CN107540718B - Preparation method of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone - Google Patents
Preparation method of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone Download PDFInfo
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Abstract
The invention relates to 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone, in particular to a preparation method of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone, which comprises the following steps of reacting 2-hydroxypyrimidine hydrochloride with glacial acetic acid/ iodine chloride solution to generate 5-iodo-2-pyrimidone, reacting 5-iodo-2-pyrimidone with 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose to generate 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone, and finally generating a target product from the 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone.
Description
Technical Field
The invention relates to 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone, in particular to a preparation method of kinds of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone.
Background
1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidinone (IPdR) is potential oral TdR radiosensitizers that can penetrate rapidly proliferating tumor cells, bone marrow, intestinal epithelial cells, IPdR was successfully used in phase I clinics for treating advanced lymphoma as a single drug in 2012, and phase 0 clinics using IPdR as a radiosensitizer, completed by the national institute of health in the United states in 2013, achieved the expected results.IPdR has the following structural formula:
US4782142 discloses a process for the preparation of species of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidinone, comprising the steps of:
(1) 2-pyrimidine (6g, 62.44mmol) and n-iodosuccinimide (14.7g, 65.3mmol) were stirred in anhydrous Dimethylformamide (DMF) (30ml) at room temperature in the absence of light and under anhydrous conditions for 48 h. The mixture was added to 50ml of diethyl ether and the supernatant was poured into another container. The precipitate was collected by filtration and washed repeatedly with acetone and finally with methanol until the filtrate became light yellow. Vacuum drying to obtain 5-iodo-2-pyrimidone yellow granule product, and purifying 5-iodo-2-pyrimidone by chromatography and spectrum, wherein element analysis shows that the product contains trace amount of DMF, and the yield is 11.35g and 77.5%.
(2) A suspension of 0.86g (3.87mmol) of 5-iodo-2-pyrimidone was refluxed in 15ml of hexamethyldisilazane and 0.3ml of trimethylchlorosilane for 2 hours (under anhydrous conditions), and cooled in vacuo to collect a yellow oil which was 5-iodo-2-oxy-trimethylsilane. The remaining solvent was transferred by co-evaporation with 1, 2-dichloroethane (2X 10 ml).
(3)1.65g (3.84mmol) of 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose are added to the above oil; the mixture was dissolved in 50ml of anhydrous 1, 2-dichloroethane and cooled in the air. To the cooled solution 0.2ml (1.7mmol) of SnCl was added dropwise4In 25ml of anhydrous dichloroethane. The mixture was stirred at 0 ℃ for 2.5 hours until chromatography (17% ethyl acetate in dichloromethane) indicated disappearance of the starting material indicating substantial completion of the reaction.
(4) The mixture was diluted in 60ml of dichloroethane and 50ml of saturated bicarbonate and the resulting emulsion was filtered over celite and the precipitate washed several times with 1, 2-dichloroethane the organic layer was washed with 50ml of water, dried over anhydrous magnesium sulphate and collected until 2 equal intensity points of chromatography appeared this residue was chromatographed on 90g of silica gel and eluted in dichloromethane with 0-25% ethyl acetate the final product, including the isomer of form α which was gradually converted, was collected and dried weighing 0.48g, yield 20.14% white crystalline compound obtained by recrystallization from ethanolic acetone, melting point 175-.
In the patent, when 5-iodine-2-hydroxypyrimidinone reflows in hexamethyldisilazane, a large amount of solid is generated to sublimate and easily block the orifice of the backflow pipe, so that potential safety hazards exist, a 5-iodine-2-oxy-trimethylsilane intermediate is easily decomposed in water and is not easy to store, and in addition, the yield of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodine-2-pyrimidone in the patent is low and is only 20.14%.
For the reasons, the preparation of IPdR is generally completed in a laboratory at present, and industrial mass production cannot be realized.
Disclosure of Invention
The invention aims to provide a preparation method of kinds of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone, which has stable intermediate and is convenient for industrial production.
