CN112028940A - Tenofovir phosphate crystal form and preparation and application thereof - Google Patents

Tenofovir phosphate crystal form and preparation and application thereof Download PDF

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CN112028940A
CN112028940A CN202010376938.9A CN202010376938A CN112028940A CN 112028940 A CN112028940 A CN 112028940A CN 202010376938 A CN202010376938 A CN 202010376938A CN 112028940 A CN112028940 A CN 112028940A
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propyl
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高中强
张登科
金伟丽
张海峰
郭维博
张艳侠
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Xi'an Xintong Pharmacy Research Co ltd
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Priority to CN202111001673.5A priority patent/CN113583048B/en
Priority to CN202111001802.0A priority patent/CN113583050B/en
Priority to CN202111001795.4A priority patent/CN113683641B/en
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Abstract

The invention provides a crystal form of tenofovir phosphate (9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxygen-1, 3, 2-diphosphinoxahexa-2-methoxy ] propyl ] adenine fumarate). The invention also provides a pharmaceutical composition comprising the crystal form and application thereof in preparing medicaments.

Description

Tenofovir phosphate crystal form and preparation and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a crystal form of (9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate and application thereof.
Background
The structure of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclic-2-methoxyl ] propyl ] adenine fumarate is shown as formula (I):
Figure BDA0002480316560000011
the compound is a tenofovir prodrug compound (HTS) in the prodrug compound disclosed in Chinese patent No. 200580018611.8, and can be used for treating or preventing liver diseases or metabolic diseases, including hepatitis B and the like.
Chinese patent No. 201310283713.9 discloses a crystal of tenofovir prodrug (HTS), and specifically describes a preparation method of crystal-I type crystal of succinate (9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-dioxaphosphorinane-2-methoxy ] propyl ] adenine succinate) of tenofovir prodrug.
The inventor efficiently prepares 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexacyclo-2-methoxy ] propyl ] adenine fumarate, and under the condition that whether fumarate of tenofovir prodrug can form new (mono) crystal form can not be expected, the existing solvents and mixed solvents which can be used for crystallization are more than astronomical numbers, however, the inventor does not contract, carries out long-term hard research and finds that 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexacyclo-2-methoxy ] propyl ] adenine fumarate is crystallized, the crystal distribution is very complex, polycrystal is often crystallized, single crystal is not easy to obtain, but the inventor finally unexpectedly and effectively crystallizes to obtain a series of crystals, and 5 different single crystals are preferably selected from the crystals, so that the stability is superior, and the production, the storage and the transportation are convenient and/or the safety of liver targeted therapy is improved.
Disclosure of Invention
The invention aims to provide a novel crystal form of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxygen-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate. In addition, the invention also provides a preparation method of the crystal form, a medicament containing the crystal form, application in treatment, a detection method and the like.
Specifically, in a first aspect, the present invention provides a crystal of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexacyclo-2-methoxy ] propyl ] adenine fumarate selected from one of crystal form a, crystal form b, crystal form c, crystal form d and crystal form e.
Wherein form a has an X-ray powder diffraction pattern substantially as shown in figure 1. In a particular embodiment of the invention, form a has an X-ray powder diffraction pattern at 2 θ (°, ± 0.2): diffraction peaks are arranged at 5.9 degrees, 12.1 degrees, 24.8 degrees and 31.2 degrees; in addition, the differential thermal analysis curve of the a-type crystal has a sharp endothermic peak at 151.7 ℃;
form b has an X-ray powder diffraction pattern substantially as shown in figure 2. In a particular embodiment of the invention, form b has an X-ray powder diffraction pattern at 2 Θ (°, ± 0.2): : diffraction peaks exist at 9.8 degrees, 10.4 degrees, 11.6 degrees, 12.5 degrees, 13.3 degrees, 15.2 degrees, 15.5 degrees, 16.9 degrees, 17.3 degrees, 19.5 degrees, 22.1 degrees, 23.3 degrees, 24.9 degrees and 31.2 degrees; in addition, the differential thermal analysis curve of the b-type crystal has a sharp endothermic peak at 152.3 ℃.
