CN114276266A - Preparation method of 4-amino-2-fluorobenzamide - Google Patents
Preparation method of 4-amino-2-fluorobenzamide Download PDFInfo
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- CN114276266A CN114276266A CN202111654684.3A CN202111654684A CN114276266A CN 114276266 A CN114276266 A CN 114276266A CN 202111654684 A CN202111654684 A CN 202111654684A CN 114276266 A CN114276266 A CN 114276266A
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- WIKPEQHEEAWUBH-UHFFFAOYSA-N 4-amino-2-fluorobenzamide Chemical compound NC(=O)C1=CC=C(N)C=C1F WIKPEQHEEAWUBH-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 69
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 48
- 238000006467 substitution reaction Methods 0.000 claims abstract description 46
- 230000007062 hydrolysis Effects 0.000 claims abstract description 44
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 43
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 31
- FDUGOYTWYJZNNP-UHFFFAOYSA-N 4-amino-2-fluorobenzonitrile Chemical compound NC1=CC=C(C#N)C(F)=C1 FDUGOYTWYJZNNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 20
- LJFDXXUKKMEQKE-UHFFFAOYSA-N 2,4-difluorobenzonitrile Chemical compound FC1=CC=C(C#N)C(F)=C1 LJFDXXUKKMEQKE-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 4
- 239000011737 fluorine Substances 0.000 claims abstract description 4
- 150000003949 imides Chemical class 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 230000003301 hydrolyzing effect Effects 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical group OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 229960002317 succinimide Drugs 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- DEGPIRUPAKWDBU-UHFFFAOYSA-N isoindole-1,3-dione;sodium Chemical compound [Na].C1=CC=C2C(=O)NC(=O)C2=C1 DEGPIRUPAKWDBU-UHFFFAOYSA-N 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- BYXYCUABYHCYLY-UHFFFAOYSA-N isoindole-1,3-dione;potassium Chemical group [K].C1=CC=C2C(=O)NC(=O)C2=C1 BYXYCUABYHCYLY-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000000643 oven drying Methods 0.000 claims 1
- 238000003756 stirring Methods 0.000 description 16
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 13
- 239000012043 crude product Substances 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 239000011521 glass Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical group [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 5
- 208000007536 Thrombosis Diseases 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- WUPVYJJCKYSGCR-UHFFFAOYSA-M sodium;3-oxoisoindol-1-olate Chemical compound [Na+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 WUPVYJJCKYSGCR-UHFFFAOYSA-M 0.000 description 2
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 108010080805 Factor XIa Proteins 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of organic chemistry, in particular to a preparation method of 4-amino-2-fluorobenzamide, which comprises the following steps: mixing 2, 4-difluorobenzonitrile with a substitution reagent to perform substitution reaction so as to substitute fluorine at the 4-position with imide; under the action of a deprotection hydrolysis reagent, carrying out deprotection hydrolysis on a product obtained by the substitution reaction to obtain 4-amino-2-fluorobenzonitrile; mixing the 4-amino-2-fluorobenzonitrile with a cyano hydrolysis reagent to perform a cyano hydrolysis reaction to obtain the 4-amino-2-fluorobenzamide. Compared with the existing method, the preparation method of the 4-amino-2-fluorobenzamide has the advantages of high safety, simple production process, short period, low cost and less three wastes.
Description
Technical Field
The invention relates to the field of organic chemistry, in particular to a preparation method of 4-amino-2-fluorobenzamide.
Background
Thrombotic diseases seriously affect the quality of life of human beings, and the incidence rate of the thrombotic diseases tends to rise year by year. At present, drugs clinically used for treating thrombotic diseases are mainly anticoagulant drugs, and although the antithrombotic effect is good, the drugs are often accompanied with bleeding risks. In recent years, the research shows that the factor xia (fxia) inhibitor can reduce the incidence rate of venous thrombosis without obviously influencing bleeding, and thus has important potential value in the aspect of treating thrombotic diseases. Therefore, the FXIa inhibitor can be used as a novel antithrombotic drug. 4-amino-2-fluorobenzamide is an important intermediate for the novel FXIa inhibitors 4- { [ (2S) -2- {4- [ 5-chloro-2- (4-chloro-1H-1, 2-triazol-1-phenyl ] -5-methoxy-2-oxopyridin-1 (2H) -yl } butanoyl ] amino } -2-fluorobenzoyl (formula III) and 4- ({ (2S) -2- [4- { 5-chloro-2- [4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl ] -5-methoxy-2-oxopyridin-1 (2H) -yl ] butanoyl ] amino) -2-fluorobenzamide (formula IV).
