CN102838594B - Preparation and refining methods of dasatinib - Google Patents
Preparation and refining methods of dasatinib Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to the synthesis field of dasatinib and novel preparation and refining methods of the dasatinib. The preparation method of the dasatinib comprises the step of allowing an intermediate N-(2-chlorine-6-methoxyphenyl)-2[(6-chlorine-2-methyl-4-pyrimidyl) amino]-5-thiazole formamide to perform homogeneous nucleophilic substitution reaction with 1-(2-ethoxyl) piperazine in a high-polar solvent. The preparation method solves the problems that n-butyl alcohol is adopted as a solvent in the traditional synthesis method, the cost is high, the reaction time is long, the reaction temperature is high, and the requirements on a reaction vessel are high. The invention provides a simple and feasible refining method, which improves the purity of the dasatinib effectively.
Description
Technical field
The present invention relates to medicinal chemistry art, particularly relate to the synthesis field of Dasatinib, relate in particular to a kind of new preparation and process for purification of Dasatinib.
Background technology
Dasatinib, it is a kind of TYR kinase inhibitor researched and developed by Bristol-Myers Squibb Co., for to the past Endodontic failure or all stadium patients of Adult chronic's myelogenous leukemia (CML) of not tolerating, be also used for the treatment of other therapy resistances or the acute lymphoblastic leukemia adult patient (ph+ALL) of Philadelphia Chromosome Positive that do not tolerate simultaneously.Its chemistry N-(the chloro-6-aminomethyl phenyl of 2-)-2-by name [[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] is amino]-5-thiazole carboxamides, molecular formula is C
22h
28clN
7o
2s, molecular weight is 488.01, and structural formula is:
In the synthetic method of current Dasatinib more commonly:
One, by intermediate N (the chloro-6-aminomethyl phenyl of 2-)-2 [(6-chloro-2-methyl-4-pyrimidyl) is amino]-5-thiazole carboxamides and 1-(2-hydroxyethyl) piperazine generation nucleophilic substitution reaction prepares Dasatinib.
Its two, 2-methyl-4,6-dichloro pyrimidine and N-(2-hydroxyethyl) piperazine generation substitution reaction, then be obtained by reacting Dasatinib with 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides.
They are three years old, 2-methyl-4-amino-6-chloropyrimide and N-(2-hydroxyethyl) piperazine generation substitution reaction, then react with isothiocyanic acid benzene methyl and generate thiocarbamide, then with N, the condensation of dinethylformamide acetal generates imines, and last closed loop obtains Dasatinib.
Due to the Pd (OAc) that the second synthetic method needs to use a large amount of toluene to be solvent and costliness
2with BINAP(dinaphthalene hexichol phosphorus) be catalyzer, do not meet environmental friendliness, the theory such as with low cost and easy and simple to handle, and severe reaction conditions, yield is not high.Meanwhile, the third method steps is various, and yield is low, and production cost is higher.So the method for current more use is first method, namely in n-butanol solvent, by intermediate N (the chloro-6-aminomethyl phenyl of 2-)-2 [(6-chloro-2-methyl-4-pyrimidyl) is amino]-5-thiazole carboxamides and 1-(2-hydroxyethyl) piperazine generation nucleophilic substitution reaction prepares Dasatinib.
But, find from a large amount of experiments, Dasatinib intermediate N (2-chloro-6-aminomethyl phenyl)-2 [(6-chloro-2-methyl-4-pyrimidyl) the is amino] solubleness of-5-thiazole carboxamides in propyl carbinol is very little, 1g Dasatinib intermediate needs 20ml propyl carbinol, reaction solution is in the state of being suspended all the time, carries out inhomogeneous reaction.This reaction requires backflow, and temperature of reaction is higher is 120 DEG C, and hot conditions proposes high requirement to conversion unit, and the reaction times is more than 5 hours.When solvent drops to 15 milliliters every gram from 20 milliliters every gram, the reaction times obviously extends, and finds that raw material fails to disappear completely (about having 3%) by HPLC monitoring.Adopt propyl carbinol as reaction solvent thus, not only cost is higher, and the reaction times is longer, and reaction is carried out in high reaction temperatures, has higher requirement to reaction vessel.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of preparation method of Dasatinib, particularly with intermediate N (the chloro-6-aminomethyl phenyl of 2-)-2 [(6-chloro-2-methyl-4-pyrimidyl) is amino]-5-thiazole carboxamides and 1-(2-hydroxyethyl) piperazine generation nucleophilic substitution reaction prepares the method for Dasatinib.Thus making solvent with propyl carbinol in solution prior synthesizing method, cost is high, long reaction time, temperature of reaction are high, require harsh problem to reaction vessel.
Another goal of the invention of the present invention is to provide a kind of process for purification of Dasatinib crude product, thus the problem that the part Dasatinib that solution process for purification purification step is loaded down with trivial details and high temperature dehydration causes is rotten.
Goal of the invention of the present invention is achieved through the following technical solutions,
A kind of method for synthesizing dasatinib, comprises the following steps:
S1. by chloro-for N-(2-6-aminomethyl phenyl)-2 [(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides is dissolved in intensive polar solvent completely;
S2. in the solution of S1,1-(2-hydroxyethyl is added) piperazine and diisopropylethylamine, 70-90 DEG C of reaction 2-3h, is cooled to room temperature;
Reaction equation:
S3. add Virahol in solution after reacting to S2, have solid to separate out, cooling, stir 2h, separate out completely, filtration;
S4. a small amount of isopropyl alcohol and water of filter cake washs successively, obtains Dasatinib crude product.
As the optimal way of intensive polar solvent described in the present invention, the invention discloses described intensive polar solvent is aprotic intensive polar solvent.Wherein again with dimethyl sulfoxide (DMSO) (DMSO), hexamethylphosphoramide (HMPA), N,N-DIMETHYLACETAMIDE (DMAC), acetonitrile for preferred solvent, be particularly preferably dimethyl sulfoxide (DMSO).
As preferred reacting material ratio: the chloro-6-aminomethyl phenyl of described N-(2-)-2 [(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides and 1-(2-hydroxyethyls) mol ratio of piperazine is 1:(3-5), the chloro-6-aminomethyl phenyl of N-(2-) mol ratio of-2 [(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides and diisopropylethylamine is 1:2;
As preferred reaction conditions: described intensive polar solvent consumption is every gram of chloro-6-aminomethyl phenyl of N-(2-)-2 [(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides is dissolved in the intensive polar solvent of 3-5ml.Described intensive polar solvent and Virahol amount ratio are 1:3(V:V).
As the preferred temperature of reaction of one, when temperature of reaction is 75-85 DEG C, its reaction is more complete.
Improved though of the present invention is the dissolving ratio increasing Dasatinib intermediate, makes it as much as possible homogeneous reaction occur.Because the polarity of Dasatinib intermediate is very large, solubleness in general alcoholic solvent is all less, so We conducted great many of experiments, is optimized gropes reaction solvent, experimental result shows, the solubleness of Dasatinib intermediate in intensive polar solvent is better.Therefore, in line with reduction production cost, reduce the consumption of solvent, alleviate objects such as the loads of plant and instrument, optimize the synthetic environment of Dasatinib, select intensive polar solvent, particularly aprotic intensive polar solvent is as solution environmental.
After adopting preparation method provided by the invention, its beneficial effect is apparent.Not only greatly reduce the consumption of solvent, save cost, and Dasatinib intermediate has higher solubleness in intensive polar solvent, reaction solution is made to be homogeneous reaction, accelerate the speed of reaction significantly, the reaction times is significantly shortened, and temperature of reaction significantly reduces, greatly reduce the load of instrument like this, make this reactive adaptation in industrialized production.
On above basis of improving, the invention also discloses a kind of process for purification of Dasatinib, comprise the following steps:
(1) the Dasatinib crude product will obtained according to above-mentioned preparation method, dissolve with the mixing solutions of 95% second alcohol and water, be heated to 70-80 DEG C, make it dissolve completely, the blending ratio of described 95% second alcohol and water is 5:1(V:V);
(2) filtered while hot, filtrate naturally cools to room temperature, then cryogenic freezing crystallization;
(3) filter, with the mixed solution washing of 50% cold on a small quantity second alcohol and water, obtain white solid, the blending ratio of described 50% second alcohol and water is 1:1(V:V);
(4) by white solid at the dry 3-4 hour of 45-55 DEG C of temperature section normal pressure forced air drying;
(5) pulverize and sieve;
(6) 100-110 DEG C of vacuum-drying, obtains anhydrous Dasatinib.
