CN106188016A - Dihydrate of his Wei of hydrochloric acid Dacca and preparation method thereof - Google Patents
Dihydrate of his Wei of hydrochloric acid Dacca and preparation method thereof Download PDFInfo
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- CN106188016A CN106188016A CN201610516656.8A CN201610516656A CN106188016A CN 106188016 A CN106188016 A CN 106188016A CN 201610516656 A CN201610516656 A CN 201610516656A CN 106188016 A CN106188016 A CN 106188016A
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- wei
- hydrochloric acid
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- dihydrate
- dacca
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention relates to dihydrate of his Wei of hydrochloric acid Dacca and preparation method thereof, his Wei dihydrate of described hydrochloric acid Dacca, in its X ray powder diffraction pattern, at the angle of diffraction (2 θ)=9.574,11.901,13.188,18.603,20.865,22.608,23.362,24.733,25.201,26.879,27.034,29.101,30.410, there is characteristic absorption peak at 33.480,35.221, present invention also offers preparation method and the purposes of this dihydrate.
Description
Technical field
The invention belongs to the preparation field of medical compounds, be specifically related to his Wei dihydrate and preparation side thereof of hydrochloric acid Dacca
Method.
Background technology
His Wei of hydrochloric acid Dacca, English name: Daclatasvir dihydrochloride, entitled ((the 1S)-1-of chemistry
(((2S)-2-(5-(4'-(2-((2S)-1-((2S)-2-((methoxycarbonyl group) amino)-3-methylbutyryl base)-2-pyrrolidine
Base)-1H-imidazoles-5-base)-4-xenyl)-1H-imidazoles-2-base)-1-pyrrolidinyl) carbonyl)-2-methyl-propyl) amino first
Acid methyl ester dihydrochloride, molecular formula: C40H52Cl2N8O6, molecular weight: 811.80, chemical structural formula is lower formula I:
His Wei Shi European Union of the hepatitis C new drug hydrochloric acid Dacca of Bristol-Myers Squibb Co., the first potent NS5A of Japan's approval
Replication complex inhibitor, mainly combines other drug, for all 1,2,3,4 genotype chronic hepatitis C (HCV) adults
The treatment of the infected.In addition the safety of his Wei treatment hepatitis C of hydrochloric acid Dacca, is obtaining in various different groups
Prove, including gerontal patient, with receptor colony after end-stage liver disease colony, liver transplantation and HIV/HCV coinfection colony.
His Wei of hydrochloric acid Dacca is to have the first for hepatitis C of direct antivirus action by what the method for genetics found
A kind of NS5A of clinical trial replicates complex inhibitor.In the 46th European hepatopathy EASD annual meeting, disclose hydrochloric acid
Dacca he an II clinical trial phase result of Wei show: for the patients with chronic hepatitis C of Genotype I, use hydrochloric acid Dacca he
The treatment that Wei Lianhe Peg-IFN alpha-2b a and ribavirin terminate a course for the treatment of, the continued viral response rate after 12 weeks can
Up to 92%.The anti-hepatitis C medicine Suo Feibuwei combination developed with lucky Leadd B.V, cure rate is up to 100%.
International patent application WO2009020828 discloses synthetic method and crystal formation.Meanwhile, Bristol-Myers Squibb Co. exists
China has applied for crystal formation patent CN101778840B and synthetic method patent CN200880102448.7 of his Wei of hydrochloric acid Dacca.
The present invention, during his the Wei crystallization of research hydrochloric acid Dacca, is found surprisingly that its dihydrate has excellent reason
Change character, the more important thing is simultaneously, his Wei dihydrate novel crystal forms good fluidity of the hydrochloric acid Dacca of the present invention, can be without system
Grain, add appropriate excipient after, be directly used in capsule fill,.
Summary of the invention
It is an object of the invention to provide the hydrate of his Wei of a kind of hydrochloric acid Dacca.
Described hydrate is dihydrate.
Described dihydrate is crystalline structure.
The characteristic peak of described dihydrate crystal formation X-ray powder diffraction figure represents with 2 θ (± 0.2 °) and is positioned at 9.574,
11.901,13.188,18.603,20.865,22.608,23.362,24.733,25.201,26.879,27.034,29.101,
30.410,33.480,35.221。
Another object of the present invention is to provide the preparation method of his Wei hydrate of a kind of hydrochloric acid Dacca, the letter of the method technique
Single, achieve that under room temperature condition.
