CN112209977B - Decitabine intermediate compound VI - Google Patents
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- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- C07H1/00—Processes for the preparation of sugar derivatives
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Abstract
The invention belongs to the technical field of chemical synthesis, and provides a decitabine intermediate compound; the preparation method is simple and convenient to operate, does not need special equipment, has good product purity and high yield, and is suitable for industrial production; the compound is used for further synthesizing decitabine, and has high stereoselectivity and good purity.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a decitabine intermediate compound.
Background
Decitabine (Decistabine) is known by the chemical name 4-amino-1- (2-deoxy-beta-D-erythro-ribofuranose) -1,3, 5-triazin-2 (1H) -one, and has the structure:
is mainly used for treating myelodysplastic diseases. 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.
The literature reports some synthetic methods of decitabine. The synthetic route reported by PISKALA for decitabine is: condensing dihydro-S-triazine protected by trimethylsilane and chlorodeoxyribose under the catalysis of stannic chloride to obtain the product. Ji Jingjing et al report another route for the synthesis of decitabine, which uses 2-deoxy-D-ribose as starting material and reacts with acetic anhydride under pyridine to give 1,3, 5-tri-D-acetyl-2-deoxy-D-ribose, which is condensed with 5-azacytosine activated with HMDS under the catalysis of trimethylsilyl triflate to give decitabine, followed by ammonolysis deprotection and methanol recrystallization. None of these reports discloses how the two isomers of the final product, alpha, beta (decitabine is beta form), are separated, while the separation of the two isomers of alpha, beta is difficult, which makes the production of decitabine very costly.
In recent years, development of nucleoside analogues with low toxicity and high antitumor and antiviral activities has become a research hotspot, and particularly single enantiomers of the beta configuration have received much attention. Since nucleoside analogues of the beta configuration have better similarity to natural nucleosides, how to stereoselectively synthesize nucleoside analogues of the beta configuration in a more economical way is also a technical difficulty which has been constantly sought to be solved and improved.
The decitabine is a beta isomer, the existing preparation technology is used for obtaining a general alpha, beta racemate, and then the decitabine is obtained through a recrystallization technology, and the yield is dependent on the content ratio of the intermediate alpha, beta generated in the decitabine coupling reaction step; in the preparation method of WO2009086687A1, fmoc- (fluorenylmethoxycarbonyl) is adopted as a synthesis strategy of a protecting group, so that the protecting group can be conveniently removed, but methoxy substitution is adopted in a reaction site in the process, and when alpha and beta mixed decitabine precursors 1- (2-deoxy-3, 5-di-O-acyl-D-ribose) -4-amino-1, 3, 5-s-triazine-2-ketone are prepared, the process discloses that the alpha:beta is more than 3:2, the beta isomer ratio of the synthesized target product is smaller, the yield is low, and the requirement of modern industrial production cannot be met. CN102070679a has definitely adopted Fmoc- (fluorenylmethoxycarbonyl) as a protecting group, an acetoxy group is adopted for substitution on a reaction site, and when preparing alpha, beta-racemic decitabine, the proportion of alpha: beta=1:1, the beta-isomer of the synthesized target product is smaller.
CN102037003a gives a combined anomer up to α: β=12:88. The same route CN108239128A uses 1-chloro-3, 5-di-O-p-chlorobenzoyl-deoxy-D-ribofuranose as raw material to couple to obtain a key intermediate, and the key intermediate is detected: beta configuration 80.8%, alpha configuration 12.2%, maximum single impurity 1.5%. CN102209467A uses 1-chloro-3, 5-di-O-p-chlorobenzoyl-deoxy-D-ribofuranose as raw material to couple to obtain key intermediate, and the ratio of alpha anomer to beta anomer is 15-30% to 40-60%.
CN103739636a is a route for synthesizing decitabine, and although the process is simple and easy to operate, the method has the problems of poor selectivity and low yield of beta-isomer. Literature (Journal of Organic Chemistry,51 (16), 3211-13; 1986) reports a process for the synthesis of decitabine, starting from 2-deoxy-D-ribose, with methanol to give methylglycoside, protecting the 3, 5-dihydroxy with 9-fluorenylmethoxycarbonyl, then with hydrogen chloride to give 1-chlorofluorene sugar, again reacting the 1-chlorofluorene sugar with silylated 5-azacytosine, then deprotecting the group and refining to give decitabine. α: β=1:0.9. CN102827224a uses 2-deoxy-D-ribose as raw material, reacts with methanol to obtain methyl glycoside, the 3, 5-dihydroxyl is protected by 9-fluorene methoxycarbonyl, then reacts with hydrogen chloride to obtain 1-chloro-fluorene sugar, and then reacts with silanized 5-aza-cytosine to obtain the product with highest alpha/beta isomer ratio of alpha/beta=1:1.31.
Therefore, the formation of isomers of decitabine prepared by the prior art cannot be avoided in the glycosylation reaction process, and the decitabine often contains an alpha isomer, and the structure of the decitabine is shown as follows.
In order to minimize the formation of the alpha isomer, researchers have made a great deal of research and have achieved a series of results. In the progress of the research on the stereoselectivity of the literature beta-nucleoside, a method for selectively synthesizing the beta-nucleoside with a single configuration is introduced, and the comprehensive summary of how to inhibit the formation of an alpha isomer is provided, including a chemical method, an enzymatic method and a chemical-enzymatic method. In the chemical synthesis method, the beta configuration product can be efficiently obtained by introducing different groups at the positions of sugar 1, sugar 3 and sugar 5 to change the proportion of alpha and beta configurations, for example, introducing a sulfan bond at the position of sugar 1, using NBS as a catalyst, or introducing an amid formate group at the position of sugar 3 has the same effect. The methods are favorable for the generation of beta-configuration products in the reaction process, but have complex operation and high cost, and most of the methods stay in the small-scale research stage, so that the method is unfavorable for industrial mass production.
The improvement of the beta configuration ratio by changing the hydroxyl protecting groups at the 3-position and the 5-position of the sugar has been proved to be an effective method, for example, protecting groups such as p-chlorobenzoyl chloride, fluorenylmethoxycarbonyl chloride, p-methylbenzoyl chloride and the like can improve the beta configuration product ratio to a certain extent, and the method has the advantages of simple operation and high yield, such as patent CN103739636A.
A great deal of research shows that the principle of glycosylation is that 1-position sugar on nucleoside forms carbonium ion under the catalysis of Lewis acid and silylated 5-azacytosine undergoes SN 1 The process forms glycosidic bonds.
The inventor studies the glycosylation reaction mechanism in detail, and finds that the hydroxyl protecting group at the 3-position of the sugar is a main reason for changing the configuration proportion of the glycosylation product, which is consistent with the prior study result. The electron-rich group on the protecting group is beneficial to the formation of beta configuration, and the inventor combines the easiness of hydroxyl protection, and by trying to change the hydroxyl protecting group at the 3-position of the sugar, the intermediate shown in the formula VI is unexpectedly discovered, and a higher proportion of beta configuration products can be obtained when glycosylation reaction is carried out.
Disclosure of Invention
In view of the deficiencies of the prior art, the present invention provides an intermediate compound VI and a novel route for the synthesis of decitabine using the intermediate compound. The synthesis of decitabine by the route can effectively inhibit the formation of alpha configuration in glycosylation reaction, and improve the yield of decitabine.
The invention is realized by the following technical scheme:
decitabine intermediate compound with the structural formula as follows
A process for the preparation of an intermediate compound VI comprising the steps of:
wherein, step 1. The compound III synthesizes the compound V and includes the following route:
the step 1 of synthesizing the compound V from the compound III specifically comprises the following steps: and (3) adding the compound III and the organic base B into the organic solvent A, dropwise adding a solution of the organic solvent A of PvCl (namely pivaloyl chloride) to generate a compound IV with a primary hydroxyl group having a protecting group, directly adding 3-methylthio propionyl chloride without separation and purification, and generating a compound V through an acylation reaction.
The reaction temperature for synthesizing the compound V from the compound III in the step 1 is-15-0 ℃, preferably-5 ℃.
The molar ratio of the compound III to the organic base B in the step 1 is 1:2 to 4, preferably 1:3.
the molar ratio of the compound III to the PvCl in the step 1 is 1:1 to 1.05, preferably 1:1.02.
the mass volume ratio of PvCl to organic solvent a in the solution of PvCl (i.e. pivaloyl chloride) organic solvent a in step 1 is preferably 1:10, g/ml.
The molar ratio of the compound III to the 3-methylthiopropionyl chloride in the step 1 is 1:1 to 1.1, preferably 1:1.05.
the mass volume ratio of the compound III to the organic solvent A in the step 1 is 1:5 to 10 g/ml, preferably 1:10.
the organic base B in the step 1 is selected from one or more of pyridine, imidazole, triethylamine and DIPEA, preferably triethylamine.
The organic solvent A in the step 1 is one or two selected from chloroform, dichloromethane, 1, 2-dichloroethane and acetonitrile, preferably chloroform.
