CN109796455B - Salt of aminopyrane derivative, crystal form of salt, preparation method and application of salt - Google Patents
Salt of aminopyrane derivative, crystal form of salt, preparation method and application of salt Download PDFInfo
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Abstract
The invention relates to a salt of an aminopyrane ring derivative, a crystal form of the salt, a preparation method of the crystal form and application of the crystal form in medicine, and specifically, the aminopyrane ring derivative is a compound shown in a formula (I).
Description
Technical Field
The invention relates to a salt of an aminopyrane derivative, a crystal form of the salt, a preparation method of the crystal form and application of the crystal form in medicine.
Background
Diabetes is a major medical problem worldwide. Diabetes is generally classified into type I diabetes (or insulin dependent diabetes mellitus, IDDM) and type II diabetes (or non-islet dependent diabetes mellitus, NIDDM). The most common type of diabetes is type II diabetes, which accounts for approximately 90% of all diabetes worldwide. The incidence of type II diabetes is on an increasing trend due to modern unhealthy lifestyles, such as reduced exercise and high calorie diets. The enormous market potential has attracted a large number of pharmaceutical companies and research centers to develop new anti-diabetic targets and drugs.
Glucagon-like peptide-1 (GLP-1) can participate in the regulation of blood sugar homeostasis of an organism, improve the function of pancreatic islets and delay or even reverse the progression of the disease course of type II diabetes through multiple ways. However, endogenous GLP-1 is rapidly cleaved by dipeptidyl peptidase IV (DPP-4) and becomes inactive after secretory release into the blood. The DPP-4 inhibitor can selectively inhibit the enzymatic activity of DPP-4, prevent GLP-1 from being cracked and inactivated, improve the plasma level of active GLP-1, enhance the physiological action of the active GLP-1, and reduce HbA1, fasting blood sugar and postprandial blood sugar levels of type II diabetes patients.
WO2015192701 discloses a novel dipeptidyl peptidase IV (DPP-4) inhibitor shown in a formula (II), which has a good inhibition effect on the enzymatic activity of DPP-4 and has the potential of preventing and treating type II diabetes. The compound of formula (II) has the following structure:
disclosure of Invention
The invention aims to provide a stable compound with good solubility shown in the formula (I) and a crystal form thereof, so as to improve the physical and chemical properties and the pharmacokinetic characteristics of the compound.
It is a further object of the present invention to provide pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I).
It is a further object of the present invention to provide the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a disease associated with diabetes, preferably type II diabetes.
Specifically, the compound shown in the formula (I):
wherein HA is selected from benzenesulfonic acid, salicylic acid, benzoic acid, acetic acid, S- (+) -mandelic acid, propionate, crotonate, furoate, cinnamic acid, ethanesulfonic acid, glycolate, lactic acid, fumaric acid, formic acid, sulfuric acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, tartaric acid, citric acid, glycolic acid, hydrochloric acid, p-toluenesulfonic acid, maleic acid, succinic acid, oxalic acid, methanesulfonic acid, malonic acid, or malic acid;
n is selected from 1, 1.5 or 2.
In one embodiment of the present invention, the compound of formula (I) is in solid crystalline form.
In one embodiment of the present invention, the compound of formula (I), HA, is selected from benzenesulfonic acid, fumaric acid, furoic acid, methanesulfonic acid, formic acid, p-toluenesulfonic acid, trifluoroacetic acid, oxalic acid, malic acid, benzoic acid, tartaric acid, succinic acid, hydrochloric acid, hydrobromic acid, cinnamic acid, glycolic acid, lactic acid, ethanesulfonic acid, or acetic acid.
In one embodiment of the present invention, the compound represented by formula (I), HA is preferably benzenesulfonic acid, fumaric acid, furoic acid, benzoic acid, acetic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, tartaric acid, hydrochloric acid, p-toluenesulfonic acid, maleic acid or succinic acid, and further preferably benzenesulfonic acid, fumaric acid or furoic acid;
in one embodiment of the present invention, the compound of formula (I), HA is selected from benzenesulfonic acid, fumaric acid or furoic acid; n is selected from 1.
In one embodiment of the present invention, the compound of formula (I), n is 1.
n is selected from 1 or 1.5, more preferably n is 1.
In one embodiment of the present invention, the compound of formula (I) is in solid crystalline form.
In one embodiment of the present invention, a compound of formula (I), HA is benzenesulfonic acid, n is 1, which is crystalline form I, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 θ positions using Cu-ka radiation: 7.87 degrees +/-0.3 degrees, 10.17 degrees +/-0.3 degrees, 12.72 degrees +/-0.3 degrees, 15.38 degrees +/-0.3 degrees, 16.76 degrees +/-0.3 degrees, 17.65 degrees +/-0.3 degrees, 18.33 degrees +/-0.3 degrees, 18.93 degrees +/-0.3 degrees, 19.79 degrees +/-0.3 degrees, 20.04 degrees +/-0.3 degrees, 20.53 degrees +/-0.3 degrees, 20.88 degrees +/-0.3 degrees, 21.33 degrees +/-0.3 degrees, 21.90 degrees +/-0.3 degrees, 23.05 degrees +/-0.3 degrees, 24.21 degrees +/-0.3 degrees, 24.72 degrees +/-0.3 degrees, 25.59 degrees +/-0.3 degrees, 27.26 degrees +/-0.3 degrees, 29.35 degrees +/-0.3 degrees, 30.82 degrees +/-0.3 degrees, 31.88 degrees +/-0.3 degrees.
The compound shown in the formula (I), HA is benzenesulfonic acid, n is 1, the compound is in a crystal form I, Cu-Kalpha radiation is used, and an X-ray powder diffraction pattern of the compound is shown in figure 1.
A compound shown as a formula (I), HA is benzenesulfonic acid, n is 1, the compound is in a crystal form I, and a Differential Scanning Calorimetry (DSC) curve shows an endotherm-first and then exotherm curve, wherein an endothermic peak T isStart of＝220.2℃，TPeak(s)Exothermic peak T at 223.4 deg.CPeak(s)225.7 ℃. The compound shown in the formula (I), HA is benzenesulfonic acid, n is 1, the compound is in a crystal form I, and a differential scanning calorimetry analysis curve of the compound is shown in figure 2.
The compound shown in the formula (I) HAs the structure that HA is benzenesulfonic acid, n is 1, the compound is in the I crystal form, and the thermogravimetric analysis curve is shown in figure 3.
In one embodiment of the invention, the compound of formula (I), HA is selected from fumaric acid, n is 1, which is crystalline form I, and its X-ray powder diffraction pattern, using Cu-ka radiation, HAs characteristic diffraction peaks at the following 2 θ positions: 6.94 degrees +/-0.3 degrees, 11.47 degrees +/-0.3 degrees, 12.67 degrees +/-0.3 degrees, 13.39 degrees +/-0.3 degrees, 13.89 degrees +/-0.3 degrees, 14.20 degrees +/-0.3 degrees, 14.93 degrees +/-0.3 degrees, 15.31 degrees +/-0.3 degrees, 15.98 degrees +/-0.3 degrees, 16.47 degrees +/-0.3 degrees, 17.02 degrees +/-0.3 degrees, 17.42 degrees +/-0.3 degrees, 18.21 degrees +/-0.3 degrees, 18.66 degrees +/-0.3 degrees, 20.01 degrees +/-0.3 degrees, 21.26 degrees +/-0.3 degrees, 21.84 degrees +/-0.3 degrees, 22.35 degrees +/-0.3 degrees, 23.10 degrees +/-0.3 degrees, 25.10 degrees +/-0.3 degrees, 25.70 degrees +/-0.3 degrees, 26.09 degrees, 26.71 degrees +/-0.3 degrees, 30.42 degrees +/-0.3 degrees.
Further, the compound shown in the formula (I), HA is fumaric acid, n is 1, the compound is in a crystal form I, Cu-Kalpha radiation is used, and an X-ray powder diffraction pattern of the compound is shown in figure 4.
In one embodiment of the present invention, a compound of formula (I), HA is selected from furoic acid, n is 1, which is crystalline form I, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ positions using Cu-ka radiation: 5.32 degrees +/-0.3 degrees, 8.53 degrees +/-0.3 degrees, 9.33 degrees +/-0.3 degrees, 10.34 degrees +/-0.3 degrees, 12.36 degrees +/-0.3 degrees, 14.43 degrees +/-0.3 degrees, 15.89 degrees +/-0.3 degrees, 16.32 degrees +/-0.3 degrees, 16.89 degrees +/-0.3 degrees, 18.34 degrees +/-0.3 degrees, 19.57 degrees +/-0.3 degrees, 20.46 degrees +/-0.3 degrees, 21.10 degrees +/-0.3 degrees, 21.58 degrees +/-0.3 degrees, 22.82 degrees +/-0.3 degrees, 23.32 degrees +/-0.3 degrees, 24.44 degrees +/-0.3 degrees, 25.03 degrees +/-0.3 degrees, 26.54 degrees +/-0.3 degrees, 27.42 degrees +/-0.3 degrees, 28.69 degrees +/-0.3 degrees, 31.10 degrees 0.3 degrees and 31.59 degrees +/-0.3 degrees.
Further, the compound shown in the formula (I) HAs the structure that HA is furoic acid, n is 1, the compound is in the I crystal form, Cu-Kalpha radiation is used, and the X-ray powder diffraction pattern of the compound is shown in figure 5.
Further, the compound shown in the formula (I) HAs the structure that HA is furoic acid, n is 1, and the compound is I crystalForm (I) of which the differential scanning calorimetry curve (DSC) shows an endotherm in which TStart of＝165.3℃，TPeak(s)＝167.6℃。
Further, the compound shown in the formula (I) HAs the structure that HA is furoic acid, n is 1, the compound is in the I crystal form, and a differential scanning calorimetry analysis curve is shown in figure 6.
Further, the compound shown in the formula (I) HAs the structure that HA is furoic acid, n is 1, the compound is in the I crystal form, and a thermogravimetric analysis curve is shown in figure 7.
