CN107033015A - A kind of synthetic method of pharmaceutical intermediate - Google Patents
A kind of synthetic method of pharmaceutical intermediate Download PDFInfo
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- CN107033015A CN107033015A CN201710407022.3A CN201710407022A CN107033015A CN 107033015 A CN107033015 A CN 107033015A CN 201710407022 A CN201710407022 A CN 201710407022A CN 107033015 A CN107033015 A CN 107033015A
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- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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Abstract
The present invention relates to medicinal chemistry arts, more particularly to a kind of synthetic method of pharmaceutical intermediate.This method is using chemical compounds I as raw material, in the presence of lithium hexamethyldisilazide catalyst, and chemical compounds I is passed through and organometallic reagent reaction generation compound ii.The present invention is for current synthetic route in industrialized production, production route length, the problem of yield is relatively low, the prepare compound II of innovative use lithium hexamethyldisilazide catalyst in high yield, synthesis cost is low, technique is simple, is adapted to industrial mass production.
Description
Technical field
The invention belongs to medical chemistry synthesis field, and in particular to a kind of synthetic method of pharmaceutical intermediate.
Background technology
Compound ii is a kind of important intermediate, and its Chinese name is referred to as the fluoro- benzophenone of 2- amino -4`-；Chemical constitution
Formula is：
Preparing the method for the fluoro- benzophenone of 2- amino -4`- at present mainly has three kinds：
First, using isatoic anhydride as raw material, the adjacent chloroformyl phenyl ester of isocyanic acid is first generated with thionyl chloride effect, then carry out with fluorobenzene
Friedel-Crafts reaction is made；
2nd, using anthranilic acid as raw material, first amino is protected with paratoluensulfonyl chloride, then chlorination obtains acyl chlorides, then with fluorobenzene
Carry out Friedel-Crafts reaction and Deprotection is made.
3rd, it is to represent using phthalic anhydride as raw material in the document CN1690042A methods reported, first enters with fluorobenzene
Row Friedel-Crafts reaction obtains 2- to fluorobenzoyl yl benzoic acid, then obtains 2- to fluoro benzoyl benzoyl through chloride, amidatioon
Ammonia, eventually passes Hofmann degradation synthesis compound ii.Its reaction scheme is as follows：
In above-mentioned three kinds of preparation methods, first method and second method use Friedel-Crafts reaction, it is understood that Fu Ke is anti-
Answer side reaction many, therefore first method and second method synthesis yield maximum are only capable of reaching 44%.Although the third method does not have
Friedel-Crafts reaction is used, but its reactions steps is long, total recovery is low, and industrial production cost is high.
The content of the invention
For side reaction present in current existing synthetic method is more, step length, the problems such as yield is low, cost is high, this hair
It is bright to disclose the new fluoro- benzophenone synthetic methods of 2- amino -4`- of two classes, specifically：
The invention discloses a kind of synthetic method of pharmaceutical intermediate, this method is in or be not in catalyst using chemical compounds I as raw material
In the presence of, with p-fluorophenyl magnesium chloride or p-fluorophenyl bromination reactive magnesium generation compound ii, its reaction scheme is as follows：
；
Described catalyst is lithium hexamethyldisilazide.
Preferably, reaction dissolvent is selected from least one of dichloromethane, tetrahydrofuran, ether, toluene.It is mentioned here
At least one refers to that one kind can be selected, or a variety of can be used as reaction dissolvent using miscible solvent.
Meanwhile, the present invention further preferably discloses reaction temperature for 0 DEG C ~ 70 DEG C.
In some embodiments it is preferred that ground is molten by lithium hexamethyldisilazide catalyst under the conditions of 0 ~ 20 DEG C of temperature
Liquid and p-fluorophenyl magnesium chloride solution are added in reaction bulb, and addition is added dropwise chemical compounds I after finishing and reacted again, obtains compound
Ⅱ.Meanwhile, in this synthesis mode, preferred solvent is tetrahydrofuran；The dropping temperature of chemical compounds I is 0 ~ 20 DEG C, reaction temperature
Spend for 30 ~ 70 DEG C.
The present invention further preferably discloses the reaction mol ratio of each material, chemical compounds I：P-fluorophenyl magnesium chloride：
Lithium hexamethyldisilazide=1：2~4：5 ~ 15, preferred compound I：P-fluorophenyl magnesium chloride：Lithium hexamethyldisilazide=
1：3~4：5~8.
In some embodiments：It is preferably under the conditions of 0 ~ 20 DEG C of temperature that lithium hexamethyldisilazide catalyst is molten
Liquid and p-fluorophenyl bromide solution are added in reaction bulb, and addition is added dropwise chemical compounds I after finishing and reacted again, obtains compound
Ⅱ.Meanwhile, in this synthesis mode, preferred solvent is dichloromethane；The dropping temperature of chemical compounds I is 0 ~ 20 DEG C, reaction temperature
Spend for 0 ~ 70 DEG C.
The present invention further preferably discloses the reaction mol ratio of each material, chemical compounds I：P-fluorophenyl magnesium bromide：
Lithium hexamethyldisilazide=1：2~4：5 ~ 15, preferred compound I：P-fluorophenyl magnesium chloride：Lithium hexamethyldisilazide=
1：3~4：5~8.
For target product, the present invention also discloses another synthetic method, this method using chemical compounds I as raw material, or
Not in the presence of catalyst, chemical compounds I is passed through generates compound ii with the reaction of p-fluorophenyl lithium, and the reaction scheme of this method is such as
Under：
；
Described catalyst is lithium hexamethyldisilazide.
Preferably, reaction dissolvent is selected from least one of dichloromethane, tetrahydrofuran, ether, toluene in the reaction.This
In described at least one refer to that one kind can be selected, or a variety of reaction dissolvent can be used as using miscible solvent.
Meanwhile, the reaction temperature that the present invention further discloses the reaction is -70 ~ 30 DEG C.
In some embodiments it is preferred that ground under the conditions of temperature -70 ~ 0 DEG C by lithium hexamethyldisilazide catalyst
Solution and p-fluorophenyl lithium solution are added in reaction bulb, and addition is added dropwise chemical compounds I after finishing and reacted again, obtains compound
Ⅱ.This preferred embodiment in, reaction dissolvent is preferably tetrahydrofuran；The dropping temperature of chemical compounds I is -70 ~ 0 DEG C, instead
It is 0 ~ 30 DEG C to answer temperature.
The present invention further preferably discloses the reaction mol ratio of each material, chemical compounds I：P-fluorophenyl lithium：Double three
Methylsilyl amido lithium=1：2~4：5 ~ 15, preferred compound I：P-fluorophenyl lithium：Lithium hexamethyldisilazide=1：3~4：5~8
。
This Fa Ming are to use chemical compounds I first for initiation material, through single step reaction prepare compound II, so as to overcome Fu
The side reaction problem that gram reaction zone comes, and the cost and receipts that reactions steps long during using phthalic anhydride as raw material are brought
Rate problem.
Meanwhile, the present invention is using chemical compounds I as raw material, and raw material is cheap, and source is wide；Pass through the double trimethyl silicanes of innovative use
The prepare compound II of base amido lithium catalyst in high yield；Route of the present invention only has single step reaction, and synthesis cost is low, technique letter
It is single, it is adapted to industrial mass production.
Embodiment
With reference to embodiment, the present invention will be further described, but protection scope of the present invention not limited to this：
Embodiment 1
Lithium hexamethyldisilazide is added in flask（352mmol）, 0 DEG C is cooled to, the tetrahydrochysene of p-fluorophenyl magnesium chloride is added dropwise
Tetrahydrofuran solution（178mmol）.After being added dropwise to complete, at room temperature, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry tetrahydrochysene
Furans（50ml）In, it is cooled to 0 DEG C.The tetrahydrofuran solution of chemical compounds I is added into lithium hexamethyldisilazide dropwise to urge
In the mixed solution of agent and p-fluorophenyl magnesium chloride, stirring is warming up to backflow, reacts 5-7h.Reaction adds acetic acid after terminating
Aqueous ammonium 50g（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration removes solvent,
Crude product is recrystallized with absolute ethyl alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 84%.
Embodiment 2
Lithium hexamethyldisilazide is added in flask（352mmol）, control temperature to 20 DEG C, p-fluorophenyl magnesium chloride be added dropwise
Tetrahydrofuran solution（178mmol）.After being added dropwise to complete, at room temperature, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry
Tetrahydrofuran（50ml）In, control temperature is to 20 DEG C.The tetrahydrofuran solution of chemical compounds I is added to double trimethyl silicon substrates dropwise
In the mixed solution of amido lithium catalyst and p-fluorophenyl magnesium chloride, stirring is warming up to 30 DEG C, reacts 12h.Reaction adds after terminating
Enter ammonium acetate aqueous solution 50g（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration is gone
Except solvent, crude product is recrystallized with absolute ethyl alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 80%.
Embodiment 3
Lithium hexamethyldisilazide is added in flask（352mmol）, 10 DEG C are cooled to, the tetrahydrochysene of p-fluorophenyl magnesium chloride is added dropwise
Tetrahydrofuran solution（178mmol）.After being added dropwise to complete, at room temperature, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry tetrahydrochysene
Furans（50ml）In, it is cooled to 10 DEG C.The tetrahydrofuran solution of chemical compounds I is added into lithium hexamethyldisilazide dropwise to urge
In the mixed solution of agent and p-fluorophenyl magnesium chloride, stirring is warming up to 45 DEG C, reacts 5-10h.Reaction adds acetic acid after terminating
Aqueous ammonium 50g（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration removes solvent,
Crude product is recrystallized with absolute ethyl alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 89%.
Embodiment 4
Lithium hexamethyldisilazide is added in flask（352mmol）, 0 DEG C is cooled to, the tetrahydrochysene of p-fluorophenyl magnesium chloride is added dropwise
Tetrahydrofuran solution（178mmol）.After being added dropwise to complete, at room temperature, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry toluene
（50ml）In, it is cooled to 0 DEG C.The toluene solution of chemical compounds I is added to lithium hexamethyldisilazide catalyst and right dropwise
In the mixed solution of fluorophenyl magnesium chloride, stirring is warming up to backflow, reacts 5-7h.Reaction adds ammonium acetate aqueous solution after terminating
50g（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration removes solvent, crude product nothing
Water-ethanol recrystallize, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 84%.
Embodiment 5
Lithium hexamethyldisilazide is added in flask（352mmol）, -20 DEG C are cooled to, the tetrahydrochysene furan of p-fluorophenyl lithium is added dropwise
Mutter solution（178mmol）.After being added dropwise to complete, at room temperature, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry tetrahydrochysene furan
Mutter（50ml）In, it is cooled to -20 DEG C.The tetrahydrofuran solution of chemical compounds I is added into lithium hexamethyldisilazide dropwise to urge
In the mixed solution of agent and p-fluorophenyl lithium, stirring is warming up to room temperature, reacts 5-7h.Reaction adds ammonium acetate water after terminating
Solution 50g（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration removes solvent, crude product
Recrystallized with absolute ethyl alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 95%.
Embodiment 6
Lithium hexamethyldisilazide is added in flask（352mmol）, -70 DEG C are cooled to, the tetrahydrochysene furan of p-fluorophenyl lithium is added dropwise
Mutter solution（178mmol）.After being added dropwise to complete, at room temperature, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry tetrahydrochysene furan
Mutter（50ml）In, it is cooled to -70 DEG C.The tetrahydrofuran solution of chemical compounds I is added into lithium hexamethyldisilazide dropwise to urge
In the mixed solution of agent and p-fluorophenyl lithium, stirring heats up 0 DEG C, reacts 5-7h.Reaction adds ammonium acetate aqueous solution after terminating
50g（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration removes solvent, crude product nothing
Water-ethanol recrystallize, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 92%.
Embodiment 7
Lithium hexamethyldisilazide is added in flask（352mmol）, 0 DEG C is cooled to, the tetrahydrofuran of p-fluorophenyl lithium is added dropwise
Solution（178mmol）.After being added dropwise to complete, at room temperature, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry tetrahydrofuran
（50ml）In, it is cooled to 0 DEG C.The tetrahydrofuran solution of chemical compounds I is added to lithium hexamethyldisilazide catalyst dropwise
In the mixed solution of p-fluorophenyl lithium, stirring heats up 30 DEG C, reacts 5-7h.Reaction adds ammonium acetate aqueous solution 50g after terminating
（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration removes solvent, and crude product is with anhydrous
Ethyl alcohol recrystallization, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 90%.
Embodiment 8
Lithium hexamethyldisilazide is added in flask（352mmol）, -20 DEG C are cooled to, the tetrahydrochysene furan of p-fluorophenyl lithium is added dropwise
Mutter solution（178mmol）.After being added dropwise to complete, at room temperature, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry toluene
（50ml）In, it is cooled to -20 DEG C.Dropwise by the toluene solution of chemical compounds I be added to lithium hexamethyldisilazide catalyst and
In the mixed solution of p-fluorophenyl lithium, stirring is warming up to room temperature, reacts 5-7h.Reaction adds ammonium acetate aqueous solution 50g after terminating
（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration removes solvent, and crude product is with anhydrous
Ethyl alcohol recrystallization, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 95%.
Embodiment 9
Lithium hexamethyldisilazide is added in flask（352mmol）, 0 DEG C is cooled to, the tetrahydrochysene of p-fluorophenyl magnesium bromide is added dropwise
Tetrahydrofuran solution（178mmol）.After being added dropwise to complete, at room temperature, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry tetrahydrochysene
Furans（50ml）In, it is cooled to 0 DEG C.The tetrahydrofuran solution of chemical compounds I is added into lithium hexamethyldisilazide dropwise to urge
In the mixed solution of agent and p-fluorophenyl magnesium bromide, stirring is warming up to backflow, reacts 5-7h.Reaction adds acetic acid after terminating
Aqueous ammonium 50g（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration removes solvent,
Crude product is recrystallized with absolute ethyl alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 92%.
Embodiment 10
Lithium hexamethyldisilazide is added in flask（352mmol）, keep to 20 DEG C, the tetrahydrochysene of p-fluorophenyl magnesium bromide be added dropwise
Tetrahydrofuran solution（178mmol）.After being added dropwise to complete, at room temperature, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry tetrahydrochysene
Furans（50ml）In, keep to 20 DEG C.The tetrahydrofuran solution of chemical compounds I is added into lithium hexamethyldisilazide dropwise to urge
In the mixed solution of agent and p-fluorophenyl magnesium bromide, stirring is warming up to backflow, reacts 5-7h.Reaction adds acetic acid after terminating
Aqueous ammonium 50g（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration removes solvent,
Crude product is recrystallized with absolute ethyl alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 89%.
Embodiment 11
Lithium hexamethyldisilazide is added in flask（352mmol）, 10 DEG C are cooled to, the tetrahydrochysene of p-fluorophenyl magnesium bromide is added dropwise
Tetrahydrofuran solution（178mmol）.After being added dropwise to complete, at room temperature, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry tetrahydrochysene
Furans（50ml）In, it is cooled to 10 DEG C.The tetrahydrofuran solution of chemical compounds I is added into lithium hexamethyldisilazide dropwise to urge
In the mixed solution of agent and p-fluorophenyl magnesium bromide, stirring is warming up to 45 DEG C, reacts 10h.Reaction adds ammonium acetate after terminating
Aqueous solution 50g（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration removes solvent, slightly
Product are recrystallized with absolute ethyl alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 92%.
Embodiment 12
Flask is cooled to 0 DEG C, and the tetrahydrofuran solution of p-fluorophenyl magnesium bromide is added dropwise（218mmol）.After being added dropwise to complete, room temperature
Under, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry tetrahydrofuran（50ml）In, it is cooled to 0 DEG C.Dropwise by chemical combination
The tetrahydrofuran solution of thing I is added in p-fluorophenyl bromide solution, stirring, is warming up to backflow, reacts 5-7h.Reaction terminates
Ammonium acetate aqueous solution 50g is added afterwards（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）It is dense
Contracting removes solvent, and crude product recrystallizes with absolute ethyl alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield
75%。
Embodiment 13
Flask is cooled to 0 DEG C, and the tetrahydrofuran solution of p-fluorophenyl magnesium chloride is added dropwise（163mmol）.After being added dropwise to complete, room temperature
Under, by the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry tetrahydrofuran（50ml）In, it is cooled to 0 DEG C.Dropwise by chemical combination
The tetrahydrofuran solution of thing I is added in p-fluorophenyl magnesium chloride solution, stirring, is warming up to backflow, reacts 5-7h.Reaction terminates
Ammonium acetate aqueous solution 50g is added afterwards（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）It is dense
Contracting removes solvent, and crude product recrystallizes with absolute ethyl alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield
62%。
Embodiment 14
Flask is cooled to -20 DEG C, and the tetrahydrofuran solution of p-fluorophenyl lithium is added dropwise（178mmol）.After being added dropwise to complete, at room temperature,
By the chemical compounds I after dehydration（54.6mmol）It is dissolved in dry tetrahydrofuran（50ml）In, it is cooled to -20 DEG C.Dropwise by chemical combination
The tetrahydrofuran solution of thing I is added in the solution of p-fluorophenyl lithium, stirring, is warming up to room temperature, reacts 5-7h.After reaction terminates
Add ammonium acetate aqueous solution 50g（Ammonium acetate 7.5g/ water 42.5g）Reaction is quenched, adds clear water and washs three times（60ml*3）Concentration
Remove solvent, crude product recrystallizes with absolute ethyl alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 72%.
Claims (8)
1. a kind of synthetic method of pharmaceutical intermediate, it is characterised in that：This method is using chemical compounds I as raw material, with p-fluorophenyl chlorine
Change magnesium or p-fluorophenyl bromination reactive magnesium generation compound ii, reaction synthetic route is as follows：
。
2. the synthetic method of pharmaceutical intermediate according to claim 1, it is characterised in that：Reaction dissolvent is selected from dichloromethane
At least one of alkane, tetrahydrofuran, ether, toluene.
3. the synthetic method of pharmaceutical intermediate according to claim 1, it is characterised in that：Reaction temperature is 0 DEG C ~ 70 DEG C.
4. the synthetic method of pharmaceutical intermediate according to claim 1, it is characterised in that：Also include catalysis in reaction
Agent, described catalyst is lithium hexamethyldisilazide.
5. a kind of synthetic method of pharmaceutical intermediate, it is characterised in that：This method is using chemical compounds I as raw material, with p-fluorophenyl lithium
Reaction generation compound ii, reaction synthetic route is as follows：
。
6. the synthetic method of pharmaceutical intermediate according to claim 5, it is characterised in that：Reaction dissolvent is selected from dichloromethane
At least one of alkane, tetrahydrofuran, ether, toluene.
7. the synthetic method of pharmaceutical intermediate according to claim 5, it is characterised in that：Reaction temperature is -70 ~ 30 DEG C.
8. the synthetic method of pharmaceutical intermediate according to claim 5, it is characterised in that：Also include catalysis in reaction
Agent, described catalyst is lithium hexamethyldisilazide.
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| CN106061480A (en) * | 2013-12-30 | 2016-10-26 | 莱福斯希医药公司 | Therapeutic inhibitory compounds |
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