Gilotrif|Afatinib|阿法替尼 | Yaopha.com

Gilotrif|Afatinib|阿法替尼

Boehringer Ingelheim’s Afatinib (Trade Name: Giotrif (EU), Gilotrif (US), Synonym: BIBW 2992, Tomtovok, Tovok, Chinese Name:阿法替尼) was approved by US FDA on July 12, 2013 for the treatment of patients with late stage (metastatic) non-small-cell lung cancer (NSCLC).

Synthetic Scheme for the Preparation of Gilotrif? （Afatinib)   肺癌新药阿法替尼的制备路线

Procedures for the Preparation of Gilotrif? （Afatinib)   肺癌新药阿法替尼的制备方法

7-Chloroquinazolin-4(1H)-one

2-Amino-4-chlorobenzoic acid  (5.0 g, 29.1 mmol) and formamidine acetate (6.1 g, 58.3 mmol) in methoxyethanol (35 mL) were stirred at reflux overnight. The clear reaction mixture was then cooled to rt, the solvent was removed under vacuum and the solid residue was washed several times with aqueous NH3 (0.01M) to yield a light brown powder (94%): mp 254255 °C; MS (APCI) m/z 181.3, 183.1; 1H NMR (DMSOd6, 300 MHz) δ 7.54 (dd, J = 8.5, 1.9 Hz, 1H), 8.72 (d, J = 1.9 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.14 (s, 1H), 12.40 (br s, 1H).

7-chloro-6-nitro-3H-quinazolin-4-one

A solution of 7-chloroquinazolin-4(1H)-one (1.18 g, 6.5 mmol) in conc. H2SO4 (3.5 mL, 65 mmol) and fuming HNO3 (3.5 mL) was heated at 100 °C for 1 h. After cooling to rt, the solution was poured onto icewater and the precipitant was collected by filtration. The light yellow solid was crystallized twice from AcOH to give 30 as a bright yellow solid (70%): mp (AcOH) >230 °C; MS (APCI) m/z 224.1, 226.0; 1H NMR (DMSOd6, 300 MHz) δ 8.05 (s, 1H), 8.32 (s, 1H), 8.69 (s, 1H), 12.79 (br s, 1H).

4-(3-Chloro-4-fluoro-phenylamino)-7-chloro-6-nitro-quinazoline

20g 7-chloro-6-nitro-3H-quinazolin-4-one are suspended in 80 ml acetonitrile and combined with 16.5 g phosphorus oxychloride. Then 10.8 g triethylamine are slowly added dropwise and the mixture is heated to about 80° C. After 5 hours a solution of 15.5 g 3-chloro-4-fluoroaniline in 100 ml dioxane is added dropwise and the mixture is stirred for another hour. Then 80 ml of water is added, the mixture is cooled to 20° C. and made slightly alkaline with KOH solution. The suspension is suction filtered, washed with water 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 g 4-(3-chloro-4-fluoro-phenylamino)-7-chloro-6-nitro-quinazoline and 302 g (1.3 eq) benzenesulphonic acid sodium salt are suspended at 20° C. in 1500 ml DMF, heated to 90° C. and kept for 6 h at this temperature. After cooling the reaction mixture the suspension is suction filtered and the residue is rinsed with 1.5 l methanol, 10 l water and 0.5 l methanol. The residue is dried at 50° C. for about 12 h under reduced pressure. Yield: 631.2 g (86.2% of theoretical/DMF solvate). m.p.: 284-286° C.

4-[(3-Chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline

810 g of 4-(3-chloro-4-fluoro-phenylamino)-7-(phenylsulphonyl)-6-nitro-quinazoline and 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.-butoxide in THF (24%) (3.6 eq) are added dropwise at 20° C. and then stirred for 4 h at 25° C. After a further 2 h at 40° C. the mixture is heated to 45° C. for about 2 h. 2.8 l of water are added and then about 3 l solvent are distilled off under reduced pressure. 2.8 l water are added again and about 900 ml solvent are distilled off under reduced pressure. After the addition of 1.6 l methanol the mixture is cooled to 20° C. The suspension is suction filtered and rinsed with a mixture of 3.2 l water and 1.6 l methanol. The residue 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 of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline are hydrogenated in 400 ml DMF in the presence of 33.1 g Raney nickel and 18.7 g ammonium chloride at 40° C., until the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is added dropwise to 1.2 l water. The suspension is stirred for 2.5 h at 0° C., suction filtered and washed with 500 ml of water. The residue is dried overnight at 55° C. under reduced pressure. 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 of tetrahydrofuran 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 thus obtained is designated solution A.

