CN105985258B - A kind of Preparation Method And Their Intermediate of benzamide compounds - Google Patents
A kind of Preparation Method And Their Intermediate of benzamide compounds Download PDFInfo
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- CN105985258B CN105985258B CN201510047515.1A CN201510047515A CN105985258B CN 105985258 B CN105985258 B CN 105985258B CN 201510047515 A CN201510047515 A CN 201510047515A CN 105985258 B CN105985258 B CN 105985258B
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Abstract
The invention discloses a kind of Preparation Method And Their Intermediates of benzamide compounds.The present invention provides a kind of preparation methods of benzamide compounds 3; it includes the following steps: in the case where protective gas is protected; in polar non-solute; in the presence of catalyst such as shown in formula A, cuprous halide and inorganic base; compound 1 and compound 2 are subjected to coupling reaction, obtain benzamide compounds 3.This method high income, easy to operate, highly-safe, clean and environmental protection are suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of Preparation Method And Their Intermediates of benzamide compounds.
Background technique
U.S. FDA approval has been obtained at present for treating the metastatic castration-resistant prostate after docetaxel is treated
Cancer, and there is data to show, the patient that the miscellaneous Shandong amine of grace is used to treat without docetaxel is also effective.Researcher's discovery, grace are miscellaneous
Shandong amine can significantly postpone the time that chemotherapy starts, when significantly optimizing prostate-specific antigen (PSA) reactivity, PSA progress
Between, objective soft tissue reactivity, and first appear the time of bone dependent event.In follow-up in 26 months, the miscellaneous Shandong amine of grace is controlled
Treatment group does not show that median survival interval, placebo are 31 months.In addition, En Zalu amine treatment group quality of life reactivity is close
40%, and this number of placebo is 22.9%.FACT-P it is all consider aspect the miscellaneous Shandong amine of grace compared to placebo
Group can significantly improve the quality of life of patient.
The miscellaneous Shandong amine of grace is synthesized by University of California's research earliest, reference compound patent CN101222922:
The route steps are long, and committed step yield is very low, and wherein this synthetic method uses and made in acid condition with iron powder
The fluoro- N-methyl-benzamide compound of catalyst preparation 4- amino -2- can generate a large amount of waste water, and product in this preparation process
Yield and purity is not high, is not suitable for large-scale industrial production；Furthermore oxidant, hydroxyl cyanogen third are made using the chromium trioxide of severe toxicity
Ketone has biggish toxic action to human body and environment, and brings risk factor to industrialized production.
Therefore, Medivation company improves its synthesis technology, referenced patent document CN103108549A with
The specific synthetic route of WO2011106570 is as follows:
But valuable reagent and extremely toxic substance involved in route, therefore its is cumbersome, safety is low, pollution environment, simultaneously
The route yield is low.
Therefore, it is badly in need of a kind of high income, easy to operate, highly-safe, clean and environmental protection in pharmaceuticals industry, is suitable for industrial metaplasia
The preparation method of the miscellaneous Shandong amine of the grace of production.
Summary of the invention
The technical problem to be solved by the present invention is to the preparation method yields in order to overcome existing benzamide compounds
Low, cumbersome, the defects of safety is low, pollution environment and provide a kind of preparation method and wherein of benzamide compounds
Mesosome, this method high income, easy to operate, highly-safe, clean and environmental protection are suitable for industrialized production.
The present invention provides a kind of preparation methods of benzamide compounds 3 comprising following step: protecting in protective gas
Under shield, in polar non-solute, in the presence of catalyst such as shown in formula A, cuprous halide and inorganic base, by compound
1 and compound 2 carry out coupling reaction, obtain benzamide compounds 3；
In the coupling reaction, the protective gas can be the protective gas of this field routine, preferably helium
One of gas, argon gas, nitrogen and neon are a variety of.
In the coupling reaction, the polar non-solute can be the polarity of the coupling reaction of this field routine
Aprotic solvent, preferably n,N-Dimethylformamide and/or N-Methyl pyrrolidone.
In the coupling reaction, the volume mass ratio of the polar non-solute and compound 1 can be ability
The volume mass ratio of the coupling reaction of domain routine, preferably 3mL/g~8mL/g are more preferably 5mL/g~6mL/g.
In the coupling reaction, the molar ratio of the compound A and compound 1 can be the coupling of this field routine
The molar ratio of reaction, preferably 0.1~0.5 are more preferably 0.12~0.3.
In the coupling reaction, the cuprous halide can be the cuprous halide of the coupling reaction of this field routine,
Preferably one of stannous chloride, cuprous bromide and cuprous iodide or a variety of are more preferably stannous chloride.
In the coupling reaction, the molar ratio of the cuprous halide and compound 1 can be the idol of this field routine
The molar ratio of connection reaction, preferably 0.1~0.7, it is more preferably 0.2~0.5.
In the coupling reaction, the inorganic base can be the inorganic base of the coupling reaction of this field routine, preferably
Ground is one of potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate or a variety of, is more preferably potassium carbonate.
In the coupling reaction, the molar ratio of the inorganic base and compound 1 can be the coupling of this field routine
The molar ratio of reaction, preferably 2.0~3.5 are more preferably 2.5~3.0.
In the coupling reaction, the molar ratio of the compound 2 and compound 1 can be the coupling of this field routine
The molar ratio of reaction, preferably 1.2~2.5 are more preferably 1.5~1.8.
The temperature of the coupling reaction can for this field routine coupling reaction temperature, preferably 100 DEG C~150
DEG C, it is more preferably 115 DEG C~125 DEG C.
The process of the coupling reaction can by traditional test methods in this field (such as thin-layered chromatography, HPLC,
NMR it) monitors, as reaction end when generally no longer being reacted using compound 1；The time of the coupling reaction be preferably 8h~
It for 24 hours, is more preferably 10h~15h.
The coupling reaction preferably carries out in presence of water；The molar ratio of the water and compound 1 can be this
The molar ratio of the coupling reaction of field routine, preferably 1.0~3.0, it is more preferably 1.3~2.0.
The present invention also provides a kind of preparation methods of benzamide compounds 4, can be method 1 or method 2；
The method 1 includes the following steps: that (1) prepares benzene according to the preparation method of above-mentioned benzamide compounds 3
Benzamide compound 3；(2) under protective gas protection, in R1In OH, under the conditions of existing for the thionyl chloride, step (1) is made
Standby benzamide compounds 3 carry out esterification, obtain benzamide compounds 4；The R1For C1~C4Alkyl
Or benzyl；
The method 2 includes the following steps: 1. to prepare benzene first according to the preparation method of above-mentioned benzamide compounds 3
Amide compound 3；2. under protective gas protection, in polar non-solute, under the conditions of existing for the inorganic base, by step
1. the benzamide compounds 3 and R that prepare1X carries out substitution reaction, obtains benzamide compounds 4；The R1For C1
~C4Alkyl or benzyl, the X is halogen, but R1X is not iodomethane；
In the esterification, the C1~C4Alkyl be preferably methyl, ethyl, propyl or isopropyl, more
It goodly is methyl or ethyl.
In the esterification, the protective gas can be the protective gas of this field routine, preferably helium
One of gas, argon gas, nitrogen and neon are a variety of.
In the esterification, the R1The mass ratio of OH and the benzamide compounds 3 can be ability
The mass ratio of the esterification of domain routine, preferably 3~7, it is more preferably 4~5.
In the esterification, the molar ratio of the thionyl chloride and the benzamide compounds 3 can be
The molar ratio of the esterification of this field routine, preferably 1~8, it is more preferably 5~6.
The temperature of the esterification can for this field routine esterification temperature, preferably 40 DEG C~90
DEG C, it is more preferably 60 DEG C~70 DEG C, such as 65 DEG C.
The process of the esterification can by traditional test methods in this field (such as thin-layered chromatography, HPLC,
NMR it) monitors, as reaction end when generally no longer being reacted using benzamide compounds 3；The time of the esterification is preferably
It is more preferably 6h~8h for 3h~10h.
In the substitution reaction, the C1~C4Alkyl be preferably methyl, ethyl, propyl or isopropyl, more
It goodly is ethyl.
In the substitution reaction, the halogen is preferably fluorine, chlorine, bromine or iodine, is more preferably bromine.
In the substitution reaction, the protective gas can be the protective gas of this field routine, preferably helium
One of gas, argon gas, nitrogen and neon are a variety of.
In the substitution reaction, the polar non-solute can be the polarity of the substitution reaction of this field routine
One of aprotic solvent, preferably n,N-Dimethylformamide, dimethyl sulfoxide and N-Methyl pyrrolidone are a variety of.
In the substitution reaction, the volume of the polar non-solute and the benzamide compounds 3
Molar ratio can for this field routine substitution reaction Molar ratio, preferably 0.7L/mol~2.5L/mol, more preferably
For 1L/mol~2L/mol.
In the substitution reaction, the inorganic base is the inorganic base of the substitution reaction of this field routine, preferably
It is more preferably potassium carbonate for one of potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate or a variety of.
In the substitution reaction, the molar ratio of the inorganic base and the benzamide compounds 3 can be this
The molar ratio of the substitution reaction of field routine, preferably 1.0~2.5, it is more preferably 1.5~2.0.
In the substitution reaction, the R1The molar ratio of X and the benzamide compounds 3 can be this field
The molar ratio of conventional substitution reaction, preferably 1.5~3.0, it is more preferably 2.2~2.5.
The temperature of the substitution reaction can for this field routine substitution reaction temperature, preferably 20 DEG C~50
DEG C, it is more preferably 30 DEG C~35 DEG C.
The process of the substitution reaction can by traditional test methods in this field (such as thin-layered chromatography, HPLC,
NMR it) monitors, as reaction end when generally no longer being reacted using benzamide compounds 3；The time of the substitution reaction is preferably
It is more preferably 6h~8h for 5h~10h.
The substitution reaction preferably carries out in presence of water；The water and the benzamide compounds 3
Molar than can be this field routine substitution reaction Molar ratio, preferably 0.002L/mol~0.01L/
Mol is more preferably 0.0025L/mol~0.003L/mol.
The present invention also provides a kind of preparation methods of benzamide compounds 6 comprising following step: (a) according to upper
The preparation method for the benzamide compounds 4 stated prepares benzamide compounds 4；(b) under protective gas protection, organic molten
In agent, the benzamide compounds 4 of step (a) preparation and compound 5 are subjected to annulation, obtain benzamide compounds 6
?；The organic solvent is sulfone class solvent and/or esters solvent；
Wherein, R1For C1~C4Alkyl or benzyl, but not be methyl；Preferably ethyl, propyl, isopropyl or benzyl,
It is more preferably ethyl.
In the annulation, the protective gas can be the protective gas of this field routine, preferably helium
One of gas, argon gas, nitrogen and neon are a variety of.
In the annulation, the sulfone class solvent can be the sulfone class solvent of the substitution reaction of this field routine,
Preferably dimethyl sulfoxide；The esters solvent can be the esters solvent of the substitution reaction of this field routine, preferably second
One of acetoacetic ester, isopropyl acetate and butyl acetate are a variety of.
In the annulation, the organic solvent is preferably dimethyl sulfoxide and/or isopropyl acetate, more preferably
Ground is the organic solvent for being 1:1~1:2 by the volume ratio that dimethyl sulfoxide and isopropyl acetate form.
In the annulation, the Molar ratio of the organic solvent and the benzamide compounds 4
It can be the Molar ratio of the annulation of this field routine, preferably 0.5L/mol~1.3L/mol is more preferably 0.7L/
Mol~1.0L/mol.
In the annulation, the molar ratio of the compound 5 and the benzamide compounds 4 can be this
The molar ratio of the annulation of field routine, preferably 1.5~2.8, it is more preferably 1.9~2.5.
The temperature of the annulation can for this field routine annulation temperature, preferably 55 DEG C~90
DEG C, it is more preferably 70 DEG C~85 DEG C.
The process of the annulation can by traditional test methods in this field (such as thin-layered chromatography, HPLC,
NMR it) monitors, as reaction end when generally no longer being reacted using benzamide compounds 4, the time of the annulation is preferably
It is more preferably 15h~20h for 12h~25h.
The present invention also provides a kind of preparation methods of benzamide compounds 4, can be method 1 or method 2；
The method 1 includes the following steps: in the case where protective gas is protected, in R1In OH, the item existing for thionyl chloride
Under part, benzamide compounds 3 are subjected to esterification, obtain benzamide compounds 4；The R1For C1~C4's
Alkyl or benzyl；
The method 2 includes the following steps: in the case where protective gas is protected, in polar non-solute, in inorganic base
Under the conditions of existing, by benzamide compounds 3 and R1X carries out substitution reaction, obtains benzamide compounds 4；R1For C1
~C4Alkyl or benzyl, the X is halogen, but R1X is not iodomethane；
In the esterification, the C1~C4Alkyl be preferably methyl, ethyl, propyl or isopropyl, more
It goodly is methyl or ethyl.
In the esterification, the protective gas can be the protective gas of this field routine, preferably helium
One of gas, argon gas, nitrogen and neon are a variety of.
In the esterification, the R1The mass ratio of OH and the benzamide compounds 3 can be ability
The mass ratio of the esterification of domain routine, preferably 3~7, it is more preferably 4~5.
In the esterification, the molar ratio of the thionyl chloride and the benzamide compounds 3 can be
The molar ratio of the esterification of this field routine, preferably 1~8, it is more preferably 5~6.
The temperature of the esterification can for this field routine esterification temperature, preferably 40 DEG C~90
DEG C, it is more preferably 60 DEG C~70 DEG C, such as 65 DEG C.
The process of the esterification can by traditional test methods in this field (such as thin-layered chromatography, HPLC,
NMR it) monitors, as reaction end when generally no longer being reacted using benzamide compounds 3；The time of the esterification is preferably
It is more preferably 6h~8h for 3h~10h.
In the substitution reaction, the C1~C4Alkyl be preferably methyl, ethyl, propyl or isopropyl, more
It goodly is ethyl.
In the substitution reaction, the halogen is preferably fluorine, chlorine, bromine or iodine, is more preferably bromine.
In the substitution reaction, the protective gas can be the protective gas of this field routine, preferably helium
One of gas, argon gas, nitrogen and neon are a variety of.
In the substitution reaction, the polar non-solute can be the polarity of the substitution reaction of this field routine
One of aprotic solvent, preferably n,N-Dimethylformamide, dimethyl sulfoxide and N-Methyl pyrrolidone are a variety of.
In the substitution reaction, the volume of the polar non-solute and the benzamide compounds 3
Molar ratio can for this field routine substitution reaction Molar ratio, preferably 0.7L/mol~2.5L/mol, more preferably
For 1L/mol~2L/mol.
In the substitution reaction, the inorganic base is the inorganic base of the substitution reaction of this field routine, preferably
It is more preferably potassium carbonate for one of potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate or a variety of.
In the substitution reaction, the molar ratio of the inorganic base and the benzamide compounds 3 can be this
The molar ratio of the substitution reaction of field routine, preferably 1.0~2.5, it is more preferably 1.5~2.0.
In the substitution reaction, the R1The molar ratio of X and the benzamide compounds 3 can be this field
The molar ratio of conventional substitution reaction, preferably 1.5~3.0, it is more preferably 2.2~2.5.
The temperature of the substitution reaction can for this field routine substitution reaction temperature, preferably 20 DEG C~50
DEG C, it is more preferably 30 DEG C~35 DEG C.
The process of the substitution reaction can by traditional test methods in this field (such as thin-layered chromatography, HPLC,
NMR it) monitors, as reaction end when generally no longer being reacted using benzamide compounds 3；The time of the substitution reaction is preferably
It is more preferably 6h~8h for 5h~10h.
The substitution reaction preferably carries out in presence of water；The water and the benzamide compounds 3
Molar than can be this field routine substitution reaction Molar ratio, preferably 0.002L/mol~0.01L/
Mol is more preferably 0.0025L/mol~0.003L/mol.
The present invention also provides a kind of preparation methods of benzamide compounds 6 comprising following step: (I) is according to upper
The preparation method for the benzamide compounds 4 stated prepares benzamide compounds 4；(II) under protective gas protection, organic
In solvent, the benzamide compounds 4 of step (I) preparation and compound 5 are subjected to annulation, obtain benzamide compounds
6；The organic solvent is sulfone class solvent and/or esters solvent；
Wherein, R1For C1~C4Alkyl or benzyl, but not be methyl；Preferably ethyl, propyl, isopropyl or benzyl,
It is more preferably ethyl.
In the annulation, the protective gas can be the protective gas of this field routine, preferably helium
One of gas, argon gas, nitrogen and neon are a variety of.
In the annulation, the sulfone class solvent can be the sulfone class solvent of the substitution reaction of this field routine,
Preferably dimethyl sulfoxide；The esters solvent can be the esters solvent of the substitution reaction of this field routine, preferably second
One of acetoacetic ester, isopropyl acetate and butyl acetate are a variety of.
In the annulation, the organic solvent is preferably dimethyl sulfoxide and/or isopropyl acetate, more preferably
Ground is the organic solvent for being 1:1~1:2 by the volume ratio that dimethyl sulfoxide and isopropyl acetate form.
In the annulation, the Molar ratio of the organic solvent and the benzamide compounds 4
It can be the Molar ratio of the annulation of this field routine, preferably 0.5L/mol~1.3L/mol is more preferably 0.7L/
Mol~1.0L/mol.
In the annulation, the molar ratio of the compound 5 and the benzamide compounds 4 can be this
The molar ratio of the annulation of field routine, preferably 1.5~2.8, it is more preferably 1.9~2.5.
The temperature of the annulation can for this field routine annulation temperature, preferably 55 DEG C~90
DEG C, it is more preferably 70 DEG C~85 DEG C.
The process of the annulation can by traditional test methods in this field (such as thin-layered chromatography, HPLC,
NMR it) monitors, as reaction end when generally no longer being reacted using benzamide compounds 4, the time of the annulation is preferably
It is more preferably 15h~20h for 12h~25h.
The present invention also provides a kind of preparation methods of benzamide compounds 6 comprising following step: in protective gas
Under protection, in organic solvent, benzamide compounds 4 and compound 5 is subjected to annulation, obtain benzamide compounds
6；The organic solvent is sulfone class solvent and/or esters solvent；
Wherein, R1For C1~C4Alkyl or benzyl, but not be methyl；Preferably ethyl, propyl, isopropyl or benzyl,
It is more preferably ethyl.
In the annulation, the protective gas can be the protective gas of this field routine, preferably helium
One of gas, argon gas, nitrogen and neon are a variety of.
In the annulation, the sulfone class solvent can be the sulfone class solvent of the substitution reaction of this field routine,
Preferably dimethyl sulfoxide；The esters solvent can be the esters solvent of the substitution reaction of this field routine, preferably second
One of acetoacetic ester, isopropyl acetate and butyl acetate are a variety of.
In the annulation, the organic solvent is preferably dimethyl sulfoxide and/or isopropyl acetate, more preferably
Ground is the organic solvent for being 1:1~1:2 by the volume ratio that dimethyl sulfoxide and isopropyl acetate form.
In the annulation, the Molar ratio of the organic solvent and the benzamide compounds 4
It can be the Molar ratio of the annulation of this field routine, preferably 0.5L/mol~1.3L/mol is more preferably 0.7L/
Mol~1.0L/mol.
In the annulation, the molar ratio of the compound 5 and the benzamide compounds 4 can be this
The molar ratio of the annulation of field routine, preferably 1.5~2.8, it is more preferably 1.9~2.5.
The temperature of the annulation can for this field routine annulation temperature, preferably 55 DEG C~90
DEG C, it is more preferably 70 DEG C~85 DEG C.
