CN108840908A - A kind of novel crystal forms of telavi and preparation method thereof - Google Patents
A kind of novel crystal forms of telavi and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
Abstract
The invention belongs to pharmaceutical technology fields, disclose a kind of novel crystal forms and preparation method thereof of telavi, the X-ray powder diffraction collection that telavi novel crystal forms disclosed by the invention are indicated with the 2 θ ± 0.2 ° angles of diffraction shows characteristic diffraction peak at 10.78,11.62,18.04,20.90,23.12,27.72,31.00,31.90,32.86,33.44,37.30,46.78 and 47.10 degree, entirely different with the prior art.The invention also discloses the preparation methods of telavi novel crystal forms, and the preparation method is simple to operation, and yield and purity is high, reaction condition is mild, are suitble to large-scale production.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to novel crystal forms of telavi and preparation method thereof.
Background technique
Hepatitis C (hepatitis) is a kind of liver disease caused by Hepatitis C Virus (Hepatitis C Virus, HCV)
Disease.The virus can cause acute or chronic hepatitis, its severity from the mild disease in persistently several weeks to lifelong serious disease not
Deng.Acute hepatitis c virus infection usually not symptom, and only just will lead to the disease of threat to life under very rare cases, about
There is the infected of 15%-45% that can voluntarily remove virus within infection 6 months without any treatment.Remaining 55% -85%
The infected chronic hepatitis C virus infection can occur.In these chronic hepatitis Cs virus infection person, there is cirrhosis in 20 years
Danger is 15% -30%.The whole world is in advance in respect of 71,000,000 people by chronic hepatitis C infection.The mid-90, educational circles and industrial circle are
Exploitation hepatitis C virus protease inhibitors has paid a large amount of effort.
A kind of telavi (telaprevir) Hepatitis C Virus (HCV) NS3/4A serpin is used
In receiving interferon therapy invalid or untreated before and suffer from the hepatitis adult patients of other hepatopathys such as cirrhosis.Its Chinese
Chemical name is (1S, 3aR, 6aS)-(2S) -2- cyclohexyl-N- (pyrazinylcarbonyl) glycyl -3- methyl-L- valyl
Base-(cyclopropylamino) oxoacetyl) butyl) octahydro cyclopentano [c] pyrroles's -1- formamide;English language Chemical name (1S, 3aR,
6aS)-(2S)-2-cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-((1S)-
1-((cyclopropylamino)oxoacetyl)butyl)octahydrocyclopenta[c]pyrrole-1-
carboxamide.In May, 2011, the telavi listing of U.S. FDA approved Vertex drugmaker, trade name
Incivek, English name:telaprevir.In August, 2011, Incivek also get the Green Light in Canada.September 21 in 2011
Day, European Union ratifies the hepatitis treatment new drug telavi listing of Janssen pharmacy, trade name Incivo.By combining virus
And preventing its proliferation to work, the interferon (PR) and Ribavirin (RBV) of telavi and Pegylation are combined and are made
With 1 type chronic hepatitis C of therapeutic gene.
Many compounds can exist in the form of different crystal form or polymorph, they have different physics, change
And spectral characteristic.For example, certain polymorphs of compound compared to other polymorphs may be more soluble in specific solvent,
It may be more easier to flow, or may be easier to be compressed.See, e.g., P.Di.Martino et al, J Thermal
Anal,1997,48:447-458.For drug, certain solid forms have higher biological utilisation compared to other forms
Degree, and other forms may be more stable under certain preparations, storage and biotic factor.From the point of view of management, this point is very
It is important, because only that they could be by such as U.S.'s food and medicine office when drug meets stringent purity and characteristic standard
The approval such as (U.S.Food and Drug Administration) mechanisms.In fact, one kind of compound has certain stablize
The approval that the polymorph of property and physical chemistry (including spectrum) property obtains management organization is usually not meant to this chemical combination
Other polymorphs of object can also be given the ratification.
The polymorph of compound a kind of known in pharmaceutical field will affect the solubility of such as compound, stability,
Mobility, graded properties (fractability) and compressibility, and the drug products containing the compound safety and effectively
Property.See, e.g., Knapman, K.Modern Drug Discoveries, 2000, p53.Thus, it is found that the new polycrystalline of drug
Type object can provide many benefits.