Form c has an X-ray powder diffraction pattern substantially as shown in figure 3. In a particular embodiment of the invention, form c has an X-ray powder diffraction pattern at 2 θ (°, ± 0.2): diffraction peaks exist at 9.7 degrees, 10.4 degrees, 11.6 degrees, 12.5 degrees, 13.3 degrees, 15.2 degrees, 16.8 degrees, 17.2 degrees, 19.5 degrees, 21.5 degrees, 22.1 degrees, 23.2 degrees, 24.8 degrees, 26.0 degrees and 31.1 degrees; in addition, the differential thermal analysis curve of the c-type crystal has a sharp endothermic peak at 152.6 ℃.
Form d has an X-ray powder diffraction pattern substantially as shown in figure 4. In a particular embodiment of the invention, form d has an X-ray powder diffraction pattern at 2 θ (°, ± 0.2): diffraction peaks exist at 9.9 degrees, 10.4 degrees, 12.6 degrees, 13.4 degrees, 13.8 degrees, 17.2 degrees, 18.3 degrees, 19.5 degrees, 20.2 degrees, 20.9 degrees, 22.0 degrees, 23.3 degrees and 25.1 degrees; in addition, the differential thermal analysis curve of the d-type crystal has a sharp endothermic peak at 149.2 ℃.
Form e has an X-ray powder diffraction pattern substantially as shown in figure 5. In a particular embodiment of the invention, form e has an X-ray powder diffraction pattern at 2 Θ (°, ± 0.2): diffraction peaks exist at 9.8 degrees, 10.5 degrees, 11.6 degrees, 12.6 degrees, 13.4 degrees, 13.9 degrees, 15.3 degrees, 17.4 degrees, 19.6 degrees, 21.0 degrees, 22.1 degrees, 23.4 degrees, 25.0 degrees and 26.2 degrees; in addition, the differential thermal analysis curve of the e-form crystal has a sharp endothermic peak at 151.4 ℃.
In this context, unless indicated to the contrary, the terms "crystal" and "crystalline form" are used interchangeably to refer to a solid in which the internal particles are periodically and repeatedly arranged in three dimensions; the terms "crystalline form"(s) "and" crystalline form "(s)" are used interchangeably to refer to a particular crystal in which it is specifically referred to. Preferably the crystal of the first aspect of the invention is a single crystal.
In the prior art, the variety of solvents used for crystallization is wide, the mixed solvents consisting of solvents of different types and proportions cannot be counted, the crystallization practice is basically still empirical, and the crystallized crystal form cannot be predicted according to the crystallization condition. The present inventors have studied 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexacyclo-2-methoxy ] propyl ] adenine fumarate for a long time and have found a solvent which can be used for crystallizing 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexacyclo-2-methoxy ] propyl ] adenine fumarate and a method for producing the same by taking advantage of some lucidity. Thus in a second aspect, the present invention provides a process for the preparation of the crystal of the first aspect of the invention.
For the crystal form a, the preparation method comprises the following steps: mixing 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate with methanol, heating to 60-70 ℃, dissolving, cooling to 20-25 ℃, collecting crystals and drying. Wherein, the 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxygen-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate can be amorphous, and can also be b crystal form, c crystal form, d crystal form or e crystal form.
For the b crystal form, the preparation method comprises the following steps: mixing 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexacyclo-2-methoxy ] propyl ] adenine fumarate with water and acetonitrile, heating to 65 ℃, dissolving, cooling to 20-25 ℃, collecting crystals and drying. Wherein, the 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxygen-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate can be amorphous, and can also be a crystal form or c crystal form.
For the crystal form c, the preparation method comprises the following steps: mixing and heating (9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate and tetrahydrofuran to 65 ℃, dissolving, cooling to 20-25 ℃, collecting crystals and drying, wherein the 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate can be amorphous, and can also be in a crystal form or an e crystal form.
For the crystal form d, the preparation method comprises the following steps: mixing (9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxy ] propyl ] adenine fumarate with water, heating to 80 ℃, dissolving, cooling to 20-25 ℃, collecting crystals and drying, wherein the 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxy ] propyl ] adenine fumarate can be amorphous or alpha crystal form.
For the e crystal form, the preparation method comprises the following steps: mixing (9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclo-2-methoxy ] propyl ] adenine fumarate with isopropanol, heating to 70 ℃, collecting crystals and drying, wherein the 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclo-2-methoxy ] propyl ] adenine fumarate can be amorphous, and can also be in a crystal form or c crystal form.