The purpose of the present invention is achieved through the following technical solutions:
His Wei dihydrate of hydrochloric acid Dacca, is the compound shown in lower formula II:
Shown in the characteristic peak table specific as follows of its X-ray powder diffraction:
The preparation method of his Wei dihydrate of a kind of hydrochloric acid Dacca, comprises the steps: to join his Wei of hydrochloric acid Dacca
Organic solvent and water volume ratio are in the mixed solvent system of 8～12:1, stir molten clear after, be slowly added dropwise acetone to separating out crystalline substance
Body.The usage amount of mixed solvent is that his Wei of 1g hydrochloric acid Dacca needs 4～10mL, and the suspension solution of formation stirs 5～10 minutes,
Make suspension molten clearly under heating condition, and be slowly added dropwise acetone to crystallize, then be down to room temperature, separated, be dried.
Wherein, described mixed solvent, control the ratio of organic solvent and water 8～12:1, preferably 10:1.
Wherein, described organic solvent is methanol, isopropanol, preferably methanol.
Wherein, described Devitrification step, after stirring 5～10min, adds acetone and is allowed to crystallize.
Wherein, described recrystallization temperature is at 55 ± 5 DEG C, optimal for 53～58 DEG C.
Wherein, the time of described dropping acetone is wanted slowly, and the concrete time is 2～4h, most preferably 2.5～3.5h.
Wherein, described cool time is more than 1h, is more preferably 1～3h, optimal for 1.5～2.5h.
Wherein, the described temperature being cooled to room temperature is sky temperature on the same day, and optimum temperature is 25 DEG C.
Wherein, described be cooled to room temperature after, also need to stir more than 6h and be allowed to abundant crystallize, most preferably 12～16h.
The X-ray powder diffraction of his the Wei dihydrate of hydrochloric acid Dacca of the present invention uses D8Advance type X-ray diffraction
Instrument, condition determination is: Cu target, ceramic X-ray tube, tube voltage 40KV, tube current 40mA.
Beneficial effects of the present invention is further illustrated below by way of experimental data.
1, the stability experiment of his Wei dihydrate of hydrochloric acid Dacca of the present invention
| Project | 0 month | March | June |
| Outward appearance | Pale yellow powder crystallizes | Pale yellow powder crystallizes | Pale yellow powder crystallizes |
| Purity (normalization method) | 99.8% | 99.8% | 99.7% |
| Moisture | 4.3% | 4.2% | 4.3% |
2, his Wei dihydrate of hydrochloric acid Dacca of the present invention is under the conditions of accelerating (temperature 40 DEG C ± 2 DEG C, humidity 75% ± 5%)
Do X-ray powder diffraction after placing six months, compare with initial data.Data compare and see table:
Conclusion: contrast above-mentioned XRD spectra data, 2 θ angles of diffraction maximum are consistent.Hydrochloric acid Dacca he adding by Wei dihydrate
After placing six months under the conditions of speed (temperature 40 DEG C ± 2 DEG C, humidity 75% ± 5%), crystal formation does not changes.Prove hydrochloric acid Dacca
He has good stability by Wei dihydrate.
3, compare and draw moist experiment
Be 25 DEG C ± 1 DEG C in temperature, under conditions of relative humidity is 80%, in thermostatic drier, take hydrochloric acid Dacca he
Wei and his Wei dihydrate of hydrochloric acid Dacca carry out accurately weighed after, be respectively placed under equivalent environment be dried tool plug glass weighing botle
In, place 24h under the conditions of constant temperature and humidity, carry out the weighing of precision afterwards.
Result shows, under these experimental conditions, reach the weightening finish after balance is his Wei dihydrate of hydrochloric acid Dacca
0.15%, moist almost without drawing, by contrast, his Wei of hydrochloric acid Dacca, under equivalent assay conditions, increases weight after reaching balance
5.3%, belong to great draw moist.
From drawing moist test, after making his Wei dihydrate of hydrochloric acid Dacca, it will be apparent that reduction is drawn moist, more conducively salt
The storage of his Wei of acid Dacca, reduces the requirement of storage environment.
4, differential scanning calorimetry
Instrument: Pyris 1 DSC differential scanning calorimeter instrument (PerKinElmer, USA)
Scope: room temperature to 300 DEG C
Programming rate: 10 DEG C/min
His Wei dihydrate of hydrochloric acid Dacca is its dehydration peak the endothermic peak of 124 DEG C, and 276 DEG C is its fusing point.
5, In Vitro Dissolution curve
With hydrochloric acid solution (PH 1.0) as dissolution medium, rotating speed is 50 turns ± 2 turns per minute, has investigated his Wei of hydrochloric acid Dacca
With his Wei dihydrate of hydrochloric acid Dacca herein, the 300mg specification tablet made with formulation and technology identical below same particle sizes
| Composition | Consumption/mg |
| His Wei (or hydrate) of hydrochloric acid Dacca | 65.93 |
| Lactis Anhydrous | 100 |
| Microcrystalline Cellulose | 110.07 |
| Cross-linking sodium carboxymethyl cellulose | 16 |
| Colloidal silica | 3.5 |
| Magnesium stearate | 4.5 |
| Tablet weight | 300 |
With the hydrochloric acid solution (PH 1.0) stripping curve as dissolution medium.Measurement result, stripping curve are as follows:
With water as dissolution medium, rotating speed is 50 turns per minute, investigated his Wei of hydrochloric acid Dacca and hydrochloric acid Dacca herein he
Wei dihydrate, the 300mg specification tablet made with formulation and technology identical below same particle sizes is with hydrochloric acid solution (PH
1.0) it is the stripping curve of dissolution medium.Measurement result, stripping curve are as follows:
Result shows, compared with his Wei of hydrochloric acid Dacca, faster, dissolution is the most special for his the Wei dihydrate dissolution of hydrochloric acid Dacca
Point.
6, the crystal formation that the present invention obtains with other documents is compared, and has the effect of good fluidity, and it is the most right to carry out for this
Than experiment:
Prepared by contrast crystal formation: prepare 2 kinds of crystal according to method described in document 1,2:
Wherein,
Document 1 is A review of the effect of multiple conformers on
crystallization from solution and strategies for crystallizing slow inter-
converting conformers
Document 2 is patent CN101778840B
In sum, the hydrochloric acid Dacca of the present invention he have the advantage that by Wei dihydrate
1, for a kind of crystalline structure compound brand-new, that there is excellent stability；
2, itself draw moist weak, be more easy to preserve with transport；
3, there is more preferable In Vitro Dissolution, good fluidity；
4, preparation method simple and fast, is suitable to large-scale commercial and produces.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRPD) figure of his Wei of hydrochloric acid Dacca.
Fig. 2 is X-ray powder diffraction (XRPD) figure of his Wei dihydrate of hydrochloric acid Dacca.
Fig. 3 is the means of differential scanning calorimetry spectrogram of his Wei dihydrate of hydrochloric acid Dacca
Fig. 4 is that tablet stripping curve in PH 1.0 hydrochloric acid solution compares
Fig. 5 is that tablet stripping curve in water compares
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited to
This.
The preparation of his Wei dihydrate of embodiment 1 hydrochloric acid Dacca
By his Wei of 1.0g hydrochloric acid Dacca, add 5.0ml methanol, add purified water 0.5ml, stir 5 minutes formation suspendibles
Solution, is heated to 53～58 DEG C of stirrings and makes suspension molten clearly, is slowly added dropwise acetone 16.5mL, during dropping under 53～58 DEG C of stirrings
Between 3h, be cooled to room temperature, continue stirring 16h, be allowed to abundant crystallize, more separated, drying under reduced pressure obtains yellow crystalline powder
0.91g.Products obtained therefrom moisture is: 4.2% (the moisture theoretical value 4.2% of his Wei dihydrate of hydrochloric acid Dacca), purity is
99.8%.
1HNMR (300MHz, DMSO-d6) δ (ppm): 15.28 (br, 2H), 14.81 (br, 2H), 8.18 (s, 2H), 7.94
～8.04 (dd, 8H), 7.31～7.37 (m, 2H), 5.19～5.22 (m, 2H), 3.85～4.15 (m, 6H), 3.55 (s, 6H),
3.44 (s, 6H), 2.09～2.21 (m, 10H), 0.77～0.93 (m, 12H).
The preparation of his Wei dihydrate of embodiment 2 hydrochloric acid Dacca
By his Wei of 1.0g hydrochloric acid Dacca, add 15.0ml isopropanol, add purified water 1.5ml, the suspension solution of formation
Stir 5 minutes, make suspension molten clearly under the conditions of water-bath 50～60 DEG C, be placed under 50～60 DEG C of stirrings, be slowly added dropwise acetone
16.5mL, drips about 3h, separates out crystal, then is slowly dropped to 25 DEG C, temperature fall time about 2h, continues stirring 16h, is allowed to fully analyse
Crystalline substance, more separated, drying under reduced pressure about light yellow crystal powder 0.91g.Products obtained therefrom moisture is: 4.2% (his Wei of hydrochloric acid Dacca
The moisture theoretical value 4.2% of dihydrate), purity is 99.8%.
1HNMR (300MHz, DMSO-d6) δ (ppm): 15.03 (br, 2H), 14.69 (br, 2H), 8.13 (s, 2H), 7.95
(m, 8H), 7.25～7.28 (m, 2H), 5.15～5.19 (m, 2H), 4.10～4.16 (m, 2H), 3.86～3.93 (m, 4H),
3.55 (s, 6H), 3.44 (s, 6H), 2.03～2.41 (m, 10H), 0.86～0.94 (m, 12H).
The preparation of embodiment 3 capsule
Single dose prescription:
The crystal formation 500mg of embodiment 1
Carboxymethylstach sodium 100.0mg
Magnesium stearate 10mg
Preparation method:
Supplementary material in above-mentioned prescription is sufficiently mixed uniformly, obtains and always mixes granule, measures granule angle of repose 30 °～40 ° of (granules
Mobility is suitable for capsule charge), i.e. obtain capsule, capsule content uniformity in filling hydroxypropyl methylcellulose capsules shell
Little.
The preparation of embodiment 4 tablet
Single dose prescription:
The crystal formation 500mg of embodiment 1
Carboxymethylstach sodium 100.0mg
Magnesium stearate 10mg
Preparation method:
According to above-mentioned prescription, former, adjuvant, it is sufficiently mixed uniformly, obtains and always mix granule, tabletting and get final product.
Claims (9)
1. his Wei dihydrate crystal formation of a hydrochloric acid Dacca, it is characterised in that in its X-ray powder diagram of described crystal formation,
9.574,11.901,13.188,18.603,20.865,22.608,23.362,24.733,25.201,26.879,27.034,
29.101,30.410,33.480,35.221 there is characteristic absorption peak at place.
2. the preparation method of his Wei dihydrate crystal formation of hydrochloric acid Dacca described in claim 1, it is characterised in that include walking as follows
Rapid: his Wei of 1g hydrochloric acid Dacca to be joined 4～10mL organic solvents and heating for dissolving in the mixed solvent of water, after dissolving under stirring
Add 10-20mL acetone to separating out crystal, be cooled to room temperature, continue stirring 10-20 hour, filter, be dried to obtain crystallization.
Preparation method the most according to claim 2, it is characterised in that described mixed solvent, organic solvent therein and water
Volume ratio be 8～12:1.
Preparation method the most according to claim 2, it is characterised in that described mixed solvent, organic solvent therein and water
Volume ratio be 10:1.
Preparation method the most according to claim 2, it is characterised in that described mixed solvent, organic solvent therein is selected from
Methanol, isopropanol.
Preparation method the most according to claim 2, it is characterised in that described mixed solvent, organic solvent therein is selected from
Methanol.
Preparation method the most according to claim 2, it is characterised in that described heating-up temperature is 50～60 DEG C.
Preparation method the most according to claim 2, it is characterised in that described heating makes redissolution heating-up temperature be 53～58
℃。
Preparation method the most according to claim 2, it is characterised in that step is as follows:
By his Wei of 1.0g hydrochloric acid Dacca, add 5.0ml methanol, add purified water 0.5ml, stir 5 minutes formation suspension solutions,
Being heated to 53～58 DEG C of stirrings makes suspension molten clearly, is slowly added dropwise acetone 16.5mL, time for adding 3h under 53～58 DEG C of stirrings,
It is cooled to room temperature, continues stirring 16h, be allowed to abundant crystallize, more separated, drying under reduced pressure obtains yellow crystals.
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| CN201610516656.8A CN106188016A (en) | 2016-07-04 | 2016-07-04 | Dihydrate of his Wei of hydrochloric acid Dacca and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101778840A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Crystalline form of methyl ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt |
| WO2015109445A1 (en) * | 2014-01-21 | 2015-07-30 | 杭州普晒医药科技有限公司 | Salt of compound and crystalline or amorphous substance thereof, preparation method therefor, pharmaceutical composition containing same and use thereof |
| CN105566303A (en) * | 2016-01-25 | 2016-05-11 | 上海众强药业有限公司 | Novel daclatasvir crystal form and preparing method thereof |
-
2016
- 2016-07-04 CN CN201610516656.8A patent/CN106188016A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101778840A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Crystalline form of methyl ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt |
| WO2015109445A1 (en) * | 2014-01-21 | 2015-07-30 | 杭州普晒医药科技有限公司 | Salt of compound and crystalline or amorphous substance thereof, preparation method therefor, pharmaceutical composition containing same and use thereof |
| CN105566303A (en) * | 2016-01-25 | 2016-05-11 | 上海众强药业有限公司 | Novel daclatasvir crystal form and preparing method thereof |
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Application publication date: 20161207 |