It is all that CN102382170A is disclosed for treating and preventing many diseases and illness, including but not limited to the third type liver
Scorching telavi.In addition, using the distinct methods for synthesizing telavi or some salt.For example, W02007/
022459A2 and Turner et al. (Chemical Communications 2010,46,7918), which are disclosed, is used to prepare Te La
The method of Wei.Telavi can also be prepared as described in the bibliography quoted from W02009/032198Al.
Kwong et al. (2011) describes the crystal form A of telavi.However, there is about 0.0045mg/ in water in the crystal form
The problem of poorly water-soluble of mL.W02009/032198Al, W02007098270A2 and W02008/106151A2 describe Te La
The eutectic of Wei and the eutectic forming agent of such as 2,5- dihydroxy-benzoic acid and its from such as paraffin wax and dichloromethane mixture
Preparation method.The eutectic should have improved dissolution rate and higher water solubility.However, in the presence of relevant to eutectic forming agent
Safety issue.
US2012/0083441A1 is disclosed through spray drying preparation telavi and polymer such as HPMC (light propyl
Methylcellulose) or HPMCAS (cruel acid bluffs the light propyl methocel of amber acid) polymer and surfactant solid dispersion
Body.The spray drying of commercial scale is high cost investment, and especially state in use solvent disclosed in patent application or
When solvent mixture.
In view of the above drawbacks, so needing to prepare the new polymorphic forms of telavi, it can be developed further into and treat this
The preparation of a little diseases, and generate a large amount of preparation, preparation and treatment benefit.
Summary of the invention
Summary of the invention
The present invention includes the polymorph of telavi.In some aspects, the present invention provides be defined herein as novel crystal forms
The compound polymorph.The invention also includes the mixtures of these forms.In a further embodiment, this hair
It is bright to provide the method for preparation, separation and the qualitative polymorph.
Detailed description of the invention
Fig. 1 provides exemplary x-ray powder diffraction (XRPD) figure of telavi novel crystal forms;
Fig. 2 provides typical thermogravimetry (TGA) curve of telavi novel crystal forms;
Fig. 3 provides typical differential scanning calorimetry (DSC) curve of telavi novel crystal forms.
Detailed description of the invention
Definition
Unless otherwise indicated, term " polymorph " and " polymorphic forms " refer to consolidating for compound or compound in the text
Body crystal form.The different polymorphs of same compound can have different physics, chemistry and/or spectral characteristic.Different
Physical characteristic includes but is not limited to stability (such as stability to heat or light).Compressibility and density are (for preparation and product
Preparation be important) and dissolution rate (bioavilability can be influenced).The difference of stability can by chemical reactivity (such as
Differential oxidation, so that the dosage form containing a kind of polymorph is just more quickly faded than the dosage form containing another polymorph)
Or mechanical features (for example, tablet is disintegration in storage, is transformed into thermodynamically more steady from kinetically advantageous polymorph
Fixed polymorph) or the two (for example, a kind of tablet of polymorph at high humidity more easy disintegrating) variation and cause.
The different physical characteristics of polymorph can influence their processing.For example, compared to other polymorphs, due to the property of its particle
Shape or size distribution, a kind of polymorph are more likely to form solvent compared to alternatively possible, or may be more difficult to filtering or
Wash away impurity.
The polymorph of compound can be obtained by many methods known in the art.This method includes but is not limited to:
Melting recrystallization, melting cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, at a slow speed cooling, benefit of vapor diffusion,
Distillation and mashing.It can be detected, be identified with well known technology, classification and qualitative polymorph, these technologies are such as, but not limited to:Difference
Show scanning calorimetric (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectrum, solution
Calorimetric, solid-state nuclear magnetic resonance (ssNMR), infrared (IR) spectrum, Raman spectrum, scanning electron microscope (SEM), electron crystal, Yi Jiding
Measure analysis, grain size analysis (PSA), surface region analysis, solubility and dissolution rate.
The present invention relates to the polymorphs of telavi, have following structure:
It is prepared by the method that the compound can be described according to CN102382170A patent.
The polymorph of telavi can be obtained by techniques known in the art, the technology include solvent recrystallization,
Desolvation, rapid evaporation, evaporates at a slow speed, is quickly cooled down and cools down at a slow speed at benefit of vapor diffusion.Polymorph can be by raised
At a temperature of the telavi of constant weight is dissolved in various solvents to prepare.Then the solution of the compound is filtered and in open bottles
In (quick thermal evaporation) or in the bottle covered with porose aluminium foil (thermal evaporation at a slow speed) evaporate.Polymorph can also be from slurry
Liquid obtains.Can with various methods from solution or slurries crystalline polymorph.For example, shape at elevated temperatures can be filtered quickly
At solution, then allow to cool to room temperature.Once reaching room temperature, uncrystallized sample is moved into refrigerator, is then filtered.Or
Solid can be dissolved in solvent in raised temperature by person, then cooling to cool down solution rapidly with dry ice/solvent bath.
One embodiment of the invention includes the novel crystal forms of telavi.The novel crystal forms are a kind of non-solvated crystal
Substance can be obtained from single solvent system or mixed solvent system.
The data of novel crystal forms described herein experimental method described in embodiment provided below obtains.
Novel crystal forms can be obtained with multi-solvents, including but not limited to water, methanol, ethyl alcohol, isopropanol, glycol dinitrate
Ether or its mixed solvent.Fig. 1 shows the typical XRPD figure of novel crystal forms.The figure with about 10.78,11.62,18.04,20.90,
23.12, effective peak of 27.72,31.00,31.90,32.86,33.44,37.30,46.78 and 47.10 degree of 2 θ ± 0.2 ° is spy
Sign.For TGA data as shown in Fig. 2, weight change is small before when being shown in up to 263 DEG C, this illustrates that it is non-solvated object
Matter.The weight loss of the generation more than 263 DEG C is as caused by decomposing.DSC data has a suction when as shown in figure 3, being shown in 234 DEG C
Thermal spike, this illustrates that it is melted at such a temperature, and fusing point is 234 DEG C.
The present invention also provides a kind of preparation method of telavi novel crystal forms, the specific steps are:
The preparation method of telavi novel crystal forms, it is characterised in that include the following steps:
Step (1) takes telavi, and solvent is added, is heated to 70 DEG C and dissolves;
To 40-60 DEG C, water is added dropwise in step (1) acquired solution by step (2);
Step (3) insulated and stirred is complete to crystallization, filters, and washes, dry, obtains telavi.
Preferably, solvent described in step (1) be selected from methanol, ethyl alcohol, isopropanol, normal heptane, glycol dimethyl ether, water and
The mixed solvent of methanol, the mixed solvent of water and ethyl alcohol, water and isopropanol mixed solvent, water and glycol dimethyl ether mixing
Solvent;The mass volume ratio of the telavi and solvent is 1g:10ml~1g:50ml;Step (2) telavi and water
Mass volume ratio be 1g:10ml~1g:50ml.
It is further preferred that solvent described in step (1) is selected from the mixed of methanol, ethyl alcohol, glycol dimethyl ether, water and methanol
Bonding solvent, the mixed solvent of water and ethyl alcohol, water and glycol dimethyl ether mixed solvent;The quality volume of telavi and solvent
Than for 1g:25ml;The mass volume ratio of step (2) telavi and water is 1g:20ml~1g:30ml.
Preferably, step (3) rearing crystal time is 1h~5h;Step (3) drying temperature is 40 DEG C~80 DEG C.
In the present invention, the telavi can be telavi solid mixture to be further purified, spy's drawing
Wei may be marketable material or is prepared by art methods, resulting crystal form result in error range,
For novel crystal forms of the present invention.
Specific embodiment
Technical solution of the present invention is described in detail with embodiment below, it will help to technical solution of the present invention
The advantages of, effect have further understanding, the scope of protection of the present invention is not limited for embodiment, and protection scope of the present invention is by weighing
Benefit requires to determine.
Embodiment
The preparation method of telavi crude product is as follows:
Step 1:Prepare 2- ((S) -2- ((S) -2- amino -2- cyclohexylacetamido) -3,3- dimethylbutanoyl) eight
Hydrogen cyclopenta [c] pyrroles-l- carboxylic acid (lS, 3aR, 6aS)-tert-butyl ester
Into the 3L three neck round bottom of outfit overhead, thermocouple, addition funnel, nitrogen outlet and ice water bath
It is packed into HOBtH2O (51.74g, 1.05 molar equivalents), EDCHCl (64.8g;1.05 molar equivalents), then it is packed into DMF
(200ml) starts to stir.So that slurry is cooled to 0-5 DEG C, 2- aminocyclohexyl acetic acid (98.45g is then added;1.05 mole working as
Amount) in DMF (172.4g;Solution in 182.9ml), and be packed into addition funnel.It was added into batch of material, is tieed up with about 30 minutes
Temperature is held at 0-5 DEG C.Once addition is completed, i.e., reaction mixture is stirred 2 hours at 0-5 DEG C.By 2- (amino -3 (S) -2-,
3- dimethylbutanoyl)-octahydro cyclopenta [c] pyrroles-l- carboxylic acid (lS, 3aR, 6aS)-tert-butyl ester isopropyl acetate it is molten
Liquid is packed into addition funnel, is added dropwise with 1 hour, maintains temperature at 0-5 DEG C.After 3 hours, the water of potassium carbonate (57.8g) is added
(585ml) solution stirs the mixture for 0.5 hour.Each layer is separated, with (2 times, each 235ml) extraction water layers 2 of isopropyl acetate
It is secondary.Combined organic phase is washed with 18%HCl aqueous solution (585ml), then uses NaHCO3The water (585ml) of (43.25g) is molten
Liquid washing.Each layer is separated, product 2- ((S) -2- ((S) -2- amino -2- cyclohexylacetamido) -3,3- dimethyl butyryl is obtained
Base) octahydro cyclopenta [c] pyrroles-l- carboxylic acid (lS, 3aR, 6aS)-pale yellow solution of the tert-butyl ester in isopropyl acetate,
Weight 1159.3g (1275ml).
1H NMR(DMSO-d6,400MHz):7.7 4(1H,d),7.36(5H,m),7.34-7.26(1H,m),5.01
(2H,s),4.51(1H,d),4.02(1H,t),3.96(1H,d),3.73(1H,m),3.66(1H,m),3.68(1H,m),2.53
(1H,m),1.86-1.76(2H,m),1.70-1.30(10H,m),1.39(9H,s),1.15-0.85(5H,m).
Step 2:Prepare 2- ((S) -2- ((S) -2- cyclohexyl -2- (pyrazine -2- formamido group) acetylamino) -3,3- two
Methylbutyryl) octahydro cyclopenta [c] pyrroles-l- carboxylic acid (lS, 3aR, 6aS)-tert-butyl ester
Pyrazine -2- carboxylic acid (1.6070g, 12.95mmol) and DMF (4ml) are added into 100ml round-bottomed flask.In 20-25
DEG C stirring slurry.Meanwhile burn CDI (2.1012g, 12.96mmol, 1 molar equivalent) and DMF (8.80g, 9.3ml) in 25ml
Combination system slightly heats (30 DEG C) promotion dissolutions for CDI solution in bottle.So that CDI solution is cooled to 20-25 DEG C, is added into pyrrole
In piperazine -2- carboxylic acid slurry material.Continue stirring 1.5 hours to ensure sour activation completely, generates carbon dioxide by-product.Meanwhile making 2-
((S) -2- ((S) -2- amino -2- cyclohexylacetamido) -3,3- dimethylbutanoyl) octahydro cyclopenta [c] pyrroles -
L- carboxylic acid (lS, 3aR, 6aS)-tert-butyl ester (5.0002g, 10.78mmol) is dissolved in DMF (l4.15g, 15ml), is slightly heated up to
30 DEG C of promotion dissolution of raw material.The solution is set to be cooled to 20-25 DEG C.The pyrazine solution of activation is set also to be cooled to about 15 DEG C.By 2-
((S) -2- ((S) -2- amino -2- cyclohexylacetamido) -3,3- dimethylbutanoyl) octahydro cyclopenta [c] pyrroles -
L- carboxylic acid (lS, 3aR, 6aS)-tert-butyl ester solution is added in the pyrazine -2- carboxylic acid of activation, while temperature being made to maintain 30 DEG C about
1 hour.It allows the solution to be cooled to 20-25 DEG C, is then added in water (100mL) solution of potassium carbonate (0.25g) at 0 DEG C.It will mix
Object filtering is closed, is washed with water (4 times, each 50ml).Filter cake is started to be dried in vacuo at 20-25 DEG C, 30 DEG C are warmed to after 24 hours,
Until filter cake weight is constant, 2- ((S) -2- ((S) -2- cyclohexyl -2- (pyrazine -2- formamido group) acetylamino) -3,3- is obtained
Dimethylbutanoyl) octahydro cyclopenta [c] pyrroles-l- carboxylic acid (lS, 3aR, the 6aS)-tert-butyl ester (5.99g).
