(5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5H-cycloheptyl [b] pyridine-9-ol L-tartrate 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. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and specifically relates to a remegipam intermediate (5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5H-cyclohepta[b]pyridine-9-ol L-tartrate and a preparation method thereof. Background Art

[0002] Rimegepant sulfate is a new oral small molecule antagonist targeting CGRP receptors developed by Biohaven Pharmaceuticals in the United States. It targets the key components of migraine by reversibly blocking CGRP receptors, thereby inhibiting the biological cascade that leads to migraine attacks. In February 2020, the drug was first approved in the United States, and in May 2021, it was approved for expanded indications. It is the first oral CGRP receptor antagonist approved for both acute and preventive treatment of migraine in adults. Subsequently, it was approved for marketing in Europe in April 2022.

[0003] The chemical name of Remegipam 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-imidazole[4,5-b]pyridin-1-yl)-1-piperidinyl carboxylate hemisulfate sesquihydrate, and its structural formula is:

[0004]

[0005] Patent CN102656159A discloses the following preparation method of Remedipam, which is to reduce compound 1 to compound 2 using sodium borohydride, then react with NCS to convert it into chloride 8, then react with sodium azide to convert it into azide 9, deprotect it with TBAF to obtain compound 10, then condense it with RHP to obtain compound 7, and finally reduce it under trimethylphosphine treatment in tetrahydrofuran / water to obtain Remedipam. The reaction process is as follows:

[0006]

[0007] In the above preparation method, compound 1 needs sodium borohydride to reduce the carbonyl group. Since the stereoselectivity of sodium borohydride reduction is general, chiral isomer impurities of the carbon atom connected to the hydroxyl group will be produced. At the same time, due to the strong reducing property of sodium borohydride, the dehalogenation side reaction will lead to the generation of defluorinated impurities. These impurities will gradually be converted into related derivative impurities in compound 10 and Remigipam in the subsequent steps. Since these impurities are extremely similar to the chemical structures of compound 10 and Remigipam, they are difficult to remove by conventional solvent refining methods. The reaction process is as follows:

[0008]

[0009] In addition, the key intermediate compound 10 needs to be purified using preparative HPLC, which is difficult to scale up for production.

[0010] Finally, the above preparation method reduces the azide group to the amino group only in the last step of the synthesis route. Since azide compounds are mutagenic impurities, the allowable limit in the finished product of Remigipam is only 20 ppm, which will lead to a greater risk of exceeding the residue limit in the finished product.

[0011] Patent US8669368B discloses the following preparation method of Remegipam. The method is to reduce and aminize compound VI to compound III, then hydrolyze compound II, and then condense with compound V to obtain Remegipam. The synthesis route is as follows:

[0012]

[0013] In the above reductive amination preparation step, since the palladium-carbon hydrogenation reduction of enamine has basically no stereoselectivity, it will lead to the generation of a large amount of chiral isomer impurities of the carbon atom connected to the amino group. At the same time, the dehalogenation side reaction caused by the palladium-carbon reduction will also lead to the generation of defluorinated impurities, which will gradually be converted into the key intermediate compound II and related derivative impurities in Remigipam and are difficult to remove. The reaction process is shown as follows:

[0014]

[0015] In addition, in the subsequent step of preparing remegipam by condensation reaction of compound II and compound V, since compound II is in the form of dihydrochloride and is highly hygroscopic, the presence of water will cause hydrolysis of compound V under the alkaline conditions of the reaction system, resulting in incomplete reaction and low yield.

[0016] In summary, compound II or its analogues are key intermediates for the preparation of remigipam. The existing synthesis methods have many defects, resulting in a low yield of remigipam and a purity that is difficult to meet the clinical drug standards and quality. Therefore, it is urgent to develop a remigipam production route suitable for industrialization that can effectively control the quality standards of intermediates. Summary of the invention

[0017] The present invention provides a remegipam intermediate having a compound structure of formula I, which has a structure of

[0018]

[0019] The present invention provides a remegipam intermediate having a structure of a compound of formula I, wherein the compound of formula I has a crystalline form (I), and has peak maxima at 2θ angles 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° in an X-ray diffraction pattern measured by using a Cu K-α1 radiation source.

