highly finished product (12.59g, yield 81.0%, HPLC purity 99.91%) through DMF- water crystallization, to
Upper razaxaban crystallization filtrate carries out liquid chromatograph mass spectrography detection, the liquid phase in liquid chromatograph mass spectrography testing result
Chromatographic results are as shown in table 4:
Table 4:
In table 4, the peak number of razaxaban is 4.The peak further progress liquid chromatogram-matter for being 1 to the peak number in table 4
Mass Spectrometer Method in spectrum combination, Mass Spectrometer Method result are as follows: MS (m/z): 468 [M+H]+,490[M+Na]+.This mass spectrometric data
It is consistent with the mass spectrometric data of compound shown in formula I obtained in embodiment 3, illustrate the method for compound shown in Chinese style I of the present invention
Compound shown in prepared formula I be exactly the chromatographic peak peak number in embodiment 12 in razaxaban crude product obtained be 1 it is miscellaneous
Matter (compound that chromatographic peak peak number is 1 i.e. in table 1).
Claims (11)
1. a kind of related substance of razaxaban or its salt shown in formula I；
2. the as described in claim 1 related substance of razaxaban or its salt shown in formula I, which is characterized in that it is described as
Salt of the razaxaban shown in Formulas I in relation to substance is the salt that compound and acid shown in formula I are formed；The acid is inorganic acid
Or organic acid.
3. the related substance of razaxaban or its salt shown in formula I as claimed in claim 2, which is characterized in that described inorganic
Acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid；And/or the organic acid is formic acid, acetic acid, propionic acid, grass
Acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid or
Glutamic acid.
4. a kind of related substance of razaxaban shown in formula I or its salt as described in claims 1 to 3 any claim
Preparation method, it is characterised in that:
When preparing the related substance of razaxaban shown in formula I comprising the following steps: in organic solvent, in the effect of alkali
Under, such as Formulas I will be made such as formula III compound represented or its hydrochloride and such as formula IV compound represented progress acylation reaction
Shown in razaxaban related substance；It is described as formula III compound represented with such as mole of formula IV compound represented
Than for 1:(1~1.5)；The temperature of the acylation reaction is -10 DEG C~30 DEG C；
When preparing the salt of razaxaban shown in formula I in relation to substance comprising the following steps: in organic solvent, in alkali
Under effect, it will be made such as such as formula III compound represented or its hydrochloride and such as formula IV compound represented progress acylation reaction
The related substance of razaxaban shown in Formulas I；It is described as formula III compound represented or its hydrochloride with as shown in formula IV
The molar ratio of compound is 1:(1~1.5)；The temperature of the acylation reaction is -10 DEG C~30 DEG C；Then in a solvent, will
The related substance of razaxaban shown in formula I and acid obtained carry out salt-forming reaction, and the benefit for being made shown in formula I cuts down sand
Salt of the class in relation to substance；
5. preparation method of the razaxaban as claimed in claim 4 in relation to substance or its salt, it is characterised in that:
When preparing the related substance of razaxaban shown in formula I comprising the following steps: by organic solvent, alkali and such as formula III
Compound represented or the mixing of its hydrochloride, then mixed with the organic solution of such as formula IV compound represented, acylation reaction is carried out,
The related substance of razaxaban shown in formula I is made；It is described such as formula III compound represented and the chemical combination as shown in formula IV
The molar ratio of object is 1:(1~1.5)；The temperature of the acylation reaction is -10 DEG C~30 DEG C；
When preparing the salt of razaxaban shown in formula I in relation to substance comprising the following steps: by organic solvent, alkali and such as
Formula III compound represented or the mixing of its hydrochloride, then mixed with the organic solution of such as formula IV compound represented, it is acylated
Reaction, is made the related substance of razaxaban shown in formula I；It is described as formula III compound represented with as shown in formula IV
Compound molar ratio be 1:(1~1.5)；The temperature of the acylation reaction is -10 DEG C~30 DEG C；Then in a solvent,
The related substance of razaxaban shown in formula I obtained and acid are subjected to salt-forming reaction, the benefit for being made shown in formula I is cut down
Salt of the husky class in relation to substance.
6. preparation method of the razaxaban as claimed in claim 4 in relation to substance or its salt, it is characterised in that:
When preparing the related substance of razaxaban shown in formula I or its salt, the temperature of the acylation reaction is -5~20 DEG C；
And/or it is described as formula III compound represented or its hydrochloride and the molar ratio such as formula IV compound represented be 1:(1~
1.4)；And/or the organic solvent in the acylation reaction is in halogenated hydrocarbon solvent, aromatic hydrocarbon solvent and esters solvent
It is one or more；And/or the alkali is triethylamine, n,N-diisopropylethylamine, sodium bicarbonate, saleratus, sodium carbonate
With one of potassium carbonate or a variety of；And/or the alkali with such as the molar ratio of formula III compound represented or its hydrochloride
For 1:1~2:1；And/or the organic solvent in the acylation reaction with such as formula III compound represented or its hydrochloride
Volume mass ratio is 10mL/g~50mL/g；
When preparing the salt of razaxaban shown in formula I in relation to substance, the acid is inorganic acid or organic acid；And/or institute
The solvent for the salt-forming reaction stated is water and/or organic solvent；When using organic solvent in the salt-forming reaction, it is described at
Organic solvent in reactant salt is one of amide solvent, sulfoxide type solvents, the alcohols solvent of C1~C4 and ketones solvent
Or it is a variety of；And/or the volume mass ratio of the solvent in the salt-forming reaction and compound shown in formula I be 1mL/g~
4mL/g；And/or the molar ratio of the acid and the compound shown in formula I is 1:1~4:1；And/or it is described
The temperature of salt-forming reaction is 0~5 DEG C；And/or the time of the salt-forming reaction is 0.5~1h.