1H NMR(DMSO-d6,400MHz):9.19ppm (1H, d, J=1.3Hz), 8.90ppm (1H, d, J=2.5Hz),
8.76ppm (1H, dd, J=2.4Hz, 1.5Hz), 8.50ppm (1H, d, J=9.2Hz), 8.22ppm (1H, d, J=9.0Hz),
4.68ppm (1H, dd, J=9.1Hz, 6.6Hz), 4.53ppm (1H, d, J=9.0Hz), 3.96ppm (1H, d, J=4.2Hz),
3.73ppm (1H, dd, J=10.5Hz, 7.5Hz), 3.68ppm (1H, dd, J=10.6Hz, 3.4Hz), 2.68-2.7 4ppm
(1H,m),2.52-2.58ppm(1H,m),1.70-1.88ppm(3H,m),1.51-1.69ppm(7H,m),1.31-1.44ppm
(2H,m),1.39ppm(9H,s),1.00-1.19ppm(4H,m),0.97ppm(9H,s),0.91-0.97ppm(lH,m).
Step 3:Prepare telavi
With nitrogen by be equipped with overhead, condenser, thermocouple and nitrogen outlet 500ml three neck round bottom blow it is several
Minute.By 2- ((S) -2- ((S) -2- cyclohexyl -2- (pyrazine -2- formamido group) acetylamino) -3,3- dimethylbutanoyl)
Octahydro cyclopenta [c] pyrroles-l- carboxylic acid (lS, 3aR, 6aS)-dichloromethane a heatable brick bed of the tert-butyl ester (28.64g) in dichloromethane a heatable brick bed
Solution is added in reaction flask, is subsequently added into 15%w/w NaBr (13ml) aqueous solution and 7.5%w/w NaHCO3(52ml) water
Solution.The solution is set to be cooled to 5 DEG C in ice bath.Reaction mixture is added in the TEMPO (0.7g) that methylene chloride (3ml) will be dissolved in
It is interior.In individual Erlenmeyer flask, 10-13%NaOCl solution (23.25ml, concentration 108mg/ are diluted with water (70ml)
ML, 2.51g, 33.7mmol, 1.12 molar equivalent).NaOCl solution is added in reaction mixture through addition funnel, addition
Rate makes temperature be maintained at less than 8 DEG C.Reaction mixture is allowed to stir at 5 DEG C 1 hour.Each layer is separated, by organic layer with 10% (w/w)
Na2SO3(l00mL) aqueous solution quenches, and is washed with water (l00mL).Make organic phase decompression reduction drying, by solid acetic acid second
Ester (l00mL) grinding, is filtered on Buchner funnel.It is dry, obtain telavi 16.6g.
1H NMR(DMSO-d6,400MHz)δ1.84-2.09(m,5H),2.29-2.63(m,1H),3.18-3.24(m,
1H), 4.04 (t, J=7.2Hz, 1H), 4.77 (d, J=2.7Hz, 1H), 6.35 (d, J=3.3Hz, 1H), 6.59-6.64 (m,
1H), 7.07 (s, 1H), 7.15-7.42 (m, 6H), 7.51 (t, J=9.0Hz, 1H), 7.70 (d, J=3.9Hz, 1H), 8.12
(d, J=2.4Hz, 1H), 8.23 (d, J=3.2Hz, 1H), 8.60 (s, 1H), 8.67 (s, 1H), 10.67 (brs, 1H),13C
NMR(DMSO-d6,100MHz)δ24.27MHz)δ24.27,29.16,47.10,60.84,60.98,107.81,122.97,
126.04,127.93,128.19,128.68,128.97,129.35,131.91,133.95,134.99,145.66,146.01,
149.80,157.11,169.05,171.60,181.50.LC/MS(ESI)m/z:680.19[M+H]+.HRMS(m/z):calcd
for C36H53N7O6,HPLC tR=28.57min, 98.0%.