[0020] The present invention provides a remegipam intermediate having a structure of a compound of formula I, wherein the compound of formula I is in crystalline form (I), and the X-ray diffraction pattern measured by using a Cu K-α1 radiation source has a 2θ angle as shown in Table 1.

[0021] Table 1

[0022]

[0023]

[0024] The present invention provides a remegipam intermediate having a structure of a compound of formula I, wherein the compound of formula I is in crystalline form (I), and in a thermogravimetric analysis (TGA) graph, when heated from about 27°C to about 100°C, its thermogravimetric analysis graph contains a mass loss of less than about 0.5%.

[0025] The present invention provides a remegipam intermediate having a compound structure of formula I, wherein the compound of formula I is a crystalline form (I) and has an endothermic peak at an initial temperature of about 195° C. in a differential scanning calorimetry (DSC) diagram.

[0026] The present invention also provides a method for preparing a remegipam intermediate having a compound structure of formula I, and the synthetic route is as follows:

[0027]

[0028] Step 1—Compound RM-7-2 reacts with sodium azide in an organic solvent to synthesize compound RM-7-3;

[0029] Step 2—Compound RM-7-3 is subjected to hydrogenation reaction under certain temperature conditions in a continuous hydrogenation device in the presence of a metal-supported catalyst, and then treated with a hydrogen chloride ethanol solution to form a salt to obtain compound RM-8;

[0030] Step 3—Compound RM-8 is first heated with water to remove the TIPS protecting group, and then alkaline is added to hydrolyze the salt to obtain an oily substance, and then an organic solvent is added to form a salt with L-tartaric acid under certain temperature conditions to obtain the compound of formula I.

[0031] In step 1, compound RM-7-2 reacts with sodium azide in an organic solvent to synthesize compound RM-7-3.

[0032] The molar ratio of RM-7-2 to sodium azide in step 1 is 1:(1-6), preferably 1:(5-6).

[0033] The reaction temperature of RM-7-2 and sodium azide in step 1 is 20-80° C., preferably 50-60° C. The reaction time is 4-24 h, preferably 12-16 h.

[0034] The organic solvent in step 1 is selected from N,N-dimethylformamide or N,N-dimethylacetamide.

[0035] In step 2, compound RM-7-3 is hydrogenated under certain temperature conditions by continuous hydrogenation equipment in the presence of a metal-supported catalyst, and after treatment, it is salted with a hydrogen chloride ethanol solution to obtain compound RM-8.

[0036] The reaction temperature of the hydrogenation reaction of compound RM-7-3 in step 2 by continuous hydrogenation equipment is 20-50°C, preferably 20-30°C.

[0037] The metal supported catalyst 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.

[0038] The organic solvent used in the reaction in step 2 is one or more of methanol, ethanol, and isopropanol, preferably ethanol.

[0039] The organic solvent for forming L-tartrate in step 3 is one or more of an alcohol solvent, a ketone solvent, and a nitrile solvent, wherein the alcohol solvent is one or more of methanol, ethanol, isopropanol, and tert-butanol, preferably ethanol; wherein the ketone solvent is acetone; and wherein the nitrile solvent is acetonitrile.

[0040] Wherein in step 3, the alkali is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide.

[0041] The molar ratio of compound 8 to L-tartaric acid in step 3 is 1:(1-2), preferably 1:(1.2-1.6).

[0042] The reaction temperature for forming L-tartrate in step 3 is room temperature-solvent reflux reaction, and the reaction time is 0.5-3 hours.

[0043] The present invention also provides a method for preparing Remigipam, and the synthetic route is as follows:

[0044]

[0045] Wherein, in an organic solvent under alkaline conditions, the compound of formula I is directly reacted with the compound RMM at a certain temperature without undergoing desalting treatment to synthesize remigipam.

[0046] Wherein, the organic solvent of the reaction is one or more of a halogenated hydrocarbon solvent, an ether solvent, and an aprotic polar solvent.

[0047] 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.

[0048] Wherein, the reaction base is selected from one or more of potassium hydroxide, potassium carbonate, sodium tert-butoxide, and potassium tert-butoxide, preferably potassium tert-butoxide.

[0049] Wherein, the reaction temperature is 0-30°C, preferably 0-10°C, and the reaction time is 3-6 hours. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 The compound of formula I 1 HNMR spectrum

[0051] Figure 2 XRPD diffraction pattern of the crystalline form (I) of the compound of formula I

[0052] Figure 3 DSC curve of the compound of formula I

[0053] Figure 4 TG curve of the compound of formula I

[0054] Figure 5 HPLC spectrum of related substances of the compound of formula I (ethanol as salt solvent)

[0055] Figure 6 HPLC chromatogram of isomers of the compound of formula I (ethanol as salt solvent)

[0056] Figure 7 Compound II 1 HNMR spectrum

[0057] Figure 8 XRPD diffraction pattern of compound Ⅱ

[0058] Fig. 9 HPLC spectrum of related substances of compound Ⅱ

[0059] Fig.10 HPLC spectrum of related substances of Remegipam (compound of formula Ⅰ as raw material)

[0060] Fig.11 HPLC spectrum of isomers of Remegipam (compound of formula Ⅰ as raw material)

[0061] Fig.12 HPLC spectrum of related substances of Remigipam (Compound Ⅱ as raw material)

[0062] The present invention achieves beneficial effects:

[0063] 1. The present invention reports for the first time the tartrate of the compound of formula I and its crystal form. The compound of formula I prepared by the present invention has good crystallinity, is non-hygroscopic, is easy to dry and store, and is particularly suitable for quality control as a pharmaceutical intermediate.

[0064] 2. After obtaining compound RM-7-3, the present application uses a continuous hydrogenation device to reduce it under the action of a metal-supported catalyst to obtain compound RM-8, thereby avoiding the introduction of azide at the end of the synthesis route. After multiple steps of intermediates and refining, the possibility of residual azide-type mutagenic impurities in the finished product is effectively reduced, and there is no need to use highly dangerous hydrogenation kettle equipment, thereby improving the safety production risk factor. DETAILED DESCRIPTION

[0065] The preparation method of the present invention is further described in detail below in conjunction with the examples.

[0066] Example 1 - Preparation of compound (5R,6S,9R)-5-azido-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (RM-7-3)

[0067] Add RM-7-2 (20.68 g, 44.4 mmol), DMF (220 ml) and sodium azide (16.24 g, 250 mmol) to a 500 ml reaction bottle, protect with nitrogen, stir, heat to 50-55 ° C for 15 h, and the reaction is complete by TLC detection. Add n-hexane (400 ml), purified water (120 ml), stir, stand and separate, wash the organic layer with saturated sodium chloride aqueous solution (120 ml), and dry with anhydrous sodium sulfate. Filter, and concentrate the filtrate to dryness under reduced pressure to obtain RM-7-3, 18.8 g of oil, with a yield of 89.6%.

[0068] Example 2 - Preparation of compound (5S,6S,9R)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cycloheptyl[b]pyridin-5-amine dihydrochloride (RM-8)

[0069] Add RM-7-3 (18.0 g, 38.0 mmol) and ethanol (200 ml) to a 500 ml reaction bottle, stir to dissolve, add activated carbon (0.7 g) after dissolving, stir for 10 min, filter, and retain the filtrate. Purge the fixed bed reactor with nitrogen for 5 min, fill the metal-loaded catalyst Pd / C, purge nitrogen again for 5 min, and turn off the nitrogen. Adjust the back pressure valve pressure to 2.2-2.5 MPa, and adjust the temperature of the fixed bed reactor to 20-30 ° C. Turn on the plunger pump and hydrogen at the same time, set the plunger pump flow rate to 0.1 ml / min, and the hydrogen flow rate to 40 ml / min. The two enter the reaction system continuously, and the residence time of the reaction material in the reactor is 30 min. The product was collected after flowing out from the material outlet, placed in a 50°C water bath and spun dry, and isopropanol (140ml), isopropyl acetate (280ml) and 35% ethanolic hydrogen chloride solution (8.6g, 82.2mmol) were added, and stirred at room temperature for 1h. Filtered, the wet product was placed at 50°C and dried under reduced pressure to obtain RM-8, an off-white solid of 15.7g, with a yield of 79.3%.