6.39 kg (17.05 mol) of N⁴-(3-chloro-4-fluoro-phenyl)-7-(tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine are placed in 26.5 l tetrahydrofuran and combined at 40° C. with solution A and stirred for 2 hours at 30° C. 64 l of tert.-butylmethylether are added to the suspension and after cooling to 20° C. the precipitate is removed by centrifuging. It is washed with a mixture of 16 l tetrahydrofuran and 16 l tert.-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 %

Dimethylaminoacetaldehyde-Hydrogen Sulphite Adduct

40 g of dimethylaminoacetaldehyde diethylacetal are heated to 40° C. in a mixture of 48 g conc. hydrochloric acid and 20 ml of water for 3 h. Then a solution of 42.4 g sodium pyrosulphite in 72 ml of water (sodium hydrogen sulphite solution) is added dropwise and the mixture is stirred for 1 h. 200 ml of ethanol are added and then the mixture is stirred for 2 h at 0° C. The suspension is suction filtered, washed with 160 ml of ethanol and dried at 45° C. in vacuo. Yield: 42.5 g (89.6% of theoretical).decomp.: from 180° C.

(E)-4-Dimethylamino-but-2-enoic acid-[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}-phosphonate and 0.8 g lithium chloride are suspended in 60 ml of ethanol and cooled to ?5° C. 11 g of 45% potassium hydroxide solution is added dropwise first of all and then 4.8 g dimethylaminoacetaldehyde-hydrogen sulphite adduct in 48 ml of water is added. The reaction solution is stirred for 1 h and then 60 ml of water are added. The suspension is suction filtered, washed with 40 ml of water and dried in vacuo at 45° C.

(E)-4-dimethylamino-but-2-enoic acid-(4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetra-hydrofuran-3-yloxy)-quinazolin-6yl)-amide dimaleate (Afatinib Dimaleate, Gilotrif)

6.0 kg (12.35 mol) of (E)-4-dimethylamino-but-2-enoic acid-(4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-yl)-amide are placed in 84 litres of ethanol and heated to 70° C. and combined with a solution of 2.94 kg (25.31 mol) of maleic acid in 36 liters of ethanol. After crystallisation has set in, first the mixture is cooled to 20° C. and stirred for 2 hours, then for 3 hours at 0° C. The precipitate is suction filtered, washed with 19 liters of ethanol and dried in vacuo at 40° C. Yield: 8.11 kg (91.5%); Melting point: 178° C; ¹H-NMR (CD₃OD): δ=2.47+2.27 (m+m, 2H), 2.96 (s, 6H), 4.03 (m, 2H), 4.07+3.92 (m+m, 2H), 4.18+4.03 (m+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

Source:

Schroeder,Juergen;Dziewas,Georg;Fachinger,Thomas;Jaeger,Burkhard;Reichel, Carsten;Renner,Svenja; A process for producing aminocrotonylamino-?substituted quinazoline derivatives and their intermediates;WO2007085638; US patent 7,960,546

Soyka,Rainer;Rall,Werner;Schnaubelt,Juergen;Sieger,Peter; Kulinna, Christian;Method for the production of amino crotonyl compounds;  WO2005037824; US Patent number 8,426,586

Afatinib
Trade Name: Gilotrif(US), Giotrif (EU)
Synonym: BIBW 2992, Tomtovok, Tovok
Chinese Name:阿法替尼
Chemical IUPAC Name: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(aftinib dimaleate)
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 inhibits tyrosine kinase autophosphorylation

肺癌新药阿法替尼(Afatinib)2013 年7月获美国食品和药品管理局批准，用于经由美国食品和药品管理局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。阿法替尼是德国勃林格殷格翰公司开发的第二代表皮生长因子受体和人表皮生长因子受体2酪氨 酸激酶的强效、不可逆的双重抑制剂。

阿法替尼
商品名： Gilotrif (美国), Giotrif (欧盟)
通用名：Afatinib
别名: BIBW 2992, Tomtovok, Tovok
中文名: 阿法替尼
化学名: (E) -4- 二甲基氨基-丁 -2-烯酸-[4- (3_氯_4_氟-苯基氨基)_7_ (⑶-四氢呋 喃-3-基氧）-喹唑啉-6-基]-酰胺
英文名：N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]- 6 – quinazolinyl] – 4(dimethylamino)-2-butenamide
CAS登记号: 850140-72-6(阿法替尼); 850140-73-7(阿法替尼二马来酸盐)
药物公司: 勃林格殷格翰公司 （Boehringer Ingelheim)
适应症: 非小细胞肺癌
批准日期: 2013年7月12日 (美国); 2013年9月25日(欧盟)
美国专利号： 8,426,586 (下载阿法替尼美国专利）
专利到期: 2029年10月10日 (阿法替尼专利到期信息来源于美国食品和药品管理局的黄皮书)
国际专利：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）
中国相关专利：CN1867564（下载）；CN101402631（下载）

肺癌新药阿法替尼的合成路线

阿法替尼中国相关专利

1）氨基巴豆基化合物的制备方法 Process for preparing amino crotonyl compounds  （下载）

申请号：200480030555.5
公开(公告)号：CN1867564
发明(设计)人：沃纳?拉尔;雷纳?索伊卡;克里斯琴?库林纳;于尔根?施诺贝尔特;彼得?西格
摘要
本发明是关于一种用于制备4-[(3-氯-4-氟苯基)氨基]-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)-喹唑啉以及相关 的氨基巴豆基化合物的改良方法，以及用作医药活性物质的4-[(3-氯-4-氟苯 基)氨基]-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)-喹唑啉的适宜的盐的制备。

