CN108017576B - Preparation method of betrixaban and hydrochloride thereof, and crystal forms of betrixaban and hydrochloride thereof - Google Patents
Preparation method of betrixaban and hydrochloride thereof, and crystal forms of betrixaban and hydrochloride thereof Download PDFInfo
- Publication number
- CN108017576B CN108017576B CN201610935421.2A CN201610935421A CN108017576B CN 108017576 B CN108017576 B CN 108017576B CN 201610935421 A CN201610935421 A CN 201610935421A CN 108017576 B CN108017576 B CN 108017576B
- Authority
- CN
- China
- Prior art keywords
- degrees
- hydrochloride
- betrixaban
- compound
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of betrixaban and hydrochloride thereof, and crystal forms of betrixaban and hydrochloride thereof. The method comprises the following steps: reacting the compound III or hydrochloride thereof with thionyl chloride to obtain a compound VIII or hydrochloride thereof, and then carrying out acylation reaction on the compound VIII or hydrochloride thereof and a compound IV under the action of alkali 1 to obtain betrixaban hydrochloride shown in a formula II; the obtained betrixaban hydrochloride further reacts with alkali 2 to prepare betrixaban as shown in formula I. The preparation method of the betrixaban and the betrixaban hydrochloride has the advantages of mild reaction conditions, simple operation, economy and effectiveness, and the betrixaban hydrochloride can be directly obtained by crystallization from a reaction system without further purification, so that the preparation method is suitable for industrial mass production; the purity of the obtained betrixaban and the hydrochloride thereof can reach more than 99.5 percent, and the betrixaban and the hydrochloride thereof have new crystal forms, stable properties and storage aspects and are beneficial to the preparation of subsequent products.
Description
Technical Field
The invention relates to the field of organic chemistry and pharmacy, in particular to a method for preparing betrixaban and hydrochloride thereof, and crystal forms of the betrixaban and the hydrochloride thereof.
Background
The compound is betrixaban (structural formula is shown in formula I), has a chemical name of N- (5-chloropyridine-2-yl) -2- [ [4- (N, N-dimethylamidino) benzoyl ] amino ] -5-methoxybenzamide, is a novel oral factor Xa inhibitor anticoagulant developed by Portola pharmaceutical company in America, and is currently in phase III clinical research abroad.
Patents such as patent documents WO2012031017, WO2001019788, WO2007056517 and CN104693114 successively disclose preparation methods of betrixaban.
Patent document WO2012031017 discloses the following preparation method (see scheme 1):
as shown in scheme 1, the preparation method comprises the step of carrying out condensation reaction on a compound III and a compound IV under the action of an EDC catalyst to obtain the betrixaban. The shrinking agent EDC (1-ethyl- (3-dimethyl aminopropyl) carbonyldiimine) used in the method, urea derivatives generated in the reaction and post-treatment processes and betrixaban belong to compounds with strong polarity, are very easy to dissolve in water and cannot be removed by a split-phase extraction washing method, bring great difficulty to the purification of the betrixaban and are not beneficial to the implementation of industrial production.
Patent document WO2001019788 discloses another route to betrixaban (see scheme 2):
the preparation method comprises the steps of carrying out amidation reaction on a compound IV and a compound V which are used as initial raw materials to obtain a compound VI, completely reacting the compound VI in a hydrogen chloride gas solution of methanol, then concentrating the solution to remove the hydrogen chloride gas, and reacting with dimethylamine to obtain the betrixaban. The method needs a large amount of hydrogen chloride gas, has strong corrosivity and large environmental pollution, and needs column chromatography to separate and purify the betrixaban, thereby being not beneficial to industrialized mass production.
In view of the deficiencies of the process of scheme 2, the patent document WO2007056517 improves the process (scheme 3):
the improved preparation method obtains the compound VI through amidation reaction of the compound IV and the compound V. Hexyl lithium and dimethylamine react in tetrahydrofuran to generate dimethylamine lithium, and then the dimethylamine lithium reacts with a compound VI to obtain the betrixaban, wherein the yield of the two steps is about 58 percent, and the purity is about 98 percent. The betrixaban prepared by the method contains 1.14% of dechlorination impurities (formula VII), and because the dechlorination impurities are similar to the betrixaban in structure and character, the dechlorination impurities are difficult to be reduced to be below 0.1% only by a one-time recrystallization or salification purification method, which brings great difficulty to the purification of the betrixaban; in addition, an active metal reagent n-hexyllithium is used in the reaction, so that the price is high, the transportation and storage conditions are harsh, and a reaction system needs strict anhydrous conditions, thereby being not beneficial to the implementation of industrial production.
Patent document CN104693114 discloses another process for preparing betrixaban (see scheme 4),
the preparation method comprises the steps of carrying out amidation reaction on compounds V and IV under the action of triethylamine and tetrahydrofuran as a solvent to obtain a compound VI, and reacting the compound VI with dimethylamine under the action of a Grignard reagent to obtain the betrixaban or salts thereof. The method has low yield, the yield of the two steps is about 64 percent, the operation is relatively complicated, and after the reaction is finished, the pH value is regulated to 2-3 by hydrochloric acid, and the solid of the betrixaban hydrochloride can be obtained by decompression and concentration. The obtained betrixaban hydrochloride solid needs to be further dissolved in N, N-dimethylformamide, added with toluene dropwise, cooled and crystallized and purified, and the purity can reach more than 99.5%; in addition, active metal reagent format reagents are used in the reaction, the transportation and storage conditions are harsh, and the reaction system needs strict anhydrous conditions, thereby greatly restricting the implementation of industrial production.
In summary, the prior art has the following defects in the process of preparing betrixaban: the reaction operation conditions are harsh, the yield is low, the single impurity content of the product is high, the operation is complicated, the purification is difficult, and the method is not suitable for industrial production and the like. Therefore, the improvement of the preparation method of the betrixaban is needed, so that the yield and the purity of the betrixaban are improved, the defects of complex operation and difficult purification are overcome, and the betrixaban is more suitable for industrial production.
Disclosure of Invention
Based on the defects of the preparation method of the betrixaban and the hydrochloride thereof, the inventor researches the preparation method and provides a new method for preparing the betrixaban and the hydrochloride thereof.
Therefore, on the one hand, the invention provides a preparation method of betrixaban hydrochloride shown in the formula II,
the method is characterized in that: the method comprises the following steps:
(1) reacting the compound III or hydrochloride thereof with thionyl chloride to obtain a compound shown as a formula VIII or hydrochloride thereof;
(2) carrying out acylation reaction on the compound VIII or hydrochloride thereof obtained in the step (1) and a compound IV under the action of alkali 1 to obtain betrixaban hydrochloride shown in a formula II,
wherein:
the solvent used in step (1) is an aprotic solvent such as tetrahydrofuran, methyl tert-butyl ether, n-hexane, n-heptane, acetone or dichloromethane, and other aprotic solvents which can perform the same function can also be used.
Optionally, a catalytic amount of N, N-dimethylformamide is added as a catalyst in step (1) of the above method, so that the reaction can be accelerated, and the reaction time can be shortened.
Further, the molar ratio of the thionyl chloride to the compound III or the hydrochloride thereof is 1:1 to 10: 1. Preferably 1:1 to 3:1, which can not only ensure the reaction to be fully performed, but also reduce the corrosion of the excessive thionyl chloride to the instrument.
Further, in the above method, the reaction temperature in the step (1) or (2) is 0 to 80 ℃, preferably 5 to 40 ℃.
Further, the reaction time in step (2) in the above method is 1 to 10 hours, preferably 2 to 5 hours.
Further, the molar ratio of compound IV to compound III or the hydrochloride thereof is 1:1 to 5:1, preferably 1:1 to 2: 1.
Further, in the above method, the base 1 is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, diisopropylethylamine or diisopropylamine, and other bases that can perform the same function may be used, preferably one or more of sodium bicarbonate, sodium carbonate, triethylamine or pyridine.
In the method, the alkali 1 is mainly used as an acid-binding agent to absorb the hydrogen chloride generated in the acylation reaction in the step (2) and neutralize the decomposition product of the thionyl chloride in the step (1), but when strong alkali such as sodium hydroxide, potassium hydroxide and the like is used, partial amidino is hydrolyzed, the product yield is slightly low, but the generated hydrolysis product is dissolved in a solvent, and the betrixaban hydrochloride is separated out from the reaction system, so the purity can still reach more than 99.5%; when medium-strength alkali such as sodium carbonate and potassium carbonate or weak alkali such as triethylamine is used, the amidino is not easy to hydrolyze, the product yield is high and reaches more than 85%, and the purity reaches more than 99.5%.
Further, in the above method, the solvent used in step (2) is selected from one or more of N, N-dimethylformamide, ethyl acetate, tetrahydrofuran, dichloromethane, acetonitrile, dimethyl sulfoxide, acetone, methyl tert-butyl ether, isopropyl ether, water, N-hexane or N-heptane, and other solvents that can perform the same function may be used, preferably one or more of N, N-dimethylformamide, tetrahydrofuran, acetone, dichloromethane or water.
Furthermore, when the solvent used in the step (1) and the solvent used in the step (2) are the same and are poor solvents of the betrixaban hydrochloride, the betrixaban hydrochloride is directly separated out from the reaction system like dichloromethane, acetone or tetrahydrofuran, and the purity can reach more than 99.5%. Because the used solvents are the same, the solvent is favorable for recycling and reusing, and the industrial waste is reduced.
Further, the molar ratio of the base 1 to the compound III or the hydrochloride thereof in the above method is 1:1 to 20:1, preferably 1:1 to 8: 1.
