CN110407840A - A kind of Ai Wei replaces the preparation method of Buddhist nun - Google Patents
A kind of Ai Wei replaces the preparation method of Buddhist nun Download PDFInfo
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- CN110407840A CN110407840A CN201910753602.7A CN201910753602A CN110407840A CN 110407840 A CN110407840 A CN 110407840A CN 201910753602 A CN201910753602 A CN 201910753602A CN 110407840 A CN110407840 A CN 110407840A
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- Prior art keywords
- preparation
- buddhist nun
- reaction
- dissolved
- tbu
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses the preparation methods that a kind of Ai Wei replaces Buddhist nun, comprising the following steps: A, by 2,4-, bis- chloropyrrolo [2,3-d and XPhos, Pd2(dba)3It is dissolved in propanol solvent with the fluoro- 4- of 3- (4- methylpiperazine-1-yl) aniline, reaction obtains intermediate compound I；B, the tBu 3- nitrophenol protected is dissolved in alcohol solvent, iron powder and ammonium chloride is added, obtain the 3- amino-phenol of tBu protection；C, the 3- amino-phenol of tBu protection and diisopropylethylamine are dissolved in methylene chloride, iso-amylene acyl chlorides is added dropwise, reaction obtains intermediate II；D, intermediate II flows back in trifluoroacetic acid solvent, takes off tBu protection, obtains intermediate III；E, by intermediate compound I, intermediate III and dimethylformamide hybrid reaction, final product is obtained.This method is easy to operate, and yield is high.
Description
Technical field
The invention belongs to technical field of medicine synthesis, it particularly relates to which a kind of Ai Wei replaces the preparation method of Buddhist nun.
Background technique
Lung cancer is divided into non-small cell lung cancer (NSCLC) and Small Cell Lung Cancer (SCLC), and wherein NSCLC accounts for lung cancer morbidity rate
85%, when most of NSCLC patient assessments, has been in unresectable Locally Advanced or far-end transfer.Epidermal growth factor receptor
Body (EGFR) is one of the target spot that current treatment non-small cell lung cancer drug field attracts most attention.The EGFR inhibitor listed is total
There is three generations.First generation EGFR inhibitor such as Gefitinib, Tarceva and EGFR Irreversible binding, specificity for EGFR19 and
The sensitive mutation of 21 exons, but also in conjunction with Wild type EGFR, cause the toxic side effects such as diarrhea fash.Use the first generation
The patient of EGFR usually generates drug resistance in 1~2 year, wherein 50% drug resistance is mutated derived from T790M.Second generation EGFR inhibits
Agent can be but bad to T790M mutation effect with EGFR Irreversible binding, and remains to generate toxicity in conjunction with wild type.Third
For EGFR inhibitor Austria it is uncommon for Buddhist nun in 2015 the U.S., 2017 in Discussion on Chinese Listed, can treat T790M mutation cause it is resistance to
Medicine.
It is a kind of third generation EGFR tyrosine kinase inhibitor of Chinese independent research that maleic acid Ai Wei, which replaces Buddhist nun, can be special
Property inhibit EGFR19 and 21 exons sensitizing mutation and first generation EGFR tyrosine kinase inhibitor generate T790M it is resistance to
Pharmacological property mutation, while it is also Bruton ' s tyrosine (BTK) kinase inhibitor.The examination of II phase clinic is completed for Buddhist nun in Ai Wei at present
It tests, listing is declared in preparation.But current only a small amount of document report Ai Wei replaces the preparation method of Buddhist nun.
Summary of the invention
The technical issues of preparing for Ai Wei for Buddhist nun, the present invention provides the preparation method that a kind of Ai Wei replaces Buddhist nun, method letters
Single, yield is high.
To achieve the above object, the technology originating party case that the present invention uses is:
A kind of Ai Wei replaces the preparation method of Buddhist nun, comprising the following steps:
A, by bis- chloropyrrolo [2,3-d of 2,4- and XPhos, Pd2(dba)3With the fluoro- 4- of 3- (4- methylpiperazine-1-yl) aniline
It is dissolved in propanol solvent, reaction obtains intermediate compound I；
B, the tBu 3- nitrophenol protected is dissolved in alcohol solvent, iron powder and ammonium chloride is added, obtain tBu protection
3- amino-phenol；
C, the 3- amino-phenol of tBu protection and diisopropylethylamine are dissolved in methylene chloride, iso-amylene acyl chlorides are added dropwise,
Reaction obtains intermediate II；
D, intermediate II flows back in trifluoroacetic acid solvent, takes off tBu protection, obtains intermediate III；
E, by intermediate compound I, intermediate III and dimethylformamide hybrid reaction, final product is obtained.
