CN111606826B - Preparation method of edoxaban intermediate - Google Patents
Preparation method of edoxaban intermediate Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, and particularly discloses a preparation method of an edoxaban intermediate. The preparation method comprises the following steps: carrying out diene synthesis on a thiophene derivative of a compound II and acrylic acid, and carrying out chiral resolution to obtain a compound IV; carrying out amidation reaction with dimethylamine hydrochloride to obtain a compound V; reacting with di-tert-butyl dicarbonate in a hydrogen atmosphere to obtain a compound VI and a compound VI'; and performing amino deprotection and manual resolution to obtain a compound I, namely the edoxaban intermediate. The preparation method provided by the invention has the advantages of simple operation steps and high diastereomer selectivity, is favorable for improving the product yield and reducing the production cost, does not use a dangerous reagent sodium azide, does not involve low-temperature reaction, reduces the production risk, and ensures the safety and operability of the reaction.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of an edoxaban intermediate.
Background
Edoxaban (Edoxaban), the first anticoagulant to be administered orally, is a factor x (fxa) blocker. The chemical name of edoxaban is N- (5-chloropyridin-2-yl) -N' - [ (1S,2R,4S) -4- (N, N-dimethylcarbamoyl) ] -2- [ (5-methyl-4, 5,6, 7-tetrahydro-1, 3-thiazolo [5,4-c ] -pyridine-2-carboxamide) cyclohexyl ] oxamide, and the active ingredient of the commercially available medicine is the tosylate monohydrate of edoxaban.
At present, edoxaban is mostly synthesized from an intermediate represented by a compound I, namely tert-butyl [ (1R,2S,5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate through a plurality of steps. The existing synthesis process of [ (1R,2S,5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamic acid tert-butyl ester mainly comprises the following steps: the cyclohexylaminoalcohol is treated through the processes of methanesulfonic acid esterification, sodium azide substitution, hydrolysis, amidation and hydroammoniation, and the azidation of dimethyl amide substituted cyclohexylamino methanesulfonate. The former has low reaction yield (about 30 percent) in the process of nitridizing the mesylate, low diastereomer selectivity, more tedious steps, low yield and higher cost; in the latter new process, although the total yield of the reaction is improved by adding a phase transfer catalyst of dodecyl pyridine chloride, the use of a dangerous reagent of sodium azide is inevitable.
In summary, the existing synthesis process still has the defects of low ester group or amide para-azide yield, low diastereomer selectivity, high risk of production by using explosive hazardous reagent sodium azide, complicated conversion steps and the like, and the synthesis process of the edoxaban intermediate needs to be improved, so that the yield is improved, and the production cost is reduced.
Disclosure of Invention
Aiming at the technical problems in the existing synthesis process of the edoxaban intermediate, the invention provides a preparation method of the edoxaban intermediate.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a preparation method of an edoxaban intermediate is provided, the edoxaban intermediate is prepared by the following reaction steps,
the specific reaction steps comprise:
s1: carrying out diene synthesis on the compound II and acrylic acid to obtain a compound III, and carrying out chiral resolution to obtain a compound IV;
s2: carrying out amidation reaction on the compound IV and dimethylamine hydrochloride to obtain a compound V;
s3: adding a reduction catalyst into the compound V and di-tert-butyl dicarbonate in a hydrogen atmosphere to react to obtain a compound VI and a compound VI';
s4: and (3) carrying out amino deprotection on the compound VI and the compound VI 'to obtain a compound I and a compound I', and carrying out chiral resolution to obtain the compound I, namely the edoxaban intermediate.
Compared with the prior art, the preparation method of the edoxaban intermediate provided by the invention is characterized in that a compound II thiophene derivative and acrylic acid are used as raw materials, and the edoxaban intermediate [ (1R,2S,5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamic acid tert-butyl ester is obtained through diene synthesis (Diels-Alder reaction), chiral resolution, amidation reaction, hydrogenation reduction and Boc protection, amino deprotection and chiral resolution. Diastereomer selectivity in the steps S1 and S3 is high, and the reactions of desulfurization, double bond hydrogenation, nitro reduction and Boc protection in the step S3 are completed simultaneously in one step without separation, so that the operation steps are simplified, the cost is reduced, and the product yield is improved. In addition, the invention avoids the use of a dangerous reagent sodium azide, reduces the production risk, does not involve low-temperature reaction, and further improves the safety and operability of the reaction.