[0070] Example 3-(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol L-tartrate (compound of formula I)

[0071] In a 250 ml reaction bottle, add RM-8 (15.5 g, 29.8 mmol) and water (80 ml), heat to 80-85 ° C and stir for 5 h. The reaction is complete when detected by TLC. Add toluene (40 ml) for washing, retain the water layer, add dichloromethane (80 ml), adjust the pH to 8 with 10% sodium carbonate aqueous solution, and after adjustment, stand for separation. The aqueous phase is extracted once with dichloromethane (40 ml), the organic phases are combined, and concentrated to dryness under reduced pressure to obtain (5S, 6S, 9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-ol, 9.0 g of oil.

[0072] In a 100 ml reaction bottle, add the above 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), L-tartaric acid (4.5 g, 30.0 mmol), heat to 70-80 ° C and stir to react for 2 h, then slowly cool to 10-20 ° C and stir to crystallize for 2 h, filter, and place the wet product on a 60 ° C hot air dryer to obtain the compound of formula I as a white solid of 7.6 g with a yield of 89.0%.

[0073] 1HNMR (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).

[0074] Comparative experiment:

[0075] In a 100 ml reaction bottle, add 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) prepared in Example 3, isopropanol (10 ml), isopropyl acetate (20 ml), and add 35% hydrogen chloride ethanol solution (2.9 g, 27.8 mmol) dropwise at 10-20°C. After the addition is complete, continue to react at this temperature for 0.5 h. Filter, and dry the wet product under reduced pressure at 60°C to obtain compound II (dihydrochloride), 3.2 g of off-white solid, with a yield of 90.8%.

[0076] 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).

[0077] The comparative test results of related substances of the compound of formula I and compound II are listed in Table 2 below.

[0078] Table 2

[0079]

[0080]

[0081] The above-mentioned related substance detection results show that the impurity removal effect of (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-ol in the form of L-tartrate is better than that of compound II (dihydrochloride).

[0082] The comparative test results of the hygroscopicity test of the compound of formula I and compound II are listed in Table 3 below.

[0083] Table 3

[0084]

[0085] The above results show that the compound of formula I is not hygroscopic, while compound II (dihydrochloride) is extremely hygroscopic, absorbing 31.3% of moisture after being placed in a humidity environment of 92.5% for 24 hours.

[0086] Example 4—Preparation of Crystalline Forms of Compounds of Formula I

[0087] In the following examples, the experimental methods are performed under conventional conditions or conventional test conditions, and the compounds used in the examples are obtained by commercial or homemade methods.

[0088] X-ray diffraction measurement parameters for measuring the crystalline form (I) of the compound of formula I

[0089]

[0090] DSC and TGA test conditions for measuring the crystalline form (I) of the compound of formula I

[0091]

[0092] The compound of formula I prepared in the above Example 3 was subjected to crystal form determination.

[0093] Attached Figure 2 The XRPD diffraction pattern of crystalline form (I) is provided in .

[0094] Among them in the attached Figure 3 A DSC curve of crystalline form (I) is provided in , which comprises an endothermic peak with an onset temperature of about 195°C.

[0095] Among them in the attached Figure 4 The TGA curve of crystalline form (I) is provided in the accompanying drawings, and its thermogravimetric analysis chart contains less than about 0.5% mass loss when heated from about 27°C to about 100°C. Figure 8 The XRPD diffraction pattern of compound II (dihydrochloride) is provided in , and compound II (dihydrochloride) is amorphous.

[0096] Example 4 - Salt-forming effect using other salt-forming reagents

[0097] According to the content of Example 3, we investigated the reaction effects of forming D-tartaric acid, L-camphorsulfonic acid, D-camphorsulfonic acid, L-dibenzoyltartaric acid and D-dibenzoyltartaric acid salt, see Table 4.

[0098] Table 4

[0099]

[0100] No salt formation was observed using any of the above salts.

[0101] Example 5 - Preparation of Remigipam

[0102] In a 250ml reaction bottle, add the compound of formula I (5.0g, 11.4mmol), RMM (6.6g, 21.1mmol), DMF (50ml), stir, cool to 0-10℃, add potassium tert-butoxide (7.0g, 62.4mmol) in THF (50ml) solution dropwise, continue to react for 5h after the addition is complete, and the basic reaction is monitored by TLC spot plate. After the reaction is completed, adjust pH to 7 with 20% citric acid aqueous solution, add dichloromethane (150ml), stir, stand and separate, wash the organic phase with 50ml of water × 3 times, and spin dry the organic phase in a 45℃ water bath. Add ethanol (20ml), stir and beat for 2h, filter, and dry the wet product in 50℃ hot air to obtain Remegipam, 4.9g of white solid, with a yield of 80.7%. HPLC purity is 99.89%, ee value is 100.0%, de value is 100.0%, impurity RM-E is 0.086%, impurities RM-B and RM-F are not detected, and the maximum single impurity of other is 0.02%.

[0103] Comparative experiment:

[0104] In a 100ml reaction bottle, compound II (dihydrochloride) (1.3g, 2.7mmol), RMM (1.6g, 5.1mmol), DMF (10ml), stirred, cooled to 0-10℃, and potassium tert-butoxide (1.7g, 15.1mmol) in THF (10ml) solution was added dropwise. After the addition was completed, the reaction continued for 5h. The TLC spot plate monitored that compound II remained more. The reaction time was extended to 7h. The TLC spot plate monitored that the reaction did not progress. Post-treatment: adjust pH to 7 with 20% citric acid aqueous solution, add dichloromethane (50ml), stir, stand and separate, wash the organic phase with 20ml×3 water three times, and place the organic phase in a 45℃ water bath and spin dry to obtain 1.2g of oil. HPLC purity 22.86%, of which the raw material RM-9 (free base of compound II) remained 70.78%.

[0105] It should be pointed out that the above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol L-tartrate (compound of formula I):

2. A compound of formula I as claimed in claim 1 is in crystalline form (I), characterized in that The 2θ angle in the X-ray diffraction pattern measured by using a Cu K-α1 radiation source has peak maximum 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 claimed in claim 2, which has a differential scanning calorimetry pattern comprising an endothermic peak with an onset temperature of about 195°C.

4. The crystalline Form (I) of the compound of Formula I as claimed in claim 2, which has a thermogravimetric analysis profile comprising less than about 0.5% mass loss when heated from about 27°C to about 100°C.

5. A method for preparing the compound of formula I as claimed 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 subjected to hydrogenation reaction under certain temperature conditions in a continuous hydrogenation device in the presence of a metal-supported catalyst, and then treated with a hydrogen chloride ethanol solution to form a salt to obtain compound RM-8; Step 3—Compound RM-8 is first heated with water to remove the TIPS protecting group, and then alkaline is added to hydrolyze the salt to obtain an oily substance, and then an organic solvent is added to form a salt with L-tartaric acid under certain temperature conditions to obtain the compound of formula I.

6. A method for preparing a compound of formula I as claimed in claim 5, characterized in that: The organic solvent described 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°C, and the reaction time is 4-24h.

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

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

9. A method for preparing a compound of formula I as claimed 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 remegipam, comprising preparing a compound of formula I according to the method of claim 5, characterized in that: In an organic solvent, under alkaline conditions, the compound of formula I is directly reacted with the compound RMM at a certain temperature without desalting to synthesize Remigipam. The synthesis route is as follows:

11. The method for preparing Remigipam according to claim 10, characterized in that: The reaction organic solvent is one or more of a halogenated hydrocarbon solvent, an ether solvent, and an aprotic polar solvent.

12. The method for preparing Remigipam according to 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 Remigipam according to claim 10, characterized in that: The reaction base is selected from one or more of potassium hydroxide, potassium carbonate, sodium tert-butoxide and potassium tert-butoxide.

14. The method for preparing Remigipam according to claim 10, characterized in that The reaction temperature is 0-30°C and the reaction time is 3-6 hours.

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