CN108530349A - The preparation method and products thereof of betrixaban intermediate and betrixaban - Google Patents
The preparation method and products thereof of betrixaban intermediate and betrixaban Download PDFInfo
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- CN108530349A CN108530349A CN201810309075.6A CN201810309075A CN108530349A CN 108530349 A CN108530349 A CN 108530349A CN 201810309075 A CN201810309075 A CN 201810309075A CN 108530349 A CN108530349 A CN 108530349A
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- IQBYLMGZIWCWHZ-UHFFFAOYSA-N CCOC(c(cc1)ccc1C(Nc(ccc(OC)c1)c1C(Nc(nc1)ccc1Cl)=O)=O)=N Chemical compound CCOC(c(cc1)ccc1C(Nc(ccc(OC)c1)c1C(Nc(nc1)ccc1Cl)=O)=O)=N IQBYLMGZIWCWHZ-UHFFFAOYSA-N 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
Abstract
The present invention relates to the preparation methods of a kind of betrixaban intermediate or its salt, under the action of catalyst by formula SM III compounds and formula SM Compound Is or its salt, amide coupling agent condensation reaction is added dropwise and forms formula III compound or its salt, this condensation reaction generates in organic solvent.And betrixaban intermediate or its salt are further prepared into betrixaban or its salt.By the betrixaban that is prepared of the present invention or its hydrochloride substantially free of dechlorination impurity V and demethyl impurity VI, purity is high, the method increase product yield, the use for reducing highly corrosive raw material, cost are relatively low, is suitble to industrialized production.
Description
Technical field
The invention belongs to field of medicine preparation, are related to preparation method and its production of betrixaban intermediate and betrixaban
Product.
Background technology
Betrixaban is a kind of important pharmaceutical intermediate, such as it is oral anticoagulant object shellfish Qu Shaban of new generation
Intermediate, molecular structural formula are as follows：
But the pertinent literature of the less synthesis about II compound or its salt of formula in existing technology is reported, and actually
The production cost and product quality of II compound or its salt of III compound of formula and formula are directly related to final drug such as shellfish Qu Shaban
Manufacturing cost and drug quality.Patent document CN1391555A, CN101595092A, CN102762538A etc. are successively disclosed
The preparation method of betrixaban.
Patent document CN1391555A is disclosed (square case 1) following preparation method：
Scheme 1
As shown in scheme 1, which reacted in the hydrogen chloride methanol solution of saturation with III compound of formula, is then evaporated
Hydrogen chloride and methanol, then reacted with dimethylamine, most high-purity type I compound is obtained through column chromatography for separation afterwards.The preparation process adopts
The mode of evaporation is taken to remove hydrogen chloride and methanol, energy consumption is big, the period is long；In addition, last column chromatography purifying is also unfavorable for industrializing
Implementation.
For the deficiency of scheme 1, patent document CN101595092A improves technique, i.e., first in tetrahydrofuran
It is reacted with dimethylamine with hexyllithium and generates dimethyl amine lithium, then the hydrochloric acid reactant salt of dimethyl amine lithium and III compound of formula,
Through handling isolated type I compound, yield wherein contains shown in formula V and takes off up to 76.7%, HPLC purity about 98.0%
Chlorine impurity is up to 1.1% (square case 2).
Scheme 2
As shown in scheme 2, although this method avoids the use of hydrogen chloride gas, reduces the production cycle, but the party
The impurity for containing more difficult removing in type I compound prepared by method, such as dechlorination impurity V and demethyl impurity VI；Further, specially
Sharp document CN102762538A also indicates that the type I compound that this method is prepared in lab scale, pilot scale stage is easy, and there are two kinds of by-products
Object, i.e. dechlorination impurity V and demethyl impurity VI；Even across at salt, recrystallization purifying, their content is also difficult to reach
0.1% or less.
Patent document CN102762538A discloses another preparation route (square case 3) of type I compound：
As shown in Scheme 3, which be condensed in the presence of coupling reagent with III-I compound of formula and III-II compound of formula
High-purity type I compound is made.Wherein III-I compound is made using two methods：The preparation method of method 1 is similar to scheme
1；The preparation method of method 2 is similar to scheme 2.Program route is longer, and key intermediate still takes scheme 1 or scheme 2
Preparation method, with the above method deficiency；In addition III-I compound of formula during preparation there are it is degradable, be difficult to point
The problem low from, yield；
Scheme 3
Based on the deficiency of the above shellfish Qu Shaban methods, the present invention studies preparation method, and has developed one
The improved method for kind preparing betrixaban, the method increase product yield, the use for reducing highly corrosive raw material, cost compared with
It is low, it is suitble to industrialized production.
Invention content
In view of this, the present invention studies preparation method, the method that first purpose offer prepares betrixaban
And products thereof, the method increase product yield, the use for reducing highly corrosive raw material, cost are relatively low, it is suitble to industry metaplasia
Production.
In order to achieve the above objectives, the present invention provides the following technical solutions：
1. the preparation method of betrixaban intermediate or its salt, the betrixaban intermediate structure as shown in formula III,
Preparation method is following steps：
Under the action of catalyst by formula SM-III compounds and formula SM-I compound or its salts, amide coupling agent contracting is added dropwise
It closes reaction and forms formula III compound or its salt, this reaction generates in organic solvent；
The formula SM-I compounds are：
III compounds of formula SM- are：
Further, the organic solvent is dimethylformamide, decil amide, dichloromethane, ethyl acetate, tetrahydrochysene
Furans, acetonitrile or/and acetone；The catalyst is pyridine, triethylamine, N-methylmorpholine or/and 4-dimethylaminopyridine；It is described
Amide coupling agent is 2- chlorine-4,6-dimethoxy-1,3,5-triazines, N, N '-dicyclohexylcarbodiimides, N, N '-diisopropyls
Base carbodiimide, carbonyl dimidazoles or/and 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides.
Further, the formula SM-I compound or its salts, formula SM-III chemical combination, amide coupling agent object, catalyst and have
Solvent molar ratio is 1:1~3:1~10:0.1~10:1~20.
Further, the formula SM-I compound or its salts, formula SM-III chemical combination, amide coupling agent object, catalyst and have
Solvent molar ratio is 1:1.1~1.2:2~3:0.2~0.3:1~10.
2. the betrixaban intermediate or its salt that are obtained by any of the above item preparation method.
3. the betrixaban intermediate or its salt that are obtained using technical solution 1 prepare betrixaban or the method for its salt,
It is characterized in that, the betrixaban structure is shown in formula I：
The method is following steps：
(1) by III compound of formula and C2-4Alkanol or C2-4The combination solvent of alkane alcohol and solvent 1 is passed through hydrogen chloride gas, is passed through
Shi Wendu is 0~5 DEG C, after being passed through, is warming up to 15~20 DEG C, is stirred to react 48~72 hours, after completion of the reaction with evaporation
Mode obtain the hydrochloride of formula IV compound；Or solvent 2 is added after completion of the reaction and obtains formula in a manner of filtering re-dry
The hydrochloride of IV compounds；
(2) it takes the hydrochloride of formula IV compound obtained by step (1) that solvent 3 is added, pH to 8~9, control is adjusted with triethylamine
Temperature is at 0~5 DEG C；Filter cake is washed with ethyl alcohol to neutrality after filtering；Gained filter cake is dried under reduced pressure at 15~20 DEG C, obtains formula IV
Close object；
(3) it takes formula IV compound obtained by step (2) that solvent 4 is added, is added with stirring the salt of dimethylamine or dimethylamine, heat up
To 40~50 DEG C of insulation reactions 6~12 hours, control temperature was evaporated to dryness under reduced pressure less than 50 DEG C；
(4) ethyl alcohol, maleic acid, at 40~50 DEG C of temperature, stirring and dissolving is added in the obtained compound of step (3) again
Gained reaction solution is cooled to 10~15 DEG C under stiring afterwards, and triethylamine is added and adjusts pH to 8~9, control temperature is at 10~15 DEG C；
Filter cake uses C after filtering2-4Alkanol is washed to neutrality；Gained filter cake is dried under reduced pressure at 30~40 DEG C, obtains compound of formula I；
The formula IV compound structure is：
Wherein R is selected from C2-4Alkyl.
Further, solvent C described in step (1)2-4Alkanol is ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, secondary
Butanol or isobutanol.
Further, solvent 1 described in step (1) is ethyl acetate, tetrahydrofuran, dichloromethane, isopropyl acetate, first
The one such or a variety of combination of benzene, chloroform, hexamethylene, normal heptane, 1,4- dioxane, methyl tertiary butyl ether(MTBE).
Further, solvent 2 is with solvent 1 described in step (1), both for inert diluents solvent.
Further, solvent 3 described in step (2) is C1-4Alkanol or C1-4Alkanol and ethyl acetate, tetrahydrofuran, dichloromethane
The group of alkane, isopropyl acetate, toluene, chloroform, hexamethylene, normal heptane, 1,4- dioxane or/and methyl tertiary butyl ether(MTBE)
It closes.
Further, solvent 4 described in step (3) is methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, Zhong Ding
Alcohol, isobutanol, ethyl acetate, tetrahydrofuran, dichloromethane, isopropyl acetate, toluene, chloroform, hexamethylene, normal heptane,
1,4- dioxane or/and methyl tertiary butyl ether(MTBE)；
Further, III compound and C described in step (1)2-4The weight ratio of alkanol is 1:1~20.
Preferably, III compound and C described in step (1)2-4The weight ratio of alkanol is 1:7~10.
Further, hydrogen chloride and total solvent mass ratio in reaction system are 0.05~1：1.
Further, the salt of the step (3) dimethylamine is hydrochloride.
Further, the mass ratio of IV compounds, solvent 4 and the salt of dimethylamine or dimethylamine is 1 in the step (3)：1~
20：0.1~3.
Further, the C2-4Alkanol is ethyl alcohol, and gained compound structure is as shown in Formula II：
The beneficial effects of the present invention are：1, the present invention takes with formula SM-III compounds and formula SM-I compound or its salts
Coupling condensation prepares high-purity formula III compound or its salt, and method is simple, mild condition.2, by formula III compound or its salt with
Ethyl alcohol or combinations thereof solvent is reacted at reaction conditions to form formula IV compound or its salt, is further existed with dimethylamine or its salt
I compound or its salt of production is reacted under temperate condition under reaction condition, is further carried out high-purity betrixaban free alkali
It prepares.It is pure by the betrixaban that is prepared of the present invention or its hydrochloride substantially free of dechlorination impurity V and demethyl impurity VI
Degree is high, the method increase product yield, the use for reducing highly corrosive raw material, cost are relatively low, is suitble to industrialized production.
Description of the drawings
In order to keep the purpose of the present invention, technical solution and advantageous effect clearer, the present invention provides following attached drawing and carries out
Explanation：
Fig. 1 is the HPLC report figures of embodiment 1；
Fig. 2 is the HPLC report figures of embodiment 2；
Fig. 3 is the HPLC report figures of embodiment 3；
Fig. 4 is the HPLC report figures of embodiment 4；
Fig. 5 is the HPLC report figures of embodiment 5；
Fig. 6 is the HPLC report figures of embodiment 6；
Fig. 7 is the HPLC report figures of embodiment 7；
Fig. 8 is the HPLC report figures of embodiment 8；
Fig. 9 is the HPLC report figures of embodiment 9.
Specific implementation mode
Below in conjunction with attached drawing, the preferred embodiment of the present invention is described in detail.It is not specified in embodiment specific
The experimental method of condition, usually according to conventional conditions or according to the manufacturer's recommendations.
Embodiment 1：The preparation of III compound of formula
2- chlorine-4,6-dimethoxy-1,3,5-triazines 79.0g (0.45mol, 2.5eq) is taken to be dissolved in 100.0g dimethyl methyls
It is spare in amide；I compound 50.0g (0.18mol, 1.0eq) of formula SM-, III compound 29.1g of SM- are added in round-bottomed flask
(0.20mol, 1.1eq), 4-dimethylaminopyridine 4.4g (0.036mol, 0.2eq), dimethylformamide 400.0g；It is stirring
Under, the dimethyl formamide solution that 2- chlorine-4,6-dimethoxy-1,3,5-triazines are added dropwise controls temperature at 0~10 DEG C；It drips
Finish and be warming up to 25~30 DEG C of insulation reactions 2 hours, passes through HPLC detection reactions and complete；With vigorous stirring, 500.0g water is added；
Filtering；Filter cake washs to obtain III compound 64.0g of formula using ethyl alcohol, for off-white color to faint yellow solid；Yield：87.3%；
HPLC purity 98.5%.Fig. 1 is the HPLC report figures of embodiment 1；Wherein HPLC spectrum datas are referring to the area ratio in report figure
Example data reporting.
Embodiment 2:The preparation of III compound of formula
2- chlorine-4,6-dimethoxy-1,3,5-triazines 70.2g (0.4mol, 2.5eq) is taken to be dissolved in 100.0g dimethyl formyls
It is spare in amine；Hydrochloride 50.0g (0.16mol, 1.0eq), III compounds of SM- of I compounds of formula SM- are added in round-bottomed flask
25.8g (0.18mol, 1.1eq), 4-dimethylaminopyridine 3.9g (0.032mol, 0.2eq), dimethylformamide 400.0g；
Under stirring, the dimethyl formamide solution that 2- chlorine-4,6-dimethoxy-1,3,5-triazines are added dropwise controls temperature at 0~10 DEG C；Drop
It adds to finish and is warming up to 25~30 DEG C of insulation reactions 2 hours, pass through HPLC detection reactions and complete；With vigorous stirring, it is added
500.0g water；Triethylamine is added to pH=8~9；Filtering；Filter cake washs to obtain III compound 55.0g of formula using ethyl alcohol, is class
White is to faint yellow solid；Yield：85.0%；HPLC purity 98.2%.Fig. 2 is the HPLC report figures of embodiment 2；Wherein HPLC
Spectrum data is referring to the area ratio data reporting in report figure.
Embodiment 3:The preparation of III compound hydrochloride of formula
2- chlorine-4,6-dimethoxy-1,3,5-triazines 79.0g (0.45mol, 2.5eq) is taken to be dissolved in 100.0g tetrahydrofurans
In it is spare；I compound 50.0g (0.18mol, 1.0eq) of formula SM-, III compound 29.1g of SM- are added in round-bottomed flask
(0.20mol, 1.1eq), 4-dimethylaminopyridine 4.4g (0.036mol, 0.2eq), tetrahydrofuran 400.0g；Under stiring, it drips
The tetrahydrofuran solution of 2- chlorine-4,6-dimethoxy-1,3,5-triazines is added to control temperature at 0~10 DEG C；It is added dropwise and is warming up to
25~30 DEG C of insulation reactions 2 hours pass through HPLC detection reactions and complete；With vigorous stirring, hydrogen chloride gas is passed through to pH=2
~3；Filtering；Filter cake washs to obtain III compound hydrochloride 71.8g of formula using tetrahydrofuran, ethyl alcohol, is yellow solid；Yield：
90.0%；HPLC purity 98.8%.Fig. 3 is the HPLC report figures of embodiment 3；Wherein HPLC spectrum datas are referring in report figure
Area ratio data reporting.
By III compound of formula and C2-4Alkanol is reacted at reaction conditions to form IV compound or its salt of formula, below with second
Alcohol is embodiment, IV compound structure of formula：
Wherein R is selected from C2-4Alkyl.
Embodiment 4:The preparation of II compound of formula
III compound 50.0g (prepared by embodiment 1) of formula, ethyl alcohol 450.0g are added in round-bottomed flask；Under stirring, it is passed through
Dry hydrogen chloride gas 135.0g, control temperature is at 0 to 5 DEG C；After being passed through, it is warming up to 15 to 20 DEG C；At 15 to 20 DEG C
It is stirred to react 48 hours, reaction is detected by HPLC and is completed；Under stiring, it opens vacuum to be evaporated reaction solution, obtains the change of formula II
The hydrochloride 59.0g for closing object, is yellow solid；
The hydrochloride 59.0g of II compound of above-mentioned formula is taken, ethyl alcohol 590.0g is added；Under stirring, pH to 8 is adjusted with triethylamine
~9, control temperature is at 0 to 5 DEG C；Filtering, filter cake are washed using ethyl alcohol to neutrality；Gained filter cake depressurizes dry at 15 to 20 DEG C
It is dry, obtain II compound 51.1g of formula.Yield：92.0%；HPLC purity 95.2%.Fig. 4 is the HPLC report figures of embodiment 4；Wherein
HPLC spectrum datas are referring to the area ratio data reporting in report figure.
