CN106316889A

CN106316889A - Preparation method of Edoxaban intermediate

Info

Publication number: CN106316889A
Application number: CN201510330875.2A
Authority: CN
Inventors: 吕辉; 黎苏磊
Original assignee: Shanghai Sun Sail Pharmaceutical Science and Technology Co Ltd
Current assignee: Nanjing Changao Pharmaceutical Science and Technology Co Ltd
Priority date: 2015-06-15
Filing date: 2015-06-15
Publication date: 2017-01-11
Anticipated expiration: 2035-06-15
Also published as: CN106316889B

Abstract

The invention discloses a preparation method of an Edoxaban intermediate. The preparation method comprises a, preparing a compound 2 from a compound 1 as a raw material, b, producing a novel compound (1S, 3S, 6R)-7-oxabicyclo[4. 1. 0]heptane-3-carboxylic acid as a compound 3c from the compound 2 under conditions of a certain temperature, an alkali and a solvent, c, producing a novel compound (1S, 3S, 4R)-3-amino-4-hydroxycyclohexanecarboxylic acid as a compound 4c from the compound 3c under conditions of a certain temperature, ammonium hydroxide and a solvent, and d, producing a compound 5c from the compound 4c under conditions of a certain temperature, an alkali, a solvent and di-tert-butyl dicarbonate (Boc2O). Compared with the prior art, the preparation method has the advantages of high yield, good product quality, simple operation, purification easiness, good process operationality and large scale production easiness.

Description

Preparation method of edoxaban intermediate

Technical Field

The invention relates to a preparation method of a compound, in particular to an improved chemical method for preparing an intermediate of a coagulation factor X (FXa) retarder edoxaban, and more particularly relates to a high-yield, high-purity and easily-controlled chemical method for preparing the edoxaban intermediate.

Background

Edoxaban, the first three companies in japan, was licensed for sale in japan on day 22 of 2011 under the brand name Lixiana. Edoxaban 15mg and 30mg oral tablets are used to prevent Venous Thromboembolism (VTE) after major orthopedic surgery. Clinical studies show that edoxaban can reversibly inhibit coagulation factor Xa, has good therapeutic benefits for patients undergoing total knee joint replacement surgery, total hip joint replacement surgery and hip fracture surgery, and has effectiveness superior to that of currently and commonly used enoxaparin.

In month 1 of 2015, Edoxaban (Edoxaban) obtained FDA approval for marketing in the united states under the brand name Savaysa, a 60mg once daily oral tablet. Suitable for reducing the risk of stroke and Systemic Embolism (SE) in non-valvular atrial fibrillation (NVAF) patients. In other areas such as europe, it is in phase III clinical development. Regulatory agencies are also reviewing applications for the treatment of Venous Thromboembolism (VTE) by edoxaban.

An intermediate of edoxaban, having the structure:

the existing methods for preparing the intermediate Edox-C mainly comprise two methods:

method one [ WO2003000657, WO2003000680 ]:

as shown in the following first synthesis method of Edox-C, the route takes (1S) -3-cyclohexene-1-carboxylic acid (compound 1) as a raw material, and the Edox-C is obtained through 12 steps of reaction, wherein the total yield is 10.0%. The route is long, column chromatography separation and purification are needed in multi-step reaction, in the process of preparing the compound 4a by aminolysis of the compound 3a, ester groups in the compound 3a are easy to aminolysis, and the reaction is difficult to control.

Synthesis method I of Edox-C

Method two [ CN200680033991, WO2014081047 ]:

as shown in the following synthesis method II of Edox-C, the route takes (1S) -3-cyclohexene-1-carboxylic acid (compound 1) as a raw material, and the Edox-C is obtained through 8 steps of reaction, and the total yield is 30.1%. The reaction conditions of this route are mild, and no column chromatography separation and purification step is performed in the whole route, but when compound 4b is prepared according to the patented conditions, it is found that compound 2b is not itself ring-closed after ammonolysis in aqueous dimethylamine solution to give compound 3b, compound 4b is obtained, 50% of compound 3b is not converted even if strong base is added, and a large part of the dicarboxamide group of compound 3b is hydrolyzed.

