CN112209976A - Decitabine intermediate compound V - Google Patents

Decitabine intermediate compound V Download PDF

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CN112209976A
CN112209976A CN201910617371.7A CN201910617371A CN112209976A CN 112209976 A CN112209976 A CN 112209976A CN 201910617371 A CN201910617371 A CN 201910617371A CN 112209976 A CN112209976 A CN 112209976A
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decitabine
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张贵民
郑艺
白文钦
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Lunan Pharmaceutical Group Corp
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Abstract

The invention belongs to the technical field of chemical synthesis, and provides a decitabine intermediate compound; the preparation route takes the oxide of the 1-hydroxyl of the 2-deoxy-D-ribose as the raw material, respectively protects the 3-hydroxyl and the 5-hydroxyl, and the compound is obtained by further processing; the compound is used for further synthesizing decitabine, and has high stereoselectivity and good purity.

Description

Decitabine intermediate compound V
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a decitabine intermediate compound.
Background
Decitabine (decitabine) is chemically named 4-amino-1- (2-deoxy- β -D-erythro-ribofuranose) -1,3, 5-triazin-2 (1H) -one and has the following structure:
Figure BDA0002124387390000011
is mainly used for treating myelodysplastic diseases. Developed by Super Gen corporation of usa and marketed in 2006. Decitabine has unique effect of a methyltransferase inhibitor, 2 '-deoxycytidylic acid substances are converted into 5' -deoxycytidylic acid substances in vivo, and the substances are doped into DNA under the action of DNA polymerase to inhibit the synthesis and methylation of the DNA, so that the aim of inhibiting the growth of tumor cells is fulfilled.
Some methods of synthesis of decitabine have been reported in the literature. The synthetic route of decitabine reported by PISKALA is as follows: the dihydro-S-triazine protected by trimethylsilane and chlorodeoxyribose are condensed under the catalytic action of stannic chloride to obtain the product. The quaternary competition and the like report another synthesis route of decitabine, 2-deoxy-D-ribose is used as a raw material and reacts with acetic anhydride under the action of pyridine to obtain 1,3, 5-tri-D-acetyl-2-deoxy-D-ribose, the 1,3, 5-tri-D-acetyl-2-deoxy-D-ribose and 5-azacytosine activated by HMDS are catalyzed by trimethylsilyl trifluoromethanesulfonate to obtain a condensation product, and then aminolysis deprotection and methanol recrystallization are carried out to obtain the decitabine. None of these reports discloses how the final product, the two isomers, α, β (decitabine is the β form), is separated, while the separation of the two isomers, α, β is difficult, which makes decitabine expensive to produce.
In recent years, the development of nucleoside analogues with low toxicity, high antitumor and antiviral activity has been a focus of research, and especially the single enantiomer in the beta configuration has received much attention. Because the beta-configuration nucleoside analogue has better similarity with natural nucleoside, the technical difficulty of solving and improving how to stereoselectively synthesize the beta-configuration nucleoside analogue in a more economical way is always needed.
Decitabine is a beta-type isomer, a racemic body of alpha and beta is usually obtained by the existing preparation technology, and then the decitabine is obtained by a recrystallization technology, wherein the yield depends on the content ratio of the alpha and beta of an intermediate generated in the coupling reaction step of the decitabine; in the preparation method of WO2009086687A1, Fmoc- (fluorenylmethoxycarbonyl) is adopted as a synthesis strategy of a protecting group, the protecting group can be conveniently removed, but the process adopts methoxy substitution on a reaction site, and when preparing alpha and beta mixed rotation decitabine precursor 1- (2-deoxy-3, 5-di-O-acyl-D-ribose) -4-amino-1, 3, 5-s-triazine-2-ketone, the process discloses that alpha: beta is more than 3: 2, the proportion of the beta-isomer of the synthesized target product is small, the yield is low, and the requirement of modern industrial production cannot be met. CN102070679A has already definitely adopted Fmoc- (fluorenylmethoxycarbonyl) as a protective group, acetoxyl group is adopted to substitute a reaction site, alpha to beta is 1 to 1 when alpha and beta mixed-rotation decitabine is prepared, and the proportion of synthesized target product beta-type isomer is smaller.
