CN103483420A - Telaprevir intermediate in B crystal form and synthesis method thereof - Google Patents
Telaprevir intermediate in B crystal form and synthesis method thereof Download PDFInfo
- Publication number
- CN103483420A CN103483420A CN201310438815.3A CN201310438815A CN103483420A CN 103483420 A CN103483420 A CN 103483420A CN 201310438815 A CN201310438815 A CN 201310438815A CN 103483420 A CN103483420 A CN 103483420A
- Authority
- CN
- China
- Prior art keywords
- crystal formation
- methyl
- glycyl
- cyclohexyl
- valine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Abstract
The invention relates to a telaprevir intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl)-glycyl-3-methyl-L-valine in a B crystal form, and a synthesis method thereof, and belongs to the technical field of drug synthesis. The telaprevir intermediate in the B crystal form is subjected to Cu-Ka radiation by adopting X-ray powder diffraction at the angle of 2 times of Theta, characteristic peaks appear at the points of 5.5+/-0.2, 7.4+/-0.2, 10.7+/-0.2, 16.7+/-0.2, 17.4+/-0.2, 17.6+/-0.2, 18.4+/-0.2, 19.2+/-0.2, 20.5+/-0.2, 21.5+/-0.2, and 22.1+/-0.2; the solid is white, the melting point is 221.6-229.3 DEG C, the moisture content is 0.1-0.5 percent, and the residue solvent is 8-12 percent. The invention further discloses the synthesis method for the telaprevir intermediate in the B crystal form. The telaprevir intermediate in the B crystal form is good in appearance, small in moisture content, high in temperature and humidity stability, and high in purity.
Description
Technical field
The present invention relates to a kind of VX-960 intermediate and synthetic method thereof, be specifically related to a kind of VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation and synthetic method thereof, belong to technical field of medicine synthesis.
Background technology
VX-960 (TVR); chemical name: (1S; 3aR; 6aS)-(2S)-2-cyclohexyl-N-(carbonyl pyrazine)-glycyl-3-methyl-L-valyl-N-(1S)-1-[(cyclopropylamino)-oxo ethanoyl] butyl-octahydro ring penta [c] pyrroles-1-methane amide; CAS registration number: 402957-28-2; be a kind of HCV gene 1 type NS3/4A serine protease to be had to restraining effect, can stop the medicine that HCV copies.Can and prevent that thereby its propagation from playing the effect of protease inhibition by combination virus.The VX-960 structural formula is as follows:
In May, 2011, the listing of the VX-960 of U.S. FDA approved Vertex drugmaker, commodity are called Incivek, for accepting before the invalid or untreated of interferon therapy, and suffer from the third liver adult patients of other hepatopathys.In July, 2011, the Interferon, rabbit of medication management office direction EU Committee of European Union suggestion approval VX-960 and PEGization; AlPHa and ribavirin are combined use, can significantly improve the third hepatopath's curative ratio, and can significantly shorten treatment course for the treatment of, within 48 weeks, foreshorten to 24 weeks by standard the course for the treatment of.In August, 2011, Incivek also gets the Green Light in Canada.The Janssen pharmacy obtains the approval listing VX-960 of European Union, and commodity are called Incivo, can use in each member states of European Union, is used for the treatment of the third liver adult patients.
Therefore because this medicine is safe, and administration time is short, can reduce the untoward reaction that long-term prescription brings to the patient, is the most effective HCV medicine since two thousand one.
And (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine is the important intermediate of VX-960, CAS registration number: 402958-96-7, structural formula is as follows:
In prior art, the document of relevant VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine has:
As pct international patent (publication number: WO2011103932A1) with Anass Znabet, the people's such as Marloes M.Polak (A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions, The Royal Society of Chemistry46 (2010) 7918-7920), they all relate to synthetic VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, and concrete synthetic route is as follows:
And for example U.S.'s patent of invention (publication number: US201029686), it has related to the synthetic method of a kind of VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, and concrete synthetic route is as follows:
Yvonne Yip and for example, the people's such as Frantz Victor (P4and P1 ' optimization of bicycloproline P2bearing tetrapeptidyl α-ketoamides as HCV protease inhibitors, Bioorganic& Medicinal Chemistry Letters14 (2004) 5007-5011) also disclose the method for a kind of synthetic VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine in, concrete synthetic route is as follows:
Although three kinds of above-mentioned synthetic methods have finally all been synthesized VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, but the synthetic VX-960 intermediate obtained is white solid (white solid), purity is not high, and in above-mentioned three kinds of documents, all crystal formation and some other physical properties of this intermediate is not described, and these all may affect the drug effect of the finished product.
Summary of the invention
The present invention is directed to the above-mentioned problems in the prior art, carry out unexpected discovery the in a large amount of system experimentation research at the crystal formation to VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, can make it more stable synthetic certain crystallized form of VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, and there is no the research report about VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine crystal formation in prior art.The invention provides a kind of temperature and humidity good stability, the new crystal of the VX-960 intermediate (2S) that purity is high-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, i.e. B crystal formation for this reason.
VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, use the Cu-Ka radiation, with 2 θ angles, mean that the X-ray powder diffraction has characteristic peak 5.5 ± 0.2,7.4 ± 0.2,10.7 ± 0.2,16.7 ± 0.2,17.4 ± 0.2,17.6 ± 0.2,18.4 ± 0.2,19.2 ± 0.2,20.5 ± 0.2,21.5 ± 0.2,22.1 ± 0.2.
The X-ray powder diffraction test of VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation has been measured under envrionment temperature and ambient moisture." envrionment temperature " is generally 0-40 ℃; " ambient moisture " is generally the relative humidity of 30%-80%.
VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-representational X-ray powder diffraction of 3-methyl-Valine B crystal formation is shown in accompanying drawing 1." representational X-ray powder diffraction " refers to the whole pattern that compound collection of illustrative plates of X-ray powder diffraction feature of this crystal formation shows, be understandable that in test process, due to the impact that is subject to many factors, the treatment process of sample, instrument, test parameter, test operation etc. during as the granularity of specimen, test, the X-ray powder diffraction that the same crystal formation is measured go out peak position or peak intensity has certain difference.Therefore, the X-ray powder diffraction of VX-960 intermediate B crystal formation of the present invention, the experimental error of its diffraction peak 2 θ values is generally ± and 0.2.
VX-960 intermediate (2S) of the present invention-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, its DSC scanning has first endotherm(ic)peak between 150～180 ℃, particularly 172.19 ℃ of left and right, maximum endotherm(ic)peak is arranged.Second endotherm(ic)peak, between 215～250 ℃, particularly has maximum endotherm(ic)peak 203.05 ℃ of left and right.And second endotherm(ic)peak obviously is better than first endotherm(ic)peak.The DSC spectrogram of VX-960 intermediate B crystal formation of the present invention is shown in Fig. 2.
The outward appearance of VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation is white solid, fusing point is 221.6～229.3 ℃, water content 0.1%～0.5%, residual solvent 8%～12%.Wherein, described residual solvent is included as halohydrocarbon, anhydrous saturated alkane class, anhydrous ester class, one or more in anhydrous ethers.Further preferably, described halohydrocarbon comprises methylene dichloride, ethylene dichloride, and described anhydrous saturated alkane class is normal heptane, and described anhydrous ester class comprises ethyl acetate, and described anhydrous ethers comprises methyl tertiary butyl ether, ether, isopropyl ether.
The chemical shift of the proton nmr spectra of VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation is 12.5 (bs, 1H), 9.2 (d, J=1.6Hz, 1H), 8.91 (d, J=2.4Hz, 1H), 8.77 (dd, J=1.2Hz, 2.4Hz, 1H), (8.51 d, J=10.8Hz, 1H), (8.22 d, J=8.8Hz, 1H), 4.69 (dd, J=6.8Hz, 9.2Hz, 1H), 4.11 (d, J=8.8Hz, 1H), 1.58～1.81 (m, 6H), 1.08～1.11 (m, 18H).The proton nmr spectra spectrogram of VX-960 intermediate B crystal formation of the present invention is shown in Fig. 3.
The chiral purity of VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation is 100.00%, and its chiral chromatography spectrogram is shown in Fig. 5.
Liquid phase-the mass spectrum of VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation is LC/MS=377(M
++ 1), 399(M
++ Na), its liquid phase-mass spectrogram is shown in Fig. 6.
Another object of the present invention is to provide the synthetic method of above-mentioned VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, described synthetic method comprises following method, but is not limited to following method:
Method one: VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine is added in good solvent, be heated to the reflux temperature of good solvent to the solution clarification, solution is concentrated into dry, then add the poor solvent processing of pulling an oar, standing rear suction filtration is collected crystal, drying, obtain VX-960 intermediate B crystal formation.
Method two: under stirring, good solvent is added in VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, reflux temperature to the VX-960 intermediate that is heated to good solvent all dissolves, then add poor solvent to solid all to separate out, standing after stirring, suction filtration is collected crystal, and drying, obtain VX-960 intermediate B crystal formation.
Method three: under stirring, poor solvent is added in VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, be heated to the reflux temperature of poor solvent, reflux and stir after 5～8 hours, suction filtration is collected crystal, drying, obtain VX-960 intermediate B crystal formation.
Method four: under stirring, good solvent is added in VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine A crystal formation, be heated to the reflux temperature of good solvent to the solution clarification, solution is concentrated into dry, add again poor solvent to be pulled an oar, after making beating, suction filtration is collected crystal, and drying, obtain VX-960 intermediate B crystal formation.
The crystallization condition difference of same compound, especially recrystallisation solvent difference, the crystal habit obtained also may be different.The present invention is screened by the recrystallisation solvent to VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, optimizes the crystallization method and the recrystallisation solvent that are applicable to forming VX-960 intermediate B crystal formation.
In the synthetic method of above-mentioned four kinds of VX-960 intermediates (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, as preferably, described good solvent is alkyl alcohol, aromatic alcohol, alkyl acid, ketone, or one or more in tetrahydrofuran (THF), acetonitrile, DMF, methyl-sulphoxide.VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine has higher solubleness in described good solvent, can reduce the consumption of solvent, cost-saving.Further preferably, described alkyl alcohol comprises methyl alcohol, ethanol, propyl alcohol, and described aromatic alcohol comprises phenylcarbinol, phenylethyl alcohol, and described alkyl acid comprises formic acid, acetic acid, and described ketone comprises acetone, butanone, Propiophenone.
In the synthetic method of above-mentioned four kinds of VX-960 intermediates (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, as preferably, described poor solvent is halohydrocarbon, anhydrous saturated alkane class, anhydrous ester class, one or more in anhydrous ethers.These poor solvent polarity are little, low to the solubleness of VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine.Further preferably, described halohydrocarbon comprises methylene dichloride, ethylene dichloride, and described anhydrous saturated alkane class comprises normal heptane, and described anhydrous ester class comprises ethyl acetate, and described anhydrous ethers comprises methyl tertiary butyl ether, ether, isopropyl ether.
Wherein, described VX-960 intermediate A crystal formation can be synthetic by following two kinds of methods:
VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine is joined in good solvent, slowly dripping poor solvent to solid under reflux separates out, cooling, standing, suction filtration is collected crystal, the dry VX-960 intermediate A crystal formation that obtains.
Or VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine is joined in poor solvent, slowly dripping good solvent to solid after reflux just dissolves, cooling, standing rear suction filtration, the dry VX-960 intermediate A crystal formation that obtains.
Wherein, in the synthetic method of above-mentioned VX-960 intermediate A crystal formation, described good solvent is selected from one or more in methyl alcohol, ethanol, phenylcarbinol, phenylethyl alcohol, formic acid, acetic acid, acetone, tetrahydrofuran (THF), acetonitrile, DMF, methyl-sulphoxide.Described poor solvent is alkyl alcohol and water, aromatic alcohol and water, and alkyl acid and water, a kind of mixed solvent in ketone and water, in described mixed solvent, the mass percent of water is 50%～100%.
