CN105541593B - A kind of synthetic method of pharmaceutical intermediate - Google Patents
A kind of synthetic method of pharmaceutical intermediate Download PDFInfo
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- CN105541593B CN105541593B CN201610101681.XA CN201610101681A CN105541593B CN 105541593 B CN105541593 B CN 105541593B CN 201610101681 A CN201610101681 A CN 201610101681A CN 105541593 B CN105541593 B CN 105541593B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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Abstract
The invention discloses a kind of synthetic method of pharmaceutical intermediate, it is by cyano-acetate and 3,5 bis trifluoromethyl halogeno-benzenes are dissolved in solvent the generation decarboxylation cyanomethylation reaction in the presence of palladium catalyst and organophosphor ligand and obtain 2 (3,5 bis trifluoromethyl phenyls) acetonitrile, again 2 (3 are obtained with methylating reagent reaction, 5 bis trifluoromethyl phenyls) 2 methyl propionitrile are that carboxyl obtains target product finally by alkali conversion cyano group.The method for the synthetic intermediate that the present invention is provided is simple to operate, and raw material is cheap and easily-available, and synthesis is easy, will not occur side reaction, with higher yield.
Description
First, technical field
The present invention relates to a kind of synthetic method of pharmaceutical intermediate, belong to medicine and chemical technology field.
2nd, background technology
How appropriate pyrrole smooth (Netupitant) is a kind of new drug, for preventing cancer chemotherapy to start rear acute stage and period of delay
The nausea and vomiting that (after chemotherapy 25 hours to 120 hours) are produced.Structural formula is：
Wherein, 2- (3,5- bis trifluoromethyl phenyl) -2 Methylpropionic acidIn being its crucial synthesis fragment
Mesosome.At present it is known that 2- (3,5- bis trifluoromethyl phenyl) -2 Methylpropionic acid synthetic method have：
1st, the route of F.Hoffmann-La Roche companies Fabienne Hoffmann-Emery et al. reports：
The route is very brief, and yield is very high.But raw material 2- (3,5- bis trifluoromethyl phenyl) acetic acid price is very high, and
Easily there is the appearance of monomethyl accessory substance during large-scale production.
2nd, the route of F.Hoffmann-La Roche companies Fabienne Hoffmann-Emery et al. reports：
The route is succinct, and yield is very high.But second step needs to use high pressure carbon monoxide, processing safety is very poor.
3rd, the route of Bayer Aktiengesellschaft et al. reports：
The route is longer, and first step yield is relatively low.
4th, the route of refined husbands of big Bridge et al. report：
The route is cumbersome, and yield is medium.
3rd, the content of the invention
It is specifically how appropriate in view of the deficiencies of the prior art, the present invention provides a kind of synthetic method of pharmaceutical intermediate
The synthetic method of pyrrole smooth intermediate 2- (3,5- bis trifluoromethyl phenyl) -2 Methylpropionic acid, this method technique is simple, and cost is low
It is honest and clean, safe operation, it is adaptable to industrialized production.
The synthetic method of pharmaceutical intermediate of the present invention, be specifically how smooth intermediate 2- (3, the 5- dual-trifluoromethyl benzenes of appropriate pyrrole
Base) -2 Methylpropionic acid synthetic method, comprise the following steps：
1st, by cyano-acetateWith 3,5- bis trifluoromethyl halogeno-benzenesIt is dissolved in solvent
In, inert gas (nitrogen or argon gas) displaced air and weak air-flow protection, in the presence of palladium catalyst and organophosphor ligand
The reaction of generation decarboxylation cyanomethylation obtains 2- (3,5- bis trifluoromethyl phenyls)-acetonitrileWherein M represents alkali
Metal or alkaline-earth metal, X represent chlorine or bromine；
The ratio between amount of material of cyano-acetate described in step 1 and 3,5- bis trifluoromethyl halogeno-benzenes is 0.8~1.2：
1。
Solvent described in step 1 is benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethylformamide, dimethyl
Acetamide, 1-METHYLPYRROLIDONE, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, TRIGLYME, DPG two
At least one of ether.The ratio between the mass number of the solvent and the mass number of 2- cyano group -2 Methylpropionic acid salt are 2~10：1.