II compound structure of formula：
Embodiment 5：The preparation of II compound of formula
III compound 50.0g of formula, ethyl alcohol 450.0g are added in round-bottomed flask.Under stirring, it is passed through dry hydrogen chloride gas
135.0g, control temperature is at 0 to 5 DEG C；After being passed through, it is warming up to 15 to 20 DEG C；It is stirred to react at 15 to 20 DEG C 48 hours,
Reaction is detected by HPLC to complete；Under stiring, toluene 225.0g is added to be sufficiently stirred；Filtering；Filter cake subtracts at 15 to 20 DEG C
It press dry dry, obtains the hydrochloride 58.0g of II compound of formula.
The hydrochloride 58.0g of II compound of above-mentioned formula is taken, ethyl alcohol 580.0g is added；Under stirring, pH to 8 is adjusted with triethylamine
~9, control temperature is at 0 to 5 DEG C；Filtering, filter cake are washed using ethyl alcohol to neutrality；Gained filter cake depressurizes dry at 15 to 20 DEG C
It is dry, obtain II compound 50.9g of formula.Yield：91.6%；HPLC purity 98.2%.Fig. 5 is the HPLC report figures of embodiment 5；Wherein
HPLC spectrum datas are referring to the area ratio data reporting in report figure.
III compound of formula in the present embodiment and C2-4The reaction of alkanol can also be by III compound of formula and C2-4Alkanol and
The combination solvent of solvent 1 is passed through hydrogen chloride gas, and the solvent 1 is ethyl acetate, tetrahydrofuran, dichloromethane, isopropyl acetate
Ester, toluene, chloroform, hexamethylene, normal heptane, Isosorbide-5-Nitrae-dioxane or methyl tertiary butyl ether(MTBE) and combination thereof, effect
For inert diluents solvent.
Embodiment 6：The preparation of II compound of formula
III compound 50.0g of formula, ethyl alcohol 150.0g, ethyl acetate 300.0g are added in round-bottomed flask.Under stirring, it is passed through
Dry hydrogen chloride gas 135.0g, control temperature is at 0 to 5 DEG C；After being passed through, it is warming up to 15 to 20 DEG C；At 15 to 20 DEG C
It is stirred to react 48 hours, reaction is detected by HPLC and is completed；Under stiring, ethyl acetate 225.0g is added to be sufficiently stirred；Filtering；
Filter cake is dried under reduced pressure at 15 to 20 DEG C, obtains the hydrochloride 57.0g of II compound of formula.
The hydrochloride 57.0g of II compound of above-mentioned formula is taken, ethyl alcohol 570.0g is added.Under stirring, pH to 8 is adjusted with triethylamine
~9, control temperature is at 0 to 5 DEG C；Filtering, filter cake are washed using ethyl alcohol to neutrality；Gained filter cake depressurizes dry at 15 to 20 DEG C
It is dry, obtain II compound 50.1g of formula.Yield：90.2%；HPLC purity 98.5%.Fig. 6 is the HPLC report figures of embodiment 6；Wherein
HPLC spectrum datas are referring to the area ratio data reporting in report figure.
Addition ethyl acetate in the present embodiment be sufficiently stirred can also use tetrahydrofuran, dichloromethane, isopropyl acetate,
Toluene, chloroform, hexamethylene, normal heptane, 1,4- dioxane or methyl tertiary butyl ether(MTBE) and combination thereof are dilute as inertia
Release solvent.
