CN114249786A - Preparation and application of nucleoside intermediate containing N, N-diacyl structure - Google Patents
Preparation and application of nucleoside intermediate containing N, N-diacyl structure Download PDFInfo
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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
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
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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
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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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
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention discloses preparation and application of a nucleoside intermediate containing an N, N-diacyl structure, and belongs to the technical field of medical intermediates. Guanosine is taken as a raw material, and is selectively protected with a silicon reagent or DMT to obtain 5'-OH, and then is subjected to saturation protection with excessive benzoyl chloride to obtain a 2',3 '-OBz-2-amido-N, N-dibenzoyl nucleoside intermediate, and the intermediate is subjected to 5' protecting group removal to obtain a guanosine intermediate I containing an N, N-diacyl structure. The guanosine intermediate I containing the N, N-diacyl structure and the conventional 2',3' -OBz-2-NH2Protective intermediate II or 2',3' -OBz-2-NHBz protective intermediate III comparison, structureThe method has the advantages of novelty, good solubility and good reaction performance, and has good application prospect in the field of nucleosides.
Description
Technical Field
The invention relates to preparation of nucleoside compounds, in particular to preparation and application of nucleoside intermediates containing N, N-diacyl structures, belonging to the technical field of medical intermediates.
Background
Nucleoside monomers (guanosine, adenosine and the like) are important intermediates of food and medical products, and have wide application. For example, the compound can be used for synthesizing food freshener 5' -disodium guanylate, disodium flavor nucleotide and nucleoside antiviral drugs such as ribavirin and acyclovir, and can also be used for preparing nucleoside drugs and common raw material monomers in gene therapy drugs.
The physicochemical properties of the compounds have an important characteristic that the compounds have poor solubility in conventional organic solvents (such as alcohols, ethers, esters, dichloromethane, chloroform, toluene and the like) and have low solubility in large polar solvents (such as DMF, DMSO and the like). This will limit the application of nucleoside monomers to chemical reactions or derivatization studies in conventional solvents, which derivatization reactions generally have the characteristics of high reaction temperature, long reaction time, low yield, etc.
From the technical aspect, the solubilizing ability of nucleoside monomers is generally improved by derivatization with a protecting group, but the improvement of the solubilizing ability is limited by conventional protection on a hydroxyl group (except 5-hydroxyl group) and an amino group.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a nucleoside intermediate containing an N, N-diacyl structure, in particular guanosine nucleoside. The intermediate has the advantages of good solubility in a conventional solvent, good reaction performance, high reaction speed, high product yield and the like.
The invention provides a guanosine intermediate containing an N, N-diacyl structure, which has the following structural formula:
wherein: r1Is a large steric hindrance benzyl ether protecting group such as hydrogen, p-methoxybenzyl, 3, 4-dimethoxybenzyl, p-phenylbenzyl, benzhydryl, trityl, p-methoxyphenyl diphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl and the like; silicon group protecting groups with larger steric hindrance, such as triisopropyl silicon group, dimethyl isopropyl silicon group, diethyl isopropyl silicon group, 1, 2-trimethyl propyl dimethyl silicon group, tert-butyl diphenyl silicon group, tribenzyl silicon group, tri-p-methylbenzyl silicon group, triphenyl silicon group, diphenyl methyl silicon group, di-tert-butyl methyl silicon group and the like; r2、R3Containing C1-C9 acyl radicals, e.g. formazanAcyl, acetyl, propionyl, pivaloyl, benzoyl, and the like; r4Is hydrogen or contains C1-C9 acyl groups, such as formyl, acetyl, propionyl, pivaloyl, benzoyl and the like.
Further, in the above structure, the acyl group containing C1-C9 is selected from benzoyl group or substituted benzoyl group. The protecting group can be easily removed besides ensuring the reaction performance, and the benzoic acid or substituted benzoic acid can be recovered by removing byproducts, thereby reducing the three-waste treatment cost of the production process at the use end.
