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CN116589451B - New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound - Google Patents

New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound Download PDF

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CN116589451B
CN116589451B CN202310102052.9A CN202310102052A CN116589451B CN 116589451 B CN116589451 B CN 116589451B CN 202310102052 A CN202310102052 A CN 202310102052A CN 116589451 B CN116589451 B CN 116589451B
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oxaspiro
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CN116589451A (en
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黄翠
谷慧科
杨海龙
陈洪
王颖
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Chengdu Shuoder Pharmaceutical Co ltd
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract

The application relates to the field of medicine crystal forms, in particular to a (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride crystal form and a preparation method thereof. The crystal form of the compound of the formula (I) obtained by the application has excellent stability, and the used crystallization solvent has low toxicity and low residue, and is suitable for large-scale production and amplification.

Description

New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound
Technical Field
The invention belongs to the field of medicine crystal forms, and particularly relates to a (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride crystal form and a preparation method thereof.
Background
There have been studies showing that there are three different types of molecules and pharmacologies of Opioid Receptors (ORs): delta, kappa and mu. Opioid drugs are primarily conducted through the opioid μ receptor. Mu receptor is classical GPCR, and a great deal of research shows that the mu receptor biased agonist has better analgesic effect and can reduce related side effects. This provides the possibility to develop ideal opioids. Currently, trevena's TRV130 (oliceridine) is marketed under FDA approval at month 8 of 2020 for postoperative analgesia. The TRV130 three-phase clinical results showed: under the dosage of the same analgesic effect, the toxic and side effects of the TRV130 are lower than those of morphine, but no obvious difference exists, the toxic and side effects are large, the daily accumulated dosage of the TRV130 is not more than 27mg, and the safety window is narrow.
The invention provides (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride on the basis of the existing domestic and foreign researches, and the compound is solid at normal temperature, and has good pharmacokinetic property, long half-life period, good analgesic effect and good drug forming property.
The structural formula of the (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride is shown as the formula (I):
The relevant crystalline forms of compound I have not been reported in the literature. As is well known, the crystal forms of the medicines have influence on the quality of the preparation and the production process, and research on the crystal forms of the medicines can provide references for preparation workers in the aspects of prescription development, new medicament design, production process optimization, medicine quality control and clinical efficacy. Different crystal forms of the same medicine may be significantly different in appearance, solubility, melting point, dissolution rate, bioequivalence and the like, thereby affecting the stability, bioavailability and curative effect of the medicine. Therefore, research on the crystal forms of the compound I is necessary, and one or more crystal forms which are simple in preparation method, good in solubility, high in stability, high in purity, not easy to absorb moisture and suitable for industrial production are developed.
Disclosure of Invention
The invention aims to provide a plurality of crystal forms of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride, and part of the crystal forms have good crystal form stability and chemical stability and can be better applied to clinic.
The invention provides a crystal form A of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form A has characteristic peaks at angles of 2 theta of 6.32+/-0.2 degrees, 14.30+/-0.2 degrees, 16.44+/-0.2 degrees, 17.60+/-0.2 degrees, 18.50+/-0.2 degrees, 19.30+/-0.2 degrees, 21.46+/-0.2 degrees and 23.68 +/-0.2 degrees.
The invention provides a crystal form A of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at angles of 6.32±0.2°、13.14±0.2°、13.62±0.2°、14.30±0.2°、16.44±0.2°、16.78±0.2°、17.60±0.2°、19.30±0.2°、19.96±0.2°、20.58±0.2°、21.46±0.2°、21.78±0.2°、22.46±0.2°、23.68±0.2°、24.14±0.2°、25.66±0.2°、26.00±0.2°、26.76±0.2°、27.90±0.2° and 29.44+/-0.2 degrees of 2 theta.
Form a of the present application uses Cu-Ka radiation, X-ray powder diffraction patterns expressed in terms of 2θ, with characteristic diffraction peaks near 6.32±0.2°、13.14±0.2°、13.62±0.2°、14.30±0.2°、16.44±0.2°、16.78±0.2°、17.60±0.2°、19.30±0.2°、19.96±0.2°、20.58±0.2°、21.46±0.2°、21.78±0.2°、22.46±0.2°、23.68±0.2°、24.14±0.2°、25.66±0.2°、26.00±0.2°、26.76±0.2°、27.90±0.2° and 29.44±0.2°.
Preferably, the X-ray powder diffraction pattern of form a is substantially as shown in figure 1.
The thermogravimetric analysis (TGA) of form a is shown in figure 2, where it is seen that form a loses 2.3% weight in the range of 30-130 ℃.
The invention also relates to a method for preparing the crystal form A, which specifically comprises the following steps: ethyl acetate was added to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine until it was dissolved, and then a solution of hydrogen chloride-ethyl acetate was slowly added dropwise at 0-20 ℃ with stirring for 3-24 hours, followed by filtration and drying to give crystalline form a.
The invention provides a crystal form B of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form B has characteristic peaks at angles of 2 theta of 6.14+/-0.2 degrees, 14.48+/-0.2 degrees, 17.38+/-0.2 degrees, 18.50+/-0.2 degrees, 20.62 +/-0.2 degrees, 23.72+/-0.2 degrees, 24.78+/-0.2 degrees and 29.40+/-0.2 degrees.
The invention provides a crystal form B of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form B has characteristic diffraction peaks at angles of 6.14±0.2°、10.68±0.2°、12.30±0.2°、13.60±0.2°、14.48±0.2°、15.58±0.2°、16.76±0.2°、17.38±0.2°、18.50±0.2°、18.90±0.2°、20.62±0.2°、23.10±0.2°、23.72±0.2°、24.78±0.2°、26.30±0.2°、27.96±0.2° and 29.40+/-0.2 degrees of 2 theta.
