CN111320580A - Preparation method of Lunvatinib intermediate - Google Patents
Preparation method of Lunvatinib intermediate Download PDFInfo
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- CN111320580A CN111320580A CN201811536337.9A CN201811536337A CN111320580A CN 111320580 A CN111320580 A CN 111320580A CN 201811536337 A CN201811536337 A CN 201811536337A CN 111320580 A CN111320580 A CN 111320580A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000002425 crystallisation Methods 0.000 claims abstract description 10
- 230000008025 crystallization Effects 0.000 claims abstract description 10
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 238000007098 aminolysis reaction Methods 0.000 claims description 13
- 238000005917 acylation reaction Methods 0.000 claims description 12
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 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 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000011084 recovery Methods 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 2
- OFQLBCBNNWFEPV-UHFFFAOYSA-N 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC1=CC=C(N)C(Cl)=C1 OFQLBCBNNWFEPV-UHFFFAOYSA-N 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 12
- 238000012544 monitoring process Methods 0.000 description 9
- 238000005070 sampling Methods 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- UWXSAYUXVSFDBQ-CYBMUJFWSA-N 4-n-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-6-n-[(4r)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]quinazoline-4,6-diamine Chemical compound C[C@@H]1COC(NC=2C=C3C(NC=4C=C(Cl)C(OCC=5SC=CN=5)=CC=4)=NC=NC3=CC=2)=N1 UWXSAYUXVSFDBQ-CYBMUJFWSA-N 0.000 description 5
- 229950006605 varlitinib Drugs 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- PNLPXABQLXSICH-UHFFFAOYSA-N 4-amino-3-chlorophenol Chemical compound NC1=CC=C(O)C=C1Cl PNLPXABQLXSICH-UHFFFAOYSA-N 0.000 description 1
- ZBTVNIDMGKZSGC-UHFFFAOYSA-N 4-chloro-7-methoxyquinoline-6-carboxamide Chemical compound C1=CC(Cl)=C2C=C(C(N)=O)C(OC)=CC2=N1 ZBTVNIDMGKZSGC-UHFFFAOYSA-N 0.000 description 1
- 240000006570 Euonymus japonicus Species 0.000 description 1
- 235000016796 Euonymus japonicus Nutrition 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 208000015799 differentiated thyroid carcinoma Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 229960003784 lenvatinib Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of a Ranuncutinib intermediate, which comprises the steps of carrying out nucleophilic substitution reaction on a compound shown in a formula I and a compound shown in a formula II with strong base, and adding water into reaction liquid for crystallization after the reaction is finished to obtain a compound shown in a formula III, namely the Ranuncutinib intermediate. The method provided by the invention has the advantages of convenient operation, mild conditions, convenient waste liquid recovery, low production cost, safety, environmental protection, high purity and high yield, reduces the requirements on equipment, and is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a varenib intermediate.
Background
Lunvatinib (Lenvatinib), chemical name: 4- (3-chloro-4- (3-cyclopropylureido) phenoxy) -7-methoxyquinoline-6-carboxamide, which has the following structural formula:
the varlitinib mesylate is originally developed by Euonymus japonicus and is an oral multi-Receptor Tyrosine Kinase (RTK) inhibitor, and the dosage form of the varlitinib mesylate is a capsule. FDA approval was first marketed in the united states at 2 months in 2015, japanese approval was marketed at 3 months in 2015, and european union approval was marketed at 6 months in 2015 for the treatment of refractory differentiated thyroid cancer. The name of the medicine commodity
Specifications of 4mg and 10mg (in terms of Ranatinib) are currently marketed in China.
The currently reported preparation method of the Lunvatinib is complex in operation, high in production cost, inconvenient in waste liquid recovery and low in yield.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provides a preparation method of a Ranuncutinib intermediate, which has the advantages of convenient operation, low production cost, convenient waste liquid recovery, high yield, safety and environmental protection, and is suitable for industrial production.