The existing preparation method of 4-amino-2-fluorobenzamide takes para-fluoroaniline as a starting raw material and is prepared by ten steps of reactions such as amidation, nitration, deprotection, diazotization and the like, a nitration diazotization bromination reaction is required in the reaction process, the reaction risk is high, the total yield is very low, the production process is very complicated, the cost is high, the production period is long, and three wastes are more.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, it is an object of the present invention to provide a method for preparing 4-amino-2-fluorobenzamide, which solves the problems of the prior art.
In order to achieve the above objects and other related objects, the present invention provides a method for preparing 4-amino-2-fluorobenzamide, comprising the steps of:
1) and (3) substitution reaction: mixing 2, 4-difluorobenzonitrile with a substitution reagent to perform substitution reaction so as to substitute fluorine at the 4-position with imide;
2) hydrolysis deprotection reaction: under the action of a deprotection hydrolysis reagent, carrying out deprotection hydrolysis on a product obtained by the substitution reaction to obtain 4-amino-2-fluorobenzonitrile;
3) and (3) cyano hydrolysis reaction: mixing the 4-amino-2-fluorobenzonitrile with a cyano hydrolysis reagent to perform a cyano hydrolysis reaction to obtain the 4-amino-2-fluorobenzamide.
The substitution reagent is phthalimide potassium salt, phthalimide sodium salt, phthalimide, succinimide or maleimide.
In the hydrolysis deprotection reaction, the deprotection hydrolysis reagent is selected from hydrazine hydrate, HCl and H2SO4、HBr。
In the cyano hydrolysis reaction, the cyano hydrolysis reagent is selected from hydrogen peroxide or hydrochloric acid.
As described above, the method for preparing 4-amino-2-fluorobenzamide according to the present invention has the following advantageous effects: compared with the prior method, the method has the advantages of high safety, simple production process, short period, low cost and less three wastes.
Detailed Description
The invention provides a preparation method of 4-amino-2-fluorobenzamide, which comprises the following steps:
1) and (3) substitution reaction: reacting 2, 4-difluorobenzonitrile with a substitution reagent to substitute the fluorine at the 4-position with an imide;
2) hydrolysis deprotection reaction: under the action of a deprotection hydrolysis reagent, carrying out deprotection hydrolysis on a product obtained by a substitution reaction to obtain 4-amino-2-fluorobenzonitrile shown in the formula I
3) And (3) cyano hydrolysis reaction: reacting 4-amino-2-fluorobenzonitrile with a cyano hydrolysis reagent to obtain 4-amino-2-fluorobenzamide (formula II)
The substitution reagent is selected from phthalimide potassium salt, phthalimide sodium salt, phthalimide, succinimide or maleimide. Preferably, the substitution reagent is selected from the group consisting of potassium phthalimide, sodium phthalimide, phthalimide. Further preferably, the substitution reagent is selected from the group consisting of potassium phthalimide salt and sodium phthalimide salt.
In one embodiment, the substitution reaction shown in step 1) is reacted in the presence of a catalyst.
In one embodiment, the catalyst is a basic catalyst.
In certain embodiments of the invention, the catalyst is selected from K2CO3、Na2CO3、Cs2CO3Any one or more of NaOMe, NaOtBu, NaH.
Preferably, the catalyst is selected from K2CO3、Na2CO3、Cs2CO3Any one or more of.
In certain embodiments of the invention, the substitution reaction is carried out in a solvent. One skilled in the art can select the proper solvent type and amount to sufficiently disperse the reactants in the reaction system. The solvent may be an organic solvent. More specifically, the solvent may be selected from any one or more of DMSO, DMF, DMAC, toluene, NMP, or pyridine.
The reaction temperature of the substitution reaction is 90-160 ℃. In certain embodiments of the invention, the reaction temperature is 110-150 ℃. Preferably, the reaction temperature is 120-140 ℃.
