A kind of addition salt of s1p1 receptor agonist and its crystal form and pharmaceutical composition
A crystal form and compound technology, applied in the field of pharmaceutical chemical preparation and crystallization, can solve problems such as obvious polymorphism, and achieve good application value, good bioavailability, and good storage stability
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Problems solved by technology
Method used
Image
Examples
preparation example 1
[0129] Preparation Example 1 The preparation of compound shown in formula A
[0130] The compound represented by formula A can be prepared by referring to the preparation method in Example 2 of patent document CN103450171A.
[0131] Specifically: at room temperature, 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde (9.0g, 27.8mmol) , 3-azetidinecarboxylic acid (2.8g, 27.8mmol) and acetic acid (10mL) in methanol-tetrahydrofuran (200mL / 200mL) solution was stirred for 2 hours, and a methanol solution of sodium cyanoborohydride (10.3g, 163.5mmol) was added (600 mL) and continue to stir at room temperature for 16 hours, filter, wash the filter cake with methanol (100 mL), and dry to obtain 2.0 g of white solid product.
[0132] 1 H-NMR (400MHz, CD3OD) δ: 8.13 (d, J = 8.4Hz, 2H), 8.05 (m, 1H), 7.97 (m, 1H), 7.68 (t, J = 8.0Hz, 7.6Hz, 1H) ,7.42(d,J=8.4Hz,2H),4.40(s,2H),4.15(m,4H),3.41(m,1H),2.61(d,J=7.2Hz,2H),1.95(m, 1H), 0.94 (d, J=7.2Hz, 6H), shown as the c...
preparation example 2
[0133] Preparation example 2 Salt screening and preparation of compounds represented by formula A
[0134] 2.1 Salt sieve
[0135] According to the structure of the compound shown in formula A, 12 kinds of I acid and 3 kinds of I base were selected, and the salt screening experiment was carried out.
[0136] The experimental settings and results are shown in Table 1 below.
[0137] Table 1. Salt sieve experiment setup and results
[0138]
[0139]
[0140] 2.2 Preparation of some salts
[0141] Select acetone and water as the reaction solvent, select the free state of the compound shown in formula A to form a salt with a molar ratio of 1:1.2 to the ion, select IC to detect the salt-forming ratio, and prepare the citrate of the compound shown in the formula A, formula A The phosphate salt of the compound shown, the hydrochloride salt of the compound shown in formula A, the potassium salt of the compound shown in formula A and the calcium salt of the compound shown in...
Embodiment 1
[0142] Example 1 The preparation of the sodium salt of compound shown in formula A
[0143] Weigh 14.50 mg of the compound shown in Formula A prepared in Preparation Example 1, add 0.5 mL of methanol and stir to form a suspension, add sodium hydroxide solution (1.75 mg of sodium hydroxide to 0.45 mL of methanol) dropwise to the compound shown in Formula A In the methanol suspension, stir at room temperature for about 10 minutes to form a clear liquid, continue to stir for 3 hours at room temperature and blow nitrogen to remove the solvent to 0.2mL, to obtain a colorless transparent clear liquid, cool to 5°C to obtain a suspension, centrifuge, and solid at room temperature Vacuum-dried for 16 hours to obtain the sodium salt of the compound represented by formula A of the present invention.
[0144] IC characterization shows that the sodium salt of the compound shown in formula A is the compound shown in formula A and sodium ions react with a molar ratio of 1:1 to form a salt....
PUM
| Property | Measurement | Unit |
|---|---|---|
| solubility (mass) | aaaaa | aaaaa |
| solubility (mass) | aaaaa | aaaaa |
Abstract
Description
Claims
Application Information
Login to View More