Boehringer Ingelheim’s
First generation reversible EGFR (epidermal growth factor receptor)tyrosine kinase inhibitors (TKIs) such as
Second generation EGFR tyrosine kinase inhibitors (TKIs) are basedon anilinoquinazoline template of gefitinib and contain anacrylamide functionality that covalently binds to cysteine 797 ofthe epidermal growth factor receptor (EGFR) via a Michael addition.Afatinib inhibits both epidermal growth factor receptor 1 (EGFR,ErB1) and human epidermal growth factor receptor-2 (HER2, ErB2)tyrosine kinases while Pfizer’s
7-Chloroquinazolin-4(1H)-one
2-Amino-4-chlorobenzoic acid
7-chloro-6-nitro-3H-quinazolin-4-one
A solution of
4-(3-Chloro-4-fluoro-phenylamino)-7-chloro-6-nitro-quinazoline
20g 7-chloro-6-nitro-3H-quinazolin-4-one are suspended in 80 mlacetonitrile and combined with 16.5 g phosphorus oxychloride. Then10.8 g triethylamine are slowly added dropwise and the mixture isheated to about 80° C. After 5 hours a solution of 15.5 g3-chloro-4-fluoroaniline in 100 ml dioxane is added dropwise andthe mixture is stirred for another hour. Then 80 ml of water isadded, the mixture is cooled to 20° C. and made slightly alkalinewith KOH solution. The suspension is suction filtered, washed withwater and ethanol and dried at 50° C. in vacuo. Yield: 29.07 g(89.5% of theoretical/dioxane solvate)
4-(3-Chloro-4-fluoro-phenylamino)-7-(phenylsulphonyl)-6-nitro-quinazoline
500 g4-(3-chloro-4-fluoro-phenylamino)-7-chloro-6-nitro-quinazoline and302 g (1.3 eq) benzenesulphonic acid sodium salt are suspended at20° C. in 1500 ml DMF, heated to 90° C. and kept for 6 h at thistemperature. After cooling the reaction mixture the suspension issuction filtered and the residue is rinsed with 1.5 l methanol, 10l water and 0.5 l methanol. The residue is dried at 50° C. forabout 12 h under reduced pressure. Yield: 631.2 g (86.2% oftheoretical/DMF solvate). m.p.: 284-286° C.
4-[(3-Chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline
810 g of4-(3-chloro-4-fluoro-phenylamino)-7-(phenylsulphonyl)-6-nitro-quinazolineand 175.5 g (S)-3-hydroxytetrahydrofuran (1.3 eq) are placed at 20°C. in 1.04 l tert-butanol and 198 ml DMF, 2556 g K-tert.-butoxidein THF (24%) (3.6 eq) are added dropwise at 20° C. and then stirredfor 4 h at 25° C. After a further 2 h at 40° C. the mixture isheated to 45° C. for about 2 h. 2.8 l of water are added and thenabout 3 l solvent are distilled off under reduced pressure. 2.8 lwater are added again and about 900 ml solvent are distilled offunder reduced pressure. After the addition of 1.6 l methanol themixture is cooled to 20° C. The suspension is suction filtered andrinsed with a mixture of 3.2 l water and 1.6 l methanol. Theresidue is dried overnight at 50° C. under reduced pressure.Yield:598.6 g (89.6% of theoretical). m.p.: 238-240° C.
4-[(3-Chloro-4-fluorophenyl)amino]-6-amino-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline
100 g of4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineare hydrogenated in 400 ml DMF in the presence of 33.1 g Raneynickel and 18.7 g ammonium chloride at 40° C., until the calculatedamount of hydrogen has been taken up. The catalyst is filtered offand the filtrate is added dropwise to 1.2 l water. The suspensionis stirred for 2.5 h at 0° C., suction filtered and washed with 500ml of water. The residue is dried overnight at 55° C. under reducedpressure. Yield: 84.36 g (97.1% of theoretical). m.p.: 120-130°C.
Diethyl{[4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]-methyl}-phosphonate
3.58 kg 1,1-carbonyldiimidazole (22.16 mol) are placed in 12.8 l oftetrahydrofuran and combined at 40° C. with 4.52 kg (22.16 mol)diethylphosphonoacetic acid, dissolved in 6.5 l tetrahydrofuran.The mixture is stirred for 30 minutes at 40° C. The solution thusobtained is designated solution A.