Further, in step S1, the reaction temperature of diene synthesis is 130-140 ℃ and the time is 4-8 h, so that the reaction is ensured to be fully performed, the diastereomer selectivity is improved, and the product yield is increased.
Further, in step S1, the molar ratio of the compound II to acrylic acid is 1: 1.05-1.10, and the compound II and the reaction temperature act together to improve diastereomer selectivity and increase product yield.
Further, in step S1, the organic solvent is diethylene glycol dimethyl ether, which helps to improve diastereoselectivity.
Further, in step S1, after the diene synthesis reaction is finished, crystallization, washing, suction filtration and drying treatment are further included, wherein the crystallization temperature is 0-10 ℃, and the time is 0.5-1.5 h; the detergent is diethylene glycol dimethyl ether pre-cooled at 0-10 ℃; the drying temperature is 45-55 ℃.
Further, in the step S2, the temperature of the amidation reaction is 5-15 ℃ and the time is 5-6 h.
Further, in step S2, the molar ratio of the compound IV to dimethylamine hydrochloride is 1: 1.10-1.15, and the compound IV and dimethylamine hydrochloride act together with reaction temperature and time parameters to ensure full reaction and improve the product yield.
Further, in step S2, the reaction solvent is dichloromethane, after the reaction is completed, purified water is added for liquid separation, the obtained organic phase is subjected to acid washing and alkali washing, concentrated and then n-heptane is added for crystallization, and the corresponding product is obtained after drying.
Further, in the step S3, the reaction temperature is 45-50 ℃ and the reaction time is 6-7 h, so that the simultaneous desulfurization, double bond hydrogenation, nitro reduction and Boc protection reaction are ensured, the diastereomer selectivity is improved, the operation steps are simplified, and the cost is reduced.
In step S3, the molar ratio of the compound V to di-tert-butyl dicarbonate is 1: 1.4-1.6.
Further, in step S3, the reducing catalyst is raney nickel, and the addition amount of raney nickel is 12-18% of the mass of the compound v, so as to ensure smooth proceeding of desulfurization, double bond hydrogenation and nitro reduction reaction.
Further, in step S3, the reaction solvent is absolute ethanol, and after the reaction, the process further includes filtering, concentrating, crystallizing, and drying.
Further, in step S4, the amino deprotection reaction solvent is methanol, ammonia water is added, and then alkaline hydrolysis is performed to remove trifluoroacetyl group, the reaction temperature for amino deprotection is 45-55 ℃, the time is 6-7 h, complete removal of trifluoroacetyl group is ensured, and the product yield is improved.
Further, in step S4, after the reaction is completed, the system is concentrated, isopropyl acetate is added to dissolve the system, n-heptane is added to perform crystallization, and the corresponding product is obtained after filtration, washing and drying.
Further, in step S1, the chiral resolution reagent is R-naphthylethylamine or R-phenylethylamine, the molar ratio of the resolution reagent to the compound III is 0.4-1.5: 1,
further, in step S1, after the compound iii is treated with a resolving agent, an amine salt of the compound iv is obtained, and after the amine salt is dissolved in water and then the pH is adjusted to 3-4, the compound iv is obtained after liquid separation, washing and concentration.
Further, in step S4, the resolving agent for chiral resolution is R-mandelic acid or R-di-p-methylbenzoyl tartaric acid; the ratio of the amount of the substance of the resolving agent to the total amount of the compound I and the compound I' is 0.4-1.5: 1.
Further, in step S4, after the compound I and the compound I' are treated by a resolving reagent, a compound I salt is obtained, the compound I salt is dissolved by water, the pH value is adjusted to 11-12, and then the compound I is obtained after liquid separation, washing and concentration.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention provides a preparation method of an edoxaban intermediate, the edoxaban intermediate is prepared through the following reaction steps,
the specific reaction steps comprise:
s1: dissolving a thiophene derivative of a compound II and acrylic acid in an organic solvent, carrying out Diels-Alder reaction to obtain a compound III, and carrying out chiral resolution to obtain a compound IV;
s2: carrying out amidation reaction on the obtained compound IV and dimethylamine hydrochloride to obtain a compound V;
s3: adding a reduction catalyst into the obtained compound V and di-tert-butyl dicarbonate in a hydrogen atmosphere, and simultaneously carrying out desulfurization, double bond hydrogenation, nitro reduction and Boc protection reaction to obtain a compound VI and a compound VI';
s4: and (3) carrying out amino deprotection on the compound VI and the compound VI 'under the alkaline condition, removing trifluoroacetyl group to obtain a compound I and a compound I', and then carrying out manual resolution to obtain the compound I, namely the edoxaban intermediate.
