A method for preparing 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine

Abstract

The invention discloses a preparation method of a Remdesivir key intermediate 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine. 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine is obtained by reacting pyrrolo[2,1-f][1,2,4]triazin-4-amine with iodine in the presence of an oxidant. An iodine / oxidant system is selected as the iodinating reagent, the dosage of iodine is greatly reduced, the yield can reach 91%, and the product purity is over 99%. Compared with the existing process, this process greatly reduces the production cost, has high economic benefits, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of drug intermediate synthesis, and more particularly to a method for preparing 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine, a key intermediate of remdesivir. Background Art

[0002] Remdesivir is a nucleotide analogue prodrug developed by Gilead Sciences. It is triphosphorylated in the human body to inhibit RNA-dependent RNA polymerase (RdRp), thereby blocking the replication of viral RNA. It has good broad-spectrum antiviral activity and can inhibit including severe acute respiratory syndrome (SARS coronavirus), Ebola coronavirus and many other coronaviruses (bioRxiv. 2020). At present, remdesivir has been clinically studied in many countries, and its safety and activity against COVID-19 coronavirus have been confirmed. On October 22, 2020, it was approved by the US FDA, and remdesivir became the first drug approved for the treatment of patients with COVID-19 in the United States. In addition, the drug has been approved for marketing in Japan and the UK for the treatment of hospitalized patients with novel coronavirus pneumonia (COVID-19).

[0003] Triazine amine derivatives are important intermediates for synthesizing drug precursors, and nucleoside drugs such as remdesivir can be prepared through multiple steps of reactions (J. Med. Chem. 2017, 60, 1648). The molecular structure of remdesivir consists of three parts: a ribonucleic acid mother nucleus, a pyrrolotriazine and a phosphoramidite phenoxy ester side chain. Compound of formula I (7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine) is a key intermediate for synthesizing remdesivir.

[0004]

[0005] The specific synthesis methods of the compound of formula I are disclosed in multiple patents such as WO2015069939A1 / WO20170275290A1, and its synthetic route is as follows:

[0006]

[0007] This method uses DMF as a solvent, and the compound of formula II reacts with N-iodosuccinimide (NIS) at 0 °C or room temperature to obtain the compound of formula I. Due to the relatively high raw material cost of NIS, it brings great constraints to large-scale production; using DMF as a solvent, the amount of three wastes is large, and diiodo by-products are easily generated during the reaction, and it is difficult to obtain 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine with high purity. Therefore, this process is not suitable for industrial production.

[0008] With the market launch of the drug Remdesivir, the research on the activity of triazineamine derivatives and their related applications will attract increasing attention from medicinal chemists. Among them, the market demand for the key intermediate of Remdesivir, 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine, will continue to expand. Therefore, it is necessary to develop a practical synthesis route that is simple in process, low in cost, easy to separate and purify, and suitable for large-scale production. Summary of the Invention

[0009] Object of the Invention: The object of the present invention is to provide a method for synthesizing 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine, so as to solve the defects of the existing process of 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine, which has a high use cost, easily generates diiodo by-products during the reaction process, and it is difficult to obtain high-purity 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine, and is not suitable for industrial production.

[0010] On the one hand, the present invention provides a method for preparing a compound of formula I:

[0011]

[0012] The compound of formula II reacts with iodine in the presence of an oxidizing agent to form the compound of formula I.

[0013] In some embodiments, the oxidizing agent is selected from one or more of sodium hypochlorite, iodic acid, hydrogen peroxide, urea peroxide, or potassium peroxymonosulfate;

[0014] In some embodiments, the oxidizing agent is selected from one or more of iodic acid, hydrogen peroxide, or urea peroxide;

[0015] In some embodiments, the oxidizing agent is iodic acid;

[0016] In some embodiments, the solvent used is selected from one or more of methanol / water, ethanol / water, 1,2-dichloroethane, or isopropyl acetate;

[0017] In some embodiments, the solvent used is isopropyl acetate;

[0018] In some embodiments, the molar ratio of the compound of formula II to iodine ranges from 1:0.4 to 0.8;

[0019] In some embodiments, the molar ratio of the compound of formula II to the oxidizing agent ranges from 1:0.1 to 0.5;

[0020] In some embodiments, the reaction temperature ranges from 20 to 60 °C.

[0021] Advantageous Effects

[0022] The object of the present invention is to overcome the defects of the existing synthesis process of 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine, such as high cost, high three wastes, and difficulty in obtaining high-purity products; the market price of iodine is half of that of N-iodosuccinimide (NIS); an iodine / oxidant system is selected as the iodinating reagent, and the yield is significantly increased compared with the case without using an oxidant (the yield is increased from 61% to 91%), the dosage of iodine is also significantly reduced (from 2.4 equivalents to about 0.5 equivalents), and the product purity can be as high as 99.8%; the selected solvent can be recycled, and compared with the existing process, the production cost is significantly reduced. In summary, the technical solution provided by the present invention is suitable for industrial production and has high economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention.

[0024] Figure 1 1H-NMR spectrum of the end product of Example 1 of the present invention 1 ;

[0025] Figure 2 GC spectrum of the end product of Example 1 of the present invention;

[0026] Figure 3 MS spectrum of the end product of Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0027] The following further clarifies the present invention in conjunction with specific embodiments. These embodiments are implemented on the premise of the technical solution of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

[0028] Example 1

[0029]

[0030] Preparation of the compound of formula I:

[0031] In a 50 L reactor, isopropyl acetate (16.9 kg) was added. While stirring, the compound of formula II (1500 g, 11.18 mol, 1.0 eq.) was added, and after stirring evenly, it formed an off-white suspension. At room temperature, iodine (1702.8 g, 6.71 mol, 0.6 eq.) was added in one portion, and the mixture was heated to 30 °C. An iodic acid (786.8 g, 4.48 mol, 0.4 eq., dissolved in 1.5 L of water) solution was added dropwise. After addition, the temperature was raised to 45 °C and the reaction was maintained for 10 h. LC-MS detection showed that the raw materials were completely reacted. A 15% sodium sulfite solution was added dropwise to the reaction system until the system became milky white. After passing the detection, the temperature was lowered to room temperature, and the mixture was stirred overnight. Isopropyl acetate was removed by reduced pressure concentration. After cooling to room temperature, the pH was adjusted to 10 - 11 with 20% NaOH solution, and then filtered by suction. The filter cake was washed with water, dried, and recrystallized and purified with tetrahydrofuran / n-heptane to obtain 2644 g of the compound of formula I as an off-white solid, with a yield of 91%.

[0032] 1 1H-NMR (400 MHz, DMSO) (ppm): 7.9230 (s, 1H), 7.8026 (s, 2H), 7.0101 - 6.9990 (d, J = 4.44 Hz, 1H), 6.8473 - 68362 (d, J = 4.44 Hz, 1H); (ESI-TOF) m / z: [M + H]+ calcd for C6H5N4I: 260; found: 261; The purity detected by GC was 99.85%.

[0033] Comparative Example 1

[0034]

[0035] Referring to the method of Reference Example 1, the investigation results of the iodine feeding amount, oxidant, temperature, and solvent are shown in Table 1.

[0036] Table 1

[0037]

[0038]

Claims

1. A method for preparing a compound of formula I, characterized in that: A compound of formula II reacts with iodine in the presence of an oxidizing agent to form a compound of formula I; The oxidizing agent is selected from one or more of iodic acid, hydrogen peroxide or urea peroxide; The solvent is selected from one or more of methanol / water, ethanol / water, 1,2-dichloroethane or isopropyl acetate; The molar ratio of the compound of formula II to iodine ranges from 1:0.4 to 0.8; The molar ratio of the compound of formula II to the oxidizing agent ranges from 1:0.1 to 0.5; The reaction temperature ranges from 20 to 60 °C.

2. The preparation method according to claim 1, characterized in that: The oxidizing agent is iodic acid.

3. The preparation method according to claim 1, characterized in that: The solvent used is isopropyl acetate.

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