CN113336733B - Preparation method of L-proline co-crystal of SGLT-2 inhibitor - Google Patents
Preparation method of L-proline co-crystal of SGLT-2 inhibitor Download PDFInfo
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Abstract
The invention relates to the technical field of pharmaceutical chemistry, and particularly discloses a preparation method of an L-proline co-crystal of an SGLT-2 inhibitor, which comprises the following steps: (1) adding n-heptane into the dissolving kettle, performing filter pressing on the n-heptane to a crystallization kettle, and heating to 65-75 ℃; (2) adding a compound shown in the formula I, ethanol and purified water into a dissolving kettle, heating a reaction system to 55-65 ℃ under stirring, adding L-proline, and heating the reaction system to 60-70 ℃; (3) filter-pressing the obtained feed liquid and transferring the feed liquid into a crystallization kettle, keeping the temperature and stirring, slowly cooling the reaction system to 5-10 ℃, keeping the temperature and crystallizing; (4) centrifuging or suction filtering, leaching the filter cake with n-heptane, vacuum drying at 35-45 ℃, and detecting whether the solvent residue is qualified. The invention improves the fluidity of the system by adding a specific amount of n-heptane, solves the technical problems of thickening the system and difficult stirring in the crystallization process, and does not influence the yield and the product quality.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to preparation of an L-proline co-crystal of an SGLT-2 inhibitor.
Background
SGLT-2 (sodium-glucose cotransporter 2) inhibitor is a novel oral hypoglycemic medicament which is recommended to treat type 2 diabetes internationally. It selectively inhibits SGLT-2 receptors of kidney proximal convoluted tubule, reduces glucose reabsorption to promote urine glucose excretion, and lowers blood glucose concentration.
Compared with the traditional hypoglycemic drugs, the SGLT-2 inhibitor has the characteristic advantages of lasting drug effect, difficulty in causing hypoglycemia risk, reduction of the weight of a diabetic patient, convenience in once-a-day oral administration and the like. Recently published data confirm that such drugs can bring cardiovascular and renal benefits to type 2 diabetic patients, opening a new mode of treatment for diabetic patients.
SGLT-2 inhibitors have the following advantages over other antidiabetic drugs: improve beta cell function, improve insulin resistance; reduces the possibility of water-sodium retention and reduces the risk of cardiovascular diseases. The compound (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3S, 5S) -bicyclo [3.1.0] hex-3-yl) oxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (in the specification, the compound is abbreviated as the compound of formula (1), and is described in patent application 201410004395.2) which is shown in formula (1) is an SGLT-2 inhibitor compound, has high selectivity to SGLT-2 and has good pharmacokinetic properties in vivo.
In order to meet the requirements of preparation, production, transportation and the like, Chinese patent application with publication number CN109476624A researches the crystal form of the compound shown in formula (1), and provides an L-proline cocrystal of the compound shown in formula (1), which has excellent bioavailability, good blood sugar reducing effect, good properties and fluidity and is convenient for detection, preparation, transportation and storage. However, the coarse product of the canagliflozin prepared by the technical scheme has fine material particles and small bulk density, so that the stirring is difficult during crystallization due to the fact that the material is viscous in the production process; on the other hand, if the volume of the crystallization solvent is increased, the yield is lowered, the cost is increased, and the method is not suitable for industrial production.
Therefore, a new method suitable for industrialization for preparing the cocrystal is urgently needed to be developed, and the technical problems of viscosity and difficult stirring of a system in a crystallization process are solved while yield and product quality are not influenced.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide a preparation method of an L-proline cocrystal of an SGLT-2 inhibitor, wherein the SGLT-2 inhibitor is a compound shown as a formula I:
in order to realize the purpose of the invention, the technical scheme of the invention is as follows:
in one aspect, the invention provides a preparation method of an SGLT-2 inhibitor L-proline co-crystal, which is characterized by comprising the following steps:
(1) adding n-heptane into the dissolving kettle, performing filter pressing on the n-heptane to a crystallization kettle, and heating to 65-75 ℃ for later use;
(2) adding the SGLT-2 inhibitor, ethanol and purified water into a dissolving kettle, heating a reaction system to 40-70 ℃ under stirring, preferably 55-65 ℃, adding L-proline with the same molar weight as the SGLT-2 inhibitor, heating the reaction system to 60-75 ℃, preferably 60-70 ℃, and stirring until a solution is clear;
(3) filter-pressing the feed liquid obtained in the step (2) and transferring the feed liquid into the crystallization kettle in the step (1), keeping the temperature and stirring, slowly cooling the reaction system to 5-10 ℃, keeping the temperature and crystallizing for at least 15 hours;
(4) and centrifuging or performing suction filtration, leaching a filter cake with n-heptane, performing vacuum drying at 35-45 ℃, and detecting whether the solvent residue is qualified to obtain the co-crystal.
