CN110452268A - A kind of preparation method of third phenol tenofovir, half fumaric acid monocrystalline - Google Patents
A kind of preparation method of third phenol tenofovir, half fumaric acid monocrystalline Download PDFInfo
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- CN110452268A CN110452268A CN201910771531.3A CN201910771531A CN110452268A CN 110452268 A CN110452268 A CN 110452268A CN 201910771531 A CN201910771531 A CN 201910771531A CN 110452268 A CN110452268 A CN 110452268A
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- tenofovir
- phenol
- fumaric acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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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
Abstract
The invention discloses a kind of preparation methods of half fumaric acid monocrystalline of third phenol tenofovir, comprising the following steps: (1) takes half fumaric acid of the third phenol tenofovir to be dissolved in acetonitrile and obtain mixed solution；(2) it draws a certain amount of mixed solution to be placed in glass container after filtering, normal heptane is slowly added into glass container；(3) glass container is placed in far from vibration source and avoids the place of illumination, incubated at room temperature 12h-48h obtains colorless and transparent monocrystalline.Using preparation method provided by the invention, it is fast to prepare speed；Obtained single-crystal fault is few；Reproducibility is good.
Description
Technical field
The invention belongs to drug crystal forms fields, and in particular to a kind of preparation side of half fumaric acid monocrystalline of third phenol tenofovir
Method.
Technical background
Third phenol tenofovir, half fumaric acid (Tenofovir alafenamide fumarate, TAF) is also known as fumaric acid phosphorus
Third tenofovir, tenofovir Chinese mugwort draw phenol amine, are that a kind of of Gilead company exploitation treats chronic hepatitis B (HBV) patient's generation
The drug of repaying property hepatopathy, the drug are approved to list in the U.S. on November 10th, 2016, list at home in November, 2018, TAF
It is the prodrug of tenofovir (PMPA), in the clinical phase, TAF is just shown with its drug effect for decupling tenofovir disoproxil (TDF)
Its very high antiviral activity has no drug resistance, while can reduce the toxic side effect to kidney and bone, has following knot
Structure formula:
So-called monocrystalline (monocrystal, monocrystalline, single crystal), i.e. particle inside crystalline solid
It is in regularly, is periodically arranged in three-dimensional space, the entirety of crystal is on three-dimensional by the same space grid in other words
It constitutes, particle is arranged as long-range order in space in entire crystal.Single crystal X-ray diffraction is to be spread out using monocrystalline to X-ray
Effect is penetrated to measure the experimental method of crystal structure, it can determine crystals atom (molecule, ion) spatial arrangement and
Structural symmetry measures interatomic bond distance, bond angle, distribution of charges, inquires into the microstructure and macro property of various compounds
Relationship, for unknown material, single crystal structure determination is most authoritative identification of means, thus be widely used in chemistry, biology, doctor
The fields such as, material and geology.
Third phenol tenofovir, half fumaric acid is free of halogenated atom since the alkyl chain carbon atom of its molecular structure is more,
This compound monocrystal with hand-type central carbon atom is obtained for those skilled in the art with certain difficulty, but
It is that half fumaric acid monocrystalline of the third phenol tenofovir has very important meaning for the research of compound crystal form and absolute configuration.
Chinese patent CN108546274A reports a kind of preparation method of half fumaric acid monocrystalline of third phenol tenofovir, passes through
A kind of half fumaric acid monocrystalline of third phenol tenofovir is prepared in volatility process (slow solvent flashing), which is rhombic system, empty
Between group are as follows: P212121, cell parameter are as follows: a=18.2550(2), b=18.2550(2), c=35.4219(7), but the monocrystalline
Preparation method there are many defects: 1) evaporation rate of solvent is not easily controlled, and the reproducibility of single crystal cultivation is bad；2)
The monocrystalline crystal defect arrived is more.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of half fumaric acid monocrystalline of third phenol tenofovir, and this method can
Overcome the shortcomings of existing preparation method, preparation speed is fast, and obtained single-crystal fault is few, and reproducibility is good.
A kind of method of third phenol tenofovir, half fumaric acid monocrystalline provided by the invention, specifically includes the following steps:
(1) it takes half fumaric acid of the third phenol tenofovir to be dissolved in acetonitrile and is configured to mixed solution.
