Crystal form of heterocyclic compound as well as preparation method and application of crystal form

A compound and crystal form technology, applied in the field of medicinal chemistry, can solve problems such as unrelated compound crystal forms, and achieve strong economic value, convenient storage, and high reproducibility

Pending Publication Date: 2022-01-14
WUHAN LL SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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  • Crystal form of heterocyclic compound as well as preparation method and application of crystal form
  • Crystal form of heterocyclic compound as well as preparation method and application of crystal form
  • Crystal form of heterocyclic compound as well as preparation method and application of crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0176] Embodiment 1: the preparation of formula A compound

[0177]

[0178] Step 1 (S)-2-((2-(4-bromo-2,6-difluorophenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine - Preparation of 4-tert-butyl carboxylate

[0179]

[0180] In a 100mL round bottom flask, (S)-2-ethynylmorpholine-4-carboxylic acid tert-butyl ester (3.1g, 1.0eq, intermediate 1-4), 4-bromo-2,6-difluorobenzene Formaldehyde (2.76g, 1.0eq, compound 172-1), 4-chloropyridin-2-amine (1.61g, 1.0eq, compound 172-2), CuCl (0.37g, 0.3eq), Cu(OTf) 2(1.36g, 0.3eq), isopropanol (50mL), nitrogen replacement 3 times, heated in an oil bath at 80°C overnight, TLC detected that the starting compound 172-2 disappeared. Isopropanol was spin-dried, extracted with EA and ammonia water in sequence, the EA phase was taken, washed with saturated brine, citric acid, dried over anhydrous sodium sulfate, and spin-dried through the column to obtain intermediate 172-3, a white solid (3.0g, The purity is 78%). LC-MS: [M+H]...

Embodiment 2

[0197] Embodiment 2: post-processing of raw materials

[0198] Referring to Example 1, 11.1 g of Compound A was prepared. Add 20 mL of acetone, reflux at 65° C. (under nitrogen protection) for 2.0 h, spin dry the acetone directly, and vacuum-dry at 40° C. for 12 h. NMR shows that about 1% acetone remains. It was vacuum dried again at 80°C for 12 hours, and nuclear magnetic resonance showed that acetone remained. Take 5.3g of it and dry it under vacuum again at 80°C for 12h. NMR shows that there is still acetone residue. This batch of product was added to acetonitrile (16mL), refluxed at 85°C (nitrogen protection) for 2.0h, directly spin-dried the acetonitrile, and then vacuum-dried at 80°C for 12h, nuclear magnetic resonance showed that it was qualified and there was no residue, and 5.2g was put into storage. The purity of the product is 99.29%, and it is in the form of white powder.

[0199] The results of PLM and XRPD show that the raw material is an irregular crystal with...

Embodiment 3

[0200] Embodiment 3: Preparation and characterization of the amorphous compound of formula A

[0201] 3.1 Compound A was dissolved in a certain amount of THF, and concentrated to dryness under reduced pressure to obtain an amorphous sample. XRPD characterization see attached Figure 37 .

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Abstract

The invention discloses a crystal form of a heterocyclic compound as well as a preparation method and application of the crystal form. The crystal form of the compound is as shown in a formula A. The crystal form is a crystal form I, a crystal form II, a crystal form III, a crystal form IV, a crystal form V, a crystal form VI, a crystal form VII, a crystal form VIII or a crystal form IX. The invention discloses a preparation method of the crystal form, a composition and application of the crystal form in preparation of a P2X3 receptor antagonist. The invention also relates to the application of the compound in preparation of medicines for preventing and/or treating pains, urinary tract diseases or respiratory system diseases. The P2X3 receptor antagonist has the advantages of high P2X3 antagonistic activity, good selectivity, low toxicity, good metabolic stability and small taste influence.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a crystal form of a heterocyclic compound and a preparation method and application thereof. Background technique [0002] ATP receptors are classified into two major families, P2Y- and P2X-purinergic receptors, based on molecular structure, transduction mechanism, and pharmacological properties. P2X-purinergic receptors are a family of ATP-gated cation channels of which several subtypes have been cloned, including: six homomeric receptors, P2X1; P2X2; P2X3; P2X4; P2X5; and P2X7; and three heteromeric receptors Receptors P2X2 / 3, P2X4 / 6, P2X1 / 5. The study found that P2X3 receptors are specifically expressed in the primary afferent nerve fibers of "hollow viscera", such as the lower urinary tract and respiratory tract. [0003] Cough is the main symptom of respiratory diseases. In the outpatient department of respiratory department, 70% to 80% of patients have cough symptoms. W...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/5377A61P11/00A61P11/06A61P13/00A61P37/02A61P13/10A61P25/16A61P25/28A61P25/08A61P25/20A61P25/18A61P9/10A61P29/00A61P7/00A61P7/12A61P27/00
CPCC07D471/04A61P11/00A61P11/06A61P13/00A61P37/02A61P13/10A61P25/16A61P25/28A61P25/08A61P25/20A61P25/18A61P9/10A61P29/00A61P7/00A61P7/12A61P27/00C07B2200/13
Inventor 王亮娄军洪华云郭晓丹钱丽娜张轶涵陈永凯王朝东
Owner WUHAN LL SCI & TECH DEV
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