A preparation method of Remigipam

Abstract

The present invention discloses a method for preparing remegpam. Specifically, the method comprises the steps of: 1) reacting a compound of formula III with a compound of formula IV in solvent 1 in the presence of a base; 2) after the reaction, adding solvent 2 and adjusting the pH to <10; and 3) concentrating the organic phase to obtain a crude compound of formula II. The method of the present invention has mild conditions, high yield, and high product purity, meeting the impurity requirements of existing ICH regulations. It is also simple to operate and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of Remigipam. Background Art

[0002] Rimegepant (Formula II) is a potent, selective, competitive, orally active calcitonin gene-related peptide (CGRP) antagonist used for the acute treatment of migraine in adults. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on February 27, 2020.

[0003] WO2011046997 reports two synthetic methods of Remigipam:

[0004] Route 1:

[0005]

[0006] Route 2:

[0007]

[0008] Route 1 involves an azidation step, which is known to pose significant safety risks. The azidation product itself is a high-energy compound, posing safety risks in storage and transportation. Furthermore, the remedipam purification method disclosed in WO2011046997 utilizes FCC (flash column chromatography), which is unsuitable for large-scale industrial production.

[0009] WO2011046997 only discloses Route 2, without corresponding examples. WO2012050764 supplements Route 2 with an example, achieving a yield of 78.3%. When repeating the method of Example 3 of WO2012050764, the inventors discovered that the solubility of the compound of Formula IV in Route 2 in the solvent tetrahydrofuran was extremely poor. During the reaction, the reaction system remained in a slurry state, with no clearing process. 10-20% of the raw material remained, and even with extended reaction time, the raw material was no longer converted. Increasing the reaction temperature significantly increased the number of byproducts. Under the optimal conditions, this method yielded only 66% of remedipam, with an HPLC purity of 93%.

[0010] Furthermore, the marketed pharmaceutical crystalline form of Remigipam is the hemisulfate sesquihydrate (hereinafter referred to as the compound of Formula V) reported in WO2013130402. The maximum daily dose of Remigipam is 75 mg. According to ICH Q3A requirements for impurities, known impurities must be controlled below 0.15%, and unknown impurities must be controlled below 0.10%. However, the solubility of the compound of Formula II in conventional solvents is extremely poor (less than 0.02 g / mL), making it difficult to purify to a purity exceeding 99.5%. Summary of the Invention

[0011] The present invention aims to provide a method for preparing remegpam with mild conditions, high yield, high product purity, simple operation and suitability for industrial production.

[0012] In a first aspect, the present invention provides a method for preparing Remigipam, comprising the steps of:

[0013] 1) In solvent 1, in the presence of a base, the compound of formula III reacts with the compound of formula IV;

[0014] 2) After the reaction is completed, solvent 2 is added to adjust the pH to <10; and

[0015] 3) concentrating the organic phase to obtain a crude product of the compound of formula II;

[0016]

[0017] Wherein, the solvent 1 is selected from the following group: dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, methyl isobutyl ketone, or a combination thereof, preferably dimethyl sulfoxide or N,N-dimethylformamide.

[0018] In another preferred embodiment, the base is selected from the group consisting of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, or a combination thereof, preferably sodium tert-butoxide or potassium tert-butoxide.

[0019] In another preferred embodiment, the method further has one or more of the following features:

[0020] (a) the solvent 2 is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, ethyl acetate, methyltetrahydrofuran or a combination thereof, preferably dichloromethane;

[0021] (b) the pH is adjusted to 7-10, such as 7, 8 or 9;

[0022] (c) the molar ratio of the compound of formula IV to the compound of formula III is 1:1 to 2.5, preferably 1:1.3 to 1.5;

[0023] (d) the molar ratio of the base to the compound of formula III is 1:1.5-4.5, preferably 1:2-3; and / or

[0024] (e) The reaction temperature is 10-40°C, preferably 20-35°C.

[0025] In another preferred embodiment, in step (3), the organic phase is washed with water 1-3 times, preferably 2-3 times, before concentration.

[0026] In another preferred embodiment, the method further comprises the following refining step:

[0027] i) beating the crude compound of formula II obtained in step 3) with solvent 3, and then filtering to obtain a refined compound of formula II;

[0028] The solvent 3 is selected from the following group: n-heptane, petroleum ether, methyl tert-ether, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, isopropyl acetate, ethanol, methanol, isopropanol, butanol, acetone, butanone, or a combination thereof, preferably ethyl acetate, a mixed solvent of acetonitrile and n-heptane (such as a volume ratio of 1:0.5-2, preferably 1:0.8-1.2, more preferably 1:1), or a mixed solvent of tetrahydrofuran and n-heptane (such as a volume ratio of 1:0.5-2, preferably 1:0.8-1.2, more preferably 1:1).

[0029] In a second aspect, the present invention provides a method for purifying Remigipam, comprising the steps of:

[0030] 1) adding solvent X to a solution of the crude compound of formula II in solvent 4, and collecting the solid to obtain the compound of formula I;

[0031] 2) slurrying the compound of formula I obtained in step 1) in solvent 5, collecting the solid to obtain a high-purity fine product of the compound of formula II;

[0032] The reaction formula is as follows:

[0033]

[0034] The solvent X is methyl tert-butyl ether or isopropyl ether.

[0035] In another preferred embodiment, step 1) comprises: adding solvent 4 to the crude compound of formula II, heating to 40-80° C., adding solvent X after the solid is dissolved, stirring for 0.5-1.5 hours, cooling (0-30° C.), and collecting the solid to obtain the compound of formula I.

[0036] In another preferred embodiment, step 2) comprises: adding the compound of formula I to solvent 5, heating to 50-70° C., beating for 0.5-1.5 hours, cooling to 0-30° C., and collecting the solid to obtain a high-purity fine product of the compound of formula II.

