CN107868039A - A kind of shellfish Qu Shaban intermediate Ns（5- chloro-2-pyridyls）- 2-（4- cyanobenzoyls）Amino ］ -5- methoxy benzamides preparation method - Google Patents

Abstract

The invention discloses a preparation method of betrixaban intermediate N-(5-chloro-2-pyridyl)-2-[(4-cyanobenzoyl)amino]-5-methoxybenzamide. The present invention adopts the following technical scheme, comprising the following steps: ① chlorination of 5-methoxy-2-nitrobenzoic acid (1) with phosphorus oxychloride, and then amidation with 2-aminopyridine to obtain compound 2; ② compound 2 Compound 3 was obtained through catalytic hydrogenation; 3. compound 3 was condensed with p-cyanobenzoyl chloride to obtain compound 4; 4. compound 4 was chlorinated to obtain compound 5 with a total yield of 57.2%. The cost is low, and the generation of by-products is reduced, which is beneficial to industrial production.

Description

A kind of betrixaban intermediate N-(5-chloro-2-pyridyl)-2-[(4-cyanobenzoyl) Base) amino] the preparation method of-5-methoxybenzamide

technical field

The present invention relates to a preparation method of betrixaban intermediate N-(5-chloro-2-pyridyl)-2-[(4-cyanobenzoyl)amino]-5-methoxybenzamide .

Background technique

Betrixaban (Betrixaban), chemical name: N-(5-chloro-2-pyridyl)-2-[[4-[(dimethylamino)iminomethyl]benzoyl]amino]-5- Methoxybenzamide (6) is a highly selective factor Xa inhibitor developed by Portola Pharmaceuticals. Betrixaban inhibits the conversion of prothrombin to thrombin by binding to the active site of factor Xa, and hinders the formation of fibrin, thereby effectively inhibiting the formation of thrombus. The drug was approved by the FDA on June 23, 2017, under the trade name Bevyxxa, for the prevention of venous thromboembolism and pulmonary embolism in patients with acute onset but no surgery.

N-(5-chloro-2-pyridyl)-2-[(4-cyanobenzoyl)amino]-5-methoxybenzamide is an important intermediate for the synthesis of betrixaban, patent document CN1391555A , WO0164643A2, WO2007056517A2, WO2008057972A1, US2010197929A1, CN101595092B, CN102762538A, CN104693114A, CN105732490A successively disclosed the preparation method of betrixaban.

WO0164643A2 reported that 5-methoxy-2-nitrobenzoic acid was used as the starting material, reacted with 2-amino-5-chloropyridine in the presence of phosphorus oxychloride, and then reacted with platinum carbon poisoned by sulfur Pressurized hydrogenation reduces the nitro group to an amino group, and the resulting amino compound is condensed with p-cyanobenzoyl chloride to obtain N-(5-chloro-2-pyridyl)-2-[(4-cyanobenzoyl)amino] -5-methoxybenzamide (5). In this method, expensive platinum sulfide carbon is used, which increases the production cost and easily leads to the hydrogenolysis of the 5-position chlorine on the pyridine ring, resulting in an increase in impurities.

Among them, WO2008057972A1 reported a similar synthetic route, the difference is that the patent uses tin dichloride to reduce the nitro group, but this reduction method forms more impurities during the reaction process, which is not conducive to the separation of products, so it is not conducive to industrial production . CN104693114A reports the use of iron powder-acetic acid system to reduce nitro groups, but the reaction process needs to add a large amount of acetic acid, and the iron powder is also in large excess, resulting in a large amount of waste acid and iron sludge, resulting in an increase in three wastes.

CN105732490A report takes 5-methoxy isatoic anhydride as raw material, reacts with 2-amino-5-chloropyridine under the effect of potassium tert-butoxide, then reacts with p-cyanobenzoyl chloride to obtain N-(5-chloro -2-pyridyl)-2-[(4-cyanobenzoyl)amino]-5-methoxybenzamide (5). Although the route is short, the starting material 5-methoxyisatoic anhydride is not easy to obtain and is expensive. There are free amino groups in the intermediate formed in the process, which is easy to continue to react with the raw material 5-methoxyisatoic anhydride to form Impurities.

CN106518758 has reported that with 5-methoxy-2-aminobenzoic acid as starting material, esterification reaction occurs with benzyl alcohol, then reacts with p-cyanobenzoyl chloride, and then obtains free carboxyl through hydrogenolysis debenzylation, and finally reacts with 2-Amino-5-chloropyridine is reacted to form N-(5-chloro-2-pyridyl)-2-[(4-cyanobenzoyl)amino]-5-methoxybenzamide (5). The steps of this route are cumbersome, and the cyano group is easily reduced during hydrogenolysis to remove the benzyl group, which increases the impurities during the reaction process, which is not conducive to the separation and purification of compound 5.

