CN111377982B - Method for synthesizing decitabine key intermediate by solid acid catalysis - Google Patents

Method for synthesizing decitabine key intermediate by solid acid catalysis Download PDF

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CN111377982B
CN111377982B CN201811648511.9A CN201811648511A CN111377982B CN 111377982 B CN111377982 B CN 111377982B CN 201811648511 A CN201811648511 A CN 201811648511A CN 111377982 B CN111377982 B CN 111377982B
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白文钦
郑艺
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Lunan Pharmaceutical Group Corp
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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and relates to a method for synthesizing a decitabine key intermediate (formula II) by solid acid catalysis, which uses silicon dioxide loaded tin tetrachloride (SnCl) 4 ) The glycosylation reaction is carried out for the catalyst. The invention not only solves the problem of complex post-treatment of the liquid acid catalyst, but also can effectively improve the content of the beta-configuration intermediate.

Description

Method for synthesizing decitabine key intermediate by solid acid catalysis
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for synthesizing a decitabine key intermediate by solid acid catalysis.
Background
Decistabine (formula I) is known as 4-amino-1- (2-deoxy-beta-D-erythro-ribofuranose) -1,3, 5-triazin-2 (1H) -one, and is used for treating myelodysplastic disorders. Developed by Super Gen corporation in the united states and marketed in 2006. Decitabine has unique methylation transferase inhibitor effect, and is converted from 2 '-deoxycytidine cytokinin into 5' -deoxycytidine cytokinin in vivo, and is doped into DNA under the action of DNA polymerase to inhibit synthesis and methylation of DNA, so that the purpose of inhibiting tumor cell growth is achieved.
Figure GDA0004172683310000011
There are many routes for the synthesis of decitabine, which are largely divided into three methods.
The first is the deoxidization method of azacitidine, which takes azacitidine as raw material, firstly protects 3' and 5' hydroxyl, then removes 2' hydroxyl, and then removes 3' and 5' hydroxyl protecting groups to generate decitabine. The route is as follows:
Figure GDA0004172683310000012
TiPSCh 1, 3-dichloro-1, 3-tetraisopropyl disiloxane; TTMSS: tris- (trimethylsilyl) silane; ALBN: azobisisobutyronitrile.
The second method, namely the earliest synthesis of decitabine by Pliml and Storm in 1964, is the deprotection of protected 2-deoxy-D-ribose after cyclization with urea to prepare decitabine. The route is as follows:
Figure GDA0004172683310000021
the method uses expensive silver isocyanate, the ring is closed after glycosylation, the synthetic route is longer, the isomer is difficult to separate, the operation condition is harsh, and less operation condition is adopted.
The third is the 5-azacytosine direct glycosylation method: the 5-azacytosine is reacted with Hexamethyldisilazane (HMDS) to produce the silicon-based protector. Then directly condensing with protected 2-deoxy-D-ribose, removing protecting group, and separating isomer to obtain the decitabine. The method has the advantages of easily available raw materials and simple operation, is a main method used in the current industrial production, and is also a research hotspot. The route is as follows:
Figure GDA0004172683310000022
different synthetic routes are formed according to the difference of the leaving group L at the 1 position of the 2-deoxy-d-ribose and the difference of the hydroxyl protecting groups R at the 3,5 positions.
The synthesis of decitabine is disclosed in patents CN1018201278A, CN102010455A, CN103739636a, EP2050757, EP2048151, US2010249394, CN101560232a and WO2010129211, all of which were developed on the basis of method three. The glycosylation reaction mainly uses tin tetrachloride (SnCl 4 ) Inorganic or organic Lewis acid catalysis such as trimethylsilyl triflate (TMSOTF), the post-treatment process of the catalyst is complex, the yield is low, the product purity is low, and the catalyst can be used for subsequent reactions only by column chromatography. Furthermore, the β configuration in the glycosylation product is difficult to take an absolute advantage.
No catalyst is found in the prior art which can lead the glycosylation reaction to produce beta-configuration products in a high proportion, but in some documents (for example CN 108239128A), the beta/alpha ratio of the glycosylation reaction catalyzed by the triflic acid or the triflate can reach more than 2.5, but the beta/alpha ratio of the glycosylation reaction catalyzed by the tin tetrachloride is still about 1.
In summary, in order to solve the ratio and yield of β -configuration products, a new synthetic route is urgently required.