Synthesis method II of Edox-C

Therefore, a feasible process method for synthesizing the edoxaban intermediate, which is economical, safe and easy to process and amplify, is urgently needed.

Disclosure of Invention

The invention aims to solve the technical problem of providing a preparation method of an edoxaban intermediate, which has the advantages of higher yield, better quality, simple and convenient operation and easy purification compared with the existing method, and the method has strong process operability and is easy for scale-up production.

The present invention provides a new important intermediate for the synthesis of Edox-C, compound 5C.

Compound 5c has the structure:

compared with other routes for synthesizing the Edox-C, the route for preparing the Edox-C by the compound 5C has high yield and is easy to purify.

The invention provides a preparation method of an edoxaban intermediate compound 5c, which comprises the following steps:

(a) referring to the patent WO2003000657 and WO2003000680, the compound 1 is used as a raw material to prepare (1S,4S,5S) -4-iodine-6-oxabicyclo [3.2.1] -octane-7-ketone, namely the compound 2.

(b) The compound 2 generates a new compound (1S,3S,6R) -7-oxabicyclo [4.1.0] heptane-3-carboxylic acid, namely a compound 3c, under the conditions of certain temperature, alkali and solvent.

(c) The compound 3c generates a new compound (1S,3R,4R) -3-amino-4-hydroxycyclohexane carboxylic acid, namely the compound 4c, under the conditions of a certain temperature, a solvent and ammonia water.

(d) Compound 4c is prepared from base, solvent and di-tert-butyl dicarbonate (Boc) at a certain temp₂O) to produce compound 5 c.

(e) Under the conditions of certain temperature, alkali, condensing agent and solvent, the compound 5c generates tert-butyl { (1R, 2R, 5S) -5- [ (dimethylamino) hydroxy ] -2-hydroxycyclohexyl carbonyl } carbamate, namely the compound 6 b.

(f) Reference is made to patent CN200680033991, WO2014081047, which process prepares Edox-C from compound 6b via compounds 7b and 8 b.

The process is as follows:

wherein,

in step (b), the certain temperature is 0 to 100 ℃, preferably 20 to 30 ℃.

In the step (b), the alkali is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and the like.

In the step (b), the solvent is any one or more of the following solvents: diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, acetonitrile, dioxane, water, etc.

In step (c), the certain temperature is 0 to 100 ℃, preferably 30 to 50 ℃.

In the step (c), the solvent is any one or more of the following solvents: methanol, ethanol, isopropanol, tert-butanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, acetonitrile, dioxane, water, etc.

In step (d), the certain temperature is-20 to 100 ℃, preferably 20 to 30 ℃.

In the step (d), the base comprises an organic base and an inorganic base, wherein the organic base is one or more selected from triethylamine, diisopropylethylamine, pyridine, N, N-dimethylpyridine, N-methylmorpholine and the like, and the inorganic base is one or more selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium bicarbonate, sodium carbonate and the like.

In the step (d), the solvent is any one or more of the following solvents: methanol, ethanol, isopropanol, tert-butanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, acetonitrile and water.

In step (e), the certain temperature is 0-100 ℃, preferably 20-30 ℃;

in the step (e), the base comprises one or more of triethylamine, diisopropylethylamine, pyridine, N, N-dimethylpyridine, N-methylmorpholine and the like;

in the step (e), the condensing agent comprises one or more of Carbonyldiimidazole (CDI), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), 1-Hydroxybenzotriazole (HOBT) and the like;

in the step (e), the solvent is any one or more of the following solvents: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, etc.; riddle such as tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, methyl tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, etc.; aromatic hydrocarbons such as toluene, chlorobenzene, xylene, etc.; alkanes such as petroleum ether, n-heptane, n-hexane, cyclohexane, etc.; esters such as ethyl acetate, methyl acetate, isopropyl acetate, and the like.