Contents of the invention

Aiming at the problems existing in the existing routes, the present invention provides a synthetic betrixaban intermediate N-(5-chloro-2-pyridyl)-2-[(4-cyanobenzoyl)amino]-5 -The new method of methoxybenzamide (5), its route is as follows:

Using 5-methoxy-2-nitrobenzoic acid (1) as the starting material, chlorination with phosphorus oxychloride, and amidation with 2-aminopyridine to obtain compound 2, and compound 2 to obtain compound 3 through catalytic hydrogenation , compound 3 was condensed with p-cyanobenzoyl chloride to obtain compound 4, and compound 4 was chlorinated to obtain compound 5.

Step 1: Compound 1 is chlorinated with phosphorus oxychloride, and then amidated with 2-aminopyridine to obtain compound 2.

Step 2: compound 2 is hydrogenated by palladium carbon to obtain compound 3.

Step 3: compound 3 is condensed with p-cyanobenzoyl chloride under basic conditions to obtain compound 4.

Step 4: compound 4 was chlorinated by NCS to obtain compound 5.

As a preferred version of the above technical solution, in step 1, the synthesis process of compound 2 is as follows: take compound 1 and add it to acetonitrile, add phosphorus oxychloride dropwise, add 2-aminopyridine and pyridine after the reaction is complete, add dropwise Add appropriate amount of water, filter, wash the filter cake until neutral, and dry under reduced pressure to obtain compound 2.

Further preferably, the molar ratio of compound 1, 2-aminopyridine, pyridine, and phosphorus oxychloride is 1:1:(3-5):(1-2), wherein pyridine is an acid-binding agent; The solvent is selected from one or more combinations of tetrahydrofuran, acetonitrile, benzene, toluene, methylene chloride, ethyl acetate, N, N-dimethylformamide, the preferred solvent of the present invention is acetonitrile, the compound 1 and acetonitrile The mass volume ratio is 1: (10-15); the acylating reagent is selected from phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosphorus oxybromide, phosphorus tribromide, pentabromide Phosphorus, the preferred reagent of the present invention is phosphorus oxychloride.

As a preferred version of the above technical solution, in step 2, the synthesis process of compound 3 is as follows: take compound 2 and palladium carbon and add them to methanol, hydrogenate at normal pressure, filter after the reaction is complete, and concentrate under reduced pressure to obtain compound 3.

Further preferably, the mass ratio of compound 2 to palladium on carbon is (15-20):1.

As a preferred version of the above-mentioned technical scheme, in step 3, the synthesis process of compound 4 is as follows: take compound 3 and pyridine and add it to dichloromethane, slowly add dropwise the solution made of 4-cyanobenzoyl chloride and dichloromethane, After the reaction was complete, the mixture was washed and separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4.

Further preferably, the solvent is selected from water, tetrahydrofuran, dioxane, acetonitrile, toluene, xylene, benzene, methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, butyl acetate, isopropyl acetate , N, N-dimethylformamide, N, N-diethylacetamide, triethylamine, pyridine, diethylisopropylamine, acetone, butanone or one or more combinations, the present invention preferably two Chloromethane is the solvent.

Further preferably, the base used includes sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium tert-butoxide, sodium tert-butoxide, magnesium tert-butoxide, sodium amide, sodium hydride, calcium hydride, ammonia, triethylamine, pyridine, 4-dimethylaminopyridine, diethylisopropylamine, DBU, aniline, N,N-dimethylaniline, N-methylaniline, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, hydrogen Sodium oxide, potassium hydroxide, calcium hydroxide, the present invention is preferably pyridine.

Further preferably, the molar ratio of compound 3 to p-cyanobenzoyl chloride is 1:(1-2); the reaction temperature is -10°C to 40°C, preferably 20°C to 30°C in the present invention.

As a preferred version of the above-mentioned technical solution, in step 4, the synthesis process of compound 5 is as follows: compound 4, chlorinated reagent, and initiator are added to N,N-dimethylformamide, and the reaction is heated. After the reaction is complete, add Dichloromethane and water were washed and separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and recrystallized with tetrahydrofuran-ethanol mixed solvent to obtain compound 5.

Further preferably, the solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N-diethylacetamide, dichloro Methane, chloroform, carbon tetrachloride, benzene, toluene, cyclopentane, n-pentane, cyclohexane, n-hexane, cycloheptane, n-heptane, tetrahydrofuran, dioxane, acetonitrile, one in water In the present invention, N, N-dimethylformamide is preferred as the solvent, and the mass volume ratio of compound 4 to N, N-dimethylformamide is 1: (5-10).

