CN109776639B - Synthetic method of arabinoside compound impurity - Google Patents
Synthetic method of arabinoside compound impurity Download PDFInfo
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- CN109776639B CN109776639B CN201910163405.XA CN201910163405A CN109776639B CN 109776639 B CN109776639 B CN 109776639B CN 201910163405 A CN201910163405 A CN 201910163405A CN 109776639 B CN109776639 B CN 109776639B
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Abstract
The invention provides a method for synthesizing an arabinoside compound impurity, which takes a 2',3',5' -trihydroxy protected arabinoside compound as a raw material and carries out deprotection under the action of phenylhydrazine, acetic acid and ammonium bicarbonate.
Description
Technical Field
The invention relates to an arabinoside compound, in particular to a method for synthesizing an arabinoside compound impurity, belonging to the technical field of medicine synthesis.
Background
The arabinoside compounds have excellent physiological and pharmacological activities, and are widely used as anticancer and antiviral drugs (such as fludarabine, flufarabine, clofarabine, nelarabine and the like in the following formulas) in clinic. Therefore, the synthesis of such compounds is of great interest to pharmaceutical workers.
The main difference between nucleoside and arabinoside is that the configuration of 2' -hydroxyl of arabinosyl is different, the 2' -hydroxyl of nucleoside is in alpha type, the 2' -hydroxyl of arabinoside is in beta type, nucleoside is a bulk chemical which is cheap and easy to obtain, and arabinoside is expensive; therefore, in the synthesis of the arabinoside drugs, nucleosides are generally adopted as starting materials, and 2' -hydroxyl is converted from alpha type to beta type through a series of chemical changes. The conversion of the configuration of the 2' -hydroxyl on arabinose is a key step in the synthesis of the compounds. Because nucleosides have three adjacent hydroxyl groups, the 2' -hydroxyl group cannot be directly converted from the alpha-type to the beta-type by reaction in general, and the other two hydroxyl groups need to be protected and then subjected to a series of chemical reactions to perform configuration transformation (as shown in the following formula).
2-hydroxy configuration conversion process
Therefore, in the 2-hydroxyl configuration conversion process, the selective removal of the 2' -acetyl group is a necessary step for configuration conversion. In the 2' hydroxyl deprotection process, three hydroxyls, particularly the hydroxyls at the 2' and 3' positions, have no good selectivity, the situation that the hydroxyls at the 2' and 3' positions are protected and removed simultaneously is easy to occur, and the serious adverse effect can be caused on the quality research of the bulk drugs because the hydroxyls are close to the structure of a target compound and have similar chemical properties. Therefore, it is an important research topic to control the generation of the key impurities and the influence of derivatives on the product quality. Due to the poor selectivity of the deprotection process, the key impurity cannot be obtained by conventional synthesis means. In the prior art, 2' and 3' hydroxyl deprotection products with higher purity are usually obtained from byproducts generated in the selective removal process of 2' acetyl through liquid-mass separation for many times.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide a synthesis method of an arabinoside compound impurity (formula II), which is simple and easy to obtain in operation, can be synthesized in a large amount, does not need a complicated liquid preparation process, and lays a good foundation for the quality research of arabinoside medicines.
The purpose of the invention is realized as follows:
a synthetic method of an arabinoside compound impurity (formula II) takes a 2',3',5 '-trihydroxy protected arabinoside compound (formula I) as a substrate (raw material), and deprotection is carried out under the action of phenylhydrazine, acetic acid and ammonium bicarbonate to generate a 5' -hydroxyl protected arabinoside compound (formula II).
The synthetic route of the impurity (formula II) of the arabinoside compound is as follows:
wherein the content of the first and second substances,
x is selected from amino, hydroxyl, methoxy, fluorine, chlorine, bromine and hydrogen;
y is selected from amino, hydroxyl, fluorine, chlorine, bromine and hydrogen;
r is acetyl or benzyl.
