CN101845045A - Novel method for synthesizing dasatinib - Google Patents
Novel method for synthesizing dasatinib Download PDFInfo
- Publication number
- CN101845045A CN101845045A CN201010177587A CN201010177587A CN101845045A CN 101845045 A CN101845045 A CN 101845045A CN 201010177587 A CN201010177587 A CN 201010177587A CN 201010177587 A CN201010177587 A CN 201010177587A CN 101845045 A CN101845045 A CN 101845045A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- dasatinib
- obtains
- reaction
- 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.)
- Pending
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a novel method for synthesizing dasatinib, which comprises the following steps of: reacting a compound of a formula I with a compound of a formula II to obtain a compound of a formula III; and then using the compound of the formula III to directly connect 2-chloro-6-methylaniline and/or 1-(2-ethoxyl) piperazine respectively so as to synthesize the dasatinib, wherein R4 in the formula II and the formula III is C1-C6 alkoxy or substituted C1-C6 alkoxy.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, specifically, relate to a kind of new method for synthesizing dasatinib.
Background technology
Dasatinib (Dasatinib), trade(brand)name SPRYCEL
TM, be a kind of oral tyrosine kinase inhibitor by BMS company research and development, the chronic myelogenous leukemia (CML) that is used to be grown up also can be used for treating the acute lymphoblastic leukemia of Philadelphia chromatin-positive.Its chemical name is N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-the 5-thiazole carboxamides, chemical structure is as follows:
J reaches this grade in disclosed Chinese patent application on May 8th, 2002, and publication number CN1348370A discloses a kind of method of synthetic Dasatinib.This method is a starting raw material with 2-t-butoxycarbonyl amino thiazole-5-carboxylic acid ethyl ester, thereby synthesizes Dasatinib by following route:
In addition, Chen Bangchi etc. are in disclosed Chinese patent application on June 13rd, 2007, and publication number CN1980909A discloses the method for another kind of synthetic Dasatinib.This method forms thiazole ring by using isocyanic ester or thiocarbamide, thus synthetic Dasatinib:
Perhaps
Li etc. in the international application for patent (publication No. WO2007/106879 A2) of announcing on September 20th, 2007, described another kind of synthetic Dasatinib method-it adopts another thiourea derivative to synthesize the thiazole ring of trityl as protecting group amino; pass through deprotection again; with 2-methyl-4; 6-dichloro pyrimidine, the reaction of 1-(2-hydroxyethyl) piperazine, thus Dasatinib obtained:
Das etc. are at J.Med.Chem.2006; 49; 6819-6832 (2-Aminothiazole as aNovel Kinase Inhibitor Temple.Structure-Activity Relationship Studies towardthe Discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-pyperizinyl]-2-methyl-4-pyrimidinyl] amino]-1; the method of another kind of synthetic Dasatinib is disclosed 3-thiazole-5-carboxamide); with 2-diuril azoles is starting raw material; adopt the protection of 4-methoxy-benzyl amino, thus synthetic Dasatinib:
However, still there is such serious hope in this area: a kind of be suitable for suitability for industrialized production, with the raw material of the easy acquisition novel method of synthesis of high purity Dasatinib quickly and easily.
Summary of the invention
The contriver through a large amount of research successfully develop a kind of be suitable for industrialized production and be the method for the synthetic Dasatinib of initiator with easy acquisition raw material, overcome the deficiencies in the prior art.
The synthetic method that the purpose of this invention is to provide a kind of Dasatinib.
Second purpose of the present invention provides the preparation method of high purity Dasatinib.
Specifically, the present invention realizes by following technical proposal:
The invention provides a kind of synthetic method of Dasatinib, comprise the following steps: the reaction of formula I compound and formula II compound, thereby obtain the formula III compound:
Wherein,
In formula II and formula III, R
4Be the alkoxyl group of the alkoxyl group of C1-C6 or the C1-C6 that replaces, here, described substituting group is selected from the aryl of C1-C6 alkyl, aryl or replacement; Described aryl is selected from phenyl; Described substituted aryl is selected from the phenyl of one or more C1-C4 alkyl or alkoxyl group, halogen or nitro replacement, preferably, and R
4Be methoxyl group, benzyloxy, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, sec-butoxy, isobutoxy, pentyloxy or hexyloxy;
With the formula III compound hydrolysis, thereby obtain formula IV compound:
Here, R in the formula III compound
4Definition as above;
Then, formula IV compound obtains formula V compound under the chloride reagent effect, and here, described chloride reagent is selected from phosphorus trichloride, phosphorus pentachloride, thionyl chloride or oxalyl chloride, preferably, is selected from oxalyl chloride:
Formula V compound reacts with 2-chloro-6-monomethylaniline again, obtains formula VI compound:
Perhaps formula IV compound at amide condensed dose (for example, phosphorus dichloride acid phenenyl ester (PDCP), dicyclohexylcarbodiimide (DCC), DIC (DIC), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU) and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI) etc.) exist down and the reaction of 2-chloro-6-monomethylaniline, obtain formula VI compound;
Formula VI compound obtains Dasatinib with the reaction of 1-(2-hydroxyethyl) piperazine again.
In embodiments of the invention, after above-mentioned synthetic method provided by the present invention obtains the formula III compound, comprise the reaction of formula III compound and 1-(2-hydroxyethyl) piperazine further, thereby obtain formula VII compound:
Here, R in formula III and the formula VII compound
4Definition as above;
Then, formula VII compound hydrolysis obtains formula VIII compound:
Formula VIII compound and hydroxyl protection reagent react, thus formula IX compound obtained: and here, described hydroxyl protection reagent is the reagent of following hydroxyl protecting group: the C1-C4 alkanoic acid ester or the carbonic ether protecting group that are selected from C1-C4 alkanoic acid ester or replacement; Described alkanoic acid ester is selected from formyl radical, ethanoyl, propionyl, butyryl radicals, benzoyl, to phenyl benzoyl etc.; Described carbonic ether is selected from methoxy methyl esters, 9-fluorenes methyl esters, 2-(front three is silica-based) ethyl ester, isobutyl ester, vinyl acetate, allyl ester, p-nitrophenyl ester or benzyl ester etc., see PETER G.M.WUTS etc. " (GREENE ' SPROTECTIVE GROUP IN ORGANIC SYNTHESIS " for details, the 4th edition, 2007, A JohnWiley ﹠amp; Sons, Inc., Publication, 16-366 page or leaf;
Formula IX compound obtains formula X compound under the chloride reagent effect, here, Pg is a hydroxyl protecting group among formula IX and the X; Described chloride reagent is selected from phosphorus trichloride, phosphorus pentachloride, thionyl chloride or oxalyl chloride, preferably, is selected from oxalyl chloride:
Formula X compound reacts with 2-chloro-6-monomethylaniline again, then, removes the protecting group Pg on the hydroxyl, thereby obtains Dasatinib;
Perhaps formula IX compound at amide condensed dose (for example; phosphorus dichloride acid phenenyl ester (PDCP), dicyclohexylcarbodiimide (DCC), DIC (DIC), 2-(7-azo benzotriazole)-N; N; N '; N '-tetramethyl-urea phosphofluoric acid ester (HATU) and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI) etc.) exist down and the reaction of 2-chloro-6-monomethylaniline; then, remove the protecting group Pg on the hydroxyl, thereby obtain Dasatinib.
In embodiments of the invention, after above-mentioned synthetic method provided by the present invention obtains the formula III compound, comprise 1-(2-hydroxyethyl) the piperazine reaction of formula III compound and hydroxyl protection further, thereby obtain formula XI compound:
Here, R in formula III and the formula XI compound
4Definition as above; Pg is a hydroxyl protecting group and for hydrogen, be selected from the ether protecting group; That described ether is selected from C1-C4 alkyl oxide replacement or unsubstituted, replacement or unsubstituted benzyl oxide or silicon ether; The C1-C4 alkyl oxide of described replacement is preferably from the methyl ether or the ether that replace, more preferably, be selected from methoxymethyl ether, uncle's fourth oxygen methyl ether, 2-methoxy (ethoxy) methyl ether, methylthio group methyl ether, (phenyl dimethyl silyl) methoxymethyl ether, benzyloxy methyl ether, (4-methoxy phenoxy) methyl ether, oxygen in the Meng (menthoxy) methyl ether, THP trtrahydropyranyl ether, tetrahydrofuran base ether, 1-ethoxyethylether, allyl ethers etc.; The benzyl oxide of described replacement is preferably to methoxy-benzyl ether, 3,4-dimethoxy-benzyl ether, to the nitro benzyl oxide etc.; Described silicon ether is preferably from di-isopropyl silicon ether, tertiary butyl dimethyl-silicon ether, tert-butyl diphenyl silicon ether etc.; See PETER G.M.WUTS etc. " GREENE ' S PROTECTIVE GROUP IN ORGANIC SYNTHESIS " for details, the 4th edition, 2007, A John Wiley ﹠amp; Sons, Inc., Publication, 16-366 page or leaf; Then, formula XI compound hydrolysis obtains formula IX compound:
Formula IX compound obtains formula X compound under the chloride reagent effect, here, Pg is a hydroxyl protecting group among formula IX and the X; Described chloride reagent is selected from phosphorus trichloride, phosphorus pentachloride, thionyl chloride or oxalyl chloride, preferably, is selected from oxalyl chloride:
Formula X compound reacts with 2-chloro-6-monomethylaniline again, then, removes the protecting group Pg on the hydroxyl, thereby obtains Dasatinib;
Perhaps formula IX compound at amide condensed dose (for example; dicyclohexylcarbodiimide (DCC), DIC (DIC), 2-(7-azo benzotriazole)-N; N; N '; N '-tetramethyl-urea phosphofluoric acid ester (HATU) and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI) etc.) exist down and the reaction of 2-chloro-6-monomethylaniline; then, remove the protecting group Pg on the hydroxyl, thereby obtain Dasatinib.
