CN111875646A - Preparation method of 2' -oxy-uridine propiolate - Google Patents
Preparation method of 2' -oxy-uridine propiolate Download PDFInfo
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- CN111875646A CN111875646A CN202010838926.3A CN202010838926A CN111875646A CN 111875646 A CN111875646 A CN 111875646A CN 202010838926 A CN202010838926 A CN 202010838926A CN 111875646 A CN111875646 A CN 111875646A
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Abstract
The invention discloses a preparation method of 2' -oxygen-propinyluridine. The method comprises the following steps: (1) enabling the compound with the structure shown in the formula 2 to be acted by benzoyl chloride to obtain a compound with the structure shown in the formula 3; (2) mixing a compound with a structure shown as a formula 3 with an acidic aqueous solution, and reacting to obtain a compound with a structure shown as a formula 4; and (3) reacting the compound with the structure shown in the formula 4 in an alkaline aqueous solution to obtain the compound with the structure shown in the formula 5.
Description
Technical Field
The invention relates to the field of chemical synthesis, and in particular relates to a preparation method of 2' -oxy-uridine propiolate.
Background
Nucleic acids are compounds of biological macromolecules polymerized from many nucleotides and are one of the most fundamental substances of all life. 2' -O-propynyluridine, as a non-natural nucleic acid, is useful for various diseases such as cancer, infectious disease, cardiovascular disease and the like, and therefore its synthetic research is of great significance. Meanwhile, the nucleic acid with alkynyl can also be used as a part of a connecting group to participate in the click chemical reaction with azide, so that the modification method of single-stranded DNA/RNA is greatly enriched.
2' -O-propiolyuridine consists of two important building blocks, ribose and uracil. The currently reported synthetic routes for 2' -oxo-propynyluridine are mainly the following three.
The first starting material was compound 6, which was obtained by BuNBr, Bu2SnO, DMF and 3-bromopropyne react to obtain compounds 7 and 8. And finally, removing the protecting group to obtain the target compound. Since the selectivity at the 2 'and 3' positions is not significant, this route gives a ratio of compound 7 to compound 8 of 1: 1. the reaction conditions are harsh, the subsequent purification is difficult, the yield of the final product is low, and the method has low operability in industry.
The second synthetic route is that compound 9 is used as a starting material, 3-bromopropyne reacts with BEMP to obtain compound 10, and the target product is obtained by removing a protecting group from compound 10. The route has expensive starting materials, more byproducts and difficult subsequent purification, and also has difficult application in industrial production.
The third synthetic route is to deaminate the compound 2 by deaminase, so that the yield is low, the reaction time is long, a large amount of enzyme reagent is needed, the subsequent treatment is difficult, the reaction yield is difficult to stabilize, and the method is difficult to implement in industrial production.
Therefore, there is a strong need in the art to provide a preparation method for 2' -oxy-propinyluridine that is low in cost, reliable in route, simple in post-treatment operation, and controllable in product quality.
Disclosure of Invention
The invention aims to provide a preparation method of 2' -oxygen-propynyluridine.
The invention provides a preparation method of a compound with a structure shown as a formula 5, which comprises the following steps:
(1) enabling the compound with the structure shown in the formula 2 to be acted by benzoyl chloride to obtain a compound with the structure shown in the formula 3;
(2) mixing a compound with a structure shown as a formula 3 with an acidic aqueous solution, and reacting to obtain a compound with a structure shown as a formula 4; and
(3) reacting a compound with a structure shown as a formula 4 in an alkaline aqueous solution to obtain a compound with a structure shown as a formula 5;
wherein Bz is benzoyl.
In another embodiment, the action of step (1) is carried out at 10-50 ℃; the mol ratio of the compound with the structure shown in the formula 2 to benzoyl chloride is 1:3-1: 6.
In another embodiment, the reaction of step (2) is carried out at 90-130 ℃.
In another embodiment, the acidic substance is present in an amount of 50 to 90% by mass based on the total mass of the acidic aqueous solution of step (2); the acidic substance is selected from one or more than two of the following substances: acetic acid, citric acid, formic acid, boric acid, and oxalic acid.
In another embodiment, the reaction time in step (2) is from 4 to 8 hours.
In another embodiment, the reaction of step (3) is carried out at 10-50 ℃; the mass-volume ratio of the compound with the structure shown as the formula 4 in the alkaline aqueous solution is 1:5-1: 20.
In another embodiment, the content of the alkaline substance is 25-35% by mass of the total mass of the alkaline aqueous solution in the step (3); the alkaline substance is selected from one or more than two of the following substances: potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, ammonia, pyridine, and triethylamine.
In another embodiment, the compound with the structure shown in the formula 2 is obtained by ammonolysis of the compound with the structure shown in the formula 1 by ammonia water; the aminolysis is carried out at 10-50 ℃; the mass-volume ratio of the compound with the structure shown as formula 1 to ammonia water is 1:10-1: 30;
accordingly, the invention provides a preparation method of 2' -oxy-propiolic uridine, which has the advantages of low cost, reliable route, simple post-treatment operation and controllable product quality.
Detailed Description
The inventors of the present invention have extensively studied and found that a cytidine compound having a structure represented by formula 3 can be directly converted into uridine (a compound having a structure represented by formula 4) in an acidic aqueous solution. On the basis of this, the present invention has been completed.
The compounds related to the invention are shown in the following table, and as used herein, "the compound having the structure shown in formula 1" and "compound 1" can be used interchangeably, and refer to the compound having the structure corresponding to the number 1 in the following table, and so on.
Specifically, the preparation method of the compound 2' -O-propynyluridine with the structure shown in the formula 5 comprises the following steps:
the first step, reacting a compound with a structure shown as a formula 2 with benzoyl chloride to obtain a compound with a structure shown as a formula 3;
secondly, reacting the compound with the structure shown as the formula 3 with an acidic aqueous solution to obtain a compound with the structure shown as the formula 4;
and thirdly, reacting the compound with the structure shown as the formula 4 with an alkaline aqueous solution to obtain the compound with the structure shown as the formula 5.
The reaction in the first step is carried out at 10-50 ℃, preferably at 10-30 ℃; the reaction time is generally 1 to 3 hours.
In one embodiment of the present invention, the molar ratio of the compound having the structure represented by formula 2 to benzoyl chloride in the first step is 1:3 to 1:6, such as, but not limited to, 1:3 to 1:4, 1:3 to 1:5, 1:3.5 to 1:4.5, 1:4 to 1:5.5, etc.
In one embodiment of the present invention, the reaction solvent of the first step is selected from pyridine and/or dichloromethane.
In one embodiment of the present invention, in the first step, the compound represented by formula 2 may be reacted with 2, 4-dimethylbenzoyl chloride, acetyl chloride, or the like to obtain a compound similar to formula 3, wherein Bz is an amide protecting group such as 2, 4-dimethylbenzoyl, acetyl, or the like.
In one embodiment of the present invention, the compound 2 used in the first step can be obtained by aminolysis of a compound represented by the following formula 1 with ammonia water; the temperature of the ammonolysis reaction is 10-50 ℃, preferably 10-30 ℃; the mass volume ratio of the compound 1 to the ammonia water is 1:10-1:30, preferably 1: 20; the aminolysis reaction can be carried out in acetonitrile.
The reaction of the second step is carried out at 90-130 deg.C, such as but not limited to 95-125 deg.C, 105-115 deg.C, etc., preferably at 100-120 deg.C; the reaction time is generally 4 to 8 hours. The reaction time is generally matched with the reaction temperature, and the reaction time is short when the reaction temperature is high, and vice versa.
The acidic aqueous solution used in the above-mentioned second step may contain 50 to 90 w/w% of the acidic substance, preferably 70 to 80 w/w% of the acidic substance, based on the total mass thereof.
In one embodiment of the present invention, the acidic substance forming the acidic aqueous solution in the second step may be one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, chloric acid, sulfurous acid, acetic acid, citric acid, and boric acid.
In one embodiment of the present invention, the second step is to react the compound having the structure represented by formula 3 with an acidic aqueous solution, such as but not limited to 1:10-1:12, 1:11-1:14, 1:13-1:15, etc., in a mass-to-volume ratio of 1:10-1: 15.
The compound 4 obtained in the above-mentioned second step can be directly used in the third step.
The reaction in the third step is carried out at 10 to 50 ℃ such as, but not limited to, 10 to 30 ℃, 20 to 45 ℃, 15 to 25 ℃ and the like; the reaction time is generally 6 to 24 hours, such as, but not limited to, 8 to 20 hours, 10 to 15 hours, and the like.
In an embodiment of the present invention, the mass-to-volume ratio of the compound having the structure represented by formula 4 to the alkaline aqueous solution in the third step is 1:5 to 1:20, such as, but not limited to, 1:10 to 1:20, 1:8 to 1:15, and the like.
The aqueous alkaline solution used in the above-mentioned third step may contain 25 to 35 w/w% of an alkaline substance, preferably 28 to 32 w/w% of an alkaline substance, based on the total mass thereof.
In one embodiment of the present invention, the basic substance forming the basic aqueous solution in the third step may be one or more of potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, ammonia water, pyridine, and triethylamine.
In one embodiment of the present invention, the reaction solvent of the third step is selected from methanol and/or ethanol.