Disclosure of Invention
In order to solve the technical problems, the invention provides a method for synthesizing a decitabine key intermediate by solid acid catalysis. The invention adopts the solid acid catalyst to replace the traditional Lewis acid catalyst, and the solid acid catalyst can be removed by filtering after the reaction is finished, thereby greatly simplifying the post-treatment procedure and obviously improving the yield of the intermediate and the beta/alpha ratio.
The specific technical scheme of the invention is as follows:
a method for synthesizing a decitabine key intermediate by solid acid catalysis, wherein the intermediate is shown as a formula II, and the method comprises the following steps: under low temperature, in the presence of an organic solvent and a solid acid catalyst, carrying out glycosylation reaction on 5-acetyl-2- (acetylmethyl) -3-acetyl-2-deoxidization-D-ribose (formula III) and 2- { N- (trimethylsilyl) } amino-4- (trimethylsiloxy) -1,3, 5-triazine (formula IV) to obtain an intermediate II; the reaction formula is as follows:
Figure GDA0004172683310000031
the low temperature is-10 to 10 ℃; the solid acid is SnCl 4 /SiO 2 。
The organic solvent is one or more of dichloromethane, chloroform, ethyl acetate and toluene. Chloroform is preferred.
The molar ratio of the compound III to the compound IV is 1:1.1-1.3.
The molar ratio of the compound III to the solid acid catalyst is 1:0.3-0.5, wherein the molar amount of the solid acid catalyst is calculated by the molar amount of the supported acid.
The mass-volume ratio of the compound III to the organic solvent is 1:10-15 g/ml.
Filtering to remove solid acid after the reaction is finished, and then quenching the filtrate with alkali, wherein the alkali is organic alkali or inorganic alkali; the organic base is triethylamine or pyridine.
The inorganic base is Na 2 CO 3 ，NaHCO 3 One or more than two of NaOH and LiOH, preferably NaHCO 3 。
In addition, tin tetrachloride supported by silica gel with different mesh numbers or particle sizes can be used for catalyzing glycosylation reaction smoothly, but the ratio of beta/alpha configuration in the products is obviously different. The invention further screens the particle size specificationThe SiO is 2 The grain diameter is between 200 and 140 mu m, between 130 and 80 mu m, and between 70 and 30 mu m.
In a preferred embodiment, TLC detects completion of the reaction. Filtering, washing the filtrate with alkali or alkali water solution and saturated saline respectively, and concentrating the organic phase under reduced pressure to obtain the decitabine key intermediate.
The invention has the advantages that:
1. the invention improves the selectivity of glycosylation reaction, the beta/alpha proportion configuration of the intermediate can reach more than 7.7, and the yield is more than 80%.
2. The silicon dioxide supported stannic chloride is used for replacing the traditional Lewis acid catalyst, so that the problem of easy emulsification during post-treatment is avoided, the treatment is simple, and the method is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The purity of the decitabine key intermediate is determined by an HPLC method, and the HPLC conditions are as follows: normalization method, chromatographic column C 18 Columns (4.6 mm. Times.250 mm,5 μm); mobile phase: methanol: acetonitrile: water = 40:35:25, a step of selecting a specific type of material; the detection wavelength is 240nm; the flow rate was 1.0ml/min.
The material source used in the invention is obtained by purchasing in the market or preparing by the method disclosed in the prior art. Intermediates III and IV as used in the present invention are commercially available or can be prepared using prior art techniques, but do not limit the scope of the invention.
Example 1 preparation of intermediate III
Figure GDA0004172683310000041
VI (200 g) and freshly distilled pyridine (600 ml) were placed in a 250ml three-necked flask equipped with mechanical stirring. Introducing nitrogen, cooling the reaction liquid to 0-5 ℃, slowly dropwise adding acetic anhydride (471 g), after the dropwise adding is finished, heating the reaction liquid to room temperature for reaction for 25h, and detecting the completion of the reaction by TLC (developing agent: ethyl acetate). 1000ml of chloroform was added to the reaction mixture, the pH of the reaction mixture was adjusted to 7 to 8 with saturated sodium hydrogencarbonate, and the mixture was separated. The organic phase is washed by 1000ml of 1N hydrochloric acid and 1000ml of 5% sodium bicarbonate water solution respectively, the organic phase is separated out, dried by anhydrous sodium sulfate and evaporated to dryness under reduced pressure, 280.5g of oily matter III is obtained; and (5) standby.
Example 2 preparation of intermediate IV
Figure GDA0004172683310000051
To a 100ml three-necked flask, VII (150 g), HMDS (600 ml), ammonium sulfate (2.5 g) were successively added, and the mixture was heated to reflux, and after the reaction solution was dissolved, the reflux reaction was continued for 4 hours, and was evaporated to dryness under reduced pressure. 310.5g of white solid IV is obtained for later use.