CN102037003A gave a combined anomer up to α: β of 12: 88. In the same way, CN108239128A takes 1-chloro-3, 5-di-O-p-chlorobenzoyl-deoxy-D-ribofuranose as a raw material to be coupled to obtain a key intermediate, and the key intermediate is detected as follows: beta configuration 80.8%, alpha configuration 12.2%, maximum single hetero 1.5%. CN102209467A is a key intermediate obtained by coupling 1-chloro-3, 5-di-O-p-chlorobenzoyl-deoxy-D-ribofuranose, wherein the ratio of alpha anomer to beta anomer is 15-30: 40-60%.
CN103739636A a route for synthesizing decitabine, although the process is simple and the operation is simple, the method has the problems of poor selectivity and low yield of beta-isomer. The document (Journal of Organic Chemistry, 51(16), 3211-13, 1986) reports a synthesis method of decitabine, which uses 2-deoxy-D-ribose as a raw material to react with methanol to obtain methyl glycoside, 3, 5-dihydroxy is protected by 9-fluorenylmethoxycarbonyl, then the methyl glycoside reacts with hydrogen chloride to obtain 1-chlorofluorenylsugar, the 1-chlorofluorenylsugar reacts with silanized 5-azacytosine, then a protecting group is removed, and the decitabine is obtained after purification. Beta is 1: 0.9. CN102827224A takes 2-deoxy-D-ribose as raw material, reacts with methanol to obtain methyl glycoside, 3, 5-dihydroxy is protected by 9-fluorenylmethyloxycarbonyl, then reacts with hydrogen chloride to obtain 1-chlorofluorenylsugar, and the 1-chlorofluorenylsugar reacts with silanized 5-azacytosine to obtain the product with the highest alpha to beta ratio of alpha to beta isomers being 1 to 1.31.
It can be seen. Decitabine prepared by the prior art can not avoid the generation of isomers in the glycosylation reaction process, and the decitabine often contains alpha-type isomers, and the structure of the decitabine is shown as a formula VIII.
Figure BDA0002124387390000021
In order to minimize the formation of the alpha isomer, researchers have conducted extensive research and have achieved a series of results. The selective synthesis method of single-configuration beta-nucleoside is introduced in the research progress of beta-nucleoside stereoselectivity, and the comprehensive summary of how to inhibit the generation of alpha-isomer is made, including chemical method, enzymatic method and chemical-enzymatic method. In the chemical synthesis method, the ratio of alpha configuration and beta configuration is changed by introducing different groups at sugar 1, sugar 3 and sugar 5 positions, for example, a glucosidic bond is introduced at the sugar 1 position, NBS is used as a catalyst to efficiently obtain a beta configuration product, and the same effect is also achieved by introducing an amide formate group at the sugar 3 position. The methods are beneficial to the generation of beta configuration products in the reaction process, but the operation is complex, the cost is high, most of the methods still stay in a small-scale research stage, and the methods are not beneficial to industrial mass production.
The method for improving the proportion of the beta configuration by changing the protecting groups of hydroxyl at the 3-position and the 5-position of the sugar proves to be effective, for example, the protecting groups such as p-chlorobenzoyl chloride, fluorenylmethoxycarbonyl chloride, p-methylbenzoyl chloride and the like can improve the proportion of the beta configuration product to a certain extent, and the method has the advantages of simple operation and high yield, for example, patent CN 103739636A.
A great deal of research shows that the principle of the glycosidation reaction is that firstly, under the catalysis of Lewis acid, a carbon positive ion is formed at the 1-position of the sugar on the nucleoside, and the carbon positive ion and silanized 5-azacytosine undergo SN reaction1Glycosidic linkages are formed throughout the process.
Figure BDA0002124387390000031
The inventors studied the mechanism of glycosylation reaction in detail and found that the protecting group of hydroxyl group at position 3 of sugar is the main cause of the change of configuration ratio of glycosylation product, which is consistent with the results of the prior studies. The electron-rich group on the protecting group is favorable for the generation of beta configuration, and the inventor combines the simplicity of hydroxyl protection, and through trying to change the protecting group of the hydroxyl at the 3-position of the sugar, the inventor unexpectedly finds that the intermediate shown in the formula V can obtain a higher proportion of beta configuration products when the glycosylation reaction is carried out.