In embodiments of the invention, after above-mentioned synthetic method provided by the present invention obtained the formula III compound, formula III compound and the reaction of 2-chloro-6-monomethylaniline obtained formula VI compound:
Here, formula XII compound is a formula VI compound;
Then, the reaction of formula XII compound and 1-(2-hydroxyethyl) piperazine obtains Dasatinib.
In above-mentioned embodiment provided by the present invention, removing of described hydroxyl protecting group, same, can be with reference to " (GREENE ' S PROTECTIVE GROUP INORGANIC SYNTHESIS " of PETER G.M.WUTS etc., the 4th edition, 2007, A John Wiley ﹠amp; Sons, Inc., Publication; Those skilled in the art can select the condition that removes that suits in view of the above.
On the other hand, the invention provides a kind of purifying mode of Dasatinib: comprise reaction is finished the back by the Dasatinib crude product that concentrates or the mode of suction filtration obtains, add in the specific organic solvent; Heating under agitation makes its dissolving, drips the mixed solvent system of water and organic solvent; Dropwise, stir and slowly to be cooled to 0～10 ℃ down solid is separated out fully and growing the grain, solid collected by filtration, and the dry purity that makes is greater than 99.50% high purity Dasatinib.
Here, described Dasatinib crude product purity is more than 95%, and the purity that is preferably crude product is more than 97%;
Described this specific organic solvent is non-proton property polar solvent, is preferably N, dinethylformamide, N, N-dimethyl methyl ethanamide, dimethyl sulfoxide (DMSO), or its mixture;
Described heating under agitation makes its dissolving, and Heating temperature is selected from room temperature to reflux temperature herein, is preferably 40～100 ℃;
The mixed solvent system of described dropping water and organic solvent, organic solvent can be insoluble or sl. sol. one or more the mixed solvent of Dasatinib herein.
The Dasatinib purifying is by the Dasatinib crude product is dissolved in dimethyl formamide or the dimethyl sulphoxide solution under the situation of heating in the present invention, keeping under the certain temperature, the mixed solution that adds the insoluble organic solvent of a certain amount of Dasatinib or water and organic solvent, after forcing the method for analysing that Dasatinib is separated out, obtain solid by filtration or centrifugal mode, obtain highly purified Dasatinib by the exsiccant mode.
Concrete mode is: Dasatinib crude product and dimethyl formamide or the dimethyl sulfoxide (DMSO) of foreign matter content about 3% pressed mass volume ratio usually greater than 1: 1 mixed, preferably be selected from 1: 2 above mixed, most preferably be selected from 1: 3 above mixed, room temperature to the heating situation under with its dissolving, concrete Heating temperature can be below the reflux temperature, preferably be selected from below 120 ℃, be selected from the most electedly below 100 ℃, under the situation that keeps solvent temperature, the mixed solution that adds the insoluble organic solvent of a certain amount of Dasatinib or water and organic solvent, solution that adds and Dasatinib dimethyl formamide or dimethyl sulfoxide (DMSO) ratio usually should be greater than 1: 1, the ratio that preferably is selected from was greater than 1: 2, the ratio that most preferably is selected from was greater than 1: 3, under stirring state, it is separated out solid, reduce to 0～10 ℃, be incubated 1～2 hour after-filtration, drying.
Compared with prior art, useful technique effect of the present invention is embodied in:
1. each synthetic route provided by the invention and method are simple and direct, are more conducive to suitability for industrialized production
In the synthetic route of the present invention, can select to adopt the common marketable material of wide material sources, for example: select among the present invention in the suitable route related with common marketable material 2-methyl-4, the 6-dichloro pyrimidine through with various thiazolamines-5-manthanoate and 1-(2-hydroxyethyl) piperazine condensation after, obtain Dasatinib with 2-methyl-6-chloroaniline condensation again through hydrolysis.Can avoid utilizing in the prior art amino loaded down with trivial details step of reacting again on the Boc radical protection thiazolamine manthanoate, reactions steps be shortened to 4 from 6 steps go on foot.This not only can reduce reactions steps and loaded down with trivial details synthesis procedure, has more significantly reduced the generation of the three wastes, is easy to environmental protection, greatly reduces cost.The technological reaction mild condition that the present invention simultaneously uses, post-treating method is simple, and purification of intermediate is simple, is more suitable for technology production.
2. existing method for synthesizing dasatinib all is to adopt different synthetic route or preparation methods to obtain 2-(6-chloro-2-methylpyrimidine-4-amino)-N-(2-chloro-6-toluene) thiazole-5-methane amide, obtains Dasatinib with 1-(2-hydroxyethyl) piperazine condensation again.And the invention provides a kind of synthetic route of novelty, and can avoid step in the end to use the route and the method for the simple and direct synthetic Dasatinib of 4-hydroxyethyl piperazine, more help the quality control and the raising of finished product.
3. synthetic method provided by the invention respectively goes on foot the recovery rate height.
According to the yield of existing each method of putting down in writing in the disclosed data between 15%～49%.Select the simplest and the most direct synthetic route among the present invention, for example: select among the present invention among the embodiment 1 to embodiment 8 by 2-methyl-4,6-dichloro pyrimidine and thiazolamine-5-methyl-formiate is that raw material is higher than the synthetic recovery rate of existing methods through the total recovery of the synthetic Dasatinib of four-step reactions such as condensation, hydrolysis.
4. the poorly soluble characteristics of Dasatinib and key intermediate thereof make the difficulty that the highly purified Dasatinib of preparation becomes to be difficult to prepare the high finished product of purity according to existing synthetic route.And technology provided by the invention and purifying mode can prepare purity up to 99.9% Dasatinib.
Description of drawings
What Fig. 1 represented is the Dasatinib color atlas, and its analytical results table is as follows:
| Peak number | Retention time | Peak height | Peak area | Content |
| ??1 | ??5.873 | ??97.721 | ??1355.550 | ??0.0032 |
| ??2 | ??8.582 | ??1498534.125 | ??41887600.00 | ??99.9509 |
| ??3 | ??12.532 | ??81.957 | ??1653.400 | ??0.0039 |
| ??4 | ??14.232 | ??218.811 | ??17573.600 | ??0.0419 |
| Amount to | ??1498932.615 | ??41908182.550 | ??100.000 |
Embodiment
Represent the specific embodiment of the present invention as follows, but the present invention is not limited thereto the method shown in the legend.
The preparation of embodiment 1:2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 4, R5 are methyl)
Method A:
(1.8g 0.045mol) is suspended among the THF (45ml), is cooled to 0 ℃ with 60% sodium hydride.Add thiazolamine-5-methyl-formiate (compound 3, R5 are methyl) (2.4g 0.015mol), stirred 30 minutes in batches.Add 2-methyl-4, (2.5g 0.015mol), was warming up to back flow reaction 4.5 hours to 6-dichloro pyrimidine (compound 2), and the cool to room temperature reaction is spent the night in batches.Temperature control drips 2N hydrochloric acid down for 0～5 ℃, and neutralization reaction was dripped complete insulated and stirred growing the grain 1 hour.Suction filtration, the filter cake washing, drying obtains target compound 4,3.1g.(yield 72.1%)
Ultimate analysis: C
10H
9ClN
4O
2S theoretical value: C, 42.18; H, 3.19; N, 19.68 measured values: C, 42.12; H, 3.26; N, 19.61
Same method:
Prepare by thiazolamine-5-ethyl formate (compound 3, R5 are ethyl) and compound 2: 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-ethyl formate (compound 4, R5 are ethyl) (yield: 81.2%)
Ultimate analysis: C
11H
11ClN
4O
2S theoretical value: C, 44.22; H, 3.71; N, 18.75 measured values: C, 44.28; H, 3.65; N, 18.70
Prepare by thiazolamine-5-isopropyl formate (compound 3, R5 are sec.-propyl) and compound 2: 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-isopropyl formate (compound 4, R5 are sec.-propyl) (yield: 72.5%)
Ultimate analysis: C
12H
13ClN
4O
2S theoretical value: C, 46.08; H, 4.19; N, 17.91 measured values: C, 46.12; H, 4.25; N, 17.98
Method B:
In four-hole bottle, add thiazolamine-5-methyl-formiate (compound 3, R5 are methyl) (30g, 0.19mol), 2-methyl-4,6-dichloro pyrimidine (compound 2) (37.2g, 0.23mol), and DMF (150ml).Add Cs after the stirring and dissolving
2CO
3(123.6g, 0.38mol).Be warming up to 40 ℃ of stirring reactions 4 hours.Suction filtration, filter cake is with an amount of DMF drip washing.Merging filtrate adds entry (600ml), stirs slowly to add 6N hydrochloric acid (30ml) down.Stir suction filtration after 30 minutes.Filter cake adds methyl alcohol (180ml), is warming up to 50 ℃ and stirs 30 minutes.Suction filtration, small amount of methanol drip washing filter cake.50 ℃ of forced air dryings are to constant weight.Get yellow solid target compound 4,29g.(yield: 54%)
Same method:
Prepare by thiazolamine-5-ethyl formate (compound 3, R5 are ethyl) and compound 2: 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-ethyl formate (compound 4, R5 are ethyl) (yield: 49.8%)
Ultimate analysis: C
11H
11ClN
4O
2S theoretical value: C, 44.22; H, 3.71; N, 18.75 measured values: C, 44.16; H, 3.80; N, 18.78
Prepare by thiazolamine-5-isopropyl formate (compound 3, R5 are sec.-propyl) and compound 2: 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-isopropyl formate (compound 4, R5 are sec.-propyl) (yield: 51.3%)
Ultimate analysis: C
12H
13ClN
4O
2S theoretical value: C, 46.08; H, 4.19; N, 17.91 measured values: C, 46.12; H, 4.26; N, 17.86
The preparation of embodiment 2:2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 5)
(31.0g, (10.0g, 0.25mol) in water (250ml) solution, the stirring at room reaction is spent the night 0.11mol) to add the NaOH for preparing in advance with 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 4, R5 are methyl).Suction filtration, filtrate change in the reaction flask, and temperature control is regulated pH to 6～6.5 with 6N hydrochloric acid down for 20～25 ℃, stirs growing the grain 2 hours.Suction filtration, drying obtain compound 5,23.7g (yield: 80.3%)
Ultimate analysis: C
9H
7ClN
4O
2S theoretical value: C, 39.93; H, 2.61; N, 20.70 measured values: C, 39.98; H, 2.69; N, 20.75;
Same method:
Prepare by 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-ethyl formate (compound 4, R5 are ethyl): compound 5 (yield: 79.9%)
Prepare by 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-isopropyl formate (compound 4, R5 are sec.-propyl): compound 5 (yield: 75.6%)
The preparation of embodiment 3:2-(6-chloro-2-methylpyrimidine-4-amino)-N-(2-chloro-6-toluene) thiazole-5-methane amide (compound 8)
Method A
With 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 5) (35.2g, 0.13mol), THF (350ml) and DMF (3ml) add in the reaction flask, temperature control drips oxalyl chloride (33.0g down for 10～20 ℃, 0.26mol) methylene dichloride 100ml solution, drip and finish, stirring at room reaction 6 hours.Be evaporated to driedly, obtain 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-formyl chloride (compound 6), it is changed in the reaction flask with the 500ml acetonitrile.Stir, temperature control drips compound 7 (28.3g, acetonitrile 500ml solution 0.20mol) down for 10～15 ℃.Drip and finish, (72.8g, 0.5mol), 30 ℃ of reactions of temperature control are spent the night to add DIPEA.Cool to 0～5 ℃ and add 1N hydrochloric acid 1200ml, stirred 2 hours.Suction filtration, the washing filter cake, drying obtains target compound 8,25.3g (yield: 49.3%).
Ultimate analysis: C
16H
13Cl
2N
5OS theoretical value: C, 48.74; H, 3.32; N, 17.76 measured values: C, 48.70; H, 3.39; N, 17.81
Method B:
Under the nitrogen protection; with 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 5) (6.8g; 0.025mol); PDCP (4.5ml; 0.03mol) and 2-chloro-6-monomethylaniline (compound 7) (3.7ml, 0.03mol) in the adding methylene dichloride (350ml), the stirring cooling; in 0 ℃ drip triethylamine (12.3ml, 0.09mol).Drip and finish, the stirring at room reaction is spent the night.Add saturated sodium bicarbonate aqueous solution and stir suction filtration after 15 minutes.60 ℃ of forced air dryings obtain target compound 8,7.8g (yield: 78.8%).
Ultimate analysis: C
16H
13Cl
2N
5OS theoretical value: C, 48.74; H, 3.32; N, 17.76 measured values: C, 48.70; H, 3.40; N, 17.81
Method C:
Under the nitrogen protection; with 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 4; R5 is a methyl) (0.57g; 2mmol); salt of wormwood (0.3g; 3mmol) and 2-chloro-6-monomethylaniline (compound 7) (0.2ml 2mmol) adds in the acetonitrile (10ml), is warming up to back flow reaction.Reaction is finished, and cooling adds 1N hydrochloric acid, suction filtration.60 ℃ of forced air dryings are to constant weight.Get target compound 8,0.3g (yield: 38.0%).
Ultimate analysis: C
16H
13Cl
2N
5OS theoretical value: C, 48.74; H, 3.32; N, 17.76 measured values: C, 48.69; H, 3.42; N, 17.80
Embodiment 4: the preparation of Dasatinib (compound 1)
With 2-(6-chloro-2-methylpyrimidine-4-amino)-N-(2-chloro-6-toluene) thiazole-5-methane amide (compound 8) (7.9g, 0.02mol), 1-(2-hydroxyethyl) piperazine (compound 9) (13.0g, 0.10mol) Virahol (120ml) and DIPEA (6.5g, 0.05mol) drop in the reaction flask back flow reaction 6 hours.Be evaporated to dried Dasatinib (compound 1) crude product (purity: 97.3%) that obtains.
Dasatinib (compound 1) crude product is added among the DMF (40ml), be warming up to 60 ℃ and make dissolving, insulation adds the mixed solution of 120ml water and acetone (1: 1) down, is cooled to 0 ℃ of growing the grain 2 hours after separating out crystal under stirring.Suction filtration, filter cake with water wash after water and acetone (1: 1) mixed solution drip washing and drain.Filter cake reduces pressure in about 50 ℃, and (0.095MPa) drying helps driedly with Vanadium Pentoxide in FLAKES, obtain white solid target compound 1,6.7g.(yield 68.4%, 99.0%)
Ultimate analysis: C
22H
26ClN
7O
2S theoretical value: C, 54.15; H, 5.37; N, 20.09 measured values: C, 54.11; H, 5.02; N, 20.10
Embodiment 5:2-(the preparation of 6-(4-(2-hydroxyethyl) piperazine-1-)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 10, R5 are methyl)
With 1-(2-hydroxyethyl) piperazine (compound 9) (32.6g, 0.25mol), 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 4, R5 is a methyl) (14.2g, 0.05mol), propyl carbinol (150ml) and DIPEA (19ml, 0.1mol) drop in the reaction flask back flow reaction 6 hours.Reducing to the room temperature crystallization spends the night.The propyl carbinol drip washing of suction filtration, filter cake.Drying obtains target compound 10,14.2g (yield 75.1%)
Ultimate analysis: C
16H
22N
6O
3S theoretical value: C, 50.78; H, 5.86; N, 22.21: measured value: C, 50.76; H, 5.90; N, 22.25
Same method:
By 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-ethyl formate (compound 4, R5 is an ethyl) prepare 2-(6-(4-(2-hydroxyethyl) piperazine-1-)-2-methylpyrimidine-4-amino) thiazole-5-ethyl formate (compound 10, R5 are ethyl) (yield: 79.5%) with compound 9
Ultimate analysis: C
17H
24N
6O
3S theoretical value: C, 52.02; H, 6.16; N, 21.41 measured values: C, 52.08; H, 6.21; N, 21.46
By 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-isopropyl formate (compound 4, R5 is a sec.-propyl) prepare 2-(6-(4-(2-hydroxyethyl) piperazine-1-)-2-methylpyrimidine-4-amino) thiazole-5-isopropyl formate (compound 10, R5 are sec.-propyl) (yield: 72.0%) with compound 9
Ultimate analysis: C
18H
26N
6O
3S theoretical value: C, 53.18; H, 6.45; N, 20.67 measured values: C, 53.20; H, 6.51; N, 20.62
Embodiment 6: the preparation of Dasatinib (compound 1)
Under the nitrogen protection; with 2-(6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 10, R5 are methyl) (0.5g, 1.3mmol); salt of wormwood (0.2g; 2.0mmol) and 2-chloro-6-monomethylaniline (compound 7) (0.18ml 1.5mmol) adds in the acetonitrile (10ml), is warming up to back flow reaction; reaction is finished; cooling adds 1N hydrochloric acid, suction filtration.60 ℃ of forced air dryings are to constant weight.Get Dasatinib (compound 1), 0.1g (yield: 15.6%).ESI(M+1)：490.30
Embodiment 7:2-(6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (preparation of compound 11)
Method A:
With NaOH (8.0g, 0.2mol) and water (190ml) add in the reaction flask stirring and dissolving.(37.8g, 0.1mol), the stirring at room reaction is spent the night to add 2-(6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 10, R5 are methyl).Temperature control is regulated pH to 6～6.5 with 6mol/L hydrochloric acid down for 20～25 ℃, insulation growing the grain 2 hours.Suction filtration, drying obtain target compound 11,29.6g.(yield: 81.4%)
Ultimate analysis: C
15H
20N
6O
3S theoretical value: C, 49.44; H, 5.53; N, 23.06 measured values: C, 49.46; H, 5.54; N, 23.03
Same method:
Prepare by (6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-ethyl formate (compound 10, R5 are ethyl): compound 11 (yield: 75.3%)
Prepare by 2-(6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-isopropyl formate (compound 10, R5 are sec.-propyl): compound 11 (yield: 76.8%)
Method B:
In four-hole bottle, add lithium hydroxide (23.4g, 0.35mol), water (265ml), stirring and dissolving.Adding 2-(6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 10, R5 are methyl) (37.8g, 0.1mol).50 ℃ were reacted 3 hours, reduced to room temperature and transferred PH to 6～6.5 with 6N hydrochloric acid.The refrigeration growing the grain spends the night.Suction filtration is dried to constant weight.Get target compound 11,35.2g (yield: 96.7%).
Fusing point:＞250 ℃
HPLC purity: 98.2%
Ultimate analysis: C
15H
20N
6O
3S theoretical value: C, 49.44; H, 5.53; N, 23.06 measured values: C, 49.43; H, 5.53; N, 23.05
1H-NMR (500MHz, DMSO-d
6): (d, 3H), 3.119 (s, 2H), 3.206 (s, 2H), 3.596 (s, 2H), 3.817 (s, 4H), 4.316 (s, 2H), 5.405 (s 1H) adds D to δ (ppm) 2.448～2.509
2Disappear behind the O, 6.197 (s, 1H), 7.978 (s, 1H), 10.962～11.759 (d 1H) adds D
2Disappear behind the O, 12.835 (s 1H) adds D
2Disappear behind the O.
13C-NMR(500MHz，DMSO-d
6)：δ(ppm)25.939，40.495，41.027，51.154，55.561，58.315，84.083，122.135，145.401，157.660，162.451，163.731，165.847.
ESI(M+1)：365.43，(M-1)：363.42
Embodiment 8: the preparation of Dasatinib (compound 1)
Method A-1:
With 2-(6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 11) (36.4g, 0.1mol), THF (180ml) and DMF (5ml) add in the reaction flask, temperature control drips oxalyl chloride (25.4g down for 10～20 ℃, 0.2mol) methylene dichloride (75ml) solution, drip and finish, stirring at room reaction 6 hours.Be evaporated to driedly, it changed in the reaction flask with (300ml) acetonitrile.Stir, temperature control drips 2-chloro-6-monomethylaniline (compound 7) (21.3g, acetonitrile 0.15mol) (500ml) solution down for 10～15 ℃.Drip and finish, (56g, 0.4mol), 30 ℃ of reactions of temperature control are spent the night to add DIPEA.Suction filtration, filter cake acetonitrile (100ml) drip washing.Filter cake taken out add water (200ml) and stir and wash 30 minutes, suction filtration, filter cake washes with water.The taking-up filter cake adds to heat up in 80% alcohol-water (300ml) makes dissolving, adds the 1g activated carbon decolorizing, suction filtration, and filtrate refrigeration crystallization spends the night.Suction filtration, drying obtain Dasatinib (compound 1), and 28.5g (yield: 58.4%, purity: 99.4%).
Ultimate analysis: C
22H
26ClN
7O
2S theoretical value: C, 54.15; H, 5.37; N, 20.09 measured values: C, 54.17; H, 5.38; N, 20.09
Method A-2:
With 2-(6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 11) (18.2g, 0.05mol), THF (90ml) and DMF (2.5ml) add in the reaction flask, temperature control drips oxalyl chloride (12.7g down for 10～20 ℃, 0.1mol) methylene dichloride (40ml) solution, drip and finish, stirring at room reaction 6 hours.Be evaporated to driedly, it changed in the reaction flask with (150ml) acetonitrile.Stir, temperature control drips 2-chloro-6-monomethylaniline (compound 7) (10.8g, acetonitrile 0.08mol) (250ml) solution down for 10～15 ℃.Drip and finish, (28g, 0.2mol), 30 ℃ of reactions of temperature control are spent the night to add DIPEA.Suction filtration, filter cake acetonitrile (50ml) drip washing.Filter cake taken out add water (100ml) and stir and wash 30 minutes, suction filtration, filter cake washes with water.Add dimethyl sulfoxide (DMSO) 75ml, stir down and be warming up to 60～70 ℃, wait to dissolve the mixed solution that the back insulation adds 230ml water and acetone (1: 1) down, be cooled to 0 ℃ of growing the grain 10 minutes after separating out crystal under the stirring.Suction filtration, filter cake with water wash after water and acetone (1: 1) mixed solution drip washing and drain.Filter cake reduces pressure in about 50 ℃, and (0.095MPa) drying helps dried with Vanadium Pentoxide in FLAKES.Suction filtration, drying obtain Dasatinib (compound 1), and 13.7g (yield: 56.2%, purity: 99.92%).
Ultimate analysis: C
22H
26ClN
7O
2S theoretical value: C, 54.15; H, 5.37; N, 20.09 measured values: C, 54.21; H, 5.46; N, 20.13
Method B-1: the preparation of Dasatinib (compound 1)
With 2-(6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 11) (36.4g, 0.1mol), DMF (720ml) and 2-chloro-6-monomethylaniline (compound 7) (17.0g, 0.12mol) add in the reaction flask, temperature control adds HATU (49.4g down for 20 ℃, 0.13mol) and triethylamine (25.3g, 0.25mol), stirring at room reaction is spent the night.Add entry (3600ml), suction filtration.Filter cake got add water (300ml) and stir and wash 30 minutes, suction filtration, filter cake washes with water.The taking-up filter cake adds to heat up in 80% alcohol-water (600ml) makes dissolving, adds the 1.5g activated carbon decolorizing, suction filtration, and filtrate refrigeration crystallization spends the night.Suction filtration, drying obtains Dasatinib (compound 1) after filter cake is re-refined, 35.4g (yield: 72.5%, purity: 99.7%)
Ultimate analysis: ultimate analysis: C
22H
26ClN
7O
2S theoretical value: C, 54.15; H, 5.37; N, 20.09 measured values: C, 54.14; H, 5.37; N, 20.07
Method B-2: the preparation of Dasatinib (compound 1)
With 2-(6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 11) (36.4g, 0.1mol), DMF (720ml) and 2-chloro-6-monomethylaniline (compound 7) (17.0g, 0.12mol) add in the reaction flask, temperature control adds HATU (49.4g down for 20 ℃, 0.13mol) and triethylamine (25.3g, 0.25mol), stirring at room reaction is spent the night.Add entry (3600ml), suction filtration.Filter cake got add water (300ml) and stir and wash 30 minutes, suction filtration, filter cake washes with water.Add dimethyl sulfoxide (DMSO) 150ml, stir down and be warming up to 60～70 ℃, wait to dissolve the mixed solution that the back insulation adds 600ml water and ethanol (1: 1) down, be cooled to 0 ℃ of growing the grain 10 minutes after separating out crystal under the stirring.Suction filtration, filter cake with water wash after water and ethanol (1: 1) mixed solution drip washing and drain.Filter cake in about 50 ℃, reduce pressure (0.095MPa) drying helps driedly with Vanadium Pentoxide in FLAKES, obtain Dasatinib (compound 1), 38.6g (yield: 79.1%, purity: 99.91%)
Ultimate analysis: C
22H
26ClN
7O
2S theoretical value: C, 54.15; H, 5.37; N, 20.09 measured values: C, 54.09; H, 5.45; N, 20.13
Method C: the preparation of Dasatinib (compound 1)
Under the nitrogen protection; with 2-(6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 11) (7.3g; 0.02mol); PDCP (3.4ml; 0.023mol) and 2-chloro-6-monomethylaniline (compound 7) (2.8ml, 0.023mol) in the adding methylene dichloride (35ml), the stirring cooling; in 0 ℃ drip triethylamine (8.4ml, 0.062mol).Drip and finish, the stirring at room reaction is spent the night.Add saturated sodium bicarbonate aqueous solution and stir suction filtration after 15 minutes, obtain Dasatinib (compound 1) crude product (purity: 97.2%).
Filter cake is added in the dimethyl sulfoxide (DMSO) (36ml), stir down and be warming up to 60～70 ℃, wait to dissolve the mixed solution that the back insulation adds 145ml water and ethanol (1: 1) down, be cooled to 0 ℃ of growing the grain 10 minutes after separating out crystal under the stirring.Suction filtration, filter cake with water wash after water and ethanol (1: 1) mixed solution drip washing and drain.Filter cake in about 50 ℃, reduce pressure (0.095MPa) drying, help with Vanadium Pentoxide in FLAKES dried, Dasatinib (compound 1), 7.9g (yield: 80.9%, purity: 99.95%, see Fig. 1).