Further, the ethanol in the step (2) is preferably absolute ethanol, and the dosage of the ethanol corresponding to each gram of SGLT-2 inhibitor shown as the formula I is 2mL/g-4.5 mL/g.
Further, the n-heptane in step (1) is used in an amount of 3mL/g to 7mL/g per gram of the SGLT-2 inhibitor represented by the formula I.
Preferably, in the step (3), the temperature of the reaction system is controlled to be reduced to 5-10 ℃ at a cooling rate of 10 ℃/h.
Preferably, in the step (3) of the invention, after the feed liquid is filter-pressed and transferred to the crystallization kettle, the mixture is stirred for 30 minutes under heat preservation.
By adopting X-ray diffraction crystallization analysis, the crystal form obtained by the method is consistent with the crystal form obtained by directly adopting an absolute ethyl alcohol crystallization process, and the yield and the product quality are not influenced.
Meanwhile, the invention also provides a pharmaceutical composition of the L-proline cocrystal of the compound of formula (1) prepared according to the method of the invention and one or more pharmaceutically acceptable carriers and/or diluents, which is in any pharmaceutically acceptable dosage form and is administered to a patient in need thereof by oral, parenteral, rectal or pulmonary administration or the like. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray.
The invention also provides the application of the L-proline cocrystal of the compound shown in the formula (1) prepared by the method in preparing a medicament for treating and/or preventing non-insulin-dependent diabetes mellitus, hyperglycemia, hyperlipidemia and insulin resistance diseases.
The present invention also provides a method for treating and/or preventing non-insulin dependent diabetes mellitus and complications thereof, an insulin resistant disease and/or obesity, comprising administering the crystal to a patient in need thereof.
The present invention also provides the use of L-proline co-crystals of the compound of formula (1) prepared according to the process of the invention for the treatment and/or prevention of non-insulin dependent diabetes mellitus and its complications, insulin resistant diseases and/or obesity.
The diabetic complications include, but are not limited to: diabetic nephropathy, diabetic ocular complications, diabetic foot, diabetic cardiovascular complications, diabetic cerebrovascular disease, and diabetic neuropathy.
The raw materials or reagents involved in the invention are all common commercial products, and the operations involved are all routine operations in the field unless otherwise specified.
The above-described preferred conditions may be combined with each other to obtain a specific embodiment, in accordance with common knowledge in the art.
The invention has the beneficial effects that:
the invention improves the fluidity of the system by adding a specific amount of n-heptane on the basis of the prior crystallization process. Through two-phase crystallization, most of the precipitated solid is suspended in n-heptane, so that the technical problems of viscosity and difficult stirring in the crystallization process are solved, and the yield and the product quality are not influenced.
Detailed Description
In order that the above objects, features and advantages of the present invention may be more clearly understood, a solution of the present invention will be further described below. It should be noted that the embodiments of the present invention and features of the embodiments may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those described herein; it is to be understood that the embodiments described in this specification are only some embodiments of the invention, and not all embodiments.
Preferred embodiments of the present invention will be described in detail with reference to the following examples. It is to be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention. Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the spirit and scope of this invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
This example is intended to illustrate the application of the process of the invention in practical production, and specifically comprises the following steps:
(1) n-heptane (243kg) was added to the dissolution tank, and pressure-filtered into the crystallization tank. Heating to 70 deg.C for use.
(2) A dissolution vessel was charged with the compound of the formula (I) (37.62kg), absolute ethanol (83.13kg) and purified water (13.2 kg). The reaction was warmed to 60 ℃ with stirring, and L-proline (18.81kg) was added. Heating the reaction system to 65 ℃, and stirring and dissolving the mixture to be clear.
(3) Controlling the temperature to 65-75 ℃, hydraulically filtering and transferring the materials in the dissolving kettle into a crystallization kettle, and stirring for 30 minutes under heat preservation. The reaction system is controlled to slowly cool (about 10 ℃/hour) to 5-10 ℃. And (5) carrying out heat preservation and crystallization for at least 15 hours.
(4) And (4) centrifuging. The filter cake was rinsed with n-heptane (51.5 kg). And (3) transferring the filter cake into a drier, controlling the temperature to be 35-45 ℃, performing vacuum drying, detecting that the solvent residue is qualified, and collecting to obtain a proline crude product of the compound shown in the formula (I), wherein the proline crude product is 43.93kg, and the yield is as follows: 77.9 percent.
The crystal obtained above was examined by referring to the X-ray powder diffraction measurement method described in the publication of chinese patent application No. CN201780032964.6, and it was confirmed to be the same as the crystal form I described in the above patent document.
Comparative example 1
In the comparative example, the industrial preparation of the crystal form I is carried out by amplifying the use amount of the raw materials to 100 times according to the technical scheme described in examples 1 to 3 in the publication with Chinese patent application No. CN 201780032964.6. In the process of preparing the crystal form I according to the schemes of the examples 1 to 3, the obtained solution has the phenomena of viscous system and difficult stirring in the crystallization process. The precipitated products are agglomerated and the wall hanging is serious. The yield of the scale-up production is seriously reduced, and impurities and solvents are easily wrapped, so that the final product is unqualified.
In contrast, most of the solid precipitated by the preparation method is suspended in n-heptane, so that the solid can be normally stirred and recovered, and the yield and the quality are not obviously influenced.
The foregoing are merely exemplary embodiments of the present invention, which enable those skilled in the art to understand or practice the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (4)
1. A preparation method of an L-proline cocrystal of an SGLT-2 inhibitor is characterized by comprising the following steps:
(1) adding n-heptane into the dissolving kettle, performing filter pressing on the n-heptane to a crystallization kettle, and heating to 65-75 ℃ for later use; the dosage of the n-heptane corresponding to each gram of SGLT-2 inhibitor is 3mL/g-7 mL/g;
(2) adding an SGLT-2 inhibitor, ethanol and purified water into a dissolving kettle, heating a reaction system to 40-70 ℃ under stirring, adding L-proline, wherein the molar ratio of the SGLT-2 inhibitor to the L-proline is 1:1-1:3, heating the reaction system to 60-75 ℃, and stirring until the solution is clear; the ethanol is absolute ethanol, and the dosage of the ethanol corresponding to each gram of SGLT-2 inhibitor is 2mL/g-4.5 mL/g;
(3) filter-pressing the feed liquid obtained in the step (2) and transferring the feed liquid into the crystallization kettle in the step (1), keeping the temperature and stirring, slowly cooling the reaction system to 5-10 ℃, keeping the temperature and crystallizing for at least 15 hours;
(4) centrifuging or performing suction filtration, leaching a filter cake with n-heptane, performing vacuum drying at 35-45 ℃, and detecting whether the solvent residue is qualified to obtain the co-crystal;
the structure of the SGLT-2 inhibitor is shown as a formula I:
2. the method according to claim 1, wherein the step (2) is: adding the SGLT-2 inhibitor, ethanol and purified water into a dissolving kettle, heating a reaction system to 55-65 ℃ under stirring, adding L-proline, wherein the molar ratio of the SGLT-2 inhibitor to the L-proline is 1:2, heating the reaction system to 60-70 ℃, and stirring until the solution is clear.
3. The preparation method according to claim 1, wherein in the step (3), the temperature of the reaction system is controlled to be reduced to 5-10 ℃ at a rate of 10 ℃/hr.
4. The preparation method according to claim 3, wherein the feed liquid is pressure-filtered and transferred to the crystallization kettle in the step (3), and then stirred for 30 minutes under heat.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910769A (en) * | 2012-12-31 | 2014-07-09 | 上海璎黎科技有限公司 | Compound of glucose derivative and proline, crystal, preparation method and application |
| EP2891654A1 (en) * | 2014-01-03 | 2015-07-08 | Xuanzhu Pharma Co., Ltd. | Optically pure benzyl-4-chlorophenyl-C-glucoside derivatives as SGLT inhibitors (diabetes mellitus) |
| CN104761522A (en) * | 2014-01-03 | 2015-07-08 | 山东轩竹医药科技有限公司 | Optically pure benzyl-4-chlorophenyl C-glucoside derivatives |
| WO2017206827A1 (en) * | 2016-05-28 | 2017-12-07 | 山东轩竹医药科技有限公司 | Crystal form of sodium-glucose cotransporter 2 inhibitor |
| CN108239055A (en) * | 2016-12-23 | 2018-07-03 | 杭州领业医药科技有限公司 | A kind of THR1442 L-Aspartic acids eutectic, preparation method and pharmaceutical composition |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910769A (en) * | 2012-12-31 | 2014-07-09 | 上海璎黎科技有限公司 | Compound of glucose derivative and proline, crystal, preparation method and application |
| EP2891654A1 (en) * | 2014-01-03 | 2015-07-08 | Xuanzhu Pharma Co., Ltd. | Optically pure benzyl-4-chlorophenyl-C-glucoside derivatives as SGLT inhibitors (diabetes mellitus) |
| CN104761522A (en) * | 2014-01-03 | 2015-07-08 | 山东轩竹医药科技有限公司 | Optically pure benzyl-4-chlorophenyl C-glucoside derivatives |
| WO2017206827A1 (en) * | 2016-05-28 | 2017-12-07 | 山东轩竹医药科技有限公司 | Crystal form of sodium-glucose cotransporter 2 inhibitor |
| CN108239055A (en) * | 2016-12-23 | 2018-07-03 | 杭州领业医药科技有限公司 | A kind of THR1442 L-Aspartic acids eutectic, preparation method and pharmaceutical composition |
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Denomination of invention: Preparation method of L-proline co crystal for SGLT-2 inhibitor Granted publication date: 20220218 Pledgee: Industrial and Commercial Bank of China Limited Meihekou Branch Pledgor: Jilin Huisheng Biopharmaceutical Co.,Ltd. Registration number: Y2024220000070 |