Further, in the above method, the weight ratio of the solvent used in step (2) to the compound III or its hydrochloride is 1:1 to 100:1, preferably 5:1 to 50: 1.
The purity of the betrixaban hydrochloride prepared by the method is not lower than 99.5%.
Further, when the solvent used in step (2) is dichloromethane, crystalline form I of betrixaban hydrochloride is obtained.
The powder X-ray diffraction pattern (Cu-Kalpha diffraction) of the crystal form I of the betrixaban hydrochloride provided by the invention is characterized in that: the main characteristic diffraction peaks are corresponding to the positions of 12.1 +/-0.2 degrees, 12.4 +/-0.2 degrees, 13.8 +/-0.2 degrees, 14.5 +/-0.2 degrees, 14.7 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.7 +/-0.2 degrees, 22.8 +/-0.2 degrees, 23.3 +/-0.2 degrees, 23.6 +/-0.2 degrees, 24.4 +/-0.2 degrees, 24.9 +/-0.2 degrees, 26.2 +/-0.2 degrees, 26.5 +/-0.2 degrees, 27.6 +/-0.2 degrees and 28.5 +/-0.2 degrees of the 2 theta value.
Further, the powder X-ray diffraction pattern (Cu-ka diffraction) of the crystal form I of betrixaban hydrochloride provided by the present invention is characterized by: diffraction peaks are correspondingly found at 11.6 +/-0.2 °, 12.1 +/-0.2 °, 12.4 +/-0.2 °, 13.8 +/-0.2 °, 14.5 +/-0.2 °, 14.7 +/-0.2 °, 16.3 +/-0.2 °, 17.4 +/-0.2 °, 18.0 +/-0.2 °, 18.8 +/-0.2 °, 19.7 +/-0.2 °, 21.2 +/-0.2 °, 21.5 +/-0.2 °, 22.8 +/-0.2 °, 23.3 +/-0.2 °, 23.6 +/-0.2 °, 24.4 +/-0.2 °, 24.9 +/-0.2 °, 26.2 +/-0.2 °, 26.5 +/-0.2 °, 26.8 +/-0.2 °, 27.6 +/-0.2 °, 28.5 +/-0.2 °, 30.5 +/-0.2 °, 30.8 +/-0.2 °, and 35.3 +/-0.2 ° of the 2 theta value.
Further, the invention provides crystalline form I of betrixaban hydrochloride having the characteristics represented by the powder X-ray diffraction pattern substantially as shown in figure 1.
The betrixaban hydrochloride solid prepared by the above method can be separated by a conventional method in the art such as filtration, and optionally, the solid obtained by separation can be washed with a suitable solvent such as dichloromethane or acetone.
Further, when the solvent used in the step (2) is acetone, crystalline form II of betrixaban hydrochloride is obtained.
The powder X-ray diffraction pattern (Cu-Kalpha diffraction) of the crystal form II of the betrixaban hydrochloride provided by the invention is characterized in that: main characteristic diffraction peaks are correspondingly arranged at 4.5 +/-0.2 degrees, 7.8 +/-0.2 degrees, 8.8 +/-0.2 degrees, 11.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.7 +/-0.2 degrees, 23.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 27.4 +/-0.2 degrees and 27.8 +/-0.2 degrees of the 2 theta value.
Further, the powder X-ray diffraction pattern (Cu-ka diffraction) of the betrixaban hydrochloride form II provided by the present invention is characterized by: characteristic diffraction peaks are correspondingly arranged at the 2 theta values of 4.5 +/-0.2 degrees, 7.8 +/-0.2 degrees, 8.8 +/-0.2 degrees, 11.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.7 +/-0.2 degrees, 18.3 +/-0.2 degrees, 18.9 +/-0.2 degrees, 21.0 +/-0.2 degrees, 23.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 26.0 +/-0.2 degrees, 27.4 +/-0.2 degrees, 27.8 +/-0.2 degrees, 28.8 +/-0.2 degrees, 30.2 +/-0.2 degrees and 31.6 +/-0.2 degrees.
Further, the invention provides crystalline form II of betrixaban hydrochloride having the characteristics represented by the powder X-ray diffraction pattern substantially as shown in figure 2.
The betrixaban hydrochloride solid obtained in step (2) of the above method may be isolated by a conventional method in the art such as filtration, and optionally, the isolated solid may be washed with a suitable solvent such as dichloromethane or acetone.
On the other hand, the invention also provides a preparation method of the betrixaban shown in the formula I,
the method is characterized in that: the betrixaban hydrochloride obtained by the method of the invention is further reacted with alkali 2 to obtain the betrixaban hydrochloride.
