CN109988108B - Preparation method of cabozantinib - Google Patents
Preparation method of cabozantinib Download PDFInfo
- Publication number
- CN109988108B CN109988108B CN201711475428.1A CN201711475428A CN109988108B CN 109988108 B CN109988108 B CN 109988108B CN 201711475428 A CN201711475428 A CN 201711475428A CN 109988108 B CN109988108 B CN 109988108B
- Authority
- CN
- China
- Prior art keywords
- compound
- cabozantinib
- formula
- preparing
- molar ratio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 title claims abstract description 36
- 229960001292 cabozantinib Drugs 0.000 title claims abstract description 36
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 27
- -1 cabozantinib compound Chemical class 0.000 claims abstract description 21
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 claims abstract description 12
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical group [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000004795 grignard reagents Chemical class 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical group [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000007818 Grignard reagent Substances 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims 1
- FDKLLWKMYAMLIF-UHFFFAOYSA-N cyclopropane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CC1 FDKLLWKMYAMLIF-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006482 condensation reaction Methods 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000008213 purified water Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- 238000001816 cooling Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- BQEDPQDMNWOYLK-UHFFFAOYSA-N methyl 1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carboxylate Chemical compound C=1C=C(F)C=CC=1NC(=O)C1(C(=O)OC)CC1 BQEDPQDMNWOYLK-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WRVHQEYBCDPZEU-UHFFFAOYSA-N 4-chloro-6,7-dimethoxyquinoline Chemical compound C1=CC(Cl)=C2C=C(OC)C(OC)=CC2=N1 WRVHQEYBCDPZEU-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- IQZLUWLMQNGTIW-UHFFFAOYSA-N acetoveratrone Chemical compound COC1=CC=C(C(C)=O)C=C1OC IQZLUWLMQNGTIW-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- FSPQCTGGIANIJZ-UHFFFAOYSA-N 2-[[(3,4-dimethoxyphenyl)-oxomethyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=C(C(N)=O)C(CCCC2)=C2S1 FSPQCTGGIANIJZ-UHFFFAOYSA-N 0.000 description 1
- QOGPNCUTXVZQSL-UHFFFAOYSA-N 6,7-dimethoxy-1h-quinolin-4-one Chemical compound C1=CC(O)=C2C=C(OC)C(OC)=CC2=N1 QOGPNCUTXVZQSL-UHFFFAOYSA-N 0.000 description 1
- 102100022014 Angiopoietin-1 receptor Human genes 0.000 description 1
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 description 1
- 101000753291 Homo sapiens Angiopoietin-1 receptor Proteins 0.000 description 1
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 description 1
- 101000807561 Homo sapiens Tyrosine-protein kinase receptor UFO Proteins 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 101710151245 Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 101710147108 Tyrosinase inhibitor Proteins 0.000 description 1
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- OZQXEOSNFMMMRD-UHFFFAOYSA-M [Cl-].CC(C)[Mg+].C1CCOC1 Chemical compound [Cl-].CC(C)[Mg+].C1CCOC1 OZQXEOSNFMMMRD-UHFFFAOYSA-M 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- DMHSCCFHYJAXNG-UHFFFAOYSA-N sodium;bis(trimethylsilyl)azanide;oxolane Chemical compound [Na+].C1CCOC1.C[Si](C)(C)[N-][Si](C)(C)C DMHSCCFHYJAXNG-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention belongs to the field of medicinal chemistry, and relates to a preparation method of cabozantinib. The method prepares the compound shown in the formula III by reacting 4-halogenated-6, 7-dimethoxyquinoline with 4-aminophenol, prepares the compound shown in the formula V by reacting cyclopropane-1, 1-dicarboxylic acid/ester with para-fluoroaniline, and then prepares the cabozantinib compound by condensation reaction. The preparation method provided by the invention has the advantages of simple operation, high yield, low cost, wide industrialization prospect and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry and organic chemistry, and particularly relates to synthesis of cyclopropane-1, 1-dicarboxylic acid [4- (6, 7-dimethoxyquinolin-4-yloxy) -phenyl ] -amide (4-fluorophenyl) -amide (Cabozantinib) and an intermediate thereof.
Background
Cabozantinib (Cabozantinib), the chemical name is cyclopropane-1, 1-dicarboxylic acid [4- (6, 7-dimethoxy quinoline-4-yloxy) -phenyl ] -amide (4-fluorophenyl) -amide, and the structure is shown in formula I.
Cabozantinib is a multi-receptor tyrosine kinase inhibitor (tyrosine kinases inhibitor) developed by Exelixis corporation, targeting RET, MET, VEGFR-1, -2, -3, KIT, TRKB, FLT-3, AXL, TIE-2, etc. Tyrosine kinase plays an important role in the process of generating and developing tumors, and the research and development of drugs by taking tyrosine kinase as a target point become a hot spot of the research of antitumor drugs internationally. The tyrosinase inhibitor realizes the anti-tumor effect by inhibiting the damage repair of tumor cells, blocking cell division in a G1 stage, inducing and maintaining apoptosis, resisting neovascularization and other multiple ways; it has wide anticancer spectrum and has become the first-line medicine for treating various kinds of cancer.
By searching patent documents, the currently reported cabozantinib synthesis methods mainly comprise the following methods:
1) patent WO2005030140 is a compound patent of primary research company, in which the synthesis method of cabozantinib is reported as follows:
the method is to prepare cabozantinib by condensation after preparing 3 and 5 separately in two routes. One route is to prepare 3 by using cyclopropane-1, 1-dicarboxylic acid as a raw material through condensation and substitution. The other route is to prepare 5 by taking 1- (3, 4-dimethoxyphenyl) ethanone as a raw material and carrying out nitration, reduction, cyclization and substitution. The method has high energy consumption, uses genotoxic reagent, and has fussy operation and low yield.
2) Patent CN103459373A is a patent of preparation method of original research company, and the route is as follows:
the method is to prepare cabozantinib by condensation after preparing 3 and 6 separately in two routes. One route is to prepare 3 by using 4-hydroxy-6, 7-dimethoxyquinoline as a raw material through chlorination and substitution. The other route is to prepare 5 by condensing and chloridizing cyclopropane-1, 1-dicarboxylic acid as a raw material, and then condensing to prepare the cabozantinib. The method has the disadvantages of complicated operation of thionyl chloride post-treatment and low industrial production efficiency.
Disclosure of Invention
The invention aims to solve the problems and provides a novel preparation method of cabozantinib, which comprises the following synthesis steps:
condensing a compound of formula III with a compound of formula V to provide a compound of formula I cabozantinib:
wherein R is1Is C1～C10Alkyl of (2), preferably methyl, ethyl, propyl and isopropyl, R2Is C1～C10Preferably H, methyl, ethyl, propyl and isopropyl.
Preferably, the feeding molar ratio of the compound of formula III to the compound of formula V is 1:0.5 to 5, preferably 1:0.5 to 2, and more preferably 1:1.2 to 2.
Preferably, the reaction temperature is-20 to 80 ℃, preferably-10 to 30 ℃, and more preferably 20 to 30 ℃.
Preferably, the molar ratio of the used amount of the base to the fed compound of the formula III is 1-20: 1, preferably 5 to 10:1, more preferably 5 to 8: 1.
according to the method of the invention, the compound of formula IV and para-fluoroaniline are reacted under the action of alkali or a condensing agent to prepare the compound of formula V,
wherein the condensing agent can be selected from EDC & HCl or DCC; the base can be t-BuONa, t-BuOK, LHMDS, NaHMDS, KHMDS or Grignard reagent, preferably NaHMDS, KHMDS or Grignard reagent.
Preferably, the molar ratio of the compound of formula IV to the para-fluoroaniline feed is 1:0.5 to 5, preferably 1:0.5 to 2, and more preferably 1:1.2 to 2.
Preferably, the reaction temperature is-20 to 80 ℃, preferably-10 to 30 ℃, and more preferably 20 to 30 ℃.
Preferably, the molar ratio of the amount of the condensing agent to the compound of the formula IV is 1-10: 1, preferably 1.2 to 5: 1.
preferably, the molar ratio of the base to the compound of formula IV is 1-20: 1, preferably 5-20: 1, more preferably 5-10: 1.
According to the method of the invention, the compound of formula II reacts with 4-aminophenol under the action of alkali to prepare the compound of formula III,
wherein X is selected from F, Cl, Br or I.
Preferably, the base is selected from sodium tert-butoxide or potassium tert-butoxide. .
Preferably, the reaction temperature is 90-120 ℃.
Preferably, the feeding molar ratio of the alkali to the compound of the formula II is 1-8: 1.
The novel preparation method of cabozantinib and the intermediate thereof provided by the invention has the advantages of simple preparation method, low reaction cost, convenience in operation, avoidance of toxic reagents, high yield of the prepared product, good purity and suitability for industrial production.
Detailed Description
The following specific examples are presented to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention. The solvents, reagents, raw materials and the like used in the present invention are commercially available products.
EXAMPLE 14 preparation of- ((6, 7-dimethoxy-4-yl) oxy) aniline
Adding 4-chloro-6, 7-dimethoxyquinoline (10g,0.045mol,1.0eq.) and 4-aminophenol (6.9g,0.063mol,1.4eq.) into 50mL of N, N-dimethylacetamide, cooling to 0 ℃, slowly adding sodium tert-butoxide (6.1g,0.063mol,1.4eq.) and a suspension of 50mL of N, N-dimethylacetamide, after the addition, heating to 100 ℃, reacting for 5 hours, cooling the reaction liquid to 0 ℃, adding 400mL of purified water, and stirring for crystallization for 15-16 hours. Stirring is stopped, filtration is carried out, and 20mL of purified water is used for washing a filter cake to obtain 11.2g of 4- ((6, 7-dimethoxy-4-yl) oxy) aniline with the yield of 84.5% and the purity of 99.1%.
MS(ESI)：m/z 297.20[M+H]+.
1H NMR(DMSO-d6,400MHz):δ3.94(s,6H),5.19(s,2H),6.38(d,J＝2.8Hz,1H),6.68(d,J＝8.4Hz,2H),6.93(d,J＝8.8Hz,2H),7.37(s,1H),7.51(s,1H),8.43(d,J＝5.2Hz,1H).
EXAMPLE 24 preparation of- ((6, 7-dimethoxy-4-yl) oxy) aniline
Adding 4-chloro-6, 7-dimethoxyquinoline (10g,0.045mol,1.0eq.) and 4-aminophenol (6.9g,0.063mol,1.4eq.) into 50mL of N, N-dimethylacetamide, cooling to 0 ℃, slowly adding sodium tert-butoxide (6.1g,0.063mol,1.4eq.) and a suspension of 50mL of N, N-dimethylacetamide, after the addition, heating to 110 ℃, reacting for 4 hours, cooling the reaction liquid to 0 ℃, adding 400mL of purified water, and stirring for crystallization for 15-16 hours. Stirring is stopped, filtering is carried out, and 20mL of purified water of a filter cake is washed to obtain 11.8g of 4- ((6, 7-dimethoxy-4-yl) oxy) aniline with the yield of 89.1% and the purity of 99.1%.
The mass and hydrogen spectra data are essentially identical to those of example 1.
EXAMPLE 34 preparation of- ((6, 7-dimethoxy-4-yl) oxy) aniline
Adding 4-chloro-6, 7-dimethoxyquinoline (10g,0.045mol,1.0eq.) and 4-aminophenol (6.9g,0.063mol,1.4eq.) into 50mL of N, N-dimethylacetamide, cooling to 0 ℃, slowly adding a suspension of potassium tert-butoxide (7.1g,0.063mol,1.4eq.) and 50mL of N, N-dimethylacetamide, after the addition, heating to 100 ℃, reacting for 5 hours, cooling the reaction liquid to 0 ℃, adding 400mL of purified water, and stirring for crystallization for 15-16 hours. Stirring is stopped, filtering is carried out, and 20mL of purified water of a filter cake is washed to obtain 11.1g of 4- ((6, 7-dimethoxy-4-yl) oxy) aniline with the yield of 83.8 percent and the purity of 99.2 percent.
The mass and hydrogen spectra data are essentially identical to those of example 1.
