METHOD FOR PREPARING NALDEMEDINE

Abstract

Provided is a cost-effective process for preparing naldemedine having high purity with high yields.

Claims

1. A process for preparing naldemedine of the following formula (1), which comprises the steps of: (i) reacting a compound of the following formula (2) with diethyl pyrocarbonate, followed by treating with a base to obtain a compound of the following formula (3); (ii) subjecting the compound of the following formula (3) to a combination reaction with a compound of the following formula (4), followed by adding hydrochloric acid to obtain a compound of the following formula (5); and (iii) deprotecting the compound of the following formula (5): ##STR00009##

2. The process according to claim 1, wherein the base of the step (i) is sodium ethoxide.

3. The process according to claim 1, further comprising the step of purifying the compound of formula (3) obtained from the step (i) by recrystallization.

4. The process according to claim 1, wherein the compound of formula (2) is synthesized by protecting a compound of the following formula (6) with a benzyl group: ##STR00010##

5. The process according to claim 4, wherein the protection is carried out by reacting the compound of formula (6) with benzyl bromide in the presence of a base.

6. The process according to claim 5, wherein the base is potassium carbonate in the form of a fine powder.

7. The process according to claim 5, wherein a solvent in the protection is acetone.

8. The process according to claim 1, wherein the combination reaction of the step (ii) is carried out in the absence of a separate reaction reagent.

9. The process according to claim 1, wherein the combination reaction of the step (ii) is carried out under a heating under reflux condition, and a solvent in the combination reaction is toluene.

10. The process according to claim 1, further comprising the step of purifying the compound of formula (5) obtained from the step (ii) by recrystallization.

11. The process according to claim 1, wherein the deprotection of the step (iii) is carried out using concentrated hydrochloric acid in acetic acid.

12. A process for preparing an acid addition salt of naldemedine, which comprises the step of adding an acid to the naldemedine prepared by the process according to claim 1.

13. The process according to claim 12, wherein the acid is p-toluenesulfonic acid, acetic acid, or hydrochloric acid.

14. The process according to claim 12, wherein the acid addition salt is a p-toluenesulfonic acid salt.

15. A compound of the following formula (5): ##STR00011##

Description

BEST MODE

[0038] Hereinafter, the present invention will be described in more detail by the following examples. It will be obvious to those skilled in the art that these examples are merely described for illustration of the present invention and the scope of the present invention is not limited thereto.

Preparation Example 1

Synthesis of Compound of Formula (4)

[0039] t-Butoxycarbonylamino isobutyric acid (200 g, 1.0 equiv) was added to n-propyl acetate (1400 mL, 7 vol.) followed by stirring, and then N,N-diisopropylethylamine (DIPEA, 188.5 mL, 1.1 equiv) was added thereto at 0° C. Then, isobutyl chloroformate (IBCF, 134.7 mL, 1.05 equiv) was added dropwise thereto at 0° C., and the resulting mixture was stirred for 1 hour. A solution of benzamide oxime (140.7 g, 1.05 equiv) in n-propyl acetate (800 mL, 4 vol.) was added and stirred at 0° C. for 1 hour. Then, the resulting mixture was heated at 95° C. for 5 hours. After confirming that the reaction was completed with TLC (CH.sub.2Cl.sub.2:MeOH=20:1), the reaction product was quenched with 0.1 N HCl solution (3000 mL, 10 vol.), and the organic phase was washed with saturated NaHCO.sub.3 solution (3000 mL, 10 vol.) and water (3000 mL, 10 vol.). After drying over Na.sub.2SO.sub.4 and concentration, the residue (300 g) was diluted with 4 N HCl in dioxane (3000 mL, 10 vol), and stirred at 20° C. for 2 hours. After filtration of the resulting white solid, the filter cake was washed with methyl t-butyl ether (MTBE, 300 mL, 1 vol.). The filtrate was evaporated, and MTBE (500 mL, 10 vol.) was added and stirred, followed by filtration. The filter cake was washed with MTBE (50 mL, 1 vol.). The filter cakes were combined and dried in a vacuum oven to give the HCl salt of the compound of formula (4) (228 g, 97.6% yield) as a white solid. Then, saturated sodium hydrogen carbonate solution (2 L) and MTBE (2 L) were added thereto and strongly stirred for 30 minutes, and then the organic layer was separated, followed by concentration. The obtained solid was dried in a vacuum oven to obtain the compound of formula (4) (190 g, 98% yield) as a white solid.

[0040] .sup.1H NMR (300 MHz, DMSO): 9.16 (3H, s), 8.05-8.02 (2H, m), 7.65-7.59 (3H, m), 1.79 (6H, s).

[0041] m/z [M+H]=204.1

Preparation Example 2

Synthesis of Compound of Formula (2)

[0042] The compound of formula (6) (100 g, 1 equiv), BnBr (41 mL, 1.3 equiv) and K.sub.2CO.sub.3 (110 g, 3 equiv) were added to acetone (1000 mL, 10 vol.) and stirred, followed by heating at 60° C. for 20 hours. After confirming that the reaction was completed with TLC (CH.sub.2Cl.sub.2:MeOH=15:1), the reaction product was cooled to room temperature and filtered. Then, the filter cake was washed with acetone (200 mL×2, 2 vol.). The filtrate was evaporated, and the residue was diluted with 2N HCl solution (300 mL, 3 vol.) and washed with MTBE (300 mL×2, 3 vol.). After that, it was neutralized with NH.sub.3.Math.H.sub.2O and extracted with CH.sub.2Cl.sub.2 (300 mL×2, 3 vol.). The organic phases were combined and dried over Na.sub.2SO.sub.4, followed by evaporation to obtain the compound of formula (2) (106.93 g, 93.6% yield) as a pale yellow gum.

[0043] .sup.1H NMR(300 MHz, CDCl.sub.3): 7.47-7.44 (2H, m), 7.37-7.25 (3H, m), 6.72-6.54 (2H, dd, J=8.1 Hz), 5.31-5.18 (3H, m), 4.68 (1H, s), 3.18-3.16 (1H, d), 3.06-3.00 (2H, m), 2.76-2.12 (7H, m), 1.96-1.83 (1H, m), 1.64-1.53 (2H, m), 0.98-0.77 (1H, m), 0.57-0.53 (2H, m), 0.15-0.13 (2H, m);

[0044] .sup.13C NMR(300 MHz, CDCl.sub.3): δ=208.5, 145.5, 141.8, 137.5, 129.8, 128.3, 127.7, 125.6, 119.4, 118.0, 90.4, 72.1, 70.1, 62.0, 59.2, 50.7, 43.5, 36.2, 31.5, 30.7, 22.6, 9.4, 3.9, 3.8.

[0045] m/z [M+H]=432.2

Example 1

Synthesis of Compound of Formula (3)

[0046] A stirred mixture of the compound of formula (2) (106.9 g, 1 equiv) and diethyl pyrocarbonate (DEPC, 1000 mL, 10 vol.) was heated at 110° C. for 20 hours. The volatiles were evaporated, and the residue was diluted with EtOH (1000 mL, 10 vol.). To the resulting mixture was added dropwise EtONa (107 mL, 1 vol., 20% solution in EtOH), and the mixture was stirred at 20° C. for 1 hour. After confirming that the reaction was completed with TLC (CH.sub.2Cl.sub.2:MeOH=15:1), the reaction mixture was neutralized with 1 N HCl solution at 0° C. The resulting mixture was concentrated and the residue was diluted with CH.sub.2C.sub.2 (1000 mL, 10 vol.) and water (500 mL, 5 vol.). The organic layer was separated, and the separated aqueous layer was extracted with CH.sub.2Cl.sub.2 (300 mL). The organic layers were combined and dried over Na.sub.2SO.sub.4, followed by concentration. The crude product was purified by crystallization (EA:MeOH=2 vol.:4 vol.) and filtered. The filter cake was washed with MeOH (1 vol.). The filtrate was evaporated and recrystallized again. The two filter cakes were combined and dried in a vacuum oven to obtain the compound of formula (3) (110 g, 88% yield, 98.4% purity) as a white solid.

[0047] .sup.1H NMR(300 MHz, CDCl.sub.3): 12.06 (1H, s), 7.43-7.39 (2H, m), 7.34-7.25 (3H, m), 6.74-6.54 (2H, dd, J=8.1 Hz), 5.20-5.18 (2H, t, J=4.2 Hz), 4.95 (1H, s), 4.89 (1H, br), 4.17-4.14 (2H, m), 3.23-3.21 (1H, d), 3.09-3.03 (1H, d), 2.69-2.25 (7H, m), 2.03-1.98 (1H, d), 1.75-1.65 (2H, d), 1.28-1.23 (3H, t, J=6.9), 0.97-0.77 (1H, m), 0.57-0.54 (2H, m), 0.15-0.12 (2H, m);

[0048] .sup.13C NMR(300 MHz, CDCl.sub.3): δ=172.1, 164.4, 145.3, 141.9, 137.3, 131.0, 128.3, 127.8, 126.2, 119.0, 117.7, 98.4, 87.0, 71.9, 70.0, 61.2, 60.9, 59.4, 46.5, 43.3, 31.1, 29.9, 22.9, 14.1, 9.3, 4.1, 3.6.

[0049] m/z [M+H]=504.2

Example 2

Synthesis of Compound of Formula (5)

[0050] The compound of formula (3) (100 g, 1 equiv) and the compound of formula (4) (60.54 g, 1.5 equiv) were added to toluene (200 mL, 2 vol.), followed by stirring and then heating at 110° C. for 4 days. After confirming that the reaction was completed with TLC (CH.sub.2Cl.sub.2:MeOH=15:1), the reaction mixture was diluted with CH.sub.2Cl.sub.2 (1000 mL, 10 vol.), and washed with 0.1 N HCl solution (500 mL×5, 5 vol.), saturated NaHCO.sub.3 solution (500 mL, 5 vol.) and brine (500 mL, 5 vol.). The separated organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude product (65 g) was diluted with EA (688 mL, 7.5 vol.) and 4 N HCl solution (26 mL, 1.05 equiv) in dioxane was added dropwise thereto. After dropwise addition, the mixture was heated under reflux to give a clear solution. The clear solution was slowly cooled to room temperature. The formed solid was filtered, and the filter cake was washed with EA (32 mL, 0.5 vol.) and MTBE (65 mL, 1 vol.). The filter cake was dried in a vacuum oven to obtain the compound of formula (5) (47 g, 73% yield, 99.5% purity) as a white solid.

[0051] .sup.1H NMR(300 MHz, DMSO): 13.30 (1H, s), 8.23 (1H, br), 8.00 (1H, s), 7.99-7.97 (2H, m), 7.59-7.53 (3H, m), 7.41-7.28 (5H, m), 6.96-6.73 (2H, dd, J =8.1 Hz), 5.17-5.12 (2H, m), 5.04 (1H, s), 4.04-4.02 (1H, d), 3.47-2.04 (9H, m), 1.72-1.70 (6H, d), 1.66-1.60 (1H, d), 1.17-1.06 (1H, m), 0.75-0.61 (2H, m), 0.55-0.39 (2H, m);

[0052] .sup.13C NMR(300 MHz, DMSO): δ=183.4, 171.4, 167.8, 161.4, 145.1, 142.1, 137.2, 132.0, 129.7, 129.6, 128.8, 128.7, 128.3, 127.4, 126.6, 124.1, 120.3, 117.4, 98.4, 86.5, 70.8, 70.0, 60.4, 57.2, 52.1, 45.9, 45.0, 30.9, 28.0, 26.7, 26.5, 24.0, 6.1, 5.7, 2.8.

[0053] m/z [M+H]=661.3

Example 3

Synthesis of Naldemedine of Formula (1)

[0054] The compound of formula (5) (10 g, 1 equiv) and conc. HCl (20 mL, 2 vol.) were added to acetic acid (40 mL, 4 vol.) and stirred, followed by heating at 60° C. for 3 hours.

[0055] After confirming that the reaction was completed with TLC (CH.sub.2Cl.sub.2:MeOH=15:1), the reaction mixture was cooled to room temperature and added dropwise to a mixture of NH.sub.3.Math.H.sub.2O (75 mL, 7.5 vol.) and water (75 mL, 7.5 vol.) at 0° C. The precipitated white solid was filtered, and then the filter cake was washed with water (20 mL×2, 2 vol.). The separated solid was diluted with EtOAc (80 mL, 8 vol.), and dried over Na.sub.2SO.sub.4, followed by concentration. MTBE (10 mL, 10 vol.) was added to the residue and stirred to solidify the product, followed by filtration. The product was used in the next step without additional purification.

[0056] .sup.1H NMR(300 MHz, DMSO): 13.40 (1H,br), 9.16 (1H, br), 8.08 (1H, br), 7.99-7.95 (2H, m), 7.58-7.52 (3H, m), 6.60-6.53 (2H, m), 4.77 (1H, br), 4.72 (1H, s), 3.33-1.97 (8H, m), 1.69-1.58 (6H, m), 1.43-1.14 (2H, m), 0.88-0.81 (1H, m), 0.53-0.47 (2H, m), 0.15-0.14 (2H, m).

[0057] m/z [M+H]=571.2

Example 4

Synthesis of Naldemedine Tosylate

[0058] To a solution of the compound of formula (1) (6.5 g, 1 equiv) in MeOH (65 mL, 10 vol.) was added p-toluenesulfonic acid (PTSA, 2.1 g, 1 equiv), followed by stirring at 20° C. for 16 hours. Then, the resulting mixture was evaporated, and ACN and MTBE (ACN:MTBE=1:10) were added to the residue and stirred, followed by filtration. The filter cake was washed with MTBE (1 vol.). Then, it was diluted with MC (10 vol.) and stirred for 2 days. The resulting white solid was crystallized (unsolvated) (99.8% purity).