7. preparation method of the razaxaban as claimed in claim 5 in relation to substance or its salt, it is characterised in that:
When preparing the related substance of razaxaban shown in formula I or its salt, the temperature of the acylation reaction is -5~20 DEG C；
And/or the organic solvent in the acylation reaction is one of halogenated hydrocarbon solvent, aromatic hydrocarbon solvent and esters solvent
Or it is a variety of；And/or the alkali is triethylamine, n,N-diisopropylethylamine, sodium bicarbonate, saleratus, sodium carbonate and carbonic acid
One of potassium is a variety of；And/or the solute in the organic solution such as formula IV compound represented is as shown in formula IV
Compound, the organic solvent in the organic solution such as formula IV compound represented is aromatic hydrocarbon solvent, halogenated hydrocarbon
One of solvent and esters solvent are a variety of；And/or it is described such as the solute of the organic solution of formula IV compound represented
Mass percent be 20%~35%, the percentage refer to the quality such as formula IV compound represented account for as described in such as formula IV
The percentage of the gross mass of the organic solution of compound represented；And/or it is described such as formula III compound represented or its salt
Hydrochlorate is 1:(1~1.4 with the molar ratio such as formula IV compound represented)；And/or the alkali is changed with as shown in formula III
The molar ratio for closing object or its hydrochloride is 1:1~2:1；And/or the organic solvent in the acylation reaction with such as formula III institute
The volume mass ratio of the compound or its salt hydrochlorate shown is 10mL/g~50mL/g；
When preparing the salt of razaxaban shown in formula I in relation to substance, the acid is inorganic acid or organic acid；And/or institute
The solvent for the salt-forming reaction stated is water and/or organic solvent；When using organic solvent in the salt-forming reaction, it is described at
Organic solvent in reactant salt is one of amide solvent, sulfoxide type solvents, the alcohols solvent of C1~C4 and ketones solvent
Or it is a variety of；And/or the volume mass ratio of the solvent in the salt-forming reaction and compound shown in formula I be 1mL/g~
4mL/g；And/or the molar ratio of the acid and the compound shown in formula I is 1:1~4:1；And/or it is described
The temperature of salt-forming reaction is 0~5 DEG C；And/or the time of the salt-forming reaction is 0.5~1h.
8. preparation method of the razaxaban as described in claim 6 or 7 in relation to substance or its salt, it is characterised in that:
The inorganic acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid；And/or the organic acid is first
Acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid,
Methanesulfonic acid, ethanesulfonic acid or glutamic acid.
9. preparation method of the razaxaban as described in claim 4 or 5 in relation to substance or its salt, which is characterized in that described
The preparation method of razaxaban shown in formula I in relation to substance or its salt, further comprises the following steps: solvent or without molten
In agent, under conditions of 50 DEG C~120 DEG C, by hydrazine hydrate and such as Formula II compound represented carry out it is as follows react, make
It is described such as formula III compound represented；Alternatively, solvent or it is solvent-free in, under conditions of 50 DEG C~120 DEG C, will be hydrated
Hydrazine and such as Formula II compound represented carry out it is as follows react, be made described such as formula III compound represented, then exist
, will be obtained described as formula III compound represented and hydrochloric acid carry out salt-forming reaction in organic solvent, it is made described such as formula
The hydrochloride of III compound represented；
10. preparation method of the razaxaban as claimed in claim 9 in relation to substance or its salt, it is characterised in that:
When preparation it is described such as formula III compound represented when, the temperature of the reaction is 80 DEG C~100 DEG C；And/or
In the preparation reaction such as formula III compound represented, the solvent is water and/or organic solvent, described in preparation
The reaction such as formula III compound represented in when using organic solvent, the preparation such as formula III compound represented it is anti-
Organic solvent in answering is one of alcohols solvent, ether solvent and heteroaryl hydrocarbon solvent of C1~C4 or a variety of；And/or
The hydrazine hydrate is 2:1~25:1 with the molar ratio such as Formula II compound represented；And/or when preparation it is described such as formula III
When compound represented, the time of the reaction is 8~12 hours；
When the preparation such as hydrochloride of formula III compound represented, the organic solvent in the salt-forming reaction be alcohols solvent,
One of ketones solvent and nitrile solvents are a variety of；And/or when the preparation such as hydrochloride of formula III compound represented, institute
The HCl in the hydrochloric acid in the salt-forming reaction stated, the molar ratio with such as formula III compound represented are 1:1~6:1；With/
Or, when the preparation such as hydrochloride of formula III compound represented, the organic solvent in the salt-forming reaction with such as formula
The volume mass ratio of III compound represented is 1mL/g~5mL/g；And/or the salt when preparation such as formula III compound represented
When hydrochlorate, the temperature of the salt-forming reaction is 0~5 DEG C；And/or the hydrochloride when preparation such as formula III compound represented
When, the time of the salt-forming reaction is 4~6h.
11. a kind of purposes of razaxaban shown in formula I in relation to substance as described in claims 1 to 3 any claim,
It is characterized in that, the compound shown in formula I is used as the related substance reference substance of razaxaban quality control, or it is used for
The impurity of razaxaban is identified.
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| CN105315269A (en) * | 2014-08-01 | 2016-02-10 | 国药集团国瑞药业有限公司 | Rivaroxaban related substance or salt thereof, intermediate thereof, preparation method therefor and use thereof |
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| CN105315269A (en) * | 2014-08-01 | 2016-02-10 | 国药集团国瑞药业有限公司 | Rivaroxaban related substance or salt thereof, intermediate thereof, preparation method therefor and use thereof |
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