The process of the annulation can by traditional test methods in this field (such as thin-layered chromatography, HPLC,
NMR it) monitors, as reaction end when generally no longer being reacted using benzamide compounds 4, the time of the annulation is preferably
It is more preferably 15h~20h for 12h~25h.
The present invention also provides a kind of benzamide compounds 4,
Wherein, R1It is as defined above, but be not methyl；Preferably ethyl, propyl, isopropyl or benzyl, more preferably
Ground is ethyl or benzyl.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: it is preparation method high income of the invention, easy to operate, highly-safe, clear
Clean environmental protection is suitable for industrialized production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
The manufacturer of compound A: Shanghai Mei Hechen flavors and fragrances Co., Ltd.
The preparation of 1 benzamide compounds 3 of embodiment
Compound 1 (200g, 0.86mol) is added in the three-necked bottle of 3L, compound 2 (133g, 1.29mol), protochloride
Copper (16.8g, 0.17mol), compound A (20.8g, 0.1mol) and potash solid (303.6g, 2.2mol), are then added
The distilled water of 1 liter of DMF and 20ml, displacement nitrogen is three times.Unlatching heats to 115 degree, and TLC detection is former after 10 hours
Material completely disappears.Stop reaction.It is cooled to room temperature.
Filtering removes solid insoluble, and filter residue is washed with a little DMF again, merging filtrate, evaporated under reduced pressure, and 400ml water is added
It is completely dissolved system, is extracted 2 times with 400ml isopropyl acetate, removes the organic impurities of raffinate.Water phase under stiring, Xiang Qi
Middle dropwise addition saturated citric acid solution, adjusts the PH=4-5 of reaction system, is then cooled to 10 degree hereinafter, there is a large amount of light green colors solid
Body is precipitated.Filtering, filter cake are beaten 30 minutes with 800ml water, filtering；Filter cake uses the isopropyl acetate of 200ml to be beaten 1 hour again,
Filtering, 60 degree are dried under vacuum to constant weight, obtain beige solid 201.1g, yield 92%, HPLC purity 99.1%.
The preparation of 2 benzamide compounds 3 of embodiment
Compound 1 (200g, 0.86mol) is added in the three-necked bottle of 3L, compound 2 (133g, 1.29mol), protochloride
Copper (16.8g, 0.17mol), compound A (20.8g, 0.1mol) and potash solid (303.6g, 2.2mol), are then added
1 liter of DMF, displacement nitrogen is three times.Unlatching heats to 115 degree, and TLC detection, after 15 hours, raw material is completely disappeared.Stop
Only react.It is cooled to room temperature.
Filtering removes solid insoluble, and filter residue is washed with a little DMF again, merging filtrate, evaporated under reduced pressure, and 400ml water is added
It is completely dissolved system, is extracted 2 times with 400ml isopropyl acetate, removes the organic impurities of raffinate.Water phase under stiring, Xiang Qi
Middle dropwise addition saturated citric acid solution, adjusts the PH=4-5 of reaction system, is then cooled to 10 degree hereinafter, there is a large amount of light green colors solid
Body is precipitated.Filtering, filter cake are beaten 30 minutes with 800ml water, filtering；Filter cake uses the isopropyl acetate of 200ml to be beaten 1 hour again,
Filtering, 60 degree are dried under vacuum to constant weight, obtain beige solid 196.7g, yield 90%, HPLC purity 99.2%.
The preparation of 3 benzamide compounds 4 of embodiment
Benzamide compounds 3 (15g, 59mmol) and 75 grams of methanol, stirring are added in the there-necked flask of 250ml
Under thionyl chloride (45g, 378mmol) is added dropwise thereto, finish, flow back, and at such a temperature continue stirring 6 hours, TLC inspection
It surveys, raw material completely disappears.
It is concentrated under reduced pressure, steams solvent, then slowly pour into reaction solution in saturated sodium bicarbonate aqueous solution, regulation system
PH=7-8. it is precipitated at this time with a large amount of white solids.Filtering, filter cake are beaten 30 minutes with 80ml water, filter, obtain white again
Color solid is dried under vacuum to constant weight under 60 degree, obtains 15g, yield 90%, HPLC purity 98.5%.
The preparation of 4 benzamide compounds 4 of embodiment
Benzamide compounds 3 (15g, 59mmol) is added in the there-necked flask of 250ml, potassium carbonate (12.3g,
89mmol), DMF (60ml) and pure water (0.15ml) after displacement nitrogen 3 times, heat to 30 degree under mechanical stirring, and
And bromoethane liquid (14.5g, 132mmol) is added dropwise at such a temperature, it finishes, this is allowed to continue stirring 6 hours at such a temperature,
TLC detection, raw material completely disappear.It is cooled to room temperature.
It is slowly added into 120 milliliters of distilled water into reaction system, is precipitated with a large amount of white solids.Filtering, filter cake are used
80ml water is beaten 30 minutes, is filtered again, is obtained white solid, be dried under vacuum to constant weight under 60 degree, obtain 16.5g, yield
98.9%, HPLC purity 99.3%.
1H-NMR (400MHz, CDCl3) δ 7.90 (t, 1H, J=8.6Hz), 7.26 (br, 1H), 6.60-6.57 (m, 1H),
6.20-6.15 (m, 1H), 4.57 (s, 1H), 4.22-4.16 (dd, J=6.8,14Hz, 2H), 2.99 (d, J=4.8Hz, 3H),
1.50(s,6H),1.30-1.20(m,3H).LCMS(M+H)+:283.0.
The preparation of 5 benzamide compounds 4 of embodiment
Benzamide compounds 3 (15g, 59mmol) is added in the there-necked flask of 250ml, potassium carbonate (12.3g, 89mmol)
And DMF (60ml) heats to 30 degree, and bromoethane is added dropwise at such a temperature after replacing nitrogen 3 times under mechanical stirring
Liquid (14.5g, 132mmol), finishes, this is allowed to continue stirring 10 hours, TLC detection at such a temperature, and raw material completely disappears.It is cold
But room temperature is arrived.
It is slowly added into 120 milliliters of distilled water into reaction system, is precipitated with a large amount of white solids.Filtering, filter cake are used
80ml water is beaten 30 minutes, is filtered again, is obtained white solid, be dried under vacuum to constant weight under 60 degree, obtain 16.3g, yield
98.0%, HPLC purity 99.4%.
1H-NMR (400MHz, CDCl3) δ 7.90 (t, 1H, J=8.6Hz), 7.26 (br, 1H), 6.60-6.57 (m, 1H),
6.20-6.15 (m, 1H), 4.57 (s, 1H), 4.22-4.16 (dd, J=6.8,14Hz, 2H), 2.99 (d, J=4.8Hz, 3H),
1.50(s,6H),1.30-1.20(m,3H).LCMS(M+H)+:283.0.
The preparation of 6 benzamide compounds 4 of embodiment
Benzamide compounds 3 (15g, 59mmol) is added in the there-necked flask of 250ml, potassium carbonate (12.3g, 89mmol)
And DMF (60ml) heats to 30 degree after replacing nitrogen 3 times under mechanical stirring, and benzyl bromine is added dropwise at such a temperature
(22.5g, 132mmol), finishes, this is allowed to continue stirring 10 hours, TLC detection at such a temperature, and raw material completely disappears.It is cooled to
Room temperature.
It is slowly added into 120 milliliters of distilled water into reaction system, is precipitated with a large amount of white solids.Filtering, filter cake are used
80ml water is beaten 30 minutes, is filtered again, is obtained white solid, be dried under vacuum to constant weight under 60 degree, obtain 19.0g, yield
93.5%, HPLC purity 98.6%.
1H-NMR (400MHz, CDCl3) δ 7.90 (t, 1H, J=8.6Hz), 7.26 (br, 1H), 7.18 (m, 5H), 6.60-
6.57 (m, 1H), 6.20-6.15 (m, 1H), 5.32 (s, 2H), 4.57 (s, 1H), 2.99 (d, J=4.8Hz, 3H), 1.50 (s,
6H).LCMS(M+H)+:345.0.
The preparation of 7 benzamide compounds 4 of embodiment
Benzamide compounds 3 (15g, 59mmol) is added in the there-necked flask of 250ml, potassium carbonate (12.3g,
89mmol), DMF (60ml) and pure water (0.15ml) after displacement nitrogen 3 times, heat to 30 degree under mechanical stirring, and
And benzyl bromine (22.5g, 132mmol) is added dropwise at such a temperature, and it finishing, this is allowed to continue stirring 6 hours at such a temperature, TLC is detected,
Raw material completely disappears.It is cooled to room temperature.
It is slowly added into 120 milliliters of distilled water into reaction system, is precipitated with a large amount of white solids.Filtering, filter cake are used
80ml water is beaten 30 minutes, is filtered again, is obtained white solid, be dried under vacuum to constant weight under 60 degree, obtain 19.1g, yield
94.1%, HPLC purity 98.4%.
1H-NMR (400MHz, CDCl3) δ 7.90 (t, 1H, J=8.6Hz), 7.26 (br, 1H), 7.18 (m, 5H), 6.60-
6.57 (m, 1H), 6.20-6.15 (m, 1H), 5.32 (s, 2H), 4.57 (s, 1H), 2.99 (d, J=4.8Hz, 3H), 1.50 (s,
6H).LCMS(M+H)+:345.0.
The preparation of 8 benzamide compounds 6 of embodiment
Benzamide compounds 4 (120g, 0.43mol) is added in 1 liter of there-necked flask, compound 5 (187g,
0.83mol), DMSO (96ml) and isopropyl acetate (204ml) heat to 85 degree after replacing nitrogen 3 times under stirring,
The reaction was continued 15 hours, then cools to 70 degree, and the ethyl alcohol of 15ml is added, and is stirred to react 1 hour.It is cooled to room temperature, is added
The methylene chloride of 500ml water and 500ml, layering, water phase are extracted with dichloromethane once again, merge organic phase.It is concentrated into
Dry, dissolution is added in the isopropanol that 3250ml is added, and is cooled to room temperature, a large amount of white solids are precipitated, the methylene chloride of 500ml is added
The active carbon of 7g is added again, is heated to 40 degree, is stirred to react 30 minutes for dissolution.Diatomite filtering is padded, filtrate decompression is concentrated,
Then the normal heptane that 500ml is added is beaten 1 hour, filtering, obtains white solid, and 65 degree of vacuum drying obtain 160.05g white
Solid is target molecule benzamide compounds 6 by identification.Yield is 80%, HPLC purity 99.7%.
1H-NMR (400MHz, CDCl3) δ 8.26 (t, 1H, J=8.4Hz), 8.00-7.96 (m, 2H), 7.85-7.82 (m,
1H),6.76-6.72(br,1H),3.07(d,J 4.8Hz,3H),1.61(s,6H).LCMS(M+H)+:465.0.
The preparation of 1 benzamide compounds 3 of comparative example
Compound 1 (20g, 86mmol) is added in the three-necked bottle of 250ml, compound 2 (13.3g, 129mmol), chlorination
Cuprous (1.7g, 17mmol), 2- acetyl cyclohexanone (1.5g, 10.7mmol) and potash solid (30.0g, 0.21mol),
Then 100 milliliters DMF and 2.0 milliliter of distilled water is added, displacement nitrogen is three times.Unlatching heats to 105 degree, weak reflux shape
State, TLC detection, after 20 hours, there are also a small amount of remaining for raw material.Stop reaction.It is cooled to room temperature.
Filtering removes solid insoluble, and filter residue is washed with a little DMF again, merging filtrate, evaporated under reduced pressure, and 40ml water is added
It is completely dissolved system, is extracted 2 times with 40ml isopropyl acetate, removes the organic impurities of raffinate.Water phase under stiring, thereto
Saturated citric acid solution is added dropwise, adjusts the PH=4-5 of reaction system, is then cooled to 10 degree hereinafter, there are a large amount of light green solids
It is precipitated.Filtering, filter cake are beaten 30 minutes with 80ml water, filtering；Filter cake uses the isopropyl acetate of 20ml to be beaten 1 hour again, filtering,
60 degree are dried under vacuum to constant weight, obtain beige solid 16.5g, yield 78%, HPLC purity 99.0%.
Claims (10)
1. a kind of preparation method of benzamide compounds 3, which is characterized in that include the following steps: in the case where protective gas is protected,
In polar non-solute, in the presence of catalyst such as shown in formula A, cuprous halide and inorganic base, by compound 1 and change
It closes object 2 and carries out coupling reaction, obtain benzamide compounds 3；The polar non-solute is N, N- dimethyl methyl
Amide and/or N-Methyl pyrrolidone；The cuprous halide is stannous chloride；The temperature of the coupling reaction is 115 DEG C
~125 DEG C；
2. preparation method as described in claim 1, which is characterized in that in the coupling reaction, the protective gas
For one of helium, argon gas, nitrogen and neon or a variety of；
And/or in the coupling reaction, the volume mass ratio of the polar non-solute and the compound 1
For 3mL/g~8mL/g；
And/or in the coupling reaction, the molar ratio of the compound A and the compound 1 is 0.1~0.5；
And/or in the coupling reaction, the molar ratio of the cuprous halide and compound 1 is 0.1~0.7；
And/or in the coupling reaction, the inorganic base is in potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate
It is one or more；
And/or in the coupling reaction, the molar ratio of the inorganic base and compound 1 is 2.0~3.5；
And/or in the coupling reaction, the molar ratio of the compound 2 and compound 1 is 1.2~2.5；
And/or the time of the coupling reaction is 8h~for 24 hours.
3. preparation method as claimed in claim 2, which is characterized in that in the coupling reaction, the non-matter of the polarity
The volume mass ratio of sub- solvent and the compound 1 is 5mL/g~6mL/g；
And/or in the coupling reaction, the molar ratio of the compound A and the compound 1 is 0.12~0.3；
And/or in the coupling reaction, the molar ratio of the cuprous halide and compound 1 is 0.2~0.5；
And/or in the coupling reaction, the inorganic base is potassium carbonate；
And/or in the coupling reaction, the molar ratio of the inorganic base and compound 1 is 2.5~3.0；
And/or in the coupling reaction, the molar ratio of the compound 2 and compound 1 is 1.5~1.8；
And/or the time of the coupling reaction is 10h~15h.
4. preparation method as described in claim 1, which is characterized in that the coupling reaction carries out in presence of water.