In a preferred embodiment of the present invention, the crude compound 5 obtained by the third step may be purified by column chromatography. The stationary phase used for column chromatography can be silica gel column, alkaline alumina column, resin column, etc.; the mobile phase of column chromatography can be one or more than two of the following: dichloromethane, methanol, ethyl acetate, ethanol, acetone, n-propanol, acetonitrile, tert-butyl methyl ether, isopropanol, isobutanol, tert-butanol and tert-amyl alcohol.
In one embodiment of the present invention, the preparation method of the compound 2' -O-propynyluridine with the structure shown in formula 5 comprises the following steps:
(i) carrying out ammonia ammonolysis on the compound with the structure shown in the formula 1 to obtain a compound with the structure shown in the formula 2;
(ii) enabling the compound with the structure shown in the formula 2 to be acted by benzoyl chloride to obtain a compound with the structure shown in the formula 3;
(iii) mixing a compound with a structure shown as a formula 3 with an acidic aqueous solution, and reacting to obtain a compound with a structure shown as a formula 4;
(iv) reacting the compound with the structure shown in the formula 4 in an alkaline aqueous solution to obtain the compound with the structure shown in the formula 5.
To make the features and effects of the present invention comprehensible to those skilled in the art, general description and definitions are made below with reference to terms and expressions mentioned in the specification and claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The theory or mechanism described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, i.e., the present disclosure may be practiced without limitation to any particular theory or mechanism.
All features defined herein as numerical ranges or percentage ranges, such as values, amounts, levels and concentrations, are for brevity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to cover and specifically disclose all possible subranges and individual numerical values (including integers and fractions) within the range. As used herein, the term "about" when used to modify a numerical value means within + -5% of the error margin measured for that value.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All features disclosed in this specification may be combined in any combination, provided that there is no conflict between such features and the combination, and all possible combinations are to be considered within the scope of the present specification. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The main advantages of the invention are:
1. the preparation method of the 2' -O-propiolic uridine provided by the invention has less pollution, and can avoid the defects of difficult subsequent purification, overlong reaction route, lower product yield, expensive raw materials and the like.
2. The preparation method of the 2' -O-propiolic uridine provided by the invention is simple to operate, strong in stability, higher in yield, high in product purity and easy for industrial large-scale production.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified. The weight volume percentage units in the present invention are well known to those skilled in the art and refer to, for example, the weight of solute in a 100ml solution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
In the following examples, the HPLC assay of the compounds was as follows:
liquid phase column: luna 5 μm C18(2), 150 × 4.6 mm;
flow rate: 1 mL/min;
column temperature: 25 ℃;
a detector: UV (diode array detector, preferably 260nm) or ELSD (evaporative light scattering detector);
mobile phase: solution A: 10mmol ammonium acetate water solution; and B, liquid B: chromatographic grade acetonitrile.
In the analysis process, helium gas of the liquid A and the liquid B is degassed on line, and the flow rate of the helium gas is 50 ml/min.
Gradient:
| time (min) | ％A | ％B |
| 0 | 65 | 35 |
| 3 | 65 | 35 |
| 15 | 5 | 95 |
| 20 | 5 | 95 |
| 25 | 65 | 35 |
| 30 | 65 | 35 |
Example 1
Preparation of 2' -O-propiolic cytidine (compound 2)
Adding 23.0g of compound 1 powder, 200mL of acetonitrile and 400mL of ammonia water into a 500mL three-necked flask, stirring and reacting at 20 ℃ for 18h, concentrating the reaction solution to dryness after the reaction is finished, washing the crude product twice by using acetonitrile, drying the filter cake to obtain 18g of compound 2, wherein the yield is 90.0%, the purity is 97.8%, and the crude product is directly put into the next step for reaction.
HRMS(ESI):Calcd.for C12H15N3O5(M+H+):281.1012,Found:281.1010。
Example 2
Preparation of 2 ' -oxo-propyne-3 ', 5 ' -benzoylcytidine (Compound 3)
In a 500mL three-necked flask, 10.0g of compound 2 prepared in the above step and 100mL of pyridine were added, and 3.5 equivalents of benzoyl chloride were added. Reacting for 2h at 10-30 ℃, and spin-drying after the reaction is finished. Dissolving with DCM, washing with citric acid solution twice, washing with sodium bicarbonate solution 2, and washing with Na2SO4Drying and spin-drying to obtain 15g of crude product, the yield is 71%, and the purity is 98.1%.
HRMS(EI):Calcd.for C33H26N3O8(M+H+):592.1720,Found:592.1715
Example 3
Preparation of 2 ' -O-propyne-3 ', 5 ' -benzoyluridine (Compound 4)
Adding 15g of compound 3 into a 500mL three-necked flask, adding 10 times volume of 80% acetic acid aqueous solution, reacting at 110 ℃ for 6 hours, concentrating the reaction solution to dryness after the reaction is finished, dissolving with 150mL of DCM, separating out an organic phase, washing with sodium bicarbonate solution 2, washing with saturated saline once, and washing with Na2SO4Drying and spin-drying to obtain 10 g of crude product, the yield is 80.7%, the purity is 96.8%, and the crude product is continuously and directly put into the next step.