Prepare telavi novel crystal forms
The telavi of 14.8g is mixed with 370mL glycol dimethyl ether, 70 DEG C is heated to and dissolves.Solution is cooling
To 50 DEG C, water (440mL) is added dropwise into system, after stirring 2-4 hours, filtering, 50 DEG C are dried in vacuo 12 hours, obtain 13.9g
Telavi white powder.
Obtained white powder is detected through XRPD, DSC and TGA.
XRPD
Use Bruker AXS D8 advance powder x-ray diffraction, Cu-K α radiation, wavelengthX is obtained to penetrate
Line diffraction data, is shown in Fig. 1.
TGA
TGA measurement is carried out using TGA Q500 V20, and temperature range is 25-350 DEG C, 10 DEG C/min, sees Fig. 2.
DSC
Use the DSC (DSC Q2000, TA Instruments USA) equipped with RCS90 cooling attachment, example weight
3.42mg, 10 DEG C/min, is shown in Fig. 3 by 30-350 DEG C of temperature range.
Claims (6)
1. a kind of novel crystal forms of telavi, the X-ray powder diffraction collection that is indicated with the 2 θ ± 0.2 ° angles of diffraction 10.78,
11.62, it shows at 18.04,20.90,23.12,27.72,31.00,31.90,32.86,33.44,37.30,46.78 and 47.10
It is shown with characteristic diffraction peak.
2. a kind of novel crystal forms of telavi according to claim 1, which is characterized in that measured using Cu-K alpha ray
The X-ray powder diffraction figure arrived is as shown in Figure 1.
3. a kind of preparation method of telavi novel crystal forms as claimed in claim 1 or 2, it is characterised in that including walking as follows
Suddenly:
Step (1) takes telavi, and solvent is added, is heated to 70 DEG C, stirs evenly;
Step (1) acquired solution is adjusted the temperature to 40-60 DEG C by step (2), and water is added dropwise;
Step (3) insulated and stirred is complete to crystallization, filters, and washes, dry, obtains telavi.
4. a kind of preparation method of telavi novel crystal forms as claimed in claim 3, which is characterized in that described in step (1)
Solvent is selected from water, methanol, ethyl alcohol, isopropanol, normal heptane, glycol dimethyl ether, the mixed solvent of water and methanol, water and ethyl alcohol
Mixed solvent, the mixed solvent of water and isopropanol, water and glycol dimethyl ether mixed solvent;Step (1) described telavi
Mass volume ratio with solvent is 1g:10ml~1g:50ml;The mass volume ratio of step (2) telavi and water is 1g:
10ml~1g:50ml.
5. a kind of preparation method of telavi novel crystal forms as claimed in claim 4, which is characterized in that described in step (1)
Solvent be selected from water, methanol, ethyl alcohol, glycol dimethyl ether, water and the mixed solvent of methanol, the mixed solvent of water and ethyl alcohol, water and
The mixed solvent of glycol dimethyl ether;The mass volume ratio of step (1) telavi and solvent is 1g:25ml;Step (2)
The mass volume ratio of the telavi and water is 1g:20ml~1g:30ml.
6. a kind of preparation method of telavi novel crystal forms as claimed in claim 3, which is characterized in that step (3) is described to support
The brilliant time is 1h~5h;Step (3) drying temperature is 40 DEG C~80 DEG C.
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CN102875649A (en) * | 2012-09-26 | 2013-01-16 | 深圳翰宇药业股份有限公司 | Method for preparing telaprevir and intermediate thereof and intermediate |
CN104870439A (en) * | 2012-12-21 | 2015-08-26 | 桑多斯股份公司 | Novel forms of telaprevir |
CN103342736A (en) * | 2013-07-04 | 2013-10-09 | 苏州永健生物医药有限公司 | Synthesis method of telaprevir |
CN105646653A (en) * | 2014-11-11 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | Stable telaprevir compound |
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