4-(2-Fluoro-3chloro-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

6-Quinolinecarboxamide, 4-[3-chloro-4-[[(cyclopropylamino)carbonyl]amino]-2-fluorophenoxy]-7-methoxy-

N-(4-(6-Aminocarbonyl-7-methoxyquinolin-4-yl)oxy-2-chloro-3-fluorophenyl)-N’-cyclopropylurea

cas 2304405-29-4

C₂₁ H₁₈ Cl F N₄ O₄

444.84CN109134365 discloses an active compound or medicinal salt with multi-target effects of VEGFR1~3, fibroblast growth factor receptor 1~3, RET, Kit and PDGFR, and its chemical structure formula is as follows: Formula I:

Chemical name: 4-(2-Fluoro-3chloro-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide, the drug name is fluvatinib. The compound has strong activity and provides a potential new treatment option for patients with tumors such as liver and kidney.

PATENT

CN109134365

PATENT

WO 2020187188

https://patents.google.com/patent/WO2020187188A1/enProcess A

Example 1A

At 20-30°C, 4-chloro-7-methoxyquinoline-6-carboxamide (550.0 g) was added to the reaction kettle. At 20-30°C, DMSO (16.5L) was added to the reactor. At 20-30°C, 2-fluoro-3chloro-4-aminophenol was added to the reactor. At 20-35°C, sodium tert-butoxide (229g) was slowly added to the reaction kettle under stirring for 10-15 minutes. The reaction kettle was heated to 96°C (internal temperature) in 1.5 hours. The reaction was stirred at 96-100°C for 6.5 hours, and no 4-amino-3-chloro-2 fluorophenol remained. The reaction was cooled to 20-30°C. Under stirring, 23.1L of water was slowly added to the reaction solution. During the process, a dark brown solid was precipitated. Keep the internal temperature below 40°C. Stir at 30-40°C for 0.5 hour. Cool to 20-30°C and filter. At 20-30°C, the filter cake and 3.5L of water are added to the reactor. Stir for 0.5 hour at 20-30°C. filter. At 20-30°C, the filter cake and 4.0L of water are added to the reactor. Stir for 0.5 hour at 20-30°C. After filtering, the filter cake was dried in a vacuum dryer at 40°C for 18 hours (phosphorus pentoxide used as a desiccant, and the oil pump was vacuumed). The solid was pulverized to obtain 758 g of off-white solid and dried at 40° C. for 18 hours (phosphorus pentoxide was used as the desiccant, and the oil pump was vacuumed) to obtain Example 1A.LCMS(ESI)m/z:362.0[M+1] ⁺¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.68 (br s, 2H), 7.82-7.96 (m, 1H), 7.67-7.82 (m, 1H), 7.46-7.59 (m, 1H), 7.12-7.26 (m, 1H), 6.67-6.80 (m, 1H), 6.43-6.58 (m, 1H), 5.84 (s, 2H), 4.04 (s, 3H).Example 1B

Example 1A (6.05g) was added to a three-necked flask containing NMP (60mL), pyridine (1.32g) and phenyl chloroformate (5.20g) were added to the reaction system, and the reaction system was at room temperature (25-30°C). ) After stirring for 1 hour, the reaction was complete. Cyclopropylamine (2.84g) was also added to the reaction system. The reaction solution was stirred at room temperature (25-30°C) for 0.5 hours. The reaction was completed. Add 20 mL of ethanol to the reaction system and stir. Tap water (500 mL) was added to the reaction system, a solid was precipitated, filtered, and the filter cake was spin-dried under reduced pressure to obtain a crude product (orange solid, 5.26 g); the crude product was passed through a chromatography column (DCM: MeOH = 20/1～10 /1) Purification to obtain the product (orange solid, 3.12 g), the product was added with 4 mL of absolute ethanol and stirred at room temperature for 18 hours, filtered, the filter cake was washed with 1 mL of ethanol, and dried under reduced pressure to obtain Example 1B. This compound is obtained by adding 1 equivalent of hydrochloric acid, sulfuric acid or methanesulfonic acid in acetone or ethanol solution to obtain the corresponding salt.LCMS(ESI)m/z:445.0[M+1] ⁺¹ H NMR (400MHz, DMSO-d ₆ ) ppm 8.66-8.71 (m, 2H), 8.12-8.20 (m, 2H), 7.72-7.93 (m, 2H), 7.45 (t, J = 9.16 Hz, 1H) ,7.28(d,J=2.76Hz,1H),6.58(d,J=5.02Hz,1H),4.05(s,3H),2.56-2.64(m,1H),0.38-0.77(m,4H)Example 1

Example 1B (1.5g, 3.37mmol) was added to EtOH (45mL), the reaction temperature was raised to 60°C, at this temperature, CH ₃ SO ₃ H (324.07mg, 3.37mmol, 240.05μL) was added dropwise to the reaction In the solution, after the dripping is completed, the reaction solution is dissolved, and the temperature of the reaction solution is naturally cooled to 15-20°C under stirring, and the reaction solution is stirred at this temperature for 2 hours. A large amount of brown solid precipitated, filtered, and the filter cake was rinsed with absolute ethanol (5 mL), and the obtained filter cake was spin-dried under reduced pressure at 50° C. without purification, and Example 1 was obtained.LCMS(ESI)m/z:445.0[M+1] ⁺¹ H NMR(400MHz,DMSO-d ₆ )δppm 9.02(d,J=6.53Hz,1H)8.72(s,1H)8.18-8.27(m,2H)7.87-8.03(m,2H)7.65(s,1H )7.53(t,J＝9.03Hz,1H)7.32(br s,1H)7.11(d,J＝6.27Hz,1H)4.08(s,3H)2.55-2.62(m,1H)2.35(s,3H) 0.34-0.75(m,4H)

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021143954&tab=FULLTEXT&_cid=P12-KSZPW4-91508-1Example 1 Preparation of fluvatinib crystal form I 
Add the free base of fluvatinib of formula I (50mg, 112.40umol) to EtOH (2mL), stir at 15-20℃ for 12h, filter to obtain a filter cake, add the filter cake to 200mL acetone, stir at 15-20℃ After 12h, filter and spin-dry the filter cake under reduced pressure at 40°C to obtain fluvatinib solid. The result of XRPD detection is shown in Figure 1, named as the crystalline form I of fluvatinib, and the detection results of DSC and TGA are shown in Figure 2. And Figure 3. 
Example 2 Preparation of crystal form I of fluvatinib mesylate (also referred to herein as “fluvatinib mesylate”) 
The 4-[3-chloro-4-(cyclopropylaminocarbonylamino)-2-fluoro-phenoxy]-7-methoxy-quinoline-6-carboxamide i.e. fluvatinib (0.5g, 1.12mmol) was added to EtOH (10mL) solvent, heated to 55～60℃, and methanesulfonic acid (108.02mg, 1.12mmol, 80.02μL, 1eq) was added to the reaction flask under stirring at this temperature, and the reaction solution was dissolved. , The reaction solution was cooled to 20 ~ 30 ℃, stirred at this temperature for 1 h, a brown solid precipitated out under vacuum filtration, the filter cake was rinsed with ethanol (2mL*2), and the filter cake was spin-dried at 40 ~ 50 ℃ under reduced pressure. The solid product, named as the crystalline form I of fluvatinib mesylate, was tested by XRPD, DSC, and TGA. The XRPD test results are shown in Table 1 and Figure 4 below, and the DSC and TGA test results are shown in Figure 5. Melting point is about 232-237°C.

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NC(=O)c1cc2c(ccnc2cc1OC)Oc1ccc(NC(=O)NC2CC2)c(Cl)c1F

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