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A sulfate salt of an intestinal type 2b sodium phosphate cotransporter inhibitor and its crystalline form

A technology of crystallization and sulfuric acid, which is applied in the field of sulfate and its crystal form of intestinal 2B sodium phosphate cotransporter inhibitors, can solve problems such as easy caking, poor product stability, and difficult filtration, and achieve repeatable and reproducible production processes control, good crystal form stability, and stable production process

Active Publication Date: 2020-07-28
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally speaking, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor fluidity, etc.

Method used

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  • A sulfate salt of an intestinal type 2b sodium phosphate cotransporter inhibitor and its crystalline form
  • A sulfate salt of an intestinal type 2b sodium phosphate cotransporter inhibitor and its crystalline form
  • A sulfate salt of an intestinal type 2b sodium phosphate cotransporter inhibitor and its crystalline form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] N 1 -Methyl-N 1 -(2-morpholine ethyl)-N 3-Synthesis of (3-(4-phenylethylphenylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)isophthalamide

[0037]

[0038] The first step: the synthesis of 2-cyano-N-(4-phenethylphenyl)acetamide

[0039] 4-Phenylethylaniline a (2.15g, 10.91mmol, prepared by the well-known method literature "Journal of Medicinal Chemistry, 56(5), 2139-2149; 2013") and 2-cyanoacetic acid (1.39g, 16.37mmol) was dissolved in 5mL N,N-dimethylformamide, cooled to 0°C, added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.14g, 16.37 mmol), rose to room temperature, and stirred for 2h. Add 10mL of water, stir for 30min, solid precipitates, filter, and dry the filter cake to obtain the crude title product 2-cyano-N-(4-phenylethylphenyl)acetamide b (2.68g, white solid), the product is not After purification, proceed directly to the next reaction.

[0040] MS m / z(ESI):263.3[M-1]

[0041] The second step: the synthesis of 2-cyano-2-cyc...

Embodiment 2

[0052] Take (500mg, 0.77mmol) N 1 -Methyl-N 1 -(2-morpholine ethyl)-N 3 -(3-(4-phenylethylphenylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)isophthalamide (prepared according to Example 1) In a 25mL single-necked bottle, add 5mL dimethyl sulfoxide, heat to dissolve at 40°C, then add 5mL water, then add sulfuric acid aqueous solution (27.5%, 356mg, 1.00mmol) dropwise, after dropping, react at 40°C for 1h, stop heating , stirred and crystallized. The next day, it was filtered with suction and dried to obtain 492 mg of solid, with a yield of 85.6%. For the X-ray diffraction of this crystalline sample see figure 1 where the There are characteristic peaks near (4.33). See the DSC spectrum figure 2 , DSC has no endothermic peak at <350°C, and this crystal form is defined as I crystal form.

Embodiment 3

[0054] Take (500mg, 0.77mmol) N 1 -Methyl-N 1 -(2-morpholine ethyl)-N 3 -(3-(4-phenylethylphenylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)isophthalamide (prepared according to Example 1) Add 5mL N,N-dimethylformamide to a 25mL single-necked bottle, heat to dissolve at 40°C, then add 5mL water, then add sulfuric acid aqueous solution (27.5%, 356mg, 1.00mmol) dropwise, and react at 40°C for 1h , stop heating, stir and crystallize. The next day, it was filtered with suction and dried to obtain 473 mg of solid, with a yield of 82.3%. The X-ray diffraction and DSC patterns of the crystalline sample are studied and compared, and it is determined that the product is the I crystal form.

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Abstract

The invention relates to a sulfate of an intestine type 2B sodium phosphate co-transporter inhibitor and its crystal form and particularly relates to N1-methyl-N1-(2-morpholin-ethyl)-N3-(3-(4-phenethylphenylcarbamoyl)-4, 5, 6, 7-tetrahydrobenzo[b]thiophene-2-yl)-m-phthalamide sulfate (compound shown in the formula (I)) and its type I crystal and preparation method. The type I crystal of the compound shown in the formula (I) has good chemical stability and crystal form stability and the used crystallization solvent has low toxicity and low residue content and can be used for clinical treatment.

Description

technical field [0001] The present invention relates to N 1 -Methyl-N 1 -(2-morpholine ethyl)-N 3 -(3-(4-Phenylethylphenylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)isophthalamide sulfate, its Form I crystal and preparation method. Background technique [0002] Inorganic phosphate (Pi) is an essential component of bone mineral. About 80% of human phosphate is in the extracellular matrix (such as bone and tooth) outside the body, 18% is in the cell, and 2% is in the extracellular fluid. Under normal physiological conditions, excess phosphate is taken up by the small intestine, and phosphate homeostasis is regulated by the excretion and reabsorption of the kidneys. Too much or too little phosphate in the body can lead to dysfunction of the body and cause disease: if it is too low, it will cause hypophosphatemia, rickets, and cardiac dysfunction; if it is too high, it will induce hyperphosphatemia, soft tissue and blood vessels. Calcification and renal dysfunction....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/68A61K31/5377A61P7/00A61P3/12
CPCC07B2200/13C07D333/68
Inventor 武乖利李文海尹玉祥卢韵
Owner JIANGSU HENGRUI MEDICINE CO LTD
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