EXAMPLE 3 solid acid catalyst SnCl 4 /SiO 2 Preparation
Weighing 10g of SiO with the grain diameter of 200-140 mu m 2 Soaking in dilute nitric acid for 24h, filtering, washing with deionized water to neutrality, and oven drying. To be dried SiO 2 、15gSnCl 4 Adding the mixture into 200ml of ethanol, heating to reflux, reacting for 4 hours at a constant temperature, and evaporating to dryness under reduced pressure to obtain 26g of solid catalyst. And (5) standby.
Preparation of Decitabine key intermediate (V)
20g (0.077 mol) of intermediate III was taken as an oil, 21.6g (0.085 mol) of intermediate IV was dissolved in 200ml of methylene chloride, the reaction mixture was cooled to-10℃and 13.3g of SnCl prepared as described above was added 4 /SiO 2 (0.031 mole) catalyst. The reaction mixture was warmed to room temperature, stirred for 5h, and tlc was complete. The mixture was filtered, the pH was adjusted to 7 to 8 with a 5% aqueous sodium hydroxide solution, and the organic phase was separated and washed with 300ml of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a reddish brown foamy solid in 86.5% yield with an HPLC purity (α+β) of 97.6% and a HPLC assay of β/α=7.8.
EXAMPLE 4 solid acid catalysisChemical agent SnCl 4 /SiO 2 Preparation
Weighing 10g of SiO with the particle size of 130-80 mu m 2 Soaking in dilute nitric acid for 24h, filtering, washing with deionized water to neutrality, and oven drying. To be dried SiO 2 、15gSnCl 4 Adding the mixture into 200ml of ethanol, heating to reflux, reacting for 4 hours at a constant temperature, and evaporating to dryness under reduced pressure to obtain 26g of solid catalyst. And (5) standby.
Preparation of Decitabine key intermediate (V)
20g (0.077 mol) of intermediate III was taken, 21.6g (0.092 mol) of intermediate IV was dissolved in 220ml of chloroform, the reaction mixture was cooled to 5℃and 10g of SnCl prepared as described above was added 4 /SiO 2 (0.023 mol) catalyst. The reaction mixture was warmed to room temperature, stirred for 5h, and tlc was complete. The mixture was filtered, the pH was adjusted to 7 to 8 with triethylamine, and the organic phase was separated and washed with 300ml of a saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a reddish brown foamy solid in 89.5% yield with an HPLC purity (α+β) of 99.5% and a HPLC assay of β/α=8.1.
EXAMPLE 5 solid acid catalyst SnCl 4 /SiO 2 Preparation
Weighing 10g of SiO with the particle size of 130-80 mu m 2 Soaking in dilute nitric acid for 24h, filtering, washing with deionized water to neutrality, and oven drying. To be dried SiO 2 、15gSnCl 4 Adding the mixture into 200ml of ethanol, heating to reflux, reacting for 4 hours at a constant temperature, and evaporating to dryness under reduced pressure to obtain 26g of solid catalyst. And (5) standby.
Preparation of Decitabine key intermediate (V)
20g (0.077 mol) of intermediate III was taken as an oil, 25.6g (0.1 mol) (1.3) of intermediate IV was dissolved in 240ml of ethyl acetate, the reaction mixture was cooled to 0℃and 16.67g of SnCl prepared as described above was added 4 SiO2 (0.038 mol) (0.5) catalyst. The reaction mixture was warmed to room temperature, stirred for 5h, and tlc was complete. The mixture was filtered, the pH was adjusted to 7 to 8 with a saturated aqueous sodium hydrogencarbonate solution, and the organic phase was separated and washed with 300ml of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a reddish brown foamy solid with a yield of 88.8%HPLC purity (α+β) was 99.3%, and HPLC method determines β/α=8.1.
EXAMPLE 6 solid acid catalyst SnCl 4 /SiO 2 Preparation
Weighing 10g of SiO with the particle size of 130-80 mu m 2 Soaking in dilute nitric acid for 24h, filtering, washing with deionized water to neutrality, and oven drying. To be dried SiO 2 、15g SnCl 4 Adding the mixture into 200ml of ethanol, heating to reflux, reacting for 4 hours at a constant temperature, and evaporating to dryness under reduced pressure to obtain 26g of solid catalyst. And (5) standby.