Disclosure of Invention
In view of the defects of the prior art, the invention provides an intermediate compound V and a new route for synthesizing decitabine by using the intermediate compound. The synthesis of decitabine by the route can effectively inhibit the generation of alpha configuration in glycosylation reaction, and improve the yield of decitabine.
The invention is realized by the following technical scheme:
a decitabine intermediate compound with the structural formula as follows
Figure BDA0002124387390000041
A preparation method of an intermediate compound V comprises the following steps:
protecting the primary hydroxyl of the compound III by using PvCl (pivaloyl chloride) to generate a compound IV, and performing acylation reaction with 3-dimethylamino propionyl chloride or a salt thereof to generate a compound V; the reaction route is as follows:
Figure BDA0002124387390000042
preferably, the synthesis of compound V from compound III comprises the following steps: adding a compound III and organic base C, PvCl into an organic solvent B, reacting at controlled temperature, detecting by TLC until the reaction is complete to generate a compound IV with a primary hydroxyl group having a protective group, adding 3-dimethylamino propionyl chloride hydrochloride without separation and purification, carrying out acylation reaction, detecting by TLC until the reaction is complete, and processing to obtain a compound V.
Preferably, the reaction temperature for synthesizing the compound IV from the compound III is-10 ℃ to 0 ℃, and further preferably-5 ℃.
Preferably, the molar ratio of the compound III to the organic base C is 1: 3 to 5, and more preferably 1: 3.
preferably, the compound iii is present in a molar ratio to PvCl of 1:1 to 1.05, and more preferably 1: 1.02.
preferably, the PvCl can be dissolved in a suitable amount of organic solvent B for dropwise addition; the mass-to-volume ratio of the PvCl to the organic solvent B is 1: 8-10 g/ml.
Preferably, the acylation reaction temperature of the compound V generated by the compound IV is-5-10 ℃, and further preferably 0 ℃.
Preferably, the molar ratio of the compound III to the 3-dimethylaminopropionyl chloride or hydrochloride thereof is 1:1 to 1.2, and more preferably 1: 1.1.
preferably, the mass volume ratio of the compound III to the organic solvent B is 1: 4-8, g/mL, more preferably 1: 7.
preferably, the organic base C is selected from one or more of pyridine, imidazole, triethylamine, DIPEA, ethylenediamine, and further preferably triethylamine.
Preferably, the organic solvent B is selected from one or two of trichloromethane, dichloromethane, tetrahydrofuran, 1, 2-dichloromethane, acetonitrile and 1, 4-dioxane; further preferred is chloroform.
Preferably, TLC detection: petroleum ether/ethyl acetate (volume ratio 3/1) is used as a developing agent, the intermediate III Rf is approximately equal to 0 (phosphomolybdic acid color development), the intermediate IV Rf is approximately equal to 0.3 (ultraviolet lamp GF is equal to 254), and the intermediate V Rf is approximately equal to 0.7 (ultraviolet lamp GF is equal to 254).
Preferably, the post-treatment process: adding a proper organic solvent into the reaction solution for extraction, washing the reaction solution by using 0.5-1 mol/L HCl aqueous solution, collecting a water phase, adjusting the pH value to 9-10 by using 15% sodium hydroxide solution, stirring and crystallizing for 2-5 h, filtering, and drying a filter cake under reduced pressure to obtain a white solid V; the organic solvent is preferably chloroform or dichloromethane, and may be optionally added according to the organic solvent B.
In addition, compound III can be prepared according to the schemes disclosed in the prior art.
The compound V is applied to the preparation of decitabine.
In addition, the invention provides a preparation method of decitabine, which comprises the following steps: step 1: TMSOTf is used for catalyzing 5-azacytosine (shown in a formula VI) subjected to trimethyl silanization to perform glycosylation reaction with a compound V to generate a compound VII; step 2: and removing the protecting groups of 3, 5-hydroxy of the compound VII to obtain a final product decitabine I. The reaction route is as follows
Step 1
Figure BDA0002124387390000051
Step 2
Figure BDA0002124387390000052
Preferably, the step 1 for preparing the intermediate compound VII comprises the following specific steps: and (2) reacting the intermediate compound V with the compound VI in an organic solvent B under the catalysis of TMSOTf, detecting by TLC until the reaction is complete, adding a proper amount of an extracting agent into the reaction liquid or directly adding a sodium bicarbonate solution to adjust the pH value to 7-8, concentrating the obtained organic phase containing the compound VII under reduced pressure, dissolving the obtained oily substance in ethyl acetate, slowly adding the oily substance into stirred petroleum ether, filtering and drying to obtain a white solid compound VII.
