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1、Lazertinib （拉泽替尼）合成检索总结报告一、Lazertinib （拉泽替尼）简介2019年10月,Janssen与Yuhan开启非小细胞肺癌药物Lazertinib二期临床研究。2020年3月11日获FDA突破性疗法认定。Lazertinib （拉泽替尼）分子结构式如下:英文名称:Lazertinib 中文名称：拉泽替尼本文主要对Lazertinib （拉泽替尼）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结o二、Lazertinib （拉泽替尼）合成路线一三、Lazertinib （拉泽替尼）合成路线二操作方法50mL with magnetic sti
2、rring and condensing tube, add ethanol/water mixture to a single-mouth flask (15 mL, 2/1) and compound 18 (200 mg, 375 mmol), reduced iron powder (209 mg, 3.75 mmol) with stirring, and ammonium chloride (lOOmg, 1.87mmol), the temperature was raised to 85 under nitrogen, and the reaction was stirred
3、for 1 h with heat. After cooling to room temperature, the insoluble solid 19 was filtered off, and the organic solvent was evaporated. Dry over anhydrous sodium sulfate, filtered, and evaporated. The yield was 92.7%.CN108947974;(2018); (A) Chinese（五）Lazertinib （拉泽替尼）中间体13的合成（路线二）合成方法实验步骤参考文献操作方法3-Ch
4、loropropionyl chloride (6.6 g, 0.052 mol) was added to a mixture of Ni -(4-(4-(dimethylamino)methyl)-3-phenyl- 1 H-pyrazol-1 -yl)pyrimidin-2-yl)-6-methoxy-4-morpholino benzene-i,3-diamine 19 (20.0 g, 0.039 mol), methyl ethyl ketone (160.0 mL), and sodium bicarbonate (10.1 g, 0.120 mol). The reaction
5、 mixture was stirred at 20-30 for 2 hours. Dichloromethane (10.() mL) and purified water (10.0 mL) were added to the reaction mixture, which was then stirred. The separated organic layer was concentrated under reduced pressure and then methyl ethyl ketone (300.0 mL) and tnethylamine (40.4 g, 0.400 m
6、ol) were added thereto, followed by refluxing under stirring for 1() hours. The reaction mixture was cooled to 0-5 and then stirred for 2 hours. The resulting solid was filtered under reduced pressure and then dried in vacuo to obtain 17.7 g of the titled compound 13. (Yield: 79.9%).WO2019/22485;(20
7、19); (Al) English操作方法With magnetic stirring 50mL, add dry dichloromethane (10 mL) to a three-neck flask and compound 19 (175 mg, 347mmol), Stir and dissolve, cool to -109 add triethylamine (105 mg, 1.04 mmol), Slowly add acryloyl chloride (47 mg, 521 umol) under nitrogen. Dichloromethane (1mL) solut
8、ion, drip, The reaction was stirred at -10 for 30 minutes. The reaction was quenched by the addition of saturated aqueous Na2cO3 (5 mL) and stirred for 10 min. The organic layer was separated and the aqueous phase wasCN108947974;(2018); (A) Chineseextracted with dichloromethane (10 mLx2).The combine
9、d organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. Residue over silica gel. The column has a white solid lOOmg, The yield was 51.6%.o四、Lazertinib （拉泽替尼）合成路线一检索总结报告(一)Lazertinib（拉泽替尼）中间体2的合成（路线一）1合成方法实验步骤参考文献操作方法A mixture of 4-fluoro-2-methoxy-5-nitroaniline 1 (60.0 g
10、, 0.322 mol) and dichloromethane (500.0 mL) was cooled to 0-5. A solution of dibutyl dicarbonate (91.5 g, 0.419 mol) in dichloromethane (120.0 mL), 4-dimethylaminopyridine (3.9 g, 0.032 mol), and triethylamine (65.2 g, 0.645 mol) were added to the mixture. The reaction mixture was stilted at 20-30 f
11、or 4 hours and then concentrated under reduced pressure to obtain 92.3 g of the titled compound 2. (Yield: 100.0%)WO2019/22487;(2019); (Al) English操作方法A solution of 4-fluoro-2-methoxy-5-nitroaniline 1 (8.0g, 43.0 mmol) in DCM (dichloromethane) (100 mL) was cooled to 0-5 in an ice/water bath. BocaO (
12、9.4g, 43.0 mmol) in DCM (30 mL) was added to the mixture slowly. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The crude productwas purified by flash silica chromatography, with gradient 1
13、0-40% EtOAc in hexane to yield intermediate (2)Journal of Chemical Research; vol. 39; nb. 6; (2015); p. 318-320;Bioorganic and Medicinal Chemistry; vol. 26; nb. 8; (2018);(12.0 g, 42.1 mmol, 98%) as a yellow solid, m.p. 88-90.p. 1810-1822.操.法After dissolving 1 (10 g, 1.0 eq) in acetonitrile (30 mL),