The purpose of the invention can be realized by the following technical scheme:
a preparation method of a Ranuncutinib intermediate comprises the steps of carrying out nucleophilic substitution reaction on a compound (4-chloro-7-methoxyquinoline-6-amide) in a formula I and a compound (4-amino-3-chlorophenol) in a formula II with strong base, adding water into a reaction liquid after the reaction is finished for crystallization to obtain a compound (4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-formamide) in a formula III, namely the Ranuncutinib intermediate,
wherein the crystallization temperature is 20-30 ℃, and the proportion of the compound shown in the formula I and water is 1kg: 5-8L, preferably 1kg: 5-7L, and more preferably 1kg: 6L.
The strong base is solid and is one or more of sodium hydroxide, potassium hydroxide and potassium tert-butoxide, and the molar amount of the strong base is 1.1-1.5 times, preferably 1.2-1.3 times that of the compound in the formula I.
Wherein the molar amount of the compound of the formula II is 1.1-1.5 times, preferably 1.3-1.5 times of that of the compound of the formula I.
Wherein the reaction solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide and N, N-dimethylacetamide; the reaction temperature is 50-110 ℃, preferably 50-80 ℃, and further preferably 60-80 ℃; the reaction time is 1-10 h, preferably 2-5 h.
Preferably, the preparation method of the varlitinib intermediate comprises the following steps: adding a compound shown in the formula I, a compound shown in the formula II and a strong base into a reaction solvent, heating to 60-80 ℃ under an inert atmosphere, after the reaction is finished, adding water into a reaction solution, cooling to 20-30 ℃ and crystallizing to obtain a compound shown in the formula III.
The inert atmosphere is preferably a nitrogen atmosphere.
The preparation method of the varlitinib intermediate further comprises the following steps:
the compound of the formula III, phenyl chloroformate and an acid-binding agent are subjected to acylation reaction to obtain a compound of a formula IV, the compound of the formula IV is directly subjected to aminolysis reaction with cyclopropylamine without separation to obtain a compound of a formula V, namely, the Rivatinib,
the reaction solvent of the acylation reaction is one or more of N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, and the reaction temperature of the acylation reaction is-20 ℃, preferably-20-0 ℃; the reaction temperature of the aminolysis reaction is-10-40 ℃, and preferably 0-20 ℃.
In the acylation reaction, the water content of the compound shown in the formula III is 4.5-7.5 wt%, preferably 5-6 wt%; the molar amount of the phenyl chloroformate is 2 to 5 times, preferably 2 to 3 times, and more preferably 2.3 to 2.5 times that of the compound of formula III.
In the acylation reaction, the acid-binding agent is one or more of triethylamine, N-diisopropylethylamine, pyridine, potassium carbonate and ammonia water, and the molar amount of the acid-binding agent is 2-5 times, preferably 2.5-3.5 times of that of the compound shown in the formula III.
In the aminolysis reaction, the molar amount of cyclopropylamine is 4-6 times, preferably 5-6 times that of the compound shown in the formula III; and after the aminolysis reaction is finished, adding one or more of water, acetone and isopropanol into the reaction solution for crystallization to obtain the compound shown in the formula V.
Preferably, the preparation method of the varlitinib intermediate further comprises the steps of: adding the compound shown in the formula III and an acid-binding agent into a reaction solvent, cooling to-20-0 ℃ in an inert atmosphere, adding phenyl chloroformate, adding cyclopropylamine after the reaction is finished, and heating to 0-20 ℃ for reaction to obtain the compound shown in the formula V.
Has the advantages that: the method provided by the invention has the advantages of convenient operation, mild conditions, convenient waste liquid recovery, low production cost, safety, environmental protection, high purity and high yield, reduces the requirements on equipment, and is suitable for large-scale industrial production.
Detailed Description
The present invention will now be described in detail with reference to examples, which should not be construed as limiting the scope of the invention.