In step A of the present invention and E step, addition Na2CO3Participate in reaction.
Preferably, the Na2CO3Addition quality it is identical as intermediate compound I.
In step A of the present invention, reacted in 100 DEG C of stirred under nitrogen atmosphere.
It is aqueous in the alcohol solvent of step B of the present invention, and the volume ratio of ethyl alcohol and water is 1:1.
Contain 10% water in the trifluoroacetic acid solvent of D step of the present invention.
The beneficial effects of the present invention are: present invention optimizes reaction routes, simplify reaction step, and yield is higher, behaviour
Work is simpler, is suitable for industrialization large-scale production.
Specific embodiment
It embodiments of the present invention will be explained in detail below.
Embodiment 1
A kind of Ai Wei replaces the preparation method of Buddhist nun, and reaction route is as follows:
The following steps are included:
A, by bis- chloropyrrolo [2,3-d of 2,4- and XPhos, Pd2(dba)3With the fluoro- 4- of 3- (4- methylpiperazine-1-yl) aniline
It is dissolved in propanol solvent, reaction obtains intermediate compound I；
B, the tBu 3- nitrophenol protected is dissolved in alcohol solvent, iron powder and ammonium chloride is added, obtain tBu protection
3- amino-phenol；
C, the 3- amino-phenol of tBu protection and diisopropylethylamine are dissolved in methylene chloride, iso-amylene acyl chlorides are added dropwise,
Reaction obtains intermediate II；
D, intermediate II flows back in trifluoroacetic acid solvent, takes off tBu protection, obtains intermediate III；
E, by intermediate compound I, intermediate III and dimethylformamide hybrid reaction, final product is obtained.Pass through the HPLC of preparation
Or the LC/MS of preparation, or by the purification technique of other standards, separate and purify final product.(yield 70%.M+H+=
479.5.1H NMR(500MHz,MeOD) δ8.07 (s, 1H), 7.69 (t, J=2.0Hz, 1H), 7.57 (dd, J=8.2,
1.0Hz, 1H), 7.43 (t, J=8.2Hz, 1H), 7.30 (dd, J=15.2,2.5Hz, 1H), 7.03-6.88 (m, 2H),
6.78 (t, J=9.5Hz, 1H), 6.45 (dd, J=17.0,9.9Hz, 1H), 6.37 (dd, J=17.0,2.0Hz, 1H), 5.78
(dd, J=9.9,2.0Hz, 1H), 3.94 (s, 3H), 2.99 (br s, 4H), 2.62 (brs, 4H), 2.35 (s, J=6.2Hz,
3H)13C NMR(126MHz,MeOD) δ166.29(s),162.07(s),158.04(s),156.11(s),155.29(s),
154.60 (s), 144.75 (s), 141.44 (s), 138.09 (d, J=11.1Hz), 137.15 (s), 134.70 (d, J=
9.8Hz), 132.55 (s), 131.07 (s), 128.26 (s), 120.31 (d, J=4.1Hz), 118.88 (s), 118.28
(s), 115.45-115.14 (m), 107.96 (d, J=26.4Hz), 58.81 (s), 56.19 (s, 2C), 51.83 (d, J=
2.6Hz,2C),46.25(s).)
Embodiment 2
The present embodiment is on the basis of embodiment 1:
In the step A and E step, addition Na2CO3Participate in reaction, and Na2CO3Addition quality and intermediate compound I
It is identical.Yield is 72%.
Embodiment 3
The present embodiment is on the basis of embodiment 1:
In the step A and E step, addition Na2CO3Participate in reaction, and Na2CO3Addition quality and intermediate compound I
It is identical.
In the step A, reacted in 100 DEG C of stirred under nitrogen atmosphere.Yield is 71%.
Embodiment 4
The present embodiment is on the basis of embodiment 1:
In the step A and E step, addition Na2CO3Participate in reaction, and Na2CO3Addition quality and intermediate compound I
It is identical.
In the step A, reacted in 100 DEG C of stirred under nitrogen atmosphere.
It is aqueous in the alcohol solvent of the step B, and the volume ratio of ethyl alcohol and water is 1:1.Yield is 73%.
Embodiment 5
The present embodiment is on the basis of embodiment 1:
In the step A and E step, addition Na2CO3Participate in reaction, and Na2CO3Addition quality and intermediate compound I
It is identical.