The amount of the substitution reagent in the substitution reaction is usually an equivalent amount or an excess amount in terms of molar amount with respect to 2, 4-difluorobenzonitrile. In certain embodiments of the invention, the molar ratio of the substitution reagent to 2, 4-difluorobenzonitrile is from 0.9 to 2: 1. In a preferred embodiment, the molar ratio of the substitution reagent to the 2, 4-difluorobenzonitrile is 1.0 to 1.5: 1. In a more preferred embodiment, the molar ratio of the substitution reagent to 2, 4-difluorobenzonitrile is from 1.0 to 1.2: 1.
In certain embodiments of the invention, the hydrolytic deprotection reaction is carried out in a solvent. One skilled in the art can select the proper solvent type and amount to sufficiently disperse the reactants in the reaction system. The solvent may be an organic solvent. The solvent is selected from polar solvents. In particular, the solvent may be selected from solvents having a relatively high polarity. More specifically, the solvent is selected from one or a combination of more of ethanol, methanol, n-propanol, isopropanol, n-butanol and isoamyl alcohol; the preferable solvent is one or the combination of more of methanol, ethanol and isopropanol.
The reaction temperature of the hydrolysis deprotection reaction is 0-60 ℃. In certain embodiments of the invention, the reaction temperature of the hydrolytic deprotection reaction is 10-40 ℃. Preferably, the reaction temperature is 20-35 ℃.
In the hydrolytic deprotection reaction, the amount of deprotected hydrolytic reagent is usually equal to or in excess in terms of molar amount with respect to the product obtained by the substitution reaction. In certain embodiments of the invention, the molar ratio of deprotected hydrolysis reagent to substitution reaction-derived product is 1.0 to 4: 1. In a preferred embodiment, the molar ratio of the deprotecting hydrolysis reagent to the product obtained by the substitution reaction is 1.5-3: 1. In a more preferred embodiment, the molar ratio of the deprotecting hydrolysis reagent to the product obtained by the substitution reaction is 1.5-2.5: 1.
In the hydrolysis deprotection reaction, the deprotection hydrolysis reagent is selected from hydrazine hydrate, HCl and H2SO4, HBr. In certain embodiments of the invention, the deprotecting hydrolyzing reagent is selected from hydrazine hydrate or HCl. In a preferred embodiment, the deprotecting hydrolyzing reagent is selected from hydrazine hydrate. The reaction using acids as deprotecting hydrolysis reagents is slow and the reaction using hydrazine hydrate is fast.
In certain embodiments of the present invention, the cyano hydrolyzing reagent in the cyano hydrolyzing reaction is selected from hydrogen peroxide or hydrochloric acid. The concentration of the hydrochloric acid in percentage by mass may be 25 wt% or more, 30 wt% or more, 35 wt% or more, or 37 wt% or more. The cyano group hydrolyzing reagent is usually introduced into the reaction system in a manner of batch addition (e.g., dropwise addition) to prevent a vigorous reaction from instantaneously occurring in the reaction system.
In one embodiment, the cyano hydrolysis reaction is reacted in the presence of a catalyst.
In one embodiment, the catalyst is a basic catalyst.
In certain embodiments of the invention, the catalyst is selected from K2CO3、Na2CO3、KOH、NaOH、NaOCH3Any one or more of NaOtBu.
In a preferred embodiment, the catalyst is selected from KOH, NaOH, NaOCH3Any one or more of.
In the cyano hydrolysis reaction, the molar ratio of the selected catalyst to the 4-amino-2-fluorobenzonitrile is 0.1-1.0: 1.
In some preferred embodiments of the present invention, the molar ratio of the selected catalyst to the 4-amino-2-fluorobenzonitrile in the hydrolysis of the cyano group is 0.2 to 0.8: 1.
In a more preferred embodiment, the molar ratio of the selected catalyst to the 4-amino-2-fluorobenzonitrile in the hydrolysis of the cyano group is 0.3 to 0.5: 1.
In certain embodiments of the present invention, the cyano hydrolysis reaction is carried out in the presence of a solvent. The solvent is selected from water or organic solvent or water/organic solvent mixed solvent.
Specifically, the solvent is selected from any one or more of water, methanol, ethanol, isopropanol or DCM (dichloromethane).
In one embodiment, the solvent is selected from one or a mixture of water, methanol and DCM.
The reaction temperature of the cyano hydrolysis reaction is 0-60 ℃. In certain embodiments of the invention, the reaction temperature of the hydrolytic deprotection reaction is 10-50 ℃. Preferably, the reaction temperature is 20-35 ℃.