It will be appreciated that, as is well known in the art of differential scanning calorimetry, the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details.
The crystalline structure of the present invention may be analyzed using various analytical techniques known to those of ordinary skill in the art, including, but not limited to, X-ray powder diffraction (XRD), Differential Scanning Calorimetry (DSC), and/or Thermogravimetry (TG). Thermogravimetric Analysis (TGA), also known as Thermogravimetry (TG).
The X-ray powder diffraction, TGA (thermogravimetric analysis) or DSC (differential scanning calorimetry) patterns disclosed herein, which are substantially the same, are also within the scope of the present invention.
The invention relates to a preparation method of a compound shown in a formula (I),
dissolving a compound shown as a formula (II) in a first solvent at room temperature, adding a second solvent in which HA is dissolved, stirring, separating out a solid, and collecting the solid;
wherein HA is selected from benzenesulfonic acid, salicylic acid, benzoic acid, acetic acid, S- (+) -mandelic acid, propionic acid, crotonic acid, furoic acid, cinnamic acid, ethanesulfonic acid, glycolic acid, lactic acid, fumaric acid, formic acid, sulfuric acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, tartaric acid, citric acid, glycolic acid, hydrochloric acid, p-toluenesulfonic acid, maleic acid, succinic acid, oxalic acid, methanesulfonic acid, malonic acid or malic acid, preferably benzenesulfonic acid, fumaric acid, furoic acid, benzoic acid, acetic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, tartaric acid, hydrochloric acid, p-toluenesulfonic acid, maleic acid or succinic acid, further preferably benzenesulfonic acid, fumaric acid or furoic acid;
n is selected from 1, 1.5 or 2, preferably 1 or 1.5, more preferably 1.
In one embodiment of the invention, HA is selected from benzenesulfonic acid, fumaric acid or furoic acid and n is selected from 1.
The present invention relates to an embodiment of the process for preparing the compound of formula (I), wherein the first solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, diethyl ether and methyl tert-butyl ether.
The invention relates to an embodiment of a preparation method of a compound shown in a formula (I), wherein the second solvent is selected from one or more of methanol, ethanol, ethyl acetate, isopropanol, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether and water.
In one embodiment of the process for preparing the compound of formula (I), the first solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, diethyl ether and methyl tert-butyl ether, preferably ethyl acetate, isopropyl acetate, acetone or diethyl ether, more preferably ethyl acetate;
the second solvent is selected from one or more of methanol, ethanol, ethyl acetate, isopropanol, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether and water, preferably ethyl acetate, isopropyl acetate, acetone, ethanol or methanol, and more preferably ethyl acetate, ethanol or methanol.
The invention relates to an embodiment of a preparation method of a compound shown in a formula (I), wherein the first solvent is selected from ethyl acetate;
the second solvent is selected from methanol, ethanol or ethyl acetate.
The invention relates to an embodiment of a preparation method of a compound shown in a formula (I), wherein the reaction temperature is 0-reflux, preferably 10-50 ℃, and further preferably 20-30 ℃.
The invention relates to a preparation method of a compound shown in a formula (I),
wherein HA is selected from benzenesulfonic acid, fumaric acid or furoic acid, and n is 1;
the preparation method comprises the steps of dissolving the compound shown in the formula (II) in a first solvent at room temperature, adding a second solvent dissolved with HA, stirring, precipitating a solid, and collecting the solid;
wherein the first solvent is selected from ethyl acetate; the second solvent is selected from methanol, ethanol or ethyl acetate.
In one embodiment of the process for the preparation of the compound of formula (I) according to the invention, wherein HA is selected from benzenesulfonic acid, fumaric acid or furoic acid, n is 1 and the molar ratio of the compound of formula (II) to HA is 1: 1-1.5. In some embodiments, the molar ratio of the compound of formula (II) to HA is from 1:1 to 1.2. The molar ratio of the compound shown in the formula (II) to HA is 1:1-1.
The invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound shown in the formula (I) and a pharmaceutically acceptable carrier or excipient.
The invention also provides application of the compound shown in any formula (I) or the pharmaceutical composition thereof in preparing a medicament for treating diseases related to diabetes.
Preferably, the diabetes comprises type II diabetes.
The present invention also provides a method for treating diabetes-related diseases, preferably type II diabetes, comprising administering a compound represented by any one of the above formula (I) or a pharmaceutical composition thereof.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.
"pharmaceutical composition" means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt thereof with other ingredients, wherein the other ingredients comprise physiologically/pharmaceutically acceptable carriers and excipients.
"carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
Drawings
FIG. 1: an X-ray powder diffraction pattern of the crystalline form of compound 4I.
FIG. 2 is a drawing: differential Scanning Calorimetry (DSC) profile of crystalline form 4I of Compound 4.
FIG. 3: thermogravimetric analysis curve of the crystalline form of compound 4I.
FIG. 4 is a drawing: an X-ray powder diffraction pattern of the crystalline form of compound 7I.
FIG. 5: an X-ray powder diffraction pattern of crystalline form of compound 16I.
FIG. 6: a differential scanning calorimetry thermogram of the crystalline form of compound 16I.
FIG. 7: thermogravimetric analysis profile of the crystalline form of compound 16I.
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), deuterated acetonitrile (CD)3CN), internal standard Tetramethylsilane (TMS).
MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.
In the examples, the room temperature is 20 ℃ to 30 ℃ unless otherwise specified.
Example 1:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine methanesulfonate (Compound 1)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；methanesulfonic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10mL) into a reaction flask, and stirring at room temperature until the solution is clear; dripping solution of methanesulfonic acid (0.19g, 2mmol) in ethyl acetate (1mL) to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine methanesulfonate (compound 1) as a white solid, 0.93g, yield: 83.03 percent.
1H NMR(400MHz,CD3OD)δ7.87(s,1H),7.46-7.31(m,1H),7.31-7.15(m,2H),5.00(d, 1H),4.80-4.72(m,1H),4.10-4.00(m,2H),3.94-3.86(m,2H),3.75(td,1H),3.70-3.59(m,1H), 3.35(s,3H),2.73-2.58(m,4H),2.36-2.18(m,1H).
Example 2:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-aminecarboxylate (Compound 2)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；formic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10mL) into a reaction flask, and stirring at room temperature until the solution is clear; dripping ethyl acetate (1mL) solution of formic acid (0.092g, 2mmol) to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amineformate (compound 2) as a white solid (0.77 g, yield: 75.49 percent.
1H NMR(400MHz,CD3OD)δ8.37(s,1H),7.87(s,1H),7.38-7.29(m,1H),7.29-7.15(m, 2H),4.89(d,1H),4.78-4.66(m,1H),4.08-3.98(m,2H),3.89(dd,2H),3.67-3.56(m,1H),3.50 (td,1H),3.35(d,3H),2.55(d,1H),2.26-2.03(m,1H).
Example 3:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine p-toluenesulfonate (Compound 3)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；4-methylbenzenesulfonic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10mL) into a reaction flask, and stirring at room temperature until the solution is clear; dripping p-toluenesulfonic acid (0.38g, 2mmol) ethanol (1mL) solution to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine p-toluenesulfonate (compound 3), 0.95g of white solid, yield: 74.21 percent.
1H NMR(400MHz,CD3OD)δ7.86(s,1H),7.73-7.65(m,2H),7.41-7.33(m,1H),7.29- 7.15(m,4H),4.98(d,1H),4.79-4.71(m,1H),4.05-3.96(m,2H),3.86(dd,2H),3.79-3.67(m, 1H),3.67-3.57(m,1H),3.35(s,3H),2.69-2.53(m,1H),2.35(s,3H),2.30-2.15(m,1H).
Example 4:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine benzenesulfonate (Compound 4)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；benzenesulfonic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10ml) into a reaction bottle, and stirring at room temperature until the solution is clear; dripping solution of benzenesulfonic acid (0.37g, 2mmol) in ethanol (1ml) to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-aminebenzenesulfonate (compound 4) as a white solid in 0.87g, yield: 67.96 percent.
1H NMR(400MHz,CD3OD)δ7.85(d,1H),7.84-7.79(m,2H),7.44-7.34(m,4H),7.29- 7.18(m,2H),4.99(d,1H),4.80-4.71(m,1H),4.07-3.94(m,2H),3.91-3.80(m,2H),3.79-3.68 (m,1H),3.68-3.57(m,1H),3.35(s,3H),2.68-2.56(m,1H),2.34-2.16(m,1H).
Example 5:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine maleate (Compound 5)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；maleic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10ml) into a reaction bottle, and stirring at room temperature until the solution is clear; dripping into ethanol (1ml) solution of maleic acid (0.23g, 2mmol) to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine maleate (compound 5) as a white solid in an amount of 0.98g, yield: 83.76 percent.
1H NMR(400MHz,CD3OD)δ7.87(s,1H),7.42-7.31(m,1H),7.31-7.19(m,2H),6.25(s, 2H),4.98(d,1H),4.79-4.73(m,1H),4.09-3.99(m,2H),3.96-3.80(m,2H),3.78-3.58(m,2H), 3.36(s,3H),2.59(d,1H),2.34-2.13(m,1H).
Example 6:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine benzoate (Compound 6)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；benzoic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10ml) into a reaction bottle, and stirring at room temperature until the solution is clear; dripping 0.24g (2 mmol) of benzoic acid in 1ml of ethanol to obtain a clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-aminebenzoate (compound 6) as a white solid in an amount of 0.18g, yield: 15.65 percent.
1H NMR(400MHz,CD3OD)δ8.03-7.95(m,2H),7.85(s,1H),7.58-7.48(m,1H),7.47- 7.37(m,2H),7.33-7.26(m,1H),7.23-7.10(m,2H),4.77(d,1H),4.72-4.61(m,1H),4.10-3.98 (m,2H),3.93-3.83(m,2H),3.62-3.50(m,1H),3.34(s,3H),3.28-3.20(m,1H),2.54-2.41(m, 1H),2.16-1.99(m,1H).