The preparation method of the 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone comprises the following steps:
(1) 5-iodo-2-pyrimidones
Reacting 2-hydroxypyrimidine hydrochloride with iodine chloride to obtain 5-iodo-2-pyrimidone;
(2)1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone
Reacting 5-iodo-2-pyrimidone with N, O-bis (trimethylsilyl) trifluoroacetamide and then with 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose in the presence of tin tetrachloride to give 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone;
(3)1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidinone
Reacting 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranosyl ] -5-iodo-2-pyrimidone with methanol and ammonia gas to obtain 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone.
The more specific steps are as follows:
(1) preparation of 5-iodo-2-pyrimidones
Reacting 2-hydroxypyrimidine hydrochloride with glacial acetic acid/ iodine chloride solution in the presence of glacial acetic acid, cooling, adding ethyl acetate, preserving heat, stirring, filtering, standing and layering filtrate to obtain an organic phase and a water phase, mixing the water phase, a filter cake and the ethyl acetate, repeatedly preserving heat, stirring, filtering, standing and layering the filtrate, adding the ethyl acetate into the water phase and the filter cake, adjusting the pH value, then adding the ethyl acetate, filtering, and drying the filter cake to obtain 5-iodo-2-pyrimidinone;
(2) preparation of 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone
Adding dichloromethane and N, O-bis (trimethylsilyl) trifluoroacetamide into the 5-iodo-2-pyrimidone obtained in the step (1) for reaction, cooling under the protection of nitrogen, dropwise adding anhydrous stannic chloride/dichloromethane solution, adding 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose for reaction, then adding the obtained product into sodium bicarbonate solution for quenching, filtering, standing and layering the filtrate, drying the organic phase, concentrating under reduced pressure, filtering, and drying a filter cake to obtain 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone;
(3) preparation of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone
And (2) under the protection of nitrogen, introducing ammonia gas into an anhydrous methanol system, adding the 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranosyl ] -5-iodo-2-pyrimidone obtained in the step (2) to react, filtering, concentrating the filtrate under reduced pressure, adding ethyl acetate, cooling, crystallizing, filtering, and drying a filter cake to obtain the 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone.
Wherein:
in the step (1), the mass ratio of the glacial acetic acid, the 2-hydroxypyrimidine hydrochloride and the glacial acetic acid/ iodine chloride solution is 4-6:10-14:18-22, and the mass ratio of the glacial acetic acid to iodine chloride in the glacial acetic acid/ iodine chloride solution is 0.9-1.1: 6.5-7.5.
In the step (1), the reaction is terminated when the reaction temperature of the 2-hydroxypyrimidine hydrochloride and the glacial acetic acid/ iodine chloride solution is 45-55 ℃ and the content of 5-iodo-2-pyrimidinone is more than 70 wt.%.
In the step (1), cooling to 10-15 ℃, preserving heat and stirring for 15-20 minutes; the pH value is 5.0-7.0; the drying temperature is 35-45 deg.C, and the drying time is 20-30 h.
In the step (2), the mass ratio of the 5-iodine-2-pyrimidone, the dichloromethane, the N, O-bis (trimethylsilyl) trifluoroacetamide, the anhydrous stannic chloride/dichloromethane solution and the 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose is 24-30: 420: 510:57-69:80-95: 50-60; wherein in the anhydrous stannic chloride/dichloromethane solution, the mass ratio of stannic chloride to dichloromethane is 1.5-2.5: 8-10.
In the step (2), 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose is added for reaction at the temperature of-35 to-30 ℃; the reaction was terminated when the content of 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose was <2 wt.%.
In the step (2), the temperature during the reduced pressure concentration is 40-50 ℃, the drying temperature of the filter cake is 35-45 ℃, and the drying time of the filter cake is 10-20 h.
In the step (3), the mass ratio of the anhydrous methanol to the 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone is 20-24: 2.5-3.5.
In the step (3), the temperature of the system is-15-0 ℃ when ammonia gas is introduced; stopping introducing ammonia gas when the ammonia gas in the system is more than or equal to 25 wt.%; the reaction temperature is 5-12 ℃, and the reaction time is 13-15 h.
In the step (3), the temperature is 15-20 ℃ when the temperature is reduced and the crystallization is carried out, the drying temperature is 30-35 ℃ and the drying time is 8-12 h.