Embodiment 7：The preparation of type I compound
II compound 50.0g of formula (0.11mol, as obtained in embodiment 6), tetrahydrofuran are added in round-bottomed flask
350.0g；Dimethylamine gas 20.0g (0.44mol, 4.0eq) is passed through under stirring；After being passed through, it is warming up to 40~50 DEG C of heat preservations
Reaction 6 hours detects reaction by HPLC and completes；Under stiring, control temperature is evaporated to dryness under reduced pressure less than 50 DEG C, obtains the change of formula I
Object 51.0g is closed, is off-white powder；HPLC purity 98.0%.
Take above-mentioned type I compound 51.0g, ethyl alcohol 510.0g, maleic acid 52.4g；At 40~50 DEG C of temperature, stirring is molten
Solution；After dissolving, gained reaction solution is cooled to 10~15 DEG C under stiring；After reaching assigned temperature, triethylamine is added and adjusts
PH to 8~9, control temperature is at 10~15 DEG C；Filtering；Filter cake is washed using ethyl alcohol to neutrality；Gained filter cake is at 30~40 DEG C
It is dried under reduced pressure, obtains type I compound 41.4g, be off-white powder；Yield：83.0%；HPLC purity 99.7%, wherein dechlorination
Impurity 0.02%, demethyl impurity does not detect.Fig. 7 is the HPLC report figures of embodiment 7；Wherein HPLC spectrum datas are referring to report
Accuse the area ratio data reporting in figure.
Tetrahydrofuran can also use methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, Zhong Ding in the present embodiment
Alcohol, isobutanol, ethyl acetate, dichloromethane, isopropyl acetate, toluene, chloroform, hexamethylene, normal heptane, 1,4- dioxies six
Ring or the one such or a variety of combination of methyl tertiary butyl ether(MTBE).
Embodiment 8：The preparation of type I compound
Hydrochloride 55.0g (0.11mol, as obtained in embodiment 3), the ethyl alcohol of II compound of formula are added in round-bottomed flask
350.0g；Dimethylamine gas 24.8g (0.55mol, 5.0eq) is passed through under stirring；After being passed through, it is warming up to 40~50 DEG C of heat preservations
Reaction 6 hours detects reaction by HPLC and completes；Under stiring, control temperature is evaporated to dryness under reduced pressure less than 50 DEG C, obtains the change of formula I
The hydrochloride 54.5g for closing object, for off-white color to faint yellow solid；HPLC purity 98.4%.
Take the hydrochloride 54.0g, ethyl alcohol 540.0g, maleic acid 52.4g of above-mentioned type I compound；At 40~50 DEG C of temperature,
Stirring and dissolving；After dissolving, gained reaction solution is cooled to 10~15 DEG C under stiring；After reaching assigned temperature, three second are added
Amine adjusts pH to 8~9, and control temperature is at 10~15 DEG C；Filtering；Filter cake is washed using ethyl alcohol to neutrality；Gained filter cake 30~
It is dried under reduced pressure at 40 DEG C, obtains type I compound 42.0g, be off-white powder；Yield：84.1%；HPLC purity 99.5%,
Middle dechlorination impurity 0.01%, demethyl impurity does not detect.Fig. 8 is the HPLC report figures of embodiment 8；Wherein HPLC spectrum datas
Referring to the area ratio data reporting in report figure.
