CN103483385B - New crystal of tenofovir monoester fumarate and preparation method thereof - Google Patents
New crystal of tenofovir monoester fumarate and preparation method thereof Download PDFInfo
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- CN103483385B CN103483385B CN201310472450.6A CN201310472450A CN103483385B CN 103483385 B CN103483385 B CN 103483385B CN 201310472450 A CN201310472450 A CN 201310472450A CN 103483385 B CN103483385 B CN 103483385B
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Abstract
New crystal that the present invention relates to tenofovir monoester fumarate and preparation method thereof, the crystal formation of fumaric acid Tenofovir adopts fumaric acid Tenofovir to be dissolved in ethyl acetate, and at a certain temperature, slowly add isopropyl ether, crystallization obtains.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, relate to a kind of crystal formation of fumaric acid Tenofovir, also relate to the preparation method of fumaric acid Tenofovir crystal formation.
Background technology
Tenofovir disoproxil is a kind of new oral broad-spectrum antiviral drug, by suppressing viral dna polymerase and cryotron transcriptase, suppress the Transcription and replication of virus, there is stronger restraining effect to hepatitis B virus and hiv virus etc., also have stronger restraining effect to the hepatitis B virus of lamivudine resistance.Also do not find the variant to tenofovir disoproxil resistance at present, this feature has very large clinical value.
Tenofovir disoproxil can be converted into tynofovir rapidly in vivo, plays antiviral curative effect.But tenofovir disoproxil is due to its physics and chemistry poor stability, easily to be hydrolyzed, take off an esterified group to generate Tenofovir or take off two esterified groups generation tynofovirs, drug quality is changed, reduce its oral administration biaavailability, need to carry out content monitoring to Tenofovir and tynofovir for this reason in its pharmaceutical preparation or its bulk drug.Therefore, prepare the reference substance of highly purified Tenofovir as monitoring and detection, the content of monitoring Tenofovir, very important to Drug's control.
So far, the relevant report of existing Tenofovir synthesis.Wherein all describe in patent specification 102491995.A and patent specification 102040626.A and obtain Tenofovir by tynofovir Ester hydrolysis; Patent specification 200610056926.8 describes and synthesizes corresponding Tenofovir by tynofovir and ester group in addition, and on this basis, synthesize the mixture of the various salt of Tenofovir, but different from the ester group of usually said tenofovir disoproxil in its various ester group.
Tenofovir has above relevant report, and fumaric acid Tenofovir sees relevant report so far not yet.
The present invention utilizes the side reaction in tynofovir synthesis tenofovir disoproxil process, and extract compound Tenofovir, further purification just can obtain highly purified Tenofovir, and does not affect the object of original synthesis tenofovir disoproxil.In addition, the present invention has also synthesized the salt the same with the tenofovir disoproxil on market and fumaric acid Tenofovir further, and after salify, comparatively monoesters has better stability.Fumaric acid Tenofovir bitter taste is lower than tenofovir disoproxil fumarate simultaneously, is more suitable for children and orally uses.
Further, the present invention also finds a kind of crystal formation of fumaric acid Tenofovir, than unformed fumaric acid Tenofovir, there is more satisfactory stability.
Summary of the invention
The object of this invention is to provide a kind of fumaric acid Tenofovir, structure is as shown in the formula 1:
Another object of the present invention is to provide crystal formation of a kind of fumaric acid Tenofovir and preparation method thereof.
Fumaric acid Tenofovir of the present invention, preparation method is as follows:
Route is described below particularly:
Tynofovir reacts with chloromethyl propylene carbonate under the effect of acid binding agent triethylamine, control temperature of reaction and time, generate tenofovir disoproxil and its intermediate state Tenofovir (only having an ester group to be connected), according to the two different solubility and being separated in water, aqueous phase is purified further just can obtain highly purified Tenofovir, and organic phase obtains corresponding tenofovir disoproxil; The two reacts to fumaric acid respectively and just can obtain the desirable corresponding product of purity, and one is the tenofovir disoproxil fumarate on market, and another one is formula 1 fumaric acid Tenofovir of the present invention.
On the basis of fumaric acid Tenofovir, the further crystallization of the present invention obtains the crystal formation of fumaric acid Tenofovir.Concrete method is described below:
The fumaric acid Tenofovir that aforesaid method obtains at room temperature is dissolved in ethyl acetate, stirs at a certain temperature, slowly adds isopropyl ether, separate out solid, continue constant temperature stirring and crystallizing for some time, filter, washing, dry, obtain the fumaric acid Tenofovir of corresponding crystal formation.