Form B of the present application uses Cu-Ka radiation, X-ray powder diffraction patterns expressed in terms of 2θ, with characteristic diffraction peaks around 6.14±0.2°、10.68±0.2°、12.30±0.2°、13.60±0.2°、14.48±0.2°、15.58±0.2°、16.76±0.2°、17.38±0.2°、18.50±0.2°、18.90±0.2°、20.62±0.2°、23.10±0.2°、23.72±0.2°、24.78±0.2°、26.30±0.2°、27.96±0.2° and 29.40±0.2°.
Preferably, the X-ray powder diffraction pattern of form B is substantially as shown in figure 3.
The thermogravimetric analysis (TGA) of form B is shown in fig. 4, where it is seen that form B loses 2.8% weight in the range of 30-130 ℃.
The invention also relates to a method for preparing the crystal form B, which specifically comprises the following steps: ethyl acetate is added into (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine until the ethyl acetate is dissolved, concentrated hydrochloric acid is slowly added dropwise at the temperature of 0-20 ℃, and the mixture is fully stirred for 3-24 hours, filtered and dried to obtain a crystal form B.
The invention provides a crystal form C of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form C has characteristic peaks at angles of 2 theta of 6.04+/-0.2 degrees, 15.80+/-0.2 degrees, 19.02+/-0.2 degrees, 22.94+/-0.2 degrees, 25.80+/-0.2 degrees and 28.88 +/-0.2 degrees.
The invention provides a crystal form C of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form C has characteristic diffraction peaks at angles of 2 theta of 6.04+/-0.2 degrees, 11.82+/-0.2 degrees, 14.00+/-0.2 degrees, 15.80+/-0.2 degrees, 18.10+/-0.2 degrees, 19.02+/-0.2 degrees, 21.16+/-0.2 degrees, 22.94+/-0.2 degrees, 25.80+/-0.2 degrees and 28.88 +/-0.2 degrees.
Form C of the present application uses Cu-Ka radiation with an X-ray powder diffraction pattern expressed in terms of 2θ, wherein there are characteristic diffraction peaks around about 6.04±0.2°, 11.82±0.2°, 14.00±0.2°, 15.80±0.2°, 18.10±0.2°, 19.02±0.2°, 21.16±0.2°, 22.94±0.2°, 25.80±0.2° and 28.88 ±0.2°.
Preferably, the X-ray powder diffraction pattern of form C is substantially as shown in fig. 5.
The thermogravimetric analysis (TGA) of form C is shown in fig. 6, where it is seen that form C loses 2.3% weight in the range of 30-130 ℃.
The invention also relates to a method for preparing the crystal form C, which specifically comprises the following steps: adding acetone into (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine until the acetone is dissolved, slowly dropwise adding concentrated hydrochloric acid at the temperature of 0-20 ℃, fully stirring for 3-24 hours, filtering and drying to obtain a crystal form C.
The invention provides a crystal form D of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form D has characteristic diffraction peaks at angles of 6.21±0.2°、12.08±0.2°、13.36±0.2°、14.60±0.2°、15.61±0.2°、16.75±0.2°、17.98±0.2°、19.19±0.2°、20.08±0.2°、24.09±0.2°、24.58±0.2°、26.89±0.2° and 30.61+/-0.2 degrees of 2 theta.
The invention provides a crystal form D of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form D has characteristic diffraction peaks at angles of 6.21±0.2°、6.84±0.2°、12.08±0.2°、13.36±0.2°、14.60±0.2°、15.61±0.2°、16.75±0.2°、17.98±0.2°、18.67±0.2°、19.19±0.2°、20.08±0.2°、20.98±0.2°、21.75±0.2°、21.99±0.2°、23.17±0.2°、23.48±0.2°、24.09±0.2°、24.58±0.2°、24.97±0.2°、25.93±0.2°、26.89±0.2°、27.96±0.2°、30.38±0.2°、30.61±0.2° and 31.11+/-0.2 degrees of 2 theta.
Form D of the present application uses Cu-Ka radiation, an X-ray powder diffraction pattern expressed in terms of 2θ, with characteristic diffraction peaks around 6.21±0.2°、6.84±0.2°、12.08±0.2°、13.36±0.2°、14.60±0.2°、15.61±0.2°、16.75±0.2°、17.98±0.2°、18.67±0.2°、19.19±0.2°、20.08±0.2°、20.98±0.2°、21.75±0.2°、21.99±0.2°、23.17±0.2°、23.48±0.2°、24.09±0.2°、24.58±0.2°、24.97±0.2°、25.93±0.2°、26.89±0.2°、27.96±0.2°、30.38±0.2°、30.61±0.2° and 31.11±0.2°.
Preferably, the X-ray powder diffraction pattern of form D is substantially as shown in fig. 7.
The thermogravimetric analysis (TGA) of form D is shown in fig. 8, where it is seen that form D loses 3.7% weight in the range of 30-130 ℃.
The invention also relates to a method for preparing the crystal form D, which specifically comprises the following steps: amorphous (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride is added into N-heptane, stirred for more than 20 hours at room temperature, filtered and dried to obtain a crystal form D.
The invention provides a crystal form E of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form E has characteristic peaks at angles of 2 theta of 5.32+/-0.2 degrees, 14.53+/-0.2 degrees, 14.92+/-0.2 degrees, 16.14+/-0.2 degrees, 17.39+/-0.2 degrees, 18.86+/-0.2 degrees, 19.93+/-0.2 degrees, 22.52+/-0.2 degrees, 25.14+/-0.2 degrees and 27.82+/-0.2 degrees.