Example 7:
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；fumaric acid
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine fumarate (Compound 7)
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10ml) into a reaction bottle, and stirring at room temperature until the solution is clear; dripping fumaric acid (0.23g, 2mmol) in ethanol (1ml) to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, and drying the filter cake under reduced pressure at 40 ℃ for 30min to give (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine fumarate (compound 7) as a white solid (0.77 g, yield: 66.38 percent.
1H NMR(400MHz,CD3OD)δ7.90-7.83(m,1H),7.39-7.30(m,1H),7.28-7.14(m,2H), 6.70(s,2H),4.91(d,1H),4.79-4.67(m,1H),4.10-3.99(m,2H),3.94-3.82(m,2H),3.60-3.48 (m,2H),3.35(s,3H),2.62-2.48(m,1H),2.27-2.08(m,1H).
Example 8:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine trifluoroacetate (Compound 8)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；2,2,2-trifluoroacetic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10ml) into a reaction bottle, and stirring at room temperature until the solution is clear; dropping trifluoroacetic acid (0.23g, 2mmol) in ethyl acetate (1ml) to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to give (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine trifluoroacetate (compound 8) as a white solid in an amount of 0.85g, yield: 73.27 percent.
1H NMR(400MHz,CD3OD)δ7.87(s,1H),7.41-7.32(m,1H),7.29-7.19(m,2H),4.99(d, 1H),4.80-4.73(m,1H),4..08-4.00(m,2H),3.95-3.85(m,2H),3.78-3.57(m,2H),3.35(s,3H), 2.66-2.55(m,1H),2.34-2.16(m,1H).
Example 9:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine oxalate (Compound 9)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；oxalic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10mL) into a reaction flask, and stirring at room temperature until the solution is clear; dripping oxalic acid (0.18g, 2mmol) in ethanol (1mL) to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amin-e oxalate (compound 9) as a white solid in 1.01g, yield: 90.99 percent.
1H NMR(400MHz,CD3OD)δ7.92(s,1H),7.38(s,1H),7.32-7.18(m,2H),5.05(d,1H), 4.80(s,1H),4.12-4.02(m,2H),3.99-3.87(m,2H),3.84-3.62(m,2H),3.41(s,3H),2.78-2.48 (m,1H),2.43-2.21(m,1H).
Example 10:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine malate (Compound 10)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；2-hydroxybutanedioic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10mL) into a reaction flask, and stirring at room temperature until the solution is clear; dripping a solution of malic acid (0.27g, 2mmol) in methanol (1mL) to obtain a clear solution; gradually precipitating colloidal solid under stirring at room temperature, and continuously stirring for 4 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine malate (compound 10) as a white solid in an amount of 0.72g, yield: 60 percent.
1H NMR(400MHz,CD3OD)δ7.86(s,1H),7.38-7.27(m,1H),7.28-7.15(m,2H),4.88(d, 1H),4.77-4.65(m,1H),4.39-4.27(m,1H),4.07-3.98(m,2H),3.94-3.84(m,2H),3.66-3.54 (m,1H),3.55-3.42(m,1H),3.35(s,3H),2.83-2.71(m,1H),2.60-2.48(m,2H),2.24-2.08(m, 1H).
Example 11:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine tartrate (Compound 11)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；(2S,3S)-2,3-dihydroxybutanedioic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10mL) into a reaction flask, and stirring at room temperature until the solution is clear; dripping tartaric acid (0.30g, 2mmol) in methanol (1mL) to obtain clear solution; gradually precipitating colloidal solid under stirring at room temperature, and continuously stirring for 4 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine tartrate (compound 11) as a white solid in a yield of 1.02 g: 82.92 percent.
1H NMR(400MHz,CD3OD)δ7.86(s,1H),7.41-7.36(m,1H),7.28-7.14(m,2H),4.96(d, 1H),4.79-4.65(m,1H),4.40(s,2H),4.10-4.00(m,2H),3.89(d,2H),3.71-3.54(m,2H),3.34(s, 3H),2.77-2.56(m,1H),2.36-2.14(m,1H).
Example 12:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine succinate (Compound 12)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；succinic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10mL) into a reaction flask, and stirring at room temperature until the solution is clear; dripping a solution of succinic acid (0.24g, 2mmol) in methanol (1mL) to obtain a clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine succinate (compound 12) as a white solid in an amount of 0.72g, yield: 61.53 percent.
1H NMR(400MHz,CD3OD)δ7.85(s,1H),7.36-7.25(m,1H),7.24-7.10(m,2H),4.78(s, 1H),4.73-4.62(m,1H),4.09-3.98(m,2H),3.91-3.76(m,2H),3.62-3.48(m,1H),3.36-3.33 (m,4H),2.54(s,4H),2.52-2.44(m,1H),2.19-2.02(m,1H).