Palladium catalyst described in step 1 is Metal Palladium, acid chloride, palladium bichloride, two (acetonitrile) palladium chlorides, trifluoroacetic acid
At least one of palladium, three (dibenzalacetone) two palladium, dimerization allyl palladium chloride, two (dibenzalacetone) palladiums.It is described
The consumption of palladium catalyst is calculated as 0.1%mol~1.0%mol of the amount of the material of 2- cyano group -2 Methylpropionic acid salt with palladium.
Organophosphor ligand described in step 1 be triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2- dicyclohexylphosphontetrafluoroborate -2,
4,6- tri isopropyl biphenyls, 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl, 2- (di-t-butyl phosphino-) biphenyl, 2- (two rings
Hexyl phosphino-) biphenyl, 2- dicyclohexylphosphontetrafluoroborates -2- (N, N- dimethyl amido) biphenyl, (the diphenylphosphines of 9,9- dimethyl -4,5- two
Base) xanthene, 9,9- dimethyl -4,5- two (di-t-butyl phosphino-) xanthene, 2- dicyclohexylphosphontetrafluoroborates -2', 6'- diisopropyl oxygen
Base -1,1'- biphenyl, (±) -2,2'- be double-and (diphenyl phosphine) -1,1'- dinaphthalenes, (±) -2,2'- be double-(di-p-tolyl phosphino-) -
At least one of 1,1'- dinaphthalenes and double (diphenylphosphino) ferrocene of 1,1'-.The organophosphor ligand and palladium catalyst material
The ratio between amount be 1~3: 1.
The reaction temperature that decarboxylation cyanomethylation reacts in step 1 is 120-160 DEG C, and the reaction time is 12-24h.
2nd, 2- (3,5- bis trifluoromethyl phenyl)-acetonitrile is added in solvent, in highly basic hydride and methylating reagent
In the presence of, 2- (3,5- bis trifluoromethyl phenyl)-acetonitrile is changed into 2- (3,5- double fluoroforms by control temperature below 50 DEG C
Base phenyl) -2- methyl propionitrile
Solvent described in step 2 is ring-type ethers solvent, preferably tetrahydrofuran or dioxane, and the mass number of solvent is
5-15 times of 2- (3,5- bis trifluoromethyl phenyls)-acetonitrile mass number.
Highly basic hydride described in step 2 is at least one of sodium hydride, hydrofining or calcium hydride.The highly basic hydrogenation
The mole of thing is 2-5 times of 2- (3,5- bis trifluoromethyl phenyls) acetonitrile mole.
Methylating reagent described in step 2 is iodomethane, bromomethane, chloromethanes, dimethyl suflfate, trifluoromethayl sulfonic acid first
At least one of ester.The mole of the addition of the methylating reagent is 2- (3,5- bis trifluoromethyl phenyls)-acetonitrile mole
2-10 times of amount.
3rd, 2- (3,5- bis trifluoromethyl phenyl) -2- methyl propionitrile is added in solvent, in the presence of base, in 100-
2- (3,5- bis trifluoromethyl phenyls) -2- methyl propionitrile is changed into 2- (3,5- bis trifluoromethyl phenyls) -2- methyl at 150 DEG C
Propionate, is cooled to after normal temperature by sulfuric acid or hydrochloric acid that (h 2 so 4 concentration is 5%-98%, and hydrochloric acid mass concentration is 5%-
36%) it is acidified to after pH value≤3, filtering and obtains 2- (3,5- bis trifluoromethyl phenyl) -2 Methylpropionic acid
Solvent described in step 3 is at least one of water, alcohols, preferably high boiling polyol, further preferred second two
At least one of alcohol, glycerine.The mass number of the solvent and the matter of 2- (3,5- bis trifluoromethyl phenyls) -2- methyl propionitrile
It is 1~10 to measure the ratio between number：1.
Alkali described in step 3 is at least one of sodium hydroxide, potassium hydroxide, barium hydroxide.The mass number of the alkali
For 1-10 times of 2- (3,5- bis trifluoromethyl phenyls) -2- methyl propionitrile mass numbers.
Reaction scheme is as follows：
Compared with the prior art, beneficial effects of the present invention are embodied in：
Preparation method of the present invention avoids the use of hypertoxic class methylating reagent (such as iodomethane, dimethyl suflfate), whole
Individual system green safety, it is not necessary to low-temp reaction, reduces the difficulty of production；Improve reaction yield and reduce cost, have very
Big economic benefit.