In the hydrolysis of cyano group, the amount of the cyano group hydrolyzing reagent is usually equal to or in excess in terms of molar amount with respect to 4-amino-2-fluorobenzonitrile. In the cyano-group hydrolysis reaction, the molar ratio of a cyano-group hydrolysis reagent to 4-amino-2-fluorobenzonitrile is 1-6: 1. In certain embodiments of the invention, the molar ratio of cyanohydrolyzing reagent to 4-amino-2-fluorobenzonitrile is 2.0 to 4.0: 1. In some embodiments of the invention, in the cyano hydrolysis reaction, the molar ratio of the cyano hydrolysis reagent to the 4-amino-2-fluorobenzonitrile is 2.5-3.5: 1;
in the substitution reaction, hydrolysis deprotection reaction, and cyano hydrolysis reaction, the reaction time can be appropriately adjusted by those skilled in the art according to the progress of the reaction, and a method for detecting the progress of the reaction is known to those skilled in the art, and may be, for example, an analytical method such as chromatography. Generally, the end point of the reaction may be the substantial disappearance of the starting substrate.
In the substitution reaction, hydrolysis deprotection reaction, and cyano hydrolysis reaction, those skilled in the art can select an appropriate post-treatment method to perform post-treatment on the product obtained from each reaction. The post-treatment is, for example, distillation, filtration, drying or recrystallization.
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments, and is not intended to limit the scope of the present invention; in the description and claims of the present application, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.
Example 1
And (3) substitution reaction:
80g of potassium phthalimide and 250g of DMAC are added into a 500mL glass reaction bottle, the stirring is started, the temperature is raised to 100 ℃, 100g of DMAC is evaporated by carrying water under reduced pressure, and the aim of reducing the moisture in the raw materials and auxiliary materials and avoiding side reaction is fulfilled. Adding 50g of 2.4-difluorobenzonitrile, heating to 120 ℃, reacting for 3 hours, evaporating DMAC under reduced pressure, adding water, stirring for 1 hour at 20 ℃, performing suction filtration to obtain a wet crude product, adding methanol, pulping for one time, performing suction filtration, and drying to obtain 87g of off-white solid, wherein the GC purity is 89.35%, and the yield of the crude product is 90.9%
Hydrolysis deprotection reaction:
adding 48g of crude product and 480g of methanol into a 1000mL glass reaction bottle, starting stirring, dropwise adding 40g of 50% hydrazine hydrate at 25-30 ℃, dropwise adding for 1 hour, reacting for 5 hours, evaporating the methanol, adding water, pulping for 1 hour at 10-15 ℃, performing suction filtration to obtain a wet product, rectifying, and recrystallizing isopropanol to obtain 20.8g of 4-amino-2-fluorobenzonitrile, wherein the GC purity is 98.5%, and the yield is as follows: 94.7 percent
And (3) cyano hydrolysis reaction:
adding 20g of 4-amino-2-fluorobenzonitrile, 8g of water, 2.35g of sodium hydroxide and 40g of dichloromethane into a 250mL glass reaction bottle, starting stirring, dropwise adding 46.67g of 30% hydrogen peroxide at 35-40 ℃, dropwise adding for 3 hours, finishing the reaction for 3 hours, cooling to 5-10 ℃, stirring for 1 hour, performing suction filtration, and recrystallizing a crude product by using 3 times of water to obtain 21.7g of 4-amino-2-fluorineBenzamide, HPLC purity 99.6%, yield 96.0%
Example 2
And (3) substitution reaction:
adding 240g of potassium phthalimide and 600g of DMAC into a 2000mL glass reaction bottle, starting stirring, heating to 164 ℃ for reflux, distilling 150g of DMAC with water, cooling to 130 ℃, adding 150g of 2.4-difluorobenzonitrile, heating to 140 ℃, reacting for 3 hours, distilling DMAC under reduced pressure, adding water, stirring for 1 hour at 20 ℃, performing suction filtration to obtain a wet crude product, adding methanol, pulping for one time, performing suction filtration, and drying the wet product to obtain 263g of quasi-white solid, wherein the GC purity is 88.53%, and the crude product yield is 91.6%.