In step 1, the reaction process is controlled by TLC; preferably, in TLC detection, the developing agent is petroleum ether/ethyl acetate (volume ratio 3/1) as the developing agent; wherein intermediate iii Rf (phosphomolybdic acid color development) is approximately 0, intermediate iv Rf (ultraviolet lamp gf=254) is approximately 0.2, and intermediate v Rf (ultraviolet lamp gf=254) is approximately 0.5.
Preferably, the concentration of the dilute hydrochloric acid is 1.2mol/L in the post-treatment of the step 1.
Preferably, in the post-treatment of the step 1, the mass-volume ratio of the oily matter to the chloroform or the dichloromethane is 1:3-8,g/ml; further preferably 1:5.
Preferably, in the post-treatment of the step 1, the mass-volume ratio of the oily matter to the methyl tertiary butyl ether is 1:10-20, g/ml; further preferably 1:15.
The mass-volume ratio of the oily matter to the chloroform or the dichloromethane in the step 2 is 1:3-8,g/ml, preferably 1:5.
The mass-volume ratio of the oily matter to the methyl tertiary butyl ether in the step 2 is 1:8-14, g/ml, preferably 1:10.
The reaction temperature in step 2 is 0 ℃ to 20 ℃, preferably 10 ℃.
The mass volume ratio of the compound V to the organic solvent A in the step 2 is 1:10 to 20 g/ml, preferably 1:15.
the molar ratio of the compound V to the acetic anhydride in the step 2 is 1:3 to 6, preferably 1:5.
the mass-volume ratio of the compound V to the concentrated sulfuric acid in the step 2 is 1:0.08 to 0.12 g/ml, preferably 1:0.1.
the alkali for adjusting the pH value to 7-8 in the step 2 is preferably 5% NaHCO 3 An aqueous solution.
The intermediate compound VI is applied to the preparation of decitabine.
The invention also provides a method for preparing decitabine by using the intermediate VI, which comprises the following steps: step a: by SnCl 4 The 5-azacytosine (shown as a formula VII) catalyzing the trimethylsilylation and VI undergo glycosylation reaction to generate a compound VIII; step b: removing hydroxyl protecting groups from the compound VIII to obtain a final product decitabine I; the reaction route is as follows:
step a:
step b:
the specific steps for preparing the intermediate compound VIII in the step a are as follows: intermediate VI and compound VII in SnCl in organic solvent A 4 After the completion of the TLC (Petroleum ether/ethyl acetate=3/1) detection reaction, adding a saturated sodium bicarbonate solution to adjust the pH value to 7-8, adding a proper amount of extractant (the solvent used for the reaction can be not added and can be used for generating layering), obtaining an organic phase, concentrating the organic phase under reduced pressure until the organic phase is dry, dissolving the concentrate in ethyl acetate, adding the concentrate into stirred normal hexane, stirring for crystallization, filtering and drying to obtain the compound VIII.
The mass-volume ratio of the oily matter to the ethyl acetate in the step a is 1:3-6, g/ml, preferably 1:5.
The mass-volume ratio of the oily matter to the normal hexane in the step a is 1:12-18 g/ml, preferably 1:15.
The mass volume ratio of the intermediate VI to the organic solvent A in the step a is 1:3 to 6 g/ml, preferably 1:4.
the reaction temperature in step a is 15℃to 25℃and preferably 20 ℃.
The molar ratio of the compound VI to the compound VII in the step a is 1:1 to 1.2, preferably 1:1.1.
step a the road compound VI and SnCl 4 The mass ratio is 1:0.3 to 0.4, preferably 1:0.35.
the specific steps for preparing the decitabine in the step b are as follows: methanol is used as a solvent, an intermediate compound VIII is subjected to removal of a protecting group under the action of sodium methoxide, glacial acetic acid is added for neutralization after the reaction is completed, stirring crystallization is carried out, a crude product of decitabine is obtained after filtration and drying, and the crude product of decitabine is recrystallized by methanol and dried to obtain the decitabine.
The deprotection reaction in step b, the mass-volume ratio of the intermediate VIII to the methanol is 1:6-10, g/ml, preferably 1:8.
the deprotection reaction in step b has a molar ratio of intermediate VIII to sodium methoxide of 1:2 to 3, preferably 1:2.5.
the reaction temperature for removing the protecting group in the step b is 10-30 ℃, preferably 20 ℃.
The mass volume ratio of the crude product of decitabine to the methanol for recrystallization in the step b is 1: 70-90 g/ml, preferably 1:70.
compound iii can be prepared by reference to methods known in the art; similar methods are used in the prior patent or literature to obtain the compound III with high purity.