4th, embodiment
In order to further appreciate that the present invention, the preferred embodiment of the invention is described with reference to embodiment, still
It should be appreciated that these descriptions are simply to further illustrate the features and advantages of the present invention, rather than to the claims in the present invention
Limitation.
Embodiment 1：
1st, the preparation of cyanoacetic acid sodium：
25L methanol is added in 50L glass kettles, stirring adds 1.60kg sodium hydroxides (40.0mol), and stirring is cooled to room
Wen Hou, is added dropwise stirring reaction 1h after the solution of 3.40kg cyanoacetic acids (40.0mol) and 10L methanol composition, completion of dropping；Reaction solution
It is spin-dried for, after solid is washed with a small amount of absolute ethyl alcohol, 50 DEG C of drying obtain 4.07kg cyanoacetic acid sodium, molar yield 95%.
2nd, the preparation of 2- (3,5- bis trifluoromethyl phenyls) acetonitrile：
50L glass kettle wash cleans, drying adds 20kg trimethylbenzenes under nitrogen flowing, opens stirring, nitrogen purging degassing
After 15min, stirring is lower to add 5.0kg 3,5- bis trifluoromethyls chlorobenzene (20.1mol), 2.5kg cyanoacetic acids sodium (21.0mol),
8.0g allyl palladium chlorides dimer (0.0217mol, 0.22mol%), 27g 2- dicyclohexyl phosphine -2', 6'- dimethoxy connection
Benzene (0.066mol, 0.66mol%)；Under nitrogen flowing, temperature of reaction system is progressively warming up to 145 DEG C of reaction 20h, then will
Reaction system is down to room temperature, is filtered to remove the sodium chloride that reaction is produced, and filtrate is spin-dried for reclaiming trimethylbenzene, obtains 5.5kg concentrations residual
Excess, is 2- (3,5- bis trifluoromethyl phenyl) acetonitrile crude product, GC detection purity is 92%, yield 81%.
3rd, the preparation of 2- (3,5- bis trifluoromethyl phenyls) -2- methyl propionitrile：
50L glass kettle wash cleans, drying adds 2kg60% sodium hydrides (50mol), and 20kg dioxies are added under nitrogen flowing
Six rings, open in stirring, nitrogen purging degassing 15min, two constant pressure funnels and are separately added into 4.4kg 2- (3,5- double trifluoros
Aminomethyl phenyl) acetonitrile (GC purity 92%, 16mol) and 5.0kg dimethyl suflfates (40mol), under agitation simultaneously by two perseverances
The material in dropping funel is pressed to add in reaction system, control temperature of reaction system is no more than 45 DEG C, and time for adding control exists
10h；After completion of dropping, system is down to 15-20 DEG C, nitrogen press filtration is used, filtrate is collected, filter cake is scattered with 5kg dioxane, uses
Nitrogen press filtration, collects merging filtrate, and filtrate decompression is distilled and reclaims dioxane in 55 DEG C, remains light-red oil, carefully
20kg water is added, and is heated to 55 DEG C -60 DEG C, reacts 5 hours, is cooled to room temperature；It is extracted twice, is merged with 10kg ethyl acetate
Organic layer, with 1kg saturated common salt water washings, divides after liquid, organic layer azeotropic water removing, vacuum rotary steam reclaims ethyl acetate, obtains
3.3kg concentration residues, are 2- (3,5- bis trifluoromethyl phenyl) -2- methyl propionitrile crude products, GC detection purity is 91%, yield
67%.
4th, the preparation of 2- (3,5- bis trifluoromethyl phenyls) -2 Methylpropionic acid：
15kg glycerine is added in 50L glass reaction kettles, stirring adds 3kg NaOH, after dissolving cooling, adds 3.0kg2-
(3,5- bis trifluoromethyl phenyl) -2- methyl propionitrile crude product (GC purity 91%, 9.7mol), sealing, gas outlet picks out tracheae extremely
Exhaust gas absorption cell (ammonia is put in reaction), is progressively warming up to 145 DEG C, reaction releases (about 12h) to there is no ammonia, system under stirring
It is down to room temperature；30kg deionized waters are added into reaction system, centrifugation removes a small amount of solid insoluble, and filter residue is washed with deionized water
Merge after washing with filtrate, and diluted again with 30kg deionized waters, then with salt acid for adjusting pH value to 1, separate out a large amount of solids, from
The heart, obtains 2- (3,5- bis trifluoromethyl phenyl) -2 Methylpropionic acid crude product (GC purity 93% after giving money as a gift).Crude product is dissolved in 2 times
In the toluene of quality, agitating and heating backflow azeotropic water removing, until there is no water removing；System decrease temperature crystalline, centrifugation, mother liquor concentrations
To after 1/3, recrystallize, centrifugation, merging is crystallized twice, in 50 DEG C of vacuum drying, obtain 2.43kg 2- (3,5- bis trifluoromethyls
Phenyl) -2 Methylpropionic acid (GC purity 98.3%), molar yield 82%.
Structural characterization：1H NMR(CDCl3, 400MHz) and 12-10 (broad, 1H), 7.85 (s, 2H) 7.81 (s, 1H), 1.69
(s, 6H)；mp 105-107℃.
Embodiment 2：
1st, the preparation of cyanoacetic acid potassium：
25L methanol is added in 50L glass kettles, stirring adds 2.24kg sodium hydroxides (40.0mol), and stirring is cooled to room
Wen Hou, is added dropwise stirring reaction 1h after the solution of 3.40kg cyanoacetic acids (40.0mol) and 10L methanol composition, completion of dropping；Reaction solution
It is spin-dried for, after solid is washed with a small amount of absolute ethyl alcohol, 50 DEG C of drying obtain 4.5kg cyanoacetic acid potassium, molar yield 92.2%.2、2-
The preparation of (3,5- bis trifluoromethyl phenyls) acetonitrile：
50L glass kettle wash cleans, drying adds 20kg trimethylbenzenes under nitrogen flowing, opens stirring, nitrogen purging degassing
After 15min, stirring is lower to add 5.0kg3,5- bis trifluoromethyls chlorobenzene (20.1mol), 2.583kg cyanoacetic acid potassium
(21.0mol), 8.0g allyl palladium chlorides dimer (0.0217mol, 0.22mol%), 27g 2- dicyclohexyl phosphines -2', 6'-
Dimethoxy-biphenyl (0.066mol, 0.66mol%)；Under nitrogen flowing, temperature of reaction system is progressively warming up to 145 DEG C of reactions
20h, is then down to room temperature by reaction system, is filtered to remove the sodium chloride that reaction is produced, and filtrate is spin-dried for reclaiming trimethylbenzene, obtained
5.5kg concentration residues, are 2- (3,5- bis trifluoromethyl phenyl) acetonitrile crude product, GC detection purity is 87%, yield 76.6%.
3rd, the preparation of 2- (3,5- bis trifluoromethyl phenyls) -2- methyl propionitrile：
50L glass kettle wash cleans, drying adds 2kg60% sodium hydrides (50mol), and 20kg dioxies are added under nitrogen flowing
Six rings, open in stirring, nitrogen purging degassing 15min, two constant pressure funnels and are separately added into 4.4kg 2- (3,5- double trifluoros
Aminomethyl phenyl) acetonitrile (GC purity 92%, 16mol) and 5.0kg dimethyl suflfates (40mol), under agitation simultaneously by two perseverances
The material in dropping funel is pressed to add in reaction system, control temperature of reaction system is no more than 45 DEG C, and time for adding control exists
10h；After completion of dropping, system is down to 15-20 DEG C, nitrogen press filtration is used, filtrate is collected, filter cake is scattered with 5kg dioxane, uses
Nitrogen press filtration, collects merging filtrate, and filtrate decompression is distilled and reclaims dioxane in 55 DEG C, remains light-red oil, carefully
20kg water is added, and is heated to 55 DEG C -60 DEG C, reacts 5 hours, is cooled to room temperature；It is extracted twice, is merged with 10kg ethyl acetate
Organic layer, with 1kg saturated common salt water washings, divides after liquid, organic layer azeotropic water removing, vacuum rotary steam reclaims ethyl acetate, obtains
3.3kg concentration residues, are 2- (3,5- bis trifluoromethyl phenyl) -2- methyl propionitrile crude products, GC detection purity is 91%, yield
67%.
