CN104151359A - Quinazoline compound as well as preparation method and application thereof in preparing tyrosine kinase inhibitor - Google Patents
Quinazoline compound as well as preparation method and application thereof in preparing tyrosine kinase inhibitor Download PDFInfo
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- CN104151359A CN104151359A CN201410337267.XA CN201410337267A CN104151359A CN 104151359 A CN104151359 A CN 104151359A CN 201410337267 A CN201410337267 A CN 201410337267A CN 104151359 A CN104151359 A CN 104151359A
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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Abstract
The invention relates to a novel quinazoline compound and a method for preparing a quinazoline crotyl compound for treating or preventing various adaptation diseases related to EGFR and HER2 kinase functions from the quinazoline compound. The method comprises the following steps: firstly, reacting a raw material with amino with diethylphosphonoacetic acid and N,N'-carbonyl dimidazole in a solvent at 25 DEG C to 50 DEG C, so as to transform the amino in the raw material into diethyl phosphorus acetamido to obtain an intermediate, and subsequently reacting the intermediate with N,N'-di-substituted acetaldehyde in a solvent in the presence of an alkali substance at minus 30 DEG C to minus 20 DEG C, thereby generating the target compound. By adopting the procedures, by virtue of simple aftertreatment, the target product of which the purity is greater than 98% is obtained, the total yield of the target product is as high as 74%, and in addition, by adopting the method, preparation of kilo-rate target products is successfully achieved, and batch production is easy to achieve.
Description
Technical field
The present invention relates to medical preparing technical field, be specifically related to quinazoline compounds, its preparation method and its application in preparing TYR kinase inhibitor.
Background technology
CN102838550A discloses the quinazoline crotonyl compounds with general formula (I),
Wherein: R
1for CH
2f, CHF
2, C
2～C
12fluoro alkyl, C
2～C
12chloro alkyl; R
2, R
3be hydrogen independently, C
1～C
12alkyl.
Above-mentioned quinazoline crotonyl compounds is proved to be desirable efficient double non reversibility tyrosine kinase inhibitor, can be by acting on EGFR intracellular portion and ATP competitive binding, suppress kinase whose activity and phosphorylation, thereby and seal EGFR SRCA TP binding site and reach the object that specificity suppresses EGFR.This compounds can be used for preparation treatment or prevents the various indications relevant with HER2 kinase function with EGFR, includes but not limited to the Several Kinds of Malignancy diseases such as mammary cancer, ovarian cancer, gastrointestinal cancer, the esophageal carcinoma, lung cancer, incidence squama cancer, carcinoma of the pancreas, epidermis squama cancer, prostate cancer, neurospongioma and nasopharyngeal carcinoma.
CN102838550A also discloses structural formula and has been the synthetic route of the quinazoline crotonyl compounds of formula Ia, specific as follows:
In above-mentioned route, the total molar yield from compound 2 to Compound I a only has 37% left and right.Although wherein the reduction reaction from compound 2 to compound 1 can obtain 97.8% yield,, this just only 10 grams of scale techniques can reappear completely, cannot amplify production; Reaction from compound 1 to Compound I a is anhydrous response, and low conversion rate is in 50%, and crude product purity is lower than 70%; And compound 1 can not transform completely, product is complicated, impurity is many, and gained crude product is that oily matter is difficult to solidify, and must carry out purifying with column chromatography, batch yields poorly.Generally speaking, the method yield is low, purification is difficult, cost is high, criticizes and yields poorly, and is unsuitable for the suitability for industrialized production of such quinazoline crotonyl compounds.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, and a kind of new quinazoline compounds is provided, and it is the desirable intermediate of preparing quinazoline crotonyl compounds.
The present invention also will provide the preparation method of quinazoline compounds simultaneously and utilize it to prepare the method for quinazoline crotonyl compounds.
For solving above technical problem, a kind of technical scheme that the present invention takes is as follows:
The quinazoline compounds with structure shown in formula (IV),
Wherein, R
1for CH
2f, CHF
2, C
2～C
12fluoro alkyl or C
2～C
12chloro alkyl.