The invention provides a crystal form E of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form E has characteristic diffraction peaks at angles of 5.32±0.2°、10.37±0.2°、14.53±0.2°、15.26±0.2°、17.39±0.2°、18.86±0.2°、19.93±0.2°、21.63±0.2°、22.52±0.2°、23.71±0.2°、24.73±0.2°、25.14±0.2° and 27.82+/-0.2 degrees of 2 theta.
The invention provides a crystal form E of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form E has characteristic diffraction peaks at angles of 2 theta of 5.32±0.2°、10.37±0.2°、12.34±0.2°、14.53±0.2°、15.26±0.2°、17.01±0.2°、17.39±0.2°、17.90±0.2°、18.86±0.2°、19.93±0.2°、21.63±0.2°、22.52±0.2°、23.71±0.2°、24.73±0.2°、25.14±0.2°、26.99±0.2°、27.82±0.2° and 30.51 plus or minus 0.2 degrees.
Form E of the present application uses Cu-Ka radiation, X-ray powder diffraction patterns expressed in terms of 2θ, with characteristic diffraction peaks around 5.32±0.2°、10.37±0.2°、12.34±0.2°、14.53±0.2°、15.26±0.2°、17.01±0.2°、17.39±0.2°、17.90±0.2°、18.86±0.2°、19.93±0.2°、21.63±0.2°、22.52±0.2°、23.71±0.2°、24.73±0.2°、25.14±0.2°、26.99±0.2°、27.82±0.2° and 30.51 ±0.2°.
Preferably, the X-ray powder diffraction pattern of form E is substantially as shown in figure 9.
The thermogravimetric analysis (TGA) of form E is shown in figure 10, where it is seen that form E loses 3.2% weight in the range of 30-130 ℃.
The invention also relates to a method for preparing the crystal form E, which specifically comprises the following steps: amorphous (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride is added into isopropyl acetate, stirred for more than 20 hours at room temperature, filtered and dried to obtain a crystal form E.
The invention provides a crystal form F of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form F has characteristic peaks at angles of 2 theta of 9.31+/-0.2 degrees, 12.46+/-0.2 degrees, 14.58+/-0.2 degrees, 16.56+/-0.2 degrees, 18.64+/-0.2 degrees, 20.40+/-0.2 degrees, 24.57+/-0.2 degrees and 25.91+/-0.2 degrees.
The invention provides a crystal form F of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form F has characteristic diffraction peaks at angles of 7.30±0.2°、9.31±0.2°、11.01±0.2°、12.46±0.2°、14.58±0.2°、16.56±0.2°、17.20±0.2°、18.35±0.2°、18.64±0.2°、20.40±0.2°、22.38±0.2°、24.57±0.2°、25.91±0.2°、28.99±0.2°、33.45±0.2° and 37.71+/-0.2 degrees of 2 theta.
Form F in the present application uses Cu-Ka radiation, an X-ray powder diffraction pattern expressed in terms of 2θ, with characteristic diffraction peaks around 7.30±0.2°、9.31±0.2°、11.01±0.2°、12.46±0.2°、14.58±0.2°、16.56±0.2°、17.20±0.2°、18.35±0.2°、18.64±0.2°、20.40±0.2°、22.38±0.2°、24.57±0.2°、25.91±0.2°、28.99±0.2°、33.45±0.2° and 37.71±0.2°.
Preferably, the X-ray powder diffraction pattern of form F is substantially as shown in fig. 11.
The thermogravimetric analysis (TGA) of form F is shown in figure 12, where it is seen that form F loses 0.4% weight in the range of 30-130 ℃.
The invention also relates to a method for preparing the crystal form F, which specifically comprises the following steps: adding the (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride crystal form A into acetonitrile, stirring for more than 20 hours at 60 ℃, filtering and drying to obtain a crystal form F.
The invention provides a crystal form G of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form G has characteristic peaks at angles of 2 theta of 5.87+/-0.2 degrees, 6.77+/-0.2 degrees, 11.84+/-0.2 degrees, 15.67+/-0.2 degrees, 22.81 +/-0.2 degrees, 23.87+/-0.2 degrees, 26.54+/-0.2 degrees and 29.98+/-0.2 degrees.
The invention provides a crystal form G of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form G has a characteristic diffraction peak at a position with a 2 theta angle of 5.87±0.2°、6.77±0.2°、11.84±0.2°、13.62±0.2°、14.45±0.2°、15.67±0.2°、17.83±0.2°、19.03±0.2°、20.49±0.2°、22.81±0.2°、23.87±0.2°、24.83±0.2°、26.54±0.2°、29.98±0.2°.
Form G of the present application uses Cu-Ka radiation, an X-ray powder diffraction pattern expressed in terms of 2θ, with a characteristic diffraction peak near 5.87±0.2°、6.77±0.2°、11.84±0.2°、13.62±0.2°、14.45±0.2°、15.67±0.2°、17.83±0.2°、19.03±0.2°、20.49±0.2°、22.81±0.2°、23.87±0.2°、24.83±0.2°、26.54±0.2°、29.98±0.2°.
Preferably, the X-ray powder diffraction pattern of form G is substantially as shown in fig. 13.
The thermogravimetric analysis (TGA) of form G is shown in fig. 14, where form G is known to lose 2.9% weight in the range of 30-130 ℃.
The invention also relates to a method for preparing the crystal form G, which specifically comprises the following steps: at room temperature, dissolving (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride crystal form A in methanol, slowly dropwise adding methyl tertiary butyl ether, then continuing stirring at room temperature for 3-60h, filtering and drying to obtain crystal form G.
