CN110078633A - A kind of fluoro- 3- methoxyl group -5- methylaniline hydrochloride preparation method of 4- - Google Patents
A kind of fluoro- 3- methoxyl group -5- methylaniline hydrochloride preparation method of 4- Download PDFInfo
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- C07C37/60—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by oxidation reactions introducing directly hydroxy groups on a =CH-group belonging to a six-membered aromatic ring with the aid of other oxidants than molecular oxygen or their mixtures with molecular oxygen
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Abstract
The invention discloses a kind of preparation methods of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, belong to organic synthesis field.A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, synthetic route are as follows:A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- of the invention, using the bromo- 2- toluene fluoride of 5- cheap and easy to get as starting material, it reacts to obtain the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- by 5 steps, technological operation is convenient, at low cost, safety, total recovery are high and environmentally friendly, suitable for industrialized production, have broad application prospects.
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of system of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-
Preparation Method.
Background technique
2012, Hui Li, Santa Clara, CA (US) et al. were starting material using such as with the fluoro- 3- methylphenol of 2-
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of product 4- is made (referring to US2012/28923 through the reaction of 4 steps in lower route；
(2012)；(A1)English).Although the method processing step is less, starting material is not easily-synthesized, and price is very high, reaction
Condition is harsh, and quantity of three wastes is huge.Especially in first step bromo, third step nitrification, by autoclave, react dangerous is the 4th step
Number is higher, and pollution discharge amount is big, easily causes environmental pollution.
Summary of the invention
In view of the above problems, the present invention provides a kind of systems of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-
Preparation Method, this preparation method is raw materials used to be easy to get, is at low cost, technological operation convenience, safety, total recovery are high and to environment friend
It is good.
The technical solution adopted by the present invention are as follows:
A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, synthetic route are as follows:
Further, the preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of a kind of 4-, including the following steps:
S1. the bromo- 2- toluene fluoride of 5- and diisopropylamine are added sequentially in the there-necked flask equipped with organic solvent, at 0 DEG C
The cyclohexane solution dissolved with butyl lithium is added dropwise in there-necked flask, is added dropwise, system is cooled to -50~-80 DEG C of 1~2h of reaction, so
The tetrahydrofuran solution of trimethylborate or boric acid isopropyl ester is added drop-wise in reaction system afterwards, after being added dropwise, the reaction was continued 2
~4h；To end of reaction, water quenching reaction, separation, extraction, concentration are carried out, the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5- is obtained；
S2. the fluoro- 3- methylphenylboronic acid of the bromo- 2- of the 5- is dissolved in after organic solvent and system is cooled to 0~10 DEG C, then
Oxidant is added dropwise, is added dropwise, in a nitrogen atmosphere, system is warming up to 5~10h of reaction at room temperature, to end of reaction, is carried out
Sour quenching reaction, separation, extraction, concentration obtain the fluoro- 3- methylphenol of the bromo- 2- of 5-；
S3. the fluoro- 3- methylphenol of the bromo- 2- of the 5- is dissolved in organic solvent, aqueous slkali is then added, in nitrogen atmosphere
Under, then dimethyl suflfate or iodomethane or methanol is added dropwise, it is added dropwise, system temperature is risen to 60~80 DEG C, reacts 1~2h,
To end of reaction, system temperature is down to room temperature, water quenching reaction, separation, extraction, concentration is then carried out, it is fluoro- to obtain the bromo- 2- of 5-
3- methylanisole；
S4. the fluoro- 3- methylanisole of the bromo- 2- of the 5- is dissolved in carbinolamine or ethyl alcohol, catalyst, nitrogen gas is then added
System is warming up to 40~60 DEG C under atmosphere, reacts 2~5h, to end of reaction, system temperature is down to room temperature, water quenching is carried out and goes out instead
It answers, separate, extract, be concentrated, obtain the fluoro- 3- methoxyl group -5- methylaniline of 4-；
S5. the fluoro- 3- methoxyl group -5- methylaniline of the 4- is dissolved in methanol or ethyl alcohol, hydrogen chloride or chlorination is then added
System is warming up to 60~80 DEG C, back flow reaction 1~2h of body under nitrogen atmosphere, to end of reaction, by system temperature by ethanolic hydrogen solution
Degree is down to room temperature, and methyl tertiary butyl ether(MTBE) is added dropwise into system while stirring, is then filtered, dries, obtains the fluoro- 3- methoxy of 4-
Base -5- methylaniline hydrochloride.
Further, the fluoro- toluene of the bromo- 2- of 5- described in the S1, butyl lithium, diisopropylamine, trimethylborate or boric acid
The molar ratio of isopropyl ester is 1:1.0~1.5:1.0~1.5:1.0~1.5.
Further, oxidant described in the S2 is hydrogen peroxide, sodium hypochlorite or sodium hypobromite.
Further, the molar ratio of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5- described in the S2 and oxidant be 1:2.0~
5.0。
Further, the fluoro- 3- methylphenol of the bromo- 2- of 5- described in the S3, dimethyl suflfate or iodomethane or methanol
Molar ratio is 1:1.0~2.
Further, the mass ratio of the fluoro- 3- methylanisole of the bromo- 2- of 5- described in the S4 and catalyst be 1:0.01~
0.1。
Further, organic solvent described in the S1 be tetrahydrofuran, ether, methyl tertiary butyl ether(MTBE), in toluene extremely
Few one kind；The mass ratio of the organic solvent and the fluoro- toluene of the bromo- 2- of 5- is 5~10:1.
Further, organic solvent described in the S2 is tetrahydrofuran, methylene chloride, dioxane, methyl tertbutyl
At least one of ether；The mass ratio of the organic solvent and the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5- is 5~10:1.
Further, organic solvent described in the S3 is tetrahydrofuran, dioxane, at least one of DMF；It is described
The mass ratio of organic solvent and the fluoro- 3- methylphenol of the bromo- 2- of 5- is 5~10:1.
Specifically, extractant used in the extraction is methyl tertiary butyl ether(MTBE), ethyl acetate, in methylene chloride it is a kind of or two
Kind；Aqueous slkali described in the S3 is at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide solution；The S4
Described in catalyst be manganese, iron, nickel, zinc, copper, palladium, rhodium, caesium, platinum, ruthenium or cobalt and its complex compound or its complex；In the S4
The mass ratio of carbinolamine or ethyl alcohol and the fluoro- 3- methylanisole of the bromo- 2- of 5- is 0.6~1:1；Methanol or ethyl alcohol and 4- in the S5
The mass ratio of fluoro- 3- methoxyl group -5- methylaniline is 5~10:1.