5. a kind of preparation method of benzamide compounds 4 is method 1 or method 2；
The method 1 includes the following steps: (1) according to the described in any item benzamide compounds 3 of Claims 1 to 4
Preparation method prepares benzamide compounds 3；(2) under protective gas protection, in R1In OH, the condition existing for thionyl chloride
Under, the benzamide compounds 3 of step (1) preparation are subjected to esterification, obtain benzamide compounds 4；Described
R1For C1~C4Alkyl or benzyl；
1. the method 2 includes the following steps: according to the system of the described in any item benzamide compounds 3 of Claims 1 to 4
Preparation Method prepares benzamide compounds 3；2. in polar non-solute, existing in inorganic base under protective gas protection
Under conditions of, 1. benzamide compounds 3 and R that step is prepared1X carries out substitution reaction, obtains benzamide compounds 4 i.e.
It can；The R1For C1~C4Alkyl or benzyl, the X is halogen, but R1X is not iodomethane；
6. preparation method as claimed in claim 5, which is characterized in that in the esterification, the C1~C4Alkane
Base is methyl, ethyl, propyl or isopropyl；
And/or in the esterification, the protective gas is one of helium, argon gas, nitrogen and neon or more
Kind；
And/or in the esterification, the R1The mass ratio of OH and the benzamide compounds 3 is 3~7；
And/or in the esterification, the molar ratio of the thionyl chloride and the benzamide compounds 3 is 1
~8；
And/or the temperature of the esterification is 40 DEG C~90 DEG C；
And/or the time of the esterification is 3h~10h；
And/or in the substitution reaction, the C1~C4Alkyl be methyl, ethyl, propyl or isopropyl；
And/or in the substitution reaction, the halogen is fluorine, chlorine, bromine or iodine；
And/or in the substitution reaction, the protective gas is one of helium, argon gas, nitrogen and neon or more
Kind；
And/or in the substitution reaction, the polar non-solute is n,N-Dimethylformamide, dimethyl sulfoxide
With one of N-Methyl pyrrolidone or a variety of；
And/or in the substitution reaction, the body of the polar non-solute and the benzamide compounds 3
Product molar ratio is 0.7L/mol~2.5L/mol；
And/or in the substitution reaction, the inorganic base is in potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate
It is one or more；
And/or in the substitution reaction, the molar ratio of the inorganic base and the benzamide compounds 3 is 1.0
~2.5；
And/or in the substitution reaction, the R1The molar ratio of X and the benzamide compounds 3 is 1.5~
3.0；
And/or the temperature of the substitution reaction is 20 DEG C~50 DEG C；
And/or the time of the substitution reaction is 5h~10h.
7. preparation method as claimed in claim 6, which is characterized in that in the esterification, the C1~C4Alkane
Base is methyl or ethyl；
And/or in the esterification, the R1The mass ratio of OH and the benzamide compounds 3 is 4~5；
And/or in the esterification, the molar ratio of the thionyl chloride and the benzamide compounds 3 is 5
~6；
And/or the temperature of the esterification is 60 DEG C~70 DEG C；
And/or the time of the esterification is 6h~8h；
And/or in the substitution reaction, the C1~C4Alkyl be ethyl；
And/or in the substitution reaction, the halogen is bromine；
And/or in the substitution reaction, the body of the polar non-solute and the benzamide compounds 3
Product molar ratio is 1L/mol~2L/mol；
And/or in the substitution reaction, the inorganic base is potassium carbonate；
And/or in the substitution reaction, the molar ratio of the inorganic base and the benzamide compounds 3 is 1.5
~2.0；
And/or in the substitution reaction, the R1The molar ratio of X and the benzamide compounds 3 is 2.2~
2.5；
And/or the temperature of the substitution reaction is 30 DEG C~35 DEG C；
And/or the time of the substitution reaction is 6h~8h.
8. preparation method as claimed in claim 5, which is characterized in that the substitution reaction carries out in presence of water.
9. a kind of preparation method of benzamide compounds 6, which is characterized in that include the following steps: (a) according to claim 5
The preparation method of~8 described in any item benzamide compounds 4 prepares benzamide compounds 4；(b) it is protected in protective gas
Under, in organic solvent, the benzamide compounds 4 of step (a) preparation and compound 5 are subjected to annulation, obtain benzene first
Amide compound 6；The organic solvent is sulfone class solvent and/or esters solvent；
Wherein, R1For C1~C4Alkyl or benzyl, but not be methyl.
10. preparation method as claimed in claim 9, which is characterized in that in the annulation, the R1For ethyl,
Propyl, isopropyl or benzyl；
And/or in the annulation, the protective gas is one of helium, argon gas, nitrogen and neon or more
Kind；
And/or in the annulation, the sulfone class solvent is dimethyl sulfoxide；The esters solvent is acetic acid second
One of ester, isopropyl acetate and butyl acetate are a variety of；
And/or in the annulation, the Molar of the organic solvent and the benzamide compounds 4
Than for 0.5L/mol~1.3L/mol；
And/or in the annulation, the molar ratio of the compound 5 and the benzamide compounds 4 is
1.5~2.8；
And/or the temperature of the annulation is 55 DEG C~90 DEG C；
And/or the time of the annulation is 12h~25h.
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| CN115536591A (en) * | 2022-09-27 | 2022-12-30 | 爱斯特（成都）生物制药股份有限公司 | Method for preparing enzalutamide by continuous flow |
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