The invention provides a crystal form H of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form H has characteristic peaks at angles of 2 theta of 6.83+/-0.2 degrees, 11.88+/-0.2 degrees, 14.52+/-0.2 degrees, 15.73+/-0.2 degrees, 17.30+/-0.2 degrees, 19.53+/-0.2 degrees, 22.85+/-0.2 degrees and 23.92+/-0.2 degrees.
The invention provides a crystal form H of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form H has a characteristic diffraction peak at a position with a 2 theta angle of 5.94±0.2°、6.83±0.2°、11.88±0.2°、12.43±0.2°、13.63±0.2°、14.52±0.2°、15.73±0.2°、16.40±0.2°、17.30±0.2°、18.15±0.2°、19.02±0.2°、19.53±0.2°、20.52±0.2°、22.85±0.2°、23.92±0.2°、24.83±0.2°.
The invention provides a crystal form H of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form H has a characteristic diffraction peak at a position with a 2 theta angle of 5.94±0.2°、6.83±0.2°、11.88±0.2°、12.43±0.2°、13.24±0.2°、13.63±0.2°、14.52±0.2°、15.73±0.2°、16.40±0.2°、17.30±0.2°、18.15±0.2°、18.74±0.2°、19.02±0.2°、19.53±0.2°、20.52±0.2°、22.85±0.2°、23.92±0.2°、24.83±0.2°、26.02±0.2°、26.59±0.2°.
Form H of the present application uses Cu-Ka radiation, an X-ray powder diffraction pattern expressed in terms of 2θ, with a characteristic diffraction peak near 5.94±0.2°、6.83±0.2°、11.88±0.2°、12.43±0.2°、13.24±0.2°、13.63±0.2°、14.52±0.2°、15.73±0.2°、16.40±0.2°、17.30±0.2°、18.15±0.2°、18.74±0.2°、19.02±0.2°、19.53±0.2°、20.52±0.2°、22.85±0.2°、23.92±0.2°、24.83±0.2°、26.02±0.2°、26.59±0.2°.
Preferably, the X-ray powder diffraction pattern of form H is substantially as shown in figure 15.
The thermogravimetric analysis (TGA) of form H is shown in fig. 16, where it is seen that form H loses 4.0% weight in the range of 30-130 ℃.
The invention also relates to a method for preparing the crystal form H, which specifically comprises the following steps: at 50 ℃, (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine dihydrochloride form A is dissolved in methanol, and the solvent is dried by spin evaporation to obtain form H.
The invention provides a crystal form I of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form I has characteristic peaks at angles of 2 theta of 6.44+/-0.2 degrees, 15.34+/-0.2 degrees, 16.80+/-0.2 degrees, 19.36+/-0.2 degrees, 20.20+/-0.2 degrees, 22.11+/-0.2 degrees, 23.66+/-0.2 degrees and 28.29+/-0.2 degrees.
The invention provides a crystal form I of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form I has a characteristic diffraction peak at a position with a 2 theta angle of 6.44±0.2°、8.52±0.2°、10.50±0.2°、13.05±0.2°、14.28±0.2°、15.34±0.2°、16.80±0.2°、17.55±0.2°、18.72±0.2°、19.36±0.2°、20.20±0.2°、21.08±0.2°、22.11±0.2°、23.66±0.2°、24.19±0.2°、27.23±0.2°、28.29±0.2°、33.64±0.2°.
Form I of the present application uses Cu-Ka radiation, an X-ray powder diffraction pattern expressed in terms of 2θ, with a characteristic diffraction peak near 6.44±0.2°、8.52±0.2°、10.50±0.2°、13.05±0.2°、14.28±0.2°、15.34±0.2°、16.80±0.2°、17.55±0.2°、18.72±0.2°、19.36±0.2°、20.20±0.2°、21.08±0.2°、22.11±0.2°、23.66±0.2°、24.19±0.2°、27.23±0.2°、28.29±0.2°、33.64±0.2°.
Preferably, the X-ray powder diffraction pattern of form I is substantially as shown in figure 17.
The thermogravimetric analysis (TGA) of form I is shown in figure 18, where it is seen that form I loses 1.4% weight in the range of 30-130 ℃.
The invention also relates to a method for preparing the crystal form I, which specifically comprises the following steps: at 60 ℃, dissolving (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride crystal form A in ethanol, and spin-drying the solvent by a rotary evaporator to obtain crystal form I.
The invention provides a crystal form J of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form J has characteristic peaks at angles of 2 theta of 5.43+/-0.2 degrees, 9.41+/-0.2 degrees, 15.73+/-0.2 degrees, 17.71+/-0.2 degrees, 20.05+/-0.2 degrees, 20.75+/-0.2 degrees, 25.80+/-0.2 degrees and 27.95+/-0.2 degrees.
The invention provides a crystal form J of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form J has a characteristic diffraction peak at a position with a 2 theta angle of 5.43±0.2°、9.41±0.2°、10.03±0.2°、12.02±0.2°、15.73±0.2°、16.14±0.2°、17.71±0.2°、20.05±0.2°、20.75±0.2°、21.08±0.2°、25.80±0.2°、27.95±0.2°.
The invention provides a crystal form J of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form J has a characteristic diffraction peak at a position with a 2 theta angle of 5.43±0.2°、9.41±0.2°、10.03±0.2°、12.02±0.2°、15.73±0.2°、16.14±0.2°、16.64±0.2°、17.71±0.2°、18.82±0.2°、20.05±0.2°、20.75±0.2°、21.08±0.2°、21.56±0.2°、23.98±0.2°、25.28±0.2°、25.80±0.2°、27.39±0.2°、27.95±0.2°.