EXAMPLE 41 preparation of methyl- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylate
Monomethyl 1, 1-cyclopropyldicarboxylate (10g,0.069mol,1.0eq.) and para-fluoroaniline (11.6g,
0.104mol,1.5eq.) was added to 150mL of dichloromethane, and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (20g,0.104mol,1.5eq.) was added with stirring and reacted at room temperature for 2 h. Concentrating to remove dichloromethane, adding 30mL of methanol into the concentrated solution, stirring to dissolve, adding 150mL of purified water, stirring to crystallize, filtering, purifying the filter cake with 20mL of water, and washing to obtain 14.5g of methyl 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylate, wherein the yield is 96.7% and the purity is 99.8%.
MS(ESI)：m/z 238.27[M+H]+,260.17[M+Na]+.
1H NMR(DMSO-d6,400MHz):δ1.37～1.44(m,4H),3.68(s,3H),7.12～7.18(m,2H),7.61～7.66(m,2H),10.35(s,1H).
EXAMPLE 51 preparation of methyl- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylate
Dimethyl 1, 1-cyclopropyldicarboxylate (10.9g,0.069mol,1.0eq.) and para-fluoroaniline (11.6g,0.104mol,1.5eq.) were added to 100mL of tetrahydrofuran, the temperature was reduced to 0 ℃ and 2M sodium bis (trimethylsilyl) amide (NaHMDS)/tetrahydrofuran (207mL,0.414mol,6.0eq.) was added with stirring and reacted at room temperature for 2 hours. And after the reaction is finished, adding 1.8L of purified water, stirring and crystallizing for 5-6 h, filtering, and washing 20mL of filter cake purified water to obtain 13.7g of methyl 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylate, wherein the yield is 91.3% and the purity is 99.7%.
The mass and hydrogen spectra data are essentially identical to those of example 4.
Example 6 preparation of Cabozantinib Compounds
Adding 4- ((6, 7-dimethoxy-4-yl) oxy) aniline (10g,0.034mol,1.0eq.) and methyl 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylate (11.3g,0.048mol,1.4eq.) into 100mL of tetrahydrofuran, cooling to 0 ℃, slowly adding 2M NaHMDS tetrahydrofuran solution (102mL,0.204mol,6.0eq.), reacting at room temperature for 4h, cooling the reaction liquid to 0 ℃, slowly adding purified water 1200mL, stirring and crystallizing for 5-6 h, filtering, and washing with 20mL of purified water to obtain the cabozantinib solid 16g, wherein the yield is 94.6% and the purity is 99.6%.
MS(ESI)：m/z 502.48[M+H]+,524.37[M+Na]+.
1H NMR(DMSO-d6,400MHz):δ1.49(s,4H),3.94(s,3H),3.95(s,3H),6.43(d,J＝5.2Hz,1H),7.13～7.19(m,2H),7.24(d,J＝9.2Hz,2H),7.40(s,1H),7.51(s,1H),7.64～7.67(m,2H),7.78(d,J＝8.8Hz,2H),8.47(d,J＝5.2Hz,1H),10.08(s,1H),10.20(s,1H).
Example 7 preparation of Cabozantinib Compounds
Adding 4- ((6, 7-dimethoxy-4-yl) oxy) aniline (10g,0.034mol,1.0eq.) and methyl 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylate (11.3g,0.048mol,1.4eq.) into 100mL of tetrahydrofuran, cooling to 0 ℃, slowly adding a 2M KHMDS tetrahydrofuran solution (102mL,0.204mol,6.0eq.), reacting at room temperature for 4h, cooling the reaction liquid to 0 ℃, slowly adding purified water 1200mL, stirring and crystallizing for 5-6 h, filtering, and washing with 20mL of purified water to obtain 15.7g of cabozantin solid, wherein the yield is 92.8% and the purity is 99.7%.
The mass and hydrogen spectra data are essentially identical to those of example 6.
EXAMPLE 8 preparation of Cabozantinib Compounds
Adding 4- ((6, 7-dimethoxy-4-yl) oxy) aniline (10g,0.034mol,1.0eq.) and methyl 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylate (11.3g,0.048mol,1.4eq.) into tetrahydrofuran 100mL, cooling to 0 ℃, slowly adding 2M isopropyl magnesium chloride tetrahydrofuran solution (102mL,0.204mol,6.0eq.), reacting at room temperature for 4h, cooling the reaction liquid to 0 ℃, slowly adding purified water 1200mL, stirring and crystallizing for 5-6 h, filtering, and washing with 20mL of purified water to obtain cabozantinib solid 15.5g, yield 91.6%, and purity 99.6%.