The synthetic route of the invention is as follows:
wherein the compound comprises 1, 2-hydroxypyrimidine hydrochloride, 2, 5-iodine-2-pyrimidinone, 3, 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose, 4, 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranosyl ] -5-iodine-2-pyrimidinone and 5, 1- (2-deoxy- β -D-ribofuranosyl) -5-iodine-2-pyrimidinone.
The invention has the following beneficial effects:
in the preparation method of the 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone, all intermediates are stable and convenient for industrial production, and in addition, the yield of the 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone reaches 45-55%, and the purity is more than 99.7%.
Drawings
FIG. 1 is a schematic representation of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidinone of example 11H nuclear magnetic resonance spectrogram;
FIG. 2 is a schematic representation of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidinone of example 113C nuclear magnetic resonance spectrogram;
FIG. 3 is a mass spectrum of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone of example 1;
FIG. 4 is a liquid chromatogram of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone of example 1;
FIG. 5 is a schematic representation of 5-iodo-2-pyrimidone of example 11H nuclear magnetic resonance spectrogram;
FIG. 6 is a scheme showing the preparation of 5-iodo-2-pyrimidone in example 113C nuclear magnetic resonance spectrogram;
FIG. 7 is a mass spectrum of 5-iodo-2-pyrimidone in example 1;
FIG. 8 shows 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranosyl in example 1]Process for preparing (E) -5-iodo-2-pyrimidinones1H nuclear magnetic resonance spectrogram;
FIG. 9 is the drawing of 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranosyl group in example 1]Process for preparing (E) -5-iodo-2-pyrimidinones13C nuclear magnetic resonance spectrogram;
FIG. 10 is a mass spectrum of 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone in example 1;
FIG. 11 is a NOE two-dimensional nuclear magnetic spectrum of 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidinone of example 1.
Detailed Description
The invention is further described with reference to the following examples.
Example 1
(1) Preparation of 5-iodo-2-pyrimidones
Adding 96kg of purified water into a reaction tank, starting stirring, adding 24kg of 2-hydroxypyrimidine hydrochloride, stirring until the mixture is clear, adding 10kg of glacial acetic acid, starting an external bath to heat the system to 45 ℃, dropwise adding glacial acetic acid/ iodine chloride solution (5kg of glacial acetic acid and 35kg of iodine chloride) prepared in a 20L glass reactor at the temperature of 48 ℃, and after dropwise adding, keeping the temperature at 45 ℃ for reaction for 6 hours.
Sampling (taking 0.2mL of supernatant of the reaction system, adding 0.8mL of DMSO) and sending to HPLC to detect the reaction progress, and terminating the reaction when the content of the 5-iodo-2-pyrimidone in the system is more than 70 wt.%. Cooling the system to 10 ℃, adding 48kg of ethyl acetate, keeping the temperature at 10 ℃, stirring for 15 minutes, starting a flat plate centrifuge for filtering, standing and layering filtrate, and temporarily storing an organic phase.
Mixing the obtained water phase and filter cake, adding 36kg of ethyl acetate, stirring for 15 minutes at 10 ℃, and starting a flat plate centrifuge for filtration; standing and layering the filtrate, and temporarily storing an organic phase; mixing the obtained water phase and filter cake, adding 36kg of ethyl acetate, stirring for 15 minutes at 10 ℃, and starting a flat plate centrifuge for filtering; standing and layering the filtrate, and temporarily storing an organic phase; mixing the obtained water phase and filter cake, adding 36kg of ethyl acetate, stirring for 15 minutes at 10 ℃, and starting a flat plate centrifuge for filtering; standing and layering the filtrate, and temporarily storing an organic phase. And then cooling the finally obtained water phase to 5 ℃, adding 20kg of ethyl acetate while stirring, adding sodium bicarbonate solid in portions, controlling the temperature to be 5 ℃, adding the filter cake into the system, and continuously adjusting the pH value to 5.0 by using the sodium bicarbonate solid while stirring. Adding 20kg of ethyl acetate into the system, stirring for 15 minutes, and starting a flat plate type centrifuge for filtering; and leaching the filter cake with cold purified water for 2 times, leaching with ethyl acetate for 2 times, and filtering to obtain a wet product.