{[4- (3-氯-4-氟-苯基氨基）-7-(⑶-四氢呋喃_3_基氧）-喹唑啉_6_基氨甲 酰基]_甲基}_膦酸二乙基酯

将3. 58kg的1，1_羰基二咪唑（22. 16摩尔）放入12. 8升四氢呋喃中，并在40°C 温度下将其与溶解于6. 5升四氢呋喃的4. 52kg(22. 16摩尔)的二乙基膦酰乙酸混合。在 40°C温度下将该混合物搅拌30分钟。所得的溶液被称为溶液A。

将6. 39kg (17. 05摩尔）的N4-(3_氯_4_氟-苯基）_7_ (四氢呋喃_3_基氧）喹 唑啉-4，6- 二胺放入26. 5升四氢呋喃并在40°C与溶液A混合，并在30°C温度下搅拌2小 时。向该悬浮液中加入64升叔丁基甲基醚并且在冷却至20°C后，通过离心分离除去沉淀。 使用16升四氢呋喃与16升叔丁基甲基醚的混合物洗涤之，并然后使用32升水洗涤并在 50°C下干燥。

产率：6. 58kg(69. 8% )的白色晶体，含量=HPLC 99. IFl%

(E) -4- 二甲基氨基-丁 -2-烯酸-[4- (3_氯_4_氟-苯基氨基)_7_ (⑶-四氢呋 喃-3-基氧）-喹唑啉-6-基]-酰胺

将5. 6升30%的盐酸（53. 17摩尔）加入至4. 4升水中。然后在30°C温度下在20 分钟内逐滴加入4. 28kg的95%的（二甲基氨基）_乙醛-二乙基缩醛（26. 59摩尔）。在 35°C温度下搅拌该反应溶液8小时，冷却至5°C并在氩气中保持。该溶液被称为溶液B。

将4. 55kg (68. 06摩尔）氢氧化钾溶解于23. 5升水中并冷却至_5°C。该溶液被称 为溶液C。

将5. 88kg (10. 63摩尔）（(4_ (3_氯_4_氟-苯基氨基）_7_ (四氢呋喃_3_基 氧）-喹唑啉-6-基氨甲酰基）-甲基）_膦酸二乙酯以及0.45kg氯化锂（10. 63摩尔）放 入23. 5升四氢呋喃中并冷却至-7°C。在10分钟内加入冷的溶液C。然后在_7°C温度下在 1小时内加入溶液B。在_5°C温度下再搅拌1小时后将该反应混合物加热至20°C并与15 升水混合。在冷却至；TC温度后，抽滤该悬浮液，使用水洗涤沉淀物并干燥。产率：5.21kg 的粗产品，100 %，含水量：6. 7 %。使用乙酸丁酯/甲基环己烷实施该粗产品的结晶。产率：78%，纯度:HPLC99. 4F1%，含水量：5. 4%

(E) -4- 二甲基氨基-丁 -2-烯酸-(4- (3_氯_4_氟-苯基氨基)~7~ ((S)-四氢呋 喃-3-基氧）-喹唑啉-6-基）-酰胺二马来酸盐

将 6. Okg (12. 35 摩尔)的(E_) _4_ 二甲基氨基 _ 丁 _2_ 烯酸-(4_ (3_ 氯 _4_ 氟-苯 基氨基)-7- ((S)-四氢呋喃-3-基氧)-喹唑啉-6-基）-酰胺放入84升乙醇中并加热至 70°C，并且与溶于36升乙醇的2.94kg(25.31摩尔）马来酸溶液混合。在开始结晶后，首先 将该混合物冷却至20°C并搅拌2小时，然后在0°C温度下搅拌3小时。抽滤沉淀物，使用19 升乙醇冲洗并在40°C温度下在真空中干燥。产率：8. Ilkg(91. 5% )熔点：178°C; 1H-NMR(CD3OD) ： δ = 2. 47 + 2. 27 (m+m, 2H) , 2. 96 (s , 6H) , 4. 03 (m, 2Η), 4. 07+3. 92 (m+m, 2Η) ,4. 18+4. 03 (m+m，2Η)，5. 32 (m, 1Η)，6. 26(s，4H)，6. 80 (m, 1H)，6. 99 (m, 1H)，7? 27 (s，1Η)，7? 30 (t, 1Η)，7? 66 (m, 1Η)，7? 96 (dd, 1Η)，8? 62 (s, 1Η)，9? 07 (s, 1Η) ppm

2）氨基喹唑啉二马来酸盐、其制备方法及其用途 （下载）

申请号：200810166484.1
公开(公告)号：CN101402631
发明(设计)人：沃纳?拉尔;雷纳?索伊卡;克里斯琴?库林纳;于尔根?施诺贝尔特;彼得?西格
摘要
本发明涉及氨基喹唑啉二马来酸盐、其制备方法及其用途。具体地， 本发明涉及4-[(3-氯-4-氟苯基)氨基]-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)-喹唑啉二马来酸盐、其制备方法，包含 该化合物的药物组合物及其在用于制备药物中的用途。