4th, the preparation of 2- (3,5- bis trifluoromethyl phenyls) -2 Methylpropionic acid：
15kg glycerine is added in 50L glass reaction kettles, stirring adds 3kg NaOH, after dissolving cooling, adds 3.0kg2-
(3,5- bis trifluoromethyl phenyl) -2- methyl propionitrile crude product (GC purity 91%, 9.7mol), sealing, gas outlet picks out tracheae extremely
Exhaust gas absorption cell (ammonia is put in reaction), is progressively warming up to 145 DEG C, reaction releases (about 12h) to there is no ammonia, system under stirring
It is down to room temperature；30kg deionized waters are added into reaction system, centrifugation removes a small amount of solid insoluble, and filter residue is washed with deionized water
Merge after washing with filtrate, and diluted again with 30kg deionized waters, then with salt acid for adjusting pH value to 1, separate out a large amount of solids, from
The heart, obtains 2- (3,5- bis trifluoromethyl phenyl) -2 Methylpropionic acid crude product (GC purity 93% after giving money as a gift).Crude product is dissolved in 2 times
In the toluene of quality, agitating and heating backflow azeotropic water removing, until there is no water removing；System decrease temperature crystalline, centrifugation, mother liquor concentrations
To after 1/3, recrystallize, centrifugation, merging is crystallized twice, in 50 DEG C of vacuum drying, obtain 2.43kg 2- (3,5- bis trifluoromethyls
Phenyl) -2 Methylpropionic acid (GC purity 98.3%), molar yield 82%.
Structural characterization：Be the same as Example 1.
The explanation of above example is only intended to the method and its core concept for helping to understand the present invention.It should be pointed out that pair
, under the premise without departing from the principles of the invention, can also be to present invention progress for those skilled in the art
Some improvement and modification, these are improved and modification is also fallen into the protection domain of the claims in the present invention.
The foregoing description of the disclosed embodiments, enables professional and technical personnel in the field to realize or using the present invention.
A variety of modifications to these embodiments will be apparent for those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, it is of the invention
The embodiments shown herein is not intended to be limited to, and is to fit to and principles disclosed herein and features of novelty phase one
The most wide scope caused.
Claims (10)
1. a kind of synthetic method of pharmaceutical intermediate, it is characterised in that comprise the following steps：
(1) by cyano-acetateWith 3,5- bis trifluoromethyl halogeno-benzenesIt is dissolved in solvent, it is lazy
Property gas shield, obtain 2- in the presence of palladium catalyst and organophosphor ligand (3,5- is double in reacting 12-24h at 120-160 DEG C
Trifluoromethyl)-acetonitrile；Wherein M is alkali metal or alkaline-earth metal, and X is chlorine or bromine；
(2) 2- (3,5- bis trifluoromethyl phenyl)-acetonitrile is added in solvent, in the presence of highly basic hydride and methylating reagent
Under, 2- (3,5- bis trifluoromethyl phenyl)-acetonitrile is changed into 2- (3,5- dual-trifluoromethyl benzenes by control temperature below 50 DEG C
Base) -2- methyl propionitrile；
(3) 2- (3,5- bis trifluoromethyl phenyl) -2- methyl propionitrile is added in solvent, in the presence of base, in 100-150 DEG C
It is lower that 2- (3,5- bis trifluoromethyl phenyls) -2- methyl propionitrile is changed into 2- (3,5- bis trifluoromethyl phenyls) -2 Methylpropionic acid
Salt, is cooled to after normal temperature to be acidified to after pH value≤3, filtering by sulfuric acid or hydrochloric acid and obtains 2- (3,5- dual-trifluoromethyl benzenes
Base) -2 Methylpropionic acid.
2. synthetic method according to claim 1, it is characterised in that：
The ratio between amount of material of cyano-acetate described in step (1) and 3,5- bis trifluoromethyl halogeno-benzenes is 0.8~1.2：1.
3. synthetic method according to claim 1, it is characterised in that：
Solvent described in step (1) is benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide (DMSO), dimethylformamide, dimethyl second
Acid amides, 1-METHYLPYRROLIDONE, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, TRIGLYME, DPG diethyl
At least one of ether；The quality of the solvent and the mass ratio of cyano-acetate are 2~10：1.
4. synthetic method according to claim 1, it is characterised in that：
Palladium catalyst described in step (1) be Metal Palladium, acid chloride, palladium bichloride, two (acetonitrile) palladium chlorides, palladium trifluoroacetate,
At least one of three (dibenzalacetone) two palladium, dimerization allyl palladium chloride, two (dibenzalacetone) palladiums；The palladium is urged
The consumption of agent is calculated as 0.1%mol~1.0%mol of the amount of the material of cyano-acetate with palladium.