Example 1:
first step, preparation of 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide (III):
adding a compound (400g) of a formula I, a compound (315.5g) of a formula II and potassium hydroxide (123.4g) into DMSO (2400ml), replacing with nitrogen, heating to 75-80 ℃, reacting for 2 hours, sampling and monitoring, adding water (2400ml) after the reaction is finished, cooling to 20-25 ℃, filtering, and drying in vacuum at 45 ℃ to obtain a compound 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-formamide of a formula III, wherein the dry weight is as follows: 586.2g, yield 96.7% (anhydrous basis), water content 5.2%, HPLC purity: 99.49 percent.
Second step, preparation of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (V):
adding 150g of the compound of the formula III prepared in the first step and 172.8g of pyridine into 1500ml of N, N-dimethylformamide, replacing with nitrogen, cooling to-5-0 ℃, dropwise adding phenyl chloroformate (148.04g), reacting for 30min, sampling and monitoring, after the reaction is finished, dropwise adding cyclopropylamine (97.2g), after the dropwise adding is finished, heating to 0-5 ℃, reacting for 3 hours, sampling and monitoring, after the reaction is finished, adding acetone (3000ml) and water (450ml), crystallizing, filtering, and pulping a filter cake with acetone to obtain the compound of the formula V, namely 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide, wherein the dry weight is: 150.6g, yield: 80.8%, HPLC purity: 99.54 percent.
Example 2:
first step, preparation of 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide (III):
adding a compound (3.0kg) of a formula I and a compound (2.37kg) of a formula II into DMSO (18L), replacing with nitrogen, heating to 65-70 ℃, reacting for 2 hours, sampling and monitoring, adding water (18L) after the reaction is finished, cooling to 20-25 ℃, filtering, and drying in vacuum at 45 ℃ to obtain a compound 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-formamide of a formula III, wherein the dry weight of the compound is as follows: 4.53kg, yield 98.8% (anhydrous basis), water content 5.1%, HPLC purity: 99.81 percent.
Second step, preparation of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (V):
adding the compound (3.30kg) of the formula III prepared in the first step and pyridine (1.91kg) into a reaction solution of N, N-dimethylformamide (33.2L), replacing nitrogen, cooling to-10-5 ℃, dropwise adding phenyl chloroformate (3.78kg), reacting for 30min, sampling and monitoring, after the reaction is finished, dropwise adding cyclopropylamine (2.76kg), heating to 5-10 ℃ after the dropwise adding is finished, reacting for 3 hours, sampling and monitoring, adding acetone (49.8L) and water (16.6L) for crystallization after the reaction is finished (the peak area ratio of the compound of formula IV is less than 0.1% by HPLC (high performance liquid chromatography) to complete the reaction, filtering, and leaching a filter cake with acetone (15L) to obtain the compound of formula V, namely 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide, wherein the dry weight is as follows: 3.50kg, yield: 85.4%, HPLC purity: 98.94 percent.
Example 3
First step, preparation of 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide (III):
adding a compound (3.0kg) of a formula I and a compound (2.37kg) of a formula II into DMSO (18L), replacing with nitrogen, heating to 60-65 ℃, reacting for 2 hours, sampling and monitoring, adding water (18L) after the reaction is finished, cooling to 23-28 ℃, filtering, and drying in vacuum at 45 ℃ to obtain a compound 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-formamide of a formula III, wherein the dry weight of the compound is as follows: 4.47kg, yield 97.1% (anhydrous basis), water content 5.1%, HPLC purity: 99.50 percent.
Second step, preparation of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (V):
adding 3.30kg of the compound of the formula III prepared in the first step and 1.91kg of pyridine into a reaction solution of N, N-dimethylformamide (33.3L), replacing with nitrogen, cooling to-8-3 ℃, dropwise adding phenyl chloroformate (3.48kg), carrying out sampling monitoring after reaction for 30min, dropwise adding cyclopropylamine (2.77kg) after the reaction is finished, heating to 3-8 ℃ after the dropwise adding is finished, carrying out sampling monitoring after the reaction is finished for 3 h, adding 49.5L of acetone and 16.5L of water for crystallization after the reaction is finished, filtering, and pulping a filter cake with acetone (33L) to obtain the compound of the formula V, namely 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide, wherein the dry weight is: 3.47kg, yield: 84.7%, HPLC purity: 99.58 percent.