Form J of the present application uses Cu-Ka radiation in an X-ray powder diffraction pattern expressed in terms of 2θ, with a characteristic diffraction peak near about 5.43±0.2°、9.41±0.2°、10.03±0.2°、12.02±0.2°、15.73±0.2°、16.14±0.2°、16.64±0.2°、17.71±0.2°、18.82±0.2°、20.05±0.2°、20.75±0.2°、21.08±0.2°、21.56±0.2°、23.98±0.2°、25.28±0.2°、25.80±0.2°、27.39±0.2°、27.95±0.2°.
Preferably, the X-ray powder diffraction pattern of form J is substantially as shown in figure 19.
The thermogravimetric analysis (TGA) of form J is shown in figure 20, where form J is known to lose 13.1% weight in the range of 30-130 ℃.
The invention also relates to a method for preparing the crystal form J, which specifically comprises the following steps: amorphous (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride is added into toluene, and is suspended for more than 20 hours at room temperature, filtered and dried to obtain a crystal form J.
The invention provides a crystal form K of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form K has characteristic peaks at angles of 2 theta of 5.36+/-0.2 degrees, 14.36+/-0.2 degrees, 15.37+/-0.2 degrees, 16.52 +/-0.2 degrees, 17.64+/-0.2 degrees, 19.35+/-0.2 degrees, 21.46+/-0.2 degrees and 24.21+/-0.2 degrees.
The invention provides a crystal form K of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form K has a characteristic diffraction peak at a position with a 2 theta angle of 5.36±0.2°、6.43±0.2°、10.64±0.2°、13.69±0.2°、14.36±0.2°、15.37±0.2°、16.52±0.2°、17.64±0.2°、19.35±0.2°、20.58±0.2°、21.46±0.2°、22.50±0.2°、23.71±0.2°、24.21±0.2°.
The invention provides a crystal form K of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form K has a characteristic diffraction peak at a position with a 2 theta angle of 5.36±0.2°、6.43±0.2°、10.64±0.2°、11.79±0.2°、13.69±0.2°、14.36±0.2°、15.37±0.2°、16.52±0.2°、17.64±0.2°、18.45±0.2°、19.35±0.2°、20.08±0.2°、20.58±0.2°、21.46±0.2°、22.50±0.2°、23.71±0.2°、24.21±0.2°、26.80±0.2°、27.59±0.2°、30.59±0.2°.
Form K of the present application uses Cu-Ka radiation, an X-ray powder diffraction pattern expressed in terms of 2θ, with a characteristic diffraction peak around 5.36±0.2°、6.43±0.2°、10.64±0.2°、11.79±0.2°、13.69±0.2°、14.36±0.2°、15.37±0.2°、16.52±0.2°、17.64±0.2°、18.45±0.2°、19.35±0.2°、20.08±0.2°、20.58±0.2°、21.46±0.2°、22.50±0.2°、23.71±0.2°、24.21±0.2°、26.80±0.2°、27.59±0.2°、30.59±0.2°.
Preferably, the X-ray powder diffraction pattern of form K is substantially as shown in figure 21.
The thermogravimetric analysis (TGA) of form K is shown in figure 22, where form K is known to lose 2.3% weight in the range of 30-130 ℃.
The invention also relates to a method for preparing the crystal form K, which specifically comprises the following steps: adding (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine dihydrochloride crystal form I into ethyl acetate, suspending for more than 20 hours at room temperature, filtering and drying to obtain crystal form K.
The beneficial effects brought by the invention are as follows:
1. The crystal form prepared by the application is not easy to absorb moisture, has good solubility and excellent stability.
2. The preparation method of the crystal form has mild conditions and is simple to operate. By controlling each key parameter in the crystal form preparation process, the preparation method provided by the application can obtain a single crystal form, has good process reproducibility and high purity, realizes controllable industrial production conditions, and is beneficial to large-scale industrialization.
Drawings
Figure 1 is an XRD pattern of form a obtained in example 1.
FIG. 2 is a TGA spectrum of form A obtained in example 1.
Figure 3 is an XRD pattern of form B obtained in example 2.
FIG. 4 is a TGA spectrum of form B obtained in example 2.
Fig. 5 is an XRD pattern of form C obtained in example 3.
FIG. 6 is a TGA spectrum of form C obtained in example 3.
Fig. 7 is an XRD pattern of form D obtained in example 4.
FIG. 8 is a TGA spectrum of form D obtained in example 4.
Figure 9 is an XRD pattern of form E obtained in example 5.
FIG. 10 is a TGA spectrum of form E obtained in example 5.
Fig. 11 is an XRD pattern of form F obtained in example 6.
FIG. 12 is a TGA spectrum of form F obtained in example 6.
Fig. 13 is an XRD pattern of form G obtained in example 7.
FIG. 14 is a TGA spectrum of form G obtained in example 7.
Figure 15 is an XRD pattern of form H obtained in example 8.
FIG. 16 is a TGA spectrum of form H obtained in example 8.
Figure 17 is an XRD pattern of form I obtained in example 9.
FIG. 18 is a TGA spectrum of form I obtained in example 9.
Figure 19 is an XRD pattern of form J obtained in example 10.
FIG. 20 is a TGA spectrum of form J obtained in example 10.
Figure 21 is an XRD pattern of form K obtained in example 11.
FIG. 22 is a TGA spectrum of form K obtained in example 11.
FIG. 23-1 is an XRD contrast pattern of form A before and after placement of influencing factors.
Figure 23-2 is an XRD contrast pattern of form A before and after placement of the influencing factors (high humidity).
FIG. 24-1 is an XRD contrast pattern of form B before and after placement of influencing factors.
Figure 24-2 is an XRD contrast pattern of form B before and after placement of the influencing factors (high humidity).
FIG. 25-1 is an XRD contrast pattern of form C before and after placement of influencing factors.
