CN111039937A - Preparation method of rivaroxaban intermediate - Google Patents
Preparation method of rivaroxaban intermediate Download PDFInfo
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Abstract
The invention provides a preparation method of a rivaroxaban intermediate, which comprises the following steps: (1) reacting the compound A with the compound B in alcohol or an alcohol water solution to obtain a compound C; (2) reacting the compound C with N, N' -carbonyl diimidazole, wherein the reaction solvent is selected from acetonitrile or butyronitrile, obtaining reaction liquid containing the compound D, cooling and crystallizing to obtain the compound D
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a rivaroxaban intermediate.
Background
Rivaroxaban tablets, trade name xaritol (Xarelto), are an oral anticoagulant drug developed by bayer corporation, germany, and the active ingredient is Rivaroxaban (Rivaroxaban). The mechanism of action is to inhibit thrombosis by specifically and directly inhibiting free and bound coagulation factor Xa, blocking the outbreak of thrombin generation. The preparation is mainly used for preventing the formation of deep vein thrombosis and pulmonary embolism of patients after hip joint and knee joint replacement in clinic, and can also be used for preventing cerebral apoplexy and non-central nervous system embolism of patients with non-valvular atrial fibrillation, and reducing the risk of coronary artery syndrome recurrence.
The chemical name for rivaroxaban is 5-chloro-N- { [ (5S) -2-oxo-3- (4- (3-oxomorpholin-4-yl) phenyl) -1, 3-oxazolin-5-yl ] methyl } thiophene-2-carboxamide, the structural formula is shown below:
one key intermediate in the preparation of rivaroxaban is 2- { [ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl ] methyl } -1H-isoindole-1, 3(2H) -dione, which has the following structural formula:
patent document US7351823 discloses a preparation method of rivaroxaban, comprising the following steps:
a) reacting the compound (II) with the compound (III) to obtain a compound (V);
b) reacting the compound (V) with N, N' -Carbonyldiimidazole (CDI) in toluene, and adding ethanol for crystallization to obtain a compound (VI);
c) the compound (VI) generates a compound (VII) under the action of methylamine and hydrochloric acid;
d) and reacting the compound (VII) with 5-chlorothiophene-2-formyl chloride to obtain rivaroxaban (I).
The reaction scheme is as follows:
the purity and ee value of the product of each step are not disclosed in this document. The inventor conducts repeated experiments and finds that the preparation method has the following defects:
(1) the imidazole impurity generated in the step b) has low solubility in toluene and can be separated out along with the product, so that the HPLC purity of the compound (VI) in the product is only 95% -97%, the product also contains 2% -3% of imidazole impurity, and the compound (V) and the impurity F, G which are not completely reacted (the structural formula of the impurity F, G is shown in the summary part of the specification of the application). The compound (VI) is used as a key intermediate for synthesizing rivaroxaban, so that the purity and impurity level cannot meet the quality requirement of a raw material medicine intermediate, the quality of rivaroxaban is seriously influenced, and the cost is greatly increased if purification operation is added;
(2) after the steps a) and b), the ee values of the compound (V) and the key intermediate compound (VI) are not improved, and the means for improving the ee value of rivaroxaban through subsequent reactions is limited, in this case, the ee value of rivaroxaban still mainly depends on the initial raw material compound (II), but the compound (II) with high ee value (for example, the ee value is more than or equal to 99.0%) is not easy to obtain, so that the cost of the whole route is increased;
(3) the mixed solvent is used in the reaction (toluene and ethanol are used in the step b), and the solvent recovery cost is high in industrial production.
