Remegapam intermediate and preparation method thereof

Abstract

The invention discloses (5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5H-cycloheptyl [b] pyridine-9-alcohol L-tartrate (a compound in a formula I) and a preparation method thereof, a remegapam intermediate with controllable quality can be safely and reliably prepared according to a preferred method, the HPLC (High Performance Liquid Chromatography) purity is up to 99.7% or above, and the ee value and de value are up to 99.9% or above. The invention discloses a crystal form of (5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5H-cycloheptyl [b] pyridine-9-ol L-tartrate, which has the characteristics of obvious non-hygroscopicity, easiness in drying and storage and the like. The invention further discloses a preparation method for preparing remegapam by directly condensing (5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5H-cycloheptyl [b] pyridine-9-ol L-tartrate with another fragment without salt dissolving treatment, the preparation method is mild in reaction condition, simple in post-treatment and high in reaction yield, special equipment and reagents are not needed, and the preparation method is suitable for industrial production. The method is suitable for industrial production.

Description

A Remepiride Intermediate and Its Preparation Method Technical Field

[0003] This invention belongs to the field of drug synthesis, specifically relating to a retinoic acid intermediate (5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptane[b]pyridine-9-ol L-tartrate and its preparation method. Background Technology

[0005] Rimegepant, developed by Biohaven Pharmaceuticals, is a novel oral small-molecule antagonist targeting the CGRP receptor. It works by reversibly blocking the CGRP receptor to target key components of migraines, thereby inhibiting the biological cascade that triggers migraine attacks. It was first approved in the United States in February 2020, and its expanded indications were approved in May 2021, making it the first oral CGRP receptor antagonist simultaneously approved for the acute and preventative treatment of migraines in adults. Subsequently, it was approved for marketing in Europe in April 2022.

[0006] The chemical name of Remegapan sulfate is: (5S, 6S, 9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptane[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazol[4,5-b]pyridin-1-yl)-1-piperidinecarboxylate hemisulfate sesquihydrate, and its structural formula is:

[0007]

[0008] Patent CN102656159A discloses a method for preparing retemapam as follows: Compound 1 is reduced to compound 2 using sodium borohydride, then chlorinated with NCS to form chloride 8, followed by reaction with sodium azide to form azide 9. After deprotection with TBAF, compound 10 is obtained, which is then condensed with RHP to obtain compound 7. Finally, retemapam is reduced in tetrahydrofuran / water under trimethylphosphine treatment to obtain retemapam. The reaction process is shown below:

[0009]

[0010] In the above preparation method, compound 1 requires sodium borohydride to reduce the carbonyl group. Due to the general stereoselectivity of sodium borohydride reduction, chiral isomer impurities will be generated at the carbon atom bonded to the hydroxyl group. At the same time, the dehalogenation side reaction caused by the strong reducing property of sodium borohydride will lead to the generation of defluorination impurities. These impurities will be gradually converted into related derivative impurities in compound 10 and lempimethanil in subsequent steps. Since these impurities are very similar to the chemical structures of compound 10 and lempimethanil, they are difficult to remove by conventional solvent purification methods.

[0011] The reaction process is as follows:

[0012]

[0013] Furthermore, the critical intermediate compound 10 requires preparative HPLC purification, making it difficult to scale up production.

[0014] Finally, the azide group is reduced to the amino group in the last step of the above preparation method. Since azide group compounds are mutagenic impurities, the allowable limit in the finished product of Remepiride is only 20 ppm, which will lead to a greater risk of residue exceeding the limit in the finished product.

[0015] Patent US8669368B discloses the following method for preparing retemapam. This method involves reducing and amination of compound VI to compound III, then hydrolyzing it to compound II, and finally condensing it with compound V to obtain retemapam. The synthetic route is shown below:

[0016]

[0017] In the above-mentioned reductive amination preparation step, the hydrogenation of palladium on carbon to enamine has virtually no stereoselectivity, leading to the formation of a large number of chiral isomer impurities at the carbon atom bonded to the amino group. Simultaneously, the dehalogenation side reaction caused by the reduction of palladium on carbon also results in the formation of defluorinated impurities, which will gradually transform into the key intermediate compound II and related derivative impurities in lempizoline, making them difficult to remove. The reaction process is shown below:

[0018] Furthermore, in the subsequent condensation reaction of compound II and compound V to prepare retinoic acid, since compound II is in the form of a dihydrochloride salt, it is highly hygroscopic. The presence of water will cause compound V to hydrolyze under alkaline conditions in the reaction system, resulting in incomplete reaction and low yield.