The mass and hydrogen spectra data are essentially identical to those of example 6.
Example 9 preparation of Cabozantinib Compounds
Adding 4- ((6, 7-dimethoxy-4-yl) oxy) aniline (10g,0.034mol,1.0eq.) and methyl 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylate (11.3g,0.048mol,1.4eq.) into 100mL of tetrahydrofuran, slowly adding 2M LHMDS tetrahydrofuran solution (102mL,0.204mol,6.0eq.) at normal temperature, reacting at room temperature for 4h, slowly adding 1200mL of purified water into the reaction solution, stirring and crystallizing for 5-6 h, filtering, and washing with 20mL of purified water to obtain 15g of Carbotinib solid with yield of 88.9% and purity of 99.8%.
The mass and hydrogen spectra data are essentially identical to those of example 6.
Claims (21)
1. A process for preparing a cabozantinib compound comprising: condensing the compound of the formula III with the compound of the formula V under alkaline condition to obtain the compound of the formula I, namely cabozantinib,
wherein R is1Is selected from C1～C10The base is selected from LHMDS, NaHMDS, KHMDS or grignard reagents.
2. The method of claim 1, wherein R is1Selected from methyl, ethyl, propyl and isopropyl.
3. The method of claim 1, wherein the molar ratio of compound of formula III to compound of formula V is 1:0.5 to 5.
4. The method for preparing cabozantinib compound according to claim 1, wherein the molar ratio of the compound of formula III to the compound of formula V is 1: 0.5-2.
5. The method for preparing cabozantinib compound according to claim 1, wherein the molar ratio of the compound of formula III to the compound of formula V is 1: 1.2-2.
6. The method for preparing cabozantinib compound according to claim 1, wherein the molar ratio of the used amount of the base to the fed amount of the compound of formula III is 1-20: 1.
7. the method for preparing cabozantinib compound according to claim 1, wherein the molar ratio of the used amount of the base to the fed amount of the compound of formula III is 5-10: 1.
8. the method for preparing cabozantinib compound according to claim 1, wherein the molar ratio of the used amount of the base to the fed amount of the compound of formula III is 5-8: 1.
9. the preparation method of cabozantinib compound according to claim 1, characterized in that compound of formula IV and para-fluoroaniline are reacted in the presence of base or condensing agent to prepare compound of formula V,
wherein R is2Is selected from C1～C10Alkyl or H.
10. The method of claim 9, wherein R is2Selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl.
11. The process for preparing cabozantinib compound according to claim 9, wherein the condensing agent is selected from EDC-HCl or DCC; the base can be selected from LHMDS, NaHMDS, KHMDS or Grignard reagent.
12. The method for preparing cabozantinib compound according to claim 9, wherein the reaction temperature is-20 ℃ to 80 ℃.
13. The method for preparing cabozantinib compound according to claim 9, wherein the reaction temperature is-10 ℃ to 30 ℃.
14. The method for preparing cabozantinib compound according to claim 9, wherein the reaction temperature is 20 ℃ to 30 ℃.
15. The method of claim 9, wherein the molar ratio of the amount of the condensing agent to the compound of formula IV is 1 to 10: 1.
16. the method of claim 9, wherein the molar ratio of the amount of the condensing agent to the compound of formula IV is 1.2 to 5: 1.
17. the method for preparing cabozantinib compound according to claim 9, wherein the molar ratio of the amount of base to the compound of formula IV is 1-20: 1.
18. The method for preparing cabozantinib compound according to claim 9, wherein the molar ratio of the amount of base to the compound of formula IV is 5-10: 1.
19. The method of claim 1, wherein the compound of formula II is reacted with 4-aminophenol under the action of a base to produce the compound of formula III,
wherein X is selected from F, Cl, Br or I.