The preparation method of the quinazoline compounds that the present invention is above-mentioned is as follows: make formula (III) compound, diethyl phosphorus acetic acid, N, N'-carbonyl dimidazoles, in solvent, reacts production (IV) compound at 25～50 ℃ of temperature, and reaction equation is as follows:
According to the present invention, described solvent can be tetrahydrofuran (THF), toluene, dioxane, dimethyl formamide, methylene dichloride etc., wherein preferred tetrahydrofuran (THF).
Preferably, formula (III) compound, diethyl phosphorus acetic acid, N, N'-carbonyl dimidazoles three's molar ratio is 1:2.05～2.2:2.05～2.2.
According to a concrete and preferred aspect, aforesaid method is specifically implemented as follows: formula (III) compound and diethyl phosphorus acetic acid are dissolved in respectively in described solvent, be warming up to 25～50 ℃, the solution of diethyl phosphorus acetic acid is dropped in the solution of formula (III) compound, insulated and stirred reaction, TLC monitors to formula (III) compound and reacts completely, and finishes reaction.
Further, finish after reaction, add methyl tertiary butyl ether stirring reaction 1～2 hour, filter, the mixed solution washing of methyl tertiary butyl ether and described solvent for filter cake, then wash, with the mixed solution of methyl tertiary butyl ether and described solvent, wash again, after washing, vacuum-drying, obtains formula (IV) compound.Further, vacuum-drying can for example carried out at 30～40 ℃.
Further, described preparation method also comprises makes formula (II) compound and hydrogen under catalyzer exists, the step of the production that reacts in mixed solvent (III) compound, in this step, mixed solvent is comprised of by weight 3～8:1 tetrahydrofuran (THF) and methyl alcohol, and reaction equation is as follows:
In the above-mentioned step of preparing compound (III), described catalyzer can be the conventional hydrogenation catalyst in this area, such as Raney's nickel, platinum, palladium and rhodium etc.
Formula of the present invention (IV) compound is desirable quinazoline crotonyl compounds intermediate, and for this reason, the present invention is also particularly related to this compound for the preparation of the purposes with the quinazoline crotonyl compounds of general formula (I),
Wherein: R
1for CH
2f, CHF
2, C
2～C
12fluoro alkyl, C
2～C
12chloro alkyl; R
2, R
3be hydrogen independently, C
1～C
12alkyl.
The another technical scheme that the present invention takes is: a kind of preparation method with the quinazoline crotonyl compounds of general formula (I),
Wherein: R
1for CH
2f, CHF
2, C
2～C
12fluoro alkyl, C
2～C
12chloro alkyl; R
2, R
3be hydrogen independently, C
1～C
12alkyl,
This preparation method makes formula (IV) compound and N, and N'-bis-replaces acetaldehyde in solvent, and under alkaline matter exists, at and temperature-30 ℃～-20 ℃, reaction generates described formula (I) compound, and reaction equation is as follows:
In above formula, R
4, R
5be hydrogen or alkyl independently.
Further, described solvent can and be selected from one or more the mixed solvent in tetrahydrofuran (THF), toluene, dioxane, dimethyl formamide, methylene dichloride, the wherein combination of preferably water and tetrahydrofuran (THF) for water.
Further, described alkaline matter can be one or more the combination in sodium alkoxide, potassium alcoholate.Concrete can be for example sodium tert-butoxide.
According to the present invention, N, N'-bis-replaces acetaldehyde and can be obtained by the hydrolysis of disubstituted amido acetaldehyde contracting glycol.The general structure of disubstituted amido acetaldehyde contracting glycol is as follows:
wherein, R
4, R
5definition the same, R
6, R
7can, for any alkyl, be preferably C
1～C
6alkyl, is specifically as follows methyl, ethyl etc.
Preferably, R
4, R
5be C independently
1～C
6alkyl, is specifically as follows hydrogen, methyl, ethyl, propyl group, the tertiary butyl or n-hexyl etc.