The beneficial effects of the present invention are: a kind of preparation side of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- of the invention
Method reacts to obtain the fluoro- 3- methoxyl group -5- methylbenzene of 4- by 5 steps using the bromo- 2- toluene fluoride of 5- cheap and easy to get as starting material
Amine hydrochlorate, technological operation is convenient, at low cost, safety, total recovery are high and environmentally friendly, is suitable for industrialized production, has wide
Wealthy application prospect.
Detailed description of the invention
The nuclear magnetic resoance spectrum of the fluoro- 3- methylphenol of the bromo- 2- of Fig. 1 5-；
The nuclear magnetic resoance spectrum of the fluoro- 3- methylanisole of the bromo- 2- of Fig. 2 5-；
The nuclear magnetic resoance spectrum of the fluoro- 3- methoxyl group -5- methylaniline of Fig. 3 4-；
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of Fig. 4 4-.
Specific embodiment
Embodiment of the present invention can be replaced by the difference of specific range based on the above technical solution,
Available numerous embodiment, therefore, several embodiments as described below are only merely the more excellent reality in numerous embodiment
Example is applied, any technology replacement done in above-mentioned technical proposal all belongs to the scope of protection of the present invention.
Embodiment 1
A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, including the following steps:
The preparation of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of S1.5-
By the bromo- 2- toluene fluoride (50g, 1.0eq) of 5-, diisopropylamine (34.8g, 1.3eq) is added sequentially to fill tetrahydro furan
It mutters in the there-necked flask of (500g), at 0 DEG C, hexamethylene (100g) solution of butyl lithium (22g, 1.3eq) is added dropwise, is added dropwise
Afterwards, system is cooled to -65 DEG C, and system reacts 2h, then that the tetrahydrofuran (100g) of boric acid isopropyl ester (64.7g, 1.3eq) is molten
Drop is added in reaction system, after being added dropwise, the reaction was continued 3h.After reaction, it is slowly added to water to reaction system, separated
Organic phase, water phase extract product, concentration organic phase to dry, column chromatography (PE:MTBE=20:1) with methyl tertiary butyl ether(MTBE) (500g)
Obtain the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5-, yield: 90%.
The preparation of the fluoro- 3- methylphenol of the bromo- 2- of S2.5-
The fluoro- 3- methylphenylboronic acid (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in tetrahydrofuran (500g), is cooled to 5 DEG C, is delayed
Slow be added dropwise hydrogen peroxide (30g, 2.0eq) is added dropwise into reaction system, in a nitrogen atmosphere, system is raised to room temperature reaction
7h then extracts organic phase with methyl tertiary butyl ether(MTBE) (250g), has to after completion of the reaction, be slowly added to hydrochloric acid to reaction system
Machine is mutually concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the fluoro- 3- methylphenol of the bromo- 2- of 5-, yield: 90%.
The preparation of the fluoro- 3- methylanisole of the bromo- 2- of S3.5-
The fluoro- 3- methylphenol (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in DMF (250g), potassium hydroxide solution is then added
(27.3g, 2.0eq) in a nitrogen atmosphere, then is added dropwise iodomethane (65g, 2.0eq), is added dropwise, system temperature is risen to 70
DEG C, 2h is reacted, system is down to room temperature by raw material end of reaction, and water is added into system and carries out quenching reaction, uses methyl tertbutyl
Ether (500g) extracts organic phase, separates organic phase, and organic phase is concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the bromo- 2- of 5-
Fluoro- 3- methylanisole, yield: 90%.
The preparation of the fluoro- 3- methoxyl group -5- methylaniline of S4.4-
The fluoro- 3- methylanisole (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in methanol amine aqueous solution (30g, 2.0eq), addition is urged
System temperature is risen to 50 DEG C in a nitrogen atmosphere by agent 5g, reacts 2h to end of reaction and system is down to room temperature, Xiang Ti
Water is added in system and carries out quenching reaction, extracts organic phase with methyl tertiary butyl ether(MTBE) (100g), organic phase is concentrated to dryness, column chromatography
(PE:MTBE=20:1), the fluoro- 3- methoxyl group -5- methylaniline of 4-, yield: 90% are obtained.
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of S5.4-
The fluoro- 3- methoxyl group -5- methylaniline (50g, 1.0eq) of 4- is dissolved in ethyl alcohol (250g), hydrogen chloride second is then added
System temperature is risen to 70 DEG C, back flow reaction 2h, to end of reaction, by body in a nitrogen atmosphere by alcoholic solution (40g, 2.0eq)
System is down to room temperature, and methyl tertiary butyl ether(MTBE) (250g) is added into system while stirring, has a large amount of solids to be precipitated, and stirs several minutes,
Filtering, drying, obtains the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, yield: 90%.
Embodiment 2
A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, including the following steps:
The preparation of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of S1.5-
By the bromo- 2- toluene fluoride (50g, 1.0eq) of 5-, diisopropylamine (34.8g, 1.3eq) is added sequentially to fill tetrahydro furan
It mutters in the there-necked flask of (500g), at 0 DEG C, hexamethylene (100g) solution of butyl lithium (22g, 1.3eq) is added dropwise, is added dropwise
Afterwards, system is cooled to -50 DEG C, and system reacts 1.5h, then by the tetrahydrofuran (100g) of boric acid isopropyl ester (64.7g, 1.3eq)
Solution is added drop-wise in reaction system, after being added dropwise, the reaction was continued 4h.After reaction, it is slowly added to water to reaction system, point
From organic phase, water phase extracts product with ethyl acetate (500g), and to doing, column chromatographs (PE:MTBE=20:1) and obtains concentration organic phase
To the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5-, yield: 75%.