(2) it draws a certain amount of mixed solution to be placed in glass container after filtering, be slowly added dropwise just into glass container
Heptane forms the interface being obviously layered.
(3) glass container is placed in far from vibration source to and is avoided the place of illumination, incubated at room temperature 12h-48h obtains colorless and transparent
Monocrystalline.
Further, the mass ratio of the additional amount of the acetonitrile and half fumaric acid of the third phenol tenofovir is 40:1-120:1.
Further, the mass ratio of the additional amount of the acetonitrile and half fumaric acid of the third phenol tenofovir is 80:1.
Further, the volume ratio of mixed solution is 1:1-3:1 in the additional amount of the normal heptane and glass container.
Further, the volume ratio of mixed solution is 1:1 in the additional amount of the normal heptane and glass container.
Further, the monocrystalline space group are as follows: P4 (2) 2 (1) 2, cell parameter are as follows: a=18.0819 (2), b=
18.0819 (2), c=17.5155 (5), α=90 °, β=90 °, γ=90 °；Molecular number is 4 in structure cell, and unit cell volume is
5726.8(2) Å3。
The present invention provides a kind of preparation methods of half fumaric acid monocrystalline of third phenol tenofovir, using preparation side of the invention
The advantages of method, is: (1) it is fast to prepare speed；(2) single-crystal fault made from is few；(3) reproducibility is good；Monocrystalline obtained is conducive to
The structural identification of third phenol tenofovir hemifumarate.
Detailed description of the invention
Attached drawing 1 is half fumaric acid monocrystalline theoretical modeling PXRD of the third phenol tenofovir produced by the present invention figure；
Attached drawing 2 is half fumaric acid monocrystalline molecular structure mallet figure of the third phenol tenofovir produced by the present invention.
Specific embodiment
Embodiment 1
It weighs a certain amount of third phenol tenofovir, half fumaric acid to be added in 250ml single port bottle, acetonitrile, the wherein addition of acetonitrile is added
Amount and the mass ratio of half fumaric acid of the third phenol tenofovir are 80:1, and being heated to 40-50 DEG C makes it sufficiently dissolve to obtain mixed solution, uses
Syringe draws 10ml mixed solution, is transferred in glass tube through filter, is slowly added to 10ml positive heptan to the upper layer of glass tube solution
Alkane, forms apparent upper layer and lower layer, and glass container is placed in far from vibration source and avoids the place of illumination, room by preservative film sealing
The lower culture of temperature for 24 hours colorless and transparent monocrystalline.Structure elucidation is carried out to resulting monocrystalline.
Using Brooker D8 Venture X-ray single crystal diffractometer, Cu-K radiation, λ=1.54, time for exposure 10
S, surface detector to sample distance are 40 mm, and test temperature is 100 (2) K, and detector is CMOS surface detector, and resolution ratio is
0.8, pipe pressure is 50kV, Guan Liuwei 1.2A.
After carrying out integral reduction to diffraction data using SAINT program, experience suction is carried out to data using SADABS program
Receive correction；Mono-crystalline structures are parsed by direct method using SHELXT2014, and refine, hydrogen are carried out to structure using least square method
Atom reconditioning process takes isotropism calculation processing to obtain, and the upper hydrogen atom of N is obtained by Residual electron density, and the upper hydrogen of C-H is former
Son adds hydrogen to obtain by calculating, and striding type model is taken to handle its refine.
Testing result data are as follows:
Embodiment 2
It weighs a certain amount of third phenol tenofovir, half fumaric acid to be added in 250ml single port bottle, acetonitrile, the wherein addition of acetonitrile is added
Amount and the mass ratio of half fumaric acid of the third phenol tenofovir are 40:1, and being heated to 50-60 DEG C makes it sufficiently dissolve to obtain mixed solution, uses
Syringe draws 10ml mixed solution, is transferred in glass tube through filter, is slowly added to 10ml positive heptan to the upper layer of glass tube solution
Alkane, forms apparent upper layer and lower layer, and glass container is placed in far from vibration source and avoids the place of illumination, room by preservative film sealing
The lower culture 12h of temperature obtains colorless and transparent monocrystalline.