Preparation of Decitabine key intermediate (V)
20g (0.077 mol) of intermediate III was taken, 23.6g (0.092 mol) of intermediate IV was dissolved in 280ml of chloroform, the reaction mixture was cooled to 5℃and 13.3g of SnCl prepared as described above was added 4 SiO2 (0.031 mol) catalyst. The reaction mixture was warmed to room temperature, stirred for 5h, and tlc was complete. The mixture was filtered, the pH was adjusted to 7 to 8 with a saturated aqueous sodium hydrogencarbonate solution, and the organic phase was separated and washed with 300ml of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a reddish brown foamy solid in 93.7% yield with an HPLC purity (α+β) of 99.6% and a HPLC assay of β/α=8.2.
EXAMPLE 7 solid acid catalyst SnCl 4 /SiO 2 Preparation
Weighing 10g of SiO with the particle size of 70-30 mu m 2 Soaking in dilute nitric acid for 24h, filtering, washing with deionized water to neutrality, and oven drying. To be dried SiO 2 、15gSnCl 4 Adding the mixture into 200ml of ethanol, heating to reflux, reacting for 4 hours at a constant temperature, and evaporating to dryness under reduced pressure to obtain 26g of solid catalyst. And (5) standby.
Preparation of Decitabine key intermediate (V)
20g (0.077 mol) of intermediate III was taken, 25.6g (0.1 mol) of intermediate IV was dissolved in 260ml of chloroform, the reaction mixture was cooled to 10℃and 13.3g of SnCl prepared as described above was added 4 /SiO 2 (0.031 mole) catalyst. The reaction mixture was warmed to room temperature, stirred for 5h, and tlc was complete. Filtering, adjusting pH to 7-8 with saturated sodium bicarbonate aqueous solution, separating out organic phase, and saturating with 300mlAnd washing the organic phase with an aqueous solution of a salt. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a reddish brown foamy solid in 88.4% yield with an HPLC purity (α+β) of 99.7% and a HPLC assay of β/α=8.1.
EXAMPLE 8 solid acid catalyst SnCl 4 /SiO 2 Preparation
Weighing 10g of SiO with the particle size of 250-220 mu m 2 Soaking in dilute nitric acid for 24h, filtering, washing with deionized water to neutrality, and oven drying. To be dried SiO 2 、15gSnCl 4 Adding the mixture into 200ml of ethanol, heating to reflux, reacting for 4 hours at a constant temperature, and evaporating to dryness under reduced pressure to obtain 26g of solid catalyst. And (5) standby.
Preparation of Decitabine key intermediate (V)
20g (0.077 mol) of intermediate III was taken, 25.6g (0.1 mol) of intermediate IV was dissolved in 260ml of chloroform, the reaction mixture was cooled to 10℃and 13.3g of SnCl prepared as described above was added 4 /SiO 2 (0.031 mole) catalyst. The reaction mixture was warmed to room temperature, stirred for 5h, and tlc was complete. The mixture was filtered, the pH was adjusted to 7 to 8 with a saturated aqueous sodium hydrogencarbonate solution, and the organic phase was separated and washed with 300ml of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a reddish brown foamy solid in 89.7% yield with an HPLC purity (α+β) of 98.6%, and β/α=7.8 as determined by HPLC.
EXAMPLE 9 solid acid catalyst SnCl 4 /SiO 2 Preparation
Weighing 10g of SiO with the particle size of 130-80 mu m 2 Soaking in dilute nitric acid for 24h, filtering, washing with deionized water to neutrality, and oven drying. To be dried SiO 2 、15gSnCl 4 Adding the mixture into 200ml of ethanol, heating to reflux, reacting for 4 hours at a constant temperature, and evaporating to dryness under reduced pressure to obtain 26g of solid catalyst. And (5) standby.
Preparation of Decitabine key intermediate (V)
20g (0.077 mol) of intermediate III was taken as an oil, 25.6g (0.1 mol) of intermediate IV was dissolved in 260ml of methylene chloride, the reaction mixture was cooled to 10℃and 19.8g of SnCl was added thereto 4 /SiO 2 (0.046 mol) catalyst. Heating the reaction solutionThe reaction was stirred for 5h to room temperature and was completed by tlc. The mixture was filtered, the pH was adjusted to 7 to 8 with a saturated aqueous sodium hydrogencarbonate solution, and the organic phase was separated and washed with 300ml of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a reddish brown foamy solid in 92.9% yield with an HPLC purity (α+β) of 99.0% and a HPLC assay of β/α=8.2.