And (3) placing the wet product in a low-temperature vacuum drying oven, and carrying out vacuum drying for 25 hours at 35 ℃ to obtain the 5-iodo-2-pyrimidone. The obtained 5-iodo-2-pyrimidone was subjected to nuclear magnetic resonance and mass spectrometry, as shown in fig. 5, 6, and 7.
(2) Preparation of 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone
468kg of dichloromethane is added into a reaction tank, 63kg of N, O-bis (trimethylsilyl) trifluoroacetamide and 27kg of 5-iodo-2-pyrimidone are sequentially added into the system, stirring is started, the system is heated to 35 ℃ by opening an external bath, the temperature is kept for 14 hours for reaction, the reaction system is cooled to-35 ℃ under the protection of nitrogen, prepared anhydrous tin tetrachloride/dichloromethane solution (72 kg of dichloromethane and 16kg of tin tetrachloride) is dropwise added, and after the dropwise addition is finished, 54.6kg of 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose is added into the reaction system in batches at the temperature of-35 ℃ for reaction at the temperature of-35 ℃.
Detecting that the reaction is stopped when the content of the 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose is less than 2 wt.%. The reaction solution was added to a prepared sodium bicarbonate solution (81 kg of sodium bicarbonate solid and 270kg of purified water) at 10 ℃ to quench it, stirred at the temperature for 1 hour, and allowed to stand for 2 hours.
Filtering to obtain filtrate A and a filter cake, soaking and washing the filter cake with dichloromethane by 27kg, filtering to obtain filtrate B, combining the filtrate A and the filtrate B, standing for layering, adding anhydrous magnesium sulfate into the obtained organic phase for 18kg, drying for 1 hour, filtering, discarding the filter cake, concentrating the filtrate under reduced pressure at the temperature of 45 ℃ in an external bath, and concentrating to obtain a total volume of about 150L; adding 72.9kg of ethyl acetate into the concentrated solution, continuously concentrating at the external bath temperature of 45 ℃ until the total volume is about 150L; adding 67.5kg of ethyl acetate into the concentrated solution, continuously concentrating at the external bath temperature of 45 ℃ until the total volume is about 150L; 40.5kg of ethyl acetate was added to the concentrated solution, and the mixture was further concentrated at 45 ℃ in an external bath to a total volume of about 150L.
After the concentration is finished, stirring for 0.5 hour at 45 ℃, then cooling to 15 ℃, stirring for 10 minutes, and starting a flat plate centrifuge for filtering; adding the obtained filter cake into ethyl acetate, heating to 45 ℃, stirring for 0.5 hour, cooling the system to 15 ℃, stirring for 10 minutes, starting a flat plate type centrifuge for filtering, leaching the filter cake with 21.6kg of ethyl acetate, and filtering to obtain a wet product.
And (3) placing the wet product in a vacuum drying oven, and carrying out vacuum drying for 15 hours at the temperature of 35 ℃ to obtain the 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone.
The obtained 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranosyl ] -5-iodo-2-pyrimidone was subjected to nuclear magnetic resonance and mass spectrometry, as shown in FIG. 8, FIG. 9, FIG. 10, and FIG. 11.
(3) Preparation of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone
Adding 175kg of anhydrous methanol into a reaction tank under the protection of nitrogen, starting stirring, cooling the system to-10 ℃, and introducing NH into the system3Until the content is more than or equal to 25wt.% (titration detection), stirring and heating to 5 ℃, and adding 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranosyl]24kg of 5-iodo-2-pyrimidone.
After the addition was completed, the reaction was incubated at 10 ℃ for 13 hours, and the reaction system was filtered. The filtrate was concentrated under reduced pressure at 28 ℃ on an external bath, to a volume of 1/2 (about 120L) and terminated.
Adding 108kg of ethyl acetate into the concentrated solution, stirring, cooling to 15 ℃, and crystallizing for 5 h. Filtering, leaching a filter cake with 4kg of anhydrous methanol, and filtering to obtain a wet product.
And (3) placing the wet product in a vacuum drying oven, and carrying out vacuum drying at the temperature of 30 ℃ for 10 hours to obtain the 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidinone, wherein the yield is 48%, and the purity is 99.718%.