6.39 kg (17.05 mol) of N4-(3-chloro-4-fluoro-phenyl)-7-(tetrahydrofuran-3-yloxy)quinazoline-4,6-diamineare placed in 26.5 l tetrahydrofuran and combined at 40° C. withsolution A and stirred for 2 hours at 30° C. 64 l oftert.-butylmethylether are added to the suspension and aftercooling to 20° C. the precipitate is removed by centrifuging. It iswashed with a mixture of 16 l tetrahydrofuran and 16 ltert.-butylmethylether and then with 32 l water and dried at 50° C.Yield: 6.58 kg (69.8%) white crystals. Content: HPLC 99.1 Fl %
Dimethylaminoacetaldehyd
40 g of dimethylaminoacetaldehyd
(E)-4-Dimethylamino-but-2-enoicacid-[4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-yl]-amide
10 g of diethyl{[4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]-methyl}-phosphonateand 0.8 g lithium chloride are suspended in 60 ml of ethanol andcooled to ?5° C. 11 g of 45% potassium hydroxide solution is addeddropwise first of all and then 4.8 gdimethylaminoacetaldehyd
(E)-4-dimethylamino-but-2-enoicacid-(4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetra-hydrofuran-3-yloxy)-quinazolin-6yl)-amidedimaleate (Afatinib Dimaleate, Gilotrif)
6.0 kg (12.35 mol) of (E)-4-dimethylamino-but-2-enoicacid-(4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-yl)-amideare placed in 84 litres of ethanol and heated to 70° C. andcombined with a solution of 2.94 kg (25.31 mol) of maleic acid in36 liters of ethanol. After crystallisation has set in, first themixture is cooled to 20° C. and stirred for 2 hours, then for 3hours at 0° C. The precipitate is suction filtered, washed with 19liters of ethanol and dried in vacuo at 40° C. Yield: 8.11 kg(91.5%); Melting point: 178° C;
Schroeder,Juergen;Dziewas,Georg;Fachinger,Thomas;Jaeger,Burkhard;Reichel,Carsten;Renner,Svenja;
Soyka,Rainer;Rall,Werner;Schnaubelt,Juergen;Sieger,Peter; Kulinna,Christian;Methodfor the production of amino crotonylcompounds;
Afatinib
Trade Name: Gilotrif(US), Giotrif (EU)
Synonym: BIBW 2992, Tomtovok, Tovok
Chinese Name:阿法替尼
Chemical IUPACName:N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide
CAS number: 850140-72-6(Afatinib);850140-73-7(aftinibdimaleate)
Patent:US Patent number 8,426,586
Patent Expiration Date:Oct 10, 2029
Developer: Boehringer Ingelheim
Indication: non-small cell lung cancer
Approval Date: July 12, 2013 (US); September 25, 2013(EU)
Mechanism of Action:covalently binds to the kinase domains of EGFR(ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibitstyrosine kinase autophosphorylation
阿法替尼(Afatinib，商品名Gilotrif)是德国勃林格殷格翰公司(BoehringerIngelheim)开发的第二代表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER2）酪氨酸激酶的强效、不可逆的双重抑制剂，通过和EGFR中第797位半胱氨酸的巯基发生麦克尔加成（Michaelreaction），不可逆地抑制该络氨酸激酶的活性。于2013年7月美国FDA批准的抗非小细胞肺癌新药，用于经由FDA批准的试剂盒证实肿瘤表皮生长因子受体（EGFR）19号外显子缺失或21号外显子突变（L858R）的转移性非小细胞肺癌（NSCLC）患者的治疗。
阿法替尼专利：WO200250043A1（化合物）；WO2003094921A2（抗癌用途）；WO2003066060A2（抗炎用途）；US2005085495A1（工艺）；WO2005037824A2（工艺）；WO2007085638A1（工艺）；US2011207932A1（工艺）；WO2011084796A2（氘代）；WO2012121764A1（晶型）；WO2013052157A1（晶型）
相关专利:
许学农;
摘要:本发明揭示了一种阿法替尼(Afatinib，I)的制备方法，包括如下步骤：2-腈基-4-[4-(N，N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基-5-[(S)-(四氢呋喃-3-基)氧基]苯胺(II)和N，N-二甲基甲酰胺二甲基缩醛(DMF-DMA)进行缩合反应形成中间态(III)，该中间态(III)不需经过分离，直接和4-氟-3-氯苯胺进行环合反应制得阿法替尼(I)。该制备方法使得阿法替尼的制造步骤明显减少，成本大幅降低。
许学农;
摘要 :本发明揭示了一种阿法替尼的制备方法，包括如下步骤：4-氟-3-氯苯胺和N，N-二甲基甲酰胺二甲基缩醛(DMF-DMA)进行缩合反应形成希夫碱(III)，不需经过分离，再和2-腈基-4-[4-(N，N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基-5-[(S)-(四氢呋喃-3-基)氧基]苯胺进行环合反应，制得阿法替尼。该制备方法使得阿法替尼的制造步骤明显减少，成本大幅降低。
许学农;
摘要:本发明揭示了一种阿法替尼(Afatinib，I)的制备方法，包括如下步骤：4-氯-6-氨基-7-羟基喹唑啉(II)和(S)-3-羟基四氢呋喃发生醚化反应生成4-氯-6-氨基-7-[(S)-(四氢呋喃-3-基)氧基]喹唑啉(III)，该化合物(III)与4-(N,N-二甲基氨基)-2-烯-丁酰氯进行酰化反应生成4-氯-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-[(S)-(四氢呋喃-3-基)氧基]喹唑啉(IV)，化合物(IV)与4-氟-3-氯苯胺进行缩合反应制得阿法替尼(I)。该制备方法工艺简洁、经济和环保，适合工业化放大的要求。
联系客服