Further preferably, the chlorination reagent is selected from N-chlorosuccinimide, N-chloro-o-sulfonylbenzimide, N-chlorophthalimide, 1,3-dichloro-5 , 5-dimethylhydantoin, 1,3-dichloro-5-methyl-5-ethylhydantoin, chlorine, the preferred chlorination reagent of the present invention is N-chlorosuccinimide, and compound 4 and The molar ratio of N-chlorosuccinimide is 1: (1.0-2.0).

Further preferably, the initiator is one or more combinations of benzoyl peroxide, tert-butyl hydroperoxide, cyclohexanone peroxide, azobisisobutyronitrile, azobisisoheptanonitrile, The present invention is preferably benzoyl peroxide, and the molar ratio of compound 4 to benzoyl peroxide is 1: (0.05-0.1).

Further preferably, the reaction temperature is 0°C to 100°C, preferably 70°C to 80°C in the present invention.

Further preferably, the reaction time is 2h-8h, preferably 3h in the present invention.

Further preferably, the recrystallization solvent is selected from tetrahydrofuran, dioxane, ethyl acetate, methanol, ethanol, n-propanol, isopropanol, n-butanol, dichloromethane, n-hexane, cyclohexane One or several combinations, the preferred solvent of the present invention is a mixed solvent of tetrahydrofuran and ethanol.

Compared with the prior art, p-betrixaban intermediate N-(5-chloro-2-pyridyl)-2-[(4-cyanobenzoyl)amino]-5-methoxybenzene of the present invention The improvement of formamide overcomes many shortcomings, and the total yield is 57.2%. Its main advantages are that the material is easy to obtain, the operation is simple, the cost is low, and the generation of by-products is reduced, which is beneficial to industrial production.

Detailed ways

The following examples further illustrate the invention, but the invention is not limited thereto.

Example:

Example 1 Preparation of Compound 2

Get compound 1 (20g, 102mmol) and join in 150ml acetonitrile, dropwise add phosphorus oxychloride (23g, 300mmol) at room temperature, add, add 2-aminopyridine (9.5g, 101mmol) and pyridine (23.7g, 300mmol), the reaction was continued at room temperature for 4h. 150ml of water was slowly added dropwise, filtered, the filter cake was washed with water until neutral, and dried under reduced pressure at 50°C to obtain 24.6g of compound 2 with a yield of 98.04%.

Example 2 Preparation of Compound 3

Add compound 2 (16g, 59mmol) and 10% palladium carbon (1g) to 300ml of methanol, hydrogenate at normal pressure, react at room temperature for 6h, filter, and concentrate the yellow-green solution under reduced pressure to obtain 13.6g of compound 3 with a yield of 94.82% . ¹ H NMR (500MHz, DMSO-d ₆ ) δ10.55(s, 1H), 8.46-8.32(m, 1H), 8.13(d, J=8.4Hz, 1H), 7.84(m, J=8.3, 7.8 , 1.9Hz, 1H), 7.33(d, .J=2.9Hz, 1H), 7.23-7.07(m, 1H), 6.93(dd, J=8.9, 2.9Hz, 1H), 6.78(d, J=8.9 Hz, 1H), 6.00(s, 2H), 3.77(s, 3H).

Example 3 Preparation of compound 4

Take compound 3 (10g, 41mmol) and 5ml of pyridine and add it to 100ml of dichloromethane, slowly add dropwise at room temperature the solution prepared by 4-cyanobenzoyl chloride (8.16g, 49mmol) and 10ml of dichloromethane. The reaction was continued for 3 h, washed with 80 ml of water, 80 ml of saturated sodium bicarbonate, and 80 ml of water respectively, separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain 12.3 g of compound 4 with a yield of 80.62%. ¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.14(s, 1H), 10.91(s, 1H), 8.50-8.35(m, 1H), 8.18-7.96(m, 6H), 7.96-7.76(m, 1H), 7.49(d, J=2.9Hz, 1H), 7.21(m, J=7.5, 4.2Hz, 2H), 3.90(s, 3H).