The invention also provides a preparation method of the guanosine intermediate containing the N, N-diacyl structure, which comprises the following steps: guanosine is taken as a raw material, and is firstly selectively protected by 5' -OH with a silicon reagent or a benzyl reagent, and then reacted with excessive benzoyl chloride for saturation protection to obtain a 2',3' -OBz-2-amido-N, N-dibenzoyl nucleoside intermediate, and the silicon reagent is removed from the intermediate to obtain a guanosine intermediate I containing an N, N-diacyl structure.
Further, in the above technical solution, the silicon reagent is selected from trimethylchlorosilane, triethylchlorosilane, triisopropylchlorosilane, dimethylisopropylchlorosilane, diethylisopropylchlorosilane, 1, 2-trimethylpropyldimethylchlorosilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, tribenzylchlorosilane, tri-p-methylbenzylchlorosilane, triphenylchlorosilane, diphenylmethylchlorosilane, di-tert-butylmethylchlorosilane, and the like.
Further, in the above technical solution, the benzyl reagent is selected from benzyl p-methoxychloride, benzyl 3, 4-dimethoxychloride, benzyl p-phenylbenzylchloride, diphenylchloromethane, triphenylchloromethane, p-methoxyphenyldiphenylchloromethane, bis (p-methoxyphenyl) phenylchloromethane, tris (p-methoxyphenyl) chloromethane, etc.
Further, in the above technical solution, the molar ratio of the silicon reagent or benzyl reagent to guanosine is 1-2: 1.
further, in the above technical solution, the mole ratio of benzoyl chloride to guanosine is 4-8: 1.
further, in the above technical solution, the desiliconization reagent is tetra-n-butylammonium fluoride, hydrogen fluoride, hydrofluoric acid or a hydrogen fluoride/pyridine solution.
The invention also provides application of the guanosine intermediate I containing the N, N-diacyl structure in guanosine phosphorylation reaction.
Further, in the above technical solution, the guanosine is phosphorylated to guanosine-5' -monophosphate and guanosine uridine phosphate (abbreviated as bisglycosidic phospholipid).
The guanosine intermediate I containing the N, N-diacyl structure and the conventional 2',3' -OBz-2-NH2Compared with the intermediate II or the 2',3' -OBz-2-NHBz protective intermediate III, the intermediate II or the 2',3' -OBz-2-NHBz protective intermediate III has the advantages of novel structure, good solubility and good reaction performance, and has good application prospect in the field of nucleosides.
Investigation of solubility
Compound II and Compound III (R)1＝R2＝R3Bz), in a conventional reaction solvent (e.g., THF, DCM, acetonitrile, ethyl acetate, etc.; alcoholic solvents can interfere with the substrate hydroxyl groups and are not suitable), and when the solvent amount/substrate volume/mass ratio is increased to 100:1, the sample is still largely suspended and the solubility is still very small. Namely, the solubility of guanosine compounds having 2 to 3 Bz protecting groups is still deficient. Compound II and compound III (R) in a conventional reaction solvent at a volume/mass ratio of solvent to substrate of 10-20:11＝R2＝R3Bz) leads to poor reactivity when coupled to certain nucleoside monomers.
In the application, the substituted substrate I is very soluble in the conventional reaction solvent (such as THF, DCM, acetonitrile, ethyl acetate and the like), especially in the acetonitrile reaction solvent, and the reaction is relatively smooth.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Suspending the compound 1(28.3g,0.1mol) in 566mLDMF in a three-mouth reaction bottle, sequentially adding triethylamine (10.1g,0.1mol), DMAP (1.4g) and TBDMSCl (22.5g,0.15mol), and heating to 70 ℃ for reacting for 2-4 h; pouring the reaction liquid into water to separate out a large amount of solid, stirring for half an hour, filtering, washing with water, pulping with acetone, purifying, drying to constant weight to obtain 30.6g of white-like solid product with yield of 77%.
Example 2
In a three-port reaction bottle, 200mL of dichloromethane, compound 2(10g,25.2mmol), triethylamine (20.34g,0.201mol,8.0eq) and DMAP (0.5g, 5% wt) are sequentially added, benzoyl chloride (24.6g,0.17mol,7eq) is added dropwise at the temperature controlled below 15 ℃, and the reaction is carried out at room temperature overnight; washing with water gave a dichloromethane solution of compound 3.