In a third aspect, the present invention provides a medicament for the treatment or prevention of a liver disease or metabolic disease, comprising, preferably consisting of, the crystal of the first aspect of the present invention and a pharmaceutically acceptable excipient. Herein, pharmaceutically acceptable excipients refer to nontoxic fillers, stabilizers, diluents, adjuvants or other formulation excipients. For example, diluents, excipients, such as water, physiological saline, microcrystalline cellulose, and the like; fillers, such as starch, sucrose, and the like; binders, such as starch, cellulose derivatives, alginates, gelatin and/or polyvinylpyrrolidone; humectants, such as glycerol; disintegrating agents, such as agar, calcium carbonate and/or sodium bicarbonate; absorption promoters, such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and/or bentonite clay; lubricants, such as talc, calcium/magnesium stearate, polyethylene glycol, and the like. In addition, the pharmaceutical composition of the invention can further contain other auxiliary materials, such as flavoring agents, sweetening agents and the like. The medicament of the third aspect of the present invention may further comprise other active ingredients for treating or preventing liver diseases or metabolic diseases.
Preferably in the medicament of the third aspect of the present invention, the pharmaceutically acceptable excipients include mannitol, pregelatinized starch, magnesium stearate and/or silicon dioxide.
According to the well-known technology in the field, the pharmaceutical composition can be prepared into various dosage forms according to the requirements of treatment purposes and administration routes, preferably the composition is in a unit administration dosage form, such as a freeze-dried preparation, a tablet, a capsule, powder, emulsion, a water injection or a spray, more preferably the pharmaceutical composition is in an injection dosage form (such as a freeze-dried powder injection) or an oral dosage form, and more preferably the pharmaceutical composition is in an oral dosage form (such as a tablet or a capsule). The medicaments may be administered by conventional routes, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules; or parenterally, for example in the form of injectable solutions or suspensions; or nasal use.
In a fourth aspect, the present invention provides the use of a crystal of the first aspect of the invention in the manufacture of a medicament for the treatment or prevention of a liver disease or a metabolic disease. The medicament of the present invention is administered in an effective dose, wherein the effective dose is usually in the amount of the crystal of the first aspect of the present invention. The effective dose may be the amount in a unit dosage form (e.g., a tablet, a needle, a pill, or a dose) of the drug, or may be a unit dose (e.g., a unit weight dose) of the patient for which treatment/prevention is desired. The pharmaceutical manufacturer can easily convert the unit weight dose of the patient to be treated/prevented into the content of the drug in the unit administration dosage form by the average weight of the patient population to be treated/prevented, for example, the average weight of the adult patient may be 60kg, and thus the content of the drug in the unit administration dosage form for the adult can be obtained by multiplying the average weight by the unit weight dose for the adult.
Preferably, the use of the fourth aspect of the invention is in the manufacture of a medicament for the treatment or prophylaxis of hepatitis b. Also preferred for use in the fourth aspect of the invention is the use in the manufacture of a medicament for reducing the level of hepatitis B virus in a patient.
In a fifth aspect, the present invention provides a method of detecting a crystal of the first aspect of the invention, characterised in that an X-ray powder diffraction pattern is determined for a suspected crystal and the X-ray powder diffraction pattern obtained is compared to an X-ray powder diffraction pattern as shown in figure 1 or 2 or 3 or 4 or 5. According to spectral line position (usually expressed in degrees of Bragg's 2 theta angle), line height, relative abundance and/or interplanar distance d (usually expressed in degrees of the Bragg's 2 theta angle) of the spectrum
Figure BDA0002480316560000051
Expression), etc., one skilled in the art can compare whether a suspected crystal is the crystal of the first aspect of the invention.
The invention has the beneficial effects that the crystal with excellent property of the 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxygen-1, 3, 2-diphosphono-hexacyclic-2-methoxyl ] propyl ] adenine fumarate is obtained, the crystal has good temperature and humidity stability and high purity, does not contain solvent and moisture, is more convenient for the adaptability of the preparation process and is also convenient for long-term storage.
For ease of understanding, the present invention incorporates by reference publications which are intended to more clearly describe the invention and which are incorporated herein by reference in their entirety as if fully set forth herein.