After adopting this process for purification, its beneficial effect is apparent.First, process for purification provided by the invention is easy and simple to handle, and the used time is shorter, is conducive to save energy.Secondly, Dasatinib is stable under this extraction temperature.Therefore process for purification of the present invention have easy and simple to handle, yield good, purity is high, the advantage of good stability, the anhydrous Dasatinib outward appearance adopting process for purification disclosed in the present invention to obtain is good, purity high (>=99.91%).
Accompanying drawing explanation
Fig. 1 DMSO is anhydrous Dasatinib chromatograms prepared by reaction solvent
Fig. 2 HMPA is anhydrous Dasatinib chromatograms prepared by reaction solvent
Fig. 3 DMAC is anhydrous Dasatinib chromatograms prepared by reaction solvent
Fig. 4 CH
3cN is anhydrous Dasatinib chromatograms prepared by reaction solvent
Fig. 5 anhydrous Dasatinib DSC graphic representation
Fig. 6 anhydrous Dasatinib TG graphic representation
Fig. 7 anhydrous Dasatinib X-ray powder diffraction pattern
Fig. 8 synthesizes and refines the chromatograms of the anhydrous Dasatinib of pilot product
Fig. 9 sample DS-H
2o X-ray powder diffraction pattern
Figure 10 sample DS-OH X-ray powder diffraction pattern
Embodiment
Embodiment 1
The preparation of Dasatinib and refining
The preparation of Dasatinib
By chloro-for N-(2-6-aminomethyl phenyl)-2 [(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides 100g is dissolved in 300ml dimethyl sulfoxide (DMSO), add 1-(2-hydroxyethyl respectively) piperazine 98.9g and diisopropylethylamine 65.5g, heat 80 DEG C, stir 2-3h, HPLC monitors, disappear completely to raw material, stopped reaction.Naturally cool to room temperature, in reaction solution, add Virahol 900ml, have solid to separate out, cooling, stir 2h.Separate out completely, filter, a small amount of isopropyl alcohol and water of filter cake washs successively, obtains Dasatinib crude product 101.2g.Calculated yield is 78.8%.
Refining of Dasatinib
By Dasatinib crude product 95% alcohol-water (2L:0.4L) mixed dissolution obtained in above-mentioned test, be heated to 70 DEG C, dissolve completely, filtered while hot, filtrate naturally cools to room temperature, then cryogenic freezing crystallization.Filter, with cold on a small quantity 50% alcohol-water (1:1/v:v) washing, obtain white solid, 50 DEG C of normal pressure forced air dryings 3 hours, pulverize, sieve, and 105 DEG C of vacuum-drying 2 hours, obtain anhydrous Dasatinib 74.9g, calculated yield is 74.0%, and purity is 99.98%.
The anhydrous Dasatinib chromatograms obtained after refining as shown in Figure 1.
The structural identification of Dasatinib
Take test volume refining after anhydrous Dasatinib, and respectively conveniently working method to Dasatinib carry out mass spectrum,
1h-NMR, DSC, TG, water content, crystalline form detect.Detected result is as follows:
Mass spectrum m/z=488 ([M+H]
+), 486([M-H]
+)
1H-NMR：δppm 2.25（3H，s）；2.42（3H，s）；2.45（2H，t）；2.50（4H，m）；3.51（4H，m）；3.54（2H，m）；4.41（1H，s）；6.07（1H，s）；7.25（1H，t）；7.28（1H，d）；7.40（1H，d）；8.23（1H，s）；9.85（1H，s）；11.42(1H,s)。
DSC:286.3, measurement result is as shown in Figure 5;
TG: measurement result as shown in Figure 6;
DSC, TG figure shows, and sample has no crystal water;
Karl Fischer aquametry measures water content: 0.31%.
X-ray powder diffraction measures anhydrous Dasatinib crystalline form, and as shown in Figure 7, be following 2 θ values: 6.880,11.140,12.260,13.160,13.780,16.700,20.800,24.200,24.800, crystalline form is N-6 to PXRD characteristic peak.