The invention has the advantages that:
1) The adopted reagents are easy to obtain, and the method is effective in treating the generated pollutants, and has small environmental pollution. The whole method is simple and easy to operate, and meanwhile, the reaction conditions of 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 high purity solid can be obtained by a simple recrystallization operation.
3) By using the intermediate compound provided by the invention to carry out glycosylation reaction, an expensive triflate trimethylsilyl catalyst is not required, and even if cheap stannic chloride is used, the beta configuration proportion in the product can be obviously improved, wherein the beta configuration proportion in the compound VIII can reach more than 90%.
Drawings
FIG. 1 is a HPLC chromatogram of the beta configuration content of intermediate compound VIII obtained in example 13.
FIG. 2 is a HPLC purity profile of decitabine obtained in example 18.
Detailed Description
The advantages of the invention will now be further described by the following examples, which are given for illustrative purposes only and are not to be construed as limiting the invention, since obvious improvements and modifications to the invention will be apparent to those skilled in the art and are within the scope of the invention.
Noun interpretation: pvcl=pivaloyl chloride.
Compound structure confirmation and detection method:
compound v [ HPLC normalization: chromatographic column C18 column (4.6 mm. Times.250 mm,5 μm); mobile phase acetonitrile-water (70:30); the detection wavelength is 240nm; the flow rate was 1.0ml/min ].
ESI-MS(m/z):335.15(M+H) + ；
1 HNMR(400MHz,DMSO-d 6 )δ：5.63～5.71(m,1H,H-1'),2.19～2.51(m,2H,H-2'),4.83～5.04(m,1H,H-3'),4.67～4.77(m,1H,H-4'),4.19～4.44(m,2H,H-5'),3.58(s,3H,OCH3)，1.26(s,9H,OPv),2.39～2.48(t,2H,OCOCH 2 CSC),3.62～3.71(t,2H,OCOCCH 2 SC),2.14(S,3H,OCOCCSCH 3 )。
Compound VI: [ HPLC normalization method: chromatographic column C18 column (4.6 mm. Times.250 mm,5 μm); mobile phase acetonitrile-water (70:20); the detection wavelength is 240nm; the flow rate was 1.0ml/min ].
ESI-MS(m/z):363.14(M+H) + ；
1 HNMR(400MHz,DMSO-d 6 )δ：6.78～6.93(m,1H,H-1'),2.21～2.33(m,2H,H-2'),4.83～4.95(m,1H,H-3'),4.63～4.74(m,1H,H-4'),4.21～4.39(m,2H,H-5'),3.34(s,3H,OCOCH3)，1.24(s,9H,OPv),2.42～2.52(t,2H,OCOCH 2 CSC),3.65～3.74(t,2H,OCOCCH 2 SC),2.09(S,3H,OCOCCSCH 3 )。
Compound viii [ HPLC 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]。
ESI-MS(m/z):415.16(M+H) + ；
1 HNMR(400MHz,DMSO-d 6 )δ8.17(s,1H,H-6),5.88～5.93(m,1H,H-l'),2.27～2.71(m,2H,H-2')，5.06～5.21(m,1H,H-3')，4.51～4.62(m,1H,H-4')，4.23～4.65(m,2H,H-5')，1.32(s,9H,OPv),2.41～2.50(t,2H,OCOCH 2 CSC),3.64～3.74(t,2H,OCOCCH 2 SC),2.07(S,3H,OCOCCSCH 3 )。
Decitabine HPLC conditions
[ HPLC normalization method: chromatographic column C18 column (4.6 mm. Times.250 mm,5 μm); mobile phase n-hexane-ethanol (60:40); the detection wavelength is 240nm; the flow rate was 1.0ml/min ].
ESI-MS(m/z):229.34(M+H) + ；
1 H NMR(DMSO-d 6 )δ：8.52(s，1H,H-6)，7.38(s,2H,NH 2 )，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').
Intermediate compound V synthesis
Example 1
25g of oily compound III, 250ml of dichloromethane and 40.08g of pyridine are added, stirring and cooling are carried out to-5 ℃, a dichloromethane solution of PvCl (20.78 g of PvCl is dissolved in 208ml of dichloromethane) is slowly added dropwise, stirring and reacting are continued for 1h after about 2h, after TLC detection is finished, 24.65g of 3-methylthiopropionyl chloride is added, stirring and reacting are continued for 3h, after TLC detection is finished, an organic phase is washed by 200ml of 1.2mol/L HCl and evaporated to dryness under reduced pressure, and 51.91g of oily compound III is obtained; dissolving the obtained oily matter in 260ml of chloroform, dropwise adding 780ml of methyl tertiary butyl ether, stirring and crystallizing for 2 hours after the dropwise adding, filtering and drying to obtain an intermediate V; the total yield is 87.5% and the purity is 97.57%.
Example 2
25g of oily compound III, 250ml of 1, 2-dichloroethane and 43.68g of DIPEA are added, the temperature is reduced to minus 15 ℃ by stirring, a1, 2-dichloroethane solution of PvCl (20.37 g of PvCl is dissolved in 204ml of 1, 2-dichloroethane) is slowly added dropwise, the dropwise addition is completed for about 2 hours, the stirring reaction is continued for 1 hour, after the TLC detection is completed, 25.83g of 3-methylthiopropionyl chloride is added, the stirring reaction is continued for 3 hours, after the TLC detection is completed, the organic phase is washed by 200ml of 1.2mol/L HCl and evaporated to dryness under reduced pressure, and 50.21g of oily compound III is obtained; dissolving the obtained oily matter in 402ml of chloroform, dropwise adding 1004ml of methyl tertiary butyl ether, stirring for crystallization for 2 hours after the dropwise adding, filtering and drying to obtain an intermediate V; the total yield is 83.3% and the purity is 97.11%.
Example 3
25g of oily compound III, adding 225ml of acetonitrile and 68.38g of triethylamine, stirring and cooling to 0 ℃, slowly dropwise adding an acetonitrile solution of PvCl (21.39 g of PvCl is dissolved in 214ml of acetonitrile), continuously stirring and reacting for 1h after about 2h, adding 23.48g of 3-methylthiopropionyl chloride after TLC detection reaction is finished, continuously stirring and reacting for 3h, adding 200ml of chloroform after TLC detection reaction is finished, washing with 200ml of 1.2mol/L HCl, and evaporating under reduced pressure to obtain 50.78g of oily compound III; dissolving the obtained oily matter in 305ml of chloroform, dropwise adding 914ml of methyl tertiary butyl ether, stirring for crystallization for 2 hours after the dropwise adding, filtering and drying to obtain an intermediate V; the total yield is 84.5% and the purity is 97.18%.
Example 4
25g of oily compound III, adding 175ml of dichloromethane and 34.51g of imidazole, stirring and cooling to-10 ℃, slowly dropwise adding a dichloromethane solution of PvCl (20.78 g of PvCl is dissolved in 208ml of dichloromethane), continuously stirring and reacting for 1h after about 2h, adding 24.65g of 3-methylthiopropionyl chloride after TLC detection reaction is finished, continuously stirring and reacting for 3h after TLC detection reaction is finished, washing an organic phase with 200ml of 1.2mol/L HCl, and evaporating under reduced pressure to obtain 52.47g of oily substance; dissolving the obtained oily matter in 210ml of chloroform, dropwise adding 630ml of methyl tertiary butyl ether, stirring for crystallization for 2 hours after the dropwise adding is finished, and filtering and drying to obtain an intermediate V; the total yield was 82.1%. The purity was 97.66%.
Example 5
25g of oily compound III, adding 125ml of chloroform and 26.72g of pyridine, stirring and cooling to 0 ℃, slowly dropwise adding a chloroform solution of PvCl (20.98 g of PvCl is dissolved in 210ml of chloroform), continuously stirring and reacting for 1h after about 2h, adding 23.48g of 3-methylthiopropionyl chloride after TLC detection reaction is finished, continuously stirring and reacting for 3h, after TLC detection reaction is finished, washing an organic phase with 200ml of 1.2mol/LHCl, and evaporating under reduced pressure to obtain 51.34g of oily compound; dissolving the obtained oily matter in 154ml of chloroform, dropwise adding 512ml of methyl tertiary butyl ether, stirring for crystallization for 2 hours after the dropwise adding is finished, and filtering and drying to obtain an intermediate V; the total yield was 83.9%. The purity was 97.13%.
Synthesis of intermediate compound VI
Example 6
25g of intermediate V is taken and dissolved in 250ml of chloroform, 22.90g of acetic anhydride is added, the temperature of the reaction solution is reduced to 0 ℃, 2ml of concentrated sulfuric acid is added dropwise, the reaction is continued to be stirred for 1h after the completion of the dropwise addition, and TLC detection reaction is completed. With 5% NaHCO 3 The pH of the reaction solution was adjusted to 7-8, the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 24.66g of an oil, the oil was dissolved in 74ml of methylene chloride, 197ml of methyl tert-butyl ether was added dropwise, stirred and crystallized for 2 hours, and intermediate VI was obtained after filtration and drying, and the total yield was 82.1% and the purity was 96.16%.
Example 7
25g of intermediate V is taken and dissolved in 375ml of dichloromethane, 30.54g of acetic anhydride is added, the temperature of the reaction solution is reduced to 10 ℃, 2.5ml of concentrated sulfuric acid is added dropwise, the reaction is continued to be stirred for 1h after the dropwise addition, and TLC detection is completed. With 5% NaHCO 3 The pH of the reaction solution is regulated to 7-8, the organic phase is dried by anhydrous sodium sulfate and then evaporated to dryness under reduced pressure, 25.47g of oily substance is obtained, the oily substance is dissolved in 102ml of chloroform, 255ml of methyl tertiary butyl ether is added dropwise, stirring crystallization is carried out for 2h, intermediate VI is obtained after filtration and drying, the total yield is 85.3%, and the purity is 96.26%.
Example 8
25g of intermediate V is taken and dissolved in 500ml of acetonitrile, 38.17g of acetic anhydride is added, the temperature of the reaction solution is reduced to 20 ℃, 3ml of concentrated sulfuric acid is added dropwise, the reaction is continued to be stirred for 0.5h after the completion of the TLC detection reaction. 500ml of chloroform was added, followed by 5% NaHCO 3 The pH of the reaction solution is regulated to 7-8, the organic phase is dried by anhydrous sodium sulfate and then evaporated to dryness under reduced pressure, 25.74g of oily matter is obtained, the oily matter is dissolved in 154ml of chloroform, 309ml of methyl tertiary butyl ether is added dropwise, stirring crystallization is carried out for 2h, intermediate VI is obtained after filtration and drying, the total yield is 85.4%, and the purity is 96.17%.
Example 9
25g of intermediate V was taken and dissolved in 375ml of 1, 2-dichloroethane, and 45.81g of acetic anhydride was added thereto to reactCooling the solution to 15 ℃, dropwise adding 2ml of concentrated sulfuric acid, continuously stirring the solution for reaction for 1h after the completion of the reaction, and detecting the completion of the reaction by TLC. With 5% NaHCO 3 The pH of the reaction solution is regulated to 7-8, the organic phase is dried by anhydrous sodium sulfate and then evaporated to dryness under reduced pressure, 24.12g of oily matter is obtained, the oily matter is dissolved in 193ml of chloroform, 338ml of methyl tertiary butyl ether is added dropwise, stirring crystallization is carried out for 2h, intermediate VI is obtained after filtration and drying, the total yield is 81.9%, and the purity is 96.69%.
Example 10
25g of intermediate V is taken and dissolved in 375ml of chloroform, 38.17g of acetic anhydride is added, the temperature of the reaction solution is reduced to 10 ℃, 2.5ml of concentrated sulfuric acid is added dropwise, the reaction is continued to be stirred for 1h after the dropwise addition, and TLC detection reaction is completed. With 5% NaHCO 3 The pH of the reaction solution is regulated to 7-8, the organic phase is dried by anhydrous sodium sulfate and then evaporated to dryness under reduced pressure, 26.55g of oily matter is obtained, the oily matter is dissolved in 133ml of chloroform, 266ml of methyl tertiary butyl ether is added dropwise, stirring crystallization is carried out for 2h, intermediate VI is obtained after filtration and drying, the total yield is 87.0%, and the purity is 97.11%.
Synthesis of intermediate compound VIII
Example 11
30g of intermediate VI is taken and dissolved in 150ml of chloroform, 23.34g of compound VII is added, the mixture is stirred for 0.5h, the temperature is regulated to 20 ℃, and 10.5g of SnCl is added dropwise 4 Stirring reaction for 0.5h, TLC detection reaction is completed, saturated sodium bicarbonate is used for regulating the pH value of the reaction solution to 7-8, the organic phase is decompressed and evaporated to dryness to obtain 32.94g of oily substance, the oily substance is dissolved in 165ml of ethyl acetate, the oily substance is quickly added into 593ml of n-hexane which is stirred, stirring crystallization is continued for 5min, and the intermediate VIII is obtained after filtration and drying, the total yield is 89.2%, and the beta configuration content is 90.34%.
Example 12
30g of intermediate VI is taken and dissolved in 180ml of 1, 2-dichloroethane, 23.34g of compound VII is added, the mixture is stirred for 0.5h, the temperature is regulated to 15 ℃, and 12g of SnCl is added dropwise 4 Stirring for 0.5h, TLC detection reaction is completed, saturated sodium bicarbonate is used for regulating the pH value of the reaction liquid to 7-8, the organic phase is decompressed and evaporated to dryness to obtain 33.28g of oily substance, the oily substance is dissolved in 200ml of ethyl acetate, quickly added into 566ml of n-hexane which is stirred, stirring and crystallization are continued for 5min, intermediate VIII is obtained after filtration and drying, and the total yield is 913%, beta configuration content 91.17%.
Example 13
30g of intermediate VI is taken and dissolved in 120ml of acetonitrile, 23.34g of compound VII is added, the mixture is stirred for 0.5h, the temperature is regulated to 20 ℃, and 10.5g of SnCl is added dropwise 4 Stirring for 0.5h, detecting the completion of the reaction by TLC, adding 150ml of chloroform, regulating the pH of the reaction solution to 7-8 by using saturated sodium bicarbonate, evaporating the organic phase under reduced pressure to obtain 33.97g of oily substance, dissolving the oily substance in 170ml of ethyl acetate, rapidly adding the oily substance into 509ml of n-hexane, stirring and crystallizing for 5min, filtering and drying to obtain an intermediate VIII, wherein the total yield is 93.1%, and the beta configuration content is 92.46%.
Example 14
30g of intermediate VI is taken and dissolved in 150ml of dichloromethane, 25.46g of compound VII is added, the mixture is stirred for 0.5h, the temperature is regulated to 25 ℃, and 10.5g of SnCl is added dropwise 4 Stirring reaction for 0.5h, TLC detection reaction is completed, saturated sodium bicarbonate is used for regulating the pH value of the reaction solution to 7-8, the organic phase is decompressed and evaporated to dryness to obtain 33.62g of oily substance, the oily substance is dissolved in 134ml of ethyl acetate, quickly added into 471ml of stirring normal hexane, stirring crystallization is continued for 5min, and intermediate VIII is obtained after filtering and drying, the total yield is 91.1%, and the beta configuration content is 90.26%.
Example 15
30g of intermediate VI is taken and dissolved in 90ml of chloroform, 21.22g of compound VII is added, the mixture is stirred for 0.5h, the temperature is regulated to 15 ℃, and 9g of SnCl is added dropwise 4 Stirring reaction for 0.5h, TLC detection reaction is completed, saturated sodium bicarbonate is used for regulating the pH value of the reaction solution to 7-8, the organic phase is decompressed and evaporated to dryness to obtain 33.97g of oily substance, the oily substance is dissolved in 102ml of ethyl acetate, the oily substance is quickly added into 408ml of n-hexane, stirring crystallization is continued for 5min, and the intermediate VIII is obtained after filtering and drying, the total yield is 89.1%, and the beta configuration content is 91.98%.
Decitabine synthesis
Example 16
Adding 20g of compound VIII and 160ml of absolute methanol into a three-mouth bottle with mechanical stirring, regulating the temperature to 25 ℃, stirring to a solution state, adding 6.52g of sodium methoxide, continuously stirring for reaction for 1h, adding 7.25g of glacial acetic acid, stirring for crystallization for 5h, filtering and drying to obtain 10.65g of crude decitabine, adding 852ml of absolute methanol for recrystallization, standing for 24h for crystallization, filtering and drying to obtain white solid, wherein the total yield is 72.0%, and the purity is 99.92%.
Example 17
Adding 20g of compound VIII and 120ml of absolute methanol into a three-mouth bottle with mechanical stirring, regulating the temperature to 40 ℃, stirring to a solution state, adding 7.83g of sodium methoxide, continuously stirring for reaction for 0.5h, adding 8.70g of glacial acetic acid, stirring for crystallization for 5h, filtering and drying to obtain 10.42g of decitabine crude product, adding 834ml of absolute methanol for recrystallization, standing for 24h for crystallization, filtering and drying to obtain white solid with the total yield of 70.5% and the purity of 99.89%.
Example 18
Adding 20g of compound VIII and 160ml of absolute methanol into a three-mouth bottle with mechanical stirring, regulating the temperature to 20 ℃, stirring to a solution state, adding 6.52g of sodium methoxide, continuously stirring for reaction for 1h, adding 7.25g of glacial acetic acid, stirring for crystallization for 5h, filtering and drying to obtain 10.76g of crude decitabine, adding 861ml of absolute methanol for recrystallization, standing for 24h for crystallization, filtering and drying to obtain white solid with the total yield of 73.2% and the purity of 99.93%.
