CN109867696A - A kind of tenofovir dipivoxil tripolymer compound, preparation method and application - Google Patents
A kind of tenofovir dipivoxil tripolymer compound, preparation method and application Download PDFInfo
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- CN109867696A CN109867696A CN201711262789.8A CN201711262789A CN109867696A CN 109867696 A CN109867696 A CN 109867696A CN 201711262789 A CN201711262789 A CN 201711262789A CN 109867696 A CN109867696 A CN 109867696A
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- scheme
- compound
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- tenofovir dipivoxil
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 67
- 150000001875 compounds Chemical class 0.000 title claims abstract description 51
- 229960004556 tenofovir Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 238000011109 contamination Methods 0.000 claims abstract description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 238000007445 Chromatographic isolation Methods 0.000 claims description 18
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 16
- 238000006482 condensation reaction Methods 0.000 claims description 16
- 229920002866 paraformaldehyde Polymers 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 11
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
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- 238000005070 sampling Methods 0.000 claims description 3
- 239000003643 water by type Substances 0.000 claims description 3
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical group 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- LTVDTKRMOQDRCH-UHFFFAOYSA-N furan;1h-pyrrole Chemical compound C=1C=CNC=1.C=1C=COC=1 LTVDTKRMOQDRCH-UHFFFAOYSA-N 0.000 claims description 2
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- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000005829 trimerization reaction Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of tenofovir dipivoxil tripolymer, preparation method and applications.The present invention provides a kind of tenofovir dipivoxil tripolymer compound or its salts shown in formula I.Application the present invention also provides tenofovir dipivoxil tripolymer compound I or its salt as the contamination levels product of tenofovir disoproxil fumarate.Tenofovir dipivoxil tripolymer compound I through the invention is as reference substance, the analysis method of Lai Jianli tenofovir disoproxil fumarate quality control, so that the safety and validity of tenofovir disoproxil fumarate clinical application can be improved.
Description
Technical field
The present invention relates to a kind of tenofovir dipivoxil tripolymer compound, preparation method and applications.
Background technique
Tenofovir disoproxil fumarate (Tenofovir disoproxil fumarate, TDF), the entitled 9- of chemistry
[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]propyl]adeninefumarate(1:1)(ZL
97197460, ZL 98807435).TDF by Gliead company, the U.S. research and develop, 2001 for the first time the U.S. listing for treat at
People human immunodeficiency virus (HIV) infection, FDA in 2008 ratify it again and are used to treat Adult chronic hepatitis type B virus
(HBV) it infects.Since the Anti-HBV activity effect of this product is better than Aldoforwe ester, drug resistance incidence is low, and to most of HBV persisters
Effectively, therefore it has broad application prospects in the treatment of HBV infection.
HIV, HBV infection patient need Long-term taking medicine, and in existing tenofovir disoproxil fumarate product, by
It is more to prepare the impurity brought into.In addition, tenofovir disoproxil fumarate is in 2~8 DEG C of closed guarantors according to existing standards of pharmacopoeia
It deposits, keeping life is 36 months.It since preservation condition requires height, if preservation is improper, is also easily denaturalized, impurity increases
It is more.
If contaminant overstandard standard exists, the safety and validity of TDF necessarily will affect, to the clinical application band of TDF
Carry out risk.For this purpose, regulation in the import drugs registered standard (standard No.: JX20120124) in China, total impurities must not mistake
2.5%, and the content for illustrating the specific impurity in part limits.(see the table below)
And be even more to provide in United States Pharmacopeia, wherein impurity A ((S)-enantiomter, (S)-
Tenofovirdisoproxil) it is no more than 1.0%, impurity B (9- acrylic adenine, 9-propenyl adenine) does not surpass
0.0005% (5 μ g/g) is crossed, other impurity are no more than 0.10%, and total impurities are no more than 3.0%.Practical at present existing more than 20 kinds miscellaneous
Matter is isolated from tenofovir disoproxil fumarate product, and as standard reference material, provides for the quality of TDF
Certain guarantee.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of tenofovir dipivoxil tripolymers, preparation method
And application.The reference substance of tenofovir dipivoxil tripolymer compound through the invention, point of Lai Jianli TDF mass control
Analysis method, so that the safety and validity of TDF clinical application can be improved.