Further, the method is specifically implemented as follows: disubstituted amido acetal is dropped in hydrochloric acid, at 20～35 ℃, stirring reaction generates N, N'-bis-replaces acetaldehyde, after completion of the reaction, adds alkali to be neutralized to system and is neutral, remove by filter salt, obtain N, N'-bis-replaces the solution of acetaldehyde, standby; Formula (IV) compound is dissolved in solvent, be cooled to-30 ℃～-20 ℃, add described alkaline matter, maintain the temperature between-30 ℃～-20 ℃, under stirring, drip described N, N'-bis-replaces the solution of acetaldehyde, controls temperature in dropping process between-30 ℃～-20 ℃, dropwise, insulation reaction, TLC monitors to formula (IV) compound and reacts completely, and finishes reaction.Further, after reaction finishes, add water, fully stir, filter, filter cake is washed with water to neutrality, then washes and starches with heptane, and vacuum-drying obtains described formula (I) compound.Further, vacuum-drying can be carried out at 20～30 ℃.
Preferably, described method also comprises and takes the above-mentioned method of the present invention to carry out preparation formula (IV) compound.
Preferably, the molar ratio of formula (IV) compound, disubstituted amido acetal, alkaline matter is 1:3～5:8～12.
According to the present invention, in preferred general formula (I) compound, R
1for CH
2f, CHF
2, C
2～C
6fluoro alkyl, C
2～C
6chloro alkyl; R
2, R
3be C independently
1～C
6alkyl.
More preferably, in general formula (I) compound, R
1for CHF
2, R
2, R
3be methyl.
Preferably, in step (2), N, N'-bis-replaces acetaldehyde and is specially N, N'-dimethyl acetaldehyde.
Due to the employing of above technical scheme, the present invention compared with prior art tool has the following advantages:
Formula of the present invention (IV) compound is the desirable intermediate of preparing quinazoline crotonyl compounds.The variation route from formula (III) compound to target product that the present invention proposes, can obtain without column chromatography purification the target product that purity is greater than 98% by simple aftertreatment, and target product total recovery is up to more than 74%; In addition, the inventive method successfully realizes the preparation of feather weight target product, easily batch production.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further details.Should be understood that these embodiment are for ultimate principle of the present invention, principal character and advantage are described, and the present invention is not limited by the following examples.The implementation condition adopting in embodiment can be done further adjustment according to specific requirement, and not marked implementation condition is generally the condition in normal experiment.
Embodiment 1 shortening is prepared compound III a
1, reaction equation is as follows:
2, charge ratio is as following table:
| Name of material | Molecular weight | Actual charging capacity | Mol ratio | Weight ratio |
| Compound I Ia | 384.70 | 600.0g | 1 | 1 |
| THF(1) | 72.11 | 4.0kg | ? | 6.7 |
| Methyl alcohol | 32.04 | 0.7kg | ? | 1.2 |
| Raney's nickel | 85.67 | 120.0g | 0.9 | 0.2 |
| Ammonium chloride | 53.49 | 60.0g | 0.7 | 0.1 |
| Saturated aqueous common salt (1) | / | 4.2kg | ? | 7 |
| Saturated aqueous common salt (2) | / | 3.2kg | ? | 5.3 |
| THF(2) | 72.11 | 1000mL | ? | 0.75 |
3, technological operation step
Compound I Ia is joined in 10L double-jacket glass reaction still, then add THF (1) and methyl alcohol in reactor, stir Compound I I is dissolved.Add Raney's nickel and ammonium chloride again, be warming up to approximately 35 ℃, pass into hydrogen after nitrogen replacement, insulated and stirred reaction, monitors to reacting complete (24-48h), developping agent DCM:MeOH=8:1 with TLC.After reaction finishes, decompress filter, elimination Raney's nickel, Raney's nickel reclaims.Filtrate is washed once with saturated aqueous common salt (1), then uses saturated aqueous common salt (2) to wash once again, and water layer merges the back extraction with THF (2), organic layer merging is spin-dried for, then is less than 1% in approximately 35 ℃ of vacuum-drying to moisture, obtains 542g compound III a, purity 97%, molar yield 98%.
The preparation of embodiment 2 compound IV a
1, reaction equation is as follows:
2, charge ratio is as following table:
| Name of material | Molecular weight | Actual charging capacity | Mol ratio | Weight ratio |
| Compound III a | 354.71 | 516.5g | 1 | 1 |
| Diethyl phosphorus acetic acid | 196.14 | 599.9g | 2.1 | 1.2 |
| N, N'-carbonyl dimidazoles (CDI) | 162.15 | 495.9g | 2.1 | 1.0 |
| THF(1) | 72.11 | 1.81kg | ? | 3.5 |
| THF(2) | 72.11 | 729.3g | ? | 1.4 |
| THF(3) | 72.11 | 2.29kg | ? | 4.4 |
| Methyl tertiary butyl ether (MTBE) | 88.15 | 12.91kg | ? | 25 |
| MTBE:THF mixed solution (1) | / | 2804.8g | ? | 5.4 |
| Purified water | 18 | 1452.7g | ? | 2.8 |
| MTBE:THF mixed solution (2) | / | 1874.9g | ? | 3.6 |
3, technological operation step
CDI is joined in 10L reactor, then add THF (1), stir and be warming up to 30 ℃.
Diethyl phosphorus acetic acid is dissolved in THF (2), drops in reactor, mixture stirs 60min, is labeled as solution A, standby.
Compound III is dissolved in THF (3), is warming up to 30 ℃, drip solution A, 3.5h dropwises, and insulated and stirred reaction is spent the night, and TLC monitors to compound III completely dissolve.Methyl tertiary butyl ether (MTBE) is joined in reaction system to stirring reaction 1h.Filter, MTBE:THF mixed solution for filter cake (1) (MTBE:THF=1:1.2 (w/w)) is washed and starched, then with purifying washing, then uses MTBE:THF mixed solution (2) (MTBE:THF=1:1.2 (w/w)) to wash and starch.30-40 ℃ of vacuum-drying is spent the night, and obtains 620g solid, is compound IV a, purity 98.5%, molar yield 80%.
Compound IV a characterization data is as follows:
1absorption peak: δ 10.07 (H-9, s, 1H) in H-NMR (500MHz, DMSO) spectrogram, 9.86 (H-4, s, 1H), 8.92 (H-5, s, 1H), 8.58 (H-8, s, 1H), 8.10-8.08 (H-12, dd, 1H), 7.77-7.74, (H-10, m, 1H), 7.55 (H-7, s, 1H), 7.45-7.42 (H-11, t, 1H) (H-6, t, 1H), (4.12-4.07 H-2, q, 4H), (3.32 H-3, m, 2H), 1.27-1.14 (H-1, t, 6H).
13absorption peak: δ 164.1 (C-4) in C-NMR (500MHz, DMSO) spectrogram, 157.5 (C-10,1C), 155.0 (C-13,1C), 154.9-153.0 (C-17, d, 1C, J
f-C=972Hz), 148.4-147.6 (C-6,1C, J
f-C=429Hz), 136.8 (C-14,1C), 127.7 (C-5,1C), 124.6 (C-19,1C), 123.5 (C-15,1C), 119.3 (C-12,1C), 119.1 (C-18,1C), 118.1 (C-11,1C), (117.0-116.9 C-16,1C), 118.5-116.5-114.4 (C-7, t, 1C, J
f-C=198Hz), 113.7 (C-8,1C), 112.2 (C-9,1C), 62.3 (C-2,2C), 36.1-35.0 (C-3,1C, J
p-C=520Hz), 16.6 (C-1,2C).
Mass spectrum m/s:[MH]+: 533.2.
Embodiment 3-7
Embodiment 3～7 provides respectively the method for being prepared respective compound (IV) by different compounds (III), and step is substantially with embodiment 2, and condition is with reference to table 1 (preparation method of compound (III) is with reference to CN10283550A embodiment 1).
Table 1
The preparation of embodiment 8 Compound I a
1, reaction equation is as follows:
2, charge ratio is as following table:
| Name of material | Molecular weight | Actual charging capacity | Mol ratio | Weight ratio |
| Compound IV a | 532.85 | 576.7g | 1 | 1 |
| Dimethylamino acetal | 161.24 | 688.2g | 4 | 1.2 |
| Sodium tert-butoxide | 96.1 | 1039.8g | 10 | 1.8 |
| Concentrated hydrochloric acid | 36.46 | 840.9g | ? | 1.5 |
| Purified water (1) | 18 | 926.2g | ? | 1.6 |
| Tetrahydrofuran (THF) (THF) | 72.11 | 7.55kg | ? | 13 |
| Purified water (2) | 18 | 85.4kg | ? | 150 |
| Normal heptane | 100.2 | 8.89L | ? | 10 |
3, technological operation step
1. concentrated hydrochloric acid adds after purified water (1) dilution, is transferred in 10L reactor, is warming up to approximately 30 ℃.Under nitrogen protection, dimethylamino acetal is slowly dropped in the hydrochloric acid after dilution, about 2h dropwises, and 30 ℃ of left and right stirring reactions spend the night.Before using, with solid sodium carbonate, be neutralized to neutrality, elimination inorganic salt are standby.
2. compound IV is joined in 20L reactor, then THF is added, stir, be cooled to approximately-30 ℃.Sodium tert-butoxide is joined in reactor in batches, maintain the temperature at-30 ℃～-20 ℃, reinforced complete stirring 15min.Drip the 1. solution of preparation again, drip process need rapid stirring and control temperature at-30 ℃～-20 ℃, 2.5-3h dropwises.Sampling adds THF dilution, and TLC monitoring (EA:MeOH=15:1) is complete to compound IV reaction, is transferred in 100L aftertreatment still and (adds in advance purified water (2)), fully stirs, and filters, and filter cake is washed till neutrality by purified water.With normal heptane, wash and starch, vacuum-drying under approximately 25 ℃ of conditions, obtains 479g Compound I a, purity 98.5%, molar yield 95%, cryopreservation.
Hydrogen nuclear magnetic resonance 1H-NMR (400MHz, the CD3OD) result of Compound I a is as follows: δ 8.91 (s, 1H), 8.51 (s, 1H), 8.03-8.01 (dd, 1H), 7.68-7.61 (dd, 1H), 7.50 (s, 1H), 7.33-6.97 (t, j=72Hz, 1H), 7.26-7.22 (t, 1H), 7.06-6.99 (m, 1H), 6.52-6.49 (d, 1H), 3.30-3.21 (d, 2H), 3.32 (s, 6H).
Embodiment 9-13
Embodiment 9～13 provides respectively the method for being prepared respective compound (I) by different compounds (IV), and step is substantially with embodiment 8, and condition is referring to table 2.
Table 2
Embodiment 14 further amplifies preparation
According to the identical technological operation of embodiment 1,2,8, further amplify and prepared Compound I a, charge ratio is as following table:
Above the present invention is described in detail; the explanation of embodiment is just for helping to understand method of the present invention and core concept thereof; its object is to allow the personage who is familiar with this art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences that spirit is done according to the present invention change or modify, within all should being encompassed in protection scope of the present invention.
Claims (16)
1. the quinazoline compounds with structure shown in formula (IV),
Wherein, R
1for CH
2f, CHF
2, C
2～C
12fluoro alkyl or C
2～C
12chloro alkyl.
2. the preparation method of a quinazoline compounds as claimed in claim 1, it is characterized in that, make formula (III) compound, diethyl phosphorus acetic acid, N, N'-carbonyl dimidazoles is in solvent, at 25～50 ℃ of temperature, react production (IV) compound, reaction equation is as follows:
3. preparation method according to claim 2, is characterized in that: described solvent is one or more the mixed solvent being selected from tetrahydrofuran (THF), toluene, dioxane, dimethyl formamide, methylene dichloride.
4. preparation method according to claim 2, is characterized in that, formula (III) compound, diethyl phosphorus acetic acid, N, and N'-carbonyl dimidazoles three's molar ratio is 1:2.05～2.2:2.05～2.2.
5. according to the preparation method described in claim 2 or 3 or 4, it is characterized in that, the method is specifically implemented as follows: formula (III) compound and diethyl phosphorus acetic acid are dissolved in respectively in described solvent, be warming up to 25～50 ℃, the solution of diethyl phosphorus acetic acid is dropped in the solution of formula (III) compound, insulated and stirred reaction, TLC monitors to formula (III) compound and reacts completely, and finishes reaction.
6. preparation method according to claim 5, it is characterized in that, finish, after reaction, to add methyl tertiary butyl ether stirring reaction 1～2 hour, filter, the mixed solution washing of methyl tertiary butyl ether and described solvent for filter cake, wash again, then wash with the mixed solution of methyl tertiary butyl ether and described solvent, after washing, vacuum-drying, obtains described formula (IV) compound.
7. preparation method according to claim 2, it is characterized in that, described preparation method also comprises makes formula (II) compound and hydrogen under catalyzer exists, in mixed solvent, react and generate the step of described formula (III) compound, in this step, described mixed solvent is comprised of by weight 3～8:1 tetrahydrofuran (THF) and methyl alcohol, and reaction equation is as follows:
8. quinazoline compounds claimed in claim 1 is for the preparation of the purposes with the quinazoline crotonyl compounds of general formula (I),
Wherein: R
1for CH
2f, CHF
2, C
2～C
12fluoro alkyl, C
2～C
12chloro alkyl; R
2, R
3be hydrogen independently, C
1～C
12alkyl.
9. a preparation method with the quinazoline crotonyl compounds of general formula (I),
Wherein: R
1for CH
2f, CHF
2, C
2～C
12fluoro alkyl, C
2～C
12chloro alkyl; R
2, R
3be hydrogen independently, C
1～C
12alkyl,
It is characterized in that, make formula (IV) compound and N, N'-bis-replaces acetaldehyde in solvent, and under alkaline matter exists, at and temperature-30 ℃～-20 ℃, reaction generates described formula (I) compound, and reaction equation is as follows:
In above formula, R
4, R
5be hydrogen or alkyl independently.
10. preparation method according to claim 9, is characterized in that: described solvent is water and is selected from one or more the mixed solvent in tetrahydrofuran (THF), toluene, dioxane, dimethyl formamide, methylene dichloride.
11. preparation methods according to claim 9, is characterized in that, described alkaline matter is one or more the combination in sodium alkoxide, potassium alcoholate.
12. according to the preparation method described in claim 9 or 10 or 11, it is characterized in that, the method is specifically implemented as follows: disubstituted amido acetal is dropped in hydrochloric acid, and at 20～35 ℃, stirring reaction generates N, and N'-bis-replaces acetaldehyde, after completion of the reaction, add alkali to be neutralized to system and be neutral, remove by filter salt, obtain N, N'-bis-replaces the solution of acetaldehyde, standby; Formula (IV) compound is dissolved in solvent, be cooled to-30 ℃～-20 ℃, add described alkaline matter, maintain the temperature between-30 ℃～-20 ℃, under stirring, drip described N, N'-bis-replaces the solution of acetaldehyde, controls temperature in dropping process between-30 ℃～-20 ℃, dropwise, insulation reaction, TLC monitors to formula (IV) compound and reacts completely, and finishes reaction.
13. preparation methods according to claim 12, is characterized in that, after reaction finishes, add water, fully stir, and filter, and filter cake is washed with water to neutrality, then washes and starches with heptane, and vacuum-drying obtains described formula (I) compound.
14. preparation methods according to claim 9, is characterized in that, described method also comprises takes the method described in any one claim in claim 2 to 7 to carry out preparation formula (IV) compound.