Preferably, the ratio of the moles of the compound V to the moles of the compound VI in the intermediate compound V in the step 1 is 1: 1.0 to 1.2, and more preferably 1: 1.1.
preferably, the reaction temperature in step 1 is 5 ℃ to 15 ℃, and more preferably 10 ℃.
Preferably, the molar ratio of the road intermediate compound v to TMSOTf in step 1 is 1: 0.9 to 1.2, and more preferably 1: 1.1.
preferably, the mass-to-volume ratio of the intermediate V to the ethyl acetate in the step 1 is 1: 15 to 25 g/ml, more preferably 1: 20.
preferably, the mass-to-volume ratio of the intermediate V to the petroleum ether in the step 1 is 1: 60 to 100 g/ml, more preferably 1: 80.
preferably, the specific steps of synthesizing decitabine in step 2 are as follows: and (2) taking methanol as a solvent, removing the 3-and 5-protecting groups from the intermediate compound VII under the action of sodium methoxide, adding glacial acetic acid for neutralization after the reaction is finished, stirring for crystallization, filtering and drying to obtain a crude product of decitabine, recrystallizing with methanol, filtering and drying to obtain the decitabine.
Preferably, the mass-to-volume ratio of the intermediate VII to methanol in the step 2 is 1: 10-15, g/ml, and further preferably 1: 12.
preferably, in the alkaline hydrolysis reaction in the step 2, the molar ratio of the intermediate VII to the sodium methoxide is 1: 2-3, more preferably 1: 2.5.
preferably, the alkaline hydrolysis reaction temperature in step 2 is 10 ℃ to 40 ℃, and more preferably 30 ℃.
Preferably, the mass-to-volume ratio of the recrystallized decitabine crude product to methanol in the step 2 is 1: 70-90 g/ml, more preferably 1: 70.
compared with the prior art, the invention has the following advantages:
1) the adopted various reagents are easy to obtain, and the method has an effective treatment method for the generated pollutants and has small environmental pollution. The whole method is simple and easy to operate, and meanwhile, the reaction conditions in each step are mild and easy to control.
2) The intermediate compound provided by the invention is easy to synthesize and has high purity. The product is easily dissolved in water under acidic condition, and high-purity solid can be separated out by adjusting to alkalescence without recrystallization or column chromatography operation.
3) By using the intermediate compound provided by the invention to carry out glycosylation reaction, the beta configuration proportion in the product is obviously improved, wherein the beta configuration proportion in the compound VII can reach more than 85%.
Drawings
FIG. 1 is an HPLC chromatogram for detecting the content of alpha and beta of the compound VII obtained in example 9.
FIG. 2 is an HPLC chromatogram of the purity measurement of decitabine obtained in example 15.
Detailed Description
The benefits of the present invention will now be further illustrated by the following examples, which are intended for the purpose of illustration only and should not be construed as limiting the invention, and all such obvious modifications and variations that may be apparent to those skilled in the art are intended to be included within the scope of the invention.
Compound v [ HPLC normalization method: column C18 (4.6 mm. times.250 mm, 5 μm); mobile phase acetonitrile-water (80: 20); the detection wavelength is 220 nm; flow rate 1.0ml/min ].
ESI-MS(m/z):332.25(M+H)+。
H1NMR(400MHz,DMSO-d6)δ：5.53～5.56(m,1H,H-1'),2.18～2.61(m,2H,H-2'),4.92～5.14(m,1H,H-3'),4.63～4.72(m,1H,H-4'),4.16～4.41(m,2H,H-5'),3.56(s,3H,OCH3)，1.25(s,9H,OPv),2.38(t,2H,OCOCH2CNCC),3.85(t,2H,OCOCCH2NCC),2.78(S,6H,OCOCCNCH3CH3)。
Compound vii [ HPLC normalization: chromatography column C18Columns (4.6 mm. times.250 mm, 5 μm); mobile phase: methanol: acetonitrile: water-40: 35: 25; the detection wavelength is 220 nm; flow rate 1.0ml/min]。
ESI-MS(m/z):412.48(M+H)+；
1HNMR(400MHz,DMSO-d6)δ8.17(s,1H,H-6),5.88～5.93(m,1H,H-l'),2.27～2.71(m,2H,H-2')，5.08～5.18(m,1H,H-3')，4.52～4.61(m,1H,H-4')，4.14～4.54(m,2H,H-5')，1.32(s,9H,OPv),2.41(t,2H,OCOCH2CNCC),3.89(t,2H,OCOCCH2NCC),2.83(S,6H,OCOCCNCH3CH3)。
Decitabine:
[ HPLC normalization method: column C18 (4.6 mm. times.250 mm, 5 μm); mobile phase n-hexane-ethanol (60: 40); the detection wavelength is 220 nm; flow rate 1.0ml/min ].
ESI-MS(m/z):229.34(M+H)+；
1H NMR(DMSO-d6)δ：8.52(s，1H,H-6)，7.38(s,2H,NH2)，5.81～5.95(m，1H,H-l')，2.11～2.34(m，2H,H-2')，3.88～4.03(m,1H,H-3'),4.52～4.61(m,1H,H-4'),4.62～3.73(m,2H,H-5')。
Synthesis of intermediate Compound V
Example 1
Dissolving 20g of the oily matter of the intermediate III in 140ml of trichloromethane, adding 41.03g of triethylamine, cooling the reaction liquid to-5 ℃, slowly dropwise adding a trichloromethane solution of PvCl (16.54g of PvCl is dissolved in 165ml of trichloromethane), continuously stirring for reacting for 1.5h after about 3h of dropwise adding, adding 25.57g of 3-dimethylaminopropionyl chloride hydrochloride, and continuously stirring for reacting for 1 h. Washing the reaction solution by using 300ml of 0.5mol/L HCl, collecting a water phase, adjusting the pH value to 9-10 by using a 15% NaOH aqueous solution, stirring and crystallizing for 2 hours, filtering and drying to obtain a white solid compound V, wherein the yield is 87.9%, and the purity is 97.56%.
Example 2
Dissolving 20g of the oily matter of the intermediate III in 120ml of dichloromethane, adding 27.61g of imidazole, cooling the reaction liquid to-5 ℃, slowly dropwise adding a dichloromethane solution of PvCl (16.22PvCl is dissolved in 163ml of dichloromethane), continuously stirring for reacting for 1.5h after about 3h of dropwise addition, adding 23.25g of 3-dimethylaminopropionyl chloride hydrochloride, and continuously stirring for reacting for 1 h. Washing the reaction solution by 300ml of 0.5mol/L HCl, collecting a water phase, adjusting the pH value to 9-10 by using 15% NaOH water solution, stirring and crystallizing for 2 hours, filtering and drying to obtain a white solid compound V, wherein the yield is 84.5%, and the purity is 97.17%.
Example 3
Dissolving 20g of the oily matter of the intermediate III in 80ml of tetrahydrofuran, adding 68.38g of triethylamine, cooling the reaction liquid to-10 ℃, slowly dropwise adding a tetrahydrofuran solution of PvCl (17.11g of PvCl is dissolved in 171ml of tetrahydrofuran), continuously stirring for reacting for 1.5h after about 3h of dropwise addition, and adding 27.90g of 3-dimethylaminopropionyl chloride hydrochloride for continuously stirring for reacting for 1 h. Adding 200ml of trichloromethane into the reaction solution, washing with 200ml of 0.5mol/L HCl, collecting a water phase, adjusting the pH value to 9-10 by using a 15% NaOH aqueous solution, stirring for crystallization for 2 hours, filtering and drying to obtain a white solid compound V, wherein the yield is 84.1%, and the purity is 96.34%.
Example 4
20g of the intermediate III oily matter is dissolved in 120ml of 1, 2-dichloroethane, 87.36g of DIPEA is added, the temperature of the reaction liquid is reduced to-5 ℃, a1, 2-dichloroethane solution of PvCl (16.86g of PvCl is dissolved in 169ml of 1, 2-dichloroethane) is slowly added dropwise, and the reaction is continued for 1.5h after about 3h of dropwise addition. The reaction solution is heated to 5 ℃, and 25.58g of 3-dimethylamino propionyl chloride hydrochloride is added to continue stirring and reacting for 1 h. Washing the reaction solution by using 250ml of 0.5mol/L HCl, collecting a water phase, adjusting the pH value to 9-10 by using 15% NaOH water solution, stirring and crystallizing for 2 hours, filtering and drying to obtain a white solid compound V, wherein the yield is 83.4%, and the purity is 95.85%.
Example 5
Dissolving 20g of the oily matter of the intermediate III in 100ml of acetonitrile, adding 54.70g of triethylamine, cooling the reaction liquid to 0 ℃, slowly dropwise adding an acetonitrile solution of PvCl (16.70g of PvCl is dissolved in 168ml of acetonitrile), continuously stirring for reacting for 1.5h after about 3h of dropwise addition, adding 25.58g of 3-dimethylaminopropionyl chloride hydrochloride, and continuously stirring for reacting for 1 h. Adding 200ml of trichloromethane into the reaction solution, washing the reaction solution by using 300ml of 0.5mol/L HCl, collecting a water phase, adjusting the pH value to 9-10 by using a 15% NaOH aqueous solution, stirring the solution for crystallization for 2 hours, filtering and drying the solution to obtain a white solid compound V, wherein the yield is 84.0%, and the purity is 97.31%.
Example 6
Dissolving 20g of oily matter of the intermediate III in 160ml of 1, 4-dioxane, adding 42.76g of pyridine, cooling the reaction liquid to-10 ℃, slowly dropwise adding a1, 4-dioxane solution of PvCl (16.62g of PvCl is dissolved in 166ml of 1, 4-dioxane), continuously stirring and reacting for 1.5h after about 3h of dripping, heating the reaction liquid to-5 ℃, adding 23.25g of 3-dimethylaminopropionyl chloride hydrochloride, and continuously stirring and reacting for 1 h. Adding 300ml of trichloromethane into the reaction solution, washing the trichloromethane with 300ml of 0.5mol/L HCl, collecting a water phase, adjusting the pH value to 9-10 with 15% NaOH aqueous solution, stirring and crystallizing for 2 hours, filtering and drying to obtain a white solid compound V, wherein the yield is 82.5%, and the purity is 96.02%.
Synthesis of intermediate compound VII
Example 7
Adding 30g of intermediate V, 27.82g of compound VI and 120ml of acetonitrile into a three-neck flask with mechanical stirring in sequence, cooling to 15 ℃, dropwise adding 22.13g of TMSOTf, continuously stirring for reacting for 4 hours after about 0.5 hour of dropwise adding, detecting by TLC (developing agent: petroleum/ethyl acetate: 5/1), detecting the disappearance of raw material points, adding 120ml of trichloromethane, and using 5% NaHCO3Adjusting the pH value to 7-8. Drying the organic phase by using anhydrous sodium sulfate, then decompressing and evaporating to dryness to obtain a reddish brown oily substance, dissolving the oily substance in 750ml of ethyl acetate, quickly adding the oily substance into 3000ml of petroleum ether under stirring, continuously stirring for 10min, filtering and drying to obtain a white solid compound VII with the total yield of 85.7 percent and the beta/alpha of approximately 10 percent.
Example 8
Adding 30g of intermediate V, 25.50g of compound VI and 180ml of 1, 2-dichloroethane into a mechanically-stirred three-necked flask in sequence, cooling to 10 ℃, dropwise adding 24.14g of TMSOTf, continuing stirring for reaction for 4 hours after about 0.5 hour of dropwise addition, detecting the disappearance of raw material points by TLC (developing agent: petroleum/ethyl acetate: 5/1), and using 5 percent of solventNaHCO3Adjusting the pH value to 7-8. Drying the organic phase by using anhydrous sodium sulfate, then decompressing and evaporating to dryness to obtain a reddish brown oily substance, dissolving the oily substance in 690ml of ethyl acetate, quickly adding the oily substance into stirred 2700ml of petroleum ether, continuously stirring for 10min, filtering and drying to obtain a white solid compound VII with the total yield of 84.3 percent and the beta/alpha of approximately 10 percent.
Example 9
Adding 30g of intermediate V, 27.82g of compound VI and 150ml of acetonitrile into a mechanically-stirred three-neck flask in sequence, cooling to 10 ℃, dropwise adding 22.13g of TMSOTf, continuously stirring for reacting for 4 hours after about 0.5 hour of dropwise adding, detecting by TLC (developing agent: petroleum/ethyl acetate: 5/1), detecting the disappearance of a raw material point, adding 150ml of chloroform, and using 5% NaHCO3Adjusting the pH value to 7-8. Drying the organic phase by using anhydrous sodium sulfate, then decompressing and evaporating to dryness to obtain a reddish brown oily substance, dissolving the oily substance in 600ml of ethyl acetate, quickly adding the oily substance into 2400ml of stirred petroleum ether, continuously stirring for 10min, filtering and drying to obtain a white solid compound VII with the total yield of 92.1 percent and the beta/alpha of approximately 11.
Example 10
Adding 30g of intermediate V, 25.50g of compound VI and 120ml of dichloromethane into a mechanically stirred three-neck flask in sequence, cooling to 10 ℃, dropwise adding 20.12g of TMSOTf, continuously stirring for reacting for 4 hours after about 0.5 hour of dropwise adding, detecting by TLC (developing agent: petroleum/ethyl acetate: 5/1), detecting the disappearance of raw material points, and using 5% NaHCO3Adjusting the pH value to 7-8. Drying the organic phase by using anhydrous sodium sulfate, then decompressing and evaporating to dryness to obtain a reddish brown oily substance, dissolving the oily substance in 540ml of ethyl acetate, quickly adding the oily substance into 2100ml of petroleum ether under stirring, continuously stirring for 10min, filtering and drying to obtain a white solid compound VII with the total yield of 83.2 percent and the beta/alpha of approximately 9.4.
Example 11
Adding 30g of intermediate V, 23.20g of compound VI and 90ml of chloroform into a three-neck flask with mechanical stirring in sequence, cooling to 5 ℃, dropwise adding 18.11g of TMSOTf, continuously stirring for reacting for 4 hours after about 0.5 hour of dropwise adding, detecting by TLC (developing agent: petroleum/ethyl acetate: 5/1), detecting the disappearance of raw material points, and using 5% NaHCO3Adjusting the pH value to 7-8. Drying the organic phase with anhydrous sodium sulfate, evaporating to dryness under reduced pressure to obtain reddish brown oily substance, and collecting the oily substanceDissolving in 450ml ethyl acetate, quickly adding into 1800ml petroleum ether, continuously stirring for 10min, filtering and drying to obtain white solid compound VII with the total yield of 81.3 percent and beta/alpha being approximately equal to 9.0.
Decitabine synthesis
Example 12
Adding 20g of the compound VII and 300ml of anhydrous methanol into a three-necked bottle with mechanical stirring, adjusting the temperature to 25 ℃, stirring to a clear solution state, adding 6.57g of sodium methoxide, continuing to stir for reaction for 1h, adding 7.30g of glacial acetic acid, stirring for crystallization for 6h, filtering and drying to obtain 10.42g of a crude product of decitabine, adding 834ml of anhydrous methanol for recrystallization, standing at room temperature for crystallization for 24h, filtering and drying to obtain white solid decitabine, wherein the total yield is 70.5%, and the purity is 99.94%.
Example 13
Adding 20g of the compound VII and 280ml of anhydrous methanol into a three-necked bottle with mechanical stirring, adjusting the temperature to 40 ℃, stirring to a clear solution state, adding 7.88g of sodium methoxide, continuing to stir for reaction for 0.5h, adding 8.76g of glacial acetic acid, stirring for crystallization for 6h, filtering and drying to obtain 10.54g of a crude product of decitabine, adding 843ml of anhydrous methanol for recrystallization, standing at room temperature for crystallization for 24h, filtering and drying to obtain white solid decitabine, wherein the total yield is 71.3%, and the purity is 99.93%.
Example 14
Adding 20g of the compound VII and 240ml of anhydrous methanol into a three-necked bottle with mechanical stirring, adjusting the temperature to 30 ℃, stirring to a clear solution state, adding 6.57g of sodium methoxide, continuing stirring for reaction for 1h, adding 7.30g of glacial acetic acid, stirring for crystallization for 6h, filtering and drying to obtain 10.20g of a crude product of decitabine, adding 816ml of anhydrous methanol for recrystallization, standing at room temperature for crystallization for 24h, filtering and drying to obtain white solid decitabine, wherein the total yield is 71.3%, and the purity is 99.97%.
Example 15
Adding 20g of the compound VII and 200ml of anhydrous methanol into a three-necked bottle with mechanical stirring, adjusting the temperature to 10 ℃, stirring to a clear solution state, adding 5.25g of sodium methoxide, continuing stirring for reaction for 2 hours, adding 5.84g of glacial acetic acid, stirring for crystallization for 6 hours, filtering and drying to obtain 10.31g of a crude product of decitabine, adding 825ml of anhydrous methanol for recrystallization, standing at room temperature for crystallization for 24 hours, filtering and drying to obtain white solid decitabine, wherein the total yield is 69.8%, and the purity is 99.90%.

Claims (9)

1. A decitabine intermediate compound is shown as formula V, and the structural formula is as follows:
Figure FDA0002124387380000011
2. a process for the preparation of an intermediate compound as claimed in claim 1, which process comprises the steps of: protecting the primary hydroxyl of the compound III by using PvCl (pivaloyl chloride) to generate a compound IV, and performing acylation reaction with 3-dimethylamino propionyl chloride or a salt thereof to generate a compound V; the reaction route is as follows:
Figure FDA0002124387380000012
3. the process for the preparation of an intermediate compound according to claim 2, comprising in particular the steps of: adding a compound III, an organic base C and PvCl into an organic solvent B, carrying out temperature control reaction to generate a compound IV with a primary hydroxyl group having a protective group, directly adding 3-dimethylamino propionyl chloride hydrochloride without separation and purification, carrying out acylation reaction, and processing to obtain a compound V.
4. The process for preparing an intermediate compound according to claim 2, wherein the reaction temperature of the compound III to the compound IV is-10 ℃ to 0 ℃; preferably-5 ℃.
5. The process for preparing an intermediate compound according to claim 2, wherein the acylation of compound iv to compound v is carried out at a temperature of-5 ℃ to 10 ℃; preferably 0 deg.c.
6. A process for the preparation of an intermediate compound as claimed in claim 2, wherein the organic base C is selected from one or more of pyridine, imidazole, triethylamine, DIPEA, ethylenediamine; triethylamine is preferred.
7. The process for preparing an intermediate compound according to claim 2, wherein the organic solvent B is one or two selected from the group consisting of chloroform, dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane and acetonitrile; chloroform is preferred.
8. Use of compound V according to claim 1 for the preparation of decitabine.
9. A preparation method of decitabine is characterized by comprising the following steps: step 1: TMSOTf is used for catalyzing 5-azacytosine subjected to trimethyl silanization, namely a compound VI and a compound V to perform glycosylation reaction to generate a compound VII; step 2: removing the protecting group of 3, 5-hydroxy group from the compound VII to obtain a final product decitabine I; the reaction route is as follows:
step 1
Figure FDA0002124387380000021
Step 2
Figure FDA0002124387380000022
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102037003A (en) * 2007-10-10 2011-04-27 西拉格股份公司 Method of producing 2'-deoxy-5-azacytidine (decitabine)
CN103739636A (en) * 2014-01-09 2014-04-23 山东新时代药业有限公司 Preparation method of decitabine intermediate
CN108239128A (en) * 2016-12-23 2018-07-03 江苏奥赛康药业股份有限公司 The preparation method of beta-nucleosides class compound

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102037003A (en) * 2007-10-10 2011-04-27 西拉格股份公司 Method of producing 2'-deoxy-5-azacytidine (decitabine)
CN103739636A (en) * 2014-01-09 2014-04-23 山东新时代药业有限公司 Preparation method of decitabine intermediate
CN108239128A (en) * 2016-12-23 2018-07-03 江苏奥赛康药业股份有限公司 The preparation method of beta-nucleosides class compound

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