Example 13:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine hydrochloride (Compound 13)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；hydrochloride
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10mL) into a reaction flask, and stirring at room temperature until the solution is clear; dripping concentrated hydrochloric acid (0.20g) ethyl acetate (1mL) solution to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine hydrochloride (compound 13) as a white solid in an amount of 0.96g, yield: 95.05 percent.
1H NMR(400MHz,CD3OD)δ7.88(s,1H),7.43-7.32(m,1H),7.30-7.14(m,2H),5.00(d, 1H),4.80-4.74(m,1H),4.10-4.04(m,2H),4.03-3.86(m,2H),3.80-3.63(m,2H),3.36(s,3H), 2.70-2.56(m,1H),2.34-2.13(m,1H).
Example 14:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine hydrobromide (Compound 14)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；hydrobromide
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.93g, 2mmol) and ethyl acetate (10mL) into a reaction flask, and stirring at room temperature until the solution is clear; dropwise adding ethyl acetate (1mL) solution of hydrobromic acid (0.4g) to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine hydrobromide (compound 14) as a white solid in 0.92g, yield: 84.40 percent.
1H NMR(400MHz,CD3OD)δ7.88(s,1H),7.45-7.33(s,1H),7.30-7.19(m,2H),5.00(d, 1H),4.79-4.72(m,1H),4.09-4.00(m,2H),3.81-3.61(m,2H),3.80-3.62(m,2H),3.36(s,3H), 2.71-2.49(m,1H),2.35-2.14(m,1H).
Example 15:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine cinnamate (Compound 15)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；(E)-3-phenylprop-2-enoic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.70g, 1.5mmol) and ethyl acetate (7mL) to a reaction flask, and stirring at room temperature to a clear solution; adding ethyl acetate (3mL) solution of cinnamic acid (0.22g, 1.5mmol) dropwise to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine cinnamate (compound 15) as a white solid in 0.72g, yield: 78.26 percent.
1H NMR(400MHz,CD3OD)δ7.90(s,1H),7.60-7.45(m,3H),7.43-7.27(m,4H),7.27- 7.17(m,2H),6.49(d,1H),4.90(s,2H),4.10-3.99(m,2H),3.98-3.85(m,2H),3.69-3.58(m,1H), 3.53-3.43(m,1H),3.39(s,3H),2.60-2.50(m,1H),2.22-2.13(m,1H).
Example 16:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine furoate (Compound 16)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；furan-2-carboxylic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.70g, 1.5mmol) and ethyl acetate (7mL) to a reaction flask, and stirring at room temperature to a clear solution; dripping furfuryl acid (0.22g, 1.5mmol) in ethanol (1mL) to obtain a clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to give (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-aminfuroate (compound 16) as a white solid (0.56 g, yield: 65.12 percent.
1H NMR(400MHz,CD3OD)δ7.86(s,1H),7.58-7.51(m,1H),7.37-7.30(m,1H),7.27- 7.14(m,2H),7.02-6.94(m,1H),6.51-6.43(m,1H),4.92(d,1H),4.78-4.67(m,1H),4.09-3.96 (m,2H),3.93-3.81(m,2H),3.66-3.50(m,2H),3.35(s,3H),2.66-2.51(m,1H),2.29-2.11(m, 1H).
Example 17:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine glycolate (Compound 17)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；2-hydroxyacetic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.70g, 1.5mmol) and ethyl acetate (7mL) to a reaction flask, and stirring at room temperature to a clear solution; a solution of glycolic acid (0.11g, 1.5mmol) in ethanol (1mL) was added dropwise to obtain a clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to obtain (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine glycolate (compound 17) as a white solid in 0.37g, yield: 45.68 percent.
1H NMR(400MHz,CD3OD)δ7.87(s,1H),7.38-7.30(m,1H),7.27-7.16(m,2H),4.91(d, 1H),4.79-4.65(m,1H),4.09-4.00(m,2H),3.98(s,4H),3.94-3.84(m,2H),3.57-3.50(m,1H), 3.35(s,3H),2.64-2.49(m,1H),2.30-2.11(m,1H).
Example 18:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine lactate (Compound 18)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；2-hydroxypropanoic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.70g, 1.5mmol) and ethyl acetate (7mL) to a reaction flask, and stirring at room temperature to a clear solution; dripping lactic acid (0.14g, 1.5mmol) solution in ethanol (1mL) to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine lactate (compound 18) as a white solid in 0.40g, yield: 48.19 percent.
1H NMR(400MHz,CD3OD)δ7.86(s,1H),7.36-7.27(m,1H),7.25-7.14(m,2H),4.85(s, 1H),4.75-4.64(m,1H),4.13-3.99(m,3H),3.94-3.84(m,2H),3.65-3.53(m,1H),3.44-3.36 (m,1H),3.35(s,3H),2.57-2.45(m,1H),2.21-2.05(m,1H),1.34(d,3H).
Example 19:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amineethanesulfonate salt (Compound 19)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；ethanesulfonic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (0.70g, 1.5mmol) and ethyl acetate (7mL) to a reaction flask, and stirring at room temperature to a clear solution; dripping ethyl acetate (1mL) solution of ethanesulfonic acid (0.17g, 1.5mmol) to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 3 h; filtration under reduced pressure, drying the filter cake under reduced pressure at 40 ℃ for 30min to give (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amineethanesulfonate (compound 19) as a white solid in an amount of 0.67g, yield: 77.91 percent.
1H NMR(400MHz,CD3OD)δ7.87(s,1H),7.43-7.34(m,1H),7.30-7.19(m,2H),4.99(d, 1H),4.80-4.73(m,1H),4.12-4.01(m,2H),3.95-3.84(m,2H),3.79-3.70(m,1H),3.70-3.59 (m,1H),3.35(s,3H),2.32-2.72(m,2H),2.69-2.58(m,1H),2.34-2.14(m,1H),1.34-1.25(m, 3H).
Example 20:
(2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine acetate (Compound 20)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5- yl)-6-(trifluoromethyl)tetrahydropyran-3-amine；acetic acid
Adding (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine (1.00g, 2.46mmol) and ethyl acetate (10mL) to a reaction flask, and stirring at room temperature to a clear solution; adding acetic acid (0.27g, 2.10mmol) solution in ethyl acetate (2mL) dropwise to obtain clear solution; gradually precipitating a large amount of white solid under stirring at room temperature, and continuously stirring for 1 h; filtration under reduced pressure and drying of the filter cake under reduced pressure at 40 ℃ for 30min gave (2R,3S,5R,6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3,4-c ] pyrazol-5-yl) -6- (trifluoromethyl) tetrahydropyran-3-amine acetate (compound 20) as a white solid in 0.79g, yield: 70.0 percent.
1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.46-7.10(m,3H),4.84-4.67(m,1H),4.49(d, 1H),3.99-3.87(m,2H),3.74(ddd,2H),3.54-3.38(m,4H),3.00(td,1H),2.38-2.24(m,1H),1.91 (s,4H),1.87-1.70(m,1H).
Test example
1. Stability data
Samples were tested at elevated temperature (40 ℃ and 60 ℃), light (5500 + -500 lx), and high humidity (RH 75% and RH 92.50%), respectively, and purity (in%) was determined by HPLC, the results of which are shown in Table 2.
Purity conditions by HPLC are shown in Table 1.
Table 1 stability testing HPLC conditions
Table 2 stability test results
And (4) conclusion: the compounds of the invention all have good stability.
2. Solubility test
Adding 2mL of physiological saline into a BD centrifuge tube, adding samples one by one, and strongly shaking or ultrasonically treating at room temperature after adding the samples each time. After a certain amount of sample is added, the solution becomes turbid, and the turbidity phenomenon cannot disappear even if the solution is shaken vigorously or subjected to ultrasound at room temperature. The results are shown in Table 3.
Table 3 solubility test results
And (4) conclusion: the compounds of the invention have good solubility. Compared with the compound shown in the formula II, the solubility of the compound is obviously improved by more than about 10 times, particularly the solubility of the compound 4 is improved by about 100 times.
Claims (18)
1. A compound of formula (I):
wherein HA is selected from benzenesulfonic acid, fumaric acid or furoic acid;
n is selected from 1.
2. The compound of claim 1, HA is benzenesulfonic acid, n is 1, which is crystalline form I, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ positions using Cu-ka radiation: 7.87 degrees +/-0.3 degrees, 10.17 degrees +/-0.3 degrees, 12.72 degrees +/-0.3 degrees, 15.38 degrees +/-0.3 degrees, 16.76 degrees +/-0.3 degrees, 17.65 degrees +/-0.3 degrees, 18.33 degrees +/-0.3 degrees, 18.93 degrees +/-0.3 degrees, 19.79 degrees +/-0.3 degrees, 20.04 degrees +/-0.3 degrees, 20.53 degrees +/-0.3 degrees, 20.88 degrees +/-0.3 degrees, 21.33 degrees +/-0.3 degrees, 21.90 degrees +/-0.3 degrees, 23.05 degrees +/-0.3 degrees, 24.21 degrees +/-0.3 degrees, 24.72 degrees +/-0.3 degrees, 25.59 degrees +/-0.3 degrees, 27.26 degrees +/-0.3 degrees, 29.35 degrees +/-0.3 degrees, 30.82 degrees +/-0.3 degrees, 31.88 degrees +/-0.3 degrees.
3. The compound of claim 2, HA is benzenesulfonic acid, n is 1, which is crystalline form I, and its X-ray powder diffraction pattern using Cu-ka radiation is shown in fig. 1.
4. The compound of claim 2, HA is benzenesulfonic acid, n is 1, is crystalline form I, and HAs a differential scanning calorimetry analysis curve as shown in fig. 2.
5. The compound of claim 2, HA is benzenesulfonic acid, n is 1, and is form I, and its thermogravimetric analysis curve is shown in fig. 3.