Compared with the prior art, the invention has the beneficial effects that: the method uses (1S) -3-cyclohexene-l-carboxylic acid to obtain the Edox-C through eight-step reaction, the total yield is 41.5 percent, and the yield is improved compared with that of the prior method I (10.0 percent) and method II (30.1 percent) (see the method I and the method II in the background art). The method overcomes the defects that in the process of preparing the compound 4a by aminolysis of the compound 3a in the first method, the ethyl ester is easy to aminolysis and the reaction is difficult to control. The method also overcomes the defects that in the second method, after the compound 2b is ammonolyzed in dimethylamine aqueous solution to obtain the compound 3b, the compound 3b can not be closed by itself to obtain the compound 4b, 50 percent of the compound 3b can not be completely converted even if strong alkali is added, and the diformylamide group of the compound 3b is partially hydrolyzed. The process of the present invention is significantly superior to existing processes.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

In all examples, the thermometer was uncorrected;¹H-NMR was recorded using a Varian Mercury 400 NMR spectrometer with chemical shifts expressed in (ppm); the mass spectrum is measured by an Agilent 6120LC-MS liquid chromatograph-mass spectrometer, and the content is measured by an HPLC external standard method.

Reference example 1: synthesis of Compound 2

Compound 1(160.0g, 1.27mol) was dissolved in dichloromethane (750ml) and water (750ml), potassium iodide (231.7g, 1.40mol) was added and the temperature was lowered to 0 ℃ in an ice bath, sodium bicarbonate (117.1g, 1.40mol) was added in portions (large bubbles were bubbled, so the rate of addition was carefully controlled and the temperature rise was not significant). After the addition of sodium bicarbonate was completed and the bubbles disappeared, iodine (353.9g, 1.40mol) was added, and the addition of iodine was completed. The reaction was carried out in an ice bath for 0.5 hour, and then the system was allowed to naturally warm to room temperature for 3 hours. The TLC plate monitors that the reaction is complete, and sodium thiosulfate is added to change the color of the system from purple black to colorless. Stirring, standing for layering, and back-extracting the water phase with dichloromethane. The dichloromethane phases were combined and concentrated under reduced pressure to give the product (314g, 98.4%) as an off-white solid, compound 2.

Example 1: synthesis of Compound 4c

Compound 2(160.0g, 634.8mmol) was dissolved in tetrahydrofuran (400ml) and water (100ml), sodium hydroxide (50.0g, 1269.6mmol) was added and the two phases were mixed well with vigorous stirring. The reaction was carried out at 45 ℃ for 2 hours and monitored by TLC plate to obtain compound 3 c. Aqueous ammonia (150ml) was added to the reaction solution, and the temperature of the system was raised to 45 ℃ to react for 24 hours. The reaction mixture was concentrated, and tetrahydrofuran and ammonia were distilled off under reduced pressure to obtain an oil (250g, Compound 4 c).

Example 2: synthesis of Compound 4c

Compound 2(16.0g, 63.5mmol) was dissolved in dioxane (40ml) and water (10ml), sodium hydroxide (5.1g, 127.0mmol) was added and the two phases were mixed well with vigorous stirring. The reaction was carried out at 45 ℃ for 2 hours and monitored by TLC plate to obtain compound 3 c. Ammonia water (15ml) was added to the reaction mixture, and the temperature was raised to 45 ℃ to react for 20 hours. The reaction mixture was concentrated, and dioxane and aqueous ammonia were distilled off under reduced pressure to give an oil (24.0g), compound 4 c.

Example 3: synthesis of Compound 4c

Compound 2(16.0g, 63.5mmol) was dissolved in acetone (40ml) and water (10ml), potassium hydroxide (7.1g, 127.0mmol) was added, and the two phases were mixed well with vigorous stirring. The reaction was carried out at 20 ℃ for 2 hours and monitored by TLC plate to complete the reaction to give compound 3 c. Ammonia water (15ml) was added to the reaction mixture, and the temperature was raised to 50 ℃ to react for 20 hours. The reaction mixture was concentrated, and acetone and aqueous ammonia were distilled off under reduced pressure to give an oil (24.6g), compound 4 c.