15. preparation methods according to claim 9, is characterized in that, in described general formula (I) compound, and R
1for CH
2f, CHF
2, C
2～C
6fluoro alkyl, C
2～C
6chloro alkyl; R
2, R
3be C independently
1～C
6alkyl.
16. preparation methods according to claim 15, is characterized in that, in described general formula (I) compound, and R
1for CHF
2, R
2, R
3be methyl.
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| CN106908523A (en) * | 2015-12-22 | 2017-06-30 | 江苏万邦生化医药股份有限公司 | A kind of high efficient liquid phase analysis method of diethyl phosphorus acetic acid |
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| CN107488153A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of afatinib intermediate compound |
| CN108853109A (en) * | 2018-07-10 | 2018-11-23 | 杭州华东医药集团新药研究院有限公司 | It steps China and replaces nylon 6 combination, related compound and its preparation method and application |
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| US10065931B2 (en) * | 2015-05-05 | 2018-09-04 | Hangzhou Huadong Medicine Group Biopharmaceutical Co. Ltd. | Quinazolin crotyl compound dimaleate crystals and preparation methods and uses thereof |
| US10640470B2 (en) | 2015-05-05 | 2020-05-05 | Hangzhou Huadong Medicine Group Biopharmaceutical Co. Ltd. | Quinazolin crotyl compound dimaleate crystals and preparation methods and uses thereof |
| CN105859641A (en) * | 2015-05-05 | 2016-08-17 | 杭州华东医药集团新药研究院有限公司 | Bis-maleic acid salt crystals of quinazoline crotonic compound and preparation methods and functions of bis-maleic acid salt crystals |
| CN105859641B (en) * | 2015-05-05 | 2018-11-16 | 杭州华东医药集团新药研究院有限公司 | The crystal and its preparation method and application of quinazoline crotonyl compounds 2-maleate |
| JP2018515508A (en) * | 2015-05-05 | 2018-06-14 | 杭州華東医薬集団新薬研究院有限公司 | Quinazoline rotyl compound dimaleate crystals and methods for their preparation and use |
| CN106908523B (en) * | 2015-12-22 | 2019-11-22 | 江苏万邦生化医药股份有限公司 | A kind of high efficient liquid phase analysis method of diethyl phosphorus acetic acid |
| CN106908523A (en) * | 2015-12-22 | 2017-06-30 | 江苏万邦生化医药股份有限公司 | A kind of high efficient liquid phase analysis method of diethyl phosphorus acetic acid |
| CN107488153A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of afatinib intermediate compound |
| CN107488171A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of Afatinib preparation method |
| CN107488153B (en) * | 2016-06-10 | 2020-06-23 | 山东新时代药业有限公司 | Afatinib intermediate compound |
| CN107488171B (en) * | 2016-06-10 | 2020-08-28 | 山东新时代药业有限公司 | Preparation method of afatinib |
| CN108853109A (en) * | 2018-07-10 | 2018-11-23 | 杭州华东医药集团新药研究院有限公司 | It steps China and replaces nylon 6 combination, related compound and its preparation method and application |
| WO2020011020A1 (en) * | 2018-07-10 | 2020-01-16 | 杭州华东医药集团生物医药有限公司 | Mefatinib composition, related compound, preparation method therefor and use thereof |
| CN110693846A (en) * | 2018-07-10 | 2020-01-17 | 杭州华东医药集团新药研究院有限公司 | Mewatinib pharmaceutical composition and preparation method thereof |
| CN110693846B (en) * | 2018-07-10 | 2021-07-27 | 杭州华东医药集团新药研究院有限公司 | Mewatinib pharmaceutical composition and preparation method thereof |
| CN108853109B (en) * | 2018-07-10 | 2021-10-08 | 杭州华东医药集团新药研究院有限公司 | Mewatinib composition, related compound, preparation method and application thereof |
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| CN107141261B (en) | 2020-05-05 |
| CN107141261A (en) | 2017-09-08 |
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