In the above method, the solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol or n-propanol, or other alcohol solvent with the same effect can be used, preferably methanol, ethanol or isopropanol; and the used solvent is a good solvent of the betrixaban hydrochloride and a poor solvent of the betrixaban, so that the generated betrixaban can be directly separated out from the reaction system. The weight ratio of the solvent used to the betrixaban hydrochloride of formula II is from 5:1 to 20:1, preferably from 5:1 to 10: 1. Furthermore, a proper amount of water can be added into the solvent, and the weight ratio of the water to the betrixaban hydrochloride shown in the formula II is preferably 30:1 to 50:1, so that the precipitation of the betrixaban solid is facilitated.
In the above method, the alkali 2 is selected from sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide, and other alkalis which play the same role and are more than that of betrixaban, and preferably sodium methoxide, sodium carbonate or potassium carbonate.
The betrixaban solid obtained in the above method can be separated by a conventional method in the art such as filtration.
The purity of the betrixaban prepared by the method is not lower than 99.5%.
In another aspect, the invention provides a crystalline form D of betrixaban.
The powder X-ray diffraction pattern (Cu-Kalpha diffraction) of the crystal form D of the betrixaban provided by the invention is characterized in that: the main characteristic diffraction peaks are correspondingly arranged at the 2 theta values of 9.9 +/-0.2 degrees, 12.9 +/-0.2 degrees, 18.3 +/-0.2 degrees, 18.8 +/-0.2 degrees, 22.7 +/-0.2 degrees, 24.1 +/-0.2 degrees and 26.7 +/-0.2 degrees.
Further, the invention provides a crystalline form D of betrixaban, characterized in that powder X-ray diffraction using Cu-Kalpha radiation at 2 theta angles (°) has characteristic diffraction peaks at the following positions: 9.9 +/-0.2 degrees, 12.9 +/-0.2 degrees, 18.3 +/-0.2 degrees, 18.5 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.7 +/-0.2 degrees, 22.7 +/-0.2 degrees, 24.1 +/-0.2 degrees, 26.2 +/-0.2 degrees, 26.7 +/-0.2 degrees, 27.9 +/-0.2 degrees and 28.9 +/-0.2 degrees.
Further, the crystalline form D of betrixaban provided by the present invention has a powder X-ray diffraction pattern characteristic substantially as shown in figure 3.
The powder X-ray diffraction pattern basically shown in the figure refers to that the X-ray diffraction characteristics of the crystal form or amorphous powder accord with the overall appearance displayed by the pattern, and it can be understood that in the test process, the peak position or peak intensity of the X-ray diffraction pattern measured by the same crystal form has certain difference due to the influence of various factors (such as the granularity of a test sample, a sample processing method during the test, an instrument, test parameters, test operation and the like). In general, the experimental error of the diffraction peak 2 θ value in the X-ray powder diffraction pattern may be. + -. 0.2 °, preferably. + -. 0.1 °. The experimental error of the relative peak intensities in the X-ray powder diffraction pattern may be. + -. 20%, preferably. + -. 10%, more preferably. + -. 5%.
The main characteristic diffraction peak means a characteristic diffraction peak having a relative intensity of more than 20%.
The characteristic diffraction peak refers to a characteristic diffraction peak with a relative intensity of more than 10%.
Relative peak intensity refers to the peak height ratio of the diffraction peak to the strongest diffraction peak.
Compared with the prior art, the invention has the following advantages: the preparation method of the betrixaban and the betrixaban hydrochloride has the advantages of mild reaction conditions, simple operation, economy and effectiveness, the betrixaban hydrochloride can be obtained by directly crystallizing from a reaction system, further purification is not needed, the yield is high, and the method is more suitable for industrial mass production; the purity of the obtained betrixaban and the hydrochloride thereof can reach more than 99.5 percent, and all single impurities are less than 0.1 percent. The preparation method of the crystal form D of the betrixaban and the crystal forms I and II of the betrixaban hydrochloride provided by the invention is simple, high in purity, good in stability, convenient to store and beneficial to preparation of subsequent products.
Drawings
FIG. 1: a powder X-ray diffraction pattern of crystalline form I of betrixaban hydrochloride.
FIG. 2: a powder X-ray diffraction pattern of crystalline form II of betrixaban hydrochloride.
FIG. 3: a powder X-ray diffraction pattern of crystalline form D of betrixaban.
FIG. 4 is a schematic view of: a powder X-ray diffraction pattern of form D of betrixaban after 12 months of standing.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. Various alterations and modifications can be made without departing from the spirit of the invention as defined by the general knowledge and customary practice in the art. Are intended to be included within the scope of the present invention.
The powder X-ray diffraction test conditions in the following examples are: XRD D8 ADVANCE, Cu-K α diffraction; the tube voltage is 40kV and 150 mA; the scanning range is 2.0-40.0 degrees, the scanning step is 0.02 degrees, and continuous scanning is realized.