Example 4: synthesis of Compound 4c

Compound 2(16.0g, 63.5mmol) was dissolved in diethyl ether (40ml) and water (10ml), and lithium hydroxide, monohydrate (5.3g, 127.0mmol) was added and stirred vigorously to mix the two phases. The reaction was carried out at 30 ℃ for 2 hours and monitored by TLC plate to obtain compound 3 c. Ammonia water (15ml) was added to the reaction mixture, and the temperature was raised to 30 ℃ to react for 24 hours. The reaction mixture was concentrated, and diethyl ether and aqueous ammonia were distilled off under reduced pressure to give an oil (24.0g), compound 4 c.

Example 5: synthesis of Compound 4c

Compound 2(16.0g, 63.5mmol) was dissolved in methyl t-butyl ether (40ml) and water (10ml), and potassium carbonate (17.6g, 127.0mmol) was added and stirred vigorously. The reaction was carried out at 0 ℃ for 2 hours and monitored by TLC plate to obtain compound 3 c. Ammonia water (15ml) was added to the reaction mixture, which was cooled to 0 ℃ in an ice bath and reacted for 24 hours. The reaction mixture was concentrated, and methyl t-butyl ether and aqueous ammonia were distilled off under reduced pressure to give an oil (24.5g), Compound 4 c.

Example 6: synthesis of Compound 4c

Compound 2(16.0g, 63.5mmol) was dissolved in acetonitrile (40ml) and water (10ml), and lithium hydroxide, monohydrate (5.3g, 127.0mmol) was added and stirred vigorously to mix the two phases. The reaction was carried out at 30 ℃ for 2 hours and monitored by TLC plate to obtain compound 3 c. Ammonia water (15ml) was added to the reaction solution, and the temperature of the system was raised to 30 ℃ for 24 hours. The reaction mixture was concentrated, and acetonitrile and aqueous ammonia were distilled off to obtain an oil (24.8g), compound 4 c.

Example 7: synthesis of Compound 5c

To compound 4c (250g) was added methanol (800ml), triethylamine (64.1g, 634.8mmoL), dissolved with stirring, cooled to 0 ℃ in an ice bath and added (Boc) in portions₂O (166.0g, 761.8mmol), reacting for 30 minutes, monitoring by LC-MS, reacting completely, distilling off methanol under reduced pressure, dissolving with ethyl acetate (600 ml)/water (200ml), cooling to 0-10 deg.C in ice bath, adding dilute hydrochloric acid to adjust pH to about 6, and adding ethyl acetate (300ml ×) into water phase2) The ethyl acetate phases were washed, combined, dried over anhydrous sodium sulfate and concentrated to give a yellow oil (159.5g), compound 5 c.

Compound 5 c:¹H-NMR(400MHz,CDCl3)6.81(s,1H),4.71(s,1H),4.29(s,1H),2.93(s,1H),2.22(t,J＝10.8Hz,3H),1.93(s,1H),1.84(s,1H),1.69(s,1H),1.49(s,9H).

MS：[M+H]260.0

example 8: synthesis of Compound 5c

To compound 4c (25g) was added ethanol (80ml) to dissolve, followed by sodium bicarbonate (5.3g, 63.5mmoL), cooled in an ice bath to-20 deg.C and added (Boc) in portions₂O (16.6g, 76.2mmol), reacting for 30 minutes, monitoring by LC-MS, completely reacting, distilling off ethanol, dissolving with ethyl acetate (60ml) and water (20ml), cooling to 0-10 ℃ in ice bath, adding dilute hydrochloric acid to adjust the pH value to about 6, washing the water phase with ethyl acetate (30ml × 2), combining the ethyl acetate phases, drying with anhydrous sodium sulfate, and concentrating to obtain yellow oily substance (15.8g), namely compound 5 c.