The invention takes a compound II thiophene derivative and acrylic acid as raw materials, and obtains a gradient Saxaban intermediate [ (1R,2S,5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamic acid tert-butyl ester through Diels-Alder reaction, chiral resolution, amidation reaction, hydrogenation Boc reaction, amino deprotection and chiral resolution.
To better illustrate the preparation of the edoxaban intermediate provided by the examples of the present invention, further examples are provided below.
Example 1
A preparation method of an edoxaban intermediate specifically comprises the following reaction steps:
s1: 100.0g (1.00eq.) of thiophene derivative of the compound II, 31.5g (1.05eq.) of acrylic acid and 500mL (5.0vol.) of diethylene glycol dimethyl ether are added into a 1L four-port bottle, the temperature is raised to 135 ℃, the reaction is kept, and the reaction is stopped (6h) after the content of the raw material compound II is detected to be less than or equal to 1.0 percent. Cooling to 5 ℃, preserving heat for 1h, crystallizing, filtering the system, washing and filtering the system by using 50mL (0.5vol.) of diethylene glycol dimethyl ether precooled at 5 ℃, drying a filter cake at 50 ℃ to obtain 119.6g of a compound III, wherein the yield is 92 percent, and the purity (HPLC) is 99.0 percent,1HNMR(MeOD)3.98(d,J＝12.2Hz,1H),3.60(t,J＝12.4Hz,1H),2.80(m,1H),2.11(m,2H)。
carrying out chiral resolution on the compound III, adding 500mL (5.0vol.) of methanol into a reaction bottle, heating to 25 ℃, starting stirring, adding 100.0g (1.00eq.) of the compound III and 21.3g (0.55eq.) of R-phenethylamine, and stirring for 1h under heat preservation. After the reaction is finished, cooling to 5 ℃, stirring for 1h, crystallizing, filtering the system, washing with 500mL of methanol precooled at 5 ℃, and draining to obtain the compound III amine salt.
Adding 5.0vol of water into a reaction bottle, controlling the temperature to be 25 ℃, starting stirring, adding 2.0vol of the amine salt of the compound III and isopropyl acetate, dropwise adding 6N hydrochloric acid to adjust the pH value to 3, keeping the temperature and stirring for 1h, carrying out static liquid separation, washing an obtained organic phase with semi-saturated saline solution, and concentrating to obtain 45.0g of a compound IV, wherein the yield is 45.0%, the purity (HPLC) is 99.2% and the chiral purity (HPLC) is 99.3%.
S2: adding DCM200mL (5vol.), controlling the temperature to be 5 ℃, adding compound IV 45.0g (1.00eq.) and triethylamine 36.5g (2.50eq.) with stirring, then adding HOBT20.5g (1.05eq.) in one portion, adding carbonyldiimidazole 24.6g (1.05eq.) slowly into the system, stirring for 30min, then adding dimethylamine hydrochloride 12.9g (1.10eq.) slowly into the system, controlling the temperature to be 10 ℃, and keeping the temperature for reaction for 5.5 h. After the reaction is finished, 90mL of purified water is added into a reaction bottle, the mixture is stirred for 15min, the mixture is kept stand for 15min, liquid separation is carried out, the obtained organic phase is washed by 5% dilute hydrochloric acid and then by 5% sodium hydroxide, n-heptane is added for crystallization after concentration, the mixture is filtered and dried at 50 ℃ to obtain 44.5g of a compound V, the yield is 91.0%, the purity (HPLC) is 99.0%,1HNMR(CDCl3)3.98(d,J＝12.2Hz,1H),3.60(t,J＝12.4Hz,1H),2.96(m,3H),2.80(m,1H),2.77(s,3H),2.11(m,2H)。
s3: to a hydrogenation flask was added 200mL (5.0vol) of absolute ethanol, stirring was turned on, and 40.0g (1.0eq) of Compound V and Boc2O31.9g (1.5 eq.). Heating to 25 deg.C, stirring for 0.8h to ensure the system is clear, stopping stirring, and adding 6.0g Raney nickel. The system was replaced 3 times with nitrogen and 3 times with hydrogen, each time pressurized to 0.2MPa and vented to 0.05 MPa. Pressurizing the system to 0.5MPa, heating to 48 ℃, preserving heat and reacting for 6.5h, and finishing the reaction. Cooling the system to 25 deg.C, replacing with nitrogen for three times (pressurizing to 0.2MPa each time, discharging to 0.05MPa), filtering the system, washing the filter cake with anhydrous ethanol twice, with 30g of each time, and mixing the mother liquor. Heating the mother liquor to 45 deg.C, vacuum degree less than or equal to-0.08 MPa, concentrating until no fraction is produced, adding methyl tert-butyl ether, crystallizing, filtering, drying to obtain product compound VI and compound VI' 42.7g, yield 95.0%, purity (HPLC) 99.5%,1HNMR(CDCl3)4.12(m,1H),4.10(m,1h),2.96(m,3H),2.80(t,J＝12.4Hz,1H),2.77(s,3H),1.72～1.83(m,3H),1.63(t,J＝22.7Hz,1H),1.37～1.49(m,2H),1.30(s,9H)。