1H-NMR(500MHz，DMSO-d
6)：δ(ppm)2.245(s，3H)，2.413～2.446(s，5H)，2.491～2.509(m，4H)，3.521～3.557(q，6H)，4.46(s，1H)，6.05(s，1H)，7.248～7.305(m，3H)，8.226(s，1H)，9.883(s，1H)，11.476(s，1H)
1H-NMR(500MHz，DMSO-d
6，D
2O)：δ(ppm)2.233(s，3H)，2.403～2.435，(s，5H)，2.473～2.507(d，4H)，6.047(s，1H)，7.238～7.292(m，2H)，7.386～7.400(d，1H)，8.218(s，1H)
13C-NMR(500MHz，DMSO-d
6)：δ(ppm)18.756，26.034，44.098，53.186，58.997，60.658，83.098，126.157，127.458，128.612，129.474，132.910，134.002，139.285，141.286，157.410.160.393，162.964，165.629
ESI(M+1)：490.27
The preparation of embodiment 9:2-(6-(4-(2-acetyl oxygen ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 12, Pg are ethanoyl)
(30g, 0.082mol), pyridine (300ml) and DMAP (0.3g), 30 ℃ of temperature controls drip aceticanhydrides (25ml) down to add 2-(6-(4-(2-hydroxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 11) in four-hole bottle.Drip and finish, be warming up to 50 ℃ of insulation reaction and spend the night.Reaction is finished, and reduces to the room temperature growing the grain and spends the night.Suction filtration, an amount of eluent methylene chloride.Take out filter cake and added methylene dichloride (150ml) stirring at room 30 minutes, suction filtration, 60 ℃ of forced air dryings are to constant weight.Get pale yellow to off-white color solid target compound 12 (Pg is an ethanoyl), 24g (yield: 71.7%).
Fusing point: 241 ℃
Purity: 98.3% (HPLC, normalization method)
Ultimate analysis: C
17H
22N
6O
4S theoretical value: C, 50.23; H, 5.46; N, 20.68 measured values: C, 50.25; H, 5.48; N, 20.62;
1H-NMR (500MHz, DMSO-d
6): (s, 3H), 2.455 (s, 3H), 2.548 (s, 4H), 3.118～3.214 (d, 4H), 3.591 (s, 2H), 4.340 (s, 2H), 6.165 (s, 1H), 7.984 (s, 1H), 11.312～11.736 (d 1H) adds D to δ (ppm) 2.093
2Disappear behind the O, 12.824 (s 1H) adds D
2Disappear behind the O.
13C-NMR(500MHz，DMSO-d
6)：δ(ppm)21.262，25.943，40.916，41.092，51.096，54.578，58.671，84.015，122.143，145.407，157.651，162.424，163.743，165.864，170.532。
ESI：(M+1)：406.48，M：405.47
Same method:
Prepare 2-(6-(4-(2-benzoyl oxygen ethyl) piperazine-1-)-2-methylpyrimidine-4-amino) thiazole-5-formic acid: compound 12 (Pg is a benzoyl) (yield: 74.2%) by benzoyl oxide
Ultimate analysis: C
22H
24N
6O
4S theoretical value: C, 56.40; H, 5.16; N, 17.94 measured values: C, 56.45; H, 5.11; N, 17.92;
Embodiment 10: the preparation of the Dasatinib (compound 14, Pg are ethanoyl) of ethanoyl protection
Method A:
In four-hole bottle, add 2-(6-(4-(2-acetyl oxygen ethyl) piperazine-1-yl)-2-methylpyrimidine 4-amino) thiazole-5-formic acid (compound 12, Pg are ethanoyl) (30g, 0.074mol), methylene dichloride (270ml) and DMF (3ml).Cooling, in 0 ℃～drip methylene dichloride (30ml) solution of oxalyl chloride (12.7ml) below 5 ℃.Dripped the Bi Shengzhi room temperature reaction 3 hours.Suction filtration adds filter cake and methylene dichloride (300ml) in the reaction flask, stirs and is cooled to 0 ℃, adds 2-chloro-6-monomethylaniline (compound 7) (13.6ml, 0.11mol)), and drips DIPEA (21ml, methylene dichloride 0.12mol) (30ml) solution.Drip to finish, in room temperature reaction 2 hours.Reaction is finished, and adds saturated sodium bicarbonate aqueous solution and stirs suction filtration after 30 minutes.60 ℃ of forced air dryings are to constant weight.Get target compound 14 (Pg is an ethanoyl), 16g (yield: 40.8%).
Fusing point: 295.2 ℃
Purity: 98.5% (HPLC, normalization method)
Ultimate analysis: C
24H
28ClN
7O
3S theoretical value: C, 54.38; H, 5.32; N, 18.50 measured values: C, 54.42; H, 5.40; N, 18.55;
1H-NMR(500MHz，DMSO-d
6)：δ(ppm)2.030(s，3H)，2.245(s，3H)，2.372～2.414(d，3H)，2.584～2.605(t，6H)，3.517(s，4H)，4.133～4.155(t，2H)，6.056(s，1H)，7.248～7.305(m，2H)，7.400～7.414(t，1H)，8.226(s，1H)，9.883(s，1H)，11.845(s，1H)
1H-NMR(500MHz，DMSO-d
6，D
2O)：δ(ppm)2.020～2.055(d，3H)，2.240～2.278(d，3H)，2.367～2.441(t，3H)，2.491～2.501(d，4H)，2.546～2.592(q，2H)，3.423(s，1H)，3.514(s，lH)，4.122～4.144(t，1H)，6.054(s，1H)，7.240～7.296(m，2H)，7.391～7.406(d，1H)，8.230(m，1H)。
13C-NMR(500MHz，DMSO-d
6)：δ(ppm)18.759，21.237，26.034，44.053，52.866，56.480，61.695，83.198，126.080，127.458，128.594，129.473，132.921，134.036，139.297，141.320，157.532，160.411，163.001，165.617，170.780
ESI：(M)531.29
Same method:
(6-(4-(2-benzoyl oxygen ethyl) piperazine-1-)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 12, Pg are benzoyl) prepares the Dasatinib of benzoyl protection: compound 14 (Pg is a benzoyl) (yield: 43.1%) by 2-
Ultimate analysis: C
29H
30ClN
7O
3S theoretical value: C, 58.83; H, 5.11; N, 16.56 measured values: C, 58.89; H, 5.19; N, 16.58;
Method B:
Under the nitrogen protection; with 2-(6-(4-(2-acetyl oxygen ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 12; Pg is an ethanoyl) (8.5g; 0.021mol), PDCP (3.4ml, 0.023mol) and 2-chloro-6-monomethylaniline (compound 7) (2.81ml; 0.023mol) add in the methylene dichloride (34ml); stir, lower the temperature in 0 ℃ drip triethylamine (8.4ml, 0.062mol).Drip and finish, the stirring at room reaction is spent the night.Add saturated sodium bicarbonate aqueous solution and stir suction filtration after 10 minutes.60 ℃ of forced air dryings are to constant weight.Get pale yellow to off-white color solid target compound 14 (Pg is an ethanoyl), 7.98g (yield: 71.7%).
Fusing point: 295.5 ℃
Ultimate analysis: C
24H
28ClN
7O
3S theoretical value: C, 54.38; H, 5.32; N, 18.50 measured values: C, 54.32; H, 5.38; N, 18.57;
Same method:
(6-(4-(2-benzoyl oxygen ethyl) piperazine-1-)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 12, Pg are benzoyl) prepares the Dasatinib of benzoyl protection: compound 14 (Pg is a benzoyl) (yield: 76.3%) by 2-
Ultimate analysis: C
29H
30ClN
7O
3S theoretical value: C, 58.83; H, 5.11; N, 16.56 measured values: C, 58.87; H, 5.19; N, 16.61;
Embodiment 11: the preparation of Dasatinib (compound 1)
In four-hole bottle, add sodium hydroxide (9.5g, 0.24mol), water (150ml), the Dasatinib (compound 14, Pg are ethanoyl) of ethanoyl protection (30g, 0.057mol), in 50 ℃ of insulation reaction 2 hours.Be cooled to below 25 ℃, transfer PH to 4 with 6N hydrochloric acid.The room temperature growing the grain spends the night.Suction filtration obtains Dasatinib (compound 1) crude product (purity 97.6%).Add in the dimethyl sulfoxide (DMSO) (100ml), stir down and be warming up to 60～70 ℃, wait to dissolve the mixed solution that the back insulation adds 400ml water and ethanol (1: 1) down, be cooled to 0 ℃ of growing the grain 2 hours after separating out crystal under the stirring.Suction filtration, filter cake with water wash after water and ethanol (1: 1) mixed solution drip washing and drain.Filter cake in about 50 ℃, reduce pressure (0.095MPa) drying, help with Vanadium Pentoxide in FLAKES dried, Dasatinib (compound 1) 24.5g.(yield: 88.7%, purity: 99.93%)
1H-NMR(500MHz，DMSO-d
6)：δ(ppm)2.243(s，3H)，2.411～2.440(s，3H)，2.484～2.507(d，4H)，3.513～3.554(q，6H)，4.443～4.464(t，1H)，6.052(s，1H)，7.246～7.304(m，2H)，7.398～7.413(d，1H)，8.223(s，1H)，9.881(s，1H)，11.474(s，1H)
Same method:
Dasatinib (compound 14, Pg are benzoyl) by the benzoyl protection prepares Dasatinib: and compound 1 (yield: 82.5%, purity: 99.55%)
The preparation of embodiment 12:2-(6-(4-(2-benzyloxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 16, R5 are methyl, and Pg is a benzyl)
In four-hole bottle, add 2-(6-chloro-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 4, R5 are methyl) (4.3g, 0.015mol), benzyloxy ethyl piperazidine (compound 15, Pg are benzyl) (11g, 0.05mol) and propyl carbinol (55ml).Stir adding DIPEA (5.3ml) down, be warming up to back flow reaction 5 hours, reaction is finished the room temperature growing the grain and is spent the night.Suction filtration, filter cake is with an amount of freezing propyl carbinol drip washing.60 ℃ of forced air dryings are to constant weight.Get yellow solid target compound 16 (R5 is a methyl, and Pg is a benzyl), 4.3g (yield: 60.6%).