Figure 25-2 is an XRD contrast pattern of form C before and after placement of the influencing factors (high humidity).
Figure 26 is an XRD comparison pattern before and after placement of form F influencing factors.
Detailed Description
The present invention is described in further detail below with reference to examples, but is not limited to the following examples, and any equivalents in the art, which are in accordance with the present disclosure, are intended to fall within the scope of the present invention.
The abbreviations used in the present application are explained as follows:
XRD: powder diffraction by X-rays
The X-ray powder diffraction (XRD) test of the application in examples 1-3 and experimental example 1 was carried out by using a Liaoning Dandong Duoyuan DX-2700B powder diffractometer, and the specific parameters are as follows:
The X-ray powder diffraction (XRD) measurements described in examples 4-11 of the present application were collected using a powder diffractometer from the Marvelanaceae Empyrea, the specific parameters being as follows:
TGA: thermogravimetric analyzer
The thermogravimetric analysis (TGA) is measured by adopting METTLER TOLEDO model TGA-2, the heating rate is 10 ℃/min, the temperature range is 30-300 ℃, and the nitrogen purging rate in the test process is 20mL/min.
Room temperature: 15-30 DEG C
Example 1: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride crystalline form A
To 4.600g of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (purity: 99.92%) was added 184mL of ethyl acetate, which was dissolved by stirring, 10.35mL of ethyl hydrogen chloride solution (concentration: 2 mol/L) was slowly added at 5℃and stirred at 5℃for 3 hours after the completion of the dropwise addition, and the mixture was filtered and dried under vacuum at 60℃to give 4.049g of a white solid with a yield of 75.62% and a purity of 99.98%. The hydrochloric acid content was found to be 14.10% (theoretical 14.09%) by titration.
This form was designated form a.
The obtained samples were subjected to X-ray powder measurement using Cu-ka rays, and the spectra thereof had diffraction angles, interplanar spacings, and relative intensities as shown in Table 1:
TABLE 1 diffraction angle, interplanar spacing and relative intensity for form A
The error of the 2 theta diffraction angle is + -0.20 deg..
Further, form a prepared in example 1 has an X-ray powder diffraction pattern substantially as shown in figure 1.
The thermogravimetric analysis (TGA) of form a is shown in figure 2, where it is seen that form a loses 2.3% weight in the range of 30-130 ℃.
As can be seen from the embodiment 1, the preparation method of the crystal form A has mild conditions and is simple to operate; and the single crystal form with higher purity is obtained through parameter control in the preparation process.
Example 2: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride crystalline form B
To 5.100g of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (purity: 99.92%) was added 204mL of ethyl acetate, which was dissolved by stirring, 1.961mL of concentrated hydrochloric acid (36% strength) was slowly added at 5℃and stirred at 5℃for 3 hours after the addition, and the mixture was filtered and dried under vacuum at 60℃to give 5.094g of a white solid with a yield of 85.81% and a purity of 99.98%. The hydrochloric acid content was found to be 14.00% (theoretical 14.09%) by titration.
The obtained samples were subjected to X-ray powder measurement using Cu-ka rays, and the spectra thereof had diffraction angles, interplanar spacings, and relative intensities as shown in table 2:
TABLE 2 diffraction angle, interplanar spacing and relative intensity for form B
The error of the 2 theta diffraction angle is + -0.20 deg..
Further, form B prepared in example 2 has an X-ray powder diffraction pattern substantially as shown in figure 3.
The thermogravimetric analysis (TGA) of form B is shown in fig. 4, where it is seen that form B loses 2.8% weight in the range of 30-130 ℃.
Example 3: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride crystalline form C
To 5.100g of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (purity: 99.92%) was added 125mL of acetone, and then dissolved by stirring, 2.46g of concentrated hydrochloric acid (36% strength) was slowly added at 5℃and stirred at 5℃for 3 hours after the dropwise addition, and the mixture was filtered and dried under vacuum at 60℃to give 5.450g of a white solid with a yield of 91.80% and a purity of 99.97%. The hydrochloric acid content was found to be 14.80% (theoretical 14.09%) by titration.
This form was designated form C.
The obtained samples were subjected to X-ray powder measurement using Cu-ka rays, and the spectra thereof had diffraction angles, interplanar spacings, and relative intensities as shown in Table 3:
TABLE 3 diffraction angle, interplanar spacing and relative intensity for form C
The error of the 2 theta diffraction angle is + -0.20 deg..
Further, form C prepared in example 3 has an X-ray powder diffraction pattern substantially as shown in figure 5.
The thermogravimetric analysis (TGA) of form C is shown in fig. 6, where it is seen that form C loses 2.3% weight in the range of 30-130 ℃.
Example 4: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride form D
To 1.5g of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine dihydrochloride form A was added 5mL of methanol, heated to 60℃until the solid was completely dissolved, and then the solvent was dried by rotary evaporator to give 1.46g of amorphous form. 30mg of amorphous form was added to 300. Mu.L of n-heptane, and the mixture was suspended at room temperature for 20 hours and filtered to obtain a white solid.
This form was designated form D.
The obtained samples were subjected to X-ray powder measurement using Cu-ka rays, and the spectra thereof had diffraction angles, interplanar spacings, and relative intensities as shown in Table 4:
TABLE 4 diffraction angle, interplanar spacing and relative intensity for form D
The error of the 2 theta diffraction angle is + -0.20 deg..
Further, form D prepared in example 4 has an X-ray powder diffraction pattern substantially as shown in figure 7. The thermogravimetric analysis (TGA) of form D is shown in fig. 8, where it is seen that form D loses 3.7% weight in the range of 30-130 ℃.