Embodiment 3
It weighs a certain amount of third phenol tenofovir, half fumaric acid to be added in 250ml single port bottle, acetonitrile, the wherein addition of acetonitrile is added
Amount and the mass ratio of half fumaric acid of the third phenol tenofovir are 80:1, and being heated to 40-50 DEG C makes it sufficiently dissolve to obtain mixed solution, uses
Syringe draws 10ml mixed solution, is transferred in glass tube through filter, is slowly added to 15ml positive heptan to the upper layer of glass tube solution
Alkane, forms apparent upper layer and lower layer, and glass container is placed in far from vibration source and avoids the place of illumination, room by preservative film sealing
The lower culture 30h of temperature obtains colorless and transparent monocrystalline.
Embodiment 4
It weighs a certain amount of third phenol tenofovir, half fumaric acid to be added in 250ml single port bottle, acetonitrile, the wherein addition of acetonitrile is added
Amount and the mass ratio of half fumaric acid of the third phenol tenofovir are 120:1, and being heated to 40-50 DEG C makes it sufficiently dissolve to obtain mixed solution,
10ml mixed solution is drawn with syringe, is transferred in glass tube through filter, is being slowly added to 30ml just to the upper layer of glass tube solution
Heptane forms apparent upper layer and lower layer, and glass container is placed in far from vibration source and is avoided the place of illumination by preservative film sealing,
Culture 40h obtains colorless and transparent monocrystalline at room temperature.
Comparative example 1
It weighs a certain amount of third phenol tenofovir, half fumaric acid to be added in 250ml single port bottle, acetonitrile, the wherein addition of acetonitrile is added
Amount and the mass ratio of half fumaric acid of the third phenol tenofovir are 80:1, and being heated to 40-50 DEG C makes it sufficiently dissolve to obtain mixed solution, uses
Syringe draws 10ml mixed solution, is transferred in glass tube through filter, is slowly added to 10ml toluene to the upper layer of glass tube solution,
Apparent upper layer and lower layer are formed, glass container is placed in far from vibration source and avoids the place of illumination, at room temperature by preservative film sealing
Culture 72h obtains white powder precipitating, cannot obtain monocrystalline.
Comparative example 2
It weighs a certain amount of third phenol tenofovir, half fumaric acid to be added in 250ml single port bottle, acetonitrile, the wherein addition of acetonitrile is added
Amount and the mass ratio of half fumaric acid of the third phenol tenofovir are 80:1, and being heated to 40-50 DEG C makes it sufficiently dissolve to obtain mixed solution, uses
Syringe draws 10ml mixed solution, is transferred in glass tube through filter, is slowly added to 10ml dichloro to the upper layer of glass tube solution
Methane forms apparent upper layer and lower layer, and glass container is placed in far from vibration source and is avoided the place of illumination by preservative film sealing,
Culture 72h obtains white powder precipitating at room temperature, cannot obtain monocrystalline.
Comparative example 3
It weighs a certain amount of third phenol tenofovir, half fumaric acid to be added in 250ml single port bottle, isopropyl acetate is added, wherein acetic acid
The mass ratio of the additional amount of isopropyl ester and half fumaric acid of the third phenol tenofovir is 80:1, and being heated to 40-50 DEG C dissolves it sufficiently
Mixed solution is obtained, 10ml mixed solution is drawn with syringe, is transferred in glass tube through filter, it is slow to the upper layer of glass tube solution
10ml normal heptane is added, forms apparent upper layer and lower layer, glass container is placed in far from vibration source and avoids light by preservative film sealing
According to place, at room temperature cultivate 72h obtain white powder precipitating, monocrystalline cannot be obtained.
Claims (6)
1. a kind of preparation method of half fumaric acid monocrystalline of third phenol tenofovir, which is characterized in that the method specifically includes following
Step:
(1) it takes half fumaric acid of the third phenol tenofovir to be dissolved in acetonitrile and obtains mixed solution；
(2) it draws a certain amount of mixed solution to be placed in glass container after filtering, normal heptane is slowly added into glass container；
(3) glass container is placed in far from vibration source and avoids the place of illumination, incubated at room temperature 12h-48h obtains colorless and transparent list
It is brilliant.
2. preparation method according to claim 1, which is characterized in that the additional amount of the acetonitrile and the third phenol tenofovir half
The mass ratio of fumaric acid is 40:1-120:1.
3. preparation method according to claim 2, which is characterized in that the additional amount of the acetonitrile and the third phenol tenofovir half
The mass ratio of fumaric acid is 80:1.
4. preparation method according to claim 1, which is characterized in that mixed in the additional amount and glass container of the normal heptane
The volume ratio for closing solution is 1:1-3:1.
5. the preparation method according to claim 4, which is characterized in that mixed in the additional amount and glass container of the normal heptane
The volume ratio for closing solution is 1:1.
6. described in any item preparation methods according to claim 1 ~ 5, which is characterized in that the monocrystalline space group are as follows: P4 (2) 2
(1) 2, cell parameter are as follows: a=18.0819 (2)；b=18.0819(2) Å；c=17.5155(5) Å；α=90°；β=90°；γ=
90 °, molecular number is 4 in structure cell, and unit cell volume is 5726.8 (2)3。
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103732594A (en) * | 2011-08-16 | 2014-04-16 | 吉联亚科学公司 | Tenofovir alafenamide hemifumarate |
| CN104558036A (en) * | 2014-12-11 | 2015-04-29 | 杭州和泽医药科技有限公司 | Tenofovir alafenamide hemi-fumarate crystal form and preparation method thereof |
| CN105237571A (en) * | 2014-11-28 | 2016-01-13 | 成都苑东药业有限公司 | Salt of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl) ethyl] amino] phenoxy-phosphinyl] methoxyl] propyl] adenine |
| WO2017037608A1 (en) * | 2015-08-28 | 2017-03-09 | Laurus Labs Private Limited | Solid forms of tenofovir alafenamide and salts thereof, processes for its preparation and pharmaceutical compositions thereof |
| CN107226826A (en) * | 2016-03-25 | 2017-10-03 | 江苏奥赛康药业股份有限公司 | Tenofovir Chinese mugwort draws phenol amine fumarate compound and its pharmaceutical composition |
| CN108546274A (en) * | 2018-06-29 | 2018-09-18 | 成都倍特药业有限公司 | A kind of tenofovir Chinese mugwort draws the preparation method of phenol amine hemifumarate |
| CN108794530A (en) * | 2017-04-26 | 2018-11-13 | 上海医药工业研究院 | A kind of the third phenol of tenofovir amidic-salt crystal form and its preparation method and application |
-
2019
- 2019-08-21 CN CN201910771531.3A patent/CN110452268A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103732594A (en) * | 2011-08-16 | 2014-04-16 | 吉联亚科学公司 | Tenofovir alafenamide hemifumarate |
| CN105237571A (en) * | 2014-11-28 | 2016-01-13 | 成都苑东药业有限公司 | Salt of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl) ethyl] amino] phenoxy-phosphinyl] methoxyl] propyl] adenine |
| CN104558036A (en) * | 2014-12-11 | 2015-04-29 | 杭州和泽医药科技有限公司 | Tenofovir alafenamide hemi-fumarate crystal form and preparation method thereof |
| WO2017037608A1 (en) * | 2015-08-28 | 2017-03-09 | Laurus Labs Private Limited | Solid forms of tenofovir alafenamide and salts thereof, processes for its preparation and pharmaceutical compositions thereof |
| CN107226826A (en) * | 2016-03-25 | 2017-10-03 | 江苏奥赛康药业股份有限公司 | Tenofovir Chinese mugwort draws phenol amine fumarate compound and its pharmaceutical composition |
| CN108794530A (en) * | 2017-04-26 | 2018-11-13 | 上海医药工业研究院 | A kind of the third phenol of tenofovir amidic-salt crystal form and its preparation method and application |
| CN108546274A (en) * | 2018-06-29 | 2018-09-18 | 成都倍特药业有限公司 | A kind of tenofovir Chinese mugwort draws the preparation method of phenol amine hemifumarate |
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Application publication date: 20191115 |