CN105884750A - Preparation method of Afatinib - Google Patents
Preparation method of Afatinib Download PDFInfo
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- CN105884750A CN105884750A CN201410557479.9A CN201410557479A CN105884750A CN 105884750 A CN105884750 A CN 105884750A CN 201410557479 A CN201410557479 A CN 201410557479A CN 105884750 A CN105884750 A CN 105884750A
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- compound
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- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 title claims abstract description 15
- 229960001686 afatinib Drugs 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- -1 3-chloro-4-fluorophenyl Chemical group 0.000 claims description 5
- 150000002118 epoxides Chemical class 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 2
- 229910052794 bromium Chemical group 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 239000000460 chlorine Substances 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 abstract description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 2
- GRWPTSXPZYCYOM-UHFFFAOYSA-N 2-(dimethylamino)acetaldehyde Chemical compound CN(C)CC=O GRWPTSXPZYCYOM-UHFFFAOYSA-N 0.000 abstract 1
- BIQABKFYKJRXII-NSHDSACASA-N 4-n-(3-chloro-4-fluorophenyl)-7-[(3s)-oxolan-3-yl]oxyquinazoline-4,6-diamine Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(N)=CC2=C1NC1=CC=C(F)C(Cl)=C1 BIQABKFYKJRXII-NSHDSACASA-N 0.000 abstract 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 208000035126 Facies Diseases 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000013461 design Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000005785 Fluquinconazole Substances 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- DGBBAVQSFAKOIB-LBPRGKRZSA-N O=C(C=P)Nc(c(O[C@@H]1COCC1)c1)cc2c1ncnc2Nc(cc1)cc(Cl)c1F Chemical compound O=C(C=P)Nc(c(O[C@@H]1COCC1)c1)cc2c1ncnc2Nc(cc1)cc(Cl)c1F DGBBAVQSFAKOIB-LBPRGKRZSA-N 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 238000011938 amidation process Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of Afatinib (I) (a structural formula is as follows). The preparation method comprises the following steps: N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furanyl]oxy]-4,6-quinazolinediamine is used as an initial raw material, a reaction is carried out between the initial raw material and chloroacetyl chloride, trialkylphosphine or triphenyl phosphine is added for reaction in order to generate an intermediate, dimethylamino acetaldehyde is added for reaction, and Afatinib is obtained. The preparation method has the advantages of few steps, low cost, and less environmental pollution, and the method is suitable for industrial production.
Description
Technical field:
The invention belongs to organic synthetic route design and crude drug thereof and intermediate preparing technical field, particularly to the preparation method of a kind of Afatinib.
Background technology:
Afatinib is by a kind of Mutiple Targets small-molecule drug of the Boehringer Ingelheim company research and development of Germany, it belongs to EGF-R ELISA (EGFR) and the irreversible inhibitor of people's epidermal receptor (HER2) tyrosine kinase, is also first lung cancer therapy medicine after epidermal growth factor receptor inhibitor Endodontic failure.Can be clinically used for advanced Non-small cell lung and advanced breast cancer, the treatment of intestinal cancer.This medicine on February 15th, 2008 by FDA (Food and Drug Adminstration) (FDA) quickly examine passage, trade name Tovok.Afatinib (Afatinib, I), chemistry entitled 4-[(3-chloro-4-fluorophenyl) amino]-6-{ [4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino }-7-[(S)-(oxolane-3-base) epoxide] quinazoline.No. WO0250043A1 and No. WO03094921A2 preparation method reporting Afatinib of the former world patent ground of Boehringer Ingelheim company: with parent nucleus 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-Fluquinconazole quinoline (IV) as initiation material, with the substitution reaction of S-3-dihydroxy-tetrahydro furan generation halogens fluorine under base catalyst potassium tert-butoxide is catalyzed, generate 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-[(S)-(oxolane-3-base) epoxide] quinazoline (V)；The intermediate (V) the nitro reduction through 6-position, obtains corresponding amino-compound VI；This compound VI and bromo .beta.-methylacrylic acid acyl chlorides generation amidation process obtain intermediate VII, and this intermediate VII, through the aminating reaction with dimethylamine, obtains Afatinib (I).
It is therefore seen that, Afatinib technology of preparing it is crucial that the structure design of quinazoline parent nucleus and the selection on cyclization opportunity.The preparation method of Afatinib at present, is the modified with functional group being carried out 7-and 6-position by the quinazoline parent nucleus IV of 4-position official energy dough successively.The method is first to prepare quinazoline parent nucleus, then carries out side chain functionalities conversion.The method is more due to step, and total recovery is relatively low, and most step needs to be separated by column chromatography and purification, thus is not suitable for the requirement of industrialization.
Summary of the invention
It is an object of the invention to seek new prepare approach, synthesize theory according to the Atom economy of Green Chemistry, it is provided that the preparation method of the Afatinib of a kind of improvement, this preparation method is simple, economic and environmental protection, is suitable for the requirement that industrialization is amplified.
Detailed description of the invention
The present invention is expanded on further below in conjunction with specific embodiment.Following embodiment is interpreted as being merely to illustrate the present invention rather than for limiting the scope of the invention.