In addition, VX-960 intermediate of the present invention also can be scattered in by B crystal formation that will be residual containing solvent β and be dissolved in solvent α containing the residual B crystal formation of solvent α, and under the reflux temperature of solvent α, reflux is after 5～8 hours, and cooling suction filtration obtains.Wherein, as preferably, described solvent α and solvent β are selected from respectively anhydrous saturated alkane class, anhydrous ester class, a kind of in anhydrous ethers.Further preferably, described anhydrous saturated alkane class is selected from a kind of in normal heptane, normal hexane, Skellysolve A, described anhydrous ester class is selected from a kind of in ethyl acetate, isopropyl acetate, and described anhydrous ethers is selected from a kind of in methyl tertiary butyl ether, isopropyl ether.
The present invention has the following advantages:
1, the outward appearance of VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation is good, and water content is few, the temperature and humidity good stability, and purity is high.
2, the synthetic method of VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation is simple to operate, used time is shorter, suitability for industrialized production is easy to operate, quality controllable, is conducive to save energy.
The accompanying drawing explanation
Fig. 1 is that VX-960 intermediate B crystal formation does not add the powder x-ray diffraction figure that monochromator obtains, and length axis means diffracted intensity, and axis of abscissa means diffraction angle (2 θ).
The DSC spectrogram that Fig. 2 is VX-960 intermediate B crystal formation.
The proton nmr spectra spectrogram that Fig. 3 is VX-960 intermediate B crystal formation.
The liquid chromatography spectrogram that Fig. 4 is VX-960 intermediate B crystal formation.
The chiral chromatography spectrogram that Fig. 5 is VX-960 intermediate B crystal formation.
Liquid phase-mass spectrogram that Fig. 6 is VX-960 intermediate B crystal formation.
Fig. 7 is according to (the publication number: the liquid chromatography spectrogram of VX-960 intermediate WO2011103932A1) obtained of pct international patent in prior art.
Embodiment
In order to make technical problem solved by the invention, technical scheme and beneficial effect clearer, below in conjunction with the specific embodiments and the drawings explanation, the present invention is further elaborated.Should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not intended to limit the present invention.
In accompanying drawing of the present invention explanation, relevant VX-960 intermediate (2S) in Fig. 1-7-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation contains 0.17% moisture content, 10% residual methyl tert-butyl ether solvent.
10g VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine is joined in the 25mL dehydrated alcohol, after 80 ℃ of lower reflux to solution is clarified, under the condition of 40 ℃, be concentrated into dry, then add the making beating of 50mL ethyl acetate after 4 hours, standing, suction filtration is collected crystal, and drying, obtain 9.3g VX-960 intermediate B crystal formation (containing a small amount of ethyl acetate solvent in lattice).Purity is 99.10%, and chiral purity is 100%.
Under stirring, the 30mL dehydrated alcohol is added in 10g VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, be heated to the VX-960 intermediate and all dissolve the formation reaction solution under 80 ℃, when being cooled to 30 ℃, reaction solution add normal heptane to solid all to separate out, stir standing after 4 hours, suction filtration is collected crystal, and drying, obtain 8.7 gram VX-960 intermediate B crystal formations.Purity is 99.36%, and chiral purity is 99.86%.
Under stirring, the 40mL methylene dichloride is added in 5g VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, 40 ℃ of lower reflux after 3 hours, naturally cool to room temperature, suction filtration is collected crystal, drying, obtain 4.2g VX-960 intermediate B crystal formation.Purity is 99.30%, and chiral purity is 99.62%.
