CN112876524B - Preparation method of Reideciclovir intermediate - Google Patents

Preparation method of Reideciclovir intermediate Download PDF

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CN112876524B
CN112876524B CN202110103155.8A CN202110103155A CN112876524B CN 112876524 B CN112876524 B CN 112876524B CN 202110103155 A CN202110103155 A CN 202110103155A CN 112876524 B CN112876524 B CN 112876524B
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iodopyrrolo
aminopyrrole
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CN112876524A (en
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唐家邓
王小梅
茆勇军
张诗伟
余志明
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Shanghai Famo Biotechnology Co ltd
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    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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Abstract

The invention discloses a preparation method of a Reidesciclovir intermediate, which comprises the steps of firstly reacting 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine with N, N-dimethylformamide dimethyl acetal, then adding i-PrMgCl or butyl lithium into the product obtained in the previous step for reaction, then adding 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone, and finally removing a protecting group to obtain the Reidesciclovir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (benzyl) -D-ribofuranose. According to the preparation method of the Ruidexilvir intermediate, the product which is mature in the current market is selected as the reactant, the raw materials are easy to obtain, and the production cost is reduced; the method has the advantages of simple process, short time consumption, high production efficiency, high yield, mild reaction conditions, simple and convenient post-treatment, suitability for amplified preparation and wide application prospect.

Description

Preparation method of Reidesciclovir intermediate
Technical Field
The invention belongs to the technical field of organic synthesis and preparation of raw material medicines, relates to a preparation method of a medical intermediate, and particularly relates to a novel preparation method of an intermediate of an antiviral drug Rudexilvir.
Background
Reddeivir (Remdesivir) is a drug developed by Jilide science, a nucleoside analogue with antiviral activity, and has an EC50 value of 74nM for SARS-CoV and MERS-CoV in HAE cells and an EC50 value of 30nM for murine hepatitis virus in delayed brain tumor cells. Reidesciclovir has a broad spectrum of antiviral activity and has been shown to be effective against a variety of emerging viral pathogens in vitro and in vivo studies in animal models, including Ebola virus, marburg virus, middle East Respiratory Syndrome (MERS), and atypical pneumonia (SARS) virus. In 22 months 10 in 2020, the antiviral drug Rideciclovir of Gilidd science has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of Xinguan inpatients, becoming the first officially approved Xinguan therapeutic drug in the United states.
In the chemical synthesis of the Reidesciclovir, the key intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (benzyl) -D-ribofuranose (A) is most difficult to synthesize, and the chemical structure is shown as the following formula:
Figure BDA0002916765020000011
with respect to the synthesis of compound a, two main types of methods are now reported:
method one (WO 2012012776; WO2014035140; WO2015069939; US20160122374; CN 111793101, CN 111620876, nature, 381-385, 2016J. Med.chem.,60,1648-1661,2017, org.Process Res.Dev.,24, 1772-1777), the synthetic route is shown in formula I. The method takes 7-bromopyrrolo [2,1-f ] [1,2,4] triazine-4-amine (B) or 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine (C) as a raw material, and the raw material reacts with 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone (D) under different conditions to obtain A. The bromide B is used as a raw material, TMSCl is used for protecting amino, and n-butyl lithium is used as alkali for reaction, and the yield is about 20-40% (method a, method B). The iodo matter C is used as a raw material, TMSCl is used for protecting amino, and a Grignard reagent is used as an alkali for reaction, so that the yield is improved to 40-69% (method C and method d). However, because the benzyloxyribose (D) is active in property and is easily destroyed and decomposed by strong base, if the qualified product A is obtained by the methods, column chromatography purification is usually needed, and the production and the application of the methods are restricted to a certain extent.
Figure BDA0002916765020000021
The second method (CN 109748921 and CN 111187269) is improved on the basis of the first method, and the synthetic route is shown as formula II. The preparation method comprises the steps of adopting a protecting group introducing mode to prepare a BOC protected pyrrolotriazine-4-amine compound (E, F, G), reacting with benzyloxyribose (D) under different conditions, and removing the BOC to obtain A. LDA or n-butyllithium is adopted as alkali, the yield fluctuation of different substrates is large, reported methods are laboratory small-scale methods, and products need to be purified by column chromatography and are not suitable for large-scale preparation.
Figure BDA0002916765020000022
Therefore, there is a need to improve the prior art to overcome the defects in the prior art, and to provide a preparation method with easily available raw materials, simple process, convenient operation and higher yield.
Disclosure of Invention
The invention aims to overcome the defects that the existing preparation method is difficult to amplify and prepare and has low production efficiency, and provides a method for preparing a Rudexilvir intermediate (specifically 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -2,3, 5-trioxa- (benzyl) -D-ribofuranose) with easily obtained raw materials, simple process, convenient operation and higher yield.
In order to achieve the purpose, the invention provides the following technical scheme:
a process for the preparation of a ridciclovir intermediate which is 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose having the formula:
Figure BDA0002916765020000031
the preparation route of the ridciclovir intermediate is shown as the following formula:
Figure BDA0002916765020000032
first, 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine (compound C in the above formula) is reacted with N, N-dimethylformamide dimethyl acetal (DMF-DMA) to produce N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H in the above formula);
then, adding I-PrMgCl or butyl lithium into the product N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide in the previous step for reaction, then adding 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone (namely the compound D in the formula) to generate the compound I in the formula, and finally removing the protecting group to obtain the Reidesciclovir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (benzyl) -D-ribofuranose (namely the compound A in the formula).
According to the preparation method of the Ruidexiwei intermediate, the 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine which is a mature product in the current market is selected as a reactant, so that the production cost can be obviously reduced, the yield of an acetal reaction is high (up to 91%), the post-treatment is convenient, the three wastes are less, in addition, the whole process is simple, the whole time consumption is short, the time consumption of the subsequent treatment process is short, the process is simple and convenient to operate, meanwhile, the yield can reach 60-70%, compared with the prior art, the yield is greatly improved, the reaction time is greatly shortened, and meanwhile, the preparation method is suitable for large-scale preparation and has a great application prospect.
As a preferable technical scheme:
in the preparation method of the Rudexilvir intermediate, in the step (1), the reaction temperature is 70-100 ℃.
In the preparation method of the Rudexilvir intermediate, in the step (2), the reaction temperature of the reaction with i-PrMgCl or butyl lithium and the reaction with 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone is the same or different, and is-70 ℃ to-20 ℃.
In the preparation method of the above described redciclovir intermediate, in step (2), recrystallization purification is required to be carried out on the product after the protecting group is removed.
In the above method for preparing a ridciclovir intermediate, in the step (2), the deprotection is performed by adding an aqueous ammonium chloride solution to the reaction solution. The protection scope of the present invention is not limited to the above limitations, and only one feasible technical solution is given here, and one skilled in the art can adjust the reaction temperature at each stage according to actual needs and select appropriate technical means to remove the protecting group.
Has the advantages that:
(1) According to the preparation method of the Rudexilvir intermediate, the 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine which is a mature product in the current market is selected as a reactant, raw materials are easy to obtain, and the production cost can be obviously reduced;
(2) The preparation method of the Ruidexilvir intermediate has the advantages of simple overall process, short overall time consumption, high production efficiency, high yield, mild reaction conditions, simple and convenient post-treatment, suitability for scale-up preparation and great application prospect.
Detailed Description
The present invention will be described in detail with reference to the following embodiments, but it should be apparent that the embodiments are only a few examples of the present invention and are not all examples.
Example 1
A preparation method of a Ruidesacvir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (benzyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H):
adding 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine (26.0g, 0.1mol) into a 500mL three-necked bottle, adding 260mL of ethanol, then adding N, N-dimethylformamide dimethyl acetal (DMF-DMA) (13.1g, 0.11mol), heating to 70-80 ℃ for reacting for 2 hours to generate solid suspension, cooling the reaction solution to room temperature, stirring in an ice water bath for 1 hour, carrying out suction filtration on generated solid, washing a filter cake with ethanol (15 mL multiplied by 2 times), and drying at 50 ℃ for 8 hours to obtain light yellow solid powder H (28.0 g, 91%);
(2) Preparation of 1-C- (4-Aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-Trioxy- (phenylmethyl) -D-ribofuranose (i.e., compound A, hereinafter referred to as A):
taking N' - (7-iodopyrrolo [2,1-f ]][1,2,4]Triazin-4-yl) -N, N-dimethylformamide (H) (15.7 g,0.05 mol) was charged into a 500mL three-necked flask, 120mL of anhydrous tetrahydrofuran was added, nitrogen was substituted for 3 times, and the mixture was cooled to-20 to-30 ℃. 1.3M i-PrMgCl was added dropwise thereto . LiCl complex tetrahydrofuran solution (58mL, 0.075mol), controlled at-20-30 ℃ for 30min reaction. 2,3, 5-Tribenzyloxy-D-ribono-1, 4-lactone (D) (23.0 g, 0.055mol) was dissolved in 40mL of anhydrous tetrahydrofuran, and was added dropwise to the reaction mixture, and the reaction was carried out at-20 to-30 ℃ for 30min. 20mL of a saturated aqueous ammonium chloride solution was added dropwise to the reaction mixture, followed by addition of 200mL of water, and the mixture was stirred at room temperature for 30min. Ethyl acetate (300 mL) was added, and the mixture was stirred, allowed to stand, and subjected to liquid separation. The organic layer was washed with water (300 mL. Times.1). The organic phase was concentrated to dryness under reduced pressure to give 29g of a light brown foamy solid. To the solid was added isopropyl acetate15mL of the ester was dissolved by stirring at 60 ℃ and then 100mL of methyl t-butyl ether was added and stirred at 0 to 10 ℃ for 4 hours to gradually precipitate a solid. The filter cake was washed with suction and methyl tert-butyl ether (10 mL. Times.2) and dried at 40 ℃ for 6h to give A as a white solid (19.6 g, 71%).
The nuclear magnetic resonance spectrum of the compound H prepared in the step (1) is as follows:
1 H NMR(400MHz,DMSO-d 6 ):δ3.16(s,3H),3.22(s,3H),6.93(dd,J＝ 13.6,4.4Hz,2H),8.15(s,1H),8.92(s,1H)；
13 C NMR(100MHz,DMSO-d 6 ):δ35.4,41.5,72.0,105.3,120.2,124.2, 148.6,158.7,160.1；
HRMS(ESI)calcd for:C 9 H 11 IN 5 [M+H] + 316.00591,Found:316.00540.
the nuclear magnetic resonance spectrum of the compound A prepared in the step (2) is as follows:
H-NMR(400MHz,DMSO-d 6 ):δ8.06(brs,2H),7.99(s,1H),7.37-7.22(m, 11H),7.19-7.10(m,3H),7.03-6.97(m,2H),6.95(d,J＝4.8Hz,1H),5.39(d,J＝ 5.9Hz,1H),5.05(d,J＝5.2Hz,1H),4.61-4.54(m,2H),4.52-4.42(m,4H), 4.06-3.98(m,1H),3.93(dd,J＝5.9,4.4Hz,1H),3.69(dd,J＝10.1,3.4Hz,1H), 3.47(dd,J＝10.0,6.4Hz,1H)；
13 C-NMR(100MHz,DMSO-d 6 ):δ187.98,155.88,148.96,138.63,138.43, 138.14,128.67,128.14,128.12,127.82,127.54,127.44,127.26,127.21,127.09, 118.60,117.51,103.15,102.30,81.91,80.92,72.50,72.33,71.74,71.44,69.42；
ESI-MS(m/z)553.3[M+H] + .
high Performance Liquid Chromatography (HPLC) test results:
HPLC: column: inertSustain C18 (250 mm. Times.4.6 mm. Times.5 μm); detection wavelength: 210nm, 244nm; flow rate: 0.8mL/min; column temperature: 30 ℃; sample introduction amount: 1 mu L of the solution; solvent: meOH; concentration: 0.2mg/mL; operating time: 30min; mobile phase A: water; mobile phase B: methanol/formic acid =100/0.1; and (3) elution: mobile phase a/mobile phase B =10/90; t is t R =9.175min, purity: 99.9% (210 nm), 98.2% (244 nm).
Example 2
A preparation method of a Ruideciclovir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H):
adding 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine (26.0 g, 0.1mol) into a 250mL three-necked bottle, adding 100mL DMF, then adding N, N-dimethylformamide dimethyl acetal (DMF-DMA) (13.1g, 0.11mol), heating to 90-100 ℃ for reacting for 0.5H, cooling the reaction solution to room temperature, distilling the solvent out under reduced pressure to obtain a brown oily substance, adding 250mL ethanol into the oily substance, stirring in an ice water bath for 1H, precipitating a solid, performing suction filtration, washing the oily substance with ethanol (5 mL multiplied by 2 times), and drying at 50 ℃ for 8H to obtain a light yellow solid H (25.2 g, 81%);
(2) Preparation of 1-C- (4-Aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose (i.e., compound A, hereinafter referred to as A):
adding N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-yl) -N, N-dimethylformamide (H) (15.7 g,0.05 mol) into a 250mL three-necked bottle, adding 120mL of anhydrous tetrahydrofuran, replacing 3 times with nitrogen, cooling to-20 to-30 ℃, dropwise adding a 2M i-PrMgCl tetrahydrofuran solution (38 mL,0.075 mol) into the three-necked bottle, and reacting at-20 to-30 ℃ for 30min for later use;
adding 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone (D) (23.0 g, 0.055mol) into a 500mL three-necked bottle, adding 80mL of anhydrous tetrahydrofuran, replacing 3 times with nitrogen, and cooling to-20-30 ℃;
transferring the standby solution to a constant-pressure dropping funnel, dropwise adding the solution into a 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone (D) tetrahydrofuran solution, controlling the temperature to be between-20 and-30 ℃ for reaction for 30min, dropwise adding 50mL of saturated ammonium chloride aqueous solution into the reaction solution, heating to room temperature, concentrating the solvent under reduced pressure to obtain brown paste, adding 300mL of ethyl acetate and 200mL of water, stirring, standing, separating, washing an organic layer with water (200 mL multiplied by 2 times), and concentrating and drying the organic phase under reduced pressure to obtain 27g of light brown foamy solid;
the product was purified by column chromatography to give 13.3g of pale yellow foamy solid A, 48% yield, 94% high performance liquid purity.
Preparation of Compound H from step (1) 1 H NMR、 13 Results of C NMR and HRMS (ESI) and of Compound A obtained in step (2) 1 H NMR、 13 The C NMR, HRMS (ESI) results and HPLC detection results were the same as in example 1.
Example 3
A preparation method of a Ruidesacvir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (benzyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H):
adding 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine (26.0g, 0.1mol) into a 250mL three-necked bottle, adding N, N-dimethylformamide dimethyl acetal (DMF-DMA) (60g, 0.50mol), heating to 90-100 ℃, reacting for 0.5H, cooling the reaction liquid to room temperature, distilling the solvent out under reduced pressure to obtain a brown oily substance, adding 150mL of methanol into the oily substance, stirring in an ice-water bath for 1H, separating out a solid, performing suction filtration, washing a filter cake with methanol (5 mL multiplied by 2 times), and drying at 50 ℃ for 8H to obtain a light yellow solid H (21.1g, 67%);
(2) Preparation of 1-C- (4-Aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-Trioxy- (phenylmethyl) -D-ribofuranose (i.e., compound A, hereinafter referred to as A):
adding N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (H) (15.7 g,0.05 mol) into a 500mL three-necked bottle, adding 120mL of anhydrous tetrahydrofuran, replacing with nitrogen for 3 times, and cooling to-60 to-70 ℃; 2.5M n-BuLi (i.e. butyl lithium) tetrahydrofuran solution (30mL, 0.075 mol) is dripped into the mixture to react for 30min at the temperature of-60 to-70 ℃; dissolving 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone (D) (23.0 g, 0.055mol) in 40mL of anhydrous tetrahydrofuran, dropwise adding into the reaction solution, and reacting at-60-70 deg.C for 30min; 30mL of a saturated aqueous ammonium chloride solution was added dropwise to the reaction mixture, 200mL of water was added, and the mixture was stirred at room temperature for 30min. Adding 300mL of ethyl acetate, stirring, standing and separating liquid; the organic layer was washed with water (300 mL. Times.1); decompressing and concentrating the organic phase to obtain 31g of light brown foamy solid; adding 15mL of isopropyl acetate into the solid, stirring and dissolving at 60 ℃, adding 100mL of methyl tert-butyl ether, stirring for 4h at 0-10 ℃, and then dropwise adding 20mL of n-heptane to gradually separate out the solid; performing suction filtration, washing a filter cake (10 mL multiplied by 2 times) by methyl tert-butyl ether, and drying for 6h at 40 ℃ to obtain a white soft solid A (14.1g, 51%); the purity of the high-efficiency liquid phase is 92 percent.
Preparation of Compound H from step (1) 1 H NMR、 13 C NMR and HRMS (ESI) chart and preparation of Compound A from step (2) 1 H NMR、 13 The C NMR, HRMS (ESI) and HPLC detection results are the same as in example 1.
Example 4
A preparation method of a Ruidesacvir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (benzyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H) was the same as described in example 1;
(2) Preparation of 1-C- (4-Aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose (i.e., compound A, hereinafter referred to as A):
adding N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (H) (15.7 g,0.05 mol) into a 500mL three-necked bottle, adding 120mL of anhydrous tetrahydrofuran, replacing 3 times with nitrogen, and cooling to-20 to-25 ℃; 2M i-PrMgCl tetrahydrofuran solution (38 mL,0.075 mol) is dripped into the mixture to react for 30min at the temperature of-20 to-25 ℃; dissolving 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone (D) (23.0 g, 0.055mol) in 40mL of anhydrous tetrahydrofuran, dropwise adding into the reaction solution, and reacting at-20-25 deg.C for 30min; 50mL of a saturated aqueous ammonium chloride solution was added dropwise to the reaction mixture, and 200mL of water was added thereto, followed by stirring at room temperature for 30min. Concentrating the solvent under reduced pressure to obtain a light brown paste; to this solution were added 200mL of ethyl acetate and 100mL of water, followed by stirring at room temperature for 30min, standing and liquid separation. The organic layer was washed with brine (100 mLx1 times). Decompressing and concentrating the organic phase to obtain light brown foamy solid 30g; to the solid, 15mL of isopropyl acetate was added, the mixture was stirred at 60 ℃ and dissolved, then 100mL of methyl t-butyl ether was added, the mixture was stirred at 0 to 10 ℃ for 4 hours, and 15mL of n-heptane was added dropwise to gradually precipitate a solid. Performing suction filtration, washing a filter cake (10 mL multiplied by 2 times) by methyl tert-butyl ether, and drying at 40 ℃ for 6h to obtain a white solid A (18.8g, 68%); the purity of the high-efficiency liquid phase is 97 percent.
Preparation of Compound H from step (1) 1 H NMR、 13 C NMR and HRMS (ESI) charts and of Compound A obtained in step (2) 1 H NMR、 13 The C NMR, HRMS (ESI) and HPLC detection results were the same as in example 1.
Example 5
A preparation method of a Ruidesacvir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (benzyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H) was the same as described in example 1;
(2) Preparation of 1-C- (4-Aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose (i.e., compound A, hereinafter referred to as A) is the same as described in example 2.
Example 6
A preparation method of a Ruidesacvir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (benzyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H) was the same as described in example 1;
(2) Preparation of 1-C- (4-Aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose (i.e., compound A, hereinafter referred to as A) is the same as described in example 3.
Example 7
A preparation method of a Ruidesacvir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (benzyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H) was the same as described in example 2;
(2) Preparation of 1-C- (4-Aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose (i.e., compound A, hereinafter referred to as A) is the same as described in example 1.
Example 8
A preparation method of a Ruideciclovir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H) was the same as described in example 2;
(2) Preparation of 1-C- (4-Aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose (i.e., compound A, hereinafter referred to as A) is the same as described in example 3.
Example 9
A preparation method of a Ruidesacvir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (benzyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H) was the same as described in example 2;
(2) The preparation of 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose, compound A, hereinafter denoted A, is the same as described in example 4.
Example 10
A preparation method of a Ruidesacvir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (benzyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H) was the same as described in example 3;
(2) Preparation of 1-C- (4-Aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose (i.e., compound A, hereinafter referred to as A) is the same as described in example 1.
Example 11
A preparation method of a Ruideciclovir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H) was the same as described in example 3;
(2) Preparation of 1-C- (4-Aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose (i.e., compound A, hereinafter referred to as A) is the same as described in example 2.
Example 12
A preparation method of a Ruideciclovir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose comprises the following steps:
(1) Preparation of N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide (i.e., compound H, hereinafter referred to as H) was the same as described in example 3;
(2) Preparation of 1-C- (4-Aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose (i.e., compound A, hereinafter referred to as A) is the same as described in example 4.
Proved by verification, the preparation method of the Rudexilvir intermediate selects the mature product 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine in the current market as a reactant, the raw materials are easy to obtain, and the production cost can be obviously reduced; the whole process is simple, the whole time consumption is short, the production efficiency is high, the yield is high, the reaction condition is mild, the post-treatment is simple and convenient, and the method is suitable for amplified preparation and has wide application prospects.
Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these embodiments are merely illustrative and various changes or modifications may be made without departing from the principles and spirit of the invention.

Claims (4)

1. A preparation method of a ridciclovir intermediate, which is 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-trioxo- (phenylmethyl) -D-ribofuranose, characterized by comprising the following steps:
(1) Reacting 7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-amine with N, N-dimethylformamide dimethyl acetal to produce N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -N, N-dimethylformamide;
(2) Adding i-PrMgCl or butyl lithium into N' - (7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-yl) -N, N-dimethylformamide for reaction, then adding 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone for reaction, and finally adding ammonium chloride aqueous solution into the reaction solution for removing protective groups to prepare the Rudexilvir intermediate 1-C- (4-aminopyrrole [2,1-f ] [1,2,4] triazine-7-yl) -2,3, 5-trioxa- (benzyl) -D-ribofuranose.
2. A process for preparing a ridciclovir intermediate according to claim 1, wherein in step (1), the reaction temperature is 70-100 ℃.
3. A process for preparing a ridciclovir intermediate according to claim 1, wherein in step (2), the reaction temperature for the reaction with i-PrMgCl or butyllithium and the reaction with 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone is the same or different and is-70 ℃ to-20 ℃.
4. A process for preparing a ridciclovir intermediate according to claim 1, characterized in that in step (2), the product is subjected to recrystallization purification after removing the protecting group.
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