HRMS(EI):Calcd.for C26H22N2O8(M+H+):490.1376,Found:490.1377
The inventors used room temperature (20-40 ℃) in example 3, and the reaction conversion was less than 5%.
The inventors used a 30% aqueous acetic acid solution in example 3, and the reaction conversion was only 21% after 24 hours.
Example 4
Preparation of 2' -O-propinyluridine (Compound 5)
In a 500mL three-necked flask, 10.0g of Compound 4, 100mL of a methanol solution, and 50mL of aqueous ammonia (25 to 35% by mass) were added, the mixture was stirred at 40 ℃ and reacted for 6 hours, and after the reaction was completed, the reaction mixture was concentrated to dryness. The crude product was directly purified by silica gel column (100g silica gel, 100 mesh 200) in a solvent system of dichloromethane and methanol 20/1-10/1 (vol.%), to give 5.3 g of compound 5 in 92.1% yield and 99.6% purity.
Compound 5 was a white solid with Rf 0.24 in TLC (dichloromethane/methanol 9: 1);
1H NMR(500MHz,DMSO-d6)11.33(s,1H),7.65(d,J＝8.1Hz,1H),6.13(m,1H),5.63(m,1H)5.60(d,J＝8.1Hz,1H),5.02(m,1H),4.16(d,J＝2.4Hz,2H),4.13-4.02(m,2H),3.72-3.49(m,3H),3.44(t,J＝2.3Hz,1H)ppm；13C NMR(100MHz,DMSO-d6)163.1,150.4,141.9,100.6,83.2,82.8,82.4,79.5,77.6,72.5,59.9,57.5ppm.
the foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.
Claims (10)
1. A preparation method of a compound with a structure shown as a formula 5 is characterized by comprising the following steps:
(1) enabling the compound with the structure shown in the formula 2 to be acted by benzoyl chloride to obtain a compound with the structure shown in the formula 3;
(2) mixing a compound with a structure shown as a formula 3 with an acidic aqueous solution, and reacting to obtain a compound with a structure shown as a formula 4;
(3) reacting a compound with a structure shown as a formula 4 in an alkaline aqueous solution to obtain a compound with a structure shown as a formula 5;
wherein Bz is benzoyl.
2. The method according to claim 1, wherein the action of step (1) is carried out at 10 to 50 ℃; the mol ratio of the compound with the structure shown in the formula 2 to benzoyl chloride is 1:3-1: 6.
3. The method of claim 1, wherein the reaction of step (2) is carried out at 90-130 ℃.
4. The method according to claim 1, wherein the acidic substance is contained in an amount of 50 to 90% by mass based on the total mass of the acidic aqueous solution in the step (2).
5. The method according to claim 4, wherein the acidic substance is one or two or more selected from the group consisting of: acetic acid, citric acid, formic acid, boric acid, and oxalic acid.
6. The method according to claim 1, wherein the reaction time in the step (2) is 4 to 8 hours.
7. The method according to claim 1, wherein the reaction of step (3) is carried out at 10 to 50 ℃; the mass-volume ratio of the compound with the structure shown as the formula 4 in the alkaline aqueous solution is 1:5-1: 20.
8. The method according to claim 1, wherein the content of the basic substance is 25 to 35% by mass based on the total mass of the basic aqueous solution in the step (3); the alkaline substance is selected from one or more than two of the following substances: potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, ammonia, pyridine, and triethylamine.
9. The method according to any one of claims 1 to 8, wherein the compound having the structure represented by formula 2 is obtained by aminolysis of a compound having the structure represented by formula 1 with ammonia;
10. the method of claim 9, wherein the aminolysis is carried out at 10-50 ℃; the mass-volume ratio of the compound with the structure shown as the formula 1 to ammonia water is 1:10-1: 30.
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Non-Patent Citations (3)
| Title |
|---|
| ANTONIN HOLY，等: "ACID-CATALYSED MIGRATION OF N4-ACYL GROUPS IN CYTOSINE DERIVATIVES", 《COLLECTION CZECHOSLOV. CHEM. COMMUN.》 * |
| LINE LOLK，等: "A Click Chemistry Approach to Pleuromutilin Conjugates with Nucleosides or Acyclic Nucleoside Derivatives and Their Binding to the Bacterial Ribosome", 《J. MED. CHEM.》 * |
| 吉卯祉: "《药物合成》", 31 July 2009, 中国中医药出版社 * |
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