CN107488172A - A kind of preparation method of Afatinib - Google Patents
A kind of preparation method of Afatinib Download PDFInfo
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- CN107488172A CN107488172A CN201610406782.8A CN201610406782A CN107488172A CN 107488172 A CN107488172 A CN 107488172A CN 201610406782 A CN201610406782 A CN 201610406782A CN 107488172 A CN107488172 A CN 107488172A
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- afatinib
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- tert
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Abstract
The invention belongs to pharmaceutical technology field, specifically discloses a kind of preparation method of Afatinib, including substitution reaction occurs with intermediate II and (S) 3 hydroxyl tetrahydrofuran and obtains Afatinib I.This method technique is simple, economic and environment-friendly, finished product purity is high, is adapted to the requirement of technology amplification.
Description
Technical field
The present invention is medicinal chemistry art, more particularly to a kind of new preparation process of afatinib compound.
Background technology
Maleic acid Afatinib is a kind of oral small molecule for the Mutiple Targets researched and developed by the Bo Linge Yin Han nurses company of Germany
Medicine, it is the irreversible inhibitor of EGF-R ELISA (EGFR) and people's epidermal receptor 2 (HER2) EGFR-TK.It is
The tyrosine kinase inhibitor of second generation efficient double non reversibility.The medicine examining by U.S. FDA on July 12nd, 2013
Batch.Trade name Gilotrif.Afatinib, entitled 4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- { [4- (N, the N- diformazans of chemistry
Base amino) -1- oxos -2- butene-1s-yl] amino } -7- ((S)-tetrahydrofuran -3- bases epoxide)-quinazoline.
The original of Boehringer Ingelheim company grinds No. CN1867564B preparation method for reporting Afatinib of Chinese patent：With
Parent nucleus 4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- nitro -7- Fluquinconazoles quinolines are initiation material, in base catalyst potassium tert-butoxide
The lower substitution reaction that halogens fluorine occurs with S-3- dihydroxy-tetrahydros furans of catalysis, generates 4- [(the chloro- 4- fluorophenyls of 3-) amino] -6-
Nitro -7- [(S)-(tetrahydrofuran -3- bases) epoxide] quinazoline；Intermediate reduces by the nitro of 6- positions, obtains corresponding ammonia
Based compound；The compound occurs amidation process with diethyl phosphorus acetic acid and obtains intermediate, and the intermediate passes through and dimethylamine
Wittig-Horner-Emmons reactions occur for ethylhexanal diethyl acetal, obtain Afatinib.
All it is with starting material 4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- nitro -7- fluorine quinolines with reference to other document analysises
Oxazoline is docked with chiral intermediate S-3- dihydroxy-tetrahydro furans, is then carried out subsequent reactions, is obtained Afatinib.Experiment discovery,
Following defect be present in existing literature：
1) chiral intermediate S-3- dihydroxy-tetrahydros furans is expensive, and loses in follow-up multistep reaction larger；
2) with intermediate 3 carry out Wittig-Horner-Emmons reaction caused by finished product Afatinib, impurity compared with
It is more, it is not easy to remove.
For problem above, more economical, practical route synthesis Afatinib is found, is highly desirable.
The content of the invention
It is an object of the invention to seek new preparation approach, theory is synthesized according to the Atom economy of Green Chemistry, is carried
For a kind of preparation method of Afatinib, the raw material of the preparation method is easy to get, and concise in technology is economic and environment-friendly, is advantageous to the medicine
Industrialized production, promote the development of the economic technology of the bulk drug.
To achieve these goals, main technical schemes provided by the present invention are as follows：A kind of preparation of Afatinib (I)
Method, substitution reaction is occurred with intermediate (II) and (S) -3- hydroxyl tetrahydrofurans and obtains Afatinib (I)；
The preparation method of the Afatinib, by compound (II), (S) -3- hydroxyl tetrahydrofurans, alkali A, organic solvent B
Add progress substitution reaction in reaction vessel and obtain compound (I).
The preparation method of described Afatinib, alkali A in sodium hydride, hydrofining, calcium hydride, potassium tert-butoxide one
Kind, preferably potassium tert-butoxide.
The preparation method of described Afatinib, organic solvent B are selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenation
Hydro carbons, alcohols, ethers, amide-type, diol, derivatives class, esters solvent or phenol；It is preferred that benzene, toluene, hexamethylene, methanol, second
One or more in alcohol, the tert-butyl alcohol, ether, acetone, trichloro ethylene, ethyl acetate；More have and elect the mixed of the tert-butyl alcohol and methanol as
Bonding solvent.
The preparation method of described Afatinib, (S) -3- hydroxyl tetrahydrofurans (88.11) rub with intermediate II (417)
Your ratio is 1-3:1, preferably 1.2-1.5:1.
The volume mass ratio of the preparation method of described Afatinib, organic solvent B and intermediate II is 10-20ml/g,
It is preferred that 12-15ml/g.
Route of the present invention is novel, and finished product impurity is few, and cost is low, is adapted to industrial requirement.
Intermediate II is prepared by following route：
Embodiment
In order that those skilled in the art more fully understands technical scheme, it is non-that some are disclosed further below
Limiting embodiment, the present invention is described in further detail.
Embodiment 1
The first step：
Take 3.4g compounds V, 153mgFeCl3, the mixed solution (ethanol of 50mL ethanol and acetone：Acetone volume ratio is
3:4) single port bottle is put into, starts electromagnetic agitation, nitrogen displacement air 3 times, hydrogen displacement nitrogen 3 times, heat-insulation pressure keeping reacts 4h, instead
It should finish, decompression, which filters, removes catalyst, and filtrate is rotated to dry, dry intermediate IV, yield 99.6%.
Second step：
2.0g diethyl phosphorus acetic acid is taken, 50ml tetrahydrofurans are put into 250ml there-necked flasks, start stirring, be slowly added to
2.0gCDI, 40 DEG C of insulation reaction 1h, 3.0g intermediates IV are then added, continue insulation reaction 1h, reaction finishes, and separates out a large amount of
Solid, adds 50ml methyl tertiary butyl ether(MTBE)s, after stirring 1h, filters, dry intermediate III, yield 98.1%.
3rd step：
Dimethylamino acetal deprotection generation dimethylamino acetaldehyde first.
Weigh 4.5g intermediates III to be placed in 250ml there-necked flasks, add 50ml tetrahydrofurans, 40ml dimethylamino acetaldehyde
Tetrahydrofuran solution, stirring and dissolving, ice bath are cooled to 0 DEG C, start that the 30g25% KOH aqueous solution, 0-5 DEG C of temperature control, drop is added dropwise
Finish, warm naturally to room temperature, reaction is finished, and reaction solution is poured into 300ml water, stirring and crystallizing 2h, is filtered, dry intermediate
II, yield 97.4%, purity 99.8%.
Embodiment 2
40.0g intermediate IIs are weighed, are placed in 5000ml there-necked flasks, the 400ml tert-butyl alcohols is added, adds 8.5g (S) -3-
Hydroxyl tetrahydrofuran, potassium tert-butoxide is slowly added to, temperature control is no more than 50 DEG C, finished, stirring reaction 1h, and reaction is finished, by reaction solution
Pour into 2000ml drinking water, adjust PH to 6 with 10% aqueous acetic acid, filter, dry the yield 90.1% of Afatinib I,
Purity 99.6%, list is miscellaneous to be less than 0.1%.
Embodiment 3
40.0g intermediate IIs are weighed, are placed in 5000ml there-necked flasks, add the 600ml tert-butyl alcohols and 200ml methanol, then add
Enter 25.5g (S) -3- hydroxyl tetrahydrofurans, be slowly added to potassium tert-butoxide, temperature control is no more than 50 DEG C, finished, stirring reaction 1h, instead
It should finish, reaction solution is poured into 4000ml drinking water, adjust PH to 7 with 10% aqueous acetic acid, filter, dry Afatinib
I, yield 90.3.1%, purity 99.6%, list is miscellaneous to be less than 0.1%.
Embodiment 4
40.0g intermediate IIs are weighed, are placed in 5000ml there-necked flasks, the 400ml tert-butyl alcohols and 80ml methanol is added, adds
10.2g (S) -3- hydroxyl tetrahydrofurans, potassium tert-butoxide is slowly added to, temperature control is no more than 50 DEG C, finished, stirring reaction 1h, reacts
Finish, reaction solution is poured into 3000ml drinking water, adjust PH to 6.5 with 10% aqueous acetic acid, filter, dry Afatinib
I, yield 91.9%, purity 99.7%, list is miscellaneous to be less than 0.1%.
Embodiment 5
40.0g intermediate IIs are weighed, are placed in 5000ml there-necked flasks, add the 450ml tert-butyl alcohols and 150ml methanol, then add
Enter 12.75g (S) -3- hydroxyl tetrahydrofurans, be slowly added to potassium tert-butoxide, temperature control is no more than 50 DEG C, finished, stirring reaction 1h, instead
It should finish, reaction solution is poured into 3000ml drinking water, adjust PH to 6 with 10% aqueous acetic acid, filter, dry Afatinib
I, yield 92.5%, purity 99.8%, list is miscellaneous to be less than 0.1%.
Comparative example 1
40.0g intermediate IIs are weighed, are placed in 5000ml there-necked flasks, the 150ml tert-butyl alcohols and 50ml methanol is added, adds
4.23g (S) -3- hydroxyl tetrahydrofurans, potassium tert-butoxide is slowly added to, temperature control is no more than 50 DEG C, finished, stirring reaction 1h, reacts
Finish, reaction solution is poured into 1000ml drinking water, adjust PH to 6 with 10% aqueous acetic acid, filter, dry Afatinib I,
Yield 75.5%, purity 95.8%.