In the experimental process, the compound of the formula I can be successfully deprotected by using a deprotection agent formed by phenylhydrazine, acetic acid and ammonium bicarbonate to produce the compound of the formula II, but the dosage proportion of the compound of the formula I, phenylhydrazine, acetic acid and ammonium bicarbonate has very obvious influence on the reaction selectivity, and once the control is not good, a large amount of the compound of the formula III (the existing deprotection agent mainly generates the compound of the formula III) and the compound of the formula IV are easy to appear. After extensive experiments and repeated researches, the inventors found that the substrate (formula I): phenylhydrazine: acetic acid: the molar ratio of ammonium bicarbonate is 1: 3-5: 1-2: 5-10 can effectively reduce the generation amount of the compound shown in the formula III and the compound shown in the formula IV, and simultaneously improve the yield and purity of the reaction.
Further, in a preferred embodiment of the present invention, the solvent used in the present invention includes pyridine or a solution of DMF, DMA, dichloromethane with a pyridine content of 20% to 100%. Furthermore, the dosage of the solvent is 10-20 ml/g substrate.
Further, in a preferred embodiment of the present invention, the reaction temperature is 10 to 25 ℃.
Compared with the prior art, the invention has the beneficial effects that:
in the prior art, 2',3',5' -trihydroxy protected arabinoside compounds are subjected to a hydroxyl deprotection process, and deprotection products mainly comprise compounds in a formula III. As in US5602246A, the ratio of compounds of formula I, formula II, formula III and formula IV at the end of the reaction is approximately 10:15:55:20, and conventional recrystallization methods cannot be used for purification. Due to low content, if the compound of the formula II with high purity is obtained, multiple liquid-mass separation is needed, and the yield is not higher than 5%. In the method provided by the invention, the deprotection product is mainly the compound shown in the formula II. At the end of the reaction, the purity of the compound of formula II is more than 75%, the purity of the compounds of formula I, formula III and formula IV is about 5%, 10% and 5%, respectively, and the compound of formula II with the purity higher than 95% can be obtained by a suitable recrystallization method, and the yield can reach about 50%. The method changes the deprotection selectivity of the compounds, and improves the yield by more than 10 times compared with the prior means.
In general, the invention provides a method for synthesizing an arabinoside compound impurity, which takes a 2',3',5' -trihydroxy protected arabinoside compound as a raw material and carries out deprotection under the action of phenylhydrazine, acetic acid and ammonium bicarbonate.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
12g of 2-amino-6-methoxy-9 β -D- (2',3',5' -trioxobenzyl-arabinofuranosyl) purine and 180ml of a 50% pyridine-containing dichloromethane solution were charged into a reaction flask at 10 ℃ and stirred, then 11g of phenylhydrazine, 3.0g of acetic acid and 19.7g of ammonium bicarbonate were added thereto, and the reaction was stirred for 18 hours (control: 76.5% purity by HPLC, 10.3% and 5.2% for the compounds of the formulae III and IV, respectively). 12ml of acetone are added and stirring is continued for 2 hours. Concentrated to dryness under reduced pressure, added with 240ml of toluene, stirred and dispersed at room temperature, and filtered. The filter cake was added to 100ml of water, slurried with stirring at room temperature for 2 hours, and filtered. The filter cake was then recrystallized sequentially from a 1:1 solution of water/ethanol, and a 1:1 solution of water/acetone to give 5.5g of the desired product (2.1% for compound III and 0.3% for compound IV) with an HPLC purity of 96.6%.