Embodiment 2
:
Dasatinib drying conditions is investigated
Take Dasatinib crude product 120g, be heated to 75 DEG C with 95% alcohol-water (2L:0.4L), dissolve completely, filtered while hot, filtrate is chilled to room temperature, freezing crystallization.Filter, with cold 50% alcohol-water (1:1/v:v) washing on a small quantity, 50 DEG C of normal pressure forced air dryings 3 hours, obtain white solid 90.4g, yield is 75.3%, pulverizes and sieves, and precision takes every part of 10.0g totally 8 parts, 105 DEG C of vacuum-dryings, investigates time of drying, in table 1.
Table 1 Dasatinib drying conditions is investigated
| Numbering | Temperature (DEG C) | Pressure | Time (h) | Water content (%) | Color |
| 1 | 0 | 3.66 | White | ||
| 2 | 105 | Vacuum | 2 | 0.70 | White |
| 3 | 105 | Vacuum | 4 | 0.38 | White |
| 4 | 105 | Vacuum | 6 | 0.36 | White |
| 5 | 105 | Vacuum | 8 | 0.33 | White |
| 6 | 105 | Vacuum | 10 | 0.31 | White |
| 7 | 105 | Vacuum | 12 | 0.32 | White |
| 8 | 105 | Vacuum | 24 | 0.31 | White |
Result shows: by moisture determination result, known in conjunction with DSC, TG figure, and Dasatinib prepared by 105 DEG C of more than vacuum-drying 2h is not all containing crystal water.
Embodiment 3:
The preparation of Dasatinib and refining
The preparation of Dasatinib
By chloro-for N-(2-6-aminomethyl phenyl)-2 [(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides 100g is dissolved in 500ml hexamethylphosphoramide (HMPA), add 1-(2-hydroxyethyl respectively) piperazine 165.1g and diisopropylethylamine 65.5g, be heated to 75 DEG C, stir 2-3h, HPLC monitoring to raw material and disappear completely, stopped reaction, be cooled to room temperature, in reaction solution, add Virahol 1500ml, have solid to separate out, cooling, stirs 2h.Separate out completely, filter, a small amount of isopropyl alcohol and water of filter cake washs successively, obtains crude product 98.2g.Yield: 76.5%.
Refining of Dasatinib
Crude product 95% alcohol-water (2L:0.4L) mixed dissolution, is heated to 80 DEG C, and dissolve completely, filtered while hot, filtrate is chilled to room temperature, freezing crystallization.Filter, with cold 50% alcohol-water (1:1/v:v) washing on a small quantity, obtain white solid, 45 DEG C of normal pressure forced air dryings 4 hours, pulverize and sieve, 110 DEG C of vacuum-drying 2 hours, obtain anhydrous Dasatinib 72.5g, yield is 73.8%, and purity is 99.95%.
The anhydrous Dasatinib chromatograms obtained after refining as shown in Figure 2.
The structural identification of Dasatinib
Take test volume refining after Dasatinib, and respectively conveniently working method to Dasatinib carry out mass spectrum,
1h-NMR, DSC, TG, water content, crystalline form detect.Detected result is as follows:
Mass spectrum m/z=488 ([M+H]
+), 486([M-H]
+)
1H-NMR：δppm 2.28（3H，s）；2.43（3H，s）；2.46（2H，t）；2.51（4H，m）；3.51（4H，m）；3.57（2H，m）；4.40（1H，s）；6.11（1H，s）；7.26（1H，t）；7.30（1H，d）；7.42（1H，d）；8.26（1H，s）；9.89（1H，s）；11.47(1H,s)。
DSC：286.1；
DSC, TG measurement result shows, and sample has no crystal water;
Karl Fischer aquametry measures water content: 0.33%.
PXRD characteristic peak is following 2 θ values: 6.880,11.140,12.260,13.160,13.780,16.700,20.800,24.200,24.800, and crystalline form is N-6.
Embodiment 4:
The preparation of Dasatinib and refining
The preparation of Dasatinib
By chloro-for N-(2-6-aminomethyl phenyl)-2 [(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides 100g is dissolved in 400ml N,N-DIMETHYLACETAMIDE (DMAC), add 1-(2-hydroxyethyl respectively) piperazine 132.0g and diisopropylethylamine 65.5g, be heated to 85 DEG C, stir 2-3h, HPLC and monitor raw material disappearance completely.Stopped reaction, is cooled to room temperature, adds Virahol 1200ml in reaction solution, has solid to separate out, cooling, stirs 2h.Separate out completely, filter, a small amount of isopropyl alcohol and water of filter cake washs successively, obtains crude product 95.6g.Yield: 74.5%.