14、 Boc anhydride (14 g, 1.2 eq) was added dropwise at 25, then raised to 60, reaction time 10 h, some solvent was distilled off, cooled, and filtered. The filter cake was obtained, and the filter cake was washed with an acetonitrile solvent to obtain a pure intermediate 2. To the obtained filtrate, BO
15、C anhydride (8 g) was added to continue the reaction, and after 10 hours, the second cooling crystallization was carried out, and the operation was repeated 5 times to obtain Intermediate 2, a pale yellow solid, 14 g, yield 91%.CN2019/110283162; (2019); (A)操作方法 四4-fluoro-2-methoxy-5-nitroaniline 1 (
16、50g, 0.269mol), Boc anhydride (58.62g, 0.269mol) is dissolved in acetonitrile (IL),Heated to 55 for 7 hours, The acetonitrile was distilled off under reduced pressure, and ethyl acetate (500 mL) was added to dissolve it. Then, petroleum ether (100 mL) was added dropwise with stirring, a solid was pr
17、ecipitated, and filtered, 61.5 g of a yellow solid 2 was obtained, yield: 81%.CN2019/1103578 63; (2019); (A);CN2019/1104078 52; (2019); (A);CN2019/110396095; (2019); (A).操作方法 五Compound 1 (11.16 g, 60 mmol) was dissolved in 150 ml of dichloromethane, di-tert-butyl dicarbonate (15.60 g, 72 mmol), trie
18、thylamine (12.24 g, 120 mmol) and 4-dimethylaminopyridine (0.74 g of, 6 mmol) were added and stirred at room temperature for 18 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was concentrated under reduced pressure, isolated and purified by col
19、umn chromatography PE:EA=80:20 to give the title compound 2 (12.56 g, 73%).US2017/8889;(2017); (Al) English;US2017/57957;(2017); (Al) English.（Zl） Lazertinib （拉泽替尼）中间体4的合成（路线-/。23/J H4一）合成方法实验步骤参考文献操作方法Appropriate alkyl amine 3 (27.0 mmol) was added to a solutionof intermediate 2 (6.3 g, 22.0 mmol)
20、and DIPEA (N,N-Diisopropylethylamine) (3.82 mL, 22.0 mmol) in DMF (100 mL). Themixture was heated to 60 and stirred at this temperature for 2 h. Water (200 mL) was added to the reaction mixture, whichwas then extracted with DCM (50 mLx3). The combined extracts were dried over anhydrousBioorganic and
21、 Medicinal Chemistry; vol. 26; nb. 8; (2018); p. 1810-1822.magnesium sulfate. The solvent was removed under vacuum to afford compounds 4, respectively, which were used without further purification.操作方法Intermediate 2 (1.5 g, 1 eq), morpholine 3 (0.54 g, 1.2 eq), Potassium carbonate (1.45 g, 2 eq) was
22、 added to a 100 ml eggplant bottle and heated to 80. The reaction time was 4 h, and the reaction was complete by TLC. After the reaction is completed, water is added to the eggplant type bottle, and the insoluble matter is precipitated, filtered, and the filter cake is washed with water. 1.739g of i
23、ntermediate 4 solid, The recovery rate is 97%.CN108558865;(2018); (A) Chinese操伊法A mixture of tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl)- carbamate 2 (92.3 g, 0.322 mol), acetonitrile (600.0 mL), diisopropylethylamine (54.1 g, 0.419 mol), and morpholine 3 (36.5 g, 0.419 mol) was refluxed under sti
24、rring for about 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 99.0 g of the titled compound 4.WO2019/22487;(2019); (Al) English（H） Lazertinib （拉泽替尼）中间体5的合成（路线一）合成方法实验步骤参考文献操作方法A mixture of tert-butyl (2-methoxy-4-morpholino-5-nitro- phenyl)carbamate 4 (120.0 g,0.340
25、 mol), tetrahydrofuran (1.2 L), ethanol (1.2 L), ammonium formate (180.0 g, 2.854 mol), and palladiumlcarbon (12.0 g) was stirred at 15-25 for 2 hours and then filtered through a celite pad. The resulting filtrate was concentrated under reducedpressure. Dichloromethane (1.4 L) and purified water (1.
