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Salt of 3-amino-tetrahydropyrane derivative, polycrystalline type, preparation method and application thereof

A technology of crystal form and pyran, applied in the field of salts of 3-aminotetrahydropyran derivatives and their polymorphs, their preparation and application, can solve the problem of lack of long-acting drugs, lack of DPP-2/8/ 9 Enzyme selectivity, inhibitory activity is not satisfactory, etc.

Inactive Publication Date: 2018-08-28
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In recent years, a variety of DPP-4 inhibitors with new structural types have been listed one after another, but the inhibitory activity of these compounds on DPP-4 is not satisfactory enough, lack of selectivity to DPP-2 / 8 / 9 enzymes, and there is still a lack of long-acting drugs

Method used

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  • Salt of 3-amino-tetrahydropyrane derivative, polycrystalline type, preparation method and application thereof
  • Salt of 3-amino-tetrahydropyrane derivative, polycrystalline type, preparation method and application thereof
  • Salt of 3-amino-tetrahydropyrane derivative, polycrystalline type, preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0140] In the preparation of the above-mentioned acid addition salt, there are no special restrictions on the solvent used and its ratio, as long as it does not hinder the reaction and has a certain solubility to the raw materials, for example: alcohols with 1-10 carbon atoms , hydrocarbons (including alkanes, halogenated alkanes, alkenes, alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxane class)), ketones, nitriles or esters, such as methanol, ethanol, isopropanol, chloroform (chloroform), tetrahydrofuran, acetone, methyl tert-butyl ether, ethyl acetate or acetonitrile, or by A mixed solvent formed by two or more solvents, the mixed solvent refers to a mixed solvent composed of two or more organic solvents in a certain volume ratio, or a mixed solvent composed of an organic solvent and water in a certain volume ratio . The ratio of the above-mentioned organic solvent can be any feasible ratio, incl...

preparation example 1

[0159] Preparation Example 1: Formula (I) compound (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)isoindole The preparation method of hydrin-2-yl)tetrahydro-2H-pyran-3-amine

[0160]

[0161] The first step: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)isoindoline-2-yl)tetrahydro-2H-pyridine Preparation of tert-butyl pyran-3-carbamate

[0162] At room temperature, 5-(methylsulfonyl)isoindoline trifluoroacetate (100 mg) and (2R,3S)-2-(2,5-difluorophenyl)-5-carbonyl-2H - tert-butylpyran-3-carbamate (199 mg, 0.6 mmL) was dissolved in MeOH (3 mL). After stirring for 4 hours, sodium cyanoborohydride (93 mg, 1.5 mmL) was added and stirred for 13 hours, a solid precipitated, the solid was filtered, and the filter cake was washed with methanol (5 mL*2) and ethyl acetate (5 mL*2), respectively. After drying, the target product (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)isoindoline-2-yl)tetrahydro-2H- tert-butyl pyran-3-carbamate (29 mg), yield 17...

Embodiment 1

[0174] Embodiment 1: the preparation of free base crystal

[0175] The formula (I) compound (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)isoindoline-2 obtained in the above Preparation Example 1 -yl)tetrahydro-2H-pyran-3-amine was prepared according to the following method to obtain the free base crystal form I.

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Abstract

The invention relates to a free alkali crystal form of a compound shown in a formula (I), a specific acid addition salt and a crystal form, a preparation method thereof, and application of the crystalform for treating and preventing diseases including diabetes, in particular to type 2 diabetes. The formula is shown in the description.

Description

technical field [0001] The present invention relates to free base crystal forms, salts and crystal forms of 3-aminotetrahydropyran derivatives, their preparation methods, and their use as medicines for the treatment and prevention of diabetes, especially type II diabetes. Background technique [0002] Diabetes is a chronic metabolic disease, the clinical symptom is hyperglycemia, including type I diabetes (insulin-dependent), type II diabetes (non-insulin dependent), gestational diabetes and other special types. Among them, type II diabetes accounts for about 90% of diabetic patients. [0003] At present, the drugs for treating diabetes mainly include sulfonylureas (SU) and biguanides, etc., but they are accompanied by weight gain, limited tolerance, side effects such as hypoglycemia, and adverse reactions such as gradual decrease in drug efficacy. Along with the research on the targets of new therapeutic drugs, the research on drugs targeting dipeptidyl peptidase-IV (DPP-4...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04A61K31/4035A61P3/10A61P3/04A61P3/06A61P5/50
CPCC07B2200/07C07B2200/13C07D405/04
Inventor 游泽金何云王亚军李路王浩东张继超朱军王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD