TWI821074B - Process for preparing cedazuridine - Google Patents

Abstract

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

comprising: subjecting a 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 on the compound of formula (M3) is independently selected from the group consisting of Ac (acetyl), Bz (benzoyl), p-nitrobenzoyl and 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.

Description

Method for preparing CEDAZURIDINE

The present invention relates to a method for preparing cidaluridine.

Cedazuridine and decitabine, sold under the trade name Inqovi®, is a fixed-dose combination medicine used to treat patients with myelodysplastic syndrome (MDS) and chronic granulosa mononuclear cell disease leukemia (CMML) in adults. Decitabine/cidaluri is scheduled to be approved for medical use in the United States and Canada in July 2020.

The Sidaluri formula is shown in formula (I):

The chemical name of cidaluridine is "(4R)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine" or "(4R)-1- [(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolane-2-yl]-4-hydroxy-1,3-diazin-2-one ." The molecular formula of cidaluridine is C ₉ H ₁₄ F ₂ N ₂ O ₅ and the molecular weight is 268.21Da.

The synthesis of hydralidine has been a challenging and costly task due to the presence of multiple functional groups in its chemical structure. A variety of synthesis methods have been reported in relevant literature regarding the synthesis of hydralidine.

U.S. Patent No. 9,567,363 B2 and J. Med. Chem. 2014 , 57, 2582-2588 disclose a preparation method of hidaluridine, as shown in Scheme 1 . Hydallidine can be prepared by hydrogenation and hydrolysis of gemcitabine, followed by reduction in NaBH ₄ in MeOH. The crude hidaluridine was then purified by preparative HPLC. The overall yield is approximately 18%.

U.S. Patent No. 9,834,576 B2 discloses another route to prepare hidaluridine, as shown in Scheme 2 . It also involves hydrolysis and hydrogenation of the gemcitabine intermediate, followed by reduction with CeCl ₃ .7H ₂ O in NaBH ₄ in DCM/EtOH, followed by deprotection of the Bz group with NH ₃ /MeOH and DBU/CH ₃ CN is subjected to epimerization to obtain crude hydralidine. After purification, the yield of cidaluri was determined to be 73-86.1%.

流程2：US 9,834,576 B2中所示的合成路徑

Process 2: Synthetic route shown in US 9,834,576 B2

WO2021071890A1 has confirmed a similar route for preparing cidaluridine, as shown in Scheme 3 . WO2021071890A1 also involves the hydrolysis and hydrogenation of gemcitabine intermediates, followed by reduction with CeCl ₃ .7H ₂ O in a solution of NaBH ₄ in DCM/EtOH. The improvement of deprotection in WO2021071890A1 is to post-process and separate the deprotected compound under anhydrous conditions. Simplification of procedures. Thereafter, before recrystallizing the crude hidaluridine, the mixture is subjected to an epimerization reaction using ACN _(aq) as a solvent and DBU to obtain crude hidaluridine. Afterwards, crystallization with acetone/water can give hidaludine with a yield of 61%. The five-step synthesis of hidaluridine yielded an overall yield of 28%.

Notwithstanding the above methods, there is still a need to develop improved methods for the preparation of hidaluridine. The present invention addresses this need and provides related advantages.

This application claims priority from U.S. Provisional Application No. 63/293,765, filed on December 25, 2021, the entire contents of which are incorporated herein for all purposes.

包含： 將式(M3)化合物

The present invention provides a one-pot method for preparing cidaluridine of formula (I):

Contains: Compounds of formula (M3)

In the presence of a catalyst, a deprotection reaction is carried out in a reactor, followed by an epimerization reaction, to obtain a reaction mixture containing hidaluridine, wherein R on the compound of formula (M3) is independently selected from Ac (acetyl), Bz (benzoyl), p-nitrobenzyl and tertiary butoxycarbonyl group, the deprotection reaction and the epimerization reaction are in the same reaction It is carried out in a device without separation after the deprotection reaction and before the epimerization reaction; and the hidaluridine is separated from the reaction mixture.

Preferably, R on the compound of formula (M3) is Bz (benzoyl).

The isolation step may comprise crystallizing the hydralidine from the reaction mixture. Crystallization is preferably carried out in the presence of cidaludine seed crystals.