Example 9: synthesis of Compound 5c

Tetrahydrofuran (80ml) was added to compound 4c (25g) to dissolve, followed by addition of sodium hydroxide (2.5g, 63.4mmoL) in portions (Boc)₂O (16.6g, 76.2mmmol), refluxing for 30 minutes, monitoring by LC-MS, completing the reaction, dissolving with ethyl acetate (60ml) and water (20ml), cooling to 0-10 ℃ in ice bath, adding dilute hydrochloric acid to adjust the pH value to about 6, washing the water phase with ethyl acetate (30ml × 2), combining the ethyl acetate phases, drying with anhydrous sodium sulfate, and concentrating to obtain yellow oily substance (15.6g), namely compound 5 c.

Example 10: synthesis of Compound 5c

To compound 4c (25g) was added acetone (80ml) to dissolve, followed by addition of sodium carbonate (6.7g,63.5mmoL) added in portions (Boc)₂O (16.6g, 76.1mmmol), reacting at 20 ℃ for 30 minutes, monitoring by LC-MS, completely reacting, removing acetone by spinning off, dissolving by using ethyl acetate (60ml)/(20ml), cooling to 0-10 ℃ in an ice bath, adding dilute hydrochloric acid to adjust the pH value to about 6, back-extracting the water phase by using ethyl acetate (30ml × 2), combining the ethyl acetate phases, drying by using anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance (15.5g), namely a compound 5 c.

Example 11: synthesis of Compound 5c

To compound 4c (25g) was added diethyl ether (80ml) dissolved, followed by potassium carbonate (8.8g, 63.5mmoL) added in portions (Boc)₂O (16.6g, 76.1mmmol), 30 ℃ for 30 minutes, monitored by LC-MS, the reaction was complete, dissolved in ethyl acetate (60ml) and water (20ml), cooled in an ice bath to 0 ℃, pH adjusted to about 6 with dilute hydrochloric acid, the aqueous phase extracted with ethyl acetate (30ml × 2), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give a yellow oil (15.0g), compound 5 c.

Example 12: synthesis of Compound 5c

To compound 4c (25g) was added acetonitrile (80ml) to dissolve, followed by pyridine (4.4g, 63.5mmoL) and added in portions (Boc)₂O (16.6g, 76.1mmol), reacting at 80 ℃ for 30 minutes, monitoring by LC-MS, completely reacting, removing acetonitrile by screwing, dissolving with ethyl acetate (60ml) and water (20ml), cooling to 0-10 ℃ in an ice bath, adding dilute hydrochloric acid to adjust the pH value to about 6, washing the water phase with ethyl acetate (30ml × 2), combining the organic phases, drying with anhydrous sodium sulfate, and concentrating to obtain yellow oily matter (15.4g), namely the compound 5 c.

Example 13: synthesis of Compound 6b

Compound 5c (168.4g, 634.8mmol) was dissolved in dichloromethane (800ml), N-methylmorpholine (288.9g, 2856.6mmol), dimethylamine hydrochloride (124.2g, 1523.5mmol), EDC.HCl (182.5g, 952.2mmol), HOBT (128.7g, 952.2mmol) were added, stirring was carried out, the reaction was carried out at 0 ℃ for 3 hours, LC-MS monitoring showed completion of the reaction, water (800ml) was added, stirring was carried out, the solution was allowed to stand, the dichloromethane phase was washed with water, and the saturated sodium chloride solution was washed with water. Dried over anhydrous sodium sulfate for 24h and concentrated to give a pale yellow oil (177.8g, 97.8%) as compound 6 b.

