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Figure PCTCN2020079540-appb-000005


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


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.




WO 2020187188 A

Figure PCTCN2020079540-appb-000012

Example 1A

Figure PCTCN2020079540-appb-000013

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

Figure PCTCN2020079540-appb-000014

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

Figure PCTCN2020079540-appb-000015

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 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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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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