The present invention provides a kind of tenofovir dipivoxil tripolymer compound or its salts shown in formula I:
The present invention provides a kind of preparation methods of above-mentioned compound of formula I, are scheme one or two；
The scheme one includes the following steps:
Compound shown in formula II and formaldehyde or paraformaldehyde are subjected to condensation reaction, obtain compound shown in the formula I,
?；
The scheme two includes the following steps:
In the presence of formaldehyde or paraformaldehyde, compound shown in compound shown in formula III and formula II be condensed anti-
It answers, obtains compound shown in the formula I；
In the scheme one or two, the reaction condition of the condensation reaction can be the anti-of such reaction routine of this field
Answer condition, such as following reaction conditions:
In the scheme one or two, the condensation reaction can be conventional organic molten in such condensation reaction of this field
Agent (such as amide solvent, in another example n,N-Dimethylformamide, n,N-dimethylacetamide (DMA) and hexylmethylphosphoramide
One of or it is a variety of, in another example n,N-Dimethylformamide) carry out, the organic solvent with do not influence reaction carry out
?.
In the scheme one or two, the organic solvent and the formaldehyde or the paraformaldehyde (paraformaldehyde
Molecular weight is in terms of formaldehyde) the Molar Molar ratio more conventional than that can be such reaction of this field, such as 3.6mL/mmol
~7.2mL/mmol.
When its for scheme for the moment, the formaldehyde or paraformaldehyde (the paraformaldehyde molecular weight is in terms of formaldehyde) with it is described
Formula II compound molar ratio can be conventional for such reaction of this field molar ratio, such as 2~3.
When it is scheme two, the molar ratio of the Formula II compound and the formula III compound can be this field
The conventional molar ratio of such reaction, such as 3~4.
When it is scheme two, the formaldehyde or paraformaldehyde (the paraformaldehyde molecular weight is in terms of formaldehyde) with it is described
Formula II compound molar ratio can be conventional for such reaction of this field molar ratio, such as 3~4.
In the scheme one or two, the temperature that the temperature of the condensation reaction can be conventional for such reaction of this field,
Such as 0 DEG C~100 DEG C (such as 60 DEG C~80 DEG C).
In the scheme one or two, the routine monitoring method (example in this field is can be used in the process of the condensation reaction
Such as TLC, HPLC or NMR) it is monitored；When its for scheme for the moment, as reaction end when generally no longer being reacted using compound II, instead
It can be 5h~15h (such as 8h~10h) between seasonable；It is reaction when generally no longer being reacted with compound III when it is scheme two
Terminal, reaction time can be 5h~15h (such as 8h~10h).
The present invention also provides a kind of preparation method of above-mentioned compound of formula I, include the following steps: that the Formulas I will be contained
The tenofovir dipivoxil of compound or its salt carry out chromatographic isolation；The chromatographic column of the chromatographic isolation is reverse phase silicon
Rubber column gel column；The mobile phase of the chromatographic isolation is ammonium acetate aqueous solution and acetonitrile.
The chromatographic column of the chromatographic isolation can be the reverse phase silica gel column of this field routine, such as octadecylsilane bonded silica
Glue (in another example Waters Xbridge, C18,5 μm, 19 × 150mm).
The mobile phase of the chromatographic isolation, preferably mobile phase A: 10mmoL ammonium acetate aqueous solution；Mobile phase B: acetonitrile；
More preferably the mobile phase A and the Mobile phase B carry out gradient elution with following ratio:
| Time | A phase | B phase |
| 0 minute | 65% | 35% |
| 8 minutes | 20% | 80% |
| 15 minutes | 20% | 80% |
The percentage is percent by volume of the total volume.
In the chromatographic isolation, in addition to mobile phase and chromatographic column, other chromatographic conditions can be the chromatostrip of this field routine
Part, the preferably following chromatographic condition of the present invention: column temperature is 25~40 DEG C (such as 30~35 DEG C)；Flow velocity be 1.0mL/min~
2.0mL/min (preferably 1.5mL/min)；Sampling volume is 1~120 μ L (preferably 20 μ L).
The tenofovir dipivoxil containing the compound of formula I or its salt can be for by by two pyrroles of tenofovir
At 25 DEG C ± 2 DEG C of temperature, humidity 60%RH ± 5%RH, avoid light place obtains the bulk pharmaceutical chemicals of furan ester or its salt (such as fumarate)
Obtain (such as placing 1 year).