Wherein, fumaric acid Tenofovir in preparation process described above: ethyl acetate: isopropyl ether=1:1-10:1-30, the preferred fumaric acid Tenofovir of the present invention: ethyl acetate: isopropyl ether=1:2-8:2-15, particularly preferably fumaric acid Tenofovir: ethyl acetate: isopropyl ether=1:3:9; In addition, the scope of certain temperature described above is-20 ~ 20 DEG C, and the present invention is particularly preferably-10 DEG C; Further, the scope of for some time described above is 0.5-8h, the preferred 1h of the present invention; Further, described drying, also can be able to be common drying for vacuum-drying, the temperature of drying of the present invention is preferred≤and 60 DEG C, particularly preferably 40 DEG C.
DSC and the X-ray powder diffraction data of fumaric acid Tenofovir crystal formation is as follows:
Wherein DSC collection of illustrative plates is accompanying drawing 1; X-ray powder diffraction is accompanying drawing 2 in addition, and described in it, crystal formation exists: 40KV, 40mA, beam wavelength CuKa1.
dS=SS=1 °, RS=0.3mm, sweep limit 5 ~ 45 °, measures under the condition of scanning speed 2.4 °/min, and X-ray powder diffraction pattern characterizes following (only listing Intensity%>=20%):
| NO. | 2theta | d value | Intensity% |
| 1 | 5.040 | 17.5191 | 21 |
| 2 | 6.480 | 13.6288 | 48 |
| 3 | 9.640 | 9.1672 | 86 |
| 4 | 10.080 | 8.7680 | 37 |
| 5 | 13.960 | 6.3386 | 20 |
| 6 | 15.140 | 5.8471 | 71 |
| 7 | 15.640 | 5.6613 | 49 |
| 8 | 16.260 | 5.4468 | 43 |
| 9 | 18.080 | 4.9024 | 47 |
| 10 | 19.020 | 4.6622 | 32 |
| 11 | 19.460 | 4.5577 | 38 |
| 12 | 20.620 | 4.3039 | 24 |
| 13 | 21.080 | 4.2110 | 20 |
| 14 | 22.300 | 3.9833 | 48 |
| 15 | 23.580 | 3.7699 | 43 |
| 16 | 24.000 | 3.7048 | 100 |
| 17 | 24.540 | 3.6245 | 27 |
| 18 | 25.300 | 3.5173 | 36 |
| 19 | 26.080 | 3.4139 | 75 |
| 20 | 27.200 | 3.2758 | 35 |
| 21 | 30.580 | 2.9210 | 22 |
Crystal formation data listed by the present invention, owing to being subject to the impact of many factors, X-ray powder diffraction measured by same crystal formation go out that peak position or intensity can there is some difference, therefore, the experimental error value of the diffraction peak 2theta value in its X-ray powder diffraction of crystal formation of the present invention can be ± and 0.2.
In addition, for better illustrating that fumaric acid Tenofovir crystal formation of the present invention has satisfactory stability, by stability experiment comparison fumaric acid Tenofovir amorphous article and fumaric acid Tenofovir crystal formation of the present invention, the result obtained is as follows:
As seen from the above table, fumaric acid Tenofovir crystal formation of the present invention is in 6 months, and purity change is very little, and it has than fumaric acid Tenofovir amorphous article more satisfactory stability.
Accompanying drawing explanation
Accompanying drawing 1: the X-ray powder diffraction of fumaric acid Tenofovir;
Accompanying drawing 2: the DSC collection of illustrative plates of fumaric acid Tenofovir.
Embodiment
By the following examples the present invention done and illustrate further, but do not represent embodiment limitation of the present invention.
The preparation of embodiment 1. Tenofovir
Get tynofovir 100.g+DMF1000mL+ triethylamine 166g, stirring at normal temperature 1h, rear intensification drips chloromethyl propylene carbonate 250g at controlling reaction solution≤50 DEG C, dropwise rear continuation stirring reaction 6h, close heating, be cooled to room temperature, filter and remove solid, add 2000ml ethanol, reaction solution controls to be concentrated at 50 DEG C and dryly obtains jelly.Add 500ml water again to stir, become white opacity, add 300ml*2 extraction, liquid becomes clarification, and point water-yielding stratum adds 200ml ethanol several times and helps precipitation, is concentrated into dryly to obtain jelly at 50 DEG C.First use 100ml Virahol heating for dissolving, more slowly add sherwood oil 900ml, naturally cooling, separate out white solid, suction filtration, dry and obtain 40g Tenofovir solid, yield: 28.52%, purity 99.50%.
The preparation of embodiment 2. fumaric acid Tenofovir
Get 5.76g fumaric acid+100ml Virahol, stirring and dissolving under normal temperature, more slowly add the Tenofovir 10g in embodiment 3, Tenofovir separates out again white powder solid after first dissolving, and filters, and dries and obtains 12.5g fumaric acid Tenofovir, yield: 97.05%, purity 99.88%.
Structure elucidation
1hNMR determination data: in table 1
Table 1 sample nuclear magnetic resonance hydrogen modal data
| Chemical shift (ppm) | Multiplicity | Hydrogen number | Coupling constant | Ownership |
| 1.05-1.06 | d | 3 | 6.0Hz | 12 |
| 1.19-1.21 | d | 6 | 6.5Hz | 17,18 |
| 3.60-3.71 | m | 3 | 11，13 | |
| 4.16-4.20 | dd | 1 | 6.0Hz,14.0Hz | 10a or 10b |
| 4.30-4.33 | dd | 1 | 3.0Hz,14.0Hz | 10b or 10a |
| 4.75-4.78 | m | 1 | 16 | |
| 5.40-5.47 | m | 2 | 14 | |
| 6.64 | d | 2 | 20，20’ | |
| 8.08 | brs | 2 | D 2O disappears after exchanging | 19 |
| 8.19 | s | 1 | 8 | |
| 8.23 | s | 1 | 2 | |
| 13.16-13.20 | brs | 2 | D 2O disappears after exchanging | 21,22 |
Resolve:
(1) δ 1.05-1.06ppm, doublet, 3H, J=6.0Hz, be classified as C
12-CH
3.
(2) δ 1.19-1.21ppm, doublet, 6H, J=6.5Hz, be classified as 2 methyl hydrogen C of sec.-propyl
17,18-CH
3.
(3) δ 3.60 ~ 3.71ppm, multiplet, 3H, is classified as C
13-CH
2and C
11-C
h.
(4) δ 4.16-4.20ppm, dd peak, 1H, J=6.0Hz, 14.0Hz, be classified as C
10-H
aor C
10-H
b.
(5) δ 4.30-4.33ppm, dd peak, 1H, J=3.0Hz, 14.0Hz, be classified as C
10-H
bor C
10-H
a.
(6) δ 4.75-4.78ppm, multiplet, 1H, is classified as C
16-CH.
(7) δ 5.40-5.47ppm, multiplet, 2H, is classified as C
14-CH
2.
(8) δ 6.64ppm, doublet, 2H, is classified as C
20,20 '-CH.
(9) δ 8.08ppm, wide unimodal, 2H, D
2o disappears after exchanging, and is classified as 22 primary amino-NH2.
(10) δ 8.19ppm, unimodal, and 1H is classified as C
8-CH.
(11) δ 8.23ppm, unimodal, and 1H is classified as C
2-CH.
(12) δ 13.16-13.20ppm, wide unimodal, 2H, D
2o disappears after exchanging, and is classified as the hydrogen-OH on 21 and 22 hydroxyls.
Conclusion
Learn from 1HNMR spectrum, the corresponding proton of sample conforms to completely with molecular structure.
Mass spectrometric detection
INSTRUMENT MODEL: Agilent1100 type mass spectrograph
Condition: electron spray(ES), ESI(-) 70V
Resolve
M/z402.2 is (M-H)
-peak, with the molecular formula C of Tenofovir
14h
22n
5o
7p conforms to.
In sum, sample
1hNMR,
1hNMR+D
2o, MS spectrum rationally can make ownership to molecular structure, and the product that confirmation obtains is fumaric acid Tenofovir.