Example 4 Preparation of Compound 5

Get compound 4 (10g, 27mmol), NCS (3.6g, 27mmol), benzoyl peroxide (0.5g, 2.1mmol) and join in N,N-dimethylformamide (80ml), and the reaction solution is heated to 70 ℃～80℃ and reacted for 3h, cooled to room temperature, added dichloromethane (100ml) to the reaction solution and washed with 150ml saturated sodium bicarbonate and 150ml water respectively, separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain The residue was recrystallized with 70 ml of tetrahydrofuran-ethanol mixed solvent to obtain 8.39 g of compound 5 with a yield of 76.38%. MS (ESI) m/z: [M+Na] ⁺ 429.1, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 11.03 (s, 1H), 8.47 (s, 1H), 8.15 (d, J=9.0Hz, 1H), 8.05(q, J=8.2Hz, 4H), 8.00-7.93(m, 2H), 7.44(d, J=2.9Hz, 1H), 7.20(dd, J= 8.9, 2.8Hz, 1H), 3.88(s, 3H).

Claims (10)

1. one kind prepares shellfish Qu Shaban intermediate Ns (5- chloro-2-pyridyls) -2- [(4- cyanobenzoyls) amino] -5- methoxies The method of yl-benzamide, it comprises the following steps：

(1) under alkali effect, 5- methoxyl group -2- amino-N- (pyridine -2- bases) benzamides (3) to cyano-benzoyl chloride with contracting Conjunction obtains 2- [(4- cyanobenzoyls) amino] -5- methoxyl groups-N- (pyridine -2- bases) benzamide (4)；

(2) 2- [(4- cyanobenzoyls) amino] -5- methoxyl groups-N- (pyridine -2- bases) benzamide (4) obtains shellfish through chloro Qu Shaban intermediate Ns (5- chloro-2-pyridyls) -2- [(4- cyanobenzoyls) amino] -5- methoxy benzamides (5).

2. method as claimed in claim 1, it is characterised in that：The preparation of the compound 4, solvent for use be water, tetrahydrofuran, Dioxane, acetonitrile, toluene, dimethylbenzene, benzene, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, butyl acetate, acetic acid are different Propyl ester, DMF, N, in N- diethyl acetamides, triethylamine, pyridine, diethylisopropylamide, acetone, butanone One or more combination, the present invention are preferably dichloromethane.

3. method as claimed in claim 1, it is characterised in that：The preparation of the compound 4, alkali used include sodium methoxide, ethanol Sodium, sodium isopropylate, potassium tert-butoxide, sodium tert-butoxide, tert-butyl alcohol magnesium, Sodamide, sodium hydride, calcium hydride, ammoniacal liquor, triethylamine, pyridine, DMAP, diethylisopropylamide, DBU, aniline, DMA, methylphenylamine, potassium carbonate, sodium carbonate, Cesium carbonate, sodium acid carbonate, saleratus, sodium hydroxide, potassium hydroxide, calcium hydroxide, the present invention are preferably pyridine.

4. method as claimed in claim 1, it is characterised in that：The preparation of the compound 4, compound 3 and to Cyanophenacyl The mol ratio of chlorine is 1: (1~2)；Reaction temperature is -10 DEG C~40 DEG C, and the present invention is preferably 20 DEG C~30 DEG C.

5. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, chlorinating agent used in chlorination are Chloro- 5, the 5- dimethyl sea of N-chlorosuccinimide, N- chloros saccharin, N- chloros phthalimide, 1,3- bis- Cause, the chloro- 5- methyl -5- ethylhydantoins of 1,3- bis-, chlorine, the present invention preferably N-chlorosuccinimide, and compound 4 and N- The mol ratio of chlorosuccinimide is 1: (1.0~2.0).

6. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, initiator used are peroxide benzene first One or more combination in acyl, TBHP, peroxide cyclohexanone, azodiisobutyronitrile, ABVN, this hair Bright is preferably benzoyl peroxide, and compound 4 and the mol ratio of benzoyl peroxide are 1: (0.05~0.1).

7. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, solvent for use N, N- dimethyl methyl Acid amides, DMA, N, N- diethylformamides, N, N- diethyl acetamides, dichloromethane, chloroform, four Chlorination carbon, benzene, toluene, pentamethylene, pentane, hexamethylene, n-hexane, cycloheptane, normal heptane, tetrahydrofuran, dioxane, second One or more combination in nitrile, water, the present invention preferably DMF, and compound 4 and N, N- dimethyl methyl The mass volume ratio of acid amides is 1: (5~10).

8. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, reaction temperature are 0 DEG C~100 DEG C, The present invention is preferably 70 DEG C~80 DEG C.

9. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, reaction time are 2h~8h, this hair Bright is preferably 3h.

10. method as claimed in claim 1, it is characterised in that：The preparation of the compound 5, recrystallization solvent are selected from tetrahydrochysene furan Mutter, in dioxane, ethyl acetate, methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol, dichloromethane, n-hexane, hexamethylene One or more combination, preferred solvent of the present invention is tetrahydrofuran and alcohol mixed solvent.