The invention will be described in detail below by means of specific embodiments and the accompanying drawings. It is to be expressly understood that the description is illustrative only and is not intended as a definition of the limits of the invention. Many variations and modifications of the present invention will be apparent to those skilled in the art in light of the teachings of this specification.
Drawings
FIG. 1: an X-ray powder diffraction pattern of the 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate a crystal form.
FIG. 2: an X-ray powder diffraction pattern of the 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate b crystal form.
FIG. 3: an X-ray powder diffraction pattern of the 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate c crystal form.
FIG. 4: an X-ray powder diffraction pattern of a crystal form d of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate.
FIG. 5: an X-ray powder diffraction pattern of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate e crystal form.
FIG. 6: DSC atlas of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclo-2-methoxy ] propyl ] adenine fumarate a crystal form
FIG. 7: DSC atlas of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclo-2-methoxy ] propyl ] adenine fumarate b crystal form
FIG. 8: DSC atlas of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclo-2-methoxy ] propyl ] adenine fumarate c crystal form
FIG. 9: DSC atlas of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclo-2-methoxy ] propyl ] adenine fumarate d crystal form
FIG. 10: DSC atlas of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclo-2-methoxy ] propyl ] adenine fumarate e crystal form
Detailed Description
The present invention will be explained in detail with reference to examples, which are only used to illustrate the technical solutions of the present invention, but the scope of the present invention is not limited thereto.
Test instrument for experiments
X-ray powder diffraction pattern
The instrument comprises the following steps: PHI-5400X-ray photoelectron analyzer (available from PE corporation, USA)
The test parameters are: voltage: 46kv, current: 40mA, copper k α radiation, λ:
Figure BDA0002480316560000072
thermogram for heat difference analysis (DSC)
The instrument comprises the following steps: SII Nano, EXSTAR, DSC6220
Temperature rise rate: 10 ℃/min
Temperature range: 50 to 250 DEG C
Carrier gas: high purity nitrogen gas
Example 1
Preparation of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphtho-2-methoxy ] propyl ] adenine fumarate
The method comprises the following specific steps:
Figure BDA0002480316560000071
Regent MW. feed amount mol Molar ratio of Remarks for note
Tenofovir 287 28.7g 0.1 1
Diols 186 18.6g 0.1 1
Oxalyl chloride 127 50.8g 0.4 4
DEF 101 10.9g 0.11 1.08
Titanium tetrachloride 189.7 19.0g 0.1 1
Triethylamine 100 42.0g 0.42 4.2
Dichloromethane 1 / 900mL / /
Methanol / 1000mL / /
Water (W) / 370mL / /
Acetone (II) / 200mL / /
Methyl tert-butyl ether / 510mL / /
Succinic acid 118.1 11.8g 0.1 1
Fumaric acid 116.1 11.6g 0.1 1
Adding 18.6g of glycol and 90mL of dichloromethane into a dry and clean 250mL reaction bottle, stirring and cooling to 0-5 ℃, starting to dropwise add 19.0g of titanium tetrachloride into the reaction system, dropwise adding 42.0g of triethylamine into the reaction solution, and recording the solution as reaction solution A.
Adding 370mL of dichloromethane into a 1.0L reaction bottle at normal temperature, starting stirring, adding 28.7g of tenofovir and 50.8g of DEF, dropwise adding 10.9g of oxalyl chloride at 10-25 ℃, starting heating until reflux is finished; carrying out reflux reaction for 2-3 h, stopping heating, cooling to below 10 ℃, and dropwise adding the reaction solution A to 1.0L of a reaction system; after the dropwise addition, the reaction was stirred for 1 hour.
Adding methanol and water into the reaction system, stirring for 5min, separating liquid, extracting the water phase with dichloromethane for 4 times, combining the organic phases, washing with saturated saline solution, separating liquid, and drying the organic phases with anhydrous magnesium sulfate; filtering, washing a filter cake with dichloromethane, and concentrating a filtrate under reduced pressure until no fraction is obtained; the concentrated solution is added with ethanol for dissolution, transferred to a 500mL reaction bottle, added with 32mL of acetic acid and heated and refluxed for 5-6 h. Concentrating under reduced pressure at 60-70 deg.C until no fraction is obtained, adding methanol and succinic acid, stirring and reacting for 1 hr; stirring, cooling, crystallizing, filtering, and blowing and drying a filter cake at 55-65 ℃ for 5 hours to obtain 30g of succinate.
