CN106800536A - A kind of preparation method of the miscellaneous Shandong amine of grace - Google Patents
A kind of preparation method of the miscellaneous Shandong amine of grace Download PDFInfo
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- CN106800536A CN106800536A CN201710014635.0A CN201710014635A CN106800536A CN 106800536 A CN106800536 A CN 106800536A CN 201710014635 A CN201710014635 A CN 201710014635A CN 106800536 A CN106800536 A CN 106800536A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
Abstract
The invention discloses a kind of preparation method of the miscellaneous Shandong amine of grace; it is raw material with the nitrobenzoic acid of 2 fluorine 4; the fluorobenzoate of 4 amino 2 is prepared through esterification and Pd/C hydrogenation reductions; reaction 2 (the methoxycarbonyl base of 3 fluorine 4) phenylamino methyl isobutyrates of generation are carried out with 2 bromo acid methyl esters, then cyclization and the methylamine reaction generation miscellaneous Shandong amine of grace are carried out with the isothiocyano benzonitrile of 2 trifluoromethyl 4.Using cleaning procedure technology of preparing, the miscellaneous Shandong amine of antiandrogen medicine grace can be largely prepared, be adapted to batch production, high income, purity is good.
Description
Technical field
The present invention relates to field of medicine and chemical technology, and in particular to a kind of preparation method of the miscellaneous Shandong amine of antiprostate cancer grace.
Background technology
Prostate cancer (Prostate Cancer, PCa) is a kind of common male malignancy, quick in recent years
A kind of global tumor disease is risen to, in many American-European countries, prostate-cancer incidence accounts for male malignancy first, extremely
The rate of dying accounts for second.220,800 male's oj C prostate cancers are there are about in the U.S. within 2015, wherein about 20,710 patients are dead
Die.Ranked first position and second respectively in all male tumors.Recently as the raising of prostatic cancer early diagnosis level,
Prostate cancer rises year by year in China's incidence of disease, its common cancer that will turn into influence China men's health.
Prostate cancer is in early days androgen-dependent, androgen ablation therapies (Androgen Deprivation
Therapy, ADT) it is the first-selected treatment method for treating prostate cancer, including operation castration method and androgen deprivation method.But it is several
There is resistance phenomenon after experiencing 12~18 months in all patients, and metastases develop into and are difficult to cure and easily cause to suffer from
The dead emasculation Researches on Hormonal Refractory Prostate Cancer (Castration-Resistant Prostate Cancer, CRPC) of person.Go
The generation development of gesture resistance type prostate cancer involves the interaction of a series of complex signaling molecule, wherein androgen receptor
The gene mutation and overexpression of (Androgen Receptor, AR) are castration resistance type prostate cancer main development mechanism.
The miscellaneous Shandong amine (enzalutamide, MDV3100) of grace is second generation nonsteroidal androgen receptor inhibitor, can be with
The signal path conduction of blocking tumour cell androgen receptor, is new the one of United States drug developer Medivation companies exploitation
For oral antiandrogen medicine, be mainly used in treatment advanced prostate cancer (CRPC) patient (1. Menon MP, Higano CS.,
Enzalutamide,a second generation androgen receptor antagonist:development and
clinical applications in prostate cancer.CurrOncol Rep.2013,15(2),69-75。②
Chris Tran,SamedyOuk,Nicola J.et.al,Development of a Second-Generation
Antiandrogen for Treatment of Advanced Prostate Cancer,Science,2009,324,787-
790), it is approved listing by U.S. FDA within 2012.Through count 5.8 hundred million dollars of grace miscellaneous Shandong amine market sale 2013,2014 years 10
Hundred million dollars, 2015 2200000000 dollars.