The tenofovir dipivoxil or its salt can be prepared for the method for this field routine, such as according to
It is prepared by the method for WO9804569；Its purity is up to 99% (such as 99.53%).
The present invention also provides a kind of above-mentioned tenofovir dipivoxil tripolymer compound I or its salt as tenofovir
The application of dipivoxil contamination levels product.
The present invention also provides a kind of tenofovir dipivoxil or the bulk pharmaceutical chemicals of its salt, are containing percentage composition
0.01%~1.0% tenofovir dipivoxil tripolymer compound I as described in claim 1 or its salt (such as 0.02%,
0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%,
0.5%, 0.6%, 0.7%, 0.8% and 0.9%).The percentage composition is surveyed according to the method for HPLC in WHO quality standard
It is fixed, it is obtained by calculated by peak area.
The present invention also provides a kind of tenofovir dipivoxil or the preparations of its salt comprising as claimed in claim 10
Tenofovir dipivoxil or its salt bulk pharmaceutical chemicals and pharmaceutic adjuvant.
HPLC detection method in the WHO quality standard, specific as follows:
Chromatographic column: octadecylsilane chemically bonded silica (AgelaC18, 5 μm, 4.6 × 250mm)
Mobile phase A: the acetonitrile of 2 volumes, the water of the volume of phosphate buffer pH 6.0 and 78 of 20 volumes.
Mobile phase B: the acetonitrile of 65 volumes, the water of the volume of phosphate buffer pH 6.0 and 15 of 20 volumes.
Phosphate-buffered is prepared by the way that 3.50g potassium dihydrogen phosphate and 1.70g 4-butyl ammonium hydrogen sulfate to be dissolved in 800ml water
PH is adjusted to 6.0 by the way that sodium hydroxide (1mol/L) is added, is diluted with water to 1000 milliliters by liquid pH6.0.
System suitability: referring to WHO quality standard.
Detection wavelength is 260nm；Column temperature is 30 DEG C；Flow velocity is 1.0ml per minute.
The mobile phase A and the Mobile phase B carry out gradient elution with following ratio:
| Time (minute) | A phase (%v/v) | B phase (%v/v) |
| 0-5 | 81 | 19 |
| 5-40 | 81to 49 | 19to 51 |
| 40-60 | 49to 0 | 51to 100 |
| 60-65 | 0 | 100 |
| 65-70 | 0to 81 | 100to 19 |
| 70-80 | 81 | 19 |
The percentage is percent by volume of the total volume.
" salt " in described " tenofovir dipivoxil or its salt ", with " the tenofovir dipivoxil trimerization
Salt in body compound I or its salt " is identical, for example, fumaric acid.
Term " salt " indicates the salt formed by suitable organic acid, inorganic acid, organic base or inorganic base and compound.It is described
Organic acid can for this field it is conventional can be at the various organic acids of salt, such as methanesulfonic acid, p-methyl benzenesulfonic acid, maleic acid, rich horse
Acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, hydroxyl second
One of base sulfonic acid, naphthalene sulfonic acids and salicylic acid are a variety of.The inorganic acid can for this field it is conventional can be at the various of salt
One of inorganic acid, such as hydrochloric acid, sulfuric acid and phosphoric acid are a variety of.The organic base can for this field it is conventional can be at salt
One of various organic bases, such as pyridines, imidazoles, Pyrazine, indoles, fast quinoline class, tertiary amines and phenyl amines are more
Kind.Tertiary amines the organic bases such as triethylamine and/or N, N- diisopropylethylamine.The phenyl amines organic bases such as N,
Accelerine.The pyridines organic bases such as pyridine, picoline, 4-dimethylaminopyridine and 2- methyl -5- second
One of yl pyridines are a variety of.The inorganic base can for this field it is conventional can be at the various inorganic bases of salt, such as alkali gold
Belong to hydride, the hydroxide of alkali metal, the alkoxide of alkali metal, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, bicarbonate
One of potassium and sodium bicarbonate are a variety of.The alkali metal hydride such as sodium hydride and/or hydrofining.The alkali gold
The hydroxide of category such as one of sodium hydroxide, potassium hydroxide and lithium hydroxide or a variety of.The alcoxyl of the alkali metal
One of compound such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide is a variety of.
Term " bulk pharmaceutical chemicals " expression is made of the controllable impurity of key agents active constituent and content.