Adding 300L of water into a reaction bottle, adding 30g of HTS succinate and 200mL of acetone, heating to 30-40 ℃ to dissolve, and extracting with methyl tert-butyl ether. Discarding an organic phase, and adjusting the pH of a water phase to 8-9 by using a saturated sodium bicarbonate solution; the aqueous phase was extracted with dichloromethane. The organic phases were combined and washed 1 time with saturated sodium chloride, the organic phase was dried over anhydrous magnesium sulfate, filtered and the filter cake was washed with dichloromethane. And concentrating the filtrate at 30-40 ℃ under reduced pressure until no fraction is obtained. About 18g of the oily substance was obtained, and after adding methanol to dissolve the oily substance, the oily substance was added to a reaction flask, about 11.6g of fumaric acid was added thereto with stirring, and the mixture was reacted at 30 ℃ or lower with stirring for 30 minutes. Stirring, cooling, crystallizing, filtering, and blowing and drying the filter cake at 55-65 ℃ for more than 10 hours. About 15g of white powder was obtained.
The nuclear magnetic data for this compound are as follows:
1H NMR(600MHz,DMSO):13.1～13.2(2H,s)，8.145(1H,s),8.082(1H,s),7.45(2H,m),7.395-7.403(2H,m),7.259(2H,s)7.216-7.233(1H,m),6.647(2H,s),5.633-5.648(1H,d),4.488-4.513(1H,m),4.29-4.297(1H,m),4.213-4.247(1H,m),4.042-4.062(1H,t),3.942-3.999(2H,m),2.051-2.055(2H,d),1.117-1.127(3H,d)。
example 2
Preparation and characterization of form a crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 5g of the white powder obtained in the example 1 into 25ml of methanol, heating to 60-70 ℃, stirring until the white powder is completely dissolved, then cooling to 20-25 ℃, finding out crystal precipitation, performing suction filtration, retaining the crystal, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed a-type single crystal as shown in FIGS. 1 and 6.
Example 3
Preparation and characterization of form a crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 3g of b-type crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclo-2-methoxy ] propyl ] adenine fumarate into 18ml of methanol, heating to 60-70 ℃, stirring until the b-type crystals are completely dissolved, cooling to 20-25 ℃, finding that crystals are separated out, carrying out suction filtration, retaining the crystals, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed a-type single crystal.
Example 4
Preparation and characterization of form a crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 2g of c-type crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclo-2-methoxy ] propyl ] adenine fumarate into 11ml of methanol, heating to 60-70 ℃, stirring until the c-type crystals are completely dissolved, cooling to 20-25 ℃, finding that crystals are separated out, carrying out suction filtration, retaining the crystals, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed a-type single crystal.
Example 5
Preparation and characterization of form a crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 2g of type d crystal of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate into 11ml of methanol, heating to 60-70 ℃, stirring until the D crystal is completely dissolved, cooling to 20-25 ℃, finding out crystal precipitation, carrying out suction filtration, retaining the crystal, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed a-type single crystal.
Example 6
Preparation and characterization of form a crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 2g of e-type crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclo-2-methoxy ] propyl ] adenine fumarate into 10ml of methanol, heating to 60-70 ℃, stirring until the crystals are completely dissolved, cooling to 20-25 ℃, finding that the crystals are separated out, carrying out suction filtration, retaining the crystals, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed a-type single crystal.
Example 7
Preparation and characterization of form b crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 5ml of water and 60ml of acetonitrile into 6g of the white powder obtained in the example 1, heating to 65 ℃ for dissolution, cooling to 20-25 ℃ to find that crystals are separated out, performing suction filtration, retaining the crystals, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed b-type single crystal as shown in FIGS. 2 and 7.
Example 8
Preparation and characterization of form b crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 3g of a type a crystal of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclo-2-methoxy ] propyl ] adenine fumarate into 2ml of water and 30ml of acetonitrile, heating to 65 ℃ for dissolution, cooling to 20-25 ℃ to find that a crystal is separated out, performing suction filtration, retaining the crystal, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed b-type single crystal.
