PROCESS FOR PREPARING CEDAZURIDINE

Abstract

A one-pot process for preparing cedazuridine of formula (I),

##STR00001##

comprising: subjecting a compound of formula (M3)

##STR00002##

to deprotection and then epimerization in a reactor in the presence of a catalyst to obtain a reaction mixture comprising cedazuridine, wherein R on the compound of formula (M3) is independently selected from the group consisting of Ac (acetyl), Bz (benzoyl), p-nitrobenzoyl and OtBu (tert-butyloxycarbonyl), and the deprotection and epimerization are conducted in the same reactor without isolating after the deprotection and before the epimerization; and isolating cedazuridine from the reaction mixture.

Claims

1. A one-pot process for preparing cedazuridine of formula (I), ##STR00012## comprising: subjecting a compound of formula (M3) ##STR00013## to deprotection and then epimerization in a reactor in the presence of a catalyst to obtain a reaction mixture comprising cedazuridine, wherein R on the compound of formula (M3) is independently selected from the group consisting of Ac (acetyl), Bz (benzoyl), p-nitrobenzoyl and OtBu (tert-butyloxycarbonyl), and the deprotection and epimerization are conducted in the same reactor without isolating after the deprotection and before the epimerization; and isolating cedazuridine from the reaction mixture.

2. The process of claim 1 wherein R on the compound of formula (M3) is Bz (benzoyl).

3. The process of claim 1 wherein the isolating comprises crystallizing the cedazuridine from the reaction mixture.

4. The process of claim 3 wherein the crystallizing is conducted in the presence of a cedazuridine seed.

5. The process of claim 1, wherein the catalyst is selected from the group consisting of 1,1,3,3-tetramethylguanidine (TMG), 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), 2-tert-butyl-1,1,3,3-tetramethylguanidine (Barton’s base), and combinations thereof.

6. The process of claim 1, wherein the catalyst is 1,1,3,3-tetramethylguanidine (TMG).

7. The process of claim 1, wherein the process further comprises reducing particle size with D90 of the isolated cedazuridine to no greater than 100 .Math.m.

8. The process of claim 7, wherein the particle size with D90 of the isolated cedazuridine is reduced to no greater than 60 .Math.m.

9. The process of claim 7, wherein the particle size with D90 of the isolated cedazuridine is reduced to no greater than 20 .Math.m.

10. The process of claim 7, comprising a further step of purifying which comprises: 1) mixing the reduced cedazuridine with a solvent; 2) performing slurry the reduced cedazuridine in the solvent to obtain a purified cedazuridine.

11. The process of claim 10, wherein the solvent is selected from the group consisting of acetone, THF, MeCN, water, and combinations thereof.

12. The process of claim 11, wherein the solvent is a co-solvent system of acetone and water.

13. A process for preparing a purified cedazuridine of formula (I), ##STR00014## comprising: d) reducing a particle size with D90 of crude cedazuridine to no greater 100 .Math.m; e) mixing the reduced cedazuridine obtained in step a) with a solvent to obtain a mixture comprising cedazuridine; and f) isolating cedazuridine from the mixture of step b) to obtain the purified cedazuridine.

14. The process of claim 13 wherein the isolating comprises performing slurry the reduced cedazuridine in the solvent to obtain the purified cedazuridine.

15. The process of claim 13 wherein the particle size with D90 of the crude cedazuridine is reduced to no greater than 60 .Math.m.

16. The process of claim 13 wherein the particle size with D90 of the crude cedazuridine is reduced to no greater than 20 .Math.m.

17. The process of claim 13 comprising, prior to the step of reducing: subjecting a compound of formula (M3) ##STR00015## to deprotection and then epimerization in a reactor in the presence of a catalyst to obtain a reaction mixture comprising cedazuridine, wherein R on the compound of formula (M3) is independently selected from the group consisting of Ac (acetyl), Bz (benzoyl), p-nitrobenzoyl and OtBu (tert-butyloxycarbonyl), and the deprotection and epimerization are conducted in the same reactor without isolating after the deprotection and before the epimerization; and isolating the crude cedazuridine from the reaction mixture.

Description

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

Examples

[0027] The following examples are provided to illustrate, but not to limit, the present invention.

[0028] The synthetic route for the preparation of cedazuridine is described below:

##STR00011##

Example 1: Preparation of 3′,5′-Di-O-benzoyl-2′-Deoxy-2′,2′-difluoro-1,3-diazinan-2,4-dione (M2)

[0029] EtOAc (596 mL), 5%NaHCO.sub.3 (197 mL) and M1 (3′,5′-Di-O-benzoyl-2′-deoxy-2′,2′-difluorocytidine hydrochloride) (39.73 g) were added to the hydrogenator. Formic acid (14.8 mL) and Pd/C (1.59 g) were added to the hydrogenator. The reaction mixture was stirred under pressure of H.sub.2 at 60-70° C. for overnight. The mixture was filtered to remove Pd/C and washed with EtOAc (198 mL). The water layer was removed from filtrate by phase separation. The organic layer was washed with 5% NaHCO.sub.3 and water. The organic layer was concentrated by reducing pressure and recrystallized by adding n-heptane (358 mL). The solid was filtrated and dried to obtain M2 (37.11 g) in 87% yield with 99.55% purity.