Example 4
As in example 1, the only difference is:
first step, preparation of 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide (III):
the strong base is sodium hydroxide solid, and the molar amount of the strong base is 1.1 times that of the compound in the formula I. The molar amount of the compound of formula II is 1.1 times that of the compound of formula I. The reaction solvent is N, N-dimethylformamide; the reaction temperature is 50-55 ℃. To obtain the compound 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-formamide of the formula III.
Second step, preparation of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (V):
the reaction solvent is N-methyl pyrrolidone. In the acylation reaction, the reaction temperature is-20 to-15 ℃, and the molar amount of the phenyl chloroformate is 2 times of that of the compound in the formula III. The acid-binding agent is triethylamine, and the molar amount of the acid-binding agent is 2 times of that of the compound in the formula III. In the aminolysis reaction, the molar amount of the cyclopropylamine is 4 times that of the compound in the formula III; the reaction temperature of the aminolysis reaction is-10 to-5 ℃. And after the aminolysis reaction is finished, adding water and isopropanol into the reaction solution for crystallization to obtain the compound 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide shown in the formula V.
Example 5
As in example 1, the only difference is:
first step, preparation of 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide (III):
the strong base is potassium tert-butoxide solid, and the molar amount of the strong base is 1.5 times that of the compound in the formula I. The molar amount of the compound of the formula II is 1.5 times of that of the compound of the formula I. The reaction solvent is N, N-dimethylacetamide; the reaction temperature is 105-110 ℃. To obtain the compound 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-formamide of the formula III.
Second step, preparation of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (V):
the reaction solvent is dimethyl sulfoxide. In the acylation reaction, the reaction temperature is 15-20 ℃, and the molar amount of phenyl chloroformate is 5 times of that of the compound shown in the formula III. The acid-binding agent is ammonia water, and the molar amount of the acid-binding agent is 5 times of that of the compound shown in the formula III. In the aminolysis reaction, the molar amount of the cyclopropylamine is 6 times that of the compound in the formula III; the reaction temperature of the aminolysis reaction is 35-40 ℃. To obtain the compound 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide of the formula V.
Claims (10)
1. A preparation method of an intermediate of formula III of Ranuncutinib is characterized in that a compound of formula I and a compound of formula II are subjected to nucleophilic substitution reaction with strong base, water is added into a reaction solution after the reaction is finished for crystallization to obtain a compound of formula III,
2. the process according to claim 1, wherein the crystallization temperature is 10 to 40 ℃, preferably 20 to 30 ℃, and the ratio of the compound of formula I to water is 1kg: 5-8L, preferably 1kg: 5-7L, more preferably 1kg: 6L.
3. The method according to claim 1, wherein the strong base is a solid, preferably one or more of sodium hydroxide, potassium hydroxide and potassium tert-butoxide, and the molar amount of the strong base is 1.1 to 1.5 times, preferably 1.2 to 1.3 times that of the compound of formula I.
4. The method according to claim 1, wherein the compound of formula II is used in a molar amount of 1.1-1.5 times, preferably 1.3-1.5 times, that of the compound of formula I.
5. The method of claim 1, wherein the nucleophilic substitution reaction solvent is one or more of N, N-dimethylformamide, dimethylsulfoxide, N-dimethylacetamide; the reaction temperature is 50-110 ℃, preferably 50-80 ℃, and further preferably 60-80 ℃; the reaction time is 1-10 h, preferably 2-5 h.
6. The method of claim 1, further comprising the steps of:
the compound of the formula III, phenyl chloroformate and an acid-binding agent are subjected to acylation reaction to obtain a compound of a formula IV, the compound of the formula IV is directly subjected to aminolysis reaction with cyclopropylamine without separation to obtain the Ranvatinib shown in the compound of the formula V,
7. the method according to claim 6, wherein the reaction solvent of the acylation reaction is one or more of N-methyl pyrrolidone, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, and the reaction temperature of the acylation reaction is-20 ℃, preferably-20-0 ℃; the reaction temperature of the aminolysis reaction is-10-40 ℃, and preferably 0-20 ℃.
8. The method according to claim 6, wherein the water content in the compound of formula III in the acylation reaction is 4.5-7.5 wt%, preferably 5-6 wt%; the molar amount of the phenyl chloroformate is 2 to 5 times, preferably 2 to 3 times, and more preferably 2.3 to 2.5 times that of the compound of formula III.
9. The method according to claim 6, wherein in the acylation reaction, the acid-binding agent is one or more of triethylamine, N-diisopropylethylamine, pyridine, potassium carbonate and ammonia water, and the molar amount of the acid-binding agent is 2-5 times, preferably 2.5-3.5 times that of the compound of formula III.
10. The method as claimed in claim 6, wherein the amount of cyclopropylamine used in the aminolysis reaction is 4 to 6 times, preferably 5 to 6 times, the molar amount of cyclopropylamine used in the compound of formula III; and after the aminolysis reaction is finished, adding one or more of water, acetone and isopropanol into the reaction solution for crystallization to obtain the compound shown in the formula V.
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| CN113372270A (en) * | 2021-06-24 | 2021-09-10 | 江西国药有限责任公司 | Lunvatinib and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106660964A (en) * | 2014-08-28 | 2017-05-10 | 卫材R&D管理有限公司 | High-purity quinoline derivative and method for manufacturing same |
| CN107739335A (en) * | 2017-12-01 | 2018-02-27 | 南京奇可药业有限公司 | A kind of pleasure cuts down the synthetic method for Buddhist nun |
| CN108299294A (en) * | 2017-01-11 | 2018-07-20 | 江苏恒瑞医药股份有限公司 | A kind of pleasure is cut down for the preparation method of Buddhist nun's impurity |
| WO2018145621A1 (en) * | 2017-02-07 | 2018-08-16 | 恩瑞生物医药科技（上海）有限公司 | Quinoline compound, preparation method and medical use therefor |
| CN108623521A (en) * | 2018-03-22 | 2018-10-09 | 盐城师范学院 | A kind of pleasure cuts down the preparation method for Buddhist nun |
| CN108658859A (en) * | 2017-03-30 | 2018-10-16 | 中国科学院成都有机化学有限公司 | A kind of pleasure cuts down the synthetic method for Buddhist nun |
-
2018
- 2018-12-14 CN CN201811536337.9A patent/CN111320580B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106660964A (en) * | 2014-08-28 | 2017-05-10 | 卫材R&D管理有限公司 | High-purity quinoline derivative and method for manufacturing same |
| CN108299294A (en) * | 2017-01-11 | 2018-07-20 | 江苏恒瑞医药股份有限公司 | A kind of pleasure is cut down for the preparation method of Buddhist nun's impurity |
| WO2018145621A1 (en) * | 2017-02-07 | 2018-08-16 | 恩瑞生物医药科技（上海）有限公司 | Quinoline compound, preparation method and medical use therefor |
| CN108658859A (en) * | 2017-03-30 | 2018-10-16 | 中国科学院成都有机化学有限公司 | A kind of pleasure cuts down the synthetic method for Buddhist nun |
| CN107739335A (en) * | 2017-12-01 | 2018-02-27 | 南京奇可药业有限公司 | A kind of pleasure cuts down the synthetic method for Buddhist nun |
| CN108623521A (en) * | 2018-03-22 | 2018-10-09 | 盐城师范学院 | A kind of pleasure cuts down the preparation method for Buddhist nun |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113372270A (en) * | 2021-06-24 | 2021-09-10 | 江西国药有限责任公司 | Lunvatinib and preparation method thereof |
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