Preparation process of cedazuridine

Abstract

Formula (I): [Formula 1] A one-pot process for preparing cedazuridine of TIFF2024545875000017.tif32170, comprising: Formula (M3): [chemical 2] TIFF2024545875000018.tif39170 to deprotection and then epimerization in a reactor in the presence of a catalyst to obtain a reaction mixture comprising cedazuridine, wherein R of 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 carried out in the same reactor without isolation after the deprotection and before the epimerization; and isolating cedazuridine from the reaction mixture.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 293,765, filed December 25, 2021, which is incorporated in its entirety for all purposes.

[0002] The present disclosure relates to a process for the manufacture of cedazuridine. [Background technology]

[0003] Cedazuridine and decitabine, sold under the brand name Inqovi®, are a fixed-dose combination drug for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Decitabine / cedazuridine was approved for medical use in the United States and Canada in July 2020.

[0004] Cedazuridine has the formula (I): [ka] It is expressed as:

[0005] Cedazuridine has the chemical name "(4R)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine" or "(4R)-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one". 14 It has a molecular formula of F2N2O5 and a molecular weight of 268.21 Da.

[0006] The synthesis of cedazuridine has been a difficult and expensive task due to the presence of multiple functional groups in the chemical structure. Several synthetic methods have been reported in the relevant literature for the synthesis of cedazuridine.

[0007] US Patent No. 9,567,363B2 and J.Med.Chem.2014,57,2582-2588 disclose the preparation of cedazuridine as shown in Scheme 1. Cedazuridine can be prepared from the conversion of gemcitabine via hydrogenation and hydrolysis of gemcitabine followed by reduction under NaBH4 in MeOH. The crude cedazuridine is then purified by preparative HPLC. The total yield is about 18%.

[0008] [ka]

[0009] US Patent No. 9,834,576 B2 discloses an alternative route for preparing cedazuridine, as shown in Scheme 2. It also involves hydrolysis and hydrogenation of the gemcitabine intermediate, followed by reduction under NaBH4 in DCM / EtOH with CeCl3·7H2O / as adduct. Subsequent deprotection of the Bz group with NH3 / MeOH and epimerization with DBU / CH3CN gives crude cedazuridine. After purification, the yield of cedazuridine is 73-86.1%.

[0010] [ka]

[0011] WO2021071890A1 shows a similar route to prepare cedazuridine, as shown in Scheme 3. WO2021071890A1 also involves hydrolysis and hydrogenation of the gemcitabine intermediate, followed by reduction under NaBH4 in DCM / EtOH with CeCl3·7H2O / as adduct. The improved deprotection in WO2021071890A1 is the simplification of the work-up and isolation procedure of the deprotected compound under non-aqueous conditions. The mixture is then diluted with ACN prior to recrystallization of the crude cedazuridine. (aq)should be epimerized with DBU as the solvent to give crude cedazuridine. Crystallization with acetone / water can then give cedazuridine in 61% yield. The overall yield of the five steps of cedazuridine synthesis is 28%.

[0012] [ka]

[0013] Notwithstanding the above processes, there remains a need for the development of improved processes for the preparation of cedazuridine. The present disclosure addresses this need and provides related advantages as well. Summary of the Invention

[0014] The present invention relates to a compound of formula (I): [ka] A one-pot process for preparing cedazuridine represented by Formula (M3): [ka] subjecting the compound of formula (M3) to deprotection and then epimerization in a reactor in the presence of a catalyst to obtain a reaction mixture comprising cedazuridine, wherein R of 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 carried out in the same reactor without isolation after the deprotection and before the epimerization; and Isolating cedazuridine from said reaction mixture. The present invention provides a one-pot process comprising:

[0015] Preferably, R in the compound of formula (M3) is Bz (benzoyl).

[0016] Isolating may include crystallizing the cedazuridine from the reaction mixture. The crystallization is preferably carried out in the presence of cedazuridine seeds.

[0017] The catalyst may be 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, more preferably 1,1,3,3-tetramethylguanidine (TMG).