5. synthetic method according to claim 1, it is characterised in that：
Organophosphor ligand described in step (1) be triphenylphosphine, tricyclohexyl phosphine, tri-butyl phosphine, 2- dicyclohexylphosphontetrafluoroborates -2 ',
4 ', 6 '-tri isopropyl biphenyl, 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl, 2- (di-t-butyl phosphino-) biphenyl, 2- (two
Cyclohexylphosphino) biphenyl, 2- dicyclohexylphosphontetrafluoroborates -2 '-(N, N- dimethyl amido) biphenyl, (the diphenyl of 9,9- dimethyl -4,5- two
Phosphino-) xanthene, 9,9- dimethyl -4,5- two (di-t-butyl phosphino-) xanthene, 2- dicyclohexylphosphontetrafluoroborates -2', 6'- diisopropyl oxygen
Base -1,1'- biphenyl, (±) -2,2'- be double-and (diphenyl phosphine) -1,1'- dinaphthalenes, (±) -2,2'- be double-(di-p-tolyl phosphino-) -
At least one of 1,1'- dinaphthalenes and double (diphenylphosphino) ferrocene of 1,1'-；The organophosphor ligand and palladium catalyst material
The ratio between amount be 1~3: 1.
6. synthetic method according to claim 1, it is characterised in that：
Solvent described in step (2) is ring-type ethers solvent, and the quality of solvent is 2- (3,5- bis trifluoromethyl phenyl)-acetonitrile matter
5-15 times of amount.
7. synthetic method according to claim 1, it is characterised in that：
Highly basic hydride described in step (2) is at least one of sodium hydride, hydrofining or calcium hydride；The highly basic hydride
Mole be 2-5 times of 2- (3,5- bis trifluoromethyl phenyls) acetonitrile mole.
8. synthetic method according to claim 1, it is characterised in that：
Methylating reagent described in step (2) is iodomethane, bromomethane, chloromethanes, dimethyl suflfate, trifluoromethayl sulfonic acid methyl esters
At least one of；The mole of the methylating reagent addition is 2- (3,5- bis trifluoromethyl phenyls)-acetonitrile mole
2-10 times.
9. synthetic method according to claim 1, it is characterised in that：
Solvent described in step (3) is at least one of water, alcohols, quality and 2- (3, the 5- bis trifluoromethyls of the solvent
Phenyl) -2- methyl propionitrile mass ratio be 1~10：1.
10. synthetic method according to claim 1, it is characterised in that：
Alkali described in step (3) is at least one of sodium hydroxide, potassium hydroxide, barium hydroxide；The quality of the alkali is 2-
1-10 times of (3,5- bis trifluoromethyl phenyls) -2- methyl propionitrile quality.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008076427A2 (en) * | 2006-12-18 | 2008-06-26 | Amgen Inc. | Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof |
| CN101326161A (en) * | 2005-10-06 | 2008-12-17 | 阿斯利康(瑞典)有限公司 | Novel compounds |
| CN101973911A (en) * | 2010-10-11 | 2011-02-16 | 中国科学技术大学 | Method for synthesizing anastrozole intermediate-2,2'-(5-methyl-1,3-phenylene)-bis-(2-methyl propionitrile) |
| CN102056897A (en) * | 2008-06-05 | 2011-05-11 | 旭化成制药株式会社 | Sulfonamide compound and application thereof |
-
2016
- 2016-02-24 CN CN201610101681.XA patent/CN105541593B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101326161A (en) * | 2005-10-06 | 2008-12-17 | 阿斯利康(瑞典)有限公司 | Novel compounds |
| WO2008076427A2 (en) * | 2006-12-18 | 2008-06-26 | Amgen Inc. | Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof |
| CN102056897A (en) * | 2008-06-05 | 2011-05-11 | 旭化成制药株式会社 | Sulfonamide compound and application thereof |
| CN101973911A (en) * | 2010-10-11 | 2011-02-16 | 中国科学技术大学 | Method for synthesizing anastrozole intermediate-2,2'-(5-methyl-1,3-phenylene)-bis-(2-methyl propionitrile) |
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