s4: adding 200mL (5.0vol) of methanol, 40.0g (1.00eq.) of the compound VI and 40.0g (1.5eq.) of the compound VI', adding 22.0g (1.5eq.) of 25% ammonia water at 25 ℃ under the protection of nitrogen, heating to 50 ℃, keeping the temperature for reaction for 6.5h, and detecting the completion of the reaction. Concentrating the system at 45 deg.C under vacuum degree of-0.08 MPa or less until no fraction is produced, adding 100.0g of isopropyl acetate into the concentrated system, heating to 55 deg.C, stirring for 0.8 hr, slowly adding 375.0g of n-heptane dropwise into the system, slowly cooling to 7 deg.C after dropwise addition, stirring for 1.5 hr, and crystallizing. Filtering, leaching the filter cake with 50.0g of n-heptane, collecting the filter cake, drying for 7h at 45 ℃ under the condition that P is less than or equal to-0.08 MPa to obtain 28.1g of the product compound I and the compound I', the yield is 94.0%, and the purity (HPLC) is 99.5%.
Carrying out chiral resolution on a compound I and a compound I ', adding 125mL (5.0vol) of methanol into a reaction bottle, heating to 25 ℃, starting stirring, adding 25.0g (1.00eq.) of the compound I and the compound I' and 8.0g (0.55eq.) of R-mandelic acid, keeping the temperature and stirring for 1h, and finishing the reaction. And cooling to 5 ℃, stirring for 1h under controlled temperature, crystallizing, filtering the system, leaching with 12mL of precooled methanol at 5 ℃, and pumping to dryness to obtain the compound I salt.
Adding 5.0vol water into a reaction bottle, controlling the temperature to be 25 ℃, starting stirring, adding the obtained compound I salt and 50mL (2.0vol) of isopropyl acetate, dropwise adding a sodium hydroxide solution to adjust the pH value to 11, and stirring for 1h under the condition of heat preservation. Standing, separating, washing the obtained organic phase with half saturated saline solution, and concentrating to obtain compound I, i.e., [ (1R,2S,5S) -2-amino-5- [ (dimethylamino) carbonyl ] Edoxaban intermediate]Cyclohexyl radical]13.0g of tert-butyl carbamate, yield 52.0%, purity (HPLC) 99.8%, chiral purity 99.5%,1HNMR(CDCl3)4.10(m,1H),3.32(m,1H),2.96(m,3H),2.80(m,1H),2.77(s,3H),1.72～1.83(m,3H),1.63(t,J＝22.7Hz,1H),1.37～1.49(m,2H),1.30(s,9H)。
example 2
A preparation method of an edoxaban intermediate specifically comprises the following reaction steps:
s1: 100.0g (1.00eq.) of thiophene derivative of the compound II, 32.4g (1.08eq.) of acrylic acid and 500mL (5.0vol.) of diethylene glycol dimethyl ether are added into a 1L four-port bottle, the temperature is raised to 130 ℃, the reaction is kept, and the reaction is stopped (8h) after the content of the raw material compound II is detected to be less than or equal to 1.0 percent. Cooling to 0 deg.C, maintaining for 1h, crystallizing, filtering, and pre-cooling at 0 deg.C50mL (0.5vol.) of diethylene glycol dimethyl ether is washed and filtered, a filter cake is dried at 45 ℃ to obtain 122.2g of a compound III, the yield is 94 percent, the purity (HPLC) is 99.3 percent,1HNMR(MeOD)3.98(d,J＝12.2Hz,1H),3.60(t,J＝12.4Hz,1H),2.80(m,1H),2.11(m,2H)。
carrying out chiral resolution on the compound III, adding 500mL (5.0vol.) of methanol into a reaction bottle, heating to 20 ℃, starting stirring, adding 100.0g (1.00eq.) of the compound III and 15.5g (0.4eq.) of R-phenethylamine, and stirring for 1h under heat preservation. After the reaction is finished, cooling to 0 ℃, stirring for 1h, crystallizing, filtering the system, washing with 500mL of methanol precooled at 0 ℃, and draining to obtain the compound III amine salt.