Subjecting the obtained 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone to nuclear magnetic resonance and mass spectrometry, as shown in FIG. 1, FIG. 2 and FIG. 3, and subjecting the obtained 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone to liquid phase detection, as shown in FIG. 4. the data on peaks in FIG. 4 are shown in Table 1, wherein the content of 1- (2-deoxy- α -D-ribofuranosyl) -5-iodo-2-pyrimidone is 0.034 wt.%, that is, the content of α type diastereomer is extremely low.
TABLE 1 data sheet on peaks
| Peak # | Retention time | Area of | Height | Area% | Degree of separation | Theoretical plate | Tailing factor | |
| 1 | 3.796 | 2661 | 547 | 0.010 | 0.000 | 12423 | 1.274 | |
| 2 | 7.762 | 43312 | 1725 | 0.160 | 13.155 | 4424 | 2.841 | |
| 3 | 13.998 | 9111 | 1038 | 0.034 | 17.608 | 53782 | 0.941 | |
| 4 | 15.444 | 26951571 | 614448 | 99.718 | 2.051 | 2791 | 1.106 | |
| 5 | 21.434 | 13642 | 2666 | 0.050 | 9.107 | 344359 | 1.070 | |
| 6 | 29.757 | 7359 | 1169 | 0.027 | 53.268 | 511577 | 1.807 | |
| Total of | 27027657 | 621592 | 100.000 |
Example 2
(1) Preparation of 5-iodo-2-pyrimidones
Adding 103kg of purified water into a reaction tank, starting stirring, adding 28kg of 2-hydroxypyrimidine hydrochloride, stirring until the mixture is clear, adding 10.7kg of glacial acetic acid, starting an external bath to heat the system to 45 ℃, dropwise adding glacial acetic acid/ iodine chloride solution (5.2kg of glacial acetic acid and 37.1kg of iodine chloride) prepared in a 20L glass reactor at the temperature of 45 ℃, and after dropwise adding, keeping the temperature at 50 ℃ for reaction for 5 hours.
Sampling (taking 0.2mL of supernatant of the reaction system, adding 0.8mL of DMSO) and sending to HPLC to detect the reaction progress, and terminating the reaction when the content of the 5-iodo-2-pyrimidone in the system is more than 70 wt.%. Cooling the system to 14 ℃, adding 50kg of ethyl acetate, keeping the temperature at 14 ℃, stirring for 15 minutes, starting a flat plate centrifuge for filtering, standing and layering filtrate, and temporarily storing an organic phase.
Mixing the obtained water phase and filter cake, adding ethyl acetate 40kg, stirring at 10 deg.C for 15 min, and filtering with a flat centrifuge; standing and layering the filtrate, and temporarily storing an organic phase; mixing the obtained water phase and filter cake, adding ethyl acetate 40kg, stirring at 10 deg.C for 15 min, and filtering with a flat centrifuge; standing and layering the filtrate, and temporarily storing an organic phase; mixing the obtained water phase and filter cake, adding ethyl acetate 40kg, stirring at 10 deg.C for 15 min, and filtering with a flat centrifuge; standing and layering the filtrate, and temporarily storing an organic phase. And then cooling the finally obtained water phase to 8 ℃, adding 15kg of ethyl acetate while stirring, adding sodium bicarbonate solid in portions, controlling the temperature to be 5 ℃, adding the filter cake into the system, and continuously adjusting the pH value to 6.5 by using the sodium bicarbonate solid while stirring. Adding 25kg of ethyl acetate into the system, stirring for 15 minutes, and starting a flat plate type centrifuge for filtering; and leaching the filter cake with cold purified water for 2 times, leaching with ethyl acetate for 2 times, and filtering to obtain a wet product.
And (3) placing the wet product in a low-temperature vacuum drying oven, and carrying out vacuum drying for 30 hours at 40 ℃ to obtain the 5-iodo-2-pyrimidone.