Formula 1：The miscellaneous Shandong amine chemical structural formula of grace
The miscellaneous Shandong amine synthetic route of grace for having document report at present mainly has three：Method one, American scholar Jung etc. are reported
With the fluoro- 4- nitrotoleunes of 2- as raw material, by oxidation, chlorination, amination and reduction generation 2- fluoro- 4- (1,1- dimethyl cyano group) first
Aminobenzoyl methylamine；The cyclization generation miscellaneous Shandong amine of product grace is carried out with the reaction of 2- trifluoromethyl -4- isothiocyanos benzonitrile again
(Jung ME,Ouk S,Yoo D,et.al,Journal ofMedicinal Chemistry 2010,53,2779)；Method
Two, Medivation house journals of the U.S. are reported with the fluoro- 4- bromobenzoic acids of 2- as raw material, by chlorination, methylamine and 2- amino
Isobutyric acid carries out Ullmann condensation reactions generation 2- (the fluoro- 4- first carbamyls of 3-) phenylamino isobutyric acid, carries out the 2- that methylates to obtain
(the fluoro- 4- first carbamyls of 3-) phenylamino methyl isobutyrate, then carry out ring with the reaction of 2- trifluoromethyl -4- isothiocyanos benzonitrile
Symphysis is into the miscellaneous Shandong amine of product grace.(Thompson A, Lamberson C, Greenfield S, W02011/106570A1,
2011)；Method three generates 2- (3- with the bromo- 2- fluobenzoic acids of 4- as raw material by being reacted with 2- bromo acids methyl esters after esterification
Fluoro- 4- methoxycarbonyls base) phenylamino methyl isobutyrate carried out with 2- trifluoromethyl -4- isothiocyanos benzonitriles again cyclization generation 4-
(3- (4- cyano group -3- (trifluoromethyl) phenyl)-thio oxo-imidazoles of 5,5- dimethyl -4- oxos -2- are alkane -1- bases) -2- is fluoro-
Methyl benzoate, then prepare the miscellaneous Shandong amine of grace (Chinese patent, the preparation of the miscellaneous Shandong amine of grace, CN 104803918A) with methylamine reaction；
Wherein method one has used the acetone of severe toxicity to close hydrogen cyanide, and condensation has used microwave reactor, has been not suitable for industrial metaplasia
Produce；Method two has used the Ullmann condensation reactions under stannous chloride catalysis, and total recovery is low, and waste water is more, and pollution is big；Method three
Methylated using the iodomethane of severe toxicity, production cost is high, it is difficult to industrialized production.
The content of the invention
Purpose：To solve the deficiencies in the prior art, the present invention provides a kind of preparation method of the miscellaneous Shandong amine of grace, overcomes existing skill
Synthesis yield is low in the miscellaneous Shandong amine preparation process of grace in art, and production cost is high and be cleaning procedure production skill the problems such as environmental pollution
Art, technological operation is easy, is adapted to largely prepare the miscellaneous Shandong amine of antiprostate cancer grace.
Technical scheme：In order to solve the above technical problems, the technical solution adopted by the present invention is：
A kind of preparation method of the miscellaneous Shandong amine of grace, with the fluoro- 4- nitrobenzoic acids of 2- as raw material, through esterification and Pd/C hydrogenating reductions
Reaction prepares the 4- amino fluoro- benzoic ethers of -2-, then carries out reaction generation 2- (the fluoro- 4- methoxies first of 3- with 2- bromo acids methyl esters
Acyl group) phenylamino methyl isobutyrate, then carry out cyclization and methylamine reaction generation with 2- trifluoromethyl -4- isothiocyanos benzonitriles
The miscellaneous Shandong amine of grace.Synthetic route is as follows：
The preparation method of the miscellaneous Shandong amine of described grace, it is characterised in that：Specifically include following steps：
(1) with the fluoro- 4- nitrobenzoic acids of 2- as raw material, alcohol organic solvent and acidic catalyst, reaction solution heating are added
Back flow reaction 16-48 hours, TLC tracking reactions, after reaction terminates, decompression steams most of alcohol, cools down, and is poured into water, and has heavy
Precipitation goes out, and stands, filtering, and the fluoro- 4- nitrobenzoyls acid esters of light gray solid 2- is obtained after drying；
(2) to organic solvent and Pd/C catalyst is added in the fluoro- 4- nitrobenzoyls acid esters of 2- obtained in step (1), in room
Temperature is lower to remove oxygen, is passed through hydrogen, and hydrogenation reaction 4-8 hours in the environment of 2-10 atmospheric pressure, reaction is filtered after being fully completed
Pd/C catalyst is reclaimed, filtrate is reclaimed organic solvent, obtains light yellow solid 4- amino -2- fluorobenzoates under reduced pressure；
(3) to addition 2- bromo acids methyl esters and base catalysis in 4- amino -2- fluorobenzoates obtained in step (2)
Agent, carried out at 120-150 DEG C reaction 24-48 hour reaction generate 2- (the fluoro- 4- methoxycarbonyls bases of 3-) phenylamino methyl isobutyrate,
(the fluoro- 4- ethoxycarbonyls of 3-) phenylamino methyl isobutyrate or (the fluoro- 4- isopropyls oxygen formoxyls of 3-) phenylamino methyl isobutyrate；
(4) to 2- obtained in step (3) (the fluoro- 4- methoxycarbonyls bases of 3-) phenylamino methyl isobutyrate, (the fluoro- 4- ethoxies of 3-
Formoxyl) phenylamino methyl isobutyrate, add in (the fluoro- 4- isopropyls oxygen formoxyls of 3-) phenylamino methyl isobutyrate organic solvent,
2- trifluoromethyl -4- isothiocyano benzonitriles, after carrying out reaction reaction in 8-12 hours at 100-120 DEG C, add methyl alcohol and salt
Aqueous acid carries out cyclization, and (- 2- is thio for -5,5- dimethyl -4- oxos for 3- (4- cyano group -3- (trifluoromethyl) phenyl) for generation 4-
Oxo-imidazole is alkane -1- bases) the fluoro- benzoic ethers of -2-；
(5) to (3- (4- cyano group -3- (trifluoromethyl) phenyl) -5,5- dimethyl -4- oxos -2- of 4- obtained in step (4)
Thio oxo-imidazole is alkane -1- bases) organic solvent, methylamine water solution are added in the fluoro- benzoic ethers of -2-, carried out at 100-120 DEG C
The 8-12 hours reaction generation miscellaneous Shandong amine of grace of reaction.
Preferably, described alcohol organic solvent is one or more in methyl alcohol, ethanol, isopropanol.
Preferably, the acidic catalyst is in sulfuric acid, p-methyl benzenesulfonic acid, dry hydrogen chloride, phosphoric acid
One or more.
Preferably, the organic solvent in step (2) is the one kind or several in methyl alcohol, ethyl acetate, methyl acetate
Kind.
Preferably, the base catalyst in step (3) is triethylamine, DIPEA, sodium carbonate, carbon
Sour potassium, four butyl bromation amine, one or more in tetrabutyl iodate amine.
Preferably, the organic solvent in step (4) is pyridine, 2- picolines, 3- picolines, 4- methyl pyrroles
One or more in pyridine.
Preferably, the organic solvent in step (5) is acetonitrile, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, methyl alcohol, second
One or more in alcohol.
Beneficial effect：The preparation method of the miscellaneous Shandong amine of a kind of grace that the present invention is provided, with advantages below：1st, using cleaner
Skill technology of preparing, can largely prepare the miscellaneous Shandong amine of antiandrogen medicine grace, be adapted to batch production, and high income, purity is good；Wherein Pd/C
The process recovery ratio that catalytic hydrogenation obtains 4- amino -2- fluorobenzoates is (98%) high, good product purity (more than 98%), the technology
It is green process for cleanly preparing technology, is suitable to largely prepare 4- amino -2- fluorobenzoates；2- (the fluoro- 4- methoxycarbonyls bases of 3-)
Phenylamino methyl isobutyrate carries out condensation reaction with 2- trifluoromethyl -4- isothiocyanos benzonitriles under catalyst action, reacts
High income, post processing is easy, suitable industrialized production；2nd, wastewater flow rate is few, and catalyst and organic solvent are recyclable；3rd, it is anti-
Should be gentle, more than 30% (in terms of 4- amino -2- fluobenzoic acids), general total recovery is 10% in the prior art for synthesis total recovery
Left and right (US20070254933A1).
Specific embodiment
The present invention is illustrated with reference to specific embodiment：
Embodiment 1：The fluoro- 4- nitrobenzene methyls of 2-
The fluoro- 4- nitrobenzoic acids (185g, 1.0mol) of 2-, methyl alcohol (1600ml), the concentrated sulfuric acid are added in reaction bulb
(7.0ml), heating reflux reaction 48 hours, TLC tracking reactions, decompression steams big portion's methyl alcohol after reaction terminates, and residue is poured into
In water, filtering is dried, and obtains the fluoro- 4- nitrobenzene methyls of light yellow solid 2- (187.5g, yield 94.2%), molten point 69.5-
71.2℃。
Embodiment 2：4- amino -2- fluorophenyl carbamates
The fluoro- 4- nitrobenzoyls acid esters (187.5g, 0.94mol) of 2-, methyl alcohol (1500ml), 10% are added in reaction bulb
Pd/C catalyst (19g), is passed through hydrogen at room temperature, is reacted 2 hours in the environment of 10 atmospheric pressure hydrogen, and reaction is fully completed
After Pd/C catalyst is recovered by filtration, filtrate reclaims methyl alcohol under reduced pressure, with the heavy 4- amino -2- fluorophenyl carbamates of methyl alcohol
153.5g, yield 96.4%.
Embodiment 3：2- (the fluoro- 4- methoxycarbonyls bases of 3-) phenylamino methyl isobutyrate
4- amino -2- fluorophenyl carbamates (153.5g, 0.91mol), 2- bromo acid methyl esters are added in reaction bulb
(270g, 1.48mol), triethylamine (150g, 1.48mol), four butyl bromation amine (3g) is sealed after addition, is heated at 120 DEG C
Reaction 24 hours, decompression steams big portion's organic matter after reaction terminates, and cooling is poured into water, and filtering is dried, with recrystallizing methanol,
Obtain white solid 2- (the fluoro- 4- methoxycarbonyls bases of 3-) phenylamino methyl isobutyrate (203.5g, yield 83.1%).lHNMR
(400MHz, DMSO-d6),δ(ppm)：7.77-7.81 (d, J=8.1Hz, 1H), 7.51 (s, 1H), 7.46 (br, 1H), 7.36-
7.39 (d, J=8.1Hz, 1H), 3.75 (s, 3H), 3.66 (s, 3H), 1.59 (s, 3H).
Embodiment 4：4- (3- (4- cyano group -3- (trifluoromethyl) phenyl) -5, the 5- dimethyl -4- oxos thio oxo miaows of -2-
Azoles is alkane -1- bases) the fluoro- methyl benzoates of -2-
2- (the fluoro- 4- methoxycarbonyls bases of 3-) phenylamino methyl isobutyrate (135.0g, 0.50mol) is added in reaction bulb,
2- trifluoromethyls -4- isothiocyanos benzonitrile (125g, 0.55mol), pyridine (1250ml), 100 DEG C are heated to by reaction solution,
Reacted 16 hours at 100 DEG C, TLC tracking reactions, decompression steams most of pyridine after reaction terminates, and adds toluene (500ml) again
The pyridine of toluene and residual is steamed, methyl alcohol (1500ml) and 10% hydrochloric acid (1000ml) is added, reacted 1 hour at 70 DEG C,
Decompression steams most methyl alcohol after reaction terminates, and residue is poured into water (1000ml), is extracted with ethyl acetate, and dries, filtering,
After steaming ethyl acetate, then with recrystallisation from isopropanol, dry, obtain white solid 4- (3- (4- cyano group -3- (trifluoromethyl) benzene
Base)-thio the oxo-imidazoles of 5,5- dimethyl -4- oxos -2- be alkane -1- bases) the fluoro- methyl benzoates of -2- (203g, yield
87.3%),lH NMR (400MHz, DMSO-d6),δ(ppm)：8.37-8.40 (d, J=8.0Hz, 1H), 8.26 (s, 1H),
8.04-8.09(m,2H),7.48-7.52(dd,J1=11.0Hz, J2=1.6Hz, 1H), 7.37-7.40 (dd, J1=8.4Hz,
J2=1.6Hz, 1H), 3.85 (s, 3H), 1.52 (s, 3H).
Embodiment 5：The miscellaneous Shandong amine of grace
4- is added in reaction bulb, and (- 2- is thio for -5,5- dimethyl -4- oxos for 3- (4- cyano group -3- (trifluoromethyl) phenyl)
Oxo-imidazole is alkane -1- bases) the fluoro- benzoic ethers of -2- (200g, 0.43mol) and acetonitrile (360ml) be cooled to 0 DEG C, dropwise addition 40%
Methylamine water solution, reacts 12 hours at room temperature, TLC tracking reactions, and decompression steams big portion's acetonitrile after reaction terminates, and residue falls
Enter in water, filtering, with recrystallisation from isopropanol, is dried, and obtains white solid 4- (3- (4- cyano group -3- (trifluoromethyl) phenyl) -5,5-
The thio oxo-imidazoles of dimethyl -4- oxos -2- are alkane -1- bases) the fluoro- N-methyl-benzamides of -2-, 164.5g, yield 82.4%.
Molten point：195~196.5 DEG C.1H NMR(300MHz,DMSO-d6) δ 8.54-8.36 (m, 2H), 8.30 (d, J=1.9Hz, 1H),
8.09 (dd, J=8.2,1.9Hz, 1H), 7.79 (t, J=8.1Hz, 1H), 7.44 (dd, J=10.7,1.9Hz, 1H), 7.34
(dd, J=8.2,1.9Hz, 1H), 2.80 (d, J=4.6Hz, 3H), 1.55 (s, 6H)
13C NMR(126MHz,CDCl3), δ：22.84,25.99,65.61,109.41,113.69,116.78,116.99,
119.71,121.60,121.69,121.89,125.17 (d, J=3.4Hz) 126.04 (d, J=4.6Hz), 131.11,
(d, J=3.5Hz), 132.35,132.36 134.29,135.81,137.97 (d, J=10.4Hz), 138.01,158.35,
160.34,161.67 (d, J=3.3Hz), 173.41,178.72.19F NMR(471MHz,CDCl3), δ：-110.70,-
61.99.
Embodiment 6：The fluoro- 4- ethyl nitrobenzoates of 2-
The fluoro- 4- nitrobenzoic acids (185g, 1.0mol) of 2-, ethanol (1600ml), to methylbenzene sulphur are added in reaction bulb
Sour (12.0g, 1.0mol), heating reflux reaction 24 hours, TLC tracking reactions, decompression steams big portion's ethanol after reaction terminates, residual
Stay thing to be poured into water, filter, dry, recrystallized with 50% ethanol water, obtain the fluoro- 4- nitrobenzoic acids second of pale solid 2-
Ester (152.0g, yield 71.4%)；73.0-74.5 DEG C of molten point.
Embodiment 7：4- amino -2- ethyl fluoro benzoates
The addition fluoro- 4- ethyl nitrobenzoates (152g, 0.71mol) of 2- in reaction bulb, ethyl acetate (1200ml),
10%Pd/C catalyst (8g), is passed through hydrogen at room temperature, is reacted 4 hours in 10 atmospheric pressure hydrogen environments, and reaction is tied completely
Pd/C catalyst is recovered by filtration after beam, filtrate reclaims ethyl acetate under reduced pressure, 4- amino -2- fluorobenzene first is obtained with ethyl alcohol recrystallization
Acetoacetic ester 123.5g, yield 94.9%, fusing point:110.3–112.5℃.
Embodiment 8：2- (the fluoro- 4- ethoxycarbonyls of 3-) phenylamino methyl isobutyrate
4- amino -2- ethyl fluoro benzoates (123.5g, 0.67mol), 2- bromo acid methyl esters are added in reaction bulb
(245g, 1.34mol), DIPEA (173g, 1.34mol), tetrabutyl iodate amine (5g) is sealed after adding, heating
Reacted 48 hours to 120 DEG C, decompression steams big portion's organic matter after reaction terminates, and cooling is poured into water, filtering is dried, with different
Propyl alcohol is recrystallized, and obtains white solid 2- (the fluoro- 4- ethoxycarbonyls of 3-) phenylamino methyl isobutyrate (148.5g, yield
78.2%).
Embodiment 9：4- (3- (4- cyano group -3- (trifluoromethyl) phenyl) -5, the 5- dimethyl -4- oxos thio oxo miaows of -2-
Azoles is alkane -1- bases) the fluoro- methyl benzoates of -2-
2- (the fluoro- 4- ethoxycarbonyls of 3-) phenylamino methyl isobutyrate (141.5g, 0.50mol) is added in reaction bulb,
2- trifluoromethyls -4- isothiocyanos benzonitrile (125g, 0.55mol), 2- picolines (100ml), 100 are heated to by reaction solution
DEG C, to be reacted 8 hours at 100 DEG C, TLC tracking reactions after reaction terminates, steam big portion 2- picolines under reduced pressure, add
Toluene (300ml), then the pyridine of toluene and residual is steamed, methyl alcohol (1200ml) and 10% hydrochloric acid (800ml) are added, at 60 DEG C
Lower reaction 2 hours, reaction steams most methyl alcohol under being depressurized after terminating, and residue is poured into water (1000ml), uses ethyl acetate
Extraction, dries, filtering, after steaming ethyl acetate, then with recrystallisation from isopropanol, dries, and obtains white solid 4- (3- (4- cyano group -3-
(trifluoromethyl) phenyl)-thio the oxo-imidazoles of 5,5- dimethyl -4- oxos -2- be alkane -1- bases) the fluoro- ethyl benzoates of -2-
(106.5g, yield 76.2%).
Embodiment 10：The miscellaneous Shandong amine of grace
4- is added in reaction bulb, and (- 2- is thio for -5,5- dimethyl -4- oxos for 3- (4- cyano group -3- (trifluoromethyl) phenyl)
Oxo-imidazole is alkane -1- bases) the fluoro- ethyl benzoates of -2- (100g, 0.35mol) and 1,4- dioxane (280ml) be cooled to 0
DEG C, 40% methylamine water solution is added dropwise, to be reacted 24 hours at 40 DEG C, TLC tracking reactions, decompression steams big portion 1 after reaction terminates,
4- dioxane, residue into water, filtering, with recrystallisation from isopropanol, is dried, and obtains white solid 4- (3- (4- cyano group -3-
(trifluoromethyl) phenyl)-thio the oxo-imidazoles of 5,5- dimethyl -4- oxos -2- be alkane -1- bases) the fluoro- N- toluyls of -2-
Amine (130.1g, yield 79.9%), molten point：194.8~196.4 DEG C.
Embodiment 11：The fluoro- 4- nitrobenzoyls isopropyl propionates of 2-
The fluoro- 4- nitrobenzoic acids (185g, 1.0mol) of 2-, isopropanol (1000ml), the concentrated sulfuric acid are added in reaction bulb
(6.0ml), toluene (100ml) is heated to reflux dehydration, and reaction 36 hours, TLC tracking reactions are reacted decompression after terminating and steamed greatly
Portion's toluene and isopropanol, residue into water, filtering are dried, and with recrystallisation from isopropanol, obtain the fluoro- 4- nitre of pale solid 2-
Yl benzoic acid isopropyl acid esters (162.0g, yield 71.3%).
Embodiment 12：4- amino -2- fluobenzoic acid isopropyl esters
The addition fluoro- 4- nitrobenzoyls isopropyl propionates (162g, 0.71mol) of 2- in reaction bulb, methyl acetate (1200ml),
10%Pd/C catalyst (16g), is passed through hydrogen at room temperature, is reacted 12 hours in the environment of 10 atmospheric pressure hydrogen, has reacted
Pd/C catalyst is recovered by filtration after terminating entirely, filtrate reclaims ethyl acetate under reduced pressure, and 4- amino -2- is obtained with recrystallisation from isopropanol
Fluobenzoic acid isopropyl ester (112g, yield 80.1%).
Embodiment 13：2- (the fluoro- 4- isopropyls oxygen formoxyls of 3-) phenylamino methyl isobutyrate
4- amino -2- fluobenzoic acids isopropyl ester (112g, 0.567mol), 2- bromo acid methyl esters are added in reaction bulb
(246g, 1.35mol), sodium carbonate (143g, 1.35mol), tetrabutyl iodate amine (10g) is sealed after adding, and is heated at 130 DEG C
Reaction 36 hours, decompression steams big portion's organic matter after reaction terminates, and cooling is poured into water, and filtering is dried, and is tied again with isopropanol
Crystalline substance, obtains white solid 2- (the fluoro- 4- isopropyls oxygen formoxyls of 3-) phenylamino methyl isobutyrate (116g, yield 68.7%).
Embodiment 14：4- (3- (4- cyano group -3- (trifluoromethyl) phenyl) -5, the 5- dimethyl -4- oxos thio oxos of -2-
Imidazoles is alkane -1- bases) the fluoro- isopropyl benzoates of -2-
In reaction bulb add 2- (the fluoro- 4- isopropyls oxygen formoxyls of 3-) phenylamino methyl isobutyrate (148.5g,
0.50mol), 2- trifluoromethyls -4- isothiocyanos benzonitrile (125g, 0.55mol), 3- picolines (200ml), by reaction solution
80 DEG C are heated to, are reacted 6 hours at 80 DEG C, TLC tracking reactions after reaction terminates, steam big portion 3- methyl pyrroles under reduced pressure
Pyridine, adds toluene (500ml), then steams toluene and the 3- picolines for remaining, and adds methyl alcohol (1500ml) and 10% hydrochloric acid
(1000ml), reacts 4 hours at 50 DEG C, and reaction steams most methyl alcohol under being depressurized after terminating, and residue pours into water (800ml)
In, it is extracted with ethyl acetate, dry, filtering, after steaming ethyl acetate, then with recrystallisation from isopropanol, dry, obtain white solid 4-
(3- (4- cyano group -3- (trifluoromethyl) phenyl)-thio oxo-imidazoles of 5,5- dimethyl -4- oxos -2- are alkane -1- bases) -2- is fluoro-
Ethyl benzoate (163g, yield 66.1%).
Embodiment 15：The miscellaneous Shandong amine of grace
4- is added in reaction bulb, and (- 2- is thio for -5,5- dimethyl -4- oxos for 3- (4- cyano group -3- (trifluoromethyl) phenyl)
Oxo-imidazole is alkane -1- bases) (100g, 0.20mol) and tetrahydrofuran (280ml) are cooled down at least in the fluoro- isopropyl benzoates of -2-
0 DEG C, 40% methylamine water solution is added dropwise, reacts 48 hours at room temperature, TLC tracking reactions, decompression steams big portion after reaction terminates
Tetrahydrofuran, residue into water, filtering, with recrystallisation from isopropanol, is dried, and obtains white solid 4- (3- (4- cyano group -3- (three
Methyl fluoride) phenyl)-thio the oxo-imidazoles of 5,5- dimethyl -4- oxos -2- be alkane -1- bases) the fluoro- N-methyl-benzamides of -2-
(80.2g, yield 86.4%).
Below the present invention is disclosed with preferred embodiment, so it is not intended to limiting the invention, all use equivalents
Or the technical scheme that equivalent transformation mode is obtained, it is within the scope of the present invention.
Claims (8)
1. the preparation method of the miscellaneous Shandong amine of a kind of grace, it is characterised in that with the fluoro- 4- nitrobenzoic acids of 2- as raw material, through esterification and Pd/
C hydrogenation reductions prepare the 4- amino fluoro- benzoic ethers of -2-, then carry out reaction generation 2- (3- with 2- bromo acids methyl esters
Fluoro- 4- methoxycarbonyls base) phenylamino methyl isobutyrate, then carry out cyclization and first with 2- trifluoromethyl -4- isothiocyanos benzonitriles
Aminating reaction generates the miscellaneous Shandong amine of grace.
2. the preparation method of the miscellaneous Shandong amine of grace according to claim 1, it is characterised in that：Specifically include following steps：
Step（1）：With the fluoro- 4- nitrobenzoic acids of 2- as raw material, alcohol organic solvent and acidic catalyst, reaction solution heating are added
Back flow reaction 16-48 hours, TLC tracking reactions, after reaction terminates, decompression steams most of alcohol, cools down, and is poured into water, and has heavy
Precipitation goes out, and stands, filtering, and the fluoro- 4- nitrobenzoyls acid esters of 2- is obtained after drying；
Step（2）：To step（1）Organic solvent and Pd/C catalyst are added in the obtained fluoro- 4- nitrobenzoyls acid esters of 2-, in room
Temperature is lower to remove oxygen, is passed through hydrogen, and hydrogenation reaction 4-8 hours in the environment of 2-10 atmospheric pressure, reaction is filtered after being fully completed
Pd/C catalyst is reclaimed, filtrate is reclaimed organic solvent, obtains 4- amino -2- fluorobenzoates under reduced pressure；
Step（3）：To step（2）2- bromo acids methyl esters and alkalescence is added to urge in obtained 4- amino -2- fluorobenzoates
Agent, 24-48 hours reaction generation 2- (the fluoro- 4- methoxycarbonyls bases of 3-) phenylamino isobutyric acid first of reaction is carried out at 120-150 DEG C
Ester, (the fluoro- 4- ethoxycarbonyls of 3-) phenylamino methyl isobutyrate or (the fluoro- 4- isopropyls oxygen formoxyls of 3-) phenylamino isobutyric acid first
Ester；
Step（4）：To step（3）Obtained 2- (the fluoro- 4- methoxycarbonyls bases of 3-) phenylamino methyl isobutyrate, (the fluoro- 4- ethoxies of 3-
Formoxyl) phenylamino methyl isobutyrate, add in (the fluoro- 4- isopropyls oxygen formoxyls of 3-) phenylamino methyl isobutyrate organic solvent,
2- trifluoromethyl -4- isothiocyano benzonitriles, after carrying out reaction reaction in 8-12 hours at 100-120 DEG C, add methyl alcohol and salt
Aqueous acid carries out cyclization, generates 4-（3-（4- cyano group -3-（Trifluoromethyl）Phenyl）- 2- is thio for -5,5- dimethyl -4- oxos
Oxo-imidazole is alkane -1- bases）The fluoro- benzoic ethers of -2-；
Step（5）：To step（4）Obtained 4-（3-（4- cyano group -3-（Trifluoromethyl）Phenyl）- 5,5- dimethyl -4- oxos -
The thio oxo-imidazoles of 2- are alkane -1- bases）Organic solvent, methylamine water solution are added in the fluoro- benzoic ethers of -2-, is entered at 100-120 DEG C
The 8-12 hours reaction generation miscellaneous Shandong amine of grace of row reaction.
3. the preparation method of the miscellaneous Shandong amine of grace according to claim 2, it is characterised in that：Described alcohol organic solvent is first
One or more in alcohol, ethanol, isopropanol.
4. the preparation method of the miscellaneous Shandong amine of grace according to claim 2, it is characterised in that：The acidic catalyst be sulfuric acid,
One or more in p-methyl benzenesulfonic acid, dry hydrogen chloride, phosphoric acid.
5. the preparation method of the miscellaneous Shandong amine of grace according to claim 2, it is characterised in that：Step（2）In organic solvent be
One or more in methyl alcohol, ethyl acetate, methyl acetate.
6. the preparation method of the miscellaneous Shandong amine of grace according to claim 2, it is characterised in that：Step（3）In base catalyst
It is triethylamine, N, the one kind or several in N- diisopropylethylamine, sodium carbonate, potassium carbonate, four butyl bromation amine, tetrabutyl iodate amine
Kind.
7. the preparation method of the miscellaneous Shandong amine of grace according to claim 2, it is characterised in that：Step（4）In organic solvent be
One or more in pyridine, 2- picolines, 3- picolines, 4- picolines.
8. the preparation method of the miscellaneous Shandong amine of grace according to claim 2, it is characterised in that：Step（5）In organic solvent be
One or more in acetonitrile, 1,4- dioxane, tetrahydrofuran, methyl alcohol, ethanol.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651256A (en) * | 2018-11-20 | 2019-04-19 | 上海健康医学院 | A kind of preparation method of the miscellaneous Shandong amine of the grace of formula (VIII) |
| CN113717166A (en) * | 2021-03-12 | 2021-11-30 | 杭州科巢生物科技有限公司 | Method for synthesizing prochloraz |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104803919A (en) * | 2014-01-26 | 2015-07-29 | 上海医药工业研究院 | Preparation method of enzalutamide intermediate F |
| CN104803918A (en) * | 2014-01-26 | 2015-07-29 | 上海医药工业研究院 | Preparation method of enzalutamide |
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2017
- 2017-01-10 CN CN201710014635.0A patent/CN106800536A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104803919A (en) * | 2014-01-26 | 2015-07-29 | 上海医药工业研究院 | Preparation method of enzalutamide intermediate F |
| CN104803918A (en) * | 2014-01-26 | 2015-07-29 | 上海医药工业研究院 | Preparation method of enzalutamide |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651256A (en) * | 2018-11-20 | 2019-04-19 | 上海健康医学院 | A kind of preparation method of the miscellaneous Shandong amine of the grace of formula (VIII) |
| CN113717166A (en) * | 2021-03-12 | 2021-11-30 | 杭州科巢生物科技有限公司 | Method for synthesizing prochloraz |
| CN113717166B (en) * | 2021-03-12 | 2024-04-05 | 杭州科巢生物科技有限公司 | Synthesis method of pramipexole |
| 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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