Example 9
Preparation and characterization of form b crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 3g of c-type crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclo-2-methoxy ] propyl ] adenine fumarate into 2ml of water and 30ml of acetonitrile, heating to 65 ℃ for dissolution, cooling to 20-25 ℃ to find that crystals are separated out, performing suction filtration, retaining the crystals, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed b-type single crystal.
Example 10
Preparation and characterization of form c crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 35ml of tetrahydrofuran into 3g of the white powder obtained in the example 1, heating the white powder to a solvent of 65 ℃, cooling the white powder to 20-25 ℃, finding out crystal precipitation, performing suction filtration, retaining the crystal, and then directly drying the crystal in a drying oven of 55 ℃. X-ray powder diffraction and DSC detection showed c-type single crystal as shown in FIGS. 3 and 8.
Example 11
Preparation and characterization of form c crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 30ml of tetrahydrofuran into 3g of a type a crystal of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate, heating to a solvent at 65 ℃, cooling to 20-25 ℃ to find that crystals precipitate, performing suction filtration, retaining the crystals, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed c-type single crystal.
Example 12
Preparation and characterization of form c crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 2g of b-type crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclo-2-methoxy ] propyl ] adenine fumarate into 22ml of tetrahydrofuran, heating to a solvent at 65 ℃, cooling to 20-25 ℃ to find that crystals precipitate, performing suction filtration, retaining the crystals, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed c-type single crystal.
Example 13
Preparation and characterization of form c crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 18ml of tetrahydrofuran into 2g of d-type crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate, heating to a solvent at 65 ℃, cooling to 20-25 ℃ to find that crystals precipitate, performing suction filtration, retaining the crystals, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed c-type single crystal.
Example 14
Preparation and characterization of form d crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 30ml of water into 3g of the white powder obtained in the example 1, heating to 80 ℃ for dissolving, cooling to 20-25 ℃ to find crystals separated out, performing suction filtration, retaining the crystals, and then directly drying in a 55 ℃ oven. X-ray powder diffraction and DSC detection showed d-type single crystal as shown in FIGS. 4 and 9.
Example 15
Preparation and characterization of form d crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 5g of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate a-type crystal into 40ml of water, heating to 80 ℃ for dissolving, cooling to 20-25 ℃ to find that crystal is separated out, performing suction filtration, retaining the crystal, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed d-type single crystal.
Example 16
Preparation and characterization of form d crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexanaphthacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 2g of b-type crystal of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphinohetero-hexacyclic-2-methoxyl ] propyl ] adenine fumarate into 22ml of water, heating to 80 ℃ for dissolving, cooling to 20-25 ℃ to find that crystals precipitate, performing suction filtration, retaining the crystals, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed d-type single crystal.
Example 17
Preparation and characterization of form e crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 3g of the white powder obtained in the example 1 into 30ml of isopropanol, heating to 70 ℃ of solvent, cooling to 20-25 ℃ to find crystals separated out, performing suction filtration, retaining the crystals, and then directly drying in a 55 ℃ oven. X-ray powder diffraction and DSC detection showed e-type single crystal as shown in FIGS. 5 and 10.
Example 18
Preparation and characterization of form e crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 5g of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclic-2-methoxyl ] propyl ] adenine fumarate a-type crystal into 45ml of isopropanol, heating to a solvent at 70 ℃, cooling to 20-25 ℃ to find that crystals precipitate, performing suction filtration, retaining the crystals, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed e-type single crystal.
Example 19
Preparation and characterization of form e crystals of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphonohexacyclo-2-methoxy ] propyl ] adenine fumarate
Adding 3g of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorphenyl) -2-oxo-1, 3, 2-diphosphono-hexacyclic-2-methoxyl ] propyl ] adenine fumarate c-type crystal into 35ml of isopropanol, heating to a solvent at 70 ℃, cooling to 20-25 ℃ to find that crystals precipitate, performing suction filtration, retaining the crystals, and then directly drying in an oven at 55 ℃. X-ray powder diffraction and DSC detection showed e-type single crystal.
Example 20
Stability of a-type crystals
This example describes the stability test of the crystalline form a crystal of the present invention.
The stability test of the a-type crystal was conducted under three conditions of high temperature, high humidity, and light, and the results are shown in the following table (table 1), which indicates that the crystal of the present invention is stable under high temperature, high humidity, and light conditions.
