CN113292620B - Improved process for preparing clofarabine intermediate 3 ', 5' -di-O-benzoyl-2-chloroadenosine - Google Patents
Improved process for preparing clofarabine intermediate 3 ', 5' -di-O-benzoyl-2-chloroadenosine Download PDFInfo
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Abstract
The invention provides an improved process for preparing clofarabine intermediate 3 ', 5' -di-O-benzoyl-2-chloroadenosine, which completes silicification/glycosylation reaction in one step and selective partial deprotection/isomerization reaction in one step, simplifies the preparation process and improves the production efficiency; the method utilizes the positive influence of the surprisingly discovered trifluoroacetamide on selectivity in the presence of organic amine as alkali, avoids the use of hydrazine with strong toxicity, ensures the safety of operators, and reduces the time and cost burden brought by the analysis and detection of low-level impurities.
Description
Technical Field
The invention relates to a novel process for preparing clofarabine intermediate 3 ', 5' -di-O-benzoyl-2-chloroadenosine.
Background
Clofarabine is a novel purine nucleoside anti-cancer drug Cllar active ingredient developed by Ilex Oncology, clofarabine is approved by the Food and Drug Administration (FDA) of 28 Japan and America in 2004 through a quick channel for treating refractory or recurrent acute lymphocytic leukemia of children, and is the only drug which can be specifically used for treating acute myelocytic leukemia (ALL) of children at present.
CN102311472B provides a method for synthesizing clofarabine, which comprises silylation reaction (step 1), nucleoside reaction (step 2), selective deprotection (step 3), isomerization reaction (step 4), sulfonylation reaction (step 5), fluorination reaction (step 6) and deprotection reaction (step 7). Wherein step 1 comprises reacting a compound of formula A
A
Carrying out silanization reaction to generate a compound of a formula B;
B
after the silylation reaction is completed, reacting with a compound of formula C
C
Obtaining a compound shown in a formula II through a nucleoside reaction;
Ⅱ
followed by selective deprotection using hydrazine hydrate to effect partial debenzoylation of the compound of formula II to give formula I
Ⅰ
And a mixture of compounds of the formula E,
E
in the coupling step of step2, NaHCO is used in the process 3 The solution and the solvent methyl tert-butyl ether (MTBE) are washed and extracted, and the mass extraction/washing reduces the production efficiency; and the coupling step (step 2) requires prior silica-alkylation of 2-chloroadenine (step 1). Although step 1 and step2 are carried out in one reaction vessel, the reaction must be stopped after step 1 and allowed to stand long enough to add the compound of formula C and triflic acid (TfOH) at a reasonable temperature. This will result in increased time costs for production.
Whereas the compound of formula II is partially debenzoylated using hydrazine, the resulting mixture of formula I and formula E contains a significant amount of AcOH-pyridine, requiring a significant amount of organic solvent and aqueous acid and base solutions to remove the AcOH and pyridine. Furthermore, hydrazine is a known genotoxic compound, the benzoyl derivative thereof (BzNHNH) 2 ) Are potentially genotoxic compounds (PGIs). Both compounds, although controlled at low levels, ultimately contribute to the air pollution index. Although they can be controlled under the corresponding standards in the bulk drug code, which means that their concentrations are within safe limits, it is highly desirable to replace hydrazine with a non-genotoxic agent. Substitution of hydrazine with non-genotoxic agents not only reduces potential future regulatory concerns over the use of genotoxic agents, but also greatly alleviates the analytical testing of these low levels of impuritiesTime/cost burden of measurement.
Disclosure of Invention
In order to solve the problems, the invention provides an improved process for preparing the clofarabine intermediate 3 ', 5' -di-O-benzoyl-2-chloroadenosine.