1HNMR(DMSO-d6)δ2.02(s,3H,CH3),2.10(s,3H,CH3),4.1-4.33(m,3H),5.24(dd,1H,H-3’),5.72(d,1H,H-1’),5.91(d,1H),7.85(bs,2H,NH2),8.21(s,1H,H-8)；13CNMR(DMSO-d6)20.22,20.62,63.47,70.92,72.27,79.33,87.35,117.81,141.05,150.55,158.24,158.39,169.8ppm；MS(m/z)340(M+H)+
Example 2
10g of 2-hydroxy-6-amino-9 beta-D- (2',3',5' -trioxyacetyl-arabinofuranosyl) purine and 100ml of pyridine were put into a reaction flask at 25 ℃ and stirred to dissolve, 11.5g of phenylhydrazine, 2.9g of acetic acid and 19.1g of ammonium hydrogencarbonate were added thereto, and the reaction was stirred for 24 hours (control: HPLC purity 75.9%, compounds of formula III and formula IV were 11.1% and 4.1%, respectively). 20ml of acetone are added and stirring is continued for 2 hours. Concentrating under reduced pressure to dryness, adding 100ml of toluene, stirring at room temperature for dispersion, and filtering. The filter cake was added to 100ml of water, slurried with stirring at room temperature for 2 hours, and filtered. The filter cake was then recrystallized sequentially from ethanol and 1:1 aqueous/ethanol solution to yield 4.9g of the desired product (2.9% for compound III, 0.8% for compound IV) with an HPLC purity of 95.0%.1H NMR(DMSO-d6)δ2.00(s,3H,CH3),2.13(s,3H,CH3),4.3-4.45(m,3H),4.94(ρ,1H,OH),5.24(dd,1H,H-3’),5.72(d,1H,H-1’),5.99(d,1H,OH),7.93(bs,2H,NH2),8.28(s,1H,H-8)；13CNMR(DMSO-d6)20.41,20.62,63.31,70.88,72.22,79.37,87.30,118.11,140.15,150.68,158.01,158.55,169.85ppm；MS(m/z)326(M+H)+
Example 3
10g of 2-hydroxy-6-hydroxy-9 β -D- (2',3',5' -trioxobenzyl-arabinofuranosyl) purine and 200ml of a 20% pyridine-containing DMF solution were charged into a reaction flask at 20 ℃ and stirred, followed by addition of 13.0g of phenylhydrazine, 2.0g of acetic acid and 13.2g of ammonium hydrogencarbonate and stirring for 24 hours (control: 76.7% purity by HPLC, 11.0% and 5.4% for the compounds of the formulae III and IV, respectively). 10ml of acetone are added and stirring is continued for 2 hours. Concentrated to dryness under reduced pressure, added with 200ml of toluene, stirred and dispersed at room temperature, and filtered. The filter cake was added to 100ml of water, slurried with stirring at room temperature for 2 hours, and filtered. The filter cake was then recrystallized sequentially from a 1:1 solution of water/ethanol, and a 1:1 solution of water/acetone to give 4.2g of the desired product (2.3% for compound III and 0.7% for compound IV) with an HPLC purity of 96.0%.1HNMR(DMSO-d6)δ2.01(s,3H,CH3),2.19(s,3H,CH3),4.32-4.55(m,3H),5.01(ρ,1H,OH),5.27(dd,1H,H-3’),5.88(d,1H,H-1’),6.6-6.92(bs,2H,OH),8.33(s,1H,H-8)；13C NMR(DMSO-d6)20.42,20.58,63.44,70.82,72.28,79.31,87.37118.15140.21,150.66,158.07,158.49,169.75ppm；MS(m/z)327(M+H)+
Example 4
10g of 2-fluoro-6-amino-9 β -D- (2',3',5' -trioxobenzyl-arabinofuranosyl) purine and 120ml of a 50% pyridine-containing DMF solution were charged into a reaction flask at 20 ℃ and stirred to dissolve, 13.6g of phenylhydrazine, 2.5g of acetic acid and 16.5g of ammonium hydrogencarbonate were added thereto and the reaction was stirred for 18 hours (control: HPLC purity 75.2%, compounds of formula III and formula IV were 10.7% and 4.5%, respectively). 10ml of acetone are added and stirring is continued for 2 hours. Concentrated to dryness under reduced pressure, added with 200ml of toluene, stirred and dispersed at room temperature, and filtered. The filter cake was added to 100ml of water, slurried with stirring at room temperature for 2 hours, and filtered. The filter cake was then recrystallized sequentially from 1:1 water/ethanol and 1:1 water/acetone solutions to give 4.4g of the desired product (1.8% for compound of formula III, 0.4% for compound of formula IV) with an HPLC purity of 97.2%.1HNMR(DMSO-d6)δ2.04(s,3H,CH3),2.12(s,3H,CH3),4.2-4.4(m,3H,H-4’,2H-5’),4.94(ρ,1H,OH),5.26(dd,1H,H-3’),5.82(d,1H,H-1’),7.9(bs,2H,NH2),8.35(s,1H,H-8)；13C NMR(DMSO-d6)20.47,20.68,63.21,70.73,72.25,79.37,87.39,117.61,140.07,150.63,158.17,158.56,169.60,170.06ppm；MS(m/z)328(M+H)+