EXAMPLE 10 solid acid catalyst SnCl 4 /SiO 2 Preparation
Weighing 10g of SiO with the particle size of 130-80 mu m 2 Soaking in dilute nitric acid for 24h, filtering, washing with deionized water to neutrality, and oven drying. To be dried SiO 2 、15gSnCl 4 Adding the mixture into 200ml of ethanol, heating to reflux, reacting for 4 hours at a constant temperature, and evaporating to dryness under reduced pressure to obtain 26g of solid catalyst. And (5) standby.
Preparation of Decitabine key intermediate (V)
20g (1, 0.077 mol) of intermediate III was taken as an oil, 25.6g (0.1 mol) of intermediate IV was dissolved in 260ml of toluene, the reaction mixture was cooled to 20℃and 13.3g of SnCl prepared as described above was added 4 /SiO 2 (0.031 mole) catalyst. The reaction mixture was warmed to room temperature, stirred for 5h, and tlc was complete. The mixture was filtered, the pH was adjusted to 7 to 8 with a saturated aqueous sodium hydrogencarbonate solution, and the organic phase was separated and washed with 300ml of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a reddish brown foamy solid in a yield of 84.9% and with an HPLC purity (α+β) of 96.8%, determined by HPLC method as β/α=7.8.
EXAMPLE 11 solid acid catalyst SnCl 4 /SiO 2 Preparation
Weighing 10g of SiO with the particle size of 30-20 mu m 2 Soaking in dilute nitric acid for 24h, filtering, washing with deionized water to neutrality, and oven drying. To be dried SiO 2 、15gSnCl 4 Adding the mixture into 200ml of ethanol, heating to reflux, reacting for 4 hours at a constant temperature, and evaporating to dryness under reduced pressure to obtain 26g of solid catalyst. And (5) standby.
Preparation of Decitabine key intermediate (V)
20g (1, 0.077 mol) of intermediate III was taken as an oil, 25.6g (0.1 mol) of intermediate IV was dissolved in 260ml of dichloroCooling the reaction solution to 20 ℃ in methane, and adding 13.3g of SnCl prepared by the method 4 /SiO 2 (0.031 mole) catalyst. The reaction mixture was warmed to room temperature, stirred for 5h, and tlc was complete. The mixture was filtered, relatively viscous, and the mixture was more strongly adsorbed, and the mixture was adjusted to pH 7 to 8 with a saturated aqueous sodium bicarbonate solution, and the organic phase was separated and washed with 300ml of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a reddish brown foamy solid in a yield of 74.3% and with an HPLC purity (α+β) of 98.8%, determined by HPLC method as β/α=8.1.

Claims (6)

1. A method for synthesizing a decitabine key intermediate by solid acid catalysis is shown as a formula II, and is characterized by comprising the following steps: under low temperature, in the presence of an organic solvent and a solid acid catalyst, carrying out glycosylation reaction on 5-acetyl-2- (acetylmethyl) -3-acetyl-2-deoxidization-D-ribose (formula III) and 2- { N- (trimethylsilyl) } amino-4- (trimethylsiloxy) -1,3, 5-triazine (formula IV) to obtain an intermediate II; the reaction formula is as follows:
Figure QLYQS_1
；
the low temperature is-10 to 10 ℃; the solid acid is SnCl 4 /SiO 2 ；
Wherein the SiO is 2 The particle size specification is 200 μm to 140 μm, or 130 μm to 80 μm, or 70 μm to 30 μm;
the molar ratio of the compound III to the compound IV is 1:1.1-1.3; the molar ratio of the compound III to the solid acid catalyst is 1:0.3-0.5, and the molar amount of the solid acid catalyst is calculated by the molar amount of the supported acid.
2. The method according to claim 1, wherein the organic solvent is one or a mixture of more than two of dichloromethane, chloroform, ethyl acetate and toluene.
3. The method according to claim 1, wherein the mass-to-volume ratio of the compound III to the organic solvent is 1:10-15 g/mL.
4. The method according to claim 1, wherein the filtrate is quenched with a base after removal of solid acids by filtration after completion of the reaction, the base being an organic or inorganic base.
5. The method according to claim 4, wherein the organic base is triethylamine or pyridine.
6. The method according to claim 4, wherein the inorganic base is Na 2 CO 3 ，NaHCO 3 One or more than two of NaOH and LiOH.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101560233A (en) * 2009-05-15 2009-10-21 上海清松制药有限公司 Preparation method of decitabine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101560233A (en) * 2009-05-15 2009-10-21 上海清松制药有限公司 Preparation method of decitabine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
地西他滨的合成研究;李谢等;化工时刊;第24卷(第11期);42-44 *
李宗磊. 地西他滨的合成研究.中国优秀硕士学位论文工程科技Ⅰ辑 .2010,B016-152. *

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