Embodiment 9:The preparation of type I compound hydrochloride
In round-bottomed flask be added II compound 50.0g of formula (0.11mol, as obtained in embodiment 3), ethyl alcohol 350.0g,
The hydrochloride 35.8g (0.44mol, 4.0eq) of dimethylamine；Under stiring, 40~50 DEG C of insulation reactions are warming up to 6 hours, passed through
HPLC detection reactions are completed；Under stiring, control temperature is evaporated to dryness under reduced pressure less than 50 DEG C；250g isopropyls are added under stiring
Alcohol stirs 1.0 hours；Filtering；The hydrochloride 45.8g for obtaining type I compound, for off-white color to faint yellow solid；Yield：
85.0%；HPLC purity 99.0%.Wherein dechlorination impurity, demethyl impurity do not detect.Fig. 9 is that the HPLC of embodiment 9 is reported
Accuse figure；Wherein HPLC spectrum datas are referring to the area ratio data reporting in report figure.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
It crosses above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand that, can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (10)
1. the preparation method of betrixaban intermediate or its salt, which is characterized in that the betrixaban intermediate structure such as formula III
It is shown,
Preparation method is following steps：
Under the action of catalyst by formula SM-III compounds and formula SM-I compound or its salts, it is anti-that amide coupling agent condensation is added dropwise
Formula III compound or its salt should be formed, this condensation reaction generates in organic solvent；
The formula SM-I compounds are：
III compounds of formula SM- are：
2. preparation method according to claim 1, which is characterized in that the organic solvent is dimethylformamide, diformazan
Amine acetamide, dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile or/and acetone；The catalyst is pyridine, triethylamine, N-
Methyl morpholine or/and 4-dimethylaminopyridine；The amide coupling agent be 2- chlorine-4,6-dimethoxy-1,3,5-triazines, N,
N '-dicyclohexylcarbodiimides, N, N '-diisopropylcarbodiimide, carbonyl dimidazoles or/and 1- (3- dimethylamino-propyls)-
3- ethyl-carbodiimide hydrochlorides.
3. preparation method according to claim 1 or 2, which is characterized in that the formula SM-I compound or its salts, formula SM-
III chemical combination, amide coupling agent object, catalyst and organic solvent molar ratio are 1:1~3:1~10:0.1~10:1~20.
4. the betrixaban intermediate or its salt that are obtained by any one of claim 1-3 preparation methods.
5. betrixaban intermediate according to claim 4 or its salt prepare betrixaban or the method for its salt, feature
It is,
The betrixaban structure is shown in formula I：
The method is following steps：
(1) by III compound of formula and C2-4Alkanol or C2-4The combination solvent of alkane alcohol and solvent 1 is passed through hydrogen chloride gas, temperature when being passed through
Degree is 0~5 DEG C, after being passed through, is warming up to 15~20 DEG C, is stirred to react 48~72 hours, after completion of the reaction with the side of evaporation
Formula obtains the hydrochloride of formula IV compound；Or solvent 2 is added after completion of the reaction and obtains formula IV in a manner of filtering re-dry
Close the hydrochloride of object；
(2) it takes the hydrochloride of formula IV compound obtained by step (1) that solvent 3 is added, adjusts pH to 8~9 with triethylamine, control temperature
At 0~5 DEG C；Filter cake is washed with ethyl alcohol to neutrality after filtering；Gained filter cake is dried under reduced pressure at 15~20 DEG C, obtains formula IV chemical combination
Object；
(3) it takes formula IV compound obtained by step (2) that solvent 4 is added, is added with stirring the salt of dimethylamine or dimethylamine, is warming up to 40
~50 DEG C of insulation reactions 6~12 hours, control temperature are evaporated to dryness under reduced pressure less than 50 DEG C；
(4) ethyl alcohol, maleic acid, at 40~50 DEG C of temperature, institute after stirring and dissolving is added in the obtained compound of step (3) again
It obtains reaction solution and is cooled to 10~15 DEG C under stiring, triethylamine is added and adjusts pH to 8~9, control temperature is at 10~15 DEG C；Filtering
Filter cake uses C afterwards2-4Alkanol is washed to neutrality；Gained filter cake is dried under reduced pressure at 30~40 DEG C, obtains compound of formula I；
The formula IV compound structure is：
Wherein R is selected from C2-4Alkyl.
6. according to the method described in claim 5, it is characterized in that, (1) III compound of the step and C2-4The weight ratio of alkanol
It is 1:1~20.
7. according to the method described in claim 5, it is characterized in that, total solvent mass ratio is 0.05 in hydrogen chloride and reaction system
~1：1.
8. according to the method described in claim 5, it is characterized in that, the salt of the step (3) described dimethylamine is hydrochloride.
9. according to the method described in claim 5, it is characterized in that, IV compounds, solvent 4 and dimethylamine in the step (3)
Or the mass ratio of the salt of dimethylamine is 1：1~20：0.1~3.
10. according to the method described in claim 5, it is characterized in that, the C2-4Alkanol is ethyl alcohol, and gained compound structure is such as
Shown in Formula II：
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