Refining of Dasatinib
Crude product 95% alcohol-water (2L:0.4L) mixed dissolution, is heated to 75 DEG C, and dissolve completely, filtered while hot, filtrate is chilled to room temperature, freezing crystallization.Filter, with cold 50% alcohol-water (1:1/v:v) washing on a small quantity, obtain white solid, 55 DEG C of normal pressure forced air dryings 3 hours, pulverize and sieve, 100 DEG C of vacuum-drying 3 hours, obtain anhydrous Dasatinib 72.3g, yield is 75.6%, and purity is 99.91%.
The anhydrous Dasatinib chromatograms obtained after refining as shown in Figure 3
The structural identification of Dasatinib
Take test volume refining after Dasatinib, and respectively conveniently working method to Dasatinib carry out mass spectrum,
1h-NMR, DSC, TG, water content, crystalline form detect.Detected result is as follows:
Mass spectrum m/z=488 ([M+H]
+), 486([M-H]
+)
1H-NMR：δppm 2.24（3H，s）；2.40（3H，s）；2.43（2H，t）；2.48（4H，m）；3.50（4H，m）；3.53（2H，m）；4.38（1H，s）；6.08（1H，s）；7.24（1H，t）；7.27（1H，d）；7.41（1H，d）；8.23（1H，s）；9.87（1H，s）；11.44(1H,s)。
DSC：286.2；
DSC, TG measurement result shows, and sample has no crystal water;
Karl Fischer aquametry measures water content: 0.32%.
PXRD characteristic peak is following 2 θ values: 6.880,11.140,12.260,13.160,13.780,16.700,20.800,24.200,24.800, and crystalline form is N-6.
Embodiment 5:
The preparation of Dasatinib and refining
The preparation of Dasatinib
By chloro-for N-(2-6-aminomethyl phenyl)-2 [(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides 100g is dissolved in 450ml acetonitrile, add 1-(2-hydroxyethyl respectively) piperazine 165.1g and diisopropylethylamine 65.5g, be heated to 90 DEG C, stir 2-3h, HPLC and monitor raw material disappearance completely.Stopped reaction, is cooled to room temperature, adds Virahol 1350ml in reaction solution, has solid to separate out, cooling, stirs 2h.Separate out completely, filter, a small amount of isopropyl alcohol and water of filter cake washs successively, obtains crude product 94.0g.Yield: 73.2%.
Refining of Dasatinib
Crude product 95% alcohol-water (2L:0.4L) mixed dissolution, is heated to 75 DEG C, and dissolve completely, filtered while hot, filtrate is chilled to room temperature, freezing crystallization.Filter, with cold 50% alcohol-water (1:1/v:v) washing on a small quantity, obtain white solid, 50 DEG C of normal pressure forced air dryings 3 hours, pulverize and sieve, 105 DEG C of vacuum-drying 2 hours, obtain anhydrous Dasatinib 70.0g, yield is 74.4%, and purity is 99.93%.
The anhydrous Dasatinib chromatograms obtained after refining as shown in Figure 4
The structural identification of Dasatinib
Take test volume refining after Dasatinib, and respectively conveniently working method to Dasatinib carry out mass spectrum,
1h-NMR, DSC, TG, water content, crystalline form detect.Detected result is as follows:
Mass spectrum m/z=488 ([M+H]
+), 486([M-H]
+)
1H-NMR：δppm 2.23（3H，s）；2.39（3H，s）；2.43（2H，t）；2.47（4H，m）；3.50（4H，m）；3.53（2H，m）；4.39（1H，s）；6.04（1H，s）；7.23（1H，t）；7.27（1H，d）；7.38（1H，d）；8.20（1H，s）；9.85（1H，s）；11.41(1H,s)。
DSC：286.1；
DSC, TG measurement result shows, and sample has no crystal water;
Karl Fischer aquametry measures water content: 0.33%.
PXRD characteristic peak is following 2 θ values: 6.880,11.140,12.260,13.160,13.780,16.700,20.800,24.200,24.800, and crystalline form is N-6.
Embodiment 6:
The preparation of Dasatinib and refining pilot scale
By chloro-for N-(2-6-aminomethyl phenyl)-2 [(6-chloro-2-methyl-4-pyrimidyl) amino]-5-thiazole carboxamides 1.2kg drops into reactor, again dimethyl sulfoxide (DMSO) 4.8L is dropped in reactor, add 1-(2-hydroxyethyl respectively) piperazine 1.18kg and diisopropylethylamine 0.78kg, be heated to 80 DEG C, stir 2h, HPLC and monitor raw material disappearance completely.Stopped reaction, is cooled to room temperature, adds Virahol 14.4L, stirring at normal temperature in reaction solution, has solid to separate out, cooling and stirring 2h.Filter, a small amount of isopropyl alcohol and water of filter cake washs successively, obtains crude product 1.2kg, yield 77.8%.
Crude product and 95% alcohol-water (24L:4.8L) are dropped into reactor, is heated to 75 DEG C, dissolve completely, slightly cold, filtered while hot, filtrate naturally cools to room temperature, freezing crystallization.Filter, with cold 50% alcohol-water (1:1/v:v) washing on a small quantity, obtain white solid.Product is evenly laid in stainless steel pallet, paving disc thickness <2cm.50 DEG C of air blast, dry 3h, dry end, pulverizes with pulverizer, crosses 80 mesh sieves.Product after being pulverized and mixed evenly is laid in stainless steel pallet, paving disc thickness <2cm.100-110 DEG C, vacuum-drying 2h.Dry end, obtain anhydrous Dasatinib 0.91kg, yield 75.8%, as shown in Figure 8, purity is 99.95% to Dasatinib chromatograms.
Mass spectrum m/z=488 ([M+H]
+), 486([M-H]
+)
1H-NMR：δppm 2.26（3H，s）；2.43（3H，s）；2.47（2H，t）；2.52（4H，m）；3.52（4H，m）；3.56（2H，m）；4.43（1H，s）；6.10（1H，s）；7.27（1H，t）；7.30（1H，d）；7.43（1H，d）；8.23（1H，s）；9.86（1H，s）；11.41(1H,s)。
DSC：286.3；
DSC, TG measurement result shows, and sample has no crystal water;
Karl Fischer aquametry measures water content: 0.35%.
PXRD characteristic peak is following 2 θ values: 6.840,11.140,12.340,13.100,13.700,16.680,21.080,24.360,24.900, and crystalline form is N-6.
The Study on Transformation of embodiment 7 Dasatinib crystal formation
Sample DS-H
2o: take anhydrous Dasatinib (N-6) 1.5g, throw in the single port reaction flask of 100ml, in single port reaction flask, add purified water 30ml, keep stirring at room temperature 24h, filter, the a small amount of purified water of filter cake is washed, filter cake is through 40 DEG C, and vacuum-drying 8h, obtains white solid 1.37g, identify that its crystal formation is H1-7 by PXRD, see Fig. 9.
PXRD characteristic peak: 4.692,9.321,11.313,12.431,13.932,14.804,15.374,16.305,17.462,18.077,18.514,19.254,19.664,20.331,21.349,22.379,23.271,23.696,24.548,25.152,25.985,28.133,30.0269,34.767,35.276,39.400 ± 0.02.
Sample DS-OH: take anhydrous Dasatinib (N-6) 1.5g, throw in the single port reaction flask of 100ml, in single port reaction flask, add phosphate buffered saline buffer (pH 6.8) 30ml, keep stirring at room temperature 24h, filter, the a small amount of purified water of filter cake is washed, filter cake is through 40 DEG C, and vacuum-drying 8h, obtains white solid 1.35g, identify that its crystal formation is H1-7 by PXRD, see Figure 10.
PXRD characteristic peak: 4.711,9.313,11.302,12.432,13.957,14.789,15.352,16.353,18.081,18.537,19.272,19.687,20.319,21.366,22.397,23.298,23.716,24.562,25.163,26.012,28.138,28.740,30.0292,34.100,34.775,35.272.
Claims (5)
1. a synthetic method for Dasatinib, is characterized in that, comprises the following steps:
S1. N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) is amino]-5-thiazole carboxamides is dissolved in DMSO completely;
S2. in the solution of S1, add 1-(2-hydroxyethyl) piperazine and diisopropylethylamine, 70-90 DEG C of reaction 2-3h, is cooled to room temperature;
Reaction equation:
S3. add Virahol in solution after reacting to S2, have solid to separate out, cooling, stir 2h, separate out completely, filtration;
S4. a small amount of isopropyl alcohol and water of filter cake washs successively, obtains Dasatinib crude product.
