CN-121991096-A - Process for preparing heterocyclic fumaric acid complexes

CN121991096ACN 121991096 ACN121991096 ACN 121991096ACN-121991096-A

Abstract

The invention discloses a preparation method of a heterocyclic compound fumaric acid compound. The invention discloses a preparation method of a fumaric acid compound shown in a formula I-3B, which mainly comprises the following steps of crystallizing a mixed solution of the compound shown in the formula I-3B, a good solvent and fumaric acid to prepare the fumaric acid compound shown in the formula I-3B, wherein the good solvent is acetone or ethanol. The heterocyclic compound fumaric acid compound prepared by the preparation method has one or more of the following advantages of (1) high yield, (2) meeting the requirement of the compound on acid content, ensuring stable and qualified acid content, (3) good reproducibility and easy mass production, and (4) the prepared compound can be used for treating inflammatory bowel diseases and has good safety.

Inventors

Zong qiao
PAN TONG
TANG JING
XIA QINGFENG
YUE YANG
LI YUAN
QIAN LINA
ZHANG XUEJUN
ZANG YANG
LI QUN
YU TENGFEI

Assignees

湖北生物医药产业技术研究院有限公司

Dates

Publication Date: 20260508
Application Date: 20251107
Priority Date: 20241107

Claims (16)

1. A method for preparing a fumaric acid compound shown in a formula I-3B, wherein the molar ratio of the compound shown in the formula I-3B to fumaric acid in the compound is 1:1; the preparation method is as follows method 1 or method 2: The method 1 comprises the following steps of crystallizing a mixed solution of a compound shown as a formula I-3B, a good solvent and fumaric acid to prepare the fumaric acid compound of the compound shown as the formula I-3B, Wherein the good solvent is acetone or ethanol; The method 2 comprises the steps of mixing a compound shown as a formula I-3B, a mixed solution of a good solvent and fumaric acid and a poor solvent, crystallizing to prepare the fumaric acid compound shown as the formula I-3B, Wherein the good solvent is acetone or ethanol, the poor solvent is n-heptane, and the ratio of the volume ratio of the poor solvent to the good solvent is more than 1; 。
2. A method for preparing a fumaric acid compound shown in a formula I-3B, wherein the molar ratio of the compound shown in the formula I-3B to fumaric acid in the compound is 1:1; the preparation method is as follows method 1 or method 2: The method 1 comprises the following steps of crystallizing a solution of a fumaric acid compound of a compound shown in a formula I-3B to prepare the fumaric acid compound of the compound shown in the formula I-3B, wherein a solvent is a good solvent, and the good solvent is acetone or ethanol; Mixing a solution of a fumaric acid compound shown in the formula I-3B with a poor solvent, crystallizing to prepare the fumaric acid compound shown in the formula I-3B, wherein the solvent is a good solvent, the good solvent is acetone or ethanol, the poor solvent is n-heptane, and the ratio of the poor solvent to the good solvent is more than 1; ; The preparation method of the fumaric acid compound shown in the formula I-3B is a preparation method of a crystal form of the fumaric acid compound shown in the formula I-3B.
3. Process for the preparation of fumaric acid complexes of compounds of the formula I-3B according to claim 1 or 2, characterised in that they fulfil one or more of the following conditions: (1) In the method 1, the temperature of the mixed solution or the solution is 30-60 ℃, for example 50 ℃; (2) In the method 1, the crystallization is performed at 0-10 ℃, for example, at 5 ℃; (3) The preparation method of the fumaric acid compound shown in the formula I-3B is a preparation method of fumaric acid eutectic of the compound shown in the formula I-3B.
4. The method of claim 1 or 2, wherein in the method 1, the good solvent is ethanol, the method 1 further uses seed crystals of the fumaric acid compound of formula I-3B, for example, the mixed solution or the solution is mixed with the seed crystals, and the mass ratio of the seed crystals to the compound of formula I-3B may be 0.5% or more than 0.5%, for example, 0.5% -1.5%, further for example, 1%, and the temperature of the mixed solution or the solution may be 30-60 ℃, for example, 50 ℃, when the mixed solution or the solution is mixed with the seed crystals.
5. The process for preparing a fumaric acid complex of the compound of the formula I-3B according to claim 1, The method 1 comprises the steps of mixing a good solvent solution of a compound shown as a formula I-3B with fumaric acid to dissolve and crystallize the fumaric acid, preparing a fumaric acid compound shown as the formula I-3B, Wherein the good solvent is acetone or ethanol; the method 2 comprises the following steps of sequentially mixing a good solvent solution of a compound shown as a formula I-3B with fumaric acid and a poor solvent, crystallizing to prepare a fumaric acid compound of the compound shown as the formula I-3B, Wherein the good solvent is acetone or ethanol, the poor solvent is n-heptane, and the ratio of the volume ratio of the poor solvent to the good solvent is more than 1.
6. Process for the preparation of fumaric acid complexes of compounds of formula I-3B according to claim 1 or 5, characterised in that they fulfil one or more of the following conditions: (1) In the method 1, the dissolving of the fumaric acid is carried out so that the fumaric acid is fully dissolved, and the fully dissolved means that the fumaric acid is fully dissolved or is dissolved to a saturated state; (2) In the method 1, the volume-mass ratio of the good solvent to the compound shown in the formula I-3B is 2-6 mL/g, for example 3 mL/g; (3) In the method 1, the molar ratio of the compound shown as the formula I-3B to the fumaric acid is 1 (0.9-1.5), preferably 1 (1.1-1.5), and more preferably 1:1.1 or 1:1.2; (4) In the method 2, the volume-mass ratio of the good solvent to the compound shown in the formula I-3B is 2-4mL/g, for example 3 mL/g; (5) In the method 2, the molar ratio of the compound shown in the formula I-3B to the fumaric acid is 1 (0.9-1.5), preferably 1:1; (6) In the method 2, the volume ratio of the poor solvent to the good solvent is (2-4) 1, for example, 3:1; (7) In the method 2, after the good solvent solution of the compound shown in the formula I-3B is mixed with fumaric acid, the poor solvent is added in batches, preferably, the poor solvent is added in 2 batches, and the volume ratio of the first batch to the second batch of the poor solvent is 1 (3-4), for example, 1:3.5.
7. The process for preparing a fumaric acid complex of the compound of the formula I-3B according to claim 5, the method 1 is characterized in that the good solvent is ethanol.
8. The process for preparing a fumaric acid complex of the compound of formula I-3B according to claim 7, wherein one or more of the following conditions are satisfied: (1) When the compound is mixed with fumaric acid, the temperature of a good solvent solution of the compound shown in the formula I-3B is 30-60 ℃, for example 50 ℃; (2) The method 1 further uses seed crystals of the fumaric acid compound shown in the formula I-3B, for example, in a solution obtained after fumaric acid is fully dissolved, and then adds the seed crystals, preferably, the mass ratio of the seed crystals to the amount of the compound shown in the formula I-3B is 0.5% or more than 0.5%, for example, 0.5% -1.5%, further for example, 1%, and the temperature of the solution can be 30-60 ℃, for example, 50 ℃ when the seed crystals are added.
9. The method for preparing the fumaric acid compound shown in the formula I-3B according to claim 7, wherein the method 1 specifically comprises the steps of mixing a good solvent solution of the compound shown in the formula I-3B with fumaric acid at 30-60 ℃, carrying out heat preservation and stirring for 0.5-1.5 h, filtering while hot, collecting filtrate, adding seed crystals of the fumaric acid compound shown in the formula I-3B into the filtrate, carrying out heat preservation and stirring for 0.5-3 h, slowly cooling to 0-10 ℃, stirring for 1-3 h, filtering, taking a filter cake, and drying at 50-70 ℃, wherein the mass ratio of the seed crystals to the feed amount of the compound shown in the formula I-3B is 0.5% -1.5%.
10. A process for the preparation of a fumaric acid complex of a compound of formula I-3B according to claim 9, wherein one or more of the following conditions are met: (1) Mixing a good solvent solution of a compound shown as the formula I-3B with fumaric acid at 50 ℃; (2) The temperature after the slow cooling is 5 ℃; (3) The stirring time after the slow cooling is 2 hours; (4) The drying temperature is 60 ℃; (5) The mass ratio of the seed crystal to the compound shown in the formula I-3B is 1%; (6) When the seed crystal is added, the temperature of the filtrate is 30-60 ℃, such as 50 ℃; (7) The drying mode is air blast drying; (8) The drying time is 4-8 hours, for example 6 hours.
11. The method for preparing fumaric acid complex of the compound of the formula I-3B according to claim 5, wherein the good solvent is acetone in the method 1, and the method 1 comprises the steps of mixing the good solvent solution of the compound of the formula I-3B with fumaric acid, heating and stirring, fully dissolving, cooling and crystallizing.
12. A process for the preparation of a fumaric acid complex of a compound of formula I-3B according to claim 11, wherein one or more of the following conditions are met: (1) The temperature is raised to 50-55 ℃, for example, the temperature is raised to 55 ℃; (2) The stirring is carried out for 1-3 h, for example 2h; (3) The cooling crystallization is carried out by cooling to 0-10 ℃, stirring for 1-3 h, for example, cooling to 5 ℃ and stirring for 2h; (4) After crystallization, filtering, and taking a filter cake for drying, wherein the drying is for example blast drying; (5) After crystallization, filtering, and drying a filter cake, wherein the drying temperature is 50-70 ℃, for example 60 ℃; (6) And after crystallization, filtering, and taking a filter cake for drying, wherein the drying time is 1-3 hours, for example 2 hours.
13. The method for preparing the fumaric acid compound of the formula I-3B according to claim 5, wherein the method 2 specifically comprises the steps of mixing a good solvent solution of the formula I-3B with fumaric acid, heating, dropwise adding the poor solvent, and cooling for crystallization; preferably, the temperature is raised to 40-55 ℃, for example, 50 ℃; preferably, the filter cake is taken out for drying after cooling and crystallization.
14. The method for producing a fumaric acid complex of a compound of formula I-3B according to any one of claims 1, 2 and 5, wherein the method for producing a fumaric acid complex of a compound of formula I-3B is a method for producing a crystalline form of a fumaric acid complex of a compound of formula I-3B, which has diffraction peaks at 20.5±0.2°, 15.9±0.2°, 26.6±0.2°, 18.9±0.2° and 22.5±0.2° using Cu-ka radiation, an X-ray powder diffraction pattern expressed in terms of 2θ angle; Preferably, the crystalline form of the fumaric acid complex of the compound of formula I-3B also satisfies one or more of the following conditions: (1) The crystal form of the compound fumaric acid compound shown in the formula I-3B is a compound fumaric acid eutectic shown in the formula I-3B; (2) The crystal form of the fumaric acid compound shown in the formula I-3B also has diffraction peaks at one or more of 22.3+/-0.2 o, 26.4+/-0.2 o, 10.8+/-0.2 o, 17.4+/-0.2 o and 17.5+/-0.2 o in an X-ray powder diffraction pattern expressed in terms of a2 theta angle by using Cu-K alpha radiation; Preferably, the crystalline form of the fumaric acid complex of the compound shown in formula I-3B has diffraction peaks at 20.5+ -0.2 o, 15.9+ -0.2 o, 26.6+ -0.2 o, 18.9+ -0.2 o, 22.5+ -0.2 o, 22.3+ -0.2 o and 26.4+ -0.2 o using X-ray powder diffraction pattern expressed in terms of 2 theta angle by Cu-K alpha radiation; Preferably, the crystalline form of the fumaric acid complex of the compound shown in formula I-3B has a diffraction peak at 20.5+ -0.2 o, 15.9+ -0.2 o, 26.6+ -0.2 o, 18.9+ -0.2 o, 22.5+ -0.2 o, 22.3+ -0.2 o, 26.4+ -0.2 o, 10.8+ -0.2 o, 17.4+ -0.2 o and 17.5+ -0.2 o using Cu-K alpha radiation and X-ray powder diffraction pattern expressed in terms of 2 theta angle; Preferably, the crystalline form of the fumaric acid complex of the compound of formula I-3B, which uses Cu-K alpha radiation, has an X-ray powder diffraction pattern expressed in terms of 2 theta angles with diffraction peaks as shown in the following table: , ; More preferably, the crystalline form of the fumaric acid complex of the compound of formula I-3B is prepared by using Cu-K alpha radiation, and the X-ray powder diffraction pattern is substantially as shown in figure 1; (3) The differential scanning calorimetric curve of the crystal form of the fumaric acid compound shown as the formula I-3B has a starting point of an endothermic peak at 165.2+/-3 ℃ and/or reaches the peak value of the endothermic peak at 167.2 +/-3 ℃; Preferably, the differential scanning calorimetry curve of the crystalline form of the fumaric acid complex of the compound of formula I-3B is substantially as shown in figure 2; (4) The thermogravimetric analysis curve of the crystalline form of the fumaric acid complex of the compound of formula I-3B loses weight by about 0.36% in the temperature range of 26.2+ -3 ℃ to 120+ -3 ℃; preferably, the thermogravimetric analysis of the crystalline form of the fumaric acid complex of the compound of formula I-3B is substantially as shown in FIG. 2.
15. The method of preparing a fumaric acid complex of a compound of formula I-3B according to any of claims 1,2 and 5, wherein the fumaric acid complex of a compound of formula I-3B is a crystalline form of the fumaric acid complex of a compound of formula I-3B, which satisfies one or more of the following conditions: The crystal form (1) has the following unit cell parameters of orthorhombic system, space group P2 1 2 1 2 1 , a= 6.4400 (4) a, alpha=90°, b= 11.9376 (8) a, beta=90°, c= 33.139 (2) a, gamma=90°, preferably unit cell volume= 2547.7 (3) a 3 , asymmetric unit number Z=4 in unit cell, density 1.451 Mg/m 3 ; (2) The crystal form is a single crystal of the fumaric acid compound shown in the formula I-3B.
16. The process for preparing a fumaric acid complex of a compound of formula I-3B according to any of claims 4, 8 and 9, wherein the seed crystal is a crystalline form of a fumaric acid complex of a compound of formula I-3B according to claim 14 or 15.

Description

Process for preparing heterocyclic fumaric acid complexes Technical Field The invention relates to a preparation method of a heterocyclic compound fumaric acid compound. Background The 15-hydroxy prostaglandin dehydrogenase (15-PGDH) gene is located on chromosome 4, 4q 34-q 35, with a span of about 31kb, 7 exons in total, and a molecular weight of 29kD.15-PGDH consists of 266 amino acids, belongs to the family of short-chain dehydrogenases (SDR-chain dehydrogenases), and consists of two identical subunits forming a dimer, but it is also considered that it is enzymatically active in the presence of monomers. 15-PGDH is a key enzyme for degradation and inactivation of Prostaglandins (PGs) and related eicosanoids, and is widely found in normal tissues such as the lung, kidney, gastrointestinal tract, thyroid gland, prostate gland and placenta of humans and mammals, and can catalyze the oxidation of active 15-hydroxy Prostaglandins to 15-keto Prostaglandins with greatly reduced activity on the one hand, and degrade polycyclic aromatic hydrocarbons other than Prostaglandins in the presence of NAD + coenzyme factors, and reduce the generation of carcinogens and pro-carcinogens under physiological or pathological conditions through oxidation reactions. The compound shown in the formula I-3B has the defects of difficult solidification, extremely easy oil precipitation in the crystallization process, easy viscosity change after filtration, inconvenience in material drying and storage, high burning residue, difficult mass production in the crystallization process and the like although the dispersion effect of the solid in water is good. Therefore, in order to facilitate the subsequent further research thereon, there is a need for a solidification refining method that overcomes the above-mentioned drawbacks. Disclosure of Invention The invention aims to solve the technical problem of difficult curing of a compound shown in a formula I-3B, and provides a preparation method of a heterocyclic compound fumaric acid compound. The heterocyclic compound fumaric acid compound prepared by the preparation method has one or more of the following advantages of (1) high yield, (2) meeting the requirement of the compound on acid content, ensuring stable and qualified acid content, (3) good reproducibility and easy mass production, and (4) the prepared compound can be used for treating inflammatory bowel diseases and has good safety. The present invention solves the above-mentioned problems by the following method. The invention provides a preparation method of a fumaric acid compound shown in a formula I-3B, wherein the molar ratio of the compound shown in the formula I-3B to fumaric acid in the compound is 1:1; the preparation method is as follows method 1 or method 2: The method 1 comprises the following steps of crystallizing a mixed solution of a compound shown as a formula I-3B, a good solvent and fumaric acid to prepare the fumaric acid compound of the compound shown as the formula I-3B, Wherein the good solvent is acetone or ethanol; The method 2 comprises the steps of mixing a compound shown as a formula I-3B, a mixed solution of a good solvent and fumaric acid and a poor solvent, crystallizing to prepare the fumaric acid compound shown as the formula I-3B, Wherein the good solvent is acetone or ethanol, the poor solvent is n-heptane, and the ratio of the volume ratio of the poor solvent to the good solvent is more than 1; 。 In one embodiment of the present invention, the method 1 comprises the steps of crystallizing a solution of the fumaric acid complex of the compound of the formula I-3B, thereby preparing the fumaric acid complex of the compound of the formula I-3B, wherein the solvent is the good solvent. In one embodiment of the present invention, the method 2 comprises the steps of mixing a solution of the fumaric acid complex of the compound of the formula I-3B with a poor solvent, and crystallizing to obtain the fumaric acid complex of the compound of the formula I-3B, wherein the solvent is the poor solvent. In one embodiment of the present invention, in the method 1, the temperature of the mixed solution or the solution is 30 to 60 ℃, for example, 50 ℃. In one embodiment of the present invention, the good solvent is ethanol, the method 1 further uses seed crystals of fumaric acid complex of the compound of formula I-3B, for example, the mixed solution or the solution is mixed with the seed crystals, the mass ratio of the seed crystals to the compound of formula I-3B may be 0.5% or more than 0.5%, for example, 0.5% -1.5%, further for example, 1%, and the temperature of the mixed solution or the solution may be 30-60 ℃, for example, 50 ℃ when the mixed solution or the solution is mixed with the seed crystals. In one embodiment of the present invention, in the method for preparing a fumaric acid complex of a compound of formula I-3B, the molar ratio of the compound of formula I-3B to fumaric acid in the complex is 1