Example 1: preparation of betrixaban hydrochloride
10g of compound III (43.7mmol), 80mL of dichloromethane, 0.2mL of N, N-dimethylformamide (2.6mmol) and 6.3mL of thionyl chloride (87.4mmol) are added into a 500mL three-necked flask, and the temperature is controlled at 30 ℃ to react for 1h to obtain a solution of compound VIII for later use.
Adding 14.6g of compound IV (52.6mmol), 160mL of dichloromethane and 18mL of triethylamine (0.13mol) into a 1000mL three-necked flask, controlling the temperature to be 15 ℃, dropwise adding the solution of the compound VIII, reacting for 3h after dropwise adding, filtering, washing with dichloromethane, and drying in vacuum to obtain 18.7g of off-white solid, wherein the yield is 87.5%, the HPLC purity is 99.7%, and all single impurities are less than 0.1%.
The off-white bestroban hydrochloride solid obtained from example 1 has form I. The X-ray diffraction pattern of the powder of the crystal form I of the betrixaban hydrochloride is shown in figure 1, and the pattern data is shown in table 1 (taking the measured values corresponding to diffraction peaks within the range of 2 theta angle 2.0-40.0 degrees):
table 1 bestroban hydrochloride form I powder obtained in example 1 data of main characteristic peaks by X-ray diffraction
| 2θ(°) | Relative peak intensity (%) |
| 12.1 | 21.1 |
| 12.4 | 22.9 |
| 13.8 | 52.0 |
| 14.5 | 74.2 |
| 14.7 | 88.9 |
| 18.8 | 100.0 |
| 19.7 | 46.5 |
| 22.8 | 98.6 |
| 23.3 | 41.3 |
| 23.6 | 61.1 |
| 24.4 | 59.5 |
| 24.9 | 57.1 |
| 26.2 | 33.8 |
| 26.5 | 48.4 |
| 27.6 | 34.3 |
| 28.5 | 79.0 |
An appropriate amount of the betrixaban hydrochloride form I sample of example 1 was taken, sealed in an ampoule, placed at 25 ℃ ± 2 ℃ and a relative humidity of 60% ± 5% for 12 months, sampled at the end of 12 months, and subjected to powder X-ray diffraction analysis. The results show that: the powder X-ray diffraction pattern of the crystal form I of the betrixaban hydrochloride of the invention after being placed for 12 months for a long time is basically consistent with the pattern of 0 month, which shows that the crystal form I of the betrixaban hydrochloride of the invention has good stability.
Example 2: preparation of betrixaban hydrochloride
10g of compound III (43.7mmol), 70mL of acetone, 0.2mL of N, N-dimethylformamide (2.6mmol) and 4.8mL of thionyl chloride (66.2mmol) are added into a 500mL three-necked flask, and the temperature is controlled at 15 ℃ to react for 2h, so as to obtain a solution of compound VIII for later use.
12.2g of compound IV (43.9mmol), 150mL of acetone and 9.2g of sodium bicarbonate (0.11mol) are added into a 1000mL three-necked bottle, the temperature is controlled at 20 ℃, the solution of the compound VIII is dropwise added, the reaction is carried out for 2h after the dropwise addition, the suction filtration, the acetone washing and the vacuum drying are carried out, 18.6g of off-white solid is obtained, the yield is 87.1%, the HPLC purity is 99.7%, and all single impurities are less than 0.1%.
The off-white betrixaban hydrochloride solid obtained from example 2 has crystalline form II. The measured powder X-ray diffraction pattern of the crystal form II of the betrixaban hydrochloride is shown in a figure 2, and the pattern data is shown in a table 2 (taking the measured values corresponding to diffraction peaks within the range of 2 theta angle 2.0-40.0 degrees):
table 2 main characteristic peak data of X-ray diffraction of crystal form II powder of betrixaban hydrochloride obtained in example 2
| 2θ(°) | Relative peak intensity (%) |
| 4.5 | 43.8 |
| 7.8 | 91.6 |
| 8.8 | 52.5 |
| 11.5 | 22.4 |
| 13.6 | 23.1 |
| 15.3 | 45.5 |
| 15.9 | 37.9 |
| 17.7 | 81.2 |
| 23.4 | 89.8 |
| 23.7 | 100.0 |
| 27.4 | 28.0 |
| 27.8 | 37.8 |
An appropriate amount of the betrixaban crystal form hydrochloride crystal form II sample of example 2 was taken, sealed in an ampoule, placed at 25 ℃ ± 2 ℃ and a relative humidity of 60% ± 5% for 12 months, sampled at the end of 12 months, and subjected to powder X-ray diffraction analysis. The results show that: the powder X-ray diffraction pattern of the crystal form II of the betrixaban hydrochloride of the invention after being placed for 12 months for a long time is basically consistent with the pattern of 0 month, which shows that the crystal form II of the betrixaban hydrochloride of the invention has good stability.
Example 3: investigation of solvent and base 1 types
Referring to example 1 preparation of betrixaban hydrochloride, examination of reaction solvent of compound VIII with compound IV and type of base 1:
| base 1 | Solvent(s) | Reaction time (h) | Yield (%) | Purity (%) | Crystal form | |
| Sodium | Methylene dichloride | 3 | 84.9 | 99.6 | I | |
| Sodium hydroxide | Acetone (II) | 3 | 84.2 | 99.5 | II | |
| Pyridine compound | Methylene dichloride | 3 | 87.5 | 99.7 | I | |
| Sodium | Methylene dichloride | 3 | 86.6 | 99.7 | I |
From the above table, it can be seen that: when strong base, medium-strength base or weak base is selected, the purity of the betrixaban hydrochloride can reach more than 99.5 percent (including 99.5 percent); the yield of the product which selects alkali with medium strength or weak alkali as the acid-binding agent is higher than that which selects strong alkali as the acid-binding agent.
Example 4: preparation of betrixaban
15g of betrixaban hydrochloride (30.7mmol) from example 1 was added to a 500mL three-necked flask, 150mL of methanol and 550mL of water were added to the reaction flask, 4.63g of sodium carbonate (43.7mmol) were added, the mixture was stirred at 20 ℃ for 1h, filtered with suction, washed with methanol and water in this order, and dried under vacuum to give 12.6g of a pale yellow solid with a yield of 90.8%, an HPLC purity of 99.7%, and less than 0.1% of all the simple impurities.
The pale yellow betrixaban solid obtained from example 4 has form D. The X-ray diffraction pattern of the betrixaban powder is shown in figure 3, and the pattern data is shown in table 3 (taking the measured value corresponding to the main characteristic diffraction peak within the 2 theta angle range of 2.0-40.0 degrees):
table 3 main characteristic peak data of powder X-ray diffraction of betrixaban form D obtained in example 4
| 2θ(°) | Relative Strength (%) |
| 9.9 | 26.8 |
| 12.9 | 23.6 |
| 18.3 | 46.0 |
| 18.5 | 17.3 |
| 18.8 | 21.3 |
| 19.7 | 15.6 |
| 22.7 | 38.7 |
| 24.1 | 100.0 |
| 26.2 | 17.4 |
| 26.7 | 38.5 |
| 27.9 | 17.4 |
| 28.9 | 10.5 |
An appropriate amount of the Betriciban crystal form D sample in the example 4 is sealed in a glass tube injection bottle, the glass tube injection bottle is placed for 12 months under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 60 +/-5%, sampling is carried out at the end of 12 months, other investigation indexes are tested after the appearance is compared, the purity is more than 99.5%, the single impurity content is less than 0.1%, the detection index has no obvious change, and the property is stable. Performing powder X-ray diffraction analysis, observing whether the crystal form is consistent with the crystal form of 0 month, wherein the obtained result is shown in the attached figure 4, and the map data is shown in the table 4:
table 4 main characteristic peak data of powder X-ray diffraction after 12 months of the crystal form D of betrixaban obtained in example 4
| 2θ(°) | Relative Strength (%) |
| 9.9 | 22.6 |
| 12.9 | 20.0 |
| 18.3 | 43.5 |
| 18.5 | 17.6 |
| 18.8 | 17.6 |
| 19.7 | 14.1 |
| 22.7 | 38.3 |
| 24.1 | 100.0 |
| 26.2 | 18.1 |
| 26.7 | 41.9 |
| 27.9 | 18.1 |
| 28.9 | 10.7 |
The powder X-ray diffraction analysis result shows that: the powder X-ray diffraction pattern of the crystal form D of the betrixaban is basically consistent with the pattern of 0 month after being placed for 12 months for a long time, which shows that the crystal form D of the betrixaban has good stability.
Example 5: examination of the types of solvent and base 2
Referring to the method for preparing betrixaban in example 4, the reaction solvent and the type of base 2 for preparing betrixaban from betrixaban hydrochloride were examined, and the results were as follows:
| base 2 | Solvent(s) | Time (h) | Yield (%) | Purity (%) | Crystal form |
| Sodium carbonate | Methanol | 1 | 85.3 | 99.7 | D |
| Sodium methoxide | Methanol | 1 | 86.1 | 99.7 | D |
| Sodium methoxide | Isopropyl alcohol | 1 | 87.6 | 99.7 | D |
| Sodium methoxide | Methanol-water | 1 | 92.3 | 99.8 | D |
From the above table, it can be seen that: under the condition of the invention, the purity of the obtained betrixaban product can reach more than 99.5 percent (including 99.5 percent), the reaction yield is more than 85 percent, and the obtained crystal forms are crystal forms D; when strong alkali and lower alcohol-water mixed solvent are selected, the reaction yield can reach more than 90%.
Claims (14)
1. A method for preparing betrixaban hydrochloride shown as a formula II,
the method is characterized in that: the method comprises the following steps:
(1) reacting the compound III or hydrochloride thereof with thionyl chloride to obtain a compound VIII or hydrochloride thereof;
(2) carrying out acylation reaction on the compound VIII or hydrochloride thereof obtained in the step (1) and a compound IV under the action of alkali 1 to obtain betrixaban hydrochloride shown in a formula II,
2. the process according to claim 1, wherein the molar ratio of thionyl chloride to compound III or the hydrochloride thereof in the step (1) is 1:1 to 10: 1; the reaction temperature is 0-80 ℃; the reaction time is 1 to 10 hours; the reaction solvent is one or more selected from tetrahydrofuran, methyl tert-butyl ether, n-hexane, n-heptane, acetone or dichloromethane.
3. The method of claim 1, wherein: the molar ratio of the compound IV to the compound III or the hydrochloride thereof is 1:1 to 5: 1.
4. The method of claim 1, wherein: the molar ratio of the compound IV to the compound III or the hydrochloride thereof is 1:1 to 2: 1.
5. The method of claim 1, wherein: in the step (2), the alkali 1 is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, pyridine, diisopropylethylamine or diisopropylamine; the molar ratio of base 1 to compound III or its hydrochloride salt is from 1:1 to 20: 1.
6. The method of claim 1, wherein: the alkali 1 in the step (2) is selected from one or more of sodium bicarbonate, sodium carbonate, triethylamine or pyridine; the molar ratio of the base 1 to the compound III or the hydrochloride thereof is 1:1 to 8: 1.
7. The method of claim 1, wherein: the solvent used in the step (2) is one or more selected from N, N-dimethylformamide, ethyl acetate, tetrahydrofuran, dichloromethane, acetonitrile, dimethyl sulfoxide, acetone, methyl tert-butyl ether, isopropyl ether, water, N-hexane or N-heptane; the weight ratio of the solvent to the compound III or the hydrochloride thereof is 1:1 to 100: 1.
8. The method of claim 1, wherein: the solvent used in the step (2) is selected from one or more of N, N-dimethylformamide, tetrahydrofuran, acetone, dichloromethane or water; the weight ratio of the solvent to the compound III or the hydrochloride salt thereof is 5:1 to 50: 1.
9. The method of claim 1, wherein: the purity of the obtained betrixaban hydrochloride is not lower than 99.5%.
10. The method of claim 1, wherein: the obtained betrixaban hydrochloride is in a crystal form I, Cu-Kalpha radiation is used, and powder X-ray diffraction represented by a 2 theta angle has main characteristic diffraction peaks at the following positions: 12.1 +/-0.2 degrees, 12.4 +/-0.2 degrees, 13.8 +/-0.2 degrees, 14.5 +/-0.2 degrees, 14.7 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.7 +/-0.2 degrees, 22.8 +/-0.2 degrees, 23.3 +/-0.2 degrees, 23.6 +/-0.2 degrees, 24.4 +/-0.2 degrees, 24.9 +/-0.2 degrees, 26.2 +/-0.2 degrees, 26.5 +/-0.2 degrees, 27.6 +/-0.2 degrees and 28.5 +/-0.2 degrees.
11. The method of claim 1, wherein: the obtained betrixaban hydrochloride is in a crystal form II, Cu-Kalpha radiation is used, and powder X-ray diffraction represented by a 2 theta angle has main characteristic diffraction peaks at the following positions: 4.5 +/-0.2 degrees, 7.8 +/-0.2 degrees, 8.8 +/-0.2 degrees, 11.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.3 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.7 +/-0.2 degrees, 23.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 27.4 +/-0.2 degrees and 27.8 +/-0.2 degrees.
12. A preparation method of betrixaban as shown in formula I,
the method is characterized in that: the betrixaban hydrochloride of formula II obtained in claim 1 is further reacted with a base 2 to obtain betrixaban hydrochloride, wherein the base 2 is sodium methoxide, the solvent is a mixed solvent of methanol and water, the weight ratio of methanol to betrixaban hydrochloride is 5:1 to 10:1, and the weight ratio of water to betrixaban hydrochloride is 30:1 to 50: 1.
13. The method of manufacturing according to claim 12, wherein: the purity of the obtained betrixaban is not less than 99.5%.