Patent document WO201232533a2 discloses that compound (VIII) reacts with carbonyldiimidazole in dichloromethane at 30 ℃ for 20 hours, water is added for extraction, and the dichloromethane layer is concentrated to dryness to obtain rivaroxaban key intermediate compound (III); further, compound (III) is purified by recrystallization from N, N-dimethylformamide and acetone or N, N-dimethylformamide and methanol
The preparation method has long reaction time and complicated operation, and the inventor repeatedly finds that the compound (III) is easy to separate out in a dichloromethane layer during extraction, the layering is influenced, the compound (VIII) which is not completely reacted and impurities are in the product, the purity of the product is only 90-93 percent, and the product can be used for the next reaction only by repeated recrystallization purification.
In summary, the preparation method of the rivaroxaban key intermediate in the prior art has many defects, and a new preparation method for obtaining a high-quality intermediate needs to be developed in the field so as to reduce the cost of the whole route and improve the quality of rivaroxaban.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of a rivaroxaban key intermediate compound D, which has the advantages of simple process, low cost, no need of adding complex purification treatment, suitability for industrial production, high purity and high ee value of the compound D and capability of meeting the requirement of a high-quality bulk drug intermediate.
The structural formula of the compound D is as follows:
according to the purpose of the invention, the invention provides a preparation method of a rivaroxaban intermediate compound D, which comprises the following steps:
(1) reacting the compound A with the compound B in alcohol or an alcohol water solution to obtain a compound C;
(2) reacting the compound C with N, N' -carbonyl diimidazole, wherein the reaction solvent is selected from acetonitrile or butyronitrile, obtaining reaction liquid containing the compound D, cooling and crystallizing to obtain the compound D
According to the preparation method of the present invention, in the step (1), the molar ratio of the compound a to the compound B is 1: 1.0 to 1.5; preferably, the molar ratio of compound a to compound B is 1: 1.1 to 1.3.
According to the production method of the present invention, in the step (1), the alcohol is ethanol or isopropanol.
According to the preparation method, in the step (1), the volume percentage of the alcohol in the alcohol aqueous solution is more than or equal to 80 percent.
According to the preparation method, in the step (1), the volume mass ratio of the alcohol or the aqueous solution of the alcohol to the compound A is 8-30 ml: 1 g; preferably, the volume mass ratio of the alcohol or the aqueous alcohol solution to the compound A is 10-20 ml: 1 g.
According to the preparation method of the invention, in the step (1), the reaction temperature is 60 ℃ to the reflux temperature of the solvent; preferably, the temperature of the reaction is the solvent reflux temperature.
According to the preparation method, in the step (1), the reaction progress is monitored by an HPLC method until the reaction is completed, and the reaction time of the step (1) is 15-30 hours; preferably, the reaction time of step (1) is 18 to 24 hours.
According to the preparation method of the invention, in the step (1), after the reaction is finished, the compound C is obtained by post-treatment by conventional technical means such as cooling to precipitate solid, filtering or centrifuging, drying and the like. The specific operation is as follows: and (2) after the reaction in the step (1) is finished, cooling the reaction liquid to 20-30 ℃, filtering, washing a filter cake, and carrying out vacuum drying at 50-100 ℃ for 3-10 hours to obtain a compound C. Preferably, the solvent for washing the filter cake can be ethanol, isopropanol, or an aqueous solution of 80% -95% (v/v) ethanol or isopropanol.
According to the production method of the present invention, in the step (2), the molar ratio of the compound C to the N, N' -carbonyldiimidazole is 1.0: 1.0 to 2.0; preferably, the molar ratio of the compound C to the N, N' -carbonyldiimidazole is 1.0: 1.1-1.5.
According to the preparation method of the invention, in the step (2), the volume mass ratio of the reaction solvent to the compound C is 3-20 ml: 1 g; preferably, the volume mass ratio of the reaction solvent to the compound C is 5-10 ml: 1 g.
According to the preparation method of the invention, in the step (2), the reaction temperature is 50 ℃ to the reflux temperature of the solvent; preferably, the temperature of the reaction is the solvent reflux temperature.
According to the preparation method of the present invention, in the step (2), the progress of the reaction is monitored by the HPLC method until the completion of the reaction. The reaction time in the step (2) is 1-10 hours; preferably, the reaction time of the step (2) is 2-5 hours.