[0037] The solvent 4 is selected from the following group: dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, methyl isobutyl ketone, methanol, dichloromethane, chloroform or a combination thereof; preferably, it is selected from dimethyl sulfoxide, N,N-dimethylformamide or 1,4-dioxane.

[0038] The solvent 5 is a mixed solvent of an organic solvent and water, and the organic solvent is selected from the following group: ethanol, methanol, isopropanol, acetone, tetrahydrofuran, or a combination thereof, preferably ethanol / water or tetrahydrofuran / water.

[0039] The volume ratio of the organic solvent to water in the solvent 5 is 5 to 30:1, preferably 5 to 20:1, such as 8:1, 10:1, 15:1 or 18:1.

[0040] In another preferred embodiment, the weight ratio of solvent 4 to the compound of formula I is 1:2-5, such as 1:3 or 1:4.

[0041] In another preferred embodiment, the volume ratio of solvent 4 to solvent X is 1:3-15, preferably 1:5-10.

[0042] In another preferred embodiment, the purity of the crude compound of formula II is 80-95%.

[0043] In another preferred embodiment, the crude compound of formula II is prepared according to the first aspect of the present invention.

[0044] In another preferred embodiment, the purity of the high-purity fine product of the compound of formula II is >99.5%, preferably ≥99.7%, ≥99.8%.

[0045] In a third aspect, the present invention provides a compound of formula I, which is a solvate of a compound of formula II, and has the following structural formula:

[0046]

[0047] Wherein, X is methyl tert-butyl ether or isopropyl ether.

[0048] In another preferred embodiment, the molar ratio of the compound of formula II to X is 1:1.

[0049] In another preferred embodiment, the compound of formula I is a methyl tert-butyl ether solvate of the compound of formula II, and its X-ray powder diffraction pattern has characteristic peaks at the following 2θ values: 4.2±0.2o, 14.9±0.2o, 16.8±0.2o, 18.2±0.2o, and 20.6±0.2o.

[0050] In another preferred embodiment, the compound of formula I is a methyl tert-butyl ether solvate of the compound of formula II, and its X-ray powder diffraction pattern also has characteristic peaks at one or more of the following 2θ values: 8.3±0.2o, 12.6±0.2o, 15.4±0.2o, 20.4±0.2o, 21.0±0.2o.

[0051] In another preferred embodiment, the compound of formula I is a methyl tert-butyl ether solvate of the compound of formula II, and its X-ray powder diffraction pattern has characteristic peaks at the following 2θ values: 4.2±0.2o, 8.3±0.2o, 8.9±0.2o, 10.1±0.2o, 12.6±0.2o, 13.1±0.2o, 14.9±0.2o, 15.4±0.2o, 15.9±0.2o, 16.8±0.2o, 18. 2±0.2o, 19.0±0.2o, 19.4±0.2o, 20.4±0.2o, 20.6±0.2o, 21.0±0.2o, 22.5±0.2o, 23.2±0.2o, 2 4.1±0.2o, 24.6±0.2o, 25.1±0.2o, 26.4±0.2o, 27.8±0.2o, 30.4±0.2o, 35.3±0.2o, 39.4±0.2o.

[0052] In another preferred embodiment, the methyl tert-butyl ether solvate of the compound of formula II further has one or more technical features selected from the following group:

[0053] (1) The differential scanning calorimetry (DSC) of the methyl tert-butyl ether solvate of the compound of formula II has an endothermic peak in the range of 164 to 182°C;

[0054] (2) the methyl tert-butyl ether solvate of the compound of formula II has an infrared absorption spectrum with absorption peaks at 3387±10, 3324±10, 3150±10, 2976±10, 2866±10, 1702±10, 1595±10, and 1572±10 cm-1; and / or

[0055] (3) The thermogravimetric analysis (TGA) of the methyl tert-butyl ether solvate of the compound of formula II shows a weight loss of about 12.2±0.2% in the range of 155°C to 200°C.

[0056] In another preferred embodiment, the differential scanning calorimetry (DSC) of the methyl tert-butyl ether solvate of the compound of formula II has an initial value of 164.0±2°C and / or a peak value of 172.7±2°C;

[0057] In another preferred embodiment, the methyl tert-butyl ether solvate of the compound of formula II further has one or more technical features selected from the following group:

[0058] (1) The X-ray powder diffraction pattern of the methyl tert-butyl ether solvate of the compound of formula II is substantially as follows Figure 1 As shown;

[0059] (2) The differential scanning calorimetry (DSC) of the methyl tert-butyl ether solvate of the compound of formula II is substantially as follows: Figure 2 As shown;

[0060] (3) The infrared absorption spectrum of the methyl tert-butyl ether solvate of the compound of formula II is substantially as follows Figure 3 as shown; and / or

[0061] (4) The thermogravimetric analysis (TGA) of the methyl tert-butyl ether solvate of the compound of formula II is substantially as follows: Figure 4 shown.

[0062] In another preferred embodiment, the compound of formula I is an isopropyl ether solvate of the compound of formula II, and its X-ray powder diffraction pattern has characteristic peaks at the following 2θ values: 4.2±0.2o, 16.9±0.2o, 20.5±0.2o, 16.7±0.2o, and 15.8±0.2o.

[0063] In another preferred embodiment, the compound of formula I is an isopropyl ether solvate of the compound of formula II, and its X-ray powder diffraction pattern also has characteristic peaks at one or more of the following 2θ values: 8.4±0.2o, 12.6±0.2o, 15.6±0.2o, 19.4±0.2o, 22.7±0.2o.

[0064] In another preferred embodiment, the compound of formula I is an isopropyl ether solvate of the compound of formula II, and its X-ray powder diffraction pattern has characteristic peaks at the following 2θ values: 4.2±0.2o, 4.7±0.2o, 8.4±0.2o, 12.6±0.2o, 13.9±0.2o, 14.8±0.2o, 15.1±0.2o, 15.2±0.2o, 15.6±0.2o, 15.8±0.2o, 16.7±0.2o, 16.9± 0.2o, 18.1±0.2o, 18.7±0.2o, 18.9±0.2o, 19.2±0.2o, 19.4±0.2o, 20.5±0.2o, 21.6±0.2o, 22.7±0. 2o, 22.9±0.2o, 23.8±0.2o, 24.7±0.2o, 26.3±0.2o, 26.5±0.2o, 30.3±0.2o, 30.4±0.2o, 34.2±0.2o.

[0065] In another preferred embodiment, the isopropyl ether solvate of the compound of formula II further has one or more technical features selected from the following group:

[0066] (1) The differential scanning calorimetry (DSC) of the isopropyl ether solvate of the compound of formula II has an endothermic peak in the range of 105-160°C;

[0067] (2) the isopropyl ether solvate of the compound of formula II has an infrared absorption spectrum with absorption peaks at 3384±10, 3328±10, 3166±10, 2937±10, 2829±10, 1596±10, 1572±10, and 1469±10 cm-1; and / or

[0068] (3) The thermogravimetric analysis (TGA) of the isopropyl ether solvate of the compound of formula II shows a weight loss of about 15.0±0.2% in the range of 105°C to 170°C.

[0069] In another preferred embodiment, the differential scanning calorimetry (DSC) of the isopropyl ether solvate of the compound of formula II has an initial value of 105.0±2°C and / or a peak value of 157.9±2°C.

[0070] In another preferred embodiment, the isopropyl ether solvate of the compound of formula II further has one or more technical features selected from the following group:

[0071] (1) The X-ray powder diffraction pattern of the isopropyl ether solvate of the compound of formula II is substantially as follows Figure 7 As shown;

[0072] (2) The differential scanning calorimetry (DSC) of the isopropyl ether solvate of the compound of formula II is substantially as follows: Figure 8 As shown;

[0073] (3) The infrared absorption spectrum of the isopropyl ether solvate of the compound of formula II is substantially as follows Figure 9 as shown; and / or

[0074] (4) The thermogravimetric analysis (TGA) of the isopropyl ether solvate of the compound of formula II is substantially as follows Figure 10 shown.

[0075] In a fourth aspect, the present invention provides a method for preparing a compound of formula I, comprising the steps of: 1) adding solvent X to a solution of a crude compound of formula II in solvent 4, and collecting the solid to obtain a compound of formula I, wherein the solvent X is methyl tert-butyl ether or isopropyl ether.

[0076] In another preferred embodiment, step 1) comprises: adding solvent 4 to the crude compound of formula II, heating to 40-80° C., adding solvent X after the solid is dissolved, stirring for 0.5-1.5 hours, cooling (0-30° C.), and collecting the solid to obtain the compound of formula I.

[0077] In another preferred embodiment, the weight ratio of solvent 4 to the compound of formula I is 1:2-5, such as 1:3 or 1:4.

[0078] In another preferred embodiment, the volume ratio of solvent 4 to solvent X is 1:3-15, preferably 1:5-10.

[0079] In another preferred embodiment, the purity of the crude compound of formula II is 80-95%.

[0080] In another preferred embodiment, the crude compound of formula II is prepared according to the first aspect of the present invention.

[0081] In another preferred embodiment, the purity of the compound of formula I is >99.5%, preferably ≥99.7%, ≥99.8%.

[0082] Furthermore, when the purity of the crude compound of formula II is about 80%, no further purification is required and the compound of formula I with a high purity of more than 99.5% can be directly obtained by the method of the fourth aspect of the present invention.

[0083] In a fifth aspect, the present invention provides use of the compound of formula I according to the fourth aspect of the present invention as an intermediate for preparing remigipam or remigipam hemisulfate sesquihydrate.

[0084] The compound of formula I of the present invention is easier to obtain with high purity (>95%) and is very suitable as an intermediate substance of high purity (such as purity>99.5%, preferably ≥99.7%, ≥99.8%) remegpam.

[0085] Furthermore, the solubility of the compound of formula I is much enhanced compared to that of the compound of formula II. It can be dissolved in conventional solvents such as THF, DCM, EtOH, and MeOH at room temperature, and thus can be conveniently used to prepare the hemisulfate sesquihydrate of remegpam (compound of formula V). The salt formation process does not increase the amount of impurities or generate new impurities.

[0086] In a sixth aspect, the present invention provides a method for preparing remegipam hemisulfate sesquihydrate (compound of formula V), comprising the steps of:

[0087] 1) dissolving the compound of formula I in solvent 6, adding sulfuric acid solution dropwise, and collecting the solid to obtain the compound of formula V;

[0088] The reaction formula is as follows:

[0089]

[0090] Wherein, X is methyl tert-butyl ether or isopropyl ether.

[0091] In another preferred embodiment, the solvent 6 is a mixed solvent of an organic solvent and water, and the organic solvent is selected from the following group: ethanol, methanol, isopropanol, acetone, tetrahydrofuran, preferably ethanol / water or tetrahydrofuran / water.

[0092] In another preferred embodiment, the method comprises the steps of: adding the compound of formula I to solvent 5, heating to 50-70°C to dissolve the solid; adding sulfuric acid solution dropwise and stirring for 1-2 hours; cooling (0-30°C) and collecting the solid to obtain the compound of formula V.

[0093] In another preferred embodiment, the volume ratio of the organic solvent to water in the solvent 6 is 3 to 15:1, preferably 3 to 10:1, such as 5:1 or 8:1.

[0094] In another preferred embodiment, the compound of formula I is prepared according to the fourth aspect of the present invention.

[0095] In another preferred embodiment, the purity of the compound of formula I is >99.5%, preferably ≥99.7%, ≥99.8%.

[0096] In another preferred embodiment, the purity of the compound of formula V is >99.5%, preferably ≥99.7%, ≥99.8%.

[0097] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] Figure 1 is the PXRD pattern of the remegipam methyl tert-butyl ether solvate of the present invention;

[0099] Figure 2 is the DSC spectrum of the remegipam methyl tert-butyl ether solvate of the present invention;

[0100] Figure 3 is the IR spectrum of the remegipam methyl tert-butyl ether solvate of the present invention;

[0101] Figure 4 is the TGA spectrum of the remegipam methyl tert-butyl ether solvate of the present invention;

[0102] Figure 5 The present invention is the remegipam methyl tert-butyl ether solvate 1 H-NMR spectrum;

[0103] Figure 6 is the HPLC spectrum of the remegipam methyl tert-butyl ether solvate of the present invention;

[0104] Figure 7 is the PXRD pattern of the remigipam isopropyl ether solvate of the present invention;

[0105] Figure 8is the DSC spectrum of the remigipam isopropyl ether solvate of the present invention;

[0106] Figure 9 is the IR spectrum of the remegpam isopropyl ether solvate of the present invention;

[0107] Figure 10 is the TGA spectrum of the remigipam isopropyl ether solvate of the present invention;

[0108] Figure 11 is the PXRD pattern of the remedipam hemisulfate sesquihydrate of the present invention;

[0109] Figure 12 The HPLC spectrum of the remegipam hemisulfate sesquihydrate of the present invention is shown in FIG. DETAILED DESCRIPTION

[0110] After extensive and in-depth research, screening, and testing, the present inventors have developed a method for preparing remdepam. This method features mild conditions, high yield, high product purity, and simple operation, making it suitable for industrial production. Furthermore, the present invention provides a purification method for obtaining high-purity remdepam or a pharmaceutically acceptable crystalline form thereof. The present inventors unexpectedly discovered that by forming a specific solvate intermediate, the purity of the previously difficult-to-purify remdepam product can be increased to over 99.5%. This was the basis for the present invention.

[0111] the term

[0112] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0113] As used herein, when used in reference to a specific recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0114] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0115] As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40°C, preferably, 25±5°C.

[0116] Preparation method of Remigipam

[0117] A method for preparing Remigipam comprises the steps of:

[0118] 1) In solvent 1, in the presence of a base, the compound of formula III reacts with the compound of formula IV;

[0119] 2) After the reaction is completed, solvent 2 is added to adjust the pH to <10; and

[0120] 3) concentrating the organic phase to obtain a crude compound of formula II;

[0121]

[0122] Preferably, the base is selected from the group consisting of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, or a combination thereof, preferably sodium tert-butoxide or potassium tert-butoxide.

[0123] Preferably, the solvent 1 is selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, methyl isobutyl ketone, or a combination thereof, preferably dimethyl sulfoxide or N,N-dimethylformamide. During the reaction, both the reaction substrate and the product are completely soluble in the solvent 1.

[0124] Preferably, the solvent 2 is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, ethyl acetate, methyltetrahydrofuran or a combination thereof, preferably dichloromethane.

[0125] Preferably, in step (3), the organic phase is washed with water 1-3 times, preferably 2-3 times, before concentration. Solvent 2 is immiscible with water, and the washing step effectively removes solvent 1 and water-soluble impurities, while retaining the remedifam that is readily soluble in solvent 2 in the organic phase.

[0126] Furthermore, the method further comprises the following refining steps:

[0127] i) beating the crude compound of formula II obtained in step 3) with solvent 3, and then filtering to obtain a refined compound of formula II;

[0128] The solvent 3 is selected from the following group: n-heptane, petroleum ether, methyl tert-ether, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, isopropyl acetate, ethanol, methanol, isopropanol, butanol, acetone, butanone, or a combination thereof, preferably ethyl acetate, a mixed solvent of acetonitrile and n-heptane (such as a volume ratio of 1:0.5-2, preferably 1:0.8-1.2, more preferably 1:1), or a mixed solvent of tetrahydrofuran and n-heptane (such as a volume ratio of 1:0.5-2, preferably 1:0.8-1.2, more preferably 1:1); preferably, when using a mixed solvent, the crude compound of formula II is first dissolved with a good solvent (such as acetonitrile or tetrahydrofuran), and then a poor solvent (such as n-heptane or ethyl acetate) is added for slurrying to precipitate the fine compound of formula II.

[0129] Purification method

[0130] Furthermore, a method for purifying Remigipam is provided, comprising the steps of:

[0131] 1) adding solvent X to a solution of the crude compound of formula II in solvent 4, and collecting the solid to obtain the compound of formula I;

[0132] 2) slurrying the compound of formula I obtained in step 1) in solvent 5, collecting the solid to obtain a high-purity fine product of the compound of formula II;

[0133] The reaction formula is as follows:

[0134]

[0135] The solvent X is methyl tert-butyl ether or isopropyl ether.

[0136] The present inventors unexpectedly discovered that by preparing a relatively low-purity crude compound of Formula II into its methyl tert-butyl ether solvate or isopropyl ether tert-butyl solvate, the product purity can be increased to over 99.5%. This solves the problem of difficult purification of crude Remigipam and achieves the purity (>99.5%) and impurity (known impurities <0.15%, unknown impurities <0.10%) requirements for its pharmaceutical use.

[0137] Based on this, the methyl tert-butyl ether solvate of the compound of formula II and the isopropyl ether tert-butyl solvate of the compound of formula II of the present invention are very suitable as intermediates for preparing high-purity remegpam or its pharmaceutically acceptable salts.

[0138] Preferably, the crude compound of formula II is prepared by the above method of the present invention.

[0139] Solvates

[0140] The present invention also provides a methyl tert-butyl ether solvate of the compound of formula II, and an isopropyl ether tert-butyl solvate of the compound of formula II (as shown in formula I).

[0141] The structural formula is as follows:

[0142]

[0143] wherein X is methyl tert-butyl ether or isopropyl ether, and wherein the molar ratio of the compound of formula II to X is 1:1.

[0144] Preferably, the methyl tert-butyl ether solvate of the compound of formula II of the present invention further has an X-ray powder diffraction pattern having characteristic peaks at one or more of the following 2θ values: 8.3±0.2o, 12.6±0.2o, 15.4±0.2o, 20.4±0.2o, 21.0±0.2o.

[0145] Preferably, the X-ray powder diffraction pattern of the methyl tert-butyl ether solvate of the compound of formula II is substantially as follows Figure 1 The X-ray powder diffraction peak table is basically as shown in Table 1;

[0146] Table 1

[0147]

[0148]

[0149] The differential scanning calorimetry (DSC) of the methyl tert-butyl ether solvate of the compound of formula II is substantially as follows: Figure 2 shown.

[0150] The infrared absorption spectrum of the methyl tert-butyl ether solvate of the compound of formula II is substantially as follows Figure 3 shown.

[0151] The thermogravimetric analysis (TGA) diagram of the methyl tert-butyl ether solvate of the compound of formula II is substantially as follows: Figure 4 shown.

[0152] Furthermore, the isopropyl ether solvate of the compound of formula II provided by the present invention has characteristic peaks in its X-ray powder diffraction pattern at the following 2θ values: 4.2±0.2o, 16.9±0.2o, 20.5±0.2o, 16.7±0.2o, and 15.8±0.2o.

[0153] Preferably, the X-ray powder diffraction pattern of the isopropyl ether solvate of the compound of formula II is substantially as follows Figure 7 The X-ray powder diffraction peak table is basically as shown in Table 2;

[0154] Table 2

[0155]

[0156]

[0157] In addition, the differential scanning calorimetry (DSC) of the isopropyl ether solvate of the compound of formula II of the present invention is substantially as follows Figure 8 shown.

[0158] The infrared absorption spectrum of the isopropyl ether solvate of the compound of formula II is substantially as follows Figure 9 shown.

[0159] The thermogravimetric analysis (TGA) of the isopropyl ether solvate of the compound of formula II is substantially as follows Figure 10 shown.

[0160] The present invention also provides use of the solvate for preparing an intermediate of remigipam or remigipam hemisulfate sesquihydrate.

[0161] In addition, the present invention also provides a method for preparing the above-mentioned solvate, comprising the steps of: 1) adding solvent X to a solution of a crude compound of formula II in solvent 4, and collecting the solid to obtain a compound of formula I, wherein the solvent X is methyl tert-butyl ether or isopropyl ether.

[0162] Preferably, the solvent 4 is selected from the following group: dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, methyl isobutyl ketone, methanol, dichloromethane, chloroform or a combination thereof; more preferably, it is selected from dimethyl sulfoxide, N,N-dimethylformamide or 1,4-dioxane.

[0163] Preparation method of remegipam hemisulfate sesquihydrate (compound of formula V)

[0164] Furthermore, the present invention also provides a method for preparing remegipam hemisulfate sesquihydrate (compound of formula V), comprising the steps of:

[0165] 1) dissolving the compound of formula I in solvent 6, adding sulfuric acid solution dropwise, and collecting the solid to obtain the compound of formula V;

[0166] The reaction formula is as follows:

[0167]

[0168] Wherein, X is methyl tert-butyl ether or isopropyl ether.

[0169] The solvate of the present invention (compound of formula I) is used as a raw material. Its solubility is much enhanced compared to the compound of formula II. It can be dissolved in conventional solvents such as THF, DCM, EtOH, and MeOH at room temperature. Therefore, it can be conveniently used to prepare the hemisulfate sesquihydrate of remegpam (compound of formula V). The salt formation process does not increase the amount of impurities or generate new impurities.

[0170] Preferably, the compound of formula I is prepared by the above method of the present invention.

[0171] The main advantages of the present invention include:

[0172] 1) During the reaction process for preparing the compound of formula II, the reactant system remains homogeneous, the conversion rate of the compound of formula III can reach 100%, the post-reaction treatment is simple, and the yield of the compound of formula II can reach up to 95%.

[0173] 2) The inventors unexpectedly discovered that by preparing the compound of formula I, compounds of formula II and formula V can be obtained at over 99.8% yield, with purification yields exceeding 95%. Furthermore, no unknown impurities greater than 0.10% were present, meeting the ICH Q3A requirements for impurities, and both residual solvent and ROI (residue on ignition) were found to be acceptable.

[0174] The present invention will be further described below in conjunction with specific implementation. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0175] The raw materials compound of formula III and compound of formula IV can be prepared by the method disclosed in WO2012050764.

[0176] General method:

[0177] 1. XRPD pattern determination method

[0178] X-ray powder diffraction instrument: BRUKER AXSD2 PHASER X-ray powder diffractometer; Radiation source: Intensity ratio α1 / α2 is 0.5; generator kV: 30.0 kV; generator mA: 10.0 mA; starting 2θ: 2.000°, scanning range: 2.0000 to 40.000°.

[0179] 2.DSC measurement method

[0180] METTLEER DSC1 differential scanning calorimeter temperature program: 20℃~300℃, 10℃ / min.

[0181] 3. TGA determination method

[0182] Instrument model: METTLEER TGA / DSC1 thermogravimetric analyzer. Heating program: 30°C to 450°C, 10°C per minute.

[0183] 4. Infrared absorption measurement method

[0184] Instrument model: PerkinElmer Spectrun Two Fourier transform infrared spectrometer, potassium bromide tablet scanning range 4400-450cm -1 Resolution of 4cm -1 Scan 4 times.

[0185] 5.HPLC detection conditions:

[0186] Instrument: Agilent 1260 series HPLC.

[0187] Column: Waters XSelect CSH C18, 4.6 mm × 250 mm, 5 μm

[0188] Column temperature: 15°C

[0189] Sample chamber temperature: 25°C

[0190] Mobile phase A: 0.02% H3PO4 in water

[0191] Mobile phase B: chromatographic grade acetonitrile

[0192] Table 3

[0193] Time (min) % Mobile phase A % mobile phase B 0 98 2 5 98 2 10 80 20 18 78 22 25 70 30 33 5 95 37 5 95 37.1 98 2 55 98 2

[0194] Flow rate: 1 ml / min

[0195] Measurement time: 55 minutes

[0196] Detection wavelength: 210 nm.

[0197] Example 1 Preparation of Compound of Formula II

[0198] Under nitrogen, DMSO (3500 mL), 100 g (344 mmol) of the compound of Formula III, and 154 g (482 mmol) of the compound of Formula IV were added to a reaction kettle at room temperature. The mixture was stirred, and 96 g (826 mmol) of potassium tert-butoxide was added. The reaction was allowed to react at room temperature for 6 hours. The conversion of the compound of Formula III was monitored by HPLC. DCM (1000 mL) was added, and the pH was adjusted to 7-9 with 2N aqueous hydrochloric acid. The layers were separated, and the aqueous phase was extracted three times with DCM (200 mL). The organic phases were combined, washed once with water (200 mL), and concentrated to dryness to obtain 251 g of the compound of Formula II as a foamy solid with an HPLC purity of 82.6%. THF (1250 mL) was added to the foamy solid and stirred at room temperature for 0.5-1 hour to dissolve the solid. n-Heptane (1250 mL) was added, and a large amount of white solid precipitated. Stirring was continued for 1 hour. Filtration afforded 206 g of the compound of Formula II with a yield of 100% and an HPLC purity of 94.4%.

[0199] Example 2 Preparation of Compound of Formula II

[0200] Under nitrogen protection, in a reaction kettle at room temperature, DMF (8000mL), 100g (344mmol) of the compound of formula III and 143g (447mmol) of the compound of formula IV were added, stirred, and 117g (963mmol) of potassium tert-butoxide were added. The reaction was allowed to react at room temperature for 8 hours. HPLC monitoring confirmed that the compound of formula III was completely converted. DCM (1500mL) was added and 3N aqueous hydrochloric acid was used to adjust the pH to 8-9. The mixture was separated and the aqueous phase was extracted twice with DCM (200mL). The organic phases were combined and washed twice with water (300mL). The organic phases were concentrated to 300mL to obtain a DCM solution of the compound of formula II with an HPLC purity of 82.2%. 150mL of the above solution was taken and concentrated to dryness to obtain 126g of a foamy solid with an HPLC purity of 82.4%. The foamy solid was purified according to the method of Example 1 to obtain 102g of the compound of formula II with a yield of 99% and an HPLC purity of 94.1%.

[0201] Example 3 Preparation of Compound of Formula II

[0202] Under nitrogen protection, DMSO (600 mL), 150 g (516 mmol) of the compound of formula III, and 231 g (723 mmol) of the compound of formula IV were added to a reaction kettle at room temperature, stirred, and 126 g (1290 mmol) of sodium tert-butoxide were added. The reaction was allowed to react at room temperature for 10 hours. HPLC monitoring confirmed the complete conversion of the compound of formula III. DCM (1500 mL) was added and the pH was adjusted to 7-8 with 2N aqueous hydrochloric acid. The layers were separated and the aqueous phase was extracted three times with DCM (300 mL). The organic phases were combined and washed twice with water (300 mL). The organic phases were concentrated to dryness and ethyl acetate (750 mL) was added to precipitate a large amount of solid. The mixture was cooled to 0-10° C. and filtered to obtain 295 g of the compound of formula II in a yield of 99% with an HPLC purity of 95.8%.

[0203] Comparative Example 1 Preparation of Compound of Formula II

[0204] Under nitrogen protection, at room temperature, THF (30mL), 2g of compound III and 3.6g (11.5mmol) of compound IV were added to the reaction flask, stirred, and 14g (24mmol) of 20% potassium tert-butoxide in THF were added. The reaction was allowed to react at room temperature for 2 hours until the system was in a slurry state. HPLC monitoring of the reaction showed a 13% residual raw material content, which remained substantially unchanged after an additional 2 hours. 20% aqueous sodium chloride solution (12mL) was added, followed by 20% citric acid (6mL), and the mixture was separated. The organic phase was washed with 20% aqueous sodium chloride solution (30mL) and concentrated to dryness to obtain a viscous liquid. Dichloromethane (50mL) was added, dried over anhydrous sodium sulfate, and concentrated to dryness, yielding a HPLC purity of 66.1%. The crude product was recrystallized from ethanol and n-heptane to obtain 2.4g of compound II in a 66% yield and 93.7% HPLC purity.

[0205] Comparative Example 2 Purification of Formula II Compound

[0206] The compounds of formula II obtained in Example 1, Example 3 and Comparative Example 1 were purified using different conventional solvents, and the results obtained were not much different, as shown in Table 4:

[0207] Table 4

[0208] Solvent system Solution state Yield purity 1 EtOH 15V, reflux for 2 hours pulpy 62.5％ 98.20％ 2 CH3CN 15V, reflux for 3 hours pulpy 90％ 97.98％ 3 EtOH 15V, water 1V, reflux for 1 hour pulpy 62.5％ 98.90％ 4 CH3CN 4V, DCM 1V, 40℃ 2 hours pulpy 89.6％ 98.03％ 5 Dissolve DMF4V, add toluene 6V at 40-50℃ clarify No precipitation / 6 EA 10V, reflux 2 hours pulpy 94％ 95.0％

[0209] As can be seen from Table 4, it is difficult to meet the requirement of increasing the purity of the crude compound of Formula II to above 99.5% by purifying the crude compound of Formula II with a purity of about 94% using conventional methods.

[0210] Example 4 Preparation of the compound of formula I (methyl tert-butyl ether solvate)

[0211] 100 g of the white solid compound of formula II prepared in Example 1 (HPLC purity 94.4%) and DMF (400 mL) were added to the reaction kettle, stirred, and heated to 45-60°C to dissolve the solid. MTBE (2000 mL) was added to precipitate a large amount of solid, and stirring was continued at 45-60°C for 0.5-1 hour. The mixture was cooled to 10-20°C, filtered, and the solid was washed twice with MTBE (200 mL). It was dried under vacuum at 45-60°C to obtain 104 g of compound of formula I with a yield of 94.9% and an HPLC purity of 99.86%. There was no unknown impurity greater than 0.10%. The HPLC spectrum was as shown below. Figure 6 PXRD, DSC, IR, TGA and 1 H-NMR detection, spectrum as Figure 1-5 shown.

[0212] Example 5 Preparation of the compound of formula I (methyl tert-butyl ether solvate)

[0213] To a reaction vessel, 100 g of the foamy solid compound of Formula II obtained in Example 1 (HPLC purity 82.6%) and 320 mL of DMF were added and heated to 45-60°C to dissolve the solid. MTBE (1400 mL) was added to dissolve the solid. A large amount of solid precipitated, and stirring was continued at 45-60°C for 1-2 hours. The mixture was cooled to 5-15°C, filtered, and the solid was washed with MTBE (200 mL). The mixture was then dried under vacuum at 45-60°C to obtain 91.2 g of the compound of Formula I, with a yield of 95.0% and an HPLC purity of 99.86%, with no greater than 0.10% unknown impurities.

[0214] Example 6 Preparation of the compound of formula I (methyl tert-butyl ether solvate)

[0215] A DCM solution (150 mL) of the compound of Formula II prepared in Example 2 and DMF (300 mL) were added to a reaction vessel and heated to 45-60°C. MTBE (1500 mL) was added, causing a large amount of solid to precipitate. Stirring was continued at 45-60°C for 0.5-1 hour. The mixture was cooled to 10-20°C, filtered, and the solid was washed twice with MTBE (100 mL). The solid was then dried under vacuum at 45-60°C to obtain 94 g of the compound of Formula I in a 94.0% yield with an HPLC purity of 99.79% and no unknown impurities greater than 0.10%.

[0216] Example 7 Preparation of the compound of formula I (methyl tert-butyl ether solvate)

[0217] 53 g of the compound of formula II prepared in Example 3 and DMSO (150 mL) were added to a reaction vessel and heated to 45-55°C to dissolve the solid. MTBE (1000 mL) was added to precipitate a large amount of solid. Stirring was continued at 45-55°C for 0.5-1 hour, then cooled to 15-25°C, filtered, and the solid was washed twice with MTBE (100 mL). The solid was then dried under vacuum at 45-60°C to obtain 53 g of the compound of formula I in a yield of 90.1% with an HPLC purity of 99.80% and no unknown impurities greater than 0.10%.

[0218] Example 8 Preparation of the compound of formula I (isopropyl ether solvate)

[0219] 53 g of the compound of formula II prepared in Example 3 and DMF (150 mL) were added to the reaction kettle and heated to 50-60° C. to dissolve the solid. Isopropyl ether (750 mL) was added to precipitate a large amount of solid. Stirring was continued at 50-60° C. for 1 hour, cooled to 15-25° C., filtered, and the solid was washed twice with isopropyl ether (100 mL). It was dried under vacuum at 45-55° C. to obtain 55.6 g of the compound of formula I with a yield of 92%. The HPLC purity was 99.85%, and there was no unknown impurity greater than 0.10%. PXRD, DSC, IR and TGA detection were performed, and the spectrum was as shown. Figure 7-10 shown.

[0220] Example 10 Preparation of high-purity compound of formula II

[0221] At room temperature, the compound of Formula I prepared in Example 5 (20 g, 36.8 mmol) and ethanol / water (20:1 volume ratio, 200 mL) were added to a reaction kettle with stirring. The mixture was heated to 55-70°C until the system became heterogeneous and stirring was continued for 0.5-1.5 hours. The mixture was cooled to 10-30°C, filtered, and dried to obtain 16.6 g of the compound of Formula II in a 97% yield with an HPLC purity of 99.86% and no unknown impurities greater than 0.10%.

[0222] Example 11 Preparation of Compound of Formula V

[0223] Under nitrogen protection, at room temperature, the reaction kettle was added with the compound of formula I (90 g, 145 mmol) prepared in Example 5 and ethanol / water (volume ratio 5:1, 720 mL) and stirred. Heat to 50-70°C, add concentrated sulfuric acid (4 mL, 72.5 mmol) in ethanol / water (volume ratio 5:1, 270 mL) dropwise, and add completely over 0.5-1 hour. Maintain 50-70°C and continue stirring for 1-2 hours. Cool to 5-15°C, filter, and vacuum dry at 25-30°C to obtain 83 g of a white solid with a yield of 95%, an HPLC purity of 99.9%, and no unknown impurities greater than 0.10%. The HPLC spectrum is as shown below. Figure 12 As shown. PXRD detection was performed, and the PXRD pattern was as shown Figure 11 As shown, it is basically consistent with that disclosed in WO2013130402, with ROI: 0.05%.

[0224] Example 12 Preparation of Compound of Formula V

[0225] Under nitrogen, add the compound of Formula I prepared in Example 5 (180 g, 290 mmol) and THF / water (4:1 volume ratio, 1260 mL) to a reaction kettle at room temperature and stir. Heat to 50-60°C. Add a solution of concentrated sulfuric acid (8 mL, 145 mmol) in THF (540 mL) dropwise over 0.5-1 hour. Maintain 50-60°C and continue stirring for 1-2 hours. Cool to 5-10°C, filter, and dry under vacuum at 25-30°C to obtain 162 g of a white solid in a 93% yield with an HPLC purity of 99.86% and no greater than 0.10% unknown impurities.

[0226] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A solvate of formula I, having the following structural formula: in, X is methyl tert-butyl ether or isopropyl ether; When X is methyl tert-butyl ether, the X-ray powder diffraction pattern of the solvate has characteristic peaks at the following 2θ values: 4.2±0.2°, 14.9±0.2°, 16.8±0.2°, 18.2±0.2°, and 20.6±0.2°; When X is isopropyl ether, the X-ray powder diffraction pattern of the solvate has characteristic peaks at the following 2θ values: 4.2±0.2°, 16.9±0.2°, 20.5±0.2°, 16.7±0.2°, and 15.8±0.2°.

2. The compound of formula I according to claim 1, wherein The compound of formula I is a methyl tert-butyl ether solvate of the compound of formula II, and its X-ray powder diffraction pattern also has characteristic peaks at one or more of the following 2θ values: 8.3±0.2°, 12.6±0.2°, 15.4±0.2°, 20.4±0.2°, and 21.0±0.2°.

3. The compound of formula I according to claim 1, wherein The compound of formula I is an isopropyl ether solvate of the compound of formula II, and its X-ray powder diffraction pattern also has characteristic peaks at one or more of the following 2θ values: 8.4±0.2°, 12.6±0.2°, 15.6±0.2°, 19.4±0.2°, and 22.7±0.2°.

4. A method for preparing the solvate according to claim 1, characterized in that: The method comprises the steps of: 1) adding solvent X to a solution of a crude compound of formula II in solvent 4, and collecting the solid to obtain a compound of formula I, wherein the solvent X is methyl tert-butyl ether or isopropyl ether; Wherein, the solvent 4 is selected from the following group: dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, methyl isobutyl ketone, methanol, dichloromethane, chloroform or a combination thereof.

5. Use of the solvate according to any one of claims 1 to 3 as an intermediate for preparing remigipam or remigipam hemisulfate sesquihydrate, wherein the purity of the prepared remigipam or remigipam hemisulfate sesquihydrate is >99.5%.

6. Use of the solvate according to any one of claims 1 to 3 in purifying Remigipam.

7. A method for purifying a compound of formula II, characterized in that: The following steps are involved: 1) adding solvent X to a solution of the crude compound of formula II in solvent 4, and collecting the solid to obtain the compound of formula I; 2) slurrying the compound of formula I obtained in step 1) in solvent 5, collecting the solid to obtain a high-purity fine product of the compound of formula II; The reaction formula is as follows: The solvent X is methyl tert-butyl ether or isopropyl ether, the compound of formula I is a methyl tert-butyl ether solvate of the compound of formula II, and its X-ray powder diffraction pattern has characteristic peaks at the following 2θ values: 4.2±0.2°, 14.9±0.2°, 16.8±0.2°, 18.2±0.2°, 20.6±0.2°; or the compound of formula I is an isopropyl ether solvate of the compound of formula II, and its X-ray powder diffraction pattern has characteristic peaks at the following 2θ values: 4.2±0.2°, 16.9±0.2°, 20.5±0.2°, 16.7±0.2°, 15.8±0.2°; The solvent 4 is selected from the following group: dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, methyl isobutyl ketone, methanol, dichloromethane, chloroform or a combination thereof, The solvent 5 is a mixed solvent of an organic solvent and water, and the organic solvent is selected from the group consisting of ethanol, methanol, isopropanol, acetone, tetrahydrofuran, or a combination thereof; The purity of the obtained high-purity fine product of formula II is greater than 99.5%.

8. The method according to claim 7, wherein The crude compound of formula II is prepared by a method comprising the following steps: 1) In solvent 1, in the presence of a base, the compound of formula III reacts with the compound of formula IV; 2) After the reaction is completed, solvent 2 is added to adjust the pH to <10; 3) concentrating the organic phase to obtain a crude compound of formula II; Wherein, the solvent 1 is selected from the following group: dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, methyl isobutyl ketone, or a combination thereof, The solvent 2 is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, ethyl acetate, methyltetrahydrofuran or a combination thereof.

9. The method according to claim 7, wherein The purity of the crude compound of formula II is 80-95%.

10. A method for preparing remegipam hemisulfate sesquihydrate, comprising the steps of: 1) dissolving the solvate represented by formula I according to claim 1 in solvent 6, adding sulfuric acid solution dropwise, and collecting the solid to obtain the compound of formula V, i.e., remedipam hemisulfate sesquihydrate; The reaction formula is as follows: in, X is methyl tert-butyl ether or isopropyl ether; The solvent 6 is a mixed solvent of an organic solvent and water, and the organic solvent is selected from the group consisting of ethanol, methanol, isopropanol, acetone, and tetrahydrofuran; The purity of the obtained compound of formula V is greater than 99.5%.

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