Example 2: Preparation of 3′,5′-Di-O-benzoyl-2′-Deoxy-2′,2′-difluoro-4-hydroxy-1,3-diazinan-2-one (M3a)

[0030] CeCl.sub.3.7H.sub.2O (70.68 g) and M2 (90 g, 189.7 mmol) were dissolved in MeOH (360 mL) and THF (540 mL). NaBH.sub.4 (12.92 g) was added to the mixture and stirred for 5 hours. The resulting mixture was then quenched with acetone (90 mL). The mixture was washed with brine and 5% NaHCO.sub.3 and then extracted with EtOAc (450 mL). The organic layer was separated, and extracted aqueous layer by EtOAc (450 mL). Combined organic layers were washed with water and then the solvent-swap was carried out with EtOAc. The EtOAc layer was concentrated by reducing pressure and crystallized by adding n-heptane (1350 mL). The solid was filtrated and dried to give M3a (74.42 g) in 82.34% yield with 98.71% purity.

Example 3: One-pot Reaction for the Preparation of Crude Cedazuridine

[0031] M3a (10.00 g, 20.92 mmol) and TMG (0.132 g, 1.05 mmol) were charged into a suitable reactor and dissolved in MeOH (300 mL). The mixture was stirred at 15° C. for 18 hours. The resulting mixture was concentrated and then MeCN (170 mL) was added to the mixture. Then the solution mixture was concentrated and the water (5.0 mL) and cedazuridine seed were added to the mixture. The mixture was concentrated and stirred at 10-20° C. for 1 hour, then the solvent-swap was carried out with MeCN. The solution was filtrated and dried to obtain dried product (4.92 g) in 83% yield. The dried product was further micronized to give crude cedazuridine particles having a D90 equal to or less 100 .Math.m.

Example 4: Purification of Crude Cedazuridine

[0032] The crude cedazuridine (10.00 g, 37.28 mmol, D90=117 .Math.m) was added with co-solvent of acetone (13 mL, 3.2 vol) and water (6 mL, 0.6 vol) at room temperature. The slurry mixture was heated to 40° C. then cooled to RT for two cycles to give cedazuridine with 0.92% alpha-epimer with purity 99.92% (excluding alpha-epimer).

[0033] The crude cedazuridine (10.00 g, 37.28 mmol, D90=60 .Math.m) was added with co-solvent of acetone (13 mL, 3.2 vol) and water (6 mL, 0.6 vol) at room temperature. The slurry mixture was heated to 40° C. then cooled to RT for two cycles to give Cedazuridine with 0.63% alpha-epimer with purity 99.94% (excluding alpha-epimer).

[0034] The crude cedazuridine (10.00 g, 37.28 mmol, D90=11.3 .Math.m) was added with co-solvent of acetone (13 mL, 3.2 vol) and water (6 mL, 0.6 vol) at room temperature. The slurry mixture was heated to 40° C. then cooled to RT for two cycles to give cedazuridine with 0.21% alpha-epimer with purity 99.96% (excluding alpha-epimer).

TABLE-US-00001 US 9,834,576 B2 WO2021071890A1 Embodiment of Present invention Deprotection 95% Total:65.6% 87% Total: 69.6% 83% Epimerization 69% 80% Purification (Cedazuridine/Alpha-epimer) 86.1 (98.6/1.4) 61% (99.6/0.4) 81% (99.79/0.21) Yield from M3 to Cedazuridine 56% 42% 67%

[0035] As can be seen in Table 1 above, the present invention provides an improved process in comparison with prior art documents. The present invention can not only reduce the reaction steps but also increase overall yield.

TABLE-US-00002 Before Purification D90 (.Math.m) Purification Alpha epimer Purity (excluding alpha epimer) alpha epimer Purity (excluding alpha epimer) 1.45% 99.82% 117 0.92% 99.92% 60 0.63% 99.94% 11 0.21% 99.96% Cedazuridine from RLD (INQOVI®)* NA 0.3% NA *RLD: reference listed drug which is an approved drug product to which new generic versions are compared to show that they are bioequivalent.

[0036] To meet the criteria of RLD, the present invention found that controlling the particle size (D90) of the crude cedazuridine below 100 .Math.m can obtain pure cedazuridine having the alpha-epimer less than 1% as shown in Table 2.