6. The compound of claim 1, HA is fumaric acid, n is 1, which is form I, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ positions using Cu-ka radiation: 6.94 degrees +/-0.3 degrees, 11.47 degrees +/-0.3 degrees, 12.67 degrees +/-0.3 degrees, 13.39 degrees +/-0.3 degrees, 13.89 degrees +/-0.3 degrees, 14.20 degrees +/-0.3 degrees, 14.93 degrees +/-0.3 degrees, 15.31 degrees +/-0.3 degrees, 15.98 degrees +/-0.3 degrees, 16.47 degrees +/-0.3 degrees, 17.02 degrees +/-0.3 degrees, 17.42 degrees +/-0.3 degrees, 18.21 degrees +/-0.3 degrees, 18.66 degrees +/-0.3 degrees, 20.01 degrees +/-0.3 degrees, 21.26 degrees +/-0.3 degrees, 21.84 degrees +/-0.3 degrees, 22.35 degrees +/-0.3 degrees, 23.10 degrees +/-0.3 degrees, 25.10 degrees +/-0.3 degrees, 25.70 degrees +/-0.3 degrees, 26.09 degrees, 26.71 degrees +/-0.3 degrees, 30.42 degrees +/-0.3 degrees.
7. The compound of claim 6, HA is fumaric acid, n is 1, which is form I, having an X-ray powder diffraction pattern as shown in figure 4 using Cu-ka radiation.
8. The compound of claim 1, HA is furoic acid, n is 1, which is crystalline form I, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ positions using Cu-ka radiation: 5.32 degrees +/-0.3 degrees, 8.53 degrees +/-0.3 degrees, 9.33 degrees +/-0.3 degrees, 10.34 degrees +/-0.3 degrees, 12.36 degrees +/-0.3 degrees, 14.43 degrees +/-0.3 degrees, 15.89 degrees +/-0.3 degrees, 16.32 degrees +/-0.3 degrees, 16.89 degrees +/-0.3 degrees, 18.34 degrees +/-0.3 degrees, 19.57 degrees +/-0.3 degrees, 20.46 degrees +/-0.3 degrees, 21.10 degrees +/-0.3 degrees, 21.58 degrees +/-0.3 degrees, 22.82 degrees +/-0.3 degrees, 23.32 degrees +/-0.3 degrees, 24.44 degrees +/-0.3 degrees, 25.03 degrees +/-0.3 degrees, 26.54 degrees +/-0.3 degrees, 27.42 degrees +/-0.3 degrees, 28.69 degrees +/-0.3 degrees, 31.10 degrees 0.3 degrees and 31.59 degrees +/-0.3 degrees.
9. The compound of claim 8, HA is furoic acid, n is 1, is crystalline form I, and HAs an X-ray powder diffraction pattern as shown in figure 5 using Cu-ka radiation.
10. The compound of claim 8, HA is furoic acid, n is 1, crystalline form I, and a differential scanning calorimetry trace is shown in figure 6.
11. The compound of claim 8, wherein HA is furoic acid, n is 1, and is form I, and the thermogravimetric analysis curve is shown in FIG. 7.
12. A process for preparing a compound of formula (I),
dissolving a compound shown as a formula (II) in a first solvent at room temperature, adding a second solvent in which HA is dissolved, stirring, separating out a solid, and collecting the solid;
wherein HA and n are as defined in claim 1.
13. The method of claim 12, wherein the first solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, diethyl ether, and methyl tert-butyl ether.
14. The method of claim 12, wherein the second solvent is selected from one or more of methanol, ethanol, ethyl acetate, isopropanol, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, and water.
15. The process of claim 12 wherein the first solvent is selected from the group consisting of ethyl acetate;
the second solvent is selected from methanol, ethanol or ethyl acetate.
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 11, together with pharmaceutically acceptable carriers and excipients.
17. Use of a compound according to any one of claims 1 to 11 or a composition according to claim 16 for the manufacture of a medicament for the treatment of a disease associated with diabetes.
18. The use according to claim 17, wherein the diabetes is type II diabetes.
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| CN101410400A (en) * | 2006-03-28 | 2009-04-15 | 默克公司 | Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
| CN102272136A (en) * | 2008-11-13 | 2011-12-07 | 默沙东公司 | Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| WO2014018350A1 (en) * | 2012-07-23 | 2014-01-30 | Merck Sharp & Dohme Corp. | Treating diabetes with dipeptidyl peptidase-iv inhibitors |
| WO2015192701A1 (en) * | 2014-06-17 | 2015-12-23 | 四川海思科制药有限公司 | Amino pyranoid ring derivative and composition and use thereof |
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| CN101410400A (en) * | 2006-03-28 | 2009-04-15 | 默克公司 | Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
| CN102272136A (en) * | 2008-11-13 | 2011-12-07 | 默沙东公司 | Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| WO2014018350A1 (en) * | 2012-07-23 | 2014-01-30 | Merck Sharp & Dohme Corp. | Treating diabetes with dipeptidyl peptidase-iv inhibitors |
| WO2015192701A1 (en) * | 2014-06-17 | 2015-12-23 | 四川海思科制药有限公司 | Amino pyranoid ring derivative and composition and use thereof |
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