Terms " formulation " expression is made of the controllable impurity of key agents active constituent and content and/or auxiliary material, root
According to the standard that pharmacopeia or drug surveilance department ratify, the medicinal application form prepared to meet the needs of clinical treatment or prevention
The specific kind of (dosage form).
The substance of term " impurity " expression any influence pharmaceutical purity.The impurity is generally divided into three by its physicochemical property
Class: organic impurities, inorganic impurity and residual solvent.According to its source, it is (including not anti-in synthesis that impurity can be divided into process impurity
Answer complete reactant and reagent, intermediate, by-product etc.), catabolite, mixed impurity etc. from reactant and reagent.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: tenofovir dipivoxil tripolymer compound I through the invention makees
For reference substance, the analysis method of Lai Jianli tenofovir disoproxil fumarate quality control, so that fumaric acid can be improved for promise
The safety and validity of good fortune Wei dipivoxil clinical application.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Embodiment 1
Our researcher has found that the structure of tenofovir disoproxil fumarate is extremely unstable in practical applications；Such as
Fruit storage is improper, easily generates new impurity.Especially after storing a period of time, carried out with WHO quality standard it is related
In substance detection, when relative retention time is 1.54, there are a newly generated impurity peaks, with time or the shadow of storage environment
It rings, content can reach 0.1% or more, more than the standard of States Pharmacopoeia specifications, its quality seriously affected, to the safe medication of patient
Bring great risk.But since there is presently no correlative studys, it is not known that the specific structure of impurity lacks standard items,
The pharmacological toxicology of impurity can not be conducted further research, the content and detection method for the impurity in product also lack
More accurate reasonable standard.It therefore, is the safety and validity that guarantee TDF, on the basis of existing standards of pharmacopoeia, ability
Domain is badly in need of confirming the impurity, and can largely provide the standard items of the impurity, and further to study, the quality of TDF is continuously improved
Research level.
For this purpose, inventor's (two pyrrole furan of fumaric acid tenofovir from the tenofovir disoproxil fumarate for place 1 year
Ester is to prepare according to the method for WO9804569, purity 99.53%, lot number 20151007；Placement condition: 25 DEG C ± 2 DEG C of temperature,
Humidity 60%RH ± 5%RH, is protected from light), pass through the isolated impurity of chromatographic column.Separation condition is as follows:
Chromatographic column: octadecylsilane chemically bonded silica (Waters Xbridge, C18, 5 μm, 19 × 150mm)
Mobile phase A: 10mmoL ammonium acetate aqueous solution；Mobile phase B: acetonitrile
Detection wavelength is 260nm；Column temperature is 30 DEG C；Flow velocity 15mL/min.
| Time (minute) | A phase (%v/v) | B phase (%v/v) |
| 0 | 65 | 35 |
| 8 | 20 | 80 |
| 15 | 20 | 80 |
Its Structural Identification data is as follows:
MS,[M+H]+=1582.37；HRMS,[M+Na]+=1604.5087, C59H90N15O30P3；
1H NMR(400MHz,CDCl3) δ 8.48 (d, J=36.1Hz, 3H), 8.01 (d, J=64.8Hz, 4H), 7.50 (s,
1H), 6.01 (s, 4H), 5.75-5.55 (m, 12H), 4.97-4.83 (m, 6H), 4.37 (dd, J=18.4,7.1Hz, 3H),
4.18 (dt, J=14.3,7.1Hz, 3H), 3.95 (dt, J=12.8,8.9Hz, 6H), 3.76 (dd, J=13.8,8.9Hz,
3H),1.33-1.19(m,45H)；
13C NMR(101MHz,CDCl3)δ154.21(s),152.97-152.37(m),152.18(s),150.82(s),
149.53 (s), 141.61 (s), 141.23 (s), 119.44 (d, J=8.0Hz), 84.07 (dd, J=10.8,5.7Hz),
76.44 (t, J=11.9Hz), 73.04 (s), 63.67 (d, J=6.3Hz), 61.99 (d, J=6.0Hz), 53.39 (s),
47.71 (s), 21.35 (s), 16.25 (d, J=4.7Hz)；
31P NMR(162MHz,CDCl3) δ 20.89 (d, J=4.8Hz)
Pass through above-mentioned analysis data, it may be determined that the chemical structure of the impurity is tenofovir dipivoxil tripolymer compound
I:
According to above structure, we has designed and synthesized above-mentioned tenofovir dipivoxil tripolymer compound I.
Embodiment 2
Compound shown in 3.0g formula II, 0.15g paraformaldehyde, 36mL N,N-dimethylformamide are placed in 50mL there-necked flask
In.Reaction system is heated to 80 DEG C, keeps the temperature 10h.Removed under reduced pressure solvent, is added 20mL water, 20mL methylene chloride, and liquid separation has
Machine Xiang Shuixi (20mL × 2).Organic phase anhydrous sodium sulfate is dry, wet process loading, and 50g silica gel fills column, column chromatography, eluant, eluent dichloro
Methane: methanol (50:1)-(30:1) obtains light yellow oil 1.5g.The light yellow oil continues to use preparation liquid phase separation,
Compound shown in formula I is obtained, colorless oil 220mg, HPLC purity 98.73% (measures) according to the method for WHO.
MS,[M+H]+=1582.37；HRMS,[M+Na]+=1604.5087, C59H90N15O30P3；
1H NMR(400MHz,CDCl3) δ 8.48 (d, J=36.1Hz, 3H), 8.01 (d, J=64.8Hz, 4H), 7.50 (s,
1H), 6.01 (s, 4H), 5.75-5.55 (m, 12H), 4.97-4.83 (m, 6H), 4.37 (dd, J=18.4,7.1Hz, 3H),
4.18 (dt, J=14.3,7.1Hz, 3H), 3.95 (dt, J=12.8,8.9Hz, 6H), 3.76 (dd, J=13.8,8.9Hz,
3H),1.33-1.19(m,45H)；
13C NMR(101MHz,CDCl3)δ154.21(s),152.97-152.37(m),152.18(s),150.82(s),
149.53 (s), 141.61 (s), 141.23 (s), 119.44 (d, J=8.0Hz), 84.07 (dd, J=10.8,5.7Hz),
76.44 (t, J=11.9Hz), 73.04 (s), 63.67 (d, J=6.3Hz), 61.99 (d, J=6.0Hz), 53.39 (s),
47.71 (s), 21.35 (s), 16.25 (d, J=4.7Hz)；
31P NMR(162MHz,CDCl3) δ 20.89 (d, J=4.8Hz)
Its MS, HRMS,1H NMR(400MHz,CDCl3)、13C NMR(101MHz,CDCl3) and31P NMR(162MHz,
CDCl3) with it is above-mentioned same by isolated impurity phase in 1 year tenofovir disoproxil fumarate from placing.
Embodiment 3
Compound shown in 1.0g formula III, compound shown in 2.0g formula II, 0.15g paraformaldehyde, 36mL N, N- dimethyl methyl
Amide is placed in 50mL there-necked flask.Reaction system is heated to 80 DEG C, keeps the temperature 10h.Post-processing approach as described in Example 1, obtains
To compound 280mg shown in formula I, HPLC purity 98.15% (measures) according to the method for WHO.
MS,[M+H]+=1582.37；HRMS,[M+Na]+=1604.5087, C59H90N15O30P3；
1H NMR(400MHz,CDCl3) δ 8.48 (d, J=36.1Hz, 3H), 8.01 (d, J=64.8Hz, 4H), 7.50 (s,
1H), 6.01 (s, 4H), 5.75-5.55 (m, 12H), 4.97-4.83 (m, 6H), 4.37 (dd, J=18.4,7.1Hz, 3H),
4.18 (dt, J=14.3,7.1Hz, 3H), 3.95 (dt, J=12.8,8.9Hz, 6H), 3.76 (dd, J=13.8,8.9Hz,
3H),1.33-1.19(m,45H)；
13C NMR(101MHz,CDCl3)δ154.21(s),152.97-152.37(m),152.18(s),150.82(s),
149.53 (s), 141.61 (s), 141.23 (s), 119.44 (d, J=8.0Hz), 84.07 (dd, J=10.8,5.7Hz),
76.44 (t, J=11.9Hz), 73.04 (s), 63.67 (d, J=6.3Hz), 61.99 (d, J=6.0Hz), 53.39 (s),
47.71 (s), 21.35 (s), 16.25 (d, J=4.7Hz)；
31P NMR(162MHz,CDCl3) δ 20.89 (d, J=4.8Hz)
Its MS, HRMS,1H NMR(400MHz,CDCl3)、13C NMR(101MHz,CDCl3) and31P NMR(162MHz,
CDCl3) identical as the data in Examples 1 and 2.