The preparation of the fluoro- 3- methylphenol of the bromo- 2- of S2.5-
The fluoro- 3- methylphenylboronic acid (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in tetrahydrofuran (500g), is cooled to 0 DEG C, is delayed
Slow be added dropwise hydrogen peroxide (30g, 2.0eq) is added dropwise into reaction system, in a nitrogen atmosphere, system is raised to room temperature reaction
10h then extracts organic phase, organic phase with ethyl acetate (250g) to after completion of the reaction, be slowly added to hydrochloric acid to reaction system
It is concentrated to dryness, column chromatography (PE:MTBE=20:1) obtains the fluoro- 3- methylphenol of the bromo- 2- of 5-, yield: 82%.
The preparation of the fluoro- 3- methylanisole of the bromo- 2- of S3.5-
The fluoro- 3- methylphenol (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in DMF (250g), potassium hydroxide solution is then added
(27.3g, 2.0eq) in a nitrogen atmosphere, then is added dropwise iodomethane (65g, 2.0eq), is added dropwise, system temperature is risen to 60
DEG C, 1.5h is reacted, system is down to room temperature by raw material end of reaction, and water is added into system and carries out quenching reaction, uses ethyl acetate
(500g) extracts organic phase, separates organic phase, and organic phase is concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the bromo- 2- of 5-
Fluoro- 3- methylanisole, yield: 80%.
The preparation of the fluoro- 3- methoxyl group -5- methylaniline of S4.4-
The fluoro- 3- methylanisole (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in methanol amine aqueous solution (30g, 2.0eq), addition is urged
System temperature is risen to 40 DEG C in a nitrogen atmosphere by agent 0.5g, reacts 3h to end of reaction and system is down to room temperature, to
Water is added in system and carries out quenching reaction, extracts organic phase with ethyl acetate (100g), organic phase is concentrated to dryness, column chromatography (PE:
MTBE=20:1), the fluoro- 3- methoxyl group -5- methylaniline of 4-, yield: 78% are obtained.
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of S5.4-
The fluoro- 3- methoxyl group -5- methylaniline (50g, 1.0eq) of 4- is dissolved in ethyl alcohol (250g), hydrogen chloride second is then added
System temperature is risen to 80 DEG C, back flow reaction 1.5h in a nitrogen atmosphere by alcoholic solution (40g, 2.0eq), will to end of reaction
System is down to room temperature, and ethyl acetate (250g) is added into system while stirring, has a large amount of solids to be precipitated, and stirs several minutes, mistake
Filter, drying, obtains the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, yield: 79%.
Embodiment 3
A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, including the following steps:
The preparation of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of S1.5-
By the bromo- 2- toluene fluoride (50g, 1.0eq) of 5-, diisopropylamine (34.8g, 1.3eq) is added sequentially to fill tetrahydro furan
It mutters in the there-necked flask of (500g), at 0 DEG C, hexamethylene (100g) solution of butyl lithium (22g, 1.3eq) is added dropwise, is added dropwise
Afterwards, system is cooled to -80 DEG C, and system reacts 1h, then that the tetrahydrofuran (100g) of boric acid isopropyl ester (64.7g, 1.3eq) is molten
Drop is added in reaction system, after being added dropwise, the reaction was continued 2h.After reaction, it is slowly added to water to reaction system, separated
Organic phase, water phase extract product with methylene chloride (500g), and to doing, column chromatography (PE:MTBE=20:1) obtains concentration organic phase
The fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5-, yield: 80%.
The preparation of the fluoro- 3- methylphenol of the bromo- 2- of S2.5-
The fluoro- 3- methylphenylboronic acid (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in tetrahydrofuran (500g), is cooled to 10 DEG C,
Hydrogen peroxide (30g, 2.0eq) is slowly added dropwise into reaction system, is added dropwise, in a nitrogen atmosphere, it is anti-that system is raised to room temperature
5h is answered, to after completion of the reaction, be slowly added to hydrochloric acid to reaction system, then extracts organic phase with methylene chloride (250g), it is organic
It is mutually concentrated to dryness, column chromatography (PE:MTBE=20:1) obtains the fluoro- 3- methylphenol of the bromo- 2- of 5-, yield: 82%.
The preparation of the fluoro- 3- methylanisole of the bromo- 2- of S3.5-
The fluoro- 3- methylphenol (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in DMF (250g), potassium hydroxide solution is then added
(27.3g, 2.0eq) in a nitrogen atmosphere, then is added dropwise iodomethane (65g, 2.0eq), is added dropwise, system temperature is risen to 80
DEG C, 1h is reacted, system is down to room temperature by raw material end of reaction, and water is added into system and carries out quenching reaction, uses methylene chloride
(500g) extracts organic phase, separates organic phase, and organic phase is concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the bromo- 2- of 5-
Fluoro- 3- methylanisole, yield: 85%.
The preparation of the fluoro- 3- methoxyl group -5- methylaniline of S4.4-
The fluoro- 3- methylanisole (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in ethanol solution (65g, 2.0eq), catalysis is added
System temperature is risen to 60 DEG C in a nitrogen atmosphere by agent 2.5g, reacts 5h to end of reaction and system is down to room temperature, Xiang Ti
Water is added in system and carries out quenching reaction, extracts organic phase with methylene chloride (100g), organic phase is concentrated to dryness, column chromatography (PE:
MTBE=20:1), the fluoro- 3- methoxyl group -5- methylaniline of 4-, yield: 83% are obtained.
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of S5.4-
The fluoro- 3- methoxyl group -5- methylaniline (50g, 1.0eq) of 4- is dissolved in methanol (250g), hydrogen chloride second is then added
System temperature is risen to 60 DEG C, back flow reaction 1h, to end of reaction, by body in a nitrogen atmosphere by alcoholic solution (40g, 2.0eq)
System is down to room temperature, and methylene chloride (250g) is added into system while stirring, has a large amount of solids to be precipitated, and stirs several minutes, filtering,
Drying, obtains the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, yield: 85%.
Embodiment 4
A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, including the following steps:
The preparation of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of S1.5-
By the bromo- 2- toluene fluoride (50g, 1.0eq) of 5-, diisopropylamine (34.8g, 1.3eq) is added sequentially to fill tetrahydro furan
It mutters in the there-necked flask of (500g), at 0 DEG C, hexamethylene (100g) solution of butyl lithium (22g, 1.3eq) is added dropwise, is added dropwise
Afterwards, system is cooled to -65 DEG C, and system reacts 2h, then that the tetrahydrofuran (100g) of trimethylborate (35.8g, 1.3eq) is molten
Drop is added in reaction system, after being added dropwise, the reaction was continued 3h.After reaction, it is slowly added to water to reaction system, separated
Organic phase, water phase extract product, concentration organic phase to dry, column chromatography (PE:MTBE=20:1) with methyl tertiary butyl ether(MTBE) (500g)
Obtain the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5-, yield: 85%.