14. The method of manufacturing according to claim 12, wherein: the obtained betrixaban is a crystal form, Cu-Kalpha radiation is used, and powder X-ray diffraction expressed by 2 theta angles has main characteristic diffraction peaks at the following positions: 9.9 +/-0.2 degrees, 12.9 +/-0.2 degrees, 18.3 +/-0.2 degrees, 22.7 +/-0.2 degrees, 24.1 +/-0.2 degrees and 26.7 +/-0.2 degrees.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610935421.2A CN108017576B (en) | 2016-11-01 | 2016-11-01 | Preparation method of betrixaban and hydrochloride thereof, and crystal forms of betrixaban and hydrochloride thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610935421.2A CN108017576B (en) | 2016-11-01 | 2016-11-01 | Preparation method of betrixaban and hydrochloride thereof, and crystal forms of betrixaban and hydrochloride thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108017576A CN108017576A (en) | 2018-05-11 |
| CN108017576B true CN108017576B (en) | 2022-06-21 |
Family
ID=62070537
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610935421.2A Active CN108017576B (en) | 2016-11-01 | 2016-11-01 | Preparation method of betrixaban and hydrochloride thereof, and crystal forms of betrixaban and hydrochloride thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108017576B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007056517A2 (en) * | 2005-11-08 | 2007-05-18 | Millennium Pharmaceuticals, Inc. | Pharmaceutical salts and polymorphs of n- (5-chl0r0-2-pyridinyl) -2- [ [4- [ (dimethylamino) iminomethyl] benzoyl] amino] -5-meth oxy-benzamide, a factor xa inhibitor |
| CN104341343A (en) * | 2013-07-24 | 2015-02-11 | 四川海思科制药有限公司 | Crystal forms of betrixaban, and preparing method and uses thereof |
| CN105085387A (en) * | 2014-05-20 | 2015-11-25 | 四川海思科制药有限公司 | Betrixaban salt, preparation method and application thereof |
| CN105732490A (en) * | 2016-03-25 | 2016-07-06 | 重庆医科大学 | Preparation method of betrixaban |
-
2016
- 2016-11-01 CN CN201610935421.2A patent/CN108017576B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007056517A2 (en) * | 2005-11-08 | 2007-05-18 | Millennium Pharmaceuticals, Inc. | Pharmaceutical salts and polymorphs of n- (5-chl0r0-2-pyridinyl) -2- [ [4- [ (dimethylamino) iminomethyl] benzoyl] amino] -5-meth oxy-benzamide, a factor xa inhibitor |
| CN104341343A (en) * | 2013-07-24 | 2015-02-11 | 四川海思科制药有限公司 | Crystal forms of betrixaban, and preparing method and uses thereof |
| CN105085387A (en) * | 2014-05-20 | 2015-11-25 | 四川海思科制药有限公司 | Betrixaban salt, preparation method and application thereof |
| CN105732490A (en) * | 2016-03-25 | 2016-07-06 | 重庆医科大学 | Preparation method of betrixaban |
Non-Patent Citations (1)
| Title |
|---|
| 贝曲西班的合成工艺;赵华 等;《中国新药杂志》;20141203;第23卷(第24期);第2902-2904、2911页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108017576A (en) | 2018-05-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2951158B1 (en) | Process for the preparation of ivacaftor and solvates thereof | |
| CN103641890A (en) | Synthetic method of kyprolis | |
| US11420948B2 (en) | Synthesis method for cariprazine | |
| CN109516998B (en) | Synthesis method of Barosavir intermediate | |
| WO2011160594A1 (en) | New preparation method of lapatinib | |
| US10927095B2 (en) | Processes for the preparation of Niraparib and intermediates thereof | |
| CN107778223B (en) | Preparation method of betrixaban maleate | |
| US20090137821A1 (en) | Method of making dorzolamide hydrochloride | |
| CN102532109B (en) | Synthetic method of lapatinib and salt of lapatinib | |
| CN105712919B (en) | The amide condensed dose of application in vildagliptin synthetic method | |
| CN108017576B (en) | Preparation method of betrixaban and hydrochloride thereof, and crystal forms of betrixaban and hydrochloride thereof | |
| CN111004233A (en) | Novel preparation method of nicergoline | |
| CN115197150A (en) | Preparation method of L-carnosine | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| WO2022017317A1 (en) | Method for large-scale synthesis of tetrodotoxin | |
| KR100743617B1 (en) | Process for the preparation of chiral 3-hydroxy pyrrolidine compound and derivatives thereof having high optical purity | |
| US20060009644A1 (en) | Novel crystalline forms of sodium 1,2-benzisoxazole-3-methanesulfonate, processes of preparing same and use thereof in the synthesis of zonisamide | |
| US7745471B2 (en) | Derivatives of 1,2-benzisoxazole-3-methane sulfonic acid as novel intermediates for the synthesis of zonisamide | |
| JP6856471B2 (en) | A method for producing a lactone compound and a method for producing biotin using the lactone compound. | |
| JP2020070296A (en) | Method for producing linagliptin | |
| CN103073498A (en) | Novel preparation method for (R)-Alpha-amino-e-caprolactam | |
| WO2018207120A1 (en) | A process for the preparation of 4-fluoro-2-methoxy-5-nitroaniline | |
| CN114105961B (en) | Preparation method of IDO1 inhibitor (LY-3381916) | |
| CN111574540B (en) | Preparation method of Degatinib | |
| CN113493385B (en) | Method for synthesizing butenafine hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |