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Crystal form of oxalate of dipeptidyl peptidase inhibitor and preparation method and application thereof

A technology of dipeptidyl peptidase and cyanopyrrolidine oxalate, which is applied in the field of new crystal forms of medicines, can solve the problems of unimproved stability of the compound of formula 1, poor compound stability, compound stability problems and the like, To achieve the effect of product safety assurance, easy storage and transportation, and cost reduction

Active Publication Date: 2012-05-02
CHENGDU DIAO PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In this application, the amorphous compound of formula 1 was prepared, which has obvious advantages in terms of therapeutic activity and toxicity compared with previous similar compounds, and can effectively treat and / or prevent diseases related to DPP-IV, type 2 Diabetes, impaired glucose tolerance, autoimmune diseases or inflammation, etc. have good application prospects, but there are certain problems in the stability of this compound under light and heat conditions
[0010] In the field of pharmaceuticals, late preparation methods are often used to make up for the defects of poor stability of compounds
At present, there is no relevant report on improving the stability of the compound of formula 1

Method used

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  • Crystal form of oxalate of dipeptidyl peptidase inhibitor and preparation method and application thereof
  • Crystal form of oxalate of dipeptidyl peptidase inhibitor and preparation method and application thereof
  • Crystal form of oxalate of dipeptidyl peptidase inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1 Preparation of crystal form of the present invention

[0062] Take (s)-1-(2-(2-(3-(3,4-dimethoxyphenyl)-2-oxo-1-imidazolidinyl)ethylamino)acetyl)-2- Add 30g of cyanopyrrolidine oxalate and 600g of anhydrous methanol into a 2000ml round bottom flask with a reflux device, heat and reflux in a water bath until completely dissolved, then cool to room temperature, a large number of white flaky crystals precipitate, filter, and put in an oven at 50°C After drying, 28.5 g of the product was obtained, the purity (HPLC) was 99.5%, and the melting point was 154°C-156°C. The endothermic transition is at about 151°C, the results of thermogravimetric-differential thermal analysis are shown in the attached image 3 .

[0063] X-ray powder diffraction results are as follows:

[0064]

[0065] Infrared spectrum wave number is (cm -1 )为3429.25;2999.07;2959.16;2833.85;1685.83;1661.91;1589.66;1519.92;1487.29;1430.86;1321.39;1274.38;1249.11;1173.64;1116.60;1025.58;857.3...

Embodiment 2

[0080] Embodiment 2 Preparation of crystal form of the present invention

[0081] Take (s)-1-(2-(2-(3-(3,4-dimethoxyphenyl)-2-oxo-1-imidazolidinyl)ethylamino)acetyl)-2- Add 20g of cyanopyrrolidine oxalate and 320g of methanol containing 5% water into a 1000ml round bottom flask with a reflux device, heat and reflux in a water bath until completely dissolved, then cool to room temperature, a large number of white flaky crystals are precipitated, filtered, 50 Oven-dried at ℃ to obtain 18.5 g of the product with a melting point of 155°C-156°C and a purity (HPLC) of 99.5%.

[0082] X-ray powder diffraction results are as follows

[0083] 2θ

[0084] 4.5

[0085] 5.6

[0086] 9.1

[0087] 10.8

[0088] 16.5

[0089] 17.8

[0090] 18.2

[0091] 22.0

[0092] 22.6

[0093] 25.7

[0094] 28.2

[0095] 28.4

[0096] 32.1

Embodiment 3

[0097] Embodiment 3 Preparation of crystal form of the present invention

[0098] Take (s)-1-(2-(2-(3-(3,4-dimethoxyphenyl)-2-oxo-1-imidazolidinyl)ethylamino)acetyl)-2- 20 g of cyanopyrrolidine oxalate and 300 grams of methanol containing 10% water were added into a 1000 ml round-bottomed flask with a reflux device, heated under reflux in a water bath until completely dissolved, then cooled to room temperature, a large amount of white flaky crystals were precipitated, filtered, Oven-dried at 50°C to obtain 18.5g of product with a melting point of 155.5°C-157°C and a purity (HPLC) of 99.5%.

[0099] X-ray powder diffraction results are as follows:

[0100] 2θ

[0101] 4.6

[0102] 5.6

[0103] 9.1

[0104] 10.9

[0105] 16.3

[0106] 17.8

[0107] 18.1

[0108] 22.0

[0109] 22.6

[0110] 25.5

[0111] 28.1

[0112] 28.5

[0113] 32.0

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Abstract

The invention discloses a novel crystal form of oxalate of dipeptidyl peptidase inhibitor, namely, (s)-1-(2-(2-(3-(3,4-dimethoxyphenyl)-2-oxo-1-imidazolidinyl)ethylamino)acetyl)-2-cyanpyrrolidine oxalate. In X-ray powder diffraction of the crystal form, characteristic peaks occur at 2 theta diffraction angles of 4.5+ / -0.1, 5.5+ / -0.1, 9.0+ / -0.1, 10.9+ / -0.1, 16.4+ / -0.1, 17.7+ / -0.1, 18.1+ / -0.1, 22.0+ / -0.1, 22.7+ / -0.1, 25.6+ / -0.1, 28.1+ / -0.1, 28.4+ / -0.1 and 32.0+ / -0.1. The crystal form disclosed by the invention is superior to the original oxalate in stability, and is more stable for light, heat and humidity and convenient to store and transport; the cost of the DPP-IV (dipeptidyl peptidase-IV) inhibitor in transportation and preservation processes is decreased; and the safety of the product is further guaranteed.

Description

technical field [0001] The present invention relates to a new crystal form of a drug, in particular to a dipeptidyl peptidase inhibitor—(s)-1-(2-(2-(3-(3,4-dimethoxyphenyl) -2-oxo-1-imidazolidinyl)ethylamino)acetyl)-2-cyanopyrrolidine oxalate crystal form, and preparation method thereof; also relates to the use of the crystal form and containing the crystal form pharmaceutical composition. Background technique [0002] Dipeptidyl peptidase IV (DPP-IV) is a peptide that cleaves the N-terminus starting from H-Xaa-Pro (where Xaa is any amino acid, preferably a lipophilic amino acid and Pro is proline) The dipeptide serine protease is widely present in the epithelial layers of various tissues, mesoderm cells of some tissues, and the surface of specific T lymphocyte subsets, with the highest content in the renal cortex, followed by the lung, adrenal gland, jejunum, liver, etc. Expressed in a transmembrane and soluble form. [0003] DPP-IV can affect insulin and blood sugar lev...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/4178A61P3/10A61P5/48A61P3/06A61P3/04A61P3/00A61P9/10A61P15/08A61P15/00A61P19/02A61P37/06A61P37/00A61P31/18A61P1/00A61P19/10A61P37/02A61P29/00
Inventor 钟朝斌王学超杜勇华张斌肖桂平姬建新李伯刚
Owner CHENGDU DIAO PHARMA GROUP
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