26、0 L) were added to theresulting residue, which was then stirred for 1 hour. The separated organic layer wasconcentrated under reduced pressure to obtain 100.5 g of the titled compound 5. (Yield:9 1.5%)WO2019/22487;(2019); (Al) English操作方法To a solution of 4 (22.6 mmol) in ethanol (150 mL) was added 1
27、0% Pd/C (0.5 g). The reaction mixture was stirred at room temperature under an atmosphere of H2 for 9 h. After completion of the reaction, the resulting mixture was filtered through Celite, andthe filtered catalyst was washed with ethanol. The filtrate was concentratedunder high vacuum to afford com
28、pound 5, respectively.Bioorganic and Medicinal Chemistry; vol. 26; nb. 8; (2018); p. 1810-1822.Intermediate 4 (1.622 g, 10 eq) was dissolved in 1,4-dioxane.Thereafter, ferric chloride (0.37 g, 3 eq) containing six water操作方法CN108558865;(2018); (A) Chineseof crystallization, activated carbon (30 mg, 6
29、 eq), 80% hydrazine hydrate (6.88 g, 300 eq), reacted at 60 for 8 h, and the reaction was completely detected by TLC dot plate. After filtration with celite, ethyl acetate was added and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. Spin dr
30、y to 1.06 g of intermediate 5 under reduced pressure. The recovery rate is 70%.（四）Lazertinib （拉泽替尼）中间体7的合成（路线一）合成方法实验步骤参考文献操作方法To a solution of 5 (2.0 g, 7.9 mmol) and DIPEA (1.38 mL, 7.9mmol) in CH2CI2 (50 mL) at 0, acryloyl chloride 6 (0.64 mL, 7.9mmol) was added dropwise. The mixture was stirred
31、for 1 h, then extracted with water (2-50 mL). The organic layer was dried over anhydrous Na2so4, and evaporated to give the crude residue. Compounds 7 was obtained as a pale-yellow solid after purificationby silica gel column chromatography (CH2C12:MeOH, 30:1 tol5:l v/v).Bioorganic and Medicinal Che
32、mistry; vol. 26; nb. 8; (2018); p. 1810-1822.操作方法Intermediate 5 (1 g, 1 eq) was dissolved in tetrahydrofuran (4 mL), then N,N-diisopropylethylamine (0.823 g, 2 eq), acryloyl chloride 6 (0.365 g, 1.5 eq) was reacted at 25 for 6 h. The reaction was complete by TLC. After the reaction is completed, an
33、excess of sodium hydrogencarbonate is added to the mother liquor to quench the acryloyl chloride. It was dissolved in ethyl acetate, washed twice with brine, and dried over anhydrous sodium sulfate. Filtration, vacuum drying, 820 mg of intermediate 7, The recovery rate is 70%.CN108558865;(2018); (A)
34、 Chinese（五）Lazertinib （拉泽替尼）中间体8的合成（路线一）合成方法实验步骤参考文献A mixture of tert-butyl (5-acrylamido-2-methoxy-4- morpholinophenyl)carbamate 7 (38.0 g, 0.100 mol), ethanol操作方法(380.0 mL), and cone, hydrochloric acid (52.4 g, 0.503 mol) was stirred at 50-60 for 2 hours. The reaction mixture was cooled to 20-30.
35、Dichloromethane (500 mL), purified water (500 mL), and sodium bicarbonate (63.4 g, 0.755 mol) were added to the reaction mixture, which was then stirred for 1 hour. The separated organic layer was concentrated under reduced pressure to obtain 25.4 g of the titled compound 8. (Yield: 91.7%).WO2019/22
36、487;(2019); (Al) English操作方法TFA (20 mmol) was added to a solution of 7 (2 mmol) inCH2cL (50 mL) at room temperature. The reaction mixture wasstirred for 2-7 h, and was monitored by TLC. The mixture wasextracted with water (2x100 mL), the combined aqueous layerwas neutralized with aqueous K2CO3 to pH
37、 7-8. The precipitatewas filtered and dried to generate the compounds 8, respectively.Bioorganic and Medicinal Chemistry; vol. 26; nb. 8; (2018); p. 1810-1822.操修法Intermediate 7 (190 mg, 1 eq) was dissolved in dichloromethane, then trifluoroacetic acid (828.5 mg, 15 eq). The reaction time was 3 h, an
38、d the reaction was complete by TLC. After the reaction was completed, sodium hydrogen carbonate was added to the reaction solution to adjust pH = 10, and ethyl acetate was added to dissolve. Wash twice with saturated brine, dry over anhydrous sodium Column chromatography, 100 mg of intermediate 8, T
39、he recovery rate is 69%.CN108558865;(2018); (A) Chinese（A） Lazertinib （拉泽替尼）中间体11的合成（路线一）合成方法实验步骤参考文献操作方法A mixture of 2,4-dichloropyrimidine 10 (30.0 g, 0.201 mol), potassium carbonate (55.6g, 0.402 mol), and dimethylfomiamide (180.0 mL) was cooled to 0-5 and then 3-pheny 1-1 H-pyrazole-4-carbaldehy
40、de 9 (41.6 g, 0.242 mol) was added thereto. The reaction mixture was stilted for 15 hours and then purified water (1.2 L) was added thereto. The resulting solid was filtered and then dried in vacuo to obtain 48.8 g of the titled compound 11. (Yield: 85.1%)WO2019/22487;(2019); (Al) English（七）Lazertin
41、ib （拉泽替尼）中间体12的合成（路线一）合成方法实验步骤参考文献操作方法A mixture of N-(5-amino-4-methoxy-2-morpholinophenyl)- acrylamide 8 (0.2g, 0.721 mmol), tetrahydrofuran (2.0 mL),-(2- chloropyrimidin-4-yl)-3-phenyl-l H-pyrazole-4- carbaldehyde 11 (0.2 g, 0.721 mmol), tris(dibenzylideneacetone)dipalladium (0.03 g, 0.036 mmol),
42、4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.04 g, 0.072 mmol), and cesium carbonate (0.47 g, 1.442 mmol) was refluxed under stirring for 16 hours. The reaction mixture was cooled to 20-30 and then purified water (2.0 mL) was slowly added. The resulting solid was filtered and then dried in vac
43、uo to obtain 0.32 g of the titled compound 12. (Yield: 84.4%)WO2019/22487;(2019); (Al) English+（/V） Lazertinib （拉泽替尼）13的合成（路线一）合成方法实验步骤参考文献操作方法A mixture of N-(5-(4-(4-formyl-3-phenyl-1 H-pyrazol-1 -yl)- pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acryl amide 12 (3.0 g, 0.006 mol), dimethylacet
44、amide (30.0 mL), dimethylamine hydrochloride (0.9 g, 0.011 mol), and diisopropylethylamine (3.7 g, ().029 mol) was stirred at 20-30 for 1 hour. Sodium triacetoxyborohydride (3.6 g, 0.017 mol) was added to the reaction mixture, which was then stirred at 20-30 for 1 hour. Purified water (30.0 mL) was
45、added to the reaction mixture, which was then stirred for 1 hour. The resulting solid was filtered under reduced pressure and then driedin vacuoto obtain 2.9 g of the titled compound 13. (Yield: 92.0%).WO2019/22486;(2019); (Al) English;WO2019/22487;(2019); (Al) English.五、Lazertinib （拉泽替尼）合成路线二检索总结报告
46、CICIoCI +O（一）Lazertinib （拉泽替尼）中间体16的合成（路线二）15合成方法实验步骤参考文献操作方法A mixture of N-(2-methoxy-4-morpholino-5-nitrophenyl)- formamide 14 (15.0 g, 0.05 mol), tetrahydrofuran (40.0 mL), and dimethylacetamide (60.0 mL) was cooled to 0-5.Sodium tert-butoxide (5.6 g, 0.06 mol) and 4-chloro-2-(methylsulfonyl)pyri
47、midine 15 (11.3 g, 0.06 mol) were added to the mixture, which was then stirred at 0-10 for 1 hour. A 2N NaOH solution (75.0 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour and then purified water (150.0 mL) was added thereto. The resulting solid
48、 was filtered and then dried in vacuo to obtain 16.1 g of the titled compound 16. (Yield: 82.6%).WO2019/22485;(2019); (Al) English操作方法Compound 14 (2.81 g, 10 mmol) was added to a 100 mL three-necked flask equipped with magnetic stirring.And dry DMF (15 ml), cooled to 0, NaH (60%, 480 mg, 12 mmol) was added.The reaction was stirred at room temperature under nitrogen for half an hour and then cooled to 0.Slowly add dry compound 15 (1.93 g, 1