The preparation of the fluoro- 3- methylphenol of the bromo- 2- of S2.5-
The fluoro- 3- methylphenylboronic acid (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in tetrahydrofuran (500g), is cooled to 5 DEG C, is delayed
Slow be added dropwise sodium hypochlorite (120g, 2.0eq) is added dropwise into reaction system, in a nitrogen atmosphere, it is anti-that system is raised to room temperature
7h is answered, to after completion of the reaction, be slowly added to hydrochloric acid to reaction system, then extracts organic phase with methyl tertiary butyl ether(MTBE) (250g),
Organic phase is concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the fluoro- 3- methylphenol of the bromo- 2- of 5-, yield: 88%.
The preparation of the fluoro- 3- methylanisole of the bromo- 2- of S3.5-
The fluoro- 3- methylphenol (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in DMF (250g), potassium hydroxide solution is then added
(27.3g, 2.0eq) in a nitrogen atmosphere, then is added dropwise iodomethane (65g, 2.0eq), is added dropwise, system temperature is risen to 70
DEG C, 2h is reacted, system is down to room temperature by raw material end of reaction, and water is added into system and carries out quenching reaction, uses methyl tertbutyl
Ether (500g) extracts organic phase, separates organic phase, and organic phase is concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the bromo- 2- of 5-
Fluoro- 3- methylanisole, yield: 86%.
The preparation of the fluoro- 3- methoxyl group -5- methylaniline of S4.4-
The fluoro- 3- methylanisole (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in methanol amine aqueous solution (30g, 2.0eq), addition is urged
System temperature is risen to 50 DEG C in a nitrogen atmosphere by agent 2.5g, reacts 2h to end of reaction and system is down to room temperature, to
Water is added in system and carries out quenching reaction, extracts organic phase with methyl tertiary butyl ether(MTBE) (100g), organic phase is concentrated to dryness, column chromatography
(PE:MTBE=20:1), the fluoro- 3- methoxyl group -5- methylaniline of 4-, yield: 85% are obtained.
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of S5.4-
The fluoro- 3- methoxyl group -5- methylaniline (50g, 1.0eq) of 4- is dissolved in ethyl alcohol (250g), hydrogen chloride second is then added
System temperature is risen to 70 DEG C, back flow reaction 2h, to end of reaction, by body in a nitrogen atmosphere by alcoholic solution (40g, 2.0eq)
System is down to room temperature, and methyl tertiary butyl ether(MTBE) (250g) is added into system while stirring, has a large amount of solids to be precipitated, and stirs several minutes,
Filtering, drying, obtains the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, yield: 88%.
Embodiment 5
A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, including the following steps:
The preparation of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of S1.5-
By the bromo- 2- toluene fluoride (50g, 1.0eq) of 5-, diisopropylamine (34.8g, 1.3eq) is added sequentially to fill tetrahydro furan
It mutters in the there-necked flask of (500g), at 0 DEG C, hexamethylene (100g) solution of butyl lithium (22g, 1.3eq) is added dropwise, is added dropwise
Afterwards, system is cooled to -65 DEG C, and system reacts 2h, then that the tetrahydrofuran (100g) of boric acid isopropyl ester (64.7g, 1.3eq) is molten
Drop is added in reaction system, after being added dropwise, the reaction was continued 3h.After reaction, it is slowly added to water to reaction system, separated
Organic phase, water phase extract product, concentration organic phase to dry, column chromatography (PE:MTBE=20:1) with methyl tertiary butyl ether(MTBE) (500g)
Obtain the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5-, yield: 90%.
The preparation of the fluoro- 3- methylphenol of the bromo- 2- of S2.5-
The fluoro- 3- methylphenylboronic acid (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in tetrahydrofuran (500g), is cooled to 5 DEG C, is delayed
Slow be added dropwise sodium hypobromite (150g, 2.0eq) is added dropwise into reaction system, in a nitrogen atmosphere, it is anti-that system is raised to room temperature
7h is answered, to after completion of the reaction, be slowly added to hydrochloric acid to reaction system, then extracts organic phase with methyl tertiary butyl ether(MTBE) (250g),
Organic phase is concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the fluoro- 3- methylphenol of the bromo- 2- of 5-, yield: 90%.
The preparation of the fluoro- 3- methylanisole of the bromo- 2- of S3.5-
The fluoro- 3- methylphenol (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in DMF (250g), potassium hydroxide solution is then added
(27.3g, 2.0eq) in a nitrogen atmosphere, then is added dropwise dimethyl suflfate (61.5g, 2.0eq), is added dropwise, by system temperature
70 DEG C are risen to, 2h is reacted, system is down to room temperature by raw material end of reaction, and water is added into system and carries out quenching reaction, uses methyl
Tertbutyl ether (500g) extracts organic phase, separates organic phase, and organic phase is concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains
The fluoro- 3- methylanisole of the bromo- 2- of 5-, yield: 88%.
The preparation of the fluoro- 3- methoxyl group -5- methylaniline of S4.4-
The fluoro- 3- methylanisole (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in methanol amine aqueous solution (30g, 2.0eq), addition is urged
System temperature is risen to 50 DEG C in a nitrogen atmosphere by agent 2.5g, reacts 2h to end of reaction and system is down to room temperature, to
Water is added in system and carries out quenching reaction, extracts organic phase with methyl tertiary butyl ether(MTBE) (100g), organic phase is concentrated to dryness, column chromatography
(PE:MTBE=20:1), the fluoro- 3- methoxyl group -5- methylaniline of 4-, yield: 85% are obtained.
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of S5.4-
The fluoro- 3- methoxyl group -5- methylaniline (50g, 1.0eq) of 4- is dissolved in ethyl alcohol (250g), hydrogen chloride second is then added
System temperature is risen to 70 DEG C, back flow reaction 2h, to end of reaction, by body in a nitrogen atmosphere by alcoholic solution (40g, 2.0eq)
System is down to room temperature, and methyl tertiary butyl ether(MTBE) (250g) is added into system while stirring, has a large amount of solids to be precipitated, and stirs several minutes,
Filtering, drying, obtains the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, yield: 87%.
Embodiment 6
A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, including the following steps:
The preparation of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of S1.5-
By the bromo- 2- toluene fluoride (50g, 1.0eq) of 5-, diisopropylamine (34.8g, 1.3eq) is added sequentially to fill tetrahydro furan
It mutters in the there-necked flask of (500g), at 0 DEG C, hexamethylene (100g) solution of butyl lithium (22g, 1.3eq) is added dropwise, is added dropwise
Afterwards, system is cooled to -65 DEG C, and system reacts 2h, then that the tetrahydrofuran (100g) of trimethylborate (35.8g, 1.3eq) is molten
Drop is added in reaction system, after being added dropwise, the reaction was continued 3h.After reaction, it is slowly added to water to reaction system, separated
Organic phase, water phase extract product, concentration organic phase to dry, column chromatography (PE:MTBE=20:1) with methyl tertiary butyl ether(MTBE) (500g)
Obtain the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5-, yield: 88%.
The preparation of the fluoro- 3- methylphenol of the bromo- 2- of S2.5-
The fluoro- 3- methylphenylboronic acid (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in tetrahydrofuran (500g), is cooled to 5 DEG C, is delayed
Slow be added dropwise sodium hypobromite (150g, 2.0eq) is added dropwise into reaction system, in a nitrogen atmosphere, it is anti-that system is raised to room temperature
7h is answered, to after completion of the reaction, be slowly added to hydrochloric acid to reaction system, then extracts organic phase with methyl tertiary butyl ether(MTBE) (250g),
Organic phase is concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the fluoro- 3- methylphenol of the bromo- 2- of 5-, yield: 85%.
The preparation of the fluoro- 3- methylanisole of the bromo- 2- of S3.5-
The fluoro- 3- methylphenol (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in DMF (250g), potassium hydroxide solution is then added
(27.3g, 2.0eq) in a nitrogen atmosphere, then is added dropwise methanol (100g, 2.0eq), is added dropwise, system temperature is risen to 70
DEG C, 2h is reacted, system is down to room temperature by raw material end of reaction, and water is added into system and carries out quenching reaction, uses methyl tertbutyl
Ether (500g) extracts organic phase, separates organic phase, and organic phase is concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the bromo- 2- of 5-
Fluoro- 3- methylanisole, yield: 85%.
The preparation of the fluoro- 3- methoxyl group -5- methylaniline of S4.4-
The fluoro- 3- methylanisole (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in methanol amine aqueous solution (30g, 2.0eq), addition is urged
System temperature is risen to 50 DEG C in a nitrogen atmosphere by agent 2.5g, reacts 2h to end of reaction and system is down to room temperature, to
Water is added in system and carries out quenching reaction, extracts organic phase with methyl tertiary butyl ether(MTBE) (100g), organic phase is concentrated to dryness, column chromatography
(PE:MTBE=20:1), the fluoro- 3- methoxyl group -5- methylaniline of 4-, yield: 86% are obtained.
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of S5.4-
The fluoro- 3- methoxyl group -5- methylaniline (50g, 1.0eq) of 4- is dissolved in ethyl alcohol (250g), hydrogen chloride second is then added
System temperature is risen to 70 DEG C, back flow reaction 2h, to end of reaction, by body in a nitrogen atmosphere by alcoholic solution (40g, 2.0eq)
System is down to room temperature, and methyl tertiary butyl ether(MTBE) (250g) is added into system while stirring, has a large amount of solids to be precipitated, and stirs several minutes,
Filtering, drying, obtains the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, yield: 83%.
Embodiment 7
A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, including the following steps:
The preparation of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of S1.5-
By the bromo- 2- toluene fluoride (50g, 1.0eq) of 5-, diisopropylamine (34.8g, 1.3eq) is added sequentially to fill methyl- tert
In the there-necked flask of butyl ether (250g), at 0 DEG C, hexamethylene (100g) solution of butyl lithium (22g, 1.3eq) is added dropwise, drips
Bi Hou, system are cooled to -65 DEG C, and system reacts 2h, then by the tetrahydrofuran (100g) of boric acid isopropyl ester (64.7g, 1.3eq)
Solution is added drop-wise in reaction system, after being added dropwise, the reaction was continued 3h.After reaction, it is slowly added to water to reaction system, point
From organic phase, water phase extracts product with methyl tertiary butyl ether(MTBE) (500g), concentration organic phase to dry, column chromatography (PE:MTBE=20:
1) the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5-, yield: 80% are obtained.
The preparation of the fluoro- 3- methylphenol of the bromo- 2- of S2.5-
The fluoro- 3- methylphenylboronic acid (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in methyl tertiary butyl ether(MTBE) (250g), is cooled to 5
DEG C, hydrogen peroxide (30g, 2.0eq) is slowly added dropwise into reaction system, is added dropwise, in a nitrogen atmosphere, system is raised to room temperature
7h is reacted, to after completion of the reaction, be slowly added to hydrochloric acid to reaction system, is then extracted with methyl tertiary butyl ether(MTBE) (250g) organic
Phase, organic phase are concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the fluoro- 3- methylphenol of the bromo- 2- of 5-, yield: 82%.
The preparation of the fluoro- 3- methylanisole of the bromo- 2- of S3.5-
The fluoro- 3- methylphenol (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in tetrahydrofuran (400g), potassium hydroxide is then added
Solution (27.3g, 2.0eq) in a nitrogen atmosphere, then is added dropwise iodomethane (65g, 2.0eq), is added dropwise, by system temperature liter
To 70 DEG C, 2h is reacted, system is down to room temperature by raw material end of reaction, and water is added into system and carries out quenching reaction, uses methyl- tert
Butyl ether (500g) extracts organic phase, separates organic phase, and organic phase is concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains 5-
The bromo- fluoro- 3- methylanisole of 2-, yield: 85%.
The preparation of the fluoro- 3- methoxyl group -5- methylaniline of S4.4-
The fluoro- 3- methylanisole (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in methanol amine aqueous solution (40g, 2.67eq), is added
System temperature is risen to 50 DEG C in a nitrogen atmosphere by catalyst 2.5g, reacts 2h to end of reaction and system is down to room temperature,
Water is added into system and carries out quenching reaction, extracts organic phase with methyl tertiary butyl ether(MTBE) (100g), organic phase is concentrated to dryness, column layer
It analyses (PE:MTBE=20:1), obtains the fluoro- 3- methoxyl group -5- methylaniline of 4-, yield: 82%.
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of S5.4-
The fluoro- 3- methoxyl group -5- methylaniline (50g, 1.0eq) of 4- is dissolved in ethyl alcohol (500g), hydrogen chloride second is then added
System temperature is risen to 70 DEG C, back flow reaction 2h, to end of reaction, by body in a nitrogen atmosphere by alcoholic solution (40g, 2.0eq)
System is down to room temperature, and methyl tertiary butyl ether(MTBE) (250g) is added into system while stirring, has a large amount of solids to be precipitated, and stirs several minutes,
Filtering, drying, obtains the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, yield: 83%.
Embodiment 8
A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, including the following steps:
The preparation of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of S1.5-
By the bromo- 2- toluene fluoride (50g, 1.0eq) of 5-, diisopropylamine (34.8g, 1.3eq) is added sequentially to fill ether
In the there-necked flask of (400g), at 0 DEG C, hexamethylene (100g) solution of butyl lithium (22g, 1.3eq) is added dropwise, after being added dropwise,
System is cooled to -65 DEG C, and system reacts 2h, then by tetrahydrofuran (100g) solution of boric acid isopropyl ester (64.7g, 1.3eq)
It is added drop-wise in reaction system, after being added dropwise, the reaction was continued 3h.After reaction, it is slowly added to water to reaction system, separation has
Machine phase, water phase extract product with methyl tertiary butyl ether(MTBE) (500g), and to doing, column chromatographs (PE:MTBE=20:1) and obtains concentration organic phase
To the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5-, yield: 75%.
The preparation of the fluoro- 3- methylphenol of the bromo- 2- of S2.5-
The fluoro- 3- methylphenylboronic acid (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in dioxane (250g), is cooled to 5 DEG C, is delayed
Slow be added dropwise hydrogen peroxide (30g, 2.0eq) is added dropwise into reaction system, in a nitrogen atmosphere, system is raised to room temperature reaction
7h then extracts organic phase with methyl tertiary butyl ether(MTBE) (250g), has to after completion of the reaction, be slowly added to hydrochloric acid to reaction system
Machine is mutually concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the fluoro- 3- methylphenol of the bromo- 2- of 5-, yield: 80%.
The preparation of the fluoro- 3- methylanisole of the bromo- 2- of S3.5-
The fluoro- 3- methylphenol (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in dioxane (500g), it is molten that sodium carbonate is then added
Liquid (51.7g, 2.0eq) in a nitrogen atmosphere, then is added dropwise iodomethane (65g, 2.0eq), is added dropwise, system temperature is risen to
70 DEG C, 2h is reacted, system is down to room temperature by raw material end of reaction, and water is added into system and carries out quenching reaction, with methyl- tert fourth
Base ether (500g) extracts organic phase, separates organic phase, and organic phase is concentrated to dryness, and it is bromo- that column chromatography (PE:MTBE=20:1) obtains 5-
The fluoro- 3- methylanisole of 2-, yield: 78%.
The preparation of the fluoro- 3- methoxyl group -5- methylaniline of S4.4-
The fluoro- 3- methylanisole (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in methanol amine aqueous solution (50g, 3.3eq), addition is urged
System temperature is risen to 50 DEG C in a nitrogen atmosphere by agent 0.5g, reacts 2h to end of reaction and system is down to room temperature, to
Water is added in system and carries out quenching reaction, extracts organic phase with methyl tertiary butyl ether(MTBE) (100g), organic phase is concentrated to dryness, column chromatography
(PE:MTBE=20:1), the fluoro- 3- methoxyl group -5- methylaniline of 4-, yield: 75% are obtained.
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of S5.4-
The fluoro- 3- methoxyl group -5- methylaniline (50g, 1.0eq) of 4- is dissolved in ethyl alcohol (400g), hydrogen chloride second is then added
System temperature is risen to 70 DEG C, back flow reaction 2h, to end of reaction, by body in a nitrogen atmosphere by alcoholic solution (40g, 2.0eq)
System is down to room temperature, and methyl tertiary butyl ether(MTBE) (250g) is added into system while stirring, has a large amount of solids to be precipitated, and stirs several minutes,
Filtering, drying, obtains the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, yield: 80%.
Embodiment 9
A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, including the following steps:
The preparation of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of S1.5-
By the bromo- 2- toluene fluoride (50g, 1.0eq) of 5-, diisopropylamine (26.7g, 1eq) is added sequentially to fill tetrahydrofuran
In the there-necked flask of (500g), at 0 DEG C, hexamethylene (100g) solution of butyl lithium (16.92g, 1eq) is added dropwise, after being added dropwise,
System is cooled to -65 DEG C, and system reacts 2h, then by tetrahydrofuran (100g) solution of boric acid isopropyl ester (49.77g, 1.3eq)
It is added drop-wise in reaction system, after being added dropwise, the reaction was continued 3h.After reaction, it is slowly added to water to reaction system, separation has
Machine phase, water phase extract product with methyl tertiary butyl ether(MTBE) (500g), and to doing, column chromatographs (PE:MTBE=20:1) and obtains concentration organic phase
To the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5-, yield: 85%.
The preparation of the fluoro- 3- methylphenol of the bromo- 2- of S2.5-
The fluoro- 3- methylphenylboronic acid (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in tetrahydrofuran (500g), is cooled to 5 DEG C, is delayed
Slow be added dropwise hydrogen peroxide (45g, 3.0eq) is added dropwise into reaction system, in a nitrogen atmosphere, system is raised to room temperature reaction
7h then extracts organic phase with methyl tertiary butyl ether(MTBE) (250g), has to after completion of the reaction, be slowly added to hydrochloric acid to reaction system
Machine is mutually concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the fluoro- 3- methylphenol of the bromo- 2- of 5-, yield: 80%.
The preparation of the fluoro- 3- methylanisole of the bromo- 2- of S3.5-
The fluoro- 3- methylphenol (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in DMF (250g), potassium hydroxide solution is then added
(27.3g, 2.0eq) in a nitrogen atmosphere, then is added dropwise iodomethane (32.5g, 1.0eq), is added dropwise, system temperature is risen to
70 DEG C, 2h is reacted, system is down to room temperature by raw material end of reaction, and water is added into system and carries out quenching reaction, with methyl- tert fourth
Base ether (500g) extracts organic phase, separates organic phase, and organic phase is concentrated to dryness, and it is bromo- that column chromatography (PE:MTBE=20:1) obtains 5-
The fluoro- 3- methylanisole of 2-, yield: 75%.
The preparation of the fluoro- 3- methoxyl group -5- methylaniline of S4.4-
The fluoro- 3- methylanisole (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in methanol amine aqueous solution (30g, 2.0eq), addition is urged
System temperature is risen to 50 DEG C in a nitrogen atmosphere by agent rhodium (2.5g), reacts 2h to end of reaction and system is down to room
Temperature, is added water into system and carries out quenching reaction, extracts organic phase with methyl tertiary butyl ether(MTBE) (100g), and organic phase is concentrated to dryness,
Column chromatographs (PE:MTBE=20:1), obtains the fluoro- 3- methoxyl group -5- methylaniline of 4-, yield: 90%.
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of S5.4-
The fluoro- 3- methoxyl group -5- methylaniline (50g, 1.0eq) of 4- is dissolved in ethyl alcohol (250g), hydrogen chloride second is then added
System temperature is risen to 70 DEG C, back flow reaction 2h, to end of reaction, by body in a nitrogen atmosphere by alcoholic solution (40g, 2.0eq)
System is down to room temperature, and methyl tertiary butyl ether(MTBE) (250g) is added into system while stirring, has a large amount of solids to be precipitated, and stirs several minutes,
Filtering, drying, obtains the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, yield: 89%.
Embodiment 10
A kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, including the following steps:
The preparation of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of S1.5-
By the bromo- 2- toluene fluoride (50g, 1.0eq) of 5-, diisopropylamine (40.15g, 1.5eq) is added sequentially to fill tetrahydro furan
It mutters in the there-necked flask of (500g), at 0 DEG C, hexamethylene (100g) solution of butyl lithium (25.38g, 1.5eq) is added dropwise, drips
Bi Hou, system are cooled to -65 DEG C, and system reacts 2h, then by the tetrahydrofuran of boric acid isopropyl ester (74.65g, 1.5eq)
(100g) solution is added drop-wise in reaction system, after being added dropwise, the reaction was continued 3h.After reaction, slowly add to reaction system
Enter water, separate organic phase, water phase extracts product with methyl tertiary butyl ether(MTBE) (500g), concentration organic phase to dry, column chromatography (PE:
MTBE=20:1 the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5-, yield: 75%) are obtained.
The preparation of the fluoro- 3- methylphenol of the bromo- 2- of S2.5-
The fluoro- 3- methylphenylboronic acid (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in tetrahydrofuran (500g), is cooled to 5 DEG C, is delayed
Slow be added dropwise hydrogen peroxide (75g, 5.0eq) is added dropwise into reaction system, in a nitrogen atmosphere, system is raised to room temperature reaction
7h then extracts organic phase with methyl tertiary butyl ether(MTBE) (250g), has to after completion of the reaction, be slowly added to hydrochloric acid to reaction system
Machine is mutually concentrated to dryness, and column chromatography (PE:MTBE=20:1) obtains the fluoro- 3- methylphenol of the bromo- 2- of 5-, yield: 80%.
The preparation of the fluoro- 3- methylanisole of the bromo- 2- of S3.5-
The fluoro- 3- methylphenol (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in DMF (250g), potassium hydroxide solution is then added
(27.3g, 2.0eq) in a nitrogen atmosphere, then is added dropwise iodomethane (48.75g, 1.5eq), is added dropwise, system temperature is risen to
70 DEG C, 2h is reacted, system is down to room temperature by raw material end of reaction, and water is added into system and carries out quenching reaction, with methyl- tert fourth
Base ether (500g) extracts organic phase, separates organic phase, and organic phase is concentrated to dryness, and it is bromo- that column chromatography (PE:MTBE=20:1) obtains 5-
The fluoro- 3- methylanisole of 2-, yield: 89%.
The preparation of the fluoro- 3- methoxyl group -5- methylaniline of S4.4-
The fluoro- 3- methylanisole (50g, 1.0eq) of the bromo- 2- of 5- is dissolved in methanol amine aqueous solution (30g, 2.0eq), addition is urged
System temperature is risen to 50 DEG C in a nitrogen atmosphere by agent palladium (0.5g), reacts 2h to end of reaction and system is down to room
Temperature, is added water into system and carries out quenching reaction, extracts organic phase with methyl tertiary butyl ether(MTBE) (100g), and organic phase is concentrated to dryness,
Column chromatographs (PE:MTBE=20:1), obtains the fluoro- 3- methoxyl group -5- methylaniline of 4-, yield: 80%.
The fluoro- 3- methoxyl group -5- methylaniline hydrochloride of S5.4-
The fluoro- 3- methoxyl group -5- methylaniline (50g, 1.0eq) of 4- is dissolved in ethyl alcohol (250g), hydrogen chloride second is then added
System temperature is risen to 70 DEG C, back flow reaction 2h, to end of reaction, by body in a nitrogen atmosphere by alcoholic solution (40g, 2.0eq)
System is down to room temperature, and methyl tertiary butyl ether(MTBE) (250g) is added into system while stirring, has a large amount of solids to be precipitated, and stirs several minutes,
Filtering, drying, obtains the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, yield: 82%.
The nuclear-magnetism testing result of the fluoro- 3- methylphenol of the bromo- 2- of 5-:1H NMR (400MHz, (CD3) 2SO): δ 6.91 (1H,
S), 6.86 (1H, s), 2.17 (3H, s), as shown in Figure 1.
The nuclear-magnetism testing result of the fluoro- 3- methylanisole of the bromo- 2- of 5-:1H NMR (400MHz, (CD3) 2SO): δ 7.15
(1H, s), 7.03 (1H, s), 3.82 (3H, s), 2.19 (3H, s), as shown in Figure 2.
The nuclear-magnetism testing result of the fluoro- 3- methoxyl group -5- methylaniline of 4-: the core of the fluoro- 3- methoxyl group -5- methylaniline of 4-
Magnetic testi result: 1HNMR (400MHz, (CD3) 2SO): δ 7.00 (1H, s), 6.82 (1H, s), 3.82 (3H, s), 2.23 (3H,
S), as shown in Figure 3.
The nuclear-magnetism testing result of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-:1H NMR (400MHz, (CD3) 2SO):
δ 7.00 (1H, s), 6.82 (1H, s), 3.82 (3H, s), 2.23 (3H, s), as shown in Figure 4.
Claims (10)
1. a kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4-, which is characterized in that synthetic route are as follows:
2. a kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- as described in claim 1, feature exist
In, including the following steps:
S1. the bromo- 2- toluene fluoride of 5- and diisopropylamine are added sequentially in the there-necked flask equipped with organic solvent, are added dropwise at 0 DEG C
Dissolved with butyl lithium cyclohexane solution in there-necked flask, be added dropwise, system is cooled to -50~-80 DEG C of 1~2h of reaction, then will
The tetrahydrofuran solution of trimethylborate or boric acid isopropyl ester is added drop-wise in reaction system, and after being added dropwise, the reaction was continued 2~
4h；To end of reaction, water quenching reaction, separation, extraction, concentration are carried out, the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5- is obtained；
S2. the fluoro- 3- methylphenylboronic acid of the bromo- 2- of the 5- is dissolved in after organic solvent and system is cooled to 0~10 DEG C, be then added dropwise
Oxidant is added dropwise, and in a nitrogen atmosphere, system is warming up to 5~10h of reaction at room temperature, to end of reaction, carries out acid and quench
It goes out reaction, separation, extraction, concentration, obtains the fluoro- 3- methylphenol of the bromo- 2- of 5-；
S3. the fluoro- 3- methylphenol of the bromo- 2- of the 5- is dissolved in organic solvent, aqueous slkali is then added, in a nitrogen atmosphere,
Dimethyl suflfate or iodomethane or methanol are added dropwise again, is added dropwise, system temperature is risen to 60~80 DEG C, 1~2h is reacted, to anti-
It should finish, system temperature is down to room temperature, then carry out water quenching reaction, separation, extraction, concentration, obtain the fluoro- 3- first of the bromo- 2- of 5-
Base methyl phenyl ethers anisole；
S4. the fluoro- 3- methylanisole of the bromo- 2- of the 5- is dissolved in carbinolamine or ethyl alcohol, catalyst, nitrogen atmosphere is then added
It is lower that system is warming up to 40~60 DEG C, 2~5h is reacted, to end of reaction, system temperature is down to room temperature, water quenching is carried out and goes out instead
It answers, separate, extract, be concentrated, obtain the fluoro- 3- methoxyl group -5- methylaniline of 4-；
S5. the fluoro- 3- methoxyl group -5- methylaniline of the 4- is dissolved in methanol or ethyl alcohol, hydrogen chloride or hydrogen chloride second is then added
System is warming up to 60~80 DEG C under nitrogen atmosphere by alcoholic solution, and back flow reaction 1~2h of body drops system temperature to end of reaction
To room temperature, methyl tertiary butyl ether(MTBE) is added dropwise into system while stirring, is then filtered, dries, obtains the fluoro- 3- methoxyl group -5- of 4-
Methylaniline hydrochloride.
3. a kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- as claimed in claim 2, feature exist
In, the fluoro- toluene of the bromo- 2- of 5- described in the S1, butyl lithium, diisopropylamine, the molar ratio of trimethylborate or boric acid isopropyl ester
For 1:1.0~1.5:1.0~1.5:1.0~1.5.
4. a kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- as claimed in claim 2, feature exist
In oxidant described in the S2 is hydrogen peroxide, sodium hypochlorite or sodium hypobromite.
5. a kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- as claimed in claim 2, feature exist
In the molar ratio of the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5- described in the S2 and oxidant is 1:2.0~5.0.
6. a kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- as claimed in claim 2, feature exist
In, the molar ratio of the fluoro- 3- methylphenol of the bromo- 2- of 5- described in the S3, dimethyl suflfate or iodomethane or methanol be 1:1.0~
2。
7. a kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- as claimed in claim 2, feature exist
In the mass ratio of the fluoro- 3- methylanisole of the bromo- 2- of 5- described in the S4 and catalyst is 1:0.01~0.1.
8. a kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- as claimed in claim 2, feature exist
In organic solvent described in the S1 is at least one of tetrahydrofuran, ether, methyl tertiary butyl ether(MTBE), toluene；It is described organic
The mass ratio of solvent and the fluoro- toluene of the bromo- 2- of 5- is 5~10:1.
9. a kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- as claimed in claim 2, feature exist
In organic solvent described in the S2 is at least one of tetrahydrofuran, methylene chloride, dioxane, methyl tertiary butyl ether(MTBE)；
The mass ratio of the organic solvent and the fluoro- 3- methylphenylboronic acid of the bromo- 2- of 5- is 5~10:1.
10. a kind of preparation method of the fluoro- 3- methoxyl group -5- methylaniline hydrochloride of 4- as claimed in claim 2, feature exist
In organic solvent described in the S3 is tetrahydrofuran, dioxane, at least one of DMF；The organic solvent and 5-
The mass ratio of the bromo- fluoro- 3- methylphenol of 2- is 5~10:1.
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| CN110885291A (en) * | 2019-12-13 | 2020-03-17 | 阿里生物新材料（常州）有限公司 | Synthetic method of 3-chloro-5- (difluoromethoxy) benzylamine |
| CN111018740A (en) * | 2019-12-20 | 2020-04-17 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester |
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| CN103201280A (en) * | 2010-07-28 | 2013-07-10 | 里格尔药品股份有限公司 | Compositions and methods for inhibition of the jak pathway |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110885291A (en) * | 2019-12-13 | 2020-03-17 | 阿里生物新材料（常州）有限公司 | Synthetic method of 3-chloro-5- (difluoromethoxy) benzylamine |
| CN110885291B (en) * | 2019-12-13 | 2022-04-05 | 阿里生物新材料（常州）有限公司 | Synthetic method of 3-chloro-5- (difluoromethoxy) benzylamine |
| CN111018740A (en) * | 2019-12-20 | 2020-04-17 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester |
| CN111018740B (en) * | 2019-12-20 | 2022-04-05 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester |
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