Example 5
11g of 2-chloro-6-fluoro-9 β -D- (2',3',5' -trioxobenzyl-arabinofuranosyl) purine and 165ml of a DMA solution containing 50% pyridine were put into a reaction flask at 15 ℃ and stirred, 11.2g of phenylhydrazine, 2.5g of acetic acid and 16.5g of ammonium hydrogencarbonate were added thereto and the reaction was stirred for 24 hours (control: HPLC purity 75.8%, and compounds of formula III and formula IV were 9.8% and 5.5%, respectively). 11ml of acetone are added and stirring is continued for 2 hours. Concentrating under reduced pressure to dryness, adding 220ml toluene, stirring for dispersion, and filtering. The filter cake was added to 100ml of water, slurried with stirring at room temperature for 2 hours, and filtered. The filter cake was then recrystallized sequentially from ethanol, 1:1 aqueous/acetone to yield 5.0g of the desired product (2.5% for compound III, 0.6% for compound IV) with an HPLC purity of 96.1%.1H NMR(DMSO-d6)δ2.01(s,3H),2.16(s,3H),4.1-4.36(m,2H),5.83(τ,1H),6.22(τ,1H),6.50(s,1H),8.0(bs,2H),8.38(s,1H)；13CNMR(DMSO-d6)20.15,20.28,62.07,68.46,78.72,84.06,85.03,117.61,140.01,150.15,157.75,158.51ppm；MS(m/z)347(M+H)+
In summary, the method for synthesizing the key impurities of the arabinoside compounds provided by the embodiment takes the 2',3',5' -trihydroxy protected arabinoside compounds as raw materials, and carries out deprotection under the action of phenylhydrazine, acetic acid and ammonium bicarbonate.
While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Claims (1)
1. A synthetic method of an arabinoside compound impurity (formula II) takes a 2',3',5 '-trihydroxy protected arabinoside compound (formula I) as a substrate, and deprotection is carried out under the action of phenylhydrazine, acetic acid and ammonium bicarbonate to generate a 5' -hydroxyl protected arabinoside compound (formula II); the synthetic route is as follows:
wherein the content of the first and second substances,
x is selected from amino, hydroxyl, methoxy, fluorine, chlorine, bromine and hydrogen;
y is selected from amino, hydroxyl, fluorine, chlorine, bromine and hydrogen;
r is acetyl or benzyl;
the substrate (formula I): phenylhydrazine: acetic acid: the molar ratio of ammonium bicarbonate is 1: 3-5: 1-2: 5-10; the solvent used in the reaction is pyridine or DMF, DMA and dichloromethane solution with 20-100% pyridine content; the dosage of the solvent is 10-20 ml/g of substrate; the reaction temperature is 10-25 ℃.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5602246A (en) * | 1992-11-25 | 1997-02-11 | Schering Aktiengesellschaft | Process for the preparation of fludarabine or fludarabine phosphate from guanosine |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5602246A (en) * | 1992-11-25 | 1997-02-11 | Schering Aktiengesellschaft | Process for the preparation of fludarabine or fludarabine phosphate from guanosine |
Non-Patent Citations (4)
| Title |
|---|
| Regioselective O2",O3"-Deacetylation of Peracetylated Ribonucleosides by Using Tetra-n-butylammonium Fluoride;Babu Kumar, Arun et al.;《European Journal of Organic Chemistry》;20141231;第2014卷(第17期);第3551-3555页 * |
| Selective deacylation of peracylated ribonucleosides;Rigoli, Jared W et al.;《Tetrahedron Letters》;20090203;第50卷(第15期);第1751-1753页 * |
| Selective Removal of the 2"- and 3"-O-Acyl Groups from 2",3",5"-Tri-O-acylribonucleoside Derivatives with Lithium Trifluoroethoxide;Nowak, Ireneusz et al.;《Journal of Organic Chemistry》;20060317;第71卷(第8期);第3077-3081页 * |
| Synthesis of capped oligoribonucleotides by use of protected 7-methylguanosine 5"-diphosphate derivatives;Sekine, Mitsuo et al.;《Journal of the Chemical Society, Perkin Transactions 1》;19891231;第969-978页 * |
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