Example 5: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride form E
30Mg of the amorphous form obtained in example 4 was added to 200. Mu.L of isopropyl acetate, and the mixture was suspended at room temperature for 20 hours and filtered to obtain a white solid.
This form was designated form E.
The obtained samples were subjected to X-ray powder measurement using Cu-ka rays, and the spectra thereof had diffraction angles, interplanar spacings, and relative intensities as shown in Table 5:
TABLE 5 diffraction angle, interplanar spacing and relative intensity for form E
The error of the 2 theta diffraction angle is + -0.20 deg..
Still further, form E prepared in example 5 has an X-ray powder diffraction pattern substantially as shown in figure 9. The thermogravimetric analysis (TGA) of form E is shown in figure 10, where it is seen that form E loses 3.2% weight in the range of 30-130 ℃.
Example 6: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride crystalline form F
To 300mg of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine dihydrochloride form A was added 4mL of acetonitrile, suspended at 60℃for 20h, and filtered to give a white solid.
This form was designated form F.
The obtained samples were subjected to X-ray powder measurement using Cu-ka rays, and the spectra thereof had diffraction angles, interplanar spacings, and relative intensities as shown in Table 6:
TABLE 6 diffraction angle, interplanar spacing and relative intensity for form F
The error of the 2 theta diffraction angle is + -0.20 deg..
Further, form F prepared in example 6 has an X-ray powder diffraction pattern substantially as shown in figure 11. The thermogravimetric analysis (TGA) of form F is shown in figure 12, where it is seen that form F loses 0.4% weight in the range of 30-130 ℃.
Example 7: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride crystalline form G
30Mg of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride form A was dissolved in 60. Mu.L of methanol at room temperature, 1mL of methyl tert-butyl ether was slowly added dropwise, followed by stirring at room temperature for 60h, and filtration to give a white solid.
This form was designated form G.
The obtained samples were subjected to X-ray powder measurement using Cu-ka rays, and the spectra thereof had diffraction angles, interplanar spacings, and relative intensities as shown in Table 7:
TABLE 7 diffraction angle, interplanar spacing and relative intensity of form G
The error of the 2 theta diffraction angle is + -0.20 deg..
Still further, form G prepared in example 7 has an X-ray powder diffraction pattern substantially as shown in figure 13. The thermogravimetric analysis (TGA) of form G is shown in fig. 14, where form G is known to lose 2.9% weight in the range of 30-130 ℃.
Example 8: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride crystalline form H
To 100mg of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine dihydrochloride form A was added 400. Mu.L of methanol, heated to 50℃until the solid was completely dissolved, and then the solvent was dried by rotary evaporation to give a white solid.
This form was designated form H.
The obtained samples were subjected to X-ray powder measurement using Cu-ka rays, and the spectra thereof had diffraction angles, interplanar spacings, and relative intensities as shown in Table 8:
TABLE 8 diffraction angle, interplanar spacing and relative intensity for form H
The error of the 2 theta diffraction angle is + -0.20 deg..
Still further, form H prepared in example 8 has an X-ray powder diffraction pattern substantially as shown in figure 15. The thermogravimetric analysis (TGA) of form H is shown in fig. 16, where it is seen that form H loses 4.0% weight in the range of 30-130 ℃.
Example 9: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride crystalline form I
To 1.5g of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine dihydrochloride form A was added 25mL of ethanol, the solid was heated to 60℃to completely dissolve, and the solvent was then dried by rotary evaporation to give a white solid.
This form was designated form I.
The obtained samples were subjected to X-ray powder measurement using Cu-ka rays, and the spectra thereof had diffraction angles, interplanar spacings, and relative intensities as shown in Table 9:
TABLE 9 diffraction angle, interplanar spacing and relative intensity for form I
The error of the 2 theta diffraction angle is + -0.20 deg..
Further, form I prepared in example 9 has an X-ray powder diffraction pattern substantially as shown in figure 17. The thermogravimetric analysis (TGA) of form I is shown in figure 18, where it is seen that form I loses 1.4% weight in the range of 30-130 ℃.
Example 10: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride form J
30Mg of the amorphous form obtained in example 4 was added to 300. Mu.L of toluene, and the mixture was suspended at room temperature for 20 hours and filtered to obtain a white solid.
This form was designated form J.
The obtained samples were subjected to X-ray powder measurement using Cu-ka rays, and the spectra thereof had diffraction angles, interplanar spacings, and relative intensities as shown in Table 10:
TABLE 10 diffraction angle, interplanar spacing and relative intensity for form J
The error of the 2 theta diffraction angle is + -0.20 deg..
Further, form J prepared in example 10 has an X-ray powder diffraction pattern substantially as shown in figure 19. The thermogravimetric analysis (TGA) of form J is shown in figure 20, where form J is known to lose 13.1% weight in the range of 30-130 ℃.
Example 11: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride crystalline form K
30Mg of the crystalline form I obtained in example 9 was added to 400. Mu.L of ethyl acetate, and the mixture was suspended at room temperature for 20 hours and filtered to obtain a white solid.
This form was designated form K.
The obtained samples were subjected to X-ray powder measurement using Cu-ka rays, and the spectra thereof had diffraction angles, interplanar spacings, and relative intensities as shown in Table 11:
TABLE 11 diffraction angle, interplanar spacing and relative intensity for form K
The error of the 2 theta diffraction angle is + -0.20 deg..
Still further, form K prepared in example 11 has an X-ray powder diffraction pattern substantially as shown in figure 21. The thermogravimetric analysis (TGA) of form K is shown in figure 22, where form K is known to lose 2.3% weight in the range of 30-130 ℃.