20g VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine (purity 98.4%) is joined in the Virahol of 60mL, drip the mixed solvent of 35mL acetone and 70mL water to just having solid to separate out under 85 ℃ of lower reflux, after naturally cooling to room temperature, standing, suction filtration is collected crystal, dried overnight under the condition of 50 ℃, obtain 17.8g VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine A crystal formation;
Under stirring, the 30mL dehydrated alcohol is added in the above-mentioned 10g VX-960 intermediate (2S) made-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine A crystal formation, reflux molten clear after, be concentrated into dry, after adding the 50mL methyl tertiary butyl ether at room temperature to pull an oar 4 hours, suction filtration is collected crystal again, drying, obtain 9.5g VX-960 intermediate B crystal formation (containing a small amount of methyl tert-butyl ether solvent in lattice).Purity is 99.8%, and chiral purity is 100%.
Under stirring, the VX-960 B crystal formation (containing ethyl acetate solvent in lattice) obtained in 3.0g embodiment 1 is added in the methyl tertiary butyl ether of 30mL to the reflux making beating after 5 hours, naturally cool to room temperature, suction filtration is collected crystal, drying, obtain 2.8g VX-960 B crystal formation (containing methyl tert-butyl ether solvent in lattice).Purity is 99.64%, and chiral purity is 100%.
Comparative Examples
In prior art, pct international patent (publication number: the VX-960 intermediate (2S) WO2011103932A1)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, its purity 98.4%, 185.1～185.5 ℃ of fusing points, water content 0.23%.
Randomly draw VX-960 intermediate (2S) in VX-960 intermediate (2S) in the embodiment of the present invention-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal form samples and Comparative Examples-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine and carry out the stability contrast experiment.Carried out high-temperature stability test (12h, 48h, 72h) at 75 ℃, test result is as shown in table 1.
Table 1: the stability test result of VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine in VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation and Comparative Examples
As can be drawn from Table 1, VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation has better high-temperature stability than (2S)-2-cyclohexyl-N-of the prior art (2-pyrazinyl carbonyl) glycyl-3-methyl-Valine.
The VX-960 intermediate of randomly drawing in VX-960 intermediate (2S)-2-cyclohexyl-N-in the embodiment of the present invention (2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal form samples and Comparative Examples is detected by liquid chromatography.
Testing conditions: instrument: Agilent 1100 high performance liquid chromatographs;
Chromatographic column: Luna C18,4.6mm * 250mm, 5 μ m;
Column temperature: 25 ℃;
Flow velocity: 1.0mL/min;
Detect wavelength: 210nm;
Sampling volume: 5.0 μ L;
Moving phase: acetonitrile: 0.1% phosphate aqueous solution=60:40 (v/v);
Working time: 30min.
Detect the liquid chromatography spectrogram of VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal form samples in the rear embodiment of the present invention as shown in Figure 4; Analytical results is as shown in table 2.
Table 2: VX-960 intermediate (2S)-2-cyclohexyl-N-in the embodiment of the present invention (2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal form samples liquid-phase chromatographic analysis result
After detecting, the liquid chromatography spectrogram of comparative example as shown in Figure 7; Analytical results is as shown in table 3.
Table 3: the liquid-phase chromatographic analysis result of VX-960 intermediate sample in Comparative Examples
From Fig. 4 and 7, table 2 and table 3 can be found out: the purity of VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation is higher, reach 99.86%, and in Comparative Examples, the purity of VX-960 intermediate is only 98.3959%.
Extracting immediately VX-960 intermediate (2S) in the embodiment of the present invention-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal form samples detects by chiral chromatography.As shown in Figure 5, analytical results is as shown in table 4 for chiral chromatography spectrogram after detection.
Table 4: the chiral chromatographic analysis result of VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal form samples
From Fig. 5 and table 4, can find out, VX-960 intermediate of the present invention (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation chiral purity is high, reaches 100.00%.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any modifications of doing within the spirit and principles in the present invention, be equal to and replace and improvement etc., within all should being included in protection scope of the present invention.
Claims (8)
1. a VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, it is characterized in that, described VX-960 intermediate B crystal formation: use the Cu-Ka radiation, with 2 θ angles, mean that the X-ray powder diffraction has characteristic peak 5.5 ± 0.2,7.4 ± 0.2,10.7 ± 0.2,16.7 ± 0.2,17.4 ± 0.2,17.6 ± 0.2,18.4 ± 0.2,19.2 ± 0.2,20.5 ± 0.2,21.5 ± 0.2,22.1 ± 0.2.