The main content of the invention comprises:
an improved process for the preparation of clofarabine intermediates having formula I, comprising the step of selective partial deprotection reaction,
Ⅰ
the step of selective partial deprotection is a step of preparing a compound having formula I using a compound having formula II,
Ⅱ
the method comprises the following substeps:
s1, preparing a mixture containing a compound with a formula II, wherein the mixture contains a certain amount of trifluoroacetamide;
s2, carrying out partial deprotection and isomerization reaction on the mixture in methanol, ethanol or a mixture of methanol and acetonitrile or toluene under the condition that organic amine is used as alkali, and filtering out a solid;
s3, washing with methanol, and drying in vacuum to obtain the compound with the formula I.
Preferably, the step of preparing the mixture containing the compound having formula ii in step S1 includes a silicidation/glycosylation sub-step; wherein the silicidation/glycosylation reaction substep refers to the use of a compound having the formula III
Ⅲ
And compounds having formula IV
Ⅳ
Substeps of preparing a mixture of compounds having formula ii.
Preferably, the silicidation/glycosylation reaction substep is as follows:
s11, respectively adding a compound with a formula III and a compound with a formula IV, acetonitrile and N, O-bis (trimethylsilyl) trifluoroacetamide (BSTFA) into a bottle under nitrogen, stirring the mixture, adding trifluoromethanesulfonic acid (TfOH), and heating and refluxing until the glycosylation reaction is completed;
s12, dropwise adding water into the mixture obtained in the step S11 for cooling, and adding 15-40% of K 2 HPO 4 .3H 2 O, stirring to obtain an acetonitrile solution;
s13, stirring and filtering the acetonitrile solution obtained in the step S12, and evaporating in vacuum to obtain an intermediate concentrated solution, wherein the intermediate concentrated solution contains the compound with the formula II and acetonitrile.
Preferably, the intermediate concentrate obtained in S13 is used in the reaction of step S2.
Preferably, the step of using the intermediate concentrated solution obtained in the step S13 for the reaction in the step S2 comprises the steps of:
adding the intermediate concentrated solution into methanol and 4-Dimethylaminopyridine (DMAP), stirring and heating to a certain temperature for a certain time, cooling to a certain temperature, stirring for a certain time, and filtering to obtain a solid.
Preferably, the intermediate concentrated solution obtained in S13 is evaporated again to dryness to obtain a crude solid mixture containing 25w% of trifluoroacetamide; the crude solid mixture was then used in the reaction of step S2.
Preferably, the step of using the crude solid mixture for the reaction of step S2 comprises the steps of:
adding the crude solid mixture, DMAP, acetonitrile, methanol and toluene into a bottle, stirring the mixture, heating to a certain temperature, keeping for a certain time, cooling to a certain time, stirring for a certain time, and filtering to obtain a solid.
Preferably, the intermediate concentrate obtained in S13 is concentrated to dryness by evaporation again to give a crude mixture comprising 25w% of trifluoroacetamide; the crude mixture was then used in the reaction of step S2.
Preferably, the use of the crude mixture for the reaction of step S2 comprises the steps of:
the crude mixture, DMAP and ethanol were added to a bottle, the mixture was stirred and heated under reflux for a period of time, the mixture was cooled to a temperature and stirred for a period of time, and the solid was filtered off.
Preferably, the use of the crude mixture for the reaction of step S2 comprises the steps of:
adding the crude mixture, the base component and methanol to a bottle, stirring and heating the mixture to a certain temperature for a certain time, cooling to a certain temperature and stirring for a certain time, and filtering out the solid.
Preferably, the base component is one of 2-amino-2-methyl-1-propanol, (1S,2S) - (+) -1, 2-cyclohexanediamine, (1S,2S) - (+) -N, N' -dimethylcyclohexane-1, 2-diamine, and benzylamine.
Preferably, the mixture of S1 containing the compound of formula II is obtained by adding an acid additive to the purified compound of formula II.
Preferably, the acid additive is one of trifluoroacetamide, acetic acid, maleic acid, 4-nitrobenzoic acid, citric acid, formic acid, benzoic acid, and succinic acid.
