CN107033015B - A kind of synthetic method of pharmaceutical intermediate - Google Patents
A kind of synthetic method of pharmaceutical intermediate Download PDFInfo
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- CN107033015B CN107033015B CN201710407022.3A CN201710407022A CN107033015B CN 107033015 B CN107033015 B CN 107033015B CN 201710407022 A CN201710407022 A CN 201710407022A CN 107033015 B CN107033015 B CN 107033015B
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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, and under the action of lithium hexamethyldisilazide catalyst, chemical compounds I is reacted with organometallic reagent generates compound ii.The present invention is for current synthetic route in industrialized production, the problem that production route is long, yield is lower, the innovative prepare compound II using lithium hexamethyldisilazide catalyst high yield, synthesis cost is low, simple process is suitble to industrial mass production.
Description
Technical field
The invention belongs to medical chemistries to synthesize field, and in particular to a kind of synthetic method of pharmaceutical intermediate.
Background technique
Compound ii is a kind of important intermediate, and Chinese name is known as the fluoro- benzophenone of 2- amino -4`-；Chemical structure
Formula are as follows:
There are mainly three types of the methods for preparing the fluoro- benzophenone of 2- amino -4`- at present:
One, using isatoic anhydride as raw material, first with thionyl chloride effect generate isocyanic acid neighbour chloroformyl phenyl ester, then with fluorobenzene
Friedel-Crafts reaction is carried out to be made；
Two, using anthranilic acid as raw material, first amino to be protected with paratoluensulfonyl chloride, then chlorination obtains acyl chlorides, then with
Fluorobenzene carries out Friedel-Crafts reaction and Deprotection is made.
Three, be to represent using phthalic anhydride as raw material in the method that document CN1690042A is reported, elder generation and fluorobenzene into
Row Friedel-Crafts reaction obtains 2- to fluorobenzoyl yl benzoic acid, then obtains 2- to fluoro benzoyl benzoyl through chloride, amidation
Ammonia finally synthesizes compound ii by Hofmann degradation.Its reaction route 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
Gram reaction side reaction is more, therefore first method and second method synthesis yield maximum are only capable of reaching 44%.Though the third method
Friedel-Crafts reaction is not so used, but its reaction step is long, total recovery is low, and industrial production cost is high.
Summary of the invention
For the problems such as side reaction is more, step is long, yield is low, at high cost present in current existing synthetic method, this hair
It is bright to disclose the new fluoro- benzophenone synthetic method 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 and urges using chemical compounds I as raw material
Under the action of agent, is reacted with p-fluorophenyl magnesium chloride or p-fluorophenyl magnesium bromide and generate compound ii, reaction route is such as
Under:
；
The catalyst is lithium hexamethyldisilazide.
Preferably, reaction dissolvent is selected from least one of methylene chloride, tetrahydrofuran, ether, toluene.It is mentioned here
At least one, which refers to, can choose one kind or a variety of solvents that can be miscible as reaction dissolvent.
Meanwhile it is 0 DEG C ~ 70 DEG C that the present invention, which further preferably discloses reaction temperature,.
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 flask, and chemical compounds I is added dropwise after addition again and is reacted, compound is obtained
Ⅱ.Meanwhile in this synthesis mode, preferred solvent is tetrahydrofuran；The dropping temperature of chemical compounds I is 0 ~ 20 DEG C, reaction temperature
Degree is 30 ~ 70 DEG C.
The reaction molar ratio that the present invention further preferably discloses each substance is 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: 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 flask, and chemical compounds I is added dropwise after addition again and is reacted, compound is obtained
Ⅱ.Meanwhile in this synthesis mode, preferred solvent is methylene chloride；The dropping temperature of chemical compounds I is 0 ~ 20 DEG C, reaction temperature
Degree is 0 ~ 70 DEG C.
The reaction molar ratio that the present invention further preferably discloses each substance is 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,
It is in or be not under the action of catalyst, chemical compounds I is reacted with p-fluorophenyl lithium generates compound ii, the reaction route of this method
It is as follows:
；
The catalyst is lithium hexamethyldisilazide.
Preferably, reaction dissolvent is selected from least one of methylene chloride, tetrahydrofuran, ether, toluene in the reaction.This
In described at least one refer to and can choose one kind or a variety of solvents that can be miscible as reaction dissolvent.
Meanwhile it is -70 ~ 30 DEG C that the present invention, which further discloses the reaction temperature of the reaction,.
In some embodiments it is preferred that ground is under the conditions of temperature -70 ~ 0 DEG C by lithium hexamethyldisilazide catalyst
Solution and p-fluorophenyl lithium solution are added in reaction flask, and chemical compounds I is added dropwise after addition again and is reacted, compound is obtained
Ⅱ.In the preferred embodiment, reaction dissolvent is preferably tetrahydrofuran；The dropping temperature of chemical compounds I is -70 ~ 0 DEG C, instead
Answering temperature is 0 ~ 30 DEG C.
The reaction molar ratio that the present invention further preferably discloses each substance is 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 is to use chemical compounds I for starting material for the first time, through single step reaction prepare compound II, to overcome Fu
Gram reaction bring side reaction problem, and reaction step bring cost and receipts that using phthalic anhydride as raw material when is too long
Rate problem.
Meanwhile the present invention, using chemical compounds I as raw material, raw material is cheap, and source is wide；Pass through the innovative double trimethyl silicanes of use
The prepare compound II of base amido lithium catalyst high yield；Route of the present invention only has single step reaction, and synthesis cost is low, technique letter
It is single, it is suitble to industrial mass production.
Specific embodiment
Below with reference to embodiment, the present invention will be further described, and but the scope of the present invention is not limited thereto:
Embodiment 1
Lithium hexamethyldisilazide (352mmol) is added in flask, is cooled to 0 DEG C, p-fluorophenyl magnesium chloride is added dropwise
Tetrahydrofuran solution (178mmol).After being added dropwise to complete, at room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry
In tetrahydrofuran (50ml), it is cooled to 0 DEG C.The tetrahydrofuran solution of chemical compounds I is added to double trimethyl silicon substrate amidos dropwise
In the mixed solution of lithium catalyst and p-fluorophenyl magnesium chloride, stirring is warming up to reflux, reacts 5-7h.It is added after reaction
Ammonium acetate aqueous solution 50g(ammonium acetate 7.5g/ water 42.5g) quenching reaction, clear water washing (60ml*3) concentration removal three times is added
Solvent, crude product are recrystallized with dehydrated alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 84%.
Embodiment 2
Lithium hexamethyldisilazide (352mmol) is added in flask, controls temperature to 20 DEG C, p-fluorophenyl chlorination is added dropwise
The tetrahydrofuran solution (178mmol) of magnesium.After being added dropwise to complete, at room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry
In dry tetrahydrofuran (50ml), temperature is controlled to 20 DEG C.The tetrahydrofuran solution of chemical compounds I is added to double trimethyls dropwise
In the mixed solution of silicon substrate amido lithium catalyst and p-fluorophenyl magnesium chloride, stirring is warming up to 30 DEG C, reacts 12h.Reaction terminates
Ammonium acetate aqueous solution 50g(ammonium acetate 7.5g/ water 42.5g is added afterwards) quenching reaction, it is dense three times (60ml*3) that clear water washing is added
Contracting removal solvent, crude product recrystallizes with dehydrated alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield
80%。
Embodiment 3
Lithium hexamethyldisilazide (352mmol) is added in flask, is cooled to 10 DEG C, p-fluorophenyl magnesium chloride is added dropwise
Tetrahydrofuran solution (178mmol).After being added dropwise to complete, at room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry
In tetrahydrofuran (50ml), it is cooled to 10 DEG C.The tetrahydrofuran solution of chemical compounds I is added to double trimethyl silicon substrate amidos dropwise
In the mixed solution of lithium catalyst and p-fluorophenyl magnesium chloride, stirring is warming up to 45 DEG C, reacts 5-10h.It is added after reaction
Ammonium acetate aqueous solution 50g(ammonium acetate 7.5g/ water 42.5g) quenching reaction, clear water washing (60ml*3) concentration removal three times is added
Solvent, crude product are recrystallized with dehydrated alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 89%.
Embodiment 4
Lithium hexamethyldisilazide (352mmol) is added in flask, is cooled to 0 DEG C, p-fluorophenyl magnesium chloride is added dropwise
Tetrahydrofuran solution (178mmol).After being added dropwise to complete, at room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry
In toluene (50ml), it is cooled to 0 DEG C.The toluene solution of chemical compounds I is added to lithium hexamethyldisilazide catalyst dropwise
In the mixed solution of p-fluorophenyl magnesium chloride, stirring is warming up to reflux, reacts 5-7h.Ammonium acetate water is added after reaction
Solution 50g(ammonium acetate 7.5g/ water 42.5g) quenching reaction, clear water washing (60ml*3) concentration removal solvent three times, crude product is added
Recrystallized with dehydrated alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 84%.
Embodiment 5
Lithium hexamethyldisilazide (352mmol) is added in flask, is cooled to -20 DEG C, the four of p-fluorophenyl lithium are added dropwise
Hydrogen tetrahydrofuran solution (178mmol).After being added dropwise to complete, at room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry four
In hydrogen furans (50ml), it is cooled to -20 DEG C.The tetrahydrofuran solution of chemical compounds I is added to double trimethyl silicon substrate amidos dropwise
In the mixed solution of lithium catalyst and p-fluorophenyl lithium, stirring is warming up to room temperature, reacts 5-7h.Acetic acid is added after reaction
Aqueous ammonium 50g(ammonium acetate 7.5g/ water 42.5g) quenching reaction, clear water washing (60ml*3) concentration removal solvent three times is added,
Crude product is recrystallized with dehydrated alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 95%.
Embodiment 6
Lithium hexamethyldisilazide (352mmol) is added in flask, is cooled to -70 DEG C, the four of p-fluorophenyl lithium are added dropwise
Hydrogen tetrahydrofuran solution (178mmol).After being added dropwise to complete, at room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry four
In hydrogen furans (50ml), it is cooled to -70 DEG C.The tetrahydrofuran solution of chemical compounds I is added to double trimethyl silicon substrate amidos dropwise
In the mixed solution of lithium catalyst and p-fluorophenyl lithium, stirring heats up 0 DEG C, reacts 5-7h.Ammonium acetate water is added after reaction
Solution 50g(ammonium acetate 7.5g/ water 42.5g) quenching reaction, clear water washing (60ml*3) concentration removal solvent three times, crude product is added
Recrystallized with dehydrated alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 92%.
Embodiment 7
Lithium hexamethyldisilazide (352mmol) is added in flask, is cooled to 0 DEG C, the tetrahydro of p-fluorophenyl lithium is added dropwise
Tetrahydrofuran solution (178mmol).After being added dropwise to complete, at room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry tetrahydro
In furans (50ml), it is cooled to 0 DEG C.The tetrahydrofuran solution of chemical compounds I lithium hexamethyldisilazide is added to dropwise to urge
In the mixed solution of agent and p-fluorophenyl lithium, stirring heats up 30 DEG C, reacts 5-7h.It is water-soluble that ammonium acetate is added after reaction
Liquid 50g(ammonium acetate 7.5g/ water 42.5g) quenching reaction, clear water washing is added, and (60ml*3) concentration removal solvent, crude product are used three times
Dehydrated alcohol recrystallization, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 90%.
Embodiment 8
Lithium hexamethyldisilazide (352mmol) is added in flask, is cooled to -20 DEG C, the four of p-fluorophenyl lithium are added dropwise
Hydrogen tetrahydrofuran solution (178mmol).After being added dropwise to complete, at room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry first
In benzene (50ml), it is cooled to -20 DEG C.The toluene solution of chemical compounds I is added to lithium hexamethyldisilazide catalyst dropwise
In the mixed solution of p-fluorophenyl lithium, stirring is warming up to room temperature, reacts 5-7h.Ammonium acetate aqueous solution is added after reaction
50g(ammonium acetate 7.5g/ water 42.5g) quenching reaction, clear water washing (60ml*3) concentration removal solvent three times, crude product nothing is added
Water-ethanol recrystallization, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 95%.
Embodiment 9
Lithium hexamethyldisilazide (352mmol) is added in flask, is cooled to 0 DEG C, p-fluorophenyl magnesium bromide is added dropwise
Tetrahydrofuran solution (178mmol).After being added dropwise to complete, at room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry
In tetrahydrofuran (50ml), it is cooled to 0 DEG C.The tetrahydrofuran solution of chemical compounds I is added to double trimethyl silicon substrate amidos dropwise
In the mixed solution of lithium catalyst and p-fluorophenyl magnesium bromide, stirring is warming up to reflux, reacts 5-7h.It is added after reaction
Ammonium acetate aqueous solution 50g(ammonium acetate 7.5g/ water 42.5g) quenching reaction, clear water washing (60ml*3) concentration removal three times is added
Solvent, crude product are recrystallized with dehydrated alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 92%.
Embodiment 10
Lithium hexamethyldisilazide (352mmol) is added in flask, keeps to 20 DEG C, p-fluorophenyl magnesium bromide is added dropwise
Tetrahydrofuran solution (178mmol).After being added dropwise to complete, at room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry
In tetrahydrofuran (50ml), keep to 20 DEG C.The tetrahydrofuran solution of chemical compounds I is added to double trimethyl silicon substrate amidos dropwise
In the mixed solution of lithium catalyst and p-fluorophenyl magnesium bromide, stirring is warming up to reflux, reacts 5-7h.It is added after reaction
Ammonium acetate aqueous solution 50g(ammonium acetate 7.5g/ water 42.5g) quenching reaction, clear water washing (60ml*3) concentration removal three times is added
Solvent, crude product are recrystallized with dehydrated alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield 89%.
Embodiment 11
Lithium hexamethyldisilazide (352mmol) is added in flask, is cooled to 10 DEG C, p-fluorophenyl magnesium bromide is added dropwise
Tetrahydrofuran solution (178mmol).After being added dropwise to complete, at room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry
In tetrahydrofuran (50ml), it is cooled to 10 DEG C.The tetrahydrofuran solution of chemical compounds I is added to double trimethyl silicon substrate amidos dropwise
In the mixed solution of lithium catalyst and p-fluorophenyl magnesium bromide, stirring is warming up to 45 DEG C, reacts 10h.Vinegar is added after reaction
Sour aqueous ammonium 50g(ammonium acetate 7.5g/ water 42.5g) quenching reaction, clear water washing is added, and (60ml*3) concentration removal is molten three times
Agent, crude product are recrystallized with dehydrated 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 (218mmol) of p-fluorophenyl magnesium bromide is added dropwise.After being added dropwise to complete,
At room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry tetrahydrofuran (50ml), is cooled to 0 DEG C.Dropwise will
The tetrahydrofuran solution of chemical compounds I is added in p-fluorophenyl bromide solution, and stirring is warming up to reflux, reacts 5-7h.Reaction
After ammonium acetate aqueous solution 50g(ammonium acetate 7.5g/ water 42.5g is added) quenching reaction, clear water washing (60ml* three times is added
3) concentration removal solvent, crude product recrystallizes with dehydrated alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, receive
Rate 75%.
Embodiment 13
Flask is cooled to 0 DEG C, and the tetrahydrofuran solution (163mmol) of p-fluorophenyl magnesium chloride is added dropwise.After being added dropwise to complete,
At room temperature, dewatered chemical compounds I (54.6mmol) is dissolved in dry tetrahydrofuran (50ml), is cooled to 0 DEG C.Dropwise will
The tetrahydrofuran solution of chemical compounds I is added in p-fluorophenyl magnesium chloride solution, and stirring is warming up to reflux, reacts 5-7h.Reaction
After ammonium acetate aqueous solution 50g(ammonium acetate 7.5g/ water 42.5g is added) quenching reaction, clear water washing (60ml* three times is added
3) concentration removal solvent, crude product recrystallizes with dehydrated alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, receive
Rate 62%.
Embodiment 14
Flask is cooled to -20 DEG C, and the tetrahydrofuran solution (178mmol) of p-fluorophenyl lithium is added dropwise.After being added dropwise to complete, room temperature
Under, dewatered chemical compounds I (54.6mmol) is dissolved in dry tetrahydrofuran (50ml), is cooled to -20 DEG C.It will change dropwise
The tetrahydrofuran solution for closing object I is added in the solution of p-fluorophenyl lithium, is stirred, and room temperature is warming up to, and reacts 5-7h.Reaction terminates
Ammonium acetate aqueous solution 50g(ammonium acetate 7.5g/ water 42.5g is added afterwards) quenching reaction, it is dense three times (60ml*3) that clear water washing is added
Contracting removal solvent, crude product recrystallizes with dehydrated alcohol, filtering and washing it is dry chartreuse acicular crystal compound ii, yield
72%。
Claims (6)
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 the reaction of p-fluorophenyl magnesium bromide generate compound ii, reaction synthetic route is as follows:
；
It also include catalyst in reaction, the catalyst is lithium hexamethyldisilazide.
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. 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 generates compound ii, and reaction synthetic route is as follows:
；
It also include catalyst in reaction, the catalyst is lithium hexamethyldisilazide.
5. the synthetic method of pharmaceutical intermediate according to claim 4, it is characterised in that: reaction dissolvent is selected from dichloromethane
At least one of alkane, tetrahydrofuran, ether, toluene.
6. the synthetic method of pharmaceutical intermediate according to claim 4, it is characterised in that: reaction temperature is -70 ~ 30 DEG C.
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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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| WO2017040450A1 (en) * | 2015-09-03 | 2017-03-09 | Bristol-Myers Squibb Company | Triazolopyridine inhibitors of myeloperoxidase |
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2017
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| CN102812003A (en) * | 2009-12-18 | 2012-12-05 | 欧洲筛选有限公司 | Pyrrolidine Or Thiazolidine Carboxylic Acid Derivatives, Pharmaceutical Composition And Methods For Use In Treating Metabolic Disordersas As Agonists Of G- Protein Coupled Receptor 43 (GPR43) |
| WO2011117254A1 (en) * | 2010-03-22 | 2011-09-29 | Prosidion Limited | Piperidine amides as modulators of the ghrelin receptor |
| CN106061480A (en) * | 2013-12-30 | 2016-10-26 | 莱福斯希医药公司 | Therapeutic inhibitory compounds |
| WO2017035114A1 (en) * | 2015-08-25 | 2017-03-02 | Janssen Pharmaceutica Nv | Benzimidazole derivatives useful as cb-1 inverse agonists |
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