2. VX-960 intermediate according to claim 1 (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, it is characterized in that, the DSC scanning of described VX-960 intermediate B crystal formation has first endotherm(ic)peak between 150～180 ℃, and second endotherm(ic)peak is between 215～250 ℃.
3. VX-960 intermediate according to claim 1 (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, it is characterized in that, the outward appearance of described VX-960 intermediate B crystal formation is white solid, fusing point is 221.6～229.3 ℃, water content 0.1%～0.5%, residual solvent 8%～12%.
4. VX-960 intermediate according to claim 1 (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, it is characterized in that, the chemical shift of the proton nmr spectra of described VX-960 intermediate B crystal formation is 12.5 (bs, 1H), 9.2 (d, J=1.6Hz, 1H), 8.91 (d, J=2.4Hz, 1H), 8.77 (dd, J=1.2Hz, 2.4Hz, 1H), 8.51 (d, J=10.8Hz, 1H), 8.22 (d, J=8.8Hz, 1H), 4.69 (dd, J=6.8Hz, 9.2Hz, 1H), 4.11 (d, J=8.8Hz, 1H), 1.58～1.81 (m, 6H), 1.08～1.11 (m, 18H).
5. the synthetic method of VX-960 intermediate as described as arbitrary claim in claim 1-4 (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, it is characterized in that, this synthetic method comprises the following steps: VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine is joined in good solvent, be heated to the reflux temperature of good solvent to the solution clarification, solution is concentrated into dry, then add the poor solvent processing of pulling an oar, standing rear suction filtration is collected crystal, dry, obtain VX-960 intermediate B crystal formation.
6. the synthetic method of VX-960 intermediate as described as arbitrary claim in claim 1-4 (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, it is characterized in that, this synthetic method comprises the following steps: under stirring, good solvent is added in VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, be heated to the reflux temperature of good solvent to all dissolving, then add poor solvent to solid all to separate out, standing after stirring, suction filtration is collected crystal, dry, obtain VX-960 intermediate B crystal formation.
7. the synthetic method of VX-960 intermediate as described as arbitrary claim in claim 1-4 (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, it is characterized in that, this synthetic method comprises the following steps: under stirring, poor solvent is added in VX-960 intermediate (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine, be heated to the reflux temperature of poor solvent, reflux and stir after 5～8 hours, suction filtration is collected crystal, drying, obtain VX-960 intermediate B crystal formation.
8. the synthetic method of VX-960 intermediate as described as arbitrary claim in claim 1-4 (2S)-2-cyclohexyl-N-(2-pyrazinyl carbonyl) glycyl-3-methyl-Valine B crystal formation, it is characterized in that, this synthetic method comprises the following steps: under stirring, good solvent is added in VX-960 intermediate A crystal formation, be heated to the reflux temperature of good solvent to the solution clarification, solution is concentrated into dry, add again poor solvent to be pulled an oar, after making beating, suction filtration is collected crystal, drying, obtain VX-960 intermediate B crystal formation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310438815.3A CN103483420B (en) | 2013-09-24 | 2013-09-24 | A kind of Telaprevir intermediate in B crystal form and synthetic method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310438815.3A CN103483420B (en) | 2013-09-24 | 2013-09-24 | A kind of Telaprevir intermediate in B crystal form and synthetic method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103483420A true CN103483420A (en) | 2014-01-01 |
| CN103483420B CN103483420B (en) | 2015-09-16 |
Family
ID=49824061