Ultimate analysis: C
23H
28N
6O
3S theoretical value: C, 58.95; H, 6.02; N, 17.94 measured values: C, 58.89; H, 6.09; N, 17.95
Same method:
By to methoxyl group benzyloxy ethyl piperazidine (compound 15, Pg is for to methoxy-benzyl) prepare 2-(6-(4-(2-is to methoxyl group benzyloxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate: compound 16 (R5 is a methyl, and Pg is to methoxy-benzyl) (yield: 55.3%)
Ultimate analysis: C
24H
30N
6O
4S theoretical value: C, 57.81; H, 6.06; N, 16.86 measured values: C, 57.71; H, 6.19; N, 16.80
By methoxyl group methoxy ethyl piperazidine (compound 15, Pg is a methoxymethyl) prepare 2-(6-(4-(2-methoxyl group methoxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate: compound 16 (R5 is a methyl, and Pg is a methoxymethyl) (yield: 59.5%)
Ultimate analysis: C
18H
26N
6O
4S theoretical value: C, 51.17; H, 6.20; N, 19.89 measured values: C, 51.12; H, 6.27; N, 19.88;
By oxyethyl group ethoxyethyl piperazine (compound 15, Pg is an ethoxyethyl group) prepare 2-(6-(4-(2-oxyethyl group ethoxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate: compound 16 (R5 is a methyl, and Pg is an ethoxyethyl group) (yield: 45.8%)
Ultimate analysis: C
20H
30N
6O
4S theoretical value: C, 53.32; H, 6.71; N, 18.65 measured values: C, 53.29; H, 6.83; N, 18.60;
By methylthio group methoxyethyl piperazine (compound 15, Pg is a methylthiomethyl) prepare 2-(6-(4-(2-methylthio group methoxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate: compound 16 (R5 is a methyl, and Pg is a methylthiomethyl) (yield: 43.1%)
Ultimate analysis: C
18H
26N
6O
3S
2Theoretical value: C, 49.30; H, 5.98; N, 19.16 measured values: C, 49.35; H, 6.03; N, 19.10;
The preparation of embodiment 13:2-(6-(4-(2-benzyloxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 12, Pg are benzyl)
In four-hole bottle, add sodium hydroxide (1.27g, 0.032mol), water (25ml), add 2-(6-(4-(2-benzyloxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 16 below 60 ℃, R5 is a methyl, and Pg is a benzyl) (4.95g, 0.011mol).Be warming up to 80 ℃ of reactions 4 hours.Reaction is finished, and reduces to room temperature and transfers PH to 2 with 6N hydrochloric acid.The room temperature growing the grain spends the night.Suction filtration, 60 ℃ of forced air dryings are to constant weight.Get faint yellow solid target compound 12 (Pg is a benzyl), 4.7g (yield: 97.9%).
Ultimate analysis: C
22H
26N
6O
3S theoretical value: C, 58.13; H, 5.77; N, 18.49 measured values: C, 58.18; H, 5.83; N, 18.43;
Same method:
By 2-(6-(4-(2-is to methoxyl group benzyloxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 16, R5 is a methyl, and Pg is for to methoxy-benzyl) obtain 2-(6-(4-(2-is to methoxyl group benzyloxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid: compound 12 (Pg for to methoxy-benzyl) (yield: 92.2%)
Ultimate analysis: C
23H
28N
6O
4S theoretical value: C, 57.01; H, 5.82; N, 17.34 measured values: C, 57.10; H, 5.90; N, 17.30;
By 2-(6-(4-(2-methoxyl group methoxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 16, R5 is a methyl, and Pg is a methoxymethyl) prepare 2-(6-(4-(2-methoxyl group methoxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid: compound 12 (Pg is a methoxymethyl) (yield: 94.7%)
Ultimate analysis: C
17H
24N
6O
4S theoretical value: C, 49.99; H, 5.92; N, 20.57 measured values: C, 50.03; H, 5.99; N, 20.61;
By 2-(6-(4-(2-oxyethyl group ethoxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 16, R5 is a methyl, and Pg is an ethoxyethyl group) prepare 2-(6-(4-(2-oxyethyl group ethoxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid: compound 12 (Pg is an ethoxyethyl group) (yield: 95.2%)
Ultimate analysis: C
19H
28N
6O
4S theoretical value: C, 52.28; H, 6.47; N, 19.25 measured values: C, 52.25; H, 6.43; N, 19.21;
By 2-(6-(4-(2-methylthio group methoxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 16, R5 is a methyl, and Pg is a methylthiomethyl) obtain 2-(6-(4-(2-methylthio group methoxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid: compound 12 (Pg is a methylthiomethyl) (yield: 91.5%)
Ultimate analysis: C
17H
24N
6O
3S
2Theoretical value: C, 48.09; H, 5.70; N, 19.80 measured values: C, 48.13; H, 5.79; N, 19.77;
Embodiment 14: the preparation of the Dasatinib of benzyl protection (compound 14, Pg are benzyl)
Under the nitrogen protection; with 2-(6-(4-(2-benzyloxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 12; Pg is a benzyl) (13.6g; 0.03mol), PDCP (5.4ml, 0.036mol) and 2-chloro-6-monomethylaniline (compound 7) (4.4ml; 0.036mol) add in the methylene dichloride (55ml); stir, lower the temperature in 0 ℃ drip triethylamine (12.3ml, 0.09mol).Drip and finish, the stirring at room reaction is spent the night.Add saturated sodium bicarbonate aqueous solution and stir suction filtration after 10 minutes.60 ℃ of forced air dryings are to constant weight.Get target compound 14 (Pg is a benzyl), 11.2g (yield: 64.7%).
Ultimate analysis: C
29H
32ClN
7O
2S theoretical value: C, 60.25; H, 5.58; N, 16.96 measured values: C, 60.21; H, 5.51; N, 16.92;
Same method:
Prepare Dasatinib by 2-(6-(4-(2-is to methoxyl group benzyloxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 12, Pg are to methoxy-benzyl): compound 14 (Pg is to methoxy-benzyl) (yield: 59.1%) to the methoxybenzyl protection
Ultimate analysis: C
30H
34ClN
7O
3S theoretical value: C, 59.25; H, 5.64; N, 16.12 measured values: C, 59.21; H, 5.70; N, 16.18;
Prepare the Dasatinib of methoxymethyl protection by 2-(6-(4-(2-methoxyl group methoxy ethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 12, Pg are methoxymethyl): compound 14 (Pg is a methoxymethyl) (yield: 66.4%)
Ultimate analysis: C
24H
30ClN
7O
3S theoretical value: C, 54.18; H, 5.68; N, 18.43 measured values: C, 54.22; H, 5.71; N, 18.40;
Prepare the Dasatinib of ethoxyethyl group protection by 2-(6-(4-(2-oxyethyl group ethoxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-methyl-formiate (compound 12, Pg are ethoxyethyl group): compound 14 (Pg is an ethoxyethyl group) (yield: 48.6%)
Ultimate analysis: C
26H
34ClN
7O
3S theoretical value: C, 55.75; H, 6.12; N, 17.50 measured values: C, 55.71; H, 6.19; N, 17.54;
Obtain the Dasatinib of methylthiomethyl protection by 2-(6-(4-(2-methylthio group methoxyethyl) piperazine-1-yl)-2-methylpyrimidine-4-amino) thiazole-5-formic acid (compound 12, Pg are methylthiomethyl): compound 14 (Pg is a methylthiomethyl) (yield: 59.5%)
Ultimate analysis: C
24H
30ClN
7O
2S
2Theoretical value: C, 52.59; H, 5.52; N, 17.89 measured values: C, 52.61; H, 5.60; N, 17.83;
Embodiment 15: the preparation of Dasatinib (compound 1)
(5.8g 0.01mol) adds in the anhydrous methylene chloride (20ml) with the Dasatinib (compound 14, Pg are benzyl) of benzyl protection; be cooled to-15 ℃, and the dichloromethane solution of dropping 1M boron trichloride (60ml, 0.06mol); drip to finish, the insulated and stirred reaction after 5 hours room temperature reaction spend the night.Reaction solution is slowly added in the frozen water.Suction filtration, obtain Dasatinib (compound 1) crude product (purity: 98.3%), filter cake is directly added in the dimethyl sulfoxide (DMSO) (20ml), be warming up to 60～70 ℃ under stirring, wait to dissolve the mixed solution that the back insulation adds 80ml water and ethanol (1: 1) down, be cooled to 0 ℃ of growing the grain 10 minutes after separating out crystal under stirring.Suction filtration, filter cake with water wash after water and ethanol (1: 1) mixed solution drip washing and drain.Filter cake reduces pressure in about 50 ℃, and (0.095MPa) drying helps dried with Vanadium Pentoxide in FLAKES.Get Dasatinib (compound 1), 4.01g.(yield: 82.2%, purity: 99.92%)
Same method:
Prepare Dasatinib by Dasatinib (compound 14, Pg are to methoxy-benzyl) to the methoxybenzyl protection: compound 1 (yield: 77.3%, purity: 99.72%)
Dasatinib (compound 14, Pg are methoxymethyl) by the methoxymethyl protection prepares Dasatinib: and compound 1 (yield: 70.6%, purity: 99.80%)
Dasatinib (compound 14, Pg are ethoxyethyl group) by the ethoxyethyl group protection prepares Dasatinib: and compound 1 (yield: 72.5%, purity: 99.53%)
Dasatinib (compound 14, Pg are methylthiomethyl) by the methylthiomethyl protection prepares Dasatinib: and compound 1 (yield: 80.7%, purity: 99.61%).
Claims (10)
1. the synthetic method of a Dasatinib comprises the following steps: the reaction of formula I compound and formula II compound, thereby obtains the formula III compound:
Here, in formula II and formula III, R
4Alkoxyl group for the alkoxyl group of C1-C6 or the C1-C6 that replaces;
With the formula III compound hydrolysis, thereby obtain formula IV compound:
Then, formula IV compound obtains formula V compound under the chloride reagent effect:
Formula V compound reacts with 2-chloro-6-monomethylaniline again, obtains formula VI compound:
Perhaps formula IV compound reacts with 2-chloro-6-monomethylaniline in the presence of amide condensed dose, obtains formula VI compound;
Formula VI compound obtains Dasatinib with the reaction of 1-(2-hydroxyethyl) piperazine again.
2. method according to claim 1, wherein, R in formula II and formula III
4Be methoxyl group, benzyloxy, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, sec-butoxy, isobutoxy, pentyloxy or hexyloxy;
Described chloride reagent is selected from phosphorus trichloride, phosphorus pentachloride, thionyl chloride or oxalyl chloride, preferably, is oxalyl chloride;
Described amide condensed dose is selected from phosphorus dichloride acid phenenyl ester (PDCP), dicyclohexylcarbodiimide (DCC), DIC (DIC), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU) or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI).
3. the synthetic method of a Dasatinib comprises the following steps: the reaction of formula I compound and formula II compound, thereby obtains the formula III compound:
Here, in formula II and formula III, R
4Alkoxyl group for the alkoxyl group of C1-C6 or the C1-C6 that replaces;
The reaction of formula III compound and 1-(2-hydroxyethyl) piperazine, thus formula VII compound obtained:
Here, R in the formula VII compound
4Definition as above;
Then, formula VII compound hydrolysis obtains formula VIII compound:
Formula VIII compound and hydroxyl protection reagent react, thus formula IX compound obtained;
Formula IX compound obtains formula X compound under the chloride reagent effect, here, Pg is a hydroxyl protecting group among formula IX and the X:
Formula X compound reacts with 2-chloro-6-monomethylaniline again, then, removes the protecting group Pg on the hydroxyl, thereby obtains Dasatinib;
Perhaps formula IX compound reacts with 2-chloro-6-monomethylaniline in the presence of amide condensed dose, then, removes the protecting group Pg on the hydroxyl, thereby obtains Dasatinib.
4. method according to claim 3, wherein, R in formula II and formula III
4Be methoxyl group, benzyloxy, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, sec-butoxy, isobutoxy, pentyloxy or hexyloxy;
Described hydroxyl protection reagent is the reagent of following hydroxyl protecting group: the C1-C4 alkanoic acid ester or the carbonic ether protecting group that are selected from C1-C4 alkanoic acid ester or replacement;
Described chloride reagent is selected from phosphorus trichloride, phosphorus pentachloride, thionyl chloride or oxalyl chloride, preferably, is oxalyl chloride;
Described amide condensed dose is selected from phosphorus dichloride acid phenenyl ester (PDCP), dicyclohexylcarbodiimide (DCC), DIC (DIC), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU) or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI).
5. the synthetic method of a Dasatinib comprises the following steps: the reaction of formula I compound and formula II compound, thereby obtains the formula III compound:
Here, in formula II and formula III, R
4Alkoxyl group for the alkoxyl group of C1-C6 or the C1-C6 that replaces;
Then, the reaction of the 1-of formula III compound and hydroxyl protection (2-hydroxyethyl) piperazine, thus obtain formula XI compound:
Here, R in formula III and the formula XI compound
4Definition as above; Pg is a hydroxyl protecting group and for hydrogen;
Then, formula XI compound hydrolysis obtains formula IX compound:
Formula IX compound obtains formula X compound under the chloride reagent effect, here, Pg is a hydroxyl protecting group among formula IX and the X;
Formula X compound reacts with 2-chloro-6-monomethylaniline again, then, removes the protecting group Pg on the hydroxyl, thereby obtains Dasatinib;
Perhaps formula IX compound reacts with 2-chloro-6-monomethylaniline in the presence of amide condensed dose, then, removes the protecting group Pg on the hydroxyl, thereby obtains Dasatinib.
6. method according to claim 5, wherein, R in formula II and formula III
4Be methoxyl group, benzyloxy, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, sec-butoxy, isobutoxy, pentyloxy or hexyloxy;
Described hydroxyl protection reagent is the reagent of following hydroxyl protecting group: the C1-C4 alkanoic acid ester or the carbonic ether protecting group that are selected from C1-C4 alkanoic acid ester or replacement;
Described chloride reagent is selected from phosphorus trichloride, phosphorus pentachloride, thionyl chloride or oxalyl chloride, preferably, is oxalyl chloride;
Described amide condensed dose is selected from phosphorus dichloride acid phenenyl ester (PDCP), dicyclohexylcarbodiimide (DCC), DIC (DIC), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU) or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI).
7. the synthetic method of a Dasatinib comprises the following steps: the reaction of formula I compound and formula II compound, thereby obtains the formula III compound:
Here, in formula II and formula III, R
4Alkoxyl group for the alkoxyl group of C1-C6 or the C1-C6 that replaces;
Then, formula III compound and the reaction of 2-chloro-6-monomethylaniline obtain formula XII compound:
Then, the reaction of formula XII compound and 1-(2-hydroxyethyl) piperazine obtains Dasatinib.
8. method according to claim 7, wherein, R in formula II and formula III
4Be methoxyl group, benzyloxy, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, sec-butoxy, isobutoxy, pentyloxy or hexyloxy.
9. the purification process of a Dasatinib comprises arbitrary claim in the claim 1 to 8 is reacted the back Dasatinib crude product that obtains by the mode of concentrated or suction filtration that finishes, and adds in the specific organic solvent; Heating under agitation makes its dissolving, drips the mixed solvent system of water and organic solvent; Dropwise, stir and slowly to be cooled to 0～10 ℃ down solid is separated out fully and growing the grain, solid collected by filtration, and the dry purity that can make is greater than 99.50% high purity Dasatinib.
10. method according to claim 9, wherein, the purity of Dasatinib crude product is greater than 95%, and the purity that is preferably crude product is greater than 97%;
Described specific organic solvent is non-proton property polar solvent, is preferably N, dinethylformamide, N, N-dimethyl methyl ethanamide, dimethyl sulfoxide (DMSO), or its mixture;
Described heating under agitation makes its dissolving, and Heating temperature is selected from room temperature to reflux temperature herein, is preferably 40～100 ℃;
The mixed solvent system of described dropping water and organic solvent, organic solvent is insoluble or sl. sol. one or more the mixed solvent of Dasatinib herein.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010177587A CN101845045A (en) | 2010-02-02 | 2010-05-07 | Novel method for synthesizing dasatinib |
| PCT/CN2011/070826 WO2011095125A1 (en) | 2010-02-02 | 2011-01-30 | Synthesis methods and purification methods of dasatinib |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010104295.9 | 2010-02-02 | ||
| CN201010177587A CN101845045A (en) | 2010-02-02 | 2010-05-07 | Novel method for synthesizing dasatinib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101845045A true CN101845045A (en) | 2010-09-29 |
Family
ID=42769878
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010177587A Pending CN101845045A (en) | 2010-02-02 | 2010-05-07 | Novel method for synthesizing dasatinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101845045A (en) |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011095125A1 (en) * | 2010-02-02 | 2011-08-11 | 南京卡文迪许生物工程技术有限公司 | Synthesis methods and purification methods of dasatinib |
| WO2011095059A1 (en) * | 2010-02-08 | 2011-08-11 | 南京卡文迪许生物工程技术有限公司 | Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof |
| WO2011095126A1 (en) * | 2010-02-02 | 2011-08-11 | 南京卡文迪许生物工程技术有限公司 | Synthesis process of dasatinib and intermediate thereof |
| CN102161660A (en) * | 2010-02-21 | 2011-08-24 | 中国医学科学院药物研究所 | Preparation method of 2-(6-chloro-2-methylpyrimidinyl-4-amino)-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide |
| CN102786517A (en) * | 2011-05-18 | 2012-11-21 | 中国医学科学院药物研究所 | Pyrimidine thiazole amine derivative having GK (glucokinase) and PPAR (peroxidase proliferator-activated receptor) dual agonist activities |
| CN104130250A (en) * | 2013-05-07 | 2014-11-05 | 郑州泰基鸿诺药物科技有限公司 | Deuterated dasatinib, and preparation method and application thereof |
| CN104788446A (en) * | 2011-06-24 | 2015-07-22 | 南京圣和药业股份有限公司 | Preparation and refinement method for anhydrous Dasatinib |
| CN104997737A (en) * | 2015-08-05 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Composition dry suspension of medicine dasatinib tablet for treating leukemia |
| CN105055327A (en) * | 2015-07-30 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Dasatinib composite granules capable of treating leukaemia |
| CN105055367A (en) * | 2015-08-18 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | SprycelTM composition capsule medicine for treating leukemia |
| CN106674080A (en) * | 2015-11-10 | 2017-05-17 | 南京卡文迪许生物工程技术有限公司 | Synthesis method of panobinostat |
| CN104292223B (en) * | 2013-07-17 | 2017-07-04 | 常州锐博生物科技有限公司 | A kind of new synthetic method of Dasatinib |
| CN107043375A (en) * | 2017-04-28 | 2017-08-15 | 江苏食品药品职业技术学院 | A kind of new method for preparing Dasatinib and its intermediate |
| CN109265455A (en) * | 2018-11-09 | 2019-01-25 | 新发药业有限公司 | A kind of preparation method of Dasatinib |
| CN110862387A (en) * | 2018-08-27 | 2020-03-06 | 鲁南制药集团股份有限公司 | Novel dasatinib crystal form and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1348370A (en) * | 1999-04-15 | 2002-05-08 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| 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 |
| WO2007106879A2 (en) * | 2006-03-15 | 2007-09-20 | Bristol-Myers Squibb Company | Process for preparing n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide and related metabolites thereof |
| CN101597284A (en) * | 2009-07-22 | 2009-12-09 | 北京莱博赛路森药物科技有限公司 | A kind of preparation method of antineoplastic compound |
-
2010
- 2010-05-07 CN CN201010177587A patent/CN101845045A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1348370A (en) * | 1999-04-15 | 2002-05-08 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| 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 |
| WO2007106879A2 (en) * | 2006-03-15 | 2007-09-20 | Bristol-Myers Squibb Company | Process for preparing n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide and related metabolites thereof |
| CN101597284A (en) * | 2009-07-22 | 2009-12-09 | 北京莱博赛路森药物科技有限公司 | A kind of preparation method of antineoplastic compound |
Cited By (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011095126A1 (en) * | 2010-02-02 | 2011-08-11 | 南京卡文迪许生物工程技术有限公司 | Synthesis process of dasatinib and intermediate thereof |
| WO2011095125A1 (en) * | 2010-02-02 | 2011-08-11 | 南京卡文迪许生物工程技术有限公司 | Synthesis methods and purification methods of dasatinib |
| US9108954B2 (en) | 2010-02-02 | 2015-08-18 | Nan Jing Cavendish Bio-Engineering Technology Co., Ltd. | Synthesis process of dasatinib and intermediate thereof |
| WO2011095059A1 (en) * | 2010-02-08 | 2011-08-11 | 南京卡文迪许生物工程技术有限公司 | Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof |
| US8884013B2 (en) | 2010-02-08 | 2014-11-11 | Nan Jing Cavendish Bio-Engineering Technology Co., Ltd. | Polymorphs of Dasatinib, preparation methods and pharmaceutical compositions thereof |
| CN102161660A (en) * | 2010-02-21 | 2011-08-24 | 中国医学科学院药物研究所 | Preparation method of 2-(6-chloro-2-methylpyrimidinyl-4-amino)-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide |
| CN102161660B (en) * | 2010-02-21 | 2015-05-20 | 中国医学科学院药物研究所 | Preparation method of 2-(6-chloro-2-methylpyrimidinyl-4-amino)-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide |
| CN102786517B (en) * | 2011-05-18 | 2017-06-06 | 中国医学科学院药物研究所 | The pyrimidine thiazole amines derivative of GK and PPAR double excitation activity |
| CN102786517A (en) * | 2011-05-18 | 2012-11-21 | 中国医学科学院药物研究所 | Pyrimidine thiazole amine derivative having GK (glucokinase) and PPAR (peroxidase proliferator-activated receptor) dual agonist activities |
| CN104788446A (en) * | 2011-06-24 | 2015-07-22 | 南京圣和药业股份有限公司 | Preparation and refinement method for anhydrous Dasatinib |
| CN104130250A (en) * | 2013-05-07 | 2014-11-05 | 郑州泰基鸿诺药物科技有限公司 | Deuterated dasatinib, and preparation method and application thereof |
| CN104130250B (en) * | 2013-05-07 | 2016-06-22 | 郑州泰基鸿诺药物科技有限公司 | Deuterated Dasatinib and its preparation method and application |
| CN104292223B (en) * | 2013-07-17 | 2017-07-04 | 常州锐博生物科技有限公司 | A kind of new synthetic method of Dasatinib |
| CN105055327A (en) * | 2015-07-30 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Dasatinib composite granules capable of treating leukaemia |
| CN104997737A (en) * | 2015-08-05 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Composition dry suspension of medicine dasatinib tablet for treating leukemia |
| CN105055367A (en) * | 2015-08-18 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | SprycelTM composition capsule medicine for treating leukemia |
| CN106674080A (en) * | 2015-11-10 | 2017-05-17 | 南京卡文迪许生物工程技术有限公司 | Synthesis method of panobinostat |
| CN107043375A (en) * | 2017-04-28 | 2017-08-15 | 江苏食品药品职业技术学院 | A kind of new method for preparing Dasatinib and its intermediate |
| 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 |
| CN110862387A (en) * | 2018-08-27 | 2020-03-06 | 鲁南制药集团股份有限公司 | Novel dasatinib crystal form and preparation method thereof |
| CN110862387B (en) * | 2018-08-27 | 2023-05-16 | 鲁南制药集团股份有限公司 | Novel dasatinib crystal form and preparation method thereof |
| CN109265455A (en) * | 2018-11-09 | 2019-01-25 | 新发药业有限公司 | A kind of preparation method of Dasatinib |
| CN109265455B (en) * | 2018-11-09 | 2020-08-18 | 新发药业有限公司 | Preparation method of dasatinib |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101812060B (en) | Simple novel method for preparing high-purity Sprycel, and intermediate compound | |
| CN101845045A (en) | Novel method for synthesizing dasatinib | |
| CN102812019B (en) | Prepare method and the intermediate of lapatinibditosylate | |
| CN104725327B (en) | A kind of environment-friendly preparation method of erlotinib Hydrochloride | |
| CN103664912B (en) | A kind of synthesis technique of prucalopride | |
| CN102869650B (en) | Novel crystal of erlotinib base and the preparation method thereof | |
| CN105418483A (en) | Preparation method of crystalline nintedanib esylate | |
| CN105753944B (en) | His Wei of Dacca and its derivative prepare intermediate | |
| CN103304492B (en) | The synthetic method of a kind of EGFR inhibitor Dacomitinib | |
| CN101985442A (en) | Convenient and quick method for preparing high-purity imatinib and mesylate thereof | |
| WO2011095125A1 (en) | Synthesis methods and purification methods of dasatinib | |
| CN103554099B (en) | Preparation method of Dasatinib | |
| TWI541235B (en) | Process of preparing a quinazoline derivative | |
| CN109988108B (en) | Preparation method of cabozantinib | |
| KR101456347B1 (en) | Synthesis process of Dasatinib and intermediate thereof | |
| CN100584829C (en) | 6-methoxyl group-1,2,3, the preparation method of 9-tetrahydrochysene-4H-carbazole-4-ketone | |
| CN104230825B (en) | The preparation method of Erlotinib alkali monohydrate crystal form Form I | |
| CN109265455A (en) | A kind of preparation method of Dasatinib | |
| CN110372600A (en) | A kind of synthetic method of the chloro- 4- cyanopyrimidine of 2- | |
| CN104418845B (en) | Prepare the method and intermediate of Lapatinib | |
| CN103588764B (en) | The synthetic method of Azilsartan or its salt and intermediate thereof | |
| CN103145628B (en) | Erlotinib-hydrate crystal form I preparation method | |
| CN103360325A (en) | Preparation method of erlotinib hydrochloride crystal form A | |
| CN103288751B (en) | A kind of preparation method of high-purity nifekalant hydrochloride | |
| CN104610237B (en) | A kind of Preparation Method And Their Intermediate of ticagrelor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| DD01 | Delivery of document by public notice |
Addressee: Xu Yongxiang Document name: Notification of Acceptance of Patent Application |
|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20100929 |