Hydrolysis deprotection reaction:
adding 263g of crude product and 2630g of methanol into a 5000mL glass reaction bottle, starting stirring, dropwise adding 123g of 80% hydrazine hydrate at 25-30 ℃, dropwise adding for 1 hour, reacting for 5 hours, performing suction filtration, rinsing a filter cake with 500g of methanol to obtain a filtrate, concentrating the filtrate to dryness, stirring and extracting with 750 g of water and 1000g of ethyl acetate, extracting a water phase with 250g of ethyl acetate once again, combining organic phases, washing with water to obtain an organic phase, rectifying, recrystallizing isopropanol to obtain 112.1g of similar white solid, 4-amino-2-fluorobenzonitrile, wherein the GC purity is 98.5%, and the yield is as follows: 94.2 percent.
And (3) cyano hydrolysis reaction:
adding 32.5g of 4-amino-2-fluorobenzonitrile, 13g of water, 3.82g of sodium hydroxide and 65g of dichloromethane into a 250mL glass reaction bottle, starting stirring, dropwise adding 72.2g of 31.5% hydrogen peroxide at 35-40 ℃, dropwise adding for 3.5 hours, finishing the reaction for 3 hours, cooling to 5-10 ℃, stirring for 1 hour, performing suction filtration, and recrystallizing a crude product by using 3 times of water to obtain 35.5g of 4-amino-2-fluorobenzamide, wherein the HPLC purity is 99.7%, and the yield is as follows: 96.5 percent.
Example 3
Adding 59g of phthalimide, 100g of potassium carbonate powder and 200g of DMAC into a 1000mL glass reaction bottle, starting stirring, heating to 110 ℃ for reflux, distilling 50g of DMAC with water under reduced pressure, adding 50g of 2, 4-difluorobenzonitrile, heating to 120 ℃, reacting for 9 hours, distilling DMAC under reduced pressure, adding 500g of water and 250g of methanol, stirring for 1 hour at 20 ℃, carrying out suction filtration and drying to obtain 84.8g of crude product, wherein the GC purity is 87.5% and the crude product yield is 88.6%.
Example 4
Adding 39g of succinimide, 100g of potassium carbonate powder and 200g of DMAC into a 1000mL glass reaction bottle, stirring, heating to 100 ℃ for reflux, carrying out reduced pressure water-carrying evaporation to remove 50g of DMAC, adding 50g of 2, 4-difluorobenzonitrile, heating to 120 ℃ for reaction for 8 hours, then keeping the reaction, removing the rest 27% of the raw material 2, 4-difluorobenzonitrile, carrying out reduced pressure evaporation to remove DMAC, adding 500g of water and 250g of methanol, stirring for 1 hour at 20 ℃, carrying out suction filtration and drying to obtain 67.7g of crude product, wherein the GC purity is 86.8%, and the yield of the crude product is 87.1%.
Comparative example 1
Adding 400g of 2, 4-difluorobenzonitrile and 800g of THF into a 2000mL autoclave, starting stirring, introducing 245g of ammonia gas, sealing, heating to 110 ℃, reacting for 10 hours, obtaining 103.8g of off-white solid by GC isomerization ratio 6:4 (target product 4), performing suction filtration, rectifying filtrate, and recrystallizing isopropanol, wherein the yield is 28.9%, and the GC purity is 98.5%.
The above examples are intended to illustrate the disclosed embodiments of the invention and are not to be construed as limiting the invention. In addition, various modifications of the invention set forth herein, as well as variations of the methods of the invention, will be apparent to persons skilled in the art without departing from the scope and spirit of the invention. While the invention has been specifically described in connection with various specific preferred embodiments thereof, it should be understood that the invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described embodiments which are obvious to those skilled in the art to which the invention pertains are intended to be covered by the scope of the present invention.
Claims (10)
1. A method for preparing 4-amino-2-fluorobenzamide, which is characterized by comprising the following steps:
1) and (3) substitution reaction: mixing 2, 4-difluorobenzonitrile with a substitution reagent to perform substitution reaction so as to substitute fluorine at the 4-position with imide;
2) hydrolysis deprotection reaction: under the action of a deprotection hydrolysis reagent, carrying out deprotection hydrolysis on a product obtained by the substitution reaction to obtain 4-amino-2-fluorobenzonitrile;
3) and (3) cyano hydrolysis reaction: mixing the 4-amino-2-fluorobenzonitrile with a cyano hydrolysis reagent to perform a cyano hydrolysis reaction to obtain the 4-amino-2-fluorobenzamide.