[0018] According to a preferred embodiment, the process involves controlling the cedazuridine to have a particle size with a D90 of 100 μm or less, preferably 60 μm or less, more preferably 20 μm or less.

[0019] According to a preferred embodiment, the process includes a further purification step which may include: 1) adding a solvent to the crude cedazuridine; 2) slurrying the reduced cedazuridine in the solvent to obtain purified cedazuridine. The purification step is preferably carried out after the particle size control of cedazuridine described above. The solvent is preferably selected from the group consisting of acetone, THF, MeCN, water, and combinations thereof. In another preferred embodiment, the solvent is a co-solvent system of acetone and water.

[0020] In another aspect, the present invention provides a method for producing a composition comprising: Formula (I): [ka] 1. A process for preparing purified cedazuridine comprising: a) reducing the D90 particle size of crude cedazuridine to 100 μm or less; b) mixing the reduced cedazuridine obtained in step a) with a solvent to obtain a mixture containing cedazuridine; and c) isolating cedazuridine from the mixture of step b) to obtain purified cedazuridine. The present invention provides a process including:

[0021] Preferably, isolating comprises slurrying the reduced cedazuridine in a solvent to obtain the purified cedazuridine.

[0022] The particle size D90 in step b) can be controlled to be less than 100 μm, preferably less than 60 μm, and less than 20 μm.

[0023] The solvent in step c) may be selected from the group consisting of acetone, THF, MeCN, water, and combinations thereof. In a preferred embodiment, the solvent may be a co-solvent system of acetone and water.

[0024] Preferably, prior to the step of controlling the particle size of the cedazuridine, the process further comprises: Formula (M3): [ka] subjecting the compound of formula (M3) to deprotection and then epimerization in a reactor in the presence of a catalyst to obtain a reaction mixture comprising cedazuridine, wherein R of 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 carried out in the same reactor without isolation after the deprotection and before the epimerization; and isolating the crude cedazuridine from the reaction mixture. Includes. EXAMPLES

[0025] The following examples are offered to illustrate, but not to limit, the present invention.

[0026] A synthetic route for the preparation of cedazuridine is described below.

[0027] [ka]

[0028] Example 1: Preparation of 3',5'-di-O-benzoyl-2'-deoxy-2',2'-difluoro-1,3-diazinan-2,4-dione (M2) EtOAc (596 mL), 5% NaHCO3 (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 overnight at 60-70 °C under H2 pressure. The mixture was filtered to remove Pd / C and washed with EtOAc (198 mL). The aqueous layer was removed from the filtrate by phase separation. The organic layer was washed with 5% NaHCO3 and water. The organic layer was concentrated under reduced pressure and recrystallized by adding n-heptane (358 mL). The solid was filtered and dried to give M2 (37.11 g) with 99.55% purity in 87% yield.

[0029] Example 2: Preparation of 3',5'-di-O-benzoyl-2'-deoxy-2',2'-difluoro-4-hydroxy-1,3-diazinan-2-one (M3a) CeCl3·7H2O (70.68 g) and M2 (90 g, 189.7 mmol) were dissolved in MeOH (360 mL) and THF (540 mL). NaBH4 (12.92 g) was added to the mixture and stirred for 5 h. The resulting mixture was then quenched with acetone (90 mL). The mixture was washed with brine and 5% NaHCO3, then extracted with EtOAc (450 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (450 mL). The combined organic layers were washed with water, then solvent exchanged with EtOAc. The EtOAc layer was concentrated under reduced pressure and crystallized by the addition of n-heptane (1350 mL). The solid was filtered and dried to give M3a (74.42 g) with 98.71% purity in 82.34% yield.

[0030] Example 3: One-pot reaction for the preparation of crude cedazuridine A suitable reactor was charged with M3a (10.00 g, 20.92 mmol) and TMG (0.132 g, 1.05 mmol) 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. The solution mixture was then concentrated and water (5.0 mL) and cedazuridine seeds were added to the mixture. The mixture was concentrated and stirred at 10-20° C. for 1 hour and then solvent exchanged with MeCN. The solution was filtered and dried to obtain the dried product (4.92 g) in 83% yield. The dried product was further micronized to obtain crude cedazuridine particles with D90 of 100 μm or less.

[0031] Example 4: Purification of crude cedazuridine Crude cedazuridine (10.00 g, 37.28 mmol, D90=117 μm) was added at room temperature along with co-solvents acetone (13 mL, 3.2 vol) and water (6 mL, 0.6 vol). The slurry mixture was heated to 40° C. and then cooled to room temperature in two cycles to give cedazuridine with 0.92% α-epimer for a purity of 99.92% (excluding α-epimer).

[0032] Crude cedazuridine (10.00 g, 37.28 mmol, D90=60 μm) was added at room temperature along with co-solvents acetone (13 mL, 3.2 vol) and water (6 mL, 0.6 vol). The slurry mixture was heated to 40° C. and then cooled to room temperature in two cycles to give cedazuridine with 0.63% α-epimer for a purity of 99.94% (excluding the α-epimer).

[0033] Crude cedazuridine (10.00 g, 37.28 mmol, D90=11.3 μm) was added at room temperature along with co-solvents acetone (13 mL, 3.2 vol) and water (6 mL, 0.6 vol). The slurry mixture was heated to 40° C. and then cooled to room temperature in two cycles to give cedazuridine with 0.21% α-epimer for a purity of 99.96% (excluding the α-epimer).

[0034] [Table 1]

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

[0036] [Table 2]

[0037] In order to meet the RLD criteria, the present invention found that by controlling the particle size (D90) of crude cedazuridine to less than 100 μm, pure cedazuridine with less than 1% α-epimer can be obtained, as shown in Table 2.

Claims

1. Formula (I): 【Chemistry 1】 1. A one-pot process for preparing cedazuridine of the formula Formula (M3): 【Chemistry 2】 subjecting the compound of formula (M3) to deprotection and then epimerization in a reactor in the presence of a catalyst to obtain a reaction mixture comprising cedazuridine, wherein R of 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 carried out in the same reactor without isolation after the deprotection and before the epimerization; and Isolating cedazuridine from said reaction mixture. A one-pot process comprising:

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

3. 2. The process of claim 1, wherein said isolating comprises crystallizing said cedazuridine from said reaction mixture.

4. The process of claim 3, wherein the crystallization is carried out in the presence of cedazuridine seeds.

5. 2. 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. 2. The process of claim 1, wherein the process further comprises reducing the D90 particle size of the isolated cedazuridine to 100 μm or less.

8. 8. The process of claim 7, wherein the D90 particle size of the isolated cedazuridine is reduced to 60 μm or less.

9. 8. The process of claim 7, wherein the D90 particle size of the isolated cedazuridine is reduced to 20 μm or less.

10. 8. The process of claim 7, comprising the further steps of purifying comprising: 1) mixing the reduced cedazuridine with a solvent; and 2) slurrying the reduced cedazuridine in the solvent to obtain purified cedazuridine.

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

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

13. Formula (I): 【Chemistry 3】 1. A process for preparing purified cedazuridine comprising: a) reducing the D90 particle size of crude cedazuridine to 100 μm or less; b) mixing the reduced cedazuridine obtained in step a) with a solvent to obtain a mixture containing cedazuridine; and c) isolating cedazuridine from said mixture of step b) to obtain purified cedazuridine. A process including.

14. 14. The process of claim 13, wherein said isolating comprises slurrying the reduced cedazuridine in the solvent to obtain the purified cedazuridine.

15. 14. The process of claim 13, wherein the D90 particle size of the crude cedazuridine is reduced to 60 μm or less.

16. 14. The process of claim 13, wherein the D90 particle size of the crude cedazuridine is reduced to 20 μm or less.

17. Prior to the reducing step, Formula (M3): 【Chemistry 4】 subjecting the compound of formula (M3) to deprotection and then epimerization in a reactor in the presence of a catalyst to obtain a reaction mixture comprising cedazuridine, wherein R of 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 carried out in the same reactor without isolation after the deprotection and before the epimerization; and isolating the crude cedazuridine from the reaction mixture.

14. The process of claim 13, comprising:

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