20. The method of claim 19, wherein the base is selected from sodium tert-butoxide and potassium tert-butoxide.
21. The method of claim 19, wherein the reaction temperature is 90 ℃ to 120 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711475428.1A CN109988108B (en) | 2017-12-29 | 2017-12-29 | Preparation method of cabozantinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711475428.1A CN109988108B (en) | 2017-12-29 | 2017-12-29 | Preparation method of cabozantinib |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109988108A CN109988108A (en) | 2019-07-09 |
| CN109988108B true CN109988108B (en) | 2022-04-29 |
Family
ID=67109665
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711475428.1A Active CN109988108B (en) | 2017-12-29 | 2017-12-29 | Preparation method of cabozantinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109988108B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112390749B (en) * | 2019-08-19 | 2024-12-03 | 鲁南制药集团股份有限公司 | A method for synthesizing cabozantinib and its intermediates |
| CN110903240A (en) * | 2019-12-12 | 2020-03-24 | 上海玉函化工有限公司 | Preparation method of broad-spectrum anticancer drug cabozantinib |
| CN111217745B (en) * | 2020-02-25 | 2021-05-11 | 漯河医学高等专科学校 | Preparation method of cabozantinib |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103068384A (en) * | 2010-04-29 | 2013-04-24 | 德西费拉制药有限责任公司 | Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activites |
| WO2014000713A1 (en) * | 2012-06-29 | 2014-01-03 | Zhejiang Beta Pharma Incorporation | NOVEL FUSED PYRIDINE DERIVATIVES USEFUL AS c-MET TYROSINE KINASE INHIBITORS |
| WO2017029362A1 (en) * | 2015-08-19 | 2017-02-23 | Sandoz Ag | Asymmetric bisamidation of malonic ester derivatives |
-
2017
- 2017-12-29 CN CN201711475428.1A patent/CN109988108B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103068384A (en) * | 2010-04-29 | 2013-04-24 | 德西费拉制药有限责任公司 | Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activites |
| WO2014000713A1 (en) * | 2012-06-29 | 2014-01-03 | Zhejiang Beta Pharma Incorporation | NOVEL FUSED PYRIDINE DERIVATIVES USEFUL AS c-MET TYROSINE KINASE INHIBITORS |
| WO2017029362A1 (en) * | 2015-08-19 | 2017-02-23 | Sandoz Ag | Asymmetric bisamidation of malonic ester derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109988108A (en) | 2019-07-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108699063B (en) | Synthesis process of luccotinib | |
| CN100503601C (en) | Process of preparing troipisetron | |
| US20100267949A1 (en) | Method of Synthesizing 6,7-Substituted 4-Anilino Quinazoline | |
| CN109988108B (en) | Preparation method of cabozantinib | |
| CN109836382B (en) | Preparation method of cabozantinib malate and intermediate thereof | |
| WO2011147102A1 (en) | Synthetic method for 6,7-substituents-4-aniline quinazoline | |
| JP7038263B2 (en) | Method for Producing Morpholine Quinazoline Compound and its Intermediate | |
| CN104884427A (en) | Compounds useful in the synthesis of benzamide compounds | |
| CN103570633B (en) | The preparation method of Gefitinib | |
| CN101717359B (en) | Method for synthesizing indapamide | |
| CN111039921A (en) | Synthesis process of imatinib and imatinib mesylate | |
| CN105566215A (en) | Preparation method of Stivarga | |
| CN109988107B (en) | Preparation method of cabozantinib | |
| CN111087394A (en) | Synthetic method of 2, 9-substituted 4-halo-1, 10-phenanthroline | |
| CN102105433B (en) | 6-nitroacetophenone compound, its preparation method and use | |
| KR101728443B1 (en) | Method for Producing Benzyl Ester 2-aminonicotinicotinate Derivative | |
| CN112979544B (en) | Preparation method of cabozitinib or salt thereof | |
| CN114621109B (en) | Synthesis method of apatamide and intermediate thereof | |
| CN106916148B (en) | Method for synthesizing brexpiprazole | |
| CN117105931A (en) | Method for preparing pyridopyrimidine compounds and intermediate thereof | |
| CN109836381A (en) | The preparation method of polyceptor tyrosine kinase inhibitor and its intermediate | |
| CN105272921A (en) | Method for preparing Ceritinib and intermediate compound of Ceritinib | |
| CN108727214B (en) | A kind of synthetic method of anesthetic bupivacaine impurity | |
| KR101457453B1 (en) | Process for preparing gefitinib and an intermediate used for preparing thereof | |
| CN102123981A (en) | The preparation methods of 6-substituted amino-3-cyanoquinoline and the intermediates thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |