CN117447338A - Synthesis method of lenvatinib intermediate - Google Patents
Synthesis method of lenvatinib intermediate Download PDFInfo
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- CN117447338A CN117447338A CN202311342896.7A CN202311342896A CN117447338A CN 117447338 A CN117447338 A CN 117447338A CN 202311342896 A CN202311342896 A CN 202311342896A CN 117447338 A CN117447338 A CN 117447338A
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- 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 title claims abstract description 13
- 229960003784 lenvatinib Drugs 0.000 title claims abstract description 13
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 20
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims abstract description 12
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000006136 alcoholysis reaction Methods 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- YUPQMVSYNJQULF-UHFFFAOYSA-N methyl 4-amino-2-methoxybenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1OC YUPQMVSYNJQULF-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 150000008064 anhydrides Chemical class 0.000 claims description 8
- 150000004820 halides Chemical class 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical group FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 claims description 3
- JFKMVXDFCXFYNM-UHFFFAOYSA-N (2,2,2-tribromoacetyl) 2,2,2-tribromoacetate Chemical compound BrC(Br)(Br)C(=O)OC(=O)C(Br)(Br)Br JFKMVXDFCXFYNM-UHFFFAOYSA-N 0.000 claims description 2
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical compound ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 claims description 2
- RDBMNMVDVKRYKW-UHFFFAOYSA-N 2,2,2-tribromoacetyl chloride Chemical compound ClC(=O)C(Br)(Br)Br RDBMNMVDVKRYKW-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical group FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 abstract 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N methyl phenyl ether Natural products COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 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 description 2
- CAJCPYDCXVZYBI-UHFFFAOYSA-N tert-butyl n-(3-methoxyphenyl)carbamate Chemical compound COC1=CC=CC(NC(=O)OC(C)(C)C)=C1 CAJCPYDCXVZYBI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- -1 3-methoxy-4- (trichloroacetyl) phenyl Chemical group 0.000 description 1
- UKWUOTZGXIZAJC-UHFFFAOYSA-N 4-nitrosalicylic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1O UKWUOTZGXIZAJC-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229940123424 Neuraminidase inhibitor Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229940101545 mi-acid Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
- C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of a lenvatinib intermediate, which relates to the technical field of drug synthesis, and the invention prepares 2-methoxy-4-methyl aminobenzoate by taking meta-amino anisole as an initial raw material through amino protection reaction, friedel-crafts acylation reaction, amino deprotection reaction and alcoholysis reaction, wherein the total yield reaches more than 70%, the raw materials are cheap and easy to obtain, the reaction conditions are mild, the used organic solvent can be recycled, the environment is friendly, and the industrial mass production is easy, so that the application of the 2-methoxy-4-methyl aminobenzoate as the lenvatinib intermediate is better promoted.
Description
Technical field:
the invention relates to the technical field of drug synthesis, in particular to a synthesis method of a lenvatinib intermediate.
The background technology is as follows:
lenvatinib (CAS: 857890-39-2) is an oral multi-target neuraminidase inhibitor developed by Japanese health and well-established company. The lenvatinib has excellent effect on treating liver cancer induced by hepatitis B, is more suitable for Chinese liver cancer patients, and provides a new therapeutic drug for Chinese advanced liver cancer patients.
J.Med. Chem.2008,51,6,1649-1667 reports the synthesis of lenvatinib by condensation with Mi's acid, addition, up to Wen Huange, etc. starting from methyl 2-methoxy-4-aminobenzoate (compound 2, CAS: 27492-84-8), the synthetic route being as follows:
among them, methyl 2-methoxy-4-aminobenzoate is an important intermediate of lenvatinib. The prior art reports that the 2-methoxy-4-aminobenzoic acid methyl ester is prepared by taking 2-hydroxy-4-nitrobenzoic acid as a raw material through methylation and esterification reaction and reduction reaction, and the synthetic route is as follows:
however, the initial raw materials of the synthetic route are expensive, the dimethyl sulfate as the reaction reagent in the first step is a highly toxic methylation reagent, and the hydrogenation reduction reaction in the second step has a large potential safety hazard, so that the method is not suitable for large-scale industrial production.
The invention comprises the following steps:
the invention aims to solve the technical problem of providing a synthesis method of a lenvatinib intermediate, which has the advantages of easily available raw materials, low cost, high economic value and strong practicability, and avoids the potential safety hazard problem of hydrogenation reduction.
The technical problems to be solved by the invention are realized by adopting the following technical scheme:
the invention aims to provide a synthesis method of a lenvatinib intermediate, which takes meta-aminoanisole as an initial raw material, wherein the meta-aminoanisole and Boc anhydride undergo an amino protection reaction to obtain a compound of a formula I, the compound of the formula I and trihaloacetyl halide or trihaloacetic anhydride undergo a Friedel-crafts acylation reaction to obtain a compound of a formula II, and the compound of the formula II undergoes an amino deprotection reaction and then undergoes an alcoholysis reaction with sodium methoxide to obtain 2-methoxy-4-methyl aminobenzoate.
The synthetic route is as follows:
in the formula II, X is F, cl and Br.
Preferably, the molar use ratio of the meta-aminoanisole to the Boc anhydride is 1 (1-2).
Preferably, the temperature of the amino protection reaction is 20-80 ℃ and the time is 2-12 h.
Preferably, the solvent for the amino protection reaction is at least one of methanol, ethanol, tertiary butanol, dichloromethane, ethyl acetate, tetrahydrofuran and dioxane.
Preferably, the friedel-crafts acylation reaction is carried out in the presence of a lewis acid; the Lewis acid is at least one of aluminum chloride, zinc chloride, ferric trichloride, titanium chloride and boron trifluoride.
Preferably, the solvent of the friedel-crafts acylation reaction is at least one of dichloromethane, tetrahydrofuran, dioxane, N-dimethylformamide and dimethyl sulfoxide.
Preferably, the trihaloacetyl halide is trifluoroacetyl chloride, trichloroacetyl chloride or tribromoacetyl chloride.
Preferably, the trihaloacetic anhydride is trifluoroacetic anhydride, trichloroacetic anhydride or tribromoacetic anhydride.
Preferably, the molar ratio of the compound of formula I to the trihaloacetyl halide or trihaloacetic anhydride is 1 (1-1.5).
Preferably, the temperature of the Friedel-crafts acylation reaction is 20-100 ℃ and the time is 6-14 h.
Preferably, the amino deprotection reaction is carried out in the presence of an acid which is at least one of hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid.
Preferably, the solvent for the amino deprotection reaction and the alcoholysis reaction is at least one of methanol, ethanol, isopropanol, ethyl acetate and dioxane.
Preferably, the temperature of the amino deprotection reaction is 10-50 ℃ and the time is 0.5-5 h.
Preferably, the alcoholysis reaction is carried out at a temperature of 30-70 ℃ for 4-12 hours.
The second purpose of the invention is to provide an intermediate for synthesizing 2-methoxy-4-aminobenzoic acid methyl ester, which has a structure shown in a formula II:
in the formula II, X is F, cl and Br.
The invention further provides a synthesis method of the intermediate, wherein m-aminoanisole is used as a starting material, amino protection reaction is carried out on the m-aminoanisole and Boc anhydride to obtain a compound of a formula I, and Friedel-crafts acylation reaction is carried out on the compound of the formula I and trihaloacetyl halide or trihaloacetic anhydride to obtain a compound of a formula II.
In the formula II, X is F, cl and Br.
The reaction conditions for the synthesis of the compounds of formula II are as above.
The beneficial effects of the invention are as follows: according to the invention, m-aminoanisole is used as a starting material, and the 2-methoxy-4-aminobenzoic acid methyl ester is prepared through an amino protection reaction, a Friedel-crafts acylation reaction, an amino deprotection reaction and an alcoholysis reaction, the total yield reaches more than 70%, the raw materials are cheap and easy to obtain, the reaction conditions are mild, the used organic solvents can be recycled, the environment is friendly, and the industrial mass production is easy, so that the application of the 2-methoxy-4-aminobenzoic acid methyl ester as a lenvatinib intermediate is better promoted.
Description of the drawings:
FIG. 1 is a nuclear magnetic resonance spectrum of methyl 2-methoxy-4-aminobenzoate prepared in example 5 of the present invention.
The specific embodiment is as follows:
the invention is further described below with reference to specific embodiments and illustrations in order to make the technical means, the creation features, the achievement of the purpose and the effect of the implementation of the invention easy to understand.
Example 1: preparation of N-BOC-3-methoxyaniline (Compound of formula I)
M-aminoanisole (123 g,1 mol) and Boc anhydride (262 g,1.2 mol) were dissolved in 1L ethanol, heated to reflux and kept at room temperature for reaction for 12h, cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was recrystallized from 500mL of n-hexane to give 212g as a white solid in 95% yield.
Example 2: preparation of N-BOC-3-methoxyaniline (Compound of formula I)
M-aminoanisole (123 g,1 mol) and Boc anhydride (262 g,1.2 mol) were dissolved in 1L tetrahydrofuran, and the mixture was stirred at 50℃for 10 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was recrystallized from 500mL of n-hexane to obtain 200.5g of a white solid with a yield of 90%.
Example 3: preparation of tert-butyl N- [ 3-methoxy-4- (trichloroacetyl) phenyl ] carbamate (Compound of formula II)
Into a reaction flask were added 1000mL of dichloromethane, the compound of formula I (111.5 g,0.5 mol) and AlCl 3 (66.8 g,0.5 mol), trichloroacetyl chloride (55.8 mL,0.5 mol) dissolved in 100mL of Dichloromethane (DCM) was slowly added dropwise at 30-40℃and the reaction was continued with stirring at constant temperature for 8h after the addition. After the reaction was completed, 100mL of ice water and 100mL of DCM were added to quench and dilute the reaction solution, and then the solution was washed 3 times with 50mL of 2M NaOH solution and 1 time with 50mL of saturated brine, and the solvent was evaporated to dryness to give 169.2g of pale yellow solid in 92% yield.
Example 4: preparation of tert-butyl N- [ 3-methoxy-4- (trifluoroacetyl) phenyl ] carbamate (Compound of formula II)
Into a reaction flask was charged 100mL of tetrahydrofuran, the compound of formula I (111.5 g,0.5 mol) and AlCl 3 (66.8 g,0.5 mol) of trifluoroacetic anhydride (83.4 mL,0.5 mol) dissolved in 100mL of tetrahydrofuran was slowly added dropwise at room temperature, and the reaction was warmed to reflux and stirred for 10h after the addition. After the reaction was completed, 100mL of ice water and 600mL of DCM were added to quench and dilute the reaction solution, and then the solution was washed 3 times with 100mL of 2M NaOH solution and 1 time with 100mL of saturated brine, and the solvent was evaporated to dryness to give 141.6g of pale yellow solid in 89% yield.
Example 5: preparation of methyl 2-methoxy-4-aminobenzoate
N- [ 3-methoxy-4- (trichloroacetyl) phenyl group]Tert-butyl carbamate (36.9 g,0.1 moL) was added to a 4moL/L solution of hydrochloric acid in methanol (100 mL) and stirred at 30℃for 3h, during which time a white solid was produced, indicating complete reaction when the amount of solid did not increase. Evaporating the solvent, adding 30wt% sodium methoxide methanol solution (100 mL), heating to 50 ℃, preserving heat and stirring for 12h, spot-plate confirming that the reaction is complete, adding 100mL of water after evaporating the methanol, pulping for 2h at room temperature, filtering, and drying to obtain 16.8g of light yellow solid with the yield of 93%. 1 H NMR(400MHz,CDCl 3 )7.72(d,1H),6.26-6.15(m,2H),4.17(s,2H),3.92-3.62(m,6H).MS(ESI,m/z)found 182.2([M+H] + ).
Example 6: preparation of methyl 2-methoxy-4-aminobenzoate
Tert-butyl N- [ 3-methoxy-4- (trifluoroacetyl) phenyl ] carbamate (31.9 g,0.1 moL) was added to a solution of 4moL/L hydrochloric acid in methanol (100 mL) and stirred at 30℃for 3h with a warm-up period, during which white solids were produced, indicating completion of the reaction when the amount of solids did not increase. After evaporating the solvent, adding 30wt% sodium methoxide methanol solution (100 mL), heating to reflux reaction, maintaining the temperature and stirring for 8h, then spot-plating to confirm that the reaction is complete, evaporating the methanol, adding 100mL of water, pulping at room temperature for 2h, filtering, and drying to obtain 17.2g of pale yellow solid with the yield of 95%.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. A synthesis method of a lenvatinib intermediate is characterized by comprising the following steps of: taking meta-aminoanisole as an initial raw material, performing amino protection reaction on the meta-aminoanisole and Boc anhydride to obtain a compound shown in a formula I, performing Friedel-crafts acylation reaction on the compound shown in the formula I and trihaloacetyl halide or trihaloacetic anhydride to obtain a compound shown in a formula II, performing amino deprotection reaction on the compound shown in the formula II, and performing alcoholysis reaction on the compound shown in the formula II and sodium methoxide to obtain 2-methoxy-4-aminobenzoic acid methyl ester;
the synthetic route is as follows:
in the formula II, X is F, cl and Br.
2. An intermediate for synthesizing methyl 2-methoxy-4-aminobenzoate, which is characterized by having a structure shown in a formula II:
in the formula II, X is F, cl and Br.
3. The method for synthesizing an intermediate according to claim 2, characterized in that: taking meta-aminoanisole as an initial raw material, performing amino protection reaction on the meta-aminoanisole and Boc anhydride to obtain a compound of a formula I, and performing Friedel-crafts acylation reaction on the compound of the formula I and trihaloacetyl halide or trihaloacetic anhydride to obtain a compound of a formula II;
in the formula II, X is F, cl and Br.
4. A synthetic method according to claim 1 or 3, characterized in that: the molar use ratio of the meta-aminoanisole to the Boc anhydride is 1 (1-2);
preferably, the temperature of the amino protection reaction is 20-80 ℃ and the time is 2-12 h;
preferably, the solvent for the amino protection reaction is at least one of methanol, ethanol, tertiary butanol, dichloromethane, ethyl acetate, tetrahydrofuran and dioxane.
5. A synthetic method according to claim 1 or 3, characterized in that: the friedel-crafts acylation reaction is carried out in the presence of a lewis acid; the Lewis acid is at least one of aluminum chloride, zinc chloride, ferric trichloride, titanium chloride and boron trifluoride;
preferably, the solvent of the friedel-crafts acylation reaction is at least one of dichloromethane, tetrahydrofuran, dioxane, N-dimethylformamide and dimethyl sulfoxide.
6. A synthetic method according to claim 1 or 3, characterized in that: the trihaloacetyl halide is trifluoro acetyl chloride, trichloroacetyl chloride or tribromoacetyl chloride;
preferably, the trihaloacetic anhydride is trifluoroacetic anhydride, trichloroacetic anhydride or tribromoacetic anhydride.
7. A synthetic method according to claim 1 or 3, characterized in that: the molar use ratio of the compound of the formula I to the trihaloacetyl halide or the trihaloacetic anhydride is 1 (1-1.5);
preferably, the temperature of the Friedel-crafts acylation reaction is 20-100 ℃ and the time is 6-14 h.
8. A synthetic method according to claim 1 or 3, characterized in that: the amino deprotection reaction is carried out in the presence of acid, wherein the acid is at least one of hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid;
preferably, the temperature of the amino deprotection reaction is 10-50 ℃ and the time is 0.5-5 h.
9. A synthetic method according to claim 1 or 3, characterized in that: the solvent for the amino deprotection reaction and the alcoholysis reaction is at least one of methanol, ethanol, isopropanol, ethyl acetate and dioxane.
10. A synthetic method according to claim 1 or 3, characterized in that: the alcoholysis reaction temperature is 30-70 ℃ and the time is 4-12 h.
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