TABLE 1 stability test results for type a crystals (high temperature, high humidity, light exposure)
Figure BDA0002480316560000131
Figure BDA0002480316560000141
The results of the stability test at 40 ℃ over 6 months are shown in the following table (table 2), which indicates that the crystals of the present invention have good stability and are suitable for long-term storage.
Stability test at 240 ℃ over 6 months
Sample 1 Total impurities Impurity A Impurity B Impurity C Impurity D
0 month 1.82 0.71 0.45 0.29 0.11
3 month 1.89 0.70 0.44 0.28 0.13
6 month 1.98 0.74 0.42 0.27 0.10
Example 21
Stability of b-type crystals
This example describes the stability test of the crystalline form b crystal of the present invention.
The stability test of the b-type crystal was conducted under three conditions of high temperature, high humidity and light, and the results are shown in the following table (table 3), which indicates that the crystal of the present invention is stable under high temperature, high humidity and light conditions.
TABLE 3 stability test results of b-type crystals (high temperature, high humidity, light irradiation)
Figure BDA0002480316560000142
Figure BDA0002480316560000151
The results of the stability test at 40 ℃ over 6 months are shown in the following table (table 4), which indicates that the crystals of the present invention have good stability and are suitable for long-term storage.
Stability test at 440 ℃ over 6 months
Sample 1 Total impurities Impurity A Impurity B Impurity C Impurity D
0 month 1.82 0.71 0.45 0.29 0.11
3 month 1.91 0.72 0.44 0.29 0.13
6 month 1.99 0.74 0.43 0.27 0.11
Example 22
Stability of c-type crystals
This example describes stability experiments for crystalline form c crystals of the present invention.
The stability test of the c-type crystal was conducted under three conditions of high temperature, high humidity and light, and the results are shown in the following table (table 5), which indicates that the crystal of the present invention is stable under high temperature, high humidity and light conditions.
TABLE 5 stability test results for type c crystals (high temperature, high humidity, light exposure)
Figure BDA0002480316560000152
Figure BDA0002480316560000161
The results of the stability test at 40 ℃ over 6 months are shown in the following table (table 6), which indicates that the crystals of the present invention have good stability and are suitable for long-term storage.
TABLE 6-month stability test at 640 deg.C
Sample 1 Total impurities Impurity A Impurity B Impurity C Impurity D
0 month 1.82 0.71 0.45 0.29 0.11
3 month 1.91 0.73 0.44 0.29 0.12
6 month 1.99 0.74 0.45 0.30 0.11
Example 23
Stability of d-type crystals
This example describes the stability test of crystalline form d crystals of the present invention.
The stability test of the d-type crystal was conducted under three conditions of high temperature, high humidity and light, and the results are shown in the following table (table 7), which indicates that the crystal of the present invention is stable under high temperature, high humidity and light conditions.
TABLE 7 stability test results for d-type crystals (high temperature, high humidity, light exposure)
Figure BDA0002480316560000162
Figure BDA0002480316560000171
The results of the stability test at 40 ℃ over 6 months are shown in the following table (Table 8), which indicates that the crystals of the present invention are excellent in stability and suitable for long-term storage.
Table stability test at 840 ℃ over 6 months
Sample 1 Total impurities Impurity A Impurity B Impurity C Impurity D
0 month 1.82 0.71 0.45 0.29 0.11
3 month 1.89 0.72 0.44 0.29 0.12
6 month 1.98 0.73 0.43 0.28 0.10
Example 24
Stability of e-type crystals
This example describes stability experiments for crystalline form e crystals of the present invention.
The stability test of the e-type crystal was conducted under three conditions of high temperature, high humidity and light, and the results are shown in the following table (table 9), which indicates that the crystal of the present invention is stable under high temperature, high humidity and light conditions.
TABLE 9 stability test results for form e crystals (high temperature, high humidity, light exposure)
Figure BDA0002480316560000172
The results of the stability test for 6 months at 40 ℃ are shown in the following table (Table 10), which indicates that the crystals of the present invention are excellent in stability and suitable for long-term storage.