According to the preparation method, in the step (2), the cooling crystallization temperature is 0-30 ℃, and the cooling crystallization time is 1-10 hours; preferably, the cooling crystallization temperature is 0-10 ℃, and the cooling crystallization time is 1-3 hours.
According to the preparation method of the invention, after the step (2) is finished, the compound D is obtained by post-treatment by adopting conventional technical means such as filtration, centrifugation, drying and the like. The specific operation is as follows: and (3) after the step (2) is finished, filtering the material, and drying the filter cake for 2-10 hours in vacuum at the temperature of 30-100 ℃ to obtain a compound D.
The process impurities which may be generated in the preparation method of the invention are: generating an over-ammoniated byproduct impurity E in the step (1), wherein the impurity E reacts with CDI in the step (2) to generate an impurity F and an impurity G, and the structural formulas of the impurities F and the impurity G are shown as follows:
in the invention, the content of impurities is detected by an HPLC method.
In the present invention, the compound a and the compound B can be obtained commercially or prepared by the methods of the references, for example: for the preparation of compound a, reference is made to patent document CN100430384C, and for the preparation of compound B, reference is made to patent document CN 102311400A. Wherein the HPLC purity of the compound A is more than or equal to 95.0 percent; the HPLC purity of the compound B is more than or equal to 95.0 percent, the content of single impurity is less than or equal to 3.0 percent, and the ee value is more than or equal to 96.0 percent.
Compared with the prior art, the invention has the unexpected remarkable advantages that:
1. compound D has high HPLC purity and high ee value. The HPLC purity of the compound D reaches more than 99.5 percent, the impurity E, F, G is not detected, and the content of the compound C which is not completely reacted is less than 0.1 percent; meanwhile, the ee value of the compound D is more than or equal to 99.5 percent, which meets the requirement of a high-quality bulk drug intermediate.
2. The process has good tolerance and strong impurity removal capability. In the rivaroxaban intermediate process optimization process, the inventor surprisingly discovers that acetonitrile or butyronitrile is used as a reaction solvent in the step (2), impurity removal in the whole process and ee value improvement of a compound D have unexpected excellent effects which are not possessed by other processes, particularly the preparation method has low requirements on purity and ee value of a starting material, and the compound D with HPLC purity of more than or equal to 99.5% and ee value of more than or equal to 99.5% can be obtained from the starting material compound B with HPLC purity of more than or equal to 95.0% and ee value of more than or equal to 96.0%.
3. The method has the advantages of easily obtained starting materials, low cost, simple process operation, no need of adding complex purification treatment, and suitability for industrial production.
4. The single solvent is used in each step of reaction, the solvent recovery rate is high in industrial production, and three wastes are less.
Detailed Description
For a better understanding of the present invention, the following examples are set forth to illustrate, but are not to be construed as the limit of the present invention.
The various starting materials and reagents used in the examples are all commercially available unless otherwise specified.
The invention adopts the following detection instruments and conditions:
1. by NMR1H-NMR) the structure of the product was characterized with a 400MHz nuclear magnetic resonance spectrometer Bruker Avance 400.
2. Detecting the purity of the product by high performance liquid chromatography: agilent 1200 liquid chromatograph, column: agilent SB-C18 (4.6X 150mm, 5 μm), detection wavelength 241nm, column temperature 25 ℃, flow rate 1.0ml/min, mobile phase: 0.1% aqueous phosphoric acid solution-acetonitrile (70: 30 by volume), and the sample amount was 20. mu.l.
3. Detecting the content of the product and the enantiomer thereof by high performance liquid chromatography: the detection conditions are as follows: shimadzu LC-20A/UV; a chromatographic column: CHIRALCEL OD-H (4.6 mm. times.250 mm, 5 μm), mobile phase: n-hexane-ethanol-diethylamine (volume ratio 40:60:0.2), flow rate: 1mL/min, column temperature: 25 ℃, detection wavelength: 248 nm.
Example 1: preparation of Compound B
92.6g of phthalimide potassium salt is added into a 1000mL reaction flask, 400mL of (S) -epichlorohydrin is added, the temperature is raised to 70 ℃, the reaction is carried out for 1 hour, the solvent is concentrated and recovered, and the residue is recrystallized by 500mL of absolute ethyl alcohol, so that 84g of compound B with HPLC purity: 95.1%, molar yield: 83%, ee value: 96.0 percent.
Nuclear magnetic data:1H-NMR(DMSO-d6)δ(ppm):2.59(1H,m),2.76(1H,m),3.22(1H,m)，3.78(2H,d,J＝4.56Hz),7.86(2H,m),7.89(2H,m)
example 2: preparation of Compound B
92.6g of phthalimide potassium salt was put into a 1000mL reaction flask, 600mL of (S) -epichlorohydrin was added, the temperature was raised to 40 ℃, reaction was carried out for 3 hours, the solvent was concentrated and recovered, and the residue was recrystallized from 500mL of anhydrous ethanol twice (500 mL. times.2), to obtain 65g of Compound B, HPLC purity: 98.2%, molar yield: 64%, ee value: 97.5 percent.
The nuclear magnetic data of compound B obtained in example 2 was consistent with that of example 1.
Example 3: preparation of Compound B
92.6g of phthalimide potassium salt was added to a 1000mL reaction flask, 600mL of (S) -epichlorohydrin was added, the temperature was raised to 40 ℃, the reaction was carried out for 3 hours, the solvent was concentrated and recovered, the residue was recrystallized once from 500mL of absolute ethanol and once from 200mL of ethyl acetate to obtain 53g of Compound B, HPLC purity: 99.8%, molar yield: 52%, ee value: 98.5 percent.
The nuclear magnetic data of compound B obtained in example 3 was consistent with that of example 1.
Example 4: preparation of Compound C
A reaction flask was charged with 96g of compound a (prepared as described in example CN100430384C, HPLC purity 96.0%), 960mL of 95% (v/v) ethanol aqueous solution and 120g of compound B (prepared as described in example 1), heated under reflux for 15 hours, cooled to 20 ℃, filtered, washed with 200mL of 95% ethanol aqueous solution, and dried under vacuum at 70 ℃ for 5 hours to give 188g of compound C as off-white solid in molar yield: 95%, HPLC purity: 95.0%, impurity E content of 2.8%, ee value: 96.2 percent. Nuclear magnetic data:1H-NMR(DMSO-d6)δ(ppm):3.03(1H,m),3.16(1H,m),3.61(2H,m),3.62(1H,m),3.66(1H,m),3.93(2H,m),4.01(1H,m),4.14(2H,s),6.61(2H,d,J＝8.70Hz)7.03(2H,d,J＝8.70Hz),7.83(2H,m),7.87(2H,m)
example 5: preparation of Compound C
A reaction flask was charged with 96g of compound a (HPLC purity 96.0%), 2880mL isopropanol and 111g compound B (prepared according to the method of example 1), heated under reflux for 20 hours, cooled to 20 ℃, filtered, washed with 300mL isopropanol, dried under vacuum at 50 ℃ for 10 hours to give 188g compound C, off-white solid, molar yield: 95%, HPLC purity: 96.0%, impurity E content of 1.9%, ee value: 96.4 percent.
The nuclear magnetic data of compound C obtained in example 5 are consistent with those of example 4.
Example 6: preparation of Compound C
A reaction flask was charged with 96g of compound a (HPLC purity 96.0%), 1920mL of ethanol and 131g of compound B (prepared according to example 1), heated at reflux for 24 hours, cooled to 30 ℃, filtered, washed with 100mL of ethanol, and dried under vacuum at 60 ℃ for 10 hours to give 170g of compound C, a white solid, molar yield: 86%, HPLC purity: 97.2%, content of impurity E1.6%, ee value: 96.0 percent.