Embodiment one:
The first step: add compound (II) (37.5g in 500mL there-necked flask, 0.10mol), triethylamine (15.2g, 0.15mol) with dichloromethane 300mL, stirring is lower adds dropping chloracetyl chloride (13.5g, 0.12mol), temperature control stirs 2 hours at 5～10 DEG C.Pouring 200ml water into, separate organic facies, organic facies is dried, and decompression evaporates solvent, obtains 42.8g (IX), light tan solid, and yield is 95%.
Second step: adding compound (IX) (45.1g, 0.10mol) and toluene 300mL in 500mL there-necked flask, add triphenylphosphine (28.8g, 0.11mol) under stirring in batches, temperature control is stirred at room temperature overnight.Being subsequently adding 120ml sodium hydrate aqueous solution (1mol/L), be stirred at room temperature 4 hours, solid is completely dissolved, and separates organic facies, is dried, and decompression evaporates toluene.Obtaining 61g (X), white solid, yield is 90%.
3rd step: adding compound (X) (67.7g, 0.10mol), compound (VIII) (9.6g, 0.11mol) and toluene 300mL in 500mL there-necked flask, temperature control is stirred at room temperature overnight.Then decompression evaporates toluene, gained solid ethyl alcohol recrystallization.Obtaining 43.7g (l), white solid, yield is 90%.
Embodiment two:
The first step: add compound (II) (37.5g in 500mL there-necked flask, 0.10mol), triethylamine (15.2g, 0.15mol) with dichloromethane 300mL, stirring is lower adds dropping bromoacetyl chloride (18.9g, 0.12mol), temperature control stirs 2 hours at 5-10 DEG C.Pouring 200ml water into, separate organic facies, organic facies is dried, and decompression evaporates solvent, obtains 46.1g (XII), light tan solid, and yield is 93%.
Second step: adding compound (XII) (49.6g, 0.10mol) and toluene 300mL in 500mL there-necked flask, add tri-n-butyl phosphine (22.3g, 0.11mol) under stirring in batches, temperature control is stirred at room temperature overnight.Being subsequently adding 120ml sodium hydrate aqueous solution (1mol/L), be stirred at room temperature 4 hours, solid is completely dissolved, and separates organic facies, is dried, and decompression evaporates toluene.Obtaining 56.1g (XI), white solid, yield is 91%.
3rd step: adding compound (XI) (61.7g, 0.10mol), compound (VIII) (9.6g, 0.11mol) and toluene 300mL in 500mL there-necked flask, temperature control is stirred at room temperature overnight.Then decompression evaporates toluene, gained solid ethyl alcohol recrystallization.Obtaining 43.7g (l), white solid, yield is 90%.Fusing point: 178 DEG C.1H-NMR(CD3OD): δ=2.47-2.27 (m, 2H), 2.96 (s, 6H), 4.03 (m, 2H), 3.92-4.07 (m, 2H), 4.03-4.18 (m, 2H), 5.32 (m, 1H), 6.26 (s, 4H), 6.80 (m, 1H), 6.99 (m, 1H), 7.27 (s, 1H), 7.30 (t, 1H), 7.66 (m, 1H), 7.96 (dd, 1H), 8.62 (s, 1H), 9.07 (s, 1H) ppm
It is pointed out that above-described embodiment is only technology design and the feature of the explanation present invention, its object is to allow ripe
The personage knowing technique will appreciate that present disclosure and implements according to this, can not limit the scope of the invention with this.All equivalence changes made according to spirit of the invention or modification, all should contain within protection scope of the present invention.
Claims (5)
1. Afatinib (4-[(3-chloro-4-fluorophenyl) amino]-6-{ [4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino }-7-[(S)-(oxolane-3-base) epoxide] quinazoline, the preparation method of (I)；
。
2. the preparation method of claim 1 compound comprises the following steps:
The first step: make the compound of logical formula (II) react in suitable solvent with the compound of logical formula (III), the compound of logical formula (IV) can be prepared；
Wherein R1 is chlorine or bromine；R2 is chlorine, bromine or hydroxyl.
Second step: make the compound of logical formula (IV) react in suitable solvent with the compound of logical formula (VI), the compound of logical formula V can be prepared；
Wherein R is the direct-connected alkyl of phenyl or C1-C5；
3rd step: use the compound of logical formula V to react in suitable solvent with the equivalent of the compound of logical formula (VIII) or corresponding aldehyde, the compound of logical formula (I) can be prepared.
The most according to claim 2, method, the solvent of the first step needs Non-aqueous processing.
The most according to claim 2, method, the first step needs to complete under nitrogen protection.
The most according to claim 2, method, the 3rd step needs to carry out in anhydrous conditions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410557479.9A CN105884750A (en) | 2014-10-21 | 2014-10-21 | Preparation method of Afatinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410557479.9A CN105884750A (en) | 2014-10-21 | 2014-10-21 | Preparation method of Afatinib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105884750A true CN105884750A (en) | 2016-08-24 |
Family
ID=57000526
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410557479.9A Pending CN105884750A (en) | 2014-10-21 | 2014-10-21 | Preparation method of Afatinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105884750A (en) |
-
2014
- 2014-10-21 CN CN201410557479.9A patent/CN105884750A/en active Pending
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Legal Events
| Date | Code | Title | Description |
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| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160824 |
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| WD01 | Invention patent application deemed withdrawn after publication |