[0019] In summary, compound II or its analogues are key intermediates in the preparation of retemapam. Existing synthetic methods have many defects, resulting in low yields and low purity that fail to meet clinical drug standards and quality requirements. Therefore, there is an urgent need to develop a suitable industrial-scale production route for retemapam that can effectively control the quality standards of intermediates. Summary of the Invention

[0021] This invention provides a remdesivir intermediate having the structure of compound I, the structure of which is as follows:

[0022] .

[0023] This invention provides a remdesivir intermediate having the structure of compound I, wherein compound I has a crystalline form (I) and, in an X-ray diffraction pattern measured using a Cu K-α1 radiation source, the 2θ angle has peak values ​​at 11.34°, 11.72°, 15.85°, 16.86°, 18.30°, 19.26°, 20.66°, 21.30°, 21.74°, 22.58°, 23.30°, 24.76°, 25.95°, 26.74°, 28.78°, and 30.86°.

[0024] This invention provides a remiglitazone intermediate having the structure of compound I, wherein compound I is in crystalline form (I), as shown in Table 1 in the X-ray diffraction pattern at 2θ angle measured using a Cu K-α1 radiation source.

[0025] Table 1

[0026]

[0027] The present invention provides a remigelpam intermediate having the structure of a compound of formula I, wherein the compound of formula I is in crystalline form (I), and its thermogravimetric analysis (TGA) plot shows a mass loss of less than about 0.5% when heated from about 27°C to about 100°C.

[0028] This invention provides a remigelpam intermediate having the structure of compound I, wherein compound I is in crystalline form (I), and in the differential scanning calorimetry (DSC) chromatogram, there is an endothermic peak at an initial temperature of approximately 195°C.

[0029] This invention also provides a method for preparing a remdesivir intermediate having the structure of compound I, the synthetic route of which is as follows:

[0030]

[0031] Step 1—Reaction of compound RM-7-2 with sodium azide in an organic solvent to synthesize compound RM-7-3;

[0032] Step 2—Compound RM-7-3 is hydrogenated under certain temperature conditions in a continuous hydrogenation device with a metal-supported catalyst. After treatment, it is salted with hydrogen chloride ethanol solution to obtain compound RM-8.

[0033] Step 3—Compound RM-8 is first reacted with water by heating to remove the TIPS protecting group, and then an alkaline hydrolysis salt is added to obtain an oily substance. Then an organic solvent is added, and under certain temperature conditions, it is salted with L-tartaric acid to obtain compound I.

[0034] In step 1, compound RM-7-2 is reacted with sodium azide in an organic solvent to synthesize compound RM-7-3.

[0035] In step 1, the molar ratio of RM-7-2 to sodium azide is 1:(1-6), preferably 1:(5-6).

[0036] In step 1, the reaction temperature of RM-7-2 with sodium azide is 20-80℃, preferably 50-60℃. The reaction time is 4-24h, preferably 12-16h.

[0037] The organic solvent mentioned in step 1 is selected from N,N-dimethylformamide or N,N-dimethylacetamide.

[0038] In step 2, compound RM-7-3 is hydrogenated under certain temperature conditions in a continuous hydrogenation device with a metal-supported catalyst. After treatment, it is salted with hydrogen chloride ethanol solution to obtain compound RM-8.

[0039] In step 2, the reaction temperature of the hydrogenation reaction of compound RM-7-3 in a continuous hydrogenation device is 20-50℃, preferably 20-30℃.

[0040] The metal-supported catalyst mentioned in step 2 is selected from Pd / C or Pd(OH)2 / C. The mass ratio of catalyst to RM-7-3 is (1%-10%):1.

[0041] The organic solvent used in step 2 is one or more of methanol, ethanol, and isopropanol, with ethanol being preferred.

[0042] In step 3, the organic solvent that forms L-tartrate is one or more of alcohol solvents, ketone solvents, and nitrile solvents. The alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, and tert-butanol, preferably ethanol. The ketone solvent is selected from acetone. The nitrile solvent is selected from acetonitrile.

[0043] In step 3, the alkali is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, and potassium hydroxide.

[0044] In step 3, the molar ratio of compound 8 to L-tartaric acid is 1:(1-2), preferably 1:(1.2-1.6).

[0045] In step 3, the reaction temperature for forming L-tartrate is room temperature followed by solvent reflux, and the reaction time is 0.5-3 hours.

[0046] This invention also provides a method for preparing retinoic acid, the synthetic route of which is as follows:

[0047]

[0048] In one method, under alkaline conditions in an organic solvent, compound I reacts directly with compound RMM at a certain temperature to synthesize Remepiride without salt desalting.

[0049] The organic solvent used in the reaction is one or more of the following: a haloalkanes, ethers, or aprotic polar solvents.

[0050] The halogenated hydrocarbon solvent is selected from dichloromethane; the ether solvent is selected from tetrahydrofuran; and the aprotic polar solvent is selected from N,N-dimethylformamide or N,N-dimethylacetamide.

[0051] The reaction alkali is selected from one or more of potassium hydroxide, potassium carbonate, sodium tert-butoxide, and potassium tert-butoxide, preferably potassium tert-butoxide.

[0052] The reaction temperature is 0-30℃, preferably 0-10℃, and the reaction time is 3-6 hours. Attached Figure Description

[0054] Figure 1. Compound I 1 HNMR spectrum

[0055] Figure 2. XRPD diffraction pattern of the crystalline form (Ⅰ) of compound I.

[0056] Figure 3. DSC curve of compound I

[0057] Figure 4. TG curve of compound I

[0058] Figure 5. HPLC chromatogram of related substances of compound I (ethanol as salt solvent).

[0059] Figure 6. HPLC chromatograms of the isomers of compound I (ethanol as the salt solvent)

[0060] Figure 7. Compound II 1HNMR spectrum

[0061] Figure 8. XRPD diffraction pattern of compound II

[0062] Figure 9. HPLC chromatogram of related substances of compound II

[0063] Figure 10. HPLC chromatogram of related substances of Remepiride (based on compound I).

[0064] Figure 11. HPLC chromatograms of the isomers of retinoic acid (based on compound I).

[0065] Figure 12. HPLC chromatogram of related substances of Remepiride (compound II as raw material).

[0066] The present invention achieves the following beneficial effects:

[0067] 1. This invention is the first to report the tartrate salt of Formula I and its crystal form. The Formula I compound product prepared by this invention has good crystallinity, is non-hygroscopic, easy to dry and store, and is particularly suitable as a pharmaceutical intermediate for quality control.

[0068] 2. After obtaining compound RM-7-3, this application reduces it to compound RM-8 through a continuous hydrogenation device under the action of a metal-supported catalyst. This avoids the introduction of azides at the end of the synthesis route. After multiple intermediates and purification, the possibility of residual azide-like mutagenic impurities in the finished product is effectively reduced. Furthermore, it eliminates the need for high-risk hydrogenation reactor equipment, thereby improving the safety production risk factor. Detailed Implementation

[0070] The preparation method of the present invention will be further described in detail below with reference to the embodiments, without limitation.

[0071] Example 1 - Preparation of compound (5R, 6S, 9R)-5-azido-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cycloheptane[b]pyridine (RM-7-3)

[0072] RM-7-2 (20.68 g, 44.4 mmol), DMF (220 ml), and sodium azide (16.24 g, 250 mmol) were added to a 500 ml reaction flask. Under nitrogen protection, the mixture was stirred and heated to 50-55 °C for 15 h. The reaction was monitored by TLC until completion. Hexane (400 ml) and purified water (120 ml) were added, and the mixture was stirred and allowed to stand. The layers were separated, and the organic layer was washed with saturated sodium chloride aqueous solution (120 ml) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give RM-7-3, 18.8 g of oil, with a yield of 89.6%.

[0073] Example 2 - Preparation of compound (5S, 6S, 9R)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cycloheptane[b]pyridine-5-amine dihydrochloride (RM-8)

[0074] Add RM-7-3 (18.0 g, 38.0 mmol) and ethanol (200 ml) to a 500 ml reaction flask, stir to dissolve, and after clear dissolution, add activated carbon (0.7 g), stir for 10 min, filter, and retain the filtrate. Purge the fixed-bed reactor with nitrogen for 5 min, fill with the metal-supported catalyst Pd / C, purge again with nitrogen for 5 min, and then turn off the nitrogen. Adjust the back pressure valve pressure to 2.2-2.5 MPa and the fixed-bed reactor temperature to 20-30 °C. Simultaneously turn on the plunger pump and hydrogen, setting the plunger pump flow rate to 0.1 ml / min and the hydrogen flow rate to 40 ml / min, allowing both to continuously enter the reaction system. The residence time of the reactants in the reactor is 30 min. Collect the product after it flows out of the material outlet, place it in a 50 °C water bath to evaporate to dryness, add isopropanol (140 ml), isopropyl acetate (280 ml), and 35% hydrogen chloride ethanol solution (8.6 g, 82.2 mmol), and stir at room temperature for 1 h. The sample was filtered, and the wet sample was dried under reduced pressure at 50°C to obtain RM-8, a white solid weighing 15.7 g, with a yield of 79.3%.

[0075] Example 3: Preparation of (5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5H-cycloheptyl[b]pyridine-9-ol L-tartrate (Compound I)

[0076] Add RM-8 (15.5 g, 29.8 mmol) and water (80 ml) to a 250 ml reaction flask, heat to 80-85 °C and stir for 5 h. The reaction was confirmed by TLC. Wash with toluene (40 ml), retain the aqueous layer, add dichloromethane (80 ml), and adjust the pH to 8 with 10% sodium carbonate aqueous solution. After adjustment, allow to stand and separate the phases. Extract the aqueous phase once with dichloromethane (40 ml), combine the organic phases, and concentrate to dryness under reduced pressure to obtain 9.0 g of (5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5H-cyclohepta[b]pyridine-9-ol, an oil.

[0077] In a 100 ml reaction flask, the above-mentioned oily substance (5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5H-cyclohepta[b]pyridine-9-ol (5.9 g, 19.4 mmol), ethanol (60 ml), and L-tartaric acid (4.5 g, 30.0 mmol) were added. The mixture was heated to 70-80 °C and stirred for 2 h. Then, the mixture was slowly cooled to 10-20 °C and stirred for 2 h to induce crystallization. The mixture was filtered, and the wet product was dried in hot air at 60 °C to obtain compound I, a white solid, 7.6 g, with a yield of 89.0%.

[0078] 1 HNMR (DMSO): δ8.50 (1H, d), δ7.88 (1H, d), δ7.40 (1H, dd), δ7.31 (1H, dd), δ7.10 (1H, dd), δ6.87 (1H, s), δ 5.02 (1H, d), δ4.53 (1H, d), δ4.09 (2H, s), δ3.40 (1H, s), δ2.13 (1H, s), δ2.06-1.96 (2H, m), δ1.67 (1H, m).

[0079] Comparative experiment:

[0080] In a 100 ml reaction flask, the oily substance (5S, 6S, 9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-ol (2.9 g, 9.7 mmol), isopropanol (10 ml), and isopropyl acetate (20 ml) prepared in Example 3 were added dropwise. A 35% hydrogen chloride ethanol solution (2.9 g, 27.8 mmol) was added dropwise at a controlled temperature of 10-20 °C. After the addition was complete, the reaction was continued at this temperature for 0.5 h. The mixture was filtered, and the wet product was dried under reduced pressure at 60 °C to give compound II (dihydrochloride), a white solid, 3.2 g, with a yield of 90.8%.

[0081] 1 HNMR (DMSO): δ9.25 (3H, s), 8.76 (1H, d), δ8.62 (1H, d), δ8.01 (1H, t), δ7.38 (1H, dd), δ7.35 (1H, s), δ7.22 ( 1H, m), δ5.56 (1H, m), δ5.28 (1H, s), δ3.60 (1H, s), δ2.12 (1H, m), δ2.02 (1H, m), δ1.87 (1H, m), δ1.75 (1H, m).

[0082] Table 2 below lists the comparative detection results of related substances for compounds of formula I and II.

[0083] Table 2

[0084]

[0085] The above-mentioned test results indicate that the L-tartrate form of (5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5H-cycloheptyl[b]pyridine-9-ol is more effective at removing impurities than the compound II (dihydrochloride) form.

[0086] Table 3 below lists the comparative test results of the hygroscopicity test for compounds of formula I and II.

[0087] Table 3

[0088]

[0089] The above results indicate that compound I is non-hygroscopic, while compound II (dihydrochloride) is highly hygroscopic, absorbing 31.3% moisture after being placed in a 92.5% humidity environment for 24 hours.

[0090] Example 4—Preparation of the crystal form of compound I

[0091] In the following examples, the experimental methods were performed under conventional conditions or conventional testing conditions, and the compounds used in the examples were obtained by commercially available or self-made methods.

[0092] Measurement parameters of X-ray diffraction for measuring the crystalline form (I) of compound I.

[0093] X-ray Cu, KαKα (Å): 1.5406 X-ray tube settings: 40 kV, 30 mA Divergence slit: 1° Scan range (°²Theta): 2-40° Scan time per step (s): 0.6 Scan step size (°²Theta): 0.02° surface

[0094] Test conditions for DSC and TGA used to measure the crystalline form (I) of compound I.

[0095] Parameters: TA DSC 250, TA TGA 550; Temperature range: 40-400 °C (room temperature -400 °C); Scan rate: 10 °C / min; Sample tray: aluminum tray (capped, open). surface

[0096] The crystal form of the compound of formula I prepared in Example 3 above was determined.

[0097] Figure 2 shows the XRPD diffraction pattern of crystalline form (Ⅰ).

[0098] Figure 3 shows the DSC curve of crystalline form (Ⅰ), which includes an endothermic peak at an initial temperature of approximately 195°C.

[0099] Figure 4 shows the TGA curve of crystalline form (Ⅰ), and its thermogravimetric analysis shows a mass loss of less than about 0.5% when heated from about 27°C to about 100°C. As comparative data, Figure 8 shows the XRPD diffraction pattern of compound II (dihydrochloride), which is amorphous.

[0100] Example 4 - Salt-forming effect using other salt-forming reagents

[0101] Based on the content of Example 3, we investigated the reaction effects of D-tartaric acid, L-camphor sulfonic acid, D-camphor sulfonic acid, L-dibenzoyl tartaric acid and D-dibenzoyl tartrate, as shown in Table 4.

[0102] Table 4

[0103]

[0104] No salt formation was observed when the above salts were used.

[0105] Example 5 - Preparation of Remepiride

[0106] In a 250 ml reaction flask, compound I (5.0 g, 11.4 mmol), RMM (6.6 g, 21.1 mmol), and DMF (50 ml) were added. The mixture was stirred and cooled to 0-10 °C. A solution of potassium tert-butoxide (7.0 g, 62.4 mmol) in THF (50 ml) was added dropwise. After the addition was complete, the reaction was continued for 5 h. TLC monitoring showed that the reaction was essentially complete. After the reaction was complete, the pH was adjusted to 7 with 20% citric acid aqueous solution, and dichloromethane (150 ml) was added. The mixture was stirred, allowed to stand, and separated. The organic phase was washed three times with 50 ml of water each time. The organic phase was then evaporated to dryness in a 45 °C water bath. Ethanol (20 ml) was added, and the mixture was stirred and slurried for 2 h. The mixture was filtered, and the wet product was dried in hot air at 50 °C to obtain 4.9 g of rememepam, a white solid, with a yield of 80.7%. The HPLC purity was 99.89%, ee value was 100.0%, de value was 100.0%, impurity RM-E was 0.086%, impurities RM-B and RM-F were not detected, and the maximum single impurity was 0.02%.

[0107] Comparative experiment:

[0108] In a 100 ml reaction flask, compound II (dihydrochloride) (1.3 g, 2.7 mmol), RMM (1.6 g, 5.1 mmol), and DMF (10 ml) were stirred and cooled to 0-10 °C. A solution of potassium tert-butoxide (1.7 g, 15.1 mmol) in THF (10 ml) was added dropwise. After the addition was complete, the reaction continued for 5 h. TLC monitoring showed that a significant amount of compound II remained. The reaction time was extended to 7 h, but TLC monitoring showed no further progress. Post-treatment: The pH was adjusted to 7 with 20% citric acid aqueous solution. Dichloromethane (50 ml) was added, stirred, and allowed to stand before separation. The organic phase was washed three times with 20 ml of water each time. The organic phase was then evaporated to dryness in a 45 °C water bath to obtain 1.2 g of oil. The HPLC purity was 22.86%, with 70.78% of the starting material RM-9 (the free base of compound II) remaining.

[0109] It should be noted that the above embodiments are merely illustrative of the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. (5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5H-cycloheptyl[b]pyridine-9-ol L-tartrate (Compound of Formula I) 。 2. A compound of formula I as described in claim 1 is in crystalline form (I), characterized in that... The 2θ angle in the X-ray diffraction pattern measured using a Cu K-α1 radiation source has peak values ​​at 11.34°, 11.72°, 15.85°, 16.86°, 18.30°, 19.26°, 20.66°, 21.30°, 21.74°, 22.58°, 23.30°, 24.76°, 25.95°, 26.74°, 28.78°, and 30.86°.

3. The crystalline form (I) of the compound of formula I as described in claim 2, wherein the differential scanning calorimetry plot contains an endothermic peak at an initial temperature of about 195°C.

4. The crystalline form (I) of the compound of formula I as described in claim 2, when heated from about 27°C to about 100°C, has a thermogravimetric analysis plot showing a mass loss of less than about 0.5%.

5. A method for preparing the compound of formula I as described in claim 1, characterized in that... Step 1—Compound RM-7-2 reacts with sodium azide in an organic solvent to synthesize compound RM-7-3; Step 2—Compound RM-7-3 is hydrogenated under certain temperature conditions in a continuous hydrogenation device with a metal-supported catalyst, and then reacted with hydrogen chloride in an ethanol solution to form a salt to obtain compound RM-8; Step 3—Compound RM-8 is first reacted with water by heating to remove the TIPS protecting group, and then an alkaline hydrolysis salt is added to obtain an oily substance. Then an organic solvent is added, and under certain temperature conditions, it reacts with L-tartaric acid to form a salt to obtain compound I.

6. The method for preparing a compound of formula I as described in claim 5, characterized in that: The organic solvent mentioned in step 1 is selected from N,N-dimethylformamide or N,N-dimethylacetamide; the molar ratio of RM-7-2 to sodium azide in step 1 is 1:(1-6); the reaction temperature of RM-7-2 and sodium azide in step 1 is 20-80℃, and the reaction time is 4-24h.

7. The method for preparing a compound of formula I as described in claim 5, characterized in that: In step 2, the compound RM-7-3 is hydrogenated in a continuous hydrogenation device at a reaction temperature of 20-50℃; the metal-supported catalyst in step 2 is selected from Pd / C or Pd(OH)2 / C, and the mass ratio of the supported catalyst to RM-7-3 is (1%-10%):1; the organic solvent in step 2 is one or more of methanol, ethanol, and isopropanol.

8. The method for preparing a compound of formula I as described in claim 5, characterized in that: The organic solvent used to form L-tartrate in step 3 is one or more of alcohol solvents, ketone solvents, and nitrile solvents. The molar ratio of compound 8 to L-tartrate in step 3 is 1:(1-2). The reaction temperature for forming L-tartrate in step 3 is room temperature to solvent reflux, and the reaction time is 0.5-3 hours. The base used in step 3 is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, and potassium hydroxide.

9. The method for preparing a compound of formula I as described in claim 8, characterized in that: The alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, and tert-butanol; the ketone solvent is selected from acetone; and the nitrile solvent is selected from acetonitrile.

10. A method for preparing retinoic acid, comprising preparing a compound of formula I according to claim 5, characterized in that, In an organic solvent under alkaline conditions, compound I was directly reacted with compound RMM at a certain temperature to synthesize rimexazol without salt desalting. The synthetic route is as follows: 。 11. The method for preparing Remdesivir as described in claim 10, characterized in that, The organic solvent used in the reaction is one or more of the following: a haloalkanes, ethers, and nonprotic polar solvents.

12. The method for preparing Remdesivir as described in claim 11, characterized in that, The halogenated hydrocarbon solvent is selected from dichloromethane; the ether solvent is selected from tetrahydrofuran; and the aprotic polar solvent is selected from N,N-dimethylformamide or N,N-dimethylacetamide.

13. The method for preparing Remdesivir as described in claim 10, characterized in that, The base used in the reaction is selected from one or more of potassium hydroxide, potassium carbonate, sodium tert-butoxide, and potassium tert-butoxide.

14. The method for preparing Remdesivir as described in claim 10, characterized in that, The reaction temperature is 0-30℃, and the reaction time is 3-6 hours.

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