TABLE 1040 deg.C stability test over 6 months
Sample 1 Total impurities Impurity A Impurity B Impurity C Impurity D
0 month 1.82 0.71 0.45 0.29 0.11
3 month 1.90 0.72 0.47 0.32 0.11
6 month 1.99 0.72 0.46 0.34 0.10
Example 25
Pharmaceutical composition comprising a-type crystal of the present invention
According to the formulation of table 11, the a-type crystals of the present invention were mixed with silicon dioxide, sieved, added with mannitol and pregelatinized starch, mixed well, added with magnesium stearate, and tableted and coated to prepare tablets.
TABLE 11 crystalline tablet formulation of type a
Figure BDA0002480316560000181
Example 26
Pharmaceutical composition comprising b-type crystal of the present invention
According to the formulation of table 12, the b-type crystal of the present invention was mixed with silicon dioxide, sieved, added with mannitol and pregelatinized starch, mixed well, added with magnesium stearate, and tableted and coated to prepare tablets.
TABLE 12 b Crystal tablet formulation
Figure BDA0002480316560000182
Figure BDA0002480316560000191
Example 27
Pharmaceutical composition comprising c-type crystal of the present invention
According to the formulation of table 13, the c-type crystals of the present invention were mixed with silicon dioxide, sieved, added with mannitol and pregelatinized starch, mixed well, added with magnesium stearate, and tableted and coated to prepare tablets.
TABLE 13C type Crystal tablet formulation
Figure BDA0002480316560000192
Example 28
Pharmaceutical composition comprising d-form crystal of the present invention
According to the formulation of table 14, the d-form crystals of the present invention were mixed with silicon dioxide, sieved, added with mannitol and pregelatinized starch, mixed well, added with magnesium stearate, and tableted and coated to prepare tablets.
TABLE 14 d Crystal tablet formulation
Figure BDA0002480316560000193
Figure BDA0002480316560000201
Example 29
Pharmaceutical composition comprising e-form crystal of the present invention
According to the formulation of table 15, the e-form crystals of the present invention were mixed with silicon dioxide, sieved, then added with mannitol and pregelatinized starch, mixed well, then added with magnesium stearate, tableted, and coated to make tablets.
TABLE 15E type Crystal tablet formulation
Figure BDA0002480316560000202

Claims (10)

  1. A crystal of 9- [ (2R) -2- [ (2R,4S) -4- (3-chlorophenyl) -2-oxo-1, 3, 2-diphosphinoheteroahcyclohex-2-methoxy ] propyl ] adenine fumarate characterized as having an X-ray powder diffraction pattern substantially as shown in figure 1, 2, 3, 4 or 5.
  2. 2. The crystal of claim 1 having a differential thermal analysis curve with a sharp endothermic peak at 151.7 ℃, 152.3 ℃, 152.6 ℃, 149.2 ℃ or 151.4 ℃.
  3. 3. The crystal of claim 1, which is a single crystal.
  4. 4. A medicament for treating or preventing liver diseases or metabolic diseases, which comprises the crystal of any one of claims 1 to 3 and a pharmaceutically acceptable excipient.
  5. 5. The medicament of claim 4, which is an oral dosage form, preferably a tablet.
  6. 6. The medicament of claim 4, wherein the pharmaceutically acceptable excipients comprise mannitol, pregelatinized starch, magnesium stearate and/or silicon dioxide.
  7. 7. Use of the crystal of any one of claims 1-3 in the manufacture of a medicament for treating or preventing a liver disease or a metabolic disease.
  8. 8. The use according to claim 7 in the manufacture of a medicament for the treatment or prophylaxis of hepatitis B.
  9. 9. The use of claim 7 in the manufacture of a medicament for reducing the level of hepatitis B virus in a patient.
  10. 10. A method of detecting crystals as claimed in any of claims 1 to 3, characterized in that the suspected crystals are subjected to an X-ray powder diffraction detection and the resulting X-ray powder diffraction pattern is compared with an X-ray powder diffraction pattern as shown in one of the figures 1 to 5.
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CN103333209A (en) * 2013-07-05 2013-10-02 西安新通药物研究有限公司 Novel crystal of tenofovir prodrug
CN104710477A (en) * 2013-12-16 2015-06-17 安徽贝克联合制药有限公司 Tenofovir cyclic phosphonate compound and pharmaceutically acceptable salt thereof, and preparation methods and applications thereof
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