The catalyst can 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 Base-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), 2-tert-butyl-1,1,3,3-tetramethylguanidine (Barton base) The group consisting of its combination is more preferably 1,1,3,3-tetramethylguanidine (TMG).

According to a preferred embodiment, the method includes controlling the D90 particle size of cidaluridine to be equal to or less than 100 μm, preferably equal to or less than 60 μm, and more preferably equal to or less than 20 μm.

According to a preferred embodiment, the method includes further purification steps, which may include: 1) adding a solvent to the crude hidaludine; 2) slurrying the reduced hidaludine in the solvent to obtain purified hydralidine. This purification step is preferably performed after controlling the particle size of hildaluridine as 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.

In another aspect, the invention provides a method for preparing hydralidine of formula (I),

Comprising: a) reducing the D90 particle size of crude hidaludine to no more than 100 μm; b) mixing the reduced hidaludine obtained in step a) with a solvent to obtain a hydridine-containing hidaludine. mixture; and c) separating hidaluridine from the mixture of step b) to obtain purified hidaluridine.

Preferably, the separation step includes slurrying the reduced hidaluridine in the solvent to obtain purified hidaluridine.

The D90 particle size of step b) can be controlled to be equal to or less than 100 μm, preferably equal to or less than 60 μm, and equal to or less than 20 μm.

The solvent of 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.

Preferably, before the step of controlling the particle size of hildaluridine, the method includes: adding a compound of formula (M3)

In the presence of a catalyst, a deprotection reaction is carried out in a reactor, followed by an epimerization reaction, to obtain a reaction mixture containing hidaluridine, wherein R on the compound of formula (M3) is independently selected from Ac (acetyl), Bz (benzoyl), p-nitrobenzyl and tertiary butoxycarbonyl group, the deprotection reaction and the epimerization reaction are in the same reaction It is carried out in a device without separation after the deprotection reaction and before the epimerization reaction; and the crude hidaluridine is separated from the reaction mixture.

Example

The following examples are provided to illustrate but not to limit the invention.

The synthetic route to prepare hidaluridine is described below:

Example 1: 3',5'-di-O-benzyl-2'-deoxy-2',2'-difluoro-1,3-diazipyran-2,4-dione (M2 ) preparation

Add EtOAc (596 mL), 5% NaHCO ₃ (197 mL) and M1 (3',5'-di-O-benzoyl-2'-deoxy-2',2'-difluorocytidine hydrochloride )(39.73g) was 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 _H2 pressure at 60-70 °C overnight. 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 obtain M2 (37.11 g) in 87% yield and 99.55% purity.

Example 2: 3',5'-di-O-benzyl-2'-deoxy-2',2'-difluoro-4-hydroxy-1,3-diazin-2-one (M3a ) preparation

CeCl ₃ .7H ₂ O (70.68 g) and M2 (90 g, 189.7 mmol) were dissolved in MeOH (360 mL) and THF (540 mL). _NaBH4 (12.92g) 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% _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, followed by solvent exchange with EtOAc. The EtOAc layer was concentrated under reduced pressure and crystallized by adding n-heptane (1350 mL). The solid was filtered and dried to obtain M3a (74.42g) with a yield of 82.34% and a purity of 98.71%.

Example 3: Preparation of crude cidaluridine in one pot reaction

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 before MeCN (170 mL) was added to the mixture. The solution mixture was then concentrated and water (5.0 mL) and hidaluridine seed crystals were added to the mixture. The mixture was concentrated and stirred at 10-20°C for 1 hour before solvent exchange with MeCN. The solution was filtered and dried to obtain dry product (4.92 g) in 83% yield. The dried product is further micronized to obtain crude hidaluridine particles having a D90 equal to or less than 100 μm.

Example 4: Purification of crude cidaludine

Crude hydralidine (10.00 g, 37.28 mmol, D90 = 117 μm) was added to a co-solvent of acetone (13 mL, 3.2 volumes) and water (6 mL, 0.6 volumes) at room temperature. The slurry mixture was heated to 40°C and then cooled to room temperature for two cycles to obtain a mixture containing 0.92% α-epimer and a purity of 99.92% (excluding α-epimer). Daluliding.

Crude hydralidine (10.00 g, 37.28 mmol, D90 = 60 μm) was added to a co-solvent of acetone (13 mL, 3.2 volumes) and water (6 mL, 0.6 volumes) at room temperature. The slurry mixture was heated to 40°C, then cooled to room temperature, and two cycles were performed to obtain 0.63% α-epimer and a purity of 99.94% (excluding α-epimer). Daluliding.

To crude hydralidine (10.00 g, 37.28 mmol, D90 = 11.3 μm) was added a co-solvent of acetone (13 mL, 3.2 times the volume) and water (6 mL, 0.6 times the volume) at room temperature. The slurry mixture was heated to 40°C, then cooled to room temperature, and two cycles were performed to obtain a slurry containing 0.21% α-epimer and a purity of 99.96% (excluding α-epimer). Daluliding.

As shown in Table 1 above, the present invention provides an improved method compared to the prior art literature. The present invention can not only reduce reaction steps, but also increase the overall yield.

In order to meet the RLD standard, the present invention found that by controlling the particle size (D90) of crude hidaluridine below 100 μm, pure hidaluridine with less than 1% α-epimer can be obtained, as shown in the table 2 shown.

Claims (17)

A one-pot method for preparing cidaluridine of formula (I),

Contains: Compounds of formula (M3)

In the presence of a catalyst, a deprotection reaction is carried out in a reactor, followed by an epimerization reaction, to obtain a reaction mixture containing hidaluridine, wherein R on the compound of formula (M3) is independently selected from Ac (acetyl), Bz (benzoyl), p-nitrobenzyl and tertiary butoxycarbonyl group, the deprotection reaction and the epimerization reaction are in the same reaction It is carried out in a device without separation after the deprotection reaction and before the epimerization reaction; and the hidaluridine is separated from the reaction mixture. The method of claim 1, wherein R on the compound of formula (M3) is Bz (benzoyl). The method of claim 1, wherein the separating comprises crystallizing hidaludine from the reaction mixture. The method of claim 3, wherein the crystallization is carried out in the presence of cidaluridine seed crystals. The method according to 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-tertiary-butyl-1,1,3,3 -Tetramethylguanidine (Barton base) and the group consisting of its combinations. The method of claim 1, wherein the catalyst is 1,1,3,3-tetramethylguanidine (TMG). The method as described in claim 1, wherein the method further includes reducing the D90 particle size of the isolated cidaludine to no more than 100 μm. The method of claim 7, wherein the D90 particle size of the isolated cidaluridine is reduced to no more than 60 μm. The method of claim 7, wherein the D90 particle size of the isolated cidaluridine is reduced to no more than 20 μm. The method of claim 7, comprising a further purification step, which includes: 1) mixing the isolated hidaluridine with a solvent; 2) mixing the isolated hidaluridine in the solvent Slurry to obtain purified hydralidine. The method of claim 10, wherein the solvent is selected from the group consisting of acetone, THF, MeCN, water and combinations thereof. The method of claim 11, wherein the solvent is a co-solvent system of acetone and water. A method for preparing purified cidaluridine of formula (I),

Comprising: a) reducing the D90 particle size of crude hidaludine to no more than 100 μm; b) mixing the crude hidaludine obtained in step a) with a solvent to obtain a mixture containing hidaludine ; and c) separating hidaluridine from the mixture of step b) to obtain purified hidaluridine. The method of claim 13, wherein the separation comprises slurrying the crude hidaluridine in the solvent to obtain purified hidaluridine. The method as claimed in claim 13, wherein the D90 particle size of the crude hidaluridine is reduced to no more than 60 μm. The method as claimed in claim 13, wherein the D90 particle size of the crude hidaluridine is reduced to no more than 20 μm. The method as described in claim 13, before step a), further includes: adding the compound of formula (M3)

In the presence of a catalyst, a deprotection reaction is carried out in a reactor, followed by an epimerization reaction, to obtain a reaction mixture containing hidaluridine, wherein R on the compound of formula (M3) is independently selected from Ac (acetyl), Bz (benzoyl), p-nitrobenzyl and tertiary butoxycarbonyl group, the deprotection reaction and the epimerization reaction are in the same reaction It is carried out in a device without separation after the deprotection reaction and before the epimerization reaction; and the crude hidaluridine is separated from the reaction mixture.