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Canagliflozin monohydrate and its crystal forms, their preparation method and use

A technology of monohydrate and canagliflozin, which is applied in the field of canagliflozin monohydrate and its crystal form, can solve the problem of poor stability, poor production reproducibility and difficulty in repetition of canagliflozin hemihydrate crystal form hH1 And other issues

Active Publication Date: 2017-08-29
CHONGQING PHARMA RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The present inventor has carried out repeated tests and properties on canagliflozin and its crystal form A, crystal form B, crystal form C and crystal form D disclosed in the above documents, canagliflozin hemihydrate crystal form hH1 and crystal form hH2 The test results show that the known canagliflozin and its crystal form A have poor stability, and cannot maintain their original crystal form in the stability competition experiment in water, and all of them will undergo crystal transformation; the known canagliflozin The crystal forms of ggliflozin form B, C and D have poor stability and are difficult to repeat; the known crystal form hH1 of canagliflozin hemihydrate has poor stability. It cannot maintain its original crystal form, and crystal form transformation will occur; the known crystal form of canagliflozin hemihydrate hH2 has poor crystal stability and is difficult to repeat
The above properties make its pharmaceutical preparations have problems such as unstable content of active substances, poor production reproducibility, increased impurities during storage, and decreased drug efficacy.
In addition, the known canagliflozin is an amorphous substance, and those skilled in the art know that the amorphous substance has poor stability and is easy to absorb moisture, so it is not suitable for solid preparation applications

Method used

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  • Canagliflozin monohydrate and its crystal forms, their preparation method and use
  • Canagliflozin monohydrate and its crystal forms, their preparation method and use
  • Canagliflozin monohydrate and its crystal forms, their preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0133] Preparation Example 1 (preparation of known canagliflozin)

[0134] The known canagliflozin can be prepared according to the method described in Example 1 of the patent document US7943788B2 or according to the following method.

[0135]

[0136]The specific preparation method is: 5-bromo-1-[5-(4-fluorophenyl)-2-thienylmethyl]-2-methylbenzene (2.65 grams) is dissolved in tetrahydrofuran (20 milliliters)-toluene ( 40 mL), and the mixture was cooled to -78°C under argon atmosphere. To the mixture was added n-butyllithium (2.44M hexane solution, 2.9 mL) dropwise, and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (2.3 g) in toluene (50 ml) was added dropwise, and at the same temperature The mixture was stirred for an additional 1 hour, resulting in lactoalcoholate. Without isolation of the compound, a solution of methanesulfonic acid (1.0 ml) in methanol (50 ml) was added to th...

preparation example 2

[0139] Preparation example 2 (preparation of known canagliflozin crystal form A)

[0140] The known crystal form A of canagliflozin can be prepared according to the method described in Example 9 of patent document WO2009 / 035969A1.

[0141] 9.7 g of canagliflozin prepared in Preparation Example 1, 0.6 ml of water and 27.5 ml of ethyl acetate were added to a 100 ml three-neck round bottom flask. The resulting solution was heated to 35°C with stirring under argon. Heptane was added dropwise until the solution became cloudy for a total of 16.0 mL of heptane. After stirring at 35°C for 2 hours, add 3.0 ml of heptane, continue to stir for 30 minutes, filter under reduced pressure, wash the filter cake with 5.0 ml of 56% ethyl acetate / 44% heptane solution, and dry the filter cake at 40°C for 24 hours to obtain Canagliflozin Form A.

[0142] 1 H-NMR (CD 3 OD): 2.32(s, 3H), 3.35-3.53(m, 4H), 3.71(d, 1H, J=11.9Hz), 3.90(d, 1H, J=11.9Hz), 4.13(d, 1H, J =9.3Hz), 4.17(s, 2H), 4.9(s...

preparation example 3

[0144] Preparation example 3 (preparation of known canagliflozin hemihydrate crystal form hH1)

[0145] The known crystal form of canagliflozin hemihydrate hH1 can be prepared according to the method described in Example 1 of the patent document US7943582B2 or according to the following method.

[0146] The specific preparation method is: take 1 gram of canagliflozin prepared in Preparation Example 1, add 2.2 ml of water: acetonitrile (10:1) mixed solvent, stir at room temperature for 24 hours, filter under reduced pressure, and dry at 40°C for 24 hours to obtain canagliflozin Ggliflozin hemihydrate crystal form hH1.

[0147] 1 H-NMR (DMSO-d 6 )2.26(s, 3H), 3.13-3.28(m, 4H), 3.44(m, 1H), 3.69(m, 1H), 3.96(d, 1H, J=9.3Hz), 4.10(m, 1H), 4.15(m, 1H,) 4.43(t, 1H, J=5.8Hz), 4.72(d, 1H, J=5.6Hz), 4.92(d, 2H, J=4.8Hz), 6.80(d, 1H, J = 3.5Hz), 7.11-7.15 (m, 2H), 7.18-7.25 (m, 3H), 7.28 (d, 1H, J = 3.5Hz), 7.59 (dd, 2H, J = 8.8, 5.4Hz). Shown as canagliflozin hemihydrate.

[01...

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Abstract

The present invention relates to a monohydrate of canagliflozin and its crystal form. Compared with the prior art, the monohydrate of canagliflozin and its crystal form have high stability in water or an aqueous system, and are more suitable for wet It can be prepared by legal granulation process or made into suspension, and has good storage stability. The present invention also relates to the preparation method of the canagliflozin monohydrate and its crystal form, its pharmaceutical composition and its use in the preparation of medicines for treating diabetes, diabetic complications, obesity and other diseases.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical crystals. Specifically, it relates to canagliflozin monohydrate and its crystal form, as well as the preparation method of the crystal form, its pharmaceutical composition and use. Background technique [0002] Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor, which can reduce blood glucose concentration by preventing glucose in the renal tubule from being reabsorbed smoothly into the blood and excreted with urine. Developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, it was approved by the US FDA in March 2013 under the product name INVOKANA. This drug is approved for the treatment of type 2 diabetes in adults and not for type 1 diabetes or diabetic ketoacidosis. The dosage form is capsule-shaped film-coated tablet, which has two specifications of 100mg and 300mg. The 100mg tablet is yellow, and the 300mg tablet is white. The active ingredient is ca...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D409/10A61K31/381A61P3/10A61P9/10A61P25/28A61P13/12A61P17/02A61P5/50A61P3/06A61P3/04A61P9/12
CPCA61K9/0053A61K9/0095A61K9/10A61K9/1623A61K9/2018A61K9/2853A61K9/4866A61K31/381A61K31/7042A61K47/36A61P3/04A61P3/06A61P3/10A61P5/50A61P9/10A61P9/12A61P13/12A61P17/02A61P25/28C07D409/10A61K9/2009A61K9/2013A61K9/2054A61K9/2813A61K9/4858A61K47/12A61K47/14C07B2200/13
Inventor 赵坤宋小叶盛晓霞盛晓红
Owner CHONGQING PHARMA RES INST
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