To the above solution were added 50mL of acetonitrile and 20mL of hydrofluoric acid at room temperature, and the reaction was stirred at room temperature for 2-3 hours, followed by purification by post-treatment to give 14.6g of product 4 with a yield of 83% in two steps.1HNMR(400MHz,DMSO-d6):13.61(s,1H),8.33(s,1H),7.96(d,J＝7.5Hz,2H),7.80(d,J＝7.5Hz,4H),7.75(d,J＝7.7Hz,2H),7.66(dd,J＝20.1,7.5Hz,2H),7.57-7.48(m,4H),7.43(t,J＝7.4Hz,6H),6.22(d,J＝6.1Hz,1H),5.92(m,1H),5.79(s,1H),5.51(s,1H),4.45(d,J＝3.2Hz,1H),3.69(dt,J＝11.7,7.0Hz,2H).MS:m/z[M+1]+:701.1
Example 3
Adding 20mL of dichloromethane, compound 2(2.0g,5.0mmol), triethylamine (3.1g,30mmol,6.0eq) and DMAP (0.1g, 5% wt) in sequence into a three-port reaction bottle, controlling the temperature below 15 ℃, dropwise adding benzoyl chloride (4.2g,30mmol,6.0eq) and reacting at room temperature overnight; washing with water gave a dichloromethane solution of intermediate 3.
10mL of acetonitrile and 2mL of hydrofluoric acid were added to the above solution at room temperature, and the reaction was stirred at room temperature for 2 to 3 hours to remove the silicon protecting group. Work-up purification gave 2.88g of Compound 4 in 82% yield over two steps.
Example 4
120mL of dichloromethane, compound 2(15g,37.7mmol), triethylamine (19.12g,0.189mol,5.0eq) and DMAP (0.75g, 5% wt) were sequentially added to a three-port reaction flask, benzoyl chloride (18.55g,0.132mol,3.5eq) was added dropwise at a temperature controlled below 15 ℃, and the mixture was reacted at room temperature overnight; washing with water gave compound 5 as a dichloromethane solution.
30mL of acetonitrile and 10mL of hydrofluoric acid were added to the above solution at room temperature, and the mixture was stirred at room temperature for reaction for 2 to 3 hours, followed by purification by post-treatment to obtain 17.5g of Compound 6 in a yield of 78% in two steps.1HNMR(400MHz,DMSO-d6):12.34(s,1H),11.87(s,1H),8.46(s,1H),8.05-7.93(m,4H),7.84-7.77(m,2H),7.70(dd,J＝15.9,7.4Hz,2H),7.65-7.50(m,5H),7.40(t,J＝7.8Hz,2H),6.42(d,J＝6.8Hz,1H),6.25-6.18(m,1H),5.91(dd,J＝5.5,2.8Hz,1H),5.49(t,J＝5.3Hz,1H),4.55(dd,J＝6.3,3.4Hz,1H),3.85(m,2H).MS:m/z[M]+:596.1
Example 5
In a three-neck reaction flask, 120mL of dichloromethane, compound 2(9.9g,25.0mmol), triethylamine (7.59g,75mmol,3.0eq) and DMAP (0.5g, 5% wt) are sequentially added, benzoyl chloride (7.73g,55mmol,2.2eq) is added dropwise at a temperature controlled below 15 ℃, and the mixture is reacted at room temperature overnight; washing with water gave a solution of compound 7 in dichloromethane.
30mL of acetonitrile and 15mL of hydrofluoric acid were added to the above solution at room temperature, and the reaction was stirred at room temperature for 2 to 3 hours, followed by purification by post-treatment to obtain 9.0g of Compound 8, which was found to have a yield of 73.6% in two steps.1HNMR(400MHz,DMSO-d6):10.74(s,1H),8.10(d,J＝14.9Hz,1H),7.99(d,J＝7.3Hz,2H),7.91-7.76(m,2H),7.73(t,J＝7.4Hz,1H),7.66(t,J＝7.4Hz,1H),7.55(dd,J＝16.2,8.5Hz,2H),7.51-7.41(m,2H),6.55(s,2H),6.31(d,J＝6.7Hz,1H),6.23-6.11(m,1H),5.89(dd,J＝5.4,2.8Hz,1H),5.53(t,J＝5.4Hz,1H),4.53(d,J＝3.0Hz,1H),3.85(m,2H).MS:m/z[M]+:492.2
Example 6
Under the protection of nitrogen, compound 4(700mg,1.0mmol) and iodoglycoside analogue 9(942mg,1.1mmol) are mixed, dried acetonitrile is added, water is added for concentration for 2 times, and then 5.0mL of dried acetonitrile is added; the temperature is controlled below 25 ℃, the activating agent 1H-tetrazole (140mg,2.0mmol) is added in batches, and the reaction is carried out for 1 to 2 hours at room temperature.
Weighing iodine simple substance (381mg,1.5mmol) and 5mL THF/H2The O/Pyridine (66:33:1) mixed solvent is prepared into solution. Controlling the temperature below 25 ℃, and dropwise adding the iodine solution into the reaction system for reaction for 0.5 hour. The reaction solution was poured into an ice sodium thiosulfate aqueous solution, extracted with dichloromethane three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in a water bath at 40 ℃. The concentrate was purified by column chromatography using a dichloromethane/methanol system to give a pale yellow solid foam of 10 in 85% yield.1HNMR(400MHz,CDCl3):8.05(d,J＝6.8Hz,1H),7.96-7.88(m,3H),7.85(d,J＝7.4Hz,4H),7.79(s,1H),7.64(s,1H),7.61-7.49(m,2H),7.38(m,8H),7.34-7.27(m,10H),7.25-7.13(m,2H),6.84(d,J＝8.7Hz,4H),6.26(d,J＝5.6Hz,1H),6.09-5.99(m,1H),5.16(s,1H),4.61-4.47(m,1H),4.47-4.32(m,2H),4.27(d,J＝26.0Hz,1H),4.17(d,J＝5.2Hz,1H),4.09-3.98(m,1H),3.83-3.67(m,6H),3.40(d,J＝2.6Hz,2H),3.30(s,1H),2.64(dd,J＝11.9,6.2Hz,2H),2.54(dd,J＝13.6,6.4Hz,1H),2.36(d,J＝5.7Hz,1H).
Example 7
Under the protection of nitrogen, compound 4(700mg,1mmol), bis-cyanoethyl-N, N-diisopropyl-phosphoramidite (1.2eq) and activator 1H-tetrazole (140mg,2mmol) are mixed, 3.5mL of anhydrous acetonitrile is added, reaction is carried out for 1-2 hours at room temperature, iodine (381mg,1.5mmol) and THF/H are dropwise added under the condition that the temperature is controlled to be 25 DEG C2O/Pyridine (66:33: 1; 5mL), stirring for reaction for 15min,the reaction solution was poured into an aqueous solution of ice sodium thiosulfate, extracted with dichloromethane, washed with saturated brine, dried and concentrated to obtain intermediate 11.
Dissolving the intermediate 11 in methanol with 6 times of volume, adding ammonia water with 3 times of volume, and reacting for 48 hours at room temperature. The reaction solution was concentrated, and the concentrate was passed through a cation exchange resin to obtain the objective compound 12 in a yield of 67% in two steps. Nuclear magnetic data and literature [ Science China Chemistry,2020,63,244-]The consistency is achieved; MS M/z [ M + Na ]]+:386.9.
Comparative example 1
The operation is the same as that of example 6, three Bz protective guanosine intermediates 6 can not be dissolved in acetonitrile with 100 times of volume, and the iodoglycoside analogue 9 and 1H-tetrazole are added into a turbid system and basically do not react.
Reason analysis: 1) the reaction is strictly operated without water, materials are dissolved by acetonitrile and then carry water to achieve the aim of removing water, but the compound 6 is insoluble and possibly wraps trace moisture; 2) the oxyphosphoramide substrate is sensitive to water vapor and air, and can slowly deteriorate after being stirred for a long time; 3) the dissolution degree of the raw materials is too small, the reaction contact is insufficient, and the reaction effect is poor.
Comparative example 2
The procedure is as in example 7, the amount of acetonitrile used is 100 times the volume, and starting material 6 is still insoluble and essentially unreactive.
Comparative example 3
The operation is the same as example 6, the acetonitrile dosage is changed to 100 times of the volume, the raw material 8 still can not be dissolved clearly, and basically no reaction is carried out.
Comparative example 4
The procedure is as in example 7, the amount of acetonitrile used is 100 times the volume, and starting material 8 is still insoluble and essentially unreactive.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (10)
1. A guanosine intermediate containing an N, N-diacyl structure is characterized in that the structural formula is as follows:
wherein: r1Is hydrogen, p-methoxybenzyl, 3, 4-dimethoxybenzyl, p-phenylbenzyl, diphenylmethyl, trityl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, 1, 2-trimethylpropyldimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-methylbenzylsilyl, triphenylsilyl, diphenylmethylsilyl or di-tert-butylmethylsilyl; r2、R3Is a C1-C9 acyl group; r4Is hydrogen or contains C1-C9 acyl.
2. The guanosine intermediate having an N, N-diacyl structure according to claim 1, wherein: the acyl containing C1-C9 is selected from formyl, acetyl, propionyl, pivaloyl or benzoyl.
3. The guanosine intermediate having an N, N-diacyl structure according to claim 2, wherein: the acyl containing C1-C9 is selected from benzoyl or substituted benzoyl.
4. The method of preparing a guanosine intermediate having an N, N-diacyl structure according to claim 3 comprising the steps of: guanosine is taken as a raw material, and is firstly selectively protected by 5' -OH with a silicon reagent or a benzyl reagent, and then reacted with excessive benzoyl chloride for saturation protection to obtain a 2',3' -OBz-2-amido-N, N-dibenzoyl nucleoside intermediate, and the silicon reagent is removed from the intermediate to obtain a guanosine intermediate I containing an N, N-diacyl structure.
5. The method for preparing guanosine intermediate having an N, N-diacyl structure according to claim 4, wherein the method comprises the steps of: the silicon reagent is selected from trimethylchlorosilane, triethylchlorosilane, triisopropylchlorosilane, dimethylisopropylchlorosilane, diethylisopropylchlorosilane, 1, 2-trimethylpropyldimethylchlorosilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, tribenzylchlorosilane, tri-p-methylbenzylchlorosilane, triphenylchlorosilane, diphenylmethylchlorosilane or di-tert-butylmethylchlorosilane.
6. The method for preparing guanosine intermediate having an N, N-diacyl structure according to claim 4, wherein the method comprises the steps of: the benzyl reagent is selected from p-methoxy benzyl chloride, 3, 4-dimethoxy benzyl chloride, p-phenyl benzyl chloride, diphenyl chloromethane, triphenyl chloromethane, p-methoxy phenyl diphenyl chloromethane, di (p-methoxy phenyl) phenyl chloromethane or tri (p-methoxy phenyl) chloromethane.
7. The method for preparing guanosine intermediate having an N, N-diacyl structure according to claim 4, wherein the method comprises the steps of: the molar ratio of the silicon reagent or the benzyl reagent to the guanosine is 1-2: 1.
8. the method for preparing guanosine intermediate having an N, N-diacyl structure according to claim 4, wherein the method comprises the steps of: the mole ratio of benzoyl chloride to guanosine is 4-8: 1.
9. the method for preparing guanosine intermediate having an N, N-diacyl structure according to claim 4, wherein the method comprises the steps of: the desiliconization reagent adopts tetra-n-butylammonium fluoride, hydrogen fluoride, hydrofluoric acid or hydrogen fluoride/pyridine solution.
10. Use of a guanosine intermediate I containing an N, N-diacyl structure as defined in any of the claims 1 to 3 for a guanosine phosphorylation reaction.
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