The preparation of embodiment 3. fumaric acid Tenofovir crystal formation
Get above-mentioned fumaric acid Tenofovir 5g, under room temperature, use 15ml acetic acid ethyl dissolution, cooling, be cooled to-10 DEG C, slowly drip 45ml isopropyl ether, become muddy gradually, rear a large amount of white solid is separated out, and dropwises, continues constant temperature stirring and crystallizing 1h, filter, a little isopropyl ether washing, solid, 40 DEG C of vacuum-dryings, obtains the fumaric acid Tenofovir 4.8g of corresponding crystal formation, yield 96%, purity 99.95%.
The preparation of embodiment 4. fumaric acid Tenofovir crystal formation
Get above-mentioned fumaric acid Tenofovir 7.5g, under room temperature, use 15ml acetic acid ethyl dissolution, cooling, be cooled to-10 DEG C, slowly drip 45ml isopropyl ether, become muddy gradually, rear a large amount of white solid is separated out, and dropwises, continues constant temperature stirring and crystallizing 1h, filter, a little isopropyl ether washing, solid, 40 DEG C of vacuum-dryings, obtains the fumaric acid Tenofovir 7.4g of corresponding crystal formation, yield 98.7%, purity 99.93%.
Claims (11)
1. fumaric acid Tenofovir crystal formation, its X-ray powder diffraction data is as follows:
Described crystal formation exists: 40KV, 40mA, beam wavelength
dS=SS=1 °, RS=0.3mm, sweep limit 5 ~ 45 °, measures under the condition of scanning speed 2.4 °/min, and X-ray powder diffraction pattern characterizes as follows:
。
2. the preparation method of the fumaric acid Tenofovir crystal formation of claim 1, it is characterized in that, through as follows: fumaric acid Tenofovir is at room temperature dissolved in ethyl acetate, stirs at a certain temperature, slowly adds isopropyl ether, separate out solid, continue constant temperature stirring and crystallizing for some time, filter, washing, drying, to obtain final product.
3. preparation method according to claim 2, is characterized in that, fumaric acid Tenofovir: ethyl acetate: isopropyl ether=1:1-10:1-30.
4. preparation method according to claim 2, is characterized in that, fumaric acid Tenofovir: ethyl acetate: isopropyl ether=1:2-8:2-15.
5. preparation method according to claim 2, is characterized in that, fumaric acid Tenofovir: ethyl acetate: isopropyl ether=1:3:9.
6. preparation method according to claim 2, is characterized in that, the temperature range of described certain temperature is-20 ~ 20 DEG C.
7. preparation method according to claim 2, is characterized in that, described certain temperature is-10 DEG C.
8. preparation method according to claim 2, is characterized in that, the time range of described for some time is-0.5-8h.
9. preparation method according to claim 2, is characterized in that, described for some time is 1h.
10. preparation method according to claim 2, is characterized in that, described drying, is vacuum-drying or common drying, dry temperature≤60 DEG C.
11. preparation methods according to claim 2, is characterized in that, described drying, are vacuum-drying or common drying, and dry temperature is 40 DEG C.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264387A (en) * | 1997-07-25 | 2000-08-23 | 吉里德科学公司 | Nucleotide analog composition and synthesis method thereof |
| CN1745755A (en) * | 1997-07-25 | 2006-03-15 | 吉里德科学公司 | Nucleotide analog composition and synthesis method |
| WO2012016506A1 (en) * | 2010-08-01 | 2012-02-09 | 江苏正大天晴药业股份有限公司 | Crystals of tenofovir disoproxil fumarate |
| CN103232490A (en) * | 2013-01-31 | 2013-08-07 | 洛阳聚慧投资股份有限公司 | Nucleoside compounds with HIV-1/HBV viral replication inhibition activity, preparation methods thereof, and antiviral applications thereof |
-
2013
- 2013-10-11 CN CN201310472450.6A patent/CN103483385B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264387A (en) * | 1997-07-25 | 2000-08-23 | 吉里德科学公司 | Nucleotide analog composition and synthesis method thereof |
| CN1745755A (en) * | 1997-07-25 | 2006-03-15 | 吉里德科学公司 | Nucleotide analog composition and synthesis method |
| WO2012016506A1 (en) * | 2010-08-01 | 2012-02-09 | 江苏正大天晴药业股份有限公司 | Crystals of tenofovir disoproxil fumarate |
| CN103232490A (en) * | 2013-01-31 | 2013-08-07 | 洛阳聚慧投资股份有限公司 | Nucleoside compounds with HIV-1/HBV viral replication inhibition activity, preparation methods thereof, and antiviral applications thereof |
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