Comparative example 2
40.0g intermediate IIs are weighed, are placed in 5000ml there-necked flasks, add the 700ml tert-butyl alcohols and 300ml methanol, then add
Enter 33.8g (S) -3- hydroxyl tetrahydrofurans, be slowly added to potassium tert-butoxide, temperature control is no more than 50 DEG C, finished, stirring reaction 1h, instead
It should finish, reaction solution is poured into 5000ml drinking water, adjust PH to 6 with 10% aqueous acetic acid, filter, dry Afatinib
I, yield 78.5%, purity 96.1%.
Comparative example 3
Weigh 40.0g intermediate IIs, be placed in 5000ml there-necked flasks, add 600ml n-hexanes, add 12.75g (S)-
3- hydroxyl tetrahydrofurans, sodium hydroxide is slowly added to, temperature control is no more than 50 DEG C, finished, stirring reaction 1h, and reaction is finished, and will be reacted
Liquid is poured into 3000ml drinking water, is adjusted PH to 6.5 with 10% aqueous acetic acid, is filtered, dry Afatinib I, yield
74.3%, purity 94.8%.
Claims (10)
1. a kind of preparation method of Afatinib I, it is characterised in that taken with intermediate II and (S) -3- hydroxyl tetrahydrofurans
In generation, reacts to obtain Afatinib I；
2. the preparation method of Afatinib according to claim 1, it is characterised in that by intermediate II, (S) -3- hydroxyls four
Hydrogen furans, alkali A, organic solvent B add progress substitution reaction in reaction vessel and obtain chemical compounds I.
3. the preparation method of Afatinib according to claim 2, it is characterised in that alkali A be selected from sodium hydride, hydrofining,
One kind in calcium hydride, potassium tert-butoxide, preferably potassium tert-butoxide.
4. the preparation method of Afatinib according to claim 2, it is characterised in that organic solvent B be selected from arene,
Fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohols, ethers, amide-type, diol, derivatives class, esters solvent or phenol.
5. the preparation method of Afatinib according to claim 2, it is characterised in that organic solvent B be selected from benzene, toluene,
One or more in hexamethylene, methanol, ethanol, the tert-butyl alcohol, ether, acetone, trichloro ethylene, ethyl acetate.
6. the preparation method of Afatinib according to claim 2, it is characterised in that organic solvent B is the tert-butyl alcohol and first
The mixed solvent of alcohol.
7. the preparation method of Afatinib according to claim 2, it is characterised in that (S) -3- hydroxyl tetrahydrofurans are with
The mol ratio of mesosome II is 1-3:1.
8. the preparation method of Afatinib according to claim 2, it is characterised in that (S) -3- hydroxyl tetrahydrofurans are with
The mol ratio of mesosome II is 1.2-1.5:1.
9. the preparation method of Afatinib according to claim 2, it is characterised in that organic solvent B and intermediate II
Volume mass ratio is 10-20ml/g.
10. the preparation method of Afatinib according to claim 2, it is characterised in that organic solvent B and intermediate II
Volume mass ratio is 12-15ml/g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610406782.8A CN107488172B (en) | 2016-06-10 | 2016-06-10 | Preparation method of afatinib |
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| CN201610406782.8A CN107488172B (en) | 2016-06-10 | 2016-06-10 | Preparation method of afatinib |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003094921A2 (en) * | 2002-05-11 | 2003-11-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Utilization of inhibitors of egfr-mediated signal transduction for the treatment of benign prostatic hyperplasia (bph)/prostatic hypertrophy |
| CN1867564A (en) * | 2003-10-17 | 2006-11-22 | 贝林格尔·英格海姆国际有限公司 | Process for preparing amino crotonyl compounds |
| CN104710413A (en) * | 2013-12-16 | 2015-06-17 | 江苏豪森药业股份有限公司 | Preparation method of afatinib dimaleate |
-
2016
- 2016-06-10 CN CN201610406782.8A patent/CN107488172B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003094921A2 (en) * | 2002-05-11 | 2003-11-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Utilization of inhibitors of egfr-mediated signal transduction for the treatment of benign prostatic hyperplasia (bph)/prostatic hypertrophy |
| CN1867564A (en) * | 2003-10-17 | 2006-11-22 | 贝林格尔·英格海姆国际有限公司 | Process for preparing amino crotonyl compounds |
| CN104710413A (en) * | 2013-12-16 | 2015-06-17 | 江苏豪森药业股份有限公司 | Preparation method of afatinib dimaleate |
Non-Patent Citations (1)
| Title |
|---|
| DISCLOSED ANONYMOUSLY: ""PROCESS FOR THE PREPARATION OF AFATINIB"", 《IP.COM JOURNAL》 * |
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Denomination of invention: A preparation method of afatinib Effective date of registration: 20211224 Granted publication date: 20200612 Pledgee: Industrial and Commercial Bank of China Limited Feixian sub branch Pledgor: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980016193 |
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Date of cancellation: 20221028 Granted publication date: 20200612 Pledgee: Industrial and Commercial Bank of China Limited Feixian sub branch Pledgor: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980016193 |
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Denomination of invention: A preparation method of alfatinib Effective date of registration: 20221103 Granted publication date: 20200612 Pledgee: Industrial and Commercial Bank of China Limited Feixian sub branch Pledgor: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Registration number: Y2022980020531 |
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