Example 14: synthesis of Compound 6b

Compound 5c (168.4g, 634.8mmol) was dissolved in ethyl acetate (800ml), N-methylmorpholine (288.9g, 2856.6mmol), dimethylamine hydrochloride (124.2g, 1523.5mmol), EDC.HCl (128.5g, 952.2mmol), HOBT (128.7g, 952.2mmol) were added, the reaction was then allowed to proceed for 3 hours at 40 ℃ and monitored by LC-MS for completion of the reaction, water (800ml) was added and the mixture was stirred, allowed to stand for liquid separation, washed with an ethyl acetate phase and washed with a saturated sodium chloride solution. Dried over anhydrous sodium sulfate for 24h and concentrated to give a pale yellow oil (170g), compound 6 b.

Example 15: synthesis of Compound 6b

Compound 5c (168.4g, 634.8mmol) was dissolved in diethyl ether (800ml), N-lutidine (288.9g), dimethylamine hydrochloride (124.2g), carbonyldiimidazole (154.4g) were added and the reaction was completed at 20 ℃ for 3 hours, monitored by LC-MS, water (800ml) was added and the reaction was stirred, and the mixture was allowed to stand for liquid separation, and the diethyl ether phase was washed with water and saturated sodium chloride solution. Dried over anhydrous sodium sulfate for 24h and concentrated to give a pale yellow oil (175g), compound 6 b.

Example 16: synthesis of Compound 6b

Compound 5c (168.4g, 634.8mmol) was dissolved in toluene (800ml), triethylamine (288.9g), dimethylamine hydrochloride (124.2g), carbonyldiimidazole (154.4g) were added, the mixture was stirred, reacted at 100 ℃ for 3 hours, monitored by LC-MS for completion of the reaction, water (800ml) was added, the mixture was stirred, allowed to stand for liquid separation, washed with toluene phase and washed with saturated sodium chloride solution. Dried over anhydrous sodium sulfate overnight and concentrated to give a pale yellow oil (168g), compound 6 b.

Example 17: synthesis of Compound 6b

Compound 5c (168.4g, 634.8mmol) was dissolved in tetrahydrofuran (800ml), pyridine (110.0g), dimethylamine hydrochloride (124.2g), carbonyldiimidazole (154.4g) were added and the reaction was carried out at 30 ℃ for 3 hours, LCMS monitored and the reaction was complete, water (800ml) was added and the mixture was stirred, allowed to stand for liquid separation, and the tetrahydrofuran phase was washed once with water and once with saturated aqueous sodium chloride. Dried over anhydrous sodium sulfate overnight and concentrated to give a pale yellow oil (170g), compound 6 b.

Example 18: synthesis of Compound 6b

Compound 5c (168.4g, 634.8mmol) was dissolved in n-heptane (800ml), diisopropylethylamine (288.9g), dimethylamine hydrochloride (124.2g), carbonyldiimidazole (154.4g) were added and the reaction was carried out at 30 ℃ for 3 hours, and upon completion of the monitoring by LC-MS, water (800ml) was added and the mixture was stirred, allowed to stand for liquid separation, and the n-heptane phase was washed with water and a saturated sodium chloride solution. Dried over anhydrous sodium sulfate overnight and concentrated to give a pale yellow oil (165g), compound 6 b.

Reference example 19: synthesis of Compound 7b

Compound 6b (177.8g, 0.62mol) was dissolved in ethyl acetate (800ml), triethylamine (125.2g, 1.24mol) was added, the temperature was reduced to 0 ℃ in an ice bath, and MsCl (72ml, 0.93mol) was added dropwise, completing the addition. The ice bath was removed, the reaction was allowed to proceed for 3 hours at room temperature and then was monitored by LCMS for completion of the reaction, water (1L) was added to the reaction solution, followed by stirring for liquid separation, and the aqueous phase was back-extracted with ethyl acetate (250 ml. times.2). The ethyl acetate phases were combined and concentrated to give a yellow solid. Slurried with n-heptane (60ml) and ethyl acetate (30ml) under reflux for 1 hour, cooled to 0-10 ℃ in an ice bath and filtered to give a white solid (192.0g, 85.0%) as compound 7 b.