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310438815.3A Expired - Fee Related CN103483420B (en) | 2013-09-24 | 2013-09-24 | A kind of Telaprevir intermediate in B crystal form and synthetic method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103483420B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103113288A (en) * | 2013-02-04 | 2013-05-22 | 苏州永健生物医药有限公司 | Synthesis method of octahydro-cyclopenta[c]pyrrole carboxylic acid derivative |
| WO2013131978A1 (en) * | 2012-03-07 | 2013-09-12 | Dipharma Francis S.R.L. | Process for the preparation of intermediates useful in the preparation of a viral protease inhibitor |
-
2013
- 2013-09-24 CN CN201310438815.3A patent/CN103483420B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013131978A1 (en) * | 2012-03-07 | 2013-09-12 | Dipharma Francis S.R.L. | Process for the preparation of intermediates useful in the preparation of a viral protease inhibitor |
| 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 |
| CN103113288A (en) * | 2013-02-04 | 2013-05-22 | 苏州永健生物医药有限公司 | Synthesis method of octahydro-cyclopenta[c]pyrrole carboxylic acid derivative |
Non-Patent Citations (1)
| Title |
|---|
| ANASS ZNABET ET AL: "A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions", 《CHEM COMMUN》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103483420B (en) | 2015-09-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108424388B (en) | Preparation method of medicine for treating chronic anemia | |
| CN103086993B (en) | Method for crystallizing valsartan | |
| US20190248750A1 (en) | Method for producing (4s)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro pyrimidine-5-carbonitrile | |
| CN108947949B (en) | Anxiolytic deuterated compounds and medical application thereof | |
| CN103435532A (en) | Synthetic method of boceprevir intermediate | |
| CN105646633A (en) | Method for preparing obeticholic acid type 1 | |
| CN105503854A (en) | New crystal form substance of Dasatinib anhydrous substance and preparation method thereof | |
| WO2012167413A1 (en) | Method for preparing optically pure (-)-clausenamide compound | |
| CN103483420B (en) | A kind of Telaprevir intermediate in B crystal form and synthetic method thereof | |
| CN104557899B (en) | A kind of preparation method of Azilsartan I crystal crystal | |
| CN105884644A (en) | Advantage forms and preparation method of neutral endopeptidase inhibitor salt | |
| RU2631323C2 (en) | Method for production of 4-benzyl-1-phenethyl-piperazin-2,6-dione, intermediate compound and method for its production | |
| CN102898439B (en) | Preparation method of descarbamoyl cefuroxime lactone | |
| CN103483419B (en) | A kind of Telaprevir intermediate C crystal form and synthetic method thereof | |
| CN110804022B (en) | Preparation method of dexrazoxane | |
| RU2669785C2 (en) | Polymorphic form of sodium hyodeoxycholate (nahdc) and preparation process thereof | |
| CN103497234B (en) | Telaprevir intermediate crystal form-A and synthesis method thereof | |
| CN103242244B (en) | Canertinib preparation method | |
| CN103739568A (en) | Preparation method of 2-(3-cyan-4-isobutoxyphenyl)-4-methylthiazole-5-formic acid A crystal | |
| CN108373437A (en) | A kind of preparation method of Atorvastatin calcium isomers | |
| CN104693131A (en) | Efficient chemical synthesizing method of 3-methyl-quinoxaline-2-carboxylic acid | |
| CN105399683A (en) | Benzimidazole derivative and preparation method therefor. | |
| CN104817546A (en) | Method for recovering olmesartan medoxomil mother solution | |
| CN114874132A (en) | Preparation method of recombinant human receptor protein FKBP12 ligand | |
| JP2015034141A (en) | Method for producing 4-methoxy cinnamic acid 2-ethylhexyl compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| CB03 | Change of inventor or designer information |
Inventor after: Hu Fan Inventor after: Wang Shenyong Inventor after: Li Sheng Inventor after: Wang Xiaojun Inventor after: Hu Changchun Inventor before: Hu Fan Inventor before: Wang Shenyong Inventor before: Li Sheng Inventor before: Wang Xiaojun Inventor before: Hu Juankai |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: HU FAN WANG SHENYONG LI SHENG WANG XIAOJUN HU JUNKAI TO: HU FAN WANG SHENYONG LI SHENG WANG XIAOJUN HU CHANGCHUN |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150916 Termination date: 20210924 |