Preferably, when the acid additive is trifluoroacetamide, the mixture containing the compound of formula ii has a ratio of trifluoroacetamide to the purity of the compound of formula ii of greater than 0.5%.
The invention has the beneficial effects that:
(1) the deprotection reaction and the isomerization reaction are completed in one step, acid-base aqueous solution washing is not needed, the steps are simplified, the operation is simple, and the production efficiency is higher;
(2) the method utilizes the positive influence of surprisingly discovered acid additives such as trifluoroacetamide and the like on selective partial deprotection reaction, and uses amino with lower toxicity to replace genotoxic hydrazine, thereby not only ensuring the safety of operators, but also having mild and controllable reaction and being beneficial to large-scale production.
Detailed Description
The technical solution protected by the present invention is specifically explained below.
A novel process for preparing a compound of formula I using a compound of formula II.
The first step is as follows: a compound of formula II is prepared.
In the first mode, a pure substance containing the compound of formula II is taken, and the mixture is subjected to a partial deprotection reaction and an isomerization reaction in one container under the condition that DMAP is used as a base by adding an acid additive (the method for performing the partial deprotection reaction and the isomerization reaction in one step is described in detail below), wherein the acid additive is one of Trifluoroacetamide (TFAA), acetic acid, maleic acid, 4-nitrobenzoic acid, citric acid, formic acid, benzoic acid and succinic acid.
Among these, other acids are more acidic than trifluoroacetamide and the reaction proceeds more slowly, thus requiring higher reaction temperatures and longer reaction times, and the following table gives the effect of selectivity of the respective acidic additives in the presence of DMAP as base:
the second method is to prepare a mixture containing a compound of formula II containing TFAA by a silicidation/glycosylation reaction, specifically, using a compound of formula III and a compound of formula IV, in a single vessel, in a single step, with the following steps:
example one
Under nitrogen (g), 2-chloroadenine (compound of formula III, 60.0 g, 0.354 mol,1.0 eq.), 1-O-acetyl-2, 3, 5-tris-O-benzoyl- β -d-ribofuranol (compound of formula IV, 178.5 g,1.0 eq.), acetonitrile (360 mL) and BSTFA (187.8 mL,2.0 eq.) were added to the vial separately. The mixture was stirred, TfOH (1.56 mL,0.05 eq.) was added, and heated to reflux (about 81 ℃) until the mixture was almost clear (about 2 h).
Cooled to 30 ℃ and water (28 mL,4.4 eq.) was added dropwise at a temperature below 35 ℃. The mixture was stirred for one hour. Adding 40% of K 2 HPO 4 .3H 2 O aq. solution (360 mL) was stirred for 40 min. The middle layer (acetonitrile solution) was separated. 12g of diatomaceous earth was added to the acetonitrile layer, stirred for 30 min and filtered, leaving about 379g of intermediate concentrate (about 120ml acetonitrile) by vacuum distillation at 45 ℃. The intermediate concentrate of compound of formula II/acetonitrile concentrate (about 80 g of trifluoroacetamide and about 204 g of compound of formula II) can be used directly in the next step of selective partial deprotection and isomerization.
The compound of formula II/acetonitrile concentrate (intermediate concentrate) was added to methanol (960 mL), DMAP (51.9 g), heated to 50 ℃ with stirring for 20 h, cooled to 30 ℃ and stirred for 30 min. The solid was filtered off, washed with methanol (240 mL x 2) and dried in vacuo to give 119 g of the compound of formula I with purity 95.6% and net yield 63%.
Example two
This example used the intermediate concentrate obtained in example one to obtain a crude solid mixture for selective partial deprotection and isomerization.