Adding 5.0vol of water into a reaction bottle, controlling the temperature to be 20 ℃, starting stirring, adding the amine salt of the compound III and 2.0vol of isopropyl acetate, dropwise adding 6N hydrochloric acid to adjust the pH value to 4, keeping the temperature and stirring for 1h, carrying out static liquid separation, washing the obtained organic phase with semi-saturated saline solution, and concentrating to obtain a free acid to obtain 47.0g of a compound IV, wherein the yield is 47.0%, the purity (HPLC) is 99.3%, and the chiral purity is 99.4%.
S2: adding DCM200mL (5vol.), controlling the temperature at 0 ℃, adding compound IV 45.0g (1.00eq.) and triethylamine 36.5g (2.50eq.) with stirring, then adding HOBT20.5g (1.05eq.) in one portion, adding carbonyldiimidazole 24.6g (1.05eq.) slowly into the system, stirring for 30min, then adding dimethylamine hydrochloride 13.1g (1.12eq.) slowly into the system, controlling the temperature at 5 ℃, and keeping the temperature for reaction for 5 h. After the reaction is finished, 90mL of purified water is added into a reaction bottle, the mixture is stirred for 10min, the mixture is kept stand for 10min, liquid separation is carried out, the obtained organic phase is washed by 5% dilute hydrochloric acid and then by 5% sodium hydroxide, n-heptane is added for crystallization after concentration, the mixture is filtered and dried at the temperature of 45 ℃ to obtain 45.5g of a compound V, the yield is 93.0%, the purity (HPLC) is 99.2%,1HNMR(CDCl3)3.98(d,J＝12.2Hz,1H),3.60(t,J＝12.4Hz,1H),2.96(m,3H),2.80(m,1H),2.77(s,3H),2.11(m,2H)。
s3: to a hydrogenation flask was added 200mL (5.0vol) of absolute ethanol, stirring was turned on, and 40.0g (1.0eq) of Compound V and Boc2O29.8g (1.4 eq.). Heating to 20 ℃, stirring for 1h, stopping stirring after ensuring that the system is clear, and adding 4.8g of Raney nickel. The system was replaced 3 times with nitrogen, hydrogenReplacing with gas for 3 times, pressurizing to 0.2MPa each time, and discharging to 0.05 MPa. Pressurizing the system to 0.4MPa, heating to 45 ℃, preserving heat and reacting for 7 hours, and finishing the reaction. Cooling the system to 20 ℃, replacing the nitrogen for three times (pressurizing to 0.2MPa each time, discharging to 0.05MPa each time), filtering the system, washing a filter cake twice by using anhydrous ethanol, wherein the dosage is 28g each time, and combining mother liquor. Heating the mother liquor to 40 deg.C, vacuum degree less than or equal to-0.08 MPa, concentrating until no fraction is produced, adding methyl tert-butyl ether, crystallizing, filtering, drying to obtain product compound VI and compound VI' 42.8g, yield 95.3%, purity (HPLC) 99.6%,1HNMR(CDCl3)4.12(m,1H),4.10(m,1h),2.96(m,3H),2.80(t,J＝12.4Hz,1H),2.77(s,3H),1.72～1.83(m,3H),1.63(t,J＝22.7Hz,1H),1.37～1.49(m,2H),1.30(s,9H)。
s4: adding 200mL (5.0vol) of methanol, 40.0g (1.00eq.) of the compound VI and 40.0g (1.5eq.) of the compound VI', adding 22.0g (1.5eq.) of 25% ammonia water at 20 ℃ under the protection of nitrogen, heating to 45 ℃, keeping the temperature for reaction for 7 hours, and detecting the completion of the reaction. Concentrating the system at 40 deg.C under vacuum degree of-0.08 MPa or less until no fraction is produced, adding 100.0g isopropyl acetate into the concentrated system, heating to 50 deg.C, stirring for 1h, slowly adding 375.0g n-heptane dropwise into the system, slowly cooling to 5 deg.C after dropwise addition, stirring for 1h, and crystallizing. Filtering, leaching the filter cake with 50.0g of n-heptane, collecting the filter cake, drying for 8h at 40 ℃ under the condition that P is less than or equal to-0.08 MPa, and obtaining 28.7g of the product compound I and the compound I', the yield is 96.0%, and the purity (HPLC) is 99.6%.
Carrying out chiral resolution on a compound I and a compound I ', adding 125mL (5.0vol) of methanol into a reaction bottle, heating to 20 ℃, starting stirring, adding 25.0g (1.00eq.) of the compound I and the compound I' and 5.8g (0.4eq.) of R-mandelic acid, keeping the temperature and stirring for 1h, and finishing the reaction. And cooling to 0 ℃, stirring for 1h under controlled temperature, crystallizing, filtering the system, leaching with 12mL of precooled methanol at 0 ℃, and pumping to dryness to obtain the compound I salt.
Adding 5.0vol water into a reaction bottle, controlling the temperature to be 20 ℃, starting stirring, adding the obtained compound I salt and 50mL (2.0vol) of isopropyl acetate, dropwise adding a sodium hydroxide solution to adjust the pH value to 12, and stirring for 1h under the condition of heat preservation. Standing for separating, and collecting organic phase with half saturated salt solutionWashing, and concentrating to obtain compound I, i.e., [ (1R,2S,5S) -2-amino-5- [ (dimethylamino) carbonyl ] edoxaban intermediate]Cyclohexyl radical]13.2g of tert-butyl carbamate, yield 53.0%, purity (HPLC) 99.7%, chiral purity 99.5%,1HNMR(CDCl3)4.10(m,1H),3.32(m,1H),2.96(m,3H),2.80(m,1H),2.77(s,3H),1.72～1.83(m,3H),1.63(t,J＝22.7Hz,1H),1.37～1.49(m,2H),1.30(s,9H)。
example 3
A preparation method of an edoxaban intermediate specifically comprises the following reaction steps:
s1: 100.0g (1.00eq.) of thiophene derivative of the compound II, 33.0g (1.10eq.) of acrylic acid and 500mL (5.0vol.) of diethylene glycol dimethyl ether are added into a 1L four-port bottle, the temperature is raised to 140 ℃, the reaction is kept at the temperature, and the reaction is stopped (4h) after the content of the raw material compound II is detected to be less than or equal to 1.0 percent. Cooling to 10 ℃, preserving heat for 1h, crystallizing, filtering the system, washing and filtering with 50mL (0.5vol.) of 10 ℃ precooled diethylene glycol dimethyl ether, drying a filter cake at 55 ℃ to obtain 120.9g of a compound III, wherein the yield is 93 percent, and the purity (HPLC) is 99.1 percent,1HNMR(MeOD)3.98(d,J＝12.2Hz,1H),3.60(t,J＝12.4Hz,1H),2.80(m,1H),2.11(m,2H)。
carrying out chiral resolution on the compound III, adding 500mL (5.0vol.) of methanol into a reaction bottle, heating to 30 ℃, starting stirring, adding 100.0g (1.00eq.) of the compound III and 58.1g (1.5eq.) of R-phenethylamine, and stirring for 1h under heat preservation. After the reaction is finished, the temperature is reduced to 10 ℃, the mixture is stirred for 1h, crystallization is carried out, the system is filtered, and the mixture is washed by 500mL of methanol precooled at 10 ℃, and then is pumped to be dried, so that 90.2g of amine salt of the compound III, the purity (HPLC) of 99.0 percent and the chiral purity of 99.3 percent are obtained.
Adding 5.0vol of water into a reaction bottle, controlling the temperature to be 30 ℃, starting stirring, adding 90.2g (1.00eq) of amine salt of the compound III and 2.0vol of isopropyl acetate, dropwise adding 6N hydrochloric acid to adjust the pH value to be 4, keeping the temperature and stirring for 1h, carrying out static liquid separation, washing the obtained organic phase with half-saturated saline, and concentrating to obtain 46.0g of compound IV, wherein the yield is 46.0%, the purity (HPLC) is 99.1% and the chiral purity is 99.2%.