2. the preparation method of Dasatinib according to claim 1, is characterized in that: described DMSO consumption is the DMSO that every gram of N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) is amino]-5-thiazole carboxamides is dissolved in 3-4ml.
3. the preparation method of Dasatinib according to claim 1, it is characterized in that: the mol ratio of described N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) is amino]-5-thiazole carboxamides and 1-(2-hydroxyethyl) piperazine is 1:(3-5), the mol ratio of N-(the chloro-6-aminomethyl phenyl of 2-)-2-[(6-chloro-2-methyl-4-pyrimidyl) is amino]-5-thiazole carboxamides and diisopropylethylamine is 1:2.
4. the preparation method of Dasatinib according to claim 1, is characterized in that: described DMSO and Virahol consumption are 1:3 (V:V).
5. the preparation method of Dasatinib according to claim 1, is characterized in that: temperature of reaction is preferably 75-85 DEG C.
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|---|---|---|---|
| CN201110173049.3A CN102838594B (en) | 2011-06-24 | 2011-06-24 | Preparation and refining methods of dasatinib |
| CN201510176667.1A CN104788446A (en) | 2011-06-24 | 2011-06-24 | Preparation and refinement method for anhydrous Dasatinib |
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|---|---|---|---|
| CN201110173049.3A CN102838594B (en) | 2011-06-24 | 2011-06-24 | Preparation and refining methods of dasatinib |
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| Publication Number | Publication Date |
|---|---|
| CN102838594A CN102838594A (en) | 2012-12-26 |
| CN102838594B true CN102838594B (en) | 2015-06-24 |
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| CN103408542B (en) * | 2013-08-13 | 2016-06-29 | 南京优科生物医药研究有限公司 | A kind of preparation method of highly purified Dasatinib anhydride |
| CN108239086B (en) * | 2016-12-27 | 2023-06-16 | 四川科伦药物研究院有限公司 | Preparation method of dasatinib N-6 anhydrous crystal |
| CN107043375B (en) * | 2017-04-28 | 2020-03-20 | 江苏食品药品职业技术学院 | Novel method for preparing dasatinib and intermediate thereof |
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| WO2006052810A2 (en) * | 2004-11-04 | 2006-05-18 | Bristol-Myers Squibb Company | Combination of a src kinase inhibitor and a bcr-abl inhibitor for the treatment of proliferative diseases |
| CN1980909A (en) * | 2004-02-06 | 2007-06-13 | 布里斯托尔-迈尔斯·斯奎布公司 | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| WO2009053854A2 (en) * | 2007-10-23 | 2009-04-30 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
| CN101812060A (en) * | 2010-02-02 | 2010-08-25 | 南京卡文迪许生物工程技术有限公司 | Simple novel method for preparing high-purity Sprycel, and intermediate compound |
| CN101891738A (en) * | 2010-02-08 | 2010-11-24 | 南京卡文迪许生物工程技术有限公司 | Dasatinib polymorph and preparation method and medical composite thereof |
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| CN101845045A (en) * | 2010-02-02 | 2010-09-29 | 南京卡文迪许生物工程技术有限公司 | Novel method for synthesizing dasatinib |
| CN102010407A (en) * | 2010-11-16 | 2011-04-13 | 上海科胜药物研发有限公司 | New method for synthesizing dasatinib |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1980909A (en) * | 2004-02-06 | 2007-06-13 | 布里斯托尔-迈尔斯·斯奎布公司 | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| WO2006052810A2 (en) * | 2004-11-04 | 2006-05-18 | Bristol-Myers Squibb Company | Combination of a src kinase inhibitor and a bcr-abl inhibitor for the treatment of proliferative diseases |
| WO2009053854A2 (en) * | 2007-10-23 | 2009-04-30 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
| CN101812060A (en) * | 2010-02-02 | 2010-08-25 | 南京卡文迪许生物工程技术有限公司 | Simple novel method for preparing high-purity Sprycel, and intermediate compound |
| CN101891738A (en) * | 2010-02-08 | 2010-11-24 | 南京卡文迪许生物工程技术有限公司 | Dasatinib polymorph and preparation method and medical composite thereof |
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| CN104788446A (en) | 2015-07-22 |
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