The evaporation of the formula II/acetonitrile concentrate to dryness was continued to give a crude solid of formula II containing about 25w% trifluoroacetamide (crude solid mixture). The crude solid compound of formula II containing about 25w% trifluoroacetamide (48.0 g), DMAP (8.7 g, 1.2 eq.), acetonitrile (20.0 mL), methanol (160 mL), toluene (20.0 mL) was added to the bottle. The mixture was stirred and heated to 50 ℃ for 29 hours. Cooling to less than 30 deg.C, and stirring for 20 min. The solid was filtered, washed with methanol (150 mL) and dried in vacuo to give 18 g of the compound of formula I, 96.6% pure in 56% yield.
EXAMPLE III
This example utilized the intermediate concentrate obtained in example one to further process to obtain a crude mixture for selective partial deprotection and isomerization.
The compound of formula II/acetonitrile concentrate is further concentrated by evaporation to dryness to give a crude compound of formula II containing about 25w% trifluoroacetamide (crude mixture). The crude compound of formula II containing about 25w% trifluoroacetamide (7.0 g), DMAP (1.3 g, 1.2 eq.) and ethanol (27 mL) was added to the bottle. The mixture was heated under reflux with stirring for 30h, the mixture was cooled to less than 30 ℃ and stirring was continued for 20 min, the solid was filtered off, washed with methanol (21 mL) and dried in vacuo to give 1.9 g of the compound of formula I in 96.8% purity in 43% yield.
Examples one, two and three were all run with DMAP as base and it was found experimentally that 0.02eq. (1 eq. for the compound of formula II) trifluoroacetamide had a significant effect on the course of the compound of formula I in step2 and that selectivity increased with increasing trifluoroacetamide usage, but when DAMP was increased to 1eq, more trifluoroacetamide had less effect on selectivity and therefore did not need to be removed from the mixture prepared in step one and dissolved in the ACN layer during water treatment and also did not need additional trifluoroacetamide, the following is the effect of TFAA on selectivity in the solution in which DMAP was present:
example four
This example differs from example three in that other organic amines are used as bases.
The compound of formula II/acetonitrile concentrate (intermediate concentrate) is further concentrated by evaporation to dryness to give a crude compound of formula II (crude mixture) containing about 25w% trifluoroacetamide. The crude compound of formula II containing about 25% trifluoroacetamide (7.0 g), 2-amino-2-methyl-1-propanol (0.30 g, 0.4 eq.) and methanol (65 mL) was added to the bottle. The mixture was stirred and heated to 50 ℃ for 30h, cooled to less than 30 ℃ and stirred for 20 min, the solid was filtered off, washed with methanol (21 mL) and dried in vacuo to give 1.1 g of the compound of formula I in 94.5% purity and 26% yield.
EXAMPLE five
This example differs from example three in that other organic amines are used as bases.
The compound of formula II/acetonitrile concentrate (intermediate concentrate) is further concentrated to dryness by evaporation to give a crude compound of formula II (crude mixture) containing about 25w% trifluoroacetamide. The crude compound of formula II containing about 25w% trifluoroacetamide (7.0 g), (1S,2S) - (+) -1, 2-cyclohexanediamine (0.40 g, 0.4 eq.) and methanol (65 mL) was added to the bottle. The mixture was stirred and heated to 50 ℃ for 30h, cooled to less than 30 ℃ and stirred for 20 min, the solid was filtered off, washed with methanol (21 mL) and dried in vacuo to give 1.6 g of the compound of formula I in 97.1% purity in 37% yield.
EXAMPLE six
This example differs from example three in that other organic amines are used as bases.
The compound of formula II/acetonitrile concentrate (intermediate concentrate) is further concentrated to dryness by evaporation to give a crude compound of formula II (crude mixture) containing about 25w% trifluoroacetamide. The crude compound of formula II containing about 25w% trifluoroacetamide (7.0 g), (1S,2S) - (+) -N, N' -dimethylcyclohexane-1, 2-diamine (0.49 g, 3.4 mmol, 0.4 eq.) and methanol (65 mL) was added to the bottle. The mixture was stirred and heated to 50 ℃ for 30h, cooled to less than 30 ℃ and stirred for 20 min, the solid was filtered off, washed with methanol (21 mL), and dried in vacuo to give 1.5 g of the compound of formula I in 96.3% purity and 35% yield.
EXAMPLE seven
This example differs from example three in that other organic amines are used as bases.
The compound of formula II/acetonitrile concentrate (intermediate concentrate) is further concentrated by evaporation to dryness to give a crude compound of formula II (crude mixture) containing about 25w% trifluoroacetamide. The crude compound of formula II containing about 25% trifluoroacetamide (7.0 g), benzylamine (0.28 mL, 2.5 mmol, 0.2 eq.), and methanol (65 mL) was added to the bottle. The mixture was stirred and heated to 50 ℃ for 2 days. Cooled to less than 30 ℃ and stirred for 20 min, the solid was filtered off, washed with methanol (21 mL) and dried in vacuo to give 1.5 g of the compound of formula I in 94.8% purity and 35% yield.
Example eight
2-chloroadenine (compound of formula III 8.6 g,50.6 mmol,1.0 eq.), compound of formula IV (25.5 g,1.0 eq.), acetonitrile (51 mL) and BSTFA (26.8 mL,2.0 eq.) were added to the bottle under nitrogen (g). The mixture was stirred, TfOH (0.22 mL,0.05 eq.) was added, and heated to reflux (about 81 ℃) until the mixture was almost clear (about 2 h).
Cooled to less than 30 ℃ and water (4ml,4.4 eq.) is added dropwise at a controlled temperature below 35 ℃. The mixture was stirred for one hour. Adding 40% of K 2 HPO 4 aq. solution (51 mL), stirred for 40 min. The middle layer (acetonitrile solution) was separated.
Toluene (150 mL) was added to the prepared acetonitrile solution of the compound of formula II. The mixture was concentrated in vacuo at 45 ℃ until concentrated to about 161.0 g (about 138 mL of toluene). The compound of formula II/toluene concentrate containing about 8 w% trifluoroacetamide was added to methanol (69 mL) and DMAP (7.41 g) in a bottle, stirred and heated to 50 ℃ for 2 days. The mixture was cooled to less than 30 ℃. The solid was washed by filtration with methanol (35 mL) and dried under vacuum to give 12g of the compound of formula I in 97.9% purity and 47% yield.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (14)
1. An improved process for preparing a clofarabine intermediate of formula I, which is characterized by comprising the step of selective partial deprotection reaction,
the step of selective partial deprotection is a step of preparing a compound having formula I using a compound having formula II,
the method comprises the following substeps:
s1, preparing a mixture containing a compound with a formula II, wherein the mixture contains a certain amount of trifluoroacetamide;
s2, carrying out partial deprotection and isomerization reaction on the mixture in methanol, ethanol or a mixture of methanol and acetonitrile or toluene under the condition that organic amine is used as alkali, and filtering out a solid;
and S3, washing with methanol, and drying in vacuum to obtain the compound shown in the formula I.
2. The improved process for the preparation of clofarabine intermediates of formula i as claimed in claim 1, wherein the step of preparing the mixture containing the compound of formula ii in step S1 comprises a silicidation/glycosylation sub-step; wherein the silicification/glycosylation substep is performed using a compound of formula III
And compounds having formula IV
Substeps of preparing a mixture of compounds having formula ii.
3. An improved process for the preparation of clofarabine intermediates of formula i according to claim 2, wherein the silicidation/glycosylation reaction substeps are as follows:
s11, respectively adding a compound with a formula III, a compound with a formula IV, acetonitrile, N, O-bis (trimethylsilyl) trifluoroacetamide into a bottle under nitrogen, stirring the mixture, adding trifluoromethanesulfonic acid, and heating and refluxing until the glycosylation reaction is completed;
s12, dropwise adding water into the mixture obtained in the step S11, cooling, and adding 15% -40% of K 2 HPO 4 .3H 2 O, stirring to obtain an acetonitrile solution;
s13, stirring and filtering the acetonitrile solution obtained in the step S12, and evaporating in vacuum to obtain an intermediate concentrated solution, wherein the intermediate concentrated solution contains the compound with the formula II and acetonitrile.
4. The improved process for the preparation of clofarabine intermediates of formula i as claimed in claim 3, wherein the intermediate concentrate obtained in S13 is used in the reaction of step S2.
5. The improved process for preparing clofarabine intermediates of formula i as claimed in claim 4, wherein the step of subjecting the intermediate concentrate obtained in S13 to the reaction of step S2 comprises the steps of:
adding the intermediate concentrated solution into methanol and 4-dimethylaminopyridine, stirring and heating to a certain temperature for a certain time, cooling to a certain temperature, stirring for a certain time, and filtering to obtain a solid.
6. The improved process for the preparation of clofarabine intermediates of formula i as claimed in claim 3, wherein the intermediate concentrate obtained in S13 is dried by evaporation again to obtain a crude solid mixture comprising 25w% of trifluoroacetamide; the crude solid mixture was then used in the reaction of step S2.
7. The improved process for the preparation of clofarabine intermediates of formula i as claimed in claim 6, wherein the use of the crude solid mixture in the reaction of step S2 comprises the steps of:
adding the crude solid mixture, 4-dimethylaminopyridine, acetonitrile, methanol and toluene into a bottle, stirring the mixture, heating to a certain temperature for a certain time, cooling to a certain time, stirring for a certain time, and filtering to obtain a solid.
8. The improved process for the preparation of the clofarabine intermediate of formula i as claimed in claim 3, wherein the intermediate concentrate obtained in S13 is concentrated to dryness by re-evaporation to obtain a crude mixture comprising 25w% of trifluoroacetamide; the crude mixture was then used in the reaction of step S2.
9. The improved process for the preparation of the clofarabine intermediate of formula i as claimed in claim 8, wherein the use of the crude mixture of formula i in the reaction of step S2 comprises the steps of:
adding the crude mixture, 4-dimethylaminopyridine and ethanol to a flask, stirring and heating the mixture under reflux for a period of time, cooling the mixture to a temperature and stirring for a period of time, and filtering off the solid.
10. The improved process for the preparation of the clofarabine intermediate of formula i in claim 8, wherein the step of subjecting the crude mixture of formula i to the reaction of step S2 comprises the steps of:
adding the crude mixture, the base component and methanol to a bottle, stirring and heating the mixture to a certain temperature for a certain time, cooling to a certain temperature and stirring for a certain time, and filtering out the solid.
11. The improved process for the preparation of clofarabine intermediates of formula i as claimed in claim 10, wherein the base component is one of 2-amino-2-methyl-1-propanol, (1S,2S) - (+) -1, 2-cyclohexanediamine, (1S,2S) - (+) -N, N' -dimethylcyclohexane-1, 2-diamine and benzylamine.
12. The improved process for the preparation of clofarabine intermediates of formula i as claimed in claim 1 wherein the mixture of S1 containing the compound of formula ii is prepared by adding an acid additive to the neat compound of formula ii.
13. The improved process for the preparation of clofarabine intermediate of formula i as claimed in claim 12, wherein the acid additive is one of trifluoroacetamide, acetic acid, maleic acid, 4-nitrobenzoic acid, citric acid, formic acid, benzoic acid and succinic acid.
14. The improved process for the preparation of the intermediate of clofarabine of formula i in claim 13, wherein when the acid additive is trifluoroacetamide, the ratio of the amount of trifluoroacetamide to the amount of the neat compound of formula ii in a mixture comprising a compound of formula ii is greater than 0.5%.
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| EP2937420A1 (en) * | 2014-04-23 | 2015-10-28 | Synbias Pharma AG | Method for the synthesis of clofarabine |
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