(2) Preparation of 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone
Adding 500kg of dichloromethane into a reaction tank, sequentially adding 68kg of N, O-bis (trimethylsilyl) trifluoroacetamide and 30kg of 5-iodo-2-pyrimidone into the system, starting stirring, heating the system to 38 ℃ by opening an external bath, preserving heat for reaction for 15 hours, cooling the reaction system to-30 ℃ under the protection of nitrogen, dropwise adding a prepared anhydrous tin tetrachloride/dichloromethane solution (75 kg of dichloromethane and 16.1kg of tin tetrachloride), controlling the temperature to-30 ℃ after dropwise adding, and adding 58kg of 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose to the reaction system in batches at-30 ℃ for reaction.
Detecting that the reaction is stopped when the content of the 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose is less than 2 wt.%. The reaction solution was added to a prepared sodium bicarbonate solution (90 kg of sodium bicarbonate solid, 300kg of purified water) at 15 ℃ to quench it, stirred at the temperature for 1 hour, and allowed to stand for 2 hours.
Filtering to obtain filtrate A and filter cake, soaking and washing the filter cake with dichloromethane by 30kg, filtering to obtain filtrate B, combining the filtrate A and the filtrate B, standing for layering, adding anhydrous magnesium sulfate 20kg into the obtained organic phase, drying for 1 hour, filtering, discarding the filter cake, concentrating the filtrate under reduced pressure at 50 ℃ in an external bath, and concentrating to obtain a total volume of about 150L; adding 75kg of ethyl acetate into the concentrated solution, continuously concentrating at 50 ℃ in an external bath, and concentrating to obtain a total volume of about 150L; adding 68kg of ethyl acetate into the concentrated solution, continuously concentrating at 50 ℃ in an external bath, and concentrating to obtain a total volume of about 150L; then, 45kg of ethyl acetate was added to the concentrated solution, and the mixture was further concentrated by external bathing at 50 ℃ to a total volume of about 150L.
After the concentration is finished, stirring for 0.5 hour at 50 ℃, then cooling to 18 ℃, stirring for 10 minutes, and starting a flat plate centrifuge for filtering; adding the obtained filter cake into ethyl acetate, heating to 50 ℃, stirring for 0.5 hour, cooling the system to 20 ℃, stirring for 10 minutes, starting a flat plate type centrifuge for filtering, leaching the filter cake with 25kg of ethyl acetate, and filtering to obtain a wet product.
And (3) placing the wet product in a vacuum drying oven, and carrying out vacuum drying for 20 hours at the temperature of 40 ℃ to obtain the 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone.
(3) Preparation of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone
Adding 180kg of anhydrous methanol into a reaction tank under the protection of nitrogen, starting stirring, cooling the system to-15 ℃, and introducing NH into the system3Until the content is more than or equal to 25wt.% (titration detection), stirring and heating to 10 ℃, and adding 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranosyl]25kg of-5-iodo-2-pyrimidone.
After the addition, the reaction was carried out at 12 ℃ for 15 hours, and the reaction system was filtered. The filtrate was concentrated under reduced pressure at 25 ℃ in an external bath, to a volume of 1/2 (about 120L) and terminated.
Adding 125kg of ethyl acetate into the concentrated solution, stirring, cooling to 18 ℃, and crystallizing for 5 h. Filtering, leaching a filter cake with 6kg of anhydrous methanol, and filtering to obtain a wet product.
And (3) placing the wet product in a vacuum drying oven, and carrying out vacuum drying at 35 ℃ for 12h to obtain the 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone with the yield of 53% and the purity of 99.709%.
Claims (9)
- A method for preparing kinds of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidinone, characterized by comprising the steps of:(1) 5-iodo-2-pyrimidonesReacting 2-hydroxypyrimidine hydrochloride with iodine chloride to obtain 5-iodo-2-pyrimidone;(2)1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidoneReacting 5-iodo-2-pyrimidone with N, O-bis (trimethylsilyl) trifluoroacetamide and then with 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose in the presence of tin tetrachloride to give 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone;(3)1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidinoneReacting 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranosyl ] -5-iodo-2-pyrimidone with methanol and ammonia gas to obtain 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone;the preparation process of the 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone in the step (2) is as follows:adding dichloromethane and N, O-bis (trimethylsilyl) trifluoroacetamide into the 5-iodo-2-pyrimidone obtained in the step (1) for reaction, cooling under the protection of nitrogen, dropwise adding anhydrous stannic chloride/dichloromethane solution, adding 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose for reaction, then adding into sodium bicarbonate solution for quenching, filtering, standing and layering the filtrate, drying the organic phase, concentrating under reduced pressure, filtering, and drying the filter cake to obtain 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranone ] -5-iodo-2-pyrimidone.
- 2. The method for preparing 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone according to claim 1, wherein the 5-iodo-2-pyrimidone prepared in the step (1) is prepared by the following steps:reacting 2-hydroxypyrimidine hydrochloride with glacial acetic acid/ iodine chloride solution in the presence of glacial acetic acid, cooling, adding ethyl acetate, keeping the temperature and stirring, filtering, standing and layering the filtrate to obtain an organic phase and a water phase, mixing the water phase, the filter cake and the ethyl acetate, repeatedly keeping the temperature and stirring, filtering, standing and layering the filtrate, adding ethyl acetate into the water phase and the filter cake, adjusting the pH value, then adding the ethyl acetate, filtering, and drying the filter cake to obtain the 5-iodo-2-pyrimidone.
- 3. The process for preparing 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidinone according to claim 1, wherein the process for preparing 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidinone of step (3) is as follows:and (2) under the protection of nitrogen, introducing ammonia gas into an anhydrous methanol system, adding the 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranosyl ] -5-iodo-2-pyrimidone obtained in the step (2) to react, filtering, concentrating the filtrate under reduced pressure, adding ethyl acetate, cooling, crystallizing, filtering, and drying a filter cake to obtain the 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone.
- 4. The process for the preparation of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone according to claim 2, wherein:in the step (1), the mass ratio of the glacial acetic acid to the 2-hydroxypyrimidine hydrochloride to the glacial acetic acid/ iodine chloride solution is 4-6:10-14:18-22, and the mass ratio of the glacial acetic acid to the iodine chloride in the glacial acetic acid/ iodine chloride solution is 0.9-1.1: 6.5-7.5;in the step (1), when the reaction temperature of the 2-hydroxypyrimidine hydrochloride and the glacial acetic acid/ iodine chloride solution is 45-55 ℃ and the content of 5-iodo-2-pyrimidinone is more than 70wt.%, the reaction is terminated;in the step (1), cooling to 10-15 ℃, preserving heat and stirring for 15-20 minutes; the pH value is 5.0-7.0; the drying temperature is 35-45 deg.C, and the drying time is 20-30 h.
- 5. The process for producing 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone according to claim 1, wherein in the step (2), the mass ratio of 5-iodo-2-pyrimidone, dichloromethane, N, O-bis (trimethylsilyl) trifluoroacetamide, anhydrous tin tetrachloride/dichloromethane solution, and 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose is 24-30: 420-.
- 6. The process for the preparation of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone according to claim 1, wherein:in the step (2), 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose is added for reaction at the temperature of-35 to-30 ℃; terminating the reaction when the content of 1-chloro-3, 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose is less than 2 wt.%;in the step (2), the temperature during the reduced pressure concentration is 40-50 ℃, the drying temperature of the filter cake is 35-45 ℃, and the drying time of the filter cake is 10-20 h.
- 7. The process for preparing 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone according to claim 3, wherein in the step (3), the mass ratio of anhydrous methanol to 1- [ (3, 5-di-p-chlorobenzoyloxy) -2-deoxy- β -D-erythro-pentofuranosyl ] -5-iodo-2-pyrimidone is 20-24: 2.5-3.5.
- 8. The preparation method of 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone according to claim 3, wherein in step (3), the temperature of the system is-15 to 0 ℃ when ammonia gas is introduced, the introduction of ammonia gas is stopped when the ammonia gas content in the system is more than or equal to 25wt.%, and the reaction temperature is 5 to 12 ℃ and the reaction time is 13 to 15 hours.
- 9. The process for preparing 1- (2-deoxy- β -D-ribofuranosyl) -5-iodo-2-pyrimidone according to claim 3, wherein in the step (3), the temperature for cooling and crystallization is 15 to 20 ℃, the drying temperature is 30 to 35 ℃, and the drying time is 8 to 12 hours.
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