2. The method of claim 1, wherein the substitution reagent is a potassium phthalimide salt, a sodium phthalimide salt, a phthalimide, a succinimide, or a maleimide.
3. The method according to claim 1, wherein the substitution reaction is carried out in the presence of a catalyst; preferably, the catalyst is a basic catalyst; more preferably, the catalyst is selected from K2CO3、Na2CO3、Cs2CO3Any one or more of NaOMe, NaOtBu, NaH.
4. The method of claim 1, wherein the substitution reaction further comprises one or more of the following features:
1) the substitution reaction is carried out in a solvent; preferably, the solvent is an organic solvent;
2) the reaction temperature of the substitution reaction is 90-160 ℃; preferably, the reaction temperature is 110-150 ℃; more preferably, the reaction temperature is 120-140 ℃;
3) the molar ratio of the substitution reagent to the 2, 4-difluorobenzonitrile is 0.9-2: 1; preferably, the molar ratio of the substitution reagent to the 2, 4-difluorobenzonitrile is 1.0-1.5: 1; more preferably, the molar ratio of the substitution reagent to the 2, 4-difluorobenzonitrile is 1.0-1.2: 1.
5. The method of claim 1, wherein the deprotecting hydrolysis reagent is selected from hydrazine hydrate, HCl, H2SO4 or HBr.
6. The method of claim 1, wherein the hydrolytic deprotection reaction further comprises one or more of the following features:
1) the hydrolysis deprotection reaction is carried out in a solvent; preferably, the solvent is an organic solvent; more preferably, the solvent is a polar solvent;
2) the reaction temperature of the hydrolysis deprotection reaction is 0-60 ℃; preferably, the reaction temperature is 10-40 ℃; more preferably, the reaction temperature is 20-35 ℃;
3) the molar ratio of the deprotection hydrolysis reagent to a product obtained by the substitution reaction is 1.0-4: 1; preferably, the molar ratio of the deprotected hydrolysis reagent to the product obtained by the substitution reaction is 1.5-3: 1; more preferably, the molar ratio of the deprotected hydrolysis reagent to the product obtained by the substitution reaction is 1.5-2.5: 1.
7. The preparation method according to claim 1, wherein in the cyano hydrolysis reaction, the cyano hydrolysis reagent is selected from hydrogen peroxide or hydrochloric acid.
8. The production method according to claim 1, wherein the cyano hydrolysis reaction is carried out in the presence of a catalyst; preferably, the catalyst is a basic catalyst; more preferably, the catalyst is selected from K2CO3、Na2CO3、KOH、NaOH、NaOCH3Any one or more of NaOtBu.
9. The method of claim 8, wherein the cyano hydrolysis reaction further comprises one or more of the following features:
1) the cyano hydrolysis reaction is carried out in the presence of a solvent; preferably, the solvent is selected from water or an organic solvent or a mixed solvent of water and an organic solvent; more preferably, the solvent is selected from any one or more of water, methanol, ethanol, isopropanol or DCM;
2) the reaction temperature of the cyano hydrolysis reaction is 0-60 ℃; preferably, the reaction temperature of the hydrolysis deprotection reaction is 10-50 ℃;
3) in the cyano hydrolysis reaction, the molar ratio of the selected catalyst to the 4-amino-2-fluorobenzonitrile is 0.1-1.0: 1;
4) in the cyano-group hydrolysis reaction, the molar ratio of a cyano-group hydrolysis reagent to 4-amino-2-fluorobenzonitrile is 1-6: 1; preferably, the molar ratio of the cyano hydrolytic reagent to the 4-amino-2-fluorobenzonitrile is 2.0-4.0: 1; more preferably, the molar ratio of the cyano hydrolyzing reagent to the 4-amino-2-fluorobenzonitrile is 2.5-3.5: 1.
10. The method according to claim 1, wherein the substitution reaction, the hydrolysis deprotection reaction, and the cyano hydrolysis reaction further comprise post-treating a product obtained by each reaction; preferably, the post-treatment is distillation, filtration, recrystallization or oven drying.
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| CN110354128A (en) * | 2013-10-18 | 2019-10-22 | 卫材R&D管理有限公司 | Pyrimidine FGFR4 inhibitor |
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