Example 19
Adding 20g of compound VIII and 200ml of absolute methanol into a three-mouth bottle with mechanical stirring, regulating the temperature to 10 ℃, stirring to a solution state, adding 5.22g of sodium methoxide, continuously stirring for reaction for 2 hours, adding 5.80g of glacial acetic acid, stirring for crystallization for 5 hours, filtering and drying to obtain 10.54g of crude decitabine, adding 843ml of absolute methanol for recrystallization, standing for 24 hours for crystallization, filtering and drying to obtain white solid with the total yield of 71.2% and the purity of 99.90%.
Claims (14)
1. A decitabine intermediate compound is shown in a formula VI, and has a structural formula as follows:
2. a process for preparing an intermediate compound according to claim 1, comprising the steps of (1) protecting a primary hydroxyl group of a compound III with Pvcl, i.e., pivaloyl chloride to form a compound IV, and then carrying out an acylation reaction with 3-methylthiopropionyl chloride without separation and purification to form a compound V; step 2, under the catalysis of concentrated sulfuric acid, the compound V and acetic anhydride undergo an acetylation reaction to obtain a compound VI; the synthetic route is as follows:
step 1, synthesizing a compound V from a compound III
Step 2, synthesis of Compound VI from Compound V
3. The process for the preparation of an intermediate compound according to claim 2, wherein the synthesis of compound v from compound iii in step 1 comprises the steps of: adding a compound III and organic base B, pvCl into an organic solvent A to generate a compound IV with a primary hydroxyl group having a protecting group, directly adding 3-methylthiopropionyl chloride without separation and purification, and generating a compound V through an acylation reaction.
4. A process for the preparation of an intermediate compound according to claim 2 or 3, wherein the reaction temperature in step 1 is-15 ℃ to 0 ℃.
5. A process for the preparation of an intermediate compound according to claim 2 or 3, wherein the reaction temperature in step 1 is-5 ℃.
6. A process for the preparation of an intermediate compound according to claim 3, wherein the organic base B of step 1 is selected from one or more of pyridine, imidazole, triethylamine, DIPEA.
7. A process for the preparation of an intermediate compound according to claim 3, wherein step 1 organic base B is selected from triethylamine.
8. The process for the preparation of intermediate compounds according to claim 2, characterized in that step 2 of synthesizing compound vi comprises in particular the following steps: adding a compound V and acetic anhydride into an organic solvent A, and performing an acetylation reaction under the catalysis of concentrated sulfuric acid to generate a compound VI.
9. The process for producing an intermediate compound according to claim 8, wherein the reaction temperature in step 2 is 0℃to 20 ℃.
10. The process for preparing an intermediate compound according to claim 8, wherein the reaction temperature in step 2 is 10 ℃.
11. The process for producing an intermediate compound according to claim 3 or 8, wherein the organic solvent a is one or two selected from the group consisting of chloroform, methylene chloride, acetonitrile and 1, 2-dichloroethane.
12. A process for the preparation of an intermediate compound according to claim 3 or 8, wherein the organic solvent a is selected from chloroform.
13. Use of compound VI of claim 1 for the preparation of decitabine.
14. A method for preparing decitabine, which is characterized by comprising the following steps: step a) using SnCl 4 Carrying out glycosylation reaction on 5-azacytosine shown in a formula VII of catalytic trimethyl silanization and a compound VI to generate a compound VIII; step b), removing hydroxyl protecting groups from the compound VIII to obtain a final product decitabine I; the reaction route is as follows:
step a:
step b:
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| CN101311184A (en) * | 2007-05-25 | 2008-11-26 | 上海医药工业研究院 | 2-deoxy-D-ribose derivates, preparation method and use thereof |
| CN101570553A (en) * | 2008-05-04 | 2009-11-04 | 上海医药工业研究院 | Derivative of 2-deoxy-D-ribose, preparation method and application thereof |
| CN102037003A (en) * | 2007-10-10 | 2011-04-27 | 西拉格股份公司 | Method of producing 2'-deoxy-5-azacytidine (decitabine) |
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| CN101311184A (en) * | 2007-05-25 | 2008-11-26 | 上海医药工业研究院 | 2-deoxy-D-ribose derivates, preparation method and use thereof |
| CN102037003A (en) * | 2007-10-10 | 2011-04-27 | 西拉格股份公司 | Method of producing 2'-deoxy-5-azacytidine (decitabine) |
| CN101570553A (en) * | 2008-05-04 | 2009-11-04 | 上海医药工业研究院 | Derivative of 2-deoxy-D-ribose, preparation method and application thereof |
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