Embodiment 4
On this basis, it using the detection method of WHO quality standard, is further verified by HPLC.The specific method is as follows:
Chromatographic column: octadecylsilane chemically bonded silica (AgelaC18, 5 μm, 4.6 × 250mm)
Mobile phase A: the acetonitrile of 2 volumes, the water of the volume of phosphate buffer pH 6.0 and 78 of 20 volumes.
Mobile phase B: the acetonitrile of 65 volumes, the water of the volume of phosphate buffer pH 6.0 and 15 of 20 volumes.
Phosphate-buffered is prepared by the way that 3.50g potassium dihydrogen phosphate and 1.70g 4-butyl ammonium hydrogen sulfate to be dissolved in 800ml water
PH is adjusted to 6.0 by the way that sodium hydroxide (1mol/L) is added, is diluted with water to 1000 milliliters by liquid pH6.0.
System suitability: referring to WHO quality standard.
Detection wavelength is 260nm；Column temperature is 30 DEG C；Flow velocity is 1.0ml per minute.
Mobile phase A and Mobile phase B carry out gradient elution with following ratio:
The percentage is percent by volume of the total volume.
The HPLC for the tenofovir dipivoxil tripolymer that the embodiment of the present invention 1 is prepared, with the rich horse for placing 1 year
The HPLC of sour tenofovir dipivoxil, the related datas such as retention time difference are as follows:
The HPLC result data of 1 tenofovir dipivoxil tripolymer of table
Table 2 places the HPLC result data of 1 year tenofovir disoproxil fumarate
By table 1 and 2 it is found that the fumaric acid tenofovir of tenofovir dipivoxil tripolymer of the invention and placement 1 year
The retention time of the new impurity generated in dipivoxil is identical.In conjunction with above-mentioned, of the invention tenofovir dipivoxil tripolymer
It can be used as contamination levels product, further increase the quality of tenofovir disoproxil fumarate, can especially monitor and put for a long time
The mass change for the product set really guarantees the safety and validity of TDF, reduces application risk.
Claims (11)
1. a kind of tenofovir dipivoxil tripolymer compound or its salt shown in formula I:
2. a kind of preparation method of tenofovir dipivoxil tripolymer compound as described in claim 1, which is characterized in that
It is scheme one or two；
The scheme one includes the following steps:
Compound shown in formula II and formaldehyde or paraformaldehyde are subjected to condensation reaction, obtain compound shown in the formula I, i.e.,
It can；
The scheme two includes the following steps:
In the presence of formaldehyde or paraformaldehyde, compound shown in compound shown in formula III and formula II is subjected to condensation reaction, is obtained
To compound shown in the formula I；
3. preparation method as claimed in claim 2, which is characterized in that when it is scheme a period of time, the condensation reaction is having
It is carried out in solvent；
And/or when its for scheme for the moment, the molar ratio of the formaldehyde or paraformaldehyde and the Formula II compound is 2~
3；
And/or when its for scheme for the moment, the organic solvent is with the Molar of the formaldehyde or paraformaldehyde ratio
3.6mL/mmol~7.2mL/mmol
And/or when it is scheme a period of time, the temperature of the condensation reaction is 0 DEG C~100 DEG C；
And/or when it is scheme a period of time, it is that reaction is whole that the time of the condensation reaction, which is when no longer being reacted with compound II,
Point；
And/or when it is scheme two, the condensation reaction carries out in organic solvent；
And/or when it is scheme two, the molar ratio of the Formula II compound and the formula III compound is 3~4；
And/or when it is scheme two, the molar ratio of the formaldehyde or paraformaldehyde and the Formula II compound is 3~
4；
And/or when it is scheme two, the organic solvent is with the Molar of the formaldehyde or paraformaldehyde ratio
3.6mL/mmol~7.2mL/mmol
And/or when it is scheme two, the temperature of the condensation reaction is 0 DEG C~100 DEG C；
And/or when it is scheme two, it is that reaction is whole that the time of the condensation reaction, which is when no longer being reacted with compound III,
Point.
4. preparation method as claimed in claim 3, which is characterized in that when it is scheme a period of time, the organic solvent is acyl
Amine solvent；
And/or when it is scheme a period of time, the temperature of the condensation reaction is 60 DEG C~80 DEG C；
And/or when it is scheme two, the organic solvent is amide solvent；
And/or when it is scheme two, the temperature of the condensation reaction is 60 DEG C~80 DEG C.
5. preparation method as claimed in claim 4, which is characterized in that when it is scheme a period of time, the organic solvent is N,
One of dinethylformamide, n,N-dimethylacetamide and hexylmethylphosphoramide are a variety of；
And/or when its be scheme two when, the organic solvent be n,N-Dimethylformamide, n,N-dimethylacetamide and
One of hexylmethylphosphoramide is a variety of.
6. a kind of preparation method of tenofovir dipivoxil tripolymer compound as described in claim 1, which is characterized in that
Including the following steps: will the tenofovir dipivoxil containing the compound of formula I or its salt progress chromatographic isolation；Institute
The chromatographic column for stating chromatographic isolation is reverse phase silica gel column；The mobile phase of the chromatographic isolation is ammonium acetate aqueous solution and acetonitrile.
7. preparation method as claimed in claim 6, which is characterized in that the chromatographic column of the chromatographic isolation is octadecylsilane
Bonded silica gel；
And/or in the mobile phase of the chromatographic isolation, mobile phase A: 10mmoL ammonium acetate aqueous solution；Mobile phase B: acetonitrile；
And/or the column temperature of the chromatographic isolation is 25~40 DEG C；
And/or the flow velocity of the chromatographic isolation is 1.0mL/min~2.0mL/min；
And/or the sampling volume of the chromatographic isolation is 1~120 μ L；
And/or the tenofovir dipivoxil containing the compound of formula I or its salt is by by two pyrrole furan of tenofovir
At 25 DEG C ± 2 DEG C, humidity 60%RH ± 5%RH of temperature, avoid light place obtains the bulk pharmaceutical chemicals of ester or its salt.
8. preparation method as claimed in claim 7, which is characterized in that the chromatographic column of the chromatographic isolation is Waters
Xbridge, C18,5 μm, 19 × 150mm；
And/or the mobile phase A and the Mobile phase B, gradient elution is carried out with following ratio:
The percentage is percent by volume of the total volume；
And/or the column temperature of the chromatographic isolation is 30~35 DEG C；
And/or the flow velocity of the chromatographic isolation is 1.5mL/min；
And/or the sampling volume of the chromatographic isolation is 20 μ L；
And/or the tenofovir dipivoxil containing the compound of formula I or its salt is by by fumaric acid tenofovir
Dipivoxil or its salt are at 25 DEG C ± 2 DEG C, humidity 60%RH ± 5%RH, avoid light place 1 year of temperature.
9. tenofovir dipivoxil tripolymer compound or its salt as described in claim 1 is as tenofovir dipivoxil
Or the application of the contamination levels product of its salt.
10. the bulk pharmaceutical chemicals of a kind of tenofovir dipivoxil or its salt, which is characterized in that it is 0.01% that it, which contains percentage composition,
~1.0% tenofovir dipivoxil tripolymer compound I as described in claim 1 or its salt.
11. the preparation of a kind of tenofovir dipivoxil or its salt, which is characterized in that including replacing promise as claimed in claim 10
The bulk pharmaceutical chemicals and pharmaceutic adjuvant of good fortune Wei dipivoxil or its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| CN111157644A (en) * | 2020-01-02 | 2020-05-15 | 正大天晴药业集团股份有限公司 | Tenofovir disoproxil related substance, preparation method and detection method thereof |
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| CN104341452A (en) * | 2014-09-26 | 2015-02-11 | 中国药科大学 | Preparation method of tenofovir disoproxil fumarate impurities |
| CN105294761A (en) * | 2014-07-29 | 2016-02-03 | 浙江九洲药物科技有限公司 | Impurities of tenofovir disoproxil fumarate or tenofovir, and preparation method thereof |
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| WO2007013086A1 (en) * | 2005-07-26 | 2007-02-01 | Hetero Drugs Limited | Novel polymorphs of tenofovir disoproxil fumarate |
| CN105294761A (en) * | 2014-07-29 | 2016-02-03 | 浙江九洲药物科技有限公司 | Impurities of tenofovir disoproxil fumarate or tenofovir, and preparation method thereof |
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| CN111157644A (en) * | 2020-01-02 | 2020-05-15 | 正大天晴药业集团股份有限公司 | Tenofovir disoproxil related substance, preparation method and detection method thereof |
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