In the step A, reacted in 100 DEG C of stirred under nitrogen atmosphere.
It is aqueous in the alcohol solvent of the step B, and the volume ratio of ethyl alcohol and water is 1:1.
Contain 10% water in the trifluoroacetic acid solvent of the D step.Yield is 72%.
Embodiment 6
The 3- nitrophenol raw material preparation of tBu protection: 3- nitrophenol is dissolved in alcohol solvent, DMAP and uncle is added
Butanol is added EDCI, is stirred to react 2 hours under an inert atmosphere, is concentrated in vacuo, is dissolved in ethyl acetate, with water extraction two
It is secondary, it is then extracted twice with saturated sodium bicarbonate aqueous solution, by organic solution drying and is concentrated in vacuo, obtains the 3- of tBu protection
Nitrophenol.
A specific embodiment of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously
Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention
Protect range.
Claims (6)
1. the preparation method that a kind of Ai Wei replaces Buddhist nun, which comprises the following steps:
A, by bis- chloropyrrolo [2,3-d of 2,4- and XPhos, Pd2(dba)3It is dissolved with the fluoro- 4- of 3- (4- methylpiperazine-1-yl) aniline
In propanol solvent, reaction obtains intermediate compound I；
B, the tBu 3- nitrophenol protected is dissolved in alcohol solvent, iron powder and ammonium chloride is added, obtain the 3- of tBu protection
Amino-phenol；
C, the 3- amino-phenol of tBu protection and diisopropylethylamine are dissolved in methylene chloride, iso-amylene acyl chlorides, reaction is added dropwise
Obtain intermediate II；
D, intermediate II flows back in trifluoroacetic acid solvent, takes off tBu protection, obtains intermediate III；
E, by intermediate compound I, intermediate III and dimethylformamide hybrid reaction, final product is obtained.
2. Ai Wei replaces the preparation method of Buddhist nun according to claim 1, which is characterized in that in the step A and E step,
Na is added2CO3Participate in reaction.
3. Ai Wei replaces the preparation method of Buddhist nun according to claim 2, which is characterized in that the Na2CO3Addition quality in
Mesosome I is identical.
4. Ai Wei replaces the preparation method of Buddhist nun according to claim 1, which is characterized in that in the step A, at 100 DEG C
Stirred under nitrogen atmosphere reaction.
5. Ai Wei replaces the preparation method of Buddhist nun according to claim 1, which is characterized in that in the alcohol solvent of the step B
It is aqueous, and the volume ratio of ethyl alcohol and water is 1:1.
6. Ai Wei replaces the preparation method of Buddhist nun according to claim 1, which is characterized in that the trifluoroacetic acid solvent of the D step
In contain 10% water.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910753602.7A CN110407840A (en) | 2019-08-15 | 2019-08-15 | A kind of Ai Wei replaces the preparation method of Buddhist nun |
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| CN201910753602.7A CN110407840A (en) | 2019-08-15 | 2019-08-15 | A kind of Ai Wei replaces the preparation method of Buddhist nun |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103748096A (en) * | 2012-08-06 | 2014-04-23 | 美国艾森生物科学公司 | Novel pyrrolopyrimidine compounds as inhibitors of protein kinases |
| CN107949388A (en) * | 2015-10-09 | 2018-04-20 | 艾森生物科学公司 | Pharmaceutical salts, physical aspect and composition of pyrrolopyrimidine kinase inhibitor and preparation method thereof |
| WO2018184206A1 (en) * | 2017-04-07 | 2018-10-11 | ACEA Therapeutics, Inc. | Pharmaceutical salts, physical forms, and compositions of pyrrolopyrimidine kinase inhibitors, and methods of making same |
-
2019
- 2019-08-15 CN CN201910753602.7A patent/CN110407840A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103748096A (en) * | 2012-08-06 | 2014-04-23 | 美国艾森生物科学公司 | Novel pyrrolopyrimidine compounds as inhibitors of protein kinases |
| CN107949388A (en) * | 2015-10-09 | 2018-04-20 | 艾森生物科学公司 | Pharmaceutical salts, physical aspect and composition of pyrrolopyrimidine kinase inhibitor and preparation method thereof |
| WO2018184206A1 (en) * | 2017-04-07 | 2018-10-11 | ACEA Therapeutics, Inc. | Pharmaceutical salts, physical forms, and compositions of pyrrolopyrimidine kinase inhibitors, and methods of making same |
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Application publication date: 20191105 |