Reference example 20: synthesis of Edox-C

Sodium azide (8.17g, 125.5mmol) and dodecylpyridinium chloride (8.95g, 31.6mmol) were dissolved in water (23ml), stirred for 1 hour, and then water was removed with toluene (200ml) under reduced pressure at 60 ℃. As water was removed, a yellow solid precipitated. When no water was distilled off, compound 7b (23g, 63.1mmol) was added and the reaction was warmed to 65 ℃ for 48 hours and was monitored by LCMS for completion to give compound 8 b. Water (100ml) and ethyl acetate (100ml) were added thereto, and the mixture was stirred for liquid separation, and the organic phase was washed with a saturated sodium chloride solution (100 ml). Methanol (160ml), ammonium formate (4.9g, 77.1mmol) and palladium hydroxide as a catalyst were added to the organic phase and heated to 30 ℃ for 1 h. TLC plate monitoring raw material reaction complete, filtration, filtrate concentration get oily product, add acetonitrile (100ml), oxalic acid dihydrate (8.5g) stirring filtration, get (9.4g, 52.3%) as white solid, get Edox-C.

Edox-C：¹H-NMR(400MHz,D₂O)1.30(s,9H),1.37-1.49(s,2H),1.63(t,1H，J＝2.7Hz),1.72-1.83(m,3H),2.77(s,3H),2.80(t,1H,J＝12.4Hz),2.96(m,3H),3.32(d,1H,J＝12.2Hz),4.10(br,1H).

Reference example 2: synthesis by Process two of the background Art

1. Synthesis of Compound 2b

Compound 1(20.4g) was dissolved in ethyl acetate (100ml), and N-bromosuccinimide (30.22g) and calcium oxide (0.96g) were added to react at room temperature for 2 hours. TLC plate monitoring, reaction complete, adding sodium thiosulfate, stirring, standing for layering, and back extracting the water phase once with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give the product (22.5g, 67.7%) as an off-white solid, compound 2 b.

2. Synthesis of Compound 4b

Compound 2b (20g) was dissolved in acetone (125ml), 50% aqueous dimethylamine solution (35.2g) was added and the reaction was allowed to proceed at 10 ℃ for 15 hours, monitored by TLC plate and completed, and the solvent was distilled off to give an oil (15.5g), Compound 4 b.

3. Synthesis of Compound 6b

After 28% aqueous ammonia (5ml) was added to compound 4b (1g) at room temperature and stirred at 40 ℃ for 5 hours, the solvent was concentrated under reduced pressure to give an oil (1.18 g). The obtained crude product was dissolved in water (5ml), and di-tert-butyl dicarbonate (1.93g) and a 10N aqueous sodium hydroxide solution (1.5ml) were added thereto at room temperature, followed by stirring at 40 ℃ for 2 hours, followed by extraction with 4-methyl-2-pentanone (5ml) 3 times, followed by distillation under reduced pressure of the extractant, addition of 4-methyl-2-pentanone (3ml) to the residue and stirring at room temperature. The crystals were collected by filtration and dried to obtain Compound 6b (1.26 g).

4. Synthesis of Compound 7b

Compound 6b (214.59g) from the above step was dissolved in 4-methyl-2-pentanone (1875ml), MsCl (159.07g) was added, triethylamine (170.62g) was added to the reaction mixture at room temperature, and after 1 hour of reaction at room temperature, water was added to the reaction mixture, and the organic phase was concentrated to give a yellow solid. To the residue was added 4-methyl-2-pentanone (750ml), stirred at room temperature for 3 hours, and filtered to give a white solid (242.57g), compound 7 b.