Test example 1: stability investigation experiment
To examine the stability of each of the crystal forms prepared in the present invention, the crystal form a prepared in example 1, the crystal form B prepared in example 2 and the crystal form C prepared in example 3 were left for 20 days under three conditions of high temperature (60 ℃), high humidity (75% rh) and light (4500 lx±500 lx), respectively, sampled for 5 days, 20 days, tested for XRD and HPLC, and compared with the results of 0 days, and the results are shown in tables 12 to 14;
Form F samples prepared in example 6 were left for 30 days under three conditions of high temperature (60 ℃), high humidity (92.5% rh) and light (4500 lx±500 lx), sampled for 10 days, 30 days, tested for XRD and HPLC, and compared with the results for 0 days, as shown in table 15:
TABLE 12 factor of influence stability test data for form A
TABLE 13 factor influence stability test data for form B
TABLE 14 factor influence stability test data for form C
TABLE 15 stability test data on influencing factors for form F
As can be seen from tables 12 to 14 and fig. 23 to 25, form a remained stable in crystal morphology when left under three conditions of high temperature (60 ℃), high humidity (75% rh) and light irradiation for 20 days, and the purity did not significantly decrease, and form B was converted to form a when left under high humidity (75% rh); form C converts to form a under three conditions, high temperature (60 ℃), high humidity (75% rh) and light;
from Table 15 and FIG. 26, it is understood that form F was stable in crystal morphology without significant decrease in purity when left under three conditions of high temperature (60 ℃), high humidity (92.5% RH) and light irradiation for 30 days.
The experimental results show that the crystal form A and the crystal form F have better crystal form stability and chemical stability.
Test example 2: solubility test
The solubility of crystalline forms a-K was examined according to the solubility test method described in the fifteenth edition of chinese pharmacopoeia guide to the use, 2020, and the results are shown in table 16:
TABLE 16 solubility results for each of the crystalline forms of the application
The solubility test results show that the solubility of the crystal form A, B, C, D, E, F, G, H, I, J, K in pure water is greater than 300mg/mL, which indicates that various crystal forms disclosed by the invention are soluble crystal forms.
It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds of the present application and the process for preparing them without departing from the spirit or scope of the application, and thus the scope of the application encompasses numerous modifications and variations as come within the scope of the claims and their equivalents.

Claims (10)

1. A crystalline form a of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride, characterized in that the X-ray powder diffraction pattern of the crystalline form a is 6.32±0.2°, 14.30±0.2°, 16.44±0.2° at a 2Θ angle,
Characteristic peaks at 17.60+ -0.2 °, 18.50+ -0.2 °, 19.30+ -0.2 °, 21.46+ -0.2 ° and 23.68 + -0.2 °.
2. Form a of claim 1, wherein: the X-ray powder diffraction pattern of the crystal form A is 6.32+/-0.2 degrees, 13.14+/-0.2 degrees, 13.62+/-0.2 degrees, 14.30+/-0.2 degrees, 16.44+/-0.2 degrees, 16.78+/-0.2 degrees, 17.60+/-0.2 degrees, 19.30+/-0.2 degrees, and the angle of 2 theta,
19.96±0.2°、20.58±0.2°、21.46±0.2°、21.78±0.2°、22.46±0.2°、23.68±0.2°、24.14±0.2°、25.66±0.2°、
Characteristic peaks at 26.00.+ -. 0.2 °, 26.76.+ -. 0.2 °, 27.90.+ -. 0.2 ° and 29.44.+ -. 0.2 °.
3. Form a according to claim 1 or 2, characterized in that: the X-ray powder diffraction pattern of form a is substantially as shown in figure 1.
4. A process for the preparation of crystalline form a according to any one of claims 1 to 3, wherein ethyl acetate is added to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine until it is dissolved, and the solution of hydrogen chloride-ethyl acetate is slowly added dropwise at 0-20 ℃ and stirred thoroughly for 3-24 hours, filtered and dried to give crystalline form a.
5. A crystalline form B of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride, characterized by: the X-ray powder diffraction pattern of the crystal form B is 6.14+/-0.2 degrees, 14.48+/-0.2 degrees, 17.38+/-0.2 degrees, and the angle of 2 theta,
Characteristic peaks at 18.50.+ -. 0.2 °, 20.62.+ -. 0.2 °, 23.72.+ -. 0.2 °, 24.78.+ -. 0.2 ° and 29.40.+ -. 0.2 °.
6. Form B according to claim 5, characterized in that: the X-ray powder diffraction pattern of the crystal form B is 6.14+/-0.2 degrees, 10.68+/-0.2 degrees, 12.30+/-0.2 degrees, 13.60+/-0.2 degrees, 14.48+/-0.2 degrees, 15.58+/-0.2 degrees, 16.76+/-0.2 degrees, 17.38+/-0.2 degrees, and the angle of 2 theta,
Characteristic peaks at 18.50+ -0.2 °, 18.90+ -0.2 °, 20.62 + -0.2 °, 23.10+ -0.2 °, 23.72+ -0.2 °, 24.78+ -0.2 °, 26.30+ -0.2 °, 27.96 + -0.2 ° and 29.40+ -0.2 °.
7. Form B according to claim 5, characterized in that: the X-ray powder diffraction pattern of form B is substantially as shown in figure 3.
8. Use of a crystalline form of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine dihydrochloride according to any one of claims 1 to 3,5 to 7 for the preparation of a mu receptor agonist drug.
9. The use according to claim 8, wherein: the use is in the preparation of analgesic drugs.
10. Use according to claim 8 or 9, characterized in that: the use is in the manufacture of a medicament for moderate to severe pain.
CN202310102052.9A 2022-02-11 2023-01-30 New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound Active CN116589451B (en)

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