The nuclear magnetic data of compound C obtained in example 6 was consistent with that of example 4.
Example 7: preparation of Compound C
A reaction flask was charged with 96g of Compound A (96.0% HPLC purity), 768mL of 90% (v/v) aqueous isopropanol and 102g of Compound B (prepared according to the method of example 1), heated under reflux for 18 hours, cooled to 30 ℃, filtered, washed with 200mL of 80% aqueous ethanol, and dried under vacuum at 100 ℃ for 3 hours to give 170g of Compound C, a white solid, molar yield: 86%, HPLC purity: 97.6%, content of impurity E1.5%, ee value: 96.2 percent.
The nuclear magnetic data of compound C obtained in example 7 was consistent with that of example 4.
Example 8: preparation of Compound C
A reaction flask was charged with 96g of compound a (HPLC purity 96.0%), 1500mL of 80% (v/v) aqueous ethanol and 153g of compound B (prepared according to the method of example 1), warmed to 60 ℃ for reaction for 30 hours, cooled to 20 ℃, filtered, washed with 200mL of 95% aqueous ethanol, and dried under vacuum at 70 ℃ for 10 hours to give 176g of compound C, a white solid, molar yield: 89%, HPLC purity: 97.4%, impurity E content 1.5%, ee value: 96.2 percent.
The nuclear magnetic data of compound C obtained in example 8 was consistent with that of example 4.
Example 9: preparation of Compound C
A reaction flask was charged with 96g of compound a (HPLC purity 96.0%), 1500mL of 80% (v/v) aqueous ethanol and 120g of compound B (prepared according to the method of example 2), heated under reflux for 16 hours, cooled to 25 ℃, filtered, washed with 200mL of 80% aqueous ethanol, and dried under vacuum at 70 ℃ for 10 hours to give 182g of compound C, a white solid, molar yield: 92%, HPLC purity: 98.8%, impurity E content 0.4%, ee value: 97.7 percent.
The nuclear magnetic data of compound C obtained in example 9 was consistent with that of example 4.
Example 10: preparation of Compound D
100g of compound C (prepared in example 4) and 1000mL of acetonitrile are added into a reaction flask, 82g of CDI is added under stirring, the temperature is raised to reflux, the reaction is carried out for 1 hour, the temperature is reduced to 10 ℃, the temperature is kept for 1 hour, the filtration is carried out, and a filter cake is dried in vacuum for 2 hours at 100 ℃ to obtain 99g of compound D, a white solid, the molar yield is 93 percent, and the HPLC purity is as follows: 99.90%, the content of compound C is 0.05%, impurity E, F, G is not detected, ee value: 99.5 percent. Nuclear magnetic data:1H-NMR(DMSO-d6)δ(ppm)：3.71(2H,m),3.94(2H,m),3.97(2H,m),4.00(1H,m),4.20(2H,s),4.22(1H,m),4.96(1H,m),7.41(2H,d,J＝8.94Hz),7.53(2H,d,J＝8.94Hz),7.87(2H,m),7.91(2H,m)
example 11: preparation of Compound D
100g of compound C (prepared in example 5) and 300mL of acetonitrile are added into a reaction flask, 61g of CDI is added under stirring, the temperature is raised to reflux, the reaction is carried out for 3 hours, the temperature is reduced to 0 ℃, the temperature is kept for 2 hours, the filtration is carried out, and a filter cake is dried in vacuum at 30 ℃ for 10 hours to obtain 101g of compound D, a white solid, the molar yield is 95%, and the HPLC purity is as follows: 99.95%, the content of compound C is 0.03%, impurity E, F, G is not detected, ee value: 99.5 percent.
The nuclear magnetic data of compound D obtained in example 11 was consistent with that of example 10.
Example 12: preparation of Compound D
100g of compound C (prepared in example 6) and 500mL of acetonitrile were added to a reaction flask, 45g of CDI was added with stirring, the temperature was raised to 60 ℃ and the reaction was carried out for 5 hours, the temperature was lowered to 20 ℃ and the reaction was kept for 3 hours, and the mixture was filtered, and the filter cake was dried under vacuum at 50 ℃ for 5 hours to obtain 102g of compound D as a white solid with a molar yield of 96% and an HPLC purity: 99.95%, the content of compound C is 0.05%, impurity E, F, G is not detected, ee value: 99.5 percent.
The nuclear magnetic data of compound D obtained in example 12 was consistent with that of example 10.
Example 13: preparation of Compound D
Adding 100g of compound C (prepared according to the method of example 6) and 2000mL of butyronitrile into a reaction flask, adding 42g of CDI while stirring, heating to 50 ℃, reacting for 10 hours, cooling to 10 ℃, keeping the temperature for 5 hours, filtering, and drying a filter cake at 50 ℃ in vacuum for 4 hours to obtain 100g of compound D, a white solid, the molar yield of 94%, the HPLC purity: 100%, ee value: 99.5 percent.
The nuclear magnetic data of compound D obtained in example 13 was consistent with that of example 10.
Example 14: preparation of Compound D
100g of compound C (prepared in example 9) and 1000mL of acetonitrile are added into a reaction flask, 45g of CDI is added under stirring, the mixture is heated to reflux and reacted for 5 hours, the temperature is reduced to 0 ℃ and the mixture is kept for 1 hour, the mixture is filtered, and a filter cake is dried in vacuum at 60 ℃ for 2 hours to obtain 103g of compound D, a white solid, the molar yield is 97%, and the HPLC purity is as follows: 99.98%, neither compound C nor impurity E, F, G was detected, ee value: 99.9 percent.
The nuclear magnetic data of compound D obtained in example 14 was consistent with that of example 10.
Example 15: preparation of Compound D
Adding 100g of compound C (prepared according to the method of example 5) and 500mL of butyronitrile into a reaction flask, adding 53g of CDI while stirring, heating up, refluxing for reaction for 2 hours, cooling to 30 ℃, preserving the temperature for 10 hours, filtering, and drying a filter cake in vacuum at 30 ℃ for 10 hours to obtain 99g of compound D, a white solid, the molar yield of 93%, and the HPLC purity: 99.98%, the content of compound C is 0.02%, impurity E, F, G is not detected, ee value: 99.8 percent.
The nuclear magnetic data of compound D obtained in example 15 was consistent with that of example 10.
Comparative example 1: preparation of Compound D (investigation of other solvents)
100g of compound C (prepared according to the method of example 6) and 500mL of tetrahydrofuran are added into a reaction flask, 53g of CDI is added under stirring, the mixture is heated to reflux and reacted for 2 hours, the temperature is reduced to 30 ℃, the temperature is kept for 10 hours, the mixture is filtered, and a filter cake is dried in vacuum at 30 ℃ for 10 hours to obtain 96g of compound D, a white solid, the molar yield is 90%, and the HPLC purity is as follows: 98.4%, compound C content 0.7%, impurity F content: 0.3%, content of impurity G: 0.6%, no impurity E detected, ee value: 96.8 percent.
The nuclear magnetic data of compound D obtained in comparative example 1 was consistent with that of example 10.
Comparative example 2: preparation of Compound D (prepared according to patent document US 7351823)
Adding 100g of compound C (prepared according to the method of example 6) and 800mL of toluene into a reaction flask, adding 50g of CDI while stirring, heating to reflux, reacting for 1 hour, cooling to 60 ℃, adding 160mL of absolute ethanol, cooling to 25 ℃, filtering, washing with 100mL of ethanol, and drying a filter cake at 50 ℃ in vacuum for 6 hours to obtain 100g of compound D, a white solid with the molar yield of 94%, and the HPLC purity: 96.5%, impurity imidazole content: 2.3%, compound C content 0.2%, impurity F content: 0.4%, content of impurity G: 0.6%, no impurity E detected, ee value: 96.4 percent.
The nuclear magnetic data of compound D obtained in comparative example 2 is consistent with that of example 10.
Claims (10)
1. A preparation method of a rivaroxaban intermediate compound D comprises the following steps:
(1) reacting the compound A with the compound B in alcohol or an alcohol water solution to obtain a compound C;
(2) reacting the compound C with N, N' -carbonyl diimidazole, wherein the reaction solvent is selected from acetonitrile or butyronitrile, obtaining reaction liquid containing the compound D, cooling and crystallizing to obtain the compound D
2. The process according to claim 1, wherein in step (1), the molar ratio of compound a to compound B is 1: 1.0 to 1.5; preferably, the molar ratio of compound a to compound B is 1: 1.1 to 1.3.
3. The method according to claim 1, wherein, in step (1), the alcohol is ethanol or isopropanol; the volume percentage of the alcohol in the alcohol aqueous solution is more than or equal to 80 percent; the volume mass ratio of the alcohol or the aqueous alcohol solution to the compound A is 8-30 ml: 1 g; preferably, the volume mass ratio of the alcohol or the aqueous alcohol solution to the compound A is 10-20 ml: 1 g.
4. The method according to claim 1, wherein in step (1), the temperature of the reaction is 60 ℃ to the reflux temperature of the solvent; preferably, the temperature of the reaction is the solvent reflux temperature; the reaction time of the step (1) is 15-30 hours; preferably, the reaction time of step (1) is 18 to 24 hours.
5. The method according to claim 1, wherein in step (1), after the reaction is finished, the solid is cooled and precipitated, filtered or centrifuged, and dried to obtain compound C; preferably, after the reaction in the step (1) is finished, cooling the reaction solution to 20-30 ℃, filtering, washing a filter cake, and vacuum-drying at 50-100 ℃ for 3-10 hours to obtain a compound C; preferably, the solvent for washing the filter cake can be ethanol, isopropanol, or an aqueous solution of 80% -95% ethanol or isopropanol.
6. The process according to any one of claims 1 to 5, wherein in step (2), the molar ratio of compound C to N, N' -carbonyldiimidazole is 1.0: 1.0 to 2.0; preferably, the molar ratio of the compound C to the N, N' -carbonyldiimidazole is 1.0: 1.1-1.5.
7. The method according to any one of claims 1 to 5, wherein in step (2), the volume-to-mass ratio of the reaction solvent to the compound C is 3 to 20 ml: 1 g; preferably, the volume mass ratio of the reaction solvent to the compound C is 5-10 ml: 1 g.
8. The process according to any one of claims 1 to 5, wherein, in step (2), the temperature of the reaction is from 50 ℃ to the reflux temperature of the solvent; preferably, the temperature of the reaction is the solvent reflux temperature; the reaction time in the step (2) is 1-10 hours; preferably, the reaction time of the step (2) is 2-5 hours.
9. The method according to any one of claims 1 to 5, wherein in the step (2), the cooling crystallization temperature is 0 to 30 ℃, and the cooling crystallization time is 1 to 10 hours; preferably, the cooling crystallization temperature is 0-10 ℃, and the cooling crystallization time is 1-3 hours.
10. The method according to any one of claims 1 to 5, wherein after completion of step (2), compound D is obtained by filtration or centrifugation, and drying; preferably, after the step (2) is finished, filtering the material, and drying the filter cake for 2-10 hours at 30-100 ℃ in vacuum to obtain the compound D.
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| CN111675705A (en) * | 2020-08-11 | 2020-09-18 | 北京鑫开元医药科技有限公司 | Preparation method of 4- (4-aminophenyl) morpholine-3-one derivative |
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