S2: DCM200mL (5vol.) was charged into a reaction flask, and 45.0g (1 g) of Compound IV was added with stirring at a temperature of 10 deg.C00eq.) and 36.5g triethylamine (2.50eq.), then adding once HOBT20.5g (1.05eq.), then slowly adding 24.6g carbonyldiimidazole (1.05eq.) into the system, stirring for 30min, then slowly adding 13.5g dimethylamine hydrochloride (1.15eq.) into the system, controlling the temperature at 15 ℃, and keeping the temperature for reaction for 6 h. After the reaction is finished, 90mL of purified water is added into a reaction bottle, the mixture is stirred for 20min, the mixture is kept stand for 20min, liquid separation is carried out, the obtained organic phase is washed by 5% dilute hydrochloric acid and then by 5% sodium hydroxide, n-heptane is added for crystallization after concentration, the mixture is filtered and dried at 55 ℃ to obtain 45.0g of a compound V, the yield is 92.0%, the purity (HPLC) is 99.0%,1HNMR(CDCl3)3.98(d,J＝12.2Hz,1H),3.60(t,J＝12.4Hz,1H),2.96(m,3H),2.80(m,1H),2.77(s,3H),2.11(m,2H)。
s3: to a hydrogenation flask was added 200mL (5.0vol) of absolute ethanol, stirring was turned on, and 40.0g (1.0eq) of Compound V and Boc2O34.0g (1.6 eq.). The temperature is increased to 30 ℃, stirring is carried out for 0.5h, stirring is stopped after the system is ensured to be clear, and 7.2g of Raney nickel is added. The system was replaced 3 times with nitrogen and 3 times with hydrogen, each time pressurized to 0.2MPa and vented to 0.05 MPa. Pressurizing the system to 0.6MPa, heating to 50 ℃, preserving heat and reacting for 6h, and finishing the reaction. Cooling the system to 30 ℃, replacing the nitrogen for three times (pressurizing to 0.2MPa each time, discharging to 0.05MPa), filtering the system, washing a filter cake twice by using anhydrous ethanol, wherein the dosage is 32g each time, and combining mother liquor. Heating the mother liquor to 50 deg.C, vacuum degree less than or equal to-0.08 MPa, concentrating until no fraction is produced, adding methyl tert-butyl ether, crystallizing, filtering, drying to obtain product compound VI and compound VI' 43.2g, yield is 96.2%, purity (HPLC) is 99.6%,1HNMR(CDCl3)4.12(m,1H),4.10(m,1h),2.96(m,3H),2.80(t,J＝12.4Hz,1H),2.77(s,3H),1.72～1.83(m,3H),1.63(t,J＝22.7Hz,1H),1.37～1.49(m,2H),1.30(s,9H)。
s4: adding 200mL (5.0vol) of methanol, 40.0g (1.00eq.) of the compound VI and 40.0g (1.5eq.) of the compound VI', adding 22.0g (1.5eq.) of 25% ammonia water at 30 ℃ under the protection of nitrogen, heating to 55 ℃, keeping the temperature for reaction for 6 hours, and detecting the completion of the reaction. Concentrating the system at 50 deg.C under vacuum degree of-0.08 MPa or less until no fraction is produced, adding 100.0g isopropyl acetate into the concentrated system, heating to 60 deg.C, stirring for 0.5 hr, slowly adding 375.0g n-heptane dropwise into the system, slowly cooling to 10 deg.C after dropwise addition, stirring for 2 hr, and crystallizing. Filtering, leaching the filter cake with 50.0g of n-heptane, collecting the filter cake, drying for 6h at 50 ℃ under the condition that P is less than or equal to-0.08 MPa, and obtaining 28.4g of a product compound I and a compound I', wherein the yield is 95.0%, and the purity (HPLC) is 99.6%.
Carrying out chiral resolution on a compound I and a compound I ', adding 125mL (5.0vol) of methanol into a reaction bottle, heating to 30 ℃, starting stirring, adding 25.0g (1.00eq.) of the compound I and the compound I' and 21.8g (1.5eq.) of R-mandelic acid, keeping the temperature and stirring for 1h, and finishing the reaction. And cooling to 10 ℃, stirring for 1h under controlled temperature, crystallizing, filtering the system, leaching with 12mL of 10 ℃ precooled methanol, and pumping to dryness to obtain the compound I salt.
Adding 5.0vol water into a reaction bottle, controlling the temperature to be 30 ℃, starting stirring, adding the obtained compound I salt and 50mL (2.0vol) of isopropyl acetate, dropwise adding a sodium hydroxide solution to adjust the pH value to 12, and stirring for 1h under the condition of heat preservation. Standing, separating, washing the obtained organic phase with half saturated saline solution, and concentrating to obtain compound I, i.e., [ (1R,2S,5S) -2-amino-5- [ (dimethylamino) carbonyl ] Edoxaban intermediate]Cyclohexyl radical]13.5g of carbamic acid tert-butyl ester, the yield is 54.0%, the purity (HPLC) is 99.8%, the chiral purity is 99.5%,1HNMR(CDCl3)4.10(m,1H),3.32(m,1H),2.96(m,3H),2.80(m,1H),2.77(s,3H),1.72～1.83(m,3H),1.63(t,J＝22.7Hz,1H),1.37～1.49(m,2H),1.30(s,9H)。
the data show that the preparation method of the edoxaban intermediate provided by the invention has the advantages of concise operation steps and higher diastereomer selectivity, is favorable for improving the product yield and reducing the production cost, does not use a dangerous reagent sodium azide, does not involve low-temperature reaction, reduces the production risk, and ensures the safety and operability of the reaction.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A preparation method of an edoxaban intermediate is characterized in that the edoxaban intermediate is prepared through the following reaction steps,
the specific reaction steps comprise:
s1: carrying out diene synthesis on the compound II and acrylic acid to obtain a compound III, and carrying out chiral resolution to obtain a compound IV;
s2: carrying out amidation reaction on the compound IV and dimethylamine hydrochloride to obtain a compound V;
s3: adding a reduction catalyst into the compound V and di-tert-butyl dicarbonate in a hydrogen atmosphere to react to obtain a compound VI and a compound VI';
s4: and (3) carrying out amino deprotection on the compound VI and the compound VI 'to obtain a compound I and a compound I', and carrying out chiral resolution to obtain the compound I, namely the edoxaban intermediate.
2. The process for the preparation of edoxaban intermediates of claim 1, wherein: in the step S1, the reaction temperature of diene synthesis is 130-140 ℃, and the time is 4-8 h.
3. The process for the preparation of edoxaban intermediates of claim 1, wherein: in step S1, the molar ratio of the compound II to acrylic acid is 1: 1.05-1.10.
4. The process for the preparation of edoxaban intermediates of claim 1, wherein: in the step S2, the temperature of the amidation reaction is 5-15 ℃ and the time is 5-6 h.
5. The process for the preparation of edoxaban intermediates of claim 1, wherein: in step S2, the molar ratio of the compound iv to dimethylamine hydrochloride is 1:1.10 to 1.15.
6. The process for the preparation of edoxaban intermediates of claim 1, wherein: in the step S3, the reaction temperature is 45-50 ℃ and the reaction time is 6-7 h.
7. The process for the preparation of edoxaban intermediates of claim 1, wherein: in step S3, the molar ratio of the compound V to di-tert-butyl dicarbonate is 1: 1.4-1.6.
8. The process for the preparation of edoxaban intermediates of claim 6, wherein: in step S3, the reducing catalyst is raney nickel.
9. The process for the preparation of edoxaban intermediates of claim 1, wherein: in the step S4, the reaction temperature for deprotection of the amino group is 45-55 ℃, and the time is 6-7 h.
10. The process for the preparation of edoxaban intermediates as claimed in any one of claims 1 to 9, wherein: in step S1, the chiral resolution reagent is R-naphthylethylamine or R-phenylethylamine, the molar ratio of the resolution reagent to the compound III is 0.4-1.5: 1, or
In step S4, the resolving agent for chiral resolution is R-mandelic acid or R-di-p-methylbenzoyl tartaric acid; the ratio of the amount of the substance of the resolving agent to the total amount of the compound I and the compound I' is 0.4-1.5: 1.
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Denomination of invention: A preparation method for the intermediate of Yidusaban Effective date of registration: 20230913 Granted publication date: 20220222 Pledgee: Industrial and Commercial Bank of China Limited Cangzhou Bohai New Area Branch Pledgor: CANGZHOU SENARY CHEMICAL SCIENCE-TEC CO.,LTD. Registration number: Y2023980056576 |