5. Synthesis of Edox-C

To a toluene solution (100ml) of compound 7b (20g) was added sodium azide (7.14g) and dodecylpyridinium chloride (7.80g) at room temperature, and reacted at 60 ℃ for 72 hours to give compound 8b, water was added to the reaction solution, and the organic phase was washed with a saturated sodium chloride solution. Methanol, 10% Pd/C and ammonium formate were added to the organic phase. Heated to 40 ℃ and reacted for 1 h. Filtration and concentration of the filtrate gave an oily product, acetonitrile (200ml), anhydrous oxalic anhydride (4.94g) were added, stirring was carried out at room temperature for 17 hours, and crystals were collected by filtration. The resulting crystals were added to acetonitrile (200ml), stirred at 40 ℃ for 24 hours, and the dried crystals were collected by filtration to give Edox-C (12.7 g).

Claims

1. The preparation method of the edoxaban intermediate is characterized in that the edoxaban intermediate is a compound 5c, and the structural formula of the edoxaban intermediate is as follows:

the preparation method comprises the following steps:

(a) taking the compound 1 as a raw material to prepare (1S,4S,5S) -4-iodo-6-oxabicyclo [3.2.1] -octane-7-one, namely a compound 2;

(b) under the conditions of certain temperature, alkali and solvent, the compound 2 generates a new compound (1S,3S,6R) -7-oxabicyclo [4.1.0] heptane-3-carboxylic acid, namely a compound 3 c;

(c) the compound 3c generates a new compound (1S,3R,4R) -3-amino-4-hydroxycyclohexane carboxylic acid, namely a compound 4c, at a certain temperature under the conditions of a solvent and ammonia water;

(d) compound 4c is prepared from base, solvent and di-tert-butyl dicarbonate (Boc) at a certain temp₂O) to produce a compound 5 c;

the reaction formula is as follows:

2. the method of claim 1, wherein the step of preparing compound 5C to yield Edox-C comprises the steps of:

(e) under the conditions of certain temperature, alkali, condensing agent and solvent, the compound 5c generates tert-butyl { (1R, 2R, 5S) -5- [ (dimethylamino) hydroxy ] -2-hydroxycyclohexyl carbonyl } carbamate, namely the compound 6 b;

(f) preparing Edox-C from the compound 6b through the compounds 7b and 8 b;

the reaction formula is as follows:

3. the method according to claim 1, wherein in the step (b), the certain temperature is 0 to 100 ℃; the alkali is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate; the solvent is any one or more of the following solvents: diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, acetonitrile, dioxane and water.

4. The method according to claim 3, wherein the certain temperature is 20 to 30 ℃ in the step (b).

5. The method according to claim 1, wherein in the step (c), the certain temperature is 0 to 100 ℃; the solvent is any one or more of the following solvents: methanol, ethanol, isopropanol, tert-butanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, acetonitrile, dioxane and water.

6. The method of claim 5, wherein in step (c), the certain temperature is 30 to 50 ℃.

7. The method of claim 1, wherein in step (d), the certain temperature is in the range of-20 to 100 ℃; the base comprises organic base and inorganic base, wherein the organic base is one or more selected from triethylamine, diisopropylethylamine, pyridine, N, N-dimethylpyridine and N-methylmorpholine; the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium bicarbonate and sodium carbonate; the solvent is any one or more of the following solvents: methanol, ethanol, isopropanol, tert-butanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, acetonitrile and water.

8. The method of claim 7, wherein in step (d), the certain temperature is 20 to 30 ℃.

9. The method of claim 2, wherein in step (e), the certain temperature is 0 to 100 ℃; the alkali is selected from one or more of triethylamine, diisopropylethylamine, pyridine, N, N-dimethylpyridine and N-methylmorpholine; the condensing agent is selected from one or more of carbonyldiimidazole, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole; the solvent is any one or more of the following solvents: halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane; the riddle comprises tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, methyl tetrahydrofuran, dioxane and ethylene glycol dimethyl ether; aromatic hydrocarbons include toluene, chlorobenzene, xylene; alkanes including petroleum ether, n-heptane, n-hexane, cyclohexane; esters include ethyl acetate, methyl acetate, isopropyl acetate.

10. The method of claim 9, wherein in step (e), the certain temperature is 20 to 30 ℃.